NCCN CLINICAL PRACTICE GUIDELINES IN ONCOLOGY

Hematopoietic Cell Transplantation, Version 2.2020

Ayman Saad, MD1,*; Marcos de Lima, MD2,*; Sarah Anand, MD3; Vijaya Raj Bhatt, MBBS4,*; Ryan Bookout, PharmD5; George Chen, MD6,*; Daniel Couriel, MD, MS7; Antonio Di Stasi, MD8; Areej El-Jawahri, MD9; Sergio Giralt, MD10; Jonathan Gutman, MD11; Vincent Ho, MD12; Mitchell Horwitz, MD13; Joe Hsu, MD14; Mark Juckett, MD15; Mohamed Kharfan Dabaja, MD16,*; Alison W. Loren, MD, MSCE17; Javier Meade, MD18; Marco Mielcarek, MD, PhD19,*; Jonathan Moreira, MD20; Ryotaro Nakamura, MD21; Yago Nieto, MD, PhD22; Julianna Roddy, PharmD, BCOP1,*; Gowri Satyanarayana, MD23; Mark Schroeder, MD24,*; Carlyn Rose Tan, MD25; Dimitrios Tzachanis, MD, PhD26; Jennifer L. Burns27; and Lenora A. Pluchino, PhD27

ABSTRACT NCCN CATEGORIES OF EVIDENCE AND CONSENSUS Category 1: Based upon high-level evidence, there is uniform Hematopoietic cell transplantation (HCT) involves the infusion of hema- NCCN consensus that the intervention is appropriate. topoietic progenitor cells into patients with hematologic disorders with Category 2A: Based upon lower-level evidence, there is uniform the goal of re-establishing normal hematopoietic and immune function. NCCN consensus that the intervention is appropriate. HCT is classified as autologous or allogeneic based on the origin of he- ’ Category 2B: Based upon lower-level evidence, there is NCCN matopoietic cells. Autologous HCT uses the patient sowncellswhile consensus that the intervention is appropriate. allogeneic HCT uses hematopoietic cells from a human leukocyte antigen-compatible donor. Allogeneic HCT is a potentially curative Category 3: Based upon any level of evidence, there is major treatment option for patients with certain types of hematologic malig- NCCN disagreement that the intervention is appropriate. nancies, and autologous HCT is primarily used to support patients under- All recommendations are category 2A unless otherwise going high-dose chemotherapy. Advances in HCT methods and supportive noted. care in recent decades have led to improved survival after HCT; however, disease relapse and posttransplant complications still commonly occur Clinical trials: NCCN believes that the best management of in both autologous and allogeneic HCT recipients. Allogeneic HCT re- any patient with cancer is in a clinical trial. Participation in cipients may also develop acute and/or chronic graft-versus-host clinical trials is especially encouraged. disease (GVHD), which results in immune-mediated cellular injury of sev- PLEASE NOTE eral organs. The NCCN Guidelines for Hematopoietic Cell Transplantation focus on recommendations for pretransplant recipient evaluation and the The NCCN Clinical Practice Guidelines in Oncology (NCCN ® management of GVHD in adult patients with malignant disease. Guidelines ) are a statement of evidence and consensus of the authors regarding their views of currently accepted appro- J Natl Compr Canc Netw 2020;18(5):599–634 aches to treatment. Any clinician seeking to apply or consult doi: 10.6004/jnccn.2020.0021 the NCCN Guidelines is expected to use independent medi- cal judgment in the context of individual clinical circumstances to determine any patient’s care or treatment. The National ® ® 1The Ohio State University Comprehensive Cancer Center - James Cancer Comprehensive Cancer Network (NCCN ) makes no repre- Hospital and Solove Research Institute; 2Case Comprehensive Cancer Center/ sentations or warranties of any kind regarding their content, University Hospitals Seidman Cancer Center and Cleveland Clinic Taussig use, or application and disclaims any responsibility for their Cancer Institute; 3University of Michigan Rogel Cancer Center; 4Fred & Pamela application or use in any way. Buffett Cancer Center; 5Moffitt Cancer Center; 6Roswell Park Comprehensive © National Comprehensive Cancer Network, Inc. 2020. All Cancer Center; 7Huntsman Cancer Institute at the University of Utah; 8O’Neal rights reserved. The NCCN Guidelines and the illustrations Comprehensive Cancer Center at UAB; 9Massachusetts General Hospital herein may not be reproduced in any form without the express 10 11 Cancer Center; Memorial Sloan Kettering Cancer Center; University of written permission of NCCN. Colorado Cancer Center; 12Dana-Farber/Brigham and Women’s Cancer Center; 13Duke Cancer Institute; 14Stanford Cancer Institute; 15University of Wisconsin Disclosures for the NCCN Hematopoietic Cell Carbone Cancer Center; 16Mayo Clinic Cancer Center; 17Abramson Cancer Transplantation Panel 18 Center at the University of Pennsylvania; The Sidney Kimmel Comprehensive At the beginning of each NCCN Guidelines Panel meeting, Cancer Center at Johns Hopkins; 19Fred Hutchinson Cancer Research Center/ fl 20 panel members review all potential con icts of interest. NCCN, Seattle Cancer Care Alliance; Robert H. Lurie Comprehensive Cancer Center in keeping with its commitment to public transparency, of Northwestern University; 21City of Hope National Medical Center; 22The 23 publishes these disclosures for panel members, staff, and University of Texas MD Anderson Cancer Center; Vanderbilt-Ingram Cancer NCCN itself. Center; 24Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine; 25Fox Chase Cancer Center; 26UC San Diego Individual disclosures for the NCCN Hematopoietic Cell Moores Cancer Center; and 27National Comprehensive Cancer Network Transplantation Panel members can be found on page 634. (The most recent version of these guidelines and accompanying *Discussion Writing Committee Member. disclosures are available at NCCN.org.) The complete and most recent version of these guidelines is See page 645 for related commentary. available free of charge at NCCN.org.

JNCCN.org | Volume 18 Issue 5 | May 2020 599 NCCN GUIDELINES® Hematopoietic Cell Transplantation, Version 2.2020

Overview Marrow Transplant Research (CIBMTR) estimated that Hematopoietic cell transplantation (HCT) involves the 9,028 allogeneic transplants and 14,709 autologous trans- infusion of hematopoietic progenitor cells into patients plants were performed in the United States in 2018.4 Acute with malignant or nonmalignant hematologic disorders myeloid leukemia (AML), acute lymphocytic leukemia with the goal of re-establishing normal hematopoietic (ALL), and myelodysplastic syndromes (MDS) were and immune function.1,2 HCT is a potentially curative the most common malignancies treated with alloge- treatment option for patients with certain types of neic HCT, while autologous HCT was used most fre- hematologic malignancies and is also used to support quently in multiple myeloma, non-Hodgkin lymphoma, patients undergoing high-dose chemotherapy for the and Hodgkin lymphoma.4 treatment of certain solid tumors. HCT is classified as Outcomes of HCT vary according to the type and autologous or allogeneic based on the origin of he- stage of the disease being treated, the overall health of matopoietic cells. An autologous HCT uses the patient’s the patient, the degree of HLA-mismatch between donor own cells while an allogeneic HCT uses hematopoietic and recipient (for allogeneic HCT), and the source of cells from a human leukocyte antigen (HLA)-compatible the hematopoietic cells.2 Hematopoietic cells can be donor. Prior to HCT, most patients receive chemother- obtained from peripheral blood, BM, or umbilical cord apy, serotherapy, and/or radiation for pretransplant blood (UCB). Several clinical factors should be consid- conditioning (preparative regimen). In allogeneic HCT, ered when determining the optimal graft source for an in- preparative regimens are administered to eradicate dividual patient, including disease type, disease stage, patient malignant cells in the bone marrow (BM; if using comorbidities, and the urgency for transplantation.5 Mo- myeloablative regimen) and induce immunosuppres- bilization of peripheral blood progenitor cells (PBPCs) by sion so that engraftment of healthy donor cells occurs.1 granulocyte-colony stimulating factor has largely replaced In autologous HCT, high-dose myeloablative regimens use of BM grafts (in particular for autologous HCT) due to are used to treat the malignancy. This is followed by theeaseofcollection,avoidance of general anesthesia, rescue infusion of the patient’s own cells, which are more rapid engraftment rates, reduced risk of graft failure, harvested before high-dose therapy, to restore hema- and lower transplant-related mortality.6–8 However, allo- topoiesis and reconstitute the immune system. geneic PBPC transplants are associated with an increased The number of HCTs has increased in the United States risk of graft-versus-host disease (GVHD) compared with in recent years.3 The Center for International Blood and BM transplants.8,9 Allogeneic BM transplant continues to

600 © JNCCN—Journal of the National Comprehensive Cancer Network | Volume 18 Issue 5 | May 2020 Hematopoietic Cell Transplantation, Version 2.2020 NCCN GUIDELINES®

be indicated in certain conditions such as severe aplastic Advances in HCT methods and supportive care have led anemia and other nonmalignant disorders, owing to a to improved survival after HCT.11 However, disease relapse lower risk of GVHD. Furthermore, several investigators and long-term complications continue to pose a major have advocated for the use of BM grafts for haploidentical threat to HCT survivors. Disease relapse is higher with ad- HCT10 and unrelated donor HCT.9 Advantages of using vanced disease and with the use of nonmyeloablative UCB grafts include rapid cell procurement, lower in- conditioning regimens. Posttransplant complications are cidence of GVHD, and less-stringent HLA matching re- common after both allogeneic and autologous HCT. quirements. However, use of UCB is limited by the cell These complications are often caused by the preparative doses that can be achieved in recipients with high body regimen,12,13 delayed immune reconstitution, and GVHD. weight, which is also associated with delayed engraftment, The risk and type of complications are also influenced higher risk for graft failure, higher rates of infectious by patient-related factors such as age, performance complications, and higher costs for procurement. The status, and comorbidities.14–16 Early complications outcome of UCB transplant is more favorable in pediatric (generally occurring within the first 100 days post-HCT) populations, likely due to the feasibility of using higher include prolonged cytopenia/graft failure, infections, sinu- graft cell doses (given smaller body weight) and lower soidal obstruction syndrome, and organ toxicities.12,17 Late incidence of comorbidities in pediatric populations. UCB complications (after the first 100 days) include infections, late transplant is typically reserved for patients without an HLA- radiation-related toxicities (eg, cataracts and hypothyroid- matched donor. Patients without an HLA-matched donor ism), late chemotherapy-related toxicities (eg, heart failure), may also be candidates for haploidentical HCT. Advantages organ dysfunctions, and secondary malignancies, including of haploidentical HCT include lower costs for procurement MDS.12,17 Allogeneic HCT recipients may also develop acute and rapid availability of the cell products, and disadvantages and/or chronic GVHD, in which the donor lymphocytes include increased risk of graft failure and GVHD as com- recognize the recipient’s tissues as foreign, resulting in pared with HLA-matched HCT. immune-mediated cellular injury of several bodily organs,

JNCCN.org | Volume 18 Issue 5 | May 2020 601 NCCN GUIDELINES® Hematopoietic Cell Transplantation, Version 2.2020

such as the skin, gastrointestinal (GI) tract, and liver. Com- chemotherapy are reinfused back into the patient after mon causes of nonrelapse mortality (NRM) after allogeneic administration of the preparative regimen. High-dose HCT include GVHD, infections, interstitial pneumonia, and chemotherapy with autologous HCT is an effective organ failure.18–21 Common causes of NRM after autologous treatment of several hematologic malignancies, includ- HCT include organ toxicity and infectious complications.4,22,23 ing multiple myeloma,25–29 relapsed/refractory Hodgkin Therefore, posttransplant care plans including optimal lymphoma,30,31 and relapsed/refractory non-Hodgkin supportive care are essential to optimize long-term out- lymphoma.32–34 Autologous HCT is also used in patients comes in both autologous and allogeneic HCT recipients. undergoing high-dose chemotherapy for the treatment The NCCN Clinical Practice Guidelines in Oncology of certain solid tumors, including testicular germ cell (NCCN Guidelines) for HCT focus on the management of tumors35–38 and some central nervous system tumors,39–43 adult patients with malignant disease. This initial version of for which hematologic toxicity would otherwise limit the NCCN Guidelines addresses pretransplant recipient chemotherapy administration. Additionally, autologous evaluation and management of acute and chronic GVHD HCT is sometimes used as consolidation therapy for (to view the most recent version of these guidelines, in- certain patients with AML or ALL. cludinginformationontheliteraturesearchcriteriaand Because autologous HCT uses the patient’s own cells, guidelines update methodology,24 visit NCCN.org). these patients do not develop GVHD. Additionally, these patients often have a lower risk of infectious complications Autologous HCT because they do not receive posttransplant immuno- Autologous HCT is performed to replace or “rescue” he- suppression. Therefore, autologous HCT is associated with matopoietic cells damaged by the high-dose chemotherapy less morbidity and mortality than allogeneic HCT; how- used to treat certain advanced or high-risk hematologic ever, risk of disease relapse is often higher with autologous malignancies and solid tumors. Hematopoietic cells col- HCT when compared with allogeneic HCT. Furthermore, lected from the patient prior to receipt of high-dose clinical studies demonstrated no benefit of graft purging

602 © JNCCN—Journal of the National Comprehensive Cancer Network | Volume 18 Issue 5 | May 2020 Hematopoietic Cell Transplantation, Version 2.2020 NCCN GUIDELINES®

(ex vivo manipulation to eliminate residual neoplastic donor is a first-degree relative who matches half the HLA cells) prior to autologous HCT.44,45 markers of the patient. Emerging data suggest that hap- loidentical HCT may yield comparable outcomes to HLA- Allogeneic HCT matched HCT.47,48 However, a recent study found that use Allogeneic HCT is performed to replace malignant (or de- of haploidentical donors beyond first-degree relatives may fective) hematopoietic tissue using a healthy donor’she- negatively affect survival.49 UCB transplant was first matopoietic cells. A preparative regimen consisting of reported to cure a child with Fanconi anemia,50 and chemotherapy (often high-dose), serotherapy, and/or total was subsequently used successfully in patients with body (or lymphoid) irradiation is given before allogeneic hematologic malignancies.51,52 Although the outcomes HCT to eliminate residual malignant cells and to suppress of UCB transplants have been comparable to HLA- – the recipient’s immune system, which is necessary to allow matched transplants in some reports,46,53 56 delayed for engraftment of the donor-derived cells and prevent engraftment and delayed immune reconstitution of- graft rejection. There are 3 potential donor sources tenresultinincreasedrisksofinfectiouscomplica- for hematopoietic cells: related donor (family members), tions. Additionally, the high degree of HLA-disparity unrelated volunteers (from donor registries), and UCB units. that typically occurs with haploidentical or UCB do- HLA matching is the most imperative factor when choosing nors has been associated with an increased risk of graft – a donor. An HLA-matched sibling remains the preferred failure.1,46,53 56 donor source. However, posttransplant survival is compa- Allogeneic HCT has been shown to improve out- rable among patients receiving hematopoietic cells from comesinpatientswithmalignanciessuchasrefractory HLA-matched unrelated donors for several diseases.14,46 AML,57 ALL,58 MDS,59 chronic myeloid leukemia,60 chronic When a patient has no HLA-matched related or unrelated lymphocytic leukemia,61 multiple myeloma,62 primary and donors, as is common among minority ethnic groups, a secondary myelofibrosis,63 Hodgkin lymphoma,64 and non- haploidentical donor or UCB may be used. A haploidentical Hodgkin lymphoma.65 Donor-derived immune cells often

JNCCN.org | Volume 18 Issue 5 | May 2020 603 NCCN GUIDELINES® Hematopoietic Cell Transplantation, Version 2.2020

exert an immune-mediated cytotoxic effect against the (see HCT-2, page 602, and HCT-3, page 603). Physio- recipient’s neoplastic cells (ie, graft-versus-tumor effect). logic age rather than chronologic age should be used to This phenomenon was described several decades ago, and determine eligibility for HCT.5 Selected older patients its clinical impact was demonstrated in a seminal CIBMTR with limited comorbidities and good functional status study of more than 2,000 patients that showed a reduced can safely receive HCT with a relatively low and ac- relapse risk among patients with GVHD.66 Graft-versus- ceptable risk of NRM.69,70 Ongoing studies, such as BMT tumor effect is considered a major mechanism for sus- CTN 1704, are assessing the utility of geriatric assess- tained response after allogeneic HCT, in particular with ment tools in predicting outcome of HCT in elderly reduced intensity or nonmyeloablative HCT.67,68 patients (ClinicalTrials.gov identifier: NCT03992352). Determining functional status (Karnofsky’sorECOG Indications for Transplantation performance status) and HCT-comorbidity index Indications for HCT (allogeneic or autologous) vary by dis- (HCT-CI) score71 are essential to determine candidacy ease type and remission status. Information on indications for HCT (in particular for allogeneic HCT). HCT-CI for HCT can be found in disease-specific NCCN Guidelines, score has been validated to predict the risk of NRM available at NCCN.org (see HCT-1, page 601, for a list of and estimated survival after allogeneic transplant.72,73 NCCN Guidelines containing disease-specific indications HCT-CI has also been shown to predict survival after for HCT). The American Society for Transplantation and autologous transplant.74,75 Furthermore, an updated Cellular Therapy has also published clinical practice guide- composite-age HCT-CI has been also shown to have lines on indications for autologous and allogeneic HCT.5 the same utility.76 Detailed clinical assessment of HCT- CI has been published.77 HLA typing of the donor and Pretransplant Recipient Evaluation recipient per FACT (Foundation for the Accreditation The pretransplant recipient evaluation generates data to of Cellular Therapy) guidelines78 is recommended estimate the risks of relapse, NRM, and overall mortality before allogeneic HCT.

604 © JNCCN—Journal of the National Comprehensive Cancer Network | Volume 18 Issue 5 | May 2020 Hematopoietic Cell Transplantation, Version 2.2020 NCCN GUIDELINES®

Management of GVHD GVHD (aGVHD) depending on several factors, including The development of acute and/or chronic GVHD is a donor source and graft source. The skin, GI tract (upper major complication of allogeneic HCT and is associated and lower), and liver are the 3 organs primarily affected with significant morbidities and NRM in allogeneic HCT by aGVHD, which is characterized by maculopapular recipients.79–81 Increasing incidence of GVHD has been rash, GI complications, and hyperbilirubinemia.86,87 Al- observed in recent years, primarily due to the increased though pathologic confirmation of aGVHD should be use of unrelated and/or HLA-mismatched donors and considered whenever possible, especially before escalat- granulocyte-colony stimulating factor–mobilized PBPCs, ing systemic immunosuppression, reliance on pathologic among other factors.8,82–84 Mild manifestations limited to diagnosis is not required for the diagnosis or treatment of a single organ are often managed with close observation, aGVHD, because biopsy is not absolutely sensitive. topical treatment, or by slowing the tapering of immu- nosuppressive agents.85 More severe manifestations or multiorgan involvement typically require systemic cor- Diagnosis and Grading ticosteroid treatment (with or without secondary sys- If aGVHD is suspected, additional tests such as stool temic agents).81 Management of GVHD can be optimized testing, imaging studies, and/or viral reactivation testing by providing coordinated care from a multidisciplinary should be performed to rule out non-GVHD causes of the symptoms (see GVHD-1, above). Organ-directed bi- team, preferably in medical centers with access to opsies can then be performed as clinically indicated to specialized transplant services. confirm the presence of aGVHD (ie, lower GI biopsy for diarrhea, upper GI biopsy for nausea/vomiting, skin Acute GVHD biopsy for rash). Rectosigmoid biopsies were shown in Despite prophylaxis with immunosuppressive agents, one study to have higher sensitivity and negative pre- 20%–80% of allogeneic HCT recipients develop acute dictive value than biopsies at other sites, whether the

JNCCN.org | Volume 18 Issue 5 | May 2020 605 NCCN GUIDELINES® Hematopoietic Cell Transplantation, Version 2.2020

patient presented with diarrhea, nausea, or vomiting.88 More recently, MAGIC (Mount Sinai Acute GVHD Liver function tests should be routinely monitored after International Consortium) criteria were developed.94 allogeneic HCT for early detection of hepatic aGVHD, which A joint task force of the European Society for Blood is often asymptomatic. Liver biopsy may be considered in and Marrow Transplantation (EBMT), National Insti- patients presenting with unexplained abnormal liver tutes of Health (NIH), and CIBMTR published a po- function tests without evidence of aGVHD elsewhere, if sition statement on standardized terminology for the information obtained would inform treatment. After GVHD.95 Furthermore, blood biomarkers are being the diagnosis of aGVHD is made, the organ staging and actively investigated for their utility as a predictive tool overall grade of aGVHD should be determined to guide in aGVHD.96–98 choice of therapy and disease monitoring (see GVHD-A, page 609, for aGVHD grading criteria). First-Line Therapy of aGVHD The clinical grade of aGVHD is predictive of sur- vival. Grading criteria for aGVHD have been developed Grade I over the past several decades. Glucksberg aGVHD Grade I aGVHD affects only the skin (stage 1–2, ,50% grading criteria were first proposed in 1974.89 Modified body surface area nonbullous rash), with no GI or Glucksberg (consensus or Keystone) criteria were further liver involvement.79 First-line therapy options for these developed in 1994 (see GVHD-A, page 609, for modified patients include continuing (or restarting) the original Glucksberg grading criteria).79 The IBMTR Severity Index immunosuppressive agent and administering topical was subsequently developed,90 and was shown to be skin-directed steroids (eg, triamcinolone, clobetasol) more predictive of HCT outcome when compared with and/or topical tacrolimus (see GVHD-2, above). Medium- the original Glucksberg criteria.91 Minnesota criteria have to high-potency topical steroid formulations are rec- also been devised to identify patients with “high-risk” ommended, except on the face where low-potency aGVHD who could benefit from early escalated therapy.92,93 hydrocortisone is to be used (to avoid skin atrophy,

606 © JNCCN—Journal of the National Comprehensive Cancer Network | Volume 18 Issue 5 | May 2020 Hematopoietic Cell Transplantation, Version 2.2020 NCCN GUIDELINES®

telangiectasia, and acneiform eruptions). Antihistamines if aGVHD developed during tapering of immunosup- may be used for symptomatic relief of itching as needed. pressive therapy. A phase III randomized controlled trial Alternatively, the patient can be observed without showed that initial treatment with low-dose systemic treatment if the rash is asymptomatic and stable. If there prednisone (0.5 mg/kg/day) in conjunction with GI topical is a response to first-line therapy, as indicated by a steroids (beclomethasone dipropionate 6 budesonide) resolution of the rash and associated symptoms, the was safe and effective for managing upper GI symptoms immunosuppressive agent should be tapered as clinically (ie, nausea, vomiting, anorexia) in patients with grade II feasible and topical steroids can be discontinued. Op- aGVHD, with or without skin involvement (,50% body tions for patients with no response to first-line therapy surface area), with diarrhea volumes ,1,000 mL/day.99 (eg, refractory pruritic rash) include enrollment in a well- In patients with higher grade aGVHD, use of low-dose designed clinical trial or treatment according to the prednisone was associatedwithanincreasedriskof recommendations for grade II–IV aGVHD. requiring secondary immunosuppressive therapy, but with no difference in survival. Thus, patients with Grades II–IV gradeIIaGVHDmaybetreatedwith0.5–1 mg/kg/day Enrollment in a well-designed clinical trial is encouraged of methylprednisone (or prednisone dose equivalent). for all patients presenting with grade II–IV aGVHD. Patients with higher grade aGVHD should be treated Administration of systemic corticosteroids (6 topical with higher doses of systemic steroids (1–2 mg/kg/day steroids) is the standard first-line treatment option methylprednisolone or prednisone dose equivalent). (unless contraindicated or associated with severe in- There is no role for escalation of methylprednisolone tolerance) for patients with grades II–IV aGVHD (see above 2 mg/kg/day.100 The addition of other systemic GVHD-3, above).86,87,99 Additionally, the original immu- agents in conjunction with systemic corticosteroids as first- nosuppressive agent should be restarted, continued, line therapy for aGVHD should only be done in the or escalated (with or without therapeutic drug targeting) context of a well-designed clinical trial.

JNCCN.org | Volume 18 Issue 5 | May 2020 607 NCCN GUIDELINES® Hematopoietic Cell Transplantation, Version 2.2020

If patients respond to first-line therapy, as indicated These results suggest that MMF plus corticosteroids is by a complete resolution of GVHD or improvement in at a potentially promising regimen for initial therapy of least 1 organ without any progression in any other or- aGVHD. Accordingly, a phase III multicenter double- gans, the steroids should be tapered as clinically feasible. blinded clinical trial (BMT CTN 0802) was initiated Options for patients without a complete response (CR) to comparing the combination of methylprednisolone first-line therapy include enrollment in a well-designed at 1.6 mg/kg/day (or prednisone dose equivalent) plus clinical trial or the addition of other systemic agent(s) to MMF versus methylprednisolone plus placebo as first-line the corticosteroids, with steroid taper as clinically feasible. therapy for aGVHD.102 A futility rule for GVHD-free sur- See “Suggested Agents for Steroid-Refractory aGVHD” vival at day 56 was met at a planned interim analysis after (page 611) for more information. 235 patients (of 372) were enrolled. Outcomes of both Alternative regimens have been investigated as first- arms were equivalent in OS, 1-year incidence of chronic line therapy for aGVHD. BMT CTN 0302 was a ran- GVHD (cGVHD), and infection risk. Therefore, MMF domized 4-arm phase II clinical trial (n5180) that provided no benefit when added to corticosteroids as first- compared different agents (etanercept, mycophenolate line therapy for aGVHD. mofetil [MMF], denileukin diftitox, and pentostatin) in BMT CTN 1501 was an open-label, randomized combination with methylprednisolone at 2 mg/kg per phase II trial that evaluated sirolimus versus prednisone day (or prednisone dose equivalent) for treatment of as initial treatment of standard risk (SR) aGVHD as de- newly diagnosed aGVHD.101 The day 28 overall response fined by the Minnesota (MN) GVHD clinical risk score rates (ORRs) were etanercept 26%, MMF 60%, denileukin and the Ann Arbor (AA) biomarker status.103 A total of 127 53%, and pentostatin 38%. The corresponding 9-month MN-SR patients and 122 AA-SR patients were random- overall survival (OS) rates were 47%, 64%, 49%, and 47%, ized to receive either sirolimus or prednisone as first-line respectively. Risk of severe infections were etanercept, therapy for aGVHD. The day 28 ORRs were similar (65% 48%; MMF, 44%; denileukin, 62%; and pentostatin, 57%. and 73% for sirolimus and prednisone, respectively) and

608 © JNCCN—Journal of the National Comprehensive Cancer Network | Volume 18 Issue 5 | May 2020 Hematopoietic Cell Transplantation, Version 2.2020 NCCN GUIDELINES®

there were no differences in disease-free survival, disease Chronic Graft-versus-Host Disease relapse, NRM, or OS. Patients in the sirolimus group cGVHD is the leading cause of NRM after allogeneic HCT encountered less hyperglycemia and had reduced risk of and has a profound impact on quality of life.21 cGVHD infections but were at an increased risk for thrombotic usually develops within the first year after HCT in most microangiopathy as compared with patients in the patients, but it can also develop many years later. cGVHD prednisone group (10% vs 1.6%). Thus, sirolimus seems affects multiple organ systems and is characterized by to be an appropriate alternative to systemic corticoste- fibrosis and variable clinical features resembling auto- roids as first-line therapy for patients with SR aGVHD as immune disorders.105 The NIH Consensus Development defined by the clinical MN score or the AA biomarker Project has published detailed recommendations for the score. However, a randomized phase III study is needed management of cGVHD including diagnosis, assessment to confirm this finding. of organ involvement, monitoring response to treatment, and supportive care interventions.85,106–109 A thorough Additional Therapy understanding of the various clinical manifestations of Due to a lack of high-quality evidence, the NCCN Panel does cGVHD is essential for the early recognition of signs and not prefer any specific agent(s) for second-line therapy and symptoms. Multidisciplinary care aimed at avoiding encourages that patients with steroid-refractory aGVHD organ damage and preserving function is strongly be managed as part of a clinical trial.87 Currently, recommended. ruxolitinib is the only therapy approved by the United States FDA for steroid-refractory aGVHD with out- Diagnosis and Grading comes, in particular 6-month survival, seemingly In all cases of suspected cGVHD, additional tests are comparable to other agents.104 See “Suggested Agents often performed to rule out non-GVHD causes of for Steroid-Refractory aGVHD” (page 611) for more symptoms, such as infection, drug-induced injury or information. toxicity, malignancy, or other causes. Although a biopsy

JNCCN.org | Volume 18 Issue 5 | May 2020 609 NCCN GUIDELINES® Hematopoietic Cell Transplantation, Version 2.2020

may be done to confirm the presence of cGVHD, a biopsy prednisone dose equivalent). The initial corticosteroid is not always feasible and is not mandatory if the patient dose may vary depending on the organs involved, the has at least one of the diagnostic findings of cGVHD defined severity of GVHD, and patient comorbidities. Topical by the NIH Consensus Development Project (see GVHD-B, steroids, such as triamcinolone, clobetasol, topical es- above, for diagnostic signs and symptoms of cGVHD).85 trogen (for vulvovaginal cGVHD), topical tacrolimus, or Manifestations of cGVHD include bronchiolitis obliterans dexamethasone oral rinse (for oral cGVHD), may be used syndrome (BOS), a devastating inflammatory lung condi- as clinically indicated. Patients with lung involvement tion. Unless it is pathologically diagnosed (via lung biopsy), should receive inhaled steroids (eg, budesonide or flu- clinical characteristics of BOS (assessed by pulmonary ticasone) 6 azithromycin (eg, FAM [fluticasone, azi- function tests) are only diagnostic of lung cGVHD if dis- thromycin, and montelukast]). Azithromycin should be tinctive features of cGVHD are present in another organ used only for the treatment of BOS and not for BOS (see GVHD-B 2 of 3, page 611, for the complete criteria prophylaxis due to data suggesting an increased risk for required for diagnosis of BOS). cGVHD grading is done cancer relapse in HCT patients receiving azithromycin according to the NIH Consensus Development Project for BOS prophylaxis.110 Patients with progressive or criteria (see GVHD-C, page 613).85 worsening lung cGVHD following 2 to 3 lines of therapy may be evaluated for lung transplant. First-Line Therapy of cGVHD If patients respond to first-line therapy according to Enrollment in a well-designed clinical trial is encouraged the NIH Response Criteria,95 steroids should be tapered for all patients presenting with cGVHD (see GVHD-4, as clinically feasible to mitigate long-term side effects page 608). Options for first-line therapy include and risk of infection. Options for patients with no re- restarting, continuing, or escalating the original immu- sponse to first-line therapy include enrollment in a well- nosuppressive agent and/or administration of systemic designed clinical trial or the addition of other systemic corticosteroids (0.5–1 mg/kg/day methylprednisolone or agent(s) to the corticosteroids, with steroid taper as

610 © JNCCN—Journal of the National Comprehensive Cancer Network | Volume 18 Issue 5 | May 2020 Hematopoietic Cell Transplantation, Version 2.2020 NCCN GUIDELINES®

clinically feasible. See “Suggested Agents for Steroid- well-designed clinical trial is strongly encouraged for Refractory cGVHD” (page 622) for more information. these patients since steroid-refractory GVHD is associ- ated with poor OS and no standard, effective therapy has Additional Therapy yet been identified.86 The selection of therapy for steroid- Due to a lack of high-quality evidence, the NCCN Panel refractory GVHD should be based on physician experi- doesnotpreferanyspecific agent(s) for second-line ence, the agent’stoxicityprofile, the effects of prior therapy and encourages that patients with steroid- treatments, drug interactions, convenience/accessibility, refractory cGVHD be managed as part of a clinical trial.87 and patient tolerability. Agent selection may also depend Currently, ibrutinib is the only FDA-approved second-line on organ involvement and overall grade of cGVHD. therapy for patients with steroid-refractory cGVHD.111 Other novel agents are being evaluated in ongoing clinical Suggested Agents for Steroid-Refractory aGVHD trials.112 See “Suggested Agents for Steroid-Refractory The following systemic agents, listed in alphabetical cGVHD” (next section) for more information. Supportive order, can be used in conjunction with the original care interventions for controlling organ-specificsymptoms immunosuppressive agent and corticosteroids (typical or complications should be an integral part in the long- first-line therapy) for steroid-refractory aGVHD (see term management of patients with cGVHD.107 GVHD-E, page 620). Slow taper of systemic corticoste- roids is recommended if deemed ineffective therapy. Steroid-Refractory GVHD In patients with steroid-dependent disease, corticoste- Approximately 40%–50% of patients with acute or roid therapy may be continued until an alternative chronic GVHD develop steroid-refractory disease, which steroid-sparing agent shows a response. Currently, there is is associated with high mortality.86,113 The NIH has de- insufficient evidence to recommend one systemic agent as fined criteria for steroid-refractory acute and chronic preferred over another. However, it is worth noting that GVHD (see GVHD-D, page 618).95 Enrollment in a ruxolitinib is currently the only FDA-approved therapy for

JNCCN.org | Volume 18 Issue 5 | May 2020 611 NCCN GUIDELINES® Hematopoietic Cell Transplantation, Version 2.2020

steroid-refractory aGVHD. The following are the most infection was not a significant predictor of survival in commonly used agents among NCCN Member Institutions. this study. These data suggest that alemtuzumab has favorable activity in the treatment of steroid-refractory Alemtuzumab aGVHD and emphasizes the need for anti-infective Alemtuzumab is a humanized anti-CD52 monoclonal prophylaxis and close monitoring for patients receiving antibody that has been successfully used as part of a pre- this therapy. Currently in the United States, alemtuzu- transplant preparative regimen for GVHD prophylaxis.114,115 mab is only available via the Campath Distribution The safety and efficacy of alemtuzumab for the treatment of Program, and drug supply is patient-specific. steroid-refractory aGVHD was evaluated in a prospective clinical study of 18 patients with grade II–IV steroid- Alpha-1 Antitrypsin refractory aGVHD treated subcutaneously with 10 mg Alpha-1 antitrypsin (AAT; also known as alpha-1 pro- alemtuzumab daily for 5 consecutive days.116 The ORR to teinase inhibitor) is a circulating protease inhibitor that alemtuzumab was 83%, with 33% of patients experi- inactivates serine proteases from neutrophils and mac- encing CR. Importantly, univariate analyses of clinical rophages to protect tissues from proteolytic degrada- characteristics between responders and nonresponders tion.118 AAT is most commonly used to treat patients with showed no differences in the main organ involved, grade AAT-deficiency, an inherited condition which causes of GVHD, or time between HCT and GVHD onset. After a lung and liver damage.119 The safety and efficacy of AAT median follow-up of 9 months, 78% of patients had $1 to treat steroid-refractory aGVHD was evaluated in a pro- infectious episodes. In a retrospective analysis of 20 spective, multicenter phase II trial of 40 patients treated patients with steroid-refractory grade III–IV aGVHD re- with intravenous AAT twice weekly for up to 4 weeks at a ceiving 10 mg of intravenous alemtuzumab weekly, the dose of 60 mg/kg/day.118 TheORRandCRratesat28days ORR was 70% with a CR of 35%.117 One-year OS was were 65% and 35%, respectively. After 60 days, responses 50%. Although infectious complications were common, were maintained in 73% of patients. OS at 6 months was

612 © JNCCN—Journal of the National Comprehensive Cancer Network | Volume 18 Issue 5 | May 2020 Hematopoietic Cell Transplantation, Version 2.2020 NCCN GUIDELINES®

45% and did not differ by grade or site of organ involvement. ATG. Of the 64 patients with skin involvement, 61% Infectious mortality was 10% at 6 months. No infusion experienced a complete or partial response compared reactions or drug-related grade 3–4 toxicities were report- with 27% without skin involvement (P5.02). The prob- ed. These data suggest that AAT is an effective treatment ability of survival at 1 year for all patients was 32% (95% option for patients with steroid-refractory aGVHD. CI, 22%–42%). Bacterial, viral, and fungal infections oc- curred in 37%, 10%, and 18% of patients, respectively. Anti-Thymocyte Globulin Another early retrospective study analyzed the effi- Anti-thymocyte globulin (ATG) is a T-cell–depleting cacy of rabbit ATG (thymoglobulin) in 36 patients with antibody that has been commonly used for immuno- steroid-refractory GVHD treated at a single institution.129 suppression in the solid organ transplant setting and for Patients, most of whom (89%) had grade III–IV aGVHD, GVHD prophylaxis.120–125 Two ATG products are cur- received thymoglobulin at 2.5 mg/kg/day for either 4 to 6 rently approved by the FDA: thymoglobulin (ATG-T), a consecutive days (group 1; n513) or on days 1, 3, 5, and 7 polyclonal immunoglobulin G (IgG) derived from rabbits, (group 2; n521). The ORR was 59%, with a CR rate of 38%. and ATGAM (ATG-h), a polyclonal IgG derived from The response rate was higher in group 1 (77%) compared horses.126,127 An early retrospective study analyzed the with group 2 (48%); however, this difference was not sta- clinical response and survival outcomes of 79 patients tistically significant (P5.15). As seen in the aforementioned with steroid-refractory aGVHD treated with 1 to 5 courses study, skin aGVHD was more responsive (96% of patients) of equine ATG (ATGAM) at a dose of 15 mg/kg/day twice than GI (46%) or liver aGVHD (36%). Common adverse a day for 5 days.128 At day 28 of treatment, the ORR was events included hepatic dysfunction (25%), viral infec- 54% with 20% of patients achieving a durable CR. Re- tions (26%), fungal infections (32%), and bacteremia sponse to ATG was not associated with the initial grade of (21%). Of the 36 original patients enrolled in the study, GVHD; however, it was associated with the site of GVHD. only 2 (6%) were alive 34 months post-HCT. A more Patients with skin aGVHD were more likely to respond to recent retrospective analysis of 11 patients with

JNCCN.org | Volume 18 Issue 5 | May 2020 613 NCCN GUIDELINES® Hematopoietic Cell Transplantation, Version 2.2020

steroid-refractory aGVHD reported an ORR of 55% for intravenous basiliximab at a dose of 20 mg on days 1 and thymoglobulin administered at a median dose of 3 mg/ 4.133 The ORR was 83% with 18% of patients achieving a kg/day.130 In this study, high response rates were ob- CR. The percentage of patients experiencing a minimum served in patients with skin (100%) and GI (83%) aGVHD as one-grade reduction in aGVHD varied with organ in- compared with those with liver aGVHD (25%). One-year OS volvement (77% of patients with skin GVHD, 14% of and transplant-related mortality were 55% and 45%, re- patients with liver involvement, and 67% of patients with spectively. These data suggest that ATG may be an effective GI involvement). Although administration of basiliximab treatment option for patients with steroid-refractory did not cause any infusion-related toxicity, infections oc- aGVHD, especially for those with skin involvement. How- curred in 65% of patients. The rates of malignancy re- ever,long-termsurvivalappearstobelow,eveninre- currence and 1-year treatment-related mortality were 10% sponders.129 A comprehensive review on the use of ATG for and 45%, respectively, following immunosuppression with GVHD treatment has been published.131 basiliximab. Therefore, basiliximab appears to have some activity in the treatment of steroid-refractory aGVHD. Basiliximab Basiliximab is a chimeric monoclonal antibody that Calcineurin Inhibitors functions as an immunosuppressive agent by binding to Calcineurin inhibitors (CNI), such as tacrolimus and and blocking the interleukin-2 (IL-2) receptor.132 IL-2 cyclosporine, are immunosuppressive agents that inhibit plays a key role in the development of aGVHD by the action of calcineurin, an enzyme involved in the stimulating the activation of donor T cells in the graft, activation of T cells. CNI are commonly used for the which can attack the cells and tissues of the recipient.133 prevention and initial treatment of GVHD, often in The efficacy and feasibility of basiliximab for the treat- conjunction with other agents.134–143 However, limited ment of steroid-refractory aGVHD was evaluated in a data exist for their use in the treatment of steroid- prospective phase II trial of 23 patients treated with refractory aGVHD. In a small phase II trial, 18 patients

614 © JNCCN—Journal of the National Comprehensive Cancer Network | Volume 18 Issue 5 | May 2020 Hematopoietic Cell Transplantation, Version 2.2020 NCCN GUIDELINES®

with aGVHD that developed or progressed during ther- inhibiting the activity of TNF-a, a proinflammatory cy- apy with cyclosporine and/or other immunosuppressive tokine that acts as the master regulator of immune re- agents were treated with tacrolimus at an initial dose of sponse and is a major mediator in the pathogenesis of 0.05 mg/kg intravenously or 0.15 mg/kg orally twice per aGVHD.147 The efficacy of etanercept for the treatment of day.144 In the 13 evaluable patients, the ORR was 54%. steroid-refractory aGVHD was retrospectively evaluated The most common adverse events were renal toxicity in a cohort of 13 patients.148 Etanercept at 25 mg was (53% of patients), followed by nausea and vomiting given subcutaneously twice weekly for 4 weeks followed (31%). A recent retrospective analysis involving 42 by 25 mg weekly for 4 weeks. The ORR was 46%, with 4 patients with steroid-refractory aGVHD treated with patients achieving CR. Responses correlated with the tacrolimus in combination with sirolimus reported an overall grade of aGVHD, with grade II aGVHD patients ORR of 49% (CR rate, 42%) for patients treated in the showing higher response rates than those with grades second-line (n531) and an ORR of 27% (CR, 0) for pa- III–IV aGVHD, and were most commonly observed in tients treated in the third-line (n511).145 One-year OS patients with GI involvement (64% of clinical responses). was 42% in patients treated in the second-line and 0% in No immediate treatment-related side effects were ob- patients treated in the third-line. Infectious complica- served; however, bacterial and fungal infections oc- tions occurred in 90% of patients. Therefore, CNI may be curred in 14% and 19% of patients, respectively. At a a reasonable option for the treatment of patients with median follow-up of 429 days, OS was 67%. These results steroid-refractory aGVHD when they have not been used suggest that etanercept has favorable activity in steroid- in prophylaxis or initial therapy. refractory aGVHD.

Etanercept Extracorporeal Photopheresis Etanercept is a recombinant tumor necrosis factor-alpha Extracorporeal photopheresis (ECP) is a form of immu- (TNF-a) receptor fusion protein.146 Etanercept acts by notherapy that involves ex vivo exposure of mononuclear

JNCCN.org | Volume 18 Issue 5 | May 2020 615 NCCN GUIDELINES® Hematopoietic Cell Transplantation, Version 2.2020

cells obtained by apheresis to the photosensitizing agent 84%, followed by 65% for GI involvement. Reported rates of 8-methoxypsoralen and ultraviolet A (UVA) light, followed ECP-related mortality were extremely low. Another sys- by reinfusion of the cells back into the patient.149 The tematic review largely reached the same conclusions, clinical activity of ECP is thought to be mediated by the reporting a pooled ORR of 71% and ORRs of 86%, 60%, and immunomodulatory effects of ultraviolet light.150 The exact 68% for skin, liver, and GI involvement, respectively.154 mechanism by which ECP ameliorates GVHD (acute or These data suggest that ECP is an effective therapy for chronic) is unclear, but may involve the normalization of steroid-refractory aGVHD, especially for patients with skin CD41/CD81 lymphocyte populations, an increase in the involvement. If ECP is not available or feasible, the NCCN number of CD3-/CD561natural killer cells, and/or a de- Panel recommends the use of psoralen plus UVA irradia- crease in circulating dendritic cells.149,151 tion as an alternative treatment option. A phase II trial in patients with grade II–IV steroid- refractory aGVHD found that weekly ECP therapy Infliximab resulted in complete resolution of aGVHD symptoms in Infliximab is a genetically constructed IgG1 chimeric 82% of patients with skin involvement and 61% of pa- monoclonal antibody that binds to membrane-bound tients with liver or GI involvement.152 In a recent pro- TNF-a, blocking its activity and triggering lysis of TNF- spective single-center study involving 21 patients with a–producing cells.147,155 In a retrospective evaluation of grade III–IV aGVHD, second- or third-line treatment with 21 patients with steroid-refractory aGVHD who had re- ECPresultedinanORRof84%.153 After a median follow-up ceived treatment with single-agent infliximab (10 mg/kg of 17 months, 1-year OS was 53% and was independently once weekly for at least 4 doses), the ORR was 67% with associated with a higher number of ECP sessions. A sys- 62% of patients achieving CR.147 No toxic reactions to tematic review of prospective studies reported a pooled infliximab were observed; however, bacterial, fungal, and ORR of 69% for ECP in the treatment of steroid-refractory viral infections occurred in 81%, 48%, and 67% of pa- aGVHD.149 The ORR for skin manifestations was highest at tients, respectively. OS was 38% at a median follow-up of

616 © JNCCN—Journal of the National Comprehensive Cancer Network | Volume 18 Issue 5 | May 2020 Hematopoietic Cell Transplantation, Version 2.2020 NCCN GUIDELINES®

21 months. Another retrospective analysis of 32 patients that promotes the growth and differentiation of T cells.160 with steroid-refractory aGVHD treated with infliximab SirolimusisalsousedforGVHDprophylaxis,oftenin administered intravenously at the dose of 10 mg/kg once conjunction with the CNI tacrolimus.139–141,161–164 The weekly for a median of 3 courses reported an ORR of safety and efficacy of sirolimus in the treatment of 59%.156 Infections developed in 72% of patients. A third, steroid-refractory aGVHD was evaluated in a phase I trial more recent retrospective analysis involving 35 patients involving 21 patients with grade III–IV steroid-refractory with steroid-refractory aGVHD reported an ORR of 40% aGVHD.165 The ORR was 57%, with a CR rate of 24%. for infliximab administered intravenously at 10 mg/kg However, only 11 patients completed the full course of weekly for a median of 4 doses, with 83% of patients treatment due primarily to extensive toxicities including developing infectious complications.157 These data sug- cytopenias, hyperlipidemia, severe thrombotic micro- gest that infliximab is active in the treatment of steroid- angiopathy, and renal failure. In a retrospective analysis refractory aGVHD; however, the potential for excessive of 31 patients with steroid-refractory aGVHD treated infections should be evaluated. with sirolimus in combination with tacrolimus, the ORR was 76% and 42% of patients achieved CR.166 Median OS mTOR Inhibitors was 5.6 months and 1-year OS was 44%. Thrombotic Sirolimus (rapamycin) is a macrolide compound derived microangiopathy and hyperlipidemia occurred in 21% from the bacteria Streptomyces hygroscopicus that and 44% of patients, respectively, but were manageable. possesses immunosuppressive, antibiotic, and antitumor Another retrospective study involving 22 patients with properties. Sirolimus functions as a potent immunosup- steroid-refractory aGVHD treated with sirolimus re- pressant by inhibiting the activity of mTOR, a serine/ ported similar results.167 The ORR was 72% and OS was threonine kinase that acts as a master regulator of cell 41% after a median follow-up of 13 months. Thrombotic growth, proliferation, metabolism, and survival.158,159 By microangiopathy occurred in 36% of patients when inhibiting mTOR, sirolimus disrupts the cytokine signaling sirolimus was combined with tacrolimus or other CNI.

JNCCN.org | Volume 18 Issue 5 | May 2020 617 NCCN GUIDELINES® Hematopoietic Cell Transplantation, Version 2.2020

A third, more recent retrospective analysis involving 42 with MMF at an initial dose of 1 g twice daily for 35 days. patients with steroid-refractory aGVHD treated with OS at 6 and 12 months was 37% and 16%, respectively. sirolimus and tacrolimus reported an ORR of 48.5% (CR MMF treatment was discontinued in 4 patients because rate, 42%) for patients treated in the second-line (n531) of toxicities including neutropenia, abdominal pain, and and an ORR of 27% for patients treated in the third- pulmonary infiltrate. The same group conducted a ret- line (n511).145 For patients treated in the second-line, rospective analysis of more recent patients with steroid- 1-year OS was 42% (0% for patients treated in the refractory aGVHD (n529) and found a similar ORR to third-line). Infectious complications were common MMF therapy (48%).170 However, OS at 6 and 12 months (90% of patients). These data suggest that sirolimus is was much higher (55% and 52%, respectively). Possible an effective option for the treatment of patients with explanations for the improved OS may include improved steroid-refractory aGVHD but may result in significant management of GVHD and longer experience with the toxicities. use of MMF. In another retrospective analysis of 13 pa- tients with steroid-refractory aGVHD, the ORR to MMF Mycophenolate Mofetil (1.5 or 2 g daily) was 31% and the estimated 2-year OS MMF is a prodrug of mycophenolic acid that acts as an rate was 33%.171 Responses were observed in 31% of cases immunosuppressant by inducing apoptosis in lympho- with skin involvement, 44% of cases with liver involve- cytes through inhibition of the de novo synthesis of ment, and 23% of cases with GI involvement. Another purines.168 MMF is indicated for the prevention of organ retrospective study reported a 3-year OS rate of 40% and rejection in solid organ transplants and is a standard a CR rate of 26% in 27 patients with steroid-refractory component of GVHD prophylaxis regimens.169 In a aGVHD treated with MMF at a dose of 1–1.5 g BID orally prospective phase II trial completed in the mid-1990s, or intravenously.172 The CR rates observed with MMF Furlong et al170 reported an ORR of 47% and a CR rate of therapy were typically higher in patients with lower grade 31% in 19 patients with steroid-refractory aGVHD treated GVHD (40% for grades I–II vs 8% for grades III–IV). These

618 © JNCCN—Journal of the National Comprehensive Cancer Network | Volume 18 Issue 5 | May 2020 Hematopoietic Cell Transplantation, Version 2.2020 NCCN GUIDELINES®

data suggest that MMF has some efficacy for treating these studies may be attributed to variability in the steroid-refractory aGVHD, especially in those with lower patient populations, pentostatin doses and number of grade GVHD at the start of treatment. treatment cycles, use of additional therapies, or the assessment of treatment response.174 Pentostatin A phase I dose-escalation study involving 22 patients Pentostatin is a purine analog that acts as an immuno- with steroid-refractory aGVHD reported a high CR rate of suppressant by inducing lymphocyte apoptosis through 63%.177 However, late infections observed at the 2 mg/ inhibition of adenosine deaminase.173 A large retro- m2/day dose used in the study were considered to be spective analysis of 60 patients treated with pentostatin dose-limiting toxicities. In a follow-up phase II study of for steroid-refractory aGVHD reported an ORR of 33% 8 patients receiving a lower dose of 1.5 mg/m2/day of and a CR rate of 18%.174 All patients received pentostatin pentostatin, 4 patients died of progressive hepatic GVHD at a dose of 1.5 mg/m2 on days 1 to 3, repeated every 2 and 3 patients died of sepsis secondary to infections, weeks, for a median of 3 courses. OS at 18 months was pancytopenia, progressive hepatic GVHD, and/or acute 21% and NRM was 72%. Stratified analysis revealed renal failure.178 Two patients with renal insufficiency that patients ,60 years of age with isolated lower GI demonstrated excessive pentostatin exposure, as de- GVHD had the best outcomes, with an ORR of 48% and termined by measurement of the area under the curve, 18-month OS of 42%. An earlier retrospective study despite a 50% reduction in pentostatin dose. Although reported similar results, with an ORR of 38% and this trial was terminated before efficacy could be 2-year OS of 17% in 24 patients treated with pentos- assessed, the data suggest that pentostatin is in- tatin at a daily dose of 1 mg/m2 given intravenously effective in treating liver manifestations of GVHD and over 3 consecutive days.175 Asmallerretrospective may be inappropriate for patients with renal in- analysis of 12 patients reported a higher ORR of 50% sufficiency. The limited available data suggest activity and a CR rate of 33%.176 Discrepancies in the results of for pentostatin in the treatment of steroid-refractory

JNCCN.org | Volume 18 Issue 5 | May 2020 619 NCCN GUIDELINES® Hematopoietic Cell Transplantation, Version 2.2020

aGVHD without liver involvement; however, serious retrospective study of 54 patients who had received adverse events have been reported. The renal function ruxolitinib at a dose of 5–10 mg orally twice a day for of patients receiving pentostatin should be monitored steroid-refractory aGVHD reported an ORR of 82%, with throughout the course of treatment. a CR rate of 46% and a 6-month OS rate of 79%.181 Cytopenias and reactivation of cytomegalovirus were Ruxolitinib observed in 56% and 33% of patients, respectively. The Ruxolitinib is a selective inhibitor of JAK1 and JAK2, ongoing phase III REACH2 (ClinicalTrials.gov identifier: which are intracellular tyrosine kinases that play critical NCT02913261) and REACH3 (ClinicalTrials.gov identifier: roles in cytokine signaling and the development and NCT03112603) trials are comparing treatment with rux- function of several types of immune cells.179 In 2019, the olitinib to the best available therapy in patients with FDA approved ruxolitinib for the treatment of steroid- steroid-refractory acute (REACH2) or steroid-refractory refractory aGVHD in adult and pediatric patients aged chronic (REACH3) GVHD.179 12 years and older.180 The approval was based on data from the single-arm multicenter phase II REACH1 trial Tocilizumab that included 49 patients with grade II–IV steroid- Tocilizumab is a humanized anti-IL-6 receptor antibody refractory aGVHD.104 Patients received 5 mg ruxolitinib that functions as an immunosuppressive agent by twice daily, with an optional increase to 10 mg twice daily blocking IL-6 signaling.182 IL-6 is a proinflammatory in the absence of cytopenias. The ORR at day 28 was cytokine produced by a variety of cell types that plays a 100% for patients with grade II GVHD, 41% for patients key role in the development of aGVHD. Elevations of IL-6 with grade III GVHD, and 44% for those with grade have been detected in the serum of patients with GVHD IV GVHD. The most commonly reported adverse events and polymorphisms that result in increased IL-6 pro- were hematologic (anemia, thrombocytopenia, and duction have been associated with an increase in GVHD neutropenia) followed by infections and edema. An earlier severity.183,184 The efficacy of tocilizumab for the

620 © JNCCN—Journal of the National Comprehensive Cancer Network | Volume 18 Issue 5 | May 2020 Hematopoietic Cell Transplantation, Version 2.2020 NCCN GUIDELINES®

treatment of steroid-refractory aGVHD was evaluated in suggest that tocilizumab has activity in the treatment of several studies.185–189 A small study of 8 patients (6 pa- patients with steroid-refractory aGVHD, especially in tients had aGVHD, most of whom had grade IV) showed patients with skin or GI involvement. an ORR of 67%, with a CR rate of 33%.189 Tocilizumab was administered intravenously at a dose of 8 mg/kg once Anti-Integrins every 3 to 4 weeks. The most common adverse event in Anti-integrin agents (natalizumab and vedolizumab) this study was infectious complications (69% were bac- are currently being investigated as therapeutic mo- terial in origin). A retrospective study of 9 patients with dalities for steroid-refractory aGVHD.190–192 These grade III–IV steroid-refractory aGVHD treated with the agents are monoclonal antibodies that impair homing same dose and schedule of tocilizumab reported a lower of leukocytes (particularly T cells) to the GI endothelium ORR of 44% and a CR rate of 22%.188 Another retrospective via blocking leukocyte receptors alpha-4 integrin analysis of 15 patients conducted at the same institution (natalizumab) or alpha-4/beta-7 integrin (vedolizumab).193,194 reported improved results with the use of tocilizumab for A retrospective multicenter study evaluated the use of steroid-refractory aGVHD, with a CR rate of 40%.187 In this vedolizumab for steroid-refractory GI aGVHD in 29 study, the patients received tocilizumab every 2 to 3 weeks patients.191 The ORR was 79% with CR observed in 28% (majority received tocilizumab every 2 weeks), compared of patients. Early administration of vedolizumab was with every 3 to 4 weeks as in the previous studies. Patients associated with a greater chance of discontinuing im- with skin and/or GI involvement had the greatest response, munosuppression and a lower risk of fatal infectious while those with liver involvement showed no response. complications. However, further studies are needed to Another recent retrospective study conducted at a different confirm these findings. It should be noted that the institution reported a CR rate of 63% to tocilizumab NCCN Panel does not currently recommend the use of (8 mg/kg given every 2 weeks) in 16 patients with steroid- these agents for the treatment of steroid-refractory refractory aGVHD of the lower GI tract.185 These data aGVHD.

JNCCN.org | Volume 18 Issue 5 | May 2020 621 NCCN GUIDELINES® Hematopoietic Cell Transplantation, Version 2.2020

Suggested Agents for Steroid-Refractory cGVHD binding to (blocking) the costimulation receptors (CD80 The following systemic agents, listed in alphabetical order, and CD86) on antigen-presenting cells (costimulation can be used in conjunction with corticosteroids for steroid- blockade). The safety and efficacy of abatacept in the refractory cGVHD (see GVHD-E, page 620). Although treatment of steroid-refractory cGVHD were evaluated in a prolonged systemic corticosteroid therapy is better avoi- phase I clinical trial involving 16 patients.195 The study ded, some patients may require prolonged steroid therapy followed a 313 design with 2 escalating abatacept doses to (preferably using #0.5 mg/kg/day) for steroid-dependent determine the maximum tolerated dose (MTD). The partial cGVHD. Currently, there is insufficient evidence to rec- response rate to abatacept was 44%, and no dose-limiting ommend one systemic agent as preferred over another. toxicities were observed at the MTD of 10 mg/kg. The af- However, it is worth noting that ibrutinib is currently the fected sites with greatest improvement were the mouth, GI only FDA-approved therapy for steroid-refractory cGVHD. tract, joints, skin, eyes, and lung. The most common ad- The following are the most commonly used agents among verse events were pulmonary infections (all of which re- NCCN Member Institutions. Although the following agents solved), diarrhea, and fatigue. Importantly, treatment with may be used in any site, some agents are more commonly abatacept resulted in a 51% reduction in prednisone usage. used with particular organ involvement. These data suggest that abatacept is an effective treatment option for patients with steroid-refractory cGVHD. Abatacept Abatacept is a T-cell costimulatory inhibitor. It is a Alemtuzumab recombinant soluble fusion protein composed of the ex- The safety and efficacy of alemtuzumab for the treatment tracellular domain of cytotoxic T-lymphocyte–associated of steroid-refractory cGVHD was evaluated in a phase I antigen 4 linked to the modified fragment crystallizable (Fc) dose-escalation trial involving 13 patients.197 Six sub- region of IgG1.195,196 Abatacept acts as an immunomodu- jects had moderate and 7 subjects had severe cGVHD latory drug by selectively inhibiting T-cell activation via perNIHconsensusglobalscoringcriteria;allsubjects

622 © JNCCN—Journal of the National Comprehensive Cancer Network | Volume 18 Issue 5 | May 2020 Hematopoietic Cell Transplantation, Version 2.2020 NCCN GUIDELINES®

had involvement of skin andsubcutaneoustissues. benefit for steroid-refractory cGVHD, in particular when Alemtuzumab dosing was investigated in a 313study theyhavenotbeenusedforGVHDprophylaxisorinitial design. The MTD of alemtuzumab was 3 mg31, then therapy. 10 mg35 administered over 4 weeks. The most com- mon adverse events were infections and hematologic Etanercept toxicities. Of the 10 patients evaluable for response, the The efficacy of etanercept for the treatment of steroid- ORR was 70% with a 30% CR rate. The median decrease refractory cGVHD was retrospectively evaluated in a in steroid dose at 1 year was 62%. A prospective study cohort of 8 patients treated with subcutaneous eta- of 15 patients with steroid-refractory cGVHD treated nercept at 25 mg twice weekly for 4 weeks followed by with 1 cycle of subcutaneous alemtuzumab at 10 mg/day 25 mg once weekly for 4 weeks.148 Patients were also for 3 days followed by 100 mg intravenous rituximab on continued on CNI, MMF, and/or sirolimus. The ORR was days 14, 111, 118, and 125 reported an ORR of 100% 62% with 1 patient achieving CR. Three of 8 patients and a CR rate of 33% at day 130 evaluation.198 At day 190 (37%) treated with etanercept died of progressive disease evaluation, the partial response rate was 50%, the CR or sepsis. In 3 of the 5 patients who experienced response rate was 28%, and 21% of patients had relapsed to etanercept, corticosteroids were reduced by .50%. In cGVHD. Of the 5 evaluable patients at 1 year, 2 (40%) a phase II trial, 34 patients with either obstructive (n525) had a partial response, 2 had a CR, and 1 experienced or restrictive (n59) lung dysfunction following allogeneic cGVHD progression. These data indicate that alemtu- HCT were treated with etanercept subcutaneously at 0.4 zumab is active in steroid-refractory cGVHD. Currently mg/kg/dose twice weekly for 4 (group A) or 12 (group B) in the United States, alemtuzumab is only available via weeks.201 Obstructive lung dysfunction is commonly the Campath Distribution Program, and drug supply is associated with cGVHD, with BOS being the most patient-specific. common histopathology reported. All patients had clinical signs or symptoms of cGVHD at the onset of Calcineurin Inhibitors treatment, with diffuse skin, oral mucosal, ocular, and/or Limited data exist for the efficacy of CNI, such as hepatic involvement. All patients received concurrent tacrolimus and cyclosporine, for the treatment of immunosuppressive therapy with either CNI alone steroid-refractory cGVHD. The most common adverse (n55), CNI plus corticosteroids 6 MMF (n522), MMF 6 events typically seen with CNI use are renal toxicity, corticosteroids (n55), or sirolimus (n52). Clinical re- hypomagnesemia, hypertension, and tremors. In a phase sponse, defined as a $10% improvement in the absolute II trial, 31 patients with cGVHD that developed or pro- value for forced expiratory volume (for obstructive de- gressed during therapy with cyclosporine and/or other fects) or forced vital capacity (for restrictive defects), was immunosuppressive agents were treated with tacrolimus obtained in 32% of patients. There was no difference in at an initial dose of 0.05 mg/kg intravenously or 0.15 mg/kg ORR based on the duration of treatment (29% in group A orally twice a day. In the 26 evaluable patients, the ORR vs 35% in group B; P5.99) or the presence of restrictive or was 46%.144 Another trial evaluated the efficacy of obstructive lung dysfunction (33% vs 32%, respectively; tacrolimus administered at 0.15 mg/kg twice a day orally P5.73). No bacterial or viral infections were observed. or 0.15 mg/kg/day intravenously in 17 patients with Thus, etanercept seems to be effective for treating severe steroid-refractory cGVHD.199 The ORR was 35% steroid-refractory cGVHD of the lung (especially if as- and OS was 65% at a median follow-up of 8.4 months. sociated with BOS). The greatest responses were observed in the skin, liver, and GI tract; musculoskeletal and lung cGVHD showed Extracorporeal Photopheresis no response to treatment. Commonly reported ad- In a prospective single-center study involving 88 pa- verse events included renal toxicity, hypertension, and tients with extensive cGVHD, second- or third-line treat- infections. In a third report, 39 patients with cGVHD ment with ECP resulted in an ORR of 73%.153 Cutaneous refractory to cyclosporine and prednisone were treated and sclerotic manifestations were associated with higher with tacrolimus.200 The ORR was 21% with a CR rate of response rates. After a median follow-up of 68 months, 13%. However, 79% of patients experienced treatment 5-year OS was 65% and was independently associated failure and 23% died during continued tacrolimus with a higher number of ECP sessions and cutaneous treatment. Infectious complications were the most manifestations. A multicenter randomized phase II trial common adverse event followed by renal toxicity, which involving 95 patients with cutaneous manifestations of led to treatment discontinuation in 2 patients. Three- steroid-refractory cGVHD found that 8% of patients re- year estimated OS was 64%, and 41% of patients had ceiving ECP therapy experienced at least a 25% reduction discontinued all immunosuppressive treatment at 3 in total skin score from baseline compared with 0% of years after HCT. Therefore, CNI may provide clinical patients in the control group (P5.04).202 Treatment with

JNCCN.org | Volume 18 Issue 5 | May 2020 623 NCCN GUIDELINES® Hematopoietic Cell Transplantation, Version 2.2020

ECP resulted in an ORR of 61% in a retrospective analysis appropriate for long-term use due to the risk of of 71 patients with severe steroid-refractory cGVHD; the retinal toxicity. Periodic ophthalmologic assessment best responses were seen in the skin, liver, oral mucosa, is recommended during treatment. and eyes.203 A systematic review of prospective studies reported a pooled ORR of 64% for ECP in the treatment of Ibrutinib steroid-refractory cGVHD.149 Similar response rates were Ibrutinib is a potent and irreversible inhibitor of Bruton’s seen with skin and GI involvement; however, the ORR for tyrosine kinase, which regulates B-cell survival.111 It also cGVHD with lung involvement was only 15%, suggesting inhibits IL-2–inducible T-cell kinase, which is involved that ECP may not effectively treat lung manifestations in the selective activation of T-cell subsets.209 In 2017, of cGVHD. Reported rates of ECP-related mortality ibrutinib was approved by the FDA for the treatment of were extremely low. Another systematic review largely adult patients with cGVHD after failure of one or more reached the same conclusions, reporting a pooled ORR lines of systemic therapy.210 This approval was based on of 64% and pooled response rates of 74% and 48% for data from a single-arm multicenter trial that included 42 skin and lung involvement, respectively.204 This review patients with steroid-refractory cGVHD.111 Patients re- also reported activity for ECP in treating cGVHD with GI ceived 420 mg ibrutinib daily until cGVHD progression. involvement (ORR, 53%). These data suggest that ECP is Most patients (88%) had at least 2 organs involved at an effective therapy for steroid-refractory cGVHD, es- baseline, the most common being mouth (86%), skin pecially in those with skin involvement. If ECP is not (81%), and GI tract (33%). At a median follow-up of 14 available or feasible, the NCCN Panel recommends the months, the ORR was 67%, with 71% of responders showing use of PUVA irradiation as an alternative treatment a sustained response for $20 weeks. Improvement was option. seen in all involved organs in patients with multiorgan involvement. Median corticosteroid dose in responders Hydroxychloroquine decreased from 0.29 mg/kg/day to 0.12 mg/kg/day, Hydroxychloroquine is a 4-aminoquinoline immuno- and 5 responders discontinued corticosteroids after suppressive and antiparasitic agent that is commonly treatment with ibrutinib. The most commonly re- used for the treatment of malaria.205 Hydroxychloroquine ported adverse events were fatigue, bleeding/bruising, is believed to exert its immunomodulatory effects by diarrhea, muscle spasms, nausea, thrombocytopenia, interfering with cytokine production and antigen pro- and anemia. Grade 3 atrial fibrillation occurred in one cessing and presentation.206,207 The efficacy of hydroxy- patient. After a median follow-up of 26 months, the ORR chloroquine for the treatment of steroid-refractory cGVHD was 69% with 31% of patients experiencing CR.211 Sus- was evaluated in a phase II trial involving 40 patients tained responses of $44 weeks were seen in 55% of re- treated with hydroxychloroquine at 800 mg (12 mg/kg) per sponders. Of the patients with multiorgan involvement, day.207 The ORR was 53% among the 32 evaluable pa- 73% of those with $2 organs involved showed responses tients, with 3 patients experiencing CR. All responders in $2 organs and 60% of those with $3 organs involved tolerated a .50% reduction in steroid dose while re- showed responses in $3 organs. Corticosteroid dose was ceiving hydroxychloroquine. The highest response rates reduced to ,0.15 mg/kg/day in 64% of patients and was were observed in patients with skin, oral, and/or liver completely discontinued in 19% of patients. The most involvement; efficacy in the treatment of GI manifesta- common grade 3 adverse events were pneumonia, fa- tions was limited. tigue, and diarrhea. These data suggest that ibrutinib is One of the most serious adverse events reported with effective and may produce durable responses in pa- the long-term use (.2 years) of hydroxychloroquine is tients with steroid-refractory cGVHD. However, ibrutinib chloroquine retinopathy, a form of toxic retinopathy caused should be used with caution in patients with a history by the binding of hydroxychloroquine to melanin in the of heart arrhythmias, due to a heightened risk of retinal pigment epithelium, which can result in vision loss. atrial fibrillation, and in patients on anticoagulation The retinal toxicity of hydroxychloroquine was evaluated in or antiplatelet therapy, due to a heightened risk of a cohort of 12 patients with cGVHD treated with 800 mg bleeding. Given the high risk of bleeding, patients hydroxychloroquine per day for a median duration of should hold ibrutinib for 3 to 7 days before and after 22.8 months.208 Seven patients developed vortex surgical procedures. keratopathy and 3 patients developed retinal toxicity; retinal structure and color vision were abnormal in Imatinib 2 of the 3 patients. These data suggest that hydrox- Imatinib is a small molecule tyrosine kinase inhibitor ychloroquine is an effective treatment option for indicated for the treatment of several types of cancer, patients with steroid-refractory cGVHD, especially in including chronic myeloid leukemia.212 Imatinib has those with skin or oral involvement, but may not be activity against several tyrosine kinase enzymes,

624 © JNCCN—Journal of the National Comprehensive Cancer Network | Volume 18 Issue 5 | May 2020 Hematopoietic Cell Transplantation, Version 2.2020 NCCN GUIDELINES®

including platelet-derived growth factor receptor (PDGFR) responses were sustained in patients who received IL-2 which is implicated in skin fibrosis.213 Stimulatory for an extended period, allowing their corticosteroid dose antibodies against PDGFR have been identified in to be tapered by a mean of 60%. In a follow-up phase II cGVHD patients with cutaneous sclerosis; however, trial, 35 patients with steroid-refractory cGVHD were neither anti-PDGFR antibody level nor phosphoryla- treated with IL-2 at 13106 IU/m2 for 12 weeks.217 The tion of tissue PDGFR correlated with response to ORR in 33 evaluable patients was 61%. There were no CRs imatinib in cGVHD patients.214 The efficacy of imatinib and 3 patients developed progressive cGVHD. All re- to treat sclerotic manifestations of cutaneous steroid- sponders experienced improvement in multiple sites of refractory cGVHD was assessed in a pilot phase II trial cGVHD, including the liver, skin, GI tract, lungs, and involving 20 patients.213 Eight patients received a joints/muscle/fascia. Extended IL-2 therapy for up to 2 standard dose of 400 mg daily and 12 patients un- years was well tolerated and resulted in durable clinical derwent a dose escalation study due to poor tolera- responses in most patients. However, 2 patients in this bility (100 mg daily initial dose up to 200 mg daily study withdrew and 5 required dose reductions of IL-2 maximum). Of the 14 patients evaluable for primary due to adverse events including thrombocytopenia, response, 5 (36%) had a partial response, 7 (50%) had fatigue, flu-like symptoms, malaise, and thrombocy- stable disease, and 2 (14%) had progressive disease. topenia. A recent phase I dose-escalation trial showed After treatment with imatinib for 6 months, range of that escalation above the previously defined MTD did motion deficit was improved in 79% of patients by an not improve clinical response in 10 patients with average of 24%. Common adverse events included steroid-refractory cGVHD.219 These data suggest that hypophosphatemia, fatigue, nausea, diarrhea, and low-dose IL-2 has durable clinical activity in treating disrupted fluid homeostasis leading to edema. A ran- steroid-refractory cGVHD and is generally safe for domized phase II crossover study compared imatinib long-term use. (200 mg daily) to rituximab (375 mg/m2 intravenously weekly for 4 weeks) for the treatment of patients Low-Dose Methotrexate (n535) with cutaneous sclerosis associated with Methotrexate is an antimetabolite that exerts immu- cGVHD.215 Significant clinical response, defined as nosuppressive effects by inhibiting the activity of quantitative improvement in skin sclerosis or joint dihydrofolic acid reductase, resulting in impaired DNA range of motion, was seen in 26% of patients ran- synthesis and lymphocyte proliferation.220 In a retro- domized to imatinib and 27% of patients randomized spective study of 14 patients who had received low- to rituximab. Treatment success, defined as signifi- dose methotrexate (7.5 mg/m2/weekfor3to50weeks) cant clinical response at 6 months without crossover, for the treatment of steroid-refractory cGVHD, 71% of recurrent malignancy, or death, was achieved in 17% patients were able to reduce their prednisone dose to of patients on imatinib and 14% of patients on rit- ,1 mg/kg every other day without the addition of other uximab. In a prospective trial of 39 patients with agents.221 In this study, the most frequently involved steroid-refractory cGVHD treated with imatinib, the sites were oral mucosa (n514) and skin (n511) and no partialresponseratewas36%.216 The best responses grade 3 or higher toxicities were observed. The steroid- were seen in the skin (32%), GI tract (50%), and lungs sparing effects of methotrexate were also observed in a (35%). After a median follow-up of 40 months, the prospective study of 8 patients with steroid-refractory 3-year OS and event-free survival rates were 72% and cGVHD, which reported a reduction in corticosteroid 46%, respectively. These data suggest that low-dose dose in the range of 25%–80% in patients treated with imatinib (200 mg) is active in the treatment of pa- low-dose methotrexate (5 mg/m2/infusion).222 The ORR tients with steroid-refractory cGVHD, especially in was 75% and few toxicities were observed, the most those with cutaneous sclerosis. serious being grade 3–4 cytopenias reported in 2 pa- tients. Another retrospective review of 21 patients with Interleukin-2 steroid-refractory cGVHD reported an ORR of 76% in IL-2 is a naturally occurring pleiotropic cytokine that patients treated with low-dose methotrexate (5 or regulates the growth of T cells and is a key mediator of 10 mg/m2 infusion every 3–4days).223 The response immune response.217 The efficacy of IL-2 in the treatment rates were particularly high in patients with extensive of steroid-refractory cGVHD was evaluated in a phase I cGVHD (ORR, 92%) and were significantly higher in study involving 29 patients.218 Patients received daily patients with skin involvement (92%) compared with subcutaneous IL-2 at escalating dose levels for 8 weeks. those with liver involvement (43%; P5.009). Among The MTD was determined to be 13106 IU/m2. Of the 23 patients with cGVHD in a single organ (skin or liver), patients evaluable for a response, 12 had a significant 58% responded compared with 100% of patients with clinical response involving multiple organs. Clinical $2 organs involved. Although this trial reported severe

JNCCN.org | Volume 18 Issue 5 | May 2020 625 NCCN GUIDELINES® Hematopoietic Cell Transplantation, Version 2.2020

hematologic toxicities associated with methotrexate, the NIH Severity Score and patient-reported quality of these toxicities were reversible and did not result in life.226,227 However, more data are necessary to confirm treatment discontinuation. These data suggest that theroleofeverolimusinthetreatmentofsteroid- low-dose methotrexate is active in the treatment of refractory cGVHD. patients with steroid-refractory cGVHD, especially in those with skin and oral manifestations. Mycophenolate Mofetil The safety and efficacy of MMF for the treatment of mTOR Inhibitors steroid-refractory cGVHD was evaluated in a retro- The safety and efficacy of sirolimus for the treatment of spective study of 24 patients treated with MMF at a dose steroid-refractory cGVHD was evaluated in a phase II of 500 mg twice per day (escalated to 1 g twice a day if trial involving 35 patients.224 Patients with steroid- tolerated) in combination with cyclosporine, tacrolimus, refractory cGVHD received sirolimus at a loading dose and/or prednisone.228 The ORR was 75%, with a CR rate of 6 mg orally followed by a maintenance dose of of 21%. Only 2 patients experienced progressive disease. 2 mg/day while continuing immunosuppressive treat- The highest response rates were seen in patients with ment with tacrolimus and methylprednisolone. The ORR involvement of the skin or oral mucosa. Of the 22 pa- was 63% with 6 patients achieving CR. The highest re- tients receiving prednisone, 14 (64%) had their pred- sponse rates were observed in patients with sclerotic skin nisone dose decreased by a median of 50% by the end of involvement (73%) and involvement of the oral mucosa the 6-month observation period. The most common (75%), but responses were also observed in the lower GI adverse events were abdominal cramps (which resulted tract (67%), liver (33%), and eyes (64%). Major adverse in discontinuation of MMF in 3 patients) and infections. events included hyperlipidemia, renal dysfunction, At a median follow-up of 24 months, 83% of patients cytopenias, thrombotic microangiopathy, and infectious were alive. In a prospective phase II trial involving 23 complications. Median survival was 15 months and es- patients with steroid-refractory cGVHD, the cumulative timated actuarial survival at 2 years was 41%. In another incidence of disease resolution and withdrawal of all phase II trial, 19 patients with steroid-refractory immunosuppressive treatment was 26% at 36 months cGVHD were treated with sirolimus, CNI, and pred- after starting treatment with MMF (initial dose of 1 g nisone. Sirolimus was administered orally at a loading twice daily).170 After a median follow-up of 9.5 years, dose of 10 mg followed by a daily dose of 5 mg. Of the 52% of patients remained alive, with only one requiring 16 evaluable patients, 15 had an initial clinical re- continued treatment with immunosuppressive agents. sponse to this regimen. However, 5 patients dis- In another retrospective analysis of 13 patients with continued treatment due to renal toxicity. Of the 10 steroid-refractory cGVHD, the ORR to MMF (1.5 or 2 g patients who continued with this regimen, 3 had a daily) was 77% and the estimated 2-year OS rate was prolonged response and were able to successfully taper 54%. The most common adverse events were GI dis- off immunosuppressive agents. A retrospective study turbances (27%) and infectious complications (23%). analyzed 47 patients with steroid-refractory cGVHD These data suggest that MMF is an effective therapy treated with sirolimus (2 mg/day) in combination with option for patients with steroid-refractory cGVHD. other immunosuppressive agents (CNI [n533], MMF [n59], or prednisone [n55]).225 The ORR was 81% with Pentostatin a CR rate of 38%. The main toxicity was mild impair- In a phase II trial involving 58 patients with steroid- ment of renal function, which was more common in refractory cGVHD, treatment with pentostatin at 4 mg/m2 patients receiving sirolimus and CNI (33%) compared given intravenously every 2 weeks for a median of 12 doses with sirolimus and other immunosuppressive agents resulted in an ORR of 55%. Most patients had skin (7%). Estimated 3-year OS in all patients was 57%. involvement and more than half had oral and GI in- These data suggest that sirolimus is an effective agent volvement. The highest response rates were observed for the treatment of patients with steroid-refractory in patients with lichenoid cutaneous manifestations cGVHD and should be investigated further to find (69%) followed by patients with oral involvement the best dose schedule and combination of additional (62%); the lowest response rates were seen in patients agents to optimize clinical response while limiting with liver involvement. A total of 11 grade 3–4infections toxicity. were reported and 4 patients withdrew from treatment Although it has not been studied extensively, the due to adverse events including nausea/vomiting, renal sirolimus derivative everolimus has shown activity in toxicity, and fatigue. OS at 1 and 2 years was 78% and the treatment of steroid-refractory cGVHD. Preliminary 70%, respectively. In a retrospective analysis of 18 pa- data from 2 retrospective studies showed that treatment tients with steroid-refractory cGVHD, 12 of whom had with everolimus resulted in significant improvement in severe cGVHD, treatment with pentostatin at 4 mg/m2

626 © JNCCN—Journal of the National Comprehensive Cancer Network | Volume 18 Issue 5 | May 2020 Hematopoietic Cell Transplantation, Version 2.2020 NCCN GUIDELINES®

every 2 weeks resulted in an ORR of 56%; CR was involvement (n 5 23), 10% of patients with lung in- achieved in 1 patient. Activity was observed in all af- volvement (n 5 1), and 41% of patients with joint/fascia fected organs, with CRs observed in GI (CR, 3), skin (CR, involvement (n 5 23). The 1-year probability of treat- 4), and muscle/fascia (CR, 1) manifestations. The me- ment failure-free survival was 54%. The most common dian decrease in corticosteroid dose over 24 months adverse event was infectious complications. Another after pentostatin initiation was 38%, and median OS was recent retrospective analysis reported better outcomes 5 months. Estimated 1-year OS was 34%. Common in 19 patients treated with ruxolitinib (5 mg orally adverse events included renal toxicity and infections. twice per day) for moderate to severe steroid-refractory These data suggest that pentostatin is active in the cGVHD.232 The ORR was 100%, with 18 patients expe- treatment of steroid-refractory cGVHD. riencing an overall partial response and 1 experiencing CR. No cytopenias or infections were noted. Cortico- Rituximab steroids were successfully reduced or discontinued in Rituximab is an anti-CD20 chimeric monoclonal an- 21% and 68% of patients, respectively. An earlier retro- tibody used to treat non-Hodgkin lymphoma and spective study of 41 patients who had received ruxolitinib chronic lymphocytic leukemia. It exerts immuno- at a dose of 5–10 mg orally twice per day for moderate to suppressive effects by binding to CD20 on the surface severe steroid-refractory cGVHD reported an ORR of 85% of B cells, facilitating their destruction.229 Because and a 6-month OS rate of 97%.181 Cytopenias and cy- B cells are implicated in the pathogenesis of cGVHD, tomegalovirus reactivation were observed in 17% and the efficacy of rituximab in the treatment of steroid- 15% of patients, respectively. These data suggest that refractory cGVHD has been evaluated in several ruxolitinib is capable of producing high response rates in studies.206,230 In a systematic review and meta-analysis patients with steroid-refractory cGVHD. of 7 studies (3 prospective and 4 retrospective) in- cluding 111 patients, the pooled ORR to rituximab was Summary 66%.230 The majority of studies used rituximab at a The NCCN Guidelines for HCT provide an evidence- and dose of 375 mg/m2 once per week for 4 to 8 infusions, consensus-based approach for the pretransplant evalu- although similar results were reported with rituximab ation of potential HCT recipients and the management of administered at 50 mg/m2 perweekfor4weeks(ORR, GVHD. HCT is a potentially curative treatment option for 69%). The pooled ORR for patients with skin cGVHD patients with certain types of malignancies. However, was 60%, compared with 36% for oral mucosal cGVHD, disease relapse and transplant-related complications 29% for liver cGVHD, and 30% for lung cGVHD, sug- often limit the long-term survival of HCT recipients. To gesting that skin manifestations of cGVHD are par- determine whether HCT is a potential treatment option, ticularly susceptible to rituximab treatment. However, the pretransplant recipient evaluation should be per- it should be noted that the site-specificresponserates formed in each patient to estimate the risks of relapse, varied greatly among studies. Administration of rit- NRM, and overall mortality. Determining the HCT-CI uximab facilitated corticosteroid dose reductions in score is essential to establish candidacy for HCT and the range of 75%–86%, depending on the study. The has been validated to predict the risk of NRM and esti- steroid-sparing effect of rituximab was more pro- mated survival after allogeneic transplant. The leading nounced in patients with skin and oral mucosal cause of NRM in allogeneic HCT recipients is the de- GVHD. The most common adverse events were related velopment of GVHD. Mild manifestations of GVHD to infusion reactions or infectious complications. limited to a single organ are often managed with close Therefore, rituximab is an effective treatment option observation, topical treatment, or by slowing the tapering for patients with steroid-refractory cGVHD, especially of immunosuppressive agents. More severe manifesta- in those with skin involvement. tions or multiorgan involvement typically require systemic corticosteroid treatment (with or without secondary Ruxolitinib systemic agents). Despite these treatments, approxi- The activity of ruxolitinib in the treatment of steroid- mately 40%–50% of patients with GVHD develop steroid- refractory cGVHD has been retrospectively evaluated refractory disease. Steroid-refractory GVHD is associated in several studies. A recent analysis of 46 patients with with high mortality, and no standard, effective therapy steroid-refractory cGVHD, the majority of whom had has yet been identified. Therefore, the NCCN Panel severe cGVHD, reported an ORR of 43% and a CR rate strongly encourages patients with steroid-refractory of 13% after 12 months of ruxolitinib therapy.231 Organ- acute or chronic GVHD to participate in well-designed specific responses were seen in 25% of patients clinical trials to enable further advancements for the with skin involvement (n 5 10), 60% of patients with management of these diseases and ultimately increase mouth involvement (n 5 15), 26% of patients with eye the long-term survival of HCT recipients.

JNCCN.org | Volume 18 Issue 5 | May 2020 627 NCCN GUIDELINES® Hematopoietic Cell Transplantation, Version 2.2020

References 1. Khaddour K, Mewawalla P. Hematopoietic stem cell transplantation. in lymphoproliferative malignancies: opportunistic partnership or cause- Treasure Island, FL: StatPearls; 2019. effect relationship? Int J Mol Sci 2019;20:1373. 2. Copelan EA. Hematopoietic stem-cell transplantation. N Engl J Med 23. Jantunen E, Ital¨ a¨ M, Lehtinen T, et al. Early treatment-related mortality in 2006;354:1813–1826. adult autologous stem cell transplant recipients: a nation-wide survey of 3. Niederwieser D, Baldomero H, Szer J, et al. Hematopoietic stem 1482 transplanted patients. Eur J Haematol 2006;76:245–250. cell transplantation activity worldwide in 2012 and a SWOT analysis of 24. U.S. National Library of Medicine-Key MEDLINE® Indicators. the Worldwide Network for Blood and Marrow Transplantation Group including the global survey. Bone Marrow Transplant 2016;51: 25. Palumbo A, Cavallo F, Gay F, et al. Autologous transplantation and 778–785. maintenance therapy in multiple myeloma. N Engl J Med 2014;371: 895–905. 4. D’Souza A, Fretham C. CIBMTR Summary Slides: Current Uses and Outcomes of Hematopoietic Cell Transplantation (HCT). Accessed April 26. Child JA, Morgan GJ, Davies FE, et al. High-dose chemotherapy with hematopoietic stem-cell rescue for multiple myeloma. N Engl J Med 1, 2020. Available at: https://www.cibmtr.org/ReferenceCenter/ – SlidesReports/SummarySlides/pages/index.aspx 2003;348:1875 1883. 5. Majhail NS, Farnia SH, Carpenter PA, et al. Indications for 27. Fermand JP, Katsahian S, Divine M, et al. High-dose therapy and au- autologous and allogeneic hematopoietic cell transplantation: tologous blood stem-cell transplantation compared with conventional guidelines from the American Society for Blood and Marrow treatment in myeloma patients aged 55 to 65 years: long-term results of a randomized control trial from the Group Myelome-Autogreffe. J Clin Transplantation. Biol Blood Marrow Transplant 2015;21: – 1863–1869. Oncol 2005;23:9227 9233. 6. Hosing C. Hematopoietic stem cell mobilization with G-CSF. Methods 28. Attal M, Harousseau JL, Stoppa AM, et al. A prospective, randomized Mol Biol 2012;904:37–47. trial of autologous bone marrow transplantation and chemotherapy in multiple myeloma. Intergroupe Français du Myelome.´ N Engl J Med 7. Bensinger WI, Martin PJ, Storer B, et al. Transplantation of bone marrow 1996;335:91–97. as compared with peripheral-blood cells from HLA-identical relatives in patients with hematologic cancers. N Engl J Med 2001;344:175–181. 29. Shah N, Callander N, Ganguly S, et al. Hematopoietic stem cell trans- plantation for multiple myeloma: guidelines from the American Society 8. Anasetti C, Logan BR, Lee SJ, et al. Peripheral-blood stem cells versus for Blood and Marrow Transplantation. Biol Blood Marrow Transplant bone marrow from unrelated donors. N Engl J Med 2012;367: 2015;21:1155–1166. 1487–1496. 30. Schmitz N, Pfistner B, Sextro M, et al. Aggressive conventional che- 9. Lee SJ, Logan B, Westervelt P, et al. Comparison of patient-reported motherapy compared with high-dose chemotherapy with autologous outcomes in 5-year survivors who received bone marrow vs peripheral haemopoietic stem-cell transplantation for relapsed chemosensitive blood unrelated donor transplantation: long-term follow-up of a ran- Hodgkin’s disease: a randomised trial. Lancet 2002;359:2065–2071. domized clinical trial. JAMA Oncol 2016;2:1583–1589. 31. Perales MA, Ceberio I, Armand P, et al. Role of cytotoxic therapy with ’ 10. Luznik L, O Donnell PV, Symons HJ, et al. HLA-haploidentical bone hematopoietic cell transplantation in the treatment of Hodgkin lym- marrow transplantation for hematologic malignancies using non- phoma: guidelines from the American Society for Blood and Marrow myeloablative conditioning and high-dose, posttransplantation cyclo- Transplantation. Biol Blood Marrow Transplant 2015;21:971–983. phosphamide. Biol Blood Marrow Transplant 2008;14:641–650. 32. Philip T, Guglielmi C, Hagenbeek A, et al. Autologous bone marrow 11. McDonald GB, Sandmaier BM, Mielcarek M, et al. Survival, nonrelapse transplantation as compared with salvage chemotherapy in relapses of mortality, and relapse-related mortality after allogeneic hematopoietic chemotherapy-sensitive non-Hodgkin’s lymphoma. N Engl J Med 1995; cell transplantation: comparing 2003-2007 versus 2013-2017 cohorts. 333:1540–1545. Ann Intern Med 2020;172:229–239. 33. Oliansky DM, Czuczman M, Fisher RI, et al. The role of cytotoxic therapy 12. Majhail NS, Rizzo JD, Lee SJ, et al. Recommended screening and with hematopoietic stem cell transplantation in the treatment of diffuse preventive practices for long-term survivors after hematopoietic cell large B cell lymphoma: update of the 2001 evidence-based review. Biol – transplantation. Biol Blood Marrow Transplant 2012;18:348 371. Blood Marrow Transplant 2011;17:20–47. 13. Jim HS, Syrjala KL, Rizzo D. Supportive care of hematopoietic cell 34. Oliansky DM, Gordon LI, King J, et al. The role of cytotoxic therapy with transplant patients. Biol Blood Marrow Transplant 2012;18(1, Suppl) hematopoietic stem cell transplantation in the treatment of follicular – S12 S16. lymphoma: an evidence-based review. Biol Blood Marrow Transplant 14. Servais S, Porcher R, Xhaard A, et al. Pre-transplant prognostic factors of 2010;16:443–468. long-term survival after allogeneic peripheral blood stem cell trans- 35. Einhorn LH, Williams SD, Chamness A, et al. High-dose chemotherapy plantation with matched related/unrelated donors. Haematologica and stem-cell rescue for metastatic germ-cell tumors. N Engl J Med – 2014;99:519 526. 2007;357:340–348. 15. Giebel S, Labopin M, Socie´ G, et al. Improving results of allogeneic 36. Hamid AA, Markt SC, Vicier C, et al. Autologous stem-cell trans- hematopoietic cell transplantation for adults with acute lymphoblastic plantation outcomes for relapsed metastatic germ-cell tumors in the fi leukemia in rst complete remission: an analysis from the Acute Leu- modern era. Clin Genitourin Cancer 2019;17:58–64.e1. kemia Working Party of the European Society for Blood and Marrow Transplantation. Haematologica 2017;102:139–149. 37. Feldman DR, Sheinfeld J, Bajorin DF, et al. TI-CE high-dose chemo- therapy for patients with previously treated germ cell tumors: results and 16. Ribera JM. Allogeneic stem cell transplantation for adult acute lymphoblastic prognostic factor analysis. J Clin Oncol 2010;28:1706–1713. leukemia: when and how. Haematologica 2011;96:1083–1086. 38. Kilari D, D’Souza A, Fraser R, et al. Autologous hematopoietic stem cell 17. Trajkovska I, Georgievski B, Cevreska L, et al. Early and late complica- transplantation for male germ cell tumors: improved outcomes over 3 tions in patients with allogeneic transplantation of hematopoietic stem decades. Biol Blood Marrow Transplant 2019;25:1099–1106. cell. Open Access Maced J Med Sci 2017;5:340–343. 39. Dunkel IJ, Gardner SL, Garvin JH, Jr., et al. High-dose carboplatin, thiotepa, 18. Bacigalupo A, Sormani MP, Lamparelli T, et al. Reducing transplant- and etoposide with autologous stem cell rescue for patients with previously related mortality after allogeneic hematopoietic stem cell trans- irradiated recurrent medulloblastoma. Neuro-oncol 2010;12:297–303. plantation. Haematologica 2004;89:1238–1247. 40. Illerhaus G, Muller¨ F, Feuerhake F, et al. High-dose chemotherapy and 19. Gooley TA, Chien JW, Pergam SA, et al. Reduced mortality after allo- autologous stem-cell transplantation without consolidating radiotherapy geneic hematopoietic-cell transplantation. N Engl J Med 2010;363: as first-line treatment for primary lymphoma of the central nervous – 2091 2101. system. Haematologica 2008;93:147–148. 20. Tanaka Y, Kurosawa S, Tajima K, et al. Analysis of non-relapse mortality 41. Kasenda B, Ihorst G, Schroers R, et al. High-dose chemotherapy with and causes of death over 15 years following allogeneic hematopoietic autologous haematopoietic stem cell support for relapsed or refractory – stem cell transplantation. Bone Marrow Transplant 2016;51:553 559. primary CNS lymphoma: a prospective multicentre trial by the German 21. Wingard JR, Majhail NS, Brazauskas R, et al. Long-term survival and late Cooperative PCNSL study group. Leukemia 2017;31:2623–2629. deaths after allogeneic hematopoietic cell transplantation. J Clin Oncol 42. DeFilipp Z, Li S, El-Jawahri A, et al. High-dose chemotherapy with – 2011;29:2230 2239. thiotepa, busulfan, and cyclophosphamide and autologous stem cell 22. Marchesi F, Pimpinelli F, Di Domenico EG, et al. Association between transplantation for patients with primary central nervous system lym- CMV and invasive fungal infections after autologous stem cell transplant phoma in first complete remission. Cancer 2017;123:3073–3079.

628 © JNCCN—Journal of the National Comprehensive Cancer Network | Volume 18 Issue 5 | May 2020 Hematopoietic Cell Transplantation, Version 2.2020 NCCN GUIDELINES®

43. Soussain C, Hoang-Xuan K, Taillandier L, et al. Intensive chemotherapy 64. Sureda A, Robinson S, Canals C, et al. Reduced-intensity conditioning followed by hematopoietic stem-cell rescue for refractory and recurrent compared with conventional allogeneic stem-cell transplantation in primary CNS and intraocular lymphoma: Societ´ e´ Française de Greffe de relapsed or refractory Hodgkin’s lymphoma: an analysis from the Lym- Moelle¨ Osseuse-Therapie´ Cellulaire. J Clin Oncol 2008;26:2512–2518. phoma Working Party of the European Group for Blood and Marrow – 44. De Rosa L, Lalle M, Pandolfi A, et al. Autologous bone marrow trans- Transplantation. J Clin Oncol 2008;26:455 462. plantation with negative immunomagnetic purging for aggressive B-cell 65. Rezvani AR, Norasetthada L, Gooley T, et al. Non-myeloablative allo- non-Hodgkin’s lymphoma in first complete remission. Ann Hematol geneic haematopoietic cell transplantation for relapsed diffuse large 2002;81:575–581. B-cell lymphoma: a multicentre experience. Br J Haematol 2008;143: – 45. Bierman PJ, Sweetenham JW, Loberiza FR, Jr., et al. Syngeneic hema- 395 403. topoietic stem-cell transplantation for non-Hodgkin’s lymphoma: a 66. Horowitz MM, Gale RP,Sondel PM, et al. Graft-versus-leukemia reactions comparison with allogeneic and autologous transplantation--The Lym- after bone marrow transplantation. Blood 1990;75:555–562. phoma Working Committee of the International Bone Marrow Transplant 67. Corradini P, Dodero A, Zallio F, et al. Graft-versus-lymphoma effect in Registry and the European Group for Blood and Marrow Transplantation. relapsed peripheral T-cell non-Hodgkin’s lymphomas after reduced- – J Clin Oncol 2003;21:3744 3753. intensity conditioning followed by allogeneic transplantation of hema- 46. Weisdorf D, Eapen M, Ruggeri A, et al. Alternative donor transplantation topoietic cells. J Clin Oncol 2004;22:2172–2176. fi for older patients with acute myeloid leukemia in rst complete re- 68. Weisdorf D, Zhang MJ, Arora M, et al. Graft-versus-host disease induced mission: a center for international blood and marrow transplant research- graft-versus-leukemia effect: greater impact on relapse and disease-free – eurocord analysis. Biol Blood Marrow Transplant 2014;20:816 822. survival after reduced intensity conditioning. Biol Blood Marrow 47. Rashidi A, Hamadani M, Zhang MJ, et al. Outcomes of haploidentical vs Transplant 2012;18:1727–1733. fi matched sibling transplantation for acute myeloid leukemia in rst 69. Muffly L, Pasquini MC, Martens M, et al. Increasing use of allogeneic – complete remission. Blood Adv 2019;3:1826 1836. hematopoietic cell transplantation in patients aged 70 years and older in 48. Meybodi MA, Cao W, Luznik L, et al. HLA-haploidentical vs matched- the United States. Blood 2017;130:1156–1164. sibling hematopoietic cell transplantation: a systematic review and meta- 70. Ciurea SO, Shah MV, Saliba RM, et al. Haploidentical transplantation for – analysis. Blood Adv 2019;3:2581 2585. older patients with acute myeloid leukemia and myelodysplastic syn- 49. Bazarbachi A, Boumendil A, Finel H, et al. Influence of donor type, stem drome. Biol Blood Marrow Transplant 2018;24:1232–1236. cell source and conditioning on outcomes after haploidentical transplant 71. Sorror ML, Maris MB, Storb R, et al. Hematopoietic cell transplantation – for lymphoma - a LWP-EBMT study. Br J Haematol 2019;188:745 756. (HCT)-specific comorbidity index: a new tool for risk assessment before 50. Gluckman E, Broxmeyer HA, Auerbach AD, et al. Hematopoietic re- allogeneic HCT. Blood 2005;106:2912–2919. ’ constitution in a patient with Fanconis anemia by means of umbilical-cord 72. Sorror ML, Logan BR, Zhu X, et al. Prospective validation of the predictive – blood from an HLA-identical sibling. N Engl J Med 1989;321:1174 1178. power of the hematopoietic cell transplantation comorbidity index: a 51. Wagner JE, Rosenthal J, Sweetman R, et al. Successful transplantation of Center for International Blood and Marrow Transplant research study. HLA-matched and HLA-mismatched umbilical cord blood from un- Biol Blood Marrow Transplant 2015;21:1479–1487. related donors: analysis of engraftment and acute graft-versus-host 73. ElSawy M, Storer BE, Pulsipher MA, et al. Multi-centre validation of the – disease. Blood 1996;88:795 802. prognostic value of the haematopoietic cell transplantation- specific 52. Barker JN, Weisdorf DJ, DeFor TE, et al. Transplantation of 2 partially comorbidity index among recipient of allogeneic haematopoietic cell HLA-matched umbilical cord blood units to enhance engraftment in transplantation. Br J Haematol 2015;170:574–583. – adults with hematologic malignancy. Blood 2005;105:1343 1347. 74. Saad A, Mahindra A, Zhang MJ, et al. Hematopoietic cell transplant 53. Warlick ED, Peffault de Latour R, Shanley R, et al. Allogeneic hematopoietic comorbidity index is predictive of survival after autologous hemato- cell transplantation outcomes in acute myeloid leukemia: similar outcomes poietic cell transplantation in multiple myeloma. Biol Blood Marrow regardless of donor type. Biol Blood Marrow Transplant 2015;21:357–363. Transplant 2014;20:402–408. 54. Laughlin MJ, Eapen M, Rubinstein P, et al. Outcomes after trans- 75. Berro M, Arbelbide JA, Rivas MM, et al. Hematopoietic cell plantation of cord blood or bone marrow from unrelated donors in adults transplantation-specific comorbidity index predicts morbidity and with leukemia. N Engl J Med 2004;351:2265–2275. mortality in autologous stem cell transplantation. Biol Blood Marrow – 55. Marks DI, Woo KA, Zhong X, et al. Unrelated umbilical cord blood Transplant 2017;23:1646 1650. transplant for adult acute lymphoblastic leukemia in first and second 76. Sorror ML, Storb RF, Sandmaier BM, et al. Comorbidity-age index: a complete remission: a comparison with allografts from adult unrelated clinical measure of biologic age before allogeneic hematopoietic cell donors. Haematologica 2014;99:322–328. transplantation. J Clin Oncol 2014;32:3249–3256. 56. Rocha V, Labopin M, Sanz G, et al. Transplants of umbilical-cord blood or 77. Sorror ML. How I assess comorbidities before hematopoietic cell bone marrow from unrelated donors in adults with acute leukemia. transplantation. Blood 2013;121:2854–2863. N Engl J Med 2004;351:2276–2285. 78. Foundation for the Accreditation of Cellular Therapy and Joint Ac- 57. Othus M, Appelbaum FR, Petersdorf SH, et al. Fate of patients with creditation Committee-ISCT and EBMT. FACT-JACIE International newly diagnosed acute myeloid leukemia who fail primary induction Standards for Hematopoietic Cellular Therapy Product Collection, 7th therapy. Biol Blood Marrow Transplant 2015;21:559–564. Ed. Omaha, NE:;University of Nebraska Medical Center; 2017. 58. Yanada M, Matsuo K, Suzuki T, et al. Allogeneic hematopoietic stem cell 79. Przepiorka D, Weisdorf D, Martin P, et al. 1994 consensus conference on – transplantation as part of postremission therapy improves survival for acute GVHD grading. Bone Marrow Transplant 1995;15:825 828. adult patients with high-risk acute lymphoblastic leukemia: a meta- 80. Filipovich AH, Weisdorf D, Pavletic S, et al. National Institutes of Health analysis. Cancer 2006;106:2657–2663. consensus development project on criteria for clinical trials in chronic 59. de Witte T, Bowen D, Robin M, et al. Allogeneic hematopoietic stem cell graft-versus-host disease: I. Diagnosis and staging working group report. – transplantation for MDS and CMML: recommendations from an in- Biol Blood Marrow Transplant 2005;11:945 956. ternational expert panel. Blood 2017;129:1753–1762. 81. Flowers ME, Martin PJ. How we treat chronic graft-versus-host disease. – 60. Barrett J. Allogeneic stem cell transplantation for chronic myeloid leu- Blood 2015;125:606 615. kemia. Semin Hematol 2003;40:59–71. 82. Arai S, Arora M, Wang T, et al. Increasing incidence of chronic graft- 61. Kharfan-Dabaja MA, Kumar A, Hamadani M, et al. Clinical practice versus-host disease in allogeneic transplantation: a report from the recommendations for use of allogeneic hematopoietic cell trans- Center for International Blood and Marrow Transplant Research. Biol – plantation in chronic lymphocytic leukemia on behalf of the Guidelines Blood Marrow Transplant 2015;21:266 274. Committee of the American Society for Blood and Marrow Trans- 83. Jagasia M, Arora M, Flowers ME, et al. Risk factors for acute GVHD and plantation. Biol Blood Marrow Transplant 2016;22:2117–2125. survival after hematopoietic cell transplantation. Blood 2012;119: – 62. Bruno B, Rotta M, Patriarca F, et al. Nonmyeloablative allografting for 296 307. newly diagnosed multiple myeloma: the experience of the Gruppo 84. Flowers ME, Inamoto Y, Carpenter PA, et al. Comparative analysis of risk Italiano Trapianti di Midollo. Blood 2009;113:3375–3382. factors for acute graft-versus-host disease and for chronic graft-versus- 63. Shanavas M, Messner HA, Atenafu EG, et al. Allogeneic hematopoietic host disease according to National Institutes of Health consensus cri- – cell transplantation for myelofibrosis using fludarabine-, intravenous teria. Blood 2011;117:3214 3219. busulfan- and low-dose TBI-based conditioning. Bone Marrow Trans- 85. Jagasia MH, Greinix HT, Arora M, et al. National Institutes of Health plant 2014;49:1162–1169. Consensus Development Project on criteria for clinical trials in chronic

JNCCN.org | Volume 18 Issue 5 | May 2020 629 NCCN GUIDELINES® Hematopoietic Cell Transplantation, Version 2.2020

graft-versus-host disease: I. The 2014 diagnosis and staging working by NIH criteria: report on baseline data from the Chronic GVHD Con- group report. Biol Blood Marrow Transplant 2015;21:389–401. sortium. Blood 2011;117:4651–4657. 86. Zeiser R, Blazar BR. Acute graft-versus-host disease - biologic process, 106. Lee SJ, Wolff D, Kitko C, et al. Measuring therapeutic response in chronic prevention, and therapy. N Engl J Med 2017;377:2167–2179. graft-versus-host disease. National Institutes of Health consensus de- 87. Martin PJ, Rizzo JD, Wingard JR, et al. First- and second-line systemic velopment project on criteria for clinical trials in chronic graft-versus-host disease: IV. The 2014 Response Criteria Working Group report. Biol treatment of acute graft-versus-host disease: recommendations of the – American Society of Blood and Marrow Transplantation. Biol Blood Blood Marrow Transplant 2015;21:984 999. Marrow Transplant 2012;18:1150–1163. 107. Carpenter PA, Kitko CL, Elad S, et al. National Institutes of Health 88. Ross WA, Ghosh S, Dekovich AA, et al. Endoscopic biopsy diagnosis of Consensus Development Project on criteria for clinical trials in chronic acute gastrointestinal graft-versus-host disease: rectosigmoid biopsies graft-versus-host disease: V. The 2014 ancillary therapy and supportive care working group report. Biol Blood Marrow Transplant 2015;21: are more sensitive than upper gastrointestinal biopsies. Am J Gastro- – enterol 2008;103:982–989. 1167 1187. 108. Shulman HM, Cardona DM, Greenson JK, et al. NIH Consensus de- 89. Glucksberg H, Storb R, Fefer A, et al. Clinical manifestations of graft- velopment project on criteria for clinical trials in chronic graft-versus-host versus-host disease in human recipients of marrow from HL-A-matched disease: II. The 2014 Pathology Working Group Report. Biol Blood sibling donors. Transplantation 1974;18:295–304. Marrow Transplant 2015;21:589–603. 90. Rowlings PA, Przepiorka D, Klein JP, et al. IBMTR Severity Index for 109. Paczesny S, Hakim FT, Pidala J, et al. National Institutes of Health grading acute graft-versus-host disease: retrospective comparison with Consensus Development Project on criteria for clinical trials in chronic Glucksberg grade. Br J Haematol 1997;97:855–864. graft-versus-host disease: III. The 2014 biomarker working group report. 91. Martino R, Romero P, Subira´ M, et al. Comparison of the classic Biol Blood Marrow Transplant 2015;21:780–792. Glucksberg criteria and the IBMTR Severity Index for grading acute graft- 110. Bergeron A, Chevret S, Granata A, et al. Effect of azithromycin on airflow versus-host disease following HLA-identical sibling stem cell trans- decline-free survival after allogeneic hematopoietic stem cell transplant: plantation. International Bone Marrow Transplant Registry. Bone Marrow the ALLOZITHRO randomized clinical trial. JAMA 2017;318:557–566. Transplant 1999;24:283–287. 111. Miklos D, Cutler CS, Arora M, et al. Ibrutinib for chronic graft-versus-host 92. MacMillan ML, DeFor TE, Weisdorf DJ. What predicts high risk acute disease after failure of prior therapy. Blood 2017;130:2243–2250. graft-versus-host disease (GVHD) at onset?: identification of those at highest risk by a novel acute GVHD risk score. Br J Haematol 2012;157: 112. MacDonald KPA, Betts BC, Couriel D. Emerging therapeutics for the 732–741. control of chronic graft-versus-host disease. Biol Blood Marrow Trans- plant 2018;24:19–26. 93. MacMillan ML, Robin M, Harris AC, et al. A refined risk score for acute 113. Pidala J, Anasetti C. Glucocorticoid-refractory acute graft-versus-host graft-versus-host disease that predicts response to initial therapy, sur- – vival, and transplant-related mortality. Biol Blood Marrow Transplant disease. Biol Blood Marrow Transplant 2010;16:1504 1518. 2015;21:761–767. 114. U.S. Food and Drug Administration. Alemtuzumab Package Insert. 2001. Accessed January 14, 2020. Available at: https://www.accessdata.fda. 94. Harris AC, Young R, Devine S, et al. International, multicenter stan- gov/drugsatfda_docs/label/2007/103948s5070lbl.pdf. dardization of acute graft-versus-host disease clinical data collection: a report from the Mount Sinai Acute GVHD International Consortium. Biol 115. Khouri IF, Albitar M, Saliba RM, et al. Low-dose alemtuzumab (Campath) Blood Marrow Transplant 2016;22:4–10. in myeloablative allogeneic stem cell transplantation for CD52-positive malignancies: decreased incidence of acute graft-versus-host-disease 95. Schoemans HM, Lee SJ, Ferrara JL, et al. EBMT-NIH-CIBMTR Task Force with unique pharmacokinetics. Bone Marrow Transplant 2004;33: position statement on standardized terminology & guidance for graft- 833–837. versus-host disease assessment. Bone Marrow Transplant 2018;53: ı 1401–1415. 116. Gomez-Almaguer´ D, Ruiz-Arguelles¨ GJ, del Carmen Tar´n-Arzaga L, et al. Alemtuzumab for the treatment of steroid-refractory acute graft- 96. Major-Monfried H, Renteria AS, Pawarode A, et al. MAGIC biomarkers versus-host disease. Biol Blood Marrow Transplant 2008;14:10–15. predict long-term outcomes for steroid-resistant acute GVHD. Blood 2018;131:2846–2855. 117. Schnitzler M, Hasskarl J, Egger M, et al. Successful treatment of severe acute intestinal graft-versus-host resistant to systemic and topical ste- 97. Ali AM, DiPersio JF, Schroeder MA. The role of biomarkers in the roids with alemtuzumab. Biol Blood Marrow Transplant 2009;15: fi diagnosis and risk strati cation of acute graft-versus-host disease: a 910–918. systematic review. Biol Blood Marrow Transplant 2016;22: a 1552–1564. 118. Magenau JM, Goldstein SC, Peltier D, et al. 1-Antitrypsin infusion for treatment of steroid-resistant acute graft-versus-host disease. Blood 98. Levine JE, Braun TM, Harris AC, et al. A prognostic score for acute graft- 2018;131:1372–1379. versus-host disease based on biomarkers: a multicentre study. Lancet Haematol 2015;2:e21–e29. 119. Pye A, Turner AM. Experimental and investigational drugs for the treatment of alpha-1 antitrypsin deficiency. Expert Opin Investig Drugs 99. Mielcarek M, Furlong T, Storer BE, et al. Effectiveness and safety of lower 2019;28:891–902. dose prednisone for initial treatment of acute graft-versus-host disease: a 120. Arai Y, Jo T, Matsui H, et al. Efficacy of antithymocyte globulin for al- randomized controlled trial. Haematologica 2015;100:842–848. logeneic hematopoietic cell transplantation: a systematic review and 100. American Society for Transplantation and Cellular Therapy & Cell meta-analysis. Leuk Lymphoma 2017;58:1840–1848. Therapy Transplant Canada. Choosing Wisely: Five Things Physicians 121. Alousi AM, Brammer JE, Saliba RM, et al. Phase II trial of graft-versus- and Patients Should Question. 2019. Accessed February 26, 2020. host disease prophylaxis with post-transplantation cyclophosphamide Available at: https://www.choosingwisely.org/societies/american- after reduced-intensity busulfan/fludarabine conditioning for hemato- society-for-transplantation-and-cellular-therapy-and-cell-therapy- logical malignancies. Biol Blood Marrow Transplant 2015;21:906–912. transplant-canada/ 122. Czerw T, Labopin M, Giebel S, et al. Anti-thymocyte globulin improves 101. Alousi AM, Weisdorf DJ, Logan BR, et al. Etanercept, mycophenolate, survival free from relapse and graft-versus-host disease after allogeneic denileukin, or pentostatin plus corticosteroids for acute graft-versus-host peripheral blood stem cell transplantation in patients with Philadelphia- disease: a randomized phase 2 trial from the Blood and Marrow negative acute lymphoblastic leukemia: an analysis by the Acute Leu- Transplant Clinical Trials Network. Blood 2009;114:511–517. kemia Working Party of the EBMT. Cancer 2018;124:2523–2533. 102. Bolaños-Meade J, Logan BR, Alousi AM, et al. Phase 3 clinical trial of 123. Kroger¨ N, Solano C, Wolschke C, et al. Antilymphocyte globulin for steroids/mycophenolate mofetil vs steroids/placebo as therapy for acute prevention of chronic graft-versus-host disease. N Engl J Med 2016;374: GVHD: BMT CTN 0802. Blood 2014;124:3221–3227., quiz 3335. 43–53. 103. Pidala J, Hamadani M, Dawson P, et al. Randomized multicenter trial of 124. Kumar A, Reljic T, Hamadani M, et al. Antithymocyte globulin for graft- sirolimus vs prednisone as initial therapy for standard-risk acute GVHD: versus-host disease prophylaxis: an updated systematic review and the BMT CTN 1501 trial. Blood 2020;135:97–107. meta-analysis. Bone Marrow Transplant 2019;54:1094–1106. 104. Jagasia M, Ali H, Schroeder MA, et al. Ruxolitinib in combination with 125. Ziakas PD, Zervou FN, Zacharioudakis IM, et al. Graft-versus-host disease corticosteroids for the treatment of steroid-refractory acute graft-vs-host prophylaxis after transplantation: a network meta-analysis. PLoS One disease: results from the phase 2 REACH1 trial. Biol Blood Marrow 2014;9:e114735. Transplant 2019;25(Suppl):S52. 126. U.S. Food and Drug Administration. Thymoglobulin Package Insert. 105. Pidala J, Kurland B, Chai X, et al. Patient-reported quality of life is as- 1998. Accessed February 28, 2020. Available at: https://www.fda.gov/ sociated with severity of chronic graft-versus-host disease as measured media/74641/download

630 © JNCCN—Journal of the National Comprehensive Cancer Network | Volume 18 Issue 5 | May 2020 Hematopoietic Cell Transplantation, Version 2.2020 NCCN GUIDELINES®

127. U.S. Food and Drug Administration. Atgam Package Insert. 1981. systematic review of prospective studies. Biol Blood Marrow Transplant Accessed February 28, 2020. Available at: https://www.fda.gov/media/ 2014;20:1677–1686. 78206/download 150. Smith EP, Sniecinski I, Dagis AC, et al. Extracorporeal photo- 128. MacMillan ML, Weisdorf DJ, Davies SM, et al. Early antithymocyte chemotherapy for treatment of drug-resistant graft-vs.-host disease. Biol globulin therapy improves survival in patients with steroid-resistant acute Blood Marrow Transplant 1998;4:27–37. – graft-versus-host disease. Biol Blood Marrow Transplant 2002;8:40 46. 151. Alcindor T, Gorgun G, Miller KB, et al. Immunomodulatory effects of 129. McCaul KG, Nevill TJ, Barnett MJ, et al. Treatment of steroid-resistant extracorporeal photochemotherapy in patients with extensive chronic acute graft-versus-host disease with rabbit antithymocyte globulin. graft-versus-host disease. Blood 2001;98:1622–1625. – J Hematother Stem Cell Res 2000;9:367 374. 152. Greinix HT, Knobler RM, Worel N, et al. The effect of intensified ex- 130. Nishimoto M, Nakamae H, Koh H, et al. Response-guided therapy for tracorporeal photochemotherapy on long-term survival in patients with steroid-refractory acute GVHD starting with very-low-dose antithymo- severe acute graft-versus-host disease. Haematologica 2006;91: cyte globulin. Exp Hematol 2015;43:177–179. 405–408. 131. Ali R, Ramdial J, Algaze S, et al. The role of anti-thymocyte globulin or 153. Sakellari I, Gavriilaki E, Batsis I, et al. Favorable impact of extracorporeal alemtuzumab-based serotherapy in the prophylaxis and management of photopheresis in acute and chronic graft versus host disease: Pro- graft-versus-host disease. Biomedicines 2017;5:57. spective single-center study. J Clin Apher 2018;33:654–660. 132. U.S. Food and Drug Administration. Basiliximab Package Insert. 1998. 154. Zhang H, Chen R, Cheng J, et al. Systematic review and meta-analysis of Accessed January 14, 2020. Available at: https://www.accessdata.fda. prospective studies for ECP treatment in patients with steroid-refractory gov/drugsatfda_docs/label/1998/basnov051298lb.pdf acute GVHD. Patient Prefer Adherence 2015;9:105–111. fi 133. Schmidt-Hieber M, Fietz T, Knauf W, et al. Ef cacy of the interleukin-2 155. U.S. Food and Drug Administration. Infliximab Package Insert. 1998. receptor antagonist basiliximab in steroid-refractory acute graft-versus- Accessed January 29, 2020. Available at: https://www.accessdata.fda. – host disease. Br J Haematol 2005;130:568 574. gov/drugsatfda_docs/label/2013/103772s5359lbl.pdf 134. U.S. Food and Drug Administration. Tacrolimus Package Insert. 1994. 156. Patriarca F, Sperotto A, Damiani D, et al. Infliximab treatment for steroid- Accessed February 6, 2020. Available at: https://www.accessdata.fda. refractory acute graft-versus-host disease. Haematologica 2004;89: gov/drugsatfda_docs/label/2012/050709s031lbl.pdf 1352–1359. 135. U.S. Food and Drug Administration. Cyclosporine Package Insert. 1983. 157. Yalniz FF, Hefazi M, McCullough K, et al. Safety and efficacy of infliximab Accessed February 6, 2020. Available at: https://www.accessdata.fda. therapy in the setting of steroid-refractory acute graft-versus-host dis- gov/drugsatfda_docs/label/2012/ ease. Biol Blood Marrow Transplant 2017;23:1478–1484. 050573s035,050574s043,050625s049lbl.pdf 158. Himmelfarb J, Sayegh MH, eds. Current and emerging maintenance 136. Moiseev IS, Pirogova OV, Alyanski AL, et al. Graft-versus-host disease immunosuppressive therapy. in Chronic Kidney Disease, Dialysis, and prophylaxis in unrelated peripheral blood stem cell transplantation with Transplantation, 3rd Ed. Philadelphia, PA:W.B. Saunders; 2010. https:// post-transplantation cyclophosphamide, tacrolimus, and mycopheno- doi.org/10.1016/B978-1-4377-0987-2.00036-4 late mofetil. Biol Blood Marrow Transplant 2016;22:1037–1042. 159. Hsieh A. mTOR: the master regulator. Cell 2012;149:955–957. 137. Kanda Y, Kobayashi T, Mori T, et al. A randomized controlled trial of cyclosporine and tacrolimus with strict control of blood concentrations 160. Dumont FJ, Su Q. Mechanism of action of the immunosuppressant – after unrelated bone marrow transplantation. Bone Marrow Transplant rapamycin. Life Sci 1996;58:373 395. 2016;51:103–109. 161. Armand P, Kim HT, Sainvil MM, et al. The addition of sirolimus to the 138. Mielcarek M, Furlong T, O’Donnell PV, et al. Posttransplantation cy- graft-versus-host disease prophylaxis regimen in reduced intensity al- clophosphamide for prevention of graft-versus-host disease after HLA- logeneic stem cell transplantation for lymphoma: a multicentre ran- – matched mobilized blood cell transplantation. Blood 2016;127: domized trial. Br J Haematol 2016;173:96 104. 1502–1508. 162. Kornblit B, Maloney DG, Storer BE, et al. A randomized phase II trial of 139. Torl¨ en´ J, Ringden´ O, Garming-Legert K, et al. A prospective randomized tacrolimus, mycophenolate mofetil and sirolimus after non- trial comparing cyclosporine/methotrexate and tacrolimus/sirolimus as myeloablative unrelated donor transplantation. Haematologica 2014; graft-versus-host disease prophylaxis after allogeneic hematopoietic 99:1624–1631. stem cell transplantation. Haematologica 2016;101:1417–1425. 163. Pidala J, Kim J, Alsina M, et al. Prolonged sirolimus administration after 140. Al-Kadhimi Z, Gul Z, Abidi M, et al. Low incidence of severe cGvHD and allogeneic hematopoietic cell transplantation is associated with de- late NRM in a phase II trial of thymoglobulin, tacrolimus and sirolimus for creased risk for moderate-severe chronic graft-versus-host disease. GvHD prevention. Bone Marrow Transplant 2017;52:1304–1310. Haematologica 2015;100:970–977. 141. Cutler C, Logan B, Nakamura R, et al. Tacrolimus/sirolimus vs tacrolimus/ 164. Wang L, Gu Z, Zhai R, et al. The efficacy and safety of sirolimus-based methotrexate as GVHD prophylaxis after matched, related donor allo- graft-versus-host disease prophylaxis in patients undergoing allogeneic geneic HCT. Blood 2014;124:1372–1377. hematopoietic stem cell transplantation: a meta-analysis of randomized – 142. Gao L, Liu J, Zhang Y, et al. Low incidence of acute graft-versus-host controlled trials. Transfusion 2015;55:2134 2141. disease with short-term tacrolimus in haploidentical hematopoietic stem 165. Benito AI, Furlong T, Martin PJ, et al. Sirolimus (rapamycin) for the cell transplantation. Leuk Res 2017;57:27–36. treatment of steroid-refractory acute graft-versus-host disease. Transplantation 2001;72:1924–1929. 143. Deeg HJ, Loughran TP,Jr., Storb R, et al. Treatment of human acute graft- versus-host disease with antithymocyte globulin and cyclosporine with 166. Hoda D, Pidala J, Salgado-Vila N, et al. Sirolimus for treatment of steroid- or without methylprednisolone. Transplantation 1985;40:162–166. refractory acute graft-versus-host disease. Bone Marrow Transplant 2010;45:1347–1351. 144. Kanamaru A, Takemoto Y, Kakishita E, et al. FK506 treatment of graft- versus-host disease developing or exacerbating during prophylaxis and 167. Ghez D, Rubio MT, Maillard N, et al. Rapamycin for refractory acute graft- therapy with cyclosporin and/or other immunosuppressants. Japanese versus-host disease. Transplantation 2009;88:1081–1087. FK506 BMT Study Group. Bone Marrow Transplant 1995;15:885–889. 168. Allison AC, Eugui EM. Mycophenolate mofetil and its mechanisms of 145. Xhaard A, Launay M, Sicre de Fontbrune F, et al. A monocentric study of action. Immunopharmacology 2000;47:85–118. steroid-refractory acute graft-versus-host disease treatment with tacro- 169. U.S. Food and Drug Administration. Mycophenolate Mofetil Pack- limus and mTOR inhibitor. Bone Marrow Transplant 2020;55:86–92. age Insert. 1995. Accessed January 29, 2020. Available at: 146. U.S. Food and Drug Administration. Etanercept Package Insert. 1998. https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/ Accessed January 14, 2020. Available at: https://www.accessdata.fda. 050722s035,050723s035,050758s033,050759s041lbl.pdf gov/drugsatfda_docs/label/2018/103795s5569lbl.pdf 170. Furlong T, Martin P, Flowers ME, et al. Therapy with mycophenolate 147. Couriel D, Saliba R, Hicks K, et al. Tumor necrosis factor-alpha blockade mofetil for refractory acute and chronic GVHD. Bone Marrow Transplant for the treatment of acute GVHD. Blood 2004;104:649–654. 2009;44:739–748. 148. Busca A, Locatelli F, Marmont F, et al. Recombinant human soluble tumor 171. Kim JG, Sohn SK, Kim DH, et al. Different efficacy of mycophenolate necrosis factor receptor fusion protein as treatment for steroid refractory mofetil as salvage treatment for acute and chronic GVHD after allo- graft-versus-host disease following allogeneic hematopoietic stem cell geneic stem cell transplant. Eur J Haematol 2004;73:56–61. – transplantation. Am J Hematol 2007;82:45 52. 172. Pidala J, Kim J, Perkins J, et al. Mycophenolate mofetil for the man- 149. Abu-Dalle I, Reljic T, Nishihori T, et al. Extracorporeal photopheresis in agement of steroid-refractory acute graft vs host disease. Bone Marrow steroid-refractory acute or chronic graft-versus-host disease: results of a Transplant 2010;45:919–924.

JNCCN.org | Volume 18 Issue 5 | May 2020 631 NCCN GUIDELINES® Hematopoietic Cell Transplantation, Version 2.2020

173. U.S. Food and Drug Administration. Pentostatin Package Insert. 2007. 195. Nahas MR, Soiffer RJ, Kim HT, et al. Phase 1 clinical trial evaluating Accessed January 29, 2020. Available at: https://www.accessdata.fda. abatacept in patients with steroid-refractory chronic graft-versus-host gov/drugsatfda_docs/label/2019/020122s015lbl.pdf disease. Blood 2018;131:2836–2845. 174. Ragon BK, Mehta RS, Gulbis AM, et al. Pentostatin therapy for steroid- 196. U.S. Food and Drug Administration. Abatacept Package Insert. 2005. refractory acute graft versus host disease: identifying those who may Accessed January 29, 2020. Available at: https://www.accessdata.fda. benefit. Bone Marrow Transplant 2018;53:315–325. gov/drugsatfda_docs/label/2013/125118s171lbl.pdf 175. Schmitt T, Luft T, Hegenbart U, et al. Pentostatin for treatment of steroid- 197. Nikiforow S, Kim HT, Bindra B, et al. Phase I study of alemtuzumab for refractory acute GVHD: a retrospective single-center analysis. Bone therapy of steroid-refractory chronic graft-versus-host disease. Biol Marrow Transplant 2011;46:580–585. Blood Marrow Transplant 2013;19:804–811. 176. Pidala J, Kim J, Roman-Diaz J, et al. Pentostatin as rescue therapy for 198. Gutierrez-Aguirre´ CH, Cantu-Rodr´ ´ıguez OG, Borjas-Almaguer OD, et al. glucocorticoid-refractory acute and chronic graft-versus-host disease. Effectiveness of subcutaneous low-dose alemtuzumab and rituximab Ann Transplant 2010;15:21–29. combination therapy for steroid-resistant chronic graft-versus-host dis- – 177. Bolaños-Meade J, Jacobsohn DA, Margolis J, et al. Pentostatin in ease. Haematologica 2012;97:717 722. steroid-refractory acute graft-versus-host disease. J Clin Oncol 2005;23: 199. Tzakis AG, Abu-Elmagd K, Fung JJ, et al. FK 506 rescue in chronic graft- 2661–2668. versus-host-disease after bone marrow transplantation. Transplant Proc 178. Poi MJ, Hofmeister CC, Johnston JS, et al. Standard pentostatin dose 1991;23:3225–3227. fi reductions in renal insuf ciency are not adequate: selected patients with 200. Carnevale-Schianca F, Martin P, Sullivan K, et al. Changing from cyclo- steroid-refractory acute graft-versus-host disease. Clin Pharmacokinet sporine to tacrolimus as salvage therapy for chronic graft-versus-host – 2013;52:705 712. disease. Biol Blood Marrow Transplant 2000;6:613–620. 179. Jagasia M, Zeiser R, Arbushites M, et al. Ruxolitinib for the treatment of 201. Yanik GA, Mineishi S, Levine JE, et al. Soluble tumor necrosis factor patients with steroid-refractory GVHD: an introduction to the REACH receptor: enbrel (etanercept) for subacute pulmonary dysfunction fol- – trials. Immunotherapy 2018;10:391 402. lowing allogeneic stem cell transplantation. Biol Blood Marrow Trans- 180. U.S. Food and Drug Administration. FDA approves ruxolitinib for acute plant 2012;18:1044–1054. graft-versus-host disease. 2019. Accessed January 24, 2020. Available 202. Flowers ME, Apperley JF, van Besien K, et al. A multicenter pro- at: https://www.fda.gov/drugs/resources-information-approved-drugs/ spective phase 2 randomized study of extracorporeal photopheresis fda-approves-ruxolitinib-acute-graft-versus-host-disease for treatment of chronic graft-versus-host disease. Blood 2008;112: 181. Zeiser R, Burchert A, Lengerke C, et al. Ruxolitinib in corticosteroid- 2667–2674. refractory graft-versus-host disease after allogeneic stem cell trans- – 203. Couriel DR, Hosing C, Saliba R, et al. Extracorporeal photo- plantation: a multicenter survey. Leukemia 2015;29:2062 2068. chemotherapy for the treatment of steroid-resistant chronic GVHD. 182. U.S. Food and Drug Administration. Tocilizumab Package Insert. 2010. Blood 2006;107:3074–3080. Accessed January 28, 2020. Available at: https://www.accessdata.fda. 204. Malik MI, Litzow M, Hogan W, et al. Extracorporeal photopheresis for gov/drugsatfda_docs/label/2017/125276s114lbl.pdf chronic graft-versus-host disease: a systematic review and meta-analysis. 183. Imamura M, Hashino S, Kobayashi H, et al. Serum cytokine levels in bone Blood Res 2014;49:100–106. marrow transplantation: synergistic interaction of interleukin-6, interferon-gamma, and tumor necrosis factor-alpha in graft-versus-host 205. U.S. Food and Drug Administration. Hydroxychloroquine Package disease. Bone Marrow Transplant 1994;13:745–751. Insert. 1955. Accessed January 31, 2020. Available at: https:// www.accessdata.fda.gov/drugsatfda_docs/label/2019/ 184. Cavet J, Dickinson AM, Norden J, et al. Interferon-gamma and in- 009768Orig1s051lbl.pdf terleukin-6 gene polymorphisms associate with graft-versus-host disease in HLA-matched sibling bone marrow transplantation. Blood 2001;98: 206. Wolff D, Schleuning M, von Harsdorf S, et al. Consensus conference on 1594–1600. clinical practice in chronic GVHD: second-line treatment of chronic graft- versus-host disease. Biol Blood Marrow Transplant 2011;17:1–17. 185. Ganetsky A, Frey NV, Hexner EO, et al. Tocilizumab for the treatment of severe steroid-refractory acute graft-versus-host disease of the lower 207. Gilman AL, Chan KW, Mogul A, et al. Hydroxychloroquine for the gastrointestinal tract. Bone Marrow Transplant 2019;54:212–217. treatment of chronic graft-versus-host disease. Biol Blood Marrow Transplant 2000;6(3, 3A)327–334. 186. Gergis U, Arnason J, Yantiss R, et al. Effectiveness and safety of tocili- zumab, an anti-interleukin-6 receptor monoclonal antibody, in a patient 208. Navajas EV, Krema H, Hammoudi DS, et al. Retinal toxicity of high-dose with refractory GI graft-versus-host disease. J Clin Oncol 2010;28: hydroxychloroquine in patients with chronic graft-versus-host disease. – e602–e604. Can J Ophthalmol 2015;50:442 450. 187. Yucebay F, Matthews C, Puto M, et al. Tocilizumab as first-line therapy for 209. Dubovsky JA, Beckwith KA, Natarajan G, et al. Ibrutinib is an irreversible steroid-refractory acute graft-versus-host-disease: analysis of a single- molecular inhibitor of ITK driving a Th1-selective pressure in T lym- center experience. Leuk Lymphoma 2019;60:2223–2229. phocytes. Blood 2013;122:2539–2549. 188. Roddy JV, Haverkos BM, McBride A, et al. Tocilizumab for steroid re- 210. U.S. Food and Drug Administration. Ibrutnib Package Insert. 2013. fractory acute graft-versus-host disease. Leuk Lymphoma 2016;57: Accessed February 3, 2020. Available at: https://www.accessdata.fda. 81–85. gov/drugsatfda_docs/label/2018/210563s000lbl.pdf 189. Drobyski WR, Pasquini M, Kovatovic K, et al. Tocilizumab for the 211. Waller EK, Miklos D, Cutler C, et al. Ibrutinib for chronic graft-versus-host treatment of steroid refractory graft-versus-host disease. Biol Blood disease after failure of prior therapy: 1-year update of a phase 1b/2 study. Marrow Transplant 2011;17:1862–1868. Biol Blood Marrow Transplant 2019;25:2002–2007. 190. Fløisand Y, Lazarevic VL, Maertens J, et al. Safety and effectiveness of 212. U.S. Food and Drug Administration. Imatinib Package Insert. 2001. vedolizumab in patients with steroid-refractory gastrointestinal acute Accessed February 3, 2020. Available at: https://www.accessdata.fda. graft-versus-host disease: a retrospective record review. Biol Blood gov/drugsatfda_docs/label/2008/021588s024lbl.pdf – Marrow Transplant 2019;25:720 727. 213. Baird K, Comis LE, Joe GO, et al. Imatinib mesylate for the treatment of 191. Danylesko I, Bukauskas A, Paulson M, et al. Anti-a4b7 integrin mono- steroid-refractory sclerotic-type cutaneous chronic graft-versus-host clonal antibody (vedolizumab) for the treatment of steroid-resistant disease. Biol Blood Marrow Transplant 2015;21:1083–1090. severe intestinal acute graft-versus-host disease. Bone Marrow Trans- – 214. Chen GL, Arai S, Flowers ME, et al. A phase 1 study of imatinib for plant 2019;54:987 993. corticosteroid-dependent/refractory chronic graft-versus-host disease: 192. Fløisand Y, Lundin KEA, Lazarevic V, et al. Targeting integrin alpha4beta7 response does not correlate with anti-PDGFRA antibodies. Blood 2011; in steroid-refractory intestinal graft-versus-host disease. Biol Blood 118:4070–4078. – Marrow Transplant 2017;23:172 175. 215. Arai S, Pidala J, Pusic I, et al. A randomized phase II crossover study of 193. U.S. Food and Drug Administration. Natalizumab Package Insert. 2004. imatinib or rituximab for cutaneous sclerosis after hematopoietic cell Accessed March 2, 2020. Available at: https://www.accessdata.fda.gov/ transplantation. Clin Cancer Res 2016;22:319–327. drugsatfda_docs/label/2012/125104s0576lbl.pdf 216. Olivieri A, Cimminiello M, Corradini P, et al. Long-term outcome and 194. U.S. Food and Drug Administration. Vedolizumab Package Insert. 2014. prospective validation of NIH response criteria in 39 patients receiving Accessed March 2, 2020. Available at: https://www.accessdata.fda.gov/ imatinib for steroid-refractory chronic GVHD. Blood 2013;122: drugsatfda_docs/label/2014/125476s000lbl.pdf 4111–4118.

632 © JNCCN—Journal of the National Comprehensive Cancer Network | Volume 18 Issue 5 | May 2020 Hematopoietic Cell Transplantation, Version 2.2020 NCCN GUIDELINES®

217. Koreth J, Kim HT, Jones KT, et al. Efficacy, durability, and response 225. Jurado M, Vallejo C, Perez-Sim´ on´ JA, et al. Sirolimus as part of immu- predictors of low-dose interleukin-2 therapy for chronic graft-versus-host nosuppressive therapy for refractory chronic graft-versus-host disease. disease. Blood 2016;128:130–137. Biol Blood Marrow Transplant 2007;13:701–706. 218. Koreth J, Matsuoka K, Kim HT, et al. Interleukin-2 and regulatory T cells 226. Lutz M, Kapp M, Einsele H, et al. Improvement of quality of life in patients in graft-versus-host disease. N Engl J Med 2011;365:2055–2066. with steroid-refractory chronic graft-versus-host disease treated with the mTOR inhibitor everolimus. Clin Transplant 2014;28:1410–1415. 219. Whangbo JS, Kim HT, Mirkovic N, et al. Dose-escalated interleukin-2 therapy for refractory chronic graft-versus-host disease in adults and 227. Mielke S, Lutz M, Schmidhuber J, et al. Salvage therapy with everolimus children. Blood Adv 2019;3:2550–2561. reduces the severity of treatment-refractory chronic GVHD without impairing disease control: a dual center retrospective analysis. Bone 220. U.S. Food and Drug Administration. Methotrexate Package Insert. 1972. Marrow Transplant 2014;49:1412–1418. Accessed February 4, 2020. Available at: https://www.accessdata.fda. fi gov/drugsatfda_docs/label/2011/011719s117lbl.pdf 228. Lopez F,Parker P,Nademanee A, et al. Ef cacy of mycophenolate mofetil in the treatment of chronic graft-versus-host disease. Biol Blood Marrow 221. Giaccone L, Martin P, Carpenter P, et al. Safety and potential efficacy of Transplant 2005;11:307–313. low-dose methotrexate for treatment of chronic graft-versus-host dis- 229. U.S. Food and Drug Administration. Rituximab Package Insert. 1997. ease. Bone Marrow Transplant 2005;36:337–341. Accessed February 5, 2020. Available at: https://www.accessdata.fda. 222. de Lavallade H, Mohty M, Faucher C, et al. Low-dose methotrexate as gov/drugsatfda_docs/label/2010/103705s5311lbl.pdf salvage therapy for refractory graft-versus-host disease after reduced- 230. Kharfan-Dabaja MA, Mhaskar AR, Djulbegovic B, et al. Efficacy of rit- intensity conditioning allogeneic stem cell transplantation. uximab in the setting of steroid-refractory chronic graft-versus-host – Haematologica 2006;91:1438 1440. disease: a systematic review and meta-analysis. Biol Blood Marrow 223. Huang XJ, Jiang Q, Chen H, et al. Low-dose methotrexate for the Transplant 2009;15:1005–1013. treatment of graft-versus-host disease after allogeneic hematopoi- 231. Modi B, Hernandez-Henderson M, Yang D, et al. Ruxolitinib as salvage etic stem cell transplantation. Bone Marrow Transplant 2005;36: therapy for chronic graft-versus-host disease. Biol Blood Marrow 343–348. Transplant 2019;25:265–269. 224. Couriel DR, Saliba R, Escalon´ MP, et al. Sirolimus in combination with 232. Khoury HJ, Langston AA, Kota VK, et al. Ruxolitinib: a steroid sparing tacrolimus and corticosteroids for the treatment of resistant chronic graft- agent in chronic graft-versus-host disease. Bone Marrow Transplant versus-host disease. Br J Haematol 2005;130:409–417. 2018;53:826–831.

JNCCN.org | Volume 18 Issue 5 | May 2020 633 NCCN GUIDELINES® Hematopoietic Cell Transplantation, Version 2.2020

Individual Disclosures for the NCCN Hematopoietic Cell Transplantation Panel

Clinical Research Support/Data Safety Scientific Advisory Boards, Consultant, Promotional Advisory Boards, Panel Member Monitoring Board or Expert Witness Consultant, or Speakers Bureau Specialties

Sarah Anand, MD AbGenomics; Astellas Pharma US, Inc.; None None Medical Oncology, and Hematology/ CSL Behring; and Incyte Corporation Hematology Oncology

Vijaya Raj Bhatt, MBBS Incyte Corporation; Jazz Pharmaceuticals AbbVie, Inc.; Agios, Inc.; Incyte AbbVie, Inc. Hematology/Hematology Oncology, and Inc.; National Marrow Donor Program; Corporation;Omeros; and Takeda Hematopoietic Cell Transplantation Oncoceutics; Partnership for Health Pharmaceuticals North America, Inc. Analytic Research, LLC; and Tolero Pharmaceuticals, Inc.

Ryan Bookout, PharmDa Spectrum Pharmaceuticals, Inc. None None Hematology/Hematology Oncology, and Pharmacology

George Chen, MD Actinium Pharmaceuticals, Inc.;Bellicum None None Hematology/Hematology Oncology, and Pharmaceuticals; Equillium, Inc.; and Hematopoietic Cell Transplantation Takeda Pharmaceuticals North America, Inc.

Daniel Couriel, MD, MS Pharmacyclics, Inc. Fresenius Medical Care AG & Co.; Incyte Seattle Genetics, Inc. Hematology/Hematology Oncology; Corporation; and Merck & Co., Inc. Medical Oncology; Hematopoietic Cell Transplantation; and Internal Medicine

Marcos de Lima, MD Celgene Corporation Bristol-Myers Squibb Company; Incyte None Hematology/Hematology Oncology Corporation; and Pfizer Inc.

Antonio Di Stasi, MD None None None Medical Oncology, and Hematology/ Hematology Oncology

Areej El-Jawahri, MD None AIM Pathways None Hematology/Hematology Oncology; Medical Oncology; and Hematopoietic Cell Transplantation

Sergio Giralt, MD Amgen Inc.; Bristol-Myers Squibb AbbVie, Inc.; Amgen Inc.; Boehringer None Medical Oncology Company; Celgene Corporation; Johnson Ingelheim GmbH; Bristol-Myers Squibb & Johnson; Takeda; and Pharmaceuticals Company; Celgene Corporation; Cellerant North America, Inc. Therapeutics, Inc.; Gilead Sciences, Inc.; Karyopharm Therapeutics; Kite Pharma, Inc.; Novartis Pharmaceuticals Corporation; Pharmacyclics, Inc.; and sanofi-aventis U.S.

Jonathan Gutman, MD AICuris; Angiocrine Bioscience, Inc; Incyte Agios, Inc. None Medical Oncology Corporation; and Terumo Corporation

Vincent Ho, MD None Alexion Pharmaceuticals, Inc.; Janssen None Hematology/Hematology Oncology, and Pharmaceutica Products, LP; and Omeros Medical Oncology LLC

Mitchell Horwitz, MD AbbVie, Inc.; CSL Behring; Gamida Cell None None Hematology/Hematology Oncology, and Ltd.; Incyte Corporation;Macrogenics, Medical Oncology Inc.; Molmed; and Pfizer Inc.

Joe Hsu, MD None None None Infectious Diseases

Mark Juckett, MD None None None Hematology/Hematology Oncology

Mohamed Kharfan None Daiichi- Sankyo Co. None Hematology/Hematology Oncology Dabaja, MD

Alison W. Loren, None None None Hematology/Hematology Oncology, and MD,MSCE Hematopoietic Cell Transplantation

Javier Meade, MD Incyte Corporation None None Medical Oncology

Marco Mielcarek, MD, None None None Hematology/Hematology Oncology, and PhD Hematopoietic Cell Transplantation

Jonathan Moreira, MD None Jazz Pharmaceuticals Inc., and Pfizer Inc. Pfizer Inc. Hematology/Hematology Oncology, and Medical Oncology

Ryotaro Nakamura, MD Helocyte, Inc.; Innosense; and Miyarisan Kadmon Corporation; Magenta Hematology/Hematology Oncology Pharmaceutical Co. Therapeutics; Merck & Co., Inc.; and Viracor

Yago Nieto, MD, PhD Novartis Pharmaceuticals Corporation Affimed None Hematology/Hematology Oncology

Julianna Roddy, PharmD, None None Astellas Pharma US, Inc., and AstraZeneca Hematology/Hematology Oncology; BCOP Pharmaceuticals LP Hematopoietic Cell Transplantation; and Pharmacology

Ayman Saad, MD None Magenta Therapeutics None Hematology/Hematology Oncology, and Hematopoietic Cell Transplantation

Gowri Satyanarayana, None Incyte Corporation None Infectious Diseases MD

Mark Schroeder, MD None Astellas Pharma US, Inc.; Flatiron Health, Merck & Co., Inc., andTakeda Hematology/Hematology Oncology Inc.; Incyte Corporation;Jazz Pharmaceuticals North America, Inc. Pharmaceuticals Inc.; Partners Therapeutics; and Pfizer Inc.

Carlyn Rose Tan, MD None None None Hematology/Hematology Oncology, and Medical Oncology

Dimitrios Tzachanis, MD, Fate Therapeutics;Genentech, Inc.; Incyte Jazz Pharmaceuticals Inc.; Kite Pharma, Kite Pharma, Inc.;Takeda Pharmaceuticals Hematology/Hematology Oncology, and PhD Corporation; and Kite Pharma, Inc. Inc.;Kyowa Hakko Kirin Co., Ltd.; and North America, Inc. Medical Oncology Magenta Therapeutics

The NCCN Guidelines Staff have no conflicts to disclose. aThe following individuals have disclosed that they have an employment/governing board, patent, equity, or royalty: Ryan Bookout, PharmD: Alcon, Inc.; Biolife Solutions; Celgene Corporation; Gilead Sciences, Inc.; Novartis Pharmaceuticals Corporation; and Spectrum Pharmaceuticals, Inc.

634 © JNCCN—Journal of the National Comprehensive Cancer Network | Volume 18 Issue 5 | May 2020