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A SPECIAL MEETING REVIEW EDITION Highlights in From the 2019 American Society of Clinical Oncology Annual Meeting A Review of Selected Presentations From the 2019 ASCO Annual Meeting • May 31-June 4, 2019 • Chicago, Illinois

Special Reporting on: •  With for Stage 3/4 Classical : Three-Year Update of the ECHELON-1 Study • Umbralisib Monotherapy Demonstrates Efficacy and Safety in Patients With Relapsed/Refractory Marginal Zone Lymphoma: A Multicenter, Open Label, Registration Directed Phase II Study

• Response to Brentuximab Vedotin by CD30 Expression: Results From Five Trials in PTCL, CTCL, and B-Cell • Sintilimab for Relapsed/Refractory Extranodal NK/T-Cell Lymphoma: A Multicenter, Single-Arm, Phase 2 Trial (ORIENT-4) • Response to A+CHP by CD30 Expression in the ECHELON-2 Trial •  + and in Patients With Relapsed/Refractory : Interim Analysis of a Phase Ib/II Trial • First-Line Therapy of T-Cell Lymphoma: Allogeneic or Autologous Transplantation for Consolidation—Final Results of the AATT Study • Lisocabtagene Maraleucel (Liso-Cel) Treatment of Patients With Relapsed/Refractory B-Cell Non-Hodgkin Lymphoma and Secondary CNS Lymphoma: Initial Results From TRANSCEND NHL 001

•  Maintenance for Patients With Diffuse Large B-Cell Lymphoma in First Complete Remission: Results From a Randomized HOVON-Nordic Lymphoma Group Phase III Study

PLUS Meeting Abstract Summaries

With Expert Commentary by: Alex F. Herrera, MD Assistant Professor Department of Hematology and Hematopoietic Cell Transplantation City of Hope Medical Center Duarte, California

ON THE WEB: hematologyandoncology.net

Indexed through the National Library of Medicine (PubMed/MEDLINE), PubMed Central (PMC), and EMBASE

SPECIAL MEETING REVIEW EDITION

Brentuximab Vedotin With Chemotherapy for Stage 3/4 Classical Hodgkin Lymphoma: Three-Year Update of the ECHELON-1 Study

3-year follow-up of the ECH- by computed tomography (CT)/PET a median follow-up of 37.1 months, ELON-1 trial (A Frontline scans before and after treatment. PET the PFS rate was 83.1% with brentux- Therapy Trial in Participants status at the end of cycle 2 (PET2) was imab vedotin plus AVD vs 76.0% with AWith Advanced Classical Hodgkin considered negative among patients ABVD. Treatment with brentuximab Lymphoma) demonstrated sustained with a Deauville score of 1, 2, or 3 and vedotin plus AVD reduced the risk efficacy with brentuximab vedotin plus positive among those with a score of of progression or death at 3 years by , , and dacarba- 4 or 5. 30% compared with ABVD (HR, zine (AVD) as treatment for stage 3/4 Initial results from the phase 3 0.704; 95% CI, 0.550-0.901; P=.005; classical Hodgkin lymphoma.1 The ECHELON-1 trial showed that bren- Figure 1). Subgroup analyses based on trial compared brentuximab vedotin tuximab vedotin plus AVD improved age, International Prognostic Score, plus AVD vs doxorubicin, , outcomes, with a hazard ratio (HR) PET2 status, and stage of disease also vinblastine, and (ABVD) for modified progression-free survival reflected superior PFS with brentux- among patients from 21 countries. (PFS) of 0.77 (95% CI, 0.60-0.98).2 imab vedotin plus AVD compared The patients were randomly assigned The 3-year follow-up study evaluated with ABVD. to receive 6 cycles of brentuximab both investigator-assessed PFS among In the initial trial results, periph- vedotin plus AVD (n=664) or ABVD the intention-to-treat (ITT) popula- eral neuropathy was reported among (n=670) intravenously on days 1 and tion as well as safety, with particular 67% of patients receiving brentuximab 15 of each cycle. Patients were assessed attention to peripheral neuropathy.1 At vedotin plus AVD and 43% of those

1.0

0.9 0.8

0.7 0.6

0.5

0.4

0.3

0.2 N Events Hazard Ratio (95% CI) Log-Rank P Value

0.1 A+AVD 664 109 0.704 (0.550-0.901) P=.005 ABVD 670 151 0.0 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 42 44 46 48 50 52

Figure 1. Probability of progression-free survival among patients in a 3-year follow-up analysis of the phase 3 ECHELON-1 trial. A+AVD, brentuximab vedotin plus doxorubicin, vinblastine, and dacarbazine; ABVD, doxorubicin, bleomycin, vinblastine, and dacarbazine; ECHELON-1, A Frontline Therapy Trial in Participants With Advanced Classical Hodgkin Lymphoma. Adapted from Straus DJ et al. ASCO abstract 7532. J Clin Oncol. 2019;37(suppl 15).1

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100 80 60

40

20

0

Figure 2. Improvement in peripheral neuropathy in a 3-year follow-up analysis of the phase 3 ECHELON-1 trial. aResolution was defined as event outcome of “resolved” or “resolved with sequelae.” Improvement was defined as “improved by ≥1 grade from worst grade as of the latest assessment.” bMedian follow-up from end of treatment for the cohort with unresolved peripheral neuropathy. cTotal patients with peripheral neuropathy at end of treatment. A+AVD, brentuximab vedotin plus doxorubicin, vinblastine, and dacarbazine; ABVD, doxorubicin, bleomycin, vinblastine, and dacarbazine; ECHELON-1, A Frontline Therapy Trial in Participants With Advanced Classical Hodgkin Lymphoma. Adapted from Straus DJ et al. ASCO abstract 7532. J Clin Oncol. 2019;37(suppl 15).1 receiving ABVD (Figure 2).2 By the The study showed that initial treat- gests that brentuximab vedotin plus 3-year analysis, these cases improved ment of advanced classical Hodgkin AVD has a more favorable benefit/risk completely or partially in 78% vs 83%, lymphoma with 6 cycles of brentuximab profile compared with ABVD. respectively. Among the patients with vedotin plus AVD provided strong, sus- complete resolution of peripheral neu- tained benefits in all subgroups. Nota- References ropathy, the median time to resolution bly, brentuximab vedotin plus AVD 1. Straus DJ, Długosz-Danecka M, Alekseev S, et al. Brentuximab vedotin with chemotherapy for stage 3/4 was 28 weeks after the end of treatment improved PFS for both PET2-positive classical Hodgkin lymphoma: three-year update of the with brentuximab vedotin plus AVD and PET2-negative patients. The study ECHELON-1 study [ASCO abstract 7532]. J Clin and 14 weeks after ABVD. For those authors concluded that the 30% reduc- Oncol. 2019;37(suppl 15). 2. Connors JM, Jurczak W, Straus DJ, et al; ECH- patients with partial improvement, the tion in disease progression or death at ELON-1 Study Group. Brentuximab vedotin with median time to improvement was 40 3 years, along with improvement in chemotherapy for stage III or IV Hodgkin’s lymphoma. weeks vs 32 weeks, respectively. peripheral neuropathy over time, sug- N Engl J Med. 2018;378(4):331-344.

Umbralisib Monotherapy Demonstrates Efficacy and Safety in Patients With Relapsed/Refractory Marginal Zone Lymphoma: A Multicenter, Open Label, Registration Directed Phase II Study

mbralisib has shown evidence compared with earlier agents.1,2 A With or Without and of activity in patients with phase 1 trial showed a lower rate of TGR-1202 Alone in Patients With relapsed or refractory hema- colitis.2 Previously Treated Non-Hodgkins Utologic malignancies. This next-gener- The multicenter, multico- Lymphoma) investigated the efficacy ation phosphoinositide 3-kinase delta hort phase 2b UNITY-NHL trial and safety of umbralisib alone and in (PI3Kδ) inhibitor may have improved (Study to Assess the Efficacy and various combinations in patients with selectivity and a distinct safety profile Safety of + TGR-1202 relapsed or refractory non-Hodgkin

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Extranodal 25% Splenic Nodal 0%

–25%

–50% –75% • 86% of patients (36/42) had a reduction in tumor burden • Median time to initial response, 2.7 months –100%

Figure 3. Best percent change in tumor lesions among patients treated with umbralisib in the phase 2b UNITY-NHL trial. SPD, sum of the products of diameters; UNITY-NHL, Study to Assess the Efficacy and Safety of Ublituximab + TGR-1202 With or Without Bendamustine and TGR-1202 Alone in Patients With Previously Treated Non-Hodgkins Lymphoma. Adapted from Fowler NH et al. ASCO abstract 7506. J Clin Oncol. 2019;37(suppl 15).1 lymphoma. Dr Felipe Samaniego pre- sented results for patients with marginal ABSTRACT SUMMARY Smart Start: Final Results of Rituximab, zone lymphoma, who received single- Lenalidomide, and Lead-In Prior to Combination With agent umbralisib at an oral daily dose Chemotherapy for Patients With Newly Diagnosed Diffuse Large of 800 mg until progressive disease or B-Cell Lymphoma unacceptable toxicity.1 The primary endpoint of the study was the overall The phase 2 Smart Start trial evaluated rituximab, lenalidomide, and ibrutinib in response rate (ORR). The secondary patients with newly diagnosed DLBCL (Abstract 7508). The 49 evaluable patients endpoints were duration of response, had newly diagnosed non–germinal center B-cell DLBCL and received rituximab, PFS, time to response, and safety. lenalidomide, and ibrutinib for 2 cycles before the addition of chemotherapy. Prior The trial enrolled 72 patients to chemotherapy, the ORR was 86%, with a CR in 36%. Disease burden decreased with marginal zone lymphoma. The substantially with the combination prior to chemotherapy. After chemotherapy was interim efficacy analysis included 42 added, the ORR reached 98% in the ITT population. Approximately 50% of patients patients who received 9 or more treat- developed nausea. Peripheral sensory neuropathy and diarrhea each occurred in ment cycles, with a median duration almost half of patients. Two fatalities were reported. of 10.1 months (range, 0.7-15.7). Their median age was 67 years (range, 34-81). Among these patients, 45% had received 1 prior line of therapy, adverse events (AEs) in 5 patients. The ORR was 57% in patients with and 55% had received 2 or more prior The ORR was 52% with umbral- extranodal marginal zone lymphoma, lines of therapy. isib, according to investigator assess- 42% in those with nodal marginal The median follow-up duration ment and independent review. The zone lymphoma, and 43% in those was 12.5 months (range, 8.3-18.5 clinical benefit rate—a composite with splenic marginal zone lymphoma. months), with 55% of patients still of partial response (PR), complete ORR was 53% among patients who receiving treatment at the time of the response (CR), and stable disease— had received prior chemoimmuno- report. The cause of treatment discon- was 88%. therapy, 38% among those who were tinuation included progressive disease According to independent review, refractory to their most recent line of in 10 patients and treatment-related umbralisib had activity across subtypes. therapy, and 44% in those who had

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because of AEs that were possibly ABSTRACT SUMMARY Feasibility of Brentuximab Vedotin as related to treatment. Diarrhea was Consolidation Therapy After Autologous Stem Cell Transplantation the most common AE, ranging from in Children and Adolescents (<18 Years) With Early-Relapse Hodgkin grades 1 to 3. The prevalence of grade Lymphoma 3 diarrhea was 10%. Grade 3 eleva- tions of the liver enzymes aspartate A retrospective review examined the feasibility of consolidation therapy with bren- aminotransferase and alanine amino- tuximab vedotin following autologous SCT in pediatric patients with Hodgkin lym- transferase (ALT) each occurred in 9% phoma and early relapse (Abstract e19012). The 6 patients in the study were ages 12 of patients. Increases in liver enzymes to 18 years. Five of the patients had high-risk disease. Patients were stratified accord- mostly diminished throughout the ing to risk, and treatment was adjusted based on individual responses. Brentuximab course of the study, with only 1 patient

vedotin consolidation therapy was given every 3 weeks for a maximum of 16 cycles. showing an elevated ALT after 6 cycles. The duration of PFS ranged from 12 to 30 months. Grade 3 AEs included 2 cases of After 6 months, no patients discontin- , as well as 2 cases of neuropathy that led to treatment discontinuation. ued umbralisib owing to a treatment- related AE. relapsed after 2 or more prior lines of able patients. The estimated rate of References 12-month PFS was 66%. 1. Fowler NH, Samaniego F, Jurczak W, et al. Umbral- therapy. isib monotherapy demonstrates efficacy and safety in The median duration to initial AEs were evaluated in 69 patients, patients with relapsed/refractory marginal zone lym- response with umbralisib was 2.7 who had received umbralisib for a phoma: a multicenter, open label, registration directed median of 6.9 months. Umbralisib phase II study [ASCO abstract 7506]. J Clin Oncol. months. A reduction in tumor burden 2019;37(suppl 15). occurred in 86% of patients (Figure 3). was generally well tolerated. No deaths 2. Burris HA III, Flinn IW, Patel MR, et al. Umbra­ The median duration of response with or cases of colitis were reported. Dose lisib, a novel PI3Kδ and casein kinase-1ε inhibi- reductions owing to AEs were required tor, in relapsed or refractory chronic lymphocytic umbralisib was not reached among 22 leukaemia and lymphoma: an open-label, phase 1, evaluable patients. The median PFS by 9% of patients, and another 14% dose-escalation, first-in-human study. Lancet Oncol. was also not reached among 42 evalu- of patients discontinued umbralisib 2018;19(4):486-496.

Response to Brentuximab Vedotin by CD30 Expression: Results From Five Trials in PTCL, CTCL, and B-Cell Lymphomas

reatment with brentuximab expression and the efficacy of brentux- CD30 expression was quanti- vedotin has been studied in imab vedotin.1 This study analyzed the fied through immunohistochemistry. several types of lymphoma.1 results of 5 prospective clinical trials Patients were grouped by CD30 expres- TA component of brentuximab vedotin, evaluating brentuximab vedotin for sion levels of greater than or equal to the antimitotic drug monomethyl relapsed/refractory lymphoma. The 10%, less than 10%, and undetectable. auristatin E (MMAE), acts upon cells analysis included 275 patients who These levels were compared with data expressing the CD30 cell surface anti- received brentuximab vedotin mono- for the ORR and duration of response. gen.2 However, there are additional therapy for the treatment of relapsed/ For some patients in the ALCANZA possible explanations for the activity refractory peripheral T-cell lymphoma and 35-IST-002 trials, more than 1 of brentuximab vedotin against tumor (PTCL), cutaneous T-cell lymphoma measurement of CD30 expression was cells.1 These may include macrophage- (CTCL), or B-cell non-Hodgkin lym- available. When CD30 expression was mediated cellular phagocytosis, cellular phoma (NHL). The 5 trials were the calculated using averaged values in the immune response, and a bystander- phase 2 SGN35-012 trial (parts A and ALCANZA and 35-IST-002 studies, killing effect.3-5 Additionally, responses C), the phase 2 35-IST-030 trial, the expression was less than 10% in 140 to brentuximab vedotin have not phase 3 ALCANZA trial (Brentux- patients, including 60 patients with consistently reflected levels of CD30 imab Vedotin or Physician’s Choice undetectable expression. When the expression.6-10 A study examined the in CD30-Positive Cutaneous T-Cell analysis included the lowest measured results of 5 prospective clinical trials to Lymphoma), the phase 2 35-IST-001 CD30 values from these studies, the identify any association between CD30 trial, and the phase 2 35-IST-002 trial. number of patients with less than 10%

Clinical Advances in Hematology & Oncology Volume 17, Issue 8, Supplement 14 August 2019 11 SPECIAL MEETING REVIEW EDITION

N Events Median (months) CD30 ≥10% 26 14 15.1 CD30 <10% 6 4 16.6 100 90 80 70 60 50 40 30 20 10 0 0 3 6 9 12 15 18 21 24 27 30 33

CD30 ≥10% 26 (0) 23 (3) 15 (6) 11 (9) 7 (9) 6 (10) 3 (12) 2 (13) 1 (13) 1 (13) 0 (14) 0 (14) CD30 <10% 6 (0) 6 (0) 6 (0) 6 (0) 4 (2) 3 (3) 3 (3) 2 (4) 0 (4) 0 (4) 0 (4) 0 (4)

Figure 4. Progression-free survival according to the level of CD30 expression in an analysis of patients with CTCL treated with brentuximab vedotin in the ALCANZA trial. ALCANZA, Brentuximab Vedotin or Physician’s Choice in CD30-Positive Cutaneous T-Cell Lymphoma; CTCL, cutaneous T-cell lymphoma. Adapted from Jagadeesh D et al. ASCO abstract 7543. J Clin Oncol. 2019;37(suppl 15).1 expression was 153, of whom 80 had undetectable expression. ABSTRACT SUMMARY MAGNIFY: Phase IIIb Interim Analysis of The analysis found that ORR Induction R2 Followed by Maintenance in Relapsed/Refractory values did not consistently correspond Indolent Non-Hodgkin Lymphoma to CD expression.1 Only one com- parison, among patients with CTCL A phase 3b trial evaluated lenalidomide plus rituximab with extended rituximab in the ALCANZA trial, suggested a maintenance in patients with relapsed or refractory follicular lymphoma or marginal possible trend between higher ORR zone lymphoma (Abstract 7513). The ORR was 73% among 310 patients evaluable and high CD30 expression. However, for efficacy. Subgroup analyses showed ORRs of 74% in patients with follicular lym- the 95% CIs for ORR overlapped phoma, 65% in those with marginal zone lymphoma, 63% in those with rituximab- with each other across all categories. refractory disease, and 68% in those with early relapse. Patients refractory to both Among patients with B-cell NHL in rituximab and an alkylating agent had an ORR of 51%. Overall, the median PFS was the SGN35-012 study, no discernible 36.0 months (95% CI, 26.5 to not reached). The median PFS was 30.2 months (95% trend appeared between the level of CI, 23.0 to not reached) in patients with follicular lymphoma and 38.4 months (95% CD30 expression and ORR. CI, 26.5-38.4) in those with marginal zone lymphoma. The most frequent treatment- The level of CD30 expression emergent grade 3/4 AEs were neutropenia in 34%, in 6%, fatigue did not correspond to the median in 5%, and leukopenia in 5%. duration of response across the stud- ies. For patients with CTCL in the ALCANZA trial, based on averaged CD30 expression levels, the median duration of response was 15.1 months study, the median duration of response The study investigators concluded among those with 10% or higher was 3.9 months in those with 10% or that the response and duration of CD30 expression and 16.6 months higher CD30 expression, 8.3 months response seen with brentuximab vedo- among those with a level below 10% in those with expression below 10%, tin did not appear to be associated (P=.46; Figure 4). Among patients and 11.6 months in those with unde- with levels of CD30 expression. They with B-cell NHL in the SGN35-012 tectable expression (P=.78). suggested that further elucidation of

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this drug’s mechanisms of action may CD30 SGN-30. Blood. 2007;110(13):4370- imab vedotin for CD30+ cutaneous T-cell lym- help to improve outcomes. 4372. phoma and lymphomatoid papulosis. J Clin Oncol. 4. Müller P, Martin K, Theurich S, et al. Microtubule- 2015;33(32):3759-3765. depolymerizing agents used in antibody-drug conjugates 8. Horwitz SM, Advani RH, Bartlett NL, et al. References induce antitumor immunity by stimulation of dendritic Objective responses in relapsed T-cell lymphomas 1. Jagadeesh D, Horwitz SM, Bartlett NL, et al. cells. Cancer Immunol Res. 2014;2(8):741-755. with single-agent brentuximab vedotin. Blood. Response to brentuximab vedotin by CD30 expres- 5. Li F, Emmerton KK, Jonas M, et al. Intracellular 2014;123(20):3095-3100. sion: results from five trials in PTCL, CTCL, and released payload influences potency and bystander- 9. Jacobsen ED, Sharman JP, Oki Y, et al. Brentuximab B-cell lymphomas [ASCO abstract 7543]. J Clin Oncol. killing effects of antibody-drug conjugates in preclinical vedotin demonstrates objective responses in a phase 2019;37(suppl 15). models. Cancer Res. 2016;76(9):2710-2719. 2 study of relapsed/refractory DLBCL with variable 2. Sutherland MS, Sanderson RJ, Gordon KA, et al. 6. Kim YH, Tavallaee M, Sundram U, et al. Phase II CD30 expression. Blood. 2015;125(9):1394-1402. Lysosomal trafficking and cysteine protease metabo- investigator-initiated study of brentuximab vedotin in 10. Bartlett NL, Smith MR, Siddiqi T, et al. Brentux- lism confer target-specific cytotoxicity by peptide- and Sézary syndrome with variable imab vedotin activity in diffuse large B-cell lymphoma linked anti-CD30-auristatin conjugates. J Biol Chem. CD30 expression level: a multi-institution collaborative with CD30 undetectable by visual assessment of con- 2006;281(15):10540-10547. project. J Clin Oncol. 2015;33(32):3750-3758. ventional immunohistochemistry. Leuk Lymphoma. 3. Oflazoglu E, Stone IJ, Gordon KA, et al. Macro- 7. Duvic M, Tetzlaff MT, Gangar P, Clos AL, Sui 2017;58(7):1607-1616. phages contribute to the antitumor activity of the anti- D, Talpur R. Results of a phase II trial of brentux-

Sintilimab for Relapsed/Refractory Extranodal NK/T-Cell Lymphoma: A Multicenter, Single-Arm, Phase 2 Trial (ORIENT-4)

he fully human antibody sin- center, Single Arm, Phase 2 Study) ENKTL received sintilimab, although tilimab targets programmed evaluated sintilimab in relapsed or the planned enrollment had allotted death 1 (PD-1) with high refractory extranodal NK/T-cell lym- for 60 patients. Tumor response was Taffinity and receptor occupancy.1-3 phoma (ENKTL).1 Sintilimab was evaluated with PET/CT and CT/mag- The single-arm phase 2 ORIENT-4 administered at 200 mg every 3 weeks netic resonance imaging (MRI) with trial (Efficacy and Safety Evaluation until disease progression, death, unac- contrast. After week 24, only CT/MRI of IBI308 in Patients With Relapsed/ ceptable toxicity, or withdrawal from with contrast was used. Refractory Extranodal NK/ the trial. At the time of data cutoff, The patients’ median age was Lymphoma, Nasal Type: A Multi- 28 patients with relapsed or refractory 39.8 years (range, 19-65 years). Most patients (60.7%) were male. The Eastern Cooperative Oncology Group (ECOG) performance status was 0 in 1 10.7%, 1 in 85.7%, and 2 in 3.6%. The median time from initial diag- nosis was 22.0 months. The median 0.75 number of prior lines of chemotherapy was 3.0, and 78.6% of patients had received prior radiotherapy. Two 0.50 patients (7.1%) had undergone prior autologous stem cell transplant (SCT). Disease was refractory to asparaginase- 0.25 HR, 0.170 based therapy in 12 patients (42.9%).

P=.016 Sixteen patients had relapsed disease (57.1%). Sintilimab showed clinical activity 0 2 4 6 8 10 12 14 16 18 among patients with relapsed or refrac- tory ENKTL. The ORR was 67.9% (95% CI, 47.6-84.1). Two patients (7.1%) had a CR, and 17 patients Figure 5. Overall survival according to bone marrow involvement among patients treated with sintilimab in the phase 2 ORIENT-4 trial. HR, hazard ratio; ORIENT-4, Efficacy and (60.7%) had a PR. The ORR included Safety Evaluation of IBI308 in Patients With Relapsed/Refractory Extranodal NK/T Cell 4 patients who developed pseudopro- Lymphoma, Nasal Type: A Multicenter, Single Arm, Phase 2 Study. Adapted from Tao R et gressive disease before their response. al. ASCO abstract 7504. J Clin Oncol. 2019;37(suppl 15).1 Stable disease occurred in 5 patients

Clinical Advances in Hematology & Oncology Volume 17, Issue 8, Supplement 14 August 2019 13 SPECIAL MEETING REVIEW EDITION

(17.9%), and disease progression was seen in 3 (10.7%). One patient was not 1 evaluable. The disease control rate of 85.7% included 5 patients who experi- enced pseudoprogressive disease before developing stable disease or responding to treatment. The study authors noted 0.9 that early disease progression did not correlate with poor outcome. The median time to response was P≤.05 P≤.01 P≤.001 1.3 months (range, 1.2-5.5), and the median duration of response was 4.1 0.8 months. A total of 19 patients were still receiving sintilimab at the time of the report. At a median follow-up of 15.4 months, the median overall sur- 0.7 vival (OS) was not reached. The 1-year rate of OS was 82.1%. A subgroup 0 6 15 24 36 48 (weeks) analysis showed that a superior ORR n= 28 27 25 20 19 19 was associated with Epstein-Barr virus negativity, absence of B symptoms, normal lactate dehydrogenase, and Figure 6. Quality of life according to the EQ-5D-5L Index among patients treated with negative bone marrow involvement sintilimab in the phase 2 ORIENT-4 trial. Quality of life was measured at baseline and (Figure 5). In a subgroup analysis, the at each subsequent evaluation of tumor response. EQ-5D-5L, European Quality of Life absence of bone marrow involvement 5-Dimensions; ORIENT-4, Efficacy and Safety Evaluation of IBI308 in Patients With was associated with a higher OS (HR, Relapsed/Refractory Extranodal NK/T Cell Lymphoma, Nasal Type: A Multicenter, Single 0.17; P=.016). No association with OS Arm, Phase 2 Study; SE, standard error. Adapted from Tao R et al. ASCO abstract 7504. J was seen with relapsed vs refractory Clin Oncol. 2019;37(suppl 15).1 disease (HR, 0.604; P=.557). Most treatment-related AEs were grade 1 or 2. There were no grade 4 References patients with advanced solid tumors [ASCO abstract 1. Tao R, Fan L, Song Y, et al. Sintilimab for relapsed/ e15125]. J Clin Oncol. 2018;36(suppl 15). or 5 treatment-related AEs. The most refractory (r/r) extranodal NK/T-cell lymphoma 3. Shi Y, Su H, Song Y, et al. Safety and activity of common all-grade treatment-related (ENKTL): a multicenter, single-arm, phase 2 trial sintilimab in patients with relapsed or refractory AEs were decreased lymphocyte count (ORIENT-4) [ASCO abstract 7504]. J Clin Oncol. classical Hodgkin lymphoma (ORIENT-1): a mul- 2019;37(suppl 15). ticentre, single-arm, phase 2 trial. Lancet Haematol. (46.4%) and fever (42.9%). The 2. Xu JM, Jia R, Wang Y, et al. A first-in-human phase 2019;6(1):e12-e19. patients’ quality of life significantly 1a trial of sintilimab (IBI308), a improved from baseline (Figure 6). targeting programmed death-1 (PD-1), in Chinese

Response to A+CHP by CD30 Expression in the ECHELON-2 Trial

he antibody-drug conjugate the association between response and and (CHP) was superior brentuximab vedotin selec- levels of CD30 expression is not con- to , doxorubicin, tively interacts with the CD30 firmed.1,4-6 , and prednisone (CHOP) in Tcell surface associated with In the phase 3 ECHELON-2 trial treatment-naive patients with CD30- some lymphoproliferative disorders.1,2 (A Comparison of Brentuximab Vedo- expressing PTCL.7 A follow-up analysis A component of brentuximab vedotin, tin and CHP With Standard-of-Care evaluated whether treatment response MMAE, exhibits antimitotic activity.3 CHOP in the Treatment of Patients was related to CD30 expression among However, brentuximab vedotin may With CD30-Positive Mature T-Cell patients with angioimmunoblastic also exert antitumor activity through Lymphomas), brentuximab vedotin T-cell lymphoma (AITL; n=29) additional mechanisms of action, and plus cyclophosphamide, dox­o­rubicin, or PTCL not otherwise specified

14 Clinical Advances in Hematology & Oncology Volume 17, Issue 8, Supplement 14 August 2019 HIGHLIGHTS IN LYMPHOMA FROM THE 2019 ASCO ANNUAL MEETING Patients

≤ Median > Median Ongoing Response

0 5 10 15 20 25 30 35 40 45 50 55 60 Duration of Complete Response (months)

Figure 7. Duration of complete response according to the level of CD30 expression among patients with AITL receiving brentuximab vedotin plus CHP in the phase 3 ECHELON-2 trial. AITL, angioimmunoblastic T-cell lymphoma; CHP, cyclophosphamide, doxorubicin, and prednisone; ECHELON-2, A Comparison of Brentuximab Vedotin and CHP With Standard-of-Care CHOP in the Treatment of Patients With CD30-Positive Mature T-Cell Lymphomas. Adapted from Advani RH et al. ASCO abstract 7538. J Clin Oncol. 2019;37(suppl 15).1

CD30 expression level was 41%, and their median level was 25%. ABSTRACT SUMMARY Cost-Effectiveness of Brentuximab Vedotin Patient responses to brentuximab With Chemotherapy in Frontline Treatment of CD30-Expressing vedotin plus CHP were broadly dis- Peripheral T-Cell Lymphoma tributed across the range of CD30 An analysis of the ECHELON-2 study evaluated the cost-effectiveness of CHOP expression levels. Among patients with and brentuximab vedotin plus CHP as initial treatment for CD30-expressing PTCL AITL who had achieved a CR, 8 had (Abstract e19060). Data from the ECHELON-2 study regarding PFS, postprogres- levels of CD30 expression above the sion survival, death, and European Quality of Life 5-Dimensions were analyzed median for AITL, and 8 had levels at in conjunction with medical resources and cost data derived from a search of the or below the median (P=.84; Figure 7). literature. Brentuximab vedotin plus CHP added 2.92 undiscounted years of PFS and Among the patients with lower expres- 3.38 years of OS compared with CHOP in the predictive model. An estimated 1.79 sion, 5 had a CD30 expression level of quality-adjusted life years were added using brentuximab vedotin plus CHP, with an 10%. Among patients with AITL who incremental cost-effectiveness ratio of $98,987. This ratio ranged from $64,000 to had a PR, 1 had a CD30 expression $154,000, depending on model parameters. The authors estimated a probability of level above the median, and 3 had 75% that brentuximab vedotin plus CHP was more cost-effective than CHOP, using a levels at or below the median. willingness-to-pay threshold of $150,000. Among patients with PTCL- NOS who achieved a CR, 8 had CD30 expression above the median for this subtype, and 10 had CD30 expres- (PTCL-NOS; n=28) who had received 90% had a CD30 expression level sion at or below the median (P=.44). brentuximab vedotin plus CHP.1 of 10% to 30%, with a mean level Four patients had a CD30 expression The level of CD30 expression was of 20% and a median of 18%. The level of 10%. PRs were reported in 2 measured with immunohistochemis- patients with PTCL-NOS had a wider patients with CD30 expression above try. Among the patients with AITL, range of CD30 expression. Their mean the median, and in 2 patients below

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the median (at 10% expression). The duration of CR appeared unrelated to ABSTRACT SUMMARY Sintilimab for Relapsed/Refractory Classical CD30 expression levels for both AITL Hodgkin Lymphoma: Extended Follow-Up on the Multicenter, (P=.30) and PTCL-NOS (P=.90). Single-Arm Phase II ORIENT-1 Study This analysis therefore suggested that levels of CD30 expression did not Sintilimab showed clinical activity in patients with relapsed/refractory classical correspond to response to treatment Hodgkin lymphoma in the phase 2 ORIENT-1 study (Shi Y et al. Lancet Haematol. 1 with brentuximab vedotin plus CHP. 2019;6[1]:e12-e19). The study authors presented extended follow-up results for CRs were reported even in patients 96 patients, 70 of whom were still receiving treatment at the time of the analysis with a CD30 expression of 10%. The (Abstract 7533). Sintilimab was given at 200 mg intravenously every 3 weeks for up study authors recommended evaluation to 24 months. The ORR was 85.4% (95% CI, 76.7%-91.8%), with 29.2% of patients of CD30 expression below 10%, a level showing a CR. The disease control rate was 97.9% (95% CI, 92.7%-99.7%), and 2.1% that was not assessed in this analysis. of patients developed progressive disease. The median PFS and median duration of response both had not been reached by the median follow-up of 14 months. References Treatment-related grade 3/4 AEs occurred in 26.0% of patients. The authors noted 1. Advani RH, Horwitz SM, Iyer SP, et al. Response to A+CHP by CD30 expression in the ECHELON-2 trial that the safety profile was similar to those of other monoclonal antibody anti–PD-1 [ASCO abstract 7538]. J Clin Oncol. 2019;37(suppl 15). therapies in classical Hodgkin lymphoma. 2. Sabattini E, Pizzi M, Tabanelli V, et al. CD30 expres- sion in peripheral T-cell lymphomas. Haematologica. 2013;98(8):e81-e82. 3. Sutherland MS, Sanderson RJ, Gordon KA, et al. Lysosomal trafficking and cysteine protease metabo- lism confer target-specific cytotoxicity by peptide- 5. Müller P, Martin K, Theurich S, et al. Microtubule- killing effects of antibody-drug conjugates in preclinical linked anti-CD30-auristatin conjugates. J Biol Chem. depolymerizing agents used in antibody-drug conju- models. Cancer Res. 2016;76(9):2710-2719. 2006;281(15):10540-10547. gates induce antitumor immunity by stimulation of 7. Horwitz S, O’Connor OA, Pro B, et al; ECHELON-2 Cancer Immunol Res 4. Oflazoglu E, Stone IJ, Gordon KA, et al. Macro- dendritic cells. . 2014;2(8):741- Study Group. Brentuximab vedotin with chemotherapy phages contribute to the antitumor activity of the anti- 755. for CD30-positive peripheral T-cell lymphoma (ECH- CD30 antibody SGN-30. Blood. 2007;110(13):4370- 6. Li F, Emmerton KK, Jonas M, et al. Intracellular ELON-2): a global, double-blind, randomised, phase 3 4372. released payload influences potency and bystander- trial. Lancet. 2019;393(10168):229-240.

Polatuzumab Vedotin + Obinutuzumab and Lenalidomide in Patients With Relapsed/Refractory Follicular Lymphoma: Interim Analysis of a Phase Ib/II Trial

olatuzumab vedotin is a first- escalating doses of polatuzumab vedo- istered on a 28-day cycle for up to in-class antibody-drug conju- tin at 1.4 mg/kg or 1.8 mg/kg and 1 year) and obinutuzumab (admin- gate that targets CD79b, which lenalidomide at 10 mg, 15 mg, or 20 istered every 2 months for up to 24 Pis expressed in follicular lymphoma mg. Obinutuzumab was administered months). and diffuse large B-cell lymphoma at a standard fixed dose of 1000 mg. The trial enrolled patients ages 18 (DLBCL).1 After polatuzumab vedo- The recommended phase 2 doses were years or older with relapsed or refrac- tin binds to CD79b on tumor cells, 20 mg of lenalidomide and 1.4 mg/kg tory follicular lymphoma of grades it is internalized. It then disrupts of polatuzumab vedotin. 1 to 3a. Patients had histologically cellular division, triggering . In both phases, all patients ini- confirmed CD20-positive tumors and Dr Catherine Diefenbach and col- tially received induction treatment 1 or more bidimensionally measurable leagues presented an interim analysis consisting of 6 cycles of polatuzumab lesions reaching at least 1.5 cm in 1 of an open-label, single-arm phase vedotin, obinutuzumab, and lenalido- direction. They had an ECOG per- 1b/2 trial of polatuzumab vedotin mide. The primary efficacy endpoint formance status of 0 to 2. Exclusion plus obinutuzumab and lenalido- was CR at the end of induction, criteria were 3b disease; previous allo- mide in patients with relapsed or as assessed by independent review. geneic SCT transplant; relapse within refractory follicular lymphoma. The Patients with a CR, PR, or stable 100 days of autologous SCT; periph- patients were initially enrolled in a disease could receive maintenance eral neuropathy of grade 2 or higher; dose-escalation cohort.2 They received treatment with lenalidomide (admin- resistance to lenalidomide; insufficient

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0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25

Figure 8. Duration of response among patients with relapsed or refractory follicular lymphoma treated with polatuzumab vedotin plus obinutuzumab and lenalidomide in a phase 1b/2 trial. CR, complete response; PD, progressive disease; PR, partial response. Adapted from Diefenbach C et al. ASCO abstract 7505. J Clin Oncol. 2019;37(suppl 15).2 hematologic, renal, or hepatic func- Lugano criteria and 78% by Lugano neutropenia (52%), thrombocyto- tion; or a positive test for hepatitis. 2014 criteria. The study authors attrib- penia (37%), infusion-related reac- The interim analysis population uted this discrepancy to 3 patients with tion (35%), pyrexia (35%), anemia consisted of 52 patients who had bone marrow–positive disease who had (33%), diarrhea (29%), and rash completed induction therapy and PET/CT results that were negative at (21%). Peripheral neuropathy was were evaluable for safety. In the dose- the end of induction, but then did reported in 17% of patients, but all escalation portion, 16 patients received not undergo follow-up bone marrow cases were grade 1 to 2 and reversible. treatment at the phase 2 dose. In the assessment. According to the modi- The most common grade 3/4 AE was dose-expansion portion, 36 patients fied Lugano criteria, these patients neutropenia, occurring in 46% of the were treated at the phase 2 dose. are considered CR unconfirmed and safety population. Febrile neutropenia Among the patients treated at the categorized as PRs. An additional 6% occurred in 4% of patients. In 31% of recommended phase 2 dose, 18 were of patients had stable disease. patients, an AE required a reduction in evaluable for efficacy. At a median duration of follow-up the dose of lenalidomide. Treatment The patients’ median age was 58 of 16.6 months, the median PFS was with lenalidomide was interrupted in years in the efficacy population and 62 not reached (Figure 8). The 12-month 52% of patients and discontinued in years in the safety population. These PFS rate was 90%. Among the 17 15% owing to AEs. patients were heavily pretreated; at least responders, 2 patients developed dis- 3 prior lines of therapy were reported ease progression. References by 61% of the efficacy population and In the safety population, grade 3 1. Polson AG, Yu SF, Elkins K, et al. Antibody-drug conjugates targeted to CD79 for the treatment of non- 58% of the safety population. In each to 4 AEs occurred in 75% of patients. Hodgkin lymphoma. Blood. 2007;110(2):616-623. population, 50% of patients were refrac- Most of these events consisted of 2. Diefenbach C, Kahl B, Banerjee L, et al. Polatu- tory to their most recent prior therapy. myelosuppression, particularly neu- zumab vedotin (pola) + obinutuzumab (G) and lenalid- omide (len) in patients (pts) with relapsed/refractory The ORR for the efficacy popula- tropenia. Serious AEs were reported in (R/R) follicular lymphoma (FL): interim analysis of a tion was 89%.2 The CR by indepen- 40% of patients. The most common phase Ib/II trial [ASCO abstract 7505]. J Clin Oncol. dent review was 67% by modified all-grade AEs were infection (56%), 2019;37(suppl 15).

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First-Line Therapy of T-Cell Lymphoma: Allogeneic or Autologous Transplantation for Consolidation—Final Results of the AATT Study

he prospective, randomized large-cell lymphoma in 14%. The was reported in 61% of patients. An AATT trial (Autologous or remaining patients had enteropathy ECOG performance status of higher Allogeneic Transplantation in type T-cell lymphoma, hepatosplenic than 1 was seen in 20% of patients, T-CellT Lymphoma) evaluated clinical T-cell lymphoma, and subcutaneous stage III/IV disease was reported in outcomes in patients with T-cell lym- panniculitis-type T-cell lymphoma. 88%, and 61% had more than 1 extra- phoma who underwent autologous The hypothesis was that allogeneic nodal site of disease. SCT or allogeneic SCT as consolida- SCT would improve 3-year event-free A total of 65% of patients com- tion therapy. Dr Norbert Schmitz pre- survival from 35% to 60%. The trial pleted the study as per protocol (63% sented the results.1 The trial recruited design designated enrollment of 140 of the autologous SCT arm and 67% more than 100 patients from 44 sites in patients to detect an alpha of 5% with of the allogeneic SCT arm). Fifty-eight Germany and France to receive front- 80% power. A planned interim analy- patients underwent SCT. Among the line chemotherapy and subsequent sis showed a probability of approxi- patients who left the study before SCT, consolidation with autologous SCT mately 10% to detect a difference of 28% did so because of progressive or allogeneic SCT. Patients who were 25% in event-free survival, so a data disease. Notably, 7 patients randomly randomly assigned to autologous SCT safety monitoring committee stopped assigned to allogeneic SCT underwent underwent peripheral blood stem cell the study after accrual of 104 patients.2 an autograft transplant. Six of these harvest. The study enrolled patients Among the 54 patients in the patients lacked a fully matched donor, ages 18 to 60 years, with an ECOG autologous SCT arm, 57% were and the allogeneic SCT arm was closed performance status between 0 and male. The allogeneic SCT arm had 49 before 1 patient could undergo the 3. The most common types of T-cell patients, 69% of whom were male.1 procedure. lymphoma included AITL in 38%, The median age across both treatment The 3-year rate of event-free sur- PTCL-NOS in 29%, and anaplastic arms was 50 years (range, 24-60 years). vival was 38% in the autologous SCT lymphoma kinase–negative anaplastic An elevated lactate dehydrogenase level arm and 43% in the allogeneic SCT

1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3

0.2 =.583 0.1 0.0 0 10 20 30 40 50 60 70 80 30 26 22 9 5 1 1 0 28 24 22 15 8 3 0 0

Figure 9. Event-free survival among patients with T-cell lymphoma treated with CHOEP followed by autologous or allogeneic SCT in the AATT trial. AATT, Autologous or Allogeneic Transplantation in T-Cell Lymphoma; alloSCT, allogeneic stem cell transplant; autoSCT, autologous stem cell transplant; CHOEP, cyclophosphamide, doxorubicin, etoposide, vincristine, and prednisone; SCT, stem cell transplant. Adapted from Schmitz N et al. ASCO abstract 7503. J Clin Oncol. 2019;37(suppl 15).1

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arm, a difference that was not signifi- difference might be attributed to the with rates of 17% in the autologous cant (P=.583; Figure 9).1 Among the fact that one-third of the patients ran- arm and 8% in the allogeneic arm. patients who underwent transplant, domly assigned to treatment could not In the ITT population, death from the 3-year event-free survival rate was proceed to SCT, in most cases because lymphoma was reported in 13 patients 61% in the autologous SCT arm and of refractory disease or early relapse. vs 11 patients, respectively. Among 65% in the allogeneic SCT arm, a Significant differences in clinical out- the 58 patients who underwent SCT, difference that was also not significant come might have been observed had deaths occurred in 8 patients in the (P=.430). Although no significant dif- the analysis been limited to patients autologous group and 9 patients in the ferences were observed, Dr Schmitz who had undergone SCT. The rate of allogeneic group. noted that the Kaplan-Meier curve for 3-year OS was significantly improved References the patients who underwent allogeneic among patients with an International 1. Schmitz N, Truemper L, Ziepert M, et al. First-line SCT appeared more stable. Prognostic Index score of 0 or 1 vs a therapy of T-cell lymphoma: allogeneic or autologous Among the ITT cohort (n=103), score of 2 or 3 (P=.012). transplantation for consolidation—final results of the AATT study [ASCO abstract 7503]. J Clin Oncol. the rate of 3-year OS was 70% with Across the entire trial, the rate of 2019;37(suppl 15). autologous SCT and 57% with alloge- CR/unconfirmed CR was 45%. This 2. Schmitz N, Nickelsen M, Altmann B, et al. Alloge- neic SCT, which was not significantly rate was 39% in the autologous SCT neic or autologous transplantation as first-line therapy 1 for younger patients with peripheral T-cell lymphoma: different (P=.408). Dr Schmitz sug- arm and 51% in the allogeneic SCT results of the interim analysis of the AATT trial [ASCO gested that this lack of a significant arm. The overall rate of PR was 13%, abstract 7503]. J Clin Oncol. 2015;33(suppl 15).

Lisocabtagene Maraleucel (Liso-Cel) Treatment of Patients With Relapsed/Refractory B-Cell Non-Hodgkin Lymphoma and Secondary CNS Lymphoma: Initial Results From TRANSCEND NHL 001

he safety and efficacy of liso- enrolled patients with relapsed or Following lymphodepletion, pat­ cabtagene maraleucel were refractory NHL with secondary central ients were treated with lisocabtagene investigated in the phase 1 nervous system lymphoma. They had maraleucel at 50 × 106 CAR+ T cells TTRANSCEND-NHL-001 trial (Study either DLBCL (n=8) treated with at (n=3) or 100 × 106 CAR+ T cells (n=6). Evaluating the Safety and Pharmaco- least 2 prior therapies, or mantle cell The study permitted a second dose of kinetics of JCAR017 in B-Cell Non- lymphoma (n=1) treated with at least treatment for patients who developed Hodgkin Lymphoma).1 The study 1 prior therapy. progressive disease after an initial CR.

Table 1. Summary of Efficacy Among Patients Treated With Lisocabtagene Maraleucel

Initial Lisocabtagene Retreatmenta,b All Patients With Patients With Maraleucel Infusiona (n= 6) (n=2) DLBCL (n=8) MCL (n=1)c Best ORR,d n 4 0 4 0 Best CR rate, n 4 0 4 0 Time to CR, median (range) 1.4 (0.9-8.7) NA 1.4 (0.9-8.7) NA PFS, median (95% CI), months 2.9 (0.2-NR) NA 2.9 (0.2-NR) NA OS, median (95% CI), months 10.7 (0.5-NR) NA 10.7 (0.5-NR) NA Follow-up, median, months (95% CI) 24.1 (12.3-24.1) NA 24.1 (12.3-24.1) NA Patients still in response, n 2 0 2 0 Patient deaths (disease progression), n 4 2 6 0 aIncludes only patients with DLBCL. bRetreatment was defined as a second dose of lisocabtagene maraleucel given to patients who achieved a complete response after the first dose of lisocabtagene maraleucel, but who later progressed.c Best response was stable disease. dBest ORR was considered the response to the dose of lisocabtagene maraleucel that was administered after secondary CNS lymphoma was diagnosed. CNS, central nervous system; CR, complete response; DLBCL, diffuse large B-cell lymphoma; MCL, mantle cell lymphoma; NA, not available; NR, not reached; ORR, overall response rate; OS, overall survival; PFS, progression-free survival. Adapted from Abramson JS et al. ASCO abstract 7515. J Clin Oncol. 2019;37(18 suppl).1

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The patients’ median age was 60 The median follow-up was 24.1 lisocabtagene maraleucel, and in the 2 years, and they had received a median months (95% CI, 12.3-24.1) for the 6 patients who received a second course of 3 lines of prior therapy.1 The time to patients with DLBCL receiving initial of treatment. All patients in this study peak CAR+ T-cell expansion occurred lisocabtagene maraleucel. The median developed treatment-emergent AEs, at a median of 11 days (range, 7-112). PFS for these patients was 2.9 months and these events were grade 3 or 4 in Among the 6 patients with DLBCL (95% CI, 0.2 to not reached; Table most cases. No dose-limiting toxicities who received only 1 dose of liso- 1). The median OS was 10.7 months occurred, and no patients died from cabtagene maraleucel, best responses (95% CI, 0.5 to not reached). Two treatment-related causes. included a CR in 4 and progressive patients were still in response at the Reference disease in 2. Two patients received time of the analysis. For the patient 1. Abramson JS, Palomba ML, Arnason JE, et al. Liso- an additional dose of lisocabtagene with mantle cell lymphoma, the best cabtagene maraleucel (liso-cel) treatment of patients maraleucel after progressive disease. response was stable disease. (pts) with relapsed/refractory (R/R) B-cell non-Hodg- kin lymphoma (NHL) and secondary CNS lymphoma: The second dose did not lead to an Death from disease progression initial results from TRANSCEND NHL 001 [ASCO additional response. occurred in 4 patients receiving initial abstract 7515]. J Clin Oncol. 2019;37(suppl 15).

Rituximab Maintenance for Patients With Diffuse Large B-Cell Lymphoma in First Complete Remission: Results From a Randomized HOVON-Nordic Lymphoma Group Phase III Study

n the phase 3 HOVON 84 NHL given every 8 weeks for 12 doses or the maintenance stage of the trial was trial (Randomized Phase III Study until relapse (n=191).1,2 In the ritux- disease-free survival (DFS), based on on the Effect of Early Intensifica- imab maintenance arm, 6 enrolled either relapse or death, measured from tionI of Rituximab in Combination patients went off-protocol before treat- the time of randomization to mainte- With 2-Weekly CHOP Chemotherapy ment began. The primary endpoint of nance or observation. Followed by Rituximab Maintenance in Elderly Patients [66-80 Years] With 100 Diffuse Large B-Cell Lymphoma), maintenance with rituximab did not provide an advantage vs observation following induction therapy with 75 rituximab plus CHOP (R-CHOP) in patients with DLBCL.1 The trial consisted of 2 stages. The first exam- 50 ined rituximab intensification during induction therapy, and showed no ben- efit in CR or PFS with this approach compared with standard R-CHOP 25 Observation 195 61 induction therapy.1-3 Throughout the Maintenance 191 55 induction stage, the 3-year and 5-year Cox LR =.31 (adjusted) rates of PFS did not differ substantially 0 between the treatments. OS also did 0 24 48 72 96 not differ between the treatment arms, and no subgroups benefited from 195 166 147 108 17 rituximab intensification. 191 171 153 102 14 The patients in the maintenance stage of the trial had been in a CR Figure 10. Disease-free survival among patients with DLBCL who received rituximab for at least 4 weeks following their maintenance or underwent observation in the phase 3 HOVON 84 NHL trial. DLBCL, 1 last cycle of R-CHOP. Patients in diffuse large B-cell lymphoma; HOVON 84, Randomized Phase III Study on the Effect of the maintenance stage were randomly Early Intensification of Rituximab in Combination With 2-Weekly CHOP Chemotherapy assigned to an observation arm with no Followed by Rituximab Maintenance in Elderly Patients (66-80 Years) With Diffuse Large therapy (n=195) or a maintenance arm B-Cell Lymphoma; LR, likelihood ratio. Adapted from Lugtenburg EJ et al. ASCO abstract consisting of intravenous rituximab 7507. J Clin Oncol. 2019;37(suppl 15).1

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Patients received rituximab main- maintenance improved DFS. The rate considered potentially related to the tenance for a median of 22.5 months. of OS was similar for patients receiving study in 15 patients. At a median follow-up of 79.9 months, rituximab maintenance or observa- the median DFS was not reached. The tion (HR, 0.87; 95% CI, 0.57-1.31; References 5-year rate of DFS was 79% in patients P=.50).1 However, the rate of 5-year 1. Lugtenburg EJ, de Nully Brown P, van der Holt B, et al. Rituximab maintenance for patients with diffuse receiving rituximab maintenance vs OS among patients in first CR after large B-cell lymphoma in first complete remission: 74% in those undergoing observation R-CHOP was high, at 84%. results from a randomized HOVON-Nordic Lym- (HR, 0.83; 95% CI, 0.57-1.19; P=.31; A total of 149 patients (81%) phoma Group phase III study [ASCO abstract 7507]. J Clin Oncol. 2019;37(suppl 15). Figure 10). Based on competing risk completed maintenance therapy with 2. Netherlands Trial Register. Trial NL986 (NTR1014). regression analysis, there were also no rituximab. Most treatment discon- https://www.trialregister.nl/trial/986. Accessed July 1, 2019. significant differences in time to relapse tinuations were in response to toxicity 3. Lugtenburg PJ, de Nully Brown P, van der Holt 1 B, et al. Randomized phase III study on the effect of (HR, 0.82; 95% CI, 0.52-1.31; P=.42) (n=15) or relapse (n=14). Grade 3/4 early intensification of rituximab in combination with or time to death (HR, 0.87; 95% CI, AEs occurred in 23% of patients who 2-weekly CHOP chemotherapy followed by rituximab 0.48-1.59; P=.66) between the study received rituximab maintenance.1 Seri- or no maintenance in patients with diffuse large B-cell lymphoma: results from a HOVON-Nordic Lym- arms. Univariate analyses revealed no ous AEs occurred in 36 patients receiv- phoma Group study [ASCO abstract 7504]. J Clin patient subgroups in which rituximab ing rituximab (19%); these events were Oncol. 2016;34(suppl 15).

Highlights in Lymphoma From the 2019 American Society of Clinical Oncology Annual Meeting: Commentary

Alex F. Herrera, MD

t the 2019 American Society or use of subsequent anticancer therapy a strategy used in the S0816 study and of Clinical Oncology annual following less than a complete response. the RATHL trial.3,4 An appealing aspect meeting, several presentations The 3-year analysis also evaluated PFS of using A+AVD is that it obviates the providedA insight into the management according to whether the patient’s posi- need for dose escalation to BEACOPP, of a range of lymphomas, including tron emission tomography (PET) scan which is a regimen that can be associ- non-Hodgkin (NHL) and Hodgkin was positive or negative. The important ated with myelosuppression, infertility, lymphomas. Studies were presented overall conclusion from the 3-year and secondary malignancies. on stem cell transplant, as well as analysis is that remissions obtained with The ECHELON-2 trial showed novel therapies, including antibody- A+AVD appeared to be durable. At 2 a superior outcome with the combi- drug conjugates, such as brentuximab years, the rate of PFS was 84%, com- nation of brentuximab vedotin plus vedotin and polatuzumab vedotin; pared with 83.1% at 3 years. There were cyclophosphamide, doxorubicin, and targeted therapies, such as umbralisib few PFS events during the most recent prednisone as compared with cyclo- and ibrutinib; and immunotherapies, year of follow-up. Among patients with phosphamide, doxorubicin, vincristine, such as sintilimab. a negative PET scan at the end of cycle and prednisone (CHOP).5 Dr Ranjana 2 (PET2), the 3-year PFS was 87.2%. Advani and colleagues analyzed data Brentuximab Vedotin A striking finding was that among from this trial to determine the asso- Dr David Straus presented a 3-year patients who were PET2-positive and ciation between response and degree follow-up analysis of the ECHELON-1 young (<60 years), 3-year traditional of CD30-positivity in patients with study.1 This study compared bren- PFS was 69.2% in those who continued angioimmunoblastic T-cell lymphoma tuximab vedotin plus doxorubicin, with A+AVD vs 54.7% among those or peripheral T-cell lymphoma (PTCL) vinblastine, and dacarbazine (A+AVD) treated with ABVD. The data from not otherwise specified.6 The ECH- vs doxorubicin, bleomycin, vinblas- this PET2 analysis are compelling. The ELON-2 study enrolled patients with tine, and dacarbazine (ABVD) among outcomes seen with continuation of CD30 expression of 10% or higher. In patients with advanced-stage Hodgkin A+AVD compare favorably with those the analysis by Dr Advani, patients were lymphoma.2 The current analysis evalu- reported when treatment is changed stratified according to whether their ated standard progression-free survival to escalated bleomycin, etoposide, level of CD30 expression was above or (PFS), as opposed to the modified PFS doxorubicin, cyclophosphamide, vin- below the median. that was the primary endpoint of the cristine, procarbazine, and prednisone A previous study of patients with original study. Modified PFS encom- (escBEACOPP) in patients with a posi- relapsed or refractory T-cell lymphoma passed the time to progression, death, tive PET2 scan after 2 cycles of ABVD, showed that CD30 expression did not

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correspond to response.7 The study cell lymphoma (ENKTL).10 This study plus obinutuzumab was effective in by Dr Advani confirmed this find- was performed in Asia, where the patients with follicular lymphoma.15 ing, showing no association between incidence of ENKTL is much higher In the study by Dr Diefenbach, most response and degree of CD30 expres- than in the West. In smaller prelimi- patients had advanced-stage disease, sion.6 These data suggest that patients nary studies, the anti–PD-1 antibody had received 3 or more prior lines of with CD30 expression of 10% or was associated with treatment, and were refractory to their higher should receive brentuximab response rates of 57% to 100%.11,12 most recent prior therapy.13 vedotin, regardless of the degree of This larger study enrolled 28 patients Among the 18 patients treated, CD30 expression. who had received a median of 3 lines the early data on efficacy were promis- of prior therapy. All patients had ing, with a complete response rate of Novel Treatments and received previous treatment with an 78% and an overall response rate of Regimens L-asparaginase–containing regimen. 89% according to the 2014 Lugano Traditionally, treatments for patients ENKTL is an aggressive disease, and classification.13 After a median follow- with marginal zone lymphoma (MZL) patients with relapsed or refractory dis- up of 16 months, 2 of 17 patients who have been limited to standard che- ease traditionally have a poor progno- responded to treatment had developed motherapies. Several novel therapies sis. In the study by Dr Tao, the overall disease progression. The 12-month have been evaluated for patients with response rate in patients with relapsed/ rate of PFS was 90%. These data are MZL. The US Food and Drug Admin- refractory ENKTL was 68%, which is preliminary, but promising for a group istration recently approved the Bruton a promising outcome in this high-risk of patients who were mostly refractory tyrosine kinase (BTK) inhibitor ibru- population.10 The disease control rate to their last treatment and had received tinib for relapsed/refractory disease was 86%. The rate of 1-year overall a median of 3 prior lines of therapy. and lenalidomide combined with survival was 82%, and the median The combination regimen did not rituximab for previously treated MZL. overall survival was not reached. As a show any unexpected safety signals. A study by Dr Felipe Samaniego comparison, the study authors cited a The most common side effects were and coworkers evaluated the phos- median overall survival of 4.8 months neutropenia and thrombocytopenia, phoinositide 3-kinase (PI3K) inhibitor in a retrospective Chinese study of which were expected because lenalido- umbralisib in relapsed or refractory 46 patients with relapsed/refractory mide and polatuzumab vedotin are MZL.8 Most patients had received ENKTL treated with various standard each associated with cytopenias. Infec- prior chemoimmunotherapy. Accord- salvage chemotherapy regimens.10 In tions were relatively common. There ing to an independent review com- the study by Dr Tao, benefits were were some gastrointestinal toxicities, mittee, umbralisib produced an overall more pronounced among patients with including diarrhea. Infusion-related response rate of 52%. Stable disease nodal disease, rather than bone mar- reactions were seen, as would be was reported in 36% of patients. row involvement, with excellent sur- expected with obinutuzumab. Grade Investigator assessment of the interim vival in this subgroup. The side effect 3 or 4 adverse events were primarily efficacy population found that the esti- profile of sintilimab was consistent hematologic; neutropenia was the mated 12-month PFS was 66%. with that of other anti–PD-1 antibod- most common. Overall, umbralisib appeared to ies. This larger study confirmed that Dr Jason Westin presented results have activity in MZL, and the treat- most patients with relapsed/refractory of the Smart Start study, which evalu- ment was well tolerated. There was ENKTL respond to PD-1 blockade. ated lead-in treatment with rituximab, some gastrointestinal toxicity, includ- A study presented by Dr Cath- lenalidomide, and ibrutinib, follow- ing diarrhea and nausea, as well as erine Diefenbach evaluated polatu- ing by administration of this triplet mild myelosuppression. The options zumab vedotin, obinutuzumab, and in combination with chemotherapy, for MZL are expanding beyond stan- lenalidomide in patients with relapsed among patients with newly diagnosed dard chemoimmunotherapy to include or refractory follicular lymphoma.13 non–germinal center B-cell subtype BTK inhibitors and now, potentially, Lenalidomide is an effective therapy for (non-GCB) diffuse large B-cell lym- PI3K inhibitors. the treatment of patients with previ- phoma (DLBCL).16 Patients with non- Sintilimab is an anti–programmed ously untreated or relapsed/refractory GCB DLBCL typically have poorer death 1 (PD-1) antibody developed follicular lymphoma. A recent study outcomes after standard R-CHOP in China, where it was approved showed similar outcomes with first- treatment. The response rate after the for Hodgkin lymphoma in 2018. line chemoimmunotherapy vs ritux- lead-in period with the triplet of ritux- Anti–PD-1 are effective in imab plus lenalidomide in the first-line imab, lenalidomide, and ibrutinib was natural killer/T-cell lymphomas.9 A treatment of follicular lymphoma.14 86%, with a complete response rate of study from Dr Rong Tao evaluated sin- Studies have also demonstrated that nearly 40%. At the end of treatment tilimab in extranodal natural killer/T- the combination of lenalidomide with the triplet plus chemotherapy,

22 Clinical Advances in Hematology & Oncology Volume 17, Issue 8, Supplement 14 August 2019 HIGHLIGHTS IN LYMPHOMA FROM THE 2019 ASCO ANNUAL MEETING

among 49 evaluable patients, the com- treatment. An important issue with chemotherapy for stage III or IV Hodgkin’s lymphoma. plete response rate was 96%, which is this study concerns the selection N Engl J Med. 2018;378(4):331-344. 3. Johnson P, Federico M, Kirkwood A, et al. very high for patients with non-GCB of myeloablative conditioning for Adapted treatment guided by interim PET-CT scan DLBCL. Among the 19 patients with the patients undergoing allogeneic in advanced Hodgkin’s lymphoma. N Engl J Med. double-expresser DLBCL, PFS was stem cell transplant. In recent years, 2016;374(25):2419-2429. 4. Press OW, Li H, Schöder H, et al. US Intergroup 94% at 1 year. reduced-intensity conditioning has Trial of response-adapted therapy for stage III to IV After 1 year of follow-up, there been increasingly utilized in patients Hodgkin lymphoma using early interim fluorode- were 3 progression events. More time with NHL. Rates of event-free sur- oxyglucose-positron emission tomography imaging: Southwest Oncology Group S0816. J Clin Oncol. will be needed to assess the long-term vival were similar between the arms 2016;34(17):2020-2027. durability of the excellent responses in the intention-to-treat population. 5. Horwitz S, O’Connor OA, Pro B, et al. Brentux- to this regimen. One patient who had Among the patients who underwent imab vedotin with chemotherapy for CD30-positive peripheral T-cell lymphoma (ECHELON-2): a global, received corticosteroids before starting transplant, there was no statistically double-blind, randomised, phase 3 trial. Lancet. the triplet lead-in regimen developed significant difference in the rates of 2019;393(10168):229-240. central nervous system aspergillosis. A event-free survival or overall survival 6. Advani RH, Horwitz SM, Iyer SP, et al. Response to A+CHP by CD30 expression in the ECHELON-2 trial study amendment then prohibited the between the treatments. Transplant- [ASCO abstract 7538]. J Clin Oncol. 2019;37(suppl 15). prephase use of corticosteroids, and related mortality reached 16% in the 7. Horwitz SM, Advani RH, Bartlett N, et al. Objective no other fungal infections were seen. allogeneic transplant arm vs 0% in responses in relapsed T-cell lymphomas with single- agent brentuximab vedotin. Blood. 2014;123(20):3095- There were no major toxicity signals, the autologous arm. The number of 3100. aside from rash, which is known to deaths from lymphoma was similar in 8. Fowler NH, Samaniego F, Jurczak W, et al. Umbral- occur with the combination of lenalid- both groups. There were more cases isib monotherapy demonstrates efficacy and safety in patients with relapsed/refractory marginal zone lym- omide and ibrutinib. There was a of relapsed disease in the autologous phoma: a multicenter, open label, registration directed reasonably high rate of grade 4 neutro- group vs the allogeneic group, but this phase II study [ASCO abstract 7506]. J Clin Oncol. penia, which could be expected given difference was mitigated by the higher 2019;37(suppl 15). 9. Kwong Y-L, Chan TSY, Tan D, et al. PD1 blockade that chemotherapy was combined with rates of transplant-related morbidity with pembrolizumab is highly effective in relapsed or lenalidomide and ibrutinib, which are and mortality in the allogeneic trans- refractory NK/T-cell lymphoma failing L-asparaginase. both associated with myelosuppres- plant group. For patients with PTCL Blood. 2017;129(17):2437-2442. 10. Tao R, Fan L, Song Y, et al. Sintilimab for relapsed/ sion. Febrile neutropenia occurred in who respond to initial therapy, the refractory (r/r) extranodal NK/T-cell lymphoma nearly one-quarter of patients, a higher typical treatment has been consolida- (ENKTL): a multicenter, single-arm, phase 2 trial rate than might be expected with tive autologous stem-cell transplant in (ORIENT-4) [ASCO abstract 7504]. J Clin Oncol. 2019;37(suppl 15). standard chemotherapy. Therefore, patients who achieved a first response. 11. Kwong YL, Chan TSY, Tan D, et al. PD1 blockade the promising outcomes corresponded This study confirmed this practice, with pembrolizumab is highly effective in relapsed or to some degree of increased toxicity. showing that the morbidity and mor- refractory NK/T-cell lymphoma failing l-asparaginase. Blood. 2017;129(17):2437-2442. However, these results are extremely tality associated with allogeneic stem- 12. Li X, Cheng Y, Zhang M, et al. Activity of pembro- promising, and they could potentially cell transplant are unacceptably high, lizumab in relapsed/refractory NK/T-cell lymphoma. J inform the design of a larger, more without a concomitant improvement Hematol Oncol. 2018;11(1):15. 13. Diefenbach C, Kahl B, Banerjee L, et al. Polatu- definitive study. Results from longer- in outcomes in this setting. zumab vedotin (pola) + obinutuzumab (G) and lenalid- term follow-up are eagerly awaited. omide (len) in patients (pts) with relapsed/refractory Disclosure (R/R) follicular lymphoma (FL): interim analysis of a phase Ib/II trial [ASCO abstract 7505]. J Clin Oncol. Allogeneic vs Autologous Dr Herrera is a consultant for Bristol- 2019;37(suppl 15). Transplant Myers Squibb, , Merck & Co, 14. Morschhauser F, Fowler NH, Feugier P, et al; REL- A randomized study presented by Dr Kite Pharma/Gilead, Seattle Genetics, EVANCE Trial Investigators. Rituximab plus lenalido- mide in advanced untreated follicular lymphoma. N Norbert Schmitz compared allogeneic and Adaptive Biotechnologies. Dr Her- Engl J Med. 2018;379(10):934-947. vs autologous transplant as frontline rera has received research funding/grants 15. Fowler NH, Neelapu SS, Samaniego F, et al. Activ- therapy for younger patients with from Genentech, Bristol-Myers Squibb, ity of the immunologic doublet of lenalidomide plus obinutuzumab in relapsed follicular lymphoma: results PTCL, a lymphoma subtype associ- Immune Design, AstraZeneca, Merck of a phase I/II study [ASCO abstract 7531]. J Clin ated with a poor prognosis.17 Patients & Co, Pharma­cyclics, Seattle Genetics, Oncol. 2017;35(suppl 15). first received 4 cycles of CHOP plus Kite Pharma, and Gilead Sciences. 16. Westin J, Nastoupil LJ, Fayad L, et al. Smart Start: final results of rituximab, lenalidomide, and ibrutinib etoposide. They then received 1 cycle lead in prior to combination with chemotherapy for of dexamethasone, cytarabine, and References patients with newly diagnosed diffuse large B-cell cisplatin. Patients who were randomly 1. Straus DJ, Długosz-Danecka M, Alekseev S, et al. lymphoma [ASCO abstract 7508]. J Clin Oncol. Brentuximab vedotin with chemotherapy for stage 3/4 2019;37(suppl 15). assigned to autologous transplant classical Hodgkin lymphoma: three-year update of the 17. Shmitz N, Nickelsen M, Altmann B, et al. Alloge- underwent harvesting for stem cells. ECHELON-1 study [ASCO abstract 7532]. J Clin neic or autologous transplantation as first-line therapy Patients who were randomly assigned Oncol. 2019;37(suppl 15). for younger patients with peripheral T-cell lymphoma: 2. Connors JM, Jurczak W, Straus DJ, et al; ECH- results of the interim analysis of the AATT trial [ASCO to allogeneic transplant proceeded to ELON-1 Study Group. Brentuximab vedotin with abstract 7503]. J Clin Oncol. 2015;33(suppl 15).

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