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Therapeutic Apheresis for Patients with Cancer Laura S

Therapeutic Apheresis for Patients with Cancer Laura S

Therapeutic is an important

treatment modality frequently used to

manage specific complications in patients

with underlying malignant disease.

Ray Paul. Dark Shadows, 2010. Acrylic, latex, enamel on canvas, 30" × 30".

Therapeutic Apheresis for Patients With Cancer Laura S. Connelly-Smith, MBBCh, DM, and Michael L. Linenberger, MD

Background: Disease complications associated with certain malignancies may be mediated by cells or soluble molecules that traffic in the bloodstream. Because of this, therapeutic apheresis (TA) methodologies have been used to selectively remove or manipulate specific molecules, antibodies, or cellular elements to treat the underlying pathological process. For some disorders, TA is utilized as a rapid-acting and short-term adjunct to conventional chemotherapy or immunotherapy. For others, a series of scheduled treatments is recommended for optimal management. In all cases, the risks, benefits, and costs must be strongly considered. Methods: The current literature and published guidelines were reviewed to summarize the use of TA in the management of certain complications of cancer. Results: Although TA is relatively safe and useful as a first-line or salvage modality for some disorders, few prospective, randomized clinical trials exist and the majority of evidence is derived from observational studies. Expert-based, clinical practice guidelines have been developed to inform /oncology professionals and apheresis physicians about the efficacy and limitations of TA for malignancy-related indications. Conclusions: Certain oncological conditions respond to TA and consensus guidelines are available to support clinical decision-making. However, well-designed, prospective intervention trials are needed to better define the role of TA for a variety of disorders.

Introduction In general, TA is a relatively safe procedure; however, Therapeutic apheresis (TA) is used to treat certain insufficient clinical evidence to support the econom- disease complications in patients with cancer with ic cost of TA can be a limitation to its use for some the intention of removing or manipulating a specific conditions. Evidence-based clinical practice guidelines molecule, antibody, or cellular element thought to be have been developed and periodically updated by the contributing to the underlying pathological process. American Society for Apheresis (ASFA) to help sup- port the decision making of health care professionals regarding the use of TA.1 From the Seattle Cancer Care Alliance (LSC-S, MLL), the Division of In this article, we provide a brief overview of TA Hematology (LSC-S, MLL) of the School of Medicine at the University of Washington, and the Fred Hutchinson Cancer Research Center and discuss considerations for its use as a treatment (MLL), Seattle, Washington. option. The apheresis modalities most commonly Address correspondence to Laura S. Connelly-Smith, MBBCh, DM, used to treat patients with cancer include the ther- Seattle Cancer Care Alliance, 825 East Eastlake Avenue, Seattle, WA, apeutic plasma exchange (TPE), leukocytapheresis, 98109. E-mail: [email protected] extracorporeal (ECP), thrombocyta- Submitted June 15, 2014; accepted October 8, 2014. pheresis, and erythrocytapheresis. Herein, we review No significant relationships exist between the authors and the companies/organizations whose products or services may be the known oncological diseases or associations for referenced in this article. which specific TA modalities have been successfully

60 Cancer Control January 2015, Vol. 22, No. 1 Table 1. — Indications for Therapeutic Apheresis in Patients With Cancer Therapeutic Indication Disease Condition Categorya Gradeb Apheresis Modality Therapeutic plasma Hyperviscosity in Symptomatic I 1B exchange (TPE) monoclonal gammopathies Prophylaxis for I 1C Myeloma kidney/myeloma cast nephropathy II 2B Paraneoplastic neurological syndromes Lambert Eaton myasthenic syndrome II 2C (see also Table 4) Other paraneoplastic III 2C neurological syndromes Hematopoietic transplantation– Refractory III 2C associated thrombotic microangiopathy Therapeutic Hyperleukocytosis With clinical signs I 1B leukocytapheresis and symptoms Prophylaxis (asymptomatic) III 2C Extracorporeal Cutaneous T-cell lymphoma, Erythrodermic I 1B photopheresis , Sézary syndrome Nonerythrodermic III 2C GVHD Skin chronic GVHD II 1B Skin acute GVHD II 1C Non–skin acute and chronic GVHD III 2B Thrombocytapheresis Thrombocytosis with Symptomatic II 2C myeloproliferative neoplasm Prophylactic III 2C Erythrocytapheresis vera/primary erythrocytosis I 1B aDenotes American Society for Apheresis category. bDenotes American Society for Apheresis grade. For more information, refer to Tables 2 and 3. GVHD = graft-vs-host disease. Data from reference 1. employed. Table 1 summarizes these modalities, clin- anticoagulated during the procedure. The fluid ical conditions, and the most recent ASFA guideline returned back to the patient contains the undesired recommendations.1 However, well-designed, prospec- blood components along with , crystal- tive intervention trials are still required to fully define loid, and/or . Membrane filtration the role of TA for many of these disorders. systems separate and collect plasma on a principle TA plays an important role in the management similar to and ultrafiltration, namely of various oncological diseases. It is a procedure in using membranes permeable to high-molecular-weight which blood is separated from a patient, a portion proteins but not cellular elements. The predominant of which is then removed or otherwise manipulated instruments and methodologies used for TA proce- and the remainder is then returned to the patient. TA dures in the United States utilize centrifugation.2 procedures include TPE (in which plasma is replaced with a colloid or crystalloid ) and modalities Clinical Adverse Events that selectively remove and dispose of plasma solutes TA can be associated with minimal to potentially fa- (), white blood cells (WBCs; leukocy- tal adverse events, although the overall incidence is tapheresis), or (thrombocytapheresis). ECP relatively low (5%–12%).3 Hypersensitivity reactions is a type of leukocytapheresis procedure whereby the due to plasma or replacement fluid can removed white cells are manipulated prior to being range from urticarial to anaphylactoid-type reactions. reinfused into the patient. Hypocalcemia secondary to citrate anticoagulant can Apheresis procedures can utilize centrifugation to manifest as paresthesia, , vomiting, lighthead- separate blood components into layers within a rapid- edness, and twitching. due to fluid shifts ly rotating separation chamber based on their relative or vasovagal reaction may manifest as , density — with red blood cells (RBCs) being the most muscle cramps, and headache. Rare, serious adverse dense, plasma the least dense — and intermediate events requiring the procedure to be interrupted or layers, moving from the axis of rotation outward and abandoned (0.8% incidence) or resulting in fatality consisting of -rich plasma, , and (≤ 0.5%) due to cardiovascular events can include .1 Specific kits are designed to remove arrhythmia or ischemia, , pulmo- RBCs or plasma or cells of intermediate density from nary embolism, and respiratory arrest; neurological

January 2015, Vol. 22, No. 1 Cancer Control 61 complications can also occur and may include tetany, of peripheral veins compared with CVCs has not been seizures, and cerebrovascular accident.3 Hemorrhage, explained by differences in patient age, sex, the me- thrombosis, and are uncommon. The causes dian number of treatments per patient, or the type of death have included respiratory arrest, anaphylaxis, of apheresis procedure.13 Nevertheless, peripheral and catheter-associated .3 venous access is underutilized in TA procedures and is the access of choice because it is associated with a Vascular Access lower risk of infection relative to CVCs and placement The majority of apheresis procedures are centrifuga- can be done immediately with a low risk of other tion based; therefore, they require withdrawal blood serious complications.10 Complications of peripheral flow rates of 50 to 150 mL/minute.4-7 Peripheral an- cannulation include risk of infection, venous infiltra- tecubital veins that can be cannulated using 16- to tion, patient discomfort, thrombosis and sclerosis of 18-gauge polytetrafluoroethylene- or silicone-coat- veins, and the loss of future venous access. Peripheral ed, -type steel needles will accommodate vein access for TA is not a viable option in children blood flow rates of 80 mL/minute and is adequate due to their small venous caliber. for centrifugation techniques. By contrast, filtration Peripherally inserted central catheters are too therapies require a blood flow rate of at least 150 to small in caliber (4–5 Fr) to accommodate the neg- 200 mL/minute, which is unsuitable for antecubital ative pressure and blood flow rates required for TA veins.4-7 Other considerations specific to TA include procedures.10 Arteriovenous fistulas and grafts are vi- whether the treatment relies on discontinuous, se- able options for long-term access when the treatment quential blood exchange cycles (1 lumen is sufficient) duration is expected to be over a period of several or continuous processing (2 lumens are needed).4-6 months or years.13 When a (CVC) is necessary for a limited (< 2 weeks) course of TA, a nontunneled, Evidence and Decision Making semi-rigid polyethylene catheter should be consid- Hematologists and oncologists who may have incom- ered.8 For a longer duration (> 2 weeks) of TA, a tun- plete knowledge of the indications, limitations, risks, neled CVC is preferred over a nontunneled CVC due and relative efficacy of the procedure might request TA. to less risk of infection.9 Typically, tunneled catheters Because many procedures are for uncommon and infre- designed for long-term use (weeks to months) are quent indications, few randomized clinical trials or other made of silicone and are more biocompatible, flexible, high-level evidence studies are available to guide clinical and have the least thrombogenicity. The preferred ve- decision-making. Therefore, the ASFA has undertaken a nous site of CVC insertion is the internal jugular vein, critical evaluation of published studies and observations, and both ultrasonographic guidance and fluoroscopy publishing periodic, evidence-based systematic reviews have been shown to be associated with a lower rate of TA applications since 2007. The ASFA clinical practice of complications during insertion.10 guidelines use the GRADE system, adopted from Guyatt Central venous access is not always required.11-13 et al,20 whereby each disease, including specific clini- The Canadian Apheresis Study Group found that 67% cal presentations, is categorized for the role of TA and of 5,234 TPE procedures could be completed with graded for the strength of recommendation and quality peripheral venous access alone.11 The frequency of based on the published evidence (Tables 2 and 3).1,20 complications due to CVC placement exceeds the fre- quency of complications directly related to the proce- Table 2. — American Society for Apheresis Categories 14 dure. Central venous access has been identified as Category Description a major risk factor for complications of TPE in other I Disorders for which apheresis is accepted as a first-line 10,14-16 studies. CVCs are associated with a higher total therapy, either primary stand-alone treatment or in complication rate. These include infection (2%–28%), conjunction with another mode of treatment. thrombosis (0.2%–11%), hemorrhage (2%–14%), and II Disorders for which apheresis is accepted as a venous stenosis (10%–26%) with internal jugular cath- second-line therapy, either as a stand-alone treatment eters and up to 42% with subclavian vein catheters.17 or in conjunction with other modes of treatment. In most series, the incidence of total ad- III Optimum role of therapeutic apheresis is not established. Decision making should be individualized. verse events associated with all vascular access is 6,18,19 IV Disorders for which published evidence demonstrates or low at 1% to 2%. Data from the Internation- suggests apheresis to be ineffective or harmful. Institutional al Apheresis Registry 2007 report that peripheral Review Board approval is desired if apheresis treatment is veins are commonly used in Europe and Australia undertaken in these circumstances. (66%–70% of apheresis treatments),7 whereas CVCs From Schwartz J, Winters JL, Padmanabhan A, et al. Guidelines on the use of therapeutic apheresis in clinical practice-evidence-based approach from the are the most common vascular access type used for Writing Committee of the American Society for Apheresis: the sixth special issue. TA procedures in North America, South America, and J Clin Apher. 2013;28(3):145-284. Reprinted with permission from the American Asia (84%–98%).7 This regional difference in the use Society for Apheresis.

62 Cancer Control January 2015, Vol. 22, No. 1 Table 3. — American Society for Apheresis Grading Recommendations Recommendation Description Quality of Evidence Application Grade IA Strong recommendation; high- RCTs without important limitations or Strong recommendation; can apply to most quality evidence overwhelming evidence from observational patients in most circumstances without studies reservation Grade IB Strong recommendation; RCTs with important limitations (inconsistent Strong recommendation; can apply to most moderate quality evidence results, methodological flaws, indirect, or patients in most circumstances without imprecise) or exceptionally strong evidence reservation from observational studies Grade IC Strong recommendation; low- Observational studies or case series Strong recommendation; may change when quality or very-low-quality higher-quality evidence becomes available evidence Grade 2A Weak recommendation; RCTs without important limitations or Weak recommendation; best action may high-quality evidence overwhelming evidence from observational differ depending on circumstances or studies patient or societal values Grade 2B Weak recommendation; RCTs with important limitations (inconsistent Weak recommendation; best action may moderate-quality evidence results, methodologic flaws, indirect, or differ depending on circumstances or imprecise) or exceptionally strong evidence patient or societal values from observational studies Grade 2C Weak recommendation; low- Observational studies or case series Very weak recommendations; other alterna- quality or very-low-quality tives may be equally reasonable evidence RCT = randomized controlled trial. Adapted from Guyatt GH, Cook DJ, Jaeschke R, et al. Grades of recommendation for antithrombotic agents: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th ed). Chest. 2008;133(6 suppl):123S-31S. Reprinted with permission from the American College of Chest Physicians.

ASFA category I and II indications are those for which extravascular spaces; during TPE, the extravascular TA is considered first-line or second-line therapy, respec- molecules can move into the intravascular space. tively. Category III indications acknowledge the lack of Therefore, TPE may remove more total solute than high-level evidence to recommend the TA procedure might be predicted based on the pretreatment con- as primary or second line; however, the treatment may centration because of re-equilibration occurring be beneficial and, thus, individualized decision-making from the extravascular to the intravascular com- should be used to guide inclusion of TA in the treatment partment. plan. Category IV reflects ineffectiveness or harm by TA Because TPE removes normal plasma coagula- with the risks outweighing benefits.21 tion factors, the activities of factors V, VII, VIII, IX, The 6th edition published in 2013 is a compilation and X, as well as (vWF), may of 78 diseases or medical conditions assigned ASFA significantly decline.26,27 Activities of factor VIII, fac- categories I to IV.1 All TA procedures discussed within tor IX, and vWF return to normal within 4 hours this review are referenced according to the category after TPE, whereas the remaining factors and recommended grade per the ASFA 2013 guide- achieve pre-TPE activity levels within 24 hours.26 The lines with further updates as indicated.1 exception to this is , which reaches 66% of preapheresis levels within 72 hours.28 TPE may also Therapeutic Plasma Exchange remove medications, especially those highly protein TPE involves the removal of a large volume of plasma bound. The clinical impact of this effect is understood and replacement with plasma, albumin, or both. The for relatively few drugs.29,30 major mechanism of action of TPE is the removal of a Albumin is the most commonly used replace- pathological solute, such as autoantibodies, immune ment fluid for TPE procedures. Normal plasma has complexes, cryoglobulins, myeloma light chains, or the same oncotic pressure as 5% albumin.31,32 Thus, cytokines. Of note, TPE may also have an immuno- replacing plasma with 4% to 5% human serum albu- modulatory effect, including the modulation of the min will maintain plasma volume and avoid hypoten- Th1/Th2 T-cell balance toward Th2,22 the suppression sion. However, because albumin is expensive,33 some of interleukin 2 and interferon γ production,23,24 and health care professionals may prefer to use albumin an increase in suppressor T-cell function. and , with the majority of the albumin being A standard TPE procedure exchanges 1 to given at the end of the procedure. The combination 1.5 plasma volumes resulting in the removal of 60% of albumin and saline is hypo-oncotic and has been to 70% of intravascular large molecular weight sol- associated with a greater frequency of hypovolemic utes.25 Some large molecules (eg, immunoglobulin reactions and edema compared with using albumin [Ig] G) distribute in both the intravascular and the alone.16 Another disadvantage is that albumin does

January 2015, Vol. 22, No. 1 Cancer Control 63 not replace coagulation factors, which may lead to to reduce the likelihood of blindness from retinal significant post-treatment coagulopathy. hemorrhages or retinal detachment.42,43 TPE is a safe Plasma is used as replacement fluid with TPE in a and well-tolerated procedure in this setting.44 It is limited number of disorders. It avoids postprocedure not typically necessary to reduce the plasma viscos- coagulopathy and immunoglobulin depletion. Its dis- ity to normal levels to relieve symptoms. However, advantages include transfusion reactions, citrate toxic- some evidence suggests that patients with monoclonal ity, and the potential for viral transmission. Plasma is IgM antibodies that produce neuropathy or other indicated as replacement fluid to replace ADAMTS13 target organ dysfunction may benefit from a more when treating thrombotic thrombocytopenic purpura aggressive effort to maintain serum viscosity near (TTP) or when coagulopathy must be corrected.34 normal levels.45,46 Neither plasma nor solvent/ Hyperviscosity with WM is an ASFA category I detergent–treated plasma has been shown to offer any indication for TPE (grade 1B recommendation).1 Gen- advantage over standard plasma for any indication.34 erally, 1 to 1.5 plasma volumes are exchanged per ses- A meta-analysis of 3 trials comparing sion, and usually consists of albumin and cryosupernatant plasma for the initial treatment of and saline in various proportions. Plasma exchange re- TTP did not reveal any benefit for patients receiving duces plasma viscosity by approximately 20% to 30% cryosupernatant plasma.35 Similarly, controlled studies per session.47 Thus, 1 or 2 procedures can return the failed to establish superiority of solvent/detergent–treat- plasma viscosity to near normal levels and reduce the ed plasma over fresh frozen plasma.34 The only cohort IgM concentration for several weeks. Concurrent che- of patients with TTP who may benefit from the use of motherapy is required to treat underlying disease and solvent/detergent–treated plasma are those with severe prevent rebound HVS. allergies to standard plasma.36 For asymptomatic patients with a serum viscosity level above 3 to 3.5 cp, an IgM concentration greater Hyperviscosity in Monoclonal Gammopathies than 3 to 4 g/dL, or both, some experts suggest that Hyperviscosity syndrome (HVS) refers to the clinical TPE can be prophylactically used prior to starting sequelae caused by the altered physiology related to rituximab therapy because significant transient in- plasma hyperviscous states, most typically seen in creases in IgM levels can occur following single-agent Waldenström macroglobulinemia (WM; also known rituximab therapy (considered a “flare”) in 30% to as lymphoplasmacytic lymphoma) associated with 70% of patients.38,48,49 Based on this concern, the ASFA monoclonal IgM or, less frequently, with multiple my- guidelines have recommended TPE as prophylaxis eloma associated with monoclonal IgA or IgG3. Spe- treatment prior to rituximab to lower IgM concentra- cific signs and symptoms include mucosal , tions of less than 5 g/dL (grade 1C recommendation).1 visual impairment with retinal hemorrhage or retinal The flare phenomenon may be less with regimens that detachment, headache, dizziness, vertigo, nystagmus, use chemotherapy prior to rituximab or regiments that hearing loss, somnolence, coma, and seizure. Other omit rituximab for the first 1 or 2 cycles. manifestations include congestive heart failure (re- Patients with myeloma and IgG3 subclass mono- lated to plasma volume overexpansion), respiratory clonal paraproteinemia are more likely to develop compromise, coagulation abnormalities, anemia, fa- HVS than other patients with myeloma.50,51 This usu- tigue, peripheral (depending on the ally occurs at higher than 4 g/dL of monoclonal IgG3 specific Ig properties), and anorexia. in the plasma. In cases of IgG-associated HVS, the WM represents approximately 2% of all cases of increase in serum viscosity is approximately propor- non-Hodgkin lymphoma.37 When the IgM protein as- tional to the concentration of the paraprotein.52 HVS sociated with WM exceeds a concentration of 4 g/dL, may also occasionally occur in IgA and light-chain the relative plasma viscosity can exceed 4 centipoise myeloma because of the formation of polymers; in (cp; relative to water: normal range, 1.4–1.8 cp) and the majority of these cases, it occurs when the con- HVS can occur.38 Unlike the situation with IgG, IgM centration of monoclonal IgG exceeds 6 to 7 g/dL. is predominantly intravascular (> 80%) and increased viscosity with IgM can become exponential above a Myeloma Cast Nephropathy concentration of 3 g/dL. In turn, a small reduction Nearly 50% of patients with devel- in IgM concentration can have a significant effect on op renal disease.53,54 from cast lowering serum viscosity. nephropathy, also known as “myeloma kidney,” is the TPE is an effective, short-term treatment for com- most common type and accounts for 30% to 80% of plications of HVS.39-41 Because bleeding is the most cases.55,56 The development of acute kidney injury common sign of HVS and retinal examination findings is associated with worse 1-year survival rates and correlate with the symptomatic threshold for HVS in reduces the overall therapeutic options available to patients with WM, urgent TPE should be carried out patients.53,54 Cast nephropathy is due to the interaction

64 Cancer Control January 2015, Vol. 22, No. 1 and aggregation of filtered free light chains (FLCs) indicate potential reversibility (eg, absence of fibrosis and Tamm–Horsfall protein, thus causing intratubular of all affected glomeruli) may be important predictors obstruction and damage. When the light chain pro- of success.60,62 duction overcomes the capacity of the tubular cells The ASFA evidence-based guidelines lists TPE as to endocytose and catabolize the FLCs, the increased a category II indication for myeloma kidney due to light chains in the tubular fluid of the distal tubule and light-chain cast nephropathy.1 After initial manage- thick ascending loop of Henle form tubular casts with ment, especially in the case of nonoliguric patients, the Tamm–Horsfall protein.57,58 As tubular obstruction focus should be on fluid (2.5–4 L/day), progresses, the decline in renal function becomes alkalinization of the urine, and chemotherapy. If se- irreversible. Other factors, such as , diuret- rum creatinine remains elevated after several days, ics, hypercalcemia, hyperuricemia, and intravenous then renal biopsy should be considered to assess for contrast media, may all potentiate cast formation and cast nephropathy. If cast nephropathy is highly sus- acute kidney injury. pected or confirmed, then TPE can be initiated by The key to treating cast nephropathy is the rapid processing 1 to 1.5 total plasma volumes every 1 to 2 lowering of FLCs. In addition to hydration and ag- days and using 5% albumin in saline as replacement gressive supportive care, antimyeloma chemotherapy fluid. Some studies support a course of 10 to 12 TPE is necessary, whether it be with an alkylating agent procedures over 2 to 3 weeks and repeating this de- and prednisone therapy or one of the recent immune pending on patient response and clinical course.1 For modulators (thalidomide, lenalidomide) and protea- patients who are oliguric, excrete at least 10 g of light some inhibitors (bortezomib). These latter agents have chains per 24 hours, or whose serum creatinine level emerged as effective therapy and have been referred is at least 6 mg/dL, TPE may be included as adjunct to as “renoprotective.”59 Supportive care with hemo- therapy to initial chemotherapy and hemodialysis. If dialysis or peritoneal dialysis may also be needed. TPE and hemodialysis are to be performed on the TPE has been used in hopes of reducing the same day, then the procedures can be performed in delivery of plasma FLCs to the renal glomerulus for tandem without compromising the efficiency of the filtration. Two studies suggested that TPE was ben- hemodialysis. eficial.60,61 In addition, a small prospective compari- son of forced diuresis, melphalan, and prednisone Paraneoplastic Neurological Syndromes (10 patients) vs forced diuresis, melphalan, predni- Paraneoplastic neurological syndromes (PNS) are sone, and TPE (11 patients) found a trend in favor of symptoms or signs resulting from damage to the TPE, and a subgroup analysis of patients dependent central or peripheral nervous system, including the on dialysis revealed that renal function recovered neuromuscular junction and muscle, removed from in 43% of the TPE group compared with 0% in the the site of the malignancy or its metastases, and not control group.62 These studies led to an endorsement due to remote effects caused by infection, ischemia, of TPE for myeloma kidney by the Scientific Advisors or metabolic disruptions.68 PNS can affect up to 1% of of the International Myeloma Foundation.63 Subse- patients with cancer but may occur more frequently quently, a large randomized trial of bortezomib-con- in those with non-Hodgkin lymphoma, small-cell lung taining chemotherapy and supportive care, with or cancer, and thymomas.69-72 In the majority of patients, without TPE, failed to demonstrate a benefit for 5 to PNS develop prior to the cancer diagnosis. 7 TPE procedures over 10 days.64 However, this study The pathogenesis of PNS is thought to be im- has been criticized for the lack of FLC measurements, mune-mediated as a result of a cross-reaction against the lack of histological evidence of cast nephropathy, shared by the tumor and nervous system and the failure to consider early end points more spe- cells.68,73 Many antibodies are associated with para- cific to the recovery of renal function. In a report from neoplastic syndromes (Table 4).68,73,74 Their role in the Mayo Clinic, plasma exchange in combination neuronal dysfunction is unclear and they can occur with bortezomib-based chemotherapy in 7 patients in fewer than 50% of patients with PNS.75 No studies was associated with 6 patients (86%) having at least have proven that these antibodies are pathogenic; a partial response.65 however, these antibodies have become useful diag- Collectively, these observations suggest that a sub- nostic markers, particularly in monitoring for relapse. group of patients with cast nephropathy might ben- The severity of the majority of PNS cases is due to the efit from TPE, particularly those in nonoliguric renal early and nonreversible destruction of neural struc- failure who do not require dialysis.56,60 The severity tures by the inflammatory process; in many cases, of myeloma cast formation, including the need for the patient is severely debilitated within weeks to dialysis, has been identified as the major factor associ- months.76,77 Prompt initiation of therapy following the ated with nonreversible renal failure, even in patients diagnosis of PNS may stabilize symptoms and prevent undergoing TPE.60,63,66,67 Moreover, biopsy findings that PNS spreading to further areas in syndromes with

January 2015, Vol. 22, No. 1 Cancer Control 65 Table 4. — Paraneoplastic Neurological Syndromes and Their Associated Tumor Types, Symptoms, and Antibodies Syndrome Frequency of Major Symptoms Associated Tumor Frequently Associated Paraneoplastic Types Paraneoplastic Origin (%) Antibodies Lambert–Eaton 60 Muscle weakness, autonomic dysfunction SCLC VGCC antibodiesa myasthenic syndrome Paraneoplastic 50 Truncal, limb ataxia, dysarthria, saccadic Ovary Anti-Yo cerebellar degeneration gaze pursuit, nystagmus Breast Anti-Hu SCLC Anti-VGCC Hodgkin lymphoma Anti-CV2/CRMP5 Paraneoplastic opsoclonus/ 20 Saccades, ataxia, other cerebellar signs, Neuroblastoma Anti-Ri (ANNA-2) myoclonus generalized myoclonus, altered mental Breast state, stupor, coma SCLC Sensory neuronopathy 20 Pain, paresthesias (arms > legs), SCLC Anti-Hu numbness, ataxia Anti-CV2/CRMP5 Anti-amphiphysin Limbic encephalitis 20 Seizures, short-term memory deficits, SCLC Anti-Hu behavioral and psychiatric disturbances Testicular ANNA-1 Paraneoplastic 10 Seizures, subacute dementia, personality SCLC ANNA-1 encephalomyelitis changes (limbic encephalitis), subacute Anti-Hu cerebellar signs, autonomic nervous system dysfunction Cancer-associated Subacute visual loss, photosensitivity, SCLC Recoverin antibodies retinopathy night blindness, impaired color vision Cervical Melanoma Paraneoplastic 5–20 Stiffness predominantly upper limbs, Breast Antiamphiphysin stiff-person syndrome painful spasms precipitated by sensory Colon stimuli Lung Hodgkin lymphoma Malignant thymoma Chronic intestinal Weight loss, constipation, abdominal SCLC Anti-Hu pseudo-obstruction distension, esophageal dysmotility, Anti-CV2/CRMP5 gastroparesis 30 Proximal myopathy, heliotrope rash, Ovarian scaly plaques on dorsal hands Lung Pancreatic Stomach Colorectal Non-Hodgkin lymphoma aPresent in nearly all patients with the paraneoplastic and nonparaneoplastic form of Lambert–Eaton myasthenic syndrome. Data from references 68, 73, and 74. ANNA = antineuronal nuclear antibody, SCLC = small cell lung cancer, VGCC = voltage-gated calcium channel. onconeural antibodies.78 For patients with an identi- Initial therapies often include corticosteroids, TPE, fied tumor, antitumor therapy should be rapidly insti- intravenous immunoglobin (IVIG), immune adsorp- tuted for stabilization or symptom improvement. The tion, and/or rituximab. More aggressive second-line use of immunomodulatory therapy does not substan- immunosuppression with cyclophosphamide, tacro- tially modify the neurological outcome of patients limus, mycophenolate, or cyclosporine may be used whose tumors are successfully treated.76,79 For many when no response to initial treatments is seen and the paraneoplastic syndromes, removal of the tumor is patient continues to lose neurological functions. More the only effective treatment.80,81 severe neurological deficits associated with antibodies The role and timing of immunotherapy for PNS against Yo, Hu, and CRMP5 are also the most refrac- is not well defined; however, many reports indicate tory to immunosuppressive treatment. Survival from its apparent benefit.82,83 No systematic studies exist time of diagnosis is significantly worse in patients concerning the type of immunosuppressive therapy, with anti-Yo (median, 13 months) or anti-Hu (medi- and no RCTs or quasi-RCTs exist on which to base an, 7 months) than in patients with anti-Tr (median, treatment or practice.84 In patients without detectable > 113 months) or anti-Ri (median, > 69 months).85 tumor but with a prior history of malignancy and clin- However, patients who receive antitumor treatment, icopathological findings consistent with progressive with or without immunotherapy, live significantly lon- PNS, it is appropriate to empirically start immunosup- ger than those who do not.76,84 pressive therapy with or without antitumor treatment. The rationale for TPE with PNS is that plasma

66 Cancer Control January 2015, Vol. 22, No. 1 antibody levels can be reduced and thereby amelio- 6 weeks.86 This may be due to the slower turnover of rate the damage to the peripheral nervous system in the presynaptic voltage-gated calcium channel com- tissues. Plasma exchange can also reduce circulating pared with the postsynaptic acetylcholine receptor. levels of cytokines and other mediators of inflamma- The effectiveness of immunosuppressive ther- tion that may contribute to the effectiveness of TPE apy in non-LEMS PNS with onconeural antibodies as immunomodulatory therapy. By comparison, PNS is not supported by higher level evidence.84,87 Few involving the central nervous system do not typically studies prove efficacy, although several retrospective respond to TPE, a fact likely due to the inability of and small prospective studies support the benefit plasma therapy to decrease intrathecal antibody titers. of immunosuppression for some patients and select Patients with acquired neuromyotonia and anti- syndromes.88-91 The ASFA guidelines have assigned bodies directed against voltage-gated potassium chan- a grade 2C recommendation for this category III in- nels or paraneoplastic cerebellar degeneration with dication.1 Procedures are performed daily or every anti-Tr antibodies may be more likely to respond to other day for a total of 5 to 6 exchanges over 2 weeks, TPE; however, many do not have malignancy. In 50% although the exact number of exchanges should be of cases, encephalitis associated with anti–N-methyl adjusted for each patient. Some patients will require D-aspartate receptor antibodies responds to first-line maintenance therapy on a monthly or less frequent treatment with corticosteroids, IVIG, or TPE. Although basis. TPE cannot be considered as standard therapy immunosuppression with corticosteroids, TPE, and/or for PNS. Most patients treated with TPE have also re- IVIG may benefit those with LGI1- and CASPR2-an- ceived immunosuppressive drugs as well as specific tibody associated syndromes, residual memory im- anticancer therapy. pairment is common. However, large case series on long-term outcomes are currently lacking. Even less Hematopoietic Stem Cell Transplantation– is known about the treatment and prognosis of oth- Associated Thrombotic Microangiopathy er neuronal cell-surface antibody syndromes (eg, Thrombotic microangiopathy (TMA) refers to a histo- γ-aminobutyric acid [B], α-amino-3-hydroxy-5-methyl- pathological appearance, describing arteriolar throm- 4-isoxazolepropionic acid receptor). Typically, they bi associated with intimal swelling and fibrinoid ne- are treated similar to anti–N-methyl D-aspartate re- crosis of the vessel wall.92 The microscopic injury ceptor encephalitis. Disorders such as paraneoplas- results from a variety of insults that can cause the tic cerebellar degeneration are generally associated activation of intravascular platelets with the subse- with neuronal loss; because they subacutely evolve quent formation of platelet-rich thrombi within the and treatment is often delayed, the neurons die, thus microcirculation. TMA following allogeneic hemato- making recovery impossible.85 Some central nervous poietic stem cell transplantation (HSCT), also called system disorders, such as opsoclonus–myoclonus transplant-associated TMA, appears to be primarily syndrome, may not involve cellular loss and, in fact, triggered by mechanisms of endothelial cell injury, may have no identifiable pathological features. Thus, including conditioning chemotherapy,93-95 irradiation,96 patients with these disorders, like those with the Lam- immunosuppressive agents (eg, mammalian target bert–Eaton myasthenic syndrome (LEMS), have the of rapamycin, calcineurin inhibitor drugs),97-100 graft- potential for recovery. vs-host disease (GVHD),101-103 and opportunistic in- LEMS is a syndrome that involves the neuromus- fections.104,105 The damaged endothelial cells release cular junction and can typically respond well to immu- microparticles and vWF, which induce platelet adhe- nosuppression and, subsequently, to treatment of the sion/aggregation and a procoagulant state.106-108 This underlying tumor. TPE may be useful adjunct therapy process consumes platelets and induces mechanical for patients whose neurological deficit is severe or damage to RBCs as they impact microthrombi or fibrin rapidly developing or among those who cannot toler- strands obstructing the microcirculation. ate treatment with IVIG (ASFA category II; grade 2C The clinical hallmarks of TMA include micro- recommendation).1 Reports of benefit are tempered angiopathic hemolytic anemia and thrombocytope- by the observation that responses can be slow and nia, and the associated laboratory findings include symptoms can worsen following the completion of schistocytes, increased serum lactate dehydrogenase, TPE if additional immunosuppressive therapy is not decreased serum haptoglobin, and indirect hyper- employed. bilirubinemia. Hemoglobinuria, either frank or mi- The reported TPE regimens for LEMS vary from croscopic, is frequent. Kidneys are the major target 5 to 15 regiments of daily TPE over 5 to 19 days to organs of transplant-associated TMA; thus, renal func- 8 to 10 regimens of TPE carried out at 5- to 7-day tion abnormalities are common. Unlike idiopathic intervals. Most reports employed 1.25 plasma vol- TTP, in which severe deficiency of the vWF-cleaving ume exchanges.1 However, the peak effect is usually protease, ADAMTS13 (a disintegrin and metallopro- demonstrated after 2 weeks and largely subsides after tease with thrombospondin-1-like domains), leads to

January 2015, Vol. 22, No. 1 Cancer Control 67 the presence of ultra-large multimers of vWF and tion).1 TPE for transplant-associated TMA is usually systemic platelet agglutination, multiple studies in performed daily until a response is seen and is then post-transplantation TMA have failed to document a either discontinued or tapered off, a process simi- severe deficiency of ADAMTS13.109-111 lar to treatment for idiopathic TTP. The therapeutic TMA can occur within the first few weeks follow- end point may be difficult to determine because the ing transplantation or as a late complication, particu- platelet count, schistocytes, and lactate dehydrogenase larly in association with GVHD. One-year cumulative levels could be affected by incomplete engraftment incidences of 13% and 15% were reported in patients and other post-transplantation complications. undergoing nonmyeloablative conditioning and Based on the data from anecdotal reports, other high-dose conditioning, respectively.112 Most large, salvage treatment options for transplant-associated retrospective studies report a prevalence of 10% to TMA might include daclizumab, defibrotide, and ritux- 25%.113 Transplant-associated TMA carries a poor imab.121-123 Such anecdotal reports of clinical response prognosis. In a literature review of 35 published to eculizumab suggest that transplant-associated TMA articles involving more than 5,423 allogeneic HSCT could involve aberrant and autonomous complement recipients, 447 study volunteers (8.2%) developed activation and include some patients who may have transplant-associated TMA and had a median mortal- an inherent defect in complement regulation.124,125 ity rate of 75% within 3 months of the diagnosis.114 Clinical risk factors associated with transplant-associ- Therapeutic Leukocytapheresis ated TMA include high-dose conditioning regimens, The majority of leukocytapheresis procedures are car- acute GVHD, female sex, older age, active , ried out to treat hyperleukocytosis and complications receiving transplantations from unrelated donors, and of leukostasis associated with acute . the combination of mammalian target of rapamycin and calcineurin inhibitor drugs.115 Leukocytapheresis for Acute Currently, no consensus exists regarding the ap- and Leukostasis With Hyperleukocytosis proach to treatment of transplant-associated TMA, and Hyperleukocytosis is variably defined as a WBC or leu- no randomized clinical trial data exist. Initial man- kemic blast cell count above 50,000/μL or 100,000/μL. agement involves the reduction or discontinuation of The incidence of hyperleukocytosis ranges between the mammalian target of rapamycin and calcineurin 5% and 13% in adult acute myeloid leukemia (AML) inhibitor drugs (especially if used in combination) and between 10% and 30% in acute lymphoblas- along with aggressive treatment of underlying GVHD tic leukemia (ALL).126 Although hyperleukocyto- and infections. A role for TPE in this disorder remains sis does not appear to have a major impact in early unclear. Response rates of transplant-associated TMA mortality in ALL unless the WBC count is more than to TPE are significantly lower (< 50%)116 than the high 250,000/μL, it is associated with an increased likelihood responses in idiopathic TTP (≤ 85%).117-119 A systematic of induction death and reduced likelihood of achieving review published in 2004 noted an 82% mortality rate complete remission in cases of AML.127,128 among 176 study volunteers with transplant-associat- Hyperleukocytosis with AML and ALL may be ed TMA who underwent TPE compared with a 50% associated with disseminated intravascular coagu- mortality rate among 101 study volunteers not treated lopathy, tumor lysis syndrome, and leukostasis. Leu- with TPE, suggesting that the toxicity of the procedure kostasis refers to end-organ complications due to mi- outweighs the potential benefits.114 Similarly high cu- crovascular leukoaggregates, hyperviscosity, tissue mulative mortality rates were cited by the Blood and ischemia, infarction, and hemorrhage as a result of Marrow Transplant Clinical Trials Network Toxicity high numbers of leukocytes. The pathophysiology of Committee in a consensus statement recommending leukostasis is based on the rheological properties of that TPE not be considered as standard of care for the blasts, which is a function of the deformability of transplant-associated TMA.120 The difference seen in the blasts (rigidity) and the volume of the blasts (cell mortality rates may partly reflect the significant co- fraction) in the blood,129 and the cytoadhesive inter- morbidity of the post-transplantation state; however, actions between the blasts and the endothelium.130 it also supports the available data that indicate that This second mechanism is based on the activation of transplant-associated TMA results from mechanisms the endothelium by blasts to secrete cytokines that distinct from those involved in idiopathic TTP. in turn mediate the expression of specific receptors Because some patients with transplant-associat- such as intercellular adhesion molecule 1, vascular cell ed TMA appear to respond to treatment, a trial of adhesion protein 1, selectins, and others that promote TPE could be considered as salvage therapy for se- blast adhesion.130 Leukostasis in ALL usually occurs lect patients with persistent, progressive, end-organ with WBC counts higher than 400,000/μL.131 Com- complications despite a resolution of infections and pared with lymphoid blasts, myeloid blasts are larger, GVHD (ASFA category III; grade 2C recommenda- less deformable, and their cytokine products are more

68 Cancer Control January 2015, Vol. 22, No. 1 prone to activate inflammation and the molecular ex- observational, and all had a moderate to high risk of pression of endothelial cell adhesion. A blast count confounding bias.136 above 100,000/μL is a good predictor of leukostasis Prophylactic leukocytapheresis remains a consid- in the myeloid phenotype AML (FAB M1, M2, M3v). eration for patients with AML and WBC counts above The blast count is less reliable in monocytic lineage 100,000/μL without overt leukostasis manifestations AML (FAB M4, M5) in which severe leukostasis can as a means to rapidly reduce blood viscosity and occur with WBC counts above 50,000/μL.132 facilitate safe RBC transfusion as well as to avoid Central nervous system manifestations of leu- leukostasis that might occur following the start of che- kostasis can include confusion, somnolence, dizziness, motherapy, particularly with the M4 or M5 subtype.137 headache, , coma, and parenchymal hemor- Among children and adults with ALL, clinical rhage, and pulmonary complications can include hy- symptoms of leukostasis develop in less than 3% at poxemia, diffuse alveolar hemorrhage, and respiratory WBC counts lower than 400,000/μL.131 Therefore, failure with interstitial infiltrates, alveolar infiltrates, prophylactic leukocytapheresis offers no advantage or both. Both pulmonary and neurological manifesta- over aggressive induction chemotherapy and sup- tions are associated with increased rates of mortality portive care, including among those with tumor lysis in adults and children. In cases of hyperleukocytosis syndrome. By comparison, pulmonary and central in AML, the mortality rate has been reported to be nervous system complications develop in more than between 5% and 30%.133 50% of children with ALL and WBC counts above Definitive treatments for hyperleukocytosis in the 400,000/μL, suggesting that prophylactic leukocyta- setting of AML or ALL involve induction chemotherapy pheresis might be beneficial in that setting.131 with aggressive supportive care. Hydroxyurea, cytara- For patients with ALL or AML and clinical leu- bine, or both are useful in temporizing cytoreductive kostasis complications, ASFA category I (grade 1B agents for AML. Hyperuricemia and tumor lysis syn- recommendation) has been assigned and is based on drome are treated with intravenous fluids, numerous reports and retrospective case series that replacement, allopurinol or rasburicase, alkaliniza- describe the rapid reversal of pulmonary and central tion of the urine, and dialysis. Bleeding and coagu- nervous system manifestations following cytoreduc- lopathy are managed with plasma, , tion with leukocytapheresis.1 However, improvement and/or platelet transfusions. However, RBC transfu- may not be observed if severe end-organ injury or sions should be deferred to avoid augmenting hyper- hemorrhage has already occurred. The ASFA catego- viscosity and promoting leukostasis. ry III (grade 2C recommendation) for prophylactic Leukocytapheresis allows for the rapid reduction leukocytapheresis probably reflects the limited and of the intravascular leukemic cellular burden, thereby conflicting data available in the literature to guide resolving leukostatic microvascular occlusion and im- treatment in patients who are asymptomatic.1 proving tissue perfusion. No randomized prospective A single leukocytapheresis procedure can reduce studies of leukocytapheresis for hyperleukocytosis the WBC count by 30% to 60%.1 Daily — or, on occasion, or leukostasis have been published. Published data twice-daily — procedures for life-threatening cases can regarding the clinical value of therapeutic leukocy- be performed by processing 1.5 to 2 blood volumes and tapheresis are limited, observational, and conflict- using crystalloid or 5% albumin as the replacement fluid. ing. This is partly due to different WBC thresholds RBC priming may be employed for adults with severe prompting leukocytapheresis, patient selection, and anemia; however, undiluted packed RBCs should be therapeutic end points. avoided in small children with hyperviscosity. For pa- Previous multiple retrospective cohort studies tients with AML and leukostasis complications, apheresis of AML demonstrate reduced early mortality; how- must be discontinued when the blast cell count is less ever, leukocytapheresis offers no benefit to overall than 50,000 to 100,000/μL and clinical manifestations are outcome.134,135 Recently, a and me- resolved or maximum benefit is achieved. Chemotherapy ta-analysis using an intent-to-treat approach evaluated should not be postponed and is required to prevent the and low-dose chemotherapy interven- rapid reaccumulation of circulating blasts. tions in patients with AML and WBC counts above 100,000/μL.136 Data were reviewed from 15 of the Leukocytapheresis for Chronic Myeloid Leukemia studies in which leukocytapheresis was used. In the With Hyperleukocytosis and Priapism analysis, the mean early mortality rate of 20.1% during The incidence of leukostasis as a result of hyperleu- the first month of induction chemotherapy in patients kocytosis in adults presenting with CML has been with hyperleukocytosis was not reduced by leukocy- estimated to be between approximately 12% and 60% tapheresis (or low-dose chemotherapy), suggesting among children with CML.138,139 The most recognized limited benefit.136 The authors noted limitations of the features of hyperleukocytosis in CML are constitution- primary studies: the studies were small, retrospective, al (malaise and fever), cardiorespiratory, neurological,

January 2015, Vol. 22, No. 1 Cancer Control 69 or vascular, including retinal hemorrhage, myocardial of advanced cutaneous T-cell lymphoma (CTCL). In ischemia, and priapism. 1988, ECP was approved by the US Food and Drug Priapism occurs in 1% to 2% of males present- Administration (FDA) for the treatment of advanced ing with chronic phase CML and WBC counts above forms of CTCL, and has since become a recommended 500,000/μL.140-142 It is characterized by a prolonged, first-line therapy for selected patients with advanced painful erection. Priapism in this setting is a urologi- stage CTCL (ASFA category I).1,153,154 cal emergency with a poor prognosis, and the risk of ECP is also currently utilized for patients with impotence in adults is 50% despite appropriate man- acute and/or chronic skin and nonskin GVHD (ASFA agement.143 The primary mechanism is the aggregation categories II and III, respectively) and for solid organ of leukemic cells in the corpora cavernosa and the (ASFA category II).1 Its use is also dorsal vein of the penis.144 A contributing factor is the expanding into the treatment of select autoimmune venous congestion of the corpora cavernosa due to diseases such as pemphigus vulgaris, scleroderma, in- mechanical pressure on the abdominal veins by the flammatory bowel disease, and nephrogenic systemic enlarged spleen. Increased production of cytokines fibrosis (ASFA category III). and adhesion molecules by leukemic cells can also The molecular mechanisms for the therapeutic be seen and will result in the activation of endothelial effects of ECP are not fully understood. The cytotoxic cells and lead to the increased sequestration of cells effects and the role of other cell populations, includ- in the microvasculature.145 ing dendritic cells, T cells, and natural killer cells, No standard treatment has been recommended continue to be investigated. Detailed discussions of for leukemic priapism. Systemic therapies include cy- all the cellular mediators in the process described toreductive agents, such as high-dose hydroxyurea below are beyond the scope of this article but have and tyrosine kinase inhibitors, with or without the been reviewed elsewhere.155-158 addition of leukocytapheresis to reduce hyperviscos- Cell death by apoptosis appears to be a major ity.138,146 A review of the published literature revealed mechanism of action that occurs within 24 to 72 hours that 3 of 4 patients with ischemic priapism treated of photoactivation; however, 5% to 15% of the total by leukocytapheresis had a resolution of priapism population is exposed to treatment during compared with 3 of 15 patients treated with chemo- each procedure.159 Thus, additional and/or comple- therapy alone.147 Some case series have reported on mentary mechanisms of action are also important. the successful use of therapeutic leukocytapheresis Exposed undergo apoptosis later than in combination with cytotoxic therapy to treat pria- lymphocytes but a portion differentiate into imma- pism.142,144,146,148,149 Although some of these studies indi- ture dendritic cells.159 These dendritic cells have been cated that a conservative approach may be successful identified as key mediators of peripheral tolerance157 in preserving erectile function, a combined modality and are found in patients treated with ECP for chronic approach is strongly recommended by the American GVHD.160 Together with , these immature Urological Association so that systemic treatment for dendritic cells are the -presenting cells that the underlying disorder and intracavernous treatment recognize, engulf, and display cellular determinants be concurrently administered.147 from the apoptotic lymphocytes. After engulfing apop- totic cells, the immature dendritic cells differentiate Leukocytapheresis for Other Chronic Leukemias into semi-mature dendritic cells, migrate to lymph and Leukostasis With Hyperleukocytosis nodes, and present antigenic peptides to T lympho- Leukostasis complications with other leukemias are cytes. This brings about a shift from a Th1 to a Th2 rare but may occur with chronic myelomonocytic immune response, an increase in anti-inflammatory leukemia150 and WBC counts higher than 100,000/μL cytokines (eg, interleukin 10, transforming growth with a high level of lactate dehydrogenase. In cases factor β), a decrease in proinflammatory cytokines, of chronic lymphocytic leukemia, leukostasis is rare and the proliferation of T-regulatory cells. These T-reg- and is predominantly described in patients with WBC ulatory cells down-regulate the GVHD process by counts above 1,000,000/μL.151 inactivating T-effector cells158,161-163 and encouraging peripheral tolerance. In the treatment of CTCL, the Extracorporeal Photopheresis apoptotic tumor debris is thought to provide target ECP is an immunomodulating cell therapy whereby a antigens for cytotoxic CD8+ lymphocytes.164 patient’s circulating WBCs are collected via a leukocy- tapheresis procedure, exposed ex vivo to photo-acti- Cutaneous T-Cell Lymphoma vatable 8 methoxypsoralen, irradiated with ultraviolet Cutaneous lymphomas are characterized by the lo- A light, and then reinfused into the patient. ECP was calization of malignant lymphocytes in the skin. originally introduced in 1987 by Edelson et al152 for Approximately two-thirds of these lymphomas are the treatment of Sézary syndrome, an aggressive form of T-cell origin. The most common form of CTCL is

70 Cancer Control January 2015, Vol. 22, No. 1 mycosis fungoides, which makes up 60% of CTCL HSCT. Despite an overall improvement in human leu- cases.153 By contrast, Sézary syndrome, which is kocyte antigen typing, conditioning regimens, sup- an aggressive form of advanced CTCL, occurs in portive care, and post-transplantation immunosup- about 5% of patients.165 In Sézary syndrome, the pression, the overall incidence of GVHD has increased prognosis is generally poor and has a median because an increasing number of older patients are survival rate of less than 3 years.166 A meta-analysis of undergoing allogeneic HSCT and the use of hap- 19 studies that utilized ECP for patients at all loidentical, double-cord blood and human leukocyte stages of CTCL showed overall response rates antigen–mismatched donors are being used.171,172 of 55.5% and 55.7% with ECP alone and ECP in GVHD following HSCT is classified as an acute, combination with other therapies, respectively.167 chronic, or overlap syndrome. Despite prophylactic Scarisbrick et al154 concluded that all patients therapy with immunosuppressive agents, 20% to 80% with erythrodermic CTCL (major criteria) are of patients develop acute GVHD following allogeneic candidates for ECP, and those with a peripheral HSCT. Acute GVHD results from the activation of do- blood T-cell clone and/or circulating Sézary cells nor T cells by host antigen–presenting cells, leading to comprising more than 10% of the lymphocytes T-cell– and cytokine-mediated tissue injury.171 Chronic and/or have a CD4:CD8 ratio higher than 10 (mi- GVHD is due to dysregulated allogeneic or autoreac- nor criteria) may also benefit from ECP. Response tive T cells, B cells, antigen-presenting cells, and nat- to ECP has been linked to a short duration of disease, ural killer cells, thus leading to fibrosis, inflammation, the absence of bulky lymphadenopathy or internal sclerosis, and atrophy of affected tissues.163 Moder- organ involvement, a WBC count lower than ate-to-severe GVHD is the leading cause of impaired 20,000/µL, fewer than 20% Sézary cells, normal or mild- immune function, compromised functional status, ly abnormal natural killer cell activity, a level of CD8+ and transplantation-related deaths. High-dose corti- T cells above 15%, lack of prior intensive chemo- costeroids are first-line therapy for moderate-to-severe therapy, and plaque-stage disease involving 10% acute and chronic GVHD with or without the use of to 15% of the skin surface.154 Fewer patients with calcineurin inhibitors.173 Patients with chronic GVHD nonerythrodermic CTCL have been treated with ECP require prolonged immunosuppressive treatment for and 1 randomized crossover study alone suggested an average of 2 to 3 years from the initial diagnosis, no ECP benefit.168 with 10% of those surviving for at least 7 years still Guidelines from the National Comprehensive Can- requiring immunosuppressive treatment at that time cer Network recommend ECP as an option for advanced or beyond.174 Severe GVHD unresponsive to treat- mycosis fungoides and Sézary syndrome (stage 2B, 3, ment carries a high risk of death or severe morbidity or 4) when the disease is refractory to skin-directed due to end-organ complications, infections, or both, treatment.169 However, ECP is not expected to increase and the transplantation-related mortality rate exceeds survival; typically, the treatment delays the progression 40%.175,176 To date, the US Food and Drug Administra- of disease and improves pruritus.170 tion has not approved a treatment option for GVHD. The standard schedule of ECP for the treatment Therapies for steroid-refractory acute GVHD of CTCL consists of procedures performed on 2 con- include mycophenolate mofetil, denileukin diftitox, secutive days every 2 to 4 weeks and generally con- sirolimus, infliximab, etanercept, pentostatin, horse tinued for up to 6 months to assess response.1,154 The vs rabbit antithymocyte globulin, and alemtuzum- median time for a response to ECP is 5 to 6 months, ab.173,177,178 Evidence does not suggest that any one although response may take as long as 10 months in second-line agent is superior to another.173 As a re- some patients. Those who respond after 6 to 8 cycles sult, decisions on which agent to use at individual appear to have an improved long-term outcome. When treatment centers often vary according to the clini- maximal response is achieved, ECP treatments can be cal experience of health care professionals, cost, and reduced to once every 6 to 12 weeks with the goal treatment availability. of discontinuation if relapses do not occur. If CTCL ASFA has reviewed the data available on the over- recurs in more than 25% of the skin, then ECP once all response rates to ECP for steroid-refractory acute or twice monthly should be reinstituted. If evidence GVHD and found that overall response rates in pe- exists of disease progression after 6 months of ECP diatric and adult patients ranged from 52% to 100%, alone, combination therapy should be considered. If with responses in cutaneous (66%–100%), gastrointes- minimal or no response is seen after 3 months of com- tinal tract (40%–83%), and hepatic (27%–71%) acute bination therapy, then ECP should be discontinued.1 GVHD.1 Higher response rates have been reported in early-onset GVHD179; however, the strongest pre- Extracorporeal Cellular Therapy dictor for response to ECP in a multivariate analysis in Graft-vs-Host Disease was GVHD severity (100% response in grade 2 dis- GVHD remains a major complication of allogeneic ease vs 30% in grade 3/4).180 Complete responses and

January 2015, Vol. 22, No. 1 Cancer Control 71 improved survival rates are often reported among either a response or for 8 to 12 weeks, followed by a acute GVHD cohorts; however, the nonrandomized taper to every 2 to 4 weeks until maximal response.1 and retrospective results for ECP are not superior to One author has proposed 2 to 3 procedures per week results reported for alternative salvage approaches depending on disease severity for 4 weeks or more.189 for steroid-refractory acute GVHD. Clinical response should be assessed weekly in acute Therapies for steroid-refractory/dependent chron- GVHD and every 8 to 12 weeks in chronic GVHD; ic GVHD include sirolimus, mycophenolate mofetil, ECP should be discontinued in cases of no or minimal azathioprine, thalidomide, ECP, total lymphoid irradi- response. Some studies indicate that approximately ation, mesenchymal cells, imatinib, pentostatin, vari- 10% of patients with chronic GVHD given ECP may ous monoclonal antibodies, and others.177,178 Approx- benefit from treatment longer than 12 to 24 months.181 imately 30% to 65% of patients with chronic GVHD Clinical practice guidelines and consensus state- and dependent on steroids improve with ECP, but ments addressing the use of ECP for GVHD collective- most experience partial responses alone.1 Skin, oral, ly consider ECP as an established second-line therapy and ocular chronic GVHD manifestations respond in option for steroid-refractory chronic GVHD, partic- 30% to 100% of cases, whereas liver, joint, and gas- ularly involving the skin.1,190-192 ECP has also been trointestinal complications improve in 30% to 80%, recommended as an adjunctive first-line modality for 50%, and 0% to 50% of cases, respectively.1 A review bronchiolitis obliterans syndrome and select pediatric of 23 studies totaling 735 patients treated with ECP patients with acute GVHD.1,190-192 More recently, a UK for steroid-resistant, intolerant, or dependent chronic group has provided its consensus statement and guid- GVHD noted that overall and complete response rates ance on the use of ECP in adult and pediatric patients were observed in 64% and 35% of cases with skin with acute GVHD.188 The proven effectiveness of ECP involvement, in 56% and 27% cases of oral GVHD, in both acute and chronic GVHD cases is mirrored and in 47% to 57% with gastrointestinal tract chron- in the ASFA guidelines, which recommend ECP for ic GVHD.181 ECP has also been reported to stabilize chronic (category II; grade 1B recommendation) and lung function with bronchiolitis obliterans syndrome acute (category II; grade 2C recommendation) GVHD.1 related to chronic GVHD182; however, response rates for lung involvement are typically lower, ranging from Thrombocytapheresis 0% to 66%.183,184 Patients responding to ECP also have Thrombocytosis Associated With Myeloproliferative a better probability of survival, both in children (96% Neoplasms vs 58% 5-year survival)185 and in adults (88% vs 18% Thrombocytosis is defined as a peripheral blood at 2 years; relative risk, 11.6; P = .022).186 platelet count above 350,000 to 400,000/μL. Reac- Maximal responses for chronic GVHD usual- tive thrombocytosis is the most common cause of an ly require 2 to 6 months of treatment. The single, elevated platelet count and can be caused by iron randomized controlled trial using ECP for steroid-re- deficiency, inflammatory conditions, infections, ma- sistant skin chronic GVHD observed no statistically lignancy, acute bleeding, , and asplenia. significant difference in total skin score at 12 weeks Because the platelets in these conditions are func- of ECP plus salvage GVHD therapy compared with tionally normal, the increased platelet count does not salvage therapy alone.187 However, unblinded assess- normally predispose to thrombosis or acute bleed- ments recorded 40% complete and partial responses at ing. However, functionally abnormal platelets are 12 weeks in the ECP-treated group compared with associated with the elevated platelet counts seen in 10% in the non-ECP group (P < .001).187 More rapid patients with myeloproliferative neoplasms (eg, es- skin improvement was also observed at weeks 12 to sential , , chronic 24 of ECP and corticosteroids could be more quickly myelogenous leukemia, primary myelofibrosis) and tapered. Among 29 control patients from this study refractory anemia with ringed sideroblasts associated who crossed over to receive 24 weeks of ECP for with marked thrombocytosis. Functionally abnormal refractory disease, objective responses occurred in thrombocytosis is associated with an increased inci- the skin and extracutaneous tissue in 33% and up to dence of thrombohemorrhagic events.193,194 Accurate 70%, respectively.187 diagnoses of thrombocytosis are important for both No national consensus exists on the duration and prognostication and treatment.195 discontinuation of ECP procedures. For acute GVHD, Diagnoses of essential thrombocythemia and ECP is recommended on 2 consecutive days (1 cycle) polycythemia vera are currently in accordance with per week until disease response and then tapered to criteria from the World Health Organization and are alternate weeks before discontinuation.1 Some centers based on a composite assessment of clinical and lab- have recommended a minimum of 8 weeks.188 For oratory (hematological, morphological, and molecu- chronic GVHD, 1 weekly cycle (or consider biweekly lar) features.196 When evaluating thrombocytosis, the if treating mucocutaneous chronic GVHD alone) until detection of the clonal mutation JAK2 V617F confirms

72 Cancer Control January 2015, Vol. 22, No. 1 the presence of an underlying myeloproliferative neo- generally quite brief, repeat procedures are often nec- plasm. However, the absence of this mutation does essary, and it is generally recommended that plate- not rule out the possibility. Up to 50% of patients let-lowering agents be given whenever possible to pre- with essential thrombocythemia might be JAK2 V617F vent rapid reaccumulation of circulating platelets.205,206 negative; however, finding a mutation in a newly de- Each thrombocytapheresis procedure (treating scribed genetic marker, CALR, or, less commonly, MPL, 1.5–2 blood volumes) lowers the platelet count by can identify the majority of cases that are JAK2 mu- about 30% to 60%. Pre- and post-platelet counts tation negative.197 should be closely monitored to gauge the effective- Current risk stratification in essential thrombo- ness of platelet removal and to guide subsequent cythemia and polycythemia vera is designed to es- treatments. The goal of thrombocytapheresis in acute timate the likelihood of thrombotic complications. thromboembolism or hemorrhage is the normalization High risk is defined by age older than 60 years or of the platelet count and maintenance of a normal history of the presence of thrombosis, whereas low platelet count until pharmacological cytoreductive risk is defined by the absence of both of these 2 risk therapy takes effect. The goal for prophylaxis in high- factors.198-200 Extreme thrombocytosis (platelet count risk patients who are pregnant or undergoing surgery > 1,000,000/μL) can be associated with acquired von or postsplenectomy should be based on the patient’s Willebrand syndrome and, thus, a risk for bleeding.201 history of bleeding or thrombosis. Risk factors for shortened survival rates in both poly- cythemia vera and essential thrombocythemia include Erythrocytapheresis advanced age, , and a history of throm- Polycythemia Vera/Primary Erythrocytosis bosis.198,199,202 Polycythemia vera is characterized by Major thrombotic complications with essential hypercellularity, atypical megakaryocyte hyperplasia, thrombocythemia and polycythemia vera include leukocytosis, thrombocytosis, splenomegaly, and a , transient ischemic attacks, myocardial infarc- clinical predilection for thromboembolism, bleeding, tion, peripheral arterial thrombosis, lower extremity hyperviscosity complications, and the evolution to deep venous thrombosis, pulmonary embolism, and myelofibrosis or AML. The JAK2 V617F mutation is venous thrombosis in unusual sites such as hepat- found in more than 90% of cases.213,214 ic (Budd Chiari syndrome), portal, and mesenteric In polycythemia vera, viscosity in- veins.203 The risk of thrombosis in essential throm- creases significantly as the level exceeds bocythemia and polycythemia vera exceeds 20% and 50%. Malaise, headache, visual disturbances, pruritus, a substantial portion of patients experience micro- dizziness, confusion, slow mentation, and myalgia circulation disturbances.204 The most frequent bleed- are the most common symptoms. Similar to essen- ing events are hemorrhages from the gastrointestinal tial thrombocythemia, 15% to 40% of patients with tract followed by hematuria and other mucocutane- polycythemia vera may experience major arterial ous hemorrhages. Hemarthrosis and large muscle cerebrovascular or cardiovascular thromboembolic hematomas are uncommon.203 Patients with essen- events, deep venous thrombosis, pulmonary embo- tial thrombocythemia and low risk of thrombosis are lism, or intra-abdominal venous thrombotic events. given low-dose aspirin if microvascular symptoms Thrombotic risk factors with polycythemia vera in- are present but do not require cytoreductive thera- clude uncontrolled erythrocytosis (hematocrit > 55%), py. High-risk patients are treated with cytoreductive age older than 60 years, history of prior thrombosis, therapy, such as hydroxyurea, interferon α, or, less cardiovascular comorbidities, immobilization, preg- commonly, anagrelide in conjunction with low-dose nancy, and surgery.215 aspirin. RBC depletion by manual phlebotomy or by Thrombocytapheresis has been used to treat acute automated therapeutic erythrocytapheresis can cor- thromboembolism or hemorrhage in select patients rect hyperviscosity complications with uncontrolled with essential thrombocythemia or polycythemia vera polycythemia vera by lowering the hematocrit level, associated with uncontrolled thrombocytosis.205-207 The thereby reducing capillary shear and increasing micro- current ASFA guidelines are based on observational circulatory blood flow and tissue perfusion. Classical case studies or case reports (category II; grade 2C manual phlebotomy is a simple, safe, and low-cost recommendation).1 Thrombocytapheresis should also method. However, it can require a significant number be electively considered for cytoreduction in patients of procedures to reach target values.216-218 Adverse at increased risk of hemorrhage in whom hydroxyurea events related to hypovolemia with manual phlebot- is contraindicated, such as in cases of pregnancy,208-210 omy occur in a substantial number of patients, and, or if cytoreductive therapy with hydroxyurea is likely thus, this treatment modality may not be tolerated in to be too slow (eg, urgent surgery is required).211,212 the elderly, those with small blood volumes, and those Because the beneficial effect of platelet reduction is with cardiovascular compromise. However, with auto-

January 2015, Vol. 22, No. 1 Cancer Control 73 mated therapeutic erythrocytapheresis, up to 800 mL maintenance treatment costs as a result of the fewer of RBCs per single procedure can be separated from treatment procedures needed to reach recommend- other blood components and concurrently exchanged ed target values.221 One group developed a simple with a crystalloid or colloid solution, thus offering a and practical mathematical model for predicting the far more efficient method in removing RBCs while efficiency of a single cycle of therapeutic erythrocy- maintaining isovolemic conditions. tapheresis compared with a single phlebotomy pro- In the past 2 decades, 1 randomized trial and a cedure, which could in daily clinical practice aid in number of small case series have described the advan- optimizing therapeutic erythrocytapheresis use and tages of automated therapeutic erythrocytapheresis selecting a proper treatment modality for the individu- for the treatment of hereditary hemochromatosis and al patient.228 For example, the researchers determined erythrocytosis with improvements seen in treatment that therapeutic erythrocytapheresis would not be efficiency, morbidity, and patient experience.219-223 For optimal for patients with a small blood volume and/ patients with polycythemia vera and acute throm- or marginal achievable change in hematocrit level.228 boembolism, severe microvascular complications, or For patients with polycythemia vera, the goal of bleeding, automated therapeutic erythrocytapheresis therapeutic erythrocytapheresis is rapid normalization may be a useful alternative to emergent large-volume of hematocrit (ie, < 45%). A single procedure should phlebotomy, particularly if the patient is hemody- be designed to achieve the desired postprocedure namically unstable. Automated therapeutic erythro- hematocrit level. Automated instruments allow the cytapheresis can also be successfully utilized with operator to choose a postprocedure hematocrit level polycythemia vera complicated by thrombocytosis; and calculate the volume of blood removal necessary during the same session, the hematocrit level can be to attain the goal. Saline boluses may be required lowered to 42% ± 45% and the platelets reduced to during the procedure to reduce blood viscosity in the 500,000 to 600,000/μL.220,224 Therapeutic erythrocy- circuit and avoid pressure alarms.1 tapheresis may also be appropriate prior to surgery to reduce the high risk of perioperative thrombotic Conclusions complications in a patient with polycythemia vera and Therapeutic apheresis (TA) is an important treatment a hematocrit level of more than 55%. option utilized in patients to manage specific compli- A number of studies have been published sup- cations associated with malignancy. TA has been used porting the use of therapeutic erythrocytapheresis as an emergent procedure, including as a therapeutic as maintenance therapy. One study of 76 patients plasma exchange to treat symptomatic hyperviscosity with polycythemia vera saw improvement in platelet or leukocytapheresis for the treatment of leukostasis. function, as measured by thromboelastography, after TA can be effective as first-line therapy — as seen in therapeutic erythrocytapheresis, suggesting that the the use of extracorporeal photopheresis for erythro- hemodilution achieved with the procedure may re- dermic cutaneous T-cell lymphoma — although often duce thrombotic risk.225 A retrospective cohort analysis TA is attempted as salvage or adjunct therapy for con- of 98 patients, including 6 with polycythemia vera ditions not responding to conventional chemotherapy and 92 with secondary erythrocytosis, observed that or immunotherapy. Examples of such circumstances chronic automated therapeutic erythrocytapheresis include therapeutic plasma exchange for the removal allowed significantly greater treatment intervals (me- of antibodies associated with underlying paraneoplas- dian, 135–150 days; range, 2–7 months) to maintain tic processes or the use of extracorporeal photopher- the target hematocrit level compared with chronic esis for non–skin-associated graft-vs-host disease. phlebotomy (median, 40 days; range, 20–60 days).226 TA modalities are relatively safe procedures; how- The advantage of therapeutic erythrocytapheresis may ever, they are not without risk. In order for these mo- be due to the relatively greater loss of iron that is dalities to be performed, experienced staff members associated with this modality that, in turn, limits the are required. In all cases, the risks, benefits, and costs growth of hematopoietic cells.227 must be strongly considered before prescribing. The The ASFA guidelines designate polycythemia vera expert-based practice guidelines from the American as a category I indication (grade 1B recommendation) Society for Apheresis have been developed to inform for therapeutic erythrocytapheresis.1 Decisions to use hematology/oncology professionals and apheresis an automated procedure over simple phlebotomy re- physicians about the efficacy and limitations of TA for main based on clinical urgency, necessity, cost, and malignancy-related indications as well as to support consideration of the risk of adverse events that may clinical decision-making. However, well-designed, pro- be associated with automated procedures. Although spective intervention trials are still needed to better the costs of a single therapeutic erythrocytapheresis define the role of TA for a variety of disorders. procedure are substantially higher than phlebotomy, cost analysis has shown no significant difference in

74 Cancer Control January 2015, Vol. 22, No. 1 33. Winters JL, Brown D, Hazard E, et al. Cost-minimization analysis of References the direct costs of TPE and IVIg in the treatment of Guillain-Barré syndrome. 1. Schwartz J, Winters JL, Padmanabhan A, et al. Guidelines on the use BMC Health Serv Res. 2011;11:101. of therapeutic apheresis in clinical practice-evidence-based approach from 34. McLeod BC. Plasma and plasma derivatives in therapeutic plasma- the Writing Committee of the American Society for Apheresis: the sixth special pheresis. Transfusion. 2012;52(suppl 1);38S-44S. issue. J Clin Apher. 2013;28(3):145-284. 35. Michael M, Elliot EJ, Craig JC, et al. Interventions for hemolytic uremic 2. Burgstaler EA. Current instrumentation for apheresis. In: McLeod BC, syndrome and thrombotic thrombocytopenic purpura: a systematic review of Szc zepiorkowski ZM, Weinstein R, et al, eds. Apheresis: Principles and Prac- randomized controlled trials. Am J Kidney Dis. 2009;53(2):259-272. tice. 3rd ed. Bethesda, MD: AABB Press. 2010;95-130. 36. McLeod B, Gregory SA. Solvent/detergent plasma replacement in a 3. Okafor C, Ward DM, Mokrzycki MH, et al. Introduction and overview highly plasma allergic patient with TTP. J Clin Apher. 2001;16:98. of therapeutic apheresis. J Clin Apher. 2010;25(5):240-249. 37. Wang H, Chen Y, Li F, et al. Temporal and geographic variations of 4. Madore F. Plasmapheresis. Technical aspects and indications. Crit Care Waldenstrom macroglobulinemia incidence: a large population-based study. Clin. 2002;18(2):375-392. Cancer. 2012;118(15):3793-3800. 5. Linenberger ML, Price TH. Use of cellular and plasma apheresis in 38. Treon SP. How I treat Waldenström macroglobulinemia. Blood. the critically ill patient: part 1: technical and physiological considerations. 2009:114(12);2375-2385. J Intensive Care Med. 2005;20(1):18-27. 39. Fahey JL, Barth WF, Solomon A. Serum hyperviscosity syndrome. 6. Stegmayr B, Wikdahl AM. Access in therapeutic apheresis. Ther Apher JAMA. 1965;192(6):120-123. Dial. 2003;7(2):209-214. 40. Schwab PJ, Fahey JL. Treatment of Waldenström’s macroglobulinemia 7. Malchesky PS, Koo AP, Skibinski CI, et al. Apheresis technologies and by plasmapheresis. N Engl J Med. 1960;263(2):574-579. clinical applications: the 2007 International Apheresis Registry. Ther Apher 41. Solomon A, Fahey JL. Plasmapheresis therapy in macroglobulinemia. Dial. 2010;14(1):52-73. Ann Intern Med. 1963;58(5):789-800. 8. Schönermarck U, Bosch T. Vascular access for apheresis in intensive 42. Thomas EL, Olk RJ, Markman M, et al. Irreversible visual loss in care patients. Ther Apher Dial. 2003;7(2):215-220. Waldenström’s macroglobulinaemia. Br J Ophthalmol.1983;67(2):102-106. 9. Lok CE, Mokrzycki MH. Prevention and management of catheter-related 43. Menke MN, Feke GT, McMeel JW, et al. Ophthalmologic techniques infection in hemodialysis patients. Kidney Int. 2011;79(6):587-598. to assess the severity of hyperviscosity syndrome and the effect of plasma- 10. Golestaneh L, Mokrzycki MH. Vascular access in therapeutic apheresis: pheresis in patients with Waldenström’s macroglobulinemia. Clin Lymphoma update 2013. J Clin Apher.2013; 28(1):64-72. Myeloma. 2009;9(1):100-103. 11. Sutton DM, Nair RC, Rock G. Complications of plasma exchange. 44. Stone MJ, Bogen SA. Evidence-based focused review of management Transfusion. 1989;29(2):124-127. of hyperviscosity syndrome. Blood. 2012;119(10):2205-2208. 12. Noseworthy JH, Shumak KH, Vandervoort MK; Canadian Cooperative 45. Stone MJ. Pathogenesis and morbidity of autoantibody syndromes Study Group. Long-term use of antecubital veins for plasma in Waldenström’s macroglobulinemia. Clin Lymphoma Myeloma Leuk. exchange. Transfusion. 1989;29(7):610-613. 2011;11(1):157-159. 13. Grishaber JE, Cunningham MC, Rohret PA, et al. Analysis of venous 46. Frase LL, Stone MJ, Sammons CA. Long-term survival in Waldenström’s access for therapeutic plasma exchange in patients with neurological disease. macroglobulinemia. Am J Med. 1998;104(5):507-508. J Clin Apher.1992;7(3):119-123. 47. Ballestri M, Ferrari F, Magistroni R, et al. Plasma exchange in acute 14. Couriel D, Weinstein R. Complications of therapeutic plasma exchange: and chronic hyperviscosity syndrome: a rheological approach and guidelines a recent assessment. J Clin Apher. 1994;9(1):1-5. study. Ann Ist Super Sanita. 2007;43(2):171-175. 15. Basic-Jukic N, Kes P, Glavas-Boras S, et al. Complications of thera- 48. Dimopoulos MA, Zervas C, Zomas A, et al. Treatment of Waldenström’s peutic plasma exchange: experience with 4857 treatments. Ther Apher Dial. macroglobulinemia with rituximab. J Clin Oncol. 2002;20(9):2327-2333. 2005;9(5):391-395. 49. Ansell SM, Kyle RA, Reeder CB, et al. Diagnosis and management of 16. Shemin D, Briggs D, Greenan M. Complications of therapeutic Waldenström macroglobulinemia: Mayo stratification of macroglobulinemia and plasma exchange: a prospective study of 1,727 procedures. J Clin Apher. risk-adapted therapy (mSMART) guidelines. Mayo Clin Proc. 2010; 85(9):824-833. 2007;22(5):270-276. 50. Capra JD, Kunkel HG. Aggregation of gammaG3 proteins: relevance 17. Allon M. Current management of vascular access. Clin J Am Soc to the hyperviscosity syndrome. J Clin Invest. 1970;49(3):610-621. Nephrol. 2007;2(4):786-800. 51. Bloch KJ, Maki DG. Hyperviscosity syndromes associated with immu- 18. Mokrzycki MH, Kaplan AA. Therapeutic plasma exchange: complica- noglobulin abnormalities. Semin Hematol. 1973;10(2):113-124. tions and management. Am J Kidney Dis. 1994;23(6):817-827. 52. Fahey JL, Barth WF, Solomon A. Serum hyperviscosity syndrome. 19. Mokrzycki MH, Balogun RA. Therapeutic apheresis: a review of compli- JAMA.1965;192(6):120-123. cations and recommendations for prevention and management. J Clin Apher- 53. Dimopoulos MA, Kastritis E, Rosinol L, et al. Pathogenesis and treat- esis. 2011;26(5):243-248. ment of renal failure in multiple myeloma. Leukemia. 2008;22(8):1485-1493. 20. Guyatt GH, Cook DJ, Jaeschke R, et al. Grades of recommendation for 54. Knudsen LM, Hjorth M, Hippe E; Nordic Myeloma Study Group. Renal antithrombotic agents: American College of Chest Physicians Evidence-Based failure in multiple myeloma: reversibility and impact on the prognosis. Eur J Clinical Practice Guidelines (8th ed). Chest. 2008;133(6 suppl):123S-31S. Haematol. 2000;65(3):175-181. 21. Shaz BH, Schwartz J, Winters JL. How we developed and use the 55. Montseny JJ, Kleinknecht D, Meyrier A, et al. Long-term outcome ac- American Society for Apheresis guidelines for therapeutic apheresis proce- cording to renal histological lesions in 118 patients with monoclonal gammop- dures. Transfusion. 2014;54(1):17-25. athies. Nephrol Dial Transplant. 1998;13(6):1438-1445. 22. Goto H, Matsuo H, Nakane S, et al. Plasmapheresis affects T helper 56. Pillon L, Sweeting RS, Arora A, et al. Approach to acute renal failure type-1/T helper type-2 balance of circulating peripheral lymphocytes. Ther in biopsy proven myeloma cast nephropathy: is there still a role for plasma- Apher. 2001;5(6):494-496. pheresis? Kidney Int. 2008;74(7):956-961. 23. Kambara C, Matsuo H, Fukudome T, et al. Miller Fischer syndrome 57. Huang ZQ, Sanders PW. Localization of a single binding site for im- and plasmapheresis. Ther Apher. 2002;6(6):450-453. munoglobulin light chains on human Tamm-Horsfall glycoprotein. J Clin In- 24. Shariatmadar S, Nassiri M, Vincek V. Effect of plasma exchange on vest.1997;99(4):732-736. cytokines measured by multianalyte bead array in thrombotic thrombocytopenic 58. Ying WZ, Sanders PW. Mapping the binding domain of immunoglobulin purpura. Am J Hematol. 2005;79(2):83-88. lightchains for Tamm-Horsfall protein. Am J Pathol. 2001;158(5):1859-1866. 25. Szczepiorkowski ZM, Winters JL, Bandarenko N, et al. Guidelines on 59. Heher EC, Goes NB, Spitzer TR, et al. Kidney disease associated with the use of therapeutic apheresis in clinical practice: evidence-based approach plasma cell dyscrasias. Blood. 2010;116(9):1397-1404. from the Apheresis Applications Committee of the American Society for Apher- 60. Pozzi C, Pasquali S, Donini U, et al. Prognostic factors and effective- esis. J Clin Apher. 2010;25(3):83-177. ness of treatment in acute renal failure due to multiple myeloma: a review of 26. Flaum MA, Cuneo RA, Appelbaum FR, et al. The hemostatic imbalance 50 cases. Report of the Italian Renal Immunopathology Group. Clin Nephrol. of plasma-. Blood. 1979;54(3):694-702. 1987;28(1):1-9. 27. Chirnside A, Urbaniak SJ, Prowse CV, et al. Coagulation abnormalities 61. Zucchelli P, Pasquali S, Cagnoli L, et al. Controlled plasma exchange trial following intensive plasma exchange on the cell separator. II. Effects on factors in acute renal failure due to multiple myeloma. Kidney Int. 1988;33(6):1175-1180. I, II, V, VII, VIII, IX, X and antithrombin III. Br J Haematol.1981;48(4):627-634. 62. Johnson WJ, Kyle RA, Pineda AA, et al. Treatment of renal failure 28. Orlin JB, Berkman EM. Partial plasma exchange using albumin re- associated with multiple myeloma. Plasmapheresis, hemodialysis, and che- placement: removal and recovery of normal plasma constituents. Blood. motherapy. Arch Intern Med. 1990;150(4):863-869. 1980;56(6):1055-1059. 63. Durie BG, Kyle RA, Belch A et al. Myeloma management guidelines: 29. Ibrahim RB, Liu C, Cronin SM, et al. Drug removal by plasmapheresis: a consensus report from the Scientific Advisors of the International Myeloma an evidence-based review. Pharmacotherapy. 2007;27(11):1529-1549. Foundation. Hematol J. 2003;4(6):379-398. 30. Kintzel PE, Eastlund T, Calis KA. Extracorporeal removal of antimicro- 64. Clark WF, Stewart AK, Rock GA, et al; Canadian Apheresis Group. bials during plasmapheresis. J Clin Apher. 2003;18(4):194-205. Plasma exchange when myeloma presents as acute renal failure: a random- 31. Finlayson JS. Albumin products. Semin Thromb Hemost.1980;6:85-120. ized, controlled trial. Ann Intern Medicine. 2005;143(11):777-784. 32. Matejtschuk P, Dash CH, Gascoigne EW. Production of human albumin 65. Burnette BL, Leung N, Rajkumar SV. Renal improvement in myeloma with solutions: a continually developing colloid [Erratum appears in Br J Anaesth. bortezomib plus plasma exchange. N Engl J Med. 2011;364(24):2365-2366. 2001;86(2):301]. Br J Anaesth. 2000;85(6):887-895. 66. Bladé J, Rosiñol L. Renal, hematologic and infectious complications

January 2015, Vol. 22, No. 1 Cancer Control 75 in multiple myeloma. Best Pract Res Clin Haematol. 2005;18(4):635-652. 97. Nacar A, Kiyici H, Oğüş E, et al. Ultrastructural examination of glomer- 67. Torra J, Bladé A, Cases A, et al. Patients with multiple myeloma and renal ular and tubular changes in renal allografts with cyclosporine toxicity. Ren Fail. failure requiring long-term dialysis: presenting features, response to therapy, and 2006;28(7):543-547. outcome in a series of 20 cases. Br J Haematol. 1995;91(4):854-859. 98. Burke GW, Ciancio G, Cirocco R, et al. Microangiopathy in kidney and 68. Darnell RB, Posner JB. Paraneoplastic syndromes involving the nervous simultaneous pancreas/kidney recipients treated with :evidence of system. N Eng J Med. 2003;349(16):1543-1554. endothelin and cytokine involvement. Transplantation. 1999;68(9):1336-1342. 69. Antoine JC, Camdessanché JP. Peripheral nervous system involvement 99. Labrador J, López-Corral L, López-Godino O, et al. Risk factors for in patients with cancer. Lancet Neurol. 2007;6(1):75-86. thrombotic microangiopathy in allogeneic hematopoietic stem cell recipients 70. Elrington GM, Murray NM, Spiro SG, Newsom-Davis J. Neurological receiving GVHD prophylaxis with tacrolimus plus MTX or sirolimus. Bone paraneoplastic syndromes in patients with small cell lung cancer. A prospective Marrow Transplant. 2014;49(5):684-690. survey of 150 patients. J Neurol Neurosurg Psychiatry. 1991;54(9):764-767. 100. Henry N, Li S, Kim HT, et al. Sirolimus and thrombotic microangiopathy 71. Levy Y, Afek A, Sherer Y, et al. Malignant thymoma associated with after allogeneic stem cell transplantation. Blood. 2004;104:508a. autoimmune diseases: a retrospective study and review of the literature. Semin 101. Fuge R, Bird JM, Fraser A, et al. The clinical features, risk factors and Arthritis Rheum. 1998;28(2):73-79. outcome of thrombotic thrombocytopenic purpura occurring after bone marrow 72. Sculier JP, Feld R, Evans WK, et al. Neurologic disorders in patients transplantation. Br J Haematol. 2001;113(1):58-64. with small cell lung cancer. Cancer. 1987;60(9):2275-2283. 102. Biedermann BC, Sahner S, Gregor M, et al. Endothelial injury mediated 73. Darnell RB. Onconeural antigens and paraneoplastic neurologic dis- by cytotoxic T lymphocytes and loss of microvessels in chronic graft versus orders: At the intersection of cancer, immunity, and the brain. Proc Natl Acad host disease. Lancet. 2002;359(9323):2078-2083. Sci USA. 1996;93(10):4529-4536. 103. Martinez MT, Bucher CH, Stussi G, et al. Transplant-associated micro- 74. Rosenfeld MR, Dalmau JO. Paraneoplastic disorders of the CNS angiopathy (TAM) in recipients of allogeneic hematopoietic stem cell trans- and autoimmune synaptic encephalitis. Continuum (Minneap Minn). plants. Bone Marrow Transplant. 2005;36(11):993-1000. 2012;18(2):366-383. 104. Matsuda Y, Hara J, Miyoshi H, et al. Thrombotic microangiopathy as- 75. Graus F, Delattre JY, Antoine JC, et al. Recommended diagnostic criteria sociated with reactivation of human herpesvirus-6 following high-dose che- for paraneoplastic neurological syndromes. J Neurol Neurosurg Psychiatry. motherapy with autologous bone marrow transplantation in young children. 2004;75(8):1135-1140. Bone Marrow Transplant. 1999;24(8):919-923. 76. Keime-Guibert F, Graus F, Fleury A, et al. Treatment of paraneoplastic 105. Grigg A, Clouston D. Disseminated fungal infection and early onset neurological syndromes with antineuronal antibodies (anti-Hu, anti-Yo) with a microangiopathy after allogeneic bone marrow transplantation. Bone Marrow combination of immunoglobulins, cyclophosphamide, and methylprednisolone. Transplant. 1995;15(5):795-797. J Neurol Neurosurg Psychiatry. 2000;68(4):479-482. 106. Cohen H, Bull HA, et al. Vascular endothelial cell function and ultra- 77. Vernino S, O’Neill BP, Marks RS, et al. Immunomodulatory treatment structure in thrombotic microangiopathy following allogeneic bone marrow trial for paraneoplastic neurological disorders. Neuro Oncol. 2004;6(1):55-62. transplantation. Eur J Haematol. 1989;43(3):207-214. 78. Dalmau J, Rosenfeld MR. Paraneoplastic syndromes of the CNS. 107. Jimenez JJ, Jy W, Mauro LM. Endothelial microparticles released in Lancet Neuro. 2008;7(4):327-340. thrombotic thrombocytopaenic purpura express von Willebrand factor and 79. Bradley WH, Dottino PR, Rahaman J. Paraneoplastic cerebellar degen- markers of endothelial activation. Br J Haematol. 2003;123(5):896-902. eration in ovarian carcinoma: case report with review of immune modulation. 108. Jy W, Jimenz J, Mauro LM, et al. Endothelial microparticles induce Int J Gynecol Cancer. 2008;18(6):1364-1367. formation of platelet aggregates via a von Willebrand factor/ristocetin depen- 80. Croteau D, Owainati A, Dalmau J, et al. Response to cancer therapy in a dent pathway, rendering them resistant to dissociation. J Thromb Haemost. patient with a paraneoplastic choreiform disorder. Neurology. 2001;57(4):719-722. 2005;3(6):1301-1308. 81. Vigliani MC, Palmucci L, Polo P, et al. Paraneoplastic opsoclonus-myoc- 109. Elliott MA, Nichols WL, Plumhoff EA, et al. Posttransplantation thrombot- lonus associated with renal cell carcinoma and responsive to tumour ablation. ic thrombocytopenic purpura: a single-center experience and a contemporary J Neurol Neurosurg Psychiatry. 2001;70(6):814-815. review. Mayo Clin Proc. 2003;78(4):421-430. 82. Widdess-Walsh P, Tavee JO, Schuele S, et al. Response to intravenous 110. Arai S, Allan C, Streiff M, et al. Von Willebrand-cleaving protease activity immunoglobulin in anti-Yo associated paraneoplastic cerebellar degeneration: and proteolysis of von Willebrand factor in bone marrow transplant-associated case report and review of the literature. J Neurooncol. 2003;63(2):187-190. thrombotic microangiopathy. Hematol J. 2001;2(5):292-299. 83. David YB, Warner E, Levitan M, et al. Autoimmune paraneoplastic cere- 111. Allford SL, Bird JM, Marks DI. Thrombotic thrombocytopenic purpura bellar degeneration in ovarian carcinoma patients treated with plasmapheresis following stem cell transplantation. Leuk Lymphoma. 2002;43(10):1921-1926. and immunoglobulin: a case report. Cancer. 1996;78(10):2153-2156. 112. Willems E, Baron F, Seidel L, et al. Comparison of thrombotic microan- 84. Giometto B, Vitaliani R, Lindeck-Pozza E, et al. Treatment for parane- giopathy after allogeneic hematopoietic cell transplantation with high-dose or oplastic neuropathies. Cochrane Database Syst Rev. 2012;(12):CD007625. nonmyeloablative conditioning. Bone Marrow Transplant. 2010;45(4):689-693. 85. Shams’ili S, Grefkens J, De Leeuw B, et al. Paraneoplastic cerebellar 113. Laskin BL, Goebel J, Davies SM, et al. Small vessels, big trouble in degeneration associated with antineuronal antibodies: analysis of 50 patients. the kidneys and beyond: hematopoietic stem cell transplantation-associated Brain. 2003;126(pt 6):1409-1418. thrombotic microangiopathy. Blood. 2011;118(6):1452-1462. 86. Newsom-Davis J, Murray NM. Plasma exchange and immunosuppres- 114. George JN, Li X, McMinn JR, et al. Thrombotic thrombocytopenic pur- sive drug treatment in the Lambert-Eaton myasthenic syndrome. Neurology. pura-hemolytic uremic syndrome following allogeneic HPC transplantation: a 1984;34(4):480-485. diagnostic dilemma. Transfusion. 2004;44(2):294-304. 87. Greenlee JE. Treatment of paraneoplastic cerebellar degeneration. 115. Batts ED, Lazarus HM. Diagnosis and treatment of transplantation-as- Curr Treat Options Neurol. 2013;15(2):185-200. sociated thrombotic microangiopathy: real progress or are we still waiting? 88. Vernino S, O’Neill BP, Marks RS, et al. Immunomodulatory treatment Bone Marrow Transplant. 2007;40(8):709-719. trial for paraneoplastic neurological disorders. Neuro Oncol. 2004;6(1):55-62. 116. Daly AS, Xenocostas A, Lipton JH. Transplantation associated throm- 89. van Broekhoven F, de Graaf MT, Bromberg JE, et al. Human chorionic botic microangiopathy: twenty-two years later. Bone Marrow Transplant. gonadotropin treatment of anti-Hu-associated paraneoplastic neurological 2002;30(11):709-715. syndromes. J Neurol Neurosurg Psychiatry. 2010;81(12):1341-1344. 117. Rock G, Shumak KH, Sutton DM, et al; Members of the Canadian 90. Shams’ili S, de Beukelaar J, Gratama JW, et al. An uncontrolled trial Apheresis Group. Cryosupernatant as replacement fluid for plasma exchange of rituximab for antibody associated paraneoplastic neurological syndromes. in thrombotic thrombocytopenic purpura. Br J Haematol. 1996;94(2):383-386. J Neurol. 2006;253(1):16-20. 118. Korkmaz S, Keklik M, Sivgin S, et al. Therapeutic plasma exchange in 91. Widdess-Walsh P, Tavee JO, Schuele S, et al. Response to intravenous patients with thrombotic thrombocytopenic purpura: a retrospective multicenter immunoglobulin in anti-Yo associated paraneoplastic cerebellar degeneration: study. Transfus Apher Sci. 2013;48(3):353-358. case report and review of the literature. J Neuro Oncol. 2003,63(2):187-190. 119. Brunskill SJ, Tusold A, Benjamin S, et al. A systematic review of ran- 92. Laszik Z, Silva F. Hemolytic-uremic syndrome, thrombotic thrombocy- domized controlled trials for plasma exchange in the treatment of thrombotic topenic purpura, and systemic sclerosis (). In: Jennet thrombocytopenic purpura. Transfus Med. 2007;17(1):17-35. JC, Olson JL, Schwartz MM, et al, eds. Heptinstall’s Pathology of the Kidney. 120. Ho VT, Cutler C, Carter S, et al. Blood and marrow transplant clinical Philadelphia: Lippincott-Raven; 1998:1003-1057. trials network toxicity committee consensus summary: thrombotic microan- 93. Chow AY, Chin C, Dahl G, Rosenthal DN. Anthracyclines cause giopathy after hematopoietic stem cell transplantation. Biol Blood Marrow endothelial injury in pediatric cancer patients: a pilot study. J Clin Oncol. Transplant. 2005;11(8):571-575. 2006;24(6):925-928. 121. Wolff D, Wilhelm S, Hahn J, et al. Replacement of calcineurin inhibitors 94. Nagaya S, Wada H, Oka K, et al. Hemostatic abnormalities and in- with daclizumab in patients with transplantation-associated microangiopathy creased vascular endothelial cell markers in patients with red cell fragmentation or renal insufficiency associated with graft versus host disease. Bone Marrow syndrome induced by mitomycin C. Am J Hematol. 1995;50(4):237-243. Transplant. 2006;38(6):445-451. 95. Oner AF, Gürgey A, Kirazli S, et al. Changes of hemostatic factors in 122. Corti P, Uderzo C, Tagliabue A, et al. Defibrotide as a promising treat- children with acute lymphoblastic leukemia receiving combined chemotherapy ment for thrombotic thrombocytopenic purpura in patients undergoing bone including high dose methylprednisolone and L-asparaginase. Leuk Lymphoma. marrow transplantation. Bone Marrow Transplant. 2002;29(6):542-543. 1999;33(3-4):361-364. 123. Au WY, Ma ES, Lee TL, et al. Successful treatment of thrombotic mi- 96. Fajardo LF. The pathology of ionizing radiation as defined by morpho- croangiopathy after haematopoietic stem cell transplantation with rituximab. logic patterns. Acta Oncol. 2005;44(1):13-22. Br J Haematol. 2007;137(5):475-478.

76 Cancer Control January 2015, Vol. 22, No. 1 124. Jodele S, Fukuda T, Vinks A, et al. Eculizumab therapy in children and chronic graft-versus-host disease. Br J Dermatol. 2008;158(4):659-678. with severe hematopoietic stem cell transplantation-associated thrombotic 155. Heshmati F. Updating ECP action mechanisms. Transfus Apher Sci. microangiopathy. Biol Blood Marrow Transplant. 2014;20(4):518-525. 2014;50(3):330-339. 125. Peffault de Latour R, Xhaard A, Fremeaux-Bacchi V, et al. Successful 156. Goussetis E, Varela I, Tsirigotis P. Update on the mechanism of action use of eculizumab in a patient with post-transplant thrombotic microangiopathy. and on clinical efficacy of extracorporeal photopheresis in the treatment of Br J Haematol. 2013;161(2):279-280. acute and chronic graft versus host disease in children. Transfus Apher Sci. 126. Porcu P, Cripe LD, Ng EW et al. Hyperleukocytic leukemias and leu- 2012;46(2):203-209. kostasis: a review of pathophysiology, clinical presentation and management. 157. Mueller DL. Mechanisms maintaining peripheral tolerance. Nat Immu- Leuk Lymphoma. 2000;39(1-2):1-18. nol. 2010;11(1):21-27. 127. Estey EH, Keating MJ, McCredie KB, et al. Causes of initial remission 158. Alcindor T, Gorgun G, Miller KB, et al. Immunomodulatory effects of induction failure in acute myelogenous leukemia. Blood. 1982;60(2):309-315. extracorporeal photochemotherapy in patients with extensive chronic graft- 128. Eguiguren JM, Schell MJ, Crist WM, et al. Complications and outcome versus-host disease. Blood. 2001;98(5):1622-1625. in childhood acute lymphoblastic leukemia with hyperleukocytosis. Blood. 159. Berger CL, Xu AL, Hanlon D, et al. Induction of human tumor-loaded 1992;79(4):871-875. dendritic cells. Int J Cancer. 2001;91(4):438-447. 129. Lichtman MA, Rowe JM. Hyperleukocytic leukemias: rheological, clinical 160. Spisek R, Gasova Z, Bartunkova J. Maturation state of dendritic cells and therapeutic considerations. Blood. 1982;60(2):279-283. during the extracorporeal photopheresis and its relevance for the treatment 130. Stucki A, Rivier AS, Gikic M, et al. Endothelial cell activation by myelo- of chronic graft-versus-host disease. Transfusion. 2006;46(1):55-65. blasts: molecular mechanisms of leukostasis and leukemic cell dissemination. 161. Yoo EK, Rook AH, Elenitsas R, et al. Apoptosis induction by ultraviolet Blood. 2001;97(7):2121-2129. light A and photochemotherapy in cutaneous T-cell lymphoma: relevance to 131. Lowe EJ, Pui CH, Hancock ML, et al. Early complications in children mechanism of therapeutic action. J Invest Dermatol. 1996;107(2):235-242. with acute lymphoblastic leukemia presenting with hyperleukocytosis. Pediatr 162. Heshmati F, Andreu G. Extracorporeal photochemotherapy: a historical Blood Cancer. 2005;45(1):10-15. perspective. Transfus Apher Sci. 2003;28(1):25-34. 132. Novotny JR, Nückel H, Dührsen U. Correlation between expression of 163. Rook AH, Suchin KR, Kao DMF, et al. Photopheresis: clinical applica- CD56/NCAM and severe leukostasis in hyperleukocytic acute myelomonocytic tions and mechanism of action. J Invest Dermatol Symp Proc. 1999;4(1):85-90. leukaemia. Eur J Haematol. 2006;76(4):299-308. 164. Girardi M, Berger CL, Wilson LD, et al. Transimmunization for cutaneous 133. Marbello L, Ricci F, Nosari AM, et al. Outcome of hyperleukocytic adult T cell lymphoma: a phase I study. Leuk Lymphoma. 2006;47(8):1495-1503. acute myeloid leukaemia: a single-center retrospective study and review of 165. Zic JA. Photopheresis in the treatment of cutaneous T-cell lymphoma: literature. Leuk Res. 2008;32(8):1221-1227. current status. Curr Opin Oncol. 2012;(24 suppl 1):S1-S10. 134. Bug G, Anargyrou K, Tonn T, et al. Impact of leukapheresis on early 166. Scarisbrick JJ. Staging and management of cutaneous T-cell lymphoma. death rate in adult acute myeloid leukemia presenting with hyperleukocytosis. Clin Exp Dermatol. 2006;31(2):181-186. Transfusion. 2007;47(10):1843-50. 167. Zic JA. The treatment of cutaneous T-cell lymphoma with photopheresis. 135. Giles FJ, Shen Y, Kantarjian HM, et al. Leukapheresis reduces early Dermatol Ther. 2003;16(4):337-346. mortality in patients with acute myeloid leukemia with high white cell counts 168. Child FJ, Mitchell TJ, Whittaker SJ, et al. A randomized cross-over study but does not improve long-term survival. Leuk Lymphoma. 2001;42(1-2):67-73. to compare PUVA and extracorporeal photopheresis in the treatment of plaque 136. Oberoi S, Lehrnbecher T, Phillips B, et al. Leukapheresis and low- stage (T2) mycosis fungoides. Clin Exp Dermatol. 2004;29(3):231-236. dose chemotherapy do not reduce early mortality in acute myeloid leuke- 169. National Comprehensive Cancer Network. NCCN clinical practice mia hyperleukocytosis: a systematic review and meta-analysis. Leuk Res. guidelines: non-Hodgkin lymphoma. http://www.nccn.org/professionals/phy- 2014;38(4):460-468. sician_gls/pdf/nhl.pdf. Accessed October 26, 2014. 137. Porcu P, Farag S, Marcucci G, et al. Leukocytoreduction for acute 170. Agar NS, Wedgeworth E, Crichton S, et al. Survival outcomes and leukemia. Ther Apher. 2002;6(1):15-23. prognostic factors in mycosis fungoides/Sézary syndrome: validation of the 138. Adams BD, Baker R, Lopez JA, et al. Myeloproliferative disorders and revised International Society for Cutaneous Lymphomas/European Organi- the hyperviscosity syndrome. Emerg Med Clin North Am. 2009;27(3):459-476. sation for Research and Treatment of Cancer staging proposal. J Clin Oncol. 139. Rowe JM, Lichtman MA. Hyperleukocytosis and leucostasis: a com- 2010;28(31):4730-4739. mon features of childhood chronic myelogenous leukemia. Blood. 1984;63(5): 171. Ferrara JL, Levine JE, Reddy P, et al. Graft-versus-host disease. Lancet. 1230-1234. 2009;373(9674):1550-1561. 140. Shafique S, Bona R, Kaplan AA. A case report of therapeutic leu- 172. Flowers ME, Inamoto Y, Carpenter PA, et al. Comparative analysis of kapheresis in an adult with chronic myelogenous leukemia presenting with risk factors for acute graft-versus-host disease and for chronic graft-versus-host hyperleukocytosis and leukostasis. Ther Apher Dial. 2007;11(2):146-149. disease according to National Institutes of Health consensus criteria. Blood. 141. Ponniah A, Brown CT, Taylor P. Priapism secondary to leukemia: effec- 2011;117(11):3214-3219. tive management with prompt leukapheresis. Int J Urol. 2004;11(9):809-810. 173. Martin PJ, Rizzo JD, Wingard JR, et al. First- and second-line sys- 142. Rodgers R, Latif Z, Copland M. How I manage priapism in chronic temic treatment of acute graft-versus-host disease: recommendations of the myeloid leukaemia patients. Br J Haematol. 2012;158(2):155-164. American Society of Blood and Marrow Transplantation. Biol Blood Marrow 143. El Bahnasawy MS, Dawood A, Farouk A. Low-flow priapism: risk factors Transplant. 2012;18(8):1150-1163. for erectile dysfunction. BJU. 2002;89(3):285-290. 174. Martin PJ, Inamoto Y, Carpenter PA, et al. Treatment of chronic graft- 144. Jameel T, Mehmood K. Priapism - an unusual presentation in chron- versus-host disease: Past, present and future. Korean J Hematol. ic myeloid leukaemia:case report and review of the literature. Biomedica. 2011;46(3):153-163. 2009;25:197-199. 175. Stewart BL, Storer B, Storek J, et al. Duration of immunosuppressive 145. Stucki A, Rivier AS, Gikic M, et al. Endothelial cell activation by myelo- treatment for chronic graft-versus-host disease. Blood. 2004;104(12):3501-3506. blasts: molecular mechanisms of leukostasis and leukemic cell dissemination. 176. Vigorito AC, Campregher PV, Storer BE, et al. Evaluation of NIH Blood. 2001;97(7):2121-2129. consensus criteria for classification of late acute and chronic GVHD. Blood. 146. Shafique S, Bona R, Kaplan AA. A case report of therapeutic leu- 2009;114(3):702-708. kapheresis in an adult with chronic myelogenous leukemia presenting with 177. Inamoto Y, Flowers ME. Treatment of chronic graft-versus-host disease hyperleukocytosis and leukostasis. Ther Apher Dial. 2007;11(2):146-149. in 2011. Curr Opin Hematol. 2011;18(6):414-420. 147. Montague DK, Jarow J, Broderick GA, et al. American Urological As- 178. Garnett C, Apperley JF, Pavlů J. Treatment and management of graft- sociation guideline on the management of priapism. J Urol. 2003;170(4 pt versus-host disease: improving response and survival. Ther Adv Hematol. 1):1318-1324. 2013;4(6):366-378. 148. Castagnetti M, Sainati L, Giona F, et al. Conservative management of 179. Perfetti P, Carlier P, Strada P, et al. Extracorporeal photopheresis for priapism secondary to leukemia. Pediatr Blood Cancer. 2008;51(3):420-423. the treatment of steroid refractory acute GVHD. Bone Marrow Transplant. 149. Ponniah A, Brown CT, Taylor P. Priapism secondary to leukemia: effec- 2008;42(9):609-617. tive management with prompt leukapheresis. Int J Urol. 2004;11(9):809-810. 180. Berger M, Pessolano R, Albiani R, et al. Extracorporeal photopheresis 150. Stemmler J, Wittmann GW, Hacker U, Heinemann V. Leukapheresis in for steroid resistant graft versus host disease in pediatric patients: a pilot single chronic myelomonocytic leukemia with leukostasis syndrome: elevated serum institution report. J Pediatr Hematol Oncol. 2007;29(10):678-687. lactate levels as an early sign of microcirculation failure. Leuk Lymphoma. 181. Pierelli L, Perseghin P, Marchetti M, et al. Extracorporeal photopheresis 2002;43(7):1427-1430. for the treatment of acute and chronic graft-versus-host disease in adults and 151. Ganzel C, Becker J, Mintz PD, et al. Hyperleukocytosis, leukostasis children: best practice recommendations from an Italian society of hemapheresis and leukapheresis: practice management. Blood Rev. 2012;26(3):117-122. and cell manipulation (SIdEM) and Italian group for bone marrow transplantation 152. Edelson R, Berger C, Gasparro F, et al. Treatment of cutaneous T-cell (GITMO) consensus process. Transfusion. 2013;53(10):2340-2352. lymphoma by extracorporeal photochemotherapy. Preliminary results. N Engl 182. Lucid CE, Savani BN, Engelhardt BG, at al. Extracorporeal photophere- J Med. 1987;316(6):297-303. sis in patients with refractory bronchiolitis obliterans developing after allo-SCT. 153. Trautinger F, Knobler R, Willemze R, et al. EORTC consensus recom- Bone Marrow Transplant. 2011;46(3):426-429. mendations for the treatment of mycosis fungoides/Sezary syndrome. Eur J 183. Perotti C, Del Fante C, Tinelli C, et al. Extracorporeal photochemother- Cancer. 2006;42(8):1014-1030. apy in graft-versus-host disease: a longitudinal study on factors influencing the 154. Scarisbrick JJ, Taylor P, Holtick U, et al. U.K. consensus statement on the response and survival in pediatric patients. Transfusion. 2010;50(6):1359-1369. use of extracorporeal photopheresis for treatment of cutaneous T-cell lymphoma 184. Hildebrandt GC, Fazekas T, Lawitschka A, et al. Diagnosis and treatment

January 2015, Vol. 22, No. 1 Cancer Control 77 of pulmonary chronic GvHD: report from the consensus conference on clinical 2005;434(7037):1144-1148. practice in chronic GvHD. Bone Marrow Transplant. 2011;46(10):1283-1295. 215. Barosi G, Mesa R, Finazzi G, et al. Revised response criteria for polycy- 185. Kanold J, Messina C, Halle P, et al; Paediatric Diseases Working Party themia vera and essential thrombocythemia: an ELN and IWG-MRT consensus of the European Group for Blood and Marrow Transplantation. Update on project. Blood. 2013;121(23):4778-4781. extracorporeal photochemotherapy for graft-versus-host disease treatment. 216. Brissot P, Ball S, Rofail D, et al. Hereditary hemochromatosis: pa- Bone Marrow Transplant. 2005;(35 suppl 1):S69-S71. tient experiences of the disease and phlebotomy treatment. Transfusion. 186. Perseghin P, Galimberti S, Balduzzi A, et al. Extracorporeal photoche- 2011;51(6):1331-1338. motherapy for the treatment of chronic graft-versus-host disease: trend for a 217. McDonnell SM, Grindon AJ, Preston BL, et al. A survey of phlebotomy possible cell dose-related effect? TherApher Dial. 2007;11(2):85-93. among persons with hemochromatosis. Transfusion. 1999;39(6):651-656. 187. Flowers ME, Apperley JF, van Besien K, et al. A multicenter prospective 218. McDonnell SM, Preston BL, Jewell SA, et al. A survey of 2,851 patients phase 2 randomized study of extracorporeal photopheresis for treatment of with hemochromatosis: symptoms and response to treatment. Am J Med. chronic graft-versus-host disease. Blood. 2008;112(7):2667-2674. 1999;106(6):619-624. 188. Das-Gupta E, Dignan F, Shaw B, et al. Extracorporeal photopheresis for 219. Kaboth U, Rumpf KW, Lipp T, et al. Treatment of polycythemia vera by treatment of adults and children with acute GVHD: UK consensus statement and isovolemic large-volume erythrocytapheresis. Klin Wochenschr. 1990;68(1):18-25. review of published literature. Bone Marrow Transplant. 2014;49(10:1251-1258. 220. Kaboth U, Rumpf KW, Liersch T, et al. Advantages of isovolemic 189. Heshmati F. Extra corporeal photo chemotherapy (ECP) in acute and large-volume erythrocytapheresis as a rapidly effective and long-lasting treat- chronic GVHD. Transfus Apher Sci. 2010;43(2):211-215. ment modality for depletion in patients with polycythemia vera. 190. Dignan FL, Clark A, Amrolia P, et al; Haemato-oncology Task Force of Ther Apher. 1997;1(2):131-134. British Committee for Standards in Haematology; British Society for Blood and 221. Rombout-Sestrienkova E, Nieman FH, Essers BA, et al. Erythrocyta- Marrow Transplantation. Diagnosis and management of acute graft-versus-host pheresis versus phlebotomy in the initial treatment of HFE hemochromatosis disease. Br J Haematol. 2012;158(1):46-61. patients: results from a randomized trial. Transfusion 2012;52(3):470-477. 191. European Dermatology Forum. Guideline on extracorporeal photopheresis. 222. Vecchio S, Leonardo P, Musuraca V, et al. A comparison of the results http://www.euroderm.org/index.php/edf-guidelines. Accessed October 26, 2014. obtained with traditional phlebotomy and with therapeutic erythrocytapheresis 192. Martin PJ, Rizzo JD, Wingard JR, et al. First and second-line systemic in patients with erythrocytosis. . 2007;5(1):20-23. treatment of acute graft-versus-host disease: recommendations of the Amer- 223. Wijermans P, Egmond van L, Ypma P, et al. Isovolemic erythrocyta- ican Society of Blood and Marrow Transplantation. Biol Blood Marrow Trans- pheresis technique as an alternative to conventional phlebotomy in patients plant. 2012;18(8):1150-1163. with polycythemia rubra vera and hemochromatosis. Transfus Apher Sci. 193. Carobbio A, Thiele J, Passamonti F, et al. Risk factors for arterial and 2009;40(2):137. venous thrombosis in WHO-defined essential thrombocythemia: an interna- 224. Gerson SL, Lazarus HM. Hematopoietic emergencies. Semin Oncol. tional study of 891 patients. Blood. 2011;117(22):5857-5859. 1989;16(6):532-542. 194. Finazzi G,Carobbio A, Thiele J, et al. Incidence and risk factors 225. Rusak T, Ciborowski M, Uchimiak-Owieczko A, et al. Evaluation of for bleeding in 1104 patients with essential thrombocythemia or prefibrot- hemostatic balance in blood from patients with polycythemia vera by means ic myelofibrosis diagnosed according to the 2008 WHO criteria. Leukemia. of thromboelastography: the effect of isovolemic erythrocytapheresis. Platelets. 2012;26(4):716-719. 2012;23(6):455-462. 195. Barbui T, Thiele J, Passamonti F, et al. Survival and disease progression 226. Vecchio S, Leonardo P, Musuraca V, et al. A comparison of the results in essential thrombocythemia are significantly influenced by accurate morpho- obtained with traditional phlebotomy and with therapeutic erythrocytapheresis logic diagnosis: an international study. J Clin Oncol. 2011;29(23):3179-3184. in patients with erythrocytosis. Blood Transfus. 2007;5(1):20-23. 196. Tefferi A, Thiele J, Orazi A, et al. Proposals and rationale for revision 227. .Kabot U, Vehmeyer K, Liersch T. Polycythemia vera: reduced prolifera- of the World Health Organization diagnostic criteria for polycythemia vera, tive capacity of erythroid progenitor cells after large volume erythrocyte-apher- essential thrombocythemia, and primary myelofibrosis: recommendations esis apparently due to the massive loss of iron. J Clin Apheresis.1993;8:43. from an ad hoc international expert panel. Blood. 2007;110(4):1092-1097. 228. Evers D, Kerkhoffs JL, Van Egmond L, et al. The efficiency of thera- 197. Nangalia J, Massie CE, Baxter EJ, et al. Somatic CALR mutations peutic erythrocytapheresis compared to phlebotomy: a mathematical tool for in myeloproliferative neoplasms with nonmutated JAK2. N Engl J Med. predicting response in hereditary hemochromatosis, polycythemia vera, and 2013;369(25):2391-2405. secondary erythrocytosis. J Clin Apher. 2014;29(3):133-138. 198. Passamonti F, Rumi E, Arcaini L, et al. Prognostic factors for thrombosis, myelofibrosis, and leukemia in essential thrombocythemia: a study of 605 patients. Haematologica. 2008;93(11):1645-1651. 199. Passamonti F, Rumi E, Pungolino E, et al. Life expectancy and prog- nostic factors for survival in patients with polycythemia vera and essential thrombocythemia. Am J Med. 2004;117(10):755-761. 200. Di Nisio M, Barbui T, Di Gennaro L, et al; Collaboration on Low-dose Aspirin in Polycythemia Vera (ECLAP) Investigators. The haematocrit and platelet target in polycythemia vera. Br J Haematol. 2007;136(2):249-259. 201. Budde U, Schaefer G, Mueller N, et al. Acquired von Willebrand’s dis- ease in the myeloproliferative syndrome. Blood. 1984;64(5):981-985. 202. Gangat N, Wolanskyj AP, McClure RF, et al. Risk stratification for survival and leukemic transformation in essential thrombocythemia: a single institutional study of 605 patients. Leukemia. 2007;21(2):270-276. 203. Elliott MA, Tefferi A. Thrombosis and haemorrhage in polycythaemia vera and essential thrombocythaemia. Br J Haematol. 2005;128(3):275-290. 204. Tefferi A, Elliott M. Thrombosis in myeloproliferative disorders: preva- lence, prognostic factors, and the role of leukocytes and JAK2V617F. Semin Thromb Hemost. 2007;33(4):313-320. 205. Grima KM. Therapeutic apheresis in hematological and oncological diseases. J Clin Apheresis. 2000;15(1-2):28-52. 206. Taft EG, Babcock RB, Scharfman WB, et al. Platelet pheresis in the management of thrombocytosis. Blood.1977;50(5):927-933. 207. Budde U, van Genderen PJJ. Acquired von Willebrand disease in pa- tients with high platelet counts. Semin Thromb Hemost. 1997;23(5):425-431. 208. Tefferi A, Silverstein MN, Hoagland HC. Primary thrombocythemia. Semin Oncol. 1995;22(4):334-340. 209. Kaibara M, Kobayashi T, Matsumoto S. Idiopathic thrombocythemia and pregnancy: report of a case. Obstet Gynecol 1985;65(3 suppl):18S-19S. 210. Beard J, Hillmen P, Anderson CC, et al. Primary thrombocythaemia in pregnancy. Br J Haematol.1991;77(3):371-374. 211. Schött U. Essential thrombocythemia and coronary artery bypass sur- gery. J Cardiothorac Vasc Anesth 1994;8(5):552-555. 212. Hsiao HT, Ou SY. Successful microsurgical tissue transfer in a patient with postsplenectomy thrombocytosis treated with platelet-phoresis. J Reconstr Microsurg 1997;13(8):555-558. 213. Kralovics R, Passamonti F, Buser AS, et al. Again-of-function mutation of JAK2 in myeloproliferative disorders. N Engl J Med. 2005;352(17):1779-1790. 214. James C, Ugo V, Le Couedic JP, et al. A unique clonal JAK2 mu- tation leading to constitutive signalling causes polycythaemia vera. Nature.

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