Hematopoietic Cell Transplantation, Version 2.2020, NCCN Clinical Practice Guidelines in Oncology

Hematopoietic cell transplantation (HCT) involves the infusion of hematopoietic progenitor cells into patients with hematologic disorders with the goal of re-establishing normal hematopoietic and immune function. HCT is classified as autologous or allogeneic based on the origin of hematopoietic cells. Autologous HCT uses the patient’s own cells while allogeneic HCT uses hematopoietic cells from a human leukocyte antigen-compatible donor. Allogeneic HCT is a potentially curative treatment option for patients with certain types of hematologic malignancies, and autologous HCT is primarily used to support patients undergoing high-dose chemotherapy. Advances in HCT methods and supportive care in recent decades have led to improved survival after HCT; however, disease relapse and posttransplant complications still commonly occur in both autologous and allogeneic HCT recipients. Allogeneic HCT recipients may also develop acute and/or chronic graft-versus-host disease (GVHD), which results in immune-mediated cellular injury of several organs. The NCCN Guidelines for Hematopoietic Cell Transplantation focus on recommendations for pretransplant recipient evaluation and the management of GVHD in adult patients with malignant disease.

Overview

Hematopoietic cell transplantation (HCT) involves the infusion of hematopoietic progenitor cells into patients with malignant or nonmalignant hematologic disorders with the goal of re-establishing normal hematopoietic and immune function.1,2 HCT is a potentially curative treatment option for patients with certain types of hematologic malignancies and is also used to support patients undergoing high-dose chemotherapy for the treatment of certain solid tumors. HCT is classified as autologous or allogeneic based on the origin of hematopoietic cells. An autologous HCT uses the patient’s own cells while an allogeneic HCT uses hematopoietic cells from a human leukocyte antigen (HLA)-compatible donor. Prior to HCT, most patients receive chemotherapy, serotherapy, and/or radiation for pretransplant conditioning (preparative regimen). In allogeneic HCT, preparative regimens are administered to eradicate malignant cells in the bone marrow (BM; if using myeloablative regimen) and induce immunosuppression so that engraftment of healthy donor cells occurs.1 In autologous HCT, high-dose myeloablative regimens are used to treat the malignancy. This is followed by rescue infusion of the patient’s own cells, which are harvested before high-dose therapy, to restore hematopoiesis and reconstitute the immune system.

The number of HCTs has increased in the United States in recent years.3 The Center for International Blood and Marrow Transplant Research (CIBMTR) estimated that 9,028 allogeneic transplants and 14,709 autologous transplants were performed in the United States in 2018.4 Acute myeloid leukemia (AML), acute lymphocytic leukemia (ALL), and myelodysplastic syndromes (MDS) were the most common malignancies treated with allogeneic HCT, while autologous HCT was used most frequently in multiple myeloma, non-Hodgkin lymphoma, and Hodgkin lymphoma.4

Outcomes of HCT vary according to the type and stage of the disease being treated, the overall health of the patient, the degree of HLA-mismatch between donor and recipient (for allogeneic HCT), and the source of the hematopoietic cells.2 Hematopoietic cells can be obtained from peripheral blood, BM, or umbilical cord blood (UCB). Several clinical factors should be considered when determining the optimal graft source for an individual patient, including disease type, disease stage, patient comorbidities, and the urgency for transplantation.5 Mobilization of peripheral blood progenitor cells (PBPCs) by granulocyte-colony stimulating factor has largely replaced use of BM grafts (in particular for autologous HCT) due to the ease of collection, avoidance of general anesthesia, more rapid engraftment rates, reduced risk of graft failure, and lower transplant-related mortality.68 However, allogeneic PBPC transplants are associated with an increased risk of graft-versus-host disease (GVHD) compared with BM transplants.8,9 Allogeneic BM transplant continues to be indicated in certain conditions such as severe aplastic anemia and other nonmalignant disorders, owing to a lower risk of GVHD. Furthermore, several investigators have advocated for the use of BM grafts for haploidentical HCT10 and unrelated donor HCT.9 Advantages of using UCB grafts include rapid cell procurement, lower incidence of GVHD, and less-stringent HLA matching requirements. However, use of UCB is limited by the cell doses that can be achieved in recipients with high body weight, which is also associated with delayed engraftment, higher risk for graft failure, higher rates of infectious complications, and higher costs for procurement. The outcome of UCB transplant is more favorable in pediatric populations, likely due to the feasibility of using higher graft cell doses (given smaller body weight) and lower incidence of comorbidities in pediatric populations. UCB transplant is typically reserved for patients without an HLA-matched donor. Patients without an HLA-matched donor may also be candidates for haploidentical HCT. Advantages of haploidentical HCT include lower costs for procurement and rapid availability of the cell products, and disadvantages include increased risk of graft failure and GVHD as compared with HLA-matched HCT.

Advances in HCT methods and supportive care have led to improved survival after HCT.11 However, disease relapse and long-term complications continue to pose a major threat to HCT survivors. Disease relapse is higher with advanced disease and with the use of nonmyeloablative conditioning regimens. Posttransplant complications are common after both allogeneic and autologous HCT. These complications are often caused by the preparative regimen,12,13 delayed immune reconstitution, and GVHD. The risk and type of complications are also influenced by patient-related factors such as age, performance status, and comorbidities.1416 Early complications (generally occurring within the first 100 days post-HCT) include prolonged cytopenia/graft failure, infections, sinusoidal obstruction syndrome, and organ toxicities.12,17 Late complications (after the first 100 days) include infections, late radiation-related toxicities (eg, cataracts and hypothyroidism), late chemotherapy-related toxicities (eg, heart failure), organ dysfunctions, and secondary malignancies, including MDS.12,17 Allogeneic HCT recipients may also develop acute and/or chronic GVHD, in which the donor lymphocytes recognize the recipient’s tissues as foreign, resulting in immune-mediated cellular injury of several bodily organs, such as the skin, gastrointestinal (GI) tract, and liver. Common causes of nonrelapse mortality (NRM) after allogeneic HCT include GVHD, infections, interstitial pneumonia, and organ failure.1821 Common causes of NRM after autologous HCT include organ toxicity and infectious complications.4,22,23 Therefore, posttransplant care plans including optimal supportive care are essential to optimize long-term outcomes in both autologous and allogeneic HCT recipients.

The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for HCT focus on the management of adult patients with malignant disease. This initial version of the NCCN Guidelines addresses pretransplant recipient evaluation and management of acute and chronic GVHD (to view the most recent version of these guidelines, including information on the literature search criteria and guidelines update methodology,24 visit NCCN.org).

Autologous HCT

Autologous HCT is performed to replace or “rescue” hematopoietic cells damaged by the high-dose chemotherapy used to treat certain advanced or high-risk hematologic malignancies and solid tumors. Hematopoietic cells collected from the patient prior to receipt of high-dose chemotherapy are reinfused back into the patient after administration of the preparative regimen. High-dose chemotherapy with autologous HCT is an effective treatment of several hematologic malignancies, including multiple myeloma,2529 relapsed/refractory Hodgkin lymphoma,30,31 and relapsed/refractory non-Hodgkin lymphoma.3234 Autologous HCT is also used in patients undergoing high-dose chemotherapy for the treatment of certain solid tumors, including testicular germ cell tumors3538 and some central nervous system tumors,3943 for which hematologic toxicity would otherwise limit chemotherapy administration. Additionally, autologous HCT is sometimes used as consolidation therapy for certain patients with AML or ALL.

Because autologous HCT uses the patient’s own cells, these patients do not develop GVHD. Additionally, these patients often have a lower risk of infectious complications because they do not receive posttransplant immunosuppression. Therefore, autologous HCT is associated with less morbidity and mortality than allogeneic HCT; however, risk of disease relapse is often higher with autologous HCT when compared with allogeneic HCT. Furthermore, clinical studies demonstrated no benefit of graft purging (ex vivo manipulation to eliminate residual neoplastic cells) prior to autologous HCT.44,45

Allogeneic HCT

Allogeneic HCT is performed to replace malignant (or defective) hematopoietic tissue using a healthy donor’s hematopoietic cells. A preparative regimen consisting of chemotherapy (often high-dose), serotherapy, and/or total body (or lymphoid) irradiation is given before allogeneic HCT to eliminate residual malignant cells and to suppress the recipient’s immune system, which is necessary to allow for engraftment of the donor-derived cells and prevent graft rejection. There are 3 potential donor sources for hematopoietic cells: related donor (family members), unrelated volunteers (from donor registries), and UCB units. HLA matching is the most imperative factor when choosing a donor. An HLA-matched sibling remains the preferred donor source. However, posttransplant survival is comparable among patients receiving hematopoietic cells from HLA-matched unrelated donors for several diseases.14,46 When a patient has no HLA-matched related or unrelated donors, as is common among minority ethnic groups, a haploidentical donor or UCB may be used. A haploidentical donor is a first-degree relative who matches half the HLA markers of the patient. Emerging data suggest that haploidentical HCT may yield comparable outcomes to HLA-matched HCT.47,48 However, a recent study found that use of haploidentical donors beyond first-degree relatives may negatively affect survival.49 UCB transplant was first reported to cure a child with Fanconi anemia,50 and was subsequently used successfully in patients with hematologic malignancies.51,52 Although the outcomes of UCB transplants have been comparable to HLA-matched transplants in some reports,46,5356 delayed engraftment and delayed immune reconstitution often result in increased risks of infectious complications. Additionally, the high degree of HLA-disparity that typically occurs with haploidentical or UCB donors has been associated with an increased risk of graft failure.1,46,5356

Allogeneic HCT has been shown to improve outcomes in patients with malignancies such as refractory AML,57 ALL,58 MDS,59 chronic myeloid leukemia,60 chronic lymphocytic leukemia,61 multiple myeloma,62 primary and secondary myelofibrosis,63 Hodgkin lymphoma,64 and non-Hodgkin lymphoma.65 Donor-derived immune cells often exert an immune-mediated cytotoxic effect against the recipient’s neoplastic cells (ie, graft-versus-tumor effect). This phenomenon was described several decades ago, and its clinical impact was demonstrated in a seminal CIBMTR study of more than 2,000 patients that showed a reduced relapse risk among patients with GVHD.66 Graft-versus-tumor effect is considered a major mechanism for sustained response after allogeneic HCT, in particular with reduced intensity or nonmyeloablative HCT.67,68

Indications for Transplantation

Indications for HCT (allogeneic or autologous) vary by disease type and remission status. Information on indications for HCT can be found in disease-specific NCCN Guidelines, available at NCCN.org (see HCT-1, page 601, for a list of NCCN Guidelines containing disease-specific indications for HCT). The American Society for Transplantation and Cellular Therapy has also published clinical practice guidelines on indications for autologous and allogeneic HCT.5

Pretransplant Recipient Evaluation

The pretransplant recipient evaluation generates data to estimate the risks of relapse, NRM, and overall mortality (see HCT-2, page 602, and HCT-3, page 603). Physiologic age rather than chronologic age should be used to determine eligibility for HCT.5 Selected older patients with limited comorbidities and good functional status can safely receive HCT with a relatively low and acceptable risk of NRM.69,70 Ongoing studies, such as BMT CTN 1704, are assessing the utility of geriatric assessment tools in predicting outcome of HCT in elderly patients (ClinicalTrials.gov identifier: NCT03992352). Determining functional status (Karnofsky’s or ECOG performance status) and HCT-comorbidity index (HCT-CI) score71 are essential to determine candidacy for HCT (in particular for allogeneic HCT). HCT-CI score has been validated to predict the risk of NRM and estimated survival after allogeneic transplant.72,73 HCT-CI has also been shown to predict survival after autologous transplant.74,75 Furthermore, an updated composite-age HCT-CI has been also shown to have the same utility.76 Detailed clinical assessment of HCT-CI has been published.77 HLA typing of the donor and recipient per FACT (Foundation for the Accreditation of Cellular Therapy) guidelines78 is recommended before allogeneic HCT.

Management of GVHD

The development of acute and/or chronic GVHD is a major complication of allogeneic HCT and is associated with significant morbidities and NRM in allogeneic HCT recipients.7981 Increasing incidence of GVHD has been observed in recent years, primarily due to the increased use of unrelated and/or HLA-mismatched donors and granulocyte-colony stimulating factor–mobilized PBPCs, among other factors.8,8284 Mild manifestations limited to a single organ are often managed with close observation, topical treatment, or by slowing the tapering of immunosuppressive agents.85 More severe manifestations or multiorgan involvement typically require systemic corticosteroid treatment (with or without secondary systemic agents).81 Management of GVHD can be optimized by providing coordinated care from a multidisciplinary team, preferably in medical centers with access to specialized transplant services.

Acute GVHD

Despite prophylaxis with immunosuppressive agents, 20%–80% of allogeneic HCT recipients develop acute GVHD (aGVHD) depending on several factors, including donor source and graft source. The skin, GI tract (upper and lower), and liver are the 3 organs primarily affected by aGVHD, which is characterized by maculopapular rash, GI complications, and hyperbilirubinemia.86,87 Although pathologic confirmation of aGVHD should be considered whenever possible, especially before escalating systemic immunosuppression, reliance on pathologic diagnosis is not required for the diagnosis or treatment of aGVHD, because biopsy is not absolutely sensitive.

Diagnosis and Grading

If aGVHD is suspected, additional tests such as stool testing, imaging studies, and/or viral reactivation testing should be performed to rule out non-GVHD causes of the symptoms (see GVHD-1, above). Organ-directed biopsies can then be performed as clinically indicated to confirm the presence of aGVHD (ie, lower GI biopsy for diarrhea, upper GI biopsy for nausea/vomiting, skin biopsy for rash). Rectosigmoid biopsies were shown in one study to have higher sensitivity and negative predictive value than biopsies at other sites, whether the patient presented with diarrhea, nausea, or vomiting.88 Liver function tests should be routinely monitored after allogeneic HCT for early detection of hepatic aGVHD, which is often asymptomatic. Liver biopsy may be considered in patients presenting with unexplained abnormal liver function tests without evidence of aGVHD elsewhere, if the information obtained would inform treatment. After the diagnosis of aGVHD is made, the organ staging and overall grade of aGVHD should be determined to guide choice of therapy and disease monitoring (see GVHD-A, page 609, for aGVHD grading criteria).

The clinical grade of aGVHD is predictive of survival. Grading criteria for aGVHD have been developed over the past several decades. Glucksberg aGVHD grading criteria were first proposed in 1974.89 Modified Glucksberg (consensus or Keystone) criteria were further developed in 1994 (see GVHD-A, page 609, for modified Glucksberg grading criteria).79 The IBMTR Severity Index was subsequently developed,90 and was shown to be more predictive of HCT outcome when compared with the original Glucksberg criteria.91 Minnesota criteria have also been devised to identify patients with “high-risk” aGVHD who could benefit from early escalated therapy.92,93 More recently, MAGIC (Mount Sinai Acute GVHD International Consortium) criteria were developed.94 A joint task force of the European Society for Blood and Marrow Transplantation (EBMT), National Institutes of Health (NIH), and CIBMTR published a position statement on standardized terminology for GVHD.95 Furthermore, blood biomarkers are being actively investigated for their utility as a predictive tool in aGVHD.9698

First-Line Therapy of aGVHD

Grade I

Grade I aGVHD affects only the skin (stage 1–2, <50% body surface area nonbullous rash), with no GI or liver involvement.79 First-line therapy options for these patients include continuing (or restarting) the original immunosuppressive agent and administering topical skin-directed steroids (eg, triamcinolone, clobetasol) and/or topical tacrolimus (see GVHD-2, above). Medium- to high-potency topical steroid formulations are recommended, except on the face where low-potency hydrocortisone is to be used (to avoid skin atrophy, telangiectasia, and acneiform eruptions). Antihistamines may be used for symptomatic relief of itching as needed. Alternatively, the patient can be observed without treatment if the rash is asymptomatic and stable. If there is a response to first-line therapy, as indicated by a resolution of the rash and associated symptoms, the immunosuppressive agent should be tapered as clinically feasible and topical steroids can be discontinued. Options for patients with no response to first-line therapy (eg, refractory pruritic rash) include enrollment in a well-designed clinical trial or treatment according to the recommendations for grade II–IV aGVHD.

Grades II–IV

Enrollment in a well-designed clinical trial is encouraged for all patients presenting with grade II–IV aGVHD. Administration of systemic corticosteroids (± topical steroids) is the standard first-line treatment option (unless contraindicated or associated with severe intolerance) for patients with grades II–IV aGVHD (see GVHD-3, above).86,87,99 Additionally, the original immunosuppressive agent should be restarted, continued, or escalated (with or without therapeutic drug targeting) if aGVHD developed during tapering of immunosuppressive therapy. A phase III randomized controlled trial showed that initial treatment with low-dose systemic prednisone (0.5 mg/kg/day) in conjunction with GI topical steroids (beclomethasone dipropionate ± budesonide) was safe and effective for managing upper GI symptoms (ie, nausea, vomiting, anorexia) in patients with grade II aGVHD, with or without skin involvement (<50% body surface area), with diarrhea volumes <1,000 mL/day.99 In patients with higher grade aGVHD, use of low-dose prednisone was associated with an increased risk of requiring secondary immunosuppressive therapy, but with no difference in survival. Thus, patients with grade II aGVHD may be treated with 0.5–1 mg/kg/day of methylprednisone (or prednisone dose equivalent). Patients with higher grade aGVHD should be treated with higher doses of systemic steroids (1–2 mg/kg/day methylprednisolone or prednisone dose equivalent). There is no role for escalation of methylprednisolone above 2 mg/kg/day.100 The addition of other systemic agents in conjunction with systemic corticosteroids as first-line therapy for aGVHD should only be done in the context of a well-designed clinical trial.

If patients respond to first-line therapy, as indicated by a complete resolution of GVHD or improvement in at least 1 organ without any progression in any other organs, the steroids should be tapered as clinically feasible. Options for patients without a complete response (CR) to first-line therapy include enrollment in a well-designed clinical trial or the addition of other systemic agent(s) to the corticosteroids, with steroid taper as clinically feasible. See “Suggested Agents for Steroid-Refractory aGVHD” (page 611) for more information.

Alternative regimens have been investigated as first-line therapy for aGVHD. BMT CTN 0302 was a randomized 4-arm phase II clinical trial (n=180) that compared different agents (etanercept, mycophenolate mofetil [MMF], denileukin diftitox, and pentostatin) in combination with methylprednisolone at 2 mg/kg per day (or prednisone dose equivalent) for treatment of newly diagnosed aGVHD.101 The day 28 overall response rates (ORRs) were etanercept 26%, MMF 60%, denileukin 53%, and pentostatin 38%. The corresponding 9-month overall survival (OS) rates were 47%, 64%, 49%, and 47%, respectively. Risk of severe infections were etanercept, 48%; MMF, 44%; denileukin, 62%; and pentostatin, 57%. These results suggest that MMF plus corticosteroids is a potentially promising regimen for initial therapy of aGVHD. Accordingly, a phase III multicenter double-blinded clinical trial (BMT CTN 0802) was initiated comparing the combination of methylprednisolone at 1.6 mg/kg/day (or prednisone dose equivalent) plus MMF versus methylprednisolone plus placebo as first-line therapy for aGVHD.102 A futility rule for GVHD-free survival at day 56 was met at a planned interim analysis after 235 patients (of 372) were enrolled. Outcomes of both arms were equivalent in OS, 1-year incidence of chronic GVHD (cGVHD), and infection risk. Therefore, MMF provided no benefit when added to corticosteroids as first-line therapy for aGVHD.

BMT CTN 1501 was an open-label, randomized phase II trial that evaluated sirolimus versus prednisone as initial treatment of standard risk (SR) aGVHD as defined by the Minnesota (MN) GVHD clinical risk score and the Ann Arbor (AA) biomarker status.103 A total of 127 MN-SR patients and 122 AA-SR patients were randomized to receive either sirolimus or prednisone as first-line therapy for aGVHD. The day 28 ORRs were similar (65% and 73% for sirolimus and prednisone, respectively) and there were no differences in disease-free survival, disease relapse, NRM, or OS. Patients in the sirolimus group encountered less hyperglycemia and had reduced risk of infections but were at an increased risk for thrombotic microangiopathy as compared with patients in the prednisone group (10% vs 1.6%). Thus, sirolimus seems to be an appropriate alternative to systemic corticosteroids as first-line therapy for patients with SR aGVHD as defined by the clinical MN score or the AA biomarker score. However, a randomized phase III study is needed to confirm this finding.

Additional Therapy

Due to a lack of high-quality evidence, the NCCN Panel does not prefer any specific agent(s) for second-line therapy and encourages that patients with steroid-refractory aGVHD be managed as part of a clinical trial.87 Currently, ruxolitinib is the only therapy approved by the United States FDA for steroid-refractory aGVHD with outcomes, in particular 6-month survival, seemingly comparable to other agents.104 See “Suggested Agents for Steroid-Refractory aGVHD” (page 611) for more information.

Chronic Graft-versus-Host Disease

cGVHD is the leading cause of NRM after allogeneic HCT and has a profound impact on quality of life.21 cGVHD usually develops within the first year after HCT in most patients, but it can also develop many years later. cGVHD affects multiple organ systems and is characterized by fibrosis and variable clinical features resembling autoimmune disorders.105 The NIH Consensus Development Project has published detailed recommendations for the management of cGVHD including diagnosis, assessment of organ involvement, monitoring response to treatment, and supportive care interventions.85,106109 A thorough understanding of the various clinical manifestations of cGVHD is essential for the early recognition of signs and symptoms. Multidisciplinary care aimed at avoiding organ damage and preserving function is strongly recommended.

Diagnosis and Grading

In all cases of suspected cGVHD, additional tests are often performed to rule out non-GVHD causes of symptoms, such as infection, drug-induced injury or toxicity, malignancy, or other causes. Although a biopsy may be done to confirm the presence of cGVHD, a biopsy is not always feasible and is not mandatory if the patient has at least one of the diagnostic findings of cGVHD defined by the NIH Consensus Development Project (see GVHD-B, above, for diagnostic signs and symptoms of cGVHD).85 Manifestations of cGVHD include bronchiolitis obliterans syndrome (BOS), a devastating inflammatory lung condition. Unless it is pathologically diagnosed (via lung biopsy), clinical characteristics of BOS (assessed by pulmonary function tests) are only diagnostic of lung cGVHD if distinctive features of cGVHD are present in another organ (see GVHD-B 2 of 3, page 611, for the complete criteria required for diagnosis of BOS). cGVHD grading is done according to the NIH Consensus Development Project criteria (see GVHD-C, page 613).85

First-Line Therapy of cGVHD

Enrollment in a well-designed clinical trial is encouraged for all patients presenting with cGVHD (see GVHD-4, page 608). Options for first-line therapy include restarting, continuing, or escalating the original immunosuppressive agent and/or administration of systemic corticosteroids (0.5–1 mg/kg/day methylprednisolone or prednisone dose equivalent). The initial corticosteroid dose may vary depending on the organs involved, the severity of GVHD, and patient comorbidities. Topical steroids, such as triamcinolone, clobetasol, topical estrogen (for vulvovaginal cGVHD), topical tacrolimus, or dexamethasone oral rinse (for oral cGVHD), may be used as clinically indicated. Patients with lung involvement should receive inhaled steroids (eg, budesonide or fluticasone) ± azithromycin (eg, FAM [fluticasone, azithromycin, and montelukast]). Azithromycin should be used only for the treatment of BOS and not for BOS prophylaxis due to data suggesting an increased risk for cancer relapse in HCT patients receiving azithromycin for BOS prophylaxis.110 Patients with progressive or worsening lung cGVHD following 2 to 3 lines of therapy may be evaluated for lung transplant.

If patients respond to first-line therapy according to the NIH Response Criteria,95 steroids should be tapered as clinically feasible to mitigate long-term side effects and risk of infection. Options for patients with no response to first-line therapy include enrollment in a well-designed clinical trial or the addition of other systemic agent(s) to the corticosteroids, with steroid taper as clinically feasible. See “Suggested Agents for Steroid-Refractory cGVHD” (page 622) for more information.

Additional Therapy

Due to a lack of high-quality evidence, the NCCN Panel does not prefer any specific agent(s) for second-line therapy and encourages that patients with steroid-refractory cGVHD be managed as part of a clinical trial.87 Currently, ibrutinib is the only FDA-approved second-line therapy for patients with steroid-refractory cGVHD.111 Other novel agents are being evaluated in ongoing clinical trials.112 See “Suggested Agents for Steroid-Refractory cGVHD” (next section) for more information. Supportive care interventions for controlling organ-specific symptoms or complications should be an integral part in the long-term management of patients with cGVHD.107

Steroid-Refractory GVHD

Approximately 40%–50% of patients with acute or chronic GVHD develop steroid-refractory disease, which is associated with high mortality.86,113 The NIH has defined criteria for steroid-refractory acute and chronic GVHD (see GVHD-D, page 618).95 Enrollment in a well-designed clinical trial is strongly encouraged for these patients since steroid-refractory GVHD is associated with poor OS and no standard, effective therapy has yet been identified.86 The selection of therapy for steroid-refractory GVHD should be based on physician experience, the agent’s toxicity profile, the effects of prior treatments, drug interactions, convenience/accessibility, and patient tolerability. Agent selection may also depend on organ involvement and overall grade of cGVHD.

Suggested Agents for Steroid-Refractory aGVHD

The following systemic agents, listed in alphabetical order, can be used in conjunction with the original immunosuppressive agent and corticosteroids (typical first-line therapy) for steroid-refractory aGVHD (see GVHD-E, page 620). Slow taper of systemic corticosteroids is recommended if deemed ineffective therapy. In patients with steroid-dependent disease, corticosteroid therapy may be continued until an alternative steroid-sparing agent shows a response. Currently, there is insufficient evidence to recommend one systemic agent as preferred over another. However, it is worth noting that ruxolitinib is currently the only FDA-approved therapy for steroid-refractory aGVHD. The following are the most commonly used agents among NCCN Member Institutions.

Alemtuzumab

Alemtuzumab is a humanized anti-CD52 monoclonal antibody that has been successfully used as part of a pretransplant preparative regimen for GVHD prophylaxis.114,115 The safety and efficacy of alemtuzumab for the treatment of steroid-refractory aGVHD was evaluated in a prospective clinical study of 18 patients with grade II–IV steroid-refractory aGVHD treated subcutaneously with 10 mg alemtuzumab daily for 5 consecutive days.116 The ORR to alemtuzumab was 83%, with 33% of patients experiencing CR. Importantly, univariate analyses of clinical characteristics between responders and nonresponders showed no differences in the main organ involved, grade of GVHD, or time between HCT and GVHD onset. After a median follow-up of 9 months, 78% of patients had ≥1 infectious episodes. In a retrospective analysis of 20 patients with steroid-refractory grade III–IV aGVHD receiving 10 mg of intravenous alemtuzumab weekly, the ORR was 70% with a CR of 35%.117 One-year OS was 50%. Although infectious complications were common, infection was not a significant predictor of survival in this study. These data suggest that alemtuzumab has favorable activity in the treatment of steroid-refractory aGVHD and emphasizes the need for anti-infective prophylaxis and close monitoring for patients receiving this therapy. Currently in the United States, alemtuzumab is only available via the Campath Distribution Program, and drug supply is patient-specific.

Alpha-1 Antitrypsin

Alpha-1 antitrypsin (AAT; also known as alpha-1 proteinase inhibitor) is a circulating protease inhibitor that inactivates serine proteases from neutrophils and macrophages to protect tissues from proteolytic degradation.118 AAT is most commonly used to treat patients with AAT-deficiency, an inherited condition which causes lung and liver damage.119 The safety and efficacy of AAT to treat steroid-refractory aGVHD was evaluated in a prospective, multicenter phase II trial of 40 patients treated with intravenous AAT twice weekly for up to 4 weeks at a dose of 60 mg/kg/day.118 The ORR and CR rates at 28 days were 65% and 35%, respectively. After 60 days, responses were maintained in 73% of patients. OS at 6 months was 45% and did not differ by grade or site of organ involvement. Infectious mortality was 10% at 6 months. No infusion reactions or drug-related grade 3–4 toxicities were reported. These data suggest that AAT is an effective treatment option for patients with steroid-refractory aGVHD.

Anti-Thymocyte Globulin

Anti-thymocyte globulin (ATG) is a T-cell–depleting antibody that has been commonly used for immunosuppression in the solid organ transplant setting and for GVHD prophylaxis.120125 Two ATG products are currently approved by the FDA: thymoglobulin (ATG-T), a polyclonal immunoglobulin G (IgG) derived from rabbits, and ATGAM (ATG-h), a polyclonal IgG derived from horses.126,127 An early retrospective study analyzed the clinical response and survival outcomes of 79 patients with steroid-refractory aGVHD treated with 1 to 5 courses of equine ATG (ATGAM) at a dose of 15 mg/kg/day twice a day for 5 days.128 At day 28 of treatment, the ORR was 54% with 20% of patients achieving a durable CR. Response to ATG was not associated with the initial grade of GVHD; however, it was associated with the site of GVHD. Patients with skin aGVHD were more likely to respond to ATG. Of the 64 patients with skin involvement, 61% experienced a complete or partial response compared with 27% without skin involvement (P=.02). The probability of survival at 1 year for all patients was 32% (95% CI, 22%–42%). Bacterial, viral, and fungal infections occurred in 37%, 10%, and 18% of patients, respectively.

Another early retrospective study analyzed the efficacy of rabbit ATG (thymoglobulin) in 36 patients with steroid-refractory GVHD treated at a single institution.129 Patients, most of whom (89%) had grade III–IV aGVHD, received thymoglobulin at 2.5 mg/kg/day for either 4 to 6 consecutive days (group 1; n=13) or on days 1, 3, 5, and 7 (group 2; n=21). The ORR was 59%, with a CR rate of 38%. The response rate was higher in group 1 (77%) compared with group 2 (48%); however, this difference was not statistically significant (P=.15). As seen in the aforementioned study, skin aGVHD was more responsive (96% of patients) than GI (46%) or liver aGVHD (36%). Common adverse events included hepatic dysfunction (25%), viral infections (26%), fungal infections (32%), and bacteremia (21%). Of the 36 original patients enrolled in the study, only 2 (6%) were alive 34 months post-HCT. A more recent retrospective analysis of 11 patients with steroid-refractory aGVHD reported an ORR of 55% for thymoglobulin administered at a median dose of 3 mg/kg/day.130 In this study, high response rates were observed in patients with skin (100%) and GI (83%) aGVHD as compared with those with liver aGVHD (25%). One-year OS and transplant-related mortality were 55% and 45%, respectively. These data suggest that ATG may be an effective treatment option for patients with steroid-refractory aGVHD, especially for those with skin involvement. However, long-term survival appears to be low, even in responders.129 A comprehensive review on the use of ATG for GVHD treatment has been published.131

Basiliximab

Basiliximab is a chimeric monoclonal antibody that functions as an immunosuppressive agent by binding to and blocking the interleukin-2 (IL-2) receptor.132 IL-2 plays a key role in the development of aGVHD by stimulating the activation of donor T cells in the graft, which can attack the cells and tissues of the recipient.133 The efficacy and feasibility of basiliximab for the treatment of steroid-refractory aGVHD was evaluated in a prospective phase II trial of 23 patients treated with intravenous basiliximab at a dose of 20 mg on days 1 and 4.133 The ORR was 83% with 18% of patients achieving a CR. The percentage of patients experiencing a minimum one-grade reduction in aGVHD varied with organ involvement (77% of patients with skin GVHD, 14% of patients with liver involvement, and 67% of patients with GI involvement). Although administration of basiliximab did not cause any infusion-related toxicity, infections occurred in 65% of patients. The rates of malignancy recurrence and 1-year treatment-related mortality were 10% and 45%, respectively, following immunosuppression with basiliximab. Therefore, basiliximab appears to have some activity in the treatment of steroid-refractory aGVHD.

Calcineurin Inhibitors

Calcineurin inhibitors (CNI), such as tacrolimus and cyclosporine, are immunosuppressive agents that inhibit the action of calcineurin, an enzyme involved in the activation of T cells. CNI are commonly used for the prevention and initial treatment of GVHD, often in conjunction with other agents.134143 However, limited data exist for their use in the treatment of steroid-refractory aGVHD. In a small phase II trial, 18 patients with aGVHD that developed or progressed during therapy with cyclosporine and/or other immunosuppressive agents were treated with tacrolimus at an initial dose of 0.05 mg/kg intravenously or 0.15 mg/kg orally twice per day.144 In the 13 evaluable patients, the ORR was 54%. The most common adverse events were renal toxicity (53% of patients), followed by nausea and vomiting (31%). A recent retrospective analysis involving 42 patients with steroid-refractory aGVHD treated with tacrolimus in combination with sirolimus reported an ORR of 49% (CR rate, 42%) for patients treated in the second-line (n=31) and an ORR of 27% (CR, 0) for patients treated in the third-line (n=11).145 One-year OS was 42% in patients treated in the second-line and 0% in patients treated in the third-line. Infectious complications occurred in 90% of patients. Therefore, CNI may be a reasonable option for the treatment of patients with steroid-refractory aGVHD when they have not been used in prophylaxis or initial therapy.

Etanercept

Etanercept is a recombinant tumor necrosis factor-alpha (TNF-α) receptor fusion protein.146 Etanercept acts by inhibiting the activity of TNF-α, a proinflammatory cytokine that acts as the master regulator of immune response and is a major mediator in the pathogenesis of aGVHD.147 The efficacy of etanercept for the treatment of steroid-refractory aGVHD was retrospectively evaluated in a cohort of 13 patients.148 Etanercept at 25 mg was given subcutaneously twice weekly for 4 weeks followed by 25 mg weekly for 4 weeks. The ORR was 46%, with 4 patients achieving CR. Responses correlated with the overall grade of aGVHD, with grade II aGVHD patients showing higher response rates than those with grades III–IV aGVHD, and were most commonly observed in patients with GI involvement (64% of clinical responses). No immediate treatment-related side effects were observed; however, bacterial and fungal infections occurred in 14% and 19% of patients, respectively. At a median follow-up of 429 days, OS was 67%. These results suggest that etanercept has favorable activity in steroid-refractory aGVHD.

Extracorporeal Photopheresis

Extracorporeal photopheresis (ECP) is a form of immunotherapy that involves ex vivo exposure of mononuclear cells obtained by apheresis to the photosensitizing agent 8-methoxypsoralen and ultraviolet A (UVA) light, followed by reinfusion of the cells back into the patient.149 The clinical activity of ECP is thought to be mediated by the immunomodulatory effects of ultraviolet light.150 The exact mechanism by which ECP ameliorates GVHD (acute or chronic) is unclear, but may involve the normalization of CD4+/CD8+ lymphocyte populations, an increase in the number of CD3-/CD56+natural killer cells, and/or a decrease in circulating dendritic cells.149,151

A phase II trial in patients with grade II–IV steroid-refractory aGVHD found that weekly ECP therapy resulted in complete resolution of aGVHD symptoms in 82% of patients with skin involvement and 61% of patients with liver or GI involvement.152 In a recent prospective single-center study involving 21 patients with grade III–IV aGVHD, second- or third-line treatment with ECP resulted in an ORR of 84%.153 After a median follow-up of 17 months, 1-year OS was 53% and was independently associated with a higher number of ECP sessions. A systematic review of prospective studies reported a pooled ORR of 69% for ECP in the treatment of steroid-refractory aGVHD.149 The ORR for skin manifestations was highest at 84%, followed by 65% for GI involvement. Reported rates of ECP-related mortality were extremely low. Another systematic review largely reached the same conclusions, reporting a pooled ORR of 71% and ORRs of 86%, 60%, and 68% for skin, liver, and GI involvement, respectively.154 These data suggest that ECP is an effective therapy for steroid-refractory aGVHD, especially for patients with skin involvement. If ECP is not available or feasible, the NCCN Panel recommends the use of psoralen plus UVA irradiation as an alternative treatment option.

Infliximab

Infliximab is a genetically constructed IgG1 chimeric monoclonal antibody that binds to membrane-bound TNF-α, blocking its activity and triggering lysis of TNF-α–producing cells.147,155 In a retrospective evaluation of 21 patients with steroid-refractory aGVHD who had received treatment with single-agent infliximab (10 mg/kg once weekly for at least 4 doses), the ORR was 67% with 62% of patients achieving CR.147 No toxic reactions to infliximab were observed; however, bacterial, fungal, and viral infections occurred in 81%, 48%, and 67% of patients, respectively. OS was 38% at a median follow-up of 21 months. Another retrospective analysis of 32 patients with steroid-refractory aGVHD treated with infliximab administered intravenously at the dose of 10 mg/kg once weekly for a median of 3 courses reported an ORR of 59%.156 Infections developed in 72% of patients. A third, more recent retrospective analysis involving 35 patients with steroid-refractory aGVHD reported an ORR of 40% for infliximab administered intravenously at 10 mg/kg weekly for a median of 4 doses, with 83% of patients developing infectious complications.157 These data suggest that infliximab is active in the treatment of steroid-refractory aGVHD; however, the potential for excessive infections should be evaluated.

mTOR Inhibitors

Sirolimus (rapamycin) is a macrolide compound derived from the bacteria Streptomyces hygroscopicus that possesses immunosuppressive, antibiotic, and antitumor properties. Sirolimus functions as a potent immunosuppressant by inhibiting the activity of mTOR, a serine/threonine kinase that acts as a master regulator of cell growth, proliferation, metabolism, and survival.158,159 By inhibiting mTOR, sirolimus disrupts the cytokine signaling that promotes the growth and differentiation of T cells.160 Sirolimus is also used for GVHD prophylaxis, often in conjunction with the CNI tacrolimus.139141,161164 The safety and efficacy of sirolimus in the treatment of steroid-refractory aGVHD was evaluated in a phase I trial involving 21 patients with grade III–IV steroid-refractory aGVHD.165 The ORR was 57%, with a CR rate of 24%. However, only 11 patients completed the full course of treatment due primarily to extensive toxicities including cytopenias, hyperlipidemia, severe thrombotic microangiopathy, and renal failure. In a retrospective analysis of 31 patients with steroid-refractory aGVHD treated with sirolimus in combination with tacrolimus, the ORR was 76% and 42% of patients achieved CR.166 Median OS was 5.6 months and 1-year OS was 44%. Thrombotic microangiopathy and hyperlipidemia occurred in 21% and 44% of patients, respectively, but were manageable. Another retrospective study involving 22 patients with steroid-refractory aGVHD treated with sirolimus reported similar results.167 The ORR was 72% and OS was 41% after a median follow-up of 13 months. Thrombotic microangiopathy occurred in 36% of patients when sirolimus was combined with tacrolimus or other CNI. A third, more recent retrospective analysis involving 42 patients with steroid-refractory aGVHD treated with sirolimus and tacrolimus reported an ORR of 48.5% (CR rate, 42%) for patients treated in the second-line (n=31) and an ORR of 27% for patients treated in the third-line (n=11).145 For patients treated in the second-line, 1-year OS was 42% (0% for patients treated in the third-line). Infectious complications were common (90% of patients). These data suggest that sirolimus is an effective option for the treatment of patients with steroid-refractory aGVHD but may result in significant toxicities.

Mycophenolate Mofetil

MMF is a prodrug of mycophenolic acid that acts as an immunosuppressant by inducing apoptosis in lymphocytes through inhibition of the de novo synthesis of purines.168 MMF is indicated for the prevention of organ rejection in solid organ transplants and is a standard component of GVHD prophylaxis regimens.169 In a prospective phase II trial completed in the mid-1990s, Furlong et al170 reported an ORR of 47% and a CR rate of 31% in 19 patients with steroid-refractory aGVHD treated with MMF at an initial dose of 1 g twice daily for 35 days. OS at 6 and 12 months was 37% and 16%, respectively. MMF treatment was discontinued in 4 patients because of toxicities including neutropenia, abdominal pain, and pulmonary infiltrate. The same group conducted a retrospective analysis of more recent patients with steroid-refractory aGVHD (n=29) and found a similar ORR to MMF therapy (48%).170 However, OS at 6 and 12 months was much higher (55% and 52%, respectively). Possible explanations for the improved OS may include improved management of GVHD and longer experience with the use of MMF. In another retrospective analysis of 13 patients with steroid-refractory aGVHD, the ORR to MMF (1.5 or 2 g daily) was 31% and the estimated 2-year OS rate was 33%.171 Responses were observed in 31% of cases with skin involvement, 44% of cases with liver involvement, and 23% of cases with GI involvement. Another retrospective study reported a 3-year OS rate of 40% and a CR rate of 26% in 27 patients with steroid-refractory aGVHD treated with MMF at a dose of 1–1.5 g BID orally or intravenously.172 The CR rates observed with MMF therapy were typically higher in patients with lower grade GVHD (40% for grades I–II vs 8% for grades III–IV). These data suggest that MMF has some efficacy for treating steroid-refractory aGVHD, especially in those with lower grade GVHD at the start of treatment.

Pentostatin

Pentostatin is a purine analog that acts as an immunosuppressant by inducing lymphocyte apoptosis through inhibition of adenosine deaminase.173 A large retrospective analysis of 60 patients treated with pentostatin for steroid-refractory aGVHD reported an ORR of 33% and a CR rate of 18%.174 All patients received pentostatin at a dose of 1.5 mg/m2 on days 1 to 3, repeated every 2 weeks, for a median of 3 courses. OS at 18 months was 21% and NRM was 72%. Stratified analysis revealed that patients <60 years of age with isolated lower GI GVHD had the best outcomes, with an ORR of 48% and 18-month OS of 42%. An earlier retrospective study reported similar results, with an ORR of 38% and 2-year OS of 17% in 24 patients treated with pentostatin at a daily dose of 1 mg/m2 given intravenously over 3 consecutive days.175 A smaller retrospective analysis of 12 patients reported a higher ORR of 50% and a CR rate of 33%.176 Discrepancies in the results of these studies may be attributed to variability in the patient populations, pentostatin doses and number of treatment cycles, use of additional therapies, or the assessment of treatment response.174

A phase I dose-escalation study involving 22 patients with steroid-refractory aGVHD reported a high CR rate of 63%.177 However, late infections observed at the 2 mg/m2/day dose used in the study were considered to be dose-limiting toxicities. In a follow-up phase II study of 8 patients receiving a lower dose of 1.5 mg/m2/day of pentostatin, 4 patients died of progressive hepatic GVHD and 3 patients died of sepsis secondary to infections, pancytopenia, progressive hepatic GVHD, and/or acute renal failure.178 Two patients with renal insufficiency demonstrated excessive pentostatin exposure, as determined by measurement of the area under the curve, despite a 50% reduction in pentostatin dose. Although this trial was terminated before efficacy could be assessed, the data suggest that pentostatin is ineffective in treating liver manifestations of GVHD and may be inappropriate for patients with renal insufficiency. The limited available data suggest activity for pentostatin in the treatment of steroid-refractory aGVHD without liver involvement; however, serious adverse events have been reported. The renal function of patients receiving pentostatin should be monitored throughout the course of treatment.

Ruxolitinib

Ruxolitinib is a selective inhibitor of JAK1 and JAK2, which are intracellular tyrosine kinases that play critical roles in cytokine signaling and the development and function of several types of immune cells.179 In 2019, the FDA approved ruxolitinib for the treatment of steroid-refractory aGVHD in adult and pediatric patients aged 12 years and older.180 The approval was based on data from the single-arm multicenter phase II REACH1 trial that included 49 patients with grade II–IV steroid-refractory aGVHD.104 Patients received 5 mg ruxolitinib twice daily, with an optional increase to 10 mg twice daily in the absence of cytopenias. The ORR at day 28 was 100% for patients with grade II GVHD, 41% for patients with grade III GVHD, and 44% for those with grade IV GVHD. The most commonly reported adverse events were hematologic (anemia, thrombocytopenia, and neutropenia) followed by infections and edema. An earlier retrospective study of 54 patients who had received ruxolitinib at a dose of 5–10 mg orally twice a day for steroid-refractory aGVHD reported an ORR of 82%, with a CR rate of 46% and a 6-month OS rate of 79%.181 Cytopenias and reactivation of cytomegalovirus were observed in 56% and 33% of patients, respectively. The ongoing phase III REACH2 (ClinicalTrials.gov identifier: NCT02913261) and REACH3 (ClinicalTrials.gov identifier: NCT03112603) trials are comparing treatment with ruxolitinib to the best available therapy in patients with steroid-refractory acute (REACH2) or steroid-refractory chronic (REACH3) GVHD.179

Tocilizumab

Tocilizumab is a humanized anti-IL-6 receptor antibody that functions as an immunosuppressive agent by blocking IL-6 signaling.182 IL-6 is a proinflammatory cytokine produced by a variety of cell types that plays a key role in the development of aGVHD. Elevations of IL-6 have been detected in the serum of patients with GVHD and polymorphisms that result in increased IL-6 production have been associated with an increase in GVHD severity.183,184 The efficacy of tocilizumab for the treatment of steroid-refractory aGVHD was evaluated in several studies.185189 A small study of 8 patients (6 patients had aGVHD, most of whom had grade IV) showed an ORR of 67%, with a CR rate of 33%.189 Tocilizumab was administered intravenously at a dose of 8 mg/kg once every 3 to 4 weeks. The most common adverse event in this study was infectious complications (69% were bacterial in origin). A retrospective study of 9 patients with grade III–IV steroid-refractory aGVHD treated with the same dose and schedule of tocilizumab reported a lower ORR of 44% and a CR rate of 22%.188 Another retrospective analysis of 15 patients conducted at the same institution reported improved results with the use of tocilizumab for steroid-refractory aGVHD, with a CR rate of 40%.187 In this study, the patients received tocilizumab every 2 to 3 weeks (majority received tocilizumab every 2 weeks), compared with every 3 to 4 weeks as in the previous studies. Patients with skin and/or GI involvement had the greatest response, while those with liver involvement showed no response. Another recent retrospective study conducted at a different institution reported a CR rate of 63% to tocilizumab (8 mg/kg given every 2 weeks) in 16 patients with steroid-refractory aGVHD of the lower GI tract.185 These data suggest that tocilizumab has activity in the treatment of patients with steroid-refractory aGVHD, especially in patients with skin or GI involvement.

Anti-Integrins

Anti-integrin agents (natalizumab and vedolizumab) are currently being investigated as therapeutic modalities for steroid-refractory aGVHD.190192 These agents are monoclonal antibodies that impair homing of leukocytes (particularly T cells) to the GI endothelium via blocking leukocyte receptors alpha-4 integrin (natalizumab) or alpha-4/beta-7 integrin (vedolizumab).193,194 A retrospective multicenter study evaluated the use of vedolizumab for steroid-refractory GI aGVHD in 29 patients.191 The ORR was 79% with CR observed in 28% of patients. Early administration of vedolizumab was associated with a greater chance of discontinuing immunosuppression and a lower risk of fatal infectious complications. However, further studies are needed to confirm these findings. It should be noted that the NCCN Panel does not currently recommend the use of these agents for the treatment of steroid-refractory aGVHD.

Suggested Agents for Steroid-Refractory cGVHD

The following systemic agents, listed in alphabetical order, can be used in conjunction with corticosteroids for steroid-refractory cGVHD (see GVHD-E, page 620). Although prolonged systemic corticosteroid therapy is better avoided, some patients may require prolonged steroid therapy (preferably using ≤0.5 mg/kg/day) for steroid-dependent cGVHD. Currently, there is insufficient evidence to recommend one systemic agent as preferred over another. However, it is worth noting that ibrutinib is currently the only FDA-approved therapy for steroid-refractory cGVHD. The following are the most commonly used agents among NCCN Member Institutions. Although the following agents may be used in any site, some agents are more commonly used with particular organ involvement.

Abatacept

Abatacept is a T-cell costimulatory inhibitor. It is a recombinant soluble fusion protein composed of the extracellular domain of cytotoxic T-lymphocyte–associated antigen 4 linked to the modified fragment crystallizable (Fc) region of IgG1.195,196 Abatacept acts as an immunomodulatory drug by selectively inhibiting T-cell activation via binding to (blocking) the costimulation receptors (CD80 and CD86) on antigen-presenting cells (costimulation blockade). The safety and efficacy of abatacept in the treatment of steroid-refractory cGVHD were evaluated in a phase I clinical trial involving 16 patients.195 The study followed a 3+3 design with 2 escalating abatacept doses to determine the maximum tolerated dose (MTD). The partial response rate to abatacept was 44%, and no dose-limiting toxicities were observed at the MTD of 10 mg/kg. The affected sites with greatest improvement were the mouth, GI tract, joints, skin, eyes, and lung. The most common adverse events were pulmonary infections (all of which resolved), diarrhea, and fatigue. Importantly, treatment with abatacept resulted in a 51% reduction in prednisone usage. These data suggest that abatacept is an effective treatment option for patients with steroid-refractory cGVHD.

Alemtuzumab

The safety and efficacy of alemtuzumab for the treatment of steroid-refractory cGVHD was evaluated in a phase I dose-escalation trial involving 13 patients.197 Six subjects had moderate and 7 subjects had severe cGVHD per NIH consensus global scoring criteria; all subjects had involvement of skin and subcutaneous tissues. Alemtuzumab dosing was investigated in a 3+3 study design. The MTD of alemtuzumab was 3 mg×1, then 10 mg×5 administered over 4 weeks. The most common adverse events were infections and hematologic toxicities. Of the 10 patients evaluable for response, the ORR was 70% with a 30% CR rate. The median decrease in steroid dose at 1 year was 62%. A prospective study of 15 patients with steroid-refractory cGVHD treated with 1 cycle of subcutaneous alemtuzumab at 10 mg/day for 3 days followed by 100 mg intravenous rituximab on days +4, +11, +18, and +25 reported an ORR of 100% and a CR rate of 33% at day +30 evaluation.198 At day +90 evaluation, the partial response rate was 50%, the CR rate was 28%, and 21% of patients had relapsed cGVHD. Of the 5 evaluable patients at 1 year, 2 (40%) had a partial response, 2 had a CR, and 1 experienced cGVHD progression. These data indicate that alemtuzumab is active in steroid-refractory cGVHD. Currently in the United States, alemtuzumab is only available via the Campath Distribution Program, and drug supply is patient-specific.

Calcineurin Inhibitors

Limited data exist for the efficacy of CNI, such as tacrolimus and cyclosporine, for the treatment of steroid-refractory cGVHD. The most common adverse events typically seen with CNI use are renal toxicity, hypomagnesemia, hypertension, and tremors. In a phase II trial, 31 patients with cGVHD that developed or progressed during therapy with cyclosporine and/or other immunosuppressive agents were treated with tacrolimus at an initial dose of 0.05 mg/kg intravenously or 0.15 mg/kg orally twice a day. In the 26 evaluable patients, the ORR was 46%.144 Another trial evaluated the efficacy of tacrolimus administered at 0.15 mg/kg twice a day orally or 0.15 mg/kg/day intravenously in 17 patients with severe steroid-refractory cGVHD.199 The ORR was 35% and OS was 65% at a median follow-up of 8.4 months. The greatest responses were observed in the skin, liver, and GI tract; musculoskeletal and lung cGVHD showed no response to treatment. Commonly reported adverse events included renal toxicity, hypertension, and infections. In a third report, 39 patients with cGVHD refractory to cyclosporine and prednisone were treated with tacrolimus.200 The ORR was 21% with a CR rate of 13%. However, 79% of patients experienced treatment failure and 23% died during continued tacrolimus treatment. Infectious complications were the most common adverse event followed by renal toxicity, which led to treatment discontinuation in 2 patients. Three-year estimated OS was 64%, and 41% of patients had discontinued all immunosuppressive treatment at 3 years after HCT. Therefore, CNI may provide clinical benefit for steroid-refractory cGVHD, in particular when they have not been used for GVHD prophylaxis or initial therapy.

Etanercept

The efficacy of etanercept for the treatment of steroid-refractory cGVHD was retrospectively evaluated in a cohort of 8 patients treated with subcutaneous etanercept at 25 mg twice weekly for 4 weeks followed by 25 mg once weekly for 4 weeks.148 Patients were also continued on CNI, MMF, and/or sirolimus. The ORR was 62% with 1 patient achieving CR. Three of 8 patients (37%) treated with etanercept died of progressive disease or sepsis. In 3 of the 5 patients who experienced response to etanercept, corticosteroids were reduced by >50%. In a phase II trial, 34 patients with either obstructive (n=25) or restrictive (n=9) lung dysfunction following allogeneic HCT were treated with etanercept subcutaneously at 0.4 mg/kg/dose twice weekly for 4 (group A) or 12 (group B) weeks.201 Obstructive lung dysfunction is commonly associated with cGVHD, with BOS being the most common histopathology reported. All patients had clinical signs or symptoms of cGVHD at the onset of treatment, with diffuse skin, oral mucosal, ocular, and/or hepatic involvement. All patients received concurrent immunosuppressive therapy with either CNI alone (n=5), CNI plus corticosteroids ± MMF (n=22), MMF ± corticosteroids (n=5), or sirolimus (n=2). Clinical response, defined as a ≥10% improvement in the absolute value for forced expiratory volume (for obstructive defects) or forced vital capacity (for restrictive defects), was obtained in 32% of patients. There was no difference in ORR based on the duration of treatment (29% in group A vs 35% in group B; P=.99) or the presence of restrictive or obstructive lung dysfunction (33% vs 32%, respectively; P=.73). No bacterial or viral infections were observed. Thus, etanercept seems to be effective for treating steroid-refractory cGVHD of the lung (especially if associated with BOS).

Extracorporeal Photopheresis

In a prospective single-center study involving 88 patients with extensive cGVHD, second- or third-line treatment with ECP resulted in an ORR of 73%.153 Cutaneous and sclerotic manifestations were associated with higher response rates. After a median follow-up of 68 months, 5-year OS was 65% and was independently associated with a higher number of ECP sessions and cutaneous manifestations. A multicenter randomized phase II trial involving 95 patients with cutaneous manifestations of steroid-refractory cGVHD found that 8% of patients receiving ECP therapy experienced at least a 25% reduction in total skin score from baseline compared with 0% of patients in the control group (P=.04).202 Treatment with ECP resulted in an ORR of 61% in a retrospective analysis of 71 patients with severe steroid-refractory cGVHD; the best responses were seen in the skin, liver, oral mucosa, and eyes.203 A systematic review of prospective studies reported a pooled ORR of 64% for ECP in the treatment of steroid-refractory cGVHD.149 Similar response rates were seen with skin and GI involvement; however, the ORR for cGVHD with lung involvement was only 15%, suggesting that ECP may not effectively treat lung manifestations of cGVHD. Reported rates of ECP-related mortality were extremely low. Another systematic review largely reached the same conclusions, reporting a pooled ORR of 64% and pooled response rates of 74% and 48% for skin and lung involvement, respectively.204 This review also reported activity for ECP in treating cGVHD with GI involvement (ORR, 53%). These data suggest that ECP is an effective therapy for steroid-refractory cGVHD, especially in those with skin involvement. If ECP is not available or feasible, the NCCN Panel recommends the use of PUVA irradiation as an alternative treatment option.

Hydroxychloroquine

Hydroxychloroquine is a 4-aminoquinoline immunosuppressive and antiparasitic agent that is commonly used for the treatment of malaria.205 Hydroxychloroquine is believed to exert its immunomodulatory effects by interfering with cytokine production and antigen processing and presentation.206,207 The efficacy of hydroxychloroquine for the treatment of steroid-refractory cGVHD was evaluated in a phase II trial involving 40 patients treated with hydroxychloroquine at 800 mg (12 mg/kg) per day.207 The ORR was 53% among the 32 evaluable patients, with 3 patients experiencing CR. All responders tolerated a >50% reduction in steroid dose while receiving hydroxychloroquine. The highest response rates were observed in patients with skin, oral, and/or liver involvement; efficacy in the treatment of GI manifestations was limited.

One of the most serious adverse events reported with the long-term use (>2 years) of hydroxychloroquine is chloroquine retinopathy, a form of toxic retinopathy caused by the binding of hydroxychloroquine to melanin in the retinal pigment epithelium, which can result in vision loss. The retinal toxicity of hydroxychloroquine was evaluated in a cohort of 12 patients with cGVHD treated with 800 mg hydroxychloroquine per day for a median duration of 22.8 months.208 Seven patients developed vortex keratopathy and 3 patients developed retinal toxicity; retinal structure and color vision were abnormal in 2 of the 3 patients. These data suggest that hydroxychloroquine is an effective treatment option for patients with steroid-refractory cGVHD, especially in those with skin or oral involvement, but may not be appropriate for long-term use due to the risk of retinal toxicity. Periodic ophthalmologic assessment is recommended during treatment.

Ibrutinib

Ibrutinib is a potent and irreversible inhibitor of Bruton’s tyrosine kinase, which regulates B-cell survival.111 It also inhibits IL-2–inducible T-cell kinase, which is involved in the selective activation of T-cell subsets.209 In 2017, ibrutinib was approved by the FDA for the treatment of adult patients with cGVHD after failure of one or more lines of systemic therapy.210 This approval was based on data from a single-arm multicenter trial that included 42 patients with steroid-refractory cGVHD.111 Patients received 420 mg ibrutinib daily until cGVHD progression. Most patients (88%) had at least 2 organs involved at baseline, the most common being mouth (86%), skin (81%), and GI tract (33%). At a median follow-up of 14 months, the ORR was 67%, with 71% of responders showing a sustained response for ≥20 weeks. Improvement was seen in all involved organs in patients with multiorgan involvement. Median corticosteroid dose in responders decreased from 0.29 mg/kg/day to 0.12 mg/kg/day, and 5 responders discontinued corticosteroids after treatment with ibrutinib. The most commonly reported adverse events were fatigue, bleeding/bruising, diarrhea, muscle spasms, nausea, thrombocytopenia, and anemia. Grade 3 atrial fibrillation occurred in one patient. After a median follow-up of 26 months, the ORR was 69% with 31% of patients experiencing CR.211 Sustained responses of ≥44 weeks were seen in 55% of responders. Of the patients with multiorgan involvement, 73% of those with ≥2 organs involved showed responses in ≥2 organs and 60% of those with ≥3 organs involved showed responses in ≥3 organs. Corticosteroid dose was reduced to <0.15 mg/kg/day in 64% of patients and was completely discontinued in 19% of patients. The most common grade 3 adverse events were pneumonia, fatigue, and diarrhea. These data suggest that ibrutinib is effective and may produce durable responses in patients with steroid-refractory cGVHD. However, ibrutinib should be used with caution in patients with a history of heart arrhythmias, due to a heightened risk of atrial fibrillation, and in patients on anticoagulation or antiplatelet therapy, due to a heightened risk of bleeding. Given the high risk of bleeding, patients should hold ibrutinib for 3 to 7 days before and after surgical procedures.

Imatinib

Imatinib is a small molecule tyrosine kinase inhibitor indicated for the treatment of several types of cancer, including chronic myeloid leukemia.212 Imatinib has activity against several tyrosine kinase enzymes, including platelet-derived growth factor receptor (PDGFR) which is implicated in skin fibrosis.213 Stimulatory antibodies against PDGFR have been identified in cGVHD patients with cutaneous sclerosis; however, neither anti-PDGFR antibody level nor phosphorylation of tissue PDGFR correlated with response to imatinib in cGVHD patients.214 The efficacy of imatinib to treat sclerotic manifestations of cutaneous steroid-refractory cGVHD was assessed in a pilot phase II trial involving 20 patients.213 Eight patients received a standard dose of 400 mg daily and 12 patients underwent a dose escalation study due to poor tolerability (100 mg daily initial dose up to 200 mg daily maximum). Of the 14 patients evaluable for primary response, 5 (36%) had a partial response, 7 (50%) had stable disease, and 2 (14%) had progressive disease. After treatment with imatinib for 6 months, range of motion deficit was improved in 79% of patients by an average of 24%. Common adverse events included hypophosphatemia, fatigue, nausea, diarrhea, and disrupted fluid homeostasis leading to edema. A randomized phase II crossover study compared imatinib (200 mg daily) to rituximab (375 mg/m2 intravenously weekly for 4 weeks) for the treatment of patients (n=35) with cutaneous sclerosis associated with cGVHD.215 Significant clinical response, defined as quantitative improvement in skin sclerosis or joint range of motion, was seen in 26% of patients randomized to imatinib and 27% of patients randomized to rituximab. Treatment success, defined as significant clinical response at 6 months without crossover, recurrent malignancy, or death, was achieved in 17% of patients on imatinib and 14% of patients on rituximab. In a prospective trial of 39 patients with steroid-refractory cGVHD treated with imatinib, the partial response rate was 36%.216 The best responses were seen in the skin (32%), GI tract (50%), and lungs (35%). After a median follow-up of 40 months, the 3-year OS and event-free survival rates were 72% and 46%, respectively. These data suggest that low-dose imatinib (200 mg) is active in the treatment of patients with steroid-refractory cGVHD, especially in those with cutaneous sclerosis.

Interleukin-2

IL-2 is a naturally occurring pleiotropic cytokine that regulates the growth of T cells and is a key mediator of immune response.217 The efficacy of IL-2 in the treatment of steroid-refractory cGVHD was evaluated in a phase I study involving 29 patients.218 Patients received daily subcutaneous IL-2 at escalating dose levels for 8 weeks. The MTD was determined to be 1×106 IU/m2. Of the 23 patients evaluable for a response, 12 had a significant clinical response involving multiple organs. Clinical responses were sustained in patients who received IL-2 for an extended period, allowing their corticosteroid dose to be tapered by a mean of 60%. In a follow-up phase II trial, 35 patients with steroid-refractory cGVHD were treated with IL-2 at 1×106 IU/m2 for 12 weeks.217 The ORR in 33 evaluable patients was 61%. There were no CRs and 3 patients developed progressive cGVHD. All responders experienced improvement in multiple sites of cGVHD, including the liver, skin, GI tract, lungs, and joints/muscle/fascia. Extended IL-2 therapy for up to 2 years was well tolerated and resulted in durable clinical responses in most patients. However, 2 patients in this study withdrew and 5 required dose reductions of IL-2 due to adverse events including thrombocytopenia, fatigue, flu-like symptoms, malaise, and thrombocytopenia. A recent phase I dose-escalation trial showed that escalation above the previously defined MTD did not improve clinical response in 10 patients with steroid-refractory cGVHD.219 These data suggest that low-dose IL-2 has durable clinical activity in treating steroid-refractory cGVHD and is generally safe for long-term use.

Low-Dose Methotrexate

Methotrexate is an antimetabolite that exerts immunosuppressive effects by inhibiting the activity of dihydrofolic acid reductase, resulting in impaired DNA synthesis and lymphocyte proliferation.220 In a retrospective study of 14 patients who had received low-dose methotrexate (7.5 mg/m2/week for 3 to 50 weeks) for the treatment of steroid-refractory cGVHD, 71% of patients were able to reduce their prednisone dose to <1 mg/kg every other day without the addition of other agents.221 In this study, the most frequently involved sites were oral mucosa (n=14) and skin (n=11) and no grade 3 or higher toxicities were observed. The steroid-sparing effects of methotrexate were also observed in a prospective study of 8 patients with steroid-refractory cGVHD, which reported a reduction in corticosteroid dose in the range of 25%–80% in patients treated with low-dose methotrexate (5 mg/m2/infusion).222 The ORR was 75% and few toxicities were observed, the most serious being grade 3–4 cytopenias reported in 2 patients. Another retrospective review of 21 patients with steroid-refractory cGVHD reported an ORR of 76% in patients treated with low-dose methotrexate (5 or 10 mg/m2 infusion every 3–4 days).223 The response rates were particularly high in patients with extensive cGVHD (ORR, 92%) and were significantly higher in patients with skin involvement (92%) compared with those with liver involvement (43%; P=.009). Among patients with cGVHD in a single organ (skin or liver), 58% responded compared with 100% of patients with ≥2 organs involved. Although this trial reported severe hematologic toxicities associated with methotrexate, these toxicities were reversible and did not result in treatment discontinuation. These data suggest that low-dose methotrexate is active in the treatment of patients with steroid-refractory cGVHD, especially in those with skin and oral manifestations.

mTOR Inhibitors

The safety and efficacy of sirolimus for the treatment of steroid-refractory cGVHD was evaluated in a phase II trial involving 35 patients.224 Patients with steroid-refractory cGVHD received sirolimus at a loading dose of 6 mg orally followed by a maintenance dose of 2 mg/day while continuing immunosuppressive treatment with tacrolimus and methylprednisolone. The ORR was 63% with 6 patients achieving CR. The highest response rates were observed in patients with sclerotic skin involvement (73%) and involvement of the oral mucosa (75%), but responses were also observed in the lower GI tract (67%), liver (33%), and eyes (64%). Major adverse events included hyperlipidemia, renal dysfunction, cytopenias, thrombotic microangiopathy, and infectious complications. Median survival was 15 months and estimated actuarial survival at 2 years was 41%. In another phase II trial, 19 patients with steroid-refractory cGVHD were treated with sirolimus, CNI, and prednisone. Sirolimus was administered orally at a loading dose of 10 mg followed by a daily dose of 5 mg. Of the 16 evaluable patients, 15 had an initial clinical response to this regimen. However, 5 patients discontinued treatment due to renal toxicity. Of the 10 patients who continued with this regimen, 3 had a prolonged response and were able to successfully taper off immunosuppressive agents. A retrospective study analyzed 47 patients with steroid-refractory cGVHD treated with sirolimus (2 mg/day) in combination with other immunosuppressive agents (CNI [n=33], MMF [n=9], or prednisone [n=5]).225 The ORR was 81% with a CR rate of 38%. The main toxicity was mild impairment of renal function, which was more common in patients receiving sirolimus and CNI (33%) compared with sirolimus and other immunosuppressive agents (7%). Estimated 3-year OS in all patients was 57%. These data suggest that sirolimus is an effective agent for the treatment of patients with steroid-refractory cGVHD and should be investigated further to find the best dose schedule and combination of additional agents to optimize clinical response while limiting toxicity.

Although it has not been studied extensively, the sirolimus derivative everolimus has shown activity in the treatment of steroid-refractory cGVHD. Preliminary data from 2 retrospective studies showed that treatment with everolimus resulted in significant improvement in the NIH Severity Score and patient-reported quality of life.226,227 However, more data are necessary to confirm the role of everolimus in the treatment of steroid-refractory cGVHD.

Mycophenolate Mofetil

The safety and efficacy of MMF for the treatment of steroid-refractory cGVHD was evaluated in a retrospective study of 24 patients treated with MMF at a dose of 500 mg twice per day (escalated to 1 g twice a day if tolerated) in combination with cyclosporine, tacrolimus, and/or prednisone.228 The ORR was 75%, with a CR rate of 21%. Only 2 patients experienced progressive disease. The highest response rates were seen in patients with involvement of the skin or oral mucosa. Of the 22 patients receiving prednisone, 14 (64%) had their prednisone dose decreased by a median of 50% by the end of the 6-month observation period. The most common adverse events were abdominal cramps (which resulted in discontinuation of MMF in 3 patients) and infections. At a median follow-up of 24 months, 83% of patients were alive. In a prospective phase II trial involving 23 patients with steroid-refractory cGVHD, the cumulative incidence of disease resolution and withdrawal of all immunosuppressive treatment was 26% at 36 months after starting treatment with MMF (initial dose of 1 g twice daily).170 After a median follow-up of 9.5 years, 52% of patients remained alive, with only one requiring continued treatment with immunosuppressive agents. In another retrospective analysis of 13 patients with steroid-refractory cGVHD, the ORR to MMF (1.5 or 2 g daily) was 77% and the estimated 2-year OS rate was 54%. The most common adverse events were GI disturbances (27%) and infectious complications (23%). These data suggest that MMF is an effective therapy option for patients with steroid-refractory cGVHD.

Pentostatin

In a phase II trial involving 58 patients with steroid-refractory cGVHD, treatment with pentostatin at 4 mg/m2 given intravenously every 2 weeks for a median of 12 doses resulted in an ORR of 55%. Most patients had skin involvement and more than half had oral and GI involvement. The highest response rates were observed in patients with lichenoid cutaneous manifestations (69%) followed by patients with oral involvement (62%); the lowest response rates were seen in patients with liver involvement. A total of 11 grade 3–4 infections were reported and 4 patients withdrew from treatment due to adverse events including nausea/vomiting, renal toxicity, and fatigue. OS at 1 and 2 years was 78% and 70%, respectively. In a retrospective analysis of 18 patients with steroid-refractory cGVHD, 12 of whom had severe cGVHD, treatment with pentostatin at 4 mg/m2 every 2 weeks resulted in an ORR of 56%; CR was achieved in 1 patient. Activity was observed in all affected organs, with CRs observed in GI (CR, 3), skin (CR, 4), and muscle/fascia (CR, 1) manifestations. The median decrease in corticosteroid dose over 24 months after pentostatin initiation was 38%, and median OS was 5 months. Estimated 1-year OS was 34%. Common adverse events included renal toxicity and infections. These data suggest that pentostatin is active in the treatment of steroid-refractory cGVHD.

Rituximab

Rituximab is an anti-CD20 chimeric monoclonal antibody used to treat non-Hodgkin lymphoma and chronic lymphocytic leukemia. It exerts immunosuppressive effects by binding to CD20 on the surface of B cells, facilitating their destruction.229 Because B cells are implicated in the pathogenesis of cGVHD, the efficacy of rituximab in the treatment of steroid-refractory cGVHD has been evaluated in several studies.206,230 In a systematic review and meta-analysis of 7 studies (3 prospective and 4 retrospective) including 111 patients, the pooled ORR to rituximab was 66%.230 The majority of studies used rituximab at a dose of 375 mg/m2 once per week for 4 to 8 infusions, although similar results were reported with rituximab administered at 50 mg/m2 per week for 4 weeks (ORR, 69%). The pooled ORR for patients with skin cGVHD was 60%, compared with 36% for oral mucosal cGVHD, 29% for liver cGVHD, and 30% for lung cGVHD, suggesting that skin manifestations of cGVHD are particularly susceptible to rituximab treatment. However, it should be noted that the site-specific response rates varied greatly among studies. Administration of rituximab facilitated corticosteroid dose reductions in the range of 75%–86%, depending on the study. The steroid-sparing effect of rituximab was more pronounced in patients with skin and oral mucosal GVHD. The most common adverse events were related to infusion reactions or infectious complications. Therefore, rituximab is an effective treatment option for patients with steroid-refractory cGVHD, especially in those with skin involvement.

Ruxolitinib

The activity of ruxolitinib in the treatment of steroid-refractory cGVHD has been retrospectively evaluated in several studies. A recent analysis of 46 patients with steroid-refractory cGVHD, the majority of whom had severe cGVHD, reported an ORR of 43% and a CR rate of 13% after 12 months of ruxolitinib therapy.231 Organ-specific responses were seen in 25% of patients with skin involvement (n = 10), 60% of patients with mouth involvement (n = 15), 26% of patients with eye involvement (n = 23), 10% of patients with lung involvement (n = 1), and 41% of patients with joint/fascia involvement (n = 23). The 1-year probability of treatment failure-free survival was 54%. The most common adverse event was infectious complications. Another recent retrospective analysis reported better outcomes in 19 patients treated with ruxolitinib (5 mg orally twice per day) for moderate to severe steroid-refractory cGVHD.232 The ORR was 100%, with 18 patients experiencing an overall partial response and 1 experiencing CR. No cytopenias or infections were noted. Corticosteroids were successfully reduced or discontinued in 21% and 68% of patients, respectively. An earlier retrospective study of 41 patients who had received ruxolitinib at a dose of 5–10 mg orally twice per day for moderate to severe steroid-refractory cGVHD reported an ORR of 85% and a 6-month OS rate of 97%.181 Cytopenias and cytomegalovirus reactivation were observed in 17% and 15% of patients, respectively. These data suggest that ruxolitinib is capable of producing high response rates in patients with steroid-refractory cGVHD.

Summary

The NCCN Guidelines for HCT provide an evidence- and consensus-based approach for the pretransplant evaluation of potential HCT recipients and the management of GVHD. HCT is a potentially curative treatment option for patients with certain types of malignancies. However, disease relapse and transplant-related complications often limit the long-term survival of HCT recipients. To determine whether HCT is a potential treatment option, the pretransplant recipient evaluation should be performed in each patient to estimate the risks of relapse, NRM, and overall mortality. Determining the HCT-CI score is essential to establish candidacy for HCT and has been validated to predict the risk of NRM and estimated survival after allogeneic transplant. The leading cause of NRM in allogeneic HCT recipients is the development of GVHD. Mild manifestations of GVHD limited to a single organ are often managed with close observation, topical treatment, or by slowing the tapering of immunosuppressive agents. More severe manifestations or multiorgan involvement typically require systemic corticosteroid treatment (with or without secondary systemic agents). Despite these treatments, approximately 40%–50% of patients with GVHD develop steroid-refractory disease. Steroid-refractory GVHD is associated with high mortality, and no standard, effective therapy has yet been identified. Therefore, the NCCN Panel strongly encourages patients with steroid-refractory acute or chronic GVHD to participate in well-designed clinical trials to enable further advancements for the management of these diseases and ultimately increase the long-term survival of HCT recipients.

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NCCN CATEGORIES OF EVIDENCE AND CONSENSUS

Category 1: Based upon high-level evidence, there is uniform NCCN consensus that the intervention is appropriate.

Category 2A: Based upon lower-level evidence, there is uniform NCCN consensus that the intervention is appropriate.

Category 2B: Based upon lower-level evidence, there is NCCN consensus that the intervention is appropriate.

Category 3: Based upon any level of evidence, there is major NCCN disagreement that the intervention is appropriate.

All recommendations are category 2A unless otherwise noted.

Clinical trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.

PLEASE NOTE

The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) are a statement of evidence and consensus of the authors regarding their views of currently accepted approaches to treatment. Any clinician seeking to apply or consult the NCCN Guidelines is expected to use independent medical judgment in the context of individual clinical circumstances to determine any patient’s care or treatment. The National Comprehensive Cancer Network® (NCCN®) makes no representations or warranties of any kind regarding their content, use, or application and disclaims any responsibility for their application or use in any way.

© National Comprehensive Cancer Network, Inc. 2020. All rights reserved. The NCCN Guidelines and the illustrations herein may not be reproduced in any form without the express written permission of NCCN.

Disclosures for the NCCN Hematopoietic Cell Transplantation Panel

At the beginning of each NCCN Guidelines Panel meeting, panel members review all potential conflicts of interest. NCCN, in keeping with its commitment to public transparency, publishes these disclosures for panel members, staff, and NCCN itself.

Individual disclosures for the NCCN Hematopoietic Cell Transplantation Panel members can be found on page 634. (The most recent version of these guidelines and accompanying disclosures are available at NCCN.org.)

The complete and most recent version of these guidelines is available free of charge at NCCN.org.

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Individual Disclosures for the NCCN Hematopoietic Cell Transplantation Panel

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