-
1.
Hematopoietic Cell Transplantation in the Management of Myelodysplastic Syndrome: An Evidence-Based Review from the American Society for Transplantation and Cellular Therapy Committee on Practice Guidelines
DeFilipp, Z., Ciurea, S. O., Cutler, C., Robin, M., Warlick, E. D., Nakamura, R., Brunner, A. M., Dholaria, B., Walker, A. R., Kröger, N., et al
Transplantation and Cellular Therapy. 2023;29(2):71-81
Abstract
The sole curative therapy for myelodysplastic syndrome (MDS) is allogeneic hematopoietic cell transplantation (HCT). Here this therapeutic modality is reviewed and critically evaluated in the context of the evidence. Specific criteria were used for searching the published literature and for grading the quality and strength of the evidence and the strength of the recommendations. A panel of MDS experts comprising transplantation and nontransplantation physicians developed consensus treatment recommendations. This review summarizes the standard MDS indications for HCT and addresses areas of controversy. Recent prospective trials have confirmed that allogeneic HCT confers survival benefits in patients with advanced or high-risk MDS compared with nontransplantation approaches, and the use of HCT is increasing in older patients with good performance status. However, patients with high-risk cytogenetic or molecular mutations remain at high risk for relapse. It is unknown whether administration of novel therapies before or after transplantation may decrease the risk of disease relapse in selected populations. Ongoing and future studies will investigate revised approaches to disease risk stratification, patient selection, and post-transplantation approaches to optimize allogeneic HCT outcomes for patients with MDS.
-
2.
Patient-reported treatment response in chronic graft-versus-host disease
Im, A., Pusic, I., Onstad, L., Kitko, C. L., Hamilton, B. K., Alousi, A. M., Flowers, M. E., Sarantopoulos, S., Carpenter, P., White, J., et al
Haematologica. 2023
Abstract
Chronic graft vs. host disease (GVHD) treatment response is assessed using NIH Consensus criteria in clinical trials, and by clinician assessment in routine practice. Patient-reported treatment response is central to the experience of chronic GVHD manifestations as well as treatment benefit and toxicity, but how they correlate with clinician- or NIH-responses has not been well studied. We aimed to characterize 6-month patient-reported response, determine associated chronic GVHD baseline organ features and changes, and evaluate which patientreported quality of life and chronic GVHD symptom burden measures correlated with patientreported response. From two nationally representative Chronic GVHD Consortium prospective observational studies, 382 subjects were included in this analysis. Patient and clinician responses were categorized as improved (completely gone, very much better, moderately better, a little better) vs. not improved (about the same, a little worse, moderately worse, very much worse). At 6 months, 270 (71%) patients perceived chronic GVHD improvement, while 112 (29%) perceived no improvement. Patient-reported response had limited correlation with either clinician-reported (kappa 0.37) or NIH chronic GVHD response criteria (kappa 0.18). Notably, patient-reported response at 6 months was significantly associated with subsequent failure-free survival. In multivariate analysis, NIH responses in eye, mouth, and lung had significant association with 6-month patient-reported response, as well as a change in Short Form 36 general health and role physical domains and Lee Symptom Score skin and eye changes. Based on these findings, patient-reported responses should be considered as an important complementary endpoint in chronic GVHD clinical trials and drug development.
-
3.
Durable discontinuation of systemic therapy in patients affected by chronic graft versus host disease
Chen, G. L., Onstad, L., Martin, P. J., Carpenter, P., Pidala, J., Arai, S., Cutler, C., Hamilton, B. K., Lee, S. J., Arora, M.
Haematologica. 2022
Abstract
Successful treatment of chronic graft-versus-host disease (GVHD) often requires long term systemic therapy (ST). Durable discontinuation of ST reflects the resolution of active chronic GVHD. We evaluated the factors associated with durable ST discontinuation, defined as cessation of all ST for ≥12 months, using data from 2 prospectively followed cohorts from the chronic GVHD Consortium (N=684). Transplant sources were peripheral blood (89%), bone marrow (6.6%), and cord blood (4.4%) from HLA matched related (37.6%), HLA matched unrelated (45%), and other donor types (18%). Half received non-myeloablative conditioning. The median time from HCT to chronic GVHD diagnosis was 7.7 (range 1.0 - 141.3) months, and the median time from chronic GVHD onset to enrollment into the cohorts was 0.9 (range 0.0-12.0) months. The cumulative incidence estimate of durable ST discontinuation was 32% (95% CI: 28%-37%) at 10 years after cohort enrollment. Among patients who discontinued ST, the median time from chronic GVHD diagnosis to durable ST discontinuation was 3.6 (range 1.2-10.5) years. In multivariate analysis, patients who received myeloablative conditioning, had chronic GVHD manifested as moderate / severe lower gastrointestinal (GI) involvement, and had a higher (worse) Lee symptom overall score were less likely to attain durable ST discontinuation. In contrast, mild lower GI involvement and cord blood (vs. peripheral blood) as a graft source were associated with a greater likelihood of ST discontinuation. Although a minority of patients can discontinue systemic treatment permanently, most patients require prolonged systemic treatment. Viewing chronic GVHD in this way has implications for management approaches.
-
4.
ASTCT Clinical Practice recommendations for transplant and cellular therapies in multiple myeloma
Dhakal, B., Shah, N., Kansagra, A., Kumar, A., Lonial, S., Garfall, A., Cowan, A., Poudyal, B. S., Costello, C., Gay, F., et al
Transplantation and cellular therapy. 2022
Abstract
Over the past decade, therapeutic options in multiple myeloma (MM) have changed dramatically. Given the unprecedented efficacy of novel agents, the role of hematopoietic cell transplantation (HCT) in MM remains under scrutiny. Rapid advances in myeloma immunotherapy including the recent approval of chimeric antigen receptor (CAR) T-cell therapy will impact the MM therapeutic landscape. The American Society for Transplantation and Cellular Therapy (ASTCT) convened an expert panel to formulate clinical practice recommendations for role, timing, and sequencing of autologous (auto-HCT), allogeneic (allo-HCT) and CAR T-cell therapy for patients with newly diagnosed (NDMM) and relapsed/refractory MM (RRMM). The RAND-modified Delphi method was used to generate consensus statements. Twenty consensus statements were generated. The panel endorsed continued use of auto-HCT consolidation for patients with NDMM as a standard-of-care option, whereas in the front line allo-HCT and CAR-T were not recommended outside the setting of clinical trial. For patients not undergoing auto-HCT upfront, the panel recommended its use in first relapse. Lenalidomide as a single agent was recommended for maintenance especially for standard risk patients. In the RRMM setting, the panel recommended the use of CAR-T in patients with 4 or more prior lines of therapy. The panel encouraged allo-HCT in RRMM setting only in the context of clinical trial. The panel found RAND-modified Delphi methodology effective in providing a formal framework for developing consensus recommendations for the timing and sequence of cellular therapies for MM.
-
5.
Harmonizing Definitions for Diagnostic Criteria and Prognostic Assessment of Transplant Associated Thrombotic Microangiopathy: A Report on Behalf of the European Society for Blood and Marrow Transplantation (EBMT), American Society for Transplantation and Cellular Therapy (ASTCT), Asia-Pacific Blood and Marrow Transplantation Group (APBMT) and the Center for International Blood and Marrow Transplant Research (CIBMTR)
Schoettler, M., Carreras, E., Cho, B., Dandoy, C. E., Ho, V. T., Jodele, S., Moissev, I., Sanchez-Ortega, I., Srivastava, A., Atsuta, Y., et al
Transplantation and cellular therapy. 2022
Abstract
BACKGROUND/RATIONALE Transplant-associated thrombotic microangiopathy (TA-TMA) is an increasingly recognized complication of hematopoietic cell transplant (HCT) associated with significant morbidity and mortality. However, TA-TMA is a clinical diagnosis and multiple criteria are proposed without universal application. While some patients have a self-resolving disease, others progress to multi-organ failure and/or death. Poor prognostic features are also not uniformly accepted. The lack of harmonization of diagnostic and prognostic markers have precluded multi-institutional studies to better understand incidence and outcomes. Even current interventional trials use different criteria, making it challenging to interpret the data. To address this urgent need, the American Society for Transplantation and Cellular Therapy, Center for International Bone Marrow Transplant Research, Asia-Pacific Blood and Marrow Transplantation, and European Society for Blood and Marrow Transplantation nominated representatives, forming an expert panel to come to a consensus on diagnostic and prognostic criteria. METHODS The panel reviewed literature, generated consensus statements using the Delphi Method regarding diagnostic and prognostic features of TA-TMA, and identified future directions of investigation. SUMMARY OF CONSENSUS STATEMENTS Consensus was reached on four key concepts. 1) TA-TMA can be diagnosed using clinical and laboratory criteria or tissue biopsy of kidney or gastrointestinal tissue. However, a biopsy is not required. 2) Consensus diagnostic criteria are proposed using modified Jodele criteria with additional definitions of anemia and thrombocytopenia. TA-TMA is diagnosed when ≥ 4/7 following features occur twice within 14 days: anemia, defined as failure to achieve transfusion independence despite neutrophil engraftment, hemoglobin decline by ≥1 gm/dL, or new onset transfusion dependence, thrombocytopenia defined as failure to achieve platelet engraftment, higher than expected transfusion needs, refractory to platelet transfusions, or ≥ 50% reduction in baseline platelet count after full platelet engraftment, lactate dehydrogenase (LDH) >ULN, schistocytes, hypertension, sC5b-9>ULN and proteinuria (≥ 1mg/mg random urine protein creatinine ratio, rUPCR). 3) Patients with any of the following features have an increased risk of non-relapse mortality and should be stratified as high-risk TA-TMA: elevated sC5b-9, LDH ≥2X ULN, rUPCR ≥1 mg/mg, multiorgan dysfunction, concurrent grade II-IV acute graft versus host disease, or infection (bacterial or viral). 4) All allogeneic and pediatric autologous HCT recipients with neuroblastoma should be screened weekly for TA-TMA during the first 100 days post-HCT. If patients are diagnosed with TA-TMA, they should be risk stratified. Patients with high-risk disease should be offered participation in a clinical trial for TA-TMA-directed therapy if available. FUTURE DIRECTIONS We propose that these criteria and risk stratification features be used in data registries, prospective studies, and clinical practice across international settings. This harmonization will facilitate the investigation of TA-TMA across populations diverse in race, ethnicity, age, disease indication, and transplant characteristics. As these criteria are broadly utilized, we expect continued refinement as necessary. Efforts to identify more specific diagnostic and prognostic biomarkers are a top priority of the field. Lastly, an investigation of the impact of TA-TMA-directed treatment, particularly in the setting of concurrent highly morbid complications such as steroid-refractory GVHD and infection, is critically needed.
-
6.
Guidelines for Pediatric Unrelated Cord Blood Transplantation-Unique Considerations
Dahlberg, A., Kurtzberg, J., Boelens, J., Martinez, C., Carpenter, P.
Transplantation and cellular therapy. 2021
Abstract
Cord blood (CB) is the stem cell source of choice for approximately 30% of pediatric patients undergoing hematopoietic cell transplantation. Cord blood is readily available and is a particularly appealing stem cell source for patients who lack appropriate HLA matched related or unrelated donors. Pediatric cord blood transplant (CBT) recipients have low rates of disease relapse in the malignant setting and very low rates of chronic GVHD. In addition, CB has unique properties that make it the stem cell source of choice for some non-malignant conditions such as metabolic disorders. This review provides evidence-based and experience-based pediatric specific guidelines for CBT including considerations for infectious disease management, CB unit selection and infusion, conditioning regimen selection, and GVHD management. In addition, it covers unique bedside considerations for pediatric patients and CB banking. In concert with the other topic specific CB guidelines previously published in this series, it provides a comprehensive overview of the clinical management of pediatric CBT.
-
7.
A Phase 3, Single-arm, Prospective Study of Remestemcel-L, Ex-vivo Culture-Expanded Adult Human Mesenchymal Stromal Cells, for the Treatment of Pediatric Patients who Failed to Respond to Steroid Treatment for Acute GVHD
Kurtzberg, J., Abdel-Azim, H., Carpenter, P., Chaudhury, S., Horn, B., Mahadeo, K., Nemecek, E., Neudorf, S., Prasad, V., Prockop, S., et al
Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation. 2020
-
-
-
Free full text
-
Editor's Choice
Abstract
Steroid-refractory acute graft-versus-host disease (SR-aGVHD) following hematopoietic cell transplantation (HSCT) is associated with poor clinical outcomes. Currently, there are no safe and effective therapies approved for use in the pediatric population under the age of 12 years. Accordingly, there is an urgent need for new treatments that are safe, well-tolerated and effective in managing this debilitating and potentially fatal complication of HSCT. In early phase clinical trials, Mesenchymal stromal cells (MSCs) have demonstrated efficacy in the treatment of acute GVHD (aGVHD) in pediatric patients. We now report the results of a phase 3, prospective, single arm, multicenter study (NCT02336230) in 54 children with primary SR-aGVHD who were naive to other immunosuppressant therapies (IST) for aGVHD treated with MSC product (remestemcel-L) dosed at 2x10(6) cells/kg twice weekly for four weeks. Remestemcel-L therapy significantly improved day 28 overall response rate (OR) compared to the pre-specified control OR value of 45% (70.4% versus 45%, P =0.0003). The statistically significant OR (70.4%) was sustained through day 100 including an increase in complete response (CR) from 29.6% at day 28 to 44.4% at day 100. Overall survival was 74.1% at day 100 and 68.5% at day 180. Overall response in all participants at day 28 was highly predictive of improved survival through 180 days and survival was significantly greater in day 28 responders compared with non-responders through day 100 (86.8% vs. 47.1% for responders and non-responders, respectively, P=0.0001) and through day 180 (78.9% vs. 43.8%, p=0.003). Remestemcel-L was well-tolerated with no identified infusion-related toxicities or other safety concerns. This study provides robust, prospective evidence of the safety, tolerability and efficacy of remestemcel-L as first-line therapy after initial steroid failure in pediatric SR-aGVHD.
PICO Summary
Population
Children with primary steroid refractory aGVHD, naive to other immunosuppressant therapies (n=54)
Intervention
Mesenchymal stromal cell product (remestemcel-L) dosed at 2x10(6) cells/kg twice weekly for four weeks.
Comparison
None
Outcome
Remestemcel-L therapy significantly improved day 28 overall response rate (OR) compared to the pre-specified control OR value of 45% (70.4% versus 45%). The statistically significant OR (70.4%) was sustained through day 100 including an increase in complete response (CR) from 29.6% at day 28 to 44.4% at day 100. Overall survival was 74.1% at day 100 and 68.5% at day 180. Overall response in all participants at day 28 was highly predictive of improved survival through 180 days and survival was significantly greater in day 28 responders compared with non-responders through day 100 (86.8% vs. 47.1% for responders and non-responders, respectively) and through day 180 (78.9% vs. 43.8%) Remestemcel-L was well-tolerated with no identified infusion-related toxicities or other safety concerns.
-
8.
Maintenance Therapies for Hodgkin and Non-Hodgkin Lymphomas After Autologous Transplantation: A Consensus Project of ASBMT, CIBMTR, and the Lymphoma Working Party of EBMT
Kanate, A. S., Kumar, A., Dreger, P., Dreyling, M., Le Gouill, S., Corradini, P., Bredeson, C., Fenske, T. S., Smith, S. M., Sureda, A., et al
JAMA oncology. 2019
-
-
Free full text
-
Abstract
Importance: Maintenance therapies are often considered as a therapeutic strategy in patients with lymphoma following autologous hematopoietic cell transplantation (auto-HCT) to mitigate the risk of disease relapse. With an evolving therapeutic landscape, where novel drugs are moving earlier in therapy lines, evidence relevant to contemporary practice is increasingly limited. The American Society for Blood and Marrow Transplantation (ASBMT), Center for International Blood and Marrow Transplant Research (CIBMTR), and European Society for Blood and Marrow Transplantation (EBMT) jointly convened an expert panel with diverse expertise and geographical representation to formulate consensus recommendations regarding the use of maintenance and/or consolidation therapies after auto-HCT in patients with lymphoma. Observations: The RAND-modified Delphi method was used to generate consensus statements where at least 75% vote in favor of a recommendation was considered as consensus. The process included 3 online surveys moderated by an independent methodological expert to ensure anonymity and an in-person meeting. The panel recommended restricting the histologic categories covered in this project to Hodgkin lymphoma (HL), mantle cell lymphoma (MCL), diffuse large B-cell lymphoma (DLBCL), and follicular lymphoma. On completion of the voting process, the panel generated 22 consensus statements regarding post auto-HCT maintenance and/or consolidation therapies. The grade A recommendations included endorsement of: (1) brentuximab vedotin (BV) maintenance and/or consolidation in BV-naive high-risk HL, (2) rituximab maintenance in MCL undergoing auto-HCT after first-line therapy, (3) rituximab maintenance in rituximab-naive FL, and (4) No post auto-HCT maintenance was recommended in DLBCL. The panel also developed consensus statements for important real-world clinical scenarios, where randomized data are lacking to guide clinical practice. Conclusions and Relevance: In the absence of contemporary evidence-based data, the panel found RAND-modified Delphi methodology effective in providing a rigorous framework for developing consensus recommendations for post auto-HCT maintenance and/or consolidation therapies in lymphoma.
-
9.
Prognosis of relapse after hematopoietic cell transplant (HCT) for treatment of leukemia or myelodysplastic syndrome (MDS) in children
Dahlberg, A., Leisenring, W., Bleakley, M., Meshinchi, S., Baker, K. S., Summers, C., Hadland, B., Delaney, C., Mallhi, K., Burroughs, L., et al
Bone marrow transplantation. 2019
Abstract
We studied 232 consecutive children transplanted between 1990 and 2011 with relapse after first hematopoietic cell transplant (HCT). Kaplan-Meier survival and hazard ratios for mortality were calculated for factors known at time of relapse using Cox proportional hazards models. The median (range) age at time of first HCT was 10.9 (0.5-20.9) years, time to relapse was 6.1 (0.2-89.5) months after HCT, and age at relapse was 11.7 (0.7-23.6) years. The 3-year overall survival (OS) after relapse was 13% (95% confidence interval (CI): 9%, 18%).The median (range) follow-up for the 18 surviving patients was 7.2 (3.0-24.4) years after relapse. The remaining 214 died after a median of 3 months (0.02-190.4). OS was not significantly different for patients with ALL as compared to AML. Fifty-one patients proceeded to second transplant of whom nine survive. Factors associated with improved survival included late relapse (>12 months), ALL in first CR at the time of first transplant and chemotherapy-based first conditioning regimens. These results can be used to counsel patients at the time of relapse after first transplant and as a baseline for comparison as to the effectiveness of newer therapies which are greatly needed for treatment of post-transplant relapse.
-
10.
Clinical Practice Recommendations for Use of Allogeneic Hematopoietic Cell Transplantation in Chronic Lymphocytic Leukemia on Behalf of the Guidelines Committee of the American Society for Blood and Marrow Transplantation. [Review]
Kharfan-Dabaja, M. A., Kumar, A., Hamadani, M., Stilgenbauer, S., Ghia, P., Anasetti, C., Dreger, P., Montserrat, E., Perales, M. A., Alyea, E. P., et al
Biology of Blood & Marrow Transplantation. 2016;22(12):2117-2125
Abstract
We sought to establish clinical practice recommendations to redefine the role of allogeneic hematopoietic cell transplantation (allo-HCT) for patients with chronic lymphocytic leukemia (CLL) in an era of highly active targeted therapies. We performed a systematic review to identify prospective randomized controlled trials comparing allo-HCT against novel therapies for treatment of CLL at various disease stages. In the absence of such data, we invited physicians with expertise in allo-HCT and/or CLL to participate in developing these recommendations. We followed the Grading of Recommendations Assessment, Development and Evaluation methodology. For standard-risk CLL we recommend allo-HCT in the absence of response or if there is evidence of disease progression after B cell receptor (BCR) inhibitors. For high-risk CLL an allo-HCT is recommended after failing 2 lines of therapy and showing an objective response to BCR inhibitors or to a clinical trial. It is also recommended for patients who fail to show an objective response or progress after BCR inhibitors and receive BCL-2 inhibitors, regardless of whether an objective response is achieved. For Richter transformation, we recommend allo-HCT upon demonstration of an objective response to anthracycline-based chemotherapy. A reduced-intensity conditioning regimen is recommended whenever indicated. These recommendations highlight the rapidly changing treatment landscape of CLL. Newer therapies have disrupted prior paradigms, and allo-HCT is now relegated to later stages of relapsed or refractory CLL. Copyright © 2016 The American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.