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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.
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Impact of Conditioning Intensity and Genomics on Relapse After Allogeneic Transplantation for Patients With Myelodysplastic Syndrome
Dillon, L. W., Gui, G., Logan, B. R., Fei, M., Ghannam, J., Li, Y., Licon, A., Alyea, E. P., Bashey, A., Devine, S. M., et al
JCO precision oncology. 2021;5
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Abstract
PURPOSE Patients with myelodysplastic syndrome (MDS) are at risk of relapse after allogeneic hematopoietic cell transplantation. The utility of ultra-deep genomic testing to predict and the impact of conditioning intensity to prevent MDS relapse are unknown. METHODS Targeted error-corrected DNA sequencing was performed on preconditioning blood samples from patients with MDS (n = 48) from the Blood and Marrow Transplant Clinical Trials Network 0901 phase III randomized clinical trial, which compared outcomes by allogeneic hematopoietic cell transplantation conditioning intensity in adult patients with < 5% marrow myeloblasts and no leukemic myeloblasts in blood on morphological analysis at the time of pretransplant assessment. Clinical end points (53-month median follow-up) included transplant-related mortality (TRM), relapse, relapse-free survival (RFS), and overall survival (OS). Of the 48 patients examined, 14 experienced TRM, 23 are relapse-free, and 11 relapsed, of which 7 died. RESULTS Using a previously described set of 10 gene regions, 42% of patients (n = 20) had mutations detectable before random assignment to reduced intensity conditioning (RIC) or myeloablative conditioning (MAC). Testing positive was associated with increased rates of relapse (3-year relapse, 40% v 11%; P = .022) and decreased OS (3-year OS, 55% v 79%, P = .045). In those testing positive, relapse rates were higher (3-year relapse, 75% v 17%; P = .003) and RFS was lower (3-year RFS, 13% v 49%; P = .003) in RIC versus MAC arms. Testing additional genes, including those associated with MDS, did not improve prognostication. CONCLUSION This study provides evidence that targeted DNA sequencing in patients with MDS before transplant can identify those with highest post-transplant relapse rates. In those testing positive, random assignment to MAC lowered but did not eliminate relapse risk.
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Hematopoietic Cell Transplantation with Cryopreserved Grafts for Severe Aplastic Anemia
Eapen, M., Zhang, M. J., Tang, X. Y., Lee, S. J., Fei, M. W., Wang, H. L., Hebert, K. M., Arora, M., Chhabra, S., Devine, S. M., et al
Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation. 2020
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Editor's Choice
Abstract
With the COVID-19 pandemic and the ensuing barriers to the collection and transport of donor cells, it is often necessary to collect and cryopreserve grafts before initiation of transplantation conditioning. The effect on transplantation outcomes in nonmalignant disease is unknown. This analysis examined the effect of cryopreservation of related and unrelated donor grafts for transplantation for severe aplastic anemia in the United States during 2013 to 2019. Included are 52 recipients of cryopreserved grafts who were matched for age, donor type, and graft type to 194 recipients who received noncryopreserved grafts. Marginal Cox regression models were built to study the effect of cryopreservation and other risk factors associated with outcomes. We recorded higher 1-year rates of graft failure (hazard ratio [HR], 2.26; 95% confidence interval, 1.17 to 4.35; P=.01) and of 1-year overall mortality (HR, 3.13; 95% CI, 1.60 to 6.11; P=.0008) after transplantation of cryopreserved compared with noncryopreserved grafts, with adjustment for sex, performance score, comorbidity, cytomegalovirus serostatus, and ABO blood group match. The incidence of acute and chronic graft-versus-host disease did not differ between the 2 groups. Adjusted probabilities of 1-year survival were 73% (95% CI, 60% to 84%) in the cryopreserved graft group and 91% (95% CI, 86% to 94%) in the noncryopreserved graft group. These data support the use of noncryopreserved grafts whenever possible in patients with severe aplastic anemia.
PICO Summary
Population
Patients with severe aplastic anaemia, who underwent HSCT and were reported to CIBMTR registry
Intervention
Cryopreseverved graft (n=52)
Comparison
Matched controls who received non-cryopreserved grafts (n=194)
Outcome
. We recorded higher 1-year rates of graft failure and of 1-year overall after transplantation of cryopreserved compared with noncryopreserved grafts, with adjustment for sex, performance score, comorbidity, cytomegalovirus serostatus, and ABO blood group match. The incidence of acute and chronic graft-versus-host disease did not differ between the 2 groups. Adjusted probabilities of 1-year survival were 73% in the cryopreserved graft group and 91% in the noncryopreserved graft group.
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Fludarabine/busulfan conditioning based allogeneic hematopoietic cell transplantation for myelofibrosis: Role of ruxolitinib in improving survival outcomes
Chhabra, S., Narra, R. K., Wu, R., Szabo, A., George, G., Michaelis, L. C., D'Souza, A., Dhakal, B., Drobyski, W. R., Fenske, T. S., et al
Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation. 2020
Abstract
Allogeneic hematopoietic cell transplantation (HCT) is the only curative treatment modality for primary myelofibrosis (MF) and related myeloproliferative neoplasms. Older age at diagnosis and age-related comorbidities make most patients ineligible for alloHCT, given concerns for non-relapse mortality (NRM). Herein, we report the outcomes of 37 consecutive recipients of allogeneic HCT for MF performed at a single center between 2009 and 2018 with a standardized institutional protocol. Most patients received ruxolitinib prior to HCT (n=32), and those with splenomegaly >22 cm received pre-transplant splenic irradiation. Median age at HCT was 60 years (range, 40-74): 68% carried JAK2 driver mutation. All patients received fludarabine/busulfan-based conditioning: 22 patients (59%) received reduced intensity conditioning. All patients received peripheral blood grafts. Sixteen (43%) patients had matched sibling donor, and others had unrelated (n=20) or haploidentical-related donor (n=1). Sixty one percent had an HCT-CI score ≥3, 40% had KPS <90 and 24% had a high-risk DIPSS Plus score. With a median follow-up of 40.2 months (range, 16.9-115), the 3-year overall and relapse-free survival were 81.1% (95% Confidence Interval [95%CI], 64.4-90.5%) and 78.4% (95% CI, 61.4-88.5%), respectively. Only two patients relapsed/progressed after transplant. NRM at 2 years was 16.2% (95% CI, 6.5-29.9%). All patients engrafted. Sixteen patients were treated with ruxolitinib post-transplant for treatment of GVHD, graft rejection/relapse and persistent MF. These results suggest that pre-transplant ruxolitinib, fludarabine/busulfan-based conditioning and splenic management are keys to improved transplant outcomes in MF.
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Myeloablative vs. reduced-intensity hematopoietic cell transplantation in myelodysplastic syndromes: a systematic review and meta-analysis
Rashidi, A., Meybodi, M. A., Cao, W., Chu, H., Warlick, E. D., Devine, S., Pasquini, M. C., Weisdorf, D. J., Hamadani, M.
Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation. 2020
Abstract
In a systematic review and meta-analysis, we compared allogeneic transplant outcomes after myeloablative (MAC) vs. reduced-intensity (RIC) conditioning in patients with MDS. Only two published randomized clinical trials were found, with a pooled sample size of 183 (RIC: 92; MAC: 91). Both studies suggested an overall survival advantage after RIC, with a pooled hazard ratio (HR) of 0.67 (95% confidence interval [CI] 0.41-1.09) for RIC vs. MAC. Relapse results were also concordant, with a pooled HR of 1.55 (95%CI 0.74-3.25) for RIC vs. MAC. Neither result was statistically significant. Comparisons for other outcomes were unremarkable. In conclusion, the evidence for the optimal conditioning intensity in MDS is weak. Post-transplant maintenance strategies and incorporation of genomic information into decision-making may improve post-transplant outcomes.
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An updated single center experience with plerixafor and granulocyte colony-stimulating factor for stem cell mobilization in light chain amyloidosis
Badar, T., Dhakal, B., Szabo, A., Padmanabhan, A., Johnson, B. D., Heidtke, S., Esselmann, J., Chhabra, S., Hamadani, M., Hari, P., et al
Journal of clinical apheresis. 2019
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Abstract
The use of granulocyte-colony stimulating factor (G-CSF) with or without chemotherapy to mobilize hematopoietic progenitor cells (HPCs) can result in significant morbidity in light chain (AL) amyloidosis patients. Plerixafor, a strong inducer and mobilizer of HPCs, can be used as an adjunct to G-CSF to improve mobilization efficiency. We describe the outcomes for combined G-CSF/plerixafor mobilized patients with AL amyloidosis. We reviewed data of 53 consecutive AL amyloidosis patients who underwent combined G-CSF/plerixafor HPC mobilization between May 2011 and October 2017 at our institution. We evaluated patients for HPC collection efficiency, perimobilization toxicity and postautologous hematopoietic cell transplantation (autoHCT) outcomes. Median CD34(+) cell collection was 12.4 x 10(6) cells/kg (range 2.5 x 10(6) to 34.1 x 10(6) cells/kg) and 45 (85%) patients had collections of ≥5.0 x 10(6) CD34(+) cells/kg. There were no mobilization failures or perimobilization mortality. During mobilization, 37 (70%) patients had weight gain (median 1.3 kg, range 0.1-4) but none >10% body weight, 5 (10%) patients had diarrhea, and one patient each had hypotension and cardiac arrhythmia. Among the 31 patients analyzed for CD34 collection efficiency (CE), the median CD34 CE was 47% (range 36-62). At 5 years follow-up 82% and 84% of patients were progression-free and alive, respectively. Our results suggest that G-CSF/plerixafor mobilization is safe, well tolerated, and effective in AL amyloidosis.