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1.
Transplant Outcomes of Myelofibrosis with Busulfan and Fludarabine Myeloablative Conditioning
Joseph, J., Srour, S. A., Milton, D. R., Ramdial, J. L., Saini, N. Y., Olson, A. L., Bashir, Q., Oran, B., Alousi, A. M., Hosing, C., et al
Transplantation and cellular therapy. 2023
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Editor's Choice
Abstract
BACKGROUND Outcomes of myelofibrosis with allogeneic stem cell transplantation (allo-SCT) have improved over the past decade and are partly related to advances in supportive treatments and conditioning regimens. Several factors are known to predict transplant outcomes. However, most studies lack homogeneity in the conditioning regimen used, which limits their ability to assess prognostic factors on transplant outcomes. OBJECTIVE We aimed to determine the risk factors that predict transplant outcomes in patients with myelofibrosis who underwent matched or mismatched allo-SCT using a uniform myeloablative conditioning regimen consisting of busulfan and fludarabine with tacrolimus and methotrexate-based graft-versus-host disease prophylaxis. STUDY DESIGN This single-center study included patients with myelofibrosis who underwent allo-SCT with a matched unrelated donor (MUD), matched related donor (MRD), or mismatched unrelated donor (MMUD) and received busulfan and fludarabine conditioning with methotrexate/tacrolimus-based GVHD prophylaxis. RESULTS Sixty-five patients with myelofibrosis met the criteria and were included in the study. At a median follow-up of 35.6 months, the 3-year cumulative incidence of relapse (CIR), non-relapse mortality (NRM), and overall survival (OS) for all study patients were 27%, 20%, and 65%, respectively. In a multivariable analysis for CIR, prior use of JAK inhibitors was significantly associated with a decreased risk of relapse (HR [95% CI], 0.33 [0.11-0.99]; p = 0.048). For NRM, HCT-CI (≥3 vs. <3, 10.09 [2.09-48.76]; p=0.004) and donor type (MUD vs. MRD, 5.38 [1.14-25.30]; p=0.033 and MMUD vs. MRD, 10.73 [1.05-109.4]; p=0.045) were associated with an increased risk of mortality. Likewise for OS, HCT-CI (≥3 vs. <3, 3.31 [1.22-8.99]; p = 0.019) and donor type (MMUD vs. MRD, 5.20 [1.35-19.98]; p = 0.016) were significantly associated with inferior survival. Longer time from diagnosis to allo-SCT seemed to confer worse survival but this didn't reach statistical significance (>12 months vs. ≤12 months: NRM, 7.20 [0.96-53.94]; p=0.055 and OS, 2.60 [0.95-7.14]; p=0.06). CONCLUSIONS In a homogenous cohort of myelofibrosis patients uniformly treated with busulfan/fludarabine myeloablative conditioning and methotrexate-based GVHD prophylaxis, we showed that donor choice and HCT-CI are the two strongest predictors for improved survival after allo-SCT.
PICO Summary
Population
People with myelofibrosis who underwent allo-SCT with a matched unrelated donor (MUD), matched related donor (MRD), or mismatched unrelated donor (MMUD) at a single centre in USA (n=176)
Intervention
Cohort for analysis: all who received myeloablative conditioning regimen consisting of busulfan and fludarabine with tacrolimus and methotrexate-based graft-versus-host disease prophylaxis (n=65)
Comparison
None
Outcome
At a median follow-up of 35.6 months, the 3-year cumulative incidence of relapse (CIR), non-relapse mortality (NRM), and overall survival (OS) for all study patients were 27%, 20%, and 65%, respectively. In a multivariable analysis for CIR, prior use of JAK inhibitors was significantly associated with a decreased risk of relapse (HR [95% CI], 0.33 [0.11-0.99]). For NRM, HCT-CI (>/=3 vs. <3, 10.09 [2.09-48.76]) and donor type (MUD vs. MRD, 5.38 [1.14-25.30] and MMUD vs. MRD, 10.73 [1.05-109.4]) were associated with an increased risk of mortality. Likewise for OS, HCT-CI (>/=3 vs. <3, 3.31 [1.22-8.99];) and donor type (MMUD vs. MRD, 5.20 [1.35-19.98]) were significantly associated with inferior survival. Longer time from diagnosis to allo-SCT seemed to confer worse survival but this didn't reach statistical significance (>12 months vs. </=12 months: NRM, 7.20 [0.96-53.94] and OS, 2.60 [0.95-7.14]).
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2.
Optimizing the Conditioning Regimen for HCT in Myelofibrosis: Long-term Results of a Prospective Phase II Clinical Trial
Popat, U., Mehta, R. S., Bassett, R., Kongtim, P., Chen, J., Alousi, A. M., Anderlini, P., Ciurea, S., Hosing, C., Jones, R., et al
Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation. 2020
Abstract
BACKGROUND Optimal conditioning regimen for older patients with myelofibrosis undergoing allogeneic hematopoietic cell transplantation (HCT) is not known. Likewise, role of dose intensity is not clear. METHODS We conducted a non-randomized prospective phase II trial using low-dose, later escalated to high-dose (MAC) busulfan with fludarabine (Bu-Flu) in myelofibrosis patients up to 74 years. First 15 patients received intravenous busulfan 130 mg/m(2)/day on days -3 and -2 ("low dose"); 31 received high dose - either 100 mg/m(2)/day (days -5 to -2; n=4) or pharmacokinetic-guided area under the curve of 4,000 mumol.min (days -5 to -2; n=27). Primary endpoint was day 100 non-relapse mortality (NRM). FINDINGS Median age was 58 years (interquartile range (IQR) 53-63). Dynamic international prognostic scoring system (DIPSS)-plus was intermediate (n=28) or high (n=18). Donors were related (n=19) or unrelated (n=27). Cumulative incidence of NRM was 9.7% (95% confidence interval (CI) 0-20.3) at day 100 and at 3 years in the high dose, while it was 0% in the low dose group at day 100, and increased to 20% (95% CI 0-41.9) at 3 years. With a median follow up of 5.1 years (IQR 3.8-6), 3-year relapse was 32.3% (95% CI 15.4-49.1) in high dose versus 53.3% (95% CI 26.6-80.1) in low dose; event-free survival was 58% (95% CI 43-78%) versus 27% (95% CI 12-62%), and overall survival was 74% (95% CI 60-91%) versus 60% (95% CI 40-91%) respectively. In multivariate analysis, high dose busulfan had a trend towards lower relapse (Hazard ratio (HR) 0.44, 95% CI, 0.18-1.07, p=0.07), with no impact on NRM. INTERPRETATION Intensifying Bu-Flu regimen using pharmacokinetic-monitoring appears promising in reducing relapse without increasing non-relapse mortality. FUNDING The study was supported partly by Otsuka pharmaceutical and partly by the Cancer Center Support Grant (NCI Grant P30 CA016672).
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Mixed myeloid chimerism and relapse of myelofibrosis after allogeneic stem cell transplantation
Srour, S. A., Olson, A., Ciurea, S. O., Desai, P., Bashir, Q., Oran, B., Bose, P., Mehta, R., Patel, K. P., Pemmaraju, N., et al
Haematologica. 2019
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4.
Allogeneic Stem Cell Transplantation for Advanced Myelodysplastic Syndrome: Comparison of Outcomes between CD34(+) Selected and Unmodified Hematopoietic Stem Cell Transplantation
Tamari, R., Oran, B., Hilden, P., Maloy, M., Kongtim, P., Papadopoulos, E. B., Rondon, G., Jakubowski, A. A., Andersson, B. S., Devlin, S. M., et al
Biology of Blood and Marrow Transplantation : Journal of the American Society for Blood and Marrow Transplantation. 2018;24(5):1079-1087
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Abstract
In this study, we compared transplantation outcomes of allogeneic hematopoietic stem cell transplantation (HSCT) in patients with advanced myelodysplastic syndrome (MDS) who received a CD34(+) cell-selected and those who received an unmodified allograft. This analysis initially included 181 patients, 60 who received a CD34(+) cell-selected transplant and 121 who received an unmodified transplant. Owing to significant differences in disease characteristics, the analysis was limited to patients with <10% blasts before HSCT (n = 145). Two groups were defined: low risk, with low- and intermediate-risk cytogenetics (CD34(+), n = 39; unmodified, n = 46), and high risk: poor and very poor risk cytogenetics (CD34(+), n = 19; unmodified, n = 41). In the low-risk group, the incidence of grade II-IV acute graft-versus-host disease (aGVHD) at 1 year post-transplantation was 18% in the CD34(+) subgroup versus 41.3% in the unmodified subgroup (P = .015). There were no differences between the subgroups in the incidence of grade III-IV aGVHD. The incidence of chronic graft-versus-host disease (cGVHD) at 3 years in the 2 subgroups was 5.3% and 56%, respectively (P < .001). At 3 years post-transplantation, relapse, overall survival (OS), and relapse-free survival (RFS) were similar in the CD34(+) and unmodified subgroups: 8.1% versus 19.4% (P = .187), 58.5% versus 53.7% (P = .51), and 59.5% versus 52.4% (P = .448). However, the composite outcome combining extensive cGVHD-free status and relapse-free status (CRFS) at 3 years was 59.5% in the CD34(+) group versus 19.2% in the unmodified group (P < .001). In the high-risk group, grade II-IV aGVHD at 1 year was 31.6% in the CD34(+) subgroup versus 24.4% in the unmodified subgroup (P = .752). There were no differences between the subgroups in the incidence of grade III-IV aGVHD. The incidence of cGVHD at 3 years in the 2 subgroups was 0% versus 27.6% (P = .013). At 3 years post-transplantation, relapse, OS, RFS, and CRFS in the 2 subgroups were 31.6% versus 69.3% (P = .007), 35.5% versus 14.5% (P = .068), 31.6% versus 10.7% (P = .045), and 31.6% versus 6.1% (P = .001), respectively. Cytogenetic abnormalities at diagnosis and transplant type had significant univariate associations with RFS in the high-risk cohort. Only cytogenetics (P = .03) remained associated with this outcome in a multivariate model. OS was similar in the 2 transplant groups; however, CRFS was superior in the CD34(+) cell-selected transplant group.
Clinical Commentary
What is known?
NIHMS1528310
What did this paper set out to examine?
What did they show?
What are the implications for practice and for future work?
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5.
Impact of Induction Therapy on the Outcome of Immunoglobulin Light Chain Amyloidosis after Autologous Hematopoietic Stem Cell Transplantation
Afrough, A., Saliba, R. M., Hamdi, A., Honhar, M., Varma, A., Cornelison, A. M., Rondon, G., Parmar, S., Shah, N. D., Bashir, Q., et al
Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation. 2018
Abstract
BACKGROUND With the availability of immunomodulatory agents (IMiD) and proteasome inhibitors (PI), most patients with immunoglobulin light chain amyloidosis (AL) receive induction therapy prior to autologous hematopoietic stem cell transplant (auto-HCT). In this study, we evaluated the type of induction therapy and its impact on the outcome of auto-HCT in AL. METHODS We identified 128 patients with AL who underwent high-dose chemotherapy and auto- HCT at our institution between 1997 and 2013. Patients were divided into 3 groups: 1) no induction 2) conventional chemotherapy (CC) - based induction (melphalan, steroids), and 3) IMiD/PI- based induction (thalidomide, lenalidomide or bortezomib). The hematologic (HR) and organ responses were defined according to the established criteria. RESULTS Median age at auto-HCT was 58 years (range, 35 - 75). Twenty patients (15.5%) received no induction, 25 (19.5%) received CC and 83 (65%) received IMiD/PI. One, 2, or 3 or more organs were involved in 90 (70%), 20 (16%), 18 (14%) patients, respectively. Post auto-HCT, 12 of 20 (60%), 15 of 24 (62%) and 72 of 83 (87%) evaluable patients achieved HR at 100-day in no induction, CC and IMiD/PI groups, respectively (p=0.001). Organ response at 1-year post auto-HCT was seen in 7 of 18 (39%), 14 of 24 (58%) and 37 of 79 (47%) evaluable patients in no induction, CC and IMiD/PI groups, respectively, (P=0.3). Achieving a hematologic CR was associated with a significantly higher probability of achieving an organ response (p=0.02). After a median follow up of 26 months, 2-year progression-free survival were 67%, 56% and 73% in no induction, CC and IMiD/PI groups, respectively (p=0.07, HR 0.5, 95% CI 0.3-1.1). 2-year overall survival (OS) was 73%, 76%, and 87% in no induction, CC and IMiD/PI, respectively (p=0.05, HR 0.4, 95% CI 0.2-0.9). On multivariate analysis, a low beta 2 microglobulin (p=0.01, HR 0.3, 95% CI 01-0.7) and induction therapy with IMiD/PI (p=0.01, HR 0.3, 95% CI 0.1-0.7) were associated with a better OS. CONCLUSIONS Induction therapy with either CC or IMiD/PI is safe and feasible in selected patients with AL. IMiD/PI-based induction is associated with a longer OS compared to patients who received no induction or conventional chemotherapy before auto-HCT.
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6.
Cytogenetics and comorbidity predict outcomes in older myelodysplastic syndrome patients after allogeneic stem cell transplantation using reduced intensity conditioning
Yucel, O. K., Saliba, R. M., Rondon, G., Ahmed, S., Alousi, A., Bashir, Q., Ciurea, S. O., Popat, U., Khouri, I., Marin, D., et al
Cancer. 2017;123(14):2661-2670
Abstract
BACKGROUND Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is the only treatment with a curative potential for myelodysplastic syndrome (MDS) patients. Allo-HSCT has substantial risks, particularly in the elderly, and its role for older MDS patients has yet to be defined. METHODS We analyzed 88 MDS patients aged>=60 years with allo-HSCT after reduced intensity conditioning regimens over the last decade. The study cohort had high risk features; 47 of 88 (53.4%) patients were>65 years of age, 24 (27%) patients had cytogenetic abnormalities consistent with monosomal karyotype (MKpos), 33 (38%) patients had histological subtype of RAEB-1 and RAEB-2 at diagnosis, and 45 (51%) patients had a hematopoietic cell transplantation-comorbidity index (HCT-CI) of>=3. RESULTS The 3-year incidence of progression, transplant-related mortality (TRM), and overall survival (OS) were 26% (95% confidence interval [CI], 18%-37%), 35% (95% CI, 26%-47%), and 41% (95% CI, 30%-52%), respectively. MKpos was the only prognostic factor that increased the risk of disease progression compared with good-risk cytogenetics (hazard ratio [HR]=9.5, P=.003) as well as MKneg (HR=3.3, P=.01). For TRM, HCT-CI>=3, but not age >65 years, was associated with worse outcomes (HR=3.1, P=.007). Cytogenetics and HCT-CI enabled us to identify prognostic groups for OS. MKpos patients had the worst 3-year OS (17%), whereas patients with good-risk cytogenetics and HCT-CI<3 had the best OS (92%). CONCLUSION Our results confirm that allo-HSCT can provide long-term survival in older MDS patients. Cytogenetics and HCT-CI identify prognostic risk groups and guide selection of older MDS patients who are candidates for allo-HSCT. Cancer 2017;123:2661-70. © 2017 American Cancer Society.