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Impact of T-cell dose on the outcome of T-cell replete HLA matched allogeneic peripheral blood stem cell transplantation
Saad, A., Lamb, L., Wang, T., Hemmer, M. T., Spellman, S., Couriel, D., Alousi, A., Pidala, J., Abdel-Azim, H., Agrawal, V., et al
Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation. 2019
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Abstract
BACKGROUND Data on whether T-cell dose of allogeneic peripheral blood stem cell (PBSC) product influences transplant outcome are conflicting. METHODS Using CIBMTR database, we identified 2,736 adult patients who underwent first allogeneic peripheral blood stem cell (PBSC) transplant for acute leukemia (AML, ALL) or myelodysplastic syndrome (MDS) between 2008-2014 using an HLA-matched sibling donor (MSD) or 8/8-matched unrelated donor (MUD). We excluded ex-vivo and in-vivo T-cell depleted transplants. Correlative analysis was performed between CD3+ T-cell dose and risk of graft-versus-host-disease (GVHD), relapse, non-relapse mortality (NRM), disease free survival (DFS) and overall survival (OS). RESULTS Using maximum likelihood estimation method, we identified CD3+ T-cell cell dose cutoff that separated risk of acute GVHD (aGVHD) grade II-IV in both MSD and MUD groups. A CD3+ T-cell dose cutoff of 14x10(7) cells/kg identified MSD/low CD3+ (n=223) and MSD/high CD3+ (n=1214), and a dose of 15x10(7) cells/kg identified MUD/low CD3+ (n=197) and MUD/high CD3+ (n=1102). With univariate analysis, MSD/high CD3+ group had higher cumulative incidence of day 100 aGVHD grade II-IV of 33% vs 25% when compared to MSD/low CD3+ group (P value =0.009). There was no other difference between both groups in engraftment rate, risk of aGVHD grade III-IV or chronic GVHD (cGVHD), NRM, relapse, DFS, or OS. MUD/high CD3+ group had higher cumulative incidence of day 100 aGVHD grade II-IV of 49% vs 41% when compared to MUD/low CD3+ group (P value =0.04). There was no other difference between both groups in engraftment rate, risk of severe aGVHD or cGVHD, NRM, relapse, DFS, or OS. Multivariate analysis of MSD and MUD groups failed to show an association between CD3+ T-cell dose and risk of either aGVHD grade II-IV (p value =0.1 and 0.07 respectively) or cGVHD (p value=0.8 and 0.3 respectively). Sub-analysis of CD4, CD8 and CD4/CD8 ratio failed to identify cutoff values predictive of transplant outcome. Using log-rank test, the sample size was, however, suboptimal to identify difference at these cutoff cell dose. CONCLUSION In this registry study, CD3+ T-cell dose of PBSCT product did not influence risk of aGVHD or cGVHD or other transplant outcomes when using HLA-matched sibling or 8/8 unrelated donors. Subset analysis of CD4+ and CD8+ T-cell dose was not possible for small sample size.
PICO Summary
Population
Patients reported to CIBMTR database with acute leukaemia (ALL or AML) or myelodysplastic syndrome between 2008-2014 (n=2736)
Intervention
First allogeneic peripheral blood stem cell using an HLA-matched sibling donor (MSD)
Comparison
8/8-matched unrelated donor (MUD)
Outcome
Using maximum likelihood estimation method, we identified CD3+ T-cell cell dose cutoff that separated risk of acute GVHD (aGVHD) grade II-IV in both MSD and MUD groups. A CD3+ T-cell dose cutoff of 14x10(7) cells/kg identified MSD/low CD3+ (n=223) and MSD/high CD3+ (n=1214), and a dose of 15x10(7) cells/kg identified MUD/low CD3+ (n=197) and MUD/high CD3+ (n=1102). With univariate analysis, MSD/high CD3+ group had higher cumulative incidence of day 100 aGVHD grade II-IV of 33% vs 25% when compared to MSD/low CD3+ group. MUD/high CD3+ group had higher cumulative incidence of day 100 aGVHD grade II-IV of 49% vs 41% when compared to MUD/low CD3+ group. Multivariate analysis of MSD and MUD groups failed to show an association between CD3+ T-cell dose and risk of either aGVHD grade II-IV or cGVHD. Sub-analysis of CD4, CD8 and CD4/CD8 ratio failed to identify cutoff values predictive of transplant outcome.
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2.
Lower GVHD and relapse risk in PTCy-based Haploidentical vs Matched Sibling Donor RIC Transplant for Hodgkin Lymphoma
Ahmed, S., Kanakry, J. A., Ahn, K. W., Litovich, C., Abdel-Azim, H., Aljurf, M., Bacher, V. U., Bejanyan, N., Cohen, J. B., Farooq, U., et al
Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation. 2019
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Editor's Choice
Abstract
Classical Hodgkin lymphoma (cHL) patients with relapsed or refractory disease may benefit from allogeneic hematopoietic cell transplantation (allo-HCT), but many lack a matched sibling donor (MSD). Herein, we compare outcomes of two reduced-intensity conditioning (RIC) HCT platforms in cHL: T cell-replete related donor haploidentical (haplo) HCT with post-transplantation cyclophosphamide (PTCy)-based approach versus MSD/calcineurin inhibitor (CNI)-based approach. The study included 596 adult patients who underwent a first RIC allo-HCT for cHL between 2008-2016, using either haplo-PTCy (n=139) or MSD/CNI-based (n=457) approach. Overall survival (OS) was the primary endpoint. Secondary endpoints included acute (a) and (c) graft-versus-host disease (GVHD), non-relapse mortality (NRM), relapse/progression, and progression-free survival (PFS). On multivariate analysis, there was no significant difference between haplo/PTCy and MDS/CNI-based approaches in terms of OS (hazard ratio [HR]=1.07; 95%CI=0.79-1.45; p=0.66) or PFS (HR=0.86; 95%CI=0.68-1.10; p=0.22). Haplo/PTCy was associated with a significantly higher risk of grade 2-4 aGVHD (odds ratio [OR]=1.73, 95%CI=1.16-2.59, p=0.007), but the risk of grade 3-4 aGVHD was not significantly different between the two cohorts (OR=0.61, 95%CI=0.29-1.27, p=0.19). The haplo/PTCy platform provided a significant reduction in cGVHD risk (HR=0.45, 95%CI=0.32-0.64, p<0.001), and a significant reduction in relapse risk (HR=0.74, 95%CI=0.56-0.97, p=0.03). There was a statistically non-significant trend towards higher NRM with haplo/PTCy approach (HR=1.65, 95%CI=0.99-2.77, p=0.06). Haplo/PTCy-based approaches are associated with lower incidence of cGVHD and relapse, with PFS and OS outcomes comparable to MSD/CNI-based approaches. There was a leaning towards higher NRM with haplo/PTCy-based platform. These data show that haplo/PTCy allo-HCT in cHL results in survival comparable to MSD/CNI-based allo-HCT.
PICO Summary
Population
Adult patients who underwent a first RIC allo-HCT for classical Hodgkin lymphoma between 2008-2016 (n=596)
Intervention
T cell-replete related donor haploidentical HCT with post-transplantation cyclophosphamide (Haplo/PTCy) (n=139)
Comparison
Matched Sibling Donor with calcineurin inhibitor (MSD/CNI) (n=457)
Outcome
On multivariate analysis, there was no significant difference between Haplo/PTCy and MSD/CNI-based approaches in terms of overall survival or progression-free survival. Haplo/PTCy was associated with a significantly higher risk of grade 2-4 aGVHD, but the risk of grade 3-4 aGVHD was not significantly different between the two cohorts. The haplo/PTCy platform provided a significant reduction in cGVHD risk, and a significant reduction in relapse. There was a statistically non-significant trend towards higher NRM with haplo/PTCy approach.
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The Outcome of Haplo-Identical Transplantation in Patients with Relapsed Multiple Myeloma: An EBMT/CIBMTR Report
Sahebi, F., Garderet, L., Kanate, A. S., Eikema, D. J., Knelange, N. S., Alvelo, O. F. D., Koc, Y., Blaise, D., Bashir, Q., Moraleda, J. M., et al
Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation. 2018
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Editor's Choice
Abstract
Allogeneic hematopoietic cell transplantation (allo-HCT) using siblings and matched donors has the potential for long-term disease control in a subset of high-risk multiple myeloma (MM) patients. However, the data on using haploidentical donors in this disease are limited. We conducted a retrospective analysis to examine the outcomes of patients with MM who underwent haploidentical allo-HCT within EBMT/CIBMTR centers. A total of 96 patients underwent haploidentical transplantation between 2008 and 2016. With a median follow up of 24.0 months (range, 13.2-24.9 months), 97% (95%CI, 93%-100%) of patients had neutrophil engraftment by day 28, and 75% (95%CI, 66%-84%) achieved platelet recovery by day 60. Two-year progression-free survival (PFS) was 17% (95%CI, 8%-26%), and overall survival (OS) was 48% (95%CI, 36%-59%). At 2 years, the cumulative risk of relapse/progression was 56% (95%CI, 45%-67%), and 1-year non-relapse mortality (NRM) was 21% (95%CI, 13%-29%). The incidence of acute graft-versus-host-disease (GVHD) grades II-IV by 100 days and chronic GVHD at 2 years were 39% (95%CI, 28%-49%) and 46% (95%CI, 34%-59%), respectively. On univariate analysis, use of post-transplant cyclophosphamide (PT-Cy) (54% [95%CI, 41%-68%] vs 25% [95%CI, 1%-48%], p=0.009), and use of bone marrow as source of stem cells (72% [95%CI, 55%-89%] vs 31% [95%CI, 17%-46%], p=0.001), were associated with improved OS at 2 years. Disease status, patient gender, intensity of conditioning regimen, recipient/donor gender mismatch, and CMV status had no impact on OS, PFS, or NRM. Haploidentical transplantation is feasible for patients with multiply relapsed or high-risk MM, with an encouraging 2-year OS of 48% and an NRM rate of 21% at 1 year, supporting further investigation of haploidentical transplantation in suitable candidates with MM.
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Myeloablative vs reduced-intensity conditioning allogeneic hematopoietic cell transplantation for chronic myeloid leukemia
Chhabra, S., Ahn, K. W., Hu, Z. H., Jain, S., Assal, A., Cerny, J., Copelan, E. A., Daly, A., DeFilipp, Z., Gadalla, S. M., et al
Blood advances. 2018;2(21):2922-2936
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Editor's Choice
Abstract
Allogeneic hematopoietic cell transplantation (allo-HCT) is a potentially curative treatment of chronic myeloid leukemia (CML). Optimal conditioning intensity for allo-HCT for CML in the era of tyrosine kinase inhibitors (TKIs) is unknown. Using the Center for International Blood and Marrow Transplant Research database, we sought to determine whether reduced-intensity/nonmyeloablative conditioning (RIC) allo-HCT and myeloablative conditioning (MAC) result in similar outcomes in CML patients. We evaluated 1395 CML allo-HCT recipients between the ages of 18 and 60 years. The disease status at transplant was divided into the following categories: chronic phase 1, chronic phase 2 or greater, and accelerated phase. Patients in blast phase at transplant and alternative donor transplants were excluded. The primary outcome was overall survival (OS) after allo-HCT. MAC (n = 1204) and RIC allo-HCT recipients (n = 191) from 2007 to 2014 were included. Patient, disease, and transplantation characteristics were similar, with a few exceptions. Multivariable analysis showed no significant difference in OS between MAC and RIC groups. In addition, leukemia-free survival and nonrelapse mortality did not differ significantly between the 2 groups. Compared with MAC, the RIC group had a higher risk of early relapse after allo-HCT (hazard ratio [HR], 1.85; P = .001). The cumulative incidence of chronic graft-versus-host disease (cGVHD) was lower with RIC than with MAC (HR, 0.77; P = .02). RIC provides similar survival and lower cGVHD compared with MAC and therefore may be a reasonable alternative to MAC for CML patients in the TKI era.
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Staging Systems for Newly Diagnosed Myeloma Patients undergoing Autologous Hematopoietic Cell Transplant: The Revised International Staging System shows the most Differentiation between Groups
Scott, E. C., Hari, P., Kumar, S., Fraser, R., Davila, O., Shah, N., Gale, R. P., Diaz, M. A., Agrawal, V., Cornell, R. F., et al
Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation. 2018
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Editor's Choice
Abstract
The revised International Staging System (R-ISS) and the International Myeloma Working Group 2014 (IMWG 2014) are newer staging systems used to prognosticate multiple myeloma (MM) outcomes. We hypothesized that these would provide better prognostic differentiation for newly diagnosed multiple myeloma (MM) compared to ISS. We analyzed the Center for International Blood and Marrow Transplant Research database from 2008-2014 to compare the 3 systems (N=628) among newly diagnosed MM undergoing upfront AHCT. The median follow up of survivors was 48 (3-99) months. The R-ISS provided the greatest differentiation between survival curves for each stage (for OS, the differentiation was 1.74 using the R-ISS, 1.58 using ISS, and 1.60 using the IMWG 2014) . Univariate analyses at 3 years for overall survival showed R-ISS I at 88 (CI 95% 83-93)%, II at 75 (70-80)% and III at 56 (43-69)% (p<0.001). An integrated Brier score function demonstrated the R-ISS had the best prediction for PFS, though all systems had similar prediction for OS. Among available systems, the R-ISS is the most optimal among available prognostic tools for newly diagnosed MM undergoing AHCT. We recommend that serum LDH and cytogenetic data be performed on every MM patient at diagnosis to allow accurate prognostication.
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Autologous transplantation versus allogeneic transplantation in patients with follicular lymphoma experiencing early treatment failure
Smith, S. M., Godfrey, J., Ahn, K. W., DiGilio, A., Ahmed, S., Agrawal, V., Bachanova, V., Bacher, U., Bashey, A., Bolanos-Meade, J., et al
Cancer. 2018
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Editor's Choice
Abstract
BACKGROUND Early treatment failure (ETF) in follicular lymphoma (FL), defined as relapse or progression within 2 years of frontline chemoimmunotherapy, is a newly recognized marker of poor survival and identifies a high-risk group of patients with an expected 5-year overall survival (OS) rate of approximately 50%. Transplantation is an established option for relapsed FL, but its efficacy in this specific ETF FL population has not been previously evaluated. METHODS This study compared autologous hematopoietic stem cell transplantation (auto-HCT) with either matched sibling donor (MSD) or matched unrelated donor (MUD) allogeneic hematopoietic cell transplantation (allo-HCT) as the first transplantation approach for patients with ETF FL (age ≥ 18 years) undergoing auto-HCT or allo-HCT between 2002 and 2014. The primary endpoint was OS. The secondary endpoints were progression-free survival, relapse, and nonrelapse mortality (NRM). RESULTS Four hundred forty FL patients had ETF (auto-HCT, 240; MSD hematopoietic stem cell transplantation [HCT], 105; and MUD HCT, 95). With a median follow-up of 69 to 73 months, the adjusted probability of 5-year OS was significantly higher after auto-HCT (70%) or MSD HCT (73%) versus MUD HCT (49%; P = .0008). The 5-year adjusted probability of NRM was significantly lower for auto-HCT (5%) versus MSD (17%) or MUD HCT (33%; P < .0001). The 5-year adjusted probability of disease relapse was lower with MSD (31%) or MUD HCT (23%) versus auto-HCT (58%; P < .0001). CONCLUSIONS Patients with high-risk FL, as defined by ETF, undergoing auto-HCT for FL have low NRM and a promising 5-year OS rate (70%). MSD HCT has lower relapse rates than auto-HCT but similar OS. Cancer 2018. (c) 2018 American Cancer Society.