Abstract

The American Society for Transplantation and Cellular Therapy (ASTCT) published its first white paper on indications for autologous and allogeneic hematopoietic cell transplantation (HCT) in 2015. It was identified at the time that periodic updates of indications would be required to stay abreast with state of the art and emerging indications and therapy. In recent years, the field has not only seen an improvement in transplantation technology thus widening the therapeutic scope of HCT, but additionally a whole new treatment strategy using modified immune effector cells including chimeric antigen receptor T-cell (CART-cell) and T-cell receptors (TCRs) has emerged. The guidelines review committee of the ASTCT deemed it optimal to update the ASTCT recommendations for indications for HCT to include new data and to incorporate indications for immune effector cell therapy (IECT) where appropriate. The guidelines committee established multi-stakeholder task force consisting of transplant experts, payer representatives and a patient advocate to provide guidance on indications for HCT and IECT. This manuscript presents the updated recommendations from the ASTCT on indications for HCT and IECT. Indications for HCT/IECT were categorized as (1) Standard of care, where indication is well defined and supported by evidence, (2) Standard of care, clinical evidence available, where large clinical trials and observational studies are not available but has been shown to be effective therapy, (3) Standard of care, rare indication, for rare diseases where demonstrated effectiveness exist but large clinical trials and observational studies are not feasible, (4) Developmental, for diseases where pre-clinical and/or early phase clinical studies show HCT/IECT to be a promising treatment option, and (5) Not generally recommended, where available evidence does not support the routine use of HCT/IECT. The ASTCT will continue to periodically review these guidelines and update them as new evidence becomes available.

Abstract

Peripheral blood stem cells (PBSC) have been increasingly used for allogeneic hematopoietic cell transplantation compared to bone marrow stem cells. Currently, the National Marrow Donor Program (NMDP) policy recommends 5 days of daily filgrastim followed by either 1 or 2 days of apheresis for unrelated donors, depending on collection center choice. To date, there are no studies that compare the differences in donor experience between one and two days of apheresis. We examined 22,348 adult unrelated donor collections in 184 centers from 2006-2016. 20,004 (89.5%) donors had collections on 1 day vs. 2,344 (9.5%) over 2 days. Information on why donors were apheresed in one day vs. two days were not available. Donors who underwent apheresis in 1 day were more likely to be male (67% vs. 46%, p<0.001), younger (age <30 years 48% vs. 36%, p<0.001) and have a higher body weight (83.0 kg vs. 75.9 kg, p<0.001) and BMI (BMI>30: 30% vs. 22%, p<0.001). Successful collection of the requested CD34(+) cell count was achieved on the first day in 82% of one day collections vs 16% of 2-day collections. Despite not administering filgrastim the evening after the first day of collection in patients who underwent 2 days of apheresis, the median concentration of CD34(+) cells/L in the product on the second day of apheresis was higher than the first day (23.8x10(6) CD34(+)/L 1(st) day vs. 28.7x10(6) CD34(+)/L 2(nd) day, p<0.001). Donors collected in one day were less likely to experience citrate toxicity (36% vs 52%, p<0.001), hospitalizations (1% vs 6%, p<0.001), and other side effects related to apheresis (Modified Toxicity Criteria incidence: 20% vs. 26%, p<0.001). Female sex, older age, collection via central lines, and greater BMI were factors associated with greater likelihood for development of toxicity whereas less toxicity was noted in those with higher CD34(+) counts and more blood processed on the first day of collection. We conclude that although unrelated donors can be successfully collected in one or two days, one day apheresis procedures were associated with less overall toxicity and we therefore recommend single day collections, especially if the requested number of cells have been collected in one day.

Abstract

Modern combinations of therapies for multiple myeloma have led to improvement in survival outcomes with near 100% overall response rate and 25% complete response rates, particularly with autologous hematopoietic cell transplant (AHCT). Minimal residual disease (MRD) assessment with multiparameter flow cytometry is a valid prognostic biomarker for progression-free survival (PFS) and overall survival (OS). However, few data exist regarding whether MRD positivity or negativity will meaningfully influence treatment decisions. We evaluated 433 patients who received induction therapy, followed by AHCT. Participants had MRD assessment by multiparameter flow cytometry before and at days +100 and +365 following AHCT. They also received either lenalidomide, bortezomib, or no maintenance therapy following AHCT. Maintenance treatment with lenalidomide improved MRD negativity at day +365 compared to bortezomib (92.9% vs 41.6%, p = 0.01), or no maintenance therapy (92.9% vs 24.4%, p = 0.012). The median PFS for patients who were MRD negative at day + 365 was 42 vs 17.5 months (p < 0.001) and median OS was 80.6 vs 59 months (p = 0.02). Maintenance therapy following AHCT for multiple myeloma improves the depth of response as assessed by MRD.

Abstract

Following chemotherapy, secondary acute myeloid leukemia (sAML), occurring after antecedent hematologic diseases, previous chemotherapy or radiation, has an inferior prognosis compared with de novo AML. To define the outcome of sAML in the context of allogeneic stem cell transplantation (alloSCT), a retrospective, registry-based comparison was performed, including 11,439 patients with de novo and 1325 with sAML. Among transplants in first complete remission (CR1) (n = 8,600), the 3-year cumulative incidence of relapse (RI) and non-relapse mortality (NRM) was 28.5% and 16.4% for de novo, and 35% and 23.4% for sAML. Three-year overall survival (OS), leukemia-free survival (LFS) and Graft-versus-Host Disease/relapse-free survival (GRFS) was 60.8%, 55.1%, and 38.6% for de novo, and 46.7%, 41.6%, and 28.4% for sAML, respectively. In multivariate analysis, sAML was associated with a lower OS (HR = 1.33 [95% CI = 1.21-1.48]; p < 10(-5)), LFS (HR = 1.32 [95% CI = 1.19-1.45]; p < 10(-5)) and GRFS (HR = 1.2 [95% CI = 1.1-1.31]; p < 10(-4)) and higher NRM (HR = 1.37 [95% CI = 1.17-1.59]; p < 10(-4)) and RI (HR = 1.27 [95% CI = 1.12-1.44]; p < 10(-3)). Results of the Cox model were confirmed in a matched-pair analysis. In contrast, results did not differ between de novo and sAML after alloSCT in induction failure or relapse. Hence, this analysis identified sAML as an independent risk factor for outcome after alloSCT in CR1.

Abstract

There are limited data on the effect of donor body mass index (BMI) on peripheral blood stem cell (PBSC) mobilization response to granulocyte colony-stimulating factor (G-CSF), especially in unrelated donors. Obesity has been associated with persistent leukocytosis, elevated circulating progenitor cells, and enhanced stem cell mobilization. Therefore, we hypothesized that adequate collection of CD34+ cells may be achieved with lower doses (per kilogram of body weight) of G-CSF in donors with higher BMI compared with donors with lower BMI. Using the Center for International Blood and Marrow Transplant Research database, we evaluated the impact of donor BMI on G-CSF-mobilized PBSC yield in healthy unrelated donors. We examined 20 884 PBSC donations collected at National Marrow Donor Program centers between 2006 and 2016. We found significantly higher collection yields in obese and severely obese donors compared with normal and overweight donors. An increase in average daily G-CSF dose was associated with an increase in stem cell yield in donors with normal or overweight BMI. In contrast, an increase in average daily G-CSF dose beyond 780 mug per day in obese and 900 mug per day in severely obese donors did not increase cell yield. Pain and toxicities were assessed at baseline, during G-CSF administration, and postcollection. Obesity was associated with higher levels of self-reported donation-related pain and toxicities in the pericollection and early postdonation recovery periods. This study suggests a maximum effective G-CSF dose for PBSC mobilization in obese and severely obese donors, beyond which higher doses of G-CSF add no increased yield.

Abstract

Allogeneic hematopoietic cell transplantation (HCT) is the only curative therapy for myelofibrosis (MF). In this large multicenter retrospective study, overall survival (OS) in MF patients treated with allogeneic HCT (551 patients) and without HCT (non-HCT) (1377 patients) was analyzed with Cox proportional hazards model. Survival analysis stratified by the Dynamic International Prognostic Scoring System (DIPSS) revealed that the first year of treatment arm assignment, due to upfront risk of transplant-related mortality (TRM), HCT was associated with inferior OS compared with non-HCT (non-HCT vs HCT: DIPSS intermediate 1 [Int-1]: hazard ratio [HR] = 0.26, P < .0001; DIPSS-Int-2 and higher: HR, 0.39, P < .0001). Similarly, in the DIPSS low-risk MF group, due to upfront TRM risk, OS was superior with non-HCT therapies compared with HCT in the first-year post treatment arm assignment (HR, 0.16, P = .006). However, after 1 year, OS was not significantly different (HR, 1.38, P = .451). Beyond 1 year of treatment arm assignment, an OS advantage with HCT therapy in Int-1 and higher DIPSS score patients was observed (non-HCT vs HCT: DIPSS-Int-1: HR, 2.64, P < .0001; DIPSS-Int-2 and higher: HR, 2.55, P < .0001). In conclusion, long-term OS advantage with HCT was observed for patients with Int-1 or higher risk MF, but at the cost of early TRM. The magnitude of OS benefit with HCT increased as DIPSS risk score increased and became apparent with longer follow-up.

Abstract

The ideal stem cell graft source remains unknown in haploidentical haematopietic cell transplantation (haplo-HCT) with posttransplantation cyclophosphamide (PTCy). This study compared outcomes of bone marrow (BM) versus peripheral blood (PB) stem cell graft for haplo-HCT in acute lymphoblastic leukemia (ALL). A total of 314 patients with ALL (BM-157; PB-157) were included in this study. The cumulative incidence of engraftment at day 30 was higher in the PB group compared with BM (93% vs. 88%, p < 0.01). The incidences of acute graft-versus-host disease (GVHD) and chronic GVHD were not significantly different between the study cohorts. In the multivariate analysis, there were tendencies toward a higher incidence of grade II-IV acute GVHD (hazard ratio (HR) = 1.52, p = 0.07), chronic GVHD (HR = 1.58, p = 0.05), and nonrelapse mortality (NRM) (HR = 1.66, p = 0.06) in patients receiving PB versus BM graft, respectively. The use of PB grafts was associated with lower leukemia-free survival (LFS) (HR = 1.43, p = 0.05), overall survival (OS) (HR = 1.59, p = 0.02), and GVHD-free, relapse-free survival (GRFS) (HR = 1.42, p = 0.03) compared with BM grafts. There was no difference in relapse incidence (HR = 1.23, p = 0.41) between the study groups. In conclusion, use of BM graft results in better survival after haplo-HCT with PTCy in patients with ALL, compared with PB stem cell graft.

Abstract

A mismatched unrelated (MMUD) donor represents an alternative therapeutic option for patients who need allogeneic hematopoietic cell transplantation (allo-HCT) and do not have a human leukocyte antigen (HLA) matched donor. We studied outcomes of patients with acute leukemia transplanted from ≥2 HLA allele MMUD. The study population consisted of 465 patients. The median follow-up period was 63 and 75 months in the AML and ALL groups, respectively. The incidence of grade II-IV and grade III-IV acute (a) graft-versus-host disease (GVHD) during the first 100 days was 37% and 16%, respectively. Total and extensive chronic (c) GVHD rates at 2 years were 38% and 17%, respectively. In the entire population, the 5-year relapse incidence (RI), non-relapse mortality (NRM), leukemia-free survival (LFS), overall survival and refined GVHD-free, relapse-free survival (GRFS) was 33%, 31%, 37%, 41%, and 27%, respectively. In the multivariate analysis, HLA-DR mismatch was a poor prognostic factor, giving a significantly higher NRM [hazard ratio (HR), 1.67, p = 0.02]; poorer LFS (HR, 1.42, p = 0.03); OS (HR, 1.46, p = 0.03) and higher aGVHD grade II-IV (HR, 1.46, p = 0.05). In this study, allo-HCT from ≤6/8 HLA allele MMUD in acute leukemia patients resulted in acceptable LFS and refined GRFS. HLA-DR mismatch was a poor prognostic factor.

Abstract

There is a lack of large comparative study on the outcomes of reduced intensity conditioning (RIC) in acute myeloid leukemia (AML) transplantation using fludarabine/busulfan (FB) and fludarabine/melphalan (FM) regimens. Adult AML patients from Center for International Blood and Marrow Transplant Research who received first RIC allo-transplant between 2001 and 2015 were studied. Patients were excluded if they received cord blood or identical twin transplant, total body irradiation in conditioning, or graft-versus-host disease (GVHD) prophylaxis with in vitro T-cell depletion. Primary outcome was overall survival (OS), secondary end points were leukemia-free survival (LFS), nonrelapse mortality (NRM), relapse, and GVHD. Multivariate survival model was used with adjustment for patient, leukemia, and transplant-related factors. A total of 622 patients received FM and 791 received FB RIC. Compared with FB, the FM group had fewer transplant in complete remission (CR), fewer matched sibling donors, and less usage of anti-thymocyte globulin or alemtuzumab. More patients in the FM group received marrow grafts and had transplantation before 2005. OS was significantly lower within the first 3 months posttransplant in the FM group (hazard ratio [HR] = 1.82, P < .001), but was marginally superior beyond 3 months (HR = 0.87, P = .05). LFS was better with FM compared with FB (HR = 0.89, P = .05). NRM was significantly increased in the FM group during the first 3 months of posttransplant (HR = 3.85, P < .001). Long-term relapse was lower with FM (HR = 0.65, P < .001). Analysis restricted to patients with CR showed comparable results. In conclusion, compared with FB, the FM RIC showed a marginally superior long-term OS and LFS and a lower relapse rate. A lower OS early posttransplant within 3 months was largely the result of a higher early NRM.

Abstract

The optimal myeloablative conditioning (MAC) for patients undergoing haploidentical hematopoietic cell transplantation (haplo-HCT) is unknown. We studied the outcomes of total body irradiation (TBI) versus chemotherapy (CT) based MAC regimens in acute myeloid leukemia (AML) patients. The study included 1008 patients who underwent first haplo-HCT with post-transplant cyclophosphamide, following TBI (N=89, 9%) or CT (n=919, 91%) based MAC. Patients in the TBI cohort were younger (median age, 38 vs. 47 yrs, p<0.01) and more likely to receive BM graft (57% vs. 43%, p=0.01). Two-year overall chronic GVHD (cGVHD) incidence was 42% vs. 27% (p<0.01) and extensive cGVHD incidence was 9% vs. 12% (p=0.33) in TBI and CT cohorts, respectively. Graft failure was reported in 2 (2%) TBI- and 65 (7%) CT-MAC recipients (p=0.08). Death from veno-occlusive disease was reported in 1(3%) TBI and 11(3%) CT patients who died during the study period. In the multivariate analysis, TBI was associated with increased risk for overall cGVHD (hazard ratio=1.95, 95% confidence interval:1.2-3.1, p<0.01) compared to CT-based MAC. The choice of conditioning regimen did not impact relapse incidence, leukemia-free survival, non-relapse mortality, overall survival or GVHD-relapse-free survival in multivariate analysis. In conclusion, major transplant outcomes were not statistically different between TBI-based MAC and CT-based MAC in patients with AML after haplo-HCT/PTCy. This article is protected by copyright. All rights reserved.