This study investigated the efficacy and safety of azacitidine maintenance in the posttransplant setting based on the encouraging phase 1/2 reports for azacitidine maintenance in patients with acute ...myeloid leukemia/myelodysplastic syndrome (AML/MDS). Between 2009 and 2017, a total of 187 patients aged 18 to 75 years were entered into a randomized controlled study of posttransplant azacitidine if they were in complete remission. Patients randomized to the treatment arm (n = 93) were scheduled to receive azacitidine, given as 32 mg/m2 per day subcutaneously for 5 days every 28 days for 12 cycles. The control arm (n = 94) had no intervention. Eighty-seven of the 93 patients started azacitidine maintenance. The median number of cycles received was 4; a total of 29 patients relapsed on study, and 23 patients withdrew from the study due to toxicity, patient's preference, or logistical reasons. Median relapse-free survival (RFS) was 2.07 years in the azacitidine group vs 1.28 years in the control group (P = .43). There was also no significant difference for overall survival, with a median of 2.52 years vs 2.56 years in the azacitidine and control groups (P = .85), respectively. Multivariate Cox regression analysis revealed no improvement in RFS or overall survival with the use of azacitidine as maintenance compared with the control group (hazard ratios of 0.73 95% confidence interval, 0.49-1.1; P = .14 and 0.84 95% confidence interval, 0.55-1.29; P = .43). This randomized trial with azacitidine maintenance showed that a prospective trial in the posttransplant setting was feasible and safe but challenging. Although RFS was comparable between the 2 arms, we believe the strategy of maintenance therapy merits further study with a goal to reduce the risk of relapse in patients with AML/MDS. This trial was registered at www.clinicaltrials.gov as #NCT00887068.
•In this phase 3, open-label, randomized trial, azacitidine maintenance did not improve RFS after transplant in high-risk AML/MDS.•We believe that posttransplant maintenance strategy merits further study to decrease the risk of relapse in AML/MDS patients.
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Clonal hematopoiesis (CH) is associated with older age and an increased risk of myeloid malignancies and cardiovascular complications. We analyzed donor DNA samples in patients with AML/MDS who ...underwent first allogeneic stem cell transplant (SCT) to investigate the association between donor CH and transplant outcomes. We performed targeted deep sequencing of 300 genes on donor blood samples and identified CH with the minimum variant allele frequency of 2%. Among 363 donors, 65 (18%) had CH. The most frequently mutated genes were DNMT3A (31 of 65; 48%), TET2 (16 of 65; 25%), PPM1D (5 of 65, 8%), and ASXL1 (7 of 65; 11%). Transplant outcomes: time to neutrophil and platelet recovery, relapse incidence, transplant-related mortality and progression-free survival, were comparable by donor CH. However, risk of grade II-IV and III-IV acute graft versus host disease (aGvHD) at 6 months after transplant was higher with donor CH vs. without donor CH (hazard ratio (HR) = 2.4, 95% Confidence Interval (CI) = 1.6-3.6, p < 0.001 and HR = 3.8, 95% CI = 1.6-8.9, p = 0.003). In this homogenous population of AML/MDS patients, donor CH was associated with increased risk of grade II-IV and III-IV aGvHD. Further studies to investigate the mechanisms of increased aGvHD and therapeutic interventions to improve aGvHD in the context of donor CH are warranted.
HLA-DPB1 mismatches between donor and recipient are commonly seen in allogeneic hematopoietic stem cell transplantation from an unrelated donor. HLA-DPB1 mismatch, conventionally determined by the ...similarity of the T-cell epitope (TCE), is associated with an increased risk of acute graft-versus-host disease (GVHD) and a decreased risk of disease relapse. We investigated the clinical impact of HLA-DPB1 molecular mismatch quantified by mismatched eplets (ME) and the Predicted Indirectly Recognizable HLA Epitopes Score (PS) in a cohort of 1,514 patients receiving hematopoietic stem cell transplants from unrelated donors matched at HLA-A, -B, -C, -DRB1/3/4/5, and - DQB1 loci. HLA-DPB1 alloimmunity in the graft-versus-host direction, determined by high graft-versus-host ME/PS, was associated with a reduced risk of relapse (hazard ratio HR=0.83, P=0.05 for ME) and increased risk of grade 2-4 acute GVHD (HR=1.44, P<0.001 for ME), whereas high host-versus-graft ME/PS was only associated with an increased risk of grade 2-4 acute GVHD (HR=1.26, P=0.004 for ME). Notably, in the permissive mismatch subgroup classified by TCE grouping, high host-versus-graft ME/PS was associated with an increased risk of relapse (HR=1.36, P=0.026 for ME) and grade 2-4 acute GVHD (HR=1.43, P=0.003 for PS-II). Decision curve analysis showed that graftversus- host ME outperformed other models and provided the best clinical net benefit for the modification of acute GVHD prophylaxis regimens in patients with a high risk of developing clinically significant acute GVHD. In conclusion, molecular assessment of HLA-DPB1 mismatch enables separate prediction of host-versus-graft or graft-versus-host alloresponse quantitatively and allows further refinement of HLA-DPB1 permissiveness as defined by conventional TCE grouping.
Background
Despite the well‐defined role of minimal residual disease (MRD) monitoring by real‐time quantitative polymerase chain reaction (RT‐PCR) for RUNX1/RUNX1T1 and CBFB‐MYH11 transcripts in core ...binding factor (CBF) acute myeloid leukemia (AML) after intensive chemotherapy, there has been a paucity of data assessing the utility of MRD monitoring at and after allogeneic hematopoietic stem cell transplantation (HSCT).
Methods
Patients with CBF AML who underwent HSCT in complete remission (first or second) from January 2007 through December 2018 were included in this analysis.
Results
MRD by polymerase chain reaction at HSCT was assessed in 50 of 76 patients, and 44 (88%) had evidence of MRD (MRDpos). MRDpos patients had 3‐year overall survival (OS) and leukemia‐free survival (LFS) rates of 69.3% and 66.3%, respectively. Six MRD‐negative patients had 3‐year OS and LFS rates of 100% and 100%, respectively. Thirty‐five of the 70 evaluable patients (50%) had a day +100 MRD assessment by RT‐PCR, and 14 (40%) were MRDpos. The presence of MRD by RT‐PCR on day +100 was not associated with lower estimates of LFS (75% vs 82.2%; P = .3) but was associated with a higher relapse incidence, although the difference did not reach statistical significance (27.6% vs 9.7%; P = .2).
Conclusions
Durable complete remissions can be achieved in patients with CBF AML with HSCT even if they are MRDpos by RT‐PCR at HSCT. The clinical impact of frequent MRD monitoring for identifying a group at high risk for early relapse and then for determining the best time point for therapeutic interventions to prevent impending relapse warrants investigation in prospectively designed clinical trials.
Positive minimal residual disease (MRD) monitoring by real‐time quantitative polymerase chain reaction (RT‐PCR) before transplantation is not associated with an increased risk of relapse in patients with core binding factor (CBF) acute myeloid leukemia (AML). Frequent MRD monitoring by RT‐PCR at early time points after transplantation may allow the identification of patients with CBF AML at higher risk of relapse.
Our aim was to improve outcome prediction after allogeneic hematopoietic stem cell transplantation in acute myeloid leukemia by combining cytogenetic and molecular data at diagnosis with minimal ...residual disease assessment by multicolor flow-cytometry at transplantation. Patients with acute myeloid leukemia in first complete remission in whom minimal residual disease was assessed at transplantation were included and categorized according to the European LeukemiaNet classification. The primary outcome was 1-year relapse incidence after transplantation. Of 152 patients eligible, 48 had minimal residual disease at the time of their transplant. Minimal residual disease-positive patients were older, required more therapy to achieve first remission, were more likely to have incomplete recovery of blood counts and had more adverse risk features by cytogenetics. Relapse incidence at 1 year was higher in patients with minimal residual disease (32.6% versus 14.4%, P=0.002). Leukemia-free survival (43.6% versus 64%, P=0.007) and overall survival (48.8% versus 66.9%, P=0.008) rates were also inferior in patients with minimal residual disease. In multivariable analysis, minimal residual disease status at transplantation independently predicted 1-year relapse incidence, identifying a subgroup of intermediate-risk patients, according to the European LeukemiaNet classification, with a particularly poor outcome. Assessment of minimal residual disease at transplantation in combination with cytogenetic and molecular findings provides powerful independent prognostic information in acute myeloid leukemia, lending support to the incorporation of minimal residual disease detection to refine risk stratification and develop a more individualized approach during hematopoietic stem cell transplantation.
Background
There have been concerns regarding increased peritransplantation complications, especially severe acute graft‐versus‐host disease (aGVHD), in patients with prior use of checkpoint ...inhibitors (CPI) before hematopoietic stem cell transplantation (HSCT).
Methods
The authors performed a retrospective study of 43 patients with acute myeloid leukemia and/or myelodysplastic syndromes who were treated with an antiprogrammed cell death protein 1 (PD‐1) (32 patients) or anticytotoxic T‐lymphocyte–associated protein 4 (CTLA‐4) (9 patients) blockade or both (2 patients) prior to HSCT with the primary outcome of aGVHD by day 100 after HSCT. Outcome analyses were stratified by GVHD prophylaxis as use of post‐HSCT cyclophosphamide (PTCy) (22 patients) or not (non‐PTCy) (21 patients).
Results
The PTCy group demonstrated a trend toward lower grade 3 to 4 aGVHD when compared with the non‐PTCy group (5% vs 22%), although the rates of grade 2 to 4 aGVHD were comparable (49% vs 56%). The interval between CPI and HSCT did not appear to impact the incidence of aGVHD. However, a higher incidence of grade 3 to 4 aGVHD was observed in patients who received >4 treatments of CPI prior to HSCT if they were not given PTCy as GVHD prophylaxis (43% vs 12%). Matched control analyses using patients with no prior use of CPI confirmed the increase in grade 3 to 4 aGVHD with those agents. However, that increased risk was limited to patients who did not receive PTCy and was not observed in patients who received PTCy as GVHD prophylaxis. Despite persistent improvement in GVHD with the use of PTCy, disease control was not compromised and progression‐free survival at 1 year was found to be superior for patients treated with PTCy compared with those not receiving PTCy among patients with prior use of CPI (55% vs 22%).
Conclusions
The results of the current study indicated that HSCT with prior use of CPI appears feasible in patients with acute myeloid leukemia and/or myelodysplastic syndromes and the use of PTCy as GVHD prophylaxis improves outcomes.
The use of checkpoint inhibitors (CPI) prior to hematopoietic stem cell transplantation (HSCT) in patients with acute myeloid leukemia and/or myelodysplastic syndromes affects transplantation outcomes, with an especially increased incidence of grade 3 to 4 acute graft‐versus‐host disease (aGVHD). The use of post‐HSCT cyclophosphamide as GVHD prophylaxis in patients treated with CPI prior to transplantation is found to lead to improved transplantation outcomes, including grade 3 to 4 aGVHD.
Background
A myeloablative conditioning regimen can be safely given to older patients and those with comorbidities without increasing nonrelapse mortality (NRM) by fractionating the dose of ...intravenous busulfan. How this approach compares in efficacy with traditional, nonfractionated, lower dose regimens is unknown.
Methods
Outcomes were compared in patients with acute myeloid leukemia (AML) or myelodysplastic syndrome who received either myeloablative, fractionated busulfan (f‐Bu) dosed to achieve an area under the curve of 20,000 μmol per minute (f‐Bu20K) over 2 weeks (n = 84) or a standard, nonfractionated, lower busulfan dose regimen of 16,000 μmol per minute (Bu16K) over 4 days (n = 78). Both groups also received fludarabine 40 mg/m2 intravenously for 4 days. Graft‐versus‐host disease prophylaxis was tacrolimus and methotrexate. Patients in the Bu16K group who had unrelated donors also received antithymocyte globulin. The primary endpoint was progression‐free survival.
Results
Roughly one‐half of the patients were aged >65 years, approximately 40% had poor‐risk cytogenetics, approximately 40% of those with AML were not in complete remission, and approximately 40% had a comorbidity index >3. At 2 years, progression‐free survival was significantly improved in the f‐Bu20K group compared with the Bu16K group (45% vs 24%, respectively; hazard ratio HR, 0.6; 95% CI, 0.4‐0.8; P = .004). This was because of a significant reduction in progression (34% vs 59%, respectively; HR, 0.5; 95% CI, 0.3‐0.8; P = .003) without any increase in NRM (21% vs 15%, respectively; HR, 1.4; 95% CI, 0.7‐3; P = .3), which resulted in improved overall survival (51% vs 31%, respectively; HR, 0.6; 95% CI, 0.3‐0.9; P = .01).
Conclusions
A myeloablative, fractionated busulfan regimen reduces relapse and improves survival without increasing NRM in older patients with AML and myelodysplastic syndrome.
A myeloablative, fractionated regimen of busulfan reduces relapse and improves survival without increasing nonrelapse mortality in older patients with acute myeloid leukemia and myelodysplastic syndrome.
•Outcomes of 93 adult patients with FLT3-negative AML/MDS who received post-alloHCT AZA maintenance were compared to 357 patients who received no maintenance.•Three-year incidence of progression was ...29% versus 33% in the AZA and control groups, respectively (P = .09).•A protective effect of AZA on progression was observed in high-risk AML/MDS (HR = 0.4, 95% CI = 0.2-0.8, P = .009).
Maintenance after allogeneic hematopoietic cell transplantation (alloHCT) with hypomethylating agents has yielded conflicting results.
We conducted a single center retrospective matched-control analysis with the study group (5-azacitidine AZA group) including adults with FLT3-negative acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) who received post-transplant AZA maintenance off clinical trial (n = 93). A matched control group was comprised of contemporaneous AML/MDS patients who did not receive any maintenance (n = 357). Primary endpoint was disease progression.
The AZA and control groups had comparable patient and disease characteristics except for older age (median: 61 vs. 57 years, P = .01) and lower hematopoietic comorbidity index (median: 2 vs. 3, P = .04) in the AZA group. The 3-year cumulative incidence of progression in the AZA and control groups was 29% vs. 33% (P = .09). The protective effect of AZA on progression was limited to patients with high-risk AML/MDS (HR = 0.4, 95% CI = 0.2-0.8, P = .009). This led to improved progression-free survival both in high-risk AML and MDS patients with maintenance (HR = 0.2, 95% CI = 0.1-0.6, P = .004 and HR = 0.4, 95% CI = 0.2-0.9, P = .04).
AZA maintenance was associated with a lower progression rate in patients with high-risk FLT3-negative AML or MDS, and AZA maintenance should be considered for post-alloHCT maintenance in this subset.
Outcomes of 93 adult patients with FLT3-negative AML/MDS who received post-alloHCT AZA maintenance were compared to 357 patients who received no maintenance. Three-year incidence of progression was 29% versus 33% in the AZA and control groups, respectively (P = .09). A protective effect of AZA on progression was observed in high-risk AML/MDS (HR = 0.4, 95% CI = 0.2-0.8, P = .009).
We investigated the impact of donor-recipient HLA-DPB1 matching on outcomes of allogeneic hematopoietic stem cell transplantation with in vivo T-cell depletion using antithymocyte globulin (ATG) for ...patients with hematological malignancies. All donor-recipient pairs had high-resolution typing for HLA-A, HLA-B, HLA-C, HLA-DRB1, HLA-DQB1, HLA-DPB1, and HLA-DRB3/4/5 and were matched at HLA-A, HLA-B, HLA-C, and HLA-DRB1. HLA-DPB1 mismatches were categorized by immunogenicity of the DPB1 matching using the DPB T-cell epitope tool. Of 1004 donor-recipient pairs, 210 (21%) were DPB1 matched, 443 (44%) had permissive mismatches, 184 (18%) had nonpermissive mismatches, in graft-versus-host (GVH) direction, and 167 (17%) had nonpermissive mismatches in host-versus-graft (HVG) direction. Compared with HLA-DPB1 permissive mismatched pairs, nonpermissive GVH mismatched pairs had the highest risk for grade II to IV acute graft-versus-host disease (aGVHD) (hazard ratio HR, 1.4; P = .01) whereas matched pairs had the lowest risk (HR, 0.5; P < .001). Grade III to IV aGVHD was only increased with HLA-DPB1 nonpermissive GVH mismatched pairs (HR, 2.3; P = .005). The risk for disease progression was lower with any HLA-DPB1 mismatches, permissive or nonpermissive. However, the favorable prognosis of HLA-DPB1 mismatches on disease progression was observed only in peripheral blood stem cell recipients who were in the intermediate-risk group by the Disease Risk Index (HR, 0.4; P = .001) but no other risk groups. Our results suggest avoidance of nonpermissive GVH HLA-DPB1 mismatches for lowering the risk for grade II to IV and III to IV aGVHD. Permissive or nonpermissive HVG HLA-DPB1 mismatches may be preferred over HLA-DPB1 matches in the intermediate-risk patients to decrease the risk for disease progression.
•After HSCT with in vivo T-cell depletion using ATG, HLA-DPB1 nonpermissive mismatches at the GVH direction increase the risk for aGVHD.•HLA-DPB1–matched pairs have an increased risk for disease progression if intermediate risk by the Disease Risk Index.
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