Lower intensity therapy with cladribine/low dose cytarabine/venetoclax in older patients with acute myeloid leukemia compares favorably with intensive chemotherapy among patients undergoing allogeneic stem cell transplantation.

BACKGROUND: Allogeneic stem cell transplantation (SCT) remains the best consolidative modality in most patients with acute myeloid leukemia (AML). Along with factors directly pertaining to SCT, pretransplantation disease control, performance status, and prior treatment-related complications are important factors that affect posttransplantation survival outcomes. METHODS: The authors compared the survival outcomes of patients ≥60 years of age treated on the phase 2 clinical trial of venetoclax (Ven) added to cladribine (CLAD) and low dose cytarabine (LDAC) alternating with azacitidine (CLAD/LDAC/Ven arm) (NCT03586609) who underwent allogeneic SCT in first remission to a retrospective cohort of patients ≥60 years of age who underwent SCT after intensive chemotherapy. Intensive chemotherapy was defined as the use of cytarabine >1 g/m2 and anthracyclines during induction/consolidation. RESULTS: Thirty-five patients at median age of 68 years in the CLAD/LDAC/Ven arm were compared to 42 patients at a median age of 62 years in the intensive therapy arm. The 2-year relapse-free survival was superior with CLAD/LDAC/Ven versus intensive chemotherapy (88% vs. 65%; p = .03) whereas the 2-year overall survival (OS) was comparable (84% vs. 70%; p = .14). On a competing event analysis, the 2-year cumulative incidence of relapse (CIR) was significantly lower with CLAD/LDAC/Ven versus intensive chemotherapy (2.9% vs. 17.2%, Gray's p = .049) whereas nonrelapse mortality was comparable (16.2% vs. 17.1%; p = .486). CONCLUSION: In conclusion, treatment with CLAD/LDAC/Ven was associated with favorable outcomes in older patients who underwent subsequent allogeneic SCT. The OS was comparable to that with intensive chemotherapy followed by allogeneic SCT, but the CIR rate was significantly lower.

Germ line predisposition variants occur in myelodysplastic syndrome patients of all ages.

The frequency of pathogenic/likely pathogenic (P/LP) germ line variants in patients with myelodysplastic syndrome (MDS) diagnosed at age 40 years or less is 15% to 20%. However, there are no comprehensive studies assessing the frequency of such variants across the age spectrum. We performed augmented whole-exome sequencing of peripheral blood samples from 404 patients with MDS and their related donors before allogeneic hematopoietic stem cell transplantation. Single-nucleotide and copy number variants in 233 genes were analyzed and interpreted. Germ line status was established by the presence of a variant in the patient and related donor or for those seen previously only as germ line alleles. We identified P/LP germ line variants in 28 of 404 patients with MDS (7%), present within all age deciles. Patients with P/LP variants were more likely to develop higher-grade MDS than those without (43% vs 25%; P = .04). There was no statistically significant difference in outcome parameters between patients with and without a germ line variant, but the analysis was underpowered. P/LP variants in bone marrow failure syndrome genes were found in 5 patients aged less than 40 years, whereas variants in DDX41 (n = 4), telomere biology disorder genes (n = 2), and general tumor predisposition genes (n = 17) were found in patients aged more than 40 years. If presumed germ line variants were included, the yield of P/LP variants would increase to 11%, and by adding suspicious variants of unknown significance, it would rise further to 12%. The high frequency of P/LP germ line variants in our study supports comprehensive germ line genetic testing for all patients with MDS regardless of their age at diagnosis.

Blinatumomab maintenance after allogeneic hematopoietic cell transplantation for B-lineage acute lymphoblastic leukemia.

Patients with B-lineage acute lymphoblastic leukemia (ALL) are at high-risk for relapse after allogeneic hematopoietic cell transplantation (HCT). We conducted a single-center phase 2 study evaluating the feasibility of 4 cycles of blinatumomab administered every 3 months during the first year after HCT in an effort to mitigate relapse in high-risk ALL patients. Twenty-one of 23 enrolled patients received at least 1 cycle of blinatumomab and were included in the analysis. The median time from HCT to the first cycle of blinatumomab was 78 days (range, 44 to 105). Twelve patients (57%) completed all 4 treatment cycles. Neutropenia was the only grade 4 adverse event (19%). Rates of cytokine release (5% G1) and neurotoxicity (5% G2) were minimal. The cumulative incidence of acute graft-versus-host disease (GVHD) grades 2 to 4 and 3 to 4 were 33% and 5%, respectively; 2 cases of mild (10%) and 1 case of moderate (5%) chronic GVHD were noted. With a median follow-up of 14.3 months, the 1-year overall survival (OS), progression-free survival (PFS), and nonrelapse mortality (NRM) rates were 85%, 71%, and 0%, respectively. In a matched analysis with a contemporary cohort of 57 patients, we found no significant difference between groups regarding blinatumomab's efficacy. Correlative studies of baseline and posttreatment samples identified patients with specific T-cell profiles as "responders" or "nonresponders" to therapy. Responders had higher proportions of effector memory CD8 T-cell subsets. Nonresponders were T-cell deficient and expressed more inhibitory checkpoint molecules, including T-cell immunoglobulin and mucin domain 3 (TIM3). We found that blinatumomab postallogeneic HCT is feasible, and its benefit is dependent on the immune milieu at time of treatment. This paper is posted on ClinicalTrials.gov, study ID: NCT02807883.

Eltrombopag improves platelet engraftment after haploidentical bone marrow transplantation: Results of a Phase II study.

Slow platelet recovery frequently occurs after haploidentical hematopoietic stem cell transplantation (haplo-HSCT) with bone marrow graft and post-transplant cyclophosphamide (PCy)-based graft-versus-host disease (GVHD) prophylaxis. Improved platelet recovery may reduce the need for transfusions and improve outcomes. We investigated the safety and efficacy of eltrombopag, a thrombopoietin receptor agonist, at enhancing platelet recovery post-haplo-HSCT. The prospective study included patients ≥18 years of age who received haplo-HSCT with bone marrow graft and PCy. Patients received eltrombopag 300 mg/day starting on Day +5. The primary objective was to estimate platelet engraftment (>50 000/µL by Day 60). In a post hoc analysis, they were compared to a contemporary matched control group who did not receive eltrombopag. One hundred ten patients were included in the analysis (30 eltrombopag and 80 control). Seventy-three percent and 50% of patients in the eltrombopag group and control group, respectively, attained >50 000/µL platelet count by Day 60 (p = .043). No eltrombopag-related grade ≥4 adverse events were observed. Median time to platelet recovery (>20 000/µL) was 29 days with eltrombopag and 31 days for controls (p = .022), while its cumulative incidence was 90% (95% confidence interval [CI]: 78%-100%) with eltrombopag versus 67.5% (95% CI: 57%-78%) for controls (p = .014). Number of platelet transfusions received, overall survival, progression-free survival, GVHD rate, relapse rate, and non-relapse mortality were similar between groups. Overall, eltrombopag is safe and improves platelet recovery in patients undergoing haplo-HSCT with bone marrow graft and PCy.

Molecular disparity of HLA-DPB1 is associated with the development of subsequent solid cancer after allogeneic hematopoietic stem cell transplantation.

BACKGROUND: An increased incidence of subsequent solid cancers (SSCs) has been reported in long-term survivors of allogeneic hematopoietic stem cell transplantation (allo-HSCT), and SSC is associated with inferior mortality and morbidity. Previous studies showed that the incidence of SSC is significantly higher in those who underwent allo-HSCT from HLA-mismatched donors, suggesting that persistent alloimmunity may predispose patients to SSCs. It was recently reported that, in a cohort of patients who received allo-HSCT from an unrelated donor matched at HLA-A, -B, -C, -DRB1/3/4/5, and -DQB1 loci, HLA-DPB1 alloimmunity determined by high mismatched eplets (MEs) and Predicted Indirectly Recognizable HLA Epitopes (PIRCHE) score (PS), was associated with relapse protection and increased risk of acute graft-versus-host disease (GVHD). METHODS: In the present study, the impact of HLA-DPB1 alloimmunity assessed by molecular mismatch algorithms on the development of SSCs in a cohort of 1514 patients who underwent allo-HSCT for hematologic malignancies was further investigated. ME load at the HLA-DPB1 locus was measured using the HLAMatchmaker module incorporated in HLA Fusion software, and the PS for mismatched HLA-DPB1 was calculated using the HSCT module from the PIRCHE online matching service. RESULTS: In multivariable analysis after adjusting for baseline risk factors, higher ME, PS-I, and PS-II in the GVH direction, but not in the HVG direction, were associated with an increased risk of SSCs (ME: subdistribution hazard ratio [SHR] 1.58, p = .01; PS-I: SHR 1.59, p = .009; PS-II: SHR 1.71, p = .003). In contrast, nonpermissive HLA-DPB1 mismatches defined by the conventional T-cell epitope algorithm were not predictive of the risk of SSCs. Moreover, posttransplant cyclophosphamide-based GVHD prophylaxis was associated with a reduced risk of subsequent solid cancer (SHR 0.34, p = .021). CONCLUSIONS: These results indicate for the first time that increased GVH alloreactivity could contribute to the development of SSCs in allo-HSCT survivors.

Association between the choice of the conditioning regimen and outcomes of allogeneic hematopoietic cell transplantation for myelofibrosis.

Allogeneic hematopoietic cell transplantation (allo-HCT) remains the only curative treatment for myelofibrosis. However, the optimal conditioning regimen either with reduced-intensity conditioning (RIC) or myeloablative conditioning (MAC) is not well known. Using the Center for International Blood and Marrow Transplant Research database, we identified adults aged ≥18 years with myelofibrosis undergoing allo-HCT between 2008-2019 and analyzed the outcomes separately in the RIC and MAC cohorts based on the conditioning regimens used. Among 872 eligible patients, 493 underwent allo-HCT using RIC (fludarabine/ busulfan n=166, fludarabine/melphalan n=327) and 379 using MAC (fludarabine/busulfan n=247, busulfan/cyclophosphamide n=132). In multivariable analysis with RIC, fludarabine/melphalan was associated with inferior overall survival (hazard ratio [HR]=1.80; 95% confidenec interval [CI]: 1.15-2.81; P=0.009), higher early non-relapse mortality (HR=1.81; 95% CI: 1.12-2.91; P=0.01) and higher acute graft-versus-host disease (GvHD) (grade 2-4 HR=1.45; 95% CI: 1.03-2.03; P=0.03; grade 3-4 HR=2.21; 95%CI: 1.28-3.83; P=0.004) compared to fludarabine/busulfan. In the MAC setting, busulfan/cyclophosphamide was associated with a higher acute GvHD (grade 2-4 HR=2.33; 95% CI: 1.67-3.25; P<0.001; grade 3-4 HR=2.31; 95% CI: 1.52-3.52; P<0.001) and inferior GvHD-free relapse-free survival (GRFS) (HR=1.94; 95% CI: 1.49-2.53; P<0.001) as compared to fludarabine/busulfan. Hence, our study suggests that fludarabine/busulfan is associated with better outcomes in RIC (better overall survival, lower early non-relapse mortality, lower acute GvHD) and MAC (lower acute GvHD and better GRFS) in myelofibrosis.

The mutational landscape in chronic myelomonocytic leukemia and its impact on allogeneic hematopoietic cell transplantation outcomes: a Center for Blood and Marrow Transplantation Research (CIBMTR) analysis.

Somatic mutations are recognized as an important prognostic factor in chronic myelomonocytic leukemia (CMML). However, limited data are available regarding their impact on outcomes after allogeneic hematopoietic cell transplantation (HCT). In this registry analysis conducted in collaboration with the Center for International Blood and Marrow Transplantation Registry database/sample repository, we identified 313 adult patients with CMML (median age: 64 years, range, 28- 77) who underwent allogeneic HCT during 2001-2017 and had an available biospecimen in the form of a peripheral blood sample obtained prior to the start of conditioning. In multivariate analysis, a CMML-specific prognostic scoring system (CPSS) score of intermediate-2 (HR=1.46, P=0.049) or high (HR=3.22, P=0.0004) correlated significantly with overall survival. When the molecularly informed CPSS-Mol prognostic model was applied, a high CPSS-Mol score (HR=2 P=0.0079) correlated significantly with overall survival. The most common somatic mutations were in ASXL1 (62%), TET2 (35%), KRAS/NRAS (33% combined), and SRSF2 (31%). DNMT3A and TP53 mutations were associated with decreased overall survival (HR=1.70 [95% CI: 1.11-2.60], P=0.0147 and HR=2.72 [95% CI: 1.37-5.39], P=0.0042, respectively) while DNMT3A, JAK2, and TP53 mutations were associated with decreased disease-free survival (HR=1.66 [95% CI: 1.11-2.49], P=0.0138, HR=1.79 [95% CI: 1.06-3.03], P=0.0293, and HR=2.94 [95% CI: 1.50-5.79], P=0.0018, respectively). The only mutation associated with increased relapse was TP53 (HR=2.94, P=0.0201). Nonetheless, the impact of TP53 mutations specifically should be interpreted cautiously given their rarity in CMML. We calculated the goodness of fit measured by Harrell's C-index for both the CPSS and CPSS-Mol, which were very similar. In summary, via registry data we have determined the mutational landscape in patients with CMML who underwent allogeneic HCT, and demonstrated an association between CPSS-Mol and transplant outcomes although without major improvement in the risk prediction beyond that provided by the CPSS.

Younger haploidentical donor versus older matched unrelated donor for patients with AML/MDS.

Optimal donor selection is fundamental to successful allogeneic hematopoietic cell transplantation (HCT), and donor age influences survival after both matched unrelated donor (MUD) and haploidentical donor HCT. Though recent studies have shown similar outcomes between MUD and haploidentical HCT, it is unknown if outcomes differ following HCT with younger haploidentical donors compared to HCT with older MUDs. Therefore, we performed a retrospective analysis comparing outcomes of myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) patients who underwent HCT with younger (≤35 years) haploidentical donors (n = 494) or older (>35 years) MUDs (n = 1005). Patients in the haploidentical and MUD groups received post-transplant cyclophosphamide (PTCy) and conventional graft-versus-host-disease (GVHD) prophylaxis, respectively. In multivariate analysis, use of younger haploidentical donors was associated with improved overall survival (hazard ratio [HR] 0.81, 95% confidence interval [CI] 0.69-0.95, p = .01) and lower rates of grade II-IV acute GVHD (HR 0.64, 95% CI 0.53-0.77, p < .001), grade III-IV acute GVHD (HR 0.37, 95% CI 0.25-0.53, p < .001), and chronic GVHD (HR 0.49, 95% CI 0.40-0.60, p < .001). Relapse rates were similar among those who received myeloablative conditioning but were higher in patients of the younger haploidentical group who received reduced intensity conditioning (HR 1.49, 95%CI 1.18-1.88, p = .001). The younger haploidentical group had significantly lower non-relapse mortality ≥3 months post-HCT (HR 0.59, 95% CI 0.38-0.90, p = .02). Our data support the use of younger haploidentical donors with PTCy over older MUDs with conventional prophylaxis in patients with MDS or AML. Further studies on the importance of donor age in haploidentical and MUD HCT with PTCy prophylaxis are warranted.

Characteristics and clinical outcomes of patients with myeloid malignancies and DDX41 variants.

DDX41 is the most frequently mutated gene in myeloid neoplasms associated with germline predisposition including myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML). We analyzed 3795 patients with myeloid neoplasms and identified 151 (4%) with DDX41 variants and a diagnosis of AML (n = 96), MDS (n = 52), and chronic myelomonocytic leukemia (n = 3). The most frequent DDX41 variants were the somatic variant p.R525H, followed by the germline variants p.M1I and p.D140fs. Most neoplasms had a normal karyotype (59%) and the most frequent co-mutations were TP53 (16%) and ASXL1 (15%). 30% of patients had no concomitant mutations besides DDX41 mutation. Patients with myeloid malignancies and DDX41 variants responded well to therapy, with an overall response rate for patients with treatment naïve AML and MDS of 87% and 84%, respectively. The median overall survival (mOS) of patients with treatment-naïve AML or MDS was 49 and 71 months, respectively. Patients with AML treated with low-intensity regimens including venetoclax had an improved survival (2-year OS 91% vs. 60%, p = .02) and lower cumulative incidence of relapse compared to those treated without venetoclax (10% vs. 56%, p = .03). In the 33% of patients receiving hematopoietic stem cell transplantation, the 2-year OS was 80% and 85% for AML and MDS, respectively.

Is there an optimal conditioning for older patients with AML receiving allogeneic hematopoietic cell transplantation?

The optimal conditioning regimen for older patients with acute myeloid leukemia (AML) remains unclear. In this study, we compared outcomes of AML patients >60 years of age undergoing allogenic hematopoietic stem cell transplantation at our institution. All 404 consecutively treated patients received 1 of the following conditioning regimens: (1) fludarabine+melphalan 100 mg/m2 (FM100), (2) fludarabine+melphalan 140 mg/m2 (FM140), (3) fludarabine+IV busulfan AUC ≥ 5000/d × 4 d (Bu≥20000), and (4) fludarabine+IV busulfan AUC 4000/d × 4 d (Bu16000). A propensity score analysis (PSA) was used to compare outcomes between these 4 groups. Among the 4 conditioning regimens, the FM100 group had a significantly better long-term survival with 5-year progression-free survival of 49% vs 30%, 34%, and 23%, respectively. The benefit of the FM100 regimen resulted primarily from the lower nonrelapse mortality associated with this regimen, an effect more pronounced in patients with lower performance status. The PSA confirmed that FM100 was associated with better posttransplantation survival, whereas no significant differences were seen between the other regimen groups. In summary, older patients with AML benefited from a reduced-intensity conditioning regimen with lower melphalan doses (FM100), which was associated with better survival, even though it was primarily used in patients who could not receive a more intense conditioning regimen.

Refined HLA-DPB1 mismatch with molecular algorithms predicts outcomes in hematopoietic stem cell transplantation.

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.

Fractionated busulfan myeloablative conditioning improves survival in older patients with acute myeloid leukemia and myelodysplastic syndrome.

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.

Cytogenetics and Blast Count Determine Transplant Outcomes in Patients with Active Acute Myeloid Leukemia.

Acute myeloid leukemia (AML) patients not in remission and beyond first or second complete remission are considered allogeneic stem cell transplant (SCT) candidates. We present 361 patients who underwent SCT from matched related or unrelated donors between 2005 and 2013. The purpose was to identify a subgroup of patients with active disease at the time of transplant that benefit. Cox proportional hazards regression analysis was used for univariate and multivariate analyses to predict overall survival (OS). Variables considered were age, sex, SWOG cytogenetic risk group, bone marrow (BM) and peripheral blood (PB) blast percentage, regimen intensity, and type of AML. At a median of 26 months after transplantation, OS, progression-free survival (PFS), non-relapse mortality, and relapse rates were 26, 24, 23, and 48%, respectively. In a univariate analysis, risk cytogenetics (p < 0.001) and BM blasts >4% (p = 0.006) or any blasts in PB (p < 0.001) indicated worse OS. In a multivariate analysis, patients with <5% BM blasts or absence of circulating blasts and good or intermediate risk cytogenetics had significantly superior OS (46%), PFS (44%), and disease progression at 3 years. Based on these findings, patients not in remission with good or intermediate risk cytogenetics and low blast counts should be considered for SCT.

Optimizing the Conditioning Regimen for Hematopoietic Cell Transplant in Myelofibrosis: Long-Term Results of a Prospective Phase II Clinical Trial.

Optimal conditioning regimens for older patients with myelofibrosis undergoing allogeneic hematopoietic cell transplant are not known. Likewise, the role of dose intensity is not clear. We conducted a nonrandomized, prospective, phase II trial using low-dose, later escalated to high-dose (myeloablative conditioning), busulfan with fludarabine (Bu-Flu) in myelofibrosis patients up to age 74 years. The first 15 patients received i.v. busulfan 130 mg/m2/day on days -3 and -2 ("low dose"); 31 patients received high-dose conditioning, either 100 mg/m2/day (days -5 to -2; n = 4) or pharmacokinetic-guided area under the curve of 4000 µmol/min (days -5 to -2; n = 27). The primary endpoint was day 100 nonrelapse mortality (NRM). Median age was 58 years (interquartile range [IQR], 53-63). Dynamic international prognostic scoring system-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 group and 0% in the low-dose group at day 100, which 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). In multivariate analysis, high-dose busulfan had a trend toward lower relapse (hazard ratio, .44; 95% CI, .18-1.07; P = .07), with no impact on NRM. Intensifying the Bu-Flu regimen using pharmacokinetic-monitoring appears to be promising in reducing relapse without increasing NRM.

Significance of minimal residual disease monitoring by real-time quantitative polymerase chain reaction in core binding factor acute myeloid leukemia for transplantation outcomes.

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.

Posttransplantation cyclophosphamide improves transplantation outcomes in patients with AML/MDS who are treated with checkpoint inhibitors.

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.

Effect of nonpermissive HLA-DPB1 mismatches after unrelated allogeneic transplantation with in vivo T-cell depletion.

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.

Development and validation of a risk assessment tool for BKPyV Replication in allogeneic stem cell transplant recipients.

BACKGROUND: BK polymavirus (BKPyV), a member of the family Polyomaviridae, is associated with increased morbidity and mortality in allogeneic stem cell transplant recipients. METHODS: In our previous retrospective study of 2477 stem cell transplant patients, BKPyV replication independently predicted chronic kidney disease and poor survival. In this study, using the same cohort, we derived and validated a risk grading system to identify patients at risk of BKPyV replication after transplantation in a user-friendly modality. We used 3 baseline variables (conditioning regimen, HLA match status, and underlying cancer diagnosis) that significantly predicted BKPyV replication in our initial study in a subdistribution hazard model with death as a competing risk. We also developed a nomogram of the hazard model as a visual aid. The AUC of the ROC of the risk-score-only model was 0.65. We further stratified the patients on the basis of risk score into low-, moderate-, and high-risk groups. RESULTS: The total risk score was significantly associated with BKPyV replication (P < .0001). At 30 days after transplantation, the low-risk (score ≤ 0) patients had a 9% chance of developing symptomatic BKPyV replication, while the high-risk (score ≥ 8) of the population had 56% of developing BKPyV replication. We validated the risk score using a separate cohort of 1478 patients. The AUC of the ROC of the risk-score-only model was 0.59. Both the total risk score and 3-level risk variable were significantly associated with BKPyV replication in this cohort (P < .0001). CONCLUSIONS: This grading system for the risk of symptomatic BKPyV replication may help in early monitoring and intervention to prevent BKPyV-associated morbidity, mortality, and kidney function decline.

Characterization of Viral Infections after Antithymocyte Globulin-Based Conditioning in Adults Undergoing Allogeneic Hematopoietic Stem Cell Transplantation.

Antithymocyte globulin (ATG) has been shown to reduce the incidence of graft-versus-host-disease (GVHD) after matched related donor (MRD) and matched unrelated donor (MUD) hematopoietic stem cell transplantation (HCT); however, because of increased risks of infection and relapse, this use has not translated into a significant improvement in post-transplant survival. The goal of this single-center, retrospective cohort analysis was to quantify the incidence of viral reactivation and viral end-organ disease (EOD) within the first 100 days after MUD HCT with ATG-based conditioning compared with MRD HCT without ATG. Fifty-nine adult patients underwent ATG-based MUD HCT compared with 64 patients receiving MRD HCT without ATG. Cytomegalovirus reactivation was the most frequent event in both groups (65% MUD versus 61% MRD), followed by BK virus reactivation (26% versus 24%) and Epstein-Barr virus reactivation (20% versus 9%). A higher percentage of MUD patients experienced viral EOD by day +100 when compared with MRD patients (34% versus 16%, P = .022). This was most notable for EOD involving BK virus (15% versus 6%, P = .14) and Epstein-Barr virus (7% versus 0%, P = .050). Correspondingly, more patients in the MUD group experienced virus-related complications, including hospitalization (24% versus 3%, P < .001), intensive care unit admission (10% versus 6%, P = .19), and mortality (8% versus 4%, P = .44). There were no significant differences in either relapse-free survival (RFS; 62% versus 78%, P = .07) or overall survival (OS; 72% versus 86%, P = .07) at 6 months post-HCT. However, when using the final time point of 21 months in the MUD/ATG group and 23 months in the MRD/no ATG group, MUD patients who received ATG had inferior survival (OS: 27% versus 77%, P = .009; RFS: 40% versus 59%, P = .042). Our results add to and further quantify the infectious risks associated with the use of ATG in MUD transplants and promote the implementation of more intensive preemptive viral monitoring practices in patients receiving ATG-based MUD transplants.

Allotransplants for Patients 65 Years or Older with High-Risk Acute Myeloid Leukemia.

The outcome of persons > 65 years with acute myeloid leukemia (AML) is poor. A transplant from an HLA-identical sibling or an HLA-matched unrelated donor can cure some of these patients but is associated with a substantial transplant-related mortality and a high relapse risk. We analyzed 185 subjects > 65 years with high-risk AML receiving conventional (n = 42) or reduced-intensity (n = 143) pretransplant conditioning and a transplant from an HLA-identical sibling (n = 66) or a 10/10 loci HLA-matched unrelated donor (n = 119). Two-year survival was 37%. Subjects with serious adverse events during before chemotherapy for their leukemia had a poor outcome after stem cell transplantation. Patients who had active leukemia or measurable residual disease (MRD) before transplantation had a worse outcome. Delayed hematologic recovery after induction or consolidation chemotherapy, high-risk AML genetics, donor-recipient HLA-DRß3/4/5-DP mismatches, and history of cardiovascular disease were also correlated with survival in multivariate analyses. The 57 MRD-negative patients with few other adverse prognostic factors had an excellent outcome (2-year overall survival, 76%), whereas the 58 patients with detectable leukemia and more than 1 other additional factor fared poorly (2-year overall survival, 8%). These data indicate it is possible to identify persons > 65 years with high-risk AML likely to benefit from an allotransplant. Validation of this prediction is needed.