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Total body irradiation (TBI) at a dose of 12 Gy combined with cyclophosphamide (CyTBI12Gy) is one of the standard myeloablative regimens for patients with acute myeloid leukemia (AML) treated with allogeneic hematopoietic cell transplantation (allo-HCT). In clinical practice, cyclophosphamide may be substituted with fludarabine (FluTBI12Gy) to reduce toxicity. We retrospectively compared outcomes of CyTBI12Gy with FluTBI12Gy for patients with AML treated in complete remission (CR) with allo-HCT from either a matched sibling or unrelated donor. Of 1684 adults who met inclusion criteria, 109 patients in each group were included in a matched-pair analysis. The cumulative incidence of relapse at 2 years was 25% in the FluTBI12Gy compared to 28% in the CyTBI12Gy group (p =.44) while non-relapse mortality (NRM) was 17% versus 19%, (p =.89) respectively. The rates of leukemia-free survival and overall survival were 65% versus 54% (p =.28) and 70% versus 60.5% (p =.17). Cumulative incidence of grade 2–4 acute graft-versus-host disease (GVHD) was significantly lower for FluTBI12Gy than CyTBI12Gy (16% vs. 34%, p =.005), while the incidences of grade 3–4 acute GVHD and chronic GVHD did not differ significantly. The probability of GVHD and relapse-free survival was 49% in the FluTBI12Gy and 41% in the CyTBI12Gy group (p =.17). We conclude that for patients with AML treated with allo-HCT in CR, cyclophosphamide may be substituted with fludarabine in a regimen based on TBI at a dose of 12 Gy without negative impact on the efficacy. FluTBI12Gy is associated with reduced risk of grade 2–4 acute GVHD and encouraging survival rates.

Background: The effectiveness and safety of non-heparin anticoagulants for the treatment of heparin-induced thrombocytopenia (HIT) are not fully established, and the optimal treatment strategy is unknown. In a systematic review and meta-analysis, we aimed to determine precise rates of platelet recovery, new or progressive thromboembolism (TE), major bleeding, and death for all non-heparin anticoagulants and to study potential sources of variability. Methods: Following a detailed protocol (PROSPERO: CRD42020219027), EMBASE and Medline were searched for all studies reporting clinical outcomes of patients treated with non-heparin anticoagulants (argatroban, danaparoid, fondaparinux, direct oral anticoagulants [DOAC], bivalirudin, and other hirudins) for acute HIT. Proportions of patients with the outcomes of interest were pooled using a random-effects model for each drug. The influence of the patient population, the diagnostic test used, the study design, and the type of article was assessed. Findings: Out of 3’194 articles screened, 92 studies with 119 treatment groups describing 4’698 patients were included. The pooled rates of platelet recovery ranged from 74% (bivalirudin) to 99% (fondaparinux), TE from 1% (fondaparinux) to 7% (danaparoid), major bleeding from 1% (DOAC) to 14% (bivalirudin), and death from 7% (fondaparinux) to 19% (bivalirudin). Confidence intervals were mostly overlapping, and results were not influenced by patient population, diagnostic test used, study design, or type of article. Interpretation: Effectiveness and safety outcomes were similar among various anticoagulants, and significant factors affecting these outcomes were not identified. These findings support fondaparinux and DOACs as viable alternatives to conventional anticoagulants for treatment of acute HIT in clinical practice. Registration Information: PROSPERO: CRD42020219027. Funding Information: This study was supported by a research grant of the Swiss National Science Foundation (#179334). Declaration of Interests: Conflict-of-interest disclosure: M.N. received research grants from Bayer Healthcare. A.C. has served as a consultant for synergy and his institution has received research support on his behalf from alexion, Bayer, Novartis, novo Nordisk, Pfizer, Sanofi, spark, and Takeda. All other authors declare that no conflict of interest exists.

Karyotypic analysis at time of diagnosis has an important value in determining initial response to treatment, remission duration and overall survival (OS) in acute myeloid leukemia (AML). Less is known about its value before allogeneic hematopoietic cell transplantation (allo-HCT) in patients transplanted with active disease, either relapsed or primary refractory (Rel-Ref) AML. We explored the impact of cytogenetic risk (stratification according to MRC-UK) in 2089 patients with either Ref (n = 972) or Rel AML (n = 1117) transplanted during the period 2000-2017. Overall, 154 patients had a favorable risk, 1283 had an intermediate risk and 652 had an adverse cytogenetic risk. Median follow-up was 49 months. Compared to the favorable risk group, intermediate and adverse risk patients were associated with worse leukemia-free survival and OS and also with a higher incidence of relapse. In a subgroup analysis of patients in the intermediate risk group harboring Fms-like tyrosine kinase 3-internal tandem duplication (FLT3-ITD), this remained an important prognostic factor, being associated with worse outcomes. When analyzing patients according to the intensity of the conditioning regimen, no differences were observed for the main transplant outcomes. In conclusion, in patients diagnosed with AML and transplanted with active disease, karyotype remains an important prognostic factor, allowing splitting patients into different risk groups according to their cytogenetics. Similarly, FLT3-ITD mutation also remains a negative prognostic factor in this population.

While evidence for measurable residual disease (MRD) is a harbinger of inferior outcome in acute myeloid leukemia (AML) patients referred for allogeneic stem cell transplantation (allo-SCT), the exact clinical trajectory of specific patient subsets in this clinical setting is undefined. Using a recently published prognostic cytogenetic model (Canaani et al. Leukemia 2019) we evaluated whether this model applied also to studies of patients with positive MRD. The analysis comprised MRD+ patients in first complete remission undergoing allo-SCT from a matched sibling donor or unrelated donor. Seven hundred and seventy-five patients were evaluated with a median follow-up duration of 22 months. Cytogenetic risk score was favorable, intermediate/FLT3wt intermediate/FLT3-ITD3, and adverse in 15%, 28.3%, 37% and 19.7% of the patients, respectively. Favorable and intermediate/FLT3wt risk patients had 2-year leukemia-free survival rates of 78% and 61%, respectively, compared with only 50% and 37% for intermediate/FLT3-ITD3 and adverse risk patients, respectively (P < .001). In multivariate analysis adverse and intermediate/FLT3-ITD3 risk patients were more likely to experience disease relapse compared with favorable risk patients [hazard ratio (HR) = 3.9, 95% confidence interval (CI), 2.1-7.3; P < .001, and HR = 4.4, CI 95%, 2.4-7.8; P < .001, respectively]. The European society for blood and marrow transplantation cytogenetic risk score is a valuable adjunct for risk stratification of MRD+ AML patients.

Haploidentical hematopoietic cell transplantation (haplo-HCT) is being increasingly used in acute leukemia patients as an alternative transplant modality when matched sibling or matched unrelated donors are unavailable. As several potential haploidentical relative donors are typically available for a given patient, optimizing donor selection to improve clinical outcome is crucial. The impact of donor age and kinship on the outcome of acute leukemia patients is not clearly established in this setting. Using the multinational registry of the acute leukemia working party of the European society for blood and marrow transplantation we retrospective analyzed the clinical outcome of 1270 acute myeloid leukemia and acute lymphoblastic leukemia patients who underwent haplo-HCT between 2005 and 2015. Patients over the age of 40 were significantly affected by increasing donor age resulting in higher non-relapse mortality (NRM) [Hazard ratio (HR)=1.86, confidence interval (CI) 95%, 1.18-2.94; P = .007], inferior leukemia-free survival (LFS) (HR = 1.59, CI 95%, 1.13-2.24; P = .007), and overall survival (OS) (HR = 1.74, CI 95%, 1.22-2.47; P = .002) when donors were over the age of 40. Additionally, kinship was found to be prognostically significant as patients transplanted from children donors over the age of 35 experienced an increased rate of NRM (HR = 1.82, CI 95%, 1.13-2.9; P = .01), inferior LFS (HR = 1.5, CI 95%, 1.05-2.13; P = .03), and OS (HR = 1.5, CI 95%, 1.04-2.15; P = .03). For patients younger than 40 years, donor age and kinship were mostly not clinically impactful. Our data establish donor age and kinship as significant determinants of outcome following haplo-HCT for acute leukemia patients.

The T Cell Project was the largest prospective trial to explore the incidence, treatment patterns, and outcomes for T cell lymphomas. The rare subtypes of T cell lymphomas, including hepatosplenic T cell lymphoma (HSTCL), enteropathy associated T cell lymphoma (EATL), and peripheral gamma delta T cell lymphomas (PGDTCLs) are poorly represented in most studies and there is little data regarding treatment patterns. We report results from 115 patients with hepatosplenic (n = 31), enteropathy associated (n = 65), and PGDTCLs (n = 19). While anthracycline regimens were most commonly used as first line therapy, response rates ranged from 20%−40% and were suboptimal for all groups. Autologous stem cell transplantation was performed as a consolidation in first remission in a small number of patients (33% of HSTCL, 7% of EATL, and 12% of PGDTCL), and four patients with HSTCL underwent allogeneic stem cell transplantation in first remission. The progression free survival at 3 years ranged from 28%−40% for these rare subtypes, and the overall survival at 3 years was most favorable for PGDTCL (70%). These data highlight the need for novel treatment approaches for rare subtypes of T cell lymphomas and for their inclusion in clinical trials.

International audience; Acute myeloid leukemia (AML) in first remission (CR1) with isolated NPM1 mutation (iNPM1m) is considered a good prognosis genotype, although up to one-third relapse. To evaluate the best transplant strategy, we retrospectively compared autologous stem cell transplantation (auto-SCT), related (MSD), and fully matched unrelated (MUD) allogeneic stem cell transplantation (allo-SCT). We identified 256 adult patients including 125 auto-SCT, 72 MSD, and 59 MUD. The 2-year leukemia-free survival (LFS) was 62% in auto-SCT, 69% in MUD, and 81% in MSD (P = .02 for MSD vs others). The 2-year overall survival (OS) was not different among auto-SCT, MUD, and MSD, reaching 83% (P = .88). The 2-year non-relapse mortality (NRM) was 2.5% in auto-SCT and 7.5% in allo-SCT (P = .04). The 2-year cumulative incidence of relapse (RI) was higher after auto-SCT (30%) than after MUD (22%) and MSD (12%, P = .01). In multivariate analysis, MSD versus auto-SCT but not MUD versus auto-SCT was associated with lower RI (P

Therapy-related acute myeloid leukemia (t-AML) arises as a late complication following antecedent solid tumors or hematologic diseases and their associated treatments. There are limited data regarding risk factors and outcomes following allogeneic hematopoietic cell transplantation (HCT) for t-AML following a prior solid tumor, and furthermore, the impact of myeloablative (MAC) vs reduced-intensity conditioning (RIC) on survival is unknown. The acute leukemia working party (ALWP) of the European society for blood and bone marrow transplantation (EBMT) performed a large registry study that included 535 patients with t-AML and prior solid tumor who underwent first MAC or RIC allogeneic HCT from 2000-2016. The primary endpoints of the study were OS and LFS. Patients receiving RIC regimens had an increase in relapse incidence (hazard ratio [HR], 1.52; 95% confidence interval [CI] 1.02-2.26; P = 0.04), lower LFS (HR, 1.52; 95% CI 1.12-2.05, P = 0.007), and OS (HR, 1.51; CI 1.09-2.09; P = 0.012). There were no differences in NRM and GRFS. Importantly, LFS and OS were superior in patients receiving ablative regimens due to a decrease in relapse. As NRM continues to decline in the current era, it is conceivable that outcomes of HCT for t-AML with prior solid tumor may be improved by careful patient selection for myeloablative regimens.

Patients with acute myeloid leukemia (AML) in morphological first complete remission (CR1) pre-allogeneic hematopoietic cell transplantation (HCT) may have measurable residual disease (MRD) by molecular and immunophenotyping criteria. We assessed interactions of MRD status with HCT conditioning regimen intensity in patients aged50 years (y) or ≥50y. This was a retrospective study by the European Society for Blood and Marrow Transplantation registry. Patients were18y with AML CR1 MRD NEG/POS and recipients of HCT in 2000-2015. Conditioning regimens were myeloablative (MAC), reduced intensity (RIC) or non-myeloablative (NMA). Outcomes included leukemia free survival (LFS), overall survival (OS), relapse incidence (RI), non-relapse mortality (NRM), chronic graft-vs-host (cGVHD), and GVHD-free and relapse-free survival (GRFS). The 2292 eligible patients were categorized into four paired groups:50y MRD POS MAC (N = 240) vs RIC/NMA (N = 58);50y MRD NEG MAC (N = 665) vs RIC/NMA (N = 195); ≥50y MRD POS MAC (N = 126) vs RIC/NMA (N = 230), and ≥50y MRD NEG MAC (N = 223) vs RIC/NMA (N = 555). In multivariate analysis RIC/NMA was only inferior to MAC for patients in the50y MRD POS group, with worse RI (HR 1.71) and LFS (HR 1.554). Patients50Y MRD NEG had less cGVHD after RIC/NMA HCT (HR 0.714). GRFS was not significantly affected by conditioning intensity in any group. Patients aged50y with AML CR1 MRD POS status should preferentially be offered MAC allo-HCT. Prospective studies are needed to address whether patients with AML CR1 MRD NEG may be spared the toxicity of MAC regimens. New approaches are needed for ≥50y AML CR1 MRD POS.

The optimal conditioning regimen to employ before hematopoietic stem cell transplantation in acute lymphoblastic leukemia (ALL) is still undecided, and while cyclophosphamide/total body irradiation (Cy/TBI) is the most commonly used myeloablative regimen, there are concerns regarding long-term toxicity for patients conditioned with this regimen. Thiotepa-based conditioning is an emerging radiation-free regimen with recent publications indicative of comparable clinical outcomes to TBI-based conditioning. In this analysis of the acute leukemia working party of the EBMT, we performed a retrospective matched-pair analysis, evaluating the outcome of adult patients with ALL who received thiotepa-based conditioning (n = 180) with those receiving Cy/ TBI conditioning (n = 540). The 2-year leukemia-free survival and overall survival (OS) rates of both conditioning regimens were comparable, 33% for thiotepa [95% confidence interval (CI): 26.4-42.8] versus 39% for Cy/TBI (95% CI: 34.8-44.5] (P = .33) and 46.5% [95% CI: 38.6-56.1] versus 48.8% [95% CI: 44.2-54] (P = .9), respectively. There was no significant difference between the two regimens in the incidence of either acute graft versus host disease (GVHD) or chronic GVHD. Multivariate analysis demonstrated increased relapse incidence for thiotepa conditioning compared to Cy/TBI (HR = 1.78, 95% CI, 1.07-2.95; P = .03) which did not affect OS. Our results indicate that thiotepa-based conditioning may not be inferior to Cy/TBI for adult patients with ALL.

Up to 20% of acute myeloid leukemia (AML) patients present initially with hyperleukocytosis, placing them at increased risk for early mortality during induction. Yet, it is unknown whether hyperleukocytosis still retains prognostic value for AML patients undergoing hematopoietic stem cell transplantation (HSCT). Furthermore, it is unknown whether hyperleukocytosis holds prognostic significance when modern molecular markers such as FLT3-ITD and NPM1 are accounted for. To determine whether hyperleukocytosis is an independent prognostic factor influencing outcome in transplanted AML patients we performed a retrospective analysis using the registry of the acute leukemia working party of the European Society of Blood and Marrow Transplantation. A cohort of 357 patients with hyperleukocytosis (159 patients with white blood count [WBC] 50 K-100 K, 198 patients with WBC >= 100 K) was compared to 918 patients without hyperleukocytosis. Patients with hyperleukocytosis were younger, had an increased rate of favorable risk cytogenetics, and more likely to be FLT3 and NPM1 mutated. In multivariate analysis, hyperleukocytosis was independently associated with increased relapse incidence (hazard ratio [HR] of 1.55, 95% confidence interval [CI], 1.14-2.12; P = .004), decreased leukemia-free survival (HR of 1.38, 95% CI, 1.07-1.78; P = .013), and inferior overall survival (HR of 1.4, 95% CI, 1.07-1.84; P = .013). Hyperleukocytosis retains a significant prognostic role for AML patients undergoing HSCT.

Predictive models may help in determining the risk/benefit ratio of allogeneic hematopoietic stem cell transplantation (HSCT) in acute leukemia (AL). Using a machine-learning algorithm we have previously developed the AL- European Society for Blood and Marrow Transplantation (EBMT) score for prediction of mortality following transplantation. We report here the first external validation of the AL-EBMT score in a cohort of AL patients from the Italian national transplantation network. A total of 1848 patients transplanted between the years 2000-2014 were analyzed. The median age was 45.9. Indications for HSCT were Acute Myeloid Leukemia (68.1%) and Acute Lymphoblastic Leukemia (31.9%). The majority of patients were in first complete remission (60.4%), and received myeloablative conditioning (81.3%). Median follow-up was 2 years. The score was well-calibrated for prediction of day 100 mortality and 2-year overall survival (OS), leukemia free survival (LFS), and nonrelapse related mortality, with corresponding area under the receiver-operator curves of 0.698, 0.651, 0.653, and 0.651, respectively. Increasing score intervals were associated with a decreasing probability of 2-year OS and LFS. The highest scoring group was associated with a hazard ratio of 3.16, 2.8, and 2.27 for 2-year OS, LFS, and NRM, respectively. In conclusion, the AL-EBMT score identified three distinct risk groups and was predictive of OS. It is a valid tool for stratifying the risk of acute leukemia patients undergoing allogeneic HSCT.

Introduction: Notwithstanding recent advances in the molecular characterization of acute myeloid leukemia (AML), the 2016 world health organization (WHO) classification system of AML still recognizes AML, not otherwise specified (NOS) as a major category. AML, NOS patients are further morphologically subcategorized according to the French, American, and British (FAB) classification system, widely used by pathologists and hematologists. While recent data proposes that the FAB classification does not provide additional prognostic information for patients for whom NPM1 status is available (Walter, 2013), it is unknown whether FAB classification still retains a prognostic role in the current era of molecular and cytogenetic prognostication in predicting outcome of AML patients undergoing an allogeneic stem cell transplant (ASCT). Thus, we set out to determine whether the FAB classification system complemented with molecular stratification provides prognostic information in AML, NOS patients undergoing an ASCT in CR1. Patients and Methods: Using the European Society of Blood and Bone Marrow Transplantation (EBMT) registry we identified patients with available FAB data and the following inclusion criteria: age over 18, de-novo non-M3 AML, and ASCT in complete remission (CR1) from a fully matched sibling or a 10/10 HLA matched unrelated donor. Patients with recurrent genetic abnormalities, AML with myelodysplasia-related changes, and patients with therapy-related myeloid neoplasms were excluded from the analysis. Multivariate analyses was used to assess whether the FAB type was independently associated with leukemia free survival (LFS), overall survival (OS), relapse incidence (RI), and non-relapse mortality (NRM). Age, gender, cytogenetics, donor type, FLT3 status, NPM1 status, and conditioning intensity were covariates for regression modeling. Results: A cohort of 1690 patients transplanted between 2005-2014, at a median age of 50 years (range 18-74 years) with a median follow up duration of 34.7 months, was analyzed (baseline characteristics of the cohort summarized per FAB category are shown in table 1). The different FAB subtypes had comparable rates of donor type (62% HLA identical sibling donors for the entire cohort), and conditioning intensity (55% underwent myeloablative conditioning). FAB M6/M7 patients underwent transplant at an older age while FAB M0 and M7 had increased rates of poor risk cytogenetics (26% and 60%, respectively). NPM1 mutations were more prevalent among FAB M4 (53%) whereas FAB M1 patients had increased rates of mutated FLT3 (55%). Multivariate analysis of the entire cohort showed that FAB M6/M7 was significantly associated with decreased LFS compared to the other FAB subtypes grouped together (hazard ratio (HR) of 1.41, 95% confidence interval (CI), 1.01-1.99; p=0.046), and increased NRM (HR, 1.79; 95% CI, 1.06-3.01; p=0.028). Next, to align our data with the recently introduced 2016 WHO AML, NOS classification we restricted our analysis to the NPM1 negative subset of the cohort (n=712), and found on multivariate regression analysis that FAB M6/M7 was significantly associated with increased NRM (HR, 2.17; 95% CI, 1.14-4.16; p=0.019) compared to the other FAB subtypes. RI, LFS, and OS rates were not significantly different between FAB M6/M7 and the other FAB subtypes. Finally, we wanted to ascertain whether in FLT3 mutated patients FAB classification retains prognostic significance post-transplant. We did not find any statistically significant difference in terms of outcome between M6/M7 versus all other FAB subtypes, possibly due to the small cohort of M6/M7 FLT3+ patients (n=18). Conclusion: FAB classification may predict outcome following transplantation in NPM1 negative AML, NOS patients. Table Baseline characteristics of study cohort per FAB category Table. Baseline characteristics of study cohort per FAB category Figure Clinical outcome in NPM1 negative AML, NOS patients after ASCT* *Adjusted for age, gender, donor type, cytogenetics, FLT3 status and conditioning regimen Figure. Clinical outcome in NPM1 negative AML, NOS patients after ASCT*. / *Adjusted for age, gender, donor type, cytogenetics, FLT3 status and conditioning regimen Disclosures No relevant conflicts of interest to declare.

ABO incompatibility is commonly observed in stem cell transplantation and its impact in this setting has been extensively investigated. HLA-mismatched unrelated donors (MMURD) are often used as an alternative stem cell source but are associated with increased transplant related complications. Whether ABO incompatibility affects outcome in MMURD transplantation for acute myeloid leukemia (AML) patients is unknown. We evaluated 1,013 AML patients who underwent MMURD transplantation between 2005 and 2014. Engraftment rates were comparable between ABO matched and mismatched patients, as were relapse incidence [34%; 95% confidence interval (CI), 28-39; for ABO matched vs. 36%; 95% CI, 32-40; for ABO mismatched; P = .32], and nonrelapse mortality (28%; 95% CI, 23-33; for ABO matched vs. 25%; 95% CI, 21-29; for ABO mismatched; P = .2). Three year survival was 40% for ABO matched and 43% for ABO mismatched patients (P = .35), Leukemia free survival rates were also comparable between groups (37%; 95% CI, 32-43; for ABO matched vs. 38%; 95% CI, 33-42; for ABO mismatched; P = .87). Incidence of grade II-IV acute graft versus host disease was marginally lower in patients with major ABO mismatching (Hazard ratio of 0.7, 95% CI, 0.5-1; P = .049]. ABO incompatibility probably has no significant clinical implications in MMURD transplantation. ispartof: American Journal of Hematology vol:92 issue:8 pages:789-796 ispartof: location:United States status: published

In this study, we analyzed a thiotepa-based conditioning regimen for allogeneic stem cell transplantation in adults with acute lymphoblastic leukemia, using the EBMT database. A total of 323 patients were identified. The median age was 43 years. Disease status at transplant was first complete remission (CR1) in 48.9%, CR2 in 21.7%, CR3 in 6.2%, while 23.2% of the patients had an active disease at the time of transplant. This was performed from a HLA-matched sibling (49.8%) or a matched-unrelated donor (51.2%). The incidence of acute graft-vs.-host disease (GvHD) (grade > II) was 26.6%, while chronic GvHD occurred in 35.9% of the patients at 1 year (24.6% with extensive disease). With a median follow-up of 16.8 months, the nonrelapse mortality was 12.4 and 25.3% at 100 days and 1 year, respectively. The relapse incidence at 1 year was 33.3% with no difference for patients in CR1 (27%). The one-year leukemia-free survival (LFS) and overall survival (OS) were 57 and 66%, respectively for the entire cohort and 50 and 66%, respectively in patients in CR1. Thiotepa/busulfan ± melphalan (n = 213) in comparison to thiotepa/other (n = 110) conditioning regimen resulted in higher relapse incidence at 1 year (34.9 vs. 30.3%, P = 0.016) and lower LFS (38.8 vs. 45.9%, P = 0.0203), while nonrelapse mortality (23.8 vs. 26.3%, n.s.) and OS (59.6 vs. 51.1%, P = 0.109) did not differ. This large study suggests that a thiotepa-based conditioning for allogeneic transplantation in acute lymphoblastic leukemia is feasible and effective, with the main outcomes being comparable to those achieved with other regimens. Am. J. Hematol. 92:18-22, 2017. © 2016 Wiley Periodicals, Inc.

Patients with acute myeloid leukemia (AML) who relapse after autologous stem cell transplantation (ASCT) can be rescued by allogeneic SCT. We identified 537 adult patients with AML allografted in second complete remission (CR2) or first relapse after ASCT in the European Society for Blood and Marrow Transplantation (EBMT) registry. At 3 years post allograft, leukemia free survival (LFS) was 31.4% [95%CI 27.3-35.6], overall survival (OS) 39.5% [95%CI 35.1-43.9], relapse incidence (RI) 34.6% [95%CI 30.4-38.8], and nonrelapse mortality (NRM) 33.7% [95%CI 29.6-37.9]. RI was higher in patients transplanted in relapse in comparison to those transplanted in CR2 (HR 1.76, P = .004) and in patients who relapsed later after ASCT (HR 0.97 per month, P < 10-3 ), both translating into better LFS/ OS. Relapse was also lower in patients undergoing allogeneic stem cell transplantation (allo-HSCT) from an unrelated donor (UD) in comparison to those transplanted from a matched sibling donor (MSD) (HR 0.49, P < 10-3 ). NRM was increased in patients who received total body irradiation (TBI) pre-ASCT (HR 2.43; P < 10-4), translating into worse LFS/OS. LFS/OS did not differ between patients allotransplanted with reduced intensity (RIC) or myeloablative (MAC) conditioning. In conclusion, one third of adult patients with AML relapsing post ASCT can be rescued with allo-HSCT, with better LFS/OS in patients who relapsed later post ASCT, those transplanted in CR2 and those who had not received TBI pre-ASCT. ispartof: AMERICAN JOURNAL OF HEMATOLOGY vol:93 issue:12 pages:1532-1542 ispartof: location:United States status: published

Autologous CD19 chimeric-antigen receptor (CAR) T cells demonstrated remarkable remission rates in relapsed and refractory acute lymphoblastic leukemia (R/R ALL). Here, we report results from a phase 1b/2 study of in-house produced CD19 CAR with a CD28 costimulatory domain. Twenty-one patients with R/R ALL were enrolled, and 20 infused. The median age was 11 years (range, 5-48). Patients had a median of 4 prior regimens, including blinatumomab in 6 and prior stem-cell transplantation in 10. In total 8 patients had extramedullary (EM) leukemic involvement, and prior to lymphodepletion and CAR 7 had active lesions, a group underrepresented in previous trials. In vivo expansion of CAR T cells was observed in 18 patients. In total 16 patients developed cytokine release syndrome, and 11 patients developed neurotoxicity, with no toxic deaths. All responding patients were referred to an allogeneic hematopoietic stem-cell transplantation. The remission rate was 90%, including resolution of all refractory EM sites. Four responding patients relapsed, 3 who had a PCR-MRD positive remission at 28 days following CAR-T cells and 1 patient 21 months after an MRD-negative response. The estimated 1-year event-free survival and overall survival are 73% and 90%, respectively. Patients with R/R EM ALL may also benefit from CAR-T cell therapy.

Autologous stem cell transplantation remains a clinical option to consolidate some adult patients with acute myelogenous leukemia (AML) in first complete remission (CR1). In a small cohort of patients, we have previously shown better outcomes following Busulfan and Melphalan (BUMEL) over Busulfan and Cyclophosphamide (BUCY). To identify the subpopulations that might get the highest benefit with BUMEL, we designed a larger study. All adult patients with primary AML and available cytogenetics, autografted from January 2000 to December 2016 in CR1, were included: 1137 patients received BUCY and 512 BUMEL. All factors differing in distribution between the 2 conditioning groups were introduced in multivariate analyzes. In a primary analysis, we found an interaction between conditioning and the poor risk group defined as poor cytogenetics and/or presence of the FLT3-ITD mutation. During analysis of the poor risk group, 176 patients received BUCY and 62 BUMEL. BUMEL was associated with a lower RI at 5 years (53% versus 69%, HR: 0.52, P = .002), a better Leukaemia-free survival (LFS) (42% versus 25%, HR: 0.54, P = .002) and a better OS (54% versus 36%, HR: 0.61, P = .02). During analysis of the non poor risk group, 961 patients received BUCY and 450 BUMEL. At 5 years, the RI was 50% and 47%, the LFS 45% and 48% and the OS 56% and 60% respectively, with no significant difference. We conclude that BUMEL is the preferable conditioning regimen for the poor risk leukemic patients, while in AML patients without poor risk cytogenetics or FLT3 both conditioning regimens are valid.

Acute myeloid leukemia with monosomal karyotype (MK AML) carries a very poor prognosis, even after allogeneic stem cell transplantation (SCT). However, SCT remains the only curative option in this high-risk population. Because myeloablative conditioning regimen (MAC) is associated with less relapse, we hypothesized that more intensive conditioning regimen might be beneficial for MK AML patients. We reviewed 303 patients over age 45 diagnosed with either de novo or secondary MK AML. One hundred and five patients received a MAC and 198 a reduced-intensity conditioning (RIC). The median age at SCT was 57-year-old, significantly lower in the MAC (53-year-old) than in the RIC group (59-year-old). The median follow-up was 42 months (range, 3-156 months). The 3-year overall survival (OS), leukemia-free survival (LFS), and relapse rate (RR) were not significantly different between both groups with overall values of 34%, 29%, and 51%, respectively. On the contrary, the 3-year nonrelapse mortality (NRM) was significantly higher in MAC recipients (28%) compared with RIC patients (16%, P=0.004). The incidence of Grades II to IV acute graft-versus-host disease (GvHD) was significantly higher after a MAC (30.5%) than after a RIC (19.3%, P=0.02). That of chronic GvHD was comparable between both groups (35%) and did not impact on LFS. Interestingly, within our MK AML cohort, hypodiploidy was significantly associated with worse outcomes. Due to reduced toxicity and comparable OS, LFS, and RR, RIC appears as a good transplant option in the very high-risk population, including older patients, diagnosed with MK AML. Am. J. Hematol. 90:719-724, 2015. (c) 2015 Wiley Periodicals, Inc.