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Post-transplant cyclophosphamide (PT-Cy) is effective for graft-versus-host disease (GVHD) prophylaxis, but it may cause dose-dependent toxicities, particularly in frail patients. Therefore, we compared the outcomes with a reduced PT-Cy total dose (70 mg/kg) to those with the standard PT-Cy dose (100 mg/kg) in haploidentical hematopoietic cell transplantation (HCT) patients aged ≥ 65 years and those with cardiac comorbidities. All consecutive patients with a hematological malignancy receiving peripheral blood stem cells (PBSCs) after a thiotepa-based conditioning with low-dose antithymocyte globulin were included. Thirty-three patients received PT-Cy at 70 mg/kg and 25 at 100 mg/kg. PT-Cy dose reduction did not increase the risk of GVHD and was associated with faster neutrophil and platelet recovery, and lower cumulative incidences of bacteremia (38% versus 72%, p = 0.004) and cardiac complications (12% versus 44%, p = 0.028). At 2 years, GVHD-free, relapse-free survival (GRFS) was higher with the reduced dose compared to the standard dose (60% versus 33%, p = 0.04). In conclusion, reducing PT-Cy total dose to 70 mg/kg is a safe and valid approach for elderly patients and those with cardiac comorbidities underdoing haploidentical HCT with PBSCs and low-dose antithymocyte globulin. The reduced PT-Cy dose was associated with improved hematological count recovery, lower incidence of toxicities, and higher GRFS., (© 2023. The Author(s), under exclusive licence to Springer Nature Limited.)

For acute lymphoblastic leukemia (ALL) patients, total body irradiation (TBI)- based conditioning regimens are the first choice specially in young population. However, several studies have shown an equivalence in clinical outcomes with thiotepa-based conditioning regimen. We performed a retrospective study to evaluate the outcome of adult ALL patients who received allogeneic hematopoietic stem cell transplantation (allo-HCT) with a thiotepa-busulfan-fludarabine (TBF) myeloablative conditioning regimen with reduced toxicity. Fifty-five patients received a TBF regimen. The median age of the patients was 51 years (range, 17 to 72.4). Most patients had a diagnosis of B-ALL (93%) with 7% having T-ALL. Two - and 5-year overall survival was 73.2% and 64%, respectively. At 2 years, leukemia-free survival and GVHD-free, relapse-free survival were 59.5% and 57.6%, and at 5 years, 53.4% and 51.8%, respectively. The 5-year non-relapse mortality was 15%. The day 180 cumulative incidence (CI) of grade II-IV acute GVHD and grade III-IV acute GVHD were 38.2% and 5.5%, respectively. At 2 years, the CI of chronic GVHD and extensive chronic GVHD was 16.9% and 1.9%, respectively. Our study results do suggest that using TBF as the conditioning regimen in adult ALL patients is a promising option with acceptable toxicity., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)

Clofarabine (CLO) is a nucleoside analog with efficacy in relapsed/refractory acute lymphoblastic leukemia (ALL). This randomized phase 3 study aimed to evaluate whether CLO added to induction and whether consolidation would improve outcome in adults with newly diagnosed ALL. Treatment of younger (18-40 years) patients consisted of a pediatric-inspired protocol, and for older patients (41-70 years), a semi-intensive protocol was used. Three hundred and forty patients were randomized. After a median follow-up of 70 months, 5-year event-free survival (EFS) was 50% and 53% for arm A and B (CLO arm). For patients ≤40 years, EFS was 58% vs 65% in arm A vs B, whereas in patients >40 years, EFS was 43% in both arms. Complete remission (CR) rate was 89% in both arms and similar in younger and older patients. Minimal residual disease (MRD) was assessed in 200 patients (60%). Fifty-four of 76 evaluable patients (71%) were MRD- after consolidation 1 in arm A vs 75/81 (93%) in arm B (P = .001). Seventy (42%) patients proceeded to allogeneic hematopoietic stem cell transplantation in both arms. Five-year overall survival (OS) was similar in both arms: 60% vs 61%. Among patients achieving CR, relapse rates were 28% and 24%, and nonrelapse mortality was 16% vs 17% after CR. CLO-treated patients experienced more serious adverse events, more infections, and more often went off protocol. This was most pronounced in older patients. We conclude that, despite a higher rate of MRD negativity, addition of CLO does not improve outcome in adults with ALL, which might be due to increased toxicity. This trial was registered at www.trialregister.nl as #NTR2004., (© 2022 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Haploidentical transplantation has extended the availability of allogeneic hematopoietic stem cell transplant (alloHCT) to almost all patients. Sequential conditioning regimens have been proposed for the treatment of hematological active disease. Whether these new transplantation procedures affect the prognosis of critically ill alloHCT recipients remains unknown. We evaluated this question in a retrospective study including consecutive alloHCT patients admitted to the intensive care unit of a tertiary academic center from 2010 to 2017. During the study period, 412 alloHCTs were performed and 110 (27%) patients-median age 55 (36-64) years-were admitted to ICU in a median time of 58.5 (14-245) days after alloHCT. Twenty-nine (26%) patients had received a haploidentical graft and 34 (31%) a sequential conditioning. Median SOFA score was 9 (6-11). Invasive mechanical ventilation (MV) was required in 61 (55%) patients. Fifty-six (51%) patients died in the hospital. Independent factors associated with in-hospital mortality were as follows: MV (OR=8.44 [95% CI 3.30-23.19], p<0.001), delta SOFA between day 3 and day 1 (OR=1.60 [95% CI 1.31-2.05], p<0.0001), and sequential conditioning (OR=3.7 [95% CI 1.14-12.92], p=0.033). Sequential conditioning was also independently associated with decreased overall survival (HR=1.86 [95% CI 1.05-3.31], p=0.03). Other independent factors associated with reduced overall survival were HCT-specific comorbidity index ≥2 (HR=1.76 [95% CI 1.10-2.84], p=0.02), acute GVHD grade ≥2 (HR=1.88 [95% CI 1.14-3.10], p=0.01), MV (HR=2.37 [95% CI 1.38-4.07, p=0.002), and vasopressors (HR=2.21 [95% CI 1.38-3.54], p=0.001). Haploidentical transplantation did not affect outcome. Larger multicenter studies are warranted to confirm these results., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

The phase 3 ALFA-0701 trial demonstrated improved outcomes with fractionated-dose gemtuzumab ozogamicin (GO) combined with standard chemotherapy vs. standard chemotherapy alone in adults with de novo acute myeloid leukemia (AML). We examined post-transplant outcomes and occurrence of hepatic veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS) in patients who received hematopoietic stem cell transplantation (HSCT) as follow-up therapy in ALFA-0701. Patients aged 50-70 years were randomized to standard chemotherapy with or without GO (3 mg/m2 on days 1, 4, and 7 of induction and day 1 on each of two consolidation courses). Allogeneic HSCT was recommended for patients in first complete remission with matched (related or unrelated) donor, except those with core-binding factor AML or normal karyotype and either NPM1+/FLT3-ITDwt or CEBPA+ AML. Eighty-five patients (GO: n = 32; control: n = 53) received HSCT in first complete remission or after relapse/primary induction failure. Three patients (GO: n = 2; control: n = 1 [received GO as follow-up therapy]) developed VOD/SOS after HSCT or conditioning. Post-transplant survival, non-relapse mortality, and relapse were not different between arms. Results indicate fractionated-dose GO as part of induction and consolidation chemotherapy for AML does not induce excess post-transplant VOD/SOS or mortality and thus does not preclude the use of HSCT as consolidation treatment.

We assessed the outcomes associated with thiotepa, busulfan and fludarabine (TBF) conditioning regimen in a cohort of 29 consecutive patients allografted for myelofibrosis (MF). The median age was 56 (range 42-70) years. According to the refined Dynamic International Prognostic Scoring System (DIPSS-plus), 15 (52%) patients were classified as high risk. Graft source was peripheral blood stem cells in 27 patients. Donor type was HLA-matched related ( n  = 5), matched unrelated ( n  = 16), mismatched unrelated ( n  = 1), and haploidentical ( n  = 7). All but 2 patients engrafted. The cumulative incidence (CI) of grade II-IV acute graft-versus-host disease (GVHD) was 21% (95% CI, 10-42) at day 100. The CI of chronic GVHD was 39% (95% CI, 23-65) at 3 years. The median follow-up period was 39 (range 14-60) months. Overall survival was 69% (95% CI, 50-83) at 3 years. No relapse was observed. TBF is a valid conditioning strategy in patients with MF.

Introduction/background: Azacytidine (AZA) has been used as a promising treatment for relapse after allogeneic transplantation. A clear benefit has been demonstrated when treating patients with a reduced disease burden, thus a prophylactic and preemptive approach to these patients has emerged., Materials and Methods: We retrospectively analyzed patients with myeloid malignancies treated with azacytidine in the posttransplantation setting between September 2013 and April 2018 in a single tertiary care hospital. Of 32 patients analyzed, 21 were treated for prophylactic use and 11 preemptively, with a median follow-up of 20 months. Prophylactic treatment consisted of AZA at 32 mg/m 2 for 5 days every 28 days, and preemptive treatment of AZA 75 mg/m 2 for 5 or 7 days per cycle. In addition, 10 patients received one or more donor lymphocyte infusions (DLIs). Two patients presented with infectious complications demanding hospitalization, and 13 patients (10 in the prophylactic group and 3 in the preemptive group) presented graft-versus-host disease (GvHD). Of patients who had GvHD, 3 needed treatment discontinuation. Overall, 12 patients suspended treatment, 8 for disease progression and 1 due to patient request., Results: In the prophylactic group, all patients are alive at 1 year with an event-free survival (EFS) of 95%, as only 1 patient relapsed. In the preemptive group, 1-year EFS was 54% and 1-year overall survival was 82%., Conclusion: Low-dose AZA in posttransplantation patients with myeloid neoplasms is a well-tolerated therapy with the potential to prevent relapse and maintain stable remissions. Randomized prospective trials are needed to determine patient selection and dosage, timing, and duration of treatment., (Copyright © 2019 Elsevier Inc. All rights reserved.)

We report results of a thiotepa-based conditioning in haploidentical stem cell transplantation (haplo-SCT) with posttransplant cyclophosphamide (PT-CY) and antithymocyte globulin (ATG), for unmanipulated peripheral blood stem cell (PBSC) transplants, in 80 patients with hematological malignancies. Patients in complete remission (CR) received a thiotepa-busulfan-fludarabine (TBF) regimen, while patients with relapsed/refractory (R/R) malignancies received a sequential regimen consisting of thiotepa-etoposide-cyclophosphamide (TEC) and reduced-intensity conditioning (RIC). The median age was 52 (range, 17-72) years, 44% patients had R/R disease at transplant, and the median follow-up was 417 (range, 180-1595) days. The median days to neutrophil engraftment was 17 (range, 12-34). The cumulative incidences (CI) of acute graft-versus-host disease (GVHD) grade III to IV, severe chronic GVHD, nonrelapse mortality (NRM), and relapse were 16%, 16%, 26, and 26%, respectively. The 2-year overall survival (OS) and disease-free survival (DFS) were 53% and 47%, respectively. There were no significant differences between the patients in CR and R/R patients in terms of engraftment, GVHD, NRM, relapse, OS, or DFS. We conclude that thiotepa-based regimen with PT-CY can be modified with PBSC and ATG, still providing low toxicity, protection against GVHD, and low relapse incidence. Particularly encouraging are the results with the modification to sequential regimen in R/R patients.

Optimization of the salvage regimen is required to improve prognosis in primary refractory or relapsed acute myeloid leukemia (AML). In fit patients, a bridge to allogeneic transplant is the primary purpose of salvage. We tested the combination of fractionated gemtuzumab ozogamicin with cytarabine and mitoxantrone (MYLODAM schema) with primary endpoint of efficacy and safety. We also attempted to define predictive factors for survival and response after salvage. We included 58 patients with a median age at salvage of 56 years. The overall response rate was 67%. Leukemia-free survival (LFS) and overall survival (OS) at 2 years was 36% (95% CI: 23-49) and 54% (95% CI: 39-68), respectively. Treatment-related mortality was 7%. Three veno-occlusive diseases (SOS/VOD) occurred during salvage. In the allogeneic group of 28 patients (48%), LFS and OS at 2 years was 57 % (95% CI: 36.3-77.5) and 69 % (95% CI: 49.3-88.7), respectively. Incidences of nonrelapse mortality, grade II-IV acute graft-versus-host disease (GVHD) and chronic GVHD were 16%, 40%, and 45%, respectively. A GO-based intensive regimen is a viable option for salvage therapy and a feasible schedule as a bridge to allogeneic transplant.

Background: Patients diagnosed with acute myeloid leukemia (AML) with Fms-like tyrosine kinase 3 (FLT3) mutations have a very poor prognosis, despite use of allogeneic hematopoietic stem cell transplantation (allo-HSCT) and salvage treatments., Patients and Methods: We previously reported the safety and efficacy of sorafenib, an FLT3 inhibitor, as a maintenance agent after allo-HSCT in patients diagnosed with AML with FLT3 mutations. We provide an update on the 27 patients with FLT3-mutated AML in our original report, who received sorafenib as a single maintenance agent., Results: Since our previous report, others have confirmed our reported significant overall survival and progression-free survival in patients who received sorafenib before and/or after allo-HSCT. In this update on the 27 patients with FLT3-mutated AML in our original report, we show persistence of the previously reported impressive long-term disease control., Conclusion: Our results, with longer follow-up than in our previous report, together with those of others, further support the use of sorafenib as a maintenance agent after allo-HSCT., (Copyright © 2019 Elsevier Inc. All rights reserved.)

We report the outcomes of 51 patients who underwent unmanipulated haploidentical hematopoietic stem cell transplantation (haplo-HSCT) with post-transplantation cyclophosphamide (PT-Cy) and antithymocyte globulin (ATG), from peripheral blood stem cells (PBSCs) or bone marrow, after receipt of a TBF (thiotepa, busulfan, and fludarabine) conditioning regimen. Their median age was 55 years (range, 16 to 72 years). Hematologic diagnoses included acute leukemias (n = 31), lymphoid neoplasm (n = 12), myeloproliferative neoplasm (n = 5), and myelodysplastic syndromes (n = 3). Thirty-seven patients (73%) were in complete remission. Graft-versus-host disease (GVHD) prophylaxis consisted of cyclosporine and mycophenolate for all patients, associated with ATG in 39 patients (76.5%). The median time to neutrophil engraftment was 17 days (range, 12 to 34 days). The cumulative incidences of grade II-IV and grade III-IV acute GVHD were 27.5% and 14%, respectively. In patients receiving a PBSC graft and ATG prophylaxis, grade II-IV aGVHD occurred in 16% of patients. The use of ATG and a lower thiotepa dose (5 mg/kg versus 10 mg/kg) were associated with a reduced cumulative incidence of grade II-IV acute GVHD (P = .03 and .005, respectively). The 2-year cumulative incidence of chronic GVHD was 29% and was significantly reduced to 13% with the lower thiotepa dose (P = .002). After a median follow-up of 25 months (range, 12 to 62 months), the cumulative incidences of nonrelapse mortality, relapse, overall survival (OS), disease-free survival (DFS), and GVHD-free, relapse-free survival (GFRFS) were 20%, 22.5%, 67%, 58%, and 51%, respectively. Pretransplantation disease status (complete remission versus others) was the main factor associated with OS, DFS, and GFRFS. In conclusion, the TBF conditioning regimen is an appealing platform in the haplo-HSCT setting with PT-Cy in terms of engraftment rate, toxicity, and disease control. We found no benefit of a thiotepa dose of 10 mg/kg compared with a dose of 5 mg/kg. ATG reduced the risk of acute GVHD without comprising outcomes., (Copyright © 2019. Published by Elsevier Inc.)

Background: Sorafenib has shown encouraging results in patients with Fms-like tyrosine kinase 3 (FLT3)-positive acute myeloid leukemia. Its role after allogeneic stem cell transplantation (HSCT) has been reported in a few cases with encouraging results., Methods: The authors describe the use of sorafenib as a maintenance agent after HSCT in 27 patients with FLT3-positive acute myeloid leukemia., Results: The median age of the patients was 46 years (range, 15-57 years). Sorafenib was introduced at a median of 70 days (range, 29-337 days) after HSCT. The median treatment duration was 8.4 months (range, 0.2-46 months). Eleven patients experienced treatment toxicities, mainly of grade 1 to 2 (graded according to the National Cancer Institute Common Toxicity Criteria [version 4.0]). Dose reduction or withdrawal was required in 4 patients and 4 patients, respectively. The persistence of toxicity prompted treatment withdrawal in 1 patient. Clinical improvement followed dose modifications. Thirteen patients experienced chronic graft-versus-host disease (limited in 9 patients and extensive in 4 patients), resulting in dose reduction in 5 patients followed by withdrawal in 1 of these individuals. At a median follow-up of 18 months (range, 4-48 months), 25 patients were alive (all of whom were in complete molecular remission) and 18 were still receiving treatment, with 1-year overall survival and progression-free survival rates of 92% ± 6% and 92% ± 5%, respectively., Conclusions: Sorafenib treatment after HSCT appears to be feasible and highly effective with dose individualization according to patient tolerability. Further analysis is needed to evaluate the immunomodulating role of sorafenib after HSCT. The data from the current support prospective controlled trials of sorafenib after HSCT. Cancer 2017;123:2867-74. © 2017 American Cancer Society., (© 2017 American Cancer Society.)

The outlook for adults with refractory and relapsed acute lymphocytic leukemia (ALL) is poor. CD52 is expressed in most patients with ALL. Alemtuzumab is an anti-CD52 humanized monoclonal antibody. This phase II study assessed the efficacy of alemtuzumab combined with granulocyte-colony stimulating factor (G-CSF) to boost antibody-dependent cell cytotoxicity mediated by neutrophils. Twelve patients with relapsed (n = 11) or refractory (n = 1) ALL, including four relapses postallogeneic stem cell transplantation, were treated and monitored between October 2006 and January 2011. Patients received 1 wk of alemtuzumab every other day at increasing doses of 3, 10, and 30 mg to test tolerance and 30 mg three times a week for 12-18 infusions. If in complete remission (CR), patients received maintenance therapy for 1 wk, every 2 months. G-CSF was administered at 5 μg/kg per day during alemtuzumab administration. The primary endpoint was disappearance of blast cells on a marrow aspirate. CD52 was expressed in all patients. Four patients reached CR. In one additional patient, clearance of blast cells was observed in peripheral blood but not in the marrow. The most frequent adverse events during course 1 of treatment were fever and chills (n = 3), skin rash (n = 3), and bronchospasm (n = 2). Tumor lysis syndrome was observed at treatment initiation in one patient who reached CR. All patients progressed within a few months and all but one died. The surviving patient is still alive after relapse and a second allogeneic stem cell transplantation. This study shows that in relapse/refractory ALL, alemtuzumab with G-CSF can produce good responses of short duration., (© 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: Reticulated platelets (RPs) are the youngest circulating platelets (PLTs). The aim of our study was to predict PLT recovery with RP percentage (RP%) and therefore to identify PLT transfusions that could be avoided after autologous peripheral blood progenitor cell (PBPC) transplantation., Study Design and Methods: With a whole-blood dual-labeling flow cytometric method, RP% was prospectively assessed in 47 patients who received myeloablative chemotherapy followed by autologous PBPC transplantation. Retrospective analysis of RP evolution identified three time points: nadir of the RP% (NRP), imminent PLT recovery (IPR) corresponding to an RP% of greater than 7 percent, and PLT transfusion autonomy (PTA)., Results: Median occurrences of NRP, IPR, and PTA were on Days +5, +8, and +12 after transplantation, respectively. The RP% value at NRP (4%) was significantly lower compared to the IPR (15%) and PTA (14%). Thirty patients (64%) achieved PTA within 4 days after IPR. On Day +8, if RP% was greater than 7 percent, positive and negative predictive values for PTA within 4 days, specificity, and sensitivity were 79, 63, 66, and 76 percent, respectively. Fever between IPR and PTA was the only factor found to negatively influence PLT recovery (p = 0.02). All patients required at least one PLT transfusion. Among patients with rapid PLT recovery (IPR-PTA interval < 4 days; n = 30), half of them received one PLT transfusion after RP increase, which could be avoided., Conclusion: These encouraging results may allow us to reduce the prophylactic PLT transfusion according to patients RP% increase.

Background: The present study evaluated the relative survival benefits associated with enasidenib and current standard of care (SoC) therapies for patients with relapsed/refractory (R/R) acute myeloid leukemia (AML) and an isocitrate dehydrogenase 2 (IDH2) mutation who are ineligible for hematopoietic stem cell transplantation (HSCT). Methods: Propensity score matching (PSM) analysis compared survival outcomes observed with enasidenib 100 mg daily in the phase I/II AG221‐C‐001 trial and SoC outcomes obtained from a real‐world chart review of patients in France. Results: Before matching, enasidenib (n = 195) was associated with numerically improved overall survival (OS) relative to SoC (n = 80; hazard ratio [HR], 0.82; 95% confidence interval [CI], 0.61–1.11). After matching and adjusting for covariates (n = 78 per group), mortality risk was significantly lower with enasidenib than with SoC (HR, 0.67; 95% CI, 0.47–0.97). The median OS was 9.26 months for enasidenib (95% CI, 7.72–13.24) and 4.76 months for SoC (95% CI, 3.81–8.21). Results remained robust across all sensitivity analyses conducted. Conclusions: PSM analyses indicate that enasidenib significantly prolongs survival relative to SoC among patients with R/R AML and an IDH2 mutation who are ineligible for HSCT. Future prospective studies are needed to validate these findings using other data sources and to assess the comparative efficacy of enasidenib for other treatment outcomes. [ABSTRACT FROM AUTHOR]

The results of conventional allogeneic stem cell transplantation (SCT) in refractory hematologic malignancies are poor. Sequential strategies have shown promising results in refractory acute myelogenous leukemia (AML), but have not been validated in a haploidentical (Haplo) transplant setting. We have developed a new sequential approach combining chemotherapy with broad antitumor activity (thiotepa 10 mg/kg, etoposide 400 mg/m 2 , and cyclophosphamide 1600 mg/m 2 from day -15 to day -10), followed after 3 days of rest by a reduced-intensity conditioning regimen (fludarabine 150 mg/m 2 , i.v. busulfan 6.4 mg/kg, and thymoglobulin 5 mg/kg from day -6 to day -2). High-dose post-transplantation cyclophosphamide was added in cases with Haplo donors. Seventy-two patients (median age, 54 years) with a refractory hematologic malignancy (44 with acute myelogenous leukemia, 7 with acute lymphoblastic leukemia, 15 with myelodysplastic syndrome/myeloproliferative neoplasms, and 6 with lymphomas) were included in this retrospective multicenter study. Donors were Haplo (n = 27), matched related (MRD; n = 16), and unrelated (UD; n = 29). With a median follow-up of 21 months, the 2-year overall survival (OS) and event-free survival (EFS) were 54.7% and 49.3%, respectively, in recipients of Haplo transplants, 49.2% and 43.8%, respectively, in recipients of MRD transplants, and 37.9% and 28%, respectively, in recipients of UD transplants. Compared with UD, the outcomes were improved in Haplo in terms of the incidences of acute grade II-IV graft-versus-host disease (GVHD) (11.1% versus 41.4%; P  < .001) and GVHD-free, relapse-free survival (44.4 versus 10.3%; P  = .022). These results support the safety and efficacy of a thiotepa-based sequential approach in allogeneic SCT with a Haplo donor with post-transplantation immune modulation. Thus, in patients with refractory hematologic malignancies, there seems to be no benefit in searching for a UD when a Haplo donor is readily available. [ABSTRACT FROM AUTHOR]