Allogeneic blood or marrow transplantation using haploidentical grandchildren donors and post-transplant cyclophosphamide-based graft-versus-host disease prophylaxis.

BACKGROUND: High-dose post-transplant cyclophosphamide allows safe and effective use of allografts from haploidentical relatives (siblings, parents and children) in patients undergoing allogeneic blood or marrow transplant (alloBMT). More recently, second- and third-degree relatives have also been shown to be safe allograft donors. An increasing number of older patients undergoing alloBMT have been receiving allografts from haploidentical donors. However, older patients are more likely to have older siblings and children, and older donor age is associated with worse outcomes. OBJECTIVE: In the current study, we report the safety and utility of grandchildren as haploidentical donors and compared with children as donors in patients undergoing alloBMT. METHODS: We compared characteristics and outcomes of alloBMT patients aged 55 years and older with children older than 30 years as donors (C group; n = 276) and those with grandchildren as donors (GC group; n = 40). Because many important baseline characteristics predict outcomes after alloBMT, we performed propensity score matched analysis based on recipient age, alloBMT year, disease, graft source and haematopoietic cell transplantation comorbidity index (HCT-CI). RESULTS: The median age of recipients was 67 years (range 55-79) in the C group and 73 years (range 57-78) in the GC group. More than 70% of recipients in the GC group were older than 70 years, compared with 27% in the C group. The median donor age was 37 years (range 31-52) in the C group and 20 years (range 14-34) in the GC group. More patients in the GC group had HCT-CI scores ≥3 than in the C group (32.5% vs. 23%, p = 0.27). Two-year overall survival did not differ between the two groups (GC 62% vs. C 60%, hazard ratio [HR] 0.96, 95% confidence interval [CI] 0.53-1.75, p = 0.90) despite recipients of allografts from grandchildren being older. The 2-year RFS was 55% in the C group compared with 50% in the GC group (HR 1.05, 95% CI 0.62-1.77, p = 0.85). Non-relapse mortality subdistribution [SD] (SDHR 1.36, 95% 0.70-2.63, p = 0.36), relapse (SDHR 0.72, 95% CI 0.33-1.58, p = 0.42) or relapse-free survival (HR 1.05, 95% CI 0.62-1.77, p = 0.85). Propensity score matching analysis showed no significant differences in 2-year overall survival (GC 64% vs. C 53%; HR 0.77, 95% CI 0.42-1.42, p = 0.40), non-relapse mortality (SDHR 1.26, 95% 0.66-2.41, p = 0.48), relapse (SDHR 0.57, 95% CI 0.21-1.52, p = 0.26) or relapse-free survival (HR 0.94, 95% CI 0.57-1.54, p = 0.81). CONCLUSION: Our results indicate that outcomes of alloBMT patients with grandchild donors are similar to those with child donors, despite recipients' older age and higher comorbidities in the GC group. Grandchildren should be considered when selecting a donor for older alloBMT recipients.

Allogeneic stem cell transplantation for inherited metabolic disorders: 35 years' experience at a single institution.

Hematopoietic stem cell transplants for inherited metabolic disorders performed at Tokai University Hospital between June 5, 1986, and May 28, 2021, were analyzed and compared between the period before 2007 and the period from 2007 onward based on availability of medical resources. Transplants were performed for 38 patients with mucopolysaccharidosis, 33 with adrenoleukodystrophy, and 16 with another disorder. Before 2007, oral busulfan-based regimens were mainly used. From 2007 onward, intravenous busulfan-based regimens or 4 Gy of thoracoabdominal irradiation (TAI), fludarabine, and melphalan (Mel)/treosulfan were adopted. Between 2002 and 2010, adrenoleukodystrophy was treated with 12 Gy of TAI and Mel. HLA-identical sibling bone marrow was used in 43% of cases before 2007 and 15% from 2007 onward, while alternative donors were selected for other transplants. Overall survival and event-free survival (EFS) before 2007 and from 2007 onward were 76% and 62%, and 97% and 85%, respectively (P = 0.006 and 0.017). Transplant era predicted superior overall survival and EFS, while myeloablative conditioning also predicted EFS. The incidence of primary graft failure decreased from 2007 onward, especially in cord blood transplant when 4 Gy of TAI with 150 mg/m2 fludarabine and 180 mg/m2 Mel or 42 g/m2 treosulfan were used as conditioning.

Allogeneic Stem Cell Transplantation in Refractory Acute Myeloid Leukaemia.

Refractory acute myeloid leukaemia is very difficult to treat and represents an unmet clinical need. In recent years, new drugs and combinations of drugs have been tested in this category, with encouraging results. However, all treated patients relapsed and died from the disease. The only curative option is allogeneic transplantation through a graft from a healthy donor immune system. Using myeloablative conditioning regimens, the median overall survival regimens is 19%. Several so-called sequential induction chemotherapies followed by allogeneic transplantation conditioned by reduced intensity regimens have been developed, improving the overall survival to 25-57%. In the allogeneic transplantation field, continuous improvements in practices, particularly regarding graft versus host disease prevention, infection prevention, and treatment, have allowed us to observe improvements in survival rates. This is true mainly for patients in complete remission before transplantation and less so for refractory patients. However, full myeloablative regimens are toxic and carry a high risk of treatment-related mortality. In this review, we describe the results obtained with the different modalities used in more recent retrospective and prospective studies. Based on these findings, we speculate how allogeneic stem cell transplantation could be modified to maximise its therapeutic effect on refractory acute myeloid leukaemia.

Graft failure after allogeneic hematopoietic stem cell transplantation in pediatric patients with acute leukemia: autologous reconstitution or second transplant?

BACKGROUND: Graft failure (GF) is a rare but serious complication after allogeneic hematopoietic stem cell transplantation (HSCT). Prevention of graft failure remains the most advisable approach as there is no clear recommendation for the best strategies for reversing this complication. Administration of growth factor, additional hematopoietic progenitor boost, or a salvage HSCT are current modalities recommended for the treatment of GF. Autologous recovery without evidence of disease relapse occurs rarely in patients with GF, and in the absence of autologous recovery, further salvage transplantation following a second conditioning regimen is a potential treatment option that offers the best chances of long-term disease-free survival. The preconditioning regimens of second HSCT have a significant impact on engraftment and outcome, however, currently there is no consensus on optimal conditioning regimen for second HSCT in patients who have developed GF. Furthermore, a second transplant from a different donor or the same donor is still a matter of debate. OBSERVATIONS: We present our experience in managing pediatric patients with acute leukemia who encountered graft failure following stem cell transplantation. CONCLUSIONS AND RELEVANCE: Although a second transplantation is almost the only salvage method, we illustrate that some pediatric patients with acute leukemia who experience graft failure after an allogeneic stem cell transplant using Myeloablative conditioning (MAC) regimen may achieve long-term disease-free survival through autologous hematopoiesis recovery.

Graft Failure Incidence, Risk Factors, and Outcomes in Patients Undergoing Non-Myeloablative Allogeneic Hematopoietic Cell Transplantation Using Post-Transplant Cyclophosphamide.

Graft failure (GF) is a major complication of allogeneic hematopoietic cell transplantation (alloHCT) that results in significant morbidity and mortality. Post-transplant cyclophosphamide (PTCy)-based graft-versus-host disease (GVHD) prophylaxis has emerged as an effective regimen across the spectrum of donor-match settings, but few studies have investigated the characteristics of GF in the setting of PTCy-based GVHD prophylaxis. The objective was to detail the incidence, clinical features, risk factors, and outcomes for patients with primary graft failure (PGF) and secondary graft failure (SGF). In this retrospective study at a single institution, 958 consecutive patients undergoing first nonmyeloablative (NMA) alloHCT with PTCy-based GVHD prophylaxis were analyzed. PGF was defined as a failure to achieve an ANC ≥ 500 cells/m3 by day 30 of transplant in the absence of residual disease. SGF was defined as complete loss of donor chimerism after initial engraftment. The incidences of PGF and SGF were 3.8% (n = 37) and 1.8% (n = 17), respectively. Neither PGF nor SGF were associated with HLA disparity. In a multivariate analysis, risk factors for PGF in this cohort included age ≥ 65 (OR 2.4, 95% CI 1.2 to 4.8, P = .0120), an underlying diagnosis of MDS, MPN, or MDS/MPN overlap (OR 2.8, 95% CI 1.4 to 5.7, P = .0050), post-transplant viremia with HHV-6 (OR 2.9, 95% CI 1.5 to 5.7, P = .0030), and low CD34+ dose (OR 0.7, 95% CI 0.5 to 0.9, P = .0080). Patients with PGF had poor overall survival, driven primarily by a high rate of nonrelapse mortality (59% at 36 months). SGF was associated with use of a bone marrow graft source and a diagnosis of Hodgkin lymphoma. Patients with SGF had excellent clinical outcomes with only one of seventeen patients experiencing relapse and relapse-related mortality. The incidence of PGF and SGF in patients receiving NMA conditioning and PTCy is low and is not impacted by HLA disparities between donors and recipients. PGF is more common in recipients with age ≥ 65, a diagnosis of MDS, MPN, or MDS/MPN-overlap, post-transplant HHV-6 viremia, and low CD34+ cell dose. Low total nucleated cell dose is also a risk factor for PGF in patients receiving a bone marrow graft source. Patients who experience PGF have poor outcomes due to high rates of nonrelapse mortality, whereas patients who experience SGF have excellent long-term outcomes.

Significant impact of antibiotic exposure on GI-GVHD, NRM, and GRFS following allogeneic HCT with non-myeloablative Flu-TBI conditioning.

BACKGROUND: Acute gastro-intestinal graft-versus-host disease (GI-GVHD) and non-relapse mortality (NRM) after allogeneic HCT are closely related to loss of microbial diversity and intestinal dominance by single taxa resulting from the use of antibiotics, dietary changes, and mucosal barrier injury. There is a paucity of data on the impact of use of antibiotics in HCT after Flu-TBI-based non-myeloablative (NMA) conditioning where there is absence of mucositis and limited malnutrition. METHODS: We did a retrospective single-center analysis of patients receiving Flu-TBI-based NMA HCT for a high-grade myeloid malignancy, mostly AML, and MDS, or acute lymphoblastic leukemia (ALL). We analyzed the impact of pre-engraftment antibiotic exposure, prophylactic ciprofloxacin, and or treatment with broad-spectrum cephalosporin/carbapenem, on HCT outcomes, with a focus on the incidence of acute GI-GVHD by day 180 and NRM at 1 year. RESULTS: A total of 150 patients were evaluable with a median age of 62 years. Antibiotics were used in 90 patients; 60 prophylactic use only and 30 therapeutic use with or without previous prophylaxis. Antibiotic use resulted in a significant higher incidence of GI-GVHD Stage 1-4; 29% (26/90) versus 5% (3/60) in those not receiving antibiotics (OR 8.1 (95% CI 2.3-28.3), p = 0.001). Use of antibiotics resulted in higher 1-year NRM (19% (17/90) versus 10% (6/60), HR 2.3, p = 0.06), and decreased 2-year GRFS (42% (38/90) versus 55% (33/60), HR 1.7, p = 0.04), but did not impact RFS or OS. CONCLUSIONS: Use of antibiotics was related to the occurrence of GI-GVHD, NRM, and GRFS in patients receiving truly NMA HCT. Therefore, in the absence of mucositis and low incidence of bacteremia, antibiotics can and should be used restrictively in this setting.

Graft CD8 T-cell-based risk system predicts survival in antithymocyte globulin-based myeloablative haploidentical peripheral blood stem cell transplantation.

Objective: This study investigated the cellular composition of peripheral blood grafts for anti-thymocyte globulin (ATG)-based myeloablative haploidentical haematopoietic stem cell transplantation (haplo-HSCT). Methods: Clinical characteristics were retrospectively evaluated in a training cohort with ATG-based myeloablative haplo-HSCT between January 2016 and February 2020 and confirmed in a validation cohort between March 2020 and June 2021. Results: A higher dose of graft CD8+ T cells (≥ 0.85 × 108 kg-1) was significantly improved overall survival (OS; hazard ratio [HR], 1.750; P = 0.002) and disease-free survival (DFS; HR, 1.751; P < 0.001) in the training cohort, according to multivariate Cox regression analysis. Higher doses of mononuclear cells (MNCs) demonstrated better OS (HR, 1.517; P = 0.038) and DFS (HR, 1.532; P = 0.027). Older patient age (> 46 years), older donor age (≥ 50 years) and a higher refined disease risk index (rDRI) were also related to OS. A graft CD8+ T-cell risk system based on graft CD8+ T-cell dose, donor age and rDRI was constructed using a nomogram model after LASSO Cox regression analysis. It showed acceptable discrimination, with a C-index of 0.62 and 0.63, respectively. Graft CD8+ T-cell dose was negatively correlated with donor age (P < 0.001) and positively correlated with a higher lymphocyte percentage in the peripheral blood before mobilisation (P < 0.001). Conclusion: A higher CD8+ T-cell dose in peripheral blood-derived grafts improves patients' survival with ATG-based myeloablative haplo-HSCT. Younger donors with higher lymphocyte percentages improved patients' survival with an intermediate rDRI risk.

Feasibility of allogeneic hematopoietic stem cell transplantation in advanced age.

Although it is known that increasing age is associated with increased morbidity and mortality in allogeneic transplantation (allo-HSCT), individualization of the process may allow to perform it in progressively older patients.This study analyzed the outcome of 97 patients older than 60 years with a first allo-HSCT performed at our institution between 2011 and 2019.Median age was 66 years (range 60-79) and 15.4% were older than 70 years. The most frequent diagnosis was acute leukemia (50.5%), and 58.8% received a myeloablative conditioning. With a median follow-up of 33.9 months (range 7.9-111.5), at 3-years overall survival (OS) was 50%; progression-free survival (PFS), 46%; cumulative incidence of relapse, 22%; and non-relapse mortality (NRM), 32%. There were no significant differences in OS (p = 0.415), PFS (p = 0.691), cumulative incidence of relapse (p = 0.357) or NRM (p = 0.658) between patients of 60-64 years (n = 37), 65-69 (n = 45) and ≥ 70 years (n = 15). No differences were observed either depending on the intensity of the conditioning regimen in terms of OS (p = 0.858), PFS (p = 0.729), cumulative incidence of relapse (p = 0.416) or NRM (p = 0.270).In conclusion, older adults can safely and effectively undergo allo-HSCT with proper patient selection and individualized transplantation procedures.

Myeloablative or reduced-intensity/non-myeloablative hematopoietic cell transplantation for Philadelphia-positive acute lymphoblastic leukemia in adults older than 40 years old - a secondary analysis of a CIBMTR database.

Few studies have addressed the role of reduced-intensity conditioning (RIC) and non-myeloablative (NMA) regimens in older adults with Philadelphia acute lymphoblastic leukemia (Ph + ALL). The objective of this current study was to compare the outcomes of RIC/NMA versus TBI-based myeloablative (MAC) regimens in Ph + ALL patients older than 40 years old who underwent hematopoietic cell transplantation (HCT) in CR1. We used a freely available database from the CIBMTR. Transplants were performed between 2013 and 2017. With a median follow-up of 37.6 months, we have included 629 patients. We used propensity score weighting. Three-year OSs were 64% in the TBI-MAC group and 66% in the RIC/NMA group. OS was not different (HR = 0.92; p = 0.69). Three-year relapse incidences were 21.6% and 27.6% in the TBI-MAC and RIC/NMA groups. RIC/NMA was not associated with an increase in relapse rate (HR 1.02; p = 0.91). Three-year NRMs were 24.3% in the TBI-MAC group and 20.3% in the RIC/NMA group. RIC/NMA was not associated with superior NRM (HR 0.88; p = 0.57). In summary, we have shown that RIC/NMA regimens achieve outcomes comparable to TBI-based MAC in Ph+ ALL older patients in CR1 who may tolerate a TBI-based MAC regimen.

Effect of Conditioning Regimens and Graft-versus-Host Disease Prophylaxis on the Outcomes of Umbilical Cord Blood Transplantation Performed with Cyclophosphamide/Total Body Irradiation-Based Regimens.

Umbilical cord blood (UCB) is a valuable alternative donor source for allogeneic hematopoietic stem cell transplantation. Various conditioning regimens and graft-versus-host disease (GVHD) prophylaxis regimens aimed at improving the outcomes of umbilical cord blood transplantation (UCBT) have been explored; however, the differences in their effects remain unclear. This study was conducted to elucidate the differences in the effects of conditioning and GVHD prophylaxis regimens on UCBT outcomes by disease type in a nationwide, retrospective study. We retrospectively analyzed the effects of conditioning and GVHD prophylaxis regimens on the outcomes of UCBT performed with cyclophosphamide (Cy)/total body irradiation (TBI)-based regimens in patients with acute myeloid leukemia (AML; n = 1126), acute lymphoblastic leukemia (ALL; n = 620), myelodysplastic syndrome (MDS; n = 170), and lymphoma (n = 128). Multivariate analysis for overall survival (OS) demonstrated the benefit of adding high-dose cytarabine to the Cy/TBI regimen for the AML group (relative risk [RR], .76; P = .003) and lymphoma group (RR, .54; P = .02), but not for the ALL and MDS groups. In the ALL group, adding etoposide to the Cy/TBI regimen was associated with a lower OS (RR, 1.45; P = .03). For GVHD prophylaxis, a tacrolimus/methotrexate regimen was associated with a lower OS compared with a cyclosporine/methotrexate regimen in the AML group (RR, 1.26; P = .01); this difference was not observed in the other groups. These differences in OS according to the conditioning and GVHD prophylaxis regimen were attributable mainly to differences in relapse risk. Our data show that the effects of conditioning regimens and GVHD prophylaxis on UCBT outcomes differed according to disease type. UCBT outcomes could be improved by selecting optimal conditioning regimens and GVHD prophylaxis for each disease type.

Prognostic implication of pre-transplant FEV1 on long-term outcomes following allogeneic hematopoietic stem cell transplantation.

BACKGROUND: Pre-transplant pulmonary function testing (PFT) is essential before allogeneic hematopoietic stem cell transplant (HCT), yet the optimal cutoff value for affecting transplant outcomes remains poorly defined. STUDY DESIGN: Retrospective analysis of pre-HCT PFT data from 605 consecutive patients at the Princess Margaret Cancer Centre between January 1, 2004 and December 31, 2013 used binary recursive partitioning to identify cutoff values for overall survival (OS) as an endpoint of transplant outcomes. These values were compared to HCT comorbidity index (HCT-CI) FEV1 cutoffs for OS, cumulative incidence of relapse and non-relapse mortality. RESULTS: FEV1 ≥ 81% was the identified cutoff point. The OS rate at 3 years showed 49.8% (FEV1 ≥ 81%) vs. 36.6% (<81%, p < .001). For HCT-CI cutoffs, the OS rate at 3 years for FEV1 ≥ 80%, 66%-80% and ≤65% were 49.0%, 38.1% and 37.6% (p = .011), respectively. Multivariate analysis confirmed that FEV1 ≥ 81% predicted reduced mortality (HR 0.682, p = .001). Subgroup analysis showed both FEV1 ≥ 81% and FEV1 by HCT-CI cutoffs may stratify patients according to OS and NRM risk in subgroups receiving myeloablative, but not reduced intensity conditioning. CONCLUSION: FEV1 ≥ 81% can predict OS and NRM in our cohort and is potentially simpler when risk stratifying patients undergoing allogeneic HCT, particularly those receiving myeloablative conditioning.

Allogeneic stem cell transplant outcomes between TBI-containing reduced intensity and myeloablative conditioning regimens for ALL in complete remission.

Total-body irradiation (TBI)-based conditioning regimen is preferred in acute lymphoblastic leukemia (ALL). We retrospectively evaluated allogeneic stem cell transplant (alloSCT) outcomes of 86 adult ALL patients in complete remission (CR) who received TBI-containing reduced intensity (RIC) (Flu/Mel/TBI = 31) and myeloablative conditioning (MAC) (VP16/TBI = 47; CY/TBI = 8) between January 2005 and December 2019. All patients received peripheral blood allografts. Patients in the RIC group were older than the MAC group (61 years old versus 36 years, p < .001). Donor was 8/8 HLA-matched in 83% and unrelated in 65% of patients. Three-year survival was 56.04% for RIC and 69.9% for MAC (HR 0.64; p = .19). Propensity score-based multivariable Cox analyses (PSCA) did not demonstrate any difference in grade III-IV acute graft versus host disease (GVHD) (SHR 1.23, p = .91), chronic GVHD (SHR 0.92, p = .88), survival (HR 0.94, p = .92), and relapse-free survival (HR 0.66, p = .47) between both groups, while relapse rate was lower (SHR 0.21, p = .02) for MAC compared to RIC. Our study did not demonstrate any difference in survival for TBI-containing RIC and MAC alloSCT for adult ALL in CR.

Sequence matters: Total body irradiation (TBI)-based myeloablative conditioning with post-transplant cyclophosphamide may reduce the early nonrelapse mortality compared with pretransplant cyclophosphamide plus TBI.

OBJECTIVES: High-dose total body irradiation (TBI) is considered a cornerstone of myeloablative conditioning for allogeneic stem cell transplantation (allo-SCT). We retrospectively compared the main outcomes of an HLA matched or 1-allele mismatched related or unrelated allo-SCT in adult patients affected by acute leukemia (AL) or myelodysplastic syndromes (MDS). METHODS: Fifty-nine patients received cyclophosphamide (Cy)-TBI (13.5 Gy) and graft-versus-host disease (GVHD) prophylaxis with a calcineurin-inhibitor plus methrotrexate (CyTBI group) and 28 patients received fludarabine-TBI (8.8-13.5 Gy) and GVHD prophylaxis with PTCy and tacrolimus (FluTBI-PTCy group). RESULTS: Median follow-up for survivors was 82 and 22 months. The 12-month probability of overall survival and progression-free survival were similar (p = .18, p = .7). The incidence of Grades 2-4 and 3-4 acute GVHD, and the incidence of moderate-to-severe chronic GVHD were higher in the CyTBI group (p = .02, p < .01and p = .03). Nonrelapse mortality (NRM) at 12 months posttransplant was higher in the CyTBI group (p = 0.05), while the incidence of relapse was similar in both groups (p = 0.7). The number of GVHD-free and relapse-free patients without systemic immunosuppression (GRFS) at 1-year posttransplant was higher in the FluTBI-PTCy group (p = 0.01). CONCLUSIONS: The study confirms the safety and efficacy of a novel FluTBI-PTCy platform with reduced incidence of severe acute and chronic GVHD, and early improvement of NRM.

Appropriate pre-transplant strategy for patients with myelodysplastic syndromes receiving allogeneic haematopoietic stem cell transplantation after myeloablative conditioning.

Purpose: Appropriate pre-transplant strategies in patients with myelodysplastic syndromes (MDS) remain challenging. We sought to assess the effect of different pre-transplant therapies and transplantation interval times on patient prognosis. Methods: We retrospectively analysed clinical data for 371 consecutive MDS patients after myeloablative transplantation between 2007 and 2019. Results: The median age of the patients was 38 years (range, 12-64 years). A total of 114 patients (31%) received supportive care (SC), 108 (29%) hypomethylating agents (HMAs), and 149 (40%) chemotherapy-based therapy before transplantation. In patients who received HMA or SC, there was no significant difference in overall survival (OS; P=0.151) or relapse-free survival (RFS; P=0.330), except that HMA-treated patients had a lower rate of non-relapse mortality (5-year NRM: 18% vs. 32%, P=0.035). However, compared with patients who received HMA, those who received chemotherapy-based therapy had a lower 5-year OS rate (56% vs. 69%, P=0.020) and a slightly higher 5-year NRM rate (28% vs. 18%, P=0.067). Compared to the delayed transplant group (transplant interval ≥6 months), the early transplant group (transplant interval <6 months) had a superior 5-year OS (66% vs. 51%, P=0.001) and a lower 5-year cumulative incidence of NRM (22% vs. 36%, P=0.001). Conclusion: The findings of the study indicate that receiving an appropriate pre-transplant strategy (SC/HMA + <6 months) significantly improves OS and decreases NRM in MDS patients after myeloablative transplantation.

Addition of venetoclax to myeloablative conditioning regimens for allogeneic hematopoietic stem cell transplantation in high-risk AML.

BACKGROUND: Venetoclax monotherapy is an effective option for patients with acute myeloid leukemia (AML). Venetoclax has also been used in non-myeloablative conditioning allogeneic hematopoietic stem cell transplantation (allo-HSCT) for high-risk AML with a tolerable toxicity profile. However, the efficacy and safety of a venetoclax-containing myeloablative conditioning (MAC) allo-HSCT regimen for high-risk AML have not been evaluated. OBJECTIVE: To evaluate the safety and efficacy of a MAC regimen containing venetoclax for high-risk AML. STUDY DESIGN: From 25 February 2021 to 4 September 2022, a total of 31 patients with high-risk AML who underwent allo-HSCT and a MAC regimen with venetoclax were analyzed. RESULTS: At the time of transplantation, 21 patients were in first complete remission (CR1), 4 were in a second complete remission (CR2), and 6 in non-remission (NR). Twenty-four patients (77.4%) were minimal residual disease (MRD)-positive before transplant. The FLT3-ITD gene mutation was present in 51.6% of patients. NUP98 rearrangement, MLL rearrangement or MLL-PTD and DEK::CAN fusion genes were found in 5 (16.1%), 7(22.6%) and 2 (6.5%) patients, respectively. Twenty-nine (93.6%) patients underwent haploidentical allo-HSCT. The median follow-up time was 278 days (range: 52-632 days). The 100-day cumulative incidence of grade 3 to 4 acute graft-versus-host disease (aGVHD) was 16.1% (95%CI, 7.2-36.0%). The 180-day cumulative incidence of moderate to severe chronic graft-versus-host disease (cGVHD) was 7.1% (95%CI, 1.9-26.9%). Cumulative incidence of 100-day cytomegalovirus (CMV) viraemia and 100-day Epstein-Barr virus (EBV) viraemia was 61.6% (95%CI, 46.5-81.4%) and 3.2% (95%CI, 0.4-22.2%), respectively. The 600-day overall survival (OS) and leukemia-free survival (LFS) were 80.9% (95%CI, 63.5-93.6%) and 81.3% (95%CI, 64.2-93.7%), respectively. The 600-day relapse incidence (RI) and non-relapse mortality (NRM) was 6.9% (95%CI, 1.8-26.3%) and 11.7% (95%CI, 3.9-35.0%). CONCLUSION: Our study shows that the addition of venetoclax to a MAC allo-HSCT was feasible, safe and effective for high-risk AML patients.

Busulfan, fludarabine, and melphalan are effective conditioning for pediatric and young adult patients with myeloid malignancies underdoing matched sibling or alternative donor transplantation.

BACKGROUND: Allogeneic hematopoietic cell transplantation (allo-HCT) remains a curative option for patients with high-risk myeloid malignancies. PROCEDURE: We present our 10-year experience (October 2012 to October 2021) of consecutive allo-HCT in patients with myeloid malignancies treated on the pediatric HCT service and conditioned with myeloablative targeted dose-busulfan (BU), fludarabine (FLU), and melphalan (MEL). Twenty-three children, adolescents, and young adult patients (CAYA) (median age 15.4 years) with acute myeloid leukemia (AML, n = 17), myelodysplastic syndrome (MDS, n = 4), or chronic myeloid leukemia (CML, n = 2) underwent allo-HCT post-BU-FLU-MEL. Four patients had treatment-related AML/MDS. Donor/stem cell source was matched sibling donor (MSD) PBSC (n = 7), matched unrelated donor (MUD) PBSC (n = 2), umbilical cord blood (UCB) (n = 3), or haploidentical-BMT (n = 11). Risk stratification was low (n = 2), intermediate (n = 15), high (n = 3), and very high risk (n = 1). The two patients with CML had failed tyrosine kinase inhibitor therapies. RESULTS: With a median follow-up of 41.6 months, the relapse rate is only 4.5% with an overall survival (OS) 100%, progression-free survival (PFS) 95.5%, and graft-versus-host-free-relapse-free survival (GRFS) 67.8%. The donor source and the acute graft-versus-host disease (GvHD) prophylaxis regimen significantly impacted grade II-IV aGvHD 66.7% versus 19.2% (p = .039) and chronic graft-versus-host-disease (cGvHD) 66.7% versus 0% (p = .002) in the patients receiving MSD or MUD PBSC compared to haplo-BMT, respectively, resulting in improved GRFS in haplo-BMT, 83.3% compared to 40% matched donor peripheral blood stem cell transplant (PBSCT) (p = .025). CONCLUSIONS: Our results demonstrate that BU-FLU-MEL is efficacious conditioning for disease control in young patients with myeloid malignancies undergoing MSD or alternative donor allo-HCT, but in the setting of PBSC grafts with cyclosporine A-methotrexate (CSA-MTX) GvHD prophylaxis, it results in an unacceptably high incidence of GvHD.

Phase I trial of myeloablative conditioning with 3-day total marrow and lymphoid irradiation for leukemia.

This prospective phase I trial aimed to determine the recommended dose of 3-day total marrow and lymphoid irradiation (TMLI) for a myeloablative conditioning regimen by increasing the dose per fraction. The primary end-point of this single-institution dose escalation study was the recommended TMLI dose based on the frequency of dose-limiting toxicity (DLT) ≤100 days posthematopoietic stem cell transplantation (HSCT); a 3 + 3 design was used to evaluate the safety of TMLI. Three dose levels of TMLI (14/16/18 Gy in six fractions over 3 days) were set. The treatment protocol began at 14 Gy. Dose-limiting toxicities were defined as grade 3 or 4 nonhematological toxicities. Nine patients, with a median age of 42 years (range, 35-48), eight with acute lymphoblastic leukemia and one with chronic myeloblastic leukemia, received TMLI followed by unrelated bone marrow transplant. The median follow-up period after HSCT was 575 days (range, 253-1037). Three patients were enrolled for each dose level. No patient showed DLT within 100 days of HSCT. The recommended dose of 3-day TMLI was 18 Gy in six fractions. All patients achieved neutrophil engraftment at a median of 19 days (range, 14-25). One-year overall and disease-free survival rates were 83.3% and 57.1%, respectively. Three patients experienced relapse, and no nonrelapse mortality was documented during the observation period. One patient died due to disease relapse 306 days post-HSCT. The recommended dose of 3-day TMLI was 18 Gy in six fractions. The efficacy evaluation of this regimen is currently being planned in a phase II study.

Clofarabine and Busulfan Myeloablative Conditioning in Allogeneic Hematopoietic Cell Transplantation for Patients With Active Myeloid Malignancies.

Patients with refractory or relapsed and refractory myeloid malignancies have a poor prognosis. Allogeneic hematopoietic cell transplantation (HCT) with myeloablative conditioning (MAC) in patients with active, chemotherapy-refractory myeloid disease is historically associated with high rates of relapse and nonrelapse mortality (NRM). A MAC regimen combining clofarabine with busulfan (Clo/Bu4) has been reported to exhibit antileukemic activity with acceptable toxicity in patients age ≤70 years. Here we describe the clinical outcomes of a real-world population of patients with active myeloid malignancies undergoing allogeneic HCT with Clo/Bu4 MAC. In a single-center retrospective descriptive analysis, we identified patients who underwent HCT for myeloid malignancies not in remission using Clo/Bu4 MAC between 2012 and 2020. We report event-free survival (EFS) and overall survival (OS), cumulative incidences of relapse and NRM, and the incidence and severity of acute and chronic graft-versus-host disease (GVHD). We identified 69 patients with a median age of 60 years (range, 22 to 70 years). Most patients had relapsed/refractory or primary refractory acute myelogenous leukemia (AML; n = 55) or refractory myelodysplastic syndrome (MDS; n = 12); 1 patient had chronic myelogenous leukemia, and 1 patient had a blastic plasmacytoid dendritic cell neoplasm. Fifty patients (72.5%) had complete remission at day 100 post-transplantation. Two-year EFS and OS were 30% (95% confidence interval [CI], 20% to 44%) and 40% (95% CI, 29% to 54%), respectively. Patients with AML had a 2-year EFS and OS of 28% (95% CI, 18% to 44%) and 38% (95% CI, 27% to 54%), respectively; those with MDS had a 2-year EFS and OS of 47% (95% CI, 25% to 88%) and 56% (95% CI, 33% to 94%), respectively. The cumulative incidence of relapse at 2 years was 39% (95% CI, 27% to 51%) for all patients, including 45% (95% CI, 31% to 58%) in the patients with AML and 18% (95% CI, 2% to 45%) in those with MDS. NRM at 2 years was 31% (95% CI, 20% to 42%), including 27% (95% CI, 15% to 39%) in patients with AML and 35% (95% CI, 10% to 63%) in those with MDS. The total incidence of acute GVHD (aGVHD) of any severity was 80%, and the incidence of grade III-IV aGVHD was 22%. In patients who achieved remission, those who required systemic immunosuppression for aGVHD (58%) had poorer 2-year EFS (29% versus 54%; P = .05) and 2-year OS (39% versus 70%; P = .04) compared to those who did not. The 2-year cumulative incidence of chronic GVHD was 44% (95% CI, 28% to 58%). Clo/Bu4 MAC followed by allogeneic HCT for patients with active myeloid malignancies is an effective transplantation strategy for patients up to age 70, particularly those with advanced MDS. The high incidence of and poor outcomes associated with aGVHD highlight the importance of optimizing preventative strategies.