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Reduced-intensity/reduced-toxicity conditioning and allogeneic T-cell replete hematopoietic stem cell transplantation are curative in patients with hemophagocytic lymphohistiocytosis (HLH). Unstable donor chimerism (DC) and relapses are clinical challenges . We examined the effect of a reduced-intensity conditioning regimen based on targeted busulfan to enhance myeloid DC in HLH. The European Society for Bone and Marrow Transplantation–approved reduced-intensity conditioning protocol comprised targeted submyeloablative IV busulfan, IV fludarabine, and serotherapy comprising IV alemtuzumab (0.5-0.8 mg/kg) for unrelated-donor and IV rabbit anti–T-cell globulin for related-donor transplants. We assessed toxicity, engraftment, graft-versus-host disease (GHVD), DC in blood cell subtypes, and overall survival/event-free survival. Twenty-five patients from 7 centers were treated (median age, 0.68 year). The median total dose and cumulative area under the curve of busulfan was 13.1 mg/kg (6.4-26.4) and 63.1 mg/L × h (48-77), respectively. Bone marrow, peripheral blood stem cell, or cord blood transplants from HLA-matched related (n = 7) or unrelated (n = 18) donors were administered. Donor cells engrafted in all patients (median: neutrophils d+20/platelets d+28). At last follow-up (median, 36 months; range, 8-111 months), the median DC of CD15(+) neutrophils, CD3(+) T cells, and CD16(+)56(+) natural killer cells was 99.5% (10-100), 97% (30-100), and 97.5% (30-100), respectively. Eight patients (32%) developed sinusoidal obstruction syndrome, resolving after defibrotide treatment. The 3-year overall survival and event-free survival rates were both 100%. None of the patients developed acute grade III to IV GHVD. Limited chronic GVHD was encountered in 4%. This regimen achieves excellent results with stable DC in patients with HLH.

Introduction: High relapse rate and transplant-related mortality (TRM) are the major obstacles for the second allogeneic hematopoietic stem cell transplantation (allo-HSCT). Reduced-toxicity conditioning (RTC) can decrease TRM and healthier donor may provide stronger anti-leukemia and anti-infection effects. Objective:In current clinical study, the safety and efficacy of the second allo-HSCT with RTC and donor change were examined. Methods: Between April 2018 and June 2021, total 48 patients with hematological malignancies (B-ALL 26, T-ALL/LBL 4,AML16,MDS 2) who failed to the first allo-HSCT(relapsed 47, secondary rejection 1) and underwent the second allo-HSCT in our hospital were enrolled. The median age was 25(5-55) years old. Male to female was 25:23. Before the second allo-HSCT, 35 (72.9%) patients were in complete remission (CR) (minimal residual disease (MRD) negative in 28, MRD positive in 7), and 13 (27.1%) cases (B-ALL7,T-ALL/LBL2,AML3,MDS1) in non-remission(NR). The median interval between twoallo-HSCTs was 19.5 (8-77) months. For better donor selection, the functions of hematopoiesis and immune (subsets of lymphocyte, immune globulin,and granzyme and perforin of NK cell) as well as hematological and immunological hereditary predisposition gene variants for potential donors were tested. The types of the first allo-HSCT included haploidentical (n=33), unrelated (n=8), identical sibling (n=5), and unrelated cord blood (n=2). All donors were changed for the second allo-HSCT(haploidentical 35, unrelated 13)except one recipient no other donor available. RTC regimens were mainly total body irradiation(TBI)/fludarabine (FLU)-based(n=39) or busulfan (BU)/FLU-based (n=7).Two patients were with total marrow irradiation (TMI)/FLU-basedregimen. For TBI/FLU regimen, fractionated TBI (8Gy in 32, 10Gy in 7), cytarabine 1-2g/m 2 for 3 days,FLU 30mg/m 2 for 5 days, Me-CCNU 250mg/m 2 for 1 day, and ATG were used. For BU/FLU regimen, BU 0.8mg/kg q6h for 3 days, cytarabine 1-2g/m 2 for 3 days,FLU 30mg/m 2 for 5 days, Me-CCNU 250mg/m 2 for 1 day, and ATG were used. For TMI/FLU regimen, the same conditioning as TBI/FLU was used except fractionated TMI 10-12Gy instead of TBI. Decitabine (20mg/m 2, 3 days) or etoposide (200mg/m 2, 2 days) were administrated in some patients in NR or MRD positive. Cyclosporine, mycophenolate mofetil and short-term methotrexate were employed for graft-versus-host disease (GVHD) prophylaxis. Some patients received maintenance therapy post-transplant with targeted medicine based on their fusion genes or gene mutations. Results: ALL patients became full donor chimerism. The median time for neutrophil and platelet recovery was 15 (11-22) days and 16 (10-240) days. The incidences of grade II-IV acute GVHD (aGVHD) and chronic GVHD(cGVHD) were 18.8%, 47.5% (limited 25%, extensive 22.5%), respectively. The incidences of CMV and EBV reactivation were 31.3% and 6.3%. No severe hemorrhagic cystitis occurred. The median follow-up was 13(1-38) months. One-year disease-free survival (DFS) and overall survival (OS) of all patients were 68.7% (95% CI:0.511;0.811) and 78.9% (95% CI:0.62;0.889) . Nine patients died(relapse 7,GVHD and infection 2).The relapse rate was 22.9%.TRM was only 4.2%. NR before transplant and TP53 mutation were high risk for disease recurrence post-HSCT. Relapse rates were 53.8% vs. 11.4% in NR and CR patients, and 50% vs. 17.5% in the patients with or without TP53 mutation. Disease status before transplant was key impact factor for survival after the second allo-HSCT. One-year OS in CR and NR settings were81.4 % and 70%, respectively, p=0.13. One-year DFS in CR and NR settingswere79.6%, and 41.9%, respectively, p=0.005. No significant difference of DFS was seen in haploidentical and unrelated transplants(68.1% vs.71.8%, p=0.627). Conclusions: With our strategy of RTC regimens and donor change, excellent outcomes of the second allo-HSCT in hematological malignancies have been achieved. One-year DFS and OS are 68.7% and 78.9%. Both TRM and relapse rate are low (4.2%, 22.9%). The most important factor on prognosis of the second allo-HSCT is disease status before transplant but not donor type. TP53 mutation also has negative impact on DFS after the second allo-HSCT. Disclosures No relevant conflicts of interest to declare.

Haematopoietic stem cell transplantation currently remains the only curative treatment of primary forms of haemophagocytic lymphohistiocytosis (HLH). Rapid diagnosis, efficient primary treatment of hyperinflammation, and conditioning regimens tailored to this demanding condition have substantially improved prognosis in the past 40 years. However, refractory hyperinflammation, central nervous system (CNS) involvement, unavailability of matched donors, susceptibility to conditioning-related toxicities, and a high frequency of mixed chimaerism remain a challenge in a substantial proportion of patients. Gene therapeutic approaches for several genetic defects of primary HLH are being developed at pre-clinical and translational levels.

Improving outcomes among class 3 thalassemia patients receiving allogeneic hematopoietic stem cell transplantations (HSCT) remains a challenge. Before HSCT, patients who were ≥ 7 years old and had a liver size ≥ 5 cm constitute what the Center for International Blood and Marrow Transplant Research defined as a very high–risk subset of a conventional high-risk class 3 group (here referred to as class 3 HR). We performed HSCT in 98 patients with related and unrelated donor stem cells. Seventy-six of the patients with age < 10 years received the more conventional myeloablative conditioning (MAC) regimen (cyclophosphamide, busulfan, ± fludarabine); the remaining 22 patients with age ≥ 10 years and hepatomegaly (class 3 HR), and in several instances additional comorbidity problems, underwent HSCT with a novel reduced-toxicity conditioning (RTC) regimen (fludarabine and busulfan). We then compared the outcomes between these 2 groups (MAC versus RTC). Event-free survival (86% versus 90%) and overall survival (95% versus 90%) were not significantly different between the respective groups; however, there was a higher incidence of serious treatment-related complications in the MAC group, and although we experienced 6 graft failures in the MAC group (8%), there were none in the RTC group. Based on these results, we suggest that (1) class 3 HR thalassemia patients can safely receive HSCT with our novel RTC regimen and achieve the same excellent outcome as low/standard-risk thalassemia patients who received the standard MAC regimen, and further, (2) that this novel RTC approach should be tested in the low/standard-risk patient population.

Thirty-day readmission (30-DR) has become an important quality-of-care measure. Allogeneic hematopoietic cell transplantation (allo-HCT) presents a medical setting with higher readmission rates. We analyzed factors affecting 30-DR and its impact on patient outcomes and on health care costs in 91 patients who underwent reduced-toxicity conditioning (RTC) allo-HCT with fludarabine and busulfan. The patient cohort was divided into 2: the readmission group (R-gp) or the no-readmission group (NR-gp). Overall, 38% (n = 35) required readmission with a median time to readmission of 14 days. In multivariate analysis, only documented infection during the index admission predicted 30-DR, P = .01. With a median follow-up of 18 months (range, 1 to 69) for surviving patients, the 2-year overall survival was 49% and 58% in the R-gp and NR-gp respectively, P = .48. The 1-year nonrelapse mortality in R-gp and NR-gp was 18% and 13% respectively, P = .43. The median post-transplantation hospital charges in the R-gp and NR-gp were $85,115 (range, $32,015 to $242,519) and $45,083 (range, $10,715 to $485,456), P = .0002. In conclusion, only documented infections during the index hospitalization influenced 30-DR after RTC allo-HCT. Although 30-DR did not adversely affect mortality or survival, it was associated with significantly increased 100-day post-transplantation hospital charges, thus supporting its role as a quality-of-care measure in allo-HCT patients.

Introduction HSCT is the curative therapeutic option in PIDs. Due to the increase in survival rates, reduced-toxicity conditioning regimens with treosulfan have become another alternative. The purpose of this retrospective study was to analyze the outcome of treosulfan-based conditioning before HSCT for patients with PID. Method A total of 15 patients that received a treosulfan-based conditioning regimen for HSCT were recruited. Type of diagnosis, donor and stem cell source, pretransplant organ damage, infections, engraftment, chimerism, and transplant-related toxicities were analyzed. Results At a median follow-up time of 32 months, the overall survival was 86.7%. Following HSCT, 14 of 15 patients had engraftment, with 86.7% of the cohort having full-donor chimerism. The most common toxicity was seen on the skin (53.3%). Acute GVHD and chronic GVHD were documented in 53% and 20% of the study population, respectively. Although the cohort consisted of patients with pretransplant liver damage, SOS manifestations were documented in 20%. Conclusion Treosulfan-based conditioning regimens before HSCT are associated with lower toxicity compared to myeloablative regimens, are safe, and have high engraftment rates with full-donor chimerism in patients having PID, regardless of the specified genetic diagnosis and donor type.

Although reduced-intensity conditioning has become standard of care for patients with hematologic malignancies undergoing allogeneic hematopoietic cell transplantation (HCT), the optimum regimen has yet to be defined, and may depend on pretransplantation patient– and/or disease-specific risk factors. We report here results in 100 adults, ages 18 to 69, with high-risk hematologic malignancy who received conditioning with fludarabine, carmustine, melphalan, and rabbit antithymocyte globulin (FBM-A). Outcomes were stratified using the disease risk index (DRI) as published by Armand et al. (Blood 2012;120:905-913). Median age was 56, and patients were ineligible for standard myeloablative conditioning because of age, organ dysfunction, or prior autologous HCT. Patients underwent transplantation for myeloid (acute myelogenous leukemia, n = 40; myelodysplastic syndrome, n = 24; myelofibrosis, n = 13; other myeloid, n = 2) or lymphoid (acute lymphoblastic leukemia, n = 8; non-Hodgkin lymphoma, n = 8; Hodgkin lymphoma, n = 4, chronic lymphocytic leukemia, n = 1) malignancy. Donors were related in 26 patients (22 matched, 4 mismatched at 1 antigen) and unrelated in 74 (mismatched at 1 or 2 HLA loci in 33); grafts were peripheral blood stem cells in 97 patients, bone marrow in 2, and double cord in 1. According to the DRI, 68 patients were classified as low (n = 1) or intermediate risk (n = 67), and 32 were classified as high (n = 28) or very high risk (n = 4). With a median follow-up of surviving patients of 18 months, the Kaplan-Meier estimate of overall survival at 2 years for patients in the low/intermediate risk group is 80%, compared with 66% in the high/very high group (P = .11). Two-year cumulative incidence of relapse and nonrelapse mortality in the low/intermediate group are 9.9% and 15%, versus 25% and 19% in the high/very high group (respective P values .07 and .81). The cumulative incidence of acute graft-versus-host (GVHD) grades III to IV at 100 days was 8.1%, and the incidence of National Institutes of Health–defined moderate to severe chronic GVHD was 22% at 2 years. No deaths were attributable to chronic GVHD. Survival was not influenced by age, hematopoietic comorbidity index score, donor type, donor gender, or presence of mismatch. We conclude that FBM-A is an effective and safe conditioning regimen for adults up to age 69 with hematologic malignancies who have low-, intermediate-, or high-risk scores according to the DRI.

Pediatric allogeneic stem cell transplant (AlloSCT) patients are at substantial risk of developing kidney injury (KI), and KI contributes to transplant-related morbidity and mortality. We compared the estimated creatinine clearance (eCrCl) at 1, 3, 6, 9, and 12 months post-AlloSCT in 170 patients following reduced toxicity conditioning (RTC) versus myeloablative conditioning (MAC) to baseline. eCrCl was calculated using the Schwartz equation. Patients with ≥50% drop in eCrCl from the baseline were considered to have KI. Patients received tacrolimus and mycophenolate mofetil (MMF) for graft-versus-host disease (GVHD) prophylaxis. The logistic regression model was used for assessing risk factors for KI. Seventy-six patients (median age = 10.6 years) received RTC AlloSCT; 94 patients (median age = 8.5 years) received MAC AlloSCT. The incidence of KI at 1 month post-AlloSCT was significantly higher in MAC versus RTC AlloSCT (43/94 [45.7%] versus 13/76 [17.1%] P < .0001). There was no statistical difference in KI at 3, 6, 9, and 12 months post-AlloSCT between the 2 conditioning groups. On multivariate analysis, only MAC was a significant risk factor for KI (odds radio [OR] 3.44, 95% confidence interval [CI] 1.59-7.42, P = .002). In multivariate analysis for risk factors affecting overall survival (OS), the following were statistically significant: MAC versus RTC (hazard ratio [HR] 2.66, P = .0008), average versus poor-risk disease status (HR 2.09, P = .004), matched sibling donor (MSD) and matched unrelated donor (MUD) versus umbilical cord blood (UCB) (HR 2.31, P = .013), no KI versus KI (HR 2.00, P = .005). In children, MAC is associated with significant risk of KI in the first month after transplant, and KI in the first month post-AlloSCT is associated with a significantly decreased OS.

Streszczenie Przeszczepianie komorek hematopoetycznych (HSC T) jest procedurą, w ktorej krwiotworcze komorki macierzyste, pochodzące od dawcy (autologicznego, allogenicznego, syngenicznego) z jakiegokolwiek źrodla (szpik, krew obwodowa, krew pepowinowa) są podawane biorcy po przeprowadzeniu terapii kondycjonującej, w celu repopulacji i zastąpienia jego wlasnego ukladu krwiotworczego w calości lub w cześci. Podstawą postepowania kondycjonującego jest podanie chemioterapii wysokodawkowej lub calkowitego napromieniowania organizmu (TBI) w celu uzyskania efektu mieloablacyjnego, immunosupresyjnego i przeciwnowotworowego. Poza efektem mieloablacyjnym na szpik kostny, drugim istotnym mechanizmem w allo-HSC T jest efekt biologiczny, ktory opiera sie na reakcji przeszczepionych komorek krwiotworczych przeciwko komorkom nowotworowym (graft-versus-leukemia; GVL, graft-versus-tumor; GV T), jak tez innym komorkom organizmu biorcy (graft-versus-host; GV H). Lekami najcześciej stosowanymi podczas tzw. chemioterapii kondycjonującej są busulfan, cyklofosfamid, melfalan i etopozyd (I generacja). Dzieki zastosowaniu fludarabiny (II generacja) stworzono mozliwości prowadzenia postepowania przygotowawczego o zredukowanej intensywności. Treosulfan jest stosunkowo nowym lekiem, coraz cześciej stosowanym w transplantacjach komorek krwiotworczych. Wlaściwości przeciwnowotworowe, mieloablacyjne i immunosupresyjne treosulfanu, w polączeniu z jego niską toksycznością i korzystną farmakokinetyką powodują, ze lek ten wydaje sie byc bardzo korzystnym skladnikiem stosowanym w kondycjonowaniu przedprzeszczepowym. Bezpieczenstwo i efektywnośc związana z tym lekiem sprawiają, ze moze on byc istotną opcją terapeutyczną dla pacjentow z chorobami nienowotworowymi kwalifikowanymi do transplantacji komorek macierzystych.

Feasibility of umbilical cord blood transplantation with a myeloablative, reduced toxicity-conditioning regimen

In reduced-toxicity conditioning hematopoietic stem cell transplantation, several studies failed to demonstrate the superiority of one conditioning over another. This study described 51 patients (median age of 58 years) allografted with the new FB3-ATG2 conditioning regimen for myeloid (66%) or lymphoid disease (33%). Comorbidity index ≥3 was noted in 23.5% of patients. Toxicities were close to those observed with RIC. One-year cumulative incidence of acute and chronic GVHD was 18.9% and 39.2%. The 2-year-NRM, DFS and OS were 25%, 57.5% and 66%. The FB3-ATG2 regimen is safe and efficient in both lymphoid and myeloid disorders. However, prospective comparative studies are needed.

Escolar et al.1 have reported that early transplantation of asymptomatic newborns affected by Krabbe's disease favorably alters the course of the disease. Twenty-five newborns and infants underwent an unrelated cord blood transplantation after a standard myeloablative conditioning regimen with busulphan and cyclophoshamide and the survival was significantly better among asymptomatic newborns than symptomatic infants or untreated controls.