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Background: Peripheral T‐cell lymphomas (PTCL) frequently result in relapsed or refractory diseases. Upfront autologous hematopoietic stem cell transplantation (ASCT) using the BEAM (carmustine, etoposide, cytarabine, and melphalan) regimen is recommended. However, relapses are common in PTCL, highlighting a critical need for improved survival outcomes in these patients. Objective: Anthracycline drugs are essential in treating PTCL. We compared the efficacy and tolerability of a high‐dose mitoxantrone‐based conditioning regimen [mitoxantrone, cyclophosphamide, and etoposide (MCE)] to the BEAM regimen in upfront ASCT for newly diagnosed PTCL patients who achieved complete or partial remission after induction therapy. Study Design: A retrospective study was conducted to analyze the treatment response, progression‐free survival (PFS), overall survival (OS), hematologic engraftment time, and adverse events of 64 patients between two regimens, who achieved complete or partial remission after induction chemotherapy. Twenty‐eight patients received the MCE regimen, while 36 patients were treated with the BEAM regimen. Results: There were no significant differences in clinical characteristics or the incidence of adverse events between the two groups. However, the median OS significantly favored the MCE group at 102.4 (95% CI, 87.0–117.8) months compared to 62.6 (95% CI, 50.8–74.5) months in the BEAM group (p = 0.023). Similarly, the median PFS was longer in the MCE group at 87.8 (95% CI, 65.8–109.8) months versus 42.5 (95% CI, 30.0–55.0) months in the BEAM group (p = 0.031). Conclusion: ASCT with the mitoxantrone‐based conditioning regimen is tolerable and appears to significantly improve the prognosis of PTCL patients, offering a promising alternative to the current standard of care. [ABSTRACT FROM AUTHOR]

Background: Haploidentical hematopoietic stem cell transplant (HSCT) is a curative treatment especially for countries where bone marrow registries are nonexistent. We present our experience with haploidentical HSCT in pediatric patients. Methods: Retrospective data collected and analyzed for patients ≤18 years, from January 2017 to December 2022. Results: The cohort consisted of 20 patients with median age at transplant of 61.5 (IQR: 124) months. Fourteen (70%) were malignant and 6 (30%) were benign diseases. Donors were father in majority (9/20; 45%). Stem cell source was peripheral blood 8, marrow 8, and combined 4. c‐specific antibodies were positive in 6 (30%). Median CD34 cell dose infused: 9.35 × 106/kg. Median engraftment time: 15 (IQR: 17) days. Acute and chronic graft‐versus‐host disease (GVHD) occurred in 12/20 (60%) and 5/20 (25%), respectively. Complications included infection/sepsis (14/20; 70%), cytomegalovirus reactivation (14/20; 70%), sinusoidal obstruction syndrome (1/20; 5%), primary graft failure (PGF) (6/20; 30%), and secondary graft failure (4/20; 20%). PGF was more common in benign conditions (p = 0.003) and less prevalent in cases with aGVHD (p = 0.007). aGVHD was more common in malignant conditions (p = 0.007). Overall survival (OS), relapse‐free survival (RFS), and treatment‐related mortality (TRM) were 40%, 50%, and 35%, respectively. Median time of survival and relapse were 8 (IQR: 15) and 9 (IQR: 13) months, respectively. Conclusion: OS was comparable to that of other low–middle‐income countries. GVHD was a major challenge, along with sepsis and CMV infection. Half of the leukemias relapsed. Graft failure was a major concern in nonmalignant diseases. [ABSTRACT FROM AUTHOR]

Background: High‐dose chemotherapy followed by autologous stem cell transplantation (ASCT) remains an effective treatment for non‐Hodgkin lymphoma (NHL). The limited availability of carmustine has prompted the exploration of novel alternative conditioning regimens. This study aimed to compare the efficacy and safety profile of GBM/GBC (gemcitabine, busulfan, and melphalan or cyclophosphamide) conditioning compared with the standard BEAM/BEAC regimens (carmustine, etoposide, cytarabine, and melphalan or cyclophosphamide) for ASCT in patients with NHL. Methods: A retrospective analysis was conducted on 231 NHL patients, who underwent ASCT from October 2010 to October 2021 at the Institute of Hematology & Blood Disease Hospital, including both first‐line and salvage settings. This resulted in the inclusion of 112 patients in the GBM/GBC arm and 92 in the BEAM/BEAC arm. Propensity score matching was employed to validate the results. Results: Disease subtype distribution was similar between the GBM/GBC and BEAM/BEAC groups, with diffuse large B‐cell lymphoma being the most common (58.9% vs. 58.7%), followed by PTCL (17.0% vs. 18.5%) and MCL (14.3% vs. 14.1%). At 3 months post‐ASCT, complete response (CR) rates were comparable (GBM/GBC 93.5% vs. BEAM/BEAC 91.1%; p = 0.607). The 4‐year progression‐free survival (78.4% vs. 82.3%; p = 0.455) and 4‐year overall survival (88.1% vs. 87.7%; p = 0.575) were also similar. Both groups exhibited low non‐relapse mortality at 4 years (GBM/GBC 1.8% vs. BEAM/BEAC 3.5%; p = 0.790) with no transplant‐related mortalities reported. The GBM/GBC cohort demonstrated a higher incidence of grade 3/4 oral mucositis and hepatic toxicity, whereas the BEAM/BEAC group had more frequent cases of bacteremia or sepsis (13 cases vs. 5 in GBM/GBC). Conclusions: The GBM/GBC regimen is effective and well‐tolerated, offering outcomes that are highly comparable to those in NHL patients conditioned with BEAM/BEAC, as demonstrated in a prognostically matched cohort. [ABSTRACT FROM AUTHOR]

Objectives: Allogeneic hematopoietic stem‐cell transplantation (HCT) is the only curative option for most hematologic malignancies. However, HSCT can cause early menopause and various complications in premenopausal women. Therefore, we aimed to investigate risk factors predicting early menopause and its clinical implications among survivors post HCT. Methods: We retrospectively analyzed 30 adult women who had received HCT at premenopausal status between 2015 and 2018. We excluded patients who had received autologous stem cell transplantation, had relapsed, or died of any cause within 2 years of HCT. Results: The median age at HCT was 41.6 years (range, 22–53). Post‐HCT menopause was identified in 90% of myeloablative conditioning (MAC) HCT and 55% of reduced‐intensity conditioning (RIC) HCT (p =.101). In the multivariate analysis, the post‐HCT menopausal risk was 21 times higher in a MAC regimen containing 4 days of busulfan (p =.016) and 9.3 times higher in RIC regimens containing 2–3 days of busulfan (p =.033) than that of non‐busulfan‐based conditioning regimens. Conclusions: Higher busulfan dose in conditioning regimens is the most significant risk factor affecting post‐HCT early menopause. Considering our data, we need to decide on conditioning regimens and individualized fertility counseling before HCT for premenopausal women. [ABSTRACT FROM AUTHOR]

Summary: Patients with acute megakaryoblastic leukaemia of Down syndrome (DS‐AMKL) have an excellent survival rate; however, patients with non‐DS‐AMKL experience poor outcomes. Therefore, this study retrospectively analysed 203 children with non‐DS‐AMKL who underwent their first haematopoietic cell transplantation (HCT) from 1986 to 2015 using a nationwide Japanese HCT registry data to assess HCT outcomes for non‐DS‐AMKL. The 5‐year overall survival (OS) and event‐free survival (EFS) rates were 43% and 38% respectively. The 5‐year OS rate was significantly higher for patients who underwent HCT in the first complete remission (CR1, 72%) than for those in the second CR (CR2, 23%) and non‐CR (16%) (p < 0.001), and for those from a human leukocyte antigen (HLA)‐matched (52%) than for those from an HLA‐mismatched donor (27%) (p < 0.001). Multivariate analysis for OS revealed that HCT in CR2 and non‐CR was a significant risk factor (hazard ratio, 5.86; 95% confidence interval, 3.56–9.53; p < 0.001). The 3‐year EFS in patients who received HCT in CR1 using reduced‐intensity conditioning (RIC, 35%) was significantly lower than in those using myeloablative conditioning (busulfan‐based, 71%; total body irradiation‐based, 58%) (p < 0.001). Risk stratification in patients with non‐DS‐AMKL should be established to determine HCT indication in CR1. [ABSTRACT FROM AUTHOR]

Aim: The MEAM regimen consisting of ranimustine (MCNU), etoposide (ETP), cytarabine (Ara‐C), and melphalan (MEL) is widely used before auto‐peripheral blood stem cell transplantation (auto‐PBSCT) for malignant lymphoma in Japan. The MEAM regimen generally consists of 200–400 mg/m2 for 4 days, but we decided to increase the dosage of Ara‐C from the standard to 2 g/m2 for 2 days with the aim of increasing drug transferability to the central nervous system. We evaluate the safety and therapeutic efficacy of high‐dose Ara‐C MEAM therapy. Methods: The high‐dose Ara‐C MEAM protocol consisted of MCNU 300 mg/m2 on day –7, ETP 200 mg/m2 on days –6, –5, –4, –3 and Ara‐C 2 g/m2 on day –4 –3, and MEL 140 mg/m2 on day –2. We retrospectively analyzed 37 cases of malignant lymphoma at our institution between May 2014 and July 2020. Results: All patients got engraftment and there were no cases of treatment‐related mortality. In all cases, the 3‐year overall survival (OS) and progression‐free survival (PFS) after transplantation were 80.6% and 65.7%, respectively. Twenty‐one cases of diffuse large B‐cell lymphoma recurrence, for which there is proven usefulness of auto‐PBSCT, showed good results after transplantation, with the 3‐year OS and PFS after transplantation being 100% and 74.3%, respectively. Conclusion: The safety and efficacy of high‐dose Ara‐C MEAM therapy were demonstrated, but the expected therapeutic effect on central nervous system lesions could not be fully evaluated owing to the small number of cases. [ABSTRACT FROM AUTHOR]

The impact of conditioning intensity on different donor groups has been unclear in allogeneic transplantation. The objective of this study was to clarify the effect of conditioning intensity on disease‐free survival (DFS), relapse, non‐relapse mortality (NRM), neutrophil engraftment, and graft‐versus‐host disease for each donor type. We retrospectively evaluated the effect of conditioning intensity on transplant outcomes for patients with acute leukemia or myelodysplastic syndrome aged between 16 and 60 years in Japan using the transplant conditioning intensity (TCI) scoring system. A total of 8526 patients who received first allogeneic transplantation from 6/6 antigen‐matched sibling donor (MSD, n = 2768), 8/8 allele‐matched unrelated donor (MUD, n = 2357), and unrelated single‐cord blood (UCB, n = 3401) were eligible for the analyses. Compared to conditioning with TCI score 4.0, which was corresponds to conventional myeloablative conditioning, including cyclophosphamide with total body irradiation 12 Gy or busulfan 12.8 mg, and was considered as the reference group in the multivariate analyses, intensified conditioning with TCI score ≥4.5 improved DFS (hazard ratio [HR],0.81, P < 0.001) and relapse rate (HR, 0.70, P < 0.001) but only after UCB transplants and not MSD and MUD transplants. In contrast, NRM was higher after intensified conditioning with TCI score ≥4.5 for MSD (HR, 1.39, P = 0.008) and MUD (HR, 1.47, P = 0.002) transplants but not UCB transplants (HR, 1.12, P = 0.240). Neutrophil engraftment was also significantly higher after intensified conditioning with TCI score ≥4.5 but only for UCB transplants (HR, 1.24, P < 0.001), whereas it was significantly lower after reduced‐intensity conditioning with TCI score ≤3.5 for MSD transplants only (HR, 0.82, P < 0.001). These data demonstrated that an intensified conditioning regimen improved survival and engraftment rate only after a UCB transplants. Therefore, TCI scoring system could enable the optimization of conditioning intensity according to donor type, particularly in terms of survival and engraftment. [ABSTRACT FROM AUTHOR]

Objective: The aim of this study was to evaluate the expression of BPIFA proteins in the saliva and salivary glands of hematopoietic cell transplant (HCT) patients. Material and Methods: This longitudinal study included patients who had undergone autologous HCT (auto‐HCT) and allogeneic HCT (allo‐HCT), and unstimulated saliva was collected at three time points, with a fourth collection at oral chronic graft‐versus‐host disease (cGVHD) onset. BPIFA expression was analysed by Western blotting in saliva and immunostaining in the minor salivary glands of cGVHD patients. Results: Auto‐HCT patients showed increased levels of BPIFA1 (p =.021) and BPIFA2 at D+7 (p =.040), whereas allo‐HCT group demonstrated decreased expression of BPIFA2 at D+8 (p =.002) and at D+80 (p =.001) and a significant association between BPIFA2 low levels and hyposalivation was observed (p =.02). BPIFA2 was significantly lower in the cGVHD patients when compared to baseline (p =.04). Conclusions: The results of this study show distinct pattern of expression of BPIF proteins in both auto‐HCT and allo‐HCT recipients with decreased levels of BPIFA2 during hyposalivation and cGVHD. Further studies are necessary to elucidate these proteins mechanisms and their clinical implications in these groups of patients. [ABSTRACT FROM AUTHOR]

Background: Juvenile myelomonocytic leukemia (JMML) is a rare hematological malignancy in young children and can only be cured through the allogeneic stem cell transplantation. Procedure: We have retrospectively analyzed the outcomes of nine children with JMML after unrelated cord blood transplantation (UCBT). Results: Eight patients who have received a myeloablative conditioning regimen of fludarabine (FLU), busulfan (BU), and cyclophosphamide (CY) have gotten engraftment. None of the nine patients has relapsed following initial UCBT. Six patients are still alive and in complete remission after UCBT with a median observation time of 43 months (range: 10–80 months). Conclusions: This study shows that UCBT with FLU‐BU‐CY conditioning regimen can represent a suitable option for children with JMML. [ABSTRACT FROM AUTHOR]

Triple‐hit lymphoma (THL), which is classified into high‐grade B‐cell lymphoma with rearrangements of MYC, BCL2 and BCL6, presents aggressive biological behaviour. High‐dose chemotherapy followed by autologous hematopoietic stem cell transplantation (auto‐HSCT) is considered to be one of the recommended treatment options. Here, we reported 3 THL patients received carmustine, etoposide, cytarabine and cyclophosphamide (BEAC) combined with chidamide and high‐dose rituximab conditioning regimen and found that this conditioning showed good efficacy and tolerance without increase of adverse events. [ABSTRACT FROM AUTHOR]

Background: EPP is a rare disorder of heme biosynthesis in which patients present with disabling photosensitivity. A subset of patients develop severe liver disease with progressive liver failure necessitating an OLT. A HCT can potentially cure EPP by replacing the native bone marrow, which is the primary site of heme synthesis. However, due to concerns for inherent risks of treatment‐related toxicities, the use of HCT has been reserved for patients undergoing an OLT to avoid disease recurrence in the hepatic graft. Data for HCT in EPP are lacking, particularly in the pediatric population. Case (Methods/Results): We present the case of a 12‐year‐old patient with EPP photosensitivity and cirrhosis, whom we successfully treated with pre‐emptive allogeneic HCT, significantly improving the patient's quality of life. We used a matched‐unrelated donor bone marrow–derived graft. Our patient achieved full donor peripheral blood chimerism and has not had any evidence of GVHD. In addition to resolution of photosensitivity, our patient had reversal of liver fibrosis which we feel was largely due to intervention at an early stage of compensated cirrhosis. Conclusion: Our case highlights the successful application of a known RIC regimen to this rare disorder that was well tolerated with sustained donor engraftment. It also emphasizes the importance of timing for HCT in patients with EPP and liver fibrosis. HCT should be considered early in pediatric patients with EPP‐hepatopathy to prevent progression to liver failure and need for OLT with lifelong immunosuppression. [ABSTRACT FROM AUTHOR]

Aims: Treosulfan is an alkylating agent increasingly used prior to haematopoietic stem cell transplantation. The aim of this study was to develop a population pharmacokinetic (PK) model of treosulfan in paediatric haematopoietic stem cell transplantation recipients and to explore the effect of potential covariates on treosulfan PK. Also, a limited sampling model (LSM) will be developed to accurately predict treosulfan exposure suitable for a therapeutic drug monitoring setting. Methods: In this multicentre study, 91 patients, receiving a total dose of 30, 36 or 42 g/m2 treosulfan, administered over 3 consecutive days, were enrolled. A population PK model was developed and demographic factors, as well as laboratory parameters, were included as potential covariates. In addition, a LSM was developed using data from 28 patients. Results: A 2‐compartment model with first order elimination best described the data. Bodyweight with allometric scaling and maturation function were identified as significant predictors of treosulfan clearance. Treosulfan clearance reaches 90% of adult values at 4 postnatal years. A model‐based dosing table is presented to target an exposure of 1650 mg*h/L (population median) for different weight and age groups. Samples taken at 1.5, 4 and 7 hours after start of infusion resulted in the best limited sampling strategy. Conclusions: This study provides a treosulfan population PK model in children and captures the developmental changes in clearance. A 3‐point LSM allows for accurate and precise estimation of treosulfan exposure. [ABSTRACT FROM AUTHOR]

Treosulfan-based conditioning is increasingly employed in paediatric haematopoietic stem cell transplantation (HSCT). Data on treosulfan pharmacokinetics in children are scarce, and the relationship between treosulfan exposure, toxicity and clinical outcome is unresolved. In this multicentre prospective observational study, we studied treosulfan pharmacokinetics and the drug's relationship with regimen-related toxicity and early clinical outcome in 77 paediatric patients. Treosulfan dose was 30 g/m2, administered over 3 consecutive days in infants <1 year old (n = 12) and 42 g/m2 in children ≥1 year old (n = 65). Mean day 1 treosulfan exposure was 1744 ± 795 mg*h/l (10 g/m2) and 1561 ± 511 mg*h/l (14 g/m2), with an inter-individual variability of 56 and 33% in the respective groups. High treosulfan exposure (>1650 mg*h/l) was associated with an increased risk of mucosal [Odds ratio (OR) 4·40; 95% confidence interval (CI) 1·19–16·28, P = 0·026] and skin toxicity (OR 4·51; 95% CI 1·07–18·93, P = 0·040). No correlation was found between treosulfan exposure and the early clinical outcome parameters: engraftment, acute graft-versus-host disease and donor chimerism. Our study provides the first evidence in a large cohort of paediatric patients of high variability in treosulfan pharmacokinetics and an association between treosulfan exposure and early toxicity. Ongoing studies will reveal whether treosulfan exposure is related to long-term disease-specific outcome and late treatment-related toxicity. [ABSTRACT FROM AUTHOR]

Background Patients who undergo allogeneic hematopoietic stem cell transplantation (allo- HSCT) often develop bloodstream infections ( BSI). We aimed to describe the etiologies and antibiotic resistance patterns of BSI after allo- HSCT, and, as knowledge about the impact of conditioning regimen is limited, we looked at the incidence, timing, risk factors, and mortality of BSI separately for myeloablative ( MA)- and non-myeloablative ( NMA)-conditioned patients. Methods All 460 patients (207 MA- and 253 NMA-conditioned) who underwent their first allo- HSCT at our center from 2008 to 2013 were included in a historical cohort. BSI were registered from initiation of conditioning to day 360 after transplantation. Results BSI occurred in 34% (95% confidence interval [ CI]: 28%, 41%) of MA-conditioned patients and in 17% (95% CI: 12%, 22%) of NMA-conditioned patients. Of all isolates, 68% were gram-positive bacteria ( GPB), 23% gram-negative bacteria ( GNB), and 9% fungi. The GPB/ GNB ratio declined from 2008 to 2014 ( P for trend <.01). Of all GNB, 47% were multidrug resistant ( MDR), but the proportion declined over the study period. In a multivariate Cox regression model, only acute graft-versus-host disease was associated with a higher hazard of first BSI (hazard ratio 2.50, 95% CI: 1.48, 4.21). Overall 30-day survival after a BSI was higher for MA-conditioned patients than for NMA-conditioned patients (89% vs 74%, P=.04). Conclusion MA-conditioned patients experience BSI more often than NMA-conditioned patients in the year after allo- HSCT. While BSI are increasingly caused by GNB, the rate of MDR GNB is declining. [ABSTRACT FROM AUTHOR]

Background: Allogeneic hematopoietic cell transplantation (HCT) is a curative therapy for patients with acute myeloid leukemia (AML). However, post-HCT relapse and regimen-related toxicity remain significant barriers to long-term survival. In recent years, new conditioning regimens have been explored to improve transplantation outcomes in patients with AML. Treosulfan combines a potent immunosuppressive and antileukemic effect with a low toxicity profile.Methods: To investigate the role of treosulfan-based conditioning, the European Society for Blood and Marrow Transplantation Acute Leukemia Working Party performed a registry analysis of 520 adult patients with AML who received treosulfan-based conditioning and underwent HCT between 2000 and 2012, including 225 patients in first complete remission, 107 in second or later complete remission, and 188 with active/advanced disease 188 (88 with primary refractory disease). The median patient age was 57 years (range, 20-73 years). Donors were human leukocyte antigen-identical siblings (n = 187), unrelated donors (n = 235), or mismatched related donors (n = 98). Conditioning regimens included treosulfan (42 g/m2 [n = 396], 36 g/m2 [n = 109], or 30 g/ m2 [n = 15]) with fludarabine or alkylating agents followed by infusion of hematopoietic stem cells (bone marrow, n = 52; peripheral blood, n = 468).Results: At a median follow-up of 61 months, the 5-year overall survival, leukemia-free survival, relapse incidence, and nonrelapse mortality rates were 38%, 33%, 42%, and 25%, respectively. The incidence of grade II-IV acute and chronic graft-versus-host disease was 24% (grade III-V, 11%) and 38%, respectively. Only 11 patients (2%) developed veno-occlusive disease, with two deaths (0.4%) from veno-occlusive disease.Conclusions: Treosulfan-based conditioning regimens provide an acceptable long-term survival with favorable nonrelapse mortality and a very low risk of veno-occlusive disease. Further studies are needed to optimize the treosulfan-based conditioning regimen for patients with AML. Cancer 2017;123:2671-79. © 2017 American Cancer Society. [ABSTRACT FROM AUTHOR]

Background: Patients with primary refractory acute lymphoblastic leukemia (PREF ALL) who fail to achieve a complete remission (CR) after ≥2 courses of chemotherapy have a dismal prognosis without undergoing allogeneic hematopoietic cell transplantation (HCT). To the authors' knowledge, there currently are no data regarding factors influencing transplantation outcomes.Methods: The authors retrospectively studied outcomes of transplantation for cases of PREF ALL reported to European Society for Blood and Marrow Transplantation registry. Eligibility criteria for the current analysis included adult patients who underwent their first HCT for PREF ALL between 2000 and 2012. PREF disease was defined as the failure to achieve a morphological CR after ≥2 courses of induction chemotherapy.Results: Data regarding 86 adult patients were analyzed. With a median follow-up of 106 months, the probability of survival was 36% at 2 years and 23% at 5 years. The probability of leukemia-free survival was 28% and 17%, respectively, and the probability of nonrecurrence mortality was 20% and 29%, respectively, at 2 years and 5 years. For 66 patients who achieved a CR (77%), the survival at 2 years and 5 years was 36% and 29%, respectively. In multivariate analysis, use of total body irradiation was found to be associated with improved survival. Total body irradiation and infusion of female hematopoietic cells into male recipients was associated with improved leukemia-free survival. These findings were incorporated into a scoring system that identified 3 groups (those with 2, 1, or no prognostic factors) with survival rates of 57%, 22%, and 8%, respectively.Conclusions: Although overall these patients would clearly benefit from the introduction of novel antileukemic therapies, the data from the current study support the use of allogeneic HCT in selected patients with PREF ALL. Cancer 2017;123:1965-1970. © 2017 American Cancer Society. [ABSTRACT FROM AUTHOR]

Background: Previously, early results were reported for allogeneic hematopoietic cell transplantation (HCT) after nonmyeloablative conditioning with 2 Gy of total body irradiation with or without fludarabine and/or rituximab in 33 patients with mantle cell lymphoma (MCL).Methods: This study examined the outcomes of 70 patients with MCL and included extended follow-up (median, 10 years) for the 33 initial patients. Grafts were obtained from human leukocyte antigen (HLA)-matched, related donors (47%), unrelated donors (41%), and HLA antigen-mismatched donors (11%).Results: The 5-year incidence of nonrelapse mortality was 28%. The relapse rate was 26%. The 5-year rates of overall survival (OS) and progression-free survival (PFS) were 55% and 46%, respectively. The 10-year rates of OS and PFS were 44% and 41%, respectively. Eighty percent of surviving patients were off immunosuppression at the last follow-up. The presence of relapsed or refractory disease at the time of HCT predicted a higher rate of relapse (hazard ratio [HR], 2.94; P = .05). Despite this, OS rates at 5 (51% vs 58%) and 10 years (43% vs 45%) were comparable between those with relapsed/refractory disease and those undergoing transplantation with partial or complete remission. A high-risk cytomegalovirus (CMV) status was the only independent predictor of worse OS (HR, 2.32; P = .02). A high-risk CMV status and a low CD3 dose predicted PFS (HR, 2.22; P = .03).Conclusions: Nonmyeloablative allogeneic HCT provides a long-term survival benefit for patients with relapsed MCL, including those with refractory disease or multiple relapses. [ABSTRACT FROM AUTHOR]

Although allogeneic haematopoietic stem cell transplantation ( HSCT) still represents the only consolidated possibility of cure for sickle cell disease ( SCD) patients, its use has been limited by the risk of morbidity and mortality associated with conventional myeloablative therapy. The introduction of treosulfan to replace busulfan in conditioning regimens has recently been explored by virtue of its lower toxicity profile. We report our experience with a treosulfan/thiotepa/fludarabine conditioning for human leucocyte antigen ( HLA)-matched sibling or unrelated donor- HSCT in 15 children with SCD, and compare patient outcomes with those of a historical cohort (15 patients) given a busulfan-based regimen. Engraftment was achieved in 28 out of 30 patients (93%), with one case of graft failure in either group. The conditioning regimen was well tolerated in both groups, with no cases of grade III- IV regimen-related toxicity. The 7-year overall survival ( OS) and disease-free survival ( DFS) for the whole cohort were 100% and 93%, respectively, with a 93% DFS in both busulfan and treosulfan groups. No SCD-related adverse events occurred after engraftment in patients with complete or mixed donor chimerism. This retrospective analysis suggests that a treosulfan-based conditioning regimen is able to ensure engraftment with excellent OS/ DFS and low regimen-related toxicity in patients with SCD. [ABSTRACT FROM AUTHOR]

The current study was designed to assess the safety and efficacy of bortezomib in combination with fludarabine and melphalan as reduced intensity conditioning before allogeneic stem cell transplantation in patients with high risk multiple myeloma. Sixteen patients were evaluable. The median number of previous line of treatment was 3; all patients had relapsed following a prior autograft and 13 had previously received bortezomib. Fifteen of them either remained stable or improved disease status at day +100 post-transplant, including 11 patients with active disease. More specifically, nine patients (56%) and five patients (31%) reached complete remission and partial response, respectively. 25% developed grade III acute graft-versus-host disease. The cumulative incidence of non-relapse mortality, relapse and overall survival were 25%, 54% and 41%, respectively, at 3 years. Regarding the non-haematological toxicity (grade>2), two patients developed peripheral neuropathy, two patients liver toxicity and 1 pulmonary toxicity early post-transplant. The haematological toxicity was only observed during the first three cycles mostly related to low haemoglobin and platelet levels. The current trial is the first one evaluating the safety and efficacy of bortezomib as part of a reduced intensity conditioning regimen among patients with high risk multiple myeloma. [ABSTRACT FROM AUTHOR]

The intrinsic anti-leukemic effect of allogeneic hematopoietic cell transplantation ( HCT) is dependent on genetic disparity between donor and recipient, intimately associated with graft-versus-host disease ( GVHD), and mediated by lymphocytes contained in or derived from the donor hematopoietic cell graft. Three decades of intense effort have not identified clinical strategies that can reliably separate the graft-versus-leukemia ( GVL) effect from the alloimmune reaction that drives clinical GVHD. For patients who require HCT and for whom two or more human leukocyte antigen ( HLA)- A, - B, - C, and - DRB1-matched donor candidates can be identified, consideration of donor and recipient genotype at additional genetic loci both within and outside the major histocompatibility complex may offer the possibility of selecting the donor [candidate(s)] that poses the lowest probability of GVHD and the highest probability of a potent GVL effect. Strategies for engineering conventional donor lymphocyte infusion also hold promise for prevention or improved treatment of post-transplant relapse. The brightest prospects for selectively enhancing the anti-leukemic efficacy of allogeneic HCT, however, are likely to be interventions that are designed to enhance specific antitumor immunity via vaccination or adoptive cell transfer, rather than those that attempt to exploit donor alloreactivity against the host. Adoptive transfer of donor-derived T cells genetically modified for tumor-specific reactivity, in particular, has the potential to transform the practice of allogeneic HCT by selectively enhancing antitumor immunity without causing GVHD. [ABSTRACT FROM AUTHOR]

We have developed a practical conditioning regimen without anti-thymocyte globulin ( ATG), irradiation, or other myeloablative alkylating agent for low-income countries in which patients with severe aplastic anemia ( SAA), who usually have heavily transfused and a prolonged disease history. The application of ATG, Busulphan, and/or irradiation to cyclophosphamide ( Cy) to avoid graft rejection has many short- and long-term complications. In this study, we focused on evaluating a fludarabine-based conditioning regimen, among 83 patients with SAA. Patients were treated with fludarabine (40 mg/m2/d; day [−5 to −2]) and cyclophosphamide (50 mg/kg/d; day [−5 to −2]). Altogether, 81 patients indicated initial engraftment, whereas two cases showed primary graft failure. And four of the 81 cases indicated graft rejection during follow-up. Regardless of a high cumulative incidence of acute (55/83; 66.2% grade II- IV; 47/83; 56.6% III- IV) and chronic graft-versus-host disease (50/83; 60.2%), in total, 77 patients showed durable engraftment and transfusion independence, and 64 are alive at a median time of 49 months with an overall survival rate of 66%. In conclusion, this conditioning indicated well toleration, mild toxicity, durable engraftment, excellent survival as well as less cost. Its application might shed new light on SAA at high risk of graft rejection in resource-limited countries. [ABSTRACT FROM AUTHOR]

Minimal criteria requirements of stem cell replacement, conditioning regimen and modalities of infusion essential for cure of sickle cell disease (SCD) by bone marrow(BM)/stem cell transplantation or gene therapy must be established prior to clinical trials. The threshold of normal BM/stem cells for therapeutic correction of this red blood cell disorder was evaluated in the SAD murine SCD model from peripheral donor white blood cells. From 11 groups of stable chimeric SAD mice (5–92%) analyzed over ∼2 years, mice with ∼16% normal donor stem cells showed improvement of haematological and erythroid responses. Mice in the 26% chimeric group and above demonstrated substantial amelioration of organ pathologies with generalized decreased iron deposits, fibrosis and reached normal lifespan. Subsequently, the minimal myelosuppression concurrently with number and timing of infusions and number of BM cells was determined to reach therapeutic threshold in SAD mice. Higher myelosuppression (2 Gy vs. 1 Gy) and cell number in single infusion led to increased chimerism. Importantly, administration of three-equivalent cell subdoses within 28 h of mild myelosuppression resulted in 100% recipient engraftment at therapeutic levels. These studies established the long-term therapeutic chimeric threshold of normal white blood cells at ∼26% and determined the minimal fractionated BM/stem cell doses concomitant with mild myelosuppression for significant correction of SCD in SAD mice. [ABSTRACT FROM AUTHOR]

Matched unrelated donor stem cell transplantation (MUD-SCT) provides the only curative option for patients with follicular lymphoma (FL) who fail conventional therapies and do not have a sibling donor. The purpose of this study was to analyse the outcome of patients with FL treated with MUD-SCT included in the European Group for Blood and Marrow Transplantation registry. 131 patients treated with reduced-intensity conditioning (RIC, n = 87) or conventional myeloablative (CONV, n = 44) MUD-SCT between 2000 and 2005 were included. Median time from diagnosis to MUD-SCT was 47 months and the median number of previous therapeutic regimens was 4 (previous autograft: 47%). RIC recipients were significantly older, with a longer interval from diagnosis to MUD-SCT and had failed a previous autograft more frequently than CONV recipients. Non-relapse mortality (NRM) was 24% and 30% at 100-d and 1-year, respectively. After a median follow-up of 36 months, 17% of the patients developed disease progression, the 3-year progression-free survival (PFS) being 47%. Three-year overall survival (OS) for the whole series was 51%. On multivariate analysis, RIC regimens were associated with at lower NRM and a significantly longer PFS and OS. This retrospective study demonstrated that MUD-SCT results, even in heavily pre-treated populations, in a meaningful PFS and OS. [ABSTRACT FROM AUTHOR]

Eight children with FA underwent allogeneic HSCT without using irradiation for the conditioning regimen. Patients received two different conditioning regimens: first two patients received BU 1.5 mg/kg/day for four days and CY 10 mg/kg/day for four days and the other regimen was: Flu 30 mg/m2/day for five days, CY 10 mg/kg/day for two days, and ATG-Fresenius 9–10 mg/kg/day for four days. GVHD prophylaxis consisted of CsA + MTX for the first two patients and only CsA for the others. All patients received HLA-identical stem cells from related donors. Primary engraftment was demonstrated in all patients. No patient developed acute GVHD and one patient had chronic GVHD. Only one patient who received BU based regimen died because of VOD. Overall, seven patients (87.5%) are alive with stable full donor chimerism at a median follow-up time of 2.5 yr (range: 1.7–8.9 yr). None of the patients developed secondary malignancy. Based on our data, we conclude that Flu-based, non-irradiation conditioning regimen was safe with low organ toxicity and stable engraftment in FA patients undergoing HSCT from matched related donors. [ABSTRACT FROM AUTHOR]

The safety and efficacy of a preparation with treosulfan/thiotepa/fludarabine were explored in 20 thalassaemia patients given allogeneic marrow transplantation. Seventeen patients were transplanted from unrelated donors after receiving anti-thymocyte globulin. The regimen was well tolerated. Two patients experienced secondary graft failure; one died of acute graft-versus-host disease. Cumulative incidence (95% confidence interval, CI) of transplantation-related mortality and graft failure was 5% (95% CI, 0–34%) and 11% (95% CI, 3–43%), respectively. Two-year probability of survival and thalassaemia-free survival was 95% (95% CI, 85–100%) and 85% (95% CI, 66–100%), respectively. This regimen might find elective application in patients at high risk of developing life-threatening complications. [ABSTRACT FROM AUTHOR]

OS is a non-SCID immunodeficiency characterized by a poor outcome even after BMT. We report here a case of BMT without preparative conditioning regimen, and with a successful engraftment in a five-month-old infant with OS. The patient was transplanted with 15 × 108 bone marrow mononuclear cells/kg, from his HLA matched brother, without preparative regimen and GVHD prophylaxis. Immunological status was assessed before and after the BMT, and the engraftment was monitored with microchimerism analysis. Six days after BMT, an acute GVHD involving first the skin, then the liver and gut, complicated the post-transplantation course. An excellent engraftment was confirmed by donor chimerism over 95% respectively at day post-transplantation 30, 60, 90, and 150. The cellular immunity of the patient was restored, and infectious complications decreased after BMT. Later the patient experienced chronic GVHD, and he died on day post-transplantation 246 from GVHD. BMT without conditioning regimen for OS is feasible, but there must be a megadose cell transplantation, and appropriate prophylactic immunosuppressive treatment to prevent acute GVHD. [ABSTRACT FROM AUTHOR]

Summary. We evaluated transplant-related mortality (TRM), leukaemia relapse, leukaemia-free survival (LFS) and overall survival (OS) in patients receiving busulphan and cyclophosphamide (BuCy) or cyclophosphamide and total body irradiation (CyTBI) prior to allogeneic bone marrow transplantation (BMT) for acute myelogenous leukaemia (AML) in first remission. Outcomes of 381 human leucocyte antigen (HLA)-matched sibling transplants using BuCy were compared with 200 transplants using CyTBI performed between 1988 and 1996. The incidence of hepatic veno-occlusive disease was higher with BuCy (13%) than with CyTBI (6%) (P = 0·009). Risks of acute and chronic GVHD were similar. In multivariate analysis, relapse risk was higher in the BuCy group [relative risk (RR) = 1·72; 95% confidence interval (CI), 1·05–2·81; P = 0·031]. Eleven of 373 evaluable patients in the BuCy group had a central nervous system relapse in contrast to none of 194 evaluable patients in the CyTBI group (P = 0·016). There were no differences in TRM, LFS and OS. CyTBI conditioning may lower relapse risk but produces comparable TRM, LFS and OS to BuCy for HLA-matched sibling transplantation in first remission AML. [ABSTRACT FROM AUTHOR]

To improve the complete response (CR) rate in advanced multiple myeloma (MM) without increasing the toxicity of high-dose therapy, we have used a new conditioning regimen. A combination of BE-8 [an anti-interleukin 6 (IL-6) murine monoclonal antibody] and dexamethasone followed by high-dose melphalan (220 mg/m2) and autologous stem cell transplantation was used to treat a series of 16 patients with advanced multiple myeloma. A strong inhibition of IL-6 activity evaluated by quantification of C-reactive protein was observed in all patients and was correlated with the high CR rate achieved with this combination therapy. [ABSTRACT FROM AUTHOR]

High-dose chemoradiotherapy conditioning regimens for autologous stem cell transplantation (ASCT) are generally held to give similar results in multiple myeloma (MM), but no specific comparative study has been published. We addressed this issue by comparing the main high-dose chemoradiotherapy regimens used in the Spanish Registry. Patient cohorts included 315 cases treated with 200 mg/m2 melphalan (MEL200), 127 patients with 140 mg/m2 melphalan plus total body irradiation (MEL140 + TBI) and 121 cases with 12 mg/kg busulphan plus 140 mg/m2 melphalan (BUMEL). After ASCT, granulocyte and platelet recovery time was similar in all conditioning groups. There were no differences in transplant-related mortality. All regimens yielded a similar response in reference to pre-ASCT MM status, although BUMEL produced a slightly better overall response when compared with the other regimens (97% vs. 89% and 92%, P = 0·003). The 5-year overall survival (OS) with BUMEL was 47% [95% confidence interval (CI) 26–68] compared with 43% (CI 31–54) for MEL140 + TBI and 37% (CI: 18–56) for MEL200. The median survival for the BUMEL group was 64 months compared with 45 and 37 months for the MEL200 and MEL140 + TBI groups respectively. These differences were non-significant (P = 0·2). The median event-free survival (EFS) was better for BUMEL (32 months) than for MEL200 (22 months) or for MEL140 + TBI (20 months). The differences in EFS between BUMEL and the other conditioning regimens reached statistical significance (P = 0·01). Nevertheless, the adjusted multivariate analysis for OS and EFS revealed that the conditioning regimens had no independent prognostic value. We concluded that three different conditioning regimens, commonly used for ASCT in MM, have a similar antimyeloma effect. However, the trend for better results observed in our series with BUMEL requires a prospective trial. [ABSTRACT FROM AUTHOR]

What is known and Objective: Chemotherapy can increase treatment-related mortality associated with future haematopoietic stem cell transplantation (HSCT) for patients with relapsed/ refractory acute myeloid leukaemia (AML). There is usually insufficient time to find a suitable unrelated donor for these patients. We report on the use of decitabine, a DNA methyltransferase inhibitor as a conditioning regimen for a patient undergoing HSCT. Case summary: Our patient was a 21-year-old male diagnosed with AML-M1 with 845% blast cells and a normal karyotype. His risk stratum was intermediate, without specific mutations of FLT3/ITD, NPM1, CEBPA and C-kit. He underwent successful haploidentical HSCT using decitabine, a conditioning regimen. What is new and conclusion: We present the first report of a patient with refractory AML (with 58% blast cells) treated successfully with decitabine as a conditioning regimen in haploidentical HSCT. [ABSTRACT FROM AUTHOR]

Allogeneic stem cell transplantation remains the best option for young patients with SAA. With genetically identical twin as an ideal donor, the majority of SAA patients require appropriate immunosuppression before and after stem cell transplantation to obtain long-term hematopoietic reconstitution. Alkylating agents, used during conditioning, are associated with short- and long-term toxic effects that lead to poor compliance of treatment and could compromise the quality of future life. Three SAA patients, transplanted from genetically identical twins without using alkylating agents during conditioning, showed rapid and sustained hematological reconstitution without any evidence of conditioning-related toxicity. [ABSTRACT FROM AUTHOR]

Aims: Treosulfan is an alkylating agent increasingly used prior to haematopoietic stem cell transplantation. The aim of this study was to develop a population pharmacokinetic (PK) model of treosulfan in paediatric haematopoietic stem cell transplantation recipients and to explore the effect of potential covariates on treosulfan PK. Also, a limited sampling model (LSM) will be developed to accurately predict treosulfan exposure suitable for a therapeutic drug monitoring setting., Methods: In this multicentre study, 91 patients, receiving a total dose of 30, 36 or 42 g/m 2 treosulfan, administered over 3 consecutive days, were enrolled. A population PK model was developed and demographic factors, as well as laboratory parameters, were included as potential covariates. In addition, a LSM was developed using data from 28 patients., Results: A 2-compartment model with first order elimination best described the data. Bodyweight with allometric scaling and maturation function were identified as significant predictors of treosulfan clearance. Treosulfan clearance reaches 90% of adult values at 4 postnatal years. A model-based dosing table is presented to target an exposure of 1650 mg*h/L (population median) for different weight and age groups. Samples taken at 1.5, 4 and 7 hours after start of infusion resulted in the best limited sampling strategy., Conclusions: This study provides a treosulfan population PK model in children and captures the developmental changes in clearance. A 3-point LSM allows for accurate and precise estimation of treosulfan exposure., (© 2019 The Authors. British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)