Reduced-toxicity Conditioning Regimen Research Articles

Comparative analysis of reduced toxicity conditioning regimens between fludarabine plus melphalan and fludarabine plus busulfex in adult patients with acute lymphoblastic leukemia.

Reduced-toxicity conditioning (RTC) regimens aim to mitigate regimen-related toxicity while maintaining anti-leukemic efficacy in allogeneic hematopoietic stem cell transplantation (allo-HSCT). We assessed outcomes of RTC regimens utilizing melphalan versus intravenous busulfan combined with fludarabine in adult acute lymphoblastic leukemia (ALL) patients. A retrospective analysis was conducted with 149 consecutive adult ALL patients (median age 51, range 18-60) in remission undergoing allo-HSCT. Patients received either fludarabine 150 mg/BSA plus 2 days of melphalan 70 mg/BSA (FM140, n = 76) from 2009 to 2015 or fludarabine plus 3 days of busulfan 3.2 mg/kg (FB9.6, n = 73) from 2016 to 2021. At 5 years post-HSCT, FM140 demonstrated superior disease-free survival (53.4% vs. 30.5%, p = 0.007) and lower cumulative relapse (27.4% vs. 46.8%, p = 0.026) than FB9.6. Five-year overall survival and non-relapse mortality did not significantly differ. FM140 exhibited a higher incidence of acute graft-versus-host disease (GVHD) grades II-IV (49.3% vs. 30.3%, p = 0.016), though rates of acute GVHD grades III-IV and chronic GVHD were similar. Multivariate analysis identified Philadelphia chromosome and minimal residual disease positive status, and FB9.6 conditioning as predictors of increased relapse and poorer disease-free survival. FM140 RTC regimen displayed significantly reduced relapse and superior disease-free survival compared to FB9.6 in ALL patients undergoing allo-HSCT, highlighting its current clinical utility.

Reduced-toxicity conditioning regimen with low dose post-transplantation cyclophosphamide and low-dose anti-thymocyte globulin as graft-versus-host disease prophylaxis for haploidentical stem cell transplantation in older patients.

We retrospectively analyzed outcomes in 55 patients ≥ 55 years of age with hematologic malignancies treated with fludarabine, cytarabine, busulfan, and low-dose cyclophosphamide as the conditioning regimen between January 1, 2019, and November 30, 2023. Neutrophil engraftment was successful in all patients within 28 days, with 54 patients (98.2%) achieving complete donor chimerism. The cumulative incidence of non-relapse mortality was 0% at 30 days, 7.5% at 100 days, and 19% at 1 year. The cumulative incidence of grade II-IV acute graft-versus-host disease (aGVHD) was 25% (95%CI, 15-38%), whereas that of grade III-IV aGVHD was 9.1% (95% CI, 3.3-19%). The cumulative incidence of extensive chronic graft-versus-host disease at 1 year was 3.6% (95%CI, 0.66-11%). The cumulative incidences of relapse, overall survival, and GVHD-free/relapse-free survival at 1 year were 9.0%, 71.6%, and 67.1%, respectively. An RIC conditioning regimen, including a combination of lower PTCy/ATG as GVHD prophylaxis, followed by haplo-SCT, might be a promising option for appropriately selected older patients.

Allogeneic Hematopoietic cell Transplantation Using Alemtuzumab in Asian Patients with Inborn Errors of Immunity.

Alemtuzumab is used with reduced-toxicity conditioning (RTC) in allogeneic hematopoietic cell transplantation (HCT), demonstrating efficacy and feasibility for patients with inborn errors of immunity (IEI) in Western countries; however, the clinical experience in Asian patients with IEI is limited. We retrospectively analyzed patients with IEI who underwent the first allogeneic HCT with alemtuzumab combined with RTC regimens in Japan. A total of 19 patients were included and followed up for a median of 18 months. The donors were haploidentical parents (n = 10), matched siblings (n = 2), and unrelated bone marrow donors (n = 7). Most patients received RTC regimens containing fludarabine and busulfan and were treated with 0.8mg/kg alemtuzumab with intermediate timing. Eighteen patients survived and achieved stable engraftment, and no grade 3-4 acute graft-versus-host disease was observed. Viral infections were observed in 11 patients (58%) and 6 of them presented symptomatic. The median CD4+ T cell count was low at 6 months (241/µL) but improved at 1 year (577/µL) after HCT. Whole blood cells continued to exhibit > 80% donor type in most cases; however, 3/10 patients exhibited poor donor chimerism only among T cells and also showed undetectable levels of T-cell receptor recombination excision circles (TRECs) at 1 year post-HCT. This study demonstrated the efficacy and safety of alemtuzumab; however, patients frequently developed viral infections and slow reconstitution or low donor chimerism in T cells, emphasizing the importance of monitoring viral status and T-cell-specific chimerism. (238 < 250 words).

The use of thiotepa in reduced toxicity conditioning regimens before hematopoietic stem cell transplantation in primary immunodeficiencies

The use of thiotepa in reduced toxicity conditioning regimens before hematopoietic stem cell transplantation in primary immunodeficiencies

Impact of Different Fludarabine Doses in the Fludarabine-Based Conditioning Regimen for Unrelated Bone Marrow Transplantation

The purine analog fludarabine (Flu) plays a central role in reduced-intensity conditioning and myeloablative reduced-toxicity conditioning regimens because of limited nonhematologic toxicities. Few reports assess the impact of different dose of Flu on the clinical outcomes and the Flu doses vary across reports. To compare the effect of Flu dose, the clinical outcomes of patients who received Flu and busulfan (FB; n = 1647) or melphalan (Flu with melphalan (FM); n = 1162) conditioning for unrelated bone marrow transplantation were retrospectively analyzed using Japanese nationwide registry data. In the FB group, high-dose Flu (180 mg/m2; HFB) and low-dose Flu (150/125 mg/m2; LFB) were given to 1334 and 313 patients, respectively. The 3-year overall survival (OS) rates were significantly higher in the HFB group than in the LFB group (49.5% versus 39.2%, P < .001). In the HFB and LFB groups, the cumulative incidences were 30.4% and 36.6% (P = .058) for 3-year relapse and 25.1% and 28.1% (P = .24) for 3-year nonrelapse mortality (NRM), respectively. In the multivariate analysis for OS and relapse, Flu dose was identified as an independent prognostic factor (hazard ratio: 0.83, P = .03; hazard ratio: 0.80, P = .043). In the FM group, high-dose Flu (180 mg/m2; HFM) and low-dose Flu (150/125 mg/m2; LFM) were given to 118 and 1044 patients, respectively. The OS, relapse, and NRM after 3 years did not differ significantly between the HFM and LFM groups (48.3% versus 48.8%, P = .92; 23.7% versus 27.2%, P = .55; 31.9% versus 30.8%, P = .67). These findings suggest that high-dose Flu was associated with favorable outcomes in the FB group but not in the FM group.

Chapter 12 - Hematopoietic stem cell transplantation for neuromyelitis optica spectrum disorder. Can immune tolerance be reestablished?

Neuromyelitis optica (NMO), which is also referred to as Devic's disease, was originally considered an aggressive subtype of multiple sclerosis (MS) presenting as optic neuritis and/or extensive transverse myelitis in which 50% of patients become blind or in a wheelchair within 5 years of onset. Subsequently, NMO was categorized as one of a spectrum of inflammatory and demyelinating autoimmune disorders that are distinct from multiple sclerosis and termed neuromyelitis optica spectrum disorder (NMOSD). NMOSD differs from multiple sclerosis by its clinical course, presentation, magnetic resonance imaging findings, clinical presentation, serum biomarker prognosis, and response to treatment. More recently, NMOSD has been subdivided according to auto-antibody status as aquaporin 4 (AQP4) seropositive NMO, myelin oligodendrocyte glycoprotein (MOG) antibody-associated disease (MOGAD), and seronegative NMOSD. The only treatment to date that has resulted in treatment-free remissions, now lasting for more than 5-10 years with posttreatment disappearance of anti-AQP4 antibodies, is hematopoietic stem cell transplantation (HSCT) using either an allogeneic (matched sibling or unrelated) donor with a reduced toxicity conditioning regimen or an autologous stem cell source using a nonmyeloablative conditioning regimen of plasmapheresis (PLEX), cyclophosphamide (Cytoxan®), rabbit antithymocyte (ATG), and rituximab (Rituxan®). Post-HSCT long-term resolution of disease activity and disappearance of AQP4 antibodies is consistent with HSCT-induced immune tolerance.

Selecting the Right Alternative Donor: Comparison of Outcomes of HLA-Mismatched Alternative Donor Hematopoietic Cell Transplantations in Adult Patients with Acute Lymphoblastic Leukemia Regarding KIR-Ligand Mismatch

Background: Allogeneic hematopoietic cell transplantation from cord blood (CBT) or haploidentical donor (HIDT) has proved to be a viable option for patients unable to find a human leukocyte antigen (HLA)-matched conventional donor. However, few single-centered studies have compared outcomes of the two alternative donor transplantations in adult acute lymphoblastic leukemia (ALL). Aim: Our aim is to compare outcomes of adult ALL patients treated with CBT with those treated with HIDT. Secondly, we tried to find out factor that could be considered in selecting donor for alternative donor transplantation to improve clinical outcomes. Methods: We compare outcomes of adult ALL patients treated with CBT (n=134) between 2008 and 2022 with those treated with HIDT (n=47) between 2018 and 2022.Conditioning regimen for CBT consisted of total body irradiation (12Gy) plus cytarabine (9g/m 2) plus fludarabine (150mg/m 2). Graft-versus-host disease (GVHD) prophylaxis was attempted using tacrolimus and mycophenolate mofetil. For HIDT, we used reduced toxicity conditioning (RTC) regimen including fludarabine (150mg/m 2) plus busulfan (6.4mg/kg). GVHD prophylaxis was done with ATG 1.5mg for 4 days plus short course methotrexate (MTX) (15mg/m 2) plus tacrolimus. Killer cell immunoglobulin-like receptor (KIR) ligand mismatch was calculated in both GVH and HVG direction using HLA-KIR ligand database, and its effect on clinical outcomes of alternative donor transplantation was investigated. Results: In HIDT, CD34+ cell count (´10 6/kg) was significantly higher (7.4 vs. 0.1, P&amp;lt;0.001), and the patients were older (49 vs. 33.5, P&amp;lt;0.001) compared to CBT. Other characteristics, such as cytogenetic risk and leukocyte count at diagnosis, did not show significant difference between the two groups. Incidence of acute GVHD II-IV (51.1% vs. 50.0%), III-IV (25.5% vs. 17.9%), and moderate to severe chronic GVHD (10.8% vs. 11.0%) between HIDT vs. CBT were similar. After median follow-up of 39.4 months (range: 5.5-167.4), HIDT showed higher cumulative incidence of relapse (CIR) compared to CBT (47.9% vs. 18.9%, P&amp;lt;0.001), which remained true even after stratifying by age subgroup (Age&amp;lt;40: P=0.033, Age≥40: P=0.002). Conversely, CBT showed higher non-relapse mortality (NRM) than HIDT (22.8% vs. 9.0%, P=0.038), but the same was true only in the older age subgroup (Age&amp;lt;40: P=0.484, Age≥40: P=0.002). These effects summed up to produce comparable results in estimated 3-year disease-free survival (DFS) of CBT and HIDT (58.4% vs. 43.5%, P=0.103), especially in the older subgroup (38.7% vs. 40.7%, P=0.897). Multivariate analysis also revealed that HIDT was related with higher relapse (HR 3.47; 95%CI 1.92-6.27, P&amp;lt;0.001), and CBT with higher NRM (HR 4.18; 95%CI 1.42-12.3, P=0.009). GVH direction KIR ligand mismatching worked for lower 3-year DFS in CBT (40.3% vs. 74.4%, P=0.007), although CIR and NRM did not show significant difference (27.8% vs. 15.6%, P=0.178; 35.0% vs 18.4%, P=0.057, respectively). On the other hand, the mismatch resulted in lower incidence of acute GVHD II-IV (32.0% vs. 54.2%, P=0.011). The trend remained when such effect was investigated separately in CBT and HIDT, but it was not statistically significant (33.3% vs. 53.1%, P=0.082; 28.6% vs. 57.6%, P=0.053, respectively). Conclusions: Our data shows higher NRM in CBT, and unexpected higher relapse rate in HIDT. Age of the patient should be considered when choosing CBT, because in older patients CBT showed notably worse NRM compared to HIDT. Higher incidence of relapse in HIDT may be attributable to ALL disease characteristics itself or insufficient elimination of leukemic cells by RTC regimen with stronger GVHD prophylaxis. Similar to what is known in acute myeloid leukemia, GVH direction KIR incompatibility showed protective effect against acute GVHD in ALL. However, the mismatch resulted in worse DFS in ALL patients treated with CBT, but not in those treated with HIDT. Possible explanation to this phenomenon is that the number of NK cells in cord blood was insufficient for mismatch-induced graft-versus-leukemia effect, while its immune response against infected cells was suppressed by the same mechanism that resulted in lower acute GVHD. Keywords: Acute lymphoblastic leukemia, Cord blood transplantation, Haploidentical donor transplantation, HLA-mismatched transplantation, Killer-cell immunoglobulin like receptor

Fludarabine and Melphalan Reduced Toxicity Versus a Myeloablative Fludarabine and Busulfan Conditioning Regimen for Acute Myeloid Leukemia

Introduction: The optimal induction regimen for an allogeneic hematopoietic cell transplant (allo-HCT) for a young adult patient diagnosed with acute myeloid leukemia (AML) remains to be defined. Among reduced intensity regimens (RIC), retrospective registry data from both CIBMTR and EBMT would suggest that a Fludarabine / Melphalan (Flu/Mel) regimen was superior to a Fludarabine / Busulfan x 2 (Flu/Bu2) regimen. The need for a myeloablative conditioning regimen over a RIC has been evaluated in at least six randomized clinical trials (RCT), and the results have yet to be uniform. Published meta-analysis suggests equipoise. The studies are further limited by including a heterogenous group of conditioning regimens, especially in the reduced intensity arm; they all come from developed countries, a mix of AML and MDS in most studies, and variation in age groups enrolled in them. In India and developing countries, there remain significant challenges with multi-drug resistant infections, financial constraints, and challenges with intensive care support. We hypothesize that in this setting, a reduced toxicity regimen, such as a combination of Fludarabine with Melphalan (140 mg/m 2) (Flu/Mel), may be preferable to a myeloablative regimen. Methods: A single-center retrospective analysis was undertaken to study the impact of a reduced toxicity Flu/Mel regimen versus a myeloablative Fludarabine combined with Busulfan (130 mg/m 2/day x 4 days) regimen (Flu/Bu4). All consecutive patients in all age groups with a diagnosis of AML who underwent an allo-HCT between Jan 2005 and Dec 2021 were included in this analysis. The conditioning regimen used was as per physician discretion with a broad guideline within the department to use a myeloablative Flu/Bu4 regimen in a young fit patient with high-risk features such as high-risk ELN at diagnosis, CR2, and beyond, or requiring more than one cycle of induction chemotherapy to achieve a complete remission (CR). Results: 439 patients underwent an allo-HCT for a diagnosis of AML at our center in the given time. The median age was 33 years (range: 1 - 63), and there were 267 (60.8%) males. The transplants were done in CR1 in 236 (54%), CR2 in 90 (20.5%), CR3 in 13 (3%), and in relapsed/refractory or with active disease in 100 (22.8%). The majority were matched sibling/related donors (MRD) in 284 (64.7%), followed by matched unrelated (MUD) in 75 (17.1%) and haploidentical in 80 (18.2%). The conditioning regimen used was Flu/Mel in 170 (38.7%), Flu/Bu4 in 185 (42.1%), and a mix of other regimens in 84 (19.1%). At an actuarial median follow-up of 4 years, the overall survival (OS) and event-free survival (EFS) of the entire cohort were 40.8% ± 3.0% and 38.6% ± 3.0%, respectively. The EFS of cases in CR1, CR≥2, and in relapsed/refractory/active disease were 47.7% ± 3.8%, 45.0% ± 5.5%, and 12.3% ± 3.6%, respectively. The baseline characteristics and clinical outcome of cases that received a Flu/Mel condition versus Flu/Bu4 conditioning are summarized in Table 1. In summary, baseline characteristics were comparable between the two groups, except that significantly more cases underwent a haploidentical transplant in the Flu/Bu4 group. In contrast, in the Flu/Mel group, there were significantly more cases in CR1, and the median age was also significantly older. The 5-year KM EFS of the Flu/Mel and Flu/Bu4 cohort was 51.7±3.9% and 43.9±3.9% (P-value = 0.297), respectively (Figure 1). On univariate analysis, only CR1 status before transplant and the presence of chronic GVHD impacted EFS positively, and on multivariate analysis, only CR1 status affected EFS. Conclusion: In conclusion, in one of the most extensive retrospective studies comparing a uniform reduced toxicity conditioning regimen with Flu/Mel versus a standard myeloablative Flu/Bu4 conditioning regimen, we find no significant advantage of Flu/Bu4 over a Flu/Mel conditioning regimen.

Thiotepa, Busulfan and Fludarabine Conditioning Regimen in Adult Patients Undergoing Allogeneic Stem Cell Transplantation for Lymphoid Malignancies. a Study on Behalf of Geth-TC

Background: The optimal conditioning regimen in allogeneic hematopoietic stem cell transplant (alloHCT) for lymphoid malignancies remains unclear. Reduced intensity regimens (RIC) allow older and more comorbid patients to receive alloHCT since lower non-relapse mortality (NRM) is observed, but disease control may still be a concern. The use of reduced toxicity conditioning regimens allows better disease control with a cost of higher toxicity. To date, no data are available regarding the use of thiotepa, busulfan and fludarabine (TBF) in adult patients allografted for lymphoma. Our aim is to describe survival outcomes and treatment-related toxicities of patients with lymphoid malignancies conditioned with TBF. Methods: Between December 2011 and July 2022, 116 patients diagnosed with lymphoid malignancies received a first alloHCT conditioned with a TBF-based regimen in 9 Spanish institutions. All consecutive patients were included in the study and data were collected retrospectively. Low-dose TBF was defined as the use of 5 mg/kg of thiotepa (T5) while a high-dose TBF was considered as the administration of 10 mg/Kg of thiotepa (T10). Main outcome variables were overall survival (OS), progression-free survival (PFS), NRM, relapse incidence (RI), cumulative incidence of acute (aGVHD) and chronic GVHD (cGVHD), and hematological recovery. Probabilities of OS and PFS were calculated using the Kaplan-Meier estimator method, and NRM, RI, GVHD and hematological recovery as cumulative incidences. Results: Baseline characteristics are summarized in Table 1. The median age was 52 (range 23-70) years and 62.1% of the patients were males. Aggressive B-cell lymphoma was the most common diagnosis (43.1%). Seventy-seven (66.4%) patients received T10, and 39 (33.6) T5. Median follow-up among survivors was 46.9 (range 16.9-136.5) months. At 3 years, OS, PFS, NRM and RI were 54.7% (95% confidence interval [CI], 45.5-63.9%) ( Figure 1), 44.9% (95% CI, 35.7-54.1%), 34.9% (95% CI, 27.1-44.9%) and 20.2% (95% CI, 14-29.2%), respectively. Of the 53 patients who died during follow up, causes of death were: 12 relapses and 41 transplant toxicities (16=infections, 8=GVHD, 5=endothelial complications, 1=traumatism, 11=missing). Fifty-one percent of toxicity-related deaths were observed during the first 3 months from transplant. All but 2 patients engrafted. The cumulative incidence of neutrophil engraftment at day +30 was 91.4% (95% CI, 86.3-96.8%). The cumulative incidence of grade II-IV aGVHD at day +100 was 25.4% (95% IC, 18.5-34.9%), with 8 patients presenting grade III-IV aGVHD. The 3-years cumulative incidence of all grade cGVHD was 29.8% (95% CI, 22.5-39.6%), with 15 patients presenting with moderate-severe cGVHD. Seventeen patients developed venooclusive disease (14.7%) with a median time from alloHCT infusion of 14 (range 7-93) days. On univariate analysis, no prognostic factors were found in terms of NRM, OS and PFS. However, higher doses of thiotepa were associated to a lower relapse incidence (13.2% vs 35%, p=0.0075) without differences in terms of NRM. The use of myeloablative conditioning (vs RIC) showed a trend towards a lower relapse incidence although it was not statistically significant (9.4% vs 24.5%, p=0.059) with no impact in NRM rates. On multivariate analysis these results could not be confirmed. Conclusions: In our series, TBF conditioning regimen allows efficient disease control at the expense of increased incidence of severe early toxicities. Despite higher NRM, TBF conditioning regimen showed similar OS rated compared to other regimens used for lymphoid malignancies. This regimen could be considered for fit patients with high-risk lymphoid diseases.

Treosulfan-Based Reduced-Toxicity Conditioning for Elderly Patients with High-Risk Myelodysplastic and Myeloproliferative Disease for Allogeneic Hematopoietic Stem Cell Transplantation

Introduction Allogeneic hematopoietic stem cell transplantation (alloHCT) is the only potential curative treatment for patients (pts) with high-risk myeloid malignancies. Despite advances in the supportive care over the past decades, alloHCT is still associated with significant toxicity, especially in the elderly population. The choice of an adequate conditioning regimen has become essential in order to prevent treatment-related morbidity and mortality. Since myeloablative conditioning (MAC) is mostly restricted to the younger population due to the high toxicity, reduced-intensity conditioning (RIC) provides an alternative solution. However, especially for pts with high-risk disease, a potential increase in the incidence of relapse must be taken into account. The advent of reduced-toxicity conditioning regimens (RTC), mostly based on treosulfan in combination with fludarabine, offers a balance between a favorable toxicity profile and a strong anti-neoplastic effect. Considering the increasing rates of alloHCT among older pts in the past decades, finding the optimal conditioning regimen is still an unmet need for this collective. The objective of this study is to analyze the outcome of pts aged ≥60 years who underwent alloHCT for myelodysplastic or myeloproliferative disease and received a treosulfan-based conditioning. In order to maximize the anti-leukemic effect of the conditioning in this population we chose the myeloablative dose of treosulfan of 14g/m2 daily. Materials and methods We retrospectively analyzed the outcome of adult pts ≥60 years with myelodysplastic syndrome (MDS), chronic myelomonocytic leukemia (CMML) or myelofibrosis (MF) who underwent their first allo-HCT from a matched or mismatched donor over a period of 10 years at the adult Bone Marrow Transplantation Unit of our institution. The conditioning consisted of a combination of treosulfan 14 g/m2/day on days -6 to -4, fludarabine, 30 mg/m2/day on days -6 to -2, alone or combined with 2 Gy TBI (day 0) for MDS and treosulfan, 14 g/m2/day on days -6 to -4, fludarabine, 30 mg/m2/day on days -6 to -3 for CMML and MF. Endpoints of this analysis were engraftment rate (together with time to engraftment), relapse-free survival (RFS), overall survival (OS), and non-relapse mortality (NRM). Continuous variables were illustrated as median values. NRM, RFS and OS for the whole cohort were analyzed with the Kaplan-Meier method and presented as survival functions. Results Between 01/2012 and 12/2022 91 consecutive elderly pts were eligible for this analysis. Patient and transplant characteristics are listed in Table 1. The median follow-up after allo-HCT was 3.12 years (4 months-10.5 years). Median age was 65 years, 76% (n = 69) of patients had an EBMT (European Society for Blood and Marrow Transplantation) risk score of ≥ 4. In 20 of 91 pts (22%) a 9/10 matched unrelated donor was selected, due to the lack of a more suitable donor. The standard graft versus host disease (GVHD) prophylaxis was a combination of calcineurin inhibitors (CNI) +/- mycophenolate mofetil and Anti-T-lymphocyte globulin (ATG) (n= 85, 94%). Neutrophil engraftment was achieved in 98% (n= 89) of pts. The median time to engraftment was 13 days (12, 15). Fourteen of 91 pts (15%) developed severe (grade III-IV) acute GVHD, and 44% (n= 40) had chronic GVHD of any grade. Considering early toxicity, 2 patients of 91 (2%) died before day +30 after alloHCT due to transplant-related toxicity, overall 6 of 91 (7%) in the first 100 days after alloHCT. The 2-year OS was 55% (95% CI, 44.7-.66.2) (Figure 1) and RFS was 48.5% (95% CI, 38.9-60.5). The 2-year NRM was 37% (95% CI, 33.5-39.5). No significant differences have been observed in the outcome of the different disease entities. Main causes of death were infections (n= 15, 32%), GVHD (n=13, 27.7%) and disease relapse (n= 13, 27.7%). Conclusions Our retrospective analysis suggests that a treosulfan-based RTC with myeloablative potential in an elderly and frail population of pts with high-risk myeloid diseases is feasible, with an excellent engraftment rate and a limited early toxicity, and promotes disease control. We report a 2-year NRM of 37%, which was partially due to severe GvHD in a cohort of pts with a relatively high-proportion of mismatched donors (20%). The role of post-transplant cyclophosphamide as backbone of the GvHD prophylaxis of RTC regimes should be further evaluated, in prospective trials.

Successful Treatment Outcomes of Hematopoietic Stem Cell Transplantation with Reduced-Toxicity Conditioning Regimen Incorporating Treosulfan in Pediatric Patients with XIAP Deficiency

Background X-linked inhibitor of apoptosis (XIAP) defciency is an inherited primary immunodefciency characterized by chronic infammasome overactivity and associated with hemophagocytic lymphohistiocytosis (HLH) and infammatory bowel disease (IBD). Although hematopoietic stem celltransplantation (HSCT) is the only curative therapy, the outcomes of HSCT for XIAP deficiency remain unsatisfactory. Methods We have performed HSCT with treosulfan based RTC regimen for pediatric patients with non-malignant disorders since January 2016, and reviewed the medical records of patients with XIAP deficiency who underwent treosulfan based HSCT to investigate outcomes of HSCT for patients with XIAP deficiency. Results Since January 2016, 4 patients with XIAP deficiency had undergone HSCT using RTC regimen consisted of fludarabine (150-180 mg/m 2), treosulfan (42 g/m 2), rabbit ATG (5-7.5 mg/kg), and thiotepa (10 mg/kg). All patients were male and received HSCT (2 from URD and 2 from HFD) at median 13.7 years old (range, 12.8-15.3), median 2 years (range, 0.5-3.9) after diagnosis of XIAP. They all achieved engraftment and complete donor chimerism at the time of last evaluation. One patient who received HFD HSCT developed acute GI GVHD grade 3 and VOD within 1 month from HSCT, which was recovered after treatment with systemic steroid and defibrotide. Except the patient, there was no fatal acute regimen related toxicity ≥ CTCAE grade 3. Two patients developed chronic GVHD: one had limited disease which was resolved after systemic steroid therapy and the other had extensive disease. During the median 43 months (range, 33.1-63.0) follow-up, all survived without disease recurrence. Conclusions HSCT with treosulfan based RTC regimen is promising treatment option for pediatric patients with XIAP deficiency, with successful engraftment and low treatment-related toxicity. However, further studies including a larger multicenter trial and measures to refine the regimen are mandate to verify efficacy and safety of this regimen.

Myeloablative Dose of Busulfan and Fludarabine Combined with In Vivo T Cell Depletion Is Safe and Effective Conditioning for Acute Myeloid Leukemia and Myelodysplastic Syndrome Patients

Allogeneic hematopoietic stem cell transplantation (HSCT) is a curative strategy for acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS). The prediction of transplantation-related mortality (TRM) using the Hematopoietic Cell Transplantation Comorbidity Index (HCT-CI) score and an arbitrary upper age limit of 55 years for administering myeloablative conditioning (MAC) are common strategies to ensure a safe procedure. The use of reduced-toxicity conditioning regimens is an additional approach to providing safe and effective myeloablation. Herein we report the outcome of AML and MDS patients conditioned with fludarabine and a myeloablative dose of busulfan (FB4) stratified by age and HCT-CI score. The primary objective was overall survival (OS) for patients age ≥55 years. Secondary objectives were total OS, TRM, graft-versus-host disease (GVHD), and GVHD, relapse-free survival (GRFS). The 2 year OS was 72% in patients age <55 and 51% in patients age ≥55. In patients age ≥55 with an HCT-CI <2, the estimated 2 year OS was 64%, with median OS not reached. In those with HCT-CI ≥2, the 2-year OS was 43%, with a median OS of 14 months. The total cumulative incidence of relapse was 30% regardless of age or HCT-CI score. FB4 conditioning regimen offers a high rate of prolonged remission with a relapse rate similar to that reported in previous studies. These positive outcomes suggest that this conditioning platform can be offered to patients age ≥55 years in the absence of comorbidities, and that age should not be the sole determinant of conditioning intensity.

Hematopoietic stem cell transplantation with reduced toxicity conditioning regimen in mitochondrial neurogastrointestinal encephalopathy syndrome.

Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is a rare autosomal recessive disorder due to mutations in the TYMP gene. Clinical findings are characterized by neurologic manifestations and severe gastrointestinal dysfunction. The syndrome is usually fatal, the most effective treatment appears to be hematopoietic stem cell transplantation (HSCT). In this retrospective study, we evaluated HSCT that was performed using a reduced toxicity myeloablative conditioning regimen in patients with MNGIE at our center. A total of six allogeneic transplant procedures were performed in four patients. Three patients had fully matched donors, and one patient had a haploidentical donor. Treosulfan-based myeloablative conditioning regimen was applied in five of six transplants. Bone marrow was used as a stem cell source. One patient is being followed up in the 4th year of posttransplant with full chimeric and without graft versus host disease (GVHD). One patient died of acute stage IV gastrointestinal system GVHD. Two patients underwent second transplantation due to engraftment failure, one of which was the patient who had a haploidentical transplant. Treosulfan-based regimen is well tolerated, although engraftment failure with this conditioning regimen can be a significant problem. We share our haploidentical transplant experience, which will be the first reported case in the literature.

Reduced Toxicity FluBu3 Regimen Showed a Comparable Post-Transplant Outcomes to a Myeloablative BuCy Conditioing in Acute Myeloid Leukemia Patients Receiving First Allogeneic Hematopoietic Stem Cell Transplantation in MRD Negative CR1

Introduction: In a previous report, we found that post-transplant clinical outcomes were not significantly different between MAC (BuCy, CyTBI) and RIC (FluBu2TBI400) groups in AML CR1 with pre-transplant low WT1 expression. Based on this result, we expanded the use of conditioning regimen with reduced dose intensity for patients achieving deep response by minimal residual disease (MRD) assessment with available assays. FluBu3 regimen, consisting of fludarabine for 5 days (30mg/m2/day, D-6 to D-2) and busulfan for 3 days (3.2mg/kg/day, D-5 to D-3), was chosen and applied as reduced toxicity conditioning (RTC) in our institution since Jan 2017. Method: In this analysis, we compared MAC and RTC regimens; BuCy (busulfan 3.2 mg/kg/day for 4 days from D-7 to D-4 and cyclophosphamide 60 mg/kg/day for 2 days from D-3 to D-2) and FluBu3 protocols were used as MAC and RTC regimen, respectively. The inclusion criteria were set as follows: (1) adult (age ≥ 18 years) AML patients who were registered in a prospective cohort study; (2) receiving first allogeneic hematopoietic stem cell transplantation (HSCT) in CR1 between Aug 2017 and Nov 2021; (3) MRD negative at pre-transplant; (4) transplantation from either HLA-matched (8/8) sibling donor (MSD), matched unrelated donor (MUD) or 1-locus mismatched (7/8) unrelated donor (MMUD); (5) the use of either BuCy or FluBu3 conditioning. MRD negativity was defined by the absence of abnormalities in the following order; (i) <3 log reduction in RUNX1-RUNX1T1 and CBFB-MYH11, (ii) <4 log reduction of NPM1 level from diagnosis, and (iii) pre-transplant WT1 levels ≥ 250 copies for RUNX1-RUNX1T1, CBFB-MYH11, or NPM1 mutation negative AML. Peripheral blood was used as the source of stem cells in all patients, and the data was analyzed based on information available as of Jun 2022. Results: A total of 124 patients met the inclusion criteria, and 78 (62.9%) and 46 (37.1%) patients received BuCy and FluBu3 conditioning, respectively. The median age was 45 years and the patients with intermediate cytogenetics comprised the majority (71.8%). By the donor type, 64 (51.6%), 48 (38.7%) and 12 (9.7%) patients underwent MSD, MUD and MMUD transplantation. Between the two conditioning groups, patients receiving FluBu3 were older (median 39.5 vs 53 years, p<0.001) and significantly more patients in the FluBu3 group had received ATG (37.9% vs 93.5%, p<0.001). In each of the BuCy and FluBu3 groups, after median follow up of 39.5 and 53 months (p<0.001), the 2-year overall survival (OS) of 78.3% and 84.5% (p=0.358), relapse free survival (RFS) of 78.0% and 76.3% (p=0.806), cumulative incidence of relapse (CIR) of 7.7% and 21.5% (p=0.074) and non-relapse mortality (NRM) of 14.3% and 2.2% (p=0.0324) were observed. In addition, the probabilities of grade II-IV acute graft versus host disease (aGVHD) and cGVHD of moderated to severe at 2-year for BuCy and FluBu3 were 46.2% and 39.2% (p=0.306), and 59.5% and 36.0% (p=0.008), respectively. At the time of data cut-off, relapse was the main cause of HSCT failure in FluBu3 group (n=8) while NRM contributes most to HSCT failure in BuCy group (n=11). Six of 8 relapsed patients receiving FluBu3, compared to 1 out of 6 in BuCy group, had high-risk features of either poor cytogenetics or FLT3-ITD mutation. The majority of NRM in the BuCy group, 8 out of 11 cases, was due to GVHD and 4 of them received transplantation from MMUD. Conclusion: Among the AML patients in MRD negative CR1, the FluBu3 RTC regimen showed a comparable post-HSCT outcomes to a BuCy conditioing in terms of similar OS and RFS, while associated with significant reduced NRM that was offset by trend towards higher risk of relapse.

Dose of IV Busulfan in Reduced Toxicity Conditioning Regimen for Older and/or Frail Patients with AML or MDS

Introduction: Reduced intensity conditioning (RIC) based on fludarabine and busulfan (FB) is a common option to transplant patients who are unfit for a standard myeloablative conditioning (MAC) regimen. We previously reported on a prospective trial that FB RIC using a 6.4 mg/kg total dose of i.v. busulfan (over 2 days) was feasible for older patients (Blaise, Haematologica, 2015, PMID: 25425691). However, disease control after RIC remains a challenge, notably in cases of myeloid malignancy. Thus, FB regimens using higher doses of busulfan (9.6 and 12.4 mg/kg, over 3 and 4 days, respectively) were developed with promising results in patients unfit for conventional MAC. However, the optimal busulfan dose in the FB regimen is still unknown and no prospective randomized trial has been conducted so far in this setting. We here investigated the impact of busulfan dose (2 vs. 3 vs. 4 days) in a prospective randomized trial in patients unfit for MAC who underwent allogeneic transplantation for myeloid malignancies (NCT01985061). Methods: This is a prospective, open label, multicenter randomized phase II trial. Main selection criteria were diagnosis of acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS); presence of an HLA matched related (MRD) or 10/10 unrelated donor (MUD); ineligibility for MAC due to age from 55 to 65 years, or <55 years with a hematopoietic cell transplantation-specific comorbidity index (HCT-CI) score >2. All patients received a conditioning regimen with fludarabine (30 mg/m² from day-6 to day-2) and i.v. busulfan at 3.2 mg/kg/day during 2, 3 or 4 days, according to the randomization arm, respectively named Bx2, Bx3 and Bx4. Graft-versus-host disease (GVHD) prophylaxis was based on antithymocyte globulin (ATG) (2.5 mg/kg on day-3 and day-2) and cyclosporin A from day-3 to day+180. Graft source was peripheral blood stem cells. Results: Of the 169 randomized patients, 152 (90%) were transplanted and analyzed according to treatment arm (61 Bx2, 56 Bx3 and 35 Bx4). The Bx4 arm was prematurely closed after 35 treated patients because of an excess of non-relapse mortality (NRM). Median age was 61 years (IQR: 55-63), 98 (64%) and 54 (36%) patients had AML and MDS, respectively, and 53 (35%) and 99 (65%) patients received an allogeneic stem cell transplant (allo-SCT) from an MRD and an MUD, respectively. There was no significant difference in baseline characteristics between the randomization arms. Grade 2-4 acute GVHD at day+100 was 26%, 45% and 51% in Bx2, Bx3 and Bx4 groups, respectively (Bx2 vs. Bx3 p=0.121, Bx2 vs. Bx4 p=0.052, Bx3 vs. Bx4 p=0.501). No significant difference was observed in 2-year extensive chronic GVHD (Bx2=34%, Bx3=36%, Bx4=34%). NRM at 2 years was 7%, 17% and 34% in Bx2, Bx3 and Bx4 groups, respectively (Bx2 vs. Bx3 p=0.146, Bx2 vs. Bx4 p=0.001, Bx3 vs. Bx4 p=0.062), without significant difference in relapse incidence (Bx2=20%, Bx3=29%, Bx4=14%). Overall survival (OS) probability was 81%, 63%, 54% at 2 years in Bx2, Bx3 and Bx4 groups, respectively (Bx2 vs. Bx3 p=0.060, Bx2 vs. Bx4 p=0.008, Bx3 vs. Bx4 p=0.412, Figure 1). Multivariate analysis showed that higher total busulfan doses (Bx3 and Bx4) and the use of an MUD significantly increased the risk of grade 2-4 acute GVHD. Age >60 years and Bx4 were the only independent poor prognostic factors that significantly influenced NRM and OS. Conclusions: In older or unfit patients, the use of 3 or 4 days of busulfan in the FB platform failed to improve outcome of patients compared to the 2-day administration, notably, no benefit in disease control was observed. In addition, the use of 4 days of busulfan is not feasible in this situation due to a high risk of NRM. Finally, fludarabine plus 2 days of i.v. busulfan resulted in better OS with a lower incidence of NRM and may be considered as a standard RIC regimen in this setting. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Validation of the Transplant Conditioning Intensity (TCI) Score for Allogeneic Hematopoietic Cell Transplantation

Introduction: Since non-relapse mortality (NRM) after allogeneic hematopoietic cell transplantation (HCT) is influenced by the conditioning regimen, it is essential to precisely calculate its intensity for any patient. Therefore, the Acute Leukemia Working Party (ALWP) of the European Society for Blood and Marrow Transplantation (EBMT) registry previously developed the Transplant Conditioning Intensity (TCI) score to define conditioning regimens based on the sum of the doses (weight scores) for every component of the pre-transplantation regimen. HCT patients (pts) were stratified by a 3-index scheme with a low [1-2], intermediate [2.5-3.5] or high [4-6] TCI-score. (Bone Marrow Transplantation 2020; 55:1114) When tested in a large registry dataset of acute myeloid leukemia (AML) pts >45 years of age, TCI grouping was highly predictive for early and 2-year NRM, and better compared with the classical 2-index reduced intensity conditioning/ myeloablative conditioning (RIC/MAC) classification. The aim of the current study was to validate using a distinct dataset, the ability of the original TCI classification scheme to predict post-HCT NRM. Methods: TCI score was applied to a timely distinct cohort reported to the EBMT as the one used to establish the TCI classification scheme. We tested the impact of TCI in predicting early (day 180) NRM (defined as any death without previous relapse) in 55-75 years of age AML first complete remission (CR-1) pts who were transplanted between 2018 and 2021. Included pts were allografted with peripheral blood stem cells (PBSC, 96.4%) or bone marrow (BM, 3.6%) from a matched sibling donor (MSD, 25%) or unrelated donor (UD, 75%). NRM at 2 years was a secondary endpoint. Results: 4,312 AML pts (median age 63.4, interquartile range 59.5-67.2) were assigned to a TCI category, as previously described. 49% of the pts received a low [1-2], 47% an intermediate [2.5-3.5] but only 4% of the pts received a high [4-6] TCI-score regimen. As expected, there was an inverse relationship between age, Karnofsky status and hematopoietic cell transplant-specific comorbidity index (HCT-CI) and TCI group (p<0.0001). Besides a higher prevalence of MSD transplantations in the high (40%) as compared to low (21.6%) and intermediate (26.4%) TCI-groups (p<0.0001), pts were well balanced within TCI groups regarding other transplant and patient characteristics. The day (d)100, d180 and 2-year NRM ranged from 4.8-12.5%, 8.9-17%, and 17.4-23.9% between low, intemediate and high TCI scores, respectively. In univariate analysis, TCI provided a highly significant risk stratification for early and 2-year NRM (p<0.0001 for all pairwise comparisons between groups) (Figure 1). In the multivariate Cox regression analysis adjusted for age, Karnofsky status, HCT-CI and other variables, there was a significant increase in risk of early NRM with each TCI group (Table 1). Compared to low TCI, pts receiving intermediate and high score TCI regimens had a significantly increased risk for d180 NRM (hazard ratio [HR] 1.34, 95% CI, 1.03-1.74, p=0.029 and HR 2.37, 1.39-4.06, p<0.002, respectively). The HRs for d180 NRM pts receiving a high TCI [4-6] score regimen was 1.77 (1.06-2.97, p=0.029) when compared to the intermediate TCI [2.5-3.5] group. As expected, early NRM was also significantly influenced by incremental age, Karnofsky status score <90 and HCT-CI >=3. TCI grouping was also significantly associated with overall NRM. Similar results were found when the analysis was restricted to pts aged between 55 and 65 years (N=2,640). There was good concordance between RIC/MAC and low/high TCI score grouping, whereas 49% of the MAC pts and 51% of the RIC pts were re-classified as having received a reduced toxicity conditioning regimen with a TCI score of 2.5-3.5. Conclusion: Here, we validated in an independent patient cohort, the recently proposed 3-group TCI score for its ability to predict early NRM in AML pts >55 years of age. TCI predicts early NRM independently of other known prognostic factors such as age, Karnofsky, or HCT-CI. Compared to the current RIC/MAC classification model, the TCI provides a finer and more precise tool which may be easily calculated for any patient to offer safer transplantation especially in older and unfit pts. TCI may be used as a new, well-defined, and standard terminology for conditioning intensity in registry databases, in the literature and in clinical trials. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Umbilical cord blood: an undervalued and underutilized resource in allogeneic hematopoietic stem cell transplant and novel cell therapy applications.

The purpose of this review is to primarily discuss the unwarranted decline in the use of umbilical cord blood (UCB) as a source of donor hematopoietic stem cells (HSC) for hematopoietic cell transplantation (HCT) and the resulting important implications in addressing healthcare inequities, and secondly to highlight the incredible potential of UCB and related birthing tissues for the development of a broad range of therapies to treat human disease including but not limited to oncology, neurologic, cardiac, orthopedic and immunologic conditions. When current best practices are followed, unrelated donor umbilical cord blood transplant (CBT) can provide superior quality of life-related survival compared to other allogeneic HSC donor sources (sibling, matched or mismatched unrelated, and haploidentical) through decreased risks of relapse and chronic graft vs. host disease. Current best practices include improved UCB donor selection criteria with consideration of higher resolution human leukocyte antigen (HLA) typing and CD34+ cell dose, availability of newer myeloablative but reduced toxicity conditioning regimens, and rigorous supportive care in the early posttransplant period with monitoring for known complications, especially related to viral and other infections that may require intervention. Emerging best practice may include the use of ex vivo expanded single-unit CBT rather than double-unit CBT (dCBT) or 'haplo-cord' transplant, and the incorporation of posttransplant cyclophosphamide as with haploidentical transplant and/or incorporation of novel posttransplant therapies to reduce the risk of relapse, such as NK cell adoptive transfer. Novel, non-HCT uses of UCB and birthing tissue include the production of UCB-derived immune effector cell therapies such as unmodified NK cells, chimeric antigen receptor-natural killer cells and immune T-cell populations, the isolation of mesenchymal stem cells for immune modulatory treatments and derivation of induced pluripotent stem cells haplobanks for regenerative medicine development and population studies to facilitate exploration of drug development through functional genomics. The potential of allogeneic UCB for HCT and novel cell-based therapies is undervalued and underutilized. The inventory of high-quality UCB units available from public cord blood banks (CBB) should be expanding rather than contracting in order to address ongoing healthcare inequities and to maintain a valuable source of cellular starting material for cell and gene therapies and regenerative medicine approaches. The expertise in Good Manufacturing Practice-grade manufacturing provided by CBB should be supported to effectively partner with groups developing UCB for novel cell-based therapies.

Reduced-toxicity myeloablative conditioning regimen using fludarabine and full doses of intravenous busulfan in pediatric patients not eligible for standard myeloablative conditioning regimens: Results of a multicenter prospective phase 2 trial

Data regarding the safety and efficacy of reduced-toxicity conditioning regimen (RTC) prior to allogeneic stem cell transplantation (allo-SCT) to treat hematological malignancies in pediatric patients are limited. This prospective multicenter, phase 2 trial investigated a RTC regimen based on the combination of intravenous busulfan (3.2 mg/kg/d x 4 days), fludarabine (30 mg/m2/d x 5 days) and antithymocyte globulin (Thymoglobulin®, Genzyme; 5 mg/kg total dose) with the aim of delivering high dose myeloablation that would allow optimal disease control while minimizing toxicity, in a subgroup of children at very high risk of non-relapse mortality (NRM). The primary endpoint was NRM at 1 year after allo-SCT. A total of 48 high risk patients were included (median age, 13 years; range, 3-24). At 1 year, the cumulative incidence of recurrence/disease progression and NRM were 33% and 8%, respectively. With a median follow-up of 23 months, the Kaplan-Meier estimates of overall survival (OS) and disease-free survival (DFS) at 1 year were 69% and 58%, respectively. We conclude that the RTC regimen used in this prospective trial is safe, with a < 10% NRM rate noted among high-risk children and adolescents, paving the way for larger phase 3 trials incorporating novel agents pre- and post-allo-SCT.(ClinicalTrials.gov Identifier: NCT01572181).

Safety of Anti-NKG2A Blocking Antibody Monalizumab As Maintenance Therapy after Allogeneic Hematopoietic Stem Cell Transplantation: A Phase I Study

BackgroundFollowing allogeneic hematopoietic stem cell transplantation (Allo-HSCT), the phenotype and function of circulating NK Cells are altered; notably NK cells display an immature (CD56-bright/KIR -/CD57 -/NKG2A +) phenotype and a low cytotoxic activity. Since NK cells have demonstrated anti-leukemic activity in the context of Allo-HCT while less prone to induce GVHD than T cells, we hypothesized that NKG2A inhibition using the checkpoint inhibitor monalizumab (humanized IgG4 blocking monoclonal antibody) could improve NK cell mediated graft-versus-tumor effect, without triggering graft-versus-host disease. We thus performed the first clinical trial evaluating the safety of monalizumab as a prophylactic treatment after Allo-HSCT (NCT02921685).MethodThe objective was to determine the maximal tolerated dose (MTD) of a single infusion of monalizumab administered on day+75 or thereafter following Allo-HSCT. Inclusion criteria were: 1) adult patients who underwent first Allo-HSCT for hematological malignancy; 2) no prior history of GVHD, 3) reduced toxicity conditioning regimen, 4) ATG or PT-Cy based GVHD prophylaxis, and 5) GVHD prophylaxis with cyclosporine A ongoing at the time of monalizumab infusion.Four dose levels were investigated in this dose escalation study (0.04, 0.1, 0.3, and 1.0 mg/kg). Dose limiting toxicities (DLT) were defined by the occurrence of any grade 3 to 4 monalizumab-related adverse event within 28 days after infusion, including grade 3 to 4 acute GVHD and moderate to severe chronic GVHD. In case of DLT, a Bayesian continuous reassessment model (CRM) was used to predict the maximal tolerated dose (MTD) after each series of 3 patients treated at a given dose level. It was planned to treat 18 patients. Beyond clinical safety, blood samples were collected for NK and T cell immunomonitoring and receptor saturation assay.ResultsFifteen patients received monalizumab at a median time of 83 days (range: 75-103) after Allo-HSCT (3 at 0.04 mg/kg, 3 at 0.1 mg/kg, 3 at 0.3 mg/kg, and 6 at 1 mg/kg). Patients were transplanted for hematological diseases (9 AML, 3 MDS, 1 lymphoma, 1 CLL and 1 myelofibrosis), from a matched sibling (n=8), matched unrelated (n=6) or haploidentical donor (n=1).No DLT was observed during the dose escalation process or among the 6 patients treated at the highest dose level, justifying study early termination after 15 patients. Two patients developed transient low grade GVHD that spontaneously resolved without treatment (1 grade I acute GVHD on day+8 and 1 mild chronic GVHD on day+118). Systemic steroid requiring GVHD occurred in 3 patients (20%): 1 severe overlap GVHD (day+42, CR after treatment), 1 severe chronic GVHD (day+80, death from GVHD) and 1 late severe chronic GVHD after cyclosporine tapering for mixed chimerism (day+149, complete remission [CR] after treatment). No disease recurrence was observed, except for one patient with myelofibrosis who relapsed 3 years after monalizumab infusion. At a median follow up of 22 months (3-48) after monalizumab infusion, 13 out of 15 patients are in CR from their underlining malignancy without GVHD and immunosuppressive treatment at last contact.At the dose of 1 mg/kg, receptor saturation assays (RSA) showed persistent binding of monalizumab on peripheral blood NK cells. Indeed, more than 90% of NKG2A-positive NK cells were positive for monalizumab detection (Anti-IgG4-PE) until at least 14 weeks post treatment.ConclusionsMonalizumab can be safely administered after Allo-HSCT, with prolonged persistence on circulating NK cells. In the absence of DLT, MTD was not reached. Future trials will aim at measuring the clinical efficacy of monalizumab in this context, alone or in combination therapy. Disclosuresboyer Chammard: Innate Pharma: Current Employment. Chabannon: Sanofi SA: Other: Travel Support, Research Funding, Speakers Bureau; Bellicum Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees, Other: Travel Support, Speakers Bureau; Novartis: Speakers Bureau; BMS/Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Terumo BCT: Speakers Bureau; Miltenyi Biotech: Research Funding; Fresenius Kabi: Research Funding; EBMT: Membership on an entity's Board of Directors or advisory committees. Vey: Amgen: Honoraria; BMS: Honoraria; BIOKINESIS: Consultancy, Research Funding; NOVARTIS: Consultancy, Honoraria, Research Funding; SERVIER: Consultancy; JAZZ PHARMACEUTICALS: Honoraria; JANSSEN: Consultancy. Olive: ImCheck Therapeutics: Current holder of individual stocks in a privately-held company, Membership on an entity's Board of Directors or advisory committees; Alderaan Biotechnology: Current holder of individual stocks in a privately-held company, Membership on an entity's Board of Directors or advisory committees; Emergence Therapeutics: Current holder of individual stocks in a privately-held company, Membership on an entity's Board of Directors or advisory committees. Blaise: Jazz Pharmaceuticals: Honoraria.

Haploidentical Versus Cord Blood Stem Cell Transplantation As the Second Transplant for Relapsed Acute Myeloid Leukemia Patients after the First Stem Cell Transplantation

Haploidentical Versus Cord Blood Stem Cell Transplantation As the Second Transplant for Relapsed Acute Myeloid Leukemia Patients after the First Stem Cell Transplantation