Use Of Myeloablative Conditioning Regimens Research Articles

227 - Matched Related Donor Graft Recipients Seem to Benefit from the Use of Myeloablative Conditioning Regimens in Acute Myelogenous Leukemia

227 - Matched Related Donor Graft Recipients Seem to Benefit from the Use of Myeloablative Conditioning Regimens in Acute Myelogenous Leukemia

ATG-Ptcy-CSA for Gvhd Prevention in Peripheral Blood Haploidentical Hematopoietic Cell Transplantation for Adults with Hematological Malignancies

INTRODUCTION The introduction of post-transplant cyclophosphamide (PTCY) for GVHD prevention can be considered a milestone in haploidentical hematopoietic cell transplantation (haplo-HCT). And secondary to its efficacy, the use of haplo-HCT with peripheral blood stem cell (PBSC) grafts has significantly increased in last decade. However the optimal immunosuppressive agents to combine with PTCY using peripheral blood stem cell (PBSC) sources is still a matter of debate, as in a retrospective analysis conducted by CIBMTR using PBSC grafts and PTCY-based GVHD prophylaxis in the haplo-HCT setting, was associated with higher rates of acute and chronic GVHD than with using bone marrow stem cell grafts. PTCY-based prophylaxis is considered a standard of care when haploidentical donors are selected. PTCY combined with anti-thymocyte globulin and cyclosporine (PTCY-ATG-CsA) became our institutional GVHD prophylaxis for peripheral blood (PB) haplo-HCT in 2015. The present analysis aims to share updated information about our experience using ATG-PTCY-CsA for GVHD prevention in PB haplo-HCT. METHODS Between October 2015 to December 2021, 157 consecutive adults underwent haplo-HCT at our institution and were included in the study. The GVHD prophylaxis was composed of rabbit-ATG (Thymoglobulin; Genzyme-Sanofi, Lyon, France), PTCy (50 mg/kg/day on days +3 to +4), and CsA (started on day +5 and titrated to therapeutic levels ranging between 200 and 400 ng/ml). One hundred twenty (76.4%) adults received a total dose of 4.5mg/kg of ATG (0.5 mg/kg on day -3, 2 mg/kg on day -2 and 2 mg/kg on day-1), and 37 (23.5%) received 2 mg/kg (0.5 mg/kg on day -2 and 1.5 mg/kg on day -1). T-cell replete PBSC grafts were infused on day 0 in all cases. Data was collected retrospectively and updated in March 2022. To perform regression analyses, post-transplant follow-up was censored at 2 years. RESULTS Of the 157 patients, the median age was 57 years (range: 43-66), and 67 (44%) were 60 years or older. Sixty-four (44%) patients were females. Acute myeloid leukemia was the most prevalent baseline diagnosis (n=79, 50.3%), and 38 (24.2%) patients received myeloablative conditioning (MAC) regimens. Forty-six (30%) adults had a KPS ≤80%, 46 (30%) had an HCT-CI score >3, and 34 (23.4%) had a high or very-high disease risk index (DRI). Fresh products were infused in 90 (57.32%) cases. A total of 152 patients achieved engraftment. The median time for neutrophil and platelet engraftment were 17 (IQR 19-15) and 22 days (IQR: 12-28). The cumulative incidence function (CIF) of bloodstream infection at day +28 was 51.6%. The day +180 CIF of CMV and EBV reactivations were 62.5% and 65.4%, respectively, and 5 (3.2%) patients had post-transplant lymphoproliferative disorder. The CIFs of grade II-IV and grade III-IV acute GVHD estimated at day +100 were 26.3% and 9.5%, and the CIF of moderate/severe cGVHD at 1 year was 19.9%. As reported in Table 1, the use of MAC regimens (HR 2.70), the administration of 2 mg/kg of ATG (HR 4.42, P=0.003) and the selection of donors older than 40 years (HR 3.35, P=0.011) increased the risk for grade III-IV aGVHD. The infusion of frozen products was not found to be predictor for GVHD. Nevertheless, a non-significant trend to lower grade II-IV aGVHD was documented in patients receiving frozen PBSC grafts (HR 0.54, P=0.060). The median follow-up in survivors was 32 months. Overall, 73 (46.5%) patients died, and 28 (17.3%) relapsed. The leading causes of death were infection and relapse. The median of days to discontinuation of the immunosuppression in survivors was 83 days (IQR: 69-119). As shown in Figure 1, the estimated 2-year OS, RFS, NRM, CIR, and GRFS were respectively: 49.4%, 44.6%, 36.6%, 18.8%, and 35.7%. The multivariate regression analysis reported n Table 1 showed that older patients and those with high and very-high DRI were at higher risk for worse OS and higher NRM. CONCLUSION Dual T-cell depletion using PTCy and ATG (total dose of 4.5mg/kg) combined with CsA is a safe drug combination for PB haplo-HCT. The use of this prophylaxis provided an effective GVHD prevention with acceptable relapse rates. Moreover, the selection of younger donors, and the use of a total dose of 4.5mg/kg of ATG increased the effectiveness of GVHD prevention. Further research is needed to decrease rates of NRM for patients undergoing haplo-HCT using this prophylaxis. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

The late outcomes of syngeneic hematopoietic stem cell transplantation in patients with blood disorders

Introduction. Syngeneic hematopoietic stem cell transplantation is a type of allogeneic stem cell transplantation when the donor of stem cells is a genetically identical (monozygotic) twin of the recipient. After this type of transplantation, there is no immunological conflict as the graft versus host disease, but at the same time, there is no positive effect of the graft-versus-leukemia effect. Aim: to assess the overall survival, event-free survival, probability of relapse, and transplant-related mortality rates associated with syngeneic stem cell transplantation. Patients and methods. In the National Research Center for Hematology from January 1988 to December 2018 we performed 654 allo-HSCT: 17 (2.5%) of them from a syngeneic donor. We performed a «paired analysis» with patients after allo-HSCT from a HLA-identical sibling donor. We included patients after allo-HSCT from an HLA-identical related donor (n = 28) in Group 1 and patients after syngeneic stem cell transplantation in group 2 (n = 14). Patients with aplastic anemia (n = 3) were excluded from the «paired analysis». Results. Patients after syngeneic stem cell transplantation did not develop a graft-versus-host disease. The relapse developed in 50% of cases (n = 7). Five patients (35.7%) died: 4 of them due to the relapse of the disease, and 1 - due to the graft failure. The relapse probability in patients after syngeneic HSCT was higher and amounted to 18.4% versus 54.2% (p = 0.047) for allo-HSCT from HLA-identical sibling donor and a syngeneic donor, respectively. Overall and event-free survival in patients after syngeneic HSCT is comparable to those in patients after allo-HSCT from an HLA-identical sibling donor. Conclusion. Syngeneic hematopoietic stem cell transplantation is justified in the absence of another related or unrelated donor of hematopoietic stem cells. The use of myeloablative conditioning regimens, peripheral blood stem cells as a source of stem cells, or high doses of nucleated cells/kg in the case of using bone marrow will improve post-transplant parameters in patients after syngeneic hematopoietic stem cell transplantation.

Pharmacologic Strategies for Post-Transplant Maintenance in Acute Myeloid Leukemia: It Is Time to Consider!

Simple SummaryAllogeneic hematopoietic cell transplantation (allo-HCT) is a potentially curative therapeutic procedure for patients with high risk acute myeloid leukemia. Its anti-leukemic activity is mainly derived from the intensity of the conditioning regimen used and the graft-versus-leukemia effect exerted by the donor T lymphocytes. Despite major progress in the allo-HCT procedure in recent years with the achievement of lower non-relapse mortality and long-term disease control. However, up to 45% of patients still experience relapse. Therapeutic strategies post-transplant aiming at preventing disease relapse are discussed in this review.Patients with high-risk acute myeloid leukemia are offered allogeneic hematopoietic cell transplantation (allo-HCT) in first remission to reduce risk of relapse. However, disease recurrence remains the major reason of allo-HCT failure, occurring in around 35–45% of patients, and leading to dismal outcomes. Strategies to reduce the risk of relapse are greatly needed, especially in the early post-transplant phase where the graft-versus-leukemia (GVL) effect is not yet activated. Some practices include the use of myeloablative conditioning regimens, close monitoring of measurable residual disease and donor chimerism, rapid tapering of immunosuppression, and implementation of pre-emptive strategies as the use of donor lymphocyte infusion. However, it’s time to consider prophylactic pharmacologic interventions post allo-HCT that aim at maintaining leukemic clones under control by both direct cytotoxic activity and by enhancing the GVL effect. In this current review, available data on drugs targeting epigenetic pathways like azacitidine, or actionable mutations like FLT3 and IDH1/2 inhibitors used as maintenance post allo-HCT, will be discussed.

Outcomes after Haploidentical Hematopoietic Cell Transplantation with Post-Transplantation Cyclophosphamide: A Systematic Review and Meta-Analysis Comparing Myeloablative with Reduced-Intensity Conditioning Regimens and Bone Marrow with Peripheral Blood Stem Cell Grafts

Haploidentical hematopoietic cell transplantation (haplo-HCT) with post-transplantation cyclophosphamide (PTCy) may be the sole available curative option for several hematologic malignancies. However, the best choice of conditioning regimen and graft source has not been established. This study was conducted to compare myeloablative conditioning (MAC) regimens with reduced-intensity conditioning (RIC) regimens and peripheral blood stem cell (PBSC) grafts with bone marrow (BM) grafts in the haplo-HCT setting with PTCy. We performed a systematic review and meta-analysis of studies comparing MAC with RIC and PBSC with BM in the haplo-HCT. The search was conducted in PubMed and TRIALS on February 2, 2021, without a date limit. We excluded studies with >30% non-PTCy graft-versus-host disease (GVHD) prophylaxis and >30% nonmalignant diseases. We screened 570 abstracts from PubMed and TRIALS and selected 20 for full-text review and 17 for inclusion in the qualitative and quantitative analyses. For PBSC versus BM grafts, we found no difference in overall survival (OS; hazard ratio [HR], 1.05; P=.61; nPBSC=1983; nBM=2124), progression-free survival (PFS; HR, 0.95; P=.52; nPBSC=2663, nBM=2769), graft-versus-host disease (GVHD)-free relapse-free survival (GRFS; HR, 1.16; P=.07; nPBSC=1454; pBM=1647), or nonrelapse mortality (HR, 1.14; P=.13; nPBSC=1664; nBM=1862). Relapse was lower with the use of PBSC grafts (HR, 0.84; P=.001; nPBSC=2663; nBM=2769). The rates of acute GVHD (aGVHD) and chronic GVHD (cGVHD) were higher with PBSC grafts (aGVHD grade II-IV: HR, 1.67; P < .001; nPBSC=2663; nBM=2802; aGVHD grade III-IV: HR, 1.82; P < .001; nPBSC=1826; nBM=2000; cGVHD: HR, 1.46; P=.002; nPBSC=2686; nBM=2815). Engraftment was higher with PBSC grafts (HR, 1.27; P < .001; nPBSC=1461; nBM=1717). Comparing MAC and RIC, the use of MAC was associated with less relapse (HR, 0.70; P < .001; nMAC=1929; nRIC=2662), higher nonrelapse mortality (HR, 1.24; P=.002; nMAC=2016; nRIC=2790), but better PFS (HR, 0.86; P=.002; nMAC=1929; nRIC=2662). There were no differences between the 2 conditioning regimens in OS (HR, .95; P=.32; nMAC=2123; nRIC=3155), GRFS (HR, 0.97; P=.67; nMAC=1182; nRIC=1330), grade II-IV aGVHD (HR, 1.01; P=.81; nMAC=2099; nRIC=3090), or cGVHD (HR, 1.05; P=.44; nMAC=1929; nRIC=2662). This analysis shows that the use of BM grafts is associated with comparable outcomes as seen with PBSC grafts despite a lower incidence of GVHD and a higher relapse rate. The use of MAC regimens is associated with improved PFS. These results suggest that for fit patients, MAC remains the optimal conditioning regimen in terms of mortality, and that the use of PBSC grafts may further decrease relapse risk and hasten engraftment, provided that further strategies can be incorporated to decrease GVHD. Prospective comparisons are awaited.

Post-Transplant Maintenance Therapy for Patients with Acute Myeloid Leukemia: Current Approaches and the Need for More Trials.

Relapse rates following allogeneic stem cell transplantation for acute myeloid leukemia remain unacceptably high and a major cause of death. Maintenance therapies post-transplant administered either to patients with impending relapse or at high risk of relapse could present a strategy to improve survival and overall outcomes. With the increasing use of molecular and genomic characterization of the disease, more novel therapies became available as maintenance strategies. These options were, however, hindered by excessive toxicities, mostly hematologic, especially with the use of myeloablative conditioning regimens. Several key questions have also emerged including the efficacy of these therapies, the duration of maintenance, as well as the potential modulation of the graft and the immune microenvironment. These issues are further complicated by the paucity of well-designed prospective randomized clinical trials evaluating these agents. Future directions in this field should include better risk stratification and patient selection based on assays of minimal residual disease, as well as the incorporation of novel targets and pathways of leukemogenesis. In this article, we highlight the current evidence behind the use of post-transplant maintenance therapy, the optimal patient and disease selection, as well as the challenges faced by these strategies in an area that remains quite controversial. We will focus on therapies targeting leukemia stem cells that directly or indirectly modulate the allografted immune microenvironment and augment the graft-versus-leukemia impact.

Thrombotic Microangiopathy after Post-Transplantation Cyclophosphamide-Based Graft-versus-Host Disease Prophylaxis

Transplant-associated thrombotic microangiopathy (taTMA) is a systemic vascular illness associated with significant morbidity and mortality, resulting from a convergence of risk factors after allogeneic blood or marrow transplantation (alloBMT). The diagnosis of taTMA has been a challenge, but most criteria include an elevated lactate dehydrogenase (LDH), low haptoglobin, and schistocytes on peripheral blood smear. We performed a retrospective review of the 678 consecutive adults who received high-dose post-transplantation cyclophosphamide (PTCy)-based graft-versus-host disease (GVHD) prophylaxis between January 1, 2015, and August 31, 2018. In April 2016, we initiated a monitoring program of weekly LDH and haptoglobin measurements and blood smears when those 2 parameters were both abnormal on all of our adult patients undergoing alloBMT for hematologic malignancies. During the entire period, the 1-year cumulative incidence of taTMA was 1.4% (95% confidence interval, 0.5% to 2.3%). Eight patients were taking tacrolimus at the time of diagnosis, and 1 was not on any immunosuppression. Eight of 9 patients (89%) were hypertensive. Four patients had invasive infections at the time of diagnosis, 4 patients required renal replacement therapy, and 5 of 9 patients were neurologically impaired. Eculizumab was given to 6 patients (0.9%), of whom 2 died and 4 recovered with resolution of end-organ dysfunction. The paucity of events made the determination of risk factors difficult; however, the low incidence of taTMA in this cohort may be related to the limited use of myeloablative conditioning regimens, low incidence of severe GVHD, and use of PTCy. PTCy-based GVHD prophylaxis appears to be associated with a low incidence of severe taTMA.

An evaluation of the efficacy of allogeneic hematopoietic stem cell transplantation in patients with mucopolysaccharidosis type I (Hurler syndrome): the experience of the R.M. Gorbacheva Research Institute for Pediatric Oncology, Hematology and Transplantation

Mucopolysaccharidosis type I (MPS IH; Hurler syndrome) is a hereditary storage disease caused by a deficiency of the lysosomal enzyme alpha-L-iduronidase. Enzyme replacement therapy may extend the lifespan of affected patients by 6–12 years but the only currently available radical treatment option is allogeneic hematopoietic stem cell transplantation (allo-HSCT). Objectives: We aim to evaluate the influence of conditioning regimens of various intensities and “graft versus host” disease (GvHD) prophylaxis with anti-thymocyte globulin and post-transplant Cyclophosphamide (PTCy) on overall (OS) and event-free (EFS) survival, the incidence of GvHD, the normalization of alpha-L-iduronidase and glycosaminoglycan (GAG) levels over time as well as cardiovascular and cognitive recovery following allo-HSCT. The study was approved by the Independent Ethics Committee and the Scientific Council of the I.P. Pavlov First Saint Petersburg State Medical University. We included 28 patients with MPS IH who had received allo-HSCT at the clinic at the R.М. Gorbacheva Memorial Institute of Children Oncology, Haematology and Transplantation. The five-year OS was 89%, the EFS – 57%. The use of myeloablative conditioning regimens and allo-HSCT within 12 months of diagnosis improve EFS in affected patients. The cumulative incidence of grade II–IV acute GvHD and grade III–IV acute GvHD was 43% and 18% respectively. The use of PTCy results in a significantly lower incidence of this complication (69% vs 33%, p = 0.013). After allo-HSCT, normal alpha-L-iduronidase levels and urinary GAG excretion were achieved in cases where graft function was normal. Allo-HSCT is an effective treatment for patients with MPS IH. Myeloablative conditioning regimens are the preferred treatment modality for this group of patients but in cases of comorbidities or poor physical status at the time of allo-HSCT, conditioning regimens with reduced intensity may be opted for instead. PTCy may be used for GVHD prevention in patients with MPS IH without increasing the risk of cardiac toxicity.

Impact of Post-Transplant High-Dose Cyclophosphamide and Donor Sources on CMV Reactivation.

Introduction Cytomegalovirus (CMV) reactivation remains a common cause of morbidity and mortality following allogeneic hematopoietic cell transplant (HCT) despite attempts at prophylaxis. Following transplantation, surveillance of the peripheral blood CMV viral load with early aggressive treatment is commonly employed and has been an effective strategy at preventing overt infection. While a matched related donor (MRD) is often the preferred transplant type, the use of alternative donors including matched unrelated donors (MUD), mismatched unrelated donors (MMUD) and haploidentical (HI) transplants, has greatly increased over the past several years. The data regarding CMV infection among these alternative donor types is scarce. Objectives To better characterize the extent and risk factors for CMV reactivation among patients who received an allogeneic HCT for hematologic malignancies, particularly among HI transplant recipients and those who received post-transplant high-dose cyclophosphamide (PTCy) for graft-versus-host disease (GVHD) prophylaxis. Methods A retrospective analysis was performed on 88 adults with hematologic malignancies who received an allogeneic HCT at our institution from 2012-2017. Only cases with CMV seropositive donors and/or recipients were included. We compared donor types/sources, conditioning regimens, GVHD prophylaxis regimens, and assessed for CMV reactivation utilizing the peripheral blood polymerase chain reaction (PCR) values that are monitored in post-transplant clinic visits. Results Nineteen (22%) patients received MRD transplants, while the remainder received alternative donor sources, including 17 (19%) HI transplants. Overall, the rate of CMV reactivation was 27% with a significant difference noted between donor sources (p= Conclusion HI HCT transplant recipients are at high risk for CMV reactivation. The use of myeloablative conditioning regimens or PTCy did not affect the rate of CMV reactivation.

Comparative Analysis of Conditioning Regimens in Patients Undergoing Autologous Hematopoietic STEM CELL Transplant for Lymphoma in a Single Brazilian Center

Introduction The use of myeloablative conditioning regimen followed by autologous hematopoietic stem cell infusion is considered as standard of care for the first or second line treatment for diverse types of lymphoma. However, studies comparing different conditioning regimens are not frequent, and its choice can be based on transplant center's experience. In the last few years, our center had different choices due to the unavailability of some chemotherapy drugs, and the main options were BEAM, CBV and busulfan based regimen (BuMel). Objective Perform a comparative analysis among the three conditioning regimens used in our center, assessing the impact on toxicity and survival. Methods A retrospective cohort including lymphoma patients, who underwent first autologous transplant at our center from January 2014 to December 2017, were evaluated regarding toxicity - renal, hepatic, cardiovascular, gastrointestinal (including diarrhea) - as primary endpoint, doing paired analysis - according to the CTCAE (v 4.0). Results 120 patients were included – 46 patients used BEAM, 44 patients used CBV, and 30 patients used BuMel as conditioning regimen. Regarding patient's characteristics, there was no statistically difference in gender, type of lymphoma, and age. We observed distinct toxicity profiles between the groups. For renal toxicity, there was a difference between CBV (34.1%) and BEAM (11.1%), p=0.02. For hepatic toxicity, CBV (59.1%) was different than BuMel (16.7%), p=0.0008, and BEAM (13.0%), p Conclusion Our data did not show major differences in toxicities and other complications among the three conditioning groups. There was no impact on disease-free and overall survival. Therefore, all three options can be feasible as conditioning regimen for patients with lymphoma.

Risk Factors and Clinical Impact of Chronic Kidney Disease (CKD) after Allogeneic Stem Cell Transplant (allo-SCT)

Background: Although the number of long-term survivors after allo-SCT has been increasing with the recent improvements of transplant procedures, late complications have emerged as an important unsolved issue in these transplant recipients. CKD is generally recognized as a stage prior to end-stage renal disease, which requires renal replacement therapy, and the incidence of CKD among transplant recipients has been reported to be around 30%. We recently reported that administration of low-dose carperitide in the early phase of transplant had the potential to prevent development of CKD after allo-SCT. However, risk factors for CKD after allo-SCT have not been fully elucidated, so that suitable candidates for this preventive approach are unclear. To this end, this retrospective study was conducted. Patients and methods: In this study, 149 consecutive patients who underwent allo-SCT for the first time at Gunma University and Saiseikai Maebashi Hospital between 2006 and 2013 and survived without a relapse of underlying disease three months after transplant were included. There was no restriction on underlying disease, donor source, or conditioning regimen. CKD was defined as estimated glomerular filtration rate (eGFR) of less than 60 ml/min/1.73 m2 lasting more than three months, according to the KDIGO guideline. Overall survival (OS) was defined as the interval from the date of transplant to the date of death. Non-relapse mortality (NRM) was defined as any death without a relapse of underlying disease. Fisher’s exact test was used for comparison of binary variables. Cumulative incidences (CIs) of CKD were compared using the stratified Gray test, considering death without the event as a competing risk. The Fine-Gray proportional hazard model was used for multivariate analysis of risk factors for CKD. In the analysis of OS and NRM, CKD was treated as a time-dependent covariate. P < 0.05 was considered significant. Results: Of the 149 transplant recipients included in this study, 80 were male and 69 were female. The median age was 48 years (range, 18-72 years), and the median baseline eGFR was 92.2 ml/min/1.73 m2 (range, 19.4 - 172.8 ml/min/1.73 m2). Underlying diseases were acute myeloid leukemia in 77 patients, acute lymphoblastic leukemia in 39, and myelodysplastic syndrome in 20. Stem cell donors were related donors in 30 patients, unrelated donors in 78, and cord blood in 41, and almost all patients were conditioned with total body irradiation (TBI)-containing myeloablative conditioning (MAC) regimens. The 2-year cumulative incidence of CKD after transplant was 35.6%. On univariate analysis, age > 50 years, baseline eGFR < 90 ml/min/1.73 m2, use of FK506 for GVHD prophylaxis, prolonged calcineurin inhibitor use (> 6 months), and acute kidney injury (AKI) development within 90 days after transplant were significant risk factors for CKD development. Multivariate analysis showed that age > 50 years (hazard ratio [HR] = 3.322; p-value < 0.001), baseline eGFR < 90 ml/min/1.73 m2 (HR = 2.088; p-value = 0.018), use of MAC regimens (HR = 2.122; p-value = 0.035), prolonged calcineurin inhibitor use (HR = 2.078; p-value = 0.035), and AKI development within 90 days after transplant (HR = 2.697; p-value < 0.001) were independent risk factors for CKD development, but disease type, disease risk, donor type, HLA mismatch, TBI-containing conditioning regimen, transplant year, acute GVHD, and chronic GVHD were not. CKD development showed no significant impact on OS (HR = 1.063; p-value = 0.823), and CKD development was not associated with increased NRM (HR = 1.439; p-value = 0.335). Conclusion: These findings suggest that transplant recipients with some of the features mentioned above, including higher age, lower baseline eGFR, and use of MAC regimens, should be recognized as patients at high risk for CKD at the time of transplant. Thus, we plan to conduct a prospective trial to explore whether low-dose carperitide treatment can reduce the incidence of CKD after allo-SCT among such high-risk transplant recipients. DisclosuresNo relevant conflicts of interest to declare.

Acute Myeloid Leukemia Patients with Pre-Transplant Ablated Marrows Have Similar Rates of Survival and Relapse Compared to Patients in Complete Remission after Allogeneic Hematopoietic Cell Transplantation

Introduction:Pre-transplant remission status in patients with acute myeloid leukemia (AML) is one of the most important factors determining their outcomes after allogeneic hematopoietic cell transplantation (allo-HCT). Patients not in remission prior to undergoing allo-HCT continue to have a very poor prognosis. Complete remission with incomplete cell count recovery (CRi) following chemotherapy for acute myeloid leukemia (AML) has also been associated with reduced overall survival and increased risk of relapse. However, there is currently a paucity of data on transplant outcomes in AML patients with ablated marrows after prior chemotherapy. In these patients, waiting for count recovery for an extended time period leads to increased infectious complications, often making them ineligible for allo-HCT. We hypothesized that outcomes of AML patients with pre-transplant ablated marrows who undergo allo-HCT would be similar to those of patients who are in complete remission (CR) prior to allo-HCT. To answer this question, we retrospectively analyzed the outcomes of AML patients from a single institution who underwent allo-HCT in CR, CRi, or with an ablated marrow.Patient and methods:For this retrospective study, we analyzed the outcomes of 270 AML patients (median age 54 years, range 17 to 74 years, 146 males and 124 females) who underwent 6/6 HLA-matched sibling or 10/10 HLA-matched unrelated donor transplantation at Washington University School of Medicine in St. Louis between 2006 and 2013. Patients with persistent disease based on bone marrow biopsy immediately prior to transplant were excluded. Data was collected on baseline characteristics including patient and donor sex, AML type, induction therapy, conditioning regimen, stem cell source, and graft-versus-host disease (GVHD) prophylaxis. Based on their cell count and marrow recovery prior to allo-HCT, patients were divided into 3 categories: CR, CRi, and ablated marrow, using response criteria from the International Working Group. The primary outcomes were overall survival (OS) and disease-free survival (DFS), and the secondary outcomes were cumulative incidence of non-relapse mortality (NRM), cumulative incidence of relapse, acute graft vs. host disease (aGVHD), and chronic graft vs. host disease (cGVHD). Propensity-score matching was used to adjust for potential confounding effects of patient characteristics, and the between-group differences in OS or DFS were compared by Cox proportional hazards model.Results:Of the 270 patients, 206 were in CR, 45 in CRi, and 19 had ablated marrow prior to their allo-HCT. Median follow-up for the CR, CRi, and ablated groups were 524, 410, and 290 days, respectively. The patients with ablated marrows had a 3-year OS of 47% and DFS of 40%, as compared to patients in CR whose 3-year OS and DFS were 49% and 45%, respectively (Fig. 1). Using a 1:3 propensity-score matching (3 CR per 1 ablated), no significant differences were found in OS (HR=1.66, 95% CI 0.88-3.12; P = 0.12) or DFS (HR=1.39, 95% CI 0.75 - 2.58; P = 0.30). The cumulative incidence of NRM in our ablated marrow cohort was 58%, significantly higher than those in CR and CRi who had cumulative incidences of NRM of 22% (P = 0.0004) and 16% (P = 0.002), respectively (Fig. 2). The cumulative incidence of grade 2-4 aGVHD in patients with CR, CRi, and ablated marrow, were 38%, 38%, and 42%, respectively (P = 0.93). Likewise, the cumulative incidence of cGVHD in patients with CR, CRi, and ablated marrow, were 34%, 38%, and 16%, respectively (P = 0.22).Conclusions:Allo-HCT continues to be the curative therapy for patients with AML. Based on our results, overall survival and disease-free survival following transplant for patients with ablated marrows do not differ significantly from those in CR or CRi. Interestingly, there was a higher incidence of non-relapse mortality among patient with ablated marrows compared to those in Cr or CRi, which is most likely related to the use of myeloablative conditioning regimen in our ablated patients. These results could have an important bearing on patients with ablated marrows whom treating physicians might post-pone allo-HCT to wait for marrow recovery, thereby potentially putting them at increased risk for infectious and bleeding complications. Smaller cohort size is the major limitation of our study, and our results suggest investigating this important question in a large registry. [Display omitted] [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Post-Transplant Cyclophosphamide Following a Myeloablative Conditioning For Hematologic Malignancies Receiving An Unmanipulated Haploidentical Bone Marrow Transplant

BackgroundUnmanipulated family haploidentical transplants are becoming increasingly used in patients lacking an HLA identical family donor, or a well matched unrelated donor. Aim of the studyThis is an updated analysis of our program of haploidentical bone marrow transplant (hBMT) , followed by post-transplant high dose cyclophosphamide (PT-CY) in 95 patients with hematoloigic malignancies receiving a myeloablative conditioning. MethodsThe conditioning regimen consisted of thiotepa, busulfan, fludarabine (TBF) (n=47) , thiotepa melphalan fludarabine (n=5) , or 9.9-12 Gy TBI + fludarabine (n=43). The patients' median age was 49 years (17-74); the disease status at the time of transplant, was first complete remission (CR1, n=29) , CR2 (n=23), or active disease (n=38,40%). The diagnosis was AML (35%), ALL (24%), MDS (12%) myeloproliferative disorders (12%), other malignancies (17%). The total nucleated cell dose infused was 3.37 (1.4-9.17). The median follow up for surviving patients is 440 days (90-930). Graft versus host disease (GvHD) prophylaxis consisted in PT-CY on day+3 and +5 , cyclosporine (from day 0) , and mycophenolate (from day +1).▪ ResultsThe cumulative incidence of neutrophil (PMN) engraftment was (90%) and all surviving patients on day +30 had full donor chimerism. The median day for neutrophil engraftment was day +17 (11-32). The cumulative incidence (CI) of grade II-III acute GvHD was 14%, and of moderate chronic GvHD 8%, severe cGvHD 9%. The CI of transplant related mortality (TRM) is respectively 7%, 17%, 26% for patients in CR1, CR2, or with active disease. The CI of relapse is respectively 17%, 30%, 37% for patients in CR1, CR2, or with active disease. The overall actuarial survival is respectively 75%, 44%, 32% for patients in CR1, CR2, or with active disease (p=0.002) (Fig.1). The most frequent cause of death was leukemia (26%) followed by infections (9%). ConclusionsThese data confirm our first report on 50 patients and support the use of myeloablative conditioning regimens, followed by h-BMT with PT-CY. The risk of acute and chronic GvHD seems relatively low , as well as the overall transplant related mortality. We have not seen the excess relapse rate reported when patients are given a non myeloablative regimen, and disease control has been satisfactorily both for patients in remission, as well as for patients with active disease at the time of transplants. Disclosures:No relevant conflicts of interest to declare.

Conditioning Intensity in Allogeneic Hematopoietic Cell Transplantation (alloHCT) for Diffuse Large B-Cell Lymphoma (DLBCL)

Abstract 501Non-myeloablative (NMC) and reduced intensity (RIC) conditioning approaches rely primarily on a graft-vs-lymphoma (GVL) effect and aim at reducing transplant-related mortality (TRM) associated with myeloablative conditioning (MAC). We analyzed outcomes for 396 adults (228 male) receiving alloHCT for DLBCL following MAC (n=165), RIC (n=143) or NMC (n=88) regimens between 2000 and 2009 and reported to the Center for International Blood and Marrow Transplant Research (CIBMTR). Conditioning regimens were classified using consensus criteria. Engraftment, cumulative incidences of acute and chronic graft-vs-host disease (GvHD), TRM, progression and probabilities of progression-free (PFS) and overall survival (OS) were compared between MAC and NMC/RIC.Common MAC regimens were cyclophosphamide (CY) + total body irradiation (TBI) (54%) and busulfan (BU) + CY (23%). Common RIC regimens were fludarabine (Flu) with melphalan (44%) or BU (39%) and for NMC, Flu with CY (48%) and low dose TBI (33%). Practice patterns changed with declining use of MAC regimens after 2003 (> 66% of total being MAC pre-2003 and <33% after). Donors were HLA matched siblings in 40%, 26%, 30% of MAC, RIC and NMC recipients, respectively, with 67% overall receiving unrelated donor (URD) grafts. Significant (p <0.05) baseline differences between the cohorts included: RIC and NMC recipients were older (54% and 58% >50 yrs vs 39% for MAC), more likely to have received prior autoHCT (36% and 51% vs 18%), prior radiation and more prior chemotherapy regimens (55 and 70% vs 44% with >3 regimens) than those with MAC. Recipients of RIC and NMC were less likely to have chemotherapy resistant disease (30% and 26% vs. 42% for MAC); and had a longer median interval from diagnosis to alloHCT (median 27 and 36 mo vs. 17 mo).Day 100 engraftment was more frequent in RIC and NMC recipients (99% and 97% with ANC >500/cu.mm vs. 88% for MAC, p <0.001). Acute (43–44%) and chronic GvHD incidence (37–42% at 5 years) was similar across the groups. Outcomes are summarized in Table 1. TRM at day +100 and at 5 years was significantly higher for MAC compared with RIC and NMC groups (See Table 1). Lymphoma relapse/progression at 5 years was significantly lower for MAC vs. RIC and NMC but 5 year PFS and OS at 5-years did not differ significantly. In multivariable analysis, NMC (HR 0.58, p=0.026) and later year of alloHCT (HR 0.49, p<0.001) were associated with lower TRM while Karnofsky status <90 (HR 1.51, p=0.011), chemo-resistant relapse (HR 2.79, p<0.001) and URD (HR 2.32, p<0.001) were associated with higher TRM. Higher incidence of relapse/progression was associated with NMC (HR 2.14, p=0.003), non-receipt of rituximab prior to alloHCT (HR 1.69, p=0.008) and chemo-resistant disease (HR 2.06, p=0.006). Conditioning intensity did not impact OS and PFS.In selected patients with advanced DLBCL, allogeneic HCT can induce long-term PFS irrespective of the intensity of conditioning with a lower incidence of TRM with RIC and NMC regimens. Due to increased toxicity, the use of MAC regimens has been declining in recent years. However, the incidence of RIC/NMC, risk of relapse/progression was concordantly higher in the RIC/NMC recipients so that survival did not differ significantly between conditioning regimens. Further studies are needed to clarify optimal conditioning strategies for advanced DLBCL aiming to further reduce TRM.Table 1:ParameterIntensity of Conditioning (95% CI)p-valueMACRICNMCTRM @day +100 at 5 yrs32% (25–39%)24% (17–31%)17% (10–26%)0.02956% (48–64%)47% (38–56%)36% (26–46%)0.007Relapse @ 5 yrs26% (19–33%)38% (30–46%)40% (30–50%)0.031OS @ 5 yrs18% (12–25%)20% (13–29%)26% (17–36%)0.365PFS @ 5 yrs18% (12–24%)15% (9–23%)25% (16–34%)0.309 [Display omitted] Disclosures:Montoto:Genentech: Research Funding; Roche: Honoraria.

HLA-matched sibling stem cell transplantation in children with β-thalassemia with anti-thymocyte globulin as part of the preparative regimen: the Greek experience

BU combined with CY, the preferred preparatory regimen for thalassemic patients, is associated with a substantial incidence of graft rejection especially in patients with advanced disease stage. This study retrospectively analyzes the outcome of 75 consecutive pediatric patients with β-thalassemia who underwent HLA-matched sibling transplantation after anti-thymocyte globulin (ATG)-containing myeloablative conditioning regimens. With a median follow-up of 9 years (range 1-15 years), the overall survival (OS) and thalassemia free survival (TFS) rates were 96% and 92%, respectively. Both the estimated TRM and the cumulative incidence of rejection/failure were 4%. The cumulative incidences of acute GVHD grade II-III and grade III were 20% and 5.3%, respectively. No patient developed acute GVHD grade IV. Only two patients developed extensive chronic GVHD. The estimated OS and TFS for patients with Class 1 and 2 disease according to Pesaro criteria were 96.3% and 94.4%, whereas for patients with Class 3 disease they were 94.1% and 88.2%, respectively. In our series, the use of myeloablative conditioning regimens, which include ATG for the transplantation of thalassemic children from matched sibling donors, resulted in excellent outcomes with very low incidences of TRM and rejection.

HLA Association with Hematopoietic Stem Cell Transplantation Outcome: The Number of Mismatches at HLA-A, -B, -C, -DRB1, or -DQB1 Is Strongly Associated with Overall Survival

HLA matching between the donor and recipient improves the success of unrelated hematopoietic stem cell transplantation (HSCT). Because many patients in need of an unrelated transplant have only donors with mismatch, information is needed to evaluate the limits of HLA mismatching. We examined the association of survival, acute graft-versus-host disease (aGVHD) and relapse with HLA-A, -B, -C, -DRB, -DQB1, and -DPB1 mismatching in 334 patients coming from 12 French transplant centers and who received a non-T cell-depleted bone marrow graft from an unrelated donor. All patients were prepared with the use of myeloablative conditioning regimens. Our analyses demonstrate negative effects of HLA mismatching for either HLA-A, -B, -C, -DRB1, or -DQB1 loci on survival. Multivariate Cox analyses showed that a single mismatch was associated with a significant decrement in survival ( P = .046, hazard ratio [HR] = 1.41, confidence interval [CI] 95% 1.1-1.98). The presence of multiple mismatches was worse for survival ( P = .003, HR = 1.91, CI 95% 1.26-2.91) and severe aGVHD (grade III-IV) ( P = .002, HR = 2.51, CI95% 1.41-4.46). The cumulative incidences of aGVHD and relapse in those HLA-A, -B, -C, -DRB1, and -DQB1 identical pairs with 2, 1, or 0 DPB1 incompatibilities were 63%, 50%, and 51%, and 12%, 27%, and 20%, respectively, but these differences were not statistically significant. Similar differences of aGVHD and relapse, but not statistically significant, were observed in those HLA-A, -B, -C, -DRB1, and -DQB1 identical pairs with DPB1 disparities classified into permissive or nonpermissive mismatches according to Zino’s classification based on a hierarchy of the immunogenicity of the HLA-DP molecules. “Missing killer cell immunoglobulin-like receptor (KIR) ligand” evaluated on the presence of HLA-C1, -C2, and Bw4 groups in the recipients was not associated with aGVHD, survival, and relapse in this cohort of non-T cell-depleted HSCT.

Genetics of Risk Factors for Graft-Versus-Host Disease

Modern understanding of the genetic basis of graft-versus-host disease (GVHD) in allogeneic hematopoietic stem cell transplantation (HSCT) involves knowledge of human leukocyte antigen (HLA), killer immunoglobulin-like receptors (KIR), cytokine genes, and their interactions. Insights into the immunogenetic basis of GVHD come from long-standing clinical experience in the use of myeloablative conditioning regimens and donor bone marrow as the grafting source. Under these circumstances, donor T-cell recognition of host HLA can cause GVHD. The recent elucidation of HLA class I as ligands for natural killer (NK) cell inhibitory KIR demonstrates that GVHD is the result of a complex interplay between the innate and adaptive immune responses. The extent to which T cells and NK cells contribute to clinical GVHD is a function of the host post-conditioning environment, immunosuppressive treatments, and the content of the graft source. The contribution of donor and host genetic differences in cytokine genes in modulating risks of GVHD has recently been recognized.

Influence of the Intensity of the Conditioning Regimen on the Characteristics of Acute and Chronic Graft Versus Host Disease after Allogeneic Transplantation.

Although increasing numbers of allogeneic stem cell transplants are being performed worldwide using reduced intensity conditionings (allo-RIC), most of the current experience and knowledge on the characteristics of graft-versus-host disease (GVHD), especially chronic GVHD (cGVHD), comes from the use of myeloablative conditioning regimens (MCR). We have analyzed the incidence and characteristics of GVHD among 150 consecutive patients undergoing allo-RIC as compared to 88 concomitant patients undergoing MCR. All patients analized received peripheral blood stem cells (PBSC) from an HLA identical sibling and the same GVHD prophylaxis (cyclosporine and methotrexate). Incidences of acute GVHD (aGVHD) were 69% and 47% among MCR and allo-RIC, respectively (p<0.001). Incidences of grades 2–4 aGVHD were 51% vs 33%, respectively (p=0.0009). Regarding organ involvement, no signifficant differences were observed between either subgroups. Skin was the organ most frecuently involved in both subgroups (83 % vs 75.3% cases among MCR and allo-RIC patients, respectively; p=0.08). Regarding response to treatment, no significant differences were observed between both subgroups, with 66.1% vs 52.2% of patients reaching complete remission (CR) after first line therapy. Interestingly, gastrointestinal tract was the organ most frequently involved in treatment failure in both subgroups: 16 (66.6%) and 20 (80%) of MCR and allo-RIC patients (p=0.21) had gut GVHD relapse/progression/no response with or without other organs involvement. Liver was involved in treatment failure in 6 (25%) vs 12 (48%) patients undergoing MCR vs allo-RIC, respectively (p=0.02). In multivariate analysis, only type of conditioning (MCR vs RIC) significantly influenced the incidence of overall aGVHD: HR= 2.16 (95 % CI: 1.52–3.07), p<0.0001. Incidences of chronic GVHD (cGVHD) were 68% and 76% among MCR and allo-RIC patients, respectively (p=0.03), although patients who developed cGVHD, incidence of extensive cGVHD was higher in the MCR group as compared to allo-RIC (88 vs 64%, p=0.01). A higher incidence of severe skin cGVHD involvement was observed among MCR recipients (39.4% vs 9.6%, respectively; p=0.008). As far as response to immunosupressive treatment 41.4% of MCR vs 58.2% of allo-RIC patients reached CR (p=0.43). Among patients who reached CR of cGVHD, a high incidence of cGVHD relapse was observed in both subgroups (58.3% vs 50% among MCR vs allo-RIC patients), with most relapses occurring in the first year after inmunosuppression was stopped. Among patients who developed extensive cGVHD, 83.3% vs 37.9% of patients undergoing MCR vs allo-RIC required systemic immmunosupression 3 years after allogeneic PBSC transplantation (p=0.009). Thus, overall, duration of immunosupression was shorter among allo-RIC patients, since 36 months after transplant 68.8% vs 35.5% of patients receiving MCR vs RIC required systemic immunosupression (p=0.028). In conclusion, the use of reduced intensity conditioning regimens decreases the incidence of both acute and extensive cGVHD after PBSC allogeneic transplantation, thus reducing the immunosupression requirements at the long term follow up.