Conditioning Hematopoietic Stem Cell Transplantation Research Articles

Fluid Accumulation During The Early Phases Of Hematopoietic Stem Cell Transplantation (HSCT) Is Associated With An Increased Risk Of Mortality and Complications

Introduction It has been previously reported that increased fluid accumulation during peripheral blood hematopoietic stem cell (HSC) mobilization is associated with poor outcome in patients with amyloidosis who undergo autologous HSCT. It is unknown whether increased fluid accumulation during the early phases of HSCT is associated with poor survival in patients undergoing HSCT for other diseases. Objective To determine the impact of fluid accumulation during conditioning and in the first 10 days post HSC infusion on survival and risk of complications of patients who underwent both autologous and allogeneic HSCT. Methods We retrospectively reviewed the medical charts of 257 consecutive patients who underwent HSCT at our institution from January, 2007 until December, 2012. Information on patients' body weight (BW) was measured daily, starting at admission. The highest BW recorded until HSC infusion (D0) and until the first 10 days post-SCT (D+10) was used to calculate the BW increase in relation to the baseline BW. A ROC curve was built to determine the best cut-off point in BW increase that predicted for mortality. Information on the incidence of post-transplant complications was extracted from the time period that patients were admitted for transplant until discharge from the hospital. Endpoints analyzed included the presence or absence of respiratory failure, acute renal failure, sinusoidal obstruction syndrome (SOS), septic shock and requirement of diuretic use, hemodialysis, mechanical ventilation and ICU admission. Overall survival (OS) was estimated from the time of HSCT until death, and surviving patients were censored at last follow-up. Variables entered into the multivariate Cox analysis were those with a p-value<0.10 in the univariate analysis. Statistical analysis was performed with STATA (v11.0) and alfa error was defined as 5%. Results Mean age was 39.4 years old (range <1 year-76 years) and 61% were male. HSC sources included autologous (47%), matched related donors (15%), matched unrelated donors (13%), cord blood units (19%) and mismatched related/unrelated donors (6%). Diagnosis included acute leukemia or chronic myeloid disorders (37%), lymphoma/multiple myeloma (42%) and non-malignant hematological disorders (21%).The results of the ROC curve defined the cut-point of 6% BW gain by D+10 as the best predictor for OS. A total of 69 patients (27%) had a BW increase ≥6% by D+10. This was associated with an increased risk of mortality, with a 100-days OS of 67% vs. 92% (HR 3.25, p<0.0001, 95% CI 2.04-5.18; Figure). A greater than 6% gain in BW by D+10 was also associated with an increased risk of developing SOS (31% vs. 6%; p<0.0001), septic shock (29% vs. 7%; p<0.0001), respiratory failure (35% vs. 9%; p<0.0001) and requiring diuretic use (91% vs. 71%; p<0.001), hemodialysis (13% vs. 4%, p=0.007), mechanical ventilation (33% vs. 9%; p<0.0001) and ICU admission (42% vs. 24%; p<0.0001). In a multivariate analysis considering age, diagnosis, type of SCT and sex, a ≥6% BW gain by D+10 was an independent variable associated with an increased risk of mortality (HR 3.28; p<0.0001; 95% CI 2.02-5.32). We next evaluated the prognostic impact of a ≥6% BW increase in the time period from admission until D0. Our results showed that it was similarly associated with an increased risk of mortality (HR 2.26; p=0.003; 95% CI 1.32-3.86), of developing SOS (32% vs. 9%; p<0.0001), respiratory failure (27%vs. 14%; p=0.04) and requiring hemodialysis (15% vs. 5%; p=0.01) and ICU admission (37% vs. 18%; p=0.008). After adjusting for age, sex, diagnosis and type of SCT, ≥6% BW gain by D0 was associated with an increased mortality (HR 1.94; p=0.026; 95% CI 1.08-3.48). Conclusion In our cohort of patients, fluid accumulation during the early stages of conditioning regimen and HSCT, reflected by a ≥6% increase in BW, was associated with an increased mortality and risk of developing severe complications. This may reflect the presence of increased endothelial damage, and further studies are needed to better clarify the mechanism behind weight gain during HSCT. Our results demonstrate that patients who have a ≥ 6% gain in BW by D0 and D+10 have an increased risk of complications, and more intensive monitoring of these patients is needed. Disclosures: No relevant conflicts of interest to declare.

Central Nervous System Relapse In Adults With Acute Lymphoblastic Leukemia After Allogeneic Hematopoietic Stem Cell Transplantation

▪ IntroductionCentral nervous system (CNS) recurrence after allogeneic hematopoietic stem cell transplantation (HSCT) confers a poor prognosis in adult patients with acute lymphoblastic leukemia (ALL). Preventing CNS recurrence after HSCT remains a therapeutic challenge, and criteria for post-HSCT CNS prophylaxis have not been addressed. Our goal was to investigate the post-HSCT outcome of ALL patients and identify patient groups who may benefit from post-HSCT CNS prophylaxis. MethodsIn this two-center retrospective study, we studied all adult (age≥18) ALL patients who underwent HSCT at MD Anderson Cancer Center or Fred Hutchinson Cancer Research Center between 1997 and 2011. We included all adult ALL patients who were transplanted in the first or second complete remission (CR) and who received any prophylactic or therapeutic CNS therapy before HSCT. We assessed the cumulative incidence of systemic and CNS relapses in a competing risks framework with a competing risk of non-relapse death. Since data from second and subsequent relapses were not available, patients whose first relapse did not include CNS involvement were censored at the time of relapse. To analyze the association between post-HSCT CNS prophylactic therapy and CNS relapse, we used a landmark analysis, including only patients who had not relapsed or died by 3 months post HSCT. ResultsWe included 415 adult ALL patients (239 in CR1 and 176 in CR2) who were transplanted with a myeloablative total body irradiation based (MA-TBI, n=252), myeloablative non-TBI based (MA-nonTBI, n= 130), or reduced intensity conditioning regimen (RIC, n=33). Median age at HSCT was 37 years (range 18-70; 59% male). Sixty seven patients (16%) had a history of pre-HSCT CNS involvement either at diagnosis or at time of first relapse, while 339 patients (81%) had no CNS disease at any time before HSCT. Overall 175 patients (42%) received CNS prophylaxis after HSCT. CNS prophylaxis included intrathecal methotrexate, cytarabine, or both agents. Two patients received prophylactic cerebrospinal radiotherapy.The median follow-up for the 189 surviving patients was 4.2 years. Sixteen patients (3.8% of all patients, 13.2% of all relapses) developed CNS relapse (11 isolated and 5 combined with marrow relapse) at a median of 231 days (range 38-1397) after HSCT. Seven of these patients had pre-HSCT CNS disease. The 4-year cumulative incidence of relapse after HSCT among all patients was 31.7% and 28.2% for patients with and without CNS prophylaxis after HSCT, respectively (P=0.51). The 4-year cumulative incidence of CNS relapse was 6% and 2.6% for patients with and without CNS prophylaxis after HSCT, respectively (P=0.16) (Figure 1). When the analysis was limited to the patients without prior CNS involvement, there was still no benefit to post-HSCT CNS prophylaxis (P=0.63). Patients with a prior history of CNS involvement with leukemia had a significantly higher rate for CNS relapse, 11.6% vs. 2.7% (P=0.003) (Figure 2). The 4-year rate of CNS relapse was not impacted by intensity of the HSCT conditioning regimen and was 3%, 4%, and 6.5% for RIC, MA-TBI, and MA-nonTBI, respectively. ConclusionCNS relapse is an uncommon event following HSCT for ALL in CR1 or CR2. Furthermore, neither the intensity of the HSCT conditioning regimen nor the routine use of post-HSCT CNS prophylaxis made a significant difference in the rate of post-HSCT CNS relapse in patients who had received CNS prophylaxis prior to HSCT. Not surprisingly, patients with a pre-HSCT history of CNS involvement had a significantly higher risk of CNS relapse after HSCT. [Display omitted] [Display omitted] Disclosures:No relevant conflicts of interest to declare.

Comprehensive Genomic Evaluation For Inherited Bone Marrow Failure/Myelodysplastic Syndromes

▪Accurate and timely diagnosis of inherited bone marrow failure syndromes and inherited myelodysplastic syndromes (iBMFS/iMDS) is essential to guide optimal medical management and treatment. Their early diagnosis allows appropriate clinical monitoring to initiate hematopoietic stem cell transplantation (HSCT) prior to the development of leukemia, which carries a poor prognosis in these patients. Additionally these inherited syndromes typically do not respond to standard medical therapies for aplastic anemia (i.e. ATG and cyclosporine) and are associated with excessive toxicity with standard HSCT conditioning regimens. The recognition of an inherited disorder also informs donor selection as it allows unambiguous identification of affected siblings. Currently, testing of individual genes for iBMFS/iMDS is guided by clinical suspicion. Therefore, diagnosis is easily missed in patients with cryptic presentations. Moreover, sequential genetic testing is often cost-prohibitive and may not be completed within a clinically useful timeframe.To address these clinical challenges, we developed a targeted gene capture pool coupled with next generation sequencing for the exons and flanking intronic sequences of 108 genes implicated in inherited and acquired marrow failure and MDS. Median base coverage was 192X, with 94.5% of targeted bases having >50x coverage and 99.6% of targeted bases having >10X coverage. This level of coverage together with our bioinformatic pipeline enabled identification of mutations spanning all classes (point mutations, small insertions and deletions, copy number variants, and genomic rearrangements). Rigorous criteria were applied to identify functionally deleterious mutations. Mutations were validated by conventional Sanger sequencing. Both germline and acquired mutations could be discerned, depending on DNA source (fibroblasts, peripheral blood or marrow mononuclear cells). The assay was validated with a blinded analysis of 12 patients harboring known mutations spanning different mutation classes. All mutations were successfully identified, including discerning mutations in genes from those in cognate pseudogenes.We next tested for cryptic presentations of iBMFS/iMDS in 71 patients with idiopathic marrow failure. Fifty-nine subjects were drawn from the pediatric clinic and 12 from the adult clinic. Patients previously diagnosed with a known iBMFS/iMDS were excluded from this analysis. Twenty seven of the 71 subjects (38%) had a family history suggestive of an inherited marrow failure syndrome. Diagnoses of iBMFS/iMDS were made in 7 patients (10%), of whom only 2 patients had a history suggestive of familial marrow failure. An additional 4 patients had possible mutations in iBMFS/iMDS genes (TINF2 and SRP72) with functional validation pending. Deleterious mutations in GATA2 were identified in 4 patients (6%). Four additional patients had deleterious mutations in RUNX1 of which 2 were constitutional and 2 were somatically acquired. The diagnosis had previously been missed by clinical laboratory testing of these genes in 2 patients, possibly due to technical limitations of standard approaches. One additional patient with marrow failure had pathogenic mutations in a DNA repair gene not previously reported to cause iBMFS/iMDS. These data demonstrate the utility of this unbiased approach to diagnose patients irrespective of prior clinical preconceptions. The diagnosis of iBMFS/iMDS in 2 of the 12 adult patients highlights the need to consider inherited syndromes in adults with idiopathic marrow failure. More broadly, our results draw attention to the large number of patients (85-90%) remaining genetically undefined despite comprehensive screening for mutations in known iBMFS/iMDS genes.In summary, we have developed and applied a comprehensive genomic approach to diagnose iBMFS/iMDS in 10% of patients presenting with idiopathic marrow failure. Mutations in GATA2 or RUNX1 were the most common causes of idiopathic marrow failure. Testing should be considered in both pediatric and adult patients even in the absence of prior family history. This unbiased diagnostic approach has revealed previously unexpected phenotypic features of these disorders. This efficient and cost-effective (<$400 reagents/sample) clinical diagnostic assay allows comprehensive unbiased screening for cryptic presentations of iBMFS/iMDS. Disclosures:No relevant conflicts of interest to declare.

Post-Transplant Maintenance With The Deacetylase Inhibitor Panobinostat In Patients With High-Risk AML Or MDS: Results Of The Phase I Part Of The Panobest Trial

Inhibitors of class I/II histone deacetylases (HDACi) possess anti-leukemic activity and have been reported to modulate the function of immune effector cells. Thus, they could provide specific clinical benefit in the allogeneic hematopoietic stem cell transplantation (HSCT) setting. Panobinostat (PAN) is a potent, orally available pan-HDACi reported to either suppress or stimulate regulatory T cells (T reg), depending on the administered dose (Shen L & Pili R, OncoImmunology 1;7:948, 2012). The feasibility and efficacy of PAN treatment following HSCT for patients (pts) with high risk acute myeloid leukemia (AML) has not been established. We report clinical and translational results of the dose-escalation phase of the PANOBEST study with PAN as post-HSCT maintenance.Primary objectives were, based on dose-limiting toxicity (DLT), determining the maximum tolerated dose (MTD) and/or the recommended phase 2 dose (RP2D) of PAN in patients with high risk AML or myelodysplastic syndromes (MDS) in complete remission (CR) after reduced-intensity conditioning HSCT. Secondary objectives were the evaluation of safety, tolerability and immunoregulatory properties of PAN, and overall (OS) and disease-free survival (DFS) of treated patients.PAN was started at 10 mg p.o. three times a week (TIW) and escalated to 20 and 30 mg TIW using a 3+3 design. Treatment was initiated 60-150 days after HSCT and continued for up to one year. Eligibility criteria included: recovery of peripheral blood counts, adequate organ function and no severe graft versus host disease (GvHD). All pts gave written informed consent. DLT was defined as prolonged grade 4 hematologic or grade 3/4 non-hematologic toxicity within 28 days of the first PAN dose. Immunophenoytyping of lymphocyte subsets was performed pre-treatment and on days 3, 8, 30, 90, 180 and 360.12 pts (11 AML, 1 MDS), median age of 52 years (21-62) were enrolled. PAN was started within a median of 73 days (60-126) after HSCT, which was performed with active disease (n=11) or in CR2 (n=1). The RP2D was determined to be 20 mg TIW based on one DLT (fatigue grade 3) at 20 mg and two DLTs (nausea/emesis and colitis grade 3 each) at 30 mg. Grade 2-4 adverse events (AEs) were reported in 10 out of the 12 pts (83%). Grade 3/4 AEs included hematologic toxicity (50% of pts), laboratory alterations (33%), gastrointestinal symptoms (25%), fatigue, pulmonary infection (17% each), sepsis, herpes stomatitis, diabetes, syncope, deep vein thrombosis and pulmonary embolism (8% each). Toxicity was reversible and required at least one PAN dose reduction in 3 pts. Acute GvHD grade 2 (1 pt) and 3 (2 pts) was responsive to steroids in 2 pts or salvage therapy in 1 pt. Four pts developed mild (n=3) or moderate (n=1) chronic GvHD. To date, 5 pts have completed one year of PAN and 2 pts remain on treatment (days 238, 290). Five pts discontinued treatment prematurely after 10-217 days due to grade 3 toxicities (n=4) or AML relapse (n=1). With a median follow up of 579 days (129-911), 11/12 pts are alive and 10/12 in continuous CR after HSCT. Seven pts received prophylactic donor lymphocyte infusions (DLIs, 1-5 doses of 0.1-20x106 CD3+ cells/kg). Immunophenotyping revealed no impact of PAN on absolute T reg numbers (9 pts), but a significantly reduced proportion of CD4+CD25++CD127dim/- T reg to CD3+CD4+ T helper (Th) cells by day 8 after 3 doses of PAN (mean±SEM: 14.6±2.6 vs. 9.6±1.2%, p value of t test =0.03). While Treg/Th proportion continuously decreased in pts with ongoing CR, it again increased after PAN discontinuation or remained stable under PAN treatment in both relapsing patients. Outcome of the study population was compared with a historical cohort of 29 consecutive pts with active AML transplanted in Frankfurt in 2000-2009. Both cohorts were similar in age, gender, disease stage or BM blasts at time of HSCT, donor type and use of DLIs. In a landmark analysis including all pts who were in CR and without severe GvHD on day 73 after HSCT, probabilities for DFS and OS at 18 months after HSCT were 83±11% vs. 55±9% (p=0.145, log-rank test) and 92±8% vs.66±9% (p=0.085) in the PANOBEST vs. historical cohort (Fig 1). [Display omitted] PAN is well tolerated after HSCT at a RP2D of 20 mg TIW. Comparison with a historical control cohort of pts transplanted with active AML shows a low relapse rate, which appears to be associated with a PAN-induced modulation of the T reg/Th proportion. Disclosures:Bug:Novartis: Honoraria, Travel grants, support for the clinical study Other. Ottmann:Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau.

Long-Term Outcomes of Alemtuzumab-Based Reduced-Intensity Conditioned Hematopoietic Stem Cell Transplantation for Myelodysplastic Syndrome and Acute Myelogenous Leukemia Secondary to Myelodysplastic Syndrome

Allogeneic hematopoietic stem cell transplantation (HSCT) with reduced-intensity conditioning (RIC) offers a potential cure for patients with myelodysplastic syndrome (MDS) who are ineligible for standard-intensity regimens. Previously published data from our institution suggest excellent outcomes at 1 yr using a uniform fludarabine, busulfan, and alemtuzumab-based regimen. Here we report long-term follow-up of 192 patients with MDS and acute myelogenous leukemia (AML) secondary to MDS (MDS-AML) transplanted with this protocol, using sibling (n = 45) or matched unrelated (n = 147) donors. The median age of the cohort was 57 yr (range, 21 to 72 yr), and median follow-up was 4.5 yr (range, 0.1 to 10.6 yr). The 5-yr overall survival (OS), event-free survival, and nonrelapse mortality were 44%, 33%, and 26% respectively. The incidence of de novo chronic graft-versus-host disease (GVHD) was low at 19%, illustrating the efficacy of alemtuzumab for GVHD prophylaxis. Conversely, the 5-yr relapse rate was 51%. For younger patients (age <50 yr), the 5-yr OS and relapse rates were 58% and 39%, respectively. On multivariate analysis, advanced age predicted significantly worse outcomes, with patients age >60 yr having a 5-yr OS of 15% and relapse rate of 66%. Patients receiving preemptive donor lymphocyte infusions had an impressive 5-yr OS of 67%, suggesting that this protocol may lend itself to the incorporation of immunotherapeutic strategies. Overall, these data demonstrate good 5-yr OS for patients with MDS and MDS-AML undergoing alemtuzumab-based RIC-HSCT. The low rate of chronic GVHD is encouraging, and comparative studies with other RIC protocols are warranted.

Readmissions following allogeneic hematopoietic stem cell transplantation.

265 Background: Recent initiatives to improve patient safety and reduce healthcare costs have focused on preventing hospital readmissions. Historically, patients treated with allogeneic hematopoietic stem cell transplantation (HSCT) have high rates of hospital readmission. The purpose of this study was to identify the incidence and reasons for readmissions in allogeneic HSCT patients as well as associated risk factors for readmission. Methods: A retrospective review of patients receiving a myeloablative or reduced intensity conditioning (RIC) HSCT at Dana Farber/Brigham and Women’s Hospital between January 1, 2005 and December 31, 2010 was performed. Reasons for readmission, along with sociodemographic, disease, and transplant related variables were evaluated. Potential risk factors for readmission were determined by multivariate regression analysis. Results: A total of 1,097 HSCT patients were reviewed. In the myeloablative group, 130 of 495 (26.3%) patients were readmitted within 30 days of discharge, among whom the majority of patients (71.5%) had one readmission. For RICs, 105 of 602 (17.4%) patients were readmitted within 30 days, among whom 62.9% of patients had one readmission. In the myeloablative group, the most frequent reasons for readmission were infection or fever without identified source (40.7%) and graft versus host disease (GVHD) (23.7%). Similarly, the most common diagnoses at readmission in the RICs were infection or fever without source (54.9%) and GVHD (11.0%). In the RICs, a logistic regression model of the probability of being readmitted suggested active disease (OR 2.0, p=0.005), a mismatched donor (OR 2.4, p=0.029), infection during the index admission (OR 5.8, p&lt;0.0001) and non-private insurance (OR 1.8, p=0.025) are significant factors for readmission within 30 days. Conclusions: Infection and fever without a source were the most common causes of readmission after HSCT. In the RIC group, multiple disease, transplant, and sociodemographic factors were associated with readmission. Better defining the risk factors for readmission in this population will allow for more transitional care resources to be focused on high risk patients.

Allogeneic Stem Cell Transplantation with BEAM and Alemtuzumab Conditioning Immediately after Remission Induction Has Curative Potential in Advanced T-Cell Non-Hodgkin's Lymphoma

Patients with relapsed or refractory advanced T cell non-Hodgkin lymphoma have a dismal prognosis and may not even reach allogeneic hematopoietic stem cell transplantation (HSCT) in adequate condition. We present the outcome of 24 consecutive patients (age range 11 to 65 years) treated at a single institution in Kiel within a recent 5.5-year time frame with allogeneic HSCT in a rather uniform approach. Relapsed and refractory T and natural killer cell lymphomas of various subtypes were included. All patients except 1 were in progression or relapse before start of pretransplantation salvage therapy. Five patients had relapsed after autologous HSCT. With intensive remission induction therapy, usually the CLAEG (cladribine, cytosine arabinoside, and etoposide with granulocyte colony-stimulating factor support) protocol, attempts were made to improve disease control and proceed immediately to conditioning with carmustine, etoposide, cytosine arabinoside, melphalan (BEAM), and medium-dose alemtuzumab. Twenty of 21 patients who received CLAEG induction therapy benefited from this protocol and 1 patient appeared to be therapy-resistant. At the time of allogeneic HSCT, 9 patients were in complete remission (CR) (2 in CR1, 5 in CR2, and 2 in CR >2), whereas 50% had never achieved CR. Nineteen transplants were obtained from matched or partially matched unrelated donors and only 5 from siblings. With a median follow-up of 321 days (1252 days for surviving patients), 20 of 22 assessable patients reached CR. Five of these patients had hematologic or molecular relapse. With donor lymphocyte infusions, 1 patient became minimal residual disease MRD negative again and has maintained CR for more than 4 years. The frequency of grades II to IV acute graft-versus-host disease was 25% and chronic graft-versus-host disease, 30%. Intense reinduction therapy followed by reduced-intensity BEAM-alemtuzumab conditioning and allogeneic HSCT is effective and offers curative potential for patients with advanced T cell lymphomas, even for those not in remission.

A case series of CAEBV of children and young adults treated with reduced‐intensity conditioning and allogeneic bone marrow transplantation: a single‐center study

Epstein-Barr virus (EBV)-infected T or NK cells cause chronic active EBV infection (CAEBV). Allogeneic hematopoietic stem cell transplantation (HSCT) is curative treatment for CAEBV patients. However, chemotherapy prior to HSCT and optimal conditioning regimen for allogeneic HSCT are still controversial. We retrospectively analyzed five patients with CAEBV treated with reduced-intensity conditioning (RIC) consisted of fludarabine, cyclophosphamide, and low-dose total-body irradiation followed by allogeneic bone marrow transplantation in a single institute. Only one of five patients received chemotherapy prior to transplantation. We analyzed EBV-infected cells in a patient whose EBV load increased after HSCT by T-cell repertoire assay, separation of T-cell subpopulations, in situ hybridization and microsatellite analysis. All five patients achieved engraftment, complete chimera, and eradication of EBV load. All patients have been alive without any serious regimen-related toxicity for more than 16months following HSCT. However, one patient transplanted from HLA-matched sibling donor developed clonal proliferation of CD4+ Vβ3+ T cells caused by monoclonal EBV infection on day 99 after transplantation. Further analysis revealed that the CD4+ Vβ3+ T cells selectively harbored EBV genome, and these infected cells were derived from donor T cells. Allogeneic HSCT with RIC is a safe and effective treatment for better overall survival and less regimen-related toxicity in patients with CAEBV. Our first pediatric case reported in the literature suggests that we should consider the possibility of persistent EBV infection in donor T cells as well as the relapse in recipient cells if EBV load increases after allogeneic HSCT.

Outcome of Donor Lymphocyte Infusion after T Cell–depleted Allogeneic Hematopoietic Stem Cell Transplantation for Acute Myelogenous Leukemia and Myelodysplastic Syndromes

Relapse occurs in 30%-50% of recipients of T cell–depleted (TCD) reduced-intensity conditioned (RIC) hematopoietic stem cell transplantation (HSCT) for acute myelogenous leukemia (AML) and myelodysplastic syndromes (MDS). Despite limited published supportive data, donor lymphocyte infusion (DLI) is used preemptively (pDLI) to improve donor chimerism and prevent relapse, and therapeutically (tDLI) after disease recurrence. We evaluated the efficacy and toxicity of pDLI and tDLI in 113 patients after TCD (alemtuzumab, n = 99; antithymocyte globulin, n = 14) RIC HSCT for AML or MDS. Recipients of pDLI (n = 62) had an estimated 5-year overall survival (OS) of 80% and an event-free survival of 65%. More than one-half (52%; n = 32) of the patients received pDLI within 6 months post-HSCT; despite this, the 5-year incidence of graft-versus-host disease was only 31% (95% confidence interval [CI], 19%-43%). Recipients of tDLI (n = 51) had an estimated 5-year OS of 40% and a 5-year relapse/progression rate of 69% (95% CI, 54%-81%). Recipients of tDLI at >6 months post-HSCT had a significantly superior 5-year OS after tDLI compared with those treated earlier (P = .008). The cumulative incidence of graft-versus-host disease at 5 years after tDLI was 45% (95% CI, 23%-65%). We demonstrate that pDLI safely promotes durable remission after TCD RIC HSCT for AML or MDS, and that tDLI salvages patients after late relapse with greater efficacy.

Role of pharmacogenetics in busulfan/cyclophosphamide conditioning therapy prior to hematopoietic stem cell transplantation.

Hematopoietic stem cell transplantation (HSCT) is a curative treatment for several malignant and nonmalignant disorders. Busulfan (Bu) and cyclophosphamide (Cy) are the most commonly used alkylators in high-dose pretransplant conditioning for HSCT; a treatment that is correlated with drug-related toxicity and relapse. Pharmacogenetic investigations have shown that CYP450, as well as aldehyde dehydrogenase, are clearly involved with Cy metabolism and are associated with altered treatment response, Cy metabolism and the unique stem-cell sparing capacity. Moreover, glutathione-S-transferase isoenzymes have been associated with cellular outward transport of various alkylating agents, including Cy metabolites, melphalan, Bu and chlorambucil. A shift from genetic-based studies to whole-genome-based investigations of Cy- and Bu-associated markers may contribute to personalizing the conditioning therapy and enhancing the clinical outcome of HSCT.

Spontaneous conception after autologous hematopoietic stem cell transplantation: a case report

Spontaneous conception after autologous hematopoietic stem cell transplantation: a case report

Does antithymocyte globulin have a place in reduced-intensity conditioning for allogeneic hematopoietic stem cell transplantation?

A 63-year-old male patient without siblings is treated for acute myeloid leukemia with poor prognostic cytogenetics. Despite achieving a first complete remission, he relapsed within the first year of diagnosis. He then achieved a second complete remission. A search for an HLA-identical unrelated donor identified a 10/10 possible match. The patient has several comorbidities (hematopoietic stem cell comorbidity index = 3) and it is recommended that he undergo a reduced-intensity conditioning regimen for allogeneic peripheral blood stem cell transplantation. The patient is well-read on allogeneic stem cell transplantation and asks you the merits of antithymocyte globulin that you propose to include in the conditioning regimen.

Equivalent Outcome Between Reduced Intensity Versus Conventional Myeloablative Conditioning Hematopoietic Stem Cell Transplantation for Patients Older Than 35 Years with Acute Myeloid Leukemia.

AbstractAbstract 3103▪▪This icon denotes a clinically relevant abstract Introduction:Allogeneic Hematopoietic Stem Cell Transplantation (HSCT) provides the best chance of long-term survival for patients with intermediate or high-risk acute myeloid leukemia (AML). The major limitation of this procedure is the risk of treatment related mortality (TRM). Use of reduced intensity conditioning (RIC) regimen has become standard practice among older candidates with comorbidities. Although RIC regimen have been used for over a decade in older patients, the benefit of this approach in younger patients with AML compared with the risk of toxicity of standard regimen (MAC) is still discussed. We compared the outcomes for patients with AML over 35 years using RIC or MAC HSCT. Patients, methods, and transplantation characteristics:From January 2000 to December 2010, 132 consecutive patients older than 35 years with AML (18 secondary AML) received HSCT in our center, either from siblings (n=87) or HLA 10/10 allele-matched donors (n=45). MAC (n=72) and RIC (n=60) regimens were defined as previously described (Bacigalupo, 2009). Seventy-three patients were in first complete remission (CR1); 30% of patients had poor risk cytogenetics (MRC classification). Karnofsky performance status was scored at time of HSCT. Engraftment, acute and chronic graft-versus-host disease (GvHD), transplantation-related mortality (TRM), relapse rate as well as overall survival (OS) at 4 years were compared according to the intensity of the conditioning regimen. First a classical multivariable Cox analysis was conducted. In a second step, baseline confounding factors were adjusted for using inverse probability-of-treatment weighting (IPTW). Results of the comparison:Patient characteristics according to the intensity of the conditioning regimen were similar for AML type (de novo versus secondary), gender, karnofsky performance status, CR#, donor type and number of CD34+ infused. Particularly, cytogenetic risks were comparable in both groups. Patients were younger in the MAC group (median age 44 years [range 35 to 56 years] vs 54[37 to 66] for RIC, p<0,0001), received mainly bone marrow as source of stem cells (54% versus 2% for RIC, p<0,0001) and GvHD prophylaxis using cyclosporine plus methotrexate (89% versus 5% for RIC, p<0,0001). Moreover, ATG in the conditioning regimen (more ATG in RIC: 51 vs. 14%, p<0.0001), donor age (older for RIC: 49 vs. 39 years, p=0.002) and number of nucleated cells infused (higher in RIC: 11 vs. 4 × 108/kg, p<0.0001) were also different. The median follow-up was 47 months (10 to 134), and 25% of patients had a follow-up of at least 74 months. During evolution, all patients engrafted. The cumulative incidence (CIf) of acute GVHD grade II-IV was 49% (35% after RIC vs 61% after MAC, p=0.001). The 5-year CIf of chronic GVHD was 37% (40% after RIC vs 30% after MAC, p=0.32). During FU, 71 patients died. The 5-year CIf of TRM was 21% (13% after RIC vs 28% after MAC, p=0.009). Adjusting for cytogenetic risk, gender donor/recipient mismatch and infused nucleated cells, no difference was observed between RIC and MAC (HR 0.9, p=0.16). The 5-year CIf of relapse was 42% (51% after RIC vs 35% after MAC (p=0.22)). Adjusting for gender donor/recipient mismatch, donor/recipient CMV serostatus and infused CD34+ cells, no marked difference was observed between RIC and MAC (HR 0.8, 95%CI 0.4–1.5, p=0.50). The 5-year OS was 39% (50% after RIC vs 34% after MAC, p=0.38). Using both Cox regression and IPTW to account for imbalance in patients characteristics, similar OS was found after RIC and MAC (Figure 1), with adjusted HRs for MAC vs RIC of 0.9 (95%CI 0.4–1.8, p=0.68) with Cox regression and 0.9 (95%CI 0.4–1.8, p=0.76) with IPTW. Conclusion:In patients with AML over 35 years, MAC regimen lead to a non significant higher rate of treatment related mortality with no benefit in terms of relapse when compared with RIC regimen. Until prospective trials are completed, this study supports the use of a RIC regimen for patients with AML older than 35 years who are transplanted either from siblings or matched unrelated donors. [Display omitted] Disclosures:Fenaux:Amgen: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Roche: Honoraria, Research Funding; GSK: Honoraria, Research Funding; Novartis: Honoraria, Research Funding.

Tacrolimus/Sirolimus Vs. Tacrolimus/Methotrexate for Graft-Vs.-Host Disease Prophylaxis After HLA-Matched, Related Donor Hematopoietic Stem Cell Transplantation: Results of Blood and Marrow Transplant Clinical Trials Network Trial 0402

AbstractAbstract ▪739▪This icon denotes a clinically relevant abstractThe combination of a calcineurin inhibitor and methotrexate has been the standard of care in graft-vs.-host disease (GVHD) prophylaxis for over 25 years, with resultant rates of grade II-IV acute GVHD between 30–50%. The mTOR inhibitor, sirolimus, has demonstrated promise in a number of Phase II trials as an immunosuppressant used for GVHD prophylaxis. The BMT CTN, sponsored by the NHLBI and NCI, conducted a multicenter, randomized controlled trial comparing the combination of tacrolimus and sirolimus (Tac/Sir) with tacrolimus and methotrexate (Tac/Mtx) as GVHD prophylaxis after matched, related donor (MRD) hematopoietic stem cell transplantation (HSCT). Methods:Eligible patients were between ages 2 – 60 years, and had acute leukemia in remission, myelodysplasia or chronic myeloid leukemia in chronic or accelerated phase. All had adequate organ function, and a 6/6 HLA-A, B, DRB1 matched sibling donor. 304 patients were randomly assigned to either Tac/Sir (n = 151) or Tac/Mtx (n = 153) as GVHD prophylaxis after TBI-based conditioning and MRD HSCT. An intent-to-treat analysis was performed on the primary endpoint of Grade II-IV GVHD-free survival 114 days from randomization. Ten subjects who received busulfan-based conditioning and were previously reported were excluded from analysis. Three subjects who did not undergo HSCT are included in the primary analysis, but not secondary analyses. Results:Treatment groups were well balanced. The median age of participants was 44 years (range 13 – 59) and 83% had acute leukemia. Neutrophil and platelet engraftment were both faster in the Tac/Sir group (14 vs. 16 days, p < 0.001; 16 vs. 19 days, p = 0.03, respectively), but this did not affect the time to first hospital discharge (20 vs. 21 days, p = 0.37). The incidence of grade II-IV and grade III-IV acute GVHD at 100 days were lower in the Tac/Sir group (26 vs. 34%, p = 0.17; 8 vs. 15%, p = 0.05). Day 100 treatment-related mortality was no different between groups (7 vs. 7%, p = 0.43). The primary endpoint of 114-day acute GVHD-free survival was not statistically different between groups (67 vs. 62%, p = 0.38, Figure). The cumulative incidence of relapse at 2 years from transplantation was not different between groups (27 vs. 30%, p = 0.81). The competing-risk cumulative incidence of chronic GVHD was higher in the Tac/Sir arm (54 vs. 43%, p =0.044). Overall toxicities were not different between groups, with two notable exceptions. The peak and average OMAS oral mucositis scores were lower in the Tac/Sir arm (peak 0.70 vs. 0.96, p < 0.001; average 0.31 vs. 0.47, p < 0.001), however, there was an increased rate of the endothelial injury syndromes, veno-occlusive disease (11 vs. 4%, p = 0.03), and thrombotic microangiopathy (5 vs. 1%, p = 0.05) in the Tac/Sir arm. Causes of death were not different between groups. At 2 years from transplantation, disease-free (DFS) and overall survival (OS) were not different between study arms (DFS 53 vs. 53%, p = 0.76; OS 60 vs. 61%, p = 0.44). Conclusions:No difference in 114-day acute GVHD-free survival was noted between treatment arms. Compared with Tac/Mtx in MRD HSCT, Tac/Sir is associated with more rapid engraftment, less severe acute GVHD and oral mucositis, excess chronic GVHD and endothelial injury syndromes, and similar long-term outcomes. Understanding the trade-offs between regimens, Tac/Sir can be used as an alternative to Tac/Mtx in MRD HSCT. [Display omitted] Disclosures:Cutler:Pfizer, inc: Research Funding; Astellas, Inc: Consultancy, Research Funding. Off Label Use: Sirolimus - Prevention of GVHD Tacrolimus - Prevention of GVHD. Waller:Outsuka: Research Funding.

Allogeneic Hematopoietic Stem Cell Transplant Reverses the Phenotype of GATA2 Deficiency.

AbstractAbstract 3091 Background:Recently, sporadic and heritable mutations in the zinc finger transcription factor GATA2 were shown to be responsible for four different syndromes in young adults coupling opportunistic infection with a predilection to develop myelodysplastic syndrome (MDS)/acute myelogenous leukemia (AML). These four syndromes are: MonoMAC, monocytopenia with nontuberculous mycobacterial (NTM) infections; DCML, dendritic cell, monocyte and lymphoid cell deficiency; Emberger's syndrome, lymphedema and MDS with monosomy 7; and familial MDS/AML. Life-threatening infections, and the transformation to AML, either alone or together, constitute a rationale for allogeneic hematopoietic stem cell transplant (HSCT) for GATA2 deficiency. Methods:We evaluated matched related, unrelated, and umbilical cord blood as donor sources for nonmyeloablative conditioning for HSCT in GATA2 deficiency. Twelve patients with GATA2 deficiency underwent allogeneic transplant: 4 received peripheral blood stem cells (PBSCs) from matched related-donors (MRD), 4 received PBSC from matched unrelated-donors (MUD), and 4 received umbilical cord blood (UCB) units. Recipients of MRD and MUD transplant received fludarabine and 200cGy of total body irradiation (TBI), while UCB recipients received cyclophosphamide 50 mg/kg, fludarabine, and 200cGy of TBI. All patients received tacrolimus and sirolimus for GVHD prophylaxis.This cohort of patients had considerable pre-transplant morbidity: two patients required baseline oxygen for pulmonary alveolar proteinosis, one of whom was on a ventilator at the time of transplant; one patient had active hepatitis C that was not responding to therapy; one patient had RAEB-2; two patients were platelet transfusion-dependent; one patient had recurrent strokes and culture negative endocarditis two months before transplant. Results:Median follow-up for patients was 14.4 months (range 0.2–38.2 months). Ten of 11 patients engrafted at a median of 10 days (range 0–76); engraftment was not evaluable in a recipient of an UCB transplant due to death early in the post-transplant period. One rejection occurred in a recipient of a double UCB transplant who had been heavily transfused pre-transplant. All patients who engrafted had complete reconstitution of the monocyte, NK, and B-lymphocyte compartments, the three cell compartments that were severely deficient pre-transplant, and all had reversal of the infection susceptibility phenotype, characteristic of the disease. In particular, there were no recurrences of NTM infection and extensive human papilloma virus infections regressed starting around 6 months post transplant. Two patients required a single cycle of pre-transplant chemotherapy for RAEB-1 and RAEB-2, respectively. In both patients the monosomy 6 and monosomy 7 clones have not recurred, now 2.5 years and 9 months following single UCB and MUD transplant, respectively.Three patients died, two early after transplant. One recipient of UCB, who had pre-transplant hepatitis C, died on day+7 of fulminant liver failure and sepsis. A second patient, who was intubated at the time of transplant because of severe pulmonary alveolar proteinosis and pulmonary hypertension, died on day + 88 of grade IV GVHD after MRD transplant. The third patient died 9 months after transplant of sepsis. One recipient of a MRD relapsed from her MDS at 1 year following transplant and was retransplanted using a myeloablative conditioning regimen. She is alive with no evidence of MDS at 3 months. Acute GVHD developed in 6 patients, five of which were steroid-responsive. One patient developed chronic GVHD. Other complications included immune mediated cytopenias that responded to rituximab and eltrombopag. Conclusions:Nonmyeloablative HSCT in GATA2 deficiency results in reconstitution of the severely deficient monocyte, B and NK cell populations and reversal of the infection susceptibility phenotype. The TRM in this cohort of patients with severe comorbidities was 25%. Now that genetic testing for GATA2 mutations is available, we anticipate that earlier diagnosis will enable patients to be transplanted earlier in the course of disease, before significant organ damage or clonal evolution of MDS to AML. Disclosures:No relevant conflicts of interest to declare.

Outcome and Prognostic Factors for Patients Who Relapse After Allogeneic Stem Cell Transplantation.

AbstractAbstract 3069▪▪This icon denotes a clinically relevant abstractDisease relapse remains a major obstacle to the success of allogeneic hematopoietic stem cell transplantation (HSCT) for patients with hematologic malignancies (HM), and the principal cause of failure after reduced intensity conditioning HSCT. Much work has focused on identifying the risk factors for relapse and devising strategies for its prevention, but comparatively little is known about the outcome of patients who relapse and the relevant prognostic factors in this setting. We conducted a retrospective study of 1080 consecutive adult patients with HM transplanted at our institution between 2004 and 2008. 351 (33%) relapsed at a median of 4.5 months after HSCT. The 4-year post-relapse overall survival (pr-OS) was 15%, with a median post-relapse follow-up of 39 months. Significant risk factors for post-relapse mortality included shorter time to relapse, higher disease risk index1 at HSCT, myeloablative conditioning, and high HCT-CI2 at HSCT. While being on immunosuppression at the time of relapse did not significantly affect outcome in multivariable models, a history of acute or chronic graft-versus host disease (GVHD) prior to relapse conferred a higher risk for death after relapse. Based on those 5 factors and their hazard ratio for mortality in the Cox models, we constructed a simple risk score that stratified patients into 4 groups, with 4-year pr-OS ranging from 64% in patients with fewer than 3 points (13% of the cohort, among whom over one third had myeloid diseases) to 0% in those with greater than 6 points (p<0.0001) (Figure). This score performed similarly in a historical validation cohort of 276 relapsed patients who were transplanted between 1998 and 2003. An analysis of the impact of post-relapse treatment on outcome showed that immune manipulation, through either donor lymphocyte infusion or repeat HSCT, was associated with significantly better pr-OS (4-year pr-OS 28% versus 9%, p<0.0001). Even though this likely reflects in part selection bias, the difference remained significant in models that accounted for other post-relapse prognostic factors, in landmark analyses of patients who survived at least 2 months from relapse, and in patients with active GVHD at the time of relapse. The results of this study may aid with prognostication and management of patients who relapse after HSCT, as well as motivate the design of clinical trials aimed at relapse prevention or treatment in the higher-risk groups. [Display omitted] Risk factors are: •Disease Risk Index (0 points for low risk, 1 point for intermediate, 2 points for high or very high)1•Time to relapse (0 points for >24 months, 1 point for 6–24 months, 2 points for 3–6 months, 3 points for <3 months)•HCT-CI (0 points for index of 0–2, 1 point for index of 3+)2•Myeloablative conditioning (1 point)•Prior GVHD (1 point) Disclosures:No relevant conflicts of interest to declare.

Evaluation of pretransplant factors predicting cardiac dysfunction following high‐dose melphalan conditioning and autologous peripheral blood stem cell transplantation

Cardiac complications following hematopoietic stem cell transplantation (HSCT) are emerging as a significant concern given the increasing utilization of HSCT for a variety of hematologic malignancies. We utilized an existing database to determine the frequency of cardiac dysfunction (CD), namely a decrease in left ventricular ejection fraction, following conditioning with high-dose melphalan (HDM) and autologous HSCT for multiple myeloma (MM) and systemic amyloidosis (AL). We then performed a case-control study to examine variables associated with increased risk of CD in this population. In MM patients undergoing HSCT, the rate of CD was 1.6% (17/1050, 95% CI: [0.9, 2.6]). None of the examined pre-HSCT variables or HDM dose were significantly associated with development of CD in this population. In patients with AL, the rate of CD was 5.6% (24/426, 95% CI: [3.6, 8.3]). On univariate analysis, decision to administer an HDM dose <200 mg/m(2) [odds ratio (OR): 4.59 (1.27-16.57) P = 0.02], pretransplant left ventricular ejection fraction <60% [OR: 17.78 (2.29-138.33) P = 0.006], and documented amyloid involvement of ≥ 3 organs [OR: 4.0 (1.03-15.6) P = 0.046] were associated with the development of CD in the AL population. No other examined peri-transplant factors were associated with development of CD. To our knowledge, this is the first series to report a significant rate of CD following HDM conditioning and autologous HSCT in patients with AL.

Epigenetic modifiers enhance the synergistic cytotoxicity of combined nucleoside analog-DNA alkylating agents in lymphoma cell lines

Hematopoietic stem cell transplantation is used for treatment of lymphoma. In an attempt to design an efficacious and safe prehematopoietic stem cell transplantation conditioning regimen, we investigated the cytotoxicity of the combination of busulfan (B), melphalan (M), and gemcitabine (G) in lymphoma cell lines in the absence or presence of drugs that induce epigenetic changes. Cells were exposed to drugs individually or in combination and analyzed by the MTT proliferation assay, flow cytometry, and Western blotting. We used ~IC(10) drug concentrations (57 μM B, 1 μM M and 0.02 μM G), which individually did not have major effects on cell proliferation. Their combination resulted in 50% inhibition of proliferation. Reduction to almost half concentration (20 μM B, 0.7 μM M and 0.01 μM G) did not have significant effects, but addition of the histone deacetylase inhibitor suberoylanilide hydroxamic acid (0.6 μM) to this combination resulted in a marked (~65%) growth inhibition. The cytotoxicity of these combinations correlates with the activation of the ataxia telangiectasia mutated-CHK2 pathway, phosphorylation of KRAB-associated protein-1, epigenetic changes such as methylation and acetylation of histone 3, and activation of apoptosis. The relevance of epigenetic changes is further shown by the induction of DNA methyltransferases in tumor cells with low constitutive levels of DNMT3A and DNMT3B. The addition of 5-aza-2'-deoxycytidine to (BMG+suberoylanilide hydroxamic acid) further enhances cell killing. Overall, BMG combinations are synergistically cytotoxic to lymphoma cells. Epigenetic changes induced by suberoylanilide hydroxamic acid and 5-aza-2'-deoxycytidine further enhance the cytotoxicity. This study provides a rationale for an ongoing clinical trial in our institution using (BMG+suberoylanilide hydroxamic acid) as pre-hematopoietic stem cell transplantation conditioning for lymphoma.

Aprepitant Pharmacokinetics and Assessing the Impact of Aprepitant on Cyclophosphamide Metabolism in Cancer Patients Undergoing Hematopoietic Stem Cell Transplantation

Aprepitant, a neurokinin antagonist, is an effective antiemetic agent in chemotherapy for delayed nausea and vomiting. The study objective was to evaluate the pharmacokinetics of aprepitant and concurrent cyclophosphamide (CY), often a component of hematopoietic stem cell transplant (HSCT) conditioning regimen, in cancer patients undergoing HSCT. Forty subjects were randomized to either aprepitant or placebo in addition to standard antiemetics. Aprepitant or placebo was started 1 hour before the first chemotherapy or radiation dose for HSCT conditioning and administered daily until 4 days after infusion of the hematopoietic cell graft (for a total of 10-12 days). Serial blood samples were collected for aprepitant and CY plus 2 important CY metabolites. The results indicate that aprepitant is well absorbed and does not auto-induce its metabolism. No significant drug interaction was observed with CY or its metabolites. A significant portion of the patients had subtherapeutic aprepitant concentrations; however, chemotherapy-induced nausea and vomiting were effectively managed. No dosage adjustment was necessary, and administration of aprepitant in HSCT at the prescribed dosage of 125 mg orally on day 1 and 80 mg orally on each consecutive day through day +4 after HSCT was well tolerated with no significant changes in CY pharmacokinetic parameters.

Excellent outcome of matched unrelated donor transplantation in paediatric aplastic anaemia following failure with immunosuppressive therapy: a United Kingdom multicentre retrospective experience

We retrospectively analysed the outcome of consecutive children with idiopathic severe aplastic anaemia in the United Kingdom who received immunosuppressive therapy (IST) or matched unrelated donor (MUD) haematopoietic stem cell transplantation (HSCT). The 6-month cumulative response rate following rabbit antithymocyte globulin (ATG)/ciclosporin (IST) was 32·5% (95% CI 19·3-46·6) (n = 43). The 5-year estimated failure-free survival (FFS) following IST was 13·3% (95% confidence interval [CI] 4·0-27·8). In contrast, in 44 successive children who received a 10-antigen (HLA-A, -B, -C, -DRB1, -DQB1) MUD HSCT there was an excellent estimated 5-year FFS of 95·01% (95% CI 81·38-98·74). Forty of these children had failed IST previously. HSCT conditioning was a fludarabine, cyclophosphamide and alemtuzumab (FCC) regimen and did not include radiotherapy. There were no cases of graft failure. Median donor chimerism was 100% (range 88-100%). A conditioning regimen, such as FCC that avoids total body irradiation is ideally suited in children. Our data suggest that MUD HSCT following IST failure offers an excellent outcome and furthermore, if a suitable MUD can be found quickly, MUD HSCT may be a reasonable alternative to IST.