Ablative Conditioning Regimen Research Articles

Abstract B121: HLA-mismatched unrelated donor hematopoietic cell transplantation with post-transplant cyclophosphamide improves clinical outcomes for racial and ethnic minority patients with hematologic malignancies

Abstract Introduction: Racial and ethnic disparities exist in three areas related to hematopoietic cell transplantation (HCT): donor availability, access, and post-HCT outcomes. A significant barrier to access to HCT for patients (pts) of racial or ethnic minorities (REM) is the limited availability of fully matched donors (i.e., grafts matched at HLA-A, -B, -C, and -DRB1 loci) in volunteer registries. While mismatched unrelated donor (MMUD) grafts (i.e., <7/8 match) can be offered to pts without matched donors, MMUD HCT results in poor survival when traditional graft-versus-host disease (GVHD) prophylaxis (PPx) is used. GVHD PPx with post-transplantation cyclophosphamide (PTCy) is associated with favorable survival after haploidentical HCT, and promising outcomes have been reported in a prospective multicenter study utilizing PTCy in MMUD HCT. Herein, we analyzed the outcomes of an ethnically diverse cohort of pts who underwent MMUD HCT with PTCy at two large urban transplant centers. Objectives and Methods: Subjects receiving HCT from an MMUD from 2010-to 2020 at the University of Miami and Memorial Sloan-KetteringCancer Center were included. Pts were stratified by age, HCT indication, race/ethnicity, graft type, conditioning intensity, disease status, and degree of HLA mismatch. The primary study endpoint was one-year overall survival (OS). Secondary endpoints were event-free survival (EFS), non-relapse mortality (NRM), and cumulative incidence of acute and chronic GVHD. Results: A total of 82 pts were evaluated. The median age at HCT was 60 years (21-75), the most common indication for HCT was acute leukemia (51%), 41% of pts received an ablative conditioning regimen, and 50% received peripheral blood (PB) grafts. Forty-four percent identified as non-Hispanic white (NHW), and 56% identified as REM (Non-Hispanic Black: 30%; Hispanic: 64%; Asian/Pacific: 4.3%). The two groups (NHW vs. REM) were well-matched for leading HCT indication, disease-risk index, degree of mismatch, and disease status at HCT. REM pts were younger (median age at HCT 65 vs 56 years for NHW, p=0.001) and more likely to receive a PB graft (63% vs 40%, P = 0.04). One-year OS was 75%, EFS was 69%, and NRM was 16% for the entire cohort. Grade 3-4 acute GVHD at day 180 post-HCT was 15%, and one-year severe chronic GVHD was 9%. OS was comparable between 7/8-matched and highly-mismatched (<6/8) HCT recipients (75% vs. 76%, respectively; P >0.9). There were no differences in one-year OS (77% vs 74%, p = 0.9) and EFS (63% vs 72%, p = >0.9) between NHW and REM pts. Similarly, rates of acute (17% vs 13%, p = 0.5) and chronic GVHD (5.7% vs 11%, p = 0.5) were comparable between NHW and REM pts. Conclusion: PTCy resulted in encouraging clinical outcomes following MMUD HCT. Post-HCT OS, RFS, and GVHD rates were comparable between NHW and REM pts and those receiving 7/8 or highly mismatched grafts. Favorable post-HCT outcomes following MMUD with PTCy may increase HCT utilization and access for REM pts. Citation Format: Antonio M. Jimenez Jimenez, Sunil Iyer, Krishna Komanduri, Samantha Brown, Trent Wang, Stephanie Chinapen, Denise Pereira, Sean Devlin, Mark Goodman, Amer Beitinjaneh, Craig Sauter, Lazaros Lekakis, Miguel Angel Perales, Doris Ponce, Brian Shaffer. HLA-mismatched unrelated donor hematopoietic cell transplantation with post-transplant cyclophosphamide improves clinical outcomes for racial and ethnic minority patients with hematologic malignancies [abstract]. In: Proceedings of the 15th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2022 Sep 16-19; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2022;31(1 Suppl):Abstract nr B121.

Long Term Outcomes of Patients with Chronic Myeloid Leukemia Undergoing Allogeneic Hematopoietic Cell Transplantation in the Era of Oral Tyrosine Kinase Inhibitors

Introduction. Chronic Myeloid Leukemia (CML) is a myeloproliferative neoplasm (MPN) that without therapy is a uniformly lethal disease. Historically allogenic stem cell transplant (HCT) was the only curative therapy. In 2001 imatinib was the first CML specific oral tyrosine kinase inhibitor (TKI) approved and since then the treatment of CML has dramatically improved. Subsequently, 2nd and 3rd generation TKIs were developed and have been shown to be superior to imatinib either as initial therapy in certain high-risk patients and in other patients that fail imatinib. However, despite the advances in therapy, patients still die of CML, in fact, in 2020 it is estimated that 8,450 patients will be diagnosed with CML and 1,130 patients will die of CML. HCT remains a curative option for patients with CML. As the safety and availability of HCT improve, we aimed to describe the role of transplant in the modern era of CML therapy. Methods. We performed a retrospective chart review of patients who underwent their first HCT between June 28, 2006 and December 31, 2021 for CML in either chronic or accelerated phase at the time of transplant. Results. A total of 122 patients were identified. Patient and HCT characteristics are shown in Table 1. The median age at time of transplant was 45 (8-67), 72 (59%) are male. Fifty-four (44.3%) of patients received their transplant between 2006-2012 and 68 (55.7%) of patients received their transplants between 2013-2021. Fourteen (11.5%) patients were in accelerated phase CML at the time of HCT and the rest were in chronic phase. The median time from diagnosis to transplant was 23 months (1.8-307). Ninety-seven patients (79.5%) received ablative conditioning regimens. A total of 46 patients (37.7%) had matched related donors, 54 patients (44.3%) had matched unrelated donors, 14 patients (11.5%) had haploidentical donors, and 8 patients (6.7%) had a cord blood graft. 102 patients (83.6%) received peripheral blood stem cell grafts. GVHD prophylaxis always included a calcineurin inhibitor with the addition of methotrexate in 36 (29.5%) of patients, sirolimus in 60 (49.2%), Mycophenolate in 7 (5.7%), and post-transplant cyclophosphamide in 19 (15.6%) patients. Sixty-one patients (50%) had grade 2 or higher acute GVHD, and 19 (15.6%) had grade 3-4 acute GVHD. Extensive chronic GVHD was present in 81 (66.4%) of patients. Median follow-up of surviving patients was 59.3 months (3.3, 183.8) and overall the median follow-up was 30 months (0.55, 183.8). The estimated 12, 36, and 60-month Overall Survival (OS) of the cohort was 76.9% (95%CI 69.7-85), 66.1% (95% CI 57.7-75.6), and 58.4% (95% CI 49.4-69). Progression free survival (PFS) of the cohort at 12, 36, and 60 months was 71% (95% CI 63.2-79.7), 62% (95% CI 53.6-71.7) and 54.1% (45.1-65%) respectively. The median OS and PFS was not reached (Figure 1a,b). Fifty-two patients in the cohort died, 31 (59.6%) died of complications of treatment, 12 (23.1%) died of progression of disease, and 9 (17.3%) died of unknown causes. The day 100 cumulative incidence of non-relapse mortality (NRM) was 4.1% (1.7-9.7%) and the 1-year NRM was 17.2% (11.5-25.7%). Conclusion. This study shows excellent long term survival in patients who received an allo HCT for CML. And while, the modern treatment of CML largely relies on oral TKIs, in those patients who do not tolerate TKIs or fail available TKIs, allogeneic transplant remains an active, potentially curable therapy and should be considered. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

A Phase II Study of Total Marrow and Lymphoid Irradiation (TMLI) in Combination with Cyclophosphamide and Etoposide in Patients with Relapsed/Refractory Acute Leukemia Undergoing Allogeneic Hematopoietic Cell Transplantation

Background : Although total body irradiation (TBI)-based ablative conditioning regimens prior to allogeneic stem cell transplantation (alloHCT) have been demonstrated to be efficacious in multiple hematologic malignancies, the relapse rate and survival outcomes for relapsed/refractory (R/R) acute leukemia remain poor due in large part to limited disease control and high non-relapse mortality, which over time has led to the exclusion of these patients from such treatment. In one report, standard myeloablative alloHCT regimens, frequently in combination with TBI, yielded 1-year overall survival (OS) of only 29% and 28% for active acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL), respectively (Duval et al., J Clin Oncol, 2010). In response to these limitations, our group in a phase I trial reported that replacing TBI with targeted conformal total marrow and lymphoid irradiation (TMLI) at 2000 cGy as a conditioning regimen with cyclophosphamide (Cy) and etoposide (VP16) is safe in patients with R/R AML and ALL. Here, we report the results to date of a phase II study in which we combined the recommended dose of TMLI (2000 cGy) in combination with Cy and VP16. The objective is to evaluate the anti-leukemia activity and safety/tolerability of the TMLI/Cy/VP16 alloHCT conditioning regimen in patients with R/R acute leukemia.Patients and Methods : TMLI was administered on days -9 to -5, VP16 60 mg/kg (adjusted body weight) on day -4, and Cy 100 mg/kg (ideal body weight) on day -2. The radiation dose for all patients (n=35) was 2000 cGy, delivered in 200 cGy fractions twice daily. The radiation dose delivered to the liver and brain was kept at 1200 cGy. Bone marrow (n=2) or peripheral blood stem cells (n=33) were given on day 0. The primary endpoint is progression free survival (PFS); secondary endpoints include overall survival (OS), non-relapse mortality (NRM), and toxicity. Tacrolimus and sirolimus were administered for graft versus host disease (GVHD) prophylaxis. Toxicities were defined according to the Bearman and CTCAE 4.03 scales, the latter for hematologic toxicity. Stopping rules for unacceptable adverse events (AEs) were incorporated; the rate of unacceptable toxicity should not be ≥33% in the first 30 days post stem cell infusion.Results : A total of 35 patients were enrolled and treated (see Table) between 5/21/2014 and 12/14/2016, with a median follow up of 11.8 months (range 1.8-35.9) for all patients and 12.0 months (range 2.9-35.9) for surviving patients (n=17). All patients engrafted. The complete remission rate at day +30 was 100%. One-year estimates of OS and PFS were 62.4% (95% CI: 43.1-76.8) and 44.7% (95% CI: 27.1-60.9), respectively. Disease relapse/progression at 1 year was 52.4% (95% CI: 37.6-73.2). The estimates of NRM at 100 days and 1 year were both 2.9% (95% CI: 0.4-19.7). Relapsed disease after transplant occurred in 21 patients (60%). Two patients died in remission; the causes were West Nile encephalitis and infection, respectively.Acute GVHD (aGVHD) developed in 20 (57%) of patients; of those, only 2 patients (6%) developed grades 3-4. Bearman toxicity data are available for 30 patients. Among these patients, grade ≥2 toxicities were bladder (Gr 2 n=1), central nervous system (Gr 2 n=1), gastrointestinal (Gr 2 n=4), hepatic (Gr 2 n=1, Gr 3 n=1), pulmonary (Gr 2 n=1), and renal (Gr 2 =1, Gr 3 n=1). Additionally, 11 and 1 patients experienced grade 2 and 3 stomatitis, respectively. No grade 4 toxicities or toxicity-related deaths were observed. The stopping rules for unacceptable AEs were not met.Conclusions : 1) TMLI allows a dose of 2000 cGy to be safely delivered to targeted sites, with a 100 day and 1 year NRM of 2.9% in this high-risk patient population; 2) One-year OS and PFS are very encouraging in patients with R/R acute leukemia; 3) Toxicities and acute GVHD were manageable and in line with previous experience with this regimen. [Display omitted] DisclosuresStein:Amgen: Consultancy, Speakers Bureau; Stemline: Consultancy. Khaled:City of Hope: Research Funding; Daiichi Sankyo, Inc: Other: Travel Support. Salhotra:Kadmon: Consultancy.

Association of Gene Polymorphisms in Cyclophosphamide Metabolism Pathway with Complications after Haploidentical Hematopoietic Stem Cell Transplantation

INTRODUCTION Allogeneic hematopoietic stem cell transplantation (alloHSCT) has been established as a powerful treatment modality for patients with hematological malignancies. The graft-versus-leukemia effect, however, is strongly associated with the occurrence of graft-versus-host disease (GVHD) and subsequent transplant-related mortality (TRM). Several strategies are applied in order to prevent GVHD, the post-transplant cyclophosphamide (PT-Cy) is one of the most used in Haploidentical HSCT (Haplo-HSCT). Cyclophosphamide (CY) is an alkylating agent with antineoplastic and immunosuppressive activities. CY is metabolized by highly polymorphic enzymes to produce phosphoramide mustard which is a bifunctional DNA alkylating agent, is the therapeutically active metabolite. Thus, the aim of our study is to identity polymorphisms in the genes of the CY metabolism and correlated with complications post-HSCT (GVHD, TRM, veno-occlusive disease (VOD) or hemorrhagic cystitis (HC)). METHODS We selected 182 consecutive patients who received an Haplo-HSCT from 2007 to 2019. Eleven genes related to CY metabolism were analyzed (Table 1). The genotyping was performed in peripheral blood samples for recipient using an enrichment-capture custom gene panels (IDT probes) in a MiSeq platform (Illumina, USA). The bioinformatic analysis was carried out with BaseSpace software (Illumina, USA). Variants located in coding region and splicing sites were analyzed. We selected polymorphisms corresponding to read depth ≥30X in the canonical isoform with an allele frequency ≥0.4 and represented in at least 5% in our cohort. The collected clinical variables were age/gender recipient and donor, pathology, pretransplant status, conditioning regimen, total body irradiation, basal ferritin and CMV reactivation. Fisher test was used to compare the differences among groups. Statistical Package for the Social Sciences (SPSS, Chicago, USA) was used for statistical test. RESULTS The cumulative incidence rates for aGVHD of II-IV and III-IV grades at 100 days was 39% and 12% respectively. The cumulative incidence rates for cGVHD, moderate or severe cGVHD and TRM at 1000 days were 37%, 19% and 29%, respectively. Among the cases analyzed, 9% developed VOD and 25% HC. Patients who received ablative conditioning regimen presented a higher incidence of TRM (p=0.005). No other clinical data was associated with complications post HSCT. Forty polymorphisms were detected in 9 genes by bioinformatic analysis. The variants that presents some correlation (p<0.05) with complications post HSCT are shown in Table 1. Overall, polymorphisms related with decrease activity of enzymes that active cyclophosphamide (level lor active metabolite) were correlated with higher aGVHD, cGVHD, TRM and VOD (Table 1). On the other hand, polymorphisms associated with low activity in detoxification enzymes were correlated with higher toxicity (TRM). As described in bibliography, GSTM1 null allele were correlated with higher probability of developing VOD. CONCLUSIONS Genetic analysis of CY metabolism genes correlated with several post HSCT complications. The analyses of this variants before transplant could facilitate personalized risk and clinical management of patients undergoing Haplo HSCT. Results must validated in others cohorts of patients. Disclosures Kwon: Gilead: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Jazz: Consultancy, Honoraria.

Updated Analysis: Novel Machine-Learning-Based Sepsis Prediction Model for Patients Undergoing Hematopoietic Stem Cell Transplantation (Early Sepsis Prediction/Identification for Transplant Recipients: ESPRIT)

Updated Analysis: Novel Machine-Learning-Based Sepsis Prediction Model for Patients Undergoing Hematopoietic Stem Cell Transplantation (Early Sepsis Prediction/Identification for Transplant Recipients: ESPRIT)

Incorporation of Posttransplant Cyclophosphamide (PCy) As Part of Standard Immunoprophylaxis (IP) for All Allogeneic Transplants: A Retrospective, Single Institution Study

Background: The incorporation of PCy in IP has allowed transplantation of stem cells from haploidentical (HI) family members such that nearly all patients have a potential donor. Thus far, HI stem cell transplantation with PCy appears to yield comparable results to matched unrelated (MUD) and matched sibling donors (MSD) who have been treated with conventional GVHD regimens, but with less chronic GVHD (cGVHD). Particularly in light of the low incidence of cGVHD, which has not been achieved with other IP strategies after T cell-replete products, PCy is being investigated after MUD and MSD transplantation where complications from cGVHD remain the major cause of non-relapse mortality. A recent study from the BMTCTN showed that in patients conditioned with reduced intensity regimens and who received MSD and MUD stem cells, the addition of PCy to standard IP (SIP) was superior to either bortezomib or maravoric in the composite endpoint of graft-versus-host disease-free, relapse-free survival (GRFS). However, this study did not include patients who received ablative conditioning regimens and did not report on the percentage of patients who were disease-free and off immunosuppression (DFOI) at 1 year after transplant. In the present study, we have compared our experience with the addition of PCy for essentially all allogeneic stem cell transplants treated over a 2 year period with the results of patients treated with SIP in the prior two year span. Outcomes of interest included one-year overall survival (OS) and one-year GRFS as well as the percentage of patients DFOI at one year. Methods: With the exception of patients receiving umbilical cord blood transplants, beginning in April 2016, all but two patients who received allogeneic transplants were given mobilized peripheral blood stem cells and then treated with PCy on days +3 and +4 followed by tacrolimus and mycophenolate on day 5. In the absence of GVHD, mycophenolate was stopped at days +35-50 and tacrolimus was tapered beginning after day +100 unless there was low donor chimerism or a suspicion of relapse in which case tacrolimus could be tapered sooner. In order to have at least one-year follow-up, the last patient included in the study was treated before April 2018. During this time period, MSD were prioritized over MUD which in turn were chosen over haploidentical donors. For comparison, we looked at the prior 2 year period (2014-2016) in which patients were treated with SIP (including ATG in patients who received MUD stem cells). Because of a higher percentage of patients with an advanced disease risk index (DRI) in the years 2014-2016, we restricted our analysis in the SIP cohort to those patients with low and intermediate risk disease but included all patients in the more recent period who received PCy. Results: There were 68 patients treated in the PCy group, including 2 patients who received PCy after HI transplants in the years 2014 and 2015. After eliminating patients with high DRI there were 40 patients in the earlier SIP cohort of patients. The resulting patient groups were similar with respect to median age (53) and diagnosis (approximately 80% of patients with AML and ALL). There was a slightly higher percentage of patients in the SIP group with hematopoietic cell transplantation-comorbidity index scores of 3 or more (52.5 vs 48.5). In the PCy group the number of patients with early, intermediate and advanced DRI were 2, 53 and 13, whereas in the (modified) SIP category 2 patients had a low DRI and 38 had intermediate DRI. In the PCy group, HI donors comprised 26.5% of the total compared to 19.1% MSD and 54.4% MUD donors. In the SIP group, MSD and MUD donors accounted for 30% and 70% of the donors. One-year percentages of OS, GRFS and DFOI were 79.4, 47.1 and 44.1 in the PCy group compared to 72, 45 and 35 in the SIP cohort. If the analysis of the PCy group is limited to the 50 patients with MSD and MUD donors (as in the SIP cohort), the one-year OS, GRFS and DFOI are 88, 52 and 52. Conclusions: PCy in combination with SIP resulted in at least comparable results as SIP despite the inclusion of 19% of patients with a high DRI and 26.5% HI donors. The results with the addition of PCy are excellent in patients with MSD and MUD donors with more than half of the patients GRFS and DFOI at one year. Future studies on GVHD prophylaxis should report DFOI as the latter status may be the best platform for posttransplant strategies aimed at eliminating minimal residual disease and for improving QOL. Disclosures No relevant conflicts of interest to declare.

Identification of New Polymorphisms in Genes of the Immune System Associated with Acute Graft Versus Host Disease after Identical HLA-Allogeneic Stem-Cell Transplantation

INTRODUCTION Allogeneic haematopoietic stem cell transplant (allo-HSCT) could be the only curative therapy for patients with hematological malignancies due to graft effect against tumor. However, approximately 40% of patients develop post-transplantation complications such as acute graft-versus-host disease (aGVHD). Cytokines and their receptors are involved in regulatory and inflammatory processes that occur during GVHD. Therefore, the analysis of polymorphisms (SNPs) that affect the expression or activity of these genes could be used as biomarkers to predict the development of these complication. The aim of this study was to select new polymorphisms in cytokine genes (interleukins, chemokines and their receptors) to build models to predict the development of aGVHD after allo-HSCT from an HLA-identical sibling donor. METHODS We retrospectively selected 88 patients with hematological malignancies who received an allo-HSCT from an HLA-identical sibling donor from 2000 to 2015. A total of 176 pre-transplant recipient (R) and donor (D) peripheral blood samples were collected. The genotyping was performed using an enrichment-capture gene panels (include 132 genes (73 interleukins, 59 chemokines) in a HiSeq platform (Illumina, USA). The bioinformatic analysis was carried out with the GeneSystemssoftware (Sistemas Genómicos, Spain). Variants located in coding region, splicing sites, and UTR, 5'upstream and 3'downstream zones (+ 200pb) were analyzed. We selected polymorphisms corresponding to non-synonymous variants, represented in at least 5% of our cohort, with readings ≥30X in the canonical isoformwith an allele frequency ≥ 0.4. Fisher test was used to compare the differences among groups. Multiple logistic regression models were performed using combination of interleukins and chemokines polymorphisms selected previously that could be applied to clinical practice to predict aGVHD. The models with the highest AUC value, sensitivity and specificity value and the lowest number of genetic variants used were selected.Statistical Package for the Social Sciences (SPSS, Chicago, USA) was used for statistical test. RESULTS The cumulative incidence rates for aGVHD of grades II-IV and III-IV at 100 days after transplantation were 48.93% and 18.08%, respectively. The clinical variables (age, gender, pathology, stem cell source and previous transplantation) were not correlated with II-IV or III-IV aGVHD. However, patients who received ablative conditioning regimen presented a lower incidence of III-IV aGVHD (p= 0.041). Using filters defined previously, we detected 481 polymorphisms (350 coincident, 68 specific R and 63 for D) in the interleukins group. On the other hand, we detected 339 polymorphisms (267 coincident, 29 specific R and 43 for D) in the group of chemokines. Finally, 17 polymorphisms were selected in the interleukin group and 10 in the chemokine group for its correlation with the aGVHD (p <0.05). Specifically, 14 SNPs were correlated with II-IV aGVHD (Table 1) and 12 SNPs with III-IV aGVHD (Table 2). Most polymorphisms found are located in regulatory regions, which until have been little studied, but these regions are involved in the expression genes, therefore could be affecting the function of these genes. We developed multiple logistic regression models for II-IV and III-IV aGVHD in interleukins and chemokines genes (Table 3). The identification of these 15 polymorphisms could help us to prevent the developing II-IV and III-IV aGVHD. CONCLUSIONS We have identified new genetic polymorphisms correlate with the risk of developing aGVHD after allo-HSCT from an HLA-identical sibling donor. Based on these data, we have developed a genetic score that encompasses polymorphisms of greater relevance. In this way, patients at greatest risk for developing this type of post-transplantation complication who could benefit from personalized management through immunosuppression and other drugs. Disclosures No relevant conflicts of interest to declare.

Does Resetting the Immune System Fix Multiple Sclerosis?

Multiple sclerosis is the leading non-traumatic cause of disability in young adults, affecting up to 100,000 Canadians. This chronic inflammatory and neurodegenerative disease of the central nervous system leads to irreversible neurologic disability if inadequately controlled. Though many current medications are available that reduce inflammatory damage, most patients continue to show some evidence of disease activity and accrue disability. In this review, we discuss the role of immune ablation followed by autologous hematopoietic stem cell transplantation (AHSCT), a therapeutic option for select patients with a more aggressive disease course. By "resetting" the immune system with a variety of ablative conditioning regimens, followed by immune reconstitution, this therapy has shown a durable response in halting evidence of inflammatory activity in most patients, without the need for continued disease-modifying therapies (DMT). Since the introduction of this therapy, there have been advances in patient selection and supportive care, such that morbidity has significantly declined and treatment-related mortality is minimized. Recent phase-II trials have shown excellent results in efficacy and safety of AHSCT; however, challenges exist which require ongoing study. The future challenges include comparing the variety of AHSCT conditioning regimens with each other as well as with existing highly effective DMT; identifying patients with an aggressive disease course through novel biomarkers who may benefit the most from AHSCT; and surveillance of long-term outcomes of different treatment protocols. In select patients, replacing the immune system with AHSCT holds promise of fundamentally altering the trajectory of their aggressive disease course.

Defining Incidence and Risk Factors for Catheter-Associated Bloodstream Infections in an Outpatient Adult Hematopoietic Cell Transplantation Program

Allogeneic hematopoietic cell transplantation (HCT) patients are at an increased risk of developing central line–associated bloodstream infections (CLABSIs) due to prolonged periods of myelosuppression, immunosuppression, and indwelling catheter days. CLABSIs are among the most serious complications in HCT recipients and can lead to prolonged hospitalizations, intensive care unit admissions, lengthy antimicrobial therapies, and increased mortality. There is a lack of data regarding the incidence and risk factors associated with the development of CLABSIs in the HCT population undergoing outpatient transplantation. This was a single-center, retrospective analysis of adult patients who underwent allogeneic HCT between July 2012 and July 2016 in an outpatient transplant unit at a tertiary academic medical center. The primary outcome was the cumulative incidence of CLABSIs from the date of central line placement through the first 100 days post-transplantation. Secondary outcomes included risk factors for CLABSI, number of hospitalizations due to CLABSI, mortality rate at 6 months post-transplantation, and the cumulative incidence, speciation, and presence of multidrug resistance in identified microorganisms. Three hundred fifty-nine patients underwent allogeneic HCT at Vanderbilt University Medical Center and 352 were included for analysis. The cumulative incidence of CLABSIs was 9%, with the majority occurring within the first 30 days post HCT (67%). The use of a matched unrelated donor (MUD) and/or haploidentical donor (odds ratio, 3.993; 95% confidence interval [CI], 1.329 to 12.001; P = .0136) and use of an ablative conditioning regimen (odds ratio, 2.394; 95% CI, 1.052 to 5.446; P = .0374) were independently associated with development of a CLABSI on multivariate analysis. The most common organism implicated in CLABSI was Staphylococcus epidermidis (34%). Patients who developed a CLABSI had an almost 5 times higher risk of mortality at 6 months post-transplantation compared with patients who did not develop a CLABSI (hazard ratio, 4.932; 95% CI, 2.463 to 9.878; P < .001). There is a low incidence of CLABSIs in patients undergoing HCT in the outpatient setting. Patients who underwent HCT using a MUD or haploidentical donor and received ablative conditioning were at higher risk for developing CLABSIs. Overall mortality at 6 months post-transplantation was higher in patients who developed a CLABSI. Additional prospective studies are needed to confirm these observations.

Impact of Cytomegalovirus on Early Chimerism in Patients with Myeloid Disorders Undergoing Stem Cell Transplantation Using Reduced Toxicity Ablative Conditioning Regimen

Impact of Cytomegalovirus on Early Chimerism in Patients with Myeloid Disorders Undergoing Stem Cell Transplantation Using Reduced Toxicity Ablative Conditioning Regimen

Cytomegalovirus and Effect on Early Chimerism in Patients with Myeloid Disorders Undergoing Stem Cell Transplantation Using Reduced Toxicity Ablative Conditioning Regimen

Cytomegalovirus (CMV) remains a significant cause of morbidity after allogeneic hematopoietic stem cell transplantation (SCT). The influence of CMV on the chimerism in reduced toxicity ablative conditioning SCT in myeloid disorders is ill defined. A recent report published in Blood by Sellar et al showed that in patients who received alemtuzumab-based regimen, the group of patients who were recipient positive (R+)/ Donor negative (D-) had CMV-specific T cells that are exclusively of recipient origin and significantly influenced the chimerism status toward recipients. To explore the impact of seropositivity and seronegativity of CMV in recipients and donors on early chimerism, we undertook a retrospective analysis of patients with myeloid disorders who received four days of fludarabine and busulfan with or without anti-thymocyte globulin (ATG) at our center in the last 10 years.Methods: Chimerism assay was performed using a quantitative fluorescence-based short tandem repeat-polymerase chain reaction (STR-PCR) with capillary electrophoresis for PCR product resolution.Results: 42 patients were identified and included in the study. All patients received fludarabine (40 mg/m2/day x 4 doses), busulfan (3.2mg/kg/dose IV x 4 doses). Of these 42 patients, 25 had anti-thymocyte globulin. There were 28 male and 14 female patients with a median age of 62 years (range 48-74yrs). Median time to follow up was 8 months (0.8-54 months). Disease risk was considered advanced in 21 patients, intermediate in 4 and early in 17. Median blast number at time of SCT was 5%. Stem cell source included peripheral blood in all patients. There were no primary graft failures. Total recipient cell chimerism showed increase or persistence of recipient chimerism in 5/11 (45%) of R+D- vs 2/6 (33.3%) of R-D- in the group of patients who received ATG, p=1.0, with a mean of recipient chimerism at day 100 of 20.4% in the R+D- group compared to a mean of 17% in the R-D- group. In the group who did not get ATG, recipient chimerism persistence or increase was not that different between the R+D- patients 3/4 (75%) compared to 4/4 (100%) in patients who were seronegative for CMV (R-), p=1.0. The mean of recipient chimerism at day 100 in the R+D- no ATG group was 23.25% with a median of 12% while the mean and median at day 100 in the R- no ATG group were 35.25% and 19.5% respectively (p=0.573).When looking at the persistence or increase in recipient chimerism in the group of patients who were R+D-, in those who got ATG it was 45% increase vs 75% increase in those who did not get ATG (p=0.569) with a median of 12% vs 0% respectively (p=0.49). Also increase or persistence of recipient chimerism was 33.3 % in patients who were R- and got ATG vs 100% in R- no ATG patients (p=0.076)with median at day 100 of 0 vs 19.5% (p=0.098).Conclusion: In this small cohort from a single center, we found that in patients with myeloid disorders who received reduced toxicity ablative conditioning regimen, the group of patients who received ATG, there was no statistically significant increase in recipient chimersim in the R+D- group compared to R-D- group. This is different from what Sellar et al found in a small group of patients who received alemtuzumab. These results may indicate a difference between ATG and alemtuzumab in the effect of CMV seropositivity and negativity on the recipient chimerism, which need to be studied further in a larger retrospective or prospective study. This is especially important in myeloid disorders since persistent or increase in recipient chimerism may identify high-risk patient cohorts who may benefit from additional therapeutic interventions. DisclosuresNo relevant conflicts of interest to declare.

Outcomes after use of two standard ablative regimens in patients with refractory acute myeloid leukaemia: a retrospective, multicentre, registry analysis

Cyclophosphamide plus intravenous busulfan has not been compared with cyclophosphamide plus total body irradiation (TBI) in adults with advanced refractory acute myeloid leukaemia before allogeneic haemopoietic stem-cell transplantation (HCT). We aimed to assess whether survival of patients receiving ablative intravenous busulfan-based conditioning regimens before a related or volunteer-unrelated donor HCT for refractory acute myeloid leukaemia is not inferior to that of patients receiving an ablative TBI-based regimen. In this retrospective, multicentre, registry-based study, we obtained data for patients (aged >18 years) with refractory acute myeloid leukaemia in active phase of disease, who had received HCT from an HLA-identical sibling or an unrelated donor after intravenous busulfan plus cyclophosphamide or cyclophosphamide plus TBI conditioning between 2000 and 2012. Data was obtained from the European Group for Blood and Marrow Transplantation registry. The primary endpoints of the study were overall survival and leukaemia-free survival. We obtained data for 514 patients who had received intravenous busulfan plus cyclophosphamide and 338 patients who had received cyclophosphamide plus TBI. The median percentage of blasts before HCT did not differ significantly between groups (20% [range 5-100; IQR 10-32] in the intravenous busulfan plus cyclophosphamide group vs 16% [5-95; 9-33] in the cyclophosphamide plus TBI group; p=0·16). Overall survival at 2 years did not differ between the groups in the univariate analysis (31·2% [95% CI 26·8-35·5] with intravenous busulfan plus cyclophosphamide vs 33·4% [28·1-38·7] wth cyclophosphamide plus TBI; p=0·65). Leukaemia-free survival at 2 years also did not differ between groups (25·0% [95% CI 21·0-29·0] vs 28·4% [23·4-33·5]; p=0·47). In multivariable analysis adjusting for differences between both groups, no difference was noted between the two groups in terms of overall survival (hazard ratio [HR] 0·99 [95% CI 0·83-1·20]; p=0·95) or leukaemia-free survival (HR 0·97 [0·81-1·16]; p=0·71). Main causes of non-relapse mortality were graft-versus-host disease (49 [10%] in the intravenous busulfan plus cyclophosphamide group vs 25 [7%] in the cyclophosphamide plus TBI group) and infection (36 [7%] vs 18 [5%]). From a practical standpoint, the use of intravenous busulfan plus cyclophosphamide is likely to be a valid and efficient alternative to cyclophosphamide plus TBI conditioning regimen for patients with refractory acute myeloid leukaemia, especially for those transplant centres without access to radiation facilities. None.

Mismatched Unrelated Donor Allo-SCT for AML after Reduced Intensity or Ablative Conditioning Regimen—A Report from the Acute Leukemia Working Party of the EBMT

Mismatched Unrelated Donor Allo-SCT for AML after Reduced Intensity or Ablative Conditioning Regimen—A Report from the Acute Leukemia Working Party of the EBMT

High Rates of Early Donor Chimerism in Intermediate and Poor Risk Patients Undergoing Stem Cell Transplantation Using Reduced Toxicity Ablative Conditioning Regimen Incorporating Busulfan Pharmacokinetics

Abstract Reduced toxicity ablative conditioning regimens are increasingly used for allogeneic stem cell transplantation (allo-SCT). The impact of early donor cell chimerism on outcomes of T cell–replete reduced-intensity conditioning SCT in myeloid disorders is ill defined. To explore the impact of measuring busulfan pharmacokinetics in conditioning regimens on early donor chimerism, we undertook a retrospective analysis of patients with myeloid disorders who received four days of fludarabine and busulfan with or without measuring busulfan pharmacokinetics at our center in the last 10 years. Methods: Chimerism assay was performed using a quantitative fluorescence-based short tandem repeat– polymerase chain reaction (STR-PCR) with capillary electrophoresis for PCR product resolution. Results: Thirty patients were identified and included in the analysis. All patients were conditioned with fludarabine (40 mg/m2/day x 4 doses), busulfan (3.2mg/kg/dose IV x 4 doses). Of these thirty patients, 7 had busulfan pharmacokinetics measured. There were 21 male and 9 female patients with a median age of 62 years (range 48–72yrs). Median time to follow up was 13.3 months. Diagnoses included AML (N=17), MDS (N=10), MPN (N=1), CMML (N=2). Disease risk was considered advanced in 17 patients, intermediate in 3 and early in 10. All patients in the busulfan pharmacokinetic group had advanced disease except one had early disease. Regarding cytogenetics, all patients in the busulfan pharmacokinetics group had high or intermediate risk cytogenetics. Median blast number at time of SCT was 5%. Stem cell source included peripheral blood in all patients. Eleven patients received matched related donor (MRD) SCT, 15 had matched unrelated donor (MUD) SCT and 4 had mismatched unrelated donor (MMUD) SCT. Prophylaxis of GVHD consisted of tacrolimus and methotrexate in MRD, and tacrolimus, methotrexate and anti-thymocyte globulin in MUD and MMUD. All patients engrafted neutrophils and platelets promptly (median 13 and 14 days, respectively). There were no primary graft failures. Total Donor cell Chimerism analysis in the Busulfan pharmacokinetics group showed 100% donor at both time points (days 30, 100) in all patients except in one who relapsed at day 30 (85.7%). While in the non-pharmacokinetics group only 7 out of 23 (30%) patients had complete chimerism at day 30 and day 100. Complete donor chimerism at day 100 in the non-pharmacokinetics group was 47.8% compared to 85.7% in the pharmacokinetic group (p=0.18). Ten out of 23 patients (43.5%) in the non-pharmacokinetics group had decreasing donor chimerism by day 100, while in the pharmacokinetic group only one patient (14%) who relapsed had decreasing donor chimerism by day 100 with an odds ratio of 0.241 (95% Confidence Interval =0.025-2.357; p-value=0.22). None developed sinusoidal obstructive syndrome. Conclusion: In this small cohort of consecutive patients from a single center, we found that patients with myeloid disorders who received fludarabine busulfan for 4 days incorporating busulfan pharmacokinetics had a trend for higher rates of early complete donor chimerism and less decreasing donor chimerism by day100, although not statistically significant, despite having intermediate or high risk disease at time of SCT. Longer follow up is needed for our patients to see if there is effect on relapse or survival but previous studies have showed that low or decreasing donor chimerism early after SCT is an independent risk factor for relapse and impaired survival. This is especially important in myeloid disorders. Busulfan pharmacokinetics may help target better level for inducing early total donor chimerism and donor chimerism may identify high-risk patient cohorts who may benefit from additional therapeutic interventions. These results should be interpreted with caution given the retrospective design of the study and the small number of patients. Disclosures No relevant conflicts of interest to declare.

Impact of Gender: Female Related Donor Versus Male Matched Unrelated Donor on Peripheral Blood Allogeneic Stem Cell Transplant for Male Recipients

BackgroundThe female donor/male recipient combination increases the risks of graft-versus-host disease (GVHD) and non-relapse mortality (NRM) after allogeneic stem cell transplantation (allo-SCT), with a possible deleterious impact on overall survival (OS). The mammalian Y chromosome encodes male-specific minor histocompatibility (H-Y) antigens that are recognized by female T cells. Some clinical data suggest a strong correlation between H-Y Antigen disparity and GVHD. In addition, female donors are notorious for bearing memory type lymphocytes induced by previous pregnancies; such allo-immune cells may provoke unwanted immune reactions such as GVHD in the recipient. To explore the impact of Female related donor (F-MRD) versus male matched unrelated donor (M-MUD) on outcome of peripheral blood allo-SCT in male recipients, we undertook a single center retrospective analysis of male adult patients transplanted at our center in the last 10 years. MUDs were matched at the allele level for HLA-A, B, C, DRB1, and DQB1. We excluded patients who received donor lymphocyte infusion post SCT. MethodsDisease-free survival (DFS) and OS were calculated using the Kaplan-Meier estimate. Cumulative incidences (CI) were used for relapse (REL), and GVHD in a competing risks setting, NRM being a competing event for REL, and death for GVHD. The following variables were considered: recipient age (³ vs < 57 years, median age), F-MRD vs M-MUD, myeloablative (MAC) vs reduced-intensity ablative conditioning (Red ABL) vs non-myeloablative (NMA) regimen, early (CR1 or PR1 or chronic phase or untreated) vs advanced disease. Steroid-refractory (SR) GVHD was defined as acute GVHD progressing after 3 days of treatment, or unchanged after 7 days, or in incomplete response after 14 days, or chronic GVHD with no response after one month, no partial response after 2 months or progressive disease in 2 weeks of initiation of steroid treatment or during the methylprednisolone taper. RESULTSFifty-six patients were identified and included in this analysis. The median age at transplant was 57 years (19-73). Diseases were AML (n=21), ALL (n=7), NHL (n=9), Hodgkin’s disease (n=1), myeloma (n=5), MDS (n=11), CLL (n=1), and CML (n=1). Conditioning regimens were MAC (n=35), RED ABL (n=17) or NMA (n=4). Donors were F- MRD (n=24) or M-MUD (n=32). Source of stem cells was peripheral blood in all patients. GVHD prophylaxis consisted of tacrolimus and methotrexate in MRD and tacrolimus, methotrexate and anti-thymocyte globulin in MUD. Of the female donors, 63% had previous pregnancies before donation, 8% had no pregnancies and 29% were unknown. Mean age of female donors was 48 while the mean age for male donors was 35.The median follow-up was 8 months (0.8-54 months). The median OS for patients who received M-MUD was 8.1 months while it was 14.2 months for patients who received F-MRD (p= 0.72) Fig1. Median DFS for patients who received M-MUD was 6 months while it was 7.2 months for patients who received F-MRD (p= 0.94). The CI rates of aGVHD III-IV, extensive chronic GVHD, REL and NRM at 12 months in M-MUD vs F-MRD were 13% vs 16% (p=0.69), 21% vs 27% (p=0.61), 38% vs 44% (P=0.65), and 16% vs 14% (p=0.79), respectively. The CI of SR GVHD in M-MUD vs F-MRD was 24% vs 32% (The Hazard Ratio of srGVHD in M-MUD vs F-MRD is 0.711 (95% confidence interval is 0.29-1.72, p=0.45)) Fig2. Other variables considered in univariate analysis for SR GVHD were recipient age (p=0.55), disease status (p= 0.64), MAC vs other regimens (p=0.58). ConclusionIn this small cohort of consecutive patients from a single center, we found that compared to M-MUD, F-MRD had a trend for higher rates of SR GVHD after peripheral blood allo-SCT in adult male patients, although not statistically significant. There was no impact of F-MRD compared to M-MUD on OS, DFS, REL, NRM or rates of acute or chronic GVHD. However, the absence of statistical impact should be interpreted with caution given the retrospective design of the study and because we cannot exclude a possible limiting effect of a small number of patients.Fig 1 [Display omitted] Fig 2 [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Intensified Chemotherapy for Older Patients with Acute Lymphoblastic Leukemia (ALL): A Phase II Study from the Dana Farber Cancer Institute (DFCI) ALL Consortium

▪Unlike the significant advances seen with intensive chemotherapy for pediatric acute lymphoblastic leukemia (ALL) over the last two decades, long-term outcomes among patients over age 50 remain poor, with median survival less than one year. This contrast has been attributed to high-risk chromosomal features, decreased compliance with and tolerance of effective therapies, and exposure to less intensive multi-agent regimens among adults with ALL. In recent years, more intensive chemotherapeutic paradigms, derived from pediatric protocols, have been studied in adult ALL. The purpose of the current study was to determine the efficacy of an intensified multi-agent approach, derived from a completed DFCI consortium pediatric regimen used in younger adults, in an older (age >50) population of patients with ALL. For this study, modifications of the pediatric regimen included incorporation of clofarabine in consolidation, adjustment to dose and scheduling of PEG asparaginase and steroids, as well as inclusion of stem cell transplant (SCT) for eligible patients. The primary endpoint was survival rate at 1 year, with the goal of improving from the 33% historical control to 53%.Adults, aged 51-75 years, with newly diagnosed ALL or lymphoblastic lymphoma, were eligible. During induction, patients received multi-agent chemotherapy with vincristine, prednisone, doxorubicin, and PEG asparaginase. Imatinib was instituted if cytogenetics confirmed the presence of the Philadelphia chromosome. Patients received prophylactic intrathecal therapy with induction, and those with CNS involvement underwent additional IT therapy. Prednisone was administered for 21 days for those aged less than 60 and for 7 days for those aged 60 and above. Following induction, cycle one of consolidation included treatment with clofarabine, prednisone, and PEG asparaginase. After induction and first consolidation course, eligible patients proceeded to allogeneic SCT. Patients without matched sibling donors could receive unrelated donor or cord blood transplants. While those eligible under age 60 could undergo ablative conditioning regimens, those 60 and older received reduced intensity regimens. Those not eligible for SCT, went on to receive CNS, consolidation and continuation phases of treatment, as per protocol, which incorporated treatment with cycles of vincristine, doxorubicin, 6-mercaptopurine, and dexamethasone. PEG asparaginase was incorporated into the induction, consolidation I, CNS phase, and consolidation II phases of therapy.As of the most current analysis, 30 patients have been enrolled. A total of 19 of 29 evaluable patients (66%) have achieved a complete remission (CR). Three patients were refractory to induction therapy, four discontinued treatment during induction due to toxicity, of which three died, and nine patients have experienced relapse following remission. Nine patients have undergone SCT. A total of 15 patients have died on study out of 27 evaluated, and the overall survival, calculated by the method of Kaplan and Meier, at one year was 62% [95% CI, 41%-77%] (Figure 1), while disease-free survival for the 18 patients who achieved a CR following induction therapy at one year was 77% [95% CI, 49%-90%]. In total, for evaluable patients with at least one year of follow-up, the proportion surviving at one year was 61% [two-sided 80% CI, 47-75%] (16/26), significantly higher than the historical rate (33% used for this analysis, one-sided 90% exact CI) among such patients. Overall survival is also shown for Ph+ and Ph- groups (Figure 2). The most common grade 3/4 toxicities included transaminitis and hyperbilirubinemia, cytopenias, hypophosphatemia, hyperglycemia, and neutropenic fever. The major toxicity of liver injury, thought related to PEG asparaginase, prompted an amendment to the protocol to reduce the dose. Additionally, PEG asparaginase administration was limited to only those with Philadelphia chromosome-negative disease, to decrease risk of severe hepatotoxcity in patients receiving concurrent imatinib and PEG asparaginase.These data suggest that intensive multi-agent chemotherapy is tolerable in older patients with ALL, and can result in improved outcomes when compared to historical data. Additional study of similarly intensive regimens, incorporating novel therapies and alternative formulations of asparaginase, are warranted in older populations of ALL. [Display omitted] [Display omitted] DisclosuresFathi:Seattle Genetics: Research Funding; Seattle Genetics: Advisory Board, Advisory Board Other. Stone:Novartis: Research Funding.

High Rates of Early Donor Chimerism in Intermediate and Poor Risk Patients Undergoing Stem Cell Transplantation Using Reduced Toxicity Ablative Conditioning Regimen Incorporating Busulfan Pharmacokinetics

▪Reduced toxicity ablative conditioning regimens are increasingly used for allogeneic stem cell transplantation (allo-SCT). The impact of early donor cell chimerism on outcomes of T cell–replete reduced-intensity conditioning SCT in myeloid disorders is ill defined. To explore the impact of measuring busulfan pharmacokinetics in conditioning regimens on early donor chimerism, we undertook a retrospective analysis of patients with myeloid disorders who received four days of fludarabine and busulfan with or without measuring busulfan pharmacokinetics at our center in the last 10 years.Methods: Chimerism assay was performed using a quantitative fluorescence-based short tandem repeat– polymerase chain reaction (STR-PCR) with capillary electrophoresis for PCR product resolution.Results: Thirty patients were identified and included in the analysis. All patients were conditioned with fludarabine (40 mg/m2/day x 4 doses), busulfan (3.2mg/kg/dose IV x 4 doses). Of these thirty patients, 7 had busulfan pharmacokinetics measured. There were 21 male and 9 female patients with a median age of 62 years (range 48–72yrs). Median time to follow up was 13.3 months. Diagnoses included AML (N=17), MDS (N=10), MPN (N=1), CMML (N=2). Disease risk was considered advanced in 17 patients, intermediate in 3 and early in 10. All patients in the busulfan pharmacokinetic group had advanced disease except one had early disease. Regarding cytogenetics, all patients in the busulfan pharmacokinetics group had high or intermediate risk cytogenetics. Median blast number at time of SCT was 5%. Stem cell source included peripheral blood in all patients. Eleven patients received matched related donor (MRD) SCT, 15 had matched unrelated donor (MUD) SCT and 4 had mismatched unrelated donor (MMUD) SCT. Prophylaxis of GVHD consisted of tacrolimus and methotrexate in MRD, and tacrolimus, methotrexate and anti-thymocyte globulin in MUD and MMUD.All patients engrafted neutrophils and platelets promptly (median 13 and 14 days, respectively). There were no primary graft failures. Total Donor cell Chimerism analysis in the Busulfan pharmacokinetics group showed 100% donor at both time points (days 30, 100) in all patients except in one who relapsed at day 30 (85.7%). While in the non-pharmacokinetics group only 7 out of 23 (30%) patients had complete chimerism at day 30 and day 100. Complete donor chimerism at day 100 in the non-pharmacokinetics group was 47.8% compared to 85.7% in the pharmacokinetic group (p=0.18). Ten out of 23 patients (43.5%) in the non-pharmacokinetics group had decreasing donor chimerism by day 100, while in the pharmacokinetic group only one patient (14%) who relapsed had decreasing donor chimerism by day 100 with an odds ratio of 0.241 (95% Confidence Interval =0.025-2.357; p-value=0.22). None developed sinusoidal obstructive syndrome.Conclusion: In this small cohort of consecutive patients from a single center, we found that patients with myeloid disorders who received fludarabine busulfan for 4 days incorporating busulfan pharmacokinetics had a trend for higher rates of early complete donor chimerism and less decreasing donor chimerism by day100, although not statistically significant, despite having intermediate or high risk disease at time of SCT. Longer follow up is needed for our patients to see if there is effect on relapse or survival but previous studies have showed that low or decreasing donor chimerism early after SCT is an independent risk factor for relapse and impaired survival. This is especially important in myeloid disorders. Busulfan pharmacokinetics may help target better level for inducing early total donor chimerism and donor chimerism may identify high-risk patient cohorts who may benefit from additional therapeutic interventions. These results should be interpreted with caution given the retrospective design of the study and the small number of patients. DisclosuresNo relevant conflicts of interest to declare.

Impact of Vitamin D Level After Allogeneic Hematopoietic Stem Cell Transplant

AbstractAbstract 1954 Introduction:Vitamin D (VD) deficiency can cause osteomalacia, aching bone pain, muscle weakness, fatigue, increase risk of fracture and precipitate or exacerbate osteopenia/osteoporosis. Allogeneic hematopoietic stem cell transplant (HCT) patients are susceptible to low VD level secondary to poor oral intake, decreased exposure to sunlight and treatment related malabsorption. VD level has been correlated to cancer incidence and VD metabolites have been used in the treatment of myeloid leukemia. VD shows promising immunomodulatory properties and correction of low VD level may mitigate manifestations of graft versus host disease (GVHD). Reports have suggested that low VD level appears to increase the incidence of GVHD. We hypothesize that there is a relationship between low VD level and morbidity (specifically incidence of acute GVHD), mortality and relapse incidence after HCT. We therefore studied VD levels pre- and post-HCT to determine if VD level impacts these outcomes. Patients and Methods:241 patients underwent myeloblative or non-myeloablative HCT between January 1, 2009 and January 31, 2011 at our institution. Baseline demographic data, disease characteristics, transplant variables and outcomes data were obtained from the transplant database. These data were supplemented by retrospective chart review for pre- and post-transplant VD level. Categories for VD level included normal (>30 ng/ml) or abnormal (<30 ng/ml). Results:131 (54%) of patients who underwent myeloblative or non-myeloablative HCT had their VD level evaluated either pre-transplant, post-transplant or both. Pre-HCT 57 (56%) patients, 100 days post-HCT 55 (59%) patients and 365 days post-HCT 12 (32%) patients had a low VD level. 51 (38%) of patients had a reduced intensity HCT and 80 patients (62%) had an ablative conditioning regimen. 11 (8.4%) patients had acute GVHD. Comparison of VD level among those with acute GVHD did show a higher incidence of acute GVHD between those with a low or normal VD level (HR=3.14, 95% CI: 0.35–28.33) however this association was not statistically significant (p=0.3079). Survival analysis in those with a low VD level pre-HCT showed there was not a higher risk of mortality (HR=1.14, 95% CI: 0.18–7.38) after adjusting for post- VD level, and this association was not statistically significant (p=0.8921). Survival analysis in those with a low VD level post-HCT did show a higher risk of mortality (HR=2.59, 95% CI: 0.26–25) after adjusting for pre-HCT VD level, however, this association was not statistically significant (p=0.4155). The relationship between VD level and relapse at 1 year post-HCT was not able to be examined because the VD level for patients who relapsed was not available. Conclusions:Half of patients undergoing HCT had VD testing pre- or post- HCT. Just over half of the patients tested had a low VD level pre- and 100 days post-HCT. It is notable that 365 days post HCT the number of patients with low VD level had decreased. This could be attributable to less time in the hospital thus increasing sun exposure, increasing performance status allowing better ingestion and absorption of VD in the gastrointestinal tract or proper supplementation of a low level noted previously. There was no significant difference in incidence of acute GVHD by VD level though there was a trend for increased risk. Pre- and post-HCT VD level did not significantly impact mortality but there was a trend toward higher risk in those with a low VD level post-HCT. This is the first study, to our knowledge, to evaluate the impact of VD level on mortality post-HCT. Our study confirms that many patients have a low VD level pre-and post-HCT. These findings, especially the trend towards a higher mortality risk and higher incidence of acute GVHD in those who have a low VD level post-HCT, warrant further prospective investigation. VD supplementation may be a low cost, easy to implement addition to routine post HCT care that might reduce HCT associated mortality. Disclosures:Reeder:Celgene: Research Funding.

A Matched Controlled Analysis of Post-Transplant Cyclophosphamide (CY) Versus Tacrolimus and Mini-Dose Methotrexate in Matched Sibling and Unrelated Donor Transplant Recipients Receiving Reduced-Intensity Conditioning: Post-Transplant CY Is Associated with Higher Rates of Acute Gvhd

AbstractAbstract 4200Graft-vs.-Host Disease (GVHD) remains a common complication following matched sibling and unrelated donor hematopoietic cell transplantation (HCT). Standard GVHD prophylaxis calls for prolonged immune suppression, typically with a calcineurin-inhibitor. Recently, post-transplant cyclophosphamide (CY) has been studied as sole prophylaxis in matched related and unrelated bone marrow (BM) transplant recipients following an ablative conditioning regimen with busulfan (Bu) and CY and demonstrated comparable rates of acute GVHD and lower rates of chronic GVHD as traditional GVHD prophylaxis regimens. We recently conducted a phase II study of post-transplant CY following a reduced-intensity conditioning (RIC) regimen of Busulfan (Bu) and Fludaribine (Flu) in matched related and unrelated donor transplants and performed a matched-control analysis comparing their results with patients who received traditional GVHD prophylaxis with tacrolimus and mini-dose methotrexate (MTX) during the same time period.Forty-nine (49) patients were enrolled onto this study. They received Flu at a dose of 40mg/m2 over 1hour followed by intravenous Bu over 3 hours targeting a daily AUC of 4,000 microMol-min on days –6 to –3. Recipients of unrelated transplants received ATG on days –3 to –1 (total dose 4 mg/kg). CY was given as sole GVHD prophylaxis at a dose of 50 mg/kg on days +3 and +4. During the same period of time, 133 patients received a RIC regimen with intravenous Bu/Flu or Flu and melphalan (Mel) and received GVHD prophylaxis with tacrolimus plus mini-dose MTX (10mg/m2 on day +1, 5mg/m2on days +3, +6, +11). Unrelated donor transplants also received ATG. A computer generated algorithm was used to identify a comparable control group from our departmental database matching, in order of priority, on age, diagnosis, disease status, donor (matched-related versus unrelated) and graft source (PB versus BM). Matched controls (control group) were successfully identified for 37 study patients (Post-Cy group). Results:The median age for the Post- CY group and control group was 61 (range, 39–72) and 62 years (range, 37–72). Eight-one (81) % of patients in both groups had AML or MDS, 3% had ALL and 16% had NHL or CLL. Fifty-nine (59) % of patients in both groups had unrelated donors and received ATG in the conditioning. Disease status for the Post-CY and control groups respectively were CR1: 14 and 14%, CR2: 8 and 11%, >CR2: 38 and 32% and Primary Induction Failure / Untreated: 40 and 32%. Seventy (70) % of the post-CY group received BM versus 48% of the control group, whereas sex mismatching (Male donor for Female patient) occurred in 22% of the post-Cy and 8% of the control group. The cumulative incidence of grade II-IV acute GVHD and chronic GVHD in the post-CY and control groups were: 46% versus 19% (Hazard Ratio (HR): 2.8, 95% CI, 1.1–6.7; p=0.02) and 14% versus 21% (HR: 0.8, 95% CI, 0.2–2.6, p=0.7). Grades III/IV acute GVHD occurred in 14% (95% CI, 6–32) of the patients in the post-CY group whereas there were no cases of grade III/IV in the control group (p=0.02). Overall, progression-free and non-relapse mortality at 2-years are shown in the table below. Conclusion:Post-transplant CY following RIC is associated with higher rates of acute GVHD, with resultant trends for higher non-relapse mortality and lower overall survival when compared to tacrolimus and mini-dose MTX. The use of post-transplant CY as a sole GVHD prophylaxis regimen should be avoided following RIC transplant in matched-related and unrelated donors.Post-Transplant CYTacrolimus and MethotrexateHazard Ratio (95% CI, p- value)Acute GVHD Grade II-IV46% (32–66)19% (10–37)2.8 (1.1–6.7, 0.02)Chronic GVHD @ 1-year14% (6–32)21% (11–43)0.8 (0.2–2.6, 0.7)Non-Relapse Mortality @ 2-years36% (23–55)16% (7–35)2.4 (0.8–6.7, 0.1)Progression-Free Survival @ 2-years22% (10–37)33% (16–51)1.3 (0.7–2.3, 0.4)Overall Survival @ 2 years26% (13–42)46% (26–64)1.8 (0.9–3.3, 0.08) Disclosures:Off Label Use: azacitidine: off-label use as maintenance therapy following allogeneic stem cell transplant for MDS/AML.

Analysis of incidence, risk factors and clinical outcome of thromboembolic and bleeding events in 431 allogeneic hematopoietic stem cell transplantation recipients

Allogeneic hematopoietic stem cell transplantation recipients have an increasing risk of both hemorrhagic and thrombotic complications. However, the competing risks of two of these life-threatening complications in these complex patients have still not been well defined. We retrospectively analyzed data from 431 allogeneic transplantation recipients to identify the incidence, risk factors and mortality due to thrombosis and bleeding. Significant clinical bleeding was more frequent than symptomatic thrombosis. The cumulative incidence of a bleeding episode was 30.2% at 14 years. The cumulative incidence of a venous or arterial thrombosis at 14 years was 11.8% and 4.1%, respectively. The analysis of competing factors for venous thrombosis revealed extensive chronic graft-versus-host disease to be the only independent prognostic risk factor. By contrast, six factors were associated with an increased risk of bleeding; advanced disease, ablative conditioning regimen, umbilical cord blood transplantation, anticoagulation, acute III-IV graft-versus-host disease, and transplant-associated microangiopathy. The development of thrombosis did not significantly affect overall survival (P=0.856). However, significant clinical bleeding was associated with inferior survival (P<0.001). In allogeneic hematopoietic stem cell transplantation, significant clinical bleeding is more common than thrombotic complications and affects survival.