Hematopoeitic Cell Transplantation Research Articles

Effect of pre-transplant JAK1/2 inhibitors and CD34 dose on transplant outcomes in myelofibrosis.

Allogeneic hematopoeitic cell transplantation (allo-HCT) is the only curative treatment for myelofibrosis (MF). We evaluate the impact of various factors on survival outcomes post-transplant in MF. Data of 89 consecutive MF patients (primary 47%) who underwent allo-HCT between 2005 and 2018 was evaluated. Fifty-four percent patients had received JAK1/2 inhibitors (JAKi) pre-HCT. The median CD34 count was 7.1x106 cells/kg. Graft failure was seen in 10% of the patients. Grade 3-4 acute GVHD (aGVHD) and moderate/severe chronic graft versus host disease (cGVHD) occurred in 24% and 40% patients, respectively. Two-year overall survival (OS) and relapse free survival (RFS) were 51% and 43%, respectively. Cumulative incidence of relapse (CIR) and non-relapse mortality (NRM) at 2years were 11% and 46%, respectively. Higher CD34 cell dose (≤5×106 cells/kg vs 5-9 or ≥9×106 cells/kg) and lower pre-HCT ferritin (</=1000ng/ml) were associated with better OS, RFS and lower NRM. Grade 3-4 aGVHD was associated with higher NRM. Use of pre-transplant JAKi was associated with lower incidence of grade 3-4 aGVHD. In summary, higher CD34 cell dose is associated with better allo-HCT outcomes in MF and pre-HCT JAKi use is associated with reduced risk of severe aGVHD. These two modifiable parameters should be considered during allo-HCT for MF.

Hematopoeitic Cell Transplantation and CAR T-Cell Therapy: Complements or Competitors?

Allogeneic hematopoietic cell transplantation (allo-HCT) and chimeric antigen receptor T cell (CAR T) therapy are the main modalities of adoptive cellular immunotherapy that have widely permeated the clinical space. The advent of both technologies revolutionized treatment of many hematologic malignancies, both offering the chance at sustained remissions for patients who would otherwise invariably succumb to their diseases. The understanding and exploitation of the nonspecific alloreactivity of allo-HCT and the graft-versus-tumor effect is contrasted by the genetically engineered precision of CAR T therapy. Historically, those with relapsed and refractory hematologic malignancies have often been considered for allo-HCT, although outcomes vary dramatically and are associated with potential acute and chronic toxicities. Such patients, mainly with B-lymphoid malignancies, may now be offered CAR T therapy. Yet, a lack of prospective data to guide decisions thereafter requires individualized approaches on whether to proceed to allo-HCT or observe. The continued innovations to make CAR T therapy more effective and accessible will continue to alter such approaches, but similar innovations in allo-HCT will likely result in similarly improved clinical outcomes. In this review, we describe the history of the two platforms, dissect the clinical indications emphasizing their intertwining and competitive roles described in trials and practice guidelines, and highlight innovations in which they complement or inform one another.

Impact of Hematopoeitic Cell Transplantation-Co-Morbidity Index (HCT-CI) and Its Individual Components on Allogeneic Transplant Outcomes

Background Allogeneic Stem Cell Transplantation (SCT) is potentially curative for many hematological diseases, however carries a high risk of mortality and morbidity. Multiple scoring systems has been developed to predict SCT outcomes and one of the more popular one id the Hematopoeitic Cell Transplantation - Co-Morbidity Index (HCT-CI). This study evaluates the value of HCT-CI score in predicting the outcomes of patients undergoing SCT at Princess Margaret Cancer Centre (PMCC). We also looked at the impact of the individual elements of HCT-CI in predicting SCT outcomes. Methods Two experienced physicians prospectively calculated the HCT-CI score for all patients transplanted at our center. Prospective calculation was performed during the patient's pre-transplant assessment before transplant admission using a pre-prepared form. All other patient and transplant characteristics were retrospectively collected from the EPR. Non-Relapse Mortality (NRM) and Overall survival (OS) were calculated to assess the prognostic power of the scores. This was correlated with the major SCT outcomes of Non-relapse mortality (NRM) and Overall survival (OS). Separately the impact of each components of HCT-CI was assessed in Univariate and multivariable analysis for NRM and OS. Results From August 2014 to April 2017, 299 patients underwent allogeneic HCT at the Princess Margaret Cancer Centre (PMCC), Toronto. Base line characteristics of the patients are shown in Table 1. HCT-CI scores were grouped as 0-2 as group 1 and ≥3 as group 2. Nearly two thirds belonged to group 1. (Table 1) The 2 year OS for the whole cohort was 51% (45%-56%) and NRM at 2 years was 25.1% (20%-31%). For the HCT-CI scores 0-2 vs ≥3, 2-year OS was 53% vs 46% respectively (p=0.29). The NRM at 2 years was 34% (29%-39%) for the whole cohort. For the HCT-CI scores 0-2 vs ≥3, 2-year NRM was 33% vs 35% respectively (p=0.75). (Figure 1) Univariate analysis of the impact of the independent components of HCT-CI score on OS and NRM was done. A p value of 0.2 was taken as cut off for selection for multivariable analysis. For NRM, cardiac co-morbidity, Diabetes and cerebrovascular accident were considered for multivariable analysis, where as cardiac co-morbidity, diabetes, severe pulmonary comorbidity, arrythmia and cerebrovascular accident were considered for OS multivariable analysis. On multivariable analysis, diabetes was the only factor found independently impacting both NRM [HR 2.2 (95%CI 1.4-3.4), p=0.0005] and OS [HR 1.6 (95%CI 1.1-2.4), p=0.025]. Conclusion HCT-CI was not found to predict OS or NRM accurately in our cohort of patients. Among the components of HCT-CI, diabetes was the only co-morbidity that significantly impacted both OS and NRM. Future prognostic scorings should incorporate only significant elements of comorbidities along with other transplant and disease related elements while developing prognostic scores. Disclosures Mattsson: Therakos: Honoraria; Celgene: Honoraria; Gilead: Honoraria. Michelis:CSL Behring: Other: Financial Support.

Patient Age and Donor HLA Matching Can Stratify Allogeneic Hematopoietic Cell Transplantation (HCT) Patients into Prognostic Groups: A Collaborative Study

BACKGROUND: Allogeneic hematopoeitic cell transplant (HCT) is potentially curative for a variety of hematological diseases. It is however associated with significant morbidity and mortality. Numerous pre-transplant risk scores have been developed to predict outcomes, such as the Hematopoietic Cell Transplantation-Comorbidity Index (HCT-CI). This study assesses the value of the HCT-CI and related scores on a single center population, in comparison with other potential parameters influencing outcomes. A similar methodology was later applied to a different cohort of patients' data from Oslo University Hospital, Norway. METHODS: Two experienced physicians prospectively calculated the HCT-CI score for all patients transplanted at our center. The age-adjusted HCT-CI score and the augmented HCT-CI score were calculated retrospectively. Prospective calculation was performed during the patient's pre-transplant assessment before transplant admission using a pre-prepared form. The HCT-CI/age and the augmented HCT-CI (which includes ferritin, albumin and platelet count) were calculated using additional data retrospectively collected from the electronic patient records (EPR). All other patient and transplant characteristics were retrospectively collected from the EPR. Non-Relapse Mortality (NRM) and Overall survival (OS) were calculated to assess the prognostic power of the scores. We also looked at the impact of major transplant and patient related parameters in our patient population. A similar methodology was later applied to a different cohort of patients' data from Oslo University Hospital, Norway. RESULTS: From August 2014 to April 2017, 299 patients underwent allogeneic HCT at the Princess Margaret Cancer Centre (PMCC), Toronto. A similar analysis was performed in a cohort of 455 patients from Oslo University Hospital who underwent HCT between 2012 and 2018. Comparative patient characteristics are described in Table 1. On univariate analysis, 2-year OS of the PMCC cohort was 51% (95% CI 45-56%). For the HCT-CI scores 0-2 vs ≥3, 2-year OS was 53% vs 46% respectively (p=0.29). For the HCT-CI/age scores 0-2 vs ≥3, it was 56% vs 44% respectively (p=0.03). For the augmented HCT-CI scores 0-2 vs ≥3, it was 55% vs 46% respectively (p=0.05). Among other variables, age group (&lt;50 vs 50-64 vs ≥65, p=0.02) and donor mismatch (p=0.01) were significant for OS. However, age (HR 1.48 and 1.75 for age 50-64 and ≥65 respectively, p=0.047) and donor mismatch (HR 1.60, p=0.02) alone were also prognostically significant in the multivariate analysis as well. We then developed a weighted score that would better reflect risk groups in our population. Age &lt;50 and full HLA matching received 0 point each, age 50-64 and any mismatch (except DQ alone) received 1 point each, while age ≥65 received 2 points. The patients were grouped into 3 groups of 0, 1 and ≥ 2 points. This new simple 3 tier score predicted OS and NRM at 2 years with better accuracy. The 2 yr OS was 62%, 53% and 38% for the 3 groups (p value =0.0004) and 2 year NRM was 24%, 34% and 43% respectively (p value=0.015) (Table 2 and Figure 1). The same scoring system was later applied to an independent cohort of allogeneic HCT patients from the Oslo HCT registry and was found to be similarly significantly predictive of OS and NRM. In the Oslo cohort, the 2 yr OS was 69%, 65% and 35% for the 3 groups according to the new weighted score (p value &lt;0.001) and 2 year NRM was 15%, 20% and 45% respectively (p value=0.015) CONCLUSION: A simple, weighted score involving donor HLA mismatch and age predicts survival and NRM better than the HCT-CI score for patients transplanted at our center with good replicability as shown from Oslo data. Efforts should continue to strive for the development of a widely applicable pre-transplant outcome predictive scoring system. Disclosures Mattsson: Gilead: Honoraria; Therakos: Honoraria; Celgene: Honoraria. Michelis:CSL Behring: Other: Financial Support.

Combined kidney and hematopoeitic cell transplantation to induce mixed chimerism and tolerance.

Based on preclinical studies, combined kidney and hematopoietic cell transplantation was performed on fully HLA matched and haplotype matched patients at the Stanford University Medical Center. The object of the studies was to induce mixed chimerism, immune tolerance, and complete immunosuppressive drug withdrawal. Tolerance, persistent mixed chimerism, and complete withdrawal was achieved in the majority of fully matched patients. Persistent mixed chimerism and partial withdrawal has been achieved in the haplotype matched patients at present.

A Post-Hoc Analysis of the Randomized, Double-Blind, Placebo-Controlled Multicenter Phase 2 Trial to Examine the Effects of DAS181 in Hematopoeitic Cell Transplant (HCT) Recipients with Parainfluenza Virus (PIV) Lower Respiratory Tract Infection (LRTI) on Supplemental Oxygen (SO)

Background PIV infections are an important cause of morbidity and mortality in HCT recipients. DAS181, a sialidase fusion protein, has demonstrated activity in pre-clinical and clinical studies. Methods Adult immunocompromised patients (IC), including HCT recipients, diagnosed with PIV LRTI on chest imaging and required SO ≥ 2L/min were randomized 2:1 (stratified by mechanical ventilation [MV] at baseline) to nebulized DAS181 (4.5 mg in 3.5mL/day) or matching placebo for up to 10 consecutive days. The primary endpoint was the proportion of patients reaching clinical stability survival (CSS, defined as alive, resolution of SO requirement, and normalization of vital signs) by Day 45. An exploratory end point of proportion to return to room air (RTRA) was analyzed. Results Out of the 110 patients randomized, 64 HCT recipients received study drug (43 DAS181 and 21 placebo). Median age was 53 years (range, 19-77), half were male (50%), white (84%), and had received an allogeneic HCT (86%). A post-hoc analysis of the HCT recipients on SO showed that day 45 CSS was achieved by 46.5% of DAS181-treated patients compared to 33.3% of placebo (p = 0.23). In addition, when compared to placebo, HCT recipients on SO who received DAS181 within 1 year from transplant were more likely to achieve CSS at day 45 (48.4% vs. 12.5%; p = 0.071), were more likely to RTRA at day 28 and day 45 (53.3% vs. 12.5%; p = 0.04 and 60% vs. 25%; p = 0.086, respectively), more likely to be discharged from the hospital by day 45 (64.5% vs. 12.5%; p = 0.011), and had a trend for lower mortality at day 45 (25.8% vs. 62.5%, p = 0.064). The rate of adverse events was similar in both treatment groups. Conclusion DAS181 was well tolerated and a post-hoc analysis in HCT recipients with PIV LRTI on SO within 1 year of transplant, DAS181 was effective (RTRA) and showed a trend towards lower mortality by day 45. DAS181 was granted Breakthrough Therapy Designation for the treatment of PIV LRTI in IC patients and a phase 3 trial is being planned.

Hematopoeitic Cell Transplant - Comorbidity Index (HCT-CI) Score Is a Useful Tool for Predicting Induction Mortality and Overall Survival in Newly Diagnosed Acute Myeloid Leukemia Patients

Intro:Assessment of induction mortality risk in acute myeloid leukemia (AML) patients is challenging. Hematopoietic cell transplant comorbidity index (HCT-CI) score was designed for risk assessment of patients undergoing an allogeneic transplant. However, it is often used in clinical practice to assess induction mortality risk in AML patients. We analyzed the predictive power of the score to assess induction mortality risk as well as overall survival in AML patients at our institution.Methods:Between Jan 2009 and March 2013, 101 consecutive newly diagnosed AML patients treated at our institution were included for analysis. All patients received bolus HiDAC (3gm/m2) on day 1-5 and high dose mitoxantrone (80mg/m2) on day 2. The median age was 65 years (range18-90). The total number of patients in the age group <60, 60-69 and ≥70 were 30(29.7%), 35(34.6%) and 36(35.6%) respectively. HCT-CI scores were calculated before induction chemotherapy. Kaplan Meir curve was used to calculate OS and PFS. 4-week induction mortality was calculated from the date of the induction chemotherapy. The patient cohort was divided into those with HCT-CI scores of > or ≤3.Results:The number of patients with the HCT-CI score of 0,1,2 and 3 were 8,13,17 and 13 respectively. 50% of our patients (51 patients) had a score of 4 or more on the HCT-CI index. The 4 and 8-week mortality in our cohort was 3/101 (2.9%) and 7/99 (7%) respectively. 4-week induction mortality in <60, 60-69 and ≥70 years of age groups were 0/30(0%), 1/35(2.8%) and 2/36(5.5%) respectively. Similarly, in above age groups, 8-week induction mortality were 0/29(0%), 2/34(5.8%) and 5/36(13.8%) respectively. The median OS in patients with an HCT-CI score ≤3 was 87 months versus 11.5 months in those with a score >3 (log-rank, p=0.0046, Fig1). 2-yr NRM rate for patients with HCT-CI score ≤3 and >3 was 47% and 71%, respectively (p=0.01, Fig2). Hazard ratio for overall mortality in patients with HCT-CI score >3 is 1.793 with p=0.023, 95% CI = (1.083 - 2.971). HR for 8-week mortality in patients with an HCT-CI score >3 is 2.035 (p=0.412), although not statistically significant due to a low number of events. However, by Cox multivariable regression analysis HCT-CI retained a significant impact on 8-week mortality (HR=1.24, p= 0.03) and overall survival (HR=1.144, p= 0.006).Conclusion:An HCT-CI score is a valuable tool in the assessment of the induction mortality in newly diagnosed AML patients and can be used for risk assessment of overall mortality. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

ABO Mismatch Status Does Not Influence the Clinical Outcomes in Haploidentical Hematopoeitic Cell Transplantation

Background. With recent progress in modern strategies in human leukocyte antigen [HLA]-haploidentical hematopoietic cell transplantation (HCT), there has been a growing interest in the use ofhaploidentical HCT, especially when there is an urgent need to proceed to transplantation or when a donor search indicates a low likelihood of matched sibling donor (MSD) or matched unrelated donor (MUD) availability. Due to the fact that the HLA system is inherited independently of the ABO-blood group system, approximately 40-50% of allhaploidentical HCTs are performed across the blood group barrier. To the best of our knowledge, no previous studies have addressed the effect of ABO-mismatched grafts on the clinical outcomes ofhaploidentical HCTs.Methods.Our study is aretrospective cohort analysis of patients who underwent an HLA-haploidentical HCT between June 1, 2009 and April 1, 2016 at a single institution. Based on the ABO blood group, patients were placed into one of the following categories: ABO compatible, major ABO mismatch, and minor ABO mismatch. Univariate analysis was performed using χ2 test for categorical variables and Mann-Whitney Utest for continuous variables. The Kaplan-Meier estimate was implemented to compare 1-year Overall Survival rates (OS), 1-year relapse rates, cumulative incidence of 1-year acute graft versus host disease (aGVHD) of different grades, cumulative incidence of chronic GVHD (cGVHD), neutrophil engraftment, platelet engraftment, and engraftment failure rates among the three categories of patients based on ABO status. All reported P values are 2-sided, and P < .05 is considered to indicate statistical significance. A 95% Confidence Interval (CI) for the value of all outcomes of interest was reported.Results.We identified 143 patients who underwenthaplo-HCT during the study period. Of these, 91 patients were ABO compatible, 21 patients had a major ABO-mismatch status, and 27 patients had a minor ABO mismatch. Four patients had a bidirectional ABO mismatch status and were excluded from the study due to the small number. Overall, 139 patients were included in the final analysis with a median age of 51 years old (range 19-73) at the time of transplantation. 52% of the cohort was male, with 80%Caucasion, 16% African-American, and 4% belonging to other racial backgrounds. 45% of the cohort had active disease at time of transplantation, and 24% had undergone previousallo-HCTs. In the vast majority of patients (98%), G-CSF mobilized peripheral blood was used as the stem cell source. 40% of patients received amyeloablative conditioning regimen, and all patients received high dose post-transplantation cyclophosphamide as part of GVHD prophylaxis regimen.In terms of clinical outcomes, our study did not reveal a statistically significant difference between the three categories of patients based on ABO compatibility status. The 1-year OS was 49% (CI: 39-59), 52% (CI: 29-71), and 31% (CI: 14-49) for ABO compatible, major ABO mismatch, and minor ABO mismatch respectively. The 1-year relapse rate was 44% (CI: 31-56), 41% (CI: 15-65), and 42% (CI: 19-64) for ABO compatible, major ABO mismatch, and minor ABO mismatch respectively. The cumulative incidence of 1-year severeaGVHD(grade 3-4) was 13% (CI: 6-23), 14% (CI: 1-49), 6% (CI: 3-23) for ABO compatible, major ABO mismatch, and minor ABO mismatch respectively. The median neutrophil recovery time was 17 (IQR: 5), 17 (IQR: 5), and 19.5 (IQR: 10) days for ABO compatible, major ABO mismatch, and minor ABO mismatch respectively. The median platelet recovery time was 28 (IQR: 16), 27.5 (IQR: 15), and 32 (IQR: 18) days for ABO compatible, major ABO mismatch, and minor ABO mismatch respectively.Conclusion.With recent improvements in conditioning regimens and GVHD prophylaxis strategies,haplo-HCTs are becoming an increasingly available and viable option for patients without a MSD and MUD. Our retrospective cohort study, to our knowledge, is the first to examine the effect of ABO status on the clinical outcomes ofhaplo-HCTs. This study did not show any difference in clinical outcomes ofhaplo-HCTs based on major or minor ABO-compatibility status. In order to confidently conclude that ABO compatibility status does not impact the clinical outcomes ofhaplo-HCTs, well-designed prospective cohort studies with a higher number of patients are needed in the future. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Pharmacokinetics of Cefepime in Patients with Cancer and Febrile Neutropenia in the Setting of Hematologic Malignancies or Hematopoeitic Cell Transplantation.

To evaluate the steady-state pharmacokinetic parameters of standard cefepime dosing regimens in a hematologic malignancy and hematopoietic cell transplant patient population with febrile neutropenia. Open-label, single-center, prospective pharmacokinetic study. National Cancer Institute-designated cancer center. Nine adults with hematologic malignancies or hematopoietic cell transplants who had febrile neutropenia and were admitted to a hematology-oncology service between January and July 2014. Patients received empirical cefepime 2 g every 8 hours, administered as a 30-minute intravenous infusion, for febrile neutropenia. Steady-state cefepime serum concentrations were measured after at least 2 days of continuous therapy. Venous blood samples were intensively sampled between 0 and 8 hours after the start of the 30-minute infusion at steady state. Seven of the nine patients had a hematologic malignancy diagnosis of acute leukemia, lymphoma, or myeloma, and two patients had a germ cell tumor diagnosis. Noncompartmental analysis revealed mean ± SD parameters as follows at steady state: area under the plasma concentration-time curve from 0-8 hours 222.9 ± 72.9 mg hour/L, maximum concentration 120.9 ± 21.8 mg/L, clearance 9.7 ± 3.7 L/hour, apparent volume of distribution 19.2 ± 4.65 L, and elimination half-life 1.4 ± 0.3 hours. A one-compartment pharmacokinetic model identified a mean ± SD volume of distribution of 20.9 ± 1.3 L and an elimination rate constant of 0.39 ± 0.03 hour(-1) . The mean estimated percentage of time that drug concentration remains above the pathogen minimum inhibitory concentration (fT>MIC) in serum was 55%, 77%, and 99% at MICs of 16, 8, and 4 mg/L, respectively. Patients with hematologic malignancies or hematopoietic cell transplants who had febrile neutropenia demonstrated homogeneous calculated cefepime volumes and clearances. The population parameters presented in this study may aid in the calculation of patient-specific fT>MIC for similar patients.

OR40 High cell free DNA (CFDNA) recipient chimerism during early post-transplant period predicts clinically significant graft versus host disease

Aims Development of Graft versus host disease (GVHD), one of the most common and debiliating complications of allogeneic Hematopoeitic cell Transplantation (HCT) is conceptualized in the following four sequential events: killing of recipient cells by induction chemo- and radio-therapy leading to exposure of recipient antigens, activation of the antigen presenting cells, donor T cell stimulation, and target tissue destruction. As a result, the dying host tissue cells (either due to induction therapy or allo-immune responses) release small cell-free DNA molecules (cf-DNA) into the circulation. In this study, we analyzed whether recipient chimerism in circulating cf-DNA during early post-transplant period can either influence or predict ensuing GVHD. Methods cfDNA was extracted from a total of 88 serum specimens from 44 HCT recipients at one week and one month after transplant. PCR amplification of a panel of 15 fluorochrome-labelled STR markers followed by their size fractionation through capillary electrophoresis was performed to quantify recipient chimerism in cfDNA. The ’cut off’ for cfDNA recipient chimerism was determined by receiver operating characteristic (ROC) curve and its correlation with clinically significant GVHD (grade II-IV acute GVHD and/or chronic GVHD requiring systemic therapy) was analyzed using multivariate competing risk regression analysis. Results High cfDNA recipient chimerism one week after HCT was found to be associated with clinically significant GVHD (p = 0.03, Fig. 1a). Recipient cfDNA chimerism cutoff of 73% calculated by ROC analysis strongly correlated with the cumulative incidence of clinically significant GVHD (p = 0.003, HR = 7; 95% CI = 2–25.3, Fig. 1b). Recipient cfDNA chimerism one month after HCT was not associated with GVHD. Download high-res image (133KB) Download full-size image Conclusions Strong correlation of high cfDNA recipient chimerism one week after HCT with GVHD suggests that killing of host cells by induction therapy may play an important role in triggering allo-immune responses culminating into GVHD.

Serum Uric Acid Levels during Allogeneic Hematopoeitic Cell Transplantation and Subsequent Graft Versus Host Disease

Title: Serum Uric Acid Levels during Allogeneic Hematopoeitic Cell Transplantation and Subsequent Graft Versus Host DiseaseAcute graft-versus-host disease (aGVHD) is a donor T-cell driven response against host tissue that can complicate allogeneic hematopoietic cell transplantation (HCT). The initiation of aGVHD is thought to involve the stimulation of antigen presenting cells through exposure of the immune system to endogenous “danger signals” from dying cells, which can result from the cytotoxic effects of conditioning regimens. The identification of uric acid as one such critical factor released from injured cells was discovered over the past decade, and subsequent animal studies have demonstrated that suppressing uric acid can reduce T-cell activation. Furthermore, a phase I study of patients undergoing myeloablative allogeneic HCT at our institution suggested that the use of urate oxidase may modulate the development of aGHVD, presumably through lowering uric acid levels.In this retrospective study, we tested the hypothesis that patients who developed aGVHD have increased peri-transplant uric acid levels compared to those who did not. We included those who underwent myeloablative allogeneic HCT from 2007 to 2011 who were not enrolled in the aforementioned phase I study. Sixty-six patients with hematologic malignancies (AML=35, MDS=11, NHL=10 ALL=6, MPD=2, MM=1, CML=1) were analyzed. Notable transplant characteristics include conditioning regimen (Bu/Cy=26, Bu/Flu=29, Cy/TBI=7, Bu/Clo=3, Clo/TLI=1); donor status: matched related donor (MRD=40), matched unrelated donor (MUD=26); disease status: complete remission (CR=39), relapsed/refractory (R/R=27), and type of GVHD prophylaxis: cyclosporine based (CsA/MTX=24, CsA/MMF=3), tacrolimus based (Tac/MTX=16, Tac/MTX/ATG=17, Tac/MTX/Sirolimus=6). Serum uric acid levels were collected from day -7 to day +10 of transplant (up to 18 days recorded per patient). All patients received allopurinol from day -7 to day -1 per institutional protocol.On average, daily serum uric acid levels were recorded in 15.6 out of the 18 days designated per patient, and 83% (N=55) of patients had levels measured up to day +10 of transplantation. The incidence of aGVHD of any grade was 64% (N=42) and 45% (N=30) for grades II-IV. The incidence of mild or limited cGVHD was 35% (N=23) and moderate/severe or extensive cGVHD was 17% (N=11). Those who developed aGVHD had a significantly higher level of serum uric acid compared to those who did not: pre-transplant (d-7 to d0) period (p=0.003), post-transplant (d1 to d10) period (p<0.001) [Figure 1a]. Those who developed cGVHD had no statistically significant difference in serum uric acid levels compared to those who did not: pre-transplant (p=0.22), post-transplant (p=0.69) [Figure 1b]. Subgroup analyses showed that patients with R/R disease with aGVHD had significantly higher uric acid levels than those without aGVHD: pre-transplant (p<0.001); post-transplant (p<0.001), while patients in CR had similar uric acid levels: pre-transplant (p=0.48); post-transplant (p=0.45). Patients treated with cyclosporine or tacrolimus based prophylactic regimen showed similar trends in uric acid levels between aGVHD groups in the post-transplant period.These results suggest that elevated uric acid levels peri-transplantation may be associated with increased incidence of aGHVD but not cGVHD and may be more relevant in patients with more advanced disease. As a cause-effect relationship of uric acid levels and GVHD cannot be ascertained based on this retrospective data, future prospective studies will be required to clarify this association. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Haploidentical vs cord blood transplantation for adults with acute myelogenous leukemia.

Hematopoeitic cell transplantation is established as a curative treatment for patients w acute myelogenous leukemia. Haploidentical family donor and umbilical cord blood (UCB) are alternative sources of stem cells for patients lacking a matched sibling or unrelated donor. The early challenges of transplant complications related to poor engraftment and graft-vs-host disease have been overcome with new strategies such as using 2 units and increased cell dose in UCB and T-cell depletion and post transplantation cyclophosphamide in haploidentical transplantation. The outcomes of alternative transplantation for acute leukemia were compared to other traditional graft sources. For patients lacking a matched sibling or unrelated donor, either strategy is a suitable option. The choice should rely mostly on the urgency of the transplantation and the available cell dose as well as the expertise available at the transplant center. This manuscript reviews the options of alternative donor transplantation and highlights recent advances in each of these promising transplantation options.

Comparable Allogeneic Hematopoietic Cell Transplantation Outcome Of Haplo-Identical Family Donor With Matched Unrelated/Mismatched Family Donor In Adult Aplastic Anemia

Allogeneic hematopoeitic cell transplantation (alloHCT) is a curative therapy for severe/very severe aplastic anemia (sAA) in adult. alloHCT from haplo-identical family donor (HD) is an alternative approach while alloHCT from matched sibling donor (MSD) is the choice of therapy. Our previous study suggested that alloHCT from matched unrelated donor (MUD) were comparable with MSD when pre-transplantation conditions were well-matched. It means poor outcome of MUD might come from poor pre-transplantation clinical factors such as delayed alloHCT. Same will be applied to HD. In this study we compared HD with alternative donors (AD; MUD or mismatched family donor) by matched case study.We selected AD cases from KSBMT2007-01 study population who had comparable pre-transplantation clinical factors with HD by propensity-score matching. Pre-tranplatation clinical factors such as age, ATG conditioning or ABO-compatibility were matched. Therefore 48 AD cases were selected for the comparison with 16 HD cases.Male (p=0.009) and female to male transplantation (p=0.002) were more frequent in HD. AD received prior immune suppression therapy (IST) frequently (p=0.092). Cyclophosphamide (p<0.001) and total body irradiation (p=0.055) were frequent in AD while fludarabine (p=0.006) and busulfan (p<0.001) were common in HD as a conditioning regimen. Bone marrow was used frequent in AD (60.4%; p<0.001) and peripheral blood was used in all HD (100%; p<0.001) as stem cell source. Despite this differences, ATG as prior IST (p=0.769), ABO compatibility (p=0.111), T-cell ex vivo depletion (0%, both), age at diagnosis (p=0.622), age at alloHCT (p=0.400), time from diagnosis to alloHCT (p=0.822), unit of red blood cell transfusion prior to alloHCT (p=0.655), unit of platelet cell transfusion prior to alloHCT (p=0.604) and infused CD34+ cell dose (p=0.087) were similar. All transplantation outcomes except for extensive chronic graft versus host disease (GvHD) were similar. The frequencies of hepatic sinusoidal obstruction syndrome (p=1.000), acute GvHD (p=0.769), grade 3/4 acute GvHD (p=0.258), chronic GvHD (p=0.173), extensive GvHD (p=0.099), primary neutrophil engraftment failure (p=1.000), secondary graft failure (p=1.000), platelet engraftment failure (p=0.505), all graft failure (p=0.745) were similar (Table 1). Time to neutrophil engraftment was faster in HD (p=0.003) while cumulative incidence of platelet engraftment (p=0.505), acute GvHD (p=0.378), grade 3/4 acute GvHD (p=0.255), chronic GvHD (p=0.202), extensive GvHD (p=0.918) were similar. Overall survival was also similar between AD and HD (p=0.730; Figure 1). [Display omitted] In conclusion, alloHCT from HD in sAA is comparable with alloHCT from AD when pre-transplantation clinical factors were similar although extensive chronic GvHD seemed frequent in HD. Therefore alloHCT from sAA could be alternative approach of alloHCT from MUD in adult sAA. Disclosures:No relevant conflicts of interest to declare.

3-OR

Current Hematopoeitic cell transplant (HCT) donor selection strategies do not include matching at the DP locus and this locus is rarely typed for in either the related or the unrelated potential donor setting. Since the advent of the solid phase assays for detection of anti-HLA antibodies, our ability to successfully detect and determine specificity of both Class I and II antibodies has been greatly improved, particularly following the introduction of the single antigen bead platforms. We report on 3 HCT candidates who developed strong antibodies to DP (DPA/B subunits) which were found to profoundly affect the donor selection process and hence the possibility for transplant. Single Antigen HLA antibody screening was performed using One Lambda LABScreen Single Antigen kits. Results were evaluated for the presence of DP antibodies. DPA/B typing was performed using either One Lambda LabType SSO kits and/or Micro SSP trays. At our center, all candidates for HCT are screened for the presence of anti-HLA antibodies. Antibody screening results become particularly important and are used to guide donor selection in instances where patients, due to the unavailability of matched related donors or URD are restricted to mismatched, haplotype matched or cord blood donors. We report the case of 3 patients who developed strong antibodies to both the DPA1 and DPB1 subunits of DP. The strength of reactivity of the DP single antigen beads ranged from 1K- > 15K MFI and resulted in positive B-cell CDC and Flow crossmatches with appropriately MM DP donors. Finding appropriate HCT donors, lacking the offending DPA/B antigens impacts the HCT donor search process significantly. 1 patient, with rarer HLA types was unable to proceed to transplant with a URD for 2.5 years. These 3 cases highlight the influence that the presence of DP antibodies can have on the donor selection process and on the possibility of transplant. Pereira: Linkage Biosciences: Consultant; Science Med Advisor; Stockholder; Scisco Genetics: Consultant; Science Med Advisor.

Challenges and Opportunities for International Cooperative Studies in Pediatric Hematopoeitic Cell Transplantation: Priorities of the Westhafen Intercontinental Group

More than 20% of allogeneic hematopoietic cell transplantations (HCTs) are performed in children and adolescents at a large number of relatively small centers. Unlike adults, at least one-third of HCTs in children are performed for rare, nonmalignant indications. Clinical trials to improve HCT outcomes in children have been limited by small numbers and these pediatric-specific features. The need for a larger number of pediatric HCT centers to participate in trials has led to the involvement of international collaborative groups. Representatives of the Pediatric Blood and Marrow Transplant Consortium, European Group for Blood and Marrow Transplantation's Pediatric Working Group, International Berlin-Frankfurt-Munster (iBFm) Stem Cell Transplantation Committee, and Children's Oncology Group's Hematopoietic Stem Cell Transplantation Discipline Committee met on October 3, 2012, in Frankfurt, Germany to develop a consensus on the highest priorities in pediatric HCT. In addition, it explored the creation of an international consortium to develop studies focused on HCT in children and adolescents. This meeting led to the creation of an international HCT network, dubbed the Westhafen Intercontinental Group, to develop worldwide priorities and strategies to address pediatric HCT issues. This review outlines the priorities of need as identified by this consensus group.

Exostoses as a Long-Term Sequela After Pediatric Hematopoietic Progenitor Cell Transplantation: Potential Causes and Increase Risk of Secondary Malignancies from Ann & Robert H. Lurie Children's Hospital of Chicago

Allogeneic hematopoeitic progenitor cell transplantation (HPCT) is a curative therapy for pediatric patients with both malignant and nonmalignant diseases. Single or multiple benign exostoses or osteochondromas have been reported after total body irradiation (TBI), as well as after focal irradiation. Patients exposed to TBI at a young age are at highest risk of developing exostoses. The objective of this institutional review board–approved study was to look at potential factors, besides radiation, that may play a role in development of exostoses. All patients who underwent allogeneic and autologous HPCT at a single institution between March 1992 and December 2003 and who developed an exostosis identified by clinical findings or as an incidental finding on a radiologic study were included. A case-control design matched patients with controls who had the same stem cell source.

The impact of sarcopenia on transplant-related complications and number of days spent in the hospital in patients with lymphoma.

7044 Background: Sarcopenia, a state of abnormally low muscle mass, has been found to be associated with more treatment-related complications and shorter overall survival in patients with different cancers. Sarcopenia can be reliably assessed with routine computerized tomography (CT). The objectives of the study were to determine whether sarcopenia is associated with the number of complications and the number of days spent in the hospital in patients undergoing autologous hematopoietic stem cell transplantation (autoSCT) for lymphoma. Methods: Adult patients treated for non-Hodgkin's or Hodgkin's lymphoma with autoSCT between 2/2005 – 6/2/2012 at the University of Michigan (U-M) Bone Marrow Transplant (BMT) Program were eligible for inclusion if a CT of the abdomen was performed within 60 days prior to autoSCT. Total psoas area and lean psoas area were calculated for each patient with cross-sectional area and density measurements taken at the level of the fourth lumbar vertebra using algorithms programmed in the Analytic Morphomics Lab at U-M. All analyses were completed using Poisson regression models controlling for age, gender, body mass index, Hematopoeitic-Cell Transplant Co-morbidity Index (HCT-CI), and Karnofsky performance status (KPS). Results: Total and lean psoas area were calculated in the 121 patients who met inclusion criteria. Men with greater psoas muscle measures experienced fewer complications and spent fewer days in the hospital during the autoSCT admission compared to men who were sarcopenic (complications β = -0.206, p=0.001; hospital treatment days β = -0.043, p=0.029). Sarcopenia did not play a role in outcomes in women. A strong association existed between sarcopenia and re-admission days within 100 days following autoSCT among both men (β = -1.183, p&lt;0.0001) and women (β = -0.805, p&lt;0.0001). Conclusions: Muscle mass is independently associated with complication rates and duration of hospitalization in patients undergoing autoSCT for lymphoma. CT-determined psoas muscle mass may be a valuable addition to other indices used to guide optimal treatment selection and serve as a potentially modifiable host factor to improve transplant-related outcomes.

Single‐institution long‐term outcomes for patients receiving nonmyeloablative conditioning hematopoeitic cell transplantation for chronic lymphocytic leukemia and follicular lymphoma

Non-myeloablative conditioning hematopoietic cell transplantation (NMC-HCT) has improved the treatment of chronic lymphocytic leukemia (CLL) and follicular lymphoma (FL). In a cohort of 85 patients (45 with CLL and 40 with FL), we observed 5-yr overall survival (OS) and progression-free survival (PFS) of 53% and 38% in the CLL group and 81% and 76% in the FL group. In the both the CLL group and the FL group, a strong trend toward better OS and PFS was observed among patients in complete remission (CR) at HCT. Within the FL group, sixteen patients had at one or more time points in their disease history had transformed FL. In contrast to the poor survival found in patients with transformed FL in previous studies, the 5-yr OS was almost identical in patients with transformed and non-transformed FL, 83% and 78%, respectively. In conclusion, our study supports that NMC-HCT is a safe and efficacious treatment that can provide long-term survival in elderly, heavily pretreated patients with FL and CLL. Especially patients with FL, and also transformed FL, seemed to have a great benefit of NMC-HCT, and CR at the time of HCT was an important prognostic factor.

Hematopoeitic Cell Transplant (HCT) Survivorship: How Much Variance in Depressive Symptoms Can Be Accounted for by Biomedical Variables?

Hematopoeitic Cell Transplant (HCT) Survivorship: How Much Variance in Depressive Symptoms Can Be Accounted for by Biomedical Variables?

Allogeneic Peripheral Blood Stem Cell Transplantation Significantly Increases the Risk of Chronic Graft-Versus-Host Disease of Lung Compared to Bone Marrow Transplantation

Chronic graft versus host disease (GVHD) of lung is associated with higher transplant related morbidity and mortality after allogeneic hematopoeitic cell transplant (HCT). Risk factors for lung GVHD are not yet fully elucidated in detail. We attempted to identify clinical risk factors for lung GVHD after allogeneic HCT based on single center experience. 401 patients were transplanted between year 2000 and 2007 at the Princess Margaret Hospital, Toronto, Canada. 280 (70%) and 121 (30%) patients received peripheral blood stem cell (PBSC) and bone marrow (BM) as a source of stem cells, respectively. Monitoring with pulmonary function tests (PFT) were performed prior to transplant, at day 180, then annually. PFT was also performed when indicated clinically. CT scan of lung was performed to confirm the diagnosis of lung GVHD and to exclude other infectious causes. Bronchoscopic lavage was performed to exclude potential infectious cause if needed. Potential clinical risk factors for lung GVHD were examined including conditioning, age, gender, source of stem cell, diagnosis, disease status and previous episode of acute GVHD. With median follow up of 1,122 days, 68 patients (16.9%) had a diagnosis of chronic GVHD of lung with median onset of 349 days (range 71-1,880 days; 95% CI [299-398 days]), 53(78%) of whom patients received myeloablative conditioning. Fifty one(75%) patients received matched sibling donor transplant versus 17(25%) patients received unrelated donor. Overall survival rates remained similar in both cohorts. In the univariate analyses, other clinical risk factors were not associated with the risk of chronic GVHD of lung: conditioning (p = 0.9), age with cut off of 60 years (p = 0.4), donor type (p = 0.5), grade II-IV acute GVHD (p = 0.7), grade III-IV acute GVHD(p = 0.4), development of CMV reactivation (p = 0.6). However, incidence of chronic GVHD lung was significantly higher in the group receiving PBSC (13.8± 2.4% at 1 year; 23.0±3.2% at 2 years) than in those receiving BM (6.8±2.5% at 1 year; 16±3.8% at 2 years; p = 0.02, hazard ratio 1.937, 95%CI [1.100-3.410]). Multivariate analyses also confirmed PBSC transplantation as an independent risk factor for chronic GVHD of lung (p = 0.005, hazard ratio 2.359, 95%CI [1.290-4.314]). The use of PBSC increases the risk of lung GVHD compared to the use of BM for allogeneic HCT. Closer monitoring is warranted to detect lung GVHD early after PBSCT.