Hematopoietic Cell Transplantation Group Research Articles

Higher Rates of Severe Infection and Persistent Cytopenias in Long-Term CAR19 Responders Than after Autologous HCT: A Single Institution Study of 139 Subjects

Introduction: Chimeric antigen receptor (CAR) T-cell therapy is a leading treatment for relapsed or refractory aggressive and indolent lymphomas. One major adverse effect of CAR T-cell therapy is prolonged risk for infection. To quantify infectious risk after CAR, we performed a single center analysis of patients after anti-CD19 CAR T-cell therapy axicabtagene ciloleucel (axi-cel, n=78) and compared these with chemo-responsive lymphoma patients concurrently undergoing autologous hematopoietic cell transplant (HCT) with cyclophosphamide, carmustine, and etoposide conditioning (n=61). Methods: All 139 patients were treated between 09/2017 and 10/2021, with 37/78 CAR and 32/61 HCT patients treated after the first report of COVID-19 in California (02/2020). Median follow up was 718 days (range 175-1650 days). We included only patients without documented relapse of their lymphoma to avoid the confounding impact of lymphoma relapse on study endpoints. There was no significant difference in age or sex between groups. The CAR-treated cohort had fewer non-CAR prior lines of therapy (mean 3.0 vs mean 3.6, p=0.014, Wilcoxon rank sum test). Nearly all patients in the CAR group (76/78) were treated for large B-cell lymphoma (LBCL) entities, with 2/78 having follicular lymphoma with a prior LBCL history. Similarly, a minority of patients in the HCT group were treated for mantle cell lymphoma (4/61) and follicular lymphoma (5/61). Of the CAR patients 19/78 had an HCT prior to CAR, and 1/61 HCT patients had prior CAR treatment. For each patient we catalogued and graded post-treatment infections after day +30 (D+30) to focus on post-discharge events. Endpoints analyzed were any infection as well as severe infections (grade ≥3). Death and treatment for a second malignancy were considered competing events. We additionally catalogued blood count measurements including hemoglobin, platelets, white blood cell count (WBC), absolute neutrophil count (ANC) and absolute lymphocyte count (ALC) at regular intervals from pre-treatment through D+800. There was no difference in baseline WBC or ANC between groups. CAR-treated patients had a higher baseline ALC and hemoglobin while HCT-treated patients had higher baseline platelets (p<0.05 for all values, Wilcoxon rank sum test). Results: There was no difference in overall survival between groups (p=0.18, log-rank test). We performed cumulative risk regression considering infections for 1200 days starting at D+30. When considering all infections there was no significant difference in the total incidence of infections between the CAR and HCT group. However, there was increased risk in CAR-treated patients for severe (grade >= 3) infections (Figure 1A, HR 2.4, CI 1.2-4.78, Gray's p=0.013). The increased risk for severe infection was sustained when considering only infections that occurred greater than one-year post-transplant (HR 3.06, CI 1.14-8.21, Gray's p=0.021). The increased risk for severe infection in the CAR-treated cohort remained if patients with prior HCT were excluded, or if COVID-19 cases were excluded. We used linear mixed effects modeling to assess cytopenic risk longitudinally from D+28 to D+800. Age, sex, and non-CAR lines of therapy were also included in the multivariate model. CAR-treated patients demonstrated significantly reduced WBC, ANC, and ALC relative to patients treated with HCT (Figure 1B, p-value <5E-7, <0.05, and <5E-5 respectively, restricted maximum likelihood with t-test using Satterthwaite's approximation). These values remained significant if CAR patients with prior HCT were excluded from analysis. WBC and ANC were significantly reduced relative to pre-lymphodepletion baseline through D+365 (p<0.05, Wilcoxon signed-rank test). There was no difference in hemoglobin level in CAR-treated vs HCT patients using the same methods. Platelet counts in CAR-treated patients resolved to the same level as following HCT by the end of the follow up period. Conclusion: Lymphoma patients without relapse after axi-cel CAR T-cell therapy have greater risk for severe infections than a concurrent group of patients treated with autologous HCT. This risk is associated with prolonged reduction in WBC, ANC, and ALC but not platelets or hemoglobin. Clinical surveillance for infections in these immune compromised CAR-treated patients therefore remains critical, with role of additional prophylaxis strategies needing further investigation. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Increased Rates of Rhabdomyolysis in Male Hematopoietic Cell Transplantation Recipients Taking Sirolimus and Trimethoprim/Sulfamethoxazole

Hematopoietic cell transplantation (HCT) offers long-term cure against early morbidity and mortality of hemoglobinopathies, such as sickle cell disease (SCD) and beta-thalassemia. Following HCT, sirolimus is an immunosuppressant used to prevent graft-versus-host disease (GVHD) while receiving trimethoprim-sulfamethoxazole (TMP-SMX) for Pneumocystis jirovecii prophylaxis and other antimicrobial agents (including acyclovir). One rare adverse event associated with both drugs is rhabdomyolysis, defined as creatine kinase (CK) elevation at least 5 to 10 times the upper limit of normal. This study was conducted to evaluate the rate of and risk factors for developing rhabdomyolysis in the post-HCT setting. Across 4 haploidentical and matched related donor (MRD) nonmyeloablative protocols, CK levels were prospectively monitored and patients were retrospectively identified for rhabdomyolysis. The rhabdomyolysis was graded based on the severity of CK elevation and other organ injury. At diagnosis, patients were queried for concurrent medication use (ie, sirolimus, TMP-SMX, acyclovir, or statins), sex, age, donor genotype, and time from transplantation. Among 127 patients with mostly SCD, rhabdomyolysis occurred in 22 (17%), including 2 recipients of haploidentical donor HCT and 20 recipients of MRD HCT. The time to the development of rhabdomyolysis was 61 and 73 days for the 2 recipients of haploidentical HCT and a median of 73 days for the MRD HCT recipients. Among the 22 patients who developed rhabdomyolysis, 20 (91%) were receiving sirolimus (2 haploidentical HCT recipients and 18 MRD HCT recipients), and 14 (64%) were also receiving TMP-SMX (all in the MRD HCT group). Seventy-five percent of the haploidentical donors and 69% of the MRDs had sickle cell trait. All but 2 patients with rhabdomyolysis were male. No patients who developed rhabdomyolysis were receiving statins at any point. Higher-than-expected rates of rhabdomyolysis were found post-transplantation for patients with SCD and beta-thalassemia. Contributing risk factors included immunosuppression with sirolimus, TMP-SMX, male sex, and sickle trait donor. These factors differ from the excessive muscle strain or injury, seizures, infections, or HMG-CoA inhibitors typically identified in non-HCT recipients.

Unbalance in Iron Metabolism in Childhood Leukemia Converges with Treatment Intensity: Biochemical and Clinical Analysis.

Simple SummaryIn children undergoing therapy for acute leukemia or after hematopoietic cell transplantation, the following iron metabolism parameters were analyzed in the context of iron overload: (1) parameters measuring functional and storage iron pools: non-transferrin-bound iron (NTBI) and labile plasma iron (LPI) levels, iron, transferrin, total iron-binding capacity, ferritin, ferritin heavy and light chains; (2) proteins regulating iron absorption and its release from tissue stores: hepcidin, soluble hemojuvelin, soluble ferroportin-1; (3) proteins regulating the erythropoietic activity of bone marrow: erythroferrone, erythropoietin, soluble transferrin receptor. It has been shown that the occurrence of NTBI and LPI in the circulation and the intensification of disturbances in iron metabolism were associated with the intensity of anti-leukemic treatment and were the highest in the transplant group followed by the acute leukemia after treatment and de novo groups. In patients after transplantation, the most significant changes were found in NTBI, LPI, iron, ferritin, hepcidin, and ferroportin-1 levels.Objective: The aim of this study was to evaluate non-transferrin-bound iron (NTBI) and labile plasma iron (LPI) levels and other parameters of iron metabolism in children undergoing therapy for acute leukemia or after hematopoietic cell transplantation (HCT), in the context of iron overload. Patients: A total number of 85 children were prospectively included into four groups: controls, acute leukemia de novo, acute leukemia after intensive treatment, and after HCT. Methods: The following iron metabolism parameters were analyzed: (1) parameters measuring functional and storage iron pools: NTBI, LPI, iron, transferrin, total iron-binding capacity, ferritin, ferritin heavy and light chains; (2) proteins regulating iron absorption and its release from tissue stores: hepcidin, soluble hemojuvelin, soluble ferroportin-1; (3) proteins regulating the erythropoietic activity of bone marrow: erythroferrone, erythropoietin, soluble transferrin receptor. Results: Intensive treatment of leukemia in children was associated with the presence of serum NTBI and LPI, which was the highest in the HCT group followed by the acute leukemia after treatment and de novo groups. In patients after HCT, the most significant changes were found in NTBI, LPI, iron, ferritin, hepcidin, and ferroportin-1 levels. Conclusions: The occurrence of NTBI and LPI in the circulation and the intensification of disturbances in iron metabolism were associated with the intensity of the anti-leukemic treatment.

1636. Risk of Latent Tuberculosis Reactivation in Patients Treated with Checkpoint Inhibitors Immunotherapy Compared to Other Anti-Cancer Therapies including Hematopoietic Cell Transplantation

BackgroundThe risk of latent tuberculosis infection (LTBI) reactivation in cancer patients during checkpoint inhibitor immunotherapy (CPI) remains largely unknown. We sought to evaluate LTBI therapy and outcomes between cancer patients receiving CPI versus conventional chemotherapy (CC) and hematopoietic cell transplantation (HCT) recipients.MethodsWe conducted a retrospective cohort study of adult patients with LTBI (positive T-SPOT TB test) at MD Anderson Cancer Center between April 2016 and May 2020, who received CPI or combined with other conventional chemotherapy. Thereafter we compared each group to patients treated with other anti-cancer therapies including CC alone or HCT.ResultsWe identified 106 patients with LTBI, who were analyzed into 3 distinct groups: CPI (32 patients, 30%) CC alone (37 patients, 35%), and HCT (37 patients, 35% (7 autologous versus 30 allogeneic). The majority of patients in the CPI group (97%) had solid tumors compared to 54% in the CC group. Nivolumab was the most commonly used CPI agent in 13 patients (40%), followed by pembrolizumab 10 pts (31%). In the CPI group, 20 pts (62%) received LTBI therapy that included Isoniazid (INH), versus 18 patients (49%) in the HCT group and 16 patients (43%) in the CC group (p=0.26). Only 3 patients (CC group) had TB reactivations (8%; p=0.11). None of these 3 patients had received LTBI therapy or corticosteroids prior to the diagnosis. Immune-related adverse effect (IrAEs) were reported in 11 pts (34%) patients, and 9 (82%) of them received corticosteroids. Out of 20 of CPI patients whom received INH, 4 (20%) developed possible INH-induced liver toxicities leading to interruption of medication versus 1 (6%) patient which had mild hepatitis in CC group versus none of HCT patients (p=0.09).ConclusionOur data suggest that latent tuberculosis reactivation remains rare, especially in the severely immunocompromised patients on CPI, CC and steroids. However, hepatotoxicity is relatively common in patients treated with CPI and INH. Therefore, caution and close laboratory and clinical monitoring is required to avoid significant hepatic injury and interruption of LTBI therapy and lifesaving oncological therapy.Disclosures Issam I. Raad, MD, Citius (Other Financial or Material Support, Ownership interest)Cook Medical (Grant/Research Support)Inventive Protocol (Other Financial or Material Support, Ownership interest)Novel Anti-Infective Technologies (Shareholder, Other Financial or Material Support, Ownership interest)

Allogeneic Hematopoietic Stem Cell Transplant Versus No Transplant in Adult Patients with Philadelphia Chromosome Positive Acute Lymphoblastic Leukemia in First Complete Remission and Complete Molecular Remission

Allogeneic Hematopoietic Stem Cell Transplant Versus No Transplant in Adult Patients with Philadelphia Chromosome Positive Acute Lymphoblastic Leukemia in First Complete Remission and Complete Molecular Remission

Role of Allogeneic Hematopoietic Cell Transplant in Patients with Myelofibrosis in the JAK Inhibitor Era

Role of Allogeneic Hematopoietic Cell Transplant in Patients with Myelofibrosis in the JAK Inhibitor Era

Age-Based Probability of Ten-Year Overall Survival (OS) of Acute Myeloid Leukemia (AML): A National Cancer Database (NCDB) Analysis

Background: Clinical trial data suggest excellent short-term outcomes for younger patients and a subset of fit older patients. Translating findings of clinical trials into the real-world practice has challenges, and longer-term data are often not available. Hence, we utilized NCDB to determine age-based probability of ten-year OS of unselected cohorts of adults with AML. Methods: NCDB captures about 70% of all new diagnosis of cancer. We utilized NCDB to analyze ten-year OS of 15,646 patients aged ≥18 years, who were diagnosed with AML during the years 2004-2007. Univariate and multiple logistic regression models were used to determine factors associated with ten-year OS. Kaplan Meier curves were generated for OS analysis. Results: Ten-year OS was 12.7% for patients aged 18-59 years treated with chemotherapy without hematopoietic cell transplant (HCT) (Table 1, Fig. 1). Older age, male, Charlson-Deyo comorbidity score &amp;gt;0, insurance other than private, subtypes other than core-binding factor AML were associated with lower ten-year OS. Ten-year OS was 24.3% for patients aged 18-59 years treated with chemotherapy and HCT (Fig 2). Older age, male, and insurance other than private were associated with lower ten-year OS. Ten-year OS was 16.1% and 2.2% for patients older than 60 years and treated with and without HCT, respectively; multivariate analysis was not performed for older patients because of low sample size (HCT group) or low survival (non-HCT group). Detailed analysis will be presented. Conclusions: Long-term OS of adults with AML is low with less than a quarter of patients being alive at ten years. Ten-year OS is particularly poor for older patients who are treated with chemotherapy alone. Whereas recent advances and approval of eight new drugs will likely improve short-term OS at 2-3 years, innovative strategies are necessary to improve long-term OS and cure. Further study to identify the cause of death will be insightful. Disclosures Bhatt: Takeda: Consultancy; Partnership for health analytic research: Consultancy; Jazz: Research Funding; National Marrow Donor Program: Research Funding; Oncoceutics: Other; Abbvie: Consultancy, Research Funding; Incyte: Consultancy, Research Funding; Pfizer: Research Funding; Tolero: Research Funding; Rigel: Consultancy; Agios: Consultancy; Omeros: Consultancy. Chaulagain:Sanofi Genzyme: Honoraria. Gundabolu:BioMarin: Consultancy; Bristol Myers Squibb pharmaceuticals: Consultancy.

Allogeneic Hematopoietic Cell Transplantation May Improve Long-Term Outcomes in Patients with Ph-like Acute Lymphoblastic Leukemia with CRLF2 Overexpression

Allogeneic Hematopoietic Cell Transplantation May Improve Long-Term Outcomes in Patients with Ph-like Acute Lymphoblastic Leukemia with CRLF2 Overexpression

Clearance of Somatic Gene Mutations in Patients with Acute Myeloid Leukemia Prior to Allogeneic Hematopoietic Cell Transplantation (HCT) Predicts Outcome

Clearance of Somatic Gene Mutations in Patients with Acute Myeloid Leukemia Prior to Allogeneic Hematopoietic Cell Transplantation (HCT) Predicts Outcome

Impact of Hematopoietic Stem Cell Transplantation in Patients with Relapsed or Refractory Marginal Zone Lymphoma

Introduction Marginal zone lymphoma (MZL) is an indolent lymphoma, which includes extra-nodal MZL of mucosa-associated lymphoid lymphoma (MALToma), nodal MZL (NMZL), and splenic MZL (SMZL). There are currently several treatment options for patients with relapsed or refractory (R/R) MZL, including high-dose chemotherapy with autologous hematopoietic cell transplantation (HCT). Allogeneic HCT is considered to be an optional therapy for R/R MZL patients, but there is no specific data to support allogeneic HCT for R/R MZL. Objectives We retrospectively analyzed the outcomes among R/R MZL patients treated with autologous or allogeneic HCT to identify the potential clinical efficacy of allogeneic HCT. Methods Patient information was derived from the Transplant Registry Unified Management Program database, collected by the Japanese Data Center for Hematopoietic Cell Transplantation, and sponsored by the Japanese Society for Hematopoietic Cell Transplantation. The 70 patients with R/R MZL (25 MALToma, 31 NMZL, and 14 SMZL) were receiving either autologous HCT (n=56, 19 MALToma, 27 NMZL and 10 SMZL) or allogeneic HCT (n=14, 6 MALToma, 4 NMZL and 4 SMZL). Results No patients with MALToma died because of non-relapse mortality (NRM) following autologous HCT and no patients developed relapse with MALToma and NMZL at allogeneic HCT. Progression-free survival (PFS) and overall survival (OS) of R/R SMZL patients who underwent allogeneic HCT were significantly lower compared with the autologous HCT group (median PFS, 65.6% and 25.0% at 1 year after autologous and allogeneic HCT, P=0.014; median OS, 78.7% and 25.0% at 1 year after autologous and allogeneic HCT, P=0.0030). There were no significant differences in the PFS and OS of R/R MALToma and NMZL patients who underwent autologous HCT compared with allogeneic HCT. The main findings of this study indicated that both autologous and allogeneic HCT may be acceptable for patients with chemo-sensitive MALToma and NMZL, but the results of allogeneic HCT for chemo-resistant MALToma and SMZL were inconclusive. Conclusion The parameters for choosing between autologous and allogeneic HCT for R/R MZL have not been defined, and strategies aimed at improving the selection of R/R MZL patients for autologous HCT and excluding R/R chemo-resistant MALToma patients, may allow us to identify individual R/R MZL patients who are at high risk of death after both autologous and allogeneic HCT. Selecting suitable R/R SMZL patients for allogeneic HCT might reduce NRM. The introduction of novel therapies before and after receiving allogeneic HCT could improve outcomes among R/R SMZL patients.

Direct HLA Genetic Comparisons Identify Highly Matched Unrelated Donor-Recipient Pairs with Improved Transplantation Outcome.

HLA matching by allele-level genotyping is largely based on genetic similarity between a few exons that encode the antigen recognition domain (ARD) of the HLA protein. Next-generation sequencing (NGS) can identify HLA genetic polymorphisms in non-ARD-encoding exons, introns, and untranslated regions, but the impact of these polymorphisms on hematopoietic cell transplantation (HCT) outcome is unclear. We performed NGS-based sequencing of 11 HLA loci on a well-characterized retrospective cohort of 166 unrelated donor-recipient HCT pairs. Genetic differences between HCT pairs were identified and visualized using a novel bioinformatics approach that directly compares phased full-length HLA sequences. Our approach was able to correctly classify HCT pairs without known HLA allele-level mismatches and also to identify a subset of HLA allele-matched HCT pairs with very few to no genetic differences in the sequenced HLA regions. This highly HLA genetically matched unrelated HCT group shows improved overall survival and reduced acute graft-versus-host disease compared with HCT pairs with HLA allele-level mismatches. These results suggest that direct genetic matching of HLA loci may offer an additional means of HCT donor selection beyond traditional HLA allele comparisons and suggests that genetic similarity as defined by HLA sequencing may have a novel role in unrelated HCT donor selection. Finally, our approach can enable larger cohort studies with adequate power to detect differences in other HCT outcomes based on genetic similarity within the HLA loci.

Multivariable Modeling of Disease and Treatment Characteristics of Adults with B-ALL in MRD-Negative CR after CD19 CAR-T Cells Identifies Factors Impacting Disease-Free Survival

Multivariable Modeling of Disease and Treatment Characteristics of Adults with B-ALL in MRD-Negative CR after CD19 CAR-T Cells Identifies Factors Impacting Disease-Free Survival

Trends and Characteristics of Adult Acute Lymphoblastic Leukemia in a Public Safety-Net Hospital

Introduction: Outcomes for adults with acute lymphoblastic leukemia (ALL) have improved with the development of multiple regimens, including pediatric protocols. While intensive chemotherapy may achieve high remission rates, 5-yr overall survival ranges from 5% to 55%, and is influenced by age, cytogenetics, and other factors. The primary objective of the study is to assess the survival of a unique cohort of adults with ALL treated at a safety-net public hospital. Secondary objectives are to describe demographic and clinical characteristics of this population, to assess remission rates based on the treatment regimens, and to determine the referral rate to centers for hematopoietic cell transplant (HCT).Methods: We retrospectively analyzed adult (> 18 years) patients diagnosed with ALL who presented to Harbor-UCLA between 2000 and 2017. Patients with Burkitt lymphoma, chronic myelogenous leukemia in lymphoid blast phase, and biphenotypic leukemia were excluded. Baseline characteristics, including age, sex, race, ALL subtype, number of hospitalizations, and type of induction regimens were collected. Incidences of positive bacterial blood and urine cultures were recorded. Rates of complete remission (CR) and relapse were calculated. The number of referrals for HCT and number of patients who received HCT were noted. Kaplan-Meier survival analysis was performed for overall survival (OS) from the time of diagnosis. Univariate and multivariate subgroup survival analyses were performed based on different age groups, induction regimens, and consolidation treatment with HCT.Results: A total of 83 patients with ALL presented to Harbor-UCLA from 2000 to 2017 and were included in this analysis. Median age at time of diagnosis was 35 years (range: 18-63); the majority of patients were male (58%) and Hispanic (71%). Of patients whose Ph status was assessed (n=48), 15 (31%) were Ph+; 33 (69%) were Ph-. Induction regimens included pediatric protocols (n=14), HyperCVAD (n=31), Linker's regimen (n=34), and others (n=2). Two (2%) patients did not receive induction chemotherapy. The median number of hospitalizations per patient was 6 (range 1-29). Of the 81 patients who received induction chemotherapy, 63 (78%) achieved CR with induction. Median time to CR was 30 days (range 0-140 days). When stratified by induction regimens, remission rates were 92% for pediatric protocols, 68% for HyperCVAD, and 79% for Linker regimens. 36 patients (44%) had relapsed or refractory disease. 32 (39%) had positive blood cultures; 23 (28%) had positive urine cultures. 25/83 patients were referred for HCT. Out of those referred, 11 (44%) underwent HCT.We divided the study into 3 time periods: 2000-2005, 2006-2011 and 2012-2017. Over the 3 periods there was significant (p=0.04) increase 12% (n=2), 26% (n=9) and 45% (n=9) in HCT referral rates. At the time of study conclusion there were 44 deaths with a median OS of 21.9 months (95% CI, 14.4-43.4 months) and median leukemia-free survival of 23.3 months (n=59, 95% CI, 12.6-NR). 2 and 5-year survival were 46.7% (95% CI, 35.8%-60.9%) and 27.2% (95% CI, 16.8%-43.8%), respectively.We compared outcomes in different cohorts based on age, induction chemotherapy, and HCT vs no HCT. By log-rank test, median OS was significantly improved for the age group 18-40 compared with age group ≥ 40 years (34.8 months (95% CI, 24.3 months-NR) vs 9.5 months (95% CI, 4.7-21.9)), respectively (p=0.0035). OS was not correlated with the induction regimen: pediatric protocols (43.4 months), HyperCVAD (17.4 months), Linker's (21.9 months), and others (8.2 months), with p=0.69. There was a trend for improvement in OS with a pediatric protocol, albeit with a wide confidence interval given the small numbers. The 5-year OS in the HCT group compared to non-HCT group was 55.6% (n=11) vs 25.8% (n=64), p=0.17 respectively. On multivariate analysis, only younger age was significantly associated with better OS (HR=0.43 [95% CI, 0.21-0.88], p=0.0214).Conclusion: The 5-year OS of ALL patients treated at public safety-net hospital providing care to a medically underserved; predominantly Hispanic population was comparable to prior national estimates of OS. Age was the only predictor of OS in the multivariate model. HCT referral rates to tertiary centers in the past 5 years increased, with a trend towards improved survival with HCT. Improved collaboration with tertiary centers may improve outcomes. DisclosuresNo relevant conflicts of interest to declare.

Long Term Follow-up after SCRI-CAR19v1 Reveals Late Recurrences As Well As a Survival Advantage to Consolidation with HCT after CAR T Cell Induced Remission

Background: CD19 chimeric antigen receptor (CAR) T cell therapy has demonstrated robust responses in refractory/relapsed subjects with CD19+ acute lymphoblastic leukemia (ALL). Our Phase 1 clinical trial demonstrated a minimal residual disease (MRD) negative complete remission (CR) rate of 93% at 21 days following SCRI-CAR19v1 (a CD19 specific CAR T cell product) infusion (PMID: 29171004). Though remission is frequently attained, approximately half of patients recur. Controversy exists regarding the benefit of hematopoietic cell transplant (HCT) following CD19 CAR T cell therapy. Although not mandated by the study, our current institutional recommendation for relapsed/refractory patients without a history of allogeneic HCT is to undergo a HCT once in remission following SCRI-CAR19v1. Additionally, we have recommended HCT to those who have a short duration of persistence of SCRI-CAR19v1 in vivo regardless of prior HCT status. We report here the leukemia free survival (LFS) of subjects who proceeded to HCT following remission after SCRI-CAR19v1 infusion.Methods/Results: We analyzed the first 64 subjects on our Phase 1/2 trial, PLAT-02 (NCT02028455), with follow-up of ≥1 year to evaluate the potential benefit of consolidative HCT. We excluded subjects that did not respond (n=5) or relapsed prior to day 63 (n=9). Thirty-two of the evaluated subjects were treated on the Phase I dose finding portion of the study and 18 were treated on the Phase 2 portion at dose level of 1x106cells/kg. Of the 50 evaluable subjects, 33 had a history of at least one prior HCT, whereas 17 had no history of HCT. Figure A demonstrates the LFS for patients that did and did not undergo HCT following SCRI-CAR19v1.There is a trend towards improved LFS (p-value 0.057; Figure B) in patients who underwent first HCT following SCRI-CAR19v1. Of the 17 patients without a history of HCT, 3 did not pursue HCT following CAR therapy. Of those 3 subjects, only 1 remains in remission at 28 months. The other 2 subjects relapsed at 6 and 7 months with CD19+ and CD19- disease, respectively. Of the 14 patients that underwent first HCT after SCRI-CAR19v1, 2 relapsed following HCT. One had evidence of MRD by flow at the time of HCT and the other subject relapsed with CD19- disease. The role of second HCT following CAR therapy remains unclear. Of the 33 subjects with a history of HCT, 10 underwent a second HCT following SCRI-CAR19v1 infusion, and 5 are alive and remain in remission. The recurrences included 2 lineage switches and 2 CD19+ (1 was MRD positive by deep sequence prior to HCT), and one transplant related mortality (TRM). Of the 23 subjects that did not undergo a second HCT, 8 remain in remission (p-value not significant (NS); Figure C).We previously reported that subjects with a short duration of B cell aplasia (BCA) ≤63 days following SCRI-CAR19v1 have an increased risk of relapse. Here we show that subjects with short BCA who attained a CR and did not relapse prior to day 63 demonstrate a clear benefit of consolidative HCT (p-value 0.007; Figure D). Of the 15 subjects with short BCA (regardless of HCT history), 6 did not pursue HCT and all recurred (5 CD19+, 1 CD19-). Of the short BCA subjects that underwent HCT, 1 subject died of TRM (2ndHCT for this subject) and 2 subjects relapsed following HCT (1 was MRD positive prior to HCT).All events in the consolidative HCT group have occurred by 20 months following SCRI-CAR19v1. However, we continue to see late relapses following CAR T cell therapy in the group who did not proceed with HCT. Three subjects have relapsed beyond 2 years: 1 with CD19+ disease at 27months, 1 with CD19- disease at 41 months, and 1 patient with lineage switch AML at 38 months. Further analysis is needed to understand the continued long-term risk of relapse following CD19 CAR T cell therapy and the potential role and timing for consolidative HCT in patients with a previous HCT.Conclusions: We demonstrate a trend towards improved LFS for subjects without a history of HCT who undergo a consolidative HCT following CD19 CAR T cell therapy on PLAT-02. In addition, HCT appears to benefit subjects who attain a CR but are at increased risk of relapse with short-term BCA. Currently, the benefit of second HCT following CD19 CAR T cell therapy is unclear and may be restricted to those that have short functional persistence of SCRI-CAR19v1. Late relapses after SCRI-CAR19v1 have only occurred in those without consolidative HCT, but longer follow up is needed to confirm these findings. DisclosuresJensen:Juno Therapeutics, Inc.: Consultancy, Patents & Royalties, Research Funding.

Survival Differences Among Patients (pts) with Acute Myeloid Leukemia (AML) Treated with Allogeneic Hematopoietic Cell Transplantation (HCT) Versus Non-HCT Therapies: A Large Real-Time Multi-Center Prospective Longitudinal Observational Study

Introduction: Survival rates continue to improve after allogeneic HCT (Gooley et al, NEJM, 2013). Population-based studies also indicate overall improvement in survival of older (60-80 years old) AML patients (pts) (Bower, Blood Cancer Journal, 2016). Yet, only a small minority (6%-8%) of them receive HCT (Medeiros, Ann Hematol. 2015). Given these potentially incongruent findings and the changing face of survival in AML, we designed the first prospective multi-center longitudinal study dating from first presentation of adults with AML to be treated at one of 13 different referral centers that provide both AML treatment and HCT. We compared survival according to whether or not pts received HCT at later time points. Methods: We enrolled 695 pts (Table 1). Data on demographics, AML status, cytogenetic risks per European Leukemia Network (ELN), and response; age; comorbidities per the HCT-comorbidity index (CI); function including activities of daily living (ADL); frailty; geriatric assessment including cognition; QOL including the Functional Assessment of Cancer Therapy-Bone Marrow Transplant Scale (FACT-BMT), Euro-QOL 5-Dimension scale, ENRICHD Social Support Instrument, Social Activity Log, and Patient Health Questionnaire 9-item Depression Scale (PHQ-9) were collected at enrollment and at 1, 3, 6, 9, 12, 18, and 24 months thereafter. We used time-dependent Cox regression analyses to identify baseline and time-dependent risk factors associated with mortality in the overall population. The factors identified as significantly associated with mortality (p Results: Median follow-up was 16.8 months (range 0.1-52.4). In the initial multivariate analyses, the following were identified as significantly associated with an increased risk of mortality (Table 2): HCT-CI scores ≥5 (p Survival after HCT was 58% at 2-years. Initial unadjusted analyses showed significantly lower risks of mortality in association with receiving allogeneic HCT (p=0.0003). These findings were similar in pts with intermediate (p=0.0005) or unfavorable (p However, in the adjusted models, the advantage of HCT in reducing mortality rates was lost both in the overall population (p=0.21, see figure) as well as in the other groups (p>0.54, 0.40, and 0.51, respectively, Table 3). Formal tests of interactions (Table 3) showed no statistically compelling evidence that the association of HCT and mortality varies with respect to the timing of mortality or to the underlying ELN risk. Conclusions: In a prospective observational study, adjusting for key AML-specific and pt-specific variables negated the observed benefit of HCT over non-HCT therapies in reducing mortality rates among AML pts. Our results might reflect 1) improvement in supportive care and non-HCT therapies, 2) a relatively high non-relapse mortality early after HCT and the need for longer follow-up to demonstrate an adjusted benefit of HCT, and 3) the high selectivity of the transplant eligibility process, as we accounted here for variables that are often ignored in "genetic assignment" randomized studies (i.e. comorbidities and function). New randomized trials are needed; however, these trials have to be more inclusive of vulnerable pts and measure pt-specific variables. Trials focusing on reducing burden of comorbidities, frailty and poor function are needed alongside trials to treat AML with or without HCT. Disclosures Gerds:Celgene: Consultancy; Apexx Oncology: Consultancy; CTI Biopharma: Consultancy; Incyte: Consultancy. Shami:JSK Therapeutics: Employment, Equity Ownership, Membership on an entity9s Board of Directors or advisory committees; Baston Biologics Company: Membership on an entity9s Board of Directors or advisory committees; Lone Star Biotherapies: Equity Ownership; Pfizer: Consultancy. Rizzieri:Teva: Consultancy, Membership on an entity9s Board of Directors or advisory committees, Speakers Bureau; Jazz: Consultancy, Membership on an entity9s Board of Directors or advisory committees; Incyte: Consultancy, Membership on an entity9s Board of Directors or advisory committees, Speakers Bureau; Amgen: Consultancy, Membership on an entity9s Board of Directors or advisory committees; Arog: Consultancy, Membership on an entity9s Board of Directors or advisory committees; Pfizer: Consultancy, Membership on an entity9s Board of Directors or advisory committees; Novartis: Consultancy; Gilead: Consultancy, Membership on an entity9s Board of Directors or advisory committees, Speakers Bureau. Wang:Amgen: Consultancy; Pfizer: Consultancy, Membership on an entity9s Board of Directors or advisory committees; Jazz: Speakers Bureau; Novartis: Speakers Bureau; Novartis: Speakers Bureau; Amgen: Consultancy; Abbvie: Consultancy, Membership on an entity9s Board of Directors or advisory committees; Jazz: Speakers Bureau; Abbvie: Consultancy, Membership on an entity9s Board of Directors or advisory committees; Pfizer: Consultancy, Membership on an entity9s Board of Directors or advisory committees. Faderl:Jazz Pharmaceuticals: Employment, Equity Ownership. Koprivnikar:Alexion: Consultancy, Speakers Bureau; Amgen: Speakers Bureau; Otsuka: Consultancy. Sekeres:Opsona: Membership on an entity9s Board of Directors or advisory committees; Celgene: Membership on an entity9s Board of Directors or advisory committees; Celgene: Membership on an entity9s Board of Directors or advisory committees; Opsona: Membership on an entity9s Board of Directors or advisory committees. Becker:GlycoMimetics: Research Funding.

Long-term outcomes of systemic therapies for Hurler syndrome: an international multicenter comparison

PurposeEarly treatment is critical for mucopolysaccharidosis type I (MPS I), justifying its incorporation into newborn screening. Enzyme replacement therapy (ERT) treats MPS I, yet presumptions that ERT cannot penetrate the blood–brain barrier (BBB) support recommendations that hematopoietic cell transplantation (HCT) treat the severe, neurodegenerative form (Hurler syndrome). Ethics precludes randomized comparison of ERT with HCT, but insight into this comparison is presented with an international cohort of patients with Hurler syndrome who received long-term ERT from a young age. MethodsLong-term survival and neurologic outcomes were compared among three groups of patients with Hurler syndrome: 18 treated with ERT monotherapy (ERT group), 54 who underwent HCT (HCT group), and 23 who received no therapy (Untreated). All were followed starting before age 5 years. A sensitivity analysis restricted age of treatment below 3 years. ResultsSurvival was worse when comparing ERT versus HCT, and Untreated versus ERT. The cumulative incidences of hydrocephalus and cervical spinal cord compression were greater in ERT versus HCT. Findings persisted in the sensitivity analysis. ConclusionAs newborn screening widens treatment opportunity for Hurler syndrome, this examination of early treatment quantifies some ERT benefit, supports presumptions about BBB impenetrability, and aligns with current guidelines to treat with HCT.

Nocardia infections in the transplanted host.

Nocardia are uncommon pathogens that disproportionately afflict the immunocompromised host. Epidemiology and outcome data of Nocardia infections in transplant recipients are limited. We performed a retrospective chart review of all patients at Duke University Hospital with a history of solid organ transplant (SOT) or hematopoietic cell transplant (HCT) and at least one positive culture for Nocardia between 1996 and 2013. Our aim was to describe the epidemiology and outcomes of Nocardia infections in the transplanted host. During the 18-year study period, 51 patients (14 HCT and 37 SOT recipients) had Nocardia infection. Nocardia incidence was stable during the study period in all populations except heart transplants, whose incidence declined. Infection occurred earlier in the HCT group than the SOT group (median time to diagnosis of 153 and 370days, respectively). In both groups, the most common site involved was the lung. Outcomes were overall poor, especially in the HCT group with a cure rate of 29%. Heart transplant recipients had significantly better overall survival (P<.05) than other patients. Trimethoprim-sulfamethoxazole (TMP-SMX) prophylaxis did not provide complete protection from Nocardia infections, nor did it appear to select for resistant Nocardia isolates. Infections with Nocardia are typically a late post-transplant complication. The use of TMP-SMX prophylaxis was not associated with TMP-SMX-resistant Nocardia. Overall outcomes remain poor.

Impact of hematopoietic stem cell transplantation in patients with relapsed or refractory mantle cell lymphoma.

Rituximab has been shown to improve outcomes in patients with B-cell lymphoma. However, patients with relapsed or refractory (R/R) mantle cell lymphoma (MCL) still have a poor prognosis, and the choice between high-dose therapy with autologous hematopoietic cell transplantation (HCT) and allogeneic HCT remains controversial in these patients. We retrospectively analyzed the risk factors for outcomes in 162 R/R MCL patients who received autologous (n = 111) or allogeneic (n = 51) HCT between 2004 and 2014. The median overall survival (OS) rates were 48 and 65months in the autologous and allogeneic HCT groups, respectively (P = 0.20). Significant risk factors for overall survival in R/R MCL patients after autologous HCT were > 60years of age at HCT (P = 0.017), higher score of HCT-specific comorbidity index at HCT (P = 0.033), and receiving MCEC (ranimustine + carboplatin + etoposide + cyclophosphamide) regimen (P = 0.017), while higher performance status at HCT (P = 0.011) and longer interval from diagnosis to HCT (P = 0.0054) were risk factors after allogeneic HCT. Strategies that carefully select R/R MCL patients for autologous HCT may allow the identification of individuals suitable for allogeneic HCT.

Cytomegalovirus infections in lung and hematopoietic cell transplant recipients in the Organ Transplant Infection Prevention and Detection Study: A multi-year, multicenter prospective cohort study.

Most studies of post-transplant CMV infection have focused on either solid organ or hematopoietic cell transplant (HCT) recipients. A large prospective cohort study involving both lung and HCT recipients provided an opportunity to compare the epidemiology and outcomes of CMV infections in these 2 groups. Patients were followed up for 30months in a 6-center prospective cohort study. Data on demographics, CMV infections, tissue-invasive disease, recurrences, rejection, and immunosuppression were recorded. The overall incidence of CMV infection was 83/293 (28.3%) in the lung transplant group and 154/444 (34.7%) in the HCT group (P=.0706). Tissue-invasive CMV disease occurred in 8/83 (9.6%) of lung and 6/154 (3.9%) of HCT recipients with CMV infection, respectively (P=.087). Median time to CMV infection was longer in the lung transplant group (236 vs 40days, P<.0001), likely reflecting the effects of prophylaxis vs preemptive therapy. Total IgG levels of < 350mg/dL in lung recipients and graft vs host disease (GvHD) in HCT recipients were associated with increased CMV risk. HCT recipients had a higher mean number of CMV episodes (P=.008), although duration of viremia was not significantly different between the 2 groups. CMV infection was not associated with reduced overall survival in either group. Current CMV prevention strategies have resulted in a low incidence of tissue-invasive disease in both lung transplant and HCT, although CMV viremia is still relatively common. Differences between the lung and HCT groups in terms of time to CMV and recurrences of CMV viremia likely reflect differences in underlying host immunobiology and in CMV prevention strategies in the modern era.

Impact of treatment and outcomes for patients with posttransplant drug-associated thrombotic microangiopathy.

Drug-induced transplant-associated thrombotic microangiopathy (DTA-TMA) is a rare but serious complication that can occur after hematopoietic cell transplantation (HCT) or solid organ transplantation (SOT) without guidelines for optimal management of this condition. Given the ambiguity surrounding the treatment for DTA-TMA, we conducted a retrospective review to evaluate the impact of different treatment strategies in DTA-TMA patients. Our primary endpoint was to determine the overall response rate (ORR) for DTA-TMA based on the type of treatment modality chosen while secondary endpoints included the time to response, relapse rates, and overall survival for DTA-TMA cases. There were a total of 14 DTA-TMA patients of whom nine were post-HCT and five were post-SOT. Most of the DTA-TMA cases were due to tacrolimus (n = 11) with a minority related to sirolimus (n = 3). A total of nine of 14 patients demonstrated response and five had no response to therapy. The ORR among the DTA-TMA patients after HCT and SOT who received plasma exchange (PLEX) were 25 and 100%, respectively. The ORRs among the patients (includes HCT and SOT) who received rituximab (n = 3) and eculizumab (n = 5) were 67 and 60%, respectively. There were two relapses noted in our study and both were in the HCT group. While discontinuation of the offending agent may be sufficient for treatment of DTA-TMA after HCT, PLEX may be a reasonable option for DTA-TMA after SOT. Although the results are encouraging with rituximab and eculizumab in the treatment of DTA-TMA, larger prospective studies are needed to validate our findings.