Cytomegalovirus Reactivation Does Not Increase Subsequent Risk for Acute Graft-Versus-Host Disease, Malignant Disease Relapse, or Infection Following Allogeneic Hematopoietic Cell Transplantation

Abstract Background: Identifying factors that influence donor-derived immune response may ultimately enable its therapeutic redirection, lessening risk for complications following allogeneic hematopoietic cell transplantation (alloHCT) like acute graft-versus-host disease (aGvHD) and promoting protection against infection and malignant disease relapse. Viral reactivation seems poised to influence donor-derived immune response, potentially disrupting the balance between immune surveillance in eradicating malignancy and infection and immune tolerance in preventing aGvHD. Cytomegalovirus (CMV) is a clinically-significant virus with immunomodulatory capabilities. However, studies interrogating such effects are limited in the modern transplant era. The primary study aim was to estimate the cumulative incidence of initial CMV reactivation (RA) and aGvHD in alloHCT patients and to assess reciprocal influence between CMV RA and aGvHD. The secondary study aim was to define whether CMV RA predisposed alloHCT patients to infection or increased relapse risk. Methods: Consecutive adult patients (n=324) with acute lymphoblastic leukemia, acute myelogenous leukemia or myelodysplasia whom received initial matched sibling or unrelated donor (MUD) bone marrow (n=33), peripheral blood stem cell (PBSC, n=253) or umbilical cord blood (n=38) grafts from January 2010 through December 2014 at The Ohio State University Comprehensive Cancer Center comprised the study cohort. Patient-, transplant-, and infection-related data were retrospectively analyzed (Table 1). Initial CMV RA was defined as plasma quantitative CMV PCR≥1000 viral copies/ml for which CMV-directed antiviral therapy was started. Microbiologically-documented infections were recorded for the first year after alloHCT and categorized as bacterial blood stream infection, invasive fungal infection, human herpes virus 6 viremia, and respiratory viral infection. Cumulative incidences of CMV RA and aGvHD were estimated accounting for competing risks (death from any cause). Association between CMV RA and incidence of aGvHD was evaluated in a proportional sub-distribution hazards model, where CMV RA was treated as a time-dependent covariate with competing risk as death from any cause. Similarly, influence of aGvHD on incidence of CMV RA was evaluated where development of aGvHD was treated as the time-dependent covariate and CMVR RA as the end point of interest. Associations between CMV RA and subsequent infection or disease relapse were similarly analyzed. To evaluate impact of CMV and aGvHD on long-term outcomes, landmark analysis (LMA) at D100 and D365 were compared among four distinct patient groups: (1) No CMV RA, no aGvHD; (2) CMV RA, no aGvHD; (3) No CMV RA, aGvHD; and (4) CMV RA and aGvHD. Results: Most transplant patients had AML in CR1, received MUD PBSC grafts following myeloablative conditioning, and were given methotrexate and calcineurin-based GvHD prophylaxis. Patients who developed aGvHD grades 2 (HR=1.93, 95% CI 1.15-3.23, p=0.013) or grades 3 and 4 (HR=3.36, 95% CI 1.76-6.45, p<0.001) had higher risk for developing subsequent CMV RA. In contrast, patients with initial CMV RA did not have increased risk for developing future aGvHD. Similarly, CMV RA did not have a significant impact on future infection, regardless of infection type, nor impact subsequent risk of malignant disease relapse. Overall survival (OS) at 1, 2, and 3 years post-transplant were 63%, 53%, and 45%, respectively. Cumulative incidence rates for non-relapse mortality (NRM) at 1, 2, and 3 years were 16%, 19%, and 23%, respectively; for infection-related mortality (IRM), cumulative incidence rates were 10%, 13%, and 16%, respectively. OS, NRM and IRM were stratified by initial CMV RA and aGvHD status at D100 and D365 (Table 2). Among patients who were alive, patients whom had initial CMV RA and aGvHD by D100 were at higher risk for NRM (HR=2.85, 95% CI 1.24-6.56, p=0.014) and IRM (HR=3.65, 95% CI 1.39-9.57, p=0.008) than patients who experienced neither CMV RA nor aGvHD. D365 LMA did not reveal any statistically significant differences in OS, NRM, and IRM between groups. Conclusion: aGvHD associated with increased risk for CMV RA, but initial CMV RA did not associate with subsequent aGvHD risk. Furthermore, initial CMV RA did not associate with increased risk for disease relapse or infection, but did increase NRM and IRM, particularly in combination with aGvHD. Disclosures Auletta: Shire Pharmaceuticals: Consultancy. Lozanski:Genentech: Research Funding; Stemline Therapeutics Inc.: Research Funding; Boehringer Ingelheim: Research Funding; Beckman Coulter: Research Funding. Hofmeister:Janssen: Pharmaceutical Companies of Johnson & Johnson: Research Funding; Karyopharm Therapeutics: Research Funding; Signal Genetics, Inc.: Membership on an entity's Board of Directors or advisory committees; Incyte, Corp: Membership on an entity's Board of Directors or advisory committees; Celgene: Research Funding; Arno Therapeutics, Inc.: Research Funding; Takeda Pharmaceutical Company: Research Funding; Teva: Membership on an entity's Board of Directors or advisory committees. Andritsos:Hairy Cell Leukemia Foundation: Research Funding.

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Early Infection Attenuates Hematologic Malignant Disease Relapse Following Initial Allogeneic Hematopoietic Cell Transplantation

Blood ◽

10.1182/blood.v128.22.3410.3410 ◽

2016 ◽

Vol 128 (22) ◽

pp. 3410-3410

Author(s):

Jeffery J Auletta ◽

Monica I Ardura ◽

Sumithira Vasu ◽

Ying Huang ◽

Qiuhong Zhao ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Malignant Disease ◽

Hematopoietic Cell Transplantation ◽

Infection Type ◽

Early Infection ◽

Time Dependent ◽

Disease Relapse ◽

Advisory Committees ◽

Related Mortality

Abstract Background: Primary malignant disease relapse, graft-versus-host disease (GvHD) and infection are the most common causes of death following allogeneic hematopoietic cell transplantation (alloHCT). We investigated whether infection following initial alloHCT influenced subsequent risk for hematologic malignant disease relapse. Methods: Consecutive adult patients (N=324) with acute lymphoblastic leukemia (ALL), acute myelogenous leukemia (AML) or myelodysplasia (MDS) who received initial matched sibling (MSD) or unrelated donor (MUD) bone marrow (BM, n=33), peripheral blood stem cell (PBSC, n=253) or umbilical cord blood (UCB, n=38) grafts from January 2010 through December 2014 at The Ohio State University Comprehensive Cancer Center were included. Patient-, transplant-, and infection-related data were retrospectively obtained. Categories for microbiologically-documented infections included bacterial blood stream infection (BSI), viral reactivation (VRA), invasive fungal infection (IFI), and respiratory viral infection (RVI). Correlation between development of infection and relapse was assessed using multi-variable (MV) proportional sub-distribution hazards models, where infection was treated as a time‐dependent covariate and death from any cause as a competing risk. Landmark analyses (LMA) at D14, D28, D56 and D100, which included only those patients who survived without relapse at the indicated time and infection status as a covariate, were performed to predict future relapse. Results: Most transplant recipients had first complete remission AML, received MUD PBSC grafts following myeloablative conditioning, and were given methotrexate and calcineurin-based GvHD prophylaxis. Following alloHCT, 107 (33%) patients experienced disease relapse. Median progression-free survival (PFS) for the entire patient cohort was nearly two years (703 days). Grades 2-4 acute GvHD developed in 164 (51%) patients, and 145 (45%) patients developed limited or extensive chronic GvHD. One- and three-year overall survival (OS) rates for the entire cohort were 63% and 45%, respectively. Cumulative incidence of infection, overall and by infection type, is depicted in Table 1. Patient- and transplant-related factors affecting development of infection are listed in Table 2. Patients who developed infection post-transplant had future relapse risk that was 46% (HR 0.54, 95% CI: 0.36-0.80, p=0.003) less than those patients who did not develop infection, regardless of infection type, in MV proportional sub-distribution hazards model analyses. LMA showed similar patterns in reduced risk for relapse following infection. Although not all reached statistical significance, LMA showed reduced relapse risk associated with early infection: D14 (HR 0.54, 95% CI: 0.27-1.05, p=0.07), D28 (HR 0.53, 95% CI: 0.30-0.93, p=0.03), D56 (HR 0.57, 95% CI: 0.37-0.90, p=0.01), and D100 (HR 0.63, 95% CI: 0.37-1.09, p=0.10). Using infection as a time-dependent covariate, patients with infection had higher risk for infection-related mortality (IRM, HR 2.10, 95% CI: 1.45-3.05, p<0.0001) and non-relapse mortality (NRM, HR 6.42, 95% CI: 3.17-12.99, p<0.0001) versus patients not developing infection, but no difference in risk for relapse-related mortality (RRM, HR 0.97, 95% CI: 0.62-1.51, p=0.89). Interestingly, LMA at early post-HCT time points showed that infection may actually be protective for RRM: D14 (HR 0.69, 95% CI: 0.37-1.30, p=0.25), D28 (HR 0.59, 95% CI: 0.35-0.99, p=0.05), D56 (HR 0.57, 95% CI: 0.37-0.87, p=0.01), and D100 (HR 0.71, 95% CI 0.46-1.11, p=0.13). Conclusion: Early infection post-alloHCT may confer protection against hematologic malignant disease relapse, but also increases NRM and IRM. Further investigation is required to define underlying immunologic mechanisms that may mediate such putative protection in order to promote presumed enhancement in graft-versus-leukemia effect. Disclosures Auletta: Shire Pharmaceuticals: Consultancy. Lozanski:Boehringer Ingelheim: Research Funding; Genentech: Research Funding; Beckman Coulter: Research Funding; Stemline Therapeutics Inc.: Research Funding. Hofmeister:Arno Therapeutics, Inc.: Research Funding; Janssen: Pharmaceutical Companies of Johnson & Johnson: Research Funding; Celgene: Research Funding; Incyte, Corp: Membership on an entity's Board of Directors or advisory committees; Signal Genetics, Inc.: Membership on an entity's Board of Directors or advisory committees; Karyopharm Therapeutics: Research Funding; Takeda Pharmaceutical Company: Research Funding; Teva: Membership on an entity's Board of Directors or advisory committees. Andritsos:Hairy Cell Leukemia Foundation: Research Funding.

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Low Incidence of Chronic Graft-Versus-Host Disease in Myeloablative Allogeneic Hematopoietic Cell Transplantation with Post-Transplant Cyclophosphamide Using Matched Related or Unrelated Donors: Phase II Study Interim Analysis

Blood ◽

10.1182/blood-2021-147569 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 1811-1811

Author(s):

Najla H El Jurdi ◽

Daniel O'Leary ◽

Fiona He ◽

Todd E. DeFor ◽

Armin Rashidi ◽

...

Keyword(s):

Board Of Directors ◽

Cumulative Incidence ◽

Research Funding ◽

Acute Gvhd ◽

Hematopoietic Cell Transplantation ◽

Chronic Gvhd ◽

Advisory Committees ◽

Post Transplant ◽

Gvhd Prophylaxis ◽

Preparative Regimen

Abstract Introduction Allogeneic hematopoietic cell transplantation (HCT) is the only potentially curative treatment for many high-risk hematologic malignancies. Myeloablative conditioning is currently the standard of care for young and fit patients; however, graft-versus-host disease (GVHD) continues to be a major limitation to the success of HCT, increasing post-transplant morbidity and mortality. An ideal HCT is one combining strategies that reduce incidence and severity of GVHD, without compromising graft-versus-tumor effect. We hypothesized that GVHD prophylaxis regimen consisting of post-transplant cyclophosphamide (PTCy), tacrolimus (Tac) and mycophenolate mofetil (MMF) will reduce the incidence of chronic GVHD in patients receiving a standard hematopoietic myeloablative HCT without an increase in risk of malignant relapse. Methods This is an interim analysis of a phase II study using a myeloablative preparative regimen of either: 1. total body irradiation (TBI, total dose 1320 cGy administered twice a day from days -4 to -1) or 2. Busulfan 3.2mg/kg daily (cumulative AUC 19,000 - 21,000 µmol/min/L) plus fludarabine 160mg/m 2 days -5 to -2 for patients unable to receive further radiation, followed by a GVHD prophylaxis regimen of PTCy (50mg/kg days +3 and +4), Tac and MMF (beginning day +5). The primary endpoint is cumulative incidence of chronic GVHD requiring systemic immunosuppressive treatment at 1 year post-transplant. Patient and disease characteristics are detailed in Table 1. Eligibility included: age ≤ 60 years, malignant or non-malignant diagnosis, matched related (MRD) or unrelated (MUD) donor with either a bone marrow (BM) or filgrastim-mobilized peripheral blood (PB) graft. Results Through October 2020 we treated 63 patients with a median follow up of 502 days post-transplant. Of those, 48% were female and n=11 (17%) younger than 18 with median age at HCT of 36 years (range, 2-55; Interquartile range [IQR], 20-48). Donor source was 8/8 MRD in 44 patients (70%), 8/8 MUD in 18 (29%), and one with 7/8 MUD. Graft source was BM in n=28 (44%) and PB in n=35 (56%). Preparative regimen was TBI in 94% of patients. All patients achieved primary neutrophil engraftment by 42 days, median 16 days (range, 13-27). Overall, 94% achieved platelet engraftment by 6 months, median 25 days (range, 16-98). At day 100, 48 patients (86%) achieved full donor bone marrow chimerism (>95% donor DNA); 29 (52%) and 52 (95%) achieved full donor peripheral blood CD3 and CD33 chimerism (defined as >95% donor). 42 patients (66%) required total parenteral nutrition (TPN) for oral mucositis and regimen-related toxicities during their initial transplant admission. Cumulative incidence of Grade II-IV acute GVHD by 100 days post-transplant was 14% overall (95% confidence interval CI: 6-23%), 7% for MRD and 32% for the MUD group; Grade III-IV acute GVHD was 5% overall (CI: 0-10%), similar for both MRD and MUD group. At 1 year, only two patients receiving a PBSC graft developed chronic GVHD requiring immune suppression, for a cumulative incidence of 3% overall, one in the MRD group and one in the MUD group. Two-year cumulative incidence of relapse was estimated at 21% overall, 22% and 16% for the MRD and MUD groups, respectively. Two year cumulative incidence of non-relapse mortality was 13% overall, 15% and 5% for MRD and MUD, respectively. Estimated 2-year overall survival was 79% overall (CI: 65-88%), 75% for the MRD group and 95% for MUD. Estimated 2-year GVHD-free relapse free survival (GRFS) was 57% overall (CI: 42-69%), 56% and 63% in the MRD and MUD groups, respectively. Discussion Myeloablative transplantation with a TBI preparative regimen, followed by a GVHD prophylaxis regimen of PTCy, Tac, and MMF results in very low incidence of chronic GVHD. Importantly, this regimen is feasible and effective for pediatric and adult patients. Further improvement in outcomes can be achieved by incorporating post-transplant relapse mitigating strategies as well as supportive care measures to decrease regimen-related toxicities. Figure 1 Figure 1. Disclosures Arora: Kadmom: Research Funding; Pharmacyclics: Research Funding; Syndax: Research Funding. Janakiram: Bristol Meyer Squibb, Kyowa Kirin, ADCT Therapeutics: Honoraria; FATE, Nektar Therapeutics: Research Funding. Smith: Astellas Gene Therapies: Current Employment. Bachanova: Incyte: Research Funding; KaryoPharma: Membership on an entity's Board of Directors or advisory committees; FATE: Membership on an entity's Board of Directors or advisory committees, Research Funding; Gamida Cell: Membership on an entity's Board of Directors or advisory committees, Research Funding. Brunstein: BlueRock: Research Funding; AlloVir: Consultancy; FATE: Research Funding; NANT: Research Funding; GamidaCell: Research Funding. MacMillan: Equilium: Other: DSMB member; Incyte: Consultancy; Jazz Pharmaceuticals: Consultancy. Miller: Sanofi: Membership on an entity's Board of Directors or advisory committees; Magenta: Membership on an entity's Board of Directors or advisory committees; ONK Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Vycellix: Consultancy; GT Biopharma: Consultancy, Patents & Royalties, Research Funding; Fate Therapeutics, Inc: Consultancy, Patents & Royalties, Research Funding; Wugen: Membership on an entity's Board of Directors or advisory committees. Betts: Patent Disclosures: Patents & Royalties: B.C.B. holds a patent (WO2015120436A2) related to CD4+ T cell pSTAT3 as a marker and therapeutic target of acute GVHD. B.C.B. additionally holds a provisional patent (WO2017058950A1) related to the use of JAK inhibitors for rejection and GVHD prevention. . Vercellotti: Mitobridge, an Astellas Company: Consultancy, Research Funding; CSL Behring: Research Funding. Weisdorf: Fate Therapeutics: Research Funding; Incyte: Research Funding. Holtan: Generon: Consultancy; Incyte: Consultancy, Research Funding.

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Risk of Histological Transformation in Patients with Primary Refractory Follicular Lymphoma

Blood ◽

10.1182/blood-2018-99-115956 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 4145-4145

Author(s):

Sara Alonso ◽

Martina Manni ◽

Clementine Sarkozy ◽

Marielle Wondergem ◽

Attilio Guarini ◽

...

Keyword(s):

Follicular Lymphoma ◽

Board Of Directors ◽

Cumulative Incidence ◽

Research Funding ◽

Advisory Board ◽

Critical Event ◽

P Value ◽

Advisory Committees ◽

Increased Risk ◽

Histological Transformation

Abstract INTRODUCTION There is a growing interest in analyzing the biological and clinical variables that might help in identifying patients at risk of histological transformation (HT), a critical event that can still lead to reduced survival in patients with follicular lymphoma (FL). As part of the Aristotle study, we have previously reported that the risk of HT as a first event has been significantly reduced by the use of rituximab (Federico et al, Lancet Hematology 2018). However, this incidence might still be unacceptable in some groups of patients. Thus, we investigated the risk of HT in patients with primary refractory FL, a subset of patients with poor prognosis. METHODS We carried out a retrospective analysis of cumulative incidence of HT in the 289 cases with primary refractory FL retrieved from the Aristotle Study, which included a total of 6970 FL cases (grade 1, 2 or 3a), diagnosed between 1997 and 2013 and treated with systemic therapy. Refractoriness was defined as progressive disease (PD) within the end of first-line therapy. Patients with PD were compared to patients with partial response (PR) or stable disease (SD) and to patients with complete response (CR) at the end of therapy. The cumulative incidence of HT was calculated using the Nelson-Aalen estimator, with a 95 confidence interval (CI). The estimate is in absolute value, and then multiplied by 100. The overall survival (OS) and survival after relapse/progression (SAR) were calculated using Kaplan-Meier estimation, with a 95% CI. RESULTS Six hundred and twenty-eight cases (9%) were excluded for incomplete data and 6,339 were considered for analysis. The five-year cumulative incidence of HT among patients with PD was 34.2% (95% CI: 26.9-43.4), whilst it was 7.1% (95% CI: 6.0-8.5) and 3.5% (95% CI: 3.0-4.2) in the 1,954 and 4,096 patients with PR+SD and CR at the end of induction therapy, respectively. The rate observed in PD group had a Hazard Ratio (HR) of 11.4 (95CI: 8.61-15.0) compared with CR patients, and 6.14 (95% CI: 4.6-8.2), when compared with PR+SD patients. All comparisons and estimations showed a p-value below 0.001. Cumulative incidences of HT according to response to initial therapy are represented in Figure 1. The five-year SAR was 33% (95% CI: 28-39) for the PD group, with a median SAR of 1.1 year (95% CI: 0.8-1.8). At the same time point, the SAR was 56% (95% CI: 53-60) in patients with initial PR/SD, with a median SAR of 6.3 years (95% CI: 5.7-8.6). Finally, in patients with initial CR who later relapsed, the 5 year SAR was 63% (95% CI: 66-72), with a median of 10.4 years (95% CI: 10-12.2). The difference among groups was statistically significant (p-value <0.001, Figure 2). HR for PD group was 3.39 (95% CI: 2.87-4.01) compared to CR, and 2.12 (95% CI: 1.8-2.5) compared to PR/SD group. CONCLUSIONS According to the results of the present study, primary refractory FL patients have not only an already known reduced SAR (Casulo et al, JCO 2015), but also a dramatically increased risk of HT, which probably contributes to patients' adverse outcome. These findings reinforce the need to develop combined diagnostic and therapeutic strategies aimed to eradicate the disease at the "first shot", reducing the risk of refractoriness and eventually further improving the outcome of FL patients. Disclosures Sarkozy: ROCHE: Consultancy. Wondergem:NOVARTIS: Other: advisory board, educational talk; SANOFI: Other: advisory board; GILEAD: Other: educational talk. Chamuleau:Genmab: Research Funding; BMS: Research Funding; celgene: Research Funding; Gilead: Research Funding. Gomes da Silva:Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: lecture fees, Institution's payment for consultancy, Travelling support; Celgene: Other: Travelling support; Roche: Other: Institution's payment for consultancy, Travelling support; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: lecture fees; BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: lecture fees; Gilead Sciences: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: lecture fees, Research Funding. Holte:Roche, Norway: Research Funding; Novartis Pharmaceuticals Corporation: Membership on an entity's Board of Directors or advisory committees. Zucca:CELGENE: Other: Grant to the Institution + Advisory Board; Janssen: Other: Grant to the Institution; ROCHE: Other: Grant to the Institution + Advisory Board; Celltrion Healthcare + Mei Pharma + Astra Zeneca: Other: Advisory Board; AbbVie + Gilead: Other: Travel Expenses; Gilead + Bristol-Myers Squibb + MDS: Other: Expert Statement + Meetings. Aurer:Roche: Consultancy, Honoraria, Research Funding; Pfizer: Honoraria, Research Funding. Marcheselli:Fondazione Italiana Linfomi (FIL) Onlus: Employment. Salles:Novartis: Consultancy, Honoraria; Acerta: Honoraria; Abbvie: Honoraria; Morphosys: Honoraria; Epizyme: Honoraria; Amgen: Honoraria; F. Hoffmann-La Roche Ltd: Consultancy, Honoraria, Research Funding; Celgene: Honoraria, Other: Advisory Board, Research Funding; Pfizer: Honoraria; Gilead: Honoraria, Other: Advisory Board; Janssen: Honoraria, Other: Advisory Board; Merck: Honoraria; Servier: Honoraria, Other: Advisory Board; Takeda: Honoraria; BMS: Honoraria, Other: Advisory Board; Servier: Honoraria.

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Treatment and Lifestyle Risk Factors for Cardiovascular Disease Post Lymphoma Diagnosis: A Prospective Study in the Modern Treatment Era

Blood ◽

10.1182/blood-2019-127203 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 422-422

Author(s):

Nicholas J Boddicker ◽

Matthew J. Maurer ◽

Melissa C Larson ◽

Cristine Allmer ◽

Susan L. Slager ◽

...

Keyword(s):

Risk Factors ◽

Board Of Directors ◽

Cumulative Incidence ◽

Medical Records ◽

Research Funding ◽

Cardiac Risk ◽

Advisory Committees ◽

Increased Risk ◽

Modern Treatment ◽

New Onset

Background With lymphoma survival rates increasing and a growing population of long-term survivors, the development of cardiovascular disease (CVD) in this patient population is of increasing importance. Anthracyclines are critical in the management of many lymphoma subtypes. However, there is a risk of developing anthracycline-induced CVD. Here, we estimate the cumulative incidence of CVD in adult lymphoma survivors and investigate risk factors associated with post diagnosis CVD. Methods Participants were from the Mayo component of the Molecular Epidemiology Resource (MER) of the University of Iowa/Mayo Clinic Lymphoma Specialized Program of Research Excellence (SPORE). From 2002-2015, the MER offered enrollment to all patients with newly diagnosed lymphoma who are US residents and age >18 years. Participants completed a risk factor questionnaire, and clinical and treatment data were abstracted from medical records. Patients were contacted every 6 months for the first 3 years after diagnosis and annually thereafter to assess disease status, re-treatment and new onset morbidity including CVD. CVD events, including congestive heart failure (CHF), coronary artery disease (CAD), valvular heart disease (VHD), and arrhythmia were identified and validated against medical records. CHF was validated with the Cardiovascular Health Study Criteria and/or the Framingham Criteria. CAD, arrhythmia, and VHD were validated using clinical definitions. We calculated the cumulative incidence of CVD, with death modeled as a competing risk. The association of risk factors and treatments with risk of CVD was estimated using hazard ratios (HR) and 95% confidence intervals (CI) from Cox regression with a competing risk of death. Risk factors included age, sex, diabetes, smoking, body mass index (BMI), and treatment with anthracyclines or radiation therapy. Results The study consisted of 3,063 lymphoma patients after excluding those with chronic lymphocytic leukemia and CVD prior to lymphoma diagnosis. The median age at diagnosis was 59 years (range 18-95), and 56% were males. At a median follow-up was 6.9 years (range 0.8-17.1), 640 patients (21%) had died without CVD and 485 patients self-reported CVD post lymphoma diagnosis, of which 280 (57.7%) were validated. Cardiovascular events included 86 CHF, 78 CAD, 40 VHD, and 164 arrhythmias. The cumulative incidence of CVD (Figure 1) at 5 and 10 years was 6.0% (95% 5.2%-7.0%) and 10.7% (95% CI 9.5%-12.1%), respectively. In multivariable analysis, increasing age (HR=3.93 per 5 years, p<0.001), male sex (HR=1.33, p=0.03), former smoker (HR=1.04, p=0.77), current smoker (HR=1.96, p<0.001), BMI>30 kg/m2 (HR=1.50, p=0.01), and anthracycline treatment (HR=1.49. p<0.001) were all significantly associated with risk of overall CVD, while there was no association with diabetes (HR=0.92, p=0.70) or radiation therapy (HR=1.05, p=0.78) in the multivariable model. Anthracycline use was significantly associated with increased risk of CHF (HR=2.64, p<0.001) and arrhythmia (HR=1.51, p<0.01), but not VHD (HR=0.83, p=0.56) or CAD (HR=1.23, p=0.31) after adjustment for the cardiac risk factors. The number of anthracycline cycles ranged from 0 to 12. 63.2% of individuals that received anthracyclines received 6 cycles. The 5-year cumulative incidence of CVD for 0, 1-5, 6, and >6 anthracycline cycles was 5%, 6.9%, 7.4%, and 7.7%, respectively. Adjusting for cardiac risk factors, the number of anthracycline cycles was significantly associated with increased risk of CVD (1-5 cycles HR=1.34, p=0.11; 6 cycles HR=1.51, p<0.01; >6 cycles HR=2.04, p=0.03). Furthermore, the number of anthracycline cycles was associated with CHF (1-5 cycles HR=2.82, p<0.001; 6 cycles HR=2.46, p<0.001; >6 cycles HR=5.33, p<0.001) and arrhythmia (1-5 cycles HR=1.31, p=0.27; 6 cycles HR=1.60, p<0.01; >6 cycles HR=1.65, p=0.27). Conclusions In the modern treatment era, the risk of new onset CVD in patients with lymphoma without a history of CVD is approximately 1% per year after diagnosis. Arrhythmia and CHF were the most commonly occurring CVD events in this cohort. Both traditional CVD risk factors and treatment with anthracyclines was associated with an increased risk of developing CVD, and anthracyclines were a risk factor for arrhythmia and CHF in particular. Prevention of CVD in lymphoma patients will need to address both treatment and traditional lifestyle factors. Figure 1 Disclosures Maurer: Morphosys: Membership on an entity's Board of Directors or advisory committees; Nanostring: Research Funding; Celgene: Research Funding. Nowakowski:Selvita: Membership on an entity's Board of Directors or advisory committees; Genentech, Inc.: Research Funding; F. Hoffmann-La Roche Ltd: Research Funding; Curis: Research Funding; Bayer: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; NanoString: Research Funding; MorphoSys: Consultancy, Research Funding. Cerhan:NanoString: Research Funding; Celgene: Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees.

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Letermovir Prophylaxis Is Effective for Cytomegalovirus Reactivation after Allogeneic Hematopoietic Cell Transplantation: Single Center Real-World Data

Blood ◽

10.1182/blood-2019-125675 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 5650-5650

Author(s):

Patrick Derigs ◽

Maria-Luisa Schubert ◽

Paul Schnitzler ◽

Carsten Müller-Tidow ◽

Thomas Luft ◽

...

Keyword(s):

Board Of Directors ◽

Cell Transplantation ◽

Real World ◽

Cumulative Incidence ◽

Research Funding ◽

Hematopoietic Cell Transplantation ◽

Hematopoietic Cell ◽

Control Group ◽

Advisory Committees ◽

Cmv Reactivation

Background: Morbidity and mortality after allogeneic hematopoietic cell transplantation (alloHCT) are still essentially affected by reactivation of cytomegalovirus (CMV). Letermovir is the first drug approved for prophylaxis of CMV reactivation in seropositive patients who have undergone alloHCT. Letermovir shows neither myelo- nor nephrotoxicity, and significantly reduced the incidence of CMV reactivation in a pivotal phase III trial (NEJM 2017;377:2433). Therefore, we have adopted letermovir prophylaxis according to the label as standard policy in our institution in March 2018: in seropositive recipients letermovir is given from engraftment until day +100 or CMV reactivation. The purpose of this study was to investigate if the positive trial results could be reproduced under real-world conditions. Methods: The study cohort contained the first seropositive 82 patients who received letermovir prophylaxis at our institution (between March 2018 and March 2019). These were compared with a control cohort comprising another 82 patients who underwent alloHCT at our institution between January 2017 and March 2018 immediately before the introduction of letermovir. Quantitative PCR was used to monitor CMV viremia twice a week during the inpatient period and weekly thereafter. Patients reactivating CMV prior to engraftment were not considered as event in both groups. Results: Both cohorts were matched for underlying disease, CMV donor/recipient sero-status, use of ATG, and donor type. No higher grade adverse effects of letermovir intake were observed. With altogether 11 reactivation events, the cumulative incidence of CMV reactivation on day +100 was 13% (95%CI 6-21%) in the letermovir cohort which was significantly lower than in the control group (34 events, d +100 cumulative incidence 41% (95%CI 31-52%); HR 0.32 (95%CI 0.24-0.44); p<0.0001). Two hospitalizations for foscavir administration occurred in the letermovir group compared to 9 hospitalizations in the control group. The cumulative number of days on valganciclovir before d +100 was 373d for the 82 letermovir patients vs 1082d for the 82 control patients. There were 5 deaths before d +100 in the letermovir group (three NRM, two PD) and 7 deaths in the control group (four NRM, three PD). Conclusions: This observational study proves in a real-world setting the efficacy and safety of letermovir for the prophylaxis of CMV reactivation after alloHCT. Letermovir lowered the incidence of CMV reactivation to the same extent as observed in the approval trial. In terms of health economics, letermovir reduced hospitalization needs and costs for therapeutic anti-CMV agents. Longer follow-up will be needed to assess the impact of letermovir prophylaxis on non-relapse and overall mortality. Disclosures Derigs: MSD: Honoraria. Müller-Tidow:MSD: Membership on an entity's Board of Directors or advisory committees. Luft:Neovii: Research Funding; JAZZ: Research Funding. Dreger:MSD: Membership on an entity's Board of Directors or advisory committees, Other: Sponsoring of Symposia; AbbVie, AstraZeneca, Gilead, Janssen, Novartis, Riemser, Roche: Consultancy; Neovii, Riemser: Research Funding; AbbVie, Gilead, Novartis, Riemser, Roche: Speakers Bureau. Schmitt:MSD: Membership on an entity's Board of Directors or advisory committees, Other: Sponsoring of Symposia; Therakos Mallinckrodt: Other: Financial Support.

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Impact of Specific Adverse Cytogenetic Features on Outcomes after Allogeneic Hematopoietic Cell Transplantation in Myelodysplastic Syndrome with Very Poor Risk Cytogenetics: A Study from the Chronic Malignancies Working Party of EBMT

Blood ◽

10.1182/blood-2021-150892 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 3953-3953

Author(s):

Xavier Poiré ◽

Diderik-jan Eikeman ◽

Linda Koster ◽

Johan A. Maertens ◽

Jan J. Cornelissen ◽

...

Keyword(s):

Board Of Directors ◽

Cumulative Incidence ◽

Research Funding ◽

Acute Gvhd ◽

Hematopoietic Cell Transplantation ◽

Chronic Gvhd ◽

Unrelated Donor ◽

Advisory Committees ◽

Free Survival ◽

Grade Ii

Abstract INTRODUCTION: Myelodysplastic Syndrome (MDS) is a heterogenous disease which is almost incurable without an allogeneic hematopoietic cell transplantation (allo-HCT). Within the revised international scoring system (R-IPSS), MDS with poor and very poor cytogenetics have a much worse outcome after allo-HCT. The very poor cytogenetic subgroup refers to patients harboring more than 3 abnormalities and is therefore a highly heterogenous group. We have shown in acute myeloid leukemia (AML) that beyond complex karyotype, specific adverse cytogenetic features such as 7q abnormalities (abn7q), 5q abnormalities (abn5q), 17p abnormalities (abn17p) and monosomal karyotype (MK) worsen the outcomes after allo-HCT. We have therefore retrospectively reviewed MDS with very poor cytogenetics and studied the impact of adverse cytogenetic features on outcomes after transplant. METHODS: We selected MDS patients who underwent allo-HCT between 2001 and 2018 from a matched related or unrelated donor, for whom a full cytogenetic report was available in the EBMT registry. We then stratified them according to the presence of abn7q, abn5q, abn17p, MK and the number of abnormalities (≤5, 6-9 and ≥10). Graft-versus-host disease (GvHD) and relapse-free survival (GRFS) was defined as survival without grade II-IV acute GvHD, extensive chronic GvHD or relapse. RESULTS: A total of 154 patients were identified in the registry. One hundred twenty-three patients (81%) had MDS with excess of blasts and 4 (3%) had secondary AML. Median age was 59 years (interquartile range (IQR), 51-64) and the median follow-up was 38 months (95% confidence interval (CI), 34-60). The time from diagnosis to allo-HCT was a median of 6 months (IQR, 4-8). Two thirds of patients received a reduced-intensity conditioning regimen (N = 103, 67%) and 87 patients had a matched unrelated donor (57%). Almost all patients were in first complete remission at time of transplant (N= 149, 97%). Regarding specific cytogenetic features, 87 patients had abn7q (57%), 99 abn5q (64%), 59 abn17p (38%) and 120 MK (78%) with considerable overlap between groups. The 2-year overall survival (OS) and progression-free survival (PFS) was 34% (95% CI 26-42%) and 24% (95% CI 17-31%), respectively. The 2-year cumulative incidence of relapse and non-relapse mortality (NRM) was 59% (95% CI 51-67%) and 18% (95% CI 12-24%), respectively. The cumulative incidence of grade II-IV acute GvHD and chronic GvHD was 33% (95% CI 25-40%) and 44% (95% CI 36-53%) by day 100 and 2 years respectively. The 2-year GRFS was 12% (95% CI 6-17%). The presence of abn5q was associated with a significantly decreased PFS of 17% (95% CI 9-25%) versus 36% (95% CI 23-49%); p=0.05) and GRFS (6% (95% CI 1-11%) versus 23% (95% CI 11-34%); p=0.04). The presence of abn7q was associated with significantly increased NRM (25% (15-34%) versus 9% (2-16%); p=0.02) which did not translate into OS. There were no specific cytogenetic features that had an independent impact on the cumulative incidence of relapse, but age over 55 years did increase the relapse risk (<55: 45% (95% CI 31-59%); 55-65: 65% (95% CI 54-77%); >65: 66% (95% CI 50-83%); p=0.03). A continuous effect was also observed (per decade increase: HR=1.24, 95%CI 1.02-1.52; p=0.03). Patients with an interval of more than 6 months from diagnosis to allo-HCT had almost double the OS (45% (95% CI 32-58%)) compared to patients with an interval less than 6 months (27% (95% CI 17-37%); p=0.04), however a continuous effect was not observed. CONCLUSION: MDS with very poor cytogenetics according to R-IPSS is a very bad group with dismal outcomes after allo-HCT. Within this high-risk group, specific adverse cytogenetic features such as the number of abnormalities, abn7q, abn5q, abn17p or MK did not stratify outcomes further, except for abn5q which was associated with a decreased PFS. Our results might be explained in part by the low number patients and by the over-representation of adverse features within this cohort. Despite that, advancing age was associated with increased relapse. Whilst allo-HCT remains the best therapeutic option for this very high-risk patient group, efforts should focus on post-transplant preemptive intervention strategies to prevent relapse. Disclosures Byrne: Incyte: Honoraria. Schroeder: Celgene: Honoraria, Other: Travel support, Research Funding. Blaise: Jazz Pharmaceuticals: Honoraria. Hayden: Jansen, Takeda: Other: Travel, Accomodation, Expenses; Amgen: Honoraria. Scheid: Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Honoraria; Roche: Consultancy; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees. Yakoub-Agha: Jazz Pharmaceuticals: Honoraria.

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Targeted Treatment and Survival Following Relapse after Allogeneic Hematopoietic Cell Transplantation for Acute Leukemia and MDS in the Contemporary Era

Blood ◽

10.1182/blood-2019-124533 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 4567-4567

Author(s):

Sanghee Hong ◽

Lisa Rybicki ◽

Donna Corrigan ◽

Betty K. Hamilton ◽

Ronald Sobecks ◽

...

Keyword(s):

Board Of Directors ◽

Cell Transplantation ◽

Research Funding ◽

Acute Gvhd ◽

Hematopoietic Cell Transplantation ◽

Treatment Strategies ◽

Targeted Agents ◽

Advisory Committees ◽

Survival After Relapse ◽

Grade Ii

Introduction: Relapse is the most frequent cause of treatment failure after allogeneic hematopoietic cell transplantation (alloHCT). While transplant-related mortality has decreased substantially over the last few decades, little progress has been made in outcomes and no standard of care exists for patients (pts) with post-alloHCT relapse. In the recent era, several new therapies, including targeted agents, have been approved for ALL, AML, and MDS. We conducted a study to evaluate outcomes of pts with these diseases who relapse after alloHCT in the contemporary period with routine availability of these newer therapeutic agents. Methods: We performed a single-institution retrospective cohort study to review treatment strategies and outcomes of relapse post-alloHCT. We identified 420 adult pts who received their first alloHCT in 2010-2018 using any conditioning regimen or donor source. Overall, 115 (27%) pts experienced relapse (ALL=17/64 [27%], AML=67/242 [28%], MDS=31/114 [27%]) and were included in the analysis. Results: Myeloablative (54%) matched-unrelated donor grafts (50%) were the most common types of HCTs. Peripheral blood stem cell graft (49%) and bone marrow graft (48%) were used the most. Median time from alloHCT to relapse was 5 (range 1-65) months, and 83% of relapses occurred within the first year. Only 24% and 11% of pts experienced grade II-IV acute and any chronic GVHD prior to relapse, respectively. Seven of 17 pts had Philadelphia chromosome positive ALL. Mutation panel was tested in 56% of AML and MDS. Median follow-up period after relapse was 19 (range 6-80) months. The estimated survival after relapse for all diseases was 32% (95% CI 24-41%) at 6 months, 21% (14-28%) at 12 months, and 14% (8-21%) at 24 months (Fig 1). Excluding pts treated with supportive care only, the majority received a combination of different treatments; pts with ALL received median 3 (range 1-5), pts with AML received median 2 (1-4), and pts with MDS received median 1 (1-3) agent. Targeted therapies used for ALL pts included blinatumomab (n=5) and BCR-ABL targeting tyrosine kinase inhibitors with (n=2) or without (n=4) chemotherapy. Among AML pts, targeted agents were used in 15 pts (sorafenib [n=7], 2 each with enasidenib, gemtuzumab ozagamicin, and ivosidenib, and 1 each with venetoclax and SEL24 [a dual pan-PIM/FLT3 inhibitor]). One pt each was treated with enasidenib, gemtuzumab ozagamicin, and PTC299 (an inhibitor of VEGFA mRNA translation) followed by SEL24 for MDS. Second alloHCTs (n=5) were performed median 5 (range 1-16) months after first HCT and median 1 month (range 0-5 months) after relapse. Two pts received no bridging therapy, while 3 pts received chemotherapy (n=2) or donor lymphocyte infusions (DLI [n=1]) prior to the second transplant. DLI without second transplant was used in 25 pts at a median of 20 (range 3-18) months after ALL relapse, median 2 (range 0-13) months after AML relapse, and median 3 (range 1-5) months after MDS relapse. Following DLI, 53% pts developed GVHD. Targeted therapy was associated with a trend towards better survival compared to other therapies (Fig 2, HR 0.65, 95% CI 0.41-1.03, p=0.06). Based on multivariable analysis, matched unrelated (vs. matched sibling, HR 1.70, p=0.027) or haploidentical donor grafts (HR 2.69, p=0.003), presence of grade II-IV acute GVHD before relapse (HR 2.46, p<0.001), and less than 12 months from HCT to relapse (<6 vs. >12 months, HR 6.34, p<0.001; 6-12 vs. >12 months, HR 3.16, p=0.005) were adverse prognostic features with survival after relapse post-alloHCT (Table 1). Conclusion: Outcomes of pts with ALL, AML, and MDS who relapse following alloHCT remain poor in the contemporary era when several newer therapies, including targeted agents, are available for their treatment. Targeted agents were used only in a minority of post-alloHCT relapses likely due to the combination of pt status, absence of the target mutation, the agents' availability, and other factors. Pts who developed grade II-IV acute GVHD and had shorter "disease-free" duration from unrelated or haploidentical donor grafts had the significantly shorter survival following relapse. More innovative treatment strategies to prevent and treat relapse post-alloHCT are needed. Disclosures Hill: Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celegene: Consultancy, Honoraria, Research Funding; Amgen: Research Funding; TG therapeutics: Research Funding; Genentech: Consultancy, Research Funding; Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Kite: Consultancy, Honoraria; Pharmacyclics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AstraZeneca: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria; Takeda: Research Funding. Anwer:In-Cyte: Speakers Bureau; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees. Majhail:Atara Bio: Consultancy; Anthem, Inc.: Consultancy; Nkarta: Consultancy; Mallinckrodt: Honoraria; Incyte: Consultancy.

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Primary Plasma Cell Leukemia Outcomes Remain Dismal Despite Novel Agents and Hematopoietic Cell Transplantation

Blood ◽

10.1182/blood-2019-127049 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 266-266

Author(s):

Sagar Patel ◽

Saulius K. Girnius ◽

Binod Dhakal ◽

Lohith Gowda ◽

Raphael Fraser ◽

...

Keyword(s):

High Risk ◽

Board Of Directors ◽

Plasma Cell ◽

Research Funding ◽

Hematopoietic Cell Transplantation ◽

Disease Status ◽

Cell Leukemia ◽

Advisory Committees ◽

Primary Plasma Cell Leukemia ◽

Equity Ownership

Background Primary plasma cell leukemia (pPCL) is a rare plasma cell neoplasm with a high mortality rate. There have been improvements in multiple myeloma (MM) outcomes with novel induction agents and use of hematopoietic cell transplantation (HCT) with maintenance, but similar progress has not been reported for pPCL. We examined the outcomes of pPCL patients receiving novel agents with autologous (autoHCT) or allogeneic (alloHCT) approaches as reported to the Center for International Blood and Marrow Transplant Research (CIBMTR) in the modern era. Methods From 2008 to 2015, 348 pPCL pts underwent HCT (N = 277 - autoHCT and 71 - alloHCT) with 45% and 48% having research level data available, respectively. Cumulative incidences of non-relapse mortality (NRM) and relapse/progression (REL), and probability of progression-free survival (PFS) and overall survival (OS) were calculated. Cox multivariate regression was used to model survival after autoHCT only. Median follow-up in autoHCT and alloHCT was 48 and 60 months, respectively. Results AutoHCT Cohort Median age was 60 years and 93% received HCT within 12 months of diagnosis with 76% after a single line of induction (Table 1). 35% had high risk cytogenetics. 23% received bortezomib, doxorubicin, cisplatin, cyclophosphamide, and etoposide (VDPACE). Moreover, 40% received bortezomib (BTZ) and immunomodulatory drug (IMIID)-based triplets. Disease status at HCT was VGPR or better in 47%. 27% received maintenance therapy. At 4 years post-HCT, NRM was 7% (4-11%), REL 76% (69-82%), PFS 17% (13-23%), and OS 28% (22-35%) (Figures 1A, 2A, 2B). Disease status ≥VGPR at HCT and Karnofsky Performance Score >90 significantly predicted superior OS in multivariate analysis. AlloHCT Cohort Median age was 53 years and 89% received HCT within 12 months of diagnosis (Table 1). 61% received a single alloHCT, while 39% used auto-alloHCT tandem approach. 42% had high-risk cytogenetics. 61% received total body irradiation with 44% receiving myeloablative conditioning. Use of VDPACE was higher at 41% in this cohort. VGPR status at HCT was similar (48%), while maintenance was used less often (12%). Grade II-IV acute GVHD occurred in 30% and chronic GVHD in 45%. At four years post-HCT, NRM was 12% (5-21%), REL 69% (56-81%), PFS 19% (10-31%), and OS 31% (19-44%) (Figures 1A, 1B, 2A, 2B). There were no differences in outcomes based on type of HCT. A comparison of post-HCT outcomes of CIBMTR pPCL patients from 1995 to 2006 showed that PFS and OS outcomes are inferior despite lower NRM in this modern cohort (Mahindra et al. Leukemia. 2012). In addition, analysis of SEER (1995-2009) and CIBMTR databases showed that use of HCT increased from 12% (7-21%) in 1995 to 46% (34-64%) in 2009. Conclusion More newly diagnosed pPCL patients are receiving modern induction regimens translating into a higher proportion receiving HCT, but without significant further benefit post-HCT. Post-HCT relapse remains the biggest challenge and further survival in pPCL will likely need a combination of targeted and cell therapy approaches. This study provides a benchmark for future HCT studies for pPCL. Disclosures Girnius: Takeda: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Genentech: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Dhakal:Takeda: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Honoraria. Shah:University of California, San Francisco: Employment; Indapta Therapeutics: Equity Ownership; Genentech, Seattle Genetics, Oncopeptides, Karoypharm, Surface Oncology, Precision biosciences GSK, Nektar, Amgen, Indapta Therapeutics, Sanofi: Membership on an entity's Board of Directors or advisory committees; Celgene, Janssen, Bluebird Bio, Sutro Biopharma: Research Funding; Poseida: Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Nkarta: Consultancy, Membership on an entity's Board of Directors or advisory committees; Kite: Consultancy, Membership on an entity's Board of Directors or advisory committees; Teneobio: Consultancy, Membership on an entity's Board of Directors or advisory committees. Qazilbash:Amgen: Consultancy, Other: Advisory Board; Bioclinical: Consultancy; Autolus: Consultancy; Genzyme: Other: Speaker. Kumar:Celgene: Consultancy, Research Funding; Takeda: Research Funding; Janssen: Consultancy, Research Funding. D'Souza:EDO-Mundapharma, Merck, Prothena, Sanofi, TeneoBio: Research Funding; Prothena: Consultancy; Pfizer, Imbrium, Akcea: Membership on an entity's Board of Directors or advisory committees. Hari:BMS: Consultancy, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria; Kite: Consultancy, Honoraria; Amgen: Research Funding; Spectrum: Consultancy, Research Funding; Sanofi: Honoraria, Research Funding; Cell Vault: Equity Ownership; AbbVie: Consultancy, Honoraria.

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Association of MHC Class I Chain-Related Gene a (MICA) Polymorphisms with Allogeneic Hematopoietic Cell Transplantation Outcomes in Acute Myeloid Leukemia

Blood ◽

10.1182/blood-2018-99-112745 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 2075-2075

Author(s):

Sagar S. Patel ◽

Betty K. Hamilton ◽

Lisa Rybicki ◽

Dawn Thomas ◽

Arden Emrick ◽

...

Keyword(s):

Board Of Directors ◽

Binding Affinity ◽

Myeloid Leukemia ◽

Research Funding ◽

Somatic Mutations ◽

Hematopoietic Cell Transplantation ◽

Advisory Committees ◽

Post Transplant ◽

Transplant Outcomes ◽

Nkg2d Receptor

Abstract Background MHC class I chain-related gene A (MICA) is a polymorphic ligand of the natural killer (NKG2D) receptor on immune effector cells. The activating NKG2D receptor controls immune responses by regulating NK cells, NKT cells and γδ-T cells. Dimorphisms at sequence position 129 of the MICA gene confers varying levels of binding affinity to NKG2D receptor. MICA previously has been associated with post-allogeneic hematopoietic cell transplantation (alloHCT) outcomes including graft-versus-host-disease (GvHD), infection, and relapse. However, it is unclear how MICA interacts with cytogenetic and somatic mutations in regards to these outcomes in acute myeloid leukemia (AML). Methods We conducted a single center, retrospective analysis of adult AML patients in first or second complete remission (CR1, CR2), who underwent T-cell replete matched related or unrelated donor alloHCT. Analysis was limited to those who had MICA data available for donors and recipients. In addition to cytogenetic risk group stratification by European LeukemiaNet criteria (Döhner H, et al, Blood 2016), a subset of patients had a 36-gene somatic mutation panel assessed prior to alloHCT by next-generation sequencing. Dimorphisms at the MICA-129 position have previously been categorized as weaker (valine/valine: V/V), heterozygous (methionine/valine: M/V), or stronger (methionine/methionine: M/M) receptor binding affinity. Fine and Gray or Cox regression was used to identify the association of MICA and outcomes with results as hazard ratios (HR) and 95% confidence intervals (CI). Results From 2000 - 2017, 131 AML patients were identified meeting inclusion criteria. Median age at transplant was 54 years (18-74), with 98% Caucasian. Disease status at transplant included 78% CR1 and 22% CR2. Cytogenetic risk stratification showed 13% of patients as favorable, 56% as intermediate, and 31% as adverse-risk. The five most common somatic mutations were FLT3 (15%), NPM1 (14%), DNMT3A (11%), TET2 (7%), and NRAS (6%). 60% of patients had a related donor. A myeloablative transplant was performed in 84% of patients and 53% had a bone marrow graft source. The most common conditioning regimen used was busulfan/cyclophosphamide (52%). 12% of patients were MICA mismatched with their donor. The distribution of donor MICA-129 polymorphisms were 41% V/V, 53% M/V, and 6% M/M. In univariable analysis, donor-recipient MICA mismatch tended to be associated with a lower risk of infection (HR 0.49, CI 0.23-1.02, P=0.06) and grade 2-4 acute GvHD (HR 0.25, CI 0.06-1.04, P=0.06) but was not associated with other post-transplant outcomes. In multivariable analysis, donor MICA-129 V/V was associated with a higher risk of non-relapse mortality (NRM) (HR 2.02, CI 1.01-4.05, P=0.047) (Figure 1) along with increasing patient age at transplant (HR 1.46, CI 1.10-1.93, p=0.008) and the presence of a TET2 mutation (HR 6.00, CI 1.77-20.3, P=0.004). There were no differences between the V/V and the M/V+M/M cohorts regarding somatic mutational status, cytogenetics and other pre-transplant characteristics and post-transplant outcomes. With a median follow-up of 65 months for both cohorts, 45% vs. 49% of patients remain alive, respectively. The most common causes of death between the V/V and the M/V+M/M cohorts was relapse (38% vs. 62%) and infection (31% vs. 8%), respectively. Conclusion While previous studies have demonstrated associations of somatic mutations and cytogenetics with survival outcomes after alloHCT for AML, we observed mutations in TET2 and the V/V donor MICA-129 polymorphism to be independently prognostic for NRM. Mechanistic studies may be considered to assess for possible interactions of TET2 mutations with NK cell alloreactivity. The weaker binding affinity to the NKG2D receptor by the V/V phenotype may diminish immune responses against pathogens that subsequently contribute to higher NRM. These observations may have implications for enhancing patient risk stratification prior to transplant and optimizing donor selection. Future investigation with larger cohorts interrogating pre-transplant AML somatic mutations with MICA polymorphisms on post-transplant outcomes may further elucidate which subsets of patients may benefit most from transplant. Disclosures Nazha: MEI: Consultancy. Mukherjee:Pfizer: Honoraria; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Projects in Knowledge: Honoraria; BioPharm Communications: Consultancy; Bristol Myers Squib: Honoraria, Speakers Bureau; Takeda Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; LEK Consulting: Consultancy, Honoraria; Aplastic Anemia & MDS International Foundation in Joint Partnership with Cleveland Clinic Taussig Cancer Institute: Honoraria. Advani:Amgen: Research Funding; Pfizer: Honoraria, Research Funding; Glycomimetics: Consultancy; Novartis: Consultancy. Carraway:Novartis: Speakers Bureau; Balaxa: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Jazz: Speakers Bureau; FibroGen: Consultancy; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Amgen: Membership on an entity's Board of Directors or advisory committees; Agios: Consultancy, Speakers Bureau. Gerds:Apexx Oncology: Consultancy; Celgene: Consultancy; Incyte: Consultancy; CTI Biopharma: Consultancy. Sekeres:Celgene: Membership on an entity's Board of Directors or advisory committees; Opsona: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Opsona: Membership on an entity's Board of Directors or advisory committees. Maciejewski:Apellis Pharmaceuticals: Consultancy; Ra Pharmaceuticals, Inc: Consultancy; Alexion Pharmaceuticals, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Ra Pharmaceuticals, Inc: Consultancy; Alexion Pharmaceuticals, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Apellis Pharmaceuticals: Consultancy. Majhail:Incyte: Honoraria; Anthem, Inc.: Consultancy; Atara: Honoraria.

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VTE Rates and Safety Analysis of Newly Diagnosed Multiple Myeloma Patients Receiving Carfilzomib-Lenalidomide-Dexamethasone (KRD) with or without Rivaroxaban Prophylaxis

Blood ◽

10.1182/blood-2019-124403 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 1835-1835 ◽

Cited By ~ 4

Author(s):

Katrina M Piedra ◽

Hani Hassoun ◽

Larry W. Buie ◽

Sean M. Devlin ◽

Jessica Flynn ◽

...

Keyword(s):

Multiple Myeloma ◽

Venous Thromboembolism ◽

Board Of Directors ◽

Research Funding ◽

High Dose ◽

Newly Diagnosed ◽

Advisory Committees ◽

Cancer Trial ◽

Oncology Research ◽

Increased Risk

Introduction Immunomodulatory agents (IMiD's) are associated with an increased risk of venous thromboembolism (VTE), particularly when combined with high dose steroids. Studies evaluating the use of lenalidomide-bortezomib-dexamethasone (RVD) and carfilzomib-lenalidomide-dexamethasone (KRD) in the frontline setting for multiple myeloma (MM) have reported a 6% and 24% incidence of thrombosis, respectively, despite primary thrombotic prophylaxis with aspirin (ASA) (Richardson, et al. Blood. 2010; Korde, et al. JAMA Oncol 2015). Recent data, including the Hokusai VTE Cancer Trial, have suggested that safety and efficacy of direct oral anticoagulants (DOACs) are preserved in the setting of treatment of solid malignancy-associated thrombosis (Raskob, et al. N Engl J Med. 2018; Mantha, et al. J Thromb Thrombolysis. 2017). Despite this data, there is limited experience and use of DOACs in prevention of thromboses in the setting of hematologic malignancies, specifically MM. After careful review of literature, since early 2018, we changed our clinical practice and routinely placed newly diagnosed MM (NDMM) patients receiving KRD at Memorial Sloan Kettering Cancer Center (MSKCC) on concomitant rivaroxaban 10 mg once daily, regardless of VTE risk stratification. In the following abstract, we present VTE rates and safety data for newly diagnosed MM patients receiving RVD with ASA vs. KRD with ASA vs. KRD with rivaroxaban prophylaxis. Methods This was an IRB-approved, single-center, retrospective chart review study. All untreated patients with newly diagnosed MM, receiving at least one cycle of RVD or KRD between January 2015 and October 2018 were included. The period of observation included the time between the first day of therapy until 90 days after completion of induction therapy. Patients were identified by querying the pharmacy database for carfilzomib or bortezomib administration and outpatient medication review of thromboprophylaxis with rivaroxaban or ASA. VTE diagnoses were confirmed by ICD-10 codes and appropriate imaging studies (computed tomography and ultrasound). Descriptive statistics were performed. Results During the observation period, 241 patients were identified to have received RVD or KRD in the frontline (99 RVD with ASA; 97 KRD with ASA; 45 KRD with rivaroxaban). Baseline characteristics were well distributed among the three arms, with a median age of 60 (30-94) in the RVD ASA arm, 62 (33-77) in the KRD ASA arm, and 60 (24-79) in the KRD rivaroxaban arm. Patients had International Staging System (ISS) stage 3 disease in 13% (N=13), 9.3% (N=9), and 11% (N=5) of the RVD ASA, KRD ASA, and KRD rivaroxaban arms, respectively. Median weekly doses of dexamethasone were higher in both KRD arms, 40 mg (20-40) vs. 20 mg (10-40) in the RVD ASA arm. The average initial doses of lenalidomide were 22 mg in the RVD ASA arm compared to 25 mg in both the KRD ASA and KRD rivaroxaban arms. After querying the pharmacy database, no patients were identified to have a history or concomitant use of erythropoietin stimulating agent (ESA) use. Treatment-related VTE's occurred in 4 patients (4.0%) in the RVD ASA arm, 16 patients (16.5%) in the KRD ASA arm, and in 1 patient (2.2%) in the KRD rivaroxaban arm. Average time to VTE was 6.15 months (Range 5.42, 9.73) after treatment initiation in the RVD ASA group, while it was 2.61 months (Range 0.43, 5.06) in the KRD ASA group and 1.35 months in the KRD rivaroxaban group. Minor, grade 1 bleeding events per the Common Terminology Criteria for Adverse Events (CTCAE) were identified in 1 (1.1%) patient in the RVD ASA arm, 5 (5.2%) patients in the KRD ASA arm, and 1 (2.2%) patient in the KRD rivaroxaban arm. Conclusion More efficacious MM combination therapies have been found to increase the risk of VTE when using ASA prophylaxis, indicating better thromboprophylaxis is needed. We found patients receiving ASA prophylaxis with KRD were more likely to experience a VTE and these events occurred earlier compared to patients receiving ASA prophylaxis with RVD. Importantly, the rate of VTE was reduced to the same level as ASA prophylaxis with RVD when low-dose rivaroxaban 10 mg daily was used with KRD, and without necessarily increasing bleeding risk. Our retrospective data support the development of prospective clinical trials further investigating DOAC use in thromboprophylaxis for NDMM patients receiving carfilzomib-based treatments. Figure Disclosures Hassoun: Novartis: Consultancy; Janssen: Research Funding; Celgene: Research Funding. Lesokhin:BMS: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria; Janssen: Research Funding; GenMab: Consultancy, Honoraria; Serametrix Inc.: Patents & Royalties; Genentech: Research Funding; Juno: Consultancy, Honoraria. Mailankody:Juno: Research Funding; Celgene: Research Funding; Janssen: Research Funding; Takeda Oncology: Research Funding; CME activity by Physician Education Resource: Honoraria. Smith:Celgene: Consultancy, Patents & Royalties, Research Funding; Fate Therapeutics and Precision Biosciences: Consultancy. Landgren:Theradex: Other: IDMC; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: Other: IDMC; Sanofi: Membership on an entity's Board of Directors or advisory committees; Adaptive: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. OffLabel Disclosure: Off-label use of rivaroxaban for outpatient prophylaxis of venous thromboembolism (VTE) will be explicitly disclosed to the audience.

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