The Safety and Efficacy of Granulocyte Transfusions in Pediatric Recipients with Severe Neutropenia

Abstract Background: Pediatric oncology and stem cell transplant patients are at high risk for severe bacterial and fungal infections due to the myelosuppressive effects of chemotherapy and conditioning, respectively. Febrile neutropenia is one of the most concerning complications of chemotherapy. Even with the rapid initiation of empiric antibiotics, morbidity and mortality in this patient population occur frequently. Prognosis is worse in patients with proven bacteremia, with mortality rates of 18% and 5% reported in patients with gram-negative and gram-positive bacteremia, respectively (de Naurois et al. Annals of Oncology, 2010). Although gram positive organisms are known to be the most common cause of bacteremia in neutropenic patients (Kibbler et al. Curr Opin in Infect Dis, 1999), recent studies within the last 5 years have reported gram-negative organisms as the most common cause of bacteremia in this patient population (Mert et al. J Infect Dev Ctries, 2019, Islas-Muñoz et al. Int J Infect Dis, 2018, Sierra et al. Medicina, 2020, Cattaneo et al. Ann Hematol, 2018, Parodi et al. PloS one, 2019). Granulocytes harvested from healthy donors can temporarily raise the functional neutrophil counts in transfusion recipients. Data in the adult population show that while these transfusions are safe, they may be of limited efficacy, with patients receiving more than 6 x10 8 having better outcomes (Price et al. Blood, 2015). However, there is a paucity of data in the pediatric population (Atallah et al. Curr Opin in Hematol, 2006, Price et al. Semin Hematol, 2007, Estcourt et al. Cochrane Database Syst Rev, 2015). Objective: To determine the safety of granulocyte transfusions in pediatric recipients with severe neutropenia. Methods: Following IRB approval, we completed a retrospective cohort study of neutropenic pediatric recipients with various infections who received granulocyte transfusions. We reviewed the records of 74 pediatric recipients at the Maria Fareri Children's Hospital at Westchester Medical Center who received granulocyte transfusions from 2011-2019. The medical record was reviewed for patient age, underlying medical condition, indication for granulocyte transfusion, duration of fever, time to resolution of infection, mortality, and adverse reactions to the granulocyte transfusion. Mobilized granulocytes (dexamethasone) were collected from healthy donors at the New York Blood Center, as we have previously reported (Sulis/Cairo et al, Blood 2002, Price et al, Blood 2015). Results: The average age was 11 years (<1-20) with 38 male patients and 36 female patients. The majority of patients were either stem cell transplant recipients, patients with hematologic malignancies, or both. The most common indication for granulocyte transfusion was a documented bacterial infection (56.7%). Fifty-two percent had gram negative infection and 45.2% had gram positive infection. Nine percent were staph infections. Patients received granulocytes for a median of 7.5 days. 54% of the patients cleared their infection with antibiotics prior to receiving the granulocytes. In the remaining patients, infection resolved in 32.4% while receiving granulocyte transfusions in addition to antimicrobial therapy. In this subset of patients, 63.6% had bacterial infection with 71.4% having gram positive infection, all of which were staph infections. The infection cleared after a median of 4 days of granulocyte transfusions. Patients in this subset were on antibiotics for a median of 5 days prior to starting granulocytes. Adverse events related to the granulocyte infusion occurred in 6 patients, with 3 patients having a fever during the transfusion (CTCAE 1), 1 with hypothermia (CTCAE 2), and 1 with joint pain (CTCAE 1). 3 patients died during the period when they were receiving granulocytes. 2 due to infection complication and one due to seizure. 30 day survival was 86.5% and 100 day survival was 85.1%. Conclusions: Granulocyte transfusions can be safely administered to pediatric patients with severe neutropenia. 32.4% cleared the infection with granulocyte transfusion. 100 day survival is 85.1%. Adverse events had CTCAE scores of 1-2. A majority of patients had gram negative infections, but the majority of patients that had resolution of infection with granulocytes had staph infections. It is possible that granulocytes may have greater efficacy against staph infections than other types of infection. Figure 1 Figure 1. Disclosures Liu: Incyte: Honoraria; Pharmacyclics: Honoraria, Speakers Bureau; Astellas: Honoraria, Speakers Bureau; Pfizer: Research Funding; Beigene: Honoraria, Speakers Bureau; Celgene: Research Funding. Cairo: Jazz Pharmaceutical: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Speakers Bureau; Sanofi: Speakers Bureau; Servier: Speakers Bureau; Sobi: Speakers Bureau; Omeros: Membership on an entity's Board of Directors or advisory committees; Nektar: Membership on an entity's Board of Directors or advisory committees.

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Allogeneic Hematopoietic Stem Cell Transplant in Advanced Multiple Myeloma: Experience from a Single Center

Blood ◽

10.1182/blood.v126.23.5536.5536 ◽

2015 ◽

Vol 126 (23) ◽

pp. 5536-5536

Author(s):

Yizel Elena Paz Nuñez ◽

Beatriz Aguado Bueno ◽

Isabel vicuña Andrés ◽

Ángela Figuera Álvarez ◽

Miriam González-Pardo ◽

...

Keyword(s):

Multiple Myeloma ◽

Stem Cell ◽

Board Of Directors ◽

Hematopoietic Stem Cell ◽

Hematopoietic Stem Cell Transplant ◽

Stem Cell Transplant ◽

Cell Transplant ◽

Advisory Committees ◽

Hematopoietic Stem

Abstract Introduction The prognosis of patients with multiple myeloma (MM) has improved in the last years due to the important advances in the knowledge of the biology of the disease, the implementation of new drugs and the incorporation of autologous hematopoietic stem cell transplant (autoHSCT). The allogenic hematopoietic stem cell transplant (alloHSCT) continues to be controversial: it offers a curative potential but with the cost of high toxicity, limiting the procedure to those young patients with a high-risk disease. This procedure shall be performed in expert centers and, whenever possible, in the context of a clinical trial. In the following we describe the experience of our center with alloHSCT in advance multiple myeloma patients. Patients and methods A total of 18 patients were diagnosed with multiple myeloma received an alloHSCT during a 13 year period (1996-2013), with a median age of 46 ± 5.9 years. All of our patients received an allogenic HLA matched sibling donor with reduced-intensity conditioning. The majority of patients were transplanted because of advanced disease, relapse after an autologous transplant or as part of a sequential transplant in patient with a high risk disease. One patient received, in two occasions, an alloHSCT. Around 70% of patients had received more than 3 previous lines of treatment including, in nearly 95%, an autoHSCT. Patient's characteristics can be found on table 1, characteristics of the procedure can be found in table 2.Table 1.Patient«s CharacteristicsN (%)GenderMale Female10 (55,5%) 9 (44,4%)Secreted ProteinIgGκ IgG λ IgA κ BJ Plasmocitoma8 (44,4%) 4 (22,2%) 2 (11,1%) 3 (16,7%) 1 (5,6%)Debut DS stageII-A II-B III-A III-B Plasmocitoma5 (27,8%) 1 (5,6%) 8 (44,4%) 3 (16,7%) 1 (5,6%)Cytogentics at diagnosisMissing Unfavorable Favorable10 (55,5%) 6 (33,3%) 2 (11,1%)Previous lines of treatment²2 3-4 ³56 (33,3%) 10 (55,5%) 2 (11,1%)Previous autoHSCTYes No17 (94,5%) 1 (5,6%)Previous radiotherapyYes No8 (44,4%) 10 (55,6%)Disease status at transplantComplete remission Partial remission Relapse9 (50,0%) 3 (16,7%) 6 (33,3%)Table 2.Treatment characteristicsN (%)Conditioning regimenMyeloablative Reduced-intensity6 (33,3%) 12 (66.7%)Stem cell sourceBone marrow Peripheral blood4 (22.2%) 14 (77.8%)GVHD prophylaxisCsA+MTXCsA+CSCsA+MMF10 (55.6%) 3 (16.7%) 5 (27.8%)InfectionsYes No16 (88.9%) 2 (11.1%)MucositisYes No12 (66.7%) 6 (33.3%)Acute GVHDYes II-IV III-IV No4 (22.3%) 3 (16.7%) 1 (5.6%) 14 (77.8%)Chronic GVHDNo Limited Extensive8 (44.3%) 5 (27.8%) 5 (27.8%) Results: Transplant related mortality (TRM) before day 100th was one case due to a thromboembolic event. Global TRM was 16.6% (3 cases). The incidence of acute graft versus host disease (aGVHD) was 22%, controlled on most cases when corticosteroids were initiated. More than half of the patients developed chronic graft versus host disease (cGVHD), with an equal distribution on either presentation as limited or extensive. (Table 2) The total number of patients eligible for analysis was 17 (one patient was lost on follow-up). With a median follow up of 11 years, the overall survival (OS) was of 8.06 years [IC 95% 4,33-11,78] (figure 1.) and the estimated progression free survival (PFS) was of 25.83 months [IC 95% 8.87-42.79](figure 2). A total of 5 (29,4%) patients are still alive and 2 (11,7%) of them are in complete remission, of these 1 patient did not have a previous autoHSCT with a follow up of almost 15 years. Conclusions: Our results are similar to those reflected on the literature1-2. However we have to point out that our population is homogenous with advanced MM with more than 3 previous lines of treatment including in most cases auto-HSCT. In spite of this, morbility and mortality in our cohort was acceptable with the limitation of a high rate of cGVHD. There is a need of more studies including more patients to evaluate the role of alloHSCT in the era of new drugs for MM. References 1. Rosi-ol L et al. Allogeneic hematopoietic SCT in multiple myeloma: long-term results from a single institution. Bone Marrow Transplant. 2015. 2. Beaussant Y et al. Hematopoietic Stem Cell Transplantation in Multiple Myeloma: A Retrospective Study of the Société Française de Greffe de Moelle et de Thérapie Cellulaire (SFGM-TC). Biol Blood Marrow Transplant. 2015 Disclosures Alegre: Celgene Corporation: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees.

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Clinical Significance of Spatial Heterogeneity in Newly Diagnosed and Relapsed Multiple Myeloma

Blood ◽

10.1182/blood-2021-152427 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 1607-1607

Author(s):

Maximilian Merz ◽

Lei Wei ◽

Qiang Hu ◽

Almuth Maria Anni Merz ◽

Jie Wang ◽

...

Keyword(s):

Bone Marrow ◽

Board Of Directors ◽

Clinical Significance ◽

Stem Cell Transplant ◽

Plasma Cells ◽

Cell Transplant ◽

Specific Detection ◽

Advisory Committees ◽

Pet Ct

Abstract Introduction Malignant plasma cells (PC) in multiple myeloma (MM) are not homogeneously distributed in the bone marrow and spatial genomic heterogeneity is an evolving concept in MM. PC for histopathology, cytogenetic and molecular analyses and minimal residual disease (MRD) assessment are usually obtained from the iliac crest. This might introduce bias into diagnostic procedures since focal lesions (FL) occur in more than 80% of patients. Methods In April 2019, we initiated a prospective trial to compare findings from imaging-guided biopsies of FL detected by PET/CT and paired standard sampling from the posterior iliac crests (IC) in patients with newly diagnosed (NDMM) and relapsed/refractory MM (RRMM). Bone marrow aspirates from FL and paired IC samples were analyzed with next-generation flow (NGF) for phenotypic and MRD assessment (sensitivity level 10 -5) post therapy where applicable. PC from both locations were isolated using anti-CD138 magnetic beads and subjected to whole-exome sequencing (WES). Last year, we reported on longitudinal assessment of spatiotemporal immunogenomic heterogeneity in this cohort (https://doi.org/10.1182/blood-2020-142622). With a longer follow-up, we report clinical significance of the respective findings. Results In total, 18 patients (10 NDMM, 8 RRMM) underwent bone marrow aspirates from the IC and imaging-guided biopsies of paired FL. Para-medullary disease (PMD) was observed in 4 patients (1 NDMM, 3 RRMM). Unshared mutations from WES between both locations were identified in every patient. In 12 out of 18 patients (8 NDMM and 4 RRMM), less than 20% of mutations were unshared between IC and FL. Patients with >20% unshared mutations had RRMM and/or a history of PMD. The prognostic significance of unshared mutations was emphasized by lesion-specific detection of high-risk mutations (e.g. TP53) and copy number variations (e.g. gains/losses of Chr 1 and del(17p)). To investigate whether unshared mutations might be accessible for therapeutic interventions, the Drug Gene Interaction Database was queried. More interactions were found in FL (n=886) compared to IC (n=505). Furthermore, we showed spatially divergent existence of PC that contribute to resistance, e.g. against proteasome inhibition through mutations in proteasome subunit PSMC3. Next, we investigated whether MRD assessment from IC and FL provides congruent results. In three patients with MRD-negative IC bone marrow aspirates, we obtained clinically relevant divergent results from FL biopsies. In a patient in complete response (CR) after 5 cycles RVD (Lenalidomide, Bortezomib, Dexamethasone), autologous stem cell transplant (ASCT) and 5 years of lenalidomide maintenance, follow-up PET/CT showed a single new FL in the caudal right ilium. While NGF showed persistent MRD-negativity in the ICt, NGF from the FL revealed monocloncal PC. Since there were no other signs of progressive disease, the patient was followed with close surveillance. Repeat PET/CT after 5 months showed progression of the FL. Serological evaluation confirmed relapse from CR and systemic treatment was initiated. In another patient with MRD-negative IC bone marrow aspirate after 4 cycles RVD, imaging-guided biopsy of a T10 residual FL showed monoclonal PC. Mass spectrometry of supernatants from IC aspirates showed persistence of monoclonal protein in each patient. Second primary malignancies (SPM) were detected by imaging-guided biopsies: Multiple PET-positive FL occurred in a MRD-negative patient after 4 cycles of RD, ASCT and 3 years lenalidomide maintenance. NGF confirmed MRD-negativity in IC and FL aspirates. NGF detected no malignant cells in the peripheral blood but B-lymphoblasts were detected in one of the PET-positive FL. Allogeneic stem cell transplant was performed after induction therapy and there is no detectable MM or B-acute lymphoblastic leukemia. Conclusions We demonstrate clinical significance of spatial heterogeneity in NDMM and RRMM through site-specific detection of mutations and chromosomal aberrations associated with adverse outcome and drug susceptibility. Our findings showing divergent results from MRD assessments in bone marrow and FL underline the critical role of whole-body imaging for follow-up of patients in remission. Sampling plasma cells solely from the IC limits the ability for complete clinical decision-making. Disclosures Merz: Sanofi: Honoraria; Janssen: Honoraria; BMS: Honoraria; Hexal: Honoraria; GSK: Honoraria. Barnidge: The Binding Site: Current Employment. McCarthy: Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bluebird: Honoraria, Membership on an entity's Board of Directors or advisory committees; Juno: Honoraria, Membership on an entity's Board of Directors or advisory committees; Karyopharm: Honoraria, Membership on an entity's Board of Directors or advisory committees; Magenta Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Oncopeptides: 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. Hillengass: Beijing Life Oasis Public Service Center: Speakers Bureau; Beijing Medical Award Foundation: Speakers Bureau; Skyline: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Membership on an entity's Board of Directors or advisory committees; Oncotracker: Membership on an entity's Board of Directors or advisory committees; Curio Science: Speakers Bureau; GlaxoSmithKline: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Axxess Network: Membership on an entity's Board of Directors or advisory committees; Adaptive: Membership on an entity's Board of Directors or advisory committees.

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Impact of Peri-Transplant Molecular Mutations on Outcomes of AML Patients Undergoing Fludarabine/Melphalan Conditioned Allogeneic Stem Cell Transplant

Blood ◽

10.1182/blood-2021-149297 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 4833-4833

Author(s):

Mateo Mejia Saldarriaga ◽

Yassine Tahri ◽

Sangmin Lee ◽

Zhengming Chen ◽

Tsiporah B. Shore ◽

...

Keyword(s):

Multivariate Analysis ◽

Stem Cell ◽

Board Of Directors ◽

Research Funding ◽

Stem Cell Transplant ◽

Cell Transplant ◽

Allogeneic Stem Cell Transplant ◽

Advisory Committees ◽

Post Transplant ◽

Idh Mutations

Abstract Introduction: Acute myeloid leukemia (AML) is heterogenous disease with a range of cytogenetic and molecular changes. Several molecular mutations identified in AML patients at diagnosis have prognostic implications and play important roles in guiding induction and consolidative treatment decisions. The prognostic impact of mutations peri allogeneic stem cell transplant are less well characterized. In this study, we examine the significance of pre and by D100 Post-transplant mutation status in AML patients underwent Fludarabine/Melphalan conditioned reduced intensity allogeneic stem cell transplant (SCT). Methods: AML patients who are in morphologic complete remission (CR1 or greater) with available molecular mutation at diagnosis, within 6 weeks prior to allogeneic SCT, and by 100 days post-transplant were included. Variables analyzed included baseline demographics, clinical variables (CIBMTR disease risk index (DRI), type of transplant, ELN risk, performance status) and 23 recurring molecular mutations. Analysis was also performed by grouping mutations into six pre-defined gene groups based on gene function (Table 2). Multivariable cox regression analysis was adjusted for age, gender, DRI and molecular mutation. Backward selection method was used to select the best combination of genes that is associated with overall survival (OS) and relapse-free survival (RFS). Results : A total of 142 AML patients with molecular genetic data available from 2014 to June, 2020 at Weill Cornell Medicine/New York Presbyterian Hospital were analyzed. Clinical characteristics of the patients are summarized in Table 1. The median age was 58 years (range 20 -78). Total of 261 mutations were detectable at diagnosis (Table 3). Prior to allo SCT and by D100, the detectable mutations were 87 and 40 respectively, which represent 56 and 26 patients. High-dose chemotherapy was less effective on clearing DNMT3A, ASXL1, TET2 (DAT) or IDH mutations, resulting in over-representation of DAT and IDH mutations prior to transplant. With a median follow-up time of 25 months, the median overall survival for the group was 40.8 months. The presence of mutations in TP53 at diagnosis was associated with worse OS by both univariate (HR 3.67, p=0.0030, CI 1.56-8.68) and multivariate analysis (HR 4.75, p=0.0014, CI 1.82-12.39) with median OS reduced from 49.3 to 19.3 months (p=0.002). High CIBMTR DRI (HR 0.17, p=0.0018, CI 0.05-0.51) predicted reduced OS and RFS, and Age >60 at diagnosis was associated with worse OS (HR 1.7 CI 1.04-3, p 0.03). Presence of any molecular mutation prior to transplant did not impact OS or RFS. For patients with any persistent mutations by D100 post-transplant, both OS ( HR 2.04, p 0.027, CI 1.08-3.8) and RFS (HR 1.99, p 0.025, CI 1.09-3.6,) were reduced in the univariate analysis, but not on multivariate analysis (HR 1.88, p 0.5, CI 0.99-3.49). Analysis based on six mutational groups (table 2) did not show any difference in their OS or RFS. However, worse RFS was independently associated with persistent IDH1 (HR 3.8, p 0.004, CI 1.07-56,), TET2 (HR 3.9, P 0.04, CI 1.04-14.1), and FLT3-ITD (HR 4.5, p 0.01, CI 1.7-52). Worse OS was independently associated with persistent TET2 (HR 3.9, p 0.013, CI 1.04-14.1), with a trend towards worse OS for IDH1, FLT3-ITD, with a trend towards worsening OS and RFS for ASXL1 (OS HR 7.4, p 0.06, CI 0.86 -63; RFS HR 4.9, p 0.06, CI 0.9-26) and DNMT3A (OS HR 2.3, p 0.12, CI 0.86-6.9; RFS 2.9, p 0.08, CI 0.98-8). Association with worse clinical outcomes remained significant after multivariate analysis for TET2 (both OS HR 3.98 p 0.041, CI1.07- 32 and RFS HR 5.8, p 0.032, CI 1.1- 29), IDH1 (RFS HR 8.02, p 0.049, CI 1.02 - 65) and FLT3-ITD (RFS HR 11.4, p0.010, CI 2.2- 80). Conclusions: Presence of TP53 mutations was associated with worse OS. Presence of pre-transplant mutation did not impact RFS or OS. Persistent presence of mutations in TET2, IDH1 and FLT3-ITD after Fludarabine/melphalan conditioning regimen allogeneic SCT were associated with shorter RFS and OS (in the case of TET2) independent of CIBMTR DRI. This analysis supports association of adverse outcomes in AML patients with selected persistent mutations by D100 post-transplant in reduced intensity transplant setting. Post-transplant strategies that can further eliminate persistent mutations should be investigated in prospective studies. Figure 1 Figure 1. Disclosures Lee: Pin Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Innate: Consultancy, Membership on an entity's Board of Directors or advisory committees; BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees. Desai: Kura Oncology: Consultancy; Bristol Myers Squibb: Consultancy; Agios: Consultancy; Takeda: Consultancy; Janssen R&D: Research Funding; Astex: Research Funding. Ritchie: Protaganist: Consultancy, Honoraria; Incyte: Consultancy, Honoraria, Speakers Bureau; Celgene/BMS: Consultancy, Other: travel support, Speakers Bureau; Bristol Myers Squibb: Consultancy, Research Funding; ARIAD Pharmaceuticals: Ended employment in the past 24 months, Speakers Bureau; Novartis: Consultancy, Honoraria, Other: travel support, Research Funding, Speakers Bureau; Takeda: Consultancy, Honoraria; Astellas: Consultancy, Research Funding; NS Pharma: Research Funding; Abbvie: Consultancy, Honoraria; Jazz: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding. Roboz: MEI Pharma - IDMC Chair: Consultancy; Daiichi Sankyo: Consultancy; Helsinn: Consultancy; Jazz: Consultancy; Bristol Myers Squibb: Consultancy; Glaxo SmithKline: Consultancy; Novartis: Consultancy; Janssen: Consultancy; Otsuka: Consultancy; Celgene: Consultancy; Mesoblast: Consultancy; Blueprint Medicines: Consultancy; Jasper Therapeutics: Consultancy; AbbVie: Consultancy; Actinium: Consultancy; Agios: Consultancy; Amgen: Consultancy; Astex: Consultancy; Astellas: Consultancy; AstraZeneca: Consultancy; Bayer: Consultancy; Janssen: Research Funding; Pfizer: Consultancy; Roche/Genentech: Consultancy.

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Elotuzumab As Post-Autologous Stem Cell Transplant Consolidation in Patients with High-Risk Myeloma

Blood ◽

10.1182/blood-2019-129504 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 3141-3141 ◽

Cited By ~ 2

Author(s):

Nikhita Gadi ◽

Linda Schmidt ◽

Jaeil Ahn ◽

Tianmin Wu ◽

Scott D. Rowley ◽

...

Keyword(s):

High Risk ◽

Board Of Directors ◽

Research Funding ◽

Stem Cell Transplant ◽

Autologous Stem Cell Transplant ◽

Cell Transplant ◽

Advisory Committees ◽

Ultra High Risk ◽

Equity Ownership ◽

Baseline Characteristics

Introduction: Patients (pts) with high-risk multiple myeloma (HRMM) experience early disease progression post autologous stem cell transplant (ASCT). The median progression free survival (PFS) for HRMM pts undergoing ASCT with lenalidomide (len) maintenance ranges between 27 and 42 months in high risk pts and 22 months in ultra-high risk, defined by two or more adverse cytogenetic abnormalities such as: gain(1q), t(4;14), t(14;16),t(14;20), or del(17p)( Chakraborty et al, Leukemia,2018 and Jackson et al, Lancet, 2018). Elotuzumab, a humanized IgG kappa monoclonal antibody against SLAM-F7 (CS-1), is approved in combination with len and dexamethasone (ERd) in pts with relapsed MM (Dimopoulus et al, BJH, 2017). It directly activates natural killer (NK) cells and mediates myeloma cell death by antibody-dependent cell mediated cytoxicity. We hypothesized that administration of ERd as post-ASCT consolidation will enhance an immune-competent phenotype, by restoring NK cells and effector T-cell populations at a time of maximal disease de-bulking, and will ultimately improve outcomes among pts with HRMM. Methods: Thirty-one HRMM patients who achieved stable disease or better were treated beginning at 30-90 days post ASCT with ERd (29/31 pts) or elotuzumab/pomalidomide )/dex (EPd) (2/31 pts) between September 2016 and February 2019. With institutional review board approval, electronic medical records were reviewed for baseline characteristics, treatment history, adverse events (AE) while on therapy as defined by common terminology criteria for adverse events (CTCAE), and survival outcomes. Treatment with ERd or EPd was administered for 4 consecutive 28-day cycles per standard dosing regimens with a tapering or discontinuation of corticosteroids per investigator discretion with cycles 3 and 4. HRMM was defined by any of the following: ISS or Revised-ISS stage 3, CD-138 selected FISH with del 17p, 1q21 gain, t(4;14), t(14;16), and t(14;20), cytogenetics with 13q del or complex karyotype, and/or high-risk gene expression profile score. Ultra-HR pts were defined by having both del 13q and 1q21 gain by FISH based on recent unpublished COMPASS data. Minimal residual disease (MRD) was evaluated upon achievement of very good partial remission or complete remission using 10-color multiparametric flow cytometry. PFS was measured using the log-rank test. Response criteria was defined per International Myeloma Working Group criteria. Results: Baseline characteristics of all 31 patients are shown in Table 1. Thirty-four percent were ISS-3, 71% (22/31 pts) had high-risk FISH, of which 19% were ultra-high risk (6/22 pts). Seven pts (22.6%) underwent tandem-ASCT pre-consolidation. Of the 8 pts who had GEP testing, 2 (25%) were high risk. Best response to treatment by cycle is depicted in Table 2. Consolidative ERd/EPd deepened response compared to post-ASCT with 71.4% vs 19.4% achieving stringent complete remission (sCR). Post-consolidation, 19.3% vs 12.9%, pre-consolidation, achieved MRD negativity. With a median follow-up of 24.8 months, median PFS was 31.4 months (Figure 1). There was no significant association between median PFS and variables such as tandem ASCT and ultra-HR using multivariate cox regression. Although all pts experienced at least one AE while on therapy, only 1 patient (3.22%) experienced a grade 3 AE. Hematologic AEs included: anemia (48%), neutropenia (45%), and thrombocytopenia (52%), while the most common non-hematologic AEs included: fatigue (32%), malaise (23%), and back pain (19%). One patient experienced a serious AE (SAE) which was PCP pneumonia requiring hospitalization, resulting in early discontinuation from therapy. There was no treatment-related mortality. Conclusion: ERd or EPd as 4 months of fixed duration consolidation therapy post-ASCT resulted in a median PFS of 31.4 months amongst pts with HRMM, similar to or perhaps surpassing historical reports of HRMM pts receiving lenalidomide maintenance until progression. This therapy may offer comparable, if not superior, outcomes while having the advantage of allowing for significant time without therapy and perhaps improving quality of life and financial toxicity. This study is limited due to its retrospective nature. Larger prospective studies evaluating fixed duration ERd/EPd in HRMM patients post ASCT should be conducted. Disclosures Rowley: Allergan: Equity Ownership; Fate Therapeutics: Consultancy. Goldberg:COTA: Equity Ownership; Bristol-Myers Squibb: Consultancy; Cancer Outcomes Tracking and Analysis (COTA) Inc.: Equity Ownership. Siegel:Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Bristol-Myers Squibb Company: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Biran:Bristol Meyers Squibb: Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Merck: Research Funding.

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Phase II Study Of The Combination Of MLN 9708 With Lenalidomide As Maintenance Therapy Post Autologous Stem Cell Transplant In Patients With Multiple Myeloma

Blood ◽

10.1182/blood.v122.21.1983.1983 ◽

2013 ◽

Vol 122 (21) ◽

pp. 1983-1983 ◽

Cited By ~ 1

Author(s):

Jatin J. Shah ◽

Veera Baladandayuthapani ◽

Donna M. Weber ◽

Sheeba K. Thomas ◽

Raymond Alexanian ◽

...

Keyword(s):

Maintenance Therapy ◽

Board Of Directors ◽

Research Funding ◽

Stem Cell Transplant ◽

Phase Ii Study ◽

Autologous Stem Cell Transplant ◽

Cell Transplant ◽

Newly Diagnosed ◽

Time To Progression ◽

Advisory Committees

Abstract Background The role of lenalidomide for maintenance after myeloblative therapy and autologous stem cell transplant (ASCT) has been established based on the CALBG 100104 and IFM 2005-02 experience. Continuous low dose lenalidomide demonstrated a significant benefit in progression free survival (PFS), time to progression (TTP) in both trials and the CALBG trial also demonstrated a benefit in early overall survival. The benefit in PFS with lenalidomide is preserved in patients with high risk cytogenetics and in complete remission after ASCT. Proteaseome inhibitors (PI) have been studied after ASCT in a hybrid consolidation/maintenance model with a predefined course of bortezomib-based therapy, which was well tolerated and led to a significant improvement in response rates and in PFS. However long term proteasome inhibitor maintenance therapy has been limited by the route of administration. The combination of PIs and immunomodulatory agents (IMiDs) have a strong preclinical rationale, and their activity has been confirmed with high response rates in various combinations in both newly diagnosed and relapsed/refractory myeloma. MLN9708, an oral PI, may be more convenient as an oral therapy to be studied in the maintenance setting. Here we report preliminary data from a pilot study of the combination of MLN9708 and lenalidomide as maintenance therapy post ASCT. Methods This is a single arm phase II study with the primary objective to establish the safety and efficacy (PFS) of MLN 9708 (Ixazomib) and lenalidomide in the maintenance setting post ASCT. The secondary objectives were to evaluate the incidence of secondary primary malignancy, the best response rate (sCR/nCR/VGPR/PR), time to progression and time to next therapy. Patients must have undergone ASCT with melphalan as a preparative regimen within 12 months of initiation of induction for newly diagnosed myeloma. Patients started maintenance therapy 60-180 days post ASCT. Treatment consisted of 28 day cycles of oral MLN9708 4 mg on days 1, 8, 15, and oral lenalidomide 10 mg daily on days 1-28 with a dose increase to 15 mg after 3 months if tolerating well. Adverse events (AEs) were graded by NCI-CTCAE v4. Response was assessed by the modified International Uniform Response Criteria. Results A total of 16 patients have been enrolled with a median age of 60 years (range 51-74); 12/16 patients were male. 6 patients had ISS stage 1, 2 patients had stage II, 5 patients had stage III, and 3 had an unknown stage. 14 of the patients remain on trial, 2 patients have discontinued maintenance therapy. 1 patient with high risk disease, including del17p, del 13 discontinued due to rapidly progressive disease during cycle 2; 1 patient discontineud due to hospitalization for bilateral pneumonia. 3 patients had a treatment related SAE including 2 patients with PNA, 1 pt with G2 dehydration requiring hospitalization. 5 patients required a dose reduction in MLN9708 or lenalidomide due to G3/4 thrombocytopenia (n=2); dose delays for thrombocytopenia/neutropenia (n=3); one patient also had concurrent grade 3 rash. Hematologic toxicity included 3/16 patients with G3/4 thrombocytopenia, 9/16 with G1/2 thrombocytopenia, 5/16 patients with G3 neutropenia and 6/16 patients with G1/2 neutropenia. G3/4 drug-related non-hematologic AEs occurring in >1/16 of patients were limited to 2 patients with G3 creatinine elevation (in the setting of hospitalization for pneumonia). Additional non-hematologic G1/2 events included 9/16 patients with nausea, 5/16 with diarrhea, 9/16 with constipation, 4/16 with emesis, 6/16 patients with G1 rash; 1 pt with worsening of baseline G1 neuropathy. Conclusions The combination of MLN9708 and lenalidomide as maintenance therapy post ASCT for NDMM is a well-tolerated combination. 14/16 patients remain on study with only 1 patient discontinuing due to toxicity (pneumonia). The preliminary experience demonstrates the combination is safe, feasible and well tolerated with minimal toxicity and no unexpected toxicity. Disclosures: Shah: Celgene: Consultancy, Research Funding; Array: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Millenium: Consultancy, Research Funding; Onyx: Consultancy, Research Funding. Off Label Use: This abstract describes bortezomib + rituximab as 1st line induction therapy for patients with Waldenstrom macroglobulinemia. Thomas:Millenium: Research Funding; Novartis: Research Funding; Celgene: Research Funding; Immunomedics: Research Funding; Pharmacyclics: Membership on an entity’s Board of Directors or advisory committees; Onyx: Membership on an entity’s Board of Directors or advisory committees. Wang:Onyx: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Millennium: Research Funding; Pharmacyclics: Research Funding; Janssen: Research Funding; Novartis: Research Funding. Qazilbash:Otsuka Pharmaceuticals: Research Funding. Orlowski:Bristol-Myers Squibb: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Celgene: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Millennium: The Takeda Oncology Company: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Onyx: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Resverlogix: Research Funding; Array Biopharma: Honoraria, Membership on an entity’s Board of Directors or advisory committees; Genentech: Honoraria, Membership on an entity’s Board of Directors or advisory committees; Merck: Membership on an entity’s Board of Directors or advisory committees.

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Impact of Wait Times for Autologous Stem Cell Transplantation in Patients with Aggressive Non-Hodgkin Lymphoma, a Subset Analysis of the Canadian Cancer Trials Group (CCTG) LY.12 Clinical Trial

Blood ◽

10.1182/blood.v128.22.690.690 ◽

2016 ◽

Vol 128 (22) ◽

pp. 690-690

Author(s):

Tanya Skamene ◽

Wenyu Jiang ◽

Ralph M. Meyer ◽

Michael Crump ◽

John Kuruvilla ◽

...

Keyword(s):

Clinical Trial ◽

Stem Cell ◽

Board Of Directors ◽

Research Funding ◽

Stem Cell Transplant ◽

Wait Time ◽

Salvage Chemotherapy ◽

Cell Transplant ◽

Advisory Committees ◽

Stem Cell Collection

Abstract Background: High dose chemotherapy followed by autologous stem cell transplant (ASCT) is the standard curative option for patients with relapsed or refractory, chemosensitive, aggressive non-Hodgkin lymphoma (NHL). The optimal timing for ASCT following salvage chemotherapy is not known. Cancer Care Ontario (CCO)-the cancer agency for Ontario, Canada's largest province-treatment guidelines recommend that no more than 91 days should elapse from the first day of salvage chemotherapy to stem cell transplant. We evaluated the impact of time to stem cell transplant in the context of the international CCTG LY.12 phase 3 clinical trial. Methods: Patients with relapsed or refractory (R/R) aggressive NHL were randomly assigned to gemcitabine, cisplatin and dexamethasone (GDP) or dexamethasone, cytarabine, cisplatin (DHAP), with or without rituximab, followed by ASCT [Crump JCO 2014]. Time interval definitions were based on CCO guidelines: Total Wait Time (TWT) as the number of days from the first day of salvage chemotherapy to day of ASCT; Apheresis Wait Time (AWT) as the number of days from the first day of salvage to the first day of stem cell collection; Stem cell transplant Wait Time (SWT) as the number of days from the last day of stem cell collection to the day of ASCT. Patients were considered to have experienced a delay in TWT, AWT or SWT if the time intervals exceeded 91, 70 and 21 days respectively. Overall survival (OS) and event-free survival (EFS) from transplant date were compared between patients who met and exceeded TWT targets using a Cox proportional hazards model. A linear regression model was applied to analyze TWT as a continuous variable. Univariate and multivariate analyses were performed to estimate the adjusted hazard ratio (HR) for TWT for the following co-variables: age ≤60, performance status 0/1, disease stage (I/II), presence of ≤1 extranodal sites, and response after cycle 2 (complete response, CR; complete response, unconfirmed, CRu; partial response, PR). Results: Of 619 patients enrolled on LY.12, 307 (47%) had sufficient response to salvage chemotherapy and adequate stem cell collection to complete ASCT on protocol. Among these, median age was 54.6 years, 64% were male and 94% had a performance status of 0 or 1. International Prognostic Index (IPI) score at relapse was 0-1 in 45%, 2 in 31% and ≥3 in 24%. The majority of patients had poor risk disease at study entry; 58% had a best response of stable disease (SD) or progressive disease (PD) to primary therapy, or initial duration of response < 1 year. Following up to 2 cycles of salvage chemotherapy, 75/307 (24%) achieved CR/CRu, 142/307 (46%) achieved PR, 89/307 (29%) had SD. One patient had missing data. The median TWT for the total transplanted population was 91 days (range 50-217). Median AWT and SWT were 63 (range 0-151) and 26 (range 6-146) days, respectively. Fifty percent of patients exceeded TWT target of 91 days; 32% and 57% of patients exceeded AWT and SWT targets. There was no difference in median OS (HR 0.96, 95% CI 0.66-1.39, p=0.81) or EFS (HR 1.13, 95% CI 0.82-1.55, p=0.46) between patients who exceeded and met TWT targets. The 4-year OS for patients who met and exceeded TWT was 62% and 64%, respectively. The 4-year EFS for patients who met and exceeded TWT was 43% and 50%, respectively. When analyzed as a continuous variable, TWT did not affect OS (HR 0.99) or EFS (HR 0.99). Comparison of the quartiles with shortest and longest TWT demonstrated HR 0.72 (95% CI 0.42-1.26, p=0.25) for overall survival and 0.69 (95% CI 0.44-1.09, p=0.11) for EFS. Comparison of the 10th and 90th percentiles for TWT demonstrated HR 0.67 (95% CI 0.28-1.59, p=0.36) for overall survival and 0.71 (95% CI 0.35-1.44, p=0.34) for EFS. Only the presence of ≤1 extranodal sites of disease was found to be predictive of OS in the transplanted population on univariate and multivariate analysis (adjusted HR 0.51, p=0.005). The median TWT was longer for the 31 patients transplanted at Italian centers, compared to 266 transplanted at Canadian centers (median TWT 90 vs. 118 days, t < 0.0001). Conclusion: In this exploratory analysis, limited to patients who completed transplant on the LY.12 clinical trial, we did not find evidence that those meeting current CCO ASCT wait time targets had superior outcomes compared with those who did not. Table. Table. Figure 1. Figure 1. Figure 2. Figure 2. Disclosures Kuruvilla: BMS: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Amgen: Honoraria; Abbvie: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; Merck: Honoraria; Roche Canada: Consultancy, Honoraria, Research Funding; Seattle Genetics: Consultancy, Honoraria; Lundbeck: Honoraria. Luminari:Roche: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accomodations, Expenses; Takeda: Other: Travel, Accomodations, Expenses; Teva Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria. Hay:Amgen: Research Funding; Novartis: Research Funding; Janssen: Research Funding; Kite Pharmaceuticals: Research Funding.

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Comparative Analysis of Immune Reconstitution in HIV-Positive Recipients of Allogeneic and Autologous Stem Cell Transplant on the BMT CTN 0903/AMC-080 and BMT CTN 0803/AMC-071 Trials

Blood ◽

10.1182/blood-2019-129488 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 4525-4525

Author(s):

Polina Shindiapina ◽

Maciej Pietrzak ◽

Michal Seweryn ◽

Eric McLaughlin ◽

Xiaoli Zhang ◽

...

Keyword(s):

T Cells ◽

Stem Cell ◽

Board Of Directors ◽

Research Funding ◽

Stem Cell Transplant ◽

Immune Cell ◽

Cell Transplant ◽

Advisory Committees ◽

Time Points ◽

The Difference

Introduction. Our previous flow cytometry-based comparison of HIV(+) and HIV(-) autologous hematopoietic stem cell transplant (auto-HSCT) recipient immunomes at 56, 180 and 365 days post-transplant to each other and to healthy controls (HCs) showed that both sets of auto-HSCT recipient immunomes approached HCs over time, but retained significant differences. HIV(+), but not HIV(-), auto-AHCT recipients retained pro-inflammatory features consistent with chronic HIV infection. Here, we report the results of a quantitative and functional analysis of immune reconstitution in HIV(+) patients treated with allogeneic hematopoietic stem cell transplant (allo-HSCT), in comparison with HIV(+) auto-HSCT recipients and HCs. Methods. Blood samples were collected for analysis at days 56, 180 and 365 post-transplant from HIV(+) transplant recipients and at 1 time point from HCs. Whole blood analysis was performed by five-color flow cytometry across 100 immune marker combinations. Comparisons were made between HIV(+) allo-HSCT recipients (n=17, acute myeloid leukemia, acute lymphocytic leukemia, myelodysplastic syndrome, Hodgkin and non-Hodgkin lymphoma that received myeloablative or reduced intensity conditioning on the BMT-CTN-0903/AMC-080 trial), HIV(+) auto-HSCT recipients (n=36, aggressive B cell non-Hodgkin lymphoma or Hodgkin lymphoma that received myeloablative conditioning on the BMT-CTN-0803/AMC-071 trial) and 71 HCs. Unsupervised principal component analysis (PCA) examined differences in immune cell proportions, identified by flow cytometry across 100 cell subsets at each time point. Wilcoxon rank-sum tests compared median absolute counts and median proportions of cell subsets. An independent feature importance score analysis (FIS) identified contributions of immune cell populations expressing specific immune marker combinations to the differences between HIV(+) auto-HSCT recipients, HIV(+) allo-HSCT recipients and HCs. Functional responsiveness of HIV(+) allo-HSCT recipients' T cells to stimulation with CD3- and CD28-directed antibodies, NK cells to stimulation with IL-12 and IL-18 and monocytes to stimulation with lipopolysaccharide (LPS) was assessed in a preliminary mass cytometry on peripheral blood mononuclear cells isolated at the same time points (n=2) and compared to HCs (n=2). Results. PCA showed that immunomes of HIV(+) allo-HSCT recipients and HIV(+) auto-HSCT recipients clustered together with each other, but away from HCs at all time points throughout the post-transplant year. FIS identified: 1) 13 cell subsets that defined the difference between HIV(+) allo-HSCT recipients (all visits) and HCs, and 2) 11 immune cell subsets that defined the difference between HIV(+) auto-HSCT recipients (all visits) and HCs; in both of these comparisons, activated CD3+/HLA-DR+ T cells had the greatest impact on the difference between HIV(+) and HC immunomes. At 1 year, both HIV(+) transplant recipient cohorts had higher absolute numbers of activated T cells, effector T cells and CD8+ T cells than HCs (Wilcoxon rank-sum test, p<0.0031). HIV(+) autologous and allogeneic HSCT recipients also had lower numbers of CD4+ T cells, naïve T cells and activated NK cells compared to HCs (p<0.0031). FIS also identified 20 immune cell subsets that defined the difference between HIV(+) autologous and allogeneic HSCT recipients immunomes at 1 year, with CD8+/CD27- effector T cell subset exerting the highest impact on the difference. Preliminary functional mass cytometry analysis of 2 HIV(+) allo-HSCT recipients and 2 HCs showed that: 1) IFNʏ production by CD8+ T cells was increased above that of HCs at all time points. 2) Expanded populations of CD4+/T-bet+ cytotoxic cells expressing granzyme B and perforin, and CD8+ cytotoxic T cells expressing granzyme B and perforin, persisted in HIV(+) allo-HSCT recipients at all time points, but not in HCs. 3) NK cells retained an ability to produce IFNʏ in response to stimulation with IL-12 and IL-18 in HIV(+) allo-SCT recipients. 4) Monocytes showed an enhanced production of TNFα in response to stimulation with LPS in HIV(+) allo-HSCT recipients compared to HCs at 1 year post-HSCT. Conclusion. Chronic HIV infection confers the pro-inflammatory immune features on the phenotypic and functional profiling of the T lymphocyte immunome of stem cell transplant recipients, irrespective of allogeneic or autologous stem cell donor source. Disclosures Devine: Bristol Myers: Other: Grant for monitoring support & travel support; Kiadis Pharma: Other: Protocol development (via institution); Magenta Therapeutics: Other: Travel support for advisory board; My employer (National Marrow Donor Program) has equity interest in Magenta. Noy:Janssen: Consultancy; Medscape: Honoraria; Prime Oncology: Honoraria; NIH: Research Funding; Pharamcyclics: Research Funding; Raphael Pharma: Research Funding. Popat:Bayer: Research Funding; Incyte: Research Funding; Jazz: Consultancy. Hofmeister:Celgene: Honoraria; Janssen: Membership on an entity's Board of Directors or advisory committees; Nektar: Honoraria, Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Imbrium: Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Membership on an entity's Board of Directors or advisory committees. Navarro:Atara Biotherapeutics: Employment, Equity Ownership. Behbehani:Fluidigm corporation: Other: Travel funding. Lozanski:Boehringer Ingelheim: Research Funding; Beckman Coulter: Research Funding; Stemline Therapeutics Inc.: Research Funding; Genentec: Research Funding. Baiocchi:Prelude: Consultancy.

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Impact of Novel Agents on the Outcomes of Patients with Classic Hodgkin Lymphoma That Relapsed after Autologous Stem Cell Transplant

Blood ◽

10.1182/blood-2021-154038 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 1373-1373

Author(s):

Aung M Tun ◽

Yucai Wang ◽

Aasiya Matin ◽

David J. Inwards ◽

Patrick B. Johnston ◽

...

Keyword(s):

Stem Cell ◽

Board Of Directors ◽

Research Funding ◽

Stem Cell Transplant ◽

Advisory Board ◽

Novel Agents ◽

Survival Outcomes ◽

Cell Transplant ◽

Advisory Committees ◽

Scientific Advisory

Abstract Introduction: Novel therapeutic agents such as immune checkpoint inhibitor (ICI) and brentuximab vedotin (BV) are active in classic Hodgkin lymphoma (cHL), including in patients that relapse after autologous stem cell transplant (ASCT). However, optimal management strategy is unclear for patients with relapsed or refractory (RR) cHL post-ASCT. The aim of the study is to determine the impact of novel agents relative to conventional therapy and allogeneic stem cell transplant (allo-SCT) on survival outcomes of patients with cHL who relapsed after ASCT. Methods: Patients with RR cHL who underwent ASCT between 06/1993 and 10/2017 at 3 Mayo Clinic sites were included. Clinical characteristics, treatment information, and outcome data were abstracted. For patients who relapsed after ASCT, the post-relapse progression free survival (PFS) and overall survival (OS) were analyzed using the Kaplan-Meier method and Cox proportional hazards models. Statistical analyses were done in JMP v15.2.1 and EZR v1.54. Results: A total of 332 patients with RR cHL who underwent salvage therapy and ASCT were identified. After a median post-ASCT follow-up of 8.6 years (range 6.8-9.7), 136 (41%) patients had a relapse or disease progression after ASCT. Patient characteristics of the 136 cases are summarized in the Table. The median age at post-ASCT relapse was 34 years (range 20-73), and 77 (57%) were male. 59 (43%) relapsed within 6 months and 77 (57%) relapsed after 6 months following ASCT. 59 (45%) had an extranodal site involvement at relapse. 14 (10%) had therapy with ICI or BV as salvage therapy prior to ASCT or maintenance therapy post-ASCT. The median post-relapse PFS and OS was 0.8 (95% CI 0.6-1.1) and 3.2 years (95% CI 2.2-5.5) years, respectively. Compared to patients who relapse after 6 months, patients who relapsed within 6 months of ASCT had worse post-relapse PFS (median 0.5 [0.3-0.7] vs 1.3 [0.9-1.9] years, p=0.0003) and OS (median 1.3 [0.5-2.2] vs 6.4 [3.7-10.4] years, p=0.0003). Extranodal site involvement at relapse was not associated with post-relapse PFS (median 0.7 [0.5-1.2] vs 0.9 [0.6-1.3] years, p=0.28) but was associated with worse post-relapse OS (median 2.7 [1.5-4.2] vs 6.4 [2.6-NA] years, p=0.006). Prior therapy with ICI or BV was not associated with post-relapse PFS (median 0.6 [0.3-NA] vs 0.8 [0.6-1.1] year, p=0.8) and OS (median NR [1.0-NA] vs 3.2 [2.2-5.5] years, p=0.5). After post-ASCT relapse, the median lines of subsequent therapy were 2 (range 1-12). For first post-ASCT salvage therapy, novel agents (ICI or BV), compared to other therapies, were associated with superior post-relapse PFS (median 1.7 [0.7-3.6] vs 0.7 [0.5-1.0] years, p=0.004) and OS (median 7.6 [4.7-NA] vs 3.2 [2.2-5.6], p=0.02). Allo-SCT following first post-ASCT relapse (n=9) was not associated with improvement in post-relapse PFS (median 2.2 years [0.3-NA] vs 0.8 [0.6-1.1] years, p=0.1) or OS (median NR [0.5-NA] vs 5.1 [3.2-7.3] years, p=0.7). Patients who received ICI or BV at any point post-ASCT relapse had significantly better post-relapse OS (median 7.6 [4.3-16.7] vs 2.2 [1.4-3.7] years, p=0.004) compared to those who never received any novel agent (Figure 1A). In contrast, allo-SCT at any point post-ASCT relapse (n=27) did not improve post-relapse OS (median 5.6 [2.7-NA] vs 4.7 [2.7-7.3] years, p=0.3) (Figure 1B). In multivariate Cox regression models adjusted for age and sex, exposure to ICI and/or BV was associated with superior post-relapse OS (HR 0.5, 95% CI 0.3-0.8, p=0.007); however, allo-SCT was not associated with improvement in post-relapse OS (HR 0.8, 95% CI 0.4-1.5, p=0.5). Conclusions: Patients relapsing within 6 months of ASCT and those with extranodal involvement at relapse had inferior OS after post-ASCT relapse. Prior therapy with novel agents did not impact post-relapse survival outcomes. In the setting of post-ASCT relapse, novel therapeutic agents significantly improved survival outcomes while allo-SCT did not. Future multicenter studies are needed to explore the role of novel agents and allo-SCT in patients with RR cHL post-ASCT relapse. Figure 1 Figure 1. Disclosures Wang: Eli Lilly: Membership on an entity's Board of Directors or advisory committees; InnoCare: Research Funding; MorphoSys: Research Funding; Genentech: Research Funding; Novartis: Research Funding; LOXO Oncology: Membership on an entity's Board of Directors or advisory committees, Research Funding; Incyte: Membership on an entity's Board of Directors or advisory committees, Research Funding; TG Therapeutics: Membership on an entity's Board of Directors or advisory committees. Paludo: Karyopharm: Research Funding. Tun: Gossamer Bio, Acrotech: Consultancy; Mundipharma, Celgene, BMS, Acrotech, TG therapeutics, Curis, DTRM: Research Funding. Cerhan: Regeneron Genetics Center: Other: Research Collaboration; Genentech: Research Funding; Celgene/BMS: Other: Connect Lymphoma Scientific Steering Committee, Research Funding; NanoString: Research Funding. Habermann: Tess Therapeutics: Other: Data Monitoring Committee; Morphosys: Other: Scientific Advisory Board; Incyte: Other: Scientific Advisory Board; Seagen: Other: Data Monitoring Committee; Loxo Oncology: Other: Scientific Advisory Board; Eli Lilly & Co.,: Other: Scientific Advisor. Witzig: Karyopharm Therapeutics, Celgene/BMS, Incyte, Epizyme: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene/BMS, Acerta Pharma, Kura Oncology, Acrotech Biopharma, Karyopharm Therapeutics: Research Funding. Nowakowski: Celgene, MorphoSys, Genentech, Selvita, Debiopharm Group, Kite/Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene, NanoString Technologies, MorphoSys: Research Funding. Ansell: Bristol Myers Squibb, ADC Therapeutics, Seattle Genetics, Regeneron, Affimed, AI Therapeutics, Pfizer, Trillium and Takeda: Research Funding.

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Prognostic Impact of CD3 Count in Apheresis Collection in Multiple Myeloma Patients Undergoing Autologous Stem Cell Transplant

Blood ◽

10.1182/blood-2021-151439 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 3774-3774

Author(s):

Marcella Kaddoura ◽

Morie A. Gertz ◽

David Dingli ◽

Francis K. Buadi ◽

Martha Q. Lacy ◽

...

Keyword(s):

Stem Cell ◽

Board Of Directors ◽

Research Funding ◽

Stem Cell Transplant ◽

Autologous Stem Cell Transplant ◽

Prognostic Impact ◽

Cell Transplant ◽

Immune Competence ◽

Advisory Committees ◽

Stem Cell Collection

Abstract Background: The use of immunotherapeutic agents in multiple myeloma (MM) has shown improvements in clinical outcomes, emphasizing the role the host immune system plays in disease control. In recognition of this relationship, efforts aimed at identifying biomarkers of immune surveillance in MM have identified prognostic value in the peripheral absolute lymphocyte (ALC) and absolute monocyte (AMC) counts at various stages of disease and following autologous stem cell transplant (ASCT), with lower ALC and AMC serving as a surrogate for immune dysregulation and correlating with inferior progression free (PFS) and overall survival (OS). With ASCT remaining the standard of care in the treatment of MM, we sought to examine whether CD3 content of the apheresis product during stem cell collection could be used as a biomarker for immune competence and whether it influences outcomes. Methods: A retrospective study was conducted on 1086 MM patients who underwent stem cell (CD34) collection with available CD3 data and subsequent ASCT at our institution. We recorded the total absolute CD3 and CD34 cell count upon completion of mobilization, with a higher CD3 count serving as a surrogate for immune competence. In addition to investigating the absolute CD3 count, we calculated the CD3/CD34 ratio given variation in the CD34 goals. Patients were dichotomized based on whether their absolute CD3 and CD3/CD34 ratio values were above or below medians. A Kaplan-Meier model was used to compare median PFS and OS between groups. A cox proportional hazards model was used to determine its prognostic impact, adjusting for ISS stage 3, high risk FISH, achievement of CR near day 100, and maintenance therapy received post-ASCT. Results: The median length of follow-up from date of ASCT for the entire cohort (N=1086) was 34.1 months (range: 0.26-157 months) and the median time from stem cell collection to ASCT was 9 days (range: 3-3143 days). The most common mobilizing regimen was Neupogen and plerixafor (N=425, 39%) and 694 (64%) patients received ASCT in the first line setting. The median absolute total CD3 count was 4.3 x 10^6/kg (range: 0.1-21.9) with 542 patients above and 544 patients at or below the median. The median absolute total CD34 count was 8.53 x 10^6/kg (range: 0.2-37.0) and median CD3/CD34 ratio was 0.50 (range: 0.01-15), with 536 patients above and 550 patients at or below the median ratio. The median PFS among patients with a CD3 count > 4.25 x 10^6/kg was 23.1 vs. 16.9 months among patients with CD3 count ≤ 4.25 x 10^6/kg (p<0.0001) and median OS was 65.3 months vs. 41.6 months (p<0.0001), respectively. A similar trend was observed when dividing patients based on CD3/CD34 ratio, with median PFS of 22.4 vs. 17.5 months (p=.0003) and median OS of 61.5 vs. 45.7 months (p=.0001), both favoring the cohort with a CD3/CD34 ratio > 0.5 (Figure 1). The prognostic value among patients with a CD3/CD34 ratio > 0.5 was retained after adjusting for ISS stage III, high risk FISH features, and use of maintenance therapy as follows: PFS HR: 0.73 (95% CI: 0.62-0.86; p=0.0002); OS 0.71 (95% CI: 0.59-0.88; p=0.001). Conclusions: Our study demonstrates that patients who have higher CD3 content in their apheresis product have better PFS and OS following ASCT. These findings reveal a possible role for using absolute CD3 and CD3/CD34 ratios in the apheresis product as a surrogate marker for immune competence and in predicting clinical outcomes. Figure 1 Figure 1. Disclosures Gertz: Akcea Therapeutics, Alnylam Pharmaceuticals Inc, Prothena: Consultancy; Akcea Therapeutics, Ambry Genetics, Amgen Inc, Celgene Corporation, Janssen Biotech Inc, Karyopharm Therapeutics, Pfizer Inc (to Institution), Sanofi Genzyme: Honoraria; Aurora Biopharma: Other: Stock option; AbbVie Inc, Celgene Corporation: Other: Data Safetly & Monitoring; Ionis Pharmaceuticals: Other: Advisory Board. Dingli: GSK: Consultancy; Sanofi: Consultancy; Janssen: Consultancy; Alexion: Consultancy; Apellis: Consultancy; Novartis: Research Funding. Dispenzieri: Takeda: Research Funding; Pfizer: Research Funding; Alnylam: Research Funding; Oncopeptides: Consultancy; Sorrento Therapeutics: Consultancy; Janssen: Consultancy, Research Funding. Kapoor: Sanofi: Research Funding; Takeda: Research Funding; Ichnos Sciences: Research Funding; Glaxo SmithKline: Research Funding; Regeneron Pharmaceuticals: Research Funding; AbbVie: Research Funding; Karyopharm: Research Funding; Karyopharm: Consultancy; Cellectar: Consultancy; BeiGene: Consultancy; Pharmacyclics: Consultancy; Sanofi: Consultancy; Amgen: Research Funding. Kumar: Novartis: Research Funding; KITE: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Antengene: Consultancy, Honoraria; Tenebio: Research Funding; Amgen: Consultancy, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bluebird Bio: Consultancy; BMS: Consultancy, Research Funding; Oncopeptides: Consultancy; Carsgen: Research Funding; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche-Genentech: Consultancy, Research Funding; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: Research Funding; Astra-Zeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Beigene: Consultancy; Adaptive: Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: Research Funding.

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Efficacy of Panobinostat in Phase II Study in Patients with Relapsed/Refractory Hodgkin Lymphoma (HL) After High-Dose Chemotherapy with Autologous Stem Cell Transplant.

Blood ◽

10.1182/blood.v114.22.923.923 ◽

2009 ◽

Vol 114 (22) ◽

pp. 923-923 ◽

Cited By ~ 9

Author(s):

Anas Younes ◽

Tee-Chuan Ong ◽

Vincent Ribrag ◽

Andreas Engert ◽

Dina Ben-Yehuda ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Stem Cell Transplant ◽

High Dose Chemotherapy ◽

Tumor Burden ◽

Clinical Activity ◽

High Dose ◽

Cell Transplant ◽

Advisory Committees ◽

Dose Delay

Abstract Abstract 923 Introduction: Panobinostat (LBH589) is a pan-deacetylase inhibitor (pan-DACi), targeting epigenetic and non-epigenetic oncogenic pathways. In vitro, panobinostat decreases proliferation and induces apoptosis in Hodgkin lymphoma (HL) cell lines at low nanomolar concentrations. Encouraging clinical activity (objective response rate ∼40%) has been demonstrated in patients with HL who are enrolled in an ongoing Phase I study in hematologic malignancies (DeAngelo et al. EHA 2009, Abstract #1064). Methods: Utilizing a Simon two-stage design, the study will determine the efficacy of panobinostat in patients with HL with refractory/relapsed disease following high-dose chemotherapy and autologous hematopoietic stem cell transplant (AHSCT). Oral panobinostat is administered at a dose of 40 mg three times per week, every week in 21-day cycles. Treatment is continued until disease progression or intolerance. Dose delay and modification for toxicity is allowed. CT/MRI scans are conducted after every 2 cycles. Modified Cheson criteria are used to determine overall response. Results: As of July 10, 2009, 61 patients have been enrolled and treated: median age 31 years [range 18–70]; 29 male, 32 female; 48% Stage III/IV at initial diagnosis; 41% had ≥5 prior lines of therapy; median number of prior regimens is 4 (range 2–6). Of 61 patients, 53 have completed ≥2 cycles of therapy and have had ≥1 post baseline CT/MRI. Responses include one complete response (CR) and 10 partial responses (PR), with up to 92% decrease in tumor burden. Thirty-one patients had SD, of which 25 had reduction in tumor burden (up to 48%). The disease control rate (CR+PR+SD) is 79%. The CR was achieved after 4 cycles of therapy. The patient required dose reduction but continues on the study (>12 cycles) and has maintained CR with no signs of active disease on CT and PET. Another responder with mixed cellularity HL was refractory to prior systemic treatments but has maintained PR on panobinostat and continues on the study (>14 cycles). Median treatment duration is 89+ days (range 5–300+ days), and 27 of the 61 treated patients still continue on study. Common Grade 3/4 adverse events, which were suspected to be related, are thrombocytopenia (77%), anemia (20%), and neutropenia (16%). Thrombocytopenia was observed to be reversible with platelet recovery 7–8 days after drug hold (panobinostat T1/2 ∼16 hours). Conclusion: Panobinostat has demonstrated encouraging clinical activity in heavily pretreated patients with post-transplant, refractory/relapsed, classical HL. Panobinostat is generally well tolerated with reversible thrombocytopenia as the primary toxicity managed by dose delay/reduction. Stage 1 has been successfully completed with positive results. Enrollment to Stage 2 continues. Updated efficacy and safety data will be presented at the meeting. Disclosures: Younes: Novartis: Honoraria. Off Label Use: The data presented is related to investigational unapproved drug.. Ribrag:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; servier: Consultancy, Research Funding; celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; LFB: Honoraria, Research Funding; J&J: Membership on an entity's Board of Directors or advisory committees; Biogene Idec: Membership on an entity's Board of Directors or advisory committees. McCabe:Novartis: Employment. Shen:Novartis: Employment. Le Corre:Novartis: Employment. Hirawat:Novartis: Employment. Sureda:Novartis: Consultancy, Honoraria.

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