Efficacy and Long-Term Outcomes of Autologous Stem Cell Transplant (ASCT) for Patients with POEMS Syndrome (Polyneuropathy, Organomegaly, Endocrinopathy, Monoclonal Protein, Skin Changes): A CIBMTR Analysis

Abstract Introduction POEMS syndrome is a rare disease associated with a plasma cell dyscrasia with limited information regarding the role of ASCT. Small single institution series have demonstrated deep and durable responses after ASCT along with neurological improvement. Despite these benefits, ASCT is thought to have higher treatment related morbidity and mortality, limiting its use. We describe the outcomes from an international multicenter database of patients with POEMS syndrome undergoing ASCT. Methods We performed a retrospective analysis using the Center for International Blood and Marrow Transplant Research (CIBMTR) database to evaluate the outcomes of patients undergoing ASCT for POEMS syndrome. Standard descriptive methods were used to report patient characteristics. Univariate and multivariate analysis were performed to identify predicators for non-relapse mortality (NRM), relapse, progression-free and overall survival (PFS, OS). NRM was compared between POEMS and multiple myeloma (MM) patients who underwent ASCT during the same time period. Results Between 2008-2018, 331 pts with POEMS syndrome who underwent ASCT were identified. The median age was 51 years, with 66% males. Racial distribution was 65% Caucasians, 19% African American, 5% other, and 10% missing. Pre-transplant characteristics included 70% patients had Karnofsky score <90, and 50% had HCT-CI ≥ 3, reflecting underlying disease severity and symptoms. The most common comorbidity was pulmonary (52%). Only 14% of patients were in very good partial response or better at the time of ASCT and 72 (22%) patients underwent ASCT without prior treatment. The median time from diagnosis to ASCT was 7 months and 74% underwent ASCT within 12 months of diagnosis. The most common mobilization strategy was GCSF +/- plerixafor in 50% of pts and 87% of pts received conditioning with 200mg/m2 of Melphalan. The median follow up was 48 (range 3-137) months. At day 100, NRM was 0.9 % (95% CI: 0.2-2.2%). At 4 years, NRM was 4.9% (95% CI: 2.6-7.9%), relapse 15.4% (95% CI 11.3-20.1%), PFS 79.7% (95% CI 74.5-84.3%) and OS 92% (95% CI 89.2-95.6%). Subsequent neoplasms were seen in 16 (5%) with 4 myeloid malignancy and 12 solid tumors. On multivariate analysis, age ≥ 60 years was associated with greater hazards of mortality, HR 2.6 (95% CI 1.2-5.6), p 0.01. The figure shows the comparable NRM between POEMS and MM (p 0.31). Conclusions: We report outcomes of the largest ASCT series of POEMS patients. Despite a high HCT-CI and low functional status among patients with POEMS syndrome, no difference in NRM was seen when compared to MM. Post-transplant outcomes were excellent and support single center data on the role of ASCT in this rare disease. Figure 1 Figure 1. Disclosures Kansagra: Oncopeptides: Membership on an entity's Board of Directors or advisory committees; 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; BMS: Membership on an entity's Board of Directors or advisory committees; Alynylam: Membership on an entity's Board of Directors or advisory committees; Cota Health: Membership on an entity's Board of Directors or advisory committees; GSK: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees. Dispenzieri: Alnylam: Research Funding; Pfizer: Research Funding; Sorrento Therapeutics: Consultancy; Takeda: Research Funding; Oncopeptides: Consultancy; Janssen: Consultancy, Research Funding. Kumar: Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: Research Funding; BMS: Consultancy, Research Funding; Oncopeptides: Consultancy; Beigene: Consultancy; KITE: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche-Genentech: Consultancy, Research Funding; Astra-Zeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Antengene: Consultancy, Honoraria; Novartis: Research Funding; Bluebird Bio: Consultancy; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Research Funding; Carsgen: Research Funding; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Tenebio: Research Funding; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Adaptive: Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: Research Funding. Qazilbash: Bristol-Myers Squibb: Other: Advisory Board; NexImmune: Research Funding; Janssen: Research Funding; Biolline: Research Funding; Oncopeptides: Other: Advisory Board; Angiocrine: Research Funding; Amgen: Research Funding. Shah: GSK: Consultancy; Karyopharm: Consultancy; Oncopeptides: Consultancy; Indapta Therapeutics: Consultancy; Janssen: Research Funding; Nektar: Research Funding; Bluebird Bio: Research Funding; Teneobio: Research Funding; CareDx: Consultancy; BMS/Celgene: Research Funding; Sanofi: Consultancy; Sutro Biopharma: Research Funding; CSL Behring: Consultancy; Poseida: Research Funding; Precision Biosciences: Research Funding; Amgen: Consultancy; Kite: Consultancy. D'Souza: Sanofi, Takeda, Teneobio, CAELUM, Prothena: Research Funding; Imbrium, Pfizer, BMS: Membership on an entity's Board of Directors or advisory committees; Janssen, Prothena: Consultancy.

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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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Do Not Miss Karyotyping at Chronic Myeloid Leukemia Diagnosis: An Italian Campus CML Study on the Role of Complex Variant Translocations

Blood ◽

10.1182/blood-2020-139826 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 43-44

Author(s):

Massimiliano Bonifacio ◽

Chiara Elena ◽

Mariella D'Adda ◽

Luigi Scaffidi ◽

Mairi Pucci ◽

...

Keyword(s):

Board Of Directors ◽

Myeloid Leukemia ◽

Research Funding ◽

Advisory Board ◽

Newly Diagnosed ◽

Advisory Committees ◽

Optimal Response ◽

Frontline Treatment ◽

Tki Treatment

Background. The Philadelphia (Ph) chromosome (chr.) is the hallmark of chronic myeloid leukemia (CML) and typically results from the reciprocal translocation t(9;22)(q34;11.2). Complex variant translocations (CVT) involving one or more additional chr. are identified in less than 5% of newly diagnosed CML. There are conflicting reports about the prognostic impact of CVT in the achievement of optimal response to tyrosine kinase inhibitor (TKI), and very few studies addressed the role of frontline treatment with imatinib or second generation (2G)-TKI in patients with CVT. Aims. To assess the response to imatinib or 2G-TKI in a large cohort of newly diagnosed CML with CVT, and to explore the impact of the different chr. translocations on outcome. Methods. This observational retrospective study was conducted in 19 hematologic centers in the framework of Campus CML, a network of Italian physicians involved in the management of CML patients. All newly diagnosed CML from 2000 to 2019 were evaluated and patients with CVT were selected for the present analysis. Karyotypes were defined according to the 2016 International System for Human Cytogenetic Nomenclature. Responses to frontline treatment were retrospectively categorized according to the 2013 ELN recommendations, as they include cytogenetic milestones. Deep molecular response (DMR, i.e. MR4or better) was defined as BCR-ABLIS ratio ≤0.01% or undetectable disease with ≥10,000 ABL copies. Patients with DMR lasting ≥2 years and at least a Q-PCR test every 6 months were defined as stable DMR responders. Failure-free survival (FFS) was calculated from the start of frontline TKI treatment to progression to advanced phase, death, or switch to other treatments for resistance. For FFS calculation, patients were censored at TKI stop for treatment-free remission (TFR) or in case of switch for intolerance only. Differences between subgroups according to the partner chr. were presented for descriptive purposes. Results. CVT were identified in 109 (3.2%) patients from a whole population of 3,361 subjects with newly diagnosed CML. Ninety-five out of 109 patients (87%) exhibited three-way translocations, with chr. 1, 4, 6, 10, 11, 12, 14, 15 and 17 representing the most common additional partners (figure). Four- and five-way translocations were identified in 13 and 1 patients, respectively. Additional chr. abnormalities (ACA) in the Ph+ cells were observed in 15/109 (13.8%) patients and were more common in older individuals (p=0.018). Overall, median age at diagnosis was 50.6 years (range 20-90). Risk distribution according to the ELTS score was 54%, 28% and 8% for L, I and H risk, respectively (10% missing). Cytogenetic result was available before the choice of frontline treatment in 45% of cases and represented a decisive factor in 28% of them (i.e. clinicians selected a 2G-TKI or high-dose imatinib, according to the available options). Frontline TKI treatment was imatinib in 80 cases (73%) and 2G-TKI (nilotinib n=22, dasatinib n=6, bosutinib n=1) in the remaining cases. The frequency of optimal response at 3, 6 and 12 months was 48%, 45% and 53%, respectively, for imatinib-treated patients, and 76%, 83% and 76%, respectively, for the 2G-TKI cohort (p<0.05 for all comparisons). Stable DMR was achieved by 39% of patients and 42% of them attempted a TFR. After a median follow-up of 91.3 months (range 1-236), 5-year FFS was 66% (95%CI: 53.4-76.4) and 84% (95%CI: 62.4-93.6) for imatinib and 2G-TKI treated patients, respectively (p=ns). The estimated 10-year OS for the entire cohort was 84.4% (95%CI: 73.6-91). The subtype of CVT had an impact on response and long-term outcome. Patients with CVT involving chr. 1, 4, 6, 11 or 12 had a higher frequency of MMR at 12 months than patients with CVT involving chr. 10, 14, 15 or 17 (75.8% vs 30.4%, respectively, p=0.001), higher frequency of stable DMR (48.7% vs 22.2%, respectively; p=0.04) and tended to have better median FFS (p=0.07), regardless of the type of frontline TKI and of the ELTS score. Conclusions. Due to its retrospective nature, this study does not allow to define which is the optimal therapy for CML harboring CVT at diagnosis. However, our data reinforce the usefulness of bone marrow karyotyping in CML. The observed differences between partner chr. may also depend on the breaking points, which are variable. Further dissection of CVT will help to identify which are associated to a poor response to TKIs. Figure Disclosures D'Adda: Incyte: Other: Advisory board; Novartis: Other: Advisory board; Pfizer: Other: Advisory board. Galimberti:Novartis: Speakers Bureau; Incyte: Honoraria. Crugnola:Celgene: Honoraria; Janssen: Honoraria; BMS: Honoraria; Novartis: Honoraria. Bocchia:Incyte: Honoraria; CELGENE: Honoraria. Krampera:Janssen: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees. Breccia:Incyte: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Abbvie: Consultancy; Bristol-Myers Squibb/Celgene: Consultancy, Honoraria; Novartis: Consultancy, Honoraria. Saglio:Novartis: Research Funding; Ariad: Research Funding; Pfizer: Research Funding; Bristol-Myers Squibb: Research Funding; Incyte: Research Funding; Roche: Research Funding.

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High-Dose Chemotherapy (HDC) with Autologous Stem-Cell Transplant (ASCT) with Consolidative Radiation Therapy (RT) for Relapsed or Refractory (R/R) Primary Mediastinal B-Cell Lymphoma (PMBCL): 20-Year Experience at MD Anderson Cancer Center (MDACC)

Blood ◽

10.1182/blood-2020-134471 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 32-33

Author(s):

Neeraj Saini ◽

Junsheng Ma ◽

Melissa Timmons ◽

Amin M. Alousi ◽

Paolo Anderlini ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

B Cell Lymphoma ◽

Advisory Board ◽

Older Age ◽

Long Term Results ◽

Cell Transplant ◽

Research Support ◽

Advisory Committees ◽

Grant Support

Background Most PMBCL pts are cured with frontline chemoimmunotherapy ± RT. Data are scant regarding the role of HDC/ASCT for R/R PMBCL, and the benefit of RT administered peri-HDC/ASCT. Our institutional approach has focused on developing potentially more active HDC regimens, and on consideration of post-ASCT consolidation RT, especially for pts who had not achieved a CR at the time of HDC. Methods We retrospectively analyzed all patients (pts) with R/R PMBCL treated with HDC/ASCT at MDACC between 01/01/2000-12/31/2019. All pts underwent similar standard pre-SCT evaluation and met eligibility criteria as per our institutional guidelines. Response assessment differed over time and included CT and gallium scan (N=9) and PET/CT (N=49). Cox proportional hazards regression models evaluated the associations of the specific HDC regimen and clinical covariates of interest with EFS and OS. Results 58 pts received HDC/ASCT with BEAM-rituximab (N=36) or rituximab/gemcitabine/busulfan/melphalan ± vorinostat (R-GemBuMel) (n=22) (Table 1). The R-GemBuMel group included more pts pretreated with >2 lines of therapy than the R-BEAM group (55% vs. 28%, p=0.025), had fewer pts in CR (41% vs. 69%, P=0.01) and more pts in PD/SD at ASCT (32% vs. 3%, P=0.01). Prior RT at a median 44 (36-48) Gy was administered to 29 pts (20 R-BEAM, 9 R-GemBuMel, P=0.27). Nineteen pts (89% not in CR at SCT) who had not previously received full doses of RT received post-SCT RT (6 after BEAM, 13 after R-GemBuMel, P<0.001) at median 40 Gy (36-48). There were 2 treatment-related deaths in the R-BEAM arm, none in the R-GemBuMel arm. At median follow-up of 69.1 months (interquartile range, 36.5-85.2), the EFS rates were 57.6% (overall), 67.6% (R-GemBuMel) and 52.7% (R-BEAM) (Figure 1a). Their respective OS rates were 69.3%, 81.1% and 63.9% (Figure 1b). On multivariable Cox regression analyses, R-GemBuMel (vs. R-BEAM) (HR=0.29, p=0.05), and 1 organ involved (vs. >1) (HR 0.28, p=0.009) were associated with improved EFS, whereas older age (HR= 1.08 per year above median, p=0.005), refractory disease (SD/PD) at SCT (vs. CR/PR) (HR 5.44, p=0.01) correlated with worse EFS. Likewise, R-GemBuMel (HR= 0.16, p=0.03) and 1 organ involved (HR=0.17, p=0.004) significantly resulted in improved OS, whereas older age (HR= 1.11, p=0.002), and refractory (SD/PD) disease at SCT (HR= 21.27, p=0.001) correlated with worse OS. Neither sex nor disease status (primary refractory vs. relapse) nor No. prior lines (2 vs. >2) nor pre-SCT RT nor post-SCT RT correlated significantly with EFS or OS. Conclusions HDC/ASCT for R/R PMBCL pts, with post-SCT RT for pts with active disease at SCT, results in favorable long-term results. R-GemBuMel ± vorinostat seems to improve EFS and OS compared to R-BEAM. Disclosures Alousi: Incyte: Honoraria, Research Funding; Therakos: Research Funding; Alexion: Honoraria. Hosing:NKARTA Inc.: Consultancy. Kebriaei:Amgen: Other: Research Support; Ziopharm: Other: Research Support; Kite: Other: Served on advisory board; Pfizer: Other: Served on advisory board; Jazz: Consultancy; Novartis: Other: Served on advisory board. Popat:Bayer: Research Funding; Novartis: Research Funding. Qazilbash:Angiocrine: Research Funding; Bioline: Research Funding; Janssen: Research Funding; Bioclinica: Consultancy; Amgen: Research Funding. Shpall:Zelluna: Membership on an entity's Board of Directors or advisory committees; Adaptimmune: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Magenta: Membership on an entity's Board of Directors or advisory committees; Takeda: Other: Licensing Agreement. Champlin:Takeda: Patents & Royalties; Genzyme: Speakers Bureau; Cytonus: Consultancy; Omeros: Consultancy; Actinium: Consultancy; Johnson and Johnson: Consultancy; DKMS America: Membership on an entity's Board of Directors or advisory committees. Nieto:Affimed: Consultancy, Other: Grant Support; Novartis: Other: Grant Support; Astra Zeneca: Other: Grant Support; Secura Bio: Other: Grant Support.

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Prompt CR Plus Consolidation Therapy Yields Improve Survival after Allogeneic Transplantation for AML Patients Receiving Myeloablative, but Not Reduced-Intensity Conditioning: A CIBMTR Analysis

Blood ◽

10.1182/blood-2021-149962 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 414-414

Author(s):

Michael M. Boyiadzis ◽

Marcos J.G. de Lima ◽

Mei-Jie Zhang ◽

Karen Chen ◽

Christopher S. Hourigan ◽

...

Keyword(s):

Multivariate Analysis ◽

Board Of Directors ◽

Research Funding ◽

Disease Status ◽

Advisory Board ◽

Consolidation Therapy ◽

Advisory Committees ◽

Induction Cycle ◽

Relapse Rates ◽

Reduced Intensity

Abstract Leukemia relapse and treatment related mortality (TRM) remain major obstacles for successful allogeneic hematopoietic cell transplantation (allo-HCT). The number of induction cycles using intensive chemotherapy at AML diagnosis to achieve complete remission (CR) and the number of consolidation cycles and disease status at the time of allo-HCT for patients with acute myeloid leukemia (AML) may each affect TRM and relapse rates. We investigated the impact of the number of induction/consolidation cycles and disease status on the success of allo-HCT in 3113 AML patients reported to the Center for International Blood and Marrow Transplant Research (CIBMTR) (2008-2019). They received allo-HCT in first CR or with persistent leukemia (primary induction failure-PIF) receiving myeloablative (MA) or reduced-intensity (RIC) conditioning. 1473 AML patients (median age, 47 years) in CR received MAC; 862 (58%) achieved CR after 1 cycle of intensive induction chemotherapy and 74% of these had no evidence of measurable residual disease (MRD). 454 (31%) patients required 2 cycles to CR (72 % MRD negative) and 157 (11%) patients (69% MRD negative) after ≥ 3 cycles. The overall survival (OS), relapse and TRM by induction cycle number is shown in Table 1. Multivariate analysis demonstrated that CR after 1 cycle led to higher OS vs. 2 cycles (HR 1.32 95%CI 1.11-1.56, p< 0.01) or ≥ 3 cycles (HR 1.47 95%CI 1.16-1.87, p< 0.01), while OS after 2 cycles or ≥ 3 cycles were similar (HR 1.2 95%CI 0.87-1.4, p=0.38). Higher TRM was observed in patients receiving 2 or ≥ 3 cycles vs. only 1 induction cycles (HR 1.34 95%CI 1.05-1.72, p< 0.02). Relapse risk was greater in those needing ≥ 3 cycles to achieve CR. Consolidation therapy after CR was associated with improved OS vs. no consolidation therapy (HR 1.57 95%CI 1.24-1.99, p< 0.01). The need for ≥2 induction cycles plus consolidation therapy was associated with higher TRM (HR 1.34 95%CI 1.05-1.72, p< 0.02). 1162 AML patients (median age, 63 years) in CR received allo-HCT after RIC; 714 (61%) achieved CR after 1 cycle of induction chemotherapy (72% MRD negative); 310 (27%) patients after 2 cycles (67% MRD negative) and 138 (12%) patients (58% MRD negative) after ≥ 3 cycles (Table 1). Multivariate analysis demonstrated that the number of induction cycles did not affect the OS or TRM. Relapse risk was greater in patients requiring ≥2 cycles to achieve CR. The use of consolidation therapy did not affect OS or TRM. MRD status at the time of allo-HCT did not have a significant impact on OS, TRM and relapse rates after either MA or RIC conditioning. 478 AML patients received allo-HCT after PIF (328 patients with MAC [median age, 51 years], 150 patients RIC [median age, 61 years], Table 1). After MAC, OS and relapse were significantly worse in PIF patients compared to any CR patients (p<0.01). After RIC, relapse was significantly more frequent in PIF patients vs. CR patients after 1 or more induction cycles (p<0.01). TRM was similar for PIF vs CR patients after MAC or RIC allo-HCT. These data demonstrate that among patients eligible for allo-HCT, the need for only one induction cycle to achieve CR, particularly when combined with consolidation therapy is associated with better outcomes after MA conditioning. Achieving CR prior to allo-HCT needing one or more induction cycles is associated with lower relapse rates and improved OS compared to patients with PIF that receive allo-HCT. Figure 1 Figure 1. Disclosures de Lima: BMS: Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees; Miltenyi Biotec: Research Funding; Pfizer: Membership on an entity's Board of Directors or advisory committees. Hourigan: Govt. COI: Other. Litzow: Omeros: Other: Advisory Board; Pluristem: Research Funding; Jazz: Other: Advisory Board; AbbVie: Research Funding; Amgen: Research Funding; Actinium: Research Funding; Astellas: Research Funding; Biosight: Other: Data monitoring committee. Saber: Govt. COI: Other. Weisdorf: Incyte: Research Funding; Fate Therapeutics: Research Funding.

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A Study of the Role of Antiplatelet Therapy in the Prevention of Thrombosis in Patients with Calr-Mutated Low Risk Essential Thrombocythemia

Blood ◽

10.1182/blood.v126.23.1602.1602 ◽

2015 ◽

Vol 126 (23) ◽

pp. 1602-1602

Author(s):

Alberto Alvarez-Larrán ◽

Paola Guglielmelli ◽

Eduardo Arellano-Rodrigo ◽

Martin Griesshammer ◽

Chiara Paoli ◽

...

Keyword(s):

Multivariate Analysis ◽

Board Of Directors ◽

Antiplatelet Therapy ◽

Major Bleeding ◽

Research Funding ◽

Jak2 V617f ◽

Low Risk ◽

Advisory Committees ◽

Prevention Of Thrombosis

Abstract Young patients (age < 60 years) with essential thrombocythemia (ET) and no history of thrombosis are considered at low risk of thrombosis and therefore managed on a conservative approach with antiplatelet therapy or even without any treatment. JAK2 V617F and CALR exon 9 mutations are the most frequent molecular alterations observed in ET, with CALR-positive ET being considered a distinct clinical entity due to its higher platelet counts and lower incidence of thrombosis as compared with JAK2 V617F-positive ET. There is some evidence supporting a role for antiplatelet therapy in JAK2 V7617F-positive neoplasms. However, the role of antiplatelet therapy in CALR-positive ET has not been studied. The aim of the present study was to assess the effect of antiplatelet therapy in the primary prevention of thrombosis in patients with CALR-positive ET without indication of cytoreductive therapy. For such purpose, 240 patients (107 males, 133 females) diagnosed with ET at a median age of 42 years (range 13-59) were included in a multicenter retrospective study. Initial treatment consisted of antiplatelet therapy (n=109) or careful observation (n=108), whereas 23 patients received cytoreduction since diagnosis and were excluded. During a median follow up of 8 years, 137 patients were started on cytoreductive therapy because of the following indications: age > 60 years (n=10), thrombosis (n=10), bleeding (n=2), microvascular symptoms (n=18), extreme thrombocytosis (n=89), and others (n=8). Median time free of cytoreductive therapy was 3.2 years. Thrombosis-free survival restricted to the time of cytoreductive therapy abstention was calculated using the Kaplan-Meier method. Variables attaining a significant level at the univariate analysis were included in a Cox proportional hazard model. During the period of abstention of cytoreductive therapy, a total of 10 thrombotic events and 8 major bleeding episodes were registered. The probability of thrombosis at 3 years was 5% in patients managed with careful observation and 1% in those receiving antiplatelet therapy (p = 0.2). At multivariate analysis, antiplatelet therapy did not result in a lower risk of thrombosis after correction for age, sex and presence of cardiovascular risk factors. Interaction studies did not identify any subgroup of patients that benefited from antiplatelet therapy in thrombosis prevention. Regarding major bleeding, patients receiving antiplatelet therapy experienced a higher rate than those managed on observation (3-year probability of major bleeding, 5.5% and 0%, respectively, p=0.05). At multivariate analysis, antiplatelet therapy was associated with a tendency towards and increased risk of major bleeding (HR: 7.7, 95%CI: 0.9-66.2, p=0.06) independently of platelet count at diagnosis, age and gender. In conclusion, CALR-mutated low-risk ET patients under cytoreductive therapy abstention may not obtain a clear benefit from antiplatelet therapy since the increase in the rate of bleeding may offset the reduction in the rate of thrombosis Disclosures García-Gutierrez: Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Ariad: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Harrison:CTI Biopharma: Consultancy, Honoraria, Speakers Bureau; Novartis: Honoraria, Research Funding, Speakers Bureau; Gilead: Honoraria; Sanofi: Honoraria, Speakers Bureau; Shire: Speakers Bureau. Cervantes:Sanofi-Aventis: Consultancy; Novartis: Consultancy, Speakers Bureau; CTI-Baxter: Consultancy, Speakers Bureau. Vannucchi:Shire: Speakers Bureau; Baxalta: Membership on an entity's Board of Directors or advisory committees; Novartis Pharmaceuticals Corporation: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau.

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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 Role of IL-6 in POEMS Syndrome

Blood ◽

10.1182/blood-2021-149792 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 2700-2700

Author(s):

Maryam Omar ◽

Rahma M Warsame ◽

Morie A. Gertz ◽

Francis K. Buadi ◽

Ronald Go ◽

...

Keyword(s):

Overall Survival ◽

Board Of Directors ◽

Interleukin 6 ◽

Research Funding ◽

Statistical Significance ◽

Poems Syndrome ◽

Reference Ranges ◽

Time To Progression ◽

Advisory Committees

Abstract INTRODUCTION POEMS syndrome is a paraneoplastic disorder that results in multi-organ disease, and Vascular endothelial growth factor (VEGF) is associated with disease activity. There is evidence that the cytokine Interleukin- 6 (IL-6) stimulates VEGF production in several cancer cell lines. It has also been suggested that patients with POEMS syndrome experience symptoms improvement when IL-6 levels are low. Our study aims to understand the role of IL-6 and whether it is a contributor to disease activity in POEMS syndrome. METHODS We conducted a retrospective study of patients (pts) seen at Mayo Clinic within 1 year of diagnosis for POEMS syndrome with an IL-6 level within 3 months of diagnosis between 01/01/2011-05/31/2021 were included. Our database comprised 358 pts,7 were excluded because did not have official diagnosis of POEMS syndrome. Two hundred and ninety-nine pts did not have IL-6 testing within 90 days of diagnosis and were excluded. Clinical data was abstracted from our electronic medical record. Descriptive statistics were used for IL-6 levels. The majority of IL-6 laboratory testing for pts utilized the same reference range. A minority of pts had alternate reference ranges; thus, all IL-6 values and reference ranges were fold-corrected to have a unified reference to determine elevation in IL-6. High IL-6 was considered any value above the normal range, also analyzed pts in quartiles and deciles. Hematologic, VEGF and PET response criteria were utilized to group pts into responders or non-responders. Time to progression (TTP) and overall survival (OS) was calculated using the Kaplan Meier method. Differences between curves were by log rank. Statistical analysis was conducted via JMP software package (SAS, Cary, NC, USA). Univariate analysis was done to determine the prognostic value of IL-6. Statistical significance is considered with p-values <0.05. RESULTS 52 patients from among 352 met criteria and were included for analysis. Twenty-one patients (40%) had elevated IL-6 levels (IQR 5.67, 22.6) at the time of diagnosis. The fold elevation about normal was typically not very high, with a median of 3.1-fold elevation (IQR 1.3, 4.4; and range 1.0, 8.3). The percentage of males in the high IL-6 versus the normal Il-6 group were 90% versus 65%, p=0.03. Compared to normal IL-6, those with elevated IL-6 values had more instances of hepatomegaly (43% vs 16%, p=0.03), ascites (28% vs 6%, p=0 .04), abnormal DLCO (26% vs 3%, p=0.03), mixed bone lesions (57% vs 29%, p= 0.04), and lower serum albumin (range 2.3-3.5 vs 2.5-4.5 g/dL, p=0.0008).There was a trend for lower VEGF values among the high IL-6 group, but this did not meet statistical significance (median 250 vs 438 pg/mL). There was no significant difference in the time to progression between pts with high versus normal IL-6 levels (HR 1.36; p=0.456). Overall survival was significantly longer in pts with normal IL-6 compared to pts with high IL-6 levels (Median OS 67.4 vs 47.8 months, p=0.02). Forty-two pts were evaluated for VEGF response after treatment; there was a significant improvement in time to progression (85.5 vs 14.9 months, p=0.03) in pts who were VEGF responders. Among pts evaluable for a hematologic response (n=15), time to progression in pts with baseline high IL6 was longer in hematologic responders compared to non-responders (p=0.02). Conclusion Although OS was longer for pts with normal IL-6, elevated IL-6 at the time of diagnosis does not prevent pts from achieving disease remission. The study demonstrates that response to treatment rather than interleukin-6 levels in pts with POEMS syndrome is more prognostic. This study is an important initial step into understanding the utility of IL-6 in POEMS syndrome. Figure 1 Figure 1. Disclosures Gertz: Akcea Therapeutics, Alnylam Pharmaceuticals Inc, Prothena: Consultancy; Aurora Biopharma: Other: Stock option; Ionis Pharmaceuticals: Other: Advisory Board; AbbVie Inc, Celgene Corporation: Other: Data Safetly & Monitoring; Akcea Therapeutics, Ambry Genetics, Amgen Inc, Celgene Corporation, Janssen Biotech Inc, Karyopharm Therapeutics, Pfizer Inc (to Institution), Sanofi Genzyme: Honoraria. Kumar: Oncopeptides: Consultancy; KITE: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Beigene: Consultancy; Merck: Research Funding; Antengene: Consultancy, Honoraria; Tenebio: Research Funding; Novartis: Research Funding; Roche-Genentech: Consultancy, Research Funding; Carsgen: Research Funding; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astra-Zeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bluebird Bio: Consultancy; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Research Funding; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Consultancy, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Adaptive: Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: Research Funding. Dingli: GSK: Consultancy; Novartis: Research Funding; Janssen: Consultancy; Sanofi: Consultancy; Apellis: Consultancy; Alexion: Consultancy. Lin: Janssen: Consultancy, Research Funding; Merck: Research Funding; Novartis: Consultancy; Legend: Consultancy; Juno: Consultancy; Bluebird Bio: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Vineti: Consultancy; Kite, a Gilead Company: Consultancy, Research Funding; Sorrento: Consultancy; Gamida Cell: Consultancy; Takeda: Research Funding. Kapoor: Karyopharm: Consultancy; Cellectar: Consultancy; BeiGene: Consultancy; Pharmacyclics: Consultancy; Sanofi: Consultancy; Amgen: Research Funding; Ichnos Sciences: Research Funding; Regeneron Pharmaceuticals: Research Funding; Glaxo SmithKline: Research Funding; Karyopharm: Research Funding; Sanofi: Research Funding; Takeda: Research Funding; AbbVie: Research Funding. Dispenzieri: Pfizer: Research Funding; Sorrento Therapeutics: Consultancy; Oncopeptides: Consultancy; Alnylam: Research Funding; Takeda: Research Funding; Janssen: Consultancy, Research Funding.

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Marrow Ring Sideroblasts Are Highly Predictive for TP53 Mutation in MDS with Excess Blasts

Blood ◽

10.1182/blood-2019-124772 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 4244-4244

Author(s):

David M Swoboda ◽

Jung-Hoon Lee ◽

Onyee Chan ◽

Rami S. Komrokji ◽

Najla Al Ali ◽

...

Keyword(s):

Multivariate Analysis ◽

Board Of Directors ◽

Research Funding ◽

Tp53 Mutation ◽

Survival Advantage ◽

World Health ◽

Categorical Variables ◽

Cell Transplant ◽

Advisory Committees ◽

Ring Sideroblasts

Background: Myelodysplastic syndrome with ring sideroblasts (MDS-RS) is defined by the World Health Organization (WHO) as ring sideroblasts (RS) ≥15% or ≥5% with associated SF3B1 mutation and no excess blasts (EB). In MDS-RS, SF3B1 mutation defines a homogenous group with isolated erythroid dysplasia and favorable prognosis (Malcovati et al. Blood 2015). Given the separate WHO classification, patients with MDS-EB frequently are not tested for RS. SF3B1-wild type (wt) MDS with RS also has not been well characterized. Therefore, herein we characterized MDS with RS, focusing on SF3B1-wt and implications of molecular subsets. Patients and Methods: Between 2013 and 2018, 157 MDS and MDS/MPN patients with RS ≥5% and next generation sequencing performed within 6 months of diagnosis at Moffitt Cancer Center were identified with clinical variables obtained at date of diagnosis. Quantification of RS was performed in all cases by hematopathology. Baseline characteristics were compared by Fisher's exact test (categorical variables) and Mann-Whitney test (continuous variables). Survival estimates were calculated using the Kaplan-Meier method from date of diagnosis and groups were compared using log-rank test. Multivariate survival analysis performed by means of Cox proportional hazards regression. Pearson correlation coefficient was used in correlative analyses. Results: A total of 75 SF3B1-mutant (mt) and 82 SF3B1-wt cases with MDS (141) or MDS/MPN (13) and RS were identified. Median age was 71 years (38-89) with male and Caucasian predominance (62% and 94%, respectively). In the SF3B1-wt cohort, there were 77 MDS and 5 MDS/MPN patients. The MDS patients consisted of 2 MDS-SLD, 15 MDS-MLD, 3 MDS-RS-SLD, 17 MDS-RS-MLD, 24 MDS-EB1 and 16 MDS-EB2. The majority of SF3B1-wt patients (58%) were high or very high risk based on the Revised International Prognostic Scoring system (IPSS-R). Median RS% was significantly lower in SF3B1-wt compared to SF3B1-mt (18% (5-50) vs 35% (5-83) p <0.0001). TP53 was the most common mutation (54%) in the SF3B1-wt cohort (n=44; Figure 1). Additional mutations observed in >10% of the SF3B1-wt cohort were DNMT3A 18% (n=15), TET2 16% (n=13) and U2AF1 16% (n=13). Non-SF3B1 spliceosome mutations represented 27% (n=22) of the SF3B1-wt cohort. TP53-mt and non-SF3B1 spliceosome-mt were observed at significantly higher prevalence in SF3B1 wt vs mt patients (p<0.0001 and p=0.003). In univariate analysis, IPSS-R, TP53 and DNMT3A were associated with worse overall survival in SF3B1-wt patients (OS). In multivariate analysis including age, IPSS-R and BMT, only TP53 was an independent covariate for inferior survival (HR 6.3; 95% CI 2.4-16.6 p<0.0001). Given the high frequency of mutations, we then focused on TP53-mt RS patients. In the total cohort of patients with RS≥5%, 77% of MDS-EB1 and 68% of MDS-EB-2 were TP53-mt. In SF3B1 wt patients with RS≥5% and excess blasts, TP53 mutation was identified in 79% (n=19) and 81% (n=13) of MDS-EB-1 and MDS-EB-2 patients, respectively (p<0.0001 TP53-mt MDS-EB vs other). 3 patients were co-mutant for TP53 and SF3B1. Increased RS as defined as >15% vs 5-15% resulted in improved OS in the TP53-mt cohort (median OS 13.5 vs 8.6 months; HR 0.36 95% CI 0.14-0.93 p=0.034). In multivariate analysis including age, IPSS-R and BMT, the survival advantage was maintained (HR 0.35 95% CI 0.14-0.93 p=0.034). Increased RS did not significantly improve OS in any other somatic mutation. Response to hypomethylating agents was similar between TP53-mt RS >15% vs 5-15% (Complete remission (CR) 21% vs 17% p=1.0 and overall response rate (ORR) 52% vs 42% p=.72). No TP53-mt RS patients responded to lenalidomide (0/4). The proportion of patients receiving allogeneic stem cell transplant was similar between TP53-mt RS >15% vs 5-15% (14% vs 22% p=0.69). There was no difference in distribution of TP53-mt between 5-15% RS cohort vs >15% (55% n=26 vs 51% n=18 p=0.82). Finally, TP53 VAF did not correlate with RS percentage (p=.393) Conclusions: In our study, MDS-RS-EB was highly concordant with the presence of TP53 mutation occurring in 80% of SF3B1-wt patients. In TP53 mutant patients, increased ring sideroblast % was an independent covariate associated with a significant survival advantage. As therapy targeting TP53 emerges, the ability to rapidly predict TP53 mutation status based on presence of ring sideroblasts should be a priority. Figure Disclosures Komrokji: Agios: Consultancy; celgene: Consultancy; pfizer: Consultancy; DSI: Consultancy; JAZZ: Consultancy; Incyte: Consultancy; Novartis: Speakers Bureau; JAZZ: Speakers Bureau. List:Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding. Sallman:Abbvie: Speakers Bureau; Novartis: Speakers Bureau; Jazz: Research Funding; Incyte: Speakers Bureau; Celyad: Membership on an entity's Board of Directors or advisory committees; Celgene: Research Funding, Speakers Bureau.

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The Role of Clonal Hematopoiesis of Indeterminate Potential (CHIP) in Multiple Myeloma: Immunomodulator Maintenance Post Autologous Stem Cell Transplant (ASCT) Predicts Better Outcome

Blood ◽

10.1182/blood-2018-99-113059 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 749-749 ◽

Cited By ~ 5

Author(s):

Tarek H Mouhieddine ◽

Jihye Park ◽

Robert A. Redd ◽

Christopher J. Gibson ◽

Salomon Manier ◽

...

Keyword(s):

Multiple Myeloma ◽

Board Of Directors ◽

Peripheral Blood ◽

Research Funding ◽

Autologous Stem Cell Transplant ◽

P Value ◽

Cell Transplant ◽

Advisory Committees

Abstract Introduction: Multiple Myeloma (MM) is a clonal plasma cell malignancy, accounting for 10% of all hematological malignancies. Genetic analyses of large populations revealed that blood-specific somatic mutations in hematopoietic stem cells (HSCs) are commonly acquired during aging, a new entity labeled: clonal hematopoiesis of indeterminate potential (CHIP). We sought to determine the role of CHIP on survival of MM patients, specifically those receiving immunomodulator (IMiD) maintenance (Lenalidomide or Thalidomide) post autologous stem cell transplant (ASCT). Methods: We collected the cryopreserved, growth factor mobilized peripheral blood of 629 MM patients who underwent ASCT between 2003 and 2011 at the Dana-Farber Cancer Institute (DFCI). Then, we performed targeted next-generation sequencing using a 224-gene panel at a mean depth of coverage of 978X and ultra-low pass whole-genome sequencing at 0.1X to account for tumor contamination. We downloaded (dbGAP # phs000748.v6.p4) the whole-exome sequencing (WES) data of a cohort of 1144 newly diagnosed, untreated MM patients from the Multiple Myeloma Research Foundation (MMRF) Clinical Outcomes in MM to Personal Assessment of Genetic Profile (CoMMpass, NCT0145429) study (MMRC) and the WES data of a cohort of 205 newly diagnosed, untreated MM patients from the Broad Institute dataset. We analyzed their peripheral blood (average coverage of 108X) and tumor (average coverage of 107X) data separately, looking for the same CHIP genes included in our target bait panel. Results: The DFCI cohort had a median age of 58 years [range, 24-83] at time of ASCT and median follow up post ASCT of 8 years [range, 0.1-14.5]. 204 patients (32%) in the DFCI cohort had CHIP at time of ASCT. The most commonly detected mutated genes were DNMT3A, TET2, TP53, ASXL1 and PPM1D. 24 patients (3.8%) developed a second hematological malignancy at a median of 4 years [range, 1-10] post ASCT, half of whom had CHIP. Around 48% of the DFCI cohort received IMiDs as part of induction therapy. Different induction regimens had no effect on CHIP prevalence at time of ASCT. Around 56% of the DFCI cohort received IMiD maintenance, 22% of which received maintenance for at least 3 years [range, 0.06-12.8]. Among those who did not receive IMiD maintenance, patients with CHIP had worse progression free survival (PFS) (p-value < 0.001) and overall survival (OS) (p-value = 0.005). In patients receiving IMiD maintenance, having CHIP had no effect on PFS or OS. On the other hand, the MMRF cohort had a median age of 63 years [range, 27-93] and median follow up of 3.03 years [range, 0-5.9] from time of diagnosis. Around 52% of that cohort underwent ASCT and around 76% of those received IMiD maintenance with a median follow up of 2.7 years [range, 0-5.5] from time of ASCT. Furthermore, 200 patients of the MMRF cohort have follow-up samples of both tumor and peripheral blood that had targeted sequencing done by a 562-gene panel that included our genes of interest. Similarly, when studying the genomic results of 139 out of 1144 MMRF patients, as well as the 205 patients from the Broad Institute dataset, we detected CHIP in 25.6% of them and the top 5 most commonly mutated genes were similar to those of our cohort. Conclusion: CHIP is a common entity among MM patients, reaching a prevalence of up to 32%, that predicts a worse PFS and OS in those who do not receive IMiD maintenance therapy post ASCT. As expected, IMiD maintenance improves outcome in MM patients, with and without CHIP. In patients with CHIP, the use of IMiDs abrogated the deleterious effect imposed by CHIP to a point that outcome is identical to that of patients without CHIP. Figure Figure. Disclosures Bustoros: Dava Oncology: Honoraria. Munshi:OncoPep: Other: Board of director. Anderson:Gilead: Membership on an entity's Board of Directors or advisory committees; OncoPep: Equity Ownership, Other: Scientific founder; Celgene: Consultancy; C4 Therapeutics: Equity Ownership, Other: Scientific founder; Bristol Myers Squibb: Consultancy; Millennium Takeda: Consultancy. Richardson:Oncopeptides: Membership on an entity's Board of Directors or advisory committees; BMS: Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding. Soiffer:Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees. Ghobrial:Celgene: Consultancy; Janssen: Consultancy; BMS: Consultancy; Takeda: Consultancy.

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Pre-Transplant Clonal Mosaicism Is Associated with Increased Relapse and Lower Survival in Acute Lymphoblastic Leukemia Patients Undergoing Allogeneic Hematopoietic Cell Transplant

Blood ◽

10.1182/blood-2020-140342 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 9-10

Author(s):

Yiwen Wang ◽

Weiyin Zhou ◽

Junke Wang ◽

Ezgi Karaesmen ◽

Hancong Tang ◽

...

Keyword(s):

Board Of Directors ◽

Peripheral Blood ◽

Copy Number ◽

Research Funding ◽

Advanced Disease ◽

Advisory Board ◽

Cell Transplant ◽

Disease Relapse ◽

Advisory Committees ◽

Lower Survival

Clonal mosaicism, detectable in peripheral blood, can be an important predictor of developing a hematological malignancy. We sought to determine if mosaic events, in addition to clinical and demographic variables, contributed independent information about acute lymphoblastic leukemia (ALL) patient survival and risk of relapse after allogeneic hematopoietic cell transplant (HCT). HumanOmniExpress-12v1_A BeadChip SNP array data were used to detect mosaicisms >=2Mb based on the log2 relative probe intensity ratio (LRR) and B allele frequency (BAF) for each SNP measured in 773 ALL patients from DISCOVeRY-BMT cohorts. DNA was extracted from recipient peripheral blood samples taken immediately prior to start of conditioning before allogeneic HCT for ALL (2000-2011). Mosaic events include copy-number gain (LRR >0), loss (LRR <0), or copy-neutral loss of heterozygosity (CNLOH), defined as a deviation from BAF heterozygosity without LRR changes. The impact of mosaicism on overall survival (OS) probability and cumulative incidence of relapse at 1-year post-HCT were calculated using the Kaplan-Meier estimator and cumulative incidence functions, respectively. The association of clonal mosaicism with OS was evaluated with multivariable Cox proportional hazard models. For disease relapse, competing risk models were used with transplant related mortality (TRM) treated as a competing event. Stratified survival analyses were performed by cytogenetic status at diagnosis. Statistical analyses were conducted using R 3.6.1. Thirty-four patients (4.4%) had 1 or more mosaicisms (82 total detected) with almost half having advanced disease (Table 1). The median proportion of affected cells was 61% (interquartile range = 39 - 93%). Copy-number losses on chromosomes 7 (13.4%) and 9 (8.54%) and 17 (6.10%) were the most frequently detected events (Figure 1). OS at 1-year post HCT in patients with and without a mosaic event was 26.5% and 60.1%, respectively, (P=8.2×10-8, Figure 2A) and normal cytogenetic patients with mosaicism had significantly lower survival compared to all other patients (OSnormal/mosaic+= 8.3% vs. OS= 60.6%, P=3.0×10-10, Figure 2B-C). ALL patients with a mosaic event also had an increased risk of disease relapse overall (Relapsemosaic+= 50% vs. Relapsemosaic-=26%, P=0.00067) and when stratified by cytogenetic abnormalities (P=0.015) and normal cytogenetics (P=0.041) (Figure 2D-F). Multivariable models of OS and relapse included age, race/ethnicity, complete remission or advanced disease status (Figure 3). Patients with a mosaic event had ~2.5 fold increase risk of death (P=2.5×10-5), independent from cytogenetics (P=8.6×10-5, Figure 3). OS associations are likely driven by the 2.8 fold increase risk of relapse (P= 5.9×10-5) which remains highly significant when stratified by cytogenetics (Figure 3). Almost half of the copy-number losses included well-known regions on chromosomes 7, 9 and 17 (Figure 1). Deletions of 7p have been shown to correlate with lower event-free survival in ALL pediatric patients. Our findings suggest mosaic loss of 7p might be an important indicator of poor OS across the lifespan, with 5/6 patients with 7p losses aged >18 years. Higher mortality was also associated with the loss of the chr9p21.3 locus, seen in all patients (N=5) with chromosome 9p losses. This region harbors tumor suppressor CDKN2A; inactivation of CDKN2A can lead to poor survival in both children and adults with ALL. Lastly, we found that all patients (N=4) with copy-number loss of 17p13.1, which contains tumor suppressor TP53 died within 1-year post-HCT. We identified detectable mosaicism prior to transplant in 4.4% of patients and showed that mosaicism was associated with lower survival and higher disease relapse at 1-year post-HCT. While mosaicism is more common in patients with advanced disease stage, mosaic events are an independent contributor to lower survival and higher relapse in the first year after transplant. This is the first study to show that mosaic events detectable in pre-transplant peripheral blood from ALL patients are correlated with poor survival. Future studies replicating these associations in different ethnicities and age groups and evaluating specific chromosomal regions could be informative in classifying patient risk post-HCT attributable to mosaic events. Disclosures McCarthy: Karyopharm: Consultancy, Honoraria; Magenta: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Advisory Board; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Advisory Board; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Advisory Board; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Advisory Board; Genentech: Consultancy, Honoraria; Starton: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Advisory Board; Juno Therapeutics, a Bristol-Myers Squibb Company: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Advisory Board , Research Funding is to Roswell Park, Research Funding. Pasquini:Bristol Myers Squibb: Consultancy; BMS: Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Other; Novartis: Research Funding; Kite: Research Funding. Lee:Pfizer: Consultancy, Research Funding; Novartis: Research Funding; Takeda: Research Funding; Amgen: Research Funding; Kadmon: Research Funding; Incyte: Consultancy, Research Funding; AstraZeneca: Research Funding; Syndax: Research Funding.

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