Excess Mortality in Low-Risk MDS Can be Explained By MDS and AML Related Causes of Death

Abstract Background Data on causes of death (COD) in patients with lower-risk (LR-MDS) is limited and sometimes conflicting. In contrast to higher-risk MDS, many LR-MDS patients die from conditions associated with advanced age, not directly associated with the underlying disease. Infections and cardiovascular disorders (CVD) have been reported as frequent COD in LR-MDS, but whether the incidence is higher than in age-matched population, is not known. The EUMDS Registry has been collecting prospective observational data on LR-MDS since 2008. The comprehensive clinical and laboratory data provides a unique chance to assess the impact of LR-MDS on survival either by causes related to MDS or indirectly related to MDS by aggravation of co-morbidities. Objectives To assess the impact of MDS and associated co-morbidities on COD in patients with LR-MDS and to evaluate the COD in the whole group and across participating countries. Methods: We evaluated clinical and laboratory data of LR-MDS patients registered in EUMDS registry from 2008 to 2018. Data were obtained by 145 centers from 16 European countries and Israel. MDS related causes of death were defined as infection, bleeding, MDS progression and AML transformation. Overall survival(OS) and relative survival(RS) were estimated using the Stata program 'strel' with age, sex and country specific background obtained from national life tables for the CONCORD program. RS is a standard approach used to take into account competing causes of death by adjusting for the age and sex specific mortality in the general population, estimating the excess mortality in these patients compared to that seen in the general population of each country. Results Overall data on 2235 LR-MDS patients was available in the EUMDS registry. Of these, 822 (36,7%) patients had died at the time of analysis. Median age was 77 years and 65% of the patients were male. Nearly half of them (46.9%) were diagnosed as IPPS low risk. The MDS-Comorbidity Index was low, intermediate and high in 55.7%, 37.5% and 6.8% of patients respectively. The most common COD were those considered as related to MDS 41.7% (Table 1). Deaths due to cardiovascular and pulmonary diseases were reported in 10.1% and 4.9% respectively. Other reasons (e.g. liver, renal failure, second malignancy) were found in 18.2%. In 25% of patients, the precise reason of death remained unknown. The proportion of MDS related COD were different between participating countries with lower rates in Germany (30%), France (31.3%) and higher in Portugal (55%), Greece (55.2%) and Romania (63.1%). Median follow-up was 2.1 years (0.1-10 years). Five-year overall survival in the whole cohort was 47.1% (95% CI: 44.1%-49.9%) and 5-year relative survival (attributed to MDS/AML only) was 59.1% (95% CI:55.4%-62.5%)(Figure 1). One year overall and relative survival was 90.4% (95% CI:89.1%-91.6%) and 94.4% (95% CI:93%-95.5%) respectively. Conclusions: MDS- related complications are the most common causes of death in LR-MDS patients. Comparison of overall and relative survival supports that observation and indicates that excess mortality in LR-MDS patients can be mainly explained by MDS/AML related causes. Interestingly, the strongest influence of MDS/AML attributable deaths was observed during the first year from diagnosis. Disclosures Fenaux: Janssen: Honoraria, Research Funding; Jazz: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Roche: Honoraria; Otsuka: Honoraria, Research Funding. Stauder:Teva: Research Funding; Novartis: 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. Germing:Novartis: Honoraria, Research Funding; Janssen: Honoraria; Celgene: Honoraria, Research Funding. de Witte:Novartis: Research Funding; Celgene: Honoraria, Research Funding; Amgen: Consultancy, Research Funding. Smith:Jazz Pharmaceuticals: Research Funding; Johnson & Johnson: Research Funding; Gilead Sciences: Consultancy; Novartis: Research Funding.

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Expected Survival in Patients with Smoldering Multiple Myeloma and Multiple Myeloma

Blood ◽

10.1182/blood-2018-99-118084 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 4497-4497

Author(s):

Moritz Binder ◽

S. Vincent Rajkumar ◽

Arjun Lakshman ◽

Martha Q. Lacy ◽

Morie A. Gertz ◽

...

Keyword(s):

Multiple Myeloma ◽

Overall Survival ◽

High Risk ◽

General Population ◽

Board Of Directors ◽

Research Funding ◽

Excess Mortality ◽

Advisory Committees ◽

Smoldering Multiple Myeloma ◽

Similar Survival

Abstract Background: The introduction of novel therapeutics has led to improved outcomes in patients with multiple myeloma (MM). MM and its precursor lesion smoldering multiple myeloma (SMM) have traditionally been associated with increased mortality despite treatment. We aimed to assess the impact of a diagnosis of SMM and MM compared to the general population in the context of established prognostic factors. Methods: We studied the overall survival of 1697 patients with smoldering multiple myeloma (SMM, n = 582) and multiple myeloma (MM, n = 1115) diagnosed at Mayo Clinic between 01/2005 and 12/2015. Expected survival accounting for age and sex was calculated using the United States general population (US) as the reference group. Observed and expected overall survival was expressed as the standardized mortality ratio (SMR) of observed to expected deaths. Kaplan-Meier overall survival estimates were calculated and the log-rank test was used to compare overall survival in subgroups. The subgroups of interest were based on the International Staging System (ISS) and the presence of fluorescence in situ hybridization (FISH) high-risk cytogenetics: t(4;14), t(14;16), t(14;20), and del(17p). Proportional hazards regression models were used to assess the associations between the aforementioned prognostic factors and overall survival. P-values below 0.05 were considered statistically significant. Results: The median age at diagnosis in patients with SMM and MM was 65 (32 - 92) and 63 years (24 - 90), respectively. Two hundred forty-nine patients (57%) and 663 (60%) were male. The median follow-up in patients with SMM and MM was 4.7 (0.1 - 11.0) and 2.6 years (0.2 - 9.5). The median overall survival for patients with SMM and MM was 9.0 (95% CI 8.4 - 9.7) and 7.9 years (6.4 - 8.7). With age- and sex-matched population controls as the reference, the SMRs in patients with SMM and MM were 2.6 (95% CI 2.2 - 3.0) and 4.6 (4.1 - 5.2). Among those MM patients with available data on ISS staging and FISH cytogenetics, 30% (236/780) had ISS III and 21% (188/878) had high-risk cytogenetics. Patients with MM (compared to SMM) experienced worse overall survival (HR 1.5, 95% CI 1.2 - 1.8, p < 0.001, n = 1697). Patients with ISS I/II MM (compared to SMM) experienced similar survival (HR 1.0, 95% CI 0.8 - 1.3, p = 0.698, n = 1131). Patients with ISS III MM (compared to MM with high-risk cytogenetics) experienced similar survival (HR 1.3, 95% CI 0.9 - 2.0, p = 0.128, n = 329). Conclusions: Patients with SMM and MM in this cohort experienced excess mortality compared to the general population. In the absence of universal screening the true morbidity and mortality of patients with SMM and MM remains unknown and is likely overestimated in hospital-based cohorts. Overall survival in patients diagnosed with SMM and patients with ISS I/II MM receiving contemporary anti-myeloma therapy was clinically indistinguishable. Patients treated for ISS III MM experienced overall survival similar to patients with cytogenetic high-risk disease. MM remains associated with excess mortality, the magnitude of which varies considerably based on the presence of additional tumor and host factors. The outcomes with modern therapy among the ISS I/II patients highlight the potential for improving outcomes of SMM by early intervention, especially for the higher risk patients. Figure. Figure. Disclosures Lacy: Celgene: Research Funding. Gertz:Medscape: Consultancy; Alnylam: Honoraria; janssen: Consultancy; spectrum: Consultancy, Honoraria; Ionis: Honoraria; annexon: Consultancy; celgene: Consultancy; Teva: Consultancy; Prothena: Honoraria; Apellis: Consultancy; Abbvie: Consultancy; Physicians Education Resource: Consultancy; Amgen: Consultancy; Research to Practice: Consultancy. Dispenzieri:Celgene, Takeda, Prothena, Jannsen, Pfizer, Alnylam, GSK: Research Funding. Russell:Vyriad: Equity Ownership. Kapoor:Takeda: Research Funding; Celgene: Research Funding. Kumar:Roche: Research Funding; AbbVie: 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; AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding; KITE: Membership on an entity's Board of Directors or advisory committees, Research Funding; KITE: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Oncopeptides: Membership on an entity's Board of Directors or advisory committees; Novartis: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees; Merck: Membership on an entity's Board of Directors or advisory committees, Research Funding.

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Inotuzumab Ozogamicin (Ino) May Overcome the Impact of Philadelphia Chromosome (Ph)-like Phenotype in Adult Patients (pts) with Relapsed/Refractory (R/R) Acute Lymphoblastic Leukemia (ALL)

Blood ◽

10.1182/blood-2019-126940 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 1641-1641 ◽

Cited By ~ 1

Author(s):

Elias Jabbour ◽

Kathryn G. Roberts ◽

Koji Sasaki ◽

Yaqi Zhao ◽

Chunxu Qu ◽

...

Keyword(s):

Gene Expression ◽

Overall Survival ◽

Stem Cell ◽

Acute Lymphoblastic Leukemia ◽

B Cell ◽

Board Of Directors ◽

Research Funding ◽

Lymphoblastic Leukemia ◽

Advisory Committees ◽

The Impact

Background: Ino showed significant activity in phase II trials in pts with R/R ALL, that was subsequently confirmed in Phase III trial where Ino demonstrated higher response rates and superior overall survival vs standard of care chemotherapy (SOC) in adults with relapsed/refractory B-cell precursor acute lymphoblastic leukemia (R/R ALL).Ph-like or BCR-ABL1-like ALL possesses a gene expression profile similar to that of BCR-ABL1 ALL but lacks the BCR-ABL1 fusion protein. It is characterized by increased expression of hematopoietic stem-cell genes, deletion of B-cell lineage genes and kinase-activating alterations. Ph-like ALL is associated with refractoriness to standard induction/consolidation chemotherapy and poor prognosis. Aim: To evaluate the outcomes of pts with R/R Ph-like ALL treated in phase II trial with Ino monotherapy. Methods: We performed an integrated analysis of whole genome sequencing (to identify sequence mutations, structural variations and DNA copy number alterations), and transcriptome sequencing (RNAseq; to quantify gene expression, determine Ph-like gene expression profile and identify fusions) on 53 patients' samples treated with Ino between June 2010 and September 2012. Results: Fifty-three evaluable pts with R/R ALL with stored baseline samples were analyzed. Pts characteristics are summarized in Table 1. Median age was 50 years. Ino was given as Salvage 1, Salvage 2, and Salvage 3 and beyond in 20 (38%), 18 (34%), and 15 (28%) pts, respectively. Figure 1 reflects the different genomic subgroups identified among 53 evaluable pts. Ph-like gene signature was found in 12 pts (22.6%). Among these 12 pts, 6 had IGH-CRLF2, 2 IGH-EPOR, 1 SNX2-ABL1, and 3 had no fusions identified. The overall response rates (ORR) were 54% [complete remission (CR) 20%, CR with partial hematologic recovery (CRh) 32%, and marrow CR (CRi) 2%]. Among pts with morphologic remission, 46% and 82% achieved minimal residual disease (MRD) negativity at CR and at any time, respectively. The ORR for pts with Ph-like ALL, Ph-positive ALL, ALL with KMT2A, and others were 58% (CR=25%; CRh=33%), 42% (CR=8%; CRh=33%), 57% (CR=14%; CRh=29%; CRi=14%), and 56% (CR=26%; CRh=30%), respectively. The respective overall MRD negativity rates were 71%, 100%, 75%, and 83% (Table 1). The median follow-up was 60 months. The median event-free (EFS) and overall survival (OS) were 3.3 and 5.4 months, respectively. There was no difference in EFS and OS between the subgroups analyzed (P=0.464; P=0.824). The median EFS and OS were 4.5 and 4.5 months for pts with Ph-like, 3.1 and 7.2 months for those with Ph-positive ALL, 2.8 and 4.4 months for those with KMT2A, and 2.2 and 4.6 months for others (Table 1). 21 (40%) pts had subsequent allogeneic stem cell transplant; 6 (50%), 3 (25%), 4 (57%), and 8 (36%) in each subgroup, respectively. The rate of VOD was 3 (6%) with no difference among different subgroups. Conclusion: The current analysis suggest that Ino therapy may overcome the impact of Ph-like phenotype in pts with ALL. Confirmation of these findings in a larger cohort and in frontline ALL patients is needed. Disclosures Jabbour: Takeda: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Adaptive: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Cyclacel LTD: Research Funding. Sasaki:Pfizer: Consultancy; Otsuka: Honoraria. Jain:Precision Biosciences: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics, an AbbVie company: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen Pharmaceuticals, Inc.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Genentech: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Research Funding; Adaptive Biotechnologies: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Cellectis: Research Funding; AstraZeneca: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Servier: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Incyte: Research Funding; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; ADC Therapeutics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Verastem: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Ravandi:Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Xencor: Consultancy, Research Funding; Macrogenix: Consultancy, Research Funding; Menarini Ricerche: Research Funding; Selvita: Research Funding; Cyclacel LTD: Research Funding. Short:AstraZeneca: Consultancy; Takeda Oncology: Consultancy, Research Funding; Amgen: Honoraria. Garcia-Manero:Amphivena: Consultancy, Research Funding; Helsinn: Research Funding; Novartis: Research Funding; AbbVie: Research Funding; Celgene: Consultancy, Research Funding; Astex: Consultancy, Research Funding; Onconova: Research Funding; H3 Biomedicine: Research Funding; Merck: Research Funding. Konopleva:Cellectis: Research Funding; Agios: Research Funding; AbbVie: Consultancy, Honoraria, Research Funding; Ascentage: Research Funding; Eli Lilly: Research Funding; Calithera: Research Funding; Stemline Therapeutics: Consultancy, Honoraria, Research Funding; Forty-Seven: Consultancy, Honoraria; Reata Pharmaceuticals: Equity Ownership, Patents & Royalties; Kisoji: Consultancy, Honoraria; Ablynx: Research Funding; Genentech: Honoraria, Research Funding; Amgen: Consultancy, Honoraria; F. Hoffman La-Roche: Consultancy, Honoraria, Research Funding; Astra Zeneca: Research Funding. Mullighan:Illumina: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: sponsored travel; Pfizer: Honoraria, Other: speaker, sponsored travel, Research Funding; AbbVie: Research Funding; Loxo Oncology: Research Funding; Amgen: Honoraria, Other: speaker, sponsored travel. Kantarjian:Actinium: Honoraria, Membership on an entity's Board of Directors or advisory committees; Agios: Honoraria, Research Funding; Ariad: Research Funding; Novartis: Research Funding; Amgen: Honoraria, Research Funding; Immunogen: Research Funding; AbbVie: Honoraria, Research Funding; Astex: Research Funding; BMS: Research Funding; Cyclacel: Research Funding; Daiichi-Sankyo: Research Funding; Pfizer: Honoraria, Research Funding; Jazz Pharma: Research Funding; Takeda: Honoraria.

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Prolonged Overall Survival with Pomalidomide and Dexamethasone in Myeloma Characterized with End Stage Disease.

Blood ◽

10.1182/blood.v120.21.2961.2961 ◽

2012 ◽

Vol 120 (21) ◽

pp. 2961-2961

Author(s):

Xavier Leleu ◽

Murielle Roussel ◽

Bertrand Arnulf ◽

Philippe Moreau ◽

Catherine Traulle ◽

...

Keyword(s):

Overall Survival ◽

Board Of Directors ◽

Research Funding ◽

Alkylating Agents ◽

Randomized Study ◽

Historical Control ◽

Advisory Committees ◽

Line Of Therapy ◽

End Stage ◽

The Impact

Abstract Abstract 2961 Background. MM remains incurable and patients will ultimately acquire resistance to novel agents. Kumar et al. (Leukemia. 2012;26:149–157) have shown that patients with MM who relapsed following or were refractory to bortezomib and the immunomodulatory drugs had a median overall survival (OS) of 9 months, which represents a historical control standard for this patient population. The IFM2009-02 phase 2 randomized study ought to determine the impact of the combination of pomalidomide; given orally either 4 mg daily on days 1–21 of a 28-day cycle (arm 21/28) or continuously on days 1–28 of a 28-day cycle (arm 28/28); in combination with dexamethasone (oral 40 mg weekly) in patients with resistant and refractory MM to lenalidomide and bortezomib (Leleu et al, ASH 2011). We have reported an overall response rate [ORR, ≥PR] of 34.5% with 48% stable disease [SD]. In this final analysis, we aimed to further demonstrate that treatment with pomalidomide and dexamethasone translated into prolonged survival. Method. This study included MM patients who did not achieve a response (≤ SD) as per IMWG criteria with the last course of bortezomib and the last course of lenalidomide, or who were refractory tobortezomib and lenalidomide. The primary objective was ORR, assessed centrally and reviewed by an independent committee. The analysis is performed on ITT population and combines data from the 2 arms. Results. As of February 1, 2012, 84 patients (57 male and 27 female) were enrolled; 43 in arm 21/28 and 41 in arm 28/28. The median age was 60 years (range 42–83). The median time from diagnosis to enrolment in IFM 2009-02 was 70.5 months (range 9–277). The median number of prior lines of therapy was 5 (range 1–13), and 100% of the patients had received bortezomib and lenalidomide as per protocol. Additionally, 70% had received alkylating agents, 81% were previously exposed to autologous stem cell transplantation, 76% had received anthracylines and 71% had received thalidomide. Most importantly, 84.5% were refractory to their last prior line of therapy and 77% were refractory to their last prior lines of both lenalidomide and bortezomib. With a median follow up of 22.8 months, 74 patients have discontinued treatment and 53 patients (63%) have died: 25 (58%) in arm 21/28 and 28 (68%) in arm 28/28. The most common reason for treatment discontinuation was disease progression(84%), and death was considered to be related to myeloma in 95% of patients (similar in the 2 arms). Importantly, 10 patients (12%) remain on treatment after 30 months. In the ITT population, the median (95%CI) PFS and TTP was 4.6 months (4–7) and 5.4 months (CI 4–8), with a median duration of response of 7.3 months (5–15). 28% of patients were free of progression and 44% responded, at 1 year respectively. The median OS was 14.9 months (11–20), similar in the 2 arms, with 57% and 44% of patients that survived at 12 and 18 months respectively. We also compared for each patient the TTP on protocol and the TTP on the last prior line before entering in the study. The median TTP was 5 (4;8) months on study and 4 (3;5.5) months on the last prior line, with 28% and 15% of patients free of progression at 1 year; this difference in TTP dramatically increased when focusing on responders: the TTP on study has not been reached (43;-) and was 26 (20;39)months on the last prior line. 49% and 24% of patients were responders at 1year in the 2 groups, respectively. We found that TTP was greater on pomalidomide than on any other line of therapy that patientscould have access to in France at the time of the study. Interestingly, we noticed that all survival end points were significantly more prolonged in responders when compared to patients with SD. Median OS that has not been reached in responders, (18.4;-); and was 13 (8;20) months in patients with SD, (HR [95% CI) 0.45 [0.2,0.9], p=0.018). Noteworthy, 83% of responders and 50% of patients with SD were still alive after 12 months of treatment, and 69% and 36% were still alive at 18 months, respectively. Conclusion. Pomalidomide and dexamethasone is active and well tolerated in heavily pre-treated MM patients. The combination of pomalidomide and dexamethasone compared very favourably to the expected median OS reported in the historical control study in end stage MM. This study provides further evidence that pomalidomide can provide benefit for patients who have relapsed after other novel therapies. Disclosures: Leleu: Onyx: Honoraria, Speakers Bureau; Sanofi: Honoraria; Amgen: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Janssen: Honoraria, Research Funding, Speakers Bureau; Celgene: Honoraria, Research Funding, Speakers Bureau; LeoPharma: Honoraria, Speakers Bureau. Off Label Use: Pomalidomide. Kolb:janssen: Honoraria; celgene: Honoraria. Hulin:celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; janssen: Membership on an entity's Board of Directors or advisory committees. Attal:celgene: Membership on an entity's Board of Directors or advisory committees; janssen: Membership on an entity's Board of Directors or advisory committees. Facon:onyx: Membership on an entity's Board of Directors or advisory committees; celgene: Membership on an entity's Board of Directors or advisory committees; janssen: Membership on an entity's Board of Directors or advisory committees; millenium: Membership on an entity's Board of Directors or advisory committees.

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Relative Clone Size By FISH of Both Del(13q) and Del(17p) Independently Impact Overall Survival

Blood ◽

10.1182/blood.v128.22.4444.4444 ◽

2016 ◽

Vol 128 (22) ◽

pp. 4444-4444

Author(s):

Soluman Culver ◽

Nita Williams ◽

Nidhi Sharma ◽

Yvonne A Efebera ◽

Ashley E Rosko ◽

...

Keyword(s):

Multiple Myeloma ◽

Overall Survival ◽

Board Of Directors ◽

Research Funding ◽

Staging System ◽

Maximal Effect ◽

Advisory Committees ◽

Clone Size ◽

Interphase Fish ◽

The Impact

Abstract Introduction: Interphase FISH is used in the risk stratification of newly diagnosed multiple myeloma. The presence of high-risk cytogenetics is a key component of the Revised International Staging System (R-ISS), despite the fact that precise cutoffs for positivity have yet to be standardized and usage differs between institutions and reference labs. For deletion 17p, Avet-Loiseau et al (2007) used a 60% cutoff and An et al (2015) used 50% as a positive cutoff. For del(13q), Avet-Loiseau used del(13q14) 74% and An et al used 10%. Methods: Since 2011, consecutive patients in Ohio State University's myeloma clinic were consented to participate in the Ohio Myeloma Initiative (NCT01408225), an observational registry. We identified patients with multiple myeloma who had a bone marrow biopsy performed within six months of diagnosis. All FISH was performed after CD138 magnetic separation. We assessed the impact of del17p (P53) and del13q (RB1) on overall survival (OS). Results: 1,029 myeloma patient were identified, 767 patients with a FISH study within 6 months of diagnosis with an age range of 26-91. 39% of patients had an ISS 1, 34% had ISS 2, and 27% had ISS 3 disease. The median duration of follow-up for these patients was 3.17 years. 82.7% of patients had data regarding del13q, 82.5% had data regarding del17p, and 78.4% had data regarding both del13q and 17p. Using iterative survival analysis we calculated a maximal effect of del17p on OS occurring at 50% positivity on interphase FISH. Additionally, our data suggests that positivity for del13q is maximal at 40% positivity and a predictor of moderately decreased overall survival independent of 17p status. Moreover, our data suggests that intermediate FISH positivity for 17p does have a dose-dependent effect on OS with the presence of even non-dominant del17p clones exerting a measurable influence similar in effect size to del13q. Analyzing those patients with del13q >40% that were negative for del(17p) and t(4;14) (n=27), these patients suffered an inferior overall survival when compared to patients that were negative for del13q, del17p, and t(4;14) (n=116), p=0.0042. Conclusions: These findings suggest that specific cutoffs for both the del(13q) and del(17p) clones at diagnosis independently have statistically significant effects on overall survival. At the meeting, additional analyses will demonstrate the percentages of del(13q) that impact similarly on overall survival to those patients with del(17p) alone. A scoring system will be created to estimate hazard ratios for relative clone size % of del(13q) and del(17p) separately and when combined. Figure 1 Figure 1. Figure 2 Figure 2. Disclosures Hofmeister: Arno Therapeutics, Inc.: Research Funding; Signal Genetics, Inc.: Membership on an entity's Board of Directors or advisory committees; Celgene: Research Funding; Janssen: Pharmaceutical Companies of Johnson & Johnson: Research Funding; Karyopharm Therapeutics: Research Funding; Incyte, Corp: Membership on an entity's Board of Directors or advisory committees; Takeda Pharmaceutical Company: Research Funding; Teva: Membership on an entity's Board of Directors or advisory committees.

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Clinical Outcomes for Patients with Myeloid Malignancies Harboring IDH1/2mutations after Intensive Chemotherapy

Blood ◽

10.1182/blood-2018-99-119306 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 1389-1389 ◽

Cited By ~ 1

Author(s):

Swapna Thota ◽

Bhumika J. Patel ◽

Hetty E. Carraway ◽

Elizabeth A. Griffiths ◽

Amanda Przespolewski ◽

...

Keyword(s):

Overall Survival ◽

Board Of Directors ◽

Research Funding ◽

Somatic Mutations ◽

Response Rate ◽

Intensive Therapy ◽

Response To Therapy ◽

Intensive Chemotherapy ◽

Advisory Committees ◽

The Impact

Abstract Background: AML and MDS are heterogeneous myeloid neoplasias (MN) characterized by varied pathogenic mechanisms and associated with mixed clinical outcome. Five-year overall survival rates for younger AML patients (pts) are between 40-50% and for elderly pts, a dismal 10%. Until recently, molecular information has informed risk stratification for MN patients, but targeted therapies were limited (i.e ckit, flt3 inhibitors). Clinical characterization of IDH1/2mutant MN is of particular interest since the recent availability of specific IDH1/2inhibitors (i.e., enasidenib and ivosidenib). Datasets describing the outcome for patients with MN harboring IDH1/2mutations are critical to inform the potential utility of these novel IDH inhibitors as single agents or in combination with standard of care. Ongoing clinical trials are investigating the addition of IDH inhibition for upfront AML therapy. In this retrospective study, we combined cohorts from three institutions to enable reporting of the largest cohort (N=425) of IDH mutated MN pts in order to establish a baseline for therapeutic outcomes in an era which pre-dates the availability/addition of IDH inhibitors. Methods:We identified 425 patients from three large academic centers with a confirmed diagnosis of IDH1/2mutant AML (n=387), MDS (n=29) or MPN (n=9). Blood and bone marrow samples were analyzed for the presence of recurrent somatic mutations using NGS based multi-gene targeted sequencing panels. Demographic and disease related variables were annotated for initial treatment, response to therapy (IWG criteria) and subsequent survival details (overall survival, progression free survival). Time to first relapse and duration of remission was collected for 107 patients to date. Comprehensive response assessment details were available for 234 patients. Results: Of the 425 patients, 165 had a mutation inIDH1and 264 had a mutation in IDH2(82% IDH2R140, 18% R172K). Four cases had co-occurring mutations in IDH1 & IDH2. IDH1mutant cases were younger than IDH2mutant cases (62 vs. 65 years, p=0.05), predominantly male (50% vs.38%, p=0.01) and more likely to have intermediate risk AML (68% of IDH1/IDH2mutant cases had normal karyotype). A majority of these patients were treated with cytarabine-based intensive chemotherapy (n=362). Hypomethylating agents (n=29) or other less intensive therapies (n= 27) were also used. The overall response rate (ORR) to initial therapy was 65%. Response rates were similar for patients with both IDH1and IDH2mutation (i.e, 66% to any therapy). Response to intensive chemotherapy was 68% and 64% in IDH1and IDH2mutant cases respectively. As expected IDH1/2 mutant younger pts (<60 years) had a higher response rate to intensive chemotherapy (81% and 80 % respectively). The ORR for HMA therapy was 73% (64% IDH1, 80% IDH2mutants). 34% of IDH1mutants and 30%IDH2mutant patients underwent allogeneic stem cell transplantation. We have analyzed the impact of co-occurring somatic mutations on response to intensive chemotherapy. Non-responders to intensive therapy were enriched for RUNX1(26% vs.7%, p=0.002), SRSF2(34% vs.19%, p=0.045), and ASXL1 (18% vs.9%, p=0.11) mutations and were less likely to have NPM1 (24% vs. 51%, p=0.001) mutation. The median overall survival for IDH1 and IDH2 mutant MN caseswas 16.6 and 19.1 months, respectively. Conclusions: IDH1/2 mutated young AML patients appear to have chemo-sensitive disease. Despite excellent initial responses to intensive and non-intensive chemotherapy, the overall survival for IDH mutated pts was poor with shorter than expected remissions. Co-occurring mutations in RUNX1 and SRSF2 appeared to confer therapeutic resistance. Ongoing combination and maintenance strategies with targeted IDH1/2 inhibitors in conjunction with traditional therapies offer the potential to improve upon these outcomes in IDH1/2mutant MN. Future studies exploring the impact of early transplantation on overall survival for IDH1/2mutated MN are needed Disclosures Thota: Incyte: Speakers Bureau. Carraway:Novartis: Speakers Bureau; Jazz: Speakers Bureau; Agios: Consultancy, Speakers Bureau; Amgen: Membership on an entity's Board of Directors or advisory committees; FibroGen: Consultancy; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Balaxa: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Griffiths:Pfizer, Inc.: Research Funding; Novartis, Inc.: Research Funding; Celgene, Inc: Honoraria, Research Funding; Astex/Otsuka Pharmaceuticals: Honoraria, Research Funding; Alexion Inc.: Honoraria, Research Funding. Nazha:MEI: Consultancy. Gerds:CTI Biopharma: Consultancy; Apexx Oncology: Consultancy; Celgene: Consultancy; Incyte: Consultancy. Sekeres:Celgene: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Opsona: Membership on an entity's Board of Directors or advisory committees; Opsona: Membership on an entity's Board of Directors or advisory committees. Meggendorfer:MLL Munich Leukemia Laboratory: Employment. Wang:Amgen: Consultancy; Jazz: Speakers Bureau; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Speakers Bureau; Novartis: Speakers Bureau; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Jazz: Speakers Bureau; Amgen: Consultancy; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees. Maciejewski:Apellis Pharmaceuticals: Consultancy; Ra Pharmaceuticals, Inc: Consultancy; Apellis Pharmaceuticals: Consultancy; Alexion Pharmaceuticals, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Ra Pharmaceuticals, Inc: Consultancy; Alexion Pharmaceuticals, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.

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Hematopoietic Cell Transplantation with or without Sorafenib Maintenance for Patients with FLT3-ITD Acute Myeloid Leukemia in CR1

Blood ◽

10.1182/blood.v126.23.864.864 ◽

2015 ◽

Vol 126 (23) ◽

pp. 864-864 ◽

Cited By ~ 5

Author(s):

Andrew M. Brunner ◽

Shuli Li ◽

Amir T. Fathi ◽

Vincent T Ho ◽

Richard M. Stone ◽

...

Keyword(s):

Overall Survival ◽

Board Of Directors ◽

Research Funding ◽

Multivariable Analysis ◽

Control Group ◽

Advisory Committees ◽

Landmark Analysis ◽

Median Date ◽

The Impact ◽

Disease Free

Abstract Introduction: Patients with acute myeloid leukemia (AML) with internal tandem duplications in the fms-like tyrosine kinase 3 receptor (FLT3-ITD) are at high risk for relapse despite allogeneic hematopoietic cell transplantation (HCT) in first remission (CR1).We have previously shown sorafenib, an oral FLT3/multikinase inhibitor, to be safe as maintenance therapy after HCT (BBMT 2014;20:2042). We performed a retrospective study to evaluate the impact of sorafenib maintenance on outcomes of adult patients with FLT3-ITD AML undergoing HCT in CR1. Methods: We identified consecutive patients (n=80) at 2 institutions with AML between 2008 and 2014, with FLT3-ITD at diagnosis, who underwent HCT in CR1. Patients given sorafenib in remission after HCT were in the "sorafenib" group, and others were the "control" group. We identified the median date of sorafenib initiation, and performed a landmark analysis including only controls alive without relapse at that date. The primary outcome was overall survival (OS). We performed multivariable analysis, accounting for age >60, conditioning intensity, NPM1 status, cytogenetic risk, and donor type, to estimate the impact of sorafenib maintenance on OS, disease-free survival (DFS), non-relapse mortality (NRM), and time to relapse from the estimated date of sorafenib initiation. Cumulative incidence of grade 2-4 acute GVHD (aGVHD) and chronic GVHD (cGVHD) requiring systemic immunosuppression were estimated from date of transplant. Results: We identified 26 sorafenib patients and 54 control patients. Median follow up was 22.1 mo. (range, 6.3-49.8) for survivors in the sorafenib group, and 37.5 mo. (range, 12.4-88.9) in the control group (p=0.020). The median time to sorafenib was 68 days after transplant; subsequent analysis therefore included 26 sorafenib patients and 41 control patients alive without relapse at day +68. There were no significant differences in patient characteristics (Table 1). Two patients in the control group had concomitant FLT3-TKD mutations. Patients on sorafenib had improved 2-year OS compared to controls in the landmark analysis (83% vs. 58%, p=0.019, Figure 1). In multivariable analysis, sorafenib maintenance significantly improved OS (HR for death 0.146, p=0.0047) and DFS (HR 0.091, p=0.0005). Of patients alive without relapse at d+68, sorafenib maintenance was associated with improved 2-year DFS (85% vs. 52%, p=0.0047) and lower 2-year cumulative incidence of relapse (9.5% vs. 41%, p=0.0065). After 68 days, 2 sorafenib patients and 4 controls developed aGVHD. There was no difference in 2-year NRM (5.7% vs. 7.6%, p=0.61) or cumulative cGVHD at 1 year (50% vs. 37%, p=0.31). Conclusions: Sorafenib maintenance after HCT is associated with significantly improved DFS and OS among patients with FLT3-ITD AML undergoing HCT in CR1, with no difference in GVHD or NRM. These findings suggest a potential benefit of sorafenib and possibly other FLT3 inhibitors after HCT for FLT3-ITD AML, and support a randomized controlled trial of FLT3 inhibition after HCT. Table 1. Patient Demographics Control n=41 Sorafenib n=26 P-value Age (median, range) 53 (25,72) 54.5 (20,74) 0.39 HCT Age (median, range) 53 (25,73) 55 (20,74) 0.44 Gender (male, %) 12 (29%) 12 (46%) 0.20 Race (white, %) 35 (85%) 24 (92%) 1.00 ECOG at Diagnosis* 0.43 0 7 (39%) 7 (50%) 1 7 (39%) 7 (50%) 2 3 (17%) 0 3 1 (6%) 0 Antecedant Disease 0.58 De Novo 32 (78%) 22 (85%) tAML 4 (10%) 3 (12%) Prior MDS or MPN 5 (12%) 1 (4%) Cytogenetic Risk 1.00 Favorable 2 (5%) 1 (4%) Intermediate 35 (88%) 23 (88%) Adverse 3 (8%) 2 (8%) NPM1 mut# 20 (74%) 14 (56%) 0.25 CEBPA mut (n) 0 2 1.00 Induction Treatment 0.37 7+3 based induction 39 (95%) 23 (88%) Other induction 2 (5%) 3 (12%) TKI prior to HCT 10 (24%) 7 (27%) 1.00 ECOG at HCT+ 0.63 0 13 (32%) 6 (25%) 1 18 (44%) 14 (58%) 2 10 (24%) 4 (17%) HCT Intensity 1.00 Myeloablative 23 (56%) 14 (54%) Reduced intensity 18 (44%) 12 (46%) Donor Type 0.49 Matched 36 (88%) 21 (81%) Mismatched 5 (12%) 5 (19%) aGVHD prophylaxis 0.61 CNI and Methotrexate 24 (59%) 17 (65%) *Diagnosis ECOG missing in 23 control and 12 sorafenib patients #NPM1 testing performed on 27 control and 25 sorafenib patients +HCT ECOG missing in 2 sorafenib patients Figure 1. Disease-free and Overall Survival for FLT3-ITD AML patients, with or without sorafenib maintenance after HCT. Landmark analysis was performed from median date of sorafenib initiation (d+68). Figure 1. Disease-free and Overall Survival for FLT3-ITD AML patients, with or without sorafenib maintenance after HCT. Landmark analysis was performed from median date of sorafenib initiation (d+68). Figure 2. Figure 2. Disclosures Off Label Use: Sorafenib for FLT3-ITD AML. Fathi:Takeda Pharmaceuticals International Co.: Research Funding; Agios: Membership on an entity's Board of Directors or advisory committees; Exelexis: Research Funding; Merck: Membership on an entity's Board of Directors or advisory committees; Ariad: Consultancy; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees, Research Funding. Stone:Celator: Consultancy; Karyopharm: Consultancy; Pfizer: Consultancy; Celgene: Consultancy; AROG: Consultancy; Novartis: Research Funding; Abbvie: Consultancy; Sunesis: Consultancy, Other: DSMB for clinical trial; Amgen: Consultancy; Roche/Genetech: Consultancy; Merck: Consultancy; Juno: Consultancy; Agios: Consultancy. Soiffer:Gentium SpA/Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees. Chen:Bayer: Consultancy, Research Funding.

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A 40-Year Natural History Study of Overall Survival and Primary Causes of Death in Systemic Light Chain (AL) Amyloidosis

Blood ◽

10.1182/blood-2021-151804 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 155-155

Author(s):

Andrew Staron ◽

Luke Zheng ◽

Gheorghe Doros ◽

Lawreen H Connors ◽

Vaishali Sanchorawala

Keyword(s):

Overall Survival ◽

Natural History ◽

Board Of Directors ◽

Cardiac Failure ◽

Research Funding ◽

Causes Of Death ◽

Al Amyloidosis ◽

Advisory Committees ◽

Disease Outcomes ◽

Over Time

Abstract Background: Natural history studies, which describe changing disease outcomes under real-world clinical practice, can help support drug development for rare diseases by defining appropriate endpoints for clinical trials. The current study provides natural history information on survival and mortality in light chain (AL) amyloidosis, a rare disease that was historically considered inevitably fatal. With the recent expansion of effective therapeutics, patients with this disease are living longer, which in turn necessitates a better understanding of the factors leading to death in later disease course. Aims: To evaluate (1) trends in overall survival (OS) over time and (2) primary causes of death across the course of AL amyloidosis disease. Methods: We identified 2,337 patients diagnosed with systemic AL amyloidosis between 1980 and 2019 from the prospectively maintained database at the Boston University Amyloidosis Center (ClinicalTrials.gov Identifier: NCT00898235). Disease outcomes were analyzed according to date of tissue diagnosis: 1980-1989 (era 1, n = 185), 1990-1999 (era 2, n = 575), 2000-2009 (era 3, n = 865) and 2010-2019 (era 4, n =712). Survival information was verified through yearly clinical evaluations, contact by phone/letter for patients who did not return for follow-up, or the U.S. Social Security Death Index if contact was not established. We defined deaths as AL amyloidosis-related when clinical data indicated organ progression or complications from plasma cell-directed therapy. Deaths occurring while in remission, off treatment and without evidence of organ progression were considered disease-unrelated. Results: OS increased steadily across eras 1-4 with median values of 1.4, 2.6, 3.3 and 4.6 years, respectively (P < .001). Six-month mortality decreased over time from 23% to 13%. Notably, median age at diagnosis increased from 59 to 63 years (P < .001), and time interval to diagnosis from patient-reported symptom onset shortened from 10 months to 6 months (P = .065). At data cutoff (October 2020), 1,660 (71%) patients had died. Primary cause of death was ascertainable for 1,160 (70%) cases. Organ failure was most common, accounting for 564 (49%) deaths, amongst which cardiac failure predominated. Sudden unexpected death was the next most frequent cause, contributing to 266 (23%) deaths. Together, cardiac failure and sudden death decreased in proportion with longer survival from diagnosis, representing 67% (236/354) of deaths occurring within ≤6 months; 56% (322/575) within >6 months to ≤5 years; 36% (54/151) within >5 years to ≤10 years; and 36% (29/80) after >10 years (P < .001). Meanwhile, renal failure and infections emerged as important causes of later-occurring deaths. There was sufficient data on 1,243 (75%) deaths to assign relation to AL amyloidosis. The vast majority were disease-related. Yet, disease-unrelated deaths increased with longer survival from diagnosis, accounting for 2% (9/373) of deaths occurring within ≤6 months; 8% (48/616) within >6 months to ≤5 years; 16% (25/161) within >5 years to ≤10 years; and 29% (27/93) after >10 years (P < .001). Conclusions: Under changing standards of care, OS improved and early mortality declined over the last 40 years, supporting a much-improved outlook for current and future patients with AL amyloidosis. Cardiac failure and sudden deaths decreased across the course of disease. Even so, progression of amyloidosis remained a top cause of death even among long-term survivors. Figure 1 Figure 1. Disclosures Sanchorawala: Takeda: Research Funding; Celgene: Research Funding; Prothena: Membership on an entity's Board of Directors or advisory committees, Research Funding; Caelum: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Membership on an entity's Board of Directors or advisory committees; Regeneron: Membership on an entity's Board of Directors or advisory committees; Proclara: Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria; Karyopharm: Research Funding.

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Treatment Patterns and Outcomes in Elderly Patients with Newly Diagnosed Multiple Myeloma: Results from the Connect® MM Registry

Blood ◽

10.1182/blood-2019-126205 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 3129-3129

Author(s):

Hans C. Lee ◽

Sikander Ailawadhi ◽

Cristina Gasparetto ◽

Sundar Jagannath ◽

Robert M. Rifkin ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Causes Of Death ◽

Age Groups ◽

Treatment Patterns ◽

Age Group ◽

Newly Diagnosed ◽

Employment Equity ◽

Advisory Committees ◽

Equity Ownership

Background: Multiple myeloma (MM) is common among the elderly, with 35% of patients (pts) diagnosed being aged ≥75 years (y). With increasing overall life expectancy, the incidence and prevalence of newly diagnosed and previously treated MM patients ≥80 y is expected to increase over time. Because elderly pts are often excluded from clinical trials, data focused on their treatment patterns and clinical outcomes are lacking. The Connect® MM Registry (NCT01081028) is a large, US, multicenter, prospective observational cohort study of pts with newly diagnosed MM (NDMM) designed to examine real-world diagnostic patterns, treatment patterns, clinical outcomes, and health-related quality of life patient-reported outcomes. This analysis reviews treatment patterns and outcomes in elderly pts from the Connect MM Registry. Methods: Pts enrolled in the Connect MM registry at 250 community, academic, and government sites were included in this analysis. Eligible pts were adults aged ≥18 y with symptomatic MM diagnosed ≤2 months before enrollment, as defined by International Myeloma Working Group criteria; no exclusion criteria were applied. For this analysis, pts were categorized into 4 age groups: <65, 65 to 74, 75 to 84, and ≥85 y. Pts were followed from time of enrollment to the earliest of disease progression (or death), loss to follow-up, or data cutoff date of February 7, 2019. Descriptive statistics were used for baseline characteristics and treatment regimens. Survival outcomes were analyzed using Cox regression. Time to progression (TTP) analysis excluded causes of death not related to MM. Results: Of 3011 pts enrolled (median age 67 y), 132 (4%) were aged ≥85 y, and 615 (20%) were aged 75-84 y at baseline. More pts aged ≥85 y had poor prognostic factors such as ISS stage III disease and reduced hemoglobin (<10 g/dL or >2 g/dL <LLN) compared with other age groups, although no notable differences between creatinine and calcium levels were observed across age groups (Table). A lower proportion of elderly pts (75-84 and ≥85 y) received triplet regimens as frontline therapy. More elderly pts received a single novel agent, whereas use of 2 novel agents was more common in younger pts (Table). The most common frontline regimens among elderly pts were bortezomib (V) + dexamethasone (D), followed by lenalidomide (R) + D, whereas those among younger pts included RVD, followed by VD and CyBorD (Table). No pt aged ≥85 y, and 4% of pts aged 75-84 y received high-dose chemotherapy and autologous stem cell transplant (vs 61% in the <65 y and 37% in the 65-74 y age group). The most common maintenance therapy was RD in pts ≥85 y (although the use was low) and R alone in other age groups (Table). In the ≥85 y group, 27%, 10%, and 4% of pts entered 2L, 3L, and 4L treatments respectively, vs 43%, 23%, and 13% in the <65 y group. Progression-free survival was significantly shorter in the ≥85 y age group vs the 75-84 y age group (P=0.003), 65-74 y age group (P<0.001), and <65 y age group (P<0.001; Fig.1). TTP was significantly shorter in the ≥85 y group vs the <65 y group (P=0.020); however, TTP was similar among the 65-74 y, 75-84 y, and ≥85 y cohorts (Fig. 2). Overall survival was significantly shorter in the ≥85 y group vs the 75-84 y, 65-74 y, and <65 y groups (all P<0.001; Fig. 3). The mortality rate was lowest (46%) during first-line treatment (1L) in pts aged ≥85 y (mainly attributed to MM progression) and increased in 2L and 3L (47% and 54%, respectively); a similar trend was observed in the younger age groups. The main cause of death was MM progression (29% in the ≥85 y vs 16% in the <65 y group). Other notable causes of death in the ≥85 y group included cardiac failure (5% vs 2% in <65 y group) and pneumonia (5% vs 1% in <65 y group). Conclusions: In this analysis, elderly pts received similar types of frontline and maintenance regimens as younger pts, although proportions varied with decreased use of triplet regimens with age. Considering similarities in TTP across the 65-74 y, 75-84 y, and ≥85 y cohorts, these real-world data support active treatment and aggressive supportive care of elderly symptomatic pts, including with novel agents. Additionally, further clinical studies specific to elderly patients with MM should be explored. Disclosures Lee: Amgen: Consultancy, Research Funding; GlaxoSmithKline plc: Research Funding; Sanofi: Consultancy; Daiichi Sankyo: Research Funding; Celgene: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Janssen: Consultancy, Research Funding. Ailawadhi:Janssen: Consultancy, Research Funding; Takeda: Consultancy; Pharmacyclics: Research Funding; Amgen: Consultancy, Research Funding; Celgene: Consultancy; Cellectar: Research Funding. Gasparetto:Celgene: Consultancy, Honoraria, Other: Travel, accommodations, or other expenses paid or reimbursed ; Janssen: Consultancy, Honoraria, Other: Travel, accommodations, or other expenses paid or reimbursed ; BMS: Consultancy, Honoraria, Other: Travel, accommodations, or other expenses paid or reimbursed . Jagannath:AbbVie: Consultancy; Merck & Co.: Consultancy; Bristol-Myers Squibb: Consultancy; Karyopharm Therapeutics: Consultancy; Celgene Corporation: Consultancy; Janssen Pharmaceuticals: Consultancy. Rifkin:Celgene: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees. Durie:Amgen, Celgene, Johnson & Johnson, and Takeda: Consultancy. Narang:Celgene: Speakers Bureau. Terebelo:Celgene: Honoraria; Jannsen: Speakers Bureau; Newland Medical Asociates: Employment. Toomey:Celgene: Consultancy. Hardin:Celgene: Membership on an entity's Board of Directors or advisory committees. Wagner:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; American Cancer Society: Other: Section editor, Cancer journal. Omel:Celgene, Takeda, Janssen: Other: Patient Advisory Committees. Srinivasan:Celgene: Employment, Equity Ownership. Liu:TechData: Consultancy. Dhalla:Celgene: Employment. Agarwal:Celgene Corporation: Employment, Equity Ownership. Abonour:BMS: Consultancy; Celgene: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Janssen: Consultancy, Research Funding.

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Unexpected Toxicities When Nivolumab Was Given after Allogeneic Stem Cell Transplantation

Blood ◽

10.1182/blood-2019-123887 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 1956-1956

Author(s):

Amy Wang ◽

Justin Kline ◽

Wendy Stock ◽

Satyajit Kosuri ◽

Andrew S. Artz ◽

...

Keyword(s):

Clinical Trial ◽

Overall Survival ◽

Stem Cell ◽

Adverse Events ◽

Maintenance Therapy ◽

Board Of Directors ◽

Research Funding ◽

Checkpoint Inhibitors ◽

Advisory Committees ◽

Relapsed Disease

Background:Treatment options are limited for patients (pts) with hematologic malignancies who relapse after allogeneic stem cell transplantation (allo-SCT). We hypothesized that checkpoint inhibitors may offer a novel approach for maintaining remission after allo-SCT. Data from pre-clinical studies have suggested a potential role for PD-1/PD-L1 inhibitors in acute myeloid leukemia (AML) (Zhang et al., Blood 2009), so it is possible that immunomodulation with checkpoint inhibitors could stimulate the donor anti-leukemia immune response and prevent disease relapse. However, the safety of checkpoint blockade early after allografting remains to be established. Methods:We conducted a pilot study to assess the tolerability and efficacy of Nivolumab, a PD-1 inhibitor, as maintenance therapy after allo-SCT (NCT02985554). Pts were eligible if they were post allo-SCT without evidence of relapse or active graft-vs-host disease (GVHD) or history of prior greater than stage I skin acute GVHD. Nivolumab was to be administered intravenously at 1mg/kg every 2 weeks for 4 doses followed by dosing every 12 weeks. Treatment started 4 weeks after routine immunosuppression was discontinued until 2 years after the transplant. The primary objective was to determine the tolerability of Nivolumab on this schedule. Secondary objectives were evaluation of adverse events, relapse, and overall survival. Results:Four pts were enrolled from December 2017 through November 2018. (Table 1)All pts experienced immune-related adverse events (irAE) from Nivolumab, and 2 (50%) pts experienced serious adverse events. (Table 2)One pt developed grade (G) 4 neutropenia soon after the first dose. (Figure 1)The absolute neutrophil count nadired at 20 cells/µL, at which point pegfilgrastim was administered. An interim bone marrow biopsy (BMBx) confirmed no evidence of relapsed disease. Full neutrophil recovery occurred approximately 3 months after the initial dose, and no subsequent toxicities occurred. Another pt developed G3 autoimmune encephalopathy concurrently with G2 transaminitis and G2 thrombocytopenia after one dose of Nivolumab. (Figure 2)Intravenous methylprednisolone (1mg/kg daily for 3 days) and immunoglobulin (2g/kg in 4 divided doses) were administered, followed by a 7-week steroid taper with full resolution of symptoms. Relapsed disease was ruled out by a BMBx. A third pt developed G2 skin rash approximately 10 days after the first dose of Nivolumab. Skin biopsy demonstrated drug hypersensitivity reaction vs GVHD, and the pt was treated with a 3-week prednisone course (starting at 1mg/kg followed by a taper). A mild flare recurred 2 weeks later, which was treated with topical steroids only. However, Nivolumab was not resumed. The fourth pt developed G2 elevated TSH approximately 2 months into therapy and after 4 doses of Nivolumab. Thyroid hormone replacement was initiated with subsequent symptom improvement and normalization of TSH over a 4-month period. As a result of these unexpected severe toxicities, the study was closed to further enrollment, and further Nivolumab administration ceased. Thus far, one pt (#1) relapsed after a total remission duration of 530 days; the remission duration after starting Nivolumab was 318 days. One pt has mild chronic skin GVHD. All 4 patients remain alive with a median overall survival of 2.3 years (range, 1.9-4.7). Conclusions:Even at low doses, the use of Nivolumab as maintenance therapy in the post allo-SCT setting was not tolerable at the current dosing and schedule due to an unexpected number of high grade irAEs. Additional studies of dose and timing after allo-SCT are needed to improve safety and tolerability, in conjunction with correlative studies to better understand the immunomodulatory processes in the post-transplant setting. Disclosures Kline: Merck: Honoraria; Merck: Research Funding. Stock:Kite, a Gilead Company: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Daiichi: Membership on an entity's Board of Directors or advisory committees; Astellas: Membership on an entity's Board of Directors or advisory committees; Agios: Membership on an entity's Board of Directors or advisory committees; UpToDate: Honoraria; Research to Practice: Honoraria. Artz:Miltenyi: Research Funding. Larson:Agios: Consultancy; Novartis: Honoraria, Other: Contracts for clinical trials; Celgene: Consultancy. Riedell:Novartis: Research Funding; Verastem: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bayer: Honoraria, Speakers Bureau; Kite/Gilead: Honoraria, Research Funding, Speakers Bureau. Bishop:CRISPR Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Kite: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Juno: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Liu:Arog: Other: PI of clinical trial; BMS: Research Funding; Agios: Honoraria; Novartis: Other: PI of clinical trial; Karyopharm: Research Funding. OffLabel Disclosure: Nivolumab used as maintenance therapy in the post-transplant setting

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Outcome of Autologous Stem Cell Transplantation in Waldenström's Macroglobulinemia

Blood ◽

10.1182/blood-2018-99-116496 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 2149-2149

Author(s):

Romil Patel ◽

Neeraj Y Saini ◽

Ankur Varma ◽

Omar Hasan ◽

Qaiser Bashir ◽

...

Keyword(s):

Overall Survival ◽

Stem Cell ◽

Stem Cell Transplantation ◽

Board Of Directors ◽

Cell Transplantation ◽

Research Funding ◽

Advisory Committees ◽

First Remission ◽

Relapsed Disease

Abstract Introduction: The role of autologous hematopoietic stem cell transplantation (auto-HCT) in the management of patients with Waldenström Macroglobulinemia (WM), a rare, indolent lymphoma, has not been established. We had previously published our experience with auto-HCT in a small cohort of WM patients1. Here, we present an updated analysis of auto-HCT with a larger cohort of WM patients. Methods and study population: The study cohort was comprised of 29 patients who underwent high-dose chemotherapy and auto-HCT at MD Anderson Cancer Center (MDACC). The Kaplan-Meier method was used to create survival curves. Overall survival (OS) was defined as the duration from date of transplant to death or last date of follow-up in living patients. Progression-free survival (PFS) was defined as the duration from date of transplant to either progressive disease or death, whichever occurred first. Results: Median age at auto-HCT was 60 (range, 43-75 years). Eight patients (28%) had concurrent light chain amyloidosis (AL). Of the five patients who had MYD88 testing completed, 3 were positive for the MYD88 mutation. Additionally, of these 3 patients, 2 were also positive for CXCR4 mutation. Patients received a median of 2 lines (range 1-6) of therapy prior to auto-HCT; 3(10%) patients had primary refractory disease, 8(28%) were in first remission, and 18 (62%) had relapsed disease. Median time from transplant to last follow-up for the surviving patients was 5.3 years. Preparative regimens received by the patients were: Melphalan (n=20), BEAM-R (n=2), Busulfan/Melphalan (n=1), Cyclophosphomaide/Etoposide/total body irradiation (n=1), Thiotepa/Busulfan/Cyclophosphamide (n=1), and Carmustine/Thiotepa (n=1). Three patients further went on to receive allogeneic transplant either after relapse from auto-HCT or due to disease transformation to aggressive lymphoma. Twenty-eight patients achieved engraftment with a median time to neutrophil engraftment of 11 days (range, 10-15 days). One patient suffered primary graft failure due to progression of disease and died 84 days after transplant. Non-relapse mortality was 3.4% at 1 year. All patients were eligible for response evaluation. The median OS from diagnosis was 12.2 years. Overall response rate was 96%: complete response (n=8, 27.6%), very good partial response (n=5, 17.3%), partial response (n=15, 51.7%), and progressive disease (n=1, 3.4%). PFS and OS at 5 years were 43.3% and 62.9%, respectively. Median PFS and OS from auto-HCT were 4.1 and 7.3 years (Fig. 1A). The median OS from auto-HCT in first remission + primary refractory and relapsed disease was 8.2 years and 4.1 years, respectively.16 patients were alive at the time of censoring while 13 patients had died. Causes of death include relapsed disease (n=6), secondary malignancy (n=2), infection (n=1), chronic graft-versus-host disease (n=1), and unknown (n=3). 8 patients (28%) were positive for concurrent AL amyloidosis. The sites of amyloid involvement were kidneys (n=2), lungs (n=1), bone marrow (n=1), heart(n=1), lymph nodes(n=1), gastrointestinal tract (n=1) and subcutaneous fat aspirate(n=5). The median overall survival for patients with amyloid involvement (n=8) was 12 years. On univariate analyses, the number of chemotherapy regimens prior to transplant (≤ 2 vs >2 lines) was the strongest predictor of overall survival (p=0.03, HR 0.3, CI: 0.09-0.9, log-rank) and PFS (p=0.001, HR 0.24, CI: 0.07-0.85, log-rank). The median PFS in patients with ≤ 2 lines and > 2 lines of therapy was 71 months versus 19 months, respectively (Fig. 1B). Conclusion: Auto-HCT is safe and feasible in selected patients with WM, with a high response rate and durable remission even in patients with relapsed or refractory disease. References: Krina Patel et.al. Autologous Stem Cell Transplantation in Waldenstrom's Macroglobulinemia. Blood 2012 120:4533; Disclosures Thomas: Celgene: Research Funding; Bristol Myers Squibb Inc.: Research Funding; Acerta Pharma: Research Funding; Array Pharma: Research Funding; Amgen Inc: Research Funding. Lee:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies Corporation: Consultancy; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Chugai Biopharmaceuticals: Consultancy; Takeda Oncology: Consultancy, Membership on an entity's Board of Directors or advisory committees; Kite Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees. Orlowski:Takeda: Consultancy; Celgene: Consultancy; Spectrum Pharma: Research Funding; Janssen: Consultancy; Kite Pharma: Consultancy; Sanofi-Aventis: Consultancy; BioTheryX: Research Funding; Amgen: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy. Champlin:Otsuka: Research Funding; Sanofi: Research Funding. Patel:Poseida Therapeutics, Inc.: Research Funding; Takeda: Research Funding; Abbvie: Research Funding; Celgene: Research Funding.

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