scholarly journals Outcomes of Therapy with Venetoclax Combined with Hypomethylating Agents in Favorable-Risk Acute Myeloid Leukemia (AML)

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 41-42
Author(s):  
Shukaib Arslan ◽  
Jianying Zhang ◽  
Prajwal Dhakal ◽  
Jenna A. Moran ◽  
Nuthana Naidoo ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Board Of Directors ◽  
Older Patients ◽  
Research Funding ◽  
Response Rate ◽  
Hypomethylating Agents ◽  
Research Support ◽  
Advisory Committees ◽  
Lower Response Rate ◽  
Cebpa Mutations

Introduction: Venetoclax (VEN) in combination with a hypomethylating agents (HMA) is associated with a high rate of composite remission (complete remission [CR] and complete remission with incomplete recovery [CRi]) among older and unfit patients with untreated AML. However, data regarding the activity of VEN-HMA in those patients with favorable-risk AML is limited, particularly in those with core-binding factor (CBF) alterations. Although more frequent among younger patients, favorable-risk alterations are also observed among older patients, often unfit for intensive regimens. Even among the subset of older patients (>60 years) with favorable-risk AML eligible for intensive regimens, long-term outcomes are poorer in comparison to younger patients. Methods: We retrospectively analyzed outcomes of 46 patients with favorable-risk AML who underwent therapy with VEN-HMA between 2016-2020 at 4 academic cancer centers in US. Favorable-risk AML was defined by the presence of either CBF [t(8;21) and inv(16) or t(16;16)], NPM1 mutation in the absence of FLT-3 ITD mutations; or bi-allelic CEBPA mutations. Results: Forty-six patients with favorable risk AML were treated with HMA-VEN, including 26 (57%) with newly diagnosed (ND) and 20 (43%) with relapsed/refractory (R/R) AML (Table1). Ten (22%) patients had CBF, 21 (46%) had NPM1 mutations (NPM1m), and 13 (28%) had bi-allelic CEBPA mutations (CEBPAm). The median age was 70 years, and 54% were females. Patients with R/R AML were younger than ND patients (56 vs. 72 yrs, p=0.003). Twenty (44%) patients had secondary or therapy-related AML, including half of ND patients. The median lines of prior therapy were 2(1-4) in patients with R/R AML, including 6 (30%) who had failed prior allogeneic HCT. Eleven (24%) patients had received HMA prior to HMA-VEN therapy, including 1 patient in the ND cohort for prior MDS. Eleven (24%) patients received azacitidine in combination with VEN, while the rest (76%) of patients received decitabine, including 14 patients who received 10-day decitabine during the first cycle. The CR/CRi rate among the whole cohort was 80%, including 52% CR and 28% CRi. There was no statistically significant difference in CR/CRi rate between ND and R/R patients (88% vs. 70%, P =0.15). However, patients with history of prior HMA exposure had lower response rate compared to HMA-naïve patients (55% vs. 88%, p= 0.025). No difference in response was observed based on the favorable genetic alteration subgroups (80% in CBF vs. 86% in NPM1m vs. 77% in CEBPAm, p=0.44). Furthermore, no difference in response was observed according to patient age (p= 0.83), AML types (de novo vs. secondary; p= 0.47), prior transplant (p=1.00), or the type and schedule of HMA (P=0.66). Among the responders who had MRD assessment done (n= 26), 22 (85%) achieved MRD negativity by multicolor flow cytometry. Post response, 13 (35%) patients underwent allogeneic transplant consolidation. The median overall survival (OS) for the whole cohort was 18 months (12.5-NA). Median leukemia-free survival (LFS) was 13.2 months (7-20.2) for all responders, 11.2 months (1.7-NA) for ND responders, and 14.0 months (1-NA) for RR responders (p=0.986). The 30- and 60-day mortality for the whole cohort was 0% and 9%, respectively. Conclusion: In patients with favorable-risk AML, VEN-HMA combination is associated with a highly promising CR/CRi rate, with durable responses. The majority of responders achieved MRD negativity. Patients with prior use of HMA had lower response rate with VEN-HMA, nonetheless, over half of these patients responded despite most being treated in the R/R setting. Disclosures Pullarkat: Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Servier: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizer: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Genetech: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AbbVie, Inc.: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Dova: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Stein:Stemline: Consultancy, Speakers Bureau; Amgen: Consultancy, Speakers Bureau. Marcucci:Abbvie: Speakers Bureau; Merck: Other: Research Support (Investigation Initiated Clinical Trial); Novartis: Speakers Bureau; Pfizer: Other: Research Support (Investigation Initiated Clinical Trial); Takeda: Other: Research Support (Investigation Initiated Clinical Trial); Iaso Bio: Membership on an entity's Board of Directors or advisory committees. Yaghmour:Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Agios: Consultancy, Membership on an entity's Board of Directors or advisory committees; Astellas: Consultancy, Speakers Bureau; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Jazz: Consultancy, Speakers Bureau; Alexion: Consultancy, Speakers Bureau. Bhatt:Omeros: Consultancy; Agios: Consultancy; Rigel: Consultancy; Tolero: Research Funding; Pfizer: Research Funding; Abbvie: Consultancy, Research Funding; Incyte: Consultancy, Research Funding; Partnership for health analytic research: Consultancy; Takeda: Consultancy; Jazz: Research Funding; National Marrow Donor Program: Research Funding; Oncoceutics: Other. Fathi:Takeda: Consultancy, Research Funding; Jazz: Consultancy; Forty Seven: Consultancy; Daiichi Sankyo: Consultancy; Amphivena: Consultancy; Blueprint: Consultancy; Kura Oncology: Consultancy; Boston Biomedical: Consultancy; Astellas: Consultancy; Trovagene: Consultancy; Novartis: Consultancy; PTC Therapeutics: Consultancy; Agios: Consultancy, Research Funding; BMS/Celgene: Consultancy, Research Funding; Kite: Consultancy; Pfizer: Consultancy; Trillium: Consultancy; Amgen: Consultancy; Seattle Genetics: Consultancy, Research Funding; Abbvie: Consultancy; Newlink Genetics: Consultancy.

scholarly journals Iadademstat in Combination with Azacitidine Generates Robust and Long Lasting Responses in AML Patients (ALICE Trial)

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 3376-3376
Author(s):  
Olga Salamero ◽  
Tim C.P Somervaille ◽  
Antonieta Molero ◽  
Evelyn Acuña-Cruz ◽  
Jose Pérez-Simón ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Board Of Directors ◽  
Research Funding ◽  
Response Rate ◽  
Objective Response ◽  
Therapeutic Options ◽  
Dose Finding ◽  
Open Label ◽  
Advisory Committees ◽  
Platelet Recovery

Abstract Introduction: Acute Myeloid Leukemia (AML) is an aggressive hematological malignancy. Elderly patients were historically treated with chemotherapy, with ORRs below 30%. Despite treatment improvements with the recent approval of the combination venetoclax plus azacitidine, with 64% of ORR and overall survival of 14.7 months, 25% of patients continue to be refractory and 50% are estimated to relapse. The management of AML, especially in elderly or unfit patients, remains a major challenge. Lysine-specific histone demethylase 1 (LSD1) contributes to the malignant transformation event in AML. Iadademstat (iada) selectively inhibits LSD1 and has shown efficacy in preclinical models, including promoting differentiation in AML. Iada has been administered so far to +100 oncology patients in different clinical trials, showing good safety. With a favorable ADME profile and high bioactivity allowing low dosing regimens, a low DDI risk is anticipated, making iada suitable for different drug combinations and offering additional therapeutic options for patients. This is a 36-month update of the ongoing Phase II ALICE clinical trial of iadademstat plus azacitidine in front-line AML patients. Methods: ALICE (EudraCT 2018-000482-36) is an open-label, single arm, Phase IIa clinical trial to assess the safety, tolerability, dose finding and efficacy of iadademstat in combination with azacitidine for the treatment of adult AML patients. ALICE includes AML patients, who have not received prior treatment other than hydroxyurea and are considered by the investigator as ineligible for intensive chemotherapy or have refused this treatment option. Secondary end points of the study address the anti-leukemic activity of the combination (overall response rate, time to response and duration of response) along with PK/PD measures. Results: Current unaudited data corresponds to 34 patients enrolled, including 22 evaluable patients (with at least 1 bone marrow disease evaluation). Evaluable patients achieved an 73% objective response rate (ORR): 5 complete remissions (CR), 6 CR with incomplete hematological recovery (CRi) and 5 Partial Remissions (PR). The current median Time to Response is 30 days, with some durable responses, extending for more than one year in five patients, with the longest CR up to date above 930 days (still ongoing, with CR and MRD negative). Moreover, 5 patients became transfusion independent and MRD negative. The number of adverse events (AEs) reported is in line with the usual evolution of the disease and with other AML trials. Only 2 AEs (in 2 patients) were deemed as serious reactions, probably related to treatment: one differentiation syndrome (G3) and one intracranial hemorrhage (G5). The most frequent reported adverse reaction was thrombocytopenia, observed in almost half of patients (47%), although 63% of patients had presented with grade ≥3 thrombocytopenia at baseline, making difficult to unequivocally attribute observed cytopenias to treatment. Of note, patients that showed response experienced platelet recovery within the first 3 cycles of treatment. Other than the hematological events, the iada-azacitidine combination appears to be safe and well tolerated. We have not observed other significant non-hematological toxicities or other organ-related toxicities. We expect to achieve full patient recruitment of the ALICE study (36 subjects) in October 2021 and will report updated safety and efficacy results based on an October data cut-off. Conclusions: Data to date indicate that iadademstat has a good safety profile and produces robust, fast and in some cases durable responses. Iadademstat appears to be an active candidate for combination with azacitidine and other agents. Drug-related toxicity appears to be predictable, manageable, and restricted to hematologic events. Considering the novel mechanism of action of iadademstat, a pro-differentiating agent, combination strategies with iadademstat might increase therapeutic options for AML patients in first line treatment, as well as for refractory, intolerant, or relapsed patients. Disclosures Salamero: Pfizer: Consultancy; BMS/Celgene: Consultancy, Honoraria; Novartis: Consultancy, Honoraria. Somervaille: Novartis: Consultancy, Honoraria. Molero: AbbVie: Honoraria; Jansen: Honoraria; BMS-Celgene: Other: Travel, accommodation expenses. Pérez-Simón: Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Gutierrez: Oryzon Genomics: Current Employment. Buesa: Oryzon Genomics: Current Employment, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties. Bosch: Roche: Membership on an entity's Board of Directors or advisory committees, Other: Travel; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Research Funding; AbbVie: Membership on an entity's Board of Directors or advisory committees, Other: Travel; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel; TAKEDA: Membership on an entity's Board of Directors or advisory committees, Other: Travel. Montesinos: Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Tolero Pharmaceutical: Consultancy; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Sanofi: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Teva: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Stemline/Menarini: Consultancy; Forma Therapeutics: Consultancy; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Incyte: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Daiichi Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Karyopharm: Membership on an entity's Board of Directors or advisory committees, Research Funding; Glycomimetics: Consultancy; Agios: Consultancy; AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Astellas Pharma, Inc.: Consultancy, Honoraria, Other: Advisory board, Research Funding, Speakers Bureau.

scholarly journals Hypomethylating Agent Therapy for Chronic Myelomonocytic Leukemia Does Not Impact Acute Myeloid Leukemia Transformation or Survival

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 6-7
Author(s):  
Sandrine Niyongere ◽  
Yamini Kathari ◽  
Zeba Singh ◽  
Emily J. Vannorsdall ◽  
Ashkan Emadi ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Board Of Directors ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
Chronic Myelomonocytic Leukemia ◽  
Institutional Research ◽  
Research Support ◽  
Advisory Committees ◽  
Clinical Trial Research ◽  
Myelomonocytic Leukemia

Background: Chronic myelomonocytic leukemia (CMML) is a clonal hematopoietic stem cell disorder with features of both myeloproliferative neoplasm and myelodysplastic syndrome (MDS). CMML is characterized by persistent blood monocytosis >1 x 109/L, bone marrow dysplasia in one or more hematopoietic cell lines, and increased risk of transformation to acute myeloid leukemia (AML). Our review of SEER Medicare data (Haematologica 2013;98:584) demonstrated that, compared to MDS, CMML has shorter overall survival (OS) and more frequent progression to AML. Hypomethylating agents (HMAs) have become standard therapy for CMML, with reported response rates of 37-69%, but their impact on AML transformation and OS is unclear. Methods: We retrospectively reviewed CMML patients treated at the University of Maryland Greenebaum Comprehensive Cancer Center between January 2000 and December 2019. Clinical characteristics, treatments, AML progression, time to AML progression (TTP), and OS were recorded and analyzed. Descriptive statistics were used for baseline characteristics and Kaplan-Meier analysis was performed for time-to-event data. Statistical analyses were performed using GraphPad Prism 8®. Results: We identified 71 patients with CMML, 82% male and 73% white, with a median age of 69 (range 25 - 96) years; 51% had <10% bone marrow (BM) blasts and 45% had low-risk cytogenetic findings (normal karyotype or -Y). Most patients treated prior to 2005 received hydroxyurea and/or erythropoiesis-stimulating agents or were enrolled on clinical trials, while patients treated since 2005 received HMAs as primary therapy. Median follow-up was 41.1 months. The median OS of the entire cohort was 20 months, with 46% of patients progressing to AML with a median TTP of 11.5 months. By the MD Anderson Prognostic Scoring System at time of diagnosis, CMML was low-risk in 24 patients, intermediate-1 in 16, intermediate-2 in 14, and high-risk in 17. Forty-six patients received HMAs, with an overall response rate (ORR) of 54% (complete response or partial response), while 25 patients did not receive HMAs. Patient and disease characteristics were similar in HMA- and non-HMA-treated patients (Table 1). The estimated OS of HMA-treated patients was 20 months, compared to 14 months for non-HMA-treated patients (p =0.43) (Figure 1). AML transformation occurred in 52% of patients treated with HMAs, with TTP ranging from 3 to 65 months, and in 33% patients not treated with HMAs, with TTP ranging from 5 to 47 months. Most patients receiving HMAs (63%) received ≥ 6 cycles; 46% transformed to AML despite initial response, often in a sudden and unpredictable manner. HMAs were azacitidine in 13 patients, decitabine in 24, azacitidine followed by decitabine in 4, and decitabine followed by azacitidine in 5. Five CMML patients in our cohort underwent allogenic stem cell transplantation. Four of the five relapsed with transformation to AML post transplant, and only one patient remains in remission, 9 months post transplant. Conclusions: Despite a 54% ORR, HMA treatment did not have a significant impact on frequency of AML transformation, or OS in our cohort. Based on our data, favorable response rates previously reported with HMAs and also seen in our patients do not appear to translate into decreased frequency of AML transformation or prolonged OS. Though our study is a retrospective study with inherent selection bias, our results underscore the ongoing need for novel therapies and for clinical trials for CMML patients. Disclosures Niyongere: Kartos Therapeutics: Other: Received clinical trial research support with Kartos Therapeutics ; Forty Seven: Other: Received clinical trial research support with Forty Seven. Emadi:Amgen: Membership on an entity's Board of Directors or advisory committees; KinaRx: Other: co-founder and scientific advisor; NewLink Genetics: Research Funding; Genentech: Membership on an entity's Board of Directors or advisory committees; Servier: Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Research Funding. Doung:Pfizer: Membership on an entity's Board of Directors or advisory committees, Other: clinical trial research support; Incyte: Other: clinical trial research support; Astex: Other: clinical trial research support; MedPacto: Other: clinical trial research support. Baer:Takeda: Other: Institutional research funding; Oscotec: Other: Institutional research funding; Kite: Other: Institutional research funding; Incyte: Other: Institutional research funding; Forma: Other: Institutional research funding; Astellas: Other: Institutional research funding; AbbVie: Other: Institutional research funding.

scholarly journals Myeloid-Lineage Enhancers Drive Oncogene Synergy and Represent a Novel Therapeutic Target in CSF3R-CEBPA Mutant AML

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 543-543
Author(s):  
Theodore Braun ◽  
Cody Coblentz ◽  
Sarah A Carratt ◽  
Mariam Okhovat ◽  
Amy Foley ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Board Of Directors ◽  
Median Survival ◽  
Stock Options ◽  
Research Funding ◽  
Wild Type ◽  
Advisory Committees ◽  
Dana Farber Cancer Institute ◽  
Equity Ownership ◽  
Cebpa Mutations

Acute Myeloid Leukemia (AML) results from the stepwise accumulation of mutations from distinct functional classes, ultimately culminating in malignant transformation. Based on their oncogenic activity, mutations can be classified into three distinct groups. Class I mutations activate signaling pathways, produce uncontrolled proliferation, and in isolation produce a myeloproliferative phenotype. Class II mutations result from point mutations or chromosomal translocation events in lineage determining transcription factors, producing differentiation arrest and myelodysplasia in isolation. A classic example of oncogene synergy between distinct mutational classes can be found in the co-occurrence of mutations in the transcription factor CCAAT-enhancer binding protein alpha (CEBPA) with mutations in colony stimulating factor receptor 3 (CSF3R). Mutations in CEBPA occur in approximately 10% of AML where they block differentiation and convey favorable risk. In contrast, CSF3R mutations lead to constitutive receptor activation and uncontrolled neutrophil proliferation. In the absence of co-occurring Class II mutations, membrane proximal CSF3R mutations produce the myeloproliferative neoplasm chronic neutrophilic leukemia (CNL). Interestingly, patients with CEBPA mutant AML that also harbor an oncogenic CSF3R mutation have worse prognosis than those with wild type CSF3R. However, the mechanism underlying this oncogene synergy remains unknown. To model the co-occurrence of these mutations, we expressed CSF3RT618I (The most common membrane proximal CSF3R mutation) in fetal liver hematopoietic stem cells harboring compound heterozygous CEBPA mutations in the endogenous allele (CEBPAK/L). Mice transplanted with mutant CEBPA alone developed a long latency AML with a median survival of 60 weeks. In contrast, mice transplanted with mutant CSF3RT618I/CEBPAK/L cells developed a much more rapid AML with a median survival of 13 weeks. These results were corroborated in an orthogonal model in which mutant CSF3R and a C-terminal mutant CEBPA were retrovirally expressed prior to bone marrow transplant. To dissect the underlying mechanism, we performed a comprehensive transcriptomic and epigenetic analysis on cells expressing each mutation in isolation as well as the combination. This analysis revealed that mutant CSF3R activates a distinct set of enhancers that regulate genes associated with differentiation and drive neutrophil differentiation. Co-expression of mutant CEBPA blocks the activation differentiation-associated enhancers but is permissive to those associated with proliferation. Differentiation but not proliferation-associated enhancers are bound by wild type CEBPA. Thus, the dominant negative impact of mutant CEBPA at these enhancers explains its differential impact on differentiative and proliferative transcriptional programs. Enhancer activation precedes promoter activation and CEBPA mutations are thought to represent early events in AML initiation. The epigenetic mechanism underlying the observed oncogene synergy argues that CEBPA mutations must occur prior to CSF3R to impact differentiation. We therefore developed a retroviral vector system enabling temporal control of Cre-mediated oncogene expression. Using this system, we found that only when mutant CEBPA is expressed prior to mutant CEBPA is differentiation arrest observed. Furthermore, AML develops in vivo only when mutant CEBPA is expressed prior to mutant CSF3R. To develop novel therapeutic strategies for this subclass of AML with adverse prognosis, we performed medium throughput drug screening on CSF3R/CEBPA mutant AML cells and identified sensitivity to inhibitors of JAK/STAT signaling as well as Lysine Demethylase 1 (LSD1). In other subtypes of AML, LSD1 inhibitors activate enhancers associated with differentiation. We confirmed that LSD1 inhibition promotes neutrophilic differentiation in CSF3R/CEBPA and through epigenetic and transcription profiling establish that this occurs via the reactivation of differentiation-associated enhancers. We further found that the combination of ruxolitinib (JAK/STAT inhibitor) and GSK2879552 produce a complete hematologic response and double median survival in mice harboring CSF3R/CEBPA mutant AML. Thus, the combination of JAK/STAT and LSD1 inhibitors represents and exciting therapeutic strategy for CSF3R/CEBPA mutant AML. Disclosures Druker: Celgene: Consultancy; Gilead Sciences: Other: former member of Scientific Advisory Board; ICON: Other: Scientific Founder of Molecular MD, which was acquired by ICON in Feb. 2019; Monojul: Other: former consultant; Novartis: Other: PI or co-investigator on clinical trial(s) funded via contract with OHSU., Patents & Royalties: Patent 6958335, Treatment of Gastrointestinal Stromal Tumors, exclusively licensed to Novartis, Research Funding; Bristol-Myers Squibb: Other: PI or co-investigator on clinical trial(s) funded via contract with OHSU., Research Funding; Pfizer: Other: PI or co-investigator on clinical trial(s) funded via contract with OHSU., Research Funding; Beat AML LLC: Other: Service on joint steering committee; The RUNX1 Research Program: Membership on an entity's Board of Directors or advisory committees; Patient True Talk: Consultancy; GRAIL: Equity Ownership, Other: former member of Scientific Advisory Board; Cepheid: Consultancy, Honoraria; Burroughs Wellcome Fund: Membership on an entity's Board of Directors or advisory committees; Blueprint Medicines: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Beta Cat: Membership on an entity's Board of Directors or advisory committees, Other: Stock options; Aptose Biosciences: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Amgen: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; ALLCRON: Membership on an entity's Board of Directors or advisory committees; Vivid Biosciences: Membership on an entity's Board of Directors or advisory committees, Other: Stock options; OHSU (licensing fees): Patents & Royalties: #2573, Constructs and cell lines harboring various mutations in TNK2 and PTPN11, licensing fees ; Merck & Co: Patents & Royalties: Dana-Farber Cancer Institute license #2063, Monoclonal antiphosphotyrosine antibody 4G10, exclusive commercial license to Merck & Co; Dana-Farber Cancer Institute (antibody royalty): Patents & Royalties: #2524, antibody royalty; CureOne: Membership on an entity's Board of Directors or advisory committees; Pfizer: Research Funding; Aileron Therapeutics: #2573, Constructs and cell lines harboring various mutations in TNK2 and PTPN11, licensing fees , Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Patents & Royalties, Research Funding.

scholarly journals What Is the Optimal Time to Initiate Hypomethylating Agents (HMA) in Higher Risk Myelodysplastic Syndromes (MDS)?

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 3098-3098 ◽  
Author(s):  
Rami S. Komrokji ◽  
Najla Al Ali ◽  
David A Sallman ◽  
Eric Padron ◽  
Aziz Nazha ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Response Rate ◽  
Disease Risk ◽  
Response Rates ◽  
Complete Response ◽  
Optimal Time ◽  
Hypomethylating Agents ◽  
Advisory Committees ◽  
Baseline Characteristics

Abstract Background: Hypomethylating agents (HMA) are the standard of care for higher risk MDS patients (pts). Fewer than one-half will respond to therapy for an average duration of one year, thereby emphasizing the necessity to optimize the use of these disease modifying agents. HMA clinical trials have not addressed the optimal time in the disease course to initiate treatment to maximize disease-modifying potential. The current dogma is to begin HMA therapy in all higher risk MDS pts at the time of initial diagnosis. Nevertheless, a subset of higher risk MDS pts will have adequate hematopoiesis at the time of diagnosis regardless of disease risk, and for these pts therapy may be delayed and reserved for a later time when symptomatic cytopenias develop. We investigated the impact of the timing of HMA initiation on outcomes among higher risk MDS pts presenting with adequate blood counts to discern the possible benefit of early treatment based solely on disease risk. Methods: We identified MDS pts with intermediate-2 and high risk IPSS (higher risk) MDS treated with HMA among the Moffitt Cancer Center database. We included patients with adequate hematopoiesis defined for the purpose of this study as platelets >50 x 109/L, Hgb > 9 g/dl and ANC > 0.5 x 109/L and being transfusion independent to exclude those pts in need of HMA treatment for cytopenias. We divided patients into 4 groups based on the time of HMA initiation (within 30, 31-60 , 61-90 and greater than 90 days from time of diagnosis). We compared baseline characteristics, best response rate to treatment using international working group criteria (IWG 2006), leukemia free survival (LFS) and overall survival (OS) among the 4 groups. Results: We identified 320 higher risk MDS pts with adequate hematopoiesis who were treated with HMA. Baseline characteristics for the 4 groups based upon time of HMA therapy initiation are summarized in Table-1. Pts receiving treatment within 30 days had higher marrow myeloblast percentage at time of diagnosis. There was no difference in mean blood counts at time of diagnosis between the 4 groups; however, mean platelet count was lower at time of initiating HMA therapy in patients treated after 90 days from diagnosis. Table-2 summarizes somatic gene mutation data among 110 patients tested. TET-2 mutations were more common among those treated within 60 days, whereas U2AF1 mutations were more common among those treated after 60 days from diagnosis. The complete response rates were 21%, 26%, 23% and 7%, respectively for pts treated within 30 , 31-60 , 61-90 and greater than 90 days from time of diagnosis (p=0.046). The overall response rates (defined as hematological improvement or better) were 43%, 41%, 43% and 34%, respectively for pts treated within 30, 31-60 , 61-90 and greater than 90 days from date of diagnosis (p .70). There was no difference in mean duration of treatment with HMA among the groups with mean durations of 267, 204, 224 and 215 days, respectively, (p .35). The median OS from the date of diagnosis was 641, 550, 979 and 806 days, respectively for pts treated within 30, 31-60, 61-90 and greater than 90 days from date of diagnosis (p .2). There was no impact of timing for HMA initiation when adjusted for Revised-IPSS risk groups in Cox regression analysis. There was no difference in OS based on HMA initiation time when adjusted for myeloblasts % or karyotype. Further, there was no difference between groups in rate of AML transformation or LFS (p =.7 and .16, respectively). Conclusions A delay in initiating HMA therapy in higher risk MDS pts with adequate blood counts is not associated with worsened overall survival or increased frequency of leukemia transformation. Complete response rates were higher when treatment was started earlier in the disease course, however, there was no difference in overall response rate. Close observation to initiate treatment upon development of clinically significant cytopenias appears to be a safe and equally effective strategy among pts with higher risk MDS. Disclosures Komrokji: Novartis: Honoraria, Speakers Bureau; Celgene: Honoraria, Research Funding; Novartis: Honoraria, Speakers Bureau; Novartis: Honoraria, Speakers Bureau; Novartis: Honoraria, Speakers Bureau; Celgene: Honoraria, Research Funding. Sallman:Celgene: Research Funding, Speakers Bureau. Nazha:MEI: Consultancy. Steensma:Takeda: Consultancy; Syros: Research Funding; Otsuka: Membership on an entity's Board of Directors or advisory committees; Onconova: Consultancy; Novartis: Membership on an entity's Board of Directors or advisory committees; Kura: Research Funding; Janssen: Consultancy, Research Funding; H3 Biosciences: Research Funding; Celgene: Research Funding; Amphivena: Membership on an entity's Board of Directors or advisory committees; Acceleron: Consultancy. Roboz:AbbVie: Consultancy; Daiichi Sankyo: Consultancy; Jazz Pharmaceuticals: Consultancy; Cellectis: Research Funding; Novartis: Consultancy; Celltrion: Consultancy; Astex Pharmaceuticals: Consultancy; Sandoz: Consultancy; Celgene Corporation: Consultancy; Otsuka: Consultancy; Janssen Pharmaceuticals: Consultancy; Aphivena Therapeutics: Consultancy; Daiichi Sankyo: Consultancy; Orsenix: Consultancy; Bayer: Consultancy; Aphivena Therapeutics: Consultancy; Argenx: Consultancy; Orsenix: Consultancy; Novartis: Consultancy; Jazz Pharmaceuticals: Consultancy; Eisai: Consultancy; Celgene Corporation: Consultancy; AbbVie: Consultancy; Roche/Genentech: Consultancy; Cellectis: Research Funding; Otsuka: Consultancy; Bayer: Consultancy; Pfizer: Consultancy; Astex Pharmaceuticals: Consultancy; Argenx: Consultancy; Sandoz: Consultancy; Celltrion: Consultancy; Janssen Pharmaceuticals: Consultancy; Pfizer: Consultancy; Eisai: Consultancy; Roche/Genentech: 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. List:Celgene: Research Funding.

scholarly journals Anti-CD123 Targeted Therapy with Talacotuzumab in Advanced MDS and AML after Failing Hypomethylating Agents - Final Results of the Samba Trial

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 4045-4045 ◽  
Author(s):  
Anne Sophie Kubasch ◽  
Freya Schulze ◽  
Katharina S. Götze ◽  
Jan Krönke ◽  
Katja Sockel ◽  
...  
Keyword(s):  
Nk Cells ◽  
Board Of Directors ◽  
Research Funding ◽  
Treatment Initiation ◽  
Response Rate ◽  
Nk Cell ◽  
Single Agent ◽  
Hypomethylating Agents ◽  
Advisory Committees ◽  
Disease Stabilization

Abstract Introduction Recently, progress has been made in the treatment of patients with higher risk myelodysplastic syndromes (HR MDS) and acute myeloid leukemia (AML). Nevertheless, patients failing hypomethylating agents (HMA) have a dismal prognosis and very limited treatment options. Targeting CD123 on leukemic stem cells (LSC) is one promising approach in MDS and AML. Talacotuzumab (TAL, JNJ-56022473) is an IgG1 monoclonal antibody targeting CD123 preferentially via antibody-dependent cellular cytotoxicity (ADCC) mediated by natural killer cells (NKs). Aim The SAMBA trial, a phase II study of the German and French MDS study groups within the EMSCO network assessed the overall hematological response rate after 3 months of single agent TAL treatment in AML or HR MDS patients failing hypomethylating agents (HMAs). Methods TAL was given IV at a dose of 9 mg/kg once every two weeks for a total of 6 infusions, responders received up to 20 additional infusions. After the first 3 months, overall hematological response rate (either CR, PR, marrow-CR, HI, SD) was evaluated by bone marrow biopsy. The study was accompanied by an immune monitoring via flow cytometric analysis to investigate the distribution of T- and NK cells in peripheral blood (PB) and bone marrow (BM) at the time of screening and during therapy in comparison with healthy, age-matched controls. Results 24 patients (19 AML and 5 HR MDS) with a median age of 77 (range 71-90) years, who either failed to achieve complete- (CR), partial response (PR), hematological improvement (HI) or relapsed after HMA therapy were included in the study. After TAL administration, 14 patients could be assessed for response after 4 infusions and 10 patients after 6 infusions. The overall response rate (ORR) was 20.8% including 1 complete remission (CRi), 1 patient with hematologic improvement (HI-E) and additionally 3 patients with disease stabilization. The median duration of response in these patients was 3 months (range 3-14 months). Two patients are still on treatment, one patient despite losing objective response (14 months) and one patient with disease stabilization (13 months). The median overall survival for the entire cohort of patients was 3.2 months (range 0.4-11.2 months). In 10 patients (41.6%), therapy with TAL resulted in grade 3/4 infusion related side effects (pneumonia, n=1; infusion-related reaction, n=8; septic shock, n=1). Before treatment initiation, patients had lower levels of CD56dim NK-cells in PB (82% vs. 89% of NK-cells; p=0.069) expressing significantly more inhibiting NK-cell receptors like KIR2DL2 (8.8% vs. 3.2% of NK-cells; p<0.001) and less activating NK-cells receptors like NKG2D (95% vs. 99% of NK-cells; p<0.01) compared to healthy controls. Moreover, expression of PD-1 on lymphocytes and monocytes as well as their matching ligands PD-L1 and PD-L2 on blasts and monocytes in PB was significantly higher in patients compared to healthy controls (p<0.01), another evidence for an exhausted T-cell immune status in our patients prior to treatment initiation. We could not detect any difference in NK-cell levels in responding patients compared to non-responders. Interestingly, pre-treatment expression (MFI and percentage) of CD123 on immature myeloid derived suppressor cells (iMDSC) was higher in responders than in non-responders (p<0.01). Anti-CD123 targeted therapy with TAL resulted in a decreased CD123+ MFI (4239 vs. 2910; p<0.01) on iMDSCs as well as lower levels of iMDSCs in PB and BM (p<0.05).Responding patients displayed a 10-fold reduction of CD123 MFI after 3 months of treatment (2565 vs. 236; p=0.06), indicating that the CD123 molecule on immature MDSCs is targeted effectively by TAL. Conclusion Single agent TAL has limited efficacy in patients with advanced myeloid malignancies failing HMA. Expression of CD123 on immature MDSCs might serve as a biomarker of response for future anti-CD123 targeted approaches. Disclosures Götze: Celgene: Honoraria, Research Funding; JAZZ Pharmaceuticals: Honoraria; Novartis: Honoraria; Takeda: Honoraria, Other: Travel aid ASH 2017. Krönke:Celgene: Honoraria. Middeke:Roche: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding. Fenaux:Celgene: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Jazz: Honoraria, Research Funding; Otsuka: Honoraria, Research Funding. Schlenk:Pfizer: Research Funding, Speakers Bureau. Ades:JAZZ: Honoraria; Takeda: Membership on an entity's Board of Directors or advisory committees; silent pharma: Consultancy; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Platzbecker:Celgene: Research Funding.

scholarly journals Myeloablative Fractionated Busulfan with Fludarabine in Older Patients: Long Term Outcomes of Prospective Phase II Clinical Trial

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 10-11
Author(s):  
Rohtesh S. Mehta ◽  
Roland Bassett ◽  
Julianne Chen ◽  
Benigno C. Valdez ◽  
Jitesh Kawedia ◽  
...  
Keyword(s):  
High Risk ◽  
Board Of Directors ◽  
Older Patients ◽  
Research Funding ◽  
Advisory Board ◽  
Long Term Outcomes ◽  
Research Support ◽  
Advisory Committees ◽  
Gvhd Prophylaxis

Background: We started a randomized phase II trial [NCT01572662] that compared the safety of two myeloablative fractionated ("timed-sequential") busulfan with fludarabine (Bu-Flu) conditioning regimens: one with a lower dose of busulfan (area under the curve [AUC] of 16 000 μmol.min; 16K arm) and one with a higher dose (AUC of 20 000 μmol.min; 20K arm). After 49 patients were treated on the 16K group and 48 patients on the 20K group, the randomization was stopped as the higher dose arm was found to be as safe as the lower dose arm. The outcomes of those patients were previously reported, with the primary endpoint of interest being day 100 non-relapse mortality (NRM). The trial then continued enrolment as a single-arm study with increased accrual onto the higher dose arm. The current paper reports long-term outcomes of a total of 150 patients treated on the higher dose arm with an extended median follow-up of over 3.5 years. Methods: Patients with hematological malignancies up to 75 years of age were included. Bu dosing was determined on the basis of pharmacokinetic (PK) analyses conducted after day -13 and day -6 dose to achieve target AUC 20 000 ± 12% μmol.min (20K arm). On days −13 and −12, patients received 80 mg/m2 Bu IV daily as outpatient. Then, Flu 40 mg/m2 and Bu IV once daily were given as inpatient from day −6 though −3. Graft-versus-host disease (GVHD) prophylaxis consisted of tacrolimus from day −2 and methotrexate on days 1, 3, 6, and 11. Results: The median age was 61 years (interquartile range, 55-67); most were males (91; 61%) had an unrelated donor (n=93, 62%) and received peripheral blood graft (n=110, 73.3%). The most common diagnoses were acute myeloid leukemia (AML) and myelodysplastic syndrome (n = 88, 58.7%). Among AML, 41% (n=24) were in CR, 44% (n=26) had primary induction failure and 15% (n=9) had relapsed disease without attaining CR before HCT. Over half had HCT-Specific Comorbidity Index (HCT-CI) &gt;3 (n=79, 52.7%). Estimated relapse, NRM, and overall survival (OS) were 40% (95% confidence interval (CI), 32.1%-47.9%), 22% (95% CI, 15.3%-28.7%), and 49.1% (95% CI, 41.7%-57.8%) at 3 years [Table]. The highest relapse rate at 3 years was noted in patients with myeloma (70.6%), followed by MDS (51.7%), and lymphoma (46.2%), while it was the lowest in myelofibrosis (13.6%). Among AML patients not in CR, the rate of relapse was not higher than those who were in CR (37.1% and 41.7%, respectively at 3 years). NRM at 3 years ranged from 7.7% (lymphoma) to 37.1% (AML, not in CR). Lymphoma patients had the lowest NRM (7.7%) and the best OS (69.2%) at 3 years, while AML patients not in CR had the highest NRM (37.1%) and the lowest OS (31.4%) [Figure]. Patients with HCT-CI 0-2 had lower NRM (14.1%; 95% CI, 5.9%-22.3%) and better OS (57.2%; 95% CI, 46.7%-70.1%) than those with HCT-CI &gt; 3 (NRM: 29.1%; 95% CI, 19%-39.2% & OS: 41.7%; 95% CI, 32.2%-54.2%). Day 100 cumulative incidence of grade II-V acute GVHD was 38% (95% CI, 30.2%-45.8%), grade III-IV was 11.3% (95% CI, 6.2%- 16.4%). At 3 years, cumulative incidence of extensive chronic GVHD was 27% (95% CI, 20%-34%), bronchiolitis obliterans was 4.7% (95% CI, 1.3%-8.1%), and secondary malignancies was 8.7% (95% CI, 4.1%-13.2%). Conclusion: The fractionated myeloablative Bu-Flu conditioning regimen is well tolerated and leads to acceptable risk of NRM, relapse and long term survival in older patients, those with high risk disease and high comorbidities. Acknowledging the high risk study population, the long term outcomes, although acceptable, provide a framework to further improve upon. Modifications of this fractionated Bu-Flu regimen to further enhance its efficacy (with the addition of other chemotherapy agents) while reducing the toxicity and risk of NRM (with an inclusion of novel GVHD prophylaxis regimens) are currently being investigated. Disclosures Mehta: Incyte: Research Funding; Kadmon: Research Funding; CSL Behring: Research Funding. Alousi:Therakos: Research Funding; Alexion: Honoraria; Incyte: Honoraria, Research Funding. Bashir:Celgene: Research Funding; Amgen: Other: Advisory Board; KITE: Other: Advisory Board; Purdue: Other: Advisory Board; Takeda: Other: Advisory Board, Research Funding; Acrotech: Research Funding; StemLine: Research Funding. Hosing:NKARTA Inc.: Consultancy. Kebriaei:Novartis: Other: Served on advisory board; Amgen: Other: Research Support; Jazz: Consultancy; Kite: Other: Served on advisory board; Ziopharm: Other: Research Support; Pfizer: Other: Served on advisory board. Oran:Celgene: Consultancy; Arog Pharmaceuticals: Research Funding; ASTEX: Research Funding. Qazilbash:Angiocrine: Research Funding; Amgen: Research Funding; Bioclinica: Consultancy; Bioline: Research Funding; Janssen: Research Funding. Shpall:Takeda: Other: Licensing Agreement; Magenta: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Adaptimmune: Membership on an entity's Board of Directors or advisory committees; Zelluna: Membership on an entity's Board of Directors or advisory committees. Champlin:Takeda: Patents & Royalties; Johnson and Johnson: Consultancy; Actinium: Consultancy; Cytonus: Consultancy; Omeros: Consultancy; Genzyme: Speakers Bureau; DKMS America: Membership on an entity's Board of Directors or advisory committees. Popat:Bayer: Research Funding; Novartis: Research Funding.

scholarly journals Seven Year Follow up and Comparison of Dosing Strategies from the Pivotal Phase II Clinical Trial of Lenalidomide Plus Rituximab (R2) in Previously Untreated Follicular Lymphoma

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 1594-1594
Author(s):  
Nathan H. Fowler ◽  
Preetesh Jain ◽  
Loretta J. Nastoupil ◽  
F. B. Hagemeister ◽  
Sheryl G Forbes ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Follicular Lymphoma ◽  
Board Of Directors ◽  
Research Funding ◽  
Response Rate ◽  
Event Free Survival ◽  
Advisory Committees ◽  
Free Survival ◽  
Best Response

Abstract Introduction: We have previously reported the results of cohort A from a single arm, phase II clinical trial of lenalidomide with rituximab (R2) as frontline treatment for patients with previously untreated follicular lymphoma (FL), Fowler N et al Lancet Oncology 2014. Recent randomized studies (RELEVANCE) did not demonstrate superiority of either R2 or R-Chemo in untreated, high GELF FL, but follow up is short. We now report outcomes of an additional extended dosing cohort (12 mo of R2) and the long term follow up of the both dosing schedules in untreated FL. Methods: A total of 154 pts were included in the original clinical trial (FL, n=80; MZL, n=31; SLL, n=43). Characteristics were collected at the time of starting R2 treatment. Patients received lenalidomide 20 mg/day on days 1-21 of each 28-day cycle and rituximab 375 mg/m2 on day 1 of each cycle (6 cycles; schedule A) and lenalidomide 20 mg/day on days 1-21 of each 28-day cycle for cycles 1-6 then lenalidomide 10 mg/day on days 2-22 for cycles 7-12 with rituximab 375mg/m2 IV x1 weekly on cycle 1 and day 1 of every subsequent cycle (12 cycles; schedule B). Responders continued treatment for at least 6 but up to 12 cycles. The primary endpoint was overall response rate (ORR); secondary endpoints were complete and partial response (CR, PR), safety, and progression free survival (PFS). PFS was defined as time from starting treatment to disease progression or death, event free survival included time from starting treatment to discontinuation due to any cause and overall survival (OS) was defined from the time of initial diagnosis of FL to death/last follow up. Results: Eighty pts with FL were enrolled in study and followed a median of 86 months. Median age was 58 years (range, 29 to 84); 50% were males. 61% pts had grade 1 FL and 39% had grade 2 FL. Schedule A was administered in 50 pts and schedule B in 30 pts. Seventy seven pts were evaluable for initial response assessment and 76 (98%) responded. The best response rate was 95% (87% CR/CRu). At the time of last follow up, 23 patients experienced disease progression, 13 lost to follow up (all had CR as best response and had completed tx), 4 came off study due to pt choice/financial and 4 due to intolerance (2 arterio-thrombotic event, 1 respiratory failure, 1 intolerance) during therapy. After a median follow up of 86 mo, 23 pts (29%) progressed, 5 yr PFS was 75%. Five yr PFS was 70% and 82% for pts on cohort A vs B respectively (P=.30). Overall, 2 pts died, with a 5 year survival 97%, Figure-1 (A-B). The median event free survival in pts with FL was 85 months with a 5 year EFS of 59%. Subgroup analysis showed no statistically significant difference in PFS with FLIPI score, bulky disease and by initial bone marrow involvement. Pts who achieved CR had significantly longer PFS compared to those who did not achieve CR (not reached vs 78 months; p = 0.004), however the OS was not significantly different between the two groups Figure-1 (C-F). Grade 3 or 4 hematologic AEs included neutropenia (28%), thrombocytopenia (3%), and no anemia. Count recovery occurred in all pts with follow up and/or dose modification. Nine pts developed second primary cancers, including one melanoma in-situ, 3 localized skin cancers, and 2 secondary hematologic malignancies. Conclusions: A combination of lenalidomide with rituximab produced durable responses in pts with FL. At a follow up of 7 years, the majority of pts remain in remission and patients who achieved CR had the best outcomes. Five year PFS may be longer in pts who received 12mo of therapy, but will need larger analysis to confirm. Further studies are ongoing to analyze mutation dynamics and genomic profile to identify molecular biomarkers. Disclosures Fowler: Janssen: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding. Nastoupil:Novartis: Honoraria; Juno: Honoraria; Gilead: Honoraria; TG Therappeutics: Research Funding; Spectrum: Honoraria; Janssen: Research Funding; Merck: Honoraria, Research Funding; Karus: Research Funding; Genentech: Honoraria, Research Funding; Celgene: Honoraria, Research Funding. Westin:Apotex: Membership on an entity's Board of Directors or advisory committees; Celgen: Membership on an entity's Board of Directors or advisory committees; Kite Pharma: 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. Wang:Kite Pharma: Research Funding; Novartis: Research Funding; Pharmacyclics: Honoraria, Research Funding; Dava Oncology: Honoraria; Juno: Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AstraZeneca: Consultancy, Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; MoreHealth: Consultancy; Acerta Pharma: Honoraria, Research Funding. Samaniego:ADC Therapeutics: Research Funding.

scholarly journals Outcomes and Toxicities of Ibrutinib in Marginal Zone Lymphoma: A Retrospective Cohort Study at a Single Institution

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 5250-5250
Author(s):  
David M. Weiner ◽  
Nathaniel D. Robinson ◽  
Steven M. Bair ◽  
Hatcher J. Ballard ◽  
Mitchell E. Hughes ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Tyrosine Kinase ◽  
Board Of Directors ◽  
Research Funding ◽  
Marginal Zone ◽  
Response Rate ◽  
Marginal Zone Lymphoma ◽  
Advisory Committees ◽  
Bruton's Tyrosine Kinase ◽  
Anti Cd20

Background: Ibrutinib is a Bruton's tyrosine kinase (BTK) inhibitor that was recently approved by the FDA for treatment of patients (pts) with relapsed/refractory marginal zone lymphoma (MZL) who have already received one or more anti-CD20 containing treatment regimens and require systemic therapy. Approval was based on a clinical trial in 60 pts that showed durable responses and a median progression-free survival (PFS) of 14.2 months (mos) (Noy et al., Blood 2017). Since pts outside clinical trials may have different disease and demographic characteristics, our study investigates the safety and efficacy of ibrutinib when implemented in a non-trial setting. Materials and Methods: This is a retrospective analysis of MZL pts who received ibrutinib monotherapy as part of their treatment at the University of Pennsylvania. Subjects were identified by a database search for any MZL pts prescribed ibrutinib. Primary endpoints were PFS and overall survival (OS) since initiation of ibrutinib. Secondary endpoints were overall response rate (OR) and complete response rate (CR), adverse events, and reasons for discontinuation. The first patient was treated on April 10, 2014, and the data cutoff was July 1, 2019. Analyses were performed using STATA 15.0 software. Results: There were 28 pts included in this study with a median age of 69 years (range 36-90) and median ECOG performance status at diagnosis of 0 (range 0-2). All pts had advanced disease (all stage III/IV & 68% with bone marrow involvement). The distribution of MZL subtypes was 43% extranodal, 25% nodal, and 32% splenic. Most pts (89%) had received one or more treatments prior to ibrutinib (32% received first-line rituximab only). The median number of previous therapies was 2 (range 0-5), and 43% of pts were refractory to the previous line of therapy. A minority of pts (11%) received rituximab or another anti-CD20 antibody concurrently with ibrutinib. Pts started ibrutinib a median of 56 mos after their initial diagnosis (range 0.5-221 mos) with a median duration of therapy of 7 mos (range 0.7-62 mos). The median starting dose was 420 mg daily (range 70-560 mg daily). In 26 pts with response data available, the OR was 73% with CR 15%. The 12-mo PFS and OS were 77% and 87% respectively (see Figures 1 & 2, median PFS and OS not yet reached). PFS and OS at median follow-up were 55% and 69% respectively. There was no significant difference in response or survival rates among MZL subtypes. Pts who received rituximab only prior to ibrutinib had an OR of 86% compared to 69% in those with more than one previous therapy (Χ2 = 0.73, p = 0.39). Ibrutinib was discontinued in 43% of pts after a median of 2.9 mos (range 0.7-13.7 mos) due to disease progression (50%), intolerance (42%), or other reasons (8%). Most (67%) pts subsequently received other therapies. All pts who stopped due to toxicity were responding at the time of discontinuation. Ibrutinib was also temporarily held or dose-reduced in 46% of pts due to toxicity (77%), preparation for surgery (15%), or drug interactions (8%). One patient experienced acute rebound of symptoms until ibrutinib was restarted. Most commonly reported toxicities are summarized in Table 1. Grade 3 toxicities included pneumonia (7%), sepsis (4%), hemorrhage (4%), arthralgia (4%), fatigue (4%), URI (4%), and hepatitis (4%). Toxicities responsible for cessation of treatment were arthralgia, hepatitis, thyroiditis, and hemorrhage. There were no reported treatment-related deaths. Conclusion: To our knowledge, this is the first study to report the efficacy and safety of ibrutinib in a large cohort of MZL pts treated outside of a clinical trial. We found that the therapy was well-tolerated and observed response rates that compared favorably to those shown in the prospective clinical trial. Disclosures Hughes: AstraZeneca: Membership on an entity's Board of Directors or advisory committees; Genzyme: Membership on an entity's Board of Directors or advisory committees; Acerta Pharna/HOPA: Research Funding. Dwivedy Nasta:47 (Forty Seven): Research Funding; Rafael: Research Funding; Millenium/Takeda: Research Funding; Debiopharm: Research Funding; Aileron: Research Funding; ATARA: Research Funding; Pharmacyclics: Research Funding; Merck: Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria; Roche: Research Funding. Landsburg:Celgene: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Curis, INC: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Curis, INC: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Seattle Genetics: Speakers Bureau; Seattle Genetics: Speakers Bureau; Takeda: Research Funding; Takeda: Research Funding; Triphase: Research Funding; Triphase: Research Funding. Barta:Takeda: Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Honoraria, Research Funding; Bayer: Consultancy, Research Funding; Mundipharma: Honoraria; Merck: Research Funding; Celgene: Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees; Celgene: Research Funding; Mundipharma: Honoraria. Chong:Novartis: Consultancy; Merck: Research Funding; Tessa: Consultancy. Schuster:Novartis, Celgene, Genentech, Merck, Pharmacyclics, Acerta, and Gilead: Other: Grants, Research Funding; Novartis, Nordic Nanovector, and Pfizer: Membership on an entity's Board of Directors or advisory committees; Nordic Nanovector, Pfizer, AstraZeneca, Loxo Oncology, Acerta, and Celgene: Honoraria; Novartis: Other: a patent (with royalties paid to Novartis) on combination therapies of CAR and PD-1 inhibitors.. Svoboda:AstraZeneca: Consultancy; Celgene: Research Funding; Incyte: Research Funding; Pharmacyclics: Consultancy, Research Funding; Kyowa: Consultancy; Merck: Research Funding; BMS: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding. OffLabel Disclosure: This paper looked at the effectiveness of ibrutinib, a Bruton's tyrosine kinase inhibitor, in treating patients with marginal zone lymphoma (MZL). Ibrutinib is FDA approved for MZL patients who have received at least one anti-CD20 containing therapy and now require systemic treatment. Some patients in the study had not previously received an anti-CD20-based therapy and received ibrutinib off-label.

scholarly journals Impact of Chronic Graft-Versus-Host Disease on Non-Relapse Mortality

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 42-42
Author(s):  
Justin Jiang ◽  
Qiuhong Zhao ◽  
Audrey M. Sigmund ◽  
Patrick Elder ◽  
Don M. Benson ◽  
...  
Keyword(s):  
Stem Cell ◽  
Board Of Directors ◽  
Older Patients ◽  
Research Funding ◽  
Conditioning Regimen ◽  
Ohio State University ◽  
State University ◽  
Research Support ◽  
Advisory Committees ◽  
Hematopoietic Stem

Introduction-Chronic graft-versus-host disease (cGVHD) poses as a major late complication of hematopoietic stem cell transplantation. The role of cGVHD as a determinant in transplant-related morbidity and mortality, infectious complications, prolonged immune suppression, and impaired patient-reported quality of life has been extensively studied. Nonetheless, numerous advances in allogeneic hematopoietic stem cell transplant (allo-SCT) in recent years have expanded the indications for allo-SCT to a broader range of patients, including previously excluded older patients. However, long-term health status of older transplant recipients is poorly studied. Notably, the incidence of cGVHD may increase with age. Therefore, the development of cGVHD and the use of immunosuppressive therapy may lead to a higher degree of non-relapse mortality (NRM) in older patients. The objective of this study was to compare the NRM in both younger and older transplant recipients with and without cGVHD. Methods-We performed a retrospective cohort study of patients that underwent allo-SCT at the Ohio State University from 1999 to 2018. Data was analyzed from 1194 patients who survived or have been followed up with by at least day (d) 180 post-transplantation, among which 373 patients had developed cGVHD. Patients were grouped based on their age into a younger and older population. The older population was defined as ≥60 (N=373, 31%) with the younger population defined as &lt;60 (N=821, 69%) years (yr) of age. NRM was defined as death unrelated to relapse, with relapsed mortality as a competing risk. A landmark analysis approach was used to study the association between the age groups to NRM, stratified by whether or not patients had developed cGVHD by d180. Fine and Gray competing risk model was used to build the multivariable regression model controlling for confounding variables, such as gender, donor type, donor source, conditioning regimen, and diagnosis. Results-The median age at allo-SCT was 53.0 yr (range: 18-76) and 61.1% were male. Acute myeloid leukemia accounted for 36.7% of transplants, followed by non-Hodgkin's lymphoma (14.8%), acute lymphoid leukemia (12.7%), and myelodysplastic syndrome (11.0%). Additionally, 58.0% received reduced-intensity conditioning regimen. The majority of stem cell donor types were match unrelated (45.3%) and match related (39.8%). Patients who had developed cGVHD by d180, regardless of age, were at higher risk of NRM compared to patients with no cGVHD (hazard ratio [HR]: 1.52, 95% confidence interval [CI]: 1.16-1.99; p=0.002). To examine the influence of age with NRM, we stratified the analysis by cGVHD status by d180. Among patients developed cGVHD by d180, in both univariable (HR 1.22, 95% CI 0.79-1.9, p=0.373) and multivariable analysis (HR: 1.17, 95% CI: 0.74-1.87; p=0.501), there was no statistically significant difference in NRM between patients ≥60 and &lt;60 yr of age. Among patients without cGVHD by day 180, age ≥60 yr was a significant factor for increased NRM in both univariable (HR: 1.52, 95% CI 1.08-2.15; p=0.017) and multivariable (HR: 1.55, 95% CI: 1.04-2.30; p=0.031) analysis. Conclusion-This study showed that patients with cGVHD by day 180 were at higher risk for higher NRM compared to patients without cGVHD. Among cGVHD patients, there was no difference on the outcome of older patients (≥60 years old) compared to younger ones (&lt;60 years old). This suggests that cGVHD therapy is equally tolerable among different age groups. Disclosures Chaudhry: Sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees. Bumma:Sanofi: Speakers Bureau; Amgen: Speakers Bureau. Khan:Amgen: Consultancy; Janssen: Consultancy. Devarakonda:Janssen: Consultancy. Vasu:Kiadis Inc: Other: Kiadis has obtained exclusive licensing requirements from The OHio State University; Janssen: Membership on an entity's Board of Directors or advisory committees; Omeros: Membership on an entity's Board of Directors or advisory committees. Jaglowski:Novartis: Consultancy, Research Funding; Juno: Consultancy; Kite, a Gilead Company: Consultancy, Research Funding; CRISPR: Consultancy. William:Celgene: Consultancy, Honoraria; Dova: Research Funding; Guidepoint Global: Consultancy; Merck: Research Funding; Kyowa Kirin: Consultancy, Honoraria; Seattle Genetics: Research Funding; Incyte: Research Funding. Mims:Syndax Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Other: Data Safety Monitoring Board; Abbvie: Membership on an entity's Board of Directors or advisory committees; Kura Oncology: Membership on an entity's Board of Directors or advisory committees; Leukemia and Lymphoma Society: Other: Senior Medical Director for Beat AML Study; Novartis: Speakers Bureau; Agios: Consultancy. Brammer:Bristol-Myers Squibb: Research Funding; Celgene: Research Funding; Seattle Genetics: Honoraria, Speakers Bureau; Kymera: Honoraria; Verastem Oncology: Other: Travel. Saad:Magenta Therapeutics: Other: Personal Fees; Incyte Pharmaceuticals: Other: Personal Fees; Amgen: Other: research support; Kadmon: Other: research support; Orcabio: Other: research support. Efebera:Takeda: Honoraria, Speakers Bureau; Pharmacyclics: Research Funding; Celgene: Research Funding; Ohio State University: Current Employment.

Lenalidomide and Rituximab for the Initial Treatment of Patients with Chronic Lymphocytic Leukemia (CLL) A Multicenter Study of the CLL Research Consortium

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 291-291 ◽  
Author(s):  
Danelle F. James ◽  
Jennifer R. Brown ◽  
Lillian Werner ◽  
William G. Wierda ◽  
Jaqueline C. Barrientos ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Initial Treatment ◽  
Older Patients ◽  
Research Funding ◽  
Response Rate ◽  
Lymphocytic Leukemia ◽  
Stage Iii ◽  
Advisory Committees ◽  
Final Response

Abstract Abstract 291 Lenalidomide (L) is an immunomodulatory agent with therapeutic activity in CLL; rituximab (R), a CD20 mAb, has limited activity as monotherapy in CLL. In preclinical models, L resulted in NK cell expansion and synergized with R. Therefore, a phase II, 2-stage study was designed to evaluate this combination. Treatment-naïve patients (pts) were eligible if they had an indication for therapy, normal kidney function, and no history of deep vein thrombosis or pulmonary embolic events. Pts started L at 2.5 mg per day (D) and could escalate to 5 mg/D on D8 and again on C3D1 to a maximum of 10 mg/D if tolerated. Pts received L 21 of 35 D for cycle (C) 1, then for 21/28 D for C2-7 (7 cycles total). R was started at the end of C1 at 50 mg/m2 D29, 325 mg/m2 D31, 375 mg/m2 D33, C1, then 375 mg/m2 weekly × 4 for C2 and on D1 for C3-7. Pts received allopurinol 300 mg daily, and following a protocol amendment, aspirin at 81 mg daily. The study has closed to accrual with 69 pts enrolled at four CRC clinical sites. 40 pts enrolled into arm A (age under 65). 29 in arm B (age 65 or older). 57 now have final response data. The median age on arm A was 57 years (range 45–64) and arm B 70 years (range 65–80). Advanced Rai stage (III-IV) was present at baseline more frequently in arm B pts (48%) compared to arm A pts (23%) (p= 0.04). 73% of pts on arm A had an excellent performance status (ECOG 0/5) compared to only 54% of pts on arm B. Arm A pts frequently had aggressive leukemia features including unmutated IgVH genes and/or elevated CLL expression of ZAP-70 in 70%, these features were present in 52% of those on arm B. 4 pts on arm A and 2 on arm B had del(17p) by FISH whereas 5 pts in arm A and 4 in arm B had del(11q). A significantly lower proportion of pts on arm B (16/27) were able to complete the 7 cycles of therapy compared to (35/39) of eligible pts on arm A (p=0.013) mainly due to toxicity. Similarly, older patients were limited in dose escalation or maintenance of the maximum L dose (10 mg). 27/39 pts on arm A achieved a median L dose of 10 mg while only 13/27 pts on arm B tolerated the 10 mg L dose. The most frequent and severe adverse events (AEs) are summarized in Table 1. Infusion and tumor flare reactions (TFR) were observed more frequently during cycle 1 than in subsequent cycles. Neutropenia was frequently grade (G) 3/4 in severity. Severe (G3/4) AEs were reported in 72% of arm A pts and 82% of pts on arm B (p =.55), with non-heme G3/4 toxicities reported in 37% of arm A and 52% of arm B (p =.31).Table 1Frequent and Severe AEsArm AArm BGradeI/IIIII/IVI/IIIII/IVTFR32–161Neutropenia1119115Anemia153141Thrombocytopenia211131Fatigue25–142AST/ALT elevation183113Hypophosphatemia19271Hypocalcemia21–15–Infusion Reaction20–53Respiratory Infection17–5–Pneumonia–123Rash142121Neutropenic Fever–2–2PE/DVT–––2 Responses are summarized in Table 2. The overall response rate (ORR) to therapy for arm A was 94%, 90% CI (83%, 99%) with 20% (10%, 34%) achieving a complete remission (CR) and 17% a nodular PR (nPR). The ORR for arm B was 77% with 90% CI (58%, 91%) with 9% (2%, 26%) achieving a CR. Arm A patients had median follow-up of 17 months (from D 1 of treatment) with an estimated median progression free survival of 19 months. Arm B had a median follow-up of 7 months, with an estimated 85% remaining progression free at 7 months.Table 2ResponsesArm A (Age < 65) N = 35Arm B (Age >= 65) N = 22NCR N (%)nPR N (%)PR N (%)ORR N (%)NCR N (%)PR N (%)ORR N (%)All patients357 (20)6 (17)20 (57)33 (94)222 (9)15 (68)17 (77)IgVH unmutated224 (18)2 (9)15 (68)21 (96)131 (8)10 (77)11 (85)IgVH mutated133 (23)4 (31)5 (38)12 (92)91 (11)5 (56)6 (67)Median L dose 10 mg247 (29)5 (21)12 (50)24 (100)82 (25)5 (63)7 (88)Rai stage III/IV92 (22)1 (11)5 (56)8 (89)111 (9)6 (55)7 (64)17p del3002 (67)2 (67)100011q del31 (33)02 (67)3 (100)403 (75)3 (75)TFR present285 (18)5 (18)16 (57)26 (93)14011 (79)11 (79) A defined course of seven cycles of L and R administered for the initial treatment of CLL was associated with a high response rate (ORR 88%) with 16% CRs and 11% nPRs. Older patients were more likely to have advanced Rai stage at baseline and were less likely to escalate or maintain the maximum L dose and/or complete the 7 cycles of therapy, factors that may have contributed to a lower CR, and ORR rate in arm B. An additional 11 patients will have final response assessments by October 2011. Disclosures: James: Celgene: Honoraria, Research Funding. Off Label Use: Lenalidomide for Chronic lymphoyctic leukemia. Brown:Calistoga: Consultancy; Pharmacyclics: Consultancy; Celgene: Consultancy, Research Funding; Genzyme: Research Funding. Rai:Celgene: Membership on an entity's Board of Directors or advisory committees. Neuberg:Celgene: Research Funding. Kipps:Igenica: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Research Funding; Abbott Industries: Research Funding; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; Genentech: Research Funding; GSK: Research Funding; Gilead Sciences: Consultancy, Research Funding; Amgen: Research Funding.

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