Long-Term Durable Responses after Autologous Stem Cell Transplantation in POEMS Syndrome

Abstract Abstract: Background: POEMS syndrome is a constellation of symptoms of polyradiculoneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes. Other features often present in this syndrome include papilledema, extravascular volume overload, sclerotic bone lesions, Castleman disease, high vascular endothelial growth factor (VEGF) levels and thrombocytosis/polycythemia. The standard of care has not been established in the management of the disease. We had previously reported on the role of auto-HCT in a smaller cohort of POEMS patients at our institution1. Here, we present an updated analysis in a larger cohort of POEMS patients who underwent auto-HCT. Methods: We retrospectively reviewed the outcomes of POEMS patients who underwent auto-HCT at our institution from the period of January, 1999, through June, 2018. The Kaplan-Meier method was used to caculate progression-free survival (PFS) and overall survival (OS). Hematologic response was defined as per the International Myeloma Working Group (IMWG) criteria. OS was defined as the duration from the date of transplant to death or last date of follow-up in alive patients. PFS was defined as the duration from the date of transplant to either progressive disease or death, whichever occurred first. Results: 16 patients (13 males, 3 females) with POEMS syndrome received a total of 17 auto-HCTs. One patient underwent auto-HCT two times for multiple relapses. The median age at auto-HCT was 48 years (range: 18-75). The median time from diagnosis to auto-HCT was 15 months (2-141 months). All 16 (100%) patients had peripheral neuropathy and monoclonal gammopathy: IgG lambda in 7, IgA lambda in 6, IgG kappa in 2 and light chain in 1 patient. Other features were: osteosclerotic bone lesions in 13 (81%), endocrinopathy in 10 (69%), skin involvement in 8 (50%) and extravascular fluid overload in 7 (44%). Three (18%) patients had biopsy-proven co-existent Castleman disease. Among patients with available data (n=7), the mean serum VEGF level pre-transplant was 389 pg/ml (268-1622). The median HCT-CI (comorbidity index) score available for 15 patients was 2 (range 0-7). The median number of chemotherapies received before the transplant was 1 (range 1-3). Table 1 summarizes the prior systemic chemotherapies received before auto-HCT. Two patients also received plasmapheresis, and eight patients received radiation therapy for bone disease. The mobilization regimens used for collecting peripheral blood stem cells were granulocyte colony-stimulating factor (G-CSF) alone, cyclophosphamide+G-CSF and G-CSf+plerixafor in 16, 2 and one patient, respectively. The median number of CD34+ stem cells collected was 3.43 X 106 cells/kg (range 1.73 - 6.5). The overall response rate, as per the IMWG criteria, for the entire cohort was 94% (16/17): 5 (29.4%) CR, 4 (23.5%) nCR, 1 (5.8%) VGPR, and 6 (35.2%) PR. The mean serum VEGF levels improved from 389 pg/ml before transplant to a level of 35 pg/ml (31-86) post-transplant. Engraftment syndrome was seen only in 1 patient who required corticosteroid use. One-year transplant-related mortality was 0%. Median follow-up among surviving patients is 52 months (5-120 months). The median PFS and OS have not been reached yet. All 16 patients had a complete or partial resolution of their clinical symptoms after auto-HCT. 4-year PFS and OS rate for the entire cohort is 80.2% and 100% respectively. At ten years, PFS and OS rate is 59.4% and 80% respectively. Fourteen out of 16 patients were alive at the time of the last follow-up. One patient died six years after his auto-HCT secondary to gastrointestinal bleeding unrelated to his underlying disease, and the second patient died after 11 years post auto-HCT of unknown cause. Conclusions: Upfront Auto-HCT provides durable chemotherapy free remission and significant clinical improvement in patients with POEMS syndrome. References: Patel, K. et al. Durable responses with autologous hematopoietic SCT in patients with POEMS syndrome. Bone marrow transplantation49, 465-6 (2014). Figure. Figure. Disclosures Thomas: Acerta Pharma: Research Funding; Amgen Inc: Research Funding; Bristol Myers Squibb Inc.: Research Funding; Celgene: Research Funding; Array Pharma: 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:Poseida: Research Funding; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: Consultancy; Janssen Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; BioTheryX, Inc: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Consultancy; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Millenium Pharmaceuticals: Consultancy, Research Funding. Champlin:Sanofi: Research Funding; Otsuka: Research Funding. Patel:Takeda: Research Funding; Poseida Therapeutics, Inc.: Research Funding; Abbvie: Research Funding; Celgene: Research Funding.

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Clinical Features, Treatments and Outcomes of HIV-Associated Diffuse Large B-Cell Lymphoma: A Single-Center Experience

Blood ◽

10.1182/blood-2020-143253 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 20-20

Author(s):

Tylan Magnusson ◽

Greer Burkholder ◽

Nathan Erdmann ◽

Amitkumar Mehta ◽

Mayur Narkhede ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

B Cell Lymphoma ◽

Cd4 Count ◽

Advisory Committees ◽

Entire Cohort ◽

Large B Cell Lymphoma ◽

Extranodal Disease ◽

Hiv Negative

INTRODUCTION Recent studies have suggested that the prognosis of HIV-associated diffuse large B-cell lymphoma (HIV-DLBCL) may be improving with advances in anti-retroviral therapies (ART). A pooled analysis of clinical trial data showed that EPOCH may be associated with superior outcomes as compared to CHOP (Barta et al. Blood. 2013), but about two-third of patients in the combined analysis were treated without rituximab. A recent French study, however, showed similar overall survival (OS) between R-CHOP and R-EPOCH treated patients (Besson et al. AIDS 2017) and a phase III trial showed similar efficacy of R-CHOP vs. R-EPOCH in HIV-uninfected DLBCL (Bartlett et al. JCO 2019). The optimum frontline therapy in HIV-DLBCL is unknown as most clinical trials exclude HIV-infected patients or restrict accrual to those with undetectable HIV viral load and minimum CD4 count cut-off. Moreover, most existing studies include a majority (>60%) Caucasian population, and there is a paucity of studies on outcomes in African-American population. In this retrospective study, we describe the clinical features and outcomes of HIV-DLBCL patients seen at our institution and compare them with HIV negative DLBCL patients. METHODS We conducted a retrospective review of HIV+ DLBCL cases diagnosed and treated at our institution from 2008-2020. We used the Kaplan-Meier method to assess overall survival (OS). Univariate and multivariate analyses were performed to assess prognostic factors. HIV-DLBCL patients were matched 1:2 with HIV negative DLBCL by age and stage of lymphoma at diagnosis. Comparison of OS analysis was conducted using log-rank method and predictors of progression or death using Cox proportional hazards regression. RESULTS We included a total of 33 patients with HIV-DLBCL in our study. Median age was 46.6 years (IQR 40-53.3), 25 (76%) were males, and 20 (61%) were African-Americans (Table). 28 (85%) patients had stage III/IV and 24 (73%) had extranodal disease at diagnosis. The median CD4 count at diagnosis was 252 (IQR 89.5-409). 6 (18%) had CNS involvement at diagnosis, for which the median OS was 8.3 months. First-line treatment included rituximab-chemotherapy combinations in 25 (76%) patients. All patients continued ART during first line treatment. Median follow up duration of the entire cohort was 2.06 years (IQR 0.53-5.02 years) and 5 (15.2%) were lost to follow up. The 2-year OS for R-CHOP treated patients was 63% vs. 38% for R-EPOCH treated patients, although this failed to reach statistical significance (p=0.125). On multivariate analysis, the only factor significantly associated with difference in event free survival (EFS; progression or death) was female sex (HR 19.86; [2.652-148.7]; p=0.004). Trends were seen towards shorter EFS among patients who were tobacco smokers at time of DLBCL diagnosis (HR 2.69; 0.463-15.6]; p=0.271), CD4+ count <200 at time of DLBCL diagnosis (HR 2.39; [0.519-11.0]; p=0.264), IPI score >3 (HR 2.98; [0.480-18.5]; p=0.241), and presence of MYC gene rearrangement (HR 3.93; [0.569-27.2]; p=0.165). Treatment type (R-CHOP, R-EPOCH), ART use prior to lymphoma diagnosis, race, and insurance status were not correlated with EFS. 11 (33.3%) patients died within 1 year of diagnosis. The 2-year OS for the entire cohort was 64% vs. 68% in matched HIV-negative DLBCL patients (p=0.651). Median OS for HIV+ patients was 2.14 years (IQR 0.23-5.77) vs 2.97 years (IQR 0.76-6.48) in matched HIV-negative DLBCL patients (p=0.3996). One patient died from acute hypoxemic respiratory failure prior to starting treatment. Four patients died of complications during their first inpatient chemotherapy administration. CONCLUSION In our cohort, most HIV-DLBCL patients were African-Americans, presented with advanced stage and extranodal disease. The survival of HIV-associated DLBCL was similar to HIV-negative counterparts. All HIV-DLBCL continued ART during chemotherapy, suggesting the feasibility of this approach. There was no difference in OS between patients treated with R-CHOP vs. R-EPOCH, however there was a trend towards increased OS in patients treated with R-CHOP. CNS involvement at diagnosis was frequently seen. Despite limited sample size, we observed a significant association with gender, and a trend toward significant factors including tobacco use and low CD4 count at time of diagnosis. Disclosures Mehta: TG Therapeutics:Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau;Merck:Research Funding;Roche-Genentech:Research Funding;Kite/Gilead:Research Funding;Innate Pharmaceuticals:Research Funding;Seattle Genetics:Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau;Oncotartis:Research Funding;Gelgene/BMS:Research Funding;Juno Parmaceuticals/BMS:Research Funding;fortyseven Inc/Gilead:Research Funding;Takeda:Research Funding;Incyte:Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau;Affimed:Research Funding.

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Outcomes for Patients with Primary or Secondary Central System Lymphoma Treated with Ibrutinib: A Multicentre Retrospective Analysis

Blood ◽

10.1182/blood-2019-125730 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 1620-1620

Author(s):

Katharine L Lewis ◽

Kate Manos ◽

John Casey ◽

Julie Crawford ◽

Shir-Jing Ho ◽

...

Keyword(s):

Atrial Fibrillation ◽

Adverse Events ◽

Board Of Directors ◽

Research Funding ◽

Fungal Infections ◽

Invasive Fungal Infections ◽

Advisory Committees ◽

Entire Cohort ◽

Frontline Therapy

Background Primary and secondary central nervous system lymphoma (PCNSL/SCNSL) are rare brain malignancies with an aggressive clinical course and dismal outcomes. The BTK inhibitor ibrutinib has activity in a range of B-cell lymphomas. Phase I and II studies of ibrutinib monotherapy in relapsed/refractory PCNSL have demonstrated promising results, with response rates of up to 81%. Response rates of up to 69% have also been seen in SCNSL. Ibrutinib has been combined with other systemic agents (e.g. rituximab and methotrexate) in phase 1 trials with promising results (Grommes et al Blood 2019); combination with more intensive combination chemotherapy regimens also appears efficacious but has exhibited a potentially limiting toxicity profile, in particular invasive fungal infections. (Lionakis et al Cancer Cell 2017). However, data for ibrutinib in PCNSL and SCNSL outside the clinical trial setting are scarce. Methods We performed a national, multicentre, retrospective study of the clinical outcomes and safety of patients (pts) with PCNSL and SCNSL who received ibrutinib between December 2015 and June 2019. Results The baseline characteristics of the 16 eligible pts are summarised in the table (Figure 1a). 88% (n=14) had relapsed/refractory disease, with two patients receiving ibrutinib as a component of multiagent frontline therapy. The most common target daily dose was 560mg (range 420-840mg); this was reached in all pts. Among all pts, the objective response rate (ORR) was 69%, with a complete remission (CR) rate of 63%. Both patients receiving ibrutinib in combination frontline therapy achieved a CR. ORR in PCNSL pts was 50% (n=4) and SCNSL pts was 88% (n=7), (P=0.28). ORR was 80% (n=4) when ibrutinib was administered as monotherapy, 80% (n=4) when administered with chemotherapy and 75% (n=3) when administered concomitant with whole brain radiotherapy. MYD88L265P mutation at time of starting ibrutinib was only tested in two patients with PCNSL and none with SCNSL. The mutation was detected in both PCNSL cases, and both later attained a CR. With a median follow up of 14 months, calculated using median observation period among patients alive at last follow-up, median progression free survival (PFS) and overall survival (OS) were not reached. 12 month PFS was 56% for the entire cohort (95% confidence interval [CI] 29-76); 50% for PCNSL (95% CI 15-77) and 60% for SCNSL (95% CI 20-85%) (Figure 1b). 12 month OS was 66% for the entire cohort (95% CI 36-85) ; 50% for PCNSL (95% CI 15-77) and 80% for SCNSL (95% CI 20-97%) (Figure 1c). Ten pts had PFS >6 months (longest 41.3 months), and 11 pts (69%) remained alive, with 9/11 being free from disease progression. Seven pts remain on ibrutinib at time of data analysis, 3 with PCNSL and 4 with SCNSL. Nine pts (56%) have discontinued therapy; 6 due to progressive disease (PD), 1 due to atrial fibrillation with hypotension requiring inotropic support and 2 in remission, one of whom subsequently underwent autologous stem cell transplant. Dose interruptions or reductions were required in 6 pts (37%), due to bleeding (n=2), infection (n=3) and neutropenia (n=1). Grade 3/4 adverse events were infection (31%, n=5), neutropenia (25%, n=4), febrile neutropenia (12%, n=2) and one each (6%, n=1) of atrial fibrillation, thrombocytopenia, and anaemia. No invasive fungal infections were observed, despite use of 8-16mg daily dexamethasone immediately prior to or during ibrutinib therapy in 10 pts (62%). Conclusions In this small real-world, majority methotrexate-refractory population, ibrutinib demonstrates encouraging efficacy and durable responses despite doses lower than used in clinical trials. No unexpected adverse events were observed. Invasive fungal infections were not seen, despite most patients receiving concurrent dexamethasone and/or chemotherapy. We observed substantial variety in additional therapy during ibrutinib treatment, and the optimal way to use ibrutinib in this heterogenous patient group remains unclear. Disclosures Manos: NovoNordisk Pharmaceuticals: Other: Travel; Janssen: Honoraria. Ho:Celgene: Consultancy, Other: Advisory role. Grigg:Abbvie: Membership on an entity's Board of Directors or advisory committees; MSD: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Roche: Other: Travel. Gandhi:Amgen: Honoraria; Bristol Myers Squibb: 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; Gilead: Honoraria, Research Funding; Roche: Honoraria, Other: Travel Support; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: Membership on an entity's Board of Directors or advisory committees. Hawkes:Astra Zeneca: Research Funding; Mundi pharma: Research Funding; Janssen-Cilag: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Gilead: Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck KgA: Research Funding; Merck Sharpe & Dohme: Membership on an entity's Board of Directors or advisory committees; Takeda: Speakers Bureau; Bristol-Myers Squibb: Research Funding, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche/Genentech: Membership on an entity's Board of Directors or advisory committees, Other: Travel Expenses, Research Funding, Speakers Bureau. Cheah:Roche: Other: Travel expenses; Roche, Janssen, MSD, Gilead, Loxo Oncology, AstraZeneca, TG Therapeutics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene, Roche, Abbvie: Research Funding. OffLabel Disclosure: Ibrutinib is not currently approved for use in DLBCL/CNS lymphoma.

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Analysis Of Warfarin Drug-Drug Interactions With Antibiotics In The Ambulatory Care Setting

Blood ◽

10.1182/blood.v122.21.1143.1143 ◽

2013 ◽

Vol 122 (21) ◽

pp. 1143-1143

Author(s):

Nathan P Clark ◽

Thomas Delate ◽

Catherine S Riggs ◽

Daniel M Witt ◽

Elaine M Hylek ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Warfarin Dose ◽

Acute Illness ◽

Control Groups ◽

Advisory Committees ◽

Antibiotic Group ◽

The Mean ◽

Excessive Anticoagulation

Abstract Background The typical effect of antibiotic initiation on the international normalized ratio (INR) in a real-world, stable warfarin population has not been adequately described. In addition, the influence of acute illness on the risk of excessive anticoagulation is not known. Methods This retrospective, longitudinal cohort study evaluated patients who received stable warfarin therapy between January 1, 2005 and March 31, 2011. The protocol for patients receiving warfarin and initiating antibiotic therapy during the study time-frame was to continue the warfarin dose unchanged and measure an INR within 3 to 7 days. Patients who purchased an antibiotic (antibiotic group) were compared to those purchasing a warfarin refill (stable controls) and patients with upper respiratory infection who did not purchase an antibiotic (sick controls). Primary outcomes included the mean INR change between the last INR prior to study inclusion (pre-index INR) and the first follow-up INR as well as the percentage of patients with a follow-up INR ≥ 5.0. The influence of interaction mechanism on the risk of a follow-up INR ≥ 5.0 was evaluated and predictors of a follow-up INR ≥ 5.0 were identified. Results A total of 5905 (49.0%), 5579 (46.2%), and 570 (4.8%) patients were included in the antibiotic, stable control, and sick control groups, respectively. The mean age was 68.3 years and the median pre-index INR was 2.5 (IQR 2.2-2.9). The mean change in INR was greater in the antibiotic group compared to the stable and sick control groups (both p< 0.05) but the increase was not clinically relevant (i.e., mean increase was less than 0.1 INR units). There were 3.2%, 2.6%, and 1.2% of patients with a follow-up INR ≥ 5.0 in the antibiotic, sick, and stable groups respectively (antibiotics v. stable and sick v. stable p<0.001; antibiotics v. sick p=0.434). Antibiotics interfering with warfarin metabolism were more likely to result in a follow-up INR ≥ 5.0 (9.6%) than those disrupting Vitamin K synthesis (3.1%) and those without a known interaction with warfarin (2.1%) (p<0.01) (Table). Antibiotic use, acute illness, cancer diagnosis, elevated baseline INR, and female sex predicted a follow-up INR ≥ 5.0. Conclusion In the absence of antibiotics, acute illness alone increases the risk of excessive anticoagulation in previously stable warfarin patients. The risk of an INR ≥ 5.0 was greatest among antibiotics interfering with warfarin metabolism. In addition to antibiotics and acute illness, patients with cancer, elevated baseline INR, and females were most susceptible to excessive anticoagulation. Disclosures: Hylek: Bayer: Honoraria; Boehringer Ingelheim: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria; Daiichi Sankyo: Consultancy; Johnson and Johnson: Consultancy; Pfizer: Consultancy. Garcia:Bristol-Myers Squibb: Consultancy; Pfizer: Consultancy; Boehringer Ingelheim: Consultancy; Daiichi Sankyo: Consultancy; Janssen: Consultancy; Roche Diagnostics: Consultancy; CSL Behring: Consultancy. Crowther:Asahi Kasai: Membership on an entity’s Board of Directors or advisory committees; Baxter: Membership on an entity’s Board of Directors or advisory committees, Speakers Bureau; Boehringer Ingelheim: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees; CSL Behring: Speakers Bureau; Leo Pharma: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding, Speakers Bureau; Merck: Consultancy; Octapharma: Consultancy, Membership on an entity’s Board of Directors or advisory committees; Pfizer: Consultancy, Honoraria, Research Funding; Sanofi-Aventis: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Viropharma: Membership on an entity’s Board of Directors or advisory committees.

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The Use of Hypomethylating Agents (HMAs) in Patients with Relapsed and Refractory Acute Myeloid Leukemia (RR-AML): Clinical Outcomes and Their Predictors in a Large International Patient Cohort

Blood ◽

10.1182/blood.v128.22.1063.1063 ◽

2016 ◽

Vol 128 (22) ◽

pp. 1063-1063 ◽

Cited By ~ 3

Author(s):

Maximilian Stahl ◽

Nikolai A Podoltsev ◽

Michelle DeVeaux ◽

Sarah Perreault ◽

Raphaël Itzykson ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Regression Models ◽

Median Number ◽

Chromosome 7 ◽

Advisory Committees ◽

Logistic Regression Models ◽

Best Response ◽

Line Of Therapy

Abstract Introduction: Patients with RR-AML, particularly older adults, have dismal outcomes and limited therapy options. Given low response rates and high toxicity with salvage intensive chemotherapy, and frequent ineligibility for allogeneic stem cell transplantation (alloSCT), many patients are treated with HMAs. Robust data regarding use of HMAs in AML predominates in the frontline setting, while their use in RR-AML has limited supportive data. Here wesought to analyze theoutcomes and their predictors in patients with RR-AML treated with HMAs. Methods:We collected data, spanning a period from 2006 to 2016, from 7 centers in the United States and 4 centers in Europe regarding patients treated with HMAs for RR-AML. Responses were defined by International Working Group criteria. Kaplan-Meier methods estimated overall survival (OS) from initiation of HMAs to death or end of follow-up. Multivariable logistic regression models estimated odds for response, and multivariable Cox Proportional Hazard (CPH) models estimated hazards ratios (HR) for OS. Covariates considered included HMA received, age at diagnosis (in years), AML classification at diagnosis (AML with myelodysplasia-related changes [AML-MRC], therapy-related [t]-AML), disease status (relapsed vs. refractory), number of therapy lines prior to HMA (1 vs. 2 vs. >=3), duration of first complete remission (CR1), white blood cell count, peripheral blood blast percentage, bone marrow (BM) cellularity (<=20% vs. > 20%), BM blast percentage (<=20% vs. >20%), cytogenetic risk group, and the presence of complex or chromosome 7 abnormalities. Results: Of 514 patients, 217 patients (42.2%) had refractory and 297 (58%) had relapsed AML. By end of study, 415 patients (88.5%) had died. Median follow-up for living patients was 11.6 months.Median age at diagnosis was 64 years (range [R], 16-92). AML-MRC was diagnosed in 29.0% while 8.2% had t-AML. Median number of prior therapies was 2 (R, 1-7), with 48.3% receiving 1 prior line, 30.2% receiving 2 prior lines, and 21.5% receiving >=3 prior lines. Prior alloSCT was performed in 21.2%. Only 1.9% had good risk (core binding factor) karyotype, while 56.2% had intermediate risk karyotype, and 41.9% had poor risk karyotype. Azacitidine was used in 45.8% and decitabine in 54.2%; median number of azacitidine cycles was 4 (Interquartile range [IQR], 2-6) compared to 2 for decitabine (IQR, 1-4, p <0.001). Best response to HMAs was CR in 11.7% (95%CI, 9%-14%), CRi in 6.4% (95%CI, 4.3%-8.8%), hematologic improvement (HI) in 8% (95%CI, 5.7%-10.5%), stable disease (SD) in 9.8% (95%CI, 7.2%-12.5%), while 64.1% (95%CI, 57.7%-66.2%) had progressive disease (PD). Median OS from HMA initiation for all patients was 6.9 months (IQR, 3.0-13.3). There was a significant difference in OS based on best response achieved [Figure 1]. Unadjusted OS showed an insignificant trend for worsening with increasing number of prior lines of therapy [Figure 2A]. In unadjusted analyses, there was no difference in OS based on HMA received in all patients [Figure 2B] or the subset who received only 1 prior line of therapy (median OS: Azacitidine vs. decitabine 8.4 vs 7.3 months, p=0.88). Following HMA therapy, the median number of subsequent therapies was 0 (R, 0-6), and only 12.8% underwent alloSCT. In multivariate CPH models, HMA used was not significantly associated with OS (HR=0.80, 95%CI, 0.42-1.51, p=0.49), while increasing age, and presence of complex cytogenetics and chromosome 7 abnormalities were significantly associated with risk of death [Table 1]. In multivariable logistic regression models, HMA used was not associated with achieving CR+CRi (Odds ratio=0.56, p=0.32). Conclusions: In this largest reported cohort of patients with RR-AML treated with HMAs, we found that HMAs are often used as alast line of therapy, with a minority of patients receiving subsequent treatment. Nonetheless, the minority of patients who achieve CR (11.7%) with HMA therapy had a median OS of 25.6 months. Therefore, use of HMAs for management of RR-AML is a reasonable intervention in the absence of clinical trial options. There appears to be no difference in OS or probability of achieving CR+CRi based on HMA used. Ongoing analyses in this dataset include further evaluations of predictors, including genetic mutations, and the development of prediction tools for clinical outcomes with HMA therapy. Figure 1. Figure 1. Disclosures Podoltsev: Ariad: Consultancy, Honoraria; Incyte: Consultancy, Honoraria. Ritchie:Novartis: Honoraria; Incyte: Speakers Bureau; Arian: Speakers Bureau; Pfizer: Honoraria; Celgene: Speakers Bureau. Sekeres:Millenium/Takeda: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees. Komrokji:Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Speakers Bureau. Al-Kali:Onconova Therapeutics, Inc.: Research Funding; Celgene: Research Funding. Santini:Celgene: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Onconova: Consultancy; Amgen: Consultancy; Astex: Consultancy. Roboz:Cellectis: Research Funding; Agios, Amgen, Amphivena, Astex, AstraZeneca, Boehringer Ingelheim, Celator, Celgene, Genoptix, Janssen, Juno, MEI Pharma, MedImmune, Novartis, Onconova, Pfizer, Roche/Genentech, Sunesis, Teva: Consultancy. Fenaux:Celgene, Janssen,Novartis, Astex, Teva: Honoraria, Research Funding. Prebet:celgene: Consultancy, Honoraria; Novartis: Consultancy, Honoraria. Gore:celgene: Consultancy, Honoraria. Zeidan:Ariad: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Incyte: Consultancy, Honoraria; Celgene: Consultancy, Honoraria.

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The Pralatrexate - Romidepsin Doublet: A Well Tolerated and Highly Effective Combination for Patients with Relapsed or Refractory Peripheral T-Cell Lymphoma

Blood ◽

10.1182/blood.v128.22.1824.1824 ◽

2016 ◽

Vol 128 (22) ◽

pp. 1824-1824 ◽

Cited By ~ 3

Author(s):

Jennifer E Amengual ◽

Renee Lichtenstein ◽

Celeste Rojas ◽

Ahmed Sawas ◽

Changchun Deng ◽

...

Keyword(s):

T Cell ◽

Board Of Directors ◽

Research Funding ◽

Cell Lymphoma ◽

Median Number ◽

Peripheral T Cell Lymphoma ◽

Advisory Committees ◽

Genetics Research ◽

The Mean ◽

Grade 3

Abstract Peripheral T-cell lymphoma (PTCL) is a heterogeneous group of lymphomas in which only ~25% of patients experience long-term survival with CHOP chemotherapy. Recently several drugs have been approved for this entity including pralatrexate (P), romidepsin (R), and belinostat which have response rates ranging from 26%-29% as single agents. Based on our demonstration of synergy of P+R in preclinical models of TCL, we initiated a study on the safety and efficacy of P+R in a phase I-II study for relapsed or refractory lymphomas (NCT01947140) and sought to evaluate biological mechanisms of synergy. A 3+3 dose-escalation study started at P 10mg/m2 and R 12mg/m2 with escalation to P 25 mg/m2 and R 14 mg/m2. Patients were treated on 1 of 3 dosing schedules (weekly x 3 Q28D; weekly x 2 Q21D and QOW Q28D). The primary objective was to determine MTD and DLT; the secondary objective included describing ORR (CR+PR). Patients were required to have relapsed lymphoma of any subtype, ECOG PS ≤2, and adequate organ and marrow function. There was no upper limit to the number of prior therapies or transplantation. Twenty-six patients were enrolled and were evaluable for toxicity. Median age was 52 yrs (23-73) and 58% were male. The median number of prior therapies was 3 (range 1-16). Histologies included HL (N=3), B-cell (N=10 of which FL=4) and T-cell (N=13). The median number of cycles completed was 4 (range 1-12). There were 3 DLTs in cohort 4 (P 20mg/m2 & R 12mg/m2given weekly x 2 Q21D) consisting of 2 Grade 3 oral mucositis and 1 Grade 4 sepsis. The QOW Q28D schedule had no mucositis at all dose levels. Patients dosed at the MTD (P 25 mg/m2 & R 12mg/m2 QOW) did not experience any toxicities. The grade 3/4 toxicities reported in >5% of patients were: neutropenia (31%), thrombocytopenia (31%), anemia (23%), oral mucositis (15%), hyponatremia (8%), pneumonia (8%) and sepsis (8%). Twenty-two patients were evaluable for response, 1 patient is currently on therapy. The ORR in the total, non-PTCL and PTCL populations was 59%; 33% (no CR) and 77% respectively. Of the PTCL patients 4/13 (31%) achieved a CR, 6/13 (46%) achieved a PR, and 1 patient had stable disease. The mean duration of response (DOR) for all patients on the study (N=13) was 6.1 months (1.1 - 26.5), for the non-PTCL population (N=3) was 4.8 m (1.1-11) and for the PTCL population (N=10) was 6.55 months (range 1.6 - 26.5 +ongoing). The mean progression free survival (PFS) for all patients on study (N=26) was 4.8 m (.3 - 30.2), for the non-PTCL population (N=13) was 2.8 m (0.3-14.5), and for the PTCL population was 6.13 months (range 1.5 - 30.2 +ongoing). Pharmacokinetic studies were performed for P and R and data for the first 15 patients is presently available for reporting. PK analyses were performed using WinNonLin® to determine Cmax and AUC. Preliminary Cmax results for P 10 mg/m2 and P 15 mg/m2 are 1810+/-1063 ng/mL and 2748+/-995 ng/mL, respectively. Preliminary Cmax results for R 12 mg/m2 and R 14 mg/m2 are 420+/-198 ng/mL and 552+/- 346 ng/mL, respectively. After infusion with P 10 mg/m2 or 15 mg/m2 PK analysis indicate AUC0-24.08h of 3616+/-1543 h*ng/mL and 4104+/-2124 h*ng/mL, respectively. AUC0-28h after treatment with R 12 mg/m2or 14 mg/m2 was 1503+/-1286 h*ng/ml and 2535+/-2560 h*ng/mL. These values are consistent with that observed for both of these drugs in previous studies. Results from the phase I study conclude that the combination of P + R given on the QOW schedule is safe and very well tolerated. These data support the lineage specific activity of the P+R combination, which is currently being expanded to a multicenter Phase II for PTCL. Figure Figure. Disclosures Amengual: Bristol-Myers Squibb: Research Funding; Acetylon Pharmaceuticals, Inc: Research Funding. Sawas:Seattle Genetics: Honoraria; Gilead Sciences: Speakers Bureau. O'Connor:Spectrum: Research Funding; Seattle Genetics: Research Funding; Mundipharma: Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Research Funding; Mundipharma: Membership on an entity's Board of Directors or advisory committees; Spectrum: Research Funding; TG Therapeutics: Research Funding; TG Therapeutics: Research Funding; Bristol Myers Squibb: Research Funding; Bristol Myers Squibb: Research Funding; Celgene: Research Funding; Celgene: Research Funding.

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Outcomes, Causes of Discontinuation and Mutation Profile of Patients with Mantle Cell Lymphoma Who Progressed on Acalabrutinib

Blood ◽

10.1182/blood-2018-99-115179 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 4151-4151 ◽

Cited By ~ 3

Author(s):

Preetesh Jain ◽

Rashmi Kanagal-Shamanna ◽

Shaojun Zhang ◽

Chi Young Ok ◽

Makhdum Ahmed ◽

...

Keyword(s):

Disease Progression ◽

Board Of Directors ◽

Copy Number ◽

Research Funding ◽

Cell Lymphoma ◽

Median Number ◽

Copy Number Alterations ◽

Advisory Committees ◽

Mantle Cell

Abstract Introduction: Acalabrutinib is a Bruton tyrosine kinase (BTK) inhibitor approved for treatment of relapsed patients (pts) with mantle cell lymphoma. We have reported previously that ibrutinib refractory MCL pts have poor survival. However, outcomes, causes of discontinuation, management and the genomic landscape of MCL in pts who discontinued acalabrutinib are rarely reported. Method: We reviewed charts from all MCL pts treated with single agent acalabrutinib (n=28) in the relapsed setting and identified 15 pts who discontinued acalabrutinib and who are described in this analysis. Outcome after discontinuing acalabrutinib is reported. Whole-exome sequencing (WES) with SureSelect Human All Exon V6 was performed on 10 tumor specimens and 5 matched germline samples collected from 9 pts whose MCL progressed on acalabrutinib; among these pts 4 tumors were collected at baseline and 6 were collected after disease progression. One patient had sufficient DNAs available for both time points (baseline and progression). Results: The median duration on treatment with acalabrutinib was 6.5 months (1 to 29 months) and the median number of cycles of acalabrutinib treatment was 6 (range, 1-30). Seven pts had complete remission (CR) as their best response on acalabrutinib, 5 were primary refractory and 3 achieved partial remission. In 12 pts (80%) acalabrutinib was discontinued due to disease progression (2 pts transformed from classic to blastoid and pleomorphic type at progression) and 3 pts were discontinued due to intolerance (one for fatigue and idiopathic encephalopathy, one due to unrelated severe aortic stenosis and another for cytopenias secondary to therapy related myelodysplasia; all three pts were in CR). Nine pts had classic and 3 pts each had blastoid or pleomorphic features before starting acalabrutinib. Overall, median Ki-67 expression was 50% (range, 5-100) and all pts had high a MIPI score. The median number of prior treatments was 1 (range, 1-3); all chemo-immunotherapy (10 pts were previously treated with rituximab-hyper-CVAD) and none with ibrutinib. Two pts who transformed on acalabrutinib received acalabrutinib for a median duration of 12 months (range, 8-16.5). Median follow up after discontinuation was 27 months and the median survival was 25 months (26 months for progression and 1.5 months for intolerance; p <0.001, Figure-1A). Patients who discontinued due to intolerance did not get subsequent treatment for MCL. Among the 12 pts who progressed on acalabrutinib, 11 pts received systemic therapy for MCL [seven received ibrutinib based therapies (2 non responders, 3 achieved CR and 2 were PR and all pts progressed subsequently), 3 got chemo-immunotherapy and progressed and one pt did not receive any treatment and was lost to follow up and died. Six patients received a clinical trial with CAR-T cells (results will be reported separately). Overall, at the time of last follow up, 8 pts were alive and 7 were in CR. Recurrently mutated genes in these tumors included ATM (6/10; 60%), TP53 (4/10; 40%), KMT2C (3/10), MYCN (2/10), NOTCH1 (2/10), NOTCH3 (2/10), and MEF2B (2/10) (Fig. 1B). We did not detect any mutation or copy number alterations in BTK, PLCG2, TRAF2/3 and MYD88 that have been reported previously to be associated with ibrutinib resistance. Compared to tumors at baseline, ATM was mutated at a higher frequency in samples at progression (67% vs. 50%; p=NS). To investigate the mutation evolution on acalabrutinib treatment, mutation profiles, particularly the mutation variant allelic fractions (VAFs), were compared between the baseline and progression samples from pt-1 (Fig. 1C). Mutation of MYCN, MEF2B, ATM, and NOTCH1 were identified in both tumors at similar VAFs, whereas mutation of CARD11 (two mutations), NLRC5 and B2M were detected only at progression. In pt-1, both the NLRC5 and β2M mutations acquired at disease progression were truncating, suggesting loss-of-function alterations. Copy number analysis reveals frequent whole-genome doubling and intensive copy number alterations in all tumors, including recurrent losses of chromosome 9p, 17p, and chromosome 13, indicating chromosomal instability as a driver of disease progression. Conclusion: Patients who progress on acalabrutinib have a poor outcome, and newer therapies are required for their treatment. In this small cohort, we observed non-BTK mutations associated with acalabrutinib resistance and disease progression. Disclosures Nastoupil: Genentech: Honoraria, Research Funding; TG Therappeutics: Research Funding; Spectrum: Honoraria; Gilead: Honoraria; Merck: Honoraria, Research Funding; Janssen: Research Funding; Celgene: Honoraria, Research Funding; Karus: Research Funding; Novartis: Honoraria; Juno: Honoraria. Neelapu:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Cellectis: Research Funding; Poseida: Research Funding; Merck: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Acerta: Research Funding; Karus: Research Funding; Bristol-Myers Squibb: Research Funding; Unum Therapeutics: Membership on an entity's Board of Directors or advisory committees; Kite/Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees. Fowler:Janssen: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding. Wang:Acerta Pharma: Honoraria, Research Funding; MoreHealth: Consultancy; AstraZeneca: Consultancy, Research Funding; Kite Pharma: Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Dava Oncology: Honoraria; Juno: Research Funding; Pharmacyclics: Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Research Funding.

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Prophylactic Antibiotic Use and Risk of Meningococcal Infections in Patients with Paroxysmal Nocturnal Hemoglobinuria (PNH) Treated with Eculizumab Who Received Meningococcal Vaccination: Results from the International PNH Registry

Blood ◽

10.1182/blood-2019-127005 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 4802-4802 ◽

Cited By ~ 2

Author(s):

Christopher J. Patriquin ◽

Austin Kulasekararaj ◽

Régis Peffault de Latour ◽

Jun-Ho Jang ◽

Saskia Langemeijer ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Paroxysmal Nocturnal Hemoglobinuria ◽

Infection Risk ◽

Meningococcal Infection ◽

Meningococcal Infections ◽

Advisory Committees ◽

Start Date ◽

The Mean

INTRODUCTION Paroxysmal nocturnal hemoglobinuria (PNH) patients treated with eculizumab have an increased susceptibility to serious meningococcal infections. In the largest safety data set to date, representing >10 years of postmarketing pharmacovigilance surveillance of eculizumab for the treatment of PNH, the reported meningococcal infection rate was 0.24 per 100 patient-years (PY); cumulative exposure to eculizumab in PNH was 21,016 PY (Socié G, et al. Br J Haematol. 2019). To reduce infection risk, it is recommended that PNH patients receive meningococcal vaccination ≥2 weeks prior to the first dose of eculizumab; patients vaccinated <2 weeks prior to eculizumab initiation are treated with appropriate prophylactic antibiotics (P-Abx) until 2 weeks after vaccination. However, some patients may still experience meningococcal infections, as vaccination reduces but does not eliminate the risk of meningococcal infection; thus, some physicians use long-term P-Abx in addition to meningococcal vaccination to lower infection risk. The real-world use of P-Abx is not well characterized, and their effect on the incidence of meningococcal infection is unknown. The objective of this study was to assess meningococcal infection rates in PNH patients who received eculizumab with or without P-Abx. METHODS This was a cohort study consisting of eculizumab-treated PNH patients from the International PNH Registry (NCT01374360). Eligible patients received meningococcal vaccination within 6 months prior to or up to 1-month post-eculizumab initiation; had a known birth date, sex, enrollment date, and status of P-Abx use; and were evaluable for infection during the study period. To prospectively assess the rates of meningococcal infections, the start of the follow-up period was defined as the later of the registry enrollment date or eculizumab treatment start date and the end of the follow-up period was defined as the earlier of the last eculizumab treatment follow-up date or date of the first meningococcal infection (i.e., patients were censored when they developed the first meningococcal infection after registry enrollment). To compare the demographic and disease characteristics between patients who started P-Abx and those who did not (No P-Abx), data were summarized at the later of the eculizumab start date, P-Abx start date, or enrollment date for patients with P-Abx use or at the last eculizumab treatment follow-up for No P-Abx patients. Event rates and corresponding 95% CIs were calculated for meningococcal infections for patients with and those without P-Abx using Poisson regression with an offset for the log of the treatment duration. RESULTS As of January 8, 2019, 1,815 eculizumab-treated patients were enrolled in the International PNH Registry, of whom 1,231 met all inclusion criteria for this study. Of the eligible patients, 501 received P-Abx and 730 did not. For the P-Abx and No P-Abx groups, the mean age of PNH onset (37.3 vs 36.8 y, respectively) and mean age at eculizumab initiation (44.4 vs 43.1 y, respectively) were similar. P-Abx use was higher in Europe (76.6%) than in other regions (Table 1). Both P-Abx and No P-Abx groups had similar medical event histories; the mean duration of the study period was 4.3 years (SD, 2.28 years) for the P-Abx group and 3.8 years (SD, 2.48 years) for the No P-Abx group. The mean duration of P-Abx use during the study period was 0.4 years (SD, 1.01 years). The most commonly used P-Abx was penicillin (314 of 500 patients). In total, 7 patients (3 from the P-Abx group and 4 from the No P-Abx group) experienced a meningococcal infection during the study period. In these 7 patients, the mean time from meningococcal vaccination to eculizumab initiation was 0.7 months (SD, 0.23 months) for the P-Abx group and 2.4 months (SD, 1.20 months) for the No P-Abx group. The estimated rates of meningococcal infection per 100 PY were 0.1 (95% CI, 0.0-0.4) for the P-Abx group and 0.1 (95% CI, 0.1-0.4) for the No P-Abx group (Table 2). CONCLUSIONS Rates of meningococcal infection were consistent with previously reported rates and were similar in PNH patients who received eculizumab therapy with or without P-Abx. It is important to note the small number of meningococcal infections and the limited details of P-Abx use reported in the registry. Further work will assess if patients were on P-Abx at the time of infection, and what meningococcal serotypes were identified. Disclosures Patriquin: Apellis: Consultancy, Honoraria, Research Funding; Ra Pharma: Consultancy, Research Funding; Alexion: Consultancy, Honoraria, Research Funding; Octapharma: Consultancy, Honoraria, Research Funding. Kulasekararaj:Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene Corporation: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Achilleon: Consultancy; Ra Pharma: Honoraria, Membership on an entity's Board of Directors or advisory committees; Akari Therapeutics: Consultancy; Alexion: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Peffault de Latour:Novartis: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; Alexion: Consultancy, Honoraria, Research Funding; Amgen: Research Funding. Wilson:Alexion Pharmaceuticals Inc.: Employment. Jain:Alexion Pharmaceuticals Inc.: Employment. Maciejewski:Alexion: Consultancy; Novartis: Consultancy.

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Stable FIX Expression and Durable Reductions in Bleeding and Factor IX Consumption for up to 4 Years Following AMT-060 Gene Therapy in Adults with Severe or Moderate-Severe Hemophilia B

Blood ◽

10.1182/blood-2019-122535 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 2059-2059 ◽

Cited By ~ 5

Author(s):

Wolfgang Miesbach ◽

Karina Meijer ◽

Michiel Coppens ◽

Peter Kampmann ◽

Dr. Klamroth ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Factor Ix ◽

First Year ◽

Severe Hemophilia ◽

Advisory Committees ◽

The Mean ◽

Second Year

Background: The aim of gene therapy is to provide long-term therapeutic effect from a single administration, yet information on response durability is currently limited. AMT-060 is an adeno-associated virus serotype 5 (AAV5) vector with a codon-optimized wildtype human factor IX (FIX) gene and liver-specific promoter. AMT-060 is being analyzed in an ongoing study of 10 participants with severe/moderate-severe hemophilia B (Phase 1/2 study, NCT02396342). Aim: To describe efficacy and safety outcomes from a planned interim analysis at up to 4-years post-AMT-060. Methods: Adult males with FIX activity ≤2% and a severe bleeding phenotype received a single intravenous infusion of AMT-060 (5x1012gc/kg, Cohort 1, n=5) or (2×1013 gc/kg, Cohort 2, n=5). Assessments included FIX activity, FIX replacement use, annualized bleeding rate (ABR), treatment-related adverse events (TRAE), immunological and inflammatory biomarkers up to 4 years (Cohort 1) and 3.5 years (Cohort 2). Results: As of 8 May 2019, for Cohort 1 the mean yearly FIX activity (annualized to 4 years) was 6.0 as compared to 4.4% in the first year, 6.8% in the second year and 7.3% in the third year. Mean yearly FIX activity for Cohort 2 at 3 years was 7.9% as compared to 7.1% in the first year and 8.4% in the second year. Factor IX activity for each patient over the length of follow up is shown in Figure 1. Eight of 9 participants using prophylaxis at baseline were able to discontinue use. During the last 12 months of observation, the mean annualized bleed rate (ABR) was 1.7 for Cohort 1 and 0.7 for Cohort 2. Respectively, these represent a reduction in mean ABR to the year prior to treatment of 88% and 83%. During this same period the consumption of FIX replacement therapy declined 93% and 96% relative to pre-treatment respectively for Cohort 1 and Cohort 2. No participants developed FIX inhibitors or signs of sustained AAV5 capsid-specific T-cell activation. TRAE were mainly reported in the first 3.5-months after treatment, including three participants who experienced transient mild elevations in alanine aminotransferase as previously described. One new TRAE (joint swelling post-exercise) was observed during the last 12 months of observation post-treatment. Updated data, up to 4-years of observation, will be presented for the first time. Conclusions: Long-term stable endogenous FIX activity and reductions in ABR and FIX replacement use were observed following a single treatment with AMT-060. There were no additional safety concerns with longer term follow-up. These findings support the ongoing Phase III study of the enhanced construct, AMT-061, which encodes the highly active Padua FIX variant. Figure 1 Disclosures Miesbach: Bayer, BioMarin, CSL Behring, Chugai, Freeline, Novo Nordisk, Octapharma, Pfizer, Roche, Takeda/Shire, UniQure: Consultancy; Bayer, Novo Nordisk, Octapharma, Pfizer, Takeda/Shire: Research Funding; Bayer, Chugai, Novo Nordisk, Octapharma, Pfizer, Takeda/Shire, UniQure: Speakers Bureau. Meijer:Pfizer, Sanquin, Uniqure: Research Funding; Uniqure, BMS, Aspen, Boehringer Ingelheim, Sanquin, Bayer: Consultancy, Honoraria; Sanquin: Research Funding; Bayer: Research Funding. Coppens:Pfizer: Honoraria; Portola Pharmaceuticals, Inc: Honoraria; Daiichi Sankyo: Honoraria, Research Funding; Uniqure: Research Funding; Boehringer Ingelheim: Research Funding; Sanquin Blood Supply: Research Funding; Bayer: Honoraria, Research Funding; CSL Behring: Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria. Kampmann:Uniqure BV: Research Funding. Klamroth:Bayer, Biomarin, CSL Behring, Novo Nordisk, Octapharma, Pfizer, Roche, SOBI, Takeda: Consultancy; Bayer, Novo Nordisk, SOBI: Research Funding. Schutgens:Baxalta Shire, Novo Nordisk, Bayer, CSL Behring, Pfizer, UniQure BV: Research Funding. Castaman:Bayer: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novo Nordisk: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sobi: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; CSL Behring: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Takeda (SHIRE): Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Kedrion: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Roche: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Werfen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizer: Research Funding; Uniqure: 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. Seifried:Medac: Other: BSD owns IP and is contract manufacturer; Uniqure BV: Research Funding. Schwaeble:Uniqure BV: Research Funding. Bönig:Celgene, Novartis, Sandoz Hexal: Consultancy; Kiadis Pharma: Other: Contract manufacturing of ATIR101; Sandoz Hexal, Uniqure: Research Funding; Miletenyi: Speakers Bureau. Sawyer:Uniqure BV: Employment. Leebeek:CSL Behring: Research Funding; UniQure: Consultancy; Shire/Takeda: Research Funding; Novo Nordisk: Consultancy; Sobi: Other: Travel grant; Shire/Takeda: Consultancy.

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Hypomethylating Agent and Venetoclax Combination Therapy Yields Superior Outcomes When Compared to Hypomethylating Agent Monotherapy in Patients ≥70 Years with Acute Myeloid Leukemia

Blood ◽

10.1182/blood-2019-127772 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 1368-1368 ◽

Cited By ~ 1

Author(s):

Yumeng Zhang ◽

Hannah H Asghari ◽

Onyee Chan ◽

Dasom Lee ◽

Martine Extermann ◽

...

Keyword(s):

Board Of Directors ◽

Older Patients ◽

Myeloid Leukemia ◽

Research Funding ◽

Response Rates ◽

Newly Diagnosed ◽

Advisory Committees ◽

Entire Cohort ◽

Response Data

Background: Older patients with acute myeloid leukemia (AML) have inferior outcomes when compared to younger patients. Hypomethylating agents (HMA) were established as the standard of care for patients who are unfit for intensive induction chemotherapy until HMA and venetoclax (HMA+ven) combination approval by the FDA in December 2018. Approval of HMA+ven was based on an early phase study which produced high response rates; however, the combination was not compared head-to-head with HMA alone. A randomized phase 3 study is currently underway. There is no data available comparing HMA+ven to HMA monotherapy in older patients (age ≥70 years), thus we aimed to characterize responses in older patients when treated with these two regimens. Methods: We retrospectively reviewed clinical and molecular data on 225 patients at Moffitt Cancer Center and Memorial Health System with newly diagnosed AML who were ≥ 70 years old and were treated with HMA monotherapy or HMA+ven combination. Clinical data was abstracted in accordance with institutional review board approved protocol. Patients were then divided in two subgroups: Cohort A) HMA monotherapy and B) HMA+ven combination. We calculated overall response rates (ORR) defined as patients achieving complete remission (CR), CR with incomplete hematologic recovery (CRi) or morphologic leukemia free state (MLFS). Fisher's Exact method was utilized to determine significance for categorical variables. All reported p-values are two sided. Next generation sequencing (NGS) results were analyzed using the TruSight Myeloid-54 gene panel with a sensitivity of 5%, and were characterized in patients treated in cohort B. Results: Among the 225 patients, 87% (n=196) were in cohort A and 13% (n=29) in cohort B. In cohort A, 36.7% were females compared to 27.6% in cohort B. Median age in both cohorts was 76 years (range: 70-90 years in cohort A) (range: 72-86 years in cohort B). Overall, 26% of the patients had adverse risk disease as defined by European Leukemia Net (ELN) classification in cohort A and 51.7% in cohort B. Baseline characteristics are described in Table 1. Overall response rate (ORR) of the entire cohort was 43.6% (n=92) (Table 2). ORR in cohort A was 25.5% (n=47) compared to 66.7% (n=18) in cohort B (p<0.001). The median time to response in cohort A was 3.8 mos and was 1.9 mos in cohort B. Looking only at the 66 patients with ELN-defined adverse risk, response data were available in 62 patients, and the ORR in both cohorts was 25.8% (n=16), and was significantly lower in cohort A compared to B (14.9% vs. 60%, respectively, p=0.001) (Figure 1). Among the 136 patients with favorable or intermediate risk disease, response data were available in 127 patients, and the ORR was 35.4% (n=45). In cohort A the ORR in favorable/intermediate patients was 28.9% (n=37), and in cohort B it was significantly higher at 100% (n=8) (p<0.001). Ten responding patients in cohort B had NGS data available at diagnosis and at the time of best response. Mutations cleared from the bone marrow in 60% (n=6) of these patients. With a median follow up of 11.7 months, the median overall survival (mOS) of the entire cohort was 15.03 months. The median follow-up time in cohort A is 46 months and in cohort B is 5.4 months, making assessment of relapse free survival or overall survival in cohort B premature. Early mortality rate was not different between the two cohorts (1.5% vs 3.4%, p=0.42). Conclusion: Our data provides convincing support that HMA+ven combination yields significantly higher response rates when compared to HMA monotherapy in newly diagnosed AML patients ≥70 years of age; an observation that is further strengthened by the short duration of follow-up in the HMA+Ven cohort. Responses are particularly striking in favorable and intermediate risk patients when treated with HMA+Ven. Overall our data supports the use of HMA+ven in the upfront setting for older patients with newly diagnosed AML. Additional follow-up in HMA+ven arm is needed to evaluate survival outcomes. Disclosures Kuykendall: Incyte: Honoraria, Speakers Bureau; Abbvie: Honoraria; Janssen: Consultancy; Celgene: Honoraria. List:Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding. Lancet:Agios, Biopath, Biosight, Boehringer Inglheim, Celator, Celgene, Janssen, Jazz Pharmaceuticals, Karyopharm, Novartis: Consultancy; Pfizer: Consultancy, Research Funding; Daiichi Sankyo: Consultancy, Other: fees for non-CME/CE services . Komrokji:JAZZ: Speakers Bureau; Novartis: Speakers Bureau; JAZZ: Consultancy; Agios: Consultancy; Incyte: Consultancy; DSI: Consultancy; pfizer: Consultancy; celgene: Consultancy. Sallman:Celyad: Membership on an entity's Board of Directors or advisory committees. Talati:Celgene: Honoraria; Agios: Honoraria; Jazz Pharmaceuticals: Honoraria, Speakers Bureau; Daiichi-Sankyo: Honoraria; Astellas: Honoraria, Speakers Bureau; Pfizer: Honoraria. Sweet:Pfizer: Consultancy; Incyte: Research Funding; Jazz: Speakers Bureau; Stemline: Consultancy; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Celgene: Speakers Bureau; Agios: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Astellas: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees.

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Baseline Characteristics of Patients in Peak: A Global, Longitudinal Registry of Patients with Pyruvate Kinase Deficiency

Blood ◽

10.1182/blood-2020-136634 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 39-40

Author(s):

Rachael F. Grace ◽

Audra Boscoe ◽

Chris Bowden ◽

Bertil Glader ◽

Hitoshi Kanno ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Pediatric Patients ◽

Chelation Therapy ◽

Treatment Patterns ◽

Missense Mutations ◽

Private Company ◽

Advisory Committees ◽

The Mean

Background: Pyruvate kinase (PK) deficiency is a rare, inherited hemolytic anemia caused by autosomal recessive mutations in the PKLR gene, whereby a glycolytic defect causes a reduction in adenosine triphosphate generation. Current treatment options are supportive and include splenectomy, blood transfusions, and iron chelation therapy. To better understand the natural history, treatment patterns, and burden of disease, the observational PK Deficiency Natural History Study (NHS) (NCT02053480) enrolled 254 adult and pediatric patients with PK deficiency at 30 sites in 6 countries between 2014 and 2017 and followed patients for 2 years. The Peak Registry (NCT03481738) was developed to continue and expand on this research. This retrospective and prospective observational registry aims to enroll 500 adult and pediatric patients at ~ 60 sites in up to 20 countries over 7 years, with 2-9 years of follow-up. Objective: This analysis aimed to characterize the baseline demographics and clinical characteristics of patients with PK deficiency enrolled in the Peak Registry as of 24March2020. Methods: Demographic, diagnostic, medical history, laboratory, treatment, and other relevant data were collected from participating clinicians via electronic case report forms. To be eligible for inclusion in this analysis, patients were required to have genetically confirmed PK deficiency and available demographic information. All analyses reported here are descriptive and based on data as of the date of enrollment in the registry. Continuous variables are summarized by the number of non-missing observations, mean, standard deviation (SD), median, and range. Categorical variables are summarized as counts and percentages. Results: A total of 141 patients met the inclusion criteria, across 11 countries in North America and Europe. A summary of baseline demographics and clinical characteristics is shown in the Table. Fifty patients (35.5%) had completed 2 years of follow-up in the NHS and then moved to the Peak Registry; the remainder were newly recruited to the Peak Registry. The mean age of study participants at enrollment was 25.5 years (SD 19.1); 78 patients (55.3%) were female. Mean reported age at first symptoms was 5.8 years (SD 13.2) and mean age at diagnosis was 11.7 years (SD 16.0). Fifty-seven percent of patients were classified as having missense/missense mutations, 34.4% as having missense/non-missense mutations, and 8.6% as having non-missense/non-missense mutations. The mean hemoglobin at enrollment was 8.8 g/dL (range: 5.8-12.9 g/dL). Mean reticulocyte count was 19.8% (range: 2.2-42.4%), mean lactate dehydrogenase was 382 IU/L (range: 135-849 IU/L), and mean indirect bilirubin was 4.3 mg/dL (range: 0.8-23.1 mg/dL). Among the 45.2% of patients who had been splenectomized, the mean age at splenectomy was 7.2 years. Chelation therapy had been previously prescribed to 40.3% of patients. Among the 27 patients for whom ferritin data were available, the mean was 867.9 ng/L (range: 78.1-2499.0 ng/L), and 18 patients (66.7%) had a level > 500 ng/L. Ninety-nine patients (70.2%) had received at least one transfusion in their lifetime. Among the 45 patients who were known to have received at ≥ 1 transfusion in the 12 months prior to enrollment, the mean number of transfusions during that period was 5 (SD 4.3), with 18 of those patients (40.0%) having received ≥ 6 transfusions. Conclusions: New data emerging from the Peak Registry will provide valuable insights into the patient characteristics, treatment patterns, and burden associated with PK deficiency. The population is demographically heterogenous and represents a broad geography. Patients have a wide range of hemoglobin levels, and iron overload is common. The substantial rates of splenectomy, cholecystectomy, transfusions, and chelation use are indicative of a high disease and treatment burden in patients with PK deficiency. This abstract is presented on behalf of the Peak Registry Steering Committee and Peak Registry Investigators. Disclosures Grace: Novartis: Research Funding; Pfizer: Research Funding; Agios: Research Funding; Dova: Membership on an entity's Board of Directors or advisory committees. Boscoe:Agios Pharmaceuticals: Current Employment, Current equity holder in private company. Bowden:Agios Pharmaceuticals: Current Employment, Current equity holder in private company. Glader:Agios Pharmaceuticals, Inc.: Consultancy. Layton:Cerus: Membership on an entity's Board of Directors or advisory committees; 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. van Beers:Novartis: Research Funding; Pfizer: Research Funding; RR mechatronics: Research Funding; Agios: Membership on an entity's Board of Directors or advisory committees, Research Funding. Yan:Agios Pharmaceuticals: Consultancy. Bianchi:Agios Pharmaceuticals: Other: Scientific Advisor.

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