scholarly journals Antifungal Prophylaxis: Impact on Outcomes of Newly Diagnosed AML Patients Treated with a Hypomethylating Agent and Venetoclax

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 4126-4126
Author(s):  
Evan C. Chen ◽  
Yiwen Liu ◽  
Eric S. Winer ◽  
Marlise R. Luskin ◽  
Martha Wadleigh ◽  
...  
Keyword(s):  
Fungal Infection ◽  
Board Of Directors ◽  
Research Funding ◽  
Fungal Infections ◽  
Hematologic Malignancy ◽  
Antifungal Prophylaxis ◽  
Newly Diagnosed ◽  
Advisory Committees ◽  
Entire Cohort ◽  
Hypomethylating Agent

Abstract Introduction: The Phase 3 VIALE-A study established the combination of venetoclax and a hypomethylating agent (VEN/HMA) as a new standard of care option for acute myeloid leukemia (AML) patients who are ineligible for intensive chemotherapy due to age (≥ 75 years) or comorbidities. The NCCN recommends antifungal prophylaxis (AFP) for relapsed/refractory AML patients receiving VEN/HMA, but its role in newly diagnosed AML patients treated with VEN/HMA remains controversial. Additionally, the impact of VEN dose-reduction due to concomitant azole use on AML outcomes and rates of fungal infection remains unclear. We evaluated the pattern of AFP use and its association with infectious and AML outcomes in patients receiving VEN/HMA at our institution. Methods: Consecutive patients aged ≥18 who received frontline VEN/HMA for newly diagnosed AML at the Dana-Farber Cancer Institute between 2016-2021 were identified in the Hematologic Malignancy Data Repository for retrospective chart review. Antibacterial and antifungal prophylaxis use at any time during VEN/HMA therapy and reasons for hospitalizations were recorded. Invasive fungal infections (IFIs) were adjudicated as "possible," "probable," or "proven" according to consensus guidelines (Donnelly, Clin Infect Dis 2020). Rates of complete remission (CR) and CR with incomplete hematologic recovery (CRi) per European LeukemiaNet (ELN) criteria were determined. Descriptive statistics on patient characteristics were compared between groups via nonparametric testing including Wilcoxon rank-sum, chi-squared, and the Fisher's Exact tests. Overall survival (OS) was estimated using the method of Kaplan and Meier, and log-rank tests were used to compare survival between groups. Multivariable Cox proportional-hazards models were used to obtain hazard ratios between groups. Results: 131 patients met inclusion criteria, of which 22 patients (16%) received AFP at any time. For the entire cohort, the median age at AML diagnosis was 72 (range 22-89), and the majority of patients were <75 years old (66%), had ELN adverse risk (70%), and had secondary AML (sAML)/sAML-like disease (73%; "sAML-like" defined per Lindsley, Blood 2015). Frequently mutated genes include TP53 (37%), ASXL1 (22%), and RUNX1 (19%). These baseline characteristics did not differ between patients who did and did not receive AFP. However, compared to patients who never received AFP, patients receiving AFP at any time were more likely to have received HMA therapy for an antecedent hematologic malignancy (41% vs. 13%, p=0.004) and concomitant antibacterial prophylaxis at any time (82% vs. 54%, p=0.016). Among the 171 hospitalizations that occurred in 90/131 patients, bacterial infection was suspected or identified in 139 admissions, and possible/probable/proven IFIs were identified in 21. Receiving AFP prior to admission was not associated with fewer hospitalizations in which an IFI was suspected or identified (Table, p=0.36). 3/21 IFIs were deemed "probable" or "proven." All 21 IFIs prompted antifungal therapy. No patient experienced more than one hospitalization involving an IFI. After a median of two cycles (range 1-15), best response (CR/CRi) for the entire cohort was 49%. Receiving AFP at any time was associated with lower CR/CRi than never receiving AFP (57% vs. 32%, p=0.014). The median OS for the entire cohort was 11.0 months (95% CI 8.8-14.6) and did not differ based on AFP use (11.9 months for patients without AFP, 8.1 months for those receiving AFP; p=0.23). In a multivariable model that included patient age, ELN risk, and AML ontogeny, AFP use was not significantly associated with OS (HR 1.40, p=0.22). Conclusion: AFP use and incidence of invasive fungal infection were overall low at our institution. Receiving AFP was not associated with improved OS nor with decreased number of hospitalizations for a suspected or confirmed IFI. At an institution where the incidence of fungal infections is low, there is presently no clear role for antifungal prophylaxis in newly-diagnosed AML patients receiving HMA with venetoclax. Figure 1 Figure 1. Disclosures Winer: Takeda: Consultancy; Novartis: Consultancy; Abbvie: Consultancy. Lane: AbbVie: Research Funding; Stemline Therapeutics: Research Funding; Qiagen: Consultancy, Honoraria; N-of-One: Consultancy, Honoraria. Neuberg: Pharmacyclics: Research Funding; Madrigal Pharmaceuticals: Other: Stock ownership. DeAngelo: Blueprint Medicines Corporation: Consultancy; Takeda: Consultancy; GlycoMimetics: Research Funding; Autolus: Consultancy; Abbvie: Research Funding; Shire: Consultancy; Amgen: Consultancy; Agios: Consultancy; Forty-Seven: Consultancy; Pfizer: Consultancy; Incyte Corporation: Consultancy; Jazz: Consultancy; Novartis: Consultancy, Research Funding. Stone: Syros: Membership on an entity's Board of Directors or advisory committees; Innate: Consultancy; GlaxoSmithKline: Consultancy; Astellas: Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy; Aprea: Consultancy; Actinium: Membership on an entity's Board of Directors or advisory committees; BerGen Bio: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Consultancy; Janssen: Consultancy; Gemoab: Membership on an entity's Board of Directors or advisory committees; Jazz: Consultancy; Novartis: Consultancy, Research Funding; Syndax: Membership on an entity's Board of Directors or advisory committees; Onconova: Consultancy; Foghorn Therapeutics: Consultancy; Elevate Bio: Membership on an entity's Board of Directors or advisory committees; Arog: Consultancy, Research Funding; Boston Pharmaceuticals: Consultancy; Syntrix/ACI: Membership on an entity's Board of Directors or advisory committees; Agios: Consultancy, Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy; Celgene: Consultancy; Macrogenics: Consultancy. Garcia: Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Research Funding; Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Prelude: Research Funding; Pfizer: Research Funding; Genentech: Research Funding.

scholarly journals Incidence of Invasive Fungal Infections in Acute Leukemia Patients Utilizing Micafungin Prophylaxis Compared to Second-Generation Azole Prophylaxis

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 5105-5105
Author(s):  
Heather Morris ◽  
Meredith T. Moorman ◽  
Melissa C. Mackey ◽  
Harry P. Erba ◽  
Thomas W. LeBlanc ◽  
...  
Keyword(s):  
Acute Leukemia ◽  
Fungal Infection ◽  
Board Of Directors ◽  
Induction Therapy ◽  
Research Funding ◽  
Second Generation ◽  
Fungal Infections ◽  
Antifungal Prophylaxis ◽  
Invasive Fungal Infections ◽  
Advisory Committees

Introduction/Background: Standard therapy for both acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL) is myelosuppressive, and patients are expected to be neutropenic for a prolonged period. Due to the high risk of infection, antimicrobial prophylaxis is warranted and should be continued throughout neutropenia. The incidence of documented invasive fungal infections ranges from 12 to 24% in patients with AML and approximately 6.5% in patients with ALL. Guidelines currently include posaconazole as a category 1 recommendation for antifungal prophylaxis, with echinocandins and other azole antifungals as category 2B. However, posaconazole can be subject to drug-drug interactions and can increase the risk of hepatotoxicity, both of which can be problematic in acute leukemia patients undergoing chemotherapy. For patients unable to receive posaconazole or another second-generation azole antifungal, micafungin is utilized. To our knowledge, there are no studies comparing second-generation azole antifungals to micafungin as prophylaxis in both AML and ALL during initial or relapsed/refractory induction therapy. The aim of this retrospective study is to compare the incidence of invasive fungal infections in patients with acute leukemia in the setting of micafungin or second-generation azole antifungal prophylaxis during initial and/or relapsed/refractory induction therapy at an academic medical center. Methods: Retrospective, single-center study from June 22, 2013 to June 22, 2018. Detailed chart reviews were performed by hand. Results: The incidence of invasive fungal infections within 100 days of chemotherapy was 11.2% in patients who received a second-generation azole and 2.7% in patients who received micafungin (P=0.7618). The incidence of invasive fungal infections within 100 days in patients who received a high intensity AML regimen was 11.2%, low intensity AML regimen 0.9%, and ALL regimen 1.8% (P=0.5378). The incidence of invasive fungal infections within 30 days of chemotherapy was 4.5% in patients who received a second-generation azole and 2.2% in patients who received micafungin (P=0.2447). The most common reason for micafungin prophylaxis was drug-drug interactions with standard ALL regimens that utilize vincristine. Of those with a documented fungal infection, 14 patients (6.3%) had a proven invasive fungal infection, and 17 patients (7.6%) had a probable/possible invasive fungal infection. The most common site of infection was in the chest (9.8%), followed by fungemia (2.2%). Other sites of infection include the brain, sinuses, liver/spleen, and skin. Beta-D-glucan was collected in 17 patients, and galactomannan antigen was collected in 26 patients. Three patients had a positive beta-D-glucan, and 1 patient had an indeterminate beta-D-glucan. Two patients had a positive galactomannan antigen. Fusarium species accounted for 4 positive cultures in patients. For those patients who did experience an invasive fungal infection, 23 out of the 31 patients (74.2%) were on posaconazole, 6 patients on micafungin (19.4%), and 2 on voriconazole (6.5%). Ten out of the 14 proven fungal infections (71.4%) occurred while on posaconazole prophylaxis, and 3 of these patients had posaconazole levels <0.7 mcg/mL. Twenty-one patients (67.7%) with documented infections had a neutrophil nadir < 0.1x109/L. The majority (93.5%) of those with breakthrough infections while on antifungal prophylaxis were switched to another antifungal. Conclusions: Micafungin is a reasonable alternative therapy for use in patients who are unable to receive second-generation azoles as antifungal prophylaxis during induction therapy for acute leukemia. Some invasive fungal infections occurred while patients had sub-therapeutic posaconazole levels, however others had breakthrough fungal infections with therapeutic levels. Our conclusions are limited by the small sample size and non-randomized, retrospective nature of this analysis. Disclosures Erba: Agios, Amgen, Astellas Pharma, Daiichi Sankyo, ImmunoGen, Janssen, Jazz Pharmaceuticals, Juno, Millennium, Seattle Genetics: Research Funding; Celgene, Incyte, Novartis: Speakers Bureau; Amgen, Celgene, Daiichi Sankyo, ImmunoGen, Incyte, Jazz Pharmaceuticals, Millennium, Novartis, Ono, Pfizer, Seattle Genetics, Sunesis: Consultancy. LeBlanc:Seattle Genetics: Consultancy, Research Funding; Astra Zeneca: Consultancy, Research Funding; AbbVie: Membership on an entity's Board of Directors or advisory committees; Agios: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; NINR/NIH: Research Funding; Jazz Pharmaceuticals: Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees; CareVive: Consultancy; American Cancer Society: Research Funding; Daiichi-Sankyo: Membership on an entity's Board of Directors or advisory committees; Helsinn: Consultancy; Medtronic: Membership on an entity's Board of Directors or advisory committees; Otsuka: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer Inc: Consultancy; Heron: Membership on an entity's Board of Directors or advisory committees; Duke University: Research Funding; Celgene: Honoraria; Flatiron: Consultancy. Rizzieri:AROG, Bayer, Celgene, Celltron, Mustang, Pfizer, Seattle Genetics, Stemline: Consultancy; Stemline: Research Funding; Celgene, Gilead, Seattle Genetics, Stemline: Other: Speaker; AbbVie, Agios, AROG, Bayer, Celgene, Gilead, Jazz, Novartis, Pfizer, Sanofi, Seattle Genetics, Stemline, Teva: Other: Advisory Board.

scholarly journals Clonal Hematopoiesis Prevalence Increases throughout Treatment of Newly Diagnosed Multiple Myeloma Patients

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 1091-1091
Author(s):  
Tarek H. Mouhieddine ◽  
Chidimma Nzerem ◽  
Robert A. Redd ◽  
Andrew Dunford ◽  
Matthew Joseph Leventhal ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Board Of Directors ◽  
Peripheral Blood ◽  
Research Funding ◽  
Hematologic Malignancy ◽  
Newly Diagnosed ◽  
Advisory Committees ◽  
Clonal Hematopoiesis ◽  
First Time ◽  
Time Point

Abstract Background: Recent studies have identified clinical and genomic factors contributing to worse clinical outcomes in patients with multiple myeloma (MM). Clonal hematopoiesis (CH) reflects the presence of somatic driver mutations in the blood or marrow of otherwise asymptomatic individuals. Using a variant allele frequency (VAF) cutoff of 2%, we recently reported CH in 21.6% of MM patients at the time of autologous stem cell transplant (ASCT) and found it was associated with shorter overall survival (OS) and progression-free survival (PFS) in those who did not receive maintenance therapy with an immunomodulatory drug (IMiD). However, this finding was based on a single tertiary center and only included MM patients who received ASCT. Methods: We studied a larger cohort of 986 newly diagnosed MM cases. Whole-exome sequencing (WES) data of peripheral blood and bone marrow samples of 986 MM patients (523 transplanted and 463 non-transplanted) from the Multiple Myeloma Research Foundation (MMRF) Clinical Outcomes in MM to Personal Assessment of Genetic Profile (CoMMpass, NCT0145429) study were analyzed. Both peripheral blood and tumor samples were analyzed to filter out myeloma mutations that could be contaminating the peripheral blood. Given the lower depth of coverage compared to prior targeted sequencing studies, small clones with a VAF below 2% were not detected. Altogether, the WES samples had a total depth of coverage of 117.68X. All data were analyzed using R version 3.5.0 (R Core Team). Results: Among the total cohort, 113 CH mutations were detected in 101/986 (10.24%) patients. CH was detected in 42/523 (8.03%) transplanted patients, compared to 59/463 (12.74%) non-transplanted patients. The most commonly mutated genes were DNMT3A, TET2, ASXL1, PPM1D, and TP53. The median age of the cohort was 63 years (range: 27 - 93), 60% were male, and median follow-up was 3.9 years (95% CI: 3.7 - 4.0). The presence of CH was associated with age (69 vs. 62 years, P &lt; 0.001). As expected, the median age of transplanted patients was lower (60 vs. 67 years) than in the non-transplanted group, which likely explains the higher prevalence of CH detected in the non-transplanted group. CH was associated with recurrent bacterial infections (P = 0.01) and increased cardiovascular disease (P = 0.006), but not with cerebrovascular disease (P = 0.74) or coagulopathies (P = 0.65). There was a trend towards worse PFS in non-ASCT patients with CH who were not treated with IMiDs (1.8 years) compared to non-CH IMiD-treated patients (2.7 years) (P &lt; 0.001). A CH effect on PFS was not detected in ASCT patients. OS was not different in those with or without CH in both ASCT and non-ASCT groups. 8 (0.8%) patients developed a second hematologic malignancy. CH at the time of MM diagnosis was not associated with an increased risk of developing a second hematologic malignancy (P = 0.58). To determine whether CH clones emerged or evolved during treatment, we examined serial samples from 52 patients (36 ASCT patients and 16 non-transplanted patients) with sequential samples. The median time between the first and second time point was 3.1 years (range: 1.0 - 5.4 years). At the first time point, only 3/52 (5.8%) patients had CH, but that number increased to 13/52 (25.0%) at the second time point. Five out of the 13 (38%) were non-transplanted patients. All but 1 patient were exposed to IMiDs. The most common emerging mutated gene was DNMT3A, found in 7 patient samples at the second time point, compared to 2 patients at the first time point. Conclusion: Using WES in a large cohort of newly diagnosed MM patients, we detected CH in 10.2% (VAF ≥ 2%) of patients. CH and non-IMiD treatment confers a shorter PFS in non-transplanted MM patients. However, throughout IMiD-based treatment, MM patients tend to acquire and/or expand previously undetected CH clones, particularly DNMT3A. The clinical significance of this clonal expansion during therapy is yet to be elucidated, and for now, this observation does not yet change clinical management. Figure 1 Figure 1. Disclosures Steensma: Novartis: Current Employment. Ebert: Deerfield: Research Funding; GRAIL: Consultancy; Exo Therapeutics: Membership on an entity's Board of Directors or advisory committees; Celgene: Research Funding; Skyhawk Therapeutics: Membership on an entity's Board of Directors or advisory committees. Soiffer: NMPD - Be the Match, USA: Membership on an entity's Board of Directors or advisory committees; Gilead, USA: Other: Career Development Award Committee; Rheos Therapeutics, USA: Consultancy; Kiadis, Netherlands: Membership on an entity's Board of Directors or advisory committees; Juno Therapeutics, USA: Other: Data Safety Monitoring Board; Precision Biosciences, USA: Consultancy; Jazz Pharmaceuticals, USA: Consultancy; Jasper: Consultancy; Takeda: Consultancy. Sperling: Adaptive: Consultancy. Getz: Scorpion Therapeutics: Consultancy, Current holder of individual stocks in a privately-held company, Membership on an entity's Board of Directors or advisory committees; IBM, Pharmacyclics: Research Funding. Ghobrial: AbbVie, Adaptive, Aptitude Health, BMS, Cellectar, Curio Science, Genetch, Janssen, Janssen Central American and Caribbean, Karyopharm, Medscape, Oncopeptides, Sanofi, Takeda, The Binding Site, GNS, GSK: Consultancy.

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

Blood ◽  
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.

scholarly journals Differences in Presentation and Survival Outcomes for African American Patients with Newly Diagnosed Multiple Myeloma

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 5647-5647 ◽  
Author(s):  
Nisha Joseph ◽  
Vikas A. Gupta ◽  
Craig C Hofmeister ◽  
Charise Gleason ◽  
Leonard Heffner ◽  
...  
Keyword(s):  
African American ◽  
Board Of Directors ◽  
Median Time ◽  
Research Funding ◽  
Newly Diagnosed ◽  
Long Term Outcomes ◽  
Advisory Committees ◽  
Entire Cohort ◽  
Significant Difference

Abstract Background : Though the incidence of MM is two- to threefold higher in the African American (AA) population compared to Caucasians, reported long term outcomes are less favorable presumably due to inequities in access to healthcare. Little is known about the biology or disease presentation among AAs. We have conducted a retrospective analysis of our institutional data of 1000 patients treated with RVD induction therapy, specifically assessing differences in presentation, disease biology, and outcomes in AA patients. Methods: A total of 1000 newly diagnosed MM patients were treated with RVD induction therapy [R - 25 mg/day (days 1-14), V - 1.3 mg/m2 (days 1, 4 8, 11) and D - 40 mg once/twice weekly as tolerated every 21 days] from January 1st 2005 until August 31st 2016. Dose-adjustments were made based on the treating physician's discretion and patient tolerability. Demographic and outcomes data for the patients were obtained from our IRB approved myeloma database and responses were evaluated per IMWG Uniform Response Criteria. Results: Of the 1000 patients included in the analysis, 564 (56.4%) of patients were white (W), and 339 (33.9%) were AA, consistent with the demographic representation of the state of GA and our institutional referral population. Median age of this cohort was 61 years (range 16-83), 57 for AA patients (range, 24-83) compared to 62 (range, 16-81) in white patients, suggesting the onset is earlier among AA which has been previously reported in population based studies. Other notable characteristics include: 42.5%M/57.5% F for AA cohort and 61.7%M/38.3%F for white cohort. In regard to stage, AA: 73.9% stage I/II, 26.1% stage III; W: 77.1% stage I/II, 22.9% stage III, showing no difference in prognostic staging at presentation. There was no statistically significant difference in the presenting labs between AA and whites except for hemoglobin, with more AA patients presenting with Hgb≤9.9 g/dL (45.7% AA vs 32.5% W, p <.0001). In terms of prevalence of high-risk cytogenetics, there was no significant difference between the two cohorts in: complex karyotype 16% white/14.4% AA; t(14;16) 2.4% W/2.8% AA; t(4;14) 4.7% W/5.0% AA; t(11;14) 11.7% W/15.9% AA; or del1p 6.5%W/7.8%AA. However, there were significant differences found in the rates of: amp 1q 19.2% W/10.6% AA, (p<.0001), del13 28.3% W/19.6% AA (p=.003), and del17p 11.7% W/7.2% AA (p=.019), all three significantly less frequent in AAs. Median time to transplant for the entire cohort was 5 months (range, 1-124), and median time to best response was 3 months (range, 0-39). There was no significant difference in the number of patients who underwent ASCT (84% W vs 82% AA, p=.241), nor in ≥VGPR rates post-induction and 100 days post-ASCT: 69.9% W vs 64.5% AA (p=.056) and 88.1% W vs 86.7% in AA patients (p=.317), respectively. Median PFS for the entire cohort was 63 months, 62 months (54-69.9) for white patients versus 65 months (53-76.9) for AA patients (p=0.403). At a median follow up of 38 months, median OS has not yet been reached. Conclusions: This is the largest reported cohort of myeloma patients treated with RVD induction, with one-third of the patients representing the AA population. In our dataset, AAs are diagnosed 5 years younger, with lower hemoglobin at presentation and lower rates of amp1q, del13 and del17p when compared to whites. When offered the same induction regimen and opportunity for ASCT, AAs tend to experience the same survival benefits as their white counterparts. The lack of significant difference in PFS or OS suggests standardization and improved access to care could lead to better long-term outcomes in the AA population. Disclosures Hofmeister: Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Oncopeptides: Membership on an entity's Board of Directors or advisory committees; Adaptive biotechnologies: Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees. Heffner:Genentech: Research Funding; Pharmacyclics: Research Funding; ADC Therapeutics: Research Funding; Kite Pharma: Research Funding. Boise:AstraZeneca: Honoraria; Abbvie: Consultancy. Kaufman:BMS: Consultancy; Janssen: Consultancy; Karyopharm: Other: data monitoring committee; Abbvie: Consultancy; Roche: Consultancy. Lonial:Amgen: Research Funding. Nooka:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Spectrum Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; GSK: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; Adaptive technologies: Consultancy, Membership on an entity's Board of Directors or advisory committees.

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

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 1368-1368 ◽  
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&lt;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&lt;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.

scholarly journals Incidence of Breakthrough Fungal Infections in Acute Myeloid Leukemia Patients Receiving Low Intensity Therapy in the Upfront and Relapsed/Refractory Setting

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 3372-3372
Author(s):  
Kaci Shuman ◽  
Rebecca Garcia Hunt ◽  
Maho Hibino ◽  
Tyler Stone ◽  
Sarah Dralle ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Antifungal Agent ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
Treatment Initiation ◽  
Fungal Infections ◽  
Newly Diagnosed ◽  
Advisory Committees ◽  
Low Intensity ◽  
History Of

Abstract Introduction: New treatment strategies with low intensity therapy have emerged for acute myeloid leukemia (AML) patients who are not candidates for intensive therapy. To date, there is limited data on the frequency of invasive fungal infections (IFIs) in patients treated with low intensity regimens, and there is no consensus on the most appropriate prophylactic antifungal agent to use in either the newly diagnosed or relapsed/refractory setting. At our institution, fluconazole is the prophylactic antifungal agent of choice for neutropenic patients receiving low intensity therapy, however the appropriateness of fluconazole is being questioned due to the depth and duration of neutropenia observed in these patients. Rates of breakthrough IFIs need to be better characterized to optimize antifungal prophylaxis in this patient population. Methods: This is a retrospective review of AML patients treated with low intensity therapy from January 2017 through May 2020 for both newly diagnosed and relapsed/refractory disease. Patients were included if they received fluconazole as prophylaxis during periods of neutropenia and received at least two cycles of low intensity treatment. Low intensity regimens included hypomethylating agent (HMA) monotherapy or a combination of venetoclax with either a HMA or low dose cytarabine (LDAC). Any patient with a contraindication to fluconazole or those who received prophylaxis with an alternative antifungal agent (i.e. posaconazole, voriconazole, isavuconazole, and micafungin), history of previous IFI, or history of a stem cell transplant were excluded. The primary objective was to determine the incidence of breakthrough IFIs. The secondary objective was to further characterize IFI occurrences as possible, probable or proven using criteria defined by the European Organization for Research and Treatment of Cancer and the Mycoses Study Group Education and Research Consortium (EORTC/MSGERC). An occurrence of IFI was defined as receipt of any systemic antifungal agent, aside from fluconazole, for four or more days for suspected IFI. Patients were evaluated for antifungal escalation from the time of low intensity treatment initiation through 30 days after treatment discontinuation. Results: Eighty encounters were included for analysis. The median age of the cohort was 73 years (interquartile range [IQR] 67 - 80) and 70% of patients were newly diagnosed (n = 56). HMA/venetoclax was the most commonly utilized regimen (66%, n = 53) followed by HMA monotherapy (29%, n = 23) and LDAC/venetoclax (5%, n = 4). The median number of treatment cycles was 5 (IQR 3 - 9). Nineteen IFI occurrences (24%) were documented, with ten in the newly diagnosed population (18%, n = 10/56) and nine in relapsed/refractory patients (38%, n = 9/24). There were no proven, four probable and fourteen possible IFIs. Of the four probable infections, three were in relapsed/refractory patients. Median times to IFI onset from low intensity treatment initiation were 82 and 80 days for the newly diagnosed and relapsed/refractory populations, respectively. Of the patients with an IFI, 15/19 (79%) were neutropenic at IFI onset. Conclusions: IFIs are a serious complication of AML as these infections are associated with significant morbidity and mortality. With 24% of patients requiring antifungal escalation, our study demonstrates that breakthrough IFIs remain a concern for patients receiving low intensity therapy and fluconazole prophylaxis. Incidence of IFI was higher in the relapsed/refractory setting, which is an expected finding as these patients are typically subjected to multiple lines of therapy, leading to poor hematopoietic reserves and more prolonged periods of profound neutropenia. Additional analysis is needed for determination of risk factors, beyond relapsed/refractory disease, to potentially identify subsets of patients at highest risk of developing IFIs as these patients may benefit from closer monitoring and longer durations of prophylaxis. Given these findings, it is reasonable to consider prophylaxis with an extended spectrum antifungal agent against molds for patients receiving low intensity therapy. Figure 1 Figure 1. Disclosures Ellis: Rafael Pharmaceuticals: Consultancy. Pardee: Karyopharm Pharmaceuticals: Research Funding; AbbVie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Rafael Pharmaceuticals: Consultancy, Research Funding; Genetech: Membership on an entity's Board of Directors or advisory committees; BMS: Speakers Bureau; Pharmacyclics: Speakers Bureau.

scholarly journals Efficacy of Induction Thearapy with Lenalidomide, Bortezomib, and Dexamethasone (RVD) in 1000 Newly Diagnosed Multiple Myeloma (MM) Patients

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 3294-3294 ◽  
Author(s):  
Nisha Joseph ◽  
Vikas A. Gupta ◽  
Craig C Hofmeister ◽  
Charise Gleason ◽  
Leonard Heffner ◽  
...  
Keyword(s):  
High Risk ◽  
Board Of Directors ◽  
Induction Therapy ◽  
Research Funding ◽  
Response Rates ◽  
Newly Diagnosed ◽  
Advisory Committees ◽  
Entire Cohort ◽  
Risk Patients ◽  
Standard Risk

Abstract Background : Lenalidomide, bortezomib and dexamethasone (RVD) has been shown to be a well-tolerated and efficacious induction regimen in newly diagnosed myeloma patients. Two large randomized phase III trials show an overall response rate (ORR) >95% (Durie et al, Attal et al) supporting this combination regimen. We have conducted a retrospective analysis utilizing our institutional data of 1000 patients treated with RVD induction therapy at the Winship Cancer Institute of Emory University. Methods: 1000 newly diagnosed MM patients were treated with RVD induction therapy [R - 25 mg/day (days 1-14), V - 1.3 mg/m2 (days 1, 4 8, 11) and D - 40 mg once/twice weekly as tolerated every 21 days] from January 1st 2005 until August 31st 2016. Dose-adjustments were made based on the treating physician's discretion and patient tolerability. Demographic and outcomes data for the patients were obtained from our IRB approved myeloma database and responses were evaluated per IMWG Uniform Response Criteria. Results: The median age of this cohort was 61 years (range 16-83). Other notable patient characteristics include: M/F 54.3%/45.6%; W/AA 56.4%/34%; ISS I and II/III 54%/17%; Isotype IgG/IgA/FLC 59.1%/19%/15.8%; standard risk/high risk 72%/28%. High risk disease was defined as the presence of t(4;14), t(14;16), del(17p), and/or complex karyotype. A total of 835 patients (83.5%) underwent autologous stem cell transplant (ASCT) upfront after attaining at least a partial response with induction therapy, and 165 patients (16.5%) were offered deferred transplant. Among the patients that opted for deferred transplant, 56 of these patients (33.9%) underwent ASCT at first relapse with a median time to transplant of 30 months (3-96). 755 (75.5%) of patients received risk-stratified maintenance therapy following transplant. Evaluation of responses to induction therapy for the entire cohort show an ORR 97.3% with ≥VGPR of 68% post-induction therapy. Response rates 100 days post-transplant show an ORR 98% with 30.7% of patients achieving a sCR. Response rates are summarized in table 1. Median PFS was 63 months for the entire cohort, and 72 months for standard risk patients (61.75-82.25) versus 37 months for the high-risk patients (30.84-43.16), p<0.001. Median OS has not been reached at median of 38 months follow up (Figure 1). Conclusions: This is the largest reported cohort of myeloma patients treated with RVD induction. These results illustrate both the activity of this induction regimen with impressive response rates and long-term outcomes in both standard and high risk patients. Disclosures Hofmeister: Adaptive biotechnologies: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Oncopeptides: Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees. Heffner:ADC Therapeutics: Research Funding; Kite Pharma: Research Funding; Genentech: Research Funding; Pharmacyclics: Research Funding. Boise:AstraZeneca: Honoraria; Abbvie: Consultancy. Kaufman:BMS: Consultancy; Karyopharm: Other: data monitoring committee; Abbvie: Consultancy; Janssen: Consultancy; Roche: Consultancy. Lonial:Amgen: Research Funding. Nooka:GSK: Consultancy, Membership on an entity's Board of Directors or advisory committees; Adaptive technologies: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Spectrum Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees.

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

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 3129-3129
Author(s):  
Hans C. Lee ◽  
Sikander Ailawadhi ◽  
Cristina Gasparetto ◽  
Sundar Jagannath ◽  
Robert M. Rifkin ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Causes Of Death ◽  
Age Groups ◽  
Treatment Patterns ◽  
Age Group ◽  
Newly Diagnosed ◽  
Employment Equity ◽  
Advisory Committees ◽  
Equity Ownership

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

scholarly journals Long Term Outcome of Lenalidomide-Dexamethasone (Rd) Vs Melphalan-Lenalidomide-Prednisone (MPR) Vs Cyclophosphamide-Prednisone-Lenalidomide (CPR) As Induction Followed By Lenalidomide-Prednisone (RP) Vs Lenalidomide (R) As Maintenance in a Community-Based Newly Diagnosed Myeloma Population: Updated Analysis of EMN01 Phase III Study

Blood ◽  
2017 ◽  
Vol 130 (Suppl_1) ◽  
pp. 901-901
Author(s):  
Sara Bringhen ◽  
Massimo Offidani ◽  
Pellegrino Musto ◽  
Anna Marina Liberati ◽  
Giulia Benevolo ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Phase Iii ◽  
Cell Transplant ◽  
Newly Diagnosed ◽  
Community Based ◽  
Advisory Committees ◽  
Risk Of Death ◽  
Grade 3 ◽  
To Receive

Abstract Introduction : Rd and MPR showed to be effective combinations in elderly newly diagnosed multiple myeloma (NDMM) patients (pts). Cyclophosphamide is a less toxic alkylating alternative agent. EMN01 is the first trial to formally compare these three different Lenalidomide-based combinations. Maintenance with Lenalidomide has been recently approved in patients eligible for autologous stem cell transplant (ASCT). Few data are available about the best combination as maintenance in patients not eligible for ASCT. Methods : 662 pts with NDMM were randomized to receive 9 28-day cycles of Rd (lenalidomide 25 mg/day for 21 days; dexamethasone 40 mg on days 1,8,15 and 22 in pts 65-75 years old and 20 mg in those &gt;75 years), MPR (lenalidomide 10 mg/day for 21 days; melphalan orally 0.18 mg/Kg for 4 days in pts 65-75 years old and 0.13 mg/Kg in &gt;75 years pts; prednisone 1.5 mg/Kg for 4 days) or CPR (lenalidomide 25 mg/day for 21 days; cyclophosphamide orally 50 mg/day for 21 days in pts 65-75 years old and 50 mg every other day in &gt;75 years pts; prednisone 25 mg every other day). After induction, pts were randomized to receive maintenance with lenalidomide alone (R; 10 mg/day for 21 days) or with prednisone (RP; R, 10 mg/day for 21 days and P, 25 mg every other day), until disease progression. Results : Pts characteristics were well balanced in all groups; 217 pts in Rd, 217 in MPR and 220 in CPR arms could be evaluated. After a median follow-up of 63.7 months, median PFS was 23.2 months in MPR, 18.9 months in CPR and 18.6 months in Rd (MPR vs CPR p=0.02; MPR vs Rd p=0.08). Median overall survival (OS) was 79.9 months in MPR, 69.4 months in CPR and 68.1 months in Rd (MPR vs CPR p=0.98; MPR vs Rd p=0.64). The most common grade ≥3 adverse event (AEs) was neutropenia: 64% in MPR, 29% in CPR and 25% in Rd pts (p&lt;0.0001). Grade ≥3 non hematologic AEs were similar among arms. At the end of induction, 402 pts were eligible for maintenance, 198 in the RP and 204 in the R groups. PFS from start of maintenance was 22.2 months in the RP group and 17.6 in the R group, with 20% reduced the risk of death/progression for pts receiving RP maintenance (HR 0.81, p=0.07; Figure 1). A subgroup analysis was performed to determine the consistency of RP vs R treatment effect in different subgroups using interaction terms between treatment and cytogenetic abnormalities, ISS, age, sex, induction treatment and response before maintenance (Figure 1). No difference in OS was observed (HR 1.02, p=0.93) but the OS analysis was limited by the low number of events. Median duration of maintenance was 23.0 months in RP pts and 20.5 months in R pts, 14% and 13% of pts discontinued due to AEs, in RP and R groups, respectively. Conclusion : This phase III trial compared 2 different Lenalidomide-containing induction regimens and 2 different Lenalidomide-containing maintenance regimens in an elderly community-based NDMM population. MPR prolonged PFS by approximately 5 months, yet the higher incidence of hematologic toxicity should be carefully considered. The addition of low-dose prednisone to standard lenalidomide maintenance reduced the risk of death/progression by 20%, with a good safety profile. Updated results will be presented at the meeting. Disclosures Bringhen: Mundipharma: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria; Celgene: Honoraria; Bristol Myers Squibb: Honoraria; Karyipharm: Membership on an entity's Board of Directors or advisory committees. Offidani: celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Musto: Celgene: Honoraria; Janssen: Honoraria. Gaidano: Gilead: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Roche: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria. De Sabbata: Celgene: Membership on an entity's Board of Directors or advisory committees. Palumbo: Sanofi: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Binding Site: Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Merck: Consultancy, Honoraria, Research Funding; Genmab A/S: Consultancy, Honoraria, Research Funding; Janssen-Cilag: Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria, Research Funding, Speakers Bureau; Takeda: Consultancy, Employment, Equity Ownership, Honoraria, Research Funding. Hájek: Amgen, Takeda, BMS, Celgene, Novartis, Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Consultancy, Honoraria; Pharma MAR: Consultancy, Honoraria. Boccadoro: Novartis: Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; AbbVie: Honoraria; Mundipharma: Research Funding; Sanofi: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Janssen: Honoraria, Research Funding.

scholarly journals VTE Rates and Safety Analysis of Newly Diagnosed Multiple Myeloma Patients Receiving Carfilzomib-Lenalidomide-Dexamethasone (KRD) with or without Rivaroxaban Prophylaxis

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 1835-1835 ◽  
Author(s):  
Katrina M Piedra ◽  
Hani Hassoun ◽  
Larry W. Buie ◽  
Sean M. Devlin ◽  
Jessica Flynn ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Venous Thromboembolism ◽  
Board Of Directors ◽  
Research Funding ◽  
High Dose ◽  
Newly Diagnosed ◽  
Advisory Committees ◽  
Cancer Trial ◽  
Oncology Research ◽  
Increased Risk

Introduction Immunomodulatory agents (IMiD's) are associated with an increased risk of venous thromboembolism (VTE), particularly when combined with high dose steroids. Studies evaluating the use of lenalidomide-bortezomib-dexamethasone (RVD) and carfilzomib-lenalidomide-dexamethasone (KRD) in the frontline setting for multiple myeloma (MM) have reported a 6% and 24% incidence of thrombosis, respectively, despite primary thrombotic prophylaxis with aspirin (ASA) (Richardson, et al. Blood. 2010; Korde, et al. JAMA Oncol 2015). Recent data, including the Hokusai VTE Cancer Trial, have suggested that safety and efficacy of direct oral anticoagulants (DOACs) are preserved in the setting of treatment of solid malignancy-associated thrombosis (Raskob, et al. N Engl J Med. 2018; Mantha, et al. J Thromb Thrombolysis. 2017). Despite this data, there is limited experience and use of DOACs in prevention of thromboses in the setting of hematologic malignancies, specifically MM. After careful review of literature, since early 2018, we changed our clinical practice and routinely placed newly diagnosed MM (NDMM) patients receiving KRD at Memorial Sloan Kettering Cancer Center (MSKCC) on concomitant rivaroxaban 10 mg once daily, regardless of VTE risk stratification. In the following abstract, we present VTE rates and safety data for newly diagnosed MM patients receiving RVD with ASA vs. KRD with ASA vs. KRD with rivaroxaban prophylaxis. Methods This was an IRB-approved, single-center, retrospective chart review study. All untreated patients with newly diagnosed MM, receiving at least one cycle of RVD or KRD between January 2015 and October 2018 were included. The period of observation included the time between the first day of therapy until 90 days after completion of induction therapy. Patients were identified by querying the pharmacy database for carfilzomib or bortezomib administration and outpatient medication review of thromboprophylaxis with rivaroxaban or ASA. VTE diagnoses were confirmed by ICD-10 codes and appropriate imaging studies (computed tomography and ultrasound). Descriptive statistics were performed. Results During the observation period, 241 patients were identified to have received RVD or KRD in the frontline (99 RVD with ASA; 97 KRD with ASA; 45 KRD with rivaroxaban). Baseline characteristics were well distributed among the three arms, with a median age of 60 (30-94) in the RVD ASA arm, 62 (33-77) in the KRD ASA arm, and 60 (24-79) in the KRD rivaroxaban arm. Patients had International Staging System (ISS) stage 3 disease in 13% (N=13), 9.3% (N=9), and 11% (N=5) of the RVD ASA, KRD ASA, and KRD rivaroxaban arms, respectively. Median weekly doses of dexamethasone were higher in both KRD arms, 40 mg (20-40) vs. 20 mg (10-40) in the RVD ASA arm. The average initial doses of lenalidomide were 22 mg in the RVD ASA arm compared to 25 mg in both the KRD ASA and KRD rivaroxaban arms. After querying the pharmacy database, no patients were identified to have a history or concomitant use of erythropoietin stimulating agent (ESA) use. Treatment-related VTE's occurred in 4 patients (4.0%) in the RVD ASA arm, 16 patients (16.5%) in the KRD ASA arm, and in 1 patient (2.2%) in the KRD rivaroxaban arm. Average time to VTE was 6.15 months (Range 5.42, 9.73) after treatment initiation in the RVD ASA group, while it was 2.61 months (Range 0.43, 5.06) in the KRD ASA group and 1.35 months in the KRD rivaroxaban group. Minor, grade 1 bleeding events per the Common Terminology Criteria for Adverse Events (CTCAE) were identified in 1 (1.1%) patient in the RVD ASA arm, 5 (5.2%) patients in the KRD ASA arm, and 1 (2.2%) patient in the KRD rivaroxaban arm. Conclusion More efficacious MM combination therapies have been found to increase the risk of VTE when using ASA prophylaxis, indicating better thromboprophylaxis is needed. We found patients receiving ASA prophylaxis with KRD were more likely to experience a VTE and these events occurred earlier compared to patients receiving ASA prophylaxis with RVD. Importantly, the rate of VTE was reduced to the same level as ASA prophylaxis with RVD when low-dose rivaroxaban 10 mg daily was used with KRD, and without necessarily increasing bleeding risk. Our retrospective data support the development of prospective clinical trials further investigating DOAC use in thromboprophylaxis for NDMM patients receiving carfilzomib-based treatments. Figure Disclosures Hassoun: Novartis: Consultancy; Janssen: Research Funding; Celgene: Research Funding. Lesokhin:BMS: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria; Janssen: Research Funding; GenMab: Consultancy, Honoraria; Serametrix Inc.: Patents & Royalties; Genentech: Research Funding; Juno: Consultancy, Honoraria. Mailankody:Juno: Research Funding; Celgene: Research Funding; Janssen: Research Funding; Takeda Oncology: Research Funding; CME activity by Physician Education Resource: Honoraria. Smith:Celgene: Consultancy, Patents & Royalties, Research Funding; Fate Therapeutics and Precision Biosciences: Consultancy. Landgren:Theradex: Other: IDMC; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: Other: IDMC; Sanofi: Membership on an entity's Board of Directors or advisory committees; Adaptive: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. OffLabel Disclosure: Off-label use of rivaroxaban for outpatient prophylaxis of venous thromboembolism (VTE) will be explicitly disclosed to the audience.

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