scholarly journals Venetoclax in Combination with Decitabine or Azacitidine in Relapsed or Refractory Acute Myeloid Leukemia Is Comparable to Alternative Regimens

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 3-5
Author(s):  
Jenn Miller ◽  
Lindsey Shannon ◽  
Amanda Finch ◽  
Jessica K Altman ◽  
Daniel Wojenski
Keyword(s):  
Overall Survival ◽  
Board Of Directors ◽  
Research Funding ◽  
Median Overall Survival ◽  
Alternative Therapy ◽  
Advisory Committees ◽  
Number Of Patients ◽  
Refractory Acute Myeloid Leukemia ◽  
Line Of Therapy ◽  
Refractory Aml

Introduction Although newer therapies have become available for treating relapsed and refractory acute myeloid leukemia (RR AML), long-term survival and cure rates remain poor1,2. Newer therapies designed to target mutations or specific proteins may be able to improve current outcomes. Venetoclax is an oral B-cell lymphoma 2 (BCL2) inhibitor that gained FDA approval for use in combination with either azacitidine or decitabine or low-dose cytarabine for newly-diagnosed AML in adults ≥ 75 years. Venetoclax has demonstrated clinical activity in RR AML in retrospective studies1,3,4. The purpose of this study is to evaluate the safety and efficacy of venetoclax with either decitabine or azacitidine compared to alternative therapies in RR AML at a large, academic institution. Methods This was a single-center, retrospective cohort study conducted at Northwestern Memorial Hospital and Robert H. Lurie Comprehensive Cancer Center of Northwestern University in Chicago, Illinois that compared outcomes of patients who received venetoclax with a hypomethylating agent (HMA) to those who received alternative treatment regimens for RR AML. Patients were included if they were ≥18 years old, were diagnosed with either relapsed or refractory AML, had failed one or more lines of therapy, and received a chemotherapeutic agent for relapsed or refractory AML. Patients enrolled in clinical trials were excluded. The study period was from August 1, 2017 to November 30, 2019. The primary endpoint of this study was the combined rate of complete remission (CR) and complete remission with incomplete hematologic recovery (CRi). The secondary endpoints were overall survival, time to CR/CRi, duration of CR/CRi, percentage of patients who received a hematopoietic stem cell transplant (HSCT) after treatment, and safety outcomes. Safety outcomes evaluated included events that required or prolonged hospitalizations, specifically a documented infection, neutropenia, anemia, thrombocytopenia, and tumor lysis syndrome (TLS). Results During the study time period, 45 patients received venetoclax + HMA for RR AML and 35 patients received an alternative therapy. Twenty-three patients (51%) in the venetoclax + HMA arm were previously treated with HMA therapy. The most common therapies in the alternate arm were FLAG-IDA, azacitidine monotherapy, and enasidenib monotherapy. Baseline demographics were similar between groups as seen in Table 1. The majority of patients in both arms were classified according to the NCCN risk categories as either intermediate or poor. Patients in the ven + HMA arm received this treatment as a later line of therapy as compared to the line of therapy used in the alternate arm (51% vs 77%, p = 0.095). The rate of CR/CRi was 36% in the ven + HMA arm vs 40% in the alternative arm (p = 0.684) as displayed in Table 2. The median overall survival was 176 days in the ven + HMA arm and 143 days in the alternative therapy arm (p=0.824) as seen in Figure 1. Additionally, the number of patients that underwent HSCT after receiving the treatments evaluated in this study were 20% and 26% (p = 0.544). There were no statistically significant differences between groups in incidences of documented infection (29% in ven + HMA arm vs 54% in alternative therapy arm), neutropenia (58% vs 69%), anemia (36% vs 46%), thrombocytopenia (56% vs 63%), and TLS (18% vs 14%). In the subgroup analysis in the venetoclax arm, patients who previously received a HMA had a longer overall survival (179 days vs 104 days, p=0.010) and a shorter time to CR/CRi (59 days vs 70 days, p=0.164) than those who did not receive a previous HMA. However, patients with a previous HMA experienced a lower overall incidence of CR/CRi (26% vs 45%, p=0.175) and continued on to a HSCT less often than those who had not received a previous HMA (4% vs 36%, p=0.007). Conclusions Overall, rates of CR/CRi, median overall survival, and the number of patients that underwent HSCT after receiving the treatments evaluated in this study were similar between groups. Additionally, incidences of various adverse effects were comparable between the two groups. The outcomes of venetoclax in combination with a hypomethylating agent are comparable to alternative therapies in the relapsed and refractory AML setting. Disclosures Altman: ImmunoGen: Research Funding; Amphivena: Research Funding; Genentech: Research Funding; Astellas: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Cancer Expert Now: Consultancy; PeerView: Consultancy; PrIME Oncology: Consultancy; France Foundation: Consultancy; ASH: Consultancy; Novartis: Consultancy; Syros: Consultancy; Janssen: Consultancy; Immune Pharma: Consultancy; Bristol-Myers Squibb: Consultancy; Amgen: Research Funding; Aprea: Research Funding; Glycomimetics: Other: DSMC; Daiichi Sanko: Membership on an entity's Board of Directors or advisory committees; Kura: Membership on an entity's Board of Directors or advisory committees, Research Funding; Biosight: Research Funding; AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding; Fujifilm: Research Funding; Kartos: Research Funding; Celgene: Research Funding; Boehringer Ingelheim: Research Funding; Theradex: Membership on an entity's Board of Directors or advisory committees; Agios: Membership on an entity's Board of Directors or advisory committees, Research Funding. OffLabel Disclosure: venetoclax for relapsed and refractory AML

scholarly journals Mitoxantrone, Etoposide and Cytarabine (MEC) Can Induce Deep Complete Remission and Is an Effective Bridge Therapy to Allotransplantation (SCT) in Refractory/Relapsed Acute Myeloid Leukemia (AML) Patients

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 4036-4036
Author(s):  
Giovanni Marconi ◽  
Annalisa Talami ◽  
Maria Chiara Abbenante ◽  
Stefania Paolini ◽  
Chiara Sartor ◽  
...  
Keyword(s):  
Overall Survival ◽  
Complete Remission ◽  
Adverse Events ◽  
Board Of Directors ◽  
Research Funding ◽  
Median Overall Survival ◽  
Rescue Therapy ◽  
Treatment Schedule ◽  
Advisory Committees ◽  
Number Of Patients

Abstract Introduction Relapsed/refractory (R/R) AML patients continue to be a formidable clinical challenge, mainly in consideration of associated very poor outcome, with a median overall survival (OS) of less than 12 months. SCT represents the only curative option for these patients. Although, there is no standard-of-care approach which may serve as a bridge to SCT. Our study aims to investigate the effectiveness of MEC regimen as a rescue therapy for R/R AML patients by specifically addressing the CR rate, including minimal residual disease (MRD) negativity, the number of patients who subsequently underwent SCT and the presence of predictive factors of response. Methods Fifty-five consecutive adult AML patients were treated with MEC regimen in our Institution. In patients under 66 years old, we administered mitoxantrone 6 mg/sqm/die from day 1 to day 6, etoposide 100 mg/sqm/die from day 1 to day 6 and cytarabine 1000mg/sqm/die from day 1 to day 6, whereas in patients over 66 years old, the treatment schedule was reduced to 4 consecutive days. Data were retrospectively collected by using RedCap in accordance with Helsinki declaration and GCP. We used Kaplan-Meyer to estimate survival, and log rank to test differences in survival. Chi-squared, fisher's exact test and linear-by-linear correlation were used to test differences in proportions and distributions. Response was defined in accordance with 2017 ELN recommendations. CTCAE 4.03 was used to grade adverse events. MRD was assessed with WT1 or specific fusion transcripts. Results Fifty-five patients received MEC from 2008 to 2018. Age at diagnosis ranged from 17 to 72 years, with a median age of 51 years. Our set was enriched for high-risk patients. Interestingly, twenty percent of patients harbored FLT3-ITD at diagnosis (table 1). Two main groups were included: resistant AML, 28/55 patients (50,9%), and relapsed AML, 27/55 patients (49,1%). At induction, almost half of patients received "3+7" (n=25, 45,5%), while fludarabine-based regimens were administered to 14 patients (25,5%). In our set, after MEC median duration of hospitalization was 30 days (14-78); PMN >500/mm3 was reached after 26 days (range 18-67). Fever and febrile neutropenia was the most recurrent adverse events (AE). AEs were low in grade; out of 80 graded AEs, 38 (47,5%) were grade 2, 27 (33,8%) were grade 3, 9 (11,3%) were grade 4 and only 3 events resulted in death (3,8%). E. coli was the most recurrent cause of infection (10 cases). Overall, 25/55 patients (45,5%) achieved a complete remission (CR) after one course of MEC chemotherapy. Twelve patients (21.9%) achieved MRD negativity and 13 patients (23,6%) obtained an MRD+ CR or had no MRD test. Six patients (10,9%) had a partial response (PR) and 1 patient (1,8%)had hematological improvement (HI). Four patients (7.3%) died during post-MEC aplastic phase. Disease risk at diagnosis and R/R status did not influence the chance to obtain CR (figure 1 A). In 12 patients, a second MEC was administered. Four out of 12 patient improved their response with the 2nd MEC (2 patients obtained MRD - from MRD+ CR, 1 patient obtained PR and 1 patients obtained CR from hematological improvement). MEC was an effective bridge to SCT, 32/55 patients (58,2%, figure 1 B), received SCT; 15/32 patients (46,9%) received SCT directly after the 1st course of MEC, 9/32 patients (28,1%) after the 2nd course of MEC and 2 patients (6,3%) after an additional course of post-remission chemotherapy. Of note, only 6 patients (18,8%), who were not responsive to MEC, underwent SCT after an alternative rescue therapy. Median overall survival (OS) from MEC was 455 days (95% C.I. 307-602 days.); 1-year OS, 3-year OS and 5-years OS were 57,9%, 33,2% and 23,1%, respectively (std. error ± 0,067). Patients who responded to MEC (CR MRD+ or CR MRD- after 1 or 2 courses) had better OS than non-responders (median OS 1389 vs 160 days, p=.003). Stepwise multiple logistic regression analysis with COX-HR model established that pre-MEC R/R status, diagnosis class risk, response to one or two courses of MEC, and SCT were independent predictors of survival in the optimal model. Conclusions Taken together, our data indicate that MEC is an effective salvage regimen with affordable toxicity, and gives a high chance to obtain CR. MEC is particularly useful as a bridge to SCT, and has to be considered as a rescue therapy whenever a clinical trial is not available. *GM and AT equally contributed Disclosures Martinelli: Ariad/incyte: Consultancy; Pfizer: Consultancy; Celgene: Consultancy; Amgen: Consultancy; Janssen: Consultancy; Roche: Consultancy. Cavo:Takeda: 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, Research Funding, Speakers Bureau; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Adaptive Biotechnologies: Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: 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; Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Honoraria, Membership on an entity's Board of Directors or advisory committees.

scholarly journals Minimal Residual Disease Eradication with Venetoclax in Acute Myeloid Leukemia

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 12-14
Author(s):  
Alexander Coltoff ◽  
Joseph G. Jurcic ◽  
Peter Campbell ◽  
Daniel J. Lee ◽  
Mark L Heaney ◽  
...  
Keyword(s):  
Overall Survival ◽  
Board Of Directors ◽  
Research Funding ◽  
Median Overall Survival ◽  
Residual Disease ◽  
Institutional Research ◽  
Negative Group ◽  
Advisory Committees ◽  
Research Grants

Introduction The combination of the BCL-2 inhibitor venetoclax with an HMA (HMA/Ven) has improved outcomes in previously untreated patients with AML not eligible for intensive induction therapy. In a phase Ib study, 67% of patients achieved a complete remission (CR) or CR with incomplete recovery of blood counts (CRi) with a median overall survival (OS) of 17.5 months (DiNardo CD et al. Blood 2019; 133(1):7-17). HMA/Ven has also demonstrated efficacy in a heavily pretreated population with relapsed or refractory (R/R) AML, the majority of whom had prior HMA exposure (DiNardo CD et al. Am J Hematol 2018; 93(3):401-7). Measurable residual disease (MRD) is recognized as an independent prognostic indicator important for risk stratification and treatment planning (Schuurhuis GJ et al. Blood 2018; 131(12):1275-91). To date, however, there have been few reports on the effect of HMA/Ven on MRD. Methods This is a retrospective case series of patients with AML at a single-center tertiary-care institution. Patients ≥ 18 years of age who were treated with HMA/Ven between January 2017 and June 2020, either in the upfront or salvage setting, for AML were included. Outcomes included CR/CRi rate, MRD response, relapse free survival (RFS), and OS. MRD was assessed via multicolor flow cytometry with a sensitivity of 10-3 (0.1%). Results Nineteen patients were identified, 12 (63%) of whom were female. The median age at the time of HMA/Ven initiation was 71 years (range, 21 - 87 years). Ten (53%) patients had de novo AML and 9 had secondary or therapy-related AML. By 2017 ELN criteria, 3 (16%) patients had favorable-risk, 9 (47%) had intermediate-risk, and 7 (37%) had adverse-risk AML. Nine (47%) patients had R/R AML; 5 received HMA/Ven as first salvage therapy, and 4 as 2nd or greater salvage. Three (16%) patients had prior HMA exposure. No patient had prior venetoclax exposure. Median follow-up was 9.1 months (range, 1-21.1 months). Ten (53%) patients received azacitidine and 9 (47%) were given decitabine. Venetoclax doses ranged from 50 to 400 mg daily, depending on participation in a clinical trial and concomitant medications. Eight patients achieved a CR and 7 patients achieved a CRi for a combined CR/CRi rate of 79%. The CR/CRi rate was 90% (9/10) in the upfront setting, and 66% (6/9) in the salvage setting. The median time and number of cycles to best clinical response was 2.3 months (range, 0.9-3.9 months) and 2 (range, 1-3 cycles), respectively. Eleven (73%) of the 15 responders achieved MRD clearance after a median of 2 cycles (range, 1-3 cycles) (Table 1). Two of 4 (50%) MRD-positive patients relapsed, while 4 (36%) of 11 MRD-negative patients relapsed (Figure 1). Relapse occurred at a median of 2.0 months (range, 1.3-2.7 months) in the MRD positive group and 11.0 months (range, 2.8-14 months) in the MRD negative group. One patient died of infectious complications while MRD negative. Three patients, all of whom were treated for R/R disease, proceeded to an allogeneic stem cell transplant (HSCT). Two were MRD negative at the time of HSCT and all remained in remission. At the time of data cutoff, 7 (64%) of 11 MRD-negative patients were alive, and all 4 MRD-positive patients were alive. Causes of death in the MRD-negative group included disease relapse (3 patients) and infection (1 patient). Median overall survival in the entire cohort (range, 32 days-NR) was not reached. Conclusions HMA/Ven was highly effective as both upfront and salvage therapy. Surprisingly, the salvage CR/CRi rate in this series was 66%, allowing half of the responders to proceed to HSCT. The majority (73%) of responders achieved MRD negativity. While MRD status influenced RFS, 36% of MRD-negative patients relapsed. Additionally, the same percentage of MRD-negative patients died during follow-up, versus none of the patients with MRD-positivity. This indicates the need for more sensitive methods to assess MRD and for novel therapeutic strategies to eliminate MRD, thereby improving long-term outcomes. Larger prospective studies are needed to define the role of MRD assessment with venetoclax-containing regimens. Disclosures Jurcic: AbbVie:Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding;Celgene:Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding;Syros Pharmaceuticals:Research Funding;PTC Therapeutics:Research Funding;Arog Pharmaceuticals:Research Funding;Kura Oncology:Research Funding;Forma Therapeutics:Research Funding;Astellas:Research Funding;Genentech:Research Funding;Novartis:Consultancy, Membership on an entity's Board of Directors or advisory committees;Daiichi-Sankyo:Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding;BMS:Consultancy, Research Funding.Campbell:AstraZeneca:Consultancy.Lee:Genentech:Research Funding;Sumitomo Dainippon Pharma Oncology, Inc.:Research Funding;AbbVie:Research Funding;Novartis:Research Funding;Bayer:Research Funding;Celgene:Consultancy;Forty Seven:Research Funding.Heaney:Blueprint Medicines Corporation:Research Funding;BMS:Research Funding;CTI Biopharma:Consultancy, Research Funding;Deciphera:Research Funding;Incyte:Research Funding;Novartis:Consultancy, Research Funding;Sierra Oncology:Research Funding;AbbVie:Consultancy;Partner Therapeutics:Consultancy.Lamanna:Janssen:Consultancy, Membership on an entity's Board of Directors or advisory committees;Octapharma:Research Funding;Juno:Other: Institutional research grants, Research Funding;Gilead:Consultancy, Membership on an entity's Board of Directors or advisory committees;Astra Zeneca:Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Institutional research grants, Research Funding;Pharmacyclics:Consultancy, Membership on an entity's Board of Directors or advisory committees;Genentech:Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Institutional research grants, Research Funding;Bei-Gene:Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Institutional research grants, Research Funding;Abbvie:Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Institutional research grants, Research Funding;Oncternal, Verastem, TG Therapeutics:Other: Institutional research grants, Research Funding;MingSight:Other: Institutional research grants, Research Funding;Loxo:Research Funding;Celgene:Consultancy, Membership on an entity's Board of Directors or advisory committees;Columbia University Medical Center:Current Employment.

scholarly journals Dose Escalation Study of BET Inhibitor PLX2853 in Patients with Relapsed or Refractory Acute Myeloid Leukemia or High Risk Myelodysplastic Syndrome

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 1391-1391 ◽  
Author(s):  
Naveen Pemmaraju ◽  
Uma Borate ◽  
Melhem Solh ◽  
Gautam M. Borthakur ◽  
Amy E. DeZern ◽  
...  
Keyword(s):  
High Risk ◽  
Board Of Directors ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
Plasma Concentrations ◽  
Target Engagement ◽  
Advisory Committees ◽  
Refractory Acute Myeloid Leukemia ◽  
Acute Myeloid ◽  
Refractory Aml

Background: PLX2853 is an orally available, non-benzodiazepine BET (bromodomain and extraterminal domain) inhibitor that exhibits low nanomolar potency and a modest preference for binding to the second bromodomain (BD2) of the BET proteins. By regulating genes (e.g. MYC and BCL2) critical to leukemic cell growth and survival, PLX2853 demonstrated broad anti-leukemic activity both as a single agent and in combination with other therapeutic agents in preclinical models. The pharmacokinetic (PK) profile in solid tumor patients revealed a short half-life (< 3 hour) enabling high peak plasma concentrations and nearly complete elimination from the plasma 9 hour post dose. Since strong and prolonged suppression of BET proteins have often untoward effects in normal tissues, the PLX2853 PK profile is hypothesized to be associated with improved tolerability by allowing transient target engagement followed by time for recovery after daily dosing. Methods: We are conducting an open-label, Phase 1b (Ph1b) study of PLX2853 as a single oral agent administered daily in adult patients with relapsed or refractory acute myeloid leukemia (AML) or high risk myelodysplastic syndrome (MDS) using a modified continuous reassessment model (mCRM) with escalation with overdose control (EWOC) to determine the recommended phase 2 dose (RP2D). Up to 36 patients are expected to enroll. The dosing cycle and dose limiting toxicity window (DLT) is 21 days. Primary objectives include safety and PK. Secondary objectives include measures of preliminary efficacy, and exploratory objectives include pharmacodynamics (PD) biomarker assessments in various tissues. Enrollment through Cohort 2 (40 mg QD) is ongoing as of July 2019. Results: Five subjects with relapsed or refractory AML (median age 65 years) have received PLX2853 in escalating doses from 20 to 40 mg QD. Among these first 5 patients treated, the most common treatment emergent adverse events (AEs) regardless of causality in > 1 patient: decreased appetite (n=3), nausea (n=2), diarrhea (n=2), peripheral edema (n=2), cough (n=2), oropharyngeal pain (n=2), blood bilirubin increase (n=2), anemia (n=2), febrile neutropenia (n=2), fatigue (n=2), bacteremia (n=2), headache (n=2), dyspnea (n=2), and hypertension (n=2). Most were grade (G) 1-2. Treatment emergent AEs > G2 in > 1 patient included: anemia (n=2), febrile neutropenia (n=2) and hypertension (n=2). No treatment-related serious AEs or DLTs have been observed. Following a 20 mg daily dose of PLX2853, median time to reach maximal plasma concentrations (Tmax) is 1 hour and the absorption half-life (T1/2) is < 3 hours. Conclusions: In an ongoing Ph1b study, PLX2853 has now completed its first dosing cohort for patients with relapsed or refractory AML or high risk MDS, and no DLT has been observed yet. As dose escalation continues, PK, PD, preliminary safety and efficacy data will be assessed further to determine the clinical significance of target engagement. This clinical trial is registered at clinicaltrials.gov: NCT03787498. Disclosures Pemmaraju: mustangbio: Consultancy, Research Funding; abbvie: Consultancy, Honoraria, Research Funding; samus: Research Funding; celgene: Consultancy, Honoraria; cellectis: Research Funding; Stemline Therapeutics: Consultancy, Honoraria, Research Funding; novartis: Consultancy, Research Funding; plexxikon: Research Funding; Daiichi-Sankyo: Research Funding; sagerstrong: Research Funding; affymetrix: Research Funding; incyte: Consultancy, Research Funding. Borate:Novartis: Consultancy; Takeda: Consultancy; Pfizer: Consultancy; Daiichi Sankyo: Consultancy; AbbVie: Consultancy. Solh:ADC Therapeutics: Research Funding; Amgen: Speakers Bureau; Celgene: Speakers Bureau. Borthakur:Polaris: Research Funding; Arvinas: Research Funding; Agensys: Research Funding; Tetralogic Pharmaceuticals: Research Funding; Cantargia AB: Research Funding; Argenx: Membership on an entity's Board of Directors or advisory committees; BioLine Rx: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Oncoceutics, Inc.: Research Funding; Eli Lilly and Co.: Research Funding; BMS: Research Funding; AstraZeneca: Research Funding; Bayer Healthcare AG: Research Funding; Novartis: Research Funding; FTC Therapeutics: Membership on an entity's Board of Directors or advisory committees; AbbVie: Research Funding; Strategia Therapeutics: Research Funding; Cyclacel: Research Funding; Xbiotech USA: Research Funding; Eisai: Research Funding; Merck: Research Funding; BioTheryX: Membership on an entity's Board of Directors or advisory committees; Oncoceutics: Research Funding; NKarta: Consultancy; Incyte: Research Funding; Janssen: Research Funding; GSK: Research Funding; PTC Therapeutics: Consultancy. DeZern:Astex Pharmaceuticals, Inc.: Consultancy; Celgene: Consultancy. Zhang:Plexxikon Inc.: Employment. Powell:Plexxikon Inc.: Employment. Severson:Plexxikon Inc.: Employment. Inokuchi:Plexxikon Inc.: Employment. Matusow:Plexxikon Inc.: Employment. Halladay:Plexxikon Inc.: Employment. Hsu:Daiichi Sankyo, Inc.: Employment. Watkins:Plexxikon Inc.: Employment. Walling:Myovant Sciences: Consultancy; Nurix: Consultancy; Aduro Biotech: Consultancy; Plexxikon: Consultancy; CytomyX: Consultancy; Flag Therapeutics: Consultancy; Aminex: Consultancy; Immunext: Consultancy; SensenBio: Consultancy; Harpoon Therapeutics: Consultancy. Tsiatis:Plexxikon Inc.: Employment. Mims:PTC Therapeutics: Membership on an entity's Board of Directors or advisory committees; Astellas Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees; Agios Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees.

scholarly journals Is Intermediate-Dose Cytarabine a Good Control for Patients with Relapsed or Refractory Acute Myeloid Leukemia?

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 3991-3991 ◽  
Author(s):  
Sarah Bertoli ◽  
Noemie Gadaud ◽  
Suzanne Tavitian ◽  
Audrey Sarry ◽  
Emilie Bérard ◽  
...  
Keyword(s):  
Overall Survival ◽  
Complete Remission ◽  
Board Of Directors ◽  
Median Overall Survival ◽  
Daily Practice ◽  
Advisory Committees ◽  
Salvage Regimen ◽  
Platelet Recovery ◽  
Refractory Acute Myeloid Leukemia ◽  
Refractory Diseases

Abstract Intermediate dose cytarabine (IDAC) defined by daily intravenous bolus of 1g/m² during 5 days has been recently defined as the standard control arm in phase 3 placebo-controlled randomized trials for patients with relapsed or refractory acute myeloid leukemia (R/R AML). In these trials assessing clofarabine/IDAC (CLASSIC-1 study, Faderl S et al., JCO 2012) or vosaroxin/IDAC (VALOR study, Ravandi F. et al., Lancet Oncol 2015) vs placebo/IDAC, complete remission rates and median overall survival with placebo/IDAC were 17.8%/18.9% and 6.3/6.1 months in the CLASSIC-1 and VALOR studies, respectively. However, the dose-intensity of this IDAC regimen remains questioned in routine practice since many centers still use higher doses of cytarabine often in combination with an anthracycline and a third drug including fludarabine, etoposide or gemtuzumab ozogamycin (FLAG-ida, MEC or MIDAM regimen for example) although these regimen have proved little efficacy and higher toxicity. We assessed the outcome of R/R AML patients that fulfilled main VALOR inclusion criteria consecutively treated in our center with intensive salvage regimen. All patients with a diagnosis of AML in first relapse or with refractory disease were eligible for this study. Acute promyelocytic leukemia were excluded. Relapse was defined as re-emergence of at least 5% leukemia blasts in bone marrow or at least 1% blasts in peripheral blood 90 days to 24 months after first complete remission or complete remission with incomplete platelet recovery. Refractory AML was defined as persistent disease at least 28 days after initiation of induction therapy, or relapse less than 90 days after first complete remission (CR) or CR with incomplete platelet recovery (CRi). All patients have received previous induction therapy with an anthracycline. Salvage regimen used were mainly cytarabine 3 g/m²/12h, d1-4 plus idarubicine 12 mg/m²/d, d1-3 or dauno 60 mg/m²/d, d1-2 or amsacrine 200 mg/m²/d, d1-3; less frequently MiDAM (mitoxantrone 12mg/m² d1-3, cytarabine1 g/m²/12h d1-5, GO 4-6mg/m², d4) or FLAG-Ida. Cytarabine dose for patients >60 was reduced to 1g/m²/12h, d1-5. We found, in our database, 151 R/R AML according to VALOR criteria treated between 2000 and 2013: 72 patients (48%) had refractory diseases (primary refractory: n=60, 40% and relapse less than 90 days after CR: n=12, 8.0%) and 79 (52%) had relapsed (early relapse more than 90 days after CR and less than one year: n=52, 66%; late relapse between one and two years: n=27, 34%). Patients characteristics were as follows: 85 (56%) were male, median age was 48 years (interquartile range [IQR], 36-60.5; 38 (27%) were 60 years or older). Cytogenetics at diagnosis was favorable in 18 (12%); intermediate in 93 (62%); adverse in 38 (25%) or unknown in 2 (1%) patients, respectively. They were treated as first line therapy with one (42%) or two cycles (58%). Early death rates at day 30 and day 60 were 7% and 17% in the whole cohort; 6% and 12% in younger patients and 12% and 29% in patients 60 years or older. Combined CR rate (defined as CR and CRi) was 53% for the whole cohort, and 57%/42%/56%/52%/63%/50% for <60 years/≥60 years/relapses/early relapses/late relapses/refractory diseases respectively. Allogeneic-SCT was performed in 25 out of 80 patients (31%) having achieved CR after salvage treatment. Median overall survival (OS) was 8 months for the whole cohort and 9.2/5.0/7.7/7.5/13.6/9.2 months for <60 years/≥60 years/relapses/early relapses/late relapses/refractory diseases respectively. Using VALOR inclusion criteria, age is the main factor that discriminate R/R AML patients selected for clinical trials using IDAC as control arm compared to patients of daily practice. Thus, those patient populations remain hardly comparable. However, as far as CR is concerned, IDAC seems suboptimal as compared to higher-intensity regimen used in daily practice. Yet, this higher CR rates do not translate into a significant gain in survival since median OS remains close to that of IDAC with the possible exception of refractory patients who seem to benefit from higher-intensity regimen. Thus, although unsatisfactory, IDAC could be considered as a fair control arm for overall survival endpoint especially in patients older than 60 year of age. Table Table. Disclosures Tavitian: Novartis: Membership on an entity's Board of Directors or advisory committees. Huguet:Pfizer, Novartis, BMS, Ariad, Jazz, Amgen: Membership on an entity's Board of Directors or advisory committees. Recher:Celgene, Sunesis, Amgen, Novartis: Membership on an entity's Board of Directors or advisory committees; Celgene, Sunesis, Amgen, Novartis, Chugai: Research Funding.

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

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 2961-2961
Author(s):  
Xavier Leleu ◽  
Murielle Roussel ◽  
Bertrand Arnulf ◽  
Philippe Moreau ◽  
Catherine Traulle ◽  
...  
Keyword(s):  
Overall Survival ◽  
Board Of Directors ◽  
Research Funding ◽  
Alkylating Agents ◽  
Randomized Study ◽  
Historical Control ◽  
Advisory Committees ◽  
Line Of Therapy ◽  
End Stage ◽  
The Impact

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

scholarly journals Octogenarians with AML Can Have Durable Remissions with Venetoclax and Hypomethylating Agent Therapy Despite Significant Dose Reductions

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 1259-1259
Author(s):  
Ellen Madarang ◽  
Jillian Lykon ◽  
Wenhui Li ◽  
Sunil Iyer ◽  
Michele Stanchina ◽  
...  
Keyword(s):  
Overall Survival ◽  
Board Of Directors ◽  
Dose Reduction ◽  
Research Funding ◽  
Median Overall Survival ◽  
Tp53 Mutation ◽  
Newly Diagnosed ◽  
Careful Monitoring ◽  
Advisory Committees ◽  
Starting Dose

Abstract Introduction Venetoclax in combination with a hypomethylating agent (VEN-HMA) has become a standard of care for older or unfit patients with newly diagnosed AML. Although primarily administered in the outpatient setting, VEN-HMA is associated with significant cytopenias and infectious complications, requiring careful monitoring and dose adjustments. Patients treated with VEN-HMA on clinical trials had a median age of ~75 years. The optimal dose and schedule, safety, and efficacy of VEN-HMA in octo- and nonagenarians is not clearly defined. Methods We performed a retrospective analysis of AML patients ≥80-years-old who received at least 1 day of VEN-HMA at our institution from 11/2018 to 7/2021. Patients with de novo or secondary AML with or without prior HMA or chemotherapy were included. Venetoclax starting dose was 200-400 mg for 14-28 days. Dose adjustments for drug interactions with azole anti-fungals were implemented. HMA was started at 50-75 mg/m2 for 5-7 days of azacitidine or 20mg/m2 for 5 days of decitabine. Dose reduction was defined as any decrease from the starting dose and schedule. Patients who did not complete cycle 1 were included in the overall survival and safety analysis but excluded from response assessment. Results Among 21 patients ≥80-years-old treated with VEN-HMA (20 newly diagnosed, 1 relapsed/refractory), median age was 82 years (range: 80-89) (Table 1), 57% had antecedent MDS, and 38% received HMAs previously. Most patients (81%) were ELN adverse risk, 38% had a complex karyotype, 24% had a TP53 mutation, and 43% had ECOG PS of 2-3. Median overall survival for all patients was 8.0 months (0.5-31.4 months). At time of analysis, 12 patients (57%) were still alive and in remission on VEN-HMA with a median follow-up of 11.5 months (range 2.3-31.4 months). Five patients (24%) died during cycle 1 from sepsis. Of these 5 patients, 4 had a TP53 mutation, 3 had prior MDS, and 3 had received prior therapy for lymphoma. In the remaining 16 patients, median overall survival was 9.9 months (2.3-31.4 months) and the CR/CRh rate was 81% (13/16 patients). Median duration of response was 8.9 months (range 1.0-30.0). Consistent with previous reports, all patients who achieved CR/CRh did so by the end of cycle 2 (median 2 cycles). Most patients also received the standard dose and schedule of VEN (75%) and HMA (57%) during the first cycle. All patients (100%) required venetoclax dose and schedule reduction, with a median final venetoclax dose of 200 mg and duration of 14 days. Average final cycle length was 35 days. Most patients (69%) also required dose reduction of HMA. Median duration of treatment was 7.5 months (range 0.5-31.4). Treatment emergent grade 3-4 anemia occurred in 67% of patients, thrombocytopenia in 81%, and neutropenia in 86%; 17 patients (81%) had treatment emergent febrile neutropenia. There were no infectious deaths in patients who survived cycle 1. The median number of neutropenic fever episodes per patient was 1 (0 to 2). The 4 deaths after cycle 1 were due to progressive disease (n=3) or relapse (n=1). Conclusion VEN-HMA can be safely and effectively given to octogenarians with careful monitoring and dose adjustments. All patients required dose reduction of venetoclax after CR/CRh was achieved, and most also required adjustment of HMA. Despite this, over half of patients achieved durable remissions. The greatest risk of infectious death was in the first cycle, in patients who were heavily pre-treated and enriched for TP53 mutations. When compared to historical controls, outcomes in octogenarians who survive the first cycle appear similar to younger age groups. This work highlights the need for a prospective multi-center effort to optimize the dose and schedule of VEN-HMA in older patient populations. Figure 1 Figure 1. Disclosures Bradley: AbbVie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees. Sekeres: Takeda/Millenium: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees. Watts: Rafael Pharmaceuticals: Consultancy; Genentech: Consultancy; Bristol Myers Squibb: Consultancy; Takeda: Consultancy, Research Funding; Jazz Pharmaceuticals: Consultancy; Aptevo Therapeutices: Research Funding.

scholarly journals Venetoclax Therapy in a Heavily Treated Cohort of Patients with Relapsed or Refractory Acute Myeloid Leukemia: Update of the Pethema Registry Experience

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 2325-2325
Author(s):  
Jorge Labrador ◽  
Miriam Saiz-Rodríguez ◽  
Maria Dunia De Miguel ◽  
Almudena De Laiglesia ◽  
Carlos Rodriguez ◽  
...  
Keyword(s):  
Overall Survival ◽  
Acute Myeloid Leukemia ◽  
Board Of Directors ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
Tumor Lysis Syndrome ◽  
Advisory Committees ◽  
Refractory Acute Myeloid Leukemia ◽  
Acute Myeloid

Abstract Introduction The prognosis of patients with relapsed or refractory acute myeloid leukemia (RR-AML) is very poor, and treatment options are very limited. The exciting results of venetoclax (VEN) in untreated AML have led to its off-label use in RR-AML. However, evidence in RR-AML is still scarce and the available data are mostly from retrospective and single-center studies. The aim of our study was to analyze the effectiveness of VEN use in patients with RR-AML reported to the PETHEMA AML epidemiological registry. Initial results were presented previously (Labrador J, et al. ASH 2020). Here, we report an updated analysis. Methods We conducted a retrospective, multicenter, observational study of a cohort of patients with AML-RR who were treated with venetoclax in the hospitals of the PETHEMA group. We evaluated efficacy, CR/CRi rate and overall survival (OS). We performed a descriptive analysis. Overall survival (OS) was calculated using the Kaplan-Meier method. Results Fifty-one patients were included, 33 men and 18 women, with a median age of 68 years (25-82). The main characteristics of the included patients are shown in Table 1. With a median follow-up of 167 days, 10/51 patients (19%) continued to receive VEN at the time of analyses. Patients received a median of 2 cycles (0-8). VEN was administered with azacitidine (AZA) in 59%, with decitabine (DEC) in 29% and with low-dose cytarabine (LDAC) in 12% of patients, respectively. The CR/CRi and partial response (PR) rates were 12.4% and 10.4%, respectively. The CR/RCi and overall response (ORR, CR/CRi+PR) was higher in patients receiving VEN+AZA (17.9% and 32.1%) than in those receiving DEC + VEN (6.7% and 13.3%) or LDAC + VEN (0%). The presence of NPM1 or CEBPA variants were the only two variables associated with increased CR/CRi with VEN in RR-AML. Median OS was 104 days (95% CI: 56 - 151) (Figure 1A), 120 days in combination with AZA, 104 days with DEC, and 69 days with LDAC; p=0.875. Treatment response (Figure 1B) and ECOG 0 were the only variables that influenced OS in a multivariate model adjusted for age and sex (Table 2). VEN-resistant patients who received subsequent salvage therapy had superior median OS (98 vs. 5 days, p=0.004).Twenty-eight percent of patients required discontinuation of VEN due to toxicity. Sixty-one percent of patients required admission, mainly due to infections (45%), 10% due to bleeding and other causes in 12%. One case of tumor lysis syndrome was described. Conclusions Our real-life series depicts a marginal probability of CR/CRi and poor OS after venetoclax-based salvage. Patients treated with this regimen had very poor-risk features, and were heavily pre-treated, which could explain in part the observed poor outcomes. Although follow-up is still short, the small proportion of responders did not reach the median OS. Further studies will help to identify those patients potentially benefiting from venetoclax-based salvage regimens. Figure 1 Figure 1. Disclosures Belén Vidriales: Roche: Consultancy; Novartis: Speakers Bureau; Astellas: Consultancy, Speakers Bureau; Jazz: Consultancy, Speakers Bureau. Pérez-Encinas: Janssen: Consultancy. Tormo: Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Jazz Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Montesinos: Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Glycomimetics: Consultancy; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Karyopharm: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Incyte: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Daiichi Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Forma Therapeutics: Consultancy; Sanofi: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Teva: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Stemline/Menarini: Consultancy; Tolero Pharmaceutical: Consultancy; Agios: Consultancy; AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Astellas Pharma, Inc.: Consultancy, Honoraria, Other: Advisory board, Research Funding, Speakers Bureau. OffLabel Disclosure: Venetoclax for Patients with Relapsed or Refractory Acute Myeloid Leukemia

Safety and Efficacy of Subcutaneous-Administered Omacetaxine Mepesuccinate in Chronic Myeloid Leukemia (CML) Patients Who Are Resistant or Intolerant to Two or More Tyrosine Kinase Inhibitors – Results of A Multicenter Phase 2/3 Study.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 861-861 ◽  
Author(s):  
Jorge Cortes-Franco ◽  
Digumarti Raghunadharao ◽  
Purvish Parikh ◽  
Meir Wetzler ◽  
Jeffrey H. Lipton ◽  
...  
Keyword(s):  
Overall Survival ◽  
Board Of Directors ◽  
Median Duration ◽  
Research Funding ◽  
Median Overall Survival ◽  
Cytogenetic Response ◽  
Advisory Committees ◽  
Safety And Efficacy ◽  
Hematologic Response ◽  
Grade 3

Abstract Abstract 861 Background: Omacetaxine is a first-in-class cetaxine with clinical activity against Ph+ CML and a mechanism of action independent of tyrosine kinase inhibition. The development of TKI resistance and intolerance is an emerging problem and patients (Pts) who have failed multiple TKIs may benefit from an alternative therapy for CML. Study Goals: To evaluate the safety and efficacy of SC omacetaxine in CML Pts who are resistant and/or intolerant to two or more TKIs. Methods: Eligible Pts included adult CML Pts in chronic, accelerated, or blast disease phase (CP, AP, BP) with resistance and/or intolerance to at least two TKIs. Bcr-Abl mutational analysis was performed at one of 2 central reference laboratories and Pts harboring the T315I Bcr-Abl mutation were enrolled in a separate clinical trial. Induction schedule: 1.25 mg/m2 SC omacetaxine twice daily for 14 days every 28 days until hematologic response. Maintenance dosing: 1.25 mg/m2 SC omacetaxine twice daily for 7 days every 28 days. Study Results: To date, 99 Pts have enrolled, with data available for analysis on 65 Pts (30 CP, 20 AP and 15 BP). The median age was 57 yrs (23-78) with 52% male and a median disease duration of 77 mo (1-197). Nearly all (64/65, 99%) Pts failed prior IM therapy and 57% failed 3 or more prior TKIs. Baseline mutations were identified in 21 (32%) Pts with 10 non-P Loop, 7 P Loop and 4 compound mutations. Baseline clonal evolution was evident in 5 (17%) CP, 8 (40%) AP, and 13 (87%) BP Pts. Six CP Pts entered the study in CHR. The median follow-up for all Pts is 4.0 mo (0.3 to 14.7). Efficacy: In CP Pts, CHR was achieved in 18 Pts and maintained for more than 8 weeks in the 6 Pts enrolled with baseline CHR, for an overall CHR rate of 80%; median duration 4.7+ mo (1.4 to 13). Major cytogenetic response (MCyR) was achieved in 6 (20%) CP Pts (1 complete, 5 partial); median duration 1.6+ mo (0.0 to 2.9). Major molecular response was achieved in 10% of CP Pts. In AP Pts, overall hematologic response was achieved in 15 (75%) Pts; 12 CHR and 3 return to chronic phase (RCP); median duration 2.5+ mo (1.8 to 10.5). One (5%) AP Pt achieved a complete CyR, identified immediately prior to data cut-off and ongoing. In BP Pts, overall hematologic response was achieved in 8 (53.3%); 6 CHR and 2 RCP. Three Pts (2 CP, 1 AP) received bone marrow/stem cell transplants after achieving major cytogenetic response, a therapeutic option not available to them at study enrollment. No deaths occurred in CP Pts. The median overall survival for AP Pts has not been reached and 13 Pts were alive at the time of data cut-off. Median overall survival was 14.5 mo for BP Pts. Median time to progression was 11.1, 5.7, and 2.6 mo for CP, AP, and BP Pts, respectively. Safety: Grade 3/4 related events occurred in 47/65 (72%) of Pts. The most commonly reported events (>15%) were thrombocytopenia (43%), neutropenia (29%), and anemia (22%). Non-hematologic toxicities were generally grade 1/2 with the most frequently reported; diarrhea (32%), nausea (26%), pyrexia (23%), headache (20%), fatigue (19%), vomiting (17%), and asthenia (17%). Grade 3/4 non-hematologic toxicities were uncommon with no events occurring in >5% of Pts and fatigue (3%) the most common event. Treatment delays occurred in approximately 50% of the Pts with median duration of approximately 9 days for all disease phases and cycles (CP=7, AP=11, and BP=12 days). The primary causes of delay were thrombocytopenia, neutropenia and pancytopenia. Deaths occurred in 6 (9.2%) Pts, including 2 (10%) AP pts and 4 (26.7%) BP Pts. Of the deaths, one occurrence in an AP Pt was considered to be possibly related to omacetaxine treatment (febrile neutropenia). Conclusions: Omacetaxine administered by SC injection produced hematologic and cytogenetic responses with a safety profile primarily consisting of hematologic toxicities. This study demonstrated that omacetaxine may be a potential treatment option for CML Pts who have failed multiple TKIs. Disclosures: Cortes-Franco: ChemGenex: Membership on an entity's Board of Directors or advisory committees, Research Funding. Raghunadharao:ChemGenex: Research Funding. Parikh:ChemGenex: Research Funding. Wetzler:ChemGenex: Membership on an entity's Board of Directors or advisory committees, Research Funding. Lipton:ChemGenex: Membership on an entity's Board of Directors or advisory committees, Research Funding. Jones:ChemGenex: Research Funding. Hochhaus:ChemGenex: Research Funding. Kantarjian:ChemGenex: Membership on an entity's Board of Directors or advisory committees, Research Funding. Craig:ChemGenex: Employment. Benichou:ChemGenex: Employment. Humphriss:ChemGenex: Employment. Nicolini:ChemGenex: Research Funding.

Sequence of Therapy in Multiple Myeloma: Does It Matter? Retrospective Evaluation of Patients with Multiple Myeloma Who Have Received Bortezomib Followed by Lenalidomide or Vice Versa,

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 3979-3979
Author(s):  
Amila M Patel ◽  
Viet Q. Ho ◽  
Kenneth H. Shain ◽  
Daniel Sullivan ◽  
Melissa Alsina ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Overall Survival ◽  
Partial Response ◽  
Board Of Directors ◽  
Bone Disease ◽  
Research Funding ◽  
Median Overall Survival ◽  
Advisory Committees ◽  
Group A ◽  
Group B

Abstract Abstract 3979 Background: In recent years, proteasome inhibition with bortezomib (Bort) and immunomodulation with lenalidomide (Len) has resulted in improved outcomes of patients with multiple myeloma. However, neither of these treatment options offers a cure for patients, as they will eventually relapse and require alternate therapy. The optimal sequence of therapy with these two agents has yet to be established. Methods: All adult patients with multiple myeloma who received both Bort and Len non-concurrently at our institution between January 2004 and August 2010 were included in this analysis. The primary endpoints were overall survival and response (partial response or better) to therapy among two groups of patients: Group A, those who received len-based therapy followed by bort-based therapy and, Group B, those who received bort-based therapy followed by len-based therapy. Results: 208 patients were identified and divided into the two groups (97 in Group A, 111 in Group B). Baseline demographics are summarized in Table 1. Patients in Group B were younger (60 vs 57 years; p=0.03), had more bone disease (61% vs 77%; p=0.03), and were more likely to receive a stem cell transplant (57% vs 71%; p=0.04). The median overall survival was not statistically different between the 2 groups (Group A versus Group B: 78.5 vs. 74.0 months, respectively; p=0.62). The sequence of therapy was not predictive of overall survival within subgroups (including patients with poor risk cytogenetics, elevated beta2-microglobulin, presence of bone disease), with the exception of patients with a serum creatinine ≥2 mg/dl at diagnosis. In this case, Group B had a better median overall survival than Group A (24.1 vs 53.9 months, p=0.01). In addition, among patients who have received Len and Bort without intervening therapy (n= 158), no difference in overall survival was noted in Group A and B. There was also no statistically significant difference in response rates (partial response or better) to bort-based therapy between Group A and B (68.7% vs. 77.2% respectively, p= 0.265) nor to len-based therapy between Group A and B (60.4% vs. 73.6% respectively, p=0.168). Multivariable analysis identified baseline renal dysfunction and the presence of bone disease at diagnosis as predictors of worse outcomes however the sequence of therapy was not a predictor of outcome. ISS stage and b2m were not entered in the logistic regression model as these were only available on 30–40% of patients at baseline. Conclusion: To our knowledge, this is the only study that has examined the impact of sequence of therapy with immunomodulators and proteasome inhibitors in myeloma. This data suggests that the sequence of therapy with these agents is only relevant in patients who have baseline renal insufficiency (≥2 mg/dl at diagnosis); therefore, a bort-based treatment should be considered as first-line therapy in these patients. Disclosures: Alsina: Millennium: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Allergan: Research Funding. Djulbegovic:Millenium: Research Funding. Baz:Millenium: Research Funding, Speakers Bureau; Celgene: Research Funding.

scholarly journals Bing Neel Syndrome: Retrospective Australasian Experience of a Rare Treatable Complication of Waldenström Macroglobulinaemia/ Lymphoplasmacytic Lymphoma

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 5325-5325 ◽  
Author(s):  
Dipti Talaulikar ◽  
Tara Cochrane ◽  
John Gibson ◽  
Nada Hamad ◽  
Phoebe Joy Ho ◽  
...  
Keyword(s):  
Overall Survival ◽  
Board Of Directors ◽  
Research Funding ◽  
Median Overall Survival ◽  
Cortical Atrophy ◽  
High Dose ◽  
Motor Neuropathy ◽  
Lymphoplasmacytic Lymphoma ◽  
Advisory Committees ◽  
Csf Analysis

Abstract Introduction and aims:Bing Neel syndrome (BNS) is a rare complication of Waldenström Macroglobulinaemia (WM)/ Lymphoplasmacytic Lymphoma (LPL). It is a clinicopathological entity characterised by central nervous system involvement with malignant cells. It presents with diverse symptoms and can be difficult to recognise. However, it is a treatable condition amenable to systemic and intrathecal treatment. We present the Australasian experience of this rare entity. Methods:Inclusion in the study was based on cytologically or histologically confirmed presence of lymphoplasmacytic cells in the CSF or brain biopsy. Ten patients were included from 9 sites in Australia and New Zealand. Relevant retrospective data was extracted after obtaining consent from patients or next of kin. Results: Seven of the 10 patients were males with overall mean age of 63.5 years (range: 49-78 years); 4 patients were < 60 years old. Four patients (40%) did not have a prior diagnosis of WM; the remaining 6 patients were diagnosed ~ 11 years post diagnosis of WM (range: 3 -26 years) and received 1 line of treatment (except for 2 patients who received 2 lines of treatment). Treatment regimens received included R-CVP, chlorambucil-prednisolone, DRC, FCR, oral fludarabine, and RFM. At diagnosis of BNS, IgM and/or PP levels ranged between 3 - 70 g/L with 6 (60%) patients having levels < 10 g/L. One patient had a diagnosis of lymphoplasmacytic lymphoma with IgG paraprotein. Symptoms at presentation of BNS varied from headache, ptosis/ophthalmoplegia, memory loss, subacute hemiplegia, cognitive defects, hearing loss, and sensory or motor neuropathy. None of the patients had B symptoms. Lymphadenopathy was noted in 4 (40%) cases, splenomegaly in 1 (10%) and ECOG performance status ranged from 0-4 with 3 (30%) patients having an ECOG of > 2. Brain +/- spine MRI was done in all cases with 5 (50%) showing leptomeningeal involvement. Orbital infiltration or enhancement of optic or ophthalmic nerves was noted in 3 cases (30%), and 3 patients (30%) had focal signs/masses. 1 had cortical atrophy, and 3 had normal MRI. CSF analysis was abnormal in all cases on cytology with demonstration of abnormal lymphocytes. Where immunophenotyping was performed, it showed presence of CD5, CD10 negative B cells. MYD88 L265P was detected in 3 patients (30%). Treatment of BNS included systemic chemoimmunotherapy in 30%, CNS penetrating intravenous agents in 40%, Ibrutinib in 50%, intrathecal chemotherapy in 30%, and radiotherapy in 10%. More than 1 modality of treatment was used in 40% of patients. Ibrutinib was administered as frontline treatment in combination with high dose MTX or IT chemotherapy in 3 patients, and as single agent monotherapy in 1 patient. Ibrutinib was used as second line treatment in 2 patients with both achieving CR. The number of cycles administered were 2.6 (range 1-9). Response data was available in 9 patients with ORR in 6 (1 CR, 5 PR) and non-response in 3. All patients except the one treated with Ibrutinib monotherapy had at least PR. With a median follow-up time of 20 months, 3 patients have died. The median overall survival of patients was not reached. The 1-year and 3-year OS rates were 80% (95% CI 41-95%) and 60% (16-87%), respectively (Figure 1). Conclusion:BNS should be suspected in WM patients who develop focal or nonspecific neurological symptoms. It can be readily diagnosed on radiological scans i.e. brain and spinal MRI, and/or on CSF analysis. It can be treated with a number of systemic and intrathecal drugs including Ibrutinib, which crosses the blood brain barrier. Fig 1 legend:Kaplan Meir curve demonstrating median overall survival of patients (not reached) and 1-year and 3-year OS rates of 80% (95% CI 41-95%) and 60% (16-87%), respectively. Disclosures Talaulikar: Takeda: Research Funding; Novartis: Honoraria, Speakers Bureau; Amgen: Consultancy, Honoraria; Janssen: Honoraria, Speakers Bureau; Roche: Honoraria, Speakers Bureau. Ho:Celgene: Other: Travel to meeting ; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel to meeting; Novartis: 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; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Simpson:Roche: Honoraria, Research Funding; Pharmacyclics LLC, an AbbVie Company: Research Funding; Acerta: Research Funding; Merck: Honoraria, Research Funding; BeiGene: Research Funding; Sanofi: Research Funding; Bristol-Myers Squibb: Other: TRAVEL, ACCOMMODATIONS, EXPENSES; Celgene: Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES; Novartis: Other: TRAVEL, ACCOMMODATIONS, EXPENSES; MSD: Honoraria; Abbvie: Honoraria, Research Funding; Amgen: Research Funding, TRAVEL, ACCOMMODATIONS, EXPENSES; Janssen: Honoraria, Research Funding. Tam:AbbVie: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Beigene: Honoraria. Castillo:Pharmacyclics: Consultancy, Research Funding; Millennium: Research Funding; Janssen: Consultancy, Research Funding; Genentech: Consultancy; Beigene: Consultancy, Research Funding; Abbvie: Consultancy, Research Funding.

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