scholarly journals Treatment with an Allogeneic Leukemia-Derived Dendritic Cell Vaccine in AML Patients Shows MRD Conversion and Improved Survival

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 1274-1274
Author(s):  
Arjan A. Van de Loosdrecht ◽  
Jacqueline Cloos ◽  
Eva Maria Wagner ◽  
Uwe Platzbecker ◽  
Tobias A. W. Holderried ◽  
...  
Keyword(s):  
Overall Survival ◽  
Complete Remission ◽  
Board Of Directors ◽  
Research Funding ◽  
Residual Disease ◽  
Dendritic Cell Vaccine ◽  
Cell Vaccine ◽  
Advisory Committees ◽  
Dose Cohort ◽  
Intradermal Administration

Abstract Background. Persistence of measurable residual disease (MRD) is a poor prognostic factor and predicts relapse in acute myeloid leukemia (AML). In a phase I study, the allogeneic leukemia-derived dendritic cell vaccine, DCP-001, has shown safety and humoral and cellular immune responses (A.A. van de Loosdrecht, et al. Cancer Immunol. Immunother. 2018;67:1505). In the current phase II study, (Clintrials.gov: NCT03697707) we report on progress and evaluation of MRD conversion, as primary endpoint, relapse free and overall survival. Methods. AML-patients, ineligible at screening for HSCT, who are in first complete remission (CR1) but with MRD receive 4 biweekly doses of 25e6 or 50e6 cells per vaccination (cells/vc) followed by 2 doses of 10e6 cells/vc as boosts at week 14 and 18. MRD is assessed at 4 timepoints (baseline, week 14, 20 and 32) by flow cytometry and/or molecular analyses. Primary endpoints are the effect of vaccination on MRD status and safety and tolerability of the two vaccination schedules. Secondary endpoints include relapse free, overall survival and immunological response evaluation. Results. As of 28 th July 2021, 19 patients have been enrolled, of which 10 patients have been given at least 4 vaccinations with 25e6 cells/vc and 9 with 50e6 cells/vc. No serious adverse events (AE) or severe AE (grade 3 or higher) related to DCP-001 have been reported. AE's related to DCP-001 are mainly injection site reactions, occurring within 48 hours after intradermal administration. In the 25e6 cells/vc cohort all patients have completed the treatment phase up to week 32, allowing full assessment of MRD response. Three patients have converted to MRD negative, 4 patients relapsed (followed by HSCT for 1 patient), 3 patients remained MRD positive, of which 2 patients underwent HSCT immediately after completion of the full dosing schedule. In this cohort 2 patients eventually died during follow up. Treatment is still ongoing in the 50e6 dose cohort, with thus far one additional MRD conversion reported and two relapses, 3 patients with stable MRD levels, and 3 have no MRD data available yet. Median follow-up of patients in the 25e6 cells/vc cohort was 288 days (range 148 - 546). Median RFS and OS have not yet been reached, but estimated RFS and OS at 12 months is calculated at 57% and 79%, respectively (Figure 1). MRD converted patients after DCP-001 vaccination, showed improved survival, compared to patients without MRD conversion (Figure 2). All 4 patients who converted to MRD negative are still in CR and alive (FU median 423.5 days (range 140 - 546). Immunological monitoring of patients is currently being performed. As previously reported (abstract #168, ASH2020), 3 of 4 evaluable patients show at least 1 or more responses against tumor-associated antigens known to be present in DCP-001 in IFNy ELISPOT assay. Conclusion/discussion. Four patients have shown MRD conversion (3 in the 25e6 dose cohort, and 1 in the 50e6 dose cohort). Six patients remained in complete remission with stable or declining levels of MRD, 6 patients relapsed and for 3 patients no MRD data is available yet. Median RFS and OS have not yet been reached. MRD conversion showed improved relapse free and overall survival. Treatment with DCP-001 is very well tolerated, with limited side effects mainly related to intradermal administration. Immunological analyses for specific tumor-associated antigen responses and general immune profiling are currently being performed. Preliminary data from this study shows that the relapse vaccine DCP-001 is a promising treatment for patients with AML in complete remission but with residual disease aiming to deepen responses and prolong survival. Its excellent safety profile allows for future combination therapy. Figure 1 Figure 1. Disclosures Van de Loosdrecht: Novartis: Consultancy; Alexion: Consultancy; Roche: Consultancy; Amgen: Consultancy; Celgene: Consultancy, Research Funding. Cloos: Takeda: Research Funding; Novartis: Consultancy, Other, Research Funding; Navigate: Patents & Royalties; Merus: Other, Research Funding; Janssen: Research Funding; Helsinn: Other; Genentech: Research Funding; DC-One: Other, Research Funding; Astellas: Speakers Bureau. Platzbecker: AbbVie: Honoraria; Janssen: Honoraria; Novartis: Honoraria; Celgene/BMS: Honoraria; Geron: Honoraria; Takeda: Honoraria. Holderried: Gilead Sciences: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Speakers Bureau; MSD: Speakers Bureau; GSK: 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; Sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Therakos: Other: Travel support; Abbvie: Other: Travel support; Medac: Other: Travel support; Eurocept Pharmaceuticals: Other: Travel support; Janssen: Other: Travel support; Daiichi Sankyo: Other: travel support. Giagounidis: Novartis: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees. van Zeeburg: Immunicum AB: Current Employment; Kiadis: Ended employment in the past 24 months. Rovers: Immunicum AB: Current Employment. Gjertsen: KinN Therapeutics: Current holder of stock options in a privately-held company; Alden Cancer Therapy: Current holder of stock options in a privately-held company; Pfizer Inc.: Consultancy; BerGenBio: Consultancy; Novartis: Consultancy.

scholarly journals Conversion from MRD Positive to Negative Status in AML Patients in CR1 after Treatment with an Allogeneic Leukemia-Derived Dendritic Cell Vaccine

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 13-14
Author(s):  
Arjan van de Loosdrecht ◽  
Janine van Elssen ◽  
Bjørn Tore Gjertsen ◽  
Eva Maria Wagner ◽  
Tobias Holderried ◽  
...  
Keyword(s):  
Flow Cytometry ◽  
Immune Response ◽  
Dendritic Cell ◽  
Complete Remission ◽  
Immune Responses ◽  
Board Of Directors ◽  
Research Funding ◽  
Dendritic Cell Vaccine ◽  
Cell Vaccine ◽  
Advisory Committees

Background. Persistence of measurable residual disease (MRD) in patients with acute myeloid leukemia (AML) remains a poor prognostic factor and unmet medical need. The allogeneic leukemia-derived dendritic cell vaccine, DCP-001, has shown in a phase I study to generate both humoral and cellular immune responses and is safe for clinical practice (van de Loosdrecht et al., Cancer Immunol. Immunother. 2018). In the current phase II study (Clintrials.gov: NCT03697707) we show the capability of DCP-001 to convert MRD positive patients to negative, leading to deeper remissions. Additionally, it is shown that DCP-001 induces immune responses, also specifically against tumor associated antigens known to be present in DCP-001 and relevant for AML. Methods. The current trial aims to enroll up to 20 AML -patients, ineligible for HSCT, who are in in first complete remission (CR1) but who are still MRD positive. MRD is assessed in the bone marrow through flow cytometry and/or qPCR (eg NPM1). Patients receive a primary vaccination regimen of 4 times 25.106or 50.106cells per vaccination, biweekly, followed by two booster vaccinations (10.106cells/vaccination) at week 14 and 18 after start of treatment. Primary endpoints of this trial are the safety and tolerability of the two vaccination schedules and the effect of vaccination on the MRD status. Additionally, cellular and humoral immune response induced by DCP-001 are evaluated in peripheral blood using several assay methods, including flow cytometry and IFN-ϒ ELISpot against known TAA's such as WT-1, RHAMM and PRAME. Results. Up to 15 July 2020, ten patients (age 41-76; 5 male, 5 female) have been enrolled and dosed within the study, completing the first dose cohort of 25.106cells/vaccination. All vaccinations were well tolerated and adverse events to the vaccine were limited to local injection site reactions such as redness, swelling and warmth (maximum grade 2). Three of the ten patient relapsed before the vaccination schedule was completed. Four patients could be evaluated for MRD; Two patients became MRD negative at the first timepoint after the initial vaccinations (week 14), and remained negative until end of active FU (week 32), two other patients remained in CR, but with MRD positivity. For the remaining three patients, to date, no MRD outcome is available yet but patients remain in CR (see swimmers plot for overview, Figure 1). Evaluation of the immune response before, during and after DCP-001 vaccination has only be performed in a small subset of three patients thus far. Of these patients one showed a clinical response becoming MRD negative after vaccination. In this patient we observed an increase in tumor specific functional T-cells assessed by IFNγ ELISPOT, either as a recall or primary response, as shown by the response observed to WT-1 (see for example Figure 2). These tumor associated antigens are known to be expressed by DCP-001 and included WT1, PRAME and RHAMM. Induction of specific memory CD8 and CD4 cells could be observed upon vaccination which might be related to the clinical response. Conclusion/discussion.Preliminary data from this ongoing study confirms that vaccination with DCP-001 is able to generate a tumor-specific immune response and may lead to potential tumor control. Two patients were actually converted from being MRD positive at start of vaccination to MRD negative during the study. These patients continue to be in complete remission for at least a year after vaccination. This study continues to enroll patients at a higher vaccine dose of 50.106cells per vaccination and additional data on induced immune responses and MRD status will be shown. Disclosures van de Loosdrecht: novartis: Honoraria; celgene: Honoraria. Wagner:Novartis: Membership on an entity's Board of Directors or advisory committees; Shire: Other: Travel grand; MSD: Membership on an entity's Board of Directors or advisory committees; Medac: Other: Travel grand; Kite/Gilead: Membership on an entity's Board of Directors or advisory committees. Platzbecker:Amgen: Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Geron: Consultancy, Honoraria. Rovers:DCprime: Current Employment.

scholarly journals Phase I Study of Ixazomib Added to Chemotherapy in the Treatment of Acute Lymphoblastic Leukemia in Older Adults

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 41-42
Author(s):  
Philip C. Amrein ◽  
Karen K. Ballen ◽  
Kristen E. Stevenson ◽  
Traci M. Blonquist ◽  
Andrew M. Brunner ◽  
...  
Keyword(s):  
Overall Survival ◽  
Acute Lymphoblastic Leukemia ◽  
Complete Remission ◽  
Board Of Directors ◽  
Research Funding ◽  
Lymphoblastic Leukemia ◽  
Advisory Committees ◽  
Survival Estimate ◽  
Grade 3 ◽  
Experienced Grade

Introduction: While progress has been made in the treatment of childhood leukemia, the outlook for patients >60 years of age with acute lymphoblastic leukemia (ALL) is poor with complete remission rates (CR) of approximately 60% and 3-year survivals (OS) of less than 15%. Intensified treatment in a later CALGB trial showed little improvement with a CR=61% and 5-year OS=6% (Stock, Cancer 2013). Ixazomib is an oral proteasome inhibitor, which has shown single agent activity and promising combination activity in pediatric ALL patients (Messinger, Blood 2012). We sought to assess the safety and tolerability, as well as early efficacy of adding ixazomib to a current MGH-DFCI/HCC multi-agent regimen for older adults with ALL. Methods: Patients aged 51 to 75 years of age with newly diagnosed B-ALL and T-ALL were screened for eligibility. Patients with mature ALL (including Burkitt's) were excluded. Patients with Philadelphia chromosome positive ALL (BCR-ABL1+) were eligible, and dasatinib was added to the chemotherapy on Day 10 for these patients. The chemotherapy treatment schedule from induction through maintenance is outlined in Table 1. A standard 3 + 3 patient cohort dose escalation design was used to determine the maximum tolerated dose (MTD) of ixazomib during induction for these patients, the primary objective of the trial. After consolidation I, patients in complete remission (CR) with a suitable donor were offered a hematopoietic stem cell transplantation (HSCT) as per institutional guidelines. Those not going to HSCT continued therapy as noted in the table. Results: There were 19 patients with B-ALL enrolled, none with T-ALL. Among these patients, 7 harbored BCR-ABL1 rearrangements. The median age was 65 years, 74% were male, and 90% had a performance status 0 or 1. The MTD was 2.3 mg of ixazomib, as 2 patients at 3.0 mg developed DLT's: a grade 3 peripheral neuropathy and a grade 5 acute kidney injury (Table 2). Grade 3 and 4 toxicities encountered at any time consisted mainly of grade 4 neutropenia in 13 patients and grade 4 thrombocytopenia in 12 patients. One patient experienced grade 3 neutropenia and 5 patients experienced grade 3 thrombocytopenia. Two patients with grade 2 neuropathy did not meet the definition of DLT. Among the 19 patients, 15 (79%, [95% confidence interval (CI), 54-94%]) achieved CR (14) or CRi (1), and 5 patients went on to HSCT. The median follow-up time was 2 years (range, 1-5) for 8 patients remaining alive. The 1-year overall survival estimate was 53% [95% CI, 29-72%], while the 2-year overall survival estimate was 47% [95% CI, 24-67%]. Conclusions: A dose of 2.3 mg of ixazomib in combination with induction chemotherapy among older patients with ALL was well-tolerated and associated with a promising rate of complete remission. Disclosures Amrein: Takeda: Research Funding; AstraZeneca: Consultancy, Research Funding; Amgen: Research Funding. Brunner:Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Research Funding; AstraZeneca: Research Funding; Forty-Seven Inc: Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Novartis: Research Funding. Hobbs:Novartis: Honoraria; Celgene/BMS: Honoraria; Jazz: Honoraria; Constellation: Honoraria, Research Funding; Incyte: Research Funding; Merck: Research Funding; Bayer: Research Funding. Neuberg:Celgene: Research Funding; Pharmacyclics: Research Funding; Madrigak Pharmaceuticals: Current equity holder in publicly-traded company. Fathi:Takeda: Consultancy, Research Funding; Agios: Consultancy, Research Funding; PTC Therapeutics: Consultancy; Amphivena: Consultancy; Astellas: Consultancy; Daiichi Sankyo: Consultancy; Novartis: Consultancy; Newlink Genetics: Consultancy; Pfizer: Consultancy; Blueprint: Consultancy; Trillium: Consultancy; Kura Oncology: Consultancy; Forty Seven: Consultancy; Jazz: Consultancy; Boston Biomedical: Consultancy; BMS/Celgene: Consultancy, Research Funding; Kite: Consultancy; Trovagene: Consultancy; Amgen: Consultancy; Seattle Genetics: Consultancy, Research Funding; Abbvie: Consultancy. OffLabel Disclosure: MLN 9708, ixazomib is FDA approved for multiple myeloma. In this trial it is used to treat acute lymphoblastic leukemia.

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.

Trial in Progress: A Phase I Trial of BTX-A51 in Patients with Relapsed or Refractory AML or High-Risk MDS

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 18-19
Author(s):  
Brian J. Ball ◽  
Anthony S. Stein ◽  
Gautam Borthakur ◽  
Crystal Murray ◽  
Karin Kook ◽  
...  
Keyword(s):  
Overall Survival ◽  
High Risk ◽  
Complete Remission ◽  
Board Of Directors ◽  
Research Funding ◽  
Phase 1 ◽  
Cancer Center ◽  
Phase 1 Study ◽  
Advisory Committees ◽  
Expansion Phase

Background: For patients with relapsed or refractory (R/R) acute myeloid leukemia (AML) or high-risk myelodysplastic syndrome (MDS), low response rates and poor overall survival remain unmet clinical needs. AML cells evade apoptosis through overexpression of antiapoptotic genes and inactivation of p53. The antiapoptotic gene Mcl1 is overexpressed in AML cell lines resistant to venetoclax. Similarly, the sensitivity of AML patients' samples to venetoclax inversely correlates with the presence of a TP53 mutation or low expression of p53. In AML, p53 inactivation more commonly results from overexpression of its negative regulators, Mdmx and Mdm2. BTX-A51 is a novel, oral, direct inhibitor of Casein kinase 1α (CK1α), cyclin dependent kinase 7 (CDK7), and CDK9. CK1α phosphorylates Mdmx and Mdm2 leading to enhanced binding and degradation of p53. CDK7 and CDK9 phosphorylate RNA polymerase II (Pol II) to enable transcriptional initiation and elongation, particularly at large clusters of transcriptional enhancers termed super-enhancers (SE). Preclinical studies have demonstrated that BTX-A51 robustly increased p53 protein levels via CK1a inhibition and Mdm2 downregulation while preferentially decreasing SE transcription of key oncogenes such as Myc andMcl1, enabling selective apoptosis of leukemia cells. The combination of CK1α, CDK7, and CDK9 inhibition was synergistic and prolonged survival in multiple genetic and patient-derived xenograft AML models. Study Design and Methods: This is an open-label, multi-center, first-in-human Phase 1 study evaluating the safety of BTX-A51 in patients with R/R AML or high-risk MDS. The trial will be performed in two phases, a dose escalation (phase 1a) and dose expansion (phase 1b). Phase 1a utilizes a hybrid accelerated titration with single patient cohorts and a Bayesian optimal interval (BOIN) design to assess 8 potential dosing cohorts. The maximum tolerated dose (MTD) will be the dose for which the isotonic estimate of the toxicity rate is closest to the target toxicity rate of 0.3. Up to a maximum of 35 patients will be enrolled in the dose escalation phase of the study at Memorial Sloan Kettering Cancer Center, MD Anderson Cancer Center, and City of Hope Cancer Center. Following determination of the MTD, 15 patients will be enrolled in the dose expansion phase for further evaluation of dose-limiting toxicities (DLTs) and for preliminary evidence of efficacy. BTX-A51 will be dosed 3 weeks on drug, followed by 1 week off drug over a 28-day cycle. For the first cycle, patients will receive tumor lysis syndrome prophylaxis with allopurinol and intravenous fluids and be closely monitored. Key inclusion criteria are age ³ 18 years, R/R AML or R/R high-risk MDS, Eastern Cooperative Oncology Group (ECOG) £ 2 and life expectancy of ³ 6 weeks, and adequate kidney and liver function. Key exclusion criteria are receipt of cancer chemotherapy (other than hydroxyurea) within 2 weeks prior to the start of study drug, transplantation within 3 months prior to screening, active graft-versus-host disease requiring systemic immunosuppressive medications, and a white blood cell count > 20 × 109/L. The primary objective for the Phase 1 study is to determine the MTD and recommended Phase 2 dose (RP2D) of BTX-A51. Secondary objectives include evaluating overall response (complete remission, complete remission with incomplete blood count recovery, and partial remission) according to the European LeukemiaNet (ELN) 2017 criteria (Döhner et al. Blood. 2017), survival (overall survival and event-free survival) and pharmacokinetics. Correlative objectives include determining the changes in SEs and SE-driven expression of antiapoptotic genes by chromatin immunoprecipitation and RNA-sequencing. Recruitment is ongoing and this trial is registered on clinicaltrials.gov: NCT04243785 Disclosures Stein: Amgen: Consultancy, Speakers Bureau; Stemline: Consultancy, Speakers Bureau. Borthakur:BioLine Rx: Consultancy; Argenx: Consultancy; PTC Therapeutics: Consultancy; FTC Therapeutics: Consultancy; BioTherix: Consultancy; Curio Science LLC: Consultancy; Xbiotech USA: Research Funding; Oncoceutics: Research Funding; Polaris: Research Funding; PTC Therapeutics: Research Funding; Cyclacel: Research Funding; GSK: Research Funding; Jannsen: Research Funding; Abbvie: Research Funding; Novartis: Research Funding; Incyte: Research Funding; BioLine Rx: Research Funding; BMS: Research Funding; AstraZeneca: Research Funding; Nkarta Therapeutics: Consultancy; Treadwell Therapeutics: Consultancy. Murray:Salamandra: Current Employment. Kook:Salamandra: Current Employment. Chan:BioTheryx: Current Employment. Stein:Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Syros: Membership on an entity's Board of Directors or advisory committees; Syndax: Consultancy, Research Funding; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bayer: Research Funding; Biotheryx: Consultancy; Agios Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy; PTC Therapeutics: Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Consultancy; Amgen: Consultancy; Celgene Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astellas Pharmaceuticals: 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.

Interim Analysis of Lenalidomide Consolidation on Minimal Residual Disease in Patients with Chronic Lymphocytic Leukemia Following Initial FCR Chemotherapy - CLL6 Residuum Study of the Australian Leukaemia and Lymphoma Group (ALLG) and the French Innovative Leukemia Organization (FILO)

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 2053-2053 ◽  
Author(s):  
David Gottlieb ◽  
Thérèse Aurran ◽  
Constantine S. Tam ◽  
Mary Sartor ◽  
Rémi Letestu ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Overall Survival ◽  
Board Of Directors ◽  
Research Funding ◽  
Residual Disease ◽  
Consolidation Therapy ◽  
Front Line ◽  
Advisory Committees ◽  
To Receive ◽  
Minimal Residual

Abstract Introduction Patients with residual disease following initial treatment of chronic lymphocyticleukemia(CLL) withfludarabine, cyclophosphamide and rituximab (FCR) chemotherapy have reduced progression free (PFS) and overall survival (OS). The CLL6 RESIDUUM trial is a joint trial of the Australasian Leukaemia and Lymphoma Group (ALLG) and the French CLL branch of the French InnovativeLeukemiaOrganization (FILO) thatanalyzesthe role oflenalidomide(LEN) as consolidation therapy in patients following front-line treatment for CLL who do not enter minimal residual disease (MRD) negative complete remission. Methods CLL patients with CIRS score <6 requiring treatment according to iwCLLcriteria receive 6 cycles of FCR. Following completion of treatment, those with clinical, radiological and/or multiparameterflow cytometry (MFC) evidence of residual CLL in blood or bone marrow are randomized 1:1 to receive 2 years of maintenance treatment with LEN 10 mg daily or observation (OBS). Patients are reviewed for evidence of clinical progression, and peripheral blood and bone marrow are sampled regularly for evidence of MRD. CT scans are performed until resolution of lymphadenopathy and splenomegaly. Flow analysis for MRD is performed at two central laboratories using ERIC accredited methodology to achieve a sensitivity of 10-4. The primary end point of the study is time to progression or death. Results As of end of July 2016, data from 79 patients randomized on the study were analyzedfor the effects of consolidation treatment on blood and marrow MRD. Median duration from randomization was 488 days. There were 63 males and 16 females. Median age was 62 years (range 29 to 81). 37 patients were randomized to receive LEN, 42 to OBS .On the LEN arm 13, 3 and 21 patientsvs 12, 9 and 21 on the OBS arm were in CR, nodular PR and PR respectively at the time of randomization. There were 26 serious adverse events (SAEs) reported in 22 patients. 12 SAEs in 11 patients were attributed to LEN including pneumonia/chest infection (n=4), pulmonary infiltrate (1), prostatitis (1) second primary malignancy (SPM) (1), vomiting (1), neutropenia (1), tumorflare (1), acute kidney injury (1) and anal warts (1). There were 5 SAEs in the OBS arm comprising SPM (2), neutropenia (1), gout (1) and GuillainBarre syndrome(1). Peripheral blood samples were analyzedprior to consolidation and at 3, 6 and 12 months and every 6 months thereafter. MRD levels during consolidation were compared with pre-consolidation levels and categorized as increasing, decreasing, stable detectable or stable undetectable (Fig 1). MRD increased over the period of observation in 38% of patient on the LEN arm and in 62% of patients on the OBS arm (p = 0.032, Χ2). 10 patients (27%) in the LEN arm and 2 patients (5%) in the control arm had decreasing levels of MRD in the blood (p = 0.006, Χ2). There was no difference between consolidation treatments in the percentage of patients with stable blood MRD measurements, whether in the detectable or the undetectable range. The effect of LEN was most apparent in patients in PR at randomization where 5 patients (24%) taking LEN had increasing MRD in the blood compared to 15 patients (71%) on the OBS arm (p = 0.002, Χ2). Bone marrow MRD levels were assessed prior to consolidation and after 12 months in 9 patients in each arm of the study (LEN arm 2 CR, 1 nPR, 6 PR; OBS arm 4 CR, 1 nPR, 4 PR at randomization). Eight patients in the LEN arm and 2 patients in the OBS arm were observed to have a reduction in marrow MRD. There was a significant reduction between the 2 time points in the LEN arm (p=0.022 paired Wilcoxon test) but not in the OBS arm. Four of 9 patients in the LEN arm and 1 patient in the OBS arm achieved marrow MRD values below 10-4 after 1 year on trial. Conclusion LEN consolidation therapy for residual disease after FCR front-line therapy for CLL is associated with improved control of MRD in both blood and bone marrow. A large group of recently randomized patients will provide more data to determine whether these encouraging results will translate into improved progression free and overall survival. Figure 1 Percentage of patients on LEN and OBS arms with increasing, decreasing, stable detectable or stable undetectable MRD. Figure 1. Percentage of patients on LEN and OBS arms with increasing, decreasing, stable detectable or stable undetectable MRD. Disclosures Gottlieb: Indee: Membership on an entity's Board of Directors or advisory committees; Celgene: Research Funding; Abbvie: Membership on an entity's Board of Directors or advisory committees. Aurran:Janssen: Honoraria. Tam:Gilead: Honoraria; Roche: Honoraria; Abbvie: Honoraria; Janssen: Honoraria. Letestu:Roche: Honoraria; Alexion: Honoraria. Levy:Roche: Honoraria; Gilead: Honoraria; Abbive: Honoraria; Janssen: Honoraria. Leblond:Roche: Honoraria; Gilead: Honoraria; Janssen: Honoraria; Abbvie: Honoraria. Mulligan:GSK: Consultancy, Honoraria; Gilead: Consultancy, Honoraria, Speakers Bureau; Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau; AbbVie: Consultancy, Honoraria, Research Funding, Speakers Bureau; Roche: Consultancy, Honoraria, Research Funding, Speakers Bureau. Cymbalista:Abbvie: Honoraria; Roche: Honoraria; Janssen: Consultancy, Research Funding; Gilead: Consultancy, Honoraria.

Importance of Complete Remission on Predicting Overall Survival in Patients with Lower-Risk Myelodysplastic Syndromes (MDS)

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 4332-4332
Author(s):  
Aziz Nazha ◽  
Rami S. Komrokji ◽  
John Barnard ◽  
Najla H Al Ali ◽  
Gail J. Roboz ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Overall Survival ◽  
Complete Remission ◽  
Board Of Directors ◽  
Lower Risk ◽  
Research Funding ◽  
Advisory Committees ◽  
Best Response ◽  
Bone Marrow Blasts

Abstract Background Lower-risk (LR) MDS (Low/Int-1 per International Prognostic Scoring System (IPSS)) are a heterogeneous group of disorders characterized mainly by refractory anemia and transfusion dependency. As survival of this patient (pt) population is measured in years. Goals of therapy focus on decreasing blood transfusions, improving quality of life, while minimizing treatment toxicities. While achieving complete remission (CR) in higher-risk MDS correlates with improved overall survival (OS), its relationship to OS in LR MDS is not well defined. We evaluated the impact of achieving CR on OS in LR MDS and defined the clinical characteristics that may predict for this response in this pt population. Method Included pts were diagnosed with MDS (per 2008 WHO criteria) and had LR disease with clinical and pathologic data collected from MDS Clinical Research Consortium institutions. Only pts with bone marrow blasts of 5-9% who would thus qualify both as having LR MDS and for being eligible to assess CR were included. Responses (including CR, PR, HI, stable disease and progressive disease) were defined per International Working Group 2006 criteria. OS was calculated from the time of achievement of best response to time of death or last follow-up. Cox proportional hazard analysis that included all clinical variables and treatment characteristics was used to identify independent prognostic factors. Results Of 1470 pts included in the database, 999 identified with LR disease, and 174 had bone marrow blasts of 5-9%. The median age was 60 years (range, 22-87), and 37% were female. Median neutrophil count was 1.25 X 109\L (range, .10-51.0), hemoglobin was 9.8 g/dl, platelets were 109 k/ml (range, 18-562), and bone marrow blasts were 6% (range, 5-9%). Best responses to therapy included: 26 pts (15%) with CR, 10 pts (6%) with PR, and 13 pts (7%) with HI. Among pts who achieved CR/PR/HI, 27 received HMA (25 with azacidtine +/- combination and 2 with single agent decitabine), 16 intensive chemotherapy, 2 lenalidomide, and 4 received other therapies. With a median follow up from diagnosis of 31.2 months, the median time from diagnosis to best response was 11.9 months (range, .69-81.0) and was similar in pts who achieved CR compared to PR/HI (11.5 vs. 12.4 months, respectively, p = .74). The median OS from time of CR/PR/HI for the entire cohort was 21.3 months. The median OS for pts who achieved a CR was longer compared to pts with PR/HI (46.5 vs. 18.5 months, respectively, p = .03). In multivariate analyses that included clinical variables and treatment history, achieving CR remained an independent prognostic factor for longer OS (HR .32, p = .03) but no individual demographic, clinical or treatment variables were predictive of CR. Conclusions Similar to pts with higher-risk MDS, LR MDS pts who achieve CR to therapy have improved OS compared to those with PR or HI. CR is thus an important endpoint in LR MDS, though is difficult to predict. As OS is measured in years in LR MDS, CR may be used as a surrogate endpoint for OS in clinical trials in this pt population. Disclosures Komrokji: Novartis: Consultancy, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding. Roboz:Cellectis: Research Funding; Agios, Amgen, Amphivena, Astex, AstraZeneca, Boehringer Ingelheim, Celator, Celgene, Genoptix, Janssen, Juno, MEI Pharma, MedImmune, Novartis, Onconova, Pfizer, Roche/Genentech, Sunesis, Teva: Consultancy. Sekeres:Millenium/Takeda: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees.

scholarly journals First Line Treatment with Venetoclax and Ibrutinib Induction Followed By Obinutuzumab Intensification Exclusively in CLL/SLL Patients Not in Complete Remission and/or with Detectable Bone Marrow Minimal Residual Disease (NEXT STEP trial)

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 1753-1753
Author(s):  
Sabina Kersting ◽  
Mark-David Levin ◽  
Carsten Utoft Niemann ◽  
Yvette Norden ◽  
Arnon P. Kater
Keyword(s):  
Bone Marrow ◽  
Complete Remission ◽  
Board Of Directors ◽  
Research Funding ◽  
Residual Disease ◽  
Treatment Intensification ◽  
Advisory Committees ◽  
Educational Grant ◽  
Pet Ct ◽  
Travel Grant

Background Keeping the balance between long-term efficacy and toxicity of treatment in patients with chronic lymphocytic leukemia (CLL) is of utmost importance. Ibrutinib impacts BCR/adhesion signaling resulting in efficient lymph node (LN) responses and prolonged disease control despite a lack of deep remissions. Venetoclax directly kills CLL cells by antagonizing the pro-survival Bcl-2 protein leading to deep remissions (undetectable minimal residual disease (uMRD)) in the blood and bone marrow (BM) but incomplete LN clearance. Synergy between these agents is shown in our relapsed/refractory CLL HOVON 141 study with complete remission (CR) rates of 69% and blood uMRD rate of 55% after 12 full dose combination cycles with acceptable toxicity (abstract submitted; Niemann et al.). Extrapolating these data, we hypothesize that a fixed duration of a combination of venetoclax and ibrutinib will result in a substantial proportion of patients in CR and with undetectable MRD, who will have very good outcome after treatment cessation. Yet, not all patients will achieve this level of disease clearance and therefore, intensification approaches are of interest. A prior study has shown that addition of the CD20 antibody obinutuzumab lead to considerably higher uMRD rates when added after 1 year of prior ibrutinib monotherapy than when given simultaneously (BM uMRD rate of 50% versus 6% respectively; Hillmen et al. 2018). This suggests an opportunity for treatment intensification in the subset of patients who do not respond optimally to initial I+V combination treatment. In CLL, 3 compartments exist with putative differential sensitivity for targeted agents. Although the predictive role of residual leukemia cells in blood and bone marrow, as measured by MRD is increasingly appreciated, the biological and prognostic relevance of residual LN, which is often observed in venetoclax treated patients, is uncertain. 18F-fluorodeoxyglucose (FDG) PET-CT is widely used for response evaluation of lymphoma, but has not proven its value in CLL. (Conte et al. 2014) However, radiomics with computational processing of the PET/CT may provide biologic and clinical relevant information on the characteristics of residual LN and warrants exploration for guidance of treatment intensification as an MRD proxy for spleen and LN. (Lee et al. 2018) Objectives To evaluate the efficacy of 6 cycles ibrutinib+obinutuzumab in converting patients who are not in CR or who have detectable MRD after 12 cycles of ibrutinib+venetoclax to a CR with uMRD (BM). Moreover, PET/CT with radiomics is employed to assess clearance of CLL from LN and spleen. Primary endpoint CR with uMRD (BM) 3 months after end of intensification with ibrutinib+obinutuzumab in patients who are not in CR and/or uMRD on combination ibrutinib/venetoclax. Design The trial is designed as a single arm phase 2 study for treatment naïve CLL patients requiring treatment according to IWCLL criteria. 85 patients will be included. Study Treatment Patients will receive 3 lead-in cycles of ibrutinib 420 mg/day. Here-after, patients will continue with 13 induction cycles (including one bridging cycle) combining ibrutinib 420 mg/day and venetoclax 400 mg/day including a ramp up of 5-weeks starting in cycle 4 day 1. Patients with measurable disease at evaluation after 15 cycles will continue with 6 intensification cycles of ibrutinib/obinutuzumab. day 1, 2, 8, 15 for the first cycle and with obinutuzumab day 1 for the following 5 cycles in combination with ibrutinib (Figure 1). Major inclusion criteria Treatment naïve CLL or SLL patients requiring treatment by iwCLL WHO performance status 0-3 Adequate BM function defined as: Hb > 8 g/dLNeutrophil count ≥75 x 109/LPlatelet count ≥ 50,000 /μLcreatinine clearance ≥ 30ml/min Major exclusion criteria Active fungal, bacterial, and/or viral infection that requires systemic therapy; Patients requiring treatment with strong cytochrome P450 (CYP) 3A inhibitor or with vitamin K antagonists Statistical methods For the primary endpoint analyses, all patients registered and eligible for intensification treatment with ibrutinib+obinutuzumab (not in complete remission and/or uMRD) will be included. Perspective This trial helps in personalizing CLL treatment by selecting sequential time limited therapies guided by MRD. Figure 1 Disclosures Levin: Abbvie: Membership on an entity's Board of Directors or advisory committees, Other: Educational Grant; Roche: Membership on an entity's Board of Directors or advisory committees, Other: Educational Grant; Janssen: Membership on an entity's Board of Directors or advisory committees, Other: Educational Grant; Amgen: Membership on an entity's Board of Directors or advisory committees, Other: Educational grant ; Takeda: Membership on an entity's Board of Directors or advisory committees, Other: Educational grant . Niemann:Janssen: Consultancy, Other: Travel grant, Research Funding; Roche: Other: Travel grant; CSL Behring: Consultancy; Acerta: Consultancy, Research Funding; Sunesis: Consultancy; Astra Zeneca: Consultancy, Research Funding; Novo Nordisk Foundation: Research Funding; Gilead: Other: Travel grant; Abbvie: Consultancy, Other: Travel grant, Research Funding. Kater:Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche/Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Research Funding; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Acerta: Membership on an entity's Board of Directors or advisory committees, Research Funding. OffLabel Disclosure: Combination of ibrutinib and venetoclax Combination of ibrutinib and obinutuzumab

scholarly journals A Phase II Study of CPX-351 As a Novel Therapeutic Approach for Patients with Myelodysplastic Syndromes (MDS) after Hypomethylating Agent Failure

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 1-1
Author(s):  
Aziz Nazha ◽  
Sudipto Mukherjee ◽  
Anjali S Advani ◽  
Madeline Waldron ◽  
Caitlin Siebenaller ◽  
...  
Keyword(s):  
Overall Survival ◽  
Complete Remission ◽  
Board Of Directors ◽  
Phase Ii ◽  
Research Funding ◽  
Phase Ii Study ◽  
Steering Committee ◽  
Advisory Board ◽  
Consolidation Therapy ◽  
Advisory Committees

Treatment options are limited for patients (pts) diagnosed with MDS at the time of hypomethylating agent (HMA) failure. One goal is to introduce another line of therapy to reduce tumor burden and enable patients to undergo hematopoietic stem cell transplant (HSCT), which may prolong survival for a subset. CPX-351, has shown better overall response rates and improved overall survival in patients with acute myeloid leukemia with underlying MDS changes compared to 7+3, suggesting that CPX-351 can be used in an MDS patient population. We hypothesized that treating MDS pts, who were failed by HMAs or were intolerant with CPX-351 would overcome HMA resistance. This is a phase II study of single agent CPX-351 administered at the standard FDA approved dose of 44 mg/m2 (daunorubicin 44 mg/m2 and cytarabine 100 mg/m2) intravenously on days 1, 3, 5 of the induction cycle. If patients achieve complete remission (CR), marrow CR, partial remission or hematologic improvement per 2006 IWG criteria they will be eligible to continue on to consolidation therapy, which consists of CPX-351 at a dose of 15.4 mg/m2 (daunorubicin 15.4 mg/m2 and cytarabine 35 mg/m2) every 28 days. Pts can receive up to 4 cycles of consolidation therapy in the absence of toxicity. The primary objective of the trial is to evaluate the efficacy of CPX-351 as measured by overall response rate (ORR) by IWG 2006 criteria. Secondary objectives include: ,1) determine the time to response (TTR), 2) evaluate the duration of response (DOR), 3) evaluate the event-free survival and the overall survival probability during trial period. Pts are risk stratified into lower vs higher-risk prior to enrollment using the Post-HMA model (Nazha A, et al. Hematologica 2016). Eligibility includes: pts &gt;18 years with primary or secondary resistance to HMA, ECOG performance status &lt; 2 and adequate organ function. Pts are excluded if they have uncontrolled infection or active malignancy. A total of 18 pts will be enrolled to each arm (lower and higher risk). To date, three pts were enrolled. One with MDS refractory to HMA who achieved complete remission and proceeded with 4 cycles of consolidation. The pt remained in remission 6+ months after the completion of consolidation. Another patient achieved a marrow CR but had a fungal pneumonia and then was taken off the trial (patient choice for going to hospice). The third patient had MDS/MPN, completed induction and achieved stable disease with improvement in platelets and neutrophils. All patients were lower-risk per the stratification model. No unexpected toxicity was observed. In conclusion, preliminarily CPX-351 is effective in MDS patients after HMA failure who are eligible to receive intensive chemotherapy. The treatment was well tolerated and toxicities were similar to what was observed in pivotal CPX-351 trials. The trial is ongoing and the results will be updated in the meeting. Disclosures Nazha: MEI: Other: Data monitoring Committee; Novartis: Speakers Bureau; Incyte: Speakers Bureau; Jazz: Research Funding. Mukherjee:Celgene/Acceleron: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; EUSA Pharma: Consultancy; Partnership for Health Analytic Research, LLC (PHAR, LLC): Honoraria; Bristol Myers Squib: Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Aplastic Anemia and MDS International Foundation: Honoraria. Advani:Abbvie: Research Funding; Macrogenics: Research Funding; Glycomimetics: Consultancy, Other: Steering committee/ honoraria, Research Funding; Immunogen: Research Funding; Seattle Genetics: Other: Advisory board/ honoraria, Research Funding; Amgen: Consultancy, Other: steering committee/ honoraria, Research Funding; Kite: Other: Advisory board/ honoraria; Pfizer: Honoraria, Research Funding; Novartis: Consultancy, Other: advisory board; OBI: Research Funding; Takeda: Research Funding. Carraway:Jazz: Consultancy, Speakers Bureau; BMS: Consultancy, Other: Research support, Speakers Bureau; Stemline: Consultancy, Speakers Bureau; Takeda: Other: Independent Advisory Committe (IRC); Novartis: Consultancy, Speakers Bureau; Abbvie: Other: Independent Advisory Committe (IRC); ASTEX: Other: Independent Advisory Committe (IRC). Gerds:AstraZeneca/MedImmune: Consultancy; Incyte Corporation: Consultancy, Research Funding; Roche/Genentech: Research Funding; CTI Biopharma: Consultancy, Research Funding; Imago Biosciences: Research Funding; Sierra Oncology: Research Funding; Celgene: Consultancy, Research Funding; Gilead Sciences: Research Funding; Apexx Oncology: Consultancy; Pfizer: Research Funding. Patel:Alexion: Other: educational speaker. Sekeres:Takeda/Millenium: Consultancy; Pfizer: Consultancy; BMS: Consultancy. OffLabel Disclosure: CPX-351 in MDS

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.

Vemurafenib As First Treatment of Hairy Cell Leukemia

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 5482-5482
Author(s):  
Gregory Cheng ◽  
Gym Cheng ◽  
Natalie Pui Ha Chan ◽  
Chris Wong ◽  
Raymond S Wong
Keyword(s):  
Complete Remission ◽  
Board Of Directors ◽  
Hairy Cell Leukemia ◽  
Research Funding ◽  
Residual Disease ◽  
Lymphoid Cells ◽  
Hairy Cell ◽  
Cell Leukemia ◽  
Advisory Committees ◽  
Braf V600 Mutation

Abstract 44 years old lady presented with fever and pancytopenia in March 2014.CXR showed bilateral pneumonia. Hb 7.5xg/dl, plt 42x x109/l, wbc 1.2 x19neutrophils22%, lymphocytes75%.Circulating lymphocytes with hairy cytoplasmicprojections and indented nuclei were noted. Flow cytometry showed these abnormal lymphoid cells were CD19+ve, CD5-ve, CD 23-ve, FMC7+ve, CD25+ve, CD11c+ve and CD103+ve.Bone marrow biopsy revealed a hypercellular marrow with dense infiltration of lymphoid cells of the same immunophenotype. Braf V600 mutation was detected. Cladribine or pentostatin was out of stock and import of these drugs would take at least 2 months. In view of the severe pancytopenia and on -going infection, various treatment options were discussed with, the patient .Patient decided to start on vemurafenib 960mg twice daily while awaiting cladribine. After 8weeks of treatment, the peripheral blood counts were normalized. Hb 12.2g/dl, plt 153x x109/l, wbc 3.1x109/l, neutrophils 53%,lymphocytes 40%. Braf V600 mutation was no longer detected. Vemurafenib was well tolerated and the patient received treatment mainly as outpatient. Vemurafenib was discontinued after 8 weeks and the patient then received a 5-day course of cladribine. She remained in complete remission Discussion Vemurafenib had shown to be safe and effected in hairy cell leukemia patients who were refractory to or who relapsed after purine analogs.1,2 Still to be determined are the correct vemurafenib dosing strategy, the best timing , duration and scheduling of vemurafenib. Due to unusual circumstances, our patient received 8 weeks of vemurafenib as first line therapy. The patient achieved a complete remission with minimal residual disease. Follow data is needed to see how long the patient remains in remission 1. N Engl J Med 2014; 370:286-288 2. 19th Congress of the European Hematology Association (EHA): Abstract S696. Disclosures Off Label Use: Vemurafenib as first treatment of Hairy Cell Leukemia. Wong:johnson &johnson: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; GlaxoSmithKline: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Biogen-Idec: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Bayer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer, MSD, Roche, BMS, Baxter, Amgen, Alexion: Research Funding.

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