Pharmacodynamic Monitoring of the Efficacy of a Targeted Therapy with Midostaurin By Plasma Inhibitor Activity (PIA) Analysis in FLT3 -ITD Positive AML Patients within the AMLSG 16-10 Trial: A Study of the AML Study Group (AMLSG)

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 2585-2585 ◽  
Author(s):  
Frauke Theis ◽  
Peter Paschka ◽  
Daniela Weber ◽  
Verena I. Gaidzik ◽  
Lars Bullinger ◽  
...  
Keyword(s):  
Clinical Outcome ◽  
Maintenance Therapy ◽  
Board Of Directors ◽  
Induction Therapy ◽  
Research Funding ◽  
Intensive Chemotherapy ◽  
Consolidation Therapy ◽  
Inhibitor Activity ◽  
Advisory Committees ◽  
Time Points

Abstract Background: Activating mutations in receptor tyrosine kinases like FLT3 (FLT3mut) lead to an aberrant signal transduction thereby causing an increased proliferation of hematopoietic cells. Internal tandem duplications (FLT3-ITD) or mutations in the tyrosine kinase domain (FLT3-TKD) occur in about 25% of younger adult patients (pts) with acute myeloid leukemia (AML), with FLT3 -ITD being associated with an unfavourable outcome. FLT3mut present an excellent target for small molecule tyrosine kinase inhibitors (TKI). The multi-targeted kinase inhibitor midostaurin (PKC412) is currently under investigation as a FLT3-inhibitor in combination with intensive chemotherapy. Monitoring of the efficacy of such a targeted therapy and correlation of the results with clinical outcome will be of major importance. The plasma inhibitor activity (PIA) assay allows the visualization of the level of dephosphorylation of the target under TKI therapy. Preliminary data suggest a correlation between the grade of dephosphorylation, as a marker for the activity of the TKI, and clinical outcome. Aims: To individually measure the level of FLT3 dephosphorylation by PIA analysis in a large cohort of FLT3-ITD AML pts treated within our AMLSG16-10 trial (NCT: NCT01477606) which combines midostaurin with intensive chemotherapy, and to correlate the results with clinical outcome. Methods: Plasma samples from pts (age 18-70 years) with newly diagnosed FLT3-ITD AML were obtained at different time points for PIA analysis. All pts were enrolled on the ongoing AMLSG 16-10 trial applying intensive therapy in combination with midostaurin (50mg twice a day). For consolidation therapy, pts proceeded to allogeneic hematopoietic stem cell transplantation (alloHSCT) as first priority; pts not eligible for alloHSCT were intended to receive 3 cycles of age-adapted high-dose cytarabine (HiDAC) in combination with midostaurin from day 6 onwards. In all pts one year of maintenance therapy with midostaurin was intended. PIA analyses were performed at defined time points (day 15 of induction, each consolidation cycle, at the end of each treatment cycle, every 3 months during maintenance therapy) as previously described (Levis MJ, et al. Blood 2006; 108:3477-83). Results: So far, PIA analyses were performed in 63 pts (median age, 51.6 years; range, 20-70 years) during (n=63) and after (n=73) first and second induction cycle, during (n=40) and after (n=53) consolidation therapy with HiDAC as well as during maintenance therapy (n=82). During and after induction therapy median levels of phosphorylated FLT3 (p-FLT3) were 46.6% (4.5-100%, <20% in 7.9%) and 39.4% (0.3-100%, <20% in 20.5%), respectively. Co-medication with azoles had no impact on p-FLT3 levels. In pts with a FLT3-ITD mutant to wildtype ratio above our recently defined cut-off value of 0.5, levels of p-FLT3 <20% were associated with a complete remission (CR)-rate of 100%, whereas in those pts with p-FLT3 levels ≥20%, 4 out of 22 pts (18%) had resistant disease. In contrast, response in pts with a mutant to wildtype ratio below 0.5 was independent of the p-FLT3 level. During and at the end of consolidation cycles as well as during maintenance therapy p-FLT3 levels in pts treated with midostaurin were 52% (14.8-100%, <20% in 5%), 63% (7.6-100%, <20% in 7.4%) and 60.2% (11.5-100%, <20% in 3.7%), respectively. In pts concomitantly treated with azoles levels of p-FLT3 were lower without reaching significance. 39 of 63 pts received alloHSCT in first CR; those pts with p-FLT3 levels <20% after induction therapy had an in trend better survival, whereas no impact of phosphorylation levels was evident in pts receiving chemotherapy alone. Conclusion: In our study of FLT3-ITD AML pts treated with midostaurin in combination with intensive chemotherapy we could show that the lowest levels of p-FLT3 were reached during and after induction therapy. In pts with a FLT3-ITD mutant to wildtype ratio >0.5, levels of p-FLT3 <20% during and after induction therapy were associated with a high CR-rate. When receiving alloHSCT these pts had an in trend better survival compared to those with p-FLT3 levels >20%. An update of the data will be presented at the meeting. Disclosures Salwender: Celgene: Honoraria; Janssen Cilag: Honoraria; Bristol Meyer Sqibb: Honoraria; Amgen: Honoraria; Novartis: Honoraria. Horst:Amgen: Honoraria, Research Funding; Pfizer: Research Funding; Ingleheim: Research Funding; Boehringer: Research Funding; MSD: Research Funding; Gilead: Honoraria, Research Funding. Schlenk:Novartis: Honoraria, Research Funding; Boehringer-Ingelheim: Honoraria; Janssen: Membership on an entity's Board of Directors or advisory committees; Daiichi Sankyo: Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Research Funding; Teva: Honoraria, Research Funding; Arog: Honoraria, Research Funding.

scholarly journals Increased Idarubicin Dosage during Consolidation Therapy for Adult Acute Myeloid Leukemia Improves Leukemia-Free Survival

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 338-338
Author(s):  
Bradstock Kenneth ◽  
Emma Link ◽  
Juliana Di Iulio ◽  
Jeff Szer ◽  
Paula Marlton ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Complete Remission ◽  
Board Of Directors ◽  
Induction Therapy ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
Consolidation Therapy ◽  
Advisory Committees ◽  
Free Survival ◽  
Acute Myeloid

Abstract Background: Anthracylines are one of the major classes of drugs active against acute myeloid leukemia (AML). Increased doses of daunorubicin during induction therapy for AML have been shown to improve remission rates and survival. The ALLG used idarubicin in induction therapy at a dose of 9 mg/m2 x 3 days (total dose 27 mg/m2) in combination with high-dose cytarabine and etoposide (Blood 2005, 105:481), but showed that a total idarubicin dose of 36 mg/m2 was too toxic in this context (Leukemia 2001, 15:1331). In order to further improve outcomes in adult AML by anthracycline dose escalation, we conducted a phase 3 trial comparing standard to an increased idarubicin dose during consolidation therapy. Methods: Patients achieving complete remission after 1 or 2 cycles of intensive induction therapy (idarubicin 9 mg/m2 daily x3, cytarabine 3 g/m2 twice daily on days 1,3,5 and 7, and etoposide 75 mg/m2 daily x7; ICE protocol) were randomized to receive 2 cycles of consolidation therapy with cytarabine 100 mg/m2 per day for 5 days, etoposide 75 mg/m2 for 5 days, and idarubicin 9mg/m2 daily for either 2 or 3 days (standard and intensive arms respectively). No further protocol therapy was given. The primary endpoint was leukemia-free survival from randomization to consolidation therapy (LFS) with overall survival (OS) as secondary endpoint. Results: A total of 422 patients with AML (excluding cases with CBF rearrangements or APL) aged 16 to 60 years were enrolled between 2003-10, with 345 (82%) achieving complete remission, and 293 being randomized to standard (n=146) or intensive (n=147) consolidation arms. The median age was 45 years in both arms (range 16- 60), and both groups were balanced for intermediate versus unfavorable karyotypes and for frequency of mutations involving FLT3-ITD and NPM1 genes. Of the randomized patients, 120 in the standard arm (82%) and 95 in the intensive arm (65%) received the second consolidation cycle (p<0.001). The median total dose of idarubicin received in the 2 consolidation courses was 36 mg/m2 (range 17-45), or 99% (47-125%) of the protocol dose in the standard arm, versus 53 mg/m2 (18-73), or 98% (33-136%) of the protocol dose in the intensive arm. The durations of grades 3-4 neutropenia and thrombocytopenia were significantly longer in the intensive arm, but there were no differences in grade 3 or 4 non-hematological toxicities. There were no non-relapse deaths during consolidation on the standard arm and 2 in the intensive (0% vs 1%; p =0.50). Subsequently, 41 patients in the standard arm and 37 in the intensive arm underwent elective allogeneic BMT during first remission. On intention to-treat analysis uncensored for transplant and with a median follow-up time of 5.3 years (range 0.6 - 9.9), there was improvement in LFS in the intensive arm compared with the standard arm (3 year LFS 47% (95% CI 40-56%) versus 35% (28-44%); HR 0.74 (95% CI 0.55-0.99); p=0.045) (Figure 1). The 3 year OS for the intensive arm was 61% (95% CI 54-70%) and 50% (95% CI 43-59%) for the standard arm; HR 0.75 (95% CI 0.54-1.05); p=0.092). Although adverse cytogenetics, presence of FLT3-ITD mutation, and absence of NPM1 mutation were all associated with poorer outcomes, there was no evidence of a benefit of intensive consolidation being confined to specific cytogenetic or gene mutation sub-groups. Conclusion: We conclude that in adult patients in complete remission after intensive induction chemotherapy an increased dose of idarubicin delivered during consolidation therapy results in improved LFS, without increased non-hematologic toxicity. Figure 1. Figure 1. Disclosures Szer: Ra Pharma: Honoraria, Membership on an entity's Board of Directors or advisory committees; Alexion Pharmaceuticals, Inc.: Honoraria, Membership on an entity's Board of Directors or advisory committees; Alnylam: Honoraria, Membership on an entity's Board of Directors or advisory committees. Marlton:Amgen: 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; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees. Wei:Novartis: Consultancy, Honoraria, Research Funding; Roche: Consultancy, Honoraria; CTI: Consultancy, Honoraria; Abbvie: Honoraria, Research Funding; Servier: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding. Cartwright:ROCHE: Consultancy, Membership on an entity's Board of Directors or advisory committees. Roberts:Servier: Research Funding; Janssen: Research Funding; Genentech: Research Funding; AbbVie: Research Funding. Mills:Novartis: Membership on an entity's Board of Directors or advisory committees, Other: Meeting attendance sponsorship. Gill:Janssen: Membership on an entity's Board of Directors or advisory committees. Seymour:Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Genentech: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support, Speakers Bureau; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support, Research Funding, Speakers Bureau; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees.

Analysis of Long-Term Survival in Multiple Myeloma Patients after First-Line Autologous Stem Cell Transplantation: Impact of Clinical Risk Factors and Duration of Response

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 4649-4649
Author(s):  
Nicola Lehners ◽  
Natalia Becker ◽  
Axel Benner ◽  
Maria Pritsch ◽  
Elias Karl Mai ◽  
...  
Keyword(s):  
Maintenance Therapy ◽  
Board Of Directors ◽  
Induction Therapy ◽  
Research Funding ◽  
Conditional Survival ◽  
First Line ◽  
Advisory Committees ◽  
Term Survival ◽  
Long Term Survival

Abstract Background: In the last decade, the introduction of novel agents into multiple myeloma (MM) therapy has significantly improved response rates and enabled long-term survival in a subset of patients. Yet, clinical characteristics of these long-term survivors as well as the exact impact of depth and sustainment of response still remain a matter of debate. Methods: MM patients treated at our center with high-dose melphalan supported by autologous stem cell transplantation (ASCT) as part of their first-line therapy between June 1992 and July 2014 were retrospectively analyzed. Response assessment was performed 100 days after ASCT according to EBMT criteria, since 2008 response according to IMWG criteria was also available. Overall survival (OS) and progression-free survival (PFS) were calculated from day of first ASCT. Additionally, landmark analyses regarding OS were performed at 1, 2, 3, and 5 years after ASCT. Impact of variables on PFS and OS were analyzed using multivariate Cox regression models. Furthermore, in order to assess evolution of prognosis over time, the conditional survival CS(t|s), which expresses the conditional probability of surviving further t years, was calculated as the ratio of two Kaplan-Meier estimates Ŝ(t) with . Results: 865 patients were included in this analysis, median age was 57.0 years (range 24-74), 509 were male. New agents based induction therapy was administered in 358 patients, 258 patients underwent tandem ASCT. Following ASCT, 386 patients received maintenance therapy, mainly with interferon or thalidomide. 75 patients proceeded to allogeneic transplantation and were censored at that time. Median PFS was 2.1 years, median OS was 6.4 years. Analysis of clinical influence factors revealed novel agent based induction therapy (p<0.01), maintenance therapy (p<0.01) and achievement of complete response (CR) (p=0.01) to be significantly associated with prolonged PFS, while older age (p=0.01) and thrombocytes at diagnosis < 150/nl (p=0.02) were identified as risk factors; a negative trend was seen for ISS stage 3 (p=0.067). With regard to OS, novel agent based induction therapy (p<0.01), maintenance therapy (p<0.01) and duration of time to progression (p<0.01) showed a highly significant positive impact, older age (p<0.01) and renal insufficiency at diagnosis (p=0.048) exerted a negative influence. To assess the importance of duration of response, landmark analyses were performed at 1, 2, 3, and 5 years after ASCT evaluating OS of patients with sustained CR, sustained inferior responses (non-CR), lost CR and lost non-CR at these respective time points. Remarkably, sustainment of any response showed a highly significant impact on survival at each of these time points (p<0.01) with no discernable difference between sustained CR and sustained non-CR patients. Landmark analysis at 1 year is shown in Figure 1. Administration of maintenance therapy independently improved outcome (p<0.01). Conditional survival regarding the probability to survive further three years CS(3|s) was calculated starting from the time of first ASCT stratified for the different response cohorts (see Figure 2). No significant differences could be found between patients with complete and partial response. In contrast, patients with progressive disease (PD) at day 100 after ASCT had a much lower probability of surviving the following three years after ASCT compared to patients responding to ASCT. However, those patients with PD that did survive the first year after ASCT, achieved a similar conditional three-year survival to that of patients responding initially. Conclusions: In this large retrospective study, sustainment of response after first-line ASCT was revealed as a major impact factor for OS independent of the depth of response. Administration of maintenance therapy further improved outcome, supporting the hypothesis that interventions prolonging responses achieved after ASCT are essential to reach long-term survival. Figure 1 OS of patients with sustained vs not-sustained responses at 1-year landmark analysis. Figure 1. OS of patients with sustained vs not-sustained responses at 1-year landmark analysis. Figure 2 3-year-conditional survival CS(3|s) after ASCT stratified for responses achieved. Figure 2. 3-year-conditional survival CS(3|s) after ASCT stratified for responses achieved. Figure 3 Figure 3. Disclosures Hillengass: Amgen: Consultancy, Honoraria; Celgene: Honoraria; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Honoraria; Novartis: Research Funding; Sanofi: Research Funding. Goldschmidt:Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Research Funding; Chugai: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Millennium: Membership on an entity's Board of Directors or advisory committees, Research Funding; Onyx: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees. Raab:Amgen: Consultancy, Research Funding; BMS: Consultancy; Celgene: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Consultancy, Research Funding.

Azacitidine in Combination with the mTOR Inhibitor Everolimus in Relapsed and Refractory AML

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 2599-2599 ◽  
Author(s):  
Andrew H Wei ◽  
Peter T. Tan ◽  
John Catalano ◽  
Patricia A. Walker ◽  
Anthony P. Schwarer ◽  
...  
Keyword(s):  
Clinical Outcome ◽  
Clinical Response ◽  
Board Of Directors ◽  
Research Funding ◽  
Mtor Inhibitor ◽  
Mtor Inhibitors ◽  
Intensive Chemotherapy ◽  
Flt3 Ligand ◽  
Advisory Committees ◽  
Refractory Aml

Abstract Abstract 2599 Background: FLT3-ITD is a major risk factor for relapse and poor clinical outcome in AML. Markedly elevated levels of FLT3 ligand (FLT3L) occur after intensive chemotherapy and in patients with relapsed AML. In addition, elevated circulating FLT3L in relapsed/refractory FLT3-ITD+ AML has been proposed to limit the response to FLT3 inhibitors (Sato T, et al. Blood 2011; 3286). Novel agents including hypomethylating agents and mTOR inhibitors are being investigated as salvage options in AML but their impact on circulating FLT3 ligand is unknown. Aim: To investigate the effect of azacitidine in combination with mTOR inhibitors on FLT3 ligand levels in relation to clinical outcome in relapsed and refractory AML. Methods: A phase Ib/II open label dose escalation study using azacitidine 75 mg/m2 sc daily on days 1–5 and 8–9 of each 28-day cycle with 2.5, 5 or 10 mg everolimus orally on days 5–21. Serum was sampled at baseline and on days 5, 12 19 and 25 of cycle 1 and FLT3 ligand measured quantitated by ELISA. Results: 37 patients, median age 65 years (range 17–78), with relapsed (73%) or refractory (27%) AML, after failing 1 (n=16), 2 (n=13) or 3 (n=8) previous lines of chemotherapy received azacitidine in combination with 2.5mg (n=6), 5mg (n=12) or 10mg (n=19) everolimus. Poor risk karyotype was present in 10/34 (29%) and FLT3-ITD in 4/16 (25%) of those evaluable. Clinical response was 32% (2 CR, 10 PR). At a median follow up of 252 days, median OS is 211 days (194d in primary refractory and 211d in relapsed AML) and median PFS 178 days. 3/5 patients treated for relapsed AML after allo-SCT had clinical responses and remain alive at 245, 252 and 525 days. In comparison to the typically large increase in FLT3L in a patient given intensive HiDAC-based induction chemotherapy (Figure 1), only 4/26 patients given azacitidine + everolimus had FLT3L levels above 1000 pg/ml within the first month of therapy (Figure 2). Furthermore, patients A, B and C (Figure 2) achieved CR, PR or had SD on therapy, suggesting that elevated FLT3L was unlikely to affect the clinical response to this treatment regimen. Finally, of 4 patients with FLT3-ITD+ AML failing prior intensive chemotherapy, absolute changes in the number of bone marrow blasts in those given azacitidine + everolimus were −80%, −85%, +5% and +7%. Conclusion: Azacitidine in combination with the mTOR inhibitor everolimus has notable activity in chemoresistant AML, including those with FLT3-ITD and does not trigger clinically significant changes in circulating FLT3L that may impact on the efficacy of other therapeutic options. Disclosures: Wei: Novartis: Honoraria, Research Funding; Celgene: Honoraria, Research Funding. Schwarer:Novartis: 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; Janssen-Cilag: Honoraria; Hospira: Membership on an entity's Board of Directors or advisory committees. Patil:Celgene: Research Funding.

A Phase 1b Dose Escalation Safety Analysis of Lenalidomide and Azacitidine Maintenance Therapy for Poor Risk AML,

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 3625-3625
Author(s):  
Andrew H Wei ◽  
Peter T. Tan ◽  
Patricia A. Walker ◽  
Sharon Avery ◽  
Sushrut S. Patil ◽  
...  
Keyword(s):  
High Risk ◽  
Maintenance Therapy ◽  
Board Of Directors ◽  
Dose Escalation ◽  
Research Funding ◽  
Residual Disease ◽  
Maximum Tolerated Dose ◽  
Intensive Chemotherapy ◽  
Advisory Committees ◽  
Dose Escalation Study

Abstract Abstract 3625 Background: Despite achieving remission after intensive chemotherapy for AML, the majority of patients will relapse. Maintenance therapy is an attractive option, with the goal of eradicating residual disease and prolonging disease remission. The hypomethylating agent azacitidine and the immunomodulatory drug lenalidomide have been shown to be active in high risk MDS, especially in combination (Sekeres et al, Journal of Clinical Oncology 2010; 2253). Azacitidine maintenance therapy has been examined after intensive induction chemotherapy for high risk MDS and MDS progressing to AML (Grövdal et al, British Journ of Haem 2010; 293). In this study, an azacitidine dose of 75 mg/m2 resulted in excessive neutropenic toxicity. An amended dose of azacitidine 60 mg/m2 for 5 days each cycle was found to be deliverable, with acceptable hematopoietic toxicity. The goal of this study was to determine the optimal maintenance dosing schedule of azacitidine in combination with lenalidomide after intensive chemotherapy for AML in complete remission (CR) and a high risk of relapse. Methods: A phase Ib/II open label dose escalation study enrolled patients with high risk AML in CR/CRi and high risk features (age > 60, adverse risk karyotype, FLT3-ITD+ or CR2). Patients were treated with azacitidine subcutaneously on days 1–5 of each 28-day cycle combined with lenalidomide orally on days 5–25 for a maximum of 12 cycles. A 3×3 dose escalation schema to identify the maximum tolerated dose was conducted. Cohort A (Table 1) assessed the safety of azacitidine 50 mg/m2 alone. Cohorts B-H planned to investigate azacitidine 50–75 mg/m2 in combination with lenalidomide 5–25mg. Results: We report herein the analysis of the first 16 patients (M 8, F 8), median age 65 years (43–73) recruited to the study. Patients were at high-risk for relapse, based on age >60 years (n=11), CR2 (n=3), adverse risk karyotype (n=1) or FLT3-ITD+ (n=1). Neutrophil (Figure 1) and platelet (Figure 2) toxicity was modest during cycle 1. A summary of outcomes is shown in table 1. After a median follow-up of 301 days, 6/16 patients have relapsed with a median relapse-free survival (RFS) of 219 days (17–546) and median overall survival (OS) of 443 days (86–546). Dose-escalation is ongoing. Conclusion: The combination of azacitidine with lenalidomide as maintenance therapy after intensive chemotherapy for high-risk AML is well tolerated. The clinical efficacy of this regimen and the maximum tolerated dose remains to be determined. Disclosures: Wei: Celgene: Honoraria, Research Funding. Schwarer:Novartis: 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; Janssen-Cilag: Honoraria; Hospira: Membership on an entity's Board of Directors or advisory committees. Harrison:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Tam:Celgene: Honoraria.

scholarly journals Prognostic Significance of Hospitalization Status at Second Cycle of Hypomethylating Agent Induction Therapy in Acute Myeloid Leukemia Patients Ineligible for Intensive Chemotherapy

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 5102-5102
Author(s):  
Douglas Tremblay ◽  
Rafael Madero-Marroquin ◽  
Guido Lancman ◽  
Alexander Coltoff ◽  
Jonathan Feld ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Induction Therapy ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
De Novo ◽  
Performance Status ◽  
Intensive Chemotherapy ◽  
Therapeutic Approaches ◽  
Exclusion Criteria ◽  
Advisory Committees

Introduction: Hypomethylating agents (HMAs) are used as induction therapy for patients with acute myeloid leukemia (AML) who are ineligible for intensive chemotherapy. HMA therapy is frequently initiated in the hospital and some patients remain hospitalized through the initiation of cycle 2 (C2). Clinicians are often faced with the decision to administer C2 while the patient is still hospitalized, however, there is a paucity of prognostic information to guide treatment decisions in this common scenario. Methods: We conducted a retrospective review of patients diagnosed with treatment naïve, de novo and secondary AML who were ineligible for induction chemotherapy (at the discretion of the treating physician based on advanced age, comorbidities, or other reasons) at a single, tertiary, referral center. Patients were included if they received induction therapy with an HMA, including azacitidine and decitabine between 7/1/2008 and 7/1/2018. Exclusion criteria included receipt of intensive induction chemotherapy and inadequate electronic medical documentation. Patients were divided into four groups: patients who were discharged after completion of C1 and received C2 as an outpatient (discharged after C1), patients who received C1 and C2 during the same hospitalization (C1-C2 continuous hospitalization), those who received one total cycle (C1 only), and patients who received C1 as an outpatient (C1 outpatient). The groups were analyzed separately for the primary outcome of overall survival (OS), calculated by Kaplan Meier analysis. Results: Out of 105 patients identified who received an HMA, 100 patients were identified who met inclusion/exclusion criteria and their baseline characteristics are shown in Table 1. Most patients had de novo AML (39.0%), although 33.0% and 19.0% of patients had AML secondary to myelodysplastic syndrome (MDS) and myeloproliferative neoplasm (MPN), respectively. Additionally, 8 patients (8.0%) had therapy related AML. The majority of patients had an Eastern Cooperative Oncology Group (ECOG) performance status of 1 or 2 at induction. Patients who received C1 as an outpatient had a significantly better performance status than those who did not (p= 0.033) Decitabine was the most common HMA (57.0%) administered and was most often on 5-day schedule. Eight patients (8.0%) were continually hospitalized until C2, 5 because of active medical issues (most often fevers requiring intravenous antibiotics), 2 had physical debility precluding discharge home, and 1 was receiving intrathecal chemotherapy twice weekly for central nervous system involvement of AML. The median OS was 15.6 months (95% CI 2.66-28.6) in patients who received C1 outpatient, 10 months (95% CI 6.67-13.43) in patients discharged after C1, 4 months (95% CI 2.40-6.40) in the C1-C2 continuous hospitalization group, and 1 month (95% CI 0.61-1.30) in those who only received C1 as shown in Figure 1. Patients discharged after C1 had a significantly longer OS compared to the C1-C2 continuous hospitalization group (p=0.003). There was a trend (p=0.054) towards worse survival in patients who received C1 only compared to patients hospitalized continually from C1-C2. Conclusions: Continued hospitalization from C1 to C2 of HMA therapy led to an extremely poor median survival of 4 months in this cohort, compared to 10 months in patients who were able to be discharged after C1 and receive C2 as an outpatient. Patients who only received a single cycle of HMA did not have a significantly different survival as compared to patients who were continually hospitalized from C1 to C2. While this is a small retrospective series, these data suggest that AML patients still requiring hospitalization at time of C2 of HMA therapy should be re-evaluated for alternative therapeutic approaches including hospice given poorer outcomes. Although this grouping selects for patients who are sicker and unable to leave the hospital, there is apparent lack of significant benefit of continued HMA therapy in the majority of patients while inpatient. The impact on hospital length of stay, unnecessary utilization of healthcare resources, and patient's quality of life should also be considered in these cases. Prospective identification of these patients with a poorer prognosis could lead to better alternatives for therapeutic approaches. Disclosures Kremyanskaya: Incyte, Celgene, Constellation, Protagonist.: Research Funding; La Jolla: Consultancy. Navada:Onconova Therapeutics Inc: Research Funding. Mascarenhas:Merus: Research Funding; Pharmaessentia: Consultancy, Membership on an entity's Board of Directors or advisory committees; Merck: Research Funding; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Research Funding; Promedior: Research Funding; Roche: Consultancy, Research Funding; Janssen: Research Funding; CTI Biopharma: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding.

scholarly journals Ixazomib-Thalidomide-Low Dose Dexamethasone (ITd) Induction Followed By Maintenance Therapy with Ixazomib or Placebo in Newly Diagnosed Multiple Myeloma Patients Not Eligible for Autologous Stem Cell Transplantation; Results from the Randomized Phase II HOVON-126/Nmsg 21#13 Trial

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 800-800 ◽  
Author(s):  
Sonja Zweegman ◽  
Fredrik H. Schjesvold ◽  
Bronno van der Holt ◽  
Mark-David Levin ◽  
Claudia A.M. Stege ◽  
...  
Keyword(s):  
Maintenance Therapy ◽  
Board Of Directors ◽  
Phase Ii ◽  
Induction Therapy ◽  
Research Funding ◽  
Phase Ii Trial ◽  
Induction Treatment ◽  
Newly Diagnosed ◽  
Advisory Committees ◽  
Randomized Phase Ii

Abstract Introduction A triplet combination including a proteasome inhibitor (PI) and an IMiD has shown significant efficacy in newly diagnosed multiple myeloma (NDMM) patients. A role for maintenance therapy with the PI bortezomib has been suggested in non-head to head comparisons. Therefore, we investigated the efficacy and feasibility of an oral regimen including induction therapy with ixazomib in combination with thalidomide and dexamethasone, followed by a randomization between maintenance therapy with ixazomib or placebo in elderly non-transplant eligible (nte) NDMM. We here report the final analysis of induction therapy and preliminary results of the randomization phase of the study. This trial was registered at www.trialregister.nl as NTR4910. Methods In this prospective multicenter phase II trial nte-NDMM 143 patients were treated with 9 28 day-cycles consisting of ixazomib 4 mg (day 1, 8, 15), thalidomide 100 mg (day 1-28) and dexamethasone 40 mg (day 1, 8, 15, 22) followed by randomization between either ixazomib or placebo (both day 1, 8, 15/28 days) until progression. Primary objectives were comparison of progression free survival (PFS) between maintenance therapy with ixazomib or placebo (hypothesized hazard ratio (HR) 0.39) and to determine the overall response rate (ORR) of induction therapy. Frailty was assessed by a modification of the IMWG frailty index based on age, the Charlson Comorbidity Index and the WHO performance as a proxy for (instrumental) Activities of Daily Living (scoring WHO 0 as 0 points, WHO 1 as 1 point, and WHO 2-3 as 2 points). High risk cytogenetics was defined as del17p, t(4;14) and/or t(14;16). Results The median follow up (FU) from registration is 26.4 months (range 0.9-41.0 months). Patient characteristics are presented in table 1. Following induction treatment ORR (i.e. ≥PR) was 81% (95% confidence interval (CI) 74-87%), ≥ VGPR 47% (95% CI 38-55%) and ≥ CR 9% (95% CI 5-15%). Age ≥76 years, frailty (unfit or frail) or high cytogenetic risk did not affect the rate and quality of response. Median PFS from registration for all patients was 14.3 months (95%-CI 11.8-16.8). Frailty did not affect PFS. The median PFS for high risk and standard risk disease was comparable; 12.4 months (95%-CI 7.3-20.0) versus 14.6 months (95%-CI 11.5-17.4) respectively. The OS from registration at 18 months was 85% (95% CI 77-90). This was 90% (95% CI 72-97), 92% (95% CI 78-97) and 74% (95% CI 61-84) for fit, unfit and frail patients respectively. Seventy-eight patients (55%) were randomized. The reasons for not being randomized were toxicity (17% [24/143]), progressive disease (15% [21/143]), death (3% [5/143]) and other reasons (10% [15/143]). Median FU from randomization is 18.6 months (range 9.0-31.5 months). Baseline characteristics of randomized patients separately are presented in table 1. Upgrade of response occurred in 13% of patients receiving placebo and 10% of patients receiving ixazomib. The median PFS from randomization was 8.4 months (95%-CI 3.0-13.8) in the placebo arm and 10.1 months (95%-CI 5.6-24.1) in the ixazomib arm (p=0.47, figure 1). The OS from randomization at 18 months was 92% (95%-CI 77-97) in the placebo arm and 100% in the ixazomib arm (p=0.85). Toxicity is presented in table 2. The incidence of neuropathy was low; 8% grade 3 (mainly during thalidomide treatment; 5%) and no grade 4. There was no new onset neuropathy during ixazomib maintenance. During induction 24/143 (17%) patients discontinued therapy due to toxicity; 11 thalidomide-related neurotoxicity, 3 infection, 3 skin toxicity, 2 gastro-intestinal (GI) toxicity and 5 other. During maintenance 4/38 (11%) in the placebo (3 neurotoxicity and 1 other) versus 4/39 (10%) in the ixazomib arm (3 neurotoxicity and 1 GI) discontinued therapy due to toxicity. Discontinuation due to toxicity was comparable across age and frailty groups. Conclusion Induction treatment with 9 cycles of ITd in nte NDMM results in a high ORR of 81%, with 47% ≥ VGPR, independent of age, frailty status and cytogenetic risk. Our placebo controlled randomized phase II trial did not show an improvement in response and PFS with ixazomib maintenance therapy until progression. Ixazomib maintenance did not result in additional toxicity as compared to placebo. Disclosures Zweegman: Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene Corp.: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding. Schjesvold:Celgene: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Research Funding; Bristol Myers Squibb: Consultancy; Bayer: Consultancy; Adaptive: Consultancy; Janssen: Consultancy, Honoraria, Research Funding; Oncopeptides: Consultancy; Abbvie: Honoraria; Novartis: Honoraria. Levin:Celgene: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees. van de Donk:Janssen Pharmceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Amgen: Research Funding; Novartis: Research Funding; Bristol-Myers Squibb: Research Funding; Celgene: Research Funding. Sonneveld:Celgene: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Karyopharm: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; BMS: Honoraria, Research Funding. Abildgaard:Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Research Funding.

scholarly journals Post-Remission Treatment with Chemotherapy or Allogeneic Hematopoietic Stem Cell Transplantation (alloHSCT) in Adult Patients with High-Risk (HR) Philadelphia Chromosome-Negative (Ph-neg) Acute Lymphoblastic Leukemia (ALL) According to Their Minimal Residual Disease (MRD). Final Results of the Pethema ALL-HR-11 Trial

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 826-826 ◽  
Author(s):  
Josep-Maria Ribera ◽  
Mireia Morgades ◽  
Juana Ciudad ◽  
Pau Montesinos ◽  
Pere Barba ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Induction Therapy ◽  
Research Funding ◽  
High Dose ◽  
Consolidation Therapy ◽  
Research Support ◽  
Advisory Committees ◽  
E Coli ◽  
Wbc Count ◽  
Support Research

Introduction: Recent studies have shown that young to middle-aged adults who receive a pediatric-inspired chemotherapy regimen for treatment of Ph-neg ALL do not appear to require an alloHSCT if they achieve good response on MRD testing after induction and/or consolidation therapy. Patients (pts) who are not good MRD responders achieve better outcomes with alloHSCT than their counterparts who do not receive alloHSCT. However, it is not clear if this approach can specifically apply to adult ALL pts with HR features at baseline. The aim of the prospective ALL-HR-11 trial (NCT01540812) from the Spanish PETHEMA Group was to evaluate response of HR Ph-neg adult ALL patients to a different post-induction therapy (chemotherapy or alloHSCT) according to MRD levels (centrally assessed by 8-color flow cytometry [FCM]) at the end of induction (week 5) and consolidation therapy (week 17).. Patients and methods: HR ALL included one or more of the following parameters at baseline: age 30-60y, WBC count &gt;30x109/L for B-cell precursor ALL or &gt;100x109/L for thymic T-ALL, pro-B, early or mature T-ALL, 11q23 or KMT2A rearrangements or complex karyotype. Induction therapy included vincristine, prednisone, daunorubicin and asparaginase (E coli native or PEG according to center availability) for 4 weeks (Induction-1). FLAG-Ida was administered as intensified induction (Induction-2) in pts not achieving CR or in those in CR with MRD≥0.1% at the end of induction. For pts in CR and MRD&lt;0.1% early consolidation therapy included 3 cycles with rotating cytotoxic drugs with high-dose methotrexate, high-dose ARA-C and high-dose asparaginase (E coli native or PEG). These pts continued with delayed consolidation (identical to that of early consolidation) followed by maintenance therapy up to 2y in CR if MRD levels after consolidation were &lt;0.01%; otherwise they were assigned to alloHSCT. Pts in CR after Induction-2 received one consolidation cycle and were assigned to alloHSCT. Main outcome measures were: complete response (CR), overall survival (OS) and cumulative incidence of relapse (CIR), assessed by competing risk analysis. Results: On April 2019, 307 HR ALL pts were evaluable. Median (range) age was 40 (15-60) y, 192 were males, 211 precursor B-ALL and 96 T-ALL, with a median WBC count of 12.9 (0.2-564) x109/L. Results of Induction-1 (n=304, 3 on induction): therapy-related death: 12(4%), resistance: 39(13%), CR: 253(83%). MRD&lt;0.1% at the end of induction was observed in 77% of CR patients. Induction-2 was administered to 88 patients (due to no CR: 37, or to CR and MRD≥0.1%: 51). Overall response rate: 277 (91%). The 5y CIR and OS probabilities for the whole series were of 44%±8% and 48%±7% (median follow-up: 2.06y [range: 0-7.55y]). By intention-to treat after Induction-1, 94 pts were assigned to alloHSCT and 190 to delayed consolidation and maintenance. The 5y CIR and OS probabilities were of 37%±13% and 38%±11%, respectively, for pts assigned to alloHSCT, and of 48%±10% and 55%±10%, respectively, for those assigned to chemotherapy (P&lt;0.001 for OS [Figure 1], and P=0.243 for CIR). Patients with MRD&lt;0.1% at the end of induction and MRD&lt;0.01% at the end of consolidation (n=137) showed a 5y CIR and OS of 42%±11% and 66%±11%, respectively (P&lt;0.001 for both, Figure 2). Patients with MRD levels &lt;0.01% on day14 of induction-1, end-induction-1 and end-consolidation (n=17) showed 5y CIR and OS probabilities of 17%±19% and 90%±19%, respectively. Conclusions: This trial, in which post-induction therapy was only based on MRD results assessed by FCM, suggests that avoiding alloHSCT does not hamper the outcome of HR Ph-neg adult ALL pts with adequate MRD response after induction and after consolidation. Better post-remission alternative therapies are specially needed for patients with poor MRD clearance. Supported by grants PI14/01971 FIS, Instituto Carlos III, and SGR225 (GRE), Spain. Disclosures Montesinos: Novartis: Membership on an entity's Board of Directors or advisory committees, Other: Research support, Research Funding, Speakers Bureau; Teva: Membership on an entity's Board of Directors or advisory committees, Other: Research support, Research Funding, Speakers Bureau; Incyte: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Research support, Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Other: Research support, Research Funding, Speakers Bureau; Abbvie: 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, Other: Research support, Speakers Bureau; Karyopharm: Membership on an entity's Board of Directors or advisory committees, Other: Research support; Pfizer: Membership on an entity's Board of Directors or advisory committees, Other: Research support, Research Funding, Speakers Bureau. Esteve:Novartis: Consultancy, Research Funding, Speakers Bureau; Roche: Consultancy; Pfizer: Consultancy; Astellas: Consultancy, Speakers Bureau; Amgen: Consultancy; Celgene: Consultancy, Speakers Bureau; Daiichi Sankyo: Consultancy; Jazz Pharmaceuticals: Consultancy.

scholarly journals Supermobilizers with High CD34 + Cell Collection for Autologous Transplant and Impact on Survival Outcomes in Multiple Myeloma

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 1837-1837
Author(s):  
Eyal Lebel ◽  
Katherine Lajkosz ◽  
Esther Masih-Khan ◽  
Donna E. Reece ◽  
Suzanne Trudel ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Stem Cell ◽  
Maintenance Therapy ◽  
Board Of Directors ◽  
Induction Therapy ◽  
Research Funding ◽  
Survival Outcomes ◽  
Advisory Committees ◽  
Cd34 Cells

Abstract Introduction: Autologous stem cell transplantation (ASCT) is standard therapy for selected patients with newly diagnosed multiple myeloma (MM). Studies in MM and lymphoma have suggested that ability to mobilize and collect a higher yield of CD34 + cells predicts for improved survival outcomes, perhaps reflecting better bone marrow reserve (Bolwell 2007, Raschle 2011). We aimed to validate this hypothesis by correlating high CD34 + cell collection ("supermobilizers") and survival outcomes in a large myeloma cohort with long follow-up. Methods: We retrospectively reviewed MM patients (pts) who underwent ASCT at our centre 2000-2010, correlating number of CD34 + cells collected with post-transplant progression-free survival (PFS) and overall survival (OS). Stem cells were mobilized using cyclophosphamide 2.5 g/m 2 IV (day 1), G-CSF 10 ug/kg/day SC (starting on day 4), and leukapheresis (day 11), targeting 4x10 6/kg but accepting a minimum of 2x10 6/kg to support a single transplant. Using a cut-off used in previous studies, pts were categorized as "supermobilizers" if ≥8x10 6/kg CD34+ cells were collected. Results: 621 pts were analyzed. Most pts (422/605; 70%) received high dose dexamethasone (HDD) alone or in combination with vincristine and adriamycin (VAD) for pre-transplant induction therapy (pre-dating the novel agent era) with only 18% (110/605) receiving more contemporary bortezomib-based induction (mostly cyclophosphamide, bortezomib and dexamethasone; CyBORD). The median number of CD34 + cells collected for all pts was 13.9x10 6/kg (range 2.1-61.8). The median CD34 + cells re-infused was 6.2x10 6/kg (range 2.1-25), as some cells were reserved for 2 nd ASCT, but median CD34+ cells collected correlated with CD34 + cells infused (Pearson coefficient 0.81, p&lt;0.001). At a median follow-up of 74 months (m), we were surprised to report an inferior PFS of 24.1m for the supermobilizers collecting ≥8x10 6/kg vs 33.7m for the &lt;8 group (p=0.038, Figure 1a), without differences in OS (p=0.612, Figure 1b). No further discrimination in PFS was observed when using a more extreme supermobilizer cut-off of 15x10 6/kg. To further understand the counterintuitive result of shorter PFS with higher mobilization capacity, we explored the continuous relationship between CD34 + cells and PFS, identifying another optimal cut-off of 4.5x10 6/kg. Pts collecting in the mid-range (4.5-8; n=129) achieved the best PFS of 34.5m, significantly improved over 24.1m in the ≥8 group (n=478) and 11.4m in the small group at the extreme lower collection range (n=14; ≤4.5x10 6/kg)(Figure 1c). A similar pattern was seen with OS (Figure 1d). Clinical and laboratory parameters that may impact both collection capacity and survival, such as age, ISS, and kidney dysfunction, were investigated as confounders but were similar between collection groups and did not predict for PFS in multivariable analyses. Treatment variables, however, differed between groups: the lower collection groups more often received bortezomib-based induction (29%, 31% and 14% in the ≤4.5, 4.5-8 and ≥8 groups, respectively, p&lt;0.001) resulting in deeper responses pre-transplant (VGPR 50% in the ≥8 group vs 43% in the 4.5-8 group, p=0.024) (Table 1). Use of maintenance therapy post-ASCT also differed (50%, 40% and 28% in the ≤4.5, 4.5-8 and ≥8 groups, respectively, p=0.006). Discussion: In this large cohort of 621 MM patients, we report that "supermobilizers" who collected ≥8 x 10 6 CD34 + cells/kg exhibit inferior PFS from transplant than those with less robust mobilization. We suspected that this unexpected observation was due to confounding variables, and identified differences in treatment, primarily greater use of bortezomib-based induction and post-transplant maintenance therapy in the lower collection group. This group was able to achieve deeper responses (≥VGPR) even before transplant than the supermobilizer group, leading to improved PFS. Although bortezomib is routinely used as induction therapy pre-transplant currently and is not felt to be stem cell toxic, it may impair mobilization to a lesser degree, leading not to abject failure of collection but lowered capacity to achieve "supermobilizer" status. Although more research is needed to validate this hypothesis, we can at minimum conclude that high stem cell collection does not appear to predict for a long-term survival advantage. Figure 1 Figure 1. Disclosures Reece: Millennium: Research Funding; Sanofi: Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria; Takeda: Consultancy, Honoraria, Research Funding; Karyopharm: Consultancy, Research Funding; GSK: Honoraria; BMS: Honoraria, Research Funding. Trudel: Amgen: Honoraria, Research Funding; BMS/Celgene: Consultancy, Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Genentech: Research Funding; Sanofi: Honoraria; Pfizer: Honoraria, Research Funding; GlaxoSmithKline: Consultancy, Honoraria, Research Funding; Roche: Consultancy. Prica: Astra-Zeneca: Honoraria; Kite Gilead: Honoraria. Chen: Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees; Astrazeneca: Membership on an entity's Board of Directors or advisory committees; Beigene: Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy.

scholarly journals High-Dose Cytarabine (HiDAC) Improves the Cure Rate of Patients with Newly Diagnosed Acute Myeloid Leukemia (AML): Is It Better to be Given As Induction Therapy or As Consolidation Therapy?

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 3989-3989
Author(s):  
Anthony P Schwarer ◽  
Joel Wight ◽  
Kathryn Jackson ◽  
Ashanka Mahilal Beligaswatte ◽  
Jason P Butler ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Relapse Rate ◽  
Induction Therapy ◽  
Research Funding ◽  
Published Data ◽  
Consolidation Therapy ◽  
Newly Diagnosed ◽  
Advisory Committees ◽  
Hematopoietic Stem ◽  
Good Risk

Abstract Introduction: The optimal treatment approach for newly diagnosed patients with AML remains uncertain. HiDAC is widely considered to increase the proportion of patients cured compared to standard-dose cytarabine. However, it remains uncertain whether HiDAC is best given during induction or consolidation, and how many cycles of HiDAC are optimal. Many centres in Australia treat younger patients (age ≤60 yrs) with newly diagnosed AML with one of two approaches: either 7+3 induction followed by HiDAC-2 consolidation for 2 cycles; or a single course of HiDAC-3±7 induction followed by 2 cycles of lower dose cytarabine-based therapy (eg 5+2±5). Our retrospective study compared the outcomes of these 2 approaches in a large cohort of Australian patients treated at 5 centres. Methods: Consecutive patients aged ≤60 yrs with a new diagnosis of AML (de novo or secondary) were included in the study if they were planned for treatment with either: 1) cytarabine 100 mg/m2 for 7 days plus idarubicin 12 mg/m2 for 3 days (7+3) induction followed by 2 cycles of HiDAC 3 g/m2 days 1,3,5,7 plus idarubicin 12 mg/m2 for 2 days (HiDAC consolidation cohort); or 2) HiDAC 3 g/m2 days 1,3,5,7 plus idarubicin 9-12 mg/m2 for 3 days ± etoposide 75-100 mg/m2 for 7 days as induction followed mostly by cytarabine 100 mg/m2 for 5 days plus idarubicin 9-12 mg/m2 for 2 days ± etoposide 75-100 mg/m2 for 5 days as consolidation (HiDAC induction cohort). Patients were diagnosed from 1999 to June 2013, and were followed for at least 12 months with data cut off June 2014. Results: 486 patients were included: HiDAC consolidation cohort n=251; HiDAC induction cohort n=235. The HiDAC consolidation cohort had a greater median age (49 vs 47 yrs, p=0.02) and more patients with good risk cytogenetics (16% vs 8%, p=<0.005). Other baseline demographics were well matched. For the HiDAC consolidation cohort and the HiDAC induction cohort, respectively, CR1 rate was 80% vs 91% (p=0.001); TRM 8% vs 5% (p=0.14); OS (5 yrs) 49% vs 50% (p=0.7); DFS (5 yrs) 47% vs 41% (p=0.24) and the cumulative incidence of relapse (CIR) 41% vs 50% (p=0.1). The CIR was greater in the HiDAC induction cohort despite a higher allogeneic hematopoietic stem cell transplantation (alloHSCT) in CR1 rate (18% vs 29%, p=0.002) in this cohort. For the 301 patients who achieved CR1 and did not undergoing alloHSCT in CR1, CIR was greater in the HiDAC induction cohort (49% vs 60%, p=0.059) leading to a reduced DFS (58% vs 46%, p=0.058), and OS (59% vs 49%, p=0.13) in that subset of patients. Excluding patients with good risk cytogenetics from the analyses did not change the results significantly. Conclusions: OS and PFS using HiDAC as induction or consolidation therapy were similar, and compared favourably to published data. Interestingly, the better CR rate and a greater use of alloHSCT in CR1 in the HiDAC induction cohort did not lead to a better PFS or OS - because of a greater relapse rate in this cohort - primarily seen in those patients not undergoing alloHSCT in CR1. In the absence of mutational prognostic information, these data may suggest that HiDAC as induction therapy can achieve CR in patients with biologically higher risk disease who have a higher relapse rate, and that including 2 cycles of HiDAC in consolidation in the absence of alloHSCT in CR1 is a more effective therapy than a single cycle of HiDAC administered during induction therapy. Disclosures Mollee: Celgene: 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; Amgen: Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Nilelse: Research Funding.

scholarly journals Cybord-Dara Is a Highly Effective Upfront Treatment for Newly Diagnosed Multiple Myeloma. Initial Efficacy Results of the 16-Bcni-001/Ctrial-IE (ICORG) 16-02 Study

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 3242-3242
Author(s):  
Robert Henderson ◽  
Mary R Cahill ◽  
Philip Murphy ◽  
Vitaliy Mykytiv ◽  
John Quinn ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Stem Cell ◽  
High Risk ◽  
Board Of Directors ◽  
Induction Therapy ◽  
Research Funding ◽  
Liver Toxicity ◽  
Consolidation Therapy ◽  
Newly Diagnosed ◽  
Advisory Committees

Abstract Introduction : Daratumumab (DARA), a human IgG1k monoclonal antibody with single activity in multiple myeloma (MM) shows strong synergy in combination with other anti-MM agents, including immunomodulatory drug (IMiDs) and proteasome inhibitors (PI). This has led to the exploration of DARA in combination with front line regimens. Triplets including a PI and an IMiD are considered an ideal backbone with which to combine DARA prior to Autologous Stem Cell Transplantation (ASCT). However, based on the ability of Cyclophosphamide (Cy) to enhance DARA mediated antibody dependent cellular phagocytosis, we hypothesized that CyBorD may provide an alternative option (Naicker, ASH 2017). We are currently exploring the preliminary safety and efficacy of CyBorD and DARA as part of an ongoing phase 1b study in newly diagnosed MM (NDMM) pts eligible for ASCT. Last year we reported on the safety of this combination with an absence of dose limiting toxicity (DLT) with weekly subcutaneous (SQ) Bortezomib (Bor) 1.5mg/m2, Cy 300mg/m2 and DARA 16mg/kg (McEllistrim, ASH 2017). We now report on the efficacy of this regimen as pre-transplant induction, including the rate of CR post ASCT. Methods : Pts received 4 cycles of induction therapy with weekly CyBorD and DARA 16mg/kg weekly for cycles 1 and 2 and every 2 weeks for cycles 3 and 4. Following induction therapy, pts proceeded to stem cell mobilization and ASCT followed by 2 cycles of consolidation therapy with weekly CyBorD plus DARA 16mg/kg on days 1 and 15. Following completion of consolidation therapy, all pts receive DARA maintenance every 28-days for 2 yrs or until progression, unacceptable toxicity or withdrawal of consent. Pts with high-risk features receive Bor on days 1 and 15 during maintenance phase. The primary endpoints were the incidence of DLT within the first cycle of combination at each dose level and CR rate post ASCT. Secondary endpoints included: safety, CR rate at the end of induction, consolidation and maintenance, best overall response, minimal residual disease (MRD) negative rate, progression-free survival, clinical benefit rate and overall survival. Responses were investigator-assessed as per IMWG criteria. This trial is registered at www.clinicaltrials.gov as NCT02955810. Results : Eighteen pts were enrolled between Nov 2016 and Dec 2017 and received at least 1 dose of treatment. Baseline characteristics were: median age = 56 y (range 32-66); M (61%), F (39%), ISS stage I, II, III in 78%, 17% and 6% of pts, respectively. 28% patients were identified with high risk genetic features [17p deletion and/or t(4;14) by FISH and/or SKY92 (SkylineDx)]. Three patients discontinued therapy early (primary refractory, persistent liver toxicity, death, respectively). Overall, treatment was well tolerated. The most common grade (gr) 3/4 hematologic treatment emergent adverse events (TEAE) were lymphopenia (44%), neutropenia (11%) and anemia (11%). The most common gr 3/4 non-hematologic TEAE were diarrhea (11%) and infection (61%). One patient died from gr 5 diffuse alveolar damage 7 weeks post ASCT. A single patient developed gr 3 liver toxicity. DARA-associated infusion reactions were ≤ gr 2 (11%). On an intent to treat (ITT) basis 94% achieved ≥ very good partial response (VGPR) with ≥ complete response (CR) in 44% pts (Figure). Among the sixteen patients completing 4 cycles of induction ORR was 100%, ≥ VGPR (69%), ≥ CR (13%). Informative NGS data (Adaptive Biotech) are available on 11/16 patients post induction, of whom 100% are MRD negative post induction at a level of ≥ 10e4. Following the induction phase 15/16 patients readily mobilized sufficient CD34 positive progenitors and proceeded to ASCT, one patient failed repeated mobilization. One patient died prior to post ASCT response assessment and data on the last patient is pending. Thus 13/15 patients are currently evaluable for response post ASCT. Responses deepened post ASCT with 100% achieving ≥ VGPR and 62% achieving ≥ CR. Based on EBMT criteria the CR/nCR rate post ASCT was 92%. Post ASCT PET-CT scans were consistent with complete metabolic response in all 13 patients. Updated results, including MRD status post ASCT will be presented at the meeting. Conclusions: CyBorD-DARA is a highly active, well tolerated induction therapy for NDMM patients undergoing ASCT. These data support the further development of this combination as a convenient, cost effective alternative to PI-IMiD-DARA based combinations. Disclosures Quinn: Janssen: Honoraria. O'Dwyer:Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Research Funding; Glycomimetics: Research Funding; Onkimmune: Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Membership on an entity's Board of Directors or advisory committees; BMS: Research Funding.

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