Long-Term Follow-up of Combined Hypercvad (hCVAD) Regimen with Dasatinib (Db) in the Front Line Therapy of Patients (pts) with Philadelphia Chromosome Positive (Ph+) Acute Lymphoblastic Leukemia (ALL)

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 1512-1512 ◽  
Author(s):  
Hun Ju Lee ◽  
Hagop M. Kantarjian ◽  
Deborah A. Thomas ◽  
Stefan Faderl ◽  
Charles Koller ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Lymphoblastic Leukemia ◽  
Single Agent ◽  
High Dose ◽  
Cell Transplant ◽  
Newly Diagnosed ◽  
Advisory Committees ◽  
Platelet Recovery

Abstract Abstract 1512 Background: The introduction of tyrosine Kinase Inhibitors (TKI) has significantly improved the outcome of patients (pts) with Ph+ ALL. Dasatinib (Db) is a second generation dual SRC/ABL TKI with greater potency compared to Imatinib in inhibiting BCR/ABL. Aim: To determine the outcome of pts with Ph+ ALL treated with hCVAD + Db. Method: Between 9/06 and 7/09, pts with newly diagnosed Ph+ ALL received Db 50mg oral (PO) twice daily (BID) or 100mg PO daily for the first 14 days of each of 8 cycles of alternating hCVAD, and high dose cytarabine and methotrexate. Pts in complete remission (CR) continued to receive maintenance Db 50mg PO BID or 100mg PO daily, as well as monthly prednisone and vincristine for 2 years, followed by Db indefinitely. From 8/09 protocol was amended and pts received 100mg Db for the first 14 days of cycle #1 and then 70mg daily continuously for the next 7 cycles, as well as 2 doses of rituximab 375 mg/m2 during each of the first 4 cycles. Maintenance was with Db, vincristine and prednisone. Results: Sixty-one pts with newly diagnosed Ph+ ALL have been treated to date. Median age was 56 years (yrs) (range (r), 22–80) and 41 (67%) pts were >50 yrs. The median follow up is 26.1 months (mo) (r, 4–58). Central nervous system (CNS) involvement was noted in 9 (14%) pts at diagnosis. Sixteen (26%) pts had Ph+ alone, 38 (62%) pts had Ph+ with additional abnormalities, and 7 (12%) pts were Ph negative, and BCR/ABL positive. Median white blood cell count (WBC) at diagnosis was 13.4 × 109/L (r: 0.4–658), and 22 (36%) pts had WBC >30 × 109/L at diagnosis. BCR/ABL transcript was identified in 60 (98.3%) pts at diagnosis, including e1a2 in 46 (76%) pts, b2a2 in 10 (17%) pts, b2a2+b3a2 in 2 (3%) pts, b3a2 and e1a3 in 1 (1.6%) pt each. One pt had a variant transcript that was not detectable with the standard primers. The median number of induction and maintenance cycles received were 6 cycles (r: 1–8) and 13.5 cycles (r: 1–24), respectively. Fifty seven (94%) pts achieved CR1 and 1 (1.5%) pts achieved CR with incomplete platelet recovery with first induction cycle of chemotherapy. Three (4.5%) pts died before response assessment could be performed due to infections. Thirty-nine (64%) pts received maintenance, 3 (5%) pts are currently receiving induction and 19 (31%) pts had no maintenance [9 pts received allogeneic stem cell transplant (ASCT) prior to maintenance, 10 pts had progression of disease]. To date, twelve (19%) pts have relapsed and Abl kinase domain mutations were analyzed in 7 pts; mutations were noted in 4 pts. These included T315I in 2 pts, and F359V and V299L in 1 pt each. CNS relapse occurred in 5 pts. Salvage (S1) regimens included [hCVAD + another TKI in 7 pts, single agent TKI in 2 pts, single agent monoclonal antibody in 1 pt, methotrexate, vincristine, asparginase, dexamethasone (MOAD) in 1pt, intrathecal cytarabine/methotrexate plus CNS radiation and Db in 1 pt]. Eight pts achieved CR2, 3 pts were refractory (2 pts with T315I and 1 pt with F359V) and one is still undergoing salvage treatment. Median DFS and OS after S1 were 5.3 mo (r: 0.7–17.3) and 6.7 mo (r: 0.6–24.4), respectively. ASCT was performed in 15 (24%) pts, including 10 pts in CR1 and 5 pts in CR2. Donors were related in 8 (53%) and unrelated in 7 (47%) transplants. Sixteen pts have died 11 (68%) pts from infectious complications, 2 (13%) pts from multi-organ failure, 1 (6%) pt with graft versus host disease, and 2 (13%) pts from unknown causes. Three-year disease free survival (DFS) and overall survival (OS) (n=61) were 49% and 62%, respectively. Conclusion: Db plus hCVAD is an effective regimen with durable responses in pts with newly diagnosed Ph+ ALL. Disclosures: Kantarjian: BMS: Research Funding. Jabbour:Pfizer: Honoraria; BMS: Honoraria; Novartis: Honoraria. Cortes:Novartis: 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; Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding; Ariad: Membership on an entity's Board of Directors or advisory committees, Research Funding; Chemgenex: Membership on an entity's Board of Directors or advisory committees, Research Funding. Ravandi:Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Honoraria.

scholarly journals Safety and Efficacy of Midostaurin in Combination with High-Dose Daunorubicin in 7+3 Induction for Acute Myeloid Leukemia with FLT3 Mutation

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 3896-3896
Author(s):  
Yehuda E. Deutsch ◽  
Robert Wilkinson ◽  
Amanda Brahim ◽  
Stephanie Boisclair ◽  
Jose Sandoval-Sus ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
Cancer Center ◽  
High Dose ◽  
Newly Diagnosed ◽  
Advisory Committees ◽  
Safety And Efficacy ◽  
Acute Myeloid

Introduction: Acute myeloid leukemia (AML) is a heterogeneous disease with varied outcomes dependent on patient cytogenetic and mutational status. Thirty percent of adults with newly diagnosed AML have a mutation in the fms-related tyrosine kinase 3 (FLT3) gene. Midostaurin is a small molecule inhibitor that acts on multiple receptor tyrosine kinases, including FLT3. The RATIFY trial showed improved overall survival (OS) and event-free survival in patients treated with daunorubicin and cytarabine (7+3) plus midostaurin (Stone et al, NEJM 2017). In this trial, a dose of daunorubicin 60 mg/m2 was administered. High dose (HD) 90 mg/m2 daunorubicin significantly improved the rate of complete remission and overall survival, including in patients with FLT3-ITD (Luskin et al, Blood 2016). HD daunorubicin has also been shown to be more effective than idarubicin in patients with FLT3-ITD AML (Lee et al, J Clin Oncol 2017). This data raises the question of whether the combination of midostaurin and HD daunorubicin would further improve outcomes of FLT3 mutated AML patients, while maintaining a tolerable safety profile. The objective of this study is to describe the safety and efficacy endpoints of FLT3 mutated AML patients treated with HD daunorubicin plus midostaurin as part of induction therapy. Methods: We retrospectively reviewed clinical and molecular data of patients at Memorial Healthcare System, Moffitt Cancer Center, and Sylvester Cancer Center with newly diagnosed FLT3 mutated AML treated from May 1st, 2017 to July 1st, 2019. Clinical data was abstracted in accordance with institutional review board approved protocol. All patients were induced with HD daunorubicin 90 mg/m2 on days 1-3, cytarabine 100 mg/m2 on days 1-7, and midostaurin 50 mg PO twice daily on days 8-21. Growth factor and antimicrobial support were used per institutional guidelines. Demographics were analyzed using descriptive statistics. OS was analyzed using Kaplan Meier method. Other efficacy outcomes were CR, CRi (assessed according to the European Leukemia Network Criteria for AML), proportion of patients needing re-induction, and proportion of patients who underwent hematopoietic stem cell transplant (HSCT). Safety outcomes were adverse events (AEs) and early (30- and 60-day) mortality. Results: Twenty-six patients were included in the final analysis. Patient characteristics are outlined in TABLE 1. All patients were FLT3 mutated, as confirmed with molecular studies. The FLT3 subtype was ITD (high) in 3 patients, ITD (low) in 16 patients, TKD in 5 patients, and both in 2 patients. Seventy-seven percent of patients achieved a CR/CRi after one induction cycle, and 96.2% attained CR after two induction cycles. Median time to ANC and platelet recovery was 28 and 26 days, respectively. One patient died during the first 60 days, due to Enterococcus sepsis. The most common non-hematological AEs were nausea (77%), diarrhea (62%), mucositis (58%), rash (54%), and increased ALT (54%). Cumulative incidence of relapse in the cohort was 28% (n=7). Four patients relapsed pre-transplant and achieved CR2 with additional therapy. All 7 of these patients had co-occurring mutations of various types. Of the 20 patients who were considered transplant eligible, 13 (65%) underwent HSCT and 4 (20%) are pending transplant. Of the 13 transplanted patients, 3 experienced relapse post-transplant. After a median follow up of 14.5 months, median OS has not been reached. Conclusion: In our multi-center experience, induction with HD daunorubicin, cytarabine, and midostaurin is clinically effective and seems to be well tolerated. Short term mortality was low and AEs were manageable, with no unexpected safety signals. Also, CR/CRi rates were higher than previously reported, suggesting that the combination of HD daunorubicin and midostaurin may improve the outcomes of patients with FLT3 mutated AML. Future analyses with larger patient samples and longer follow up are warranted to further evaluate long-term safety and efficacy for this regimen. Figure Disclosures Sandoval-Sus: Seattle Genetics: Membership on an entity's Board of Directors or advisory committees. Bradley:AbbVie: Other: Advisory Board. Talati:Agios: Honoraria; Celgene: Honoraria; Pfizer: Honoraria; Astellas: Honoraria, Speakers Bureau; Daiichi-Sankyo: Honoraria; Jazz Pharmaceuticals: Honoraria, Speakers Bureau. Watts:Pfizer: Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees. Sallman:Abbvie: Speakers Bureau; Novartis: Speakers Bureau; Jazz: Research Funding; Incyte: Speakers Bureau; Celyad: Membership on an entity's Board of Directors or advisory committees; Celgene: Research Funding, Speakers Bureau. Sweet:Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Celgene: Speakers Bureau; Jazz: Speakers Bureau; Incyte: Research Funding; Pfizer: Consultancy; Stemline: Consultancy; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Abbvie: Membership on an entity's Board of Directors or advisory committees; Astellas: Membership on an entity's Board of Directors or advisory committees; Agios: Membership on an entity's Board of Directors or advisory committees. Lancet:Daiichi Sankyo: Consultancy, Other: fees for non-CME/CE services ; Agios, Biopath, Biosight, Boehringer Inglheim, Celator, Celgene, Janssen, Jazz Pharmaceuticals, Karyopharm, Novartis: Consultancy; Pfizer: Consultancy, Research Funding.

Phase II Study of Combination of Hypercvad with Ponatinib in Front Line Therapy of Patients (pts) with Philadelphia Chromosome (Ph) Positive Acute Lymphoblastic Leukemia (ALL)

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 2289-2289 ◽  
Author(s):  
Elias Jabbour ◽  
Hagop M. Kantarjian ◽  
Deborah A. Thomas ◽  
Koji Sasaki ◽  
Farhad Ravandi ◽  
...  
Keyword(s):  
Median Time ◽  
Research Funding ◽  
Residual Disease ◽  
Lymphoblastic Leukemia ◽  
Single Agent ◽  
Philadelphia Chromosome ◽  
High Dose ◽  
Vascular Events ◽  
Platelet Recovery

Abstract Background: Combination of cytotoxic chemotherapy with tyrosine kinase inhibitors (TKIs) is effective in the treatment of Ph+ ALL. Ponatinib is a more potent BCR-ABL inhibitor. It also suppresses the T315I clones, a common cause of relapse in pts with Ph+ ALL. The combinations of chemotherapy and ponatinib may be associated with better response rates and higher likelihood of eradication of minimal residual disease (MRD) than those reported with other TKIs. Methods: Pts with newly diagnosed Ph+ ALL received 8 cycles of hyper-CVAD (fractionated cyclophosphamide, vincristine [VCR], doxorubicin, dexamethasone) alternating with high dose methotrexate (MTX) and cytarabine every 21 days. Ponatinib was given at 45 mg po daily for the first 14 days of cycle 1 then continuously for the subsequent 7 cycles. Pts in CR received maintenance with ponatinib 45 mg po daily and vincristine and prednisone monthly for 2 years followed by ponatinib indefinitely. MRD monitoring was conducted. Results: To date, 34 pts with untreated Ph+ ALL and 3 pts previously treated (1 previous course) have received a median of 6 cycles (2-8); 10 pts are receiving maintenance in CR. 3 pts have completed the 2 years of maintenance and they are receiving single agent TKI. Median WBC at diagnosis was 8 x 109/L (0.9 -629 x 109/L). CD20 expression was reported positive in 11 pts (30%). 3 (8%) had concomitant CNS disease at diagnosis. All pts were in CR after cycle 1. 30/32 pts (94%) with Ph+ metaphases by CG analysis at baseline achieved CCyR after 1 cycle; 1 had mCyR only and 1 had no CG analysis at CR, both of them achieved CCyR after cycle 2. To date, 35 pts (95%) achieved MMR and 26 (70%) CMR. The median time to MMR and CMR were 3 and 10 weeks, respectively. MRD is negative in 35/36 (97%) pts, in whom a sample was sent for assessment. 9 (24%) received an allogeneic stem cell transplantation (ASCT) after a median of 4 cycles (3-10). Median time to neutrophil and platelet recovery for cycle 1 was 18 and 23 days, and 16 and 22 days for subsequent cycles, respectively. Grade ≥ 3 toxicity included infections during induction in 18 pts (49%), increased LFT’s in 12 (32%), thrombotic events in 3 (8%), myocardial infarction (MI) in 3 (8%, 2 unexplained, 1 in the context of sepsis ), skin rash in 4 (11%), and pancreatitis in 6 (16%). With a median follow up of 18 months (9-31), 31 pts are alive, 6 died in CR. 1 pt died in CR from an unrelated cardiac event after being taken off therapy and placed on imatinib, 1 from MOF (C2D13), 1 from NSTEMI (C2D41), 1 from potential MI (C4D42), 1 from head injury sustained after a fall (C4D13), and 1 from sepsis post ASCT. At the last follow-up, 8 pts (19%) are alive post ASCT; 13 pts remain on ponatinib at the dose of 15 mg daily in 14 and 30 mg daily in 1; Of the other 9 alive patients, 7 were switched to dasatinib, two were switched to imatinib and nilotinib (one each); 1 was lost of follow-up. All but one pt who switched to dasatinib remained in CR; the latter relapsed after a first remission of 10 months; she is receiving salvage therapy in combination with dasatinib. The 1-year progression-free and overall survival rates were 96% and 86%, respectively. Conclusion: The combination of hyperCVAD with ponatinib is highly effective in pts with Ph+ ALL. Due to the vascular events observed, some pts switched to alternative TKI; in the remaining, ponatinib dose was modified to 30 mg daily during consolidation with subsequent reduction to 15 mg in pts in CMR. Disclosures Kantarjian: ARIAD: Research Funding; Pfizer: Research Funding; Amgen: Research Funding. Kadia:GSK: Research Funding; ARIAD: Honoraria.

scholarly journals Consolidation Followed By Maintenance Therapy Versus Maintenance Alone in Newly Diagnosed, Transplant Eligible Patients with Multiple Myeloma (MM): A Randomized Phase 3 Study of the European Myeloma Network (EMN02/HO95 MM Trial)

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 242-242 ◽  
Author(s):  
Pieter Sonneveld ◽  
Meral Beksac ◽  
Bronno van der Holt ◽  
Meletios A. Dimopoulos ◽  
Angelo Michele Carella ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Progression Free Survival ◽  
Advisory Board ◽  
Primary Study ◽  
High Dose ◽  
Newly Diagnosed ◽  
Advisory Committees ◽  
High Dose Melphalan

Abstract Background The role of up-front consolidation for newly diagnosed, transplant eligible MM (NDMM) patients (pts) has not yet been prospectively addressed in the novel agents era. Methods The EMN02/HO95 trial was designed to randomly (R) compare (R1) 4 cycles of bortezomib-melphalan-prednisone (VMP) vs high-dose melphalan (HDM) and autologous stem cell transplantation (ASCT), either single or double, as intensification therapy after induction with bortezomib-cyclophosphamide-dexamethasone (VCD) (M Cavo et al, ASCO 2016, abstract #8000). A second randomization to consolidation therapy with 2 cycles of VRD vs no consolidation (R2) was performed after intensification, to be followed by lenalidomide maintenance (lenalidomide 10 mg continuously) until progression or toxicity in both arms. (VRD: bortezomib 1.3 mg/m2 intravenously days 1, 4, 8, 11; lenalidomide 25 mg orally days 1 - 21; dexamethasone 20 mg orally days 1, 2, 4, 5, 8, 9, 11, 12 of a 28 days cycle). Primary study end points were progression-free survival (PFS) from R1 and PFS from R2. A first planned interim analysis for R2 was performed in July 2016 when at least 33% (= 172) of the required events for PFS had been observed. Results From February 2011 to April 2014, 1510 pts aged ≤ 65 years with symptomatic MM were enrolled, of whom 1499 were eligible. Of these, 1211 were randomized (stratification by ISS stage) to VMP (505 pts) or HDM (1 or 2 ASCT) (706 pts). For R2 903 eligible patients were randomized to consolidation (459 pts) or no consolidation (444 pts). Median follow up from R2 was 25 months (maximum 53). Response status at time of R2 was ≥ CR (23%), ≥ VGPR (67%), ≥ PR (93%), and will be updated for status at start of maintenance. At the time of analysis, 258 events for PFS after R2 had been reported. 3-year. PFS from R2 was 62% in all patients, i.e., 60% without consolidation and 65% in patients with consolidation, and median PFS had not yet been reached. PFS from R2 with adjustment for R1 was prolonged in pts randomized to VRD (HR=0.78; 95% CI=0.61-1.00; P=0.045), a benefit retained across predefined subgroups with revised ISS stage III (HR=0.67; P=0.26) and in patients randomized in R1 to VMP (HR=0.76; P=0.19) and to HDM (HR=0.79; P=0.13). The benefit of consolidation was observed in patients with low-risk cytogenetics (HR=0.68; P=0.03), but not in patients with high-risk cytogenetics (del(17p) and/or t(4;14) and/or t(14;16); HR=1.03; P=0.91). At 3 years OS from R2 was 86% and 87%, respectively. Toxicity from VRD was limited with 5% CTCAE grade 4, mainly hematological. Conclusions Consolidation treatment with VRD followed by Lenalidomide maintenance until progression or toxicity shows promising results as compared to maintenance alone for younger NDMM pts, but further study follow-up is needed. This trial was registered at www.trialregister.nl as NTR 2528, EudraCT 2009-017903-28 This trial was supported by unrestricted grants from Celgene and Janssen. Disclosures Sonneveld: Celgene: Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Karyopharm: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria. Dimopoulos:Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria; Genesis: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Carella:Millenium: Speakers Bureau; Genentech: Speakers Bureau. Ludwig:Janssen: Speakers Bureau; BMS: Speakers Bureau; Amgen: Research Funding, Speakers Bureau; Takeda: Research Funding, Speakers Bureau. Driessen:janssen: Consultancy; celgene: Consultancy; Mundipharma-EDO: Honoraria, Membership on an entity's Board of Directors or advisory committees. Gay:Celgene: Honoraria; Mundipharma: Other: Advisory Board; Amgen: Honoraria; BMS: Honoraria; Janssen-Cilag: Other: Advisory Board; Takeda: Honoraria, Other: Advisory Board. Mellqvist:Mundipharma: Honoraria; Celgene: Honoraria; Novartis: Honoraria; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Zweegman:Celgene: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Takeda: Honoraria, Research Funding. Schjesvold:Janssen: Research Funding; Novartis: Consultancy, Honoraria, Research Funding. Palumbo:Takeda: Employment, Honoraria; Janssen Cilag: Honoraria. Cavo:Celgene: Honoraria, Research Funding, Speakers Bureau; Janssen: Honoraria, Research Funding, Speakers Bureau; Amgen: Honoraria; Bristol-Myers Squibb: Honoraria; Takeda: Honoraria.

Response Adapted Lenalidomide Based Therapy For Newly Diagnosed (ND) Standard Risk Older Adults With Multiple Myeloma (MM): An International Collaboration

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 3201-3201
Author(s):  
Rachid Baz ◽  
Hui-Yi Lin ◽  
Sung-Soo Yoon ◽  
Kihyun Kim ◽  
Melissa Alsina ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Progressive Disease ◽  
Single Agent ◽  
High Dose ◽  
Newly Diagnosed ◽  
Advisory Committees ◽  
Free Survival ◽  
The Us ◽  
Standard Risk

Abstract Introduction Older MM patients continue to have poor outcomes. Lenalidomide (L) and low dose dexamethasone (D) was found to result in better overall survival than L and high dose D in ND MM (Rajkumar et al. Lancet Oncol 2010). In an attempt to decrease toxicity from therapy in this vulnerable patient population, we have initiated two phase II clinical trials evaluating a response adapted therapy using single agent L with sequential addition of corticosteroids. The trials had similar design and were conducted in one site in the United States (US) and multiple sites in South Korea (SK). Methods Eligible patients had symptomatic standard risk MM (b2microglobulin (b2m)≤5.5, absence of t(4;14), t(14;16), 17p deletion, aneuploidy or 13q by metaphase cytogenetics) and were not eligible or not willing to undergo high-dose melphalan. Patients received L on D1-21 every 28 days for 2 cycles based on renal function. If patients had a minimal response (MR) or better (25% reduction in serum M spike) after 2 cycles, they continued on single agent L until progressive disease. If patients had stable disease (SD) after 2 cycles, prednisone 100 mg PO D1-5 (P) was added to their L. In the event of progressive disease on single agent L or on LP, therapy was changed to L (at the tolerated dose) with dexamethasone 40 mg PO weekly (D). Thromboprophylaxis was with aspirin, warfarin or low molecular weight heparin. Responses were per IMWG and the primary end point was the 1 year progression free survival (PFS)of LD. Results Between 2/2010 and 6/2013, 61 patients were enrolled (34 in SK and 27 in the US). The median age was 73 (range 48-85) and 58% were males. Compared to US, patients in SK had a younger age, lower weight and body surface area and a higher proportion of ISS 2. There were no differences in baseline performance status, hematologic parameters, creatinine clearance or baseline b2m. The overall response rate (≥PR) to single agent L was 48% (59% & 38% for US and SK) and the clinical benefit rate (≥MR) 64% (74% & 56% for the US and SK respectively). After a median follow up of 13.2 months, P was added for 16 patients (26%) and 7 (44%) had ≥PR. D was added for 14 patients (23%) and 10 patients (71%) had ≥PR. The 1 year dexamethasone free survival was 75% (84% & 67% in the US and SK respectively). To date, 3 patients progressed after the addition of D and the 1 year LD PFS was 90% (95% CI 78-96%). There were no statistical differences in grade 3/4 hematologic adverse events (table). Lenalidomide dose reduction was more frequent in the US (59% vs. 26%) however discontinuation from therapy for causes other than progressive disease or death was more frequent in SK (41% vs. 18%). Conclusion In This elderly patient population, response adapted (sequential) therapy results in outcomes comparable to LD in younger patients with MM with 78% of patients not requiring the addition of D. Social and ethnic causes of differential tolerance to therapy should be studied further. Disclosures: Baz: Celgene: Research Funding; Millenium: Research Funding; Bristol Myers Squibb: Research Funding; Novartis: Research Funding; Karyopharm: Research Funding; Sanofi: Research Funding. Off Label Use: lenalidomide in newly diagnosed myeloma. Alsina:Celgene: Membership on an entity’s Board of Directors or advisory committees, Research Funding. Shain:Onyx: Membership on an entity’s Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity’s Board of Directors or advisory committees. Kwak:celgene: Research Funding.

scholarly journals The Omission of High-Dose Cytarabine during Consolidation Therapy of Ph-Positive ALL Patients Treated with Nilotinib and Low-Intensity Chemotherapy Results in an Increased Risk of Relapses Despite Non-Inferior Levels of Late BCR-ABL1 MRD Response. First Results of the Randomized Graaph-2014 Study

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 512-512
Author(s):  
Philippe Rousselot ◽  
Yves Chalandon ◽  
Sylvie Chevret ◽  
Jean-Michel Cayuela ◽  
Francoise Huguet ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Board Of Directors ◽  
Primary Endpoint ◽  
Research Funding ◽  
Lymphoblastic Leukemia ◽  
High Dose ◽  
Cell Transplant ◽  
Advisory Committees ◽  
High Dose Cytarabine ◽  
To Receive

Abstract On behalf of the GRAALL group. Introduction. Tyrosine kinase inhibitors (TKIs) have dramatically improved the outcome of patients diagnosed with Philadelphia chromosome (Ph)-positive acute lymphoblastic leukemia (ALL). In a previous randomized trial (GRAAPH-2005; Chalandon Y., Blood 2015), our group demonstrated that anthracycline and cyclophosphamide could be safely omitted during the first Hyper-CVAD chemotherapy cycle when combined to imatinib. In the present GRAAPH-2014 trial, we investigated whether the use of nilotinib, a 2 nd generation TKI, would allow further decreasing chemotherapy intensity through the omission of high-dose cytarabine (HD-AraC) during consolidation cycles 2 and 4. Methods. From March 2016, patients aged 18-60 years old were randomized frontline to receive 4 cycles (1=3, 2=4) of chemotherapy combined with continuous nilotinib 400 mg bid. Cycle 1 and 3 were similar in both arms, identical to the less-intensive first cycle of the previous GRAAPH-2005 trial with weekly vincristine and dexamethasone and nilotinib instead of imatinib. Cycle 2 and 4 differed between control arm A (MTX 1 g/sqm over 24h, HD-AraC 3 g/sqm/12h for 2 days) and experimental arm B (MTX 1 g/sqm over 24h only). Marrow minimal residual disease (MRD) was assessed by both BCR-ABL1 and IG-TCR qPCR after each cycle (MRD1-4). Patients in complete remission (CR) after cycle 4 were eligible to receive allogeneic stem cell transplant (alloSCT). Non allografted patients had the option to receive autologous SCT (autoSCT) if a major molecular response (MMolR) (MRD4 BCR-ABL1 <0.1%) was achieved. AlloSCT and autoSCT were followed by a 2-year imatinib maintenance. The randomization was stratified on age (≤40y, >40y) and BCR-ABL1 breakpoint region (M/m-bcr). MMolR rate at MRD4 was the primary endpoint of this non-inferiority study, with a margin set at 0.15. In February 2019, the study DSMB decided to stop the randomizations after an unplanned analysis demonstrating a significant excess of relapse in arm B (without HD-AraC). An intention-to-treat analysis is provided. All patients gave informed consent. The study is registered at EudraCT under the number: 2014-002146-44. Results. A total of 156 patients were randomized (77 in arm A, and 79 in arm B). Median age was 47.1 years old (range 18.1-59.9). One-hundred and ten patients had the m-bcr (70.5%) and 46 (29.5%) the M-bcr. An IKZF1 intragenic deletion was found in 87/153 (56.9%). Median follow-up was 2.8 years (95%CI 2.6-3.1). All evaluable patients reached CR after a maximum of two cycles. Three patients died during cycle 1 (2 in arm A, 1 in arm B), and 2 during cycle 2 (1 per arm). Most patients received the 4 scheduled cycles (n=143, 91,7%). AlloSCT was performed in 91 patients (58.3%), whereas 41 patients received an autoSCT (26.3%) with no difference in allo/autoSCT rates between arms. A non-inferiority in late MRD response (MRD4) between the two arms was observed (primary endpoint). MMolR was reached in 55/75 (73.3%) and 61/78 (78.2%) of CR patients in arm A and B, respectively, with an estimated 95% CI of difference of -11% to +16% (-9.2% to +20.8% in the ITT analysis treating missing data as failures). At 3 years, overall survival (OS) was 86.0% in arm A versus 74.2% in arm B (p=.08, Figure A). Progression-free survival (PFS) was 79.6% in arm A versus 57.2% in arm B (p=.008, Figure B). Thirty-one patients experienced hematological relapse (8 in arm A and 23 in arm B). Twenty-height out of 31 relapsed patients were tested for the acquisition of BCR-ABL1 mutations, 20/28 (71%) had at least one mutation and 10/28 (36%) had a T315I mutation. At 3 years, the cumulative incidence of relapse (CIR) was 21.3%, significantly higher in arm B than in arm A (30.8% vs 10.6%, p=.007). When analyzing the CIR considering alloSCT as a competing event for relapse, a significant higher CIR was still observed in arm B as compared to arm A (Figure C). Conclusion. Four cycles of the combined administration of nilotinib and chemotherapy is very efficient for bridging younger adults with Ph-positive ALL to SCT. However, omitting HD-AraC is associated with a higher relapse incidence despite non-inferior levels of BCR-ABL1 MRD4. Figure 1 Figure 1. Disclosures Rousselot: Incyte, Pfizer: Consultancy, Research Funding. Chalandon: Incyte, BMS, Pfizer, Abbie, MSD, Roche, Novartis, Gilead, Amgen, Jazz, Astra Zenec: Other: Travel EXpenses, Accomodation; Incyte: Speakers Bureau; Incyte, BMS, Pfizer, Abbie, MSD, Roche, Novartis, Amgen: Other: Advisory Board. Huguet: Novartis: Other: Advisor; Jazz Pharmaceuticals: Other: Advisor; Celgene: Other: Advisor; BMS: Other: Advisor; Amgen: Other: Advisor; Pfizer: Other: Advisor. Vincent: Takeda: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees. Vey: Amgen: Honoraria; BMS: Honoraria; BIOKINESIS: Consultancy, Research Funding; NOVARTIS: Consultancy, Honoraria, Research Funding; SERVIER: Consultancy; JAZZ PHARMACEUTICALS: Honoraria; JANSSEN: Consultancy. Raffoux: PFIZER: Consultancy; CELGENE/BMS: Consultancy; ASTELLAS: Consultancy; ABBVIE: Consultancy. Boissel: Amgen: Consultancy, Honoraria, Research Funding; CELGENE: Honoraria; Servier: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding; Incyte: Honoraria; SANOFI: Honoraria; PFIZER: Consultancy, Honoraria; JAZZ Pharma: Honoraria, Research Funding. Dombret: Amgen: Honoraria, Research Funding; Incyte: Honoraria, Research Funding; Jazz Pharmaceuticals: Honoraria, Research Funding; Novartis: Research Funding; Pfizer: Honoraria, Research Funding; Servier: Research Funding; Abbvie: Honoraria; BMS-Celgene: Honoraria; Daiichi Sankyo: Honoraria. OffLabel Disclosure: Nilotinib as a therapy for PH-positive acute lymphoblastic leukemia

scholarly journals Title: 12 Versus 8 Prophylactic Intrathecal (IT) Chemotherapy Administration Decrease Incidence of Central Nervous System (CNS) Relapse in Patients (pts) with Newly Diagnosed Philadelphia (Ph)-Positive Acute Lymphocytic Leukemia (ALL)

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 3810-3810 ◽  
Author(s):  
Shilpa Paul ◽  
Koji Sasaki ◽  
J Michael Savoy ◽  
Adam Dipippo ◽  
Nadya Jammal ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Leptomeningeal Disease ◽  
High Dose ◽  
Molecular Response ◽  
Newly Diagnosed ◽  
Advisory Committees ◽  
Cns Relapse ◽  
Increased Risk

Introduction: The addition of tyrosine kinase inhibitors to hyperfractionated cyclophosphamide, dexamethasone, vincristine, and doxorubicin alternating with high-dose methotrexate and cytarabine (HCVAD) for the treatment of Ph-positive ALL has significantly improved outcomes. However, with the increased median survival, an increased incidence of CNS relapses were documented over time, thus suggesting an increased risk among pts with Ph-positive disease (Ravandi et al, Cancer 2015).In order to reduce this incidence, treatment protocols for Ph-positive ALL were amended in 2012 to increase prophylactic IT chemotherapy from 8 to 12 at our institution. The aim of this study is to compare the incidence of CNS relapses in pts with Ph-positive ALL treated with 8 versus 12 ITs. Methods: We conducted a retrospective chart review of 156 pts with newly diagnosed Ph-positive ALL treated with Rituximab (R)± HCVAD plus imatinib (n=35), dasatinib (n=68), or ponatinib (n=53) between July 2001 and January 2019. Pts with CNS disease at initial diagnosis were excluded. Complete molecular response (CMR) at 3 months was defined as absence of a quantifiable BCR-ABL1 transcript. CNS relapse was identified by detection of blasts or rare atypical cells in the cerebrospinal fluid (CSF) in at least 2 successive evaluations and/or findings of leptomeningeal disease on imaging. Landmark analysis was performed at 6 months at the approximate time of completion of both systemic and IT therapy. Poor risk cytogenetic abnormality was defined as the presence of +der(22)t(9;22) and/or −9/9p in the absence of high hyperdiploidy (51‐65 chromosomes). CNS relapse-free survival (RFS) was defined from the start of therapy to the time of CNS relapse. Patients who died or relapsed in bone marrow were censored at the time of death and systemic relapse, respectively. Survival was assessed with and without the censoring of allogeneic stem cell transplantation (ASCT). Results: Pt characteristics are summarized in Figure A. One hundred and twelve pts (72%) received a median of 8 ITs (range, 2-8) and 44 pts (28%) received a median of 12 (range, 9-15). There were no statistically significant differences between groups in regards to baseline characteristics with the exception that more patients in the > 8 ITs cohort received ponatinib (66% vs 21%) and thus achieved a higher rate of 3-month CMR (70% vs 52%; p=0.04). CNS relapses were identified in 11 pts overall (7%, 4 treated with imatinib and 7 with dasatinib) and all of them received 8 or less prophylactic ITs (IT ≤8, 10% vs IT >8, 0%; p=0.023). The median follow-up of the entire population was 81 months, and 97 and 43 months for pts who received ≤8 and >8 ITs, respectively. The 3 and 6-year CNS RFS was 89% and 88% in pts with ≤8 ITs and 100% in pts with >8 Its, respectively (overall P=0.041; 3-yr CNS RFS P=0.049; 6-yr CNS RFS P=0.045) (Figure B). The outcomes remained statistically significant even after censoring for ASCT (P=0.048) (Figure C). In a multivariate analysis and after adjusting for the follow-up time, a median of 12 prophylactic IT chemotherapies was a prognostic factor significantly associated with a decrease rate of CNS relapses (P=0.03; HR=0.64 95%, CI: 0.43-0.96) (Figure D). Conclusion: In pts with newly diagnosed Ph-positive ALL, incorporation of 12 prophylactic IT chemotherapy in addition to systemic therapy is a very effective strategy to reduce the long-term incidence of CNS relapses. Figure Disclosures Paul: Pfizer: Consultancy; Agios: Consultancy. Sasaki:Otsuka: Honoraria; Pfizer: Consultancy. Kadia:BMS: Research Funding; Jazz: 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, Research Funding; Bioline RX: Research Funding; Celgene: Research Funding; Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Research Funding. Garcia-Manero:Helsinn: Research Funding; Novartis: Research Funding; AbbVie: Research Funding; Amphivena: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Astex: Consultancy, Research Funding; Onconova: Research Funding; H3 Biomedicine: Research Funding; Merck: Research Funding. Ravandi:Macrogenix: Consultancy, Research Funding; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Xencor: Consultancy, Research Funding; Menarini Ricerche: Research Funding; Selvita: Research Funding; Cyclacel LTD: Research Funding. Kantarjian:BMS: Research Funding; Novartis: Research Funding; AbbVie: Honoraria, Research Funding; Actinium: Honoraria, Membership on an entity's Board of Directors or advisory committees; Ariad: Research Funding; Daiichi-Sankyo: Research Funding; Takeda: Honoraria; Pfizer: Honoraria, Research Funding; Agios: Honoraria, Research Funding; Astex: Research Funding; Jazz Pharma: Research Funding; Cyclacel: Research Funding; Immunogen: Research Funding; Amgen: Honoraria, Research Funding. Jabbour:AbbVie: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Cyclacel LTD: Research Funding; Pfizer: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Adaptive: Consultancy, Research Funding.

scholarly journals Discontinuation of Tyrosine Kinase Inhibitors (TKIs) in Philadelphia Chromosome-Positive (Ph+) Acute Lymphoblastic Leukemia (ALL)

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 3819-3819 ◽  
Author(s):  
Bachar Samra ◽  
Hagop M. Kantarjian ◽  
Koji Sasaki ◽  
Marina Y Konopleva ◽  
Rita Khouri ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Median Duration ◽  
Research Funding ◽  
Kinase Inhibitors ◽  
Lymphoblastic Leukemia ◽  
Philadelphia Chromosome ◽  
Cell Transplant ◽  
Advisory Committees ◽  
Tki Discontinuation

Background: Treatment of Ph+ ALL has significantly improved since the addition of TKIs to chemotherapy, with improvement in complete molecular remission (CMR) and overall survival (OS) rates. However, the optimal duration of TKI is not yet established and the common practice is to continue indefinitely unless allogeneic stem cell transplant (ASCT) is performed. In pediatric setting, when TKIs were discontinued after 2 years of maintenance, high rates of relapse were seen, fortunately salvaged with ASCT and other approaches (Slayton WB et al; JCO. 2018 and Schultz KR; Leukemia 2014). In chronic myeloid leukemia, patients (pts) who achieve deep and sustained molecular remissions on TKI may be able to stop therapy successfully. Herein, we reviewed outcome of pts with Ph+ ALL treated with chemotherapy + TKI without ASCT who later discontinued TKI mainly due to adverse events. Methods: We reviewed 240 pts treated at our institution on sequential protocols with Hyper-CVAD chemotherapy + TKI (dasatinib [n=100], ponatinib [n=84], or imatinib [n=56]) between 2001 and 2019. We identified 9 pts (4%) in whom TKI was discontinued, 4 (44.5%) post dasatinib therapy, 4 (44.5%) post imatinib therapy, and 1 (11%) post ponatinib. We analyzed their characteristics and outcomes including molecular relapse rates and treatment-free remission (TFR). Pts were closely monitored with monthly PCR for the first 3 months, then every other month for 3 months, then every 3 months thereafter. Molecular relapse was defined as the loss of MMR (PCR>0.1%) or positivity of PCR at two assessments within a 2-week period. TKI was resumed upon molecular relapse. TFR was defined from the date of TKI discontinuation to molecular relapse or last-follow-up. Kaplan-Meier method was used for survival analysis. Results: Baseline characteristics are summarized in table 1. The median follow up from the time of diagnosis was 138 months (range: 40-190). The median age at diagnosis was 60 years (range: 20-80). Transcript type was p190 BCR-ABL1 in 7 pts (78%). Median time to CMR was 3 months (range: 0.4-120). Median duration of TKI therapy prior to discontinuation was 70 months (range: 23-143). Median duration of CMR before TKI stop was 52 months (range: 22-141). Reasons for stopping TKI were side effects in 8/9 pts, and physician's choice in 1 pt (after completing 2+ years of maintenance). At the time of TKI stop, 8 pts were in CMR, and 1 pt with low positive transcript level (0.01%). Median follow-up post TKI discontinuation was 37 months (range: 9-75). None of the pts had morphological relapse. Three pts (33%) had molecular relapse within a median of 6 months (range: 0.8-13.2 months). All 3 resumed TKI therapy: 2 of them regained MMR after a median of 4 months (range: 4.0-4.6 months); third pt continues to respond; the BCR-ABL1 transcripts down from 17.68% to 0.36% after 7 months (Table 2). Six pts remain alive and 3 pts died of disease-unrelated causes. The median TFR was not reached; 3-y TFR was 65% (Figure 1). Though the number of pts was only 9, the duration of CMR had a tendency of successful TFR (P=0.062; HR, 0.09; [95% CI, 0.009-1.119] with duration of CMR for 2 years, and P=0.137; HR, 0.15; [95% CI, 0.01-1.80] with duration of CMR for 3 years, as a binomial variable). The median duration of CMR in pts who relapsed and who did not relapse was 22 months (range, 0-39.9) and 58 months (range, 30.9-140.6), respectively (P= 0.096). Conclusions: Our anecdotal experience reflects the feasibility of stopping TKI in a subset of pts with Ph+ ALL and sustained molecular remissions. Longer follow up and validation of these findings on a larger cohort are highly needed before attempting to discontinue TKI. Disclosures Kantarjian: Astex: Research Funding; Ariad: Research Funding; Jazz Pharma: Research Funding; AbbVie: Honoraria, Research Funding; Cyclacel: Research Funding; Immunogen: Research Funding; Actinium: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Research Funding; Takeda: Honoraria; Agios: Honoraria, Research Funding; Novartis: Research Funding; Amgen: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; Daiichi-Sankyo: Research Funding. Sasaki:Otsuka: Honoraria; Pfizer: Consultancy. Konopleva:Ascentage: Research Funding; Reata Pharmaceuticals: Equity Ownership, Patents & Royalties; Agios: Research Funding; Ablynx: Research Funding; Cellectis: Research Funding; Amgen: Consultancy, Honoraria; F. Hoffman La-Roche: Consultancy, Honoraria, Research Funding; Calithera: Research Funding; Stemline Therapeutics: Consultancy, Honoraria, Research Funding; Forty-Seven: Consultancy, Honoraria; Eli Lilly: Research Funding; AbbVie: Consultancy, Honoraria, Research Funding; Kisoji: Consultancy, Honoraria; Astra Zeneca: Research Funding; Genentech: Honoraria, Research Funding. O'Brien:Acerta: Research Funding; AbbVie: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria, Research Funding; Sunesis: Consultancy, Research Funding; Janssen: Consultancy, Honoraria; Kite: Research Funding; GlaxoSmithKline: Consultancy; Gilead: Consultancy, Research Funding; Eisai: Consultancy; Celgene: Consultancy; Astellas: Consultancy; Aptose Biosciences, Inc: Consultancy; Amgen: Consultancy; Alexion: Consultancy; TG Therapeutics: Consultancy, Research Funding; Vaniam Group LLC: Consultancy; Verastem: Consultancy; Regeneron: Research Funding; Pharmacyclics LLC, an AbbVie Company: Consultancy, Research Funding. Kadia:Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding; Jazz: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Research Funding; Bioline RX: Research Funding; BMS: Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Research Funding. Jabbour:Takeda: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Adaptive: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Cyclacel LTD: Research Funding.

scholarly journals Ixazomib-Based Induction Followed By Single-Agent Ixazomib Maintenance in Transplant Ineligible, Newly Diagnosed Multiple Myeloma Patients: Updated Results of the EMN10-Unito Trial

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 27-28
Author(s):  
Roberto Mina ◽  
Alessandra Larocca ◽  
Paolo Corradini ◽  
Nicola Cascavilla ◽  
Anna Marina Liberati ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Peripheral Neuropathy ◽  
Board Of Directors ◽  
Research Funding ◽  
Single Agent ◽  
Induction Phase ◽  
Newly Diagnosed ◽  
Advisory Committees ◽  
Grade 3

INTRODUCTION. The proteasome inhibitor (PI) Ixazomib, approved for the treatment of relapsed/refractory multiple myeloma (MM), represents an appealing option for the management of elderly patients, due to its oral administration and the lack of peripheral neuropathy. We previously presented preliminary results of the phase II EMN10-Unito study investigating Ixazomib in combination with dexamethasone (Id), Cyclophosphamide-dexamethasone (ICd), Thalidomide-dexamethasone (ITd) or Bendamustine-dexamethasone (IBd) as induction therapy followed by single-agent Ixazomib maintenance in transplant-ineligible newly diagnosed (ND) MM patients. Here we present updated results of the study with a longer follow-up. METHODS. Transplant-ineligible NDMM patients ≥65 years were enrolled. Treatment consisted of 9 28-day induction cycles of Ixazomib 4 mg on days 1,8,15 and dexamethasone 40 mg on days 1,8,15,22 or Id plus either Cyclophosphamide 300 mg/m2 orally on days 1,8,15 or Thalidomide 100 mg/day or Bendamustine 75 mg/m2 iv on days 1,8; followed by Ixazomib maintenance (4 mg on days 1,8,15) for up to 2 years. The primary endpoint was the selection of the most effective induction regimen considering a 2-year progression-free survival (PFS) ≥65% as satisfactory; secondary endpoints were very good partial response (VGPR), PFS2, overall survival (OS) and adverse events (AEs) during induction and maintenance. RESULTS. 171 patients (Id 41, ICd 59, ITd 60 and IBd 11) with a median age of 74 years were enrolled and started treatment. Two of the four investigational arms were prematurely closed due to low-enrollment (IBd arm, 11 patients enrolled) and high risk of inefficacy (Id, 41 patients enrolled). Median follow-up was 27 months. After the induction phase, ICd and ITd resulted in higher ≥ PR (75%-84% vs. 57%; p<0.05) and VGPR (46%-48% vs 24%; p<0.05) rates as compared to Id. The median PFS was 10.3 months with Id, 17.9 with ICd, 12.3 with ITd, and 13.8 with IBd, with a 2-year PFS probability of 31%, 39%, 27% and 40%, respectively. Median OS was not reached in either arm, without significant differences in the 2-year OS across arms (Id: 85%; ICd: 75%; ITd: 78%; IBd: 89%). Grade 3-4 non-hematological AEs were more frequent in the ITd arm (45%) as compared to the Id (17%), ICd (17%) and IBd (36%) arms, as well as the risk of treatment discontinuation due to AEs: ITd 17% vs Id 10%, ICd 12%, IBd 9%. Overall, 102 patients (60%) completed the induction phase and proceeded to ixazomib maintenance (median follow-up from start of maintenance: 18 months). The best response during maintenance was PR in 26%, VGPR in 29%, and complete response (CR) in 26% of patients; 18% of patients improved the response obtained during induction by at least one IMWG category. The median PFS from start of maintenance was 15 months. The median duration of maintenance was 12 months. All grades AEs occurred in 39% of patients during maintenance, while grade 3-4 AEs occurred in 10% of patients. Grade 1-2 peripheral neuropathy (PN) was reported in 15% of patients, without grade 3-4 events. Overall, 15% required at least one dose reduction of ixazomib and 12% discontinued ixazomib maintenance due to AEs. CONCLUSIONS. Safety and efficacy data suggest that Id combined with cyclophosphamide was the most promising induction strategy compared to the other investigated combinations. Continuous treatment with single-agent Ixazomib confirmed its efficacy and tolerability in elderly NDMM patients. Disclosures Mina: Amgen: Honoraria; Celgene: Honoraria; Takeda: Honoraria; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Larocca:GSK: Honoraria; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: 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; Amgen: Honoraria; Takeda: Membership on an entity's Board of Directors or advisory committees. Corradini:KiowaKirin: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Other: Travel and accommodations paid by for; Sanofi: Consultancy, Honoraria; Servier: Consultancy, Honoraria; Takeda: Consultancy, Honoraria, Other; BMS: Other; Kite: Consultancy, Honoraria; Gilead: Consultancy, Honoraria, Other: Travel and accommodations paid by for; Daiichi Sankyo: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria, Other: Travel and accommodations paid by for; Janssen: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Other: Travel and accommodations paid by for; Incyte: Consultancy; Celgene: Consultancy, Honoraria, Other: Travel and accommodations paid by for; F. Hoffman-La Roche Ltd: Consultancy, Honoraria. Liberati:CELGENE: Honoraria; BIOPHARMA: Honoraria; ARCHIGEN: Honoraria; BEIGENE: Honoraria; BMS: Honoraria; AMGEN: Honoraria; FIBROGEN: Honoraria; INCYTE: Honoraria; VERASTEM: Honoraria, Research Funding; ROCHE: Honoraria, Research Funding; PFIZER: Honoraria, Research Funding; ONCOPEPTIDES AB: Honoraria, Research Funding; TAKEDA: Honoraria, Research Funding; MORPHOSYS: Honoraria, Research Funding; ONCONOVA: Honoraria, Research Funding; ABBVIE: Honoraria, Research Funding; NOVARTIS: Honoraria, Research Funding; KARYOPHARM: Honoraria, Research Funding; JANSSEN: Honoraria. Zambello:Celgene: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees. Belotti:Amgen: Membership on an entity's Board of Directors or advisory committees; Jannsen: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees. Boccadoro:Sanofi: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding; AbbVie: Honoraria; Mundipharma: Research Funding; GlaxoSmithKline: Membership on an entity's Board of Directors or advisory committees. Bringhen:Takeda: Consultancy; Celgene: 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; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. OffLabel Disclosure: The presentation includes discussion of off-label use of a drug or drugs for the treatment of multiple myeloma (including ixazomib, dexamethasone, cyclophosphamide, thalidomide and bendamustine).

scholarly journals Prognostic and Predictive Gene Expression Profiling (GEP) Markers Confirmed in Carfilzomib, Lenalidomide, and Dexamethasone (KRd) Treated Newly Diagnosed Multiple Myeloma (NDMM) Patients (Pts)

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 2141-2141 ◽  
Author(s):  
Martin van Vliet ◽  
Jagoda Jasielec ◽  
Dominik Dytfeld ◽  
Ravi Vij ◽  
Belinda Dumee ◽  
...  
Keyword(s):  
High Risk ◽  
Board Of Directors ◽  
Research Funding ◽  
Single Agent ◽  
Fisher Exact Test ◽  
Cell Transplant ◽  
Advisory Committees ◽  
Significant Group ◽  
Cutoff Date

Abstract Introduction High rates of complete response (CR) have previously been demonstrated in KRd-treated NDMM pts in a phase 1/2 trial (trial 1; NCT01029054) and a phase 2 trial that combined KRd with autologous stem cell transplant (ASCT) (trial 2; NCT01816971). Here, we report results of extended follow-up from the 2 trials and correlate response and PFS with GEP performed using the MMprofiler GEP assay, which provides results for the SKY92 signature, 7 virtual karyotyping markers (t[4;14], t[11;14], t[14;16]/t[14;20], gain[1q], del[13q], del[17p], H-MM [virtual gain(9q)]), and 3 clusters (MF, MS, CD2). Previously, a combination of 5 markers (SKY92, virtual gain[1q], virtual t[14;16]/t[14;20], MF and CD2 clusters) was identified that predicts improved outcomes when treated with the proteasome inhibitor (PI) bortezomib (van Vliet et al, EHA 2014). We evaluated the SKY92 prognostic signature, virtual karyotyping markers, and this 5-marker PI predictor signature in order to confirm these markers as predictive signatures in the KRd setting. Materials and Methods In the consecutive trials 1 and 2, pts received 4 cycles of KRd induction, followed by extended KRd treatment with deferred ASCT (trial 1; NCT01029054) or ASCT followed by extended KRd treatment (trial 2; NCT01816971). In both trials, pts received single-agent lenalidomide as maintenance after completion of KRd. The MMprofiler GEP assay was performed on RNA from CD138+ purified plasma cells. As depth of response with KRd is associated with improved time-to-event outcomes (Jasielec et al, ASH 2013), data were analyzed for associations between any of the MMprofiler markers and the groups that achieved ≥near CR (nCR) vs <nCR by the end of 4 cycles (Fisher exact test). For progression-free survival (PFS), Kaplan-Meier curves were constructed, median survival estimates were calculated, and the Cox proportional hazards model was used to calculate hazard ratios (HR) and associated p-values. Results Based on a July 1, 2014 cutoff date, 91 pts were enrolled (53 in trial 1; 38 in trial 2). CD138+ RNA was available from 27 pts (16 from trial 1; 11 from pts in trial 2 who completed ≥4 KRd cycles). Pts with H-MM (virtual gain[9q]) were significantly less likely to achieve nCR (p=0.027) (Table 1). None of the other markers were found to have a statistically significant association with response; several markers, however, showed a trend for predictive value at the current sample size. PFS data were available for 16 pts (median follow-up: trial 1, 40 months [mo]; trial 2, 6.7 mo [with no events at the cutoff date]). Two markers were found to be significantly prognostic (Figure 1): SKY92 (5/16 pts [31%]; HR=5.7; p=0.023) and virtual gain (1q) (6/16 pts [38%]; HR=5.5; p=0.017). Virtual t(4;14) was marginally significant (HR=3.7, p=0.055). When considering the 5-marker PI predictor signature, none of the 16 pts were positive for virtual t(14;16)/t(14;20), MF or CD2 clusters. Combining the SKY92 and virtual gain(1q) markers identified a highly significant subgroup of high-risk pts (7/16; 44%) with a median PFS of 26 mo (HR=8.7; p=0.0088; Figure 1). In no-risk pts (9/16), estimated 4-year PFS was 78%. Conclusions Absence of H-MM (virtual gain[9q]) identified pts more likely to achieve ≥nCR by the end of 4 cycles of KRd, with other markers awaiting validation from ongoing enrollment to the KRd + ASCT trial. Based on combined SKY92 high-risk and virtual gain(1q) signatures, the MMprofiler assay detected a highly significant group of high-risk pts with inferior PFS compared to the no-risk group. Despite the inferior outcome, these high-risk pts appeared to have benefited from KRd when compared to historical data of treatment without PIs, suggesting that the 5-marker PI predictor signature (Van Vliet et al, EHA 2014) may also apply to carfilzomib-based treatment. We observed a 4-year PFS rate in no-risk pts in the KRd trials which trended higher than the historical outcome of the PAD arm in the HOVON65/GMMG-HD4 trial (78% vs 34%, respectively), suggesting a benefit for KRd without ASCT in this group of pts compared with other strategies with PIs; further study is needed, however. With ongoing enrollment into the KRd + ASCT trial, the findings reported here will be further validated. Updated results will be presented at the meeting. Acknowledgments This research was performed within the framework of CTMM, the Center for Translational Molecular Medicine, project BioCHIP grant 03O-102. Disclosures van Vliet: SkylineDx: Employment. Vij:Celgene: Honoraria, Research Funding; Onyx: Honoraria, Research Funding; Sanofi: Honoraria; Janssen: Honoraria; Novartis: Honoraria; Millennium: Honoraria; Array: Honoraria. Dumee:SkylineDx: Employment. Bosman:SkylineDx: Employment. deBest:SkylineDx: Employment. van Beers:SkylineDx: Employment. Jakubowiak:Bristol-Myers Squibb: 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, Speakers Bureau; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Millennium: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Onyx: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; SkylineDX: Honoraria, Membership on an entity's Board of Directors or advisory committees.

Combination of the Hypercvad Regimen with Dasatinib in Patients with Relapsed Philadelphia Chromosome (Ph) Positive Acute Lymphoblastic Leukemia (ALL) or Lymphoid Blast Phase of Chronic Myeloid Leukemia (CML-LB)

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 2578-2578 ◽  
Author(s):  
Theresa Liu-Dumlao ◽  
Susan O'Brien ◽  
Jorge E. Cortes ◽  
Deborah A. Thomas ◽  
Stefan Faderl ◽  
...  
Keyword(s):  
Research Funding ◽  
Kinase Inhibitors ◽  
Lymphoblastic Leukemia ◽  
Philadelphia Chromosome ◽  
High Dose ◽  
Molecular Response ◽  
Cell Transplant ◽  
Imatinib Resistance ◽  
Platelet Recovery

Abstract Abstract 2578 Prognosis for patients (pts) with Ph+ ALL has improved significantly with the introduction of tyrosine kinase inhibitors (TKI). Dasatinib is ∼325 times more potent than imatinib, and has shown activity in pts with imatinib resistance or intolerance, both in CML and Ph+ ALL. From 9/2006, pts with relapsed Ph+ ALL or CML-LB received dasatinib 100 mg po daily for the first 14 days of each of 8 cycles of alternating hyperCVAD, and high-dose cytarabine with methotrexate. Patients in complete remission (CR) continued to receive maintenance with dasatinib 100 mg po daily, with vincristine and prednisone monthly for 2 years, followed by dasatinib indefinitely. All patients proceeded to an allogeneic stem cell transplant as soon as feasible. From 8/2009, dasatinib dose was modified to 100mg po daily for the first 14 days of the first cycle, then at 70mg po daily continuously. Pts also received Rituximab on Days 1 and 11 of each of the first 4 cycles of therapy. A total of 32 pts with relapsed Ph+ ALL (n=18) or CML-LB (n=14) have received a median of 3 cycles (range=1–8 cycles). Twenty-three pts were treated on the initial regimen and 9 pts on the modified version. Median age was 50 yrs (range 21–77). Median number of prior regimens was 1 (range=1–2): hyperCVAD plus imatinib (n=10, 3 had transplant in first CR), other combination chemotherapy (n=12), monotherapy with TKI other than dasatinib (n=8), and investigational agents (n=2). Median WBC at start of treatment was 9.8 × 109/L (range=0.3–295.5 × 109/L). Median bone marrow blast percentage was 72% (range 0–97%; 1 pt had solitary CNS relapse). Eight (25%) patients had CNS involvement. Pre-treatment ABL mutations noted in 9 pts included: T315I(n=4), Y253F(n=1), Y253H(n=4), F359V(n=1), E459K(n=1), E255K(n=1), F317L(n=3), M351T(n=1). The overall response rate was 94%, with 23 pts (72%) achieving CR, and 7(22%) CR with incomplete platelet recovery (CRp). One pt died during induction. One pt had progressive disease. Twenty-five pts (83%) achieved complete cytogenetic remission after one cycle of therapy. Overall, 13 pts (43%) achieved complete molecular response, and 10 pts (33%) major molecular response (i.e., BCR-ABL/ABL<0.1%). Nine patients proceeded to allogeneic transplantation (ALL n=2, CML-LB n=7); one previously transplanted patient with ALL received donor lymphocyte infusion. Grade 3/4 toxicities included bleeding (GI, GU, and subdural hematomas), pleural effusions, pericardial effusions, infections, diarrhea, hypophosphatemia, hypocalcemia, elevated transaminases, and hyperbilirubinemia. The median follow-up for pts with CML-LB is 85 wks (range=12–209 wks); 3-yr OS is 76% (median not reached); and, 82% remain in CR at 3 yrs [median CR duration (CRD) not reached]. For ALL pts, median follow-up was 139 wks (range=74–175 wks); 3-yr OS is 33% (median=42 wks); and, 30% remain in CR at 3 yrs (median CRD=38 wks). The outcomes were the same for pts with CML-LB who did or did not receive a transplant (3-yr OS 83% for both cohorts). Among pts with ALL, outcome was better for those who underwent transplant (2 of 2 alive at 3 yrs as opposed to 4 of 16 without transplant). Conclusion: The combination of HyperCVAD regimen with dasatinib is effective in patients with relapsed Ph+ ALL and CML-LB. Disclosures: Cortes: Novartis: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Ariad: Consultancy, Research Funding. Jabbour:Novartis: Honoraria; Pfizer: Honoraria; BMS: Honoraria. Kantarjian:BMS: Research Funding. Ravandi:Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Honoraria.

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