Sunitinib and Intensive Chemotherapy in Patients with Acute Myeloid Leukemia and Activating FLT3 Mutations: Results of the AMLSG 10-07 Study (ClinicalTrials.gov No. NCT00783653)

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 1483-1483 ◽  
Author(s):  
Walter Fiedler ◽  
Sabine Kayser ◽  
Maxim Kebenko ◽  
Jürgen Krauter ◽  
Helmut R. Salih ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Induction Therapy ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
Single Agent ◽  
Intensive Chemotherapy ◽  
Consolidation Therapy ◽  
Flt3 Mutations ◽  
Level 1 ◽  
Acute Myeloid

Abstract Abstract 1483 Background: Activating FLT3 mutations including internal tandem duplications (FLT3-ITD) and tyrosine-kinase domain mutation (FLT3-TKD) occur in approximately one third of patients with acute myeloid leukemia (AML) and are particularly associated with a poor outcome in case of FLT3-ITD. Sunitinib is a multitargeted FLT3 inhibitor approved for the treatment of advanced/metastatic renal cancer and metastatic/unresectable malignant GIST after failure of imatinib. Sunitinib has been evaluated in refractory AML as single agent treatment resulting in transient blast count reduction and in several cases of partial response in AML with activating FLT3 mutations. Aims: To evaluate the feasibility of a standard induction and consolidation therapy in combination with orally administered sunitinib in elderly AML patients with activating FLT3 mutations. Methods: Patients aged 60 years or higher with AML with activating FLT3 mutations (FLT3-ITD, FLT3-TKD) and fit enough for intensive chemotherapy were eligible. Induction therapy included cytarabine 100 mg/m2 per continuous infusion on days 1–7 and daunorubicin 60 mg/m2 i.v. on days 1–3 (DA). A second course was allowed in responding patients, who did not achieve a complete remission (CR). In patients achieving a CR after induction therapy three consolidation cycles were intended (cytarabine 1 g/m2 i.v. bid, on days 1,3,5). A 3+3 dose escalation/de-escalation scheme was used to define the dose and scheduling of sunitinib. The first cohort of three patients received oral sunitinib continuously starting from day 1 in a dose of 25 mg/day (level 1). Dose escalation to level 2 with sunitinib 37.5 mg/day continuously or dose de-escalation to level −1 with 25 mg day 1 to 7 had been defined in the protocol. After definition of the maximally tolerated dose (MTD) an extension of the cohort at that dose was intended. Results: A total of twenty-two patients were enrolled between January 2009 and March 2011. The median age was 70 years (range 60–78), 13 were female. The type of AML was de novo in 16 pts., s-AMLin one patient and t-AML in 4 pts. Fifteen patients had a FLT3-ITD (68%) and 7 a FLT3-TKD (32%) mutation. A NPM1 mutation was present in 11 patients (50%), 15 patients exhibited a normal karyotype, 3 an intermediate-2 risk karyotype according to ELN guidelines and 2 a complex karyotype and 2 had no evaluable metaphases. In the first cohort 5 patients were treated and two experienced dose-limiting toxicity (DLT), i) prolonged hematological recovery beyond day 35 in a patient achieving a CR and ii) a hand-foot-syndrome grade III. Four of the 5 patients achieved a CR. According to the protocol the following patients received treatment at dose level −1 with sunitinib 25mg days 1 to 7. In this cohort only one DLT occurred, again prolonged hematological recovery. Thus the MTD was defined at dose level −1. Response to induction therapy in all patients was CR in 13 pts. (59%), partial remission in 1 pt. (4.5%), refractory disease in 5 pts. (23%), death in 3 pts. (13.5%). CR rate in AML with FLT3-ITD was 53% (8/15) and 71% (5/7) in those with FLT3-TKD. All 13 patients achieving CR received repetitive cycles of high-dose cytarabine consolidation therapy and 7 proceeded to single agent sunitinib maintenance therapy (median 11 months, range 1–24 months). In these patients relapse occurred in 10, one patient died due to severe colitis during consolidation therapy and two patients are in sustained CR. Two patients not achieving a CR after induction therapy underwent allogeneic stem cell transplantation form matched unrelated donors. Twelve of the 22 patients died leading to a median survival of 18.8 months and a 2 year survival of 36% (95%-CI, 19–70%). Median relapse-free survival was 11 months. Conclusion: Combination of intensive induction and consolidation therapy with oral sunitinib in AML with activating FLT3 mutations is feasible with 25 mg sunitinib given during intensive therapy on days 1 to 7 and continuously during maintenance. Disclosures: Fiedler: Novartis: Consultancy, Research Funding; Pfizer Inc.: Consultancy, Research Funding.

Azacitidine-Containing Induction Regimens Followed by Azacitidine Maintenance Therapy in High Risk Acute Myeloid Leukemia: First Results of the Randomized Phase-II AMLSG 12-09 Study (ClinicalTrials.gov No. NCT01180322)

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 412-412 ◽  
Author(s):  
Richard F Schlenk ◽  
Wolfgang Herr ◽  
Gerald Wulf ◽  
Helmut R Salih ◽  
Jürgen Krauter ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Induction Therapy ◽  
Myeloid Leukemia ◽  
Single Agent ◽  
Intensive Chemotherapy ◽  
Genetic Aberrations ◽  
Second Stage ◽  
Flt3 Mutations ◽  
Unrelated Donors ◽  
Acute Myeloid

Abstract Abstract 412 Background: A large proportion of patients are currently not eligible for genotype-adapted strategies in acute myeloid leukemia (AML), in particular those lacking specific genetic aberrations such as PML-RARA, CBFB-MYH11, RUNX1-RUNX1T1, NPM1 or activating FLT3 mutations. This subgroup of patients accounts for about one-third of all AML patients and mainly includes the large group of AML with myelodysplasia-related changes, AML with recurrent cytogenetic abnormalities [inv(3) or t(3;3), t(9;11), t(v;11q23)] and cytogenetically normal AML (CN-AML) with wild-type NPM1 and FLT3. Prognosis in this subgroup of patients is generally poor. Azacitidine has been shown to be active in AML with low blast counts frequently observed in AML with myelodysplasia-related changes and in CN-AML in the absence of specific gene mutations. Aims: To evaluate clinical efficacy of azacitidine in combination with intensive induction chemotherapy and in maintenance for two years as single agent in patients with AML who are not candidates for genotype-adapted treatment approaches. Methods: Patients with AML in the absence of specific genetic aberrations (PML-RARA, CBFB-MYH11, RUNX1-RUNX1T1, NPM1 mutation, activating FLT3 mutations) who are fit for intensive chemotherapy were eligible. Patients were up-front randomized for induction therapy into one standard arm and three experimental arms; i) ICE (standard arm), idarubicin (12 mg/m2/day, iv, days 1,3,5), cytarabine (100 mg/m2/day, cont. infusion, days 1–7), etoposide (100 mg/m2/day, iv, days 1,2,3); ii) AZA-prior, azacitidine (100 mg/m2/day, sc, days 1–5), idarubicin (12 mg/m2/day, iv, days 6, 8, 10), etoposide 100 mg/m2/day, iv, days 6,7,8); iii) AZA-concurrent, azacitidine (100 mg/m2/day, sc, days 1–5), idarubicin (12 mg/m2/day, iv, days 1,3,5), etoposide 100 mg/m2/day, iv, days 1,2,3); iv) AZA-after, idarubicin (12 mg/m2/day, iv, days 1,3,5), etoposide 100 mg/m2/day, iv, days 1,2,3), azacitidine (100 mg/m2/day, sc, days 4–8). After two induction cycles for patients achieving complete remission (CR), consolidation therapy was prioritized; first priority) allogeneic hematopoietic blood stem cell transplantation (HSCT) from matched related as well as unrelated donors, second priority) 3 courses of high-dose cytarabine followed by two-year maintenance therapy with azacitidine as single agent (50 mg/m2/day, sc, days 1–5, every 4 weeks) in patients initially randomized to experimental treatment. The primary endpoint was achievement of CR. The statistical design of the study was based on the Simon's optimal two-stage design applied for each arm separately. The null hypothesis was CR-rate equal or below 0.40 whereas the alternative hypothesis was a CR rate of at least 0.55 with a power of 80% and a level of significance of 5%. Thus, in each arm at least 12 of 26 patients with response to induction therapy were necessary after the first to proceed to the second stage. Results: During the first stage of the study 104 patients were randomized; median age was 62.5 years (range 18–82), 46% were female. Data on cytogenetics showed intermediate risk karyotype in 67% (n=50) including CN-AML (n=31) and high-risk karyotype in 33% (n=25). The most frequent serious adverse events were grade 3/4 infection with an overall incidence of 25% and ranging from 20 to 34% in the different treatment arms. The number of responding patients in the treatment arms AZA-prior and AZA-concurrent after the first stage of the study were 11 of 26 (42%) and 10 of 26 (38%)Both arms, AZA-prior and were terminated accordingly. In contrast, the treatment arms ICE and AZA-after were carried forward to the second stage of patient recruitment since responding patients at that time were 14 of 26 (54%) in both arms. In total, 100 patients each have been enrolled in both treatment arms, ICE and AZA-after, with CR-rates of 59% and 52%, respectively (p=0.39). To date, 60 patients received an allogeneic HSCT (n=36 matched unrelated donors, n=23 matched related donors, n=1 haploidentical family donor). Maintenance treatment was started in 12 patients. Conclusion: Induction therapy with ICE or idarubicin, etoposide followed by azacitidine (AZA-after) appears equally effective in producing CR in patients with AML who are not candidates for genotype-adapted treatment approaches. An amendment perpetuating the treatment arms ICE and AZA-after within a phase-III concept is planned. Disclosures: Schlenk: Celgene: Research Funding. Off Label Use: Azacitidine combined with intensive chemotherapy.

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.

Sorafenib in Combination With Intensive Chemotherapy in Elderly Patients With Acute Myeloid Leukemia: Results From a Randomized, Placebo-Controlled Trial

2013 ◽  
Vol 31 (25) ◽  
pp. 3110-3118 ◽  
Author(s):  
Hubert Serve ◽  
Utz Krug ◽  
Ruth Wagner ◽  
M. Cristina Sauerland ◽  
Achim Heinecke ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Elderly Patients ◽  
Induction Therapy ◽  
Myeloid Leukemia ◽  
Kinase Inhibitor ◽  
Controlled Trial ◽  
Intensive Chemotherapy ◽  
Consolidation Therapy ◽  
Subgroup Analyses ◽  
Acute Myeloid

Purpose The prognosis of elderly patients with acute myeloid leukemia (AML) is still dismal even with intensive chemotherapy. In this trial, we compared the antileukemic activity of standard induction and consolidation therapy with or without the addition of the kinase inhibitor sorafenib in elderly patients with AML. Patients and Methods All patients received standard cytarabine and daunorubicin induction (7+3 regimen) and up to two cycles of intermediate-dose cytarabine consolidation. Two hundred one patients were equally randomly assigned to receive either sorafenib or placebo between the chemotherapy cycles and subsequently for up to 1 year after the beginning of therapy. The primary objective was to test for an improvement in event-free survival (EFS). Overall survival (OS), complete remission (CR) rate, tolerability, and several predefined subgroup analyses were among the secondary objectives. Results Age, sex, CR and early death (ED) probability, and prognostic factors were balanced between both study arms. Treatment in the sorafenib arm did not result in significant improvement in EFS or OS. This was also true for subgroup analyses, including the subgroup positive for FLT3 internal tandem duplications. Results of induction therapy were worse in the sorafenib arm, with higher treatment-related mortality and lower CR rates. More adverse effects occurred during induction therapy in the sorafenib arm, and patients in this arm received less consolidation chemotherapy as a result of higher induction toxicity. Conclusion In conclusion, combination of standard induction and consolidation therapy with sorafenib in the schedule investigated in our trial is not beneficial for elderly patients with AML.

Induction Therapy with Idarubicin and Etoposide Combined with Sequential or Concurrent Azacitidine In Patients with High-Risk Acute Myeloid Leukemia: Pilot-Phase of the AMLSG 12-09 Study

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 2184-2184
Author(s):  
Frank G. Rücker ◽  
Stephan Stilgenbauer ◽  
Martin Bommer ◽  
Daniela Späth ◽  
Silja Mack ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
High Risk ◽  
Induction Therapy ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
Single Agent ◽  
Severe Toxicity ◽  
Overall Response ◽  
History Of ◽  
Acute Myeloid

Abstract Abstract 2184 Background: Treatment outcome in patients with cytogenetically and/or molecularly defined high-risk acute myeloid leukemia (AML) is dismal with low complete remission (CR) rates after intensive induction therapy and 5-year overall survival of about 25% in patients 60 years and younger and far below 5% in patients above the age of 60 years. In younger patients, allogeneic hematopoietic stem cell transplantation (allo-HSCT) from matched related or unrelated donors results in significantly better clinical outcome especially if patients are transplanted early in first CR (Schlenk et al., J. Clin. Oncol. 2010, in press). Azacitidine is a demethylating agent showing promising results as a single agent in AML patients with bone marrow blast counts between 20 and 30%. Therefore, the randomized AMLSG 12-09 trial will evaluate the combination of idarubicin/etoposide chemotherapy combined with azacitidine instead of cytarabine as compared to induction with idarubicin/etoposide/cytarabine (ICE) in an attempt to increase CR rates in these high-risk patients. Aim: To evaluate feasibility of the investigational induction therapy with idarubicin and etoposide in combination with sequentially or concurrently administered subcutaneous (sc) azacitidine. Methods: Patients were treated according to the investigational treatment schedules of the AMLSG 12-09 protocol. Patients received idarubicin 12 mg/sqm on days 1, 3 and 5 and etoposide 100 mg/sqm on days 1, 2 and 3 (patients above the age of 65 years received idarubicin 12 mg/sqm and etoposide 100 mg/sqm only on days 1 and 3, respectively). Azacitidine 100 mg/sqm sc was added on days -5 to -1 in 7 patients (schedule A), days 1 to 5 in 6 patients (schedule B), and days 4 to 8 in 5 patients (schedule C). Results: 18 patients have been treated (13 males and 5 females). Median age was 62.5 years (range, 28–76). The cytogenetic and molecular risk profile of the 18 AML was as follows: Eight AML had MDS-related cytogenetic changes (WHO 2008) including five exhibiting a complex karyotype and two had 3q abnormalities; three AML had balanced t(v;11q23), and six exhibited a normal karyotype together with triple negative genotype (NPM1-wt, FLT3-wt and CEBPA-wt). In one case, there were no metaphases available, however molecularly NPM1-wt, FLT3-wt, CEBPA-wt, no core binding factor AML, no t(15;17) and or t(9;11) were present. Median WBC was 4.6/nl (range, 0–6-75/nl). Overall response to induction therapy was CR n=7, partial remission (PR) n=3, refractory disease (RD) n=7 and one patient died during induction therapy (ED). Moreover, two patients with RD achieved CR after additional cycles of single agent azacitidine treatment. Overall response rates (CR and PR) according to treatment schedule were 43% (3/7), 67% (4/6) and 80% (4/5) for schedules A, B and C, respectively. Most common azacitidine-related toxicity was local reactions at injection site not exceeding CTC-grade 2. As expected, fever in neutropenia was the most common severe toxicity (83%). In addition, one patient with history of epilepsy had seizures during induction therapy and one patient with history of Crohn‘s disease had mucositis CTC-grade 3. Allo-HSCT has been performed in three patients and is planned in five. After a median time of 7.5 months, 16 of 18 patients are alive. Conclusion: Azacitidine administered sc can be given safely either sequentially or concurrently in combination with idarubicine/etoposide induction chemotherapy. Response rate of this high-risk population appears promising and the toxicity profile was favorable. The question which schedule is the most effective will be addressed in the randomized AMLSG trial (NCT01180322) Disclosures: Stilgenbauer: Amgen: Research Funding; Bayer: Consultancy, Honoraria, Research Funding; Boehringer-Ingelheim: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Genzyme: Consultancy, Honoraria, Research Funding; GSK: Consultancy, Honoraria, Research Funding; Mundipharma: Consultancy, Honoraria, Research Funding; Roche: Consultancy, Honoraria, Research Funding; Sanofi Aventis: Research Funding. Döhner: Pfizer: Research Funding. Schlenk: Celgene, Pfizer, Novartis, Cephalon, Amgen: Research Funding.

scholarly journals Interim Results of a Phase 1b/2 Study of Entospletinib (GS-9973) Monotherapy and in Combination with Chemotherapy in Patients with Acute Myeloid Leukemia

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 2831-2831 ◽  
Author(s):  
Alison R. Walker ◽  
Bhavana Bhatnagar ◽  
A. Mario Q. Marcondes ◽  
Julie DiPaolo ◽  
Sumithra Vasu ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
Single Agent ◽  
Intensive Chemotherapy ◽  
Phase 2 ◽  
Employment Equity ◽  
Phase 1B ◽  
Equity Ownership ◽  
Acute Myeloid

Abstract Background:Spleen tyrosine kinase (SYK) is a nonreceptor cytoplasmic tyrosine kinase primarily expressed in cells of hematopoietic lineage. Constitutive activation of SYK in acute myeloid leukemia (AML) has been reported and targeted inhibition of SYK induced differentiation in vitro and demonstrated anti-leukemia activity in AML mouse models. SYK has also been shown to directly phosphorylate the FLT3 receptor, modulating its activation and possibly promoting its role in leukemogenesis. Entospletinib is an orally bioavailable, selective inhibitor of SYK shown to be clinically active in B-cell malignancies. Here we evaluate the combination of entospletinib in patients with untreated AML using a 14-day window phase to assess single-agent activity, then adding standard intensive chemotherapy. Methods: In this phase 1b/2 study (NCT02343939), patients age 18 to 70 years with previously untreated AML, preserved organ function, and ECOG ≤ 2 were eligible to receive dose escalated entospletinib for 14 days as monotherapy (days -14 to 0) followed by combination with daunorubicin 60 mg/m2/d, cycle 1 day 1 to 3, and cytarabine 100 mg/m2/d, cycle 1 day 1 to 7. All patients received entospletinib monotherapy for up to 14 days prior to starting induction. Chemotherapy could be initiated after 5 days of monotherapy (and entospletinib continued for 4+ weeks) in patients with leukemia-related complications necessitating chemotherapy. Patients enrolled to dose level (DL) 0 and DL 1 received entospletinib 200 mg po BID and 400 mg po BID, respectively. Patients with residual disease two weeks after chemotherapy received a second induction cycle identical to the first. Entospletinib was continued without interruption until remission was assessed at count recovery. Results:Twelve patients enrolled with a median age of 54 (range, 18-69) years. Patients were in the following European LeukemiaNet genetic risk groups: favorable (n=1), intermediate I (n=3), intermediate II (n=2), and adverse (n=4), respectively. Three patients were not evaluable for dose limiting toxicity (DLT) assessment and were replaced (due to detection of CNS disease requiring non-study therapy (n=1), and withdrawal of consent unrelated to drug toxicity (n=2)). Single-agent entospletinib during the window period was well tolerated; toxicities after combination with intensive chemotherapy were common and typical. Among 3 patients treated at 200mg BID, no DLT was observed. Of 3 patients treated at 400mg BID, a patient with documented fungal pneumonia developed grade 3 pneumonitis that was possibly related to entospletinib. Although this did not meet DLT criteria, DL 1 was expanded with 3 additional patients, none of whom experienced DLT. Overall, the most common non hematologic adverse events (inclusive of intensive chemotherapy periods) were febrile neutropenia, nausea, and diarrhea. Based on this clinical experience and compiled pharmacokinetic data demonstrating lack of benefit to further dose escalation, 400 mg BID was selected as the recommended phase 2 dose. Responses were seen at both levels. Among the 3 patients treated at 200 mg BID, two required a second induction but all achieved a complete remission (CR) (3/3; 100%). Of the 6 patients treated at 400mg BID, none required a second induction and the CR rate was also 100%. Remarkably, an 18 year old male with 11q23-rearranged AML achieved morphologic and cytogenetic CR after only the 14 day entospletinib monotherapy window (prior to chemotherapy). Another patient with 11q23-rearranged AML had significant platelet response during the window period (this patient refused disease evaluation by marrow aspiration prior to chemotherapy). Conclusions: Entospletinib appears to have significant clinical activity in AML, and its combination at doses up to 400mg BID with intensive chemotherapy is well tolerated. An extended phase 2 program is now underway. Patients with 11q23-rearranged AML may be uniquely sensitive to SYK inhibition by entospletinib. Detailed molecular analysis of these patients is ongoing and will be presented. Disclosures Walker: Gilead Sciences: Research Funding. Bhatnagar:Karyopharm: Research Funding. Marcondes:Gilead Sciences: Employment, Equity Ownership. DiPaolo:Gilead Sciences: Employment, Equity Ownership. Abella-Dominicis:Gilead Sciences: Employment, Equity Ownership.

scholarly journals Title in Chemotherapy for Acute Myeloid Leukemia with High Leukocyte Counts.

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 5272-5272
Author(s):  
Taiichi Kyo ◽  
Ryota Imanaka ◽  
Tetsuro Ochi ◽  
Takeshi Okatani ◽  
Kohei Kyo ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Induction Therapy ◽  
Myeloid Leukemia ◽  
Single Agent ◽  
Serum Lactate Dehydrogenase ◽  
Intensive Chemotherapy ◽  
Hematopoietic Stem ◽  
Monosomy 7 ◽  
Leukocyte Counts ◽  
Acute Myeloid

Abstract Introduction Chromosomal aberration is a powerful prognostic factor for acute myeloid leukemia (AML). On the other hand, age and high leukocyte counts at diagnosis are additional prognostic factors. In the case of high leukocyte counts, chemotherapy becomes difficult since there is a possibility of developing disseminated intravascular coagulation (DIC) and tumor lysis syndrome (TLS). In our hospital, we conducted leukapheresis for leukemia patients with high leukocyte counts at diagnosis who had not developed DIC, and then we performed the original intensive chemotherapy of our institution (see below). Therefore, we targeted AML patients with leukocyte counts high at diagnosis and analyzed the outcome of the chemotherapy retrospectively. Patient and methods We examined AML patients with leukocyte counts of 50000/ul or more who received their first treatment at our institution between April 2009 and December 2013. We conducted leukapheresis for patients with leukocyte counts of 50000/ul or more who had not developed DIC, followed by our original induction therapy. It consisted of four drugs; idarubicin (IDR) 12mg/m2 (10mg/m2 for 70 years of age or older) days 1, 3, 5, 8 and behenoyl cytosine arabinoside (BH-AC) 350mg/m2 (300mg/m2 for 70 years of age or older) days 1-10, merucaptopurine (6-MP) 70mg/m2 days 1-10, predonisolone (PSL) 20mg/person days 1-6. If the patient had developed DIC, we performed this induction therapy treating the DIC with recombinant human soluble thrombomodulin (rTM) and gabexate mesylsate (FOY). Since the release of rasburicase in April 2010, we used it to prevent TLS. After induction therapy, we performed consolidation therapy, which consisted of mitoxantrone + cytarabine, and then maintenance therapy. This consisted of two courses; BAMP therapy (BH-AC, Aclarcin, 6-MP, PSL) and miniIBMP + VCR therapy (IDR, BHAC, 6- MP, PSL) alternately. We performed hematopoietic stem cell transplantation (HSCT) for patients with relapse during suitable age and other eligible cases. Result A total of 33 patients with newly diagnosed AML were examined. There were 16 men and 17 women whose median age was 70 years (range, 17-93 years). The elderly patients over the age of 60 were 21/33 (63.6%). Median follow-time was 24 months (range 2-60 months). Leukocyte counts at the time of diagnosis were 50,400-445,900/ul (median 107,700/ul), 17 patients (15.5%) had counts of over 100,000/ul. Leukapheresis was performed on 7 patients and leukocyte reduction rate was 41.7%-75.4%. Serious complications were not observed during the procedure. Serum lactate dehydrogenase (LDH) value was 283-3645 U/L (median 1111 U/L) and serum uric acid value was 2-13.7 mg/dl (median 6.5 mg/dl). We administered rasbricase to 20/33 (60.6%) patients and three (9.1%) patients developed TLS. Seventeen patients (51.5%) underwent DIC, 9 patients were at diagnosis and the remaining 8 patients were after initiation of the induction therapy. We treated DIC with FOY single agent (5 patients), rTM single agent (4 patients) and combination of rTM and FOY (8 patients) and then all patients showed improvement. Karyotype was as follows: Good risk in 3 (9.1%) patients, two had t(15;17) and one had t(8;21); intermediate risk in 23 patients (69.7%), thirteen had normal karyotype, 3 patients had trisomy 8 and 4 patients had others; poor risk in 7 patients (21.2%), six patients had complex karyotype and one patient had monosomy 7. We performed bone marrow aspiration and examination of cerebrospinal fluid after the induction therapy. Twenty-seven (81.8%) patients achieved complete remission, one (3.0%) patient had partial remission and four (12.1%) patients were refractory. There were 10 (30.3%) patients who had central nerve invasion. One patient died of pulmonary hemorrhage and TLS during the induction therapy. One patient received HSCT during the first CR and the remaining 4 patients did so after relapse. Seventeen (51.5%) patients are alive and the median survival time was 13 months, the 3-year overall survival was 40%. Conclusion Intensive chemotherapy was feasible and effective with the supporting therapy if the patient was elderly and had high leukocyte counts. Disclosures No relevant conflicts of interest to declare.

scholarly journals Mini- Vs. Regular-Dose CLAG-M (Cladribine, Cytarabine, G-CSF, and Mitoxantrone) in Medically Less Fit Adults with Newly-Diagnosed Acute Myeloid Leukemia (AML) and Other High-Grade Myeloid Neoplasms

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 1364-1364 ◽  
Author(s):  
Anna B. Halpern ◽  
Megan Othus ◽  
Kelda Gardner ◽  
Genevieve Alcorn ◽  
Mary-Elizabeth M. Percival ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
Intensive Therapy ◽  
Treatment Intensity ◽  
High Grade ◽  
Intensive Chemotherapy ◽  
Myeloid Neoplasms ◽  
Acute Myeloid

Background: Optimal treatment for medically less fit adults with acute myeloid leukemia (AML) remains uncertain. Retrospective data suggest intensive therapy may lead to better outcomes in these patients. However, these findings must be interpreted cautiously because of the possibility of selection bias and other confounders. Ideally, the optimal treatment intensity is defined via randomized trial but whether patients and their physicians are amenable to such a study is unknown. We therefore designed a trial (NCT03012672) to 1) evaluate the feasibility of randomization between intensive and non-intensive therapy in this population and 2) examine the impact of treatment intensity on response rate and survival. We used CLAG-M as high-dose cytarabine-based intensive induction therapy. Rather than selecting different classes of drugs in the 2 treatment arms- which may have different modes of action and therefore confound the question of treatment intensity - we used reduced-dose ("mini") CLAG-M as the non-intensive comparator. Methods: Adults ≥18 years were eligible if they had untreated AML or high-grade myeloid neoplasms (≥10% blasts in blood or marrow) and were medically less fit as defined by having a "treatment related mortality" (TRM) score of ≥13.1, corresponding to a &gt;10-15% 28-day mortality with intensive chemotherapy. Left ventricular ejection fraction ≤45% was the only organ function exclusion. Patient-physician pairs were first asked if they were amenable to randomized treatment allocation. If so, they were randomized 1:1 to mini- vs. regular-dose CLAG-M. If not, in order to evaluate our secondary endpoints, the patient or physician could choose the treatment arm and still enroll on study. Patients and physicians then completed surveys elucidating their decision-making processes. Up to 2 induction courses were given with mini- vs. regular-dose CLAG-M: cladribine 2 or 5 mg/m2/day (days 1-5), cytarabine 100 or 2,000 mg/m2/day (days 1-5), G-CSF 300 or 480µcg/day for weight &lt;/≥76kg in both arms (days 0-5), and mitoxantrone 6 or 18 mg/m2/day (days 1-3). CLAG at identical doses was used for post-remission therapy for up to 4 (regular-dose CLAG) or 12 (mini-CLAG) cycles. The primary endpoint was feasibility of randomization, defined as ≥26/50 of patient-physician pairs agreeing to randomization. Secondary outcomes included rate of complete remission (CR) negative for measurable ("minimal") residual disease (MRD), rate of CR plus CR with incomplete hematologic recovery (CR+CRi), and overall survival (OS). Results: This trial enrolled 33 patients. Only 3 (9%) patient/physician pairs agreed to randomization and thus randomization was deemed infeasible (primary endpoint). Eighteen pairs chose mini-CLAG-M and 12 regular-dose CLAG-M for a total of 19 subjects in the lower dose and 14 subjects in the higher dose arms. The decision favoring lower dose treatment was made largely by the physician in 5/18 (28%) cases, the patient in 11/18 (61%) cases and both in 2/18 (11%). The decision favoring the higher dose arm was made by the patient in most cases 9/12 (75%), both physician and patient in 2/12 (16%) and the physician in only 1/12 (8%) cases. Despite the limitations of lack of randomization, patients' baseline characteristics were well balanced with regard to age, performance status, TRM score, lab values and cytogenetic/mutational risk categories (Table 1). One patient was not yet evaluable for response or TRM at data cutoff. Rates of MRDneg CR were comparable: 6/19 (32%) in the lower and 3/14 (21%) in the higher dose groups (p=0.70). CR+CRi rates were also similar in both arms (43% vs. 56% in lower vs. higher dose arms; p=0.47). Three (16%) patients experienced early death in the lower dose arm vs. 1 (7%) in the higher dose arm (p=0.43). With a median follow up of 4.2 months, there was no survival difference between the two groups (median OS of 6.1 months in the lower vs. 4.7 months in the higher dose arm; p=0.81; Figure 1). Conclusions: Randomization of medically unfit patients to lower- vs. higher-intensity therapy was not feasible, and physicians rarely chose higher intensity therapy in this patient group. Acknowledging the limitation of short follow-up time and small sample size, our trial did not identify significant differences in outcomes between intensive and non-intensive chemotherapy. Analysis of differences in QOL and healthcare resource utilization between groups is ongoing. Disclosures Halpern: Pfizer Pharmaceuticals: Research Funding; Bayer Pharmaceuticals: Research Funding. Othus:Celgene: Other: Data Safety and Monitoring Committee. Gardner:Abbvie: Speakers Bureau. Percival:Genentech: Membership on an entity's Board of Directors or advisory committees; Pfizer Inc.: Research Funding; Nohla Therapeutics: Research Funding. Scott:Incyte: Consultancy; Novartis: Consultancy; Agios: Consultancy; Celgene: Consultancy. Becker:AbbVie, Amgen, Bristol-Myers Squibb, Glycomimetics, Invivoscribe, JW Pharmaceuticals, Novartis, Trovagene: Research Funding; Accordant Health Services/Caremark: Consultancy; The France Foundation: Honoraria. Oehler:Pfizer Inc.: Research Funding; Blueprint Medicines: Consultancy. Walter:BioLineRx: Consultancy; Astellas: Consultancy; Argenx BVBA: Consultancy; BiVictriX: Consultancy; Agios: Consultancy; Amgen: Consultancy; Amphivena Therapeutics: Consultancy, Equity Ownership; Boehringer Ingelheim: Consultancy; Boston Biomedical: Consultancy; Covagen: Consultancy; Daiichi Sankyo: Consultancy; Jazz Pharmaceuticals: Consultancy; Seattle Genetics: Research Funding; Race Oncology: Consultancy; Aptevo Therapeutics: Consultancy, Research Funding; Kite Pharma: Consultancy; New Link Genetics: Consultancy; Pfizer: Consultancy, Research Funding. OffLabel Disclosure: Cladribine is FDA-approved for Hairy Cell Leukemia. Here we describe its use for AML, where is is also widely used with prior publications supporting its use

scholarly journals Idarubicin Dose Escalation During Consolidation Therapy for Adult Acute Myeloid Leukemia

2017 ◽  
Vol 35 (15) ◽  
pp. 1678-1685 ◽  
Author(s):  
Kenneth F. Bradstock ◽  
Emma Link ◽  
Juliana Di Iulio ◽  
Jeff Szer ◽  
Paula Marlton ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Induction Therapy ◽  
Myeloid Leukemia ◽  
Tandem Duplication ◽  
Gene Mutations ◽  
Severe Neutropenia ◽  
Consolidation Therapy ◽  
Internal Tandem Duplication ◽  
Flt3 Internal Tandem Duplication ◽  
Acute Myeloid

Purpose Higher doses of the anthracycline daunorubicin during induction therapy for acute myeloid leukemia (AML) have been shown to improve remission rates and survival. We hypothesized that improvements in outcomes in adult AML may be further achieved by increased anthracycline dose during consolidation therapy. Patients and Methods Patients with AML in complete remission after induction therapy were randomly assigned to receive two cycles of consolidation therapy with cytarabine 100 mg/m2 daily for 5 days, etoposide 75 mg/m2 daily for 5 days, and idarubicin 9 mg/m2 daily for either 2 or 3 days (standard and intensive arms, respectively). The primary end point was leukemia-free survival (LFS). Results Two hundred ninety-three patients 16 to 60 years of age, excluding those with core binding factor AML and acute promyelocytic leukemia, were randomly assigned to treatment groups (146 to the standard arm and 147 to the intensive arm). Both groups were balanced for age, karyotypic risk, and FLT3–internal tandem duplication and NPM1 gene mutations. One hundred twenty patients in the standard arm (82%) and 95 patients in the intensive arm (65%) completed planned consolidation ( P < .001). Durations of severe neutropenia and thrombocytopenia were prolonged in the intensive arm, but there were no differences in serious nonhematological toxicities. With a median follow-up of 5.3 years (range, 0.6 to 9.9 years), there was a statistically significant improvement in LFS in the intensive arm compared with the standard arm (3-year LFS, 47% [95% CI, 40% to 56%] v 35% [95% CI, 28% to 44%]; P = .045). At 5 years, the overall survival rate was 57% in the intensive arm and 47% in the standard arm ( P = .092). There was no evidence of selective benefit of intensive consolidation within the cytogenetic or FLT3–internal tandem duplication and NPM1 gene mutation subgroups. Conclusion An increased cumulative dose of idarubicin during consolidation therapy for adult AML resulted in improved LFS, without increased nonhematologic toxicity.

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