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.

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.

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.

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 A randomized comparison of immediate versus delayed application of G-CSF in induction therapy for patients with acute myeloid leukemia unfit for intensive chemotherapy

Haematologica ◽  
2007 ◽  
Vol 92 (12) ◽  
pp. 1719-1720 ◽  
Author(s):  
M. von Lilienfeld-Toal ◽  
C. Hahn-Ast ◽  
H. Kirchner ◽  
D. Flieger ◽  
G. Dolken ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Induction Therapy ◽  
Myeloid Leukemia ◽  
Intensive Chemotherapy ◽  
Acute Myeloid

scholarly journals Outcomes of Six-Dose High-Dose Cytarabine as a Salvage Regimen for Patients with Relapsed/Refractory Acute Myeloid Leukemia

2017 ◽  
Vol 2017 ◽  
pp. 1-4 ◽  
Author(s):  
Brandi Anders ◽  
Lauren Veltri ◽  
Abraham S. Kanate ◽  
Alexandra Shillingburg ◽  
Nilay Shah ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Induction Therapy ◽  
Myeloid Leukemia ◽  
Single Agent ◽  
Disease Free Survival ◽  
High Dose ◽  
Free Survival ◽  
High Dose Cytarabine ◽  
Refractory Acute Myeloid Leukemia ◽  
Acute Myeloid

Relapsed/refractory acute myeloid leukemia (RR-AML) is associated with poor prognosis and long-term disease-free survival requires allogeneic hematopoietic cell transplantation (allo-HCT). Limited data exists, regarding the optimal regimen to obtain remission prior to allo-HCT. Single agent high-dose cytarabine (10–12 doses administered every 12 hours) has been previously used as induction therapy. Six-dose high-dose cytarabine (HiDAC-6), commonly used as a consolidation regimen, has never been evaluated as induction therapy. We present a retrospective review of 26 consecutive patients with RR-AML receiving single agent cytarabine 3 g/m2intravenously every 12 hours on days 1, 3, and 5 for a total of six doses (HiDAC-6). Median follow-up for surviving patients was 10.4 months (range 1.6–112.2 months). Complete remission was obtained in 62% (54% CR and 8% CRi) of the patients. The median relapse-free survival (RFS) was 22.3 months (range 0.7–112 months), event-free survival (EFS) was 4.7 months (range 0.5–112 months), and the overall survival (OS) was 9.6 months (range 1–112 months). Thirty-five percent of patients were able to subsequently proceed to allo-HCT. Treatment-related toxicities included neutropenic fever (38%), infection (35%), neurotoxicity (8%), and skin toxicity (8%). This is the first study to demonstrate HiDAC-6 as an active treatment option for younger patients with RR-AML which can effectively serve as a bridge to allo-HCT without significant toxicity.

A Phase I Study of Tipifarnib Combined with Conventional Induction and Consolidation Therapy for Previously Untreated Patients with Acute Myeloid Leukemia Age 60 and Over.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 899-899 ◽  
Author(s):  
Joseph M. Brandwein ◽  
Brian F. Leber ◽  
Kang Howson-Jan ◽  
Aaron D. Schimmer ◽  
Andre C. Schuh ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Phase I ◽  
Dose Level ◽  
Induction Therapy ◽  
Myeloid Leukemia ◽  
Phase I Study ◽  
Single Agent ◽  
Hematologic Toxicity ◽  
Grade Iii ◽  
Acute Myeloid

Standard induction therapy for patients over age 60 with acute myeloid leukemia (AML) has produced complete response (CR) rates of around 55%, but most patients eventually relapse. Tipifarnib (R115777, ZarnestraR) has shown activity as a single agent in AML, and is well tolerated in older patients at doses up to 600 mg BID. This agent also has additive/synergistic effects on AML cell lines when combined with daunorubicin (DNR). From 2005–2007, patients age 60 and over with previously untreated AML (de novo or secondary) were enrolled in a Phase I study combining tipifarnib with standard induction therapy. The regimen consisted of cytarabine 100 mg/m2/day continuous IV infusion on days 1–7, DNR 60 mg/m2/day IV push x 3 on days 6–8 and tipifarnib orally twice daily on days 6–15. Tipifarnib was escalated over four doses levels in successive patient cohorts (200, 300, 400 and 600 mg). Patients achieving CR were eligible to received one consolidation using the same regimen. Dose-limiting toxicity (DLT) was defined as Grade III–IV non–hematologic toxicity or hematologic recovery times > 40 days unless due to persistent leukemia. Up to 2/6 DLTs were permitted at each dose level. The following DLT’s were identified during induction: Dose level I: 2/6 (grade III hyperbilirubinemia, grade IV transient respiratory arrest), dose level II: 0/3, dose level III: 0/3 and dose level IV: 2/6 (grade III typhlitis, grade III supraventricular tachycardia). Four additional patients were enrolled at dose level IV, with one DLT (grade III diarrhea). There were no DLTs during consolidation. There were no cases of delayed hematologic recovery. Of 22 evaluable patients, there were 9 CR, 3 MLFS, 2 PR and 8 non-responders. Of 7 patients with adverse risk cytogenetics, there were 3 CR, 1 MLFS and 1 PR. In summary, this regimen was well tolerated and the DLT was not reached, although somewhat more GI toxicity was seen at dose level IV. Because of the inherent toxicity of the underlying regimen and the elderly population, it was decided not to escalate further, and tipifarnib 600 mg BID has been chosen as the recommended dose for further study using this regimen.

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