A phase I/II trial of combination of PKC412 and 5-azacytidine (AZA) for the treatment of patients with refractory or relapsed (R/R) acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS).

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 6589-6589
Author(s):  
Aziz Nazha ◽  
Hagop Kantarjian ◽  
Gautam Borthakur ◽  
Tapan M. Kadia ◽  
Stefan Faderl ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Phase I ◽  
Phase Ii ◽  
Myeloid Leukemia ◽  
Kinase Inhibitor ◽  
Performance Status ◽  
Clinical Activity ◽  
Flt3 Inhibitors ◽  
To Receive ◽  
Acute Myeloid

6589 Background: Midostaurin (PKC412) is a FLT3 kinase inhibitor with activity in acute myeloid leukemia (AML). Hypomethylating agents play an important role in the treatment of AML and MDS. We investigated the safety (phase I) and clinical activity (phase II) of combination of 5-azacytidine (AZA) and PKC412 in pts with R/R AML and MDS. Method: Pts ≥18 years with MDS, CMML or AML, who failed prior therapies with performance status <2, adequate liver (bilirubin < 2x ULN, ALT ≤ 2.5x ULN) and renal (creatinine < 2x ULN) functions were eligible. Pts received AZA 75 mg/m2 subcutaneously or intravenously for 7 days of each cycle (Days 1-7) and PKC412 at 25 mg (cohort 1) and 50 mg (cohort 2; target dose) orally twice daily for 14 days (Days 8-21). Pts were to receive up to 12 cycles if benefit from treatment. Supportive care was standard. Results: 14 pts were included in phase I. 1 pt was inevaluable for DLT (withdrawal before completing cycle#1). 6 pts treated in cohort 1 and 7 in cohort 2. 1 pt in cohort 2 received PKC412 dose as per cohort 1 dose by pt error. Pt characteristics and responses are summarized in the Table. The overall response rate (ORR) was 3/13(21%) (2 with CRi, 1 pt dropped BM blasts form 27% to 7% after 2 cycles and went to transplant. 1/4 with FLT3-ITD achieved CRi, 2 of the non-responders received prior FLT3 inhibitors (1 had developed FLT3 D835). All toxicities were grade 1 (nausea 1 pt, vomiting 1 pt, dry skin 1 pt, and rash 1 pt) with no difference between the 2 groups. No DLT was identified. Conclusions: PKC412+AZA is safe and well tolerated at the intended doses with good ORR in high risk pts with R/R AML. Phase II study is enrolling pts with FLT3-ITD. Updated result will be presented. [Table: see text]

Early Results Of a Phase I/II Trial Of Midostaurin (PKC412) and 5-Azacytidine (5-AZA) For Patients (Pts) With Acute Myeloid Leukemia and Myelodysplastic Syndrome

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 3949-3949
Author(s):  
Paolo Strati ◽  
Hagop M Kantarjian ◽  
Aziz Nazha ◽  
Gautam Borthakur ◽  
Naval G. Daver ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myelodysplastic Syndrome ◽  
Phase I ◽  
Phase Ii ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
Flt3 Mutations ◽  
Flt3 Inhibitors ◽  
Grade 3 ◽  
Acute Myeloid

Abstract Background Acute Myeloid Leukemia (AML) and Myelodysplastic Syndrome (MDS) affect primarily elderly pts. Their treatment with aggressive chemotherapy is frequently challenging. Moreover, pts with FLT3 mutations have very poor prognosis. We hypothesized that the combination of midostaurin, a FLT3 inhibitor, and 5-AZA, a hypomethylating agent, may be an effective and safe regimen. Methods Both untreated (8) and previously treated (36) pts with AML or MDS were eligible for this study, regardless of FLT3 mutation and prior exposure to FLT3 inhibitors. Pts received 5-AZA 75 mg/mq subcutaneously or intravenously on day 1-7 and midostaurin 25 mg bid (in cohort 1 of phase I) or 50 mg bid (in cohort 2 of Phase I and in Phase II) orally on day 8-21 during the first cycle and continuously thereafter, for 12 cycles of 28 days duration. Cytogenetic risk was defined according to MRC criteria. Differences between categorical variables were compared by the chi2 test. CR duration (CRD) was calculated from the time of CR achievement until relapse and estimated by the Kaplan-Meier method and compared by the log-rank test. Results Fourty-four pts were enrolled, 13 included in Phase I and 31 in Phase II. Baseline pts’ characteristics are shown in the Table. Thirty-eight pts (86%) received 50 mg bid of midostaurin, and 6 (14%; Phase I) received 25 mg bid. The median number of administered cycles was 2 (1-9). Grade 3-4 hematological toxicities consisted of 95% neutropenia, 64% anemia and 93% thrombocytopenia. Grade 3-4 non-hematological toxicities consisted of 45% infections, 23% hypokalemia, 16% hyponatremia, 7% reduction in ejection fraction, 7% hyperuricemia, 4% hyperglycemia, 4% nausea/vomiting, 4% QTc prolongation, 4% hyperbilirubinemia, and 4% elevated AST. Eleven pts (25%) achieved a CR, 9 with incomplete platelet recovery (20%), after a median time of 13 (10-16) weeks from treatment start. Five (11%) of these pts relapsed after achieving CR. Two pts (5%) received an allogeneic stem cell transplant while on study, one in CR and one primary refractory (after a blast count drop from 27 to 7%), and they are both still in CR and alive. Among 26 pts with FLT3 ITD and no D835 mutation, 9 (35%) achieved CR/CRp. Six of 18 (33%) pts not previously exposed to FLT3 inhibitors responded. There was no significant correlation of dose with response (24% with 50 mg bid vs 33% with 25 mg bid, p=0.63). After a median follow-up of 15 (3-72) weeks, 20 pts (64%) died, 3 (7%) while on study (2 died of sepsis, 1 of unknown causes with progressive disease). The median CRD was 16 (9-23) months. Factors significantly associated with a longer CRD were male sex (p=0.04), age older than 65 years (0.03) and use of 50 mg bid of midostaurin (p=0.02). Conclusions The combination of midostaurin and 5-AZA is safe and well tolerated. Its efficacy is most noticeable among pts with FLT3 mutations. A longer response duration is observed using midostaurin at 50 mg bid dose and in elderly male pts. Disclosures: Ravandi: CELGENE: Honoraria; NOVARTIS: Honoraria. Cortes:ARIAD: Consultancy, Research Funding; ASTELLAS: Research Funding; AMBIT: Research Funding; AROG: Research Funding; NOVARTIS: Research Funding.

Final Update of Phase I-II Study of the Farnesyltransferase Inhibitor Tipifarnib in Combination with Idarubicin and Cytarabine for Patients with Newly Diagnosed Acute Myeloid Leukemia or High-Risk Myelodysplastic Syndrome.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 441-441 ◽  
Author(s):  
John Delmonte ◽  
Hagop M. Kantarjian ◽  
Guillermo Garcia-Manero ◽  
Zeev Estrov ◽  
Farhad Ravandi ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
High Risk ◽  
Myelodysplastic Syndrome ◽  
Phase I ◽  
Myeloid Leukemia ◽  
Chemotherapeutic Agents ◽  
High Rate ◽  
Clinical Activity ◽  
Farnesyltransferase Inhibitor ◽  
Acute Myeloid

Background: Tipifarnib (Zarnestra, Z) is a non-peptidomimetic farnesyltransferase inhibitor (FTI) with clinical activity in hematologic malignancies, including acute myeloid leukemia (AML), myelodysplastic syndrome (MDS) and chronic myeloid leukemia. Preclinical data suggest that tipifarnib may be synergistic with some chemotherapeutic agents. Methods: We designed a phase I/II study in patients (pts) age 15–70 years, with previously untreated AML or high-risk MDS (blasts ≥ 10%), who received induction with idarubicin (Ida) 12 mg/m2/day on days 1–3, cytarabine (ara-C) 1.5 g/m2 IV over 24 hours daily on days 1–4 (days 1–3 only if age ≥ 60 years) and Z, with first cohort (n=6) receiving 200mg PO BID and all others 300 mg PO BID x 21 days every 28 days. Pts achieving a complete remission (CR) received consolidation (5 courses) with Ida 8 mg/m2/day on days 1–2, ara-C 0.75 g/m2/day on days 1–3, and Z 300 mg PO BID x 14 days every 4–6 weeks. Maintenance was with Z 300 mg PO BID x 21 days every 4–6 weeks for 6 months. Results: We treated 95 pts, median age 50 yrs (range, 17–61 yrs), and all are evaluable for response with a median followup of 61 weeks (range, 35–138). Seventy pts (73%) responded: 61 (64%) achieved a CR and 9 (9%) a CRp. Median CR duration was 72 weeks, (range, 4–121) with median OS 70 weeks (range, 1–138). Response by cytogenetics was: 34/41 (83%) for diploid, 13/19 (69%) with −5/−7, 1/2 (50%) with t(8;21), and 21/32 (65%) with other abnormalities. Response by age was 31/43 (72%) for < 50 yrs, 12/18 (67%) for ≥ 50 yrs with diploid karyotype, and 18/34 (53%) for ≥ 50 yrs with abnormal karyotype. Response by FLT3 status was 12/16 (75%) for mutated, 51/66 (78%) for unmutated. Overall response rate (CR+CRp) in a similar historical population treated with the same chemotherapy regimen, idarubicin/cytarabine (IA), without Z was 72% (p=0.847), median CR duration 52 weeks (range, 2–319) (p=0.493), median OS 65 weeks (range, 3–322) (p=0.698). The most common grade ≥ 3 adverse events have included diarrhea (39%), hypokalemia (27%), rash (21%), and hepatic dysfunction (18%). Fifty-three (56%) pts have required treatment dose reductions during induction, 21 pts (40%) during consolidation, and 3 pts (18%) during maintenance. Conclusion: We conclude that Z combined with IA induces a high rate of CR in high-risk MDS or AML, but the outcome may not be superior to what is obtained with IA alone.

Fludarabine, Cytarabine, and Attenuated-Dose Idarubicin (m-FLAI) Induction for Elderly Patients with Acute Myeloid Leukemia: Results of a Multicenter Phase II Study,

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 3626-3626
Author(s):  
Yoojoo Lim ◽  
Youngil Koh ◽  
Sung-Soo Yoon ◽  
Seonyang Park ◽  
Byoung Kook Kim ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Acute Myeloid Leukemia ◽  
Elderly Patients ◽  
Phase Ii ◽  
Myeloid Leukemia ◽  
Conflicts Of Interest ◽  
Performance Status ◽  
Free Survival ◽  
Induction Regimen ◽  
Acute Myeloid

Abstract Abstract 3626 Introduction: Although there have been remarkable improvements in treatment of acute myeloid leukemia (AML), the prognosis of AML in elderly patients remains poor, and the best induction chemotherapy for these patients remains yet unknown. To devise an effective induction regimen for elderly patients with AML, we conducted a phase II trial to evaluate the efficacy and safety of the modified fludarabine, cytarabine, and attenuated-dose idarubicin (m-FLAI) regimen in these patients. Patients and Methods: Elderly (60 years or older) AML patients who did not receive previous chemotherapy were enrolled. Patients received two consecutive cycles of m-FLAI chemotherapy as an induction. The m-FLAI regimen was comprised of fludarabine (25mg/m2, days 1–4), cytarabine (1000mg/m2, days 1–4), and attenuated-dose idarubicin (5mg/m2, days 1–3). The primary end point was complete remission (CR) rate. Results: A total of 108 patients (median age 68.4 years, M:F=64:44) were enrolled. CR was achieved in 62.9% of patients, and treatment-related mortality rate (TRM) was 25.8%. Median overall survival (OS) was 9.3 months, and median event-free survival (EFS) was 6.6 months. The mortality at 30 and 60 days was 18% and 24%, respectively. Performance status and comorbidity did not have prognostic value in these patients. Bone marrow expression of CD117 was related to long EFS and OS. Conclusion: In conclusion, m-FLAI is a safe and effective induction regimen for previously untreated AML in elderly patients. Bone marrow CD117 expression is an independent good prognostic factor in these patients. (ClinicalTrials.gov number, NCT01247493) Disclosures: No relevant conflicts of interest to declare.

scholarly journals Phase I trial of volasertib, a Polo-like kinase inhibitor, in Japanese patients with acute myeloid leukemia

2015 ◽  
Vol 106 (11) ◽  
pp. 1590-1595 ◽  
Author(s):  
Yukio Kobayashi ◽  
Takahiro Yamauchi ◽  
Hitoshi Kiyoi ◽  
Toru Sakura ◽  
Tomoko Hata ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Phase I ◽  
Myeloid Leukemia ◽  
Phase I Trial ◽  
Kinase Inhibitor ◽  
Japanese Patients ◽  
Acute Myeloid

scholarly journals Phase I study of the aurora A kinase inhibitor alisertib with induction chemotherapy in patients with acute myeloid leukemia

Haematologica ◽  
2016 ◽  
Vol 102 (4) ◽  
pp. 719-727 ◽  
Author(s):  
Amir T. Fathi ◽  
Seth A. Wander ◽  
Traci M. Blonquist ◽  
Andrew M. Brunner ◽  
Philip C. Amrein ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Phase I ◽  
Induction Chemotherapy ◽  
Myeloid Leukemia ◽  
Phase I Study ◽  
Kinase Inhibitor ◽  
Aurora A Kinase ◽  
Aurora A ◽  
Acute Myeloid

scholarly journals Infusion of Haploidentical Stem Cell after Consolidation in Younger Patients with Acute Myeloid Leukemia: Preliminary Results of a Phase I-II Study

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 1614-1614
Author(s):  
Blanca Boluda ◽  
Pau Montesinos ◽  
Rebeca Rodríguez-Veiga ◽  
David Martínez-Cuadrón ◽  
Jaime Sanz ◽  
...  
Keyword(s):  
Stem Cells ◽  
Acute Myeloid Leukemia ◽  
Stem Cell ◽  
Phase I ◽  
Myeloid Leukemia ◽  
Immunosuppressive Treatment ◽  
Consolidation Chemotherapy ◽  
Younger Patients ◽  
To Receive ◽  
Acute Myeloid

Abstract Introduction Intensive consolidation chemotherapy in acute myeloid leukemia (AML) patients induces important hematologic toxicity with potential life-threatening infections that can lead to delays in further treatment or death in complete remission (CR). Recent single and multi-center studies (Guo et al. Blood 2011, JCO 2012, ASH 2015) have shown that the infusion of HLA-mismatched peripheral stem cell without immunosuppressive prophylaxis can accelerate hematologic recovery after chemotherapy, without developing graft versus host disease (GVHD). Objectives The primary objective of this phase I-II trial is to confirm the safety (absence of GVHD) and efficacy (reduction of neutropenia duration) of HLA-mismatched stem cells infusion after consolidation chemotherapy with idarubicine and cytarabine (3+7) in 50 younger patients with intermediate/high-risk AML. Herein we present the preliminary results of the phase I trial with 9 adult patients (safety cohort). Methods Patients younger than 65 years old with AML in CR after induction therapy that were assigned to receive consolidation course with idarubicin (12 mg/m2/day IV 1-3) and cytarabine (200 mg/m2/day IV 1-7) according to PETHEMA protocol were enrolled in this study in a single Spanish institution. To determine safety of HLA-mismatched stem cells infusion a standard 3+3 design was used in this preliminary study: cohorts of 3 patients were established with decreasing immunosuppressive prophylaxis, 3 additional patients would be enrolled with the same immunosuppression if limiting toxicity (LT) was observed in 1 out of 3 patients. LT was defined as global GVHD>grade 2 or grade 4 infusion related reactions. The first cohort of 3 patients was assigned to receive immunosuppression with cyclosporine (1-1.5 mg/kg/bid) and prednisone (0.5 mg/kg/qid), the second cohort to receive only prednisone (0.5 mg/kg/qid), and the third would not receive immunosuppressive treatment. The immunosuppression resulting of this phase would be used in an expansion cohort. Stem cells were obtained after mobilization with G-CSF and apheresis from HLA-mismatched family-related donors and were infused the day 9 of the consolidation course. The donor and recipient HLA-A, HLA-B, HLA-C, HLA-DRB1 and HLA-DQB1 alleles were genotyped using a PCR-SSP method. Hematologic recovery was defined as days from start of chemotherapy to neutrophil count >0.5x109/L and to platelet count >50x109/L. G-CSF was administered only in case of severe infection. This study was approved by the Ethical Committee, and inform consent was obtained from all patients and donors. Results From March 2015 to June 2016, 9 patients were enrolled in this study. Median age was 46 (28-64) and 6 were male. All were in CR after induction therapy, 6 had intermediate risk cytogenetic, and 3 high risk cytogenetic/molecular AML. All the donors were family-related and HLA compatibility was 3/6 for 8 patients and 5/6 in one patient. HLA-mismatched stem cells infusion characteristics were: median number of mononuclear cells, CD34+ and CD3+ T cells infused per course was 4.5 (2.1-6.6)x108/kg, 3.3 (0.7-4.9)x106/kg and 1.7 (0.8-2.3)x108/kg, respectively. LT was not reached and no diagnosis of GVHD was made. Two patients developed cytarabine related rash and other 2 patients infectious diarrhea. No patient needed further immunosuppressive treatment. Median duration of neutropenia and thrombocytopenia was 30 (27-50) and 44 (22-51) days, respectively. 3 patients received G-CSF and 2 developed severe infections. Median blood cell unit and platelet units transfused was 4 (2-20) and 8 (2-32). These results are similar to those observed in a historical cohort (non-matched) of 59 patients with AML who received consolidation with 3+7 at the same institution between January 2010 to January 2015 (median duration of neutropenia and thrombocytopenia was 29 (17-57) and 36 (18-206) days, respectively). Conclusion The infusion of HLA-mismatched stem cell is safe after consolidation with idarubicin and cytarabine in younger patients. The methodology and in consequence the results of our safety cohort (with immunosuppressive prophylaxis) are not comparable to the previous experience reported by other groups. The reduction of hematologic recovery remains to be confirmed with this schedule in a larger cohort without immunosuppressive prophylaxis. Research granted by IIS La Fe (2014/0368) Disclosures Boluda: Instituto de Investigación Sanitaria La Fe: Employment.

A Multicenter Randomized Comparison of Maintenance Treatment with Androgens in Elderly Acute Myeloid Leukemia after ICL Regimen as Induction Therapy: Results of the Goelams-2002 Study.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 1983-1983 ◽  
Author(s):  
Arnaud Pigneux ◽  
Chantal Himberlin ◽  
Mathilde Hunault-Berger ◽  
Francis Witz ◽  
Christian Recher ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Maintenance Therapy ◽  
Myeloid Leukemia ◽  
Performance Status ◽  
Age Groups ◽  
Normal Karyotype ◽  
To Receive ◽  
Standard Risk ◽  
Acute Myeloid

Abstract In an attempt to improve the outcome of acute myeloid leukemia in older patients, we performed a multicenter randomized trial evaluating the possible benefit of androgens during post remission therapy. All patients received the ICL regimen as induction (Idarubicin, 8mg/m2 d1–5; Cytarabine, 100mg/m2 d1–7 and Lomustine, 200mg/m2 d1). All patients were randomized at the time of diagnosis to receive, after achieving CR or PR, a maintenance therapy including or not androgens. Maintenance therapy consisted of 6 courses of reinduction with idarubicin (8mg/m2 d1) and cytarabine (100mg/m2d1–5, subcutaneously) every 3 months, and, between these courses, a continuous regimen of methotrexate and 6-mercaptopurine. Patients randomized with androgens additionally received 10 to 20 mg according to body weigh of norethandrolone daily from CR/PR on, for up to 2 years. Between June 2002 and January 2005, 330 patients aged ≥ 60 years (median 70 yrs, range 60–86) were included. CR, PR, failure and death rates after induction were 69 %, 6%, 9% and 15% respectively. The median follow-up for the 330 patients was 26 months. Among the 249 patients who achieved remission, 119 had been randomized with norethandrolone and 130 without. The 2 arms were balanced according to age, sex-ratio, performance status, FAB, WBC as well as platelets counts, peripheral blood and bone marrow blasts counts and cytogenetic groups (low risk: t(8;21), inv(16); high risk: del(5), del(7), del(11q), complex karyotype; standard-risk: normal karyotype and other aberrations). Differences in CR rates were only related to the latter parameter of cytogenetic features (P = 0.005). For the whole cohort of patients DFS at 3-years was 23±3% (median 13 months) and OS at 3 years was 29±3% (median 15 months). For patients who achieved CR or PR and had been randomized, the addition of androgens did not influence either DFS (P = 0.6) or OS (P = 0. 9), even when considering age groups, high/low WBC, or cytogenetic features. In conclusion, the ICL regimen followed by six reinductions and two years maintenance therapy induce high CR rates and improve OS and DFS. However the addition of androgens did not decrease the relapse rate.

5-Azacytidine to Treat Acute Myeloid Leukemia In Elderly or Frail Patients: A Phase II Study (SAKK 30/07)

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 2181-2181
Author(s):  
Jakob R. Passweg ◽  
Thomas Pabst ◽  
Sabine Blum ◽  
Mario Bargetzi ◽  
Hong Sun ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Phase Ii ◽  
Myeloid Leukemia ◽  
Conflicts Of Interest ◽  
Performance Status ◽  
Hematologic Toxicity ◽  
Intensive Chemotherapy ◽  
Frail Patients ◽  
Patient Refusal ◽  
Acute Myeloid

Abstract Abstract 2181 Background: Acute Myeloid Leukemia (AML) in the elderly is notoriously difficult to treat and has a low remission rate with very few long term survivors when using standard treatment approaches. Azacytidine, a hypomethylating agent, has been shown to induce remission and prolong survival in patients with myelodysplastic syndromes; studying this approach to patients with AML is therefore warranted. We present results of an ongoing phase II trial treating elderly or frail AML patients with Azacytidine. Methods: AML elderly or frail patients, and therefore unfit for an intensive chemotherapy regimens, with a WHO performance status ≤ 3 were considered for this trial. Trial therapy consisted of 100mg/m2 of Azacytidine injected subcutaneously on 5 consecutive days every 28 days up to 6 cycles, stopping at 6 months if no hematological improvement achieved, or earlier in the case of progression or complications. Treatment was continued beyond 6 months in responding patients. Trial therapy was considered uninteresting if the response rate (CR + PR) within 6 months of therapy initiation was 15% or less and promising if 34% or more. Using the exact single-stage phase II design by A’Hern with a 5% significance level and 90% power, 43 patients were required: If 10 or fewer achieved a response within 6 months the trial therapy should not be considered for further investigation in its current format for this indication and patient population. Results: Between September 2008 and January 2010, 45 evaluable patients across 10 Swiss centers were accrued with a median follow-up of 7 months (range: 0 – 13). 27 (60%) were male, median age was 74 (range: 55 – 86) years and 35 (78.8%) had performance status 0–1. Patients had been excluded from more intensive chemotherapy regimens because of age (n = 37) or due to comorbidities or patient refusal (n=8). Five patients had therapy related AML. Patients received a median of 3 (range: 1 – 10) cycles. Treatment was stopped for not achieving a response by the 6th cycle in 2 patients and earlier in 26 patients (for disease progression in 5, toxicity in 3, patient refusal in 2, recurrent infections in 1, and death in 8). Seventeen patients remain on therapy. The median time spent in the hospital was 12 days (1 - 30) in 24/38 patients hospitalized during the first treatment cycle and 13 days (2 - 28) in 15/31 patients hospitalized during subsequent cycles. Adverse events of grade III or higher most frequently reported were constitutional or hematologic, i.e. fatigue in 5, febrile neutropenia in 8, infections in 6, dyspnea in 6, anemia in 3, neutropenia in 12 and thrombocytopenia in 10, hemorrhage in 2 and retinal detachment in 5. Based on available data on 38 patients, CR/CRi or hematologic improvement or stable disease within 6 months of trial registration was observed in a proportion of patients. Final and mature data, determining whether the predefined proportion of responding patients has been reached or not, will be presented at the conference. Up to now there were a total of 26 deaths. Median overall survival time was 5.7 months (95% CI: 3.1, 8.7). Conclusions: The current results of this slightly modified Azacytidine schedule demonstrate a feasible new therapy option for elderly or frail AML patients in an outpatient setting with moderate, mainly hematologic toxicity. Disclosures: No relevant conflicts of interest to declare.

scholarly journals The pan-class I phosphatidyl-inositol-3 kinase inhibitor NVP-BKM120 demonstrates anti-leukemic activity in acute myeloid leukemia

2015 ◽  
Vol 5 (1) ◽  
Author(s):  
Matteo Allegretti ◽  
Maria Rosaria Ricciardi ◽  
Roberto Licchetta ◽  
Simone Mirabilii ◽  
Stefania Orecchioni ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Cell Lines ◽  
Myeloid Leukemia ◽  
Kinase Inhibitor ◽  
Phosphatidyl Inositol ◽  
Class I ◽  
Clinical Activity ◽  
Dependent Manner ◽  
Acute Myeloid

Abstract Aberrant activation of the PI3K/Akt/mTOR pathway is a common feature of acute myeloid leukemia (AML) patients contributing to chemoresistance, disease progression and unfavourable outcome. Therefore, inhibition of this pathway may represent a potential therapeutic approach in AML. The aim of this study was to evaluate the pre-clinical activity of NVP-BKM120 (BKM120), a selective pan-class I PI3K inhibitor, on AML cell lines and primary samples. Our results demonstrate that BKM120 abrogates the activity of the PI3K/Akt/mTOR signaling, promoting cell growth arrest and significant apoptosis in a dose- and time-dependent manner in AML cells but not in the normal counterpart. BKM120-induced cytotoxicity is associated with a profound modulation of metabolic behaviour in both cell lines and primary samples. In addition, BKM120 synergizes with the glycolitic inhibitor dichloroacetate enhancing apoptosis induction at lower doses. Finally, in vivo administration of BKM120 to a xenotransplant mouse model of AML significantly inhibited leukemia progression and improved the overall survival of treated mice. Taken together, our findings indicate that BKM120, alone or in combination with other drugs, has a significant anti-leukemic activity supporting its clinical development as a novel therapeutic agent in AML.

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