Fludarabine, idarubicin, and cytarabine regimen together with TKI followed by haploidentical hematopoietic stem cell transplantation, a success for relapsed Ph+ acute lymphoblastic leukemia.
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ABSTRACT:
SUBMITTER: Sang W
PROVIDER: S-EPMC4831391 | biostudies-other | 2016 Apr
REPOSITORIES: biostudies-other
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Project description:The purine nucleoside analogues clofarabine and fludarabine are active in acute myeloid leukemia (AML). We conducted a phase I/II randomized study of idarubicin and cytarabine with either clofarabine (CIA) or fludarabine (FIA) for relapsed or refractory AML. Clofarabine 15?mg/m2 was identified as the recommended phase II dose. Eighty-one patients were assigned using adaptive randomization to CIA (n?=?48) or FIA (n?=?33). The complete response (CR)/CR without platelet recovery rate did not differ between CIA and FIA (38% versus 30%, respectively; p?=?.50). In both arms, more than half of patients who had received only one prior line of therapy achieved remission. The median event-free survival for CIA and FIA was 2.0 and 1.9 months (p?=?.48), and the median overall survival was 6.3 and 4.7 months, respectively (p?=?.28). No significant differences in adverse events or early mortality rates were observed. Overall, CIA and FIA resulted in similar response rates and survival in patients with relapsed/refractory AML.
| S-EPMC5773400 | biostudies-literature
Project description:To improve the outcome of allogeneic stem cell transplantation in refractory acute myeloid leukemia (AML), we conducted a single-arm phase II clinical trial to evaluate the efficacy and feasibility of conditioning regimen following cytoreduction chemotherapy with 7-day interval. Adult patients with refractory AML were enrolled in the study and received fludarabine, cytarabine, and idarubicin (FLAG-IDA) as cytoreductive chemotherapy followed by busulfan and fludarabine (Flu-BU) conditioning regimen and transfusion of mobilized peripheral stem cells from human leukocyte antigen-matched sibling or unrelated donor. The primary endpoint of the study was 2-year leukemia-free survival (LFS) and secondary endpoints included complete-remission rate, 2-year overall survival (OS), nonrelapse mortality (NRM), and relapse rate. A total of 16 patients were enrolled with median age of 36 (16-60), which included 9 primary induction failure, 2 early relapse, and 5 with relapse/refractory disease. The median cycles of previous chemotherapy were 4 (3-10) with a median of 55% (1%-90%) blasts in bone marrow. Six patients received transplantation from matched sibling and 10 from matched unrelated donors. After transplantation, 15 patients achieved bone marrow remission (11 complete remissions [CRs] and 4 bone marrow remissions without platelet recovery) at day +28. A total of 8 patients remained alive in CR with median LFS of 29.5 months (9.5-40.5 months). Four patients relapsed and 3 of them died of disease and another 4 patients died because of transplantation-related toxicity. The 2-year NRM and relapse rates were 25.0% ± 10.8% and 33.4% ± 13.8%, respectively with 2-year OS at 53.5% ± 13.1% and LFS at 50.0% ± 12.5%. Based on the Simon 2-stage design, 5 out of first eligible 14 patients remained leukemia-free for more than 2 years after allogeneic hematopoietic stem cell transplantation; thus, the null hypothesis of the study will be rejected and the study protocol is accepted as being warranted for further study. Based on the above data, our phase II study demonstrated that the sequential FLAG-IDA cytoreduction chemotherapy followed by Flu-BU conditioning regimen given at the hematological nadir was feasible and has sufficient activity to warrant further investigation prospectively with a larger patient sample (clinicaltrials.gov identifier: NCT01496547).
| S-EPMC4602511 | biostudies-literature
Project description:BACKGROUND:Fludarabine and clofarabine are purine nucleoside analogues with established clinical activity in patients with acute myeloid leukemia (AML). METHODS:Herein, the authors evaluated the efficacy and safety of idarubicin and cytarabine with either clofarabine (CIA) or fludarabine (FIA) in adults with newly diagnosed AML. Adults with newly diagnosed AML who were deemed suitable for intensive chemotherapy were randomized using a Bayesian adaptive design to receive CIA (106 patients) or FIA (76 patients). Patients received induction with idarubicin and cytarabine, plus either clofarabine or fludarabine. Responding patients could receive up to 6 cycles of consolidation therapy. Outcomes were compared with a historical cohort of patients who received idarubicin and cytarabine. RESULTS:The complete remission/complete remission without platelet recovery rate was similar among patients in the CIA and FIA arms (80% and 82%, respectively). The median event-free survival was 13 months and 12 months, respectively (P = .91), and the median overall survival was 24 months and not reached, respectively (P = .23), in the 2 treatment arms. CIA was associated with more adverse events, particularly transaminase elevation, hyperbilirubinemia, and rash. Early mortality was similar in the 2 arms (60-day mortality rate of 4% for CIA vs 1% for FIA; P = .32). In an exploratory analysis of patients aged <50 years, FIA was found to be associated with improved survival compared with idarubicin and cytarabine (2-year event-free survival rate: 58% vs 30% [P = .05] and 2-year overall survival rate: 72% vs 36% [P = .009]). CONCLUSIONS:CIA and FIA have similar efficacy in younger patients with newly diagnosed AML, although FIA is associated with a better toxicity profile. Cancer 2017;123:4430-9. © 2017 American Cancer Society.
| S-EPMC5739034 | biostudies-literature
Project description:Background: The CXCR4/SDF-1? axis plays a vital role in the retention of stem cells within the bone marrow and downstream activation of cell survival signaling pathways. LY2510924, a second generation CXCR4, showed significant anti-leukemia activity in a murine AML model. Methods: We conducted a phase I study to determine the safety and toxicity of LY2510924, idarubicin and cytarabine (IA) combination therapy in relapsed/refractory (R/R) AML. Eligible patients were 18-70 years of age receiving up to salvage 3 therapy. A peripheral blood absolute blast count of < 20,000/?L was required for inclusion. LY2510924 was administered daily for 7 days followed by IA from day 8. Two dose escalation levels (10 and 20 mg) were evaluated, with a plan to enroll up to 12 patients in the phase I portion. Results: The median age of the enrolled patients (n = 11) was 55 years (range, 19-70). Median number of prior therapies was 1 (1-3). Six and five patients were treated at dose-levels "0" (10 mg) and "1" (20 mg), respectively. Only one patient experiencing a dose limiting toxicity (grade 3 rash and myelosuppression). Three and one complete responses were observed at dose-levels "0" and "1," respectively; the overall response rate (ORR) was 36% (4 of 11 patients). A ? 50% decrease in CXCR4 mean fluorescence intensity was observed in 4 of 9 patients by flow cytometry, indicating incomplete suppression of CXCR4-receptor occupancy. Conclusions: The combination of LY2510924 with IA is safe in R/R AML. Dose-escalation to a 30 mg LY2510924 dose is planned to achieve complete blockade of CXCR4 receptor occupancy, followed by expansion phase at the recommended phase 2 dose-level.
| S-EPMC6167965 | biostudies-literature
Project description:Inhibition of cholesterol synthesis and uptake sensitizes acute myeloid leukaemia (AML) blasts to chemotherapy. A Phase 1 study demonstrated the safety of high dose pravastatin given with idarubicin and cytarabine in patients with AML and also demonstrated an encouraging response rate. The Southwestern Oncology Group (SWOG) trial, SWOG S0919, was a Phase 2 trial evaluating the complete remission (CR) rate in a larger number of patients with relapsed AML treated with idarubicin, cytarabine and pravastatin. This study closed to accrual after meeting the defined criterion for a positive study. Thirty-six patients with a median age of 59 years (range 23-78) were enrolled. The median time from diagnosis to registration was 18 months. Relapse status was first relapse, 17 patients (47%); second relapse, 15 patients (42%); third relapse, two patients (5·5%) and fourth relapse, two patients (5·5%). The response rate was 75% [95% confidence interval: 58-88%; 20 CRs, 7 CR with incomplete count recovery (CRi)], and the median overall survival was 12 months. The P-value comparing 75-30% (the null response rate based on prior SWOG experience) was 3·356 × 10(-4) . Given the encouraging CR/CRi rate, this regimen should be considered for testing in a prospective randomized trial against best conventional therapy.
| S-EPMC4188732 | biostudies-literature
Project description:PurposeEffective regimens are needed for children with relapsed acute myeloid leukemia (AML). AAML1421 is a phase I/II study of CPX-351, a liposomal preparation of daunorubicin and cytarabine. AAML1421 sought to determine the recommended phase II dose (RP2D) of CPX-351 and the response rate after up to 2 cycles of therapy.Patients and methodsChildren > 1 and ≤ 21 years of age with relapsed/refractory AML were eligible for dose finding; those in first relapse were eligible for the efficacy phase. Dose-limiting toxicity (DLT) assessment occurred during cycle 1. Two cycles of therapy were offered (cycle 1: CPX-351; cycle 2: FLAG [fludarabine 30 mg/m2/dose on days 1-5; cytarabine 2,000 mg/m2/dose on days 1-5; and granulocyte-colony stimulating factor 5 µg/kg/dose, days 1-5 and day 15 through absolute neutrophil count > 500/µL]). Response was assessed after each cycle.ResultsThirty-eight patients enrolled: 6 in the dose-finding phase and 32 in the efficacy phase. During dose finding, 1/6 patients experienced a DLT (grade 3 decrease in ejection fraction). The RP2D was 135 units/m2 on days 1, 3, and 5. Toxicities of grade ≥ 3 during cycle 1 included fever/neutropenia (45%), infection (47%), and rash (40%). There was no toxic mortality. Best responses included 20 complete response (CR; 54%), 5 CR with partial recovery of platelet count (CRp; 14%), and 5 CR with incomplete blood count recovery (14%). Twenty-one of 25 with CR/CRp had no detectable residual disease (RD; 84%) by flow cytometry. Hematopoietic stem cell transplantation (HSCT) was used as consolidation in 29/30 responders (96.7%); 20/25 (80%) had no RD before HSCT.ConclusionThe RP2D of CPX-351 is 135 units/m2/dose on days 1, 3, and 5. Toxicity was manageable, and protocol therapy was effective. Response rates are superior to prior published North American cooperative group clinical trials for children with AML in first relapse.
| S-EPMC7325367 | biostudies-literature
Project description:Relapse is a major limitation of chimeric antigen receptor (CAR) T-cell therapy. Here, we speculated that decitabine (DAC) in combination with fludarabine and cyclophosphamide (FC) as a lymphodepletion regimen may improve the efficacy of CD19/CD22 CAR T-cell therapy. Fourteen of 26 patients with relapsed/refractory B cell acute lymphoblastic leukemia (r/r B-ALL) without remission before lymphodepletion treatment were treated with DAC (total dose 100 mg/m2 in 3 days) followed by the FC regimen (DAC group), while twelve patients received the FC regimen (CON group). On Day 28 after CAR T-cells infusion, no significant differences in complete remission (CR) and minimal residual disease negative CR rates were found between both groups. However, there were significant differences in overall survival (OS) and leukemia-free survival (LFS) between two groups: 3-year OS, 92.3% (DAC) versus 41.7% (CON), P = 0.005 and 3-year LFS, 92.9% (DAC) versus 27.3% (CON), P < 0.001. There was no significant difference in the incidence of cytokine release syndrome between both groups. Median time to platelet and neutrophil counts recovery was similar in both groups. All adverse events were reversible and manageable. In conclusion, DAC in combination with the FC lymphodepletion regimen may be a new treatment option that can improve the efficacy of CAR T-cell therapy in r/r B-ALL.
| S-EPMC10084593 | biostudies-literature
Project description:The mutations of NPM1 and FLT3-ITD represent the most frequent genetic aberration in acute myeloid leukemia. Indeed, the presence of an NPM1 mutation reduces the negative prognostic impact of FLT3-ITD in patients treated with conventional "3+7" induction. However, little information is available on their prognostic role with intensified regimens. Here, we investigated the efficacy of a fludarabine, high-dose cytarabine and idarubicin induction (FLAI) in 149 consecutive fit AML patients (median age 52) carrying the NPM1 and/or FLT3-ITD mutation, treated from 2008 to 2018. One-hundred-and-twenty-nine patients achieved CR (86.6%). After a median follow up of 68 months, 3-year overall survival was 58.6%. Multivariate analysis disclosed that both NPM1mut (p < 0.05) and ELN 2017 risk score (p < 0.05) were significant predictors of survival. NPM1-mutated patients had a favorable outcome, with no significant differences between patients with or without concomitant FLT3-ITD (p = 0.372), irrespective of FLT3-ITD allelic burden. Moreover, in landmark analysis, performing allogeneic transplantation (HSCT) in first CR proved to be beneficial only in ELN 2017 high-risk patients. Our data indicate that FLAI exerts a strong anti-leukemic effect in younger AML patients with NPM1mut and question the role of HSCT in 1st CR in NPM1mut patients with concomitant FLT3-ITD.
| S-EPMC7796342 | biostudies-literature
Project description:BACKGROUND:This Phase 2 study tested the tolerability and efficacy of bortezomib combined with reinduction chemotherapy for pediatric patients with relapsed, refractory or secondary acute myeloid leukemia (AML). Correlative studies measured putative AML leukemia initiating cells (AML-LIC) before and after treatment. PROCEDURE:Patients with <400?mg/m(2) prior anthracycline received bortezomib combined with idarubicin (12?mg/m(2) days 1-3) and low-dose cytarabine (100?mg/m(2) days 1-7) (Arm A). Patients with ?400?mg/m(2) prior anthracycline received bortezomib with etoposide (100?mg/m(2) on days 1-5) and high-dose cytarabine (1?g/m(2) every 12?hours for 10 doses) (Arm B). RESULTS:Forty-six patients were treated with 58 bortezomib-containing cycles. The dose finding phase of Arm B established the recommended Phase 2 dose of bortezomib at 1.3?mg/m(2) on days 1, 4, and 8 with Arm B chemotherapy. Both arms were closed after failure to meet predetermined efficacy thresholds during the first stage of the two-stage design. The complete response (CR?+?CRp) rates were 29% for Arm A and 43% for Arm B. Counting additional CRi responses (CR with incomplete neutrophil recovery), the overall CR rates were 57% for Arm A and 48% for Arm B. The 2-year overall survival (OS) was 39?±?15%. Correlative studies showed that LIC depletion after the first cycle was associated with clinical response. CONCLUSION:Bortezomib is tolerable when added to chemotherapy regimens for relapsed pediatric AML, but the regimens did not exceed preset minimum response criteria to allow continued accrual. This study also suggests that AML-LIC depletion has prognostic value.
| S-EPMC4247259 | biostudies-literature
Project description:BackgroundTo improve outcomes of patients with Richter syndrome (RS) and relapsed/refractory chronic lymphocytic leukemia (CLL), we modified the OFAR1 regimen (oxaliplatin and cytarabine doses of the oxaliplatin, fludarabine, cytarabine, and rituximab) for this phase I-II study (OFAR2).Patients and methodsOFAR2 consisted of oxaliplatin at 30 mg/m(2) on days 1 to 4, fludarabine at 30 mg/m(2), cytarabine at 0.5 g/m(2), rituximab at 375 mg/m(2) on day 3, and pegfilgrastim at 6 mg on day 6. Fludarabine and cytarabine were given on days 2 and 3 (cohort 1), days 2 to 4 (cohort 2), or days 2 to 5 (cohort 3) every 4 weeks. Phase II followed the "3 + 3" design of phase I.ResultsThe 102 patients (CLL, 67; RS, 35) treated had heavily pretreated high-risk disease. Twelve patients were treated in phase I; cohort 2 was the phase II recommended dose. The most common toxicities were hematologic. Response rates (phase II) were 38.7% for RS (complete response [CR], 6.5%) and 50.8% for relapsed/refractory CLL (CR, 4.6%). The median survival durations were 6.6 (RS) and 20.6 (CLL) months. Among 9 patients who underwent allogeneic stem cell transplantation (SCT) as post-remission therapy, none has died (median follow-up, 15.9 months).ConclusionOFAR2 had significant antileukemic activity in RS and relapsed/refractory CLL. Patients undergoing SCT as post-remission therapy had favorable outcomes.
| S-EPMC4180513 | biostudies-literature