BackgroundPatients with CML treated with TKI can have a life expectancy comparable to that of the general population. Due to the extended duration of TKI administration, treatment discontinuation has been increasingly sought.MethodsMedical records of 100 patients with CML who were in MR4.5 and discontinued their TKI outside clinical trials were reviewed.ResultsAfter a median follow-up of 30 months (range, 5–112 months) after discontinuation, 35% and 17% lost MR4.5 and major molecular response (MMR), respectively. Only six patients lost MMR 12 months or more after discontinuation. Loss of MR4.5 was observed in 29% and 7% of patients with sustained MR4.5 duration of more than 2 and 6 years before discontinuation, respectively. By univariate analysis, there was a higher risk of loss of MR4.5 for patients who were treated for less than 87 months, received second or subsequent line TKI, never received interferon, or those with sustained MR4.5 for less than 6 years. By multivariate analysis, sustained MR4.5 for 6 years or more was the only significant predictor for durable response. Overall, 30% of patients who discontinued while in MR4.5 were retreated with 93% regaining MR4.5 at a median of 5 months.ConclusionThese results demonstrate that under proper conditions, treatment discontinuation is feasible outside of clinical trial setting. MR4.5 duration of 6 years or more before discontinuation is associated with very low risk of loss of MR4.5.
• In patients with Ph 1 ALL, achievement of CMR at 3 months is independently associated with improved survival.• CMR at 3 months may identify patients with Ph 1 ALL who have excellent long-term outcomes without SCT in first CR.The impact of achieving complete molecular response (CMR) in Philadelphia chromosomepositive (Ph 1 ) acute lymphoblastic leukemia (ALL) remains undefined. We evaluated the impact of CMR on outcomes among 85 patients with Ph 1 ALL who received first-line hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone alternating with methotrexate and high-dose cytarabine plus a tyrosine kinase inhibitor, had minimal residual disease (MRD) assessments for BCR-ABL1 by quantitative polymerase chain reaction at complete remission (CR) and at 3-month time points, and did not undergo allogeneic stem cell transplantation (SCT). MRD status at 3 months had better discrimination for overall survival (OS; P 5 .005) and relapse-free survival (RFS; P 5 .002) than did MRD status at CR (P 5 .11 and P 5 .04, respectively). At 3 months, achievement of CMR vs response less than CMR was associated with longer median OS (127 vs 38 months, respectively; P 5 .009) and RFS (126 vs 18 months, respectively; P 5 .007). By multivariate analysis, only CMR at 3 months was prognostic for OS (hazard ratio, 0.42; 95% confidence interval, 0.21-0.82; P 5 .01). Patients with Ph 1 ALL who achieve CMR at 3 months have superior survival compared with those with lesser molecular responses and have excellent long-term outcomes even without SCT. (Blood. 2016;128(4):504-507)
PURPOSE Sixty percent of newly diagnosed patients with acute myeloid leukemia (ND-AML) receiving frontline therapy attain a complete response (CR), yet 30%-40% of patients relapse. Relapsed or refractory AML (R/R-AML) remains a particularly adverse population necessitating improved therapeutic options. This phase Ib/II study evaluated the safety and efficacy of fludarabine, cytarabine, granulocyte colony-stimulating factor, and idarubicin combined with the B-cell lymphoma-2 inhibitor venetoclax in ND-AML and R/R-AML. MATERIALS AND METHODS The phase IB portion (PIB) enrolled patients with R/R-AML using a 3 + 3 dose escalation and de-escalation algorithm for identification of maximum tolerated dose and dose-limiting toxicities. The phase II portion enrolled patients into two arms to evaluate response and time-to-event end points: phase IIA (PIIA): ND-AML and phase IIB (PIIB): R/R-AML. RESULTS Sixty-eight patients have enrolled to date (PIB, 16; PIIA, 29; PIIB, 23). Median age was 46 years (range, 20-73). Grade 3 and 4 adverse events occurring in ≥ 10% of patients included febrile neutropenia (50%), bacteremia (35%), pneumonia (28%), and sepsis (12%). The overall response rate for PIB, PIIA, and PIIB was 75%, 97%, and 70% with 75%, 90%, and 61%, respectively, achieving a composite CR. Measurable residual disease–negative composite CR was attained in 96% of ND-AML and 69% of R/R-AML patients. After a median follow-up of 12 months, median overall survival (OS) for both PII cohorts was not reached. Fifty-six percent of patients proceeded to allogeneic hematopoietic stem-cell transplantation (ND-AML, 69%; R/R-AML, 46%). In R/R-AML, allogeneic hematopoietic stem-cell transplantation resulted in a significant improvement in OS (median OS, NR; 1-year OS, 87%). One-year survival post-HSCT was 94% in ND-AML and 78% in R/R-AML. CONCLUSION Fludarabine, cytarabine, granulocyte colony-stimulating factor, and idarubicin + venetoclax represents an effective intensive treatment regimen in ND-AML and R/R-AML patients, associated with deep remissions and a high rate of transition to successful transplantation.
Background Outcomes in blast phase CML (CML-BP) are historically dismal. We sought to analyse the characteristics, prognostic factors and survival outcomes in patients with CML-BP in the TKI era. Methods All patients with CML-BP (n=477) were treated with a TKI at some point during the course of their CML. Cox proportional hazard models identified characteristics which predicted for survival. Overall survival (OS) and failure free survival (FFS) were assessed. Optimal cut off points for specific parameters, were identified using CART (classification and regression tree). Results Median age was 53 years (range, 16 to 84); 64% were male. Eighty percent were initially diagnosed in chronic phase CML (CML-CP) median 41 months (0.7 to 298 months) before transformation to CML-BP. De-novo CML-BP occurred in 71 patients. Seventy two percent patients received TKI therapy prior to CML-BP. Initial therapy for CML-BP included, TKI alone (35%), TKI with chemotherapy (46%) and non-TKI therapies (19%). The median OS was 12 months and median FFS was 5 months. In multivariate analysis, myeloid immunophenotype, prior TKI, age ≥58 years, LDH ≥1227 IU/L, platelet count <102 K/μL, no stem cell transplantation (SCT), blast phase from CP/AP and presence of chromosome 15 aberrations predicted for a significantly increased risk of death. Achievement of major hematologic response and/or complete cytogenetic response to first line treatment predicted for better survival. Combination of TKI with intensive chemotherapy followed by stem cell transplant confer the best outcome. Conclusions Patients with CML-BP continue to pose a therapeutic challenge, have dismal outcomes and require newer treatment approaches.
Background The clinical efficacy of hyper-CVAD (HCVAD) + ponatinib has not been compared to that of HCVAD + dasatinib in patients with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) in a randomized clinical trial. Methods We analyzed 110 patients with newly diagnosed Ph+ ALL enrolled in two consecutive prospective phase 2 clinical trials of frontline HCVAD with either dasatinib (n=63) or ponatinib (n=47). Propensity score analysis with 1:1 matching with the nearest neighbor matching method, and inverse probability of treatment weighting (IPTW) analysis based on the propensity scores were performed to assess response rates, event-free survival (EFS), and overall survival (OS) between cohorts. Results Propensity score matching identified 41 patients in each cohort. With propensity score matching, the 3-year EFS rates for HCVAD + ponatinib and HCVAD + dasatinib were 69% and 46%, respectively (p=0.04), and the 3-year OS rates were 83% and 56%, respectively (p=0.03). Inverse probability of treatment weighting analysis using pre-matching cohorts showed that HCVAD + ponatinib had significantly higher rates of minimal residual disease negativity by flow cytometry on day 21, complete cytogenetic response at complete response (CR), major molecular response at CR and 3 months, and complete molecular response at 3 months. IPTW confirmed that HCVAD + ponatinib was associated with longer EFS (p=0.003) and OS (p=0.001) compared to HCVAD + dasatinib. Conclusion The clinical outcome of HCVAD + ponatinib appears superior to that of HCVAD + dasatinib in patients with Ph+ ALL.
Background The outcome of older patients with newly diagnosed, Philadelphia chromosome (Ph)‐negative acute lymphoblastic leukemia (ALL) is poor. The combination of targeted therapy with low‐intensity chemotherapy is safe and effective. The objective of the current analysis was to compare the outcome of patients who received a combination of inotuzumab ozogamicin plus low‐intensity chemotherapy (mini–hyperfractionated cyclophosphamide, vincristine, and dexamethasone [mini‐HCVD]) with or without blinatumomab versus the outcome of those who received the standard, intensive, hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone (HCVAD) regimen. Methods The authors analyzed 135 older patients with newly diagnosed, Ph‐negative ALL who were treated prospectively with standard HCVAD (n = 77) or with the combination of inotuzumab ozogamicin plus mini‐HCVD with or without blinatumomab (n = 58). A propensity score analysis was conducted using 1:1 matching using the nearest neighbor matching method. Results Propensity score matching identified 38 patients in each cohort. The antibody plus low‐intensity chemotherapy combination induced higher response rates (98% vs 88%), with lower rates of early death (0% vs 8%) and lower rates of death in complete remission (5% vs 17%). With propensity score matching, the 3‐year event‐free survival rates for patients who received HCVAD and those who received the combination of inotuzumab ozogamicin plus mini‐HCVD with or without blinatumomab were 34% and 64%, respectively (P = .003), and the 3‐year overall survival rates were 34% and 63%, respectively (P = .004). By multivariate analysis, age (P = .019; hazard ratio, 1.045) and the combination of inotuzumab plus mini‐HCVD with or without blinatumomab (P = .020; hazard ratio, 0.550) were identified as independent prognostic factors for survival. Conclusions The combination of inotuzumab ozogamicin plus mini‐HCVD with or without blinatumomab is safe and effective in older patients with newly diagnosed, Ph‐negative ALL and confers a better outcome compared with standard HCVAD chemotherapy.
FLT3 mutations occur in 20-35% patients with newly diagnosed (ND) acute myeloid leukemia (AML) and confer a higher risk of relapse and inferior overall survival (OS). Given modest benefit with first-generation multikinase inhibitors, second-generation FLT3 inhibitors (FLT3i) have been combined with low-intensity therapies (LIT) with encouraging results but are not curative 1-4. Venetoclax with hypomethylating agent (HMA) has emerged as the new standard for older/unfit patients with AML 5. Pre-clinical studies in FLT3 mut cell lines, primary samples, and xenografts have shown synergy between FLT3i's and venetoclax through downregulation of Mcl-1 and Bcl-x L 6-9. Clinical studies have demonstrated safety and activity of the combination of FLT3i and HMA with composite complete remission (CRc) rates of 65-80% and median OS 8.5-20 months 1,4,10 , as well as FLT3i and venetoclax which showed CRc rate of 85% in relapsed/ refractory (R/R) FLT3 mut AML including in patients with prior FLT3i exposure 11. We hypothesized that triplet therapy combining FLT3i, venetoclax, and HMA may further improve outcomes. Hence, we added FLT3i to our regimen of 10-day decitabine with venetoclax (DEC10-VEN) for FLT3 mut AML. We herein describe the first report of such a 'triplet' combination regimen for FLT3 mut AML. This phase 2 trial (NCT03404193) enrolled ND patients with AML > 60 years and R/R patients >18 years. Patients needed to have ECOG performance status ≤3. Patients with favorable-risk cytogenetics and prior Bcl-2 inhibitor exposure were excluded. Patients received decitabine 20 mg/m 2 IV for 10-days every 4-6 weeks for induction followed by decitabine for 5-days after CR/CRi, as described previously 12. Venetoclax dose was 400 mg PO daily or equivalent (with azole co-administration). Reduction of venetoclax duration to <21 days per cycle was permitted in cases of persistent myelosuppression, after confirming ≤5% blasts or hypo/acellular marrow. Addition of FLT3i of clinician's choice was allowed (Fig. S1). ND patients were admitted for the first cycle and R/R patients were admitted for the initial venetoclax rampup. Cytoreduction to WBC <10 × 10 9 /L was required prior to starting therapy and all patients received prophylaxis for tumor lysis syndrome, and antimicrobial prophylaxis. Responses were graded per the IWG criteria for AML with adapted CRc criteria per the gilteritinib ADMIRAL and quizartinib QUANTUM-R studies 13,14. The CRc included CR, CR with incomplete platelet recovery, and CR with incomplete hematologic recovery 13. OS was measured from start of therapy until death or censored at last follow-up. Progression-free survival was defined from the time of response until relapse, death, or censored at last follow-up. Duration of response was determined from the time of response till relapse or censored at last followup or at the time of death without relapse. Measurable residual disease (MRD) was assessed on bone marrow (BM) specimens using 8-color multiparametric flow
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