Patients 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. Medical records of 100 patients with CML who were in MR4.5 and discontinued their TKI outside clinical trials were reviewed. After 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. These 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.

Ibrutinib, an inhibitor of Bruton’s tyrosine kinase, and venetoclax, an inhibitor of B-cell lymphoma 2 protein, have been approved for patients with chronic lymphocytic leukemia (CLL). Preclinical investigations have indicated potential synergistic interaction of their combination.

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.

Key Points: Adult patients with ETP-ALL/LBL have poor long-term outcomes. Novel therapies are urgently needed for adult patients with ETP-ALL/LBL.

PURPOSE: The combination of venetoclax and 5-azacitidine (5-AZA) for older or unfit patients with acute myeloid leukemia (AML) improves remission rates and survival compared with 5-AZA alone. We hypothesized that the addition of venetoclax to cladribine (CLAD)/low-dose araC (low-dose cytarabine [LDAC]) alternating with 5-AZA backbone may further improve outcomes for older patients with newly diagnosed AML. METHODS: This is a phase II study investigating the combination of venetoclax and CLAD/LDAC alternating with venetoclax and 5-AZA in older (≥ 60 years) or unfit patients with newly diagnosed AML. The primary objective was composite complete response (CR) rate (CR plus CR with incomplete blood count recovery); secondary end points were overall survival, disease-free survival (DFS), overall response rate, and toxicity. RESULTS: A total of 60 patients were treated; median age was 68 years (range, 57-84 years). By European LeukemiaNet, 23%, 33%, and 43% were favorable, intermediate, and adverse risk, respectively. Fifty-six of 60 evaluable patients responded (composite CR: 93%) and 84% were negative for measurable residual disease. There was one death (2%) within 4 weeks. With a median follow-up of 22.1 months, the median overall survival and DFS have not yet been reached. The most frequent grade 3/4 nonhematologic adverse events were febrile neutropenia (n = 33) and pneumonia (n = 14). One patient developed grade 4 tumor lysis syndrome. CONCLUSION: Venetoclax and CLAD/LDAC alternating with venetoclax and 5-AZA is an effective regimen among older or unfit patients with newly diagnosed AML. The rates of overall survival and DFS are encouraging. Further study of this non–anthracycline-containing backbone in younger patients, unfit for intensive chemotherapy, as well as comparisons to standard frontline therapies is warranted.

Treatment of chronic lymphocytic leukemia (CLL) has undergone a substantial evolution with the development of oral targeted therapies.¹ The Bruton tyrosine kinase (BTK) inhibitors ibrutinib and acalabrutinib, and venetoclax, a Bcl-2 inhibitor, are approved for treatment of CLL.^2-6 Bruton tyrosine kinase inhibitors typically are administered as monotherapy continuously daily, with most responses being partial remission; complete remission (CR) is uncommon, and undetectable measurable residual disease (U-MRD) remissions are rare.^2-4 Venetoclax is typically combined with the CD20 monoclonal antibody obinutuzumab and is given for 1 year in the treatment-naive setting.⁶ The U-MRD rate was 76% in peripheral blood and 57% in bone marrow with combined venetoclax and obinutuzumab.⁶