abt-199 and Hematologic-Diseases

Patients with relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) have limited treatment options. Venetoclax is a potent BCL-2 inhibitor that induces apoptosis in CLL cells. This open-label, phase 1/2 study (NCT02265731) evaluated the safety, pharmacokinetics, and efficacy of venetoclax in Japanese patients with R/R CLL/SLL. Patients enrolled in phase 1 received 400 mg/day venetoclax monotherapy. Patients enrolled in phase 2 received 400 mg/day venetoclax, plus rituximab. Venetoclax was administered with a weekly stepwise ramp-up in doses. In phase 2, efficacy was evaluated by objective response rate (ORR). Twelve patients were enrolled, six in each arm. The most common grade ≥ 3 adverse events were neutropenia (83%), lymphopenia (67%), leukopenia (33%), and thrombocytopenia (17%). Patients receiving venetoclax monotherapy achieved an ORR of 100%, including a complete remission (CR) rate of 17%. Patients receiving combination therapy had an ORR of 67% and a CR rate of 50%. The venetoclax pharmacokinetics profile in Japanese patients was similar to that of Western patients. Venetoclax 400 mg/day monotherapy or in combination with rituximab was well-tolerated and induced promising responses in Japanese patients with R/R CLL/SLL. Although patient numbers were small, the safety profile was largely consistent with other Western studies. Clinical trial registration: clinicaltrials.gov; NCT02265731.

Topics: Adult; Aged; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Bridged Bicyclo Compounds, Heterocyclic; Female; Hematologic Diseases; Humans; Japan; Leukemia, Lymphocytic, Chronic, B-Cell; Male; Middle Aged; Molecular Targeted Therapy; Nausea; Neoplasm Proteins; Progression-Free Survival; Proto-Oncogene Proteins c-bcl-2; Rituximab; Sulfonamides; Treatment Outcome

Ibrutinib, obinutuzumab, and venetoclax demonstrate synergy in preclinical models of mantle cell lymphoma (MCL). OAsIs (NCT02558816), a single-arm multicenter prospective phase 1/2 trial, aimed to determine the maximum tolerated dose of venetoclax in combination with fixed doses of ibrutinib and obinutuzumab, in relapsed MCL patients. At the venetoclax MTD, extension cohorts were opened for relapsed and untreated patients. Safety and efficacy were secondary objectives. Minimal residual disease (MRD) was assessed by allele-specific oligonucleotide quantitative polymerase chain reaction. Between 14 October 2015 and 29 May 2018, 48 patients were enrolled. No dose-limiting toxicity was reported, and venetoclax at 400 mg per day was chosen for extension. Eighteen (75%) relapsed and 8 (53%) untreated patients experienced grade 3/4 adverse events. The complete response rate assessed by positron emission tomography at the end of cycle 6 was 67% in relapsed and 86.6% in untreated patients. MRD clearance for evaluable patients was seen in 71.5% of relapsed (10/14 patients) and 100% of untreated MRD-evaluable patients (n = 12) at the end of 3 cycles. The median follow-up for relapsed patients was 17 months (range, 10-35 months). The 2-year progression-free survival (PFS) was 69.5% (95% confidence interval [CI], 52.9%-91.4%) and 68.6% (95% CI, 49.5%-95.1%) for overall survival. The median follow-up was 14 months (range, 5-19) for untreated patients, the 1-year PFS was 93.3% (95% CI, 81.5%-100%). The combination of obinutuzumab, ibrutinib, and venetoclax is well tolerated and provides high response rates, including at the molecular level, in relapsed and untreated MCL patients. This trial was registered at www.clinicaltrials.gov as #NCT02558816.

Topics: Adenine; Aged; Aged, 80 and over; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bridged Bicyclo Compounds, Heterocyclic; Combined Modality Therapy; Female; Follow-Up Studies; Genes, p53; Hematologic Diseases; Hematopoietic Stem Cell Transplantation; Humans; Immunoglobulin Heavy Chains; Immunoglobulin Variable Region; Kaplan-Meier Estimate; Lymphoma, Mantle-Cell; Male; Maximum Tolerated Dose; Middle Aged; Mutation; Neoplasm, Residual; Piperidines; Progression-Free Survival; Prospective Studies; Sulfonamides; Treatment Outcome

Topics: Aged; Antibodies, Monoclonal; Antineoplastic Combined Chemotherapy Protocols; bcl-X Protein; Bone Marrow; Bridged Bicyclo Compounds, Heterocyclic; Chromosomes, Human, Pair 11; Chromosomes, Human, Pair 14; Combined Modality Therapy; Dexamethasone; Female; Follow-Up Studies; Genes, bcl-2; Hematologic Diseases; Hematopoietic Stem Cell Transplantation; Humans; Infections; Kaplan-Meier Estimate; Male; Middle Aged; Multiple Myeloma; Neoplasm Proteins; Proto-Oncogene Proteins c-bcl-2; Recurrence; Salvage Therapy; Signal Transduction; Sulfonamides; Translocation, Genetic

The phase 2 CAVALLI (NCT02055820) study assessed efficacy and safety of venetoclax, a selective B-cell lymphoma-2 (Bcl-2) inhibitor, with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) in first-line (1L) diffuse large B-cell lymphoma (DLBCL), including patients demonstrating Bcl-2 protein overexpression by immunohistochemistry (Bcl-2 IHC+). Eligible patients were ≥18 years of age and had previously untreated DLBCL, Eastern Cooperative Oncology Group performance status ≤2, and International Prognostic Index 2 to 5. Venetoclax 800 mg (days 4-10, cycle 1; days 1-10, cycles 2-8) was administered with rituximab (8 cycles) and cyclophosphamide, doxorubicin, vincristine, and prednisone (6-8 cycles) in 21-day cycles. Primary end points were safety, tolerability, and research_plete response (CR) at end of treatment (EOT). Secondary end points were progression-free survival (PFS) and overall survival. Comparative analyses used covariate-adjusted R-CHOP controls from the GOYA/BO21005 study, an appropriate contemporary benchmark for safety and efficacy. Safety and efficacy analyses included 206 patients. CR rate at EOT was 69% in the overall population and was maintained across Bcl-2 IHC+ subgroups. With a median follow-up of 32.2 months, trends were observed for improved investigator-assessed PFS for venetoclax plus R-CHOP in the overall population (hazard ratio [HR], 0.61; 95% confidence interval [CI], 0.43-0.87) and Bcl-2 IHC+ subgroups (HR, 0.55; 95% CI, 0.34-0.89) vs R-CHOP. Despite a higher incidence of grade 3/4 hematologic adverse events (86%), related mortality was not increased (2%). Chemotherapy dose intensity was similar in CAVALLI vs GOYA. The addition of venetoclax to R-CHOP in 1L DLBCL demonstrates increased, but manageable, myelosuppression and the potential of improved efficacy, particularly in high-risk Bcl-2 IHC+ patient subgroups.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Bridged Bicyclo Compounds, Heterocyclic; Cyclophosphamide; Doxorubicin; Fatigue; Female; Gastrointestinal Diseases; Genes, bcl-2; Granulocyte Colony-Stimulating Factor; Hematologic Diseases; Humans; Infections; Kaplan-Meier Estimate; Lymphoma, Large B-Cell, Diffuse; Male; Middle Aged; Neoplasm Proteins; Prednisone; Proto-Oncogene Proteins c-bcl-2; Rituximab; Sulfonamides; Vincristine; Young Adult

Topics: Antineoplastic Combined Chemotherapy Protocols; Epigenesis, Genetic; Hematologic Diseases; Humans; Leukemia, Myeloid, Acute; Male; Retrospective Studies; Treatment Outcome

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Azacitidine; Bridged Bicyclo Compounds, Heterocyclic; Combined Modality Therapy; Drug Resistance, Neoplasm; Female; Hematologic Diseases; Hematopoietic Stem Cell Transplantation; Humans; Leukemia, Biphenotypic, Acute; Leukemia, Myeloid, Acute; Male; Middle Aged; Mutation; Nausea; Oncogene Proteins, Fusion; Sulfonamides; Transplantation, Haploidentical; Treatment Outcome; Vomiting

The co-occurrence of BCR-ABL1 fusion and core-binding factor (CBF) rearrangements is uncommonly reported in AML. Although CBF rearrangements carry a favorable prognosis, the coexistence of BCR-ABL1 is associated with aggressive disease suggesting a potential advantage of high-intensity chemotherapy in association with tyrosine kinase inhibitors. Herein, we describe a refractory AML patient harboring BCR-ABL1 fusion and CBFB rearrangement that was successfully treated with a combination of venetoclax and hypomethylating agent.

Topics: Antineoplastic Agents; Azacitidine; Bridged Bicyclo Compounds, Heterocyclic; Fusion Proteins, bcr-abl; Hematologic Diseases; Humans; Karyotype; Leukemia, Myeloid, Acute; Male; Middle Aged; Oncogene Proteins, Fusion; Remission Induction; Sulfonamides