Venclexta (venetoclax)

P=N/A, N=27, Recruiting, Institute of Hematology & Blood Diseases Hospital, China | Not yet recruiting --> Recruiting

P1/2, N=249, Active, not recruiting, Molecular Partners AG | Recruiting --> Active, not recruiting | Trial completion date: Dec 2029 --> May 2027 | Trial primary completion date: Dec 2027 --> May 2026

P=N/A, N=321, Active, not recruiting, Gruppo Italiano Malattie EMatologiche dell'Adulto | Recruiting --> Active, not recruiting | Trial completion date: Oct 2025 --> Oct 2026

P=N/A, N=50, Not yet recruiting, The First Affiliated Hospital of Soochow University

Second, a network meta-analysis ranked the efficacy and safety of regimens including rituximab with cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP); dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin plus rituximab (DA-EPOCH-R); R-CHOP plus lenalidomide (R2-CHOP); R-CHOP plus ibrutinib (I+R-CHOP); R-CHOP plus zanubrutinib (Z+R-CHOP); and R-CHOP plus venetoclax (Ven-R-CHOP). DEL is a distinct high-risk subtype with quantifiable prognostic detriment. Z+R-CHOP emerges as a promising strategy requiring validation in prospective studies.

ACSL4-high blasts showed enhanced dasatinib sensitivity (r = -0.25, P = 4.3 x 10-8). Conversely, ACSL4-high blasts showed significant ex vivo resistance to venetoclax (r = 0.36, P = 2.5 x 10-12), linking the ferroptosis-primed monocytic state to BCL2 inhibitor failure. These findings nominate ACSL4-driven ferroptosis susceptibility as a lineage-specific vulnerability rendering monocytic AML selectively sensitive to SRC-directed therapy while resistant to BCL2 inhibition.

Pretransplant treatment was intentionally limited to 2-3 cycles: three cycles of Aza in Case 1, intensive induction chemotherapy followed by one cycle of Aza in Case 2, and two cycles of venetoclax plus Aza in Case 3. In addition, for patients with FISH-detectable TP53 abnormalities, serial FISH may provide a practical adjunct for pretransplant decision-making in routine practice. Trial Registration: The authors have confirmed clinical trial registration is not needed for this submission.

POLA demonstrated robust single-agent antitumor activity in vivo, including in PDX models derived from patients with ibrutinib-resistant MCL. This signature likely reflects core pathways associated with POLA resistance and highlights potential novel therapeutic vulnerabilities. These findings strongly support further clinical investigation of POLA in combination with VEN as a BCL2- and MCL1-targeting therapeutic strategy in patients with R/R MCL and BCL2-positive R/R DLBCL.

Using T-ALL PDXs we further show that (i) ADC-CD7-BCL-XLi displays potent anti-leukemic activity and is devoid of toxicity to platelets; (ii) ADC-CD7-BCL-XLi acts synergistically with venetoclax, a BCL-2 selective antagonist, to prolong leukemia remission and mouse survival; (iii) the anti-leukemic effect of the ADC-CD7-BCL-XLi+venetoclax combination can lead to cure when combined with chemotherapy. These pre-clinical data strongly support the evaluation of ADC-CD7-BCL-XLi in T-ALL patients, including as a potential bridging option to curative hematopoietic stem cell transplantation (HSCT).

Combination therapy with MI plus hypomethylating agent and venetoclax produced higher CR (43.3% vs 19.5%; p = 0.002) and CR+CRh rates (48.6% vs 25.8%; p = 0.007) than monotherapy...Differentiation syndrome occurred in 14.6%, and treatment-related mortality in 5.0%. MI-based therapy demonstrates meaningful activity in heavily pretreated AML, with deeper responses observed using combination strategies.

P1/2, N=34, Terminated, M.D. Anderson Cancer Center | Active, not recruiting --> Terminated; <75% participation

A significant portion of this review examines the evolving therapeutic landscape, scrutinizing Treg-depleting antibodies (e.g., mogamulizumab, RG6292), immunomodulatory small molecules (venetoclax, hypomethylating agents, TKIs), and the challenges Tregs pose to cellular therapies. Finally, we discuss novel strategies to circumvent Treg-mediated resistance, offering a perspective on restoring anti-leukemic immunity.