Combining venetoclax, a selective BCL-2 inhibitor, with low-dose navitoclax, a BCL-X L /BCL-2 inhibitor, may allow targeting of both BCL-2 and BCL-X L without dose-limiting thrombocytopenia associated with navitoclax monotherapy. The safety and preliminary efficacy of venetoclax with low-dose navitoclax and chemotherapy was assessed in this phase I dose escalation study (NCT03181126) in pediatric and adult patients with relapsed/refractory acute lymphoblastic leukemia or lymphoblastic lymphoma. Forty-seven patients received treatment. A recommended phase II dose of 50 mg navitoclax for adults and 25 mg for patients <45 kg with 400 mg adultequivalent venetoclax was identified. Delayed hematopoietic recovery was the primary safety finding. The complete remission rate was 60%, including responses in patients who had previously received hematopoietic cell transplantation or immunotherapy. Thirteen patients (28%) proceeded to transplantation or CAR T-cell therapy on study. Venetoclax with navitoclax and chemotherapy was well tolerated and had promising efficacy in this heavily pretreated patient population. Statement of Significance In this phase I study, venetoclax with low-dose navitoclax and chemotherapy was well tolerated and had promising efficacy in patients with relapsed/refractory acute lymphoblastic leukemia or lymphoblastic lymphoma. Responses were observed in patients across histological and genomic subtypes and in those who failed available therapies including stem cell transplant. Research.

We have previously demonstrated that mTOR inhibitors (MTIs) are active in preclinical models of acute lymphoblastic leukemia (ALL). MTIs may increase degradation of cyclin D1, a protein involved in dihydrofolate reductase (DHFR) synthesis. Because resistance to methotrexate may correlate with high DHFR expression, we hypothesized MTIs may increase sensitivity of ALL to methotrexate through decreasing DHFR by increasing turn-over of cyclin D1. We tested this hypothesis using multiple ALL cell lines and nonobese diabetic/severe combined immunodeficient (NOD/SCID) mice xenografted with human ALL. We found MTIs and methotrexate were synergistic in combination in vitro and in vivo. Mice treated with both drugs went into a complete and durable remission whereas single agent treatment caused an initial partial response that ultimately progressed. ALL cells treated with MTIs had markedly decreased expression of DHFR and cyclin D1, providing a novel mechanistic explanation for a combined effect. We found methotrexate and MTIs are an effective and potentially synergistic combination in ALL. (Blood. 2008;112:2020-2023 IntroductionNovel and less toxic treatment strategies are needed for patients with acute lymphoblastic leukemia (ALL). 1 Previously, we have demonstrated that mTOR inhibitors (MTIs), a class of signal transduction inhibitors, are effective as single agents in preclinical models of ALL. 2,3 Combination treatment is the next logical step in the therapeutic use of MTIs. It is important to choose rationallydesigned combinations, building on an understanding of the mechanism of action of MTIs and interactions with other agents.MTIs have been shown to prevent activation and increase degradation of cyclin-dependent kinases, including cyclin D1. 4 Cyclin D1 is involved in Rb phosphorylation and release E2Fs which are involved in dihydrofolate reductase (DHFR) synthesis. [5][6][7] Resistance to methotrexate has been shown in tumors that have high DHFR expression. 8,9 We hypothesized that MTIs may increase the sensitivity of ALL to methotrexate by decreasing cyclin D1, which would in turn would decrease DHFR. 5 We tested this hypothesis using relevant preclinical models. Methods In vitro drug testing using ALL cell linesWe used 9 previously characterized ALL cell lines for these experiments, including 4 murine ALL lines (289, 83, 420, and T309) and 5 human ALL lines (Nalm 6, Nalm16, CEM, Molt-4, and Jurkat; the phenotypes are listed in Table S1, available on the Blood website; see the Supplemental Materials link at the top of the online article). 3 Cell lines were maintained in culture using published techniques. 3 Cells were treated with chemotherapeutic agents, including sirolimus (Wyeth Pharmaceuticals, Philadelphia, PA), temsirolimus (Wyeth), methotrexate (Mayne Pharmaceuticals, Paramus, NJ), L-asparaginase (Merck, Whithouse Station, NJ), doxorubicin (Bedford Labs, Bedford, OH), vincristine (Mayne), dexamethasone (American Regent, Shirley, NY), cytarabine (American Pharmaceutical Partners, Schaumburg, IL), and et...

The excess of bilateral disease, ILNR-associated FH tumors of mixed cell type, and early ages at diagnosis in WAGR patients all fit the known phenotypic spectrum of constitutional deletion of chromosome 11p13. Despite a favorable response of their WT to treatment, WAGR patients have a high risk of ESRD as they approach adulthood. The renal pathology associated with this apparent late manifestation of WT1 deletion, and the explanation for the abnormally low birth weights in patients with del 11p13, have yet to be determined.