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Targeted Inhibitor-Chemotherapy Combinations

Leukemia Insights - Spring 2010

Phase II study of dasatinib and hyper-CVAD

Single agent activity of the second generation TKI dasatinib in previously treated Ph positive ALL has been modest with most remissions short-lived. Dasatinib has been combined with hyper-CVAD (hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone alternating with high-dose methotrexate and cytarabine) for relapsed/refractory dasatinib-naïve Ph positive ALL and CML-LBP. [Ravandi F, Blood 2009 114:Abstract 2043]. The overall response rate in 23 patients was 91% (65% CR, 26% CR with incomplete platelet recovery) despite the presence of non-T315I ABL tyrosine kinase domain mutations. Responses have been relatively durable; relapses have been associated with acquisition of new ABL tyrosine kinase domain mutations such as T315I and F317L. Accrual continues to this trial. No prior therapy with dasatinib is allowed.

Phase I-II study of 5 AZA-2 deoxycytidine and hyper-CVAD

Aberrant DNA methylation of multiple promoter CpG islands is frequently observed in patients with ALL both at initial presentation and at the time of relapse [Garcia-Manero G, Semin Hematol 2009:46, 24]. These methylation profiles remain stable in over 70% of patients with ALL at the time of relapse. Importantly, methylation of specific molecular pathways has been associated with an extremely poor prognosis in patients with ALL.

Decitabine is a potent hypomethylating agent with clinical activity in myelodysplastic syndromes and acute leukemias. It is a deoxycytidine analog that is phosphorylated to its nucleotide and incorporated into DNA. Once incorporated, it covalently binds to DNA-methyltransferases and traps the enzyme within DNA, acting as an irreversible inhibitor of DNA-methyltransferase.

In vitro, decitabine induces loss of cell viability and apoptosis in ALL-derived cell lines that have known DNA methylation alterations. Exposure of these cell lines to decitabine results in global and gene specific hypomethylation, reactivation of epigenetically silenced genes, induction of apoptosis at low concentrations and/or prolonged exposures.

The subgroup of B-lineage ALL that harbors the t(4;11)(q21;q23) karyotypic abnormality involving the MLL (mixed leukemia lineage) proto-oncogene currently has the worst outcome; relapse is nearly certain in the absence of high-dose cytarabine regimens followed by allogeneic SCT in first CR. Decitabine has been shown to induce apoptosis of MLL leukemia cells in vitro. One confirmed candidate gene of decitabine is the tumor suppressor Fragile Histidine Triad (FHIT) gene. Gene expression profiling demonstrated that expression of FHIT is down-regulated in samples from pediatric patients with MLL-rearranged ALL compared with ALL carrying unmutated MLL. Expression of FHIT was restored after exposure to decitabine, resulting in apoptosis.

A phase I dose escalation study of single agent decitabine has neared completion [Garcia-Manero G, Blood 2009 114:Abstract 2030]. Twenty-three patients were treated at 7 dose levels (10, 20, 40, 60, 80, 100 and 120 mg/m2 IV daily x 5 every other week). Overall response rate was 23% (6 patients) including 1 CR with incomplete platelet count recovery and 5 complete marrow responses (blasts less than 5% with persistent cytopenias). The most effective dose in inducing global hypomethylation was 60 mg/m2 with decrease from 61% baseline to 21% on day 28. Patients who did not respond or progressed were considered for continuation of decitabine therapy concurrently with the hyper-CVAD regimen (on days 1 – 5 of the hyper-CVAD and high dose methotrexate-cytarabine courses). A parallel phase I dose escalation study of decitabine (given in combination with standard hyper-CVAD) is ongoing.

Phase I-II study of RAD001 (everolimus) and hyper-CVAD

The mTOR (mammalian target of rapamycin inhibitor) kinase has been shown to regulate cell growth and metabolic adaptation in response to various factors including mitogenic stimuli, energy/nutrient levels, and hypoxia. Recent in vitro studies have shown that lymphoblasts acquire a glycolytic phenotype under conditions of hypoxia and hyperglycemia with upregulation of major anti-apoptotic proteins (Mcl-1), which ultimately promote resistance to standard chemotherapeutic agents. These effects could be reversed by the specific blockade of mTOR signaling with everolimus (RAD001).

The potential reversal of chemoresistance to anthracyclines and vincristine makes the combination of this agent with hyper-CVAD worthy of investigation. The phase I portion of the trial involves dose escalation of the RAD001 (given concurrently on a daily basis with the standard hyper-CVAD regimen) in order to determine the optimal dose for the phase II portion of the study. Accrual to the study has just commenced.

© 2014 The University of Texas MD Anderson Cancer Center