Three sessions at the American Association for Cancer Research Annual Meeting focused on promising, novel treatment options for patients with various forms of leukemia.
In the first study, a late-breaking abstract presented by Yoko Ogawara, PhD, of the division of hematological malignancy at the National Cancer Research Institute in Tokyo, Japan, researchers tested the validity of mutant isocitrate dehydrogenase (IDH) enzymes as targets for acute myeloid leukemia (AML) therapy. Using mouse models of mutant IDH-dependent AML, Dr. Ogawara and colleagues determined that four mutations are necessary for induction of AML: IDH2/R140Q, NPMc, SNMT3A/R882H, and FLT3/ITD. All four mutations must be present, they noted: When only three of the mutant genes were transduced, myeloproliferative neoplasms, rather than AML, more frequently resulted. To test their findings, the investigators then conditionally deleted IDH2/R140Q from the AML mice; doing this blocked 2-HG production and resulted in the loss of leukemia cells. The function of IDH2 is critical for the development and maintenance of AML stem cells; thus, IDHs are promising targets for AML treatment, the authors concluded.
Also on the AML front, Gail Roboz, MD, of the Weill Cornell Medical College in New York, reported results of a more aggressive 10-day regimen of guadecitabine (SGI-110) for older patients (≥65 years) with AML. Guadecitabine is a novel hypomethylating agent (HMA) that produced an overall complete response (CR) of 55 percent when administered over a five-day course. Dr. Roboz and colleagues enrolled 52 older patients with AML (median age = 77 years) into the current study, with guadecitabine given: at 60 mg/m2 subcutaneous injection per day for 10 days (days 1-5 and 8-12) for the first one to two cycles, followed by the five-day regimen (days 1-5) for subsequent cycles.
All patients were followed for a minimum of three months, though 50 percent of patients (n=26) were still receiving treatment at the time of data reporting. Twenty-four participants (46%) experienced overall complete response (complete response + CRi [complete remission with incomplete blood count recovery]+ CRp [complete remission with incomplete platelet recovery]), the study’s primary endpoint (TABLE). Early, all-cause 30-day and 60-day mortality occurred in two (4%) and 10 (19%) patients, respectively. Toxicity was also acceptable: grade ≥3 adverse events included febrile neutropenia (33%), thrombocytopenia (27%), neutropenia (21%), anemia (15%), bacteremia (10%), and pneumonia (6%).
“However, and although it was not a randomized comparison, the 10-day regimen did not result in a higher rate of overall complete response in previously untreated AML than what was previously reported for the five-day regimen,” the investigators concluded.
Finally, in a report about models of chronic myeloid leukemia (CML), ABL001 (a potent, specific BRC-ABL inhibitor) was shown to suppress emergence of disease resistance. ABL001, a tyrosine kinase inhibitor, dually targets BCR-ABL and was developed for use in combination with nilotinib to combat potential genetic resistance to therapy. William R. Sellers, MD, of the Novartis Institutes for BioMedical Research in Cambridge, Massachusetts, and colleagues presented the research.
Data suggest that tumors may need to co-evolve independent mutations in order to combat combination treatment within two classes; in a mouse model, dual targeting with ABL001 displayed potent anti-tumor activity with tumor regression. The findings suggest that the use of ABL001 and nilotinib together may lead to tumor regression, as the study in mice demonstrated complete tumor regression with no evidence of disease relapse during 70 days of treatment, and for more than 100 days after treatment cessation.
Currently, ABL001 is being studied in a phase I trial of patients with CML and Ph+ ALL.
- Ogawara Y, Matsunaga H, Seki T, et al. IDH mutations are promising targets for acute myeloid leukemia. Abstract #LB-252. Presented at the American Association for Cancer Research Annual Meeting, April 21, 2015.
- Roboz G, Kantarjian H, Kropf P, et al. First results of a 10-day regimen of SGI-110 (guadecitabine), a second generation hypomethylating agent (HMA) in previously untreated elderly AML who are not candidates for intensive chemotherapy. Abstract #CT321. Presented at the American Association for Cancer Research Annual Meeting, April 21, 2015.
- Sellers WR. Dual targeting of BCR-ABL with ABL001: a novel potent allosteric ABL kinase inhibitor in combination with nilotinib suppresses the emergence of disease resistance in models of CML. Presented at the American Association for Cancer Research Annual Meeting, April 19, 2015.
|TABLE. Safety and Efficacy Outcomes with Guadecitabine 60 mg/m2|
|Number of patients (%)|
|Overall complete response||24 (46%)|
|All-cause 30-day mortality||2 (4%)|
|All-cause 60-day mortality||10 (19%)|