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Safety and efficacy of combined Ruxolitinib and Decitabine in patients with blast-phase MPN and post-MPN AML
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The purpose of this study is to test the safety and tolerability of ruxolitinib at different dose levels in combination with decitabine and the effectiveness of ruxolitinib in combination with decitabine in patients with accelerated or blast phase Myeloproliferative Neoplasm (MPN). Ruxolitinib is a drug that is approved by the Federal Drug Administration (FDA) for the treatment of patients with advanced forms of myelofibrosis. A recent clinical study showed that ruxolitinib treatment could put some patients with this disease into remission. Decitabine is a chemotherapy, approved by the Federal Drug Administration (FDA), that has been used to treat acute leukemia. Ruxolitinib and decitabine will be combined in this study to find out what dose of the two medicines are safe together. Using Ruxolitinib in combination with Decitabine is experimental. The investigators want to find out what effects, good and/or bad it has on the patient and the disease.

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Hi I'm Dr. Raajit Rampal from Memorial Sloan Kettering Cancer Center here at ASH 2016 to discuss results of the Myeloproliferative Disease Research Consortium 109 trial. This is a Phase I study of the safety and efficacy of combined ruxolitinib and decitabine in patients with blast phase MPN and post-MPN AML.

Patients who experience transformation to acute leukemia from a prior MPN have a particularly poor prognosis with median survival of only two to three months. Furthermore, standard induction chemotherapy that is often used in standard AML is largely ineffective in this malignancy.

Other agents such as hypomethylating agents like azacitidine and decitabine have been utilized in the setting with limited efficacy. As well, ruxolitinib as a single agent, has been utilized in the setting with limited efficacy.

We've recently reported a pre-clinical study in which the combination of decitabine and ruxolitinib was used in a murine model of post-MPN AML with synergistic efficacy. This observation led us to conduct the Phase I trial of decitabine and ruxolitinib in patients with post-MPN AML. This was a Phase I study in which patients received ruxolitinib as a single agent from days 1 to 7 followed by the addition of decitabine at standard 20 mg per meter squared dose for five days on days 8 through 13, followed by single agent ruxolitinib again from days 14 to 35.

For cycle II and beyond, patients received the combination of both drugs from days 1 to 5 and continued to receive single agent ruxolitinib from day 6 onward. The starting dose level was 10 mg twice daily of ruxolitinib with dose level -1 of 5 mg twice daily. Four dose levels were explored; 10 mg, 15 mg, 25 mg, and 50 mg twice daily. Twenty-one patients were enrolled in total; six in the 10 mg arm, three in the 15 mg arm, six in the 25 mg arm, and six in the 15 mg arm.

Patient characteristics were largely similar across all of the cohorts studied, included a white count of median 6.9, hemoglobin of 9.1, platelets 92, and peripheral blast of 11%. Most patients did have palpable splenomegaly. The median age was 63 years old.

In terms of observed toxicities, during cycle 1, and this includes only grade 3 and 4 toxicities, a variety of different toxicities were observed which included infectious complications such as febrile neutropenia, cellulitis, and MRSA infections, as well as leukopenia, anemia, and thrombocytopenia. A variety of other toxicities were observed including fatigue, syncope, hypertension, and respiratory failure. Importantly, the dose limiting toxicity rate was below 33% for all dose levels so that the MTD was not reached in the study.

In terms of responses, the composite CR and CRi rates as per the modified Cheson criteria which included clearance of peripheral blood blast was 33% with CR observed at the 25 mg b.i.d. dose and at the 50 mg b.i.d. dose. In terms of overall response, the composite of CR, CRi, and PR for the study as a whole, the composite response rate was 57% with response rates of 50% at the 10 mg twice daily dose, 67% at the 15 mg twice daily dose, 50% at the 25 mg twice daily dose, and 67% at the 50 mg b.i.d. dose.

The median overall survival for the cohort as a whole was 10.4 months. Survival did differ slightly amongst patients from the different treatment arms. However, this was not statistically significant. In terms of the median number of cycles received, patients in the 10 mg b.i.d. cohort received the most number of cycles of therapy at 10.5. For the cohorts as a whole, the number of median cycles received was three.

To conclude, the combination of ruxolitinib up to a dose of 50 mg twice daily and decitabine was safely administered to patients with no MTD established in this Phase I study. Patients in the 10 mg twice daily cohort of ruxolitinib have the longest duration of therapy. Importantly, the highest CR/CRi rate was observed in patients in the 50 mg b.i.d. cohort. However, the largest proportion of adverse events was observed in this cohort. For this reason, the recommended Phase 2 dose was 25 mg b.i.d. for one cycle followed by 10 mg twice daily for all subsequent cycles.

Thank you very much for your attention.