The Role of Ruxolitinib in Secondary Acute Myelogenous Leukemia Evolving From Myeloproliferative Neoplasm

Description

Acute myeloid leukemia (AML) is an uncommon, but often deadly complication of myeloproliferative neoplasms (MPN). Post-MPN AML is aggressive and resistant to conventional treatment with median survival of 3-5 months. Although allogeneic stem cell transplantation (alloSCT) have some prospective of promise in these patient, most of them are ineligible for alloSCT because of advanced age at diagnosis, comorbidities and scarcity of a compatible donor. Therefore, there is an urgent need for new therapeutic strategy for post-MPN AML.

Cytogenetic and/or molecular abnormalities associated with poor prognosis are quite common in patients with post-MPN AML. Although these findings likely contribute to the aggressive natural history and resistance to standard therapies, the genetic complexity of post-MPN AML may ultimately permit targeted therapy. Among these abnormalities, Janus kinase 2 (JAK2) has come to the fore recently. JAK2 V617F mutation, which is a hallmark of MPN, has been reported to be carried in approximately 35-50% of patients with post-MPN AML. We believe that this mutation be the most oncogenic driver in post-MPN AML.

In fact, BCR/ABL(+) acute leukemia (either blast crisis of CML or Ph+ ALL) is a similar disease model of the post-MPN AML. The clinical outcome of these disease has improved dramatically with ABL tyrosine kinase inhibitors (TKIs), such as imatinib, and nilotinib. It is a standard practice to give ABL TKI along with cytotoxic chemotherapy to BCR/ABL(+) acute leukemia. On the other hand, in BCR/ABL(+) acute leukemia, it is well known that single agent ABL TKI is not sufficient to control disease.

Likewise, ruxolitinib, which is a targeted agent for JAK2, have a great possibility to show efficacy for post-MPN AML when combined with cytotoxic agents. In a previous investigational study of ruxolitinib for refractory/relapsed leukemias, 2 of 3 AML patients evolving from MPN achieved complete remission with two cycles of ruxolitinib. In fact, many clinical trials are ongoing to investigate the therapeutic efficacy of ruxolitinib in post-MPN AML as a single agent.

However, considering a lesson from BCR/ABL(+) acute leukemia, ruxolitinib as a single agent may not be enough to cure these patients with post-MPN AML. Hence, for patients who are fit for intensive chemotherapy, it would easily conjectured that ruxolitinib in combination with cytotoxic chemotherapy would be better for these patients. Therefore, combination of ruxolitinib and cytotoxic chemotherapy would be an optimal treatment for post-MPN AML. From an epidemiologic perspective, it is true that post-MPN AML develops in elderly patients frequently. However, patients who fit for intensive chemotherapy are also encountered in the clinic for post-MPN AML not infrequently, justifying this study design. NCCN guideline also recommend intensive induction treatment for patients > 60 years when there performance and comorbidity allows intensive treatment.

In this study, the therapeutic efficacy of ruxolitinib in combination with cytotoxic chemotherapy for post-MPN AML will be investigated. Unlike other clinical trials induction and consolidation treatment should include cytotoxic chemotherapeutic agents in addition to ruxolitinib.

Details