Secondary Acute Myelogenous Leukemia Evolving From Myeloproliferative Disorder Clinical Trial
Official title:
Concomitant Ruxolitinib Induction and Maintenance With Cytarabine Based Chemotherapy in Secondary Acute Myelogenous Leukemia Evolving From Myeloproliferative Neoplasm
This trial aimed to investigate the therapeutic efficacy of ruxolitinib in combination with cytotoxic chemotherapy for post-myeloproliferative neoplasm secondary acute myeloid leukemia.
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.
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