Preliminary Results from a Phase II Trial of Triapine Plus Fludarabine for Adults with Aggressive Myeloproliferative Disorders

Patients with aggressive myeloproliferative disorders (MPD) including advanced stage chronic myelomonocytic leukemia (CMML), chronic myelogenous leukemia (CML) in accelerated phase or blast crisis, and other MPD transformed into acute myelogenous leukemia (AML) have dire outcomes with conventional therapies including bone marrow transplant (BMT). One approach for malignant cell control is the ribonucleotide reductase (RR) inhibitor hydroxyurea (Hu). Triapine® is a novel RR inhibitor that binds to the M2 subunit of RR with 100 – 1000 fold greater potency than Hu and selectively depletes intracellular dATP. On this basis, we previously designed a phase I trial of Triapine® (Tri) and fludarabine (Flu) for patients with refractory acute leukemia and aggressive MPD. The overall response rate (ORR) was 21%, with the majority of responses occurring in patients with MPD. We have now conducted a phase II trial of this novel combination in 22 patients, median age 64 (50–75), with polycythemia vera (PV) transformed to AML (3); primary idiopathic myelofibrosis (PIMF) transformed to AML (5); undifferentiated MPD (2); CMML transformed to AML(10); and imatinib resistant CML in blast crisis (2). The duration of underlying MPD ranged from 1 month to 19 years. Twelve (55%) had previous exposure to Hu and 8 (36%) had received 1–3 prior induction regimens. Five patients have recurrent MPD/AML after allogeneic BMT. Poor risk cytogenetics were present in 15/22 cases (68%). Triapine® was administered at 105 mg/m² followed at 4 hours by fludarabine, 30 mg/m² daily × 5 days. At present, 61 cycles (median 3 per patient, range 1–6) have been administered on study, with ≥5 cycles being given to 5 patients. Using a Simon 2-stage design, criteria for continuation beyond an initial 18 patients was achieved with the following morbidity: 4 of the 22 patients died of multi-organ failure after less than 4 weeks of treatment; three of these four presented with hyperleukocytosis (50 – 260K/mm³) and leukostasis. Drug-related toxicities included hypoxemia (12/22), and transient methemoglobinemia (no intervention needed in most cases), acidosis, increased Cr, and tumor lysis. In patients receiving 4 or more cycles, chemotherapy was delivered every 34 days (range 22 – 61). Six patients ( 27 %) achieved complete remission (CR) lasting 2.5 – 12 months (mean 6 months, median 5.5 months) and 4 achieved partial remission, for an ORR 45%. Two patients were able to undergo BMT in CR. To determine if JAK2 mutations bore a relationship to response, we performed correlative Triapine® sensitivity assays of HEL cells that contain the JAK2 mutation, with a REH cell control. There was higher IC 50 for HEL cells relative to REH, (0.39 micromole vs. 0.22), arguing against a simple correlation of JAK2 constitutive activation with Triapine®/Fludarabine response. Similarly, SNP-A genomic analysis of amplification, deletion, and uniparental disomy identified acquired molecular abnormalities in 7 of 7 cases tested, but no specific loci correlated with either positive or negative response. In summary, the novel combination of Triapine® plus fludarabine, modeled for biochemical synergy, demonstrates clinical responses in aggressive MPDs transformed to AML. Further development of this regimen includes potential selection of responders by molecular predictors such as JAK2 mutational status. We anticipate that as formulated, this approach might be beneficial for selected patients, and serve as a bridge to bone marrow transplant. Moreover, our preliminary results suggest that combination with molecularly selective agents such as JAK2 inhibitors may enhance CR rate and duration.