Key Abstracts Yield Insights Into Combinations and Dosing in Myeloproliferative Neoplasms

Srdan Verstovsek, MD, PhD

Professor Department of Leukemia

The University of Texas MD Anderson Cancer Center, Houston, TX

Ruben A. Mesa, MD

Chair, Hematology Department of Hematology/Oncology

Mayo Medical School, Mayo Clinic Rochester, MN

Combining two commonly used drugs for myeloproliferative neoplasms achieved what the individual drugs could not: a high response rate with few side effects, as reported at the Eighth Annual Hematologic Malignancies 2012 Conference, held in Houston in October 2012.

A low-dose combination of hydroxyurea and anagrelide led to complete remission in 8 of 12 patients with polycythemia vera or essential thrombocythemia. Three other patients had partial responses. All 12 patients had Philadelphia chromosome-negative disease that had proven resistant or refractory to monotherapy. Patients have maintained remission during a mean treatment duration of 51 months.

“This is the largest number of patients and longest follow-up of hydroxyurea and anagrelide in myeloproliferative neoplasms refractory or intolerant to monotherapy,” concluded Inhye E. Ahn, MD, a hematologist at The University of Texas MD Anderson Cancer Center in Houston, and colleagues in a poster presentation.

“Rather than substitute for an agent that has had partial success or is causing dose-related side effects, adjusting the dose and adding a second agent offers highly effective therapy. In fact, future studies might explore combination therapy as initial therapy, to limit side effects and optimize response rates.”

The study was one of several that provided new and updated information about ongoing research to improve outcomes in myeloproliferative disorders.

Dose-dependent cytopenias did not reflect worsening disease status in patients with myelofibrosis treated with the JAK-2 inhibitor ruxolitinib in a large randomized clinical trial. Cytopenias tended to occur early in the course of treatment in the COMFORT- I trial and generally were manageable with dose adjustments and treatment interruptions, reported Srdan Verstovsek, MD, PhD, and colleagues.

Because thrombopoietin and erythropoietin signal exclusively through the JAK2 pathway, JAK2 inhibition would be expected to cause thrombocytopenia and anemia. COMFORT-I was a placebocontrolled trial that evaluated ruxolitinib in patients with myelofibrosis. Ruxolitinib therapy started at a dose of 15 mg twice daily for patients with platelet counts of 100 to 200 x 10⁹/L, and 20 mg twice daily for patients with higher platelet counts.

Although adverse events were monitored in the trial, the time course of cytopenias and management with dose reductions (and transfusions, in the case of anemia) had not been thoroughly examined. Analysis of the data showed that 87 of 155 patients treated with ruxolitinib required one or more dose reductions, and 49 of the 87 patients required a single dose reduction.

Dose adjustments typically occurred during the first eight to 12 weeks of treatment, and platelet counts remained stable thereafter, said Verstovsek, a professor in the Department of Leukemia at The University of Texas MD Anderson Cancer Center. Dose reductions occurred most often in patients who had baseline platelet counts of 100 to 200 x 10⁹/L.

The need for red blood cell transfusion also peaked during the first eight to 12 weeks of treatment with ruxolitinib, and then returned to baseline levels.

Another analysis of COMFORT-I examined the relationship between the final titrated dose of ruxolitinib and efficacy. The trial had a primary endpoint of at least a 35% reduction in spleen volume at week 24, as measured by abdominal MRI or CT. The principal secondary endpoint was at least a 50% reduction in total symptom score (TSS) on the modified Myelofibrosis Symptom Assessment Form.

Among patients who began treatment at 15 mg twice daily, the median final titrated dose was 10 mg twice daily, reported Ruben A. Mesa, MD, director of the Acute and Chronic Leukemias Program at the Mayo Clinic in Scottsdale, Arizona. The median for patients who began treatment at the higher dose was 20 mg twice daily.

The results showed that patients who had a final titrated dose ≤5 mg twice daily had only a 10% reduction in spleen volume. In contrast, the decline averaged 31% in patients who had a final titrated dose of 10 mg twice daily. Higher doses resulted in more modest improvement: 36% for 15 mg twice daily, 38% for 20 mg twice daily, and 41% for 25 mg twice daily.

Similarly, patients with a final titrated dose of 10 mg daily did as well or better than patients at high final doses with respect to the secondary endpoint.

“These findings suggest that ruxolitnib dose titration to 10 mg BID may be an effective and well-tolerated approach for patients with myelofibrosis starting with or developing a low platelet count (or hemoglobin level), while higher doses (≥15 mg BID) are beneficial for patients with higher platelet counts (>100 x 10⁹/L) or stable hemoglobin, as well as those with inadequate long-term response to a 10 mg BID dose,” concluded Mesa and colleagues in their poster presentation.

Another presentation at the meeting showed a near 15% discrepancy in the initial diagnosis of patients with primary idiopathic myelofibrosis and the final diagnosis made at a tertiary-care center.

The findings came from a retrospective analysis of records for 283 patients referred to MD Anderson Cancer Center from January 2007 to December 2011. The diagnosis at referral differed from the final diagnosis in 39 patients (13.8%), as reported by Cecilia Arana Yi, MD, a leukemia fellow at MD Anderson.

The discordant group consisted of 18 patients with diagnoses in the category of myeloproliferative neoplasms, 12 with diagnoses categorized as myelodysplastic syndrome/myeloproliferative neoplasm, and nine with diagnoses of myelodysplastic syndrome.

Examination of baseline characteristics identified a higher frequency of the JAK 2V617 mutation as the only significant factor (P < .005) that distinguished the patients with discordant diagnoses from those with concordant diagnoses at referral.

Patients with discordant diagnoses had a median overall survival of 36 months compared with 47 months for patients with correct diagnoses at referral, although the difference did not achieve statistical significance.

“These results demonstrate the complexity of the diagnosis of primary myelofibrosis and the need for morphologic confirmation by experienced pathologists,” concluded Yi and colleagues.