Welcome to OncoFacts for February, 2010. For this issue of OncoFacts, we are going to focus on some of the most interesting data presented at the American Society of Hematology (ASH) Annual Meeting. We will discuss some of the data presented at the ASH Annual Meeting in the areas of multiple myeloma, myeloproliferative neoplasms, and myelodysplastic syndrome (MDS). Next month, we will look at data from the ASH Annual Meeting regarding chronic myelogenous leukemia (CML), chronic lymphocytic leukemia (CLL), and lymphomas.

Myeloproliferative Neoplasms

Abstract 311
Many myeloproliferative neoplasms are characterized by a dominant gain of function mutation in JAK2 kinase. INCB018424 is an oral potent selective inhibitor of JAK1 and JAK2. Significant clinical activity has been seen with this targeted agent in myelofibrosis (MF), polycythemia vera (PV), and essential thrombocytosis (ET).

Srdan Verstovsek from M. D. Anderson Cancer Center reported the results of a phase II study of INCB018424 in 34 patients with PV and 39 patients with ET. Starting doses were 10 mg BID in PV and 25 mg BID in ET.

Ninety-four percent of the patients with PV achieved a partial response (PR) or complete response (CR). All became phlebotomy independent within 2 weeks on therapy. Seventy-five percent had at least 2 of 3 hematologic parameters return to normal with rapid and sustained reductions in white blood cell (WBC) and platelet counts. Sixty percent had at least a 50% reduction in spleen size. All patients had rapid improvement in PV associated symptoms.

Sixty-one percent of the 39 patients with ET achieved a PR or CR. Fifty percent had at least 2 of 3 hematologic parameters return to normal, including a return to normal of baseline elevated leukocyte counts. All 4 patients with baseline splenomegaly experienced >50% reduction in spleen size. Marked improvement was also seen in bone pain, pruritus, weakness, night sweats, and other disease-related symptoms.

Abstract 756
In another abstract, Srdan Verstovsek described the results of a similar phase II trial of INCB018424 in primary, post-PV, and post-ET myelofibrosis. One hundred fifty-five patients were enrolled in this study with an average drug exposure time of 15 months. Eighty-two percent were JAK2 mutation positive. Sixty-five percent were in the high-risk category. Seventy-four percent of patients remained on therapy for 1-2 years. Most patients were optimized at doses of 10 mg to 25 mg BID. Twenty-four percent discontinued therapy for a variety of reasons. Clinical responses were maintained over the entire duration of therapy. Spleen size was measured by magnetic resonance imaging (MRI) at 1, 3, and 6 months of treatment. Forty-eight percent experienced >50% reduction in spleen size regardless of JAK2 status.

There was a >50% reduction in both spleen related and cytokine related symptom scores, and the responses were durable. Randomized controlled phase III trials are underway.

Abstract 755
Another novel agent, TG101348, is an orally bioavailable potent JAK2 selective small molecule inhibitor. The results of a phase I study in 59 patients with intermediate-risk or high-risk symptomatic primary or post-PV/ET myelofibrosis were reported by Dr Animesh Pardanani from the Mayo Clinic-Rochester.

The maximum tolerated dose (MTD) proved to be 680 mg/day in a single oral dose. Twenty-five percent of patients discontinued therapy, but only one-third of them due to adverse events.

Sixty-seven percent of patients experienced a significant reduction in splenomegaly at the MTD of 680 mg daily. Improvement frequently occurred during the first or second cycle. Marked reductions in disease related symptoms were seen in most patients. Decreases in leukocytosis, thrombocytosis, and symptoms were also seen. In addition, some improvement was noted in marrow cellularity and fibrosis. A modest reduction in JAK2 allele burden was seen in 60% of patients. Adverse events primarily consisted of myelosuppression and mild GI toxicities. A phase II trial is ongoing.

Abstracts 2911 and 1904
Ruben Mesa from the Mayo Clinic-Scottsdale (abstract 2911) led a phase I-II dose finding study of pomalidomide in myelofibrosis. Nineteen patients were treated, and 16 had the JAK2-V617F mutation. The MTD was determined to be 3 mg per day, but there were no improvements in anemia at that dose because of myelosuppression. Consequently the daily dose was reduced to 0.5 mg and responses were seen at this dose. The authors recommended that 0.5 mg/day be used in future phase III trials.

Francesco Passamonti (abstract 1904) reported the results of a multicenter randomized phase II trial of pomalidomide in primary and post-PV/ET myelofibrosis. Eighty-four patients were enrolled and received pomalidomide alone at 2 mg/day or pomalidomide 2 mg/day + prednisone or pomalidomide 0.5 mg/day + prednisone. Sixteen patients (25%) experienced a response in anemia with little effect on splenomegaly. Sixty-three percent of the responders remained in remission with a median time on treatment of 19 months. No changes in marrow fibrosis or JAK2 allele burden were noted in those patients whose parameters were evaluated. No incidences of neuropathy or significant myelosuppression were noted. A phase III study is planned.

Abstract 308
The novel HDAC inhibitor, LBH589 or panobinostat, was evaluated in a phase I study reported by the group at Mount Sinai School of Medicine in New York. Eighteen patients with primary or post-PV/ET myelofibrosis were treated in 2 cohorts. Eighty-seven percent were JAK2 mutation positive. Four patients experienced clinical improvement, and 5 patients had stable disease. Thrombocytopenia was the most common adverse event and the dose limiting toxicity.

Abstract 307
A final abstract reported by Alessandro Vannucchi concerned a phase I-II trial of RAD001, an m-TOR inhibitor, in primary and post-PV/ET myelofibrosis. Cytokine-independent activation of the PI3K/AKT-m-TOR pathway has been reported in cells harboring the JAK2V617F mutation. Several dose levels were evaluated. The MTD was established as 10 mg per day. Adverse events were primarily grade 1-2 and included stomatitis, hyperlipidemia, myalgia, and anemia. Resolution of constitutional symptoms and pruritus occurred in most patients, and 5 out of 9 patients experienced a significant reduction in spleen size. Sixteen patients have been registered on the phase II trial that is underway.

Reference:
Verstovsek S, Passamonti F, Rambaldi A, et al. A phase 2 study of INCB018424, and oral, selective JAK1/JAK2 inhibitor, in patients with advanced polycythemia vera (PV) and essential thrombocythemia (ET) refractory to hydroxyurea. Blood. 2009;114(22). Abstract 311 and oral presentation at: American Society of Hematology Annual Meeting; December 5-8, 2009; San Francisco, CA.

Verstovsek S, Kantarjian H, Mesa R, et al. Long-term follow up and optimized dosing regimen of INCB018424 in patients with myelofibrosis: Durable clinical, functional and symptomatic responses with improved hematological safety. Blood. 2009;114(22). Abstract 756 and oral presentation at: American Society of Hematology Annual Meeting; December 5-8, 2009; San Francisco, CA.

Pardanani AD, Gotib JR, Jamieson C, et al. A phase I evaluation of TG101348, a selective JAK2 inhibitor, in myelofibrosis: Clinical response is accompanied by significant reduction in JAK2V617F allele burden. Blood. 2009;114(22). Abstract 755 and oral presentation at: American Society of Hematology Annual Meeting; December 5-8, 2009; San Francisco, CA.

Mesa RA, Pardanani AD, Hussein K, et al. Phase 1/2 dose finding study of pomalidomide in myelofibrosis. Blood. 2009;114(22). Abstract 2911 and oral presentation at: American Society of Hematology Annual Meeting; December 5-8, 2009; San Francisco, CA.

Passamonti F, Gottoni E, Cervantes F, et al. Pomalidomide therapy in myelofibrosis: 2-year follow-up of a randomized phase 2 study. Blood. 2009;114(22). Abstract 1904 and oral presentation at: American Society of Hematology Annual Meeting; December 5-8, 2009; San Francisco, CA.

Mascarenhas J, Wang X, Rodriguez A, et al. A phase I study of LBH589, a novel histone deacetylase inhibitor in patients with primary myelofibrosis (PMF) and post-polycythemia/essential thrombocythemia myelofibrosis (post-PV/ET MF). Blood. 2009;114(22). Abstract 308 and oral presentation at: American Society of Hematology Annual Meeting; December 5-8, 2009; San Francisco, CA.

Vannucchi AM, Guglielmelli P, Gattoni E, et al. RAD001, an inhibitor of mTOR, shows clinical activity in a phase I/II study in patients with primary myelofibrosis (PMF) and post polycythemia vera/essential thrombocythemia myelofibrosis (PPV/PET MF). Blood. 2009;114(22). Abstract 307 and oral presentation at: American Society of Hematology Annual Meeting; December 5-8, 2009; San Francisco, CA.

Myelodysplastic Syndromes >>

<< Multiple Myeloma

OncoFacts™ Editor:

James Epstein, MD

Contact

4325 Alexander Drive
Alpharetta, GA 30022
Fax: +1(770) 751-7334
www.imedex.com
Email: elearning@imedex.com

For ongoing improvement, we would appreciate your comments and suggestions. Email your suggestions to: elearning@imedex.com

OncoFacts is produced by Imedex^®, LLC (Imedex). Imedex is solely responsible for this program’s content. Although Imedex attempts to ensure that the information in our programs is accurate and timely, matters and opinions discussed and/or presented with respect to clinical matters are those of the discussion participants only, and not necessarily those of Imedex. Moreover, although Imedex attempts to identify and integrate the most qualified medical professionals and key thought leaders in our programs, TO THE FULLEST EXTENT PERMITTED BY LAW, IMEDEX EXPRESSLY DISCLAIM ALL WARRANTIES, EITHER EXPRESS OR IMPLIED, STATUTORY OR OTHERWISE, INCLUDING BUT NOT LIMITED TO THE IMPLIED WARRANTIES OF MERCHANTABILITY, NON-INFRINGEMENT OF THIRD PARTIES’ RIGHTS, AND FITNESS FOR A PARTICULAR PURPOSE, WITH RESPECT TO THE CONTENT PRESENTED. IMEDEX FURTHER MAKES NO REPRESENTATIONS OR WARRANTIES ABOUT THE ACCURACY, RELIABILITY, COMPLETENESS OR TIMELINESS OF THE CONTENT OR ANY MATERIAL PRESENTED. In addition, the material presented and related discussions are not intended to be medical advice, and the presentation or discussion of such material is not intended to create and does not establish a physician-patient relationship. Medical advice of any nature should be sought from an individual’s own physician.

Neither Imedex nor any of its subsidiaries or affiliates is affiliated with or formally endorsed by a medical society.

© 2010 Imedex, LLC. All rights reserved.