Minimal Activity of the JAK2 Inhibitor CEP 701 in Myelofibrosis

By Andrew S. Artz, MD, Division of Hematology/Oncology, Univesity of Chicago Dr. Artz reports no financial relationships relevant to this field of study.

Abstract & Commentary

Synopsis: The activation mutation JAK2 tyrosine kinase (JAK2V617F) is found in 50% of patients with myleofibrosis (MF). In this phase-2 study, CEP 701, a JAK2 inhibitor, was administered to MF patients harboring a JAK2 mutation. Among 22 patients, 6 (27%) demonstrated clinical improvement, primarily related to reduced spleen size. No partial or complete responses occurred. The primary toxicities were myelosuppression and gastrointestinal. Specifically, diarrhea and nausea occurred in 72% and 50%, respectively, with 9% of patients experiencing grade 3 to 4 diarrhea. CEP-701 has modest clinical activity in JAK2 positive myelofibrosis but frequent gastrointestinal side effects.

Source: Santos F, et al. Phase 2 study of CEP-701, an orally available JAK2 inhibitor, in patients with primary or post-polycythemia vera/essential thrombocythemia myelofibrosis. Blood. 2010;115:1131-1136.

Primary myelofibrosis (primary idiopathic myelofibrosis or agnogenic myeloid metaplasia) is a clonal myeloproliferative disorder characterized by megakaryocyte proliferation or atypia, accompanied by reticulin or collagen fibrosis without evidence of other myeloproliferative or myelodysplastic disorders.1 Essential thrombocytosis and polycythemia vera may also progress to myelofibrosis. The prognosis is poor and therapeutic options limited. Only allogeneic hematopoietic stem cell transplantation can eradicate MF, although few patients are eligible for this procedure.

The Janus Kinase 2 (JAK2) is a non-receptor tyrosine kinase that activates signals such as STAT3 and STAT5. A gain of function mutation at position 617 (V617F) has advanced our understanding of the molecular pathogenesis of myeloproliferative disorders. The JAK2 mutation is present in over 90% of cases of PV2 and around 50% of ET and primary MF cases.1 CEP-701 (lestaurtinib) is an oral multi-targeted tyrosine kinase inhibitor under investigation against Fms-like tyrosine kinase 3 (FLT3) mutated AML.3 However, CEP-701 also inhibits wild-type and mutant JAK2,4 providing a rationale for further study in JAK2 mutated MF.

Investigators at the MD Anderson Cancer Center enrolled 22 adults subjects diagnosed with JAKV617F-mutated MF requiring treatment. The majority (15/22, 68%) had primary PF with post-PV MF and post-ET MF in four and three patients, respectively. In this phase study, CEP-701 was administered at 80 mg orally twice a day. One month of treatment was considered one cycle, and responses assessments were performed after every three cycles.

Six patients (27%) responded by standard criteria.5 Of these six responders, three had primary MF, two post-PV MF, and one post-ET MF. All responses were limited to clinical improvement (i.e., no PR or CR). No patient had improvement in bone marrow fibrosis, and no cytogenetic response occurred in the three responders with an abnormal baseline karyotype. The median JAK2 allele burden did not change in responders, nor did the pre-treatment allelic burden differ by response category.

CEP-701 treatment resulted in eight patients (36%) experiencing a grade 3 or 4 toxicity, primarily myelosuppression (14% anemia, 23% thrombocytopenia) and diarrhea (9%). Gastrointestinal toxicities were frequent, with any grade of diarrhea in 73% and nausea in 50%.

Commentary

Therapeutic options for myelofibrosis (MF), whether primary MF or post-PV and post-ET MF, remain frustratingly limited. Allogeneic hematopoietic stem-cell transplantation can cure the disease, but the procedure has significant toxicity and requires a suitable donor, limiting this to a small proportion of patients. The discovery of the Janus Kinase 2 mutation (JAK2V617F) has improved diagnosis, as it can be found in 90% of PV2 and 50% of ET and primary MF,1 and shed insights into the pathogenesis of myeloproliferative diseases.

In this study, investigators explored the response and toxicity of CEP-701, an orally available inhibitor of wild-type and mutant JAK24 for JAK2 mutated MF. Most study participants had primary PF (68%), with the remainder having post-PV MF and post-ET MF. The results showed only modest activity (6/22 responded, 27%), but all responses were clinical improvement with no complete or partial responses, no change in marrow fibrosis, and no change in JAK2 allelic burden.

Numerous JAK2 inhibitors are under investigation. Preliminary data from other potentially more selective JAK2 inhibitors such as XL019 (Shah N, ASH 2008, abstract 98) and INCB018424 (Verstovsek S, ASH 2008, abstract 2802) have suggested significant splenic size reduction without serious toxicities. Still, taken together, without marrow or cytogenetic responses reported, it seems unlikely the JAK2 inhibitors as currently studied will alter the natural history of the disease.

The toxicity profile of myelosuppression may not be unexpected, particularly as CEP-701 interacts with wild-type JAK2. The high frequency of GI disturbances was somewhat surprising. The authors postulate a possible relationship to the formulation or to pre-existing problems such as enlarged spleen. The dose was higher than in a prior study for AML. None of these explanations are totally satisfactory, and one wonders whether this might relate to studying this in a more general population, rather than the select criteria required in phase-I studies.

Objective evidence for "complete" or "partial" response was not observed and certainly "clinical improvement" is subject to both patient and physician bias. Accordingly, while the drug may provide some symptomatic relief, it lacks significant single agent activity. Both patient and physician bias may impact such responses. Thus, while the drug may provide some symptomatic relief, it lacks significant single agent activity. Moreover, the toxicity was considerable. The major clinical benefit related to spleen reduction, one wonders whether hydroxyurea might be more effective or at least less toxic, since CEP-701 had reversible but significant toxicities. Still, this initial trial of targeted therapy in MF patients at least suggests that inhibiting JAK2 is feasible and may lead to some clinical benefit. Relieving symptoms of massive splenic enlargement may by itself offer a substantial benefit for some patients. Different dosing schemes, more specific and complete JAK2 inhibitors, or combination therapy will need to be explored. Most importantly, MF may be one of the most difficult diseases to treat. The influence of JAK2 inhibitors on earlier proliferative phases of diseases such as ET, PV, or pre-fibrotic MF would be of interest.

In summary, CEP-701, an orally available JAK2 inhibitor, showed very modest activity in JAK2 mu- tated myelofibrosis.

References

1. Tefferi A, et al. Proposals and rationale for revision of the World Health Organization diagnostic criteria for polycythemia vera, essential thrombocythemia, and mary myelofibrosis: recommendations from an ad hoc international expert panel. Blood. 2007;

2. James C, et al. A unique clonal JAK2 mutation leading to constitutive signaling causes polycythaemia vera. Nature. 2005;434:1144-1148.

3. Smith BD, et al. Single-agent CEP-701, a novel FLT3 inhibitor, shows biologic and clinical activity in patients with relapsed or refractory acute myeloid leukemia. Blood. 2004;103:3669-3676.

4. Hexner EO, et al. Lestaurtinib (CEP701) is a JAK2 inhibitor that suppresses JAK2/STAT5 signaling and the proliferation of primary erythroid cells from patients with myeloproliferative disorders. Blood. 2008;111: 5663-5671.

5. Tefferi A, et al. International Working Group (IWG) consensus criteria for treatment response in myelofibrosis with myeloid metaplasia, for the IWG for Myelofibrosis Research and Treatment (IWG-MRT). Blood. 2006;108:1497-1503.