short report
Momelotinib treatment-emergent neuropathy: prevalence, risk factors and outcome in 100 patients with myelofibrosis
Ramy A. Abdelrahman, Kebede H. Begna, Aref Al-Kali, William J. Hogan, Mark R. Litzow, Animesh Pardanani and Ayalew Tefferi Division of Hematology, Department of Medicine, Mayo Clinic, Rochester, MN, USA Received 28 August 2014; accepted for publication 3 October 2014 Correspondence: Ayalew Tefferi, MD, Division of Hematology, Department of Medicine,
Summary Momelotinib (a JAK1 and JAK2 inhibitor) induces both anaemia and spleen responses in myelofibrosis (MF). Momelotinib treatment-emergent peripheral neuropathy (TE-PN) was documented in 44 (44%) of 100 MF patients treated at our institution; median time of TE-PN onset was 32 weeks and duration 11 months. Improvement after drug dose reduction or discontinuation was documented in only two patients. TE-PN was significantly associated with treatment response (P = 002) and longer survival (P = 0048) but significance was lost during multivariate analysis that included treatment duration. TE-PN did not correlate with initial or maximum momelotinib dose or previous treatment with JAK inhibitor or thalidomide.
Mayo Clinic, Rochester, MN 55905, USA. E-mail: [email protected]
Keywords: momelotinib, neuropathy, myelofibrosis, myeloproliferative.
Momelotinib (a JAK1 and JAK2 inhibitor) induces both anaemia and spleen responses in patients with myelofibrosis (MF) (Pardanani et al, 2013a). The favourable effect on anaemia was a distinguishing feature for momelotinib, compared to other JAK inhibitors) (Pardanani et al, 2013a). Among the first 60 patients treated in a phase-1/2 study, the maximum tolerated dose was 300 mg/d, based on reversible Grade 3 headache and asymptomatic hyperlipasaemia (Pardanani et al, 2013a). Spleen and anaemia responses, based on the 2006 International Working Group Myeloproliferative Neoplasms Research and Treatment (IWG-MRT) criteria (Tefferi et al, 2006), were 48% and 59%. In addition, most patients experienced constitutional symptoms improvement. Grade 3/4 adverse reactions included thrombocytopenia (32%), hyperlipasaemia (5%), elevated liver transaminases (3%) and headache (3%). New onset treatment-emergent peripheral neuropathy (TE-PN) was observed in 22% of patients (sensory symptoms, Grade 1). Updated data from the core (n = 166) and extension study (n = 120) of patients receiving momelotinib therapy were recently presented in an abstract form with response rates of 39% for spleen (not confirmed by imaging studies) and 53% for anaemia (Tefferi et al, 2006). Among 72 patients who were red cell-transfused in the month prior to study entry, 68% achieved a minimum 12-week period without transfusions. Grade 3 or 4 treatment-related events included thrombocytopenia (29%), neutropenia (5%) and elevated lipase (4%). TE-PN was reported in 38% of patients, all ≤ Grade 2. Momelotinib is currently undergoing phase 3 studies versus ruxolitinib or best available therª 2014 John Wiley & Sons Ltd British Journal of Haematology, 2015, 169, 77–80
apy respectively (NCT01969838, NCT02101268). In the current study we describe the natural history and risk factors of momelotinib-associated PN, in the context of phase1/2 studies performed at our institution (Pardanani et al, 2013a).
Methods The protocol was approved by the Mayo Clinic institutional review board. All patients provided informed written consent for study sample collection as well as permission for its use in research. Patient eligibility criteria, study design, treatment plan, study test schedule and other protocol details have been previously reported (Pardanani et al, 2013a). The study patients constitute part of a larger phase 1/2 clinical trial (CCL09101; NCT00935987) using momelotinib for the treatment of MF. Momelotinib capsules (as opposed to the newer tablet formulation used in the currently ongoing phase-3 study) were used in the present study. Toxicity, including that of TE-PN, was graded by the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 (http://evs.nci.nih. gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_ 8.5x11.pdf). TE-PN was primarily assessed by clinical history and physical examination and, in some cases, with formal neurological testing including electromyogram and nerve conduction studies (EMG/NCS); the latter was left to the discretion of the treating physician and required full consultation with the patient. Baseline transfusion status, anaemia and spleen responses were all defined according to First published online 15 December 2014 doi: 10.1111/bjh.13262
Short Report the 2006 IWG-MRT criteria (Tefferi et al, 2006). Information on survival and leukaemic transformation was updated in July 2014.
Statistical analyses considered clinical and laboratory parameters obtained at the time of entry to study CCL09101. Differences in the distribution of continuous
Table I. Baseline characteristics of 100 myelofibrosis patients treated with momelotinib, stratified by whether or not they experienced treatmentemergent peripheral neuropathy (TE-PN). Characteristic
All patients
Patients with TE-PN
Patients without TE-PN
P value
Total Age, years (median, range) >65 years n (%) Males n (%) Leucocyte count, 9109/l (median, range) Platelet count, 9109/l (median, range) DIPSS-plus risk group n (%) High Intermediate-2 Intermediate-1 Myelofibrosis subtype, n (%) Primary myelofibrosis Post–polycythaemia vera myelofibrosis Post–essential thrombocythaemia myelofibrosis Constitutional symptoms n (%) Circulating blasts ≥1% n (%) Haemoglobin 25 9 109/l n (%) Platelets
Momelotinib treatment-emergent neuropathy: prevalence, risk factors and outcome in 100 patients with myelofibrosis
Ramy A. Abdelrahman, Kebede H. Begna, Aref Al-Kali, William J. Hogan, Mark R. Litzow, Animesh Pardanani and Ayalew Tefferi Division of Hematology, Department of Medicine, Mayo Clinic, Rochester, MN, USA Received 28 August 2014; accepted for publication 3 October 2014 Correspondence: Ayalew Tefferi, MD, Division of Hematology, Department of Medicine,
Summary Momelotinib (a JAK1 and JAK2 inhibitor) induces both anaemia and spleen responses in myelofibrosis (MF). Momelotinib treatment-emergent peripheral neuropathy (TE-PN) was documented in 44 (44%) of 100 MF patients treated at our institution; median time of TE-PN onset was 32 weeks and duration 11 months. Improvement after drug dose reduction or discontinuation was documented in only two patients. TE-PN was significantly associated with treatment response (P = 002) and longer survival (P = 0048) but significance was lost during multivariate analysis that included treatment duration. TE-PN did not correlate with initial or maximum momelotinib dose or previous treatment with JAK inhibitor or thalidomide.
Mayo Clinic, Rochester, MN 55905, USA. E-mail: [email protected]
Keywords: momelotinib, neuropathy, myelofibrosis, myeloproliferative.
Momelotinib (a JAK1 and JAK2 inhibitor) induces both anaemia and spleen responses in patients with myelofibrosis (MF) (Pardanani et al, 2013a). The favourable effect on anaemia was a distinguishing feature for momelotinib, compared to other JAK inhibitors) (Pardanani et al, 2013a). Among the first 60 patients treated in a phase-1/2 study, the maximum tolerated dose was 300 mg/d, based on reversible Grade 3 headache and asymptomatic hyperlipasaemia (Pardanani et al, 2013a). Spleen and anaemia responses, based on the 2006 International Working Group Myeloproliferative Neoplasms Research and Treatment (IWG-MRT) criteria (Tefferi et al, 2006), were 48% and 59%. In addition, most patients experienced constitutional symptoms improvement. Grade 3/4 adverse reactions included thrombocytopenia (32%), hyperlipasaemia (5%), elevated liver transaminases (3%) and headache (3%). New onset treatment-emergent peripheral neuropathy (TE-PN) was observed in 22% of patients (sensory symptoms, Grade 1). Updated data from the core (n = 166) and extension study (n = 120) of patients receiving momelotinib therapy were recently presented in an abstract form with response rates of 39% for spleen (not confirmed by imaging studies) and 53% for anaemia (Tefferi et al, 2006). Among 72 patients who were red cell-transfused in the month prior to study entry, 68% achieved a minimum 12-week period without transfusions. Grade 3 or 4 treatment-related events included thrombocytopenia (29%), neutropenia (5%) and elevated lipase (4%). TE-PN was reported in 38% of patients, all ≤ Grade 2. Momelotinib is currently undergoing phase 3 studies versus ruxolitinib or best available therª 2014 John Wiley & Sons Ltd British Journal of Haematology, 2015, 169, 77–80
apy respectively (NCT01969838, NCT02101268). In the current study we describe the natural history and risk factors of momelotinib-associated PN, in the context of phase1/2 studies performed at our institution (Pardanani et al, 2013a).
Methods The protocol was approved by the Mayo Clinic institutional review board. All patients provided informed written consent for study sample collection as well as permission for its use in research. Patient eligibility criteria, study design, treatment plan, study test schedule and other protocol details have been previously reported (Pardanani et al, 2013a). The study patients constitute part of a larger phase 1/2 clinical trial (CCL09101; NCT00935987) using momelotinib for the treatment of MF. Momelotinib capsules (as opposed to the newer tablet formulation used in the currently ongoing phase-3 study) were used in the present study. Toxicity, including that of TE-PN, was graded by the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 (http://evs.nci.nih. gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_ 8.5x11.pdf). TE-PN was primarily assessed by clinical history and physical examination and, in some cases, with formal neurological testing including electromyogram and nerve conduction studies (EMG/NCS); the latter was left to the discretion of the treating physician and required full consultation with the patient. Baseline transfusion status, anaemia and spleen responses were all defined according to First published online 15 December 2014 doi: 10.1111/bjh.13262
Short Report the 2006 IWG-MRT criteria (Tefferi et al, 2006). Information on survival and leukaemic transformation was updated in July 2014.
Statistical analyses considered clinical and laboratory parameters obtained at the time of entry to study CCL09101. Differences in the distribution of continuous
Table I. Baseline characteristics of 100 myelofibrosis patients treated with momelotinib, stratified by whether or not they experienced treatmentemergent peripheral neuropathy (TE-PN). Characteristic
All patients
Patients with TE-PN
Patients without TE-PN
P value
Total Age, years (median, range) >65 years n (%) Males n (%) Leucocyte count, 9109/l (median, range) Platelet count, 9109/l (median, range) DIPSS-plus risk group n (%) High Intermediate-2 Intermediate-1 Myelofibrosis subtype, n (%) Primary myelofibrosis Post–polycythaemia vera myelofibrosis Post–essential thrombocythaemia myelofibrosis Constitutional symptoms n (%) Circulating blasts ≥1% n (%) Haemoglobin 25 9 109/l n (%) Platelets
