Cancer Treatment Today » Myelofibrosis

Ruxolitinib and Revlimid for Myelofibrosis – pro

M Levin, MD — Fri, 26 Oct 2012 17:10:41 +0000

Myelofibrosis is a Philadelphia chromosome-negative myeloproliferative neoplasm with a natural history characterized by progressive anemia, spleen enlargement due to extramedullary hematopoiesis, and potential for evolution to acute myeloid leukemia (AML). For patients who require treatment and are not candidates for transplantation, available therapies are palliative. Thesy include: chemotherapy such as hydroxyurea; erythropoiesis-stimulating agents; immunomodulatory drugs such as thalidomide or lenalidomide, with or without corticosteroids; splenectomy; splenic irradiation; and clinical trials. In November 2011, only four years after commencing clinical trial evaluation, ruxolitinib became the first JAK inhibitor approved by the FDA for MF patients (intermediate- and high-risk).

The registration trials for ruxolitinib consisted of two large phase III trials: COMFORT-I was a randomized (1:1), double-blind, multicenter study comparing ruxolitinib 15 or 20 mg twice daily (dose stratified according to baseline platelet count) versus placebo, and COMFORT-II was a randomized (2:1), open-label, multicenter trial comparing ruxolitinib 15 or 20 mg bid versus best available therapy (BAT; investigator-selected including no treatment).4 Both trials met the primary endpoint of the percentage of ruxolitinib versus control patients achieving > 35 percent reduction in spleen volume at week 24 (COMFORT-I: 41.9% vs. 0.7%) and week 48 (COMFORT-II: 28.5% vs. 0%). After 24 weeks in the COMFORT-I trial, the proportion of patients with ≥50 percent improvement in total symptom score (using the myelofibrosis symptom assessment form) was 45.9 percent versus 5.3 percent (ruxolitinib vs. placebo, p<0.0001). Anemia and thrombocytopenia were common ruxolitinib-related adverse events but rarely led to drug discontinuation, and the drug was otherwise well tolerated. In an updated analysis of COMFORT-I, there was a significant overall survival benefit with ruxolitinib; at a median follow-up of 51 weeks, there were 13 (8.4%) deaths in the ruxolitinib group and 24 (15.7%) deaths in the placebo arm.

Updates at the European Hematology Association ahd ASCO in 2013 suggest that Jakafi remains helpful in reducing symmptoms at the expense of some additive toxicity and prolongs PFS but does not extend survival.

Ruxolitinib’s potency as a “spleen shrinker” and “symptom mitigator” is shared by other JAK inhibitors currently in clinical trials (e.g., SAR302503 [formerly TG101308], CYT387, SB518, etc.). Patients with or without the JAK2 V617F mutation respond similarly. In an ad hoc analysis of the COMFORT-I and COMFORT-II trials, worsening of spleen size as well as symptoms and quality-of-life scores were similar between the placebo and BAT control groups.This means that conventional therapies don’t perform well long term. Although it may be premature to abandon conventional treatments such as hydroxyurea, the comparative superiority of ruxolitinib in these trials justifies its frontline use for intermediate- and high-risk MF patients in whom the primary goal is improvement of splenomegaly and constitutional symptoms. For MF patients with anemia or RBC transfusion-dependence as the predominant clinical issue, no standard of care currently exists. Lenalidomide is anotehr new drug that elicits benefits in anemia in ~20 to 30 percent of MF patients. In regard to combining the two, there is a phase I trial: Ruxolitinib and Lenalidomide for Patients With Myelofibrosis, NCT01375140.

Verstovsek S, Mesa RA, Gotlib JR, et al. Results of COMFORT-I, a randomized double-blind phase III trial of JAK 1/2 inhibitor INCB18424 (424) versus placebo (PB) for patients with myelofibrosis (MF). J Clin Oncol. ASCO Meeting Abstracts. 2011;29:6500.

Harrison CN, Kiladjian J, Al-Ali HK, et al. Results of a randomized study of the JAK inhibitor ruxolitinib (INC424) versus best available therapy (BAT) in primary myelofibrosis (PMF), post-polycythemia vera-myelofibrosis (PPV-MF) or post-essential thrombocythemia-myelofibrosis (PET-MF). J Clin Oncol. ASCO Meeting Abstracts. 2011;29:LBA6501.

Verstovsek S, Mesa RA, Gotlib J, et al. Consistent benefit of ruxolitinib over placebo in spleen volume reduction and symptom improvement across subgroups and overall survival advantage: results from COMFORT-I.Blood. ASH Annual Meeting Abstracts. 2011;118: 278.

Mesa RA, Verstovsek S, Cervantes F, et al. Comparison of the efficacy of placebo and best available therapy for the treatment of myelofibrosis in the COMFORT studies. Blood. ASH Annual Meeting Abstracts. 2011;118:1753.

Pardanani A, Gotlib J, Gupta V, et al. An expanded multicenter phase I/II study of CYT387, a JAK- 1/2 inhibitor for the treatment of myelofibrosis. Blood. ASH Annual Meeting Abstracts. 2011;118:3849.

Bhagwat N, Koppikar P, Kilpivaara O, et al. Heterodimeric JAK-STAT activation as a mechanism of persistence to JAK2 inhibitor therapy. Blood. ASH Annual Meeting Abstracts. 2011;118:122.

For Lay version see here

Erytropoietin therapy for myelofibrosis – pro

M Levin, MD — Thu, 23 Aug 2012 02:43:24 +0000

Experience with recombinant human erythropoietin (rHuEPO) in the treatment of the anemia secondary to myelofibrosis with myeloid metaplasia (MMM) is limited.There are a number of reports of small numbers of patiens demonstrating responsiveness but also a recent report which presents a picture of non-responsiveness of transfusion dependent myelofibrosis to erythropoietin therapy.
Initial studies failed to show significant improvements in hemoglobin levels upon administration of recombinant erythropoietin (rEpo). However, more recent investigations have demonstrated significant responses and decreased transfusion dependence in anemic patients with CIMF. The rEpo doses employed in those studies were in the range of 300–1,500 U/kg weekly. This finding underscores the current uncertainty about the optimal dose and schedule of rEpo in this disease. It is important to note that many patients with CIMF have normal serum erythropoietin levels, suggesting a potential lack of efficacy of rEpo in this setting [54]. Rodriguez et al. [ showed that a serum erythropoietin level <123 mU/ml was highly predictive of response to rEpo. This was recently corroborated by Cervantes et al. [53] in a study in which rEpo was given at an initial dose of 10,000 U three times per week to 20 patients with CIMF. Nine patients (45%) responded, including four who achieved normal hemoglobin levels. A serum erythropoietin level <125 mU/ml was associated with a favorable response to rEpo in the multivariate analysis. The combination of rEpo and thalidomide may represent a valid approach for patients with advanced CIMF
Future investigation will focus on stratification. Favorable cytogenetic findings was associated with response to erythropoietin therapy in one study.

In summary, there is sufficient evidence that Procrit raises Hb levels in many myelofibrosis patients. How to select patients is not entirely clear yet and at this time, a trial for effectivenesss is standard practice.It is not known whetehr it is a better long – term approach than periodic transfusions

Tsiara S, Kapsali H, Dimos GA, Chaidos A, Stoura M, Bourantas LK, Tzouvara E, Bourantas KL:
Treatment of anemia with recombinant human erythropoietin administration in patients with myelofibrosis, Archives of Hellenic Medicine 20 (3) : 281-285 (May 2003)

S.N. Tsiara, A. Chaidos, L.K. Bourantas, H.D. Kapsali, K.L. BourantasRecombinant Human Erythropoietin for the Treatment of Anaemia in Patients with Chronic Idiopathic Myelofibrosis Heamatoloica Vol. 117, No. 3, 2007

EAuthor Huang, J. Lasho, T.L. Li, C.Y. Pardanani, A.D. Mesa, R.A. Tefferi, A.
rythropoietin Therapy Does Not Benefit Transfusion-Dependent Primary Myelofibrosis Patients and Treatment Response Is Infrequent with a Baseline Hemoglobin Level >or= 10 g/dL
BLOOD 2007, VOL 110; pages 3555

Tefferi A, Lasho TL, Schwager SM et al. The JAK2(V617F) tyrosine kinase mutation in myelofibrosis with myeloid metaplasia: lineage specificity and clinical correlates. Br J Haematol 2005;131:320–328

Imaging Spleen in Myelofibrosis – pro

M Levin, MD — Tue, 19 Jun 2012 16:05:27 +0000

Myelofibrosis is a bone marrow disorder that disrupts the body’s normal production of blood cells. The result is extensive scarring in the bone marrow, leading to severe anaemia, weakness, fatigue, and often, an enlarged spleen and liver. Splenomegaly can be massive and is occasionally the presenting symtpom, with pain, early satiety, fever and left sided tenderness. It is crucial to rule out splenic infaction, becasue left-sided pain is not uncommon in myelofibrosis, a disease in which screen is usually markedly enlarged. Splenic infarction should easily be ruled out with CT scan; ultrasound can also be used but is less sensitive. Another option is PET. Reported 18F-FDG PET scan findings in myelofibrosis include diffuse significantly increased FDG uptake in the massively enlarged spleen and liver with diffuse increased uptake in bone marrow.

S S Saboo et al, Spleen in haematological malignancies: spectrum of imaging findings
Br. J. Radiol. January 1, 2012 85:81-92

Sandeep Chunduri et al, Pulmonary extramedullary hematopoiesis in patients with myelofibrosis undergoing allogeneic stem cell transplantation
haematol October 1, 2008 vol. 93 no. 10 1593-1595

Read the Layperson version here.