Cancer Treatment Today » Myelofibrosis

Cytogenetics for myelofibrosis -Pro

M Levin, MD — Sun, 09 Mar 2014 12:28:23 +0000

Cytogenetics are now routinely recommended for myelofibrosis. Guidelines (Reilly et al) indicate that beyond a routine bone marrow aspiration and biopsy, JAK2 V617F mutation screening should be carried out routinely in patients with primary myelofibrosis (PMF). Quantitative results are not required for clinical management.BCR-ABL1 rearrangement should be excluded in cases with atypical trephine biopsy features, or if the patient lacks a mutation in JAK2 or MPL. PDGFRA and PDGFB rearrangements should be excluded in the presence of significant eosinophilia. (Screening for other mutations remains a research tool and routine screening cannot be justified, apart from in cases of diagnostic difficulty where detection of a clonal abnormality would be informative) (Evidence level 2, Grade B). This recommendation does not include cytogenetics.

Recently there is evidence that cytogenetics can refine prognostic information which can help make decision, especially about stem cell transplantation. The factors not included in the IPSS that affect survival are represented by red cell transfusion need,12 thrombocytopenia,13 and “unfavorable” karyotype. Regarding the latter, patients with unfavorable karyotype, which includes a complex karyotype or sole or 2 abnormalities such as +8, −7/7q−, i(17q), inv(3), −5/5q−, 12p−, or 11q23, had a median survival of 2 years compared with 5.2 years for those with a “favorable” karyotype, defined as no abnormality or any other apart from those included in the above category, the 5-year survival rates were 8% and 51%, respectively. The newly devised DIPSS Plus score11 incorporates these additional 3 variables for improved prognostic categorization. In a series of 793 patients, median survival times were 185, 78, 35, and 16 months for the low, intermediate-1, intermediate-2, and high-risk categories, respectively.

Based on its inclusion into a recommended prognostic tool DIPSS Plus, cytogenetics should not longer be considered investigational
.

Reilly JT, McMullin MF, Beer PA, Butt N, Conneally E, Duncombe A, Green AR, George Michaeel N, Gilleece MH, Hall GW, Knapper S, Mead A, Mesa RA, Sekhar M, Wilkins B, Harrison CN, Writing group: British Committee for Standards in Haematology. Guideline for the diagnosis and management of myelofibrosis. Br J Haematol. 2012 Aug;158(4):453-71. [123 references]
Jennifer Dunlap, MD, Katalin Kelemen, MD, PhD, Nicky Leeborg, MD, Rita Braziel, MD, Susan Olson, PhD, Richard Press, MD, PhD, James Huang, MD, Ken Gatter, JD, MD, Marc Loriaux, MD, PhD, Guang Fan, Association of JAK2 Mutation Status and Cytogenetic Abnormalities in Myeloproliferative Neoplasms and Myelodysplastic/Myeloproliferative Neoplasms Am J Clin Pathol. 2011;135(5):709-719.

Gleevec for P. Vera

M Levin, MD — Fri, 14 Dec 2012 17:13:10 +0000

Gleevec is a drug initially approved for Chronic Myelogenous Leukemia but also studied for a variety of other conditions. It was studied for P. Vera at Weil-Cornell and the study was published in 2011. It treated 37 patients with polycythemia vera with Gleevec. The overall response rate was 49%. Thirty percent had a complete response, and 19%, a partial response. These are quite good results. On the other hand, a previous study by Nussenzveig et al, did not show much activity in 27 patients. Overall, 4 (17%) patients responded: one had a complete and three partial hematological response. The median time to response was 17.5 months (range 6-28), and the median duration of response was 17 months (range 9-68). No significant changes in JAK2(V617F) mutation burden were noted during imatinib therapy when compared with pretreatment values (P = 0.46). The investigators concluded that therapy with imatinib was generally well tolerated but imatinib has minimal clinical activity in PV. Clearly more study is required before this drug can become standard for P. Vera.

For Professional version see here

Ruxolitinib and Revlimid for myelofibrosis

M Levin, MD — Fri, 26 Oct 2012 16:54:21 +0000

Myelofibrosis is a Philadelphia chromosome-negative blood condition with a natural history characterized by progressive anemia, spleen enlargement due to production for ed cells there, and potential for evolution to acute myeloid leukemia (AML). For patients who require treatment and are not candidates fostem cell transplantation, available therapies have not been curative. They 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). 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.

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.). 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. his means that conventional thhapies 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 Myelofibrosis(MF). 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.

For Professional version see here

Imaging Spleen in Myelofibrosis

M Levin, MD — Sun, 05 Aug 2012 15:12:01 +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 anemia, weakness, fatigue, and often, an enlarged spleen and liver. The enlarged spleen can produce symptoms and it can be massive. Occasionally the presenting symptom is pain, feeling full after eating just a little (early satiety), fever and left sided tenderness. It is crucial to rule out splenic infarction when there is fever or pain. Splenic infarction should easily be ruled out with CT scan; ultrasound can also be used but is less sensitive. Another option is PET. Reported and expected 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.

Read the Professional version here.