Myelofibrosis

Myelofibrosis (Part Two)

May 7, 2013 Hematology, Pharmacotherapy, Therapeutics No comments , ,

In last blog we discussed the definition, the clinical manifestations, the biology, and the first part of the management of myelofibrosis.

Let’s review the risk evaluation of myelofibrosis. According the Dynamic International Prognostic Scoring System (DIPSS) the risk grade can be divided into 5 groups.

  • No risk factors – low risk
  • 1 risk factor – intermediate 1
  • 2 or 3 risk factors – intermediate 2
  • ≥ 3 risk factors -high

These four risk groups are with respective median survivals of 15.4, 6.5, 2.9, and 1.3 years. Leukemic transformation was predicted by the presence of unfavorable karyotype or platelet count < 100 × 109/L.

For low- or intermediate 1-risk patients without symptoms, the strategy of “watch and wait” is preferred. For low- and intermediate 1-risk patients with symptoms, if clinical needed, it is reasonable to start with conventional drug therapy.

For patients with high- or intermediate 2-risk disease can be managed by conventional drug therapy, splenectomy, radiotherapy, allo-SCT, or experimental drug thearpy. We have talked about these approaches (except experimental drug therapy) in the first part. Today we focus on the experimental drug therapy or novel therapies.

Novel therapies

Pomalidomide

Pomalidomide is a thalidomide derivative classified with lenalidomide as an immunomodulatory drug. In vitro, immunomodulatory drugs antagonize angiogenesis and expression of tumor necrosis factor α and IL-6 while they facilitate production of IL-2 and interferon IFN-γ and enhance T-cell and nature killer-cell proliferation and activity;the precise mechanism of their action is not known but might include down-regulation cytokine signaling.

Due to the peripheral neuropathy or severe myelosuppression of thalidomide and lenalidomide, there was a room for improvement in both therapeutic activity and side effect profile. So pomalidomide was here.

In a phase 2 randomized study, ~ 25% of patients with anemia responded to pomalidomide alone (2mg/d) or pomalidomide (0.5 or 2 mg/d) combined with prednisone. In a subsequent phase 2 study of single-agent pomalidomide (0.5 mg/d), anemia response was documented only in the  presence of JAK2V617F (24% vs 0%) and predicted by the presence of pomalidomide-induced basophilia (38% vs 6%) or the absence of marked splenomegaly (38% vs 11%). Platelet response was seen in 58% of patients with baseline platelet count of 50-100 ×109/L, but the drug had limited activity in reducing spleen size. Unlike the case with thalidomide or lenalidomide, drug-associated neuropathy or myelosuppression was infrequent. However, higher doses of pomalidomide (> 2 mg/d) were myelosuppressive and not necessarily better in terms of efficacy.

JAK inhibitors

JAK2V617F (Janus kinase 2 mutation V617F) mutation plays an important role in the pathogenesis of myelofibrosis. JAK2V617F has been identified in approxmiately 60% of patients with myelofibrosis (half of patients with PMF and post-ET myelofibrosis and in nearly all of those with a secondary form following a previous PV).

On November 16, 2011 FDA approve ruxolitinib, a small-molecule inhibitor of JAK1 and JAK2, which is the first drug approved for the treatment of symptomatic intermediate- or high-risk myelofibrosis. For patient with symptomatic intermediate- or high-risk myelofibrosis who are not candidates for allogeneic hematopoietic stem cell transplantation, ruxolitinib is the first drug to demonstrate a significant and sustained improvement in splenomegaly and various other myelofibrosis-related symptoms. Quality-of-life measures are significantly improved with this agent, which may be its most dramatic benefit.

The recommended starting dose of ruxolitinib is based on platelet count. For patients with a platelet count of greater than 200 × 109/L, the recommended starting dose is 20 mg orally twice/day. For patients with a platelet count of 100-200 × 109/L, the recommended starting dose is 15 mg twice/day. Due to its hematologic adverse effects, interruption of treatment is warranted for patients with a platelet count less than 50 × 109/L. Once the platelet count has recovered, ruxolitinib should be restarted at the dosages in Table 1.

Table 1 Recommended Dosages for Restarting Ruxolitinib After Interruption of Therapy Due to Decreased Platelet Count

Platelet Count (× 109/L)Restarted Ruxolitinib Dosea
≥ 12520 mg twice/day
100-12415 mg twice/day
75-9910 mg twice/day
50-745 mg twice/day
< 50Withhold therapy

aRestart dose at least 5 mg twice/day less than dose before interruption.

Myelofibrosis (Part One)

April 23, 2013 Cytogenetics, Hematology, Pharmacotherapy, Therapeutics 1 comment , , , ,

Definition

Myelofibrosis (MF) is a clonal proliferative disease of hematopoietic stem cells, leading to an inappropriate cytokines release, fibrosis of the bone marrow, constitutive mobilization of committed progenitor cells into the peripheral blood and extramedullary hematopoiesis. MF is the most symptomatic and has the worst prognosis among the Philadelphia-chromosome-negative chronic myeloproliferative neoplasms (MPNs).

This disease may present either as idiopathic (primary myelofibrosis, PMF) or as transformation of an antecedent polycythemia vera (PV) or essential thrombocythemia (ET). PV and ET are phenotypically overlapping with PMF and manifestations and therapeutic approaches are virtually the same in PMF and PV/ET.

Myleofibrosis is characterized by a progressive clinical course. Established prognostic factors including age, hemoglobin level, and white blood cell count have been used for risk assessment, but these characteristics do not fully explain the risk of death or major clinical events.

Morbidity and mortality of myelofibrosis are usually the result of leukemic transformation, spleno-portal hypertension, and infections, as well as thrombosis and hemorrhage.

Table 1 Poor Prognosis Factors – International Working Group-derived International Prognostic Scoring System (IPSS)

Poor Prognosis Risk Factors
1Age > 65 yrs
2Presence of constitutional Symptoms
3Anemia (Hemoglobin < 10 g/dL)
4Leukocytosis (White blood cell count > 25 x 103/mm3)
5Circulating blast cells of 1% or greater

The presence of the factors in the table above defines risk degree of myelofibrosis:

  • No risk factors – low-risk
  • One risk factor – intermediate-1-risk
  • Two risk factors – intermediate-2-risk
  • Three or more risk factors – high-risk

What must be paied attention is that this system (IPSS) is used for risk evaluating from time of diagnosis. There is another assessment criteria called Dynamic IPSS plus (DIPSS-Plus) which can be used for risk evaluating at any time during the disease course. The DIPSS-Plus has three additional independent risk factors including red cell transfusion need, platelet count < 100 × 109/L, and unfavorable karyotype. The unfavorable karyotype includes complex karyotype or sole or 2 abnormalities that include +8, -7/7q-, i(17q), inv(3), -5/5q-, 12p-, or 11q23 rearrangement.

Note that leukocytosis can happen in patients after splenectomy due to “myeloproliferative” reaction and it does not necessarily imply disease progression.

Figure 1 The Dynamic International Prognostic Scoring System (DIPSS) plus prognostic model for primary myelofibrosis (PMF).

  • No risk factors – low risk
  • 1 risk factor – intermediate 1
  • 2 or 3 risk factors – intermediate 2
  • ≥ 3 risk factors – high

These four risk groups are with respective median survivals of 15.4, 6.5, 2.9, and 1.3 years. Leukemic transformation was predicted by the presence of unfavorable karyotype or platelet count < 100 × 109/L.

Clinical Manifestations

Symptomatic myelofibrosis can present with anemia, significant splenomegaly, aberrant production of proinflammatory cytokines (which causes constitutional symptoms such as weight loss, night sweats, fever of unknow origin), severe fatigue, cachexia, and pruritis.

These manifestations include anemia (either moderate or transfusion dependent), splenomegaly and/or hepatomegaly, the development of foci of nonhepatosplenic hematopoiesis, myeloproliferation manifesting with marked leukocytosis or thrombocytosis. and increased risk of thrombohemorrhagic complications, and a spectrum of debilitating constitutional symptoms.

Biology

JAK2V617F (Janus kinase 2 mutation V617F) mutation plays an important role in the pathogenesis of myelofibrosis. JAK2V617F has been identified in approxmiately 60% of patients with myelofibrosis (half of patients with PMF and post-ET myelofibrosis and in nearly all of those with a secondary form following a previous PV). Despite its crucial role in pathogenetic role, the clinical relevance of JAK2V617F in myelofibrosis is not completely understood. In a large retrospective survey showed that JAK2V617F mutation plays a significant and independent influence on the disease phenotype and showed that many clinical manifestations are correlated with the expansion of clonal hematopoietic cells harboring the JAK2V617F mutant allele.

Management of Myelofibrosis

The treatment of MF is guided by risk stratification and the patient’s clinical needs. As we mentioned before, the risk stratification are:

  • No risk factors – low risk
  • 1 risk factor – intermediate 1
  • 2 or 3 risk factors – intermediate 2
  • ≥ 3 risk factors – high

For low- or intermediate 1-risk disease, the respective median survival of patients exceeds 15 and 6 years and even longer for patients younger than age 65 years. Therefore, the risk of allo-SCT-associated mortality and morbidity is not justified in such patients, and it is also not prudent to subject them to investigational drug therapy, considering the limited information about long-term safety of new therapeutic agents. Similarly, there is no evidence to support the value of conventional drug therapy in asymptomatic patients with low- or intermediate 1-risk diseases. For this group of patients without symptoms, “watch and wait” is preferred.

For this group of patients with symptoms, they may occasionally experience splenomegaly, nonhepatosplenic extramedullary hematopoiesis, extramedullary hematopoiesis (EMH)-associated pulmonary hypertension, fatigue, bone (extremity) pain, pruritus, or thrombocytosis with a thrombosis history. Intermediate 1-risk patients might in addition display symptomatic anemia, marked leukocytosis, or constitutional symptoms such as drenching night sweats, fever, or weight loss (cachexia). If clinical needed, it is reasonable to start with conventional drug therapy.

However, if the patient is del(5q) present, lenalidomide is the recommended first-line therapy because significant improvement.

Figure 2 Risk-adapted therapy in primary myelofibrosis.

For patients with high- or intermediate 2-risk disease can be managed by conventional drug therapy, splenectomy, radiotherapy, allo-SCT, or experimental drug therapy. With each one of these treatment modalities except allo-SCT, the primary goal is palliation of anemia, symptomatic splenomegaly, constitutional symptoms, or disease complications from EMH (extramedullary hematopoiesis).

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Diagnosis of Myelofibrosis

February 22, 2013 Hematology No comments ,

Current diagnosis of PMF is based on the 2008 World Health Organization (WHO) criteria, which enlist histopathologic, morphologic, clinical, and molecular-cytogenetic variables. The diagnosis of post-PV or post-ET MF is according to IWG-MRT criteria.

Table 1 Diagnostic Criteria of Myelofibrosis

In all 3 MF variants, typical laboratory features include anemia, peripheral blood leukoerythroblastosis, dacryocytosis, leukocytosis/thrombocytosis, increased lactate dehydrogenase (LDH), excess circulating blasts or CD34+ cells, and bone marrow fibrosis, osteosclerosis, and angiogenesis.

Occasionally, overt bone marrow fibrosis might be absent (ie, prefibrotic PMF) and, in the presence of thrombocytosis, a spurious diagnosis of ET is made. The possibility of prefibrotic PMF, as opposed to ET, should be considered in the presence of persistently increased serum LDH, anemia, leukoerythroblastosis, anemia, leukoerythroblastosis, increased circulating CD34+ cell count, and marked splenomegaly. It is underscored that the distinction between ET and prefibrotic PMF is clinically relevant because both OS and leukemia-free survival are significantly inferior in the latter.

The differential diagnosis of PMF should also include bone marrow fibrosis associated with noneoplastic or other neoplastic conditions, including metastatic cancer, lymphoid neoplasm, or another myeloid malignancy, especially CML, MDS, chronic myelomonocytic leukemia (CMML), or AML. The presence of JAK2 or MPL mutation reliably excludes reative bone marrow fibrosis or a nonmyeloid malignancy.