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New Therapies for Patients with Myeloproliferative Diseases

Leukemia Insights - Fall 2009

Jak2 Inhibitors for Patients with Myelofibrosis

Classic Philadelphia chromosome–negative Myeloproliferative Diseases (MPD) include essential thrombocythemia (ET), polycythemia vera (PV), and primary myelofibrosis (MF). Several independent groups have described almost simultaneously a novel activating somatic point mutation in the gene encoding the cytoplasmic Janus kinase 2 (JAK2), characterized by the substitution of valine to phenylalanine at codon 617 (JAK2V617F), in patients with MPD. This mutation is present in 50% of ET and PMF patients, and 97% of PV patients, and makes the JAK2 protein active and phosphorylated all the time. JAK2 is an important protein inside the cell, as it transmits signals for the cell to grow. It is believed that the JAK2 protein (either mutated or not) is a major reason for the existence and progression of these diseases. It is highly likely, therefore, that a JAK2 inhibitor might positively affect the disease and help the MPD patient. Several clinical trials of JAK2 inhibitors are currently underway for patients with MF and described here.

Randomized Placebo-controlled Study of the JAK Inhibitor INCB018424

A recently completed Phase I/II study of the oral JAK1/2 inhibitor INCB018424 for patients with MF has accrued more than 150 patients and showed exemplary efficacy in reducing enlarged spleen and liver, reducing white blood cell and platelet counts, and improving patients’ quality of life (including weight gain, improved ability to walk, and increased performance status). Results were equal in patients with and without JAKV617F mutation. There have been minimal non-hematologic side effects. The hematologic on-target side effect was primarily thrombocytopenia. Based on these encouraging results, the Phase III approval study of INCB018424 is now open to patients with MF, regardless of the JAK2 mutation status, who have enlarged spleen (>5cm) on physical exam, poor performance status, and not lower than 100x109/L platelet count.

Selected Inclusion Criteria:

1) Age 18 years or older
2) Subjects must be diagnosed with PMF, PPV-MF or PET-MF, according to the 2008 World Health Organization criteria irrespective of JAK2 mutation status.
3) Subjects with myelofibrosis requiring therapy must be classified as high risk (3 or more prognostic factors) OR intermediate risk level 2 (2 prognostic factors). The prognostic factors, defined by the International Working Group (IWG) are:

  • Age > 65 yrs
  • Presence of constitutional symptoms (weight loss, fever, night sweats)
  • Marked anemia (hemoglobin < 10 g/dL)
  • Leukocytosis (history of white blood cell count (WBC) > 25 x 109/L)
  • Circulating blasts equal to or greater than 1%

4) Subjects in whom treatment of MF is indicated based on presence of one or more of the following: a. IWG Prognostic Category of High Risk (3 or more risk factors) b. Palpable spleen at 10 cm or more below the costal margin c. Active symptoms of MF as demonstrated by one symptom score of at least 5 (on a zero to 10 scale) on at least one of the following items OR a score of 3 or greater on at least two of the following items: early satiety, abdominal discomfort, abdominal pain, inactivity, night sweats, pruritis, bone pain.
5) Subjects who are refractory, resistant or intolerant to available therapy, or in the investigator’s judgment, are not candidates for available therapy.
6) Subjects must have discontinued all drugs used to treat underlying myelofibrosis disease no later than 4 weeks prior to the Baseline visit.
7) ECOG performance status of 0-3
8) Subjects must have a palpable spleen measuring 5 cm or greater below the costal margin.
9) Subjects with peripheral blood blast count of < 10%

Selected Exclusion Criteria:

1) Subjects in whom MF disease is well controlled with current therapy.
2) Females who are pregnant or are currently breastfeeding.
3) Any history of platelet counts < 50,000/uL or absolute neutrophil count (ANC) < 500/uL except
during either treatment for a myeloproliferative disorder or treatment with cytotoxic therapy for any other reason.
4) Inadequate liver or renal function
5) Active malignancy over the previous 5 years except treated early stage squamous cell carcinoma of the skin or treated basal cell carcinoma of the skin

Phase I Study of SB1518 for the treatment of advanced myeloid malignancies (including myelofibrosis)

SB1518 is an oral JAK2 and FLT3 inhibitor. This is a two-part study, with a dose escalation phase and an expanded cohort at the recommended therapeutic dose. The dose escalation portion of the study has been completed; patients are currently being enrolled in the expanded cohort utilizing the best therapeutic dose.

Selected Inclusion Criteria:

1) Subjects with histologically confirmed myeloid malignancy who have failed standard therapies or are not candidates for palliative therapies.
2) Adequate liver and renal function
3) Has a corrected QT interval (QTc) </= 0.47 seconds using the Bazett Formula
4) At least 2 weeks since prior therapy that is considered disease-directed

Selected Exclusion Criteria:

1) Concurrent malignancy, except those subjects with early stage squamous cell carcinoma of the skin, basal cell carcinoma of the skin, or cervical intraepithelial neoplasia
2) Known HIV-positive, known active hepatitis A, B, or C
3) Women who are pregnant or lactating

Phase I/II Open Label Multi-Centre Study of the JAK2 inhibitor AZD1480

The study is designed as a two-part trial, with a dose escalation phase and an expanded cohort at the recommended therapeutic dose. The dose escalation portion of the study is a classical 3+3 design to determine safety and tolerability; patients are currently being accrued. Efficacy will be determined at the therapeutic dose in the expanded cohort.

Selected Inclusion Criteria:

1) Age 25 years and over
2) Patients with myelofibrosis requiring therapy, including those previously treated by myelofibrosis directed therapy who have subsequently relapsed or are refractory, or if newly diagnosed should be intermediate or high risk according to Lille Scoring System (adverse prognostic risk factors are: Hgb<10g/dL,WBC<4 or >30.0 X 109/L; risk group: 0 factor=low, 1 factor =intermediate, 2 factors=high); or with symptomatic splenomegaly (causing e.g. 5-10% weight loss, significant fever, or significant splenic pain affecting performance status) that is equal to or greater than 10 cm below left costal margin.
3) ECOG performance status 0-2

Selected Exclusion Criteria:

1) Platelet count <50 x 109/L
2) Serum creatinine >1.5 x ULN, Serum total bilirubin >1.5 x ULN
3) Evidence of established interstitial lung disease on screening High Resolution Computerized Tomography (HRCT)
4) Chronic Obstructive Pulmonary Disease (COPD) with FEV1/FVC < 0.7 and spirometric classification Stage 3 or 4, i.e., FEV1 <50% predicted.
5) Diffusing capacity of the Lung for Carbon Monoxide (DL(CO) ) corrected for hemoglobic <60% predicted, pulse oximetry < 88% O2 saturation after a 6-minute flat walk.
6) Persistent asthma
7) History of pulmonary fibrosis
8) Abnormality of cornea
9) Previous allogenic bone marrow transplantation

Pomalidomide for Patients with Myelofibrosis and Anemia

Thalidomide, an agent with putative antiangiogenic (prevents new blood vessel formation) and immunomodulatory (modifies immune system) effects, has activity in MF. Improvements in blood cell counts and reduction in splenomegaly have been reported in selected patients but at the expense of significant side effects, including sedation, neurotoxicity, and constipation. When given with prednisone (corticosteroid), these side effects are diminished and patients can tolerate a prolonged course of therapy; this translates into the improvement of blood cell counts in significant numbers of patients. There is a need for more potent and less toxic analogs of thalidomide.

Revlimid is an oral thalidomide analog that has recently been approved as therapy for patients with 2 other bone marrow diseases, myelodysplastic syndrome and multiple myeloma. Clinical trials studying the efficacy and safety of revlimid +/- prednisone in MF have been recently conducted at the MD Anderson and Mayo Clinic and have shown similar results to thalidomide, at the expense of significant myelosuppression in most patients. A new analog with improved activity has been developed, called CC4047 or pomalidomide. This medication was studied in an international multicenter four-arm study a year ago and showed an improvement in anemia in up to 40% of MF patients. A new Phase II open-label single-arm study is currently open at MD Anderson for MF patients with severe anemia. Participants are required to visit MD Anderson monthly for the first 6 months and then every 3 months while on the study.

Selected Inclusion Criteria:

1) Myelofibrosis requiring therapy
2) Screening total hemoglobin level < 10 g/dL or transfusion-dependent anemia
3) Total bilirubin <3x ULN or Direct Bilirubin <2x ULN, Serum creatinine </= 2.0 mg/dL, Absolute neutrophil count >/=1,000/uL, Platelet count >/= 50,000/uL
4) No active malignancies with the exception of basal cell or squamous cell carcinoma of the skin, or carcinoma (in situ) of the cervix or breast

Selected Exclusion Criteria:

1) Known positive status for HIV, hepatitis B carrier, or active hepatitis C infection.
2) The use of any therapy within 14 days
3) Pregnant or lactating females

Dr. Srdan Verstovsek is the Leukemia Department’s MPD Program Leader. He can be reached at or 713-745-3429, or feel free to contact any Leukemia physician.

© 2015 The University of Texas MD Anderson Cancer Center