Efficacy and Safety of Ruxolitinib in the Treatment of Anemic Myelofibrosis Patients.

A Multicenter Phase II, Open Label, Single Arm Study to Evaluate the Efficacy and Safety of Ruxolitinib in the Treatment of Anemic Myelofibrosis Patients.

This was a study of treatment with ruxolitinib in patients who presented with transfusion dependent or independent anemia. Starting dose was 10 mg BID. This dose was maintained for the first 12 weeks of the study and up-titrated thereafter unless the subject met criteria for dose hold or dose reduction

This was a study of treatment with ruxolitinib in patients who present with transfusion dependent or independent anemia at screening defined as an hemoglobin <10 g/dL with 10 mg BID starting dose with subsequent up titrations (maximum dose 25 mg BID) depending on safety and efficacy. This dosing approach for anemic MF patients will be systematically studied in this prospective multicenter phase II open label single arm trial to determine if the levels of spleen length reduction and symptom improvement are consistent with those reported in previous clinical trials with ruxolitinib in patients with anemia and doses according to platelet counts at the moment of treatment initiation, and whether this lower starting dose and up titration approach may minimize the initial hemoglobin and platelet declines and transfusion requirements.

Inclusion Criteria:

Written informed consent must be obtained prior to any screening procedures.

1. Male or female patients aged ≥ 18 years of age.
2. Patients must have been diagnosed with PMF, according to the 2016 revised International Standard Criteria, PPV MF or PET-MF, irrespective of JAK2 mutation status.
3. Patients must have had palpable splenomegaly that is equal to or greater than 5 cm below the left costal margin.
4. Patients must have had hemoglobin less than 10 g/dL
5. Patients must have had a history of transfusions must have a documented transfusion record in the previous 12 weeks to baseline.
6. Patients must have had ECOG performance status of 0, 1, or 2.
7. Patients must have had a peripheral blood blast percentage count of < 10%.
8. Patients must have recovered or stabilized sufficiently from any adverse drug reactions associated with prior treatments before beginning treatment with ruxolitinib.

Exclusion Criteria:

1. Patients who had prior treatment with any JAK1 or JAK2 inhibitor.

2. Patients who had known hypersensitivity to ruxolitinib or other JAK1/JAK2 inhibitors, or to their excipients.

3. Patients who had been eligible for hematopoietic stem cell transplantation (suitable candidate and a suitable donor is available).

4. Patients who had inadequate bone marrow reserve at baseline as demonstrated by at least one of the following:

   1. ANC that is ≤ 1,000/µL.
   2. Platelet count that is <50,000/µL without the assistance of growth factors, thrombopoietic factors or platelet transfusions.
   3. Hemoglobin count that is ≤ 6.5 g/dL despite transfusions.

5. Patients who had severely impaired renal function defined by: Creatinine clearance less than 30 mL/min.

6. Patients who had inadequate liver function defined by any of these:

   1. Total bilirubin ≥ 2.5 x ULN and subsequent determination of direct bilirubin ≥ 2.5 x ULN;
   2. Alanine aminotransferase (ALT) > 2.5 x ULN;
   3. Aspartate aminotransferase (AST) > 2.5 x ULN.

7. Patients who were being treated concurrently with a strong (potent) systemic inhibitor or inducer of CYP3A4 at the time of Screening.

8. Presence of active bacterial, fungal, parasitic, or viral infection which requires therapy.

9. Known history of human immunodeficiency virus (HIV) infection or other immunodeficiency syndromes such as X-linked agammaglobulinemia and common variable immune deficiency.

10. Acute viral hepatitis or active chronic hepatitis B or C infection. Patients with inactive chronic infection (without viral replication) can be enrolled

11. History of progressive multifocal leuko-encephalopathy.

12. Impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of ruxolitinib .

13. History or current diagnosis of uncontrolled or significant cardiac disease, including any of the following:

    1. Myocardial infarction within last 6 months
    2. Uncontrolled congestive heart failure
    3. Unstable angina within last 6 months
    4. Clinically significant (symptomatic) cardiac arrhythmias (e.g. bradyarrhythmias, sustained ventricular tachycardia, and clinically significant second or third degree AV block without a pacemaker)

14. Significant concurrent, uncontrolled medical condition which, in the investigator's opinion, would have jeopardized the safety of the patient or compliance with the protocol.

15. Patients who were undergoing treatment with another investigational medication or had been treated with an investigational medication within 30 days or 5 half-lives (whichever is longer) prior to the first dose of study drug.

16. Patients who had a history of malignancy in the past 3 years, except for treated early stage squamous or basal cell carcinoma.

17. Patients who were unable to comprehend or are unwilling to sign an ICF.

18. Pregnant or nursing (lactating) women

19. Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, unless they were using highly effective methods of contraception throughout the study duration inclusive of 30 day safety follow up.