The Ruxo-BEAT Trial in Patients with High-risk Polycythemia Vera or High-risk Essential Thrombocythemia

The Philadelphia chromosome negative myeloproliferative neoplasms (MPN) comprise a group of clonal hematological malignancies that are characterized by chronic myeloproliferation, splenomegaly, different degrees of bone marrow fibrosis, and disease-related symptoms including pruritus, night sweats, fever, weight loss, cachexia, and diarrhea. In addition, due to elevated numbers of leucocytes, erythrocytes and/or platelets, the disease course can be complicated by thromboembolic disease, hemorrhage, and leukemic transformation as well as myelofibrosis.

Patients with polycythemia vera (PV) typically harbor an increased number of blood cells from all three hematopoietic cell lineages due to clonal amplification of hematopoetic stem cells, while patients with essential thrombocythemia (ET) typically show a predominant expansion of the megakaryocytic lineage. Most patients with PV below the age of 60 years are currently being treated with acetylsalicylic acid +/- phlebotomy only, and patients with low-risk ET have an almost normal life expectancy and often do not require specific treatment. However, PV- as well as ET-patients with a higher risk for complications require cytoreductive treatment. In addition, constitutional symptoms can be unbearable to patients even in the absence of bona fide high risk factors, and these patients may similarly benefit from antineoplastic therapy.

Polycythemia vera (PV) and essential thrombocythemia (ET) are classical Philadelphia-negative myeloproliferative neoplasms (MPN) that are characterized by an excess of cells in the peripheral blood, clonal bone marrow hyperplasia, and extramedullary hematopoiesis. The symptoms of these patients may range from asymptomatic disease to symptomatic disease that may significantly affect their activities of daily living, such as severe generalized pruritus, night sweats and fevers, erythromelalgia, bone and muscle pain, weight loss, and fatigue. Moreover, the patients may develop thromboembolic and hemorrhagic complications, transition to myelofibrosis (MF), and transformation to acute leukemia. In principle, the only potentially curative therapy for MPNs is allogenic stem cell transplantation (allo-SCT). However, due to significant transplant-associated morbidity and mortality, this therapeutic option is only applied in exceptional cases of ET or PV. The majority of patients do not qualify for allo-SCT since the risks of this treatment clearly outweigh the potential benefits. Moreover, even with a non-transplantation approach, patients with ET and PV have a life expectancy comparable to or close to healthy age-matched control persons. For patients with standard risk PV, phlebotomy and acetylsalicylic acid are standard of care (target hematocrit below 45 %), while patients with standard risk ET should receive either no specific treatment or acetylsalicylic acid (provided that no microvascular symptoms or secondary acquired von Willebrand syndrome are present).

However, in patients who are at high risk to develop thromboembolic or hemorrhagic complications (high-risk patients), cytoreductive treatment is generally indicated to prevent these potentially life-threatening complications. In PV and ET, high risk patients are characterized by advanced age (\> 60 years) and / or a history of thromboembolic or hemorrhagic events {1,2,3}. In ET, a platelet count \> 1500 x 109/l is associated with an increased risk of bleeding, and thus should result in a platelet lowering treatment {2}. In PV, in addition to the risk-score based therapy, cytoreduction is also required in patients with progressive or marked myeloproliferation (leukocytosis, thrombocytosis, symptomatic splenomegaly, increase of frequency of phlebotomy requirement), or devastating constitutional symptoms {1,2,4}. In Germany, best available therapy (BAT) includes approved drugs such as hydroxyurea (HU; approved for both PV and ET) and anagrelide (approved for second-line treatment of ET) and non-approved options such as alpha-interferon, pipobroman, busulfan (in elderly patients), and radioactive phosphorus (32P). In rare cases, patients may also benefit from splenic irradiation or splenectomy.

Ruxolitinib is a JAK1/2-specific tyrosine kinase inhibitor (TKI) which has been approved for the treatment of symptomatic myelofibrosis. The compound was shown to be superior to hydroxyurea in reducing splenomegaly and constitutional symptoms. Ruxolitinib is currently studied in phase 2 and phase 3 clinical trials for HU-resistant or HU-intolerant PV and ET. The aim of the present study is to assess the feasibility, efficacy, and safety of ruxolitinib treatment vs. BAT in patients with high-risk PV or -ET.

Eligibility Criteria:
Inclusion Criteria:

1. Subjects must provide written informed consent prior to studyspecific procedures or assessments which are not routinely performed for diagnosis or monitoring of PV or ET, and the subjects must be willing to comply with treatment and to follow up assessments and procedures
2. Patient must be 18 years of age or older
3. Patient´s ECOG performance status must be 0-2
4. Patient must fulfill WHO 2008 diagnostic criteria for either polycythemia vera (PV) or essential thrombocythemia (ET). Moreover, PV- and ET-patients have to be classified as high risk according to defined criteria.

   For patients with high risk PV OR PV with indication for cytoreductive therapy due to progressive myeloproliferation, AT LEAST ONE of the following must be fulfilled (according to DGHO onkopedia) (Barbui, et al., 2011). (Passamonti, 2009):
   * Age \> 60 years
   * Previous documented thrombosis or thromboembolism
   * Platelet count \> 1500 x 109/L
   * Poor tolerance of phlebotomy or frequent phlebotomy requirement
   * Symptomatic or progressive splenomegaly
   * Severe disease-related symptoms (according to the investigators definition)
   * Progressive leukocytosis with leukocyte count \> 20 x 109/L

   For patients with high risk ET, AT LEAST ONE of the following must be fulfilled (according to DGHO guidelines):
   * Age \> 60 years
   * Platelet count\> 1500 x 109/L
   * Previous thrombosis or thromboembolism
   * Previous severe hemorrhage related to ET (defined as decrease of Hgb of at least 2 g/dl)
5. Patients must fulfill the following criteria regarding prior therapy:

   PV patients:

   Never treated with cytoreductive drugs except hydroyurea, anagrelide, or interferon for up to 6 weeks maximum (phlebotomy and/or aspirin are allowed)

   ET patients:

   Naïve and pretreated patients may be entered in this trial.
6. Patient must have adequate liver function as indicated by a total bilirubin, AST, and ALT ≤ 2 of the institutional upper limit of normal (ULN) value, unless directly attributable to the patient's MPN
7. Patient must have a creatinine clearance \>40ml/min calculated according to the modified formula of Cockcroft and Gault, eGFR, or directly measured after 24h-urine collection
8. Patients must be able to swallow and retain oral medication

Exclusion Criteria:

1. Patients who meet criteria for post PV-MF or post ET-MF (IWG-MRT)
2. Patients who have received previous ruxolitinib treatment
3. Patients who have a history of anaphylaxis following exposure to the BAT drug of choice
4. Patients who have an inadequate bone marrow reserve as demonstrated by ANC ≤ 1 x 109/l OR platelet count \<50 x 109/l
5. Patients who have known hepatitis B or C or HIV infection
6. Patients who suffer from other severe, concurrent diseases, including tuberculosis, serious cardiac functional dysfunction (class III or IV as defined by the New York Heart Association Classification), uncontrolled diabetes, uncontrolled hypertension, severe pulmonary disease (i.e. COPD with hypoxemia), or major organ malfunction that could interfere with the patient's ability to participate in the study
7. Patients who have history of active substance or alcohol abuse within the last year
8. Female patients who are pregnant or nursing
9. Patients who have participated in another interventional trial and/or used investigational agents or concurrent anticancer treatment for concomitant disease within the last 4 weeks of registration
10. Any circumstance at the time of study entry that would preclude completion of the study or the required follow-up prohibits inclusion into this study
11. Subjects who have had an active malignancy during the previous 3 years except for treated cervical intraepithelial neoplasia, basal cell carcinoma of the skin, or squamous cell carcinoma of the skin, each with no evidence for recurrence in the past 3 years
12. Patients who have uncontrolled bacterial, viral, or fungal infection
13. Patients who have any medical condition requiring prolonged use of oral corticosteroids with a dose of more than 20 mg per day (\> 1 month)
14. Patients who have severe cerebral dysfunction and/or legal incapacity
15. Patients who have had active splanchnic vein thrombosis within the last 3 months (includes Budd-Chiari, portal vein, splenic and mesenteric thrombosis)
16. Patients who have thyroid dysfunction which is not adequately controlled
17. Fertile men or women of childbearing potential cannot be included unless they are:

    * surgically sterile or \> 2 years after the onset of menopause and/or
    * willing to use a highly effective contraceptive method (Pearl Index \<1) such as oral contraceptives, intrauterine device, sexual abstinence, or barrier method of contraception (i.e. condoms) in conjunction with spermicidal jelly during study treatment
18. Patients who are taking any of the following prohibited medication:

    * clarithromycin, telithromycin, troleandomycin (antibiotics)
    * ritonavir, indinavir, saquinavir, nelfinavir, amprenavir, lopinavir (HIV protease inhibitors)
    * itraconazole, ketoconazole, voriconazole, fluconazole (antifungals)
19. Patients with a diagnosis of galactose or lactose intolerance or a glucose-galactose- malabsortion