Study to Compare Busulfan-fludarabine With Thiotepa-fludarabine Regimen in Allogeneic Transplantation for Myelofibrosis
Condition: Myelofibrosis
MeSH terms: Primary Myelofibrosis
Study type: Interventional
Phase: Phase 2

Summary: 
      This study will be performed as a prospective multicenter phase II trial for compare
      busulfan-fludarabine reduced-intensity conditioning (RIC) with thiotepa-fludarabine RIC
      regimen prior to allogeneic transplantation of hematopoietic cells for the treatment of
      myelofibrosis.

      The primary endpoint for this study is to compare Progression Free Survival of two different
      RIC regimens for allogeneic stem cell transplantation in myelofibrosis.

      Progression Free Survival is defined as the time from the date of randomization to the date
      of the first documented disease progression or relapse (according to the International
      Working Group Consensus Criteria) or death due to any cause. Patients who have neither
      progressed nor died at the time of study completion or who are lost to follow-up are censored
      at the data of the last follow up for progression of disease for this study.
    

Detailed description: 
      This is the first study to explore the efficacy of two different Reduced-intensity
      conditioning (RIC) regimens for allogeneic stem cell transplantation in myelofibrosis. The
      choice of 60 patients is based on feasibility reasons. GITMO data at hand points to an
      estimated accrual of twenty patients per year over a tree-year enrolment period. Criteria for
      defining sample size do not follow statistical power estimates in order to demonstrate the
      difference of lack of it between two treatments. However, the criteria reflect the overall
      efficacy and safety of comparing the two treatments among all patients requiring the
      treatment within the health system. This criterion offers the best estimate for power of
      study.

      Myelofibrosis is a clonal hematopoietic stem cell disorder that is clinically characterized
      by progressive anemia, marked splenomegaly, extramedullary hematopoiesis, constitutional
      symptoms and a significant risk of evolution into acute leukaemia myelofibrosis can appear as
      a primitive or idiopathic disorder or, less frequently, as a secondary complication of
      essential thrombocythemia or polycythemia vera, with a clinical presentation and course
      similar to the idiopathic form. The disease affects mainly elderly people, with a median age
      at diagnosis of about 65 years. It is a heterogeneous disorder in term of presentation and
      evolution, with a median overall survival (OS) varying between 2 and 15 years, depending on
      the presence or absence of clinically defined prognostic factors. Adverse prognostic factors
      for survival have included advanced age, marked anemia, leukocytosis or leukopenia, abnormal
      karyotype, constitutional symptoms and presence of circulating blasts. Moreover, the
      prognostic value of cytogenetic abnormalities, increased number of circulating cluster of
      differentiation 34 cells in peripheral blood and Janus kinase 2 mutational status has been
      also evaluated. The available prognostic score systems are mainly based on clinical
      variables. The most widely used is the 'Lille score' (Dupriez et al.) which is based on
      hemoglobin level and leukocyte count. The Mayo Clinic Group tried to improve the Lille score
      by adding thrombocytopenia and monocytosis. The International Working Group for Myelofibrosis
      Research and Treatment recently proposed a new scoring system analyzing the largest patient
      population and recognized 5 main unfavourable variables which were: age > 65 years, presence
      of constitutional symptoms, and circulating blasts cells ≥ 1%, anemia and leucocytosis. All
      these prognostic systems could clearly separate intermediate or high risk patients (with a
      median survival ranging between 1 and 4 years) from patients with a favourable prognosis
      (median survival of 8-10 years).

      Kroger on behalf of the European Group for Blood and Marrow Transplantation reported data on
      104 patients mainly with intermediate or high risk score who received a conditioning regimen
      based on fludarabine 180 mg/mq and busulfan 8 mg/kg i.v or 10 mg/Kg p.o and hematopoietic
      stem cells coming from sibling or unrelated donors. Engraftment was 99%; 1-year
      transplant-related mortality was 16% and was significantly increased in patients older than
      50 years, in cases with intermediate and high-risk myelofibrosis and after transplants from
      mismatched donors. Five-year overall survival was 67% and 5 -year event-free-survival was
      51%. Relapse rate was higher in splenectomized patients and if disease duration prior
      transplant was >24 months. Moreover, Kroger reported that this conditioning regimen induced a
      Janus kinase 2 negativity in 78% of patients carrying the V617-JAK2 mutation before
      transplant and produced a rapid regression of bone marrow fibrosis in 59% of patients al day
      +100 and in 100% of patients at day +360. At present, the busulfan-fludarabine regimen could
      be considered as the Reduced-intensity conditioning regimen that has been tested on the
      largest patient population and demonstrated the best results in terms of feasibility and
      clinical, molecular and histological responses.

      The Principal Investigator has recently reported data on a population of 100 patients with
      myelofibrosis who underwent allogeneic hematopoietic stem cell transplantation in 26
      transplant centers that are part of the GITMO in a 20-year period between 1986 and 2006 and
      we retrospectively analyzed the influence of patient and disease clinical features before
      stem cell transplantation and of transplant procedures on transplant-related mortality (TRM)
      and overall survival. We confirmed that myelofibrosis remains a rare indication for stem cell
      transplantation with the recruitment of about 15-17 cases per year since 2002 and observed a
      great heterogeneity in terms of conditioning regimens, Graft versus Host Disease prophylaxis
      and supportive measures. Although we observed a significative and progressive improvement of
      transplant-related mortality after 1996, we couldn't recognized any significative difference
      in outcome either between patients treated with myeloablative versus reduced- intensity
      regimens or among those treated with different Reduced-intensity conditioning regimen. The
      lack of any association between intensity of conditioning or type of drugs included in the
      preparative regimen could be in part due to the great heterogeneity of transplant procedures.
      However, we showed that the regimens including thiotepa were administered to 24 out 52
      patients (46%), whereas the other patients received heterogeneous preparative regimens. The
      combination of thiotepa and cyclophosphamide was originally described for autologous
      transplants; then thiotepa was used with a 30% dose reduction as Reduced-intensity
      conditioning regimen in association with Cyclophosphamide and/or fludarabine followed by
      haematopoietic stem cells in elderly patients with acute leukemias, in heavily pretreated
      relapsed or refractory lymphomas and in myelodysplastic syndromes, showing to be highly
      feasible and effective. Both these protocols were used in Italy by researchers and physicians
      participating to GITMO.

      In conclusion, the rational of the present study are the following:

        -  myelofibrosis is a rare indication for allogeneic transplantation with a limited number
           of patients recruitable in the whole Italian region.

        -  At the present time there are not available sufficient data to support a standard
           conditioning regimen for these patients.

        -  Italian hematologists grouped in the GITMO intend to overcome the general uncertainty in
           the choice of the conditioning regimen and to test prospectively in a controlled study a
           uniform strategy of transplant procedures for this rare condition.

        -  Therefore, we want to compare two Reduced-intensity conditioning regimens, the
           thiotepa-fludarabine regimen, that has been the most common one used in Italy in the
           last 5 years , and the busulfan-fludarabine one, that has been reported in the
           literature to achieve the best results in terms of feasibility and clinical responses .
           A randomized comparison is likely to increase our knowledge on safety and efficacy of
           these conditioning regimens and consolidate assumption for the planning of a phase II
           trial.
    

Intervention name(s): A: Fludarabine + Busulphan; B: Fludarabine + Thiotepa
Intervention type(s): Drug; Drug
Intervention description(s): Fludarabine 30 mg/m2/d, day -8 to day-3 and Busulphan (Busilvex) 0,8 mg/Kg/i.v. dose x 4 doses on days -5,-4 and x 2 doses on day -3, total dose 8 mg/Kg) prior allogenic transplant (day zero); Fludarabine 30 mg/m2/d day -8 to day -3 Thiotepa 6 mg/Kg for 2 doses ( days -4, -3) prior allogeneic transplant (day zero)
Other intervention name(s): BU-FLU; THIO-FLU
Intervention MeSH terms: Vidarabine; Fludarabine; Fludarabine phosphate; Busulfan; Thiotepa
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: myelofibrosis; unfavourable prognostic factors; Allogeneic stem cell transplantation; Progression Free Survival; thrombocythemia vera; polycythemia vera; Reduced-intensity conditioning