Haplo-identical Transplantation in Patients With Myelofibrosis - A Phase 2 Prospective Multicentric Prospective Study

The only curative treatment in patients with primary or secondary myelofibrosis is allogeneic hematopoietic stem cells (HSCT). It has been reported that intermediate and higher risk patients according to international prognostic scores benefit from HSCT in terms of survival (Kröger et al, 2015). In 2013, we conducted in France a prospective trial testing the use of ruxolitinib before transplantation ("JAK-ALLO study" NCT01795677). Outcome of patients was better in patients transplanted with a matched sibling donor than an unrelated donor confirming other studies (Kröger et al, 2009; Rondelli et al, 2014). In the JAK-ALLO trial, acute GVHD incidence was high, often hyperacute and severe. Recently, the EBMT group has reported a registry study on familial haplo-identical transplantation (haplo) in patients with myelofibrosis (Raj et al, 2018). Post-transplant cyclophosphamide was used in 59% of cases. One-year overall survival (OS) and disease-free survival (DFS) were 61 and 58% which favorably compared to outcome after unrelated transplantation. Genova team has also reported impressive results after haplo-identical transplantation in their center (Bregante et al, 2015). Bregante et al have reported outcome of 2 cohorts transplanted from 2000 to 2010 and from 2011 to 2014. The main difference between the 2 periods is the more frequent use of haplo in the second period (54% versus 5%). Outcome was much better in the second period with OS at 70% versus 49% and authors suggest that this improvement is related to the best outcome among haplo transplantation. The improvement of outcome after haplo has been attributed to a better GVHD prophylaxis, especially with the use of post-transplant cyclophosphamide. Given the poor outcome after unrelated transplantation and especially in HLA mismatched unrelated setting and encouraging results in family haplo identical transplantation, this current study proposes to test haplo-identical transplantation in myelofibrosis patients without a matched related donor.

The main objective of this study is disease and rejection-free survival one year after haplo-identical transplantation in patients with primary or secondary myelofibrosis.


Eligibility Criteria:
Inclusion Criteria:

* Patients aged between 18 and 70 years
* Primary myelofibrosis or myelofibrosis secondary to essential thrombocythemia or polycythemia Vera proven by marrow biopsy
* The myelofibrosis should combine at least 2 of the following criteria:

  * constitutional symptoms: weight loss \> 10% in one year, fever (without infection), recurrent muscle, bone or join pains, extreme fatigue
  * anemia with hemoglobin \< 10 gr/dL or red blood cell transfusion requirement
  * thrombocytopenia \< 100 G/L
  * peripheral blast count \> 1% at least found 2 times
  * white blood cell count \> 25 G/L (before a cytoreductive treatment)
  * Karyotype: +8, -7/7q-, i(17q), -5, 5q-, 12p-, inv(3), 11q23
* Performance status according to ECOG at 0, 1 or 2
* With health insurance coverage
* Having signed a written informed consent
* Women agreed to take nomegestrol acetate as contraception during and up to 6 months after treatment by treosulfan
* Men agreed not to conceive child during and up to 6 months after treatment by treosulfan

Exclusion Criteria:

* Myelofibrosis transformed into acute leukemia
* Poor performance status with ECOG 3 or more
* Cardiac failure with EF \< or = 50% currently or in the past (even if corrected after treatment)
* Renal failure with creatininemia \> 130 µmol/L or clearance \< 50ml/min
* Respiratory function altered with vital capacity \< 70% or forced expired volume \< 70%
* Biological significant liver abnormalities; ASAT or ALAT\> 2 x normal range, bilirubin \> 1,5 x normal range
* HLA matched donor available
* Tutorship or curatorship
* Unwilling or unable to comply with the protocol
* Pregnant woman or breastfeeding
* Contraindications to treosulfan

  * Hypersensitivity to the active substance
  * Active non-controlled infectious disease
  * Fanconi anaemia and other DNA breakage repair disorders
  * Administration of live vaccine
* Contraindications or any circumstance that precludes the use of the drugs involved in the protocol (especially Thiotepa and Fludarabine)