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

Study Purpose

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.

Recruitment Criteria

Accepts Healthy Volunteers Healthy volunteers are participants who do not have a disease or condition, or related conditions or symptoms	No
Study Type An interventional clinical study is where participants are assigned to receive one or more interventions (or no intervention) so that researchers can evaluate the effects of the interventions on biomedical or health-related outcomes. An observational clinical study is where participants identified as belonging to study groups are assessed for biomedical or health outcomes. Searching Both is inclusive of interventional and observational studies.	Interventional
Eligible Ages	18 Years - 70 Years
Gender	All

More Inclusion & Exclusion 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)

Trial Details

Trial ID: This trial id was obtained from ClinicalTrials.gov, a service of the U.S. National Institutes of Health, providing information on publicly and privately supported clinical studies of human participants with locations in all 50 States and in 196 countries.	NCT04728490
Phase Phase 1: Studies that emphasize safety and how the drug is metabolized and excreted in humans. Phase 2: Studies that gather preliminary data on effectiveness (whether the drug works in people who have a certain disease or condition) and additional safety data. Phase 3: Studies that gather more information about safety and effectiveness by studying different populations and different dosages and by using the drug in combination with other drugs. Phase 4: Studies occurring after FDA has approved a drug for marketing, efficacy, or optimal use.	Phase 2
Lead Sponsor The sponsor is the organization or person who oversees the clinical study and is responsible for analyzing the study data.	Assistance Publique - Hôpitaux de Paris
Principal Investigator The person who is responsible for the scientific and technical direction of the entire clinical study.	N/A
Principal Investigator Affiliation	N/A
Agency Class Category of organization(s) involved as sponsor (and collaborator) supporting the trial.	Other
Overall Status	Not yet recruiting
Countries
Conditions The disease, disorder, syndrome, illness, or injury that is being studied.	Myelofibrosis

Arms & Interventions

Arms

Experimental: Allogenic transplantation using treosulfan in conditioning regimen

Haplo-identical transplantation using treosulfan in conditioning regimen Treosuflan, in the conditioning regimen will be administrated as followed 10 gr/m2 per day -4, -3 and -2 IV route In combination with: Thiotepa 5 mg/kg on day -6 Fludarabine 30 mg/m2 per day from day -5 to day -1

Interventions

Other: - Allogenic transplantation transplantation

Haplo-identical transplantation with the use of Treosulfan, Thiotepa and Fludarabine in conditioning regimen.

Contact Information

This trial has no sites locations listed at this time. If you are interested in learning more, you can contact the trial's primary contact:

Marie Robin, Dr

marie.robin@aphp.fr

+331-42-49-47-24

For additional contact information, you can also visit the trial on clinicaltrials.gov.

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