Clinical trial NCT00987480: Hematopoietic Stem Cell Transplantation for the Treatment of Patients With Fanconi Anemia Lacking a Genotypically Identical Donor, Using a Chemotherapy Only Cytoreduction With Busulfan, Cyclophosphamide and Fludarabine
Official title: A Multicenter Phase II Trial of Hematopoietic Stem Cell Transplantation for the Treatment of Patients With Fanconi Anemia Lacking a Genotypically Identical Donor, Using a Chemotherapy Only Cytoreduction With Busulfan, Cyclophosphamide and Fludarabine
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Aplastic Anemia
Leukemia
Myelodysplastic Syndrome
Keywords: Stem Cell Transplantation
Anemia
Busulfan
Cyclophosphamide
Fludarabine
08-031
Lead sponsor: Memorial Sloan Kettering Cancer Center
Sponsor class: OTHER
Collaborators: name: Boston Children's Hospital
name: Children's Hospital Medical Center, Cincinnati
name: Children's Hospital and Health System Foundation, Wisconsin
name: Rockefeller University
name: Fred Hutchinson Cancer Center
First posted: 2009-10-01
Enrollment: 45
Sex: ALL
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: This is a genetic disease (transmitted through the parents' genes) called Fanconi Anemia. Because of that genetic disease, the bone marrow has changed and now has failed, or has given rise to a preleukemia called myelodysplastic syndrome (MDS) or leukemia (acute myelogenous leukemia or AML).

Without treatment these complications of Fanconia anemia (FA) are fatal. The only treatment that can cure these complications is an allogeneic transplant of stem cells, meaning, giving the patient bone marrow cells from a healthy donor that can produce normal blood cells that will replace the bone marrow that is sick.

What has been given for the treatment of FA in the past is to use a combination of low doses of radiation to the whole body (total body irradiation) and low doses of the chemotherapy drugs (cyclophosphamide and fludarabine) before the transplant. However, the use of radiation can, later on, increase the chances of getting a second cancer of the skin, head or the neck. These chances of a second cancer are higher than normal in patients with FA.

The purpose of this study is to find out if the doctors can do the same thing with the same chemotherapy drugs used in the past. However physicians will use another chemotherapy drug called busulfan instead of the radiation. The goal of this study is to get rid of the short term and long term risks of the radiation. The first new part of this treatment will be to replace drugs for radiation with chemotherapy drugs.


Eligibility criteria: Inclusion Criteria:

* Patients must have a diagnosis of Fanconi anemia (confirmed by mitomycin C or diepoxybutane \[DEB\] chromosomal breakage testing at an approved laboratory).
* Hematologic Diagnosis and Status - Patients must have one of the following hematologic diagnoses:

  * Severe Aplastic Anemia (SAA) with bone marrow cellularity of \<25%, or Severe Isolated Single lineage Cytopenia

AND at least one of the following features:

* Platelet count \<20 x 109/L or platelet transfusion dependence\*
* ANC \<1000 x 109/L
* Hgb \<8 gm/dl or red cell transfusion dependence\*
* Myelodysplastic Syndrome (MDS) (Appendix 1: MDS Classification) - MDS at any stage, based on either one of the following classifications:

  * WHO Classification
  * Refractory anemia and transfusion dependence\*
  * Any of other stages
  * IPSS Classification
  * Low risk (score 0) and transfusion dependence\*
  * Any other risk groups Score \> or = to 0.5
* Acute Myelogenous Leukemia

  * Patients with acute leukemia are included in this trial in remission, refractory or relapsed disease.
  * Transfusion dependence will be defined as greater than ONE transfusion of platelets or red blood cells in the last year prior to evaluation on protocol.

    * Donors:
* Donor choices will be determined by the investigators at each of the centers according to their own institutional criteria.
* All patients evaluated at trial sites and eligible for this trial by virtue of disease and lack of an HLA-genotypically matched related donor will be captured in the database of this trial. Patients who will be enrolled on this protocol must have one of the following donor choices:

  * HLA-compatible Unrelated volunteer donors
  * Patients who do not have a related HLA-matched donor but have an unrelated donor who is either matched at all A, B, C and DRB1 (8/8) loci or who is mismatched at 1/8 loci (A, B, C or DRB1) (7/8) as tested by DNA analysis (high resolution), will be eligible for entry on this protocol.
  * HLA-mismatched Related donors
  * Patients who do not have a related or unrelated HLA-compatible donor must have a healthy family member who is at least HLA-haplotype identical to the recipient. First degree related donors must have a normal DEB test.
  * The donor must be healthy and willing and able to receive a 4-6 day course of G-CSF and undergo 1-3 daily leukaphereses.
  * Related and Unrelated donors must be medically evaluated and fulfill the criteria for collection of PBSCs as per institutional guidelines.

    * Patients:
* Patients and donors may be of either gender or any ethnic background.
* Patients must have a Karnofsky adult, or Lansky pediatric performance scale status \> or = 70%.
* At the time of referral for transplantation, patients must have no co-existing medical problems that would significantly increase the risk of the transplant procedure.
* Patients must have adequate physical function measured by :

  * Cardiac: asymptomatic or if symptomatic then 1) LVEF at rest must be \> or = to 50% and must improve with exercise or 2) Shortening Fraction \> or = to 29%
  * Hepatic: \< 5 x ULN SGOT and \< 2.0 mg/dl total serum bilirubin.
  * Renal: serum creatinine \< or = to 1.5 mg/dl or if serum creatinine is outside the normal range, then CrCl \> 60-ml/min/1.73 m2
  * Pulmonary: asymptomatic or if symptomatic, DLCO \> 50% of predicted (corrected for hemoglobin)
* Each patient must be willing to participate as a research subject and must sign an informed consent form. Parent or legal guardians of patients who are minors will sign the informed consent form. Assents will be obtained as age appropriate.
* Female patients and donors must not be pregnant or breastfeeding at the time of signing consent. Women must be willing to undergo a pregnancy test prior to transplant and avoid becoming pregnant while on study.

Exclusion Criteria:

* Active CNS leukemic involvement
* Female patients who are pregnant (positive serum or urine HCG) or breast-feeding. Women of childbearing age must avoid becoming pregnant while on study.
* Active uncontrolled viral, bacterial or fungal infection
* Patient seropositive for HIV-I/II; HTLV -I/II

Primary outcomes:
measure: Successful Neutrophil Engraftment
timeFrame: 2 years
measure: The Incidence of Early Transplant Related Mortality
timeFrame: 2 years
measure: The Incidence of Acute GvHD
timeFrame: 100 days
measure: The Incidence of Chronic GvHD
timeFrame: 2 years
Secondary outcomes:
measure: Overall Survival at 3 Years
timeFrame: 3 years
measure: Disease-free Survival at 3 Years
timeFrame: 3 years
Other outcomes:
Locations:
city: Boston
country: United States
facility: Children's Hospital Boston
state: Massachusetts
city: New York
country: United States
facility: Memorial Sloan Kettering Cancer Center
state: New York
city: New York
country: United States
facility: The Rockefeller University
state: New York
city: Cincinnati
country: United States
facility: Cincinnati Children's Hospital
state: Ohio
city: Seattle
country: United States
facility: Fred Hutchinson Cancer Research Center
state: Washington
city: Milwaukee
country: United States
facility: Children's Hospital of Wisconsin
state: Wisconsin
Study officials:
affiliation: Memorial Sloan Kettering Cancer Center
name: Faird Boulad, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: van Hoogdalem MW, Emoto C, Fukuda T, Mizuno T, Mehta PA, Vinks AA. Population pharmacokinetic modelling of busulfan and the influence of body composition in paediatric Fanconi anaemia patients. Br J Clin Pharmacol. 2020 May;86(5):933-943. doi: 10.1111/bcp.14202. Epub 2020 Jan 23.
citation: Mehta PA, Davies SM, Leemhuis T, Myers K, Kernan NA, Prockop SE, Scaradavou A, O'Reilly RJ, Williams DA, Lehmann L, Guinan E, Margolis D, Baker KS, Lane A, Boulad F. Radiation-free, alternative-donor HCT for Fanconi anemia patients: results from a prospective multi-institutional study. Blood. 2017 Apr 20;129(16):2308-2315. doi: 10.1182/blood-2016-09-743112. Epub 2017 Feb 8.