Study of Non-Myeloablative Haplo-identical Haematopoietic Stem Cell Transplantation in Patients With Haematological Malignancies or Acquired Aplastic Anaemia

This study is currently recruiting participants. (see Contacts and Locations)
Verified December 2013 by National University Hospital, Singapore
Sponsor:
Information provided by (Responsible Party):
National University Hospital, Singapore
ClinicalTrials.gov Identifier:
NCT01719341
First received: October 30, 2012
Last updated: December 10, 2013
Last verified: December 2013
  Purpose

Allogeneic haematopoietic stem cell transplantation (HSCT) is a potentially curative therapy for patients with both haematological and some non-haematological disorders. However, one of the major limiting factors for transplantation is the inability to identify a suitable HLA-matched donor. Development of an cost-effective and clinically efficacious alternative to HLA-identical sibling or unrelated donor transplantation would significantly expand the availability of allogeneic HSCT to patients in Singapore. Preliminary results indicate that the use of high dose post-transplant cyclophosphamide (Cy) for graft versus host disease (GVHD) prophylaxis in haplo-identical allogeneic HSCT is associated a low incidence of GVHD and low treatment related toxicity. We propose a phase II clinical trial to assess the efficacy of a haplo-identical allogeneic transplantation protocol using high dose post-transplant Cy for the treatment of patients with haematological disorders. A non-myeloablative protocol (Fludarabine-low dose cyclophosphamide-TBI) will be used for patients with bone marrow failure syndromes and indolent lymphoid disease. In view of the higher relapse risk of patients with myeloid malignancies, these patients will be treated with a reduced intensity conditioning regimen (Fludarabine-Busulphan). The primary end-point of the study will be overall survival at one year. Economic cost of the haplo-identical transplantation, as well as treatment timelines will be recorded and compared will other forms of unrelated donor allogeneic transplantation (umbilical cord blood transplantation and unrelated HLA-matched adult donor). Immunological reconstitution of patients following haplo-transplantation will be analysed and data will be utilized to guide future immunotherapy strategies post-transplantation.

One year survival after non-myeloablative haploidentical stem cell transplantation is not inferior to that observed after non-myeloablative volunteer unrelated donor or unrelated cord blood haematopoietic stem cell transplantation.


Condition
Haematological Malignancies
Acquired Aplastic Anaemia

Study Type: Observational
Study Design: Observational Model: Cohort
Time Perspective: Prospective

Resource links provided by NLM:


Further study details as provided by National University Hospital, Singapore:

Primary Outcome Measures:
  • 1 year overall survival after HLA-Haploidentical transplantation [ Time Frame: 1 year ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • Progression free survival one and 2 years post-transplantation [ Time Frame: 2 years ] [ Designated as safety issue: No ]
  • Cumulative incidence of relapse/progression at one and 2 years post-transplant [ Time Frame: 2 years ] [ Designated as safety issue: No ]

Estimated Enrollment: 21
Study Start Date: September 2012
Estimated Primary Completion Date: June 2014 (Final data collection date for primary outcome measure)
  Eligibility

Ages Eligible for Study:   18 Years to 70 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Sampling Method:   Probability Sample
Study Population

Sample size estimation based on Case and Morgan Two Stage Phase II Design with an expected duration of accrual of 2 years, assuming a power of 80% and a level of significance of 10%. With an S0 of 0.25 and SA of 0.50, an interim analysis will be performed after 14 patients are recruited with an anticipated final recruitment total of 21 patients for each arm of the study.

Criteria

Inclusion Criteria:

Patient Selection Inclusion criteria

  1. Age under 70 years and older than 18 years
  2. Absence of HLA fully compatible related donor
  3. Need for an urgent transplantation, defined as within 8 weeks of referral to the transplant centre or absence of HLA-compatible VUD after searching the international registries. Patients with a HLA-compatible VUD but whose donor is considered by the transplantation centre as unsuitable will also be eligible. 4. Informed consent.

Disease inclusion criteria:

In general this encompasses all haematological disorders where a volunteer unrelated donor (UD) transplant is clinically indicated.

1. Acute, chronic leukaemia or myelodysplastic syndrome for which allogeneic transplantation is considered as the best treatment option.

a. Acute myeloid leukaemia (AML) i. In first complete remission (CR1) with one of the following characteristics:

  1. High risk cytogenetic or molecular alterations (e.g. t(9;22), deletion 7/7q-, monosomy 5 or del(5q), 3q26 alterations, complex karyotype [3 or more anomalies], p53 alterations, 11q23 especially t(6;11) abnormalities, FLT-3 ITD, monosomal karyotype.
  2. Leukocytes at diagnosis > 50 x109/l (except in cases with good prognosis molecular rearrangements for which leukocytes should be > 100 x 109/l) b. Myelodysplastic syndromes1. International Prognosis Index (IPSS) above 1 (intermediate group 2 or high risk)

2. IPSS 0 or 0.5 in the presence of cytopenias requiring treatment. c. Therapy related AML or MDS in first CRd. AML or MDS in second (CR2) or subsequent CRe. Ph'-positive chronic myeloid leukaemia i. In first chronic phase if refractory and/or intolerance to tyrosine kinase inhibitors is clearly demonstrated ii. In second chronic phase 2. Acute lymphoblastic leukaemia (ALL)a. In CR1 with one of the following characteristics: i. Very high risk chromosome or molecular alterations (e.g. t(9;22), t(4;11), complex karyotype in adults, bcr/abl rearrangements, MLL rearrangements) ii. Slow response to induction treatment defined as the presence of >10% blasts in bone marrow at day 14 of induction treatmentiii. Adults aged > 30 yearsiv. Adults with B ALL cell line with a number of leukocytes at diagnosis >25 x 109/L or T ALL cell line with a number of leukocytes at diagnosis >100X109/Lb. In CR2 or subsequent CR 3. Non-Hodgkin's lymphomaa. Follicular NHL: in second or subsequent complete or partial remissionb. Mantle cell NHL: in second or subsequent complete or partial remissionc. High grade NHL: in second complete or very good partial remission 4. Hodgkin's diseasea. in second or subsequent complete or partial remission 5. Chronic lymphocytic leukaemia. a. in second or subsequent remissionb. with adverse risk prognostic features in first remission 6. Acquired Aplastic Anaemia 7. Myelofibrosis- Lille score -high, Cervantes score-high 8. Other haematological malignancies for which UD HSCT is indicated

Exclusion Criteria:

  1. Patients with an available 7-8/8 HLA-A, -B, -C, -DRB1 matched sibling donor or 7-8/8 unrelated bone marrow donor
  2. Availability of suitable UCB unit/s and eligible for an UCB transplant
  3. ECOG performance status worse than 2
  4. Cardiac insufficiency requiring treatment, symptomatic coronary artery disease or LVEF less than 35%.
  5. Hepatic disease, with total bilirubin greater than 2 times upper limit of normal or AST > 5 times upper limit of normal.
  6. Severe hypoxaemia, pO2 < 70 mm Hg, with decreased DLCO < 50% of predicted; or mild hypoxemia, pO2 < 80 mm Hg with severely decreased DLCO < 50% of predicted.
  7. Impaired renal function (creatinine > 2 times upper limit of normal or creatinine clearance < 50% for age, gender, weight).
  8. Previous irradiation that precludes the safe administration of an additional dose of 200 cGy of total body irradiation (TBI).
  9. HIV positive patients.
  10. Female patients who are pregnant or breast feeding due to risks to foetus from conditioning regimen and potential risks to nursing infants.
  11. Life expectancy severely limited by diseases other than the disease indication for transplant
  12. Serious concurrent uncontrolled infection e.g. active tuberculosis, mycoses or viral infection
  13. Serious psychiatric/ psychological disorders
  14. Absence of /inability to provide informed consent
  15. Patients with acute leukaemia with >5% bone marrow blasts
  16. Intermediate or high grade NHL, mantle cell NHL and Hodgkin's disease that is refractory to salvage therapy
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01719341

Contacts
Contact: Zi Yi Lim, MB ChB 65 6779 5555 Zi_Yi_Lim@nuhs.edu.sg

Locations
Singapore
National University Hospital Recruiting
Singapore, Singapore, 119074
Contact: Zi Yi Lim, MB ChB    65 6779 5555    Zi_Yi_Lim@nuhs.edu.sg   
Principal Investigator: Zi Yi Lim, MB ChB         
Sponsors and Collaborators
National University Hospital, Singapore
Investigators
Principal Investigator: Zi Yi Lim, MB ChB National University Hospital, Singapore
  More Information

Publications:
Responsible Party: National University Hospital, Singapore
ClinicalTrials.gov Identifier: NCT01719341     History of Changes
Other Study ID Numbers: 2012/00465
Study First Received: October 30, 2012
Last Updated: December 10, 2013
Health Authority: Singapore: Domain Specific Review Boards

Additional relevant MeSH terms:
Anemia
Neoplasms
Anemia, Aplastic
Hematologic Neoplasms
Hematologic Diseases
Bone Marrow Diseases
Neoplasms by Site

ClinicalTrials.gov processed this record on October 16, 2014