Allogeneic Stem Cell Transplantation in Chronic Myeloid Leukemia Failing TKIs Therapy

Sponsor
University of Milano Bicocca (Other)
Overall Status
Completed
CT.gov ID
NCT02638467
Collaborator
IRCCS San Raffaele (Other)
2
2
1
51
1
0

Study Details

Study Description

Brief Summary

Patients newly diagnosed with chronic phase chronic myeloid leukemia undergo treatment with TK inhibitors (TKI). A possible cause of TK failure is represented by the insufficient recovery of normal Ph- hematopoiesis during TKI treatment, with consequent severe cytopenias that limit TKI adequate administration. Although rare, this event happens in a proportion of 4-5% of CML patients. Our hypothesis is to circumvent this peculiar condition by providing a normal hematopoiesis from a HLA-matched donor (Human Leukocyte Antigen). The transplant procedure is therefore intended in providing a sustained hematopoiesis that will allow an early treatment with an adequate dosing of TKI. The transplant procedure planned in our study is built on all available evidences to provide the lowest incidence of acute and chronic GvHD (Graft-versus-host disease). Therefore, a bone marrow will be the preferential source and a GvHD prophylaxis based on Anti-thrombocyte globulin (ATG) and Cyclosporine/Methotrexate will be used according to standard current experience in the field of family and unrelated donors. The pre-transplant TKI will be continued until aplasia will develop, in order to decrease the tumor load as much as possible.The use of TKIs shortly after transplant carries the risk of inhibiting the newly transplanted hematopoietic cells, as Kit, an important kinase in normal bone marrow cells, is frequently blocked by Abl inhibitors. The use of bosutinib as post-transplant therapy is justified by the lack of Kit inhibition that distinguishes bosutinib from all other TKIs, and which could allow a minimal inhibitory activity against the transplanted normal bone marrow.

Condition or Disease Intervention/Treatment Phase
  • Drug: Bosutinib
  • Procedure: Bone Marrow Transplant
  • Drug: Bone Marrow cells
Phase 2

Study Design

Study Type:
Interventional
Actual Enrollment :
2 participants
Allocation:
N/A
Intervention Model:
Single Group Assignment
Masking:
None (Open Label)
Primary Purpose:
Treatment
Official Title:
Allogeneic Haematopoietic Stem Cell Transplantation From a Matched Donor in Patients With Chronic Myeloid Leukemia Failing to Gain Normal Hemopoiesis Under TKIs Therapy
Actual Study Start Date :
Nov 1, 2015
Actual Primary Completion Date :
Nov 29, 2018
Actual Study Completion Date :
Feb 1, 2020

Arms and Interventions

Arm Intervention/Treatment
Experimental: Bosutinib and Bone Marrow Transplant

Subjects will receive 400mg of bosutinib from day at least -45 to day -15 to assess the sensitivity of patient Chronic Myeloid Leukemia (CML) to this TKI. Patients will be transplanted with the aim to transplant > 3 x 106 CD34+ cells/kg Body Weight (BW) recipient from bone marrow or > 3 x 108 nucleated cells/kg BW recipient from bone marrow. Then, subjects will receive 400mg of bosutinib once daily from day +30 after transplant.

Drug: Bosutinib
Subjects will receive 400mg of bosutinib once daily from day +30 after transplant, by mouth with food, preferably in the morning. Bosutinib will also be administered from day at least -45 to day -15 to assess the sensitivity of patient CML to this TKI.
Other Names:
  • Bosulif
  • SKI-606
  • Procedure: Bone Marrow Transplant
    Samples of the unrelated stem cell graft shall be characterised with respect to the number of CD34 positive cells per kg body weight of the recipient. The number of transplanted CD34 positive cells per kg body weight (BW) of the recipient shall be recorded in the Case Report Form (CRF). If the transplant was cryopreserved the number of viable CD34 positive cells has to be determined after thawing and documented. The goal is to transplant > 3 x 106 CD34+ cells/kg BW recipient from bone marrow or > 3 x 108 nucleated cells/kg BW recipient from bone marrow

    Drug: Bone Marrow cells

    Outcome Measures

    Primary Outcome Measures

    1. Efficacy as assessed by the percentage of patients with Complete Cytogenetic Response (CCyR) [12 months]

      The percentage of patients with Complete Cytogenetic Response (CCyR) will be calculated as the complement to the percentage of failures on the total number of patients treated, where failure includes the following events: no engraftment, death within 12 months, no CCyR at 12 months.

    Secondary Outcome Measures

    1. Overall Survival [12 months]

    2. Percentage of patients with engraftment [12 months]

    3. percentage of patients with complete chimerism (95%) [Day +28, +56 and +100]

    4. Evaluation of Major Cytogenetic Response (MCyR) [12 months]

      Major Cytogenetic Response (MCyR) is < 36% Ph+ metaphases

    5. Evaluation of molecular responses [12 months]

      Molecular response is defined Complete: if there is undetectable BCR-ABL transcript Major: if ratio BCR/ABL <= 0.1% on International Scale

    6. Relapse incidence (RI) [12 months]

    7. Incidence of non-relapse mortality (NRM) [Within day +28 and +360]

    8. Incidence and severity of acute and chronic graft vs. host disease (GvHD) [12 months]

    9. Quality of Life (QoL) [12 months]

      Evaluation of QoL with EQ-5D-5L (Italian - Version 2) and FACT-Leu (Italian -Version 4)

    10. Overall Survival (OS) [36 months]

      2 years after transplantation of the last patient included (this is intended to allow evaluations of all expected major molecular responses)

    11. Progression Free Survival (PFS) [36 months]

      2 years after transplantation of the last patient included (this is intended to allow evaluations of all expected major molecular responses)

    12. Relapse Incidence (RI) [36 months]

      2 years after transplantation of the last patient included (this is intended to allow evaluations of all expected major molecular responses)

    13. Chronic Graft-versus-host Disease (cGvHD) [36 months]

      2 years after transplantation of the last patient included (this is intended to allow evaluations of all expected major molecular responses)

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    18 Years to 70 Years
    Sexes Eligible for Study:
    All
    Accepts Healthy Volunteers:
    No
    Inclusion Criteria:
    1. Chronic Myeloid Leukaemia -CML- in chronic phase (CP)

    2. Failure to achieve at least a Major Cytogenetic Response (MCyR) after a minimum of 18 months of TKIs treatment

    3. Inability to tolerate 3 months of uninterrupted full dose TKIs therapy due to hematological toxicity

    4. A minimum of three treatment interruptions due to hematological toxicity Availability of a HLA-identical related donor (Matched Related Donor, MRD)

    5. Availability of unrelated donor (Matched Unrelated Donor, MUD) satisfying the criteria of a 10/10 antigen match at (Human Leukocyte Antigen) HLA-A, -B, -C and - DRB1, -DQB1 at high resolution typing, or 9/10 with a permissive - DP disparity according to Fleischhauer model (Crocchiolo et al, Blood 2009)

    6. Target graft size (bone marrow):

    7. bone marrow: > 3 x 106 CD34+ cells/kg BW recipient or > 3 x 108 nucleated cells/kg BW

    8. Karnofsky Index > 80 %

    9. Age ≥18 and ≤70 years

    10. Adequate contraception in female patients of child-bearing potential

    11. Written informed consent

    Exclusion Criteria:
    1. Secondary malignancies

    2. A hematopoietic cell transplantation-specific comorbidity index (Sorror et al Appendix

    1. 4

    1. Known and manifested malignant involvement of the Central Nervous System (CNS)

    2. Active infectious disease

    3. Active human immunodeficiency virus (HIV), Hepatitis B virus (HBV) or Hepatitis B virus (HCV) infection

    4. Impaired liver function (Bilirubin > upper normal limit; Transaminases > 3.0 x upper normal limit)

    5. Impaired renal function (Creatinine-clearance < 60 ml/min; Serum Creatinine > 1.5 x upper normal limit).

    6. Pleural effusion or ascites > 1.0 L

    7. Pregnancy or lactation

    8. Known hypersensitivity to Busilvex and/or fludarabine 11 Non-co-operative behaviour or non-compliance 12 Psychiatric diseases or conditions that might impair the ability to give informed consent

    Contacts and Locations

    Locations

    Site City State Country Postal Code
    1 ASST-Monza Monza Italy/MB Italy 20900
    2 Ospedale San Raffaele Milano MI Italy 20132

    Sponsors and Collaborators

    • University of Milano Bicocca
    • IRCCS San Raffaele

    Investigators

    • Principal Investigator: Carlo Gambacorti-Passerini, MD, University of Milano Bicocca

    Study Documents (Full-Text)

    None provided.

    More Information

    Additional Information:

    Publications

    Responsible Party:
    University of Milano Bicocca
    ClinicalTrials.gov Identifier:
    NCT02638467
    Other Study ID Numbers:
    • alloCML
    First Posted:
    Dec 23, 2015
    Last Update Posted:
    Nov 5, 2020
    Last Verified:
    Nov 1, 2020

    Study Results

    No Results Posted as of Nov 5, 2020