Allogeneic Stem Cell Transplantation in Chronic Myeloid Leukemia Failing TKIs Therapy

University of Milano Bicocca

Status and phase: Completed; Phase 2

Conditions: Chronic; Myelogenous; BCR-ABL Positive; Leukemia

Treatments: Drug: Bone Marrow cells; Drug: Bosutinib; Procedure: Bone Marrow Transplant

Study type: Interventional

Funder types: Other

Identifiers

NCT02638467

alloCML

Details and patient eligibility

About

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.

Enrollment: 2 patients

Sex: All

Ages: 18 to 70 years old

Volunteers: No Healthy Volunteers

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 C) > 4
3. Known and manifested malignant involvement of the Central Nervous System (CNS)
4. Active infectious disease
5. Active human immunodeficiency virus (HIV), Hepatitis B virus (HBV) or Hepatitis B virus (HCV) infection
6. Impaired liver function (Bilirubin > upper normal limit; Transaminases > 3.0 x upper normal limit)
7. Impaired renal function (Creatinine-clearance < 60 ml/min; Serum Creatinine > 1.5 x upper normal limit).
8. Pleural effusion or ascites > 1.0 L
9. Pregnancy or lactation
10. 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

Trial design

Primary purpose: Treatment

Allocation: N/A

Interventional model: Single Group Assignment

Masking: None (Open label)

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2 participants in 1 patient group

Bosutinib and Bone Marrow Transplant

Experimental group

Description:

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.

Treatment:

Drug: Bone Marrow cells

Procedure: Bone Marrow Transplant

Drug: Bosutinib