Allogeneic Stem Cell Transplantation in Chronic Myeloid Leukemia Failing TKIs Therapy
Allogeneic Stem Cell Transplantation in Chronic Myeloid Leukemia Failing TKIs Therapy
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.
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