Allogeneic Stem Cell Transplantation in Chronic Myeloid Leukemia Failing TKIs Therapy

Study Overview
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Brief Summary
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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.

Official Title
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Allogeneic Haematopoietic Stem Cell Transplantation From a Matched Donor in Patients With Chronic Myeloid Leukemia Failing to Gain Normal Hemopoiesis Under TKIs Therapy

Conditions
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Leukemia, Myelogenous, Chronic, BCR-ABL Positive

Intervention / Treatment
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* Drug: Bosutinib
* Procedure: Bone Marrow Transplant
* Drug: Bone Marrow cells


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Chronic Myeloid Leukaemia -CML- in chronic phase (CP) Failure to achieve at least a Major Cytogenetic Response (MCyR) after a minimum of 18 months of TKIs treatment Inability to tolerate 3 months of uninterrupted full dose TKIs therapy due to hematological toxicity A minimum of three treatment interruptions due to hematological toxicity Availability of a HLA-identical related donor (Matched Related Donor, MRD) 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) Target graft size (bone marrow): bone marrow: > 3 x 106 CD34+ cells/kg BW recipient or > 3 x 108 nucleated cells/kg BW Karnofsky Index > 80 % Age ≥18 and ≤70 years Adequate contraception in female patients of child-bearing potential Written informed consent Exclusion Criteria: Secondary malignancies A hematopoietic cell transplantation-specific comorbidity index (Sorror et al Appendix C) > 4 Known and manifested malignant involvement of the Central Nervous System (CNS) Active infectious disease Active human immunodeficiency virus (HIV), Hepatitis B virus (HBV) or Hepatitis B virus (HCV) infection Impaired liver function (Bilirubin > upper normal limit; Transaminases > 3.0 x upper normal limit) Impaired renal function (Creatinine-clearance < 60 ml/min; Serum Creatinine > 1.5 x upper normal limit). Pleural effusion or ascites > 1.0 L Pregnancy or lactation 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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Bosutinib and Bone Marrow Transplant<br>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<br>* 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.<br>* Other names: SKI-606;Procedure: Bone Marrow Transplant<br>* 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<br>Drug: Bone Marrow cells<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Efficacy as assessed by the percentage of patients with Complete Cytogenetic Response (CCyR) | 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. | 12 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival |  | 12 months | 
| Percentage of patients with engraftment |  | 12 months | 
| percentage of patients with complete chimerism (95%) |  | Day +28, +56 and +100 | 
| Evaluation of Major Cytogenetic Response (MCyR) | Major Cytogenetic Response (MCyR) is < 36% Ph+ metaphases | 12 months | 
| Evaluation of molecular responses | Molecular response is defined Complete: if there is undetectable BCR-ABL transcript Major: if ratio BCR/ABL <= 0.1% on International Scale | 12 months | 
| Relapse incidence (RI) |  | 12 months | 
| Incidence of non-relapse mortality (NRM) |  | Within day +28 and +360 | 
| Incidence and severity of acute and chronic graft vs. host disease (GvHD) |  | 12 months | 
| Quality of Life (QoL) | Evaluation of QoL with EQ-5D-5L (Italian - Version 2) and FACT-Leu (Italian -Version 4) | 12 months | 
| Overall Survival (OS) | 2 years after transplantation of the last patient included (this is intended to allow evaluations of all expected major molecular responses) | 36 months | 
| Progression Free Survival (PFS) | 2 years after transplantation of the last patient included (this is intended to allow evaluations of all expected major molecular responses) | 36 months | 
| Relapse Incidence (RI) | 2 years after transplantation of the last patient included (this is intended to allow evaluations of all expected major molecular responses) | 36 months | 
| Chronic Graft-versus-host Disease (cGvHD) | 2 years after transplantation of the last patient included (this is intended to allow evaluations of all expected major molecular responses) | 36 months |