Clinical trial NCT02638467: Allogeneic Stem Cell Transplantation in Chronic Myeloid Leukemia Failing TKIs Therapy
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Leukemia
Myelogenous
Chronic
BCR-ABL Positive
Lead sponsor: University of Milano Bicocca
Sponsor class: OTHER
Collaborators: name: IRCCS San Raffaele
First posted: 2015-12-23
Enrollment: 2
Sex: ALL
Minimum age (years): 18
Maximum age (years): 70
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.


Eligibility criteria: 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

Primary outcomes:
measure: Efficacy as assessed by the percentage of patients with Complete Cytogenetic Response (CCyR)
timeFrame: 12 months
Secondary outcomes:
measure: Overall Survival
timeFrame: 12 months
measure: Percentage of patients with engraftment
timeFrame: 12 months
measure: percentage of patients with complete chimerism (95%)
timeFrame: Day +28, +56 and +100
measure: Evaluation of Major Cytogenetic Response (MCyR)
timeFrame: 12 months
measure: Evaluation of molecular responses
timeFrame: 12 months
measure: Relapse incidence (RI)
timeFrame: 12 months
measure: Incidence of non-relapse mortality (NRM)
timeFrame: Within day +28 and +360
measure: Incidence and severity of acute and chronic graft vs. host disease (GvHD)
timeFrame: 12 months
measure: Quality of Life (QoL)
timeFrame: 12 months
measure: Overall Survival (OS)
timeFrame: 36 months
measure: Progression Free Survival (PFS)
timeFrame: 36 months
measure: Relapse Incidence (RI)
timeFrame: 36 months
measure: Chronic Graft-versus-host Disease (cGvHD)
timeFrame: 36 months
Other outcomes:
Locations:
city: Monza
country: Italy
facility: ASST-Monza
state: Italy/MB
city: Milano
country: Italy
facility: Ospedale San Raffaele
state: MI
Study officials:
affiliation: University of Milano Bicocca
name: Carlo Gambacorti-Passerini, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Redaelli A, Bell C, Casagrande J, Stephens J, Botteman M, Laskin B, Pashos C. Clinical and epidemiologic burden of chronic myelogenous leukemia. Expert Rev Anticancer Ther. 2004 Feb;4(1):85-96. doi: 10.1586/14737140.4.1.85.
citation: Heisterkamp N, Stephenson JR, Groffen J, Hansen PF, de Klein A, Bartram CR, Grosveld G. Localization of the c-ab1 oncogene adjacent to a translocation break point in chronic myelocytic leukaemia. Nature. 1983 Nov 17-23;306(5940):239-42. doi: 10.1038/306239a0.