Allogeneic Stem Cell Transplantation in Chronic Myeloid Leukemia Failing TKIs Therapy

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

Study Overview

• Status: Completed
• Conditions: Leukemia; BCR-ABL Positive; Myelogenous; Chronic
• Intervention / Treatment: Drug: Bosutinib; Procedure: Bone Marrow Transplant; Drug: Bone Marrow cells

• Study Type: Interventional
• Enrollment (Actual): 2
• Phase: Phase 2

Contacts and Locations

Study Locations

• Italy
  • Italy/MB
    • Monza, Italy/MB, Italy, 20900
      • Asst-Monza
  • MI
    • Milano, MI, Italy, 20132
      • Ospedale San Raffaele

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 70 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / 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: SKI-606; Bosulif; 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

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: University of Milano Bicocca
• Collaborators: IRCCS San Raffaele
• Investigators: Principal Investigator: CARLO GAMBACORTI-PASSERINI, MD, University of Milano Bicocca

Publications and helpful links

General Publications

• 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.
• 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.

Helpful Links

• Cancer Facts and Figures. 2006, American Cancer Society

Study record dates

Study Major Dates

• Study Start (Actual): November 1, 2015
• Primary Completion (Actual): November 29, 2018
• Study Completion (Actual): February 1, 2020

Study Registration Dates

• First Submitted: December 9, 2015
• First Submitted That Met QC Criteria: December 22, 2015
• First Posted (Estimate): December 23, 2015

Study Record Updates

• Last Update Posted (Actual): November 5, 2020
• Last Update Submitted That Met QC Criteria: November 3, 2020
• Last Verified: November 1, 2020

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Bone Marrow Diseases; Hematologic Diseases; Myeloproliferative Disorders; Leukemia, Myeloid; Leukemia; Leukemia, Myelogenous, Chronic, BCR-ABL Positive
• Other Study ID Numbers: alloCML