Autologous Cytokine Induced Killer Cells (CIK) for Chronic Myeloid Leukemia (CML) Patients on Standard Drug Therapy

This is an extension of our ongoing clinical trial using ex vivo expanded autologous Cytokine-induced killer (CIK) cells as an adoptive cellular immunotherapy for haematological malignancies. The pre-existing clinical trial targets patient with acute myeloid leukemia or MDS, and relapsed disease post allogeneic transplant. Chronic myeloid leukemia (CML) is a disease with good response to kinase inhibitors. There are however patients in transformed phase of the disease who do not respond to these treatment. A small proportion of patients with response to Imatinib may develop mutations resulting in drug resistance. In addition, the vast majority of patients with a good response to the kinase inhibitors still have persistent CML cells detectable at a molecular level. It is known that the CML progenitors are not sensitive to the kinase inhibitors. On the other hand, immune mediated mechanism is known to be able to eradicate CML as shown by efficacy of donor lymphocyte infusion in the allogeneic transplant setting. Early clinical trials have shown clearance of bcr-abl using peptide vaccination. There is also convincing mouse data showing eradication of CML at molecular level by autologous CIK cells, but no clinical trial has been done using CIK cells for CML. We therefore plan to expand our current CIK trial to include CML as a disease, for CML patients with various degree of response to the kinase inhibitors which have already offered its maximal effect. We aim to study whether autologous CIK cells may further improve disease response, either in the eradiation of minimal residual disease, or in conjunction with chemotherapy for control of high tumour load disease.

Sex

All

Minimum age

12 Years

Maximum age

80 Years

Inclusion Criteria:

1. Blast crisis / accelerated phase patients who have failed to response to the kinase inhibitors but are fit to undergo induction chemotherapy as for the acute leukemia.
2. Blast crisis / accelerated phase patients who have achieved a haematological or cytogenetic response to the kinase inhibitors, but do not have further definitive curative options
3. Patients with resistance to genetic or haematological level, and do not have transplant as a curative option.
4. Patients who have achieved a stable but residual molecular evidence of CML, who are willing to explore additional means with a hope to eradication of MRD.

Patients must understand the trial nature of this study and the additional leukapheresis procedure needed for harvesting mononuclear cells.

Exclusion Criteria:

On recruitment :

1. Renal impairment with Cr \>200mmol/uL
2. Liver impairment with transaminase \>5x upper limit which is not due to disease
3. Limited life expectancy \<3 months

On day of infusion

1. uncontrolled infection or significant bleeding
2. unstable vital signs
3. any degree of hypoxia requiring oxygen therapy.

• BACKGROUNDBhatia R, Holtz M, Niu N, Gray R, Snyder DS, Sawyers CL, Arber DA, Slovak ML, Forman SJ. Persistence of malignant hematopoietic progenitors in chronic myelogenous leukemia patients in complete cytogenetic remission following imatinib mesylate treatment. Blood. 2003 Jun 15;101(12):4701-7. doi: 10.1182/blood-2002-09-2780. Epub 2003 Feb 6. PMID 12576334
• BACKGROUNDGraham SM, Jorgensen HG, Allan E, Pearson C, Alcorn MJ, Richmond L, Holyoake TL. Primitive, quiescent, Philadelphia-positive stem cells from patients with chronic myeloid leukemia are insensitive to STI571 in vitro. Blood. 2002 Jan 1;99(1):319-25. doi: 10.1182/blood.v99.1.319. PMID 11756187
• BACKGROUNDRousselot P, Huguet F, Rea D, Legros L, Cayuela JM, Maarek O, Blanchet O, Marit G, Gluckman E, Reiffers J, Gardembas M, Mahon FX. Imatinib mesylate discontinuation in patients with chronic myelogenous leukemia in complete molecular remission for more than 2 years. Blood. 2007 Jan 1;109(1):58-60. doi: 10.1182/blood-2006-03-011239. Epub 2006 Sep 14. PMID 16973963
• BACKGROUNDKolb HJ, Schattenberg A, Goldman JM, Hertenstein B, Jacobsen N, Arcese W, Ljungman P, Ferrant A, Verdonck L, Niederwieser D, van Rhee F, Mittermueller J, de Witte T, Holler E, Ansari H; European Group for Blood and Marrow Transplantation Working Party Chronic Leukemia. Graft-versus-leukemia effect of donor lymphocyte transfusions in marrow grafted patients. Blood. 1995 Sep 1;86(5):2041-50. PMID 7655033
• BACKGROUNDPinilla-Ibarz J, Cathcart K, Scheinberg DA. CML vaccines as a paradigm of the specific immunotherapy of cancer. Blood Rev. 2000 Jun;14(2):111-20. doi: 10.1054/blre.2000.0127. PMID 11012250
• BACKGROUNDBocchia M, Gentili S, Abruzzese E, Fanelli A, Iuliano F, Tabilio A, Amabile M, Forconi F, Gozzetti A, Raspadori D, Amadori S, Lauria F. Effect of a p210 multipeptide vaccine associated with imatinib or interferon in patients with chronic myeloid leukaemia and persistent residual disease: a multicentre observational trial. Lancet. 2005 Feb 19-25;365(9460):657-62. doi: 10.1016/S0140-6736(05)17945-8.