Work

Safety and efficacy of pulsed imatinib with or without G ‐ CSF versus continuous imatinib in chronic phase chronic myeloid leukaemia patients at 5 years follow‐up

Year: 2013

Type: article

Abstract: Despite their efficacy in inducing deep and durable responses in chronic phase (CP) chronic myeloid leukaemia (CML) patients, BCR-ABL1 tyrosine kinase inhibitors (TKI) do not eradicate leukaemia stem cells (LSC), as proven by the persistence of BCR-ABL1+ CD34+, colony forming, long-term culture-initiating cells in the bone marrow of patients in sustained molecular response 4·5 (a 4·5-log reduction of BCR-ABL1 transcript levels, MR4·5) following TKI therapy (Chomel et al, 2011). CML LSC survival is independent of BCR-ABL1 kinase activity (Hamilton et al, 2012) and their quiescence is a putative TKI-resistance mechanism causing disease persistence. Moreover TKI exert anti-proliferative rather than pro-apoptotic effects against CML LSCs and might further contribute to disease persistence (Graham et al, 2002). Promoting LSC cell-cycle entry using granulocyte-colony stimulating factor (G-CSF) has been shown in vitro to restore their sensitivity to TKI and enhance their eradication (Jorgensen et al, 2006). Based on this evidence, we performed a randomized phase II study (GIMI, EudraCT 2004-000179-33), which compared the safety and efficacy of continuous imatinib (cIM) versus pulsed imatinib (pIM) alone or with G-CSF (pIM+G) therapy administered in 4-week cycles for 48 weeks (12 cycles in total) in CP CML patients with at least a complete cytogenetic response (CCyR) on IM (Drummond et al, 2009) (see reference for study design, primary and secondary endpoints, patient demographics and disease characteristics). The exp-erimental arms were expected to improve CML LSCs eradication by reducing TKI-induced quiescence (pIM) and/or by actively pushing CML LSCs into cell-cycle (pIM+G). At 2 years follow-up no statistically significant differences for the study endpoints were observed, possibly due to the limited numbers (15 patients per arm). However, 6/30 patients across the two experimental arms exhibited either loss of CCyR or major molecular response (MMR) as compared with only 1/15 in the cIM arm, with all but one patient in the experimental arms regaining MMR on restarting continuous IM or nilotinib therapy (Drummond et al, 2009). These results raised some concerns that the experimental schedules might have contributed to the loss of response. Subsequently, a mathematical model of the safety and efficacy of the IM and G-CSF combination suggested that this approach might be detrimental in the short- to medium-term for patients with persistent disease treated with IM, by increasing the LSCs burden through enhanced proliferation, thus in turn increasing the risk of acquiring a resistance mutation and of disease progression. However, in the long-term (>2500 d, i.e. 6·8 years, from start of treatment), such an approach was predicted to prove beneficial as it would deplete the CML LSCs by increasing their susceptibility to TKI (Foo et al, 2009). Here we report the 5-year follow-up data for the GIMI study. 41/45 patients were available for analysis; four patients had died (one only as a result of CML progression). The median follow-up was 5·67 years. Using an intention to treat analysis, both CCyR and MMR rates were similar among treatment arms with no differences in progression rates. 5/15 patients in the cIM arm compared to 3/15 patients in each experimental arm changed treatment to second generation TKI (Table 1). Of note, the reduction in BCR-ABL1 transcript levels between trial entry (baseline) and 5 years was highly statistically significant in both the pIM (1·10 median log reduction, P = 0·013) and the pIM+G arms (1·43 median log reduction, P = 0·002), while not significant in the cIM arm (1·06 median log reduction, P = 0·060) (Fig 1). However, a comparison of the change from baseline between treatment arms shows that, although this was lower in the cIM arm, it was not significantly different from the change in either the pIM (P = 0·678) or pIM+G arm (P = 0·528). Although the small number of patients demands caution in interpreting these data, these findings are reassuring regarding the safety of the experimental therapeutic approaches. Moreover, the deeper and significant reduction in BCR-ABL1 transcript levels in the experimental arms compared to the cIM arm at 5 years provocatively suggests that in the long-term, as suggested by the mathematical model, these treatment strategies might become beneficial to CP CML patients with persistent disease. However caution is required when making inferences based on the mathematical model of IM and G-CSF treatment, as it predicted the effects of an indefinite duration of this treatment strategy while in our study the combination treatment was only continued for 48 weeks. Nevertheless, considering these findings, we believe that a therapeutic strategy aiming to reverse LSC quiescence in CML combining IM and G-CSF could be safely pursued and only larger studies might be able to provide a definitive answer on its efficacy. This research was supported by the Leukaemia Research Fund CTAP (UK), Chugai Pharmaceutical Co. Ltd, Chugai Pharma, France and Novartis Pharmaceuticals (UK). We are grateful to Lindsay Mitchell and Karen Stewart for their help with recruitment and assessment of patients. We thank the ‘Délégation à la recherche clinique des Hospices Civils de Lyon’ for their support in setting up this trial in France, Elodie Gadolet and Madeleine Etienne, CRAs, for their help in collecting the data for the French patients. Drs Steve O'Brien, Heather Jorgensen and Alex McMahon assisted in reviewing the data. This study was supported by the Glasgow Experimental Cancer Medicine Centre, which is funded by Cancer Research UK and by the Chief Scientist's Office, Scotland. P.G. was funded by Medical Research Council UK clinical research training fellowship grant G1000288, N.H. was funded by the Leukaemia & Lymphoma Research UK clinical research training fellowship grant 05086 and T.L.H. was funded by Cancer Research UK Programme grant C11074/A11008. PG analysed data and wrote the manuscript, JS TH and JP analysed data and reviewed the manuscript, NH, FEN, RC, JT, LM, and MD looked after patients, collected data and reviewed the manuscript, GW collected data, FM reviewed the manuscript and TLH designed trial, looked after patients, collected/analysed data and reviewed manuscript. The authors declare no competing financial interests.

Source: British Journal of Haematology

DOI: 10.1111/bjh.12532