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CD34+/Ph+ cells are still detectable in chronic myeloid leukemia patients with sustained and prolonged complete cytogenetic remission during treatment with imatinib mesylate

Leukemia volume 22, pages 426–428 (2008)Cite this article

Imatinib mesylate induces complete cytogenetic response (CCR) in more than 85% of newly chronic myeloid leukemia (CML) chronic phase (CP) patients, and a statistical survival benefit over interferon-α treatment has been recently achieved.1 Yet, some crucial issues about imatinib are still unsolved and we may refer to this pioneering drug as a ‘functional recovery’ but not a true cure for CML patients. In fact residual molecular disease persists in the majority of patients2, 3 probably due the in vitro evidence that Ph+ quiescent stem cells are insensitive to imatinib.4 As a clinical consequence, even in those patients in which BCR-ABL transcript is undetectable by the most sensitive nested reverse transcriptase-PCR method (complete molecular response (CMolR)), discontinuation of the drug is followed by disease recurrence in nearly all cases.5, 6 Not surprisingly BCR-ABL-positive stem cells can still be detected in patients in CCR after short term of imatinib treatment7 but no data are currently available regarding the real incidence of leukemic precursors persisting in patients after prolonged treatment with this drug. Thus, we evaluated the amount of bone marrow residual CD34+/Ph+ cells in 31 CML patients in stable long-lasting CCR during imatinib treatment after receiving their informed written consent. The median age was 46 years (range 19–77) with 18 male and 13 female. At imatinib start all patients were in CP, 15/31 were newly diagnosed while 16/31 have been previously refractory (10 patients) or intolerant (6 patients) to interferon-α. At the time of residual CD34+/Ph+ evaluation all patients were on 400 mg/day of imatinib for a median time of 39 months (range 24–59), and in stable CCR for a median time of 35 months (range 15–53). Whole bone marrow fluorescence in situ hybridization (FISH) analysis identified Ph+ cells in 11/31 patients (35%; median of 2% nuclei, range 1–4%), while BCR-ABL transcript was still measurable in 24/31 (77%) patients by reverse transcriptase-PCR.

After immunomagnetic sorting of about 10 ml of marrow aspirate, an adequate number of CD34+ cells (average 9.6 × 105) for FISH analysis was collected in all 31 patients and CD34+-enriched population was confirmed to be more than 90% pure by flow cytometry analysis. FISH analysis of CD34+-purified cells showed the persistence of Ph+ cells in 14/31 (45%) patients with a median number of 1% (range 1–7%). Disease characteristics and follow-up of 14 CD34+/Ph+ positive patients and 17 CD34+/Ph+ negative patients are listed in Table 1.

Table 1 Disease's characteristics at time of evaluation and follow-up of patients with CD34+/Ph+ residual cells (from patient #1 to #14) and patients without CD34+/Ph+ residual cells (from patient #15 to #31).
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Acknowledgements

This study was supported by grants from PAR 2005, MIUR 2005, SIENAIL, Fondazione Monte dei Paschi. Informed consent was obtained from patients before entering into the study. M Bocchia designed research, analyzed data and wrote the paper. M Ippoliti performed research and analyzed data. A Gozzetti analyzed data and contributed in writing the manuscript. E Abruzzese contributed in designing the research and analyzing data. S Calabrese, R Crupi, D Tozzuoli, M Amabile and G Martinelli contributed in performing research. MM Trawinska, M Defina and MT Pirrotta collected and managed the clinical data. F Lauria supervised the research and revised the manuscript.

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  1. Department of Hematology, Siena University, Siena, Italy

    M Bocchia, M Ippoliti, A Gozzetti, S Calabrese, M T Pirrotta, R Crupi, D Tozzuoli, M Defina & F Lauria

  2. Department of Hematology, Roma Tor Vergata University, Roma, Italy

    E Abruzzese & M M Trawinska

  3. Hematology and Clinic Oncology ‘Seragnoli’ Institute, Bologna University, Bologna, Italy

    M Amabile & G Martinelli

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  1. M Bocchia
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Correspondence to M Bocchia.

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Bocchia, M., Ippoliti, M., Gozzetti, A. et al. CD34+/Ph+ cells are still detectable in chronic myeloid leukemia patients with sustained and prolonged complete cytogenetic remission during treatment with imatinib mesylate. Leukemia 22, 426–428 (2008). https://doi.org/10.1038/sj.leu.2404893

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