TO THE EDITOR
The emergence of novel chromosomal aberrations in Ph (−) cells of chronic myelogenous leukemia (CML) patients treated with interferon-alpha (IFN-alpha) is a rare event; a recent review of the literature identified 10 such cases.1,2
In most CML patients, treatment with imatinib mesylate (Glivec), a specific ABL kinase inhibitor, leads to disappearance of the Ph chromosome; nevertheless, the long-term efficacy and toxicity profile of imatinib remain largely unknown. Intriguingly, over the last 2 years, several groups have demonstrated Ph (−) cytogenetically abnormal clones in patients with CML treated with imatinib, at a rate seemingly higher than the one observed with IFN-alpha.2,3,4,5,6,7,8
In our department, in a cohort of 35 CML patients treated with imatinib for a median duration of 16.0 months (range, 3–42 months), three patients developed novel chromosomal aberrations in Ph (−) cells as reported below.
A 22-year-old male was diagnosed with CML in accelerated phase in December 2001. Cytogenetic analysis of bone marrow (BM) mononuclear cells revealed t(9;22) (q34;q11) in all metaphases tested. RT-PCR identified b3a2 chimeric BCR-ABL mRNA transcripts. The patient was initially given hydroxyurea; starting from March 2002, he was put on imatinib at 400 mg/day. At 6 months on imatinib, he had attained complete hematological remission and a minimal cytogenetic response with 96% Ph(+) metaphases. Imatinib dose was then increased to 600 mg/day; at 14 months, cytogenetic analysis demonstrated major cytogenetic response (25.9% (7/27) Ph (+) metaphases) concurrently with the appearance of a novel hypodiploid clone with monosomy 7 in 8/27 metaphases, all Ph (−); interestingly, there was also a Ph (−) metaphase with trisomy 8. FISH analysis confirmed isolated trisomy 8 and monosomy 7 in 6.5 and 29% of cells, respectively. Examination of BM aspirate and biopsy samples showed no evidence of myelodysplasia. The patient underwent allogeneic matched sibling hematopoietic cell transplantation in July 2003; he remains in complete hematological, cytogenetic and molecular remission.
A 43-year-old female subject was diagnosed with CML in myeloid blast crisis (10% MPO+CD34+ BM blast cells; extramedullary myeloid tumor (chloroma) in cervical lymph nodes). Cytogenetic analysis of BM mononuclear cells demonstrated t(9;22) (q34;q11) in all metaphases tested, while RT-PCR identified b3a2 chimeric BCR-ABL mRNA transcripts. The patient entered a second chronic phase with one course of combination chemotherapy (October 2002) consisting of idarubicin (10 mg/m2 i.v. over days 1, 3 and 5) and cytarabine (100 mg/m2 in 24-h infusion over days 1–7); because of pulmonary aspergillosis, no further treatment was given until January 2003, when she was put on imatinib at 600 mg/day. Cytogenetic analysis before imatinib revealed 100% Ph (+) metaphases. At 2 months, the percentage of Ph (+) metaphases decreased to 76% (minor cytogenetic response), concurrently with the appearance of a novel, unrelated hyperdiploid clone with trisomy 8 in 5/25 metaphases, all Ph (−). A repeat analysis at 5 months showed 5% Ph (+) metaphases (major cytogenetic response) and 13/20 Ph (−) metaphases with trisomy 8. FISH analysis showed trisomy 8 in 47.5% of analyzed cells. At 10 months, cytogenetic and FISH analysis of BM mononuclear cells demonstrated 6.6 and 6.92% Ph (+) cells, respectively, and importantly disappearance of the clone with trisomy 8. The patient remains in complete hematological remission, without evidence for myelodysplasia on BM aspirate/biopsy examination.
A 40 year-old male was diagnosed with CML in chronic phase in September 1996. Cytogenetic analysis demonstrated t(9;22) (q34;q11) in all metaphases tested, while RT-PCR identified b2a2 chimeric BCR-ABL mRNA transcripts. The patient attained complete hematologic response with hydroxyurea and then underwent autologous hematopoietic cell transplantation (AHCT, in July 1997), leading to minor cytogenetic response (37.5% Ph (+) metaphases at 6 months after AHCT). Then, starting from January 1998, he was given interferon-alpha and 12 courses of per os cytarabine; nevertheless, the percentage of Ph (+) metaphases gradually increased and eventually he developed hematologic relapse with 100% Ph (+) cells. Starting in March 2001, he was put on imatinib at 400 mg/day; at 5 months, he had attained complete cytogenetic response. At 28 months on imatinib, cytogenetic analysis demonstrated absence of Ph (+) cells concurrently with loss of Y chromosome in 4/25 Ph (−) metaphases (16%). After 3 months, the karyotype showed absence of Ph (+) cells and increase in the percentage of metaphases with loss of Y chromosome (6/22 metaphases analyzed; 27.2%); FISH analysis demonstrated loss of Y chromosome in 29.6% of analyzed cells. The patient remains in complete hematological remission, without evidence of myelodysplasia on BM aspirate/biopsy examination.
Imatinib mesylate is associated with very high cytogenetic response rates in patients with both chronic and accelerated phase CML; nevertheless, the long-term impact of this drug remains largely unknown. In this context, the emergence of cytogenetically abnormal Ph (−) clones raises several important questions. It is largely unknown whether novel chromosomal aberrations in Ph (−) cells are imatinib-induced, whether they could represent disease evolution, or they are a transient effect (vide case#2 of the present report) of unknown pathogenesis and significance.
Based on available evidence, novel chromosome aberrations are rarely seen in early chronic-phase CML patients or in patients treated with imatinib upfront.2,3,4,5,6,7,8 Of the three patients reported herein, two were diagnosed in accelerated and blast phase, respectively, and required high doses of imatinib (600 mg); it is not unreasonable to speculate that such patients with a more aggressive form of the disease might be at a greater risk for development of novel genetic aberrations, possibly due to their smaller pool of Ph (−) progenitors. Case #3 is a heavily pretreated patient, who had proven resistant both to IFN-alpha and AHCT. Thus, it is possible that the patient's hematopoiesis had sustained genetic damages already before starting imatinib.
Most of the cytogenetic aberrations previously reported in Ph (−) cells after imatinib were trisomy 8 and monosomy 7 (−7/−7q).2,3,4,5,6,7,8 The karyotypic abnormalities reported herein included one case each of trisomy 8, loss of chromosome Y and coexisting (albeit in distinct Ph (−) cells) trisomy 8 and monosomy 7. Trisomy 8 is very frequent in myeloproliferative disorders (including CML), while monosomy 7 is often observed in secondary AML/MDS. Isolated loss of the Y chromosome is frequently observed in healthy elderly males and in most cases should be accepted as a normal age-related phenomenon; importantly, however, our patient showed a progressive increase of –Y metaphases (from 16 to 27.2% in a period of only 3 months). Loss of Y chromosome is also frequently observed in myeloproliferative diseases, MDS and AML; furthermore, in both CML and AML, −Y tends to occur at a younger age (as in our case) than in the general population. In AML, loss of Y chromosome is thought to have an intermediate prognosis; in MDS, the prognosis appears to be neutral or favorable; there are insufficient data for myeloproliferative diseases.9 Importantly, during cytogenetic follow-up over a period of 4–8 months, none of our patients had morphologic features (on BM aspirate/biopsy examination) suggestive of MDS or AML. This is in keeping with the recent report by O'Dwyer et al,3 who described clonal karyotypic abnormalities in Ph (−) cells in seven CML patients on imatinib: in that study, peripheral blood and BM morphology at baseline and at a median interval of 13 months after initiation of imatinib were not significantly different between patients with and without clonal aberrations in Ph (−) cells, especially with regard to dysplastic morphologic changes (mild dysplastic abnormalities were equally prevalent in both groups).
In conclusion, the true biological significance as well as the mechanism responsible for the emergence of novel chromosome aberration in Ph (−) cells of CML patients treated with imatinib is currently unknown; nevertheless, given potential clinical implications, a close follow-up of these cases is strongly recommended. Finally, our results further emphasize the value of classical cytogenetic monitoring of CML patients on imatinib, even after attainment of complete cytogenetic remission.
Fayad L, Kantarjian H, O'Brien S, Seong D, Albitar M, Keating M et al. Emergence of new clonal abnormalities following interferon-alpha induced complete cytogenetic response in patients with chronic myeloid leukemia: report of three cases. Leukemia 1997; 11: 767–771.
Andersen MK, Pedersen-Bjergaard J, Kjeldsen L, Dufva IH, Brondum-Nielsen K . Clonal Ph-negative hematopoiesis in CML after therapy with imatinib mesylate is frequently characterized by trisomy 8. Leukemia 2002; 16: 1390–1393.
O'Dwyer ME, Gatter KM, Loriaux M, Druker BJ, Olson SB, Magenis RE et al. Demonstration of Philadelphia chromosome negative abnormal clones in patients with chronic myelogenous leukemia during major cytogenetic responses induced by imatinib mesylate. Leukemia 2003; 17: 481–487.
Bumm T, Muller C, Al-Ali HK, Krohn K, Shepherd P, Schmidt E et al. Emergence of clonal cytogenetic abnormalities in Ph− cells in some CML patients in cytogenetic remission to imatinib but restoration of polyclonal hematopoiesis in the majority. Blood 2003; 101: 1941–1949.
Meeus P, Demuynck H, Martiat P, Michaux L, Wouters E, Hagemeijer A . Sustained, clonal karyotype abnormalities in the Philadelphia chromosome negative cells of CML patients successfully treated with Imatinib. Leukemia 2003; 17: 465–467.
Marktel S, Marin D, Foot N, Szydlo R, Bua M, Karadimitris A et al. Chronic myeloid leukemia in chronic phase responding to imatinib: the occurrence of additional cytogenetic abnormalities predicts disease progression. Haematologica 2003; 88: 260–267.
Schoch C, Haferlach T, Kern W, Schnittger S, Berger U, Hehlmann R et al. Occurrence of additional chromosome aberrations in chronic myeloid leukemia patients treated with imatinib mesylate. Leukemia 2003; 17: 461–463.
McMullin MF, Humphreys M, Byrne J, Russell NH, Cuthbert RJ, O'Dwyer ME . Chromosomal abnormalities in Ph− cells of patients on imatinib. Blood 2003; 102: 2700–2701.
Wiktor A, Rybicki BA, Piao ZS, Shurafa M, Barthel B, Maeda K et al. Clinical significance of Y chromosome loss in hematologic disease. Genes Chromosomes Cancer 2000; 27: 11–16.
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Sequential transient novel chromosomal translocations in a patient with chronic myelogenous leukemia in complete cytogenetic remission after therapy with imatinib mesylate
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