Ph-positive and -negative myeloproliferative syndromes may co-exist


Current thinking holds that the acquisition of the Philadelphia (Ph) translocation in a normal hematopoietic stem cell initiates chronic myelogenous leukemia (CML). Thus, suppression of the Ph-positive clone should re-establish normal hematopoiesis. Recently, chromosomal abnormalities in Ph-negative cells were observed in CML patients with cytogenetic response to imatinib, sometimes associated with myelodysplasia, raising doubts as to the ‘normality’ of the Ph chromosome-negative hematopoiesis in CML.1, 2, 3, 4, 5, 6, 7 Here, we describe a patient with coexistence of Ph-positive and Ph-negative myeloproliferative syndromes (MPS).

A 59-year old male was noted to have isolated mild thrombocytosis (maximum platelet count 578 × 109/l) between 1999 and 2002. In June 2002, splenomegaly and peripheral blood (PB) leukocytosis developed; bone marrow (BM) morphology was not evaluable (poor quality) but cytogenetics was normal (Table 1). A biopsy 3 months later revealed fibrosis, hypercellularity, and atypical megakaryocytic clustering. PB findings were unchanged; quantitative RT-PCR (qPCR) was positive for BCR-ABL. In December 2002, PB cytogenetics detected 45% Ph-positive metaphases; FISH and qPCR were positive for BCR-ABL (not shown). In January 2003, BM biopsy showed 75% Ph-positive metaphases, 40.5% BCR-ABL-positive interphases, and increasing BCR-ABL transcripts. Morphology revealed fibrosis, increased granulopoiesis, atypical megakaryocytes, and dysplastic erythropoiesis (Figure 1a). In February 2003, the patient was started on 400 mg imatinib and 3 MIU IFN-α daily within a clinical trial. After 3 months, spenomegaly had decreased and leukocytosis had resolved, but immature cells persisted in PB and anemia developed. BM assessment documented complete cytogenetic response and markedly reduced BCR-ABL mRNA. However, features of an active myeloproliferative disorder persisted morphologically (Figure 1b). In June 2003, treatment was transiently discontinued and subsequently dose-reduced because of skin toxicity. Soon after, the spleen size increased. In August 2003, cytogenetics was Ph-positive in 1/20 metaphases, and immature cells persisted in the PB (not shown). In October 2003, trial medication was stopped due to the patient's failure to achieve complete hematologic response. A search for an unrelated stem cell donor was initiated.

Table 1 Diagnostic results during follow-up
Figure 1

Hematoxylin-and-eosin-stained sections of bone marrow biopsy specimens. Biopsies taken before STI therapy (a), during therapy (b), and after therapy (c) show similar findings including increased cellularity, fibrosis, and megakaryocytic hyperplasia. Original magnification × 200.

Although the morphology, particularly the megakaryocytic abnormalities, is reminiscent of advanced essential thrombocythemia (ET), our patient never met standard diagnostic criteria, with platelets consistently <600 × 109/l. The extensive fibrosis is also consistent with myelofibrosis with myeloid metaplasia. Some patients with typical ET may be BCR-ABL-positive by RT-PCR,8 although this is not a universal finding.9 Such low-level expression does not influence prognosis, whereas the presence of a Ph rearrangement at the cytogenetic level leads to a CML-like clinical course10 and excludes the diagnosis of ET. The rapid increase in Ph-positive metaphases in our patient suggests that the Ph-positive cell clone would have prevailed in the absence of imatinib. An analogous case was recently reported, where Ph-positive CML developed in a patient with pre-existing polycythemia rubra vera.11 Our case in particular might best be described, based on its different elements, as an unclassified myeloproliferative syndrome.

Our case illustrates that Ph-positive and Ph-negative MPS may coexist. The chronology suggests that the acquisition of the Ph chromosome was a secondary event, leading to rapid expansion of a new cell clone. Unfortunately, without a marker for the Ph-negative disease, one cannot know whether the Ph translocation represents clonal evolution, an independent event in a normal stem cell or an independent event in an abnormal stem cell pool, from which both the Ph-positive and the Ph-negative disease arose. Imatinib obviously unmasked the Ph-negative disease by suppressing the Ph-positive clone.

Cases like this shed new light on an old discussion: is the Philadelphia translocation the only abnormality in chronic phase CML and does it occur in a completely normal stem cell? While the murine CML models clearly established that BCR-ABL is sine qua non for the induction of CML,12 they cannot definitely prove that BCR-ABL is the only event required for leukemogenesis. In addition, work from Phil Fialkow's laboratory showed that Ph-negative EBV-transformed lymphoblastoid cell lines established from a subset of CML patients exhibit a pattern of glucose-6-phosphate dehydrogenase isoenzyme expression that is skewed towards the pattern of the CML clone.13, 14 Equally intriguing, it was shown that ionizing radiation is more likely to induce BCR-ABL transcripts in such lines than in lines established from healthy individuals.15 Last, the epidemiology of chronic phase CML appears to be more consistent with two or three events than with a single hit.16

One must bear in mind that genetic damage becomes detectable only when it confers a growth advantage to the affected cell and leads to its clonal expansion. Thus, it is impossible to prove with certainty that the Ph-negative hematopoiesis in CML patients with a cytogenetic response is completely normal. Nonetheless, our case and an increasing number of similar observations suggest the existence of two different categories of Ph-positive MPS. ‘Pure’ BCR-ABL-positive disease as opposed to disorders, where the BCR-ABL-positive clone is only one of multiple co-existing abnormal clones, may be the result of ‘field carcinogenesis’ or represent the progeny of a genetically unstable ancestor cell.


  1. 1

    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.

  2. 2

    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.

  3. 3

    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.

  4. 4

    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.

  5. 5

    Royer-Pokora B, Hildebrandt B, Redmann A, Herold C, Kronenwett R, Haas R et al. Simultaneous occurrence of a t(9;22) (Ph) with a t(2;11) in a patient with CML and emergence of a new clone with the t(2;11) alone after imatinib mesylate treatment. Leukemia 2003; 17: 807–810.

  6. 6

    Chee YL, Vickers MA, Stevenson D, Holyoake TL, Culligan DJ . Fatal myelodysplastic syndrome developing during therapy with imatinib mesylate and characterised by the emergence of complex Philadelphia negative clones. Leukemia 2003; 17: 634–635.

  7. 7

    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.

  8. 8

    Blickstein D, Aviram A, Luboshitz J, Prokocimer M, Stark P, Bairey O et al. BCR-ABL transcripts in bone marrow aspirates of Philadelphia-negative essential thrombocytopenia patients: clinical presentation. Blood 1997; 90: 2768–2771.

  9. 9

    Emilia G, Marasca R, Zucchini P, Temperani P, Luppi M, Torelli G et al. BCR-ABL rearrangement is not detectable in essential thrombocythemia. Blood 2001; 97: 2187–2189.

  10. 10

    Martiat P, Ifrah N, Rassool F, Morgan G, Giles F, Gow J et al. Molecular analysis of Philadelphia positive essential thrombocythemia. Leukemia 1989; 3: 563–565.

  11. 11

    Ganti AK, Potti A, Mehdi SA . Chromosomal anomalies in two coexistent myeloproliferative disorders. Cancer Genet Cytogenet 2003; 145: 172–175.

  12. 12

    Daley GQ, Van Etten RA, Baltimore D . Induction of chronic myelogenous leukemia in mice by the P210bcr/abl gene of the Philadelphia chromosome. Science 1990; 247: 824–830.

  13. 13

    Fialkow PJ, Martin PJ, Najfeld V, Penfold GK, Jacobson RJ, Hansen JA . Evidence for a multistep pathogenesis of chronic myelogenous leukemia. Blood 1981; 58: 158–163.

  14. 14

    Raskind WH, Ferraris AM, Najfeld V, Jacobson RJ, Moohr JW, Fialkow PJ . Further evidence for the existence of a clonal Ph-negative stage in some cases of Ph-positive chronic myelocytic leukemia. Leukemia 1993; 7: 1163–1167.

  15. 15

    Spencer A, Granter N . Leukemia patient-derived lymphoblastoid cell lines exhibit increased induction of leukemia-associated transcripts following high-dose irradiation. Exp Hematol 1999; 27: 1397–1401.

  16. 16

    Vickers M . Estimation of the number of mutations necessary to cause chronic myeloid leukaemia from epidemiological data. Br J Haematol 1996; 94: 1–4.

Download references

Author information

Correspondence to M W Deininger.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Mauro, M., Loriaux, M. & Deininger, M. Ph-positive and -negative myeloproliferative syndromes may co-exist. Leukemia 18, 1305–1307 (2004).

Download citation

Further reading