Seminars in Hematology
Volume 40, Issue 1 , Pages 1-3, January 2003

Chronic myeloid leukemia—Past, present, and future

Department of Haematology, Imperial College at Hammersmith Hospital, London, UK

Article Outline

 

The story of chronic myeloid leukemia (CML) has fascinated clinicians and hematologists for many years—though perhaps more in the 20th than in the 19th century—and possibly the story will become even more fascinating from now on. CML was arguably the first type of leukemia to be recognized, almost simultaneously in Scotland and in Germany. In 1841 David Craigie in Glasgow saw a patient with fever, splenomegaly, and leukocytosis; he saw a second similar patient 3 years later6 and this led his colleague John Hughes Bennett, a physician and pathologist, to perform an autopsy and to describe his findings in the Edinburgh Medical and Surgical Journal in 1845.3 More or less simultaneously, Rudolph Virchow, a brilliant young medical graduate in Berlin who later gained a reputation for uncompromisingly radical political attitudes, saw a similar patient at the Berlin Charite Hospital. She died 4 months later and Virchow noted at autopsy enlargement of the spleen and “everywhere in the blood vessels a mass closely resembling pus was found.”18 His report was published in Frorieps Notizen a few weeks after Bennett's paper. In the absence of telephones or e-mail, it is unlikely that Virchow learned of Bennett's publication (or vice versa) until somewhat later. The sequence of events is recounted in some detail in an excellent recent review by Geary.10

Although cases that we would today call leukemia had been described previously, it is probably fair to attribute to Bennett and Virchow the first full descriptions. There was, however, a difference of interpretation. Bennett concluded that his patient had died from “the presence of purulent matter in the blood,” implying some occult infection as the cause. Virchow was less inclined to attribute the excess of colorless corpuscles to “pyemia” and coined the descriptive term “Weisses Blut” or “white blood”; this was based on the Greek (λϵυκos and αιμα) and became in German “Leukämie.” Bennett meanwhile produced the term “leucocythaemia” or “white cell blood.”4 The claim of priority between the two authors was debated subsequently and arguments over correct nomenclature continued acrimoniously for some years. The conflict is well summarized by Gunz11 but with hindsight one may speculate that perhaps Virchow was a fraction nearer to the truth.

By 2003 the definition of the nosological entity “chronic myeloid leukaemia” has achieved a fair level of consensus, even if the precise spelling (leukemia or leukaemia) and nomenclature (myeloid, myelogenous, or myelogenic) vary a little and accelerated-phase disease still defies a universally agreed definition. The recently published World Health Organization classification of tumors defines CML as “a myeloproliferative disease that originates in an abnormal pluripotential bone marrow stem cell and is consistently associated with a Philadelphia (Ph) chromosome and/or the BCR/ABL fusion gene.”17 This seems reasonable but no doubt there will be further attempts to define and classify CML and its various phases as the present century proceeds.

Management of leukemia in the 19th century was no success story.8 Lissauer is credited with the first published report of the use of arsenicals,13 although full details of his work are lacking. It is interesting to note that Arthur Conan Doyle, more famous for documenting the antics of Sherlock Holmes, reported the use of arsenic to treat leukemia in 1882.5 Radiotherapy entered clinical practice in the early years of the 20th century and was arguably the first reliably effective palliation. It remained standard therapy for more than 50 years. The rapid development of oral alkylating agents after World War II led to the introduction of busulfan, which had largely displaced radiotherapy by the 1960s.9 Curiously, hydroxyurea was slow to gain popularity but eventually proved superior to busulfan, by which time the value of interferon-alfa in inducing Ph negativity in some patients had been clearly established.16 In the 1980s it became clear that allogeneic stem cell transplantation, although potentially hazardous or even fatal, could induce long-term remissions and probably cure for some patients. In the late 1990s evidence from France suggested that the best treatment for CML patients not destined for allografting was probably the combination of interferon plus cytarabine,12 although more recent data from Italy cast some doubt on this conclusion.1

The last 4 years have been especially exciting in the story of treating CML. The preclinical development of STI571 (imatinib) spearheaded by Brian Druker,7 and the initial clinical studies summarized in this issue, make compelling reading, and the rapidity with which hematologists worldwide and indeed regulatory authorities in different countries have accepted the drug as an important therapeutic advance is quite remarkable. For the clinician in 2003 the major new dilemma is whether (and when) to offer an allogeneic stem cell transplant to a newly diagnosed patient who, a few years ago, would have been an obvious candidate for the procedure. For patients not eligible for transplant, there can be little doubt now that starting treatment with imatinib is the best approach if a single drug is to be used, even though unequivocal prolongation of survival compared with other approaches has not yet been demonstrated. Hopefully the advent of this compound will serve as an exemplar for other equally effective noncytotoxic drugs active in treating other diseases whose molecular basis is known.

Dare one speculate about the future of management of CML? Effective as imatinib now seems to be, it appears unlikely that this agent used alone will eliminate leukemia in any but a small proportion of patients—at best. Moreover some treated patients have become resistant to imatinib and this resistance has been linked with “acquisition” or better “expansion” of leukemic clones bearing mutations in the Abl kinase domain.2, 14, 15 For both these reasons the notion of combining imatinib with other agents (conventional cytotoxic drugs, interferon-alfa, or new molecular inhibitors) seems attractive. Some of these ideas have already been tested in the clinic and others are in gestation. An alternative approach to cure of chronic-phase disease might involve inducing a state of “minimal residual disease” with imatinib and attempting then to eradicate remaining leukemia cells by some immunotherapeutic approach; for this purpose the target antigen could be an oligopeptide from the Bcr-Abl protein (as reviewed by Schwartz et al in this issue) or it could be based on antigens thought to be involved in the still elusive graft-versus-leukemia effect most prominent in CML (reviewed here by John Barrett).

Although the indications for allografting for patients with CML have undoubtedly changed in the last 2 years, it must remain an important option for any patient who fails to respond to initial treatment with imatinib. Conversely, the use of imatinib could in fact be incorporated into a primary transplant regimen in various ways. One can speculate that imatinib as cytoreduction before allografting might reduce the risk of relapse. Of equal interest, imatinib after reduced-intensity conditioning allografting might really increase the proportion of patients with CML who are eligible for treatment by some form of transplant. Finally, one should not forget the potentially powerful clinical role of autografting in this disease. If substantial numbers of Ph-negative stem cells are present in the marrow and circulation at the time of diagnosis, as seems most probable, the use of imatinib in conjunction with an autograft technique could be the ideal approach to induction of Ph negativity in patients who do not respond to imatinib alone. There is little doubt that the coming years offer the promise of great improvement over today's management for patients with CML.

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References 

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  2. Barthe C, Gharbi M-J, Largarde V, et al.  Mutation in the ATP binding site of BCR-ABL in a patient with chronic myeloid leukaemia with increasing resistance to STI571. Br J Haematol. 2002;119:109–111
  3. Bennett JH. Case of hypertrophy of the spleen and liver in which death took place from the suppuration of the blood. Edinburgh Med Surg J. 1845;64:413–423
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Seminars in Hematology
Volume 40, Issue 1 , Pages 1-3, January 2003

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