Seminars in Hematology
Volume 40, Issue 1 , Pages 97-103, January 2003

Management decisions in chronic myeloid leukemia☆

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

Article Outline

Abstract 

Until recently, interferon-alfa or interferon plus cytarabine was considered the best initial treatment for newly diagnosed chronic myeloid leukemia (CML) patients not eligible for allogeneic stem cell transplantation. The remarkably rapid and apparently durable control of hematologic features and the high rate of cytogenetic response achieved with imatinib used as a single agent suggest that this drug could prolong life substantially. However, response to the drug is variable between patients and here criteria are tentatively suggested for defining response and nonresponse or response failure. It is likely that patients who fail to respond to imatinib may benefit from alternative therapy initiated as early as possible. The issue of whether to offer allogeneic stem cell transplant to any newly diagnosed patient is addressed and a possible strategy is suggested. Undoubtedly, the suggestions made here will require revision as we acquire further information on the utility of imatinib. Semin Hematol 40:97-103. Copyright 2003, Elsevier Science (USA). All rights reserved.

 

The challenge for the 19th century was to identify an agent that had activity in the management of leukemia without excessive toxicity; potassium arsenite in the form of Fowler's solution went some way to satisfying these basic requirements. In the 20th century, the introduction first of radiotherapy and in the 1950s of busulfan offered more effective approaches to controlling symptoms in patients with chronic myeloid leukemia (CML), but did not demonstrably prolong life. The excitement associated with the advent of interferon-alfa in the early 1980s was due to its capacity to induce Philadelphia chromosome (Ph) negativity, occasionally durable, an outcome not seen with other agents. It took some time after its introduction before its ability to prolong life in comparison with hydroxyurea or busulfan would be clearly demonstrated.4 Also in the early 1980s clinicians began the first tentative efforts to test the hypothesis that allogeneic stem cell transplantation could be effective in treating and possibly eradicating CML. Although the results of allografting in advanced phases of CML are still generally disappointing, it is clear that an allograft performed in chronic phase can indubitably cure this disease,10, 36 a result not yet achievable by any other approach.

The current importance of imatinib relates strategically to the fact that it is the first rationally designed drug to demonstrate clinical efficacy8 and thus promises to herald a new therapeutic era in which relatively nonspecific and toxic drugs for treating malignant disease are replaced by safe and tolerable agents whose precise mechanism of action is well defined at the molecular level. More specifically, imatinib is capable of inducing complete cytogenetic responses in a high proportion of patients with CML in chronic phase who have failed treatment with interferon due to intolerance or resistance22; in addition, a remarkable 68% of patients with previously untreated CML in chronic phase have achieved Ph negativity with imatinib.7 Preliminary data indicate that imatinib is significantly less toxic than interferon. These impressive cytogenetic results go far to proving the widely held belief that Ph-negative stem cells are still present although “quiescent” in the marrow of most if not all newly diagnosed patients. They also support the assumption that patients treated with imatinib will survive longer than those treated with interferon. Thus, treatment decisions for patients with CML in chronic phase, relatively straightforward until the 1980s, have now become quite complex.

Back to Article Outline

Chronic-phase disease—The new patient 

Interferon-alfa 

Multicenter studies published in the 1990s showed that survival of patients treated with interferon was in general superior to survival of comparable patients treated with busulfan or hydroxyurea.1, 14, 21, 29 This conclusion was confirmed by a meta-analysis that combined results of seven different studies published from both sides of the Atlantic.4 Thus, for the last 15 years, interferon has been accepted as the treatment of choice for newly diagnosed patients not eligible for allogeneic stem cell transplantation. There is some variability in relation to the proportion of patients who achieve complete cytogenetic remission in different series but universal agreement that those who do achieve cytogenetic responses, and especially those in whom the cytogenetic response is durable, have a significantly longer survival than those who obtain no degree of Ph negativity.23 It is especially interesting to note that a small proportion of patients who achieve Ph negativity have remained in complete cytogenetic remission for some years even after the interferon was withdrawn.3 However, very few of these patients have achieved durable molecular remissions when blood or marrow was studied for Bcr-Abl transcripts by sensitive nested primer reverse-transcriptase polymerase chain reaction (RT-PCR) techniques.15 Thus, although a small proportion of CML patients may be operationally cured by treatment with interferon, they continue to harbor low levels of Bcr-Abl transcripts and thus by implication small numbers of primitive progenitor cells carrying the BCR-ABL fusion gene.

Preliminary results derived from a French multicenter study comparing interferon alone versus interferon plus cytarabine suggested that the two-drug combination was associated with a significantly superior incidence of cytogenetic responses and improved survival.12 However, a comparable study performed in Italy failed to confirm the survival benefit associated with the two-drug combination.2 For the present, one must conclude that the addition of cytarabine to interferon confers no clear-cut advantage and should continue to be regarded as experimental.

Imatinib mesylate 

Imatinib (STI571, Glivec, Novartis, Basel, Switzerland) was introduced into clinical practice in 1998 and thus we now have more than 4 years experience with its use (reviewed in detail by Druker in this issue). Imatinib was first tested in patients with CML in chronic phase who had been deemed intolerant of or resistant to interferon. When given by mouth at a dose of 400 mg daily, it was highly effective at controlling clinical and hematologic features of CML in more than 95% of patients; it was especially exciting to observe that 41% of patients achieved a complete cytogenetic remission and 60% achieved major (complete or partial) cytogenetic remissions.22 The majority of these remissions proved durable during the next 2 years. The drug was also effective in accelerated phase35 and blastic transformation,9 but the control achieved in patients treated in blastic transformation has generally been short-lived.9 These initial results led rapidly to the design and implementation of a prospective study to compare the incidence of cytogenetic response and survival for newly diagnosed patients treated with imatinib with outcome for patients treated with interferon-alfa and cytarabine, a combination that was at that time believed to be the best primary treatment for CML patients not eligible for allogeneic stem cell transplantation. Preliminary results suggest that progression-free survival is indeed superior in the patient group receiving imatinib as primary treatment but overall survival data are not yet available.7 Imatinib is not without side effects and occasional fatalities have been reported (see Druker in this issue).

Patients who achieve cytogenetic remissions on treatment with imatinib have in many cases been studied by molecular techniques to detect low levels of Bcr-Abl transcripts in the circulation.19, 25 The general pattern for patients responding to imatinib is a very rapid reduction in transcript numbers, faster than had been seen with interferon, but numbers tend to reach a plateau at a level that is low but still measurable. The number of patients in whom Bcr-Abl transcripts have become undetectable by Taqman Realtime PCR is small and some of these have still proved positive when studied by a more sensitive two-step nested primer technique. Thus, for the present one may conclude that total eradication of cells capable of producing CML-specific transcripts is rare, if indeed it does occur with imatinib therapy. It is interesting in this context to note that a quiescent Ph-positive progenitor cell was recently identified in the blood of newly diagnosed CML patients17, 18; this progenitor cell seems to be relatively resistant to imatinib12 and could play a role in the still incompletely-defined mechanisms underlying acquired resistance to imatinib. Moreover, imatinib selectively inhibits proliferation of CML cells but does not definitively increase their level of apoptosis compared with normal cells.17 These two lines of evidence imply that nondividing CML cells may be relatively resistant to the action of imatinib and thus suggest the need for combining imatinib with other agents that act by a different mechanism.

Is imatinib the drug of choice for newly diagnosed patients? The definitive answer must await further experience and in particular analysis of the current prospective study. The high cytogenetic response rate suggests that the median survival for imatinib-treated patients could be substantially longer than survival for patients treated with interferon, but little is known of the durability of imatinib-induced cytogenetic remissions, and it would be hazardous to conclude at this stage that an imatinib-induced cytogenetic remission has the same prognostic significance as an interferon-induced remissions. Moreover, a significant minority of patients treated with imatinib obtain no cytogenetic benefit and there are even a few in whom hematologic features are not controlled. Treatment with imatinib may not offer any particular advantage for these patients.

Conversely, the relative ease with which imatinib controls features of CML in chronic phase, its capacity to induce complete cytogenetic responses in 68% of newly diagnosed patients, and the relative freedom from major toxicity all combine to make the drug more attractive than interferon alone or interferon in combination with cytarabine. Thus initial treatment with imatinib (or an imatinib-containing combination) is almost universally recommended if financial considerations permit.

Defining a response to imatinib 

Alhough the molecular characteristics of BCR-ABL–positive CML seem to be remarkably similar in different patients, it is now widely accepted that the disease is in fact highly heterogeneous. Thus Sokal et al in the 1980s were able to categorize CML patients treated with busulfan into three prognostic groups based on criteria defined at diagnosis34 and Hasford et al in the 1990s carried out a similar exercise with patients treated predominantly with interferon-alfa.13 The observed variability might theoretically have been due to the fact that the disease was diagnosed in the different patients at different points in its natural history, but it is more likely to reflect intrinsic kinetics of disease in an individual patient.33 This view is supported by the recent observation that the 15% to 20% of patients whose leukemia cells have a deletion of cytogenetic material in the vicinity of the ABL-BCR gene on chromosome 9q+ have a survival inferior to those lacking this deletion.20 Further genetic abnormalities will be identified in newly diagnosed patients. Intrinsic variability is entirely consistent with the idea that some patients are destined to achieve complete cytogenetic remission with imatinib (regardless of when within chronic phase the treatment is started) while others will remain resolutely 100% Ph-positive.

The standard dose of imatinib for newly diagnosed patients is 400 mg daily but it is possible that higher doses (600 or even 800 mg daily) could prove superior. The sequence of events in patients responding to treatment with imatinib closely parallels the pattern with other agents, but with the notable difference that the response to a standard dose of imatinib seems extremely rapid. Leukocyte counts start to fall rapidly and may reach normal values within 10 to 15 days; the percentage of Ph-positive marrow metaphases also falls such that the patients may be 100% Ph-negative within 3 months (or earlier), and the number of Bcr-Abl transcripts reaches its nadir thereafter. Thus, theoretically one could define a response on hematologic, cytogenetic, or molecular bases or use some combination of all three. We have attempted, somewhat arbitrarily, to define a series of features that would allow judgement as to whether an individual patient has failed to respond to treatment with imatinib at standard dosage (400 mg/d) or, having responded, has begun to lose the response (Table 1).

Table 1. Proposed criteria for defining a patient who fails to respond or has lost a response to imatinib
Failure to RespondLoss of Response
Hematologic
Absence of complete hematologic response by 3 monthsLoss of complete hematologic response on standard dose
Cytogenetic
Still predominantly Ph-positive (>95%) at 3 months or still >35% positive at 6 monthsLoss of complete cytogenetic response
Molecular
Not applicableFor patients known to have been in complete cytogenetic remission, Bcr-Abl transcript numbers rising into the Ph-positive range

On the basis of our experience with 145 patients with CML in chronic phase, resistant to or intolerant of interferon-alfa, we have defined factors present at the time of starting imatinib and present after treatment for 3 months that allow us to predict disease progression with reasonable accuracy. Using multivariate analysis of features assessed immediately before treatment, we identified as unfavorable a low hemoglobin level (<10.0 g/L), a high percentage of bone marrow blasts (>5%), the presence of clonal evolution, and a history of hematologic resistance to interferon-alfa. Patients were classified as good risk if they had none of these adverse features, as intermediate if they had one or two adverse features, and as high risk if they had three or four adverse features. Patients in the low-risk group had an 18-month survival rate of 100% and a progression-free survival of 90%, while these rates were 46% and 0%, respectively, in the high-risk group.28 It may be more informative to evaluate patients after 3 months of imatinib therapy. The presence of neutropenia and the failure to achieve a minor cytogenetic response defined a high-risk group with a particularly poor prognosis.27 The proportions of patients considered to be high risk on the basis of these prognostic scores in the pretreatment and the 3-month treatment analyses were 10% and 30%, respectively. These results were validated in a separate patient cohort. These various factors, as well as those included in Table 1, may contribute to the decision whether a patient should start or continue on imatinib or be offered alternative therapy, including stem cell transplantation.

How to manage the responder 

The patient who is judged to be responding to imatinib should presumably continue the drug indefinitely. This conclusion assumes that the patient can easily tolerate treatment and that no significant late toxicity is identified in other patients who have taken the drug for 2 or more years. Some patients will reasonably ask whether the disappearance of Ph-positive metaphases from their marrow means that they can safely interrupt the drug, but it seems likely that features of chronic-phase disease will recur on discontinuation of imatinib. However, by analogy with results in patients responding to interferon-alfa,3 it is possible that for undetectable or very low levels of residual Bcr-Abl transcripts, imatinib could safely be stopped without relapse of CML during many years. As imatinib acts in a manner different from interferon, there likely is a risk that the majority of imatinib responders who stop imatinib will relapse fairly rapidly.

The patient who responds well may do even better if the response is consolidated. It might be attractive to add interferon or a conventional cytotoxic drug to imatinib. Peripheral blood stem cells, presumably Ph-negative, could be collected and the patient offered an autograft while still in complete cytogenetic remission.

How to manage the nonresponder 

Once a patient considered still to be in chronic phase has been classified as a nonresponder to standard-dose imatinib, the clinician has a number of options for further management. Easiest is to increase the dose of imatinib to 600 to 800 mg daily, but these doses are generally tolerated less well. Patients who are young enough and have a suitable donor should be considered for allogeneic stem cell transplant without further delay. Although there was for a time uncertainty as to whether prior treatment with interferon-alfa adversely affected the result of an allograft, and the same uncertainty could surrounds the prior use of imatinib, it seems unlikely that treatment with imatinib for 6 to 9 months would in fact be injurious.6

Attractive as continuing imatinib with another agent, such as cytarabine, interferon-alfa, an anthracycline, or homoharringtonine, is, there has been little or no experience with this approach and it is difficult to predict how well such combination therapy would be tolerated. Alternatively, imatinib could be discontinued and a totally different drug or drug combination initiated. Logically the best drug might be interferon and the best combination interferon plus cytarabine, but many other possibilities could be considered.

Finally one should consider the possibility of an autograft with peripheral blood progenitor/stem cells collected and stored at the time of diagnosis or with cells mobilized after high-dose chemotherapy such as ICE (idarubicin, cytarabine, etoposide) or mini-ICE (see Carella et al in this issue).

Imatinib or allografting as primary treatment? 

Even in the 1990s it was relatively difficult to make any confident recommendation to a newly diagnosed patient who might be eligible for initial treatment by allogeneic stem cell transplantation. The problem has now been magnified by the advent of imatinib. On the one hand, we cannot accurately predict for an individual patient the probability of survival or of leukemia-free survival after allogeneic stem cell transplantation and therefore to define what level of risk would be acceptable to a given patient in the quest for cure. Moreover, recent studies in many centers with reduced-intensity conditioning allogeneic stem cell transplants suggest that this novel approach has the capacity to reduce the risk of transplant-related mortality yet still result in a high proportion of “cures” (see Barrett in this issue). The Jerusalem group (and others) pioneered this approach; they have recently reported results of treating 24 patients with conditioning that included low-dose busulfan with fludarabine followed by transplantation of donor-derived peripheral blood mononuclear cells.31 Graft-versus-host disease and viral reactivation were the major complications but the projected survival at 3 years was 85%, a figure that equals or exceeds what results after a conventionally conditioned allograft. On the other hand, we know with reasonable certainty that the use of interferon-alfa, while prolonging life to a modest degree (in comparison to hydroxyurea) does not offer the prospect of cure (except possibly to the very small percentage of patients who achieve durable Ph negativity and remain Ph-negative for some years after interferon is discontinued). However, we do not yet have comparable data for patients treated for 5 or more years with imatinib, and we cannot predict with any certainty whether results of using imatinib will be improved in the near future by incorporation of other drugs or procedures.

Until recently, there was great interest in the possibility that high-dose chemotherapy followed by autografting, either with progenitor cells collected at the time of diagnosis or with cells mobilized after combination chemotherapy, might be valuable in prolonging life for patients with CML (see Carella et al in this issue). This approach could again become popular either for consolidation of remission or for managing the patient who proves resistant to imatinib.

With these various considerations in mind, one can suggest two contrasting strategies for treating the CML patient newly diagnosed in chronic phase who is relatively young and who may have a suitable human leukocyte antigen (HLA)-identical or HLA-compatible donor. One approach would be to start all such patients on treatment with imatinib at standard dosage and then to follow them closely by cytogenetic and molecular markers. If a patient responds well to imatinib (see above), this drug could be continued indefinitely. If the patient satisfies criteria for imatinib failure, one could proceed promptly to an allogeneic stem cell transplant. The other approach would be to attempt to define a population of patients for whom a transplant might be recommended as initial therapy. Algorithms could be developed by balancing the predicted risk of transplant-related mortality using the major prognostic factors of age and donor histocompatibility against the risk score for survival with nontransplant therapy using the formula proposed by Sokal or by Hasford (although neither system is necessarily valid for patients treated with imatinib). The younger patient who does have a suitable donor should be offered a transplant as primary treatment, but the upper age limit for this recommendation could be modified in the light of the calculated Hasford risk score (Table 2).

Table 2. Proposed criteria for offering a patient newly diagnosed in chronic phase initial treatment with allogeneic stem cell transplant
Age up to 45 years with an HLA-identical sibling donor
Age up to 35 years with a molecularly HLA-matched unrelated donor
For patients in Hasford “good-risk” category, it may be reasonable to reduce these upper age limits for transplant by 10 years; conversely, for patients in the “poor-risk” category, the upper age limit could be increased by 10 years
For unrelated donor transplants, CMV status must also be taken into account

Imatinib or donor lymphocytes for CML in relapse? 

Since 1989 the preferred approach to managing a patient with CML who relapses after allogeneic stem cell transplantation has been transfusion of lymphocytes collected from the original transplant donor.24 Such donor lymphocyte infusions (DLI) are highly effective in the management of relapse at the molecular or cytogenetic level and slightly less effective for patients relapsed in chronic-phase disease.37 DLI is less effective in advanced-phase disease. Although early DLI studies were associated with significant complications, notably unpredictable induction of graft-versus-host disease and occasional marrow aplasia, the use of escalating-dose DLI has largely prevented these problems while retaining the graft-versus-leukemia benefit.5, 26 The question of how best to treat the patient who relapses after allografting must be readdressed since the advent of imatinib.

The occasional patient who does not respond to DLI may still do so after administration of imatinib.30 For other patients who relapse at the molecular or cytogenetic levels, one could consider first giving imatinib, followed by DLI if a molecular remission is not attained. The European Group for Blood and Marrow Transplantation is currently implementing a study that compares initial treatment with DLI with initial treatment with imatinib. The results are awaited with interest.

Back to Article Outline

Chronic-phase disease—The treated patient 

The question now often arises as to whether a patient in chronic phase currently being treated with interferon-alfa should be switched to imatinib. There can be no reliable answer until we have more long-term experience with imatinib. However, for the patient who is intolerant of interferon or who has failed to achieve a major cytogenetic response, the change to imatinib would be advisable. If, conversely, a patient is tolerating interferon well, and has in addition achieved a complete cytogenetic response, the logic for switching to imatinib is not persuasive: that such patients are known to have median survival exceeding 10 years3 argues against the change.

Back to Article Outline

Advanced-phase disease 

There has not been great progression in the management of CML in advanced phase in recent years. The median survival after onset of acceleration is difficult to calculate, mainly because the phase is highly heterogeneous and definitions differ. The median survival after onset of blastic transformation is about 6 months but may be somewhat longer if the blast cells are of lymphoid origin.

Accelerated phase 

For patients who enter an accelerated phase without previous exposure to imatinib, the use of this drug now seems advisable.35 Patients treated with 600 mg daily seem to fare better than those who receive 400 mg daily. Because some patients will regain disease control lasting more than 1 year, it may be reasonable to continue this drug until there is definite evidence of disease progression. At that point, combination chemotherapy with drugs appropriate to acute myeloid leukemia arising de novo may be considered. Moreover, the possibility of treatment by allogeneic stem cell transplantation, which was presumably excluded while the patient was in chronic phase, should be readdressed. Alternative approaches would be to start with a combination of imatinib and other agents, or to introduce other agents after some level of control has been achieved. If a suitable donor is identified, one might also consider allogeneic stem cell transplantation while the patient is still responding to imatinib.

Blastic transformation 

CML in lymphoid blastic transformation responds reasonably well to imatinib but the duration of response is typically brief.32, 38 In practice, such patients could be treated for a short time with imatinib but only as a prelude to combination chemotherapy or allogeneic stem cell transplantation. The same general principle probably applies to patients who enter myeloid transformation without previous exposure to imatinib. Reasonable treatment would be initially imatinib for 4 to 8 weeks but thereafter to consolidate any response with a course of combination chemotherapy such as FLAG (fludarabine, cytarabine, granulocyte colony-stimulating factor) or FLAG-IDA (FLAG plus idarubicin). For responding patients, an allogeneic or autologous stem cell transplant could then be considered. Patients who fail to respond to the initial imatinib or to the subsequent chemotherapy will inevitably do poorly.

Back to Article Outline

Future directions 

For the management of the new patient with CML in chronic phase, the most urgent requirement is to define as precisely as possible the role of imatinib. We need to be sure that in general the drug really does prolong survival in comparison with best available alternative therapy. We need also to establish reliable criteria of success or failure for individual patients, to predict progression, and thus to identify the population for whom other treatments must be considered. Likely imatinib in combination with other agents will eventually prove superior to the drug as a single agent, but the appropriate partner and the best dosage schedule are not yet defined. The decision as to which patient best receives imatinib or an imatinib-containing combination on a continuing basis and who is best treated by allogeneic stem cell transplantation will continue to challenge the clinician and indeed the patient for some time to come.

Back to Article Outline

References 

  1. Allan NC, Richards SM, Shepherd PC. UK Medical Research Council randomised, multicentre trial of interferon-alpha n1 for chronic myeloid leukaemia: Improved survival irrespective of cytogenetic response. The UK Medical Research Council's Working Parties for Therapeutic Trials in Adult Leukaemia. Lancet. 1995;345:1392–1397
  2. Baccarani M, Rosti G, de Vivo A, et al.  A randomized study of interferon-alpha versus interferon-alpha and low-dose arabinosyl cytosine in chronic myeloid leukemia. Blood. 2002;99:1527–1535
  3. Bonifazi F, de Vivo A, Rosti G, et al.  Chronic myeloid leukemia and interferon-alpha: A study of complete cytogenetic responders. Blood. 2001;98:3074–3081
  4. Chronic Myeloid Leukemia Trialists' Collaborative Group . Interferon alfa versus chemotherapy for chronic myeloid leukemia: A meta-analysis of seven randomized trials. J Natl Cancer Inst. 1997;89:1616–1620
  5. Dazzi F, Szydlo RM, Craddock C, et al.  Comparison of single-dose and escalating-dose regimens of donor lymphocyte infusion for relapse after allografting for chronic myeloid leukemia. Blood. 2000;95:67–71
  6. Deininger M, Schleuning C, Olavarria E, et al.  Glivec prior to allografting is safe and not associated with increased transplant-related toxicity. Blood. 2001;98(suppl 1, abstr):344b
  7. Druker BJ, for IRIS Study Group . In: Meeting of the American Society of Clinical Oncology, Orlando FL. STI571 (Gleevec/Glivec, imatinib) versus interferon (IFN) and cytarabine as initial therapy for patients with CML: Results of a randomized study. 21:2002;p. 1a; (abstr)
  8. Druker BJ, Lydon NB. Lessons learned from the development of an Abl tyrosine kinase inhibitor for chronic myelogenous leukemia. J Clin Invest. 2000;105:3–7
  9. Druker BJ, Sawyers CL, Kantarjian H, et al.  Activity of a specific inhibitor of the BCR-ABL tyrosine kinase in the blast crisis of chronic myeloid leukemia and acute lymphoblastic leukemia with the Philadelphia chromosome. N Engl J Med. 2001;344:1038–1042
  10. Goldman JM, Gale RP, Horowitz MM, et al.  Bone marrow transplantation for chronic myelogenous leukemia in chronic phase. Increased risk for relapse associated with T-cell depletion. Ann Intern Med. 1988;108:806–814
  11. Graham SM, Jorgensen HG, Allan E, et al.  Primitive, quiescent, Philadelphia-positive stem cells from patients with chronic myeloid leukemia are insensitive to STI571 in vitro. Blood. 2002;99:319–325
  12. Guilhot F, Chastang C, Michallet M, et al.  Interferon alfa-2b combined with cytarabine versus interferon alone in chronic myelogenous leukemia. French Chronic Myeloid Leukemia Study Group. N Engl J Med. 1997;337:223–229
  13. Hasford J, Pfirrmann M, Hehlmann R, et al.  A new prognostic score for survival of patients with chronic myeloid leukemia treated with interferon alfa. Writing Committee for the Collaborative CML Prognostic Factors Project Group. J Natl Cancer Inst. 1998;90:850–858
  14. Hehlmann R, Heimpel H, Hasford J, et al.  Randomized comparison of interferon-alpha with busulfan and hydroxyurea in chronic myelogenous leukemia. The German CML Study Group. Blood. 1994;84:4064–4077
  15. Hochhaus A, Reiter A, Saussele S, et al.  Molecular heterogeneity in complete cytogenetic responders after interferon-alpha therapy for chronic myelogenous leukemia: low levels of minimal residual disease are associated with continuing remission. German CML Study Group and the UK MRC CML Study Group. Blood. 2000;95:62–66
  16. Holtz MS, Slovak ML, Zhang F, et al.  Imatinib mesylate (STI571) inhibits growth of primitive malignant progenitors in chronic myelogenous leukemia through reversal of abnormally increased proliferation. Blood. 2002;99:3792–3800
  17. Holyoake T, Jiang X, Eaves C, et al.  Isolation of a highly quiescent subpopulation of primitive leukemic cells in chronic myeloid leukemia. Blood. 1999;94:2056–2064
  18. Holyoake TL, Jiang X, Jorgensen HG, et al.  Primitive quiescent leukemic cells from patients with chronic myeloid leukemia spontaneously initiate factor-independent growth in vitro in association with up-regulation of expression of interleukin-3. Blood. 2001;97:720–728
  19. Hughes T, Kaeda J, Branford S, et al.  Molecular responses to imatinib (STI571) or interferon + Ara-C as initial therapy for CML: Results of the IRIS study. Blood. 2002;99(suppl 1, abstr 345):
  20. Huntly BJ, Reid AG, Bench AJ, et al.  Deletions of the derivative chromosome 9 occur at the time of the Philadelphia translocation and provide a powerful and independent prognostic indicator in chronic myeloid leukemia. Blood. 2001;98:1732–1738
  21. Italian Cooperative Group . Interferon alfa-2a as compared with conventional chemotherapy for the treatment of chronic myeloid leukemia. The Italian Cooperative Study Group on Chronic Myeloid Leukemia. N Engl J Med. 1994;330:820–825
  22. Kantarjian H, Sawyers C, Hochhaus A, et al.  Hematologic and cytogenetic responses to imatinib mesylate in chronic myelogenous leukemia. N Engl J Med. 2002;346:645–652
  23. Kantarjian HM, Smith TL, O'Brien S, et al.  Prolonged survival in chronic myelogenous leukemia after cytogenetic response to interferon-alpha therapy. Ann Intern Med. 1995;122:254–261
  24. Kolb HJ, Mittermuller J, Clemm C, et al.  Donor leukocyte transfusions for treatment of recurrent chronic myelogenous leukemia in marrow transplant patients. Blood. 1990;76:2462–2465
  25. Lin F, Drummond M, Byrne J, et al.  Molecular monitoring of complete cytogenetic responders following treatment with imatinib (STI571): A report from the UKSTI study group. Blood. 2002;99(suppl 1, abstr 1425):
  26. Mackinnon S, Papadopoulos EB, Carabasi MH, et al.  Adoptive immunotherapy evaluating escalating doses of donor leukocytes for relapse of chronic myeloid leukemia after bone marrow transplantation: Separation of graft-versus-leukemia responses from graft-versus-host disease. Blood. 1995;86:1261–1268
  27. Marin D, Marktel S, Bua M, et al.  The use of imatinib (STI571) in chronic myeloid leukemia: Some practical considerations. Haematologica. 2002;87:979–988
  28. Marin D, Marktel S, O'Brien S, et al.  Use of imatinib mesylate in patients with CML in chronic phase resistant to interferon-alfa: Factors defined at start of therapy that predict disease progression and survival. Blood. 2002;99(suppl 1, abstr 4853):
  29. Ohnishi K, Ohno R, Tomonaga M, et al.  A randomized trial comparing interferon-alpha with busulfan for newly diagnosed chronic myelogenous leukemia in chronic phase. Blood. 1995;86:906–916
  30. Olavarria E, Craddock C, Dazzi F, et al.  Imatinib mesylate (STI571) in the treatment of relapse of chronic myeloid leukemia after allogeneic stem cell transplantation. Blood. 2002;99:3861–3862
  31. Or R, Shapira MY, Resnick I, et al: Nonmyeloablative allogeneic stem cell transplantation for the treatment of chronic myeloid leukemia in first chronic phase. Blood (in press)
  32. Sawyers CL, Hochhaus A, Feldman E, et al.  Imatinib induces hematologic and cytogenetic responses in patients with chronic myelogenous leukemia in myeloid blast crisis: Results of a phase II study. N Engl J Med. 2002;99:3530–3539
  33. Sokal JE. Prognosis in chronic myeloid leukaemia: Biology of the disease vs. treatment. Baillieres Clin Haematol. 1987;1:907–929
  34. Sokal JE, Cox EB, Baccarani M, et al.  Prognostic discrimination in “good-risk” chronic granulocytic leukemia. Blood. 1984;63:789–799
  35. Talpaz M, Silver RT, Druker BJ, et al.  Imatinib induces durable hematologic and cytogenetic responses in patients with accelerated phase chronic myeloid leukemia: Results of a phase 2 study. Blood. 2002;99:1928–1937
  36. van Rhee F, Lin F, Cross NC, et al.  Detection of residual leukaemia more than 10 years after allogeneic bone marrow transplantation for chronic myelogenous leukaemia. Bone Marrow Transplant. 1994;14:609–612
  37. van Rhee F, Lin F, Cullis JO, et al.  Relapse of chronic myeloid leukemia after allogeneic bone marrow transplant: The case for giving donor leukocyte transfusions before the onset of hematologic relapse. Blood. 1994;83:3377–3383
  38. Wadhwa J, Szydlo RM, Apperley JF, et al.  Factors impacting on duration of survival after onset of blastic transformation of chronic myeloid leukemia. Blood. 2002;99:2304–2309

☆ Address reprint requests to Prof John M. Goldman, Department of Haematology, Imperial College at Hammersmith Hospital, Du Cane Road, London W12 0NN, UK.

PII: S0037-1963(03)70047-X

Seminars in Hematology
Volume 40, Issue 1 , Pages 97-103, January 2003

Article Tools