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Blood, Vol. 94 No. 5 (September 1), 1999:
pp. 1517-1536
REVIEW ARTICLE
By
From the New York Presbyterian Hospital-Weill Medical College of
Cornell University, New York, NY; Medical College of Virginia, Fairfax,
VA; Universitat Heidelberg, Mannheim, Germany; Fred Hutchinson Cancer
Research Center, Seattle, WA; University of Nebraska Medical Center,
Omaha, NE; VA Chicago Health Care System, Lakeside Division, Chicago,
IL; Royal Postgraduate Medical School, London, UK; Hopital Jean Bernar,
Poitiers, France; M.D. Anderson Cancer Center, Houston, TX; Cleveland
Clinic Foundation, Cleveland, OH; and St Ursula Hospital, Bologna,
Italy.
Because there are differing opinions regarding treatment of patients
in the chronic phase of chronic myeloid leukemia (CML), the American
Society of Hematology convened an expert panel to review and document
evidence-based benefits and harms of treatment of CML with busulfan
(BUS), hydroxyurea (HU), recombinant interferon-
CHRONIC MYELOID (myelogenous, myelocytic,
granulocytic) leukemia (CML) is a clonal myeloproliferative disorder of
a pluripotent hematopoietic stem cell with a specific cytogenetic abnormality, the Philadelphia (Ph+) chromosome. This chromosome results
from a balanced translocation between the long arms of chromosomes 9 and 22, resulting in the bcr/abl chimeric gene that expresses
an abnormal fusion protein with altered tyrosine kinase activity. CML
accounts for 7% to 20% of all leukemias and affects an estimated 1 to
2/100,000 persons in the general population.1,2 Although
the median age of presentation is the fifth decade, all age groups are
at risk. CML is characterized by a chronic phase with a median duration
of 3 to 5 years when treated with conventional agents and an
accelerated or acute phase of approximately 3 to 6 months' duration,
inevitably terminating fatally. Initially, the chronic phase is
characterized by no or few symptoms and signs. However, in the majority
of cases, constitutional symptoms and abnormal physical findings
including extramedullary abnormalities, such as myeloblastomas,
eventually develop.3
Experts differ on the best treatment for patients in the chronic phase
of CML. Options include busulfan (BUS), hydroxyurea (HU), interferon
(IFN)-based regimens, or bone marrow transplantation (BMT). Until a few
years ago, allogeneic BMT was the treatment of choice for all eligible
patients, because it was the only treatment that appeared to change the
natural course of the disease. Therefore, randomized studies comparing
transplantation to chemotherapy (BUS, HU) were not feasible, and
follow-up reports of observational studies were not deemed necessary.
Currently, this situation has changed because IFN-based regimens have
also influenced the natural course of CML by also prolonging survival.
In 1996, the American Society of Hematology convened an Expert Panel on
Chronic Myeloid Leukemia to review and document the strength of the
evidence regarding the benefits and harms of each option and to
determine whether evidence-based treatment recommendations could be
developed. This report summarizes the Panel's evidence review and recommendations.
Panel Composition
Scope of Review
Target condition. CML was considered present only with evidence of the Ph+ chromosome and/or chimeric bcr/abl gene. Excluded were bcr-abl-negative and Ph-negative disease, juvenile CML, chronic myelomonocytic leukemia, chronic neutrophilic leukemia, chronic eosinophilic leukemia or hypereosinophilic syndrome, and Ph+ acute leukemia. Outcomes of interest. Life expectancy (survival rate) was the primary measure for defining treatment efficacy. Relevant intermediate outcomes included evidence of hematologic or cytogenetic remission (as defined below), but these parameters were considered less persuasive than survival. Potential adverse effects of treatment were considered for each option. Treatment costs, although a measure of great importance,4 were not analyzed because of lack of adequate data. Relevant evidence. Relevant evidence addressed the target condition and the efficacy of the treatments listed above in terms of survival and/or hematologic/cytogenetic remission. Admissible evidence included controlled and uncontrolled observational studies, randomized controlled trials, and letters to the editor containing primary data. Excluded studies were those with less than 5 patients in chronic-phase CML, those without English-language text, and those published before 1980. Literature search. A computerized literature search of the MEDLINE database, conducted in 1996, sought all publications in which the text words "chronic myelogenous leukemia" appeared in the title or abstract. This search term was not expanded because an initial list of 2,423 citations was retrieved, of which 960 addressed treatments of interest. Two hundred seven articles met criteria for closer inspection. The core literature assembled from the computerized search was supplemented in 1997 and 1998 with additional relevant articles identified by scanning bibliographic reference lists and by suggestions from panel members and reviewers. This included articles on chronic myeloid, myelogenous, myelocytic, and granulocytic leukemia. Criteria for evaluating quality. Both observational studies and randomized controlled trials were reviewed, but the latter were generally considered a stronger class of evidence. For both categories, the internal validity of studies was judged on the basis of explicit criteria: sample size and statistical power, selection bias, methods for allocation to treatment groups, attrition rate, definition of intervention and outcomes, confounding variables, data collection biases, and statistical methods. External validity was judged in terms of the patients, treatment protocol, and clinical setting examined in the study. The designs, results, and limitations of the studies were assembled systematically in evidence tables (see Tables 2 through 6). Development of recommendations.
Recommendations were evidence-based: this means that treatments could
not be recommended unless the evidence met explicit predetermined
criteria shown in Table 1. When such data
were lacking, the panel generally chose not to make recommendations on
the basis of indirect evidence (eg, uncontrolled observational studies)
or expert opinion.
For many years the principal options for chemotherapy for treating Ph+ CML have included BUS and HU.5,6 The superiority of HU was finally established after a randomized controlled trial compared the agents7 and showed that median survival was significantly shorter for BUS-treated patients than for those treated with HU (45 v 58 months) (P = .008). The 5-year survival rates were 32% and 44%, respectively. A recent meta-analysis of 5 other trials also supports a survival advantage for HU over BUS.8
Initial research involved the use of human leukocyte IFN,11
but subsequent clinical studies have centered on the use of recombinant
human (r) IFN- Observational Studies of rIFN-  therapy
consists of at least 30 uncontrolled observational studies initiated in
the 1980s (Table 2). The largest number of
patients have been followed at the M.D. Anderson Cancer Center
(Houston, TX) in observational studies where the probability of
complete and partial hematologic remission in CML after interferon
therapy is 70% to 80% and 6% to 10%, respectively.13-15
Remission rates reported by other investigators are generally lower and
vary more widely. In studies where only rIFN- is used, the rates of
complete and partial hematologic remissions range from 7% to 81% and
6% to 50%, respectively (Table 2) (the variations in study design preclude accurate calculation of means or medians). Reported rates for
complete and partial cytogenetic remissions range from 0% to
38% and 0% to 16%, respectively (Table 2).
Variations in study populations and response to rIFN-
Problems With Uncontrolled Observational Studies With rIFN-
Randomized Controlled Trials (RCTs) of IFN The most compelling evidence that rIFN- is more efficacious than
chemotherapy comes from 4 prospective, randomized studies (the first 4 studies in Table 4) showing a statistically
significant improvement in survival rates in patients receiving
rIFN-. Five-year survival rates in these RCTs were 50% to 59% for
patients receiving IFN and 29% to 44% for patients receiving BUS or
HU.9,10,22,26
Summary of Benefits With IFN Despite the above-mentioned limitations in the design and conduct of the clinical trials, on balance, the accumulated evidence from RCTs suggests that, compared with BUS or HU, rIFN- improves survival in
chronic-phase patients with favorable features: no or minimal prior
treatment, relatively normal hemoglobin levels and platelet counts,
less than 10% blasts in the blood, and beginning treatment especially
within 6 months of diagnosis when rIFN- is coupled with other agents
(HU or cytarabine). During early chronic phase, the treatment advantage
of rIFN- over chemotherapy is observed with varying magnitude in
patients in each Sokal score (risk) category.43 Patients
who continue rIFN- during chronic phase do better than those who
discontinue therapy. This survival advantage appears to be
statistically significant. Meta-analysis suggests the pooled 5-year
survival rate is 57% for rIFN- and 42% for chemotherapy (P < .0001),8 which results from a delay in the onset of
blast crisis.9,22
Summary of Adverse Effects With rIFN- in CML
(Table 5) comes mainly from retrospective
observational studies. These are compared to those observed in general
clinical experience in Table 5. Reported complication rates vary widely
owing to differences in patient selection and case mix, thoroughness of investigators in measuring side effects, definition of complications (eg, whether acute, subacute or chronic, mild or severe), sample size,
dose and duration of rIFN-, and length of treatment and follow-up.
The efficacy of allogeneic BMT in the treatment of chronic-phase CML
has been evaluated in a number of uncontrolled observational studies
and several prospective studies
(Table 6). Projected actuarial 3-year to 5-year survival rates in these studies range from
38% to 80%, with the higher values reported by experienced centers.
Most studies report values around 50% to 60% and slightly lower
probabilities for disease-free survival (Table 6). Reported relapse
rates within 3 to 5 years are often less than 20% (Table 6). Projected
survival curves appear to plateau (or taper more slowly) after 3 to 7 years, suggesting that allogeneic BMT offers eligible patients
(especially young adults with a genetically HLA-identical sibling
donor) a prospect for cure.
Concerns Regarding Interpretation of BMT Trials Retrospective studies. Most studies are retrospective, lack complete documentation of the clinical characteristics of the patient population, provide few details on methods for patient selection, use varied definitions of relapse, and are not randomized with controls. The largest studies tend to rely on registry data, collected from as many as 80 centers. Although some transplant studies do document inclusion criteria, they provide little additional information to ensure that results for all, rather than only some, patients meeting the criteria were analyzed. Heterogeneous study designs. Comparing outcomes across reports is difficult because of their heterogeneity. Many include patients treated by multiple protocols. Observed outcomes derive from a mixture of highly varied regimens with which clinicians and investigators have experimented over the years, making it unclear to which intervention(s) the outcome can be attributed. Allogeneic BMT is not a specific treatment but rather a general approach encompassing many different preparative regimens, stem cell sources, prophylactic regimens against GVHD, and methods of supportive care, all of which have changed dramatically in recent years. Statistical problems. Estimates of long-term survival are imprecise for statistical reasons. The median duration of follow-up in most BMT studies is either undocumented or less than 3 to 5 years. The multipliers for Kaplan-Meier calculations for patients surviving after BMT (eg, 7 to 10 years) are often drawn from a relatively small sample of patients who have lived that long. As an example, in the study with the longest follow-up (median, 84 months), van Rhee et al57 reported a 54% probability of surviving 8 years. In this study, the multipliers for survival 6 years beyond BMT were taken from only 10% of the original study population (patients who had lived that long and were considered still to be at risk). Estimates based on small numbers introduce imprecision for sample size reasons alone. The 95% confidence intervals for survival rates reveal the imprecision of such intervals which in various studies range from 26% to 86% (Table 6). Lead-time issues.
Survival estimates are also confounded by lead-time issues. Many
patients enter transplant studies well after their diagnosis, often
having tried and failed treatment with rIFN- Concerns Regarding the Comparison of BMT With rIFN- as first-line treatment for chronic-phase
CML. For reasons outlined above, the observed plateau in survival
curves for BMT, to which rIFN- is compared, is somewhat conjectural
without longer periods of follow-up. Moreover, even if the accuracy of
such curves is accepted, there is little direct evidence of how they
differ from those of comparable patients treated with rIFN-.
Survival curves for BMT show that at least half of patients remain
alive 5 to 10 years after treatment, whereas similar curves for
rIFN- show a continuous relapse rate over time, with the curves
crossing (yielding a survival advantage to BMT) at about 7 to 8 years.
This pattern is frequently cited as evidence that BMT cures CML.
Cytogenetic and Molecular Evaluation Although as noted, RT-PCR negativity has been reported in patients in long-term cytogenetic remission after rIFN- therapy,32 cytogenetic and molecular remissions are substantially more common after BMT. Molecular studies, however, show that an appreciable subset
of patients who appear to be in complete cytogenetic remission after
BMT harbor RT-PCR evidence of the bcr-abl chimeric
gene,57,59-64 which may portend an increased risk of
relapse.65 Although these data are consistent with the view
that BMT offers the best chance of cure, it is difficult to rely on
these findings to prove a survival advantage given current
uncertainties about the link between such responses and long-term
survival. In this regard, the documentation of RT-PCR positivity
for bcr-abl chimerism in presumably normal adult marrow is of
significance.66,67 Moreover, it has been suggested that
although there is a small probability that conventional RT-PCR assays
will detect "innocent" bcr-abl genes it is conceivable
that they may be the source of sporadically positive tests in leukemia
patients in long-term remission.67
Unlikely Resolution of BMT Versus IFN-Based Therapy Ideally, the best strategy for overcoming these methodologic concerns and for providing definitive evidence of benefit is to compare survival rates in a cohort of chronic-phase patients in an RCT that randomly allocates patients to receive either BMT or nontransplant therapy, a study not performed to date. The performance of such a trial, however, would be difficult in these times. Current worldwide practice indicates that clinicians would be reluctant not to offer BMT to eligible patients, and a large number of participants might be necessary to achieve the necessary statistical power to show an effect. In the absence of such evidence, there is no firm scientific basis from this evidence-based analysis for asserting that treating CML with one modality is of proven superiority over the other, and debates about the quality of the existing evidence for comparing BMT with IFN therapy will persist.Potential Harms of BMT Assuming that BMT is proven to increase the chances of survival in comparison to rIFN-, the magnitude of the incremental increase in
benefit must be weighed against the potential of serious harms and even
death that may accompany the procedure, especially in the short term.
Death rate.
The reported probability that the patient will die as a result of BMT
(transplant-related mortality) ranges from 20% to 41% (Table 7). Studies that included patients
treated in the 1980s or those who received marrow from mismatched or
unrelated donors report rates as high as 53% to 68% in certain
subgroups. On the other hand, one center has reported rates as low as
15% among patients treated in recent years with marrow from matched
siblings and receiving modern regimens for the prevention of
opportunistic infections and GVHD.68
Preparatory regimen. The preparatory regimen produces toxic effects in virtually all patients.69 Severe oral mucositis is reported in about half of patients.70 GVHD. BMT is often followed by GVHD, opportunistic infections, or other complications. Between 8% and 63% of patients experience grade II-IV acute GVHD, a possible determinant of survival72,73 and the cause of death for 2% to 13% of patients undergoing BMT (Table 7). (Some studies suggest that GVHD has an antileukemic effect and improves survival.57,73,74) The rates for chronic GVHD are 4% to 75%, with 8% to 10% mortality (Table 7). Similar findings have been reported in studies that included patients with both CML and other leukemias.75,76 Interstitial pneumonitis, veno-occlusive disease, and secondary malignancies. Between 4% and 32% of chronic-phase patients undergoing BMT die of interstitial pneumonitis, 3% to 24% die of other infections, and 1% to 4% die of hepatic veno-occlusive disease (Table 7). Long-term complications can include second malignancies,77,78 cataracts,79 and infertility. Variables Likely to Improve BMT Outcomes The accumulated evidence, confirmed by multivariate analysis, highlights key prognostic variables that are more likely to improve the outcome of BMT and improve the tradeoff between benefits and harms. Above age 20 years, the inverse relationship between age and survival appears to be continuous. Most studies suggest that patients under age 30 years have higher overall and disease-free survival and lower transplant-related mortality than patients over age 30.80-84 At certain centers using modern methods of GVHD prophylaxis, the influence of age on outcome appears to be relatively small.85 Most data suggest that instituting BMT within 1 to 2 years of diagnosis results in higher survival rates than BMT after 2 years,57,71,86 although early studies did not support this relationship.72,87 (The observed association between duration of disease and survival noted by van Rhee et al57 lost statistical significance after multivariate analysis.) Recipients of bone marrow from an HLA-matched unrelated donor generally have lower survival and are more likely to develop GVHD than those who receive a marrow transplant from an HLA-matched sibling or other relative.88,89 At one experienced center, however, survival rates after transplantation of matched unrelated donors are approaching those of matched siblings.90 Moreover, modern methods of genomic typing of class I HLA alleles adds substantially to the success of transplantation from unrelated donors.91Conditioning and pretransplant treatment regimens.
Studies have produced conflicting results regarding the optimal
conditioning regimen and protocol for reducing the risk of GVHD.
Patients who receive BUS before BMT tend to have lower survival rates
than those who receive HU.83,86 T-cell depletion reduces the risk of GVHD, but it increases the risk of relapse and lowers survival.72,82,87,92 Observational studies have produced conflicting results regarding the potential adverse effects of prior
treatment with rIFN-
Every available option for the treatment of chronic-phase
CML involves tradeoffs between benefits and harms. Which choice is best
depends on objective clinical variables that influence probabilities (eg, patient age, stage of disease, co-morbid conditions, intensity of treatment) and on subjective variables related to personal preferences. Two patients faced with the same options of
chemotherapy, rIFN-
IFN (1) Based on evidence from randomized controlled trials, patients with good prognostic factors in the early stage of chronic-phase CML should be offered rIFN-, perhaps with added chemotherapy (eg, HU or Ara-C)
to achieve the highest probability of survival. This recommendation
applies to newly diagnosed patients in chronic phase who do not suffer
from other serious conditions that limit life expectancy or
contraindicate the use of rIFN-.
Allogeneic BMT (1) If physicians and patients require evidence of benefit from BMT from randomized controlled studies to determine treatment preferences, then evidence to make such a recommendation is lacking. Randomized prospective studies with internal controls have not been conducted to show whether allogeneic BMT, either as first-line treatment or after initial treatment with chemotherapy or rIFN-, achieves longer
survival than nontransplant therapy. Uncontrolled observational studies
do report higher long-term survival rates with allogeneic BMT after
chemotherapy compared with those typically seen in patients treated
only with nontransplant approaches, and BMT appears to offer a greater
chance of long-term remission. It is uncertain to what extent these
results are due to selection biases and the analytic methods used.
Moreover, whether they can be generalized to normal practice conditions
is uncertain. Further, BMT is associated with a high risk of immediate
complications and transplant-related mortality that can offset the
benefits of treatment, especially in the short term. For physicians and patients who are comfortable accepting evidence from uncontrolled observational studies which suggest that allogeneic BMT is more effective than nontransplant approaches and who are interested in
considering transplantation, the following recommendations are offered:
Choosing the best treatment option for an individual patient requires an orderly consideration of several issues. The limitations of current evidence and issues of patient variability make it inappropriate to propose an algorithm specifying the choices that should be made at each step in the process. However, the logical sequence of decisions that must be made by the physician and patient is clear:
The recommendations contained in this analysis describe a range of approaches to the management of CML. These recommendations are not intended to serve as inflexible rules, and they are not inclusive of all proper methods of care or other methods of care that may achieve similar results. Adherence to the recommendations will not ensure a successful outcome in every case. The ultimate judgement regarding the care of a particular patient should be made by the physician in light of the clinical data and circumstances presented by the patient and the treatment options available.
We acknowledge with thanks the administrative assistance of the members of the Optimization Committee (ASH) and especially its Chairperson, James P. George, MD, and Maurice Mayrides and Martha Liggett of the Administrative Staff of ASH, and Olga Brandenberger, administrative secretary to RTS.
Submitted July 30, 1998; accepted June 2, 1999.
Adopted by the Executive Committee of the American Society of Hematology, July 1999.
Presented in part at the Education Session of the American Society of Hematology, December 5, 1998, Miami Beach, FL. Address reprint requests to Richard T. Silver, MD, Division of Hematology-Oncology, the New York Presbyterian Hospital-Weill Medical College of Cornell University, 525 E 68th St, New York, NY 10021.
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F. Bonifazi, A. de Vivo, G. Rosti, F. Guilhot, J. Guilhot, E. Trabacchi, R. Hehlmann, A. Hochhaus, P. C. A. Shepherd, J. L. Steegmann, et al. Chronic myeloid leukemia and interferon-alpha : a study of complete cytogenetic responders Blood, November 15, 2001; 98(10): 3074 - 3081. [Abstract] [Full Text] [PDF]
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J. N. George, S. H. Woolf, and G. E. Raskob The Evidence-Based Analysis of Treatment for Chronic Myeloid Leukemia: An Introduction to Its Methods and Clinical Implications Blood, September 1, 1999; 94(5): 1515 - 1516. [Full Text] [PDF]
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TOP
ABSTRACT
INTRODUCTION
(rIFN-
has been shown to be
relatively ineffective for CML
a median of about 20 months on average