6

Natural history and staging of chronic myelogenous leukaemia

JORGE CORTES MD Assistant Professor of Medicine, Leukemia Section, Department of Hematology

H A G O P M. KANTARJIAN MD Professor of Medicine, Chief, Leukemia Section, Department of Hematology

SERGIO GIRALT MD Assistant Professor of Medicine, Bone Marrow Transplant Section, Department of Hematology

M O S H E TALPAZ MD Professor of Medicine, Chairman, Department of Bioimmunotherapy

The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77O30, USA

The natural history of chronic myelogenous leukaemia has changed in recent years, partly as a result of earlier diagnosis but mostly as a consequence of the availability of effective therapies that have the potential to eradicate the Philadelphia-positive clone. The prog- nostic models designed in the pre-interferon-~ (IFN-ot) era based on clinical characteris- tics of the disease are still useful in identifying different risk groups after treatment with IFN-tx, but achieving a cytogenetic response with IFN-ct is now the most important prog- nostic factor for survival. The significance of other molecular and biological variables remains to be determined.

Key words: chronic myoloid leukaemia; stage; prognosis; interferon; cytogenetic response.

Chronic myelogenous leukemia (CML), a clonal myeloproliferative disorder, results from the neoplastic transformation of the primitive haemo- poietic stem cell (Fialkow et al, 1977). The disease is characterized by the presence of a balanced translocation between the long arms of chromosomes 9 and 22, t(9;22)(q34;qll), referred to as the Philadelphia (Ph) chromosome. This abnormality is present in over 90% of patients with CML, and 30-50% of those without cytogenetic evidence of the Ph chromosome have molecular evidence of this rearrangement (Kurzrock et al, 1988). Despite the constant Ph-related molecular events in CML, the

Bailli~re ~ Clinical Haematology-- 277 Vol. 10, No. 2, June 1997 Copyright © 1997, by Baillifre Tindall ISBN 0-7020-2343-4 All rights of reproduction in any form reserved 0950-3536/97/020277 + 14 $12.00/00

278 J. CORTES ET AL

disease is heterogeneous in its presentation and course. The incidence of CML has remained relatively constant over the past 50 years (Call et al, 1994): it accounts for 6-15% of all adult leukaemias, with approximately 1-1.5 cases diagnosed per 100 000 population (Morrison, 1994). However, the clinical characteristics, therapy and prognosis have changed signifi- cantly over the last few decades. Also, the availability of more effective therapy, including interferon a (IFN-a) and bone marrow transplantation (BMT), has changed the natural history of the disease and underscored the prognostic significance of certain clinical variables and, more recently, of molecular and other biological features.

NATURAL HISTORY

Although CML occurs in all age groups, less than 10% of cases occur in patients under 20 years of age. The median age at diagnosis of patients with CML is 55--60 years. In recent years, a slight decrease in the percentage of patients older than 60 years of age at M.D. Anderson Cancer Center was noted, from 16% before 1983 to 13% since 1983 (P=0.15). There is a slight male predominance with a male-to-female ratio of 1.4:1-2.2:1, but the clinical course is similar in both genders (Cortes et al, 1996b).

The natural history of CML is characterized by a biphasic, and some- times a triphasic, course. The disease is usually diagnosed in the chronic phase which, if treated with conventional chemotherapy (i.e. busulphan or hydroxyurea), has a median duration of 37-47 months (Hehlmann et al, 1993). After this time, the disease evolves into a blastic phase, which is sometimes preceded by an intermediate or accelerated phase. This natural history is essentially identical to that of untreated patients or those treated with radiotherapy to the spleen. Minot et al (1924) reported a series of 166 patients with CML. The average survival of untreated patients was 3.1 years compared with 3.5 years for patients treated with radiotherapy (Minot et al, 1924). They also identified the progression of the disease from a stable phase to an accelerated phase with progressive resistance to radio- therapy. The median survival of patients treated with busulphan or hydroxyurea has varied from 36 months to 65 months. In contrast, the median chronic-phase duration in patients treated with IFN-~x is about 72 months, with a median survival of 66-89 months (Hehlmann et al, 1994; Italian Cooperative Study Group on Chronic Myeloid Leukemia, 1994; Kantarjian et al, 1995). BMT offers the possibility of cure in CML, and 4 year survival probabilities as high as 86% have been reported (Cliff et al, 1994). However, the selection criteria for this treatment option make it difficult to assess the impact of BMT on the natural history of CML as a whole.

The presenting characteristics in chronic phase are variable, and include easy fatigability, left upper-quadrant abdominal discomfort, early satiety, anorexia and weight loss. Patients are frequently asymptomatic and diagnosed after a routine medical examination, and the incidence of asymptomatic presentation has increased recently, from 18% before 1983

NATURAL HISTORY AND STAGING 279

to nearly 40% after 1983. This is a result of widespread routine blood testing. The frequency of features of increased tumour burden found at diagnosis has also decreased as shown in Table 1, particularly for the incidence of splenomegaly, leukocytosis, thrombocytosis, anaemia and blastosis.

Table 1. Change in clinical characteristics of patients with chronic myelogenous leukaemia chronic phase.

Percentage with characteristics

Characteristics Category Before 1983 (N=305) Since 1983 (N= 1120) P value

Age (years) > 60 16 13 0.15 Asymptomatic Yes 18 37 < 0.001 Hepatomegaly Yes 45 13 < 0.001 Splenomegaly Yes 74 50 < 0.001 Haemoglobin (g/dl) < 12 58 45 < 0.001 WBC count (x109/1) _> 100 68 53 <0.001 Platelets (×1 &/l) > 700 24 18 0.022 Peripheral blasts Yes 63 52 0.002 Peripheral basophils (%) > 7 14 13 0.794 Marrow blasts (%) _> 5 12 7 0.004 Marrow basophils (%) > 3 35 29 0.03

WBC, white blood cell.

Earlier diagnosis might be changing the natural history of CML through detection of disease less aggressive and hence more responsive to effective therapies (i.e. IFN-ct and BMT). These regimens yield significantly better results when applied earlier (e.g. within the first 12 months from diagnosis). However, when patients with similar CML stages are treated with IFN-cz or chemotherapy in randomized studies, there is prolongation of the time to transformation (72 months versus 45 months, P<0.001) and of median survival (72 months versus 52 months, P=0.002) (Italian Cooperative Study Group on Chronic Myeloid Leukemia, 1994) with IFN-o~ therapy compared with conventional chemotherapy. This suggests that improved treatment may translate into a change in the natural history of CML. Furthermore, complete cytogenetic remissions may be durable, and 90% of patients who achieve a major cytogenetic response with IFN-ct therapy are alive at 5 years (Kantarjian et al, 1995). The probability of survival at 3 years after BMT is 80%, also reaching a plateau at this point (Clift et al, 1994). Such a plateau in the survival curve of patients with CML with effective therapy is a new feature of the natural history of the disease and dependent on therapeutic interventions.

The final phase of CML or blastic phase is characterized by the presence of at least 30% of blasts in the peripheral blood or bone marrow, or the presence of extramedullary blastic disease. The blastic transformation is of myeloid lineage in approximately 50% of the cases, of lymphoid lineage in 25% and of undifferentiated lineage in 25%. Although it was initially thought that IFN-ct therapy in chronic phase may affect the incidence of selective blastic transformations, the proportion of patients evolving to a

280 J. CORTES ET AL

lymphoid blastic phase has not changed in the IFN-o~ era (Derderian et al, 1993). The blastic phase is usually fatal, with a median survival of 3-9 months. Patients with lymphoid blastic phase have a better complete remission rate after induction chemotherapy (49%) and a longer median survival (9 months) than patients with myeloid or undifferentiated blastic phases (complete remission rate 12-19%, median survival 3 months).

The accelerated phase is a poorly defined stage of CML which represents a transitional phase between the chronic and blastic phases. From 15% to 20% of patients evolve to a blastic phase without going through an accelerated phase. There is no universally accepted definition for this phase of the disease. Based on a multivariate analysis of emerging risk factors predictive for death within 18 months, we proposed a definition which includes at least one of the following criteria: (1) > 15% peripheral blasts, (2) > 30% peripheral blasts and promyelocytes, (3) > 20% peripheral basophils, (4) platelet count <100x 109/1 unrelated to therapy and (5) cytogenetic clonal evolution (Kantarjian et al, 1990). The effect of cytogenetic clonal evolution on survival was later found to be heterogeneous and dependent on the specific chromosomal abnormality, the time to development of clonal evolution, the presence of other accelerated features and the percentage of affected metaphases. Based on these criteria, a favourable risk group can be defined which includes patients with no chromosome 17 abnormalities, < 16% abnormal metaphases and time to clonal evolution < 24 months; they have an estimated median survival of 54 months. Two poor-risk groups include patients with (1) chromosome 17 abnormalities and > 36% abnormal metaphases or (2) other accelerated features and >16% abnormal metaphases. Patients in the poor-risk groups have a median survival of 6-7 months. Patients who are in neither the good- nor the poor-risk groups have a median survival range of 13-24 months (Majlis et al, 1996).

STAGING

The course of patients with CML is heterogeneous. Even occasional patients treated in chronic phase with conventional chemotherapy may have very long times to transformation. On the other hand, approximately 25% of patients will have a fatal outcome within 2 years from diagnosis, and another 25% remain alive beyond 5 years after diagnosis. Several investigators have analysed by univariate and multivariate analyses the pre- treatment host and disease characteristics and the therapy-associated prognostic factors that may predict for differences in prognosis. The characterization of patients into risk groups based on the knowledge of prognostic factors is critical for the evaluation of clinical trials and of the effect of new regimens overall and within risk groups.

The pre-interferon era

Several characteristics have been associated with prognosis in different studies of patients with CML by univariate analysis (Table 2). Some factors

NATURAL HISTORY AND STAGING 281

such as age, spleen size, platelet count and percentage of blasts and basophils in the bone marrow or peripheral blood have been identified in most series. Others, such as race or the presence of nucleated red blood cells, have been suggested occasionally. However, the characteristics of study groups, cut-offs for different subsets and variables included in the analyses of the results were different, making comparisons difficult.

Table 2. Variables with proposed prognostic significance in patients with chronic myelogenous leukaemia.

Clinical characteristics Symptoms at diagnosis Age Race Spleen size Liver size Haemoglobin level WBC count Platelet count Nucleated red blood cells in peripheral blood Percentage of blasts in peripheral blood or bone marrow Percentage of basophils in peripheral blood or bone marrow Percentage of promyelocytes + myelocytes in peripheral blood Percentage of eosinophils in peripheral blood

Biological and molecular variables Breakpoint site in the BCR gene Expression of the ABL-BCR gene Expression of interferon-stimulated genes Serum levels of interleukin- 1 ~ and interleukin-1 receptor antagonist Serum levels of tumour necrosis factor Natural killer and lymphocyte-activated killer activity Human leukocyte antigen (HLA) phenotype Ph chromosome negative cells in long-term bone marrow culture

Prognostic models have been proposed that categorize patients into different risk groups, which can assist in planning and evaluating therapy. Four models derived from large population studies are presented in Table 3. The earlier models proposed by Tura et al (1981) and Cervantes and Rozman (1982) were based on the number of adverse prognostic features and identified three stages or risk groups with significantly different survival times. Sokal et al (1984) and Kantarjian et al (1985) later proposed alternative systems based on multivariate analyses and the calculation of the hazard ratio by solving regression equations. Patients were grouped into low-, intermediate- or high-risk groups with median survival of 53-60 months, 39 months and 25-32 months, respectively (Sokal et al, 1984; Kantarjian et al, 1985) (Table 3).

All these models have limitations such as the inclusion of population- specific prognostic factors that may not pertain to other populations or to CML patients in general, and the exclusion of unusual but potentially major prognostic factors. The Sokal model is now extensively used in clinical research studies.

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NATURAL HISTORY AND STAGING 283

A model has been proposed that includes variables consistently proven to be of prognostic significance in other models and incorporates them into a simple synthesis staging system (Kantarjian et al, 1990). This model (Table 4) includes five prognostic variables, and patients are categorized based on the number of variables into three stages. Another characteristic of this model is the inclusion of criteria for accelerated phase (stage 4) which identify a separate category of patients with very poor short-term prognosis. The median survivals of patients in these stages in the initial report were 56, 45, 30 and 30 months, respectively. Patients with stage 4 had a median survival of 30 months but a 1 year survival rate of 71% compared with 91% for patients in stage 3 (Kantarjian et al, 1990).

Table 4. Synthesis staging system.

Phase Clinical characteristics Stage Definition

Chronic Age >60 years 1 Spleen > 10cm BCM Blasts _> 3% in blood or > 5% in marrow 2 Basophils >7% in blood or _>3% in marrow Platelets > 700 x 109/1 3

Cytogenetic clonal evolution 4 Blasts >_ 15% in blood Blasts + promyelocytes > 30% in blood Basophils -> 20% in blood Platelets < 100 x 10"/1

Accelerated

0 or 1 characteristic

2 characteristics

_> 3 characteristics

_> 1 characteristic defines accelerated phase (regardless of characteristics for chronic phase)

In an analysis of factors that predict for long-term survival in patients with CML (i.e. longer than 8 years), age, the percentage of peripheral blasts, spleen size and platelet count were associated with long-term survival in a multivariate analysis. There was a significant association between Sokal's risk subgroups and survival, with 24% of patients in the low-risk group surviving longer than 8 years compared with only 12% and 2% in the intermediate- and high-risk groups (P < 0.0001). However, the positive predictive value for long-term survival was not higher than 30% as most patients in the low-risk group died before 8 years (Cervantes et al, 1994).

Although these models may be predictive in specific populations, they may not have universal applicability. For example, when the Sokal model was applied to a population from M.D. Anderson Cancer Center, no clear difference in prognosis could be identified between patients in the inter- mediate- and high-risk groups (Kantarjian et al, 1985). In a recent Japanese trial, the Sokal model did not separate patients treated with busulphan into groups with significantly different outcomes (Ohnishi et al, 1995). The same is true for Kantarjian's model applied to a German population, where overlap was reported between stage 1 and stage 4 (Hasford et al, 1996).

284 J. C O R T E S ET AL

The post-interferon era

IFN-~ has been used to treat patients with CML since the 1980s. Overall, complete haematological remissions can be achieved in 60-80% of patients treated in early chronic phase and cytogenetic remissions in 35-55% (Kantarjian et al, 1996). From 20% to 25% of the patients achieve a complete cytogenetic remission (i.e. 0% Ph-positive metaphases) and 10-15% a partial cytogenetic remission (i.e. 1-34% Ph-positive metaphases). Thus, a major cytogenetic response is achieved in 30-40% of patients (Kantarjian et al, 1996). Over 80% of major cytogenetic responses are durable for periods ranging from 2 to 8 years (Kantarjian et al, 1996). Treatment with IFN-~ has resulted in prolonged time to progression of the disease as well as prolonged survival. IFN-~ therapy is associated with significantly more toxicity than conventional chemotherapy. In 15-20% of patients, IFN-~ has to be discontinued because of toxicity, and another 30-50% of patients require dose reductions for toxicity. It is therefore desirable to identify patients who are more likely to benefit from IFN-c~ prior to starting therapy or early during IFN-et therapy.

Several characteristics have been associated with prolonged survival after IFN-ct therapy. These include higher haemoglobin level, low percent- age of peripheral blasts, normal platelet count, small spleen size at diag- nosis and low percentage of marrow basophils (Italian Cooperative Study Group on Chronic Myeloid Leukemia, 1994; Kantarjian et al, 1995). Risk groups according to Sokal's model or to the synthesis staging system are strong predictors of survival in some large series (Hehlmann et al, 1994; Italian Cooperative Study Group on Chronic Myeloid Leukemia, 1994; Kantarjian et al, 1995). The group from M.D. Anderson Cancer Center (Kantarjian et al, 1995) reported median survivals of 102, 95 and 62 months, respectively, for the low-, intermediate- and high-risk groups according to the synthesis model (P<0.01) and 104, 90 and 62 months, respectively, according to the Sokal classification (P = 0.10). Some studies have questioned the predictive efficacy of these models in IFN-ct-treated CML patients. The Japanese series found no association of Sokal's index with survival in patients treated with IFN-t~, but no association was found in the chemotherapy-treated arm either (Ohnishi et al, 1995). Similar negative results were reported by the Cancer and Leukemia Group B (CALGB) (Ozer et al, 1993). A trial from the UK Medical Research Council found similar 5 year survival rates for the low- and intermediate- risk groups both in the IFN-~-treated group (66% and 63%, respectively) and in the control group (36% and 39%). In the German trial (Hehlmann et al, 1994), the Sokal model was also unable to differentiate between the low- and intermediate-risk groups and, in a recent analysis of a subgroup of patients, neither the Sokal nor the synthesis model was able to separate patients into statistically significant different prognostic groups. Based on the results of the German trial, Hasford et al (1996) have proposed a new staging system for CML patients treated with IFN-t~ which includes the percentage of peripheral eosinophils and erythroblasts and the presence of extramedullary disease. Based on the presence or absence of these factors

NATURAL HISTORY AND STAGING 285

(0, 1 or > 1 factor), they proposed three risk groups with significantly different outcomes. This model has not been validated in other series.

Treatment with IFN-o~ induces cytogenetic remissions in a significant number of patients. Several trials have demonstrated that achieving a major cytogenetic response is a significant favourable prognostic feature for survival by landmark analysis (Kloke et al, 1993; Italian Cooperative Study Group on Chronic Myeloid Leukemia, 1994; Mahon et al, 1994; Allan et al, 1995; Kantarjian et al, 1995). Achieving a minor cytogenetic response may still have a favourable impact on survival compared with no response or treatment with conventional chemotherapy (Allan et al, 1995; Kantarjian et al, 1995; Ohnishi et al, 1995). Some studies have not found an association between achievement of a major cytogenetic response and survival (Ozer et al, 1993; Hehlmann et al, 1994), but these studies had small numbers of patients with major cytogenetic response, which may account for the lack of favourable effect. Cytogenetic response has a favourable impact on survival within each risk group. In both the M.D. Anderson Cancer Center experience (Kantarjian et al, 1995) and the Italian experience (Italian Cooperative Study Group on Chronic Myeloid Leukemia, 1994), cytogenetic response resulted in prolonged survival in each risk group whether determined by the Sokal model (Italian Cooperative Study Group on Chronic Myeloid Leukemia, 1994) or the synthesis model (Kantarjian et al, 1995) (Table 5). In a multivariate analysis including major cytogenetic response as a time-dependent variable, achievement of such a response was independently associated with prolonged survival (Italian Cooperative Study Group on Chronic Myeloid Leukemia, 1994; Kantarjian et al, 1995). Cytogenetic response was also associated with improved duration of chronic phase (Ohnishi et al, 1995). Therefore, achievement of a cytogenetic response might be the most important prognostic feature for CML patients treated with IFN-ct.

Because achieving a cytogenetic response is important, variables predictive for achieving this response have been investigated. Character- istics associated with better cytogenetic response include good perform- ance status, absence of symptoms at diagnosis, small spleen size, high haemoglobin level, low leukocyte count, normal platelet count and low peripheral blast percentage (Italian Cooperative Study Group on Chronic

Table 5. Association between stage, cytogenetic response and survival in chronic myelogenous leukaemia patients treated with interferon ct (Kantarjian et al, 1995).

Estimated survival (%) at 4 years by cytogenetic response*

Major cytogenetic Median survival Stage N response (%) (months) Yes No P value

1 149 48 102 79 62 <0.01 2 57 32 95 82 35 <0.01

3 35 20 62 ~ 83 39 <0.01 4 10 0 41 J

* Based on cytogenetic response at 12 months. Evaluable patients: stage 1,141; stage 2, 56; stage 3 or 4, 40.

286 J. CORTES ET AL

Myeloid Leukemia, 1994; Mahon et al, 1994; Kantarjian et al, 1995). Interestingly, age has not emerged as an adverse prognostic variable, and major cytogenetic responses have been reported in 26% of patients 60 years and older, albeit with more toxicity (Cortes et al, 1996a). The CML risk groups have also been associated with cytogenetic response. Depending on the scoring system used, a major cytogenetic response has been reported in 46-52% of patients in the low-risk, 32-38% in the intermediate-risk and 14-26% in the poor-risk categories (Kantarjian et al, 1995). However, the difference in the incidence of cytogenetic response among the three risk groups is not as clear in other studies (Allan et al, 1995). In a multivariate analysis, risk group was not statistically associated with cytogenetic response, and low percentage of peripheral blasts was the most significant prognostic factor (Italian Cooperative Study Group on Chronic Myeloid Leukemia, 1994).

Treatment-related factors have prognostic significance for response to IFN-~ therapy. The in vivo response to IFN-~ is a strong indicator of outcome. Patients who achieve a complete haematological response by 3-8 months from the start of IFN-a treatment have a significantly higher cytogenetic response rate. Patients with a complete haematological response within 3 months have a major cytogenetic response rate of 82% compared with 29% when such a response is not achieved (Mahon et al, 1994). In the Italian study, 50% of patients who were in haematological response at 8 months achieved a cytogenetic response, compared with only 15% if no haematological response had been achieved (Italian Cooperative Study Group on Chronic Myeloid Leukemia, 1994). Achieving a cyto- genetic response by 12 months from start of therapy (Kantarjian et al, 1995) was associated with a statistically better outcome. The time from diagnosis to treatment with IFN-o~ is also a significant prognostic factor for response. Patients in late chronic phase (i.e. more than 12 months from diagnosis) have a poor response to IFN-~: 50-60% achieve a complete haemato- logical response, but only 10-20% achieve some cytogenetic response (Kantarjian et al, 1993). There may also be a dose-response effect with IFN-c~ therapy. The studies with the best cytogenetic response to IFN-~ have consistently used a dose of 5 MU/m 2 daily (Mahon et al, 1994; Kantarjian et al, 1995). Although lower doses have been shown to be effective in some patients (Schofield et al, 1994), studies with lower cyto- genetic response rates have used lower doses of IFN-o~ (Ozer et al, 1993; Hehlmann et al, 1994; Allan et al, 1995). Definitive confirmation requires further investigation in comparative trials, and further discussion is provided elsewhere in this volume.

Biological and molecular variables with prognostic significance

Advances have been made in the understanding of the molecular mech- anisms of CML as well as of some of the mechanisms involved in the anti- leukaemic effect of IFN-~ and BMT. This has opened an opportunity to investigate the prognostic significance of biological variables that could better predict for response and/or survival. Although many results are

NATURAL HISTORY AND STAGING 287

preliminary and require further confirmation in the context of multivariate analyses, some of these features deserve discussion.

Breakpoint within the breakpoint cluster region

The breakpoint site in the BCR gene can occur between exons b3 and b4 or between exons b2 and b3. This results in two different fusion genes joining exon 2 of the ABL gene with either exon 2 of BCR (b2a2) or exon 3 of BCR (b3a2). Several groups have investigated the prognostic significance of the breakpoint site in CML patients treated with IFN-~ with controversial results (Mills et al, 1991). An association between a breakpoint in the 5' portion of BCR and longer duration of chronic phase (Eisenberg et al, 1988; Mills et al, 1988) and possibly response to IFN-~ (Inoue et al, 1992) has been suggested. Recent reports in large study groups have not confirmed these observations (Italian Cooperative Study Group on Chronic Myeloid Leukemia, 1995; Verschraegen et al, 1995).

Interferon-stimulated genes

The mechanism of action of IFN-~ in CML is not clearly understood. The expression of a number of genes, commonly known as interferon- stimulated genes, can be induced by interferons in different cells. It has been suggested that antiproliferative properties of IFN-~ in CML cells may be mediated via these genes. This stimulated interest in identifying defects in the induction of some of these genes in patients refractory to IFN-c~, but no clear correlation with response to IFN-c~ has been identified (Clauss et al, 1990; Talpaz et al, 1992; Fischer et al, 1996). Several additional candidate genes have not been investigated, and this remains an area of considerable interest.

Cytokine expression

Several cytokines have been associated with prognosis in CML. High levels of interleukin-1 [3 have been associated with transformed disease and short survival (Wetzler et al, 1994). Serum levels of tumour necrosis factor have been reported elevated in CML patients refractory to IFN-~ therapy (Hermann et al, 1992).

Other biological markers

Meseri et al (1993) reported a high natural killer or lymphokine-activated killer cytoloxicity in CML patients with a major cytogenetic response to IFN-~ compared with normal controls and non-responding patients and hypothesized a possible role of immune mechanisms in the effect of IFN-~ in patients with CML. Approximately 5% of CML patients develop auto- immune complications on IFN-~ therapy including hypothyroidism, haemolytic anaemia, thrombocytopenia, Raynaud's phenomena, arthritis, lupus erythematosus and cardiac problems. Interestingly, 91% of patients

288 J. CORTES ET AL

with immune-mediated hypothyroidism and 73% with connective tissue disorders achieve some degree of cytogenetic response (Sacchi et al, 1995). There is currently increased interest in the immune mechanisms that participate in eradicating CML after treatment with IFN-o~ or BMT, and p210 ~cR-~r has been proposed as a potential target for immune mechanisms. p210 ~cR-A~L or related peptides could bind to HLA molecules on the surface of malignant cells and trigger an immune response specific against leukaemic cells (Barrett and Jiang, 1992). A recent report has suggested that an association exists between certain HLA phenotypes, most notably HLA- B27, and response to IFN-ct (Cortes et al, 1995). ABL-BCR mRNA, the reciprocal product of BCR-ABL has been identified in up to 70% of patients with CML, and initial reports have suggested an association with response to IFN-ct (Yin et al, 1995). The presence of Ph-negative metaphases in long-term bone marrow cultures has been suggested as a predictor of response to IFN-ct (Gronthos et al, 1992).

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