Review CHRONIC MYELOGENOUS LEUKAEMIA

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1 British Journal of Haematology, 2000, 111, 993±1009 Review CHRONIC MYELOGENOUS LEUKAEMIA Chronic myelogenous leukaemia (CML) is a rare disease worldwide. However, a consistent stream of basic and clinical advances over the last 40 years have kept CML at the forefront of scientific attention. From the perspective of a laboratory researcher, CML is an ideal disease for studying leukaemogenesis given its association with a consistent genetic lesion. Clinically, CML is a prime example of the evolution of drug therapies in haematologicalal malignancies. Initial observations have been followed by large, well-designed randomized trials that establish standard practice. New agents are showing efficacy in phase II trials. Rationally designed small molecules have entered clinical testing as knowledge gained from the laboratory is brought to the bedside. From a transplanter's perspective, CML is the leading indication for stem cell transplantation with the most extensive breadth and length of experience in the literature. Although thousands of patients have been cured with allografting, there is considerable room for improvement. High treatment-related morbidity and mortality encourage innovative attempts to decrease toxicity and improve long-term disease-free survival. A number of recent excellent reviews of the biology and clinical management of CML have been published (Faderl et al, 1999a, b; Sawyers, 1999; Silver et al, 1999) In order to minimize duplication with these publications, this paper is organized to focus on the trail of discovery leading to contemporary management. An exhaustive description of published studies was avoided in lieu of an interpretation of the literature. Disproportionate attention is allotted to the major areas of clinical controversy facing the field today. Finally, a special effort was made to include interesting, but less well-known, observations. Epidemiology According to the latest US statistics, CML constitutes 14% of all leukaemias. The annual incidence is 1 6 cases per people and for every case of CML, approximately two cases of acute myelogenous leukaemia, three cases of multiple myeloma, 12 cases of non-hodgkin's lymphoma and 37 cases of lung cancer are diagnosed (Greenlee et al, 2000). The incidence of CML increases exponentially with age; the median age at diagnosis is 67 years according to Surveillance, Epidemiology and End Results (SEER) and Scandinavian data, much higher than reported in single institution series (Brincker, 1982; Baranovsky & Myers, 1986; National Cancer Institute, 1997). There is a slight Correspondence: Stephanie J. Lee, Center for Outcomes and Policy Research, Dana-Farber Cancer Institute, 44 Binney Street, Boston, MA 02115, USA. stephanie_lee@dfci.harvard.edu male predominance of 1 4:1. Ionizing radiation in high doses is the only known risk factor (Heyssel et al, 1960; Doll & Smith, 1968). Neither chemical exposure nor genetic predisposition is thought to play any role in the development of CML and patients may be counselled that this disease is neither preventable nor heritable. The Philadelphia chromosome, BCR±ABL fusion gene and p210 tyrosine kinase Most malignancies are diagnosed on the basis of clinical manifestations and histopathology. In contrast, conclusive evidence of CML relies on cytogenetic and molecular studies to detect the t(9;22)(q34;q11) translocation. Currently available diagnostic tests include standard cytogenetics, fluorescence in situ hybridization (FISH), polymerase chain reaction (PCR) and Northern or Southern blot analysis. These methods are associated with levels of detection ranging from 1 in 20 cells to 1 in 10 8 cells. This dramatically different sensitivity for the translocation has contributed to the ongoing controversy regarding the positive and negative predictive power of each test for active disease. In addition, several tests require sophisticated techniques that grew out of laboratory research and are not yet well standardized or commercially available. Most people equate CML with the Philadelphia chromosome and, indeed, approximately 90% of patients will display this abnormality when 20 or 30 cells are evaluated with cytogenetic studies. However, it is not pathognomonic as the Philadelphia chromosome is present in 25±50% of adult patients with acute lymphoblastic leukaemia and 2% with acute myelogenous leukaemia; it is absent in 5% of patients with CML and cryptic translocations detectable only by PCR or FISH. The Philadelphia chromosome (Ph 1 )is so named because it was originally described in Philadelphia and was the first chromosomal abnormality associated with a specific malignancy. Ph 1 refers to the shortened chromosome 22 created by the reciprocal translocation of a large segment of the Ableson proto-oncogene (ABL) from the long arm of chromosome 9 to the breakpoint cluster region gene (BCR) on the long arm of chromosome 22, resulting in a BCR±ABL fusion gene (Rowley, 1973; Heisterkamp et al, 1983, 1985; Gale & Canaani, 1984). Translation of BCR± ABL results in a dysregulated tyrosine kinase that is constituitively active, located in the cytoplasm, classically weighs 210 kilodaltons (p210) and has increased activity over the normal abl protein (p145) (Konopka et al, 1984). Evidence for the central role of the BCR±ABL translocation in the pathogenesis of CML is provided by the observation that transfection into mice results in a disease mimicking q 2000 Blackwell Science Ltd 993

2 Table I. Randomized controlled trials of non-transplant therapy. Reference Medical Research Council's Working Party for Therapeutic Trials in Leukaemia (1968) Medical Research Council's Working Party for Therapeutic Trials in Leukaemia (1983) Years of accrual Arms and number of patients Dosing Results Comments Conclusions 1959±64 Busulphan (48) vs. radiotherapy (54) 1972±79 Early elective splenectomy (83) vs. no splenectomy (86) Hehlmann et al (1993) 1983±91 HU (187) vs. busulphan (184) Hehlmann et al (1994) 1983±94 IFN (133) vs. HU (194) vs. busulphan (186) The Italian Cooperative Study Group on Chronic Myeloid Leukaemia (1994, 1998) 1986±88 IFN (218) vs. conventional chemotherapy (104) Allan et al (1995) 1986±94 IFN (293) vs. chemotherapy (294) The Benelux CML Study Group (1998) Busulphan started at 4 mg qd to maintain WBC /l; radiotherapy (primarily splenic) varied Splenectomy within 6 months of trial entry; all patients also received busulphan to keep WBC 5± /l HU goal WBC 5± /l, busulphan goal WBC 20± /l IFN monotherapy started at /m 2 and discontinued after 4 months if inadequate response or intolerant IFN started at 3 MU qd and escalated to 9 MU qd after 1 month; additional agents could be added after 3 months if no haematological response; 90% of conventional chemotherapy arm received HU, 10% received busulphan WBC goal of 2± /l, start IFN at 3 MU qd and escalate up to 12 MU qd 1987±92 IFN (100) vs. HU (95) Low-dose IFN 3 MU qd, 5 d/wk to keep WBC less than /l Median survival 170 weeks with busulphan, 120 weeks with radiotherapy (P, 0 01) No difference in survival or quality of life (hospitalization, transfusions, bleeding, infections) Median survival 45 months with busulphan, 58 months with HU (P ˆ 0 008) Median survival 5 5 years (IFN), 4 7 years (HU), 3 8 years (busulphan); 7% CR, 2% PR in IFN arm Median survival 76 months (IFN) vs. 52 months (chemotherapy), P ˆ 0 002; 8% CR, 11% PR in IFN arm Median survival 63 months (IFN) vs. 43 months (chemotherapy), P ˆ 0 004; 6% CR, 5% PR in IFN arm Median survival 64 months (IFN) vs. 68 months (HU), P ˆ 0 84; 9% CR, 7% PR in IFN arm Analysed on intention to treat, but both arms received a variety of additional therapies Also measured some quality-of-life parameters Study restricted to symptomatic patients; 26% low-risk Sokal scores Overlap with 1993 report; median follow-up 4 4 years; 27% low-risk Sokal score patients; 25% intolerant of IFN Treatment started within 6 months of diagnosis regardless of symptoms; 43% lowrisk Sokal in IFN group; 16% intolerant of IFN; cost of IFN 200 times that of conventional chemotherapy Started randomized treatment after disease stabilized on physician's choice of agent; 23% low-risk Sokal; 14% intolerant of IFN Median follow-up 51 months; 29% low-risk Sokal, 25% intolerant Busulphan is better than radiotherapy No survival or qualityof-life benefit with early elective splenectomy HU is better than busulphan IFN is better than busulphan, but not statistically different from HU IFN is better than conventional chemotherapy for all Sokal risk groups IFN is better than chemotherapy regardless of cytogenetic response Low-dose IFN is not better than HU 994 Review

3 Review 995 IFN is better than busulphan IFN 1 cytarabine is superior to IFN alone IFN 1 cytarabine is better in Sokal lowrisk patients, but not in intermediate 1 highrisk patients human CML (Daley et al, 1990). However, even this translocation is not pathognomonic as BCR±ABL can be detected in some normal individuals without any manifestations of the disease when extremely sensitive techniques are used (Biernaux et al, 1995). For a summary of the current state of laboratory science, please see recent reviews (Miller, 1998; Verfaillie, 1998; Faderl et al, 1999b). Median follow-up 73 months; 37% low-risk Sokal, 20% intolerant of IFN; only 32% of IFN group remained on therapy at last follow up Median survival 71 months (IFN) vs. 55 months (busulphan) (P ˆ 0 06); 9% CR, 8% PR in IFN arm Ohnishi et al (1995, 1998) 1988±91 IFN (80) vs. busulphan (79) IFN started at 3 MU qd and increased to 9 MU qd with further escalation to keep WBC /l Treatment started within 6 months of diagnosis; 47% low-risk Sokal, 26% intolerant of IFN 1 cytarabine, 27% intolerant of IFN; trial stopped early based on superiority of IFN 1 cytarabine At 3 years, overall survival 86% (IFN 1 cytarabine) vs. 80% (IFN), P ˆ 0 02; 15% CR, 26% PR in IFN 1 cytarabine arm; 9% CR, 15% PR in IFN arm IFN 5 MU/m 2 /d, cytarabine 20 mg/m 2 /d 10 d q month; discontinue cytarabine after 2 consecutive CRs Guilhot et al (1997) 1991±96 IFN (360) vs. IFN 1 cytarabine (361) Reported in abstract form; response rate in IFN-only arm lower than other studies; 50% low-risk Sokal, Mean follow-up 22 months; 7% CR, 10% PR in IFN 1 cytarabine arm; 1% CR, 8% PR in IFN arm Started with HU, then IFN at 3 MU qd and increase to 9 MU qd ^ cytarabine 40 mg/d 10 d q month Tura (1998) 1994±97 IFN (265) vs. IFN 1 cytarabine (275) CHRONIC PHASE Clinical features of chronic phase Three phases of disease activity are recognized in CML: chronic (or stable) phase, accelerated phase and blast crisis. Chronic phase is a diagnosis of exclusion dependent on the absence of aggressive features. Approximately 90% of patients are in chronic phase at diagnosis. In older series, 13±20% were discovered incidentally, but the current percentage may be much higher given the ability of molecular tests to detect subclinical disease (Medical Research Council's Working Party for Therapeutic Trials in Leukaemia, 1968; Kantarjian et al, 1985; Savage et al, 1997; Sawyers, 1999). Patients with chronic phase CML have effective immune systems and generally feel well for prolonged periods. When symptoms and signs are present, they are often mild and related to expansion of CML cells. Common symptoms include fatigue, weight loss, bony aches and discomfort caused by splenomegaly. Chronic phase CML has been described as a benign premalignant state in which 100% transformation is expected (Sokal et al, 1988). This characterization is based on the natural history of CML as the disease is easily managed with outpatient therapy during the early stage. However, after approximately 3±8 years, it transforms to an acute leukaemia that is rapidly fatal. The first 2 years after diagnosis hold the lowest risk for this transformation with only 5±10% of patients developing blast crisis (Sokal et al, 1985, 1988). After 2 years, the annual progression rate increases to 20±25%. Because this rate appears to be constant and continuous, patients surviving beyond 3 years from diagnosis face the same risk for blast crisis each year as they did the previous year. It is also consistent with the terminal transforming event occurring randomly as a firstorder function (Sokal et al, 1988). More than 80% of people diagnosed with CML will eventually die of their disease despite the older age of the affected population (Medical Research Council's Working Party for Therapeutic Trials in Leukaemia, 1968; Kantarjian et al, 1985; Sokal et al, 1985; Hasford et al, 1998). Prognostic features of chronic phase As the chronic phase of CML is so indolent and the terminal stages so fulminant, many investigators have tried to develop prognostic scales to guide patient management. Numerous risk stratification approaches have been published (Tura et al, 1981; Cervantes & Rozman, 1982; Sokal et al, 1984, 1985; Kantarjian et al, 1985, 1990; Ross et al, 1993; Hasford et al, 1996a; Rodriguez et al, 1998). The best known is the Sokal score which was derived from approximately 800 patients treated in the 1960s and

4 996 Review Table II. The effect of disease stage on survival with transplant and non-transplant therapy. Transplantation* Related donor Unrelated donor Disease stage Median survival without transplant Relapse 5±10 years disease-free survival Relapse 5 years disease-free survival Chronic phase 3±8 years 5±15% 40±80% 5±7% 40±70% Accelerated phase 1±1 5 years 10±25% 20±40% 15% 20±40% Blast crisis 4±6 months 25±58% 0±25% 50% 0±5% *Allogeneic bone marrow transplantation using methotrexate/cyclosporin for graft-vs.-host disease prophylaxis. 1970s (Sokal et al, 1984). Many of these patients received therapies not currently in use, such as busulphan, splenectomy and intensive chemotherapy. However, more recent publications confirm the general applicability of the score to modern series of patients. Many randomized studies now state their proportion of Sokal scores to aid in interpretation of results. One paper reported that disease characteristics, as measured by risk status, was a more powerful predictor of survival than therapy received, by a factor of two (Hehlmann et al, 1997). The Sokal index is typical of the other prognostic scales and uses baseline patient and disease characteristics to calculate a hazard ratio for death. Input of patient age, platelet count, peripheral blast count and spleen size at diagnosis into an equation allows separation of the population into three roughly equal groups: high, intermediate and low risk with median survivals of 3, 4, and 5 years respectively. As many patients are asymptomatic at diagnosis, one could wonder whether these risk groups reflect underlying biological differences or varying disease duration. Sokal has pointed out that, as the survival curves of the risk groups continue to diverge with time, high risk disease is indeed more aggressive and not just more advanced (Sokal et al, 1985). However, for patients with very early disease detected only by molecular testing, lead-time bias could be substantial. These patients may form a group with a much better prognosis than those who came to medical attention because of symptoms. For unknown reasons, prognostic equations developed in chemotherapy-treated patients do not perform well in interferon-treated patients. Investigators have proposed new prognostic scales that more accurately predict survival after interferon-a (IFN) therapy (Hehlmann et al, 1994, 1997; Mahon et al, 1998; Sacchi et al, 1998). The bestvalidated scale was published by Hasford et al (1998) and considers patient age, platelet count, peripheral blast count, spleen size, eosinophils and basophils when calculating risk. The use of longitudinal diagnostic studies offers a refinement in risk estimation. Serial tests measuring disease burden or cytogenetic evolution may be used to more accurately predict transformation. Gaiger et al (1995) followed 25 patients by serial quantitative PCR and showed that increased BCR±ABL expression, corrected for cell number, predicted disease progression a median of 6 months before haematologicalal evidence. Acquisition of additional cytogenetic abnormalities, such as trisomy 8, isochromosome 17 or a second Philadelphia chromosome, has also been associated with clinical disease progression (Majlis et al, 1996; Cortes et al, 1998). However, incorporation of these Fig 1. Kaplan±Meier survival curves for CML patients transplanted from HLAidentical siblings and reported to the International Bone Marrow Transplant Registry. Reprinted with permission.

5 Review 997 Fig 2. Adjusted probabilities (from Cox regression model) of survival after diagnosis of CML in persons receiving HLA-identical sibling bone marrow transplants or nontransplant therapy with hydroxyurea or interferon. Source: Gale et al (1998) (with permission of the American Society of Hematology). observations into management recommendations awaits prospective testing. It seems that a greater number of prognostic scales are available for chronic phase CML than for any other haematologicalal malignancy. While these attempts at risk stratification have proved helpful when comparing baseline study populations and issuing general recommendations, their predictive value for the individual patient trying to plan his future is less useful. Therapy of chronic phase Currently accepted therapies for chronic phase CML range from relatively non-toxic oral medications to aggressive high-dose chemoradiotherapy with allogeneic stem cell transplantation. Randomized trials have been useful to compare approaches within a single modality. However, no studies have directly compared transplant and nontransplant therapies. Nevertheless, some authors have proposed algorithms to manage patients with CML (Hughes & Goldman, 1991; Deisseroth et al, 1997; Faderl et al, 1999a; Lee et al, 1998; Sawyers, 1999). An evidence-based analysis of CML therapy was reported by an expert panel convened by the American Society of Hematology to look into this controversy (Silver et al, 1999). The panel reviewed 207 articles meeting its inclusion criteria, but was unable to make definitive treatment recommendations owing to lack of comparative evidence. Instead, it made recommendations within each modality and stressed shared decision making to acknowledge the importance of individual risk±benefit assessments. Discussion of therapy is divided below into non-transplant and transplant approaches. Non-transplant therapies The development of pharmacological therapy for chronicphase CML is a good example of the steady evolution of effective therapies in haematologicalal malignancies. In general, questions about efficacy, dosing and combination therapy have been settled by large randomized, controlled trials as shown in Table I. These trials have changed standard practice several times since the 1960s. Historically, patients with CML were treated with total body or splenic radiation therapy, leukapheresis, intensive chemotherapy or splenectomy. Busulphan was introduced in 1953 and rapidly became the treatment of choice for CML based on a small randomized trial showing superior survival compared to radiation therapy (Medical Research Council's Working Party for Therapeutic Trials in Leukaemia, 1968). Although convenient and administered orally, busulphan was associated with a number of serious side-effects including infertility and the risk of marrow aplasia and lung fibrosis. Once randomized trials documented the superior efficacy of hydroxyurea with fewer side-effects, busulphan fell into disuse (Hehlmann et al, 1993; Ohnishi et al, 1995). However, some patients may still benefit from busulphan when other therapies are ineffective. Hydroxyurea (HU) was introduced in the late 1960s and remains the mainstay of palliation in CML. The drug is widely available, given orally, safe, reversible and effective with a wide therapeutic index. However, HU does not induce cytogenetic remissions in a significant percentage of the population nor change the natural history of the disease, and it can occasionally cause gastrointestinal problems and skin rashes. It works by inhibiting DNA synthesis, and patients receiving the drug are expected to display macrocytosis and hypersegmented polymorphonuclear cells. Interferon a. Investigators at the MD Anderson in Houston, Texas, made the first observations about the effectiveness of interferon a (IFN) in treating CML (Talpaz et al, 1983, 1986). Native interferon a is a glycoprotein produced by leucocytes in response to stress. The commercially available recombinant drug is delivered by subcutaneous injection and is capable of inducing haematological control in 70±80% of patients and complete cytogenetic responses in 6±26% as a single agent. The precise mechanism of action in CML is unknown, but it has been hypothesized that IFN affects control of proliferation, adhesion and apoptosis of malignant cells. It may also work via effects on regulatory cells that interact with CML cells. Clinical trials of IFN have benefited from relatively uniform criteria for haematological and cytogenetic response. Complete haematological response requires resolution of symptoms and normalization of haematological

6 Table III. Studies of the effect of interferon (IFN) on transplantation outcome. Author Number Population Results Comments Conclusions about the effect of IFN on survival Giralt et al (1993) 77 Matched related donors, transplanted 1981±91, mixed phase CML No differences seen in engraftment, acute or chronic GVHD, 100 d mortality, relapse, or 3 years overall and disease-free survival Heterogeneous population. Median follow-up 24 months (IFN) and 13 months (no IFN) No effect 998 Review Beelen et al (1995, 1999) 153 Heterogeneous donors, transplanted 1982±93, chronic phase CML Lower 5 years overall and disease-free survival in group receiving more than 12 months IFN. No difference in acute or chronic GVHD relapse rates Median duration of IFN 14 months. Median follow-up 59 months. Increased mortality in patients receiving more than 12 months IFN owing to increased graft failure and fatal infections Duration important: more than 12 months of IFN is detrimental Shepherd et al (1995) 109 Sibling and unrelated donors, chronic phase CML No survival differences between IFNand chemotherapy-treated groups Published in abstract form only No effect Holler et al (1995) 151 Heterogeneous donors, transplanted 1985±94, mixed phase CML 20% increase in treatment-related mortality if IFN given in last 3 months before transplant Published in abstract form only Discontinuation important: within 90 d of transplant detrimental Morton et al (1998) 184 Unrelated donors, transplanted 1988±94, chronic phase CML Zuffa et al (1998) 32 Sibling donors, transplanted 1983±95, chronic phase CML Tomas et al (1998) 51 Matched sibling donors, transplanted 1990±96, chronic phase CML Pigneux et al (1998) 438 Heterogeneous donors, transplanted 1984±95, mixed phase CML Hehlmann et al (1999) 152 Heterogeneous donors, chronic phase CML Giralt et al (2000) 873 Matched sibling donors, transplanted 1987±94, chronic phase CML Increased grade III-IV acute GVHD and mortality in patients receiving IFN for more than 6 months. No difference in incidence of extensive chronic GVHD or relapse rates No difference in engraftment, acute or chronic GVHD, treatment-related mortality, relapse, or 7 years disease-free survival No difference in engraftment, acute or chronic GVHD, 5 years overall or event-free survival or relapse No differences seen in transplant outcome once adjusted for baseline characteristics and acute and chronic GVHD Increased mortality in patients receiving IFN within 90 d of transplant No difference in acute and chronic GVHD, 3 years treatment-related mortality, overall survival or leukaemia-free survival Median follow up 4 years. Increased mortality 3±12 months post transplant from chronic GVHD refractory to therapy in patients with acute GVHD who received more than 6 months of IFN IFN given for at least 6 months Published in abstract form only. Median IFN duration 9 months Patients were randomized to IFN or chemotherapy. Median follow-up 4 7 years. Increased mortality in group receiving IFN within 90 d of transplant not attributable to any specific cause 2 month median duration of IFN treatment. Median follow up 2 8 years. IFN associated with more graft failure(2% vs. 0 2%, p-0 01) and less relapse(1% vs. 8%, P ˆ 0 002) Duration important: greater than 6 months IFN therapy detrimental No effect No effect No effect Discontinuation important: within 90 d of transplant detrimental No effect

7 Table IV. Comparative studies of transplant and non-transplant therapy. Review 999 Study Data sources Method of comparison Conclusions Lee et al (1997; 1998) Literature, International Bone Marrow Transplant Registry, National Marrow Donor Program Decision analysis comparing discounted, quality-adjusted life years considering patient age, Sokal risk group, attitude towards risk, and quality of life Early allogeneic transplantation is recommended for patients less than 50 years-old with related donors and those who have unrelated donors, and who have intermediate or high risk CML; transplantation is also recommended for patients less than 40-year-old with low-risk CML and unrelated donors. Appropriate therapy for patients over the age of 75 years is unknown. A trial of IFN is recommended for all other patients. Gale et al (1998) International Bone Marrow Transplant Registry, German CML Study Group Cox modelling adjusting for differences in patient characteristics Higher early mortality (up to 4 years), but superior long-term survival (after 5 5 years) for patients transplanted with HLA-identical siblings over therapy with HU or IFN The Italian Cooperative Study Group on CML and Italian Group for Bone Marrow Transplantation (1999) Italian Cooperative Study Group on CML and Italian Group for Bone Marrow Transplantation Survival analysis stratified by Sokal risk group and age Allogeneic transplantation from an HLA-identical sibling results in better survival than conventional chemotherapy regardless of age and Sokal risk group; when transplantation was compared with IFN therapy, a benefit to transplantation was seen only for younger (less than 32 years-old) patients and those with intermediate or high-risk Sokal scores parameters. Partial haematological response requires decrease of the white count by 50% to less than /l or normalization of counts if there is persistence of symptoms. Cytogenetic responses have been classified by the MD Anderson group as none (100% Ph 1 metaphases in a standard 20 cell cytogenetic study), minor (35±99% Ph 1 metaphases) and major (, 35% Ph 1 metaphases). Major responses are further classified into partial (1±34% Ph 1 metaphases) and complete (no detectable Ph 1 metaphases) (Talpaz et al, 1991). Major cytogenetic responses are associated with prolonged survival although patients remain PCR positive if sensitive techniques are used (Hochhaus et al, 1995, 1996, 2000). Reports of IFN-treated patients becoming reverse transcription (RT)-PCR negative indicating the absence of detectable mrna may be as a result of technical differences (Kurzrock et al, 1998; Faderl et al, 1999c; Chomel et al, 2000). Several patients attaining complete cytogenetic remission have remained clinically stable for years, but their long-term prognosis is unclear. Multiple large, randomized, controlled trials and a metaanalysis of these studies have documented the survival benefit associated with IFN treatment over HU or busulphan chemotherapy. Although many of these trials had different inclusion criteria, proportions of Sokal risk groups and IFN dosing guidelines, all trials showed equivalent or superior survival for the IFN arm. Randomization to IFN treatment was associated with up to a 20 month extension of median survival and an absolute survival advantage of 15% at 5 years (Hehlmann et al, 1994; The Italian Cooperative Study Group on Chronic Myeloid Leukaemia, 1994; Allan et al, 1995; Ohnishi et al, 1995; Hasford et al, 1996b; Chronic Myeloid Leukaemia Trialist's Group, 1997; The Benelux CML Study Group, 1998). However, side-effects are common and include fatigue, myalgias, arthralgias, headaches, weight loss, depression, diarrhoea, neurologicalal symptoms, memory changes, hair thinning, autoimmune diseases and cardiomyopathy (Talpaz et al, 1991; Sacchi et al, 1995; Wetzler et al, 1995). As the randomized trials were analysed on an intention-to-treat basis and used overall survival to compare therapies, clearly IFN can affect the natural history of CML and is not just selecting for patients with a good prognosis. The prolongation of median survival seen in these trials is probably via the greatly improved survival of a small subset of the cohort rather than extension of all patients' survival by a similar amount. In fact, as 14±26% of patients discontinued IFN in the randomized studies because of side-effects, presumably prior to documented cytogenetic response, it is reasonable to assume that a patient who receives IFN, tolerates it, and has a complete cytogenetic response will do very well (Hehlmann et al, 1994; The Italian Cooperative Study Group on Chronic Myeloid Leukaemia, 1994; Allan et al, 1995; Ohnishi et al, 1995; Guilhot et al, 1997; The Benelux CML Study Group, 1998). Current efforts to improve IFN response rates seek to define the optimal single-agent dosing regimen, evaluate pegylated IFN (which is dosed weekly and

8 1000 Review may be equally effective with fewer side-effects) and combine IFN with other agents. As the median time to best IFN response is 12 months, the ability to identify patients destined to achieve cytogenetic responses would allow earlier decisions about continuing or changing therapy (Talpaz et al, 1991; Kantarjian et al, 1995, 1996). The most sophisticated predictive schemes consider both baseline and response variables. Sacchi et al (1998) have proposed guidelines to evaluate a patient's likelihood of achieving a meaningful cytogenetic response based on degree of haematological response, spleen size and platelet count at 3, 6 and 12 months after initiation of interferon. Mahon et al (1998) have suggested that haematological response by 3 months and percentage of blasts in peripheral blood could be used to predict attainment of a major cytogenetic response. Cortes et al (1998) studied the suppression of clonal evolution in 90 interferon-treated patients. They showed that patients who achieved suppression of additional cytogenetic abnormalities had much better survival than those who retained these defects. Approximately 50% of patients with low-risk Sokal scores will experience a major (partial or complete) cytogenetic response to single-agent IFN, whereas 30% of intermediaterisk and 15% of high-risk patients will respond (Allan et al, 1995; Kantarjian et al, 1995). Response rate is highest if IFN is started within 1 year of diagnosis and probably exhibits a dose±response relationship (Kantarjian et al, 1992). The trials with the highest response rates were designed to deliver 5 MU/m 2 /d. The optimal length of IFN therapy is unknown. Experts have recommended continuation for 2±3 years beyond achievement of a complete cytogenetic response (Kantarjian et al, 1996; Faderl et al, 1999a). Practical guidelines for the initiation and dose adjustment of IFN may be found in published sources and include starting at a low dose with escalation, use of accessory medications to control symptoms, evening dosing to minimize toxicity and dose adjustment for side-effects (Kantarjian et al, 1996; Silver et al, 1999). Interferon should be used cautiously in patients with a history of serious depression because it may exacerbate this problem. Similarly, age is a consideration as older patients experience greater side-effects, although they are reported to have similar response rates (Cortes et al, 1996; Hilbe et al, 1998). The benefit of IFN in patients greater than age 75 years is unknown, as these patients were excluded from all the randomized trials documenting a better survival with IFN (Lee et al, 1998). Combined interferon a and cytarabine. Addition of low-dose cytarabine to IFN increased response rates and survival in several observational and two large randomized studies, but may be associated with greater haematological, gastrointestinal and mucosal toxicity (Kantarjian et al, 1992, 1999; Guilhot et al, 1997; Tura, 1998). Guilhot et al (1997) studied 721 patients who were treated with daily IFN with or without intermittent subcutaneous cytarabine. The trial was stopped early after an interim analysis showed better survival in the combination arm. While concern remains about the greater toxicity of the combined regimen, there is sufficient compelling evidence to start patients opting for chemotherapy on combination therapy with continuation of cytarabine determined by tolerability. New approaches. The search continues for new agents with efficacy in CML. Homoharringtonine is a semisynthetic plant alkaloid that was originally described in the Chinese literature and has similar activity to IFN when given by short-course continuous infusion. Phase II studies report 15±27% major responses, although the drug is associated with diarrhoea and myelosuppression. Patients without splenomegaly are most likely to achieve a major cytogenetic response. This agent is now being studied in combination therapy (O'Brien et al, 1995, 1999). Other investigators have tried to stimulate an immune response against CML cells. Direct vaccination with tumourspecific peptides and cultivation of effector cells targeted against CML cells have been used to induce specific immunity (Falkenburg et al, 1999; Pinilla-Ibarz et al, 2000). Systemic use of immunostimulants has also been attempted. Better understanding of the molecular basis of CML has led to the discovery of small molecules aimed at these targets (Druker et al, 1996; Miller, 1998; Cobaleda & Sanchez- Garcia, 2000). The best example of this approach is probably the rationally designed drug STI 571 (CGP 57148) which is a tyrosine kinase inhibitor with specific activity against abl. Phase I/II studies show impressive activity in patients who have already failed interferon (Druker & Lydon, 2000). Investigators have reported a 96% complete haematological response rate for 24 patients receiving daily doses of 300 mg or more. These responses occur early (within 3 weeks of starting therapy) and have been sustained in all patients studied thus far. Eight per cent of patients achieved complete cytogenetic responses (Druker et al, 1999). However, the durability of this response and assessment of any long-term negative effects awaits longer follow-up. STI 571 has the advantages of excellent oral bioavailability with minimal systemic effects other than myelosuppression. Transplantation Chronic myelogenous leukaemia is the malignancy for which there are the most extensive long-term data on the effectiveness of allogeneic stem cell transplantation. Ranges of disease-free survival and relapse rates reported in the literature are summarized in Table II. Surveys of transplant physicians show that chronic-phase CML is the most recognized indication for allografting (Thomas & Clift, 1989; Gratwohl & Hermans, 1996; Gratwohl et al, 1997) and rates of transplantation have been used to compare the health policies of different industrialized nations (Silberman et al, 1994). If the procedure is performed while the patient is in chronic phase using a matched sibling donor, 1-year survival rates are 60±80% with a 10-year disease-free survival rate of approximately 50% (Clift & Storb, 1996; Gratwohl & Hermans, 1996; Horowitz et al, 1996; van Rhee et al, 1997) (Fig 1). Historically, transplantation from unrelated donors has been associated with higher morbidity

9 and mortality (Marks et al, 1993). However, in selected cohorts, the results are similar to related donor results (McGlave et al, 1996; Dini et al, 1998; Hansen et al, 1998). The clinical indolence of CML contributes to the ability to use unrelated donors by allowing time to identify a suitable match and arrange the transplant. Patients with only a less than ideal match available must decide between immediate transplantation and waiting to see if a better donor can be found. Transplantation is limited to patients who can medically tolerate the procedure and have appropriate donors (30% will match siblings, 5% will match additional family members and 50% can find unrelated donors). Patient-, donor- and disease-specific variables such as older age, poorer HLA matching, certain patient±donor gender combinations, more advanced disease and longer duration of disease result in worse outcomes (Goldman et al, 1993; Devergie et al, 1997; Gratwohl et al, 1998). Although there are some conflicting reports, the majority of evidence suggests that transplant outcomes using both related and unrelated donors are better if therapy is initiated within the first year of diagnosis (Clift et al, 1993; Goldman et al, 1993; Hansen et al, 1998). This improved survival is as a result of a decrease in treatment-related mortality, not a difference in relapse rates. In early reports, adverse effects of prolonged busulphan exposure were thought to be responsible for this observation. As HU is now used in preference to busulphan, better outcomes with shorter disease duration must be because of other factors. If these could be identified, then some of the urgency to transplant patients early might be lessened allowing greater flexibility in the timing of transplantation or exploration of alternate therapies. There is surprisingly great variability in the transplant protocols of individual centres especially with regard to the source of stem cells, type of conditioning regimen and method of acute graft-versus-host disease (GVHD) prophylaxis. In some cases different approaches have been proved equivalent. One example is conditioning regimens. Cyclophosphamide/total body irradiation seems to be similar to busulphan/cyclophosphamide and higher doses of total body irradiation result in lower relapse rates, but greater treatment-related mortality, so that overall survival is similar (Clift et al, 1991, 1994a, 1999; Devergie et al, 1995). In other areas of practice variation, such as different stem cell sources and methods of GVHD prophylaxis, trials are under way to define the advantages and disadvantages of each approach. Donor stem cells may be obtained either from peripheral blood or marrow. The putative advantages of peripheral blood include earlier engraftment, lower early mortality, better immune reconstitution and a lower relapse rate, perhaps modulated via increased chronic GVHD. One large randomized trial among patients with a variety of diseases transplanted from HLA-identical siblings has been reported in abstract form. This trial was stopped early when interim analysis showed superior survival in the entire group of patients grafted from peripheral blood (Bensinger et al, 1999). However, this finding was driven by the differences seen in patients with advanced disease. This study could not Review 1001 confirm a statistically significant improvement in survival in early stage patients, including those with chronic phase CML, probably because of inadequate patient numbers in this group. Concern remains that increased rates of chronic GVHD associated with peripheral blood transplants could offset the early benefits and longer follow-up is necessary to address this issue (Storek et al, 1997; Solano et al, 1998; Vigorito et al, 1998). The two major methods of GVHD prophylaxis are T-cell depletion and immunosuppressive therapy with methotrexate plus tacrolimus- or cyclosporin-based regimens. Choice of GVHD prophylaxis somewhat dictates the expected complications. While there are data that patients treated with either method may expect the same long-term survival, T-cell depletion has been associated with an increased risk of relapse, graft rejection and post-transplant lymphoproliferative disorders, but also less acute and chronic GVHD and immediate treatment-related mortality (Goldman et al, 1988; Wagner et al, 1998; Sehn et al, 1999). The greater genetic disparity of unrelated donors may mitigate some of the risks of T-cell depletion (Hessner et al, 1995; Wagner et al, 1998). Management of relapse following transplantation. The definition of residual or relapsed disease following allogeneic transplantation is controversial. Individual centres have different policies regarding the frequency and interpretation of haematological, cytogenetic and molecular assessments. As disease is often subclinical, failure to test patients might underestimate relapse rates. Molecular criteria for relapse are the most contentious. Some parameters to consider include: whether DNA, RNA or protein evidence of the translocation is being detected; the number and type of cells being tested; demonstration of changes over time; the type of donor and method of GVHD prophylaxis; and time since transplant. Efforts are under way to enhance comparability of reported relapse rates by codifying nomenclature (Faderl et al, 1999b,c). While the ultimate goal is to intervene early in cases of expected or documented relapse, overzealous treatment may be unnecessary or toxic if given needlessly or too aggressively. For example, it is clear that patients may be initially PCR positive early after transplantation, but convert to negative without further therapy (Radich et al, 1995; Lin et al, 1996; Drobyski et al, 1997). Between 10% and 15% of recipients of matched sibling transplants and less than 5% of matched unrelated donor recipients relapse haematologicalally following allogeneic transplantation if T cells are left in the graft. Clinical relapse is predicted by levels of BCR±ABL expression with excellent concordance in blood and marrow specimens (Radich et al, 1995; Lin et al, 1996; Drobyski et al, 1997). Patients who relapse following transplantation may respond to interferon or withdrawal of immunosuppression, or have prolonged survival (median 6 years) without therapy (Higano et al, 1992, 1997; Arcese et al, 1993; Steegmann et al, 1999). They may choose to undergo a second transplant or receive donor lymphocyte infusions. CML is exquisitely sensitive to the effects of graft-versusleukaemia and has been a model for eradicating malignant

10 1002 Review disease through manipulation of the immune system. Considerable evidence suggests that the high-dose conditioning regimens used for transplantation are rarely curative by themselves. First, patients may remain PCR positive for BCR±ABL for months after transplantation yet appear to be cured of their disease and eventually convert to PCR negativity without further therapy. Second, there is an extremely high relapse rate for autologous, syngeneic and T-cell-depleted grafts using the same myeloablative conditioning regimens used for standard non-t-cell-depleted grafts. Third, evidence of alloreactivity such as acute and chronic graft-versus-host disease is associated with lower relapse rates (Horowitz et al, 1990; Gratwohl et al, 1995; van Rhee et al, 1997). Thus, it is believed that rather than simply replacing the recipient's ablated haematopoietic stem cells, the allogeneic graft creates a new immune system that plays an active role in eradicating CML. Proof of principle is provided by the observation that 60±80% of patients who relapse cytogenetically or haematologicalally into chronic phase post transplant can be salvaged by donor lymphocyte infusions (DLI) without further cytotoxic chemotherapy (Kolb et al, 1995; Porter et al, 1994, 1999, 2000; Collins et al, 1997). Unfortunately, acute and chronic graft-vs.-host disease and marrow aplasia remain significant complications after DLI (Keil et al, 1997). Efforts to select subsets of lymphocytes, minimize the dose of donor lymphocytes, spread out the dosing schedule or expand specific T-cell clones ex vivo prior to infusion have decreased the toxicity of DLI (Giralt et al, 1995; Mackinnon et al, 1995; Falkenburg et al, 1999; Dazzi et al, 2000). Approximately 5±15% of patients successfully treated with DLI subsequently relapse again, but the remission rate is otherwise durable with the follow-up available so far. Because CML is very sensitive to immunotherapy, efforts are also under way to combine less than myeloablative chemotherapy and infusion of peripheral blood stem cells, so-called `mini-transplants', or T-cell-depleted transplants with prophylactic infusion of donor lymphocytes. Although these approaches are appealing as they potentially offer a curative option with lower risk, evaluation of the long-term effectiveness awaits more data. Impact of pretransplant interferon on transplant outcome. The effect of IFN therapy prior to allogeneic transplantation is controversial. Studies analysing the effects of prior IFN therapy on transplant outcome give conflicting results and are summarized in Table III (Giralt et al, 1993, 2000; Beelen et al, 1995, 1999; Holler et al, 1995; Shepherd et al, 1995; Morton et al, 1998; Pigneux et al, 1998; Tomas et al, 1998; Zuffa et al, 1998; Hehlmann et al, 1999). Five studies found no effect of IFN on transplant outcome (Giralt et al, 1993, 2000; Shepherd et al, 1995; Tomas et al, 1998; Zuffa et al, 1998). In studies showing an adverse effect, both the duration of IFN therapy (Beelen et al, 1995, 1999; Morton et al, 1998) and time of discontinuation prior to transplantation (Holler et al, 1995; Hehlmann et al, 1999) have been implicated. Very recent reports have noted the intriguing observation that IFN pretreatment may actually improve outcome after allogeneic transplantation, but this concept awaits further investigation. (Hehlmann et al, 1999; Giralt et al, 2000). For now, avoidance of IFN exposure is recommended if expeditious transplantation is planned. If a patient is already on IFN and preparing for transplantation, the literature suggests minimizing the duration of therapy and discontinuing treatment at least 90 d in advance of the procedure. Autologous transplantation. Although CML is a stem cell disease, it arises from a somatic mutation, and normal progenitors co-exist with malignant cells. Autologous transplantation tries to utilize these normal stem cells to reconstitute patients following destruction of malignant cells. However, in practice, autologous procedures with or without attempts to purge the marrow graft have been plagued by high transplant-related toxicity and relapse rates (McGlave et al, 1994; Bhatia et al, 1997). Comparison of transplant and non-transplant therapy for chronic phase CML No clinical trials have directly compared transplant and non-transplant therapy. Thus, indirect methods have been used to compare cohorts of patients treated with either modality and are summarized in Table IV. These studies conclude that younger patients or those with higher risk CML will do better in the long term with transplantation. Mortality is initially higher with transplant approaches, but overall survival is superior once the curve plateaus (The Italian Cooperative Study Group on Chronic Myeloid Leukaemia and Italian Group for Bone Marrow Transplantation, 1999; Lee et al, 1997, 1998; Gale et al, 1998). A representative analysis is shown in Fig 2. Gale et al (1998) compared 548 recipients of matched sibling transplants reported to the International Bone Marrow Transplant Registry with 196 patients receiving chemotherapy on the German CML trials. After adjusting for disease factors, they found that there was a significant survival advantage for chemotherapy in the first 4 years, but transplant was better after 5 5 years. The Italian Cooperative Study Group on Chronic Myeloid Leukaemia and Italian Group for Bone Marrow Transplantation (1999) compared 659 patients treated with HU or IFN on their randomized trials with 120 patients treated with allogeneic transplantation. They concluded that, while allogeneic transplantation was always better than HU, transplantation was better than IFN for younger patients or those at intermediate or high risk. Lee et al (1997, 1998) used decision analytic techniques to compare chemotherapy with unrelated donor transplantation using data from the literature and the International Bone Marrow Transplant Registry and National Marrow Donor Program. They concluded that for younger patients and those with higher risk disease, early transplantation maximized qualityadjusted life years. ADVANCED DISEASE In contrast to the scientific and clinical advances made in understanding and managing the chronic phase of CML, little meaningful progress has been made for patients with advanced disease. A number of cytogenetic and molecular

11 abnormalities are associated with accelerated phase and blast crisis, but there is little direct support of their fundamental aetiological role. Clinically, response rates of blast crisis to chemotherapy have improved, but relapse rates and long-term survival have not been appreciably affected. Clinical features of advanced disease Most patients experience progressive disease between 3 and 8 years after diagnosis. Evidence of increasing disease burden includes an inability to control leucocyte counts with previously stable doses of medication, fevers, night sweats, weight loss, splenic infarcts from massive splenomegaly and bony pain. The peripheral blood and marrow may show increasing numbers of basophils, eosinophils, promyelocytes and blasts. The platelet count may be either high or low. Approximately 40±70% will spend 4±6 months in an accelerated phase prior to blast crisis (Karanas & Silver, 1968; Griesshammer et al, 1996). Accelerated disease is defined as having disease characteristics suggesting a more aggressive course or cytogenetic abnormalities beyond the Philadelphia chromosome. Common additional abnormalities include trisomy 8, trisomy 19, a duplicate Philadelphia chromosome and isochromosome 17. Blast crisis is characterized as having 20±30% blasts plus promyelocytes in peripheral blood or marrow (Spiers, 1979; Cervantes et al, 1996; Griesshammer et al, 1996). Many different definitions for accelerated phase and blast crisis may be found in the literature; most discrepancies are because of slightly different cut-offs for haematological values and inclusion of additional diagnostic criteria. Two points of contention are whether myeloblastomas represent accelerated or blast phase and the grouping of patients with additional cytogenetic abnormalities into the accelerated phase category, as these patients seem to do better than others reaching this stage on clinical grounds. Prognostic features of advanced disease Once CML progresses beyond chronic phase, the prognosis is poor. Patients who attain the diagnosis of accelerated phase on the basis of cytogenetic progression seem to do better than those diagnosed on clinical features, both with transplant and non-transplant therapy. Blast crises may be either myeloid or lymphoid reflecting the fact that CML is a stem cell disorder. Roughly two out of three blast crises are myeloid, with a response rate to intensive chemotherapy of 20±30% (Sacchi et al, 1999). Approximately one out of three blast crises are lymphoid, with a response rate of 40±60% (Derderian et al, 1993). However, responses are not durable and patients quickly relapse (Kantarjian et al, 1987; Derderian et al, 1993; Griesshammer et al, 1996). While patients who are able to enter a second chronic phase prior to transplantation have outcomes similar to those transplanted for accelerated phase, the outcome of stem cell transplantation for patients in blast crisis is dismal, and a distinction is not made between myeloid and lymphoid phenotypes. Therapy of advanced disease All therapies are less effective in advanced disease than in chronic phase. The randomized IFN trials concentrated on patients with early stage disease, therefore no trial evidence supports the benefit of IFN once the disease progresses. Cortes et al (1998) showed that IFN could suppress cytogenetic evolution, which was associated with better survival. However, as this was a single arm study, it is possible that IFN was identifying patients destined to have better survival rather than changing the natural history of the disease. Combination chemotherapy similar to that used for acute myelogenous leukaemia and acute lymphoblastic leukaemia is appropriate for patients in blast crisis who wish aggressive treatment. Decitabine has been used in advanced disease with a 50% response rate reported for myeloid transformations (Sacchi et al, 1999). Allogeneic transplantation in late-stage CML is associated with poor outcome, primarily because of the high peritransplant mortality from regimen-related toxicity and the extremely high relapse rate. Estimates of long-term diseasefree survival after transplantation are 20±40% for patients in accelerated phase and 0±25% for patients in blast crisis depending on donor type (Gratwohl et al, 1993; Clift et al, 1994b; Horowitz et al, 1996) (Table II). SUMMARY In the last decade, improvements in both non-transplant and transplant therapy have extended the lives of patients with CML, particularly those in chronic phase. The future will probably bring a greater understanding of molecular leukaemogenesis and options for treating CML. Nontransplant therapies in development include novel agents and combination therapy. Transplant strategies seek to decrease regimen-related toxicity and directly manipulate the immune system to eradicate disease. Clinical and laboratory science seems poised to add novel therapies to the armamentarium against CML. It is exciting to contemplate what reviews of CML written 10 years from now will discuss. Center for Outcomes and Policy Research, Dana-Farber Cancer Institute, 44 Binney Street, Boston, MA 02115, USA ACKNOWLEDGMENT Review 1003 Stephanie J. Lee I thank Dr Joseph Antin for reviewing the manuscript and the International Bone Marrow Transplant Registry for providing the most recent transplant survival curves. This review was supported in part by the Amy Strelzer- Manasevit Scholars Fund and Public Health Service grant CA from the National Cancer Institute, National Institute of Health, Department of Health and Human Services.