Dr Simon J
Harrison1, Dr Peter RE Johnson2, and Dr Tessa L Holyoake
1: Haemato-oncology Section, Division of Cancer Sciences and Molecular Pathology, Level 3, Royal Infirmary, Glasgow, G31 2ER.
2: Department of Haematology, Western General Hospital, Crewe Road, Edinburgh, EH4 2XU.
Correspondence to: simonharrison@doctors.org.uk
SMJ 2004 49(3): 87-90
Abstract
The management of CML has recently become increasingly complex. The Scotland Leukaemia Registry (SLR) sent questionnaires to all 26 Scottish haematology units, of which 18 (69%) responded. From January 1999 to December 2000, 64 new cases of CML were identified by the audit (incidence 0.64/100,00/yr), of which 46 were registered with the SLR. At diagnosis, all 18 units combined bone marrow examination with cytogenetics/FISH, but only 13 performed RT-PCR. Of four units that calculated the Hasford Score, only two used it to inform clinical decisions. 52% of patients entered clinical trials, 57% involving imatinib mesylate (IM). Of the 23 patients who were tissue typed, suitable donors were found for 18, 11 sibling, and 7 unrelated, representing 28% of the total patient population. Only 13/64 patients (20%) did not have a BMT donor identified or enter a clinical trial. Although 38% of units would consider reduced intensity allografting in patients >60 years, no centres currently routinely tissue-type such patients. For first line therapy 56% of patients received hydroxyurea +/- interferon. Of the newer agents, 83% of units believed imatinib mesylate should be reserved for clinical trials, 83% would consider using oral ara-C and 89% pegylated-interferon.
Key words: Chronic Myeloid Leukaemia, Imatinib Mesylate, Bone Marrow Transplant
Introduction
CML is a malignancy of haemopoietic stem cells and accounts for 10-15% of all cases of leukaemia. It is associated with a reciprocal translocation between chromosomes 9 and 22 resulting in the Philadelphia chromosome, first described in 1960 [1] . With the development of new, targeted therapies, and developments in allogeneic stem cell transplantation, the management of CML is undergoing rapid change.
The Scotland Leukaemia Registry (SLR) was established in November 1998 with the aim of collecting data on all new cases of acute myeloid leukaemia, acute lymphoblastic leukaemia and chronic myeloid leukaemia. In collaboration with the SLR, we conducted an audit to look at the incidence, diagnosis, risk stratification, and clinical management of patients with CML in Scotland. At the time of designing the audit (September 2000) IM and low intensity allografting were both recent developments under intense evaluation. We therefore sought to gauge the opinion of Scottish haematologists as to how they felt these new options should be used in the future, and how such treatments should affect patient investigation and management.
Materials and
Methods
A questionnaire was constructed requesting data for all new patients diagnosed with CML from 1st January 1999 to 31st December 2000 incorporating incidence, diagnostic tests in routine use, and whether risk stratification was employed; it was not specified how the individual units should identify patients. Questions were designed to determine first line therapy, clinical trial entry, criteria for consideration for bone marrow transplantation (BMT), clinician’s views on “gold standard” therapy, and best practice for introducing novel agents. Questionnaires were sent to all consultant haematologists in Scotland asking for a single return from each individual unit. A reminder letter was sent out in May 2001 and the replies were initially analysed in August 2001.
Results
Replies were received from 18 of the 26 units in Scotland (69%), including two paediatric units who each reported one patient. Follow-up of the replies suggested that all major population centres were well represented in the audit returns. 64 patients were identified by the audit, of which the SLR registered 46 (72%). Of these, 3 patients were under 30 years old, 7 patients were 30-40yrs, 10 patients were 41-50yrs, 16 were 51-60yrs, and 28 were >60yrs.
For diagnostic purposes, all units performed a bone marrow (BM) aspirate with cytogenetic analysis. 16/18 recorded the peripheral blood basophil and eosinophil counts (one paediatric unit and one adult unit did not); 15/18 the peripheral blood blast count; 14/18 recorded spleen size, performed molecular tests for BCR/ABL and included a BM trephine biopsy. Only 13/18 units routinely performed a BM differential. Thus, the majority of units (72%) routinely recorded the information required to calculate a Sokal or Hasford score [2, 3] . However, only 4/18 units routinely calculated a risk score, of which only two used the score to aid clinical decision-making.
Following diagnosis, for the 61 patients requiring immediate treatment, 30/61(50%) received hydroxyurea (HU) alone as first line therapy, 19/61(31%) received interferon-a (IFN) in combination with HU, 6/61(10%) IFN alone, 2/61(3%) IFN plus ara-c, 2/61(3%) pegylated-IFN alone, 1/61(2%) allogeneic BMT, and 1/61(2%) “other” therapy. During the study period four clinical trials were available for recruitment in Scotland. CML 2000 had ethical approval in 12/18 units, but recruited no patients. Ethical approval for CML V was available in 13 units and recruited 10 patients. A pegylated-IFN study recruited 4 patients and IM studies recruited 19 patients. 31/64 patients were not entered into clinical trials. 10 patients proceeded to Allo BMT, 3 refused trial entry, 12 were thought to be ineligible (8 had suitable BMT donors), 1 patient was managed in a unit where appropriate ethical approval was not in place, and for 5 patients no specific reason was recorded.
The units were asked about their policy for tissue-typing patients and their age criteria for consideration of BMT, including sibling and matched unrelated donor (MUD) myeloablative or reduced intensity allogeneic BMT. Of the 16 adult units, 1/16 routinely tissue-typed patients only up to age 40, 7/16 to age 50 and 8/16 to age 60; no units routinely tissue-typed patients over the age of 60 years. In contrast, 6/16 units would be prepared to offer reduced intensity sibling and 2/16 reduced intensity MUD allogeneic BMT to patients over 60, even though these patients would not routinely be tissue-typed. No units considered offering myelo-ablative allogeneic BMT to patients over 60. Of the 23 patients who were tissue typed, 11 were found to have fully matched sibling donors and 5 had already undergone BMT when the audit was completed. 7 unrelated donor searches were initiated, all of which resulted in identification of a suitable donor. 5 patients had proceeded to unrelated BMT at the time of the audit.
The units were asked for their opinion regarding current gold standard therapy for patients without sibling donors. 5/18 stated that they would use IFN plus ara-c, 4/18 IFN plus HU, 1/18 IFN alone and 1/18 IFN with imatinib mesylate. A further 2/18 would use imatinib mesylate alone, 1/18 HU alone, 1/18 would proceed to unrelated allogeneic BMT if the patient were aged <40, 2/18 did not know which treatment choice to make and 1/18 would refer to a regional centre for advice. Regarding 4 separate questions related to use of IM, even early in 2001, 3/18 units considered this appropriate first line therapy for all suitable chronic phase (CP) patients, 4/18 would reserve it for patients without a sibling donor, 7/18 would limit its use to appropriate clinical trials, whilst 8/18 said that IM should only be used in the context of a randomised controlled clinical trial (some units responded positively to multiple questions). 15/18 and 16/18 respectively, stated that they would use oral ara-c with pegylated-IFN if it were currently available in combination.
Discussion
Based on a Scottish population of five million, the incidence of CML as determined by this study was 0.64/100,000 as compared to the often-quoted 1/100,000 [4-6] . This audit identified 17 cases of CML, which had not previously been registered with the SLR, confirming that registration was incomplete. However, the SLR had only been registering patients for 2 months at the start of the audit period. Validating epidemiological data is difficult since existing datasets based on deaths or discharge information are incomplete, and diseases such as CML therefore rely on voluntary registration. Studies based on retrospective questionnaires are also flawed since a previous audit performed in haematology units in Scotland showed that only 14% of units had diagnostic systems from which case diagnoses could be obtained. Registration to the SLR has subsequently been improved by additional data management assistance, increased collaboration by all consultants in Scotland, liaison with cytogenetics laboratories, a compulsory requirement to register all cases receiving imatinib mesylate, and through collaboration between the SLR and regional managed clinical networks (MCN).
The Hasford/Sokal scores have previously been shown to correlate well with progression free survival [2, 3] yet few units in Scotland employ this tool for risk stratification. With the introduction of IM the role of more intensive approaches such as myelo-ablative MUD allogeneic BMT will be questioned, not only by haematologists, but also by their patients. Therefore any additional information on likely prognosis should be considered a valuable part of the diagnostic work-up for new cases.
When this audit was designed there was uncertainty amongst haematologists regarding the optimal treatment for patients who did not have a matched sibling donor for allogeneic BMT. This uncertainty was multifactorial, arising from conflicting data for results with IFN plus ara-C [7-10] the introduction of pegylated-IFN [11] and oral ara-C [12] and from promising early results with IM in clinical trials.
Only 33/64 (52%) patients in this audit were entered into a clinical trial. This figure is disappointingly low since the inclusion criteria for trials open for recruitment at the time (CML V and CML 2000) incorporated almost every patient. However, at this time it was standard practise not to expose patients to interferon prior to an allogeneic BMT. Of the 31 patients not entered into a trial, 11 had sibling donors and 7 had unrelated donors identified. Therefore only 13/64 (20%) patients did not have a BMT donor identified or enter a clinical trial. The IM trials were the most successful during the study period, which is an expected observation given the excitement surrounding early results with this agent at the time.
The use of reduced intensity allogeneic BMT in patients over 60 is increasing and 6/16 units in this study reported that they would consider offering this therapy to patients >60 years. However, before this can be realised tissue-typing for older patients must become part of their routine initial management.
During this study, IM was unavailable as a first line agent. IFN and ara-c containing regimens were considered the initial gold standard for patients without a sibling donor. Following the recently presented IRIS study Novartis [13, 14] has been granted an extended licence allowing the use of IM in newly diagnosed patients (6th January 2003). Clearly this will have major implications for clinical management and we would encourage all suitable patients to be included in clinical trials. In Scotland, the Scottish Medicines Consortium (SMC) has approved the use of IM within the licensed indications including newly diagnosed patients (10th January 2003). All treated patients will be registered with the SLR and efficacy data, including serious adverse events, will be assessed at 6 monthly intervals. In liaison with the MCN a pharmacist has been appointed to track the toxicity and quality of life data for all patients treated with IM in Scotland. We hope these measures will also allow us to establish the true incidence of CML in Scotland.
The question of clinical trial recruitment is a more difficult problem. In our study 80% of patients were either entered into a clinical trial or were eligible for a curative procedure. This figure will be difficult to improve upon, especially in light of the MRC’s decision not to fund the SPIRIT study (www.spirit-cml.org), which would have been open for all patients with chronic phase CML unsuitable for allografting. This leaves an enormous vacuum in the UK, as currently there are no national trials open for CML patients. At a time when we are encouraged to practise evidence-based medicine, this situation is unacceptable. Imatinib mesylate appears to be the most effective agent available for newly diagnosed patients and trials such as SPIRIT are asking critical questions about the optimal dose (400mg verses 600mg) and the potential benefits of combination therapy with other agents (cytarabine and alpha interferon). These trials will be costly and the medical community needs to decide whether level A evidence is an expensive luxury or a pricey necessity.
Fortunately, in
Scotland we are in a unique position to both register and audit the management
of CML patients with consultant haematologists (via the MCN), the SLR, and the
SMC all working together towards this common goal. Thus we hope to open
recruitment to SPIRIT north of the boarder in the very near future.
References
1. Nowell, P.C. and D.A. Hungerford, A minute chromosome in human chronic granulocytic leukemia. Science, 1960. 132: p. 1497-1501.
2. Hasford, J., M. Pfirrmann, R. Hehlmann, et al., A new prognostic score for survival of patients with chronic myeloid leukaemia treated with interferon alpha. J Natl Cancer Inst, 1998. 90(11): p. 850-858.
3. Thomas, M., Validation of the Hasford score in a demografic study in chronic granulocytic leukaemia. J Clin Pathol, 2001. 54: p. 491-493.
4. Parkin, D.M., C.S. Muir, S.L. Whelan, Y.T. Gao, J. Ferlay and J. Powell, Cancer Incidence in Five Continents, Volume VI. IARC Scientific Publications. 1992, Lyon: International Agency for Research on Cancer.
5. Parker, S.L., T. Tong, S. Bolden and P.A. Wingo, Cancer statistics, 1996. [see comments.]. Ca: a Cancer Journal for Clinicians, 1996. 46(1): p. 5-27.
6. Black, R.J., F. Bray, J. Ferlay and D.M. Parkin, Cancer incidence and mortality in the European Union: cancer registry data and estimates of national incidence for 1990. [see comments.] [erratum appears in Eur J Cancer 1997 Dec;33(14):2440.]. European Journal of Cancer, 1997. 33(7): p. 1075-107.
7. Kantarjian, H.M., S. O'Brien, T.L. Smith, et al., Treatment of Philadelphia chromosome-positive early chronic phase chronic myelogenous leukemia with daily doses of interferon alpha and low-dose cytarabine. Journal of Clinical Oncology., 1999. 17(1): p. 284-92.
8. Tura, S., Italian Cooperative Study Group on CML. Cytarabine increases karyotyoic responses in alpha-IFN treated chronic myeloid leukamia patients: results of a national prospective randomized trial. Blood, 1998. 92(suppl 1): p. 317a.
9. Baccarani, M., G. Rosti, A. de Vivo, et al., A randomized study of interferon-alpha versus interferon-alpha and low-dose arabinosyl cytosine in chronic myeloid leukemia. Blood, 2002. 99(5): p. 1527-1535.
10. Guilhot, F., C. Chastang, M. Michallet, et al., Interferon alfa-2b combined with cytarabine versus interferon alone in chronic myelogenous leukemia. French Chronic Myeloid Leukemia Study Group.[comment]. New England Journal of Medicine, 1997. 337(4): p. 223-9.
11. Talpaz, M., S. O'Brien, E. Rose, et al., Phase 1 study of polyethylene glycol formulation of interferon alpha-2B (Schering 54031) in Philadelphia chromosome-positive chronic myelogenous leukemia. Blood, 2001. 98(6): p. 1708-13.
12. Maloisel, F., A. Guerci, D. Guyotat, et al., Results of a phase II trial of a combination of oral cytarabine ocfosfate (YNK01) and interferon alpha-2b for the treatment of chronic myelogenous leukemia patients in chronic phase. Leukemia., 2002. 16(4): p. 573-80.
13. Hahn, E.A. The quality of life of patients with chronic phase chronic myeloid leukemia in the iris study of interferon-alpha plus ara-c vs imatinib (STI571, Glivec©). in European Haematology Association 7. 2002. Florence.
14. Guilhot, F. Imatinib (STI571, Glivec©) as initial therapy for patients with cml: results of a randomized phase III study versus interferon (IFN) cytarabine. in European Haematology Association. 2002. Florence.