CML treatment in Asia–Pacific region

Abstract

CML in Asia seems to affect the younger age group and more patients are in the high and intermediate Sokal risk group. Cytogenetic study and molecular testing are done mostly at diagnosis, but monitoring the response is limited due to the cost and accessibility. The treatment of chronic phase CML has changed dramatically within the last decade and imatinib has become the standard treatment for CP, CML. Since the cost of imatinib is quite high, most Asian patients cannot afford it. Patients in several countries get imatinib through Glivec International Patient Assistant Program. Patients who are intolerant or resistant to imatinib usually get the second generation tyrosine kinase inhibitors (TKIs), either nilotinib or dasatinib. The National Health Insurance covers all or most of the cost of imatinib in South Korea, Hong Kong and Taiwan. Both nilotinib and dasatinib are partially or fully covered by national insurance in Australia, Japan, Singapore and Taiwan as the second-line therapy. TKIs treatment remains out of reach for many Asian CML patients, especially those in the rural areas and those who are not eligible for patient access programs or covered by the national insurance. The cytogenetic response to imatinib in Asian CML patients varies considerably, from as low as 24% to as high as 96%. The Asia CML Study Alliance was briefly presented.

Keywords:

• CML
• Treatment
• Asia–Pacific region

Introduction

The treatment of chronic phase CML has changed dramatically within the last decade, stem cell transplantation is no longer the standard upfront treatment and imatinib 400 mg daily has become the standard upfront treatment for patients with chronic phase CML. The management of CML in Asia–Pacific region is complicated by various factors, some of which will be discussed here.

CML in Asia–Pacific Region

Epidemiology

The incidence of CML in Asia is lower than in the Western countries,1 but it affects the younger populations. The median age of CML patients in the western countries was reported to be 65 while in Asian patients the median age is significantly younger, between 36–50.2 The majority of patients are diagnosed in chronic phase.

Treatment regimen

Before the tyrosine kinase inhibitor (TKI) era, most patients who were not eligible for stem cell transplantation (SCT) received either busulphan or hydroxyurea. Before the introduction of TKI, interferon was useful in a subset of patients who were ineligible for SCT, but the cost was quite high for most patients; it is partially or fully covered by national insurance in most countries in Asia–Pacific region except Hong Kong, Indonesia, Philippines, Thailand and Vietnam1 and the result was inferior to that reported from the western countries (at least in Thailand).

Owing to the introduction of imatinib, the numbers of SCT have decreased dramatically in some countries. The cost of imatinib is quite high and most patients in Asia, especially in those countries with diverse economic situations cannot afford the medication. The Glivec International Patient Assistance Program (GIPAP) implemented by Novartis in 2002, provides imatinib to qualified patients at no cost in more than 80 countries worldwide, at least two-thirds of the patients in GIPAP are in Asia–Pacific region, for example China, India, Indonesia, Malaysia, the Philippines, Thailand and Vietnam. In Thailand about 80% of CML patients get the medication through GIPAP and more than 2500 CML patients were registered to GIPAP and about 350 new cases are registered to GIPAP annually, while in India 95% of patients get access through GIPAP. At least 66% of patients who were registered to GIPAP in 2005 were alive and still active in the program at the end of 2007. In South Korea, Hong Kong and Taiwan, the National Health Insurance covers all or most of the drug cost. In Singapore Medisave and Medishield programs, run by the Government, partially cover imatinib treatment. The majority of patients in all phases are treated with imatinib except in some countries like Indonesia where only 15% of patients are treated with imatinib mainly through GIPAP and 85% of patients are still treated with hydroxyurea. In some centers in China more patients are treated with hydroxyurea, SCT and interferon than imatinib.

Asian patients, in general, respond to imatinib treatment as well as in the west although the complete cytogenetic response (CCyR) rates may be lower than those reported from the western countries. The complete hematologic response was similar to those reported from the Caucasian patients. The CCyR however ranged from as low as 24 in India to as high as 96 in China.1,3^–10

Severe but manageable neutropenia and thrombocytopenia are common in Asian patients, similar to what is experienced in western countries (42–46% of all phases). Discontinuation of imatinib due to side effects varies with the region (5% in India, 2% in Hong Kong and South Korea, 17% in one Thai Hospital 4% in IRIS trial).

Second-line treatment

Patients who are intolerant or resistant to imatinib usually get the second generation TKIs, either nilotinib or dasatinib. Both nilotinib and dasatinib are partially or fully covered by national insurance in Australia, Japan, Singapore and Taiwan as the second-line therapy. Most Asian physicians follow either ELN or NCCN Guidelines.

Disease monitoring

Cytogenetic study and molecular testing are done mostly at diagnosis in Asia–Pacific regions but monitoring the response is limited due to the cost and accessibility. In the survey done in AP region in 2010 most of the institutes participated in the survey use the in-house facilities. Most of the investigators report following ELN or NCCN guidelines; these are not always followed in the response assessment. Many hospitals lack the adequate facilities to either diagnose or monitor CML, leading to late diagnosis, delayed treatment and hence poor treatment outcome.

Asia CML Study Alliance (ACSA)

Since 2005 a group of Asian hematologists have reached consensus on establishment of Asia CML Study Alliance. Its purpose is to improve the quality and standardization of CML therapy and research in Asian countries on the basis of understanding the current situation. ACSA seeks collaboration in CML studies and sharing information for new medical discoveries in CML. ACSA has compiled all the efforts into Asia CML Registry (ACR) the data management system for collecting and sharing research outcomes. Up to the time of this manuscript, information of 3780 patients from 16 investigators in nine countries has been collected. The registered data on ACR belong to its researcher, and the data will be managed not to be used or shared without the researcher’s agreement. ACSA will send weekly report of the status of total registered data to participating Asian researchers.

Once researchers have registered their data on ACR, they will have an equal opportunity to propose any CML correlative studies, and utilize registered data of other researchers. The required data will be available for the researchers on the basis of mutual agreement between participating researchers when the proposed studies meet criteria of ACSA Scientific Study Committee. If the proposed study uses data of any researchers who consent to open their data, their name will be included in author list when the study results are published in the journals.

In addition, as the first step for ACSA collaborative studies the questionnaire on current situation of the core molecular assays in CML therapy (RQ-PCR and mutation assay) in hospitals and research institutes in Asian countries were sent.

After the 2008 AP Oncology Summit meeting, ACSA office had organized standardization/validation process for RQ-PCR and mutation assay with National Reference Laboratory in each Asian country. In addition, ACSA also set up the training program of molecular assays for participating countries where the National Reference Laboratory has not been established yet. The program is supported by Novartis and held in The Catholic University of Korea in Seoul, Korea.

CML in Thailand

CML ranks third in hematologic malignancies in Thailand. The actual incidence of CML in Thailand is unknown, and it is estimated that the annual incidence of newly diagnosed chronic phase CML is around 700–1000 cases. The median age is 36–41 years and the male to female ratio is 1·7∶1.

The Thai Society of Hematology has published the treatment guidelines for CML which is similar to ELN 2009 recommendation and NCCN Guidelines.

There are three health care systems in the country.

1. The Universal coverage system which is the majority of the population, patients get access to imatinib through GIPAP. Stem cell transplantation is not covered, but some patients may apply for SCT through the pilot project which covers for 25 cases of SCT for all hematologic malignancies in both adult and pediatric patients annually.

2. The Civil servants can get imatinib reimbursable. SCT is also covered in case the patients need the treatment.

3. The Social Security System covers for matched sibling SCT through the approval case by case. Patients who do not have matched sibling donors are not covered for imatinib. Novartis offers partial coverage for Social Security System patients if the hospital agrees to pay part of the cost. Not all hospitals agree to pay for the medication.

Diagnostic tests

The majority of patients get the cytogenetic study done at diagnosis. Molecular testing with RQ-PCR for bcr-abl with Conversion Factor is available in only Ramathibodi Hospital, Mahidol University as well as mutation analysis by direct sequencing technique. One center in the South recently received Conversion Factor confirmed. The majority of the physicians still use ELN 2006 recommendation for monitoring in terms of cytogenetic response monitoring, molecular monitoring is not done routinely in most centers due to the accessibility. Some centers send the samples to the reference laboratories for evaluation. At Ramathibodi Hospital we have been using ELN 2009 recommendation for monitoring since 2003 (especially in regard to cytogenetic monitoring).

Treatment strategies of CP, CML

The majority of chronic phase patients receive imatinib 400 mg daily as initial treatment. Patients who are intolerant or resistant to imatinib receive nilotinib as second-line treatment due to the patient assessment program through Tasigna International Patient Assistant Program and dasatinib is used as third-line treatment in the majority of cases. Patients who are resistant to all TKIs are usually put on hydroxyurea as supportive therapy. The numbers of SCT has decreased significantly since the introduction of imatinib.

CML in Ramathibodi Hospital, Mahidol University

At Ramathibodi Hospital which is a University Hospital with almost 1000 beds, we have been doing standard conventional cytogenetic study with at least 20 metaphases since 1978 in every CML patient, fluorescent in situ hybridization was established in 2000, RQ-PCR for bcr-abl with Conversion Factor in 2008. Mutation analysis with direct sequencing technique has been set up since 2009. We have been monitoring cytogenetic study according to ELN 2009 since 2003. Almost 95% of CML patients have been taken care of by one physician. The compliance of the patients has been excellent. We started using imatinib in June 2001 through the Expanded Access Program and the medication got the registration in 2002. During June 2001 through December 2010, 256 CML patients were treated with TKIs. The male/female ratio is 1·7∶1. One hundred and seventy-nine patients were in the chronic phase, 117 were in the early chronic phase (within 6 months of diagnosis) and 62 were in late chronic phase, 39 patients were in accelerated phase and 38 in blastic crisis.

More than half of our patients were in high Sokal risk group, which is different from what was reported in the literature. In the Western countries about half of CML were in low Sokal risk group, whereas almost half of the patients reported from China and Pakistan were in intermediate Sokal risk group.

At 5 years 91% of patients in early chronic phase had CCyR while 75% of late CP had CCyR. Early chronic phase patients tend to have better overall survival than late chronic phase patients (85 compared to 61% at 9 years, P = 0·08)

Clonal evolution in Ph-negative cells

There have been several reports of CML patients treated with imatinib who developed clonal evolution in Ph-negative clones; however, only seven series reported more than 100 cases and the incidence is 1·5–3·8%. In Ramathibodi Hospital during June 2001 to December 2006, of the 104 CP, CML patients we found 13 patients who developed clonal evolution in Ph-negative clones (12·5%). Patients who had clonal evolution at diagnosis were excluded. The most common abnormality was trisomy 8 (77%).

Mutation

Patients who were resistant to imatinib, 35 were tested for mutation and nine (26%) were found to have mutation. None had T315I.

Conclusion

The incidence of CML in Asian–Pacific region is lower than that in the Western countries and it affects the younger population and more patients are in the high and intermediate Sokal risk groups. More than half of Thai CML patients are in high-risk Sokal group. Monitoring the response is still limited due to the cost and accessibility. TKIs treatment remains out of reach for most Asian CML patients. Patients in several depend on the patient assistant program like GIPAP. Complete Hematologic Response in Asian patients was similar to those reported for the Caucasian patients; however, CCyR in Asian patients varies from as low as 24% in India to as high as 96% in one study from China.