Patan hospital experience in treating philadelphia chromosome/BCR-ABL1 positive chronic myeloid leukemia patients with gleevec (imatinib mesylate); the first generation specific tyrosine kinase inhibitor

Chronic myeloid leukemia (CML), is a myeloproliferative disorder caused by a translocation between chromosomes 9 and 22 that results in the Philadelphia (Ph) chromosome [t(9;22) (q34;q11)] [1]. The Ph chromosome was found to encode a reconstituted fusion gene known as BCR-ABL1, which is the principal cause of CML[2]. The BCR-ABL1 fusion gene encodes the BCR-ABL1 oncoprotein. This oncoprotein, which is constitutively active due to its uncontrolled tyrosine kinase activity, activates signal transduction pathways that lead to DNA replication and cell proliferation[3–5].

The incidence of CML is similar in countries around the world and may affect ethnic groups equally. The annual incidence of CML in the US is 1.6 cases per 100,000 adults (approximately 5000 new cases per year), with a male-to-female ratio of 1.4 to 1[6, 7]. The median age at diagnosis is approximately 55 years, with fewer than 10% of patients under the age of 20 years[8]. During the chronic phase of the disease there is clonal expansion of myeloid cells which continue to differentiate. Over time, however, the leukemic clone loses their ability to differentiate, and the disease ultimately progresses to blast crisis[3, 9, 10].

Until the 1980s, CML was regarded as incurable and thus inevitably fatal. Only some selected patients could afford treatment with, and in many cases were cured by allogeneic stem cell transplantation. However, because of the scarcity of matching donors and the high incidence of potentially fatal graft-versus-host disease in older patients, allogeneic stem cell transplantation is often not a feasible treatment strategy. Imatinib[11–16], is a potent first generation selective inhibitor of tyrosine kinase activity of BCR-ABL1. It was first approved by the Food and Drug Administration for CML in May 2001 and has been proven to be one of the most effective medications in achieving hematologic and cytogenetic remissions. Imatinib is a major break-through in the management of CML and has become the standard first line treatment strategy in the management of CML[17].

Patan hospital is the first Gleevec International Patient Assistance Program (GIPAP) center in Nepal. GIPAP was introduced by Dr. Zimmerman, the medical director of this hospital at that time, for patients with Ph chromosome/BCR-ABL1 positive CML since February 2003. Under this program patients with Philadelphia chromosome/BCR-ABL1 positive CML who cannot afford Imatinib receive it free of cost.

The prevalence of CML is more common in the 31-50y age group in our study than in most demographic studies. The demographic characteristics between patients with or without cytogenetic analysis were not significantly different. Most of the patients were from Kathmandu and Lalitpur districts. Patients who had cytogenetic analysis repeated had a longer follow up period compared to the patients who had not. The increased number of deaths seen in patients who had not repeated cytogenetic analysis might be related to not being able to assess optimum responses to therapy.

Imatinib is currently the standard frontline therapy for treatment of CML. Druker and colleagues' five year follow-up of chronic phase CML patients treated initially with imatinib showed that the cumulative best rates for complete cytogenetic responses and complete hematologic response were 87% and 98% respectively[11]. An estimated 7% of the patients progressed to accelerated or blast phase. The overall survival rate was 89%, with more patients dying from causes unrelated to CML than their disease. Review of the International Randomized Study of Interferon vs STI571 (IRIS) data suggests that 63% of patients were successfully treated by imatinib at five years, while 37% of patients were no longer receiving the drug. In our study at Patan, 89.7% of our patients had major cytogenetic response (BCR-ABL1/Ph chromosome 0-34%), 6.9% of our patients had minor cytogenetic responses (BCR-ABL1/Ph chromosome 35-64%), and 3.4% of our patients had minimal cytogenetic response (BCR-ABL1/Ph chromosome 65-94%). After a mean follow up of 27 months (median follow up 24 months), CML had not progressed to the accelerated phase or blast crisis in 90% of the patients and more than 90% of the patients are still alive. Our patients' responses to imatinib were similar to those reported in IRIS by Druker and colleagues.

Importantly, our study establishes that imatinib is safe to use in a developing county. Myelosuppression was the most common side effect, and this was easily monitored in our setting with complete blood counts. Our monitoring allowed for appropriate dose adjustments.

Quite often patients on imatinib develop resistance, and the identification of resistance should trigger mutational analysis of BCR-ABL1 kinase domain. Reviews on managing imatinib resistance have been published[18–22]. A few of our patients treated with imatinib relapsed, reflecting the emergence of resistance to imatinib. Although there are multiple mechanisms involved in the emergence of resistance, usually resistance develops because of a mutation in the adenosine triphosphate-binding pocket of the BCR-ABL1 oncoprotein, which makes imatinib binding impossible. Molecular studies of resistant CML cells have been performed and have identified mutations that mediate this effect[23–27]. Several potent inhibitors of imatinib-resistant BCR-ABL1 have been identified and approved for clinical use[28–32]. Two of our patients developed secondary hematologic failure. Subsequent mutation analyses revealed mutations in ABL domain of BCR/ABL oncogene. The patient who had the L387 M mutation responded to dose escalation of Imatinib to 600 mg/day from 400 mg/day[33–36]. Another patient who had F359V mutation did not show response even with dose escalation to 800 mg/day. He was switched to second generation tyrosine kinase inhibitor (TKI) nilotinib but the response was not satisfactory. Failure to achieve major cytogenetic response by 12 months usually defines inadequate response[37]. He was then switched to dasatinib (another second generation TKI) and the response was remarkable. He went into hematological remission within few weeks. Dasatinib seems to be more effective in F359V mutation.

The main problem in our setting is the inability of our patients to obtain regular cytogenetic and molecular analyses as recommended by the standard guidelines in the management of Ph chromosome/BCR-ABL1 positive CML. The high cost of cytogenetic or molecular analysis and lack of availability of diagnostic centers in Nepal where these tests can be easily performed are prohibitive. Quantitative cytogenetic analysis by FISH costs about 7,000 Nepalese rupees (NRs) (US $90) and quantitative molecular analysis of BCR-ABL1/ABL ratio by RT-PCR costs about NRs. 10,000 (US $130). These costs are so high because the test is not done in Nepal; the laboratories only collect the samples and dispatch them to diagnostic facilities in India. Patients are often called back for repeat sample collections because the samples they have collected are lost somewhere in the chain of transport. Only about one-third of the total patients repeated cytogenetic analysis. The cumulative survival is significantly better in this group. Cytogenetic analysis allows detection of inadequate responses or resistance to therapy at an earlier stage of the disease and allows for adjustments in the management including choosing appropriate TKIs or referral for stem cell transplantation. Most of our patients could not afford a second test. So, it is very important that the concerned authorities seriously consider establishing an advanced medical laboratory at an affordable price in our own country.

Despite the fact that our patients hailed from different parts of Nepal, most patients managed to come for follow up regularly with usual hematological and biochemical tests and the compliance with the study medication was good. Interestingly, our patients also had remarkable cytogenetic and hematologic response rates consistent with other well controlled studies done elsewhere. GIPAP has enabled many patients to receive standard of care treatment that would otherwise be prohibitive due to cost in Nepal.

Our study demonstrates that imatinib is safe to use in a developing country. Furthermore, we demonstrate that imatinib is very effective and induced long lasting responses in a high proportion of patients with Ph chromosome/BCR-ABL1 positive CML. Imatinib is well tolerated by our patients. The lack of cytogenetic analysis in the majority of our patients hindered our ability to detect inadequate responses to Imatinib and adjust therapy appropriately.