Imatinib improved the overall survival of chronic myeloid leukemia patients in low- and middle-income countries: A therapeutic goal has been reached

The management of patients with chronic myeloid leukemia (CML) has drastically changed following the introduction of different tyrosine kinase inhibitors (TKIs). In particular, long-term results obtained with imatinib, the first generation TKI, demonstrates that patients who achieved at least a complete cytogenetic response or better, a deep molecular response, have a survival similar to that of matched (age and gender) normal controls [1]. Unfortunately, the cost of therapy remained elevated with limitation of use in low and middle-income countries [2]. A global program, namely the Glivec International Patients Assistance Program (GIPAP), was created by Novartis in 2001 and provide imatinib without any cost to patients affected by CML or gastrointestinal stromal tumor (GIST). From the partnership Max Foundation database, long-term survival analysis was recently published by Chukwuemeka and colleagues [3], covering a period of 13 years: 63 000 patients received imatinib in 93 countries, the majority of them (85%) affected by CML in different stages of disease. Seven-year survival was estimated to be 87.7% for CML patients and 78.6% for GIST patients. For CML patients, survival rate of different stage of disease was also reported and although the brilliant results achieved with imatinib, the 7-year survival of accelerated and blast phase patients was 77.5% and 53%, respectively. The risk of death was higher in male patients (7% higher), in non-CML patients (24.6% higher), in older patients (increases of 1.7% for each year increase in age at enrollment), for each year increase between diagnosis and enrollment (0.4%, with increased survival in the late years of enrollment into the program). More than 17 000 patients were estimated to be saved by GIPAP program. To maintain sustainability, Novartis Pharma Industry collaborated and supported foundations and translate the GIPAP program into CMLPath to Care model, providing imatinib in 65 countries. Similar to Novartis, other Pharma industries started similar collaborations and 25 countries have now the possibility to prescribe available TKIs for the cure of this disease.

Contrasting results were reported for life expectancy of CML patients treated with imatinib: the Swedish Cancer registry reported 2662 CML patients diagnosed over a period of 40 years, showing a survival improvement, in particular in youngest ages. For younger patients, an increase in life expectancy was seen after 1990 and continued until 2013, with a largest increase seen between 1990 and 2000 and a more steady increase after 2000 [4]. Long-term follow-up of the first international trial that compared frontline imatinib versus best available therapy, namely the IRIS study, showed that 10-year estimated overall survival of patients who achieved a complete cytogenetic response was 83.3% [5].

Surveillance, Epidemiology and End Results (SEER)-Medicare database analysis was recently reported: 805 CML patients followed for 5 years were matched with non-cancer beneficiary sample. An improved survival (79%) was described only for patients with more than 85% compliance similar to that of non-cancer beneficiaries (76%), compared indeed to 62% in patients with less than 85% compliance. Decreased survival could be related to reduced access to TKIs probably insurance-related [6].

Indeed, a recent analysis of US SEER dataset using SEERaBomb software highlighted controversies on the survival topic of CML patients treated with TKIs. From a statistical analysis that showed the relative risk of death, it seems that CML patients in the US have a 2.38-fold higher risk of death than controls, completely in contrast with information reported by registries or clinical trials. Possible explanation for discordant data reported since now could be related to the access and availability of drugs, healthcare system and the unavailability of molecular monitoring [7]. In line with this analysis, Jiang and colleagues reported the impact of socio-demographics features on survival of adult Chinese CML patients: male patients with a low level of education and rural residence, with low probability of continuous molecular monitoring have a worse outcome compared with controls [8]. Some authors suggested caution in the interpretation of survival data extrapolated from clinical trials and registries [7]. Indeed, the survival analysis by Chukwuemeka et al [3] estimated the number of lives saved by the introduction of imatinib as optimal treatment. Even if this analysis has the limitation based on the absence of some prognostic features at baseline, such as the Sokal stratification, the median age at presentation was 41 years, much lower than in the high-income countries. Several studies have demonstrated that in younger patients, poor adherence and inadequate drug dosing are associated with increased relapse and decreased survival [9]. Despite the possible low compliance to treatment and appropriate molecular monitoring in low- and middle-income countries, the GIPAP program reached a therapeutic goal with a real survival increase.

Declaration of competing interest

MB received honoraria by Pfizer, Incyte, Novartis.