Molecular Response to Tyrosine Kinase Inhibitors (TKIs) for Chronic Myeloid Leukemia (CML). an Update on Experience at Tawam Hospital, Abudhabi, UAE in the Light of ELN Guidelines

Background

Chronic Myeloid Leukemia (CML) is a clonal myeloproliferative disorder characterized by the presence of a balanced reciprocal translocation involving the long arms of chromosomes 9 and 22. The fusion gene that is created by this translocation (BCR-ABL1) encodes for a constitutively active protein tyrosine kinase that is primarily responsible for the leukemic phenotype.

Targeted therapy with Tyrosine Kinase Inhibitors (TKIs) has become the recommended first-line treatment for patients with CML. Commercially available TKIs include Imatinib, Nilotinib, Dasatinib, Ponatinib and Bosutinib. The first three drugs are approved for first line therapy while the later 2 are for resistant disease. Monitoring of the response to therapy is done with quantification of the BCR-ABL transcripts by RQ-PCR–based molecular technique.

Methods

Retrospective review of charts of patients diagnosed with CML between January 2010 and June 2014. Data points were measured at 3, 6, 12, and 24 months post initiation of therapy and results were documented as per ELN guidelines.

Results

56 patients were diagnosed with CML. The median age was 33 years (range 19-73 years). Male to female ratio was 4:1. Sokal score was calculated for 53 patients (data for 3 patients was incomplete) 21 were low risk, 24 were intermediate risk and 8 were high risk.

7 patients were lost from follow up after diagnosis and are excluded from analysis. 1 patient has not reached the 3 month mark and is also excluded from analysis. 13 patients were started on initial treatment with Imatinib 400 mg while 35 with second generation TKIs (Dasatinib 100 mg daily or Nilotinib 300 mg BID) daily as upfront therapy.

With a median follow up of 27 months (range 3 month to 51 months) 4/13 (30%) patients on Imatinib as first line therapy were able to achieve optimal repsone (one at a dose of 600 mg daily). 8 patients were switched to second line therapy and 7/8 patients have achieved MMR (1 patient remains in full cytogenetic relapse due to non-compliance). 35 patients were treated with 2^ndgeneration TKIs as first line therapy. 22 out of 35 (62 %) patients have achieved optimal results within 18 months of front line therapy . Second line therapy was initiated in patients achieving suboptimal results or intolerance in 11 patients. 5 of these patients subsequently achieved MMR while 5 remain with suboptimal results. 1 patient had disease progression while one was lost to follow-up after achieving a partial cytogenetic response at 6 months.

Interestingly 12 (25%) patients achieved MMR/CMR within 6 months of starting TKIs. Of these only 1 was on Imatinib while the rest were on 2^ndgeneration TKIs. MMR 4.5 or undetectable levels of bcr-abl transcript have been documented in 10 patients (20 %) for the whole cohort.

4 patients had disease progression on TKI (treatment failure rate of 8 %). One patient had disease progression to accelerated and then blast crisis (lymphoid and myeloid) while the other 3 patients are alive with only CHR with one resistant to all TKIs, one with intolerance of all TKIs and one secondary to noncompliance.

Conclusion

We have previously reported on our experience with CML. We have now updated our report with a larger cohort of patients. The median age remains much lower as compared to Western countries, just reflecting differences in the age distribution of the population in the UAE with 80% being below the age of 65 years.

MMR report from Enestnd trial is 67-71% in favor of Nilotinib as compared to Imatinib 44%, while the Dasision trial reported a MMR of 44 % in favor of Dasatinib with faster rate to response. Our results mirror the results of these phase 3 randomized trial with optimal response of 62 % with second generation TKIs% as compared to 30 % with Imatinib as front line therapy.

Expatriates accounts for approximately 80% of the population in the UAE and many are temporary employed, having limited health care coverage, limited financial means as well as limited possibilities to attend regular follow-ups. This leads to compliance problems, loss from follow-up and suboptimal management and monitoring of their disease. These factors also complicate any chance of treatment free period for patients who achieve undetectable levels of bcr-abl transcripts. Additionally absence of technology for mutational analysis makes it impossible to determine underlying reasons for suboptimal response with accuracy.