Abstract
Background: Clinical trials demonstrate a safe discontinuation possibility of tyrosine kinase inhibitors (TKI) in patients with deep molecular response (MR). However reasons and indications for TKI cessation as a part of treatment process have not been studied.
Aims: To evaluate the eligibility of long term TKI cessation in CML patients with deep and long lasting MR. To describe the reasons of stopping therapy, principles and terms of observation without treatment, preserving and restoring of MR.
Methods: We summarized retrospectively and prospectively 25 TKI discontinuation cases in 2 clinics of Russian Federation (Moscow, St.Petersburg, 2008-2014). Inclusion criteria were: 1) Ph+CML 2) MR4 (BCR-ABL<0,01%) for >12 months confirmed by >2 consecutive analyses 3) discontinuation of TKI treatment. Chronic phase (CP)/accelerated phase (AP) at diagnosis was 24/1. Sokal score for CP patients was 15/8/1 for low/intermediate/high risl group. Therapy before discontinuation was the following: imatinib 1st line (n=16), 2nd generation TKI (TKI2) 2nd-3rd line (n=9): 5 dasatinib/ 4 nilotinib. Me TKI duration was 7,2 (range 2,5-13) years, Me MR4 duration was 50 (range 12-97) months. IFN before TKI was received by 13(52%) of 25 patients for Me 18 months (2-60 months).
Results: We specify 2 reasons of TKI discontinuation: 1) adverse events (AE) of TKI (Toxicity Group), n=18 2) self decision of patients (Active Group), n=7 (Table 1).
Table 1. Characteristics of CML patients according to reason of stopping TKI (n=25) Toxicity Group (n=18) Active Group (n=7) Ме of age, years (min-max) 55 (27-74) 36 (23-58) Ratio male/female (m:f) 9m:9f 3m:4f Ме duration of TKI therapy, years (min-max) 5,9 (2,5-13) 8,6 (4,4-10,1) Ме duration of МО4 at treatment cessation, months (min-max) 41 (12-97) 67 (33-79)
In Toxicity Group therapy was stopped for 1) AE grade 1-3 in 5 of 18 patients: unstable angina (2), hepatotoxicity (1), acute renal failure (1), menstrual dysfunction and infections (1); 2) AE grade 1-2 in 13 of 18 patients including recurrent or long lasting: fatigue, edema, arthralgia, muscle cramps, diarrhea, recurrent pleural effusion. The key clinical decision was not to restart TKI after AE termination and to continue monitoring of BCR-ABL transcript levels by RQ-PCR. For Active Group self-made discontinuation was in 7 patients with long lasting MR4 due to knowledge of safe discontinuation (4) and for conception (3). In 6 of 7 patients BCR-ABL monitoring was performed, 1 patient refused from monitoring.
Treatment was restarted at major molecular response (MMR) loss (BCR-ABL>0,1%) or by decision of physician. In case of severe AE the patients were switched to alternative TKI.
Thirteen (52%) of 25 patients were observed without treatment for Me 23 months (6-77 months), in 12 MR4 was maintained, 1 patient being off treatment for 54 months refused from monitoring (Active Group). Therapy was resumed in 10 patients with MMR loss and in 2 without MMR loss, by physician decision. All MMR loss cases occurred within first 6 months, no CML progression observed. Response restoration to MR4 was in 8 of 10 patients in 3-16 months, in other 2 it is early to estimate
Summary/Conclusion: Observation without therapy may become an option in CML patients with mostly low/intermediate Sokal risk group, stable MR4 and recurrent/severe TKI toxicity. Self declared decisions of young patients with durable deep MR should be accompanied by regular RQ-PCR especially within first 6 months after TKI discontinuation. Resuming therapy at MMR loss shows to be safe.
Disclosures
No relevant conflicts of interest to declare.
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