Abstract
Background/Aim: Imatinib (IM) is the standard-of-care treatment for most chronic myeloid leukemia (CML) patients in chronic phase (CP). However, some patients suffer from low-grade side-effects that, in the long run, severely affect the quality of life and require treatment discontinuation due to toxicities. Fortunately, there are several therapeutic alternatives for these patients. Among them, the second-generation tyrosine kinase inhibitor dasatinib (DAS), used as second-line treatment, has shown to be a valid option in patients with CP-CML after intolerance to prior IM. Patients and Methods: Herein, we report on seven CP-CML patients who achieved a stable major molecular response (MMR) with IM-therapy, but were shifted to DAS treatment due to recurrent low-grade IM-intolerances (grades 1-2). Results and Conclusion: All patients received conventional DAS treatment with a median daily dose of 83.3 mg. Treatment was well tolerated and side-effects were mild. In addition, after a median follow-up of 25 months (range=24-43 months) a deep molecular response (DMR) (either MR4 or MR4.5) was achieved in all patients after 24 months of treatment. This finding, although limited to a small cohort of CP-CML patients, supports the view that a therapy switch from IM to DAS induces a reduction of symptom burden, improves patient compliance and shows clinical efficacy in achieving and sustaining deep molecular responses.
The clinical scenario of chronic myeloid leukemia (CML) has changed significantly, since the introduction of tyrosine kinase inhibitors (TKIs) therapy. In most cases, CML has become a chronic disease, requiring both long-term treatment and molecular monitoring, allowing patient life expectancy to approach that of the general population (1) and driving them to achieve deep molecular response (DMR) in a substantial number of cases (2). Evidence has shown that most CML patients in chronic phase (CP-CML) who have achieved a stable DMR can safely discontinue TKI treatment (3). However, in the clinical aspect, a proportion of CP-CML patients had to change TKIs treatment due to the occurrence of adverse events, thus affecting the achievement of either clinical or molecular responses (4).
The classic trial International Randomized Study of Interferon and STI571 (IRIS) compared interferon-alpha combined with low-dose cytarabine therapy to imatinib (IM) 400 mg daily in newly-diagnosed CP-CML patients (5). In that investigation IM displayed markedly superior rates of complete hematological response, complete cytogenetic response (CCyR), major molecular response (MMR) and freedom from disease progression to advanced phases. In the long term, patients assigned to the IM group showed an estimated overall survival rate of 83.3% at 10 years (6). At 5 years of follow-up 49.9% of the patients had a CCyR, 50.3% of them reached a MMR and 23% a deep molecular response (MR4.5), while at 10 years of follow-up 34.4% of patients displayed a MMR and 23.3% had a MR4.5 (all data on intention to treat population). However, at the last update of this trial, 49.2% of the enrolled patients discontinued IM-therapy and in 6.9% of them it was due to adverse events (AE).
Persistent low-grade AEs may prevent patients with CP-CML from continuing TKIs therapy and can adversely impact both their quality of life (7) as well as clinical efficacy (8). In this era, the availability of second-generation TKIs has been helpful as an alternative regimen in all cases of intolerance/resistance to IM-therapy (9). Herein, we report on the efficacy of dasatinib (DAS) therapy used as second-line treatment in both improving quality of life and inducing deep molecular responses (DMR) in IM-intolerant CP-CML patients who were in stable MMR.
Patient characteristics at diagnosis and previous Imatinib treatment.
Patients and Methods
Seven patients with CP-CML (Table I) treated with IM showed persistent low-grade AEs that seriously affected their quality of life. Median age at CML diagnosis was 53 years (range=46-66 years), with a male/female ratio of 4/3. According to Sokal score patients were the following: three high-risk, two intermediate-risk and one low-risk patient; while according to EUTOS long term survival (ELTS) score: three had intermediate-risk and three low-risk score. One patient was not stratified for prognostic scores because of previous CML-unrelated splenectomy. Bone marrow cytogenetics showed the presence of the Philadelphia chromosome in all patients and one of them exhibited trisomy 8. BCR-ABL1 transcript type was e14a2 in five out of seven and e13a2 in two patients. BCR-ABL1 transcript levels were assessed at baseline and every 3 months, and transcript values were measured from peripheral blood samples using real-time PCR (RT-qPCR) using ABL1 as the reference gene at any time. BCR-ABL/GUSIS was also evaluated at diagnosis, as previously reported, and high levels of BCR-ABL/GUSIS were present in three patients, while the others showed low transcript levels (10). All molecular responses were categorized according to common accepted guidelines (11).
After informed consent, patients were started on conventional IM-therapy with a median duration of 61 months (range=14-144 months). All obtained an optimal response within 18 months of treatment according to ELN recommendations (12), but soon began to experience IM-related AEs. The most common were diarrhea, muscle spasms and periorbital edema. Intolerances were graded according to Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 (13).
Persistent AEs, although low grade, impacted seriously the patients' quality of life and therefore standard DAS treatment (100 mg/day) was administered. Median DAS daily dose was 83.3 mg with a median follow-up of 25 months (range=24-43 months). Six out of seven patients showed a stable MMR before commencing DAS-therapy. In fact, one patient had a MR4, although with a fluctuating molecular response between MMR and MR4. After switching to DAS treatment five patients out of seven achieved a DMR at 12-months (3 gained MR4 and two MR4.5) and median time to achieve DMR was 4.5 months (range=3-21 months). Then, at 18-, 21- and 24-months a DMR was reached by 4 out of 7, 6/7 and 7/7 patients. All patients experienced low grade AEs (grade 1-2), but not persistent and no grade 3/4 event was recorded (Table II). Grade 2 toxicity was resolved with dose reduction (50 mg/day) in five patients (71%). Most common DAS-related side effects were fatigue in five patients, myalgia and pleural effusion in four patients, and pericardial effusion in three patients. Infections (pulmonary and urinary tract), pleural and pericardial effusions were present in two patients, respectively. No patient had to discontinue DAS therapy because of AEs and these events did not affect their quality of life.
Results and Conclusion
The introduction of TKIs therapy revolutionized treatment and clinical outcomes in CP-CML. Nevertheless, because of long-term treatment, different rates of AEs have been described and recurrent AEs have become an important cause of quality of life impairment, lack of compliance and finally treatment discontinuation (6, 14-18). We, herein, describe seven patients who suffered from persistent low-grade AEs that impaired seriously their every-day living activities and had to discontinue IM-treatment being switched to DAS therapy. A recent investigation showed that CML patients in IM therapy reported worse disease-specific health-related quality of life outcome and symptom burden as compared to DAS treatment (19). Moreover, a prospective study showed that switching from IM to DAS because of intolerance, greatly improved patients' quality of life, leading to better compliance, despite the onset of DAS-related AEs (20). Another study on IM-intolerant patients revealed grade 3-4 AEs cross-intolerance in a minority of patients treated subsequently with DAS, while attaining improvements in both cytogenetic and molecular response (21). In our small cohort, we observed a reduction of both hematological and non-hematological AE rates, including muscle spasms and diarrhea, with no patient representing periorbital edema. On the other hand, despite the emergence of DAS-related AEs, like pleural and pericardial effusion, we noted that these AEs did not severely affect the patient's quality of life.
Therapy-related adverse events.
Second-generation TKIs and the new third-generation ponatinib have been already approved as second-line treatment and have demonstrated efficacy in the setting of CML resistance/intolerance (18, 22-24). Conversely, few studies investigated a molecular improvement from a baseline MMR. The first study investigated the efficacy of nilotinib (NIL) in CP-CML patients intolerant to first-line treatment with IM or DAS and not in DMR: only 45% of the enrolled patients had MMR baseline and were not assessed sequentially (25). In the same way the Evaluating Nilotinib Efficacy and Safety in clinical Trials-Complete Molecular Response (ENESTcmr) study investigated patients having not only CCyR, but also persistent minimal residual disease (either with or without MMR baseline) (26). The Nilotinib Switch (NILSw) trial showed the efficacy of switching to NIL treatment in CP-CML patients who had previously achieved MMR with IM therapy (27). Among thirty-eight patients enrolled in study, the cumulative incidence of achieving MR4.5 was 53.7% by 21 months.
Our data are consistent with “real life” data showing that DAS therapy might represent a safe and effective option for patients resistant/intolerant to IM (28-29) as well as it induces clinical efficacy also in atypical transcripts (30). Moreover, it was recently demonstrated as DAS treatment, as first-line therapy, indicated a significantly lower impact on CML patients' daily life as compared to their peers treated with IM (19).
In conclusion, our finding, although limited to a small group of CP-CML patients, supports the view that a therapy switch from IM to DAS induces a reduction of symptom burden, improves compliance and might be of aid in achieving deep molecular responses after a baseline MMR obtained previously with IM-therapy, making it possible for more candidates a treatment free remission path.
Footnotes
Authors' Contributions
UM and FS drafted the manuscript; UM, AB, SL, CC and FS managed the patients, analyzed and interpreted the data; SS, MLC and LT performed laboratory tests; FDR and FS supervised the clinical project. All Authors have seen and approved the final version of the manuscript.
Conflicts of Interest
The Authors declare that they have no competing interests.
- Received June 15, 2020.
- Revision received July 9, 2020.
- Accepted July 10, 2020.
- Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved
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