Targeted therapies have greatly improved patient outcomes over the past 20 years.
Chronic myeloid leukemia (CML) is a myeloproliferative neoplasm that makes up 15% of new adult leukemia diagnoses; the average age at diagnosis is 64 years.1 CML is defined by the presence of the Philadelphia (Ph) chromosome, characterized by chromosomal translocation t(9;22), which is a product of the fusion of the BCR gene and the ABL1 gene.2 This fusion leads to a constitutively active tyrosine kinase, resulting in the aberrant division of myeloid cells. Following the introduction of targeted therapies, outcomes for patients with CML have improved over the past 20 years.
History of CML
There are 3 phases of CML: chronic, accelerated, and blast. At the time of diagnosis, most patients will present in chronic. Chronic CML can transform
into accelerated or blast at any time. Risk stratification of disease transformation to accelerated or blast and related outcomes have been assessed using prognostic tools such as Sokal or Hasford scores and more recently the European Treatment and Outcome Study long-term survival score.3
Prior to the discovery of the Ph chromosome and introduction of BCR-ABL1 tyrosine kinase inhibitors (TKIs), the prognosis for patients with CML was poor, with a 10-year survival rate of 20%.2 Pre-TKI therapy options included busulfan (Busulfex; Otsuka America Pharmaceutical, Inc), hydroxyurea (Hydrea; Bristol Myers Squibb), interferon beta-1a (Rebif; Merck KGaA), and, for a small subset of patients, hematopoietic stem cell transplant.4
Today, TKIs are the mainstay of therapy and transplant remains a potentially curative therapy option for select patients. In 2001, imatinib (Gleevec; Novartis Pharmaceuticals Corporation) became the first FDA-approved TKI for CML, targeting BCR-ABL1. Since the approval of this first-generation TKI, and the subsequent approval of second- and third-generation agents, the 10-year survival rate of patients with CML has improved by 80% to 90%.2
In the era of TKI therapy, treatment response is largely divided into 3 categories: hematologic, cytogenetic, and molecular. Furthermore, patients with increased depth and rapidity of response are more likely to have durable responses and improved long-term outcomes. With TKI therapy, patients with CML are expected to have a “normal” life span that, depending on their age at the time of diagnosis, can mean long-term management of
adverse effects (AEs) and potential financial burden.
For example, serious TKI-associated AEs include pleural effusions and myelosuppression with dasatinib (Sprycel; Bristol Myers Squibb); cardiovascular events (specifically corrected QT interval prolongation and metabolic effects) with nilotinib (Tasigna; Novartis Pharmaceuticals Corporation); diarrhea with bosutinib (Bosulif; Pfizer Inc), and several severe AEs necessitating a boxed warning with ponatinib (Iclusig; Takeda Pharmaceuticals America, Inc).2 The cost of generic imatinib ranges from $4400 to $82,000 annually, and costs of second-generation TKIs (dasatinib, nilotinib, and bosutinib) all exceed $150,000 annually.2,5
Trails Assessing TKI Discontinuation
Because of TKI-induced toxicity, cost considerations, and the observed durable, deep responses to TKI therapy, studies have evaluated the outcomes of patients who have achieved these deep responses and subsequently discontinued their TKI therapy.
Increasing data to support TKI discontinuation and maintained remission, or treatment-free remission, have started discussions of a relative “cure” for patients with CML. Most studies that have evaluated the feasibility of TKI discontinuation have been smaller and focused on specific TKIs with variable discontinuation criteria. The National Comprehensive Cancer Network (NCCN) has published standardized response criteria for CML (Table 1).3
In the NCCN criteria, deep molecular response is defined as 4.0-fold or 4.5-fold reduction in BCR-ABL1 transcripts (BCR-ABL1 international scale [IS] ≤ 0.01%, BCR-ABL1 IS ≤ 0.0032%, respectively). Complete molecular response (CMR) is noted as being achieved when BCR-ABL1 transcripts are undetectable by quantitative polymerase chain reaction test (qPCR). In cases of relapse, most patients are able to achieve disease control again upon resumption of TKI therapy.
An early study evaluating treatment discontinuation was the STIM trial (NCT00478985), in which 100 patients were enrolled who had taken imatinib
for a minimum of 3 years and had at least 2 years of continued CMR. Relapse was defined as the loss of CMR, which was defined as BCR-ABL1 transcript positive qPCR (ratio of BCR-ABL to ABL of 10-5 or more). With a median overall follow-up of 17 months, 42 (61%) of 69 patients with at least 12 months of follow-up relapsed within 3 to 6 months of discontinuation. After restarting imatinib, 16 patients (38%) once again achieved CMR within a median of 3 months.6
In the largest discontinuation trial to date, the EURO-SKI trial (NCT01596114) enrolled 758 patients with the objective to determine criteria to discontinue TKI therapy (imatinib, nilotinib, or dasatinib) and the duration of major molecular response (MMR) after discontinuation. The trial investigators found that for patients with CML who discontinued their TKI after 3 years and had achieved a deep molecular response for at least 1 year, molecular relapse-free survival was 61% and 50% at 6 months and 24 months, respectively.
Of the 755 evaluable patients, 371 (49%) relapsed (MMR > 0.1% BCR-ABL1 IS) after discontinuation of their TKI.7
Upon TKI reinitiation, 321 (86%) of 371 patients were able to achieve disease control after relapse. Of note, 2 patients lost MMR despite restarting TKI therapy. Several other studies have evaluated TKI discontinuation and found similar results, which are summarized in the NCCN guidelines.3
NCCN has published guidelines for TKI discontinuation, which stem from supporting data from trials (Table 23). Of note, the novel TKI asciminib (Scemblix; Novartis Pharmaceuticals Corporation) was approved by the FDA in 2021 for patients with CML who were previously treated with 2 or more TKIs. Currently, there are insufficient data to consider patients on asciminib for TKI discontinuation and treatment-free remission.2
Patient perspective should be considered when weighing TKI discontinuation. Sharf et al surveyed more than 1000 patients with CML regarding their perspectives on discontinuation. After a discussion with their provider, 55% (n = 555) of patients were still concerned about the attempt being unsuccessful and the potential for relapsed disease. Of the 494 patients who reported having stopped treatment, 32% (n = 159) of them reported a CML relapse, requiring TKI reinitiation. Upon relapse, 59% (n = 81) of these patients strongly agreed/agreed that they were feeling scared/anxious, and 91% (n = 138) strongly agreed/agreed they were feeling disappointed.8
As evidenced by this survey, sharing decision-making with the patient and providing emotional support are important factors during TKI discontinuation. Within 1 to 2 months of stopping therapy, 25% to 30% of patients may also experience TKI withdrawal syndrome, which is characterized by diffuse musculoskeletal pain and can be managed with nonsteroidal anti-inflammatory agents or steroids.9 Upon TKI resumption, this pain typically resolves; however, it is not recommended to resume TKI therapy unless the patient has a CML relapse. Patients should be counseled on TKI withdrawal syndrome and its management prior to TKI discontinuation.
TKI discontinuation is reasonable in a subset of patients with CML who have achieved deep molecular response for at least 2 years and have been on TKI therapy for at least 3 years. Routine surveillance is needed to ensure MMR is sustained and to monitor for blast crisis, although its incidence is rare: Of the 371 patients who relapsed off TKI therapy in the EURO-SKI trial, none progressed to blast CML.7
Pharmacists can play an important role in patient counseling with respect to discontinuation and management of TKI withdrawal syndrome. The decision to discontinue TKI therapy should be a shared decision with the patient after careful consideration and discussion.
About The Authors
Caroline McCaslin, PharmD, is a postgraduate year 2 oncology pharmacy resident at University of Washington Medicine and Fred Hutchinson Cancer Center in Seattle, Washington.
Jonathan Cohen, PharmD, BCOP, is a clinical pharmacy specialist at University of Washington Medicine and the Fred Hutchinson Cancer Center in Seattle, Washington.
1. Key statistics for chronic myeloid leukemia. American Cancer Society. Updated January 12, 2022. Accessed September 10, 2022. https://www.cancer.org/cancer/chronic-myeloid-leukemia/about/statistics.html
2. Jabbour E, Kantarjian H. Chronic myeloid leukemia: 2020 update on diagnosis, therapy and monitoring. Am J Hematol. 2020;95(6):691-709. doi:10.1002/ajh.25792
3. NCCN. Clinical Practice Guidelines in Chronic Myeloid Leukemia, version 1.2023. Accessed September 10, 2022. https://www.nccn.org/professionals/physician_gls/pdf/cml.pdf
4. Goldman JM. Chronic myeloid leukemia: a historical perspective. Semin Hematol. 2010;47(4):302-311. doi:10.1053/j.seminhematol.2010.07.001
5. Shih YT, Cortes JE, Kantarjian HM. Treatment value of second-generation BCR-ABL1 tyrosine kinase inhibitors compared with imatinib to achieve treatment-free remission in patients with chronic myeloid leukaemia: a modelling study. Lancet Haematol. 2019;6(8):e398-e408. Published correction appears in Lancet Haematol. 2020;7(1):e11.
6. Mahon FX, Réa D, Guilhot J, et al; Intergroupe Français des Leucémies Myéloïdes Chroniques. Discontinuation of imatinib in patients with chronic myeloid leukaemia who have maintained complete molecular remission for at least 2 years: the prospective, multicentre Stop Imatinib (STIM) trial. Lancet Oncol. 2010;11(11):1029-1035. doi:10.1016/S1470-2045(10)70233-3
7. Saussele S, Richter J, Guilhot J, et al; EURO-SKI investigators. Discontinuation of tyrosine kinase inhibitor therapy in chronic myeloid leukaemia (EURO-SKI): a prespecified interim analysis of a prospective, multicentre, non-randomised, trial. Lancet Oncol. 2018;19(6):747-757. doi:10.1016/S1470-2045(18)30192-X
8. Sharf G, Marin C, Bradley JA, et al. Treatment-free remission in chronic myeloid leukemia: the patient perspective and areas of unmet needs. Leukemia. 2020;34(8):2102-2112. doi:10.1038/s41375-020-0867-0
9. Sweet K. Starting tyrosine kinase inhibitor cessation in chronic-phase chronic myeloid leukemia patient. The Hematologist. 2018;15(4). doi:10.1182/hem.V15.4.8717