De novo accelerated phase of chronic myeloid leukemia should be recognized even in the era of tyrosine kinase inhibitors
Authors: Tomas Hornak, Jiri Mayer, Petra Cicatkova, Lukas Semerad, Anezka Kvetkova, Hana Klamova, Edgar Faber, Petra Belohlavkova, Michal Karas, Lukas Stejskal, Eduard Cmunt, Olga Cerna, Dana Srbova, Hana Zizkova, Lucia Vrablova, Ivana Skoumalova, Jaroslava Voglova, Tereza Jurkova, Marika Chrapava, Tomas Jurcek, Ivana Jeziskova, Marie Jarosova, Katerina Machova Polakova, Tomas Papajik, Pavel Zak, Pavel Jindra, Daniela Zackova
Journal: American Journal of Hematology (2024)

Overall survival of patients classified according to the European LeukemiaNet 2020 classification. Chronic phase (CP), accelerated phase (AP), blast crisis (BC), low risk (LR), intermediate risk (IR), high risk (HR). Chronic myeloid leukemia (CML) has been described as a triphasic disease for several decades. Before the introduction of tyrosine kinase inhibitors (TKIs), the course of the disease ran from the chronic phase to the accelerated phase (AP), noticeable by changes in the complete blood count, with left shift, additional cytogenetic changes, etc.1 The original definition of AP was proposed by the MD Anderson group.2 Disease then progressed to blast crisis (BC), with a portion of blast cells in the blood or bone marrow comparable to acute leukemias. Most patients with CML experienced all three phases, with those progressing to AP and BC having a poor prognosis. This has been recognized in the most renowned CML classifications and guidelines, including the WHO3 and ICC4 classifications, and the ELN5 and NCCN guidelines. The criteria for AP and BC were defined, although some differences existed among the classifications (e.g., blast percentage thresholds and certain cytogenetic abnormalities). After the TKI revolution in CML treatment, the situation completely changed. Patients receiving TKIs rarely progress to advanced phases; in some cases, the progression to blast crisis seems to be rapid, often without signs of AP. In light of this fact, the latest WHO 2022 classification deemed AP less relevant and suggested its omission.6 This step has sparked numerous discussions. Notably, there are two distinctive groups of patients with AP: those newly diagnosed with AP without any previous CML treatment and those who progressed from previously treated CP, with the latter being more common and having worse survival.7 Here, we present the results of our nationwide CML database analysis, focusing on the prognosis of patients fulfilling the criteria of AP CML at the time of their diagnosis. This retrospective, real-world study is based on the Czech nationwide CML registry "INFINITY" with the data of patients newly diagnosed with CML who agreed and provided their written consent. The recruited subjects were adult patients diagnosed between 2005 and 2022 with sufficient data to determine the disease phase at the time of diagnosis and follow-up to assess their overall survival (OS), disease-specific survival (DSS), and progression-free survival (PFS). The phase of the disease at the time of diagnosis was determined using the ELN 2020, ICC 2022, WHO 2016, and WHO 2022 criteria. When CP was established, the EUTOS long-term survival (ELTS) score was calculated, assigning the patient to low-risk (LR), intermediate-risk (IR), or high-risk (HR) groups. OS and PFS were defined according to published guidelines. DSS was defined as the time from diagnosis to death due to CML disease or CML treatment. All patients were treated with TKI as first-line treatment. During the study period, 1660 new cases of CML were reported in the INIFINITY registry. Of these, 1500 patients had sufficient data to classify the disease phase at the time of diagnosis according to the ELN 2020 guidelines and WHO 2022 classification, and 1395 patients had data to assess the phase according to the WHO 2016 and ICC 2022 classifications. Using the ELN 2020 guidelines, groups were assigned as follows: LR CP, 784 patients (52.3%); IR CP, 421 patients (28.1%); HR CP, 227 patients (15.1%); AP, 42 patients (2.8%); and BC, 26 patients (1.7%). There were significant differences in sex, age, comorbidities, and performance scores among the patient groups. There were no significant differences in the listed parameters between the HR CP and AP CML patients. The calculated estimates of 5- and 10-year OS, respectively, were 92.5% and 87.2% for LR CP, 83.5% and 65.9% for IR CP, 76.9% and 65.5% for HR CP, 59.2% and 45.9% for AP, and 32.9% for BC, p = .031 for HR CP versus AP (Figure 1A). According to the WHO 2016 and ICC 2022 classifications 714 (51.2%) patients were diagnosed with LR CP, 374 (26.8%) with IR CP, 154 (11.0%) with HR CP, 125 (9.0%) with AP, and 28 (2.0%) with BC. Again, there were significant differences in sex, age, comorbidities, and performance scores among the patient groups. When comparing the HR CP and AP CML patients, only the age at the time of diagnosis was significantly different. The calculated estimates of the 5- and 10-year OS, respectively, were 93.2% and 87.5% for LR CP, 84.9% and 67.7% for IR CP, 80.0% and 69.5% for HR CP, 65.7% and 55.6% for AP, and 39.7% for BC, respectively. We also performed propensity score matching according to age for patients with HR CP and AP and calculated estimates of 5- and 10-year OS, respectively, were 85.4% and 74.4% for HR CP and 60.2% and 52.0% for AP, p = .003 (Figure 1B). According to the WHO 2022 classification 793 (52.9%) patients were diagnosed in LR CP, 432 (28.8%) in IR CP, 241 (16.1%) in HR CP and 34 (2.3%) for BC. The calculated estimates of the 5- and 10-year OS, respectively, were 92.6% and 87.0% for LR CP, 82.6% and 65.5% for IR CP, 74.7% and 62.7% for HR CP, and 41.2% for BC. Similar results were obtained when testing for PFS and DSS (Supplementary Figures S1–S4). The accelerated phase, as an entity in the CML course of progression, was first described in the 1960s because of the need to identify patients who progressed from the initial stages of the disease but did not yet present with blast counts comparable to acute leukemia.1 Prognostic risk scoring systems (e.g., Sokal, Hasford) were devised to identify patients with worse overall survival. A turning point in CML treatment brought about by TKIs has changed many aspects of the disease that were thought to be very well known. During more than 20 years of TKI treatment in patients with CML, new disease pattern has been routinely observed. In cases where TKI treatment fails to achieve the recommended milestones at the molecular level, dose adjustment or TKI switching often leads to a treatment response without further progression. In cases of progression to AP post-CP, the prognosis of patients is significantly worse, and even the current treatment strategies do not seem to accommodate their needs.7 More studies and analyses are required to achieve better survival in these patients. For our analysis, we decided to observe patients with newly diagnosed CML fulfilling the criteria for AP according to the current guidelines. At the time of diagnosis, the prognosis (OS, PFS, and DSS) was significantly worse in patients with AP than in those diagnosed with CP, including the high-risk group according to ELTS. This clearly supports the argument for recognizing AP as a stand-alone entity at the time of CML diagnosis and should be reflected in the treatment strategy. Implementation of the WHO 2022 classification in clinical practice may be problematic. All patients diagnosed with AP under the previous classifications will belong to the CP category. The ELTS risk score, which was established in the TKI era, was devised using the data of patients with CP only.8 Thus, if we were to include all patients previously in the AP with patients in the CP, it would be necessary to validate the ELTS risk score (and any other scoring system) with new data sets. The recognition of AP (both de novo and post-CP) is important for reporting the results of clinical studies. In clinical trials for new treatment agents and the development of new treatment strategies, patients with AP CML and their results have been reported separately. According to the new WHO classification, this approach is no longer followed by the loss of AP. This study showed a significantly worse prognosis for patients diagnosed with AP CML than for patients diagnosed with CP, even with a high-risk survival score. This finding supports the need to recognize AP as a standalone entity in newly diagnosed patients with CML. This publication was supported by the grant MUNI/A/1558/2023, Programme EXCELES, ID Project No. LX22NPO5102, and Ministry of Health of the Czech Republic grants 00023736 and 00669806. Hornak: Novartis: Consultancy, Travel grant, Speakers Bureau; Angelini Pharma: Consultancy. Mayer: BeiGene: Research Funding. Faber: Zentiva: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Angelini Pharma: Honoraria, Speakers Bureau. Jindra: Takeda: Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Speakers Bureau; AstraZeneca: Honoraria, Speakers Bureau; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Honoraria, Speakers Bureau; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees. Zackova: Pfizer: Honoraria, Travel grant, Speakers Bureau; Astra Zeneca: Travel grant; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Travel grant, Speakers Bureau; Angelini Pharma: Consultancy, Honoraria, Travel grant, Speakers Bureau, other co-authors have no disclosures. All patients signed a written consent approved by the Ethics committee. Data available on request from the authors. Data S1. Supporting information. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.