Chronic myeloid leukemia (CML) is a myeloproliferative neoplasm characterized by the presence of t(9;22)(q34;q11), resulting in the BCR::ABL fusion gene. CML typically advances through three phases: chronic phase (CP), accelerated phase, and blast phase (BP). Around 70% of cases display myeloid blasts, with 20-30% featuring lymphoid blasts during the transformation into BP.1 However, a less recognized subtype of CML involves the presence of the PML::RARA fusion clone. This subtype can manifest as de novo CML with a minor PML::RARA fusion clone, de novo CML accompanied by acute promyelocytic leukemia (APL), and CML transforming into promyelocytic blastic crisis (PBC). In this context, we present a case and the findings of a literature review, addressing various aspects such as diagnosis, clinical features, treatment, and survival specific to this unique subtype of CML. This study was approved by the Institutional Review and Ethics Board of the First Affiliated Hospital of Nanchang University (IIT2024169 and IIT2014146).
A 58-year-old female patient with CML-CP was admitted to hospital in September 2018. Cytogenetic analysis revealed the presence of a t(9;22)(q34;q11.2) translocation in bone marrow cells. The International Scale percent ratio (IS%) of the p210 BCR::ABL fusion transcript was 31%. The patient was initially treated with 400 mg of imatinib daily. After 6 months, she achieved complete hematologic remission and complete cytogenetic remission. Unfortunately, the complete hematologic remission was lost 7 months into imatinib treatment, leading to a switch to dasatinib, and subsequently, another switch to nilotinib. At 10 months of treatment with tyrosine kinase inhibitors, the patient experienced a transformation of CML to PBC. Detailed descriptions of bone marrow morphology, karyotyping, quantification of fusion genes, next-generation gene sequencing, and ABL kinase mutations are provided in Figure 1A-E and Online Supplementary Table S1.
The patient underwent induction therapy with all-trans-retinoic acid (ATRA), arsenic trioxide (ATO), idarubicin, cytarabine, and ponatinib, resulting in the achievement of complete remission of the bone marrow. The BCR::ABL p210 IS% and PML::RARA transcript levels were reduced to 6.4% and 0, respectively. Karyotyping demonstrated 20 cells with 46, XX. The maintenance treatment included ponatinib, ATRA, and oral arsenic. However, at 34 months after CML-PBC, a routine blood test revealed a white blood cell count of 14.95×109/L, hemoglobin of 99 g/L, and platelet count of 1,897×109/L. Bone marrow morphology and quantification of fusion genes indicated a relapse of CML, with BCR::ABL IS% and PML::RARA by reverse transcription polymerase chain reaction (RT-PCR) quantification being 92.34% and 0, respectively. An ABL kinase region mutation was identified as T315I. Despite the relapse, the patient chose not to pursue TKI treatment and opted for maintenance with hydroxyurea, oral arsenic, and ATRA. Unfortunately, she succumbed to a coronavirus disease 2019 infection in May 2023 with an overall survival of 56 months.
In contrast to patients with common CML, who typically exhibit favorable responses to TKI treatment and enjoy extended survival, this particular patient experienced rapid disease progression, blastic transformation, and a relatively short survival. Upon reviewing the patient’s bone marrow specimen, we made a surprising observation of 0.3% PML::RARA chimeric mRNA at the time of initial diagnosis (Figure 2A, B). Subsequently, we conducted a comprehensive review of 32 documented cases of CML-PBC (Online Supplementary Table S1).2-8 Among the 32 cases, five had been found to be positive for the PML::RARA fusion gene. In two patients with concurrent CML and APL, one tested positive for both BCR::ABL and PML::RARA, while the other was diagnosed through the presence of abnormal promyelocytes and myeloblasts. In three cases PML::RARA chimeric mRNA was retrospectively detected in previous samples. Notably, many CML patients are unaware of the presence of a PML::RARA clone in their bodies. Consequently, they do not undergo testing for the PML::RARA fusion using either fluorescence in situ hybridization or RT-PCR at the onset, nor are changes in PML::RARA fusion gene quantification monitored until the disease worsens.
In retrospect, the diagnostic boundaries for this CML case with a minor PML::RARA fusion gene clone appear ambiguous. According to the diagnostic criteria outlined in the 5th edition of the World Health Organization (WHO) Classification of CML-CP and APL, this case could be classified as either CML-CP or APL. It is worth noting that the WHO diagnostic criteria for APL do not define the proportion of promyelocytes or the quantity of fusion gene. Furthermore, the diagnosis of this case does not align with the criteria for inclusion in CML with BP, which are as follows: (i) ≥20% myeloid blasts in the blood or bone marrow; or (ii) the presence of an extramedullary proliferation of blasts; or (iii) the presence of increased lymphoblasts in peripheral blood or bone marrow. However, according to the International Consensus Classification of Myeloid Neoplasms and Acute Leukemias, the cutoff percentage for t(15;17)(q24.1;q21.2)/PML::RARA for the diagnosis of APL is ≥10%. In this case, the percentage did not meet the criteria for APL and only conformed to the diagnosis of CML-CP.
Figure 1.The presentation of bone marrow morphology, fluorescence in situ hybridization findings, karyotyping, and quantification of fusion genes in this case. (A, B) Bone marrow aspirate displayed marked myeloid hyperplasia with 32% myeloblasts and 22.5% promyelocytes. (C, D) Fluorescence in situ hybridization (FISH) was positive for the BCR::ABL1 (C) and PML::RARA (D) fusions in 94% and 76% of interphase nuclei, respectively. (E) Cytogenetic analysis of bone marrow cells with G-banding showed 46,XX,t(9;22) (q34;q11),t(15;17)(q22;q12) in all 20 cells examined. The red arrows represent the abnormalities of bone marrow morphology (A, B), FISH results (C, D) and karyotyping (E).
The median time between CML diagnosis and blast crisis is documented as 24 months. Among the 22 CML-PBC patients, 11 patients experienced blast crisis during TKI therapy at a median time of 15 months, while the remaining 11 patients were managed in the pre-TKI era and the median interval between diagnosis and blast crisis in these patients was 27 months. Interestingly, it appears that TKI therapy does not significantly delay the time to blast crisis.
Notably, during TKI therapy, the median white blood cell count at the onset of CML-PBC was 1.62×109/L, which is significantly lower than in the pre-TKI era. Lower white cell counts during TKI therapy may present challenges, potentially causing confusion with the adverse reactions of TKI and consequently delaying the diagnosis and therapy involving ATRA or ATO for CML-PBC. It is essential to be aware of fatigue and bleeding as noteworthy manifestations when the condition worsens.
Figure 2.The levels of BCR::ABL and PML::RARA transcript, as detected by reverse transcription polymerase chain reaction, in this case. (A, B) Reverse transcription polymerase chain reaction showed positivity (0.3%) PML::RARA for transcript at the time of initial diagnosis via retrospective analysis of bone marrow samples, whereas a control sample was negative. (C) Dynamic quantification of levels of BCR::ABL and PML::RARA transcripts after transformation of chronic phase chronic myeloid leukemia to blast phase.
The potential of combining TKI with ATRA or ATO treatment for CML patients initially presenting with a PML::RARA fusion gene clone is an exciting prospect. It is noteworthy that patients with de novo CML and APL often do not require allogeneic stem cell transplantation if they respond well to targeted therapies. Thus, timely recognition, initial treatment, and effective management are crucial for newly diagnosed CML patients with a PML::RARA fusion gene clone. However, for patients with CML-PBC, most cases currently receive an APL induction regimen, with or without TKI, followed by TKI combined with ATRA and/or ATO as maintenance therapy. In some cases, hematopoietic stem cell transplantation is considered.9 Notably, outcomes for CML-PBC reported in the literature are significantly less favorable compared to those of de novo CML and APL patients.2 The median survival among 23 available patients was reported as 90 days after PBC. Among the ten patients who received ATRA, ATO, or a combination of these treatments with chemotherapy, the survival time at the 53.3% survival rate threshold was 118 days. In contrast, among the ten patients who did not receive ATRA or ATO, the survival time was 30 days. Combination therapy with TKI and ATO may be more effective than the combination of TKI with retinoic acid.10 Nevertheless, the sensitivity of CML-BP to ATRA, ATO, and new generation TKI, as well as the necessity of allogeneic stem cell transplantation remain unclear. The mechanisms leading to the transformation of CML into PBC are poorly understood. Firstly, a small clone of the PML::RARA fusion gene is initially present in the CML patient’s body and gradually evolves into the dominant clone, thereby contributing to disease progression. Secondly, ABL kinase mutations, such as Y2253H, F359G, and T315I, may be associated with disease progression and recurrence. In cases of resistance, the uncontrolled activity of BCR::ABL leads to continued proliferation of leukemic cells, along with the development of secondary chromosomal or genetic defects, ultimately resulting in the evolution from CP to BP.11 Thirdly, the PML protein plays a crucial role in maintaining the quiescence of leukemia-initiating cells, making them resistant to anti-leukemic agents.12 The fusion of PML to RARα alters the intracellular distribution of the PML protein, contributing to the self-renewal capabilities of leukemic cells.13 Additionally, the collaboration between PML::RARα and BCR::ABL proteins at the CML stem cell level may induce excessive proliferation and resistance to TKI. Hence, current reports indicate that newly diagnosed CML with the coexistence of PML::RARα and CML progressing to acute PBC exhibit distinctive molecular profiles, leading to different clinical outcomes compared to de novo APL, CML, and advanced CML. There is no consensus on the diagnosis, treatment, monitoring, and survival of patients with this particular subtype of CML. Notably, neither the 5th edition of the WHO Classification of Haematolymphoid Tumors nor the new International Consensus Classification mentions this specific subtype of CML.14,15 In our opinion, quantitative detection of the PML::RARA fusion gene is necessary for newly diagnosed CML patients. Patients with CML or APL usually have a very favorable prognosis and can even be cured. However, if no intervention targets the PML::RARA clone in the early stages, the patient’s survival will be significantly shortened if the disease progresses to CML-PBC. From a risk-benefit perspective, patients should undergo PML::RARA fusion gene clone detection. If positive, patients should be recommended simultaneous therapy with TKI and ATRA, with subsequent monitoring of the amounts of BCR::ABL and PML::RARA fusion genes during treatment. If future research confirms the importance of our discoveries and the clinical interest in defining this new subtype of CML, it would make sense to include this subtype in upcoming classifications by the WHO.
Footnotes
- Received April 20, 2024
- Accepted July 30, 2024
Correspondence
Disclosures
No conflicts of interest to disclose.
Funding
References
- Shi Y, Rand AJ, Crow JH, Moore JO, Lagoo AS. Blast phase in chronic myelogenous leukemia is skewed toward unusual blast types in patients treated with tyrosine kinase inhibitors: a comparative study of 67 cases. Am J Clin Pathol. 2015; 143(1):105-119. Google Scholar
- Wolanin S, McCall RK, Pettenati MJ. PML-RARA fusion transcripts detectable 8 months prior to promyelocytic blast crisis in chronic myeloid leukemia. Case Rep Hematol. 2020; 2020:8830595. Google Scholar
- Emilia G, Sacchi S, Selleri L, Zucchini P, Artusi T, Torelli U. Promyelocytic crisis of chronic myeloid leukaemia. Br J Haematol. 1987; 66(2):276-277. Google Scholar
- Van der Merwe T, Bernstein R, Derman D. Acute promyelocytic transformation of chronic myeloid leukaemia with an isochromosome 17q. Br J Haematol. 1986; 64(4):751-756. Google Scholar
- Ben-Zeev D, Schwartz SO, Friedman IA. Promyelocytic-myelocytic leukemia as a terminal manifestation of chronic granulocytic leukemia. Report of a case. Blood. 1966; 27(6):863-870. Google Scholar
- Kim B, Chi HY, Yoon YA, Choi YJ. Promyelocytic blast phase of chronic myeloid leukemia, BCR-ABL1-positive: points to be considered at diagnosis. Ann Lab Med. 2021; 41(3):328-332. Google Scholar
- Parsi M, Budak-Alpdogan T. Promyelocytic blast crisis of chronic myeloid leukemia in a patient undergoing therapy with a tyrosine kinase inhibitor. Cureus. 2020; 12(3):e7217. Google Scholar
- Liu MS, Han XY, Qu ZG. Rapid promyelocytic blast crisis of chronic myeloid leukemia with PML-RARα fusion gene: a case report and literature review. Zhonghua Xue Ye Xue Za Zhi. 2023; 44(6):512-515. Google Scholar
- Cai B, Yang W, Zhao Y. Successful management with an effective induction regimen followed by allogeneic hematopoietic stem cell transplantation for promyelocytic blast crisis of chronic myelogenous leukemia. Ann Hematol. 2012; 91(4):621-623. Google Scholar
- Kashimura M, Ohyashiki K. Successful imatinib and arsenic trioxide combination therapy for sudden onset promyelocytic crisis with t(15;17) in chronic myeloid leukemia. Leuk Res. 2010; 34(8):e213-214. Google Scholar
- Bavaro L, Martelli M, Cavo M, Soverini S. Mechanisms of disease progression and resistance to tyrosine kinase inhibitor therapy in chronic myeloid leukemia: an update. Int J Mol Sci. 2019; 20(24):6141. Google Scholar
- Ito K, Bernardi R, Morotti A. PML targeting eradicates quiescent leukaemia-initiating cells. Nature. 2008; 453(7198):1072-1078. Google Scholar
- Daniel MT, Koken M, Romagné O. PML protein expression in hematopoietic and acute promyelocytic leukemia cells. Blood. 1993; 82(6):1858-1867. Google Scholar
- Khoury JD, Solary E, Abla O. The 5th edition of the World Health Organization classification of haematolymphoid tumours: myeloid and histiocytic/dendritic neoplasms. Leukemia. 2022; 36(7):1703-1719. Google Scholar
- Arber DA, Orazi A, Hasserjian RP. International Consensus Classification of myeloid neoplasms and acute leukemias: integrating morphologic, clinical, and genomic data. Blood. 2022; 140(11):1200-1228. Google Scholar
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