International Journal of Science Annals, Vol. 5, No. 1-2, 2022 рrint ISSN: 2617-2682; online ISSN: 2707-3637; DOI:10.26697/ijsa SOCIAL AND BEHAVIORAL SCIENCES. Health Care Sciences ORIGINAL RESEARCH Blast Crisis in Chronic Myeloid Leukemia: An Immunophenotypic Analysis Authors’ Contribution: A – Study design; Singh Ak.1 ABCDEF , Singh An.1 ABCDEF , Kanaujia S.1 BCDE , B – Data collection; Kushwaha R.1 ABCDEF , Singh U. S.1 ADE C – Statistical analysis; D – Data interpretation; 1 King George’s Medical University, India E – Manuscript preparation; F – Literature search; Received: 20.09.2022; Accepted: 27.10.2022; Published: 25.12.2022 G – Funds collection Abstract Background and There are two different phases of untreated chronic myeloid leukemia – chronic Aim of Study: phase, and blast crisis – according to the World Health Organization classification of Hematolymphoid tumors. The blast cells in the chronic myeloid leukemia blast crisis can express myeloid, lymphoid, bi-phenotypic, monocytic, megakaryocytic, and erythroid phenotypes. The immunophenotype of blast population determines how chronic myeloid leukemia – blast crisis patients respond to treatment, hence flowcytometric examination is required. The aim of the study: to assess immunophenotyping outcomes of flowcytometry performed on the chronic myeloid leukemia – blast crisis. Material and Methods: A five-year retrospective descriptive analysis was carried out in Pathology Department at King George’s Medical University Lucknow, India (2017-2021). The patient’s peripheral blood and bone marrow aspirate samples were analyzed. Clinical, hematological, and immunophenotypic data were retrieved. The flow cytometry samples were prepared using the standardized “lyse-stain-wash” method. Results: A total of 43 cases of chronic myeloid leukemia – blast crisis were retrieved from the departmental archive in 5 years. The mean age of study population was 39.62±14.86 years. There were 24 males and 19 females. 27 patients were diagnosed with myeloid blast crisis, 14 cases of B-lymphoid blast crisis and 2 cases of mixed phenotypic acute leukemia. Conclusions: Identification of the blast lineage of patients with chronic myeloid leukemia – blast crisis is crucial since the existence of atypical blast phenotypes influences the disease treatment and prognosis. Keywords: immunophenotyping, flowcytometry, chronic myeloid leukemia, lymphoid blast, myeloid blast, mixed phenotypic acute leukemia Copyright: © 2022 Singh Ak., Singh An., Kanaujia S., Kushwaha R., Singh U. S. Published by Archives of International Journal of Science Annals DOI and UDC DOI https://doi.org/10.26697/ijsa.2022.1-2.3 UDC 616-005.9 Conflict of interests: The authors declare that there is no conflict of interests Peer review: Double-blind review Source of support: This research did not receive any outside funding or support Information about Singh Akanksha (Corresponding Author) – https://orcid.org/0000-0001-5398- the authors: 6203; assiduous2007@gmail.com, MD, Senior Resident, Department of Pathology, King George’s Medical University, Lucknow, India. Singh Anurag – https://orcid.org/0000-0002-1979-8847; MD, Senior Resident, Department of Pathology, King George’s Medical University, Lucknow, India. Kanaujia Sweta – https://orcid.org/0000-0003-3369-1664; MD, Resident, Department of Pathology, King George’s Medical University, Lucknow, India. Kushwaha Rashmi – https://orcid.org/0000-0002-0581-2177; MD, Professor, Department of Pathology, King George’s Medical University, Lucknow, India. Singh Uma Shankar – https://orcid.org/0000-0002-9748-9484; MD, Professor, Head of the Department of Pathology, King George’s Medical University, Lucknow, India. 31 International Journal of Science Annals, Vol. 5, No. 1-2, 2022 рrint ISSN: 2617-2682; online ISSN: 2707-3637; DOI:10.26697/ijsa Introduction Chronic Myeloid Leukemia (CML) is a Sensitive detection of aberrant haematopoietic myeloproliferative neoplasm that is characterized by a populations is made possible by flow cytometry. Flow balanced translocation between chromosome t (9;22) cytometry has been thought to be of limited use at this (q34; q11), leading to the formation of the Philadelphia stage of the disease since CML-CP is characterised by (Ph) chromosome (Narang et al., 2016). It mainly affects proliferation of mostly granulocytes and granulocytic older persons and seldom happens in youngsters, but can precursors without immunophenotypic aberrancy or occur at any age. There is an increased number of maturation arrest. However, there are reports of aberrant granulocytes and their immature precursors, including lymphoblast populations being found when flow occasional blast cells, seen in the peripheral blood cytometry has been used, and there is conflicting smear. CML accounts about 20% of all adult leukemias information regarding the risk of the blast phase (Pandey & Pal, 2021). developing as a result. mortality (Barge et al., 2022). According to the latest updated fifth edition of the World The initial targeted treatments for CML were tyrosine Health Organization (WHO), there are two different kinase inhibitors (TKIs). The first-generation TKIs were phases of untreated CML: Chronic phase (CP), and Blast introduced as the primary therapy in 1998, and they crisis (BC). Blast crisis of CML according to the WHO stopped the disease’s natural development. With the is defined by: 1) presence of ≥ 20% myeloid blasts in the accomplishment of morphological, clinical, and peripheral blood or bone marrow; 2) presence of molecular remission targets, this has allowed patients to extramedullary blasts proliferation; or 3) presence of sustain chronic phase disease. The speed and depth of increased number of lymphoblasts in bone marrow or molecular remission have improved after the advent of peripheral blood. The significance of low-level B- second and third generation TKIs (Hodkinson et al., lymphoblasts or optimal cut-off for lymphoblasts 2022). remain unclear (Khoury et al., 2022). The blasts in the The aim of the study. To assess the immunophenotyping CML blast phase (CML-BP) can express myeloid, outcomes of flowcytometry performed on CML-BP lymphoid, bi-phenotypic, monocytic, megakaryocytic, cases at a tertiary care facility in North India. and very infrequently erythroid phenotypes (Khemka et al., 2019; Rahnemoon, 2022). Materials and Methods BC develops as a result of persistent BCR-ABL A five-year retrospective descriptive analysis was activation, which causes genomic instability and an carried out in the Pathology Department at King accumulation of further chromosomal abnormalities. George’s Medical University in Lucknow, North India Acute leukemia symptoms could be seen in patients with (January 2017 – December 2021). A total of 43 cases of blast transformation (e.g., bleeding diathesis, bone pain, CML with blast crisis were retrieved from January 2017 night sweats, weight loss, and fatigue). Complete blood to December 2021 and included in the final study. The counts, an extensive metabolic panel, a bone marrow cases in which flowcytometry analysis and/or BCR- aspiration, and a biopsy should be performed all during ABL translocation identification were not performed, the initial assessment of BC patients. Flow cytometry, were excluded from the study. The patient’s peripheral immunohistochemistry, and cytogenetics should be blood and bone marrow aspirate samples were analyzed. requested for the latter. The immunophenotype of the Clinical, hematological findings and blast population determines how CML-BP patients immunophenotypic data were retrieved from records. respond to treatment; hence, flowcytometric For immunophenotyping of blasts, peripheral blood was examination is required in every case of blast crisis used in 28 patients and bone marrow aspirate samples in (Hehlmann et al., 2016). Almost all CML-CP patients 15 patients respectively. The flow cytometry samples will develop BC in 3-5 years without treatment, were prepared by using the strict protocols and although in the tyrosine kinase inhibitor (TKI) era, this standardized “lyse-stain-wash” method. dreaded transition is now extremely uncommon. Most For immunophenotyping of the blasts the antibody panel CML-BC cases are myeloid, but up to one-third of them was comprised of CD13, cCD13, CD14, CD15, CD33, have the potential to become lymphoid BC. The B-cell cMPO, MPO, CD64, CD14, cCD79a, CD117, CD19, lineage is more prevalent, and lymphoid blast crisis CD20, CD10, CD22, cCD22, CD2, CD4, CD5. CD7, makes up about 30% of CML-BC. T-cell BC is a very CD8, CD3, sCD3, cCD3, CD34, CD38, CD25, TdT infrequent presentation for patients (Yohannam & (terminal deoxynucleotidyl transferase), and HLA-DR. George, 2022). In order to help with blast gating in all of the tubes, Most individuals with CML will respond very well to CD45PerCP was utilized as an anchor marker. 2 ml of TKI therapy when it is administered during the chronic samples (Peripheral blood or Bone marrow) were phase (CML-CP), which is characterized by collected in Ethylene Diamine Tetraacetate (EDTA) granulocytic proliferation. The prognosis is still bad for vacutainer and analyzed using a dual laser BD FACS- those who advance to the blast phase, with less than 20% Canto II, and FACS Diva software. of patients in the modern period surviving for five years. The single-cell basis of flow cytometry analysis makes Response to TKI therapy is the most crucial indicator of it possible to examine multiple populations at once and advancement. Age, spleen size, and basophil count are detect low-level aberrant populations, particularly when other variables predicting likelihood of transformation a larger number of events are studied to boost sensitivity or mortality. (Tembhare et al., 2020). 32 International Journal of Science Annals, Vol. 5, No. 1-2, 2022 рrint ISSN: 2617-2682; online ISSN: 2707-3637; DOI:10.26697/ijsa Results Table 1 The flowcytometry findings of total of 43 cases of CML- Epidemiological Profile of Study Population BP were retrieved from records. The patient’s mean age Patients included in the study was 39.62±14.86 years. There Parameters Age range number percentage were 24 males and 19 females (M:F=1.2:1) showing (n) (%) male predominance. 27 patients were diagnosed with myeloid blast crisis followed by 14 patients with B- Age 1-10 years 2 4.65 lymphoid blast crisis and 2 patients with mixed (n=43) 11-20 years 3 6.98 phenotypic acute leukemia (MPAL). Table 1 presents an 21-30 years 6 13.95 epidemiological profile of study population. The mean age of patients in myeloid blast crisis, 31-40 years 14 32.56 lymphoid blast crisis, and mixed phenotypic acute 41-50 years 8 18.60 leukemia subgroups was 41.88±14.76, 34.79±15.30, and 51-60 years 7 16.28 44.00±8.49 respectively. There was no statically significant correlation noted for age (p=0.331) and >60 years 3 6.98 gender (p=0.194) distribution in different subgroups of Total 43 100.00 blast crisis (Table 2). Gender Male 24 55.81 The results of present study showed that B-lymphoid (n=43) blast crisis had aberrant co-expression of CD13 and Female 19 44.19 CD33 in four cases (28.57%) along with three case Total 43 100.00 (12.50%) of myeloid blast crisis having aberrant expression of CD7 (Table 3). Table 2 Age and Gender Distribution in Different Subgroups of Myeloid, Lymphoid and Mixed Phenotypic Acute Leukemia – Blast Crisis Myeloid blast crisis Lymphoid blast crisis Mixed phenotypic blasts (n=27) (n=14) (n=2) Parameters p-value Standard Standard Standard Mean Mean Mean deviation deviation deviation Age (years) 41.88 14.76 34.79 15.30 44.00 8.49 0.331 Gender: Male 17 62.96 7 50.00 0 0.00 0.194 Female 10 37.04 7 50.00 2 100.00 Table 3 Immunophenotypic Profiles in Cases of CML-Blast Phase Myeloid blast crisis Lymphoid blast crisis Mixed phenotypic (n=27) (B-lineage) (n=14) blasts (n=2) Parameters p-value Positive Positive Positive n % n % n % CD13 24 92.31 4 28.57 2 100.0 <0.001* CD33 26 100.0 6 42.86 2 100.0 <0.001* cMPO 27 100.0 0 0.00 2 100.0 <0.001* CD64 2 22.22 0 0.00 0 0.0 0.523 cCD79a 0 0.00 0 - 1 100.0 0.025* CD117 16 76.19 1 10.00 1 100.0 0.002* CD19 2 8.70 11 91.67 1 100.0 <0.001* CD20 0 0.00 11 84.62 0 0.0 <0.001* CD10 2 8.00 13 100.00 1 100.0 <0.001* cCD22 0 0.00 2 100.00 1 100.0 0.821 CD5 0 0.00 0 0.00 1 100.0 0.002* CD7 3 12.50 0 0.00 1 50.0 0.080 cCD3 0 0.00 0 0.00 1 50.0 <0.001* CD34 26 100.00 10 76.92 2 100.0 0.031* CD38 5 50.00 5 71.43 0 - 0.598 CD25 1 11.11 1 16.67 1 50.0 0.462 TdT 2 10.00 9 81.82 2 100.0 <0.001* HLA-DR 24 100.00 11 100.00 1 100.0 - Note. *Significant (p<0.05) 33 International Journal of Science Annals, Vol. 5, No. 1-2, 2022 рrint ISSN: 2617-2682; online ISSN: 2707-3637; DOI:10.26697/ijsa Discussion preference. Additionally, polychemotherapy is advised CML is a disease that results from the reciprocal for these patients. Patients who have had TKI treatment translation of genes on chromosomes 9 and 22 (Asif et before and go on to develop AP or BC are regarded as al., 2016). The fused BCR-ABL protein has altered receiving TKI treatment that has not previously been tyrosine kinase activity (Rajkumar et al., 2016). given. Allogenic stem cell transplantation is the best The prognosis for CML patients depends on the disease treatment choice for CML-CP patients who have grown stage at presentation, although even for people diagnosed resistant to at least two TKIs (Hegde et al., 2020). in CP, survival rates might vary significantly. Patients After a BC diagnosis, the average survival time is thought with chronic phase CML have myeloid cells at all stages to be 2-4 months. There are noticeable differences in the of maturity (CP). Contrary to acute myeloid leukaemia proliferation, differentiation, adhesion, and apoptosis of (AML), the flow cytometry (FC) approach enables the malignant cells during the blast crisis compared to those detection of aberrant cell surface markers. FC is a during the chronic phase, which is well recognised. New, straightforward diagnostic tool for (CP-CML) since it is non-random molecular or genetic alterations are thought used to estimate the proportions of immature cells (Blast) to be the cause of the blast transformation. Trisomy 8, in the late stages of the disease. This is a disease in adults trisomy 19, isochromosome 17, and mutations in the p53, and extremely rare in childhood. This retrospective study RB, or RAS pathways are the reported most frequent analyzed 43 cases of chronic myeloid leukemia – blast genetic anomalies. In myeloid BC, inactivating mutations crisis over a period of 5 years. In the present study on of the genes p53 and RUNX1 are present, whereas flowcytometric analysis, the most common blast inactivating mutations of the genes CDKN2A/B have phenotype in the blast crisis was myeloid (62.7%) been found in lymphoid blast crisis. Response rates to followed by B-lymphoid blast crisis (32.5%) and mixed normal induction therapy are less than 20–30% for CML- phenotypic acute leukemia (4.7%). Out of two cases, of BC with an unique blast phenotype. Similar to other cases MPAL, one case was of T-Myeloid and the other was of of CML with BC, patients with the erythroid or B-Myeloid phenotypic blast crisis. A study conducted megakaryocytic blast phenotype get the same care. Cases earlier also showed similar results (Narang et al., 2016). with lymphoblastic differentiation, on the other hand, are Their study was comprised of 15 cases, which showed 14 managed as acute lymphoblastic leukaemia (Hegde et al., cases of myeloid blast crisis and a single case of 2020). lymphoid (B-lineage) blast crisis. The evolution of CML It is suggested that molecular or genetic changes, such as into blast crisis is common in myeloid type followed by trisomy 8, trisomy 19, isochromosome 17, t(3;21), lymphoid type (Shi et al., 2015). A previous study also mutations in p53, RB gene, RAS pathway, or p16/ARF showed blast crises in CML are of myeloid phenotype in pathway, are responsible for the blast transformation of the majority of cases and lymphoid phenotype in 30% of CML. T-cell acute lymphoblastic leukaemia (T-ALL) cases (Bonifacio et al., 2019). and BCR-ABL1-positive bilineage leukaemia might be Chronic immunological dysfunction and T-cell fatigue difficult to distinguish from CML blast crisis of T-cell are brought on by CML, a disease that primarily results lineage. De novo BCR-ABL1-positive T-cell ALL has from long-term immune cell activation in an several characteristics, such as bone marrow immunosuppressive milieu. involvement, small BCR breakpoint mutations, TCR In the present study, we found four cases of B-lymphoid gene rearrangement mutations, children or teenage age blast crisis with aberrant co-expression of CD13 and group, and no prior history of CML. Clonal T-cell gene CD33 along with one case of myeloid blast crisis with rearrangement (TCR) is not usually present in early aberrant expression of CD7. Another study conducted by immature T-cell neoplasms (like T-ALL), therefore its Hegde et al. (2020) on chronic myeloid leukemia showed absence does not always rule out a T-cell blast two cases displaying mixed phenotypic features catastrophe. A diagnosis of CML in a T-cell blast crisis comprising each one of myeloid and megakaryocytic would be supported by BCR-ABL1 positive in both differentiation. The treatment of CML-BP patients myeloid and lymphoid cells, as opposed to just the depends on the immunophenotype of the blast population lymphoid component as it was found in our case. hence it is mandatory to do flowcytometric analysis in 5–10% of CML patients eventually progress to advanced each and every case of blast crisis (Assi & Short, 2020; phase while on therapy, despite the ground-breaking Wang et al., 2021). Atypical lymphoblast populations in results TKI in CP-CML achieved. Most of the processes CML are listed as a potential sign of an aggressive underlying TKI failure, the development of illness, and disease course in the WHO classification of myeloid cytogenetic changes are yet unclear. TKI failure is caused neoplasms (Arber et al., 2016; Chen et al., 2020). There by BCR-ABL1 dependent mechanisms, including are some study limitations, including the fact that it was mutations in the ABL1 kinase domain, amplification of conducted at just one hospital and there was no patient the BCR-ABL1 oncogene, and high levels of BCR-ABL1 follow-up. Newly diagnosed cases of CML-BC are mRNA expression. When the anaplastic threshold is treated with first-generation TKIs, according to European achieved and additional oncogenes eventually cause Leukemia Net (ELN) 2018 data (imatinib, nilotinib, progression in a BCR-ABL1-independent manner, dasatinib and bosutinib). Third or fourth generation TKIs unchecked BCR-ABL1 signalling causes genomic should be used to treat patients who do not react to first instability and a more chaotic state. The increased generation TKIs. For patients with the BCR-ABL coding aggressive behaviour of CML clones expressing high domain T315I mutation, ponatinib is the TKI of amounts of BCR-ABL1 can be explained by both 34 International Journal of Science Annals, Vol. 5, No. 1-2, 2022 рrint ISSN: 2617-2682; online ISSN: 2707-3637; DOI:10.26697/ijsa quantitative and qualitative factors (Bonifacio et al., underscoring the limitations of imatinib in treating a 2019). more aggressive disease. Acute biphenotypic leukaemia (ABL) is uncommon and Numerous initial variables at the time of CML diagnosis predominantly affects children. ABL has no have been linked to various probabilities of progression. predetermined diagnostic standards (Ivanov et al., 2020). Current prognostic models identify high-risk patients The BCR-ABL1 inhibitor has no effect on the various who are more likely to develop AP-CML or BP-CML. leukaemia cells (mainly cells of the granular chain) in The EUTOS long-term survival (ELTS) score, in CP-CML, whereas TKIs are mostly focused at the instance, indicates three risk categories with significantly progenitor cell group. It is very predictive to use CD34 varying risks of death from progression in advanced expression. The expression of CD34 might fluctuate from phase. time to time, and this variation may be caused by the The kinetics of response to treatment is the most sensitivity of the monoclonal antibodies used, as well as important indicator of progression. Numerous studies by technical considerations (such as the sensitivity of the have shown that failure to diminish BCR-ABL1 by 10% flow cytometry method) and the standards used to obtain after three months is associated with a higher risk of a positive result. progression to the advanced phase and worse survival CML blast crisis (CML-BC), despite recent when using frontline imatinib and 2nd generation TKIs. advancements in the treatment of early-stage illness, During the first several months of treatment, measuring continues to provide a therapeutic challenge. Less than the BCR-ABL1 transcript halving time may help to 30% of patients with CML-BC respond to normal improve the sensitivity and specificity of response induction chemotherapy, making it highly resistant to the measurement. condition. When compared to de novo acute leukaemia, Finally, patients who receive consistent, standardised conventional chemotherapy has been substantially less monitoring are at a decreased risk of progression than effective in treating this illness, with non-responders those who receive less frequent monitoring. Despite having a mean survival time of only 2 to 4 months proper monitoring and an apparent satisfactory response following diagnosis of blast crisis. In CML-BC, to TKI, abrupt onset of BP may occasionally happen. We numerous chemotherapy regimens have been explored, believe that all newly diagnosed CPCML patients should with varying degrees of effectiveness. Although imatinib preferably receive frontline treatment based on the ELTS was studied in individuals with CML-BC, the majority of scoring system, and non-low-risk patients should be CML-BC instances currently occur in patients who are given consideration for 2nd generation TKIs or closely already receiving imatinib-based therapy and going monitored for an early molecular response when imatinib through the blastic phase as a result. As a result, there is is chosen as the treatment of choice (Bonifacio et al., no established standard of care for CML-BC patients. 2019). The future course of new treatment modalities will be decided by further research into the molecular Conclusions transformation processes of chronic-phase CML-BC and Identification of the blast lineage of patients with CML – strategies to address these molecular abnormalities. blast crisis is crucial since the existence of atypical blast Despite significant efforts, the prognosis for CML in the phenotypes influences the treatment strategy. Flow blast catastrophe remains depressing. Currently, cytometry with an extended panel of antibodies is utilized extending the chronic phase and postponing the start of to assist in blast lineage determination and detection of the blast crisis is the most effective way to increase aberrant antigen expression in CML – blast crisis. survival in CML (Esfahani et al., 2006). A TKI treatment was recommended before allogeneic Acknowledgments SCT for all patients in advanced phase in earlier ELN We are thankful to the Indian Council of Medical treatment guidelines. Especially for AP patients, most Research, New Delhi, India, and Mr. Hirendra Rajwanshi recent guidelines recognised the value of frontline TKI and Mr. Devendra Singh for their technical support in treatment without the necessity for a future transplant. flowcytometry procedure and laboratory-related work. Both ELN and NCCN advise treating newly diagnosed AP patients with TKI alone; transplantation is only Ethical Approval considered as a last resort for those who do not respond This study had been approved by the Institutional Ethics to treatment as expected. Only imatinib 600 mg daily has Committee, King George’s Medical University, a market authorisation in the European Union for Lucknow, India (No. 461/Ethics/2022 from 06.06.2022). frontline use in newly diagnosed patients in advanced phase, although this drug’s efficacy is constrained by the Funding Source emergence of BCR-ABL1 kinase domain mutations, This research did not receive any outside funding or which are more common in this situation than in CP. Both support. retrospective and prospective trials have shown the high efficacy of frontline treatment with nilotinib or dasatinib, References as well as the impressive DMR rates. Intriguingly, in the Arber, D. A., Orazi, A., Hasserjian, R., Thiele, J., randomised prospective studies on CP patients, the Borowitz, M. J., Le Beau, M. M., amount of benefit from 2nd generation TKIs over Bloomfield, C. D., Cazzola, M., & imatinib was more pronounced in high-risk patients, Vardiman, J. W. (2016). 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Yohannan, B., & George, B. (2022). B-Lymphoid blast Understanding and monitoring chronic myeloid phase – chronic myeloid leukemia: Current leukemia blast crisis: How to better manage therapeutics. International Journal of Molecular patients. Cancer Management and Research, 13, Sciences, 23(19), 11836. 4987-5000. https://doi.org/10.2147/CMAR.S314343 https://doi.org/10.3390/ijms231911836 Cite this article as: Singh, Ak., Singh, An., Kanaujia, S., Kushwaha, R., & Singh, U. S. (2022). Blast crisis in chronic myeloid leukemia: An immunophenotypic analysis. International Journal of Science Annals, 5(1-2), 31–37. https://doi.org/10.26697/ijsa.2022.1-2.3 The electronic version of this article is complete. It can be found online in the IJSA Archive https://ijsa.culturehealth.org/en/arhiv This is an Open Access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited (http://creativecommons.org/licenses/by/4.0/deed.en). 37