Chronic Myeloid Leukemia (CML): 2025 Update PDF

Chronic myeloid leukemia: 2025 update on diagnosis, therapy, and monitoring Supervised by: Assist.Prof.Dr.Bassam Mohamed Hameed M.B.Ch.B/ M.Sc. / Ph.D.(Pathology/Hematology) presented by Zainab M. Hussein By the end of this topic you ca...

Chronic myeloid leukemia: 2025 update on diagnosis, therapy, and monitoring Supervised by: Assist.Prof.Dr.Bassam Mohamed Hameed M.B.Ch.B/ M.Sc. / Ph.D.(Pathology/Hematology) presented by Zainab M. Hussein By the end of this topic you can be able to Definition and know the pathogenesis of CML. Can be diagnose and differential diagnosis of CML. Know about the factors influence the choice of the frontline therapy. monitor response to TKIs and how to treat resistance to TKIs.  Chronic Myeloid Leukemia CML is an MPN arising from a single genetic translocation in pluripotential HSC producing a clonal overproduction of the myeloid cell line result in majority of immature cells in the neutrophilic line. The prevalence of CML is two cases/100 000. It accounts for approximately 15% of newly diagnosed cases of leukemia in adults,with a slight male predominance. Due to the success of TKI therapy help in reducing mortality rates (2–3% per year). Pathogenesis It is the fusion of the Abelson murine leukemia (ABL1) gene on chromosome 9 with the breakpoint cluster region (BCR) gene on chromosome 22. This results in the expression of an oncoprotein termed BCR::ABL1, a constitutively active tyrosine kinase that promotes the growth and survival of CML cells through downstream signaling pathways such as RAS, RAF, JUN kinase, MYC, and signal transducer and activator of transcription (STAT). This leukemic condition occurs by creating a cytokine independent cell cycle with aberrant apoptotic signals in response to cytokine withdrawal. BCR–ABL1 is a constitutively active TK with multiple substrates. Interactions between BCR– ABL1 and secondary messengers such as GRB2, GAB2, CRKL. Lead to inhibition of apoptosis and increased proliferation through activation of the PI3K/AKT, JAK/STAT and RAS/RAF/MEK MANIFESTATIONS AND PHASES CML can be classified into two phases: 1- Chronic Phase (CP) with or without accerated phase which has become less relevant and omitted in the current classification as high risk features associated with CP progression and resistance to TKI. 2-Blastic phase. About 50% of patients diagnosed with CML are asymptomatic(the diagnosis occurs during a routine physical examination or blood tests). CML-CP(90%–95%): Common signs and symptoms result from: anemia and splenomegaly, these include fatigue, weight loss, malaise, easy satiety, and left upper quadrant fullness or pain. Rare include bleeding (low platelet count or platelet dysfunction), thrombosis (associated with thrombocytosis or marked leukocytosis), gouty arthritis( uric acid levels), retinal hemorrhages and upper gastro-intestinal ulceration or bleeding ( histamine due to basophilia).  Leukostatic symptoms (dyspnea, drowsiness, loss of coordination, and confusion) due to leukemic cells sludging in the pulmonary or cerebral vessels are uncommon in CP, despite white blood cell (WBC) counts exceeding 100 × 109/L. Splenomegaly is the most consistent physical sign and detected in more than 90% of patients. Hepatomegaly is less common (less than 5%–10%). Lymphadenopathy and infiltration of skin or other tissues are rare( they favor with Ph-negative CML or BP of CML).  Headaches, bone pain, arthralgias, pain from splenic infarction, and fever ( frequent with CML transformation). CML-BP presents as an acute leukemia (myeloid in 60%, lymphoid in 30%, megakaryocytic or undifferentiated in 10%) with worsening constitutional symptoms, bleeding, fever, and infections. LABORATORY FINDINGS CBC AND BLOOD FILM : 1)Mild to moderate normochromic normocytic anemia,NRBC can be found,reticulocyte is normal or slightly increased. 2)The plt count is elevated in about 50% of patients with median value is 400 × 109 /L. 3)Persistent unexplained leukocytosis, at the time of diagnosis is nearly always greater than 25 × 109/L and at least half the patients have greater than 100 × 109/L ,with all stages of granulocyte are present in the blood (myelocyte bulge) ,in cp no excess of blast cell about 3% ; myelocytes, metamyelocytes, and bands accounted for approximately 40%; and segmented neutrophils accounted for approximately 35% of total leukocytes.Hypersegmented neutrophils are commonly present.  4)An absolute eosinophil count : -Nearly always is increased. - Rarely, they dominate the granulocytic cells and lead to the Ph. chromosome–positive eosinophilic CML. 5)An absolute basophil count : -Increasing in almost all cases. -The basophils usually is less than10 - 15% during the chronic phase. -Rare patients appear 30-80% of the total leukocyte count during chronic phase and lead to the Ph chromosome–positive basophilic CML. Peripheral blood smear shows the classic features of chronic-phase CML: Markedly granulocytic leukocytosis with left shift, neutrophilia, myelocyte "bulge, basophilia, no increase in blasts and Granulocytes lack dysplastic features. 9)Criteria for blastic phase include: presence one of the following:  (1) ≥20% myeloid blasts in the blood or bone marrow.  (2) The presence of an extramedullary proliferation of blasts.  (3) the presence of increased lymphoblasts in peripheral blood or bone marrow. CML presenting: A-in Myeloid blast phase B-in Lymphoid blast phase LABORATORY FINDINGS Bone marrow aspiration: Will confirm the diagnosis,provide information for staging in terms of the blast and basophil percentages : 1)Hypercellular (as a result of myeloid activity). 2)Increase in the myeloid-to-erythroid ratio (>10:1 ) 3) Granulopoiesis is dominant (marked by broad zones of immature granulocytes, usually perivascular or periosteal, centrally placed mature granulocytes). 4)Erythropoiesis appear reduced in number. 5)Megakaryocytes are normal or increased in number , when increased (they often appear small with reduced nuclear lobulations). 6)Reticulin fibers are increased in approximately 20% of patients. Bone marrow aspiration shows classic features of CML including: Marked increased in Neutrophils with myelocyte bulge. M:E ratio >10:1 Reduced erythropoiesis Increased Megakaryopoiesis with small and hypolobated features. Also show a sea-blue histiocyte due to marked cell turnover. Bone marrow biopsy shows: -Packed marrow -marked increase granulocytic cells. -Increased numbers of megakaryocytes with hypolobated nuclei. -Marked fibrosis and streaming of hemopoietic cells.  Molecular and Cytogenetics Studies The presence of the Philadelphia (Ph) chromosome abnormality,the t(9;22)(q34;q11), can be detected by routine cytogenetics, or the Ph-related molecular BCR::ABL1 abnormalities by fluorescence in situ hybridization (FISH) or by molecular studies (RT PCR). A FISH analysis based on the co-localization of large genomic probes specific to the BCR and ABL1 genes. PCR Reverse transcription PCR (RT-PCR) amplifies the region around the splice junction between BCR and ABL1. It is highly sensitive in detecting minimal residual disease. PCR testing can be: → Qualitative PCR: providing information about the presence of the BCR::ABL1 useful for diagnosing CML. →Quantitative PCR: assessing the amount of BCR::ABL1 transcripts. ideal for monitoring residual disease. →Digital droplet PCR: highly sensitive and specific for BCR:ABL1. useful in the evaluation of MRs in the setting of treatment free remission(TFR). 100% of metaphases usually has the Ph chromosome. 10% - 15% of patients have additional chromosomal abnormalities (ACAs) usually co-occurring in the Ph- positive cells (clonal evolution)involving trisomy 8, iso(17), additional loss of material from 22q or double Ph and others. 90% of patients have a typical t(9;22) , 5% have variant translocations, which can be : Simply involving chr. 9 and a chromosome other than chromosome 22,but still an ABL1 translocation. complex (involving one or more chromosomes in addition to chromosomes 9 and 22). Patients with Ph-variants have a response to therapy and prognosis like Ph-positive CML. About 2%–5% of patients present with a morphologic picture of CML without the Ph-positivity by cytogenetic studies. The typical (BCR::ABL1) e13a2 or e14a2 transcripts, producing the oncoproteins p210. (1%) of patients may have e1a2/a3 transcript, resulting in shorter oncoproteins p190 (bad prognosis).  (2%–5%) of patients have e13a3 or e14a3 variants of p210 BCR::ABL1, or e19a2 transcripts (p230) (rare; indolent CML course).If not tested at diagnosis, this would give the false impression that a patient may be in complete MR on TKI therapy. ACAs detected by i(17)(q10)-7/del17q,3q26.2 rearrangements cytogenetics particularly (poor prognosis). DIFFERENTIAL DIAGNOSIS DDX Characterization 1.Leukemoid Usually WBC counts < 50 × 109/L. reactions(LR) Toxic granules with vacuolation and absence of basophilia. Need for clinical history and physical examination about origin of LR. 2.Corticosteroids Rarely cause extreme neutrophilia with a left shift, but this abnormality is transient and of short duration 3.Other MPN or Agnogenic myeloid metaplasia with or without myelofibrosis frequently MDS syndromes have splenomegaly, neutrophilia, and thrombocytosis. Polycythemia vera with associated IDA, which causes normal Hb and hematocrit values, can manifest with leukocytosis and thrombocytosis. WBC count < 25 × 109/L, and no Ph abnormality. 4.clinical picture Absence of Ph chr. or undetectable BCR::ABL1 , unresponse to TKI therapy atypical for CML and often poorer outcomes with a median survival of approximately 2–3 years. ddx(MDS/MPN Use next-generation sequencing to detecting non-ABL1 mutations,to ,CMML) distinguishing between these conditions:SETBP1(in 25% of atypical CML),SF3B1 (in 50%–70% of MDS/MPN )with ringed sideroblasts and marked thrombocytosis, CSF3R (in CNL or atypical CML ). TREATMENT: ∆TKIs interfered with the interaction between the BCR::ABL1 oncoprotein and ATP, blocking cellular proliferation of the malignant clone. ∆This improving the 10-year survival rate from approximately 20% to 80%–90% over 20 years of follow-up. Frontline Second- Third+ line TKI line TKI TKI Imatinib Bosutinib ponatinib Bosutinib Dasatinib Asciminib Dasatinib Nilotinib Allo-HSCT Nilotinib Ponatinib Current Guidelines Recommend  Frontline Therapy(imatinib, dasatinib, bosutinib, or nilotinib), as good therapeutic options with a category 1 recommendation for the initial treatment of CML-CP. Second-generation TKIs produced higher rates of early optimal responses but had no impact on the long-term survival, benefit patients with high-risk disease and may also associated with higher rates of serious adverse events. Allo-HSCT or other chemotherapy agents are not recommended as frontline therapy for CML-CP, given the excellent outcomes and long-term survival achieved with the TKIs. MONITORING TREATMENT RESPONSE The recommendation that patients have a follow-up : Bone marrow study: at 3, 6, and 12 months after starting therapy. FISH and PCR on peripheral blood: is an alternative method to traditional BM examinations (except when changing TKI or in unusual situations like unexpected myelosuppression, CML transformation ,development of MDS syndrome and other marrow conditions). Molecular response  PCR test results show the number of cells that have the BCR-ABL1 gene. There are different levels of molecular response (MR): 1.MR1 means ≤ 10 →every 100 cells (They have the BCR-ABL1 gene). 2.MR2 means ≤ 1 → every 100 cells. 3.MR3 (major molecular response) means ≤ 1→ every 1,000 cells. 4.MR4 (deep molecular response )means ≤1 → every 10,000 cells. 5.MR5 (also deep molecular response) means ≤ 1 → every 100,000 cells. Cytogenetic response This depends on how many bone marrow cells contain the Philadelphia chromosome: 1.complete cytogenetic response (CCYR) means none (or < 1%) of the bone marrow cells contain Philadelphia chromosome 2.partial cytogenetic response means between 1 - 35 → 100 bone marrow cells. 3.minor cytogenetic response means between 36 - 65 → 100 bone marrow cells. 4.minimal cytogenetic response means between 66 - 95 → 100 bone marrow cells. 5. no cytogenetic response means > 95 →100 bone marrow cells. INTERPRETATION 1.In the first year of therapy Monitoring PB by PCR every 3 months is acceptabe. Once the patient is in a confirmed MMR (MMR for 2-3 times over a 6-month period), so can be monitoring BCR::ABL1 transcripts every 6 months is adequate and safe. 2.The achievement of a CCyR Ph-positive metaphases 0%; BCR::ABL1 transcripts [IS] ≤1%) at 12 months or late. Associated with a significant survival benefit ,it is the primary endpoint of TKI therapy. 3.Achievement of MMR BCR::ABL1 transcripts [IS] ≤0.1%. Associated with modest improvements in event- free survival (EFS)rates, possible longer durations of CCyR, but not with a survival benefit. 4.Lack of achievement of MMR or should not be interpreted as a need to change TKI of DMR therapy or to consider allo-HSCT. INTERPRETATION 5.Optimal responding When BCR::ABL1 transcripts (IS) are 1% at 12 months or later. The need to change TKI therapy is indicated. 8.A more conservative approach with persistent BCR::ABL1 transcripts (IS) 1%– should be followed in older 10% at 2 years of imatinib therapy. These patients still had 10-year CML-specific survival patients rates similar to those with transcripts 1% after 12 months of therapy, loss of hematologic or cytogenetic response, or CML transformation. 2. Causes of resistance : point mutations in the kinase domain of BCR::ABL1, which impairs the activity of the available TKIs ,therefore Second-generation TKIs overcome most of the mutations that confer resistance to imatinib. Novel mutations making the leukemia resistant to second-generation TKIs(esp. T315I, known as the “gatekeeper” mutation) displays resistance to all currently available TKIs except ponatinib and asciminib ADVANCED STAGE CML The WHO recommended eliminating CML-AP as defined entity , categorizing it as high-risk CML-CP, and defining only two CML phases: CML-CP and CML-BP (20 + % blasts). The criteria of CML-AP by the presence of ACAs for example a translocation of 3q26 (or MECOM) is associated with a very poor prognosis and should prepared to allo-HSCT. De novo CML-AP(with 8-year survival rate) has a better outcome with frontline TKI therapy than CML-AP evolving from CML-CP(median survival of less than 3 years). The most frequently mutated genes were ASXL1 , IKZF1 , and RUNX1 and can be progressed to CML-BP. Patients with CML-CP and having somatic variants(ASXL1 mutations) may not benefit from the TKIs or from combination therapies and can be treated with allo-HSCT.  REFERENCES 1. Kenneth Kaushansky.Marshall A. Lichtman. Josef T. Prchal , Williams hematology ; 9th Edition. 2. Elaine M. Keochane. Catherine N.Otto. Jeanine M.Walenga ,Rodakˈs Hematology Clinical Principles and Application ;Sixth Edition. 3. American Cancer Society. Cancer Facts & Figures. 2024. Accessed June 26, 2024. 4. Kantarjian H, Jabbour E, Cortes J. Chronic myeloid leukemia. In: Loscalzo J, Fauci A, Kasper D, Hauser S, Longo D, Jameson JL, eds. Harrison's Principles of Internal Medicine. 21st ed. McGraw-Hill Education;2022. 5. Sasaki K, Haddad FG, Short NJ, et al. Outcome of Philadelphia chromosome-positive chronic myeloid leukemia in the United States since the introduction of imatinib therapy—the surveillance, epidemiology, and end results database, 2000–2019. Cancer. 2023;129:3805-3814. 6. Elias Jabbour , Hagop Kantarjian.Chronic myeloid leukemia: 2025 update on diagnosis, therapy, and monitoring.16 July 2024, DOI: 10.1002/ajh.27443. THANK YOU