Chronic Myeloid Leukemia, BCR-ABL1 Positive
Chronic myeloid leukemia (CML) represents the clonal and neoplastic proliferation of a hematopoietic stem cell with a chromosomal translocation t(9;22) and junction of the BCR-gene and ABL-gene resulting in a BCR-ABL fusion protein of 210 kD or 190 kD, and leading to growth factor independent proliferation and leucocytosis. Non-neoplastic stem cells are vergrown but differentiation and maturation are retained by neoplastic cells with sufficient production of blood cells. In untreated patients, the steady state phase (chronic phase) with sufficient production of mature blood cells usually progresses to an accelerated phase with deterioration of hematologic blood parameters and/or organomegaly. Differentiation of the transformed hemaopoietic stem cells gets lost after a period of about 3 years (median) resulting in the blast phase. Transition from chronic to accelerated and blast phase, respectively, is defined by a number of parameters, which according to WHO (Vardiman et al. 2017) are summarized in Table 1 of chapter “Chronic Myeloid Leukemia and Polcythemia Vera Progression.”
Incidence of CML in Europe is about 1.2 to 1.5 per 100,000 inhabitants per year. In Germany, about 1200 cases are newly diagnosed each year. Presentation most frequently takes place in the chronic phase of disease with mild anemia, thrombocytopenia, and leucocytosis. Abnormal peripheral blood values may be accompanied by mild B symptoms and splenomegaly. The incidence of progression in CML has changed dramatically since the introduction of tyrosine kinase inhibitors (TKI) into therapy. The chronic phase in CML has historically lasted for 3–4 years with a progression rate to blast crisis in the first 2 years of 5–10% and thereafter of 20–25% per year. Untreated patients will invariably develop progression mostly within 3–4 years after diagnosis (Kantarjian et al. 1988). In the era of TKI treatment, the 5-year progression-free survival is 80–95%. Disease progression to advanced phase (accelerated or blast phase) has been reduced to 1–1.5% per year from more than 20% per year in the pre-TKI era (Mukherjee and Kalaycio 2016).
The highest incidence of CML is in the fifth and sixth decade of living, but every age can be affected. Very rarely, CML occurs in childhood (Hijiya et al. 2016).
In CML, there is male predominance.
The bone marrow is the primary site of CML and is almost always affected. Neoplastic stem cells and precursor cells may colonize other organs, most frequently the spleen and liver, less frequently lymph nodes. Principally every organ can be affected.
Treatment in CML is directed against the underlying tyrosine kinase activation of the BCR-ABL fusion protein. Since the first TKI, imatinib, had proven its potency to cure CML, other more effective agents became available (Dasatinib, Nilotinib, Bosutinib). Therapy is guided by depth of molecular response in the peripheral blood as depicted in Table 1.
In case of therapy failure, increase of dosage of TKI or change of drug is recommended. Measurements between indicated thresholds require short-term control and in case of persistence are considered as indicators of increased risk for therapy failure. TKI-treated patients in the chronic phase who have achieved major molecular response enjoy durable responses with virtually no current progression to accelerated phase or blast crisis (Steegmann et al. 2016). Patients who have achieved stable complete molecular remission may experience in approximately 40% of cases complete continued remission in the absence of maintenance treatment (Steegmann et al. 2016). In the accelerated phase, dosage increase of TKI may be successful (Deininger 2015).
Without treatment, most patients will progress to acceleration and blast crisis after a median duration of 3 years of the chronic phase (see chapter “Progression”). The prognosis of CML patients in the blast phase is dismal with median survival ranging from 7 to 11 months (Hehlmann et al. 2016). This has dramatically changed with the introduction of TKI. Five year overall survival ranges from >90% to 99% with modern TKI (Hochhaus et al. 2017; Cortes et al. 2018.
Response to TKI treatment in CML (Melo and Barnes 2007)
Time of treatment (months)
Philadelphia chromosome: >95%
BCR-ABL RNA: >10%
Philadelphia chromosome: <35%
BCR-ABL RNA: <10%
Philadelphia chromosome: >35%
BCR-ABL RNA: >10%
Philadelphia chromosome: 0%
BCR-ABL RNA: ≤1%
Philadelphia chromosome: >1%
BCR-ABL RNA: >1%
BCR-ABL RNA: ≤0.1%
BCR-ABL RNA: ≤0.01%
Any time period
Loss of major response with BCR-ABL RNA increase ≥5 fold
Usually there is mild splenomegaly with diffuse organ enlargement; in addition, hepatomegaly and lymph node tumors may be observed. In the accelerated phase, there may be considerable splenomegaly.
Microscopic presentation of CML is dependent of the phase of disease, either chronic phase or acceleration phase or blast crisis.
During acceleration, more organs may show involvement and the proportion of precursor cells and blasts is increasing (see chapter on “Progression”).
Immunophenotyping does not play a major role in diagnosis of CML in the chronic phase. CD34 and CD117 can be applied to get a rough estimate of the blast content. However, leukemic blasts may be partly or completely negative for these markers in up to 30% of cases. Hence, in order to avoid underestimation, immunohistochemically determined blast cell content cannot be equalled with counts in bone marrow smears which is still representing the gold standard.
In blast crisis which may be manifest in the first presentation, immunophenotyping is mandatory as indicated in the chapter on “Progression.”
CML is defined by the presence of BCR-ABL fusion gene. BCR-ABL fusion represents the molecular basis of the Philadelphia chromosome generated by translocation t(9;22). The reciprocal translocation between chromosomes 9 and 22 is detectable by routine cytogenetic karyotyping in more than 90% of cases. In a small subset of cases, the translocation may be complex with involvement of more than two chromosomes or it may be hidden and demonstrable only by molecular studies of the BCR-ABL fusion. There is evidence that translocation t(9;22) is not the first event in clonal evolution of the neoplasm but rather a secondary event (Fialkow et al. 1981). The break on chromosome 22 occurs within a comparably small region of 5.5 kilo bases (kb) which accordingly has been labeled as break point cluster region (BCR). The break on chromosome 9 affects the ABL proto-oncogene and is located in the huge first intron (>100 kb) between ABL exon 1a and 1b. The split within the BCR gene affects exons 12–16 and in most cases takes place between exons 13 and 14 or 14 and 15, respectively. Rarely, exons 17–20 may be involved. These cases are characterized by marked neutrophilia or thrombocytosis (Pane et al. 1996). As a consequence of the variability in break point location in the large intron 1 of the ABL gene, DNA-based PCR is not suited to detect the gene fusion but reversely transcribed mRNA has to be utilized. The fused mRNA is also exploited to evaluate depth of molecular remission (Table 1). As alternative approach, fluorescence in-situ hybridization can be applied to detect the BCR-ABL gene fusion. In most systems, red and green dyes produce a yellow colored spot of the fusion gene. The fusion gene is translated into a 210 kilo Dalton (kDa) protein. Due to alternative splicing also, a 190 kDa variant of the BCR-ABL fusion protein may be found (Melo 1996; van Rhee et al. 1996) which in a minority of cases represents the dominating protein. These cases are characterized by marked monocytosis and have to be differentiated from chronic myelomonocytic leukemia (Melo et al. 1994). In cases with predominant 190 kDa variant of the BCR-ABL fusion protein, the break in the BCR gene is located upstream of exons 12–16 (major break point region) within the so-called minor break point region. The latter is affected in Philadelphia-chromosome positive acute lymphoblastic leukemia. Immunohistochemical detection of BCR-ABL fusion protein is not used. In blastic progression, the Philadelphia chromosome (Ph) is retained in most instances but additional changes occur (see chapter “Progression”). Additional aberrations may occur in the chronic phase (+Ph, +8, +19, iso(17), −7, 3q−, complex aberrant karyotype) and indicate an increased risk of progression. As a consequence and in order to detect advanced stages, guidelines request karyotypic analysis of CML at initial diagnosis, which cannot be replaced by molecular analysis alone (Vardiman et al. 2017).
Reactive leucocytosis (leukemoid reaction)
BCR-ABL negative atypical CML
Chronic myelomonocytic leukemia
Other types of myeloproliferative neoplasms
Exceptionally, a left-shifted blood picture with immature cells up to promyelocytes may represent a reactive change in infectious or other inflammatory conditions. In these cases, basophilia is regularly lacking. Bone marrow histology reveals normally sized megakaryocytes without the atypical features of small and mononuclear megakaryocytes in CML. Usually, hypercellularity in reactive lesions leaves more residual fatty tissue than CML bone marrow. In cases which remain questionable are encountered only very infrequently. In doubtful cases, detection of BCR-ABL fusion mRNA will enable definite discrimination.
A more difficult discrimination is provided by the differentiation of atypical CML from BCR-ABL positive CML. Left-shifted blood picture is present in both diseases. Basophilia is rare in atypical CML but it may be observed. Megakaryocytic atypia is variable in atypical CML, usually the number is reduced and preponderence of micromegakaryocytes as in BCR-ABL positive is lacking. A feature which is generally not found in atypical CML by contrast to BCR-ABL positive CML is prominent proliferation of eosinophilic precursors. Myelofibrosis can occur in both diseases but it is more frequent in BCR-ABL positive CML. Analysis of BCR-ABL is mandatory in order to achieve an adequate classification.
Some BCR-ABL negative myeloproliferative neoplasms, in particular primary myelofibrosis, may present with left-shifted leucocytosis and basophilia like in CML. Bone marrow histology usually allows differentiation because small mononuclear megakaryocytes which are typical for CML are not found but instead large, cluster-forming megakaryocytes are encountered. In addition, molecular studies will be helpful (BCR-ABL fusion transcripts and mutations of JAK2, MPL, or calreticulin). In rare cases, however, the BCR-ABL junction may be combined with JAK2 mutation (Hussein et al. 2007). In these cases, the size of megakaryocytes resembles that of JAK2 mutated myeloproliferative neoplasms and small megakaryocytes are usually missing. Sometimes, the combined JAK2 mutated neoplasm is not evident at primary diagnosis and becomes evident only after successful treatment of the BCR-ABL positive clone by TKI, usually mistaken as developing therapy resistance (see chapter on “Progression,” Fig. 4) (Hussein et al. 2007).
References and Further Reading
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