Chronic myeloid leukaemia C92.10; C92.2; C93.1;

Chronic myeloid leukemia (CML) is based on a malignant degeneration of the pluripotent stem cell of the bone marrow. The disease requires about 6 years from the initiating bcr-abl translocation (gene fusion), through a multistage course with the stable chronic phase, which can be easily influenced therapeutically, the acceleration phase and the blast phase until the diagnosis is made.

The excessively produced granulocytes of CML are functional (in contrast to the immature cell blasts of acute leukemia). The introduction of imatinib provided a major breakthrough in the treatment of CML. In all prognosis groups and at all ages, a clear superiority of imatinib over IFN-based therapy was observed and the long-term survival of CML patients of all ages was significantly improved (Hehlmann R et al. 2007).

The incidence of CML is about 1.2 to 1.5/100,000 inhabitants per year. In Germany, about 1,000 to 1,200 patients are diagnosed annually, in Switzerland and Austria about 100-120 patients per year.

Over 95% of CML patients have a specific chromosomal aberration, the translocation t(9;22)(q34;q11) with the characteristic Philadelphia chromosome, 22q-. The translocation inserts the Abelson (ABL) tyrosine kinase gene into the breakpoint cluster region (BCR) gene region. A fusion protein, BCR-ABL1, with constitutive tyrosine kinase activity is formed. The BCR-ABL1 fusion protein is responsible for the oncogenic transformation of the affected hematopoietic stem cell.

Men are affected slightly more often than women. CML occurs in all age groups, the disease peak is at 55-60 years. CML is very rare in children. Approximately 15 to 20 patients aged up to 18 years with a median age of 12 years are newly diagnosed with CML in Germany each year. (Suttorp M et al (2018).

CML is a clonal myeloproliferative disease of a pluripotent hematopoietic stem cell. Prior to the use of tyrosine kinase inhibitors (TKIs), a three-stage natural history of the disease was observed in most patients.

The clinical course of CML can be divided into three phases:

• the chronic phase
• the accelerated phase and
• the blast crisis (Melo JV et al. 2007).

Today, the use of TKIs makes it possible to maintain the chronic phase, or remission, until the end of life in most patients.

Both clinical and histological aspects go into the definition of each phase. Transitions between phases are often fluid.

The diagnosis of CML is usually made in the chronic phase. This often becomes symptomatic by anemia due to decreased erythropoiesis due to expanded granulopoiesis. Other initial symptoms may include loss of appetite, weight loss, bone pain, or upper abdominal discomfort in the setting of splenomegaly. However, the chronic phase may also be clinically asymptomatic, so that CML is not infrequently suspected as an incidental finding in a blood test. During blood analysis, the expansion of granulopoiesis with leftward shift of neutrophil granulocytes without signs of dysplasia is most noticeable. Other features such as an eosinophilia or basophilia may be initially apparent. The number of blasts is usually < 2% of the leukocytes in the chronic phase. In the bone marrow, the number of granulocytes is also increased, and the number of blasts is < 5 % of bone marrow cells. A count > 10% indicates disease progression. Distinctive histologic features include reduced megakaryocytes with hypolobulated nuclei (so-called "dwarf megakaryocytes"), pseudo-Gaucher cells, Sea-blue histiocytes, and reticulin fiber fibrosis in 30% of cases.

Criteria describing the transition to the accelerated phase include a continued elevated or increasing number of leukocytes and/or persistent thrombocytosis/penia, increasing splenomegaly, a peripheral blood basophil granulocyte count greater than 20%, and peripheral blood or bone marrow blast counts of 10-19%. In addition, other chromosomal alterations such as an extra Philadelphia chromosome or an extra chromosome 8 may be associated with disease progression. Myelodysplasia is often found in the bone marrow during the accelerated phase. Blast crisis is an acute leukemia that is fatal if untreated. Blast crisis is defined by a blast content > 20% in peripheral blood or bone marrow, focal blast proliferation in bone marrow, or extramedullary blast proliferation.

Extramedullary blast proliferation most commonly occurs in the skin, lymph nodes, spleen, or central nervous system. In 70% of cases, the blast crisis is a myeloid blast crisis, and in 20-30%, it is a lymphatic blast crisis. Undifferentiated blasts are often present, necessitating cytochemical and immunophenotypic examination of the blasts.

In children, the proportion with initial manifestation in advanced disease phase is higher at 5 - 8% (Millot F et al. 2017, Hijiya N et al. 2016).

Skin lesions in chronic myeloid leukemia.

Pustulosis acute generalized exanthematous (AGEP) Scott Ad et al (2014).

Sweet syndrome: underlying malignancies in about 20%. V.a. in acute myeloid leukemia (AML), myelodysplastic syndrome. Sweet syndrome often precedes the diagnosis of malignancy.

Specific leukemic infiltrates of the skin

Physical examination: spleen and liver size; laboratory: blood count; leukocytes with differential, platelets, hemoglobin, hematocrit; peripheral blood; multiplex PCR for BCR-ABL1 transcripts.

Bone marrow aspirate: cytology (blasts, basophils, megakaryocyte morphology, continuous left shift);

cytogenetics: metaphase analysis

Bone marrow biopsy: fibrosis? Blast number and distribution

Characteristic findings of microscopy, genetics, and differential diagnosis are compiled in the Knowledge Base, Chronic Myeloid Leukemia.

Cytogenetics: Cytogenetic monitoring should be performed from metaphases of heparinized bone marrow; in exceptional cases, peripheral blood may be used at diagnosis. The percentage of Ph-positive metaphases should be based on at least 20 evaluated metaphases. Cytogenetic response is designated complete, partial, minor and minimal. Interphase FISH should not be used to determine quantitative cytogenetic response.

Molecular monitoring: Quantitative RT-PCR from 10 ml EDTA-anticoagulated blood is performed every 3 months to quantify BCR-ABL1 mRNA in peripheral blood. BCR-ABL1 transcripts are referenced to an international scale. This allows comparability of results between different laboratories (Cross NC et al (2012). Early molecular response at 3 months (BCR-ABL1IS ≤10%) correlates with survival and the chance of achieving deep molecular remission (Hanfstein B et al. 2014). Testing intervals should be 3 months and can be extended to 6 months if remission is good, i.e. at least MMR, and stable, but should be shortened to 4 to 6 weeks after TKI discontinuation.

Significant increases in BCR-ABL1 transcript levels (5-fold, with loss of MMR) are early signs of treatment failure or for reduced compliance. Achievement of deep molecular remission (MR4, MR4.5, MR5, i.e. 4-5 log reduction) with TKI therapy and stable sustained deep molecular remission for at least 1 year are prerequisites for therapy interruption.

More than 100 different kinase domain mutations have been sequenced in relapses. The specific mutation helps in the selection of alternative TKI therapy. For example, V299L, T315A, and F317L/V/I/C are dasatinib-resistant, while Y253H, E255K/V, and F359V/C/I are nilotinib-resistant. V299L is where bosutinib loses its effect. T315I is resistant to all TKIs except ponatinib.

Differential diagnosis may include reactive leukocytosis associated with infections, rheumatic diseases and collagenoses, septic granulomatosis, or medication (corticosteroids), another chronic myeloproliferative neoplasia including atypical BCR-ABL1-negative CML or chronic neutrophil leukemia.

Once the diagnosis is confirmed, treatment is initiated. It is recommended to include patients in clinical trials or registries. In children and adolescents this is mandatory. Each patient should be informed about the therapeutic goals and the advantages and disadvantages of the different inhibitors before starting therapy. In the absence of a difference in overall survival, the individually preferred TKI is selected on the basis of efficacy and the spectrum of side effects, taking into account individual risk factors.

Chronic phase

First-line therapy with imatinib: Imatinib 400 mg/day has been the standard of care for first-line therapy of all CML patients in chronic phase after BCR-ABL1 positivity has been confirmed. In a phase 2 study after IFN failure, a good cytogenetic response (MCyR, Ph+≤35%) was achieved in 67% of 532 patients, of whom 57% achieved complete cytogenetic remission (CCyR). The 6-year survival was 76%, and the progression-free survival was 61%. Grade 3/4 nonhematologic adverse events were observed in <5% of patients (Kantarjian H et al 2002).

The superiority of imatinib over IFN (earlier first-line therapy) was demonstrated in the International Randomized Study of Interferon and STI571 (IRIS) trial. The 10-year survival with imatinib therapy is approximately 80-85%. In adult patients, annual CML-related mortality is expected to be approximately 0.5% and mortality from CML-unrelated causes is expected to be approximately 1.2% (O'Brien SG et al. 2003; Hochhaus A et al. 2009). Increased imatinib dose may improve the remission rate of patients with suboptimal response.

First-line therapy with second-generation inhibitors (nilotinib, dasatinib, bosutinib).

Other TKIs with improved efficacy have now been developed.

Nilotinib is more BCR-ABL1 specific, also inhibits the tyrosine kinases PDGFR and KIT like imatinib, and shows better cellular bioavailability.

Dasatinib is a multikinase inhibitor with effects on ABL1, SRC, PDGFR and KIT.

Bosutinib is also an SRC/ABL1 inhibitor but does not show significant efficacy against PDGF receptors and KIT.

In first-line therapy, nilotinib, dasatinib, and bosutinib showed superior efficacy compared with imatinib 400 mg/day, with higher rates of cytogenetic and molecular remission, and nilotinib and dasatinib showed a reduction in early acceleration phases or blast crises. The imatinib-typical side effects fluid retention and muscle cramps were observed significantly less frequently with nilotinib. Cardiovascular events occurred more frequently with nilotinib, and hyperglycemic metabolism and lipid metabolism may also be worsened by nilotinib. The higher rate of cytogenetic and molecular remissions compared to imatinib led to first-line approval for nilotinib, dasatinib and bosutinib for the treatment of CML. Survival rates were not improved with the use of the second-generation inhibitors compared with imatinib.

TKIs in combination with interferon alpha: The rate of molecular response with BCR-ABL1 levels < 0.01% was significantly higher in the imatinib+IFN group (30%) than in patients receiving imatinib 400mg. Gastrointestinal side effects were more frequent in the imatinib+Ara-C group, while exanthema and depression were more frequent in imatinib-IFN. In your German CML-IV trial, no advantage was found for the addition of recombinant (non-pegylated) interferon alpha over imatinib 400 mg/day (Hehlmann R et al. 2017).

However, the combination of dasatinib with pegylated interferon alpha showed high molecular remission rates with good tolerability. The combination of nilotinib with pegylated interferon alpha requires further evaluation.

Side effect profile: Concomitant diseases are now the leading cause of death in CML. They can be aggravated by TKI-associated reversible and irreversible side effects. In this respect, patient age, known pre-existing conditions and the specific TKI side effect profile must be considered when choosing therapy. Pulmonary arterial hypertension (PAH) is a rare complication of dasatinib; therefore, patients with pre-existing PAH should receive alternative TKIs. Dasatinib inhibits platelet function; therefore, patients on oral anticoagulation have a higher risk of bleeding.

Nilotinib induces hyperglycemia in high-risk patients (caveat: poorly controlled diabetes mellitus). Nilotinib has been associated with vasospastic and vaso-occlusive side effects, such as coronary artery disease, cerebrovascular disease and occlusive arterial disease . Bosutinib is associated with increased liver toxicity and a high rate of diarrhea. Patients with relevant preexisting conditions should be informed of the occurrence of these side effects. Established dose adjustment regimens should be followed.Imatinib is associated with mild to moderate long-term side effects that can significantly affect quality of life. These include muscle cramps, diarrhea, weight gain, fatigue, peripheral and periorbital edema, bone and joint pain, nausea, and others.

Basically: All available TKIs can prolong QT time. Therefore, K+ and Mg++ should be controlled and kept within normal range and regular ECG checks should be done (Steegmann JL et al.2016).

Alternative: Hydroxyurea (40 mg/kg body weight and day) can be used as initial therapy before clarification of BCR-ABL1 status if there is a risk of hyperviscosity syndrome because of the symptoms or extremely elevated leukocyte counts. TKI therapy should be started immediately after confirmation of BCR-ABL1 fusion. Hydroxyurea should be reduced after initiation of TKI therapy.

Discontinuation of TKI in sustained molecular remission: TKI discontinuation studies demonstrated the feasibility of safe discontinuation after achieving deep molecular remission. After 3 years of nilotinib therapy with at least one year of deep molecular remission (MR 4.5), 51.6% of patients showed stable MMR at 96 months (Hochhaus A et al. (2017).

Approximately 30% of patients experience the so-called discontinuation syndrome, an acute inflammatory syndrome with muscle and joint pain in the foreground. In most cases, the severity of the syndrome regresses in a few weeks. Anti-inflammatory drugs and/or glucocorticoids may be used.

Second-line therapy: The choice ofsecond-line therapy is based on clinical criteria and the presence of BCR-ABL1 mutations. The availability of a total of five approved TKIs allows individualized therapy according to cytogenetic and molecular response, clinical criteria related to the spectrum of side effects, and mutational status in case of resistance to primary therapy.

Tyrosine kinase inhibitors - high-dose therapy: The use of high-dose imatinib can be attempted if the standard dose is tolerated and resistance mutations are absent, but rarely shows long-term success. Nilotinib, dasatinib and bosutinib have been used successfully in phase II trials following imatinib resistance and intolerance in all phases of CML. Nilotinib was approved for chronic and accelerated phase after imatinib failure at a recommended dose of 2x400 mg/day. The recommended dosage of bosutinib in the second-line setting is 500 mg/day.

Individual patients with insufficient capacity of normal hematopoiesis (recurrent cytopenias, no cytogenetic remission on imatinib therapy) have a significantly lower chance of achieving remission on second- or third-line therapy. In these cases, the option of allogeneic stem cell transplantation should be considered. Comment: The success of second-line drug therapy should be critically evaluated early, especially with the option of allogeneic hematopoietic stem cell transplantation (HSCT).

Allogeneic hematopoietic stem cell trans plantation: Performing transplantation in chronic phase is associated with significantly better outcomes than in advanced stages of CML, therefore the indication should be made as early as possible. Induction of a second chronic phase by alternative TKIs with or without chemotherapy is beneficial in any case. HLA-identical siblings, or unrelated donors with 10/10 or 9/10 HLA-A, B, C and DR match in high resolution determination are recommended as donors.

Advanced stages of CML: The mechanism of CML progression is heterogeneous and not fully understood. It is probably a multistep process involving chromosomal and molecular events. In any case, second-generation inhibitors should be preferred and the option of allogeneic stem cell transplantation should be considered in suitable patients. The classification as "accelerated phase at diagnosis" is controversial and difficult to evaluate because of the heterogeneity of factors (blasts, basophils, thrombocytosis, thrombocytopenia). It is recommended to initially consider these patients as high risk.

In the blast crisis, debulking with conventional chemotherapy with or without TKI is useful before transplantation, depending on the immunological characterization of the blasts (Hehlmann R 2012).

The annual mortality of CML patients is currently about 1.7%. Thus, the prevalence of CML is increasing at a constant incidence.

Pregnancy: Pregnancy is not possible under TKI therapy because of the teratogenic risk. Therefore, for patients of childbearing potential, individualized measures are required to allow for the possibility of remission maintenance during pregnancy without the use of TKIs.

Childbearing: In male patients with childbearing potential, the possibility of sperm cryopreservation should be discussed at the time of initial diagnosis. PEG-IFN should be avoided if possible because of the accumulation of polyethylene glycol in pregnancy. If necessary, bridging cytoreduction with leukapheresis is possible in individual cases of significant leukocytosis.

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