Oncology Case Challenge: A 46-Year-Old Mother With Severe, Constant Abdominal Pain

Mounika Gangireddy, MD, MBBS

Disclosures

April 13, 2022

The pathogenesis of CML is fusion of the ABL1 gene on chromosome 9 with the BCR gene on chromosome 22, resulting in overexpression of the oncoprotein BCR-ABL1.[3] This translocation, t(9;22), is known as the Ph chromosome. Ninety percent of patients with CML harbor Ph chromosome, whereas 5% have Ph variants; the other 5% are Ph-negative by cytogenetic analysis but are positive for BCR-ABL by fluorescence in situ hybridization (FISH) and PCR. BCR-ABL1 is a tyrosine kinase that promotes growth and replication by increasing signaling pathways such as STAT, RAS, RAF, JUN kinase, and MYC.[4]

About 50% of patients with CML are asymptomatic, and the disease is diagnosed during routine blood tests. The clinical presentation consists of leukocytosis, splenomegaly, thrombocytosis, and anemia. Symptoms vary and include early satiety, left upper quadrant pain, fatigue, malaise, weight loss, thrombosis, and bleeding episodes.

The diagnosis of typical CML is based on persistent leukocytosis along with detection of the Ph chromosome abnormality and t(9;22) (q34; q11) or Ph-related molecular BCR-ABL1 abnormalities by FISH or molecular studies. Baseline chromosome banding analysis is required to evaluate for clonal evolution, i(17) (q10)-7/del7q, and 3q26.2 rearrangements.[5] These findings are associated with a relatively poor prognosis. The most common BCR-ABL transcript is p210, and p190 is rare in CML but often seen in Ph-positive acute lymphoblastic leukemia.

Because of this patient's initial presentation with thrombocytosis and bleeding, CML was always in the differential diagnosis. The peripheral blood smear that showed neutrophilia, basophilia, and eosinophilia prompted BCR-ABL PCR testing, which confirmed the diagnosis.

CML is divided into three phases: chronic, accelerated, and blast. The blast phase (BP) is defined as the presence ≥ 30% blasts. The accelerated phase (AP) is defined as peripheral blood or bone marrow blasts of 10%-19%, peripheral blood basophils ≥ 20%, or the presence of cytogenetic evolution.

To determine the phase of CML, this patient underwent bone marrow biopsy. The biopsy revealed hypercellular marrow (90%) with normal myeloid to erythroid ratio, granulopoiesis with left shift, and increased blasts (15% of marrow cellularity). The results of cytogenetic analysis were positive for t(9;22). Her CML was classified as CML-AP owing to the presence of 15% blasts in the marrow.

There are several prognostic scores for CML, such as Sokal, Euro/Hasford, EUTOS (EUropean Treatment Outcome Study), and ELTS (EUTOS long-term survival).[6,7,8] The Sokal score is a widely used prognostic index that includes age, size of the spleen, platelets, and blasts. On the basis of this score, patients are classified into low- (0.8), intermediate- (0.8-1.2), and high- (> 1.2) risk. With a score of 4.5, this patient is considered high-risk, with a 2-year overall survival of 65% and a median overall survival of 2.5-5 years.

While the results of diagnostic studies are pending, hydroxyurea can be used for cytoreduction. The recommended dosage of hydroxyurea is 20-40 mg/kg/d in divided doses until a diagnosis is obtained. Hydroxyurea, 40 mg/kg/d, was started in this patient for cytoreduction.

TKIs are the mainstay of treatment. TKIs are designed to block interaction between the BCR-ABL1 protein and adenosine triphosphate, halting the proliferation of leukemic cells. Available treatment options include:

Imatinib was the first TKI approved by the US Food and Drug Administration for chronic-phase CML (CML-CP) on the basis of the results of the International Randomized Study of Interferon and STI571 (IRIS) trial.[9,10] It improved event-free survival (80%) and 10-year overall survival (83%).

The DASISION trial compared the second-generation TKI dasatinib with imatinib. Dasatinib provided deeper and faster responses when compared with imatinib, but there was no improvement in overall survival or event-free survival.[11,12,13] The ENESTnd study and the BFORE study compared nilotinib and bosutinib with imatinib, respectively, and again revealed deeper responses without an improvement in overall survival.[14,15] Based on the results of these trials, second-generation TKIs are the first-line choice to treat CML.

Ponatinib is approved by the FDA as a second-line agent in patients who have a T315I mutation.[16,17] Omacetaxine is approved for patients who have disease progression on more than two TKIs.[18]

The doses of TKIs used in chronic and advanced phases of CML are listed in the Table.

Table. Doses of TKIs in Chronic and Advanced Phases of CML

Phase

Imatinib

Dasatinib

Bosutinib

Nilotinib

Ponatinib

Chronic

400 mg/d

100 mg/d

400 mg/d

300 mg twice daily

45 mg/d

Advanced

600 mg/d

140 mg/d

500 mg/d

400 mg twice daily

45 mg/d

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