AMP case report: A CLL/SLL case with distinctive molecular and cytogenetic changes during different stages of disease progression

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Our patient had a long disease course with multiple treatments and relapses. Drug resistance mutations were also identified in this patient during disease progression. A BTK p.C481S mutation was originally detected in the patient’s bone marrow sample collected in 2016, when he developed disease refractory to ibrutinib treatment. C481S is a well-characterized ibrutinib-resistant mutation that disrupts the irreversible covalent binding between ibrutinib and BTK.¹⁴ This mutation was not detected in the 2019 sample, indicating that the subclone harboring the resistance mutation might lose advantage in the absence of drug selection pressure and succumb to other subclones. A BTG1 p.S41R mutation was detected in the 2019 peripheral blood sample, after he failed venetoclax/rituximab, idelalisib/rituximab, and CAR T-cell therapies. BTG1 is a member of an antiproliferative gene family that regulates cell growth and differentiation. Notably, BTG1 mutations are rarely detected in untreated CLL/SLL but have been associated with resistance to venetoclax.¹⁵

In conclusion, CLL/SLL is a highly variable disease characterized by clonal and subclonal evolution of the leukemia cells. Novel mutations may appear or disappear corresponding to therapy selection. It is therefore beneficial to monitor the molecular profile longitudinally using NGS to tailor the individual therapy plan, especially when there is disease transformation.

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Dr. Xu and Dr. Kulak are PGY-4 residents; Dr. Shi is a fellow in laboratory genetics and genomics; Dr. Chen is director of hematopathology, co-director of flow cytometry, and medical director of hematology and the hematopathology laboratory; Dr. Koduru is professor of pathology and medical director of the genetics diagnostics laboratories; and Dr. Gagan is assistant professor and associate medical director of the next-generation sequencing laboratory—all at the University of Texas Southwestern Medical Center, Dallas.

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