CLL Followed by CML: A Rare Case Described

A recent case report highlights an 82-year-old man with a long history of chronic lymphocytic leukemia (CLL) who was subsequently diagnosed with secondary chronic myeloid leukemia (CML). CLL and CML coexistence is quite uncommon; the progression to CML from CLL is one classification, and the others, even rarer, are simultaneous occurrence and CML preceding CLL.

More commonly, lymphoma or a solid tumor presents secondary to CLL, but CML subsequent to CLL is clearly not impossible, the authors stated in their European Journal of Case Reports in Internal Medicine discussion.¹ And these 2 chronic leukemias coexisting poses a complex clinical challenge, particularly because the underlying mechanisms of their association remain unclear.

The subject of this case report had a 21-year history of chronic lymphocytic leukemia, and a decade of observation | Image Credit: LIghtfieldStudios - stock.adobe.com

A major issue that arises in treating concurrent CLL and CML is that using both a Bruton’s tyrosine kinase (BTK) inhibitor and a tyrosine kinase inhibitor (TKI) may result in combined cardiac toxicity and cytopenia, they noted. Specifically, imatinib (Gleevec; Novartis) and ibrutinib (Imbruvica; Janssen Biotech/Pharmacyclics) would likely be considered. Imatinib, a TKI, inhibits CYP3A4 metabolism—but this potentially increases levels of ibrutinib, a BTK inhibitor, which could predispose the patient to ibrutinib’s adverse effects.

In treating this patient, targeted therapy with dasatinib (Sprycel; Bristol Myers Squibb), a TKI, played an important role.

Patient history. This patient’s leukemia experience began 21 years earlier with his CLL diagnosis, followed by about a decade of observation. Then, escalating hyperleukocytosis emerged and he received 4 months of rituximab (Rituxan; Genentech) followed by 1 year of ABT-263 (Navitoclax; AbbVie). A bone marrow (BM) biopsy conducted at that time showed approximately 50% marrow cellularity with predominantly nodular infiltrates of CLL, and the results of a cytogenetic analysis revealed:

• 46, XY, t(6;11)(p21;q13){8}/46,XY
• Normal findings without 17p deletion, according to fluorescence in situ hybridization
• Mutation of the IGHV gene

Fast forward 11 years, and the patient had leukocytosis with a white blood cell count of 92 K/mcL. His updated diagnosis was CLL and CML.

“Further analysis revealed persistent nodular BM involvement with CLL of 5% to 10%. Additionally, he tested positive for BCR-ABL1 in the chronic phase with < 5% BM blasts and no circulating blasts,” the authors noted. “FISH revealed 46, XY, t(9;22)(q34;q11.2), indicating BCR-ABL1 positivity.

“However, even with the sensitive method of reverse transcription polymerase chain reaction, the BCR-ABL gene was not detected in the initial specimens, suggesting that the development of CML may have occurred subsequently.”

Earlier cases. In prior literature, the investigators wrote, just 18 patients had been documented to have CML diagnosed following an initial CLL finding, with timeframes ranging from 6 to 96 months.²

Individually, however, CLL and CML are both frequently diagnosed in older individuals. CLL is the most commonly diagnosed leukemia in adults in Western nations, and people with CLL are known to be more susceptible to secondary malignancies.

That susceptibility is a result of patients’ compromised immune systems or their exposure to chemotherapy, or both. The genesis of CLL and CML occurring together could be influenced by interactions between the lymphoid and myeloid cell lineages, the authors stated, noting that several mechanisms have been proposed for how this might occur.

For instance, cytotoxic agents and B-cell receptor inhibitors used to treat CLL may contribute to the development of myeloid neoplasms, possibly via genetic changes. Alternately, CLL could emerge in patients previously diagnosed with CML because BCR-ABL–transformed cells have been observed to produce cytokines, such as interleukin-3, which enhance the proliferation of B-lymphoid progenitor cells.

Resolution (for now). The patient began 100-mg daily dasatinib. Over 2 months, his white blood cell count and BCR-ABL1 levels both were reduced: from 85 to 5 K/mcL and from 48% to 13%, respectively. He was then transitioned to maintenance imatinib.

References

1. Saowapa S, Pangkanon W, Adu Y, et al. A rare case of an elderly male with progression to chronic myeloid leukaemia secondary to chronic lymphocytic leukaemia. Eur J Case Rep Intern Med.2024;11(4):004297. doi:10.12890/2024_004297. eCollection 2024.

2. Payandeh M, Sadeghi E, Khodarahmi R, Sadeghi M. Appearance and disappearance of chronic myeloid leukemia (CML) in patient with chronic lymphocytic leukemia (CLL). Int J Hematol Oncol Stem Cell Res. 2014;8(4):49-53.