Dormant Leukemia Cells May “Reawaken” During Late Relapse

Some patients deemed “cancer-free” can experience disease recurrence or relapse years after diagnosis and treatment, without any apparent cause. According to a paper published in Leukemia that looked at a case of very-late recurrence, those cancer cells may survive chemotherapy by adopting a reversible quiescent or “dormant” state and reawaken long after treatment is completed.

The researchers, led by Anthony M. Ford, PhD, from the Centre for Evolution and Cancer and the Institute of Cancer Research in London, described the genomics of a patient with childhood BCR-ABL1 positive, B-cell precursor acute lymphocytic leukemia (pre-B-ALL) whose cancer returned 21 years after it was deemed in remission, one of the longest dormancy intervals recorded.

“Adopting dormancy as a survival strategy is not unique to cancer stem cells,” Dr. Ford and co-authors noted. “Normal blood stem cells fluctuate between proliferative and quiescent or out-of-cycle phases. The capacity of cancer stem cells to avoid lethal therapy by switching to a dormant state can be seen as a legacy of evolutionary programming of protective mechanisms for essential normal stem cells.”

At 4 years old, the patient was diagnosed with ALL and had a mixed lymphoid and myeloid phenotype, with blasts positive for myeloperoxidase, CD13, CD10, and CD19. He was treated with chemotherapy and achieved a complete remission (CR); however, eight weeks following diagnosis, he developed a central nervous system relapse, which was ultimately treated successfully with cranial irradiation and intrathecal drug administration. Three months later, at 5 years old, the patient received a bone marrow transplant (BMT).

Twenty years later, at the age of 25, the patient relapsed. He presented with leukemic cells with a myeloid immunophentoype positive for CD13 and CD33 and negative for CD10 and CD19. He received chemotherapy, which resulted in CR. The patient then underwent a second BMT, but he had bone marrow relapse 35 weeks following the procedure, and ultimately died.

The researchers compared the blood and bone marrow samples taken when the patient was first diagnosed at age 4 with the samples taken upon relapse at age 25.

The researchers determined that the cancer cells that “woke up” during recurrence were similar on a molecular level to a group of cancer cells from the initial diagnosis. They also identified new genetic changes that had arisen.

The culprit and common genetic lineage linking the original and relapsing leukemia in this patient? The BCR-ABL1 mutation.

“Limited prior research assumes that late, recurring cancer is a derivative of the original clone at diagnosis, with the exception of some acute leukemia cases where physiologic rearrangement of immunoglobulin (IGH and IGK) genes provide clone-specific markers,” the authors wrote. “Our data provide unambiguous evidence that leukemia-propagating cells, most probably pre-leukemic stem cells, can remain covert and silent, but potentially reactivatable, for more than two decades.”

These findings apply to only one case study, representing an extremely rare situation. “In the future, it might be possible to speed up the growth of these precancerous dormant cells so that they can be targeted and killed using chemotherapy, to reduce the risk of relapse even further,” the authors added.

Ford AM, Mansur MB, Furness CL, et al. Protracted dormancy of pre-leukaemic stem cells. Leukemia. 2015 May 28. [Epub ahead of print].