According to the results of a study published in Blood Cancer Journal, late relapse (LR)- and very late relapse (VLR)-acute lymphoblastic leukemia (ALL) do not show characteristic differences, and no defining genetic patterns were identified for either type.

Although ALL relapse typically occurs early following treatment, within the first 2 years of the initial diagnosis, LR and VLR (defined as relapse occurring 5 to 9 years and ≥10 years after the patients’ initial ALL diagnosis, respectively) occur infrequently and have not been fully characterized to establish exact definitions.

To better understand the clonal origins of LR-ALL and VLR-ALL, the investigators retrospectively examined treatment outcomes, genetic features, and clinical outcomes in patients treated for ALL (1280 patients) at City of Hope in Duarte, CA, between 2000 and 2020.

Continue Reading

They also evaluated the clonal relationships by comparing mutation profiles between archived paired DNA samples (collected at diagnosis and relapse; n=3) using next generation sequencing.

Among the cohort, 36 patients (2.8%) had a LR or VLR, with a median latency period from the original diagnosis to the first relapse of 7 years (range, 5-28). Median age was 16 years (range, 3-40) at initial diagnosis and 25 years (9-51) at first relapse. Among the 24 patients with LR-ALL (66%), the median time to relapse was 6 years (range, 5-9). Among the 12 patients with VLR-ALL (33%), the median time to relapse was 20 years (range, 10-28), including 2 cases with relapse after approximately 30 years after the initial diagnosis.

At the time of initial diagnosis, the leukemia lineage in most patients with LR- and VLR-ALL was B cell (n=32; 89%); the remaining cases were of the T-cell lineage (n=4). At relapse, no instances of lineage switch were detected.

Cytogenetics data at initial diagnosis and first relapse was available for 18 patients (LR and VLR). At first relapse, 7 patients (39%) had different cytogenetics at first relapse. KMT2A gene rearrangement was detected at relapse in 3 cases.

Among the paired samples analyzed by next generation sequencing, the mutation profiles were different at diagnosis and at relapse in all 3 cases, indicating distinct genetics between the original ALL and LR-/VLR-ALL (latency periods were 5, 5, and 10 years).

At the time of first relapse, salvage therapy yielded a complete remission rate (CR2) of 93%. CR2 was achieved in 3 patients following 2 to 3 additional cycles of re-induction. Among novel therapies administered, 9 patients received blinatumomab (7 with CR); 2 patients received inotuzumab (2 with CR); and 3 patients received chimeric antigen receptor T cells (1 with CR). Most patients (28; 78%) patients underwent alloHCT following salvage therapy.

“We suspect that a large subset of LR-ALL patients in our cohort had a true relapse rather than a de novo ALL, supported by similar lineage (B-cell or T-cell) and cytogenetics profile (over half of the cases) at the time of first relapse,” the authors wrote. “In some cases, KMT2Ar and complex cytogenetics were detected as new findings compared to the initial cytogenetics; increasing the possibility of de novo secondary disease from prior exposure to chemotherapy.”

Limitations of the study included a small size, retrospective design, and limited availability of paired samples for genetic analysis. The authors suggested that an analysis with more paired samples is warranted to gain additional insight into the origin of LR-ALL.

Disclosure: The study author(s) declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the original reference for a full list of authors’ disclosures. 


Aldoss I, Pillai R, Yang D, et al. Late and very late relapsed acute lymphoblastic leukemia: clinical and molecular features, and treatment outcomes. Blood Cancer J. 2021;11(7):125. doi:10.1038/s41408-021-00516-1