Comment on “Acute pro-B-cell lymphoblastic leukemia evolving from myelodysplastic neoplasm post cytotoxic therapy: a case report”

It was a pleasure to read the meticulously prepared case report by Wobst et al.,¹ published in the recent issue of Haematologica. The authors convincingly demonstrated the clonal evolution of a pro-B acute lymphoblastic leukemia (ALL) in an 80-year-old patient following long-lasting therapy with lenalidomide/dexamethasone (21 cycles) more than 12.5 years earlier because of a previous multiple myeloma (MM) diagnosis. In between this 12.5-year span, the patient developed a myelodysplastic syndrome (MDS) post cytotoxic therapy (MDS-pCT) with a chromosome del 20q and a presumably pre-existing DNMT3A mutation. The authors claimed that the pro-B-ALL directly developed from the MDS-pCT clone by gaining additional chromosomal aberrations such as loss of one X-chromosome (-X) or gain of chromosome 14q (+14q). While the superbly presented fluorescense in situ hybridization data support this conclusion, there are some things however, that may have escaped the authors’ attention. Chiefly amongst these are the subtleties incurred by lenalidomide treatment on IKAROS 1 and 3 degradation.² In a series of intricate biochemical steps, lenalidomide leads to ubiquitination and proteasomal degradation of these key lymphoid transcription factors in B-cell precursors, which exactly mimics the situation observed in B-ALL. Genetic IKAROS alterations - either germline or somatically acquired - are key drivers in B-ALL development.^3-5 In turn, the lenalidomide-accompanying block in B-cell maturation is, at least in part, closely linked to its therapeutic efficiency in MM.² Thus, it is quite likely that lenalidomide therapy increases the intrinsic risk for subsequent B-ALL development,⁶ regardless of any MDS-pCT development. Along these lines, I would like to draw the attention of the scientific community to the work of Fürstenau et al.,⁷ who recently described that three of 56 patients, who had been exposed to lenalidomide, subsequently developed B-ALL. In one of these patients, Fürstenau et al., demonstrated a common B-cell origin chronic lymphocytic leukemia (CLL) and B-ALL. Interestingly, this patient also had a DNMT3A mutation, which was also observed in the patient described by Wobst et al. Unfortunately in the latter case however, it was not possible to compare the side-by-side IgH status of the MM and the pro-B-ALL since material was not available from the MM.

In summary, biochemical data supports the causal link between IKAROS degradation and lenalidomide-associated B-ALL. This hypothesis is also strengthened by recent observations of patients in whom lenalidomide discontinuation alone led to regression of incipient or overt B-ALL clones, even without any further B-ALL therapy.⁸ The latter observation calls for novel B-ALL therapies in which restoration of endogenous IKAROS levels is achieved. Pre-clinical data in animal models showed that this approach is very promising, particularly in Philadelphia chromosome-positive (Ph+) and Ph+-like B-ALL, where sustained disease remission was observed following IKAROS re-engagement.⁹

Footnotes

• Received April 23, 2025
• Accepted May 5, 2025

Correspondence

A. BORKHARDT - arndt.borkhardt@med.uni-duesseldorf.de

Disclosures

No conflicts of interest to disclose.