IGLV3-21 (Immunoglobulin Lambda Variable 3-21)

Our data confirmed unfavourable prognostic value of IGLV321 for prediction of progressionfree survival and overall survival in CLL patients with M IGHV genes, regardless of radiation anamnesis.

R110-bsAb spared polyclonal human B cells (as opposed to CD19-targeting Blinatumomab) as well as CD34+ human stem cells...In vivo, R110-bsAb specifically killed IGLV3-21R110-expressing cell lines and CLL cells while sparing peripheral blood mononuclear cells. These findings highlight bispecific antibodies as a potential off-the-shelf immunotherapy for high-risk CLL patients, offering selective targeting while preserving healthy B cells.

Further, it provides information about the poor prognosis of IGLV3 - 21 CLL. The shortened survival of the two unmutated clone groups in the IGHV unmutated group may indicate a poor prognosis.

The validation cohort of 343 Rai 0 patients confirmed these findings, with UM light chain genes predicting a 7-year treatment free probability of 42.0% versus 73.7% for M genes (p < 0.0001). These results indicate that the mutational status of the light chain genes is an independent predictor of shorter TTFT in early-stage CLL patients.

We further demonstrate in two humanized mouse models lack of cytotoxicity towards human B cells. These data provide the basis for advanced approaches of resistance-preventive and biomarker-guided cellular targeting of functionally relevant lymphoma driver mutations sparing normal B cells.

Comparing ELCLV3-21 risk groups in MBL versus a cohort of 226 CLL patients revealed ELCLV3-21 high-risk MBL individuals had significantly shorter time to therapy (P=0.003) and reduced OS (P=0.03) compared to ELCLV3-21 low-risk CLL. These results highlight the power of the ELCLV3-21 approach to identify individuals with a higher likelihood of adverse clinical outcome and may provide a more accurate approach to classify individuals with small B-cell clones.

In conclusion, by assessing the individual contribution of DME and TL to disease survival, we found that both variables offer valuable independent prognostic information when included in statistical models with poor-risk genomic lesions. TL and DME could help identify IGHV-mutated patients destined to respond poorly to (immuno-)chemotherapy, that might be more favourably treated with targeted agents.

In patients with AL amyloidosis, the ClonoSEQ assay can identify a sequence consistent with the patient's light or heavy chain isotype almost 80% of the time. Of those cases in which a clonal light chain sequence was consistent with the patient's isotype, the genes identified were from the well described AL-related light chain variable region gene repertoire. These findings indicate that the size of the AL clone does not affect this outcome and suggest that other factors related to the adaptive immune dysregulation of AL or to the multiplex PCR process may be involved.

IGLV3-21R110 was identified as an independent prognostic factor for shorter EFS in early stage CLL with intermediate/high risk score and was associated with reduced ibrutinib efficacy in the CLL12 trial.