**CORRESPONDENCE**

**OPEN**

CHRONIC LYMPHOCYTIC LEUKEMIA

# Updates of the ERIC recommendations on how to report the results from immunoglobulin heavy variable gene analysis in chronic lymphocytic leukemia

© The Author(s) 2024

*Leukemia* (2024) 38:679–680; https://doi.org/10.1038/s41375-024-02163-4

**TO THE EDITOR:**

The treatment paradigm of chronic lymphocytic leukemia (CLL) is rapidly shifting from chemoimmunotherapy (CIT) to novel targeted agents. Recent randomized studies have consistently documented the superiority of chemo-free treatment with targeted therapies over CIT in patients with CLL [1–3], rendering the latter either not recommended or a less preferred option, as also reflected in recently published international guidelines [4, 5]. On these grounds, we deem it necessary to introduce some changes to the recommendations by ERIC, the European Research Initiative on CLL [6], on how to report results from immunoglobulin heavy variable (IGHV) gene analysis in CLL in order to reflect the recent advancements in CLL therapy.

More particularly, the aim of this update is to emphasize on the need to inform clinicians about the existing knowledge (or lack thereof) on the predictive value of IGHV gene somatic hypermutation (SHM) status in the era of targeted agents (Table 1 and Supplemental Material). Specifically, ERIC proposes that the laboratory report for patients found by sequencing analysis to carry unmutated IGHV genes should also mention that these patients display shorter progression-free survival when treated with fixed-duration treatment, such as venetoclax plus obinutuzumab compared to IGHV-mutated cases [7]. Finally, the laboratory reports of patients identified as belonging to CLL stereotyped subset #2 should state that this is a prognostically adverse patient group regardless the SHM status [8, 9] while also acknowledging the lack of evidence about the predictive value of subset #2 in the era of targeted therapies.

<table><caption>**Table 1.** Proposed changes in the interpretation section of the previous examples.</caption><thead><tr><td>Example of the IGHV report</td><td>Interpretation</td></tr></thead><tbody><tr><td>IGHV-unmutated</td><td>Following the 98% germline identity cut-off which is used for discriminating CLL cases into the IGHV-mutated or IGHV-unmutated category, this case belongs to the IGHV-unmutated category which is generally associated with adverse prognosis and poor response to chemoimmunotherapy and a shorter progression-free survival when treated with fixed-duration treatments that include venetoclax plus an anti-CD20 antibody compared to IGHV-mutated cases [7].</td></tr><tr><td>Subset #2</td><td>Following the 98% germline identity cut-off which is used for discriminating CLL cases into the IGHV-mutated or IGHV-unmutated category, this case belongs to the IGHV-mutated category. However, this particular rearrangement belongs to stereotyped subset #2 which is associated with adverse prognosis and poor response to chemoimmunotherapy regardless of the somatic hypermutation status [8, 9]. The predictive value of subset #2 for patients treated with targeted therapies is currently unknown.</td></tr></tbody></table>

Thomas Chatzikonstantinou¹, Andreas Agathangelidis¹,², Anastasia Chatzidimitriou¹,³, Cristina Tresoldi⁴, Zadie Davis⁵, Véronique Giudicelli⁶, Sofia Kossida⁶, Chrysoula Belessi⁷, Richard Rosenquist⁵³,⁸, Paolo Ghia⁹,²,², Anton W. Langerak¹⁰, Frédéric Davi¹¹, Kostas Stamatopoulos¹,³ and ERIC, the European Research Initiative on CLL*

¹Institute of Applied Biosciences, Centre for Research and Technology Hellas, Thessaloniki, Greece. ²Department of Biology, School of Science, National and Kapodistrian University of Athens, Athens, Greece. ³Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden. ⁴Division of Immunology, Transplantation and Infectious Diseases, IRCCS Ospedale San Raffaele, Milan, Italy. ⁵Department of Molecular Pathology, University Hospitals Dorset, Bournemouth, UK. ⁶International ImMunoGeneTics Information System (IMGT), Institut de Génétique Humaine (IGH), Centre National de la Recherche Scientifique (CNRS), Université de Montpellier, Montpellier, France. ⁷Hematology Department, Nikea General Hospital, Pireaus, Greece. ⁸Clinical Genetics, Karolinska University Hospital, Stockholm, Sweden. ⁹Division of Experimental Oncology, Università Vita-Salute San Raffaele and IRCCS Ospedale San Raffaele, Milan, Italy. ¹⁰Department of Immunology, Laboratory Medical Immunology, Erasmus MC, Rotterdam, The Netherlands. ¹¹Department of Hematology, APHP, HôpitalPitié-Salpêtrière and Sorbonne University, Paris, France. *A list of authors and their affiliations appears at the end of the paper.

✉email: ghia.paolo@hsr.it
## REFERENCES

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2. Eichhorst B, Niemann CU, Kater AP, Furstenau M, von Tresckow J, Zhang C, et al. First-line venetoclax combinations in Chronic Lymphocytic Leukemia. N Engl J Med. 2023;388:1739-54.

3. Shanafelt TD, Wang XV, Hanson CA, Paietta EM, O'Brien S, Barrientos J, et al. Long-term outcomes for ibrutinib-rituximab and chemoimmunotherapy in CLL: updated results of the E1912 trial. Blood. 2022;140:112-20.

4. National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology. Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma Version 1.2024. 2023 Nov 3; National Comprehensive Cancer Network. Available from: https://www.nccn.org/professionals/physician_gls/pdf/cll.pdf.

5. Wendtner CMA-SO, Binder M, Dreger P, Eichhorst B, Gregor M, et al. Onkopedia guidelines on CLL; Jan 2023. Available from: https://www.onkopedia.com/de/onkopedia/guidelines/chronische-lymphatische-leukaemie-cll/@@guideline/html/index.html.

6. Agathangelidis A, Chatzidimitriou A, Chatzikonstantinou T, Tresoldi C, Davis Z, Giudicelli V, et al. Immunoglobulin gene sequence analysis in chronic lymphocytic leukemia: The 2022 update of the recommendations by ERIC, the European Research Initiative on CLL. Leukemia. 2022;36:1961-8.

7. Al-Sawaf O, Zhang C, Jin HY, Robrecht S, Choi Y, Balasubramanian S, et al. Transcriptomic profiles and 5-year results from the randomized CLL14 study of venetoclax plus obinutuzumab versus chlorambucil plus obinutuzumab in chronic lymphocytic leukemia. Nat Commun. 2023;14:2147.

8. Baliakas P, Agathangelidis A, Hadzidimitriou A, Sutton LA, Minga E, Tsanousa A, et al. Not all IGHV3-21 chronic lymphocytic leukemias are equal: prognostic considerations. Blood. 2015;125:856-9.

9. Jaramillo S, Agathangelidis A, Schneider C, Bahlo J, Robrecht S, Tausch E, et al. Prognostic impact of prevalent chronic lymphocytic leukemia stereotyped subsets: Analysis within prospective clinical trials of the German CLL Study Group (GCLLSG). Haematologica. 2020;105:2598-607.

## AUTHOR CONTRIBUTIONS

All authors contributed to the article and approved the submitted version. T.C. wrote the manuscript, A.A, A.C., C.T., Z.D., V.G., S.K., C.B., R.R., A.W.L., and F.D. edited the text and gave final approval. P.G. and K.S. wrote the manuscript, edited the text, and gave final approval.

## COMPETING INTERESTS

TC received honoraria from AbbVie, RR has received honoraria from AbbVie, AstraZeneca, Janssen, Illumina, and Roche. PG: received honoraria from AbbVie, AstraZeneca, BeiGene, BMS, Galapagos, Janssen, Loxo@LillyOncology, MSD, Roche; research funds from AbbVie, AstraZeneca, BMS; Janssen, AWL has received research support from Janssen, Gilead and Roche, FD has received honoraria from Janssen and Gilead, KS received honoraria from Janssen, Lilly, AstraZeneca; and research support from Janssen, Abbvie, AstraZeneca.

## ADDITIONAL INFORMATION

**Supplementary information** The online version contains supplementary material available at https://doi.org/10.1038/s41375-024-02163-4.

**Correspondence** and requests for materials should be addressed to Paolo Ghia.

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© The Author(s) 2024

## ERIC, THE EUROPEAN RESEARCH INITIATIVE ON CLL

Thomas Chatzikonstantinou¹, Andreas Agathangelidis¹,², Anastasia Chatzidimitriou¹,³, Cristina Tresoldi⁴, Zadie Davis⁵, Véronique Giudicelli⁶, Sofia Kossida⁶, Chrysoula Belessi⁷, Richard Rosenquist⁸,³,⁸, Paolo Ghia⁹,¹⁰, Anton W. Langerak¹⁰, Frédéric Davi¹¹ and Kostas Stamatopoulos¹,³