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Test for IGHV status 
Identify the type of CLL
TREAT accordingly

Assessing patients’ immunoglobulin heavy chain variable (IGHV) gene mutation status as a predictive biomarker is now recommended by major guidelines[1][2]

IGHV status remains one of the best-established predictive biomarkers to date and a key factor in patient stratification.[2][3]

ESMO and iwCLL guidelines recommend analysis of IGHV status as a key step in treatment decisions[1][2]

Adapted from Eichhorst B, et al. 2021.[1]

[a]CIT as alternative treatment, only if reasons against treatment with targeted therapies or non-availability. [b]BR might be considered alternatively in patients above the age of 65 years. [c]If available. [d]If approved and available.[1]

CIT=chemoimmnotherapy; CLBO=chlorambucil, obinutuzumab; FCR=fludarabine, cyclophosphamide and rituximab.

Examining IGHV status

See what opinion leaders have to say about the role IGHV status can play in tailoring treatment to achieve optimum results in newly diagnosed CLL:

IGHV testing:
An essential step towards precision medicine in CLL
IGHV status:
Guided treatment decisions to optimise patient outcomes
IGHV testing before treatment selection:
Recommended by guidelines

CLL is characterised by a highly variable clinical course[4][5]

CLL has a remarkable variation between different patient groups.[3][5]
Some patients never require treatment.[3]
Other patients have a rapidly progressive disease.[3]
Around 60% of CLL patients in need of treatment have an unmutated IGHV (uIGHV) status, therefore IGHV status remains one of the most important considerations. A uIGHV status with most currently available treatments is associated with:[1][6][7]

Lower duration of remission

Lower survival rates

It is essential to select treatment based on your patients’ IGHV status to achieve optimum outcomes[8][9][10][11]

First-line chemoimmunotherapy (CIT) is associated with a poor prognosis in patients with uIGHV CLL[7]

CLL10: Progression-free survival by IGHV status with fludarabine, cyclophoshamide and rituximab (FCR)[7]*

Adapted from Eichhorst B, et al. 2016.[7]

CLL10: Progression-free survival by IGHV status with bendamustine + rituximab (BR)[7]*

Adapted from Eichhorst B, et al. 2016.[7]

uIGHV status is independently associated with a higher risk of progression with traditional CITs vs mIGHV[7]

CLL patients with uIGHV status have a better prognosis when treated with novel targeted therapies vs CIT.[8][9][10][11]

Long-term follow-up is an important consideration in determining durability of response to treatment.[8][9]

RESONATE-2: Ibrutinib vs chlorambucil progression-free survival by IGHV status at up to 7 years[8]

Adapted from Ghia P, et al. 2021.[8]

CLL14: Progression-free survival by IGHV status with venetoclax + obinutuzumab (V+O) vs chlorambucil + obinutuzumab (C+O)[9]

Adapted from Al-Sawaf O, et al. 2021.[9][12]

Leveraging long-term data is crucial for optimising treatment in uIGHV CLL[8][9][10][11]

Determining IGHV status - important considerations from the European Research Initiative on CLL (ERIC)[13]

IGHV status is determined by amplifying the clonotypic IGHV-IGHD-IGHJ gene rearrangement by PCR, sequencing the PCR product through Sanger or next generation sequencing and assessing percentage identity to the closest germline IGHV gene[3][13]

≥98% of nucleotide identity to germline is required to achieve uIGHV classification.[13]

97–97.9% of nucleotide identity to germline is considered borderline.[13]

This subset is formally classified as mIGHV, but caution is warranted[13]

<98% of nucleotide identity to germline is required to achieve mIGHV classification.[13]

See ERIC for recommendations on assessing IGHV status

Achieve IGHV excellence by going beyond just testing in CLL

Today's decision shapes tomorrow.

Test. Type. TREAT.

*CLL10 was a randomised, open-label, international, phase III study of FCR vs. BR in fit, previously untreated CLL patients without del(17p) mutation (n=561).[7]

†RESONATE-2 is a phase III, open-label, multicentre, international, randomised study investigating the long-term efficacy and safety of ibrutinib vs chlorambucil in previously untreated patients with CLL/SLL (up to 7 years of follow-up, (n=269)).[8]

‡CLL14 is a randomised trial comparing the efficacy and safety of a combined regimen of obinutuzumab and venetoclax vs obinutuzumab and chlorambucil in previously untreated patients with CLL (n=432) and coexisting medical conditions.[9]

BR=bendamustine, rituximab; CI=confidence interval; CIT=chemoimmunotherapy; CLBO=chlorambucil, obinutuzumab; CLL=chronic lymphocytic leukaemia; C+O=chlorambucil, obinutuzumab; IGHV=immunoglobulin heavy chain variable; ERIC=European Research Initiative on CLL; ESMO=European Society for Medical Oncology; FCR=fludarabine, cyclophosphamide and rituximab; HR=hazard ratio; iwCLL=International Workshop on Chronic Lymphocytic Leukemia; m/uIGHV=mutated/unmutated IGHV; NR=not reached; PCR=polymerase chain reaction; PFS=progression-free survival; V+O=venetoclax, obinutuzumab.

References

Eichhorst B, et al. Chronic lymphocytic leukaemia: ESMO clinical practice guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2021;32(1):23–33.
Hallek M, et al. iwCLL guidelines for diagnosis, indications for treatment, response and assessment, and supportive management of CLL. Blood. 2018;131(25):2745–2760.
Crombie J and Davids MS. IGHV mutational status testing in chronic lymphocytic leukemia. Am J Hematol. 2017;92(12):1393–1397.
Orgueira AM, et al. Time to Treatment Prediction in Chronic Lymphocytic Leukemia Based on New Transcriptional Patterns. Front Oncol. 2019;9:79.
Yun X, et al. Recent progress of prognostic biomarkers and risk scoring systems in chronic lymphocytic leukemia. Biomarker Research. 2020;8:40.
Rotbain EC, et al. IGHV mutational status and outcome for patients with chronic lymphocytic leukemia upon treatment: a Danish nationwide population-based study. Haematologica. 2020;105(6):1621–1629.
Eichhorst B, et al. First-line chemoimmunotherapy with bendamustine and rituximab versus fludarabine, cyclophosphamide, and rituximab in patients with advanced chronic lymphocytic leukaemia (CLL10): an international, open-label, randomised, phase 3, non-inferiority trial. Lancet Oncol. 2016;17(7):928–942.
Ghia P, et al. Ibrutinib treatment in the first-line setting for patients with chronic lymphocytic leukemia: up to 7 years of follow-up in the RESONATE-2 study. Poster presented at: EHA2021 Virtual Congress; 9–17 June 2021. #EP636.
Al-Sawaf O, et al. Venetoclax-obinutuzumab for previously untreated chronic lymphocytic leukemia: 4-year follow-up analysis of the randomized CLL14 study. Abstract presentation at: EHA2021 Virtual Congress; 9–17 June 2021. #137.
Woyach JA, et al. Ibrutinib regimens versus chemoimmunotherapy in older patients with untreated CLL. N Engl J Med. 2018;379(26):2517–2528.
Moreno C, et al. Ibrutinib plus obinutuzumab versus chlorambucil plus obinutuzumab as first-line treatment in patients with chronic lymphocytic leukemia or small lymphocytic lymphoma: up to 4 years of extended follow-up from the phase 3 iLLUMINATE study. Poster presented at: XVIII International Workshop on CLL (IwCLL) Meeting; 20–23 September 2019; Edinburgh, United Kingdom. #2069.
Tausch E, et al. Genetic markers and outcome with front line obinutuzumab plus either chlorambucil or venetoclax -updated analysis of the CLL14 trial. Poster presented at: 16th ICML Virtual Congress; 18–22 June 2021; virtual meeting. #S144.
Rosenquist R, et al. Immunoglobulin gene sequence analysis in chronic lymphocytic leukemia: updated ERIC recommendations. Leukemia. 2017;31(7):1477–1481.
CP-275939 - February 2022