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Educational theme: Improving front-line treatment in CLL

Jan 17, 2020

The next educational theme on the Lymphoma Hub is focusing on the front-line treatment of chronic lymphocytic leukemia (CLL). CLL has a heterogeneous clinical course, ranging from indolent disease where patients do not require treatment for several years, to a very aggressive course with rapid disease progression and poorer patient outcomes. 1

The prognosis of patients with CLL has significantly improved in the past two decades, with the standard of care (SoC) first-line treatment of chemotherapy (e.g., fludarabine and cyclophosphamide, chlorambucil, or bendamustine) in combination with anti-CD20 monoclonal antibodies (e.g., rituximab, obinutuzumab, or ofatumumab). 1,2More recently, exciting data have been published, prompting a shift from chemoimmunotherapy-based regimens towards small-molecule agents.

Ibrutinib and venetoclax

The superiority of small molecule therapies, like ibrutinib and venetoclax, in the frontline setting has predominantly been demonstrated in three phase III randomized clinical trials covered by Lymphoma Hub – ECOG-ACRIN E1912, ALLIANCE A041202, and iLLUMINATE– which compared ibrutinib alone or in combination with rituximab to standard chemoimmunotherapy.

The ALLIANCEtrial ( NCT01886872), published in the New England Journal of Medicine, compared bendamustine plus rituximab versusibrutinib, or ibrutinib plus rituximab in older patients (³ 70 years old) with untreated CLL. The study demonstrated that in this patient population ibrutinib-based therapy resulted in significantly higher progression-free survival (PFS) than bendamustine with rituximab. 3Similarly, the ECOG-ACRIN E1912trial ( NCT02048813) compared fludarabine, cyclophosphamide, and rituximab (FCR) to ibrutinib plus rituximab in younger patients (< 70 years old) with previously untreated CLL. The trial demonstrated that ibrutinib plus rituximab led to superior PFS and overall survival (OS) in younger patients when compared to FCR. 4Extended follow-up from the trial (median, 45 months), presented at the 61 stAmerican Society of Hematology(ASH) annual meeting in Orlando, US, demonstrated that the combination of ibrutinib and rituximab continued to provide superior PFS compared to FCR (HR 0.39; 95% CI, 0.26–0.57; p < 0.0001). 5The iLLUMINATE( NCT02264574) study, which was published in The Lancet Oncology, compared chlorambucil plus obinutuzumab versusibrutinib plus obinutuzumab in first-line CLL. Once again, the ibrutinib combination therapy was superior, leading to a better PFS. 6All three studies demonstrated that ibrutinib should be the SoC for the majority of frontline patients with CLL, completely changing the treatment dogma in the field.

More recently, the Lymphoma Hub coveredthe randomized, phase III CLL14 trial, which was published in the New England Journal of Medicine( CLL14, NCT02242942). In this study, investigators compared venetoclax plus obinutuzumab (VenG) versuschlorambucil plus obinutuzumab in previously untreated older patients with CLL and comorbidities. VenG was associated with a superior PFS compared with chlorambucil plus obinutuzumab, which led to its approval by the US Food and Drug Administration (FDA) as a fixed-duration (one year) treatment of patients with CLL in the frontline setting. 7Updated data from the CLL14 study, presented at the 61 stASH annual meeting, demonstrated VenG sustained high response rates, including measurable residual disease (MRD)-negativity, at a median follow-up of 39.6 months, when all patients had been off therapy for a minimum of two years. 8 VenG reduced the risk of disease worsening or death by 69% compared to chlorambucil plus obinutuzumab (PFS, as assessed by investigator; HR 0.31; 95% CI, 0.22—0.44; p < 0.0001).

Ibrutinib monotherapy and VenG are approved for the first-line treatment of CLL, but there are still certain patient populations who can benefit from FCR-based chemoimmunotherapy. Patients with low-risk CLL (mutated IGHVbut without the 17p deletion or a TP53mutation) achieve remission and long-term benefits with FCR-based regimens and so for this subgroup of patients, chemoimmunotherapy is still considered the most appropriate regimen. 9 

The combination of ibrutinib and venetoclax in older patients with high-risk CLL has been studied in a phase II trial  ( NCT02756897) and was reported to be an active and tolerable regimen in these patients. 10Patients had previously untreated CLL with at least one of the following: del(17p), mutated TP53, del(11q), unmutated IGHV, aged ≥65 years. Data presented at the 61 stASH annual meeting, with a median follow-up of 27 months, reported that responses improved with ongoing therapy (65% of patients achieved bone marrow (BM) U-MRD at 12 months and 75% patients at 24 months). 11See the Lymphoma Hub summary here.

Should we treat newly diagnosed patients with CLL differently after ASH 2019?


Acalabrutinib is a highly selective Bruton tyrosine kinase inhibitor that has demonstrated durable responses and a favorable safety profile as a single agent or when combined with obinutuzumab in treatment-naïve CLL. 12In November 2019, the FDA approved acalabrutinib for the treatment of adult patients with CLL. 13

The ELEVATE-TN trial ( NCT02475681)  included 535 patients with previously untreated CLL who were randomized (1:1:1) into three treatment arms: acalabrutinib monotherapy, acalabrutinib plus obinutuzumab, and chlorambucil plus obinutuzumab. With a median follow-up of 28.3 months, PFS (IRC-assessed) was significantly improved in both acalabrutinib arms compared with chlorambucil chemotherapy plus obinutuzumab. 12See the Lymphoma Hub summary here.

What has the presentation of the ELEVATE TN trial taught us?

An ongoing, single arm, phase II investigator-initiated study ( NCT03580928) is investigating the combination of acalabrutinib, venetoclax, and obinutuzumab in patients with untreated CLL. 14Preliminary data suggest that this triplet combination leads to a high proportion of patients achieving BM U-MRD and complete responses with a favorable adverse event profile. Based on the initial results, an expansion cohort has been opened to further characterize the efficacy and safety in patients with TP53 aberrant disease. The combination of acalabrutinib, venetoclax, and obinutuzumab will also be studied head-to-head against chemoimmunotherapy and acalabrutinib plus venetoclax in the phase III trial CL-311 ( NCT03836261), which is currently enrolling.


A summary of the efficacy data from these trials is shown in Table 1below.

Table 1. Summary of trial efficacy data

AcaG, acalabrutinib + obinutuzumab; AcaVenG, acalabrutinib + venetoclax + obinutuzumab; BR, bendamustine + rituximab; CG, chlorambucil + obinutuzumab; CR, complete response; CRi, complete response with incomplete hematolgic recovery; FCR, fludarabine + cyclophosphamide + rituximab; IbruG, ibrutinib + obinutuzumab; IbruR; ibrutinib + rituximab; ORR, overall response rate; OS, overall survival; PFS, progression-free survival; PR, partial response; VenG, venetoclax + obinutuzumab



ALLIANCE A041202 3


CLL14 7,8


NCT03580928 14

Median Follow-up

45 mths

38 mths

31.3 mths

28.1 mths 7

[39.6 mths] 8

48 mths

11 cycles (10 mths)













ORR (%)









100% (after 8 or 16 cycles)

CR (%)









25% (CR+CRi)

PR (%)






(after 8 or 16 cycles)

X-mth PFS (%)


24-mth: 71


24-mth: 74



24-mth: 88.2
[ 36-mth:82]

[ 36-mth:50]

24-mth: 93


X-mth OS (%)


24-mth: 93

24-mth: 94



24-mth: 85





This is an exciting time for the frontline setting of CLL. Novel treatments are steering the SoC away from chemoimmunotherapy which has been the gold standard since the 1990s. At the Lymphoma Hub Satellite symposium at 15 thInternational Conference on Malignant Lymphoma (15-ICML) 2019, Professor Michael Hallek, University Hospital of Cologne, Cologne, DE, delivered a presentation on the evolving treatment landscape in CLL, with a focus on chemotherapy-free regimens, which can be seen here.

  1. Fischer K. & Hallek M. Hematology Am Soc Hematol Educ Program. 2017 Dec 8; 2017(1):338–45. DOI: 10.1182/asheducation-2017.1.338
  2. da Cunha-Bang C. et al. Improved survival for patients diagnosed with chronic lymphocytic leukemia in the era of chemo-immunotherapy: a Danish population-based study of 10455 patients. Blood Cancer J.2016 Nov 11; 6(11):e499. DOI: 10.1038/bcj.2016.105
  3. Woyach J.A. et al. Ibrutinib Regimens versus Chemoimmunotherapy in Older Patients with Untreated CLL. New Engl J Med. 2018 Dec 27; 379(26):2517–2528. DOI: 10.1056/NEJMoa1812836 
  4. Shanafelt T.D. et al. A Randomized Phase III Study of Ibrutinib (PCI-32765)-Based Therapy Vs. Standard Fludarabine, Cyclophosphamide, and Rituximab (FCR) Chemoimmunotherapy in Untreated Younger Patients with Chronic Lymphocytic Leukemia (CLL): A Trial of the ECOG-ACRIN Cancer Research Group (E1912). Blood. 2018 Nov 29; 132:(Suppl 1) LBA-4. DOI: 10.1182/blood-2018-120779
  5. Shanafelt T.D. et al. Ibrutinib and rituximab provides superior clinical outcome compared to FCR in younger patients with chronic lymphocytic leukemia (CLL): extended follow-up from the E1912 Trial. 2019 Dec 7; Oral Abstract #33. 61st ASH Annual Meeting & Exposition, Orlando, US 
  6. Moreno C. et al. Ibrutinib plus obinutuzumab versus chlorambucil plus obinutuzumab in first-line treatment of chronic lymphocytic leukaemia (iLLUMINATE): a multicentre, randomised, open-label, phase 3 trial. Lancet Onc.2019 Jan 1; 20(1):43–56. DOI: 10.1016/S1470-2045(18)30788-5
  7. Fischer K. et al. Venetoclax and obinutuzumab in patients with CLL and coexisting conditions. New Engl J Med. 2019 Jun 6; 380(23):2225–2236. DOI: 10.1056/NEJMoa1815281
  8. Fischer K. et al. Quantitative Analysis of Minimal Residual Disease (MRD) Shows High Rates of Undetectable MRD after Fixed-Duration Chemotherapy-Free Treatment and Serves As Surrogate Marker for Progression-Free Survival: A Prospective Analysis of the Randomized CLL14 Trial. 2019 Dec 7; Oral Abstract #36. 61st ASH Annual Meeting & Exposition, Orlando, US 
  9. Jain N. Shifting SOC for frontline therapy of CLL. Presented at: SOHO 2019 Annual Meeting. 2019 Sep 14; Houston, US
  10. Jain N. et al. Ibrutinib and venetoclax for first-line treatment of CLL. N Engl J Med. 2019 May 30; 380(22):2095–2103. DOI: 10.1056/NEJMoa1900574
  11. Jain N. et al. Combined ibrutinib and venetoclax for first-line treatment for patients with chronic lymphocytic leukemia (CLL). 2019 Dec 7;  Oral Abstract #3461st ASH Annual Meeting & Exposition, Orlando, US
  12. Sharman J.P. et al. ELEVATE TN: Phase 3 Study of Acalabrutinib Combined with Obinutuzumab (O) or Alone Vs O Plus Chlorambucil (Clb) in Patients (Pts) with Treatment-Naive Chronic Lymphocytic Leukemia (CLL). 2019 Dec 7; Oral Abstract #31. 61st ASH Annual Meeting & Exposition, Orlando, US
  13. U.S. Food and Drug Administration. Project Orbis: FDA approves acalabrutinib for CLL and SLL. URL: [Accessed Jan 15, 2020]
  14. Lampson B.L. et al. Preliminary Safety and Efficacy Results from a Phase 2 Study of Acalabrutinib, Venetoclax and Obinutuzumab in Patients with Previously Untreated Chronic Lymphocytic Leukemia (CLL). 2019 Dec 7; Oral Abstract #32. 61st ASH Annual Meeting & Exposition, Orlando, US

Expert Opinion

Treatment of patients with newly diagnosed CLL has made tremendous progress in the past years. Novel treatment options, with targeted therapies such as ibrutinib, venetoclax, and obinutuzumab have helped to serve those patients, who needed it most: the elderly patients and patients with high-risk CLL ( del(17p) or p53mut).