Part 2: Supporting Data for Ibrutinib-Based Regimens in Frontline CLL


During a live virtual event, Jose Sandoval Sus, MD, discussed with participating physicians frontline treatment options for patients with chronic lymphocytic leukemia, with questions by Targeted Oncology.

Jose Sandoval Sus, MD

Jose Sandoval Sus, MD

Assistant Member

Moffitt Malignant Hematology and Cellular Therapy at Memorial Healthcare System

Moffitt Cancer Center

Pembroke Pines, FL

Targeted OncologyTM: What data support the use of recommended treatment regimens in patients with chronic lymphocytic leukemia (CLL)?

Sandoval Sus: In the phase 3 RESONATE-2 study [NCT01722487], where ibrutinib was used for the frontline therapy, 270 patients with treatment-naïve CLL or small lymphocytic lymphoma [SLL] who were more than 65 years old and not candidates for FCR [fludarabine, cyclophosphamide, rituximab (Rituxan)], with del(17p) excluded, were stratified according to the performance status and Rai stage. Patients were randomized to 1 of 2 groups: ibrutinib 420 mg once daily, which is the approved dose, or chlorambucil 0.5 mg/kg on days 1 and 15 for up to 12 cycles.1

The Kaplan-Meier curve for progression-free survival [PFS], according to the IRC [independent review committee], after almost 18.5 months of follow-up showed ibrutinib was superior [to] chlorambucil [HR, 0.16; P < .001], with a median that was not reached with ibrutinib vs 18.9 months with chlorambucil.2

At the 5-year follow-up that was published earlier this year by the same authors, you still see prolonged PFS in the group treated with ibrutinib. The median PFS had not been reached at 5 years, but with chlorambucil stayed at 15 months [HR, 0.146; 95% CI, 0.098-0.218].3

How does ibrutinib perform in patients with high-risk cytogenetics?

PFS by subgroup analysis is interesting. There are patients with del(11q) [who have similar outcomes with ibrutinib as] patients who did not, and that was, in the past, considered as a high-risk cytogenetic alteration or mutation. In fact, there is some tendency for patients who have del(11q) to do better with the ibrutinib. That is in contrast [with what we know of] patients who are treated with chlorambucil or chemotherapy. Patients treated with chlorambucil who had del(11q) did worse than patients who did not have del(11q) [who] were treated with chlorambucil.3

The same goes for IGHV mutation status. Patients who were treated with ibrutinib had similar PFS whether they had mutated IGHV or unmutated IGHV. Both [groups] did well with a 60-month PFS rate that was above [60%].

There have been some quality-of-life [QOL] assessments of the RESONATE-2 trial that were published last year in the journal Leukemia.3 Patients treated with ibrutinib compared with chlorambucil had improved QOL, which is important when we analyzed long-term data because there are some concerns that the data from clinical trials [involve] “super patients.” Especially when they’re done in big academic centers and not in community centers, there are no other patients that we see in “real life.” There’s a concern of ibrutinib discontinuation, especially from adverse effects [AEs] in up to 42% [shown in] an assessment of the real-world data. But we do have some objective measurements of improved QOL when you compare that [with] chemotherapy [such as] chlorambucil. It is useful to have data, with objective measurement of the impact on QOL when you’re put on a clinical trial.

Are there data to support using ibrutinib in combination with any other agents?

The phase 3 trial ALLIANCE AO41202 trial [NCT01886872] was a phase 3 trial with 3 arms. Patients were randomized to single-agent ibrutinib, ibrutinib plus rituximab, or bendamustine with rituximab [BR]. That was one of the common chemoimmunotherapy regimens used in the past, especially for...patients more than 65 years old with comorbidities.4

The inclusion criteria were patients more than 65 years with an ECOG performance status of less than 2, normal neutrophil count, platelets above 30,000/mm3, a creatinine clearance of more than 40 mL/min, and normal liver function test. Classic inclusion criteria for a clinical trial. Certain things were used for a stratification; especially important was the del(11q) status, present or not, and del(17p).

Each arm [had] around 180 patients. Patients continued on ibrutinib, and the patients [who] were in the BR arm were able to cross over to the ibrutinib arm within 1 year of progressive disease. The main end point of this trial was PFS.

Both of the arms containing ibrutinib were superior to BR. The median PFS was only reached [in] the BR arm. It’s important to note that these clinical trials give us randomized data to show that the addition of rituximab to ibrutinib didn’t add much to treatment. You cannot separate the Kaplan-Meier curves [for PFS]; you cannot even put a pen between both of them. That’s something that I have adapted to; when I use ibrutinib, I do not use rituximab.

What are the safety concerns with ibrutinib in the ALLIANCE trial?

In terms of safety, ibrutinib has a different safety profile than chemoimmunotherapy. Hematologically, there were more grade 3/4 AEs with BR than with ibrutinib or ibrutinib plus the monoclonal antibody. For nonhematological grade 3/4 AEs, they were comparable in all arms. There were some cases of sudden death on the ibrutinib arm. Sometimes with that reported—not only atrial fibrillation that we can see in up to 10% to 15% of our patients with ibrutinib, but also some episodes of tachyarrhythmias—we need to keep pressing when we are discussing the risk-benefit with our patients.

What other combination with ibrutinib should be considered?

A phase 3 randomized clinical trial that is called the iLLUMINATE trial [NCT02264574] where patients with CLL who were treatment naïve and more than 65 or with comorbidities...were randomized to 2 arms of ibrutinib 420 mg daily plus obinutuzumab compared with chlorambucil with obinutuzumab.5

In the intention-to-treat analysis, the combination of ibrutinib plus obinutuzumab was superior in terms of PFS, with a median PFS that was not reached vs 19 months for chlorambucil with obinutuzumab [HR, 0.23; 95% CI, 0.15-0.37; P < .0001]. They estimate the 30-month PFS rate for the ibrutinib/obinutuzumab combination was 79% vs 31% with the chlorambucil/obinutuzumab combination. The undetected measurable residual disease in bone marrow or in blood was comparable.

Are there other Bruton tyrosine kinase (BTK) inhibitors that can be considered in this setting?

Data were presented at [a prior] ASH [American Society of Hematology Annual Meeting], and it was published in the Lancet, regarding the phase 3 Elevate CLL TN trial [NCT02475681] in treatment-naïve patients where acalabrutinib [Calquence] was compared with the usual suspect, obinutuzumab [Gazyva] plus chlorambucil vs acalabrutinib with obinutuzumab.6

This was a big trial of more than 530 participants. Patients were...more than 65 years of age and had comorbidities. Stratification was by del(17p), ECOG performance status, and geographic region. Patients were randomized in 3 groups, 1:1:1.

The primary end point was PFS, mainly comparing acalabrutinib with obinutuzumab vs obinutuzumab with chlorambucil. The secondary end points were PFS of single-agent acalabrutinib vs obinutuzumab/chlorambucil, the overall response rate for all regimens, time to next treatment, OS, and safety. Patients were able to cross over from chlorambucil/obinutuzumab to the other arms after it was allowed by independent review.

The trial met the primary end point after a median follow-up of 28 months. Clearly, the acalabrutinib-containing arms are superior in terms of PFS, and all of them were statistically significant. [In those with IGHV unmutated] status, it seems that acalabrutinib plus obinutuzumab could be somewhat more favorable in that population than single-agent acalabrutinib. OS, at this moment in time, is not different [for the 3 arms], but it’s a short follow-up.

We need to be careful with BTK inhibitors when adding a mono-clonal antibody with some of the AEs. Especially at the beginning, the rates of pneumonia were higher on the acalabrutinib plus monoclonal antibody arm than with acalabrutinib or with obinutuzumab/chlorambucil. Although febrile neutropenia was higher in the chlorambucil arm, infections [were higher with acalabrutinib].

What other classes of agents can be considered in the front line for patients with CLL?

Limited therapies right now will not run forever. A trial that was published last year, the CLL14 study [NCT02242942], was a randomized trial of more than 430 patients done in multiple parts of the world. There were 2 arms, venetoclax plus obinutuzumab, and the other was chlorambucil/obinutuzumab.7

The good thing about this trial is that the chlorambucil was continued for 12 cycles, so it was given for the same length of time as the venetoclax. Treatment was completed after 12 months. You can see that [with a median OS follow-up of] 28 months, venetoclax with obinutuzumab was superior in terms of PFS, with a 24-month PFS rate of more than 88.1% on the venetoclax combination vs the chlorambucil combination of 64.1% [HR, 0.35; 95% CI, 0.23-0.53; P < .001].

After 39.6 months of median follow-up, venetoclax continues to be far superior to the chemoimmunotherapy arm. The 36-month PFS rate with venetoclax plus obinutuzumab was 82% vs 50% on the chlorambucil/obinutuzumab arm. This is fairly superior, and you need to realize a lot of these patients have stopped treatment after 12 months, so a lot of those are without treatment, which is quite impressive.

Can you review the data leading to the approval of ibrutinib in combination with rituximab?

The phase 3 ECOG 1912 trial [NCT02048813] involved more than 500 patients who were randomized to 2 arms, ibrutinib plus rituximab vs FCR. The novelty of this trial is that it was in patients less than 70 years old with good ECOG performance status, good creatinine clearance, and low comorbidity index.8

The PFS was superior on the ibrutinib plus rituximab arm vs FCR, with a 3-year PFS rate of 89% vs 71% [HR, 0.39; P < .0001]. This was especially driven by the patients who had unmutated IGHV. The combination of ibrutinib plus rituximab was approved...based on this E1912 trial.9


1. Burger JA, Tedeschi A, Barr PM, et al. Ibrutinib as initial therapy for patients with chronic lymphocytic leukemia. N Engl J Med. 2015;373(25):2425-2437. doi:10.1056/NEJMoa1509388

2. Burger JA, Barr PM, Robak T, et al. Long-term efficacy and safety of first-line ibrutinib treatment for patients with CLL/SLL: 5 years of follow-up from the phase 3 RESONATE-2 study. Leukemia. 2020;34(3):787-798. doi:10.1038/s41375-019-0602-x

3. Woyach JA, Ruppert AS, Heerema NA, et al. Ibrutinib regimens versus chemoimmunotherapy in older patients with untreated CLL. N Engl J Med. 2018;379(26):2517-2528. doi:10.1056/NEJMoa1812836

4. Moreno C, Greil R, Demirkan F, 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 Oncol. 2019;20(1):43-56. doi:10.1016/S1470-2045(18)30788-5

5. Sharman JP, Egyed M, Jurczak W, et al. Acalabrutinib with or without obinutuzumab versus chlorambucil and obinutuzumab for treatment-naive chronic lymphocytic leukaemia (ELEVATE TN): a randomised, controlled, phase 3 trial. Lancet. 2020;395(10232):1278-1291. doi:10.1016/S0140-6736(20)30262-2

6. Fischer K, Al-Sawaf O, Bahlo J, et al. Venetoclax and obinutuzumab in patients with CLL and coexisting conditions. N Engl J Med. 2019;380(23):2225-2236. doi:10.1056/NEJMoa1815281

7. Fischer K, Ritgen M, Al-Sawaf O, 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. Blood. 2019;134(suppl 1):36. doi:10.1182/blood-2019-125825

8. Shanafelt TD, Wang V, Kay NE, 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. Blood. 2019;134(suppl 1):33.doi:10.1182/blood-2019-126824

9. FDA approves ibrutinib plus rituximab for chronic lymphocytic leukemia. News release. FDA. April 21, 2020. Accessed December 9, 2021.

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