Doctors Debate: Is Chemoimmunotherapy or Small Molecule Inhibition Most Optimal for Frontline Treatment of CLL?

During a debate made available as part of the 2020 National Comprehensive Cancer Network Virtual Annual Conference, Deborah Stephens, DO, and Mazyar Shadman, MD, MPH, discussed the most optimal frontline therapy for chronic lymphocytic leukemia.

Multiple options exist for the frontline treatment of chronic lymphocytic leukemia (CLL), but the question of which therapeutic strategy is most optimal for these patients is an open-ended question that 2 experts attempted to answer during a debate that was made available as part of the 2020 National Comprehensive Cancer Network (NCCN) Virtual Annual Conference.

Deborah M. Stephens, DO, assistant professor of internal medicine at the Huntsman Cancer Institute at the University of Utah in Salt Lake City, preferred the use of small molecule inhibitors to treat patients with CLL in the first-line setting. On the other side of the debate, Mazyar Shadman, MD, MPH, physician at Seattle Cancer Care Alliance, assistant professor in the Division of Medical Oncology at the University of Washington School of Medicine, and assistant professor in the Clinical Research Division of Fred Hutchinson Cancer Research Center in Washington, was in favor of giving standard chemoimmunotherapy as frontline treatment of CLL.

The physicians were able to find common ground on the idea that there is space in the treatment landscape for both treatment modalities; however, determining patient subgroups that may benefit from one therapy over the other is important for achieving best outcomes.

Small Molecule Inhibitors Are Optimal in Frontline CLL

Research has shown that small molecule inhibitors can prolong progression-free survival (PFS) and overall survival (OS) in patients with CLL, including some patient sets with higher-risk disease such as those withunmutated IGHV, said Stephens. In addition, there is evidence that small molecule inhibition has the potential to improve quality of life (QoL). Stephens recommends against choosing chemoimmunotherapy in the frontline setting, mainly because research suggests that it can lead to myelodysplasia.1

Treatment Evidence Supporting the Argument

One available small molecule inhibition strategy involved the use of the agent ibrutinib (Imbruvica) with or without anti-CD20 monoclonal antibodies. In the phase 3 ECOG 1912 (E1912; NCT02048813) trial, ibrutinib in combination with rituximab (Rituxan) was found to be superior to the chemoimmunotherapy regimen fludarabine, cyclophosphamide, and rituximab (FCR) in terms of PFS and OS in patients with CLL or small lymphocytic leukemia (SLL) aged 70 or younger. The updated results were presented at the 2019 American Society of Hematology (ASH) Annual Meeting and later published in Blood.2

“There are multiple clinical trials that support my stance, but the most pertinent one is E1912, led by Tait D. Shanafelt, MD. This study provides results for younger patients treated with ibrutinib plus rituximab versus FCR in the frontline setting,” Stephens told Targeted Oncology, in an interview. “I believe this highlights that even in the lower-risk group that we would traditionally recommend for frontline chemoimmunotherapy, there is an OS benefit in patients who received the targeted small molecule inhibitor, ibrutinib.”

A total of 529 patients in the E1912 study were randomized 2:1 to received either ibrutinib plus rituximab (n = 354) or FCR (n = 175).

There was a statistically significant improvement in PFS in the combination arm versus FCR

(HR, 0.39; 95% CI: 0.26-0.57; P <.0001). The median PFS was not reached in the study after a median follow-up of 48 months. The 3-year PFS rate in the ibrutinib arm was 89% versus 71% in the FCR arm.

The difference in OS between the ibrutinib combination group and the FCR group also met the threshold for statistical significance (HR, 0.34; 95% CI, 0.15-0.79; P = .009). The 3-year OS rate was 99% in the ibrutinib/rituximab arm compared with 93% in the FCR arm.

Among the IGHV-mutated subgroup, the hazard ratio for survival between the 2 arms was 0.42 (95% CI; 0.16-1.16; P = .086), and at 3 years, the survival rate was 88% in the ibrutinib/rituximab arm versus 82% in the FCR arm. Patients who had unmutated IGHV showed a statistically significant variance for survival (HR, 0.28; 95% CI, 0.17-0.48; P <.0001). At 3 years, the survival rates at 3 years in the ibrutinib group versus the FCR group were 89% and 65%, respectively.

The safety profile of the ibrutinib combination was reported at the previous year’s ASH Annual Meeting. Grade 3/4 treatment-related adverse events (TRAEs) occurred in 58% of patients who received ibrutinib plus rituximab versus 72% of those who received FCR (P = .0042). Investigators found that patients who received FCR had more frequent grade 3/4 neutropenia (44%) compared with the ibrutinib/rituximab arm (23%). The FCR arm also had more frequent infectious complications (17.7%) versus the ibrutinib combination arm (7.1%). The P values for the difference in frequent neutropenia and infectious complication were both <.0001.3

The ECOG-E1912 study ultimately led to FDA approval of ibrutinib in combination with rituximab as an initial treatment of adult patients with CLL or SLL in April 2020.4

The Case for Frontline Treatment

Above all, Stephens advocates for small molecule inhibitors in the frontline setting, which she said may improve response to therapy and QoL. This was demonstrated in a pooled analysis of the phase 1/2 PCYC-1102 (NCT01105247) and phase 3 PCYC-1112 (NCT01578707) trials in which ibrutinib monotherapy was administered to patients with CLL or SLL.The pooled analysis demonstrated overall that patients who receive ibrutinib in the first line have a better chance of achieving a CR.

The analysis included 327 patients, 31 (9.5%) of whom were treated in the first-line setting. The median number of prior lines of therapy among patients with relapsed/refractory disease in the analysis was 3 lines (range, 0-12).5

Patients were in the study for a median of 26.4 months (range, 0.3-55.6). Complete responses (CRs) were observed in 32 patients (9.8%) who were treated with ibrutinib. Of the patients from the PCYC-1102 study, 11.9% with relapsed or refractory disease achieved a CR, 25.8% were treatment-naïve. Twelve of the patients (6.2%) who had a CR were from the PCYC-1112 study. The median time to CR for the overall patient population was 14.7 months (range, 4.6-47.1).

Regarding QoL, the outcomes observed with frontline ibrutinib were improved versus chlorambucil when administered to treatment-naïve patients with CLL in the phase 3 RESONATE-2 trial (NCT01722487; NCT01724346).1

In the trial, 269 patients were randomized 1:1 to receive with ibrutinib 420 mg once daily on a continuous basis or chlorambucil 0.5 to 0.8 mg/kg for 12 cycles or fewer.6

At a median follow-up of 60 months (range, 0.1-66), treatment with ibrutinib led to a significant prolongation of PFS compared with chlorambucil, with the median not reached versus 15.0 months, respectively (95% CI, 10.2-19.4). The reduction in the risk of progressive disease (PD) or death was 85% (HR, 0.146; 95% CI, 0.098-0.218). It was estimated that at 5 years, 70% of the ibrutinib arm would be progression-free and alive.

In terms of OS, the median was not reached in either arm. However, 5-year OS rate estimates were 83% for patients in the ibrutinib compared with 68% of the chlorambucil arm.

The ORR was 92% with ibrutinib versus 37% with chlorambucil, which were predominantly partial responses (PRs), but the number of patients with a CR did increase over the course of the study. Specifically, the investigator-assessed rate of CR or CR with incomplete marrow recovery (CRi) was 11% at the time of the primary analysis, which climbed to 30% after a median follow-up of 5 years. These results were consistent across the all subgroups evaluated in this study.

Ibrutinib was well tolerated by patients with CLL/SLL overall. Most frequently, the AEs observed with ibrutinib were diarrhea (50%), cough (36%), and fatigue (36%), which mostly decreased with time on ibrutinib.

The positive results from RESONATE-2 led to durable improvements in patient-reported outcomes and disease-related toxicities, which the investigators, led by Jan A. Burger, MD, PhD, considered to be an improvement in overall QoL.

More Encouraging Data Around Small Molecule Inhibition

Ibrutinib is not the only small molecule inhibitor that Stephens considered promising for the treatment of CLL in the frontline setting.1,6

The combination of acalabrutinib (Calquence) and obinutuzumab (Gazyva) has also demonstrated promise in treatment-naïve, symptomatic patients with CLL by showing a significant improvement in PFS over the chemoimmunotherapy combination of obinutuzumab and chlorambucil, in the phase 3 ELEVATE-TN clinical trial.1,7

In the study, 535 patients were randomized 1:1:1 to receive acalabrutinib plus obinutuzumab (n = 142), single-agent acalabrutinib (n = 142), or obinutuzumab plus chlorambucil (n = 137). Forty-five patients from the chemoimmunotherapy arm crossed over to receive acalabrutinib monotherapy.7

The median PFS after a median follow-up of 28.3 months (interquartile range [IR], 25.6-33.1) was not reached in the acalabrutinib/obinutuzumab arm versus 22.6 months in the obinutzumab/chlorambucil arm, representing a 90% reduction in the relative risk of disease progression or death (HR, 0.10, 0.06-0.17; P <.0001). Among patients who received acalabrutinib monotherapy, the median PFS was significantly higher than with chemoimmunotherapy, with a hazard ratio of 0.20 (95% CI 0.13-0.30; P <.0001). A consistent benefit was seen in subgroups of patients with either IGHV-mutant CLL or those without IGHV mutation.

Aside from acalabrutinib plus obinutuzumab, a hopeful combination is that of ibrutinib plus venetoclax (Venclexta), which has been evaluated in the minimal residual disease (MRD) cohort of the phase 2 CAPTIVATE trial (NCT02910583), which was presented virtually during the 25th Congress of the European Hematology Association (EHA) by Tanya Siddiqui, MD.8

The study population was made up of 164 individuals, 148 of whom received ibrutinib lead-in as well as all 12 cycles of ibrutinib plus venetoclax. Overall, undetectable MRD (uMRD) was achieved by 75% of patients in the peripheral blood and 72% in the bone marrow, with rates improving over time.

At a median follow-up of 14.8 months (range, 14.5-21.7 months), the ORR was 97%, including CRs in 51% of patients. At 15 months, most subjects were progression free and no deaths were observed.

The safety profile of ibrutinib plus venetoclax was generally favorable. The most common AEs in the combination arm were mainly grade 1/2. The most common grade 3/4 AEs observed were neutropenia (35%), hypertension (7%), thrombocytopenia (5%), and diarrhea (5%). Five percent of patients discontinued study treatment due to AEs, but no patients died as a result of AEs.

Siddiqui concluded that the CAPTIVATE study validates the synergy between ibrutinib and venetoclax and demonstrates the combination’s low rate of discontinuation due to toxicity.

Toxicities and Continuous Therapy

Ibrutinib plus venetoclax as well as the other small molecule inhibition strategies highlighted in Stephens’ argument do incite concern with some physicians, but Stephens advised her peers not to be distracted by the toxicities observed with these combinations or with the continuous therapy strategy.1

With ibrutinib regimens, toxicities are known to improve overtime. One exception to this fact is hypertension, which is typically chronic but can be medically managed, Stephens said. In terms of infectious risk reduction, she stated that these cases are likely caused by humoral and innate improvement in immune system functions. Finally, she pointed out that the selective Bruton kinase inhibitor acalabrutinib is designed to be effective in patients while reducing ibrutinib-related toxicities.1,5

Chemoimmunotherapy is Optimal in Frontline CLL

Shadman’s countered Stephen’s arguments with evidence supporting the stance that chemoimmunotherapy, specifically FCR, is a reasonable treatment option for patients with CLL who have either mutated IGHV or unmutated TP53 and who are young and fit for chemotherapy. The ongoing interest in treating this patient population with chemoimmunotherapy is based on durable responses observed with chemoimmunotherapy, access to chemoimmunotherapy drugs, and the cost of treatment. The only exception to the benefit of chemoimmunotherapy use is in patients with abnormal TP53.

“In some patients, chemoimmunotherapy remain a viable treatment option,” Shadman told Targeted Oncology, in an interview.

Historical Agents Versus Novel Agents in CLL

Currently, chemotherapy is not a popular treatment choice and Shadman therefore refers to this time as the “chemo-free era.” However, he argues that chemoimmunotherapy is not dead for first-line treatment of patients with CLL.

In the phase 3 CLL10 study (NCT00769522), the combination of bendamustine plus rituximab was tested against FCR for non-inferiority in patients with advanced CLL. The study included 688 patients, 561 of whom were included in the intention-to-treat population with 279 in the bendamustine/rituximab arm and 282 in the FCR arm.9

Patients were observed for a median time of 37.1 months and a significant differences in median PFS were observed between the 2 arms at 41.7 months (95% CI, 34.9-45.3) in the bendamustine-containing arm versus 55.2 months (95% CI, NE) in the FCR arm. The was also no difference in OS observed between the 2 arms. The study showed that after 3 years, 95% of patients in the bendamustine plus rituximab group were still alive, as were 91% of the FCR group.

Overall the FCR regimen was more successful in the CLL10 study, despite prior research showing promise for bendamustine plus rituximab. Although FCR remained the standard frontline treatment for advanced CLL based on this study, bendamustine/rituximab was less toxic and was therefore considered a valid treatment option. These 2 regimens were solidified into the frontline CLL landscape prior to the approval of ibrutinib, Shadman highlighted during his presentation.1

FCR was also assessed in a study of IGHV-mutated CLL, led by investigators at The University of Texas MD Anderson Cancer Center. Subjects with mutated IGHV had a long-term PFS with a plateau on the PFS curve, with no relapse beyond 10.4 years. The median PFS rate at 12.8 years was 53.9% among patients with IGHV mutations versus 8.9% for those without an IGHV mutation.10

These 2 studies show that prior to 2018, most of the data favored chemoimmunotherapy for patients with IGHV mutations. After these trials, multiple head-to-head studies compared chemoimmunotherapy with novel agents in patients with different characteristics, including young and fit individuals, older patients, and those with comorbidities. These studies included E1912, which was the key basis for Stephens’ small molecule inhibition argument, as well as the A041202 (NCT01886872) and CLL14 (NCT02242942) clinical trials.1

In the multicenter, randomized, double-blind phase 3 A041202 study, in patients 65 years of age or greater with untreated CLL.11

Results published a 2018 issue of the New England Journal of Medicine showed more PFS events in the bendamustine-plus-rituximab arm than the 2 other arms. The median PFS was not reached in either the single-agent ibrutinib or ibrutinib-plus-rituximab arms, and was 43 months (95% CI, 38-NR) in the bendamustine-containing arm. At 2 years, the PFS rate was 87% in the ibrutinib monotherapy arm, 88% in the ibrutinib combination arm, and 74% in the bendamustine/rituximab arm.

OS favored bendamustine/rituximab in the A041202 study. Specifically, the 2-year OS rates observed were 90% with ibrutinib monotherapy, 94% with the ibrutinib combination, and 95% with bendamustine/rituximab.

In the CLL14 trial, obinutuzumab plus venetoclax was assessed against obinutuzumab plus chlorambucil in 432 previously treated patients with CLL who had comorbidities.12

PFS favored the venetoclax combination in the overall study population. The hazard ratio for progression or death was 0.35 (95% CI, 0.23-0.53; P <.001). At 24 months, the difference in PFS rates between the 2 arms was significant, at 88.2% in the obinutuzumab plus venetoclax versus 64.1% in the obinutuzumab plus chlorambucil group.

Among patients with IGHV-mutant CLL, PFS was higher (HR, 0.62; 95% CI, 0.28-1.46) than the PFS observed with IGHV-nonmutated patients.

Continuing the Standard Practice

Based on the major clinical trials highlighted in Shadman’s presentation, he confirmed than FCR is still beneficial for young/fit patients with IGHV-mutant CLL; bendamustine plus rituximab is best for less fit, older patients with IGHV-mutant CLL; and obinutuzumab plus chlorambucil is a desirable option for unfit, older patients with IGHV-mutant CLL. Therefore, Shadman does not find it justifiable to change standard practice for treating CLL in the first-line setting.

Although the validity of chemoimmunotherapy in this patient population has been proven, Shadman admits that is not the preferred method of treatment for most physicians. He agrees with the idea that novel agents can complement FCR, which was demonstrated in the iFCG study of ibrutinib plus FCR as frontline treatment of IGHV-mutated CLL without 17p deletion or mutated TP53, and in the iFCR study of ibrutinib plus FCR in patients with CLL and MRD (NCT00769522).13

“We have a number of clinical trials that show that ibrutinib was the superior treatment,” Shadman stated. “It’s never wrong to offer a drug like ibrutinib or even acalabrutinib or venetoclax. You can always justify your decision to give novel agents. But there are subgroups of patients for whom the data don’t show that ibrutinib is superior to chemoimmunotherapy.”

Experts Analyze the Conversation Further

Following the NCCN debate, Drs Stephens and Shadman were joined by a panel of experts who reviewed both sides of the argument. Among the panel was Julio C. Chavez, MD, MS, associate member in the Lymphoma Section of the Department of Malignant Hematology at Moffitt Cancer Center in Tampa, Florida.

In an interview with Targeted Oncology, Chavez provided key takeaways from the discussion.

“Appropriate disease stratification with FISH [fluorescence in situ hybridization] and IGVH mutational status is fundamental prior to starting treatment in patients with symptomatic CLL. As physicians, we have to consider patients’ characteristics, comorbidities, and preferences when deciding therapy for CLL. Not all patients will qualify for chemoimmunotherapy despite having low-risk CLL,” Chavez noted. “We also have to consider time-limited options in order to reduce costs and continuous exposure to therapy.”

The question of which type of treatment is most optimal for patients with CLL remains open-ended, but as a peer collective, the presenting physicians and the panelists agreed in some areas. Chavez said: “The majority of us preferred time-limited therapy. We agree that, in the appropriate setting, venetoclax/obinutuzumab would be one of [the] main choices, given that is an oral targeted agent and time-limited therapy.”


1. Shadman M, Zelenetz AD, Chacez JC, and Ma S. Debate – What is Optimal First-Line Therapy for Chronic Lymphocytic Leukemia: Chemoimmunotherapy or Small Molecule Inhibitor Therapy? Presented at: 2020 NCCN Virtual Annual Conference; March 19-22, 2020.

2. 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

3. Shanafelt TD, Wang V, Kay NE, 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; 132(suppl 1):LBA4. doi: 10.1182/blood-2018-120779

4. FDA approves ibrutinib plus rituximab for chronic lymphocytic leukemia. News release. FDA website. April 21, 2020. Accessed June 12, 2020.

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6. 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

7. Sharman JP, Banerji V, Fogliatto, 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). Blood. 2019; 134. (Supplement_1): 31. doi: 10.1182/blood-2019-128404

8. Siddiqi T, Tam CS, Allan JN, et al. First-line ibrutinib (ibr) + venetoclax (ven) for patients (pts) with chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL): efficacy and safety results from CAPTIVATE MRD cohort. Presented at: 2020 European Hematology Association Annual Congress; June 11-21, 2020. Abstract S158.

9. Eichhorst B, Fink AM, Bahlo J, 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. doi:10.1016/S1470-2045(16)30051-1

10. Thompson PA, Tam CS, O'Brien SM, et al. Fludarabine, cyclophosphamide, and rituximab treatment achieves long-term disease-free survival in IGHV-mutated chronic lymphocytic leukemia. Blood. 2016;127(3):303-309. doi:10.1182/blood-2015-09-667675

11. 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

12. Fischer K, Al-Sawf 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

13. Davids MS, Brander DM. Kim HT, et al. Ibrutinib plus fludarabine, cyclophosphamide, and rituximab as initial treatment for younger patients with chronic lymphocytic leukaemia: a single-arm, multicentre, phase 2 trial. Lancet Haematol. 2019; 6: e419–28. doi: 10.1016/ S2352-3026(19)30104-8