Novel Combination Therapies in CLL Transform the Treatment Landscape

The presence of novel combinations and oral targeted therapies are rising in the frontline treatment setting for patients with chronic lymphocytic leukemia, regardless of age. According to Nitin Jain, MD, ongoing phase III trials will bring additional modifications to the treatment landscape.

Nitin Jain, MD

The presence of novel combinations and oral targeted therapies are rising in the frontline treatment setting for patients with chronic lymphocytic leukemia (CLL), regardless of age. According to Nitin Jain, MD, ongoing phase III trials will bring additional modifications to the treatment landscape.

During a presentation at the 2019 SOHO Annual Meeting, Jain said recent clinical trial findings have helped clarify therapy choices based on the patient’s age, comorbid conditions, and mutation status but that questions about optimal regimens and the duration of therapy remain unanswered.

“The treatment options have changed quite remarkably but there are more things coming along in the pipeline,” said Jain, an associate professor in the Department of Leukemia at The University of Texas MD Anderson Cancer Center. “Hopefully, in the next 1 to 2 years, as these [phase III trials] get reported, our frontline therapy will get further refined.”

Chemoimmunotherapy with fludarabine, cyclophosphamide, and rituximab (FCR), introduced in the 2000s, has been the gold standard for young, fit patients with CLL in the frontline setting. In the past 5 years, Jain said, the introduction of ibrutinib (Imbruvica) and other oral targeted agents has provided new, less toxic options.1

In May, the FDA approved venetoclax (Venclexta) for the frontline treatment of adults with CLL or small lymphocytic lymphoma (SLL) after findings from the phase III CLL14 trial showed that the BCL2 inhibitor in combination with obinutuzumab (Gazyva; VEN+G) was more effective than obinutuzumab plus chlorambucil. The patient population in the pivotal trial had previously untreated CLL and coexisting conditions.2

Jain said the current frontline standard has been updated to include VEN+G. For patients aged <65 to 70 years without major comorbidities, the options consist of ibrutinib monotherapy and VEN+G. For those with IGHV mutation, FCR also would be considered.

The preferred regimens are ibrutinib and VEN+G for patients >65 to 70 years, those with major comorbidities, and those with chromosome 17p deletion (del[17p]) or TP53 mutations, Jain said.

A Focus on Minimal Residual Disease

In analyzing which patients derived the most benefit from the former standard of care, Jain said data from prior studies showed frontline FCR therapy resulted in favorable long-term progression-free survival (PFS) in patients with IGHV mutations who had achieved undetectable minimal residual disease (MRD).

Jain and colleagues hypothesized that improving MRD negativity would lead to improved survival. They then designed a phase II study testing the combination of ibrutinib, fludarabine, cyclophosphamide, and obinutuzumab (iFCG) for the frontline treatment of patients with CLL with mutated IGHV and without TP53 aberrations. Investigators included obinutuzumab because previous results showed that the drug induced higher rates of MRD negativity than rituximab. Patients received 3 cycles of iFCG followed by ibrutinib for 9 cycles and obinutuzumab for either 3 or 9 cycles, depending upon response and MRD levels. After 12 cycles, ibrutinib therapy stopped for those with undetectable bone marrow and continued for those with detectable MRD. The study enrolled 45 patients with a median age of 60 years (range, 25-71) with CLL categorized on the Rai stage as 0 (n = 1), I or II (n = 22), and III to IV (n = 22).1

In findings presented at the 2018 ASH Annual Meeting and updated in August 2019, investigators found that response improved over time. At 3 months, 39% of patients had complete response (CR) or CR with incomplete hematologic recovery (CRi) and 89% were MRD-negative. At 12 months, CR/CRi was 73% and MRD negativity was 100%.1

Forty-one patients reached 12-month follow-up with MRD-negativity and discontinued ibrutinib. The median follow-up after discontinuation was 18.7 months (range, 0.2-28.8), and no patient has had clinical or MRD relapse. No patient has experienced disease progression.

Jaid said those findings were superior to results from other trials evaluating 6 cycles of FCR, ibrutinib plus FCR, or FC plus obinutuzumab, for patients with IGHV-mutated disease.

Ibrutinib for Older Patients

Patients aged ≥65 years with CLL are not eligible for FCR. For that population, long-term findings of the phase III RESONATE-2 trial showed that ibrutinib could be successfully administered for more than 60 months and provided improved PFS and overall survival (OS) compared with chlorambucil.At a median follow-up of 5 years, patients treated with ibrutinib (n = 136) had an 85% reduction in the risk of progression or death versus chlorambucil (n = 133), translating into a hazard ratio of 0.146 (95% CI, 0.098-0.218), according to updated data presented at 2019 SOHO.3Moreover, 70% of ibrutinib-treated patients were progression free at 5 years compared with 12% of those who received chlorambucil. The data favored ibrutinib across all mutation subgroups.3

“That is quite amazing, quite remarkable, that the majority of patients remain in remission,” Jain said.

The median OS rates were not reached in either arm of the study. Overall, 83% of patients treated with ibrutinib were alive at 5 years compared with compared with 68% of those treated with chlorambucil (HR 0.450; 95% CI, 0.266-0.761), with crossover on progression to ibrutinib by 57% of patients receiving chlorambucil.

Ibrutinib also demonstrated improvement in PFS as monotherapy and in combination with rituximab (Rituxan; IR) compared with bendamustine plus rituximab (BR) in the phase III ALLIANCE A041202 trial. The median age was 71 years (range, 65-89) and 54% of patients had high-risk disease according to modified Rai staging. A quarter of participants had high-risk cytogenetics, including 6% with del(17p) and 19% with del(11q).4

Treatment with ibrutinib either alone or in combination produced superior PFS compared with 6 rounds of chemoimmunotherapy. The 2-year PFS was 74% for BR, 87% for ibrutinib monotherapy, and 88% for IR. There was no significant difference in median PFS was observed between the ibrutinib and IR groups (HR. 1.00; 95% CI, 0.62-1.62; P = 0.49).

Although ibrutinib is associated with clear benefits for patients with CLL, Jain said the agent has some drawbacks. It is an indefinite therapy that produces low CR rates and rarely induces MRD negativity. Physicians are excited about the possibilities of time-limited therapies that induce high rates of CR and MRD negativity.

Venetoclax Combinations

In the phase III CLL14 trial, the combination of VEN+G administered over 12 months reduced the risk for disease progression or death by 65% compared with obinutuzumab plus chlorambucil HR, 0.35; 95% CI, 0.23-0.53; P <.001).2

The study recruited patients with previously untreated CLL and coexisting conditions as assessed on the Cumulative Illness Rating Scale (CIRS) with a score above 6 and/or creatinine clearance (CrCl) below 70 mL per minute. In all, 432 patients were randomized to either VEN+G, followed by venetoclax monotherapy (Arm A; n = 216) or chlorambucil plus obinutuzumab followed by chlorambucil (Arm B; n = 216).

In Arm A, the median age was 72 years, and 33.3% of patients were ≥75 years; the mean total CIRS score was 9, and the median estimated CrCl was 65.2. In Arm B, the median age was 71, with 36.1% ≥75 years; the median total CIRS was 8, and the median estimated CrCl was 67.5.

The overall response rate was significantly higher with the VEN+G at 84.7% (P <.001), including a CR of 49.5%, versus 71.3% with the chlorambucil regimen and a 23.1% CR.

The rates of MRD-negativity in the bone marrow were 57% in the VEN+G arm compared with 17% in the obinutuzumab/chlorambucil arm. In the peripheral blood, those rates were 76% versus 35%, respectively.

Jain said 2-year PFS rates with VEN+G in CLL14 (88.2%) were comparable with those found with ibrutinib monotherapy in RESONATE-2 (89%), and ibrutinib with or without rituximab in ALLIANCE A041202 (87%).

“In the VEN+G study, the treatment is for only 1 year, then they are just being watched,” he added. “Whether that PFS will be maintained equally between the 2 groups [in studies of] ibrutinib and VEN+G, at 2 years, 3 years, 4 years, I think that is an extremely important question.”

Jain and colleagues also explored the combination of ibrutinib and venetoclax in previously untreated older and high risk patients with CLL. The combination was evaluated in a phase II study that enrolled patients with 1 of these clinical features: del(17p), mutated TP53, del(11q), unmutated IGHV, or an age of ≥65 years.5

The study enrolled 80 patients, including 43 (54%) ≥65 years and 24 (30%) ≥70 years. Additionally, 92% of participants had either unmutated IGHV, TP53 aberration, or del(11q).

Responses improved with ongoing therapy, Jain noted. Among 26 patients treated with combination therapy, 96% had a CR with or without normal blood count recovery, 4% had a partial remission, and 69% had undetectable bone marrow MRD after 18 cycles of combination therapy.1


  1. Jain N. Shifting SOC for frontline therapy of CLL. Presented at: SOHO 2019 Annual Meeting; September 11-14, 2019; Houston, Texas.
  2. 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.
  3. Burger J, Tedeschi A, Barr PM, et al. Five-year follow-up after ibrutinib therapy for first-line treatment of chronic lymphocytic leukemia. Poster presented at: SOHO 2019 Annual Meeting; September 11-14, 2019; Houston, Texas. Poster CLL-046.
  4. 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.
  5. Jain N, Keating M, Thompson P, et al. Ibrutinib and venetoclax for first-line treatment of CLL. NEngl J Med. 2019;380(22):2095-2103. doi: 10.1056/NEJMoa1900574.