The Battle for the Front Line in CLL Moves Away From Chemoimmunotherapy

Susan M. O’Brien, MD

Traditional frontline chemoimmunotherapy regimens used to be the gold standard for treating patients with newly diagnosed chronic lymphocytic leukemia (CLL). However, over time, targeted therapies have been inching out the use of chemoimmunotherapy to become the preferred approach in this setting.

“I think as time goes on, and more and more data emerge, we are getting further and further from chemotherapy,” said Susan M. O’Brien, MD, associate director for Clinical Science at the Chao Family Comprehensive Cancer Center, and medical director of the Sue and Ralph Stern Center for Clinical Trials and Research, University of California, Irvine.

Ahead of the 2020 Society of HematologicOncology (SOHO) Annual Meeting, O’Brien, the 2021 president-elect of SOHO, spoke with the SOHO Daily News about the reason for this change in the treatment paradigm for CLL, why there is still a place for chemoimmunotherapy in the armamentarium, and some of the related data that will be discussed during the meeting.

Defining the Place for Chemoimmunotherapy

Cytotoxic chemotherapy-based regimens are often difficult for patients to tolerate, especially among older patients who may be unfit or have several comorbidities. Treatments with newer targeted approaches, such as Bruton tyrosine kinase (BTK) inhibitors and BCL-2 inhibitors, are often associated with significant efficacy and manageable toxicity profiles.

O’Brien noted that the use of the common intensive chemoimmunotherapy regimen FCR (fludarabine, cyclophosphamide, and rituximab [Rituxan]), due to the degree of myelosuppression and risk of infection, is usually reserved for patients who are younger and fit. Those who are older, have significant comorbidities, or are unfit are expected to not be able to tolerate the regimen. Guidelines, such as those from the National Comprehensive Cancer Network, echo this sentiment and do not recommend the use of the FCR regimen except in patients who are under 65 years old and without significant comorbidities.¹

FCR is one of the chemoimmunotherapy regimens that has shown positive long-term data in the treatment of CLL. In the CLL8 trial, the addition of rituximab to the chemotherapy regimen induced a median progression-free survival (PFS) of 56.8 months.² The median overall survival (OS) was not reached after a median follow-up of 5.9 years compared with a median OS of 86.0 months in the chemotherapy arm (HR, 0.68; 95% CI, 0.54-0.89; P = .001).²

Many oncologists are more comfortable with such chemoimmunotherapy regimens due to their experience with the regimens and the availability of long-term data for these treatments; so, they can know what to expect long term. Many of the newer targeted therapies do not have significant long-term data available, with the exception of the first-generation BTK inhibitor ibrutinib (Imbruvica).

Additionally, for particular patient populations, the use of FCR is actually preferred over other regimens, even those with newer agents. Among patients with immunoglobulin heavy chain (IGHV)-mutated CLL, the use of FCR has led to long-term PFS benefit.

In a long-term analysis of a phase 2 study of FCR in patients with CLL, patients with IGHV-mutated disease demonstrated considerable survival benefit over those with unmutated disease. At the median follow-up mark of 12.8 years, the PFS rate was 53.9% for patients with IGHV-mutated CLL (n = 88) compared with 8.7% for those with IGHV-unmutated CLL (n = 126). In the IGHV-mutated group, 83.0% achieved a complete response and 50.7% achieved minimal residual disease (MRD) negativity compared with 72.2% and 33.0%, respectively, in the population that did not have the mutation.³

Further, a plateau was seen in the PFS curve for patients with IGHV-mutated CLL, where no relapses were seen after 10.4 years. Forty-two patients were followed after this point for a median of 2.5 years, but none experienced further relapse.

“That raises the obvious question, is there a cure fraction there? I’m willing to go out on a limb and say that I do think those patients are cured,” O’Brien said. “This is a relatively minor subset because it’s young, fit, and has mutated immunoglobulin. So that’s a very small subset where there still might be a cure fraction. So you could argue that that’s a population [for which] you might still strongly consider chemotherapy.”

BTK Versus BCL-2 Inhibition

Among a majority of patients, however, ibrutinib has demonstrated improved survival outcomes compared with FCR. In the randomized phase 3 E1912 study, in patients with previously untreated CLL who are 70 years of age or Ibrutinib has become a preferred standard of care in the treatment of CLL. The agent was approved for the frontline treatment of patients with CLL based off of findings from the RESONATE-2 trial, in which ibrutinib demonstrated superiority over chlorambucil in patients who were at least 65 years old.⁵

“Ibrutinib has produced longer progression-free survival than any chemotherapy regimen that we have—FCR, BR [bendamustine and rituximab], or chlorambucil,” O’Brien said.

Now with 5 years of follow-up for the study, the median PFS was still not yet reached in the ibrutinib arm compared with 15.0 months (95% CI, 10.2-19.4) with chlorambucil (HR, 0.146; 95% CI, 0.098-0.218). The PFS rate at 5 years was 70% with ibrutinib compared with 12% with chlorambucil. The median OS also was not reached in the ibrutinib arm. At 5 years, the estimated OS rate was 83% with ibrutinib and 68% with chlorambucil.⁶

“These are clearly really durable remissions. So the one thing that I believe [that it] has going for it is the track record. So the longevity is there,” O’Brien said.

Ibrutinib also is considered to be a well-tolerated treatment overall. However, it is associated with an increased risk of atrial fibrillation and bleeding. In the RESONATE-2 trial, the rate of any-grade atrial fibrillation was 16%, and 5% experienced a grade 3 event. The rate of major hemorrhage of any grade was 11% with ibrutinib, and grade 3 or greater major hemorrhage events were observed in 7%.

O’Brien noted that the risk of atrial fibrillation is increased in older men and in those with a history of heart disease. “But would that keep me from using ibrutinib in a 75-year-old patient who was a good candidate for a BTK inhibitor? No, it certainly would not. Because the reality is that most patients can tolerate ibrutinib very well,” she said.

Newer BTK inhibitors, such as acalabrutinib (Calquence), approved in the US, and zanubrutinib (Brukinsa), which is not yet approved for use in CLL but approved for mantle cell lymphoma, are associated with reduced rates of cardiovascular toxicity.

Acalabrutinib in combination with the anti-CD20 monoclonal antibody obinutuzumab (Gazyva) showed significant benefit over the use of chlorambucil plus obinutuzumab in the frontline setting in the phase 3 ELEVATE-TN trial. The median PFS was not reached in the acalabrutinib/obinutuzumab arm compared with 22.6 months with chlorambucil/obinutuzumab (HR, 0.10; 95% CI, 0.06-0.17; P < .0001). At 2 years, the PFS rate was 93% (95% C I, 87%-96%) with the acalabrutinib combination and 47% (95% CI, 39%-55%) with the chlorambucil combination. Median OS, however, did not vary significantly between the treatment arms.⁷

The median duration of exposure to treatment was 27.7 months with acalabrutinib/obinutuzumab compared with 5.6 months with chlorambucil/obinutuzumab. Even with the longer exposure, the rate of discontinuation due to adverse events was similar between these treatment arms at 11% with acalabrutinib/obinutuzumab and 14% with chlorambucil/obinutuzumab.

In the acalabrutinib combination arm, the most common grade 3 or greater adverse event was neutropenia in 29.8% of patients, followed by thrombocytopenia in 8.4%. Atrial fibrillation of any grade was observed in 3% of patients receiving the acalabrutinib combination and 4% of patients receiving acalabrutinib monotherapy. Grade 3 or greater bleeding events were reported in 2% of patients who received acalabrutinib and obinutuzumab.

Time-Limited Treatment

One significant benefit of a chemoimmunotherapy approach is the time-limited aspect of the administration of treatment. Whereas treatments such as ibrutinib are administered indefinitely, chemoimmunotherapy is usually given for only 6 cycles, or 6 months. The idea of taking one treatment for years without stopping may be difficult for some patients, especially for younger patients, O’Brien suggested.

“In my experience, it’s rare to find an older patient [who is] not on medication….So, those patients are often used to taking daily medications, and so taking a medication indefinitely, I think, is less of an issue because they’re more used to it. Although it could be a bigger issue in terms of copays if they’re living on fixed income and they have Medicare as their primary [insurance]. But in terms of the psychological impact, it’s less on an older patient and probably more in a younger, fit patient who is somewhat taken aback at the thought that they’re going to take this pill indefinitely,” she explained.

However, a newer agent in the CLL space, the BCL-2 inhibitor venetoclax (Venclexta), is also administered as a fixed-duration treatment. In the frontline setting, venetoclax is given for 12 cycles, and in the relapsed or refractory setting venetoclax is given for up to 24 cycles, or 2 years.

In the frontline setting, venetoclax was assessed in the phase 3 CLL14 trial in combination with obinutuzumab compared with chlorambucil and obinutuzumab in patients with CLL who also had comorbidities. The median PFS was not met in the venetoclax combination arm but showed significant benefit over the chlorambucil combination arm, leading to the regimen’s approval in the frontline setting.⁸

After more than 3 years of follow-up (median, 39.6 months), the median PFS still has not yet been met in the venetoclax arm compared with 35.6 months in the chlorambucil arm (HR, 0.31; 95% CI, 0.22-0.44; P < .001). The estimated 3-year PFS rates were 81.9% and 49.5% with venetoclax/obinutuzumab and chlorambucil/obinutuzumab, respectively. OS, however, was not significantly different between the 2 arms, and the median was not reached in either arm.9

Additionally, almost half of the patients (47.2%) in the venetoclax arm had undetectable MRD in the bone marrow compared with 7.4% in the chlorambucil arm.

The use of prophylactic treatment and ramping up the dose of venetoclax helped to prevent many cases of tumor lysis syndrome in the venetoclax arm; only 3 cases were reported in the venetoclax arm versus 5 in the chlorambucil arm.

Five patient deaths due to fatal adverse events were reported during treatment in the investigational arm compared with 4 in the control arm. After treatment, 11 deaths occurred in the investigational arm versus 4 in the control arm. Most of the fatal events in the venetoclax arm were infections or infestations (1.9% during, 1.9% after), benign or malignant neoplasms (0.5% during, 0.9% after), and cardiac disorders (1.4% after). Secondary cancers were observed in 13.7% of patients treated with the venetoclax combination regimen compared to 10.3% of patients who received the chlorambucil regimen.

Currently, there are no head-to-head comparisons between these small molecules in the upfront setting, making deciding between these available options difficult.

“It’s hard to say that one small molecule is better than another. On the other hand, it’s easy to say that all the great options are clearly producing very durable responses,” O’Brien said. “So how do we decide [between the frontline options] right now? I think we look at the fact that all of them have great efficacy.”

Moving Forward With Combinations and Newer Agents

Rather than choose between BTK or BCL-2 inhibition up front, one possible treatment option could be the use of both in the frontline setting. The use of ibrutinib in combination with venetoclax as treatment for patients with previously untreated CLL has been explored in the phase 2 CAPTIVATE trial; however, the regimen does not have FDA approval. The trial included older patients and those with high-risk disease, including chromosome 17p deletion, mutated TP53, chromosome 11q deletion, and/or unmutated IGHV. Treatment was given for a fixed duration of 24 cycles.¹⁰

PFS and OS rates at 1 year were 98% (95% CI, 94%-100%) and 99% (95% CI, 96%-100%), respectively, with the combination. Seventy-four percent of patients achieved complete remission or complete remission with incomplete count recovery.

In an MRD cohort of the CAPTIVATE trial where patients received 12 cycles of the combination prior to MRD-guided randomized treatment discontinuation, 75% of patients had undetectable MRD in the peripheral blood and 72% in the bone marrow.¹¹

“That looks really promising with the very high rates of MRD undetectability,” O’Brien said.

Similarly, an investigator-initiated phase 2 study that combined ibrutinib and venetoclax involving previously untreated high-risk and older patients with CLL demonstrated that after 12 cycles of combined treatment, 88% of the patients had complete remission or complete remission with incomplete count recovery, and 61% had remission with undetectable minimal residual disease (NCT02756897).12 With combined treatment, the proportions of patients who had complete remission (with or without normal blood count recovery) and remission with undetectable minimal residual disease increased over time.

Moving forward, O’Brien said that there’s considerable excitement around new molecules that are noncovalent BTK inhibitors; specifically, ARQ 531 and LOXO-305.

“All of the BTK inhibitors that we have approved in CLL so far bind in the same ATP binding site, and they are irreversible inhibitors of BTK. So you have to have resynthesis of the BTK in order to escape the drug,” she explained. “In patients who develop clinical resistance, the majority of them will have mutations in that binding site…but the key to the noncovalent inhibitors is that they bind in a different binding site. And so, they are effective, both in the wild-type and also in this setting where you have these resistance mutations.”

In a phase 1 dose-escalation trial of ARQ 531 in patients with relapsed or refractory B-cell lymphoid malignancies, 10 of 40 patients achieved a partial response with higher doses of the treatment. Seven of these patients had relapsed/refractory CLL. The agent was also shown to have a manageable safety profile, with the most common treatment-emergent adverse events being nausea, diarrhea, fatigue, neutrophil count decrease, dysgeusia, and rash.13

In the phase 1/2 BRUIN trial of patients with pretreated B-cell malignancies, LOXO-305 demonstrated efficacy in patients with CLL and mantle cell lymphoma. Among 8 evaluable patients, all 5 patients with CLL had a partial response, and 2 of 3 patients with mantle cell lymphoma had partial responses. All treatment-emergent adverse events were mild and of grade 1 or 2 in severity.¹⁴

“This would give us a whole other class of BTK inhibitors that could potentially work in patients who become resistant to currently approved BTK inhibitors,” O’Brien said. “So, this would give us a whole other option for a drug choice, enabling us to potentially save venetoclax and yet have a very effective drug in that setting. So I think that the preliminary data from those trials are really exciting, and that’s a new type of drug that could also be a game changer for this disease.”

With these new agents and other promising combinations emerging, newer approaches are sure to work their way into the frontline and relapsed/refractory settings, providing further options for patients with CLL.

_References:

_{1. NCCN Clinical Practice Guidelines in Oncology: Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma. Version 4.2020. NCCN. December 20, 2019. Accessed August 26, 2020. https://www.nccn.org/professionals/physician_gls/pdf/cll.pdf​}

_{2. Fischer K, Bahlo J, Fink AM, et al. Long-term remissions after FCR chemoimmunotherapy in previously untreated patients with CLL: updated results of the CLL8 trial. Blood. 2016;127(2):208-215. doi:10.1182/blood-2015-06-651125}

_{3. 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}

_{4. Shanafelt TD, Wang XV, Kay NE, et al. Ibrutinib-rituximab or chemoimmunotherapy for chronic lymphocytic leukemia. N Engl J Med. 2019;381:432-443. doi:10.1056/NEJMoa1817073}

_{5. Burger JA, Tedeschi A, Barr PM, et al; RESONATE-2 investigators. Ibrutinib as initial therapy for patients with chronic lymphocytic leukemia. N Engl J Med. 2015;373:2425-2437. doi:10.1056/NEJMoa1509388}

_{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;34:787-798. doi:10.1038/s41375-019-0602-x}

_{7. Sharman JP, Egyed M, Jurczak W, et al. Acalabrutinib with or without obinutuzumab versus chlorambucil and obinutuzmab 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}

_{8. Fischer K, Al-Sawaf O, Bahlo J, et al. Venetoclax and obinutuzumab in patients with CLL and coexisting conditions. N Engl J Med. 2019;380:2225-2236. doi:10.1056/NEJMoa1815281}

_{9. Al-Sawaf O, Zhang C, Tandon M, et al. Fixed-duration venetoclax-obinutuzumab for previously untreated patients with chronic lymphocytic leukemia: Follow-up of efficacy and safety results from the multicenter, open-label, randomized, phase III CLL14 trial. J Clin Oncol. 2020;38(suppl 15):8027. doi:10.1200/JCO.2020.38.15_suppl.8027}

_{10. Jain N, Keating M, Thompson P, et al. Ibrutinib and venetoclax for first-line treatment of CLL. N Engl J Med. 2019;380:2095-2103. doi:10.1056/NEJMoa1900574}

_{11. Tam CS, Siddiqi T, Allan JN, et al. Ibrutinib (Ibr) plus venetoclax (ven) for first-line treatment of chronic lymphocytic leukemia (cll)/small lymphocytic lymphoma (sll): results from the MRD cohort of the phase 2 CAPTIVATE study. Blood. 2019;134(suppl 1):35. doi:10.1182/blood-2019-121424}

_{12. Jain N, Keating M, Thompson P, et al. Ibrutinib and venetoclax for first-line treatment of CLL. N Engl J Med. 2019;380(22):2095-2103. doi:10.1056/NEJMoa1900574}

_{13. Woyach J, Stephens DM, Flinn IW, et al. Final results of phase 1, dose escalation study evaluating ARQ 531 in patients with relapsed or refractory B-cell lymphoid malignancies. Blood. 2019;134(suppl 1):4298. doi:10.1182/blood-2019-127260}

_{14. Mato AR, Flinn IW, Pagel JM, et al. Results from a first-in-human, proof-of-concept phase 1 trial in pretreated B-cell malignancies for LOXO-305, a next-generation, highly selective, non-covalent BTK inhibitor. Blood. 2019;134(suppl 1):501. doi:10.1182/blood-2019-127509}

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