Current Treatment Strategies in CLL

¹Except for allogeneic hematopoietic stem cell transplantation (HSCT), none of the current therapies are considered curative, but a subset of patients experience long-term remissions.²

SHIFTING TREATMENT PARADIGMS

Treatment options for the management of patients with CLL have evolved significantly in the past decades. The historical stan- dard of initial chemotherapy with chlorambucil has been largely replaced with more effective chemoimmunotherapy regimens incorporating monoclonal antibodies (mAbs) targeting CD20 (rituximab [Rituxan], obinutuzumab [Gazyva], and ofatumumab [Arzerra]), and targeted therapy with the small-molecule inhibitor of Bruton’s tyrosine kinase (BTK), ibrutinib (Imbruvica).¹Current standards of care for patients with relapsed or refractory CLL are ibrutinib, the phosphatidylinositol 3-kinase (PI3K) inhibitor idelalisib (Zydelig) alone or with rituximab, and the B cell lymphoma 2 (BCL-2) inhibitor venetoclax (Venclexta) alone or with rituximab.¹The availability of these agents has substantially changed outcomes for patients with relapsed CLL and adverse risk features, who had survival expectancies of less than 1 year in the past, but can now achieve progression-free survival (PFS) in the range of 24 months or longer.^3—5Recent trial outcomes have shown the superiority of ibrutinib over chlorambucil as a front-line treatment in older patients.⁶Yet, novel kinase inhibitors are also becoming increasingly available in the frontline setting.

CURRENT ROLE OF CHEMOTHERAPY AND CHEMOIMMUNOTHERAPY

Findings from a phase II study in 300 patients,⁷followed by outcomes of the randomized German CLL study group CLL8^,8have established chemoimmunotherapy with udarabine, cyclophosphamide (FC), and rituximab (FCR) as the standard-of-care front- line therapy for patients under 65 years of age with CLL without a 17p deletion (del[17p]) or a TP53 mutation.²

The landmark phase III CLL8 trial involving 817 physically fit previously untreated CLL patients demonstrated that the addition of rituximab to FC (6 courses of treatment) improved the overall response rate (ORR; 90% vs 80%, respectively) (TABLE 18), complete response (CR) rate (44% vs 22%; P <.0001), 3-year PFS (65% vs 45%; HR, 0.56; 95% CI, 0.46-0.69; P <.0001), and overall survival (OS; 87% vs 83%; P = .01).⁸

Recently updated results show long-term remissions in patients treated with FCR, with a 5-year OS of 80.9% in patients less than 65 years of age versus 69.2% in patients treated with FC (HR, 0.63; 95% CI, 0.47-0.84; P = .002). The overall median PFS was 56.8 months with FCR versus 32.9 months for FC (HR, 0.59; 95% CI, 0.50-0.69; P <.001); the median OS was not reached for FCR and was 86.0 months for FC (HR, 0.68; 95% CI, 0.54-0.89; P = .001).⁹Long-term remissions were also shown in the phase II study, which reported an ORR of 95% (72% CR) at a median follow-up of 12.8 years, a median PFS of 6.4 years, and an overall 12.8-year PFS rate of 30.9% (53.9% and 8.7% for patients with mutated and unmutated IGHV, respectively).²

Furthermore, 50.7% of patients with mutated IGHV had minimal residual disease (MRD) negativity after treatment, and a subset of 42 patients with mutated IGHV had no relapse after 10 years.²In an accompanying editorial, Farrukh Awan, MBBS, the assistant professor of internal medicine, The Ohio State University Wexner Medical Center, commented: &ldquo;This represents the first time in the history of CLL that a nontransplant therapeutic option has resulted in sustained disease-free intervals and raises the possibility of a cure for a subset of patients with generally good-risk disease and excellent response to therapy.&rdquo;¹⁰

Benefits of FCR come at the cost of higher toxicity, with 76% of patients treated with FCR experiencing a grade 3/4 adverse event (AE) compared with 63% among those treated with FC, particularly notable is grade 3/4 neutropenia in 34% of patients and a significant increase in infectious complications with FCR.⁸Prophylactic measures include supplementation with myeloid growth factors and antimicrobial therapy.¹¹Treatment with FCR has also been associated with a 6% to 10% incidence of secondary hematologic malignancies, including myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML).¹⁰

A combination regimen of the alkylating agent bendamustine (Treanda) and rituximab (BR) is an alternative, less myelotoxic frontline treatment option in fit patients with CLL without del(17p) or a TP53 mutation. The CLL10 trial compared FCR with BR in this patient population, and found similar ORR and OS rates (TABLE 212). In patients treated with FCR compared with those treated with BR, the ORR was 95% versus 96%, respectively and the 3-year OS rate was 91% versus 92%. However, FCR produced a higher CR rate (40% vs 31%; P = .034), more MRD negativity (59% vs 26% at 12 months; P <.0001; 55% vs 27% at 18 months; P = .002), and longer median PFS (55.2 months vs 41.7 months; P = .0003). The 3-year PFS favored FCR over BR in patients 65 years or younger (53.6 vs 38.5 months); however, for patients over the age of 65, the outcome was similar for both regimens with less toxicity for BR. More patients experienced a grade 4/5 AE with FCR, most of which were hematologic, including neutropenia, leukocytopenia, and thrombocytopenia; grade 3/4 neutropenia was also common in the BR arm.¹²An update analysis with a median follow-up of 58.2 months reported a decreased risk of secondary AML or MDS following BR treatment (0.7%) versus FCR (4.3%).¹³

FCR is also considered suitable for the treatment of patients with relapsed/refractory CLL without high-risk features based on phase II and III study outcomes showing high response rates.¹

TARGETED THERAPIES: INHIBITION OF BRUTON&rsquo;S TYROSINE KINASE MOVING TO THE FOREFRONT

Ibrutinib, an oral small-molecule irreversible inhibitor of BTK, which is central to the B-cell antigen receptor (BCR) survival pathway, was first approved for the treatment of patients with CLL who had received at least 1 previous therapy, and became available as a frontline therapy in 2016 for patients both with and without del(17p).

The approval of single-agent ibrutinib for the treatment of patients with relapsed and refractory CLL was based on data from the phase III randomized RESONATE study demonstrating ORR, PFS, and OS benefits with ibrutinib, including a 57% reduction in risk of death, compared with the anti-CD20 mAb ofatumumab in patients with advanced and high-risk disease, including del(17p) CLL.¹⁴Updated results at 16 months&rsquo; follow-up reported significantly better ORR with ibrutinib compared with ofatumumab (90% vs 25%, respectively; P <.0001), as well as median PFS (not reached vs 8.1 months; HR, 0.106; 95% CI, 0.073-0.153; P <.0001) and OS rates (18-month, 85% vs 78%).¹⁵

The frontline indication of ibrutinib is supported by outcomes of the randomized phase III RESONATE-2 study in 269 patients aged 65 years or higher with untreated CLL without del(17p) demonstrating a significantly higher ORR (86% vs 35%; P <.001) and PFS (90% vs 52% by independent review committee; P <.0001) with ibrutinib compared with those treated with chlorambucil at 18 months&rsquo; median follow-up.⁶By investigator review, patients treated with ibrutinib showed an 89% PFS rate at 18 months in both the subgroup with mutated IGHV and in those without an IGHV mutation. A recent update at a median follow-up of 28.6 months reported that PFS benefits were sustained across high-risk groups, including those with del(11q) and in those with unmutated IGHV, with an overall 88% reduction in risk for progression or death with ibrutinib versus chlorambucil.¹⁶At 24 months, the overall PFS rate was 89% with ibrutinib compared with 34% with chlorambucil (HR, 0.121; 95% CI, 0.074-0.198; P <.0001), and estimated OS rates in the intent-to-treat population were 95% and 84%, respectively, despite high crossover rates to ibrutinib (41%).

According to Steven E. Coutre, MD, professor of medicine (hematology) at Stanford University Medical Center, and co-investigator of the RESONATE-2 study, &ldquo;We&rsquo;re fortunate that we have a body of experience now from our trials, where we&rsquo;ve used ibrutinib in a variety of clinical settings for CLL; heavily pretreated, refractory patients. We have trials in the upfront setting...and what we&rsquo;ve learned is that you see efficacy across a broad range of patients. In fact, I can&rsquo;t think of a subgroup who doesn&rsquo;t benefit from treatment.&rdquo;¹⁷

Ibrutinib was generally well tolerated in clinical trials; AEs included cytopenias, pneumonia, rash, diarrhea, fatigue, and nausea, and notable AEs were bleeding (4%), hypertension (all-grade, 14%; grade 3, 4%), and atrial brillation (6%).⁶In the RESONATE-2 trial, 9% of patients discontinued treatment due to AEs compared with 23% in the chlorambucil arm.

Treatment with ibrutinib results in rapid reduction of lymphadenopathy associated with a concomitant transient increase in absolute lymphocyte count; this lymphocytosis does not signify disease progression and subsides with continued therapy.^1,11In addition, an incomplete resolution of lymphocytosis does not seem to affect PFS rates.¹⁸According to Coutre, &ldquo;It&rsquo;s well tolerable across many different types of patients; patients who are fit, patients who are unfit. We have a fair amount of long-term follow-up now to understand the safety profile.&rdquo;¹⁷

PHOSPHOINOSITIDE 3-KINASE INHIBITOR THERAPY

PI3K is a key component of BCR survival signaling downstream of BTK, and inhibition of the PI3K-delta isoform leads to increased apoptosis.¹⁹The oral PI3K-delta inhibitor idelalisib is the first PI3K inhibitor to become available for the treatment in CLL and is indicated for the treatment of relapsed/refractory CLL in combination with rituximab, based on outcomes of a phase III trial, demonstrating significantly higher ORR (81% vs 13%; P <.001) and significantly longer median PFS and OS (12-month OS, 92% vs 80%; HR, 0.28; P = .02) with the combination versus with rituximab alone.⁴Comparable efficacy was also observed across all subgroups with idelalisib and rituximab, including in those with del(17p), TP53 mutations, unmutated IGHV, or del(11q).²⁰The benefit of the combination was also consistent in those with an advanced Rai stage or high levels of beta-2 microglobulin.

AEs associated with idelalisib include hepatotoxicity causing transaminitis, pneumonitis, and colitis that may require treatment cessation, and is of major concern in younger patients treated with idelalisib.¹Therapy with idelalisib can also produce a rapid reduction in lymphadenopathy leading to transient lymphocytosis that does not signify disease progression. Febrile neutropenia and infections, including reactivation of cytomegalovirus, can also be associated with treatment of idelalisib, which is increased with the addition of a CD20 mAb or chemoimmunotherapy. Due to high numbers of infections and deaths in clinical trials investigating idelalisib and rituximab in patients with untreated CLL, it is not indicated for frontline treatment.

BCL-2 INHIBITION WITH VENETOCLAX

Venetoclax is a small-molecule BCL-2 inhibitor promoting CLL cell apoptosis.⁵Phase II study outcomes have demonstrated clinical activity in patients with relapsed/refractory CLL with del(17p), including an ORR of 79.4%, estimated 12-month PFS and OS rates of 72% and 86.7%, respectively per independent review commit- tee assessment.21 Across all subgroups with additional risk features, such as udarabine-refractory status, bulky disease, del(17p), or a TP53 mutation, the ORR was higher than 70%.

Updated results from the M13-982 trial showed that 40% of evaluable patients achieved MRD-negative status.²²Of 32 patients who achieved a CR with or without complete hematologic recovery, 22 had MRD-negative peripheral blood by flow cytometry and an estimated 24-month PFS of 100%.

Venetoclax has shown promising activity among patients who are intolerant of ibrutinib or idelalisib or failed previous therapy with either agent, and can also be combined with rituximab.¹In the phase III MURANO study of patients with relapsed/refractory CLL treated with venetoclax and rituximab, the ORR was 86%, and 41% achieved a CR or a CR with incomplete bone marrow recovery; the 2-year PFS rate was 84%.²³Additionally, 53% of the patients achieved negative marrow MRD with acceptable toxicity, which was seen in 75% of patients who had a CR/CRi. The combination received a breakthrough therapy designation from the FDA in January 2016.

Side effects of venetoclax include gastrointestinal toxicity, infections, and neutropenia, and tumor lysis syndrome (TLS), requiring gradual dose increases, monitoring, and TLS prophylaxis.¹The National Comprehensive Cancer Network recommends initiating treatment with venetoclax at 20 mg and, after 1 week, stepping up treatment over 5 weeks until reaching the target dose of 400 mg daily.

BIOLOGICS: ROLE OF CD20 ANTIBODIES

Available targeted mAbs against the transmembrane receptor CD20 include rituximab, ofatumumab, and obinutuzumab. These agents have modest activity as single agents but are widely used in combination with purine analogues and alkylating agents.¹

Based on outcomes from the CLL11 study, obinutuzumab in combination with chlorambucil was approved for the frontline treatment of CLL, and is the current standard of care for elderly patients and patients with comorbidities and absence of del(17p).¹A study in 781 patients with medical comorbidities demonstrated superior median PFS with the combination versus with chlorambucil alone (26.7, 16.3, and 11.1 months, respectively, for obinutuzumab plus chlorambucil, rituximab plus chlorambucil, and chlorambucil alone; P <.001), including in all subgroups except del(17p).²⁴Updated survival data after a mean 39 months follow-up showed significantly longer PFS with obinutuzumab plus chlorambucil versus rituximab plus chlorambucil (28.7 vs 15.7 months; HR, 0.46; 95% CI, 0.38-0.55; P <.0001), and a trend to OS benefits with obinutuzumab plus chlorambucil (P = .0932).²⁵Single-agent obinutuzumab has also shown activity in previously untreated patients (2000 vs 1000 mg dose, respectively; ORR, 67% vs 49%; CR, 20% vs 5%).²⁶AEs occurred more frequently with the addition of obinutuzumab, especially grade 3/4 neutropenia.²⁴

Ofatumumab, a CD20 mAb first approved for patients with fludarabine- and alemtuzumab-refractory CLL, was recently approved for frontline therapy in CLL, based on the ndings of the open-label, phase III COMPLEMENT study in 447 patients ineligible for udarabine-based therapy due to age or comorbidities. Patients randomized to ofatumumab plus chlorambucil had significantly higher ORR (82% vs 69%, respectively; P = .001) and median PFS (22.4 vs 13.1 months; P <.0001) than patients in the chlorambucil arm at 29 months median follow-up; median OS was not reached in either arm.²⁷AEs were higher in the combina- tion arm compared with the chlorambucil alone arm for all-grade (94% vs 87%, respectively) and grade &ge;3 events (50% vs 43%) across all age groups, including higher rates of neutropenia.

Ofatumumab is also indicated in relapsed disease in combination with FC, supported by data from the COMPLEMENT-2 study showing improved PFS with ofatumumab versus with FC alone (28.9 vs 18.8 months, respectively; HR, 0.67; P = .0032).²⁸Single-agent ofatumumab can be used for post second-line maintenance therapy, with outcomes of the PROLONG study showing improved PFS versus observation in patients with relapsed CLL after second- or third-line therapy.²⁹

In a randomized phase II CALGB 9712 study comparing concurrent or sequential rituximab with udarabine, a higher ORR was shown with the concurrent regimen (90% vs 77%; CR, 47% vs 28%), and similar median PFS (42 months) and OS (85 months) rates between the 2 arms.³⁰

IMMUNOMODULATORY AGENTS FOR MAINTENANCE REGIMENS: LENALIDOMIDE

The immunomodulatory agent lenalidomide (Revlimid) is approved for various hematologic malignancies, and is evolving as a maintenance therapy option for patients with high-risk CLL after first-line therapy. Recent reports from the CLL M1 and CONTINUUM trials have shown prolonged PFS with maintenance lenalidomide following first- and second-line treatment, respectively.³¹

In the CLL M1 study of the German CLL Study Group, patients with a high risk for disease progression after first-line treatment with BR or FCR were randomized to lenalidomide (n = 56) or placebo (n = 29) based on MRD levels and the presence of unmutated IGHV, del(17p), or mutated TP53 at baseline.³⁰Interim results at a medium follow-up of 17.7 months, demonstrated significantly longer median PFS with lenalidomide (not reached vs 14.6 months for placebo; P <.00001). Lead author Anna Fink, MD, of the Department of Internal Medicine and the Center of Integrated Oncology at the University of Cologne, Germany, commented, &ldquo;We saw conversion to MRD-negative status in the lenalidomide group. Thus far, there is no difference in survival at this interim analysis. The study confirms the prognostic significance of achieving MRD.&rdquo;³²

The CONTINUUM trial investigated lenalidomide vs placebo in patients with CLL who achieved at least a partial response to second-line therapy. Patients reported a significant increase in median PFS with lenalidomide at a median follow-up of 31.⁵months (33.9 vs 9.2 months for placebo; HR, 0.4; 95% CI, 0.29-0.55; P <.001).³³In both studies, neutropenia, gastrointestinal, nervous system, respiratory, and skin disorders were more common in the lenalidomide arms,^31,33but the CONTINUUM study noted that a clinically meaningful difference in quality of life was not found between the 2 arms.³³

As a frontline therapy, single-agent lenalidomide showed an ORR of 72% in a phase II study with a 20% CR rate.³⁴At 3 years, the PFS rate was 65% and the OS rate was 85%. AEs of note included grade 3/4 neutropenia (76%) and thrombocytopenia (28%) and grade 1/2 tumor are reaction occurred at a rate of 88%. However, tumor are reaction is correlated with a response in patients receiving lenalidomide.¹

ALLOGENEIC STEM CELL TRANSPLANTATION

Allogeneic HSCT can result in long-term PFS and has traditionally been considered in patients with high-risk disease in first remission.^1,35With the availability of effective targeted therapies, this paradigm has recently shifted.¹

Susan M. O&rsquo; Brien, MD, associate director for clinical science at the Chao Family Comprehensive Cancer Center at the Univer- sity of California Irvine Health, explained in an interview with the American Journal of Managed Care^&reg;: &ldquo;Some of our newer thera- pies are improving the outcomes even in the high-risk subsets which traditionally had been patients with 17p deletion or 11q deletion.... Now we have approved treatments including ibrutinib, idelalisib, and, most recently, venetoclax for patients with 17p. So, since we have all these effective targeted therapies, we&rsquo;d no longer recommend stem cell transplant in first remission.&rdquo;³⁶

HSCT remains a treatment option for patients with relapsed or refractory CLL, but despite the development of nonmyeloablative reduced-intensity conditioning (RIC) regimens, many patients with CLL are not eligible due to age or comorbidities, and graft- versus-host disease (GVHD) remains a major issue. A summary of prospective studies using RIC HSCT in CLL patients with a median follow-up of up to 6 years reported a 40% median PFS and a median OS of 50% to 60%, and chronic GVHD in almost 50% of patients.³⁷

According to Coutre, the current treatment landscape in CLL is &ldquo;changing dramatically, largely because of the introduction of the new oral therapies. And so, it&rsquo;s really a transformative time in managing CLL...clearly we are able to better treat this disease for a longer period of time with drugs that are better tolerated for many of our patients.&rdquo;³⁷

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