The frontline combination therapy of ibrutinib (Imbruvica) plus the chemoimmunotherapy regimen of fludarabine, cyclophosphamide, and rituximab (Rituxan) (FCR) showcased its top-shelf potential in younger and fit patients with chronic lymphocytic leukemia (CLL) in preliminary phase II data. Results showed that, of 35 patients enrolled, 83% achieved negative minimum residual disease (MRD) status in bone marrow, and 37% of patients had complete response (CR) in association with MRD negativity. The findings were presented by Matthew S. Davids, MD, during the 2017 ASH Annual Meeting. In the small study, ibrutinib plus FCR was found to induce objective responses in all patients. Forty percent of patients had CR with or without hematologic recovery at the primary endpoint assessment, which increased to 63% as best response.

Toxicity was consistent with known toxicities of ibrutinib and the FCR chemoimmunotherapy regimen used in the study. Moreover, 31 patients initiated ibrutinib maintenance after FCR. After a median follow-up of 21 months, no patient died or had disease progression.

Following these encouraging results, a 50-patient expansion trial is now being conducted with some modifications to protocol.

, Davids, associate director of the Center for Chronic Lymphocytic Leukemia at Dana-Farber Cancer Institute, Boston, shed light on the significant findings of this study and gave a look ahead to ibrutinib combination therapies in the future treatment landscape of CLL.

WHAT WAS THE RATIONALE FOR CREATING THIS TYPE OF CLINICAL TRIAL?

What we have learned over the last few years is that patients can get very durable benefit from FCR alone; there were a number of publications showing that patients, particularly who have this IGHV-mutated form of CLL, have curative potential with FCR. This is based on data that are showing remissions of 12 to 15 years in some of these patients who are probably cured of the disease. We have several newer drugs that have come along, such as ibrutinib and other novel agents, and some have made the leap to put these novel drugs together and abandon chemotherapy.

While it is certainly a promising strategy to do a chemotherapy- free approach, our strategy is a little bit different which was to build up on the curative experience from chemotherapy by adding the new drugs to chemotherapy and trying to increase that cure rate. That was the rationale from that perspective. We also know that ibrutinib and similar drugs that target the B-cell receptor can actually move CLL cells out from the lymph nodes and bone marrow and into the blood, where they are more susceptible to being killed by chemotherapy; it is a chemotherapy-sensitization strategy.

Then, the final piece was that we treated 3 patients at Dana-Farber Cancer Institute on this regimen as part of a different study, and all 3 patients had deep, durable remissions. All of the factors together were the inspiration to develop this study.

CAN YOU COMMENT ON THE SPECIFIC FINDINGS THIS TRIAL SHOWED?

The first thing is that anytime we put multiple drugs together, we want to make sure they are tolerable. In the initial safety lead-in with the first 10 patients, we didn&rsquo;t see any unexpected toxicities and we were able to proceed and accrue the full 35 patients on the phase II study as originally conceived. In terms of the toxicity profile for the full cohort, iFCR has generally been well-tolerated. One thing to note is that we require the routine use of growth factor and antimicrobial prophylaxis; by following this protocol, iFCR has been proven to be a safe regimen for these younger, fit patients.

What has been even more exciting are the efficacy data. The overall response rate was 100% and the primary endpoint of the study was quite stringent: patients had to get into a CR in terms of the scans and bone marrow, and patients also had to achieve MRD negativity in the bone marrowwe call that rate of CR with bone marrow MRD negativity.

If you look back at studies of FCR alone, that rate was somewhere around 20% and, in our study, it&rsquo;s about 37% so it nearly doubled that rate. One of the things that this study also incorporated was after finishing the iFCR combination, patients then continued on ibrutinib maintenance as a monotherapy for a couple of years. What we saw is that the rates of MRD negativity increased quite dramatically over time. When we looked at the rate of best bone marrow negativity, it was actually 83%.

As you compare across some of the different studies, including some of the ones presented at the 2017 ASH Annual Meetingand if you are looking at studies of frontline therapy for CLL that included all-comers in terms of risk categories, including those with ultra high risk del(17p) disease&mdash;our rate of 83% is the highest rate of bone marrow MRD negativity that has ever been achieved in the frontline setting for CLL. We are pretty excited about that.

The reason that is important is that if you want to develop a curative regimen, then by prerequisite we have to get to MRD negativity first to eradicate every cell.

Those are the key findings, and then based on those promising efficacy data&hellip;we were able to expand the study to accrue an additional 50 patients. Therefore, we are going to have a total of 85 on this study by the time it finishes. However, one of the key changes and new amendments to the study is rather than keeping patients on indefinite ibrutinib after the chemotherapy portion, we are now doing only 2 years of ibrutinib maintenance. Those patients who are MRD negative in the marrow after 2 years of ibrutinib maintenance then stop all therapy, with the idea being that, hopefully, if these patients are cured then they are not going to need ongoing ibrutinib.

To me, that is a critical thing in the field right now; we have lots of promising regimens. Which of these regimens are going to provide durable enough response that they can be time limited? We have seen some of the novel agents, such as CD20-directed antibodies, in combination with novel agents, and so far the MRD-negativity rates look promising. However, we don&rsquo;t know what the long-term outcomes are going to be like for those novel agentbased approaches. It is possible that patients are just barely hitting MRD and 1 or 2 years later these patients may relapse; we just don&rsquo;t know yet.

As I mentioned, we do know that with FCR; if we can get to MRD negativity, then we see long-term survival rates of up to 15 years or longer in some cases. It is hard to know which of these regimens is going to end up being better in the end. Only time will tell, really. But in terms of the data we have on hand right now, we are certainly enthusiastic about this approach with chemotherapy plus novel agents.

Our regimen is geared toward the youngest and fittest patients with CLL, so we restricted our study to age 65 or younger. The majority of patients with CLL are older and frailer and not necessarily candidates for our approach, so that is important to highlight. The chemotherapy-free based approaches are likely to be better for the more typical CLL population that is older.

PLEASE EXPAND ON THAT POINT. WHO MIGHT BE THE BEST PATIENTS TO RECEIVE THE IBRUTINIB PLUS FCR REGIMEN?

We had 4 patients on that first cohort of 35 patients who had a 17p deletion and, even though they all did respond, the depth of response is not as good as it was in the other patients. When we opened up the new cohort up of 50 patients, we decided to exclude patients with 17p deletion, as we do not think that the chemotherapy was adding much compared with ibrutinib alone. Based on our data, those patients who have 17p deletion even if they&rsquo;re young and fit&mdash;they are better served by either ibrutinib alone or ibrutinib with a different novel agent, but not with our chemotherapy backbone.

YOU MENTIONED THERE WAS A GOOD SAFETY PROFILE WITH THIS COMBINATION. WHAT TOXICITIES SHOULD PHYSICIANS TAKE NOTE OF THAT WERE OBSERVED?

The way they can think of it, based on our experience, is you have to be mindful of the risks of either regimen alone. We did have a case of atrial fibrillation on ibrutinib and we had 3 cases of minor bleeding issuesso typical ibrutinib toxicities. With FCR, we did have a couple cases of pneumonia and febrile neutropenia, which are typical toxicities. The overall message is that, basically, we saw the typical toxicities of both regimens but nothing more than that.

THIS IS OBVIOUSLY AN EXCITING COMBINATION. ARE THERE OTHERS WITH IBRUTINIB THAT ALSO HAVE POTENTIAL? OR NOVEL AGENTS IN COMBINATION WITH FCR?

Yes. One other thing is that, in parallel with the ibrutinib/FCR study, we have been running a study of FCR with duvelisib (dFCR), which is a new PI3k-&delta; and -&gamma; inhibitor. We've also seen very nice results with that combination. It is always good for patients to have options, and there are some patients who are not great ibrutinib candidates, based on cardiac risk factors, for example, and bleeding history. We believe dFCR is also a promising new approach.

As I mentioned, these chemotherapy-free approaches are going to be options for the frailer, older populations. For the older, frailer populations, there were a couple ibrutinib combinations presented at the 2017 ASH Annual Meeting that peaked my interest in particular. The most promising of these are ibrutinib/ venetoclax (Venclexta) and venetoclax with obinutuzumab (Gazyva), both of which look promising.

WHAT ARE SOME LOOKING-FORWARD THOUGHTS AS THIS 50-PATIENT EXPANSION TRIAL ACCRUES?

When our study is fully accrued, we will have a good-sized phase II experience of 85 patients and that will be informative and, hopefully, enough data to reassure people about the efficacy and safety of the regimen. A challenge in our field, in CLL research in general, is that we have a lot of these promising phase II studies coming along; how are we going to compare across these populations and decide what is best for which patient?

There are other ongoing studies in Europe that are randomized phase III studies comparing similar regimens. For example, the FLAIR study in the United Kingdom and then also a study called CLL13 in Germany; although, neither of those trials are using the ibrutinib/FCR regimen specifically.

I am hopeful that we will be able to explore iFCR in the randomized phase III setting because, ultimately, that will be the best way to answer the question about which regimen is best. We would love to be able to compare ibrutinib/FCR with other combinations in a cooperative group setting. There are efforts underway to get that going.

Davids MS, Kim HT, Brander DM, et al. A multicenter, phase II study of ibrutinib plus FCR (iFCR) as frontline therapy for younger CLL patients. In: Proceedings from the American Society of Hematology 59th Annual Meeting & Exposition; December 9-12, 2017; Atlanta, GA. Abstract 496.

Articles

Clinical Articles

Matthew S. Davids, MD,&nbsp;sheds light on the significant findings of this study and gave a look ahead to ibrutinib combination therapies in the future treatment landscape of CLL.

Lead Investigator for Ibrutinib/FCR Combo Highlights Significant Findings in CLL

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

Treatment options for the management of patients with CLL have evolved significantly in the past decades. The historical standard 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&rsquo;s tyrosine kinase (BTK), ibrutinib (Imbruvica).1 Current standards of care for patients with relapsed or refractory CLL are ibrutinib, the phosphatidylinositol 3-kinase (PI3K) inhibitor idelalisib (Zydelig) with rituximab, and the B cell lymphoma 2 (BCL-2) inhibitor venetoclax (Venclexta), according to the National Comprehensive Cancer Network guidelines.

The 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.

Recent trial outcomes have shown the superiority of ibrutinib over chlorambucil as a frontline treatment in older patients.

Yet, novel kinase inhibitors are also becoming increasingly available in the frontline setting.

ROLE OF CHEMOTHERAPY AND CHEMOIMMUNOTHERAPY

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

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 objective 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).

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).9 Long-term remissions were also shown in the phase II study, which reported an ORR of 95% (72% CR) at a median followup 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).

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.

In an accompanying editorial, Farrukh Awan, MD, 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;

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.8 Prophylactic measures include supplementation with myeloid growth factors and antimicrobial therapy.

Treatment 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).

A combination regimen of the alkylating agent bendamustine 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.12 An 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%).

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.

INHIBITION OF BRUTON&rsquo;S TYROSINE KINASE

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.

Updated 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%).

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.6 By 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 highrisk 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.16 At 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%).

Five-year follow-up data of the phase Ib/II PCYC-1102 study, which evaluated 5 years with ibrutinib therapy in both treatmentna&iuml;ve and relapsed/refractory patients with CLL/SLL, show that the agent is efficacious and safe with 89% of both patient subgroups experiencing a complete or partial response to the therapy.

Additionally, patients lived without disease progression longer when ibrutinib is administered earlier than in the third-line setting or beyond.

Most recently, at the 2017 ASH Annual Meeting, patient-reported outcomes (PROs) of the RESONATE-2 study were presented at a median follow-up of 35.7 months with ibrutinib and 34.4 with chlorambucil.

In addition to the reported survival advantage with ibrutinib, greater and sustained improvements in PROs were observed in the ibrutinib cohort, as well as significantly greater improvements over time in the Functional Assessment of Chronic Illness Therapy-Fatigue (P = .0021) and EQ-5D-5L Visual Analogue Scale (P = .0004). Other disease symptoms, such as fatigue and night sweats, improved more frequently with ibrutinib versus chlorambucil, and a greater proportion of patients with baseline cytopenia showed sustained hematologic improvement with ibrutinib compared with chlorambucil for hemoglobin (90% vs 45%; P <.0001) and platelets (83% vs 46%; P = 0.0032). For patients who were treated with chlorambucil and then crossed over to ibrutinib, their PROs also improved.

Moreover, the most common all-grade AEs with ibrutinib were diarrhea (47%), fatigue (33%), and cough (30%). Eight grade &ge;3 AEs had a prevalence of >3% in the ibrutinib arm and generally decreased or were stable over time. In the first year of treatment, there were less reports of grade &ge;3 neutropenia (8% and 18%) and anemia (6% and 8%) with ibrutinib, and other common grade &ge;3 AEs were pneumonia (5% and 2%) and hypertension (4% and 0%). Within the 3-year follow-up, grade &ge;3 bleeding occurred in 7% of patients on ibrutinib. Treatment discontinuations due to AEs occurred in 16% with ibrutinib over 34 months compared with 23% for chlorambucil over 7 months of treatment.

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 fibrillation (6%)

In 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.

In addition, an incomplete resolution of lymphocytosis does not seem to affect PFS rates.

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.

The 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.4 Comparable efficacy was also observed across all subgroups with idelalisib and rituximab, including in those with del(17p), TP53 mutations, unmutated IGHV, or del(11q).

The 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.

Therapy 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.

Venetoclax is a small-molecule BCL-2 inhibitor promoting CLL cell apoptosis.5 Phase 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 committee assessment.22 Across all subgroups with additional risk features, such as fludarabine-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.

Of 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.

As a single agent, venetoclax monotherapy was associated with an ORR of 65% in patients with relapsed/refractory CLL who failed on a BCR signaling pathway inhibitor, according to results of an interim analysis of a multicenter, open-label, nonrandomized phase II trial.

Side effects of venetoclax include gastrointestinal toxicity, infections, and neutropenia, and tumor lysis syndrome (TLS), requiring gradual dose increases, monitoring, and TLS prophylaxis.

The 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.

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.

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).

A 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).

Updated 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).26 Single-agent obinutuzumab has also shown activity in previously untreated patients (2000 vs 1000 mg dose, respectively; ORR, 67% vs 49%; CR, 20% vs 5%).

AEs occurred more frequently with the addition of obinutuzumab, especially grade 3/4 neutropenia.

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 findings of the open-label, phase III COMPLEMENT study in 447 patients ineligible for fludarabine-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.

AEs were higher in the combination 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).

Singleagent 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 secondor third-line therapy.

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.

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.

Interim 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).

The CONTINUUM trial investigated lenalidomide versus 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 31.5 months (33.9 vs 9.2 months for placebo; HR, 0.40; 95% CI, 0.29- 0.55; P <.0001), however there was no significant difference in OS (HR, 0.96; 95% CI, 0.63-1.48; P = .86).

In both studies, neutropenia, gastrointestinal, nervous system, respiratory, and skin disorders were more common in the lenalidomide arms,31,32 but the CONTINUUM study noted that a clinically meaningful difference in quality of life was not found between the 2 arms.

Allogeneic HSCT can result in long-term PFS and has traditionally been considered in patients with high-risk disease in first remission.

With the availability of effective targeted therapies, this paradigm has recently shifted.

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 graftversus- 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.

National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines): Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma. Version 2.2017. NCCN website. www.nccn.org/professionals/physician_ gls/pdf/cll.pdf. Published February 21, 2017. Accessed May 15, 2017.

Thompson PA, Tam CS, O&rsquo;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.

Byrd JC, Furman RR, Coutre SE, et al. Targeting BTK with ibrutinib in relapsed chronic lymphocytic leukemia. N Engl J Med. 2013;369(1):32-42. doi: 10.1056/NEJMoa1215637.

Furman RR, Sharman JP, Coutre SE, et al. Idelalisib and rituximab in relapsed chronic lymphocytic leukemia. N Engl J Med. 2014;370(11):997-1007. doi: 10.1056/NEJMoa1315226.

Roberts AW, Davids MS, Pagel JM, et al. Targeting BCL2 with venetoclax in relapsed chronic lymphocytic leukemia. N Engl J Med. 2016;374(4):311-322. doi: 10.1056/NEJMoa1513257.

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(25):2425-2437. doi: 10.1056/NEJMoa1509388.

Tam CS, O&rsquo;Brien S, Wierda W, et al. Long-term results of the fludarabine, cyclophosphamide, and rituximab regimen as initial therapy of chronic lymphocytic leukemia. Blood. 2008;112(4):975-980. doi: 10.1182/blood-2008-02-140582.

Hallek M, Fischer K, Fingerle-Rowson G, et al. Addition of rituximab to fludarabine and cyclophosphamide in patients with chronic lymphocytic leukaemia: a randomised, open-label, phase 3 trial. Lancet. 2010;376(9747):1164-1174. doi: 10.1016/S0140-6736(10)61381-5.

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.

Awan FT. Cure for CLL? Blood. 2016;127(3):274. doi: 10.1182/blood-2015-11-678532.

Kipps TJ, Stevenson FK, Wu CJ, et al. Chronic lymphocytic leukaemia [published correction appears in Nat Rev Dis Primers. 2017;3:17008. doi:10.1038/nrdp.2017.8]. Nat Rev Dis Primers. 2017;3:16096. doi: 10.1038/nrdp.2016.96.

Eichhorst B, Fink AM, Bahlo J, et al; German CLL Study Group. 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.

Eichhorst B, Bahlo J, Maurer C, et al. Favorable toxicity profile and long term outcome of elderly, but physically fit CLL patients (pts) receiving first line bendamustine and rituximab (BR) frontline chemoimmunotherapy in comparison to fludarabine, cyclophosphamide, and rituximab (FCR) in advanced chronic lymphocytic leukemia (CLL): Update analysis of an international, randomized study of the german CLL study group (GCLLSG) (CLL10 study). Blood. 2016;128: (Abstract 4382).

Byrd JC, Brown JR, O&rsquo;Brien S, et al; RESONATE Investigators. Ibrutinib versus ofatumumab in previously treated chronic lymphoid leukemia. N Engl J Med. 2014;371(3):213-223. doi: 10.1056/NEJMoa1400376.

Brown JR, Hillmen P, O&rsquo;Brien S, et al. Updated efficacy including genetic and clinical subgroup analysis and overall safety in the phase 3 RESONATETM trial of ibrutinib versus ofatumumab in previously treated chronic lymphocytic leukemia/small lymphocytic lymphoma. Blood. 2014;124(21): (Abstract 3331).

Barr PM, Robak T, Owen CJ, et al. Updated efficacy and safety from the phase 3 RESONATE-2 study: Ibrutinib as first-line treatment option in patients 65 years and older with chronic lymphocytic leukemia/small lymphocytic leukemia. Blood. 2016;128: (Abstract 234).

O&rsquo;Brien SM, Furman RR, Coutre SE, et al. Five-year experience with single-agent ibrutinib in patients with previously untreated and relapsed/refractory chronic lymphocytic leukemia/small lymphocytic leukemia. Blood. 2016;128(22):233.

Tedeschi A, Owen CJ, Robak T, et al. prolonged improvement in patient-reported outcomes (pros) and well-being in older patients with treatment-na&iuml;ve (tn) chronic lymphocytic leukemia treated with ibrutinib (ibr): 3-year follow-up of the RESONATE-2 study. In: Proceedings from the 2017 ASH Annual Meeting; December 9-12, 2017; Atlanta, Georgia. Abstract 1746.

The clinical course of chronic lymphocytic leukemia is highly variable, and a subset of patients may never need clinical intervention. However, most patients will eventually require treatment during their disease.

Current Treatment Strategies in CLL

Ibrutinib (Imbruvica) has played an important role in the development of treatment for patients with chronic lymphocytic leukemia (CLL), and long-term follow-up of the RESONATE and RESONATE-2 studies are evidence of the long-lasting responses with the BTK inhibitor.

The phase III RESONATE trial investigated ibrutinib in the second-line setting compared with ofatumumab (Arzerra) in patients with relapsed/refractory CLL. In the long-term followup analysis, ibrutinib demonstrated a superior progression-free survival (PFS), overall survival (OS), and objective response rate (ORR) versus ofatumumab. The median PFS was not reached with 74% of patients alive and progression free at 2 years, and second-line ibrutinib PFS outcomes were significantly improved compared with patients receiving it in later lines of therapy (P = .0348). Additionally, the ORR was higher in the ibrutinib arm in all evaluable subgroups compared with ofatumumab (P <.0001). In addition, the complete response (CR) rate improved with 7% of patients.1

Ibrutinib was investigated in the frontline setting in the phase III RESONTE-2 study for patients with CLL and small lymphocytic leukemia (SLL), which included 269 patients who were 65 years or older. At 29 months of follow-up, frontline ibrutinib reduced the risk of progression or death by 88% versus chlorambucil. 2 Additionally, the quality of responses has improved over time with 18% of patients with CLL and SLL achieving a CR or CR with incomplete platelet recovery with single-agent ibrutinib. Treatment-related adverse events decreased in frequency, allowing 79% of patients to continue treatment with ibrutinib. OS remains significantly improved, resulting in 2-year survival rate estimates of 95% in the ibrutinib arm versus 84% in the chlorambucil arm. Moreover, ORR was 92% versus 36% in the ibrutinib and chlorambucil arms, respectively (P <.0001).

Five-year follow-up data of ibrutinib is also now available. Results of the phase Ib/II PCYC-1102 study, which evaluated 5 years with ibrutinib therapy in both treatment-na&iuml;ve and relapsed/refractory patients with CLL/SLL, showed that the agent is efficacious and safe with 89% of both patient subgroups experiencing a complete or partial response to the therapy. Additionally, patients lived without disease progression longer when ibrutinib is administered earlier than in the third-line setting or beyond.3

With the PCYC-1102 study follow-up, the most frequent grade 3 or higher AEs with ibrutinib were hypertension (26%), pneumonia (22%), neutropenia (17%), thrombocytopenia (9%), and atrial fibrillation (9%). At the 2017 ASH Annual Meeting, patient-reported outcomes were investigated for patients treated with frontline ibrutinib on the RESONATE-2 trial. With 3-years of follow-up for these patients, ibrutinib showed greater sustained improvements compared with chlorambucil.4 Additionally, ibrutinib was associated with increased quality-adjusted survival time at the time of primary analysis.

Having shown significant improvements as a single agent, the next step for ibrutinib will be in combination, according to Susan O&rsquo;Brien, MD.

&ldquo;It is normal to build on single agents by looking for combination partners based on preclinical data or agents that lack overlapping toxicities,&rdquo; said O&rsquo;Brien, a hematologist and oncologist at UC Irvine Health. &ldquo;The idea of moving forward from a single agent to a combination is logical and we hope to do this further with ibrutinib.&rdquo;

, O&rsquo;Brien, discussed the tremendous impact that has been seen with ibrutinib following the long-term follow-up of the RESONATE studies and highlights where this regimen is headed in the future of treatment for patients with CLL.

TARGETED ONCOLOGY: CAN YOU DISCUSS THE LONGTERM DATA THAT WE HAVE SEEN WITH THE RESONATE AND RESONATE-2 TRIALS?

We now have 4-year follow-up from the original RESONATE study. That was the randomized trial of ibrutinib versus ofatumumab in relapsed patients, which led to the full approval of ibrutinib. We have seen very good data. The important message from this study is that responses can be very durable and that toxicity does not increase over time.

The one toxicity that is seen occurring is hypertension; therefore, we must monitor patients for that. In my experience, it is more likely to occur in patients that already had hypertension and they may just need an adjustment to their medicine. In general, the side effects that impact the patient's day-to-day living such as diarrhea, are diminished over time. We haven't seen any new safety signals.

We also know that the responses are very durable. Patients can be on this drug for years and do quite well. The follow-up on the RESONATE-2 trial is shorter, but it is about 3 years now. The RESONATE-2 trial investigated ibrutinib in the frontline setting for patients over 65. Since this is a frontline population, we see even better outcomes in that group. We saw the 3-year PFS of 85% in that frontline population. At 3 years, 75% of patients were still on ibrutinib.

In the poster that was presented at the 2017 ASH Annual Meeting, there was a quality-of-life (QoL) assessment. What was clear from that assessment in comparison with chlorambucil is that these patients have a significant improvement on several different types of quality-improvement assays. They looked at something called a Q-TWiST analysis, which is an integrative analysis incorporating both the patient-reported outcomes, toxicity, and long-term outcomes. This showed that ibrutinib was dramatically better than chlorambucil.

From both trials, the remissions are very durable and are even more impressive in the frontline setting. But, there are no unexpected toxicities from a QoL point of view versus chlorambucil. We see significant improvements in QoL.

WHAT COMMON QUESTIONS OR STATEMENTS DO YOU HEAR FROM PATIENTS REGARDING HOW THEY TOLERATE IBRUTINIB?

If you look at the data, the most common reported side effects were diarrhea. However, that toxicity is the least problematic. In my experience, patients would go to the bathroom 2 or 3 times a day and it was not associated with urgency, so they are able to go about their daily life. The patients develop tachyphylaxis so that, over time even as they stay on drugs, the diarrhea tends to resolve.

In my experience, the one toxicity that I have had to take people off drugs for is arthralgia. I have only done this rarely, but it has been problematic. I have not taken the patient off the drug because the arthralgia is severe grade 3/4, but if the patient has some discomfort or pain that can be frustrating. If a patient is going to be on ibrutinib indefinitely with no end date in sight, and that patient feels uncomfortable or has low-level discomfort on a chronic basis, that is something to consider.

ARE THERE INDICATIONS AS TO WHICH SUBGROUP(S) OF PATIENTS WILL BENEFIT THE MOST FROM IBRUTINIB?

One subgroup where some physicians may be hesitant to use the drug is in patients on anticoagulants. That is because these patients have a greater likelihood of bleeding in general. We know that there is some increased risk with the addition of ibrutinib. There is a lot of hesitation in that setting and some physicians might prefer not to use ibrutinib for those patients. There was another abstract at the 2017 ASH Annual Meeting looking at aggregated data from several randomized trials with ibrutinib, and the outcomes in terms of bleeding depended on whether the patients were on anticoagulants or antiplatelet agents.

There was no statistically significant increase in terms of serious bleeding compared with the control arm. There are rare patients who have serious bleedingcausing everyone to be more cautious when treating patients on anticoagulants. However, I do not believe that it is an absolute contraindication. I would give ibrutinib to a patient on an anticoagulant if it was the best treatment for them and the risk benefit was in favor of using it.

WHAT ARE YOUR THOUGHTS ON THE COMBINATION STRATEGIES WITH IBRUTINIB?

They look very exciting. There are combinations of ibrutinib with venetoclax (Venclexta), antibodies, and venetoclax and antibodies together making a 3-drug regimen. There was a randomized trial presented at the 2017 ASH Annual Meeting that investigated ibrutinib and an antibody in patients with relapsed CLL. There was also a small cohort of patients in the frontline setting, all of whom had a 17p deletion or p53 mutations.

This trial showed that there was a more rapid response with the addition of rituximab (Rituxan). This is because you abrogate the lymphocytosis that you normally see with B-cell receptors.

What there didn't appear to be was a large increase in complete response (CR) rates or more durable PFS. Other than achieving more rapid responses, there is not a lot to suggest that giving an antibody with ibrutinib does anything in terms of deeper or more durable remissions.

There is another trial that also asked that question. It was a large randomized frontline trial that consisted of 3 arms of bendamustine with rituximab, versus ibrutinib, versus ibrutinib and rituximab. That trial is fully accrued and finished accrual about a year and a half ago, but the follow-up is short. We have not seen any data from that trial. This will be a second trial looking at whether adding an antibody to ibrutinib makes a difference.

In contrast, there are good data showing that adding an antibody to venetoclax appears to increase the likelihood of minimal residual disease (MRD) negativity. Recently, within the past month or so, the venetoclax/rituximab combination study in relapsed patients with CLL was published. The MRD-negativity rate in this relapsed population was 55%.

There are preliminary data that were recently published in the frontline setting in a small cohort of patients with venetoclax and obinutuzumab (Gazyva), the latter of which is arguably a more potent anti-CD20 antibody than rituximab. Adding obinutuzumab to venetoclax produced very high rates of MRD negativity in the frontline setting.

There were a couple of trials investigating venetoclax and ibrutinib that were presented at the 2017 ASH Annual Meeting clearly showing that they could be combined with full doses of each agent. You get the side effects seen with each drug individually, which was expected, but there was more neutropenia with the combination since both drugs as single agents cause neutropenia.

With that combination, the response rates were dramatic. However, that brings me to 2 questions. If you are going to combine 2 small molecules, such as ibrutinib and venetoclax, will antibodies add anything? I do not think that it adds to ibrutinib, but it could potentially improve responses to venetoclax. We are not going to have randomized trial data to answer those questions, but we will have phase II data that may help.

The data with venetoclax and obinutuzumab is so impressive that one could ask a different question in that setting. When you have an antibody such as obinutuzumab and add it to venetoclax, will ibrutinib add anything beyond that? However, overall, the data seen with combinations have been exciting. We will have to compare across trials to get an idea as to which is the best treatment option for patients.

WHAT DO YOU PREDICT FOR THE ROLE OF IBRUTINIB IN THE NEXT 5 YEARS?

There are going to be more combinations. Although ibrutinib is a beneficial drug, the CR rates are lowparticularly in the relapsed setting where MRD negativity is not seen. There is room for improvement. Currently, venetoclax is the obvious candidate because it has a different mechanism of action to BCR inhibitors. There were preclinical data suggesting that the drugs would be synergistic; however, we are still unsure as to which is best.

Ibrutinib is a relatively easy drug to combine. It can be combined with chemotherapy, antibodies, and now it is being combined with venetoclax. We could envision that there might be other combinations in the future that might be effective. We may see ibrutinib in combination with chemotherapy for patients with large cell lymphoma.

Brown JR, Hillmen P, O&rsquo;Brien S, et al. Extended follow-up and impact of high-risk prognostic factors from the phase 3 RESONATE study in patients with previously treated CLL/SLL. Leukemia. 2017;32(1):83-91. doi:10.1038/ leu.2017.175.

Barr PM, Robak T, Owen CJ, et al. Updated efficacy and safety from the phase 3 RESONATE-2 study: ibrutinib as first-line treatment option in patients 65 years and older with chronic lymphocytic leukemia/small lymphocytic leukemia. Blood. 2016;128(22):234.

Tedeschi A, Owen CJ, Robak T, et al. Prolonged improvement in patient-reported outcomes (PROs) and well-being in older patients treated with treatment-na&iuml;ve (TN) chronic lymphocytic leukemia treated with ibrutinib (IBR): 3year follow&ndash; up of the RESONATE-2 study. Presented at: 2017 ASH Annual Meeting; December 9-12, 2017; Atlanta, Georgia. Abstract 1746.

Susan O&rsquo;Brien, MD,&nbsp; discusses the tremendous impact that has been seen with ibrutinib following the long-term follow-up of the RESONATE studies and highlights where this regimen is headed in the future of treatment for patients with CLL.

O'Brien Covers Evolution of Long-Term Data With Ibrutinib in CLL Landscape

With changing treatment paradigms, particularly the use of oral targeted agents, predictive value and use of prognostic factors to determine treatment choice are shifting. Traditional risk factors, including disease stage and lymphocyte doubling time, are becoming less relevant for treatment selection, and the predictive value of cytogenetic and molecular markers on response to treatment with novel agents is being redefined based on the outcomes of recent trials.

In 2008, the International Workshop on Chronic Lymphocytic Leukemia (iwCLL) published revised guidelines for the diagnosis and treatment of CLL.

These revised guidelines acted as an update to the National Cancer Institute sponsored Working Group's (NCI-WG) 1996 guidelines,

which sought to create recommendations for the design and conduct of clinical trials for patients with CLL. The iwCLL updates these guidelines following significant progress in determining prognostic markers, diagnostic parameters, treatment options, and more for the diagnosis and response to treatment for patients with CLL.

When assessing the level of response to treatment in patients with CLL, a physical exam is required, along with evaluation of the blood and marrow. Unlike response assessment in solid tumors, imaging studies, particularly CT scans, are not usually necessary.

The characterization of a complete remission (CR) as defined by the iwCLL requires the absence of clonal lymphocytes in the peripheral blood, no hepatomegaly or splenomegaly, and the absence of constitutional symptoms, all within 3 months of the completion of therapy.

Additionally, polymorphonuclear leukocyte levels should be above 1500/&mu;L, platelets above 100,000/&mu;L, and hemoglobin above 11 g/dL untransfused (TABLE 12). Previously, a CR according to the NCI-WG still had detectable minimal residual disease (MRD). A partial remission (PR) depends upon at least 1 parameter relating to the tumor load and another relating to the function of the hematopoietic system or marrow improving, with 1 of these factors lasting for at least 2 months. Progressive disease (PD) is also determined by a change in the tumor load and/or a decrease in platelet or hemoglobin levels. Additionally, the guidelines define a CR in the absence of MRD as the complete eradication of the leukemia, where blood or marrow expresses less than 1 CLL cell per every 10,000 leukocytes.

DISEASE CHARACTERISTICS AFFECTING PROGNOSIS AND GUIDING TREATMENT SELECTION

The presence of a deletion of chromosome 17p (del[17p]) and mutated TP53 represent the most relevant disease characteristics that guide the choice of therapy in patients with CLL.8 Del(17p) causes the loss of 1 TP53 allele and is associated with mutations in the remaining TP53 allele in more than 80% of patients, resulting in loss or dysfunction of TP53. Both del(17p) and mutated TP53 are associated with poor response to chemotherapy- based regimens, short progression-free survival (PFS), and poor overall survival (OS), independently of IGHV mutation status.

Recent trials have demonstrated activity of novel targeted agents in patients with del(17p)/TP53-mutant CLL, who are considered a distinct subgroup who require a specific therapeutic approach.

This has significantly changed outcomes for this subgroup for whom previous options to increase the duration of response were largely limited to stem cell transplant in eligible patients.

Ibrutinib (Imbruvica), a first-in-class oral covalent inhibitor of Bruton&rsquo;s tyrosine kinase (BTK), blocks an essential component of the B-cell receptor cascade, inhibiting survival signaling between CLL cells and the tumor microenvironment. The agent was approved by the FDA in 2014 for the treatment of patients with relapsed/refractory CLL, supported by outcomes of phase II and III studies demonstrating higher objective response rates (ORR; 43% vs 4%), and significantly improved PFS compared with treatment with ofatumumab (Arzerra); (not reached vs 8.1 months at median follow-up of 9.4 months), and OS benefit (1-year OS, 90% vs 81%; HR for death, 0.43; P = .005) (TABLE 22). Importantly, the phase III RESONATE study showed that efficacy differences were retained in patients carrying del(17p) and in those resistant to purine analogues.

The CLL indication of ibrutinib has recently been expanded to include frontline therapy, in part based on outcomes from the phase III RESONATE-2 study comparing ibrutinib with chlorambucil in 260 elderly treatment-na&iuml;ve patients with CLL.

Ibrutinib induced a significantly higher ORR (82% vs 35%), longer median PFS (not reached vs 18.9 months), and a longer OS (95% vs 84% at 2 years) (TABLE 313). This study specifically excluded patients with known del(17p) CLL; however, a recently published single-arm phase II study also demonstrated activity in previously untreated patients and in those with relapsed/refractory CLL with del(17p) or TP53- mutant disease, with an objective response rate of 97% among untreated patients and 80% among relapsed/refractory patients after a median follow-up of 2 years.

Ibrutinib is considered the preferred first-line therapy for patients with del(17p)/TP53-mutant CLL and is a category 1 recommendation for patients with CLL without del(17p)/TP53 mutation who are frail or, are &ge;65 years, or younger with significant comorbidities, according to the National Comprehensive Cancer Network (NCCN) guidelines on CLL.

A cross-trial comparison presented during the 2017 ASH Annual Meeting highlighted the use of single-agent ibrutinib versus chemoimmunotherapy for treatment-na&iuml;ve patients with CLL. Investigators compared data between single-agent ibrutinib in the RESONATE-2 trial and chemoimmunotherapy regimens of FCR from the CLL8 study, bendamustine and rituximab and FCR from the CLL10 study, obinutuzumab and chlorambucil and rituximab and chlorambucil from CLL11, and ofatumumab plus chlorambucil from the COMPLEMENT-1 trial.

Although patient criteria and study design differed among the various studies, treatment with single-agent ibrutinib was associated with a longer PFS versus FCR regimens, and the BTK inhibitor also was superior to the CLL10 study that excluded patients with del(17p), and with the chemoimmunotherapy studies that enrolled older patients with comorbidities, overall suggesting that ibrutinib may potentially

eliminate the need for chemotherapy in the frontline setting for CLL treatment. Based on the comparisons, the PFS benefit favored ibrutinib versus chlorambucil in high-risk patients, including those with unmutated IGHV or del(11q). Ibrutinib also improved OS versus chemoimmunotherapy regimens in older or less fit patients. Regarding safety, ibrutinib had the most favorable toxicity profile across the 5 studies, despite it being a longer median treatment duration of 34.1 months.

Ibrutinib has also demonstrated to be a feasible approach in high-risk patients with CLL who are asymptomatic. Although current iwCLL guidelines recommend beginning therapy for when patients progress or are symptomatic, preliminary findings of an ongoing single-stage phase II trial presented at the 2017 ASH Annual Meeting showed that treating asymptomatic, earlystage, high-risk patients with ibrutinib did not lead to unexpected adverse events (AEs).

At a median follow-up of 16 months, there were no grade 4 toxicities associated with ibrutinib; 2 patients experienced grade 3 atrial fibrillation related to treatment. Early treatment was also associated with reduction in cancer-related stress (P <.01), anxiety (P = .004), and improvement in sleep (P = .02).

With the availability of targeted therapies, which also include idelalisib (Zydelig) and venetoclax (Venclexta) for the treatment of patients with relapsed/refractory CLL, the question how to optimally sequence agents has become highly pertinent. Findings of a retrospective study evaluating outcomes with targeted therapies suggest better outcomes with ibrutinib as the first kinase inhibitor compared with idelalisib, superior outcomes with an alternate kinase inhibitor or venetoclax than with chemoimmunotherapy combinations after kinase inhibitor failure, and possibly better outcomes with venetoclax after ibrutinib failure.

Consequently, the authors emphasized the need for trials testing sequencing strategies to optimize treatment algorithms.

DEL(11Q) IS NOT A NEGATIVE PROGNOSTIC PREDICTOR FOR RESPONSE TO IBRUTINIB

The del(11q22.3) cytogenetic abnormality, which is detected in up to 20% of patients with CLL at diagnosis and at a higher frequency in relapsed/refractory CLL, has traditionally been considered an unfavorable cytogenetic alteration associated with extensive lymphadenopathy, disease progression, and shorter median survival (79 months).9 The presence of del(11q) predicts poor response to chlorambucil-, fludarabine-, or FCR (fludarabine, chlorambucil, rituximab [Rituxan])-based regimens, with shorter duration of remission and OS compared with other cytogenetic groups.9,18 Previous findings have shown that adding an alkylating agent such as cyclophosphamide to fludarabine- based chemoimmunotherapy can improve outcomes.

A recent study has now investigated whether the presence or absence of del(11q) was associated with clinical outcomes following treatment with the BTK inhibitor ibrutinib in phase III studies. Lead investigator Thomas J. Kipps, MD, PhD, from the University of California Moores Cancer Center, and colleagues presented these findings at the 2016 American Society of Hematology Annual Meeting.

The study was based on patient data from 3 phase III studies that had demonstrated superiority of single-agent ibrutinib to treatment with ofatumumab in relapsed/refractory CLL (RESONATE),3 to chlorambucil in treatment-na&iuml;ve CLL (RESONATE-2),13 and of ibrutinib in combination with bendamustine and rituximab (BR) to treatment with BR in relapsed CLL (HELIOS).

Analyses of pooled data of 1210 patients with available del(11q) data revealed that the presence of del(11q) was not an adverse prognostic factor for PFS in patients who received ibrutinib-based treatment (n = 609 patients; 179 with del(11q), 430 without) but was in those who received the respective comparator treatment (n = 601; 149 with del[11q], 452 without).

The presence versus absence of del(11q) was associated with prolonged PFS (24-month, 82% vs 75%) and OS (30-month, 93% vs 86%) in ibrutinib-treated patients, but shorter PFS (9% vs 19%) in comparator-treated patients. Furthermore, treatment with ibrutinib was associated with superior clinical outcomes versus comparators regardless of del(11q) status.

&ldquo;The data gathered on ibrutinib&rsquo;s role in treating chronic and small lymphocytic leukemia patients with del(11q) are encouraging for these patients. As physicians, we always want patients to understand that they have options and, for our part, it&rsquo;s a matter of understanding how to adjust treatment for them,&rdquo; said Kipps in a prepared statement.

IGHV MUTATIONAL STATUS AND THE SELECTION OF FRONTLINE AND SUBSEQUENT THERAPY

Mutational status of the IGHV in the CLL clone has been increasingly considered as a parameter when determining treatment choice, whereas del(11q) is no longer considered a marker with relevance for treatment selection in current guidelines by the National Comprehensive Cancer Network (NCCN).

CLL cells expressing unmutated IGHV originate from B cells that have not undergone somatic hypermutation, which has been associated with a more aggressive disease course and poor outcomes with standard chemotherapy-based regimens.21 Long-term follow-up from the CALGB 9712 study of firstline therapy with concurrent versus sequential fludarabine and rituximab found unmutated IGHV a significant independent predictor for shorter PFS and OS, and del(17p) or del(11q) independent predictors for shorter survival.

Recently updated results from the phase III CLL8 study found TP53 mutation, del(17p) and unmutated IGHV the strongest predictors of shorter PFS and OS.5 Study findings further confirmed survival benefits of FCR versus FC in physically fit previously untreated CLL patients <65 years (5-year OS, 80.9% vs 69.2%; P = .002).

In patients with mutated IGHV, FCR was associated with improved survival in all cytogenetic groups except del(17p) compared with FC (median PFS not reached vs 41.9 months, P <.001; 5-year OS, 86.3% vs 79.8%).

&ldquo;Of the patients with del(11q), considered an adverse prognostic group, patients with IGHV mutations responded very well to FCR and, as a consequence, showed an outcome similar to other (non-del[17p]) patients,&rdquo; stated lead study author Kirsten Fischer, MD, of the University of Cologne, Germany, and colleagues in their study, which was published in Blood. &ldquo;This finding may announce the emergence of a therapeutic approach that is guided by the IGHV mutational status.&rdquo;

Likewise, initial phase II results of a study presented at the 2017 ASCO Annual Meeting found that patients with IGHV-mutated CLL had high rates of MRD-negative status in bone marrow after receiving first-line treatment with a combination of ibrutinib, fludarabine, cyclophosphamide, and obinutuzumab (iFCG).22 Results showed an ORR of 100% among patients who completed 3 cycles of iFCG, and 29 patients (83%) achieved MRD-negative status.

In contrast, IGHV mutational status does not predict response to ibrutinib, according to an integrated analysis of data from the phase III RESONATE, RESONATE-2, and HELIOS studies presented at the 2017 American Association for Cancer Research Annual Meeting.23 According to Kipps et al, &ldquo;IGHV-unmutated CLL was an adverse predictor of outcome for comparator-treated, but not for ibrutinib-treated patients.&rdquo;

The pooled analysis was comprised of data from 985 CLL/ SLL participants in the 3 studies, including 494 patients who received ibrutinib (351 with IGHV-unmutated disease and 143 with mutated IGHV) and 491 patients who received the respective control treatment ofatumumab, chlorambucil, and/or BR (366 with IGHV-unmutated CLL and 125 with IGHV mutations). At a median follow-up of 21.4 months for patients receiving ibrutinib and 20.6 months for those on control treatment, PFS and OS were similar among ibrutinib- treated patients (P = .93 for ibrutinib vs control), regardless of IGHV mutation status (2-year OS, 88% vs 89% for IGHV-unmutated and mutated disease, respectively; P = .86). In patients receiving control treatments, IGHV-unmutated disease was associated with shorter survival than IGHV-mutationharboring disease, also in multivariate analyses that adjusted for age, sex, baseline ECOG performance status, del(11q) and del(17p) status, prior lines of therapy, and other prognostic variables (2-year OS, 78% vs 87%; adjusted P = .01).

PATIENT CHARACTERISTICS AND EVOLVING BASIS FOR TREATMENT DECISIONS IN CLL

Treatment decisions in CLL are generally based on the distinct molecular profile of their disease and age as well as the fitness of the patient.

However, current NCCN guideline recommendations for the group of patients with CLL who have del(17p)/ TP53 mutations are universal and not stratified by patient age or condition.

Recommended frontline therapy options in order of preference are ibrutinib, dose-dense high-dose methylprednisolone (HDMP) plus rituximab, obinutuzumab plus chlorambucil (category 3), and the anti-CD52 antibody alemtuzumab (Lemtrada) alone or in combination with rituximab.

Ibrutinib also leads the list of preferred regimens for relapsed/refractory disease, followed by venetoclax with or without rituximab, idelalisib plus rituximab, single-agent idelalisib, and other rituximab and ofatumumab-based therapies. Suggested postfirst- and second-line maintenance therapies include lenalidomide (Revlimid) in high-risk patients, and lenalidomide or ofatumumab, respectively.

In patients with CLL without del(17p)/TP53 mutations, the most important features directing treatment choices are advanced age of >65 years, the presence of medical comorbidities, and the objectives of treatment.

Preferred first-line therapies for frail patients are obinutuzumab (Gazyva) plus chlorambucil, followed by ibrutinib (both category 1 recommendations), ofatumumab plus chlorambucil, rituximab plus chlorambucil, single-agent obinutuzumab, rituximab, and chlorambucil. The same treatment options are available for patients &ge;65 years and younger patients with significant comorbidities, with the inclusion of bendamustine with rituximab following rituximab and chlorambucil in preference.

For patients <65 years without comorbidities, chemoimmunotherapy remains the standard frontline treatment, with FCR as category 1, FR, and PCR, and bendamustine plus rituximab, as well as ibrutinib (category 2A).

For the treatment of relapsed/refractory CLL without del(17p)/TP53 mutations, ibrutinib is the preferred regimen in patients of all performance groups, followed by idelalisib plus rituximab, venetoclax with or without rituximab, chemoimmunotherapy regimens that are again guided by patient performance, and various CD20 monoclonal antibody-based regimens. Lenalidomide or ofatumumab can be considered for postsecond-line maintenance therapy.

With accumulation of data from clinical trials, these recommendations are likely going to evolve in the near future.

&ldquo;Certainly for relapsed therapy, the kinase inhibitors have moved in, led by ibrutinib,&rdquo; stated Jennifer Brown, MD, PhD, of Dana-Farber Cancer Institute, in a presentation at the 2016 ASCO Annual Meeting.

Based on improved insight into chronic lymphocytic leukemia biology and pathophysiology, approaches to identify patients who are at higher risk for disease progression have been refined, as have strategies to select therapies that maximize treatment outcomes due to their selectivity for distinctive phenotypic or physiological features of the respective CLL cells.

Chronic Lymphocytic Leukemia | Evolving Paradigms

Lead Investigator for Ibrutinib/FCR Combo Highlights Significant Findings in CLL

Current Treatment Strategies in CLL

O'Brien Covers Evolution of Long-Term Data With Ibrutinib in CLL Landscape

Factors Affecting Prognosis and Treatment in CLL

Emerging Treatment Strategies in CLL

Current Approaches to Diagnosis and Risk Stratification in CLL