It wasn't that long ago when the chemoimmunotherapy regimen of fludarabine, cyclophosphamide, and rituximab (Rituxan; FCR) was the gold standard for patients with chronic lymphocytic leukemia (CLL).

However, experts in the field say that the explosive FDA approval of the BTK inhibitor ibrutinib (Imbruvica) in February 2014 in the second-line settingfollowed with the frontline indication approval in March 2016&mdash;has dramatically changed the landscape to one that is much more hopeful for patients.

Ibrutinib has demonstrated its impressive clinical activity as a single agent, and currently is also being explored in combination with other game-changing agents in the paradigm, including the BCL-2 inhibitor venetoclax (Venclexta) to further improve patient outcomes. While there may be some challenge with the novel therapy, experts explain that ibrutinib's future looks bright.

Jan A. Burger, MD, PhD, associate professor of medicine in the Department of Leukemia at The University of Texas MD Anderson Cancer Center, and Javier Pinilla-Ibarz, MD, PhD, an associate member of the Malignant Hematology and Immunology Program at H. Lee Moffitt Cancer Center, both shed their expertise on the field of CLL and the transformative role of ibrutinib in interviews with

What was the treatment landscape for CLL like prior to the approval of ibrutinib?

It was dominated by chemoimmunotherapy, and the two most used regimens were udarabine, cyclophosphamide, and rituximab, and bendamustine/rituximab [BR].

The treatment landscape was pretty bad, and was based on chemoimmunotherapy depending on the age of the patient. The classical regimen that we were using [was] FCR and BR in the high- to intermediate-stage patients. The data with chlorambucil came, including a combination of CD20-targeted antibodies plus chlorambucil, and [those were] the options that we had for our patients with CLL. Obviously, in the past, we used different drugs but chemoimmunotherapy was the main kind of regimen. Some people may [have used] single-agent anti-CD20 therapy with rituximab.

What is the treatment landscape like for CLL now?

The use of chemoimmunotherapy has declined, especially in high-risk patients, and that&rsquo;s been replaced mostly by kinase inhibitors, including ibrutinib.

We know that ibrutinib has dramatically changed the current paradigm of CLL. It is true that with certain che- moimmunotherapy in certain populations, the goal was to eradicate minimal residual disease [MRD], as well as prolong the progression-free survival [PFS] of these patients as long as we can because most of them will relapse.

However, a [greater] portion of patients belong to immunoglobulin heavy chain variable regions, which we may recognize as having very long periods of PFS. The introduction of BTK inhibition changed the paradigm because these drugs worked very well. The best example of how we best use this drug was in the

-mutant patients, for whom we didn&rsquo;t have anythingeven the single-agent monoclonal antibodies or combination therapies had a very short period of PFS. It was the first signal that these drugs were very powerful and could control high-risk disease.

However, the paradigm is changing and shifting because now we have these drugsspecifically, ibrutinib&mdash;that produce very long PFS, improved survival in high risk-patients who can take the drug until disease progression or unacceptable toxicity. But, it is to preserve progression and improve quality of life of all populations. However, eradication of the disease is rarely sustained because we still have MRD&mdash;which is well controlled, but [the disease] is there. This is kind of the challenge of the new paradigm.

What is the current prognosis for a patient with CLL?

It depends on CLL risk factors, but for many patients it&rsquo;s quite similar to age-matched healthy people. It&rsquo;s an evolution, because we don&rsquo;t know, at this time, the precise impact of the new agents on long-term survival.

All of the data that we present and discuss with a patient is from very old datamost of which is with chemotherapy or chemoimmunotherapy. But we are now changing the disease with BTK inhibitors, for sure. There are new drugs which are going to impact that survival and PFS. The selection of BCR inhibitors is changing as we talk about the natural disease of these patients. At the end, the issue here is that CLL is a very long, prolonged disease. We now know if we give these drugs in the second-line setting, we improve survival. You have to extrapolate the data and put it into perspective, but there is no doubt it is changing the natural history of the disease. [Patients] relapse after 2 to 3 lines of therapy, but previously we had nothing else for our patients. Now, we are prolonging the lives of our patients. In the less aggressive forms of CLL, we still need to see data. Data of the longer follow-up with ibrutinib in the phase I/IIb trial of a small portion of patients with treatment-naïve disease, as well as with classic refractory disease with or without a 17p deletion, is 5 years of follow-up but the frontline trials only have 30 months of median follow-up. We are still awaiting more of the data in the long run.

Do you believe that the prognosis has improved over the years?

It clearly has improved. Patients with short survival are higher-risk patients who didn&rsquo;t respond well to chemoimmuno- therapy, and those patients now have a better prognosis with the newer agents.

What is your go-to approach for patients who progress on ibrutinib?

Clinical trials, and right now, outside of clinical trials, the most established approach would be with the BCL-2 antagonist, venetoclax.

That is a very good question. Progression off of ibrutinib has been described as a very bad outcome. Progression can happen as a transformation to high-grade lymphoma or in the development of mutations that do not allow ibrutinib to work. Progression is more common in people who previously received multiple therapies; it is way less common in patients who received frontline ibrutinib. It really constitutes the most common reasons for discontinuation for switching therapy. We know there are data with other drugs, such as idelalisib [Zydelig] or with venetoclax. Now, we have tremendous success on getting these patients [other options]. It may be better to use venetoclax based on the high ef- cacy and cytotoxicity of this drug in CLL. We want to have therapies to help the patients when the drugs do not work.

What are the patient characteristics, if any, that make a patient eligible for treatment with ibrutinib?

It&rsquo;s approved for all patients with CLL in all lines of treat- ment, so basically any patient could receive ibrutinib treatment, and it&rsquo;s then an individualized decision if you want to go that route versus alternatives, and that&rsquo;s driven by risk factors. If patients have low-risk disease then chemoimmunotherapy remains a viable, and oftentimes a very good option, but those are just younger patients who have low-risk disease features, so those are not that common in standard practice.

For patient with 17p deletion, ibrutinib is the must-have drug to be used. The [younger] population is able to tolerate FCR...and can benefit from this chemoimmunotherapy, but speci cally with FCR and not BR.

For the rest of the groups, [the use of] ibrutinib is up there. We discuss the prolonged therapy of it and some people may not like being on treatment for life and may go on to BR or even chlorambucil because it&rsquo;s less time on therapy. However, it is a personal discussion with patients.

Are there any characteristics that make patients less likely to receive ibrutinib?

Ibrutinib-specific side effects can influence a decision towards not using this drug. For example, patients with a history of atrial brillation, or active and symptomatic atrial fibrillation, may experience recurrence or a worsening of their cardiac symptoms. Similarly, in patients with a recent history of serious bleeding events we may choose alternative therapy.

Do you have advice for community oncologists managing patients on ibrutinib?

Ibrutinib resistance, if that occurs, then my recommendation would be to transfer these patients to a larger center for available clinical trials and to also consider an allogeneic stem cell transplant consult for transplant-eligible patients.

Besides that, it is initially important to prepare patients for redistribution lymphocytosis, which occurs in many, but not all, patients during the first months on therapy. I explain to my patients why this happens, from mobilizing CLL cells from tissues into the blood, as part of the mechanism of how ibrutinib, and other drugs targeting the B-cell receptor pathway, work. Later, it is a matter of monitoring for durability of responses and side effects. High-risk patients, especially relapsed or refractory patients with 17p deletion, should be comanaged with specialists to monitor for emergence of resistance mutations which are more frequent in such patients. Plus, there might be clinical trial or stem cell transplant options for this particular group of high-risk patients that could be beneficial longer-term.

We are looking forward to seeing combinations with ibrutinib with other drugsmaybe in the future we may be able to discontinue the drug. The [length of time on therapy] may be some of the drawbacks for the drug. However, it is a very important discussion that needs to take place with these patients.

There is the possibility that some side effects may happen, but we don&rsquo;t have to be concerned about them. [When on ibrutinib], I see patients once a week in the rst month, then every 2 weeks in the second month. Lymphocytosis is not really a problem at all, but you want to be aware of it and ease the patients. At the end of the day, it is not a formal complication; it is just something to be aware of. It is something that we will encourage patients to get control of. It&rsquo;s going to be more like personalized experience of management of these patients. There are other side effects to be taken into consideration, such as hypertension, and diarrhea can be seen in the first month.

Are there any agents or combination approaches currently in development that you find promising?

There are a lot of second-generation kinase inhibitors in development which could further improve on the agents that are already approvedibrutinib and idelalisib&mdash;so that&rsquo;s interesting. They all have potential but then they have to go through randomized studies first to demonstrate any substantial advantages.

The combination of venetoclax with obinutuzumab [Gazyva] is a trial that is already close to enrollment and we hope to have some data in the next year by the German CLL Study Group. It is one of the things that is exciting the CLL community. Ibrutinib and venetoclax together is another combination being explored and may bring ibrutinib to a situation where we are using it in combination with other drugs.

There are many things coming up, hopefully in the next year or so. We hopefully will see the launch of chimeric antigen receptor [CAR] T cells for CLL; that is something that we know has very exciting data there. However, it is difficult for many companies to fully launch these trials. As you know there [could be potential] for approvals [of CAR T-cell therapy] in lymphomas, and CLL is going to be on the horizon.

What are the ongoing challenges in the field of CLL?

Articles

Clinical Articles

Jan A. Burger, MD, PhD and&nbsp;Javier Pinilla-Ibarz, MD, PhD shed light on the field of CLL and the transformative role of ibrutinib.

Experts Share Insight on Ibrutinib's Bright Future in CLL Landscape

The potential synergy of ibrutinib with other treatment strategies, including immunotherapeutic and targeted approaches, is currently being investigated in various clinical trials with the hope of identifying novel combinations that increase responses and improve duration of response.

New targeted agents in development in CLL include second-generation inhibitors of Bruton&rsquo;s tyrosine kinase (BTK) designed to improve safety and efficacy, and novel inhibitors of phosphoinositide 3-kinase (PI3K).

Emerging therapies in CLL also include novel immunotherapeutic regimens using immune checkpoint inhibitors and adoptive immunotherapy using modified T lymphocytes.

IMPROVING MODULATION OF APOPTOSIS WITH BTK INHIBITION

Venetoclax (Venclexta), a selective inhibitor of the B-cell lymphoma-2 (BCL-2) family of proteins, which regulate cellular apoptosis and oncogenic functions, is a standard-of-care treatment of relapsed or refractory 17p deletion (del[17p]) CLL, alone or in combination with rituximab (Rituxan), and has activity in patients relapsing or refractory to ibrutinib or idelalisib (Zydelig).

The combination of venetoclax and rituximab plus bendamustine in patients with relapsed/refractory CLL, based on findings from the phase III MURANO study.

Pretreating CLL cells with a BTK inhibitor, such as ibrutinib, has been shown to increase the dependence of CLL cells on BCL-2, enhancing CLL killing in response to venetoclax in cell culture studies.

Supported by this rationale, the clinical utility and safety of a sequenced regimen of ibrutinib monotherapy for 3 cycles followed by combination therapy with ibrutinib and venetoclax is being explored in an ongoing phase II study in 78 patients with relapsed/ refractory CLL and in previously untreated patients with high-risk CLL, defined as the presence of either del(17p), mutated TP53, 11q deletion (del[11q]), unmutated IGHV, or &ge;65 years.

A phase II study is also evaluating ibrutinib plus venetoclax as a frontline therapy in a planned cohort of 150 patients with CLL.

Potential synergy of BTK and BCL-2 inhibition is also being explored in a phase Ib/II study in patients with relapsed/refractory CLL, using a combination of obinutuzumab (Gazyva), ibrutinib, and venetoclax started sequentially, with gradual escalation of the venetoclax dose.

The regimen was tolerated with toxicities consistent with those of the single agents. Response has been evaluated in 6 of 12 patients treated in the phase Ib portion of the study, with an ORR of 100% (5 partial responses [PRs] and 1 CR).

EXPLORING SYNERGY OF IBRUTINIB WITH IMMUNOTHERAPEUTIC REGIMENS

The upregulation of inhibitory immune checkpoint pathways that control the T-cell response represents a major mechanism by which cancer cells escape elimination by the immune system. CLL cells express elevated levels of checkpoint inhibitory molecules, including programmed death 1 (PD-1), and its main ligands, PD-L1 and PD-L2.

This provides a strong rationale to investigate immunotherapy with PD-1 checkpoint inhibitors in CLL, which is expected to enhance the activity of anti-CLL T- effector cells, resulting in immune-mediated elimination of CLL cells. The small molecule inhibitor ibrutinib has immunomodulatory properties because it also blocks interleukin-2inducible T-cell kinase (ITK), in addition to BTK, producing a shift in the balance of T-helper cell populations.

Adding ibrutinib with PD-1 checkpoint blockade has enhanced antitumor activity in preclinical models, including ibrutinib-resistant lymphomas.

An ongoing phase II trial is investigating combined checkpoint inhibitor therapy with the PD-1 inhibitor nivolumab (Opdivo) and ibrutinib in patients with relapsed/refractory CLL or Richter&rsquo;s transformation (RT), or untreated patients with high-risk del(17p) CLL.

An initial report of the first 12 patients was presented at the 2016 ASH Annual Meeting, reporting activity in ibrutinib-naive patients with relapsed/refractory CLL (PRs in 3 of 5 patients) or RT (2 of 4 patients), including 1 patient with del(17p), unmutated IGHV, complex karyotype CLL.

A single-arm phase II study has previously demonstrated activity of ibrutinib in combination with rituximab in patients with high-risk CLL.

The therapy was well tolerated and produced a response rate (ORR) of 95%, including a CR of 8% and a PR of 87%, and an 18-month progression-free survival (PFS) rate of 78% in all patients and 72.4% in patients with del(17p) or a TP53 mutation.

Promising clinical activity of ibrutinib in combination with the CD20-targeted monoclonal antibody ofatumumab (Arzerra) has been reported from a phase I/II trial in 71 patients with relapsed/ refractory CLL; the combination produced a high ORR (71% to 100% in different dose schedules) and an estimated 12-month PFS of 75% to 89%.

Frontline treatment with ibrutinib plus obinutuzumab is currently being compared with chlorambucil plus obinutuzmab in the phase III iLLUMINATE study in 212 treatment-naive patients with CLL, with results expected in late 2017.

Ibrutinib has also been combined with the investigational glycoengineered CD20 antibody ublituximab (TG-1101). In a phase II study, 88% of patients (n = 41) with relapsed/refractory CLL responded to the combination, and the ORR was 95% among patients with high-risk (del(17p), del(11q), or TP53 mutation) CLL, including a subset (n = 3, 15%) who achieved negative minimal residual disease (MRD).

The phase III GENUINE study (n = 126 patients) was designed to validate this combination in patients with previously treated high-risk CLL.

According to recently released top-line data, the study met the primary endpoint by demonstrating a significant increase in ORR with ibrutinib plus ublituximab versus single-agent ibrutinib (80% vs 47%; P <.001).

&ldquo;We believe that the rapid responses seen in our phase II study with ublituximab plus ibrutinib are validated here in our phase III GENUINE study and are important markers of improved overall efficacy and patient outcomes,&rdquo; stated study chair Jeffrey Sharman, MD, medical director for hematology research for the US Oncology Network in a prepared statement.

The combination of ibrutinib with obinutuzumab is the focus of a phase I/II study in 32 previously untreated patients with CLL, with safety, tolerability, dose-limiting toxicity, and ORR as primary outcomes.

COMBINING AND COMPARING TARGETED THERAPY WITH CHEMOIMMUNOTHERAPY

Recent outcomes from the randomized, placebo-controlled, phase III HELIOS study in patients with relapsed/refractory CLL have confirmed that the addition of ibrutinib to bendamustine and rituximab (BR) was beneficial and tolerable.

After a median follow-up of 17 months, median PFS was not reached in the ibrutinib group versus 13.3 months in the placebo group (HR, 0.203; P <.0001), demonstrating a reduction of the risk of progression and death by 80%. PFS at 18 months was 79% versus 24% (P <.0001), and PFS benefits of ibrutinib were maintained in subgroups including refractoriness to purine analog therapy, del(11q), and unmutated IGHV. The ORR was 82.7% versus 67.8% (P <.0001), and the median OS was not reached in either group.

Current trials evaluating ibrutinib in combination with chemotherapy as frontline therapy include a phase II study evaluating the addition of short-course udarabine to ibrutinib

and a phase II study investigating ibrutinib plus udarabine, cyclophosphamide, and rituximab (FCR) in younger patients (<65 years).

An ongoing phase III study of the German CLL Study Group has been designed to directly compare frontline standard chemoimmunotherapy (FCR, BR) therapy in physically fit patients with CLL who do not have del(17p) or TP53 mutations with combination regimens of targeted drugs, specifically rituximab plus venetoclax, obinutuzumab plus venetoclax, and obinutuzumab plus ibrutinib plus venetoclax.

The second-generation small molecule BTK inhibitors acalabrutinib (ACP-196) and BGB-3111 (TABLE 1) exhibit greater selectivity for BTK than ibrutinib, which may reduce toxicity related to off-target activity of ibrutinib on other kinases including EGFR, ITK, and Tec family kinases, and may also overcome drug resistance related to incomplete BTK inhibition with ibrutinib.

Both agents also exhibit rapid oral bioavailability and a short half-life, allowing for twice-daily dosing, which has been associated with high plasma exposureproducing continuous and greater-than-95% blockade of BTK.

An uncontrolled, multicenter, phase I/II trial involving 61 patients with relapsed/refractory CLL, with unmutated IGHV in 75% and del(17p) in 31%, reported a 95% ORR (PR, 85%; PR with lymphocytosis, 10%; stable disease, 5%) with a median follow-up period of 14.3 months. The ORR in patients with del(17p) was 100%, and no cases of Richter transformation had occurred. Most toxicities were grade 1/2, including headache, diarrhea, increased weight, pyrexia, and upper respiratory infection.

A phase III trial of acalabrutinib versus ibrutinib in previously treated patients with high-risk CLL with either del(17) and/or del(11q) is underway.

A second ongoing phase III trial is evaluating acalabrutinib versus rituximab plus idelalisib or bendamustine in patients with relapsed/refractory CLL.

Acalabrutinib is also being investigated for the frontline treatment of CLL, based on positive outcomes of a phase I/II study in treatment-nai&Igrave;&circ;ve patients with CLL, which reported good tolerability and an ORR of 96%.

The ongoing phase III Elevate CLL TN study is comparing acalabrutinib plus obinutuzumab versus obinutuzumab plus chlorambucil as a frontline treatment.

Phase I study outcomes with BGB-3111 in patients with relapsed/refractory CLL were recently reported and included an ORR of 96% (67% PR; 28% PR with lymphocytosis) and a 100% ORR in patients with del(17p).

Three ongoing phase I trials are evaluating BGB-3111 in patients with B-cell lymphoid malignancies as a single agent and in combination with obinutuzumab and BGB-A317, an early-stage PD-1 inhibitor.

&ldquo;BGB-3111 can achieve complete target inhibition in lymph nodes while remaining highly tolerable,&rdquo; said lead investigator Constantine Tam, MD, of the Peter MacCallum Cancer Center, Australia, in a prepared statement.

Duvelisib (IPI-145) is an oral inhibitor of PI3K3&gamma; and PI3K&delta; isoforms that suppresses B-cell proliferation and promotes apoptosis in CLL cells.

Clinical activity of single-agent duvelisib was reported from a phase I trial in patients with relapsed/refractory CLL, including those with del(17p) or a TP53 mutation.

Phase III data of the DUO trial of patients with relapsed/refractory CLL/SLL showed a median PFS of 13.3 and 9.9 months for duvelisib and ofatumumab, respectively (HR, 0.52;

<.0011). Additionally, initial data from an ongoing phase Ib study of duvelisib plus FCR as frontline therapy suggested tolerability and high response rate (100% in 12 patients).

Outcomes from the phase III DUO study comparing single-agent duvelisib versus ofatumumab in patients with relapsed/refractory CLL are expected later this year.

A unique immunotherapy currently in development in CLL is adoptive immunotherapy using chimeric antigen receptor (CAR) T-cell therapy. This technology involves the genetic modification of autologous T cells ex vivo to express a fusion construct (CAR) consisting of a B cell-specific antigen, such as the pan B-cell antigen CD19, and the signaling component of T-cell receptor.

This approach results in target specificity of the effector T cell, and later-generation designs incorporate additional co-stimulatory domains to enhance antitumor activity of the modified T cells.

Clinical outcomes of CAR T-cell therapy in patients with CLL have been reported in small numbers at single institutions.

The largest triala phase I study&mdash;demonstrated a 57% ORR (8 of 14 patients; including 4 CRs and 4 PRs) among patients with heavily pretreated relapsed/refractory CLL.

CD19 CAR T-cell responses persisted for 4 years in the rst 2 patients who achieved CR, and none of the patients with CR relapsed or had detectable MRD, suggesting this treatment may be a possible cure for CLL. All patients with response developed B-cell aplasia and had cytokine release syndrome, which coincided with T-cell proliferation.

Single-arm results of a small phase I/II study of JCAR014 CAR T-cell therapy in adults with relapsed/refractory B-cell malignancies, which were presented at the 2017 SOHO Annual Meeting, showed that the subgroup of patients who met International Working Group on CLL criteria for response had no malignant IgH sequences in marrow had a PFS and OS of 100% after follow-up of 6.6 months.

A large number of early-stage clinical trials is ongoing to investigate CAR T-cell treatment in advanced B-cell malignancies, including relapsed/refractory CLL, including a phase I/II study in 189 patients with advanced CLL, acute lymphoblastic leukemia, and non-Hodgkin lymphoma.

Multiple clinical trials are underway that address ef cacy and tolerability of novel agents and agent combinations in CLL. Pertinent outcomes include the durability of remissions in patients who achieve MRD-negative CR on regimens and the effects of treatment discontinuation.

&ldquo;The field is rapidly moving into the domain of combination therapies with encouraging early results and apparently higher quality responses including high rates of MRD-negativity,&rdquo; said Tam and John Seymour, MD, also of Peter MacCallum Cancer Centre and University of Melbourne, in a commentary. &ldquo;Such combination therapies, including rationally designed novel combinations are now being evaluated in a suite of high-profile trials that will likely define optimal treatment in the near future. If these combination therapies do emerge as superior, we will again need to evaluate outcomes and treatment choices in that context.&rdquo;

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Wierda W, Chyla B, Eichhorst B, et al. Venetoclax in relapsed/refractory chronic lymphocytic leukemia (CLL) with 17p deletion: outcomes and minimal residual disease (MRD) from the full population of the pivotal M13-982 trial. Presented at 2017 SOHO Annual Meeting; September 13-16, 2017; Houston, TX Abstract Cll-102.

Deng J, Isik E, Fernandes SM, et al. Bruton&rsquo;s tyrosine kinase inhibition increases BCL-2 dependence and enhances sensitivity to venetoclax in chronic lympho- cytic leukemia [printed ahead of publication February 14, 2017]. Leukemia. doi: 10.1038/leu.2017.32.

National Institutes of Health Clinical Trials Registry. Venetoclax and ibrutinib in patients with chronic lymphocytic leukemia (CLL). ClinicalTrials.gov website. Identi er: NCT02756897. Updated April 26, 2107. Accessed May 18, 2017.

National Institutes of Health Clinical Trials Registry. Ibrutinib plus venetoclax in patients with treatment-naive chronic lymphocytic leukemia /small lymphocytic lymphoma. ClinicalTrials.gov website. Identi er: NCT02910583. Updated April 11, 2107. Accessed May 18, 2017.

Jones JA, Woyach J, Awan FT, et al. Phase 1b Results of a Phase 1b/2 Study of Obinutuzmab, Ibrutinib, and Venetoclax in Relapsed/Refractory Chronic Lympho- cytic Leukemia (CLL). Presented at: 58th ASH Annual Meeting and Exposition; December 2-6, 2016; San Diego, CA. Abstract 639.

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Sagiv-Bar I, Kohrt HE, Czerwinski DK, et al. Therapeutic antitumor immunity by checkpoint blockade is enhanced by ibrutinib, an inhibitor of both BTK and ITK. Proc Natl Acad Sci USA. 2015;112:E966-72.

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Jain N, Basu S, Thompson PA, et al. Nivolumab combined with ibrutinib for CLL and Richter transformation: a phase II trial. Presented at: 58th ASH Annual Meet- ing and Exposition; December 2-6, 2016; San Diego, CA. Abstract 59.

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National Institutes of Health Clinical Trials Registry. A multi-center study of ibru- tinib in combination with obinutuzumab versus chlorambucil in combination with obinutuzumab in patients with treatment nai&Igrave;&circ;ve CLL or SLL. ClinicalTrials.gov web- site. Identi er: NCT02264574. Updated January 4, 2017. Accessed May 18, 2017.

Sharman JP, Farber CM, Mahadevan D, et al. Ublituximab (TG-1101), a novel glycoengineered anti-CD20 antibody, in combination with ibrutinib is safe and highly active in patients with relapsed and/or refractory chronic lymphocytic leukaemia: results of a phase 2 trial. Br J Haematol. 2017;176(3):412-420.

National Institutes of Health Clinical Trials Registry. Ublituximab in combination with ibrutinib versus ibrutinib alone in patients with previously treated high- risk chronic lymphocytic leukemia (CLL). ClinicalTrials.gov website. Identi er: NCT02301156. Updated December 13, 2017. Accessed May 18, 2017.

TG Therapeutics Press Release March 6, 2017. TG Therapeutics announces positive topline data from phase 3 GENUINE study of TG-1101 in combination with ibrutinib in patients with high risk chronic lymphocytic leukemia (CLL). Available at: http:// ir.tgtherapeutics.com/releasedetail.cfm?ReleaseID=1015939. Accessed at May 18, 2017.

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An overview of emerging targeted therapies and immunotherapies in chronic lymphocytic leukemia.

Emerging Targeted Therapies and Immunotherapies 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 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&rsquo;s tyrosine kinase (BTK), ibrutinib (Imbruvica).

Current 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.

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 front-line treatment in older patients.

Yet, 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,

followed by outcomes of the randomized German CLL study group CLL8

have 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.

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).

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).

Long-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).

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, 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;

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.

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 (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.

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.

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.

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.

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 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.

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%).

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;

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%).

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.

According 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;

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.

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.

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 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.

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.

In 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%.

Additionally, 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.

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).

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 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.

AEs 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).

Single-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.

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.

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). 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;

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.

months (33.9 vs 9.2 months for placebo; HR, 0.4; 95% CI, 0.29-0.55; P <.001).

In both studies, neutropenia, gastrointestinal, nervous system, respiratory, and skin disorders were more common in the lenalidomide arms,

but the CONTINUUM study noted that a clinically meaningful difference in quality of life was not found between the 2 arms.

As a frontline therapy, single-agent lenalidomide showed an ORR of 72% in a phase II study with a 20% CR rate.

At 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.

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.

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

: &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;

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.

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;

National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines): Chronic Lymphocytic Leukemia/Small Lymphocytic Lym- phoma. 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.

Current treatment strategies for chronic lymphocytic leukemia (CLL).

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