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?

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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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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.

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

Emerging Targeted Therapies and Immunotherapies in CLL

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 rede ned 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.

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 (TABLE 2).

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 high response rates (71%),12 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 33). 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-nai&Igrave;&circ;ve patients with CLL.

Ibrutinib induced a signi cantly higher ORR (86% vs 35%), longer median PFS (not reached vs 18.9 months), and a longer OS (98% vs 85% at 2 years) (TABLE 413).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.

As Steven E. Coutre, MD, a hematologist with Stanford University and co-investigator of the RESONATE-2 trial, explained in an interview with the American Journal of Managed Care

, &ldquo;We had patients between the ages of 65 and 70, and then we had those 70 years and older. Again, those patients 70 years and older would be an average CLL patient who&rsquo;s starting therapy. And we saw benefit in both groups. There really was no distinction. It also speaks to the fact that it&rsquo;s well tolerated. So, often patients who are older, of course, have more comorbiditiesdiabetes, hypertension, the usual things that we see. And that didn&rsquo;t impact either the ef cacy or the tolerability of the treatment.&rdquo;

The long-term outcomes with first-line ibrutinib remain to be determined. Coutre added, &ldquo;The real value is going to be to see how those patients do as they continue on ibrutinib.... In the RESONATE-2 trial, there are only 3 patients who came off ibrutinib because of progressive disease. And, although follow-up of them is still shortmeasured in months, not years&mdash;none of those patients have gone on to subsequent treatment yet.

We have a limited experience from our very first trial. I have a few patients on that trial who have been receiving ibrutinib for more than 6 years now.&rdquo;

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).

The presence of del(11q) predicts poor response to chlorambucil-, udarabine-, or FCR ( udarabine, chlorambucil, rituximab [Rituxan])-based regimens, with shorter duration of remission and OS compared with other cytogenetic groups.

Previous findings have shown that adding an alkylating agent such as cyclophosphamide to udarabine-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),

to chlorambucil in treatment-nai&Igrave;&circ;ve CLL (RESONATE-2),

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 data on del(11q) 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.

Long-term follow-up from the CALGB 9712 study of first-line 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 ndings further con rmed 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 observed benefit of FCR for the majority of IGHV-mutant patients should be considered in the design of future clinical trials. First, 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).

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.

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 an- tibody 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 signifcant 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.

&ldquo;For patients with a long duration of remission to prior chemoimmunotherapy and low-risk cytogenetics, it could be reasonable to repeat chemoimmunotherapy, but that&rsquo;s not going to be the most common. For the frontline treatment of fit, young patients, chemoimmunotherapy certainly remains the standard, pending ongoing trials.&rdquo;

Considering the long-term remissions reported with FCR and unknown long-term efficacy of ibrutinib and idelalisib, many open questions in respect to the best treatment choice remain. Brown added, &ldquo;One of the ways to solve these problems is to find effective, well-tolerated combinations that induce remissions that are deep that might allow us to stop therapy after a relatively short fixed period of time.&rdquo;

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

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

Kipps TJ, Hillmen P, Demirkan F, et al. 11q Deletion (del11q) is not a prognostic factor for adverse outcomes for patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) treated with ibrutinib: pooled data from 3 ran- domized phase 3 studies. Blood. 2016;128(22): 2042.

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

Woyach JA, Ruppert AS, Heerema NA, et al. Chemoimmunotherapy with fluda- rabine and rituximab produces extended overall survival and progression-free survival in chronic lymphocytic leukemia: long-term follow-up of CALGB study 9712. J Clin Oncol. 2011; 29(10):1349-1355.

Hallek M, Cheson BD, Catovsky D, et al. Guidelines for the diagnosis and treatment of chronic lymphocytic leukemia: a report from the International Workshop on Chronic Lymphocytic Leukemia updating the National Cancer Institute-Working Group 1996 guidelines. Blood. 2008;111(12):5446-5456. doi: 10.1182/blood-2007-06-093906.

Cheson BD, Bennett JM, Grever M, et al. National Cancer Institute-sponsored Working Group guidelines for chronic lymphocytic leukemia: revised guide- lines for diagnosis and treatment. Blood. 1996;87(12):4990-4997.

Kipps TJ, Stevenson FK, Wu CJ, et al. Chronic lymphocytic leukaemia. Nat Rev Dis Primers. 2017;3:16096. doi:10.1038/nrdp.2016.96.

Do&Igrave;&circ;hner H, Stilgenbauer S, Benner A, et al. Genomic aberrations and survival in chronic lymphocytic leukemia. N Engl J Med. 2000;343:1910-1916. doi: 10.1056/NEJM200012283432602.

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

Stilgenbauer S. Prognostic markers and standard management of chronic lymphocytic leukemia. Hematology Am Soc Hematol Educ Program. 2015;2015:368-377. doi: 10.1182/asheducation-2015.1.368.

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

Burger JA, Tedeschi A, Barr PM, et al. Ibrutinib as Initial Therapy for Patients with Chronic Lymphocytic Leukemia. N Engl J Med. 2015;373:2425-2437. doi: 10.1056/NEJMoa1509388.

An overview of the factors affecting prognosis and treatment in chronic lymphocytic leukemia.

Factors Affecting Prognosis and Treatment 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.

Chronic Lymphocytic Leukemia | Evolving Paradigms

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Current Approaches to Diagnosis and Risk Stratification in Chronic Lymphocytic Leukemia