The Next Generation of Targeted Molecules for the Treatment of Chronic Lymphocytic Leukemia

With the recent approval of several new targeted therapies for chronic lymphocytic leukemia (CLL), there are now multiple options for its treatment. Inhibitors of Bruton tyrosine kinase (with ibrutinib being the first-in-class US Food and Drug Administration–approved agent) and phosphoinositide 3-kinase (with idelalisib as the first-in-class approved agent) are promising because they are generally well tolerated and highly effective against this malignancy. These agents may be particularly important in the treatment of older patients who are less able to tolerate the myelosuppression (and subsequent infections) associated with chemoimmunotherapy. As a class of medications, B-cell receptor inhibitors have some unique side effects, including redistribution lymphocytosis. Toxicities associated specifically with ibrutinib include increased risk for bleeding and atrial fibrillation. Idelalisib also has some unique toxicities: transaminitis, colitis, and pneumonitis. Targeted therapies recently approved for use in CLL include the novel anti-CD20 monoclonal antibodies obinutuzumab and ofatumumab, and the B-cell lymphoma 2 inhibitor venetoclax. This article describes the clinical data that led to approval of these B-cell receptor inhibitors for the treatment of CLL, and highlights newer agents in clinical development that target the same kinases as the currently available therapies.

Introduction

Chronic lymphocytic leukemia (CLL) is the most common leukemia in the United States, with an estimated 14,000 new cases diagnosed and more than 100,000 people living with the disease in 2015.[1] It is a clinically heterogeneous malignancy whose course is affected by cytogenetics, immunoglobulin heavy chain variable region (IgVH) gene rearrangement status, and other disease-specific characteristics. The standard of care for frontline therapy in eligible patients with CLL has been the combination of fludarabine, cyclophosphamide, and rituximab (FCR). In a large phase II trial, patients treated with FCR had an overall response rate (ORR) of 95%, with complete response (CR) in 72% of patients.[2] The 6-year overall survival (OS) and failure-free survival rates of patients treated with FCR were 77% and 51%, respectively. However, given that the average age at the time of CLL diagnosis is 71 years,[1] many patients are not candidates for myelosuppressive chemotherapy. In addition, many patients will relapse and require subsequent therapies.[2] Inhibitors of the B-cell receptor (BCR) pathway represent an attractive option to fill this need for subsequent therapy.

Inhibitors of the BCR

BCR activation is known to play a crucial role in the pathogenesis of CLL. The BCR consists of transmembrane receptors, including phosphatidylinositol (4,5)-bisphosphate and phosphatidylinositol (3,4,5)-triphosphate. Upon binding of antigen, BCR signaling induces Lyn- and Syk-dependent phosphorylation of tyrosine motifs, including phosphoinositide 3-kinase delta (PI3Kδ) and Bruton tyrosine kinase (BTK). There are many potential targets for inhibition of the BCR pathway. Agents targeting BTK and PI3K are currently available, and several small-molecule tyrosine kinase inhibitors are in development.[3]

Redistribution lymphocytosis

As a class effect, all inhibitors of the BCR appear to cause redistribution lymphocytosis. During the first few weeks of therapy, these agents can cause transient lymphocytosis due to redistribution of CLL cells from the tissue to peripheral blood.[4] Normally, these tumor cells circulate in the peripheral blood, where they are attracted to tissue stromal cells by a chemokine gradient. The CXCL12-CXCR4 axis is the predominant one for marrow homing. Inhibition of these homing mechanisms by the BTK inhibitor ibrutinib leads to the movement of CLL tumor cells from tissue sites into the peripheral blood, resulting in increased lymphocytosis. Lymphocytosis occurs concomitantly with reduction in lymph node size.[4] The transient lymphocytosis should not be confused with disease progression and should not lead to discontinuation of the drug.

Since, as a drug class, BCR inhibitors are known to cause lymphocytosis, many patients do not meet response criteria defined in the 2008 International Workshop on Chronic Lymphocytic Leukemia (IWCLL) guidelines,[5] despite clear and substantial clinical benefit. Thus, the IWCLL guidelines have been adjusted to define an initial response category called partial response with lymphocytosis (PRL), thereby ensuring that patients with a partial response (PR) who have persistent lymphocytosis are considered to be responders.[6]

BTK Inhibitors

BTK is a cytoplasmic tyrosine kinase that is essential to BCR signaling; it couples BCR-induced calcium release to activation of the nuclear factor–kappaB pathway and cellular proliferation. X-linked agammaglobulinemia (also called Bruton agammaglobulinemia), which typically presents during childhood, is characterized by an absence of mature B cells and immunoglobulins, and leads to recurrent bacterial infections. Loss-of-function mutations in the BTK gene block B-cell maturation at the pre–B-cell stage.[7]

Ibrutinib

Ibrutinib is the first BTK inhibitor studied in clinical trials; it inactivates BTK through the formation of an irreversible covalent bond with Cys-481 in the ATP binding domain.[8] Ibrutinib is also known to inhibit other kinases-including interleukin-2–inducible T-cell kinase, TEC, BMX, and epidermal growth factor receptor, which may explain some of the toxicities seen with this agent. Ibrutinib is approved by the US Food and Drug Administration (FDA) for use as initial therapy for patients with CLL, as well as for the treatment of relapsed disease.

Byrd et al reported the outcomes of 101 patients with relapsed/refractory CLL who were treated with ibrutinib.[9,10] The median age of patients was 64 years (range, 37 to 82 years). Thirty-four percent of the patients had 17p deletion, and 78% had unmutated IgVH. The median number of prior regimens was four. The ORR was 90%, with a CR rate of 7%. The estimated rate of progression-free survival (PFS) at 30 months in this heavily pretreated group was 69%. The median PFS durations in patients with 17p deletion and 11q deletion were 28 months and 38.7 months, respectively. While these results are a significant improvement over prior experience with chemotherapy regimens in this high-risk group, PFS times are clearly shorter in patients with 17p deletion. The most common toxicity was diarrhea, which occurred in 55% of patients and was predominantly grade 1 or 2. Notable grade 3/4 toxicities included bleeding (8%) and atrial fibrillation (6%).

In a randomized trial comparing ibrutinib with ofatumumab in previously treated patients with CLL, improved PFS and OS rates were demonstrated in the patients treated with ibrutinib.[11] At 12 months, the OS rate was 90% in the ibrutinib arm vs 81% in the ofatumumab arm. The ORR was 43% with ibrutinib vs 4% with ofatumumab.

Patients with CLL and 17p deletion typically have aggressive disease and respond poorly to chemotherapy regimens.[12] A recent report described the outcomes of 144 patients with 17p deletion who had failed to respond to at least one therapy and were treated with ibrutinib at 420 mg daily until disease progression.[13] The median number of prior therapies was two, with a range of one to seven prior therapies. At a median follow-up of 13 months, the median PFS had not been reached. At 12 months, 79% of patients were alive and progression-free and 88% of the responders were progression-free. Progressive disease was reported in 13% of patients; 7% of patients developed Richter’s transformation, and 7 of those cases occurred within the first 24 weeks of therapy. The most frequent adverse events were diarrhea in 36% (grade 3/4 in 2%), fatigue in 30% (grade 3/4 in 1%), cough in 24% (grade 3/4 in 1%), and arthralgia in 22% (grade 3/4 in 1%). Another report described 51 patients with CLL and 17p deletion who were treated with ibrutinib.[14] At 24 weeks, 80% of patients had an objective response: 40% had a PR, 40% had a PRL, and the remaining 20% had stable disease. The adverse effects were similar to those seen in previous reports.

The frontline trial leading to approval of ibrutinib as initial therapy randomized 269 patients 65 years of age or older to receive either ibrutinib or chlorambucil.[15] With a median follow-up of 18.4 months, the median PFS was not reached in patients treated with ibrutinib and was 18.9 months in patients treated with chlorambucil. The 24-month OS rate was 98% with ibrutinib vs 85% with chlorambucil.

Toxicity. The incidence of bleeding with ibrutinib was found to be increased. In the phase I/II studies, bruising was seen in 17% of patients, and 2% had intracranial hemorrhage.[16] Subsequent trials with ibrutinib have excluded patients on warfarin therapy. In the phase III trial of ibrutinib vs ofatumumab, the bleeding rates were 44% with ibrutinib and 12% with ofatumumab, but the rates of serious bleeding were low, at 1% vs 2%, respectively.[11] In an earlier analysis, the bleeding events with ibrutinib were attributed to effects on collagen receptor glycoprotein VI and on von Willebrand–dependent platelet functions.[17] However, a more recent analysis attributes the bleeding to inhibition of collagen-dependent platelet aggregation by ibrutinib.[18]

The incidence of atrial fibrillation is also increased with ibrutinib. In the phase III trial of ibrutinib vs ofatumumab, 10 patients in the ibrutinib arm developed atrial fibrillation vs only 1 patient in the ofatumumab arm. This led to discontinuation of ibrutinib in 1 patient.[11]

Finally, as with other BCR inhibitors, ibrutinib causes lymphocytosis. This generally resolves after 6 to 9 months of continued treatment. Approximately 20% of patients have prolonged lymphocytosis (lasting more than 12 months) with ibrutinib therapy. Development of lymphocytosis does not appear to have a detrimental impact on long-term clinical outcomes.[19]

Ibrutinib resistance. Heavily pretreated patients who fail to respond to treatment with ibrutinib have a poor clinical outcome. A previous report described treatment results for 33 patients (26% of 127 enrolled) in clinical trials of ibrutinib at the University of Texas MD Anderson Cancer Center who discontinued the drug.[20] The majority of these patients had known high-risk features, including 94% with unmutated IgVH, 58% with 17p deletion by fluorescence in situ hybridization, and 54% with complex karyotypes. The reasons for discontinuation of ibrutinib included disease transformation in 7%, progressive disease in 7%, and adverse events in 11%; 3% of the patients underwent stem cell transplantation. Seventy-six percent of the patients died after discontinuing treatment with ibrutinib, with a median OS after discontinuation of only 3 months; all who had discontinued ibrutinib had aggressive disease and were heavily pretreated. A recent analysis demonstrated that this does not hold true for patients treated with ibrutinib earlier in their disease course; outcomes in treatment-naive patients from the randomized, multicenter, phase III RESONATE-2 trial of ibrutinib in CLL were compared with those of patients who had received several lines of therapy prior to treatment with ibrutinib.[21] The median OS post ibrutinib therapy in patients who received ibrutinib as first-line or second-line therapy was not reached. The median OS in patients treated with ibrutinib as third-line therapy or beyond was only 7 to 9 months. Therefore, patients who received ibrutinib as first- or second-line therapy were less likely to progress, and they had better post-ibrutinib survival outcomes. Mutations in BTK at the binding site of ibrutinib have been described in patients who developed resistance while receiving ibrutinib therapy.[22] Cysteine-to-serine amino acid replacement in BTK at position 481 (C481S) was seen in 5 patients. The C481S mutation elicits BTK-independent activation after B-cell receptor activation.[23] Two patients had mutations in the phospholipase Cγ2 (PLCγ2) gene, a kinase downstream of BTK; one was at position 665 (R665W) and the other at L845F, leading to gain-of-function mutations that increased the risk of autonomous B-cell receptor activity. Kinases proximal to Syk and Lyn would be critical for activation of mutant PLCG2, and targeting Lyn and Syk may combat molecular resistance in cell-line models, as well as in primary CLL cells from ibrutinib-resistant patients. There has also been a report of clonal evolution leading to ibrutinib resistance. One patient acquired a new clonal mutation in SF3B1 (K666T), and 2 patients had clonal deletion in chromosome 8p.[24] Other proposed mechanisms for resistance to ibrutinib and other BCR antagonists are reviewed elsewhere.[25]

Clinical data are limited regarding how to proceed after a patient has disease progression while receiving ibrutinib. Eligible patients may be considered for stem cell transplantation.[26] This group may benefit from development of other novel therapies. Because the current second-generation BTK inhibitors bind to the same binding site as ibrutinib, using them in this setting would likely not be productive. A phase I study of the duel PI3K inhibitor duvelisib included some patients who were previously treated with ibrutinib.[27] There was one PR, and 5 patients had stable disease. For further details, refer to the section on duvelisib.

Based on ex vivo data supporting the use of selinexor, an inhibitor of the nuclear protein exportin, in the setting of acquired resistance to ibrutinib, as well as synergy of this agent with ibrutinib in CLL studies in vitro,[28] a clinical trial will be investigating the combination of selinexor and ibrutinib in patients with relapsed/refractory disease (ClinicalTrials.gov identifier: NCT02303392). There are encouraging preliminary results from a phase II study of venetoclax in patients with CLL who relapsed after treatment with ibrutinib and idelalisib.[29] In this heavily pretreated group of 54 patients (who received a median of five prior regimens), 41 had received prior treatment with ibrutinib and 13 had received prior treatment with idelalisib. In the ibrutinib pretreatment group, outcomes at 24 weeks included a CR rate of 13%, a PR rate of 48%, and a stable disease rate of 13%. In the group who had been pretreated with idelalisib, the PR rate was 50% and the stable disease rate was 25%, at 24 weeks. At 36 weeks, the ORR was 61% in the ibrutinib-pretreated group and 50% in the idelalisib-pretreated group. The drug was well tolerated, but serious adverse events were seen, including pneumonia and neutropenia, each at a rate of 7%.

Second-generation BTK inhibitors

Other BTK inhibitors in earlier clinical development include ONO-4059,[30,31] acalabrutinib (ACP-196),[32,33] and BGB-3111.[34] These all covalently bind to Cys-481, with the latter two agents leading to irreversible inhibition. The purpose of developing these second-generation treatments is to have more selective binding to BTK but with fewer off-target effects, such as diarrhea, bleeding, and atrial fibrillation.

ONO-4059. This potent and selective oral BTK inhibitor has an IC₅₀ in the sub-nmol/L range. In a phase I study, it was administered to patients with relapsed/refractory CLL.[30] Of the 16 evaluable patients, high-risk cytogenetics were present in 38% with 17p deletion and in 19% with 11q deletion. Twelve of 16 patients had unmutated IgVH. Eight of 16 patients had a TP53 mutation. The median number of prior therapies was three. This inhibitor was well tolerated; grade 3 toxicities included febrile neutropenia, and there was one case of grade 4 neutropenia. The best ORR was 70%, based on IWCLL criteria. Two patients had a PR, 5 patients had PRL, 2 had stable disease, and 1 progressed with Richter transformation. The results in 60 patients with relapsed hematologic malignancies treated with ONO-4059 were recently published.[31] Of 25 patients with relapsed CLL, 24 responded to ONO-4059 and 21 patients remain on therapy. One patient had grade 3 bleeding, but no diarrhea, cardiac events, or arthralgia were reported. Follow-up studies are ongoing.

Acalabrutinib. This second-generation BTK inhibitor binds covalently to Cys-481, with improved selectivity and in vivo target coverage.[32] Acalabrutinib was able to inhibit 94% of BTK target occupancy after 7 days of dosing in patients with CLL. The results of a phase I/II multicenter study in patients with relapsed disease were recently published.[33] The 61 patients had received a median of three prior regimens, and 31% had 17p deletion. No dose-limiting toxicities were seen. At a median follow-up of 14.3 months, the ORR was 95%, including 85% with PR and 10% with PRL. The remainder (5%) had stable disease. The response rate in the patients with 17p deletion was 100%. There is an ongoing trial looking at acalabrutinib in patients with CLL with 17p deletion (ClinicalTrials.gov identifier: NCT02337829). The FDA registration phase III study randomizes previously treated patients with high-risk CLL (deletion of 17p or 11q) to acalabrutinib or ibrutinib (ClinicalTrials.gov identifier: NCT02477696).

BGB-3111. Like ibrutinib, the BTK inhibitor BGB-3111 has promising single-agent activity. However, it appears to antagonize rituximab-induced antigen-dependent cell-mediated cytotoxicity (ADCC) by inhibiting the activity of interleukin-2–inducible T-cell kinase.[35] While this is an off-target effect, it may limit the use of rituximab with ibrutinib. In murine models, use of BGB-3111 resulted in a tenfold weaker inhibition of rituximab-induced ADCC but was threefold more potent than ibrutinib in target organs.[34] A phase I study of BGB-3111 in patients with B-cell lymphoid malignancies is ongoing (ClinicalTrials.gov identifier: NCT02343120).

PI3K Inhibitors

The PI3K pathway is a key component of survival in a variety of cancers, including CLL. There are three classes of PI3K isoforms. Class I isoforms comprise two subsets: IA, which includes p110α, p110β, and p110δ, bound by regulatory domains; and IB, which consists of p110γ together with p101.[36] The p110δ isoform is abundantly expressed in CLL, and is the most important isoform in hematologic cells. Idelalisib is the first PI3K inhibitor to be approved by the FDA, in combination with rituximab in patients with relapsed CLL. PI3K inhibitors in clinical development include duvelisib and TGR-1202.

Idelalisib

Idelalisib is an oral selective reversible inhibitor of the p110δ isoform of PI3Kδ. In a phase I study of idelalisib, 72% of patients had an objective response, with a median PFS of 16 months.[37] Furthermore, at the optimal doses, PFS was 32 months. Median OS was not reached, with a 36-month OS rate of 75%. The most common grade 3/4 adverse events were pneumonia in 20%, neutropenic fever in 11%, and diarrhea in 6% of patients. At the second interim analysis of a phase III randomized clinical trial of idelalisib with rituximab vs placebo with rituximab, the addition of idelalisib to rituximab led to an ORR of 77% vs 15% with rituximab plus placebo.[37] Furthermore, in the idelalisib-plus-rituximab arm, there was a 12-month PFS rate of 66%.[38,39] Overall, the patients enrolled in this trial had less functional reserve than those in the ibrutinib trials, with decreased renal function, therapy-induced myelosuppression, or major coexisting illness. Serious adverse events occurred in 40% of patients in the idelalisib arm. The most common adverse events were pneumonia, pyrexia, and febrile neutropenia. Grade 3 or higher transaminitis occurred in 5% of patients in the idelalisib arm, with onset at 8 to 16 weeks; in these cases, the study drug was withheld, and 4 of 6 patients were successfully rechallenged. Also in the idelalisib arm, gastrointestinal and skin toxicities led to discontinuation of the drug in 6 patients. Because PI3Kδ influences clonal expansion and differentiation of suppressor T cells, diarrhea and colitis may be expected autoimmune toxicities. A phase II trial evaluated the combination of idelalisib and rituximab in previously untreated patients with CLL/small lymphocytic lymphoma (SLL) who were 65 years of age or older.[40] This combination yielded a high ORR of 97%. However, the adverse effect profile was worse in this previously untreated cohort than in relapsed/refractory patients treated with idelalisib alone. The incidence rate of transaminitis was 67%, with a 23% rate of grade 3 or higher toxicity. Diarrhea or colitis was reported in 64% of patients, with a 42% rate of grade 3 or higher toxicity. On the colonoscopic biopsies, T-cell infiltration was present in the patients with colitis. The authors noted that T-cell levels are typically normal in previously untreated patients with CLL but are quite low in patients with relapsed/refractory disease. This is one possible reason for the increased toxicity noted in the previously untreated group compared with the relapsed/refractory group.

These findings were confirmed in another phase II trial evaluating idelalisib in the frontline setting.[41] This trial enrolled 24 patients with newly diagnosed CLL who were treated with idelalisib for 2 months, followed by 6 months of combination therapy with idelalisib and ofatumumab. Hepatotoxicity was reported in 79% of patients, with a 54% rate of grade 3 or higher toxicity. The median time to development of transaminitis was 28 days, which was prior to initiation of the idelalisib/ofatumumab combination. The transaminitis did resolve upon withholding the drug and, in some cases, with the addition of immunosuppressants in conjunction with treatment. This study showed that the toxicity was increased in the younger patients who received frontline therapy, presumably because their immune system function is superior. Clinical trials of idelalisib in the frontline setting have been discontinued because of a higher rate of infections and death compared with control arms.

Duvelisib

Duvelisib inhibits both the p110δ and the p110γ isoforms of PI3K. It antagonizes prosurvival signals activated by BCR crosslinking in primary CLL cells[42] and causes direct killing of primary CLL cells in a dose-dependent fashion, while sparing normal B cells. Furthermore, ex vivo models suggest that duvelisib may be able to overcome ibrutinib resistance resulting from the treatment-induced BTK C481S mutation.[27]

A phase I/II study of monotherapy with duvelisib enrolled 54 heavily pretreated patients with relapsed/refractory CLL.[43] Eighty-two percent of the patients had received more than three prior lines of therapy. The median time from prior therapy was 3.5 months. Cytogenetics were poor risk; 49% of the patients harbored TP53 mutations or a 17p deletion, and 89% had unmutated IgVH. The expansion cohort enrolled patients to be treated with duvelisib at a dose of either 25 mg or 75 mg, twice daily. The best ORR was 55% in 49 evaluable patients, including 1 CR and 26 PRs. There were 21 patients with stable disease (in this study, PRL was counted as stable disease) and 1 patient with progressive disease. The ORR was independent of dose or the presence of TP53 mutation or 17p deletion. Early resolution of lymphocytosis was observed. Overall, the drug was well tolerated; adverse events included transient cytopenias, with rates of 31% neutropenia, 11% thrombocytopenia, 15% febrile neutropenia, and 11% pneumonia. Treatment was discontinued in 31% of patients due to adverse events, and in another 24% of patients because of disease progression. DUO is a phase III study in relapsed/refractory CLL that is randomizing 300 patients to either duvelisib at 25 mg twice daily, or to ofatumumab, for up to 18 cycles (ClinicalTrials.gov identifier: NCT02004522).

A cohort of patients with resistance to ibrutinib was included in the phase I study.[27] These included 6 patients with relapsed/refractory CLL and 6 with aggressive B-cell non-Hodgkin lymphoma (including 2 with diffuse large B-cell lymphoma and 4 with Richter transformation). Two patients were treated with duvelisib at 25 mg twice daily and 10 patients were treated at 75 mg twice daily. All patients had received more than three prior therapies. The median time from prior therapy to initiation of treatment with duvelisib was 0.3 months, and 67% of patients received it within 2 weeks of their therapy with ibrutinib. The patients with CLL had received a median of 4 cycles of therapy. The best response in patients with relapsed/refractory disease was 1 PR; 5 patients had stable disease. Of these 6 patients, 2 remained on treatment with duvelisib for 8 and 9 months, respectively, and 4 patients discontinued the drug due to disease progression or physician decision.

TGR-1202

TGR-1202 is a second-generation PI3Kδ inhibitor. In a phase I study, patients with relapsed/refractory hematologic malignancies received monotherapy with TGR-1202 orally once daily, following a 3+3 dose-escalation design.[44] Preliminary results were notable for PRs in 4 of the 6 patients whose CLL was treated at doses above 800 mg daily. The nodal reduction occurred rapidly and was accompanied by marked lymphocytosis. Subsequent reporting revealed that of 9 evaluable patients with CLL, 8 (89%) had a PR in the nodes; median nodal reduction was 71%, with 5 patients achieving a PR by 2008 Hallek criteria.[45] Notably, in comparison with other PI3Kδ inhibitors, there were no cases of hepatotoxicity or colitis. Rates of infection and pneumonia were low at 12% and 6%, respectively, with no febrile neutropenia reported.

Based on the encouraging phase I data, the combination of TGR-1202 and ublituximab (a glycoengineered anti-CD20 monoclonal antibody) was studied in a phase I trial following a 3+3 dose-escalation design.[46] Ublituximab was administered weekly for the first 2 cycles and then on day 1 of cycles 4, 6, 9, and 12. TGR-1202 was administered daily. There were 12 patients with CLL included in the trial. Reported toxicities were day 1 infusion reactions in 44% of patients, 41% with neutropenia, 34% with diarrhea, and 28% with nausea; no grade 3/4 toxicities were observed. There were no cases of hepatotoxicity. Among the 10 patients with CLL, median PFS was 8 months. There is ongoing enrollment in the higher-dose cohort.

Combinations of ublituximab with TGR-1202, and with ibrutinib, have also been evaluated in patients with B-cell malignancies.[47] Ublituximab was dosed at 900 mg weekly for the first 2 cycles and then on day 1 of cycles 4, 6, 9, and 12. TGR-1202 was dose-escalated at 400, 600, 800, and 1,200 mg, while the ibrutinib dose was held stable at 420 mg for patients with CLL and at 560 mg for patients with non-Hodgkin lymphoma. Three patients with CLL and SLL were included. The ORR was 86%, with 2 of 3 patients with CLL/SLL responding. Twenty percent of patients had day 1 infusion reactions (none were grade 3 or 4); 20% of patients had grade 3 or 4 neutropenia; and 30% experienced diarrhea, constipation, or fatigue, with no grade 3 or 4 events. Based on these findings, phase II studies are planned.

Venetoclax

Tumor cells of patients with CLL express high levels of antiapoptotic proteins, such as B-cell lymphoma 2 (BCL-2), which make them resistant to senescence and death. In a phase I trial of the oral BCL-2 inhibitor venetoclax, 56 patients with relapsed CLL were treated in the dose-escalation cohort.[48] Clinical tumor lysis syndrome was diagnosed in 3 of these patients, with 1 patient death. Adjustments were then made in the dose-escalation schema, doses of tumor lysis syndrome prophylaxis were increased, and initial hospitalization was required for patients to receive treatment; the subsequent 60 patients treated with venetoclax tolerated the drug well. There was a 79% ORR, with a 20% rate of CRs. The 15-month PFS rate was 69% in the 400-mg cohort. Other side effects were mild diarrhea (52%), upper respiratory tract infection (48%), nausea (47%), and grade 3 or 4 neutropenia (41%). In a phase II trial, 107 patients with relapsed or refractory CLL with 17p deletion were treated with venetoclax.[49] At a median follow-up of 12 months, the ORR was 85%. The most common grade 3/4 adverse events were neutropenia (40%), infection (20%), anemia (18%), and thrombocytopenia (15%). Serious adverse events included pyrexia (7%), autoimmune hemolytic anemia (7%), pneumonia (6%), and febrile neutropenia (5%). These results led to the recent FDA approval of venetoclax for the treatment of patients with relapsed or refractory CLL and 17p deletion.

New Monoclonal Antibodies Directed Against CD20

Obinutuzumab

Obinutuzumab is a CD20 monoclonal antibody with a glycoengineered Fc portion, an alteration yielding enhanced ADCC, increased direct cell death, and lower complement-dependent cytotoxicity compared with rituximab.[50] The German CLL11 trial randomized 781 previously untreated patients with CLL and comorbidities to receive chlorambucil monotherapy, chlorambucil with rituximab, or chlorambucil with obinutuzumab. The combination of chlorambucil and obinutuzumab provided an improved PFS compared with chlorambucil alone (26.7 vs 11.1 months; P < .001).[51] Patients treated with the combination of chlorambucil and obinutuzumab also showed an improved PFS compared with those randomized to chlorambucil plus rituximab (median, 26.7 vs 16.3 months; P < .001). Chlorambucil and obinutuzumab produced a higher ORR compared with that reported for chlorambucil and rituximab (78.4% vs 65.1%; P < .001). These results led to FDA approval of the combination of chlorambucil and obinutuzumab for patients with previously untreated CLL not suitable for more aggressive chemoimmunotherapy. In a recent update, patients treated with chlorambucil and obinutuzumab had longer PFS compared with a regimen of chlorambucil and rituximab (29.2 vs 15.4 months; P < .001).[52] However, no OS difference was noted between the two study arms.

Ofatumumab

Ofatumumab is a CD20 monoclonal antibody that binds to a unique epitope that is distinct from the epitope recognized by rituximab. Ofatumumab produces more complement-dependent cytotoxicity than is seen with rituximab. When ofatumumab was used as a single agent in patients with relapsed or refractory CLL, the ORR was 45%, with a median PFS of 5 months.[53] Based on these results, ofatumumab was approved for patients with CLL refractory to fludarabine and alemtuzumab.

Ofatumumab has been combined with chlorambucil as first-line therapy (in the COMPLEMENT-1 trial) for CLL.[54] The combination of chlorambucil and ofatumumab significantly improved the ORR compared with chlorambucil monotherapy (82% vs 69%; P < .001). The combination also improved PFS compared with chlorambucil alone (median PFS, 22.4 vs 13.1 months; P < .001). Although this regimen is generally well tolerated, common side effects are infusion reactions and neutropenia. Based on these results, treatment with chlorambucil plus ofatumumab was approved for first-line treatment of patients with CLL for whom fludarabine-based therapy is considered inappropriate.

Ublituximab

Finally, ublituximab is a chimeric immunoglobulin G1 monoclonal antibody that targets a unique epitope on CD20. In a phase I trial, ublituximab demonstrated a 67% ORR in patients with relapsed/refractory CLL.[55] The combination of ublituximab and ibrutinib is being investigated. Based on an initial report of 20 patients with high-risk CLL, the ORR is 95%.[56] Final results of this trial have not yet been reported.

Summary

The advanced age of the average patient with CLL often makes administration of chemoimmunotherapy difficult. Therefore, there is an urgent need for new therapies in this population. Novel therapies are also needed for patients who fail to respond to chemoimmunotherapy. Although B-cell receptor inhibitors are promising agents, as a class of medications they have some unique side effects, including redistribution lymphocytosis. Redistribution lymphocytosis is not evidence of disease progression and is not associated with an inferior outcome. It is related to asymptomatic redistribution of lymphocytes from lymph nodes to the bloodstream. Ibrutinib has some novel toxicities, including increased risks of bleeding and atrial fibrillation. Idelalisib also has some distinct toxicities, including transaminitis, pneumonitis, and colitis. The BCL-2 inhibitor venetoclax is an effective treatment for patients with relapsed CLL and 17p deletion; however, use of this agent requires careful patient monitoring for tumor lysis syndrome. It is critical to continue to refer patients to clinical trials, in order to advance our knowledge regarding the optimal use of these targeted agents.

Financial Disclosure:Dr. O'Brien is a consultant to Amgen, Celgene, GSK, and Janssen; and she receives research support from Acerta, Gilead, Pharmacyclics, ProNAi, Regeneron, and TG Therapeutics. Dr. Jeyakumar has no significant interest in or other relationship with the manufacturer of any product or provider of any service mentioned in this article.

References:

1. National Cancer Institute Surveillance, Epidemiology, and End Results Program. SEER stat fact sheets: chronic lymphocytic leukemia (CLL). http://seer.cancer.gov/statfacts/html/clyl.html. Accessed October 9, 2016.

2. Tam CS, O’Brien S, Wierda W, et al. Long-term results of fludarabine, cyclophosphamide, and rituxan regimen as initial therapy of chronic lymphocytic leukemia. Blood. 2008;112:975-80.

3. Wiestner A. BCR pathway inhibition as therapy for chronic lymphocytic leukemia and lymphoplasmacytic lymphoma. Hematology Am Soc Hematol Educ Program. 2014;2014:125-34.

4. Woyach JA, Smucker K, Smith LL, et al. Prolonged lymphocytosis during ibrutinib therapy is associated with distinct molecular characteristics and does not indicate a suboptimal response to therapy. Blood. 2014;123:1810-7.

5. 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;111:5446-56.

6. Cheson BD, Byrd JC, Rai KR, et al. Novel targeted agents and the need to refine clinical end points in chronic lymphocytic leukemia. J Clin Oncol. 2012;30:2820-2.

7. Singh J, Petter RC, Kluge AF. Targeting covalent drugs of the kinase family. Curr Opin Chem Biol. 2010;14:475-80.

8. Dubovsky JA, Beckwith KA, Natarajan G, et al. Ibrutinib is an irreversible molecular inhibitor of ITK driving a Th-1-selective pressure in T lymphocytes. Blood. 2013;122:2539-49.

9. 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.

10. Byrd JC, Furman RR, Coutre SE, et al. Three-year follow-up in treatment-naïve and previously treated patients with CLL and SLL receiving single-agent ibrutinib. Blood. 2015;125:2497-506.

11. Byrd JC, Brown JR, O’Brien S, et al. Ibrutinib versus ofatumumab in previously treated chronic lymphoid leukemia. N Engl J Med. 2014;371:213-23.

12. Stephens DM, Byrd JC. Chronic lymphocytic leukemia with del(17p13.1): a distinct clinical subtype requiring novel treatment approaches. Oncology (Williston Park). 2012;26:1044-54.

13. O’Brien SM, Jones JA, Coutre S, et al. Efficacy and safety of ibrutinib in patients with relapsed or refractory chronic lymphocytic leukemia or small lymphocytic leukemia with 17p deletion: results from the phase II RESONATEtm-17 trial. Blood. 2014;124:327.

14. Farooqui MZ, Valdez J, Martyr S, et al. Ibrutinib for previously untreated and relapsed or refractory chronic lymphocytic leukemia with TP53 aberrations: a phase 2 single arm trial. Lancet Oncol. 2015;16:169-76.

15. Burger JA, Tedeschi A, Barr PM, et al. Ibrutinib as initial therapy for patients with chronic lymphocytic leukemia. N Engl J Med. 2015;373:2425-37.

16. Advani RH, Buggy JJ, Sharman JP, et al. Bruton tyrosine kinase inhibitor ibrutinib (PCI-32765) has significant activity in patients with relapsed/refractory B-cell malignancies. J Clin Oncol. 2013;31:88-94.

17. Levade M, David E, Garcia C, et al. Ibrutinib treatment affects collagen and von Willebrand factor-dependent platelet functions. Blood. 2014;124:3991-5.

18. Kamel S, Horton L, Ysebaert L, et al. Ibrutinib inhibits collagen-mediated but not ADP-mediated platelet aggregation. Leukemia. 2015;29:783-7.

19. Herman SE, Niemann CU, Farooqui M, et al. Ibrutinib-induced lymphocytosis in patients with chronic lymphocytic leukemia: correlative analysis from phase II study. Leukemia. 2014;28:2188-96.

20. Jain P, Keating M, Wierda W, et al. Outcomes of patients with chronic lymphocytic leukemia after discontinuing ibrutinib. Blood. 2015;125:2062-7.

21. O’Brien SM, Byrd JC, Hillmen P, et al. Outcomes with ibrutinib by line of therapy in patients with CLL: analyses from phase III data. J Clin Oncol. 2016;34(suppl):abstr 7520.

22. Woyach JA, Furmann RR, Liu TM, et al. Resistance mechanisms for the Bruton’s tyrosine kinase inhibitor ibrutinib. N Engl J Med. 2014;270:2286-94.

23. Liu TM, Woyach JA, Zhong Y, et al. Hypermorphic mutation of phospholipase C, γ2 acquired in ibrutinib-resistant CLL confer BTK independency upon B cell receptor activation. Blood. 2015;126:61-8.

24. Landau D, Hoellenriegel J, Sougnez C, et al. Clonal evolution in patients with chronic lymphocytic leukemia (CLL) developing resistance to BTK inhibition. Blood. 2013;122:866.

25. Woyach JA, Johnson AJ. Targeted therapies in CLL: mechanisms of resistance and strategies for management. Blood. 2015;126:471-7.

26. Daver N, Cortes J, Ravandi F, et al. Secondary mutations as mediators of resistance to targeted therapy in leukemia. Blood. 2015;125:3236-45.

27. Porcu P, Flinn I, Kahl BS, et al. Clinical activity of duvelisib (IPI-145), a phosphoinositide-3-kinase-δ/γ inhibitor in patients previously treated with ibrutinib. Blood. 2014;124:3335.

28. Hing ZA, Mantle R, Beckwith KA, et al. Selinexor is effective in acquired resistance to ibrutinib and synergizes with ibrutinib in chronic lymphocytic leukemia. Blood. 2015;125:3128-32.

29. Jones J, Mato AR, Coutre S, et al. Preliminary results of phase 2 open-label study of venetoclax (ABT-199/GDC-0199) monotherapy in patients with CLL relapsed after or refractory to ibrutinib or idelalisib therapy. Blood. 2015;126:715.

30. Sales G, Karlin L, Rule S, et al. A phase I study of oral BTK inhibitor ONO-4059 in patients with relapsed/refractory or high-risk chronic lymphocytic leukemia (CLL). Blood. 2013;122:676.

31. Walters HS, Rule SA, Dyer MJ, et al. A phase 1 clinical trial of the selective BTK inhibitor ONO/GS-4059 in relapsed and refractory mature B-cell malignancies. Blood. 2016;127:411-9.

32. Covey T, Barf T, Gulrajani M, et al. ACP-196: a novel covalent Bruton’s tyrosine kinase (BTK) inhibitor with improved selectivity and in vivo target coverage in chronic lymphocytic leukemia. Cancer Res. 2015;75(suppl 15):abstr 2596.

33. Byrd JC, Harrington B, O’Brien S, et al. Acalabrutinib (ACP-196) in relapsed chronic lymphocytic leukemia. N Engl J Med. 2016;374:323-32.

34. Li N, Sun Z, Liu Y, et al. BGB-311 is a novel and highly selective Bruton’s tyrosine kinase (BTK) inhibitor. Cancer Res. 2015;75:abstr 2597.

35. Kohrt HE, Sagiv-Barfi I, Rafiq S, et al. Ibrutinib antagonizes rituximab-dependent NK cell-mediated cytotoxicity. Blood. 2014;123:1957-60.

36. Herman SE, Gordon AL, Wagner AJ, et al. Phosphatidylinositol 3-kinase-δ inhibitor CAL-101 shows promising preclinical activity in chronic lymphocytic leukemia by antagonizing intrinsic and extrinsic cellular survival signals. Blood. 2010;116:2078-88.

37. Brown JR, Byrd JC, Coutre SE, et al. Idelalisib, an inhibitor of phosphatidylinositol 3-kinase p110δ, for relapsed/refractory chronic lymphocytic leukemia. Blood. 2014;123:3390-7.

38. Furman RR, Sharman JP, Coutre SE, et al. Idelalisib and rituximab in relapsed chronic lymphocytic leukemia. N Engl J Med. 2014;370:997-1007.

39. Sharman JP, Coutre SE, Furman RR, et al. Second interim analysis of a phase 3 study of idelalisib (Zydelig) plus rituximab for relapsed chronic lymphocytic leukemia: efficacy analysis in patient subpopulations with del(17p) and other adverse prognostic factors. Presented at the American Society of Hematology Annual Meeting; December 8, 2014; San Francisco, California. Abstract 330.

40. O’Brien S, Lamanna N, Kipps TJ, et al. A phase 2 study of idelalisib plus rituximab in treatment-naïve older patients with chronic lymphocytic leukemia. Blood. 2015;126:2686-94.

41. Lampson BL, Kasar SN, Matos TR, et al. Idelalisib given front-line for treatment of chronic lymphocytic leukemia causes frequent immune-mediated hepatotoxicity. Blood. 2016;128:195-203.

42. Dong S, Guinn D, Dubovsky JA, et al. IPI-145 antagonizes intrinsic and extrinsic survival signals in chronic lymphocytic leukemia cells. Blood. 2014;124:3583-6.

43. O’Brien S, Patel M, Kahl BS, et al. Duvelisib (IPI-145), a PI3Kδ,γ inhibitor, is clinically active in patients with relapsed/refractory chronic lymphocytic leukemia. Blood. 2014;124:3334.

44. Burris HA, Patel MA, Lanasa MC, et al. Activity of TGR-1202, a novel once-daily PI3Kδ inhibitor in patients with relapsed and refractory hematologic malignancies. J Clin Oncol. 2014;32(suppl 5s):abstr 2513.

45. Burris HA, Patel MR, Brander DM, et al. TGR-1202, a novel once daily PI3Kδ inhibitor, demonstrates clinical activity with a favorable safety profile, lacking hepatotoxicity, in patients with chronic lymphocytic leukemia and B cell lymphoma. Blood. 2014;124:1984.

46. Lunning MA, Vose J, Fowler NH, et al. Ublituximab plus TGR-1202 activity and safety profile in relapsed/refractory B-cell NHL and high risk CLL. J Clin Oncol. 2015;33(suppl):abstr 8548.

47. Flower NH, Nastoupil LJ, Lunning MA, et al. Safety and activity of the chemotherapy-free triplet of ublituximab, TGR-1202 and ibrutinib in relapsed B cell malignancies. J Clin Oncol. 2015;33(suppl):abstr 8501.

48. Roberts AW, Davids MS, Pagel JM, et al. Targeting BCL2 with venetoclax in relapsed chronic lymphocytic leukemia. N Engl J Med. 2016;374:311-22.

49. Stilgenbauer S, Eichhorst B, Schetelig J, et al. Venetoclax in relapsed or refractory chronic lymphocytic leukemia with 17p deletion: a multicenter, open-label, phase 2 study. Lancet Oncol. 2016;17:768-78.

50. Herter S, Herting F, Mundigl O, et al. Preclinical activity of the type II CD20 antibody GA101 (obinutuzumab) compared with rituximab and ofatumumab in vitro and in xenograft models. Mol Cancer Ther. 2013;12:2031-42.

51. Goede V, Fischer K, Busch R, et al. Obinutuzumab plus chlorambucil in patients with CLL and coexisting conditions. N Engl J Med. 2014;370:1101-10.

52. Goede V, Fischer K, Engelke A, et al. Obinutuzumab as frontline treatment of chronic lymphocytic leukemia: updated results of the CLL11 study. Leukemia. 2015;29:1602-4.

53. Österborg A, Jewell RC, Padmanabhan-Iyer S, et al. Ofatumumab monotherapy in fludarabine-refractory chronic lymphocytic leukemia: final results from a pivotal study. Haematologica. 2015;100:e311-e314.

54. Hillmen P, Robak T, Janssens A, et al. Chlorambucil plus ofatumumab versus chlorambucil alone in previously untreated patients with chronic lymphocytic leukemia (COMPLEMENT 1): a randomized multicenter, open-label phase 3 trial. Lancet. 2015;385:1873-83.

55. O’Connor OA, Schreeder MT, Deng C, et al. Ublituximab (TG-1101), a novel anti-CD20 monoclonal antibody for rituximab relapsed/refractory B cell malignancies. Presented at the Congress of the European Hematology Association (EHA); June 12-14, 2014; Milan, Italy. Abstract P444.

56. Sharman J, Farber CM, Mahadevan D, et al. Ublituximab (TG-1101), a novel glycoengineered anti-CD20 mAb, in combination with ibrutinib achieves 95% ORR in patients with high-risk relapsed/refractory CLL. Presented at the 13th International Congress on Malignant Lymphoma; June 17-20, 2015; Lugano, Switzerland. Abstract 105.