An ongoing phase II trial is testing whether combined treatment with ibrutinib and FCR (iFCR) will lead to deep and durable remissions and possibly cure in younger TN CLL patients.88 Patients are initially treated with ibrutinib for 1 week to mobilize CLL cells out of the lymph nodes into the blood, where they are more vulnerable, and then they receive 6 months of iFCR followed by 2 years of ibrutinib maintenance. Preliminary results are promising, as iFCR induced deep responses even though a significant part of the patients had adverse prognostic markers.88 Another phase II trial (NCT02629809) is investigating the possibility to limit chemotherapy to 3 cycles, potentially reducing short- and long-term toxicity, while maintaining efficacy through replacing rituximab with obinutuzumab.88 This trial includes only patients with mutated IGHV and no del(17p) or TP53 mutation. If the patients achieve CR with undetectable MRD in the bone marrow after 3 courses of iFCG, they receive ibrutinib with obinutuzumab (iG) for cycles 4 to 6, then ibrutinib only for cycles 7 to 12. Patients not achieving the primary endpoint receive iG for cycles 4 to 12. All patients with undetectable MRD at 1 year stop all therapy. Promising preliminary results have already been disclosed.88
Apart from the practice-changing ECOG-ACRIN E1912, A041202, and iLLUMINATE trials (see above in the main ibrutinib section), there are other ongoing studies that aim to assess the effectiveness of combined treatment with ibrutinib and anti-CD20 antibodies. The phase III FLAIR trial comparing IR with FCR is evaluating an MRD-based rule for stopping therapy, as the current standard practice of continuous use of ibrutinib imposes a significant financial and toxicological cost.89 The protocol of the trial was recently amended to include two additional treatment arms: ibrutinib monotherapy and ibrutinib plus venetoclax. Ibrutinib was also combined with ofatumumab in a phase Ib/II trial with CLL patients who had failed ≥2 prior therapies and most of whom had high-risk disease.90 Three different administration schedules were tested: (1) ibrutinib lead-in, (2) concurrent start, and (3) ofatumumab lead-in. The ORRs were 100%, 79%, and 71%, and the estimated 12-month PFS was 89%, 85%, and 75% in groups 1, 2, and 3, respectively. Ibrutinib-induced lymphocytosis resolved fast, an effect also observed with IR.91 However, ibrutinib increased the occurrence of mild neuropathy previously associated with ofatumumab.90 The phase II CLL2-BIO and CLL2-BIG trials follow the so-called “sequential triple-T” concept92: initial debulking with bendamustine (to decrease the risk of infusion-related reactions and to help achieve remissions faster) followed by induction and maintenance with ibrutinib-ofatumumab or ibrutinib-obinutuzumab.93 Maintenance treatment is terminated in case of a CR and MRD-negativity. Similar to the FLAIR trial, these trials will elucidate whether ibrutinib can be stopped in case of a deep remission.93
Pretreating CLL cells with ibrutinib increases their dependence on BCL-2, thus enhancing apoptosis in response to venetoclax.76 The 2 drugs have different mechanisms of action and toxicity profiles, and they complement each other regarding their activity on disease compartments (ibrutinib is particularly effective at clearing nodal disease and less so at clearing blood/marrow, whereas the opposite is true for venetoclax). Also, venetoclax is able to induce MRD-negativity, and combined treatment of CLL with ibrutinib and venetoclax thus seems very promising.76 The ongoing phase II CLARITY, CAPTIVATE, and NCT02756897 trials investigate the safety and efficacy of this combination. Preliminary results are encouraging (eg, 100% CR rate and 82% MRD-negativity in peripheral blood after 6 cycles of the combination in the CAPTIVATE trial94) and further data should clarify whether therapy can be safely stopped in patients achieving deep remission.88 Other phase II clinical trials will evaluate the combination in patients with R/R CLL (NCT03226301 and NCT03045328), high-risk CLL (NCT03128879), or CLL with ibrutinib resistance mutations (NCT03513562). Additionally, a phase III study is planned to compare ibrutinib-venetoclax against chlorambucil-obinutuzumab in elderly or otherwise unfit patients with TN CLL (NCT03462719). A strategy to achieve even deeper remissions is triple therapy with ibrutinib, venetoclax, and obinutuzumab, and this regimen is currently being evaluated in TN CLL (trials NCT02427451, NCT02758665/CLL2-GIVe, and NCT02950051/CLL13).
In a phase III trial with R/R CLL patients, addition of idelalisib to the standard BR regimen improved the ORR from 45% to 70% and increased the median PFS from 11.1 to 20.8 months.95 However, increased rate of serious AEs and efficacy similar to that of idelalisib-rituximab96 reduce the practical value of the triple combination.
The ongoing phase II CLL2-BCG trial is using initial debulking with bendamustine followed by induction and maintenance with idelalisib-obinutuzumab.93 This study should elucidate whether treatment with idelalisib can be terminated in case of a deep remission.
Deep and durable responses with unprecedented MRD-negativity rates were observed in a phase Ib trial testing the combination of venetoclax with obinutuzumab in patients with TN CLL: 100% ORR, 56.3% CR, 100% MRD-negativity in blood, 100% PFS rate at 12 months, and 90.5% PFS rate at 18 months.97 The high effectiveness of this combination is confirmed by the recently published primary endpoint analysis of the phase II CLL2-BAG trial (initial debulking with bendamustine followed by induction and maintenance with venetoclax-obinutuzumab according to the sequential triple-T concept92).98 The ORR at the end of the induction phase of this study was 95% (100% and 90% in the TN and R/R cohorts, respectively) and the MRD-negativity rate in peripheral blood was 87% (91% and 83%, respectively). The trial did not reveal unexpected or cumulative toxicities. The venetoclax-obinutuzumab combination induced good responses also in elderly patients with TN CLL and coexisting medical conditions and is currently being tested in the phase III CLL14 trial against the standard chlorambucil-obinutuzumab regimen.99 Cumulative evidence suggests that venetoclax-obinutuzumab might be one of the most efficacious treatment regimens for CLL but completion of the ongoing phase III trials will be necessary before more definitive statements about its future role in CLL therapy can be made.
Otlertuzumab (TRU-016) is a fully humanized homodimeric therapeutic protein consisting of antibody-derived single-chain variable fragments (scFv) specific for CD37 that are linked to immunoglobulin constant domains.105 Its binding to CD37 leads to ADCC and apoptosis induction through upregulation of BIM.106 Otlertuzumab does not induce CDC. In a phase II study, addition of otlertuzumab led to higher ORR (69%) and longer median PFS (15.9 months) compared to bendamustine alone (39% and 10.2 months, respectively) in patients with R/R CLL.105 An ongoing phase Ib study (NCT01644253) is evaluating the efficacy and safety of otlertuzumab in combination with either rituximab, obinutuzumab, ibrutinib, or idelalisib-rituximab.
Acalabrutinib (ACP-196) is a second-generation irreversible BTK inhibitor with higher selectivity than ibrutinib.56 It also binds to the C481 residue in BTK but is only a weak inhibitor of TEC and does not inhibit EGFR and ITK, thus having fewer adverse effects.57,107 Acalabrutinib was recently approved by the FDA for treatment of mantle cell lymphoma. Some of the ongoing clinical trials with acalabrutinib in CLL include: a phase II study evaluating its safety and efficacy in patients with R/R CLL who do not tolerate ibrutinib (NCT02717611); a phase III trial of acalabrutinib versus ibrutinib in patients with high-risk R/R CLL (NCT02477696); a phase III trial comparing acalabrutinib versus acalabrutinib-obinutuzumab versus chlorambucil-obinutuzumab in TN older patients (NCT02475681); a phase III trial comparing acalabrutinib versus idelalisib-rituximab versus BR in patients with R/R CLL (NCT02970318).45
Zanubrutinib (BGB-3111) is another irreversible BTK inhibitor that binds covalently to C481 and that is more selective than ibrutinib.45 Preliminary data from phase I trials suggest that zanubrutinib has favorable safety profile and clinical activity, alone or in combination with obinutuzumab, in patients with B-cell lymphoid malignancies, including CLL.108 A phase II clinical study in patients with R/R CLL is ongoing (NCT03206918) and a recently launched phase III trial will compare zanubrutinib versus BR as first-line therapy for CLL (NCT03336333).
Tirabrutinib (ONO/GS-4059) is yet another irreversible BTK inhibitor that is more selective than ibrutinib, although it can also inhibit the TEC kinase.45 Data from a phase I study show efficacy of tirabrutinib in patients with R/R CLL, with estimated median PFS and OS of 38.5 and 44.9 months, respectively.109,110 The most frequent grade ≥3 AES were infections (42.9%), neutropenia (25%), thrombocytopenia (14.3%), anemia (10.7%), and diarrhea (7.1%). As with all other BTK inhibitors, most patients (82%) exhibited transient lymphocytosis.109 Two newly launched phase II studies in patients with R/R CLL will evaluate the safety and efficacy of tirabrutinib combined with either idelalisib or entospletinib, with or without additional obinutuzumab (NCT02968563 and NCT02983617).
Vecabrutinib (SNS-062) binds to BTK in a noncovalent manner and inhibits it regardless of the presence of the C481S mutation, thus differing from the previously mentioned compounds.45 This drug shows potential for treating ibrutinib-resistant patients with the BTK C481S mutation, although it would not be expected to overcome resistance due to activating mutations in PLCγ2.45 A phase Ib/II study was recently initiated in patients with advanced B-cell malignancies, including CLL, with or without BTK mutation (NCT03037645).
Fenebrutinib (GDC-0853) is the most selective of all BTK inhibitors currently in clinical development.111 Like vecabrutinib, it also binds to BTK in a reversible noncovalent manner regardless of the presence of C481S substitution.111 Fenebrutinib did not induce any grade ≥3 AEs in healthy subjects.112 A phase I study in patients with R/R CLL and non-Hodgkin lymphoma also showed a favorable safety profile with the most frequent grade ≥3 AEs being infections (16.7%), anemia (12.5%), and hemorrhage (8.3%).113 Despite promising results also in cases with BTK C481S, Genentech decided to stop the trial prematurely and to develop fenebrutinib for other indications.111-113
Results from clinical trials are eagerly awaited to ultimately elucidate how selectivity profiles and binding mode of BTK inhibitors influence their safety and effectiveness.
Duvelisib (IPI-145) is an orally bioavailable, highly potent small-molecule inhibitor of the p110δ and p110γ isoforms of the catalytic subunit of PI3K.114 Both isoforms are expressed mostly in leukocytes but have distinct roles115 and a dual inhibitor would be expected to have a better effect against CLL.114 A phase I study of duvelisib demonstrated an ORR of 56% and 83% in patients with R/R and TN CLL, respectively.116 As with ibrutinib and idelalisib, the vast majority of responses were partial. The median PFS was 15.7 months in the R/R CLL group and was not reached in the TN group. The most common grade 3 to 4 AEs were neutropenia (20%), increased ALT (19.5%), increased AST (15.3%), anemia (14.3%), thrombocytopenia (14.3%), diarrhea (11.4%) and pneumonia (9.5%).116 Toxicity was mostly manageable and there were differences in AE incidence between R/R and TN CLL patients, as with idelalisib. In TN patients, addition of duvelisib to FCR substantially increased MRD-negativity rate, a strong surrogate for long-term outcome in CLL.76 The phase III DUO study comparing duvelisib with ofatumumab in R/R CLL patients met its primary endpoint, showing significantly longer median PFS in the duvelisib arm (13.3 vs 9.9 months, HR 0.52), also in patients with del(17p) and/or TP53 mutation.117 The ORR was significantly higher with duvelisib (74% vs 45%). Based on these results, duvelisib was approved by the FDA in September 2018 for treatment of R/R CLL/SLL after at least 2 prior therapies. Another trial is evaluating the safety and efficacy of duvelisib in CLL patients previously treated with a BTK inhibitor (NCT03370185).
Umbralisib (TGR-1202) is a highly selective dual inhibitor of PI3Kδ and casein kinase-1ε (CK-1ε).118 It has a reduced inhibitory activity on regulatory T cells and is less hepatotoxic compared to other PI3Kδ inhibitors.108 A phase I study of umbralisib demonstrated an ORR of 85% and median PFS of 2 years in patients with R/R CLL.119 The most common grade 3 to 4 AEs were neutropenia (13%), anemia (9%), thrombocytopenia (7%), and pneumonia (6%). Occurrences of grade ≥3 increased transaminases (in 3% patients) or colitis (2%) were less frequent compared to reported with idelalisib and duvelisib, suggesting together with other observations that PI3Kδ inhibition is not invariably associated with immune-mediated toxicities and that CK-1ε inhibition has a protective effect.119 Some of the ongoing clinical trials with umbralisib include: a phase II study in CLL patients intolerant to BTK inhibitors or other PI3K inhibitors (NCT02742090); a phase III trial comparing umbralisib-ublituximab versus chlorambucil-obinutuzumab (NCT02612311); several phase I/II studies evaluating the efficacy and safety of umbralisib in various double and triple combinations with ublituximab, obinutuzumab, ibrutinib, bendamustine, and pembrolizumab (NCT02006485, NCT02535286, NCT03283137, NCT02100852, and NCT02268851). A study is planned to test umbralisib in combination with ublituximab and venetoclax in R/R CLL (NCT03379051).
Acalisib (GS-9820) and parsaclisib (INCB050465) are the most selective inhibitors of the p110δ isoform.120 Acalisib was tested in a phase Ib trial in patients with R/R lymphoid malignancies and the ORR and median PFS of CLL patients were 53.3% and 16.6 months, respectively.121 Its safety profile was similar to that of other PI3K inhibitors and the most common grade ≥3 AEs were diarrhea (10.5%), rash (10.5%), and neutropenia (7.9%).
Copanlisib is a highly potent pan-class I PI3K inhibitor with a slight preference for the p110α and p110δ isoforms and has been recently approved by the FDA for treatment of follicular lymphoma.118 In a phase II study, copanlisib demonstrated efficacy in patients with R/R CLL (38.5% ORR) and a distinct toxicity profile.122 Hepatic and gastrointestinal toxicity were less pronounced compared with idelalisib and duvelisib but postinfusion hyperglycemia and hypertension were typical AEs.122 No further trials of copanlisib in CLL have been initiated so far.
Bimiralisib (PQR309) is a dual pan-PI3K/mTOR inhibitor with preference for the p110α isoform.123 Differently from most PI3K and mTOR inhibitors, it is able to cross the blood-brain barrier. Clinical trials in patients with R/R lymphoma, including CLL, have been initiated (NCT03127020 and NCT02249429).
Results from ongoing clinical trials should define the merits of inhibiting specific isoforms of class I PI3Ks versus inhibiting all isoforms and possibly other kinases, too.
Cerdulatinib (PRT062070) is a dual inhibitor of SYK and JAK1/3 and has been shown to inhibit BCR- and IL4-induced downstream signaling in CLL cells, to overcome stromal support, and to synergize with venetoclax.124 An ongoing phase IIa study will evaluate efficacy and tolerability of cerdulatinib in patients with R/R B-cell malignancies, including CLL (NCT01994382).
TAK-659 is a dual SYK and FLT3 inhibitor that synergizes with ibrutinib against CLL cells in vitro.124 A phase I trial of TAK-659 in patients with advanced malignancies, including CLL, is ongoing (NCT02000934).
MCL-1 is constitutively overexpressed in CLL and is related to apoptosis inhibition and worse patient outcomes.128,129 Resistance to venetoclax is also largely driven by MCL-1, thus this antiapoptotic protein is a promising target in CLL.76 Inhibitors of BCR signaling tend to decrease MCL-1 levels in CLL cells, thus providing a rationale for simultaneous use with venetoclax.130,131 More specific approaches to antagonize MCL-1 function are by using the novel MCL-1 selective BH3-mimetics (A-1210477 and S63845) that are at preclinical stage of development,132,133 or by transcriptional repression via inhibition of cyclin-dependent kinase 9 (CDK9).76 Pan-CDK inhibitors like alvocidib and dinaciclib have already been tested in clinical trials in CLL and encouraging responses were observed.134,135
CLL patients develop progressive immunodeficiency, in part due to the ability of leukemia cells to induce immune suppression as a strategy to evade immune control.136 Two main classes of drugs are able to enhance immune responses against CLL cells: thalidomide analogues, also known as IMiDs, and PD-1 checkpoint inhibitors.
Lenalidomide is the most extensively studied IMiD in CLL. Its main target is the protein cereblon that as part of an E3-ubiquitin ligase complex is able to induce degradation of several target proteins.137 Through stimulating this process, lenalidomide causes a multitude of effects: upregulation of ligands and receptors on CLL cells and enhanced immune recognition; activation of T and NK cells; increase of immunoglobulins; downregulation of inhibitory ligands on T and CLL cells; changes in the microenvironment that reduce support for CLL cells.136 Two phase III trials (CLLM1 and CONTINUUM) explored lenalidomide as maintenance treatment for CLL.138,139 The CLLM1 trial was performed in patients with high-risk CLL (high MRD levels or intermediate levels combined with an unmutated IGHV or TP53 alterations) after at least a PR to first-line chemoimmunotherapy. Median PFS was 13.3 months in the placebo group and not reached with lenalidomide maintenance after 17.9 months (HR 0.168).139 The CONTINUUM trial was done in patients with at least a PR after second-line therapy. Median PFS was significantly longer in the lenalidomide group than in the placebo group (33.9 vs 9.2 months, HR 0.46) and lenalidomide maintenance did not adversely affect response to subsequent therapy.138 However, attempts to use lenalidomide as first-line therapy for CLL have not been particularly successful, as exemplified by the phase III ORIGIN trial performed in elderly patients. In this trial, lenalidomide did not prolong PFS and was associated with a lower response rate, a higher incidence of grade ≥3 AEs, and a higher number of deaths compared with chlorambucil.140 Overall, tolerability of lenalidomide in CLL is problematic and apart from the potentially fatal TLS and tumor flare reaction that can be mitigated by slow dose escalation, it also causes a high incidence of myelosuppression (grade 3–4 neutropenia was reported in up to 80% of patients and was the main cause of dose interruption), as well as venous thromboembolism.136 As BCR signaling inhibitors and venetoclax have better benefit/risk ratios, it seems that lenalidomide can find a potential use only in particular subgroups of patients, for example, as maintenance treatment after chemoimmunotherapy in high-risk patients who are not eligible or do not have access to BCR signaling inhibitors or venetoclax, or after failure of these novel drugs if clinical trials prove lenalidomide effective in this setting.
T cells from CLL patients have elevated expression of the immune checkpoint receptor PD-1 and can exhibit a pseudo-exhaustion phenotype.141 CLL cells can also express PD-1 and/or its ligands PD-L1/2. These findings as well as encouraging preclinical data142,143 provided the rationale for clinical trials of PD-1 checkpoint inhibitors in CLL. Pembrolizumab was ineffective as monotherapy in a phase II trial in R/R CLL (ORR 0%, median PFS 2.4 months) but it benefited patients with RT (ORR 44%, median PFS 5.4 months).144 Based on these results, the protocol of the trial was amended to add a focused RT cohort and a second study with RT patients was initiated (NCT02576990). Several phase I/II studies in CLL are evaluating combinations of pembrolizumab with ibrutinib (NCT03153202), fludarabine and ibrutinib (NCT03204188), umbralisib (NCT03283137), or ublituximab and umbralisib (NCT02535286). Nivolumab is another anti-PD-1 monoclonal antibody under clinical investigation in CLL as a combination partner for ibrutinib (NCT02420912).
A promising treatment option is cellular immunotherapy and especially the use of chimeric antigen receptor (CAR) T cells that are genetically modified to target specific antigens on malignant cells.145 The target most focused on is CD19, as it is expressed only on B-lineage cells.145 CTL019 cells are autologous T cells that are engineered to express a CD19-targeting CAR that has an intracellular activation domain from the CD3-zeta chain and a costimulatory domain from CD137 (4-1BB).146 In a pilot phase I study, CTL019 cells were infused in 14 patients with R/R CLL and 8 of them (57%) responded (4 CRs).147 No patient with a CR relapsed after a median follow-up of 40 months. The median PFS and OS for all treated patients were 7 and 29 months, respectively. Clinical responses correlated with in vivo expansion of the CTL019 cells.147 CTL019 cells were recently approved under the name tisagenlecleucel by the FDA for treatment of R/R B-cell acute lymphoblastic leukemia and R/R diffuse large B-cell lymphoma and thus became the first approved gene therapy. Multiple trials with tisagenlecleucel in CLL are currently ongoing. In difference to CTL019 cells, JCAR014 and JCAR017 cells are manufactured as fixed-ratio (1:1) compositions of CD4+ and CD8+ T cells.148 In addition to the CAR, JCAR014 and JCAR017 cells express also a truncated form of EGFR that can improve safety by allowing eradication of the CAR T-cell clone using anti-EGFR monoclonal antibodies like cetuximab.148 JCAR014 cells were highly effective in high-risk R/R CLL patients experiencing progression while on ibrutinib.149 At 4 weeks after infusion, the ORR in this cohort was 71%. The malignant clone could not be detected in the marrow of 58% of tested patients. The ongoing TRANSCEND-CLL-004 trial is evaluating the safety and efficacy of JCAR017 cells (under the name lisocabtagene maraleucel) in patients with R/R CLL/SLL (NCT03331198).
One of the most important adverse effects of therapy with CAR T cells is the potentially fatal cytokine release syndrome (CRS).145 CRS is often accompanied by macrophage activation syndrome that represents a hyper-inflammatory status with hemophagocytosis and very high levels of ferritin and C-reactive protein.148 Management strategies for these syndromes include supportive care and immunosuppressive therapy with anti-IL6 antibody and/or corticosteroids for more severe cases.145,148 Another common adverse effect of CAR T-cell therapy is persisting B-cell aplasia resulting in hypogammaglobulinemia that has to be managed by intravenous immunoglobulin repletion.145,147
CARs against other proteins expressed by CLL cells are also being developed. Promising targets include CD20, CD22, CD38, CD70, CD123, the kappa light chain, and ROR-1.148 Novel generations of CARs are being developed by including 2 costimulatory domains or by adding a safety mechanism (eg, suicide genes) or constitutive production of cytokines.148
The past two decades brought enormous advancements in understanding of CLL biology that incited numerous drug development programs. Novel classes of drugs (BTK inhibitors, PI3K inhibitors, and BH3-mimetics) were introduced which fundamentally changed management of CLL and considerably improved patient outcomes, especially in subgroups that previously had very poor prognosis. In parallel, new and improved anti-CD20 antibodies were developed which not only increased effectiveness of chemoimmunotherapy but are proving in multiple ongoing clinical trials as valuable combination partners of the novel BCR pathway inhibitors and BH3-mimetics. Considerable efforts are currently focused not only on further improvement of the already successful approaches, but also on making use of recent major advances in immunology like the technology to generate tumor-targeting CAR T cells. Current exciting developments promise to further limit the use of conventional broadly cytotoxic chemotherapeutic drugs and to bring curative therapy for CLL closer to reality.
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