The Up-To-Date Role of Biologics for the Treatment of Chronic Lymphocytic Leukemia

Expert Opinion on Biological Therapy

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The up-to-date role of biologics for the treatment of chronic lymphocytic leukemia

Iwona Hus , Aleksander Salomon-Perzyński & Tadeusz Robak

To cite this article: Iwona Hus , Aleksander Salomon-Perzyński & Tadeusz Robak (2020) The up-to-date role of biologics for the treatment of chronic lymphocytic leukemia, Expert Opinion on Biological Therapy, 20:7, 799-812, DOI: 10.1080/14712598.2020.1734557 To link to this article: https://doi.org/10.1080/14712598.2020.1734557

Accepted author version posted online: 22 Feb 2020. Published online: 03 Mar 2020.

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Pobrano z https://publicum.umed.lodz.pl / Downloaded from Repository of Medical University of Lodz 2021-09-26 EXPERT OPINION ON BIOLOGICAL THERAPY 2020, VOL. 20, NO. 7, 799–812 https://doi.org/10.1080/14712598.2020.1734557

REVIEW The up-to-date role of biologics for the treatment of chronic lymphocytic leukemia Iwona Husa, Aleksander Salomon-Perzyńskia and Tadeusz Robak b aDepartment of Hematology, Institute of Hematology and Transfusion Medicine, Warsaw, Poland; bDepartment of Hematology, Medical University of Lodz and Copernicus Memorial Hospital, Lodz, Poland

ABSTRACT ARTICLE HISTORY Introduction: Chronic lymphocytic leukemia (CLL) is a genetically complex disease that affects Received 28 November 2019 a heterogeneous patient population. Therapeutic armamentarium of CLL has changed recently follow- Accepted 21 February 2020 ing the introduction of novel active agents. KEYWORDS Areas covered: This review presents the current state of knowledge about biologic drugs used in the Chronic lymphocytic treatment of patients with CLL. It also discusses the biologics under evaluation in clinical trials and their leukemia; biologics; potential future perspectives. A literature review of the MEDLINE database for articles was conducted monoclonal antibodies; via PubMed. Publications from 2000 through October 2019 were scrutinized using the search terms allogeneic hematopietic monoclonal antibodies, alloHSCT, vaccines and CAR-T in conjunction with CLL. Conference proceedings stem cell transplantation; from the previous five years of the ASH and EHA Annual Scientific Meetings were searched manually. vaccines; chimeric antigen Additional relevant publications were obtained by reviewing the references from the chosen articles. receptor T-cells Expert opinion: When used in combination with chemotherapy and, more recently, with the Bcl-2 inhibitor venetoclax, anti-CD20 monoclonal antibodies (mAbs) are among the standard methods used for CLL treatment. Among the new mAbs, anti-ROR1 directed cirmtuzumab seems to have the most promising results. Adoptive immunotherapy with CAR-T is an area of intensive research, giving hope for achieving remission in patients with CLL refractory to all other methods of treatment.

1. Introduction 2. Monoclonal antibodies Chronic lymphocytic leukemia (CLL) is the most common 2.1. Monoclonal antibodies targeting surface antigens leukemia in the Western world, with an estimated 21,000 on leukemic cells new cases and 4000 deaths in the United States in 2019 [1]. The disease affects mainly the elderly, with two out of three 2.1.1. Anti-CD20 monoclonal antibodies patients being over the age of 65, and a median age of By targeting different epitopes of the cell-surface antigen 70 years, at the time of CLL diagnosis [2]. CD20, CD20-mAbs exert a broad spectrum of anti-leukemic CLL represents a genetically complex disease that affects activity; they are able to induce CLL cell death via multiple a heterogeneous patient population. The selection of the mechanisms of action including antibody-dependent cell- optimal therapeutic strategy for individual patient is highly mediated cytotoxicity (ADCC) (rituximab, obinutuzumab and dependent on age, performance status, comorbidities and co- ofatumumab), complement-dependent cytotoxicity (CDC) medications, as well as the cytogenetic and molecular features (mainly rituximab and ofatumumab and to a lesser extent of the disease, especially deletion of the 17p13 locus (del(17p)) obinutuzumab) and direct induction of apoptosis (obinutuzu- and/or mutation(s) within the TP53 gene (TP53mut) and the mab) [7]. mutational status of the immunoglobulin heavy chain variable Despite their low clinical efficacy in monotherapy [8] incor- region (IGHV) genes in the leukemic cells [3–5]. poration of CD20-mAbs to chemotherapeutic regimens has revo- Introduction of novel active agents, initially anti-CD20 lutionized treatment of CLL in the last decade. Rituximab and monoclonal antibodies (CD20-mAbs) (rituximab and obinutu- obinutuzumab are the backbone of most therapeutic protocols. zumab), then B-cell receptor signaling inhibitors (BCRi) (ibruti- However, the introduction of novel highly-active agents, such as nib, acalabrutinib, idelalisib and duvelisib), and finally BCL-2 ibrutinib and venetoclax, questioned the leading role of immu- antagonist (venetoclax) has remarkably changed the therapeu- nochemotherapy in the treatment of CLL [9–12]. tic landscape of CLL in the last years [6]. Moving gradually from when chemotherapy was the only therapeutic option, 2.1.1.1. Rituximab. Rituximab is a chimeric mouse-human through the era of immunochemotherapy, we now have the IgG1 mAb that targets CD20, a transmembrane protein ability to effectively treat most of the CLL patients with expressed on B-cells. The key role of rituximab, a first-in-class chemo-free regimens. CD20-mAb in the frontline treatment of younger, physically fit This review presents the current state of knowledge about CLL patients has been established in the phase III CLL8 study biologic drugs used in the treatment of patients with CLL. [13]. Treatment-naive CLL patients with score ≤ 6 on the

CONTACT Tadeusz Robak [email protected] Medical University of Lodz, Copernicus Memorial Hospital, Ciolkowskiego 2, Lodz 93-0510, Poland © 2020 Informa UK Limited, trading as Taylor & Francis Group Pobrano z https://publicum.umed.lodz.pl / Downloaded from Repository of Medical University of Lodz 2021-09-26 800 I. HUS ET AL.

patients without significant comorbidities. In the phase III CLL10 Article highlights trial, FCR was found to demonstrate superiority over rituximab- bendamustine (RB) for treatment-naive physically fit (CIRS score ● Biologics are nowadays standard methods of CLL treatment, alongside chemotherapy, BCL-2 and BCR inhibitors. ≤ 6 and eGFR > 70 ml/min) CLL patients under the age of 65 ● Combination regimens comprising anti-CD20 monoclonal antibodies without del(17p) [15]. Longer PFS, higher CR rate and more and chemotherapy are recommended as first line therapy in patients MRD negativity (55% vs. 27% at 18 months; p = 0.002) were without 17p deletion/TP53 mutation, with mutated IGVH or with prolonged response after immunochemotherapy. observed in FCR compared to RB arm (Table 1); however, no ● Although the role of immunochemotherapy is currently fading, anti- significant difference in PFS was observed between the arms CD20 monoclonal antibodies can still play a strong role in CLL among > 65 years old patients (median PFS for FCR – not treatment by increasing the efficacy of venetoclax, a BCL-2 antagonist, allowing for time-limited treatment. reached, for BR – 48.5 months; p = 0.17). In addition, infectious ● Among the new monoclonal antibodies, the anti-CD20 directed complications were more frequently observed in the FCR arm in umbralisib and anti-ROR1 directed cirmtuzumab seem to have the patients older than 65 years, suggesting that elderly fit patients most promising results. ● Development of effective DC vaccines in CLL remains a challenge may benefit more from treatment with RB [15]. The results of despite their proven ability to induce leukemia-specific T-cell phase II studies also demonstrated that rituximab in combina- responses. Improvement of clinical efficacy of this personalized treat- tion with chlorambucil is efficacious for the first-line therapy in ment would require identification of more efficient combination strategies. elderly patients ineligible for fludarabine-based therapy [16,17]. ● AlloHSCT remains the only therapeutic method with curative poten- Recently, the phase III E1912 trial compared FCR with tial in CLL and should be considered in young and fit high-risk R/R a combination of ibrutinib with rituximab (iR) as first-line CLL patients, refractory or relapsing after treatment with BCR inhibitors or BCL-2 antagonist. treatment for fit CLL patients aged < 70 years without del ● CAR-T cell immunotherapy is the subject of intensive study in (17p) [18]. Ibrutinib, a first-in-class inhibitor of Bruton’s tyro- patients with CLL and will probably play an increasingly important sine kinase, has been previously found to be one of the most role, especially in the light of encouraging preliminary results regarding combined CAR-T and ibrutinib therapy. active agents in the treatment of CLL in both frontline and relapsed/refractory (R/R) settings [9,10]. Treatment with iR was This box summarizes key points contained in the article. associated with significant improvement in PFS (HR, 0.35; p < 0.001) and OS (HR, 0.17; p < 0.001) compared to FCR (Table 1). These PFS benefits were not observed in patients Cumulative Illness Rating Scale (CIRS) and estimated creatinine with IGHVmut. Safety analysis, in terms of severe infectious clearance (eGFR) > 70 ml/min were randomized to receive complications, favored iR over chemo-immunotherapy [18]. fludarabine and cyclophosphamide (FC) with or without ritux- Patients treated with iR were less likely to achieve MRD nega- imab. A higher objective response rate (ORR) and more fre- tivity compared to those treated with FCR (MRD negativity quent complete response (CR) were observed in patients rate of 8% vs. 60% at 12 months, for iR and FCR, respectively) treated with FC in combination with rituximab (FCR) com- [18]. It should be noted, that in the group of CLL patients pared to FC alone (Table 1). Notably, an FCR regimen allowed treated with ibrutinib, both the prognostic value of MRD the first recorded improvement in overall survival (OS) to be negativity and the appropriate timing for MRD assessment achieved with median not reached, as compared to 86 months remain undetermined [19]. In this context data from a longer for FC (HR, 0.68, p = 0.001) [13]. follow-up from the E1912 trial are particularly expected. As Although the incorporation of rituximab to FC has signifi- there were only 77 disease progression and 14 deaths noted cantly improved patient outcomes, the CLL8 study has also during follow-up, a longer period of observation is needed shown that the clinical benefits from adding rituximab to FC before any definite conclusions can be drawn about the were not evenly distributed throughout the entire CLL patient advantage of iR over FCR in the frontline treatment of young population. Although PFS was still improved in the subgroup and fit CLL patients [18]. of patients with del(17p) treated with FCR (median PFS of Data from the CLL8 and E1912 studies indicate the IGHV 11 months and of 9 months, respectively, for FCR and FC, mutational status plays a particularly important role in the HR, 0.49, p = 0.03), no significant differences in OS were selection of appropriate front-line therapy. Given the excellent observed among patients with del(17p) treated with FCR and results from FCR therapy in patients with IGHVmut, treatment FC alone (a median OS of 33 months and of 23 months, with immunochemotherapy may still serve as a treatment of respectively, HR, 0.66, p = 0.2) [13]. On the other hand, parti- choice for young and fit CLL with IGHVmut in the absence of cularly good outcomes with long-term remissions have been del(17p). recorded for specific patient groups, namely those with del In the next phase III study conducted by Alliance North (11q), del(13q), trisomy 12 and mutated IGHV gene (IGHVmut), American Intergroup AO41202, treatment-naive CLL patients or those who had achieved minimal residual disease (MRD) – aged > 65 years were treated with one of three regimens: negative remission following treatment with FCR [13,14]. ibrutinib monotherapy, iR or the RB protocol. PFS after 24 months Importantly, a recent sub-analysis identified a plateau on the was significantly higher in patients treated with ibrutinib (87%) PFS curve in patients with IGHVmut treated with FCR (n = 88), or iR (88%) vs. RB (74%) (Table 1)[20]. No differences in OS were with no relapses beyond 10.4 years in 42 patients [14]. noted and no clinical benefit was associated with the addition of The results of the CLL8 study have defined FCR as the gold rituximab to ibrutinib, confirming observations from a previous standard of frontline treatment for young (< 65 years old) CLL study on high-risk CLL patients [20,21].

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Table 1. The most relevant phase III clinical trials investigating combinations of monoclonal antibodies with other agents in the first-line treatment of chronic lymphocytic leukemia. Number of patients Median age Follow-up Trial Treatment (n) (years) Prognostic factors* Treatment duration ORR/CR (median) PFS OS Ref. CLL8 FCR vs. FC 817 61 del(17p), 22/311 (7%) vs. 29/305 (10%); Up to 6 cycles 90% vs. 80% 6 years median, median, [13] IGHVunm, 197/310 (64%) vs. 195/312 (63%) (p < 0.001) 57 vs. 33 months NR vs. 86 months 44% vs. 22% (HR, 0.59, p < 0.001) (HR, 0.68, p = 0.001) (p < 0.001) CLL10 RB vs. FCR 561 61 vs. 62 del(17p) not included; Up to 6 cycles 96% vs. 95% 37 months median, 3-y OS, [15] IGHVunm, 183/270 (68%) vs. 152/275 (55%) (p = 1.0) 42 vs. 55 months 92% vs 91% 31% vs. 40% (HR, 1.64, p = 0.0003) (p = 0.9) (p = 0.03) CLL11 OCh vs. RCh** 781 73 del(17p), 22/295 (7%) vs. 20/287 (7%); Up to 6 cycles 78% vs. 65% 59 months median, median, [35,36] IGHVunm, 188/305 (62%) vs.182/298 (61%) 21% vs. 7% 29 vs. 16 months NR vs. 73 months (p < 0.001) (HR, 0.49, p < 0.0001) (HR, 0.68, p = 0.02) COMPLEMENT ofaCh vs. Ch 447 69 del(17p), 10/209 (5%) vs. 17/216 (8%); Up to 3–12 cycles 82% vs. 69% 29 months median, median, [42] 1 IGHVunm, 114/201 (57%) vs. 113/203 (56%) (p = 0.001) 22 vs. 13 months NR vs. NR 14% vs. 1% (HR, 0.57, p < 0.0001) E1912 iR vs. FCR 529 mean 57 ± 7 del(17p), 2/354 (0,6%) vs. 0%; FCR up to 6 cycles; 96% vs. 81% 34 months 3-y PFS, 3-y OS, [18] IGHVunm, 210/280 (75%) vs. 71/115 (62%) iR up to 6 cycles followed by i given 17% vs. 30% 89% vs 73% 99% vs 92% continuously until PD (HR, 0.35, p < 0.001) (HR, 0.17, p < 0.001) AO41202 iR vs. i vs. RB 547 71 del(17p), 11/180 (6%) vs. 9/180 (5%) vs. 14/ iR up to 6 cycles followed by i, given 94% vs. 93% vs. 81% 38 months 2-y PFS, 88% vs. 87% vs. 2-y OS, 94% vs. 90% vs. [20] 181 (8%) continuously until PD; i given 74% 95% TP53mut, 20/168 (12%) vs. 15/168 (9%) vs. continuously until PD, RB up to 6 (HR, 039, p < 0.001) (p ≥ 0.65) 16/174 (9%) cycles IGHVunm, 70/115 (61%) vs. 77/122 (63%) vs. 71/123 (58%) iLLUMINATE iO vs. OCh 229 71 del(17p) or iO up to 6 cycles followed by i given 88% vs. 73% 31 months median, median, [37] TP53mut, 18/113 (18%) vs. 23/116 (20%); continuously until PD; (p = 0.003) NR vs. 19 months NR vs. NR THERAPY BIOLOGICAL ON OPINION EXPERT IGHVunm, 66/107 (62%) vs. 57/107 (53%) OCh up to 6 cycles; CR, 19% vs. 8% (HR, 0.23, p < 0.0001) (p = 0.009) CLL14 venO vs. OCh 432 72 del(17p), 17/200 (8.5%) vs.14/193 (7%); Up to 12 cycles (with O given for the 85% vs. 71% 28 months 2-y PFS, median, [30] TP53mut,19/171 (11%) vs. 13/157 (8%); first 6 cycles) (p < 0.001) 88% vs. 64% NR vs. NR IGHVunm, 152/171 (89%) vs.144/157 (92%) CR, 50% vs. 23% (HR, 0.35, p < 0.001) (p < 0.001) Abbreviations: FCR (fludarabine, cyclophosphamide, rituximab); FC (fludarabine, cyclophosphamide); RB (rituximab, bendamustine); iR (ibrutinib; rituximab); i (ibrutinib); OCh (obinutuzumab, chlorambucil); RCh (rituximab, chlorambucil); venO (venetoclax, obinutuzumab); O (obinutuzumab); iO (ibrutinib, obinutuzumab); ofaCh (ofatumumab, chlorambucil), Ch (chlorambucil); del(17p) (deletion of the 17p13 locus); IGHVunm (unmutated status of the immunoglobulin heavy chain variable region genes); TP53mut (mutations in TP53 gene); ORR (objective response rate); PD (progressive disease); CR (complete response); OS (overall survival); PFS (progression-free survival); HR (hazard ratio); 3-y PFS (3-years PFS rate); 2-y PFS (2-years PFS rate); 3-y OS (3-years OS rate); NR (not reached); Ref. (references). [*] Proportion of patients in each study arm for whom data regarding the presence of del(17p) or TP53 mutations or IGHVunm were available. [**] In the CLL11 trial there was also a group of patients treated with chlorambucil alone – data not included in the table. 801 802 I. HUS ET AL.

The advantage conferred by the addition of rituximab to negativity in peripheral blood (PB) at 2–3monthsaftertheend the FC protocol in terms of PFS, CR, duration of response, and of combination-therapy was associated with longer PFS and was time to new CLL treatment or death was also demonstrated in more frequently observed in venR arm compared to RB arm R/R CLL patients in the phase III REACH trial (Table 2)[22]. (62% vs. 13%). At the end of therapy (24 months), 70% of MRD- Combinations of immunochemotherapy with rituximab and negative patients maintained MRD negativity and 98% of MRD- BCRi have been evaluated in R/R CLL in phase III clinical trials. negative patients did not experience disease progression [34]. Two of these regimens are RB plus ibrutinib (RBi) [23,24] and The results of the MURANO trial have established fixed- RB plus a PI3Kdelta inhibitor, idelalisib [25]. duration venR as an important therapeutic option for patients In the HELIOS trial a significant improvement in PFS was with R/R CLL. Potential additional benefits, including observed in R/R CLL patients without del(17p) treated with RB a reduction in the risk of developing chronic toxicity and plus ibrutinib compared to those treated with RB plus placebo a lower cost burden, have also been noted. (Table 2)[23,24]. The limitation of this study was the lack of an arm with ibrutinib monotherapy. Similar results have been achieved in previous trials with ibrutinib as a single agent 2.1.1.2. Obinutuzumab. Obinutuzumab is the glycoengi- [26], which questions the clinical utility of RBi. neered type II CD20-mAb acting mainly via direct induction Idelalisib in combination with rituximab has shown an of CLL cells apoptosis and via ADCC [7]. advantage over rituximab plus placebo in the phase III trial The combination of obinutuzumab and chlorambucil (OCh) of unfit patients with R/R CLL [27]. At 24 weeks, the rate of PFS has been approved as a frontline treatment for unfit CLL was 93% in the rituximab-idelalisib group, as compared with patients based on the outcomes from the phase III CLL11 46% in the rituximab-placebo group. Recently, the long-term study [35]. Treatment-naive patients with significant comor- efficacy of rituximab plus idelalisib has been reported. After bidities (score > 6 on CIRS) or decreased renal function (eGFR a median follow-up of 18 months, median PFS in the idelalisib/ of 30 to 69 ml/min) were treated with of OCh or rituximab plus rituximab-to-idelalisib group was 20 months (Table 2)[28]. Of chlorambucil (RCh) or chlorambucil [35]. Substituting rituxi- note, high-risk patients, those with either del(17p) or TP53mut, mab with obinutuzumab has been demonstrated to consider- had a median PFS of nearly 19 months. No data exists on the ably improve PFS and OS (Table 1)[36]. Patients with del(17p) comparison between combined idelalisib and rituximab ther- did not obtain any clinical benefits from the treatment with apy and idelalisib monotherapy. OCh as compared to RCh [35]. Treatment with OCh was asso- The superiority of RB plus idelalisib over RB plus placebo ciated with higher incidence of clinically-relevant infusion- was demonstrated in a phase III trial in patients with R/R CLL, related reactions (IRRs), especially those that led to treatment including those with del(17p) or TP53mut (Table 2)[25]. discontinuation [35]. Grade ≥ 3 neutropenia was also more However, the higher efficacy of RB-idelalisib therapy was frequently seen in the OCh arm, but the risk of infection was achieved at the expense of an inferior safety profile, with not increased. both serious adverse events and opportunistic infections Recently, the phase III clinical study CLL14 found combined being observed more frequently in the active arm [25]. obinutuzumab with venetoclax (venO) to demonstrate more Venetoclax, a first-in-class BCL-2 inhibitor has shown favorable PFS compared to OCh as the frontline treatment in impressive clinical activity in the treatment of CLL as a single unfit (CIRS score > 6 or eGFR < than 70 ml/min] CLL patients agent [11,12] and its efficacy could be further improved by the (Table 1)[30]. This benefit was maintained across all prespeci- combination with the CD20-mAbs rituximab [29] and obinu- fied subgroups, including patients with del(17p) or TP53mut tuzumab [30]. and patients with non-mutated IGHV. Similarly, a substantially Recently, the phase III MURANO trial confirmed the super- higher rate of MRD negativity was seen after treatment with iority in terms of both PFS and OS, of venetoclax, given for up venO compared to OCh (MRD negativity rate in PB 75% vs. to two years, combined with rituximab, given for the first six 35%, respectively, for venO and OCh, p < 0.001; MRD negativ- months, (venR) over a total of six cycles of RB in patients with ity rate in bone marrow [BM] 60% vs. 17%, respectively, for R/R CLL, with or without del(17p) (Table 2)[29]. PFS improve- venO and OCh, p < 0.001). Both treatment with venO and OCh ment was maintained in all analyzed subgroups, including had acceptable toxicity profiles, with the most common grade patients with del(17p) or TP53mut: the two-year PFS for 3 or 4 adverse events (AEs) being neutropenia and infectious patients with del(17p) or TP53mut was 82% for venR and complications [30]. 28% for RB. Of note, prior treatment with BCRi was used in Based on the results of the CLL14 study, fixed-duration 3% (venR) and 1.5% (RB) of patients. Both febrile neutropenia venO was approved by FDA for first-line therapy of patients and clinically significant infectious complications were more with CLL in May 2019 and should be considered as an impor- frequently observed in RB arm [29]. Updated results of the tant treatment option for previously untreated unfit patients, MURANO trial were presented at the 2018 Annual Meeting of with or without del(17p) or TP53mut. the American Society of Hematology. The respective 3-year Another relevant study in the field of the modern approach PFS and OS values were 71% and 88% in the venR arm to the treatment-naive unfit or elderly CLL patients is the compared to 15% (HR, 0.16; 95% CI, 0.12–0.23) and 80% (HR, recent phase III iLLUMINATE trial [37]. Eligible patients were 0.50; 95% CI, 0.30–0.85) in the RB arm [31]. aged 65 years or older or younger than 65 years with at least MRD status has been previously shown to be a predictor of one of the following coexisting conditions: CIRS score greater both PFS and OS for CLL patients treated with immunochem- than 6, eGFR of less than 70 ml/min, presence of high-risk otherapy [32,33 ]. In the MURANO trial, achievement of MRD cytogenetic (del(17p) or molecular (TP53mut) features. Median

Table 2. The most relevant phase III clinical trials investigating combinations of monoclonal antibodies with other agents in the treatment of relapsed or refractory chronic lymphocytic leukemia. Number of patients Median age Prior lines of Follow-up Trial Treatment (n) (years) therapy Prognostic factors* Treatment duration ORR (median) PFS OS Ref. REACH FCR vs. FC 552 63 vs. 62 1 del(17p) 7% vs. 9% Up to 6 cycles 70% vs. 58% 25 months median, 31 vs. 21 months median, NR vs. 52 months [22] IGHVunm, 65% vs. 61% (p = 0,003) (HR 0,65; p < 0.001) (p = 0.28) CR, 24% vs. 13% (p < 0.001) COMPLEMENT 2 ofaFC vs. FC 365 62 vs. 61 1 del(17p) 4% vs. 8% Up to 6 cycles 84% vs. 68% 34 months median, 29 vs. 19 months median, 56 vs. 46 months [45] IGHVunm, 69% vs. 69% (p = 0.0003) (HR 0,67; p < 0.003) (HR 0.78; p = 0.14) CR, 27% vs. 7% NCT01539512 R + idela vs. 220 71 median, 3 del(17p) or TP53mut 42% vs. 45%; R up to 8 doses followed by idela/ 86%** 18 months median, median, 41 vs. 35 months [27,28] R + placebo IGHVunm, 83% vs. 85% placebo until PD CR, 1/110** 20 months** (HR, 0.8, p = 0.13) NCT01569295 RB + idela vs. RB + 416 63 median, 2 del(17p) and/or TP53mut 69/207 RB up to 6 cycles followed by 96% vs. 81% 14 months median, median, [25] placebo (33%) vs. 69/207 (33%); idela/placebo until PD CR, 17% vs. 30% 21 vs. 11 months NR vs. 32 months IGHVunm, 173/207 (84%) vs. 173/209 (HR, 0.33, p < 0.0001) (HR, 0.62, p = 0.03) (83%) HELIOS RB + i vs. RB + 578 64 vs. 63 mean, 2 del(17p), not included; RB up to 6 cycles followed by i/ 83% vs. 68% 17 months median, median, [23,24] placebo IGHVunm, 210/259 (81%) vs. 208/260 placebo until PD (p < 0,0001) NR vs. 13 months NR vs. NR (80%) CR, 10% vs. 3% (HR, 0.2, p < 0.0001) (p < 0.0001) MURANO venR vs. RB 389 65 range, 1–3 del(17p), 46/173 vs. (17%) vs. 46/169 venR: R up to 6 cycles, ven up to 92% vs. 72% 24 months median, median, [29] (27%); 2 years; CR, 8% vs. 4% NR vs. 17 months NR vs. NR TP53mut, 48/192 (25%) vs. 51/184 RB up to 6 cycles (p = 0.08) (HR, 0.17, p < 0.001)

(28%) THERAPY BIOLOGICAL ON OPINION EXPERT IGHVunm, 123/180 (68%) vs. 123/180 (68%) Abbreviations: FCR (fludarabine, cyclophosphamide, rituximab); FC (fludarabine, cyclophosphamide); RB (rituximab, bendamustine); R (rituximab); RB (rituximab, bendamustine); i (ibrutinib); venR (venetoclax, rituximab); idela (idelalisib); ofaFC (ofatumumab, fludarabine, cyclophosphamide); del(17p) (deletion of the 17p13 locus); IGHVunm (unmutated status of the immunoglobulin heavy chain variable region genes); TP53mut (mutations in TP53 gene); ORR (objective response rate); PD (progressive disease); CR (complete response); OS (overall survival); PFS (progression-free survival); HR (hazard ratio);) NR (not reached); Ref. (references). [*] Proportion of patients in each study arm for whom data regarding the presence of del(17p) or TP53 mutations or IGHVunm were available. [**] The study was terminated prematurely due to overwhelming efficacy of the combination of rituximab and idelalisib. Data regarding ORR and PFS presented here refer to the idelalisib/rituximab-to-idelalisib group. 803 804 I. HUS ET AL.

PFS was significantly longer in the ibrutinib plus obinutuzu- favorable safety profile in the treatment of CLL patients, either mab (iO) arm than in OCh arm (Table 1). MRD negativity (in BM as a single agent [40,41] or in combination with bendamustine or PB) was achieved in 35% of patients treated with iO and [42], chlorambucil [43], ibrutinib [44] and idelalisib [45]. 25% of those in OCh. PFS benefit with iO was maintained in The randomized phase III COMPLEMENT 1 trial found that the high-risk population, i.e. patients with del(17p), del(11q), the addition of ofatumumab to chlorambucil improved out- TP53mut or non-mutated IGHV, with a median PFS of comes of previously untreated CLL patients unsuitable for 15 months in the OCh arm but not reached in iO arm (HR, fludarabine-based therapy in terms of response rates and 0.15; p < 0.0001). The groups demonstrated similar numbers of PFS (Table 1) with no difference in OS [43]. The combined grade 3 or 4 AEs. The most common non-hematological toxi- therapy was associated with higher incidence of grade 3 or 4 cities were pneumonia and atrial fibrillation (iO group), as well AEs with neutropenia being the most common event. as IRRs and febrile neutropenia (OCh group) [37]. Some limita- However, both study groups demonstrated a similar frequency tions of the iLLUMINATE study need to be highlighted. Firstly, of severe infectious complications [43]. the study included a group of older (> 65 years) and fit In the randomized phase II COMPLEMENT 2 trial, examining patients for whom, based on the results of the CLL10 study, patients with R/R CLL who experienced disease progression treatment with RB might be more appropriate than with OCh after a median of one prior line of therapy, the combination of [15]. Secondly, a lack of ibrutinib monotherapy as ofatumumab and FC (ofaFC) demonstrated higher ORR and a comparator makes it impossible to determine whether the longer PFS as compared to FC (Table 2)[46]. However, there addition of obinutuzumab to ibrutinib confers additional clin- were no significant differences in OS between the study ical benefits over the use of ibrutinib as a single agent. groups (median OS of 56 months for ofaFC vs. 46 months for The superiority of obinutuzumab in combination with BCRi FC). The side-effects profile of combination therapy was pre- over OCh in the frontline treatment of unfit CLL patients is also dictable and manageable [46]. supported by the results of the phase III ELEVATE-TN study pre- Ofatumumab has also demonstrated efficacy as mainte- sented at the 2019 Annual Meeting of the American Society of nance therapy in patients with CLL who have achieved at Hematology [38]. In this trial, patients (aged 65 years or older or least partial response (PR) after second-line or third-line treat- younger than 65 years with at least one of the following coexisting ment in the phase III PROLONG trial [47]. conditions: CIRS score > 6 or eGFR < than 70 ml/min) were rando- Recently, the marketing authorization for ofatumumab has mized to the acalabrutinib plus obinutuzumab (acalO), acalabruti- been withdrawn by the European Medicines Agency at the nib alone and OCh arms. At a median follow-up of 28 months, request of the holder, for commercial reasons. treatment with acalO or acalabrutinib alone was associated with significant improvement in PFS compared to OCh (HR, 0.10; 2.1.1.4. Ublituximab. Ublituximab is a unique type I, chimeric, p < 0.0001 and HR, 0.20; p < 0.0001, for acalO and acalabrutinib glycoengineered CD20-mAb acting mainly as an inductor of B cell- alone, respectively). Estimated 30-months PFS rates with acalO, directed ADCC and CDC [48]. Monotherapy with ublituximab has acalabrutinib in monotherapy and OCh were 90%, 82%, and been shown to be active (with ORR of 45%) and well-tolerated in 34%, respectively. The PFS benefit was maintained across all pre- a phase I/II study in patients with R/R B-cell malignancies pre- specified subgroups, including patients with del(17p). Notably, viously exposed to rituximab; this group included eight patients there was a trend toward improved OS observed in both acalab- with R/R CLL (23%) [49]. rutinib arms, despite cross over for disease progression in the OCh The combination of ublituximab with ibrutinib induced arm [38]. However, a longer follow-up is needed to finally deter- a rapid response (a median time of eight weeks) in a high mine the advantage of acalO or acalabrutinib monotherapy over proportion of R/R CLL patients included in the phase II study, OChintermsofOSinthegroupofunfittreatment-naïveCLL irrespective of the cytogenetic risk associated with the pre- patients. Unfortunately, the ELEVATE-TN study was not powered sence of del(17p) or del(11q), or the molecular risk associated to compare the PFS benefit betweenthetwoacalabrutinibarms, with presence of the TP53mut: ORR of 88% for all patients and therefore, whether the obinutuzumab combination with BCRi has ORR of 95% for high-risk patients [50]. In this context, out- an advantage over monotherapy with BCRi in the frontline settings comes of the phase III trial comparing a combined ublituximab in unfit CLL patients still remains an open question. plus ibrutinib regimen with ibrutinib alone in high-risk R/R CLL Obinutuzumab was also evaluated in combination with patients are highly awaited (NCT02301156). bendamustine (OB) as part of the non-randomized phase IIIb The results of the phase I/Ib study evaluating the combina- GREEN study [39]. A total of 158 previously untreated CLL tion of ublituximab with a next-generation PI3Kdelta inhibitor, patients receiving OB were included. After a median follow- umbralisib, in patients with R/R non-Hodgkin lymphoma and up of 33 months, 2-year PFS rate was 82% and MRD negativity R/R CLL has been recently reported [51]. The ORR for all was achieved in 60% and 28% of patients in PB and BM, patients was 46% with 17% CR. The median duration of respectively. Grade 3 or more AEs occurred in 82% of patients. response was 20 months. That suggests that this combination Clinically significant IRRs were observed in almost every fifth demonstrates promising efficacy and warrants further patient. These outcomes indicate that the OB combo demon- investigation. strates meaningful clinical efficacy, but more data is needed for this regimen to be more widely used in clinical practice. 2.1.2. Anti-CD52 mAb

2.1.1.3. Ofatumumab. Ofatumumab is a type I fully human Alemtuzumab, humanized IgG1 kappa mAb specific for the cell CD20-mAb which has shown good clinical activity and surface glycoprotein CD52 was the first mAb approved in CLL

Pobrano z https://publicum.umed.lodz.pl / Downloaded from Repository of Medical University of Lodz 2021-09-26 EXPERT OPINION ON BIOLOGICAL THERAPY 805 in 2001 and was expected to play a significant role in the has been evaluated in a phase I study of 12 patients with CLL [65]. treatment of this disease. Monotherapy with alemtuzumab has Therapy was well-tolerated (with no discontinuations for toxicity been shown to be active both in the frontline and R/R settings and no dose limiting toxicities) and effective (with ORR of 67% and including patients with del(17p) or TP53mut [52–54]. IRRs, 2CRafter16–48 weeks of treatment). Of note, typical ibrutinib- cytomegalovirus reactivation and other infectious complica- induced lymphocytosis was diminished, with only a 50% mean rise tions were the main toxicities associated with alemtuzumab in absolute lymphocyte count which rapidly returned to baseline. [52,53]. The combination of alemtuzumab with fludarabine A randomized phase II study comparing cirmtuzumab with ibruti- demonstrated superior PFS and OS over fludarabine mono- nib to ibrutinib alone is ongoing (NCT03088878). therapy in a phase III trial of patients with R/R CLL [55]. The incidence of serious AEs was higher in the combination treat- 2.1.4. Antibody–drug conjugates ment group but deaths due to AEs were similar between the Antibody–drug conjugates (ADCs), in which a cytotoxic drug is groups. In the phase III study of treatment-naive CLL patients attached to a monoclonal antibody, constitute another form of comparing alemtuzumab combined with FC to FCR, substitu- immunotherapy, with four agents (brentuximab vedotin, gem- tion of rituximab by alemtuzumab did not provide any addi- tuzumab ozogamacin, inotuzumab ozogamacin and polatuzu- tional clinical benefits in terms of ORR and PFS and was mab vedotin) approved for the treatment of hematologic characterized by unacceptable toxicity. Due to excess toxicity malignancies [66]. Unfortunately, to the best of our knowl- in the active arm, recruitment to the study was halted prema- edge, none of the ADCs evaluated so far in early phase studies turely [56]. In 2012, the license for treating CLL was withdrawn (pinatuzumab vedotin and polatuzumab vedotin) have shown by the drug producer; however, CLL patients are still able to any activity in the treatment of CLL [67,68]. receive alemtuzumab through an international compassionate use program. 2.1.5. Bispecific antibodies After the success of blinatumomab in the treatment of R/R acute 2.1.3. Other mAbs lymphoblastic leukemia (R/R ALL), other bispecific monoclonal CD19 and CD37 antigens that are expressed on the surface of antibodies (BsAbs) are entering the arena of Hodgkin and non- CLL cells emerged as novel targets for immunotherapy [57– Hodgkin lymphoma therapy and are currently being investigated 59]. Anti-CD19 mAb (MOR00208) has demonstrated promising in many phase I studies [69]. BsAbs act by the simultaneous bind- activity (ORR of 30% and 67%, per radiological and clinical ing of two separate antigens located on malignant and effector criteria, respectively) and good safety profile (with IRRs being cells. BsAbs directed against CD3 and CD19 (CD3/CD19 BsAbs) are the most common toxicities) in 27 patients with heavily pre- the most widely researched [70]. These antibody constructs are treated high-risk R/R CLL when used as a single agent in the capable of simultaneously binding the CD3 antigen, a component phase I trial [60]. A phase II trial evaluating MOR00208 com- of the T-cell receptor complex, and the CD19 antigen expressed by bined with lenalidomide in CLL patients is ongoing B-cells, which leads to redirection of T-cell activity against tumor (NCT02005289). Moreover, the combination of another anti- cells [69,70]. CD19 mAb, inebilizumab (MEDI-551) with bendamustine is Preclinical studies provide increasing evidence indicating undergoing comparison to RB in patients with R/R CLL in that BsAbs possesses potent anti-cancer activity in CLL. The a randomized phase II trial (NCT01466153). novel CD3/CD19 BsAbs developed by Robinson et al. has been Otlertuzumab, a first-in-class anti-CD37 mAb demonstrated shown to be able to effectively eliminate of CLL cells in the modest single-agent activity (ORR of 23%) and acceptable mouse-xenograft model [71]. Intriguingly, this T-cell-recruiting safety profile in a phase I trial among treatment-naive and antibody construct induced more rapid killing of CLL cells pretreated CLL patients [61]. In a randomized phase II trial, the from ibrutinib-treated patients than those from treatment- combination of otlertuzumab with bendamustine has shown naive patients and demonstrated potent activity against CLL superiority over bendamustine alone in patients with R/R CLL cells from patients with acquired ibrutinib-resistance. Ibrutinib [62], with higher ORR (69% vs. 39%; p = 0,025) and longer PFS and T-cell-recruiting BsAbs have recently been reported to (median of 16 months vs. 10 months; p = 0,02) being observed demonstrate synergistic activity against CLL in another precli- in patients treated in the active arm. The incidence of neutro- nical study, in which BsAb displayed higher anti-leukemic penia was higher in the combination therapy arm; however, activity when co-cultured with T-cells isolated from patients this did not translate into a higher incidence of serious infec- treated with ibrutinib compared to T-cells isolated from tious complications [62]. Recently, another anti-CD37 mAb, BI patients who did not receive ibrutinib [72]. It is possible 836826, has demonstrated promising activity and acceptable though that ibrutinib increases the susceptibility of leukemic tolerability when used in monotherapy in 45R/R CLL patients cells to BsAbs-induced destruction. in a phase I trial, with a relatively high response rate (ORR of Taken together, these findings support further investigation of 46%) being obtained in patients with del(17p) or TP53mut T cell-recruiting BsAbs as a therapeutic option for CLL patients, (65% of all R/R CLL patients participated in the trial) [63]. especially for those who have failed treatment with ibrutinib. These findings clearly warrant further clinical investigation of BI 836826, especially in this difficult-to-treat-population. 2.2. Immunomodulatory mAbs (Checkpoint inhibitors) ROR1 is another cell-surface antigen expressed by CLL cells [64] which has more recently become a target for immunotherapy. The The introduction of checkpoint inhibitors, mainly mAbs direc- combination of cirmtuzumab, a humanized mAb directed against ted against programmed death receptor 1 (anti-PD-1 mAbs) ROR1 (given for 12 months), with ibrutinib (given in standard dose) (i.e. pembrolizumab and nivolumab) was a breakthrough in

Pobrano z https://publicum.umed.lodz.pl / Downloaded from Repository of Medical University of Lodz 2021-09-26 806 I. HUS ET AL. the treatment of various types of solid tumor [73]. By blocking small groups of patients with CLL but the greatest hope the PD-1/programmed death ligand-1 (PD-L1) pathway, the has been associated with dendritic cell (DC) vaccines. DC anti-PD-1 mAbs inhibit suppression of cytotoxic T-cell and constitute the most potent antigen-presenting cells, capable activate T-cell mediated anti-tumor immune activity [74]. of inducing both innate and adaptive immune responses. Pembrolizumab and nivolumab have an established role in Several study groups have shown that vaccination with ex the treatment of R/R Hodgkin lymphoma [75,76] and their role vivo generated monocyte-derived allogeneic or autologous in treatment of several subtypes of non-Hodgkin lymphomas DC pulsed with tumor antigens is safe, feasible and able to is currently being intensively studied [77]. induce leukemia-specific cytotoxic T-cell responses, albeit Unfortunately, pembrolizumab used as a single agent has with only modest clinical responses [87–89]. The use of shown no activity in 16 patients with R/R CLL in the phase II lenalidomide as immune adjuvant together with DC resulted study (ORR of 0%) [78]. However, in a cohort of nine patients in unexpected autoimmune toxicity [90]. Therefore, further with Richter syndrome (RS), four objective response including development of this strategy would require identification of one CR were achieved (ORR of 44%). Importantly, all of these different, more efficient and safer combinations to increase responses were observed in RS patients who experienced the efficacy of DC vaccines. disease progression after prior therapy with ibrutinib. After a median follow-up of 11 months, a median OS in the RS cohort was 10.7 months, but was not reached in RS patients 4. Allogeneic hematopoietic stem cell who progressed on ibrutinib [78]. Given the extremely poor transplantation prognosis of patients who develop RS during therapy with ibrutinib, these results require special attention [79]. Before the CLL treatment armamentarium was extended to Preclinical studies have shown synergistic antitumor activ- include the BCRi and BCL-2 antagonist, allogeneic stem cell ity between checkpoint inhibitors and ibrutinib [80]. In transplantation (alloHSCT) was considered as the only effective a recently published phase I/IIa study, the combination of therapeutic strategy providing long-term disease control in ibrutinib and nivolumab led to overall responses in 22 (61%) patients with R/R CLL, including those with high-risk cytoge- – out of 36 patients with high-risk R/R CLL, characterized by the netics and non-mutated IGHV [91 93]. Currently, especially in presence of del(17p) or del(11q), and 13 (65%) out of 20 the countries with unrestricted access to novel agents, the role patients with RS [81]. Both patients with R/R CLL and RS had of alloHSCT in management of R/R CLL has significantly a median of two prior lines of therapy. Promising clinical decreased, although it is still considered the only therapeutic activity of this chemo-free combination supports further clin- option with curative potential. In the recent retrospective ical evaluation in high-risk CLL patients, especially those analysis of nearly 2600 CLL patients who received alloHSCT with RS. between 2000 and 2010, estimated event-free survival (EFS), The clinical activity and safety profile of other checkpoint OS and non-relapse mortality (NRM) 10 years after alloHSCT inhibitors, namely, anti-PD-L1 monoclonal antibodies (i.e. ate- were 28%, 35% and 40%, respectively [94]. Fifty-one percent of zolizumab and durvalumab) in patients with CLL are currently the patients had an HLA-identical sibling donor. Seventy- under investigation in phase I/II studies (NCT02846623, seven percent of patients had received reduced-intensity NCT02500407, NCT02733042). conditioning (RIC-alloHSCT). Patients who passed the 5-year A new target for immunotherapy in patients with CLL is the landmark EFS had a 79% probability of surviving the subse- CD200 antigen. It is expressed on the surface of leukemic cells quent five years without an event. Relapse and NRM contrib- in the vast majority of CLL cases [82] and interactions between uted equally to treatment failure [94]. CD200 and its receptor CD200R, expressed on immune effec- The updated results of the prospective GCLLSG CLL3X trial tor cells, are thought to be involved in the induction of of 90R/R CLL patients who received RIC-alloHSCT between immunosuppression [83]. Samalizumab, a novel recombinant 2001 and 2007 have been recently reported [95]. After humanized mAb binding to CD200 has recently been shown a median follow-up of nearly 10 years, PFS, OS and NRM to have a good safety profile and only modest activity when were 34%, 51% and 20%, respectively. The presence of del used as single agent in the phase I study comprising 23 (17p) or TP53mut had no negative impact on PSF or OS [95]. patients with R/R CLL [84]. Together, these data indicate that alloHSCT can provide long- term survival in a significant proportion of patients with high- risk R/R CLL and should remain an important consideration for highly-selected young and fit patients refractory to BCRi and 3. Anticancer vaccines BCL-2 antagonist [5]. However, obtaining a pre-transplant Anticancer vaccines aimed at stimulating the patient’sown remission may be a challenge in this patient group, especially immune system to eliminate malignant cells have been when high-risk cytogenetic and/or molecular factors are pre- investigated in many clinical trials, both in patients with sent. Therefore, another strategy that can be considered is to solid tumors and those with hematological malignancies. offer alloHSCT to selected high-risk CLL patients who have Despite many efforts, the development of an effective cancer failed ibrutinib, but who have responded to subsequent vene- vaccine remains a challenge. Different types of vaccines, like toclax or vice versa, if the reverse drug sequence has been autologous leukemic cells (oxidized [85], irradiated [86], used. In such a clinical situation, alloHSCT would constitute expressing CD40 L and IL-2 [87]) have been studied in consolidation therapy, but the optimal timing for alloHSCT is

Pobrano z https://publicum.umed.lodz.pl / Downloaded from Repository of Medical University of Lodz 2021-09-26 EXPERT OPINION ON BIOLOGICAL THERAPY 807 unknown. AlloHSCT should be strongly considered in CLL disease, characterized by the presence of TP53mut, del(17p) or patients with RS, especially those who developed RS during complex karyotype, had received liso-cel at two dose levels follow- treatment with BCRi or BCL-2 antagonist [5,79]. ing lymphodepleting chemotherapy. All patients had been previously treated with ibrutinib, and half of them had received prior venetoclax. The best ORR in 15 evaluable patients was 87%. Seven 5. Chimeric antigen receptor T-cell therapy (47%) patients achieved CR, with or without complete blood count The chimeric antigen receptor (CAR) T-cell therapy is the most recovery. MRD negativity in PB was achieved in 10/15 patients sophisticated immunotherapeutic approach so far introduced (67%) and in 7/8 patients (88%) in BM. Therapy was characterized into clinical practice. A CAR is a complex synthetic construct by a manageable toxicity profile, with cytopenias as the most that transfected into T cells enables to recognize the specific common grade 3 or 4 treatment-emergent AEs. Grade 3 CRS and antigen on the surface of tumor cells irrespective of MHC neurotoxicity was noted in 1 patient and 3 patients, respec- restriction [96]. The manufacture of CAR T-cells is tively [103]. a technologically advanced and highly expensive process. The results of a recent phase I/II study reported by Gauthier Autologous T-cells are first collected from the patient via et al. suggest that concomitant use of ibrutinib is associated apheresis. Following this, a viral vector is used to introduce with a reduction in the incidence of severe CRS and may genetic constructs containing multiple genes for CAR into the improve response in patients with R/R CLL treated with anti- T-cells genome, which ultimately leads to CAR expression at CD19 CAR-T cell immunotherapy [104]. Two R/R CLL patient the surface of genetically modified T-cells. Once the CAR cohorts were evaluated in this study. In the first cohort, 19 T-cells are produced, they are expanded ex vivo and then re- patients received FC lymphodepletion followed by anti-CD19 infused to the patient following lymphodepleting chemother- CAR-T infusion (non-Ibru cohort). In the second cohort of 17 apy [97–99]. It is worth mentioning that considerable variation patients, concurrent ibrutinib given from at least two weeks has been found to exist between the better-studied types of prior to apheresis until at least three months after anti-CD19 anti-CD19 CAR-T cells, i.e. tisagenlecleucel (tisa-cel), axicabta- CAR-T cells infusion was used (Ibru cohort). Sixteen (94%) and gene ciloleucel (axi-cel) and lisocabtagene maraleucel (liso-cel) 18 (95%) patients in the Ibru and non-Ibru cohorts, respec- , despite being directed against the same antigen. This varia- tively, were evaluable for response. A higher proportion of tion mainly, but not only, concerns their manufacturing pro- responders was observed in the Ibru compared to the non- cess, CAR constructs, effective dose and toxicity profile [100]. Ibru cohort (ORR of 88% vs. 56%, respectively, p = 0.06). Four Both tisa-cel and axi-cel, have been recently approved by the weeks after treatment, flow cytometry revealed no residual US Food and Drug Administration and the European Medicines CLL cells in BM in 23 (64%) out 36 patients. More frequent Agency for the treatment of R/R ALL in pediatric and young adults MRD negativity, assessed in BM by sequencing techniques, (tisa-cel), and for the treatmentofR/RdiffuselargeBcelllym- was observed in the Ibru cohort compared to the non-Ibru phoma in adults (tisa-cel and axi-cel) [97–99,101]. cohort (83% vs. 60%, p = 0.35). The proportions of grade ≥1 There are several early-phase studies assessing the useful- CRS were similar between cohorts; however, the severity of ness of anti-CD19 CAR-T cell therapy for the treatment of R/R CRS was lower in the Ibru cohort (grade ≥3 CRS 0% vs 26% in CLL that merit particular attention. the Ibru and non-Ibru cohort, respectively; p = 0.05) [104]. In a phase I/II study reported by Turtle et al., 24 heavily Another recent pilot study suggested that ibrutinib may pretreated CLL patients with a median of five previous thera- enhance responses during anti-CD19 CAR-T cell therapy [105]. pies were included [102]. All patients had high-risk disease, This study was included patients with CLL who did not achieve with RS, del(17p) and complex karyotype found in 21%, 60% CR despite at least six months of ibrutinib used in the frontline and 67% of cases, respectively. Nineteen patients (80%) (five patients) or R/R settings (14 patients). Patients underwent experienced prior disease progression on ibrutinib, three lymphodepleting chemotherapy followed by anti-CD19 CAR-T (12,5%) were ibrutinib intolerant, and six (25%) were veneto- therapy. At least PR was achieved in 10 (71%) out of 14 clax refractory. Twenty of the 24 patients received anti-CD19 patients who were evaluable three months after CAR T-cell CAR-T infusion following FC lymphodepletion. At least PR was infusion. CR rate was 43%. The BM responses and MRD nega- achieved in 14 (74%) out of 19 patients who were restaged tivity (assessed by deep sequencing) at three months were four weeks after CAR T-cell infusion (CR 21%; PR 53%). MRD observed in 17 (94%) out of 18 and 14 (78%) out of 18 negativity by flow cytometry was observed in 15 (88%) out of patients, respectively [105]. 17 patients with initial BM involvement; twelve of these Advances in CAR-T cell technology, growing knowledge about patients were evaluated by IGH sequencing to detect residual their biology and increasing clinical experience in managing their CLL cells in BM, and nearly 60% of them lacked detectable toxicity mean that in the near future, CAR-T cell therapy will play an malignant IGH copies. The absence of the malignant IGH clone increasingly important role in treating patients with CLL, especially in BM was associated with 100% PFS and OS after a median those with high-risk disease who have failed treatment with BCRi follow-up of 6.6 months. The main toxicities of CAR-T cell and BCL-2 antagonist, or those who have experienced disease therapy were cytokine release syndrome (CRS) and neurotoxi- progression in the form of RS. Currently, a variety of constructs city; the former occurred in 20 (83%) of the 24 patients and are being evaluated in numerous early phase studies, including the latter in eight (33%), with two fatal cases [102]. bispecific CAR-T cells (directed against CD19 and CD20 Recently, the preliminary results of the phase I/II TRANSCEND [CT04007029; NCT03398967] or against CD19 and CD22 CLL 004 study have been reported [103]. A total of 16 heavily [NCT03398967; NCT03448393]), armored CAR-T (CAR-T cells with pretreated patients with R/R CLL, of whom 75% had high-risk additional genetic modifications to improve anti-tumor activity

Pobrano z https://publicum.umed.lodz.pl / Downloaded from Repository of Medical University of Lodz 2021-09-26 808 I. HUS ET AL. and persistence after infusion [106]) (NCT03085173), anti-CD19 However, for all small agents used in monotherapy, continuous CAR T cells in monotherapy (NCT01853631; NCT01865617; treatment is necessary and only PR could be achieved in most NCT03068416; NCT03853616; NCT03624036; NCT03331198) or in patients. Therefore, attempts have been undertaken to improve combination with ibrutinib (NCT03960840, NCT02640209; their efficacy by different combinations, including those with NCT03331198), checkpoint inhibitors (NCT00586391) or with mAbs. Clinical trials have demonstrated that the addition of ritux- alloHSCT (NCT03110640; NCT02050347), as well as anti-CD20 imab did not improve the efficacy of ibrutinib; however, the CAR T cells (NCT03277729; NCT03576807) and anti-ROR1 CAR-T MURANO trial found the combination of rituximab with venetoclax cells (NCT02706392). to result in MRD negativity in 62% of R/R CLL patients. Eradication of MRD was associated with prolonged PFS, analogous to observations from the CLL8 and CLL11 trials. These deep molecular 6. Conclusion responses achieved with venR allow this combination to be used for a fixed-duration period of two years, as indicated by both the Nowadays, biologics, especially passive immunotherapy with FDA and EMA. Since remissions were reported after re-initiation of monoclonal antibodies can be regarded alongside chemother- venetoclax,thisprotocolisemergingasaparticularlyvaluable apy, BCL-2 and BCR inhibitors as standard methods of CLL clinical option in the treatment of R/R CLL. treatment. The combination of anti-CD20 mAbs with different Regarding the first-line setting, the CLL14 clinical study chemotherapy regimens are widely used as first line therapy in reported that venO combo, used for fixed-duration treatment of patients without del(17p)/TP53mut and in relapsed patients 12 months, yielded a CR of 50% and MRD negativity of 75% (PB). with prolonged response after immunochemotherapy. Though the study population included only unfit CLL patients, Protocols with BCL-2 inhibitor venetoclax combined with anti- venO was approved by FDA in May 2019 in whole population of CD20 mAbs have recently entered clinical practice, both in CLL patients treated with first-line therapy and this protocol is relapsed and first line settings. New mAbs directed against currently under evaluation in EMA. Also, iO combination was CD20 and other antigens, as well as cellular immunotherapy approved by FDA in January 2019 in treatment-naive CLL patients with CAR-T cells, are under evaluation in clinical trials. as a first non-chemotherapy combination regimen; however, in Adoptive immunotherapy with CAR-T is an area of intensive this protocol, ibrutinib is used continuously. research in R/R CLL patients. Even with the availability of novel targeted therapies and their combinations, alloHSCT remains the only method with curative potential in patients with CLL and still should be 7. Expert opinion considered in young and fit high-risk R/R CLL, refractory to During recent years, the landscape of CLL treatment has or relapsing after the treatment with BCRi or BCL-2 antagonist, rapidly evolved from one that has placed chemotherapy as and in patients with RS. The other form of cellular immu- the mainstay of therapy, through the development of immunotherapy, DC vaccines, have so far demonstrated only mod- nochemotherapy, to the chemo-free regimens used today. The est activity in patients with CLL, despite their proven ability to incorporation of CD20-mAbs (rituximab, obinutuzumab) into induce leukemia-specific T-cell responses. Therefore, further first-line chemotherapy protocols have significantly improved development of this personalized immunotherapy would the prognosis of CLL patients, with increasing response rates require the identification of more efficient strategies. and PFS, but most of all, OS. Regarding the future perspectives for CLL therapy, the role The results of phase III clinical studies indicated that CD20- of immunochemotherapy is undoubtedly receding. However, mAbs are best used in combination with chemotherapeutic since CD20 mAbs not only significantly increase the efficacy of agents, such as FC, B or Chl, depending on the patient age and chemotherapy, and that of BCL-2 inhibitors, allowing for time- presence of comorbidities. However, no such improvement was limited treatment, their role in CLL treatment remains unwa- observed in patients with del(17p)/TP53mut, and more recently, vering. Among the new mAbs, anti-CD20 directed umbralisib patients with non-mutated IGVH were found to receive little ben- and anti-ROR1 directed cirmtuzumab seem to have the most efit from immunochemotherapy. In a recently published phase III promising results. clinical trial comparing iR with FCR as first line therapy in fit CLL A new method of biologic therapy approved for patients patients without del(17p)/TP53mut, any PFS and OS benefit asso- with lymphoid malignancies is adoptive immunotherapy with ciated with iR was mainly demonstrated by IGVH non-mutated CAR-T cells; a strategy which is also likely to play an increas- patients. On the other hand, in the CLL8 study, the plateau ingly important role in the treatment of CLL. Though earlier observed in the survival curves of the IGVHmut patients with studies have found CAR-T cells to be much less effective in MRD eradication after first line therapy with FCR suggests that patients with CLL than in those with ALL or aggressive non some of these patients might even be cured with this protocol, Hodgkin lymphomas, the preliminary results of novel strate- or at least achieve long-lasting survival after time-limited therapy. gies combining CAR-T cells with ibrutinib are much more Therefore, for the population without del(17p)/TP53mut and with encouraging, giving hope for achieving remission in patients IGHVmut, immunochemotherapy is still regarded as the treatment with CLL refractory to all other methods of treatment. of choice. New targeted therapies with small agents, like BCRi (ibrutinib, idelalisib) and BCL-2 antagonist (venetoclax) have emerged as effective treatments increasing response rates and Acknowledgments OS in patients with del(17p)/TP53mut, unmutated IGVH genes We thank Edward Lowczowski from the Medical University of Lodz for and with short response or resistance to immunochemotherapy. editorial assistance.

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Funding 13. Fischer K, Bahlo J, Fink AM, et al. Long-term remissions after FCR chemoimmunotherapy in previously untreated patients with CLL: The study was supported in part by grants funding from the Medical updated results of the CLL8 trial. Blood. 2016;127:208–215. University of Lodz, Poland: No. 503/1-093-01/503-11-004-18 •• Clinically important data on the long-term efficacy of FCR immunochemotherapy in CLL patients with mutated IGVH. 14. Thompson PA, Tam CS, O’Brien SM, et al. Fludarabine, cyclopho- Declaration of Interest sphamide, and rituximab treatment achieves long-term disease-free survival in IGHV-mutated chronic lymphocytic The authors have no other relevant affiliations or financial involvement leukemia. Blood. 2016;127:303–309. with any organization or entity with a financial interest in or financial 15. Eichhorst B, Fink A-M, Bahlo J, et al. First-line chemoimmunotherapy conflict with the subject matter or materials discussed in the manuscript with bendamustine and rituximab versus fludarabine, cyclophospha- apart from those disclosed. Writing assistance was not utilized in the mide, and rituximab in patients with advanced chronic lymphocytic production of this manuscript. leukaemia (CLL10): an international, open-label, randomised, phase 3, non-inferiority trial. Lancet Oncol. 2016;17:928–942. •• A pivotal study demonstrating the superiority of FCR over BR Reviewer Disclosures protocol in the first-line therapy of younger, fit CLL patients. 16. Foà R, Del Giudice I, Cuneo A, et al. Chlorambucil plus rituximab Peer reviewers on this manuscript have no relevant financial relationships with or without maintenance rituximab as first-line treatment for or otherwise to disclose. elderly chronic lymphocytic leukemia patients. Am J Hematol. 2014;89:480–486. 17. Hillmen P, Gribben JG, Follows GA, et al. 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