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short review memo (2020) 13:259–265 https://doi.org/10.1007/s12254-020-00615-y Fine-tuning front-line therapy in chronic lymphocytic leukemia News from ASH 2019 Jan-Paul Bohn · Dominik Wolf Received: 1 April 2020 / Accepted: 28 April 2020 / Published online: 19 May 2020 © The Author(s) 2020 Summary A deeper understanding of disease bi- (CLL). In particular, the Bruton’s kinase (BTK) in- ology and the advent of targeted drugs have im- hibitor ibrutinib and the B-cell lymphoma 2 (BCL2) plemented chemotherapy-free treatment options in inhibitor venetoclax +/– CD20 antibody have become chronic lymphocytic leukemia (CLL). With consis- front-line treatment of choice in vast parts of the tently superior outcome data and good tolerability, CLL patient spectrum based on consistently supe- the Bruton’s kinase inhibitor ibrutinib as well as the rior outcome and tolerability data when compared to B-cell lymphoma 2 inhibitor venetoclax +/– CD20 chemoimmunotherapy (CIT) [1–4]. Nonetheless, re- antibody have recently been licensed for first-line lapse due to acquired resistance and drug intolerance treatment independently of TP53 status and are cur- remain major hurdles in patient management [5]. rently recommended as therapy of choice in most Current clinical trials focus on the most promis- patient subgroups according to international man- ing sequences and combinations of targeted drugs to agement guidelines. Survival curves, however, have prevent resistance formation by enhancing eradica- not reached a plateau and relapse due to acquired tion of minimal residual disease (MRD) and optimize resistance or drug intolerance remain major hurdles drug tolerability. This short review provides an up- in CLL treatment. Clinical trials currently focus on date on currently ongoing first-line clinical trials in the most promising combinations and sequences of CLL presented at ASH (American Society of Hematol- highly effective targeted drugs aimed at avoiding drug ogy) 2019 and discusses clinically relevant obstacles resistance by further enhancing eradication of mini- to overcome. malresidualdisease andoptimizing drug tolerability. This brief review provides an update on the recently Targeting Bruton’s tyrosine kinase presented clinical trial data in first-line CLL at ASH 2019 and discusses clinically relevant obstacles to Aberrant B-cell receptor (BCR) signaling plays a key overcome. pathogenetic role in CLL by regulating several path- ways essential for B-cell proliferation and apoptosis Keywords First-line · Ibrutinib · Acalabrutinib · [6]. BTK functioning downstream of BCR can be se- Venetoclax · Obinutuzumab lectively targeted and has provided the framework for the striking efficacy seen with the BTK inhibitor ibru- tinib in CLL treatment [7]. Introduction At ASH 2019 follow-up the ECOG-ACRIN E1219 Novel scientific insights into disease biology have phase 3 study investigating ibrutinib plus the CD20 facilitated introduction of targeted therapies to the antibody rituximab versus CIT with fludarabine, cy- treatment landscape of chronic lymphocytic leukemia clophosphamide and rituximab (FCR) in treatment- naïve fit CLL patients without deletion 17p was pre- sented and confirmed prolonged progression-free J.-P. Bohn, MD, PhD ()·Prof.D.Wolf, MD survival (PFS) at 3 years with ibrutinib plus rituximab, Department of Internal Medicine V, Hematology including at least equal efficacy even in the subgroup and Oncology, Medical University of Innsbruck, of patients with unmutated immunoglobulin heavy- Anichstraße 35, 6020 Innsbruck, Austria jan-paul.bohn@i-med.ac.at chain genes (IGHV). The 3-year overall survival (OS) K Fine-tuning front-line therapy in chronic lymphocytic leukemia 259 short review Table 1 Efficacy of targeted drugs in treatment-naive CLL patients i n selected randomized controlled clinical trials presented at ASH 2019 Trial Regimen n Agea ORR CR PR uMRD PFS OS ECOG- Ibrutinib 420 mg/d, d1–28, until PD 354 58 96% 17% NA 8% 3 years 3 years ACRIN Rituximab 50/325 mg/m , d1/2, cycle 2 89% 99% IGHV E1912 [3, Rituximab 500 mg/m , d1, cycles 3–7 UM M 8] 89% 88% (n = 210) (n = 70) Fludarabine 25 mg/m , d1–3 175 57 81% 30% NA 59% 71% 65% 82% 93% Cyclophosphamide 250 mg/m , d1–3 (n = 71) (n = 44) Rituximab 50/325 mg/m , d1/2, cycle 1 Rituximab 500 mg/m , d1, cycles 2–6 ELEVATE Acalabrutinib 100 mg bid until PD 179 70 94% 13% 81% NA 2-years 2-years TN [11] Obinutuzumab 1000 mg d1, 2, 8, 15 93% 95% IGHV cycle 2 Obinutuzumab 1000 mg d1 cycles 3–6 UM M 89% 96% (n = 103) (n = 74) Acalabrutinib 100 mg bid until PD 179 70 86% 1% 85% NA 87% 87% 83% 94% (n = 119) (n = 58) Chlorambucil 0.5 mg/kg d1, 15 for 6 cy- 177 71 79% 5% 74% NA 47% 33% 76% 90% cles (n = 116) (n = 59) Obinutuzumab 1000 mg d1, 2, 8, 15 cycle 2 Obinutuzumab 1000 mg d1 cycles 3–6 CLL14 [4, Venetoclax Ramp-up starting d22 of 216 72 85% 50% 35% 76% 3-years 3-years 26] cycle 1 57% 82% 87% IGHV Venetoclax 400 mg/d cycles 3–12 (BM) Obinutuzumab 1000 mg d1, 8, 15 UM M cycle 1 ≈80% ≈90% Obinutuzumab 1000 mg d1 cycles 2–6 (n = 133) (n = 83) Chlorambucil 0.5 mg/kg d1, 15 for 12 cy- 216 71 71% 23% 48% 35% 50% ≈30% ≈75% 87% cles 17% (n = 127) (n = 86) Obinutuzumab 1000 mg d1, 8, 15 cy- (BM) cle 1 Obinutuzumab 1000 mg d1 cycles 2–6 –4 ORR overall response rate, CR complete response rate, PR partial response rate, uMRD rate of patients with undetectable minimal residual disease (<10 )in peripheral blood, BM bone-marrow, PFS progression-free survival, OS overall survival, NA not available, IGHV immunoglobulin heavy-chain genes, UM unmutated, M mutated, d day, bid twice a day, PD progressive disease, CLL chronic lymphocytic leukemia Median, years benefit for the experimental study cohort persisted PFS was significantly prolonged with acalabrutinib, based on very few events (Table 1). Nevertheless, after a benefit that was consistent across all subgroups, a median time on treatment of 15.1 months, 21% of including patients with TP53 dysfunction, deletion patients (n = 352) discontinued ibrutinib for reasons 11q and/or complex karyotype. Of interest, there other than disease progression or death, including was a trend towards an additional benefit in over- adverse events (AE) such as arterial hypertension, all response rate (ORR) and PFS when acalabrutinib cardiac events, and arthralgia in 51% of cases (Ta- was combined with obinutuzumab (Table 1). The ble 2). In these patients, median PFS after drug drug discontinuation rate of approximately 20% due discontinuation was confined to 22.5 months [8]. to reasons other than disease progression or death Facing the relatively high rate of drug discontinu- was similar among study arms and mostly due to AE ations due to AE, efforts have been made to develop (9–14%). The most common AE with acalabrutinib next-generation BTK inhibitors with a more favorable were headache, diarrhea, fatigue, and arthralgia (Ta- toxicity profile. As many AE with ibrutinib are con- ble 2). A higher incidence of neutropenia (32% vs. sidered a result of kinase inhibition beyond the BTK, 12%) as well as high-grade infections, foremost pneu- more selective second-generation BTK inhibitors such monia (6.7% vs. 2.8%), was reported with the addition as acalabrutinib have been developed [9, 10]. of obinutuzumab. Notably, low-grade bleeding events At ASH 2019 early results of ELEVATE TN, a phase 3 were more frequent with acalabrutinib with/without study investigating acalabrutinib alone or in combi- obinutuzumab compared to GClb (40% vs. 11%) [11]. nation with the CD20-antibody obinutuzumab versus A comparative controlled randomized trial in re- chlorambucil and obinutuzumab (GClb) in previously lapsed high-risk CLL patients is ongoing to help define untreated CLL patients were presented. The 2-year 260 Fine-tuning front-line therapy in chronic lymphocytic leukemia K short review Table 2 Most common adverse events of novel agents in binding site at C481 and, thus, remain susceptible to presented phase III studies resistance formation via C481S mutations [15]. Clinical trial E1912 [8] ELEVATE TN [11] CLL14 [4] Reversible BTK inhibitors such as LOXO-305 rep- Regimen IR Acala ± G VenG resent a novel class of compounds, which do not re- quire covalent binding to BTK and may be effective Baseline characteristics regardless of C481S mutations [16]. At ASH 2019 very n 354 358 216 a early results of a phase 1 study investigating LOXO-305 Age 57 70 72 in patients with relapsed B-cell malignancies demon- ECOG 0–2 0–2 0–3 strated a PR in all 5 CLL patients evaluable for re- Follow-up 48 28 28 sponse, including one patient harboring a C481S mu- Adverse events grade 1–4 tation [17]. At this early stage, however, the role of Diarrhea % NA 35–39 28 non-covalent BTK inhibitors in CLL treatment is un- Nausea % NA 20–22 19 clear and remains to be better defined in comparative Fatigue % NA 18–28 15 randomized clinical trials. Headache % NA 37–40 11 Bleeding % NA 39–43 NA Targeting B cell lymphoma 2 Cough % NA 18–22 16 The B cell lymphoma 2 (BCL2) family encompasses URTI % NA 18–21 NA pro- and anti-apoptotic proteins, which operate in Arthralgia % NA 16–22 NA concert to keep the balance between cell survival and Neutropenia % NA 11–32 58 cell death [18]. CLL cells typically evade apoptosis by Hypertension % NA 5–7 NA overexpression of prosurvival protein BCL2 via sev- Atrial fibrillation % NA 3–4 NA eral mechanisms, including BCL2 repressor deletion Adverse events grade 3–4 as a result of deletion 13q [19, 20]. Venetoclax, a BCL2 inhibitor, causes prompt apoptosis of CLL cells and Pneumonia % 7 32–39 4 has proven high ORR and durable remissions in re- Febrile neutropenia 2 1–2 5 lapsed refractory CLL patients, including those failing Neutropenia % 26 10–30 53 BTK inhibition [21, 22]. Although undetectable MRD Anemia % 4 2 8 –4 (uMRD, <10 ) is frequently observed with venetoclax Thrombocytopenia % 3 NA 14 [23], long-term monotherapy commonly leads to ac- Hypertension % 9 2–3 NA quired resistance [24]. Similar to ibrutinib, continuous Atrial fibrillation % 3 0–1 0.5 selection pressure is considered to drive clonal evolu- Drug discontinuations due to adverse events % tion towards resistance formation [25]. 14 9–11 16 Recently, venetoclax plus obinutuzumab (VenG) n number, URTI upper respiratory tract infection, IR Ibrutinib/Rituximab, was approved as first chemotherapy-free fixed-dura- Acala Acalabrutinib, G Obinutuzumab, VenG Venetoclax/Obinutuzumab, tion regimen in first-line treatment by the European NA not available, CLL chronic lymphocytic leukemia Medicines Agency. At ASH 2019, the underlying CLL14 Median, years trial, which randomized treatment-naïve CLL patients Median, months with comorbidities to VenGorGClb, was updated [4]. With a 40 month follow-up, the PFS advantage for whether acalabrutinib is indeed superior to ibrutinib the experimental study arm persisted with survival (NCT02477696). curves further separating after end of fixed-duration Despite high ORR and long-term remissions ac- treatment at month six. As seen with other novel complished with BTK inhibition even in genetic high- compounds in CLL, the PFS benefit is mainly derived risk patients, MRD frequently persists and indefinite from the subgroup of patients with unmutated IGHV- therapy appears obligatory [12]. The consequence of status with PFS curves splitting in the first 6 months. continuous selection pressure, however, may provoke Three months after completion of treatment, a re- resistance formation [13]. Indeed, CLL cells of pa- markably higher rate of uMRD was confirmed for tients progressing under ibrutinib commonly harbor VenG (Table 1). Notably, next-generation sequencing –6 cysteine to serine mutations in BTK at the cysteine analysis demonstrated uMRD of <10 in 42% of pa- 481 residue (C481S) keeping ibrutinib off its binding tients. Although uMRD appears to remain stable on site or gain-of-function mutations of PLCG2 that re- treatment, MRD kinetics off treatment reveal reoccur- activate hyperactive BCR signaling. Of interest, these rence over time. Nevertheless, uMRD correlates with resistance mutations seem to develop early after a me- PFS, as demonstrated by durable remissions in 90% dian of only 9.4 months on treatment [14]. of uMRD patients with 24 months of follow-up [26]. Although second-generation inhibitors such as VenG was generally well tolerated. Table 2 provides acalabrutinib offer more selectivity for BTK than ibru- an overview of most frequently observed AE. tinib, all of these agents share the same covalent K Fine-tuning front-line therapy in chronic lymphocytic leukemia 261 short review Table 3 Efficacy of targeted drugs in treatment-naive CLL pat ients in selected phase 2 trials presented at ASH 2019 Trial Regimen n Age ORR CR/CRi PR uMRD PFS OS CAPTIVATE Ibrutinib 420 mg/d, d1–28, cycles 1–15 164 58 100% NA NA 74% NA NA IGHV MRD Cohort Venetoclax Ramp-up starting cycle 4 68% UM M [28] Venetoclax 400 mg/d cycles 4–15 (BM) NA NA (n = 97) (n = 67) NCT02756897 Ibrutinib 420 mg/d, d1–28, cycles 1–27 80 65 100% 96% 4% 75% 2 years 2 years [29] Venetoclax Ramp-up starting cycle 4 (BM) ≈96% ≈98% IGHV Venetoclax 400 mg/d cycles 5–27 UM M NA NA (n = 63) (n = 13) NCT02629809 Ibrutinib 420 mg/d, d1–28, cycles 1–12 45 60 100% 73% 35% 100% 3 years 3 years [31] Obinutuzumab 1000 mg d1/2, 8, 15, (BM) ≈97% ≈97% cycle 1 Obinutuzumab 1000 mg d1, cycles 2–6 Fludarabine 25 mg/m , d1–3, cycles 1–3 Cyclophosphamide 250 mg/m , d1–3, cycles 1–3 Obinutuzumab 1000 mg d1, cycles 7–9 pos if PR or BM-MRD after cycle 6 Ibrutinib 420 mg/d, d1–28, until PD pos If BM-MRD after cycle 12 –4 ORR overall response rate, CR complete response rate, PR partial response rate, uMRD rate of patients with undetectable minimal residual disease (<10 )in peripheral blood, BM bone marrow, PFS progression-free survival, OS overall survival, NA not available, IGHV immunoglobulin heavy-chain genes, UM unmutated, M mutated, d day, bid twice a day, PD progressive disease Median, years frequent non-hematologic grade 3–4 toxicities seen in Combined inhibition of BTK and BCL2 10% of cases each (Table 4). One patient died of sud- A critical mechanism of action of ibrutinib relies on den cardiac death [29]. With a median follow-up of separating CLL cells from their protective microenvi- nearly 2 years in both trials, only one patient of the ronment and, thus, depriving them from essential sur- CAPTIVATE MRD cohort has experienced disease pro- vival signals [6]. As a result, preclinical data demon- gression [28]. strated increased BCL2 dependence and expression of the anti-apoptotic protein BIM in the remaining CLL The role of chemoimmunotherapy cells resulting in increased sensitivity to venetoclax [27]. CIT has widely faded into the background with novel At ASH 2019 two phase 2 studies investigating fixed- agents demonstrating superior efficacy and good tol- duration ibrutinib plus venetoclax followed by MRD- erability in most patient subgroups. FCR has long guided maintenance in a total of 244 treatment-naïve been treatment of choice for young and fit CLL pa- CLL patients were updated. Treatment schedule en- tients without high-risk genetics achieving MRD neg- compassed a 3-month induction phase of ibrutinib ativity and long-term PFS ≥10 years in most cases [30]. followed by 12 months of combination therapy in the Recently, however, the E1912 trial suggested at least CAPTIVATE MRD cohort [28] and 24 months in the comparable outcomes with ibrutinib plus rituximab investigator initiated trial by Jain and coworkers [29], even in patients with mutated IGHV status. respectively. In all, 90% of the CAPTIVATE MRD co- At ASH 2019, the 30 month follow-up of the phase 2 hort (n = 164) completed combination treatment with iFCG trial investigating CIT with fludarabine, cy- uMRD in 74% of patients (Table 3). Common grade clophosphamide, and obinutuzumab in combination 3–4 AE included neutropenia (35%), infections (8%) with ibrutinib (iFCG) in 45 treatment-naïve IGHV- and hypertension (7%) and decreased over time with mutated CLL patients was presented. Treatment 39% of AE being reported within the first three cy- schedule incorporated three cycles of iFCG followed cles of combination treatment (Table 4;[28]). In all, by 9 months of ibrutinib paralleled by MRD-guided 86% of the patients (n = 80) reported by Jain and col- courses of obinutuzumab (Table 3). All 41 patients leagues completed 24 months of combination therapy completing 12 months of treatment achieved uMRD and 75% of them achieved uMRD in the bone marrow in the bone marrow. The most common grade 3–4 AE (Table 3). Most common grade 3–4 hematologic toxi- are summarized in Table 4. Three patients discon- city was neutropenia seen in 51% of patients. Besides tinued therapy due to AE including one 26-year-old infections (19%, foremost pneumonia), atrial flutter/ patient who died of new onset congestive heart failure fibrillation and arterial hypertension were the most [31]. 262 Fine-tuning front-line therapy in chronic lymphocytic leukemia K short review Table 4 Most common Clinical trial CAPTIVATE NCT02756897 [29] NCT02629809 [31] adverse events of novel MRD Cohort [28] agents in presented phase II Regimen Ibr-Ven Ibr-Ven iFCG studies Baseline characteristics n 164 80 45 Age 58 65 60 Follow-up 15 27 34 Adverse events grade 1–4 Diarrhea % 60 50 NA Nausea % 35 40 NA Fatigue % 21 16 NA Headache % 17 8 NA Bleeding % NA 77 NA Cough % NA NA NA URTI % 25 NA NA Arthralgia % 20 50 NA Neutropenia % 40 NA NA Hypertension % 12 16 NA Atrial fibrillation % NA 15 11 Adverse events grade 3–4 Pneumonia % NA 19 6 Neutropenia % 35 51 58 Febrile neutropenia 1 NA 13 Thrombocytopenia % 5 2 40 Hypertension % 7 10 NA Atrial fibrillation % 1 10 NA Drug discontinuations due to adverse events % 5 8 7 n number, URTI upper respiratory tract infection, Ibr-Ven ibrutinib/venetoclax, iFCG ibrutinib, fludarabine, cyclophos- phamide, obinutuzumab, NA not available Median, years Median, months All infections Longer follow-up will help determine whether CIT at convenient drug tolerability possibly inhibiting sec- ± novel compounds remains an appropriate first-line ondary resistance formation. Longer follow-up will option for fit patients with low-risk disease. help elucidate whether these combined fixed-dura- tion treatment approaches embrace the ability to ul- timately cure CLL in individual patients. Conclusion The advent of novel compounds has facilitated a par- Take home message adigm shift in CLL treatment from unspecific DNA damaging agents to targeted therapy. Foremost, BTK- Targeted therapies have become r fi st-line treatment and BCL2- inhibitors allow remarkably high ORR and of choice in most patients with chronic lymphocytic long-term PFS even in genetic high-risk patients. leukemia. Indefinite treatment, however, is commonly as- Inden fi ite treatment may drive clonal evolution to- sociated with acquired resistance formation within wards resistance formation and hamper drug tolera- months unleashing the need to pursue more effec- bility. tive fixed-duration regimens. VenG has recently been Clinical trials currently focus on x fi ed-duration com- approved for front-line therapy as the first chemother- binations of highly effective targeted drugs in order apy-free fixed-duration regimen and has found inte- to prevent acquired resistance and reduce treatment- gration in widely accepted international treatment related toxicity. guidelines. Funding Open access funding provided by University of Inns- Clinical trials currently focus on the most promis- bruck and Medical University of Innsbruck. ing combinations and sequences of highly effective targeted drugs with unprecedentedly high uMRD rates K Fine-tuning front-line therapy in chronic lymphocytic leukemia 263 short review Conflict of interest J.-P. Bohn reports personal fees from invivopotencyprofile. JPharmacolExpTher. 2017;https:// AbbVie and Astra-Zeneca for advisory board participation. doi.org/10.1124/jpet.117.242909. D. Wolf declares that he has no competing interests. 10. Byrd JC, Harrington B, O’Brien S, Jones JA, Schuh A, Dev- ereux S, et al. Acalabrutinib (ACP-196) in relapsed chronic Open Access This article is licensed under a Creative Com- lymphocytic leukemia. N Engl J Med. 2015;374(4):323–32. mons Attribution 4.0 International License, which permits https://doi.org/10.1056/NEJMoa1509981. use, sharing, adaptation, distribution and reproduction in 11. SharmanJP, BanerjiV,Fogliatto LM,Herishanu Y, Mu- any medium or format, as long as you give appropriate credit nir T, Walewska R, et al. ELEVATE TN: phase 3 study to the original author(s) and the source, provide a link to of acalabrutinib combined with obinutuzumab (O) or the Creative Commons licence, and indicate if changes were alone vs O plus chlorambucil (Clb) in patients (pts) made. 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Ibrutinib(Ibr) plus Venetoclax(Ven) for first-linetreatment memo-inoncology of chronic lymphocytic leukemia (CLL)/small lymphocytic Lymphoma(SLL):ResultsfromtheMRDcohortofthephase K Fine-tuning front-line therapy in chronic lymphocytic leukemia 265
memo - Magazine of European Medical Oncology – Springer Journals
Published: Sep 1, 2020
Keywords: oncology; medicine/public health, general
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