short review memo (2018) 11:105–108 https://doi.org/10.1007/s12254-018-0414-0 David Wanner · Michael Steurer Received: 12 April 2018 / Accepted: 16 May 2018 / Published online: 1 June 2018 © The Author(s) 2018 Summary At ASH (American Society of Hematol- Venetoclax plus rituximab is a new standard of ogy) 2017 three out of a plethora of trials showed care for relapsed/refractory CLL remarkable and promising results. The combinations of venetoclax with rituximab and ibrutinib with vene- The MURANO trial, presented by John Seymour et al., toclax convinced with striking efﬁcacy together with a compared the efﬁcacy and safety of the Bcl2-in- manageable safety proﬁle in relapsed/refractory set- hibitor venetoclax in combination with rituximab to ting as well as in ﬁrst line therapy of high-risk disease. the combination of bendamustine and rituximab in These two combinations are potential new standard patients with relapsed/refractory CLL. In this mul- treatment options in chronic lymphocytic leukemia. ticenter phase III trial n = 389 patients were ran- domized to receive either venetoclax plus rituximab Keywords Chronic lymphocytic leukemia · Ibrutinib · or bendamustine plus rituximab. Inclusion criteria Venetoclax · ASH comprised prior treatment with 1–3 lines of ther- apy (including ≥1 chemo-containing regimen), age over ≥18 years and a response duration of at least Introduction 24 months if prior treatment included bendamus- Over the last years the development of novel agents tine. Primary endpoint was the local investigator like ibrutinib, idelalisib and venetoclax led to a para- (INV) assessed progression-free survival (PFS), while digm shift in the treatment of chronic lymphocytic secondary endpoints include the review committee leukemia (CLL). Immunochemotherapy regimens are (IRC) assessed complete response rate (CR), the over- now more and more being replaced by targeted thera- all response rate (ORR) and overall survival (OS) as pies due to superior efﬁcacy and better safety proﬁles, well as IRC assessed PFS and MRD(minimal residual in particular for patients with relapsed disease [1–4]. disease)-negativity. The safety proﬁle was also a key Of the plethora of clinical data presented at the last endpoint of the trial. In the venetoclax plus ritux- annual meeting of the American Society of Hematol- imab arm, venetoclax was administered at a dosage ogy (ASH) this article will focus on two relevant tri- of 400 mg daily after standard dose escalation (“ramp- als: the MURANO trial setting a new standard of care up”) over 5 weeks. Rituximab was given over 6 cy- for relapsed/refractory disease and the CLARITY trial cles with an initial dosage of 375 mg/m at cycle 1, pointing out future developments for the treatment of followed by 500 mg/m at cycles 2–6. In the control CLL. arm bendamustine and rituximab (BR) were adminis- 2 2 tered at standard dosage of 70 mg/m and 375 mg/m , respectively (cycles 1–6). The INV and IRC ORR were both signiﬁcantly higher in the VenR (venetoclax+rituximab) arm (93.3% vs. 67.7%, p ≤ 0.0001 and 92.3% vs. 72.3%, p ≤ 0.0001). Median PFS was 18.1 months in the BR arm and has not been reached in the VenR arm (p < 0.0001). Sub- D. Wanner, MD ()· M. Steurer group analyses revealed no signiﬁcant differences in Medical University Innsbruck, Innsbruck, Austria David.Wanner@tirol-kliniken.at K Chronic lymphocytic leukemia at ASH 2017 105 short review Table 1 Baseline charac- Characteristics Cohort 1 Cohort 2 teristics, IGHV, cytogenetic Median age, years (range) 59 (32–76) 64.5 (35–82) and molecular genetic mu- Male, n (%) 30 (81) 30 (75) tational status  Median prior tx, n (range) 1 (1–4) – FISH, n (%) del (17p) 11 (30) 7 (18) del (11q) 14 (38) 10 (25) Trisomy 12 5 (14) 5 (12) Negative 2(5) 5 (12) del (13q) 5 (14) 13 (33) Unmutated IGHV, n/N (%) 27/31 (87) 30/37 (81) Cytogenetics n/N (%) Complex 5/29 (17) 6/39 (15) Diploid 10/29 (34) 16/39 (41) Mutations n/N (%) TP53 10/32 (31) 7/40 (18) NOTCH1 3/32 (9) 14/40 (35) SF3B1 7/32 (22) 11/40 (28) ZAP-70 (>20% or IHC+) 21/27 (78) 33/40 (83) CD38 > 30% 22/36 (61) 23/40 (58) FISH ﬂuorescence in situ hybridization, IGHV immunoglobuline heavy chain variable region, tx therapy PFS even in the presence of high-risk markers such as approach is based on the different modes of action del (17p), TP53 mutations or unmutated IGHV status. of these two drugs and the fact that ibrutinib en- With the exception of neutropenia (57.7% vs. hances the sensitivity of CLL cells to venetoclax . 38.8%) the experimental arm was superior concern- This sensitization is at least in part mediated by the ing the occurrence of grade 3–4 AEs. Tumor lysis ibrutinib-induced increased expression of BIM (Bcl- syndrome (TLS), a well-known complication of the 2-like protein) in CLL cells. BIM is a member of Bcl-2 initial phase of venetoclax treatment, could be effec- protein family and it has been shown to interact with tively prevented by mandatory safety measurements other members of the Bcl-2 group, including Bcl-2 as given in the protocol including hydration, use of and MCL-1, while acting as an apoptotic promoter allopurinol ± rasburicase, and meticulous laboratory . As mentioned above, the varying efﬁcacy of these controls. TLS occurred in 3.1% (vs. 1.1% with BR) and drugs in different CLL compartments, i. e., peripheral had clinical signiﬁcance in one patient in each treat- blood, bone marrow and lymph nodes, is another ment arm (acute renal failure and transient increase rationale for this new combination. Ibrutinib unfolds of creatinine values, respectively) . its impact very effectively primarily in lymph nodes Summing up, treatment with VenR represents a new and the bone marrow leading to a lymphocyte mobi- standard of care for relapsed/refractory CLL. Efﬁcacy lization from the protective microenvironment of the is signiﬁcantly superior to immunochemotherapy lymphatic tissues rendering CLL cells more suscepti- with BR and it displays a favorable safety proﬁle. ble to the action of venetoclax. Venetoclax, in turn, Based on these results regulatory submissions to is highly effective in the peripheral blood , thereby, health authorities are underway and a wider indica- enhancing the effects of ibrutinib in a synergistic tion for the use of venetoclax in CLL can soon be fashion. expected. The preliminary presentation of the phase I/II CLARITY trial comprised n = 54 patients with refrac- tory/relapsed CLL. Baseline characteristics included Ibrutinib plus venetoclax for relapsed/refractory a median age of 64 years (range 31–84 years), 74% suf- CLL fered from unmutated CLL and 20% were positive for Another novel treatment strategy presented at ASH is a del (17p). The participating patients had received the combination of the Btk-inhibitor ibrutinib with a median of one prior line of therapy (range 1–6). In venetoclax. Hillmen et al. (CLARITY trial) as well all, 81% had been pretreated with FCR (ﬂudarabin, cy- as Jain et al. explored the therapeutic potential clophosphamide, rituximab) or BR, whereas idelalisib and safety proﬁle of this combination in relapsed/ had been administered in 20%. refractory CLL and ﬁrst line in high-risk CLL patients, Patients are treated with ibrutinib at a standard respectively. The rationale behind this therapeutic dosage of 420mg perday for8 weeks followed by the 106 Chronic lymphocytic leukemia at ASH 2017 K short review addition of venetoclax, applying the usual weekly dose responses, longer response duration and treatment- escalation up to 400 mg daily. MRD is assessed ev- free intervals, respectively. However, this concept has ery 3 months in peripheral blood (PB) and after 6, 12 to be further explored in larger, randomized trials. and 24 months in bone marrow (BM). If MRD neg- In conclusion, the clinical data presented at ASH ativity is achieved (including PB and BM) after 6 or 2017 show that CLL treatment is moving away from 12 months, venetoclax will be stopped, whereas ibru- immunochemotherapy regimens towards targeted tinib is to be continued. If no sustained MRD negativ- treatment with novel agents. Whereas drugs like ity is achieved venetoclax will be re-administered for ibrutinib and idelalisib have already improved the another 24 months, and ibrutinib is given as long as outcome of many CLL patients in particular of those clinically indicated. with high-risk disease, novel combinations are be- The preliminary data presented at ASH 2017 showed ing developed as shown in the trials discussed above. the imposed results after treatment after 4 and Moreover, interesting new drugs (e. g., CC-122, second 8 months, respectively (n = 38 patients reached at generation Btk/PI3K inhibitors) and cellular therapies least the 8-month cut off). ORR at 8 months was (CAR T-cells) are also coming up making the future of 100%, whereof 39% achieved CR, 8% CR with incom- CLL patients look even brighter. plete bone marrow recovery and the remaining 53% Funding Open access funding provided by University of attained PR (partial remission). Concerning adverse Innsbruck and Medical University of Innsbruck. events and toxicity neutropenia was as expected the Conﬂict of interest D. Wanner and M. Steurer declare that most prevalent AE . they have no competing interests. The second trial exploring the combination of ibru- tinib and venetoclax is carried out by Jain et al. They Open Access This article is distributed under the terms of presented early data on n = 116 patients of a phase I/II the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which per- trial, including patients with relapsed/refractory CLL mits unrestricted use, distribution, and reproduction in any as well as untreated high-risk disease. High-risk dis- medium, provided you give appropriate credit to the origi- ease was deﬁned as at least one out of the follow- nal author(s) and the source, provide a link to the Creative ing characteristics: age ≥ 65, del (11q), del (17p), mu- Commons license, and indicate if changes were made. tated TP53 or unmutated IGVH status. In contrast to the CLARITY trial, patients receive ibrutinib for 28 days (4 weeks) before venetoclax dose escalation References (max. 400 mg) is initiated. Ibrutinib is administered 1. Brown JR, Hillmen P, O’Brien S, Barrientos JC, Reddy NM, until disease progression and venetoclax will be given Coutre SE, et al. Extended follow-up and impact of high- up to a maximum of 2 years. Primary endpoints are risk prognostic factors from the phase 3 RESONATE study the CR as well as the CRi rates as deﬁned by the IW- in patients with previously treated CLL/SLL. Leukemia. CLL 2008 criteria. The baseline characteristics and the 2018;32(1):83–91. mutational status are mapped at Table 1. 2. BurgerJA,TedeschiA,BarrPM,RobakT,OwenC,GhiaP,etal. At ASH the data of 77 patients, which were divided Ibrutinib as initial therapy for patients with chronic lym- into two cohorts (cohort 1: relapsed/refractory CLL, phocytic leukemia. N Engl J Med. 2015;373(25):2425–37. 3. Furman RR, Sharman JP, Coutre SE, Cheson BD, Pagel cohort 2: 1st line treatment of high risk disease), were JM, Hillmen P, et al. Idelalisib and rituximab in re- presented. Both cohorts showed impressive initial re- lapsed chronic lymphocytic leukemia. N Engl J Med. sponse rates (100%) as well CR rates of 77% (relapsed/ 2014;370(11):997–1007. refractory) and 80% (1st line), respectively. MRD nega- 4. Roberts AW, Davids MS, Pagel JM, Kahl BS, Puvvada SD, –4 tivity assessed by 4-color ﬂow with a sensitivity of 10 Gerecitano JF, et al. Targeting BCL2 with Venetoclax in revealed increasing rates over time with a rate of 46% relapsed chronic lymphocytic leukemia. N Engl J Med. 2016;374(4):311–22. MRD negativity in cohort 1 and 100% in cohort 2 af- 5. Seymour JF, Kipps TJ, Eichhorst B, Hillmen P, D’Rozario J, ter treatment over 12 months. However, the impres- Assouline S, et al. Venetoclax-Rituximab in relapsed or sive and promising results have to be interpreted with refractory chronic lymphocytic leukemia. N Engl J Med. caution due to the low patient numbers (n=5, n=3 af- 2018;378(12):1107–20. ter 12 months). As in the CLARITY trial, neutropenia 6. Deng J, Isik E, Fernandes SM, Brown JR, Letai A, Davids MS. was the most common grade 3/4 adverse event (44 Bruton’s tyrosine kinase inhibition increases BCL-2 depen- of 77 patients). Atrial ﬁbrillation, a typical AE caused dence and enhances sensitivity to venetoclax in chronic lymphocytic leukemia. Leukemia. 2017;31(10):2075–84. by ibrutinib, was the second most AE occurring in 10 7. Gogada R, Yadav N, Liu J, Tang S, Zhang D, Schneider A, et al. out of 77 patients. Concerning TLS only 2 cases of Bim, a proapoptotic protein, up-regulated via transcription laboratory TLS were observed . factor E2F1-dependent mechanism, functions as a prosur- Summing up, the combination of ibrutinib and vival moleculein cancer. J Biol Chem. 2013;288(1):368–81. venetoclax represents an attractive novel treatment 8. O’BrienS,JonesJA,CoutreSE,MatoAR,HillmenP,TamC,et option in CLL for both relapsed/refractory and previ- al. Ibrutinib for patients with relapsed or refractory chronic lymphocytic leukaemia with 17p deletion (RESONATE-17): ously untreated disease. In particular the high rates a phase 2, open-label, multicentre study. Lancet Oncol. of MRD-negativity achievable even in high-risk pa- 2016;17(10):1409–18. tients is promising potentially allowing for deeper K Chronic lymphocytic leukemia at ASH 2017 107 short review 9. Hillmen P, Munir T, Rawstron A, Brock K, Munoz VS, Yates F, et al. Initial results of Ibrutinib plus Venetoclax in relapsed, refractory CLL (bloodwise TAP CLARITY study): For latest news from interna- highratesofoverallresponse,completeremissionandMRD tional oncology congresses see: eradication after 6 months of combination therapy. Blood. http://www.springermedizin.at/ 2017;130(Suppl 1):428. memo-inoncology 10. JainN,etal. CombinedVenetoclaxandIbrutinibforpatients with previously untreated high-risk CLL, and relapsed/ refractory CLL: a phase II trial. ASH 59th Annual Meeting andExposition; 12.2017; Atlanta. 2017. Oral Abstract#429. 108 Chronic lymphocytic leukemia at ASH 2017 K
memo - Magazine of European Medical Oncology – Springer Journals
Published: Jun 1, 2018
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