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memo (2017) 10:52–57 DOI 10.1007/s12254-017-0340-6
American Society of Hematology 2016 annual meeting Novel strategies in the management of lymphoma Daniel Heintel
Received: 2 April 2017 / Accepted: 30 May 2017 / Published online: 19 June 2017 © Springer-Verlag Wien 2017
Summary At the last meeting of the American Society of Hematology (ASH), data on first-line treatment with obinutuzumab in indolent lymphoma, as well as promising data on the long-term observation of chronic lymphocytic leukemia (CLL) patients treated with ibrutinib, were presented. In diffuse large B-cell lymphoma (DLBCL), again, a more intensified treatment approach failed to improve patient survival. Moreover, and in contrast to indolent lymphoma, the use of obinutuzumab instead of rituximab (R) did not prove to be superior in DLBCL. However, data on lenalidomide maintenance, as well as data on novel agents in primary central nervous system lymphoma (PCNL), were presented. A survival benefit for R maintenance therapy could be shown in mantle cell lymphoma (MCL). Keywords Novel monoclonal antibodies · Novel inhibitors · Risk adapded therapies · Maintenance strategies
Introduction This review discusses promising new approaches in the management of lymphoma that were recently presented at the annual ASH meeting. This article concentrates on chronic lymphocytic leukemia (CLL), follicular lymphoma (FL), diffuse large B-cell lymphoma (DLBCL), and mantle cell lymphoma (MCL). The abstracts analyzed in this review reflect a selection of data clinically relevant in the author’s opinion and does not claim to be exhaustive in this broad field. D. Heintel, MD () First Medical Department, Center for Oncology and Hematology, Wilhelminenhospital, Montleartstrasse 37, 1160 Vienna, Austria
[email protected]
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Indolent lymphomas Follicular lymphoma Immunochemotherapy induction is the standard of care for patients with advanced-stage symptomatic follicular lymphoma (FL) [1]. However, FL is incurable and most patients eventually relapse. Relapse occurs in 30% of patients within 3 years, and is associated with a poor prognosis. Obinutuzumab (GA101; G) is a glycoengineered type II anti-CD20 monoclonal antibody leading to enhanced cytotoxic activity [2]. The results of the GALLIUM study, a global, open-label, randomized phase 3 study comparing the efficacy and safety of rituximab (R) or G with chemotherapy followed by maintenance as first-line treatment in indolent lymphoma have been presented [3]. A large number (1202) of untreated FL patients (grades 1–3a) and 195 marginal zone lymphoma (MZL) patients, stage III/IV disease or stage II with tumor diameter ≥7 cm and requiring treatment, were included. The chemotherapy backbones were CHOP, CVP, or bendamustin (B). Patients were randomized 1:1 and received R 375 mg/m [2] on day 1 of each cycle or G 1000 mg on days 1, 8, and 15 of cycle 1 and day 1 of subsequent cycles, for either 8 × 21-day cycles (CHOP and CVP) or 6 × 28-day cycles (B). Patients with complete remission (CR) or partial remission (PR) received R or G maintenance every 2 months for 2 years or until disease progression. The primary endpoint was investigator-assessed progression free survival (PFS) in FL patients. Only results for FL patients were presented at the ASH meeting. Patient characteristics in treatment arms were well balanced and the median age was 59 years. After a median follow-up of 34.5 months (range, 0–54.5), there was a 34% reduction in the risk of pro-
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Fig. 1 PFS of G-chemo was significantly better than with R-chemo (3-years PFS 80.0% vs. 73.3%) [3]
gression or death (HR, 0.66; 95% confidence interval [CI], 0.51, 0.85; p = 0.001; Fig. 1). Interestingly, female patients showed a more pronounced benefit of G-chemo than did male patients (hazard ratio: 0.49 vs. 0.82). Three-year PFS rates were: G-chemo, 80.0%; R-chemo: 73.3%. The overall response rates (OR) were not significantly different. Overall survival (OS) was not different in the two treatment arms. Molecular minimal residual disease (MRD) negativity at the end of induction was high in both treatment arms, but higher for G-chemo (92.0% vs. 84.9%). This difference was statistically significant (p = 0.0041), and MRD negative patients had better PFS. G-chemo patients had a higher frequency of grade 3–5 adverse events (AEs) (74.6%) and severe adverse events (SAEs) (46.1%) compared with R-chemo patients (67.8% and 39.9%, respectively). Infections were observed in 15.6% of patients with R-chemo and 20.0% in patients with G-chemo. The frequency of fatal AEs was similar (G-chemo, 4.0%; R-chemo, 3.4%). However, the rate of infusion-related reactions (IRRs) was higher in the G-chemo arm (12.4% vs. 6.7%). Moreover, more data is needed on potential long-term implications of treatment with G. Moreover, data on the application of a flat dose of G with 1000 mg in contrast to the dosage of R are once again lacking. The analysis of fatal AEs showed an unexpectedly higher rate of fatal infections for bendamustin compared with CHOP or CVP, which is not in the line with our clinical experience. In conclusion, treatment-naïve FL patients treated with G-chemo have significantly better PFS than patients treated with R-chemo. This difference is not yet translated in longer OS. Overall, AEs, especially infections, were more common in the G-chemo treatment arm. Therefore, first-line G-chemo could be considered in selected FL patients in the future. For relapsed FL, an update analysis of the GADOLIN study, an open-label, randomized, phase 3 trial comparing the efficacy and safety of G plus bendamustin
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induction, followed by G maintenance (G-B arm), with bendamustin induction (standard of care) in rituximab-refractory patients was performed. The primary analysis showed superior PFS for the G-B arm, but survival analysis was immature. However, updated analysis of the GADOLIN study demonstrates a significant improvement in OS in the G-B arm. No new safety signals were detected [4].
Chronic lymphocytic leukemia Chronic lymphocytic (CLL) is the most common leukemia in the western hemisphere. Recent years have been characterized by a significant improvement in therapeutic strategies also in high-risk patients carrying a 17p deletion or p53 mutations.
Immunochemotherapy An update of the CLL10 study of the German CLL study group (GCLLSG) confirms superiority for FCR (fludarabine, cyclophosphamide, rituximab) compared with BR (bendamustin, rituximab) in patients younger than 65 years [5]. Moreover, it was shown that FCR-treated patients in whom MRD negativity and mutated IGHV genes was achieved reach long-term PFS [6].
Ibrutinib A large phase III study (“RESONATE 2”) including patients aged over 65 years with untreated CLL was presented at the 2015 ASH meeting and simultaneously published in the New England Journal of Medicine [7]. Patients (n = 269) were randomized to receive either chlorambucil or ibrutinib. Not surprisingly, the response rate was significantly higher in patients treated with ibrutinib (82.4% vs. 35.3%). Moreover, ibrutinib improved PFS and OS. An update of this study was presented at the last ASH meeting [8]. After a me-
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was comparatively low, such that this important evidence needs to be verified in larger patient cohorts.
Venetoclax
Fig. 2 PFS was again in the ibrutinib arm in a follow up analysis. Moreover PFS was not inferior in unmutated patients compared to mutated patients when treated with ibrutinib [8]
dian observation time of 29 months, the 2-year PFS rate was 89% in patients treated with ibrutinib. Moreover, this did not differ in patients with an unmutated IGVH status (90%) compared with patients with mutated IGVH (89%) (Fig. 2). Thus, ibrutinib first-line might be an interesting treatment option for elderly patients, especially those with unmutated CLL. In addition, other promising data on the long-term use of ibrutinib were recently presented [9]. A total of 132 patients were analyzed (31 treatment-naïve, 101 relapsed/refractory). CRs were observed in 29% of treatment-naive and 10% of relapsed/refractory patients. Ibrutinib provides better PFS outcomes if administered earlier in therapy (Fig. 3). However, the number of treatment-naïve patients analyzed here
Unfortunately, despite the availability of two licensed drugs that inhibit B-cell-receptor signaling and induce remission in refractory CLL, i.e., ibrutinib and idelalisib, some patients relapse or exhibit inacceptable toxicities. In a phase 2, open-label, two-arm study presented at the last ASH meeting, patients with CLL who relapsed after or were refractory to ibrutinib (arm A) or idelalisib (arm B) received venetoclax (VEN), starting at 20 mg with a stepwise dose ramp-up over 5 weeks to the final 400-mg daily dose [10]. In all, 64 patients were enrolled in the study. Of these, 43 patients were treated in arm and 21 in arm B. Response rates among patients with prior ibrutinib or idelalisib are shown in Table 1. In summary, 70% of patients with ibrutinib pretreatment and 48% of patients with idelalisib pretreatment responded to VEN. Due to the known risk of tumor lysis syndrome, the stepwise dose ramp-up to avoid this complication in the administration of VEN is strictly mandatory.
Idelalisib A subgroup analysis of the phase 3 study comparing idelalisib plus R versus placebo plus R, patients with a complex karyotype (defined as three or more chromosomal aberrations), another prognostically unfavorable factor, showed no significant difference in ORR, PFS, or OS [11]. However, these findings need to be confirmed in larger patient cohort. More-
Fig. 3 Long term observations showed better outcome for ibrutinib when administered earlier [9]
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Table 1 Response rates of patients treated with venetoclax with ibrutinib or venetoclax pretreatment [10]
Best response, n (%)
Ibrutinib arm n = 43
Idelalisib arm n = 21
Assessed by
Assessed by
IRC
Investigator
IRC
Investigator
ORR
30 (70)
29 (67)
10 (48)
12 (57)
CR/CRi
0/1 (2)
2 (5)/1 (2)
0/0
2 (10)/1 (5)
nPR
0
2 (5)
0
0
PR
29 (67)
24 (56)
10 (47)
9 (43)
Stable disease
–
9 (21)
–
8 (38)
Disease progression
–
1 (2)
–
1 (5)
Non-respondera
13 (30)
–
11 (52)
–
a
Non-responder was a category specific to assessments by the IRC and indicates a response less than PR (i.e., stable disease or disease progression) ORR objective response rate (includes CR, CRi, nPR, and PR), CR complete response, CRi CR with incomplete bone marrow recovery, nPR nodular partial response, PR partial response. Incomplete data for four patients in arm A for investigator-assessed responses
over, the success rate of karyotyping was only 63%. However, idelalisib treatment has been shown to induce immunologic complications due to regulatory T-cell damage, especially when given front line (e.g., transaminitis, colitis, pneumonitis). Moreover, due to the observed cytomegalovirus (CMV) reactivations or Pneumocystis jirovecii pneumonias, CMV monitoring and Pneumocystis prophylaxis is strictly recommended. However, these side effects are well characterized and can therefore be circumvented by caution in administration, monitoring, and accompanying measures. This should be borne in mind for all new targeted therapies, especially when combined with with anti-CD20 therapy, for instance.
Lenalidomide Maintenance treatment with lenalidomide resulted in a significant improvement in PFS after first-line treatment (interim analysis) [12], as well as after secondline treatment [13].
Acalabrutinib Patients with relapsed or refractory CLL and ibrutinib intolerance were treated with this “next generation BTK inhbitor.” The OR rate (CR, PR, and PR with lymphocytosis) was 79.3% [14].
Aggressive lymphomas Diffuse large B-cell lymphoma Diffuse large B-cell lymphoma (DLBCL) comprises multiple diseases with different outcomes. A small number of DLBCL tumors harbor MYC translocations, which are associated with a poorer prognosis. Primary mediastinal B-cell lymphoma (PMBL) occurs in younger patients and is typically treated with intensive or combined modality therapy. R-CHOP is the standard of care for DLBCL. DA-EPOCH-R is an al-
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ternative and more dose-intensive regimen. CALGB/ Alliance undertook a phase III randomized study to compare R-CHOP and DA-EPOCH-R in DLBCL [15]. Patients were randomized 1:1 to receive six treatment cycles of R-CHOP or DA-EPOCH-R, respectively. This study enrolled 524 patients (262 on each arm) between May 2005 and May 2013. Compared with arm A, arm B was associated with more grade 4 neutropenia (90%; 56%), grade 4 thrombocytopenia (35%; 6%), grade 3/4 febrile neutropenia (37%; 19%), and grade 3 neuropathy (motor: 8%;1% and sensory: 15%; 3%). Grade 5 events on analysis were the same in both arms. Preliminary analysis of event free survival (EFS) shows no difference between arms A and B with a hazard ratio of 1.02 and p = 0.89 at a median follow-up of 4.9 years. OS is also similar with a hazard ratio of 1.19 and p = 0.40 at median 5.0 years. In conclusion, there was no difference in EFS or OS between R-CHOP and DA-EPOCH-R when considering all patients, but DAEPOCH-R showed increased toxicity. However, subgroup analysis of “double hit lymphomas” is pending. GOYA (NCT01287741) is an open-label, multicenter, randomized phase 3 study comparing the efficacy and safety of G-CHOP with R-CHOP in 1418 patients with previously untreated DLBCL [16]. This study was presented at the last ASH meeting. For the primary endpoint of INV-assessed PFS, there was no significant difference between G-CHOP and R-CHOP (3year PFS, 69% vs. 66%; stratified HR, 0.92; 95% CI, 0.76, 1.12; p = 0.3868). Secondary endpoints, including PFS by IRC, OS, and end-of-treatment ORR/CR rate (with and without PET), were consistent with the primary endpoint, with no clinically meaningful differences observed between the treatment arms. In a subgroup analysis of INV-assessed PFS, a stratified HR of 0.72 (95% CI, 0.50, 1.01) in favor of G-CHOP over R-CHOP was determined for patients with GCB DLBCL (3-year PFS, 79% vs. 70%). No new evidence of safety was identified. In conclusion, G-CHOP did not significantly improve PFS compared with R-CHOP in previously untreated patients with DLBCL.
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The REMARC study (clinicalTrials.gov NCT01122472) is an international, multicenter, double-blind, randomized, placebo controlled, phase III trial that assessed the benefit of lenalidomide maintenance after response to R-CHOP in patients aged 60 to 80 years with untreated DLBCL [17]. Patients achieving CR or PR were randomized 1:1 to receive 2 years of lenalidomid maintenance (25 mg/day for 21 of every 28 days) or placebo. The primary endpoint of the study was PFS. Secondary endpoints were safety, PR to CR conversion rate, and OS. From 05/2009 to 05/2014, 784 patients were enrolled. With a median follow-up of 40 months, median PFS was not reached in the lenalidomid group versus 68 months in the placebo group (hazard ratio: 0.708; 95% CI 0.537–0.932; p = 0.0135). Immature OS data did not show any benefit for the lenalidomid arm. In conclusion, this study shows that 2 years of lenalidomid maintenance in patients responding to R-CHOP significantly improved PFS without an early significant impact on OS. Data on refractory DLBCL patients treated with ant-CD19 chimeric antigen receptor (CAR) T cells has been presented [18]. The ORR was 76% in 51 patients enrolled with 47% CRs and 29% PRs. PFS analysis at 1 and 3 months was 92% and 56%, respectively. The most common grade ≥3 treatment-emergent AEs were neutropenia (67%), anemia (39%), thrombocytopenia (29%), febrile neutropenia (27%), and encephalopathy (24%). Grade ≥3 cytokine release syndrome (CRS) and neurologic events occurred in 20% and 29% of patients, respectively. There was one grade 5 event of hemophagocytic lymphohistiocytosis. Both ibrutinib and lenalidomid showed activity in recurrent/refractory central nervous system lymphoma (CNSL) [19–21]. One study recruited 52 patients [19]; this interim analysis was done on the first 18 patients evaluable for response. All patients had previous high-dose methotrexate-based chemotherapy. Four patients were treated with highdose chemotherapy followed by autologous stem cell transplantation. After 2 months of ibrutinib therapy, a disease control rate was achieved in 15/18 patients (83%), with a CR in three, PR in seven, and stable disease (SD) in five patients. The main toxicities were infectious complications, and one patient developed pulmonary aspergillosis. Therefore, close monitoring for infections is strongly recommended. The other study enrolled 20 patients [20]. Three patients received 560 mg and 17 patients 840 mg of ibrutinib. After a median follow-up of 193 days, 19 of the 20 patients were evaluated for response. A 75% ORR was found (eight CR, seven PR, one SD, and three progressive diseases). Bioavailability of ibrutinib in CNS was measured and meaningful concentrations were reached at steady state on day 29. The mean ibrutinib concentrations on days 1 and 29 were above the drug concentrations required to reduce lymphoma growth in vitro. The dosage of ibrutinib used here is much higher compared with the dosage in the licensed treat-
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ment of CLL or mantle cell lymphoma (MCL). Therefore, once again, caution to prevent infectious complications appears mandatory. The results of these three studies in CNS lymphoma show promising activity of these drugs in patients that are often hard to treat or have reduced performance status. These studies are thus of clinical interest.
Mantle cell lymphoma MCL accounts for approximately 6% of non-Hodgkin’s Lymphoma (NHL) in adults. MCL commonly responds to initial therapy, but patients inevitably relapse and response duration decreases from one salvage therapy to the next. The LyMa trial (ClinicalTrials.gov, NCT00921414) is a prospective, international, randomized phase III trial that investigated R after ASCT in young, previously untreated MCL patients [22]. Induction immunochemotherapy consisted of four courses of R-DHAP every 21 days (rituximab, dexamethasone, high-dose cytarabine, salt platinum), followed by ASCT consolidation. Patients in response after ASCT were randomized (1:1) between R maintenance or no R maintenance. R maintenance consisted of one infusion of rituximab (375 mg/m2) every 2 months for 3 years. The primary endpoint was EFS calculated from time of randomization; PFS and OS from time of diagnosis and time of randomization were secondary endpoints. In total, 299 patients were enrolled. The 4-year EFS was 61.4% (95%CI; 51.3–69.9) in the no-R arm vs. 78.9% (95%CI; 69.6–85.6) in the R-maintenance arm (p = 0.0012). The 4-year PFS and OS from randomization were superior in the R-maintenance arm: 82.2% (95%CI; 73.2–88.4) vs. 64.6% (95%CI; 54.6–73) (p = 0.0005) and 88.7% (95%CI; 80.7 to 93.5) vs. 81.4% (95%CI; 72.3–87.7) (p = 0.0413). In conclusion, The LyMa trial demonstrates for the first time that R maintenance after ASCT prolongs EFS, PFS, and OS. Therefore, R maintenance should be considered as standard for younger patients after ASCT. Conflict of interest D. Heintel declares that he received professional fees and travel support from: AbbVie, Celegene, Gilead, Janssen, MSD, Roche, and Takeda.
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(the CONTINUUM trial). 58th ASH Annual Meeting & Exposition. 2016, p abstract 230. oral presentation. 14. Awan. et al. Acalabrutinib monotherapy in patients with Ibrutinib intolerance: results from the phase 1/2 ACE-CL001 clinical study. 58th ASH Annual Meeting & Exposition. 2016, p abstract 638. oral presentation. 15. Wilson WH. et al. Phase III randomized study of R-CHOP versus DA-EPOCH-R and molecular analysis of untreated diffuselargeB-cell lymphoma: CALGB/alliance50303. 58th ASH Annual Meeting &Exposition. 2016, pabstract469. oral presentation. 16. Vitolo U. et al. Obinutuzumab or rituximab plus CHOP in patients with previously untreated diffuse large B-cell lymphoma: final resultsfroman open-label, randomizedphase 3 study (GOYA). 58th ASH Annual Meeting & Exposition. 2016, p abstract 470. oral presentation. 17. Thieblemont. et al. First analysis of an international double-blind randomized phase III study of lenalidomide maintenance in elderly patients with DLBCL treated with R-CHOP in first line, the Remarc study from Lysa. 58th ASH Annual Meeting & Exposition. 2016, p abstract 471. oral presentation. 18. Neelapu SS. et al. LBA-6 Kte-C19 (anti-CD19 CAR T cells) induces complete remissions in patients with refractory diffuse large B-cell Lymphoma (DLBCL): results from the pivotal phase 2 ZUMA-1. 58th ASH Annual Meeting & Exposition. 2016, p abstract LBA-6. oral presentation. 19. ChoquetS. etal. Ibrutinibmonotherapy in relapseor refractory primary CNS lymphoma (PCNSL) and primary vitreoretinal lymphoma (PVRL). Result of the interim analysis of the iLOC phase II study from the Lysa and the French LOC network. 58th ASH Annual Meeting & Exposition. 2016, p abstract 784. oral presentation. 20. Grommes Ch. et al. Single-agent ibrutinib in recurrent/ refractory central nervous system lymphoma. 58th ASH Annual Meeting & Exposition. 2016, p abstract 783. oral presentation. 21. Ghesquieres H. et al. Rituximab-Lenalidomide (REVRI) in relapse or refractory primary central nervous system (PCNSL) or vitreo retinal lymphoma (PVRL): results of a “proof of concept” phase II study of the French LOC network. 58th ASH Annual Meeting & Exposition. 2016, p abstract 784. oral presentation. 22. Le Gouill S. et al. Rituximab maintenance after autologous stem cell transplantation prolongs survival in younger patients with mantle cell lymphoma: final results of the randomized phase 3 lyma trial of the Lysa/Goelams group. 58th ASH Annual Meeting & Exposition. 2016, p abstract 145. oral presentation.
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