ABSTRACT
Background: Optimal consolidation for young R/R FL in the rituximab age remains uncertain and the benefit of ASCT is not clearly established. Aims: The FIL FLAZ12 trial (NCT01827605) is a prospective, multicenter, randomized, phase 3 trial, comparing RIT versus ASCT, as consolidation after chemoimmunotherapy, both followed by R maintenance in R/R FL. Methods: Pts aged 18-65 yrs, with R/R FL after 1 or 2 lines of chemoimmunotherapy, without significant comorbidities were enrolled. Patients received 3 courses of therapy chosen by the investigator among RCHOP, R-DHAP, R-FM, R-ICE, R-IEV or R-B. Pts achieving at least PR (according to Cheson et al. 2007) were randomized 1:1 to either RIT or ASCT before CD34+ collection. Conditioning for ASCT was BEAM or TEAM. RIT was given as previously described (Morschhauser et al., 2008). After consolidation, pts received R maintenance every 3 months for eight courses. Primary endpoint was PFS. Considering ASCT toxicity, it was hypothesized to be a superior choice, if capable of increasing 3-years PFS from 40% to 60% (two-side log-rank test with alpha of 5% and a power of 85%). Clinical secondary endpoints were ORR, CRR, OS, EFS and TTF. Results: Between Aug 2012, and Sep 2019, 164 pts were screened and 159 enrolled by 38 FIL Centers (enrolled population). Unfortunately, the study was prematurely closed due to low accrual. The data were analyzed on an ITT basis on May 2, 2021 with a median follow-up (mFU) from enrollment of 43 months and 75 PFS events. The two arms were clinically well balanced, with median age of 57 yrs (IQR 49-62), 55% male, 57% stage IV, 20% bulky disease. Tumor re-biopsy was performed in 79% pts. POD-24, retrospectively assessed was observed in 32% of pts. Two pts (1%) did not start treatment (non-confirmed histology and withdrawal). Sixteen (10%) pts discontinued before randomization (7 SD, 3 PD, 3 AE, 1 withdrawal, 2 poor compliance) and 141 (89%) were randomized to either RIT (71) or ASCT (70) (randomized population). Of these 19 (13%) (RIT 8, ASCT 11) did not receive the planned consolidation due to 7 PD, 4 AE, 1 medical decision, 2 poor mobilization, 2 withdrawals, 1 poor compliance, 2 protocol breaches, while 63 (89%) received RIT and 59 (84%) ASCT. After RIT, 61% of pts achieved CR and 23% PR, while after ASCT these were 70% and 9%. Estimated PFS at 3 yrs was 60% (95% CI: 46%-71%) in the RIT arm vs. 59% (95% CI:45%-70%) in the ASCT arm, p = 0.8613 (HR 0.96, 95%CI: 0.57,1.59). (Figure 1) 3yrs-OS was again superimposable in the two arms: 83% (95%CI: 69%-91%) in the RIT vs 85% (95% CI: 72%-91%) in the ASCT, p = 0.8310 (HR 1.10, 95%CI: 0.45,2.72). Grade ≥ 3 hematological toxicity was 46% in the RIT vs 94% in the ASCT arm (p < 0.001). For ASCT vs RIT grade ≥3 neutropenia occurred in 94% vs 41% of pts (p < 0.001). During follow-up, 4 pts died in remission: 1 AML (RIT), 2 SARS-COV2 infections (RIT) and 1 pneumonia (ASCT). Second cancers occurred in 3 pts after RIT and 7 after ASCT (p = 0.480). Multivariable analysis for PFS indicated POD-24, male sex, LDH and refractory disease as adverse parameters. Subgroup analysis for PFS including gender, age, LDH, POD-24 and extranodal disease show no subgroup favoring RIT nor ASCT. Image: Summary/Conclusion: Even if prematurely interrupted, our study demonstrated no meaningful difference in efficacy between ASCT and RIT, but ASCT was more toxic and more demanding for pts and health service. Both strategies induced a similar and favorable long-term outcome suggesting that consolidation programs milder than ASCT require further investigation in R/R FL.
ABSTRACT
Background: Undetectable MRD (uMRD) has become an achievable endpoint for patients (pts) with CLL, in particular using the BCL2 inhibitor VEN allowing treatment discontinuation in a MRD-driven approach. uMRD can be reached in a proportion of pts with VEN mono, and in larger fraction in combination with the BTK inhibitor IBR. It remains to be established who can achieve best responses with single agent or combination strategies. Aims: This phase 2 multicenter MRD-driven Italian study aims at discontinuing treatment upon reaching uMRD in pts with relapsed/refractory CLL treated with VEN mono or through the addition of IBR in pts who did not achieve uMRD with the single agent. Methods: VEN mono (up to 400 mg/day as per label) was administered for 12 months. MRD in peripheral blood (PB) and bone marrow (BM) was evaluated using the ERIC 6-color flow panel. Pts with uMRD in both PB and BM at C12D1 discontinued VEN at C12D28. Pts with detectable MRD in PB and/or BM added IBR 420 mg/day from C13D1 and continued both drugs up to C24D28, uMRD, progression or toxicity (whichever first). After C24D28, pts with detectable MRD and still in response continued IBR alone. The primary endpoint was uMRD4 (<1 CLL cell in 104 leukocytes) in both PB and BM. Results: 38 pts (recruited from Nov 2017 to Jul 2018) started VEN. Median number of prior therapies was 1 (range 1-4), 61% were previously treated with FC+/-R;8/33 (24%) carried del(17p);10/30 (33%) TP53 mutations, and 24/30 (80%) unmutated IGHV. One pt discontinued treatment due to myelodysplasia (unrelated to VEN) and 1 pt due to COVID-19. As of 31 Jan 2021, overall response rate with VEN mono was 36/38 (95%), 19 CR and 17 PR. As per protocol, 17 pts (45%) with uMRD4 in PB and BM at C12D1 discontinued VEN at C12D28. 19 (55%) responsive cases with detectable MRD at C12D1 added IBR to VEN from C13D1. By combining IBR and VEN for a median of 7 months (range 3-10) 5/10 pts in PR improved their response to CR, 16/19 (84%) achieved uMRD4 in both PB and BM (Fig. 1), thus stopping both therapies. The remaining 3/19 continued IBR. After a median follow up of 30 months, median PFS has not been yet reached;3 pts progressed without treatment need, 1 pt restarted VEN mono as per protocol, 2 pts developed Richter transformation. 11/33 pts (33%) who discontinued treatment in uMRD, after a median observation of 30 months remain uMRD (6 treated with VEN only). No cases of clinical and/or laboratory tumor lysis syndrome were reported in 39 pts (1 excluded from the efficacy analysis because of atypical phenotype). Adverse events were mild, with no discontinuations or dose reductions;with prolonged follow-up no new relevant toxicities occurred. Summary/Conclusion: Our updated results demonstrated that a sequential MRD-guided approach is feasible and leads to an overall uMRD in 33/38 pts (87%) with either VEN mono or in combination with IBR. Interestingly, 84% of pts who did not achieve uMRD after VEN alone obtained uMRD after the addition of IBR and the remaining 3 patients who did not obtain uMRD even after the combination, could be selected for continuous IBR. Median PFS is not yet reached after 30 months of follow-up. This MRD-driven sequential approach allows to reach identical depth of response in each patient enrolled in the study using a personalized intensification avoiding unnecessary drug exposure, ultimately identifying the few pts that may benefit from continuous IBR. Time to clinical progression, response to VEN retreatment, and characteristics of pts with persistent MRD remain to be established.
ABSTRACT
The treatment of chronic lymphocytic leukemia (CLL) has been radically changed in the last years thanks to the targeted therapies, including kinase (i.e. ibrutinib) and BCL2 (i.e. venetoclax) inhibitors. Venetoclax (VEN) in particular is able to obtain undetectable minimal residual disease (uMRD), though only in a proportion of patients (pts) when given as single agent, thus warranting the need of different strategies in those not achieving uMRD. We designed a phase 2 multicenter Italian study where ibrutinib (IBR) is added to VEN based on a MRD-driven strategy aiming at obtaining uMRD and discontinuing both treatments in pts who did not achieve uMRD with VEN mono. Study treatment started with VEN (ramp up to 400 mg/day as per current label) for 12 months. MRD status in peripheral blood (PB) and bone marrow (BM) was evaluated using the 6-color flow cytometry assay recommended by ERIC (CD5/CD81/CD79b/CD19/CD43/CD20). Pts with uMRD in both PB and BM at C12D1 discontinued VEN at C12D28 and entered the follow-up phase. Pts with detectable MRD in PB and/or BM added IBR 420 mg/day starting from C13D1 and continued both drugs up to maximum C24D28, uMRD, progression or unacceptable toxicity (whichever occurs first). After C24D28, pts with detectable MRD and still in response continued IBR alone. The primary endpoint was uMRD4 (<1 CLL cell in 104 leukocytes) in both PB and BM. We report here the results as of 15Jul2020 (data cutoff). Thirty-eight pts (recruited from Nov 2017 to Jul 2018) fulfilled eligibility and started VEN. Baseline characteristics included: median number of prior therapies 1 (range 1-4) (60.6% previously treated with FCR or FC);del(17p) in 8/33 (24%);TP53 mutations in 10/30 (33%), and unmutated IGHV in 24/30 (80%). At the data cut-off, 35/38 evaluable pts still in the study have reached C24D1, 1 pt discontinued treatment due to myelodisplasia (considered unrelated to study treatment) before C12D1 and 1 pt progressed on VEN monotherapy shortly before that timepoint, 1 evaluation is still missing due to COVID-19 restrictions. At C12D1, uMRD4 in PB was achieved in 19/38 (50%) pts (Figure 1), 17/19 (89.5%) had uMRD4 confirmed in BM. Overall response rate with VEN single-agent was 36/38 (94.7%), 9 CR and 27 PR. As per protocol, the 17 pts (45%) with uMRD4 in PB and BM at C12D1 discontinued VEN at C12D28. Nineteen responsive cases with detectable MRD at C12D1 added IBR to VEN starting from C13D1. The combination of IBR and VEN led to an improved reduction of the depth of MRD in all but 3 pts with 16/19 (84%) achieving uMRD4 in both PB and BM between C16D1 (first MRD assessment after starting IBR) and C24D1, thus stopping both therapies as per protocol. After a median follow-up of 25.4 months (range 6.1-33.5) from treatment initiation, no clinical progression was observed among those discontinuing treatment in uMRD, while MRD4 relapse occurred in 21/33. Median time to MRD4 relapse in those who achieved uMRD at any timepoint and discontinued treatment was 4 months (range 2-13). Twelve pts (6 treated with VEN only) remain uMRD after stopping treatment, with a median observation of 13 months (range 3+-18+) since confirmed uMRD4. Safety data were analyzed in the intention-to-treat cohort (39 pts). No cases of clinical tumor lysis syndrome (TLS) and/or biochemical TLS were reported in the 39 pts exposed to VEN. Adverse events (AEs) were mild, with no treatment discontinuations or dose reductions. Five Serious AEs (Table 1) and 130 AEs (Table 2) occurred in 28 patients, without any SUSARs. All 5 SAEs were deemed unrelated to study drug(s) and 4/5 have resolved without sequelae. In conclusion, we here present the updated results of our study including the combination phase of VEN with IBR. This sequential MRD-guided approach was feasible and led to deeper responses in about 85% of pts not achieving uMRD4 after VEN alone. With this tailored and time-limited strategy 33 out of 38 pts (87%) obtained uMRD4 in PB and BM either after VEN monotherapy or the IBR-VEN combination, indicating we may reach identical depth of re ponse with a personalized intensification and avoid unnecessary drug exposure. Time to clinical progression and response to VEN retreatment in this cohort remain to be established as well as the biological characteristics of those pts with persistent MRD despite the combined treatment. Updated results with further sequential MRD and clinical monitoring after treatment discontinuation will be presented at the meeting. [Formula presented] Disclosures: Scarfo: Gilead: Membership on an entity's Board of Directors or advisory committees;AstraZeneca: Honoraria;Abbvie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau;Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Farina: Abbvie: Membership on an entity's Board of Directors or advisory committees;Janssen: Membership on an entity's Board of Directors or advisory committees. Gaidano: Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau;Abbvie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau;Astrazeneca: Membership on an entity's Board of Directors or advisory committees;Sunesys: Membership on an entity's Board of Directors or advisory committees. Reda: Janssen: Membership on an entity's Board of Directors or advisory committees;Abbvie: Membership on an entity's Board of Directors or advisory committees;Gilead: Membership on an entity's Board of Directors or advisory committees. Coscia: Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees;Shire: Honoraria, Membership on an entity's Board of Directors or advisory committees;Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau;Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau;Karyopharm Therapeutics: Research Funding. Laurenti: Roche: Honoraria;Gilead: Honoraria;Janssen: Honoraria;AbbVie: Honoraria. Varettoni: Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees;AbbVie: Other: Travel/accommodations/expenses;Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel/accommodations/expenses. Ghia: Lilly: Consultancy, Honoraria;Sunesis: Consultancy, Honoraria, Research Funding;Adaptive, Dynamo: Consultancy, Honoraria;MEI: Consultancy, Honoraria;Celgene/Juno: Consultancy, Honoraria;Janssen: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding;BeiGene: Consultancy, Honoraria;Acerta/AstraZeneca: Consultancy, Honoraria;ArQule: Consultancy, Honoraria;Gilead: Consultancy, Honoraria, Research Funding;AbbVie: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding;Novartis: Research Funding.
ABSTRACT
Background: Early-stage follicular lymphoma (FL) is usually managed with involved field radiotherapy (IFRT), allowing a complete and long lasting eradication of the disease only in 40-50% of patients (pts). The aim of this multicenter phase II prospective study was to evaluate the role of MRD in identifying pts unlikely to be cured by IFRT, for whom an immunotherapy consolidation could improve outcome. Methods: 110 pts with stage I/II FL were enrolled and treated with 24 Gy IFRT. Peripheral blood (PB) and bone marrow (BM) samples were centralized to the FIL (Fondazione Italiani Linfomi) MRD Network of EuroMRD-certified laboratories. In BCL2/IGH+ pts at baseline by both nested PCR (NEST) and RQ-PCR (RQ) in BM a/o PB, MRD was analyzed after IFRT and every 6 months over a 3-year period. Pts with MRD+ by both NEST and RQ in BM a/o PB after IFRT or who became MRD+ during the follow-up were treated with 8 weekly doses of the anti-CD20 MoAb ofatumumab (OFA). The primary objective of the study was to define the efficacy of immunotherapy in obtaining a negative MRD. Results: Of the 106 evaluable pts, 50 were males. Median age was 55 y (29-83). The FLIPI score was 0 in 59% of pts, 1 in 35%, 2 in 6%. 68% of pts had inguinal site involvement. At baseline, 30% of pts had a BCL2/IGH rearrangement (30 MBR, 1 MBR and mcr, 1 mcr) in BM a/ o PB;the concordance between compartments was 90%. All but one pt achieved a clinical response after IFRT;one additional pt died soon after IFRT of unrelated causes. MRD evaluation after IFRT revealed the persistence of BCL2/IGH+ cells in PB a/o BM in 60% of pts. MRD + pts, either after IFRT (n = 18) or in case of conversion to MRD+ during the follow-up (n = 6), received OFA, obtaining a conversion to MRD-in 22/24 pts (91.7%-CI 73.0-99.0), significantly superior to the expected 50% (Fig). After a median F-U of 38 m, 17 pts who achieved a MRD-with OFA are still negative;5 converted to MRD+ (2 received OFA retreatment, achieving a second MRD-;2 pts were not re-treated due to Sars-Cov2 pandemic;1 relapsed). A clinical relapse or progression was observed in 23 pts: 18 (24.6%) among the 73 “no marker” pts and 5 (15.6%) among the 32 BCL2/IGH+ at baseline (p = 0.3), with no significant difference in PFS (p = 0.25). Two early relapses were observed among the 12 pts who became MRD-after IFRT and 3 among the 24 treated at least once with OFA (1 MRD+, 1 MRD-, 1 converted from MRD-to MRD+). Only 1 Pt relapsed while MRD-after OFA. Conclusions: MRD data indicate that RT alone is often insufficient to eradicate the disease, inducing a MRD-only in 40% of pts, notably long-lasting only in half of them. The primary objective of this study-MRD conversion after immunotherapy-was largely achieved. The strategy of an immunotherapy consolidation after IFRT in MRD+ pts allowed increasing molecular responses. However, this strategy is applicable only to 30% of enrolled pts. A clinical advantage of the MRD driven treatment strategy is suggested although not significan.
ABSTRACT
Introduction: The median age of CML patients failing a first-line TKI because of resistance or intolerance is higher than 60 years. Bosutinib (BOS), dasatinib (DAS) and nilotinib (NIL) have similar second-line efficacy, but in elderly patients DAS and NIL toxicity is more frequent and more clinically relevant. BOS safety profile may be an added value in this setting, but the approved initial dose of 500 mg OAD may be higher than necessary. Aims: All TKIs have been tested in CML patients at a fixed initial dose, with dose reductions in case of toxicity. On the contrary, the aim of our study was to evaluate the efficacy and the tolerability of low-dose second-line BOS in elderly CML patients, using the molecular response at given timepoints to increase the dose only in selected patients, thus finding the minimum effective dose. Methods: A prospective phase 2 single-arm multicenter study has been designed by the GIMEMA CML Working Party (NCT02810990). Study design: All patients started BOS 200 mg OAD for 2 weeks (ârun-inâ period), then the dose was increased to 300 mg OAD;after 3 months, patients with BCR-ABLIS transcript ≤ 1% continued 300 mg OAD, while in patients with transcript > 1% the dose is furtherly increased to 400 mg OAD, in absence of relevant toxicity. The primary endpoint was the rate of MR3 at 12 months. Key inclusion criteria: > 60 yrs old, chronic phase CML, intolerance or failure of any first-line TKI (2013 ELN criteria), absence of T315I or V299L mutation. Results: Sixty-three patients have been enrolled. Median age: 73 yrs (range 60-90). Reasons for switching to BOS: Intolerance 63%, resistance 37%. First-line TKI: Imatinib 83%, DAS 11%, NIL 6%. All patients reached at least 1-year observation. Due to the emergency situation caused by SARS CoV2 spread in Italy, few data are still missing, but final results will be presented onsite. Maximum BOS dose: 400 mg OAD, 19%;300 mg OAD, 76%;200 mg OAD, 5%. At baseline, 17% of patients were already in MR3;MR3 rates at 3, 6 and 12 months were 44%, 54% and 59%, respectively. The cumulative rate of patients achieving or maintaining a MR3 by 12 months was 67%;patients achieving MR4 or MR4.5 by 12 months were 44% and 24%, respectively. Overall, 30%, 29% and 8% of patients had 1 log, 2 logs or > 3 logs reduction from baseline BCR-ABLIS transcript level (67% of patients had a molecular improvement from baseline). Selected adverse events: Acute coronary syndromes, 4 patients;pericarditis, 2 patients;peripheral arterial thrombosis, 1 patient;no pleural effusions were observed. Events leading to permanent treatment discontinuation: 2 unrelated deaths, 7 adverse events, 4 unsatisfactory responses (without progressions), 1 second neoplasia. Fourty-nine patients are still on BOS at the last contact: 10% of them on 400 mg OAD, 61% on 300 mg OAD, 29% on 200 mg OAD. Conclusions: These results trial showed that in elderly patients intolerant to or failing a first-line TKI BOS may be highly effective and better tolerated at a dose lower than 500 mg OAD, namely at 300 mg OAD.