Six-year follow-up of phase II study exploring chemo-free treatment association with idelalisib and obinutuzumab in symptomatic relapsed/ refractory patients with Waldenström’s macroglobulinemia

doi:10.21203/rs.3.rs-4978701/v1

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Six-year follow-up of phase II study exploring chemo-free treatment association with idelalisib and obinutuzumab in symptomatic relapsed/ refractory patients with Waldenström’s macroglobulinemia

https://doi.org/10.21203/rs.3.rs-4978701/v1

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published 05 Nov, 2024

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We present the 6-year update of a phase 2 study evaluating the combination of obinutuzumab and idelalisib in relapse/refractory Waldenstrom macroglobulinemia. The results of the REMODEL trial showed interesting efficacy in a high-risk genotype profile population. The primary endpoint was achieved with median PFS of 25.4 months (95% CI, 15.7 to 29.0). However, a major limitation of idelalisib is its toxicity. With median follow-up of 70.9 months, median OS was still not reached, and 5-year OS was 72.9% (95% CI, 61.3 to 86.6). We confirm that CXCR4 mutations had no impact on PFS or OS. However, TP53 mutated patients had shorter OS. At time of analysis, six patients are alive without relapse and 40 progressed. Among the 38 patients who received a new treatment, median time PFS2 was not reached in ibrutinib treated patients (n = 17) versus 30.8 months in patients treated with other options (95% CI, 16.9 to NA), p = 0.005. With longer follow-up our prospective study is the first to show an impact of TP53 mutations in patients treated with fixed duration chemo-free regimen leading to a significant shorter OS in this population. Moreover, ibrutinib remains an effective treatment after this association. This study was registered on the clinicaltrial.gov web (NCT02962401, November 9, 2016).

Waldenstrom magroglobulinemia

relapse/refractroy

obinutuzumab

idélalisib

Over the past ten years, better understanding of the biology of Waldenström’s macroglobulinemia (WM) led to identify new therapeutic targets and to develop new agents [1]. Current treatment options in relapsed/refractory (R/R) patients consist in different types of drugs including immunochemotherapy (ICT), proteasome inhibitors and BTK-inhibitors (BTKi) [2]. Other emerging drugs (BCL2-inhibitors [3], anti-CXCR4 monoclonal antibodies associated with ibrutinib [4.5]) could be an option in this population. The results of the REMODEL trial (NCT02962401) showed interesting efficacy of obinutuzumab - idelalisib combination in this high-risk genotype profile population (56.1% CXCR4^MUT, 24.4% TP53^MUT). However, a major limitation of idelalisib, a Pi3Kδ inhibitor, is its toxicity, particularly on liver and digestive tracts [6].

We report the 6-year update of idelalisib - obinutuzumab combination and evaluate the impact of mutational profile on R/R WM patients.

REMODEL was a single-arm multicenter phase II study designed to assess the efficacy and safety of idelalisib - obinutuzumab combination. The trial comprised two phases: an induction phase of six cycles during which idelalisib was administered continuously at 150mg x 2 /d PO in combination with obinutuzumab IV 100mg at D1, 900mg at D2 and 1000mg at D8 and 15 of cycle 1, then at D1 of monthly cycles 2 to 6, followed by maintenance with idelalisib monotherapy at the same dose for 18 months. Study design details have been published [6].

The primary endpoint was progression-free survival (PFS), calculated from the date of inclusion to progression or death. Secondary endpoints included response rates (according to the IWWM-6 criteria [7]), time to next treatment (TTNT), overall survival (OS), and safety. We assessed the effect of CXCR4 and TP53 mutations on survival.

Gene mutation analysis is detailed in supplementary data qualitative variables are expressed in frequency and percentage; quantitative variables in mean +/- standard deviation or median (range) depending on the distribution. Survival curves have been calculated with the Kaplan- Meier method and comparison made with the log-rank test.

Every participant provided their consent.

Fifty patients were screened, 49 analyzed between February 2017 and July 2018. Patient distribution and treatment exposure are displayed in Supplementary Fig. 1. Among them, one died (unknown cause) before any treatment and 48 received the combination induction. Among the 48 treated patients, 14 interrupted the induction phase (seven for progressive disease and seven for adverse events (AE)). Among the 27 patients who started maintenance, nine completed and 18 stopped (5 for progression, 13 for AE). The median number of prior lines of treatment (ICT in 90% of cases) was one (1–3), with three patients previously treated with ibrutinib. The mutation profile was 46 (93.9%) MYD88^L265P mutated, 27 (56.1%) CXCR4 mutated, and 11 (24.4%) TP53 mutated. Baseline characteristics of patients and mutations are listed in Supplementary Table 1.

The primary endpoint was achieved with median PFS of 25.4 months (95% CI, 15.7 to 29.0). With median follow-up of 70.9 months (95% CI, 69.2 to 74.7), median OS was still not reached, and 5-year OS was 72.9% (95% CI, 61.3 to 86.6). Sixteen patients died: six from progression (two after the first relapse and four after the second), one from Richter syndrome, four from infection, one from stroke, one from gliobastoma, one from unspecified deterioration in general condition, and two from unknown causes (including 1 before any treatment). With longer follow-up, we confirm that CXCR4 mutations had no impact on PFS or OS with median PFS of 25.7 (95% CI, 12.4 to 42.7) versus 25.3 (95% CI, 14 to 50.8) months, p = 0.9 and non-reached OS (p = 0.68) with 5-year OS at 69.2% (95% CI, 53.6 to 89.5) versus 80.9% (95% CI, 65.8 to 99.6), in CXCR4^MUT patients versus CXCR4^WT patients, respectively (Fig. 1a, 1b). However, TP53 mutated patients had shorter OS with median time of 53.5 months versus not reached and with a5-year OS at 45.5% (95% CI, 23.8 to 86.8) versus 82.3% (95% CI, 70.3 to 96.2), p = 0.005 (Fig. 1c, 1d).

At time of analysis, six patients are still alive without relapse and 40 progressed. Among the 38 patients who received a new line of therapy, median PFS was not reached (Fig. 2a) and 3-year PFS was 69.4% (95% CI, 55.2 to 87.4). According to treatment, median time PFS2 was not reached in ibrutinibtreated patients (n = 17) versus 30.8 months in patients treated with other options (n = 21 including 16 ICT − 13 bendamustine + rituximab-) (95% CI, 16.9 to NA), p = 0.005 (Fig. 2b). Patients treated with ibrutinib had 3-year PFS2 of 93.8% (95%CI, 82.6 to 100) versus 47.2% (95%CI, 28.3 to 78.6) for those treated with other treatments. Twelve secondary relapses were observed including two patients treated with ibrutinib.

The updated results of this trial with 6-year median follow-up confirmed that the fixed-duration idelalisib-obinutuzumab combination is an effective relapse treatment despite the initial toxicity. There was no evidence of delayed toxicity. Median PFS was shorter (25.4 months) than with ibrutinib (54% at 5 years [8]), acalabrutinib (82% at 24 months [9]), and zanubrutinib (78% at 42 months [10]) in R/R setting but the advantage of a fixed duration chemo-free combination led to decreased toxicity events during the treatment-free time and limited cost and potential clonal selection pressure. Moreover, ibrutinib remains an effective treatment after this association with 3-year PFS at more than 90%. The other published fixed-duration chemo-free approach with new agents showed 24-month PFS of 80% in R/R patients treated with venetoclax [3].

With longer follow-up, our prospective study is the first to show an impact of TP53 mutations in patients treated with fixed duration chemo-free regimen leading to significantly shorter OS in TP53 mutated patients. Conversely to ibrutinib, no impact of CXCR4 mutations was observed on PFS and OS. Nonetheless, considering the potential efficacy of this class of agents, next-generation PI3K inhibitors associated with obinutuzumab could overcome the toxicity profile observed in this phase II trial and may be a reasonable treatment option in double refractory patients.

Contributions

Conception and design: CT, SP, SC, VL

Collection and assembly of data: all authors

Data analysis and interpretation: CT, SP, SC, VL

Manuscript writing: CT, VL

Final approval of manuscript: all authors (CT, SP, MN, PF, CH, BM, PM, TA, OT, SL, SA, BV, OC, AL, DRW, JT, SC, VL)

Accountable for all aspects of the works: CT, SP, AL, SC, VL

Author’s disclosure of potential conflicts of interest

CT: None related to this article. Janssen, BeiGene, AstraZeneca, Abbvie (consulting)

SP: None

MN: None

PF: None

CH: None

BM: None

PM: None

TA: None

OT: None

SL: None

SA: None

BV: None

OC: None

AL: None

DRW: None related to this article. Janssen, BeiGene, AstraZeneca, Abbvie (consulting)

JT: None

SC: None

VL: None

-Ethical Approval: This study is in accordance with the principles laid down by the 18th World Medical Assembly (Helsinki, 1964) and amendments laid down by the 29th (Tokyo, 1975), the 35th (Venice, 1983) and the 41st (Hong Kong, 1989), the 48th (Somerset West, 1996), the 52nd ( Edinburg, 2000) World Medical Assemblies, the 64th (Fortazela, 2013) notes for clarification added by the WMA General Assembly on paragraph 29 (Washington 2002) and on Paragraph 30 (Tokyo 2004) and amendment laid down by the 59th (Seoul, October 2008) World Medical Assemblies.

The trial was approved by the following competent authorities: health autority (ANSM) autorisation date: August 25, 2016 and ethics comittee (CPP OUEST III): August 31, 2016.

-Funding: This study was supported and drugs were provided by Roche and Gilead.

-Competing Interests: none

-Data Availability: The sponsor has the ownership of all data and results collected during this study.

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Castillo JJ, Allan JN, Siddiqi T, Advani RH, Meid K, Leventoff C, et al. Venetoclax in Previously Treated Waldenström Macroglobulinemia. .J Clin Oncol. 2022 Jan 1;40(1):63-71.
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No competing interests reported.

SupplementaryDataAnnHematol.docx
Supplementary Table 1: Baseline characteristics of enrolled patients (n=49) Gene mutation analysis Next-generation sequencing (NGS) was performed centrally on DNA extracted from cells following Ficoll-Paque gradient centrifugation of BM samples collected at inclusion using the Ion PGM Torrent platform (Thermo Fisher Scientific). The custom gene panel included MYD88, CXCR4, TP53, BTK, and PLCG2. A mean coverage of 2000 to 25003 was obtained for all targeted regions, allowing analysis of subclonal variation with a limit of detection of 0.8%.21 In addition, droplet digital PCR was used to screen MYD88L265P and CXCR4S338X variants, with a limit of detection of 0.05%, according to the manufacturer’s recommendations (Bio-Rad). Supplementary Figure 1: Patient distribution and treatment exposure PD: progressive disease

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Journal Publication

published 05 Nov, 2024

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Editorial decision: Revision requested
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Six-year follow-up of phase II study exploring chemo-free treatment association with idelalisib and obinutuzumab in symptomatic relapsed/ refractory patients with Waldenström’s macroglobulinemia

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