The Role of mTOR in B Cell Lymphoid Malignancies: Biologic and Therapeutic Aspects
Abstract
:1. Introduction
2. The PI3K/v-akt/mTOR Pathway
2.1. PI3Ks
2.2. Akt
2.3. mTOR
3. The PI3K/Akt/mTOR Signaling Pathway in Human Leukemias and Lymphomas
3.1. Diffuse Large B Cell Lymphoma
3.2. Mantle Cell Lymphoma
4. Clinical Applications of m-TOR Inhibitors in B Cell Lymphomas
4.1. Clinical Trials with mTOR Inhibitors in Mantle Cell Lymphoma
4.1.1. Temsirolimus
Temsirolimus Monotherapy
Witzig T. et al., 2005 [58] | Ansell S. et al., 2008 [59] | Hess G. et al., 2009 [60] | Hess G. et al., 2009 [60] | Ansell S. et al., 2011 [66] | Dreyling M. et al., 2016 [62] | Jurczak W. et al., 2018 [61] | Jurczak W. et al., 2017 [61] | ||
---|---|---|---|---|---|---|---|---|---|
Setting | Phase 2 | Phase 2 | Phase 3 | Phase 3 | Phase 2 | Phase 3 | Phase 4 | Phase 4 | |
Patients | 35 | 28 | 54 | 54 | 69 | 141 | 47 | 43 | |
Dosing schedule | 250 mg/wk | 25 mg/wk | 175 mg/wk × 3 wks then 75 mg/wk | 175 mg/wk × 3 wks then 25 mg/wk | 25 mg/wk Rituximab | 175 mg/wk × 3 wks then 75 mg/wk | 175 mg/wk × 3 wks then 75 mg/wk | 75 mg/wk | |
Treatment duration | CR + 2 cycles, if CR at 6 mo 12 cycles, if PR at 6 mo 6 cycles, if SD at 6 mo or until PD at anytime | CR + 2 cycles, if CR at 6 mo 12 cycles, if PR at 6 mo 6 cycles, if SD at 6 mo or until PD at anytime | until PD or UT | until PD or UT | CR + 2 cycles, if CR at 6 mo | until PD or UT | until PD or UT | until PD or UT | |
Age (median) (range) | 70 (30–89) | 69 (51–85) | 68 (44–87) | 68.5 (43–85) | 67 (44–86) | 68 (13) | 66 (47–85) | 67 (47–86) | |
Gender (male, %) | 74 | 68 | 85 | 74 | 72 | 77 | 72 | 84 | |
Previous therapies (median) (range) | 3 (1–11) | 4 (1–9) | 3 (2–7) | 3 (2–7) | 2 (1–9) | 2 (1–9) | 3 (2–7) | 2 or 3 (1–5) | |
Blastoid (%) | NA | 14 | 0 | 17 | NA | 12 | 15 | 16 | |
PS ≥ 2 (%) | 12 | 22 | 19 | 15 | 4 | 1 | 11 | 16 | |
PS range | 0–2 | 0–2 | 60–100 | 60–100 | 0–2 | 0–2 | 0–2 | 0–2 | |
ORR (%) | 38 | 41 | 22 | 6 | 59 | 40 | 28 | 21 | |
CR (%) | 3 | 4 | 2 | 0 | 19 | 1 | 4 | 2 | |
PFS (median) | 6.5 mo | 6 mo | 4.8 mo | 3.7 mo | 9.7 mo | 6.2 mo | 4.3 mo | 4.5 mo | |
DOR (median) | 6.9 mo | 6 mo | 7.1 mo | 3.6 mo | 10.6 | 11.0 R-sens | 7.0 | 9.0 mo | 8.7 mo |
6.0 R-ref | |||||||||
Refractory | 54 | 50 | NA | NA | NA | 33 | NA | NA |
Temsirolimus Combinations
LYSA Working Group [67] | Hess et al. [60] | Inwards et al. [70] | |
---|---|---|---|
Setting | Phase IB, dose-escalation study | Phase I/II | Phase I dose-escalation study |
Patients | 41 | 29 | 17 |
Dosing schedule | R-CHOP, R-FC, RDHA and T (15 to 50 mg weekly) | BR and T (15–75 mg in phase I and 50 mg in phase II on D1,8, 15 of 28-day cycles) | R-Cladribine and T (15 mg D1 to 25 mg in 4 dose levels (1–4 weekly applications per cycle)) |
Treatment duration | 4 cycles plus 2 in case of clinical benefit | 4 cycles | 28-day cycles, up to 4 or 6 depending on response |
Age (median (range)) | 68 (56–79) | 73 (46–79) | 75 (52–86) |
Gender (male, %) | 78 | 72 | 65 |
Previous therapies, (median (range)) | 1 (1–3) | 2 (1–3) | 0 (first-line) |
Blastoid (%) | 7 | NR | NR |
PS range | 0–2 * | 0–2 ** | NR (0–3 allowed) |
Temsirolimus MTD or RP2D | 15 mg | 50 | MTD not reached, RP2D NA (phase II part abandoned) |
ORR (%) |
| 89 | 94 |
CR (%) |
| 44 | 43 |
PFS (months) |
| 18 | 18.7 |
DOR (months) |
| NR | NR |
OS (months) |
| 56% at 3 years | NR |
4.1.2. Everolimus
4.2. Clinical Trials with m-TOR Inhibitors in Other (Non-MCL) of B Cell Malignancies
4.2.1. Temsirolimus
4.2.2. Everolimus
Everolimus for R/R Aggressive B Cell Lymphomas
Everolimus in the First-Line Treatment of Aggressive B Cell Lymphomas
Everolimus as Adjuvant Therapy in DLBCL
Everolimus for Indolent B Cell Lymphomas
5. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
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Everolimus Arm (n = 372) | Placebo Arm (n = 370) | HR (95% CI) | |
---|---|---|---|
Age ≥ 65 years | 48% | 46% | NA |
Completed treatment | 177 | 249 | NA |
Discontinued (adverse event) | 113 | 48 | NA |
Discontinued (progression) | 24 | 44 | NA |
Deaths during or 28 days post-study treatment [(%)] | 5 (1.4%) ** | 2 (0.5%) | NA |
Non-infectious pneumonitis leading to discontinuation | 2% | 0.5% | NA |
2-year DFS, all patients ** | 77.8% | 77.0% | 0.92 (0.67–1.22) |
2-year OS, all patients | 90.7% | 88.3% | 0.75 (0.31–1.10) |
2-year LSS, all patients *** | 95.2% | 90.7% | 0.66 (0.41–1.07) |
2-year DFS, IPI ≥ 4 (n = 313) *** | 82% | 71% | 0.65 (0.42–1.01) |
2-year DFS, males (n = 372) *** | 82% | 75% | 0.68 (0.45–1.05) |
2-year DFS, Asian (n = 226) *** | 83% | 67% | 0.60 (0.36–1.00) |
2-year DFS, <65 years (n = 393) *** | 80% | 76% | 0.79 (0.52–1.21) |
2-year OS, IPI ≥ 4 (n = 313) *** | 91% | 82% | 0.63 (0.37–1.07) |
2-year OS, males (n = 372) *** | 91% | 86% | 0.55 (0.32–0.94) |
2-year OS, Asian (n = 226) *** | 91% | 85% | 0.51 (0.27–0.98) |
2-year OS, <65 years (n = 313) *** | 93% | 90% | 0.62 (0.34–1.13) |
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Karatrasoglou, E.A.; Dimou, M.; Piperidou, A.; Lakiotaki, E.; Korkolopoulou, P.; Vassilakopoulos, T.P. The Role of mTOR in B Cell Lymphoid Malignancies: Biologic and Therapeutic Aspects. Int. J. Mol. Sci. 2023, 24, 14110. https://doi.org/10.3390/ijms241814110
Karatrasoglou EA, Dimou M, Piperidou A, Lakiotaki E, Korkolopoulou P, Vassilakopoulos TP. The Role of mTOR in B Cell Lymphoid Malignancies: Biologic and Therapeutic Aspects. International Journal of Molecular Sciences. 2023; 24(18):14110. https://doi.org/10.3390/ijms241814110
Chicago/Turabian StyleKaratrasoglou, Eleni A., Maria Dimou, Alexia Piperidou, Eleftheria Lakiotaki, Penelope Korkolopoulou, and Theodoros P. Vassilakopoulos. 2023. "The Role of mTOR in B Cell Lymphoid Malignancies: Biologic and Therapeutic Aspects" International Journal of Molecular Sciences 24, no. 18: 14110. https://doi.org/10.3390/ijms241814110