THE EFFECT OF TP53 MUTATIONS ON THE LOCAL RESPONSE OF MANTLE CELL LYMPHOMA TO RADIATION THERAPY

IF 3.3 4区医学 Q2 HEMATOLOGY

Hematological Oncology Pub Date : 2025-06-16 DOI:10.1002/hon.70094_268

A. Deshane, J. Yahalom, N. A. Wijetunga, A. Kumar, B. Fregonese, A. Zelenetz, G. Salles, B. S. Imber

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Age and stage at RT, treatment intent, relapsed status, site of RT, and prior systemic therapy were collected. Sites treated in pts with TP53mut versus without TP53mut (TP53wt) were compared. Lesion SUV and diameter, extranodal (EN) status of the treated site, blastoid histology, RT dose, and metabolic response at first assessment were compared. Additionally, sites receiving very low dose radiotherapy (VLDRT, 4 Gy) and sites of local failure (LF) were analyzed.Results: 66 patients were identified, treated to 97 sites. 84 sites (87%) were treated in the relapsed setting. 54 sites (56%) were localized relapsed or early-stage disease. By site, median follow up after RT was 1.5 years. 61 sites (64%) treated were EN. Median RT dose was 30 Gy (4–40 Gy), median lesion diameter was 3.5 cm (0.9–22 cm), and median SUV max was 7.5 (0–61.6). 80% (n = 77) of sites had available PET response assessment at a median of 1.7 months (0.1–7.1) post-RT. 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ORR and CRR was 100% and 82% for sites receiving > 4 gy and 89% and 79% for sites receiving VLDRT.Conclusions: In this cohort of MCL treated with RT, response was excellent, and LF was rare. Most sites of LF received VLDRT. TP53mut was significantly associated with higher risk of LF in sites treated with 4 Gy. Despite excellent responses to RT at higher, definitive doses, sites of pts with TP53mut might respond less favorably to VLDRT, suggesting relative radioresistance and the need to consider dose escalation or combination therapy strategies.Keywords: non-HodgkinPotential sources of conflict of interest:J. YahalomConsultant or advisory role: Convergent R. N. R. LtdA. KumarConsultant or advisory role: AstraZeneca, Genentech, Janssen Oncology, Kite PharmaceuticalsStock ownership: BridgeBio IncA. ZelenetzConsultant or advisory role: Abbvie, Arvinas Inc, Astrazeneca, BeiGene USA, Brightly Network LLC, Curio Science, Dava Oncology, Eli Lilly, Genentech, Kite PharmaceuticalsG. SallesConsultant or advisory role: Abbvie, Aptitude Health, BeiGene USA Inc, Bristol-Myers Squibb, Celgene, Curio Science LLC, Debiopharm, Everest Clinical Research Corporation, Fondazione Ferrata Storti, GenMab, Incyte, Innate Pharma, Ipsen Pharma, Janssen Global Services LLC, Janssen Korea Ltd, Kite Pharmaceuticals, Medscape, Merck, MJH Life Sciences, ModeX Therapeutics, Novartis, Nurix, Orna, Practice Point Communications LLC, Research to Practice, Roche, Scientific Education Support, Treeline BiosciencesHonoraria: OwkinB. S. 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引用次数: 0

Abstract

Introduction: The role for radiotherapy (RT) in mantle cell lymphoma (MCL) is limited as MCL often presents in advanced stages. A broader role may be rational given MCL’s propensity for profound but inconsistent radiosensitivity. Common molecular alterations in MCL impact prognosis, namely TP53 mutations (TP53mut). TP53mut can influence systemic therapy choices but its impact on radiosensitivity, or RT decision making is unclear. Better understanding could guide precision radiotherapy.

Methods: We analyzed patients (pts) treated with RT for MCL from 2010 to 2024, focusing on a cohort with next generation sequencing (NGS) for somatic genetic alterations (n = 66). Age and stage at RT, treatment intent, relapsed status, site of RT, and prior systemic therapy were collected. Sites treated in pts with TP53mut versus without TP53mut (TP53wt) were compared. Lesion SUV and diameter, extranodal (EN) status of the treated site, blastoid histology, RT dose, and metabolic response at first assessment were compared. Additionally, sites receiving very low dose radiotherapy (VLDRT, 4 Gy) and sites of local failure (LF) were analyzed.

Results: 66 patients were identified, treated to 97 sites. 84 sites (87%) were treated in the relapsed setting. 54 sites (56%) were localized relapsed or early-stage disease. By site, median follow up after RT was 1.5 years. 61 sites (64%) treated were EN. Median RT dose was 30 Gy (4–40 Gy), median lesion diameter was 3.5 cm (0.9–22 cm), and median SUV max was 7.5 (0–61.6). 80% (n = 77) of sites had available PET response assessment at a median of 1.7 months (0.1–7.1) post-RT. Overall response rate (ORR) was 98.7%, and complete response (CR) rate (CRR) was 81% (n = 62). 32% of pts (n = 21) treated to 33 sites (34%) harbored TP53mut. ORR and CRR were 100% and 83% in TP53wt and 96% and 80% in TP53mut. RT dose (p = 0.817) and CR% (p = 0.491) did not differ by TP53 status. When analyzed by site, TP53mut had significantly worse 1-year FFLP than TP53wt (100 % vs. 85%; p = 0.002). 6 sites overall (6.2%) had LF; of note, 4 of 6 sites received only 4 Gy. TP53mut status was associated with higher risk of LF (p = 0.024). Analysis of sites treated to 4 Gy (n = 14; 14.4%) revealed that TP53mut remained associated with increased risk of LF (p = 0.002). For sites receiving > 4 Gy (n = 83; Median dose 30 Gy, Range 10–40 Gy), presence of TP53mut (n = 30) suggested association with FFLP, though not signficant (p = 0.069). ORR and CRR was 100% and 82% for sites receiving > 4 gy and 89% and 79% for sites receiving VLDRT.

Conclusions: In this cohort of MCL treated with RT, response was excellent, and LF was rare. Most sites of LF received VLDRT. TP53mut was significantly associated with higher risk of LF in sites treated with 4 Gy. Despite excellent responses to RT at higher, definitive doses, sites of pts with TP53mut might respond less favorably to VLDRT, suggesting relative radioresistance and the need to consider dose escalation or combination therapy strategies.

Keywords: non-Hodgkin

Potential sources of conflict of interest:

J. Yahalom

Consultant or advisory role: Convergent R. N. R. Ltd

A. Kumar

Consultant or advisory role: AstraZeneca, Genentech, Janssen Oncology, Kite Pharmaceuticals

Stock ownership: BridgeBio Inc

A. Zelenetz

Consultant or advisory role: Abbvie, Arvinas Inc, Astrazeneca, BeiGene USA, Brightly Network LLC, Curio Science, Dava Oncology, Eli Lilly, Genentech, Kite Pharmaceuticals

G. Salles

Consultant or advisory role: Abbvie, Aptitude Health, BeiGene USA Inc, Bristol-Myers Squibb, Celgene, Curio Science LLC, Debiopharm, Everest Clinical Research Corporation, Fondazione Ferrata Storti, GenMab, Incyte, Innate Pharma, Ipsen Pharma, Janssen Global Services LLC, Janssen Korea Ltd, Kite Pharmaceuticals, Medscape, Merck, MJH Life Sciences, ModeX Therapeutics, Novartis, Nurix, Orna, Practice Point Communications LLC, Research to Practice, Roche, Scientific Education Support, Treeline Biosciences

Honoraria: Owkin

B. S. Imber

Consultant or advisory role: GT Medical Technologies Inc, Ono Pharma, Telix Pharmaceuticals Limited

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tp53突变对套细胞淋巴瘤放射治疗局部反应的影响

导言：放射治疗在套细胞淋巴瘤（MCL）中的作用有限，因为MCL通常出现在晚期。鉴于MCL具有深刻但不一致的放射敏感性，更广泛的作用可能是合理的。MCL中常见的影响预后的分子改变，即TP53突变（TP53mut）。TP53mut可以影响全身治疗的选择，但其对放射敏感性或放疗决策的影响尚不清楚。更好的理解可以指导精准放疗。方法：我们分析了2010年至2024年期间接受RT治疗的MCL患者（pts），重点分析了采用下一代测序（NGS）检测体细胞遗传改变的队列（n = 66）。收集年龄和放疗分期、治疗意图、复发状态、放疗部位和既往全身治疗。比较携带TP53mut和不携带TP53mut的患者的治疗部位（TP53wt）。比较病变的SUV和直径、治疗部位的结外（EN）状态、囊胚组织学、RT剂量和首次评估时的代谢反应。此外，还分析了极低剂量放疗（VLDRT, 4 Gy）和局部失败（LF）的部位。结果：确诊66例，治疗97个部位。84个部位（87%）接受了治疗。54个部位（56%）为局部复发或早期疾病。按部位划分，放疗后的中位随访时间为1.5年。61处（64%）为EN。中位放疗剂量为30 Gy (4 ~ 40 Gy)，中位病灶直径为3.5 cm (0.9 ~ 22 cm)，中位SUV max为7.5（0 ~ 61.6）。80% （n = 77）的地点在rt后中位时间为1.7个月（0.1-7.1个月）时进行了PET反应评估。总缓解率（ORR）为98.7%，完全缓解率（CRR）为81% （n = 62）。33个部位（34%）携带TP53mut的患者占32% （n = 21）。TP53wt的ORR和CRR分别为100%和83%，TP53mut的ORR和CRR分别为96%和80%。放疗剂量（p = 0.817）和CR% （p = 0.491）无TP53状态差异。通过位点分析，TP53mut的1年FFLP显著低于TP53wt (100% vs 85%；P = 0.002)。6个站点（6.2%）有LF；值得注意的是，6个地点中有4个只收到4戈瑞。TP53mut状态与LF的高风险相关（p = 0.024）。4 Gy处理部位分析(n = 14；14.4%)显示TP53mut仍与LF风险增加相关（p = 0.002）。对于接收>；4 Gy (n = 83；中位剂量30 Gy，范围10-40 Gy)， TP53mut的存在（n = 30）提示与FFLP相关，但不显著（p = 0.069）。接收>；接受VLDRT的部位分别为89%和79%。结论：在这组接受RT治疗的MCL患者中，疗效非常好，LF罕见。大部分LF部位接受VLDRT。在接受4gy治疗的部位，TP53mut与较高的LF风险显著相关。尽管在更高的确定剂量下对放射治疗有良好的反应，但TP53mut患者的部位对VLDRT的反应可能不太好，这表明相对放射耐药和需要考虑剂量增加或联合治疗策略。关键词：非霍奇金利益冲突潜在来源；顾问或顾问角色：Convergent R. N. R. LtdA。顾问或顾问角色：AstraZeneca， Genentech, Janssen Oncology， Kite pharmaceuticals股权：BridgeBio IncA。顾问或顾问角色：Abbvie， Arvinas Inc, Astrazeneca, BeiGene USA, bright Network LLC, Curio Science, Dava Oncology, Eli Lilly, Genentech, Kite pharmaceuticals。顾问或顾问角色：Abbvie, Aptitude Health, BeiGene USA Inc, Bristol-Myers Squibb, Celgene, Curio Science LLC, Debiopharm， Everest临床研究公司，Fondazione Ferrata Storti, GenMab, Incyte, Innate Pharma, Ipsen Pharma，杨森全球服务有限公司，杨森韩国有限公司，Kite制药，Medscape，默克，MJH生命科学，ModeX Therapeutics，诺华，Nurix, Orna, Practice Point Communications LLC, Research to Practice，罗氏，Scientific Education Support, Treeline biosciences。顾问或顾问角色：GT Medical Technologies Inc， Ono Pharma, Telix Pharmaceuticals Limited

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来源期刊

Hematological Oncology 医学-血液学

CiteScore

4.20

自引率

6.10%

发文量

147

审稿时长

>12 weeks

期刊介绍： Hematological Oncology considers for publication articles dealing with experimental and clinical aspects of neoplastic diseases of the hemopoietic and lymphoid systems and relevant related matters. Translational studies applying basic science to clinical issues are particularly welcomed. Manuscripts dealing with the following areas are encouraged: -Clinical practice and management of hematological neoplasia, including: acute and chronic leukemias, malignant lymphomas, myeloproliferative disorders -Diagnostic investigations, including imaging and laboratory assays -Epidemiology, pathology and pathobiology of hematological neoplasia of hematological diseases -Therapeutic issues including Phase 1, 2 or 3 trials as well as allogeneic and autologous stem cell transplantation studies -Aspects of the cell biology, molecular biology, molecular genetics and cytogenetics of normal or diseased hematopoeisis and lymphopoiesis, including stem cells and cytokines and other regulatory systems. Concise, topical review material is welcomed, especially if it makes new concepts and ideas accessible to a wider community. Proposals for review material may be discussed with the Editor-in-Chief. Collections of case material and case reports will be considered only if they have broader scientific or clinical relevance.