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Article

Low-Frequency PPM1D Gene Mutations Associated with Inferior Treatment Response to CD19 Targeted CAR-T Cell Therapy in Mantle Cell Lymphoma

by
Katja Seipel
1,*,
Lynn Benninger
2,
Ulrike Bacher
3 and
Thomas Pabst
2,*
1
Department for Biomedical Research, University of Bern, 3008 Bern, Switzerland
2
Department of Medical Oncology, University Hospital Bern, 3010 Bern, Switzerland
3
Department of Hematology, University Hospital Bern, 3010 Bern, Switzerland
*
Authors to whom correspondence should be addressed.
Therapeutics 2024, 1(2), 95-105; https://doi.org/10.3390/therapeutics1020009
Submission received: 24 July 2024 / Revised: 29 August 2024 / Accepted: 19 November 2024 / Published: 29 November 2024
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Abstract

Background/Objectives: Mantle cell lymphoma (MCL) represents a rare B-cell lymphoma subtype with rather high relapse rates. Somatic mutations in the PPM1D gene were shown to be associated with adverse outcomes in patients with diffuse large B-cell lymphoma (DLBCL) who received CD19 CAR-T-cell therapy with tisa-cel, which may also apply to mantle cell lymphoma receiving brexu-cel CAR-T-cells. Methods: In this study, we determined the prevalence of PPM1D mutations in peripheral blood cells of MCL patients before CAR-T-cell infusion and analyzed the impact of low-frequency PPM1D mutations on efficacy and safety aspects of brexu-cel CAR-T-cell treatment in the first 16 r/r MCL patients enrolled at Inselspital Bern. Results: The prevalence of low-frequency PPM1D gene mutations was 25%, with variant allele frequencies (VAF) of 0.011 to 0.099. Clinical response was analyzed in the PPM1D mutated (PPM1Dmut) vs. PPM1D wild-type (PPM1Dwt) groups with median progression-free survival of 1 versus 32 months (p = 0.07) and median overall survival of 1.5 vs. 27 months (p = 0.001). Conclusions: Our data suggest that low-frequency PPM1D gene mutations in peripheral blood cells may predict inferior outcomes in patients with mantle cell lymphoma treated with CAR-T-cell therapy.

1. Introduction

Mantle cell lymphoma (MCL) is a distinct subtype of mature B-cell non-Hodgkin lymphoma (NHL) [1] with a heterogeneous clinical course, including asymptomatic, slow-growing, indolent, and symptomatic, fast-growing aggressive variants [2]. While DLBCL tends to present as fast-growing localized lymphoma, MCL is often a disseminated disease with sometimes leukemic presentation [3]. Initial treatment consists of combination immuno-chemotherapies R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) and R-DHAP (rituximab, dexamethasone, cytarabine, cisplatin), followed by consolidation therapy with high-dose chemotherapy (HDCT) and autologous stem cell transplantation (ASCT) and maintenance therapy with rituximab [4,5,6]. Chemo-immunotherapy regimens containing rituximab and cytarabine and maintenance therapy with rituximab may be applied in all MCL patients, while consolidation therapy with autologous stem cell transplantation is available only in transplant-eligible patients [7]. Rituximab is a chimeric anti-CD20 monoclonal antibody with established efficacy in patients with CD20-expressing lymphoid malignancies [8]. More recently, new therapies targeting Bruton’s tyrosine kinase have gained regulatory approval [9]. Ibrutinib treatment in combination with standard chemoimmunotherapy significantly prolonged progression-free survival [10]. The addition of ibrutinib to the standard treatment of younger, transplant-eligible patients with mantle cell lymphoma resulted in superior efficacy in the TRIANGLE study [11]. Combination treatments with ibrutinib and the proteasome inhibitor bortezomib or the monoclonal antibody rituximab are effective and well tolerated as first-line therapies in MCL [12,13], but their duration of action is limited. In a substantial proportion of patients, the disease will repeatedly relapse, additional treatment lines will be applied, and the disease may become refractory, emphasizing the need for new therapeutic options. In the management of relapsed/refractory lympho-proliferative malignancies, chimeric antigen receptor (CAR) T-cell therapies are new immunotherapeutic options. Currently, four FMC63-based anti-CD19 CAR-T-cell products, axicabta-gene ciloleucel (axi-cel, Yescarta©, Kite-Pharma Inc., Santa Monica, CA, USA), tisagen-lecleucel (tisa-cel, Kymriah©, Novartis, Basel, Switzerland), lisocabtagene maraleucel (lisa-cel, Breyanzi©, Juno Therapeutics Inc., Seattle, WA, USA), and brexucabta-gene autoleucel (brexu-cel, Tecartus©, Kite-Pharma Inc., Santa Monica, CA, USA) have been approved for medical use. Axi-cel and tisa-cel were approved in 2018 with an indication for the treatment of acute lymphoblastic leukemia (ALL), DLBCL, and transformed follicular lymphoma (trFL) [14]. Lisa-cel was approved in 2021 for the treatment of DLBCL and in 2024 for the treatment of follicular lymphoma. Brexu-cel was approved in 2020, with an indication for the treatment of adults with relapsed or refractory MCL [15]. Brexu-cel is an anti-CD19 CAR-T-cell product based on the same FMC63 construct as axi-cel, tisa-cel, and lisa-cel but a different manufacturing process in that brexu-cel includes specific T-cell selection and lymphocyte enrichment necessary for activity against MCL [16]. The phase II ZUMA-2 trial has reported promising results with CAR-T-cell therapy in MCL patients relapsing after BTK inhibitors, with an overall response rate of 93% and durable remissions in more than 60% of responding patients [17]. Similarly, with the first patients treated at our hospital, we reported CAR-T-cell therapy as effective and well tolerated even in heavily pretreated and older patients in a real-world setting [18]. CAR-T-cell infusion may induce relevant toxicities, including cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS), which require medical intervention with anti-inflammatory agents [19,20].
Clonal hematopoiesis (CH) refers to an expansion of hematopoietic cell clones, with an increase in somatic mutations with age [21,22], and differences in myeloid and lymphoid clonal hematopoiesis [23,24]. The most relevant CH driver genes include PPM1D, TP53, DNMT3A, ASXL1, and TET2, but more driver genes have been detected recently [25]. TP53 mutations can be present in tumor cell populations at very low variant allele frequency (VAF), and the presence of these small TP53 clones (VAF < 1.0%) was associated with inferior survival in the context of immuno-chemotherapy [26]. The presence of CH has been linked to inflammation and cancer, impacting leukemogenesis, disease progression, and treatment response, including CAR-T-cell therapy responses, as well as the efficacy and toxicity of immunotherapies [27]. However, there are also reports where the presence of CH in DLBCL patients had no effect on CAR-T-cell-induced toxicity, treatment response, or outcome [28]. Mutations in CH driver genes confer an advantage to hematopoietic stem cells [29]. CH affects engraftment and survival in stem cell transplant recipients. In >30% of patients with lymphoma who had received ASCT, CH was detected, with PPM1D representing the most frequent driver alteration [30,31].
The PPM1D gene on chromosome 17q comprises six exons encoding the protein phosphatase Mg2+/Mn2+-dependent 1D (PPM1D, Wip1), which targets the tumor suppressor protein p53 and other proteins involved in DNA damage response [32]. PPM1D is expressed in hematopoietic stem and progenitor cells as well as in mature cells, including neutrophils, macrophages, and B and T lymphocytes in both bone marrow and peripheral blood [33]. In lymphoma patients treated with R-CHOP, an expansion of PPM1D mutant clones was more common than other CH-driver gene mutations [34]. In DLBCL patients, the occurrence of low-frequency PPM1D gene mutations may affect the response to CD19-targeted CAR-T-cell therapy [35]. In the future, lymphoma patients with PPM1D mutations may be treated with selective and potent allosteric PPM1D inhibitors [36,37,38].
In this retrospective study, we determined the prevalence of low-frequency PPM1D gene mutations in the peripheral blood mononuclear cells (PBMC) of the first 16 r/r MCL patients enrolled for CAR-T-cell therapy at the Inselspital Bern and endeavored to analyze PPM1D mutations with respect to efficacy and safety of CD19 brexu-cel CAR-T-cells in MCL patients.

2. Materials and Methods

2.1. Clinical Study

In this retrospective single-center study at the Inselspital, University Hospital Bern, Switzerland, patients with relapsed/refractory MCL underdoing brexu-cel CAR-T-cell therapy were investigated. The analyzed cohort comprised 16 consecutive patients with relapsed/refractory MCL who received brexu-cel in the period between 01/2019 and 08/2022. All patients gave written informed consent for the inclusion of clinical and laboratory data for research purposes. Clinical follow-up was performed in all patients at one, three, six months, one year, and yearly following CAR-T-cell therapy. Patients underwent PET-CT imaging at 3 and 6 months post CAR-T-cell infusion.
Primary outcomes were survival endpoints. Progression-free survival (PFS) and OS were the interval from CAR-T-cell infusion to disease progression, death, or last follow-up. PFS and OS were censored at the last follow-up on 18 August 2023, which was also used as the data cutoff. Survival curves (Kaplan–Meyer) and univariate statistical analyses were performed on GraphPad Prism version 10 (GraphPad Software, San Diego, CA, USA). Parameters investigated for their potential prognostic significance were patient age, international prognostic index (IPI), previous treatment lines, prior radiotherapy, the need for bridging therapy before CAR-T-cell infusion, remission status at the time of CAR-T-cell treatment, number of complete responses prior to CAR-T therapy, prior ASCT, lactate dehydrogenase (LDH) before lympho-depleting therapy, the manifestation of a cytokine release syndrome (CRS), and/or an immune effector cell-associated neurotoxicity syndrome (ICANS). CAR-T-cell construct kinetics were monitored in peripheral blood using a previously established ddPCR assay [30]. The limit of detection was 20 copies/μg of DNA. Peak IL-6 and C-reactive protein (CRP) serum levels were recorded during the treatment in order to evaluate the occurrence of CRS and infections [30]. Follow-up dates were at 100 days, 6 months, and 1 year after CAR-T-cell infusion. The categorical variables were summarized as frequencies and percentages, and the continuous variables as medians and ranges.

2.2. PPM1D Gene Analysis

Genomic DNA was extracted from mononuclear cells (PBMC) isolated from the peripheral blood of 16 consecutive patients with relapsed/refractory MCL taken before CAR-T-cell infusion, as well as in eight individuals without a history of malignant disease. NGS amplicon sequencing and bioinformatics followed the previous descriptions [35].

2.3. CD19 Gene Analysis

Genomic DNA was used to amplify and sequence exons 3 and 4 of the CD19 gene as previously described [39].

3. Results

3.1. Prevalence of PPM1D Mutations in r/r MCL

We performed NGS amplicon sequencing to detect mutations in exon 6 of the PPM1D gene in peripheral blood mononuclear cells (PBMC) isolated from the 16 patients with r/r MCL who were enrolled for CD19-targeted CAR-T-cell therapy. The threshold for inclusion was the presence of a PPM1D gene mutation with a variant allele frequency (VAF) > 0.01. Thus, we were able to detect seven low-frequency PPM1D gene mutations in four MCL patients (4/16, 25%), with three in-del, one nonsense, and three missense mutations (Table 1, Figure 1), including two samples with one in-del mutation, one sample with a nonsense and a missense mutation, one sample with an in-del and three missense mutations. The VAF of PPM1D mutations called in the PBMC DNA samples ranged from 0.011 to 0.099.
All four variants with stop–gain changes are translated into phosphatase protein variants lacking the APC/C (DBOX) degron motif (AA550-557). They may not be effectively targeted for degradation by the cellular APC/C complex. Consequently, the function of the p53 tumor suppressor may be impaired in cells with mutated PPM1D genes. The function of PPM1D phosphatase in B-cells was previously presented [22].

3.2. Clinical Characteristics

Clinical characteristics of the 16 patients with relapsed/refractory MCL enrolled for brexu-cel CAR-T-cell therapy were evaluated by univariate analysis (Table 2). At initial diagnosis, the median age was 65 years (range: 48–80 years). Most patients had initial disease stage IV (88%). According to the Mantle Cell Lymphoma International Prognostic Index (MIPI), the majority of the PPM1Dwt subgroup (n = 12) scored in the intermediate risk range, whereas the majority of the PPM1Dmut subgroup (n = 4) had a high-risk score.
All patients were heavily pretreated, with an average of four treatment lines in both subgroups. Additionally, half of the patients had undergone high-dose chemotherapy (HDCT) followed by autologous hematopoietic stem cell transplantation (ASCT), including the majority of the PPM1Dmut (3/4, 75%), and a minority of the PPM1Dwt (5/12, 42%) subgroup. Complete remissions to previous treatments showed differences between both subgroups, with 17 CR in seven patients of the PPM1Dwt subgroup (7/12; 54%) and only one CR in the four patients of the PPM1Dmut subgroup (1/4; 25%).
Bridging therapies were applied in the majority of r/r MCL patients to reduce lymphoma burden before CAR-T-cell infusion, consisting of anti-CD20 monoclonal antibody rituximab in combination with bendamustine, cytarabine, dexamethasone, oxaliplatin (R-BAC, R-DHAO) or BTK inhibitor ibrutinib. The target antigen variants differed in the two subgroups (p = 0.02): all of the PPM1Dmut patients, but only 25% of the PPM1Dwt patients carried the CD19 gene single nucleotide polymorphism rs2904880. The presence of rs2904880 was associated with superior treatment outcomes in DLBCL patients receiving FMC63-anti-CD19-CAR-T-cell therapy [26].

3.3. CAR-T-Cell Therapy and Clinical Outcome

One patient with low-frequency PPM1D mutation had progressive disease and died before CAR-T-cell infusion. The majority of the patients with relapsed/refractory MCL (n = 15) received chemotherapy for three days with 300 mg/m2 cyclophosphamide and 30 mg/m2 fludarabine (day −5 to −3) for lympho-depletion, with two days of washout prior to Brexu-cel CAR-T-cells (day 0). Details of CAR-T-cell therapy and clinical outcomes were evaluated by univariate analysis (Table 3). At the time of CAR-T-cell therapy, the median patient age was 72 years (range 56–81 years). The median interval from first diagnosis to CAR-T-cell infusion was 4.5 and 1.5 years for the PPM1Dwt and PPM1Dmut patient population, respectively (p = 0.17). Median LDH levels before lympho-depletion were lower in the PPM1Dwt patients (180 U/L vs. 320 U/L, p = 0.04), indicating differences in disease progression. At the time of CAR-T-cell infusion, the disease status showed differences between the two subgroups (p = 0.009): while the majority of patients in the PPM1Dwt subgroup (58%) had remitting or stable disease, all of the patients in the PPM1Dmut subgroup had progressive disease.
Following CAR-T-cell infusion, CAR-T-cells showed a peak in the peripheral blood after a median of 13 days (median concentration, 7240 copies per μg cfDNA). The majority of patients developed low-grade cytokine release syndrome (CRS) after CAR-T-cell infusion. Immune effector cell-associated neuro-toxicity syndrome (ICANS) occurred in six patients (40%), low grade 1/2 in three patients, and high grade 3/4 in another three patients. Frequencies of CRS and ICANS were similar in patients with and without PPM1D gene mutations. Toxicity syndromes were treated with tocilizumab, anakinra, and dexametha-sone. Inflammatory markers including C-reactive protein (CRP), ferritin, and IL-6 were elevated in the PPM1Dmut subgroup (CRP, 82 mg/L vs. 37 mg/L, p = 0.077; ferritin, 5115 μg/L vs. 1501 μg/L, p = 0.031; IL-6 639 pg/mL vs. 412 pg/mL, p = 0.77). The median time to peak IL-6 levels was extended in the PPM1Dmut subgroup (25 vs. 7 days, p = 0.01).
The response to therapy was different in both subgroups (p = 0.027). Complete response (CR) was prevalent in the PPM1Dwt cohort (92%) three months after CAR-T-cell infusion, with only one patient (33%) of the PPM1Dmut subset reaching CR six months after CAR-T-cell infusion. In the PPM1Dwt subgroup (n = 12) three patients relapsed within 6 months after CAR-T-cell infusion (25%) and five patients (42%) died with a median survival time of 27 months. In the PPM1Dmut subgroup (n = 3) disease progressed in two and death occurred in all patients with a median survival time of 1.5 months after CAR-T-cell infusion. The survival time from CAR-T-cell infusion to disease progression and death varied significantly in the PPM1D wt versus PPM1Dmut MCL patients. Median survival was significantly longer in the PPM1Dwt compared to the PPM1Dmut population (27 months vs. 1 month, p = 0.001; Figure 2). There were nine patients who had progressive disease at the time of CAR-T-cell infusion: five PPM1Dwt and four PPM1Dmut. A complete response to CAR-T-cell therapy was reached in four of the five PPM1D patients infused during progressive disease (80%) and in one of the three PPM1Dmut patients (33%).

4. Discussion

We performed a retrospective single-center study including 16 consecutive patients with relapsed/refractory MCL, who received brexu-cel CAR-T-cell therapy in 2019–2022. The MCL patients in this study had received several previous treatment lines: first-line therapy had been the alternating application of combined immuno-chemotherapies R-CHOP and R-DHAP; consolidation therapy consisted of high-dose chemotherapy (HDCT) and autologous stem cell transplantation (ASCT); and maintenance therapy rituximab. Chimeric antigen receptor (CAR)-T-cell therapies are a novel option for the management of relapsed/refractory lympho-proliferative malignancies. In a previous study on CD19 targeted CAR-T-cell therapy in r/r DLBCL treated with axi-cel or tisa-cel, we described a significantly inferior survival outcome in patients with CH-related PPM1D mutations: 5 versus 37 months; p = 0.004. While the prevalent treatment outcome in the DLBCL PPM1Dwt subgroup was complete remission (56%), the majority of patients in the PPM1Dmut subgroup had only partial remission (60%) and a reduced time of relapse-free survival (3 versus 12 months; p = 0.07) [22]. We anticipated an association of PPM1D mutations with inferior response to CD19 CAR-T-cell therapy in commensurate lymphoma treatment regimens. Indeed, in r/r MCL patients treated with brexu-cel in this study, both relapse-free and overall survival times were substantially shortened in the PPM1Dmut population (1 versus 27 months; p = 0.001). Complete response (CR) was prevalent in the PPM1Dwt (92%), but only one patient (33%) of the PPM1Dmut cohort reached CR after CAR-T-cell infusion. Our data suggest an adverse prognostic and possibly predictive impact of PPM1D mutations in patients with relapsed/refractory MCL treated with brexu-cel. Moreover, patients with PPM1D mutated lymphoma had inferior outcomes in both the r/r DLBCL and r/r MCL setting treated with FMC-63-based CAR-T-cell therapies, indicating a common association of PPM1D gene mutation and CAR-T-cell response despite differences in the specific therapies including T-cell selection and lymphocyte enrichment in brexu-cel production.
Low-frequency PPM1D gene mutations were prevalent in 20% of heavily pretreated lymphoma patients in both study populations in our larger r/r DLBCL cohort [22] and in the smaller r/r MCL cohort (this study). The six identified PPM1D exon mutations resembled those previously described [18,40,41], with a majority of stop–gain changes resulting in truncated protein products, which may not be effectively targeted for degradation by the cellular APC/C complex [42]. An elevated prevalence of PPM1D somatic mutations has previously been reported in cancer patients with a history of chemotherapy and radiation exposure [17,21,29,43]. Pre-treatment LDH serum levels and post-treatment serum levels of inflammatory markers, including CRP, ferritin, and IL-6, differed in the PPM1Dwt versus PPM1Dmut populations with elevated levels in the PPM1Dmut MCL and DLBCL populations and negative association with clinical results. Elevated ferritin levels in the sera of lymphoma patients had previously been associated with aggressive disease and poor clinical outcomes [44]. Likewise, elevated CRP serum levels >30 mg/L had previously been associated with shorter survival times in lymphoma patients receiving anti-CD19 CAR-T-cell therapy [10].
The baseline and pretreatment characteristics, however, differed in the two MCL subgroups. According to the Mantle Cell Lymphoma International Prognostic Index (MIPI) the majority of the PPM1Dwt MCL patients showed intermediate risk scores, while the majority of the PPM1Dmut subgroup was associated with high risk scores. Accordingly, the PPM1Dwt subgroup showed a longer median interval from initial diagnosis to CAR-T-cell infusion as compared to the PPM1Dmut patients. The majority of PPM1Dmut patients and the minority of patients in the PPM1Dwt subgroup had undergone radiation therapy, HDCT, and ASCT. CH mutations in TP53 and PPM1D genes were linked to prior radiation and chemotherapy [17]. HDCT with melphalan has been associated with high direct mutagenic impact in myeloma and lymphoma [45,46]. Moreover, the disease status at the time of CAR-T-cell infusion showed differences between the two MCL subgroups. Whereas the majority of MCL patients in the PPM1Dwt subgroup achieved CR or had stable disease (58%), all of the PPM1Dmut MCL patients had progressive disease at CAR-T-cell infusion. The disease status at the time of CAR-T-cell infusion may affect the outcome as DLBCL patients with bulky disease had inferior outcomes to CAR-T-cell therapy [47]. In the small MCL cohort, complete response to CAR-T-cell therapy was reached in 92% of PPM1Dwt patients, including four of the five PPM1Dwt patients (80%) infused during progressive disease, but only one of the three PPM1Dmut patients (33%). Moreover, there was a difference in the frequency of CD19 rs29048800 in the two subgroups with higher prevalence in the PPM1Dmut patients. The presence of rs2904880 was associated with superior treatment outcomes in DLBCL treated with FMC63-anti-CD19-CAR-T-cell therapy [26]. Here, in combination with PPM1D gene mutations, the presence of CD19 rs2904880 was not beneficial to the outcome in mantle cell lymphoma treated with brexu-cel.
In the future, PPM1D inhibitors may present a novel therapeutic option for patients with PPM1Dmut patients. Small molecule inhibitors of PPM1D are available, including a selective and potent allosteric inhibitor GSK2830371. Moreover, other therapies may still be considered after CAR-T-cell failure including bispecific antibodies offering an effective and well-tolerated option for patients with mantle cell lymphoma relapsing after CAR-T therapy.

5. Conclusions

Our data suggest an adverse prognostic impact of PPM1D mutations in patients with relapsed/refractory MCL undergoing brexucel CD19 CAR-T-cell therapy. However, with the small number of patients in our study, the presence of PPM1D mutation and the outcome of the CAR-T-cell therapy may not be causally related. There may be other factors underlying a poor response to brexu-cel therapy in MCL patients, including initial adverse risk disease, a lower frequency of complete remissions to previous treatments, and progressive disease at the time of CAR-T-cell infusion. To confirm the adverse impact of low-frequency PPM1D mutations, larger cohorts of MCL patients receiving CD19 CAR-T-cell therapy have to be analyzed in the future.

Author Contributions

Conceptualization, K.S. and T.P.; investigation, K.S. and L.B.; methodology, K.S.; formal analysis, K.S. and L.B.; resources U.B.; writing—original draft preparation, K.S.; writing—review and editing, K.S., U.B. and T.P.; visualization, K.S.; supervision, K.S. and T.P.; project administration, T.P. All authors have read and agreed to the published version of the manuscript.

Funding

This research received no external funding.

Institutional Review Board Statement

This study was conducted according to the guidelines of the Declaration of Helsinki and approved by the Ethics Committee of the Canton of Bern, Switzerland (decision number 2024-00988 and date of approval 21 May 2024).

Informed Consent Statement

Informed consent was obtained from all subjects involved in the study according to the Declaration of Helsinki. The general consent form is available.

Data Availability Statement

Data are available upon request due to restrictions, privacy, and ethics.

Acknowledgments

The authors wish to thank the data management, apheresis, flow cytometry, and stem cell laboratory teams of the ASCT program at the University Hospital of Bern and its associated partner hospitals and collaborators for the documentation of data relevant to this study.

Conflicts of Interest

The authors declare no conflicts of interest.

References

  1. Armitage, J.O.; Longo, D.L. Mantle-Cell Lymphoma. N. Engl. J. Med. 2022, 386, 2495–2506. [Google Scholar] [CrossRef] [PubMed]
  2. Jain, P.; Wang, M.L. Mantle Cell Lymphoma in 2022—A Comprehensive Update on Molecular Pathogenesis, Risk Stratification, Clinical Approach, and Current and Novel Treatments. Am. J. Hematol. 2022, 97, 638–656. [Google Scholar] [CrossRef] [PubMed]
  3. Isaac, K.M.; Portell, C.A.; Williams, M.E. Leukemic Variant of Mantle Cell Lymphoma: Clinical Presentation and Management. Curr. Oncol. Rep. 2021, 23, 102. [Google Scholar] [CrossRef] [PubMed]
  4. Sehn, L.H.; Congiu, A.G.; Culligan, D.J.; Gironella, M.; Yoon, D.H.; Ogura, M.; Rosta, A.; Zhu, J.; Launonen, A.; Nielsen, T.; et al. No Added Benefit of Eight Versus Six Cycles of CHOP When Combined with Rituximab in Previously Untreated Diffuse Large B-Cell Lymphoma Patients: Results from the International Phase III GOYA Study. Blood 2018, 132, 783. [Google Scholar] [CrossRef]
  5. Silkenstedt, E.; Linton, K.; Dreyling, M. Mantle Cell Lymphoma—Advances in Molecular Biology, Prognostication and Treatment Approaches. Br. J. Haematol. 2021, 195, 162–173. [Google Scholar] [CrossRef]
  6. Mathys, A.; Bacher, U.; Banz, Y.; Legros, M.; Mansouri Taleghani, B.; Novak, U.; Pabst, T. Outcome of Patients with Mantle Cell Lymphoma after Autologous Stem Cell Transplantation in the Pre-CAR T-Cell Era. Hematol. Oncol. 2022, 40, 292–296. [Google Scholar] [CrossRef]
  7. Maddocks, K. Update on Mantle Cell Lymphoma. Blood 2018, 132, 1647–1656. [Google Scholar] [CrossRef]
  8. Salles, G.; Barrett, M.; Foà, R.; Maurer, J.; O’Brien, S.; Valente, N.; Wenger, M.; Maloney, D.G. Rituximab in B-Cell Hematologic Malignancies: A Review of 20 Years of Clinical Experience. Adv. Ther. 2017, 34, 2232–2273. [Google Scholar] [CrossRef]
  9. Burger, J.A. Bruton Tyrosine Kinase Inhibitors: Present and Future. Cancer J. 2019, 25, 386–393. [Google Scholar] [CrossRef]
  10. Wang, M.L.; Jurczak, W.; Jerkeman, M.; Trotman, J.; Zinzani, P.L.; Belada, D.; Boccomini, C.; Flinn, I.W.; Giri, P.; Goy, A.; et al. Ibrutinib plus Bendamustine and Rituximab in Untreated Mantle-Cell Lymphoma. N. Engl. J. Med. 2022, 386, 2482–2494. [Google Scholar] [CrossRef]
  11. Dreyling, M.; Doorduijn, J.; Giné, E.; Jerkeman, M.; Walewski, J.; Hutchings, M.; Mey, U.; Riise, J.; Trneny, M.; Vergote, V.; et al. Ibrutinib Combined with Immunochemotherapy with or without Autologous Stem-Cell Transplantation versus Immunochemotherapy and Autologous Stem-Cell Transplantation in Previously Untreated Patients with Mantle Cell Lymphoma (TRIANGLE): A Three-Arm, Randomised, Open-Label, Phase 3 Superiority Trial of the European Mantle Cell Lymphoma Network. Lancet 2024, 403, 2293–2306. [Google Scholar] [CrossRef] [PubMed]
  12. Novak, U.; Fehr, M.; Schär, S.; Dreyling, M.; Schmidt, C.; Derenzini, E.; Zander, T.; Hess, G.; Mey, U.; Ferrero, S.; et al. Combined Therapy with Ibrutinib and Bortezomib Followed by Ibrutinib Maintenance in Relapsed or Refractory Mantle Cell Lymphoma and High-Risk Features: A Phase 1/2 Trial of the European MCL Network (SAKK 36/13). eClinicalMedicine 2023, 64, 102221. [Google Scholar] [CrossRef] [PubMed]
  13. Tivey, A.; Shotton, R.; Eyre, T.A.; Lewis, D.; Stanton, L.; Allchin, R.; Walter, H.; Miall, F.; Zhao, R.; Santarsieri, A.; et al. Ibrutinib as First-Line Therapy for Mantle Cell Lymphoma: A Multicenter, Real-World UK Study. Blood Adv. 2024, 8, 1209–1219. [Google Scholar] [CrossRef] [PubMed]
  14. Sesques, P.; Ferrant, E.; Safar, V.; Wallet, F.; Tordo, J.; Dhomps, A.; Karlin, L.; Brisou, G.; Vercasson, M.; Hospital-Gustem, C.; et al. Commercial Anti-CD19 CAR T Cell Therapy for Patients with Relapsed/Refractory Aggressive B Cell Lymphoma in a European Center. Am. J. Hematol. 2020, 95, 1324–1333. [Google Scholar] [CrossRef]
  15. Huang, Z.; Chavda, V.P.; Bezbaruah, R.; Dhamne, H.; Yang, D.-H.; Zhao, H.-B. CAR T-Cell Therapy for the Management of Mantle Cell Lymphoma. Mol. Cancer 2023, 22, 67. [Google Scholar] [CrossRef]
  16. Mian, A.; Hill, B.T. Brexucabtagene Autoleucel for the Treatment of Relapsed/Refractory Mantle Cell Lymphoma. Expert Opin. Biol. Ther. 2021, 21, 435–441. [Google Scholar] [CrossRef]
  17. Wang, M.; Munoz, J.; Goy, A.; Locke, F.L.; Jacobson, C.A.; Hill, B.T.; Timmerman, J.M.; Holmes, H.; Jaglowski, S.; Flinn, I.W.; et al. KTE-X19 CAR T-Cell Therapy in Relapsed or Refractory Mantle-Cell Lymphoma. N. Engl. J. Med. 2020, 382, 1331–1342. [Google Scholar] [CrossRef]
  18. Heini, A.D.; Bacher, U.; Kronig, M.-N.; Wiedemann, G.; Novak, U.; Zeerleder, S.; Mansouri Taleghani, B.; Daskalakis, M.; Pabst, T. Chimeric Antigen Receptor T-Cell Therapy for Relapsed Mantle Cell Lymphoma: Real-World Experience from a Single Tertiary Care Center. Bone Marrow Transpl. 2022, 57, 1010–1012. [Google Scholar] [CrossRef]
  19. Gazeau, N.; Liang, E.C.; Wu, Q.V.; Voutsinas, J.M.; Barba, P.; Iacoboni, G.; Kwon, M.; Ortega, J.L.R.; López-Corral, L.; Hernani, R.; et al. Anakinra for Refractory Cytokine Release Syndrome or Immune Effector Cell-Associated Neurotoxicity Syndrome after Chimeric Antigen Receptor T Cell Therapy. Transpl. Cell Ther. 2023, 29, 430–437. [Google Scholar] [CrossRef]
  20. Bonifant, C.L.; Jackson, H.J.; Brentjens, R.J.; Curran, K.J. Toxicity and Management in CAR T-Cell Therapy. Mol. Ther. Oncolytics 2016, 3, 16011. [Google Scholar] [CrossRef]
  21. Robertson, N.A.; Latorre-Crespo, E.; Terradas-Terradas, M.; Lemos-Portela, J.; Purcell, A.C.; Livesey, B.J.; Hillary, R.F.; Murphy, L.; Fawkes, A.; MacGillivray, L.; et al. Longitudinal Dynamics of Clonal Hematopoiesis Identifies Gene-Specific Fitness Effects. Nat. Med. 2022, 28, 1439–1446. [Google Scholar] [CrossRef] [PubMed]
  22. Jaiswal, S.; Ebert, B.L. Clonal Hematopoiesis in Human Aging and Disease. Science 2019, 366, eaan4673. [Google Scholar] [CrossRef] [PubMed]
  23. Niroula, A.; Sekar, A.; Murakami, M.A.; Trinder, M.; Agrawal, M.; Wong, W.J.; Bick, A.G.; Uddin, M.M.; Gibson, C.J.; Griffin, G.K.; et al. Distinction of Lymphoid and Myeloid Clonal Hematopoiesis. Nat. Med. 2021, 27, 1921–1927. [Google Scholar] [CrossRef] [PubMed]
  24. von Beck, K.; von Beck, T.; Ferrell, P.B.; Bick, A.G.; Kishtagari, A. Lymphoid Clonal Hematopoiesis: Implications for Malignancy, Immunity, and Treatment. Blood Cancer J. 2023, 13, 5. [Google Scholar] [CrossRef] [PubMed]
  25. Bernstein, N.; Spencer Chapman, M.; Nyamondo, K.; Chen, Z.; Williams, N.; Mitchell, E.; Campbell, P.J.; Cohen, R.L.; Nangalia, J. Analysis of Somatic Mutations in Whole Blood from 200,618 Individuals Identifies Pervasive Positive Selection and Novel Drivers of Clonal Hematopoiesis. Nat. Genet. 2024, 56, 1147–1155. [Google Scholar] [CrossRef]
  26. Bomben, R.; Zucchetto, A.; Pozzo, F.; Tissino, E.; Bittolo, T.; Olivieri, J.; Chiarenza, A.; Zaja, F.; Del Principe, M.I.; Rossi, D.; et al. TP53 Mutations and Clinical Outcome in Chronic Lymphocytic Leukemia: Is a Threshold Still Needed? Hemasphere 2023, 7, e855. [Google Scholar] [CrossRef]
  27. Singh, A.; Balasubramanian, S. The Crossroads of Cancer Therapies and Clonal Hematopoiesis. Semin. Hematol. 2024, 61, 16–21. [Google Scholar] [CrossRef]
  28. Panagiota, V.; Kerschbaum, J.F.; Penack, O.; Stein, C.M.; Arends, C.M.; Koenecke, C.; Strzelecka, P.M.; Kloos, A.; Wiegand, L.; Lasch, A.; et al. Clinical Implications and Dynamics of Clonal Hematopoiesis in Anti-CD19 CAR T-Cell Treated Patients. Hemasphere 2023, 7, e957. [Google Scholar] [CrossRef]
  29. Pich, O.; Reyes-Salazar, I.; Gonzalez-Perez, A.; Lopez-Bigas, N. Discovering the Drivers of Clonal Hematopoiesis. Nat. Commun. 2022, 13, 4267. [Google Scholar] [CrossRef]
  30. Gibson, C.J.; Lindsley, R.C.; Tchekmedyian, V.; Mar, B.G.; Shi, J.; Jaiswal, S.; Bosworth, A.; Francisco, L.; He, J.; Bansal, A.; et al. Clonal Hematopoiesis Associated with Adverse Outcomes After Autologous Stem-Cell Transplantation for Lymphoma. J. Clin. Oncol. 2017, 35, 1598–1605. [Google Scholar] [CrossRef]
  31. Lackraj, T.; Ben Barouch, S.; Medeiros, J.J.F.; Pedersen, S.; Danesh, A.; Bakhtiari, M.; Hong, M.; Tong, K.; Joynt, J.; Arruda, A.; et al. Clinical Significance of Clonal Hematopoiesis in the Setting of Autologous Stem Cell Transplantation for Lymphoma. Am. J. Hematol. 2022, 97, 1538–1547. [Google Scholar] [CrossRef] [PubMed]
  32. Husby, S.; Hjermind Justesen, E.; Grønbæk, K. Protein Phosphatase, Mg2+/Mn2+-Dependent 1D (PPM1D) Mutations in Haematological Cancer. Br. J. Haematol. 2021, 192, 697–705. [Google Scholar] [CrossRef] [PubMed]
  33. Belotserkovskaya, E.; Golotin, V.; Uyanik, B.; Demidov, O.N. Clonal Haematopoiesis—A Novel Entity That Modifies Pathological Processes in Elderly. Cell Death Discov. 2023, 9, 345. [Google Scholar] [CrossRef] [PubMed]
  34. Kahn, J.D.; Miller, P.G.; Silver, A.J.; Sellar, R.S.; Bhatt, S.; Gibson, C.; McConkey, M.; Adams, D.; Mar, B.; Mertins, P.; et al. PPM1D-Truncating Mutations Confer Resistance to Chemotherapy and Sensitivity to PPM1D Inhibition in Hematopoietic Cells. Blood 2018, 132, 1095–1105. [Google Scholar] [CrossRef]
  35. Seipel, K.; Frey, M.; Nilius, H.; Akhoundova, D.; Banz, Y.; Bacher, U.; Pabst, T. Low-Frequency PPM1D Gene Mutations Affect Treatment Response to CD19-Targeted CAR T-Cell Therapy in Large B-Cell Lymphoma. Curr. Oncol. 2023, 30, 10463–10476. [Google Scholar] [CrossRef]
  36. Marcellino, B.K. PPM1D Inhibition May Allow Us to WIP Leukemia. Blood 2023, 142, 2040–2042. [Google Scholar] [CrossRef]
  37. Miller, P.G.; Sathappa, M.; Moroco, J.A.; Jiang, W.; Qian, Y.; Iqbal, S.; Guo, Q.; Giacomelli, A.O.; Shaw, S.; Vernier, C.; et al. Allosteric Inhibition of PPM1D Serine/Threonine Phosphatase via an Altered Conformational State. Nat. Commun. 2022, 13, 3778. [Google Scholar] [CrossRef]
  38. Meller, A.; De Oliveira, S.; Davtyan, A.; Abramyan, T.; Bowman, G.R.; van den Bedem, H. Discovery of a Cryptic Pocket in the AI-Predicted Structure of PPM1D Phosphatase Explains the Binding Site and Potency of Its Allosteric Inhibitors. Front. Mol. Biosci. 2023, 10, 1171143. [Google Scholar] [CrossRef]
  39. Seipel, K.; Abbühl, M.; Bacher, U.; Nilius, H.; Daskalakis, M.; Pabst, T. Clinical Impact of Single Nucleotide Polymorphism in CD-19 on Treatment Outcome in FMC63-CAR-T Cell Therapy. Cancers 2023, 15, 3058. [Google Scholar] [CrossRef]
  40. Saini, N.Y.; Swoboda, D.M.; Greenbaum, U.; Ma, J.; Patel, R.D.; Devashish, K.; Das, K.; Tanner, M.R.; Strati, P.; Nair, R.; et al. Clonal Hematopoiesis Is Associated with Increased Risk of Severe Neurotoxicity in Axicabtagene Ciloleucel Therapy of Large B-Cell Lymphoma. Blood Cancer Discov. 2022, 3, 385–393. [Google Scholar] [CrossRef]
  41. Hsu, J.I.; Dayaram, T.; Tovy, A.; De Braekeleer, E.; Jeong, M.; Wang, F.; Zhang, J.; Heffernan, T.P.; Gera, S.; Kovacs, J.J.; et al. PPM1D Mutations Drive Clonal Hematopoiesis in Response to Cytotoxic Chemotherapy. Cell Stem Cell 2018, 23, 700–713.e6. [Google Scholar] [CrossRef] [PubMed]
  42. Jeong, H.-C.; Gil, N.-Y.; Lee, H.-S.; Cho, S.-J.; Kim, K.; Chun, K.-H.; Cho, H.; Cha, H.-J. Timely Degradation of Wip1 Phosphatase by APC/C Activator Protein Cdh1 Is Necessary for Normal Mitotic Progression. J. Cell Biochem. 2015, 116, 1602–1612. [Google Scholar] [CrossRef] [PubMed]
  43. Al Hinai, A.S.A.; Grob, T.; Rijken, M.; Kavelaars, F.G.; Zeilemaker, A.; Erpelinck-Verschueren, C.A.J.; Sanders, M.A.; Löwenberg, B.; Jongen-Lavrencic, M.; Valk, P.J.M. PPM1D Mutations Appear in Complete Remission After Exposure to Chemotherapy Without Predicting Emerging AML Relapse. Leukemia 2021, 35, 2693–2697. [Google Scholar] [CrossRef] [PubMed]
  44. Kim, D.J.; Kim, T.; Jeong, J.-Y.; Jo, J.-C.; Lee, W.S.; Shin, H.-J.; Lee, J.H.; Lee, H.S. Poor Prognostic Impact of High Serum Ferritin Levels in Patients with a Lower Risk of Diffuse Large B Cell Lymphoma. Int. J. Hematol. 2020, 111, 559–566. [Google Scholar] [CrossRef]
  45. Maura, F.; Weinhold, N.; Diamond, B.; Kazandjian, D.; Rasche, L.; Morgan, G.; Landgren, O. The Mutagenic Impact of Melphalan in Multiple Myeloma. Leukemia 2021, 35, 2145–2150. [Google Scholar] [CrossRef]
  46. Samur, M.K.; Roncador, M.; Aktas Samur, A.; Fulciniti, M.; Bazarbachi, A.H.; Szalat, R.; Shammas, M.A.; Sperling, A.S.; Richardson, P.G.; Magrangeas, F.; et al. High-Dose Melphalan Treatment Significantly Increases Mutational Burden at Relapse in Multiple Myeloma. Blood 2023, 141, 1724–1736. [Google Scholar] [CrossRef]
  47. Caballero, A.C.; Escribà-Garcia, L.; Alvarez-Fernández, C.; Briones, J. CAR T-Cell Therapy Predictive Response Markers in Diffuse Large B-Cell Lymphoma and Therapeutic Options After CART19 Failure. Front. Immunol. 2022, 13, 904497. [Google Scholar] [CrossRef]
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Figure 1. Structure and variants of the PPM1D gene and the encoded Wip1 protein phosphatase. (A) PPM1D gene. (B) PPM1D protein phosphatase (Wip1) with central phosphatase domain and C-terminal degron region. (C) Lollipop plot indicating the positions of the six identified somatic mutations. NT: nucleotide; AA: amino acid. * (asterisk) = translation termination (stop) codon.
Figure 1. Structure and variants of the PPM1D gene and the encoded Wip1 protein phosphatase. (A) PPM1D gene. (B) PPM1D protein phosphatase (Wip1) with central phosphatase domain and C-terminal degron region. (C) Lollipop plot indicating the positions of the six identified somatic mutations. NT: nucleotide; AA: amino acid. * (asterisk) = translation termination (stop) codon.
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Figure 2. Clinical outcome in MCL patients treated with CD19 targeted (FMC63)-CAR-T-cell therapy. PFS (A) and OS (B) of MCL patients receiving brexu-cel CAR-T cell therapy were analyzed by Kaplan–Meyer, stratified by PPM1D status.
Figure 2. Clinical outcome in MCL patients treated with CD19 targeted (FMC63)-CAR-T-cell therapy. PFS (A) and OS (B) of MCL patients receiving brexu-cel CAR-T cell therapy were analyzed by Kaplan–Meyer, stratified by PPM1D status.
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Table 1. Overview of seven low-frequency PPM1D mutations detected in four patients with relapsed/refractory MCL.
Table 1. Overview of seven low-frequency PPM1D mutations detected in four patients with relapsed/refractory MCL.
ClassificationLocus Chr7VAFNT ChangeAA Change
indel606630770.011AT/AL450fs *
missense606630860.016A/CE451A
nonsense606631060.012C/TR458 *
indel606632520.023TG/TV507fs *
missense606633040.016C/AQ524K
indel606633330.099C/CTK535fs *
missense606634000.021A/GS556G
VAF, variant allele frequency; NT: nucleotide; AA: amino acid. * translation termination (stop) codon.
Table 2. Clinical parameters of 16 r/r MCL patients enrolled for brexu-cel CAR-T-cell therapy.
Table 2. Clinical parameters of 16 r/r MCL patients enrolled for brexu-cel CAR-T-cell therapy.
All
(n = 16)		PPM1Dwt (n = 12)PPM1Dmut (n = 4)p-Value
Sex, female5 (31%)4 (50%)1 (25%)0.26
Median age at ID (range)65 (48–80)65 (48–75)63 (52–80)0.62
Prognostic index (MIPI) 0.27
Low risk (5.3–5.4)2 (12%)2 (17%)0
Intermediate (5.7–6.5)8 (50%)7 (58%)1 (25%)
High risk (6.7–9)6 (38%)3 (25%)3 (75%)
Initial Disease Stage 0.45
II2 (12%)1 (8%)1 (25%)
IV14 (88%)11 (92%)3 (75%)
Treatment lines prior CAR-T 0.58
3–111 (69%)9 (75%)2 (50%)
8–46 (38%)4 (33%)2 (50%)
Radiotherapy8 (50%)5 (42%)3 (75%)0.57
Complete remissions 0.57
08 (50%)5 (42%)3 (75%)
2–16 (38%)5 (42%)1 (25%)
4–32 (12%)2 (12%)0
HDCT/ASCT8 (50%)5 (42%)3 (75%)0.28
Bridging chemotherapy12 (75%)9 (75%)3 (75%)0.99
Target antigen variant
CD19 rs290488007 (44%)3 (25%)4 (100%)0.02
Significance of differences: chi-square test or Fisher’s exact test; differences in median values: Mann–Whitney test. ID: initial diagnosis. HDCT: high-dose chemotherapy; ASCT: autologous stem cell transplant.
Table 3. CAR-T-cell therapy and clinical outcome in 15 r/r MCL patients.
Table 3. CAR-T-cell therapy and clinical outcome in 15 r/r MCL patients.
All (n = 15)PPM1DwtPPM1Dmutp-Value
(n = 12)(n = 3)
Median age (range)72 (56–81)72 (56–80)72 (57–81)0.79
Median interval ID to CAR-T in years (range)4.14.61.40.17
(1–24)(1.2–24)(1–16)
Disease status at CAR-T 0.09
CR, PR, SD7 (47%)7 (58%)0
PD8 (53%)5 (42%)3 (100%)
Median LDH pre-CAR-T U/L (range)1901813200.042
(126–383)(126–374)(191–383)
Median Peak CAR-T copies per μg cfDNA7240763052770.63
(range)(30–92,877)(76–92,877)(30–31,033)
Time to Peak CAR-T (days)13 (7–169)13 (7–169)12 (9–20)0.53
CRS11 (73%)9 (75%)2 (66%)0.57
Grade 1642
Grade 2550
ICANS6 (40%)5 (42%)1 (33%)0.99
Grade 1/2330
Grade 3/4321
Median Peak CRP4837820.063
mg/L (range)(4–275)(4–103)(48–275)
Median Peak IL-65924126390.77
pg/mL (range)(7–3572)(7–3572)(545–1024)
Time to Peak IL-610 (5–34)7 (5–19)25 (14–34)0.01
days (range)
Median Peak Ferritin μg/L (range)1648150151150.031
(135–16,920)(135–16,920)(3338–5239)
Admissions to IMC/ICU4 (27%)4 (33%)00.52
Relapse/Progression7 (47%)5 (42%)2 (66%)0.57
Median survival time
OS, months
PFS, months		13
12		27
32		1.5
1		0.001
0.079
Best remission status
CR12 (80%)11 (92%)1 (33%)0.027
PR2 (13%)1 (8%)1 (33%)
SD, PD1 (7%)0 (0%)1 (33%)
Significance of differences: chi-square test or Fisher’s exact test; differences in median values: Mann–Whitney test. CRS: cytokine release syndrome, ICANS: immune cell-associated neurotoxicity syndrome, IMC/ICU: intermediate care/intensive care unit. CRP: C-reactive protein; IL-6: interleukin 6. CR: complete response; PR: partial response; SD: stable disease; PD: progressive disease.
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MDPI and ACS Style

Seipel, K.; Benninger, L.; Bacher, U.; Pabst, T. Low-Frequency PPM1D Gene Mutations Associated with Inferior Treatment Response to CD19 Targeted CAR-T Cell Therapy in Mantle Cell Lymphoma. Therapeutics 2024, 1, 95-105. https://doi.org/10.3390/therapeutics1020009

AMA Style

Seipel K, Benninger L, Bacher U, Pabst T. Low-Frequency PPM1D Gene Mutations Associated with Inferior Treatment Response to CD19 Targeted CAR-T Cell Therapy in Mantle Cell Lymphoma. Therapeutics. 2024; 1(2):95-105. https://doi.org/10.3390/therapeutics1020009

Chicago/Turabian Style

Seipel, Katja, Lynn Benninger, Ulrike Bacher, and Thomas Pabst. 2024. "Low-Frequency PPM1D Gene Mutations Associated with Inferior Treatment Response to CD19 Targeted CAR-T Cell Therapy in Mantle Cell Lymphoma" Therapeutics 1, no. 2: 95-105. https://doi.org/10.3390/therapeutics1020009

APA Style

Seipel, K., Benninger, L., Bacher, U., & Pabst, T. (2024). Low-Frequency PPM1D Gene Mutations Associated with Inferior Treatment Response to CD19 Targeted CAR-T Cell Therapy in Mantle Cell Lymphoma. Therapeutics, 1(2), 95-105. https://doi.org/10.3390/therapeutics1020009

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