PPM1D mutation

Finally, expression profiling of the transformed clones revealed dysregulation of several oncogenic and tumour suppressor pathways. Our data support the oncogenic potential of PPM1D in the context of exposure to ionising radiation and oncogene-induced replication stress.

As such, screening for CH before aHSCT may inform individual patients' prognostic outcomes and influence their prospective treatment plans. Presented in part as an oral abstract at the 2022 American Society of Hematology Annual Meeting, New Orleans, LA, 2022.

Here, we analyzed 423 serial whole blood and plasma samples from 103 patients with relapsed high-grade ovarian cancer receiving carboplatin, poly(ADP-ribose) polymerase inhibitor (PARPi) and heat shock protein 90 inhibitor (HSP90i) treatment within the phase II EUDARIO trial using error-corrected sequencing of 72 genes...Together, these results provide unique insights into the architecture and the preferential selection of DDR-mutated hematopoietic clones under intense DNA-damaging treatment. Specifically, PARPi and HSP90i therapies pose an independent risk for the expansion of DDR-CH in a dose-dependent manner.

The presence of TP53 and/or PPM1D mutations in the PBSC product increases the risk of post-aPBSCT t-MN and nonrelapse mortality among patients with HL and may support alternative therapeutic strategies.

There is a higher mutation rate of CHIP-related genes in MPN patients, especially those over 60 years old. Older age, thrombosis history, CHIP-related mutations and IL-1β elevated levels are independent risk factors for CCEs in MPN. DNMT3A and ASXL1 mutations are independent risk factors for CCEs in PV patients. CHIP-related gene mutations and inflammatory cytokine IL-1 β elevated levels may be the novel risk factors for CCEs in MPN.

P2, N=71, Active, not recruiting, University Health Network, Toronto | Trial completion date: Dec 2024 --> Dec 2025 | Trial primary completion date: Dec 2022 --> Dec 2025

Median progression-free survival (PFS) was 3 vs. 12 months (p = 0.07) and median overall survival (OS) was 5 vs. 37 months (p = 0.004) for the PPM1Dmut and PPM1Dwt cohort, respectively. Our data suggest that the occurrence of PPM1D mutations in the context of CH may predict worse outcomes after CD19-targeted CAR T-cell therapy in patients with r/r DLBCL.

5 months). Clinical, functional and mechanistic studies are required to complete these findings.

A patient with diffuse large B-cell lymphoma and CHIP ( ASXL1, PPM1D, and TP53 variants) developed a TRMN (MDS-MD) 7 months after completing R-CHOP treatment...Finally, and in contrast contrast with our initial hypothesis, we found no evidence of impaired outcomes in the CHIP population. These results emphasize the need for further longitudinal follow-up.

Study treatment consisted of six cycles of carboplatin-based chemotherapy followed by maintenance therapy with Niraparib ± the HSP90 inhibitor Ganetespib. In summary, our data reveals a high prevalence of CH in patients with relapsed HGOC and provides novel insights into the clonal architecture and dynamics of CH under carboplatin and PARPi treatment with a differential selection of DDR-driven clones. Moreover, we report a relevant interference of CH-derived mutations with tumor-derived mutations in cfDNA.

Inhibition of PPM1D suppressed the colony growth of leukemic stem and progenitor cells carrying the truncated PPM1D, and remarkably, it provided protection against irradiation-induced cell growth. Altogether, we demonstrate that truncated PPM1D affects HSC maintenance, disrupts normal hematopoiesis, and that its inhibition could be beneficial in the context of therapy-induced AML.

AML treatment options included best supportive care for 8% of patients (2), 5-Azacytidine for 32% (8), intensive chemotherapy for 60% (15)...To confirm the clonal architecture, single cell sequencing analysis in 8 AML/MDS patients are ongoing. Trajectory of PPM1D mutations in ovarian cancer patients revealed a non-linear alkylating agent dependency which warrants further investigation.

The presence of CHIP mutations in MM confers a reduced overall survival (Mouhieddine, JCO 2020) but high quality, prospective evaluation of CHIP mutation evolution over the transplant sequence, including the impact of high-dose melphalan and immunomodulatory (IMiD)-based therapy, is largely under-studied. Our results using deep SmMIP sequencing show a mutation prevalence rate of 43% in a cohort of transplant-eligible, largely IMiD-naive MM pts studied after induction. These rates are higher than those generally described in the literature, which may relate to the high sensitivity of the assay used, variation in filtering between institutions, and the deliberate use of a relatively low VAF threshold with the intent to capture clinically significant variants for longitudinal tracking during the course of this ongoing study. Further studies during lenalidomide maintenance will be forthcoming.

The prevalence of CHIP is high in older lymphoma patients, with preferential expansion of clones harboring DDR mutations during treatment. Most of these DDR variants would fall below routine clinical NGS reporting thresholds if sampled at baseline, or after post-therapy contraction. DDR CHIP and CHIP overall associate with different complication rates on chemotherapy and both associate with post-treatment monocytosis.

Study treatment consisted of six cycles of carboplatin-based chemotherapy followed by maintenance therapy with Niraparib ± the HSP90 inhibitor Ganetespib. In summary, our data reveals a high prevalence of CH in patients with relapsed HGOC and provides novel insights into the clonal architecture and dynamics of CH under carboplatin and PARPi treatment with a differential selection of DDR-driven clones. Moreover, we report a relevant interference of CH-derived mutations with tumor-derived mutations in cfDNA.

Conclusions Our study highlights the utility of a MTB dedicated to CH, CHIP and CCUS for the identification of high-risk patients, early detection of hematologic malignancies, and appropriate therapeutic management. Long-term follow-up is needed to validate the CHRS but the design of a specific score for patients with cancer may be helpful due to the specific features of this population (high prevalence of PPM1D mutations, post-treatment cytopenia).

We analyzed 110 patients with relapsed/refractory B-cell non-Hodgkin lymphoma (n = 105) or acute lymphoblastic leukemia (ALL) (n = 5), treated with Axicabtagene-Ciloleucel (39%), Tisagenlecleucel (51%), or Brexucabtagene autoleucel (10%). Lastly, sequential analysis showed a modest VAF increase of 1.3% and acquisition of novel mutations within 100 days postinfusion. CH was frequent in large B-cell lymphoma/ALL patients receiving CAR T-cells but did not affect toxicity nor treatment response or outcome.

Importantly, organism-wide loss of Ppm1d in adult mice is well tolerated, supporting the tolerability of pharmacologically targeting PPM1D. Our data link PPM1D gain-of-function mutations to the clonal expansion of HSCs, inform human genetic observations, and support the therapeutic targeting of PPM1D in cancer.

Our results suggest a close relationship between inherited variants and CH mutations within the DDR genes in patients with solid tumors. Associations identified in this study might translate into enhanced clinical surveillance for CH and associated comorbidities in patients with cancer harboring these germline mutations.

P1, N=21, Completed, Dana-Farber Cancer Institute | Active, not recruiting --> Completed | N=69 --> 21

ICB setting was 1°L 41%; 2°L 47%; ≥ 3°L 11%, and the most used ICB was Pembrolizumab in 63% of pts...No pts developed hematological disease during the follow up. Conclusions CHIP is commonly found in pts with NSCLC, with a prevalence in our cohort of 48% with statistically significant worse PFS in the CHIP-positive population.

Also, the benefit of maintenance therapy was particularly strong in C2 patients. Taken together, these data indicate an impaired regenerative potential of hematopoietic stem cell grafts harboring CH with DNMT3A and PPM1D mutations.

P1, N=69, Active, not recruiting, Dana-Farber Cancer Institute | Trial completion date: Jun 2023 --> Sep 2023 | Trial primary completion date: Jun 2023 --> Sep 2023

Conclusions Though examples of such tumors with hybrid oligodendroglioma and astrocytoma molecular features have rarely been reported, this is the first case to our knowledge that has been profiled by DNA methylation, and when taken together with the histology and other supportive molecular alterations seems most compatible with the diagnosis of oligodendroglioma. The implications of such exceptional neoplasms with respect to the present guidelines for tumor classification and work-up deserves further consideration, along with the possibility that oligodendrogliomas may very rarely utilize the alternative lengthening of telomeres mechanism as a means of maintaining telomere length, as opposed to the canonical process of telomerase activation.

CHIP is independently associated with adverse outcomes in individuals with established ASCVD, with especially high risks observed in TET2 and SF3B1/SRSF2/U2AF1 CHIP.

IPSS-M improved prognostic discrimination and optimized treatments for patients with 2022 ICC-defined MDS. Patients with high, or very high-risk IPSS-M might benefit from HSCT. In addition to 2022 ICC and other parameters, IPSS-M also provided independent prognostication.

A 9 gene targeted DNA sequencing panel designed to capture common CH mutations (DNMT3A, TET2, ASXL1, PPM1D, TP53, CHEK2, SRSF2, SF3B1,JAK2) was applied to pre-treatment peripheral blood samples of 957 pts enrolled in the Alliance A031201 phase 3 trial of enzalutamide versus enzalutamide plus abiraterone/prednisone in the first line mCRPC setting. CH did not affect OS or PFS in pts with mCRPC treated with ARPIs in the A031201 trial. However, CH with VAF>10% and TET2-mutated CH were associated with an increased rate of all CV AEs, suggesting an additive effect of ARPI therapy and CH on adverse CV outcomes. Confirmatory studies are warranted to assess whether CH should be considered in the risk-benefit discussion for pts receiving ARPIs.

P1, N=69, Active, not recruiting, Dana-Farber Cancer Institute | Recruiting --> Active, not recruiting

Our study shows that CH is common, dynamic, and of potential clinical significance in this population. Our results should stimulate larger efforts to understand the biological and clinical importance of CH in solid tumor malignancies.

Concomitant BRAF L597Q mutation and PPM1D mutation are novel findings. The overall prognosis of this tumor is poor, with tumors located in the brainstem showing worse outcome.

There was no significant association between CHIP and MM progression. Our analysis showed 1 patient with CHIP progression and 2 without CHIP progression. Because the rates of CHIP and MGUS are positively correlated with characteristics like aging and a history of smoking, we expected to see high rates of CHIP in patients within our cohort.

We found a consistent prevalence of CH in patients with NSCLC by using a sequencing approach targeted for hematologic disorders. Prognostic implications of CH are under investigation and will be evaluated in the full cohort.

In conclusion, PPM1D mutations are frequently seen in both MN-pCT and non-MN-pCT. TP53 is the most frequent co-mutation in PPM1D-mutant MN-pCT cases, while high VAF of PPM1D is observed in cases without TP53 co-mutation, suggestive of an alternative pathway in the pathogenesis of MN-pCT. A large study is warranted to investigate the impacts of PPM1D variants in patients with MN-pCT and non-MN-pCT.

PPM1D mutations are frequently associated with MN-pCT and older age and are observed in other hematolymphoid neoplasms. In contrast to the literature, de novo myeloid cases with PPM1D mutations were surprisingly frequent in this cohort. While there was no statistical significance, a trend did appear showing worse survival in MN-pCT patients compared with de novo myeloid neoplasms.