Ki67-revised Risk Index to Risk-stratify Patients with Extra-nodal Natural killer/T cell Lymphoma

Background

A superior clinically feasible prediction index for extra-nodal natural killer/T-cell lymphoma (ENKTL) in the modern chemotherapy era is warranted since the proposed indexes include none of pathological index & had insufficient accuracy.

Methods

600 ENKTL patients receiving non-anthracycline based therapy from Sun Yat-sen University Cancer Center were subdivided into training and internal validation datasets. An external validation dataset included 191 patients from West China Hospital was enrolled. Ki67 proliferative index and 14 pretreatment clinical parameters were tested against overall survival (OS) and progression-free survival (PFS). A prediction model was constructed and validated.

Results

• Factors independently associated with inferior OS were as follows: Ki67 ≥ 70%; age > 60 years; ECOG PS ≥ 2; B symptoms; stage-III/-IV disease and detectable EBV-DNA copy number.
• Each of these six factors contributed one point to a prediction model that stratified patients into four risk groups: 0-1 point, low-risk; 2 points, intermediate-risk;3 points, intermediate high-risk; 4-6 points, high-risk.
• In the training dataset, the 5-year OS rates for the low-, intermediate-, intermediate high- and high-risk group were 91%, 75%, 65% and 26%, respectively (P < 0.001).
• The 5-year PFS rates were: 79%, 62%, 48% and 15%, respectively (P < 0001).
• The time-dependent area under the receiver-operator characteristic (AUROC) curve and Harrell’s C-statistic of Ki67-revised Risk Index (KRI) for OS and PFS prediction demonstrated a better performance than that of the international prognostic index (IPI), Korean prognostic index (KPI), prognostic index of natural killer lymphoma (PINK) and nomogram-revised risk index (NRI).
• Concordant results were successfully validated in both internal and external validation datasets.

Conclusions

KRI is a new promising prediction index to risk-stratify patients with ENKTL receiving non-anthracycline based therapy.

Reference

Shuo Li. Et al., Annals of Oncology (2023) 34 (suppl_2): S543-S553. 10.1016/annonc/annonc1302

Progression -free Survival Prediction of Multiple Myeloma Patients in five European Countries using Machine Learning Models

Background

The objective of this study is to apply machine learning (ML) models to multiple myeloma (MM) patient-level data to evaluate if ML models can identify high-risk features linked to faster disease progression.

Methods

Data for 15,931 MM patients in France, Spain, UK, Germany, and Italy were extracted from Oncology Dynamics (OD), a large cross-sectional survey that collects drug-treated patient-level data through a panel of cancer specialists. The analyses include 6 years (2017-2022) of records. The underlying data included treatment regime, line of therapy (LOT), ECOG status, stem cell transplant (SCT) eligibility, Durie-Salmon stage, cytogenetic risk, and age and gender. Machine Learning-based survival models (Gradient Boosted Survival Trees, Random Survival Forest) were applied to predict outcomes. Additionally, Shapley values were calculated to assess the model’s decision making and identify key risk drivers.

Results

• Data was split into Training (80%) and Test Data (20%).
• The output of the model was the ML derived risk score: higher risk score was associated with shorter PFS.
• Model performance was good (Harrell’s C-Index = 0.741). Data shows that higher LOTs and not being eligible for SCT are associated with increased risk of disease progression.
• Inversely, being in the 1st LOT, ECOG asymptomatic and certain drug regimens (e.g., Lenalidomide or Dexamethasone/Lenalidomide) are associated with longer PFS.

Conclusions

This is the first successful step in leveraging OD data for the development of a prognostic score for MM patients using machine learning algorithms. Optimal disease management and planning of clinical trials can be supported through ML models applied to secondary market research. Further investigation into country-specific differences in PFS may be studied given the heterogeneity of treatment plans across Europe,

Reference

M.L. Pleguezuelo Witte, et al., Annals of Oncology (2023) 34 (suppl_2): S543-S553. 10.1016/annonc/annonc1302

Fatal Infections among Leukemia Patients

Background

There are no studies that have reported incidence of infections which is an important cause of death in patients with leukemia. The study conducted includes a population-based analysis of fatal infections in patients with leukemia to analyze trends and address the current lack of evidence.

Methods

Data were collected from the National Cancer Institute’s Surveillance, Epidemiology, and End Results (SEER) Program registries. SMR was estimated as the ratio of the number of leukemia patients with fatal infections to the number of fatal infections in the general population with similar age, sex, race and calendar year distribution.

Results

• 2863 had a fatal infection of 137820 leukemia patients.
• The fatal infection rate per 100,000 person-years was 389.32 and the SMR was 3.38 (95% CI 3.67-3.99, p< 0.05).
• Patients with acute monocytic leukemia had the highest SMR (SMR=89.01;95% CI 50.87-144.54).
• SMR for fatal infections decreases gradually with age, with the highest being in patients aged 0-19 years SMR=222.47; 95% CI 183.18-267.69).
• Notably, the risk of fatal infections continues to rise in patients with leukemia compared to the general population, with the highest risk in patients diagnosed in 2011-2018 (SMR= 9.87; 95% CI 8.58-11.30).

Conclusions

With the introduction of novel drugs, the risk of fatal infections has increased in recent years. Prevention and treatment of fatal infections remains an important aspect of improving overall survival. Close monitoring of patients with acute monocytic leukemia, as well as younger patients, should be considered for the timely administration of antibiotics and modification of chemotherapy regimens.

Reference

H. Zhou, et al., Annals of Oncology (2023) 34 (suppl_2): S543-S553. 10.1016/annonc/annonc1302

Patients with Myeloproliferative Neoplasms and Self-care Behaviours: Preliminary Data of a Cross-sectional Study

Background

The study aims to preliminary assess self-care behaviours in patients living with myeloproliferative neoplasms (MPN), including myelofibrosis (MF), polycythaemia vera (PV) and essential thrombocythemia (ET), to improve their health.

Methods

A descriptive cross-sectional study has been conducted in 9 haematology centres in Italy since November 2021. The Self-Care in MyeloProliferative Neoplasms Inventory (SC-MPNI), a 31-item questionnaire measuring self-care behaviours according to the Middle-Range Theory of Self-Care of Chronic Illness, was developed and tested for its content validity. MPN patients were asked to complete a paper-and-pencil questionnaire during their outpatient visit or at home.

Results

• Preliminary data from 171 patients (54% male; mean age=58, SD=19) and 5 centres were analyzed (45.6% of the expected sample).
• Participants were living with overt MF (n=51), prefibrotic MF (n=24), PV (n=48) or ET (n=44).
• Concerning self-care maintenance, the most frequent behaviour was attending all scheduled clinical appointments (M=5.9, SD=0.6), & the least used one was performing activities that improve mental and physical well-being (M=3.1, SD=1.7).
• Concerning self-care monitoring, the most frequent behaviour was getting blood tests as prescribed by the haematologist (M=5.9, SD=0.5), & the least used one was checking any measurement the healthcare providers recommend (M=4.7, SD=1.4).
• Concerning self-care management, the most frequent behaviour was accurately reporting symptoms to the healthcare providers during visits to get a comprehensive response (M=5.5, SD=0.9), & the least used one was asking for psychological support to overcome emotional problems (M=2.6, SD=1.5).

Conclusions

Health professionals should support innovative interventions to promote self-care, which is crucial for MPN patients to reduce cardiovascular events and be medically fit to undergo hematopoietic stem cell transplantation. This study will contribute to assessing self-care behaviours in patients with MPN.

Reference

V. Biagioli, et al., Annals of Oncology (2023) 34 (suppl_2): S1001-S1012. 10.1016/annonc/annonc1335.

 Determining Anti-cancer Efficacy of a Reversible LSD1 Inhibitor, EXS74539, in Primary AML Tissues with Limited Thrombocytopenic Effects

Background

Acute myeloid leukaemias (AML) are characterized by distinct chromatin dynamics and aberrant histone methylation regulations. The reversible nature of such epigenetic modifications has become attractive for the design of new AML therapies. Histone methylation is controlled by histone methyltransferases and demethylases, and among them, LSD1 has recently gained interest and tractability with the emergence of new LSD1 inhibitor clinical candidates. The study described efforts to define the activity of EXS74539 transcriptionally and functionally (‘539) - a novel potent, selective and reversible LSD1 inhibitor - as a monotherapy or in combination with AML standard of care (SoC) at the single cell level, leveraging our expertise in the use of primary AML and healthy bone marrow samples as model systems (Kornauth et al, 2022).

Methods

Using primary human material as a disease relevant model system, combined with proprietary deep learning enabled high content imaging and image analysis platform, capacity of ‘539 to induce AML blast differentiation and/or improve first line SoC therapy potential both in primary AML samples and in non-transformed healthy bone marrow or peripheral blood mononuclear cells was explored. Collecting baseline and treatment condition genomics and transcriptomics, the AML specific sensitivity to ‘539 was modelled.

Results

• The study demonstrated, preclinically, the capacity of ‘539 monotherapy to induce AML cell differentiation marker expression ex vivo, and the usability of ‘539 together with SoC agents through combining single cell omics and functional response data.
• Using healthy non-transformed bone marrow and colony formation assays, the study demonstrated that an adapted drug regimen limits ‘539 thrombocytopenic potential.

Conclusions

This preclinical data demonstrated ex vivo efficacy of ‘539 against AML blast cells and supported the combinatorial potential of ‘539 with first line clinical AML treatment strategies. Leveraging the reversibility of ‘539 allowed the design of adapted drug regimens, to preserve the safety profile of this inhibitor on non-transformed healthy cells.

Reference

C. Boudesco, et al., Annals of Oncology (2023) 34 (suppl_2): S1152-S1189. 10.1016/annonc/annonc1315

Challenges and Opportunities to the Implementation of Adaptive Design in Phase III Oncology Trials: Results from a Cross-sectional Analysis

Background

Adaptive design (AD) trials have been developed as an innovative alternative to conventional design (CD) trials with the aim of accelerating innovative medicinal products (InMP) clinical development. Despite AD concept adoption by major competent authorities the use and implementation of AD remains substantially lower than CD. There is an emerging need to better understand the operational characteristics contributing to the challenges and opportunities for wider implementation of AD into oncology InMP development.

Methods

Oncology InMPs approved by the FDA in 2018 were selected for cross-sectional analysis. The ClinicalTrial.gov (CT.gov) platform was used to identify phase III trials conducted with those InMPs between 2010-2021. Analysis was then accomplished by PubMed search for full manuscripts associated with these trials, as additional source to describe trial design and methodology.

Results

• 47 (75%) were CD and 16 (25%) were AD of the 63 identified phase III trials.
• Among the AD, 81% were conducted in solid tumours and 19% in haematological malignancies.
• AD was associated with several distinct operational characteristics vs CD:
  • i) with comparable number of patients enrolled, median number of sites/trial was higher in AD (203 sites) vs CD (106 sites) leading to substantial differences in median number of patients per individual site observed in CD (35.9 patients) and AD (3.8 patients)
  • ii) AD was clearly associated with higher median number of secondary endpoints (18 endpoints) vs CD (12 endpoints) and substantially shorter median duration of trial (43 months) vs CD (60 months; p=.0129), with potential cost savings of up to 30%
  • iii) limited details on the AD methodology and decision-making process at the time of interim analysis.

Conclusions

The implementation of AD in oncology InMP development remains low as compared to CD. A degree of AD operational complexity vs CD could have been balanced by assumed stricter patient monitoring and compliance to the study protocol and collection of a larger set of scientific data. AD could substantially shorten overall study duration, which in turn leads to trial’s cost savings of up to 30%, with a comparable number of enrolled patients.

Reference

Andriy Krendyukov, et al., Annals of Oncology (2023) 34 (suppl_2): S458-S497. 10.1016/annonc/annonc1324

Activation of γ9δ2 T Cells by ICT01 as a Novel Immunotherapeutic Approach for Relapsed/Refractory Hematologic Cancers (EVICTION trial)

Background

In the ongoing phase 1/2a EVICTION Trial in advanced solid and hematologic cancers, ICT01, an anti-BTN3A targeted mAb that selectively activates γ9δ2 T cells, is being studied (NCT04243499). ICT01-activated γ9δ2 T cells are known to kill acute myeloid leukemia blasts and lymphoma cell lines both in vitro and in vivo, making γ9δ2 T cells of interest as a novel immunotherapeutic strategy against hematologic cancers. Here we present data from the EVICTION phase 1 in relapsed/refractory hematological cancers.

Methods

Patients with hematologic cancers who failed the available standard of care received IV ICT01 alone (200 μg to 75 mg) every 21 days. Antitumor assessment by imaging or bone marrow analysis was done every 8 weeks after using the Response Evaluation Criteria in Lymphoma (RECIL) and IWG Criteria for AML. Safety reviews were conducted prior to dose escalation. Disease Control Rate (DCR) was the primary efficacy endpoint and defined as the sum of complete response (CR), CR with incomplete recovery (CRi), partial response (PR) and stable disease (SD). Blood samples were collected for pharmacokinetic and pharmacodynamic analyses.

Results

• Dose escalation was completed with 26 patients (1 Diffuse Large B-cell Lymphoma, 1 Follicular Lymphoma, 24 AML), with no dose-limiting toxicities and a good safety profile similar to that in solid tumors.
• First-dose infusion-related reaction, nausea, fever and vomiting (Grade 1/2) were the most common treatment-related AEs.
• Only 2 Grade 3 events of neutropenia were reported and resolved with continued treatment.
• Target occupancy on circulating T cells ≥ 30% was observed 30 min post doses ≥ 700 μg, with activation and migration of >95% γ9δ2 T cells from the blood within 24hrs of dosing.
• ·n=10 of 26 patients were evaluable at week 8 with an observed DCR of 30%. One DLBCL patient still receiving ICT01 at 7 mg has had a PR from Wk 40 to Wk 94/C32. In the 20 mg dose group, two AML patients achieved stable disease at week 8 with one still on study at Wk 53/C19.

Conclusions

The good safety profile and encouraging clinical activity data in these last-line patients support further testing of ICT01 in a first-line AML phase 2a expansion cohort in combination with VEN/AZA (to start mid-2023).

Reference

S. Garciaz, et al., Annals of Oncology (2023) 34 (suppl_2): S543-S553. 10.1016/annonc/annonc1302

Preliminary Pharmacokinetics (PK) and Pharmacodynamic (PD) Analysis of the CD123 NK Cell Engager (NKCE) SAR443579 in Patients (pts) with Relapsed or Refractory Acute Myeloid Leukemia (R/R AML), B Cell Acute Lymphoblastic Leukemia (B-ALL) or High Risk-myelodysplasia (HR-MDS)

Background

SAR’579, a trifunctional anti-CD123 NKp46×CD16 NKCE, enabling a cytolytic synapse between natural killer (NK) cells and CD123+ tumor cells leading to NK cell activation and tumor cell killing. The study reports preliminary PK/PD of SAR’579 from a phase 1/2 trial in pts with R/R AML, B-ALL or HR-MDS (EudraCT 2021-004287-98 Apr 26, 2023/NCT05086315).

Methods

SAR’579 was administered IV twice weekly or once weekly (QW) per dose level (DL) in first 2 weeks of cycle 1 and QW for rest of induction cycles. Peripheral blood (to measure plasma concentrations and immunogenicity assessment) and bone marrow samples were collected for PK/PD analysis during each induction cycle. Analysis of cytokines, as potential safety and PD markers, including IL-6, TNFα and IFNγ, was performed using Meso Scale Discovery^®.

Results

• 19 pts were treated across 5 DLs (3 in DL1 and 4 each in DL2 to DL5) between 10-3000 μg/kg/dose (from Dec 14, 2021, to Oct 17, 2022).
• No dose limiting toxicities were observed. At 1000 μg/kg QW, 3/8 pts achieved complete remission (CR) (2 CR/1 incomplete hematologic recovery).
• Early immunogenicity was 26% with no impact on safety/efficacy. Post first administration of SAR’579, circulating maximum (max) concentration increased with dose increase with a supra-dose proportionality between DL1 and DL5.
• PK linearity was achieved at 3000 μg/kg QW (DL5) at the end of cycle 1.
• Cytokine release syndrome levels of IL-6 (>500/1000 pg/mL) were measured in a single DL1 pt.

Median (max) peak cytokine concentrations (pg/mL) observed during DL1-5

 

Conclusions

SAR’579 was well tolerated till 3000 μg/kg QW with clinical benefit in pts with R/R AML. Observed peak cytokine levels did not show significant dose-related increase and no association between elevated peak cytokine levels and clinical responses. The results are consistent with the improved safety profile compared to CD123-targeted T-cell engagers.

Reference

M. Jongen-Lavrencic, et al., Annals of Oncology (2023) 34 (suppl_2): S543-S553. 10.1016/annonc/annonc1302

Isolation of cell-free DNA of Patients with Mucosa-associated Lymphoid tissue (MALT) lymphoma

Background

Histologic assessment via multiple gastric biopsies every 3 months constitutes the current gold standard, to evaluate treatment efficacy for gastric extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue (MALT-lymphoma). Currently, non-invasive diagnostic measures including PET-MRI to monitor therapy response in MALT lymphoma patients remain experimental for the time-being. While liquid biopsies isolating cell-free DNA (cfDNA) are used in other tumor entities for diagnostic and treatment monitoring measures, no data for gastric MALT-lymphoma have been published so far. Thus, a pilot series was performed to assess cfDNA in therapy-naïve gastric MALT-lymphoma patients.

Methods

Blood from patients with MALT lymphoma was collected using PAXgene Blood ccfDNA tubes (Qiagen) for the isolation of cfDNA. cfDNA was isolated using the QIAamp Circulating Nucleic Acid Kit (Qiagen). DNA concentration was measured using fluorescence quantification (Qubit, Thermo Fisher). Quantitative data were compared to 68-Ga-Pentixafor-PET/MRI performed within 4 weeks assessing active lymphoma volumes. Clinical parameters were obtained by chart review.

Results

• A total of 15 patients (4 males, 11 females) with MALT lymphoma at a median age of 64 years (range: 44-79) were included in this study.
• cfDNA could be isolated in all patients with a median concentration of 5.4ng/ml plasma (range: 3.6-12.4ng/ml).
• Compared to a healthy control cohort (n=5), cfDNA levels were significantly increased in MALT lymphoma patients (3.8ng/ml vs. 5.9ng/ml, p=0.025). In 12/15 patients, a follow-up blood draw could be obtained after a median 3.3 months (range 0.9-7.0 months).
• cfDNA levels remained stable during that time period with a mean concentration of 5.7ng/ml at baseline and 6.3ng/ml at follow-up (p>0.05).
• A correlation between metabolically active tumor volume and cfDNA concentration will be reported as soon as radiologic reclassification is completed.

Conclusions

cfDNA may be used as a non-invasive biomarker for disease monitoring in patients with MALT lymphoma.

Reference

J.M. Berger, et al., Annals of Oncology (2023) 34 (suppl_2): S543-S553. 10.1016/annonc/annonc1302

Genomic Traits of Therapeutic Response to Anti-PD-1 Therapy in Peripheral T Cell Lymphoma

Background

The use of immune checkpoint inhibitors has revolutionized the treatment of solid tumors and hematologic malignancies, clinical evidence has demonstrated anti-PD-1 therapy to be effective tools in PTCL. However, factors that may influence primary sensitivity or resistance to anti-PD-1 therapy in PTCL, such as TMB and genomic alterations, have not yet been clarified.

Methods

The study enrolled 89 peripheral T cell lymphoma (PTCL) patients in phase II clinical trial of geptanolimab and targeted next-generation sequencing was performed for 440 cancer-associated genes. Clinical data were collected and correlated with genetic mutations. In vitro, studies were conducted to evaluate the effect of JAK3 mutations on PD-L1 expression.

Results

• PD-L1 expression was significantly elevated in complete response (CR)/ partial response (PR) patients compared to progressive disease (PD) patients, while tumor mutation burden (TMB) didn’t exhibit significant prognostic value which may be confounded by the variation across PTCL subtypes.
• The most frequent mutations occurred in TP53, KMT2C, KMT2D, JA3, LRP1B, and SETD2.
• Shorter time to death was related to mutations in SETD2 (HR=5.73, P=0.0135) or KME2D (HR=3.17, P=0.0533).
• Shorter PFS was correlated with JAK3 mutations (HR=5.97, P=0.0144).
• The subset PTCL patients (86.4%) with enrichment of non-APOBEC-related mutation signature had higher TMB level (P=0.076) and superior PFS (P=0.031) to non-APOBEC-enriched samples.
• In vitro experiments revealed JAK3 A573V, M511I, and E958K mutations led to lower PD-L1 expression through downregulated of the expression of PI3K and MAPK.

Conclusions

This study comprehensively depicted the pre-treatment mutation profiles of PTCL and identified genetic alterations with prognostic value for anti-PD-1 therapy. Notably, JAK3 mutations which are vital and prevalent in PTCL reduced PD-L1 levels in vivo and in vitro, which are of great clinical and biological sense.

Reference

N. Lou, et al., Annals of Oncology (2023) 34 (suppl_2): S543-S553. 10.1016/annonc/annonc1302