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- Maria Gomes da Silva (Lisbon, Portugal)
- Irit Avivi (Tel Aviv, Israel)
623MO - Machine learning-based prediction of germinal center, MYC/BCL2 double protein expressor status, and MYC rearrangement from whole slide images in DLBCL patients
- Charlotte Syrykh (Toulouse, France)
Abstract
Background
Diffuse Large B-Cells Lymphoma (DLBCL) is the most common type of non-Hodgkin lymphoma in adults (30-40%). In the 2016 World Health Organization (WHO), DLBCL are classified into 3 molecular subtypes according to cell of origin (COO), germinal-center, activated B-cell like and unclassified, based on gene-expression profiling (GEP). In daily routine, COO classification is replaced by immunochemistry (IHC) stains using the Hans algorithm based on the expression of CD10, BCL6 and MUM1 proteins. In addition, co-expression of BCL2 and MYC proteins is of prognostic value and defines the double-protein expressors (DPE) subtypes, associated with worse prognosis. Fluorescent In Situ Hybridization (FISH) is mandatory in the workup of DLBCL to detect MYC and BCL2 and/or BCL6 rearrangements.
Methods
565 whole-slide images (WSI) stained with hematoxylin/eosin from the LYSA trial “GHEDI” (Deciphering the Genetic Heterogeneity of Diffuse large B-cell lymphoma in the rituximab era) dataset were analyzed. A Deep Learning (DL) model was trained to predict COO and DPE status, the presence of MYC rearrangements (no MYC rearrangement/MYC-Single Hit or HGBL-Double Hit/Triple Hit) and expression of BCL6, CD10 and MUM1 proteins from WSI. Performance was evaluated using several repetitions of stratified five-fold cross-validation.
Results
The DL model achieved a ROC AUC of 0.624 for GC, 0.687 for DPE, and 0.675 for MYC rearrangement. Using Cox proportional hazard model, predictions of DPE status (HR=0.38, P=.016), and MYC rearrangements (HR=5.23, P<.001) and MUM1 expression (HR=2.80, P=.027) were associated with worse overall survival.
Conclusions
Our study demonstrates the predictive power of DL applied to WSI to predict DLBCL subtypes. Such predictive models could be used to augment pathologists analysis capacities, especially when IHC staining or FISH are not available.
Legal entity responsible for the study
Institut Carnot CALYM.
Funding
Owkin.
Disclosure
J. Schiratti: Financial Interests, Institutional, Full or part-time Employment: Owkin. E. Brion: Financial Interests, Institutional, Full or part-time Employment: Owkin. C. Maussion: Financial Interests, Institutional, Full or part-time Employment: Owkin. L. Danneaux: Financial Interests, Institutional, Full or part-time Employment: Owkin. All other authors have declared no conflicts of interest.
624MO - Retrospective analysis of clinical value of ctDNA in newly diagnosed diffuse large B cell lymphoma
- Tao Guan (Taiyuan, China)
Abstract
Background
Diffuse Large B Cell Lymphoma (DLBCL) is the most common type of non-Hodgkin's lymphoma with high incidence, strong clinical and genetic heterogeneity. Current clinical characteristics are insufficient for the prognostic stratification of DLBCL. In recently, circulating tumor DNA (ctDNA) emerging as a biomarker for DLBCL prognostic stratification. However, whether it could use ctDNA as a biomarker to detect mutated genes in samples from Chinese DLBCL patients is uncertain.
Methods
The present study evaluated ctDNA as prognostic value for clinical diagnosis prior to treatment. We enrolled 172 newly diagnosed DLBCL patients, and all patients underwent targeted NGS-based 59-gene panel. The prognostic value of ctDNA in the context of established risk factors, including the International Prognostic Index, Ann Arbor stage, Lactate Dehydrogenase level (LDH), BULK, and bone marrow involvement (BMI), were evaluated. Finally, effects of pretreatment ctDNA on outcome of DLBCL were assessed.
Results
Before therapy, ctDNA was detectable in 74.4% of patients. The most frequently mutated genes were
Conclusions
CtDNA could serve as a prognostic factor and a tumor specific biomarker for DLBCL in China. The most frequently mutated genes were PCLO. The level of pretreatment ctDNA VAF mean could predict therapy response and prognosis.
Legal entity responsible for the study
Shanxi Provincial Cancer Hospital.
Funding
Has not received any funding.
Disclosure
All authors have declared no conflicts of interest.
Invited Discussant 623MO and 624MO
- Irit Avivi (Tel Aviv, Israel)
625MO - Combination of mitoxantrone hydrochloride liposome with pegaspargase in patients with extranodal NK/T-cell lymphoma: A phase I/II clinical trial
- Yunhong Huang (Guiyang, China)
Abstract
Background
Extranodal NK/T-cell lymphoma (ENKTCL) remains a high unmet clinical need for improving outcome. This trial aimed to explore the safety, pharmacokinetics (PK) and efficacy of mitoxantrone hydrochloride liposome (PLM60) plus pegaspargase in patients (pts) with ENKTCL.
Methods
Adult pts with histologically confirmed treatment-naïve or relapsed/refractory ENKTCL were recruited. Phase I was 3+3 dose-escalation design with four dose levels of PLM60 (12, 16, 20 and 24 mg/m2) plus pegaspargase 2000 IU/m2 administered on day 1 of every cycle (21 days) for 4-6 cycles. Phase II was dose expansion at the recommended phase 2 dose (RP2D) in pts with treatment-naïve ENKTCL. The primary endpoints were safety and PK. The secondary endpoint was efficacy including complete response (CR) rate, objective response rate (ORR) as per Lugano 2014.
Results
At the cut-off data of February 15, 2022, 31 eligible pts were enrolled (phase I, n = 21 and phase II, n = 10). Phase I included 9 relapsed/refractory pts and 12 treatment-naïve pts. Two dose-limiting toxicities (grade-4 neutropenia in 20 mg/m2; grade-3 abdominal pain in 24 mg/m2) occurred. RP2D was PLM60 24 mg/m2 plus pegaspargase 2000 IU/m2. Treatment-related adverse events (TRAEs) of any grade occurred in all 31 pts, in which 27 (87.1%) were ≥ grade 3. The most common ≥ grade 3 TRAEs was neutropenia (77.4%), leucopenia (74.2%), anemia (54.8%), thrombocytopenia (45.2%), hypertriglyceridemia (22.6%), infectious pneumonia (16.1%), lymphocytopenia (16.1%), decreased fibrinogen level (16.1%), hypoglycemia (12.9%) and elevated bilirubin (12.9%). 31 pts were evaluable for response. CR rate and ORR were 61.3% (19/31, 95% CI 42.2%-78.2%) and 87.1% (27/31, 95% CI 70.2%-96.4%), respectively. Median PFS was not reached. Among 22 treatment-naïve pts (13 males) with a median age of 40.5 (range, 23-70), 9 pts (40.9%) had the presence of B symptoms and 6 pts (27.3%) were at the stage III or IV (Lugano classification). The CR rate and ORR of this cohort was 68.2% (15/22, 95% CI 45.1%-86.1%) and 90.9% (20/22, 95% CI 70.8%-98.9%).
Conclusions
PLM60 plus pegaspargase had an encouraging efficacy especially in treatment-naïve ENKTCL pts with manageable safety profiles.
Clinical trial identification
NCT04509466.
Legal entity responsible for the study
CSPC Zhongqi Pharmaceutical Technology Co., Ltd.
Funding
This trial is funded by National key R&D Program of China (2017YFA0205604), and supported by CSPC Zhongqi Pharmaceutical Technology Co., Ltd.
Disclosure
R. Zhou: Financial Interests, Personal, Full or part-time Employment: CSPC. Y. Liu: Financial Interests, Personal, Full or part-time Employment: CSPC. Z. Pan: Financial Interests, Personal, Full or part-time Employment: CSPC. J. Xue: Financial Interests, Personal, Full or part-time Employment: CSPC. D. Wang: Financial Interests, Personal, Full or part-time Employment: CSPC. All other authors have declared no conflicts of interest.
626MO - Incidence of cardiovascular disease in Swedish healthy blood stem cell donors
- Simon Pahnke (Uppsala, Sweden)
Abstract
Background
The last 20 years has seen a steady increase in the use of Granulocyte Colony-Stimulating Factor (G-CSF) in healthy donors, to obtain peripheral blood stem cells for allogeneic stem cell transplantation. There has been a concern that G-CSF could potentially increase the risk of cardiovascular disease in donors after donation.
Methods
In a Swedish national cohort study, we examined the incidence of new diagnoses of cardiovascular disease after donation, and all-cause death, in 1098 peripheral blood stem cell donors (PBSC) who donated between 1998 and 2014. By linking data from three Swedish national population-based registers; the Patient Register, the Multi-Generation Register, and the Cause of Death Register, we created a database on all cardiovascular disease diagnoses for 1098 PBSC donors, their 1222 siblings, and 854 bone marrow donors, and time of death for those that had deceased. For each PBSC donor, five population-based controls, with the same year of birth, sex, and county of residence as the donor, were drawn at random from the general Swedish population, using the Total Population Register, 5495 in total. Data linkage was performed at the Swedish National Board for Health and Welfare using national identification numbers, which were removed before delivery of the datasets for statistical analyses. The study was approved by the regional ethical review boards of Stockholm, 98–259, and Uppsala, 2016–497.
Results
The cardiovascular disease incidence for PBSC donors, 18.1 cases per 1000 person-years, was not different from matched population controls, 19.2 cases per 1000 person-years, hazard ratio 0.89 (95% confidence interval (CI) 0.75 – 1.06 , p-value 0.19), bone marrow donors or non-donating siblings, after a median follow-up time of 9.2 years. Mortality from any cause was registered for 32 of 1098 PBSC donors (2.9%) during follow up, compared to 240 of 5495 population controls (4.4%), hazard ratio 0.65 (95% CI 0.45–0.94, p-value 0.02).
Conclusions
The long-term incidence of cardiovascular disease in healthy donors was not increased after peripheral blood stem cell donation with the use of G-CSF, and donor mortality after donation was lower than age-, sex and residency-matched population controls.
Legal entity responsible for the study
Uppsala University, Uppsala, Sweden.
Funding
The Nordic Cancer Union, the Swedish Cancer Society and the Uppsala-Örebro Regional Research Council.
Disclosure
All authors have declared no conflicts of interest.
627MO - Orelabrutinib plus RCHOP for previously untreated non-germinal center b cell-like (GCB) diffuse large b cell lymphoma (DLBCL) patients with extranodal disease
- Mingyue Wang (Nanning, China)
Abstract
Background
The prognosis of patients with non-GCB DLBCL is poor, especially in those with extranodal invasion which has strong invasiveness and rapid clinical progress. How to improve the prognosis of these patients is the main challenge of DLBCL therapy. Bruton tyrosine kinase (BTK) is a member of the non-receptor tyrosine kinase Tec family; it is involved in the proliferation, adhesion and metastasis of B cells. BTK inhibitor showed activity in relapsed/refractory non-GCB DLBCL. Orelabrutinib is a new oral covalent BTK inhibitor; this study aimed to analyze the efficacy and safety of orelabrutinib plus RCHOP for previously untreated non-GCB DLBCL patients with extranodal disease.
Methods
Patients with IHC-confirmed non-GCB DLBCL and PET-CT confirmed extranodal invasion were enrolled in this study. Patients received standard RCHOP with orelabrutinib(150 mg/d, po) on a 21-day cycle for 6 cycles.Primary end point was response rate, secondary end points included progression-free survival (PFS), overall survival (OS), and safety.
Results
22 patients were enrolled, with a median age of 52 years (21-72), including 10 males,11 cases with IPI equal to or greater than 3 points,12 cases with double expressor (DE) DLBCL, and 19 cases with stage IV disease. The overall response rate was 90.9%( 20/22), complete response (CR) rate was 77.3% (17/22). The CR rate was 75% (9/12) in patients with DE DLBCL and 80% (8/10) in those with non-DE DLBCL.The median follow up was 11 months,3 patients with DE DLBCL had progressive disease, all patients survived. Serious AEs included febrile neutropenia (3 cases) and atrial flutter (1 case).
Conclusions
The efficacy of orelabrutinib plus RCHOP for non-GCB DLBCL with extranodal disease is impressive in this single center clinical practice and the toxicity is acceptable.
Legal entity responsible for the study
The authors.
Funding
Natural Science Foundation of Guangxi Province, Grant/Award Number: 2018GXNSFBA281026.
Disclosure
All authors have declared no conflicts of interest.
Invited Discussant 625MO, 626MO and 627MO
- Maria Gomes da Silva (Lisbon, Portugal)
621MO - Preclinical study of DASH CAR-T cells manufactured in 48 hours
- Haiying Wang (Shanghai, China)
Abstract
Background
Patients with acute lymphoblastic leukemia (ALL) or relapsed/refractory (r/r) large B-cell lymphoma (LBCL) often progress rapidly, and current manufacture process of chimeric antigen receptor (CAR) T cells takes too long and resulting products are less optimal for in vivo expansion and function. The “DASH CAR-T” manufacturing process we developed enabled production of CAR-T cells of naïve phenotypes within 48 hours. We examined the efficacy of DASH CAR-T cells in a murine model and laid the foundation for novel clinical trials for patients with ALL or r/r B-ALL.
Methods
DASH CAR-T process consisted of 24-hour T-cell activation and subsequent 24-hour transduction with a gamma-retrovirus vector encoding a second generation anti-CD19 CAR. The cell surface marker expression and in vitro function were accessed by flow cytometry analysis. NOG (NOD/Shi-scid/IL-2Rγnull) mouse (n=5) mice bearing Nalm6-luciferase lymphoma were treated with a graded number of control T cells that activated but not transduced (1×106) or transduced with anti-BCMA conventional CAR (1×106), anti-CD19 conventional CAR-T cells (1or 5×106), or anti-CD19 DASH CAR-T cells (1×106). Human CD45+ T cells in peripheral blood (PB) was determined by flow cytometry. Tumor burden was imaged using in vitro imaging system and survival of mice were recorded.
Results
DASH CAR-T cells were mainly “naïve” T cells (CD45RO-/CCR7+). Adoptive transfer of 1×106 DASH CAR-T cells showed an extensive expansion (increased 156 fold) in vivo at day 21, whereas 5×106 conventional CAR-T cells actually contracted (decreased 77 fold) in mice. This extraordinary CAR-T expansion led to a significantly better therapeutic effect and prolonged survival. Untreated mice, mice treated with control T cells, or 4 out of 5 mice treated with anti-BCMA CAR were dead at day 28 after cell infusion. Strikingly, 4 out 5 mice treated with one million anti-CD19 DASH CAR-T cells survived beyond 60 days. In contrast, 1 or 2 out of 5 mice treated with one million or 5 million anti-CD19 CAR-T cells survived.
Conclusions
DASH CAR-T cells manufactured in two days expanded significantly better in vivo and more effective than conventional CAR-T cells. Clinical trials are planned to use DASH CAR-T platform to rapidly generate CAR-T cells to treat patients with ALL or r/r B-ALL.
Legal entity responsible for the study
Hrain Biotechnology Co., Ltd.
Funding
Hrain Biotechnology Co., Ltd.
Disclosure
H. Wang: Financial Interests, Personal, Full or part-time Employment: Hrain Biotechnology Co., Ltd. S. Tsao: Financial Interests, Personal, Full or part-time Employment: Hrain Biotechnology Co., Ltd. Q. Xiong: Financial Interests, Personal, Full or part-time Employment: Hrain Biotechnology Co., Ltd. M. Gu: Financial Interests, Personal, Full or part-time Employment: Hrain Biotechnology Co., Ltd. C. Fu: Financial Interests, Personal, Full or part-time Employment: Hrain Biotechnology Co., Ltd. X. Li: Financial Interests, Personal, Full or part-time Employment: Hrain Biotechnology Co., Ltd. M. Zhang: Financial Interests, Personal, Full or part-time Employment: Hrain Biotechnology Co., Ltd. N. Li: Financial Interests, Personal, Full or part-time Employment: Hrain Biotechnology Co., Ltd. H. Hu: Financial Interests, Personal, Full or part-time Employment: Hrain Biotechnology Co., Ltd.
622MO - An asymmetrical CLL1/CD3 bispecific antibody, ABL602, exhibits CLL1 binding-dependent CD3 binding/activation and antitumor activity in acute myeloid leukemia (AML) mouse model and leukemia blasts from AML patients
- EUNHEE LEE (Seongnam, Korea, Republic of)
Abstract
Background
C-type lectin-like molecule 1 (CLL1) is highly expressed in acute myeloid leukemia blast cells but not in normal hematopoietic stem cells (HSCs). This limited expression of CLL1 makes it as a promising target for the AML therapy compared with other targets such as CD33 and CD123, which are also expressed in HSCs. Previously we have shown potent CLL1-specific antitumor activity using two AML cell line/models. In this study, we determined whether binding affinity of ABL602 to CD3 can be augmented upon binding to CLL1 and expanded our study to various AML cell lines and blasts from AML patients.
Methods
To determine CLL1 binding-dependent CD3 binding of ABL602, T cell binding was measured by flow cytometry in the presence of CLL1-spiked beads. ABL602-mediated antitumor activity and T cell activation were tested in CLL1 expressing AML cell lines and AML blasts from patients. In vivo antitumor activity was determined in humanized mice bearing AML tumors.
Results
ABL602 (2+1), with its CD3 binding arm sterically hindered by CLL1 binding arm, binds to CD3 with a lower affinity compared with 1+1 format in the absence of CLL1-expressing cells. By incubating T cells with beads spiked with various amounts of CLL1 in the presence of ABL602, we proved that ABL602’s binding affinity to CD3 was increased in a CLL1-dependent manner, reaching comparable level to that of 1+1. ABL602 induced superior tumor cell killing than 1+1 reference antibody JNJ-67571244. Moreover, ABL602 showed a dose-dependent anti-tumor activity with tumor regression in OCIAML2 xenograft and HL-60 orthotopic model. In AML patient blasts, CLL1 was highly expressed and ABL602 exhibited a strong T cell activation and tumor killing activity on CLL1+ AML blasts.
Conclusions
This study supports the target-specific T cell activation and tumor killing activity of 2+1 heterodimeric structure of ABL602 on both AML cell lines and patient-originated AML blasts and warrants further pre-clinical development.
Legal entity responsible for the study
ABL Bio, Inc.
Funding
Has not received any funding.
Disclosure
All authors have declared no conflicts of interest.
Invited Discussant 621MO and 622MO
- Irit Avivi (Tel Aviv, Israel)