ESMO2021 Chinese speaker comprehensively summarizes important research on hematological tumors of this conference

The 2021 European Society for Medical Oncology (ESMO) annual meeting has come to an end.
"NEJM Medical Frontiers" specially invites Dr.
Sun Mingyuan and Professor Wang Jianxiang from the Hematology Hospital of the Chinese Academy of Medical Sciences to summarize the important research results of hematological tumors announced at this ESMO annual meeting, including his team The research results of Ivosidenib in relapsed or refractory acute myeloid leukemia (R/R AML) carrying IDH1 mutation were reported at the annual meeting
.

There are a total of 8 oral reports in the field of hematology and tumors at ESMO 2021.
All of them are lymphoma-related research results except for reports by Chinese scholars
.

In addition, the annual meeting also displayed 24 posters, and the abstracts included were mostly lymphoma-related studies (more than one-third)
.

Mingyuan Sun, Jianxiang Wang* Hospital of Hematology, Chinese Academy of Medical Sciences* Corresponding author: Acute Myeloid Leukemia Chapter CS3010-101 Chinese Bridging Study (Abstract No.
825O) Acute Myeloid Leukemia (AML) is the most common type of adult leukemia, and the disease progresses rapidly, and Mostly elderly patients
.

With the deepening of cytogenetics and molecular biology research, treatment options are also different for different diagnostic types and prognostic stratification
.

At present, the treatment of AML still faces challenges.
Most AML patients will still relapse after remission, and the prognosis of patients with relapsed or refractory AML (R/R AML) is usually poor
.

In the past, patients with R/R AML lacked access to effective therapeutic drugs, and the clinical remission rate was low.
Even if intensive chemotherapy is applied, the effective rate of these patients is extremely low
.

In July 2018, the US Food and Drug Administration approved ivosidenib based on the results of the AG120-C-001 trial for the treatment of adult patients with R/R AML who carry a sensitive mutation of isocitrate dehydrogenase 1 (IDH1)
.

The drug's marketing brings new options to R/R AML patients with IDH1 mutations
.

The mechanism of action of ivosidenib is different from previous targeted drugs.
Ivosidenib targets mutated IDH1 and induces differentiation of leukemia blasts through epigenetic regulation, so that leukemia blasts differentiate into mature blood cells, and the patient’s blood picture is significantly improved and reduced.
There is a risk of severe bone marrow suppression and infection, and the quality of life is significantly improved
.

IDH1 mutation is a relatively common mutation, accounting for about 7% to 10% of AML patients in China
.

Among the AML therapies that have been approved in China, there is no effective drug specifically targeting this patient group; especially elderly AML patients have poor tolerance to chemotherapy, and IDH1 inhibitors have higher levels of IDH1 inhibitors in elderly AML patients with IDH1 mutations.
Application value and prospects
.

The CS3010-101 study is the first bridging registration trial of ivosidenib in R/R AML patients with IDH1 sensitive mutations in China
.

The so-called bridging test refers to an additional test conducted in a new region to provide information on the pharmacokinetics or effectiveness, safety, appropriate dosage, and dosing regimen related to the population in the new region, allowing the clinical data of the original region to be extrapolated to New territory
.

It is of great significance for extrapolating foreign clinical trial data, judging drug racial differences, reducing repeated trials, and shortening the time for new drug approval
.

The study included 30 adult relapsed/refractory acute myeloid leukemia (R/R AML) patients with IDH1 R132 gene mutations.
Among them, 10 patients received intensive blood sampling to assess PK/PD characteristics
.

All subjects received continuous oral administration of ivosidenib 500 mg once a day, 28 days as a cycle, with no interval between cycles
.

The treatment effect and treatment decision of all patients will be evaluated by the investigator according to the modified International Working Group (IWG) efficacy evaluation standard
.

  As of May 20, 2021, a total of 30 patients have received at least one oral administration of ivosidenib, 9 of which are still receiving treatment
.

In pre-specified intensive blood sampling PK/PD evaluable patients, after a single administration, the drug is absorbed rapidly, with a median Tmax of 3.
98 hours, Cmax of 4730 ng/mL, and AUC0-24 of 62100 ng*h/mL
.

After repeated administration of 500 mg daily, the median Tmax was 2 hours, and no significant drug accumulation was seen when the steady state was reached
.

Among the 30 evaluable patients, the primary efficacy endpoint complete remission and complete remission with partial hematological recovery (CR+CRh) rate was 36.
7% (11/30), 11 patients achieved CR, and 5 of them were ≥65 Years old
.

The 12-month CR+CRh sustained remission rate is estimated to be 90.
9%
.

The median time to CR+CRh was 3.
68 months (range: 1.
0~6.
5)
.

Two patients (6.
7%) received hematopoietic stem cell transplantation after reaching CR or CRH
.

The median event-free survival time was 5.
52 months, and the median overall survival time was 9.
1 months
.

All patients reported adverse events (TEAEs) during treatment
.

Twenty-six patients (86.
7%) reported grade 3 TEAEs, the most common ones were decreased platelet count (36.
7%), anemia (36.
7%), and decreased neutrophil count (33.
3%)
.

Observing the change trend of the patient's blood picture over time after ivosidenib treatment, no bone marrow suppression was found
.

In addition, adverse events leading to serious consequences such as dose reduction, interruption, and discontinuation are not common
.

In general, ivosidenib has good safety, no unexpected adverse events have been found, and the proportion of adverse events of particular concern is not higher than that of the AG120-C-001 study, and after treatment, it can be effectively controlled and alleviated without causing adverse consequences
.

Lymphoma: Phase 1b study of HMPL-689 in Chinese patients with relapsed/refractory lymphoma (Abstract No.
833O) HMPL-689 (a new type I PI3Kδ inhibitor) monotherapy and previous anti-CD20 antibody (single agent) Or combination therapy) in the initial safety and efficacy results of patients with relapsed/refractory lymphoma
.

The patient continuously received HMPL-689 (30 mg, QD) monotherapy during a 28-day treatment cycle until the disease progressed, intolerable toxicity or death occurred
.

The primary efficacy endpoint is the objective response rate (ORR) assessed by the investigator using the International Working Group Standard (2008) and Lugano's Remission Standard
.

As of March 30, 2021, a total of 75 patients have received at least one dose of HMPL-689, including 2 cases of chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) and 21 cases of follicular lymphoma (FL) , 14 cases of marginal zone lymphoma (MZL), 7 cases of mantle cell lymphoma (MCL) and 31 cases of diffuse large B-cell lymphoma (DLBCL)
.

The median age is 56 years (range 18-86 years)
.

41.
3% of patients had previously received ≥3 lines of treatment, and the median number of treatment lines was 2 lines (range 1-8 times)
.

The median follow-up time was 4.
0 months (95% CI, 3.
7-5.
5)
.

Of the 60 patients who received at least one post-baseline tumor assessment, 8 patients achieved complete remission (CR), including 7 FL and 1 MCL, and 23 patients achieved partial remission (PR)
.

ORR was 51.
7% (31/60)
.

The median time to remission (TTR) was 1.
9 months (95% CI, 1.
8 to 1.
9)
.

The ORR of FL patients was 77.
8% (14/18), and the CR rate was 38.
9% (7/18)
.

The most common (≥10%) TEAEs are neutropenia, elevated ALT, leukopenia, elevated AST, hypertriglyceridemia, pneumonia, and upper respiratory tract infections
.

The most common TEAEs of grade ≥3 (≥10%) are neutropenia, pneumonia, and rash
.

The results of the study show that HMPL-689 shows tolerable safety characteristics and promising single-agent clinical activity in patients with relapsed/refractory B-cell lymphoma.
Especially in FL patients, HMPL-689 can induce higher The ORR and CR rates
.

The CHRONOS-3 study of copanlisib+rituximab and placebo+rituximab in the treatment of relapsed marginal zone lymphoma (MZL) (Abstract No.
826O) This is a randomized, double-blind, placebo-controlled phase 3 study Research (NCT02367040)
.

For patients with recurrent indolent non-Hodgkin’s lymphoma (iNHL) who have progressed/ineffective after ≥12 months of rituximab (R) basic treatment or are unwilling/unsuitable to receive chemotherapy after ≥6 months, press 2:1 They were randomly divided into the PI3K inhibitor copanlisib+rituximab (C+R) group or placebo (P+R) group
.

The primary endpoint is progression-free survival
.

 MZL patients were randomly divided into 66 cases in C+R group and 29 cases in P+R group
.

MZL subtypes include lymph node type (39%), lymph node type (37%) and splenic type (24%)
.

The median follow-up time was 18.
0 months.
Compared with the P+R group, the risk of disease progression/death in the C+R group was significantly lower; the objective response rate (ORR) of the C+R group was improved
.

The median duration of remission was 25.
4 months in the C+R group and 9.
3 months in the P+R group; the median progression time was 33.
2 months in the C+R group and 11.
5 months in the P+R group
.

The median overall survival is not assessable (NE)
.

The most common TEAEs (all/3+ grades) in the C+R group were hyperglycemia (65%/54%) and hypertension (54%/45%); the most common TEAEs in the P+R group were hyperglycemia (24% /10%), cough (24%/0%) and upper respiratory tract infection (24%/0%)
.

The incidence of severe TEAE in the C+R group (57%) was higher than that in the P+R group (28%)
.

TEAEs suspected to be related to C/P include hyperglycemia (63%/24%) and hypertension (54%/17%)
.

The results of the study show that C+R is more effective than P+R in the treatment of recurrent MZL (including nodular MZL)
.

The safety of C+R and C and R monotherapy are basically the same
.

Copanlisib is the first PI3K inhibitor to be safely combined with rituximab in a Phase 3 study in relapsed MZL, showing a new potential treatment strategy
.

Results of a multi-center, open-label, single-arm phase 2 trial of geptanolimab in relapsed or refractory primary mediastinal large B-cell lymphoma in China (Abstract No.
831MO) This study enrolled 25 patients with relapsed or refractory primary Patients with mediastinal large B-cell lymphoma (PMBCL)
.

All enrolled patients received geptanolimab (fully humanized PD1 monoclonal antibody) 3 mg/kg every 2 weeks until disease progression, death, unacceptable toxicity or withdrawal from the study
.

The primary efficacy endpoint is the objective response rate (ORR) evaluated by the investigator using the International Working Group Standard (2008) and Lugano Remission Standard.
Adverse events are evaluated according to the CTCAE5.
0 standard
.

As of March 12, 2021, the median treatment period is 28 (2~56) cycles, and the follow-up period is 56 weeks (3.
86~112.
14)
.

The objective response rate (ORR) was 64% (16/25), with 6 cases (24%) in complete remission and 10 cases (40%) in partial remission
.

The median progression-free survival has not yet been reached
.

84% (21/25) of the patients had any grade of TRAEs, the most common grade 3/4 TRAEs were leukopenia (5/25, 20%), neutropenia (4/25, 16%) and lymphocytes Reduction (4/25, 16%)
.

The results of the study showed that geptanolimab showed good anti-tumor activity in Chinese patients with relapsed or refractory PMBCL, with an ORR of 64% and good safety
.

Phase 1/2 study of orelabrutinib combined with MIL62 in the treatment of R/R B-NHL patients (Abstract No.
840P) MIL62 (a glycosylated anti-CD20 antibody) treats patients with relapsed/refractory B-cell non-Hodgkin lymphoma (R/R B-NHL)
.

The standard 3+3 dosage regimen is adopted, with different dosage combinations for dose escalation: daily oral orelabrutinib 100 mg or 150 mg combined with MIL62 injection 800 mg or 1000 mg
.

A total of 14 CD20-positive R/R B-NHL patients (10 cases of diffuse large B-cell lymphoma (DLBCL), 2 cases of mantle cell lymphoma (MCL), 1 case of follicular lymphoma ( FL), 1 case of marginal zone lymphoma (MZL)
.
The
median age was 62.
5 years (range, 38-77), and 50% of patients were male
.

Overall, 78.
6% of patients received ≥2 lines of systemic therapy
.

As of On April 21, 2021, 10 patients can be evaluated for efficacy, with an objective response rate (ORR) of 70%, 3 cases of complete remission (CR), and 4 cases of partial remission (PR)
.

The ORR of DLBCL was 71.
4%, including 3 cases CR, 2 cases of PR
.

Except for 2 cases, all patients continued to receive treatment
.
The
longest treatment duration at the data cut-off date was 8.
5 months
.

No dose-limiting toxicity (DLT) or unexpected adverse events were observed
.

TEAEs of any grade were thrombocytopenia (5/14, 35.
7%), infusion-related reactions (3/14, 21.
4%), and hyperuricemia (3/14, 21.
4%)
.

Grade ≥3 TEAE was observed in only 2 patients, and leukopenia/neutropenia in 1 patient was considered to be related to treatment
.

The results of the study showed that the combined treatment of Orelabrutinib and MIL62 was generally well tolerated, without unexpected toxicity, and showed encouraging clinical efficacy in R/R B-NHL patients
.

In addition to the above clinical research results, the abstract numbered 828MO reported the exon mutation characteristics of tumor tissues and normal tissues in 53 patients with primary gastrointestinal diffuse large B-cell lymphoma (pGI-DLBCL)
.

About 10% of DLBCL cases originate in the gastrointestinal tract.
This study is currently the largest total exome sequencing study of pGI-DLBCL patients
.

The top 5 gene mutations are: IGLL5 (47%), TP53 (42%), BTG2 (28%), IGHV2-70 (26%) and P2RY8 (26%)
.

Compared with DLBCL in lymph nodes, MYD88 (0%), EZH2 (0%) or BCL2 (2%) have fewer mutations
.

The overall survival time of pGI-DLBCL patients with P2RY8 gene mutation is shorter
.

The P2RY8 gene is mutated in GCB-DLBCL and Burkitt lymphoma.
Ga13 inhibits the growth of GC B cells and promotes B cell closure.
The mutation may inhibit the expression of the P2RY8 gene on the surface
.

Abstract No.
830MO reports the results of whole exome sequencing (WES) of 15 Chinese patients with gastrointestinal NK/T-cell lymphoma (GI-NKTCL) tumor/normal samples
.

The study used Burrows-Wheeler Aligner (version 0.
7.
10) to match the original sequencing data with the human reference genome GRCh37
.

K-Means prediction was performed based on the proto-oncogene mutation map retrieved from the NCG database
.

The Bayesian-NMF method was used to analyze the GI-NKTCL mutation pattern
.

These mutations are compared with the 30 mutation characteristics in the COSMIC database
.

The results showed that the RETSAT gene mutation rate was the highest (26.
7%), followed by SNRNP70 (20%), ADGRL3 (13.
3%), ANHAK2 (13.
3%) and A6RID1B (13.
3%)
.

Among these genes, the most frequent mutations are ARID1B, ERBB3, KMT2D, POT1, TET2 and TP53 (13.
3%)
.

NMF analysis of 509 single-nucleotide variants (SNV) of 15 NK/T-cell lymphoma specimens revealed three mutation features: feature 1 (46.
69% SNV) and feature 3 (32.
09% SNV) are well-known C>T transition of CpG site
.

Similar to the feature 22 in the COSMIC database, the second feature (21.
23% SNV) is dominated by the T>A transition
.

In addition, most samples have feature 1 and feature 3 as the main mutation patterns
.

Since GI-NKTCL is a rare type of non-Hodgkin's lymphoma prevalent in East Asian countries, there are few related studies on the genetic and clinical features of GI-NKTCL
.

The research results have guiding value for the future research of NK/T cell lymphoma
.

The abstract numbered 834P evaluated serum IL-6, IL-15, and sPD-L1 levels as prognostic and predictive biomarkers of nivolumab in the treatment of relapsed/refractory Hodgkin’s lymphoma
.

The 52 enrolled R/R cHL patients received nivolumab 3 mg/kg, once every 2 weeks, intravenously, until intolerable toxicity or disease progression requires a change of treatment regimen
.

The 4-year OS rate was 93%, the 4-year PFS rate was 26%, and the median PFS was 20.
6 months
.

The serum levels of IL-6, IL-15, and sPD-L1 were measured by ELISA before treatment with nivolumab and 3 to 6 months after treatment
.

The results of the study showed that the level of sPD-L1 was positively correlated with the tumor volume before the start of nivolumab treatment
.

IL-6 and sPD-L1 will be significantly reduced after nivolumab treatment
.

In the patients in this study, serum IL-6 levels can predict the PFS and time to remission of nivolumab treatment, and further studies are needed to compare the predictive value of IL-6 levels with clinical predictive indicators
.

Myeloma: The efficacy and safety of pomalidomide combined with dexamethasone (Pd) in the treatment of Chinese patients with relapsed or refractory multiple myeloma (RRMM) (Abstract No.
848P) This is a multi-center, single-arm phase 2 In the study, 74 adult RRMM patients were enrolled from February 2017 to February 2019
.

All patients had previously received lenalidomide, and 81% of patients were resistant to lenalidomide
.

In addition, 51.
4% of patients had kidney injury, and 33.
8% of patients had high-risk RRMM
.

On days 1 to 21 of the 28-day cycle, pomalidomide 4 mg was taken orally once a day until disease progression (PD) or intolerable adverse events (AE) occurred
.

Dexamethasone was taken orally on days 1, 8, 15 and 22 of each cycle at a dose of 40 mg/day
.

The primary endpoint is the objective response rate (ORR)
.

The median follow-up time was 11.
1 months (range, 9.
9~12.
7), the ORR of the full analysis set was 36.
5%, the ORR of high-risk MM patients was 32.
0%, and the ORR of MM patients with renal impairment was 31.
6%
.

The median progression-free survival was 6.
4 months (95% CI, 3.
8 to 10.
1)
.

The most common grade 3/4 treatment period AEs were neutropenia (62.
2%) and thrombocytopenia (28.
4%)
.

Pulmonary infection (17.
6%) is the most common grade 3/4 non-hematological TEAE
.

No previously reported AEs were observed, and no venous thromboembolism occurred
.

The results of the study show that among Chinese RRMM patients, especially those refractory to lenalidomide, Pd is a safe and effective option, and the treatment meets global standards
.

The author introduces Sun Mingyuan, the attending physician at the Clinical Trial Research Center of the Hospital of Hematology, Chinese Academy of Medical Sciences
.

He is currently a member of the Hematological Disease Prevention and Treatment Committee of Tianjin Anti-aging Society, and is mainly responsible for more than 20 clinical trials of new drugs related to hematological tumors
.

Participated in the sub-project of the National Science and Technology Major Project "Building a Technical Platform for Clinical Evaluation of New Drugs for Blood System Diseases"
.

Wang Jianxiang, professor, chief physician, and doctoral supervisor
.

He is currently the deputy director of the Hematology Hospital (Institute of Hematology) of the Chinese Academy of Medical Sciences, the director of the Leukemia Diagnosis and Treatment Center, the director of the National Clinical Research Center for Hematological Diseases, the tenth chairman of the Hematology Branch of the Chinese Medical Association, and an internist of the Chinese Medical Doctor Association vice president of branch, branch vice president of Hematologists and other duties
.

National candidate for the New Century Hundred and Thousand Talents Project, Tianjin City Awarded Expert, State Council Government Special Allowance Expert, Ministry of Health Outstanding Contribution Young and Middle-aged Expert, First Prize of Wu Yang Award, First Prize and Second Prize of Tianjin Science and Technology Progress Item
.

Copyright information This article was translated, written or commissioned by the "NEJM Frontiers of Medicine" jointly created by the Jiahui Medical Research and Education Group (J-Med) and the "New England Journal of Medicine" (NEJM)
.

The Chinese translation of the full text and the included diagrams are exclusively authorized by the NEJM Group
.

If you need to reprint, please leave a message or contact nejmqianyan@nejmqianyan.
cn
.

Unauthorized translation is an infringement, and the copyright owner reserves the right to pursue legal liabilities
.