CN117180295A - Pharmaceutical composition for treating TP53 mutant myeloid tumor and application thereof - Google Patents
Pharmaceutical composition for treating TP53 mutant myeloid tumor and application thereof Download PDFInfo
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Abstract
The invention provides a pharmaceutical composition for treating TP53 mutant marrow tumors and application thereof, wherein the pharmaceutical composition comprises the following components in parts by weight: 1 part of decitabine, 2-10 parts of etoposide and pharmaceutically acceptable auxiliary materials. The composition can effectively induce tumor cell differentiation and apoptosis by inducing tumor cell differentiation rather than traditional chemotherapy killing mode, and has complete remission rate (CR) up to 71.4%, which is far higher than that of the existing D+CEG treatment scheme (63.2%), and patients with greatly reduced tumor cells in bone marrow but improved peripheral blood image but not Complete Recovery (CRi) are close to 20%, and the patients with the two treatment reactions add up to more than 90%, the median survival time of the patients is 31 months, and the progression-free survival time is 24 months; and the incidence rate of complications and treatment death can be obviously reduced in clinical application.
Description
Technical Field
The invention belongs to the technical field of biological medicines, relates to a pharmaceutical composition for treating TP53 mutant myeloid tumor and application thereof, and in particular relates to application of the composition in preparation of medicines for treating TP53 mutant myelodysplastic syndrome and acute myelogenous leukemia.
Background
Myelodysplastic syndrome (myelodysplastic syndromes, MDS) is a group of heterogeneous clonal diseases of the myeloid lineage originating from hematopoietic stem cells, characterized by abnormal differentiation and development of myeloid lineage cells, manifested by ineffective hematopoiesis, refractory cytopenia, hematopoietic failure, high risk of conversion to acute myeloid leukemia (tmal).
Although hematopoietic stem cell transplantation is the treatment of choice in patients with medium-high risk MDS, chemotherapy remains an important tool for patients who do not meet the transplantation criteria. However, high intensity chemotherapy leads to early high mortality (about 5% -20%) and short survival (6-12 months) in MDS patients. In recent years, research into the combination of demethylating agents with chemotherapy for the treatment of MDS has emerged. Aiming at TP53 mutant leukemia/myelodysplastic syndrome, no effective treatment method exists internationally, and the novel targeted drug has poor curative effect on traditional treatment of the type of marrow tumor. TP53 mutant leukemia is resistant to conventional anthracycline chemotherapy (Bowen Yan, david Claxton, suming Huang, yi Qiau. AML chemoresistance: the role of mutant TP 53: 53 subclonal expansion and therapy strategy. Exp Hematol.2020Jul;87:13-19.Doi:10.1016/j. Exphem.2020.06.003.Epub 2020Jun 20.). The traditional chemotherapy has large side effect and high treatment-related mortality, and the median survival time is 4-6 months. Novel targeting agents such as decitabine in combination with Venaiclade, treat such patients for a median survival of 5.2 months and for a relapse-free survival of 3.4 months (Kunhwa Kim, abhishaek Maiti, sanam Loghavi. Outcomes of TP53-mutant acute myeloid leukemia with decitabine and venteclax. Cancer.2021Oct 15;127 (20): 3772-3781.Doi:10.1002/cncr.33689.Epub 2021Jul 13.). The treatment of TP53 mutant leukemia/myelodysplastic syndrome with decitabine alone has been reported to have improved efficacy over conventional treatments, but is currently controversial, and median survival has been reported to be up to 12 months (Welch, J.S. et al, TP53 and Decitabine in Acute Myeloid Leukemia and Myelodysplastic Syndroms. N Engl J Med 375,2023-2036 (2016). Https:// doi. Org:10.1056/NEJMoa 1605949). TP53 mutant leukemia was treated with azacytidine in combination with Eprennetapopt (APR-246) at a complete remission rate of about 40% (David A Sallman, amy EDeZern, guillermo Garcia-Manero. Eprennetapopt (APR-246) and Azacitidine in TP-Mutant Myelodysplastic Synthemes. J Clin Oncol.202 y10;39 (14): 1584-1594.Doi:10.1200/JCO.20.02341.Epub 2021Jan 15.).
The current literature reports that CEG regimens consisting of Etoposide (Etoposide) +cytarabine) +granulocyte colony-stimulating factor (G-CSF) in combination with decitabine (d+ceg) exhibit satisfactory effects in the treatment of high risk MDS in the elderly. But the bone marrow suppression caused by the treatment of this regimen is 85.4%; the incidence rate of adverse reaction is high and is 26.8%; infection rate during myelosuppression was 85.4%; the mortality rate associated with 30 days of treatment is high, 22%, so the treatment risk is high.
Disclosure of Invention
The invention aims to overcome the defects and shortcomings of the prior art and provides a pharmaceutical composition for treating TP53 mutant myeloid tumors and application thereof. The invention is based on research and discovers that the use of cytarabine in the existing D+CEG treatment scheme can lead to serious myelosuppression caused by the treatment, has high incidence rate of adverse reaction, high mortality rate related to 30 days of treatment and high infection rate during myelosuppression, and discovers that cytarabine can not induce the TP53 mutant AML/MDS to differentiate in mechanism research, so that the invention reduces the myelosuppression degree, reduces the infection rate, the occurrence probability of adverse reaction and the treatment related mortality rate by removing the use of cytarabine in the composition; meanwhile, the CR curative effect is improved, and the curative effect for treating TP53 mutant patients is more excellent.
The aim of the invention can be achieved by the following scheme:
in a first aspect, the present invention provides a pharmaceutical composition for the treatment of TP53 mutant myeloid neoplasms, the active ingredients of said pharmaceutical composition consisting of decitabine and etoposide.
As an embodiment of the present invention, the pharmaceutical composition comprises the following components in parts by weight: 1 part of decitabine and 2-10 parts of etoposide.
As an embodiment of the present invention, the medicament comprises the following components in parts by weight: 1 part of decitabine and 2-4 parts of etoposide. When treating the myelodysplastic syndrome of TP53 mutation, the effect of selecting 1 part of decitabine and 2 parts of etoposide composition is better; when treating TP53 mutant acute myelogenous leukemia, the effect of selecting 1 part of decitabine and 4 parts of etoposide composition is better.
In a second aspect, the invention provides an application of the pharmaceutical composition in preparing a medicament for treating TP53 mutant myeloid neoplasms.
As an embodiment of the present invention, the medicament further comprises pharmaceutically acceptable excipients.
As one embodiment of the present invention, the dosage form of the drug includes at least one of powder, aqueous solution and oral preparation.
As an embodiment of the invention, the medicament is a formulation for oral, intravenous administration.
As one embodiment of the present invention, the TP53 mutant myeloid neoplasm includes TP53 mutated myelodysplastic syndrome and TP53 mutated acute myelogenous leukemia.
As one embodiment of the present invention, the TP53 mutation is a TP53 mutation at any site.
As one embodiment of the present invention, the TP53 mutation includes a double allele mutation, a deletion mutation, a frameshift mutation, a single nucleotide change mutation of TP 53. TP53 mutations also include double allele mutations of TP53 in combination with other gene mutations, deletion mutations of TP53 in combination with other gene mutations, frameshift mutations of TP53 in combination with other gene mutations, single nucleotide change mutations of TP53 in combination with other gene mutations.
Compared with the prior art, the invention has the following beneficial effects:
(1) In TP53 mutant leukemia/TP 53 mutant myelodysplastic syndrome, the composition of decitabine and etoposide can effectively induce tumor cell differentiation and apoptosis by adopting a tumor cell differentiation induction mode instead of a traditional chemotherapy killing mode.
(2) The medicine prepared by the invention is used for alleviating TP53 mutant leukemia/myelodysplastic syndrome, the complete remission rate (CR) of the medicine is up to 71.4 percent, which is far higher than that of the traditional D+CEG treatment scheme (63.2 percent), the tumor cells in the bone marrow are greatly reduced, but the peripheral blood image is improved but the patient does not reach Complete Recovery (CRi), the patients with the two treatment reactions are added to more than 90 percent, the median survival time of the patients is 31 months, and the progression-free survival time is 24 months.
(3) The medicine prepared by the invention does not contain Cytarabine, reduces the occurrence rate of complications and treatment death in the treatment process, comprises more than three stages of bone marrow suppression, infection during bone marrow suppression, adverse reaction, treatment related death and other occurrence rates, and solves the technical problems of high occurrence rate of adverse events and treatment related death of patients treated by the existing D+CEG scheme.
(4) The medicine prepared by the invention does not contain cytarabine, thereby greatly reducing the cost of the medicine.
Drawings
Other features, objects and advantages of the present invention will become more apparent upon reading of the detailed description of non-limiting embodiments, given with reference to the accompanying drawings in which:
FIG. 1 is a flow chart of patient screening and treatment in example 2;
FIG. 2 shows the gene mutation status and treatment response of patients in group D+E of example 2;
FIG. 3 is a therapeutic response of patients with TP53 mutations in the D+E group in example 2;
FIG. 4 is an OS (left panel) and PFS (right panel) of TP53 mutant and TP53 wild-type patients in the D+E group of example 2; wherein TP53 Mu represents a patient with TP53 mutation; TP53 WT represents TP53 wild-type patient;
FIG. 5 shows apoptosis rate and CD11b expression of TP53 wild-type THP-1 cell lines of example 2 at day 5 after administration.
Detailed Description
The invention will now be described in detail with reference to the drawings and specific examples. The following examples, which are presented to provide those of ordinary skill in the art with a detailed description of the invention and to provide a further understanding of the invention, are presented in terms of implementation and operation. It should be noted that the protection scope of the present invention is not limited to the following embodiments, and several adjustments and improvements made on the premise of the inventive concept are all within the protection scope of the present invention.
Example 1
The embodiment provides a drug for treating TP53 mutant marrow tumor, which is a decitabine combined etoposide (D+E) scheme and comprises the following components in parts by weight: 1 part of decitabine, 2 parts or 4 parts of etoposide; wherein the dosage of 1 part is 15mg/m 2 。
Example 2
2.1 patient data
Elderly medium-high risk MDS patients who have taken in 3 medical centers (affiliated eastern China hospitals at the university of double denier, affiliated first affiliated hospitals at the university of Zhejiang, central hospitals at the university of south China) from 1 month to 3 months at 2023, and AML patients transformed by MDS (age. Gtoreq.60 years), have 50 patients in total, and receive the treatment of decitabine combined etoposide (D+E) regimen. The ethical committee of the affiliated eastern China hospital at the university of double denier approved the study (number: 2016K 038).
2.2 criteria for patients receiving chemotherapy
(1) Diagnosing middle-high risk MDS or AML patients based on the IPSS-R score (Miyazaki Y. [ Revised international prognostic scoring system (IPSS-R) for myelodysplastic syndromes ] [ J ]. Rinsho Ketsueki,2013, 54 (6): 545-551); (2) patients met chemotherapy criteria (IPSS-R score > 5); (3) no diseases that are difficult to control by other systems; (4) Functional status was rated 0 to 2 points according to the eastern tumor collaboration group (ECOG) criteria in the united states; (5) Liver function level (TSB < 2X normal high limit) and kidney function level (Scr < 2X normal high limit) that are resistant to chemotherapy; (6) Other progressive malignant diseases, refractory mental diseases, pregnancy, etc. are excluded.
2.3 treatment regimen
As shown in FIG. 1, in the D+E regimen, low dose decitabine (15 mg/m) 2 Day 1-3), 30mg/m every 2 days from day 1 (i.e., days 1,3,5, 7) 2 Etoposide is administered intravenously at a dose of (2). After etoposide use on day 3, patients with bone penetration or AML were reviewed for peripheral blood residual diseaseFoci detection, if the original cells were reduced by less than 30% of the initial level, etoposide was added to 60mg/m 2 . Throughout the chemotherapy, e.g. hemogram WBC count < 4.0X10 9 5 μg/(kg.d) of G-CSF is administered per liter, e.g., WBC count of about 4.0 to 10X 10 9 By administering 3. Mu.g/(kg.d) of G-CSF, e.g.WBC count > 10X 10 9 G-CSF is not used. The protocol was evaluated after at least 2 consecutive courses.
2.4 efficacy assessment
Bone marrow smear, flow cytometry, chromosome and gene analysis detection are carried out before the treatment is started, and the bone marrow smear is rechecked 2-3 weeks after the treatment is completed. Routine blood testing is performed every 3d after patient chemotherapy. According to response criteria established by the International working group for MDS (IWG), efficacy includes Complete Remission (CR), complete remission with incomplete recovery of Blood cell Count (CRi), partial Remission (PR), hematological Improvement (HI) and no improvement (NR, including disease Stabilization (SD) and disease Progression (PD)), and specific efficacy assessment criteria are described in the literature (Cheson BD, greenberg PL, bennett JM, et al clinical application and proposal for modification of the International Working Group (IWG) response criteria in myelodysplasia [ J ]. Blood,2006, 108 (2): 419-425.). According to the report formulated by the 2003AML international collaboration group, the efficacy of acute leukemia includes morphological Complete Remission (CR), cytogenetic complete remission (CRc), molecular level complete remission (CRm), morphological complete remission with incomplete restoration of blood cell Count (CRi), partial Remission (PR), and treatment failure (NR). (Cheson BD, bennett JM, kopecky KJ et al J Cli Oncol,2003, 21:4642) median survival to time from disease diagnosis to patient death, median progression-free survival referring to time from patient diagnosis to progression of disease appearance.
2.5 follow-up treatment and follow-up
If the patient reached CR, CRi, or HI after 2 courses of chemotherapy, the remaining 4 cycles of chemotherapy were completed as originally, followed by 1 out-patient every 3 months in 1 year and 1 out-patient every half year in 2 years. The treatment regimen was changed if no response or disease progression occurred after 2 courses of treatment. Hematopoietic stem cell transplantation is feasible in a patient in need of hematopoietic stem cell transplantation and in remission of conditional hematopoietic stem cell transplantation.
2.6 evaluation of drug toxicity and treatment-related death
The patient received physical examination, blood routine (every 3 days), blood biochemistry (weekly), urine routine (weekly), and electrocardiogram or echocardiogram testing (monthly), among other assessments. If leukopenia or thrombocytopenia occurs during treatment above nciii level, then treatment-related leukopenia or thrombocytopenia is noted. Toxicity and adverse reactions specific references (CANCER N.Common Terminology Criteria for Adverse Events (CTCAE) v4.03, 2009[ J ].2009 ]) can be made with reference to adverse reaction time evaluation criteria (NCI-CTCAE 4.0).
2.7 statistical analysis
Statistical analysis was performed using SPSS20.0 software, with t-test for data meeting normal distribution. The metering data are expressed by Mean ± standard deviation (Mean ± SD), the metering data of the bias distribution such as the age and the blood cell count of the patient and the grading data such as the risk layering, the curative effect level, the adverse event and the like are compared by using a rank sum test, and the clinical characteristic classification data such as the sex, the diagnosis subtype, the chromosome karyotype, the mutation gene condition and the like of the patient are compared by using a chi-square test; patient total survival (OS) and asymptomatic survival (PFS) were assessed by Kaplan-Meier survival analysis;
the Log-Rank test was used to compare the difference in survival between group 2 (TP 53 mutated patients and TP53 wild-type patients); multifactor analysis was performed using cox regression. P < 0.05 represents a difference in all tests is statistically significant.
2.8 evaluation of efficacy results
Patient efficacy was rated CR, CRi, HI, PR, SD, PD based on the original cell decline profile and peripheral blood normative profile described in the reference of 2.4; wherein, SD: no change in disease; PD: disease progression is represented by NR as the sum of SD and PD values. OS: median time to live, PFS: median progression free survival time.
The efficacy of decitabine + etoposide in the treatment of elderly MDS/AML patients is shown in Table 1.
TABLE 1 therapeutic effects of decitabine and etoposide on treatment of elderly MDS/AML patients
As can be seen from table 1, first, for the decitabine+etoposide treatment regimen, the efficacy of TP53 mutant patients in elderly MDS/AML patients was higher than that of total patients, the d+e group patients had gene mutation status and treatment response as shown in the mosaic of fig. 2, bone marrow tissues of the MDS/AML patients treated for the first time were collected and sequenced, and according to whether the patients had responses to the d+e regimen, the response groups (efficacy CR, CRi, HI as responsive) and the non-response groups (we defined PR, SD, PD as non-responsive) were divided, and the analysis compared the seven gene (TP 53, NRAS, DNMT3A, TET2, EZH2, ASXL1, and RUNX 1) mutation status of the patients, and found that TP53 mutant patients were more sensitive to the d+e regimen, 15 patients reached CR (71.5%), 4 patients reached CRi (19.0%) and only 2 patients had no responses to the d+e regimen (4.8%); of the 29 TP53 wild-type patients, 13 reached CR (44.8%), 1 reached CRi (3.4%), 2 reached HI (6.9%), 3 reached PR (10.3%), 10 patients had no response to the D+E regimen (34.5%), and the decitabine+etoposide treatment regimen was more applicable to TP53 mutant patients. Wherein, the curative effect response of the D+E group TP53 mutant patient is shown in figure 3; FIG. 4 is an OS (left panel) and PFS (right panel) of TP53 mutant and TP53 wild-type patients in the D+E group; wherein TP53 Mu represents a patient with TP53 mutation; TP53 WT indicates a TP53 wild-type patient.
Secondly, compared with the existing D+CEG treatment scheme (see literature: decitabine combined etoposide is the main scheme and the analysis of the curative effect of decitabine alone on treating senile myelodysplastic syndrome, senile medicine and health care 2022,28 (04): 871-876), the decitabine+etoposide treatment scheme in the embodiment has better curative effect on TP53 mutant patients, and has better complete remission curative effect on CR (71.4%) than CR (63.2%) of the D+CEG treatment scheme; the efficacy of the D+CEG regimen is shown in Table 2 (see above).
Table 2D+CEG regimen for treatment of TP53 patients
In summary, the decitabine+etoposide treatment regimen of the present invention does not use cytarabine relative to the existing d+ceg treatment regimen, but is generally more efficacious in treating patients with TP53 mutations, particularly CR, and is significantly higher than the existing d+ceg treatment regimen.
2.9 evaluation of adverse reactions and treatment-related mortality outcomes
In the present invention, bone marrow suppression of three or more levels is defined as: (1) Hemoglobin (hemoglobin)<8g/100ml; (2) White blood cells<2000/m 3 The method comprises the steps of carrying out a first treatment on the surface of the (3) Granulocytes<1000/m 3 The method comprises the steps of carrying out a first treatment on the surface of the (4) Platelets<50000/m 3 。
Myelosuppression-period infections are those in which MDS/AML patients have been combined with myelosuppression following chemotherapy.
The patients have no liver basic disease before chemotherapy, clinical symptoms (portal vein high pressure manifestation such as ascites, varicose vein and the like) or blood biochemical abnormality (index of blood ALT, ALP, TBil and the like are increased) appear after chemotherapy, liver injury after stopping drug administration is improved, and liver injury appears more rapidly and seriously after drug administration again and is defined as liver adverse reaction.
The patients are subjected to asymptomatic serum urea nitrogen and creatinine elevation, even acute renal failure, oliguria or no urine, proteinuria and tubular urine, hematuria, unidentified oedema, hypertension and renal hypofunction, and renal hypofunction which does not accord with the condition in the process of administration is defined as renal adverse reaction.
Arrhythmia such as electrocardiogram abnormality, ventricular or supraventricular tachycardia, atrioventricular conduction block and the like of a patient or chronic myocardial lesions such as congestive heart failure, myocardial ischemia, arrhythmia, pericarditis and the like are generally defined as heart adverse reactions which can be relieved after drug withdrawal.
Treatment-related death is defined as death of a patient during treatment due to adverse reactions, disease progression, or patient intolerance to a treatment regimen.
Decitabine+etoposide treatment of elderly MDS/AML patients for adverse events and treatment-related deaths are shown in Table 3.
Table 3d+e treatment regimen patient adverse events and treatment related deaths
| Complications of the invention | Decitabine and etoposide |
| Bone marrow suppression of more than three levels | 40(80％) |
| Infection during myelosuppression | 36(72％) |
| Adverse reactions (liver and kidney or heart) | 1(2％) |
| Treatment-related death | 3(6％) |
As can be seen from table 3, the occurrence rate of adverse events and treatment-related deaths in patients of the decitabine+etoposide treatment regimen of the present invention is lower, with better patient tolerance and less toxic side effects, than the existing d+ceg treatment regimen; among them, adverse events and treatment-related deaths of patients on the d+ceg treatment regimen are shown in table 4.
Table 4d+ceg treatment regimen patient adverse events and treatment related deaths
| Complications of the invention | D+CEG |
| Bone marrow suppression of more than three levels | 35(85.4％) |
| Infection during myelosuppression | 35(85.4％) |
| Adverse reactions (liver and kidney or heart) | 11(26.8％) |
| Treatment-related death | 9(22.0％) |
In conclusion, the decitabine and etoposide treatment scheme of the invention is safe and tolerant, compared with the existing D+CEG treatment scheme, the incidence of adverse events and treatment-related death of patients is reduced due to the fact that cytarabine is not used, which indicates that the use of cytarabine can reduce the tolerance of the patients and improve the toxic and side effects of medicines.
2.10 in vitro experiments
Will be 5X 10 5 Each mL of TP53 mutant cell strain THP-1 (American atcc cell Bank) was plated into 6-well plates and treated with DMSO (control), decitabine (2.5. Mu.M) +etoposide (1.5. Mu.M) +cytarabine (25 ng/mL), respectively. After 5 days, cells were collected and the apoptosis rate was flow-detected [ Annexin V-FITC/PI Apoptosis Detection Kit, biyun Tian/Beyotidme, cat No. C1062M; holy Yeasen, cat No.: 40302ES60]And CD11b (APC anti-mouse/human CD11b, biolegend, cat# 101212).
Apoptosis rate and CD11b expression of TP53 mutant cell line (THP-1) in vitro experiments are shown in FIG. 5, and cytarabine is added on the basis of a decitabine and etoposide treatment scheme, and based on in vitro experiments, the fact that apoptosis or induced differentiation of TP53 mutant cell line (THP-1) induced by the drug is not increased is not found, namely, the fact that cytarabine is used without synergistic anti-tumor effect is verified.
The foregoing describes specific embodiments of the present invention. It is to be understood that the invention is not limited to the particular embodiments described above, and that various changes and modifications may be made by one skilled in the art within the scope of the claims without affecting the spirit of the invention.
Claims (10)
1. A pharmaceutical composition for treating TP53 mutant myeloid neoplasms, the active ingredients of the pharmaceutical composition consist of decitabine and etoposide.
2. The pharmaceutical composition according to claim 1, characterized in that it comprises the following components in parts by weight: 1 part of decitabine and 2-10 parts of etoposide.
3. The pharmaceutical composition according to claim 1, characterized in that it comprises the following components in parts by weight: 1 part of decitabine and 2-4 parts of etoposide.
4. Use of a pharmaceutical composition as claimed in any one of claims 1 to 3 for the manufacture of a medicament for the treatment of TP53 mutant myeloid neoplasms.
5. The use according to claim 4, wherein the medicament further comprises pharmaceutically acceptable excipients.
6. The use of claim 4, wherein the pharmaceutical dosage form comprises at least one of a powder, an aqueous formulation, and an oral formulation.
7. The use according to claim 4, wherein the medicament is a formulation for oral, intravenous administration.
8. The use according to claim 4, wherein the TP53 mutant myeloid neoplasm comprises TP53 mutated myelodysplastic syndrome and TP53 mutated acute myelogenous leukemia.
9. The use according to claim 8, wherein the TP53 mutation is a TP53 mutation at any site.
10. The use according to claim 9, wherein the TP53 mutation comprises a bi-allelic mutation, a deletion mutation, a frameshift mutation, a single nucleotide change mutation of TP 53.
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