WO2021160147A1 - 吡啶并[1,2-a]嘧啶酮化合物的治疗淋巴瘤的用途 - Google Patents

吡啶并[1,2-a]嘧啶酮化合物的治疗淋巴瘤的用途 Download PDF

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WO2021160147A1
WO2021160147A1 PCT/CN2021/076423 CN2021076423W WO2021160147A1 WO 2021160147 A1 WO2021160147 A1 WO 2021160147A1 CN 2021076423 W CN2021076423 W CN 2021076423W WO 2021160147 A1 WO2021160147 A1 WO 2021160147A1
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lymphoma
patient
treatment
plan
compound
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PCT/CN2021/076423
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English (en)
French (fr)
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封帆
王训强
陈莉
韩溪
吴乃营
马瑞婷
杨朝强
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正大天晴药业集团股份有限公司
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Priority to JP2022548036A priority Critical patent/JP2023512724A/ja
Priority to EP21753616.8A priority patent/EP4095137A4/en
Priority to CN202180011103.6A priority patent/CN115003674A/zh
Priority to AU2021218925A priority patent/AU2021218925A1/en
Priority to US17/798,605 priority patent/US20230132982A1/en
Priority to CA3170021A priority patent/CA3170021A1/en
Publication of WO2021160147A1 publication Critical patent/WO2021160147A1/zh

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca

Definitions

  • This application belongs to the field of medicinal chemistry, and relates to the use of pyrido[1,2-a]pyrimidinone compounds for the treatment of lymphoma.
  • the PI3K pathway is the most frequently mutated place in human cancer cells, which can lead to cell proliferation, activation, and signal amplification.
  • PI3K kinases (phosphatidylinositol-3-kinase, PI3Ks) belong to the lipid kinase family, which can phosphorylate the 3'-OH end of the inositol ring of phosphatidylinositol, which is a regulatory subunit
  • the lipid kinase composed of p85 or p101 and the catalytic subunit p110 catalyzes the phosphorylation of phosphatidylinositol 4,5-bisphosphate (PIP2) to phosphatidylinositol 3,4,5-triphosphate (phosphatidylinositol 3,4,5-trisphosphate, PIP3) and activate downstream Akt, which plays a key role in cell proliferation, survival and metabolism. Therefore, inhibition of phosphoinositide 3-kinase can affect the PI3K pathway, thereby inhibiting the proliferation and activation of cancer cells.
  • the tumor suppressor gene PTEN (phosphatase and tension homolog deleted on chromosome ten) dephosphorylates PIP3 to generate PIP2, thereby achieving negative regulation of the PI3K/Akt signaling pathway, inhibiting cell proliferation and promoting cell apoptosis.
  • PTEN phosphatase and tension homolog deleted on chromosome ten
  • WO2015192760 discloses a series of compounds as PI3K inhibitors, and also specifically discloses compounds of formula I with the following structure:
  • This application provides a compound of formula I or a pharmaceutically acceptable salt thereof for treating lymphoma in a patient:
  • the present application provides the use of the compound of formula I, or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for treating lymphoma in a patient.
  • the present application provides a method for treating lymphoma in a patient, the method comprising administering a compound of formula I, or a pharmaceutically acceptable salt thereof, to the patient.
  • the compound of formula I of the application is used as a single active agent.
  • the compound of formula I of the present application may be in the form of a pharmaceutical composition comprising a therapeutically effective amount of the compound of formula I, or a pharmaceutically acceptable salt thereof.
  • this application provides a pharmaceutical composition for treating lymphoma comprising a compound of formula I, or a pharmaceutically acceptable salt thereof, as an active ingredient.
  • the lymphoma is selected from Hodgkin's lymphoma (HL) and non-Hodgkin's lymphoma (NHL).
  • HL Hodgkin's lymphoma
  • NHL non-Hodgkin's lymphoma
  • the lymphoma is selected from B-cell lymphoma or T-cell lymphoma. In some aspects of the application, the lymphoma is selected from classical Hodgkin lymphoma (CHL), nodular lymphocytic Hodgkin lymphoma, mantle cell lymphoma (MCL), follicular lymphoma ( FL), diffuse large B-cell lymphoma (DLBCL), small lymphocytic lymphoma (SLL) or chronic lymphocytic leukemia (CLL).
  • CHL Hodgkin lymphoma
  • MCL mantle cell lymphoma
  • FL follicular lymphoma
  • DLBCL diffuse large B-cell lymphoma
  • SLL small lymphocytic lymphoma
  • CLL chronic lymphocytic leukemia
  • the non-Hodgkin's lymphoma is selected from B-cell lymphoma or T-cell lymphoma. In some aspects of the application, the non-Hodgkin lymphoma is selected from the group consisting of mantle cell lymphoma (MCL), follicular lymphoma (FL), diffuse large B cell lymphoma (DLBCL), small lymphocytic lymphoma (SLL) or chronic lymphocytic leukemia (CLL).
  • MCL mantle cell lymphoma
  • FL follicular lymphoma
  • DLBCL diffuse large B cell lymphoma
  • SLL small lymphocytic lymphoma
  • CLL chronic lymphocytic leukemia
  • the mantle cell lymphoma is selected from classic mantle cell lymphoma, leukemia-like non-lymphatic mantle cell lymphoma, or mantle cell neoplasia in situ.
  • the diffuse large B-cell lymphoma is selected from the group consisting of germinal center B-cell-like (Germinal Center B-cell-like, GCB) diffuse large B-cell lymphoma, activated B-cell-like (Activated B-cell) -like, ABC) diffuse large B-cell lymphoma, or type 3 (Type 3) diffuse large B-cell lymphoma.
  • germinal center B-cell-like Germinal Center B-cell-like, GCB
  • Activated B-cell activated B-cell-like
  • ABC activated B-cell-like
  • Type 3 type 3
  • the Hodgkin's lymphoma is selected from classic Hodgkin's lymphoma or nodular lymphocytic Hodgkin's lymphoma.
  • the classic Hodgkin's lymphoma is selected from the group consisting of nodular sclerosis, lymphocyte-rich type, mixed cell type, and lymphocyte depletion type.
  • the patient of the lymphoma has received one or two or more previous treatment schemes. In some schemes of the present application, the patient of the lymphoma has received one, two, three, four, or five prior treatment schemes.
  • the lymphoma patient has received first-line, second-line, or third-line and above prior treatment regimens for lymphoma patients.
  • the lymphoma is selected from relapsed or refractory lymphoma.
  • the disease recurs, or the patient with the lymphoma has no objective remission for the previous treatment plan.
  • the said no objective remission refers to stable disease or disease progression during treatment.
  • the patient with the lymphoma is a patient with relapsed or refractory lymphoma who has been treated by a previous treatment regimen.
  • the lymphoma patient is a CD20-positive (CD20+), CD30-positive (CD30+), CD38-positive (CD38+), and/or ZAP70-positive (ZAP70+) lymphoma patient.
  • the lymphoma patient is a CD20 positive (CD20+) lymphoma patient.
  • the lymphoma patient is a lymphoma patient who has been treated with rituximab and/or a BTK inhibitor.
  • the lymphoma patient is a relapsed or refractory lymphoma patient who has been treated with rituximab and/or a BTK inhibitor.
  • the patient of the lymphoma is CD20 positive (CD20+), and is a patient with relapsed or refractory lymphoma that has been treated with rituximab.
  • the prior treatment plan includes drug therapy, radiotherapy, or hematopoietic stem cell transplantation.
  • the drug therapy includes interferon therapy, chemotherapy, or targeted drug therapy.
  • the targeted drug therapy includes an anti-CD20 antibody, an anti-CD30 antibody, or a BTK inhibitor.
  • the anti-CD20 antibody includes rituximab, CHO-H01, ocaratuzumab, ibritumomab tiuxetan, ublituximab, or obituzumab Monoclonal antibody (obinutuzumab).
  • the anti-CD30 antibody may include brentuximab vedotin.
  • the BTK inhibitor includes ibrutinib, ICP-022, acalabrutinib, or zanubrutinib.
  • the drugs used in chemotherapy include cyclophosphamide, ifosfamide, vincristine, prednisone, prednisolone, doxorubicin, adriamycin, epirubicin, Dexamethasone, methotrexate, cytarabine, carboplatin, cisplatin, bendamustine, fludarabine, mitoxantrone, etoposide, procarbazine, gemcitabine, methylprednisolone , Methylprednisolone sodium succinate, mesna, oxaliplatin, 5-fluorouracil, chlorambucil, or azacitidine.
  • the targeted drugs include bortezomib, rituximab, CHO-H01, ocaratuzumab, ibritumomab tiuxetan, ublituximab, or Obinutuzumab, brentuximab vedotin, ibrutinib, ICP-022, acarabrutinib, zanubrutinib, palbociclib, abemaciclib, Sirolimus (temsirolimus), everolimus (everolimus), carfilzomib (carfilzomib), ixazomib (ixazomib), niraparib (niraparib), umbralisib, lenalidomide (lenalidomide), Venatoclax, vorinostat, BR-101801, tazemetostat, or abexinostat.
  • the drugs used in the drug treatment include interferon, cyclophosphamide, ifosfamide, vincristine, vinorelbine, prednisone, prednisolone, doxorubicin, boron Tezomib, Adriamycin, Epirubicin, Bleomycin, Dexamethasone, Methotrexate, Cytarabine, Carboplatin, Cisplatin, Bendamustine, Fludarabine, Mito Anthraquinone, etoposide, procarbazine, gemcitabine, carmustine, methylprednisolone, methylprednisolone sodium succinate, mesna, oxaliplatin, 5-fluorouracil, chlorambucil, dacarbazine Azine, rituximab, CHO-H01, ocaratuzumab, ibritumomab tiuxetan, u
  • the chemotherapy scheme includes ABVD scheme, AVD scheme, B scheme, BA scheme, BAC scheme, BEACOPPesc scheme, CDOP scheme, CEOP scheme, CEPP scheme, CHOP scheme, CHOEP scheme, CIFOX scheme, COP plan, COPE plan, CVP plan, DA-EPOCH plan, DHAP plan, DICE plan, EPOCH plan, ESHAP plan, FC plan, FM plan, GCVP plan, GDP plan, GDPE plan, GEMOX plan, GVD plan, HyperCVAD plan, ICE regimen, IGEV regimen, MA regimen, MINE regimen, miniBEAM regimen, NCE regimen, Stanford V regimen, VCAP regimen, high-dose cytarabine regimen or the above regimen and rituximab (when used in combination therapy, it can be (Referred to as "R") in combination; preferably, the chemotherapy regimens include ABVD, AVD, BEACOPPesc, BR, CDOP, CEOP, CEPP, CHOP, CHOEP
  • the radiotherapy is selected from total lymphatic irradiation (TLI) and subtotal lymphatic irradiation (STLI).
  • the radiotherapy includes involved field irradiation (IFRT), involved lymph node (INRT) or involved site irradiation (ISRT).
  • the hematopoietic stem cell transplantation includes Autologous Hematopoietic Stem Cell Transplantation or Allogeneic Hematopoietic Stem Cell.
  • the lymphoma is selected from Hodgkin's lymphoma and non-Hodgkin's lymphoma; optionally, the patient with the lymphoma has been treated with more than one prior treatment regimen; optionally, the lymphoma is selected from the group consisting of relapsed or refractory lymphoma; optionally, after the patient of the lymphoma has been treated with a previous treatment regimen to achieve objective remission, the disease reoccurs, or the lymphoma The patient has no objective remission for the previous treatment regimen; optionally, the patient with the lymphoma is CD20-positive (CD20+), CD30-positive (CD30+), CD38-positive (CD38+) and/or ZAP70-positive (ZAP70+) lymphoma Patient; Optionally, the first treatment regimen includes medication, radiotherapy, or hematopoietic stem cell transplantation.
  • the lymphoma is selected from Hodgkin's lymphoma.
  • the Hodgkin's lymphoma is selected from classic Hodgkin's lymphoma or nodular lymphocytic Hodgkin's lymphoma.
  • the classic Hodgkin's lymphoma is selected from the group consisting of nodular sclerosis, lymphocyte-rich type, mixed cell type, and lymphocyte depletion type.
  • the patient of Hodgkin's lymphoma has been treated by one or two or more previous treatment schemes. In some schemes of the present application, the patients with Hodgkin's lymphoma have received one, two, three, four, or five prior treatment schemes.
  • the patient of Hodgkin's lymphoma is a patient of Hodgkin's lymphoma who has been treated by first-line, second-line, or third-line and above prior treatment regimens.
  • the patient with Hodgkin's lymphoma has received the treatment of the previous treatment plan to achieve objective remission, and the disease recurs, or the patient with Hodgkin's lymphoma has no objective view of the previous treatment plan ease.
  • the said no objective remission refers to stable disease or disease progression during treatment.
  • the patient with Hodgkin's lymphoma is a patient with relapsed or refractory Hodgkin's lymphoma who has been treated by a previous treatment regimen.
  • the patient with Hodgkin's lymphoma is a patient with CD20-positive (CD20+) or CD30-positive (CD30+) Hodgkin's lymphoma.
  • the patient with Hodgkin's lymphoma is a lymphoma patient who has been treated with rituximab and/or a BTK inhibitor.
  • the patient with Hodgkin's lymphoma is a patient with relapsed or refractory Hodgkin's lymphoma who has been treated with rituximab and/or a BTK inhibitor.
  • the patient with Hodgkin's lymphoma is CD20 positive (CD20+), and is a patient with relapsed or refractory Hodgkin's lymphoma who has been treated with rituximab.
  • the prior treatment scheme for Hodgkin's lymphoma includes drug therapy, radiotherapy, or hematopoietic stem cell transplantation.
  • the drug treatment of the prior treatment scheme of Hodgkin's lymphoma includes interferon therapy, chemotherapy, or targeted drug therapy.
  • the targeted drug therapy of the prior treatment plan for Hodgkin's lymphoma includes anti-CD20 antibodies, anti-CD30 antibodies, or BTK inhibitors.
  • the anti-CD20 antibody of the prior treatment scheme for Hodgkin’s lymphoma includes rituximab, CHO-H01, ocaratuzumab, ibritumomab, utuximab, or Orbituzumab.
  • the anti-CD30 antibody of the prior treatment scheme for Hodgkin's lymphoma includes brentuximab vedotin.
  • the BTK inhibitor of the prior treatment plan for Hodgkin's lymphoma includes ibrutinib, ICP-022, acatinib, or zebutinib.
  • the chemotherapy drugs used in the prior treatment scheme of Hodgkin’s lymphoma include cyclophosphamide, ifosfamide, vincristine, prednisone, prednisolone, doxorubicin Star, doxorubicin, epirubicin, dexamethasone, methotrexate, cytarabine, carboplatin, cisplatin, bendamustine, fludarabine, mitoxantrone, etoposide , Procarbazine, gemcitabine, methylprednisolone sodium succinate, mesna, oxaliplatin, 5-fluorouracil, or azacitidine.
  • the targeted drugs of the prior treatment scheme for Hodgkin’s lymphoma include brentuximab vedotin, bortezomib, rituximab, CHO-H01, ocaratuzumab, ibrituzumab, Utuximab, Obituximab, Ibrutinib, ICP-022, Acatinib, Zebutinib, Pebecili, Abemaciclib, Tesirolimus, Everolimus, Card Fezomib, ixazomib, niraparib, umbralisib, lenalidomide, venatola, vorinostat, BR-101801, tazemetostat, or abexinostat.
  • the drugs used in the medical treatment of the prior treatment scheme of Hodgkin’s lymphoma include interferon, cyclophosphamide, ifosfamide, vincristine, vinorelbine, prednisone, Prednisolone, Doxorubicin, Bortezomib, Doxorubicin, Epirubicin, Bleomycin, Dexamethasone, Methotrexate, Cytarabine, Carboplatin, Cisplatin, Benda Mustine, fludarabine, mitoxantrone, etoposide, procarbazine, gemcitabine, carmustine, methylprednisolone, methylprednisolone sodium succinate, mesna, oxaliplatin, 5 -Fluorouracil, dacarbazine, Rituximab, CHO-H01, Ocaratuzumab, Ibrituzumab, Utux
  • the chemotherapy schemes for the prior treatment of Hodgkin’s lymphoma include ABVD scheme, AVD scheme, BEACOPPesc scheme, CHOP scheme, CVP scheme, DHAP scheme, DICE scheme, EPOCH scheme, GDP scheme, GVD plan, ICE plan, IGEV plan, MINE plan, miniBEAM plan, Stanford V plan.
  • the hematopoietic stem cell transplantation includes autologous hematopoietic stem cell transplantation or allogeneic hematopoietic stem cell transplantation.
  • the radiotherapy is selected from total lymphatic irradiation (TLI) and subtotal lymphatic irradiation (STLI).
  • the radiotherapy includes involved field irradiation (IFRT), involved lymph node (INRT) or involved site irradiation (ISRT).
  • the Hodgkin’s lymphoma is selected from relapsed or refractory Hodgkin’s lymphoma; optionally, the patient of the Hodgkin’s lymphoma has received one or more The treatment of the prior treatment regimen; optionally, the patient of the Hodgkin’s lymphoma has received the treatment of the prior treatment regimen to achieve objective remission, and the disease recurs, or the patient of the Hodgkin’s lymphoma is for the prior treatment
  • the protocol has no objective remission; optionally, the patient with Hodgkin's lymphoma is a patient with CD20-positive or CD30-positive Hodgkin's lymphoma.
  • the prior treatment regimen for Hodgkin's lymphoma includes drug therapy, radiotherapy, or hematopoietic stem cell transplantation.
  • MCL Mantle cell lymphoma
  • the lymphoma or non-Hodgkin's lymphoma is selected from mantle cell lymphoma.
  • the mantle cell lymphoma is selected from classic mantle cell lymphoma, leukemia-like non-lymphatic mantle cell lymphoma, or mantle cell neoplasia in situ.
  • the mantle cell lymphoma is selected from relapsed or refractory mantle cell lymphoma.
  • the patient of the mantle cell lymphoma has been treated by one or two or more previous treatment schemes. In some schemes of the present application, the patient of the mantle cell lymphoma has received one, two, three, four, or five prior treatment schemes.
  • the patient of the mantle cell lymphoma is a patient of mantle cell lymphoma that has been treated with first-line, second-line, or third-line and above prior treatment regimens.
  • the non-objective remission refers to stable disease or disease progression during treatment.
  • the patient of the mantle cell lymphoma has previously received systemic treatment of ⁇ 1 line but not more than 4 lines, and the most recently received treatment plan confirms that there is no objective remission (disease stability or disease progression during treatment) , Or patients with mantle cell lymphoma who develop disease progression after treatment.
  • the patient of the mantle cell lymphoma is a patient with relapsed or refractory mantle cell lymphoma who has been treated by a previous treatment regimen.
  • the patient with mantle cell lymphoma is a patient with CD20 positive (CD20+) mantle cell lymphoma.
  • the mantle cell lymphoma patient is a mantle cell lymphoma patient who has been treated with rituximab and/or a BTK inhibitor.
  • the patient with mantle cell lymphoma is a patient with relapsed or refractory mantle cell lymphoma who has been treated with rituximab and/or a BTK inhibitor.
  • the patient with mantle cell lymphoma is CD20 positive (CD20+) and is a patient with relapsed or refractory mantle cell lymphoma that has been treated with rituximab.
  • the prior treatment plan for the mantle cell lymphoma includes drug therapy, radiotherapy, or hematopoietic stem cell transplantation.
  • the drug treatment of the prior treatment scheme of the mantle cell lymphoma includes interferon therapy, chemotherapy, or targeted drug therapy.
  • the targeted drug therapy of the prior treatment plan of the mantle cell lymphoma includes anti-CD20 antibodies or BTK inhibitors.
  • the anti-CD20 antibody of the prior treatment scheme for mantle cell lymphoma includes rituximab, CHO-H01, ocaratuzumab, ibrituximab, utuximab, or Bituzumab.
  • the BTK inhibitor of the prior treatment program for mantle cell lymphoma includes ibrutinib, ICP-022, acatinib, or zebutinib.
  • the chemotherapeutic drugs used in the prior treatment scheme of mantle cell lymphoma include cyclophosphamide, ifosfamide, vincristine, prednisone, prednisolone, and doxorubicin , Doxorubicin, epirubicin, dexamethasone, methotrexate, cytarabine, carboplatin, cisplatin, bendamustine, fludarabine, mitoxantrone, etoposide, Procarbazine, gemcitabine, methylprednisolone, methylprednisolone sodium succinate, mesna, oxaliplatin, 5-fluorouracil, or azacitidine.
  • the targeted drugs of the prior treatment scheme for mantle cell lymphoma include bortezomib, rituximab, CHO-H01, ocaratuzumab, ibrituximab, utuximab Anti-, Obituzumab, Ibrutinib, ICP-022, Akatinib, Zebutinib, Pebecili, abemaciclib, Tesirolimus, Everolimus, Carfilzomib, Ixazomib, niraparib, umbralisib, lenalidomide, venatortola, vorinostat, BR-101801, tazemetostat, or abexinostat.
  • the drugs used in the prior treatment scheme of mantle cell lymphoma include cyclophosphamide, ifosfamide, vincristine, prednisone, prednisolone, and doxorubicin Star, bortezomib, adriamycin, epirubicin, dexamethasone, methotrexate, cytarabine, carboplatin, cisplatin, bendamustine, fludarabine, mitoxantrone , Etoposide, procarbazine, gemcitabine, methylprednisolone, methylprednisolone sodium succinate, mesna, oxaliplatin, 5-fluorouracil, rituximab, CHO-H01, ocaratuzumab, tiib Momomab, Utuximab, Orbituzumab, Ibrutinib, ICP-022,
  • the chemotherapy schemes for the prior treatment of mantle cell lymphoma include B scheme, CHOP scheme, CIFOX scheme, COP scheme, DHAP scheme, EPOCH scheme, FC scheme, FM scheme, BAC scheme, CHOP Regimen, HyperCVAD regimen, ICE regimen, MA regimen, VCAP regimen, high-dose cytarabine regimen or combination of the above regimens with rituximab; preferably, the chemotherapy regimen includes BR regimen, CHOP regimen, COP regimen, DHAP plan, FCR plan, FMR plan, R-BAC plan, R-CHOP plan, R-DHAP plan, R-HyperCVAD plan, R-ICE plan, R-MA plan, R-high-dose cytarabine plan or VR -CAP program.
  • the hematopoietic stem cell transplantation includes autologous hematopoietic stem cell transplantation or allogeneic hematopoietic stem cell transplantation.
  • the radiotherapy is selected from total lymphatic irradiation (TLI) and subtotal lymphatic irradiation (STLI).
  • the radiotherapy includes involved field irradiation (IFRT), involved lymph node (INRT) or involved site irradiation (ISRT).
  • the diagnosis report of the patient with mantle cell lymphoma includes morphology and evidence of Cyclin D1 (Cyclin D1) immunohistochemistry positive or t(11:14).
  • the cytogenetic test of the mantle cell lymphoma patient is positive for t(11;14) and/or immunohistochemical cyclin D1 (highly expressed).
  • the mantle cell lymphoma is selected from the group consisting of relapsed or refractory mantle cell lymphoma; optionally, the patient of the mantle cell lymphoma has received one or two or more prior treatments
  • the patient of the mantle cell lymphoma is a patient of CD20-positive mantle cell lymphoma; optionally, the prior treatment regimen of the mantle cell lymphoma includes drug therapy, radiotherapy, or hematopoietic stem cell transplantation;
  • the diagnosis report of the patient with the mantle cell lymphoma includes evidence of morphology and cyclin D1 immunohistochemistry positive or t(11:14).
  • the mantle cell lymphoma is selected from the group consisting of relapsed or refractory mantle cell lymphoma; optionally, the patient of the mantle cell lymphoma has received one or two or more prior treatments
  • the patient of the mantle cell lymphoma is a patient of CD20-positive mantle cell lymphoma; optionally, the prior treatment regimen of the mantle cell lymphoma includes drug therapy, radiotherapy, or hematopoietic stem cell transplantation;
  • the cytogenetic test of the mantle cell lymphoma patient is positive for t(11;14) and/or immunohistochemical cyclin D1 (highly expressed).
  • the lymphoma or non-Hodgkin's lymphoma is selected from follicular lymphoma.
  • the follicular lymphoma is selected from relapsed or refractory follicular lymphoma.
  • the patients with follicular lymphoma have received one or two or more previous treatment schemes. In some schemes of the present application, the patients with follicular lymphoma have received one, two, three, four, or five prior treatment schemes.
  • the patients with follicular lymphoma are patients with follicular lymphoma who have been treated with first-line, second-line, or third-line and above prior treatment regimens.
  • the patients with follicular lymphoma have previously received ⁇ 2 lines of systemic treatment, and at least one of the schemes contains relapsed or refractory follicular lymphoma with rituximab Patients with tumors.
  • the patients with follicular lymphoma have received the treatment of the previous treatment plan to achieve objective remission, and the disease recurs, or the patients with follicular lymphoma have no objective view of the previous treatment plan ease.
  • the said no objective remission refers to stable disease or disease progression during treatment.
  • the patients with follicular lymphoma are patients with relapsed or refractory follicular lymphoma who have received a previous treatment regimen.
  • the follicular lymphoma patient is a CD20-positive (CD20+) follicular lymphoma patient.
  • the follicular lymphoma patient is a follicular lymphoma patient who has been treated with rituximab and/or a BTK inhibitor.
  • the patient with follicular lymphoma is a patient with relapsed or refractory lymphoma who has been treated with rituximab and/or a BTK inhibitor.
  • the patient with follicular lymphoma is CD20 positive (CD20+), and is a patient with relapsed or refractory follicular lymphoma that has been treated with rituximab.
  • the prior treatment plan for follicular lymphoma includes drug therapy, radiotherapy, or hematopoietic stem cell transplantation.
  • the drug treatment of the prior treatment scheme of follicular lymphoma includes interferon therapy, chemotherapy, or targeted drug therapy.
  • the targeted drug therapy of the prior treatment plan of follicular lymphoma includes anti-CD20 antibodies or BTK inhibitors.
  • the anti-CD20 antibody of the prior treatment scheme of follicular lymphoma includes rituximab, CHO-H01, ocaratuzumab, ibritumomab, utuximab, or Orbituzumab.
  • the BTK inhibitor of the prior treatment program for follicular lymphoma includes ibrutinib, ICP-022, acatinib, or zebutinib.
  • the chemotherapy drugs used in the prior treatment scheme of follicular lymphoma include cyclophosphamide, ifosfamide, vincristine, prednisone, prednisolone, doxorubicin Star, doxorubicin, epirubicin, dexamethasone, methotrexate, cytarabine, carboplatin, cisplatin, bendamustine, fludarabine, mitoxantrone, etoposide , Procarbazine, gemcitabine, methylprednisolone, methylprednisolone sodium succinate, mesna, oxaliplatin, 5-fluorouracil, or azacitidine.
  • the targeted drugs of the prior treatment scheme for follicular lymphoma include bortezomib, rituximab, CHO-H01, ocaratuzumab, ibrituximab, and utuximab.
  • the drugs used in the pharmacological treatment of the prior treatment scheme of follicular lymphoma include cyclophosphamide, ifosfamide, vincristine, prednisone, prednisolone, doxorubicin Picin, bortezomib, doxorubicin, epirubicin, dexamethasone, methotrexate, cytarabine, carboplatin, cisplatin, bendamustine, fludarabine, mitoxant Quinone, etoposide, procarbazine, gemcitabine, vinorelbine, methylprednisolone, methylprednisolone sodium succinate, mesna, oxaliplatin, 5-fluorouracil, interferon, rituximab, CHO-H01, ocaratuzumab, ibrituzumab, utuximab, obet
  • the chemotherapy scheme of the first treatment scheme of follicular lymphoma includes the B scheme, the CDOP scheme, the CHOP scheme, the CVP scheme, the DHAP scheme, the DICE scheme, the EPOCH scheme, the ICE scheme, the GEMOX scheme, NCE regimen, or the above regimen in combination with rituximab; preferably, the chemotherapy regimen includes BR regimen, CHOP regimen, GEMOX regimen, R-CDOP regimen, R-CHOP regimen, R-CVP regimen, R-DHAP Plan, R-DICE plan, R-EPOCH plan, R-GEMOX plan, R-ICE plan, or R-NCE plan.
  • the hematopoietic stem cell transplantation includes autologous hematopoietic stem cell transplantation or allogeneic hematopoietic stem cell transplantation.
  • the radiotherapy is selected from total lymphatic irradiation (TLI) and subtotal lymphatic irradiation (STLI).
  • the radiotherapy includes involved field irradiation (IFRT), involved lymph node (INRT) or involved site irradiation (ISRT).
  • the patient with follicular lymphoma is a patient with grade 1-3a follicular lymphoma diagnosed by histopathology.
  • the diagnosis report of the patient with follicular lymphoma includes t(14;18) translocation or Bcl-2 protein overexpression.
  • the follicular lymphoma is selected from relapsed or refractory follicular lymphoma; optionally, the patient of the follicular lymphoma has received one or more The treatment of the previous treatment regimen; optionally, the patient of the follicular lymphoma has received the treatment of the previous treatment regimen to achieve objective remission, and the disease recurs, or the patient of the follicular lymphoma is for the previous treatment
  • the regimen has no objective relief; optionally, the patient with follicular lymphoma is a patient with CD20-positive follicular lymphoma; optionally, the prior treatment regimen for follicular lymphoma includes drug treatment, Radiotherapy, or hematopoietic stem cell transplantation; optionally, the patient with follicular lymphoma is a patient with grade 1-3a follicular lymphoma confirmed by histopathology; optionally, the patient with follicular lymphoma The patient’s diagnosis report included
  • Diffuse large B-cell lymphoma Diffuse large B-cell lymphoma
  • the lymphoma or non-Hodgkin's lymphoma is selected from diffuse large B-cell lymphoma.
  • the diffuse large B-cell lymphoma is selected from relapsed or refractory diffuse large B-cell lymphoma.
  • the patients with diffuse large B-cell lymphoma have received one or two or more previous treatment schemes. In some schemes of the present application, the patients with diffuse large B-cell lymphoma have received one, two, three, four, or five prior treatment schemes.
  • the patients with diffuse large B-cell lymphoma have received first-line, second-line, or third-line and above prior treatment regimens.
  • the patients with diffuse large B-cell lymphoma have previously received at least a 2-line (including 2-line, 3-line, 4-line, or 5-line) systemic treatment regimen.
  • a 2-line including 2-line, 3-line, 4-line, or 5-line
  • the patients with diffuse large B-cell lymphoma have received at least a 2-line systemic systemic treatment program in the past, and there is disease progression during or after the last treatment, or no objective remission is confirmed after sufficient treatment , And in the past, at least one regimen contained rituximab for adequate treatment or disease progression during rituximab treatment.
  • the patients with diffuse large B-cell lymphoma have received the treatment of the previous treatment plan to achieve objective remission, and the disease recurs, or the patients with diffuse large B-cell lymphoma are treated with respect to the previous treatment plan No objective relief.
  • the said no objective remission refers to stable disease or disease progression during treatment.
  • the patient with diffuse large B-cell lymphoma is a patient with relapsed or refractory diffuse large B-cell lymphoma who has received a previous treatment regimen.
  • the patient with diffuse large B-cell lymphoma is a patient with CD20-positive (CD20+) diffuse large B-cell lymphoma.
  • the patient with diffuse large B-cell lymphoma is a patient with diffuse large B-cell lymphoma who has been treated with rituximab and/or a BTK inhibitor.
  • the patient with diffuse large B-cell lymphoma is a patient with relapsed or refractory diffuse large B-cell lymphoma who has been treated with rituximab and/or a BTK inhibitor.
  • the patient with diffuse large B-cell lymphoma is CD20 positive (CD20+), and is a patient with relapsed or refractory diffuse large B-cell lymphoma that has been treated with rituximab .
  • the prior treatment scheme for diffuse large B-cell lymphoma includes drug therapy, radiotherapy, or hematopoietic stem cell transplantation.
  • the drug treatment of the prior treatment scheme of diffuse large B-cell lymphoma includes interferon therapy, chemotherapy, or targeted drug therapy.
  • the targeted drug therapy of the prior treatment plan for diffuse large B-cell lymphoma includes anti-CD20 antibodies or BTK inhibitors.
  • the anti-CD20 antibodies of the prior treatment scheme for diffuse large B-cell lymphoma include rituximab, CHO-H01, ocaratuzumab, ibrituximab, utuximab, Or obituzumab.
  • the BTK inhibitor of the prior treatment scheme for diffuse large B-cell lymphoma includes ibrutinib, ICP-022, acatinib, or zebutinib.
  • the chemotherapeutic drugs used in the prior treatment scheme for diffuse large B-cell lymphoma include cyclophosphamide, ifosfamide, vincristine, prednisone, prednisolone, doxolone Bicin, adriamycin, epirubicin, dexamethasone, methotrexate, cytarabine, carboplatin, cisplatin, bendamustine, fludarabine, mitoxantrone, etopo Glycoside, procarbazine, gemcitabine, methylprednisolone, methylprednisolone sodium succinate, mesna, oxaliplatin, 5-fluorouracil, or azacitidine.
  • the targeted drugs of the prior treatment scheme for diffuse large B-cell lymphoma include bortezomib, rituximab, CHO-H01, ocaratuzumab, ibrituzumab, Uto Coximab, Obituximab, Ibrutinib, ICP-022, Acartinib, Zebutinib, Pebecili, Abemaciclib, Tesirolimus, Everolimus, Carfizo Rice, ixazomib, niraparib, umbralisib, lenalidomide, venatora, vorinostat, BR-101801, tazemetostat, or abexinostat.
  • the drugs used in the drug treatment of the prior treatment scheme for diffuse large B-cell lymphoma include cyclophosphamide, ifosfamide, vincristine, prednisone, prednisolone, and Rubicin, Bortezomib, Epirubicin, Adriamycin, Dexamethasone, Methotrexate, Cytarabine, Carboplatin, Cisplatin, Bendamustine, Fludarabine, Mito Anthraquinone, etoposide, procarbazine, gemcitabine, methylprednisolone, methylprednisolone sodium succinate, mesna, oxaliplatin, 5-fluorouracil, interferon, rituximab, lenalidomide Amine, CHO-H01, ocaratuzumab, ibrituzumab, utuximab, obituzumab, ibru
  • the chemotherapy regimens used for the first treatment regimen of diffuse large B-cell lymphoma include CDOP, GDP, GDPE, CEOP, CEPP, CHOP, CHOEP, DA-EPOCH , DHAP protocol, DICE protocol, ESHAP protocol, GCVP protocol, GDP protocol, GEMOX protocol, HyperCVAD protocol, ICE protocol, MINE protocol, or combination of the above-mentioned protocols with rituximab; preferably, the diffuse large B cell lymph
  • the chemotherapy regimens used in the first treatment plan for tumors include CEOP plan, CEPP plan, CHOP plan, DA-EPOCH-R plan, DHAP plan, DICE plan, ESHAP plan, GDP plan, GDPE plan, GEMOX plan, ICE plan, MINE plan, R-CDOP plan, R-CEOP plan, R-CEPP plan, R-CHOP plan, R-CHOEP plan, R-DHAP plan, R-ESHAP plan, R-GCVP plan, R-GDP plan,
  • the hematopoietic stem cell transplantation includes autologous hematopoietic stem cell transplantation or allogeneic hematopoietic stem cell transplantation.
  • the radiotherapy is selected from total lymphatic irradiation (TLI) and subtotal lymphatic irradiation (STLI).
  • the radiotherapy includes involved field irradiation (IFRT), involved lymph node (INRT) or involved site irradiation (ISRT).
  • the diffuse large B-cell lymphoma is selected from the group consisting of germinal center B-cell-like (Germinal Center B-cell-like, GCB) diffuse large B-cell lymphoma, activated B-cell-like (Activated B-cell) -like, ABC) diffuse large B-cell lymphoma, or type 3 (Type 3) diffuse large B-cell lymphoma.
  • germinal center B-cell-like Germinal Center B-cell-like, GCB
  • Activated B-cell activated B-cell-like
  • ABC activated B-cell-like
  • Type 3 type 3
  • the diffuse large B-cell lymphoma is selected from relapsed or refractory diffuse large B-cell lymphoma; optionally, the patient with the diffuse large B-cell lymphoma has received one or Treatment of two or more prior treatment regimens; optionally, the patient with diffuse large B-cell lymphoma has received the prior treatment regimen to achieve objective remission, and the disease recurs, or the diffuse large B-cell lymphoma
  • the patient has no objective remission for the previous treatment regimen; in some regimens of the application, the patient with follicular lymphoma is a patient with CD20-positive follicular lymphoma; optionally, the diffuse large B-cell lymphoma
  • Prior treatment options for tumors include, but are not limited to, drug therapy, radiotherapy, or hematopoietic stem cell transplantation.
  • SLL Small lymphocytic lymphoma
  • CLL chronic lymphocytic leukemia
  • the lymphoma is selected from small lymphocytic lymphoma or chronic lymphocytic leukemia.
  • the non-Hodgkin's lymphoma is selected from small lymphocytic lymphoma or chronic lymphocytic leukemia.
  • the small lymphocytic lymphoma or chronic lymphocytic leukemia is selected from relapsed or refractory small lymphocytic lymphoma or chronic lymphocytic leukemia.
  • the patients of the small lymphocytic lymphoma or chronic lymphocytic leukemia have received one or two or more previous treatment schemes. In some schemes of the present application, the patients with small lymphocytic lymphoma or chronic lymphocytic leukemia have received one, two, three, four, or five prior treatment regimens.
  • the patients with small lymphocytic lymphoma or chronic lymphocytic leukemia have received first-line, second-line, or third-line and above prior treatment regimens.
  • the patients with small lymphocytic lymphoma or chronic lymphocytic leukemia have previously received at least a 1-line (including 1-line, 2-line, 3-line, or 4-line) systemic treatment regimen.
  • a 1-line including 1-line, 2-line, 3-line, or 4-line
  • the patients of the small lymphocytic lymphoma or chronic lymphocytic leukemia have received at least one-line systemic treatment.
  • the patients with small lymphocytic lymphoma or chronic lymphocytic leukemia have received at least a first-line systemic systemic treatment plan in the past, and there is disease progression during or after the last treatment, or confirmed after adequate treatment No objective relief.
  • the patient of the small lymphocytic lymphoma or chronic lymphocytic leukemia is a small lymphocytic lymphoma or chronic lymphocytic lymphoma that has relapsed or is refractory after receiving at least 1 line of systemic systemic treatment. Patients with leukemia.
  • the patient with small lymphocytic lymphoma or chronic lymphocytic leukemia has received the treatment of the previous treatment plan to achieve objective remission, and the disease recurs, or the small lymphocytic lymphoma or chronic lymphocytic leukemia Patients with leukemia have no objective relief from the previous treatment regimen.
  • the said no objective remission refers to stable disease or disease progression during treatment.
  • the patient with small lymphocytic lymphoma or chronic lymphocytic leukemia is CD20-positive (CD20+), CD38-positive (CD38+), or ZAP70-positive (ZAP70+) small lymphocytic lymphoma or chronic lymphocyte Patients with leukemia.
  • the patient with small lymphocytic lymphoma or chronic lymphocytic leukemia is a CD20 positive (CD20+) patient.
  • the patient with small lymphocytic lymphoma or chronic lymphocytic leukemia is a small lymphocytic lymphoma or chronic lymphocytic leukemia patient who has been treated with rituximab and/or BTK inhibitor .
  • the patient with small lymphocytic lymphoma or chronic lymphocytic leukemia is a relapsed or refractory small lymphocytic lymphoma that has been treated with rituximab and/or BTK inhibitors or Patients with chronic lymphocytic leukemia.
  • the patient of the small lymphocytic lymphoma or chronic lymphocytic leukemia is CD20 positive (CD20+), and is a relapsed or refractory small lymphocytic lymphoma that has been treated with rituximab Patients with tumor or chronic lymphocytic leukemia.
  • the patient with small lymphocytic lymphoma or chronic lymphocytic leukemia has del(11q), del(17p), and/or TP53 gene mutations.
  • the prior treatment scheme for small lymphocytic lymphoma or chronic lymphocytic leukemia includes drug therapy, radiotherapy, or hematopoietic stem cell transplantation.
  • the drug treatment of the prior treatment scheme of small lymphocytic lymphoma or chronic lymphocytic leukemia includes interferon therapy, chemotherapy, or targeted drug therapy.
  • the targeted drug treatment of the prior treatment scheme of small lymphocytic lymphoma or chronic lymphocytic leukemia includes anti-CD20 antibodies or BTK inhibitors.
  • the anti-CD20 antibody of the prior treatment scheme for small lymphocytic lymphoma or chronic lymphocytic leukemia includes rituximab, CHO-H01, ocaratuzumab, ibrituzumab, Uto Coximab, or obituzumab.
  • the BTK inhibitor of the prior treatment scheme for small lymphocytic lymphoma or chronic lymphocytic leukemia includes ibrutinib, ICP-022, acatinib, or zebutinib.
  • the chemotherapeutic drugs used in the prior treatment scheme of small lymphocytic lymphoma or chronic lymphocytic leukemia include cyclophosphamide, ifosfamide, vincristine, prednisone, and prednisone Dragon, doxorubicin, doxorubicin, epirubicin, dexamethasone, methotrexate, cytarabine, carboplatin, cisplatin, bendamustine, fludarabine, mitoxant Quinone, etoposide, procarbazine, gemcitabine, methylprednisolone, methylprednisolone sodium succinate, mesna, oxaliplatin, 5-fluorouracil, chlorambucil, or azacitidine.
  • the targeted drugs of the prior treatment scheme for small lymphocytic lymphoma or chronic lymphocytic leukemia include bortezomib, rituximab, CHO-H01, ocaratuzumab, and ibrituzumab Antibody, Utuximab, Obituzumab, Ibrutinib, ICP-022, Acatinib, Zebutinib, Pebecili, Abemaciclib, Tesirolimus, Everolimus , Carfilzomib, ixazomib, niraparib, umbralisib, lenalidomide, venatola, vorinostat, BR-101801, tazemetostat, or abexinostat.
  • the drugs used in the prior treatment of small lymphocytic lymphoma or chronic lymphocytic leukemia include interferon, cyclophosphamide, ifosfamide, vincristine, and vinorelbine , Prednisone, Prednisolone, Doxorubicin, Bortezomib, Adriamycin, Epirubicin, Dexamethasone, Methotrexate, Cytarabine, Carboplatin, Cisplatin, Benda Mustine, fludarabine, mitoxantrone, etoposide, procarbazine, gemcitabine, methylprednisolone, methylprednisolone sodium succinate, mesna, oxaliplatin, 5-fluorouracil, benzene Chlorambucil, Rituximab, CHO-H01, Ocaratuzumab, Titumomab, Utuximab,
  • the prior treatment of small lymphocytic lymphoma or chronic lymphocytic leukemia chemotherapy regimens include B regimen, BA regimen, BAC regimen, CDOP regimen, CEOP regimen, CEPP regimen, CHOP regimen, CIFOX Plan, COP plan, COPE plan, CVP plan, DA-EPOCH plan, DHAP plan, DICE plan, EPOCH plan, ESHAP plan, FC plan, FM plan, GCVP plan, GDP plan, GDPE plan, GEMOX plan, HyperCVAD plan, ICE Regimen, MA regimen, MINE regimen, NCE regimen, VCAP regimen or the above regimen in combination with rituximab; preferably, the chemotherapy regimen includes BR regimen, CDOP regimen, CEOP regimen, CEPP regimen, CHOP regimen, CIFOX Plan, COP plan, CVP plan, DA-EPOCH-R plan, DHAP plan, DICE plan, EPOCH plan, ESHAP plan, FCR plan, FMR plan, GDP plan, GDPE
  • the radiotherapy is selected from total lymphatic irradiation (TLI) and subtotal lymphatic irradiation (STLI).
  • the radiotherapy includes involved field irradiation (IFRT), involved lymph node (INRT) or involved site irradiation (ISRT).
  • the hematopoietic stem cell transplantation includes autologous hematopoietic stem cell transplantation or allogeneic hematopoietic stem cell transplantation.
  • the small lymphocytic lymphoma or chronic lymphocytic leukemia is selected from relapsed or refractory small lymphocytic lymphoma or chronic lymphocytic leukemia; optionally, the small lymphocytic lymphoma or Patients with chronic lymphocytic leukemia have received treatment with one or more prior treatment regimens; optionally, the patients with small lymphocytic lymphoma or chronic lymphocytic leukemia have received treatment with prior treatment regimens to achieve objective remission Later, the disease recurs, or the patient with small lymphocytic lymphoma or chronic lymphocytic leukemia has no objective relief from the previous treatment regimen; optionally, the patient with small lymphocytic lymphoma or chronic lymphocytic leukemia is CD20 Patients with positive small lymphocytic lymphoma or chronic lymphocytic leukemia; optionally, patients with small lymphocytic lymphoma or chronic lymphocytic leukemia
  • the administration period for the treatment of lymphoma of the patient is 2-6 weeks. In some schemes of the present application, the administration cycle of the lymphoma of the treatment patient is 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks or a range formed by any of the above values. In some schemes of the present application, the administration cycle for the treatment of lymphoma of the patient is 3 weeks or 4 weeks.
  • the daily dose for treating lymphoma of the patient is selected from 1 to 100 mg.
  • the daily dose for the treatment of lymphoma of the patient is selected from 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 11 mg, 12 mg, 13 mg, 14 mg, 15 mg , 16mg, 17mg, 18mg, 19mg, 20mg, 21mg, 22mg, 23mg, 24mg, 25mg, 26mg, 27mg, 28mg, 29mg, 30mg, 31mg, 32mg, 33mg, 34mg, 35mg, 36mg, 37mg, 38mg, 39mg, 40mg , 41mg, 42mg, 43mg, 44mg, 45mg, 46mg, 47mg, 48mg, 49mg, 50mg, 51mg, 52mg, 53mg, 54mg, 55
  • the number of daily administrations for the treatment of lymphoma of the patient is 1, 2, or 3 times.
  • the treatment of lymphoma of the patient is administered once every two days.
  • the dosage regimen for the treatment of lymphoma of a patient includes: a dosage period of 2 to 6 weeks, a daily dose of 1 to 40 mg, and a daily dosage of 1 to 3 times.
  • the compound of formula I of the present application, its stereoisomers, or pharmaceutically acceptable salts thereof can be administered by a variety of routes, including but not limited to the following routes: oral, parenteral, intraperitoneal, intravenous , Intraarterial, transdermal, sublingual, intramuscular, rectal, transbuccal, intranasal, inhalation, vaginal, intraocular, topical administration, subcutaneous, intrafatty, intraarticular or intrathecal. In a specific regimen, it is administered orally.
  • the method of administration can be comprehensively determined according to factors such as drug activity, toxicity, and patient tolerance.
  • the compound of the present application, its stereoisomer, or a pharmaceutically acceptable salt thereof is administered in an interval administration manner.
  • the pharmaceutical composition of the present application can be prepared by combining the compound of formula I of the present application with suitable pharmaceutically acceptable excipients, for example, can be formulated into a solid, semi-solid, liquid or gaseous preparation.
  • the pharmaceutical composition is a preparation suitable for oral administration, including tablets, capsules, powders, granules, dripping pills, pastes, powders, etc., preferably tablets and capsules.
  • the oral preparations can be prepared by conventional methods using pharmaceutically acceptable carriers known in the art.
  • Pharmaceutically acceptable carriers include diluents, binders, wetting agents, disintegrants, lubricants and the like.
  • the pharmaceutical composition is a single-dose pharmaceutical composition.
  • the pharmaceutical composition contains 1 mg to 50 mg of the compound of formula I of the present application, or a pharmaceutically acceptable salt thereof.
  • the pharmaceutical composition contains 1 mg, 2 mg, 5 mg, 8 mg, 10 mg, 12 mg, 15 mg, 18 mg, 20 mg, 22 mg, 25 mg, 28 mg, 30 mg, 32 mg, 35 mg, 38 mg, 40 mg, 42 mg, 45 mg, 48 mg or 50 mg, or any of the foregoing values as a range constituted by endpoints or any value therein, the compound of the application, or a pharmaceutically acceptable salt thereof, for example, 2 mg to 50 mg, 10 mg to 40 mg, 5 mg to 30 mg, 5 mg to 20 mg, etc. .
  • the compound of formula I of the present application has a good curative effect in reducing the growth of lymphoma or even eliminating tumors, and provides good disease control rate for the treated patients, so that the treated patients have longer Survival (such as median survival, progression-free survival, or overall survival), longer duration of disease remission.
  • the compound of formula I of the present application, or a pharmaceutically acceptable salt thereof has good safety in reducing lymphoma.
  • pharmaceutically acceptable refers to those compounds, materials, compositions, and/or dosage forms that are within the scope of reliable medical judgment and are suitable for use in contact with human and animal tissues, but not Many toxicity, irritation, allergic reactions or other problems or complications are commensurate with a reasonable benefit/risk ratio.
  • pharmaceutically acceptable salt includes a salt formed by a base ion and a free acid or a salt formed by an acid ion and a free base.
  • the amount of the compound of formula I is calculated in its free base form.
  • the compound in the pharmaceutical combination of the present application has, for example, at least one basic center, it can form an acid addition salt. If necessary, it is also possible to form a corresponding acid addition salt having a basic center additionally present.
  • Compounds having at least one acidic group for example COOH
  • patient is a mammal. In some embodiments, the patient is a human.
  • pharmaceutical composition refers to a mixture of one or more of the compounds of the application or their pharmaceutical combinations or their salts and pharmaceutically acceptable excipients.
  • the purpose of the pharmaceutical composition is to facilitate the administration of the compound of the present application or its pharmaceutical combination to a patient.
  • treatment generally refers to obtaining a desired pharmacological and/or physiological effect.
  • the effect can be therapeutic based on partial or complete stabilization or cure of the disease and/or side effects due to the disease.
  • Treatment encompasses any treatment of a patient's disease, including: (a) inhibiting the symptoms of the disease, that is, preventing its development; or (b) alleviating the symptoms of the disease, that is, causing the disease or symptoms to degenerate.
  • the term "effective amount” means (i) treating a specific disease, condition, or disorder, (ii) reducing, ameliorating, or eliminating one or more symptoms of a specific disease, condition, or disorder, or (iii) delaying what is described herein
  • the amount of the compound of the present application for the onset of one or more symptoms of a particular disease, condition, or disorder.
  • the amount of the compound of the present application that constitutes a “therapeutically effective amount” varies depending on the compound, the disease state and its severity, the mode of administration, and the age of the mammal to be treated, but it can be routinely determined by those skilled in the art. Determined by its own knowledge and this disclosure.
  • single dose refers to the smallest packaging unit containing a certain amount of medicine, for example, each medicine is a single dose; a box of medicines has seven capsules, and each capsule is a single dose; or each bottle of injection is a single dose.
  • refractory refers to a specific cancer that is resistant or unresponsive to therapy with a specific therapeutic agent. Cancers that are difficult to treat with a specific therapeutic agent can start when the specific therapeutic agent is used (that is, there is no response when the therapeutic agent is initially exposed), or it may be the first time the therapeutic agent is used. During the treatment period or during subsequent treatment with the therapeutic agent, resistance to the therapeutic agent develops as a result.
  • refractory rituximab refers to the lack of remission after adequate treatment with a rituximab-containing regimen (combined chemotherapy or monotherapy), or disease progression during treatment/full treatment within 6 months.
  • relapse refers to the recurrence of the disease after an objective remission has been achieved after receiving a certain treatment plan.
  • Objective remission includes complete remission and partial remission.
  • rituximab recurrence refers to disease progression after adequate treatment and remission, and at least one regimen contains rituximab.
  • first-line therapy refers to the first treatment of the disease. It is usually part of a standard set of treatments, such as chemotherapy and radiation therapy after surgery. When first-line therapy is used alone, it is recognized as the best therapy. If it cannot cure the disease or cause serious side effects, other treatments can be added or used.
  • second-line therapy refers to treatment given when the initial treatment (first-line treatment) fails or stops working.
  • third-line treatment or multi-line treatment can be deduced by analogy.
  • the term "has been treated with a previous treatment regimen” or “has received a certain treatment method or drug treatment” means that the patient has previously received a corresponding treatment method, treatment method or drug treatment .
  • the patient with the lymphoma is a patient with relapsed or refractory lymphoma who has been treated with rituximab” means that the lymphoma patient has received rituximab treatment in the past.
  • the drugs used in the prior treatment plan can refer to the following content, or refer to treatment guidelines or textbooks related to medicine and pharmacy:
  • ABVD regimen doxorubicin, bleomycin, vinblastine, and dacarbazine.
  • AVD regimen doxorubicin, vinblastine, and dacarbazine.
  • Option B Bendamustine.
  • BR regimen bendamustine, and rituximab.
  • BA regimen bendamustine, and azacitidine.
  • BEACOPPesc regimen etoposide, doxorubicin, cyclophosphamide, vincristine, bleomycin, prednisone, and procarbazine.
  • CDOP protocol cyclophosphamide, doxorubicin, vincristine, and prednisone.
  • CEOP protocol cyclophosphamide, etoposide, vincristine, and prednisone.
  • CEPP protocol cyclophosphamide, etoposide, prednisolone, and procarbazine.
  • CHOP regimen cyclophosphamide, doxorubicin/epirubicin, vincristine, and prednisone.
  • the CHOP plan includes but is not limited to the CHOP-21 day plan or the CHOP-14 day plan.
  • CHOEP regimen cyclophosphamide, doxorubicin/epirubicin, vincristine, etoposide, and prednisone (CHOP regimen combined with etoposide).
  • CIFOX regimen 5-fluorouracil, and oxaliplatin.
  • COP program cyclophosphamide, vincristine, and prednisone.
  • COPE protocol cyclophosphamide, vincristine, cisplatin, and etoposide.
  • CVP regimen cyclophosphamide, vincristine, and prednisone.
  • DA-EPOCH regimen etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin.
  • DA-EPOCH-R regimen etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab.
  • DHAP regimen dexamethasone, high-dose cytarabine, and cisplatin.
  • DICE protocol dexamethasone, ifosfamide, cisplatin, and etoposide.
  • EPOCH regimen etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin.
  • ESHAP protocol etoposide, methylprednisolone, high-dose cytarabine, and cisplatin.
  • FCR regimen fludarabine, cyclophosphamide, and rituximab.
  • FC protocol fludarabine, and cyclophosphamide.
  • FM protocol fludarabine, and mitoxantrone.
  • FMR regimen fludarabine, mitoxantrone, and rituximab.
  • GCVP regimen gemcitabine, cyclophosphamide, vincristine, and prednisone.
  • GDP plan gemcitabine, dexamethasone, and cisplatin.
  • GDPE program gemcitabine, dexamethasone, cisplatin, and etoposide.
  • GEMOX program gemcitabine, and oxaliplatin.
  • GVD regimen gemcitabine, vinorelbine, and doxorubicin.
  • HyperCVAD regimen regimen A: cyclophosphamide, vincristine, doxorubicin, dexamethasone, and/or mesna; regimen B: methotrexate, and cytarabine.
  • ICE protocol ifosfamide, carboplatin, and etoposide.
  • IGEV regimen ifosfamide, gemcitabine, and vinorelbine.
  • MA regimen methotrexate, and cytarabine.
  • MINE regimen mesna, ifosfamide, mitoxantrone, and etoposide.
  • miniBEAM protocol carmustine, etoposide, cytarabine, and mirfalan.
  • NCE program Vinorelbine, Cisplatin, and Etoposide.
  • R 2 Rituximab, and lenalidomide.
  • R- refers to the combination of rituximab and the treatment regimen. Including but not limited to the following:
  • R-BAC regimen rituximab, bendamustine, and cytarabine.
  • R-CDOP regimen rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone.
  • R-CEOP regimen rituximab, cyclophosphamide, etoposide, vincristine, and prednisone.
  • R-CEPP regimen rituximab, cyclophosphamide, etoposide, prednisolone, and procarbazine.
  • R-CHOP regimen rituximab, cyclophosphamide, doxorubicin/epirubicin, vincristine, and prednisone.
  • R-CHOEP regimen rituximab, cyclophosphamide, doxorubicin/epirubicin, vincristine, etoposide, and prednisone.
  • R-COPE regimen rituximab, cyclophosphamide, vincristine, cisplatin, and etoposide.
  • R-CVP regimen rituximab, cyclophosphamide, vincristine, and prednisone.
  • R-DHAP regimen dexamethasone, high-dose cytarabine, and cisplatin.
  • R-DICE regimen rituximab, dexamethasone, ifosfamide, cisplatin, and etoposide.
  • R-EPOCH regimen rituximab, etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin.
  • R-ESHAP regimen rituximab, etoposide, methylprednisolone, high-dose cytarabine, and cisplatin.
  • R-GCVP regimen rituximab, gemcitabine, cyclophosphamide, vincristine, and prednisolone.
  • R-GDP regimen rituximab, gemcitabine, dexamethasone, and cisplatin.
  • R-GDPE regimen rituximab, gemcitabine, dexamethasone, cisplatin, and etoposide.
  • R-GEMOX regimen rituximab, gemcitabine, and oxaliplatin.
  • R-HyperCVAD regimen regimen A: rituximab, cyclophosphamide, vincristine, doxorubicin, dexamethasone, and/or mesna; regimen B: rituximab, methotrexate , And Cytarabine.
  • R-ICE protocol rituximab, ifosfamide, carboplatin, and etoposide.
  • R-MA regimen rituximab, methotrexate, and cytarabine.
  • R-MINE regimen rituximab, mesna, ifosfamide, mitoxantrone, and etoposide.
  • R-NCE regimen rituximab, vinorelbine, cisplatin, and etoposide.
  • V-CAP regimen bortezomib, cyclophosphamide, doxorubicin, and prednisone.
  • VR-CAP regimen bortezomib, rituximab, cyclophosphamide, doxorubicin, and prednisone.
  • R-high-dose cytarabine rituximab and high-dose cytarabine.
  • the prednisolone can also be prednisone, and the two can be used interchangeably.
  • small lymphocytic lymphoma (SLL) and chronic lymphocytic leukemia (CLL) are different manifestations of the same disease.
  • SLL usually has no leukemia-like manifestations, while CLL is mainly involved in bone marrow and peripheral blood. Therefore, the scope of protection for the treatment of small lymphocytic lymphoma (SLL) in this application also includes chronic lymphocytic leukemia (CLL).
  • the chemotherapy regimen belongs to the prior art in the field.
  • Those skilled in the art can easily refer to treatment guidelines in the prior art or relevant medical and pharmacy textbooks (e.g. Chinese Society of Clinical Oncology (CSCO) Lymphoma Diagnosis and Treatment Guidelines 2019 or 2020) to obtain specific content (including but not limited to) chemotherapy regimens (Drugs used, dosage or period of administration).
  • CSCO Chinese Society of Clinical Oncology
  • Drug used, dosage or period of administration drugs used, dosage or period of administration
  • the above examples of the drugs used in the chemotherapy regimen in this application are exemplary.
  • the specific content of the chemotherapy regimen is subject to treatment guidelines or relevant medical and pharmacy textbooks.
  • the hydroxypropyl methyl cellulose is configured as an aqueous solution as a binder.
  • step 3 Transfer the premixed material in step 1) to the wet granulation pot and add the binder obtained in step 2) to start granulation.
  • the prepared soft and wet material is granulated, dried, and mixed with magnesium stearate.
  • the resulting tablets are coated.
  • the compound of formula I is prepared according to the method disclosed in WO2015192760.
  • Administration method Orally once every day (QD administration), continuous administration for 28 days as a treatment cycle.
  • PKT Platelet
  • Hb hemoglobin
  • ALT Alanine aminotransferase
  • AST aspartate aminotransferase
  • HbA1c Glycated hemoglobin
  • LVEF left ventricular ejection fraction
  • ORR objective response rate
  • PFS progression-free survival
  • OS overall survival
  • DCR disease control rate
  • DOR duration of remission
  • the enrolled patients are 22 lymphoma patients, 18 patients can be evaluated for efficacy, including 2 patients with CR and 9 patients with PR (both are the best efficacy).
  • the ORR was 73% (11/15) in patients in the 10 mg/qd and above dose group, and 100% (4/4) in patients in the test dose of 20 mg/qd. It is worth noting that the ORR of follicular lymphoma (FL) in the 10 mg/qd and above dose group is 75% (6/8), and all the two patients with follicular lymphoma in the 20 mg/qd group have PR. Both mantle cell lymphoma patients also all PR, and they were relapsed or refractory patients after treatment with BTK inhibitors.
  • R 2 is the combination of rituximab + lenalidomide; R maintenance is given to patients once every four weeks with rituximab.
  • the ORR was 71% (22/31).
  • DLT dose-limiting toxicity
  • Administration method Oral administration, once a day, 20 mg each time, 28 days of continuous administration is a cycle.
  • the diagnosis report must include cytogenetic test t(11;14) positive and/or immunohistochemical evidence of high expression of cyclin D1;
  • PKT Platelet
  • ALT Alanine aminotransferase
  • AST aspartate aminotransferase
  • HbA1c Glycated hemoglobin
  • Coagulation function activated partial thromboplastin time (APTT), international normalized ratio (INR), prothrombin time (PT) ⁇ 1.5 ⁇ ULN;
  • LVEF left ventricular ejection fraction
  • ORR objective response rate
  • PFS progression-free survival
  • OS overall survival
  • DCR disease control rate
  • DOR duration of remission
  • Administration method Oral administration, once a day, 20 mg each time, 28 days of continuous administration is a cycle.
  • PKT Platelet
  • ALT Alanine aminotransferase
  • AST aspartate aminotransferase
  • Coagulation function activated partial thromboplastin time (APTT), international normalized ratio (INR), prothrombin time (PT) ⁇ 1.5 ⁇ ULN;
  • LVEF left ventricular ejection fraction
  • ORR objective response rate
  • PFS progression-free survival
  • OS overall survival
  • DCR disease control rate
  • DOR duration of remission
  • the curative effect of 20 patients with follicular lymphoma was evaluated.
  • the ORR was 70% (14 cases) and the CR was 10.0% (2 cases).
  • the results show that the compound of formula I has a good therapeutic effect on follicular lymphoma.
  • the compound of formula I has good safety when used in therapy.
  • Method of administration Oral administration, once a day, 20 mg each time, for 21 consecutive days as a cycle.
  • PKT Platelets
  • ALT Alanine aminotransferase
  • AST aspartate aminotransferase
  • Blood coagulation function activated partial thromboplastin time (APTT), international normalized ratio (INR), prothrombin time (PT) ⁇ 1.5 ⁇ ULN;
  • ORR objective response rate
  • PFS progression-free survival
  • OS overall survival
  • DCR disease control rate
  • DOR duration of remission
  • the compound of formula I has a good therapeutic effect on diffuse large B-cell lymphoma. At the same time, the compound of formula I has good safety when used in therapy.
  • Administration method Oral administration, once a day, 20 mg each time, 28 days of continuous medication as a cycle.
  • PKT Platelets
  • Hb hemoglobin
  • ALT Alanine aminotransferase
  • AST aspartate aminotransferase
  • APTT Activated partial thromboplastin time
  • ILR international normalized ratio
  • PT prothrombin time
  • ORR objective response rate
  • PFS progression-free survival
  • OS overall survival
  • DCR disease control rate
  • DOR duration of remission
  • the compound of formula I has a good therapeutic effect on small lymphocytic lymphoma or chronic lymphocytic leukemia. At the same time, the compound of formula I has good safety when used in therapy.

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Abstract

本申请属于医药化学领域，涉及吡啶并[1,2-a]嘧啶酮化合物的治疗淋巴瘤的用途。具体而言，本申请涉及治疗淋巴瘤的吡啶并[1,2-a]嘧啶酮化合物或其药物组合物，吡啶并[1,2-a]嘧啶酮化合物用于治疗淋巴瘤的方法或用途。

Description

吡啶并[1,2-a]嘧啶酮化合物的治疗淋巴瘤的用途
相关申请的引用
本申请要求于2020年02月10日向中华人民共和国国家知识产权局提交的第202010084226.X号中国专利申请、于2020年02月10日向中华人民共和国国家知识产权局提交的第202010084209.6号中国专利申请、于2020年02月10日向中华人民共和国国家知识产权局提交的第202010084222.1号中国专利申请、以及于2020年09月15日向中华人民共和国国家知识产权局提交的第202010967167.0号中国专利申请的优先权和权益，在此将其全部内容以援引的方式整体并入文本中。
技术领域
本申请属于医药化学领域，涉及吡啶并[1,2-a]嘧啶酮化合物的治疗淋巴瘤的用途。
背景技术
PI3K通路是人体癌细胞中最常发生变异的地方，可导致细胞的增殖、活化、放大信号。
PI3K激酶(磷脂酰肌醇3-激酶，phosphatidylinositol-3-kinase，PI3Ks)属于脂质激酶家族，能够磷酸化磷脂酰肌醇的肌醇环3’-OH端，其为一种由调节亚单位p85或p101和催化亚单位p110组成的脂激酶，通过催化磷脂酰肌醇4,5-二磷酸(phosphatidylinositol 4,5-bisphosphate，PIP2)磷酸化为磷脂酰肌醇3,4,5-三磷酸(phosphatidylinositol 3,4,5-trisphosphate，PIP3)而激活下游的Akt等从而对细胞的增殖、生存和代谢等起关键作用。因此，抑制磷酸酯酰肌醇3激酶，可以影响PI3K通路，从而抑制癌细胞的增殖与活化。
肿瘤抑制基因PTEN(phosphatase and tension homolog deleted on chromosome ten)使PIP3去磷酸化生成PIP2，从而实现PI3K/Akt信号通路的负性调节，抑制细胞增殖和促进细胞凋亡。PI3K基因突变和扩增在癌症中频繁发生以及PTEN在癌症中缺失等都提示PI3K与肿瘤发生的密切关系。
WO2015192760公开了一系列作为PI3K抑制剂的化合物，还具体公开了如下结构的式I化合物：
Figure PCTCN2021076423-appb-000001
发明内容
本申请提供用于治疗患者的淋巴瘤的式I化合物、或其药学上可接受的盐：
Figure PCTCN2021076423-appb-000002
另一方面，本申请提供式I化合物、或其药学上可接受的盐在制备治疗患者的淋巴瘤的药物中的用途。
另一方面，本申请式I化合物、或其药学上可接受的盐在治疗患者的淋巴瘤中的用途。
另一方面，本申请提供一种治疗患者的淋巴瘤的方法，所述方法包括向患者给予式I化合物、或其药 学上可接受的盐。
在本申请的一些方案中，本申请式I化合物、或其药学上可接受的盐是作为单一活性剂使用。
在本申请的一些方案中，本申请式I化合物、或其药学上可接受的盐可处于包含治疗有效量的式I化合物、或其药学上可接受的盐的药物组合物的形式。
另一方面，本申请提供包含式I化合物、或其药学上可接受的盐作为活性成分的用于治疗淋巴瘤的药物组合物。
发明详述
淋巴瘤
在本申请的一些方案中，所述淋巴瘤选自霍奇金淋巴瘤(HL)和非霍奇金淋巴瘤(NHL)。
在本申请的一些方案中，所述淋巴瘤选自B细胞淋巴瘤或T细胞淋巴瘤。在本申请的一些方案中，所述淋巴瘤选自经典型霍奇金淋巴瘤(CHL)、结节性淋巴细胞霍奇金淋巴瘤、套细胞淋巴瘤(MCL)、滤泡性淋巴瘤(FL)、弥漫大B细胞淋巴瘤(DLBCL)、小淋巴细胞淋巴瘤(SLL)或慢性淋巴细胞白血病(CLL)。
在本申请的一些方案中，所述非霍奇金淋巴瘤选自B细胞淋巴瘤或T细胞淋巴瘤。在本申请的一些方案中，所述非霍奇金淋巴瘤选自套细胞淋巴瘤(MCL)、滤泡性淋巴瘤(FL)、弥漫大B细胞淋巴瘤(DLBCL)、小淋巴细胞淋巴瘤(SLL)或慢性淋巴细胞白血病(CLL)。
在本申请的一些方案中，所述套细胞淋巴瘤选自经典型套细胞淋巴瘤、白血病样非淋巴结性套细胞淋巴瘤、或原位套细胞瘤变。
在本申请的一些方案中，所述弥漫大B细胞淋巴瘤选自生发中心B细胞样(Germinal Center B-cell-like,GCB)弥漫大B细胞淋巴瘤、激活B细胞样(Activated B-cell-like,ABC)弥漫大B细胞淋巴瘤、或第三型(Type 3)弥漫大B细胞淋巴瘤。
在本申请的一些方案中，所述霍奇金淋巴瘤选自经典型霍奇金淋巴瘤或结节性淋巴细胞霍奇金淋巴瘤。在本申请的一些方案中，所述经典型霍奇金淋巴瘤选自结节硬化型、富于淋巴细胞型、混合细胞型和淋巴细胞消减型。
在本申请的一些方案中，所述淋巴瘤的患者已接受过一种或两种以上在先治疗方案的治疗。在本申请的一些方案中，所述淋巴瘤的患者已接受过一种、两种、三种、四种、或五种在先治疗方案的治疗。
在本申请的一些方案中，所述淋巴瘤的患者已接受过一线、二线或三线及以上在先治疗方案的治疗的淋巴瘤的患者。
在本申请的一些方案中，所述淋巴瘤选自复发或难治性淋巴瘤。
在本申请的一些方案中，所述淋巴瘤的患者已接受在先治疗方案治疗达到客观缓解后，疾病再次发生，或者所述淋巴瘤的患者对于在先治疗方案无客观缓解。在本申请的一些方案中，所述无客观缓解指治疗期间疾病稳定或疾病进展。
在本申请的一些方案中，所述淋巴瘤的患者是已接受过在先治疗方案治疗的复发或难治性淋巴瘤患者。
在本申请的一些方案中，所述淋巴瘤的患者是CD20阳性(CD20+)、CD30阳性(CD30+)、CD38阳性(CD38+)和/或ZAP70阳性(ZAP70+)的淋巴瘤的患者。
在本申请的一些方案中，所述淋巴瘤的患者是CD20阳性(CD20+)的淋巴瘤的患者。
在本申请的一些方案中，所述淋巴瘤的患者是已接受过利妥昔单抗和/或BTK抑制剂治疗的淋巴瘤患者。
在本申请的一些方案中，所述淋巴瘤的患者是已接受过利妥昔单抗和/或BTK抑制剂治疗的复发或难治性淋巴瘤患者。
在本申请的一些方案中，所述淋巴瘤的患者是CD20阳性(CD20+)，并且是已接受过利妥昔单抗治疗的复发或难治性淋巴瘤的患者。
在本申请的一些方案中，所述在先治疗方案包括药物治疗、放疗、或造血干细胞移植。
在本申请的一些方案中，所述药物治疗包括干扰素治疗、化疗、或靶向药物治疗。
在本申请的一些方案中，所述靶向药物治疗包括抗CD20抗体、抗CD30抗体、或BTK抑制剂。
在本申请的一些方案中，所述抗CD20抗体包括利妥昔单抗、CHO-H01、ocaratuzumab、替伊莫单抗(ibritumomab tiuxetan)、乌妥昔单抗(ublituximab)、或奥比妥珠单抗(obinutuzumab)。
在本申请的一些方案中，所述抗CD30抗体可包括brentuximab vedotin。
在本申请的一些方案中，所述BTK抑制剂包括伊布替尼(ibrutinib)、ICP-022、阿卡替尼(acalabrutinib)、或泽布替尼(zanubrutinib)。
在本申请的一些方案中，所述化疗所用药物包括环磷酰胺、异环磷酰胺、长春新碱、泼尼松、泼尼松龙、多柔比星、阿霉素、表阿霉素、地塞米松、甲氨蝶呤、阿糖胞苷、卡铂、顺铂、苯达莫司汀、氟达拉滨、米托蒽醌、依托泊苷、甲基苄肼、吉西他滨、甲泼尼龙、甲泼尼龙琥珀酸钠、美司那、奥沙利铂、5-氟尿嘧啶、苯丁酸氮芥、或阿扎胞苷(azacitidine)。
在本申请的一些方案中，所述靶向药物包括硼替佐米、利妥昔单抗、CHO-H01、ocaratuzumab、替伊莫单抗(ibritumomab tiuxetan)、乌妥昔单抗(ublituximab)、奥比妥珠单抗(obinutuzumab)、brentuximab vedotin、伊布替尼(ibrutinib)、ICP-022、阿卡替尼(acalabrutinib)、泽布替尼(zanubrutinib)、哌柏西利(palbociclib)、abemaciclib、替西罗莫司(temsirolimus)、依维莫司(everolimus)、卡非佐米(carfilzomib)、伊沙佐米(ixazomib)、尼拉帕利(niraparib)、umbralisib、来那度胺(lenalidomide)、维纳妥拉(venetoclax)、伏立诺他(vorinostat)、BR-101801、tazemetostat、或abexinostat。
在本申请的一些方案中，所述药物治疗所用药物包括干扰素、环磷酰胺、异环磷酰胺、长春新碱、长春瑞滨、泼尼松、泼尼松龙、多柔比星、硼替佐米、阿霉素、表阿霉素、博来霉素、地塞米松、甲氨蝶呤、阿糖胞苷、卡铂、顺铂、苯达莫司汀、氟达拉滨、米托蒽醌、依托泊苷、甲基苄肼、吉西他滨、卡氮芥、甲泼尼龙、甲泼尼龙琥珀酸钠、美司那、奥沙利铂、5-氟尿嘧啶、苯丁酸氮芥、达卡巴嗪、利妥昔单抗、CHO-H01、ocaratuzumab、替伊莫单抗(ibritumomab tiuxetan)、乌妥昔单抗(ublituximab)、奥比妥珠单抗(obinutuzumab)、brentuximab vedotin、伊布替尼(ibrutinib)、ICP-022、阿卡替尼(acalabrutinib)、泽布替尼(zanubrutinib)、哌柏西利(palbociclib)、abemaciclib、替西罗莫司(temsirolimus)、依维莫司(everolimus)、卡非佐米(carfilzomib)、伊沙佐米(ixazomib)、尼拉帕利(niraparib)、umbralisib、来那度胺(lenalidomide)、维纳妥拉(venetoclax)、伏立诺他(vorinostat)、阿扎胞苷(azacitidine)、BR-101801、tazemetostat、或abexinostat；优选地，所述药物治疗所用药物包括用环磷酰胺、异环磷酰胺、长春新碱、泼尼松、泼尼松龙、多柔比星、硼替佐米、阿霉素、表阿霉素、地塞米松、甲氨蝶呤、阿糖胞苷、卡铂、顺铂、苯达莫司汀、氟达拉滨、米托蒽醌、依托泊苷、甲基苄肼、吉西他滨、甲泼尼龙、甲泼尼龙琥珀酸钠、美司那、奥沙利铂、利妥昔单抗、brentuximab vedotin、伊布替尼、ICP-022、阿卡替尼、或泽布替尼；更优选地，所述药物治疗所用药物包括利妥昔单抗、伊布替尼、ICP-022、阿卡替尼、或泽布替尼。
在本申请的一些方案中，所述化疗的方案包括ABVD方案、AVD方案、B方案、BA方案、BAC方案、BEACOPPesc方案、CDOP方案、CEOP方案、CEPP方案、CHOP方案、CHOEP方案、CIFOX方案、COP方案、COPE方案、CVP方案、DA-EPOCH方案、DHAP方案、DICE方案、EPOCH方案、ESHAP方案、FC方案、FM方案、GCVP方案、GDP方案、GDPE方案、GEMOX方案、GVD方案、HyperCVAD方案、ICE方案、IGEV方案、MA方案、MINE方案、miniBEAM方案、NCE方案、Stanford V方案、VCAP方案、高剂量阿糖胞苷方案或上述方案与利妥昔单抗(当用于联合治疗时，可简称为“R”)联用；优选地，所述化疗的方案包括ABVD方案、AVD方案、BEACOPPesc方案、BR方案、CDOP方案、CEOP方案、CEPP方案、CHOP方案、CHOEP方案、CIFOX方案、COP方案、CVP方案、DA-EPOCH-R方案、DHAP方案、DICE方案、EPOCH方案、ESHAP方案、FCR方案、FMR方案、GDP方案、GDPE方案、GEMOX方案、GVD方案、ICE方案、IGEV方案、MINE方案、NCE方案、miniBEAM方案、R 2、R-BAC方案、R-CDOP方案、R-CEOP方案、R-CEPP方案、R-CHOP方案、R-CHOEP方案、R-COPE方案、R-CVP方案、R-DHAP方案、R-DICE方案、R-EPOCH方案、R-ESHAP方案、R-GCVP方案、R-GDP方案、R-HyperCVAD方案、R-GDPE方案、R-GEMOX方案、R-ICE方案、R-MA方案、R-MINE方案、R-NCE方案、Stanford  V方案、R-高剂量阿糖胞苷方案或VR-CAP方案。
在本申请的一些方案中，所述放疗选自全淋巴照射(TLI)和次全淋巴照射(STLI)。在本申请的一些方案中，所述放疗包括受累野照射(IFRT)、累及淋巴结(INRT)或累及部位照射(ISRT)。
在本申请的一些方案中，所述造血干细胞移植包括自体造血干细胞移植(Autologous Hematopoietic Stem Cell Transplantation)、或异体造血干细胞移植(Allogeneic Hematopoietic Stem Cell)。
在本申请的一些方案中，所述淋巴瘤选自霍奇金淋巴瘤和非霍奇金淋巴瘤；任选地，所述淋巴瘤的患者已接受过一种以上在先治疗方案的治疗；任选地，所述淋巴瘤选自复发或难治性淋巴瘤；任选地，所述淋巴瘤的患者已接受在先治疗方案治疗达到客观缓解后，疾病再次发生，或者所述淋巴瘤的患者对于在先治疗方案无客观缓解；任选地，所述淋巴瘤的患者是CD20阳性(CD20+)、CD30阳性(CD30+)、CD38阳性(CD38+)和/或ZAP70阳性(ZAP70+)的淋巴瘤的患者；任选地，所述先治疗方案包括药物治疗、放疗、或造血干细胞移植。
霍奇金淋巴瘤(HL)
在本申请的一些方案中，所述淋巴瘤选自霍奇金淋巴瘤。
在本申请的一些方案中，所述霍奇金淋巴瘤选自经典型霍奇金淋巴瘤或结节性淋巴细胞霍奇金淋巴瘤。在本申请的一些方案中，所述经典型霍奇金淋巴瘤选自结节硬化型、富于淋巴细胞型、混合细胞型和淋巴细胞消减型。
在本申请的一些方案中，所述霍奇金淋巴瘤的患者已接受过一种或两种以上在先治疗方案的治疗。在本申请的一些方案中，所述霍奇金淋巴瘤的患者已接受过一种、两种、三种、四种、或五种在先治疗方案的治疗。
在本申请的一些方案中，所述霍奇金淋巴瘤的患者已接受过一线、二线或三线及以上在先治疗方案的治疗的霍奇金淋巴瘤的患者。
在本申请的一些方案中，所述霍奇金淋巴瘤的患者已接受在先治疗方案治疗达到客观缓解后，疾病再次发生，或者所述霍奇金淋巴瘤的患者对于在先治疗方案无客观缓解。在本申请的一些方案中，所述无客观缓解指治疗期间疾病稳定或疾病进展。
在本申请的一些方案中，所述霍奇金淋巴瘤的患者是已接受过在先治疗方案治疗的复发或难治性霍奇金淋巴瘤患者。
在本申请的一些方案中，所述霍奇金淋巴瘤的患者是CD20阳性(CD20+)或CD30阳性(CD30+)的霍奇金淋巴瘤的患者。
在本申请的一些方案中，所述霍奇金淋巴瘤的患者是已接受过利妥昔单抗和/或BTK抑制剂治疗的淋巴瘤患者。
在本申请的一些方案中，所述霍奇金淋巴瘤的患者是已接受过利妥昔单抗和/或BTK抑制剂治疗的复发或难治性霍奇金淋巴瘤患者。
在本申请的一些方案中，所述霍奇金淋巴瘤的患者是CD20阳性(CD20+)，并且是已接受过利妥昔单抗治疗的复发或难治性霍奇金淋巴瘤的患者。
在本申请的一些方案中，所述霍奇金淋巴瘤的在先治疗方案包括药物治疗、放疗、或造血干细胞移植。
在本申请的一些方案中，所述霍奇金淋巴瘤的在先治疗方案的药物治疗包括干扰素治疗、化疗、或靶向药物治疗。
在本申请的一些方案中，所述霍奇金淋巴瘤的在先治疗方案的靶向药物治疗包括抗CD20抗体、抗CD30抗体、或BTK抑制剂。
在本申请的一些方案中，所述霍奇金淋巴瘤的在先治疗方案的抗CD20抗体包括利妥昔单抗、CHO-H01、ocaratuzumab、替伊莫单抗、乌妥昔单抗、或奥比妥珠单抗。
在本申请的一些方案中，所述霍奇金淋巴瘤的在先治疗方案的抗CD30抗体包括brentuximab vedotin。
在本申请的一些方案中，所述霍奇金淋巴瘤的在先治疗方案的BTK抑制剂包括伊布替尼、ICP-022、 阿卡替尼、或泽布替尼。
在本申请的一些方案中，所述霍奇金淋巴瘤的在先治疗方案的化疗所用药物包括环磷酰胺、异环磷酰胺、长春新碱、泼尼松、泼尼松龙、多柔比星、阿霉素、表阿霉素、地塞米松、甲氨蝶呤、阿糖胞苷、卡铂、顺铂、苯达莫司汀、氟达拉滨、米托蒽醌、依托泊苷、甲基苄肼、吉西他滨、甲泼尼龙琥珀酸钠、美司那、奥沙利铂、5-氟尿嘧啶、或阿扎胞苷。
在本申请的一些方案中，所述霍奇金淋巴瘤的在先治疗方案的靶向药物包括brentuximab vedotin、硼替佐米、利妥昔单抗、CHO-H01、ocaratuzumab、替伊莫单抗、乌妥昔单抗、奥比妥珠单抗、伊布替尼、ICP-022、阿卡替尼、泽布替尼、哌柏西利、abemaciclib、替西罗莫司、依维莫司、卡非佐米、伊沙佐米、尼拉帕利、umbralisib、来那度胺、维纳妥拉、伏立诺他、BR-101801、tazemetostat或abexinostat。
在本申请的一些方案中，所述霍奇金淋巴瘤的在先治疗方案的药物治疗所用药物包括干扰素、环磷酰胺、异环磷酰胺、长春新碱、长春瑞滨、泼尼松、泼尼松龙、多柔比星、硼替佐米、阿霉素、表阿霉素、博来霉素、地塞米松、甲氨蝶呤、阿糖胞苷、卡铂、顺铂、苯达莫司汀、氟达拉滨、米托蒽醌、依托泊苷、甲基苄肼、吉西他滨、卡氮芥、甲泼尼龙、甲泼尼龙琥珀酸钠、美司那、奥沙利铂、5-氟尿嘧啶、达卡巴嗪、利妥昔单抗、CHO-H01、ocaratuzumab、替伊莫单抗、乌妥昔单抗、奥比妥珠单抗、brentuximab vedotin、伊布替尼、ICP-022、阿卡替尼、泽布替尼、哌柏西利、abemaciclib、替西罗莫司、依维莫司、卡非佐米、伊沙佐米、尼拉帕利、umbralisib、来那度胺、维纳妥拉、伏立诺他、阿扎胞苷、BR-101801、tazemetostat、或abexinostat；优选地，所述药物治疗所用药物包括用环磷酰胺、异环磷酰胺、长春新碱、泼尼松、泼尼松龙、多柔比星、硼替佐米、阿霉素、表阿霉素、地塞米松、甲氨蝶呤、阿糖胞苷、卡铂、顺铂、苯达莫司汀、氟达拉滨、米托蒽醌、依托泊苷、甲基苄肼、吉西他滨、甲泼尼龙、甲泼尼龙琥珀酸钠、美司那、奥沙利铂、利妥昔单抗、brentuximab vedotin、伊布替尼、ICP-022、阿卡替尼、或泽布替尼；更优选地，所述药物治疗所用药物包括利妥昔单抗、伊布替尼、ICP-022、阿卡替尼、或泽布替尼。
在本申请的一些方案中，所述霍奇金淋巴瘤的在先治疗的化疗方案包括ABVD方案、AVD方案、BEACOPPesc方案、CHOP方案、CVP方案、DHAP方案、DICE方案、EPOCH方案、GDP方案、GVD方案、ICE方案、IGEV方案、MINE方案、miniBEAM方案、Stanford V方案。
在本申请的一些方案中，所述造血干细胞移植包括自体造血干细胞移植、或异体造血干细胞移植。
在本申请的一些方案中，所述放疗选自全淋巴照射(TLI)和次全淋巴照射(STLI)。在本申请的一些方案中，所述放疗包括受累野照射(IFRT)、累及淋巴结(INRT)或累及部位照射(ISRT)。
在本申请的一些方案中，所述霍奇金淋巴瘤选自复发或难治性霍奇金淋巴瘤；任选地，所述霍奇金淋巴瘤的患者已接受过一种或两种以上在先治疗方案的治疗；任选地，所述霍奇金淋巴瘤的患者已接受在先治疗方案治疗达到客观缓解后，疾病再次发生，或者所述霍奇金淋巴瘤的患者对于在先治疗方案无客观缓解；任选地，所述霍奇金淋巴瘤的患者是CD20阳性或CD30阳性的霍奇金淋巴瘤的患者。任选地，所述霍奇金淋巴瘤的在先治疗方案包括药物治疗、放疗、或造血干细胞移植。
套细胞淋巴瘤(MCL)
在本申请的一些方案中，所述淋巴瘤或非霍奇金淋巴瘤选自套细胞淋巴瘤。
在本申请的一些方案中，所述套细胞淋巴瘤选自经典型套细胞淋巴瘤、白血病样非淋巴结性套细胞淋巴瘤、或原位套细胞瘤变。
在本申请的一些方案中，所述套细胞淋巴瘤选自复发或难治性套细胞淋巴瘤。
在本申请的一些方案中，所述套细胞淋巴瘤的患者已接受过一种或两种以上在先治疗方案的治疗。在本申请的一些方案中，所述套细胞淋巴瘤的患者已接受过一种、两种、三种、四种、或五种在先治疗方案的治疗。
在本申请的一些方案中，所述套细胞淋巴瘤的患者是已接受过一线、二线或三线及以上在先治疗方案的治疗的套细胞淋巴瘤的患者。
在本申请的一些方案中，所述套细胞淋巴瘤的患者已接受在先治疗方案治疗达到客观缓解后，疾病再次发生，或者所述套细胞淋巴瘤的患者对于在先治疗方案无客观缓解。在本申请的一些方案中，所述无客 观缓解指治疗期间疾病稳定或疾病进展。
在本申请的一些方案中，所述套细胞淋巴瘤的患者是既往接受过≥1线但不超过4线的系统治疗，最近接受的治疗方案确认无客观缓解(治疗期间疾病稳定或疾病进展)，或在治疗后发生疾病进展的套细胞淋巴瘤的患者。
在本申请的一些方案中，所述套细胞淋巴瘤的患者是已接受过在先治疗方案治疗的复发或难治性套细胞淋巴瘤患者。
在本申请的一些方案中，所述套细胞淋巴瘤的患者是CD20阳性(CD20+)的套细胞淋巴瘤的患者。
在本申请的一些方案中，所述套细胞淋巴瘤的患者是已接受过利妥昔单抗和/或BTK抑制剂治疗的套细胞淋巴瘤患者。
在本申请的一些方案中，所述套细胞淋巴瘤的患者是已接受过利妥昔单抗和/或BTK抑制剂治疗的复发或难治性套细胞淋巴瘤患者。
在本申请的一些方案中，所述套细胞淋巴瘤的患者是CD20阳性(CD20+)，并且是已接受过利妥昔单抗治疗的复发或难治性套细胞淋巴瘤的患者。
在本申请的一些方案中，所述套细胞淋巴瘤的在先治疗方案包括药物治疗、放疗、或造血干细胞移植。
在本申请的一些方案中，所述套细胞淋巴瘤的在先治疗方案的药物治疗包括干扰素治疗、化疗、或靶向药物治疗。
在本申请的一些方案中，所述套细胞淋巴瘤的在先治疗方案的靶向药物治疗包括抗CD20抗体或BTK抑制剂。
在本申请的一些方案中，所述套细胞淋巴瘤的在先治疗方案的抗CD20抗体包括利妥昔单抗、CHO-H01、ocaratuzumab、替伊莫单抗、乌妥昔单抗、或奥比妥珠单抗。
在本申请的一些方案中，所述套细胞淋巴瘤的在先治疗方案的BTK抑制剂包括伊布替尼、ICP-022、阿卡替尼、或泽布替尼。
在本申请的一些方案中，所述套细胞淋巴瘤的在先治疗方案的化疗所用药物包括环磷酰胺、异环磷酰胺、长春新碱、泼尼松、泼尼松龙、多柔比星、阿霉素、表阿霉素、地塞米松、甲氨蝶呤、阿糖胞苷、卡铂、顺铂、苯达莫司汀、氟达拉滨、米托蒽醌、依托泊苷、甲基苄肼、吉西他滨、甲泼尼龙、甲泼尼龙琥珀酸钠、美司那、奥沙利铂、5-氟尿嘧啶、或阿扎胞苷。
在本申请的一些方案中，所述套细胞淋巴瘤的在先治疗方案的靶向药物包括硼替佐米、利妥昔单抗、CHO-H01、ocaratuzumab、替伊莫单抗、乌妥昔单抗、奥比妥珠单抗、伊布替尼、ICP-022、阿卡替尼、泽布替尼、哌柏西利、abemaciclib、替西罗莫司、依维莫司、卡非佐米、伊沙佐米、尼拉帕利、umbralisib、来那度胺、维纳妥拉、伏立诺他、BR-101801、tazemetostat、或abexinostat。
在本申请的一些方案中，所述套细胞淋巴瘤的在先治疗方案的药物治疗所用药物包括环磷酰胺、异环磷酰胺、长春新碱、泼尼松、泼尼松龙、多柔比星、硼替佐米、阿霉素、表阿霉素、地塞米松、甲氨蝶呤、阿糖胞苷、卡铂、顺铂、苯达莫司汀、氟达拉滨、米托蒽醌、依托泊苷、甲基苄肼、吉西他滨、甲泼尼龙、甲泼尼龙琥珀酸钠、美司那、奥沙利铂、5-氟尿嘧啶、利妥昔单抗、CHO-H01、ocaratuzumab、替伊莫单抗、乌妥昔单抗、奥比妥珠单抗、伊布替尼、ICP-022、阿卡替尼、泽布替尼、哌柏西利、abemaciclib、替西罗莫司、依维莫司、苯达莫司汀、长春新碱、硼替佐米、卡非佐米、伊沙佐米、氟达拉滨、尼拉帕利、umbralisib、来那度胺、维纳妥拉、或abexinostat；优选地，药物治疗所用药物包括环磷酰胺、异环磷酰胺、长春新碱、泼尼松、泼尼松龙、多柔比星、硼替佐米、阿霉素、表阿霉素、地塞米松、甲氨蝶呤、阿糖胞苷、卡铂、顺铂、苯达莫司汀、氟达拉滨、米托蒽醌、依托泊苷、甲基苄肼、吉西他滨、甲泼尼龙、甲泼尼龙琥珀酸钠、美司那、奥沙利铂、5-氟尿嘧啶、利妥昔单抗、伊布替尼、阿卡替尼、ICP-022、或泽布替尼；更优选地，所述药物治疗所用药物包括利妥昔单抗、伊布替尼、ICP-022、阿卡替尼、或泽布替尼。
在本申请的一些方案中，所述套细胞淋巴瘤的在先治疗的化疗方案包括B方案、CHOP方案、CIFOX方案、COP方案、DHAP方案、EPOCH方案、FC方案、FM方案、BAC方案、CHOP方案、HyperCVAD方案、ICE方案、MA方案、VCAP方案、高剂量阿糖胞苷方案或上述方案与利妥昔单抗联用；优选地， 所述化疗方案包括BR方案、CHOP方案、COP方案、DHAP方案、FCR方案、FMR方案、R-BAC方案、R-CHOP方案、R-DHAP方案、R-HyperCVAD方案、R-ICE方案、R-MA方案、R-高剂量阿糖胞苷方案或VR-CAP方案。
在本申请的一些方案中，所述造血干细胞移植包括自体造血干细胞移植、或异体造血干细胞移植。
在本申请的一些方案中，所述放疗选自全淋巴照射(TLI)和次全淋巴照射(STLI)。在本申请的一些方案中，所述放疗包括受累野照射(IFRT)、累及淋巴结(INRT)或累及部位照射(ISRT)。
在本申请的一些方案中，所述套细胞淋巴瘤的患者的诊断报告包括形态学和细胞周期蛋白D1(Cyclin D1)免疫组化阳性或t(11：14)的证据。
在本申请的一些方案中，所述套细胞淋巴瘤的患者的细胞遗传学检测t(11；14)阳性和/或免疫组织化学细胞周期蛋白D1阳性(高表达的)。
在本申请的一些方案中，所述套细胞淋巴瘤选自复发或难治性套细胞淋巴瘤；任选地，所述套细胞淋巴瘤的患者已接受过一种或两种以上在先治疗方案的治疗；任选地，所述套细胞淋巴瘤的患者已接受在先治疗方案治疗达到客观缓解后，疾病再次发生，或者所述套细胞淋巴瘤的患者对于在先治疗方案无客观缓解；任选地，所述套细胞淋巴瘤的患者是CD20阳性的套细胞淋巴瘤的患者；任选地，所述套细胞淋巴瘤的在先治疗方案包括药物治疗、放疗、或造血干细胞移植；任选地，所述套细胞淋巴瘤的患者的诊断报告包括形态学和细胞周期蛋白D1免疫组化阳性或t(11：14)的证据。
在本申请的一些方案中，所述套细胞淋巴瘤选自复发或难治性套细胞淋巴瘤；任选地，所述套细胞淋巴瘤的患者已接受过一种或两种以上在先治疗方案的治疗；任选地，所述套细胞淋巴瘤的患者已接受在先治疗方案治疗达到客观缓解后，疾病再次发生，或者所述套细胞淋巴瘤的患者对于在先治疗方案无客观缓解；任选地，所述套细胞淋巴瘤的患者是CD20阳性的套细胞淋巴瘤的患者；任选地，所述套细胞淋巴瘤的在先治疗方案包括药物治疗、放疗、或造血干细胞移植；任选地，所述套细胞淋巴瘤的患者的细胞遗传学检测t(11；14)阳性和/或免疫组织化学细胞周期蛋白D1阳性(高表达的)。
滤泡性淋巴瘤(FL)
在本申请的一些方案中，所述淋巴瘤或非霍奇金淋巴瘤选自滤泡性淋巴瘤。
在本申请的一些方案中，所述滤泡性淋巴瘤选自复发或难治性滤泡性淋巴瘤。
在本申请的一些方案中，所述滤泡性淋巴瘤的患者已接受过一种或两种以上在先治疗方案的治疗。在本申请的一些方案中，所述滤泡性淋巴瘤的患者已接受过一种、两种、三种、四种、或五种在先治疗方案的治疗。
在本申请的一些方案中，所述滤泡性淋巴瘤的患者是已接受过一线、二线或三线及以上在先治疗方案的治疗的滤泡性淋巴瘤的患者。
在本申请的一些方案中，所述滤泡性淋巴瘤的患者是既往接受过≥2线系统性治疗，且至少有1种方案含利妥昔单抗的复发或难治性滤泡性淋巴瘤的患者。
在本申请的一些方案中，所述滤泡性淋巴瘤的患者已接受在先治疗方案治疗达到客观缓解后，疾病再次发生，或者所述滤泡性淋巴瘤的患者对于在先治疗方案无客观缓解。在本申请的一些方案中，所述无客观缓解指治疗期间疾病稳定或疾病进展。
在本申请的一些方案中，所述滤泡性淋巴瘤的患者是已接受过在先治疗方案的复发或难治性滤泡性淋巴瘤患者。
在本申请的一些方案中，所述滤泡性淋巴瘤的患者是CD20阳性(CD20+)的滤泡性淋巴瘤的患者。
在本申请的一些方案中，所述滤泡性淋巴瘤的患者是已接受过利妥昔单抗和/或BTK抑制剂治疗的滤泡性淋巴瘤患者。
在本申请的一些方案中，所述滤泡性淋巴瘤的患者是已接受过利妥昔单抗和/或BTK抑制剂治疗的复发或难治性淋巴瘤患者。
在本申请的一些方案中，所述滤泡性淋巴瘤的患者是CD20阳性(CD20+)，并且是已接受过利妥昔单 抗治疗的复发或难治性滤泡性淋巴瘤的患者。
在本申请的一些方案中，所述滤泡性淋巴瘤的在先治疗方案包括药物治疗、放疗、或造血干细胞移植。
在本申请的一些方案中，所述滤泡性淋巴瘤的在先治疗方案的药物治疗包括干扰素治疗、化疗、或靶向药物治疗。
在本申请的一些方案中，所述滤泡性淋巴瘤的在先治疗方案的靶向药物治疗包括抗CD20抗体、或BTK抑制剂。
在本申请的一些方案中，所述滤泡性淋巴瘤的在先治疗方案的抗CD20抗体包括利妥昔单抗、CHO-H01、ocaratuzumab、替伊莫单抗、乌妥昔单抗、或奥比妥珠单抗。
在本申请的一些方案中，所述滤泡性淋巴瘤的在先治疗方案的BTK抑制剂包括伊布替尼、ICP-022、阿卡替尼、或泽布替尼。
在本申请的一些方案中，所述滤泡性淋巴瘤的在先治疗方案的化疗所用药物包括环磷酰胺、异环磷酰胺、长春新碱、泼尼松、泼尼松龙、多柔比星、阿霉素、表阿霉素、地塞米松、甲氨蝶呤、阿糖胞苷、卡铂、顺铂、苯达莫司汀、氟达拉滨、米托蒽醌、依托泊苷、甲基苄肼、吉西他滨、甲泼尼龙、甲泼尼龙琥珀酸钠、美司那、奥沙利铂、5-氟尿嘧啶、或阿扎胞苷。
在本申请的一些方案中，所述滤泡性淋巴瘤的在先治疗方案的靶向药物包括硼替佐米、利妥昔单抗、CHO-H01、ocaratuzumab、替伊莫单抗、乌妥昔单抗、奥比妥珠单抗、伊布替尼、ICP-022、阿卡替尼、泽布替尼、哌柏西利、abemaciclib、替西罗莫司、依维莫司、卡非佐米、伊沙佐米、尼拉帕利、umbralisib、来那度胺、维纳妥拉、伏立诺他、BR-101801、tazemetostat、或abexinostat。
在本申请的一些方案中，所述滤泡性淋巴瘤的在先治疗方案的药物治疗所用药物包括环磷酰胺、异环磷酰胺、长春新碱、泼尼松、泼尼松龙、多柔比星、硼替佐米、阿霉素、表阿霉素、地塞米松、甲氨蝶呤、阿糖胞苷、卡铂、顺铂、苯达莫司汀、氟达拉滨、米托蒽醌、依托泊苷、甲基苄肼、吉西他滨、长春瑞滨、甲泼尼龙、甲泼尼龙琥珀酸钠、美司那、奥沙利铂、5-氟尿嘧啶、干扰素、利妥昔单抗、CHO-H01、ocaratuzumab、替伊莫单抗、乌妥昔单抗、奥比妥珠单抗、伊布替尼、阿卡替尼、ICP-022、泽布替尼、伏立诺他、阿扎胞苷、BR-101801、umbralisib、tazemetostat或来那度胺；优选地，所述滤泡性淋巴瘤的在先治疗方案的药物治疗所用药物包括环磷酰胺、异环磷酰胺、长春新碱、泼尼松、泼尼松龙、多柔比星、硼替佐米、阿霉素、表阿霉素、地塞米松、甲氨蝶呤、阿糖胞苷、卡铂、顺铂、苯达莫司汀、氟达拉滨、米托蒽醌、依托泊苷、甲基苄肼、吉西他滨、甲泼尼龙、甲泼尼龙琥珀酸钠、美司那、奥沙利铂、5-氟尿嘧啶、干扰素、利妥昔单抗、伊布替尼、阿卡替尼、ICP-022、泽布替尼、或来那度胺；更优选地，所述滤泡性淋巴瘤的先治疗方案的药物治疗所用药物包括利妥昔单抗、伊布替尼、ICP-022、阿卡替尼、泽布替尼、苯达莫司汀、或来那度胺。
在本申请的一些方案中，所述滤泡性淋巴瘤的先治疗方案的化疗方案包括B方案、CDOP方案、CHOP方案、CVP方案、DHAP方案、DICE方案、EPOCH方案、ICE方案、GEMOX方案、NCE方案、或上述方案与利妥昔单抗联用；优选地，所述化疗方案包括BR方案、CHOP方案、GEMOX方案、R-CDOP方案、R-CHOP方案、R-CVP方案、R-DHAP方案、R-DICE方案、R-EPOCH方案、R-GEMOX方案、R-ICE方案、或R-NCE方案。
在本申请的一些方案中，所述造血干细胞移植包括自体造血干细胞移植、或异体造血干细胞移植。
在本申请的一些方案中，所述放疗选自全淋巴照射(TLI)和次全淋巴照射(STLI)。在本申请的一些方案中，所述放疗包括受累野照射(IFRT)、累及淋巴结(INRT)或累及部位照射(ISRT)。
在本申请的一些方案中，所述滤泡性淋巴瘤的患者是经组织病理学确诊的1-3a级滤泡性淋巴瘤患者。
在本申请的一些方案中，所述滤泡性淋巴瘤的患者的诊断报告包括t(14；18)易位或Bcl-2蛋白过表达。
在本申请的一些方案中，所述滤泡性淋巴瘤选自复发或难治性滤泡性淋巴瘤；任选地，所述滤泡性淋巴瘤的患者已接受过一种或两种以上在先治疗方案的治疗；任选地，所述滤泡性淋巴瘤的患者已接受在先治疗方案治疗达到客观缓解后，疾病再次发生，或者所述滤泡性淋巴瘤的患者对于在先治疗方案无客观缓 解；任选地，所述滤泡性淋巴瘤的患者是CD20阳性的滤泡性淋巴瘤的患者；任选地，所述滤泡性淋巴瘤的在先治疗方案包括药物治疗、放疗、或造血干细胞移植；任选地，所述滤泡性淋巴瘤的患者是经组织病理学确诊的1-3a级滤泡性淋巴瘤患者；任选地，所述滤泡性淋巴瘤的患者的诊断报告包括t(14；18)易位或Bcl-2蛋白过表达。
弥漫大B细胞淋巴瘤(DLBCL)
在本申请的一些方案中，所述淋巴瘤或非霍奇金淋巴瘤选自弥漫大B细胞淋巴瘤。
在本申请的一些方案中，所述弥漫大B细胞淋巴瘤选自复发或难治性弥漫大B细胞淋巴瘤。
在本申请的一些方案中，所述弥漫大B细胞淋巴瘤的患者已接受过一种或两种以上在先治疗方案的治疗。在本申请的一些方案中，所述弥漫大B细胞淋巴瘤的患者已接受过一种、两种、三种、四种、或五种在先治疗方案的治疗。
在本申请的一些方案中，所述弥漫大B细胞淋巴瘤的患者已接受过一线、二线或三线及以上在先治疗方案的治疗。
在本申请的一些方案中，所述弥漫大B细胞淋巴瘤的患者既往至少接受过2线(包括2线、3线、4线或5线)全身系统性治疗方案治疗。
在本申请的一些方案中，所述弥漫大B细胞淋巴瘤的患者既往至少接受过2线全身系统性治疗方案，最近一次治疗期间或完成后存在疾病进展，或经充分治疗后确认无客观缓解，且既往至少有一种方案含利妥昔单抗充分治疗或利妥昔单抗治疗期间疾病进展。
在本申请的一些方案中，所述弥漫大B细胞淋巴瘤的患者已接受在先治疗方案治疗达到客观缓解后，疾病再次发生，或者所述弥漫大B细胞淋巴瘤的患者对于在先治疗方案无客观缓解。在本申请的一些方案中，所述无客观缓解指治疗期间疾病稳定或疾病进展。
在本申请的一些方案中，所述弥漫大B细胞淋巴瘤的患者是已接受过在先治疗方案的复发或难治性弥漫大B细胞淋巴瘤患者。
在本申请的一些方案中，所述弥漫大B细胞淋巴瘤的患者是CD20阳性(CD20+)的弥漫大B细胞淋巴瘤的患者。
在本申请的一些方案中，所述弥漫大B细胞淋巴瘤的患者是已接受过利妥昔单抗和/或BTK抑制剂治疗的弥漫大B细胞巴瘤患者。
在本申请的一些方案中，所述弥漫大B细胞淋巴瘤的患者是已接受过利妥昔单抗和/或BTK抑制剂治疗的复发或难治性弥漫大B淋细胞巴瘤患者。
在本申请的一些方案中，所述弥漫大B细胞淋巴瘤的患者是CD20阳性(CD20+)，并且是已接受过利妥昔单抗治疗的复发或难治性弥漫大B细胞淋巴瘤的患者。
在本申请的一些方案中，所述弥漫大B细胞淋巴瘤的在先治疗方案包括药物治疗、放疗、或造血干细胞移植。
在本申请的一些方案中，所述弥漫大B细胞淋巴瘤的在先治疗方案的药物治疗包括干扰素治疗、化疗、或靶向药物治疗。
在本申请的一些方案中，所述弥漫大B细胞淋巴瘤的在先治疗方案的靶向药物治疗包括抗CD20抗体、或BTK抑制剂。
在本申请的一些方案中，所述弥漫大B细胞淋巴瘤的在先治疗方案的抗CD20抗体包括利妥昔单抗、CHO-H01、ocaratuzumab、替伊莫单抗、乌妥昔单抗、或奥比妥珠单抗。
在本申请的一些方案中，所述弥漫大B细胞淋巴瘤的在先治疗方案的BTK抑制剂包括伊布替尼、ICP-022、阿卡替尼、或泽布替尼。
在本申请的一些方案中，所述弥漫大B细胞淋巴瘤的在先治疗方案的化疗所用药物包括环磷酰胺、异环磷酰胺、长春新碱、泼尼松、泼尼松龙、多柔比星、阿霉素、表阿霉素、地塞米松、甲氨蝶呤、阿糖胞苷、卡铂、顺铂、苯达莫司汀、氟达拉滨、米托蒽醌、依托泊苷、甲基苄肼、吉西他滨、甲泼尼龙、甲泼 尼龙琥珀酸钠、美司那、奥沙利铂、5-氟尿嘧啶、或阿扎胞苷。
在本申请的一些方案中，所述弥漫大B细胞淋巴瘤的在先治疗方案的靶向药物包括硼替佐米、利妥昔单抗、CHO-H01、ocaratuzumab、替伊莫单抗、乌妥昔单抗、奥比妥珠单抗、伊布替尼、ICP-022、阿卡替尼、泽布替尼、哌柏西利、abemaciclib、替西罗莫司、依维莫司、卡非佐米、伊沙佐米、尼拉帕利、umbralisib、来那度胺、维纳妥拉、伏立诺他、BR-101801、tazemetostat、或abexinostat。
在本申请的一些方案中，所述弥漫大B细胞淋巴瘤的在先治疗方案的药物治疗所用药物包括环磷酰胺、异环磷酰胺、长春新碱、泼尼松、泼尼松龙、多柔比星、硼替佐米、表阿霉素、阿霉素、地塞米松、甲氨蝶呤、阿糖胞苷、卡铂、顺铂、苯达莫司汀、氟达拉滨、米托蒽醌、依托泊苷、甲基苄肼、吉西他滨、甲泼尼龙、甲泼尼龙琥珀酸钠、美司那、奥沙利铂、5-氟尿嘧啶、干扰素、利妥昔单抗、来那度胺、CHO-H01、ocaratuzumab、替伊莫单抗、乌妥昔单抗、奥比妥珠单抗、伊布替尼、阿卡替尼、ICP-022、泽布替尼、伏立诺他、阿扎胞苷、BR-101801、umbralisib、或tazemetostat；优选地，所述弥漫大B细胞淋巴瘤的在先治疗方案的药物治疗所用药物包括环磷酰胺、异环磷酰胺、长春新碱、泼尼松、泼尼松龙、多柔比星、硼替佐米、阿霉素、表阿霉素、地塞米松、甲氨蝶呤、阿糖胞苷、卡铂、顺铂、苯达莫司汀、氟达拉滨、米托蒽醌、依托泊苷、甲基苄肼、吉西他滨、甲泼尼龙、甲泼尼龙琥珀酸钠、美司那、奥沙利铂、5-氟尿嘧啶、干扰素、利妥昔单抗、来那度胺、伊布替尼、阿卡替尼、ICP-022、或泽布替尼；更优选地，所述弥漫大B细胞淋巴瘤的先治疗方案的药物治疗所用药物包括利妥昔单抗、来那度胺、伊布替尼、ICP-022、阿卡替尼、或泽布替尼。
在本申请的一些方案中，所述弥漫大B细胞淋巴瘤的先治疗方案的化疗所用方案包括CDOP方案、GDP方案、GDPE方案、CEOP方案、CEPP方案、CHOP方案、CHOEP方案、DA-EPOCH方案、DHAP方案、DICE方案、ESHAP方案、GCVP方案、GDP方案、GEMOX方案、HyperCVAD方案、ICE方案、MINE方案、或上述方案与利妥昔单抗联用；优选地，所述弥漫大B细胞淋巴瘤的先治疗方案的化疗所用方案包括CEOP方案、CEPP方案、CHOP方案、DA-EPOCH-R方案、DHAP方案、DICE方案、ESHAP方案、GDP方案、GDPE方案、GEMOX方案、ICE方案、MINE方案、R-CDOP方案、R-CEOP方案、R-CEPP方案、R-CHOP方案、R-CHOEP方案、R-DHAP方案、R-ESHAP方案、R-GCVP方案、R-GDP方案、R-GDPE方案、R-GEMOX方案、R-HyperCVAD方案、R-ICE方案、或R-MINE方案。
在本申请的一些方案中，所述造血干细胞移植包括自体造血干细胞移植、或异体造血干细胞移植。
在本申请的一些方案中，所述放疗选自全淋巴照射(TLI)和次全淋巴照射(STLI)。在本申请的一些方案中，所述放疗包括受累野照射(IFRT)、累及淋巴结(INRT)或累及部位照射(ISRT)。
在本申请的一些方案中，所述弥漫大B细胞淋巴瘤选自生发中心B细胞样(Germinal Center B-cell-like,GCB)弥漫大B细胞淋巴瘤、激活B细胞样(Activated B-cell-like,ABC)弥漫大B细胞淋巴瘤、或第三型(Type 3)弥漫大B细胞淋巴瘤。
在本申请的一些方案中，所述弥漫大B细胞淋巴瘤选自复发或难治性弥漫大B细胞淋巴瘤；任选地，所述弥漫大B细胞淋巴瘤的患者已接受过一种或两种以上在先治疗方案的治疗；任选地，所述弥漫大B细胞淋巴瘤的患者已接受在先治疗方案治疗达到客观缓解后，疾病再次发生，或者所述弥漫大B细胞淋巴瘤的患者对于在先治疗方案无客观缓解；在本申请的一些方案中，所述滤泡性淋巴瘤的患者是CD20阳性的滤泡性淋巴瘤的患者；任选地，所述弥漫大B细胞淋巴瘤的在先治疗方案包括但不限于药物治疗、放疗、或造血干细胞移植。
小淋巴细胞淋巴瘤(SLL)或慢性淋巴细胞白血病(CLL)
在本申请的一些方案中，所述淋巴瘤选自小淋巴细胞淋巴瘤或慢性淋巴细胞白血病。
在本申请的一些方案中，所述非霍奇金淋巴瘤选自小淋巴细胞淋巴瘤或慢性淋巴细胞白血病。
在本申请的一些方案中，所述小淋巴细胞淋巴瘤或慢性淋巴细胞白血病选自复发或难治性小淋巴细胞淋巴瘤或慢性淋巴细胞白血病。
在本申请的一些方案中，所述小淋巴细胞淋巴瘤或慢性淋巴细胞白血病的患者已接受过一种或两种以上在先治疗方案的治疗。在本申请的一些方案中，所述小淋巴细胞淋巴瘤或慢性淋巴细胞白血病的患者已 接受过一种、两种、三种、四种、或五种在先治疗方案的治疗。
在本申请的一些方案中，所述小淋巴细胞淋巴瘤或慢性淋巴细胞白血病的患者已接受过一线、二线或三线及以上在先治疗方案的治疗。
在本申请的一些方案中，所述小淋巴细胞淋巴瘤或慢性淋巴细胞白血病的患者既往至少接受过1线(包括1线、2线、3线或4线)全身系统性治疗方案治疗。
在本申请的一些方案中，所述小淋巴细胞淋巴瘤或慢性淋巴细胞白血病的患者接受过至少1线全身系统性治疗方案治疗。
在本申请的一些方案中，所述小淋巴细胞淋巴瘤或慢性淋巴细胞白血病的患者既往至少接受过1线全身系统性治疗方案，最近一次治疗期间或完成后存在疾病进展或经充分治疗后确认无客观缓解。
在本申请的一些方案中，所述小淋巴细胞淋巴瘤或慢性淋巴细胞白血病的患者是接受过至少1线全身系统性治疗方案治疗后复发或难治性的小淋巴细胞淋巴瘤或慢性淋巴细胞白血病患者。
在本申请的一些方案中，所述小淋巴细胞淋巴瘤或慢性淋巴细胞白血病的患者已接受在先治疗方案治疗达到客观缓解后，疾病再次发生，或者所述小淋巴细胞淋巴瘤或慢性淋巴细胞白血病的患者对于在先治疗方案无客观缓解。在本申请的一些方案中，所述无客观缓解指治疗期间疾病稳定或疾病进展。
在本申请的一些方案中，所述小淋巴细胞淋巴瘤或慢性淋巴细胞白血病的患者是CD20阳性(CD20+)、CD38阳性(CD38+)或ZAP70阳性(ZAP70+)的小淋巴细胞淋巴瘤或慢性淋巴细胞白血病的患者。
在本申请的一些方案中，所述小淋巴细胞淋巴瘤或慢性淋巴细胞白血病的患者是CD20阳性(CD20+)的患者。
在本申请的一些方案中，所述小淋巴细胞淋巴瘤或慢性淋巴细胞白血病的患者是已接受过利妥昔单抗和/或BTK抑制剂治疗的小淋巴细胞淋巴瘤或慢性淋巴细胞白血病患者。
在本申请的一些方案中，所述小淋巴细胞淋巴瘤或慢性淋巴细胞白血病的患者是已接受过利妥昔单抗和/或BTK抑制剂治疗的复发或难治性小淋巴细胞淋巴瘤或慢性淋巴细胞白血病患者。
在本申请的一些方案中，所述小淋巴细胞淋巴瘤或慢性淋巴细胞白血病的患者是CD20阳性(CD20+)，并且是已接受过利妥昔单抗治疗的复发或难治性小淋巴细胞淋巴瘤或慢性淋巴细胞白血病患者。
在本申请的一些方案中，所述小淋巴细胞淋巴瘤或慢性淋巴细胞白血病的患者具有del(11q)、del(17p)、和/或TP53基因突变。
在本申请的一些方案中，所述小淋巴细胞淋巴瘤或慢性淋巴细胞白血病的在先治疗方案包括药物治疗、放疗、或造血干细胞移植。
在本申请的一些方案中，所述小淋巴细胞淋巴瘤或慢性淋巴细胞白血病的在先治疗方案的药物治疗包括干扰素治疗、化疗、或靶向药物治疗。
在本申请的一些方案中，所述小淋巴细胞淋巴瘤或慢性淋巴细胞白血病的在先治疗方案的靶向药物治疗包括抗CD20抗体、或BTK抑制剂。
在本申请的一些方案中，所述小淋巴细胞淋巴瘤或慢性淋巴细胞白血病的在先治疗方案的抗CD20抗体包括利妥昔单抗、CHO-H01、ocaratuzumab、替伊莫单抗、乌妥昔单抗、或奥比妥珠单抗。
在本申请的一些方案中，所述小淋巴细胞淋巴瘤或慢性淋巴细胞白血病的在先治疗方案的BTK抑制剂包括伊布替尼、ICP-022、阿卡替尼、或泽布替尼。
在本申请的一些方案中，所述小淋巴细胞淋巴瘤或慢性淋巴细胞白血病的在先治疗方案的化疗所用药物包括环磷酰胺、异环磷酰胺、长春新碱、泼尼松、泼尼松龙、多柔比星、阿霉素、表阿霉素、地塞米松、甲氨蝶呤、阿糖胞苷、卡铂、顺铂、苯达莫司汀、氟达拉滨、米托蒽醌、依托泊苷、甲基苄肼、吉西他滨、甲泼尼龙、甲泼尼龙琥珀酸钠、美司那、奥沙利铂、5-氟尿嘧啶、苯丁酸氮芥、或阿扎胞苷。
在本申请的一些方案中，所述小淋巴细胞淋巴瘤或慢性淋巴细胞白血病的在先治疗方案的靶向药物包括硼替佐米、利妥昔单抗、CHO-H01、ocaratuzumab、替伊莫单抗、乌妥昔单抗、奥比妥珠单抗、伊布替尼、ICP-022、阿卡替尼、泽布替尼、哌柏西利、abemaciclib、替西罗莫司、依维莫司、卡非佐米、伊沙佐 米、尼拉帕利、umbralisib、来那度胺、维纳妥拉、伏立诺他、BR-101801、tazemetostat、或abexinostat。
在本申请的一些方案中，所述小淋巴细胞淋巴瘤或慢性淋巴细胞白血病的在先治疗方案的药物治疗所用药物包括干扰素、环磷酰胺、异环磷酰胺、长春新碱、长春瑞滨、泼尼松、泼尼松龙、多柔比星、硼替佐米、阿霉素、表阿霉素、地塞米松、甲氨蝶呤、阿糖胞苷、卡铂、顺铂、苯达莫司汀、氟达拉滨、米托蒽醌、依托泊苷、甲基苄肼、吉西他滨、甲泼尼龙、甲泼尼龙琥珀酸钠、美司那、奥沙利铂、5-氟尿嘧啶、苯丁酸氮芥、利妥昔单抗、CHO-H01、ocaratuzumab、替伊莫单抗、乌妥昔单抗、奥比妥珠单抗、伊布替尼、ICP-022、阿卡替尼、泽布替尼、哌柏西利、abemaciclib、替西罗莫司、依维莫司、卡非佐米、伊沙佐米、尼拉帕利、umbralisib、来那度胺、维纳妥拉、伏立诺他、阿扎胞苷、BR-101801、tazemetostat、或abexinostat；优选地，所述药物治疗所用药物包括用环磷酰胺、异环磷酰胺、长春新碱、泼尼松、泼尼松龙、多柔比星、硼替佐米、阿霉素、表阿霉素、地塞米松、甲氨蝶呤、阿糖胞苷、卡铂、顺铂、苯达莫司汀、氟达拉滨、米托蒽醌、依托泊苷、甲基苄肼、吉西他滨、甲泼尼龙、甲泼尼龙琥珀酸钠、美司那、奥沙利铂、利妥昔单抗、伊布替尼、ICP-022、阿卡替尼、或泽布替尼；更优选地，所述药物治疗所用药物包括利妥昔单抗、伊布替尼、ICP-022、阿卡替尼、或泽布替尼。
在本申请的一些方案中，所述小淋巴细胞淋巴瘤或慢性淋巴细胞白血病的在先治疗的化疗方案包括B方案、BA方案、BAC方案、CDOP方案、CEOP方案、CEPP方案、CHOP方案、CIFOX方案、COP方案、COPE方案、CVP方案、DA-EPOCH方案、DHAP方案、DICE方案、EPOCH方案、ESHAP方案、FC方案、FM方案、GCVP方案、GDP方案、GDPE方案、GEMOX方案、HyperCVAD方案、ICE方案、MA方案、MINE方案、NCE方案、VCAP方案或上述方案与利妥昔单抗联用；优选地，所述化疗的方案包括BR方案、CDOP方案、CEOP方案、CEPP方案、CHOP方案、CIFOX方案、COP方案、CVP方案、DA-EPOCH-R方案、DHAP方案、DICE方案、EPOCH方案、ESHAP方案、FCR方案、FMR方案、GDP方案、GDPE方案、GEMOX方案、ICE方案、MINE方案、NCE方案、R-BAC方案、R-CDOP方案、R-CEOP方案、R-CEPP方案、R-CHOP方案、R-CVP方案、R-DHAP方案、R-DICE方案、R-EPOCH方案、R-GCVP方案、R-HyperCVAD方案、R-ICE方案、R-MA方案、R-NCE方案或VR-CAP方案。
在本申请的一些方案中，所述放疗选自全淋巴照射(TLI)和次全淋巴照射(STLI)。在本申请的一些方案中，所述放疗包括受累野照射(IFRT)、累及淋巴结(INRT)或累及部位照射(ISRT)。
在本申请的一些方案中，所述造血干细胞移植包括自体造血干细胞移植、或异体造血干细胞移植。
在本申请的一些方案中，所述小淋巴细胞淋巴瘤或慢性淋巴细胞白血病选自复发或难治性小淋巴细胞淋巴瘤或慢性淋巴细胞白血病；任选地，所述小淋巴细胞淋巴瘤或慢性淋巴细胞白血病的患者已接受过一种或两种以上在先治疗方案的治疗；任选地，所述小淋巴细胞淋巴瘤或慢性淋巴细胞白血病的患者已接受在先治疗方案治疗达到客观缓解后，疾病再次发生，或者所述小淋巴细胞淋巴瘤或慢性淋巴细胞白血病的患者对于在先治疗方案无客观缓解；任选地，所述小淋巴细胞淋巴瘤或慢性淋巴细胞白血病的患者是CD20阳性的小淋巴细胞淋巴瘤或慢性淋巴细胞白血病的患者；任选地，所述小淋巴细胞淋巴瘤或慢性淋巴细胞白血病的患者具有del(11q)、del(17p)、和/或TP53基因突变；任选地，所述小淋巴细胞淋巴瘤或慢性淋巴细胞白血病的在先治疗方案包括药物治疗、放疗、或造血干细胞移植。
给药方案
在本申请的一些方案中，所述治疗患者的淋巴瘤的给药周期是2～6周。在本申请的一些方案中，所述治疗患者的淋巴瘤的给药周期是2周、3周、4周、5周、6周或上述任意值形成的范围。在本申请的一些方案中，所述治疗患者的淋巴瘤的给药周期是3周或4周。
在本申请的一些方案中，所述治疗患者的淋巴瘤的每日剂量选自1～100mg。在本申请的一些方案中，所述治疗患者的淋巴瘤的每日剂量选自1mg、2mg、3mg、4mg、5mg、6mg、7mg、8mg、9mg、10mg、11mg、12mg、13mg、14mg、15mg、16mg、17mg、18mg、19mg、20mg、21mg、22mg、23mg、24mg、25mg、26mg、27mg、28mg、29mg、30mg、31mg、32mg、33mg、34mg、35mg、36mg、37mg、38mg、39mg、40mg、41mg、42mg、43mg、44mg、45mg、46mg、47mg、48mg、49mg、50mg、51mg、52mg、53mg、54mg、55mg、56mg、57mg、58mg、59mg、60mg、61mg、62mg、63mg、64mg、65mg、66mg、67mg、68mg、69mg、70mg、71mg、72mg、73mg、74mg、75mg、76mg、77mg、78mg、79mg、80mg、 81mg、82mg、83mg、84mg、85mg、86mg、87mg、88mg、89mg、90mg、91mg、92mg、93mg、94mg、95mg、96mg、97mg、98mg、99mg、100mg、或上述任意值形成的范围。在本申请的一些方案中，所述治疗患者的淋巴瘤的每日剂量选自5～50mg、10～50mg、或10～40mg。
在本申请的一些方案中，所述治疗患者的淋巴瘤的每日给药次数是1次、2次或3次。
在本申请的一些方案中，所述治疗患者的淋巴瘤的每两日给药1次。
在本申请的一些方案中，所述治疗患者的淋巴瘤的给药方案包括：给药周期是2～6周，每日剂量是1～40mg，每日给药次数是1～3次。
本申请的式I化合物、其立体异构体、或其药学上可接受的盐可通过多种途径给药，所述途径包括但不限于以下途径：口服、胃肠外、腹膜内、静脉内、动脉内、透皮、舌下、肌内、直肠、透颊、鼻内、经吸入、阴道、眼内、经局部给药、皮下、脂肪内、关节内或鞘内。在一个特定的方案中，通过口服给药。
给药的方法可根据药物的活性、毒性以及患者的耐受性等因素综合确定。在部分实施方案中，以间隔给药的方式给予本申请的化合物、其立体异构体、或其药学上可接受的盐。
本申请的药物组合物可通过将本申请的式I化合物与适宜的药学上可接受的辅料组合而制备，例如可配制成固态、半固态、液态或气态制剂。
在本申请的部分方案中，所述的药物组合物是适于口服的制剂，包括片剂、胶囊剂、粉剂、颗粒剂、滴丸、糊剂、散剂等，优选片剂和胶囊剂。所述的口服制剂可使用本领域公知的药学上可接受的载体通过常规方法制得。药学上可接受的载体包括稀释剂、黏合剂、润湿剂、崩解剂、润滑剂等。
在本申请的部分方案中，所述的药物组合物为单剂量药物组合物。在部分实施方案中，所述药物组合物含有1mg至50mg的本申请的式I化合物、或其药学上可接受的盐。在部分实施方案中，所述药物组合物含有1mg、2mg、5mg、8mg、10mg、12mg、15mg、18mg、20mg、22mg、25mg、28mg、30mg、32mg、35mg、38mg、40mg、42mg、45mg、48mg或50mg、或者任意前述值作为端点构成的范围或其中的任意值的本申请的化合物、或其药学上可接受的盐，例如2mg至50mg、10mg至40mg、5mg至30mg、5mg至20mg等。
技术效果
本申请的式I化合物、或其药学上可接受的盐在减少淋巴瘤的生长或甚至消除肿瘤方面产生良好的疗效，提供给所治疗患者良好的疾病控制率，使得所治疗患者具有更长的生存期(例如中位生存期、无进展生存期或总生存期)，更长的疾病缓解持续时间。同时，本申请的式I化合物、或其药学上可接受的盐在减少淋巴瘤时具有良好的安全性。
定义和说明
除非另有说明，本申请中所用的术语具有下列含义。一个特定的术语在没有特别定义的情况下不应该被认为是不确定的或不清楚的，而应该按照本领域普通的含义去理解。当本申请中出现商品名时，意在指代其对应的商品或其活性成分。
术语“药学上可接受的”，是针对那些化合物、材料、组合物和/或剂型而言，它们在可靠的医学判断的范围之内，适用于与人类和动物的组织接触使用，而没有过多的毒性、刺激性、过敏性反应或其它问题或并发症，与合理的利益/风险比相称。
术语“药学上可接受的盐”，包括碱根离子与游离酸形成的盐或酸根离子与游离碱形成的盐。
如本申请所用，式I化合物的量，例如给药量、剂量、药物组合物中的含量，以其游离碱形式计算。
如本申请所用，本申请药物组合中的化合物如果具有例如至少一个碱性中心，则其可以形成酸加成盐。如果需要的话，还可以形成具有另外存在的碱性中心的相应的酸加成盐。具有至少一个酸性基团(例如COOH)的化合物还可以与碱形成盐。如果化合物例如既包含羧基又包含氨基，则还可以形成相应的内盐。
术语“患者”是哺乳动物。在部分实施方案中，所述患者是人。
术语“药物组合物”是指一种或多种本申请的化合物或其药物组合或其盐与药学上可接受的辅料组成的混合物。药物组合物的目的是有利于对患者给予本申请的化合物或其药物组合。
术语“治疗”一般是指获得需要的药理和/或生理效应。该效应根据部分或完全稳定或治愈疾病和/或由于疾病产生的副作用，可以是治疗性的。本文使用的“治疗”涵盖了对患者疾病的任何治疗，包括：(a)抑制疾病的症状，即阻止其发展；或(b)缓解疾病的症状，即，导致疾病或症状退化。
术语“有效量”意指(i)治疗特定疾病、病况或障碍，(ii)减轻、改善或消除特定疾病、病况或障碍的一种或多种症状，或(iii)延迟本文中所述的特定疾病、病况或障碍的一种或多种症状发作的本申请化合物的用量。构成“治疗有效量”的本申请化合物的量取决于该化合物、疾病状态及其严重性、给药方式以及待被治疗的哺乳动物的年龄而改变，但可例行性地由本领域技术人员根据其自身的知识及本公开内容而确定。
术语“单剂量”是指含有一定量药品的最小包装单元，例如每片药物为单剂量；一盒药有七粒胶囊，则每个胶囊为单剂量；或者每瓶注射液为单剂量。
在癌症背景下，术语“难治性”指，特定的癌症对于使用一种特定治疗剂的疗法有抗性或无反应。难以使用一种特定治疗剂的疗法治疗的癌症可以始于当用该特定治疗剂开始治疗的时候(即一开始暴露在该治疗剂的时候就无反应)，或者，是在使用该治疗剂首次治疗期的过程中或是使用该治疗剂进行后续治疗的期间，对该治疗剂发展出抗性的结果。例如，利妥息单抗难治指经含利妥昔单抗方案(联合化疗或单药)充分治疗未获缓解，或治疗期间/充分治疗结束6个月内疾病进展。
在癌症背景下，术语“复发”指，已接受某种治疗方案治疗达到客观缓解后，疾病再次发生。“客观缓解”包括完全缓解和部分缓解。例如，利妥昔单抗复发指经充分治疗达缓解后疾病进展，至少有一种方案含利妥昔单抗。
在癌症背景下，术语“一线治疗”(first-line therapy)指针对疾病的第一次治疗。它通常是一组标准治疗方法的一部分，例如手术后进行化学治疗和放射治疗。一线疗法单独使用时，是公认的最佳疗法。如果它不能治愈疾病或引起严重的副作用，则可以添加或使用其他治疗方法。
在癌症背景下，术语“二线治疗”(second-line therapy)指当初始治疗(一线治疗)无效或停止发挥作用时所给予的治疗。三线治疗或多线治疗的意思可以此类推。
如本申请所用，所述“已接受过在先治疗方案的治疗”或“已接受过某种治疗方法或药物治疗”指所述患者既往曾接受过相应的治疗方法、治疗方法或药物的治疗。例如，“所述淋巴瘤的患者是已接受过利妥昔单抗治疗的复发或难治性淋巴瘤患者”指所述淋巴瘤患者既往曾接受过利妥昔单抗的治疗。
如本申请所用，所述在先治疗方案所用药物可参考以下内容，也可参考治疗指南或涉及医学、药学的教科书：
ABVD方案：多柔比星、博来霉素、长春花碱、和达卡巴嗪。
AVD方案：多柔比星、长春花碱、和达卡巴嗪。
B方案：苯达莫司汀。
BR方案：苯达莫司汀、和利妥昔单抗。
BA方案：苯达莫司汀、和阿扎胞苷。
BEACOPPesc方案：依托泊苷、多柔比星、环磷酰胺、长春新碱、博来霉素、泼尼松、和甲基苄肼。
CDOP方案：环磷酰胺、多柔比星、长春新碱、和泼尼松。
CEOP方案：环磷酰胺、依托泊苷、长春新碱、和泼尼松。
CEPP方案：环磷酰胺、依托泊苷、泼尼松龙、和甲基苄肼。
CHOP方案：环磷酰胺、阿霉素/表阿霉素、长春新碱、和泼尼松。所述CHOP方案包括但不限于CHOP-21天方案或CHOP-14天方案。
CHOEP方案：环磷酰胺、阿霉素/表阿霉素、长春新碱、依托泊苷、和泼尼松(CHOP方案联合依托泊苷)。
CIFOX方案：5-氟尿嘧啶、和奥沙利铂。
COP方案：环磷酰胺、长春新碱、和泼尼松。
COPE方案：环磷酰胺、长春新碱、顺铂、和依托泊苷。
CVP方案：环磷酰胺、长春新碱、和泼尼松。
DA-EPOCH方案：依托泊苷、泼尼松、长春新碱、环磷酰胺、和阿霉素。
DA-EPOCH-R方案：依托泊苷、泼尼松、长春新碱、环磷酰胺、阿霉素、和利妥昔单抗。
DHAP方案：地塞米松、高剂量阿糖胞苷、和顺铂。
DICE方案：地塞米松、异环磷酰胺、顺铂、和依托泊苷。
EPOCH方案：依托泊苷、泼尼松、长春新碱、环磷酰胺、和阿霉素。
ESHAP方案：依托泊苷、甲泼尼龙、高剂量阿糖胞苷、和顺铂。
FCR方案：氟达拉滨、环磷酰胺、和利妥昔单抗。
FC方案：氟达拉滨、和环磷酰胺。
FM方案：氟达拉滨、和米托蒽醌。
FMR方案：氟达拉滨、米托蒽醌、和利妥昔单抗。
GCVP方案：吉西他滨、环磷酰胺、长春新碱、和泼尼松。
GDP方案：吉西他滨、地塞米松、和顺铂。
GDPE方案：吉西他滨、地塞米松、顺铂、和依托泊苷。
GEMOX方案：吉西他滨、和奥沙利铂。
GVD方案：吉西他滨、长春瑞滨、和多柔比星。
HyperCVAD方案：A方案：环磷酰胺、长春新碱、阿霉素、地塞米松、和/或美司那；B方案：甲氨蝶呤、和阿糖胞苷。
ICE方案：异环磷酰胺、卡铂、和依托泊苷。
IGEV方案：异环磷酰胺、吉西他滨、和长春瑞滨。
MA方案：甲氨蝶呤、和阿糖胞苷。
MINE方案：美司那、异环磷酰胺、米托蒽醌、和依托泊苷。
miniBEAM方案：卡氮芥、依托泊苷、阿糖胞苷、和米尔法兰。
NCE方案：长春瑞滨、顺铂、和依托泊苷。
R：利妥昔单抗。
R 2：利妥昔单抗、和来那度胺。
R-：指利妥昔单抗与治疗方案的联合。包括但不限于下述：
R-BAC方案：利妥昔单抗、苯达莫司汀、和阿糖胞苷。
R-CDOP方案：利妥昔单抗、环磷酰胺、多柔比星、长春新碱、和泼尼松。
R-CEOP方案：利妥昔单抗、环磷酰胺、依托泊苷、长春新碱、和泼尼松。
R-CEPP方案：利妥昔单抗、环磷酰胺、依托泊苷、泼尼松龙、和甲基苄肼。
R-CHOP方案：利妥昔单抗、环磷酰胺、阿霉素/表阿霉素、长春新碱、和泼尼松。
R-CHOEP方案：利妥昔单抗、环磷酰胺、阿霉素/表阿霉素、长春新碱、依托泊苷、和泼尼松。
R-COPE方案：利妥昔单抗、环磷酰胺，长春新碱，顺铂、和依托泊苷。
R-CVP方案：利妥昔单抗、环磷酰胺、长春新碱、和泼尼松。
R-DHAP方案：地塞米松、高剂量阿糖胞苷、和顺铂。
R-DICE方案：利妥昔单抗、地塞米松、异环磷酰胺、顺铂、和依托泊苷。
R-EPOCH方案：利妥昔单抗、依托泊苷、泼尼松、长春新碱、环磷酰胺、和阿霉素。
R-ESHAP方案：利妥昔单抗、依托泊苷、甲泼尼龙、高剂量阿糖胞苷、和顺铂。
R-GCVP方案：利妥昔单抗、吉西他滨、环磷酰胺、长春新碱、和泼尼松龙。
R-GDP方案：利妥昔单抗、吉西他滨、地塞米松、和顺铂。
R-GDPE方案：利妥昔单抗、吉西他滨、地塞米松、顺铂、和依托泊苷。
R-GEMOX方案：利妥昔单抗、吉西他滨、和奥沙利铂。
R-HyperCVAD方案：A方案：利妥昔单抗、环磷酰胺、长春新碱、阿霉素、地塞米松、和/或美司那；B方案：利妥昔单抗、甲氨蝶呤、和阿糖胞苷。
R-ICE方案：利妥昔单抗、异环磷酰胺、卡铂、和依托泊苷。
R-MA方案：利妥昔单抗、甲氨蝶呤、和阿糖胞苷。
R-MINE方案：利妥昔单抗、美司那、异环磷酰胺、米托蒽醌、和依托泊苷。
R-NCE方案：利妥昔单抗、长春瑞滨、顺铂、和依托泊苷。
Stanford V方案：多柔比星、长春花碱、氮芥、长春新碱、博来霉素、依托泊苷、和泼尼松。
V-CAP方案：硼替佐米、环磷酰胺、阿霉素、和泼尼松。
VR-CAP方案：硼替佐米、利妥昔单抗、环磷酰胺、阿霉素、和泼尼松。
R-高剂量阿糖胞苷：利妥昔单抗和高剂量阿糖胞苷。
如本申请所用，所述泼尼松龙亦可以是泼尼松，二者之间可以替换使用。
在癌症背景下，小淋巴细胞淋巴瘤(SLL)和慢性淋巴细胞白血病(CLL)是同一种疾病的不同表现，SLL通常无白血病样表现，CLL则以骨髓和外周血受累为主。因此，本申请治疗小淋巴细胞淋巴瘤(SLL)的保护范围也包括慢性淋巴细胞白血病(CLL)。
如本申请所用，所述化疗方案在本领域中属于现有技术。本领域技术人员易于参考现有技术中的治疗指南或相关的医学、药学的教科书(例如中国临床肿瘤学会(CSCO)淋巴瘤诊疗指南2019或2020)以获得化疗方案的具体内容(包括但不限于所用药物、给药剂量或给药周期)。本申请上述对化疗方案所用药物的举例是示例性的，化疗方案的具体内容(包括但不限于所用药物、给药剂量或给药周期)以治疗指南或相关的医学、药学的教科书为准。
在本文中，除非另有说明，否则术语“包含、包括和含有(comprise、comprises和comprising)”或等同物为开放式表述，意味着除所列出的要素、组分和步骤外，还可涵盖其它未指明的要素、组分和步骤。
为了描述和公开的目的，以引用的方式将所有的专利、专利申请和其它已确定的出版物在此明确地并入本文。这些出版物仅因为它们的公开早于本申请的申请日而提供。所有关于这些文件的日期的声明或这些文件的内容的表述是基于申请者可得的信息，并且不构成任何关于这些文件的日期或这些文件的内容的正确性的承认。而且，在任何国家，在本中对这些出版物的任何引用并不构成关于该出版物成为本领域的公知常识的一部分的认可。
具体实施方式
通过具体的实施例更详细地说明本发明。为说明目的提供以下实施例，它们不应以任何方式限制本发明。
实施例1式I化合物的片剂
表1式I化合物的片剂的处方组成
Figure PCTCN2021076423-appb-000003
Figure PCTCN2021076423-appb-000004
制备方法：
1)将式I化合物、微晶纤维素、甘露醇、交联羧甲基纤维素钠依次过粉碎整粒机，过筛后收集物料，然后进行预混，得到预混物料。
2)将羟丙甲基纤维素配置为水溶液作为粘合剂。
3)将步骤1)中的预混物料转至湿法制粒锅中加入步骤2)获得的粘合剂开始制粒。
4)制备得到的软湿材整粒，干燥，加入硬脂酸镁总混。
5)压片。
任选地，对所得片剂进行包衣。
其中，式I化合物根据WO2015192760中公开的方法进行制备。
实施例2淋巴癌
2.1给药方案
给药方法：每天空腹口服一次(QD给药)，连续给药28天为一个治疗周期。
药物：式I化合物的片剂，1mg或5mg。
2.2入组标准
1)经病理和/或细胞学明确诊断的复发或难治性淋巴瘤；
2)筛选期影像学显示，至少具有一个除脑部病灶外的可测量的靶病灶(组按照2014版Lugano会议修订的评效标准评估)；
3)年龄18～75岁；
4)ECOG(PS)评分≤1分；
5)预计生存期≥3个月；
6)筛选期主要器官功能符合以下标准：
血常规检查标准(7天内未使用生长因子或输血)：
中性粒细胞绝对值(ANC)≥1.5×10 9/L；
血小板(PLT)≥75×10 9/L，血红蛋白(Hb)≥90g/L；
血生化检查标准：
谷丙转氨酶(ALT)及谷草转氨酶(AST)≤1.5×ULN(肿瘤肝脏转移者，≤3×ULN)；
糖化血红蛋白(HbA1c)≤8.5％；
脂肪酶≤1.5×ULN；
血清总胆红素≤1.5×ULN；
血清肌酐(Cr)≤1.5×ULN；
7)多普勒超声评估：左室射血分数(LVEF)≥正常值低限(50％)；
8)女性应同意在研究期间和研究结束后6个月内必须采用避孕措施(如宫内节育器[IUD]，避孕药或 避孕套)；在研究入组前的7天内血清或尿妊娠试验阴性，且必须为非哺乳期患者；男性应同意在研究期间和研究期结束后6个月内必须采用避孕措施；
9)患者自愿加入本研究，签署知情同意书，依从性好。
2.3评价方法及指标
通过2014版Lugano会议修订的评效标准评价疗效。
主要疗效评价指标：客观缓解率(ORR)，即CR+PR例数/总例数，包含完全缓解(CR)和部分缓解(PR)的病例。
次要疗效评价指标：无进展生存期(PFS)、总生存期(OS)、疾病控制率(DCR)、缓解持续时间(DOR)。
2.4试验结果
当入组患者为22例淋巴瘤患者时，有18例可进行疗效评价，其中，CR患者2例，PR患者9例(均为最佳疗效)。在10mg/qd及以上剂量组的患者中ORR为73％(11/15)，在试验剂量20mg/qd组的患者中ORR为100％(4/4)。值得注意的是，滤泡性淋巴瘤(FL)在10mg/qd及以上剂量组的ORR是75％(6/8)，20mg/qd组两例滤泡性淋巴瘤患者全部PR。两例套细胞淋巴瘤患者也全部PR，且为BTK抑制剂治疗后复发或难治性患者。
表2淋巴瘤患者病史以及治疗史情况
患者编号 疾病 治疗史
R1018 FL 1.R-CHOP；2.R-NCE；3.CHOP；4.R-DICE
R2008 FL 1.R-CHOP；2.R-EPOCH；3.R-ICE；4.GEMOX；5.R 2
R1006 FL 1.2次CHOP
R2011 FL 1.R-CHOP；2.R-GEMOX
R1009 DLBCL 1.CDOP；2.R-DICE；3.自体造血干细胞移植
R2006 DLBCL 1.CHOP；2.R-GDPE
R2009 MCL 1.CHOP；2.R-CHOP；3.R维持
注：R 2是利妥昔单抗+来那度胺联用；R维持是每四周给予患者一次利妥昔单抗。
表3淋巴瘤患者疗效评估结果
患者编号 疾病 给药方法 用药周期 最佳疗效 病灶变化
R1018 FL 20mg/bid C2D28 SD小 -33.0％
R2008 FL 10mg/bid C2D3 SD小 -42.0％
R1006 FL 10mg/qd C5D28 PR -84.0％
R2011 FL 20mg/bid C1D14 PR -94.0％
R1009 DLBCL 10mg/qd C7D28 SD小 -37.5％
R2006 DLBCL 10mg/qd C3D28 CR -100.0％
R2009 MCL 10mg/bid C3D28 PR -71.0％
注：“SD小”指疗效评估时的病灶与基线病灶相比发生缩小变化，但未达到PR的标准。
当入组患者达35例淋巴瘤患者时，有31例淋巴瘤患者可进行疗效评价，ORR为71％(22/31)。安全性方面，与研究药物相关的主要3级不良反应和剂量限制性毒性(DLT)为高血糖症，通过停药或对症治疗后可控制并恢复到基线水平。20mg QD剂量组已入组20例患者，总体安全耐受性良好，只发生1例3级高血糖的不良反应。
当入组50例淋巴瘤患者时，有43例淋巴瘤患者可进行疗效评价，ORR为65％(28/43)。具体可参见表4结果：
表4淋巴瘤患者疗效评估结果
瘤种 患者人数 ORR，n(％) CR，n(％)
淋巴瘤 43 28(65％) 4(9.3％)
NHL 41 28(68％) 4(9.8％)
CLL 2 2(100％) ----
FL 20 15(75％) 2(10.0％)
MCL 5 5(100％) ----
DLBCL 8 4(50.0％) 2(25.0％)
上述试验结果显示式I化合物对淋巴瘤具有良好的治疗效果，并具有良好的安全性。
实施例3套细胞淋巴瘤
3.1给药方案
给药方法：口服给药，每日1次，每次20mg，连续服药28天为一个周期。
药物：式I化合物的片剂，5mg或20mg规格。
3.2入组标准
1)经组织病理学确诊的复发/难治性套细胞淋巴瘤，诊断报告需包括细胞遗传学检测t(11；14)阳性和/或免疫组织化学细胞周期蛋白D1高表达的证据；
2)既往接受过≥1线但不超过4线的系统治疗，最近接受的治疗方案确认无客观缓解(治疗期间疾病稳定或疾病进展)，或在治疗后发生疾病进展；
3)至少有一个可测量的靶病灶(按照2014版Lugano评效标准评估)；
4)年龄18～75岁；ECOG(PS)评分：0～2分；预计生存期≥3个月；
5)筛选期主要器官功能符合以下标准：
血常规检查标准(7天内未使用生长因子或输血)：
中性粒细胞绝对值(ANC)≥1.0×10 9/L；
血小板(PLT)≥75×10 9/L(有淋巴瘤骨髓浸润患者可放宽至50×10 9/L)；
血红蛋白(Hb)≥80g/L；
血生化检查标准：
谷丙转氨酶(ALT)及谷草转氨酶(AST)≤2.5×ULN(肿瘤肝脏转移者，≤5×ULN)；
糖化血红蛋白(HbA1c)≤8.5％；
血清淀粉酶和脂肪酶≤1.5×ULN；
血清总胆红素(TBIL)≤1.5×ULN(Gilbert综合症患者，≤3×ULN)；
凝血功能：活化部分凝血活酶时间(APTT)、国际标准化比值(INR)、凝血酶原时间(PT)≤1.5×ULN；
血清肌酐(Cr)≤1.5×ULN或肌酐清除率≥50mL/min；
6)多普勒超声评估：左室射血分数(LVEF)≥50％；
7)女性应同意在研究期间和研究结束后6个月内必须采用避孕措施(如宫内节育器[IUD]，避孕药或避孕套)；在研究入组前的7天内血清或尿妊娠试验阴性，且必须为非哺乳期患者；男性应同意在研究期间和研究期结束后6个月内必须采用避孕措施；
8)患者自愿加入本研究，签署知情同意书，依从性好。
3.3评价方法及指标
通过2014版Lugano会议修订的评效标准评价疗效。
主要疗效评价指标：客观缓解率(ORR)，即CR+PR例数/总例数，包含完全缓解(CR)和部分缓解 (PR)的病例。
次要疗效评价指标：无进展生存期(PFS)、总生存期(OS)、疾病控制率(DCR)、缓解持续时间(DOR)。
3.4试验结果
对21例套细胞淋巴瘤患者(其中7位患者在先经BTK抑制剂治疗，或14位患者在先经利妥昔单抗治疗，其中，有患者存在在先接受BTK抑制剂和利妥昔单抗二者治疗的情况)进行了疗效评价，ORR为76％(16例)，CR为9.5％(2例)。其中在先经BTK抑制剂治疗的7位患者中，5位达到ORR。结果显示出式I化合物对套细胞淋巴瘤具有良好的治疗效果。同时，式I化合物在治疗使用时，具有良好的安全性。
实施例4滤泡性淋巴瘤
4.1给药方案
给药方法：口服给药，每日1次，每次20mg，连续服药28天为一个周期。
药物：式I化合物的片剂，5mg或20mg规格。
4.2入组标准
1)经组织病理学确诊的1-3a级滤泡性淋巴瘤(FL)患者；
2)患者必须为既往接受过≥2线系统性治疗(至少有1种方案含利妥昔单抗)的复发或难治性FL；
3)至少有一个可测量的靶病灶(按照2014版Lugano评效标准评估)；
4)性别不限，年龄≥18岁；ECOG(PS)评分：0～2分；预计生存期≥3个月；
5)筛选期主要器官功能符合以下标准：
血常规检查标准(7天内未使用生长因子或输血)：
中性粒细胞绝对值(ANC)≥1.0×10 9/L；
血小板(PLT)≥75×10 9/L(有淋巴瘤骨髓浸润患者可放宽至50×10 9/L)；
血红蛋白(Hb)≥80g/L；
血生化检查标准：
谷丙转氨酶(ALT)及谷草转氨酶(AST)≤2.5×ULN(淋巴瘤累及肝脏或胆道阻塞者，≤5×ULN)；
血清总胆红素(TBIL)≤1.5×ULN；
凝血功能：活化部分凝血活酶时间(APTT)、国际标准化比值(INR)、凝血酶原时间(PT)≤1.5×ULN；
血清肌酐(Cr)≤1.5×ULN或肌酐清除率≥50mL/min；
6)多普勒超声评估：左室射血分数(LVEF)≥50％；
7)女性应同意在研究期间和研究结束后6个月内必须采用避孕措施(如宫内节育器[IUD]，避孕药或避孕套)；在研究入组前的7天内血清或尿妊娠试验阴性，且必须为非哺乳期患者；男性应同意在研究期间和研究期结束后6个月内必须采用避孕措施；
8)患者自愿加入本研究，签署知情同意书，依从性好。
4.3评价方法及指标
通过2014版Lugano会议修订的评效标准评价疗效。
主要疗效评价指标：客观缓解率(ORR)，即CR+PR例数/总例数，包含完全缓解(CR)和部分缓解(PR)的病例。
次要疗效评价指标：无进展生存期(PFS)、总生存期(OS)、疾病控制率(DCR)、缓解持续时间(DOR)。
4.4试验结果
对20例滤泡性淋巴瘤患者进行了疗效评价，ORR为70％(14例)，CR为10.0％(2例)，结果显示出式I化合物对滤泡性淋巴瘤具有良好的治疗效果。同时，式I化合物在治疗使用时，具有良好的安全性。
实施例5弥漫大B细胞淋巴瘤
5.1给药方案
给药方法：口服给药，每日1次，每次20mg，连续服药21天为一个周期。
药物：式I化合物的片剂，5mg或20mg规格。
5.2入组标准
1)经组织病理学确认的复发/难治性弥漫大B细胞淋巴瘤(DLBCL)；
2)既往至少接受过2线全身系统性治疗方案，最近一次治疗期间或完成后存在疾病进展，或经充分治疗后确认无客观缓解，且既往至少有一种方案含利妥昔单抗充分治疗或利妥昔单抗治疗期间疾病进展；
3)至少有一个可测量的靶病灶(按照2014版Lugano评效标准评估)；
4)筛选期主要器官功能符合以下标准：
血常规检查标准(7天内未使用生长因子或输血)：
中性粒细胞绝对值(ANC)≥1.0×10 9/L；
血小板(PLT)≥75×10 9/L(有淋巴瘤骨髓浸润患者≥50×10 9/L允许纳入)；
血红蛋白(Hb)≥80g/L；
血生化检查标准：
谷丙转氨酶(ALT)及谷草转氨酶(AST)≤2.5×ULN(淋巴瘤累及肝脏或胆道阻塞者，≤5×ULN)；
血清总胆红素(TBIL)≤1.5×ULN；
凝血功能：活化部分凝血活酶时间(APTT)、国际标准化比值(INR)、凝血酶原时间(PT)≤1.5×ULN；
血清肌酐(Cr)≤1.5×ULN或肌酐清除率≥50mL/min；
5)女性应同意在研究期间和研究结束后6个月内必须采用避孕措施(如宫内节育器[IUD]，避孕药或避孕套)；在研究入组前的7天内血清或尿妊娠试验阴性，且必须为非哺乳期患者；男性应同意在研究期间和研究期结束后6个月内必须采用避孕措施；
6)患者自愿加入本研究，签署知情同意书，依从性好。
5.3评价方法及指标
通过2014版Lugano会议修订的评效标准评价疗效。
主要疗效评价指标：客观缓解率(ORR)，即CR+PR例数/总例数，包含完全缓解(CR)和部分缓解(PR)的病例。
次要疗效评价指标：无进展生存期(PFS)、总生存期(OS)、疾病控制率(DCR)、缓解持续时间(DOR)。
5.4试验结果
式I化合物对弥漫大B细胞淋巴瘤具有良好的治疗效果。同时，式I化合物在治疗使用时，具有良好的安全性。
实施例6小淋巴细胞淋巴瘤或慢性淋巴细胞白血病
6.1给药方案
给药方法：口服给药，每日1次，每次20mg，连续服药28天为一个周期。
药物：式I化合物的片剂，5mg或20mg规格。
6.2入组标准
1)受试者自愿加入本研究，签署知情同意书；
2)性别不限，年龄≥18岁；ECOG(PS)评分：0～2；预计生存期≥3个月；
3)经流式细胞术或病理学确诊的慢性淋巴细胞白血病/小淋巴细胞淋巴瘤，且符合IWCLL2008中需要治疗的活动性疾病标准中的至少1条标准；
4)既往至少接受过1线全身系统性治疗方案，最近一次治疗期间或完成后存在疾病进展或经充分治疗后确认无客观缓解；
5)经CT或MRI评估，在2个垂直方向至少存在一个影像学可测量的肿瘤病灶(结内病灶长径＞15mm，结外病灶长径＞10mm)；
6)筛选期主要器官功能符合以下标准：
血常规检查标准(7天内未使用生长因子或输血)：
中性粒细胞绝对值(ANC)≥1.0×10 9/L；
血小板(PLT)≥75×10 9/L(有淋巴瘤骨髓浸润患者≥50×10 9/L允许纳入)；血红蛋白(Hb)≥80g/L；
血生化检查标准：
谷丙转氨酶(ALT)及谷草转氨酶(AST)≤2.5×ULN(淋巴瘤累及肝脏或胆道阻塞者，≤5×ULN)；
血清总胆红素(TBIL)≤1.5×ULN；
血清肌酐(Cr)≤1.5×ULN或肌酐清除率≥50mL/min；
凝血功能：
活化部分凝血活酶时间(APTT)、国际标准化比值(INR)、凝血酶原时间(PT)≤1.5×ULN；
7)女性应同意在研究期间和研究结束后6个月内必须采用避孕措施(如宫内节育器[IUD]，避孕药或避孕套)；在研究入组前的7天内血清或尿妊娠试验阴性，且必须为非哺乳期患者；男性应同意在研究期间和研究期结束后6个月内必须采用避孕措施。
6.3评价方法及指标
参考IWCLL2008评价标准和2014版Lugano会议修订的评效标准评价疗效。
主要疗效评价指标：客观缓解率(ORR)，即CR+PR例数/总例数，包含完全缓解(CR)和部分缓解(PR)的病例。
次要疗效评价指标：无进展生存期(PFS)、总生存期(OS)、疾病控制率(DCR)、缓解持续时间(DOR)。
6.4试验结果
式I化合物对小淋巴细胞淋巴瘤或慢性淋巴细胞白血病具有良好的治疗效果。同时，式I化合物在治疗使用时，具有良好的安全性。

Claims (18)

  1. 用于治疗患者的淋巴瘤的式I化合物、或其药学上可接受的盐：
    Figure PCTCN2021076423-appb-100001
  2. 如权利要求1所述的式I化合物、或其药学上可接受的盐，其中，所述淋巴瘤选自霍奇金淋巴瘤和非霍奇金淋巴瘤。
  3. 如权利要求1或2所述的式I化合物、或其药学上可接受的盐，其中，所述淋巴瘤选自B细胞淋巴瘤或T细胞淋巴瘤；或者，所述淋巴瘤选自经典型霍奇金淋巴瘤(CHL)、结节性淋巴细胞霍奇金淋巴瘤、套细胞淋巴瘤(MCL)、滤泡性淋巴瘤(FL)、弥漫大B细胞淋巴瘤(DLBCL)、小淋巴细胞淋巴瘤(SLL)或慢性淋巴细胞白血病(CLL)。
  4. 如权利要求2所述的式I化合物、或其药学上可接受的盐，其中，所述非霍奇金淋巴瘤选自B细胞淋巴瘤或T细胞淋巴瘤；或者，所述非霍奇金淋巴瘤选自套细胞淋巴瘤(MCL)、滤泡性淋巴瘤(FL)、弥漫大B细胞淋巴瘤(DLBCL)、小淋巴细胞淋巴瘤(SLL)或慢性淋巴细胞白血病(CLL)。
  5. 如权利要求2所述的式I化合物、或其药学上可接受的盐，其中，所述霍奇金淋巴瘤选自经典型霍奇金淋巴瘤或结节性淋巴细胞霍奇金淋巴瘤；优选地，所述经典型霍奇金淋巴瘤选自结节硬化型、富于淋巴细胞型、混合细胞型和淋巴细胞消减型。
  6. 如权利要求1-5中任一项所述的式I化合物、或其药学上可接受的盐，其中，所述淋巴瘤的患者已接受过一种或两种以上在先治疗方案的治疗；任选地，所述淋巴瘤的患者已接受过一种、两种、三种、四种、或五种在先治疗方案的治疗。
  7. 如权利要求1-6中任一项所述的式I化合物、或其药学上可接受的盐，其中，所述淋巴瘤选自复发或难治性淋巴瘤；任选地，所述淋巴瘤的患者已接受在先治疗方案治疗达到客观缓解后，疾病再次发生，或者所述淋巴瘤的患者对于在先治疗方案无客观缓解。
  8. 如权利要求1-7中任一项所述的式I化合物、或其药学上可接受的盐，其中，所述淋巴瘤的患者是已接受过利妥昔单抗和/或BTK抑制剂治疗的淋巴瘤患者；任选地，所述淋巴瘤的患者是已接受过利妥昔单抗和/或BTK抑制剂治疗的复发或难治性淋巴瘤患者。
  9. 如权利要求1-8中任一项所述的式I化合物、或其药学上可接受的盐，其中，所述淋巴瘤的患者是CD20阳性、CD30阳性、CD38阳性和/或ZAP70阳性的淋巴瘤的患者；任选地，所述淋巴瘤的患者是CD20阳性，并且是已接受利妥昔单抗治疗的复发或难治性淋巴瘤的患者。
  10. 如权利要求6所述的式I化合物、或其药学上可接受的盐，其中，所述在先治疗方案包括药物治疗、放疗、或造血干细胞移植。
  11. 如权利要求10所述的式I化合物、或其药学上可接受的盐，其中，所述药物治疗包括干扰素治疗、化疗、或靶向药物治疗；优选地，所述放疗选自全淋巴照射和次全淋巴照射，任选地，所述放疗包括受累野照射、累及淋巴结或累及部位照射；所述造血干细胞移植包括自体造血干细胞移植、或异体造血干细胞移植。
  12. 如权利要求10或11所述的式I化合物、或其药学上可接受的盐，其中，所述药物治疗所用的药物选自于由以下所组成的组中的一种或多种：干扰素、环磷酰胺、异环磷酰胺、长春新碱、长春瑞滨、泼尼松、泼尼松龙、多柔比星、硼替佐米、阿霉素、表阿霉素、博来霉素、地塞米松、甲氨蝶呤、阿糖胞苷、卡铂、顺铂、苯达莫司汀、氟达拉滨、米托蒽醌、依托泊苷、甲基苄肼、吉西他滨、卡氮芥、甲泼尼龙、甲泼尼龙琥珀酸钠、美司那、奥沙利铂、5-氟尿嘧啶、苯丁酸氮芥、达卡巴嗪、利妥昔单抗、CHO-H01、ocaratuzumab、 替伊莫单抗、乌妥昔单抗、奥比妥珠单抗、brentuximab vedotin、伊布替尼、ICP-022、阿卡替尼、泽布替尼、哌柏西利、abemaciclib、替西罗莫司、依维莫司、卡非佐米、伊沙佐米、尼拉帕利、umbralisib、来那度胺、维纳妥拉、伏立诺他、阿扎胞苷、BR-101801、tazemetostat、或abexinostat，或其组合。
  13. 如权利要求1-12中任一项所述的式I化合物、或其药学上可接受的盐，其中，所述治疗患者的淋巴瘤的给药周期是2～6周。
  14. 如权利要求1-13中任一项所述的式I化合物、或其药学上可接受的盐，其中，所述治疗患者的淋巴瘤的每日剂量选自1～100mg。
  15. 如权利要求1-14中任一项所述的式I化合物、或其药学上可接受的盐，其中，所述治疗患者的淋巴瘤的每日给药次数是1次、2次或3次。
  16. 式I化合物、或其药学上可接受的盐在制备治疗患者的淋巴瘤的药物或药物组合物中的用途。
  17. 式I化合物、或其药学上可接受的盐在治疗患者的淋巴瘤中的用途。
  18. 一种治疗患者的淋巴瘤的方法，所述方法包括向患者给予式I化合物、或其药学上可接受的盐。
PCT/CN2021/076423 2020-02-10 2021-02-10 吡啶并[1,2-a]嘧啶酮化合物的治疗淋巴瘤的用途 WO2021160147A1 (zh)

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CN202180011103.6A CN115003674A (zh) 2020-02-10 2021-02-10 吡啶并[1,2-a]嘧啶酮化合物的治疗淋巴瘤的用途
AU2021218925A AU2021218925A1 (en) 2020-02-10 2021-02-10 Use of pyrido[1,2-a]pyrimidinone compound in treating lymphoma
US17/798,605 US20230132982A1 (en) 2020-02-10 2021-02-10 Use of pyrido[1,2-a]pyrimidinone compound in treating lymphoma
CA3170021A CA3170021A1 (en) 2020-02-10 2021-02-10 Use of pyrido[1,2-a]pyrimidinone compound in treating lymphoma

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WO2015192760A1 (zh) 2014-06-17 2015-12-23 南京明德新药研发股份有限公司 作为pi3k抑制剂的吡啶并［1，2-a］嘧啶酮类似物
CN105461711A (zh) * 2014-06-17 2016-04-06 南京明德新药研发股份有限公司 作为PI3K抑制剂的吡啶并[1,2-a]嘧啶酮类似物

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