Vinblastine Sulfate

Four-year Analysis Conducted by GHSG Reported ADCETRIS + ECADD Combination Improved Progression-Free Survival, Showing Superior Efficacy and Tolerable Safety Pro Patients with Newly Diagnosed Stage IIb/III/IV Classical Hodgkin Lymphoma vs eBEACOPP, a Current Standard of Care in This Setting in Europe The HD21 Study Adds to the Body of Evidence Supporting ADCETRIS as a Backbone Agent in the Treatment of Specific Lymphomas Results To Be Featured as Oral Presentations at ASCO and EHA 2024 OSAKA, Japan & CAMBRIDGE, Mass. & NEW YORK--(BUSINESS WIRE)-- Takeda (TSE:4502/NYSE:TAK) and Pfizer (NYSE: PFE) today announced that the German Hodgkin Study Group (GHSG) will present positive results from the Phase 3 HD21 trial evaluating ADCETRIS® (brentuximab vedotin) in combination with chemotherapy as a late-breaking oral presentation at the 60th American Society of Clinical Oncology (ASCO) Annual Meeting (LBA7000) and at the 29th European Hematology Association (EHA) Annual Meeting (S225). The four-year analysis presented by the GHSG showed superior progression-free survival (PFS) and improved tolerability for patients compared to a current standard of care regimen used in Europe in this setting. The HD21 study is a Phase 3, randomized, multi-country, prospective, open-label study, sponsored by the GHSG and supported by Takeda, designed to evaluate ADCETRIS in combination with etoposide, cyclophosphamide, doxorubicin, dacarbazine and dexamethasone (BrECADD) in comparison to a standard of care treatment – escalated doses of bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, prednisone (eBEACOPP) – in patients with newly diagnosed Stage IIb/III/IV classical Hodgkin lymphoma. At a preplanned three-year analysis, the study met its co-primary endpoints, with the ADCETRIS combination regimen demonstrating significantly improved safety as assessed by treatment-related morbidity (TRMB) and non-inferior PFS. The study found that the addition of ADCETRIS to this chemotherapy regimen improved the risk-to-benefit pro the combination treatment, maintaining efficacy with significantly fewer acute and long-lasting treatment-related toxicities than the comparator arm. “We initiated the HD21 trial with the hope of improving outcomes currently being achieved by a standard of care, as many patients with newly diagnosed disease often experience a high treatment burden,” said Peter Borchmann, MD, PhD, University Hospital of Cologne, Germany, and trial chairman of the HD21 study. “The presented analysis, in which the ADCETRIS regimen demonstrates superior progression-free survival, as well as a tolerable safety profile, reveals the meaningful potential this ADCETRIS + ECADD regimen has to offer these patients.” The ASCO presentation provides details of a four-year PFS analysis of the HD21 study conducted by GHSG. After 48 months, BrECADD showed superior efficacy to BEACOPP (94.3% PFS for BrECADD and 90.9% PFS for eBEACOPP; hazard ratio [HR]: 0.66 [95% CI:88.7-93.1]; p<0.035). As previously reported in the three-year analysis, treatment with BrECADD was also associated with a significant reduction in the incidence of TRMB compared with BEACOPP (n=738; 42% vs 59%; p<0.001), as well as clinically meaningful reductions in adverse events (AEs). The safety pro ADCETRIS in patients receiving BrECADD remained consistent with other approved ADCETRIS combination regimens, and no new safety signals were identified. “In our ongoing effort to improve outcomes for patients with lymphoma, we’ve partnered with the GHSG on the HD21 study to deepen our understanding of how ADCETRIS could further benefit patients in need of new options,” said Awny Farajallah, chief medical officer, global oncology at Takeda. “We are excited about the impact these results could have on patients with newly diagnosed Hodgkin lymphoma, potentially bringing them an additional ADCETRIS-based combination regimen that may significantly reduce side effects without compromising on efficacy.” Takeda will be responsible for submission of potential regulatory filings based on the HD21 study outside of the U.S. and Canada. Under the terms of the collaboration agreement, Pfizer has U.S. and Canadian commercialization rights and Takeda has rights to commercialize ADCETRIS in the rest of the world. About the HD21 Trial The HD21 study is a Phase 3, multi-country, prospective, open-label, randomized, multicenter trial sponsored by the German Hodgkin Study Group (GHSG) with a PET-response adapted designed to assess the feasibility, efficacy, safety and tolerability of BrECADD, a novel, rationally designed, CD30-intensified frontline regimen for patients with advanced classical Hodgkin lymphoma. Enrolled patients with newly diagnosed, Stage IIb with large mediastinal mass and/or extranodal lesions, Stage III or IV Hodgkin lymphoma were randomized to receive two cycles of either escalated BEACOPP or BrECADD, respectively, followed by interim PET staging. A decision is then made if patients received a further two or four cycles of escalated BEACOPP or BrECADD. The HD21 trial aims to evaluate a modified treatment regimen to minimize side effects, while maintaining similar responses to treatment. The study has co-primary endpoints: safety is assessed by treatment-related morbidity (TRMB) (superiority), a novel endpoint focused on clinically relevant, acute toxicities of primary chemotherapy, and efficacy is assessed by PFS (non-inferiority). Secondary endpoints are tumor response (complete response [CR] rate), overall survival (OS), infertility rate at one year, second malignancies, frequency of adverse events, therapy adherence and quality of life. About Hodgkin Lymphoma Lymphoma is a general term for a group of cancers that originate in the lymphatic system affecting a type of white blood cell called lymphocytes. There are two major categories of lymphoma: Hodgkin lymphoma (HL) and non-Hodgkin lymphoma. Hodgkin lymphoma is distinguished from other types of lymphoma by the presence of one characteristic type of cell, known as the Reed-Sternberg cell, present in lymph nodes. Reed-Sternberg cells usually have a special protein on their surface called CD30, which is a key marker of HL. CD30 is present in approximately 95 percent of all cases of Hodgkin lymphoma. According to the International Agency for Research on Cancer, in 2020, over 83,000 people worldwide were diagnosed with Hodgkin lymphoma and approximately 23,000 people died from this cancer. About ADCETRIS® (brentuximab vedotin) ADCETRIS is an antibody-drug conjugate (ADC) comprising an anti-CD30 monoclonal antibody attached by a protease-cleavable linker to a microtubule disrupting agent, monomethyl auristatin E (MMAE), utilizing Pfizer’s proprietary technology. The ADC employs a linker system that is designed to be stable in the bloodstream but to release MMAE upon internalization into CD30-positive tumor cells. ADCETRIS injection for intravenous infusion has received FDA approval for seven indications: Adult patients with previously untreated Stage III/IV classical Hodgkin lymphoma (cHL) in combination with doxorubicin, vinblastine, and dacarbazine (2018) Pediatric patients 2 years and older with previously untreated high risk cHL in combination with doxorubicin, vincristine, etoposide, prednisone and cyclophosphamide (2022) Adult patients with cHL at high risk of relapse or progression as post-autologous hematopoietic stem cell transplantation (auto-HSCT) consolidation (2015) Adult patients with cHL after failure of auto-HSCT or after failure of at least two prior multi-agent chemotherapy regimens in patients who are not auto-HSCT candidates (2011) Adult patients with previously untreated systemic anaplastic large cell lymphoma (sALCL) or other CD30-expressing peripheral T-cell lymphomas (PTCL), including angioimmunoblastic T-cell lymphoma and PTCL not otherwise specified, in combination with cyclophosphamide, doxorubicin, and prednisone (2018) Adult patients with sALCL after failure of at least one prior multi-agent chemotherapy regimen. (2011) Adult patients with primary cutaneous anaplastic large cell lymphoma (pcALCL) or CD30-expressing mycosis fungoides (MF) after prior systemic therapy (2017) Health Canada granted ADCETRIS approval with conditions for relapsed or refractory Hodgkin lymphoma and sALCL in 2013, and non-conditional approval for post-autologous stem cell transplantation (ASCT) consolidation treatment of Hodgkin lymphoma patients at increased risk of relapse or progression in 2017, adults with pcALCL or CD30-expressing MF who have had prior systemic therapy in 2018, for previously untreated Stage IV Hodgkin lymphoma in combination with doxorubicin, vinblastine, and dacarbazine in 2019, and for previously untreated adult patients with sALCL, peripheral T-cell lymphoma-not otherwise specified (PTCL-NOS) or angioimmunoblastic T-cell lymphoma (AITL), whose tumors express CD30, in combination with cyclophosphamide, doxorubicin, prednisone in 2019. ADCETRIS received conditional marketing authorization from the European Commission in October 2012, and the specific obligations of the conditional marketing authorization were fulfilled in May 2022. The approved indications in the European Union are: (1) for the treatment of adult patients with previously untreated CD30-positive Stage III & IV Hodgkin lymphoma in combination with doxorubicin, vinblastine and dacarbazine (AVD), (2) for the treatment of adult patients with CD30-positive Hodgkin lymphoma at increased risk of relapse or progression following ASCT, (3) for the treatment of adult patients with relapsed or refractory CD30-positive Hodgkin lymphoma following ASCT, or following at least two prior therapies when ASCT or multi-agent chemotherapy is not a treatment option, (4) for the treatment of adult patients with relapsed or refractory sALCL, (5) for the treatment of adult patients with previously untreated sALCL in combination with CHP and (6) for the treatment of adult patients with CD30-positive cutaneous T-cell lymphoma (CTCL) after at least one prior systemic therapy. ADCETRIS has received marketing authorization by regulatory authorities in more than 70 countries for relapsed or refractory Hodgkin lymphoma and sALCL. See Important Safety Information below. ADCETRIS is being evaluated broadly in more than 70 clinical trials, including a Phase 3 study in first-line Hodgkin lymphoma (ECHELON-1) and another Phase 3 study in first-line CD30-positive peripheral T-cell lymphomas (ECHELON-2), as well as trials in many additional types of CD30-positive malignancies. Pfizer and Takeda fund joint development costs for ADCETRIS on a 50:50 basis, except in Japan where Takeda is solely responsible for development costs. ADCETRIS (brentuximab vedotin) Important Safety Information (European Union) Please refer to Summary of Product Characteristics (SmPC) before prescribing. Contraindications ADCETRIS is contraindicated for patients with hypersensitivity to brentuximab vedotin and its excipients. In addition, combined use of ADCETRIS with bleomycin causes pulmonary toxicity. Special Warnings and Precautions Progressive multifocal leukoencephalopathy (PML): John Cunningham virus (JCV) reactivation resulting in progressive multifocal leukoencephalopathy (PML) and death can occur in patients treated with ADCETRIS. PML has been reported in patients who received ADCETRIS after receiving multiple prior chemotherapy regimens. PML is a rare demyelinating disease of the central nervous system that results from reactivation of latent JCV and is often fatal. Closely monitor patients for new or worsening neurological, cognitive, or behavioral signs or symptoms, which may be suggestive of PML. Suggested evaluation of PML includes neurology consultation, gadolinium-enhanced magnetic resonance imaging of the brain, and cerebrospinal fluid analysis for JCV DNA by polymerase chain reaction or a brain biopsy with evidence of JCV. A negative JCV PCR does not exclude PML. Additional follow-up and evaluation may be warranted if no alternative diagnosis can be established. Hold dosing for any suspected case of PML and permanently discontinue ADCETRIS if a diagnosis of PML is confirmed. Be alert to PML symptoms that the patient may not notice (e.g., cognitive, neurological, or psychiatric symptoms). Pancreatitis: Acute pancreatitis has been observed in patients treated with ADCETRIS. Fatal outcomes have been reported. Closely monitor patients for new or worsening abdominal pain, which may be suggestive of acute pancreatitis. Patient evaluation may include physical examination, laboratory evaluation for serum amylase and serum lipase, and abdominal imaging, such as ultrasound and other appropriate diagnostic measures. Hold ADCETRIS for any suspected case of acute pancreatitis. ADCETRIS should be discontinued if a diagnosis of acute pancreatitis is confirmed. Pulmonary Toxicity: Cases of pulmonary toxicity, some with fatal outcomes, including pneumonitis, interstitial lung disease, and acute respiratory distress syndrome (ARDS), have been reported in patients receiving ADCETRIS. Although a causal association with ADCETRIS has not been established, the risk of pulmonary toxicity cannot be ruled out. Promptly evaluate and treat new or worsening pulmonary symptoms (e.g., cough, dyspnea) appropriately. Consider holding dosing during evaluation and until symptomatic improvement. Serious infections and opportunistic infections: Serious infections such as pneumonia, staphylococcal bacteremia, sepsis/septic shock (including fatal outcomes), and herpes zoster, cytomegalovirus (CMV) (reactivation) and opportunistic infections such as Pneumocystis jiroveci pneumonia and oral candidiasis have been reported in patients treated with ADCETRIS. Patients should be carefully monitored during treatment for the emergence of possible serious and opportunistic infections. Infusion-related reactions (IRR): Immediate and delayed IRR, as well as anaphylaxis, have been reported with ADCETRIS. Carefully monitor patients during and after an infusion. If anaphylaxis occurs, immediately and permanently discontinue administration of ADCETRIS and administer appropriate medical therapy. If an IRR occurs, interrupt the infusion and institute appropriate medical management. The infusion may be restarted at a slower rate after symptom resolution. Patients who have experienced a prior IRR should be premedicated for subsequent infusions. IRRs are more frequent and more severe in patients with antibodies to ADCETRIS. Tumor lysis syndrome (TLS): TLS has been reported with ADCETRIS. Patients with rapidly proliferating tumor and high tumor burden are at risk of TLS. Monitor these patients closely and manage according to best medical practice. Peripheral neuropathy (PN): ADCETRIS treatment may cause PN, both sensory and motor. ADCETRIS-induced PN is typically an effect of cumulative exposure to ADCETRIS and is reversible in most cases. Monitor patients for symptoms of neuropathy, such as hypoesthesia, hyperesthesia, paresthesia, discomfort, a burning sensation, neuropathic pain, or weakness. Patients experiencing new or worsening PN may require a delay and a dose reduction or discontinuation of ADCETRIS. Hematological toxicities: Grade 3 or Grade 4 anemia, thrombocytopenia, and prolonged (equal to or greater than one week) Grade 3 or Grade 4 neutropenia can occur with ADCETRIS. Monitor complete blood counts prior to administration of each dose. Febrile neutropenia: Febrile neutropenia has been reported with ADCETRIS. Complete blood counts should be monitored prior to administration of each dose of treatment. Closely monitor patients for fever and manage according to best medical practice if febrile neutropenia develops. When ADCETRIS is administered in combination with AVD or CHP, primary prophylaxis with G-CSF is recommended for all patients beginning with the first dose. Severe cutaneous adverse reactions (SCARs): Cases of SCARs, including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN) and drug reaction with eosinophilia and systemic symptoms (DRESS) have been reported with ADCETRIS. Fatal outcomes have been reported for SJS and TEN. If SJS, TEN or DRESS occur, ADCETRIS should be discontinued and appropriate medical therapy should be administered. Gastrointestinal (GI) Complications: GI complications, some with fatal outcomes, including intestinal obstruction, ileus, enterocolitis, neutropenic colitis, erosion, ulcer, perforation and haemorrhage, have been reported with ADCETRIS. Promptly evaluate and treat patients if new or worsening GI symptoms occur. Hepatotoxicity: Elevations in alanine aminotransferase (ALT) and aspartate aminotransferase (AST) have been reported with ADCETRIS. Serious cases of hepatotoxicity, including fatal outcomes, have also occurred. Pre-existing liver disease, comorbidities, and concomitant medications may also increase the risk. Test liver function prior to treatment initiation and routinely monitor during treatment. Patients experiencing hepatotoxicity may require a delay, dose modification, or discontinuation of ADCETRIS. Hyperglycemia: Hyperglycemia has been reported during trials in patients with an elevated body mass index (BMI) with or without a history of diabetes mellitus. Closely monitor serum glucose for patients who experience an event of hyperglycemia. Administer anti-diabetic treatment as appropriate. Infusion site extravasation: Extravasation during intravenous infusion has occurred. Given the possibility of extravasation, it is recommended to closely monitor the infusion site for possible infiltration during drug administration. Renal and Hepatic Impairment: There is limited experience in patients with renal and hepatic impairment. Available data indicate that MMAE clearance might be affected by severe renal impairment, hepatic impairment, and by low serum albumin concentrations. CD30+ CTCL: The size of the treatment effect in CD30 + CTCL subtypes other than mycosis fungoides (MF) and primary cutaneous anaplastic large cell lymphoma (pcALCL) is not clear due to lack of high level evidence. In two single arm phase II studies of ADCETRIS, disease activity has been shown in the subtypes Sézary syndrome (SS), lymphomatoid papulosis (LyP) and mixed CTCL histology. These data suggest that efficacy and safety can be extrapolated to other CTCL CD30+ subtypes. Carefully consider the benefit-risk per patient and use with caution in other CD30+ CTCL patient types. Sodium content in excipients: This medicinal product contains 13.2 mg sodium per vial, equivalent to 0.7% of the WHO recommended maximum daily intake of 2 g sodium for an adult. Traceability: In order to improve the traceability of biological medicinal products, the name and the batch number of the administered product should be clearly recorded. INTERACTIONS Patients who are receiving a strong CYP3A4 and P-gp inhibitor, concomitantly with ADCETRIS may have an increased risk of neutropenia. If neutropenia develops, refer to dosing recommendations for neutropenia (see SmPC section 4.2). Co-administration of ADCETRIS with a CYP3A4 inducer did not alter the plasma exposure of ADCETRIS, but it appeared to reduce plasma concentrations of MMAE metabolites that could be assayed. ADCETRIS is not expected to alter the exposure to drugs that are metabolized by CYP3A4 enzymes. PREGNANCY: Advise women of childbearing potential to use two methods of effective contraception during treatment with ADCETRIS and until 6 months after treatment. There are no data from the use of ADCETRIS in pregnant women, although studies in animals have shown reproductive toxicity. Do not use ADCETRIS during pregnancy unless the benefit to the mother outweighs the potential risks to the fetus. LACTATION (breast-feeding): There are no data as to whether ADCETRIS or its metabolites are excreted in human milk, therefore a risk to the newborn/infant cannot be excluded. A decision should be made whether to discontinue breast-feeding or to discontinue/abstain from this therapy, taking into account a potential risk of breast-feeding for the child and the benefit of therapy for the woman. FERTILITY: In non-clinical studies, brentuximab vedotin treatment has resulted in testicular toxicity, and may alter male fertility. MMAE has been shown to have anagenic properties. Therefore, men being treated with this medicine are advised to have sperm samples frozen and stored before treatment. Men being treated with this medicine are advised not to father a child during treatment and for up to 6 months following the last dose. Effects on ability to drive and use machines: ADCETRIS may have a moderate influence on the ability to drive and use machines. UNDESIRABLE EFFECTS Monotherapy: The most frequent adverse reactions (≥10%) were infections, peripheral sensory neuropathy, nausea, fatigue, diarrhea, pyrexia, upper respiratory tract infection, neutropenia, rash, cough, vomiting, arthralgia, peripheral motor neuropathy, infusion-related reactions, pruritus, constipation, dyspnea, weight decreased, myalgia and abdominal pain. Serious adverse drug reactions occurred in 12% of patients. The frequency of unique serious adverse drug reactions was ≤1%. Adverse events led to treatment discontinuation in 24% of patients. Combination Therapy: In the studies of ADCETRIS as combination therapy in 662 patients with previously untreated advanced HL (C25003) and 223 patients with previously untreated CD30+ PTCL, the most common adverse reactions (≥ 10%) were: infections, neutropenia, peripheral sensory neuropathy, nausea, constipation, vomiting, diarrhea, fatigue, pyrexia, alopecia, anemia, weight decreased, stomatitis, febrile neutropenia, abdominal pain, decreased appetite, insomnia, bone pain, rash, cough, dyspnea, arthralgia, myalgia, back pain, peripheral motor neuropathy, upper respiratory tract infection, and dizziness. In patients receiving ADCETRIS combination therapy, serious adverse reactions occurred in 34% of patients. Serious adverse reactions occurring in ≥ 3% of patients included febrile neutropenia (15%), pyrexia (5%), and neutropenia (3%). Adverse events led to treatment discontinuation in 10% of patients. ADCETRIS® (brentuximab vedotin) for injection U.S. Important Safety Information BOXED WARNING PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY (PML): JC virus infection resulting in PML, and death can occur in ADCETRIS-treated patients. CONTRAINDICATION Contraindicated with concomitant bleomycin due to pulmonary toxicity (e.g., interstitial infiltration and/or inflammation). WARNINGS AND PRECAUTIONS Peripheral neuropathy (PN): ADCETRIS causes PN that is predominantly sensory. Cases of motor PN have also been reported. ADCETRIS-induced PN is cumulative. Monitor for symptoms such as hypoesthesia, hyperesthesia, paresthesia, discomfort, a burning sensation, neuropathic pain, or weakness. Patients experiencing new or worsening PN may require a delay, change in dose, or discontinuation of ADCETRIS. Anaphylaxis and infusion reactions: Infusion-related reactions (IRR), including anaphylaxis, have occurred with ADCETRIS. Monitor patients during infusion. If an IRR occurs, interrupt the infusion and institute appropriate medical management. If anaphylaxis occurs, immediately and permanently discontinue the infusion and administer appropriate medical therapy. Premedicate patients with a prior IRR before subsequent infusions. Premedication may include acetaminophen, an antihistamine, and a corticosteroid. Hematologic toxicities: Fatal and serious cases of febrile neutropenia have been reported with ADCETRIS. Prolonged (≥1 week) severe neutropenia and Grade 3 or 4 thrombocytopenia or anemia can occur with ADCETRIS. Administer G-CSF primary prophylaxis beginning with Cycle 1 for adult patients who receive ADCETRIS in combination with chemotherapy for previously untreated Stage III/IV cHL or previously untreated PTCL, and pediatric patients who receive ADCETRIS in combination with chemotherapy for previously untreated high risk cHL. Monitor complete blood counts prior to each ADCETRIS dose. Monitor more frequently for patients with Grade 3 or 4 neutropenia. Monitor patients for fever. If Grade 3 or 4 neutropenia develops, consider dose delays, reductions, discontinuation, or G-CSF prophylaxis with subsequent doses. Serious infections and opportunistic infections: Infections such as pneumonia, bacteremia, and sepsis or septic shock (including fatal outcomes) have been reported in ADCETRIS-treated patients. Closely monitor patients during treatment for infections. Tumor lysis syndrome: Patients with rapidly proliferating tumor and high tumor burden may be at increased risk. Monitor closely and take appropriate measures. Increased toxicity in the presence of severe renal impairment: The frequency of ≥Grade 3 adverse reactions and deaths was greater in patients with severe renal impairment. Avoid use in patients with severe renal impairment. Increased toxicity in the presence of moderate or severe hepatic impairment: The frequency of ≥Grade 3 adverse reactions and deaths was greater in patients with moderate or severe hepatic impairment. Avoid use in patients with moderate or severe hepatic impairment. Hepatotoxicity: Fatal and serious cases have occurred in ADCETRIS-treated patients. Cases were consistent with hepatocellular injury, including elevations of transaminases and/or bilirubin, and occurred after the first ADCETRIS dose or rechallenge. Preexisting liver disease, elevated baseline liver enzymes, and concomitant medications may increase the risk. Monitor liver enzymes and bilirubin. Patients with new, worsening, or recurrent hepatotoxicity may require a delay, change in dose, or discontinuation of ADCETRIS. PML: Fatal cases of JC virus infection resulting in PML have been reported in ADCETRIS-treated patients. First onset of symptoms occurred at various times from initiation of ADCETRIS, with some cases occurring within 3 months of initial exposure. In addition to ADCETRIS therapy, other possible contributory factors include prior therapies and underlying disease that may cause immunosuppression. Consider PML diagnosis in patients with new-onset signs and symptoms of central nervous system abnormalities. Hold ADCETRIS if PML is suspected and discontinue ADCETRIS if PML is confirmed. Pulmonary toxicity: Fatal and serious events of noninfectious pulmonary toxicity, including pneumonitis, interstitial lung disease, and acute respiratory distress syndrome, have been reported. Monitor patients for signs and symptoms, including cough and dyspnea. In the event of new or worsening pulmonary symptoms, hold ADCETRIS dosing during evaluation and until symptomatic improvement. Serious dermatologic reactions: Fatal and serious cases of Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) have been reported with ADCETRIS. If SJS or TEN occurs, discontinue ADCETRIS and administer appropriate medical therapy. Gastrointestinal (GI) complications: Fatal and serious cases of acute pancreatitis have been reported. Other fatal and serious GI complications include perforation, hemorrhage, erosion, ulcer, intestinal obstruction, enterocolitis, neutropenic colitis, and ileus. Lymphoma with pre-existing GI involvement may increase the risk of perforation. In the event of new or worsening GI symptoms, including severe abdominal pain, perform a prompt diagnostic evaluation and treat appropriately. Hyperglycemia: Serious cases, such as new-onset hyperglycemia, exacerbation of pre-existing diabetes mellitus, and ketoacidosis (including fatal outcomes) have been reported with ADCETRIS. Hyperglycemia occurred more frequently in patients with high body mass index or diabetes. Monitor serum glucose and if hyperglycemia develops, administer anti-hyperglycemic medications as clinically indicated. Embryo-fetal toxicity: Based on the mechanism of action and animal studies, ADCETRIS can cause fetal harm. Advise females of reproductive potential of this potential risk, and to use effective contraception during ADCETRIS treatment and for 2 months after the last dose of ADCETRIS. Advise male patients with female partners of reproductive potential to use effective contraception during ADCETRIS treatment and for 4 months after the last dose of ADCETRIS. ADVERSE REACTIONS The most common adverse reactions (≥20% in any study) are peripheral neuropathy, fatigue, nausea, diarrhea, neutropenia, upper respiratory tract infection, pyrexia, constipation, vomiting, alopecia, decreased weight, abdominal pain, anemia, stomatitis, lymphopenia, mucositis, thrombocytopenia, and febrile neutropenia. DRUG INTERACTIONS Concomitant use of strong CYP3A4 inhibitors has the potential to affect the exposure to monomethyl auristatin E (MMAE). Closely monitor adverse reactions. USE IN SPECIAL POPULATIONS Lactation: Breastfeeding is not recommended during ADCETRIS treatment. Please see the full Prescribing Information, including BOXED WARNING, for ADCETRIS here. About Takeda Takeda is focused on creating better health for people and a brighter future for the world. 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Pfizer assumes no obligation to update forward-looking statements contained in this release as the result of new information or future events or developments. This release contains forward-looking information about ADCETRIS (brentuximab vedotin), including its potential benefits, its potential in newly diagnosed Stage IIb/III/IV classical Hodgkin lymphoma, and potential regulatory filings, that involves substantial risks and uncertainties that could cause actual results to differ materially from those expressed or implied by such statements. Risks and uncertainties include, among other things, uncertainties regarding the commercial success of ADCETRIS; the uncertainties inherent in research and development, including the ability to meet anticipated clinical endpoints, commencement and/or completion dates for our clinical trials, regulatory submission dates, regulatory approval dates and/or launch dates, as well as the possibility of unfavorable new clinical data and further analyses of existing clinical data; the risk that clinical trial data are subject to differing interpretations and assessments by regulatory authorities; whether regulatory authorities will be satisfied with the design of and results from our clinical studies; whether and when drug applications may be filed in particular jurisdictions for ADCETRIS with eCADD or as a single agent for any potential indication; whether and when any applications that may be pending or filed for ADCETRIS, may be approved by regulatory authorities, which will depend on myriad factors, including making a determination as to whether the product's benefits outweigh its known risks and determination of the product's efficacy and, if approved, whether ADCETRIS with eCADD or as a single agent will be commercially successful; decisions by regulatory authorities impacting labeling, manufacturing processes, safety and/or other matters that could affect the availability or commercial potential of ADCETRIS; uncertainties regarding the impact of COVID-19 on Pfizer’s business, operations and financial results; and competitive developments. A further description of risks and uncertainties can be found in Pfizer’s Annual Report on Form 10-K for the fiscal year ended December 31, 2023 and in its subsequent reports on Form 10-Q, including in the sections thereof captioned “Risk Factors” and “Forward-Looking Information and Factors That May Affect Future Results”, as well as in its subsequent reports on Form 8-K, all of which are filed with the U.S. Securities and Exchange Commission and available at and . View source version on businesswire.com: Contacts Takeda Media Contacts: Japanese Media Jun Saito jun.saito@takeda.com +81 (0) 3-3278-2325 U.S. and International Media Emy Gruppo emy.gruppo@takeda.com Pfizer Contacts: Media +1 (212) 733-1226 PfizerMediaRelations@pfizer.com Investor Relations +1 (212) 733-4848 IR@pfizer.com Source: Takeda Pharmaceutical Company Limited View this news release online at:

前言有效载荷（payload）是ADC发挥肿瘤杀伤作用的重要武器，其作用机制很大程度上决定了ADC药物的性能，而其活性和理化性质对抗肿瘤疗效也有直接影响，因此其重要性不言而喻。在日趋成熟的技术驱动下，有效载荷已经历了三代创新，从第一代ADC使用的细胞毒性载荷如甲氨蝶呤（Methotrexate）、长春花碱（Vinblastine）和阿霉素（Doxorubicin），发展到以微管蛋白抑制剂（Maytansine）为主的第二代新型高效有效载荷，以及以DNA损伤剂为代表的第三代有效载荷。当前，基于不同的作用机制和功能需求，有更多的新型载荷在探索和开发中（如图1所示）。本文从有效载荷的理想特征、多样性、作用机制等方面认识和探索其未来的创新之路。图1 ADC有效载荷的发展之路理想的有效载荷理想的有效载荷应具备以下几点：有足够强的细胞毒性有较低的免疫原性在循环系统有较高的稳定性有可修饰的功能结构提供偶联位点且不影响效力有旁观者杀伤效应有适当的水溶性作用靶点在胞内有效载荷的多样性目前，已获批ADC所使用的有效载荷包括了3种DNA损伤剂（2个calicheamicin, 1个pyrolobenzodiazepine dimer (PBD)和2个拓扑异构酶抑制剂），2种微管抑制剂（4个aurisatins和2个maytansinoids）和1种细菌毒素，前两者是现在临床试验中最常选择的有效载荷，但其他类型的有效载荷也在开发中。根据作用机制可大致分为如下几类：靶向微管的有效载荷、靶向DNA的有效载荷、靶向RNA的有效载荷、免疫类ADC有效载荷和其他新型潜力有效载荷（如图2所示）。图2 有效载荷的种类1. 靶向微管的有效载荷微管是真核细胞骨架的重要组成部分，参与多种细胞功能，包括维持细胞形态、信号转导、细胞器运输、细胞运动、细胞有丝分裂等，从而成为肿瘤治疗的重要靶点。靶向微管蛋白的抑制剂通过与微管蛋白结合，干扰微管的动态结合，使细胞生长停滞于细胞周期的G2/M期，最终导致细胞凋亡。其中，微管蛋白聚合增强剂，如奥瑞他汀类化合物MMAE和MMAF，作用于α,β微管蛋白二聚体的β亚基，使微管的生长不受调节。与之相反，微管蛋白聚合抑制剂，如美登素类化合物DM1和DM4，通过抑制微管的成熟，阻断微管蛋白二聚体的聚合。美登素类化合物（Maytansinoids）美登素最初是从非洲灌木卵圆梅藤（Maytenus ovatus）的树皮中分离出来的，是一类与微管蛋白结合并抑制微管组装的安莎类抗生素。在体外试验中，其皮摩尔级的IC50值表明美登素有很强的抑制肿瘤增殖分化的能力，同时具备很好的稳定性和水溶性使其成为ADC理想的候选有效载荷。由于天然美登素缺少反应功能结构，无法与抗体偶联，因此需要进行化学修饰。例如，将美登素C3侧链的N-乙酰基团替代为3-（甲硫基）丙醛基团，得到美登素衍生物DM1（如图3A-2），接着在DM1二硫键旁增加两个甲基基团即得到DM4（如图3A-3）。DM1和DM4通过二硫键与连接子偶联，并成为ADC药物开发中广泛使用的一类有效载荷。因为C3位点引入的修饰不会干扰药物的结合状态、亲和力和药效，因此更多针对C3位点的化学修饰研究正在开展。例如，酰化反应（如图3A-5）能进一步优化美登素衍生物的合成策略并降低多重耐药蛋白1（MDR1）介导的耐药性。图3 Maytansinoids类化合物结构示意图奥瑞他汀类化合物（Auristatins）海兔毒素（Dolastatin 10）于1987年从印度洋软体动物Dolabella auricularia中分离出来，有很强的的抗肿瘤细胞增殖作用，在纳摩尔浓度下可有效诱导肺癌细胞和其他肿瘤细胞凋亡。其水溶性合成类似物-奥瑞他汀（Auristatin），包括使用最广泛的MMAE和MMAF。MMAE由四个氨基酸构成，包括单甲基缬氨酸（MeVal）、缬氨酸（Val）、dolaisoleuine (Dil)和dolaproine (Dap)，以及C端的氨基去甲黄麻碱。把C端的氨基去甲黄麻碱替换为苯丙氨酸即得到MMAF，其结合亲和力增强，药效降低。目前，对于auristatin类似物的研究主要集中在C端或N端的化学修饰，以增强效力、提高膜渗透性、以及抑制膜外排泵作用等。例如将MMAF C端苯丙氨酸的羧酸替换成四唑或磷酸盐，其效价与MMAF作为有效载荷的效价相似。将海兔毒素N端用丙醇或叠氮化物修饰，细胞试验也显示出其不错的效力。此外，偶联位点（P2、P4）的化学修饰（如叠氮化修饰等）也为下一代auristatin衍生物的开发提供了新方向。图4 Auristatin类化合物结构示意图艾瑞布林（Eribulin）Halichondrin B是一种聚醚大环内酯类天然产物，其人工合成的新型紫杉烷类似物-甲磺酸艾瑞布林（Eribulin）于2010年被批准用于局部晚期和转移性乳腺癌患者治疗。Eribulin通过与β微管蛋白疏水和极性残基结合，抑制细胞有丝分裂。在不同的体外模型中，ADC- Eribulin对肿瘤细胞高效的清除使得eribulin成为有潜力的有效载荷。目前，第二代eribulin类似物的改造主要集中在C32侧链（如图5）。例如在C32引入低碱性胺或提高eribulin的亲脂性可以获得更好的抗肿瘤活性或扩展药物治疗的肿瘤类型。图5 Eribulin类化合物结构示意图微管蛋白抑素（Tubulysins）微管蛋白抑素（Tubulysins）是从黏菌培养基中分离出来的一种天然抗有丝分裂的线性四肽，由Mep、L-Ile、Tuv和Tup/Tut组成（如图6）。Tubulysins的化学修饰多位于Mep、Tuv和含有偶联位点的Tup。例如用五环取代N端Mep的六环对药物活性影响很小；而将Tuv残基的C11进行乙酰化修饰则会显著降低活性。图6 Tubulysins类化合物结构示意图驱动蛋白抑制剂（EG5 inhibitors）EG5在血液瘤和实体瘤中高表达，且与预后不良有关，因此成为有吸引力的癌症治疗靶点。多个EG5抑制剂如SB-715992（Ispinesib）和Filanesib（ARRY-520）都已用于临床研究中。作为ADC有效载荷，EG5抑制剂可以减少其单独使用带来的副反应，如嗜中性白血球减少症、粘膜炎、胃炎以及治疗窗口窄等。2. 靶向DNA的有效载荷与微管蛋白抑制剂相比，DNA抑制剂通过使双链DNA断裂、烷基化、嵌合、交联等，作用于整个细胞周期，引起细胞毒性作用，对实体瘤有良好的治疗效果。此外，DNA抑制剂的靶点远少于微管蛋白抑制剂，当ADC携带相同数量的有效载荷进入细胞时，DNA抑制剂可以显示出更好的杀伤效果。而且以DNA抑制剂为有效载荷的ADC可以靶向低抗原表达的肿瘤细胞。烯二炔类（Enediyne）从细菌中分离出的烯二炔是迄今为止发现的最具细胞毒性的天然产物之一，通过破坏细胞单链或双链DNA，导致细胞死亡，因此成为常用的ADC有效载荷。其中，开发最成功的卡奇霉素（Calicheamicins）是已上市ADC药物Mylotarg和Besponsa的有效载荷。卡奇霉素通过靶向与DNA结合的小沟，特异性诱导DNA双链断裂，引发自噬。虽然卡奇霉素对正常细胞的杀伤阻碍了其在临床应用中的进展，但高细胞毒性、小分子量和明确的作用机制使其成为有吸引力的有效载荷。拓扑异构酶I抑制剂（Topoisomerase I inhibitors）拓扑异构酶I（TOPO-I）是一种重要的稳定基因组和保护DNA结构的核酶，已成为ADC的热门靶点。晶体结构研究发现临床批准的抗癌药物-拓扑替康（topotecan）是一种非竞争性抑制剂，通过在酶诱导缺口处的两条DNA链之间插入碱基，与酶-底物复合物结合。因此拓扑替康类似物成为一类特别有吸引力的ADC有效载荷，例如天然五环产物喜树碱(CPT)，极低的溶解度阻碍了其被广泛使用；半合成的喜树碱SN-38（伊立替康CPT-11的活性成分），其较高的疏水性和有限的偶联位点数量增加了偶联物制备的挑战性；水溶性的CPT类似物-甲磺酸依喜替康（DX-8951f）具有很强的TOPO-I抑制和抗肿瘤活性；新型高膜渗透性TOPO-I抑制剂DXd（DX-8951衍生物）能抵制P糖蛋白介导的多重耐药性，且有较强的疗效，但其F环含有第二个手性中心，增加了合成和衍生化难度。对CPT的化学修饰主要围绕C7-C11位点，例如研究显示C10位点的羟基修饰可增强抗肿瘤活性；C11位点的氟修饰会数倍增强细胞毒性；一些化学修饰为偶联提供了可选位点。图7 TOPO-I结构示意图吡咯并[2,1-c][1,4]苯二氮杂卓（PBD）PBD是在链球菌中发现的一类具有抗肿瘤活性的天然产物，主要由芳香A环、B环和吡咯烷C环组成。PBD在DNA小沟中进行选择性烷基化，DNA链交联导致DNA损伤，引起细胞凋亡。基于强大的细胞毒性，PBD二聚体具有成为ADC有效载荷的潜力，且正在通过一系列结构修饰以改进PBD作为有效载荷的性能。例如，C8位置进行侧链修饰可以得到多种有活性的化合物，而且侧链长度缩短也具备充足的细胞毒性。在结构中引入酸性或碱性基团能改变化合物的理化性质，通过引入磺酸会导致PBD二聚体从胞质溶酶体转运至胞质和/或胞核内。二硫化修饰的PBD二聚体在GSH水平较高的细胞内表现出更好的稳定性。从结构可以看出（如下图8），PBD类化合物的偶联位点是C2和N10。其中B环的N10位点能与DNA共价连接，比C2位点更安全。未来其偶联位点的修饰或许也是研究方向之一。图8 PBD及衍生物结构示意图3. 靶向RNA的有效载荷以RNA为靶点的小分子抑制剂既能杀死处于分裂状态的肿瘤细胞，也能杀死处于休眠状态的肿瘤细胞，作为ADC有效载荷有望解决无效肿瘤休眠细胞导致的肿瘤耐药和肿瘤复发扩散问题。目前，可作为ADC有效载荷的RNA抑制剂有两种主要类型：RNA剪接抑制剂（泰兰斯他汀及其类似物）和RNA聚合酶II抑制剂（毒伞肽）。泰兰斯他汀（Thailanstatin）RNA剪接抑制剂是一种有效的抗增殖药物，能够靶向分裂活跃和静止的细胞。Thailanstatin是一种从泰国布鲁氏菌中分离出来的天然产物，通过与剪接体U2snRNA复合物的SF3b亚基结合而激活。Thailanstatin家族化合物经抑制真核mRNA剪接途径，对剪接体有较强的结合和抑制作用，从而成为ADC的潜在有效载荷。辉瑞首次探索将RNA剪接抑制剂用作与曲妥珠单抗偶联的有效载荷（如图9-87），并在体外动物模型和细胞系药效研究中取得了不错的结果。图9 Thailanstatin类化合物结构示意图毒伞肽（Amatoxins）毒伞肽（Amatoxins）是一种由核糖体合成的毒性环状八肽，是真核RNA聚合酶 II的选择性抑制剂，能导致细胞凋亡。Amatoxins含有一个由八个L型氨基酸残基构成的大环，通过亚砜部分连接色氨酸和半胱氨酸残基，其三个侧链被羟基化，因此具有良好的水溶性。迄今，研究最深入也最有效的是α-Amatoxin（如图10-88），能显著抑制肿瘤转移和复发，是抗肿瘤耐药性的潜在化合物，目前已被用于靶向BCMA的ADC药物（HDP-101），且正在进行I/Ia期临床试验，用于治疗复发/难治性多发性骨髓瘤。此外，将β-amanitin的羧基（如图10-89）偶联到IgG赖氨酸的氨基上，也能得到具有良好血浆稳定性和高细胞毒性的ADC。图10 Amatoxins类化合物结构示意图4. 免疫类ADC有效载荷ADC在肿瘤临床治疗中的成功，激发了研究者对ADC在其他治疗领域的探索，尤其是免疫学。肿瘤免疫包括T细胞、巨噬细胞、树突状细胞等，通过免疫调节将冷肿瘤转化为热肿瘤，最终增强免疫治疗的效果。然而，对于不能产生自发性T细胞应答和T细胞浸润的癌症患者（冷肿瘤）来说，免疫检查抑制剂并不能很好地发挥作用。因此，开发出能够刺激患者先天性免疫应答，以及促进肿瘤特异性T细胞招募的免疫疗法成为研究热点。与传统ADC不同，免疫刺激抗体偶联物(ISACs)既有抗体的精度靶向特点，又能基于小分子调控先天性和适应性免疫系统。一方面，偶联的免疫激动型小分子能增强免疫应答。另一方面，抗体的靶向性降低了小分子免疫激动剂的毒性。此外，传统的ADC是依赖抗原介导的内吞作用杀死癌细胞，而免疫调节ADC是通过细胞表面FcγR介导的内吞作用激活免疫细胞。目前，正在研究的免疫调节ADC的有效载荷主要包括toll样受体(TLR)激动剂和干扰素刺激因子(STING)激动剂。Toll样受体激动剂Toll样受体(TLRs)是一类重要的参与先天免疫的蛋白分子，是机体抵抗传染病的第一道屏障。激活TLR受体可以改善肿瘤微环境中树突状细胞和巨噬细胞的抗原呈递，促进CD8+T细胞的增殖。Toll样受体激动剂作为一种免疫增强剂，在肺癌、黑色素瘤、白血病和胶质瘤中直接或间接地诱导和增强抗肿瘤免疫反应，从而有效地抑制肿瘤生长。因此，TLR激动剂（主要是TLR7/8/9）成为肿瘤免疫治疗的热点之一。将其应用于ADC也能有效降低毒副作用，提高肿瘤杀伤效果。例如，以TLR8激动剂 (如下图11-91)为有效载荷的抗Her2抗体偶联物，在体外以Her2依赖的方式驱动多种抗肿瘤免疫机制，并在小鼠肿瘤模型中显示出良好的抗肿瘤效果。以TLR7激动剂 (如下图11-92)构建的一类新的免疫调节ADC（HE-S2）在体外试验中也有非常显著的抗肿瘤作用。目前，越来越多的国内外药企开始布局这一ADC差异化开发新赛道，包括恒瑞、百济、InnoventBio、Silverback等。图11 Toll样受体激动剂结构示意图STING激动剂干扰素刺激因子(STING)是天然免疫信号通路中的关键调控因子，具有启动机体自然免疫防御反应，促进T细胞形成适应性免疫的功能。STING介导的I型干扰素信号通路是自然免疫领域的重大发现，为肿瘤免疫治疗提供了新的靶点。鉴于游离STING激动剂的全身给药受到毒性限制，且广泛的生物分布可能不理想，因此可以通过与抗体偶联实现STING激动剂的肿瘤靶向递送、降低毒性，并发挥抗肿瘤作用。环二核苷酸（CDN）是STING蛋白的天然配体（如下图12-93），可通过磷酸酯、糖环和碱偶联抗体。例如，SPEROVIE通过将CDN中的硫代磷酸盐或甲酸酯与PD-1或CTLA-4抗体偶联形成了ADC药物（WO2021046426A1,2021.03.11）。此外，Mersana使用STING激动剂（图12-94）作为有效载荷获得的ADC候选药物XMT-2056也已经进入临床前研究阶段，并且基于其优秀的临床前数据，XMT-2056被FDA授予治疗胃癌的孤儿药称号。还有日本小野制药开发的一种非核酸STING激动剂（图12-95），作为有效载荷通过药物结构中的吡唑环与连接子偶联。图12 STING激动剂结构示意图5. 新型潜力有效载荷Bcl-xL抑制剂Bcl-xL是一种抗凋亡蛋白，在肿瘤形成、转移和耐药过程中发挥重要作用。理论上可以通过阻断Bcl-xL的BH3结合域，诱导癌细胞凋亡。将Bcl-xL抑制剂作为ADC药物的有效载荷，既可以保留活性，又能降低对血小板的毒性。通过一系列晶体结构和构效关系研究，发现因为Bcl-xL上E单元的抑制作用，其比W单元更重要，特别是B环。2017年，AbbVie首此将Bcl-xL抑制剂（如下图13-104）与抗B7H3抗体偶联，获得靶向EGFR 的ADC（ABBV-155），目前仍在临床研究中（ClinicalTrials.gov identifier: NCT03595059）。图13 Bcl-xL抑制剂结构示意图烟酰胺磷酸核糖转移酶（NAMPT）抑制剂烟酰胺磷酸核糖转移酶（NAMPT）是一种控制细胞内NAD+浓度的限速酶，能将烟酰胺转化为烟酰胺单核苷酸。当NAMPT被抑制时，NAD+水平下降到代谢所需的水平以下，导致能量危机，最终引起细胞死亡。虽然NAMPT抑制剂是强效的细胞毒性分子，但它们作为化疗药物在癌症治疗中的使用受到毒性的限制。但鉴于它们不同于其他有效载荷的作用机制、简单的结构和高效价，NAMPT抑制剂可以作为ADC有效载荷应用于临床。蛋白酶体抑制剂（Carmaphycins）蛋白酶体抑制剂是一类新兴的抗癌药物，对某些癌细胞具有超强的细胞毒性，如环氧酮类蛋白酶体抑制剂-carmaphycins。Carmaphycins A和B是从海洋蓝藻菌（Symploca sp.）中分离鉴定出的，它们的α,β-环氧酮可直接与甲基硫氨酸亚砜或甲基硫氨酸砜结合，抑制蛋白酶体的β5亚基。但由于较差的选择性，carmaphycins常表现出毒副作用。而作为ADC有效载荷，高毒性的carmaphycins衍生物可保持理想的效力并获得更好的耐受性。酪氨酸激酶抑制剂人类基因组包括500多种激酶，其中150多种与包括癌症在内的各种疾病有关。蛋白激酶是催化磷酸化的酶，分为3类：丝氨酸激酶、苏氨酸激酶和酪氨酸激酶。目前在临床试验中研究的小分子中有超过四分之一是蛋白激酶抑制剂，超过30种FDA批准用于癌症治疗的分子是激酶抑制剂。但是由于蛋白激酶抑制剂的效力低，因此尚未在ADC有效载荷领域进行广泛的探索。对有效载荷创新的思考除了上文介绍的有效载荷类型和一些经典的化合物，还有很多新的开发思路，如以PROTAC分子作为有效载荷，以近红外光免疫疗法（NIR-PIT）药物作为有效载荷，或开发双载荷ADC、放射性核素药物偶联物（RDC）、抗体-螯合物偶联物（ACC）、抗体-寡核苷酸偶联物（AOC）和肽-药物偶联物（PDCs）等。纵观整个ADC有效载荷开发历程，可以看到以问题为导向，不管是对天然化合物的优化改造还是对不同作用机制的探索，只要“脑洞大开”敢于尝试，终能走出自己的路。参考文献：[1] Shapiro MA. Regulatory considerations in the design, development and quality of monoclonal antibodies and related products for the diagnosis and treatment of cancer. Front Oncol. 2024 Apr 30;14:1379738. doi: 10.3389/fonc.2024.1379738. PMID: 38746685; PMCID: PMC11091260.[2] Wang Z, Li H, Gou L, Li W, Wang Y. Antibody-drug conjugates: Recent advances in payloads. Acta Pharm Sin B. 2023 Oct;13(10):4025-4059. doi: 10.1016/j.apsb.2023.06.015. Epub 2023 Jun 30. PMID: 37799390; PMCID: PMC10547921.[3] Choi Y, Choi Y, Hong S. Recent Technological and Intellectual Property Trends in Antibody-Drug Conjugate Research. Pharmaceutics. 2024 Feb 3;16(2):221. doi: 10.3390/pharmaceutics16020221. PMID: 38399275; PMCID: PMC10892729.[4] Conilh L, Sadilkova L, Viricel W, Dumontet C. Payload diversification: a key step in the development of antibody-drug conjugates. J Hematol Oncol. 2023 Jan 17;16(1):3. doi: 10.1186/s13045-022-01397-y. 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