Review of three new blood tumor drugs approved by FDA in 2016

[industry trends of China Pharmaceutical network] common hematological tumors mainly include all kinds of leukemia, multiple myeloma and malignant lymphoma Statistics from western countries show that the incidence rate of these three types of tumors is ranked the top ten of malignant tumors In 2016, the US FDA approved two new hematology drugs, including venetoclax, a B-cell Lymphoma 2 inhibitor, and nivolumab, an immunocheckpoint inhibitor approved for the treatment of malignant blood tumors In addition, the FDA has also approved defibrinide for the treatment of adults and children with small vein occlusion (VOD) and renal or lung abnormalities after HSCT (picture source of three new blood tumor drugs approved by FDA in 2016: Baidu picture) venetoclax is approved for treatment with del (17p) CLL Venetoclax is an approved oral small molecule Bcl-2 inhibitor, which can treat patients with del (17p) and chronic lymphoblastic leukemia (CLL) who have received at least one treatment before The prognosis of CLL patients with del (17p) was poor, and the median survival time was only 2-3 years Bcl-2 plays an important role in apoptosis (programmed cell death), which can prevent the apoptosis of some cells (including lymphocytes), and overexpression in some types of cancer, which is related to the formation of drug resistance However, the interaction of Bcl-2 protein family members targeting proteins greatly increases the challenge of clinical application Navitoclax, a Bcl-2 inhibitor, has a significant therapeutic effect on CLL, but was stopped because of restrictive thrombocytopenia Venetoclax is a navitoclax structure modified binding molecule (specific for Bcl-2, while retaining the circulating platelet Bcl-xL) The direct binding of venetoclax and bcl-2 protein makes it have good drug toxicity The approval of venetoclax breakthrough therapy is based on the results of an open, single arm, phase 2 study In this study, 107 patients with relapsed / refractory CLL of del (17p) were enrolled and treated with venetoclax with increasing weekly dose Meanwhile, the prevention of tumor lysis syndrome was carried out After a median follow-up of 12.1 months, the objective response rate (ORR) was 79.4%, the median response time was 0.8 months, the median response time was not reached, and 10% patients achieved complete remission (CR) with incomplete recovery of blood or partial remission of nodules (PR) Common grade 3-4 adverse reactions include neutropenia, infection, anemia and thrombocytopenia 21% of the patients needed to reduce the dose due to the toxic reaction, and 8% of the patients stopped the treatment In addition, patients with impaired renal function (creatinine clearance < 80 ml / min) are at risk of TLS and may need more intensive prevention and monitoring The prognosis of CLL patients with del (17p) is very poor, so the appearance of venetoclax represents a great progress in the treatment of this kind of disease At present, venetoclax is one of the recommended treatment options for relapsed / refractory CLL with or without del (17p) / TP53 mutation, but it is difficult to directly compare with the efficacy of the standard regimen such as the single drug regimen of irutinib and the combined regimen of idelalisib + rituximab According to the data of phase 2 reonate-17 study, the orr of CLL patients with del (17p) was 81%, which was similar to the efficacy data of venetoclax Some patient factors, such as the number, type and molecular characteristics of the previous treatment plan, may affect the choice of treatment plan In the future research, it is necessary to further clarify the best combination plan and the order of drug use in combination with other drugs when venetoclax treats CLL patients with del (17p) Nivolumab, the ligand (PD-L) of programmed death molecule 1 (PD-1) / PD-1, an immunosuppressive checkpoint inhibitor approved for blood tumor treatment, is an inhibitory costimulatory molecule and can negatively regulate the production of immune response Tumor cells can use PD-1 immune checkpoint to avoid immune surveillance In solid tumors, blocking PD-1 can produce significant antitumor activity Nivolumab is an anti-PD-1 monoclonal antibody It is a PD-1 inhibitor approved by the European Union for the treatment of malignant blood tumors It can treat adult patients with relapsed / refractory CHL after rentuximab vedotin or ASCT In May 2016, FDA has also granted the breakthrough drug qualification for the treatment of Chl These two approvals are based on the overall response rates of the 2-phase checkmate-205 and 1-Phase checkmate-039 trials The researchers analyzed the efficacy data of 95 patients with recurrent or refractory CHL after ASCT or brentuximab vedotin The objective response rate was 66%, 6% of patients achieved complete remission, 60% of patients achieved partial remission At 12 months, the progression free survival rate was 57% The median response time was 13.1 months 23% of the patients were stable Drug safety analysis showed that 21% of patients had serious adverse reactions, including transfusion related reactions, pneumonia, pleural effusion, fever, rash, etc 23% of the patients delayed the treatment because of adverse reactions, and 4.2% of the patients interrupted the treatment because of adverse reactions Six patients died of transplant related complications after treatment with nivolumab Therefore, it is necessary to pay attention to and prevent: immune related reactions such as pneumonia, enteritis, hepatitis, nephritis, renal dysfunction, endocrine disease, rash, etc.; infusion reaction; heterogeneic HSCT related complications after immunotherapy Defibrinde is a kind of polydeoxyribonucleosyl propionate, which has certain fibrinolysis and antithrombotic activity It can promote the production of prostacyclin like substances and release them into circulation from vascular tissue The drug is used to treat adult and child patients with small hepatic vein occlusion (VOD) and renal or lung abnormalities after HSCT The occlusion of hepatic venules results from the blockage of some blood vessels in the liver, which leads to edema and decrease of blood flow in the liver, which will lead to serious liver injury The drug is FDA approved for the treatment of severe hepatic venule occlusion, a rare and fatal liver disease The approval was based on a phase 2 trial in 75 patients, a phase 3 trial in 102 patients, and an extended trial in an additional 351 patients All patients were diagnosed with liver VOD and renal or pulmonary dysfunction after HSCT In phase 2 trials, 44% of patients survived 100 days after transplantation, 38% in phase 3 trials, and 45% in extended trials, while FDA noted in a report that the 100 natural survival rate of patients with severe liver VOD who were not treated with defibrin was expected to be 21% - 31% Data on the safety of the drug were based on 176 patients Common adverse reactions include hypotension, diarrhea, vomiting, nausea, and epistaxis Common serious adverse reactions include hypotension and alveolar hemorrhage The approval of defibrin can greatly meet the treatment needs of transplant patients with such rare and fatal complications Defibrin sodium is an FDA approved treatment for small vein occlusion (VOD) with renal or lung abnormalities in adults and children after HSCT Although the safety data from randomized controlled trials are insufficient, the available efficacy data confirm that defibrin can significantly improve the survival rate after 100 days Conclusion in 2016, in addition to the approval of the three new drugs, FDA also expanded the treatment indications of two anti-CD20 monoclonal antibodies, obinutuzumab and ofatumumab, and one anti-CD38 monoclonal antibody, daratumumab.