In the first half of 2020, the FDA approved new drugs and new programs for hematologic malignancies.

In the first half of 2020, what new drugs and new schemes have been approved by FDA for hematological malignancies? Multiple myeloma, myelodysplastic syndrome, acute myeloid leukemia, chronic lymphocytic leukemia, follicular lymphoma, diffuse large B-cell lymphoma... New drug progress should not be missed! On March 2, 2020, the FDA approved isatuximab irfc in combination with pomadomide and dexamethasone for recurrent / refractory adult multiple myeloma (RRMM) patients who have previously received at least two treatment regimens, including lenalidomide and a proteasome inhibitor.the approval is based on the icaria-mm study.for details of the study (FDA approved isa PD regimen for the treatment of relapsed / refractory multiple myeloma), the recommended dose of isatuximab irfc is 10mg / kg intravenously once a week for 4 weeks, and then combined with pomadolide and dexamethasone every two weeks until the disease progresses or the patient has unacceptable toxicity.on April 3, 2020, the FDA approved lupatercept AAMT for patients with myelodysplastic syndrome (mds-rs) or myelodysplastic syndrome / myeloproliferative tumor with circumferential sideroblasts and thrombocytosis (MDS / M) after failure of erythropoiesis stimulator therapy and requiring transfusion of ≥ 2 units of red blood cells (RBC) for more than 8 weeks Pn-rs-t).this approval is based on the results of the medallist study.the primary endpoint of the medallist study was the proportion of patients with RBC transfusion independent (rbc-ti, defined as no RBC transfusion for any 8 consecutive weeks between 1 and 24 weeks).a total of 229 mds-rs patients with very low, low and moderate ipss-r risk and who need more than 2 units of RBC transfusion for more than 8 weeks were enrolled.of the 153 patients treated with lupatercept AAMT, 37.9% received rbc-ti for at least 8 weeks, while only 13.2% of patients receiving placebo received rbc-ti.the most common adverse reactions (incidence > 10%) of lupatercept AAMT were fatigue, headache, musculoskeletal pain, joint pain, dizziness / vertigo, nausea, diarrhea, cough, abdominal pain, dyspnea and allergy.the recommended starting dose of lupatercept AAMT was 1mg / kg, which was injected subcutaneously every three weeks. The hemoglobin level of patients was reviewed before each administration.on April 21, 2020, the FDA expanded the indications of ibutilib, and approved its combination with rituximab for the initial treatment of adult chronic lymphoblastic leukemia (CLL) or small lymphocyte lymphoma (SLL).this approval is based on the results of the e1912 study.for details of the study, please note (FDA approved | IR protocol for initial treatment of CLL / SLL adult patients) the recommended dose of ibuprotinib is 420mg / D with 1 cup of water.starting from the second cycle, rituximab was administered at a dose of 50mg / m2 on the first day and 325mg / m2 on the second day; and 500mg / m2 was administered on the first day of each cycle in the following five cycles, totaling 6 cycles.on May 1, 2020, the FDA approved the use of daratumab and hyaluronidase fihj for the treatment of newly diagnosed or relapsed / refractory multiple myeloma (mm) in adults.the drug enables the administration of daretouximab by subcutaneous injection.daretouximab hyaluronidase has been approved for previously applicable indications for intravenous administration of daretouximab (Dara): combination of bortezomib, melphalan and prednisone (VMP) in newly diagnosed MM patients who are not suitable for autologous hematopoietic stem cell transplantation; and combination of lenalidomide and dexamethasone (RD) in the treatment of newly diagnosed mm patients who are not suitable for autologous hematopoietic stem cell transplantation Patients with relapsed or refractory MM who have received at least first-line treatment; patients who have previously received at least first-line treatment with bortezomib and dexamethasone (BD); patients who have previously received at least three-line treatment (including proteasome inhibitors [PI] and immunomodulators), or patients with dual refractory PI and immunomodulators, were treated with bortezomib and dexamethasone (BD).the Columba study (nct03277105, open label, non inferiority trial) evaluated the efficacy of daretouximab hyaluronidase (monotherapy). Patients were randomly divided into two groups: 263 patients were given daretoumab hyaluronidase and 259 patients were given daretouximab intravenously (Dara IV).the primary endpoint of the study was the overall response rate (ORR) and the maximum ctrough (pharmacokinetic [PK] endpoint) before administration on day 1 of cycle 3.the orr was 41.1% in the daretouximab hyaluronidase group and 37.1% in the Dara IV group, with a risk ratio of 1.11 (95% CI: 0.89, 1.37).the ratio of geometric mean of maximal ctrough was 108% (90% CI: 96, 122).in the multi cohort, open label Pleiades study (nct03412565), we evaluated the efficacy of d-vmp combined with daretozumab hyaluronidase (d-vmp).eligible patients must be newly diagnosed MM patients who are not suitable for transplantation. The orr was 88.1% (95% CI: 77.8, 94.7).in addition, the efficacy of d-rd in combination with d-rd was also evaluated in the Pleiades study.eligible patients have received at least first-line treatment before. The orr was 90.8% (95% CI: 81.0, 96.5).the most common adverse reaction (≥ 20%) was upper respiratory tract infection.the most common adverse reactions (≥ 20%) were upper respiratory tract infection, constipation, nausea, fatigue, fever, peripheral sensory neuropathy, diarrhea, cough, insomnia, vomiting and back pain. The most common adverse reactions (≥ 20%) were fatigue, diarrhea, upper respiratory tract infection, muscle spasm, constipation, fever, pneumonia and dyspnea.the most common hematological laboratory abnormalities (≥ 40%) were leucopenia, lymphocytopenia, neutropenia, thrombocytopenia and hemoglobin decrease.the recommended dose of daretouximab hyaluronidase is 1800mg Dara and 30000 units hyaluronidase, which is injected into the abdomen under the endothelium in about 3-5 minutes according to the recommended schedule.on June 16, 2020, FDA extended the indication of gemtuzumab ozogamicin to treat newly diagnosed CD33 positive acute myeloid leukemia (AML) ≥ 1 month old.the efficacy and safety of the drug in children were evaluated in the aaml0531 study (nct00372593).the study was a multicenter, randomized study involving 1063 newly diagnosed AML patients aged 0-29 years.patients were randomly assigned to receive 5 cycles of chemotherapy alone and gemtuzumab ozogamicin (3mg / m2) for chemotherapy (once on day 6 of induction chemotherapy cycle 1 and once on day 7 of intensive chemotherapy cycle 2). primary efficacy outcomes were assessed by event free survival (EFS) from the date of participation to induction of chemotherapy failure, recurrence, or death for any reason. The risk ratio of EFS was 0.84 (95% CI: 0.71-0.99). The estimated 5-year EFS rate was 48% (95% CI: 43% - 52%) in gemtuzumab ozogamicin + chemotherapy group and 40% (95% CI: 36% - 45%) in chemotherapy alone group. there was no significant difference in the overall survival rate between the two groups. in gemtuzumab ozogamicin treatment group, the most common grade 3 adverse reactions occurred in ≥ 5% of patients during induction chemotherapy 1 cycle and intensive chemotherapy 2 cycle, including infection, febrile neutropenia, loss of appetite, hyperglycemia, mucositis, hypoxia, hemorrhage, elevated transaminase, diarrhea, nausea and hypotension. on June 18, 2020, the FDA accelerated the approval of tazemetastat (an EZH2 inhibitor) for the treatment of adult patients with recurrent or refractory (R / R) follicular lymphoma (FL) with positive EZH2 mutation (approved by FDA) and having previously received at least second-line systemic treatment, or adult patients with R / R FL who lack effective alternative treatment. at the same time, FDA also approved Cobas EZH2 mutation detection as an auxiliary diagnostic tool for tazemetostat. the approval was based on two open label, one arm cohort results (cohort 4: EZH2 mutant FL; cohort 5: EZH2 wild-type FL) from a multicenter study (study e7438-g000-101, nct01897571), which included histologically confirmed FL patients who had received at least second-line systemic therapy. in this study, we prospectively identified EZH2 mutations in formalin fixed, paraffin embedded tumor samples, and centralized detection of samples using Cobas? EZH2 mutation detection. the patient took tazemetostat 800mg twice daily until the disease progressed or unacceptable toxicity appeared. The overall response rate (ORR) and duration of remission (DOR) were assessed by an independent review committee based on the International Working Group's criteria for efficacy evaluation of non Hodgkin's lymphoma. in 42 patients with EZH2 mutant FL, Orr was 69% (95% CI: 53%, 82%), including 12% complete response and 57% partial response; the median dor was 10.9 months (95% CI: 7.2, NE). The orr was 34% (95% CI: 22%, 48%), including 4% complete response and 30% partial response; the median dor was 13 months (95% CI: 5.6, NE). the most common adverse reactions (≥ 20%) in FL patients included fatigue, upper respiratory tract infection, musculoskeletal pain, nausea and abdominal pain. 30% of patients had serious adverse reactions, most of which were caused by infection. the second primary malignancy was the most common cause of discontinuation of treatment (2% of patients). prescription information includes warning and prevention of secondary malignancies. the recommended dose of tazemetostat is 800 mg, twice a day, orally with or without food. on June 22, 2020, the FDA accelerated the approval of selinexor for adult patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) who had previously received at least 2-line systemic treatment. the approval is based on the multicenter, single arm, open label sadal study (kcp-330-009; nct02227251), which included DLBCL patients who had received 2-5 line systematic treatment. the subjects took selinexor 60mg orally on the first and third days of each week. according to Lugano 2014 criteria, the overall response rate (ORR) and duration of remission were assessed by an independent review committee. The orr of 134 patients was 29% (95% CI: 22, 38), and the complete remission rate was 13%. of the 39 patients who had partial or complete remission before, 38% had remission lasting at least 6 months and 15% had remission lasting at least 12 months. in addition to laboratory abnormalities, the most common adverse reactions (incidence rate ≥ 20%) of DLBCL patients were fatigue, nausea, diarrhea, loss of appetite, weight loss, constipation, vomiting and fever. > the level 3-4 laboratory abnormalities of ≥ 15% patients were thrombocytopenia, lymphocytopenia, neutropenia, anemia and hyponatremia. 46% of patients had serious adverse reactions, which were usually caused by infection. thrombocytopenia is the main factor determining the dose adjustment. 80% of the patients had gastrointestinal toxicity and 61% had hyponatremia of any level. 25% of patients had adverse reactions of central nervous system, including dizziness and mental state changes. prescription information provides thrombocytopenia, neutropenia, gastrointestinal toxicity, hyponatremiaThe astx727-02 clinical study (nct03306264) included 133 adult patients with MDS or CMML, including all patients who met the FAB classification criteria, and those who were assessed as moderate-1, moderate-2 and high-risk by IPSS. in both trials, patients were randomly divided into two groups: decitabine and cedazuridine (35 mg decitabine and 100 mg cedazuridine) orally in the first cycle, and (IV) decitabine 20mg / m2 in the second cycle, or alternatively. 28 days was a treatment cycle, and both drugs were administered once a day from 1 to 5 days. since cycle 3, all patients were given decitabine and cedazuridine once a day on days 1-5 until the disease progressed or the toxicity was unacceptable. 01-B clinical trial results showed that the complete remission (CR) rate was 18% (95% CI: 10, 28), and the median duration of Cr was 8.7 months (1.1-18.2 months). of the 41 red blood cell (RBC) and / or platelet transfusion dependent patients, 20 (49%) achieved RBC and platelet transfusion independence at 56 consecutive days after baseline. of the 39 patients who were independent of RBC and platelet transfusion at baseline, 25 (64%) remained transfusion independent for 56 consecutive days after baseline. 02 the results of the clinical trial showed that the geometric mean AUC ratio of decitabine and cedazuridine daily for 5 consecutive days was 99% (90% CI: 93, 106). the results showed that 21% of patients achieved CR (95% CI: 15, 29), and the median duration of Cr was 7.5 months (1.6-7.5 months). of the 57 patients who were dependent on RBC and / or platelet transfusion at baseline, 30 (53%) became RBC and platelet transfusion independent within any 56 days after baseline, while 63% of the 76 patients who were independent of RBC and / or platelet transfusion at baseline remained transfusion independent for any 56 days after baseline. the most common adverse reactions (incidence rate ≥ 20%) of decitabine and cedazuridine were fatigue, constipation, bleeding, myalgia, mucositis, arthralgia, nausea, dyspnea, diarrhea, rash, dizziness, febrile neutropenia, edema, headache, cough, decreased appetite, upper respiratory tract infection, pneumonia and elevated transaminase. the most common level 3 or 4 laboratory abnormalities (≥ 50%) were leukopenia, thrombocytopenia, neutropenia and hemoglobin. the overall safety of oral decitabine and cedazuridine was similar to that of intravenous decitabine. the recommended dose of decitabine and cedazuridine is 1 tablet (35 mg decitabine and 100 mg cedazuridine), once a day on an empty stomach on days 1-5, with 28 days as a cycle. 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