On August 17, 2017, the U.S. Food and Drug Administration (FDA) approved a new drug for the treatment of B-cell acute lymphoblastic leukemia (ALL) –inotuzumab ozogamicin (trade name: Besponsa®, manufactured by Pfizer Inc.). This drug is administered intravenously for the treatment of B-cell acute lymphoblastic leukemia with a Philadelphia chromosome (Ph chromosome) mutation that has relapsed or is refractory to treatment with at least one previous tyrosine kinase inhibitor (TKI).
What is B-cell acute lymphoblastic leukemia relapse?
B-cell acute lymphoblastic leukemia is an aggressive leukemia that presents with an excess of B lymphocytes, which are immature white blood cells, in the bone marrow.
While many patients with B-cell acute lymphoblastic leukemia respond well to chemotherapy, there is a high rate of cancer recurrence. In 25% to 40% of patients with B-cell acute lymphoblastic leukemia, there is a specific genetic mutation, the Ph chromosome mutation, an abnormal chromosome that occurs when chromosomes 9 and 22 break and exchange places.
In patients with the Ph chromosome mutation, tyrosine kinase inhibitors that target this mutation (imatinib, etc.) are much more effective than chemotherapy. However, as with chemotherapy, leukemia cells can become resistant to targeted therapy, leading to cancer relapse.
For relapsed acute lymphoblastic leukemia, the goal of rescue therapy after failure of first-line therapy is to regain remission, making bone marrow transplantation possible for these patients.
What is inotuzumab ozogamicin?
Inotuzumab ozogamicin is a drug that targets CD22 by coupling the monoclonal antibody inotuzumab to the enediyne toxin ozogamicin, a coupling structure that helps target anti-cancer drugs to cancer cells. The CD22 antigen is a cell surface antigen expressed on about 90% of B-cell malignancies and is a good target.
The inotuzumab in inotuzumab ozogamicin binds to CD22, which takes up the enediyne toxin into the cellular lysosomes and then releases the cytotoxic agent spinosylvin into the cells of acute lymphoblastic leukemia, blocking the growth of cancer cells and causing their death.
Evidence of efficacy: 36% complete remission and 90% negative rate of microscopic residual disease
Inotuzumab ozogamicin was approved primarily based on a phase III clinical trial (INO-VATE ALL) enrolling 326 patients with ALL who carried the Ph chromosome and who had previously received at least one tyrosine kinase inhibitor (that had been FDA The study enrolled 326 patients with ALL who had received at least one prior targeted treatment with a tyrosine kinase inhibitor (approved by the FDA) for patients carrying the Ph chromosome and at least one prior chemotherapy regimen for patients without the Ph chromosome.
Inotuzumab ozogamicin treatment significantly increased the rate of complete remission (CR) (36% vs 17%) and negative minimal residual disease (MRD) compared with chemotherapy (90% vs 32%). rates (90% vs 32%).
Minimal residual disease is a major cause of cancer recurrence, and a negative MRD means that no leukemia cells are found in either the blood or bone marrow. months vs 4.9 months), and median progression-free survival was also better than with chemotherapy (5 months vs 1.9 months).
Black box warning: need to be alert for severe liver injury
Common adverse reactions to inotuzumab ozogamicin include mainly thrombocytopenia, neutropenia, infection, anemia, fatigue, bleeding, fever, nausea, headache, febrile neutropenia, liver injury (elevated transaminases and or glutamine transferases), abdominal pain, and hyperbilirubin blood.
It is important to note that the instructions for inotuzumab ozogamicin include a black box warning that the drug may cause serious liver injury, including severe or fatal veno-occlusive disease (VOD), also known as sinusoidal obstruction syndrome. VOD, also known as sinusoidal obstruction syndrome (SOS).
The FDA recommends that doctors suspend treatment or reduce the dose of inotuzumab ozogamicin once liver injury is detected. If severe hepatic vein occlusive disease occurs, the drug should be permanently discontinued and standard hepatic vein occlusive disease treatment should be received. In addition, the black box warning warns that administration of inotuzumab ozogamicin after hematopoietic stem cell transplant (HSCT) increases the risk of death in patients. other serious side effects of inotuzumab ozogamicin include bone marrow suppression, infusion reactions, and prolonged QT interval (a dangerous arrhythmia). Pregnant or breastfeeding women should not take the drug because it may cause harm to the fetus or newborn.
How do I use inotuzumab ozogamicin?
According to the approved product insert, the recommended use and dosage of inotuzumab ozogamicin is as follows:
- Glucocorticoids, antipyretics, and antihistamines are recommended prior to administration. Any signs of infusion reaction need to be noted for at least 1 hour after the end of the infusion.
- Recommended dose for cycle 1: 1.8 mg/m per cycle, 0.8 mg/m on day 1, 0.5 mg/m on day 8, and 0.58 mg/m on day 15, administered in 3 divided doses for a total of 3 weeks, or up to 4 weeks if the patient is very efficacious and tolerates the toxicity.
- Recommended dose for subsequent cycles: for patients achieving complete remission or complete remission with incomplete hematologic recovery (Cri), the recommended total dose is 1.5 mg/m per cycle on days 1, 8, and 8. 0.5 mg/m on days 1, 8 and 15 for 4 weeks; for patients who do not achieve complete remission or CRi, the recommended total dose is 1.8 mg/m per cycle, 0.8 mg/m2 on day 1 and 0.5 mg/m on days 8 and 15, respectively, for 4 weeks, but if complete remission or Cri is not achieved within 3 cycles, treatment should be discontinued. treatment.
- For patients undergoing hematopoietic stem cell transplantation, the recommended duration of therapy is 2 cycles.
- Because inotuzumab ozogamicin can cause damage to liver function, it should be used with caution if patients have problems with their own liver function.
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This drug is not yet available in China, but the remarkable efficacy of this new immunotoxin is still encouraging, and as more targeted drugs become available, it will help patients with acute lymphoblastic leukemia get the good results that are difficult to achieve with traditional chemotherapy.