Besponsa: Is this really a viable new treatment for ALL?

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August 18, 2017 – B-cell precursor acute lymphoblastic leukemia (ALL) is a aggressive and rapidly progressing type of cancer in which the bone marrow makes too many B-cell lymphocytes, an immature type of white blood cell. In the United States, the National Cancer Institute estimates that approximately 5,970 people will be diagnosed with B-cell ALL this year and approximately 1,440 will die from the disease.
The American Food and Drug Administration (FDA) has just approved Inotuzumab Ozogamicin (Besponsa) for the treatment of adults with relapsed or refractory B-cell ALL. Previously, by the End of June 2017, Inotutumab Ozogamicin (Besponsa) was already approved by the European Medicines Agency (EMA) for the same indication.Generally, for adult patients with B-cell ALL whose cancer has not responded to initial treatment or has returned after treatment, life expectancy is typically rather low and they have few treatments available. Inotutumab Ozogamicin (Besponsa) is offering a new treatment option to these patients. Inotutumab Ozogamicin (Besponsa) is an antibody-drug conjugate (ADC) comprised of a monoclonal antibody (mAb) targeting CD22, a cell surface antigen expressed on cancer cells in almost all B-ALL patients, linked to the cytotoxic agent calicheamicin. When Inotutumab Ozogamicin (Besponsa) binds to the CD22 antigen on B-cells, it is internalized into the cell, calicheamicin is released to destroy the cell by cytotoxic action.

The efficacy of Inotutumab Ozogamicin (Besponsa) was studied in a randomized trial of 326 patients with relapsed or refractory B-cell ALL who had received one or two prior treatments. Patients were randomized to receive treatment with Inotutumab Ozogamicin (Besponsa) or an alternative chemotherapy regimen. The trial measured the percentage of patients with no evidence of disease and full recovery of blood counts after treatment (complete remission (CR)). Of the 218 evaluated patients, 35.8 percent who received Inotutumab Ozogamicin (Besponsa) experienced CR for a median 8.0 months; of the patients who received alternative chemotherapy, 17.4 percent experienced CR for a median 4.9 months.

As far as the clinical safety of Inotutumab Ozogamicin (Besponsa) is concerned, there may be some serious questions arising, for both treating physicians and patients alike. From the press release by the marketing authorisation holder (MAH) at the time of approval of  Inotutumab Ozogamicin (Besponsa) in the European Union, the most common (≥ 20%) adverse reactions associated with Inotutumab Ozogamicin (Besponsa) were thrombocytopenia (51%), neutropenia (49%), infection (48%), anaemia (36%), leukopenia (35%), fatigue (35%), haemorrhage (33%), pyrexia (32%), nausea (31%), headache (28%), febrile neutropenia (26%), increased transaminases (26%), abdominal pain (23%), increased gamma-glutamyltransferase (21%), and hyperbilirubinaemia (21%). The most common serious (≥ 2%) adverse reactions associated with Inotutumab Ozogamicin (Besponsa) were serious infection (23%), febrile neutropenia (11%), haemorrhage (5%), abdominal pain (3%), pyrexia (3%), veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS) (2%), and fatigue (2%).

Moreover, according to the same source, in the Phase 3 INO-VATE ALL trial (N=164 patients treated with Inotutumab Ozogamicin (Besponsa)), VOD/SOS was reported in 22 (13%) patients including 5 (3%) patients during study therapy or in follow-up without an intervening hematopoietic stem cell transplant (HSCT). Among the 77 patients who proceeded to a subsequent HSCT (6 of whom received additional salvage therapy after treatment with Inotutumab Ozogamicin (Besponsa) before proceeding to HSCT), VOD/SOS was reported in 17 (22%) patients. Five of the 17 VOD/SOS events that occurred post-HSCT were fatal. VOD/SOS was reported up to 56 days after the last dose of Inotutumab Ozogamicin (Besponsa) without an intervening HSCT. The median time from HSCT to onset of VOD/SOS was 15 days (range: 3-57 days). Of the 5 patients who experienced VOD/SOS during treatment with Inotutumab Ozogamicin (Besponsa) but without an intervening HSCT, 2 patients had also received an HSCT before Inotutumab Ozogamicin (Besponsa) treatment. Among patients who proceeded to HSCT after Inotutumab Ozogamicin (Besponsa) treatment, VOD/SOS was reported in 5/11 (46%) patients who received an HSCT both prior to and after Inotutumab Ozogamicin (Besponsa) treatment and 12/66 (18%) patients who only received an HSCT after Inotutumab Ozogamicin (Besponsa).

Accordingly, in the US, the prescribing information for Inotutumab Ozogamicin (Besponsa) includes a Boxed Warning that severe liver damage (hepatotoxicity), including blockage of veins in the liver (veno-occlusive disease [VOD] or sinusoidal obstruction syndrome), occurred in some patients who took Inotutumab Ozogamicin (Besponsa). If hepatotoxicity occurs, doctors should pause treatment or reduce the dose of Inotutumab Ozogamicin (Besponsa). If VOD occurs, patients should stop taking Inotutumab Ozogamicin (Besponsa) and be given standard VOD treatment, if severe.The boxed warning also includes an increased risk of death for patients who take Inotutumab Ozogamicin (Besponsa) after receiving a certain type of stem cell transplant. Furthermore, other serious side effects of Inotutumab Ozogamicin (Besponsa) include a decrease in blood cell and platelet production (myelosuppression), infusion-related reactions and problems with the heart’s electrical pulses (QT interval prolongation). Women who are pregnant or breastfeeding should not take Inotutumab Ozogamicin (Besponsa) because it may cause harm to a developing fetus or a newborn baby.

Overall, as a patient, the above listing of possible, and actually quite frequent, serious adverse health effects of Inotutumab Ozogamicin (Besponsa) may remind you to reading a passage in a piece of the horror cabinet. In fact, in the interest of the patient afflicted with a potentially terminal condition, as in the case of ALL, pharmaceutical companies, regulatory authorities, treating physicians, as well as concerned patients may think twice if a drug that may prolong CR from a median of 4.9 months to a median 8.0 months is worth to take the risk of experiencing quite frequently possible fatal drug reactions. In order to make the mean of 3 months gained futile and, in terms of quality of life, as miserable as possible for many?

Is Inotutumab Ozogamicin (Besponsa) really a viable therapy option? Therapy in the sense of it’s meaning, not a treatment that generates money for the interested parties and un-necessarily prolongs sufferance of the affected? Only time will tell.

See here the FDA drug label for Inotutumab Ozogamicin (Besponsa).

See here the EMA EPAR for Inotutumab Ozogamicin (Besponsa).

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About the Author
thassodotcom Ph.D.; Professor in Pharmacology and Toxicology. Senior expert in theragenomic and personalized medicine and individualized drug safety. Senior expert in pharmaco- and toxicogenetics. Senior expert in human safety of drugs, chemicals, environmental pollutants, and dietary ingredients.

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