Antibody-based therapy in acute leukemia - beware the risks

Antibody-based therapy has started to revolutionize the treatment of acute leukemia. The CD3/CD19 bispecific antibody blinatumomab [1] and inotuzumab ozogamicin (IO), an anti-CD22 antibody conjugated to the cytotoxic antibiotic agent calicheamicin [2], have shown unprecedented remission rates and improved overall survival (OS) in relapsed and refractory acute lymphoblastic leukemia (RR-ALL). RR-ALL in adult patients is traditionally very difficult to treat and associated with poor survival. The beneficial effect of gemtuzumab ozogamicin (GO), an anti-CD33 antibody conjugated to calicheamicin, in CD33 positive acute myeloid leukemia (AML) has been less dramatic but it has been approved by the Food and Drug Administration (FDA) for several different indications. GO has shown to moderately improve OS when added to chemotherapy during induction and consolidation therapy in de novo AML [3] and when used as monotherapy for older patients with AML ineligible for intensive chemotherapy [4] and patients with RR-AML [5]. While the treatment success of antibody-based therapy in acute leukemias is undeniable, one needs to be aware of unique side effects associated with this therapeutic modality. These include cytokine release syndrome (CRS) and neurotoxicity with blinatumomab, sinusoidal obstruction syndrome (SOS) with IO and GO and, as described in the case report in Leukemia and Lymphoma, blinatumomab associated lymphoid to myeloid lineage switch. Blinatumomab leads to an activation of T cells with secondary release of cytokines including IL-6, which can result in CRS and neurotoxicity [6]. CRS initially presents as fever and malaise but can quickly progress to a massive inflammatory state manifesting as hypotension and shock as well as capillary leak and hypoxia [6]. The severity of CRS with blinatumomab treatment correlates with the dose of blinatumomab and with a larger disease burden [6]. Therefore, attempts to reduce CRS have been focused on a ramp up dosing schedule of blinatumomab and cytoreduction of patients with a high disease burden and prophylactic treatment with steroids. This led to an overall relatively low rate of CRS in the blinatumomab registration trial [1]. While treatment interruptions and discontinuation in the blinatumomab arm were required for 32% and 12% of patients, only 5% and 1% of these were due to CRS, respectively [1]. Standard of care treatment for CRS is steroids and the IL-6 receptor antagonist Tocilizumab has been shown to reduce CRS in a blinatumomab induced steroid refractory case of CRS [7]. Blinatumomab-induced neurotoxicity is less well understood compared to CRS but one mechanism proposed is the disruption of the blood brain barrier by activated T cells and cytokine release [6]. Clinical manifestations of neurotoxicity range from non-specific symptoms including headache, somnolence, disorientation and tremors to severe symptoms including aphasia, stupor, and rarely seizures. In the blinatumomab registration trial, neurotoxicity led to the to the interruption of blinatumomab in 6% of patients and the discontinuation of blinatumomab in 4% of patients [1]. The use of prophylactic antiepileptic drugs is generally not recommended as the incidence of seizures is very low with <1% of patients experiencing a seizure in the phase III registration trial [1]. Management is less well established than management for CRS but includes steroids and discontinuation of blinatumomab; for grade 3 CNS adverse events, reintroduction of blinatumomab can be considered after improvement of symptoms whereas for grade 4 CNS adverse events, permanent discontinuation of blinatumomab is mandated. Tocilizumab has not been shown to be effective for treatment of blinatumomab induced neurotoxicity, which is not