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Professor of Haematology and Stem Cell Transplanation
Department of Haematology and BMT
University of Bristol
University Hospitals Bristol NHS
Bristol, United Kingdom
David Marks, MD, PhD, has disclosed that he has received consulting fees from Amgen, Novartis, and Pfizer.
As clinicians treating patients with relapsed or refractory (R/R) acute lymphoblastic leukemia (ALL), our main therapeutic goal is to achieve CR, preferably with MRD negativity. All the while, we want our patients to be well and at home when possible to minimize inpatient stays. Doing so allows us to proceed rapidly to a curative treatment such as transplant or CAR T-cell therapy. Of course, there are certain older patients for whom cure is not a realistic goal, but we strive for deep remission, nonetheless, and a good overall performance status.
Here, I’ll discuss how I use newer immunologically derived therapies, namely, blinatumomab and inotuzumab ozogamicin, in my practice for patients with R/R ALL.
Indications and Supporting Evidence
Blinatumomab is a bispecific CD19-directed CD3 T-cell engager indicated for the treatment of adults and children with R/R B-cell precursor ALL. Accelerated FDA approval was initially granted in December 2014 for patients with Philadelphia chromosome–negative disease based on the phase III TOWER trial, which demonstrated a median OS of 7.7 months with blinatumomab vs 4.0 months with standard of care (SoC) chemotherapy. The EMA similarly issued conditional authorization of blinatumomab for this population in November 2015. FDA approval was subsequently expanded in July 2017 to include patients with Philadelphia chromosome–positive disease based on the single-arm phase II ALCANTARA trial where 36% of patients achieved a CR with at least partial hematologic recovery.
Inotuzumab ozogamicin is a CD22-directed antibody–drug conjugate indicated for the treatment of adults with R/R B-cell precursor ALL. EMA authorization in June 2017, as well as FDA approval soon after in August, was based on data from the phase III INO-VATE ALL comparing inotuzumab ozogamicin with SoC chemotherapy. Final results, after 2 or more years of follow-up, showed a CR/CR with incomplete hematologic recovery rate of 73.8% with inotuzumab ozogamicin vs 30.9% for SoC (P < .0001). Median OS was 7.7 vs 6.2 months, respectively.
Deciding Between Blinatumomab and Inotuzumab Ozogamicin
No randomized clinical trial has compared the use of blinatumomab vs inotuzumab ozogamicin among patients with R/R ALL. In selecting between these agents, then, we must consider both patient-specific factors and the desired trajectory of therapy. As an example, when definitive transplant is the ultimate goal, if an abnormal liver history or liver function test arises, I strongly suggest avoiding inotuzumab ozogamicin as your first-choice treatment. In multivariate analysis from INO-VATE ALL, elevated pretransplant bilirubin and aspartate aminotransferase/alanine aminotransferase levels predicted posttransplant veno-occlusive disease/sinusoidal obstruction syndrome in inotuzumab ozogamicin recipients.
Conversely, in persons with major CNS issues, I tend to avoid blinatumomab as my first choice. It is well recognized that neurologic adverse events (eg, dizziness, tremor, confusion, encephalopathy) sometimes occur early during administration of this agent. This potential for neurotoxicity warrants monitoring if blinatumomab is given and, when present, may necessitate steroids or blinatumomab discontinuation if severe.
Another instance where blinatumomab may not be preferred is for patients with high blast counts (ie, > 50%). Under these conditions, blinatumomab is less effective whereas inotuzumab ozogamicin activity is unperturbed. This is a key difference. However, I will mention that each drug can be an effective therapy after disease progression on the other. Inotuzumab ozogamicin rescues some patients whose disease has progressed on or after blinatumomab; similarly, blinatumomab rescues some patients whose disease has progressed on or after inotuzumab ozogamicin. There is clearly room for both of these drugs in our therapeutic arsenal.
Finally, in a patient where CAR T‑cell therapy is the intended next step, I tend to avoid other CD19‑directed therapies upfront. I want to circumvent any potential of selecting for CD19-negative cells and consequently preempting the efficacy of the CAR T-cells.
How are you using blinatumomab and inotuzumab ozogamicin in your patients with R/R ALL? I encourage you to answer the polling question and join the conversation in the discussion box.