Schema of COG protocols. (A) Schematic diagram of COG study AALL1331 showing the 4 arms of therapy and randomization time points for patients with first relapse of B-ALL to receive blinatumomab. Patients receive a common induction (block 1) and are then risk stratified based on disease response and biologic features. Those with high risk and intermediate risk receive arms A or B. Patients with low-risk disease are randomized to arms C and D. Time points for additional evaluations and consideration of stem cell transplant are depicted as are points where patients would be removed from treatment of nonresponse or relapse. (B) Schematic diagram of COG study AALL1731 showing the 2 control and 2 experimental arms taken from the AALL1331 design with additional biologic testing at defined time points after induction chemotherapy. Patients with SR-Avg and SR-high disease are randomized after consolidation and based on MRD assessments to receive 2 blocks of blinatumomab intercalated into conventional chemotherapy backbone treatment. Blina, blinatumomab; EscMTX, escalating-dose methotrexate; Exp, experimental; SR-Fav B-ALL = standard-risk favorable B-ALL; SR-Avg B-ALL = standard-risk average B-ALL; SR-High B-ALL, standard-risk high B-ALL. Schematic flow diagrams shown with permission of COG AALL1331 Study Chair Patrick Brown and AALL1731 Study Chairs Rachel Rau and Sumit Gupta.