Efficacy and Tolerability of Blinatumomab in Clinical Trial Ineligible Patients with CD19+ Leukemias
Authors: Claiborne John Preston , Li Daniel , Smith B. Douglas , Levis Mark J. , Gojo Ivana , DeZern Amy E. , Ambinder Alexander J. , Jain Tania , Prince Gabrielle T. , Gondek Lukasz P. , Karantanos Theodoros , Ghiaur Gabriel , Dalton William Brian , Webster Jonathan Allen 
Published: December 2024

Introduction: Outcomes for older patients with B ALL have improved dramatically with the approvals of blinatumomab (BLIN) and inotuzumab ozogamicin (INO). Frontline treatment combining mini-HyperCVD with INO +/- BLIN yields a 3-year relapse incidence of 11-17% and non-relapse mortality (NRM) of 32-33% in patients ≥60 years (Jabbour. Lancet Haematol 2023). Frontline BLIN with TKIs in Ph+ B ALL and as monotherapy in Ph- B ALL for patients ≥65 years demonstrates 3-year disease-free survival of 77% and 37%, respectively, with just 3% NRM (Advani. Blood Adv 2023; Advani. J Clin Oncol. 2022). Beyond these trials, BLIN has proven effective in relapsed/refractory and MRD+ disease, and in combination with chemotherapy in newly diagnosed, MRD- patients. While BLIN has shown great benefit in many settings, there is a paucity of data in patients with co-morbidities that predispose to BLIN toxicities who were excluded from these trials.

Methods: The records of patients age ≥ 18 who received BLIN at Johns Hopkins since 2015 were analyzed. Patients were included based on common exclusion criteria of BLIN trials: 1) bilirubin &gt; 2 x upper limit of normal (ULN) or AST/ALT &gt; 5 x ULN 2) creatinine &gt; 1.5 mg/dL 3) clinically relevant CNS pathology 4) autoimmune disease or organ transplantation 5) uncontrolled, serious infection or 6) concurrent, active malignancy. Incidence of patient and disease variables, response, and toxicities were collected. Overall survival (OS) was calculated from BLIN initiation to death or last follow-up using the Kaplan-Meier method.

Results: A total of 36 patients with a median age of 58 years (range: 24-79) met the inclusion criteria. This included 12 newly diagnosed B ALL patients (3 Ph+ and 9 Ph-) deemed unfit for chemotherapy, 9 patients with relapsed/refractory disease (1 Ph+ ALL, 5 Ph- ALL, 1 CML in lymphoid blast crisis (LBC), and 2 Ph- mixed phenotype acute leukemias (MPALs)), and 15 patients in remission (9 Ph+ ALL, 4 Ph- ALL, 1 CML in LBC, and 1 Ph+ MPAL) of whom 11 were MRD+. The following were reasons for inclusion: hepatic dysfunction (5), renal impairment (6), CNS pathology (13), autoimmune disease (5), prior organ transplant (2), infection (1), and other active malignancy (9). Five patients had two reasons for inclusion. Two patients had transaminitis and three had hyperbilirubinemia at a median 3.0 mg/dL (range 2.5-7.6). The median creatinine was 2.7 mg/dL (range: 1.6-4.9) among those with renal impairment. CNS pathology included seizure disorder (5), prior stroke (4), prior stroke and seizure (1), and symptomatic subdural hematoma (3). Autoimmune diseases were exclusively in those in remission and included inflammatory bowel disease (3), anterior uveitis (1), and systemic lupus erythematosus (1). Those with active malignancy had multiple myeloma (8) and renal cell carcinoma (1).

Among the 16 Ph+ patients, 14 received a TKI concurrently with BLIN. Thirty-one patients (88%) completed a full cycle of BLIN with 3 patients with relapsed/refractory disease stopping early due to disease progression, 1 newly diagnosed patient stopping due to renal failure requiring dialysis, and 1 patient with disease relapse stopping due to immune effector cell-associated neurotoxicity (ICANS). Overall rates of cytokine release syndrome and ICANS were 58% and 28% with median grades of 1 (range 1-2) and 2 (2-3), respectively. Among 13 patients with CNS pathology, 4 (31%) developed ICANS including 2 grade 3 events. None of these patients discontinued BLIN, although one patient suffered a seizure for which BLIN dosing was reduced and anti-epileptics were uptitrated. Among patients with liver or renal impairment, 60% and 33% had worsening organ function, respectively, which were transient except in the patient who developed dialysis dependence. No patients with autoimmune disease had a flare, and neither patient with prior organ transplant had rejection. Response rates were 83% in newly diagnosed patients, 33% in relapsed/refractory patients, and 82% in MRD+ patients. With a median follow-up of 51 months, 2-year OS was 48% in newly diagnosed patients, 11% in relapsed/refractory, and 82% among patients in remission. There were no BLIN-related deaths.

Conclusions: BLIN was well tolerated and highly effective in patients with co-morbidities that would have precluded clinical trial enrollment. BLIN has broad survival benefits in B ALL across many disease settings and can be used in patients with co-morbid illnesses.