Blinatumomab + Tyrosine Kinase Inhibitors with No Chemotherapy in BCR-ABL-Positive or IKZF1-Deleted or FLT3-ITD-Positive Relapsed/Refractory Acute Lymphoblastic Leukemia Patients: High Molecular Remission Rate and Toxicity Profile

BCR-ABL, IKZF1-deletions, FLT3-ITD convey the poor prognosis to acute lymphoblastic leukemia (ALL) patients (pts). Blinatumomab, a bispecific monoclonal anti-CD3/CD19 antibody, allows to achieve 36% - 44% of CR/CRh in relapsed/refractory BCR-ABL-positive and BCR-ABL-negative ALL as monotherapy. Blinatumomab + tyrosine kinase inhibitors (TKI) combination is the promising approach to treat BCR-ABL-positive ALL omitting chemotherapy. Besides BCR-ABL the tyrosine kinase targets in IKZF1-deleted and FLT3-ITD ALL allow to use TKI in these ALL subsets. In preclinical studies ATRA had activity in IKZF1-deleted ALL.

From October 2015 to August 2017 11 pts with relapsed/refractory ALL with median age 32 years (from 24 to 49 years), 8 female and 3 male, were treated by blinatumomab + TKI combination. Median follow-up is 12 months (3 - 19 months). The diagnosis was BCR-ABL-positive ALL in 8 pts (1 - primary refractory, 6 - overt relapses, 1 - cytogenetic relapse), IKZF1-deleted ALL in 2 pts (2 primary refractory), FLT3-ITD-positive ALL in 1 pt (1 primary refractory). T315I ABL mutation was diagnosed in 2 BCR-ABL-positive ALL. All pts had strong CD19 positivity. Blinatumomab continuous intravenous infusion + TKI therapy was started in all pts. Blinatumomab dose during 4-7 days in 1^st week of 1^st cycle was 9 mcg/day, 28 mcg/day - subsequent three weeks. Blinatumomab dose in subsequent 4-weeks cycles was 28 mcg/day. Blinatumomab treatment consisted of 4 - 5 cycles with 2 week intervals. 8 pts were treated initially with TKI Dasatinib, 1 - bosutinib (Dasatinib/Nilotinib intolerant), 1 - Ponatinib (T315I), 1 - Sorafenib (FLT3-ITD-positive ALL). TKIs were administered continuously in all pts. ATRA 45 mg/m²/d 1-40 days was administered in IKZF1-del ALL in 1^st blinatumomab cycle, 1- 14 days in 2-4 blinatumomab cycles. T-helper, T cytotoxic, T-regulatory and NK peripheral blood lymphocytes subpopulations were measured weekly by flow cytometry during blinatumomab treatment .

No one pt had myelosuppression which allowed to perform 2 - 4 cycles of blinatumomab in outpatient settings in 8 pts. 2 pts has neurological toxicity 1 - 2 grade (headaches in 1 pt, ulnar neuropathy in 1 pt). All pts have significant decrease of normal IgG, A, M levels and intravenous human normal immunoglobulin replacement was performed in all of them. 1 pt on sorafenib had transient palmar-plantar syndrome which completely resolved after 2 weeks of TKI temporal discontinuation. Diarrhea was observed on dasatinib in 3 pts and resolved on nilotinib in 1 pt and on bosutinib in 2 pt. CMV-colitis was diagnosed in 3 pts with diarrhea, colitis was ulcerative in 1 pt. The pts with CMV colitis were treated with ganciclovir i.v. Pyrexia observed in 9 pts in 1^st blinatumomab cycle and in 2 pts in 2^nd cycle. Skin sickness observed in 2 pts with IKZF1-deleted ALL on ATRA treatment. T-helper, T-regulatory, T-cytotoxic and NK lymphocytes subpopulations were below of lower limit of normal range during 1^st blinatumomab cycle. From 2^nd to 4^th cycles T-cytotoxic and NK returned into normal range while T-helper and T-regulatory remained lowered.

During 1^st blinatumomab cycle 10 pts achieved complete remission (CR) including 1 pt with T315I on ponatinib and 1 pt progressed (the second pt with T315I). On subsequent cycles 9 pts achieved molecular remission (MolCR), one pt with BCR-ABL-positive ALL - cytogenetic remission (CyCR). In 6 pts allo-SCT was performed including 1 from haploidentical donor and 1 pt in MolCR received auto-SCT. 1 pt with CyCR achieved MolCR after allo-SCT. 1 pt is awaiting allo-SCT and 2 pts are on Blinatumomab+TKI treatment, 1 auto-SCT and 1 allo-SCT are planned. TKIs restarted 3 - 4 weeks after transplant. At the moment 10 pts are in MolCR.

Blinatumomab + TKI treatment has minimal myelosuppression and the treatment in such a heavily pretreated patients with relapsed/refractory ALL is possible in outpatient settings. The treatment has high MolCR rate and low toxicity profile. It should be emphasized that deep B-cell depletion is accompanied by profound hypogammaglobulinemia and high prevalence of CMV infection.