Activity of blinatumomab in lymphoblastic leukemia with impaired T-cell immunity due to congenital immunodeficiency

Blinatumomab is a single-chain recombinant antibody construct of an anti-CD3 single-chain variable fragment (scFV) fused with an anti-CD19 single-chain variable fragment via a short peptide linker.¹  The cytotoxicity of the antibody is mediated by cytokines released from activated T cells after engagement of the antibody with CD19⁺ and CD3⁺ cells.²  Several studies have demonstrated its activity in the relapse/refractory and minimum residual disease (MRD) settings in children and adults.^3,4 

We describe 2 patients with CD19⁺ B-precursor acute lymphoblastic leukemia (BCP-ALL) against a background of primary T-cell immunodeficiency in whom blinatumomab as a chemotherapy toxicity-sparing agent was successful in inducing an MRD⁻ remission.

Signed consent to publish anonymized information was obtained from legal guardians.

A 6-year-old Croatian girl with a background of Schimke immuno-osseous dysplasia (SIOD) was diagnosed with BCP-ALL with a presenting white cell count of 1.62 × 10⁹/L. She had no central nervous system (CNS) disease, and her leukemia was cytogenetic good-risk with high hyperdiploidy. Six months earlier, she had developed nephrotic syndrome for which she had a suboptimal response to steroid therapy. A renal biopsy demonstrated focal segmental glomerulosclerosis of perihilar type leading to stage 4 chronic kidney disease, hypertension, and anemia. SIOD is a rare autosomal-recessive disorder⁵  caused by a mutation in SMARCAL1 (SWI/SNF-related matrix-associated actin-dependent regulator of chromatin, subfamily-a–like-1), a gene involved in maintaining the integrity of the genome.⁶  Affected patients, as in the present case, have progressive renal disease caused by focal segmental glomerulosclerosis, vasculopathy, combined immunodeficiency, and risk of lymphoproliferative disease and bone marrow failure.

Immunophenotyping demonstrated absolute lymphopenia that was disproportionate in CD3⁺CD4⁺ cells (120 × 10⁶/L). Her proportion of naive CD4⁺ T cells (CD4⁺CD45RA⁺CD27⁺) was markedly reduced for age (29%), and her T-cell receptor excision circles (TRECs) were negligible, demonstrating a significant reduction in recent thymic emigrants. Baseline immunological testing before chemotherapy was initiated is outlined in Tables 1 and 2.

Owing to the risks of excess chemotherapy toxicity reported in patients with SIOD,^7,8  she received weekly vincristine (50% of the normal dose) with prednisolone 40 mg/m² for 2 weeks instead of standard induction. Intrathecal cytarabine and hydrocortisone were administered instead of intrathecal methotrexate, to avoid the risk of delayed renal excretion and nephrotoxicity related to her preexisting poor renal function.⁹  We were satisfied that the substitution would provide effective CNS prophylaxis, given her low-risk of CNS relapse. However, she developed anuric renal failure in week 2 of therapy for which she required hemofiltration followed by hemodialysis and peritoneal dialysis, with the latter continuing to date. In view of worsening renal function, induction chemotherapy was discontinued and switched to blinatumomab therapy, with a starting rate of 5 μg/m² per day. An assessment was not performed before blinatumomab treatment began, as she was unfit for general anesthetic because she was in intensive care with unstable blood pressure and undergoing hemofiltration. Within 48 hours of the initiation of blinatumomab, she developed grade 2 cytokine release syndrome (CRS), graded according to the American Society for Transplantation and Cellular Therapy criteria.¹⁰  She required a bolus of fluid for hypotension and a brief interruption of the infusion. She had subsequent improvement in her fitness for anesthetic, and a second bone marrow aspirate (BMA) at day 12 of the infusion showed 8% blasts on flow cytometry. The blinatumomab infusion rate was increased to 15 μg/m² per day for the remaining 16 days of infusion, which she tolerated without a further episode of CRS. Her leukemia was in morphological remission with MRD of 0.009% on flow cytometry after the first cycle, which became flow- and PCR-negative after a second cycle. She subsequently received single-agent, low-dose oral mercaptopurine (15 mg/m² instead of 75 mg/m², because of myelosuppression at higher doses) with an intrathecal infusion of cytarabine in each of 3 consecutive months. She was unable to receive systemic or intrathecal methotrexate, as the drug is not dialyzed. At last follow-up, 14 months from diagnosis, her leukemia remained in molecular MRD⁻ remission.

A 9-year-old White, British boy, diagnosed with RAG1-deficient SCID with Omenn syndrome¹¹  during infancy, underwent a CD3⁺/CD19⁺–depleted maternal mismatched BMT at the age of 4 months. After the stem cell transplant (SCT), there was an early loss of myeloid donor chimerism and poor overall immune reconstitution. B-cell reconstitution did not occur, and long-term immunoglobulin replacement was necessary. The patient remained significantly CD3⁺CD4⁺ T-lymphopenic (270 × 10⁶/L), but had evidence of some thymic output (9% naive CD4⁺ T cells, 442 TRECs, Table 1). Despite the T-lymphopenia, he had a good quality of life with no significant or opportunistic infections; therefore, a second BMT was not performed because of the risk of toxicity and death. At the age of 9 years, he presented with tiredness and lethargy and was diagnosed with BCP-ALL. Cytogenetic analysis showed t(3;11) with a novel KMT2A-LARS2 fusion gene on RNA sequencing.

Owing to high-risk cytogenetics, he received a 4-drug induction as per the United Kingdom Acute Lymphoblastic Leukemia 2019 (UKALL2019) guidelines, after which he was in complete remission with a molecular MRD of 0.3% and flow MRD of 1.9%. Given concerns about resistant disease and prior unstable graft function, a second allogeneic stem cell transplant (allo-SCT) was considered during the first remission. Blinatumomab treatment was therefore commenced as a chemosparing consolidation therapy to minimize toxicity, with a view to proceeding to allo-SCT once an MRD level of <1 × 10⁻⁴ was achieved. MRD after 1 cycle of blinatumomab was negative by flow and molecular tests, which provided a bridge to a second T-cell receptor αβ/CD19–depleted paternal mismatched graft with add back of CD45RO⁺ memory T cells. The neutrophils and platelets were engrafted by days 17+ and 19+, respectively. He developed grade 2 acute graft-versus-host disease after discontinuing prophylaxis, but it resolved with a short course of systemic steroids. The leukemia remained in remission with 100% T-cell donor chimerism at 3 months after transplant. The outcome indicates that the patient had T-cell reconstitution after receiving a hemapoietic SCT.

Despite severely impaired T-cell immunity before initiation of chemotherapy, these 2 patients obtained a molecular MRD response after 1 to 2 cycles of blinatumomab, as outlined in Tables 1 and 2. This observation is in keeping with the experience in patients with severe, acquired postchemotherapy T-lymphopenia, which does not compromise the response to blinatumomab. The reasons are not entirely clear, but suggest that blinatumomab can activate and secondarily expand a small, functionally normal T-cell pool across the reticuloendothelial system and exert a therapeutic effect. T-lymphopenia, whether congenital or acquired, should not deter from the use of blinatumomab as a toxicity-sparing agent in patients with multiple comorbidities and high risk of chemotherapy-related toxicity.

Contribution: S.R. and A.C. wrote the paper and obtained consent from the parents; A.W. collected the data and contributed to clinical information; S.H.L. and M.S. contributed to clinical information and wrote the paper; and S.G. and A.V. designed the research and reviewed the paper.

Conflict-of-interest disclosure: The authors declare no competing financial interests.

Correspondence: Ajay Vora, Department of Paediatric Haematology, Great Ormond Street Hospital, London WC1N 3JH, United Kingdom; e-mail: ajay.vora@gosh.nhs.uk.