Phase I Study of Non-Engrafting Allogeneic, Mismatched, Unmanipulated Peripheral Blood Mononuclear Cell Infusions to Treat Poor-Prognosis Acute Myeloid Leukemia

BACKGROUND: Non-engrafting or microchimeric allogeneic immunotherapies might dramatically benefit patients with acute myeloid leukemia (AML). Mismatched G-CSF-mobilized peripheral blood (PB) and NK cells administered after chemotherapy increase complete remission (CR) and overall survival rates in poor-prognosis AML, without significant risk of graft-versus-host disease (GVHD). For example, as first-line therapy in elderly patients, the G-CSF-mobilized approach increased disease-free survival from 10% to 39% in a randomized trial (Guo et al, Blood 2011). By contrast, this trial addresses the safety of unprimed, unselected HLA-mismatched cell therapy in chemorefractory or relapsed AML, to avoid exposing donors to G-CSF and further minimize the risk of GVHD. Secondary objectives include describing the incidence of CR, GVHD, prolonged aplasia, and infusion reactions.

METHODS/PATIENTS: Seven patients (median 63, range 57-68 years) with primary refractory AML (n = 1) or 1st (n = 4) or 2nd (n = 2) marrow relapse at a median of 2.9 (range, 1.6-8.0) months after completing consolidation were enrolled on this ongoing dose-escalation trial (NCT 1793025). Four had intermediate-risk caryotypes or FLT3 -ITD, 3 high-risk - including 2 with extremely complex and monosomal caryotypes and deleted or mutated TP53. One had therapy-related AML, 1 likely evolved from MDS, while 1 relapsed with bilineage leukemia (myeloid + T cell). Participants were ineligible for allotransplant due to comorbidities or adverse AML genetics. They had 14%-92% marrow blasts before re-induction, with either NoVE (n = 5), high-dose ara-C/VP16 (n = 1), or high-dose ara-C/mitoxantrone (n = 1). Donors were mismatched to recipients in varying degrees (n = 3 haploidentical and 4 with 0-3/10 allele-level matches). Target CD3+ cell dose was 1 x 10⁷/kg for the 1st 4 patients and 5 x 10⁷/kg for the next 3. Unmanipulated PB mononuclear cells were infused 24-48 hours after the last dose of re-induction chemotherapy (''day 0''). Marrow was evaluated on day 14 and upon hematopoietic recovery.

RESULTS: SAFETY: Two patients experienced neutropenic fever from several hours to 5 days after cell infusion, but we observed no definite acute or delayed infusion reactions and no GVHD. One patient with cirrhosis developed septic shock with liver/renal failure prior to the infusion and declined dialysis; his long-term endpoints could not be assessed but he tolerated the infusion well. Sustained platelets > 100 × 10⁹/L and neutrophils > 1 × 10⁹/L occurred at +16-31 days and +14-39 days respectively in patients who achieved CR. RESPONSES: One patient achieved near morphologic CR (≤6% marrow blasts, normal PB) at day +29 and was consolidated with an HLA-identical sibling transplant at day +49; she remains in CR 28 months later. Two achieved CR lasting 77 and 164 days in the absence of further therapy. Three had persistent AML. BIOLOGY:Products contained mainly T cells (72%-80%) with varying proportions of NK (9%-17%), NK/T (0.6%-6%), B (7%-14%), and CD14+ (10%-17%) cells. Two broad patterns of total lymphocyte counts were observed: dramatic bursts from ≤ 0.2 to ≥ 1.0 (up to 1.4) × 10⁹/L peaking days 5-8 post infusion, vs. stability/gradual recovery; numbers are too small to draw conclusions about any association with CR (p = 0.4 Fisher exact test). Lymphocyte bursts were not seen in 45 historical controls treated with chemotherapy alone (p = 0.02 for association with cell therapy). No patient-donor pairs were predicted to exhibit NK alloreactivity mediated by C1 or C2 KIR-ligand mismatching, and only 1 pair each had predicted Bw4-mediated donor-vs-recipient and recipient-vs-donor reactivity, respectively. When tested, marrow macrochimerism was undetected (n = 2).

CONCLUSIONS: The incidence of life-threatening infections and duration of aplasia in the heavily-pretreated patients observed thus far do not exceed that expected with chemotherapy alone. Cell infusion is well-tolerated. The 42% (95% CI, 25%-84%) CR rate warrants continued dose escalation per protocol, especially because (1) we administer only 1 infusion and (2) our patients are treated with relapsed/refractory AML baring extremely poor prognostic features. Our results suggest that rejection of donor cells protects against engraftment and GVHD, and might sometimes be associated with a lymphocyte burst. Biologic correlations to identify ways to optimize anti-leukemic effects will be performed.