**1.8 CD33-targeted therapy**

*Acute Leukemias*

*1.7.1 Nivolumab*

*1.7.2 Pembrolizumab*

*1.7.3 Ipilimumab*

preclinical AML models [107].

Recent studies suggest a novel mechanism that tumor cells might evade host immune attack through increased expression of PD-L1 [106]. Immune checkpoint inhibitor treatment involves programmed cell death protein 1 (PD1) and cytotoxic Tlymphocyte- associated antigen 4 (CTLA4), both of which have been used in

Nivolumab (BMS-936558, ONO-4538, or MDX1106) is the first-in-human immunoglobulin G4 (IgG4) PD-1 immune checkpoint inhibitor antibody that disrupts the interaction of the PD-1 receptor with its ligands PD-L1 and PD-L2, thereby inhibiting the cellular immune response [108, 109]. In a phase IB/II study of nivolumab in combination with azacytidine in patients (pts) with relapsed AML 51 patients with a median age of 69 years (range 45–90) were included. From 35 patients evaluable for response, 6 (18%) achieved complete remission (CR)/(CRi) (3 CR, 3 CRi), 5 (15%) had hematologic improvement (HI), 9 (26%) had 50% BM blast reduction,3 pts. (9%) had stable disease >6 months, and 12 (34%) had progression. In the subgroup of patients who did not receive HMA prior treatment, the superiority of new regimen was even more evident with ORR at 52–22%. The median overall survival for the 35 evaluable pts was 9.3 months (range, 1.8–14.3). Grade 3/4 and Grade 2 immune mediated toxicities were observed in 7 (14%) and 6 (12%) patients, which included pneumonitis, nephritis, transaminitis, and skin rash. Steroids took effect on 88% of the patients who suffered from drug-related toxicities [110]. A single-arm, phase 2 part of the phase 1–2 study of nivolumab in combination with idarubicin and cytarabine was conducted in 44 patients with newly diagnosed acute myeloid leukaemia or high-risk myelodysplastic syndrome. The median overall survival was 18.54 months and median event-free survival was not reached. Among the 44 evaluable patients, the ORR was 77% including 63% CR and 14% CRi. Concerning drug toxicities, the grade 3–4 adverse events were observed in six patients, including rash, colitis, pancreatitis and transaminitis [111]. Using nivolumab in post-transplantation setting showed limited efficacy. Among three relapsed AML patients after allo-HSCT treated with nivolumab, one achieved

CR, one experienced stabilization, and the third failed to respond [112].

CR. With a median follow-up of 13 months, the mOS was 7 months [114].

Ipilimumab is a human IgG1 monoclonal antibody, CTLA-4 antagonist. In a phase I/Ib, open label, multicenter study of treating patients with relapsed hematological malignancies after allo-SCT with ipilimumab 12 AML patients were enrolled. Complete response was observed in five patients (23%) and the 1-year survival rate was 49%. Immune-related adverse events occurred in three patients. Response was

Pembrolizumab (MK-3475) is another drug that blocks PD-1. In a multicenter phase II study pembrolizumab was administered after high-dose cytarabine salvage chemotherapy in 26 R/R AML patients with median age of 54. The overall response rate was 42% with 9 CR/CRi, one PR, and one patient with morphologic leukemia free state. The median OS was 10.5 months. Most frequently observed grade 3 AEs included hepatitis, rash, and epigastric pain [113]. In another single center, single arm trial of pembrolizumab followed by decitabine in 10 patients R/R AML patients with median age of 62, the ORR was 20% with one patient achieving MRD-negative

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The CD33 antigen is expressed on the blast cells (85–90%) of most cases of acute myeloid leukemia [116–118]. CD33 seems to be much less expressed on normal hematopoietic stem cells and has decreased expression during the differentiation of the myeloid lineage. Mature granulocytes do not express a significant amount of CD33. That makes CD33 an promising target for AML targeted therapy [119, 120]. The only non-haematopoietic cells expressing CD33 are hepatocytes, which explains to some extent hepatic toxicity induced by anti CD33 antibodies [121, 122].
