**1.7 Checkpoint inhibitors**

The development of immune checkpoint inhibitors (ICIs) is a revolutionary milestone in the field of immuno-oncology. Immune checkpoint blockade removes inhibitory signals of T-cell activation, which enables tumor-reactive T cells to overcome regulatory mechanisms and mount an effective antitumor response [103–105]. 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 preclinical AML models [107].

#### *1.7.1 Nivolumab*

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].

#### *1.7.2 Pembrolizumab*

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

#### *1.7.3 Ipilimumab*

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

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*Target Therapy in Acute Myeloid Leukemia DOI: http://dx.doi.org/10.5772/intechopen.94422*

**2. Gemtuzumab ozogamicin (GO)**

40 patients and the MTD was determined to be 9mg/m2

Mylotarg as a 2-hour intravenous infusion, at a dose of 9 mg/m2

T cell subsets [115].

**1.8 CD33-targeted therapy**

associated with in situ infiltration of CD8+ T cells as well as enrichment of effector

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].

Gemtuzumab ozogamicin (Mylotarg) is a humanized anti-CD33 IgG4 monoclonal antibody conjugated to a cytotoxic agent N-acetyl gamma calicheamicin via an acid-labile hydrazone linker. After GO binds to CD33, calicheamicin is being released and generates single and double strand breaks with subsequent cellular death [123]. In a phase I dose escalation study of an anti-CD33 calicheamicin immunoconjugate 40 patients with relapsed or refractory CD33(+) AML were treated. Leukemia was eliminated from the blood and marrow of 8 (20%) of the

ing results from three open label phase II studies, the FDA approved GO for the treatment of patients with CD33-positive AML in first relapse who were ≥ 60 years and not suitable for intensive chemotherapy. 142 patients with AML in first relapse were enrolled in the studies with median age of 61 years. All patients received

for two doses. 30% of patients obtained complete morphological remission. High incidences of myelosuppression, grade 3 or 4 hyperbilirubinemia, and elevated hepatic transaminase levels were registered [125]. In a post-approval phase III trial gemtuzumab ozogamicin was administred during induction and postconsolidation therapy in younger patients with acute myeloid leukemia. 637 patients were randomly assigned to receive daunorubicin, cytarabine, and GO vs. standard induction therapy with daunorubicin and cytarabine alone. The CR rate was 69% for DA + GO and 70% for DA (P = 0.59). In this study, the addition of GO to induction or postconsolidation therapy failed to show improvement in CR rate, disease-free survival, or overall survival. Also addition of GO was associated with a higher early mortality during induction (5.5% vs. 1.4%). Major causes of death were fatal hemorrhage and infection. Based on these negative results GO was withdrawn from the market in 2010 [126]. In a subsequent trials different schedules of GO were investigated. Phase 3, open-label study enrolled 280 patients aged 50–70 years with previously untreated de novo AML. Patients were randomly assigned in a 1:1 ratio to standard treatment (control group) with or without five doses of intravenous gemtuzumab during induction and day 1 of each of the two consolidation chemotherapy courses. Although the CR rates were similar between the two arms, IC plus GO provided a significantly improved median event free survival (EFS) (19.6 vs. 11.9 months, p = 0.00018) and median OS (34 vs. 19.2 months, p = 0.046). Haematological toxicity, particularly persistent thrombocytopenia, was more common in the GO group than in the control group, without an increase in the risk of death from toxicity [127]. A meta-analysis of five open label, phase 3 trials comprising 3325 AML patients found that the addition of gemtuzumab ozogamicin significantly reduced

[124]. After the encourag-

, at 2-week intervals

associated with in situ infiltration of CD8+ T cells as well as enrichment of effector T cell subsets [115].
