Efficacy and resistance of gemtuzumab ozogamicin for acute myeloid leukemia

Abstract

Seventy to 80 % of patients with acute myeloid leukemia (AML) achieve complete remission following intensive chemotherapy, but more than 50 % of patients in remission subsequently relapse, which is often associated with clinical drug resistance. Therapy based on monoclonal antibodies (mAbs) has been developed to increase the selectivity of cytotoxic agents by conjugating them with a mAb. Gemtuzumab ozogamicin (GO) is a conjugate of a cytotoxic agent, a calicheamicin derivative, linked to a recombinant humanized mAb directed against the CD33 antigen, which is expressed on leukemia cells from more than 90 % of patients with AML. This conjugated mAb was introduced following promising results from phase I and II studies. However, the initial phase III study did not confirm the efficacy of GO in combination with conventional chemotherapies. Several subsequent phase III studies have shown the efficacy of GO in favorable and intermediate risk AML. Several resistance mechanisms against GO have been reported. Multidrug resistant (MDR) P-glycoprotein (P-gp), a trans-membrane glycoprotein that pumps out many anti-leukemic agents from cells, also affects GO. For this reasons, GO has been used in combination with MDR modifiers, such as cyclosporine, and in cases without P-gp. Several investigators have reported successful results of the use of GO in acute promyelocytic leukemia (APL). GO has also been described as effective in cases relapsed after treatment with all-trans retinoic acid (ATRA), arsenic acid and conventional chemotherapeutic agents. The efficacy of GO will be studied mainly in a favorable risk of AML, such as core binding factor leukemia and APL. In addition, suitable combinations with other chemotherapies and administration schedules should be discussed.

Core-binding factor acute myeloid leukemia: can we improve on HiDAC consolidation?

“…11 Upon binding to CD33, the CD33-GO complexes are rapidly internalized, providing a convenient drugdelivery mechanism into the cell. This explains why cells expressing higher levels of CD33 are more susceptible to GO.…”

“…This explains why cells expressing higher levels of CD33 are more susceptible to GO. 11 However, because patients with CD33-negative AML respond to treatment with GO, a CD33-independent endocytotic transport of the drug into the cells has been suggested. 11 GO was approved by the Food and Drug Administration in the year 2000 for the treatment of relapsed AML in patients older than 60 years who were unfit for intensive therapy, but due to safety concerns raised by an interim analysis of a following randomized trial, 12 the drug was withdrawn from the market in 2010.…”

TIM-3 as a novel therapeutic target for eradicating acute myelogenous leukemia stem cells

“…CD33 and CD123 [43] proteins are expressed at a considerably high level in normal HSCs and myeloid progenitors including CMPs and GMPs [44], suggesting that targeting these molecules should harm normal hematopoiesis. In fact, prolonged cytopenia has been observed in AML patients treated with gemtuzumab [45], a recombinant humanized anti-CD33 monoclonal antibody conjugated with the cytotoxic antibiotic calicheamicin. In contrast, CLL-1 [46], CSF1R [47], CD96 [48] and CD99 [16] are all specifically expressed in LSCs.…”

Immunotoxins, Resistance and Cancer Stem Cells: Future Perspective

“…Two inhibitors of ABCG2 and ABCB1 transporters, GF120918 and tariquidar, have been approved for clinical studies. Although CD33 is expressed in 90 % of AML patients, more than 50 % of patients show remission due to GO resistance mediated via the membrane transporters [63]. Addition of U0126, a MEK1/2 inhibitor, was reported to prevent GO resistance induced in HL-60/GO resistant cells.…”

“…Combination with cisplatin, IFN-γ, IFN-α, and etoposide were observed to enhance the cytotoxic effects of ZME-gelonin against resistant cells [75]. Other combinations with GO include G-CSF that induced AML cells to enter G2/M and hypodiploid phase and Valproic acid, a histone deacetylase inhibitor [63]. As mentioned earlier, the combination of ABT-737 with immunotoxin could enhance killing by 20-fold in resistant cell lines by neutralizing anti-apoptotic proteins and by increasing the delivery of the immunotoxin from the ER to the cytosol [26].…”