High CD33-antigen loads in peripheral blood limit the efficacy of gemtuzumab ozogamicin (Mylotarg®) treatment in acute myeloid leukemia patients

Velden, VH van der; Boeckx, Nancy; Jedema, Inge; Marvelde, JG te; Hoogeveen, Patricia G.; Boogaerts, Marc; Dongen, Jacques J. M. van

doi:10.1038/sj.leu.2403350

Cited by 109 publications

(73 citation statements)

References 17 publications

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“…This is in contrast to GO in AML patients, in which the efficacy of GO is highly dependent on the intracellular accumulation of GO via the ongoing process of saturation, internalization and renewed expression of CD33. 18,19 Consequently, a positive correlation was found between CD33 expression and the efficacy of GO. 38 Goemans et al, 39 previously postulated that the large interpatient differences in calicheamicin efficacy in pediatric AML are caused by differences in intrinsic sensitivity of these target cells to calicheamicin.…”

Section: Discussionmentioning

confidence: 91%

“…18,19 Prolonged maximal saturation of CD33 Ags by GO was crucial to obtain sufficiently high intracellular GO levels. To investigate whether this was also the case for CMC-544, we first examined the relationship …”

Section: Impact Of Intracellular Accumulation Of Calicheamicin On Effmentioning

confidence: 99%

“…Furthermore, a repeated loop of binding of GO, saturation of CD33 Ags, internalization of the complex and renewed expression of CD33 Ags was essential for intracellular accumulation of calicheamicin and for the efficacy of GO. 18,19 In the clinical trials with GO in AML patients only low dosages of GO were added to the existing AML treatment protocols to assure a reasonable tolerability of the combination of drugs. With these low concentrations the criteria of prolonged and maximal saturation will not be fulfilled, which might in part explain the low response rates observed in these clinical trials.…”

Section: Introductionmentioning

confidence: 99%

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The novel calicheamicin-conjugated CD22 antibody inotuzumab ozogamicin (CMC-544) effectively kills primary pediatric acute lymphoblastic leukemia cells

et al. 2011

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We investigated whether the newly developed antibody (Ab) -targeted therapy inotuzumab ozogamicin (CMC-544), consisting of a humanized CD22 Ab linked to calicheamicin, is effective in pediatric primary B-cell precursor acute lymphoblastic leukemia (BCP-ALL) cells in vitro, and analyzed which parameters determine its efficacy. CMC-544 induced dose-dependent cell kill in the majority of BCP-ALL cells, although IC 50 values varied substantially (median 4.8 ng/ml, range 0.1-1000 ng/ml at 48 h). The efficacy of CMC-544 was highly dependent on calicheamicin sensitivity and CD22/CMC-544 internalization capacity of BCP-ALL cells, but hardly on basal and renewed CD22 expression. Although CD22 expression was essential for uptake of CMC-544, a repetitive loop of CD22 saturation, CD22/CMC-544 internalization and renewed CD22 expression was not required to achieve intracellular threshold levels of calicheamicin sufficient for efficient CMC-544-induced apoptosis in BCP-ALL cells. This is in contrast to studies with the comparable CD33 immunotoxin gemtuzumab ozogamicin (Mylotarg) in acute myeloid leukemia (AML) patients, in which complete and prolonged CD33 saturation was required for apoptosis induction. These data suggest that CMC-544 treatment may result in higher response rates in ALL compared with response rates obtained in AML with Mylotarg, and that therefore clinical studies in ALL, preferably with multiple low CMC-544 dosages, are warranted.

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Section: Discussionmentioning

confidence: 91%

Section: Impact Of Intracellular Accumulation Of Calicheamicin On Effmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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The novel calicheamicin-conjugated CD22 antibody inotuzumab ozogamicin (CMC-544) effectively kills primary pediatric acute lymphoblastic leukemia cells

et al. 2011

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“…The effect of GO on leukemia cells in bone marrows is reportedly influenced by the amount of CD33 antigen in the peripheral blood [32]. GO may thus be lost to some extent in the circulation before it reaches the bone marrow.…”

Section: Cd33mentioning

confidence: 99%

Efficacy and resistance of gemtuzumab ozogamicin for acute myeloid leukemia

Takeshita

2013

Int J Hematol

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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.

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“…Additionally, a high CD33 antigen load in the PB simply consumes GO and thereby limits its penetration into the bone marrow. Prior chemotherapy may rapidly reduce CD33 antigen load and thus lead to a better efficacy of GO [41].…”

Section: Subsequent Treatmentmentioning

confidence: 99%

Sequence of administration and methylation of SOCS3 may govern response to gemtuzumab ozogamicin in combination with conventional chemotherapy in patients with refractory or relapsed acute myelogenous leukemia (AML)

Middeldorf¹,

Galm²,

Osieka³

et al. 2010

American J Hematol

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In older patients suffering from acute myelogenous leukemia (AML), aggressive chemotherapy is accompanied with high treatment-related morbidity and mortality. Gemtuzumab ozogamicin (GO), a humanized monoclonal anti-CD33 antibody, represents a well tolerated treatment option, but optimal treatment schedules are still unknown. Additionally, Suppressor of cytokine signaling 3 (SOCS3) inhibits the CD33-induced block on cytokine-induced proliferation. Consequently, a variable response of AML cells to anti-CD33-targeted therapy may be caused by modulation of SOCS3 expression. Twenty-four patients with refractory or relapsed CD33-positive AML received GO as a single agent before or after conventional chemotherapy. The methylation status of the SOCS3 CpG island was assessed by methylation-specific polymerase chain reaction. Response (RR) and overall survival (OS) were significantly higher in 16 patients receiving chemotherapy before GO (RR 81%, OS 14.8 months) compared to three patients who received GO single agent therapy (RR 33%, OS 7.2 months) or 16 with GO before chemotherapy (RR 0% OS 2.2 months, P 5 0.01 for RR and P < 0.001 for OS). Methylation of the SOCS3 CpG island was found in 8/24 patients. There was a trend towards a higher RR and longer OS in patients with SOCS3 hypermethylation (RR 86%, OS 25.1 months) compared to unmethylated SOCS3 (RR 56%, OS 10.3 months, P 5 0.09). Administration of GO a few days after chemotherapy seems to provide better response and survival compared to administration of GO directly before chemotherapy. The potential role of SOCS3 hypermethylation as a biomarker should be further investigated in patients undergoing GO containing therapies. Am. J. Hematol. 85:477-481, 2010. V

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High CD33-antigen loads in peripheral blood limit the efficacy of gemtuzumab ozogamicin (Mylotarg®) treatment in acute myeloid leukemia patients

Cited by 109 publications

References 17 publications

The novel calicheamicin-conjugated CD22 antibody inotuzumab ozogamicin (CMC-544) effectively kills primary pediatric acute lymphoblastic leukemia cells

The novel calicheamicin-conjugated CD22 antibody inotuzumab ozogamicin (CMC-544) effectively kills primary pediatric acute lymphoblastic leukemia cells

Efficacy and resistance of gemtuzumab ozogamicin for acute myeloid leukemia

Sequence of administration and methylation of SOCS3 may govern response to gemtuzumab ozogamicin in combination with conventional chemotherapy in patients with refractory or relapsed acute myelogenous leukemia (AML)

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