Fractionated doses of gemtuzumab ozogamicin with escalated doses of daunorubicin and cytarabine as first acute myeloid leukemia salvage in patients aged 50–70‐year old: A phase 1/2 study of the acute leukemia French association

Farhat, H.; Raffoux, Emmanuel; Berthon, Céline; Pautas, Cécile; Kammoun, L.; Chantepie, Sylvain; Gardin, Claude; Rousselot, Philippe; Chevret, Sylvie; Dombret, Hervé; Castaigné, Sylvie

doi:10.1002/ajh.22201

Cited by 34 publications

(18 citation statements)

References 15 publications

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“…CR rates between 32% and 55% were observed for combinations of GO with chemotherapy. [91][92][93] Interestingly, data from the MRC 15 trial showed that the addition of GO to induction therapy might be of significant benefit for patients with CBF AML. 94 Although GO is not easily available outside clinical trials, we try to get this drug based on published evidence in elderly relapsed patients with CD33 expression of the blasts as a bridge to transplantation.…”

Section: Targeting Cd33mentioning

confidence: 99%

How I treat refractory and early relapsed acute myeloid leukemia

Thol

Schlenk

Heuser

et al. 2015

Blood

241

180

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Between 10% and 40% of newly diagnosed patients with acute myeloid leukemia (AML) do not achieve complete remission with intensive induction therapy and are therefore categorized as primary refractory or resistant. Few of these patients can be cured with conventional salvage therapy. They need to be evaluated regarding eligibility for allogeneic hematopoietic stem cell transplantation (HSCT) as this is currently the treatment with the highest probability of cure. To reduce the leukemia burden prior to transplantation, salvage chemotherapy regimens need to be employed. Whenever possible, refractory/relapsed patients should be enrolled in clinical trials as we do not have highly effective and standardized treatments for this situation. Novel therapies include tyrosine kinase inhibitors, small-molecule inhibitors (eg, for Polo-like kinase 1 and aminopeptidase), inhibitors of mutated isocitrate dehydrogenase (IDH) 1 and IDH2, antibody-based therapies, and cell-based therapies. Although the majority of these therapies are still under evaluation, they are likely to enter clinical practice rapidly as a bridge to transplant and/or in older, unfit patients who are not candidates for allogeneic HSCT. In this review, we describe our approach to refractory/early relapsed AML, and we discuss treatment options for patients with regard to different clinical conditions and molecular profiles.

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Section: Targeting Cd33mentioning

confidence: 99%

How I treat refractory and early relapsed acute myeloid leukemia

Thol

Schlenk

Heuser

et al. 2015

Blood

241

180

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“…104,105 This observation suggests that repeated administration of lower, (near-)saturating doses of GO every 3 days may enhance intracellular accumulation of the calicheamicin-␥ 1 derivative beyond what can be achieved with 2-weekly administration. The Acute Leukemia French Association group has relatively recently reported the use of GO in fractionated, lower doses with promising efficacy and acceptable safety profile, 89,106 but comparative data with the traditional administration scheme are currently not available.…”

Section: Clinical Experience With Gomentioning

confidence: 99%

Acute myeloid leukemia stem cells and CD33-targeted immunotherapy

Walter

Appelbaum

Estey

et al. 2012

Blood

276

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Although the identification of cancer stem cells as therapeutic targets is now actively being pursued in many human malignancies, the leukemic stem cells in acute myeloid leukemia (AML) are a paradigm of such a strategy. Heterogeneity of these cells was suggested by clonal analyses indicating the existence of both leukemias resulting from transformed multipotent CD33 ؊ stem cells as well others arising from, or predominantly involving, committed CD33 ؉ myeloid precursors. The latter leukemias, which may be associated with an intrinsically better prognosis, offer a particularly attractive target for stem cell-directed therapies. Target IntroductionNormal human hematopoiesis is hierarchically organized, with tissue-specific, quiescent stem cells at the apex that have the ability to perpetuate themselves through self-renewal and generate more mature, transiently amplifying progeny through differentiation. 1 Similar to normal hematopoiesis, acute myeloid leukemia (AML) encompasses functionally diverse cells, and origination from a leukemic stem cell (LSC) was initially suspected many decades ago. 2 Observations in AML were indeed instrumental for the model of cancer stem cells as cells within a tumor that possess the capacity to self-renew and to cause the heterogeneous lineages of cancer cells that compose the tumor. 3 This model has important clinical implications as it predicts that the inability to eradicate cancer stem cells represents the cause of relapse and therapeutic failure; in turn, effective tumor therapy will require eradication of these cells. 2,3 Interest in AML has thus long focused on the nature of LSCs and their specific qualities that predict therapeutic response. The cellular origin of AMLs, however, remains unclear, with ongoing controversy as to whether they arise from transformed hematopoietic stem cells (HSCs) or emerge as a result of genetic events occurring in more mature progenitor cells. 2,[4][5][6][7] The nature of the cells giving rise to AML may have important biologic, therapeutic, and prognostic implications. Indeed, early recognition that some AMLs may predominantly or entirely involve committed myeloid progenitors led to efforts targeting underlying LSCs with antibodies recognizing the CD33 (SIGLEC-3) differentiation antigen, as exemplified by the development of the immunoconjugate, gemtuzumab ozogamicin (GO; Mylotarg). 8 In this review, we summarize studies on stem cells in AML indicating heterogeneous involvement of stem/progenitor populations, discuss emerging data on the effectiveness of CD33-directed therapy, and consider the mechanistic basis for success or failure against individual AML subsets. Heterogeneity of stem/progenitor cells in human AMLThere may be no single, unifying cellular origin across the entire spectrum of human AML. Rather, research conducted over the last several decades indicates that AML may arise in (or predominantly involve) either multipotent HSCs or more mature committed myeloid precursors downstream of HSCs. The first hint to this heterogeneity ca...

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“…GO at 3 mg/m 2 given on Days 1, 4 and 7) has been pioneered by the French ALFA group and revealed a favorable efficacy/toxicity profile. [22][23][24] For example, among 57 patients with AML in first relapse, GO monotherapy given in fractionated doses resulted in 15 (26%) CRs and 4 (7%) CRs with incomplete platelet recovery (CRps). Interestingly, relative to our study, the study by Taksin et al included adults of all ages requiring therapy for AML in first relapse with a CR duration of at least three and up to 18 months, 22 i.e.…”

Section: Discussionmentioning

confidence: 99%