Improved leukemia-free survival after postconsolidation immunotherapy with histamine dihydrochloride and interleukin-2 in acute myeloid leukemia: results of a randomized phase 3 trial

Brüne, Martin; Castaigné, Sylvie; Catalano, John; Gehlsen, Kurt R.; Ho, Anthony D.; Hofmann, Wolf‐Karsten; Hogge, Donna E.; Nilsson, Bo; Or, Reuven; Romero, Ana I.; Rowe, Jacob M.; Simonsson, Bengt; Spearing, Ruth; Stadtmauer, Edward A.; Szer, Jeffrey; Wallhult, Elisabeth; Hellstrand, Kristoffer

doi:10.1182/blood-2005-10-4073

Cited by 230 publications

(184 citation statements)

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“…Such a strategy of post remission immune therapy has engendered renewed interest in light of the recently presented results of a large randomized trial suggesting that rIL-2 immunotherapy combined with histamine dihydrochloride improved 3-year leukemia-free survival compared to untreated controls (40% vs. 26%, P 5 0.008) for 320 AML patients in first or second remission [48]. Moreover, recently presented results of CALGB trial 19808 in which patients under age 60 with untreated AML were randomized to receive IL-2 or observation after intensive post-remission therapy suggested a trend for a threeyear disease-free (56% 'v' 45%, P 5 0.11) and overall (68% 'v' 61%, P 5 0.09) survival benefit for those randomized to immunotherapy [49].…”

Section: Discussionmentioning

confidence: 99%

“…This 'dropout effect' limits the usefulness of any immunotherapy given relatively late in the post-remission setting. Large trials in adults with AML have required the enrollment of many patients at diagnosis to have an appreciable number receive post-intensification therapy [46][47][48][49]. Taken together, this experience suggests that such an immunologically-based approach might be optimally tested at the time of initial attainment of remission or after only one or two post-remission courses.…”

Section: Discussionmentioning

confidence: 99%

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Low dose interleukin‐2 following intensification therapy with high dose cytarabine for acute myelogenous leukemia in first complete remission

et al. 2008

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The most important problem in the therapy of patients with acute myeloid leukemia (AML) is relapse after intensive therapy. We sought to determine if interleukin-2 (low-dose with intermittent boluses) administration could be feasibly administered after standard therapy to potentiate anti-tumor immunity in a fashion analogous to the post-allogeneic stem cell transplant ''graft-vs-leukemic'' effect. Adults with de novo AML received daunorubicin and cytosine arabinoside induction therapy. Patients achieving complete remission received high dose ara-C (HIDAC) for three courses followed by low dose rIL-2 (Amgen), administered by continuous infusion (450,000 U/m 2 /day) for 10 weeks with intermittent boluses (500,000/U/m 2 over 2 hr) given in weekly intervals starting on Week 4. Of the 32 enrolled patients, 27 achieved CR; 8/11 who received rIL-2 completed therapy. 6/11 are long term survivors (median follow-up, 139 months). rIL-2 was well tolerated and associated with a 5-fold increase in circulating NK-lymphocytes and a 3-fold increase in circulating T-cells. Mononuclear cells from patients receiving rIL-2 exhibited enhanced cytolytic activity in vitro against cryopreserved autologous leukemia cells. This study supports further investigation of immunotherapy in the post-intensive chemotherapy setting in the management of patients with AML. Am. J. Hematol. 83:771-777, 2008. V

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Low dose interleukin‐2 following intensification therapy with high dose cytarabine for acute myelogenous leukemia in first complete remission

et al. 2008

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“…The concept of rendering a smaller dose of interleukin-2 effective by combining it with histamine dichloride has been approved, as Ceplene (Epicept Inc., NY, USA)---this has been reported to significantly improve disease-free survival when applied as maintenance after consolidation, but overall survival was not the primary end point. 14 This requires a corroborative trial.…”

Section: Post-induction Treatmentmentioning

confidence: 99%

Optimal induction and post-remission therapy for acute myeloid leukemia

Burnett

2012

Leukemia Suppl

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The approach to treatment of acute myeloid leukemia is substantially influenced by the age of the patient. Younger patients who are arbitrarily defined as those being o60 years, although comprising the minority of all patients with the disease, will always receive an intensive approach, whereas in older patients, an initial decision as to whether an intensive approach is appropriate or not has to be made. Standard chemotherapy for many years has been '3 þ 7', followed by consolidation with high-dose Ara-C at a daily dose level of 3 g/m 2 . It remains unclear as to what number of total treatment courses is optimal. Alternatives to this standard of care will be considered.Leukemia Supplements (2012) 1, S14--S15; doi:10.1038/leusup.2012.10Keywords: acute myeloid leukemia; induction; dose; immunoconjugate; consolidation; chemotherapy INDUCTION Daunorubicin doseThe question of whether daunorubicin (DA) should remain as a standard has been asked in randomized comparisons with idarubicin or mitoxantrone in several randomized trials without convincing evidence for substantial differences in survival being seen. There has always been an issue regarding dose equivalence of DA at doses of 45 mg/m 2 and 50 mg/m 2 . Recent studies have raised the issue of dose intensification of DA either by dose escalation to a 90-mg dose or daily dosing for 5 days. The E1900 trial, 1 which has been undertaken by the Eastern Cooperative Oncology Group in 657 younger patients, compared a DA dose of 90 mg/m 2 versus 45 mg/m 2 in a 3 þ 7 schedule for the first induction course. For those not in remission with course 1, an additional DA-containing course was recommended (with a 45 mg/m 2 dose). The higher doses achieved a higher overall remission rate (70% vs 56%, P ¼ o0.001) with more in complete remission (CR) after course 1 (83% vs 72%), and a better overall survival (23.7 months vs 15.7 months; P ¼ 0.003). A similar approach was taken by the HOVON-SAKK group 2 in older patients. In this study, the overall remission rate was similarly improved (64% vs 54%; P ¼ 0.002), but overall survival did not improve, except in patients in the 60-to 65-year subgroup (38% vs 23%).These data receive further support from a Korean trial 3 in 383 younger patients, in which the daunorubicin was intensified by giving DA (90 mg/m 2 vs 45 mg/m 2 ) by continuous infusion over 3 days which was also superior in the higher dose arm, CR 82% versus 72% (P ¼ 0.014)and overall survival 47% versus 35% (P ¼ 0.03).There has been discussion for a long time about dose equivalence between DA and alternatives such as idarubicin. A study from the French ALFA group 4 compared the effect of DA at a dose of 80 mg/m 2 on days 1 to 3 with idarubicin at a dose of 12 mg/m 2 for either 3 or 4 consecutive days in patients aged 50--70 years. In 468 randomized patients, idarubicin treatment for 3 or 4 days produced more remissions than DA (83% vs 78% vs 70%; P ¼ 0.04); however, this did not result in any difference in survival. A recent Japanese trial 5 in 1057 younger patients tested inte...

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“…Likewise, immunologic approaches might be used as post-remission therapy outside the RIC-HCT setting. For example, Brune et al 68 randomized 320 patients (80% in first, 20% in subsequent, CR) to receive either an IL-2 --histamine combination or no further treatment after completion of maintenance therapy and typically 4 --5 months after entering CR. IL-2 þ histamine prolonged survival and RFS by a median of 4 --6 months in CR1 patients.…”

Section: Which Investigational Induction Therapy?mentioning

confidence: 99%

How to manage high-risk acute myeloid leukemia

Estey

2011

Leukemia

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There are three general options for management of acute myeloid leukemia (AML): standard therapy, investigational therapy or no treatment other than supportive care. Given AML's natural history and the uncertain results inherent in investigational therapy, most patients intuitively prefer standard therapy, by which is usually meant 3 þ 7 or low-dose cytarabine. However, this preference assumes results with standard therapy are 'satisfactory'. Results with standard therapy of AML are, however, so variable that it is difficult to speak of a single result. Therefore, I review prognostic factors with standard therapy to permit physicians to better inform patients of the likely outcome with such therapy, realizing that the same data might prompt one patient/physician to prefer standard therapy and another investigational therapy under the assumption that although plausibly worse than standard the latter cannot be that much worse. Because even in patients aged 475 years, the principal cause of therapeutic failure is resistance to therapy not treatment-related mortality, I emphasize factors associated with resistance, principally a 'monosomal karyotype' and various molecular markers and extend the European Leukemia Net prognostic system. I also stress the value of waiting for cytogenetic and molecular results before beginning induction therapy and review various investigational options.

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Improved leukemia-free survival after postconsolidation immunotherapy with histamine dihydrochloride and interleukin-2 in acute myeloid leukemia: results of a randomized phase 3 trial

Cited by 230 publications

References 54 publications

Low dose interleukin‐2 following intensification therapy with high dose cytarabine for acute myelogenous leukemia in first complete remission

Low dose interleukin‐2 following intensification therapy with high dose cytarabine for acute myelogenous leukemia in first complete remission

Optimal induction and post-remission therapy for acute myeloid leukemia

How to manage high-risk acute myeloid leukemia

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