Deviating from safety guidelines during deferiprone therapy in clinical practice may not be associated with higher risk of agranulocytosis

Elalfy, Mohsen Saleh; Wali, Yasser; Qari, Mohamad; Damanhouri, Ghazi; Al‐Tonbary, Youssef; Yazman, Dilek; Hawsawi, Zakaria Al; Karakaş, Zeynep; Kılınç, Yurdanur; Yeşilipek, M. Akif; Badr, Mohamed; Elsafy, Usama R.; Rahman, Yousryeia Abdel; Shebl, Shebl; Stilman, Anne; Temin, Noemi Toiber; Tricta, Fernando

doi:10.1002/pbc.24920

Cited by 16 publications

(12 citation statements)

References 6 publications

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“…While weekly monitoring may seem prudent, this analysis and another study 10 do not support its value in intervening in the occurrence of agranulocytosis or the severity of its consequences. The data evaluated here suggest that most cases of neutropenia do not progress to agranulocytosis, and that the development of agranulocytosis is frequently precipitous and not the outcome of a slow decline in neutrophil count.…”

Section: Discussioncontrasting

confidence: 60%

“…No case of neutropenia progressed to agranulocytosis. Data from the CT also suggest that deferiprone use was not associated with progression of pre‐existing mild‐to‐moderate neutropenia 10, 11. This is of particular relevance in geographic areas where ethnic neutropenia co‐exists with a high prevalence of patients requiring iron chelation therapy because of hemoglobinopathies 27, 28.…”

Section: Discussionmentioning

confidence: 91%

“…To determine if neutropenia would proceed to agranulocytosis with continued deferiprone exposure, treatment was maintained in seven consecutive patients who experienced mild neutropenia; these findings have been reported separately 10. Briefly, these patients' ANC was monitored daily until resolution or a drop to <1.0 × 10 9 /L.…”

Section: Resultsmentioning

confidence: 99%

“…Accordingly, 294 patients with transfusion‐dependent anemias were enrolled into a noninterventional surveillance program designed to assess compliance in clinical practice with the recommended weekly ANC monitoring and interruption of deferiprone use at onset of neutropenia 10. If therapy was continued, the program assessed its impact on the occurrence of agranulocytosis.…”

Section: Discussionmentioning

confidence: 99%

“…Thalassemia patients frequently experience transient episodes of mild or moderate neutropenia, independent of deferiprone 5, 7, 8, 9, and neutropenia during deferiprone therapy often does not progress to agranulocytosis, even with continued treatment 5, 10, 11. Indiscriminately stopping or interrupting deferiprone at onset of neutropenia may appear to be a prudent safety measure, but may fail to balance benefits and risks for individuals.…”

Section: Introductionmentioning

confidence: 99%

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Deferiprone‐induced agranulocytosis: 20 years of clinical observations

Tricta¹,

Uetrecht

Galanello

et al. 2016

American J Hematol

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Use of the iron chelator deferiprone for treatment of iron overload in thalassemia patients is associated with concerns over agranulocytosis, which requires weekly absolute neutrophil counts (ANC). Here, we analyze all episodes of agranulocytosis (n = 161) and neutropenia (n = 250) during deferiprone use in clinical trials (CT) and postmarketing surveillance programs (PMSP). Rates of agranulocytosis and neutropenia in CT were 1.5% and 5.5%, respectively. Of the agranulocytosis cases, 61% occurred during the first 6 months of therapy and 78% during the first year. These events appeared to be independent of dose, and occurred three times more often in females than males. Their duration was not significantly shortened by use of G‐CSF. No patient with baseline neutropenia (n = 12) developed agranulocytosis during treatment, which raises questions about the validity of prior neutropenia as a contraindication to use. Only 1/7 novel neutropenia cases in CT progressed to agranulocytosis with continued treatment, indicating that neutropenia does not necessarily lead to agranulocytosis. The agranulocytosis fatality rate was 0% in CT and 15/143 (11%) in PMSP. Rechallenge with deferiprone produced agranulocytosis in 75% of patients in whom the event had already occurred, and in 10% with previous neutropenia. Weekly ANC monitoring allows early detection and interruption of therapy, but does not prevent agranulocytosis from occurring. Its relevance appears to decrease after the first year of therapy, when agranulocytosis occurs less often. Based upon analysis of data collected over the past 20 years, it appears that patient education may be the key to minimizing agranulocytosis‐associated risks during deferiprone therapy. Am. J. Hematol. 91:1026–1031, 2016. © 2016 The Authors. American Journal of Hematology Published by Wiley Periodicals, Inc.

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Section: Discussioncontrasting

confidence: 60%

Section: Discussionmentioning

confidence: 91%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Deferiprone‐induced agranulocytosis: 20 years of clinical observations

Tricta¹,

Uetrecht

Galanello

et al. 2016

American J Hematol

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Safety and efficacy of early start of iron chelation therapy with deferiprone in young children newly diagnosed with transfusion‐dependent thalassemia: A randomized controlled trial

Elalfy

Adly

Awad³

et al. 2017

American J Hematol

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Iron overload is inevitable in patients who are transfusion dependent. In young children with transfusion-dependent thalassemia (TDT), current practice is to delay the start of iron chelation therapy due to concerns over toxicities, which have been observed when deferoxamine was started too early. However, doing so may increase the risk of iron accumulation that will be manifested as toxicities later in life. This study investigated whether deferiprone, a chelator with a lower affinity for iron than deferoxamine, could postpone transfusional iron overload while maintaining a good safety profile. Recently diagnosed TDT infants (N = 64 their age ranged from 10 to 18 (median 12) months, 54.7% males; receiving ≤6 transfusions; serum ferittin (SF) >400 to < 1000 ng/mL were randomized to "early start deferiprone" (.ES-DFP) at a low dose (50 mg/kg/day) or to "delay chelation" (DC), and remained in the study until their serum ferritin (SF) level reached ≥1000 μg/L. 61 patients continued the study Levels of transferrin saturation (TSAT) and labile plasma iron (LPI) were measured as well. By approximately 6 months postrandomization, 100% of the subjects in DC group had achieved SF > 1000 µg/L and TSAT > 70% compared with none in the ES-DFP group. LPI level > 0.6 µM was observed in 97% vs. 40% of the DS and ES groups, respectively, (P < 0.001). The time to reach SF > 1000 µg/L was delayed by 6 months in the ES-DFP group (P < 0.001) without escalating DFP dose. No unexpected, serious, or severe adverse events were seen in the ES-DFP group.

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Efficacy and safety of early‐start deferiprone in infants and young children with transfusion‐dependent beta thalassemia: Evidence for iron shuttling to transferrin in a randomized, double‐blind, placebo‐controlled, clinical trial (START)

et al. 2023

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Children with transfusion‐dependent thalassemia (TDT) require regular blood transfusions that, without iron‐chelation therapy, lead to iron‐overload toxicities. Current practice delays chelation therapy (late‐start) until reaching iron overload (serum ferritin ≥1000 μg/L) to minimize risks of iron‐depletion. Deferiprone's distinct pharmacological properties, including iron‐shuttling to transferrin, may reduce risks of iron depletion during mild‐to‐moderate iron loads and iron overload/toxicity in children with TDT. The early‐start deferiprone (START) study evaluated the efficacy/safety of early‐start deferiprone in infants/young children with TDT. Sixty‐four infants/children recently diagnosed with beta‐thalassemia and serum ferritin (SF) between 200 and 600 μg/L were randomly assigned 1:1 to receive deferiprone or placebo for 12 months or until reaching SF‐threshold (≥1000 μg/L at two consecutive visits). Deferiprone was initiated at 25 mg/kg/day and increased to 50 mg/kg/day; some recipients' dosages increased to 75 mg/kg/day based on iron levels. The primary endpoint was the proportion of patients ≥SF‐threshold by month 12. Monthly transferrin saturation (TSAT) assessment evaluated iron‐shuttling. At baseline, there was no significant difference in mean age (deferiprone: 3.03 years, placebo: 2.63 years), SF (deferiprone: 513.8 μg/L, placebo: 451.7 μg/L), or TSAT (deferiprone: 47.98%, placebo: 43.43%) between groups. At month 12, there was no significant difference in growth or adverse event (AE) rates between groups. No deferiprone‐treated patients were iron‐depleted. At month 12, 66% of patients receiving deferiprone remained below SF threshold versus 39% of placebo (p = .045). Deferiprone‐treated patients showed higher TSAT levels and reached ≥60% TSAT threshold faster. Early‐start deferiprone was well‐tolerated, not associated with iron depletion, and efficacious in reducing iron overload in infants/children with TDT. TSAT results provide the first clinical evidence of deferiprone shuttling iron to transferrin.

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Deviating from safety guidelines during deferiprone therapy in clinical practice may not be associated with higher risk of agranulocytosis

Abstract: These data indicate that less frequent ANC monitoring and continuation of deferiprone therapy during neutropenia are not associated with prolonged neutropenia or with progression to agranulocytosis.

Cited by 16 publications

References 6 publications

Deferiprone‐induced agranulocytosis: 20 years of clinical observations

Deferiprone‐induced agranulocytosis: 20 years of clinical observations

Safety and efficacy of early start of iron chelation therapy with deferiprone in young children newly diagnosed with transfusion‐dependent thalassemia: A randomized controlled trial

Efficacy and safety of early‐start deferiprone in infants and young children with transfusion‐dependent beta thalassemia: Evidence for iron shuttling to transferrin in a randomized, double‐blind, placebo‐controlled, clinical trial (START)

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