Escalating intravenous methotrexate improves event-free survival in children with standard-risk acute lymphoblastic leukemia: a report from the Children's Oncology Group

Matloub, Yousif; Bostrom, Bruce; Hunger, Stephen P.; Stork, Linda C.; Angiolillo, Anne; Sather, Harland N.; La, Marzano; Gastier‐Foster, Julie M.; Heerema, Nyla A.; Sailer, Scott L.; Buckley, Patrick J.; Thomson, Blythe; Cole, Catherine; Nachman, James B.; Reaman, Gregory; Winick, Naomi J.; Carroll, William L.; Devidas, Meenakshi; Gaynon, Paul S.

doi:10.1182/blood-2010-12-322909

Cited by 127 publications

(127 citation statements)

References 34 publications

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“…Two of the most important glucocorticoids used for treating childhood ALL are PRED and DEX. Although DEX consistently shows higher antileukemic activity both in vitro and in vivo 4,[15][16][17] , PRED is used in most chemotherapy protocols due to its better toxicity profile. DEX administration is associated with higher risk of myopathy, adverse neuro-psychiatric events, osteonecrosis, sepsis, fungal infections, diabetes and pancreatitis 7 .…”

Section: Discussionmentioning

confidence: 99%

Combination of prednisolone and low dosed dexamethasone exhibits greater in vitro antileukemic activity than equiactive dose of prednisolone and overcomes prednisolone drug resistance in acute childhood lymphoblastic leukemia

Spenerova¹,

Džubák²,

Srovnal³

et al. 2014

Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub

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Introduction. Glucocorticoids, particularly prednisone/ prednisolone and dexamethasone, play a prominent role in the treatment of pediatric patients with acute lymphoblastic leukemia due to their ability to induce apoptosis in susceptible cells. Current therapeutic protocols use prednisone for both the prophase and the induction phase of the therapy because the greater antileukemic activity of dexamethasone is compromised by its high frequency of serious adverse reactions. Aim. To compare, for the first time, the in vitro antileukemic activity of prednisolone alone to that of a combination of prednisolone and dexamethasone using dexamethasone at a very low and presumably safe dosage (1/50 w/w). Methods. Lymphoblasts were isolated from bone marrow and/or blood samples from children with newly diagnosed acute lymphoblastic leukemia. The cytotoxic activity of prednisolone, dexamethasone and the prednisolone/dexamethasone combination against isolated leukemia cells was analyzed using the MTT cytotoxicity assay. Results. We observed differences in the in vitro antileukemic activity of prednisolone and dexamethasone in 21% of the tested patients. 3% of the children were prednisolone sensitive but dexamethasone resistant, while 18% were prednisolone resistant and dexamethasone sensitive. 32% were sensitive to both glucocorticoids and 18% were resistant to both. Cells from patients with good in vivo responses to prednisone monotherapy were more responsive to prednisolone in vitro than were cells from patients with poor prednisone responses (P<0.07). Importantly, we demonstrated that the use of even a minimal dose (1/50 w/w) of dexamethasone with prednisolone dramatically increases the in vitro anti-leukemic activity of prednisolone (P<0.0006). Conclusion. The high inter-individual variability of acute lymphoblastic leukemia responses to glucocorticoids suggest that either patients should be selected for prednisone or dexamethasone treatment on the basis of predictive biomarkers or that prednisone should be used directly in combination with a very low and safe dose of dexamethasone to potentiate its antileukemic activity. The latter option is likely to be cheaper and more efficient, and therefore warrants further clinical investigation to assess its efficacy and safety in treating childhood acute lymphoblastic leukemia.

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Section: Discussionmentioning

confidence: 99%

Combination of prednisolone and low dosed dexamethasone exhibits greater in vitro antileukemic activity than equiactive dose of prednisolone and overcomes prednisolone drug resistance in acute childhood lymphoblastic leukemia

Spenerova¹,

Džubák²,

Srovnal³

et al. 2014

Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub

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“…Children with ALL who present with CNS disease (CNS3) at diagnosis are at a higher risk of treatment failure (both within the CNS and systemic involvement) than are the children who are classified as CNS1 or CNS2 [19]. Some studies have reported increased risk of CNS relapse and/or inferior EFS in CNS2 patients, compared with CNS1 children, [19,17] while others have not such involvement [18,15,20].…”

Section: Cns3 (Cns Disease)mentioning

confidence: 99%

“…Some studies have reported increased risk of CNS relapse and/or inferior EFS in CNS2 patients, compared with CNS1 children, [19,17] while others have not such involvement [18,15,20].…”

Section: Cns3 (Cns Disease)mentioning

confidence: 99%

“…A traumatic lumbar puncture (≥10 erythrocytes/µL) that includes blasts at diagnosis has also been associated with increased risk of CNS relapse and overall poorer outcome in some studies, [14,18,21] but not in others patients [19,20]. Patients with CNS2, CNS3, or traumatic lumbar puncture have a higher frequency of unfavorable prognostic characteristics than do those with CNS1,including significantly higher WBC counts at diagnosis, the patients with older age (more than 10 years) at diagnosis have an increased frequency of the T-cell ALL phenotype and MLL gene rearrangements [18,20,21].…”

Section: Cns3 (Cns Disease)mentioning

confidence: 99%

“…Some clinical trial groups have approached CNS2 and traumatic lumbar puncture by utilizing more intensive therapy, primarily additional doses of intrathecal therapy during induction of remission [18,20,22]. Other groups have not changed therapy based on CNS2 status [16,19]. A child with a traumatic lumbar puncture (with blasts) should be treated as CNS3, the COG uses an algorithm relating the WBC count and red blood cell counts in the spinal fluid and the peripheral blood film [23].…”

Section: Cns3 (Cns Disease)mentioning

confidence: 99%

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Prognostic Significance of Cerebrospinal Fluid Lymphoblasts at Initial Presentation with Acute Lymphoblastic Leukemia Attending at Bangabandhu Sheikh Mujib Medical University, Bangladesh

Hafiz¹

2017

JPNC

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Background: Leukemia is characterized by persistent and enormous proliferation of immature white blood cell. Without CNS-directed therapy relapses originating from CNS are up to 75%. The presence of overt CNS disease at initial presentation (cranial nerve palsies) negatively affects the EFS of children with ALL. Early intensive intrathecal and systemic therapy is now more successful in treating and preventing CNS leukemia and reducing the cumulative risk for all relapses with CNS involvement of 4.4%, even in patients whose leukemic blast cells is iatrogenically introduced into the cerebrospinal fluid by traumatic lumbar puncture.

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Childhood lymphoblastic leukemia commentary

Saha

2013

Evidence‐Based Pediatric Oncology

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Escalating intravenous methotrexate improves event-free survival in children with standard-risk acute lymphoblastic leukemia: a report from the Children's Oncology Group

Abstract: Children's Cancer Group-1991 selected 2 components from the Children's Cancer Group studies shown to be effective in high-risk acute lymphoblastic leukemia and examined them in children with National Cancer Institute standard-risk acute B-precursor lymphoblastic leukemia. These were (

Cited by 127 publications

References 34 publications

Combination of prednisolone and low dosed dexamethasone exhibits greater in vitro antileukemic activity than equiactive dose of prednisolone and overcomes prednisolone drug resistance in acute childhood lymphoblastic leukemia

Combination of prednisolone and low dosed dexamethasone exhibits greater in vitro antileukemic activity than equiactive dose of prednisolone and overcomes prednisolone drug resistance in acute childhood lymphoblastic leukemia

Prognostic Significance of Cerebrospinal Fluid Lymphoblasts at Initial Presentation with Acute Lymphoblastic Leukemia Attending at Bangabandhu Sheikh Mujib Medical University, Bangladesh

Childhood lymphoblastic leukemia commentary

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