Incidence and prognostic value of central nervous system involvement in infants with B‐cell precursor acute lymphoblastic leukemia treated according to the MLL‐Baby protocol

Popov, Alexander; Tsaur, Grigory; Permikin, Zhan; Fominikh, Veronika; Verzhbitskaya, Tatiana; Riger, Tatyana; Demina, Anna; Shorikov, Egor; Kustanovich, Anatoly; Movchan, Liudmila; Streneva, Olga; Khlebnikova, Olga; Makarova, Olga; Arakaev, Oleg; Solodovnikov, Alexander; Бойченко, Э. Г.; Кондратчик, К. Л.; Ponomareva, Natalia; Lapotentova, Elena; Алейникова, О. В.; Miakova, Natalia; Novichkova, Galina; Karachunskiy, Alexander; Fechina, Larisa

doi:10.1002/pbc.29860

Cited by 3 publications

(2 citation statements)

References 55 publications

(99 reference statements)

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“…In the group of 50 infants with CNS involvement, as many as 28 had a recurrence (EFS = 0.27, cumulative incidence of relapse (CIR) = 0.65), while among 89 CNS patients—negative—21 experienced a relapse (EFS = 0.58, CIR = 0.26, p < 0.001) for both. In total, 11 of the 49 patients with registered relapses had CNS infiltration (five isolated CNS relapses and six combined CNS and BM relapses) [ 76 ]. CNS involvement is more frequently observed in infants than in older children with KMT2A -r and is associated with a worse prognosis.…”

Section: Clinical Outcome and Interfant Protocolmentioning

confidence: 99%

Updates in KMT2A Gene Rearrangement in Pediatric Acute Lymphoblastic Leukemia

et al. 2023

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The KMT2A (formerly MLL) encodes the histone lysine-specific N-methyltransferase 2A and is mapped on chromosome 11q23. KMT2A is a frequent target for recurrent translocations in acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), or mixed lineage (biphenotypic) leukemia (MLL). Over 90 KMT2A fusion partners have been identified until now, including the most recurring ones—AFF1, MLLT1, and MLLT3—which encode proteins regulating epigenetic mechanisms. The presence of distinct KMT2A rearrangements is an independent dismal prognostic factor, while very few KMT2A rearrangements display either a good or intermediate outcome. KMT2A-rearranged (KMT2A-r) ALL affects more than 70% of new ALL diagnoses in infants (<1 year of age), 5–6% of pediatric cases, and 15% of adult cases. KMT2A-rearranged (KMT2A-r) ALL is characterized by hyperleukocytosis, a relatively high incidence of central nervous system (CNS) involvement, an aggressive course with early relapse, and early relapses resulting in poor prognosis. The exact pathways of fusions and the effects on the final phenotypic activity of the disease are still subjects of much research. Future trials could consider the inclusion of targeted immunotherapeutic agents and prioritize the identification of prognostic factors, allowing for the less intensive treatment of some infants with KMT2A ALL. The aim of this review is to summarize our knowledge and present current insight into the mechanisms of KMT2A-r ALL, portray their characteristics, discuss the clinical outcome along with risk stratification, and present novel therapeutic strategies.

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Section: Clinical Outcome and Interfant Protocolmentioning

confidence: 99%

Updates in KMT2A Gene Rearrangement in Pediatric Acute Lymphoblastic Leukemia

et al. 2023

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“…[3][4][5][6] In contrast, infants with germline KMT2A (KMT2A-g), who account for nearly a quarter of all BCP-ALL patients in this age group, have a significantly better prognosis, 4,7 but still worse compared to patients with pediatric ALL (older than 1 year). Due to the rarity of KMT2A-g-ALL in infants, it is difficult to assess the value of prognostic factors known to be significant in infants with KMT2A-r 3,8 : the initial WBC count, age at diagnosis, central nervous system (CNS) involvement, 5,9 leukemia cell immunophenotype, 10,11 and parameters of therapy response, 12,13 including elimination of minimal residual disease (MRD). [14][15][16] In addition, recent studies have demonstrated the potential importance of newly identified genetic traits, including NUTM1 and PAX5 fusion genes (FG).…”

Section: Introductionmentioning

confidence: 99%

Genetic characteristics and treatment outcome in infants with KMT2A germline B‐cell precursor acute lymphoblastic leukemia: Results of MLL‐Baby protocol

Popov¹,

Tsaur

Permikin

et al. 2023

Pediatric Blood & Cancer

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The aim of this study was to present the diagnostic and outcome characteristics of infants with germline status of KMT2A gene (KMT2A‐g) B‐cell precursor acute lymphoblastic leukemia (BCP‐ALL) treated consistently according to the MLL‐Baby protocol, a moderate‐intensity protocol. Of the 139 patients enrolled in the MLL‐Baby study, 100 (71.9%) carried different types of rearranged KMT2A (KMT2A‐r), while the remaining 39 infants (28.1%) had KMT2A‐g. KMT2A‐g patients were generally older (77% older than 6 months), less likely to have a very high white blood cell count (greater than 100 × 109/L), less likely to be central nervous system (CNS)‐positive, and more likely to be CD10‐positive. The 6‐year event‐free survival and overall survival rates for all 39 patients were 0.74 (standard error [SE] 0.07) and 0.80 (SE 0.07), respectively. Relapse was the most common adverse event (n = 5), with a cumulative incidence of relapse (CIR) of 0.13 (SE 0.06), while the incidence of a second malignancy (n = 1) and death in remission (n = 3) was 0.03 (SE 0.04) and 0.08 (SE 0.04), respectively. None of the initial parameters, including genetics and the presence of recently described fusions of NUTM1 and PAX5 genes, was able to distinguish patients with different outcomes. Only rapidity of response, measured as minimal residual disease (MRD) by flow cytometry, showed a statistically significant impact. Moderate‐intensity therapy, as used in the MLL‐Baby protocol in infants with KMT2A‐g BCP‐ALL, yields results comparable to other infant studies. Patients with a slow multicolor flow cytometry (MFC)‐MRD response should be subjected to advanced therapies, such as targeted or immunotherapies.

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