Background
IKZF1 gene deletion is an indicator of poor prognosis in childhood B‐cell precursor acute lymphoblastic leukemia (BCP‐ALL). The AEIOP/BFM group proposed that the prognostic strength of ...IKZF1 deletion could be remarkably improved by taking into account additional genetic deletions and reported that among patients with an IKZF1 deletion those with deletions in CDKN2A/2B, PAX5, or PAR1 in the absence of ERG deletion, grouped as IKZF1plus, had the worst outcome.
Procedure
Between 1998 and 2008, 1636 patients under 18 years of age with previously untreated BCP‐ALL were registered in the EORTC 58951 trial. Those with multiplex ligation‐dependent probe amplification data were included in this analysis. Unadjusted and adjusted Cox model was used to investigate the additional prognostic value of IKZF1plus.
Results
Among 1200 patients included in the analysis, 1039 (87%) had no IKZF1 deletion (IKZF1WT), 87 (7%) had an IKZF1 deletion but not IKZF1plus (IKZF1del) and 74 (6%) had IKZF1plus. In the unadjusted analysis, both patients with IKZF1del (hazard ratio HR = 2.10, 95% confidence interval CI: 1.34–3.31) and IKZF1plus (HR = 3.07, 95% CI: 2.01–4.67) had a shorter event‐free survival compared with IKZF1WT. However, although the IKZF1plus status was associated with patients’ characteristics indicating poor prognosis, the difference between IKZF1plus and IKZF1del was not statistically significant (HR = 1.46, 95% CI: 0.83–2.57, p = .19). The results of the adjusted analysis were similar to the unadjusted analysis.
Conclusions
In patients with BCP‐ALL from the EORTC 58951 trial, the improvement of the prognostic importance of IKZF1 by considering IKZF1plus was not statistically significant.
Mixed phenotype acute leukemia (MPAL) accounts for 2-5% of leukemia in children. MPAL are at higher risk of induction failure. Lineage switch (B to M or vice versa) or persistence of only the ...lymphoid or myeloid clone is frequently observed in biphenotypic/bilineal cases, highlighting their lineage plasticity. The prognosis of MPAL remains bleak, with an event-free survival (EFS) of less than 50% in children. A lymphoid-type therapeutic approach appears to be more effective but failures to achieve complete remission (CR) remain significant. KMT2A fusions account for 75-80% of leukemia in infants under one year of age and remains a major pejorative prognostic factor in the Interfant-06 protocol with a 6 years EFS of only 36%. The search for other therapeutic approaches, in particular immunotherapies that are able to eradicate all MPAL clones, is a major issue. We describe here the feasibility and tolerance of the combination of two targeted immunotherapies, blinatumomab and Gemtuzumab Ozogamicin, in a 4-year-old infant with a primary refractory KTM2A-rearranged MPAL. Our main concern was to determine how to associate these two immunotherapies and we describe how we decided to do it with the parents' agreement. The good MRD response on the two clones made it possible to continue the curative intent with a hematopoietic stem cell transplant at 9 months of age. Despite a relapse at M11 post-transplant because of the recurrence of a pro-B clone retaining the initial lymphoid phenotype, the child is now 36 months old, in persistent negative MRD CR2 for 12 months after a salvage chemotherapy and an autologous CAR T cells infusion, with no known sequelae to date. This case study can thus lead to the idea of a sequential combination of two immunotherapies targeting two distinct leukemic subclones (or even a single biphenotypic clone), as a potential one to be tested prospectively in children MPAL and even possibly all KMT2A-rearranged infant ALL.
The
KMT2A
(
MLL
) gene rearrangements (
KMT2A
-r) are associated with a diverse spectrum of acute leukemias. Although most
KMT2A
-r are restricted to nine partner genes, we have recently revealed ...that
KMT2A
-
USP2
fusions are often missed during FISH screening of these genetic alterations. Therefore, complementary methods are important for appropriate detection of any
KMT2A
-r. Here we use a machine learning model to unravel the most appropriate markers for prediction of
KMT2A
-r in various types of acute leukemia. A Random Forest and LightGBM classifier was trained to predict
KMT2A
-r in patients with acute leukemia. Our results revealed a set of 20 genes capable of accurately estimating
KMT2A
-r. The
SKIDA1
(AUC: 0.839; CI: 0.799–0.879) and
LAMP5
(AUC: 0.746; CI: 0.685–0.806) overexpression were the better markers associated with
KMT2A
-r compared to
CSPG4
(also named
NG2
; AUC: 0.722; CI: 0.659–0.784), regardless of the type of acute leukemia. Of importance, high expression levels of
LAMP5
estimated the occurrence of all
KMT2A-USP2
fusions. Also, we performed drug sensitivity analysis using IC50 data from 345 drugs available in the GDSC database to identify which ones could be used to treat
KMT2A
-r leukemia. We observed that
KMT2A
-r cell lines were more sensitive to 5-Fluorouracil (5FU), Gemcitabine (both antimetabolite chemotherapy drugs), WHI-P97 (JAK-3 inhibitor), Foretinib (MET/VEGFR inhibitor), SNX-2112 (Hsp90 inhibitor), AZD6482 (PI3Kβ inhibitor), KU-60019 (ATM kinase inhibitor), and Pevonedistat (NEDD8-activating enzyme (NAE) inhibitor). Moreover, IC50 data from analyses of
ex-vivo
drug sensitivity to small-molecule inhibitors reveals that Foretinib is a promising drug option for AML patients carrying
FLT3
activating mutations. Thus, we provide novel and accurate options for the diagnostic screening and therapy of
KMT2A
-r leukemia, regardless of leukemia subtype.
B-cell acute lymphoblastic leukemia associated with t(5;14)(q31;q32);
is an exceptional cause of eosinophilia. The
enhancer on 14q32 is juxtaposed to the
gene on 5q31, leading to interleukin-3 ...overproduction and release of mature eosinophils in the blood. Clinical, biological and outcome data are extremely scarce in the literature. Except for eosinophilia, no relevant common feature has been highlighted in these patients. However, it has been classified as a distinct entity in the World Health Organization classification.
Eight patients with t(5;14)(q31;q32) treated by French or Austrian protocols were retrospectively enrolled. Array comparative genomic hybridization, multiplex ligation-dependent probe amplification or genomic PCR search for
deletion were performed in 7. Sixteen patients found through an exhaustive search in the literature were also analyzed. For those 24 patients, median age at diagnosis is 14.3 years with a male predominance (male to female ratio = 5). Eosinophilia-related symptoms are common (neurologic in 26%, thromboembolic in 26% or pulmonary in 50%). Median white blood cells count is high (72 × 10
/L) and linked to eosinophilia (median: 32 × 10
/L). Peripheral blasts are present at a low level or absent (median: 0 × 10
/L; range: 0-37 × 10
/L). Bone marrow morphology is marked by a low blast infiltration (median: 42%). We found an
deletion in 5 out of 7 analyzable patients Outcome data are available for 14 patients (median follow-up: 28 months): 8 died and 6 are alive in complete remission. Some of these features are concordant with those seen in patients with other
-rearranged B-cell acute lymphoblastic leukemias: young age at onset, male sex, low blast count, high incidence of
deletion and intermediate prognosis.
Based on shared epidemiological and biological features, B-cell acute lymphoblastic leukemia with t(5;14)(q31;q32) is a peculiar subset of
-rearranged B-cell acute lymphoblastic leukemia with an intermediate prognosis and particular clinical features related to eosinophilia.
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