Nijmegen breakage syndrome (NBS) is a DNA repair disorder characterized by combined immunodeficiency and a high predisposition to lymphoid malignancies. The majority of NBS patients are identified ...with a homozygous five base pair deletion in the
(
gene (c.657_661del5, p.K219fsX19) with a founder effect observed in Caucasian European populations, especially of Slavic origin. We present here an analysis of a cohort of 136 NBS patients of Eastern Slav origin across Belarus, Ukraine, Russia, and Latvia with a focus on understanding the geographic distribution, incidence of malignancy, and treatment outcomes of this cohort. Our analysis shows that Belarus had the highest prevalence of NBS (2.3 per 1,000,000), followed by Ukraine (1.3 per 1,000,000), and Russia (0.7 per 1,000,000). Of note, the highest concentration of NBS cases was observed in the western regions of Belarus and Ukraine, where NBS prevalence exceeds 20 cases per 1,000,000 people, suggesting the presence of an "Eastern Slavic NBS hot spot." The median age at diagnosis of this cohort ranged from 4 to 5 years, and delay in diagnosis was more pervasive in smaller cities and rural regions. A total of 62 (45%) patients developed malignancies, more commonly in males than females (55.2 vs. 34.2%;
=0.017). In 27 patients, NBS was diagnosed following the onset of malignancies (mean age: 8 years). Malignancies were mostly of lymphoid origin and predominantly non-Hodgkin lymphoma (NHL) (
=42, 68%); 38% of patients had diffuse large B-cell lymphoma. The 20-year overall survival rate of patients with malignancy was 24%. However, females with cancer experienced poorer event-free survival rates than males (16.6% vs. 46.8%,
=0.036). Of 136 NBS patients, 13 underwent hematopoietic stem cell transplantation (HSCT) with an overall survival of 3.5 years following treatment (range: 1 to 14 years). Indications for HSCT included malignancy (
=7) and immunodeficiency (
=6). Overall, 9% of patients in this cohort reached adulthood. Adult survivors reported diminished quality of life with significant physical and cognitive impairments. Our study highlights the need to improve timely diagnosis and clinical management of NBS among Eastern Slavs. Genetic counseling and screening should be offered to individuals with a family history of NBS, especially in hot spot regions.
Highlights • The case demonstrated a rare event of clonal heterogeneity by IKZF1 gene status in BCRABL1- ALL. • IKZF1 deletions are secondary events in ALL caused by clonal evolution during the ...treatment. • It's prognostic significance could be more crucial in BCR-ABL- rather than in BCR-ABL + ALL. • IKZF1 gene alterations may be determined and proved at the genome, expression and protein level. • IKZF1 deletions are suitable for MRD detection but not stable compared to Ig/TCR rearrangement.
Abstract Detection of minimal residual disease (MRD) during the treatment of acute lymphoblastic leukemia (ALL) by RQ-PCR analysis of clonal Ig/TCR rearrangements is used for risk group ...stratification in European treatment protocols. In Belarus patients with childhood ALL are treated according to ALL-MB protocols, which do not use MRD-based risk stratification. To evaluate the prognostic significance of MRD for ALL-MB-2002/2008 protocols, MRD was quantified by RQ-PCR in 68 ALL patients at four time points: on day 15, on day 36, before and after maintenance therapy (MT). MRD positivity, as well as quantitative level of MRD were analyzed and compared between patients who stayed in remission and relapsed. Relapse-free survival revealed to be significantly associated with MRD levels at different time points. Unfavorable prognosis was shown for MRD ≥ 10−3 on day 36 ( p < 0.001), and any positive MRD before ( p < 0.001) and after ( p = 0.001) MT. Multivariate Cox regression analysis proved MRD as independent significant prognosis factor at day 36 ( p = 0.005) and before MT ( p = 0.001). We conclude, that MRD quantified by RQ-PCR in children with ALL treated with ALL-MB protocols is feasible and independently associated with outcome. MRD may be a suitable parameter for treatment stratification in MB protocols in future.
Key Clinical Message
Partial leukocyte adhesion deficiency type 1 (LAD‐1) deficiency is extremely rare condition with milder infectious manifestation and immune system imbalance leads to increased ...risks of autoinflammatory complications, such as pyoderma gangrenosum, that can be triggered by trauma or pregnancy. In patients with spice‐site ITGB2 variants, partial expression can occur due to different β2 integrin isophorms expression.
LAD‐1, OMIM ID #116920 is a rare, autosomal recessive disorder that results from mutations in the ITGB2 gene that encodes the CD18 β2 integrin subunit. According to the CD18 expression, LAD‐1 is categorized as severe (<2%), moderate (2%–30%), or mild (>30%). Here, we describe a 22‐year‐old female, who presented with inflammatory skin disease and oral cavity, as well as respiratory tract infections during the first year of life. LAD‐1 was diagnosed at the age of 2 years by low expression of CD18 (1%). Whole‐exome sequencing identified homozygous c. 59‐10C>A variant in the ITGB2 gene. Despite severe phenotype, the patient survived to adulthood without hematopoietic stem cell transplantation and became pregnant at the age of 20 years, with pregnancy complicated by a pyoderma gangrenosum‐like lesion. During her life, CD18 expression increased from 1% to 9%; at 22 years of age, 5% of neutrophils and 9% of lymphocytes were CD18+. All CD18+‐lymphocytes were predominantly memory/effector cytotoxic T cells. However, revertant mosaicism was not being established suggesting that CD18 expression variability may be mediated by other mechanisms such as different β2 integrin isophorms expression.
In view of obscure clinical and biological significance of leukemic cells heterogeneity, we studied the efficacy of apoptosis, proliferation, and expression levels of the
Bcl-2
,
MDR1
,
LRP
, and
...BCRP
genes in sorted CD34+ and CD34− subpopulations of childhood AML leukemic samples. In five out of nine cases, CD34+ cells were less sensitive to spontaneous apoptosis and had from 1.2- to 5.0-fold higher expression levels of
Bcl-2
(eight of ten) and from 1.5- to 28.7-fold higher expression levels of
MDR1
(eight of ten). The expression levels of the
LRP
gene were from 1.1- to 1.8-fold higher in CD34+ subpopulations (five of ten cases), and the expression levels of the
BCRP
gene were from 1.1- to 22.4-fold higher in CD34+ leukemic cells (six of ten). In all M4 cases, the expression levels of
LRP
were higher in the CD34− subpopulation. Significant differences in the patterns of genes expression between patients do not allow us to conclude that the CD34+ fractions have more resistant phenotype than the CD34− subpopulations. Nevertheless, distinctions between CD34+ and CD34− cells may lead to different chemosensitivities between leukemic subpopulations in vivo and may determine the alteration of the leukemic immunophenotype during treatment and in relapse.
Summary
The prognostic value of minimal residual disease (MRD) measured by fusion‐gene transcript (FGT) detection was investigated in 76 infants (aged ≤1 year) with acute lymphoblastic leukaemia ...(ALL) with lysine methyltransferase 2A (KMT2A) rearrangements. Either at the end of induction or at later time‐points, FGT‐MRD‐positivity was associated with poor outcome. FGT‐MRD‐positivity after first consolidation or first high‐risk block detected 46·5% of infants with extremely poor outcome disease‐free survival (SE) 0·06 (0·06), cumulative incidence of relapse (SE) 0·91 (0·05), which was also confirmed in multivariable analysis. Thus, FGT‐MRD measurement at a single time‐point clearly identifies infants with ALL who are curable with conventional chemotherapy and those who would benefit only from other treatment approaches.
Although most children with acute lymphoblastic leukemia (ALL) receive fractionated total body irradiation (FTBI) as myeloablative conditioning (MAC) for allogeneic hematopoietic stem cell ...transplantation (allo-HSCT), it is an important matter of debate if chemotherapy can effectively replace FTBI. To compare outcomes after FTBI versus chemotherapy-based conditioning (CC), we performed a retrospective EBMT registry study. Children aged 2-18 years after MAC for first allo-HSCT of bone marrow (BM) or peripheral blood stem cells (PBSC) from matched-related (MRD) or unrelated donors (UD) in first (CR1) or second remission (CR2) between 2000 and 2012 were included. Propensity score weighting was used to control pretreatment imbalances of the observed variables. 3.054 patients were analyzed. CR1 (1.498): median follow-up (FU) after FTBI (1.285) and CC (213) was 6.8 and 6.1 years. Survivals were not significantly different. CR2 (1.556): median FU after FTBI (1.345) and CC (211) was 6.2 years. Outcomes after FTBI were superior as compared with CC with regard to overall survival (OS), leukemia-free survival (LFS), relapse incidence (RI), and nonrelapse mortality (NRM). However, we must emphasize the preliminary character of the results of this retrospective "real-world-practice" study. These findings will be prospectively assessed in the ALL SCTped 2012 FORUM trial.
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