Wolman disease (WD), the rapidly progressive phenotype of lysosomal acid lipase (LAL) deficiency, presents in neonates with failure to thrive and hepatosplenomegaly, and leads to multi-organ failure ...and death before 12 months of age. In clinical trials, enzyme replacement therapy (ERT) with sebelipase alfa led to improved survival, growth and biological parameters in WD patients followed up to 5 years. Long-term follow-up and health-related quality of life (HRQoL) evaluation are lacking.
We performed a nationwide, retrospective study of sebelipase alfa in WD patients. Five patients with abolished LAL activity and bi-allelic LIPA mutations were included with a median follow-up of 7 years (1-10). ERT was initiated at a median age of 1 month (0-4). Infusion tolerance was excellent on the long-term with only one patient requiring systematic pre-medication. Cholestyramine, fat-soluble vitamin supplements and a specific diet (high in medium-chain triglycerides and low in long-chain fatty acids) were prescribed. Liver function tests, plasma lipid profiles, fat-soluble vitamin levels and growth parameters improved. Three patients transiently exhibited a neuromyopathic phenotype (footdrop gait, waddling walk or muscle fatigue) but electromyography and muscle strength testing were normal. At last follow-up, all patients were alive with normal growth parameters and a satisfactory HRQoL, no patient had special education needs, and one patient required parenteral nutrition since an acute gastroenteritis.
Early ERT initiation allowed 100% survival with positive outcomes. Very long-term follow-up and hematopoietic stem cell transplantation while on ERT should be evaluated to strengthen the benefits of sebelipase alfa.
Juvenile myelomonocytic leukemia (JMML) is a rare and severe myelodysplastic and myeloproliferative neoplasm of early childhood initiated by germline or somatic RAS-activating mutations. Genetic ...profiling and whole-exome sequencing of a large JMML cohort (118 and 30 cases, respectively) uncovered additional genetic abnormalities in 56 cases (47%). Somatic events were rare (0.38 events/Mb/case) and restricted to sporadic (49/78; 63%) or neurofibromatosis type 1 (NF1)-associated (8/8; 100%) JMML cases. Multiple concomitant genetic hits targeting the RAS pathway were identified in 13 of 78 cases (17%), disproving the concept of mutually exclusive RAS pathway mutations and defining new pathways activated in JMML involving phosphoinositide 3-kinase (PI3K) and the mTORC2 complex through RAC2 mutation. Furthermore, this study highlights PRC2 loss (26/78; 33% of sporadic JMML cases) that switches the methylation/acetylation status of lysine 27 of histone H3 in JMML cases with altered RAS and PRC2 pathways. Finally, the association between JMML outcome and mutational profile suggests a dose-dependent effect for RAS pathway activation, distinguishing very aggressive JMML rapidly progressing to acute myeloid leukemia.
Primary immunodeficiencies are inherited disorders, which may be revealed in the context of autoimmune hemolytic anemia (AIHA). We report the case of a girl presenting with an enterovirus-related ...AIHA. Despite being in complete remission for her anemia after treatment, the initial CD4/CD8 lymphopenia dramatically worsened with time. Its sole clinical presentation was generalized verrucosis. Cellular quantitative and functional immunodeficiency was evidenced but no known molecular defect was identified despite extensive workup. This unlabeled profound naive T-lymphopenia was cured by bone marrow transplantation. No similar case was ever described in the scientific literature. Patients with AIHA and/or generalized verrucosis should be screened for primary immunodeficiency, before initiating any immunomodulatory treatment.
Infants with Noonan syndrome (NS) are predisposed to developing juvenile myelomonocytic leukaemia (JMML) or JMML-like myeloproliferative disorders (MPD). Whereas sporadic JMML is known to be ...aggressive, JMML occurring in patients with NS is often considered as benign and transitory. However, little information is available regarding the occurrence and characteristics of JMML in NS.
Within a large prospective cohort of 641 patients with a germline PTPN11 mutation, we identified MPD features in 36 (5.6%) patients, including 20 patients (3%) who fully met the consensus diagnostic criteria for JMML. Sixty percent of the latter (12/20) had severe neonatal manifestations, and 10/20 died in the first month of life. Almost all (11/12) patients with severe neonatal JMML were males. Two females who survived MPD/JMML subsequently developed another malignancy during childhood. Although the risk of developing MPD/JMML could not be fully predicted by the underlying PTPN11 mutation, some germline PTPN11 mutations were preferentially associated with myeloproliferation: 10/48 patients with NS (20.8%) with a mutation in codon Asp61 developed MPD/JMML in infancy. Patients with a p.Thr73Ile mutation also had more chances of developing MPD/JMML but with a milder clinical course. SNP array and whole exome sequencing in paired tumoral and constitutional samples identified no second acquired somatic mutation to explain the occurrence of myeloproliferation.
JMML represents the first cause of death in PTPN11-associated NS. Few patients have been reported so far, suggesting that JMML may sometimes be overlooked due to early death, comorbidities or lack of confirmatory tests.
Introduction: Inotuzumab ozogamicin (INO) is an anti-CD22-drug conjugate therapeutic agent, in which a cytotoxic agent, calicheamicin, is conjugated to a humanized IgG4 anti-CD22 mAb (de Vries et ...al., Leukemia, 2012). As CD22 expression is confined to the B-cell lineage and is largely expressed in mature and immature B-cell malignancies, INO represents an attractive drug to treat B-cell acute lymphoid leukemia (ALL). INO has been evaluated in clinical trials and its efficacy has been reported in adult and elderly patients (pts) with ALL (Kantarjian et al., NEJM, 2016; Lancet Oncol 2018 and Cancer 2018). Since half of the total number of cases of ALL occurs in children and teenagers and it is the most frequently diagnosed malignancy in children, with the vast majority arising from B-cell lineage (85%), INO is also a drug of interest for the 15% of pediatric pts who are not cured by current treatments. We here report French pediatric pts with refractory or relapsed (r/r) B-cell ALL who were treated by INO through a compassionate use access program.
Methods: French pediatric hematology centers provided retrospective clinical follow-up on pts' ≤ 18 years old affected by r/r B-cell ALL who received at least one dose of INO, provided by Pfizer through a compassionate use program following authorization by the French regulatory agency (ANSM) between 2015 and 2017. All pts were treated according to the adult phase 3 clinical trial dose of 1.8 mg/m2 during the first course divided as followed: 0.8 mg/m2 of body surface at day 1 and 0.5 mg/m2 at day 8 and 15. A second course could be repeated at the same dosage if the response was not complete after the first course. Then the consolidation courses of treatment could be continued at the dose of 1.5 mg/m2 divided as 0.5 mg/m2 of body surface at day 1, 8 and 15, up to 3 total cycles.
Results: Eleven pts aged from 3 to 18 years old received INO; and were: 2 between 1 and 10 years old, 4 between 10 and 15 and 5 between 15 and 18. They received from 1 to 3 cycles of INO. They were heavily pretreated, as 6 of them received INO while refractory to the treatment of a first relapse, and 5 of them in treatment of second relapse or more. Prior to INO therapy, 4/11 pts had undergone allogenic hematopoietic stem cell transplantation (HSCT) and 7/11 pts had received anti-CD19 therapy with either Blinatumomab (6/7) or CAR-T cells (1/7). Pre-INO treatment medullary status was M3 (>25% blasts) for 8/11 pts, M2 (5-25%) for 2 pts and M1 (<5%) with positive minimal residual disease (MRD) and extra-medullary disease for 1 patient (pt).
Eight pts were in complete remission (CR) after one cycle (M2/M3 marrow prior to INO: 7, M1: 1), including 2 pts with an undetectable MRD (< 10-5). These 2 pts received a second cycle of INO and were brought to HSCT; both of them are alive (20 months (m)+, 27 m+). The 6 remaining pts in CR but MRD+ subsequently died: 1) 5 received a second cycle of INO without documentation of MRD negativity. All of them relapsed whatever the following treatment (time to disease progression ranged from 1 week to 17 months). 2) 1 pt was brought to HSCT but died of cardiac failure 3 months after the procedure.
As observed in adults, hepatic and hematologic adverse events were observed. All pts developed hematologic toxicities, 10/11 pts with grade 3/4 anemia, neutropenia or thrombocytopenia. Febrile neutropenia of grade 3/4 occurred for 5 pts. Cholestasis with grade 3/4 elevations of GGT or transaminases was noted in 4/11 pts. Sinusoidal obstruction syndrome (SOS) occurred in 1 pt who had previously undergone HSCT, during his first course of INO. Two pts who subsequently underwent HSCT developed SOS during transplant. All of these 3 pts recovered normal hepatic function. None of them died from INO direct toxicities.
Conclusion: Toxicities developed by these young patients were very similar to the ones reported in adults with hepatic and infectious toxicities. The incidence of SOS seems significant in patients that underwent HSCT either before or after INO treatment. INO showed promising results in pediatric compassionate use program in our French cohort, similarly to the one reported by Bhojwani D et al. (ASCO abstract, 2017). Its safety and efficacy in r/r B-cell ALL are to be further investigated in pediatric populations within prospective clinical trials currently underway in EU and US.
Baruchel:Novartis: Membership on an entity's Board of Directors or advisory committees; Roche: Consultancy; Amgen: Consultancy; Jazz Pharmaceuticals: Consultancy, Honoraria, Other: Travel, accommodations or expenses; Celgene: Consultancy; Servier: Consultancy; Shire: Research Funding.
Beta thalassemia major (βTM) is the most common inherited hemoglobinopathy. Management essentially focuses on preventing and treating complications. Conventional treatment is based on a regular blood ...transfusion program, and chelation therapy. Management essentially focuses on preventing and treating complications. Severe complications of βTM are very rarely seen in children in Europe. In the context of the migrant crisis, pediatricians will be confronted with the challenge of managing severe complicated βTM. We report the case of 2 Syrian 10-year-old twin girls who arrived to France with numerous and severe complications of βTM: hemochromatosis, alloimmunization, hypopituitarism, osteopenia… Their clinical management, which led to successful vital and functional improvement, is reported in this article.
Context: Shwachman Diamond disease (SDS) is caused by an SBDS mutation, is typically associated with neutropenia and exocrine pancreas deficiency. Pancytopenia, myelodysplastic syndrome (MDS) or ...acute myeloid leukemia (AML), are life-threatening complications of SDS. To date, the sole risk factors identified for SDS are early symptoms (before age of 3 months) and mild chronic anemia or thrombocytopenia(1).
Methods: To determine which mutations underlie clonal development and leukemic changes in SDS, we screened a series of patients with congenital neutropenias at various time points of follow-up. We used a consensus NGS panel of 41 genes involved in the development of myeloid malignancies (Haloplex® Agilent) (2, 3). Patients with SBDS mutations included in the French Severe Congenital Neutropenia registry or followed in the Leuwen University were screened when bone marrow samples were available as well as other subtypes of congenital neutropenia.
Results: Among the 139 SDS patients, bone marrow samples of 23 patients were available for screening at various time points. We found isolated somatic TP53 mutations in 10 cases. In addition one patient had concomitant FLT3 TKD and TP53 mutations, and another patient had the recurrent IDH1 p.Arg132Cys variant. Strikingly, no TP53 mutations were observed when the screening was extended to 70 non-SDS neutropenia patients. None of the 11 SDS patients without any detectable mutations (with a threshold of detection of 0.5%) had any severe hematological expression nor presented any major hematological complications at time of sampling. By contrast, among the 12 SDS patients with somatic mutations, AML or MDS were observed in 3 cases, 1 with the IDH1 mutation (Variant allelic frequency (VAF): 42%), 1 with the recurrent TP53 p.Gly245Ser mutation (VAF:53%), 1 with two TP53 mutations (VAFs : 19% and 37%). Severe cytopenias without MDS or AML were found in 2 other cases, one with an isolated TP53 mutation at 24%, and one with both TP53 and FLT3 mutations around 45%. In the 7 remaining patients, allele frequencies of TP53 variants were found below 2% in four cases, and at 3%, 14%, and 37% in the 3 other patients. By sequential analysis in one patient we found a p.Val272Met variant (1.1% at 9 years) which was no more observed but was replaced by the recurrent p.Arg175His mutation (4% at 12 years and 14% at 15 years). Figure 1 depicts the allele frequencies of the variants with time among the 23 patients. The three patients with MDS / AML died despite hematopoietic stem cell transplantation (HSCT) in two of them. In contrast, the two patients with severe cytopenias and TP53 mutations who were transplanted are doing well three years after HSCT, and no TP53 mutation was detected one year after transplant.
Conclusion: TP53 mutations are associated with hematological complications and specifically acquired in SDS when compared to other congenital neutropenias. This is in line with the frequency of complex karyotype MDS/AML in SDS(1). Routine evaluation of TP53 load in SDS patients may offer a powerful tool to screen SDS who may be susceptible to have severe hematological complications in a preemptive transplantation strategy setting.
References: 1. J. Donadieu et al., Haematologica 97, 1312 (2012). 2. P. Hirsch et al., Nat. Commun. 7, 12475 (2016). 3. E. Papaemmanuil et al., N. Engl. J Med. 374, 2209 (2016).
Acknowledgments: The French SCN registry is supported by grants from Amgen, Chugai, Prolong Pharma, Inserm, the Association 111 les Arts, the Association RMHE, the Association Sportive de Saint Quentin Fallavier and « Le Fond de dotation Contre la Leucémie“. The authors thank the association IRIS and Mrs Grosjean and Mr Gonnot (ASSQF) for their support.
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No relevant conflicts of interest to declare.
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