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This article discusses the use of donor-derived CAR-T cells (DD-CAR) as a treatment option for patients with refractory or relapsed B-cell acute lymphoblastic leukemia (R/R B-ALL) who have failed autologous CD19 CAR-T cell therapy (tisagenlecleucel). The article presents a case study of a 4-year-old boy who experienced multiple relapses after allogeneic hematopoietic stem cell transplantation (allo-HSCT) and two unsuccessful infusions of tisagenlecleucel. The patient eventually achieved a durable complete remission (CR) after receiving DD-CAR cells manufactured using the same process as tisagenlecleucel. The study highlights the potential of DD-CAR as a therapeutic option for patients who do not respond to autologous CAR-T cell therapy. [Extracted from the article]

Background: To investigate the educational outcomes of siblings of childhood leukemia survivors, explore determinants of school difficulties, and compare the rates of repeating grades between siblings and the general population. Methods: A cross‐sectional study of childhood leukemia survivors' siblings recruited through the Leucémies de l'Enfant et de l'Adolescent cohort, a French long‐term follow‐up program, was conducted, and education‐related data were obtained via self‐report questionnaires. Adjusted logistic regression models were used to identify variables associated with school difficulties and time since diagnosis. Rates of repeating a grade in middle school were compared between siblings and the general population of the same generation. Results: A total of 564 siblings with a mean time from diagnosis of 14.1 ± 6.4 years were included, among whom 139 (24.6%) repeated a grade, at an average of 6.4 ± 4.5 years after diagnosis. In multivariate analysis, the risk factors for repeating a grade were older siblings (odds ratio [OR] 2.3, p = 0.006), family financial difficulties (OR 2.8, p = 0.008), and history of repetition in survivors (OR, 2.5, p = 0.001). Sibling hematopoietic stem cell donors were at greater risk of repeating a grade long‐term after diagnosis (p = 0.018). Overall, siblings did not have a higher risk of educational delays at the end of middle school than the general population. Conclusion: Although the results are reassuring, socioeconomic and cancer‐related factors may have an impact on siblings' schooling long after diagnosis. Paying attention to siblings contributes to identifying the most vulnerable families, allowing more attention and appropriate resources to avoid long‐term repercussions. Additionally, supportive and targeted interventions can be developed to improve the organization of education and the health care system. [ABSTRACT FROM AUTHOR]

Background: Childhood cancer confront the whole family with a traumatic event. Because brothers and sisters may encounter emotional problems that can remain for a long time and that only few studies have assessed their long‐term outcome, our present objectives were to describe the long‐term quality of life (QoL) of childhood leukemia survivors' siblings and to explore its determinant. Methods: Brothers and sisters (from 8‐year‐old) of survivors included in the French LEA Cohort completed a QoL questionnaire (according to their age). Scores were compared with those reported by age‐ and gender‐matched French general population and by survivors. Using a clustering method, siblings were categorized into 3 groups depending on their level of QoL's scores and factors likely to be linked with these clusters were explored with multivariate analyses. Results: We included 689 brothers and sisters (313 minors, 376 adults) and the mean time from diagnosis was 13.2 ± 6.6 years. Minor siblings reported higher QoL scores than general population (p < 0.001), but a lower score for relationship with family than survivors (p < 0.001). In adult siblings, Mental Component Summary score was lower than general population (p < 0.001). Level of siblings' QoL was linked with female gender, but no association was found with cancer‐related factors. Conclusion: Brothers and sisters expressed a divergent perception of their long‐term QoL depending on their age. To minimize the impact from childhood to adulthood, long‐term attention should also be paid to siblings, often referred as "forgotten children". [ABSTRACT FROM AUTHOR]

Screening for G-CSF receptor mutations in patients with secondary myeloid or lymphoid transformation of severe congenital neutropenia. In 2018, Bellanné-Chantelot et al. first reported patients with I SRP54 i mutations presenting with severe congenital neutropenia (SCN) and extra-haematopoietic organ dysfunctions close to Shwachman-Diamond syndrome (SDS) phenotypes.1,2 I SRP54 i mutations have been shown as the second most common cause of SCN in the French neutropenia registry.2 Our female patient was diagnosed with SCN at the age of five weeks: full blood cell counts showed profound neutropenia at 100 cells/ l with relative monocytosis at 1400 cells/ l. Systematic screening for immune deficiency and anti-neutrophil autoantibodies was negative. Granulocyte colony-stimulating factor receptor mutations in a patient with acute lymphoblastic leukemia secondary to severe congenital neutropenia. [Extracted from the article]

Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), emerged in China in December 2019 and rapidly spread worldwide. Patient characteristics are described in Table S1: 21 (38-8%) had severe COVID-19, including 13 transferred to ICU and eight deceased from COVID-19 outside of ICU (Figure S1). GLO:1XW/01mar21:bjh17260-fig-0001.jpg PHOTO (COLOR): 1 Survival curve after COVID-19 diagnosis. gl Haematological characteristics did not vary between patients with severe or non-severe forms of COVID-19 (Table S1). Patient collection was prospective, so no case should have been missed in the participating centres, but we cannot exclude an underestimation of the true incidence of COVID-19 among alloHSCT recipients if pauci-symptomatic patients did not report to their transplant centre. [Extracted from the article]

Introduction: Myeloablative conditioning before allogeneic HSCT during childhood exposes to serious long‐term complications, especially gonadal dysfunction. Pubertal issues are less described than other post‐HSCT sequelae in childhood. Methods: Pubertal development and biological gonadal parameters were assessed in a retrospective monocentric cohort of prepubertal patients who underwent HSCT after myeloablative conditioning with TBI or busulfan between 1981 and 2017. Results: Seventy‐four patients (28 girls and 46 boys) were included. No spontaneous pubertal development was found in 50% of girls and 10% of boys (P <.001), and delayed puberty or no spontaneous pubertal development was found in 57% of girls and 24% of boys (P =.009). HRT was used in 82% of girls and 24% of boys (P <.001). In univariate analysis, TBI conditioning (P =.05), female sex (P <.001), acute GVHD (P =.05), extensive chronic GVHD (P =.021), steroid treatment >6 months (P =.016), and malignant diseases (P =.016) were associated with no spontaneous pubertal development, whereas TBI conditioning (P =.003) and extensive chronic GVHD (P =.005) were associated with delayed puberty. In multivariate analysis, factors independently associated with no spontaneous puberty onset were female sex (P =.001) and age >10 years (P =.033). Factors independently associated with delayed puberty were extensive chronic GVHD (P =.041) and age >10 years (P =.031). Conclusion: This study highlighted the toxicity of MAC in prepubescent children: TBI did worse, but this was especially true for the most susceptible patients (girls, leukemic patients, and patients older than 10 years). It suggests a possible role of GVHD in delayed puberty. [ABSTRACT FROM AUTHOR]

Relapse remains the major cause of treatment failure in children with high-risk acute lymphoblastic leukaemia ( ALL) undergoing allogeneic haematopoietic stem-cell transplantation (allo- SCT). Prognosis is considered dismal but data on risk factors and outcome are lacking from prospective studies. We analysed 242 children with recurrence of ALL after first allo- SCT enrolled in the Berlin-Frankfurt-Munster ( BFM) ALL- SCT- BFM 2003 and ALL- SCT- BFM international 2007 studies. Median time from allo- SCT to relapse was 7·7 months; median follow-up from relapse after allo- SCT until last follow-up was 3·4 years. The 3-year event-free survival ( EFS) was 15% and overall survival ( OS) was 20%. The main cause of death was disease progression or relapse (86·5%). The majority of children (48%) received salvage therapy without second allo- SCT, 26% of the children underwent a second allo- SCT and 25% received palliative treatment only. In multivariate analyses, age, site of relapse, time to relapse and type of salvage therapy were identified as significant prognostic factors for OS and EFS, whereas factors associated with first SCT were not statistically significant. Combined approaches incorporating novel immunotherapeutic treatment options and second allo- SCT hold promise to improve outcome in children with post allo- SCT relapse. [ABSTRACT FROM AUTHOR]

Relapse after transplantation is a major cause of treatment failure in paediatric acute lymphoblastic leukaemia ( ALL). Here, we report the findings of a prospective national study designed to investigate the feasibility of immune intervention in children in first or subsequent remission following myeloablative conditioning. This study included 133 children who received a transplant for ALL between 2005 and 2008. Minimal Residual Disease ( MRD) based on T cell receptor/immunoglobulin gene rearrangements was measured on days −30, 30, 90 and 150 post-transplantation. Ciclosporin treatment was rapidly discontinued and donor lymphocyte infusions ( DLI) were programmed for patients with a pre- or post-transplant MRD status ≥10−3. Only nine patients received DLI. Pre- and post-transplant MRD status, and the duration of ciclosporin were independently associated with 5-year overall survival ( OS), which was 62·07% for the whole cohort. OS was substantially higher in patients cleared of MRD than in those with persistent MRD (52·3% vs. 14·3%, respectively). Only pre-transplant MRD status (Hazard Ratio 2·57, P = 0·04) and duration of ciclosporin treatment ( P < 0·001) were independently associated with relapse. The kinetics of chimerism were not useful for predicting relapse, whereas MRD monitoring up to 90 d post-transplantation was a valuable prognostic tool to guide therapeutic intervention. [ABSTRACT FROM AUTHOR]

The interplay between immune recovery, cytomegalovirus ( CMV)-reactivation, CMV-driven immunity and graft-versus-leukaemia effect ( GVL) was analysed in 108 children (median age: 8 years) who underwent haematopoietic-stem cell transplantation ( HSCT) for acute leukaemia. Follow-up was 2 years unless death or relapse occurred. CMV-polymerase chain reaction ( PCR) was programmed weekly until month +3 post- HSCT. Immunomonitoring consisted of sequential lymphocyte subset enumerations and analyses of T-cell proliferative and γ-interferon responses to CMV and to adenovirus. In the 108 recipients, the 2-year relapse rate ( RR) was 25% (median time to onset 4·5 months; range: 24 d-17 months). CMV reactivation occurrence was 31% (median time to onset 26 d). Donor/recipient CMV serostatus did not influence RR. Among the 89 recipients disease-free after day +120, i) early CMV-reactivation before day +30 was more frequent ( P = 0·01) in the relapse recipient group opposed to the non-relapse group. ii) CD8+/ CD28− and CD4+ CD45 RA− T-cell expansions induced by CMV did not influence RR, iii) Recovery of anti- CMV and also anti-adenovirus immunity and of naïve CD4+ T-cells was faster in the non-relapse group ( P = 0·008; 0·009 and 0·002 respectively). In contrast to adult acute myeloid leukaemia, CMV reactivation was associated with increased RR in this paediatric series. Accelerated overall immune recovery rather than CMV-driven immunity had a favourable impact on RR. [ABSTRACT FROM AUTHOR]

Minimal residual disease ( MRD) is a major predictive factor of the cure rate of acute lymphoblastic leukaemia ( ALL). Haematopoietic cell transplantation is a treatment option for patients at high risk of relapse. Between 2005 and 2008, we conducted a prospective study evaluating the feasibility and efficacy of the reduction of immunosuppressive medication shortly after a non- ex vivo T depleted myeloablative transplantation. Immunoglobulin (Ig)H/T-cell receptor MRD 30 d before transplant could be obtained in 122 of the 133 cases of high-risk paediatric ALL enrolled. There were no significant demographic differences except remission status (first or second complete remission) between the 95 children with MRD <10−3 and the 27 with MRD ≥10−3. Multivariate analysis identified sex match and MRD as being significantly associated with 5-year survival. MRD ≥10−3 compromised the 5-year cumulative incidence of relapse (43·6 vs. 16·7%). Complete remission status and stem cell source did not modify the relationship between MRD and prognosis. Thus, pre-transplant MRD is still a major predictor of outcome for ALL. The MRD-guided strategy resulted in survival for 72·3% of patients with MRD<10−3 and 40·4% of those with MRD ≥10−3. [ABSTRACT FROM AUTHOR]

The uncommon C77G polymorphism of the Protein-Tyrosine Phosphatase (PTPRC) gene ( PTPRC; previously termed CD45) could confer an increased risk of immunopathology. This study compared the outcome of children following human leucocyte antigen-matched unrelated haematopoïetic-stem cell transplantations (HSCT) from donors carrying (C77G cases: n = 8) or not (controls: n = 36) the PTPRC C77G polymorphism. Transmission of the PTPRC C77G polymorphism through the graft was suggested by unusual CD45RA phenotype in the donors and/or in the recipients after, but not before HSCT. Restriction-Fragment Length Polymorphism and sequencing confirmed the polymorphism. Overall survival rates were similar in C77G cases and controls (63% vs. 61%). Acute leukaemia relapse tended to be less frequent in C77G cases (0% vs. 32%; P = 0·09). Among recipients surviving ≥30 d, acute GVHD (aGVHD) ≥ grade 2 tended to be more frequent (100% vs. 58%; P = 0·07) and the rate of steroid-refractory or -dependant aGVHD higher (67% vs. 28%) in C77G cases. Finally, extensive chronic GVHD tended to occur more frequently (40% vs. 9%) in C77G cases. Recovery of lymphocyte subsets and virus-specific CD4 was similar in C77G cases and controls while interleukin 2 (IL2)-responses through CD3 stimulation were higher in C77G cases ( P = 0·004). In conclusion, HSCT from PTPRC C77G donors could increase GVHD risk without compromising overall survival. Altered IL2-responses could be involved in this process. [ABSTRACT FROM AUTHOR]

Gemtuzumab ozogamicin (GO) monotherapy is reported to yield a 20–30% response rate in advanced acute myeloid leukaemia (AML). This study examined the efficacy and tolerability of GO combined with cytarabine (GOCYT) in children with refractory/relapsed CD33+ AML. Seventeen children received GO 3 mg/m2 on days 1, 4 and 7 plus cytarabine 100 mg/m2/d for 7 d on a compassionate-use basis. Seven patients then received GO-based consolidation. At the outset of GOCYT, two patients were refractory; eight patients were in refractory first relapse; six patients had relapsed after stem cell transplantation (SCT); and one patient [del(5q) therapy-related AML (t-AML)] had not yet been treated. Mean follow-up was 17 months (8–33 months). Ten responses were obtained after GOCYT induction, including complete remission (CR) or CR without complete recovery of platelets (CRp) in six patients (35%). The responses improved in three children who received GOCYT consolidation, increasing the CR + CRp rate to 53%. SCT was subsequently performed in eight responders. Grade 3–4 adverse events consisted of haematological disorders ( n = 17, 100%) and documented infections ( n = 5, 29%). No cases of sinusoidal obstructive syndrome occurred. Three patients were alive at the cut-off date for this analysis, all of whom had responded to GOCYT. GOCYT combination therapy yielded a high response rate (53%) and showed acceptable toxicity in heavily pretreated children with refractory/relapsed AML. These results warrant a larger prospective study. [ABSTRACT FROM AUTHOR]

BACKGROUND: Selection of a cord blood (CB) unit for allogeneic transplantation relies on graft characterization results provided by cord blood banks (CBBs). The goal was to compare the graft characterization results obtained upon thawing and washing to those provided by CBBs at selection. STUDY DESIGN AND METHODS: With tests that assess CB graft characteristics known to impact engraftment, CB units have been analyzed after thaw and before infusion. Our results were compared to data provided by CBBs to determine the impact on engraftment and assess how CBB-supplied information can affect future CB unit selection. RESULTS: Variability was noted as to the type of information provided by the different CBBs. Also, variability was found between the information provided by CBBs and the graft characterization results obtained upon thawing and washing. In some cases, CB measures known to be predictive of engraftment were found much lower than reported by CBBs. Only the total nucleated cell count, which is the main CB graft selection criterion besides HLA matching, correlated favorably. CONCLUSIONS: Our data reveal a high degree of variability in graft characteristics provided by CBBs and often poor correlation with results obtained on thawed and washed CB units. We suggest that standardized laboratory procedures aimed at graft characterization should be used by both CBBs and transplant centers to avoid unacceptable discrepancies. [ABSTRACT FROM AUTHOR]

A correction to the article "Natural Pregnancy and Delivery After Allogeneic Bone Marrow Transplantation in a Fanconi Anaemia Patient" that was published in the previous issue is presented.

Dyskeratosis congenita (DC) is a genetic multisystem disorder with frequent involvement of the bone marrow. Haematopoietic stem cell transplantation (HSCT) is the only definitive cure to restore haematopoiesis, even though it cannot correct other organ dysfunctions. We collected data on the outcome of HSCT in the largest cohort of DC (n = 94) patients ever studied. Overall survival (OS) and event-free survival (EFS) at 3 years after HSCT were 66% and 62%, respectively. Multivariate analysis showed better outcomes in patients aged less than 20 years and in patients transplanted from a matched, rather than a mismatched, donor. OS and EFS curves tended to decline over time. Early lethal events were infections, whereas organ damage and secondary malignancies appeared afterwards, even a decade after HSCT. A non-myeloablative conditioning regimen appeared to be most advisable. Organ impairment present before HSCT seemed to favour the development of chronic graft-versus-host disease and T-B immune deficiency appeared to enhance pulmonary fibrosis. According to the present data, HSCT in DC is indicated in cases of progressive marrow failure, whereas in patients with pre-existing organ damage, this should be carefully evaluated. Further efforts to investigate treatment alternatives to HSCT should be encouraged., (© 2018 British Society for Haematology and John Wiley & Sons Ltd.)