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Summary: Establishing a precise diagnosis is essential in inborn haematological cytopenias to enable appropriate treatment decisions and avoid secondary organ damage. However, both diversity and phenotypic overlap of distinct disease entities may make the identification of underlying genetic aetiologies by classical Sanger sequencing challenging. Instead of exome sequencing, we established a systematic next generation sequencing‐based panel targeting 292 candidate genes and screened 38 consecutive patients for disease‐associated mutations. Efficient identification of the underlying genetic cause in 17 patients (44·7%), including 13 novel mutations, demonstrates that this approach is time‐ and cost‐efficient, enabling optimal management and genetic counselling. [ABSTRACT FROM AUTHOR]

The impact of persistent mixed chimerism ( MC) after haematopoietic stem cell transplantation ( HSCT) remains unclarified. We investigated the incidence of MC in peripheral blood beyond day +50 after HSCT and its impact on rejection, chronic graft-versus-host disease (c-GvHD) and relapse in 161 children receiving allogeneic HSCT for haematological malignancies. The 1-year incidence of late MC was 26%. Spontaneous conversion to complete donor chimerism ( CC) occurred in 43% of patients as compared to 62% after donor lymphocyte infusions. No graft rejection occurred. The 1-year incidence of c-GvHD was 20 ± 7% for MC, and 18 ± 4% for CC patients ( P = 0·734). The 3-year cumulative incidence of relapse ( CIR) according to chimerism status at days +50 and +100 was 22 ± 4% for CC patients vs. 22 ± 8% for MC patients (day +50; P = 0·935) and 21 ± 4% vs. 20 ± 7% (day +100; P = 0·907). Three-year CIRs in patients with persistent MC and patients with CC/limited MC were comparable (8 ± 7% vs. 19 ± 4%; P = 0·960). HSCT for acute leukaemia or myelodysplastic syndrome as secondary malignancies (hazard ratio ( HR) 4·7; P = 0·008), for AML ( HR 3·0; P = 0·02) and from mismatched donors ( HR 3·1; P = 0·03) were independent factors associated with relapse. Our data suggest that late MC neither protects from c-Gv HD nor does it reliably predict impending disease relapse. [ABSTRACT FROM AUTHOR]

Sickle cell disease ( SCD) is still associated with substantial morbidity and reduced life expectancy. Disease-related mortality rises to 14% in adolescents and young adults. Overall and disease-free survival following haematopoietic stem cell transplantation ( HSCT) is 90% and 95%, respectively. To reduce transplant-associated late effects, the feasibility of a highly immunosuppressive reduced-intensity conditioning ( RIC) regimen was explored in children with SCD and a matched sibling donor. Eight patients (median age, 9 yr) and symptomatic SCD were included. The conditioning regimen consisted of fludarabine, melphalan and either thiotepa or total lymphoid irradiation plus antithymocyte globuline or alemtuzumab. The graft was bone marrow in seven and cord blood in one case. The conditioning regimen was well tolerated and no severe infectious complications occurred. All patients displayed mixed chimaerism on day +28. After a median follow-up of 4 yr, 3/8 patients have mixed leucocyte chimaerism and 8/8 patients have 100% donor erythropoiesis. HSCT from matched sibling donors following a RIC regimen was well tolerated and resulted in cure in all patients studied. If confirmed in larger patient cohorts, these observations will have important implications for the indications of HSCT in children with SCD. [ABSTRACT FROM AUTHOR]

Chimaerism analysis was performed by polymerase chain reaction amplification of short-tandem repeat markers in 30 children following haematopoietic stem cell transplantation for juvenile myelomonocytic leukaemia (JMML). Fourteen patients always had complete chimaerism (CC); one of them relapsed after the discontinuation of the study and 13 continued in complete remission (CR). Mixed chimaerism (MC) was noted in 16 patients. Of those 12 patients demonstrated increasing MC (i-MC); 10 relapsed and two achieved CC following discontinuation of immunosuppressive therapy (IST). Four other patients demonstrating only transient MC are alive in CR. MC with up to 20% of autologous cells could be successfully eradicated without induction of severe graft-versus-host disease when IST was reduced or discontinued directly after the first demonstration of MC. At the same time, MC with up to 10% of autologous cells could disappear without intervention. The interval between MC and relapse ranged from 0-320 d (median 38 d). Donor leucocyte infusion was given to six patients with i-MC, but only one patient responded. Peripheral blood seems as valuable as bone marrow for chimaerism studies. In conclusion, serial quantitative chimaerism studies can identify patients with i-MC who are at high risk for relapse of JMML. Immediate withdrawal of IST is advised in these patients. [ABSTRACT FROM AUTHOR]