Daratumumab, an anti‐CD38 antibody, is used experimentally in the treatment of relapsed acute lymphoblastic leukemia (ALL). We treated five patients suffering from relapsed ALL with daratumumab. Four ...patients had T ALL, three of whom achieved complete remission (CR) after treatment and underwent stem cell transplant (SCT). Two of them had a second relapse and died 6 and 8 months after SCT, respectively. One transplanted T ALL patient remained in CR2 15 months after relapse. In the remaining T‐ALL patient, the disease progressed under daratumumab treatment, and the patient died early after the first relapse. The B‐cell precursor ALL patient with a second CD19‐negative relapse, whose disease turned out to be resistant to the combination of daratumumab with chemotherapy, later achieved CR3 with inotuzumab ozogamicin, underwent SCT and remained in CR3. Leukemia burden should be monitored after daratumumab, and care should be taken not to misclassify leukemic cells with false negativity of surface CD38; using an antibody reacting with nondaratumumab epitopes is advantageous.
Mutations in the Sterile alpha motif domain containing 9 (
) gene have been described in patients with severe multisystem disorder, MIRAGE syndrome, but also in patients with bone marrow (BM) failure ...in the absence of other systemic symptoms. The role of hematopoietic stem cell transplantation (HSCT) in the management of the disease is still unclear. Here, we present a patient with a novel mutation in
(c.2471 G>A, p.R824Q), manifesting with prominent gastrointestinal tract involvement and immunodeficiency, but without any sign of adrenal insufficiency typical for MIRAGE syndrome. He suffered from severe CMV (cytomegalovirus) infection at 3 months of age, with a delayed development of T lymphocyte functional response against CMV, profound T cell activation, significantly reduced B lymphocyte counts and impaired lymphocyte proliferative response. Cultured T cells displayed slightly lower calcium flux and decreased survival. At the age of 6 months, he developed severe neutropenia requiring G-CSF administration, and despite only mild morphological and immunophenotypical disturbances in the BM, 78% of the BM cells showed monosomy 7 at the age of 18 months. Surprisingly, T cell proliferation after CD3 stimulation and apoptosis of the cells normalized during the follow-up, possibly reflecting the gradual development of monosomy 7. Among other prominent symptoms, he had difficulty swallowing, requiring percutaneous endoscopic gastrostomy (PEG), frequent gastrointestinal infections, and perianal erosions. He suffered from repeated infections and periodic recurring fevers with the elevation of inflammatory markers. At 26 months of age, he underwent HSCT that significantly improved hematological and immunological laboratory parameters. Nevertheless, he continued to suffer from other conditions, and subsequently, he died at day 440 post-transplant due to sepsis. Pathogenicity of this novel
mutation was confirmed experimentally. Expression of mutant
caused a significant decrease in proliferation and increase in cell death of the transfected cells.
We describe a novel
mutation in a patient with prominent gastrointestinal and immunological symptoms but without adrenal hypoplasia. Thus, SAMD9 mutations should be considered as cause of enteropathy in pediatric patients. The insufficient therapeutic outcome of transplantation further questions the role of HSCT in the management of patients with
mutations and multisystem involvement.
Terminal complement blockade by humanised monoclonal antibody eculizumab has been used to treat transplantation-associated thrombotic microangiopathy (TA-TMA) in recent years. This retrospective ...international study conducted by the Paediatric Diseases (PDWP) and Inborn Error Working Party (IEWP) of the European Society for Blood and Marrow Transplantation (EBMT) describes outcome and response of 82 paediatric patients from 29 centres who developed TA-TMA and were treated with eculizumab between January 2014 and May 2019. The median time from hematopoietic stem cell transplantation (HSCT) to TA-TMA manifestation was 92 days (range: 7-606) and from TA-TMA diagnosis to the start of eculizumab treatment 6 days (range: 0-135). Most patients received eculizumab weekly (72%, n = 55) with a standard weight (kg)-based dose (78%, n = 64). Six months from beginning of eculizumab therapy, the cumulative incidence of TA-TMA resolution was 36.6% (95% CI: 26.2-47) and the overall survival (OS) was 47.1% (95% CI: 35.9-57.5). All 43 patients with unresolved TA-TMA died. The cause of death was HSCT-related in 41 patients. This study also documents poor outcome of patients without aGvHD and their frequent concomitant viral infections. Considering recent publications, intensified eculizumab dosing and complement monitoring could potentially improve upon outcomes observed in this study.
Background:
Allogeneic hematopoietic stem cell transplantation (HSCT) is a potentially curative therapy for a variety of malignant and non-malignant disorders. The prevalence of HSCT survivors ...continues to increase. Gonadal insufficiency and infertility are amongst the most frequent late complications.
Methods:
Data on successful pregnancies following HSCT in childhood were analyzed in 180 patients older 18 years (all transplanted at our center). Median age at the time of HSCT was 15.5 (8.0 - 19.9) years.
Results:
25 of 180 (14%) subjects (males=14, females=11) became parents. Of them non-malignant severe aplastic anemia (SAA) had 12 (48%) subjects and another 13 had malignant diagnosis: acute lymphoblastic (ALL; n=6), acute myeloid (AML; n=1) and chronic myeloid (CML; n=3) leukemia; remaining 3 patients had myelodysplastic syndrome (MDS). Forty children were born to the overall group, 34 out of 40 (85%) in term, all were healthy. First pregnancy (both spontaneous or after assisted reproduction) was documented 10.4 (2.5 - 24) years after HSCT in patient´s median age 26.3 (18.3 - 41.2) years. Spontaneous gravidity was detected in 16 subjects (males=9, spermiogram evaluated in 8 of them; females= 7, spontaneous regular menstrual cycle had 5 of them). Majority of subjects had HSCT due to SAA (75%; 7 males and 5 females) with cyclophosphamide regimen only. In 2 males full myeloablative Busulphan based conditioning was used (MDS, AML), and 2 females (MDS and CML, both with hormonal replacement therapy and possibility of some residual oocyte reserve) become pregnant after previously repeated unsuccessful assisted reproduction techniques (ART) with ovarian hyperstimulation (even one after total body irradiation 14.4 Gy based regimen). In remaining 9 subjects successful pregnancy was achieved after ART (donor sperm=1, cryopreserved sperm =2, TESE=2, donor oocytes=4).
Conclusions:
Gonadotoxicity after HSCT and infertility are the well-known posttransplant complications negatively affecting the quality of life. Fertility issues must be routinely discussed at peritransplant care. In the field of reproductive medicine impressive advances have been achieved to offer the best option for fertility preservation and pregnancy outcome. Better knowledge of pregnancy rate especially in pediatric population following HSCT will require more data for analysis in international cooperation. Unless otherwise noted, all abstracts presented at ENDO are embargoed until the date and time of presentation. For oral presentations, the abstracts are embargoed until the session begins. Abstracts presented at a news conference are embargoed until the date and time of the news conference. The Endocrine Society reserves the right to lift the embargo on specific abstracts that are selected for promotion prior to or during ENDO.
Series of observations indicate PK/PD variability challenging the accuracy of the body-weight based busulfan (Bu) dosing schedule for (HSCT) conditioning therapy. The purpose of this communication is ...to describe the frequency of dose changes in initially body-weight-based fixed IV Bu dose and to emphasize the importance of TDM.
Sixty-two children (ages 2 months-18 years) were treated with IV busulfan doses based on body weight for myeloablation. TDM utilizing a limited sample strategy (trough concentration immediately before the 5th dose, followed by samples immediately after the end of the 2-h infusion peak, 4 h, and 6 h from initiation of the infusion) was performed in 46 of 62 subjects. Busulfan concentrations were determined by high-performance liquid chromatography (HPLC). AUC was calculated according to the trapezoidal rule.
We observed trough levels of 25-1244 µg/L, peak levels of 849-4586 µg/L, and AUC of 2225-12818 µg/L·h following body weight-based high-dose busulfan. The doses were changed in 54% of cases. AUC in 5 of 9 patients with VOD were within target, in 3 patients AUS was higher, and in 1 patient AUC was lower. One of the 2 patients with neurotoxicity had higher AUC. Engraftment was 100%, but relapse occurred in 25% of cases.
Our results demonstrate that even with IV busulfan, intra-individual PK/PD variability is challenging. Although AUC does not necessarily correspond with outcomes (due to the role of other factors the fact that doses were changed in 54% of cases underlines the importance of TDM.
The atmospheric pressure plasma jet (APPJ) was used to enhance the sensitivity of industrially important polyaniline (PANI) for detection of organic vapors from amides. The gas sensing mechanism of ...PANI is operating on the basis of reversible protonation or deprotonation, whereas the driving force to improve the sensitivity after plasma modifications is unknown. Herein we manage to solve this problem and investigate the sensing mechanism of atmospheric plasma treated PANI for vapor detection of amides using urea as a model. The results from various analytical techniques indicate that the plausible mechanism responsible for the improved sensitivity after plasma treatment is operating through a cyclic transition state formed between the functional groups introduced by plasma treatment and urea. This transition state improved the sensitivity of PANI towards 15 ppm of urea by a factor of 2.4 times compared to the non-treated PANI. This plasma treated PANI is promising for the improvement of the sensitivity and selectivity towards other toxic and carcinogenic amide analytes for gas sensing applications such as improving material processing and controlling food quality.
This thesis is aimed to analyze current status of the company information system, to reveals it's weak points and then designs a new solution of information system.
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