Loss of CD22 expression and expansion of a CD22dim subpopulation in adults with relapsed/refractory B-lymphoblastic leukaemia after treatment with Inotuzumab-Ozogamicin.

Treatment options for relapsed or refractory B-lymphoblastic leukaemia (r/r B-ALL) are limited and the prognosis of these patients remains dismal, but novel immunotherapeutic options such as the anti-CD22 antibody-drug-conjugate Inotuzumab-Ozogamicin (InO) have improved outcomes in these patients. Flow cytometry is essential to assess antigen-expression prior to treatment initiation of antigen-directed immunotherapies. Here, we present flow cytometric and clinical data of three adult patients with r/r B-ALL who failed treatment with InO associated with reduced or lost antigen-expression. In addition, we present comparative data on two different diagnostic CD22-specific antibody clones that exhibit significant differences in staining intensities.

Newly diagnosed isolated myeloid sarcoma-paired NGS panel analysis of extramedullary tumor and bone marrow.

Isolated myeloid sarcoma (MS) is a rare malignancy in which myeloid blast forms tumors at various locations while the bone marrow (BM) remains cytomorphologically free from disease. We analyzed isolated MS from four patients and their BMs at initial diagnosis and follow-up, using a custom next-generation sequencing (NGS) panel. We observed possible clonal evolution and a clonal hematopoiesis of indeterminate potential (CHIP)-like finding in the BM of one of three cases with detectable mutations. Clinical presentation of one patient suggested extramedullary confined homing of blasts to distal sites in the relapse situation still sparing the BM. In summary, our findings shall motivate future work regarding signals of extramedullary blast trafficking and clonal evolution in MS.

Successful Treatment of Delayed Methotrexate Clearance Using Glucarpidase Dosed on Ideal Body Weight in Obese Patients.

Delayed methotrexate (MTX) elimination after treatment with high-dose (HD) MTX may result in life-threatening toxicities as well as acute kidney injury (AKI). Treatment includes administration of glucarpidase, an enzyme that rapidly inactivates MTX. Dosing of glucarpidase is based on body weight; however, recommendations for dosage adjustments in obese patients are lacking. We describe three obese adult patients (body mass index [BMI] range 31-43 kg/m2 ) who received HD-MTX following all precautions for its treatment. Although peak MTX concentrations were within the expected range (308-368 µmol/L), MTX concentrations after 24 hours or later were markedly increased (97, 52, and 19 µmol/L, respectively). Two patients experienced AKI. After a single intravenous dose of glucarpidase 4000 units (50 units/kg on the basis of ideal body weight [IBW]) was administered to each patient 38, 46, and 60 hours, respectively, after the start of MTX, MTX concentrations dropped quickly to 1.37, 0.07, and 0.03 µmol/L, respectively, and further decreased steadily. Over time, clinical status and renal function improved in all patients. Glucarpidase is a highly hydrophilic molecule with a volume of distribution of 3.6 L, representing the intravascular volume of an adult. Therefore, we used IBW for glucarpidase dose calculations, allowing us to reduce the dose that would have been determined by using total body weight. This approach resulted in a rapid decrease of MTX serum concentrations and may reduce treatment costs of this highly expensive drug.

Deposition of C-terminally truncated Aß species Aß37 and Aß39 in Alzheimer's disease and transgenic mouse models.

In Alzheimer's disease (AD) a variety of amyloid ß-peptides (Aß) are deposited in the form of extracellular diffuse and neuritic plaques (NP), as well as within the vasculature. The generation of Aß from its precursor, the amyloid precursor protein (APP), is a highly complex procedure that involves subsequent proteolysis of APP by ß- and γ-secretases. Brain accumulation of Aß due to impaired Aß degradation and/or altered ratios between the different Aß species produced is believed to play a pivotal role in AD pathogenesis. While the presence of Aß40 and Aß42 in vascular and parenchymal amyloid have been subject of extensive studies, the deposition of carboxyterminal truncated Aß peptides in AD has not received comparable attention. In the current study, we for the first time demonstrate the immunohistochemical localization of Aß37 and Aß39 in human sporadic AD (SAD). Our study further included the analysis of familial AD (FAD) cases carrying the APP mutations KM670/671NL, E693G and I716F, as well as a case of the PSEN1 ΔExon9 mutation. Aß37 and Aß39 were found to be widely distributed within the vasculature in the brains of the majority of studied SAD and FAD cases, the latter also presenting considerable amounts of Aß37 containing NPs. In addition, both peptides were found to be present in extracellular plaques but only scarce within the vasculature in brains of a variety of transgenic AD mouse models. Taken together, our study indicates the importance of C-terminally truncated Aß in sporadic and familial AD and raises questions about how these species are generated and regulated.

Aß38 in the brains of patients with sporadic and familial Alzheimer's disease and transgenic mouse models.

The pathogenesis of Alzheimer's disease (AD) is believed to be closely dependent on deposits of neurotoxic amyloid-ß peptides (Aß), which become abundantly present throughout the central nervous system in advanced stages of the disease. The different Aß peptides existing are generated by subsequent cleavage of the amyloid-ß protein precursor (AßPP) and may vary in length and differ at their C-terminus. Despite extensive studies on the most prevalent species Aß40 and Aß42, Aß peptides with other C-termini such as Aß38 have not received much attention. In the present study, we used a highly specific and sensitive antibody against Aß38 to analyze the distribution of this Aß species in cases of sporadic and familial AD, as well as in the brains of a series of established transgenic AD mouse models. We found Aß38 to be present as vascular deposits in the brains of the majority of sporadic AD cases, whereas it is largely absent in non-demented control cases. Aß38-positive extracellular plaques were virtually limited to familial cases. Interestingly we observed Aß38-positive plaques not only among familial cases due to AßPP mutations, but also in cases of familial AD caused by presenilin (PSEN) mutations. Furthermore we demonstrate that Aß38 deposits in the form of extracellular plaques are common in several AD transgenic mouse models carrying either only AßPP, or combinations of AßPP, PSEN1, and tau transgenes.