Mathias Schmid

Targeted Therapy With the T-Cell–Engaging Antibody Blinatumomab of Chemotherapy-Refractory Minimal Residual Disease in B-Lineage Acute Lymphoblastic Leukemia Patients Results in High Response Rate and Prolonged Leukemia-Free Survival

PURPOSE Blinatumomab, a bispecific single-chain antibody targeting the CD19 antigen, is a member of a novel class of antibodies that redirect T cells for selective lysis of tumor cells. In acute lymphoblastic leukemia (ALL), persistence or relapse of minimal residual disease (MRD) after chemotherapy indicates resistance to chemotherapy and results in hematologic relapse. A phase II clinical study was conducted to determine the efficacy of blinatumomab in MRD-positive B-lineage ALL. PATIENTS AND METHODS Patients with MRD persistence or relapse after induction and consolidation therapy were included. MRD was assessed by quantitative reverse transcriptase polymerase chain reaction for either rearrangements of immunoglobulin or T-cell receptor genes, or specific genetic aberrations. Blinatumomab was administered as a 4-week continuous intravenous infusion at a dose of 15 μg/m2/24 hours. RESULTS Twenty-one patients were treated, of whom 16 patients became MRD negative. One patient was not evaluable due to a grade 3 adverse event leading to treatment discontinuation. Among the 16 responders, 12 patients had been molecularly refractory to previous chemotherapy. Probability for relapse-free survival is 78% at a median follow-up of 405 days. The most frequent grade 3 and 4 adverse event was lymphopenia, which was completely reversible like most other adverse events. CONCLUSION Blinatumomab is an efficacious and well-tolerated treatment in patients with MRD-positive B-lineage ALL after intensive chemotherapy. T cells engaged by blinatumomab seem capable of eradicating chemotherapy-resistant tumor cells that otherwise cause clinical relapse.

The histone deacetylase (HDAC) inhibitor valproic acid as monotherapy or in combination with all-trans retinoic acid in patients with acute myeloid leukemia.

Valproic acid (VPA) inhibits histone deacetylase activity and, synergizing with all‐trans retinoic acid (ATRA), achieves differentiation induction of myeloid blast cells in vitro.

Deferasirox in iron-overloaded patients with transfusion-dependent myelodysplastic syndromes: Results from the large 1-year EPIC study

The prospective 1-year EPIC study enrolled 341 patients with myelodysplastic syndromes (MDS); although baseline iron burden was >2500ng/mL, approximately 50% were chelation-naïve. Overall median serum ferritin decreased significantly at 1 year (p=0.002). Decreases occurred irrespective of whether patients were chelation-naïve or previously chelated; changes were dependent on dose adjustments and ongoing iron intake. Sustained reductions in labile plasma iron were observed. Discontinuation rate (48.7%) and adverse event profile were consistent with previously reported deferasirox data in MDS. Alanine aminotransferase levels decreased significantly; change correlated significantly with reduction in serum ferritin (p<0.0001). This large dataset prospectively confirms the efficacy and well characterizes the safety profile of deferasirox in MDS.

Polymorphism of the tumour necrosis factor‐alpha and lymphotoxin‐alpha genes in chronic lymphocytic leukaemia

The neoplastic cells of CLL are able to produce TNF which is known to stimulate the proliferation of CLL cells in an autocrine and paracrine manner. Genetic polymorphism of molecules of the TNF ligand superfamily has been described and certain alleles were suspected to predispose to variant biological responses. Previously, the rare allele TNFB*1 of the TNF‐β/lymphotoxin (LT)‐α gene (NcoI, asparagine at amino acid position 26) was found to be associated with a stronger LT‐α response of PBMC in vitro.

Cerebrospinal fluid pleocytosis: pitfalls and benefits of combined analysis using cytomorphology and flow cytometry.

Cerebrospinal fluid samples with doubtful morphologic interpretation are a common problem in the workup of patients with clinical signs for leptomeningeal disease. The authors report on the combination of morphology and flow cytometry in the diagnosis of leptomeningeal disease in patients with radiological, clinical, or cytological findings suspicious for leukemia or lymphoma with spread into the cerebrospinal fluid.

Rare Phenomenon: Liver Metastases From Glioblastoma Multiforme

Introduction We report the case of a 69-year-old man who presented in our department with previously diagnosed glioblastoma multiforme (GBM). He suffered from severe frontal lobe syndrome and rapid progressive failure of the liver and died within a few days. Using ultrasound imaging of the liver, we could detect at least 10 lesions of necrotic and hemorrhagic aspect suspicious for metastases. The autopsy results confirmed massive metastasization of the liver with wide necrotic confluent parts. Also, immunohistopathologic analyses were positive for glial fibrillary acidic protein (GFAP) and S100 protein and met all the morphologic criteria for metastases of GBM. This case demonstrates that GBM can pass through the brain-blood barrier and may present as a generalized disease with poor outcome. Case Report A 69-year-old man was admitted to our department. The reason for admission was severe agitation in the context of the progression of GBM with frontal lobe participation. The frontal lobe syndrome had been known for approximately 1 month. Primary symptoms were treated with a patch of fentanyl and lorazepam orally. Because of inadequate clinical improvement, his private physician suggested hospitalization. Almost 2 years ago, we were able to detect WHO grade 4 GBM and confirm the diagnosis by histopathologic processing. The tumor was located in the left temporal lobe (Fig 1A). Because of the dimension of the tumor, resection was not completely possible (resection level R2). Subsequently, irradiation at a dose of 59.4 Gy followed the surgical intervention, which led to remission confirmed by magnetic resonance imaging (Fig 1B). One month later, the patient relapsed (Fig 1C). The next procedure was a micronester coil–navigated extirpation of the relapsed part.

Polymorphism of the tumour necrosis factor‐alpha and lymphotoxin‐alpha genes in hairy cell leukaemia

Hairy cell leukaemia (HCL) is a rare chronic B lymphoproliferative disorder which can lead to severe pancytopenia and several immunologic abnormalities. The pathogenetic role of tumour necrosis factor (TNF)‐α in HCL prompted us to study the potential contribution of functionally important genetic polymorphisms of the TNF gene cluster in a large group of patients with HCL. The TNF‐α (−308  bp) promoter/enhancer point mutation and two polymorphisms located within the first intron of the lymphotoxin (LT)‐α gene showed neither significant allelic deviation for the patient group nor, after analysis of clinical characteristics such as blood counts, stable or progressive disease or response to therapy.

Iron chelation therapy in MDS: what have we learnt recently?

Patients with myelodysplastic syndromes (MDS) who receive chronic blood transfusions for anaemia are at risk of developing iron overload, which can negatively affect organ function and survival. Evidence suggests that iron chelation therapy can restore iron balance in these patients and may improve their chances of survival. Recently, several guidelines on the management of patients with MDS have been published that address iron overload and the use of iron chelation therapy. While these guidelines differ in some specific details, they generally agree that patients with lower-risk MDS are most likely to develop iron overload and therefore benefit from iron chelation therapy. The oral iron chelator, deferasirox, has been shown to reduce serum ferritin levels and labile plasma iron in patients with MDS, and has an acceptable safety profile. Unlike other iron chelators, deferasirox also appears to inhibit the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kappaB) pathway in MDS blast cells, which may lead to additional beneficial effects.

Autocrine and Paracrine Regulation of Neoplastic Cell Growth in Hairy Cell Leukemia

Hairy cell leukemia (HCL), a rare haematological disorder of B-cell origin, mainly presents with bone marrow infiltration, haematopoietic insufficiency, and splenomegaly. In some cases, osteolytic lesions can be observed. Many of these clinical features, especially haematopoietic insufficiency and osteolytic lesions are likely to be caused by soluble factors, such as cytokines. There is evidence that these factors are produced by the malignant hairy cells themselves, suggesting a paracrine pathway. The importance of autocrine as well as paracrine growth loops in growth regulation of HCL-cells is supported by a series of excellent studies, performed within the last few years. It could be clearly shown that cytokines are involved in this autocrine and paracrine regulatory process. The most important cytokines which should be mentioned in this respect are tumor necrosis factor alpha, (TNF alpha). Interleukin-2 (IL-2), Interleukin-4 (IL-4), Interleukin-6 (IL-6) and B-cell-growth factor (BCGF). The role of other factors such as viruses and oncogenes remains rather unclear. Nevertheless, recent data suggest that the c-fms, which encodes for the macrophage colony stimulating factor (M-CSF) may be involved in the pathophysiological control of HCL growth. In this review, we summarise the important data and studies performed recently which shed light on the complex network of autocrine and paracrine growth regulation of HCL.

Myelodysplastic syndrome of donor origin subsequent to successful treatment of myeloid/NK-cell precursor leukaemia with allogeneic PBSCT: two very rare conditions in one patient

We report a 36-year-old male with myeloid/natural killer (NK)-cell precursor acute leukaemia with a complex aberrant karyotype, who was treated according to an acute-myeloid-leukaemia (AML) treatment protocol (idarubicine, cytarabine, and etoposide) followed by high-dose cytarabine consolidation and achieved complete remission. He underwent allogeneic matched unrelated donor (MUD) peripheral blood stem-cell transplantation (PBSCT) and remained in remission throughout his remaining life. Seven months posttransplantation, a myelodysplastic syndrome (MDS) with (20q−) of donor origin was diagnosed causing severe thrombocytopenia and finally leading to infection and death. This patient represents one of the few cases published achieving remission for a significant period of time after being diagnosed with myeloid/NK-cell precursor acute leukaemia, a very rare malignant disease. We conclude, despite the fatal outcome due to infection, that allogeneic PBSCT is a therapeutic option for patients with this entity. In addition, the development of a myelodysplastic syndrome of donor origin is extremely rare and only very few cases are published worldwide.