Minimal residual disease as a predictive factor for relapse after allogeneic hematopoietic stem cell transplant in adult patients with acute myeloid leukemia in first and second complete remission.

Allogeneic hematopoietic stem cell transplantation (allo-SCT) is potentially curative for patients with high-risk leukemia, but disease recurrence remains the leading cause of treatment failure. Our objective was to determine the impact of minimal residual disease (MRD) by any technique in adult patients with acute myeloid leukemia (AML) in morphologic first and second complete remission undergoing allo-SCT. Fifty nine patients were eligible for the study of 160 patients transplanted over ten years. For the MRD assessment we used multiparametric flow cytometry, cytogenetics and fluorescent in situ hybridization; 19 patients (32.2%) were identified as MRD positive. Patients with MRD had a consistently worse outcome over those without MRD, with 3-years leukemia-free survival (LFS) of 15.8% vs. 62.4% and overall survival (OS) of 17.5% vs. 62.3%. Relapse rate was significantly higher in MRD-positive patients; 3 years relapse rate in MRD-positive patients was 57.9% vs. 15.1% in MRD-negative patients. Detection of MRD in complete remission was associated with increased overall mortality (HR = 3.3; 95% CI: 1.45-7.57; p = 0.0044) and relapse (HR = 5.26; 95% CI: 2.0-14.0; p = 0.001), even after controlling for other risk factors. Our study showed that for patients in morphologic complete remission the presence of MRD predicts for significantly increased risk of relapse and reduced LFS and OS.

Myelodysplastic syndrome: An update on diagnosis and therapy.

Myelodysplastic syndromes (MDS) are a diverse group of disorders characterized by disorderly and ineffective hematopoiesis. Patients suffer morbidity from associated cytopenias that result in an increased risk of infection, transfusion-dependent anemia, and bleeding. Despite the variable risk of transformation to acute leukemia, the majority of deaths are due to bone marrow failure. No truly effective treatment exists for MDS, and therapy usually focuses on reducing or preventing complications of the disease. Identification of potential cellular and molecular targets, such as epigenetic modification, has led to novel therapeutic approaches in recent years. An increasing number of diagnostic markers, prognostic parameters, and therapeutic strategies are available and becoming widely accepted.

Myelodysplastic syndrome: an update on diagnosis and therapy.

Myelodysplastic syndromes (MDS) are a diverse group of disorders characterized by disorderly and ineffective hematopoiesis. Patients suffer morbidity from associated cytopenias that result in an increased risk of infection, transfusion-dependent anemia, and bleeding. Despite the variable risk of transformation to acute leukemia, the majority of deaths are due to bone marrow failure. No truly effective treatment exists for MDS, and therapy usually focuses on reducing or preventing complications of the disease. Identification of potential cellular and molecular targets, such as epigenetic modification, has led to novel therapeutic approaches in recent years. An increasing number of diagnostic markers, prognostic parameters, and therapeutic strategies are available and becoming widely accepted.

Rituximab as successful therapy in a patient with refractory paroxysmal cold hemoglobinuria.

BACKGROUND: Paroxysmal cold hemoglobinuria (PCH) is a rare autoimmune hemolytic anemia (AIHA) attributed to a biphasic hemolysin known as the Donath-Landsteiner (DL) antibody. It is most commonly encountered as an acute transient AIHA after a viral infection in children; the disease resolves after cessation of the infection. The rarest form of PCH is a chronic form in adults that is not (nowadays) associated with infection and is not responsive to conventional therapies. Rituximab has been found to be effective therapy in other forms of AIHA, such as cold agglutinin syndrome, that are refractory to conventional therapies. We describe a case of PCH refractory to steroids that responded to rituximab therapy on two separate occasions. CASE REPORT: A 64-year-old woman with fatigue was found to be profoundly anemic with laboratory findings consistent with AIHA. She was admitted for the workup and management of her disease after she failed to respond to a course of oral steroids. Laboratory evaluation demonstrated a positive DL test suggesting PCH. She was given a course of rituximab that resulted in normalization of her hemoglobin concentration. She presented 9 months later with recurrent hemolysis. She was given another course of rituximab that again resulted in termination of hemolysis. The patient remained in remission since her last dose of rituximab 19 months previously. CONCLUSION: To our knowledge, this is the first report of an adult case of refractory PCH successfully treated with rituximab.

C/EBPdelta expression in a BCR-ABL-positive cell line induces growth arrest and myeloid differentiation.

CCAAT/enhancer-binding proteins (C/EBPs) are a family of highly conserved transcription factors that have important roles in normal myelopoiesis as well as associated with myeloid disorders. The chronic myelogenous leukemia (CML) cell lines, KCL22 and K562, express exceptionally low levels of endogenous C/EBPs and provide a good model to test the effects of C/EBPs on myeloid differentiation. To explore the possibility that C/EBPdelta can promote differentiation in BCR-ABL-positive cells, we generated stable KCL22 and K562 clones that expressed an inducible C/EBPdelta gene. C/EBPdelta expression resulted in G0/G1 proliferative arrest and a moderate increase in apoptosis of the KCL22 and the K562 cells. Within 4 days of inducing expression of C/EBPdelta, myeloid differentiation of the CML blast cells occurred as shown by morphologic changes and induction of secondary granule-specific genes. We also showed that during granulocytic differentiation of KCL22 cells, the C/EBPdelta protein was detected in immunocomplexes with both Rb and E2F1. Furthermore, expression of C/EBPdelta was associated with downregulation of c-Myc and cyclin E and upregulation of the cyclin-dependent kinase inhibitor p27(Kip1) in both the KCL22 and K562 cell lines. These results show that expression of C/EBPdelta in BCR-ABL-positive leukemic cells in blast crisis is sufficient for neutrophil differentiation and point to the therapeutic potential of ectopic induction of C/EBPdelta in the acute phase of CML.