Annalisa Natale

Circulating plasma cells in newly diagnosed symptomatic multiple myeloma as a possible prognostic marker for patients with standard‐risk cytogenetics

Detection of circulating plasma cells (PCs) in multiple myeloma (MM) patients is a well‐known prognostic factor. We evaluated circulating PCs by flow cytometry (FC) in 104 patients with active MM at diagnosis by gating on CD38+ CD45‐cells and examined their relationship with cytogenetic risk. Patients had an average follow‐up of 36 months. By using a receiver operating characteristics analysis, we estimated the optimal cut‐off of circulating PCs for defining poor prognosis to be 41. Patients with high‐risk cytogenetics (n = 24) had poor prognosis, independently of circulating PC levels [PC < 41 vs. PC ≥ 41: overall survival (OS) = 0% vs. OS = 17%, P = not significant (n.s.); progression‐free survival (PFS) = 0% vs. 17%, P = n.s.]. Patients with standard‐risk cytogenetics (n = 65) showed a better prognosis when associated with a lower number of circulating PCs (PC < 41 vs. PC ≥ 41: OS = 62% vs. 24%, P = 0·008; PFS = 48% vs. 21%, P = 0·001). Multivariate analysis on the subgroup with standard‐risk cytogenetics confirmed that the co‐presence of circulating PCs ≥ 41, older age, Durie‐Salmon stage >I and lack of maintenance adversely affected PFS, while OS was adversely affected only by lactate dehydrogenase, older age and lack of maintenance. Our results indicate that the quantification of circulating PCs by a simple two‐colour FC analysis can provide useful prognostic information in newly diagnosed MM patients with standard‐risk cytogenetics.

Pregnancy outcome following hematopoietic cell transplantation for thalassemia major

The aim of this study was to investigate the methods of conception and delivery, as well as the course and outcome of 42 pregnancies occurring in 15 female patients (27 pregnancies) and partners of 8 male patients (15 pregnancies) with β–thalassemia major who were successfully treated with allogeneic hematopoietic cell transplantation (HCT). Most pregnancies (n=21) were achieved with spontaneous conception in female patients. There were two miscarriages. Five pregnancies were late preterm. Delivery was vaginal in 4 cases and by caesarean section in 18. Overall, 22 term pregnancies resulted in successful deliveries of 23 neonates. Two of 23 neonates were symmetrical small for gestational age / intrauterine growth restriction. All 15 pregnancies that occurred in partners of men who received an allogeneic HCT were achieved with spontaneous conception. No miscarriage was observed. Overall, 14 term pregnancies resulted in successful deliveries of 14 live-born singletons. Delivery was vaginal in nine cases and by caesarean section in five. All infants were full-term. Many patients with β–thalassemia major who received an allogeneic HCT retained or recovered their fertility after transplant. In these patients, pregnancy has been a practical and safe possibility and usually had a favorable outcome as in the normal population.

Secondary solid cancer following hematopoietic cell transplantation in patients with thalassemia major

Hematopoietic cell transplant (HCT) recipients have a substantial risk of developing secondary solid cancers (SSCs). The aim of this retrospective study was to compare the incidence of SSC in a monocentric cohort of thalassemia major (TM) patients (n=122) who received HCT versus an hematopoietic cell donor monocentric cohort (n=122) and versus a large multicenter cohort of age- and sex-matched TM patients (n=244) who received conventional therapy. With a median follow-up of 24 years, 8 transplanted patients were diagnosed with SSC at a median of 18 years after HCT and at a median age of 33 years. Three patients died of cancer progression and 5 are living after a follow-up ranging from 10 months to 16 years after SSC diagnosis. The 30-year cumulative incidence of developing SSC was 13.24%. The occurrence of solid cancers in the hematopoietic cell donor cohort was limited to only one case for a significantly lower cumulative incidence (3.23%, P=0.02) and to 3 cases in the cohort of nontransplant patients for a significantly lower cumulative incidence (1.32%, P=0.005). This study shows that the magnitude of increased risk of SST is fourfold to sixfold for patients treated with HCT as compared with hematopoietic cell donors and nontransplant patients.

Paroxysmal Nocturnal Hemoglobinuria after Autologous Stem Cell Transplantation: Extinction of the Clone during Treatment with Eculizumab – Pathophysiological Implications of a Unique Clinical Case

The clinical and biological spectrum of paroxysmal nocturnal hemoglobinuria (PNH) is variable, ranging from classical hemolytic forms to PNH associated with aplastic anemia or other bone marrow (BM) failure syndromes. We report a previously undescribed case of PNH occurring after autologous stem cell transplantation (ASCT) in a patient affected by relapsing non-Hodgkin’s lymphoma. The intensive chemotherapy and the ASCT resulted in a contraction of the effective hematopoietic stem cell (HSC) pool and a derangement of the immune system. The delayed engraftment and the BM hypoplasia represented a favorable environment for the expansion of the pathological clone. This case is paradigmatic even for the unexpected trend of the PNH clone during treatment with the terminal complement inhibitor eculizumab; in fact, the clone reduced until undergoing unexpected extinction, i.e. the recovery of normal hematopoiesis. Eculizumab seems not to play a direct role in HSC kinetics; the clinical remission probably occurred because the environmental conditions that led to the expansion of the PNH clone were transient and disappeared.

NOTCH and Graft-Versus-Host Disease

In allogeneic hematopoietic stem cell transplantation, which is the major curative therapy for hematological malignancies, T cells play a key role in the development of graft-versus-host disease (GvHD). NOTCH pathway is a conserved signal transduction system that regulates T cell development and differentiation. The present review analyses the role of the NOTCH signaling as a new regulator of acute GvHD. NOTCH signaling could also represent a new therapeutic target for GvHD.

Hematopoietic Stem Cell Transplantation and Cardiotoxicity

Hematopoietic stem cell transplantation (HCT) is now used worldwide in the treatment of many malignant and non-malignant hematologic disorders and in the treatment of various solid tumors. Every year, many thousands of patients receive an autologous or allogeneic transplant procedure. Cardiac complications associated with HCT have been documented in several series, but the incidence of reported cardiotoxicity has varied largely among investigators, ranging from 2% to 28% probably reflecting patient selection, differences in HCT conditioning regimens and lack of universal grading system for cardiotoxic events.This chapter will focus on the cardiac complications occurring either in the early period following HCT or in the long-term phase.