Splenic rupture following lenograstim in post-autologous stem cell transplantation treated with emergency open splenectomy: a case report and literature review.

Granulocyte-colony stimulating factors (G-CSFs) are the cornerstone of peripheral blood stem cell mobilization and apheresis. However, splenic rupture following G-CSF treatment represents a serious and potentially fatal adverse event. Here, we report the case of a patient in their late 50s with severe pancytopenia post-autologous stem cell transplantation reinfusion suffering from splenic rupture after treatment with lenograstim. We also reviewed the literature describing cases of splenic rupture during G-CSF administration.

C-Reactive Protein Monitoring and Clinical Presentation of Fever as Predictive Factors of Prolonged Febrile Neutropenia and Blood Culture Positivity after Autologous Hematopoietic Stem Cell Transplantation-Single-Center Real-Life Experience.

BACKGROUND: Febrile neutropenia (FN) is a medical emergency that requires urgent evaluation, timely administration of empiric broad-spectrum antibiotics and careful monitoring in order to optimize the patient's outcome, especially in the setting of both allogeneic and autologous hematopoietic stem cell transplant (ASCT). METHODS: In this real-life retrospective study, a total of 49 consecutive episodes of FN were evaluated in 40 adult patients affected by either multiple myeloma (thirty-eight) or lymphoma (eleven), following ASCT, with nine patients having fever in both of the tandem transplantations. RESULTS: Febrile neutropenia occurred a median of 7 days from ASCT. Median duration of FN was 2 days, with 25% of population that had fever for at least four days. Ten patients had at least one fever spike superior to 39 °C, while the median number of daily fever spikes was two. Twenty patients had positive blood cultures with XDR germs, namely Pseudomonas aeruginosa and Klebsiella pneumoniae, present in seven cases. ROC analysis of peak C-reactive protein (CRP) values was conducted based on blood culture positivity and a value of 12 mg/dL resulted significant. Onset of prolonged fever with a duration greater than 3 days was associated with the presence of both a peak number of three or more daily fever spikes (p = 0.02) and a body temperature greater than 39 °C (p = 0.04) based on odds ratio (OR). Blood culture positivity and peak CRP values greater than 12 mg/dL were also associated with prolonged fever duration, p = 0.04, and p = 0.03, respectively. The probability of blood culture positivity was also greater in association with fever greater than 39 °C (p = 0.04). Furthermore, peak CRP values below the cut-off showed less probability of positive blood culture (p = 0.02). CONCLUSIONS: In our study, clinical characteristics of fever along with peak CRP levels were associated with a higher probability of both prolonged fever duration and positive blood culture, needing extended antibiotic therapy.

Combination of Interleukin-6, C-Reactive Protein and Procalcitonin Values as Predictive Index of Sepsis in Course of Fever Episode in Adult Haematological Patients: Observational and Statistical Study.

Haematological patients represent a vulnerable population to opportunistic infections, mainly due to the disease itself and chemotherapy-induced neutropenia. The level of immune suppression strongly increases the importance of timely antibiotic treatment in order to prevent sepsis-related mortality. During the initial fever episode, serum biomarkers are usually used to estimate the probability of blood stream infection prior to the results of microbial diagnosis. A new serum biomarker combination study on a febrile haematological population, including C-reactive protein (CRP), interleukin-6 (IL-6) and procalcitonin (PCT), is proposed in order to improve their predictive accuracy. In our prospective study, CRP, IL-6 and PCT were evaluated in 34 immunosuppressed haematological patients immediately after the onset of 51 fever episodes, either during the course of standard chemotherapy or high-dose chemotherapy and autologous stem cell transplant. The fever episodes were divided into documented infections and fever alone. Receiver operating characteristic analysis (ROC) was performed for each biomarker and a combination of all three biomarkers (multiROC) to define a new predictive index. Significant differences were evidenced between the two groups (documented infection and no infection) for both PCT and IL-6 (p = 0.03 and p = 0.035, respectively), but none for CRP (p = 0.1). The composite parameter is more reliable than any single biomarker alone, with an area under the curve (AUC) of 79% and with high sensitivity and specificity. IL-6 gave the closest response compared to the composite index. Composite parameters of serum biomarkers could be used for an early diagnosis of infection at fever onset in haematological patients.

Low content of clonogenic progenitors on day+18 is associated with acute graft-versus-host disease and predicts transplant-related mortality.

A marrow reaction associated with acute-graft-versus-host disease (a-GVHD) has been demonstrated in experimental models; its existence in human transplantation is controversial. The aim of the present study was to investigate whether clonogenic marrow precursors are an early marker for a-GVHD and transplant-related mortality (TRM). We prospectively studied 133 patients for colony-forming units-granulocyte-monocyte (CFU-GM) at day +18/+19 posttransplantation. CFU-GM frequency below the 25th percentile was predictive of an acute GVHD score I°-IV° when evaluated in multivariate logistic regression analysis (odds ratio = 13.551, 95% confidence interval [CI]: 1.583-116.031, p = 0.01). In the group with a clonogenic frequency below the 25th percentile, the cumulative incidence of GVHD grades II-IV was significantly more frequent with respect to the group with a frequency greater than the 25th percentile, 86% versus 54% (Gray test: p = 0.02). In multivariate Cox proportional analysis, a CFU-GM frequency below the 25th percentile at day +18 was associated with reduced overall survival (OS) (hazard ratio = 1.778, 95% CI: 1.022-3.093, p = 0.04). Patients with a frequency of CFU-GM greater than the 25th percentile had increased TRM with respect to patients with a clonogenic cell frequency greater than the 25th percentile (33.5% vs. 13.0%, p = 0.01). Patients were divided based on median content of viable CD34+ cells, and measurement of viable CD34+ cells was predictive for OS (p = 0.005) and TRM (p = 0.003). A weak correlation was observed between CFU-GM frequency in marrow at day +18 and levels of IL-2 receptor (IL-2R) in plasma (r = -0.226, p = 0.03). We conclude that marrow progenitor cell counts, on day +18 may be a useful marker for identifying patients at risk for severe a-GVHD, TRM, and inferior survival.

Plerixafor on-demand in association with low-dose cyclophosphamide and G-CSF in the mobilization of patients with multiple myeloma: High effectiveness, low toxicity, and affordable cost.

In CD34+ cells mobilization of patients with multiple myeloma (MM), the use of Cyclophosphamide (CTX) at a dose of 2 g/m2 has low efficacy although also lower toxicity. The suboptimal mobilizing effect of low-dose CTX, however, may be overcome by plerixafor (PLX) on demand. We conducted a prospective multicenter study in 138 patients with MM to evaluate CTX 2 g/m2 in association with granulocyte-colony stimulating factor (G-CSF) and on-demand PLX. We compared results with a historical group of MM patients (n = 138) mobilized using CTX at a dose of 4 g/m2. CD34+ cells greater than 2 × 106/kg in max three aphereses were harvested in 98.6% of patients in the on-demand PLX study group while in 84.0% in the historical group, (p = 0.0001). In the on-demand-PLX study group, a successful harvest greater than 5 × 106/kg in max three aphereses was observed in 85.5% of patients versus 62.3% of patients in the historical control group, (p=0.0001). In the on-demand-PLX study group, 4.3% (6/138) of patients had febrile complications. Salvage mobilization in the on-demand PLX study group was 1.4%. In conclusions, on-demand PLX + CTX 2 g/m2 + G-CSF 10 µg/kg has higher efficacy and lower toxicity compared with CTX 4 g/m2 + G-CSF. An analysis of costs is presented.

Preliminary Results of a Combined Score Based on sIL2-Rα and TIM-3 Levels Assayed Early After Hematopoietic Transplantation.

Assays of cytokines in the plasma at the onset of graft-vs. -host disease (GVHD) can predict disease severity and treatment-related mortality (TRM); however, the optimal time during which cytokines should be tested and the specific panel of cytokines with the highest predictive ability remain unknown. We chose a predefined time point, 18 days after hematopoietic stem cell transplantation (HSCT), to measure the levels of six cytokines in the plasma: soluble interleukin-2 receptor alpha (sIL2-Rα), T-cell immunoglobulin domain and mucin domain-3 (TIM-3), suppression of tumorigenicity-2 (ST-2), intercellular adhesion molecule (ICAM-1), interferon-gamma (IFN-γ), and interleukin-6 (IL-6). The study included 95 patients, who underwent allogeneic hematopoietic transplantation at our institution. Plasma levels of sIL2-Rα and TIM-3, measured as continuous data, had predictive value for overall survival (sIL2-Rα, p = 0.002; TIM-3, p = 0.0007), while TRM could be predicted by sIL2-Rα (p = 0.0005), IFN-gamma (p = 0.01), and IL-6 (p = 0.0001). No cytokine was associated with the risk of relapse. Patients were categorized into groups, according to cytokine thresholds determined by receiver operating characteristic curve analysis (sIL2-Rα ≤ or > 8,100 pg/ml; TIM-3 ≤ or > 950 pg/ml) and multivariate analysis was conducted. High levels of both TIM-3 and sIL2-Rα were significant predictors of poor survival [TIM-3 > 950 pg/ml: hazard ratio (HR) = 6.214 (95% CI 1.939-19.910), p = 0.002 and sIL2-Rα > 8.100 pg/ml: HR = 2.644 (95% CI 1.308-5.347), p = 0.006]. Using these cutoff thresholds, we constructed a composite scoring system that could distinguish three different groups of patients with varying rates of TRM: high risk, 41.7%; intermediate risk, 10.8%; and low risk, 7.1% (Gray's test: p = 0.001). If confirmed in a validation cohort, this composite scoring system could be used to guide the modulation of post-transplant immune suppressive therapy.

Antitumor activity of bortezomib alone and in combination with TRAIL in human acute myeloid leukemia.

Acute myeloid leukemia (AML) is a malignant disease characterized by abnormal proliferation of clonal precursor cells. Although different strategies have been adopted to obtain complete remission, the disease actually progresses in about 60-70% of patients. Bortezomib has been used in multiple myeloma and other lymphoid malignancies because of its antitumor activity. Here we examined the sensitivity of bone marrow cells from AML patients (34 patients: 25 newly diagnosed, 4 relapsed, 5 refractory) to bortezomib alone or in combination with TRAIL, a member of the TNF family that induces apoptosis in tumor cells while sparing normal cells. Bortezomib induced cell death in blasts from each patient sample. The cytotoxic effect was dose- and time-dependent (concentration from 0.001 to 10 microM for 24 and 48 h) and was associated with a downregulation of Bcl-xL and Mcl-1, an upregulation of TRAIL-R1, TRAIL-R2, p21, activation of executioner caspases and a loss of the mitochondrial membrane potential. Moreover, low doses of bortezomib primed TRAIL-resistant AML cells for enhanced TRAIL-mediated killing. These results suggest that a combination of proteasome inhibitors and TRAIL could be effective for treating AML patients, even patients who are refractory to conventional chemotherapy.

Acute promyelocytic leukemia during pregnancy: report of 3 cases.

Acute promyelocytic leukemia (APL) is characterized by onset at a young age and a life-threatening hemorrhagic diathesis, which is attributed to a disseminated intravascular coagulation (DIC)-like coagulopathy. The discovery of all-trans-retinoic acid has changed the course of APL treatment by reducing the onset of DIC and inducing a complete and durable remission in more than 90% of patients. The occurrence of APL during pregnancy is not a frequent event, but the management of these patients raises many therapeutic and ethical dilemmas and requires a careful clinical case evaluation of fetal and maternal risk, coagulation status, the parents' wishes, and therapeutic options. Here we describe 3 patients with APL diagnosed during pregnancy. Clinical data and the therapeutic approaches are presented. In the discussion, we analyze clinical decisions and therapeutic options and compare our cases with those found in the literature.

Pleuric presentation of extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue: a case report and a review of the literature.

A primary pleural marginal zone B cell lymphoma of mucosa-associated lymphoid tissue (MALT) is a very rare eventuality. Here, we report a rare case of MALT lymphoma arising in the pleura and update the literature on this topic. A 74-year-old female was hospitalized for persistent cough and weakness. A chest radiograph and total-body CT scan showed only large right-sided pleural effusion, and the coexistence of pleural thickening. Video-assisted thoracoscopic exploration and a talc pleurodesis were performed and microscopic and immunohistochemical findings showed that the tumor was a pleural MALT lymphoma. The patient received immunotherapy with Rituximab and obtained a good response that lasted 2 years. To the best of our knowledge, only seven cases of primary pleural MALT lymphoma have been documented until recently, mostly from Japan with a mean age for all patients of 60.5 years. The pathogenesis of MALT lymphomas remains unclear, although a possible chronic antigenic stimulation by microbial pathogens and/or autoantigens has been hypothesized. Surgical resection was performed in most cases, and some patients received postoperative chemotherapy or immunotherapy. The clinicopathologic characteristics and management of this extremely rare disease are also discussed.