Novella Pugliese

Advanced-stage Hodgkin Lymphoma: US/Chest Radiography for Detection of Relapse in Patients in First Complete Remission—A Randomized Trial of Routine Surveillance Imaging Procedures

PURPOSE To compare the use of fluorine 18 fluorodeoxyglucose (FDG) positron emission tomography (PET)/computed tomography (CT) with the use of a combination of ultrasonography (US) and chest radiography for systematic follow-up of patients with high-risk Hodgkin lymphoma. MATERIALS AND METHODS Institutional review board approval and informed consent were obtained. In a single center between January 2001 and December 2009, patients with advanced-stage Hodgkin lymphoma who had responded completely to first-line treatment were randomly assigned (1:1) to follow-up with either PET/CT or US/chest radiography. Follow-up included clinical and imaging procedures at 4, 8, 12, 16, 20, 24, 30, 36, 48, 60, 84, and 108 months after treatment discontinuation. When clinical and/or imaging results were positive, recurrence was confirmed histologically. The primary endpoint was to compare the sensitivity of the two follow-up imaging approaches. Secondary endpoints were their specificity, positive and negative predictive values, time to recurrence detection, radiation risks, and costs. RESULTS A total of 300 patients were randomized into the two arms. The study was closed after a median follow-up time of 60 months, with a relapse rate of 27%. Sensitivity for detection of Hodgkin lymphoma was similar for the two follow-up approaches. All of the relapses (40 of 40) were identified with FDG PET/CT (100%) and 39 of 40 relapses were identified with US/chest radiography (97.5%; P = .0001 for the equivalence test). US/chest radiography showed significantly higher specificity and positive predictive value than did PET/CT (96% [106 of 110] vs 86% [95 of 110], respectively; P = .02; and 91% [39 of 43] vs 73% [40 of 55], respectively; P = .01). Exposure to ionizing radiation was estimated to be 14.5 mSv for one PET/CT examination versus 0.1 mSv for one chest radiographic examination. Estimated cost per relapse diagnosed with routine PET/CT was 10-fold higher compared with that diagnosed with routine US/chest radiography. CONCLUSION US and chest radiography are diagnostic tools that enable effective, safe, and low-cost routine surveillance imaging for patients at high risk of Hodgkin lymphoma relapse.

Selective strong synergism of Ruxolitinib and second generation tyrosine kinase inhibitors to overcome bone marrow stroma related drug resistance in chronic myelogenous leukemia.

The IC50 of TKIs is significantly increased when BCR-ABL+ K562 cell line is cultured in stroma conditioned media produced by BM mesenchymal cells. In particular, while the Imatinib IC50 in the stromal co-cultures was well above the in vivo through levels of the drug, the IC50s of second generation TKIs were still below their through levels. Moreover, we provide a formal comparison of the synergy between first and second generation TKIs with the JAK inhibitor Ruxolitinib to overcome BM stroma related TKI resistance. Taken together, our data provide a rationale for the therapeutic combination of TKIs and Ruxolitinib with the aim to eradicate primary BCR-ABL+ cells homed in BM niches.

Pulmonary damage in Hodgkin's lymphoma patients treated with sequential chemo-radiotherapy: Predictors of radiation-induced lung injury

Abstract Background. Our aim was to define predictors of late radiation-induced lung injury (RILI) in Hodgkins lymphoma (HL) survivors treated with bleomycin-containing chemotherapy and radiotherapy. Material and methods. Eighty consecutive patients treated with chemotherapy and subsequent supradiaphragmatic radiation therapy for HL were retrospectively reviewed for symptoms and/or radiological signs of RILI. Median patient age was 26 years (range 14–55). Left, right, and total lung dosimetric parameters along with clinical, disease, and treatment-related characteristics were analyzed. Multivariate logistic regression analyses were performed. A receiver operator characteristic (ROC) curve analysis was performed to find possible cutoff values dividing patients into high- and low-risk groups. Results. Seven of 80 (9%) patients had lung disease at baseline. Four of 80 (5%) had toxicity after chemotherapy and before the beginning of radiotherapy. These patients were excluded from further evaluation. At a median time of 10 months (range 9–18), 9/69 patients (13%) developed lung radiological changes on computed tomography (CT) after treatment. Four of nine patients were diagnosed RTOG grade ≥ 2. On multivariate analyses, left-lung V30 (p = 0.004, OR = 1.108 95% CI 1.033–1.189) and total-lung V30 (p = 0.009, OR = 1.146 95% CI 1.035–1.270) resulted to be predictors of lung CT changes with a cutoff value of 16% and 15%, respectively. When only symptomatic RILI was considered a left-lung V30 cutoff value of 32% was estimated. Conclusion. Bleomycin and RT may cause lung injury in a small, but significant fraction of HL patients. Left-lung V30 predicts the risk of developing asymptomatic or symptomatic RILI after sequential chemo-radiotherapy.

Complication Probability Models for Radiation-Induced Heart Valvular Dysfunction: Do Heart-Lung Interactions Play a Role?

Purpose The purpose of this study is to compare different normal tissue complication probability (NTCP) models for predicting heart valve dysfunction (RVD) following thoracic irradiation. Methods All patients from our institutional Hodgkin lymphoma survivors database with analyzable datasets were included (n = 90). All patients were treated with three-dimensional conformal radiotherapy with a median total dose of 32 Gy. The cardiac toxicity profile was available for each patient. Heart and lung dose-volume histograms (DVHs) were extracted and both organs were considered for Lyman-Kutcher-Burman (LKB) and Relative Seriality (RS) NTCP model fitting using maximum likelihood estimation. Bootstrap refitting was used to test the robustness of the model fit. Model performance was estimated using the area under the receiver operating characteristic curve (AUC). Results Using only heart-DVHs, parameter estimates were, for the LKB model: D50 = 32.8 Gy, n = 0.16 and m = 0.67; and for the RS model: D50 = 32.4 Gy, s = 0.99 and γ = 0.42. AUC values were 0.67 for LKB and 0.66 for RS, respectively. Similar performance was obtained for models using only lung-DVHs (LKB: D50 = 33.2 Gy, n = 0.01, m = 0.19, AUC = 0.68; RS: D50 = 24.4 Gy, s = 0.99, γ = 2.12, AUC = 0.66). Bootstrap result showed that the parameter fits for lung-LKB were extremely robust. A combined heart-lung LKB model was also tested and showed a minor improvement (AUC = 0.70). However, the best performance was obtained using the previously determined multivariate regression model including maximum heart dose with increasing risk for larger heart and smaller lung volumes (AUC = 0.82). Conclusions The risk of radiation induced valvular disease cannot be modeled using NTCP models only based on heart dose-volume distribution. A predictive model with an improved performance can be obtained but requires the inclusion of heart and lung volume terms, indicating that heart-lung interactions are apparently important for this endpoint.

Viral Outcome in Patients with Occult HBV Infection or HCV-Ab Positivity Treated for Lymphoma

Hepatitis B virus infection seems to protect against steatosis and insulin resistance decreasing NAFLD. Metabolic syndrome has been associated with increased risk of disease progression to cirrhosis and liver cancer in hepatitis B. HBsAg seroclearance increased over time and it could be a confounding factor when analysing NAFLD and hepatitis B prevalence.

Pegfilgrastim in primary prophylaxis of febrile neutropenia following frontline bendamustine plus rituximab treatment in patients with indolent non-Hodgkin lymphoma: a single center, real-life experience

BackgroundIn this prospective study, the impact of granulocyte colony-stimulating factors (G-2 CSF) administered during induction treatment with bendamustine plus rituximab for indolent non- Hodgkin Llymphoma (NHL) was evaluated by comparing patients who received secondary prophylaxis with filgrastim (control group) versus. patients who received pegfilgrastim as primary prophylaxis (peg-group). The primary endpoint was the incidence rate of febrile neutropenia (FN)- related chemotherapy disruptions (regarding dose-dense and/or dose-intensity of schedule). The Ssecondary endpoint included days of hospitalization due to FN, and G-CSF-related side effects (grade ≥3 WHO toxicity criteria) in each group.MethodsOne hundred twenty-two: 122 consecutive patients, with untreated indolent NHL, were referred to our outpatient unit for remission induction immuno-chemotherapy with bendamustine-rituximab. During the first period, 61 patients received secondary prophylaxis with filgrastim, given “on demand” if ANC was <1000/mm3. During the second period, 61 patients received primary prophylaxis with pegfilgrastim in a single administration.ResultsPegfilgrastim was significantly associated with fewer incidence rate of FN-related chemotherapy disruptions (11.4% in the control group vs. 1.6% in the peg-group, p = 0.04) and fewer days of hospitalization due to FN (median number 18 days in the control group vs. 6 in the peg-group, p = 0.04). In terms of G-CSF-related extra-hematological grade III side effects, no significant difference has been found in the two groups (9.8% in the control group vs. 11.5% in the peg-group, p = 0.77). Only one patient stopped the treatment in the peg-group due to intolerance.ConclusionsIn patients with indolent NHL, in front-line treatment with bendamustine plus rituximab, primary prophylaxis with pegfilgrastim seems to reduce the incidence of chemotherapy disruptions due to FN, and the days of hospitalization. Moreover, it is well- tolerated and may increase the opportunity to maintain the planned schedule of treatment. These results make pegfilgrastim an advantageous option in most cases both in terms of cost-effectiveness and quality of life. These preliminary observations need to be validated by controlled clinical trials.

Diagnostic-driven antifungal approach in neutropenic patients at high risk for chronic disseminated candidiasis: preliminary observations on the role of 1,3-β-D-glucan antigenemia and multiphasic contrast-enhanced computed tomography

Dear Editor, Chronic disseminated candidiasis (CDC) is a critical form of invasive fungal infection (IFI) that affects mainly the liver, spleen, and, occasionally, kidneys [1]. Typical clinical, microbiological, and/or radiological manifestations have late onset, leading frequently to misdiagnosis [1, 2]. A late diagnosis leads to a delay in starting an effective antifungal therapy against Candida infection resulting in a severe morbidity and high mortality [3]. Recent studies have shown effective alternatives to traditional microbiological and radiological procedures for the diagnosis of CDC, in particular, 1,3-β-Dglucan (BDG) antigenemia and contrast-enhanced computed tomography (CE-CT) [4, 5]. The preemptive approach, based on the routine surveillance with serum BDG and hepatosplenic CE-CT, has been proposed for obtaining a reliable and early diagnosis of CDC, and for establishing a proper antifungal treatment [6]. However, guidelines give moderate evidence to support recommendation for the use of such approach in clinical practice [7]. In our institution, patients with acute leukemia at high-risk for CDC underwent diagnosticdriven approach, which was based on the identification of the clinical settings requiring intensive diagnostic efforts. Between January 2013 and December 2014, 20 of 24 consecutive patients older than 18 years with several risk factors for Candida infection (and on fluconazole prophylaxis), who underwent intensive chemotherapy or autologous stem cell transplantation (SCT), developed febrile neutropenia (FN). In the event of FN, a standard diagnostic work-up (SDWU) was performed as already reported [8]. Patients with persisting fever after 4–6 days of broad-spectrum antibiotics or patients with fever relapsing after 48 h of defervescence underwent a baseline diagnostic work-up (BDWU) including serum BDG antigenemia (Fungitell, manufacturer; Associated of Cape Cod, Inc., East Falmouth, MA). An intensive diagnostic work-up (IDWU) was performed in patients with a positive BDG test (≥ 80 pg/mL). It includedmultiphasic CE helical CT of the liver and spleen, as already described [9]. Among this series of 24 patients, we report a patient suffering from CDC, which was definitively proven by ultrasonography (US)-guided core needle cutting biopsy (CNCB) of the liver. The most important aspect, revealed by the clinical case herein described, is the crucial role of the serum BDG test and the hepatosplenic multiphasic CE helical CT for the early diagnosis of deep-seated Candida infection.

Life for patients with myelofibrosis: the physical, emotional and financial impact, collected using narrative medicine—Results from the Italian ‘Back to Life’ project

PurposeMyelofibrosis (MF) is a chronic myeloproliferative neoplasm characterised by an aggressive clinical course, with disabling symptoms and reduced survival. Patients experience a severely impaired quality of life and their families face the upheaval of daily routines and high disease-related financial costs. The aim of this study was to investigate the perceptions of Italian patients and their caregivers about living with MF and the burden of illness associated with MF.MethodsA quali-quantitative questionnaire and a prompted written narrative survey were administered to patients affected by primary or post-essential thrombocythemia/post-polycythaemia vera MF and their primary caregiver in 35 Italian haematological centres.ResultsIn total, 287 questionnaires were returned by patients and 98 by caregivers, with 215 and 62, respectively, including the narrative. At the time of diagnosis, the most commonly expressed emotional states of patients were fear, distress and anger, confirming the difficulty of this phase. A high level of emotional distress was also reported by caregivers. Along the pathway of care, the ability to cope with the disease differed according to the quality of care received. The mean cost to each patient attributable to MF was estimated as €12,466 per year, with an estimated average annual cost of loss of income of €7774 per patient and €4692 per caregiver.ConclusionsBetter understanding of the personal life of MF patients and their families could improve the relationships between health workers and patients, resulting in better focused healthcare pathways and more effective financial support to maintain patients in their social roles.

Rituximab in a risk-adapted treatment strategy gives excellent therapeutic results in nodular lymphocyte-predominant Hodgkin lymphoma

Nodular lymphocyte-predominant Hodgkin lymphoma (NLP-HL) is a rare variant of Hodgkin lymphoma, histologically characterized by prominent lymphocytic proliferation mixed with histiocytes that form at least a partially nodular pattern. Due to its rarity, this type of lymphoma still lacks consolidated and widely accepted treatment guidelines. Current first-line therapy approaches are often based on radiotherapy (RT) alone for non-bulky early-stage NLP-HL, while chemotherapy regimens [ABVD (doxorubicin, bleomycin, vinblastine, dacarbazine) or CHOP (cyclophosphamide, doxorubicin, vincristine, prednisolone)] plus RT have been widely used for the most advanced stages (Eichenauer et al, 2014; Hoppe et al, 2015). The observation that malignant lymphocytes of NLP-HL, although negative for CD15 and CD30, consistently express CD20 (Hartmann et al, 2014), provides the rationale for the inclusion of anti-CD20 antibody rituximab in the treatment of this disease as a low toxic component for replacing chemotherapy and/or RT. Therefore, the outcome and side effects of 12 consecutive patients with newly diagnosed NLP-HL, who were treated in our Institution using a risk-adapted, rituximab-based protocol, were compared with those of a historical cohort of NLPHL patients, previously treated with a conventional modality approach, i.e. chemotherapy and/or RT (Table I). The clinical features of these two groups of patients were similar(see Supplementary data), except that the rituximab group presented more sub-diaphragmatic disease (P = 0 01) and the historical cohort included more patients with bulky disease (P = 0 03), thus balancing adverse prognostic factors (see Table SI). All 24 patients showed the typical CD20 positive stain in at least 30% of tumour cells without either CD15 or CD30 reactivity (Swerdlow et al, 2008). Comparing the treatments in the two series, 9 historical patients, and no patients of the rituximab group, underwent involved-field (IF)RT; cytotoxic agent administration was spared in 42% of the patients of the rituximab group (Table I). At final restaging, 23 of the 24 patients (95 8%) were in complete remission [CR; (Cheson et al, 2007)], while one historical patient showed refractory disease and was underwent rescue therapy. Patients who received rituximab-based risk-adjusted therapy showed excellent response to the treatment and had better progression-free survival (PFS, P = 0 04) but not overall survival (OS) than those of the historical cohort (see Figure S1). Indeed, during follow-up (median 4 3 years; range, 0 5–8 2 in the whole cohort), four patients, all belonging to the historical cohort and treated with ABVD IFRT, showed refractory (n = 1) or recurrent disease (n = 3). These results confirm that NLP-HL, despite a more indolent clinical behaviour than classical HL, may show late multiple relapses after conventional therapy particularly in advanced stage patients. Therefore, there is a need for novel treatment approaches that, along with low toxicity, have an increased efficacy to improve the overall prognosis. In our more recent series of NLP-HL patients, the use of rituximab as single agent in the induction phase was restricted only to stage I and II patients without risk factors. However, in order to minimize the possibility of relapses, we prolonged the anti-CD20 antibody treatment, with eight further infusions (once every 3 months) distributed over a 2year maintenance therapy in these patients with early favourable disease. Therefore, as seen in indolent non-Hodgkin lymphoma, the use of rituximab-maintenance in early favourable NLP-HL seems to delay or avoid relapse. In the remaining patients, according to a risk-adapted treatment approach, rituximab therapy was combined with polychemotherapy, giving a total of four cycles of ABVD to patients with stages I or II disease but with ≥1 risk factors (early unfavourable) and six cycles of ABVD to those who presented with advanced stages (Fig 1). Importantly, the inclusion of rituximab in this therapeutic scheme appears to provide long-term protection from relapse when compared with the classical chemo-radiotherapy. Notably, we observed a higher rate of grade 3–4 neutropenia in the historical cohort (54%) than the rituximab group (10%; P = 0 009); non-haematological toxicity was recorded only in the historical cohort and was prevalently RT-related (4/8 thyroid disease, 2/8 lung fibrosis and 2/8 osteoarthritic degeneration). Over the study period, one patient died due to bleomycin-induced pneumonitis following the last cycle of R-ABVD. These results underscore the role of anti-CD20 antibody in NLP-HL, which provides substantial benefit to many patients, avoiding the need for RT and cytotoxic agent treatment or, at least, potentially delaying the need for both, in those with early favourable stage disease. In the recent study by Advani et al (2014), rituximab was given as single agent once per week for 4 weeks to early-stage NLPHL patients, giving an overall response rate (ORR) of 100% with a 67% CR rate. The last 16 patients also had received a maintenance phase with rituximab (MR) once per week for

The use of erythropoiesis-stimulating agents is safe and effective in the management of anaemia in myelofibrosis patients treated with ruxolitinib

Erythropoiesis‐stimulating agents (ESAs) were combined with ruxolitinib in 59 anaemic myelofibrosis patients (93% with Dynamic International Prognostic Scoring System [DIPSS] intermediate‐2/high risk; 52·5% transfusion‐dependent). Anaemia response (AR) rate was 54% and 76% of patients responded at 5 years. A further 15% displayed minor improvement in anaemia and 78% of patients reduced spleen size. Endogenous erythropoietin levels <125 u/l correlated with a higher AR rate (63% vs. 20%, P = 0·008). No thrombotic events or other toxicities occurred. Overall survival was 62% at 4 years, influenced by DIPSS and transfusion dependency. ESAs seem effective in improving anaemia in ruxruxolitinib‐treated myelofibrosis patients.