Retrospective Multicenter Study of Extracorporeal Photopheresis in Steroid-Refractory Acute and Chronic Graft-versus-Host Disease.

Extracorporeal photopheresis (ECP) is an established treatment strategy in steroid-refractory graft-versus-host disease (GVHD). This study's main objective was to analyze the clinical response and impact of ECP therapy in steroid dose reduction. A retrospective observational series of 113 patients from 7 transplantation centers was analyzed. Sixty-five patients (58%) had acute GVHD (aGVHD), and 48 (42%) had chronic GVHD (cGVHD). All ECP procedures were performed with the off-line system. The median number of procedures until achievement of initial response was 3 for both patients with aGVHD and those with cGVHD. ECP was the second-line therapy in 48% of the aGVHD cases and in 50% of the cGVHD cases. 71% of the cases of aGVHD were grade III-IV, and 69% of the cases of cGVHD were severe. The overall response rate on day 28 was 53% (complete response [CR] rate, 45%) in the patients with aGVHD and 67% (CR, 23%) in those with cGVHD. Skin was the most frequently involved organ, with a response rate of 58% (CR, 49%) in the patients with aGVHD and 69% (CR 29%) in those with cGVHD. At the end of ECP treatment, 60% of patients treated for aGVHD who responded were able to stop steroid therapy, with a median dose reduction of 100%. Significant differences in overall survival were observed for patients responding to ECP with aGVHD (hazard ratio [HR], 4.3; P < .001) and with cGVHD (HR, 4.8; P = .003). Our data indicate that ECP is a valid therapeutic alternative in patients with steroid-refractory aGVHD and cGVHD, permitting significant steroid dosage reductions.

Associations between gender, disease features and symptom burden in patients with myeloproliferative neoplasms: an analysis by the MPN QOL International Working Group.

The myeloproliferative neoplasms, including polycythemia vera, essential thrombocythemia and myelofibrosis, are distinguished by their debilitating symptom profiles, life-threatening complications and profound impact on quality of life. The role gender plays in the symptomatology of myeloproliferative neoplasms remains under-investigated. In this study we evaluated how gender relates to patients' characteristics, disease complications and overall symptom expression. A total of 2,006 patients (polycythemia vera=711, essential thrombocythemia=830, myelofibrosis=460, unknown=5) were prospectively evaluated, with patients completing the Myeloproliferative Neoplasm-Symptom Assessment Form and Brief Fatigue Inventory Patient Reported Outcome tools. Information on the individual patients' characteristics, disease complications and laboratory data was collected. Consistent with known literature, most female patients were more likely to have essential thrombocythemia (48.6% versus 33.0%; P<0.001) and most male patients were more likely to have polycythemia vera (41.8% versus 30.3%; P<0.001). The rate of thrombocytopenia was higher among males than females (13.9% versus 8.2%; P<0.001) and males also had greater red-blood cell transfusion requirements (7.3% versus 4.9%; P=0.02) with shorter mean disease duration (6.4 versus 7.2 years, P=0.03). Despite there being no statistical differences in risk scores, receipt of most therapies or prior complications (hemorrhage, thrombosis), females had more severe and more frequent symptoms for most individual symptoms, along with overall total symptom score (22.8 versus 20.3; P<0.001). Females had particularly high scores for abdominal-related symptoms (abdominal pain/discomfort) and microvascular symptoms (headache, fatigue, insomnia, concentration difficulties, dizziness; all P<0.01). Despite complaining of more severe symptom burden, females had similar quality of life scores to those of males. The results of this study suggest that gender contributes to the heterogeneity of myeloproliferative neoplasms by influencing phenotypic profiles and symptom expression.

Distinct clustering of symptomatic burden among myeloproliferative neoplasm patients: retrospective assessment in 1470 patients.

Symptom burden in myeloproliferative neoplasms (MPNs) is heterogeneous even among patients within the same MPN diagnosis. Using cluster analysis from prospectively gathered symptom burden data in 1470 international patients with essential thrombocythemia (ET), polycythemia vera (PV), or myelofibrosis (MF), we assessed for the presence of clusters and relationship to disease features and prognosis. In MF (4 clusters identified), clusters significantly differed by Dynamic International Prognostic Scoring System (DIPSS) risk (P < .001), leukopenia (P = .009), thrombocytopenia (P < .001), and spleen size (P = .02). Although an association existed between clusters and DIPSS risk, high symptom burden was noted in some low and intermediate-1-risk MF patients. In PV (5 clusters identified), total symptom score increased across clusters (P < .001), but clusters did not significantly differ by PV risk or the risk assessment variable of age. Among ET patients (5 clusters identified), clusters differed by gender (P = .04), anemia (P = .01), and prior hemorrhage (P = .047). Total symptom score increased across clusters (P < .001), but clusters did not significantly differ by International Prognostic Score for ET risk including the risk assessment variables. Significant symptom heterogeneity exists within each MPN subtype, sometimes independent of disease features or prognosis.

Acral erythema worsened by intravenous infusions of cyclosporin.

Acral erythema is a frequent cutaneous reaction related to chemotherapy. A patient presented herein developed acral erythema related to cytosine arabinoside treatment and then graft versus host disease (GVHD). Subsequently, worsening of palmar erythema and pain occurred with intravenous cyclosporin infusions.

Public Cord Blood Banks as a source of starting material for clinical grade HLA-homozygous induced pluripotent stem cells.

BACKGROUND: The increasing number of clinical trials for induced pluripotent stem cell (iPSC)-derived cell therapy products makes the production on clinical grade iPSC more and more relevant and necessary. Cord blood banks are an ideal source of young, HLA-typed and virus screened starting material to produce HLA-homozygous iPSC lines for wide immune-compatibility allogenic cell therapy approaches. The production of such clinical grade iPSC lines (haplolines) involves particular attention to all steps since donor informed consent, cell procurement and a GMP-compliant cell isolation process. METHODS: Homozygous cord blood units were identified and quality verified before recontacting donors for informed consent. CD34+ cells were purified from the mononuclear fraction isolated in a cell processor, by magnetic microbeads labelling and separation columns. RESULTS: We obtained a median recovery of 20.0% of the collected pre-freezing CD34+, with a final product median viability of 99.1% and median purity of 83.5% of the post-thawed purified CD34+ population. CONCLUSIONS: Here we describe our own experience, from unit selection and donor reconsenting, in generating a CD34+ cell product as a starting material to produce HLA-homozygous iPSC following a cost-effective and clinical grade-compliant procedure. These CD34+ cells are the basis for the Spanish bank of haplolines envisioned to serve as a source of cell products for clinical research and therapy.

Therapeutic plasma exchange for myasthenia gravis, Guillain-Barre syndrome, and other immune-mediated neurological diseases, over a 40-year experience.

BACKGROUND: Therapeutic plasma exchange (TPE) was first used in neurology in the 1980s for myasthenia gravis (MG) and Guillain-Barré syndrome (GBS). Indications have since grown. Fear of complications with this treatment modality limit its use. RESEARCH DESIGN & METHODS: A study of patients undergoing TPE for neurological diseases (1981-2020) in a University Hospital in Madrid, Spain. Clinical indications, complications, procedure number, apheresis technique and replacement fluids were prospectively recorded and retrospectively analyzed. Historical trends were studied. RESULTS: 159 patients (48.69 ±18.15 years, 54.3% females) underwent TPE using central-venous catheter and replacement fluid albumin. We performed 1207 procedures over 189 cycles (6.4 ±3.8 procedures/cycle). Most patients underwent TPE for category I-II indications, mainly GBS and MG (77.7%). Complication rate was low (3.9% procedures), mostly hypotensive/vasovagal reactions (55.3%) and vascular access-related complications (38.3%). Most were mild-moderate (92.9%), permitting TPE completion, and somewhat more frequent during the first procedure (38.3%) and after periods of little TPE use. GBS patients were more prone to complications than MG patients (6.5% vs. 1.2%,p<0.001) mainly hypotensive/vasovagal reactions (3.7% vs. 1.0%,p=0.008). CONCLUSIONS: TPE is well-tolerated with low complication rate (<4% procedures), mainly hypotensive/vasovagal reactions. Patients with GBS seem more prone to them than MG patients. Acquaintance with this technique seems necessary.

Late reactivation of resolved hepatitis B virus infection: an increasing complication post rituximab-based regimens treatment?

Reactivation of hepatitis B infection is an increasing problem for patients with lymphoma, even in resolved infections, who were treated with rituximab-based regimens. Our cases point out the need of prolonged prophylaxis in HBsAg-negative patients due to the high risk of developing fatal reactivation.

Symptom burden profile in myelofibrosis patients with thrombocytopenia: Lessons and unmet needs.

Myelofibrosis is a myeloproliferative neoplasm associated with progressive cytopenias and high symptom burden. MF patients with thrombocytopenia have poor prognosis but the presence of thrombocytopenia frequently precludes the use of JAK2 inhibitors. In this study, we assessed quality of life and symptom burden in 418 MF patients with (n=89) and without (n=329) thrombocytopenia using prospective data from the MPN-QOL study group database, including the Myeloproliferative Neoplasm Symptom Assessment Form (MPN-SAF) and Total Symptom Score (MPN10). Thrombocytopenia, defined as platelet count <100×109/L (moderate 51-100×109/L; severe ≤50×109/L), was associated with anemia (76% vs. 45%, p<0.001), leukopenia (29% vs. 11%, p<0.001), and need for red blood cell transfusion (35% vs. 19%, p=0.002). Thrombocytopenic patients had more fatigue, early satiety, inactivity, dizziness, sad mood, cough, night sweats, itching, fever, and weight loss; total symptom scores were also higher (33 vs. 24, p<0.001). Patients with severe thrombocytopenia were more likely to have anemia (86% vs. 67%, p=0.04), leukopenia (40% vs. 20%, p=0.04), and transfusion requirements (51% vs. 20%, p=0.002) but few differences in symptoms when compared to patients with moderate thrombocytopenia. These results suggest that MF patients with thrombocytopenia experience greater symptomatic burden than MF patients without thrombocytopenia and may benefit from additional therapies.

PET/CT in lymphoma: prospective study of enhanced full-dose PET/CT versus unenhanced low-dose PET/CT.

UNLABELLED: PET/CT combines functional and morphologic data and increases diagnostic accuracy in a variety of malignancies. This study prospectively compares the agreement between contrast-enhanced full-dose PET/CT and unenhanced low-dose PET/CT in lesion detection and initial staging of Hodgkin's disease and non-Hodgkin's lymphoma. METHODS: Forty-seven biopsy-proven lymphoma patients underwent a 18F-FDG PET/CT study that included unenhanced low-dose CT and enhanced full-dose CT for initial staging. Patients who had undergone previous diagnostic CT for initial staging were excluded. For every patient, each modality of PET/CT images was evaluated by either of 2 pairs of readers, with each pair comprising 1 experienced radiologist and 1 experienced nuclear physician. While evaluating one of the 2 types of PET/CT, the readers were unaware of the results of the other type. Lesion detection, number of sites affected in each anatomic region, and disease stage were assessed. Agreement between techniques was determined by the kappa-statistic, and discordances were studied by the McNemar test. Clinical, analytic, histopathologic, diagnostic CT, and PET data; data from other imaging techniques; and follow-up data constituted the reference standard. RESULTS: For region-based analysis, no significant differences were found between unenhanced low-dose PET/CT and contrast-enhanced full-dose PET/CT, although full-dose PET/CT showed fewer indeterminate findings and a higher number of extranodal sites affected than did low-dose PET/CT. Agreement between the 2 types of PET/CT was almost perfect for disease stage (kappa = 0.92; P < 0.001). CONCLUSION: Our study showed a good correlation between unenhanced low-dose PET/CT and contrast-enhanced full-dose PET/CT for lymph node and extranodal disease in lymphomas, suggesting that unenhanced low-dose PET/CT might suffice in most patients as the only imaging technique for the initial staging of lymphomas, reserving diagnostic CT for selected cases.

Positron emission tomography/computed tomography in the management of Hodgkin's disease and non-Hodgkin's lymphoma.

The incidence of Hodgkin's disease (HD) and Non-Hodgkin's lymphoma (NHL) is around 8% of all malignancies. Fortunately, HD and NHL are among the few malignancies that are potentially curable with current existing treatment modalities, even in advanced or recurrent disease. Accurate staging, early therapy monitoring, and posttreatment evaluation of lymphomas are important for optimum management of these patients. We reviewed the imaging findings of patients with histologically proved lymphoma who underwent staging positron emission tomography/computed tomography (PET/CT), early monitoring therapy PET/CT (after 3 cycles of chemotherapy), and posttreatment PET/CT. PET/CT imaging findings are shown. Utility of PET/CT in recognizing false-positive and false-negative cases of CT and PET alone is addressed. Pitfalls and diagnostic difficulties are analyzed. PET/CT is a new imaging technology that improves the evaluation of lymphoma. This review will help the reader to better understand the imaging findings and applications of PET/CT in the management of lymphoma.

Symptomatic Profiles of Patients With Polycythemia Vera: Implications of Inadequately Controlled Disease.

PURPOSE: Polycythemia vera (PV) is a myeloproliferative neoplasm (MPN) associated with disabling symptoms and a heightened risk of life-threatening complications. Recent studies have demonstrated the effectiveness of JAK inhibitor therapy in patients with PV patients who have a history of prior hydroxyurea (HU) use (including resistance or intolerance), phlebotomy requirements, and palpable splenomegaly. We aimed to determine how these features contribute alone and in aggregate to the PV symptom burden. PATIENTS AND METHODS: Through prospective evaluation of 1,334 patients with PV who had characterized symptom burden, we assessed patient demographics, laboratory data, and the presence of splenomegaly by disease feature (ie, known HU use, known phlebotomy requirements, splenomegaly). RESULTS: The presence of each feature in itself is associated with a moderately high symptom burden (MPN symptom assessment form [SAF] total symptom score [TSS] range, 27.7 to 29.2) that persists independent of PV risk category. In addition, symptoms incrementally increase in severity with the addition of other features. Patients with PV who had all three features (PV-HUPS) faced the highest total score (MPN-SAF TSS, 32.5) but had similar individual symptom scores to patients with known HU use (PV-HU), known phlebotomy (PV-P), and splenomegaly (PV-S). CONCLUSION: The results of this study suggest that patients with PV who have any one of the features in question (known HU use, known phlebotomy, or splenomegaly) have significant PV-associated symptoms. Furthermore, it demonstrates that many PV symptoms remain severe independent of the number of features present.

[Clinical significance of the quantification of JAK2V617F allele burden in classical Ph-negative myeloproliferative neoplasms]. / Impacto clínico de la cuantificación de la carga mutacional de JAK2V617F en pacientes con neoplasias mieloproliferativas crónicas Ph negativas clásicas.

BACKGROUND AND OBJECTIVES: Our study has investigated the presence of the mutation V617F in the JAK2 gene in patients diagnosed with chronic myeloproliferative neoplasms (MPNs). Furthermore, we determined if JAK2 (V617F) allelic burden associates with a specific clinical phenotype and if its quantification can be used as a marker to predict outcome and complications in patients with MPNs. PATIENTS AND METHODS: A retrospective observational study was conducted from 1987 to 2011 in the Haematology Department of La Paz University Hospital. The allelic burden was measured in 114 patients diagnosed with MPNs: 39 polycythemia vera (PV) patients, 71 essential thrombocythaemia patients and 6 primary myelofibrosis patients. The quantitative real-time polymerase chain reaction (qRT-PCR) technology was used to determinate the percentage of mutated alleles in peripheral blood neutrophils. Patients were divided in 2 groups: heterozygous if the result was≤50% of the tested cells, and homozygous if it was positive in>50% of the cells. RESULTS: Sixty-nine patients were positive for the JAK2 mutation and 45 were negative. Among those positive, the mutation was associated with arterial thrombosis. In addition, we demonstrate in the homozygous group that the V617F mutation is associated to PV, advanced age, leukocytosis, marked haematopoiesis and splenomegaly. CONCLUSIONS: The presence of V617F mutation is associated with a higher incidence of thrombosis, leukocytosis and splenomegaly. The identification of mutation on the JAK2 gene could help in a better definition of evolution and prognostic stratification of the myeloproliferative disorders.

Myeloproliferative neoplasm (MPN) symptom assessment form total symptom score: prospective international assessment of an abbreviated symptom burden scoring system among patients with MPNs.

PURPOSE: Myeloproliferative neoplasm (MPN) symptoms are troublesome to patients, and alleviation of this burden represents a paramount treatment objective in the development of MPN-directed therapies. We aimed to assess the utility of an abbreviated symptom score for the most pertinent and representative MPN symptoms for subsequent serial use in assessing response to therapy. PATIENTS AND METHODS: The Myeloproliferative Neoplasm Symptom Assessment Form total symptom score (MPN-SAF TSS) was calculated as the mean score for 10 items from two previously validated scoring systems. Questions focus on fatigue, concentration, early satiety, inactivity, night sweats, itching, bone pain, abdominal discomfort, weight loss, and fevers. RESULTS: MPN-SAF TSS was calculable for 1,408 of 1,433 patients with MPNs who had a mean score of 21.2 (standard deviation [SD], 16.3). MPN-SAF TSS results significantly differed among MPN disease subtypes (P<.001), with a mean of 18.7 (SD, 15.3), 21.8 (SD, 16.3), and 25.3 (SD, 17.2) for patients with essential thrombocythemia, polycythemia vera, and myelofibrosis, respectively. The MPN-SAF TSS strongly correlated with overall quality of life (QOL; r=0.59; P<.001) and European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire C30 (EORTC QLQ-C30) functional scales (all P<.001 and absolute r≥0.50 except social functioning r=0.48). No significant trends were present when comparing therapy subgroups. The MPN-SAF TSS had excellent internal consistency (Cronbach's α=.83). Factor analysis identified a single underlying construct, indicating that the MPN-SAF TSS is an appropriate, unified scoring method. CONCLUSION: The MPN-SAF TSS is a concise, valid, and accurate assessment of MPN symptom burden with demonstrated clinical utility in the largest prospective MPN symptom study to date. This new prospective scoring method may be used to assess MPN symptom burden in both clinical practice and trial settings.

[Non-Hodgkin's lymphoma staging: a prospective study of the value of positron emission tomography/computed tomography (PET/CT) versus PET and CT]. / Estadificación de los linfomas no hodgkinianos: estudio prospectivo de la tomografía por emisión de positrones/tomografía computarizada (PET/TC) frente a la PET y a la TC.

BACKGROUND AND OBJECTIVE: To prospectively analyze the diagnostic accuracy of PET/CT in non-Hodgkin's lymphoma (NHL) and to evaluate the most appropriate study protocol of this technique. PATIENTS AND METHOD: Seventy-six biopsy proven NHL patients were enrolled in this prospective study for 3 years. Patients initially underwent a low-dose CT without intravenous contrast, then a PET emission scan and finally a full-dose CT with intravenous contrast. For every patient, two modalities of PET/CT images were reconstructed: a low-dose unenhanced PET/CT and a full-dose enhanced PET/CT. Each modality was evaluated by either of two pairs of readers, different for each modality. Enhanced CT and PET images were evaluated by an independent radiologist and nuclear medicine physician respectively. RESULTS: Agreement between reference standard and techniques was as follows: 52.2% of patients with enhanced CT (κ=0.458), 46% with PET (κ=0.335), 75% with low-dose unenhanced PET/CT (κ=0.664) and 76.8% with full-dose enhanced PET/CT (κ=0.679), with p<0.001. Although all techniques underestimated the stage in comparison to gold standard, the lowest percentage was for full-dose enhanced PET/CT (20.3%). CONCLUSIONS: PET/CT improved staging accuracy of NHL, being full-dose enhanced PET/CT the most accurate technique in our study.

Positron emission tomography/computed tomography: diagnostic accuracy in lymphoma.

An accurate initial staging of patients with non-Hodgkin lymphoma (NHL) and Hodgkin lymphoma (HL) is critical for the selection of an appropriate treatment. Computed tomography (CT) remains the standard imaging technique, although it is based on anatomic criteria. Positron emission tomography (PET) with 2-deoxy-2-[fluorine-18]fluoro-d-glucose (FDG) provides useful functional information but requires anatomical correlation to localise lesions accurately. We have prospectively compared the accuracy of combined PET/CT with that of CT and PET alone at initial staging in lymphoma patients. Forty-seven newly diagnosed patients were evaluated. PET/CT was superior compared with CT and PET in nodal evaluation and detection of extranodal disease. Using a staging algorithm with PET/CT resulted in the disease stage being increased in 11 of 47 patients (10 NHL and 1 HL) (McNemar test P = 0.012). Therefore, a different treatment strategy based on PET/CT findings was suggested for seven patients (14.8%). PET/CT markedly improves accuracy in the diagnostic work-up of patients with lymphoma.