Cristina Calderón-Cabrera

Role of 18F‐FDG‐PET/CT in the management of marginal zone B cell lymphoma

The use of PET in patients with marginal zone B cell lymphoma (MZL) is controversial because of variability of fluorodeoxyglucose (FDG) avidity. We analyzed 40 PET/CT in 25 consecutive patients to compare its performance with CT at staging and as a first‐line response assessment. Sensitivity of PET/CT and CT was 96 and 76%. Mean standard uptake value was 6.1, 6.9 and 3.4 (p = 0.3) in nodal, extranodal and splenic subtypes, respectively. Of 17 patients (extranodal: n = 9; nodal: n = 6; splenic subtype: n = 2) with both imaging tests available at diagnosis, 8 (47%) had more involved areas with PET/CT than with CT, 75% of which were extranodal lesions. PET/CT resulted in upstaging of five patients although treatment of only two of them was changed. Responses of 15 patients with post‐treatment PET/CT were the following: 9 negative and 6 positive of which 3 were isolated residual lesions. Progression was documented in two of these three patients. Response was also assessed by CT in 11 patients. Discrepancies were found in three: Two were in complete remission by CT while PET/CT detected localized residual disease; another patient was in partial remission by CT, whereas PET/CT showed only one positive lesion. Two of these three patients relapsed. Patients with negative post‐treatment PET/CT did not relapse. With a median follow‐up of 50 months (10–152 months), 3‐year overall survival was 100 and 80% for patients with negative and positive post‐treatment PET/CT (p = 0.2). Three‐year disease‐free survival was 86%; the negative predictive value (NPV) was 100%, and the positive predictive value (PPV) was 83.3%. Although a larger number of patients will be required to further confirm these data, we can conclude that PET/CT is a useful imaging tool for both staging and response assessment in patients with nodal and extranodal MZL as a result of its high sensitivity, NPV and PPV. Copyright

Multivariable time-dependent analysis of the impact of azacitidine in patients with lower-risk myelodysplastic syndrome and unfavorable specific lower-risk score

Scoring systems for lower-risk myelodysplastic syndrome (LR-MDS) recognize patients with a poorer than expected outcome. This study retrospectively analyzes the role of azacitidine in LR-MDS with adverse risk score and compared to an historical cohort treated with best supportive care or erythropoiesis-stimulating agents. Overall response to AZA was 40%. One and 2-year probabilities of survival were 62% and 45% for AZA vs. 25% and 11% (P=10(-4)). In a multivariable time-dependent analysis, response to AZA (CR/PR/HI) was associated with an improved survival (HR=0.234, 95% CI, 0.063-0.0863; P=0.029). Thrombocytopenia (<50 × 10(9)L(-1)) is confirmed as an adverse parameter in LR-MDS (HR=1.649, 95% CI, 1.012-2.687; P=0.045).

Optimisation of empirical antimicrobial therapy in patients with haematological malignancies and febrile neutropenia (How Long study): an open-label, randomised, controlled phase 4 trial

BACKGROUND Continuation of empirical antimicrobial therapy (EAT) for febrile neutropenia in patients with haematological malignancies until neutrophil recovery could prolong the therapy unnecessarily. We aimed to establish whether EAT discontinuation driven by a clinical approach regardless of neutrophil recovery would optimise the duration of therapy. METHODS We did an investigator-driven, superiority, open-label, randomised, controlled phase 4 clinical trial in six academic hospitals in Spain. Eligible patients were adults with haematological malignancies or haemopoietic stem-cell transplantation recipients, with high-risk febrile neutropenia without aetiological diagnosis. An independent, computer-generated randomisation sequence was used to randomly enrol patients (1:1) to the experimental or control group. Investigators were masked to assignment only before randomisation. EAT based on an antipseudomonal β-lactam drug as monotherapy (ceftazidime or cefepime, meropenem or imipenem, or piperacillin-tazobactam) or as combination therapy (with an aminoglycoside, fluoroquinolone, or glycopeptide) was started according to local protocols and following international guidelines and recommendations. For the experimental group, EAT was withdrawn after 72 h or more of apyrexia plus clinical recovery; for the control group, treatment was withdrawn when the neutrophil count was also 0·5 × 109 cells per L or higher. The primary efficacy endpoint was the number of EAT-free days. Primary analyses were done in the intention-to-treat population. Efficacy and safety analyses were done in the intention-to-treat population and the per-protocol population. This trial is registered with ClinicalTrials.gov, number NCT01581333. FINDINGS Between April 10, 2012, and May 31, 2016, 157 episodes among 709 patients assessed for eligibility were included in analyses. 78 patients were randomly assigned to the experimental group and 79 to the control group. The mean number of EAT-free days was significantly higher in the experimental group than in the control group (16·1 [SD 6·3] vs 13·6 [7·2], absolute difference -2·4 [95% CI -4·6 to -0·3]; p=0·026). 636 adverse events were reported (341 in the experimental group vs 295 in the control group; p=0·057) and most (580 [91%]; 323 in the experimental group vs 257 in the control group) were considered mild or moderate (grade 1-2). The most common adverse events in the experimental versus the control group were mucositis (28 [36%] of 78 patients vs 20 [25%] of 79 patients), diarrhoea (23 [29%] of 78 vs 24 [30%] of 79), and nausea and vomiting (20 [26%] of 78 vs 22 [28%] of 79). 56 severe adverse events were reported, 18 in the experimental group and 38 in the control group. One patient died in the experimental group (from hepatic veno-occlusive disease after an allogeneic haemopoietic stem-cell transplantation) and three died in the control group (one from multiorgan failure, one from invasive pulmonary aspergillosis, and one from a post-chemotherapy intestinal perforation). INTERPRETATION In high-risk patients with haematological malignancies and febrile neutropenia, EAT can be discontinued after 72 h of apyrexia and clinical recovery irrespective of their neutrophil count. This clinical approach reduces unnecessary exposure to antimicrobials and it is safe. FUNDING Instituto de Salud Carlos III, Spanish Ministry of Economy (PI11/02674).

Intermediate doses of cytarabine plus granulocyte–colony‐stimulating factor as an effective and safe regimen for hematopoietic stem cell collection in lymphoma patients with prior mobilization failure

High‐dose chemotherapy supported by autologous stem cell transplantation (ASCT) is an effective treatment for patients with lymphomas. However, failure to reach the minimum threshold of hematopoietic stem cells to proceed to ASCT may occur, even with the most effective strategies currently available.

Evaluation of Parameters Related to the Probability of Leukemic Progression in Patients With Lower-Risk Myelodysplastic Syndrome

Background: The prognosis of patients with lower‐risk myelodysplastic syndrome (LR‐MDS) is very heterogeneous. In addition to survival estimates, identification of factors related to the probability of leukemic progression might help prognosis assessment. Patients and Methods: The present study is a retrospective analysis of 409 patients with primary LR‐MDS. The probability of leukemic progression was estimated in the competing risk framework by the cumulative incidence method considering death without acute myeloid leukemia (AML) as a competing event. Results: Sixty‐six patients (16.1%) progressed to AML. The following covariates influenced the probability of leukemic progression in a multivariate competing risk regression model: intermediate karyotype versus diploid or chromosome 5 deletion, 5% to 9% bone marrow blast percentage, platelet count <50 × 10e9/L and age younger than 75 years. Conclusion: According to these, a predictive model is proposed, which categorizes patients with different probability of leukemic progression (P < .001). Validation of these results might help prognostic refinement of patients with LR‐MDS. Micro‐Abstract Several prognostic factors such as intermediate karyotype, presence of 5% to 9% bone marrow blasts, and platelet count <50 × 10e9/L are related to the probability of leukemic progression in a cohort of patients with lower‐risk myelodysplastic syndrome.

Allocation to matched-related or unrelated donor results in similar clinical outcomes without increased risk of failure to proceed to transplant among patients with acute myeloid leukemia: a retrospective analysis from the time of transplant approval

Clinical outcomes after allogeneic hematopoietic stem cell transplantation (allo-SCT) from unrelated donors (URDs) approach those of matched related donor (MRD) transplants in patients with acute myeloid leukemia (AML). Yet, available data fail to account for differences in pretransplantation outcomes between these donor selection strategies. In this regard, URD allo-HSCT is associated with longer waiting times to transplantation, potentially resulting in higher probabilities of failure to reach transplant. We retrospectively analyzed 108 AML patients accepted for first allo-HSCT from the time of approval to proceed to transplant. Fifty-eight (54%) patients were initially allocated to MRD, while URD search was initiated in 50 (46%) patients. Time to transplant was longer in patients allocated to a URD when compared with patients assigned to an MRD (median 142 days versus 100 days; p < .001). Forty-three of 58 (74%) patients in the MRD group and 35 of 50 (70%) patients in the URD group underwent transplantation (odds ratio [OR], 1.22; p = .63). Advanced disease status at the time of allo-HSCT approval was the only predictor of failure to reach transplantation in the multivariate analysis (OR, 4.78; p = .001). Disease progression was the most common cause of failure to reach allo-HSCT (66.7%) in both the MRD and URD groups. With a median follow-up from transplantation of 14.5 (interquartile range, 5 to 29) months, the 2-year estimate of overall survival (OS) from allo-HSCT was 46% in the MRD group and 57% in the URD group (p = .54). There were no differences in OS according to donor type allocation in the multivariate analysis (hazard ratio, 1.01; p = .83). When including patients from the time of transplant approval, 2-year OS was 39% in the MRD group versus 42% in the URD group. Our study suggests that allocation of AML patients to URDs may result in comparable clinical outcomes to MRD assignment without a significant increase in the risk of failure to reach transplant.

The incorporation of comorbidities in the prognostication of patients with lower-risk myelodysplastic syndrome*

Abstract Chronic medical diseases, evaluated by several comorbidities indexes have been reported to influence on overall survival in patients with myelodysplastic syndrome (MDS). However, these studies included patients with lower and higher-risk disease by IPSS. This study retrospectively evaluates the role of comorbidities (evaluated by the MDS comorbidity index; MDS-CI) together with clinical parameters in a series of 232 patients with LR-MDS (defined as either an IPSS score of low/intermediate-1 and favorable cytogenetic categories by IPSS-R). In multivariate analysis, together with age >75 years, diabetes requiring therapy and hemoglobin <10 g/dL; the incorporation of comorbidities by the MDS-CI (HR = 2.5; p< 0.0001) were independently associated to the probability of nonleukemic death (NLD). The combination of these variables allowed development of a model, which categorizes patients in three different groups with significantly different probability of NLD overtime (p< 0.001). This integrated score confirms the importance of comorbidities at diagnosis of patients with LR-MDS.

Bone marrow cellular cannibalism by medulloblastoma

Cellular cannibalism consists on the internalization of a cell into another of the same lineage. Internalized cells can maintain unaltered form (emperipolesis), suffer from degenerative passive changes, or be digested when the receptor cell is phagocytic (phagocytosis). A six-year-old girl started with endocranial hypertension due to IV ventricle tumor complicated with obstructive hydrocephalus. Tumor resection and placement of a ventriculoperitoneal shunt were accomplished. Histological diagnosis was established for large cell/anaplastic medulloblastoma (Image 1, panel 1a,b), WHO grade IV, belonging to high risk no Wnt/SHH group, probably group 3, according to international consensus [1]. Image 1. Panel 1: Histological brain section. H&E stain, 4003 (a). The inset shows complex cannibalism (wrapping o cannibalism) (b). Panel 2: Bone marrow aspirate. MGG stain, 1,0003. Classical morphological features of cannibalism phenomenon in various stages: approximation (a); gradual penetration (b–e), and complete internalization (f). Panel 3: Bone marrow aspirate. MGG stain, 1,0003. One malignant cell is internalizing into another cell and this complex is engulfed by another cell (a–c). One cell internalizing into two cells at a the same time (d–e), and in other area, two cells were seen internalizing into one another (f). Panel 4: Bone marrow aspirate. MGG stain, 1,0003. Three erythrocytes are internalized by a malignant cell (a), two erithrocytes are internalized by one malignant cell, and this complex is internalized by another cell (b). Erythroblast internalization (c).

Severe hemophagocytosis syndrome: macrophage cannibalism

A 69-yr-old man presented with abdominal pain, fever for up to 10 days, and pancytopenia (leukocytes 3.87 9 10/L, neutrophils 1 9 10/L, hemoglobin 88 g/L, mean corpuscular volume 93 fL, mean corpuscular hemoglobin 32 pg and platelets 22 9 10/L). Coagulation tests revealed low level of fibrinogen (1.1 g/L). Among biochemical data, the patient presented GGT 86 IU/L, total bilirubin 1.55 mg/dL, direct bilirubin 0.95 mg/dL, LDH 475 IU/L, and ferritin of 7698 lg/L. Triglycerides were normal. Infections such as CMV, EBV, HIV, HSV, VVZ, BHV, or CHV PCR were ruled out and infections such as parvovirus, brucella, coxiella, mycobacteria, leishmania, or parasite test were also discarded. Assays to rule out autoimmunity were also negative. Splenomegaly of 20 cm, hepathomegaly and subcentimetric paratracheal and retroperitoneal lymphadenopathies, over 1 cm in subcarinal, celiac trunk, portocaval area, and iliac lymph nodes, were observed in TAC. There were no findings suggesting malignancy in PET/CT. Bone marrow aspirate was hypercellular, with an adequate global hematopoiesis, highlighting the presence of 16% of pleomorphic and atypical macrophages, with numerous signs of activation and no evidence of malignancy (Fig. 1A). Histiocytes were large, with abnormal nuclear lobulations or kidney-shaped nucleus with peripheral displacement due to the expansion of the centrosome area and frequent big intracytoplasmic vacuoles (Fig. 1B). The most prominent finding was that 10% of these dysplastic macrophages were engulfing other cells such as erythrocytes, erythroblasts, granulocytes, and platelets, as a cannibalism phenomenon. In the images, hemophagocytosis of multiple cells was observed (Fig. 1C) as well as selective macrophage cannibalism of one (Fig. 1D), two (Fig. 1E) or three histiocytes (Fig. 1F). Cytochemical reaction of alpha-naphthyl acetate esterase was intense in histiocytic population (Fig. 1G). Bone marrow karyotype was 46,XY[20]. Bone marrow biopsy, with nearly 100% of cellularity, showed an outstanding macrophage expansion: amounts of large hystiocitic cells with partially eosinophilic cytoplasm and lobulated nucleus being observed macrophages with abundant phagocytosis of formed elements. Immunohistochemical study showed the following phenotype CD68+/ S100+/CD1a /CD43 /MPX /CD117 /CD34 /CD30 (Fig. 1H). EBV, latent viral proteins LMP-1 and EBVencoded small RNA (EBER) were not detected on paraffin sections. Those areas of the bone marrow which were not infiltrated by this cellularity, showed adequate representation of the three lineages without dysplastic features or apparent blast cells. The presence of fever, pancytopenia, splenomegaly, hyperferritinemia, hypofibrinogenemia and hemophagocytosis without evidence of malignancy define the hemophagocytic syndrome (SHF), classified as idiopathic in the absence of demonstrable etiological factors. Steroid treatment was started without changes in cytopenias or cytologic findings. Thus, etoposide and cyclosporine were added, again without response. During the following month, the patient required blood transfusions and suffered a septic shock due to klebsiella pneumoniae with successful outcome after empirical antibiotic and supportive care. However, there was no response to administered chemotherapy, with a progressive clinical worsening and he finally died due to acute renal failure. Cannibalism is the phenomenon in which a cell internalizes or phagocytes another of the same lineage. In the present case, we emphasize the prevalent feature of macrophage cannibalism observed in bone marrow. To our knowledge, there is no data related to macrophages engulfing other macrophages in HS in the reviewed literature. We consider that this phenomenon may reveal an aggressive disease behavior. Hemophagocitic Syndrome (HS), an uncommon, severe and potentially life-threatening disease, bases its diagnosis in the fulfillment of HLH (Hemophagocytic lymphohistiocytosis) – 2004 protocol. Bone marrow has variable cellularity, approximately one-third being hypercellular. Hemophagocitosis criteria are contemplated as a histological finding although percentages of histiocytes and hemophagocitosis have not yet been defined.