Chiara Pagani

P. aeruginosa bloodstream infections among hematological patients: an old or new question?

Pseudomonas aeruginosa is a well-known cause of severe and potentially life-threatening infections among hematological patients. A prospective epidemiological surveillance program ongoing at our Hematology Unit revealed an increase over time of P. aeruginosa bloodstream infections (BSI). Their impact on outcome and antibiotic susceptibility was analyzed. BSI which consecutively occurred at our institution during a 70-month period were evaluated and correlated with type of pathogen, status of underlying disease, neutropenia, previous antibiotic therapy, resistance to antibiotics, and outcome. During the observation period, 441 BSI were recorded. Frequency of Gram-negative BSI was higher than that of other pathogens (57.3%). Overall, 66 P. aeruginosa BSI were recorded; 22 out of 66 were multiresistant (MR P. aeruginosa). Thirty-day mortality for all BSI was 11.3%; it was 27.3% for P. aeruginosa BSI and 36.4% for MR P. aeruginosa. At multivariate analysis, only active hematological disease and P. aeruginosa BSI were associated to an increased risk of death. For MR P. aeruginosa, BSI mortality was 83.3% vs. 18.8% when empiric therapy included or not an antibiotic with in vitro activity against P. aeruginosa (p = 0.011). Together with active disease, the emergence of P. aeruginosa BSI, particularly if multiresistant, was responsible for an increased risk of death among hematological patients at our institution. In this scenario, reconsidering the type of combination antibiotic therapy to be used as empiric treatment of neutropenic fever was worthwhile.

High cure rates in Burkitt lymphoma and leukemia: a Northern Italy Leukemia Group study of the German short intensive rituximab-chemotherapy program

We evaluate the long-term results of a prospective clinical study enrolling more than 100 adult patients with Burkitt lymphoma/leukemia. Depending on extent of disease, treatment consisted of six to eight rituximab infusions and four to six courses of intensive chemotherapy (attenuated in patients aged >55 years) with high-dose methotrexate, fractionated ifosfamide/cyclophosphamide, other drugs in rotation, and intrathecal chemoprophylaxis. One-hundred five patients were treated (median age 47 years, range 17–78 years); 48% had Burkitt leukemia, 25% were older than 60 years, 37% had an Eastern Cooperative Oncology Group performance score >1, and 14% were positive for human immunodeficiency virus. The complete response rate and 3-year overall and disease-free survival rates were 79%, 67% and 75%, respectively, ranging from 100% to 45% for survival (P=0.000) and from 100% to 60% for disease-free survival (P=0.01) in patients with low, intermediate and high adapted International Prognostic Index scores. In multivariate analysis, only age (≤ versus >60 years) and performance status (0–1 versus >1) retained prognostic significance, identifying three risk groups with overall and disease-free survival probabilities of 88% and 87.5%, 57% and 70.5%, 20% and 28.5% (P=0.0000 and P=0.0001), respectively. The relapse rate was only 7% in patients treated with an intercycle interval ≤25 days. This regimen achieved 100% curability in patients with low adapted International Prognostic Index scores (21% of total), and very close to 90% in patients aged ≤60 years with performance score 0–1 (48% of total). Rapid diagnosis of Burkitt lymphoma/leukemia with prompt referral of patients to prevent clinical deterioration, and careful supervision of treatment without chemotherapy delay can achieve outstanding therapeutic results. ClinicalTrials.gov ID, NCT01290120

Postremission sequential monitoring of minimal residual disease by WT1 Q-PCR and multiparametric flow cytometry assessment predicts relapse and may help to address risk-adapted therapy in acute myeloid leukemia patients

Risk stratification in acute myeloid leukemia (AML) patients using prognostic parameters at diagnosis is effective, but may be significantly improved by the use of on treatment parameters which better define the actual sensitivity to therapy in the single patient. Minimal residual disease (MRD) monitoring has been demonstrated crucial for the identification of AML patients at high risk of relapse, but the best method and timing of MRD detection are still discussed. Thus, we retrospectively analyzed 104 newly diagnosed AML patients, consecutively treated and monitored by quantitative polymerase chain reactions (Q‐PCR) on WT1 and by multiparametric flow cytometry (MFC) on leukemia‐associated immunophenotypes (LAIPs) at baseline, after induction, after 1st consolidation and after 1st intensification. By multivariate analysis, the factors independently associated with adverse relapse‐free survival (RFS) were: bone marrow (BM)‐WT1 ≥ 121/104 ABL copies (P = 0.02) and LAIP ≥ 0.2% (P = 0.0001) (after 1st consolidation) (RFS at the median follow up of 12.5 months: 51% vs. 82% [P < 0.0001] and 57% vs. 81%, respectively [P = 0.0003]) and PB‐WT1 ≥ 16/104 ABL copies (P = 0.0001) (after 1st intensification) (RFS 43% vs. 95% [P < 0.0001]) Our data confirm the benefits of sequential MRD monitoring with both Q‐PCR and MFC. If confirmed by further prospective trials, they may significantly improve the possibility of a risk‐adapted, postinduction therapy of AML.

Peripheral Blood WT1 Expression Predicts Relapse in AML Patients Undergoing Allogeneic Stem Cell Transplantation

To evaluate if WT1 expression may predict relapse after allo-SCT, we analyzed WT1 levels on peripheral blood (PB) and bone marrow (BM) before and after allo-SCT in 24 AML patients with WT1 overexpression at diagnosis. Five copies of WT1/ABL × 104 from PB were identified as the threshold value that correlated with relapse after allo-SCT. The same correlation was not identified when WT1 expression was assessed from bone marrow (BM). Eight out of 11 (73%) patients with a pre-allo-SCT PB-WT1 ≥ 5 and 4/13 (31%) patients with a pre-allo-SCT PB-WT1 < 5 relapsed, respectively (P = 0.04). The incidence of relapse was higher in patients with PB-WT1 ≥ 5 measured after allo-SCT, at the 3rd (56% versus 38%; P = 0.43) and at the 6th month (71% versus 20%; P = 0.03). Patients with pretransplant PB-WT1 < 5 had significantly better 2-year OS and LFS than patients with a PB-WT1 ≥ 5 (81% versus 0% and 63% versus 20%) (P = 0.02). Our data suggest the usefulness of WT1 monitoring from PB to predict the relapse in allotransplanted AML patients and to modulate the intensity of conditioning and/or the posttransplant immunosuppression in an attempt to reduce the posttransplant relapse risk.

Peri-operative complications and hematologic improvement after first-line splenectomy for splenic marginal zone lymphoma

Giacomo Pata, Enrico Damiani, Michele Bartoli, Stefano Solari, Antonella Anastasia, Chiara Pagani, Alessandra Tucci & Fulvio Ragni Department of Medical & Surgical Sciences, 2nd Division of General Surgery, Brescia Civic Hospital, Brescia, Italy, Department of Medical & Surgical Sciences, 2nd Division of General Surgery, University of Brescia School of Medicine, Brescia, Italy, Division of Hematology, Brescia Civic Hospital, Brescia, Italy, and Division of Hematology, University of Brescia School of Medicine, Brescia, Italy

Metabolic behavior and prognostic value of early and end of treatment 18F-FDG PET/CT in adult Burkitt’s lymphoma: the role of Deauville and IHP criteria

Abstract Burkitt’s lymphoma is a lymphoma with unclear metabolic behavior at 18F-FDG-PET/CT and no validated criteria in treatment evaluation and prediction of outcome exist. Sixty-five patients were retrospectively included: all underwent baseline 18F-FDG-PET/CT, 56 interim PET/CT (iPET/CT) and 54 end of treatment PET/CT (eotPET/CT) after chemotherapy. Interim and eotPET/CT results were visually interpreted according to the criteria of the IHP and Deauville-five-point-scale. Results were correlated with PFS and OS to assess and to compare the predictive value of iPET and eotPET according to each criterion. All baseline PET/CT showed increased 18F-FDG uptake in nodal and extranodal lesions. The median PFS and OS were 44.6 and 48.2 months with 3-year and 5-year PFS of 76% and 62% and 3-year and 5-year OS of 71% and 57%, respectively. EotPET/CT results using DC and IHP significantly correlate with OS and PFS; while iPET/CT did not correlated with OS and PFS.

Post-remission intensive treatment after induction chemotherapy is feasible in selected elderly patients with acute myeloid leukemia and age ≥75 years: a retrospective analysis of the Rete Ematologica Lombarda.

response was 2 months (range, 1–8 months). The median proportion of bone marrow involvement with lymphomplasmacytic lymphoma (LPL) at the time of initiation of therapy was 80% (range, 40–90%). The median proportion at the end of therapy was 10% (range, 0–90%). The median time to progression (TTP) for the entire cohort was 9.7 months (range, 1–44 months; Fig. 1). The median time to progression for the four patients who were previously untreated was 18.6 months (range, 5–37 months). The median DOR for responders was 7.3 months (range, 1–43 months; Fig. 2). Grade 3–4 toxicities that required dose modifications/delays or interruptions included neuropathy (26%), cytopenias (20%), bacteremia (7%), rituximab reactions (7%), and atrial fibrillation (7%). One patient (7%) discontinued therapy due to toxicity with a G3 E. coli bacteremia after cycle 1 of therapy. This data demonstrate that this regimen is highly effective in WM even in patients who cannot tolerate or cannot receive rituximab. New therapeutic options such as ibrutinib or everolimus maybe used more frequently in patients with WM in the near future. However, these agents do not always induce a significant bone marrow response in comparison to the IgM response observed in the serum [7,8]. However, the significant bone marrow response in many patients with CyBorD can make it an attractive option for achieving complete remissions in patients who do not achieve adequate bone marrow responses with other agents. In addition, in the era of highly expensive combinations of chemotherapeutic agents, the combination of CyBorD may provide a less expensive and highly effective alternative that can be used more broadly in many developing countries with high responses. As with other retrospective studies, ours has many limitations including a small number of patients, selection bias, and different dosing schemas within this cohort. Despite this, it provides preliminary evidence for a highly effective regimen for WM that should be further validated in larger prospective trials. HOURY LEBLEBJIAN, KIMBERLY NOONAN, CLAUDIA PABA-PRADA, STEVEN P. TREON, JORGE J. CASTILLO,* AND IRENE M. GHOBRIAL* Harvard Medical School, Dana-Farber Cancer Institute, Boston, Massachusetts Conflict of interest: IMG is on advisory Board for Novartis and Millennium. J.J.C. and I.M.G. are co-senior authors and contributed equally to this work. Contract grant sponsors: Kirsch Lab, Heje fellowship. *Correspondence to: Irene M. Ghobrial, MD, Medical Oncology, Dana-Farber Cancer Institute, 450 Brookline Av, Boston, MA 02115. E-mail: irene_ghobrial@dfci.harvard.edu or Jorge Castillo, MD, Medical Oncology, Dana-Farber Cancer Institute, 450 Brookline Av, Boston, MA 02115. E-mail: JorgeJ_castillo@dfci.harvard.edu Received for publication: 10 February 2015; Accepted: 17 February 2015 Published online: 19 February 2015 in Wiley Online Library (wileyonlinelibrary.com) DOI: 10.1002/ajh.23985

Secondary acute myeloid leukaemia in elderly patients: Patient's fitness criteria and ELN prognostic stratification can be applied to guide treatment decisions. An analysis of 280 patients by the network rete ematologica lombarda (REL)

KI (P< .005) (Figure 1B). The BCL-2 inhibitor venetoclax may represent another therapeutic option after KI withdrawal, especially in case of CLL progression. Preliminary data of a phase 2 study showed an estimated 12-month PFS of 80% for patients previously treated with either ibrutinib or idelalisib, with 45% of patients achieving MRD negativity in the peripheral blood, and one patient achieving bone marrow negative MRD. As a conclusion, our data suggest that the use of an alternative KI after first KI discontinuation because of adverse events may be a reasonable option for CLL patients. The outcome is significantly worse for patients progressing while treated by kinase inhibitor, and venetoclax represents a better alternative treatment in this particular setting.

Still a role for surgery as first-line therapy of splenic marginal zone lymphoma? RESULTS of a prospective observational study.

AIM Assessment of hematologic improvement, survival and peri-operative morbidity after first-line splenectomy for splenic marginal zone lymphoma (SMZL). METHODS Forty-three patients undergoing open splenectomy were prospectively analyzed. Perioperative clinical course, overall and progression-free survival (OS-PFS) were evaluated. Risk factors analyzed were gender, age, ASA-grade, ECOG performance status, presence of B-symptoms, body mass index, steroidal treatment, serum albumin concentration, IIL-score, operative time, spleen size and weight. RESULTS The median follow-up was 31 months (IQR 15-76; range 24-154). Anemia and thrombocytopenia resolved in 80% of patients at 6 months; in 60% at 2 years. The 5-year and 10-year PFS were 35% and 13% respectively, with a median of 35 months (shorter in patients with ECOG performance status ≥2 and B-symptoms). Nineteen cases (44.2%) had a progression of disease within 2 years. Of these, 14 (32.6%) received adjuvant chemotherapy (mainly R-FC or R-CVP). Progression was attributed to high-grade B lymphoma in 7 (16.3%) patients. The median time between diagnosis and progression to aggressive lymphoma was 25.5 months (range 18.8-81.8). The median time to next treatment was 83.5 months (95% CI 49-118). The 5-year and 10-year OS were 75% and 53% respectively. Mortality was due to disease progression and histological transformation in high-grade B lymphoma in 50% of cases, myelodisplastic syndrome in 15%, recurrence of hemolytic anemia in 15%, Hodgkin lymphoma in 7% and to infections (mainly pulmonary) in the remaining 13% of cases. Post-operative morbidity was 2.3% (1 patient with grade-3 complication). Overall grade ≥2 complication rate was 32.5% (mainly hemorrhagic and pulmonary complications). Spleen weight was the only independent risk factor for morbidity. Mortality was nil. CONCLUSION Splenectomy is safe and effective as regards cytopenia resolution and OS, although disease progression is frequently observed at follow-up. Such results are strictly linked to accurate pre- and post-operative clinical management and optimal anesthesiologic approach.

Lenalidomide in patients with red blood cell transfusion-dependent myelodysplastic syndrome and del(5q): a single-centre “real-world” experience

“Real life” data are needed to complement published trials on the efficacy of lenalidomide in patients with myelodysplastic syndrome (MDS) and del(5q) and on the risk of inducing acute myeloid leukemia (AML) progression. Here, we present results of lenalidomide treatment in a consecutive, population-based series of 21 red blood cell (RBC) transfusion-dependent elderly patients with multiple comorbidities. Of 18 evaluable patients (median follow-up: 22 months), 17 achieved an erythroid hematologic response (HI-E) and 16 an RBC transfusion independence. Cytogenetic response (CyR) rate was 80%, median overall survival was 48 months (range 3–164), and 5-year leukemia-free survival was 84%. Three patients progressed to AML; one, with baseline TP53 mutation, achieved HI-E, partial CyR, and did not progress to AML. Eighteen patients experienced hematological adverse events. Overall, lenalidomide was very effective and well tolerated even in unselected elderly patients with multiple comorbidities and did not appear to increase the risk of AML.