Antonietta Ferretti

Epidemiology and risk factors for invasive fungal diseases in hematopoietic stem cell transplantation.

Purpose of reviewKnowledge of the epidemiology and the risk factors of invasive fungal diseases (IFDs) in hematopoietic stem cell transplant (HSCT) recipients is a critical determinant of the prevention, diagnosis and therapeutic antifungal strategy. Transplant procedures are characterized by a continuous evolution; therefore, an update of the epidemiological findings of IFDs in HSCT populations is needed. Recent findingsIn the last few years, the incidence and the clinical risk factors of IFD, mainly in allogeneic HSCT populations, have been investigated in prospective, multicenter studies. New findings in the different types and phases of transplant may be considered for a redefinition of the level of risk of IFD after HSCT. Furthermore, recent studies have uncovered associations between hosts and/or donors genetic variants and immunological risk for IFDs, in particular invasive aspergillosis. SummaryEvolution of the transplant procedures was followed by an important change in the epidemiology and clinical risk of IFD after allogeneic HSCT. A new stratification of subpopulations according to different clinical infectious risk and genetic susceptibility may be considered to predict those patients most vulnerable to IFD and update tailored antifungal strategies.

Fludarabine, cyclophosphamide and lenalidomide in patients with relapsed/refractory chronic lymphocytic leukemia. A multicenter phase I-II GIMEMA trial.

Abstract The activity and safety of a regimen combining lenalidomide with fludarabine and cyclophosphamide (FC) was investigated in patients with relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL). Treatment consisted of six monthly courses of the FC regimen combined with 14 days of lenalidomide given at the starting dose of 2.5 mg during course 1. The maximum tolerated dose of lenalidomide was 5 mg. Forty patients were assessed for response, 66% were IGHV unmutated, 45% showed deletion 11q or 17p. The overall response and complete remission rates were 62.5% and 22.5%, respectively, the median progression-free and overall survival (OS) were 19 and 45 months, respectively. Grade 3–4 granulocytopenia was observed in 65% of cases, severe infections in 7.5%, the lenalidomide-related toxicity was mild. In conclusion, the results of this study demonstrate that low-dose lenalidomide associated with the FC schedule is an effective treatment for R/R patients with CLL, associated with an acceptable safety profile.

Splenic marginal zone lymphoma: Prognostic factors, role of watch and wait policy, and other therapeutic approaches in the rituximab era

Splenic marginal zone lymphoma (SMZL) is an indolent lymphoma in which watch and wait (W&W) approach as well as splenectomy and chemo-immunotherapy are usually recommended. The role of the different approaches in relation to risk factors was evaluated. One hundred patients with SMZL were retrospectively studied. Median age was 65 years. HCV positivity was 3.1%. The 10-year overall-survival was 95.1% (CI: 90-100%). Sixty-two asymptomatic, low tumour burden patients were submitted to W&W. A low-risk group not requiring treatment was identified. Patients requiring treatment received splenectomy (36), chemotherapy-alone (27) and rituximab ± chemotherapy (16). In multivariate analysis, negative predictors for starting treatment were female-sex, splenomegaly, ECOG ≥ 1. Patients with low IIL-Score had a better 5-year TFT (24%). The median TFT of the W&W cohort was 58.5 months; at 10 years, 17% of patients were still on W&W. Splenectomy and rituximab ± chemotherapy showed similar results, while chemotherapy alone proved inferior. This real-life single-centre study of SMZL confirmed its very good prognosis with a survival likelihood overlapping that of general population. The prognostic role of IIL-Score was confirmed. The W&W approach allowed a median PFS longer than in follicular lymphoma. Finally, our data confirm the inferiority of chemotherapy compared to splenectomy and rituximab±chemotherapy.

Very short-term lenalidomide treatment associated with durable resolution of anemia in a patient with myelodysplastic syndrome with chromosome 5q deletion.

Dear Editor, Dose–response relationship and the precise mechanism of action of lenalidomide in myelodysplastic syndromes (MDS) are still unclear, despite the remarkable response rates in patients with chromosome 5q deletion (del 5q) [1, 2]. A selective effect of lenalidomide on the hematopoietic del5q clone has been described, with inhibition of proteins critical for cell survival or stimulation of tumor suppressor genes on that region [3]. In this context, a critical role of the ribosomal protein RPS14, located in the common deleted region of del5q, has been recently reported [4]. During lenalidomide treatment, most patients usually require transient dose interruption followed by dose reduction due to early adverse events (mainly neutropenia and/or thrombocytopenia) [2]. Few case reports have shown sustained long-term RBC-transfusion independency even after short-term treatment [5–7]. Here, we report a durable response achieved in a patient with del5q MDS after only 17 days of lenalidomide treatment. A 77-year-old female was referred to our hospital in September 2006 because of progressive anemia. Our laboratory tests revealed severe macrocytic anemia (hemoglobin, Hb, 7.0 g/dL; MCV, 122 fl), moderate neutropenia (WBC, 2.42×10 L; absolute neutrophil count, ANC, 1.0× 10 L) and mild thrombocytosis (platelet count, PLT, 475×10 L). A BM examination showed trilinear severe dysplasia, 12% blasts, and del5q in all analyzed metaphases [46, XX, del(5) (q13q31)] [5, 8]. The patient was thus diagnosed with RAEB-2, intermediate-2 International Prognostic Scoring System (IPSS). Treatment with recombinant human erythropoietin (EPO-α, 80.000 IU weekly) was started in October 2006. Erythroid response was achieved in January 2007, lasting until December 2007, when a relapse of anemia with transfusional requirement occurred. In October 2008, lenalidomide 10 mg daily was started. Baseline peripheral blood evaluation revealed Hb, 9.1 g/dL; ANC, 1.5×10 L; and PLT, 658×10 L. BM smear showed persistent trilineage dysplasia, 8% blasts, and isolated del5q (RAEB-1 with intermediate-1 IPSS). After 17 days of treatment, lenalidomide was halted due to severe neutropenia (ANC, 0.39×10 L) with increased transfusion requirement, severe asthenia, nausea, gastrointestinal pain, and a skin infection requiring oral antibiotics. After 2 weeks of lenalidomide deferral, neutrophil count rapidly recovered, but the patient was hospitalized because of paroxysmal atrial fibrillation and thyrotoxic crisis. In November 2008, the patient achieved a complete hematological response (Hb, 12.3 g/dL; WBC, 4.19×10 L; ANC, 2.0×10 L; PLT, 353×10 L) without therapy, and lenalidomide was definitely discontinued at the patients request. At 3 and 6 months after lenalidomide treatment, BM examination showed persistence of moderate trilinear dysplasia without blasts. Partial cytogenetic response was documented in May 2009 (46, XX, del(5) (q13q31) [7]/ 46,XX [13]) and L. Cannella : R. Latagliata (*) :M. Breccia : I. Carmosino : G. Loglisci : P. Volpicelli :A. Ferretti :M. Santopietro : F. Vozella :C. Girmenia :G. Alimena Department of Cellular Biotechnology and Hematology, Sapienza University of Rome, Via Benevento, 6, 00161 Roma, Italy e-mail: rob.lati@libero.it

Management of elderly and unfit patients with chronic lymphocytic leukemia

ABSTRACT Introduction: About 75% of patients with chronic lymphocytic leukemia (CLL) are more than 65 years at the time of diagnosis. Treatment of the elderly remains complicated due to multiple factors, such as comorbidities, decline in functional reserve and fitness. Since chronological age by itself cannot properly predict life expectancy and treatment tolerance, an accurate assessment of the fitness status is of crucial importance for an optimal treatment choice. Areas covered: This review will discuss the most relevant aspects concerning the issues experienced in the management of elderly/unfit patients with CLL. The most frequently observed age-related toxicities, fitness assessments, supportive care measures and treatment options for elderly patients and for patients who are deemed unfit will be discussed. Literature search methodology included examination of PubMed index. Expert commentary: During the last decade, different trials focusing on elderly/unfit patients have investigated more tolerable chemoimmunotherapy schedules and, more recently, the activity and safety of chemo-free regimens. Chlorambucil combined with an anti-CD20 monoclonal antibody has shown clinical activity with a relatively good profile of toxicity. The recent introduction of the B-cell receptor antagonists, ibrutinib and idelalisib, and other targeted drugs in development (e.g. venetoclax), is broadening the therapeutic armamentarium of elderly CLL patients.

Inhibitors in Hemophilia B

Abstract Hemophilia B (HB) is an X‐linked bleeding disorder caused by deficiency of factor IX (FIX). Patients with the severe form (FIX <1%) account approximately for 30 to 45% of persons with HB and usually suffer from recurrent joint, soft‐tissue, and muscle bleeds. The availability of safe plasma‐derived and recombinant products has virtually abolished the risk of viral infections and the adoption of prophylactic regimens has attenuated the impact of hemophilic arthropathy. Therefore, the development of an inhibitor against FIX is currently the most serious complication that can still occur in the new generations of HB patients. The development of an inhibitor in HB is a rare event (1.5‐3% of all patients) but is associated with a significant morbidity, related not only to the bleeding risk but also to the frequent occurrence of allergic/anaphylactic reactions and nephrotic syndrome. Due to the relative rarity of this event, few data exist about risk factors, pathophysiology, and clinical aspects of inhibitors in HB. The induction of immune tolerance is often unsuccessful and can be otherwise affected by many complications in patients with history of allergy or anaphylaxis. Therefore, alternative therapeutic strategies and new approaches are developing. The aim of this narrative review is to discuss current knowledge about risk factors, pathophysiology, and clinical aspects of this rare but serious complication.

LDH as Predictive Parameter in Treatment-Naïve Patients Affected by Chronic Lymphocytic Leukemia with Trisomy 12

Context: Complex karyotype (CK) is associated with poor prognosis in patients with chronic lymphocytic leukemia (CLL). While mutations in TP53 have been associated with CK, overlap is not complete and the genetic landscape of patients with CLL and CK remains largely undescribed. Design: We performed targeted next generation sequencing with a SureSelect custom panel of 295 genes (Agilent Technologies, Santa Clara, CA) on bone marrow aspirate collected between March 2003 and October 2015 from 71 patients with CLL and CK and compared them to a control group of 90 patients without CK, age and sex-matched. Results: In univariable analyses (UVA), CK was associated with Rai III-IV disease (61% vs 36%, p1⁄40.002), beta-2 microglobulin (B2M) > 4 mg/L (67% vs 40%, p1⁄40.001), del(17p) by FISH (33% vs 9%, p<0.001), and presence of any gene mutation (79% vs 59%, p1⁄40.01). Among patients with CK, the most common mutations (>10% of patients) were TP53 (32%), SF3B1 (15.5%) and NOTCH1 (10%). When compared to the non-CK cohort, patients with CK showed a significantly higher prevalence of TP53 (32% vs 11%, p1⁄40.001) and SETD2 mutations (6% vs 0%, p1⁄40.04). On multivariable analysis (MVA), B2M >4 mg/L (odds ratio [OR] 2.5, 95% confidence interval [CI] 1.2-5.3; p1⁄40.02) and del(17p) by FISH (OR 3.6, 95% CI 1.2-10.4, p1⁄40.02) were independently associated with CK. After a median follow-up of 17 months (range, 1-141 months), among the 71 patients with CLL and CK, 29 (41%) died, and median overall survival (OS) was 56 months (range, 1-141 months). Factors significantly associated with shorter OS in UVA were unmutated IGHV (32 months vs 132 months, p1⁄40.02), mutated NOTCH1 (17 months vs 60 months, p1⁄40.02) and mutated TP53 (32 months vs 62 months, p1⁄40.05). In MVA, unmutated IGHV (hazard ratio [HR] 5.2, 95% CI 1.2-22.7; p1⁄40.03) and mutated NOTCH1 (HR 5.8, 95% CI 1.6-20.4; p1⁄40.007) maintained their association with shorter survival. Conclusions: This is the first study specifically dissecting the genomic landscape of patients with CLL and CK. Further investigation of the role of mutated SETD2 and mutated NOTCH1 may improve the management and treatment of this very high-risk population.

Repeated successful use of eltrombopag in chronic primary immune thrombocytopenia: description of an intriguing case

Thrombopoietin receptor agonists (TPO‐RAs) are used as effective alternative treatments in ITP patients unresponsive to first‐/second‐line therapies. TPO‐RAs can also be used to normalize platelet count to safely perform invasive procedures and chemotherapy, in case of malignancies. In few responsive patients, TPO‐RAs can be suspended maintaining a sustained response.

Is pneumatosis intestinalis a contraindication to allogeneic hemopoietic stem cell transplantation

Pneumatosis intestinalis (PI) has been described as a possible complication after allogeneic stem cell transplantation (HSCT) due to graft-versus-host disease (GVHD) or infections. So far, no patient with a pre-existent PI who underwent HSCT has been reported. We describe the case of a patient with Alk-negative anaplastic large B-cell lymphoma (DLBCL anaplastic) and PI who successfully received a HSCT from an unrelated donor without complications. This case suggests that this gastrointestinal condition should not be considered an absolute contraindication for an allotransplant procedure. Correspondence to: Antonietta Ferretti, MD; Haematology, “Sapienza” University; Via Benevento, 6; Rome, Italy; Tel: +39 0649974777; E-mail: ferretti@bce.uniroma1.it

Reappraising the timing of transplant for indolent non-Hodgkin lymphomas

ABSTRACT Introduction: Indolent non-Hodgkin lymphomas (iNHL) remain incurable with standard approaches. The timing of autologous stem cell transplant (ASCT) is changing following the introduction of new drugs that can potentially defer the transplant, improved reduced intensity conditioning (RIC) and haploidentical allogeneic SCT (allo-SCT). Areas covered: The most relevant aspects concerning the role of hematopoietic stem cell transplantation in the management of iNHL are discussed. Literature search methodology included examination of PubMed index and meeting presentations. Expert commentary: ASCT is not currently employed as consolidation in first-line, being reserved to patients with refractory/relapsed disease. The curative potential of graft-versus-lymphoma (GVL) after RIC allo-SCT could be particularly beneficial in patients with iNHL relapsing after ASCT. This scenario could be modified in the near future by better definition of high-risk patients at diagnosis, by the improvement of minimal residual disease (MRD) evaluation and by the introduction of new drugs in the therapeutic algorithm.