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Concern has emerged about the prevalence of second cancers among patients with hairy cell leukemia (HCL) treated with purine analogs. We investigated 513 patients with HCL treated with cladribine over the last 30 years at 18 Italian centers and calculated their standardized incidence ratios (SIRs). We identified 24 patients with a second cancer diagnosed at a median time from treatment with cladribine of 59.9 months (range: 9.2–169.7 months). All patients with solid neoplasms presented with a limited-stage disease, except four cases of locally advanced cancer; multiple myeloma patients had a smoldering disease, while lymphoma patients had stage Ie and stage IV diseases. Response to therapy was complete in 19 cases; 1 patient is still receiving treatment for a relapsing bladder disease, while 2 patients progressed during treatment and died. These two patients died from unrelated causes: one from infection and one due to surgery complications. The median OS from HCL was 98.5 months (range: 38.4–409.2 months), while the median OS from second cancer was 27.6 months (range: 1–117.8 months). The SIR was 0.86 (95% CI: 0.54–1.30) for males and 1.13 (95% CI: 0.36–2.73) for females: no statistically significant differences were highlighted. We were not able to demonstrate an excess of second cancer or a significant association with the specific studied neoplasm.

Abstract Hairy cell leukemia (HCL) is a rare lymphoproliferative disease with an excellent prognosis after treatment with cladribine (2CDA), although relapse may occur during follow-up. The aim of the study is to review the efficacy, safety, long-term remission rate, and overall survival (OS) in those patients who received 2CDA as first-line treatment. We retrospectively reviewed data of HCL patients treated with 2CDA between March 1991 and May 2019 at 18 Italian Hematological centers: 513 patients were evaluable for study purpose. The median age was 54 years (range 24–88) and ECOG was 0 in 84.9% of cases. A total of 330 (64.3%) patients received 2CDA intravenously and 183 (35.7%) subcutaneously. ORR was 91.8%: CR was obtained in 335 patients (65.3%), PR in 96 (18.7%), and hematological response in 40 (7.8%) patients; in 42 (8.2%) no response was observed. Hemoglobin value (p = 0.044), frequency of circulating hairy cells (p = 0.039), recovery of absolute neutrophil count (p = 0.006), and normalization of spleen (p ≤ 0.001) were associated with CR compared to PR in univariable analysis. At a median follow-up of 6.83 years (range 0.04–28.52), the median time to relapse was 12.2 years. A significant difference in duration of response was identified between patients that obtained a CR and PR (19.4 years versus 4.8 years, p

IntroductionClassical Hodgkin Lymphoma (HL) is a lymphoproliferative disease typically diagnosed in the young. The excellent results obtained with current treatment lead to long survival with age-related complications affecting patients’ survival and quality of life. One issue affecting HL patients is infertility. This problem can be easily overcome in males with seminal liquid cryopreservation, however, in females it is more complex either in terms of the quality of the cryopreserved material or the patients’ age at diagnosis. Moreover, not all chemo- or radio-therapies have the same negative impact on fertility.The main objectives of this study was to collect epidemiological information on HL patients involved in fertility preservation counseling and to analyze the impact of ABVD (adriamycin, bleomycin, vinblastine, and dacarbazine), the standard treatment for HL, on ovarian function, hormonal levels and ovarian and uterine tissue morphologies. Patterns of fertility preservation were also reported.MethodsData were obtained from 270 female patients at HL onset who were interested in fertility counseling prior to therapy initiation. Each patient was assessed at HL diagnosis for levels of Anti-Mullerian Hormone (AMH), Follicle Stimulating Hormone (FSH), and 17β-oestradiol (17β-oe), with additional assessments at 6 and 12 months after chemotherapy. Patients were evaluated with ultrasound scans to study the number of ovarian follicles and the degree of uterine thickness at the same timepoints.ResultsThe average patient AMH level showed a statistically significant reduction at 6 months after chemotherapy (p=0.05) and by the 12 month time point returned to near pre-chemotherapy values. FSH and 17β-oe levels did not significantly vary throughout the study period. ABVD chemotherapy was associated with a significant reduction of both ovarian follicles and endometrial thickness at the 6 month time point followed by a recovery at the 12 time point in both ovaries. Different results were observed when patients changed treatment to a more intensive one.DiscussionBased on the results from the hormonal measurements and the follicle echography, it appears that the toxic effect of ABVD on fertility is transient, whereas, in contrast, more intensive therapies may potentially be more harmful and long-lasting.

Primary cutaneous CD30+ lymphoproliferative disorders include primary cutaneous anaplastic large cell lymphoma (pcALCL) and lymphomatoid papulosis. The prognosis of the disease is usually excellent but, in a minority of cases, it presents with extracutaneous involvement and aggressive behavior. The case we present—relapsed after surgical excision, immunosuppressive therapy, and conventional chemotherapy—is the first one treated with Autologous Stem Cell transplant followed by Brentuximab Vedotin consolidation, a scheme already used for high risk Hodgkin Lymphoma.

Abstract The multiple myeloma (MM) treatment has changed over the last years due to the introduction of novel drugs. Despite improvements in the MM outcome, MM remains an incurable disease. Daratumumab is a human IgGK monoclonal antibody targeting CD38 with tumor activity associated with immunomodulatory mechanism. In combination with standard of care regimens, including bortezomib (Vd) or lenalidomide (Rd), daratumumab prolonged progression‐free survival (PFS) in patients (pts) with relapsed/refractory multiple myeloma (RRMM) and in new diagnosis MM. We report the data of the MM GIMEMA Lazio group in 171 heavily treated pts who received daratumumab, lenalidomide and dexamethasone (DRd) or daratumumab, velcade and dexamethasone (DVd). The overall response rate was 80%, and the overall survival (OS) and PFS were 84% and 77%, respectively. In addition, pts treated with DRd showed a better median PFS compared to pts treated with DVd, at 12 and 24 months, respectively. The most common hematologic treatment‐emergent adverse events (TAEs) were neutropenia, thrombocytopenia, and anemia. The most common nonhematologic TAEs were peripheral sensory neuropathy and infections. Our data confirmed that DRd or DVd therapy is effective and safe in RRMM pts, and our real‐life analysis could support the physicians regarding the choice of optimal therapy in this setting of pts.

Background: The neutrophil/lymphocyte ratio (NLR) at baseline has been demonstrated to correlate with higher stages of disease and to be a prognostic factor in numerous cancers. However, its function as a prognostic factor for mycosis fungoides (MF) has not been yet clarified. Objective: Our work aimed to assess the association of the NLR with different stages of MF and to outline whether higher values of this marker are related to a more aggressive MF. Methods: We retrospectively calculated the NLRs in 302 MF patients at the moment of diagnosis. The NLR was obtained using the complete blood count values. Results: The median NLR among patients with early stage disease (low-grade IA-IB-IIA) was 1.88, while the median NLR for patients with high-grade MF (IIB-IIIA-IIIB) was 2.64. Statistical analysis showed positive associations of advanced MF stages with NLRs higher than 2.3. Conclusions: Our analysis demonstrates that the NLR represents a cheap and easily available parameter functioning as a marker for advanced MF. This might guide physicians in recognizing patients with advanced stages of disease requiring a strict follow-up or an early treatment.

In patients with follicular lymphoma (FL), therapeutic advances have led to improved survival, and within this framework, it is important to identify treatment strategies offering a better quality of life. Using (18)F-fluorodeoxyglucose positron emission tomography/computed tomography (PET/CT), in patients treated with R-CHOP-like or R-Bendamustine regimens, we assessed changes in the bone mineral density (BMD), musculoskeletal index (SMI), visceral adipose tissue (VAT), and subcutaneous adipose tissue (SAT) at disease onset and at the end of therapy. We evaluated whether the high-steroid regimen could lead to more significant radiological changes than those induced by the steroid-free regimen and whether a low BMD at disease onset is an unfavorable prognostic index. Seventy-nine patients between 60 and 80 years old with a new diagnosis of FL were included in the study. Evaluation of Delta values (pre- and post-therapy mean values) in the two immunochemotherapy regimens showed differences in radiomic parameters within the two patient cohorts. The R-CHOP-like regimen was associated with a significant reduction in BMD, an increase in SAT and VAT, and a reduction in skeletal muscle density (SMD) and SMI. Moreover, patients with high FLIPI showed a BMD below the cut-off value. This study represents the first study demonstrating a prognostic correlation between FLIPI and low BMD.

Introduction Gastric Diffuse large B‐cell lymphoma (DLBCL) is the most common extra-nodal site of lymphoma’s involvement (30%-40% of all extranodal lymphomas and 55%-65% of all gastrointestinal lymphomas). However, gastric localizations are also sometimes found in systemic DLBCL. Gastric complications such as bleeding, perforation and stenosis under chemotherapy are well documented. Methods We retrospectively analyzed 15 patients with newly diagnosed DLBCL with gastrointestinal involvement. Endoscopies were performed in these patients before and after treatment. Treatment consisted in cyclophosphamide low-dose pre-phase chemotherapy before conventional-dose chemotherapy. Results Endoscopy at staging detected ulcers in 12 patients (80%). After low-dose pre-phase chemotherapy GI ulcers healed in 91.6% of cases (1 ulcer detected). After the whole treatment (Low-dose pre-phase + chemotherapy) 9 patients (60%) achieved complete response, 4 patients (26.6%) partial response, 2 (13,3%) patients presented disease progression. The most frequent adverse event was neutropenia (73.3%); the most frequent non hematological adverse event was transaminases elevation (20%). Conclusion Cyclophosphamide low-dose pre-phase chemotherapy resulted a safe and effective way to prevent adverse events in systemic DLBCL with gastrointestinal involvement.

T-cell lymphomas and leukemias are highly heterogeneous groups of rare disorders. We report a case of a 68-year-old man patient who develops two different T-cell neoplasms (Large Granular Lymphocyte Leukemia [LGLL] in 2018 and Peripheral T-cell non-Hodgkin lymphoma not otherwise specified [PTCL-NOS] in 2019) with a previous diagnosis of B-cell marginal zone lymphoma in 2010, treated with two lines of chemo-immunotherapy. The coexistence of these different T-cell neoplasms is rarely reported in literature and, moreover, is usually described as an LGLL transformation into PTCL-NOS; differently from these examples, herein the simultaneous conditions appear to be driven by different T-cell clones. Furthermore, the PTCL-NOS had a quite unusual behaviour, with a good disease control without intensive treatment. Because of these features, it could belong to a subgroup of indolent PTCL-NOS, not yet described in the WHO classification of T-cell neoplasms, which could benefit of less aggressive treatment.

Abstract Occasionally, non‐Hodgkin lymphomas (NHL) occur simultaneously or subsequently to Hodgkin disease. We report on a case of a woman with Hodgkin lymphoma treated with ABVD, who developed 4 years later T‐cell NHL with both nodal and extranodal involvement. Brentuximab vedotin could be an effective choice in treating metachronous T‐cell NHL.

Abstract Background Human herpes virus 8 (HHV8) is the causative agent of Kaposi’s sarcoma and has been associated with an increasing number of hematologic diseases such as primary effusion lymphoma (PEL) (both classic and extracavitary form), multicentric Castleman disease and the germinotropic lymphoproliferative disorder. PEL is a rare B cell non-Hodgkin lymphoma that primarily affects immunocompromised patients; aggressive chemotherapy and antiretroviral therapy (ART) with protease inhibitors have been used, with poor results. We present a case of extracavitary PEL in an HIV-infected patient, regressed after ART initiation. Case presentation A 42-year-old male was admitted to the emergency room because of several months of malaise, fever and progressive deterioration of the general conditions. On physical examination soft non-painful subcutaneous masses were palpable at retronuchal, retroauricolar and thoracic regions. HIV serology resulted positive: HIV plasma viremia was 782,270 copies/mL, CD4 103 cells/mL. The excision of one of the masses, metabolically active at a positron emission tomography (PET-CT) scan, revealed an HHV8-related extracavitary PEL. HHV8 plasma viremia was 44,826 copies/mL. ART with tenofovir alafenamide/emtricitabine/dolutegravir was started together with ganciclovir for cytomegalovirus chorioretinitis. The progressive disappearance of the masses was seen after 6 weeks of ART, and a PET-CT scan resulted completely negative at 3 months. After 19 months of ART the patient was in remission of PEL, HIV viremia was undetectable (

The role of novel HBV markers in predicting Hepatitis B virus reactivation (HBV-R) in HBsAg-negative/anti-HBc-positive oncohaematological patients was examined. One hundred and seven HBsAg-negative/anti-HBc-positive oncohaematological patients, receiving anti-HBV prophylaxis for >18 months, were included. At baseline, all patients had undetectable HBV DNA, and 67.3% were anti-HBs positive. HBV-R occurred in 17 (15.9%) patients: 6 during and 11 after the prophylaxis period. At HBV-R, the median (IQR) HBV-DNA was 44 (27–40509) IU/mL, and the alanine aminotransferase upper limit of normal (ULN) was 44% (median (IQR): 81 (49–541) U/L). An anti-HBc > 3 cut-off index (COI) plus anti-HBs persistently/declining to p < 0.001)). The detection of highly sensitive (HS) HBsAg and/or HBV-DNA confirmed at >2 time points, also predicts HBV-R (OR (95% CI): 13.8 (3.6–52.6); 50% of positive vs. 7% of negative patients to these markers experienced HBV-R (p = 0.001)). HS-HBs and anti-HBc titration proved to be useful early markers of HBV-R. The use of these markers demonstrated that HBV-R frequently occurs in oncohaematological patients with signs of resolved HBV infection, raising issues of proper HBV-R monitoring.

Follicular lymphoma (FL) is an indolent hematological disease, often responsive to the first line of treatment, but characterized by repeated relapses. The therapeutic algorithm for relapsed/refractory FL patients comprises phosphatidylinositol 3-kinase inhibitors. Idelalisib showed anticancer activity, while inducing a significant rate of toxicities. Since the evidence in the literature on its use in normal clinical practice is scarce, a retrospective multicenter study was conducted to evaluate effectiveness and tolerability in a real-life context. Seventy-two patients with a median age at diagnosis of 57.2 years—mostly with an advanced stage (88.9%) and relapsed to the most recent therapy (79.1%)—were enrolled. The median number of prior therapies was three (20.8% refractory to the last therapy before idelalisib). With a median number of 4 months of treatment, the overall response rate was 41.7% (20.8% complete responses). Median disease-free survival and overall survival were achieved at 8.4 months and at 4 years, respectively. Forty-four percent of patients experienced at least one drug-related toxicity: 6.9% hematological ones and 43% non-hematological. The study confirmed that idelalisib has anticancer effectiveness and an acceptable safety profile in relapsed/refractory FL with unfavorable prognostic characteristics, even in the context of normal clinical practice.

Despite the recent availability of several new drugs in hemato-oncology, T-cell lymphomas are still incurable and PD-1 blockade could represent a therapeutic chance for selected patients affected by these malignancies, although further studies are required to understand the biological effects of anti-PD-1 mAbs on neoplastic T-cells and to identify biomarkers for predicting and/or monitoring patients’ response to therapy. Sezary Syndrome (SS) represents a rare and aggressive variant of cutaneous T cell lymphoma (CTCL) with a life expectancy of less than 5 years, characterized by the co-presence of neoplastic lymphocytes mainly in the blood, lymph nodes and skin. In this study we analyzed longitudinal blood samples and lesional skin biopsies of a patient concurrently affected by SS and melanoma who underwent 22 nivolumab administrations. In blood, we observed a progressive reduction of SS cell number and a raise in the percentage of normal CD4+ and CD8+ T cells and NK cells over total leukocytes. Eight weeks from the start of nivolumab, these immune cell subsets showed an increase of Ki67 proliferation index that positively correlated with their PD-1 expression. Conversely, SS cells displayed a strong reduction of Ki67 positivity despite their high PD-1 expression. On skin biopsies we observed a marked reduction of SS cells which were no more detectable at the end of therapy. We also found an increase in the percentage of normal CD4+ T cells with a concomitant decrease of that of CD8+ and CD4+ CD8+ T cells, two cell subsets that, however, acquired a cytotoxic phenotype. In summary, our study demonstrated that nivolumab marked reduced SS tumor burden and invigorated immune responses in our patient. Our data also suggest, for the first time, that Ki67 expression in circulating neoplastic and immune cell subsets, as well as an enrichment in T cells with a cytotoxic phenotype in lesional skin could be valuable markers to assess early on treatment SS patients’ response to PD-1 blockade, a therapeutic strategy under clinical investigation in CTCL (ClinicalTrials.gov NCT03385226, NCT04118868).

The introduction of agents inhibiting the BCR-associated kinases such as ibrutinib has dramatically changed treatments algorithms of chronic lymphocytic leukaemia (CLL) as well as the role of different adverse prognosticators. We evaluated the efficacy of ibrutinib as single agent, in a real-life context, on 180 patients with CLL mostly pre-treated, recruited from three independent cohorts from Italy. Patients received 420 mg oral ibrutinib once daily until progression or occurrence of unacceptable side effects. Seventy-three patients discontinued ibrutinib for progression or for adverse events. NOTCH1 mutations (M) were correlated with a reduced redistribution lymphocytosis, calculated at 3 months on ibrutinib (p=0.022). Moreover, NOTCH1 mutated patients showed inferior nodal response at 6 months on ibrutinib compared to NOTCH1 wild type patients (p

Background: although bronchoalveolar lavage (BAL) measurements of galactomannan antigen (GM) seems to be more sensitive than serum testing to detect invasive pulmonary aspergillosis (IPA), a consensus on the most appropriate diagnostic threshold of the BAL GM test is still unclear. Moreover, there is uncertainty as to whether BAL is a safe procedure in patients with hematological malignancies (HM) and thrombocytopenia (TC). Objectives: based on this background, 102 adult patients with HM and associated thrombocytopenia were retrospectively analyzed with the twin aims of 1) determining whether BAL is a safe and feasible procedure; and, 2) identifying the most appropriate threshold for GM positivity in the diagnosis of IPA. Patients/Methods: each BAL was considered as one case/patient. One hundred twelve BALs were carried out in 102 HM patients: at the time of the BAL, the median platelets count (PLTs) in all patients was 47x109/L (1-476) and 31 patients (27%) had PLTs< 20x109/L. Results: complications from the BAL were infrequent (3.5%) and mild. No bleeding was reported. The BAL GM cut off of >0.8 was associated with the best diagnostic accuracy (sensitivity 72.97% and specificity 80%). Antifungal treatment of patients with BAL GM >0.8resulted in a clinical-radiological improvement in 35/41patients (85%). Conclusions: BAL was a safe procedure also in thrombocytopenic patients, permitting an IPA diagnosis not otherwise identifiable using EORTC/MSG criteria. Our data suggest that a BAL GM value of>0.8 represents the most useful cut-off in terms of sensibility and specificity. Further prospective studies on a larger number of patients are needed to confirm these results.

Primary cutaneous anaplastic large cell lymphoma is a CD-30 positive lymphoproliferative disorder with good prognosis, usually treated with radiation therapy and surgery. Head, neck, and extremities are the most frequently involved sites. In this paper, we describe an unusual case of oral localization, recurring after skin-involving radiotherapy, successfully treated with sixteen cycles of brentuximab vedotin. This could be a more effective approach with a less detrimental toll for treating these rare disorders.

Cytomegalovirus (CMV) infection represents one of the main cause mortality after Stem Cell Transplantation. Recently, a protective effect of the T allele of rs12979860 IL28B Single Nucleotide Polymorphisms (SNPs) against CMV infection in the allogenic stem cell transplantation was suggested. We investigate whether the rs12979860 IL28B SNP and the relative rs368234815 (IFNλ4) genotype may affect the incidence of active CMV infection in Autologous stem cell transplantation (Auto-SCT) setting. The study included 99 patients who underwent to Auto-SCT. IL28 and IFNΔ4 SNPs were correlated with CMV reactivation along with other clinical and treatment parameters. CMV reactivation by CMV DNAemia was evaluated once a week until day 100 from Auto-SCT. CMV reactivation was documented in 50% (TT-ΔG/ΔG), 35% (CC-TT/TT) and 29.2% (CT-TT/ΔG) of the patients respectively. No differences in CMV copies number were recorded at reactivation between different IL28/IFNλ4 genotypes. The analysis of patients older than 60 years showed a significantly higher incidence of active CMV infection in the TT-ΔG/ΔG (83%) population with respect to CC-TT/TT (21%) and CT-TT/ΔG (40%) patients. Our data suggest a negative role of TT-ΔG/ΔG genotype in the CMV reactivation in Auto-SCT. The exposure to rituximab and the pre-infusion presence of anti CMV IgG also significantly influenced CMV reactivation.

ObjectivesIn onco-hematological diseases, the incidence of paranasal sinuses infection dramatically increase and requires a combination of medical and surgical therapy. Balloon dilatation surgery (DS) is a minimally invasive, tissue preserving procedure. The study evaluates the results of DS for rhinosinusitis in immunocompromised patients.MethodsA retrospective chart review was conducted in 110 hematologic patients with rhinosinusitis. Twenty-five patients were treated with DS technique and 85 patients with endoscopic sinus surgery (ESS). We considered the type of anesthesia and the extent of intra- and postoperative bleeding. Patients underwent Sino-Nasal Outcome Test (SNOT-20) to evaluate changes in subjective symptoms and global patient assessment (GPA) questionnaire to value patient satisfaction.ResultsLocal anesthesia was employed in 8 cases of DS and in 15 of ESS. In 50 ESS patients, an anterior nasal packing was placed and in 12 cases a repacking was necessary. In the DS group, nasal packing was required in 8 cases and in 2 cases a repacking was placed (P=0.019 and P=0.422, respectively). The SNOT-20 change score showed significant improvement of health status in both groups. However the DS group showed a major improvement in 3 voices: need to blow nose, runny nose, and facial pain/pressure. The 3-month follow-up GPA questionnaire showed an higher satisfaction of DS group.ConclusionBalloon DS represents a potentially low aggressive treatment and appears to be relatively safe and effective in onco-hematologic patients. All these remarks may lead the surgeon to consider a larger number of candidates for surgical procedure.

Unlike allogeneic transplant, autologous stem cell transplantation (ASCT) represents a procedure with a low-risk of cytomegalovirus (CMV) symptomatic reactivation-infection/end-organ disease (CMV complications) and invasive fungal disease (IFD). However, novel drugs for the treatment of lymphoproliferative malignancies could cause an increase of such opportunistic infections, even after ASCT. To the best of our knowledge, there are no published data demonstrating an association between CMV and IFD in the autologous setting, while this association has been widely reported in allogeneic transplantation. We have reviewed our series of 347 ASCT in myeloma and lymphoma patients performed over a period of 14 years with the aim of investigating the descriptive and analytical epidemiology of bacterial, CMV and IFD complications, focusing on the association between CMV and IFD. Patients with myeloma have significantly fewer bacterial infections and IFD than patients with lymphoma, but a similar rate of CMV complications. Descriptive epidemiological data are consistent with the literature, indicating an overall incidence of 36%, 3.5% and 15.5% for bacterial infections, IFD and CMV complications, with a case mortality rate of 4%, 16.7% and 3.7%, respectively. A strong correlation between CMV and IFD exists, with 8 cases of IFD out of a total of 12 presenting a CMV complication. At multivariate analysis, a diagnosis of lymphoma, ≥3 previous treatment lines and age ≥60 years were found to be independent risk factors for IFD. Duration of neutropenia (ANC < 500/mm3) ≥7 days represents an independent risk factor for CMV complications, where neutropenia most likely represents a crude surrogate biomarker indicating a deeper and longer state of overall immunosuppression. From our data we conclude that (1) myeloma patients are at lower risk of bacterial infections and IFD as compared with lymphoma patients but are at equal risk of CMV complications, most likely as a consequence of a selective impact of bortezomib on Herpes Viruses infection control; (2) a significant association exists between CMV and IFD, although a possible cause-effect relationship remains to be determined; (3) IFD is a rare complication after ASCT but burdened by a mortality rate of about 17%, with peak rates in older lymphoma patients who underwent more intensive therapeutic regimens.