A case of aggressive systemic mastocytosis with bulky lymphadenopathy showing response to midostaurin.

Management of systemic mastocytosis is an emerging challenge which requires a multidisciplinary diagnostic approach and personalized treatment strategy. Midostaurin can rapidly reduce the disease burden, also in cladribine refractory cases.

Biological Difference Between Epstein-Barr Virus Positive and Negative Post-transplant Lymphoproliferative Disorders and Their Clinical Impact.

Epstein-Barr virus (EBV) infection is correlated with several lymphoproliferative disorders, including Hodgkin disease, Burkitt lymphoma, diffuse large B-cell lymphoma (DLBCL), and post-transplant lymphoproliferative disorder (PTLD). The oncogenic EBV is present in 80% of PTLD. EBV infection influences immune response and has a causative role in the oncogenic transformation of lymphocytes. The development of PTLD is the consequence of an imbalance between immunosurveillance and immunosuppression. Different approaches have been proposed to treat this disorder, including suppression of the EBV viral load, reduction of immune suppression, and malignant clone destruction. In some cases, upfront chemotherapy offers better and durable clinical responses. In this work, we elucidate the clinicopathological and molecular-genetic characteristics of PTLD to clarify the biological differences of EBV(+) and EBV(-) PTLD. Gene expression profiling, next-generation sequencing, and microRNA profiles have recently provided many data that explore PTLD pathogenic mechanisms and identify potential therapeutic targets. This article aims to explore new insights into clinical behavior and pathogenesis of EBV(-)/(+) PTLD with the hope to support future therapeutic studies.

Viral Infections in HSCT: Detection, Monitoring, Clinical Management, and Immunologic Implications.

In spite of an increasing array of investigations, the relationships between viral infections and allogeneic hematopoietic stem cell transplantation (HSCT) are still controversial, and almost exclusively regard DNA viruses. Viral infections per se account for a considerable risk of morbidity and mortality among HSCT recipients, and available antiviral agents have proven to be of limited effectiveness. Therefore, an optimal management of viral infection represents a key point in HSCT strategies. On the other hand, viruses bear the potential of shaping immunologic recovery after HSCT, possibly interfering with control of the underlying disease and graft-versus-host disease (GvHD), and eventually with HSCT outcome. Moreover, preliminary data are available about the possible role of some virome components as markers of immunologic recovery after HSCT. Lastly, HSCT may exert an immunotherapeutic effect against some viral infections, notably HIV and HTLV-1, and has been considered as an eradicating approach in these indications.

Clinical and molecular characteristics of lymphoplasmacytic lymphoma not associated with an IgM monoclonal protein: A multicentric study of the Rete Ematologica Lombarda (REL) network.

Lymphoplasmacytic lymphoma (LPL) is usually associated with a serum IgM paraprotein, corresponding to Waldenström's Macroglobulinemia (WM). Cases presenting with IgG or IgA, or without a monoclonal protein are extremely rare. We analyzed clinical characteristics, frontline treatment, and the outcome of 45 patients with non-IgM LPL, and compared them with a control group of WM patients. The median age was similar, with significantly higher prevalence of females in non-IgM LPL, than in WM patients (60% vs 39%, P = .016). Patients with non-IgM LPL more frequently presented with lymphadenopathies (53% vs 15%, P < .001), splenomegaly (22% vs 8%, P = .015) or extranodal involvement (20% vs 8%, P = .05). In non-IgM LPL a serum monoclonal protein and bone marrow infiltration were less common than in WM patients (69% and 84% of cases respectively, P < .001 for both comparisons). The MYD88 (L265P) mutation was found in 8/19 patients using allele-specific polymerase chain reaction. A CXCR4 mutation was found in 4/17 cases using Sanger. In 16 patients we performed targeted next-generation sequencing of genes MYD88, CXCR4, ARID1-A, KMT2D, NOTCH2, TP53, PRDM1, CD79B, TRAF3, MYBBP1A, TNFAIP3. Seven patients (44%) had a MYD88 mutation (S219C in one), four (25%) a CXCR4 mutation, three (19%) a KMT2D mutation, one (6%) a TP53 mutation and one (6%) a TRAF3 mutation. With a median follow-up of 55.7 months, 36 non-IgM LPL patients (80%) were treated. Non-IgM LPL patients received more frequently anthracycline-containing regimens, as compared with WM patients, who mainly received alkylating-based therapies. Five-year overall survival (OS) was 84%, similar to that of WM patients.

Epidemiology and treatment approaches in management of invasive fungal infections in hematological malignancies: Results from a single-centre study.

Invasive fungal infections (IFIs) are a leading cause of morbidity and attributable mortality in oncohematologic patients. Timely diagnosis is essential but challenging. Herein we retrospectively describe 221 cases of antifungal treatments (AFT) administered in a monocentric real-life cohort of hematological malignancies. Between January 2010 and July 2017, 196 oncohematologic patients were treated with AFT at our Hematology Department. Diagnosis of IFIs was carried out according to EORTC/MSG-2008 guidelines.The most represented disease was acute myeloid leukemia (104 patients). Median age was 61 years; at fever onset 177 (80%) patients had a neutrophil count<0.5x109/L. Twenty-nine (13%) patients were receiving antifungal prophylaxis (26 posaconazole, 2 fluconazole, 1 itraconazole). The incidence of AFT was 13%. Serum galactomannan antigen (GM) was positive in 20% of the tested cases, while 85% of the patients had a CT scan suggestive for IFI. Twenty-one percent of these cases had a GM positive. Sixty-five out of 196 patients (33%) showed positive culture results, in particular Candida spp. were identified in 45 isolates, while Aspergillus spp. in 16 cases. Fourteen patients presented multiple positivity. Twenty-two (10%) cases were classified as proven IFIs, 61 (28%) as probable and 81 (37%) as possible, but 57 (26%) cases could not be classified. Fifty-nine percent of the patients received single agent AFT, 37% sequential AFT, 8% a combination regimen. Liposomal-amphotericin-B was the most used AFT. IFIs attributable mortality was 20%. This epidemiologic survey underlined a persistent significant use of AFT and a high mortality rate of IFIs. We suggest that further powerful diagnostic approaches should be investigated to improve the diagnostic accuracy and potential therapeutic implication.

Lenalidomide in Pretreated Patients with Diffuse Large B-Cell Lymphoma: An Italian Observational Multicenter Retrospective Study in Daily Clinical Practice.

BACKGROUND: Diffuse large B-cell lymphoma (DLBCL) is the most common non-Hodgkin lymphoma subtype, and approximately 50% of the patients are >60 years of age. Patients with relapsed/refractory (rr) disease have a poor prognosis with currently available treatments. Lenalidomide is available in Italy for patients with rrDLBCL based on a local disposition of the Italian Drug Agency. SUBJECTS, MATERIALS, AND METHODS: An observational retrospective study was conducted in 24 Italian hematology centers with the aim to improve information on effectiveness and safety of lenalidomide use for rrDLBCL in real practice. RESULTS: One hundred fifty-three patients received lenalidomide for 21/28 days with a median of four cycles. At the end of therapy, there were 36 complete responses (23.5%) and 9 partial responses with an overall response rate (ORR) of 29.4%. In the elderly (>65 years) subset, the ORR was 33.6%. With a median follow-up of 36 months, median overall survival was reached at 12 months and median disease-free survival was not reached at 62 months. At the latest available follow-up, 29 patients are still in response out of therapy. Median progression-free survivals differ significantly according to age (2.5 months vs. 9.5 in the younger vs. elderly group, respectively) and to disease status at the latest previous therapy (15 months for relapsed patients vs. 3.5 for refractory subjects). Toxicities were manageable, even if 30 of them led to an early drug discontinuation. CONCLUSION: Lenalidomide therapy for patients with rrDLBCL is effective and tolerable even in a real-life context, especially for elderly patients. IMPLICATIONS FOR PRACTICE: Diffuse large B-cell lymphoma (DLBCL) is the most common subtype of non-Hodgkin lymphoma, and approximately 50% of the patients are >60 years of age. Patients with relapsed/refractory (rr) disease have a poor prognosis, reflected by the remarkably short life expectancy of 12 months with currently available treatments. The rrDLBCL therapeutic algorithm is not so well established because data in the everyday clinical practice are still poor. Lenalidomide for patients with rrDLBCL is effective and tolerable even in a real-life context, especially for elderly patients.

Lamivudine prophylaxis prevents hepatitis B virus reactivation in anti-HBc positive patients under rituximab for non-Hodgkin lymphoma.

BACKGOUND: A significant proportion of hepatitis B surface antigen (HBsAg) negative/anti-hepatitis B core antigen (anti-HBc) positive patients with non-Hodgkin lymphoma (NHL) undergoing rituximab-based chemotherapy (R-CT) may suffer hepatitis B virus (HBV) reactivation. AIMS: We wanted to assess efficacy and safety of lamivudine (LMV) prophylaxis to prevent this complication. METHODS: Eighty-five consecutive HBsAg negative/anti-HBc positive NHL patients (71 years, 100% serum HBV DNA undetectable, 74% anti-HBs positive) received LMV coadministered with R-CT and for 18 months after the end of R-CT. Serum ALT, HBsAg, anti-HBs and HBV DNA were assessed every 4 months during and after end of LMV. RESULTS: During 39 (2-108) months of study period, including 21 months of LMV and 27 additional months after LMV discontinuation, one patient (2%) had HBV reactivation, 31 months after stopping LMV and during administration of new immunosuppressive regimens, without LMV prophylaxis, owing to incomplete oncological response. A 50% decline of anti-HBs titers occurred in 22/63 (35%) patients, including 12 who became anti-HBs seronegative. Five (6%) patients had ALT increase during R-CT but none required R-CT discontinuation. Seventeen (20%) patients died, all for tumour progression. CONCLUSION: LMV prophylaxis is safe and effective in preventing HBV reactivation in HBsAg negative/anti-HBc positive NHL patients receiving R-CT.

Direct-Acting Antivirals in Hepatitis C Virus-Associated Diffuse Large B-cell Lymphomas.

BACKGROUND: International guidelines suggest hepatitis C virus (HCV) eradication by direct-acting antivirals (DAAs) after first-line immunochemotherapy (I-CT) in patients with HCV-positive diffuse large B-cell lymphoma (DLBCL), although limited experiences substantiate this recommendation. Moreover, only a few data concerning concurrent administration of DAAs with I-CT have been reported. SUBJECTS, MATERIALS, AND METHODS: We analyzed hematological and virological outcome and survival of 47 consecutive patients with HCV-positive DLBCL treated at 23 Italian and French centers with DAAs either concurrently (concurrent cohort [ConC]: n = 9) or subsequently (sequential cohort [SeqC]: n = 38) to first-line I-CT (mainly rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone [R-CHOP]-like). RESULTS: Median age was 61 years, 89% of patients had stage III/IV, and 25% presented evidence of cirrhosis. Genotype was 1 in 56% and 2 in 34% of cases. Overall, 46 of 47 patients obtained complete response to I-CT. All patients received appropriate DAAs according to genotype, mainly sofosbuvir-based regimens (n = 45). Overall, 45 patients (96%) achieved sustained virological response, 8 of 9 in ConC and 37 of 38 in SeqC. DAAs were well tolerated, with only 11 patients experiencing grade 1-2 adverse events. Twenty-three patients experienced hepatic toxicity (grade 3-4 in seven) following I-CT in SeqC, compared to only one patient in ConC. At a median follow-up of 2.8 years, two patients died (2-year overall survival, 97.4%) and three progressed (2-year progression-free survival, 93.1%). CONCLUSION: Excellent outcome of this cohort of HCV-positive DLBCL suggests benefit of HCV eradication by DAAs either after or during I-CT. Moreover, concurrent DAAs and R-CHOP administration appeared feasible, effective, and ideally preferable to deferred administration of DAAs for the prevention of hepatic toxicity. IMPLICATIONS FOR PRACTICE: Hepatitis C virus (HCV)-associated diffuse large B-cell lymphomas (DLBCLs) represent a great therapeutic challenge, especially in terms of hepatic toxicity during immune-chemotherapy (I-CT) and long-term hepatic complications. The advent of highly effective and toxicity-free direct-acting antivirals (DAAs) created an exciting opportunity to easily eradicate HCV shortly after or in concomitance with first-line immunochemotherapy (usually R-CHOP). This retrospective international study reports the real-life use of the combination of these two therapeutic modalities either in the concurrent or sequential approach (DAAs after I-CT) in 47 patients. The favorable reported results on long-term outcome seem to support the eradication of HCV with DAAs in all patients with HCV-positive DLBCL. Moreover, the results from the concurrent approach were effective and safe and displayed an advantage in preventing hepatic toxicity during I-CT.

Italian real life experience with brentuximab vedotin: results of a large observational study on 234 relapsed/refractory Hodgkin's lymphoma.

A large Italian multicenter observational retrospective study was conducted on the use of brentuximab vedotin (BV) for patients with relapsed Hodgkin's lymphoma (HL) to check if clinical trial results are confirmed even in a real life context. 234 CD30+ HL patients were enrolled. Best response was observed after a median of 4 cycles in 140 patients (59.8%): 74 (31.6%) patients obtained a complete response (CR) and 66 (28.2%) achieved a partial response (PR); overall response rate at the end of the treatment was 48.3% (62 CR and 51 PR). The best response rate was higher in the elderly subset: 14 (50%) CR and 5 (17.8%) PR. Disease free survival was 26.3% at 3 years and progression free survival 31.9% at 4.5 years. Duration of response did not differ for who achieved at least PR and then either did or did not undergo consolidative transplant. Overall, the treatment was well tolerated and no death has been linked to BV-induced toxicity. Our report confirms activity in elderly patients, duration of response unrelated to the consolidation with transplant procedure, the relevance of the CR status at first restaging, and the role of BV as a bridge to transplant for chemorefractory patients.

Italian real-life experience with brentuximab vedotin: results of a large observational study of 40 cases of relapsed/refractory systemic anaplastic large cell lymphoma.

Between November 2012 and July 2014, in accordance with national law 648/96, brentuximab vedotin was available in Italy for patients with relapsed systemic anaplastic large cell lymphoma outside a clinical trial context. A large Italian observational retrospective study was conducted on the use of brentuximab vedotin in everyday clinical practice to check whether clinical trial results are confirmed in a real-life context. The primary endpoint of this study was best response; secondary endpoints were the overall response rate at the end of the treatment, duration of response, survival and safety profile. A total of 40 heavily pretreated patients were enrolled. Best response was observed after a median of four cycles in 77.5%: globally, 47.5% patients obtained a complete response, 64.2% in the elderly subset. The overall response rate was 62.5%. At the latest follow up, 15/18 patients are still in complete remission (3 with consolidation). The progression-free survival rate at 24 months was 39.1% and the disease-free survival rate at the same time was 54% (median not reached). All the long-term responders were aged <30 years at first infusion. The treatment was well tolerated even in this real-life context and no deaths were linked to drug toxicity. Brentuximab vedotin induces clinical responses quite rapidly, i.e. within the first four cycles of treatment in most responders, thus enabling timely use of transplantation. For patients ineligible for transplant or for those in whom a transplant procedure failed, brentuximab vedotin may represent a feasible effective therapeutic option in everyday clinical practice.

Interferon-free antiviral treatment in B-cell lymphoproliferative disorders associated with hepatitis C virus infection.

Regression of hepatitis C virus (HCV)-associated lymphoma with interferon (IFN)-based antiviral treatment supports an etiological link between lymphoma and HCV infection. In addition, a favorable impact of antiviral treatment on overall survival of patients with HCV-related lymphoma has been reported. Data on IFN-free regimens combining direct-acting antivirals (DAAs) in HCV-associated lymphoproliferative disorders are scanty. We analyzed the virological and lymphoproliferative disease response (LDR) of 46 patients with indolent B-cell non-Hodgkin lymphomas (NHLs) or chronic lymphocytic leukemia (CLL) and chronic HCV infection treated with DAAs. The histological distribution was 37 marginal zone lymphomas (MZLs), 2 lymphoplasmacytic lymphomas, 2 follicular lymphomas, 4 CLL/small lymphocytic lymphomas (CLL/SLLs), and 1 low-grade NHL not otherwise specified. Thirty-nine patients received a sofosbuvir-based regimen and 7 patients received other DAAs. The median duration of DAA therapy was 12 weeks (range, 6-24 weeks). A sustained virological response at week 12 after finishing DAAs was obtained in 45 patients (98%); the overall LDR rate was 67%, including 12 patients (26%) who achieved a complete response. The LDR rate was 73% among patients with MZL, whereas no response was observed in CLL/SLL patients. Seven patients cleared cryoglobulins out of 15 who were initially positive. After a median follow-up of 8 months, 1-year progression-free and overall survival rates were 75% (95% confidence interval [CI], 51-88] and 98% [95% CI, 86-100], respectively. DAA therapy induces a high LDR rate in HCV-associated indolent lymphomas. These data provide a strong rationale for prospective trials with DAAs in this setting.

A phase II study of bendamustine in combination with rituximab as initial treatment for patients with indolent non-follicular non-Hodgkin lymphoma.

The purpose of this phase 2 study was to determine the activity and safety of six cycles of bendamustine and eight rituximab (RB) as first-line treatment of adult patients with advanced stage non-follicular indolent non-Hodgkin lymphomas (INFL). The primary end-point was the complete response rate (CRR) with expected CRR of 75%. Sixty-nine patients were enrolled; median age was 65 years (45-75), 65% were male, 93% of patients had stage IV disease. Complete and overall response rates were 48% (95% CI = 35.6-60.2) and 86% (CI = 75.0-92.8). The most common grade 3/4 adverse events were neutropenia (43%), thrombocytopenia (7%) and anemia (4%); whereas the rate of febrile neutropenia was very low (3%). At a median follow-up of 22 months (1-43 months), 2-year progression-free survival was 89% (CI = 79-95) and 2-year overall survival was 96% (CI = 87-99). RB combination is active and well tolerated in patients with advanced stage previously untreated INFL.

Bendamustine and rituximab combination is safe and effective as salvage regimen in Waldenström macroglobulinemia.

According to the European Society for Medical Oncology and National Comprehensive Cancer Network guidelines on Waldenström macroglobulinemia, bendamustine (B) may be considered a suitable therapeutic option. To address the role of B in combination with rituximab (BR), we analyzed the outcome of 71 patients with relapsed/refractory disease, median age 72 years, treated with R 375 mg/m(2) day 1 and B days 1 and 2 (dosage ranging from 50 to 90 mg/m(2)). Patients had previously received a median number of 2 lines of treatment (range 1-5). Overall and major response rates were 80.2% and 74.6%. Major toxicity was grade 3/4 neutropenia occurring in 13% of courses. There was no significant association between baseline features or patients' characteristics and response achievement. Median progression-free survival was not reached after a median follow-up of 19 months (range 3-54). None of the patients developed aggressive lymphoma or secondary myelodysplastic syndrome/acute myeloid leukemia. BR was found to be an active and well-tolerated salvage regimen leading to rapid disease control.

Bendamustine salvage therapy for T cell neoplasms.

Treatment of relapsed/refractory T cell neoplasms represents an unmet medical need. We recorded, retrospectively, data on 20 consecutive adult patients with T cell neoplasms (8 T cell lymphoma not otherwise specified (T-NOS), 4 angioimmunoblastic (AILT), 3 prolymphocytic leukemia (T-PLL), 3 advance-stage mycosis fungoides (MF) or Sézary syndrome (SS), and 2 T cell large granular lymphocytic leukemia (T-LGL)), treated with bendamustine. Partial (PR) and complete response (CR) rates were reached in nine (45 %) and two (10 %) patients, respectively, including three PR in T-NOS, one CR in AILT, three PR in T-PLL, two PR in MF/SS, and one CR and one PR in T-LGL lymphoma. The 6 months estimated progression free and overall survival was 44 and 67 %, respectively. Grade 3-4 neutropenia and thrombocytopenia were registered in 44 and 25 % of cases. Four patients developed major infectious complications. At a median follow-up of 6 months (range 1-18), 13 patients are alive and 7 patients died all because of lymphoma progression. Bendamustine deserves further investigation in patients with T cell neoplasms.