A real-world analysis of PD1 blockade from the Rete Ematologica Pugliese (REP) in patients with relapse/refractory Hodgkin's lymphoma.

Checkpoint inhibitors have significantly changed the prognosis of patients with relapsing refractory classical Hodgkin's lymphoma (cHL), demonstrating excellent results in heavily pretreated patients. However, there is still limited data on the real-world experience with PD-1 inhibitors in cHL. Within the context of the Apulian hematological network (Rete Ematologica Pugliese, REP), we performed a retrospective, multicenter analysis of 66 patients with relapsing refractory cHL who had received PD-1 inhibitors in the non-trial setting. Forty-three patients (65%) were treated with nivolumab and 23 (35%) with pembrolizumab. Thirty-one (47%) and 8 (12%) patients underwent autologous or allogeneic stem cell transplantation prior to checkpoint inhibitor therapy, respectively. The median number of lines of treatment attempted prior to PD-1 inhibitor therapy was 4 (range, 3 to 7). All patients had received brentuximab vedotin prior to checkpoint inhibitor therapy. The overall response rate to PD-1 inhibitors therapy was 70% (47% complete remission (CR) and 23% partial remission (PR)). Twenty-four immune-related adverse events (19 (80%) grades 1-2; 5 (20%) grades 3-4) were documented (4 gastrointestinal, 4 hepatic, 6 fever, 4 hematological, 3 dermatological, 3 allergic rhinitis). Toxicity resolved in all patients, and there were no deaths attributed to checkpoint inhibitor therapy. After a median follow-up of 26 months (range 3-72 months), 54 patients (82%) are alive, and 12 (18%) died. The cause of death was attributed to disease progression in 9 patients and sepsis in 3 patients. After PD-1 inhibitor therapy, 22 patients (33%) relapsed or progressed. The overall survival and progression-free survival at 5 years were 65% and 54%, respectively. This study confirms the efficacy and tolerability of PD-1 inhibitor therapy in relapsed refractory cHL in a real-world setting, demonstrating similar clinical outcomes and toxicity profiles compared to clinical studies.

Efficacy and safety of netupitant/palonosetron combination (NEPA) in preventing nausea and vomiting in non-Hodgkin's lymphoma patients undergoing to chemomobilization before autologous stem cell transplantation.

PURPOSE: Prevention of chemotherapy-induced nausea and vomiting (CINV) is particularly challenging for patients receiving highly emetogenic preparative regimens before autologous stem cell transplantation (ASCT) due to the daily and continuous emetogenic stimulus of the multiple day chemotherapy. While studies have shown effective prevention of CINV during the conditioning phase with NK1 receptor antagonist (NK1RA)-containing regimens, there have been no studies evaluating antiemetic use during chemomobilization prior to ASCT. METHODS: This multicenter, open-label, phase IIa study evaluated the efficacy of every-other-day dosing of NEPA administered during chemomobilization in patients with relapsed-refractory aggressive non-Hodgkin's lymphoma. Eighty-one patients participated. RESULTS: Response rates were 77.8% for complete response (no emesis and no rescue use), 72.8% for complete control (complete response and no more than mild nausea), 86.4% for no emesis, and 82.7% for no rescue use during the overall phase (duration of chemomobilization through 48 h after). NEPA was well tolerated with no treatment-related adverse events reported. CONCLUSION: NEPA, administered with a simplified every-other-day schedule, show to be very effective in preventing CINV in patients at high risk of CINV undergoing to chemomobilization of hematopoietic stem cells prior to ASCT.

Antiemetic prophylaxis in patients undergoing hematopoietic stem cell transplantation: a multicenter survey of the Gruppo Italiano Trapianto Midollo Osseo (GITMO) transplant programs.

A survey within hematopoietic stem cell transplant (HSCT) centers of the Gruppo Italiano Trapianto Midollo Osseo (GITMO) was performed in order to describe current antiemetic prophylaxis in patients undergoing HSCT. The multicenter survey was performed by a questionnaire, covering the main areas on chemotherapy-induced nausea and vomiting (CINV): antiemetic prophylaxis guidelines used, antiemetic prophylaxis in different conditioning regimens, and methods of CINV evaluation. The survey was carried out in November 2016, and it was repeated 6 months after the publication of the Multinational Association of Supportive Care in Cancer (MASCC)/European Society for Medical Oncology (ESMO) specific guidelines on antiemetic prophylaxis in HSCT. The results show a remarkable heterogeneity of prophylaxis among the various centers and a significant difference between the guidelines and the clinical practice. In the main conditioning regimens, the combination of a serotonin3 receptor antagonist (5-HT3-RA) with dexamethasone and neurokin1 receptor antagonist (NK1-RA), as recommended by MASCC/ESMO guidelines, increased from 0 to 15% (before the publication of the guidelines) to 9-30% (after the publication of the guidelines). This study shows a lack of compliance with specific antiemetic guidelines, resulting mainly in under-prophylaxis. Concerted strategies are required to improve the current CINV prophylaxis, to draft shared common guidelines, and to increase the knowledge and the adherence to the current recommendations for CINV prophylaxis in the specific field of HSCT.

Four doses of unpegylated versus one dose of pegylated filgrastim as supportive therapy in R-CHOP-14 for elderly patients with diffuse large B-cell lymphoma.

The primary objective of this prospective, randomized study was to compare the efficacy of a reduced regimen of only four doses of unpegylated filgrastim from day +8 to +11 per cycle with a standard once per cycle administration of pegylated filgrastim to maintain dose-intensity of R-CHOP-14 (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone given every 14 d) in previously untreated elderly patients with diffuse large B-cell lymphoma (DLBCL). We included 51 patients (median age 66 years, range 60-76). Median dose intensity did not differ between the group of 24 patients receiving four doses of unpegylated filgrastim of each cycle (87·5%) and the group of 27 patients receiving pegylated filgrastim once per cycle on day 2 (89·4%) (P = 0·9). There was also no difference in the frequency of adverse events, such as episodes of neutropenic fever and unplanned hospitalizations. Patient characteristics that negatively influenced dose intensity were reduced performance status, advanced stage disease and poor-risk International Prognostic Index, with Eastern Cooperative Oncology Group performance status ≥2 being the most significant factor. In conclusion, a limited support with 4 d of filgrastim appears to be equivalent to pegylated filgrastim administered once per cycle, and appears to be sufficient to maintain dose-intensity of the R-CHOP-14 regimen in elderly patients with DLBCL without risk factors.

The use of anthracycline at first-line compared to alkylating agents or nucleoside analogs improves the outcome of salvage treatments after relapse in follicular lymphoma The REFOLL study by the Fondazione Italiana Linfomi.

Follicular lymphoma (FL) patients experience multiple remissions and relapses and commonly receive multiple treatment lines. A crucial question is whether anthracyclines should be used at first-line or whether they would be better "reserved" for relapse and whether FL outcome can be optimized by definite sequences of treatments. Randomized trials can be hardly designed to address this question. In this retrospective multi-institutional study, time-to-next-treatment after first relapse was analyzed in 510 patients who had received either alkylating agents- or anthracycline- or nucleoside analogs-based chemotherapy with/without rituximab at first-line and different second-line therapies. After a median of 42 months, median time-to-next-treatment after relapse was 41 months (CI95%:34-47 months). After adjustment for covariates, first-line anthracycline-based chemotherapy with/without rituximab was associated with better time-to-next-treatment after any salvage than alkylating agents-based chemotherapy with/without rituximab or nucleoside analogs-based chemotherapy with/without rituximab (HR:0.74, P = 0.027). The addition of rituximab to first-line chemotherapy had no significant impact (HR:1.22, P = 0.140). Autologs stem cell transplantation performed better than any other salvage treatment (HR:0.53, P < 0.001). First-line anthracycline-based chemotherapy significantly improved time-to-next-treatment even in patients receiving salvage autologs stem cell transplantation (P = 0.041). This study supports the concept that in FL previous treatments significantly impact on the outcome of subsequent therapies. The outcome of second-line treatments, either with salvage chemoimmunotherapy or with autologs stem cell transplantation, was better when an anthracycline-containing regimen was used at first-line.

Fertility preservation in lymphoma patients treated with immunochemotherapy regimens with or without radiotherapy: results of a retrospective multicenter Italian study (Ferty care).

This is a retrospective, multicentric study, aimed to describe the real-life application of fertility preservation methods during treatment in female lymphoma patients, aged 18-40 years old, diagnosed between Oct 1st/2010 and May 31st/2018. Among 414 women included, median age was 28 years old, histologies were: HL 74%, PMBCL 13%, DLBCL 10%, others 3%. First line treatments were: ABVD in 295 (71%), R-CHOP like in 102 (25%), higher intensity regimens in 17 (4%) cases. Fertility preservation strategies were: GnRHa in 315 (78%), Oral Contraceptive in 41 (10%), oocytes and ovarian tissue cryopreservation in 55 and 42 patients, respectively. After therapy, we observed a restored regular period in 293 (70%) and premature ovarian failure (POF) in 33 (8%), Furthermore we recorded 43 pregnancies, all spontaneous with 5 years median follow-up. Median age at diagnosis and number of lines of treatment correlate with higher rate of amenorrhea, risk of POF and menopause (p < 0.001).

Comparison of first-line treatment with bendamustine plus rituximab versus R-CHOP for patients with follicular lymphoma grade 3A: Results of a retrospective study from the Fondazione Italiana Linfomi.

In the setting of follicular lymphoma (FL), frontline therapy with rituximab, cyclophosphamide, doxorubicin, and prednisone (R-CHOP) has represented for many years the standard of care for patients with symptomatic advanced disease. More recently, the combination of bendamustine plus rituximab (R-B) has emerged as an alternative therapeutic option. We present a retrospective, multicenter, observational study aimed at comparing outcomes and toxicities observed in 145 patients diagnosed with grade 3A FL treated with a first line therapy in 15 Italian Fondazione Italiana Linfomi centers between the 1st of January 2014 and the 30th of May 2018. Seventy patients were treated with R-B and 75 with R-CHOP. In the R-B group, the median age at the time of diagnosis was 67 years compared with 59 years in the R-CHOP group. Patients in R-B group achieved a similar overall response rate (96% vs. 99%) and a better complete remission rate (87% vs. 80%, p=0.035) compared with patients in R-CHOP group. Progression free survival (PFS) was similar between individual treated with R-CHOP and R-B (48- month PFS 77.7% vs. 76.6% respectively, p=0.745). The overall survival was significantly longer with R-CHOP treatment (HR=0.16; 95% IC, 0.04-0.74; p=0.007); however, no statistical significant difference was observed after adjustment for age. With the limitations of the study design, our results suggest that both R-B and R-CHOP seem to be valid first-line treatment options in FL3A.

Allogeneic stem cell transplantation in patients with mantle cell lymphoma: results from the MANTLE-FIRST study on behalf of Fondazione Italiana Linfomi.

The role of allogeneic stem cell transplantation (allo-SCT) in mantle cell lymphoma (MCL) is uncertain, even more in the era of bruton's tyrosine kinase inhibitors (BTKi) and chimeric antigen receptor T-cells. We retrospectively analyzed 55 patients who underwent allo-SCT for MCL relapsed or refractory (r/r) after rituximab and high-dose cytarabine within the MANTLE-FIRST project. With a median follow-up of 3.7 years, non-relapse mortality (NRM), progression-free survival, and overall survival were 23%, 53%, and 56%, respectively. NRM was significantly higher in the case of acute graft-versus-host disease, > 2 prior lines of therapy, age > 60 years. The outcome was similar for patients with early (≤24 months) and late progression of disease. The use of BTKi as a bridge to allo-SCT did not increase the toxicity and allowed a good control of disease. Our real-life experience confirms that allo-SCT still represents an option in MCL patients, especially if young and early-relapsed.

Outcomes in first relapsed-refractory younger patients with mantle cell lymphoma: results from the MANTLE-FIRST study.

Patients with mantle cell lymphoma (MCL) that fail induction treatment represent a difficult-to-treat population, where no standard therapy exists. We evaluated outcomes in patients with first relapsed-refractory (r/r) MCL after upfront high dose cytarabine including standard regimens. Overall survival (OS-2) and progression-free survival (PFS-2) were estimated from the time of salvage therapy. The previously described threshold of 24 months was used to define patients as early- or late-progressors (POD). Overall, 261 r/r MCL patients were included. Second-line regimens consisted of rituximab-bendamustine (R-B, 21%), R-B and cytarabine (R-BAC, 29%), ibrutinib (19%), and others (31%). The four groups were balanced in terms of clinicopathological features. Adjusting for age and early/late-POD, patients treated with R-BAC had significantly higher complete remission (63%) than comparators. Overall, Ibrutinib and R-BAC were associated with improved median PFS-2 [24 and 25 months, respectively], compared to R-B (13) or others (7). In patients with early-POD (n = 127), ibrutinib was associated with inferior risk of death than comparators (HR 2.41 for R-B, 2.17 for others, 2.78 for R-BAC). In patients with late-POD (n = 134), no significant differences were observed between ibrutinib and bendamustine-based treatments. Ibrutinib was associated with improved outcome in early-POD patients.

Efficacy and safety of multiple doses of NEPA without dexamethasone in preventing nausea and vomiting induced by multiple-day and high-dose chemotherapy in patients with non-Hodgkin's lymphoma undergoing autologous hematopoietic stem cell transplantation: a phase IIa, multicenter study.

Despite the availability of several antiemetics, clinical findings show that control of chemotherapy-induced nausea and vomiting (CINV) continues to be a serious concern for hematological patients, mainly for those receiving multiple-day (MD) and high-dose (HD) chemotherapy (CT). For CINV prophylaxis, 5-hydroxytryptamine type-3 receptor antagonists (5HT3-RAs) and neurokinin 1 receptor antagonists (NK1-RAs) are usually administered together with dexamethasone, which may increase the risk of serious infections in patients undergoing myeloablative treatment. The rationale of this multicenter, open-label and phase IIa study was to explore the efficacy of multiple doses of NEPA (netupitant/palonosetron) given as an every-other-day regimen without dexamethasone in preventing CINV in patients with relapsed-refractory aggressive non-Hodgkin's lymphoma (R/R-NHL), eligible for autologous stem cell transplantation (ASCT) and treated with MD-HD-CT. Seventy patients participated to the study. According to the adopted Fleming one-stage design, the primary endpoint of this study was achieved. The CR values were 87.1% (primary endpoint, overall phase: days 1-8), 88.6% (acute phase: days 1-6), and 98.6% (delayed phase: days 7-8), while complete control (CR with no more than mild nausea) was 85.7% (overall phase), 88.6% (acute phase), and 95.7% (delayed phase). Moderate and severe episodes of nausea were reported by less than 10% of patients in the overall phase and less than 5% in both the acute and delayed phases. Regarding safety, NEPA was well tolerated with only one adverse event (constipation) evaluated as possibly related to NEPA administration. In conclusion, our study demonstrated that multiple alternate dosing of NEPA without the addition of dexamethasone is highly effective for preventing nausea and vomiting in this difficult setting, with a good tolerability profile.

Quantification of DAPK1 promoter methylation in bone marrow and peripheral blood as a follicular lymphoma biomarker.

Hypermethylation of DAPK1 promoter gene was found to be a frequent epigenetic alteration in follicular lymphoma (FL). We evaluated whether the quantification of DAPK1 methylation in the bone marrow (BM) and peripheral blood of FL patients at diagnosis and during follow-up provides important prognostic information. DAPK1 methylation was quantitated by real-time MethyLight PCR in 107 patients at diagnosis, at end of therapy, and during follow-up. Information on BCL2-IGH rearrangement and clinical characteristics were available for all patients. Aberrant DAPK1 methylation was found in 22 of 26 (85%) lymph node biopsy samples, 62 of 107 (58%) BM specimens, and 25 of 63 (40%) peripheral blood samples at diagnosis. DAPK1 methylation was greater in patients with BM infiltration and a higher Follicular Lymphoma International Prognostic Index score. The presence of aberrant DAPK1 methylation in BM significantly reduced progression-free survival following immunochemotherapy, independent of Follicular Lymphoma International Prognostic Index score. Residual or increased methylation after treatment was associated with an increased risk for relapse. With watchful waiting, greater DAPK1 methylation at diagnosis was associated with a shorter time to antilymphoma treatment. Our study indicates that quantification of DAPK1 methylation represents a prognostically relevant FL biomarker, with promising implications for risk assessment.

Anemia in diffuse large B-cell non-Hodgkin lymphoma: the role of interleukin-6, hepcidin and erythropoietin.

Anemia is a frequent sign in patients with diffuse large B-cell lymphoma (DLBCL) at diagnosis. We determined erythropoietin, hepcidin and interleukin-6 (IL-6) in plasma samples of 53 patients with DLBCL. The majority of patients (40/53, 75%) showed defective endogenous erythropoietin production, in particular when anemia was present (p = 0.01). Hepcidin plasma levels were significantly higher in patients compared to controls (p = 0.006), particularly in those with characteristics associated with a more active disease, including elevated lactate dehydrogenase (LDH) (p = 0.0004), B-symptoms (p = 0.07) and an age-adjusted international prognostic index (IPI) score > 1 (p = 0.01). Hepcidin levels correlated strongly to ferritin (r = 0.77, p < 0.0001) and weakly to IL-6 concentrations (r = 0.30, p = 0.03), but not to hemoglobin values. IL-6 inversely correlated to hemoglobin values in both univariate and multivariate analysis (p = 0.04), including hepcidin and erythropoietin as variables. Our findings suggest that elevated hepcidin levels and inadequate erythropoietin response are frequent in DLBCL, but elevated IL-6 plays the major role for the development of anemia.

Mantle cell lymphoma relapsing at the lymphedematous arm.

Lymphedema (LE) is a chronic medical condition characterized by lymphatic fluid retention, resulting in tissue swelling. Cancer treatments involving lymph nodes can damage lymph drainage routes, causing accumulation of lymph fluid in the interstitial tissue of related limbs and body areas and secondary LE. Basically, the LE has a negative impact on physical and mental quality of life. Moreover, 0.07-0.04% of long term survivors (most patients undergoing mastectomy) can develop the Stewart-Treves syndrome, a rare and aggressive multifocal lymphangiosarcoma arising within the LE region. Here we describe the case of a 45-year-old woman with a massive LE of the left arm, as a consequence of previous breast cancer, who was diagnosed after 4 years of stage IV mantle cell lymphoma (MCL). The patient, after obtaining complete remission with chemotherapy and autologous hematopoietic stem cell transplant, had a relapse of MCL in the lymphedema site.

Intravascular large B-cell lymphoma presenting as slowly progressive paraparesis with normal MRI features.

Intravascular large B-cell lymphoma (IVLBCL) is a rare, high grade extranodal B-cell lymphoma, characterized by the proliferation of tumoral cells in the lumen of small vessels of several organs without the tendency for tumor formation in other areas usually affected by lymphomas, such as lymph nodes, bone marrow, or peripheral blood. Diagnosis is generally delayed by variable presentation with non-specific constitutional and neurological symptoms, lack of reliable ancillary tests and it is often obtained only at autopsy. We report a case of IVLBCL presenting with a slowly progressing isolated paraparesis without any evidence of spinal damage at MRI though neurophysiological examinations showed signs of spinal cord injury. Laboratory findings showed markedly elevated levels of lactate dehydrogenase, low albumin values, raised ESR, mild thrombocytopenia and progressive impairment of hepatic function. Bone marrow examinations and total body CT scans were negative. Although clinical history appeared too long, we considered the hypothesis of IVLBCL on the basis of the laboratory constellation and proposed a liver biopsy, but the patient refused the procedure. The diagnosis was confirmed only at autopsy. Our case should make us aware that the disease has to be considered in the differential diagnosis of unexplained paraparesis associated with elevated level of lactate dehydrogenase and only relatively non-specific laboratory findings even without any spinal cord abnormalities at MRI.

Systemic granulomatous reaction secondary to treatment of bladder cancer with bacillus calmette-guerin.

Intravesical instillation of Bacillus Calmette-Guérin is the elective treatment for transitional cell and in situ bladder carcinoma. Severe complications occur very seldom, but must be known and promptly recognized. We describe the case of a 48-year-old man, treated with chemo-immunotherapy ten years before for a follicular lymphoma, who developed a systemic granulomatous reaction after his twelfth intravescical BCG instillation for bladder cancer.

Interleukin-6 plasma levels are modulated by a polymorphism in the NF-κB1 gene and are associated with outcome following rituximab-combined chemotherapy in diffuse large B-cell non-Hodgkin lymphoma.

Peripheral blood cytokines are known prognostic parameters in diffuse large B-cell lymphoma (DLBCL) treated with chemotherapy, but their role after the introduction of rituximab is unknown. Seven polymorphisms in the promoter regions of IL-6, IL-10 and NF-κB1 genes were assessed in 167 patients with DLBCL and 99 controls and correlated with interleukin-6 (IL-6) and IL-10 plasma levels. Outcome was analyzed in 137 patients treated with rituximab-based chemotherapy. The NF-κB1 - 94ATTG deletion was associated with increased IL-6 and IL-10 in DLBCL. High IL-6 concentration correlated with unfavorable prognostic factors included in the international prognostic index (IPI) and predicted for inferior progression-free (p = 0.007) and overall survival (p = 0.02). IL-6 levels remained a significant outcome predictor also including IPI as a covariate (p = 0.006 for progression-free survival). Our data suggest that the NF-κB1 genetic background influences IL-6 production in DLBCL, and that high IL-6 concentration is an independent prognostic factor also in the "rituximab era."

Primary pancreatic lymphoma in a patient with maturity onset diabetes of the young type 3.

Primary pancreatic lymphoma (PPL) is an extremely rare disease which occurs in pancreas, accounts for less than 1% of extra-nodal malignant lymphomas and 0,5% of cases of pancreatic masses. We report the case of PPL in a 15 year-old boy suffering from Maturity Onset Diabetes of the Young type 3 (MODY3) diagnosed at the age of 1 year.

Primary plasma cell leukemia followed by testicular plasmacytoma.

Plasma cell leukemia (PCL) is a highly aggressive plasma cell disease characterized by a poor prognosis and a low response rate to conventional therapy. Herein, we describe a 69-year-old patient with primary PCL, developing testicular disease while in complete hematological remission, following by muscle involvement and peritoneal dissemination.