Extra-hematological Toxicity Research Articles

Bendamustine-Bortezomib-Dexamethasone (BVD) in the Management of Relapsed and Refractory Multiple Myeloma: A Real-Life Experience

Abstract Introduction : Bendamustine is a bifunctional alkylating agent, with low toxicity, proved to be effective in relapsed, refractory and in new diagnosed Multiple Myeloma (MM). It has been evaluated efficacy and tolerance of Bendamustine, in combination with bortezomib-dexamethasone (BVD) in patients with relapsed and refractory MM (rrMM), whose prognosis is particularly severe. A regional retrospective real-life analysis of patients with rrMM who had been treated with BVD as salvage therapy has been performed. Methods : 56 patients (31 M/25 F), with rrMM, median age at diagnosis 57.3 years (r. 36-82), median age at start of treatment 61.8 years (r.37-83) treated with several lines of treatments (median 6, r. 2-11), every refractory to all the drugs previously received (also Bortezomib), received BVD (Bendamustine 90 mg/sqm days 1,2; Bortezomib 1.3 mg/sqm days 1,4,8,11, Dexamethasone 20 mg days 1,2,4,5,8,9,11,12, Pegfilgrastim day +4) every 28 days, until progression. ISS was equally distributed, and cytogenetic was evaluable in 12 patients, and in particular one del13q and one t(11;14). All the patients had previously been treated with schedule containing bortezomib and IMIDs, and 30% had also received radiotherapy. 67% of them had undergone at least to a single auSCT. All patients were relapsed and refractory to last therapies received before BVD. Results : Bendamustine was well tolerated, with grade 3 transfusion-dependent anemia in 41% of patients, and 37% grade 3 neutropenia (no ospedalization was required, no septic shocks were observed). No severe extrahematologic toxicity was observed, only grade 1 gastrointestinal side effect (nausea), treated by common antiemetic drugs. According to IMWG, after a median follow-up of 14 months (r.2-36), ORR was 64% (36/56: 4 CR, 7 VGPR, 16 PR, 9 MR) with 8 PD and 12 patients in SD, which can be considered as an impressive result in this subset of rrMM patients. In particular, for 11 patients, BVD was, after having achieved at least a PR, a bridge to second auSCT, and for two patients a bridge to alloSCT. Median time to response was 1.2 months (range, 1-3), median OS from diagnosis was 62.7 months (range, 6-151), median OS from start of Bendamustine was 9.8 months (range 2-36). Conclusion : BVD has shown significant efficacy in a particularly severe setting of patients, relapsed and refractory to all available therapeutic resources, and, in particular cases, it could be considered as a bridge to a second autologous or allogenic SCT. Disclosures No relevant conflicts of interest to declare.

Rituximab, Bendamustine and Cytarabine (RBAC500) As Induction Therapy in Elderly Patients with Mantle Cell Lymphoma: Final Results of a Phase 2 Study from the Fondazione Italiana Linfomi

▪Background: The combination of rituximab (R, 375 mg/m2 intravenously [IV], day 1), bendamustine (B, 70 mg/m2IV, days 2 and 3), and cytarabine (800 mg/m2, IV on days 2 to 4) was highly active in patients with mantle-cell lymphoma (MCL) in a phase 2 study [R-BAC; Visco et al, JCO 2013]. This regimen was well tolerated, but hematologic toxicity was quite relevant, especially in terms of transient grade 3 to 4 thrombocytopenia (76% of cycles). Aiming at reducing hematologic toxicity, the Fondazione Italiana Linfomi (FIL) designed a phase 2 trial adopting the R-BAC schedule, but lowering cytarabine dose to 500 mg/m2 (RBAC500).Materials and Methods: Patients with newly diagnosed MCL, aged 61 to 80 years, not eligible for autologous transplant and fit according to the comprehensive geriatric assessment, were enrolled. Patients presenting with non-nodal leukemic disease were excluded. The primary endpoints were complete remission rate (CR) measured by FDG-PET according to Cheson criteria 2007, and safety. Secondary endpoints included rate of molecular response (MR) by nested-PCR using patient specific IGH or BCL1 based targets, progression-free (PFS) and overall survival (OS). The study was conducted according to the Bryant and Day two-stage design.Results: From May 2012 to February 2014, 57 patients with MCL from 29 centers were recruited and treated. Central pathology revision was performed in 87% of cases. Median age was 71 years (range 61-79), 75% were males, and 91% had Ann Arbor stage III/IV disease. Mantle Cell International Prognostic Index (MIPI) was low in 15%, intermediate in 40%, high in 45%, Ki-67 was ≥30% in 31%, and 9% had the blastoid cytological variant. Overall, 53 patients (91%) received at least 4 cycles, while 36 (63%) had 6 cycles (median 5.3 cycles per patient). Fifteen patients (26%) discontinued treatment before reaching cycle 6 because of toxicity/adverse events, that mainly consisted of prolonged hemato-toxicity between cycles. Only one patient discontinued due to progressive disease. Grade 3 or 4 neutropenia and thrombocytopenia were observed in 49% and 52% of administered cycles, respectively. Febrile neutropenia occurred in 6% of cycles. Extra-hematologic toxicity was mainly cardiac (5%). Overall response rate was 96%, and CR was 93%. The MR rate at the end of treatment was 76% on peripheral blood and 55% on bone marrow (BM) samples. With a median follow-up of 34 months (28-52), the 2-years PFS (± confidence interval) was 81%±5% and the OS 85%±4%. Elevated Ki-67 (≥30%), and the blastoid variant were the strongest independent predictors of adverse PFS. Patients with either of these two features (33%), had a significantly inferior PFS (41% vs 97% after 34 months) compared to patients with classical/pleomorphic variants and low proliferative index (p<0.0001, Figure 1).Conclusions: The R-BAC500 regimen can be safely administered as first line therapy to elderly patients with MCL. Hematologic toxicity is substantially reduced compared to our previous experience. With 93% of FDG-PET negative CR, and a 2-years PFS of 81% without maintenance therapy, the R-BAC500 regimen is a highly effective treatment for patients with MCL, and compares favourably with previously reported regimens in this patient population, including R-bendamustine. [Display omitted] DisclosuresVisco:Gilead: Speakers Bureau; Lundbeck: Consultancy; Mundipharma: Research Funding; Celgene: Speakers Bureau. Spina:Mundipharma: Membership on an entity's Board of Directors or advisory committees, Other: Speaker Fee; Teva Pharmaceuticals Industries: Membership on an entity's Board of Directors or advisory committees, Other: Speaker Fee. Di Rocco:Celgene: Honoraria. Carella:Millenium: Speakers Bureau; Genentech: Speakers Bureau. Vitolo:Roche: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria; Gilead: Honoraria; Celgene: Honoraria.

Escalated Dose-Rates of Total Marrow Irradiation (TMI) Combined with Treosulfan and Fludarabine-Based Conditioning Chemotherapy Regimen for Chemosensitive Advanced Multiple Myeloma (MM) Patients Undergoing a Matched Allogeneic Stem-Cell Transplantation: First Results of a Phase I/II Prospective Monocentric Study (TrRaMM TMI)

BackgroundIn an effort to reduce transplantation-related morbidity and mortality in patients (pts) undergoing total body irradiation as part of myeloablative conditioning regimen for hematological malignancies candidated to allogeneic transplant, data have been emerging in support of Helical Tomotherapy to deliver radiation doses to target organs, as bone marrow and lymph nodes, sparing normal organs. We report the first results of feasibility and efficacy of myeloablative Treosulfan-based conditioning chemotherapy combined with dose-escalating (8-10-12 Gy) TMI in pts affected by chemosensitive advanced MM (TrRaMM-TMI: Eudract N° 2013-002479-16).Patients and methodsTen pts (7 females and 3 males with a median age of 60 years), affected by chemosensitive advanced MM have been treated from December 2012 to December 2015. Most of them have received previous therapies with Bortezomib (90%) and IMIDs (80%) and all pts experienced relapse after autologous transplant; active disease was present in the 30% of the pts at the time of the transplant. The pts' median score of HCT-comorbidity index was 2. All pts received a myeloablative Treosulfan-based chemotherapy (Treosulfan 14g/mq/day on days -6 to -4; Fludarabine 30mg/mq/day on days -6 to-2), combined with TMI delivery on day -2 and -1 if 8Gy and on day -3, -2 and -1 if 10 Gy or 12 Gy, using Helical Tomotherapy. Each pt had a personalized immobilization device and before any fraction the correct set-up was controlled by a mega-voltage CT scan. Three pts have been submitted as pilot cases to TMI 8 Gy, and four and three pts respectively in the two protocol cohorts of TMI 10 Gy and 12 Gy. Peripheral-blood has been the stem cell source for all the pts: three from a matched sibling donor and seven from a matched unrelated donor (10/10 HLA match in six cases and one 9/10 HLA match). A median of 5x10e6 Cd34+/kg and of 319x10e6 Cd3+/Kg have been infused and graft versus host disease (GVHD) prophylaxis with sirolimus and mycophenolate mofetil has been administered; antithymocyte globulin on days -4 to -2 and rituximab on day -1 were added in the unrelated transplant setting.ResultsAll pts received the planned TMI dose in each cohort; engraftment occurred in all pts and no secondary graft failure was observed. No grade 3 and 4 extra-hematological toxicities were observed, and lower grade toxicities, especially gastrointestinal, were completely reversible. No more than 10% of viral reactivations have been demonstrated and one case only of severe sepsis occurred, promptly resolved. No invasive fungal infections occured. No transplant related mortality (TRM) was registered and the two deaths were due to progressive disease. Immune reconstitution after transplant described a T-cell CD8+ and CD4+ repertoire recovery with a median number of 350/microL and of 100/microL on day +90 respectively; NK cells recovery was rapid with a median of 140/microL on day +90, while B cells were still missing on day +90. With a median follow-up time of 22 months on surviving pts, a 2-year PFS of 64% and a 2-year OS of 77% have been described. The day +100 cumulative incidence of grade II-IV acute GVHD was 40%; if grade >III 10%; chronic GVHD 1-year cumulative incidence was 42%; if moderate and severe 31%. 2-year relapse incidence was 36%.ConclusionsThe first data coming out from the present experience show that TMI addition to Treosulfan-based chemotherapy has not demonstrated an addition of at least short-term toxicities, confirming the combination feasibility, so that TMI 14 Gy delivery is in the plan for the third cohort of the study. Moreover the efficacy outcomes in terms of survival and acceptable TRM, suggest that myeloablative conditioning is feasible in the context of MM and especially promising even in pts with advanced and heavily pretreated disease. DisclosuresBonini:Molmed SpA: Consultancy; TxCell: Membership on an entity's Board of Directors or advisory committees. Ciceri:MolMed SpA: Consultancy.

Improved Survival in African American Patients Undergoing Autologous Transplant for Multiple Myeloma in the Chemotherapy and Novel Agent Era

African Americans (AA) have a 2- to 3-fold higher incidence of multiple myeloma (MM) when compared to other racial groups. Evidence suggests that there may be differences in the biology of MM, which confer a more favorable prognosis in AA patients. Prior studies are conflicted as to whether AA patients achieve equal or improved outcomes compared to non-African American (non-AA) patients. Our purpose was to evaluate the impact of AA race on outcomes of MM patients undergoing ASCT at a single center in both the chemotherapy and novel agent era.One hundred and twenty-nine patients who received melphalan 200 mg/m2 and ASCT between 2000 and 2013 were included in the analysis. Sixty-one (47%) patients were African-American and 68 (53%) were non-AA. Baseline characteristics including age, FISH, cytogenetics, paraprotein subtype, median number of prior therapies and International Staging System (ISS) stage were similar between racial groups. Overall, 77 (60%) patients received any novel agent prior to transplant and 52 (40%) received only chemotherapy. More non-AA patients were male (59% vs. 38%, p=0.02), received initial induction with a proteasome inhibitor (59% vs. 28%, p=0.0007), and were treated with post-ASCT maintenance therapy (41% vs. 23%, p=0.008). Time from diagnosis to ASCT in AA patients was 10 (range: 4-144) versus 8 (range: 3-54) months in non-AA patients (p=0.01). The ASCT hospital course was similar between both groups with no significant differences in time to neutrophil and platelet engraftment as well as the duration of hospitalization. Additionally, there was no significant difference in the extra-hematologic toxicity between the two groups including the incidence of diarrhea, mucositis, and infection.Response was measured using the International Myeloma Working Group criteria and was assessed immediately prior to transplant and between 90 to 180 days after transplant. No differences were observed in pre-transplant (p=0.13) or post-transplant (p=0.28) response rates between the two groups. African American patients had a significantly improved median OS compared to non-AA patients (not reached vs. 108 months, p=0.03). We further stratified analyses of OS by those treated in the chemotherapy versus novel agent era. Improved OS was observed in both the chemotherapy (93 vs. 68 months, p=0.02) and novel agent (not reached vs. 79 months, p=0.01) treatment era. In a multivariate Cox proportional hazards model, AA race was associated with improved overall survival (adjusted HR 0.30, 95% CI 0.11 to 0.81; p=0.017).Multiple myeloma has one of the most apparent ethnic disparities in incidence and outcomes among cancers. In our study, AA patients had a longer time to transplant and received less proteasome inhibitor-based induction and post-ASCT maintenance suggesting disparities in access to care. Despite these differences in treatment, we observed improved overall survival after ASCT compared to non-AA patients. We demonstrated this improved OS in patients who had received either chemotherapy or novel agents prior to ASCT. These findings provide further evidence for more favorable outcomes among AA patients. One explanation could be a difference in disease biology that may result in a lower risk disease. Investigation of these biologic differences between AA and non-AA MM patients may increase our understanding of the pathogenesis and future treatments of myeloma. DisclosuresNo relevant conflicts of interest to declare.

Multicenter Retrospective Observational Study to Assess the Clinical Characteristics and the Outcome of Patients with Relapsed or Refractory Mantle Cell Non-Hodgkin's Lymphoma Treated in Italy According to the Ibrutinib Named Patient Program

Mantle cell lymphoma (MCL) is a rare and aggressive subtype of non-Hodgkin Lymphoma. Although a typical presentation as an indolent lymphoma, without systemic symptoms and with a good performance status, the mantle cell lymphoma is an aggressive one, hardly curable with standard chemo-immunotherapy. Although current approaches to mantle cell lymphoma, including newer agents (such as bortezomib, lenalidomide, temsirolimus and ibrutinib) and autologous stem cell transplantation, have greatly improved the outcomes of affected patients, this disease is still characterized by high relapse rates, with most patients eventually dying of lymphoma progression. Before official approval by EMA, patients with relapsed/refractory mantle cell lymphoma with unsatisfied critical medical urgency were granted ibrutinib early access through a Named Patient Program in Italy (NPP, DM 8 May 2003). This observational, non-interventional, retrospective, multicenter study focuses on collecting information about the effectiveness and safety of ibrutinib as single-agent in patients who received at least one dose of ibrutinib under the NPP in the period between 29/Jul/2014 and 25/Jan/2015 in Italy. Data from patients treated with ibrutinib outside a controlled clinical trial within a NPP could give additional information about the clinical use, treatment duration, efficacy and toxicity of ibrutinib given to relapsed or refractory MCL patients in a real life context.Fifty-three heavily pretreated patients were enrolled. They had received a median of previous therapies of 3, comprising lenalidomide, bortezomib, temsirolimus and autologous stem transplant. Ninety-one percent had measurable disease and 83.0% had and ECOG performance status ≤2. At the end of therapy there were 11 complete responses (20.8%), 7 partial responses, 5 stable diseases and 30 progressions with an overall response rate of 33.9%. Twenty-six patients received ≥3 concomitant medications during ibrutinib therapy. At 20 months overall survival (OS) was 26.8% (median reached at 9 months) and disease free survival (DFS) 75% at 15 months: 10/11 patients are in continuous complete response with a median of 10.5 months. Hematological toxicities were manageable, 6 thrombocytopenia occurred, of which only 2 grade 4 (due to disease bone marrow infiltration) and the other 4 related to ibrutinib. Main extra-hematological toxicities were diarrhea (9.4%) and lung infections (7.5%) which all lead to early drug discontinuation. The observed occurrence of diarrhea by severity was 0 for CTCAE Grade 1, 4 for Grade 2, 2 for Grade 3 and 0 for Grade 4. Lung infection had a lower occurrence: 0, 2, 2 and 0 split by CTCAE Grade 1, 2, 3 and 4 respectively. There is a boundary zone in the passage from phase III to phase IV trials, i.e. from experimental to marketing and free use phases: in this zone we can find NPP and compassionate and off-label use. Despite the known potential bias of all the observational retrospective studies, reports on the real life experience make an important contribution to medical knowledge prior to widespread utilization: ibrutinib therapy is effective and tolerable also in a clinical setting mimicking the real world. Our results, in fact, are superimposable to those obtained in clinical trials: for safety, thrombocytopenia, diarrhea and lung infections are the relevant adverse events to be clinically focused on; for effectiveness, ibrutinib is confirmed to be a valid option for refractory/relapsed MCL. DisclosuresCascavilla:Janssen-Cilag: Honoraria. Zinzani:Abbvie: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; MorphoSys: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Celegene: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees.

Deferasirox in the Treatment of Iron Overload during Myeloproliferative Neoplasms (MPN)

Background Deferasirox (DFX) is an oral iron chelator widely employed in the treatment of iron overload during thalassemic syndromes and myelodysplastic syndromes.Aim At present, very few data are available on the treatment with DFX in patients with Ph- Myeloproliferative Neoplasms(MPN) and transfusional requirement.Methods To address this issue, we report here on 41 patients (M 31; F 10) with MPN and iron overload secondary to transfusional requirement enrolled in the database of our regional cooperative group who received a treatment with DFX. Of them, 36 had a primary Myelofibrosis, 4 a post Essential Thrombocythemia myelofibrotic phase and 1 a post Polycythemia Vera myelofibrotic phase.Results According to IPSS classification, 8 patients (19.5%) resulted low/intermediate-1 risk, 14 (34.1%) intermediate-2 risk and 19 (46.4%) high-risk. The main features of the patients at diagnosis and at baseline of DFX treatment are reported in the Table.Treatment with DFX was started after a median interval from diagnosis of 13.3 months [interquartile range (IR) 7.3 - 41.1] and from start of transfusion dependence of 11.5 months (IR 5.8 - 20.2), with a median of 27 packed red cells units received (IR 18 - 37). The starting DFX dose was 20 mg/Kg in 16 patients (39.1%), 15 mg/Kg in 20 patients (48.8%) and 10 mg/Kg in 5 patient (12.1%). All patients were evaluable for toxicity:extra-hematological toxicity of all WHO grades was reported in 20/41 patients (48.8%) and consisted of gastro-intestinal symptoms in 7 patients, transient renal impairment in 10 patients and skin reactions in 3 patients: however, only 3 patients (7.3%) needed a permanent discontinuation for toxicity. Thirty-nine out 41 patients were evaluable for response (> 6 months of treatment). As to chelation efficacy, after a median treatment period of 15.4 months (IR 8.1 - 22.3), 4 patients achieved ferritin levels < 500 ng/ml, 10 patients ferritin levels < 1,000 ng/ml and 2 patients presented a reduction > 50% of basal ferritin but with levels > 1,000 ng/ml, with a global response rate of 16 out 39 patients (41.0%): among the remaining 23 patients, 2 discontinued for early toxicity, 20 did not have any ferritin reduction and 1 had an early unrelated death (< 6 months of treatment). As to hematological improvement, 7/39 patients (17.9%) showed an unexpected and persistent rise of Hb levels > 1.5 g/dl, with disappearance of transfusional requirement in 5 cases. The median overall survival of the whole cohort from DFX initiation was 20.7 months (95% CI 16.0 - 25.3): the median overall survival from DFX initiation in patients with chelation response was 46.9 months (95% CI 10.7 - 83.0) compared to 14.0 months (95% CI 5.6 - 22.3) in patients without chelation efficacy (p=0.002).Conclusions Treatment with DFX is feasible and effective in MPN with iron overload. Moreover, also in this setting an hematological improvement can occur in a sizeable rate of patients. [Display omitted] DisclosuresBreccia:Novartis: Consultancy, Honoraria; Bristol Myers Squibb: Honoraria; Celgene: Honoraria; Ariad: Honoraria; Pfizer: Honoraria. Latagliata:Novartis: Consultancy, Honoraria; Bristol Myers Squibb: Honoraria; Celgene: Honoraria; Janssen: Consultancy, Honoraria; Shire: Honoraria.

Bendamustine-Bortezomib-Desametasone (BVD) in the Management of Relapsed and Refractory Multiple Myeloma : A REAL-Life Experience

Introduction :Bendamustine is a bifunctional alkylating agent, with low toxicity, proved to be effective in relapsed, refractory and in new diagnosed Multiple Myeloma (MM).It has been evaluated efficacy and tolerance of Bendamustine, in combination with bortezomib-dexamethasone (BVD) in patients with relapsed and refractory MM (rrMM), whose prognosis is particularly severe. A regional retrospective real-life analysis of patients with rrMM who had been treated with BVD as salvage therapy has been performed.Methods :56 patients (31 M/25 F), with rrMM, median age at diagnosis 57.3 years (r. 36-82), median age at start of treatment 61.8 years (r.37-83) treated with several lines of treatments (median 6, r. 2-11), every refractory to all the drugs previously received (also Bortezomib), received BVD (Bendamustine 90 mg/sqm days 1,2; Bortezomib 1.3 mg/sqm days 1,4,8,11, Dexamethasone 20 mg days 1,2,4,5,8,9,11,12, Pegfilgrastim day +4) every 28 days, until progression.ISS was equally distributed, and cytogenetic was evaluable in 12 patients, and in particular one del13q and one t(11;14). All the patients had previously been treated with schedule containing bortezomib and IMIDs, and 30% had also received radiotherapy. 67% of them had undergone at least to a single auSCT. All patients were relapsed and refractory to last therapies received before BVD.Results :Bendamustine was well tolerated, with grade 3 transfusion-dependent anemia in 41% of patients, and 37% grade 3 neutropenia (no ospedalization was required, no septic shocks were observed). No severe extrahematologic toxicity was observed, only grade 1 gastrointestinal side effect (nausea), treated by common antiemetic drugs.According to IMWG, after a median follow-up of 14 months (r.2-36), ORR was 64% (36/56: 4 CR, 7 VGPR, 16 PR, 9 MR) with 8 PD and 12 patients in SD, which can be considered as an impressive result in this subset of rrMM patients. In particular, for 11 patients, BVD was, after having achieved at least a PR, a bridge to second auSCT, and for two patients a bridge to alloSCT.Median time to response was 1.2 months (range, 1-3), median OS from diagnosis was 62.7 months (range, 6-151), median OS from start of Bendamustine was 9.8 months (range 2-36).Conclusion :BVD has shown significant efficacy in a particularly severe setting of patients, relapsed and refractory to all available therapeutic resources, and, in particular cases, it could be considered as a bridge to a second autologous or allogenic SCT. DisclosuresNo relevant conflicts of interest to declare.

Comorbidities, not age, are predictive of survival after autologous hematopoietic cell transplantation for relapsed/refractory Hodgkin's lymphoma in patients older than 50years.

Autologous hematopoietic cell transplantation (AHCT) is the standard of care for young patients with relapsed/refractory (R/R) Hodgkin's lymphoma (HL). However, there is limited experience of its efficacy and feasibility in older patients. The characteristics and outcomes of 121 patients aged ≥50years (42 of them are ≥60years old) with R/R HL who underwent AHCT were reviewed. After a median follow-up of 3.1years, overall survival (OS) and progression-free survival (PFS) at 5years were 64 and 55%, respectively, with no differences between 50-59-year-old and ≥60-year-old patients. Hematological and extra-hematological toxicities after AHCT were comparable between the two groups of age. In univariate analysis, poorer OS and PFS were associated with disease status other than complete remission, hematopoietic cell transplantation comorbidity index (HCT-CI) scores >1, and Charlson Comorbidity Index (CCI) scores >1. HCT-CI scores >1 were also associated with a higher risk of grade 3-4 extrahematologic toxicity. In multivariate analysis, HCT-CI and CCI remained significantly associated with OS and PFS after adjustment for disease status. Our data show that AHCT can be performed in selected patients with R/R HL ≥50years with acceptable outcome and toxicity. Comorbidities appear to impact AHCT outcome more than age.

Risk of thrombosis according to need of phlebotomies in patients with polycythemia vera treated with hydroxyurea.

Hematocrit control below 45% is associated with a lower rate of thrombosis in polycythemia vera. In patients receiving hydroxyurea, this target can be achieved with hydroxyurea alone or with the combination of hydroxyurea plus phlebotomies. However, the clinical implications of phlebotomy requirement under hydroxyurea therapy are unknown. The aim of this study was to evaluate the need for additional phlebotomies during the first five years of hydroxyurea therapy in 533 patients with polycythemia vera. Patients requiring 3 or more phlebotomies per year (n=85, 16%) showed a worse hematocrit control than those requiring 2 or less phlebotomies per year (n=448, 84%). There were no significant differences between the two study groups regarding leukocyte and platelet counts. Patients requiring 3 or more phlebotomies per year received significantly higher doses of hydroxyurea than the remaining patients. A significant higher rate of thrombosis was found in patients treated with hydroxyurea plus 3 or more phlebotomies per year compared to hydroxyurea with 0-2 phlebotomies per year (20.5% vs. 5.3% at 3 years; P<0.0001). In multivariate analysis, independent risk factors for thrombosis were phlebotomy dependency (HR: 3.3, 95%CI: 1.5-6.9; P=0.002) and thrombosis at diagnosis (HR: 4.7, 95%CI: 2.3-9.8; P<0.0001). The proportion of patients fulfilling the European LeukemiaNet criteria of resistance/intolerance to hydroxyurea was significantly higher in the group requiring 3 or more phlebotomies per year (18.7% vs. 7.1%; P=0.001) mainly due to extrahematologic toxicity. In conclusion, phlebotomy requirement under hydroxyurea therapy identifies a subset of patients with increased proliferation of polycythemia vera and higher risk of thrombosis.

Frontline Dasatinib Treatment in a “Real-Life” Cohort of Patients Older than 65 Years with Chronic Myeloid Leukemia

Dasatinib (DAS) has been licensed for the frontline treatment in chronic myeloid leukemia (CML). However, very few data are available regarding its efficacy and toxicity in elderly patients with CML outside clinical trials. To address this issue, we set out a “real-life” cohort of 65 chronic phase CML patients older than 65 years (median age 75.1 years) treated frontline with DAS in 26 Italian centers from June 2012 to June 2015, focusing our attention on toxicity and efficacy data. One third of patients (20/65: 30.7%) had 3 or more comorbidities and required concomitant therapies; according to Sokal classification, 3 patients (4.6%) were low risk, 39 (60.0%) intermediate risk, and 20 (30.8%) high risk, whereas 3 (4.6%) were not classifiable. DAS starting dose was 100 mg once a day in 54 patients (83.0%), whereas 11 patients (17.0%) received less than 100 mg/day. Grade 3/4 hematologic and extrahematologic toxicities were reported in 8 (12.3%) and 12 (18.5%) patients, respectively. Overall, 10 patients (15.4%) permanently discontinued DAS because of toxicities. Pleural effusions (all WHO grades) occurred in 12 patients (18.5%) and in 5 of them occurred during the first 3 months. DAS treatment induced in 60/65 patients (92.3%) a complete cytogenetic response and in 50/65 (76.9%) also a major molecular response. These findings show that DAS might play an important role in the frontline treatment of CML patients >65 years old, proving efficacy and having a favorable safety profile also in elderly subjects with comorbidities.

Imatinib and polypharmacy in very old patients with chronic myeloid leukemia: effects on response rate, toxicity and outcome.

BackgroundAbout 40% of all patients with chronic myeloid leukemia are currently old or very old. They are effectively treated with imatinib, even though underrepresented in clinical studies. Furthermore, as it happens in the general population, they often receive multiple drugs for associated chronic illnesses. Aim of this study was to assess whether or not in imatinib-treated patients aged >75 years the exposure to polypharmacy (5 drugs or more) had an impact on cytogenetic and molecular response rates, event-free and overall survival, as well as on hematological or extra-hematological toxicity.Methods296 patients at 35 Italian hematological institutions were evaluated.ResultsPolypharmacy was reported in 107 patients (36.1%), and drugs more frequently used were antiplatelets, diuretics, proton pump inhibitors, ACE-inhibitors, beta-blockers, calcium channel blockers, angiotensin II receptors blockers, statins, oral hypoglycemic drugs and alpha blockers. Complete cytogenetic response was obtained in 174 patients (58.8%), 78 (26.4%) within 6 month, 63 (21.3%) between 7 and 12 months. Major molecular response was obtained in 153 patients (51.7%), 64 (21.6%) within the 12 month. One hundred and twenty-eight cases (43.2%) of hematological toxicity were recorded, together with 167 cases (56.4%) of extra-hematological toxicity. Comparing patients exposed to polypharmacy to those without, no difference was observed pertaining to the dosage of imatinib, cytogenetic and molecular responses and hematological and extra-hematological toxicity.ConclusionNotwithstanding the several interactions reported in the literature between imatinib and some of the medications considered herewith, this fact does not seem to have a clinical impact on response rate and outcome.

Iron Overload Exacerbates Busulfan-Melphalan Toxicity Through a Pharmacodynamic Interaction in Mice.

Busulfan-melphalan high-dose chemotherapy followed by autologous stem cell transplantation is an essential consolidation treatment of high-risk neuroblastoma in children. Main treatment limitation is hepatic veno-occlusive disease, the most severe and frequent extra-hematological toxicity. This life threatening toxicity has been related to a drug interaction between busulfan and melphalan which might be increased by prior disturbance of iron homeostasis, i.e. an increased plasma ferritin level. We performed an experimental study of busulfan and melphalan pharmacodynamic and pharmacokinetics in iron overloaded mice. Iron excess dramatically increased the toxicity of melphalan or busulfan melphalan combination in mice but it did not modify the clearance of either busulfan or melphalan. We show that prior busulfan treatment impairs the clearance of melphalan. This clearance alteration was exacerbated in iron overloaded mice demonstrating a pharmacokinetic interaction. Additionally, iron overload increased melphalan toxicity without altering its pharmacokinetics, suggesting a pharmacodynamic interaction between iron and melphalan. Based on iron homeostasis disturbance, we postulated that prior induction of ferritin, through Nrf2 activation after oxidative stress, may be associated with the alteration of melphalan metabolism. Iron overload increases melphalan and busulfan-melphalan toxicity through a pharmacodynamic interaction and reveals a pharmacokinetic drug interaction between busulfan and melphalan.

Frequency and prognostic value of resistance/intolerance to hydroxycarbamide in 890 patients with polycythaemia vera.

The clinical significance of resistance/intolerance to hydroxycarbamide (HC) was assessed in a series of 890 patients with polycythaemia vera (PV). Resistance/intolerance to HC was recorded in 137 patients (15·4%), consisting of: need for phlebotomies (3·3%), uncontrolled myeloproliferation (1·6%), failure to reduce massive splenomegaly (0·8%), development of cytopenia at the lowest dose of HC to achieve a response (1·7%) and extra-haematological toxicity (9%). With a median follow-up of 4·6 years, 99 patients died, resulting in a median survival of 19 years. Fulfilling any of the resistance/intolerance criteria had no impact on survival but when the different criteria were individually assessed, an increased risk of death was observed in patients developing cytopenia [Hazard ratio (HR): 3·5, 95% confidence interval (CI): 1·5-8·3, P = 0·003]. Resistance/intolerance had no impact in the rate of thrombosis or bleeding. Risk of myelofibrotic transformation was significantly higher in those patients developing cytopenia (HR: 5·1, 95% CI: 1·9-13·7, P = 0·001) and massive splenomegaly (HR: 9·1, 95% CI: 2·3-35·9, P = 0·002). Cytopenia at the lowest dose required to achieve a response was also an independent risk factor for transformation to acute leukaemia (HR: 20·3, 95% CI: 5·4-76·5, P < 0·001). In conclusion, the unified definition of resistance/intolerance to HC delineates a heterogeneous group of PV patients, with those developing cytopenia being associated with an adverse outcome.

Cyclophosphamide, Gemcitabine, Vinorelbine and Prednisone (CGEV) As Salvage Therapy for Relapsed or Refractory Hodgkin´s Lymphoma before Hematopoietic Stem Cell Transplantation: A Single Center Experience

Background and Objectives:Although the therapy of advanced-stage Hodgkin Lymphoma (HL) has improved, up to 10% of patients with advanced-stage HL will not achieve complete remission (CR) with standard therapy, and 20%-30% of responders will relapse after treatment.The disease status before autologous stem cell transplantation remains the most important factor predicting outcome for patients with relapsed or refractory HL. The IGEV regimen (Ifosfamide, gemcitabine, vinorelbine and prednisolone) is a good option for salvage induction therapy before autologous stem cell transplantation, with a reported overall response rate of 81%. Due to the high cost of the IGEV regimen, and the financial constrains of our population, we decided to modify the original regimen using cyclophosphamide instead of ifosfamide.Design and methods:From January 2011 to January 2015, 19 patients with relapsed or refractory HL received the protocol consisting of four cycles of cyclophosphamide, gemcitabine, vinorelbine and prednisone (CGEV). It was administrated in outpatient setting. The CGEV regimen consists of cyclophosphamide 600 mg/m2 on days 1 to 3, gemcitabine 800 mg/m2 on days 1 and 4, vinorelbine 20 mg/m2 on day 4, prednisone 100 mg on days 1 to 4 and granulocyte colony-stimulating factor (G-CSF) from day 7 to 12 of each course. Four courses of chemotherapy were planned before autologous stem cell transplantation, after the third course, autologous peripheral blood stem cells (PBSC) were collected.Results:Nineteen patients with primary refractory or relapsed HL received the CGEV regimen. There were 10 males and 9 females. Nodular sclerosis was the most frequent histological subtype in 73%. At diagnosis, there were 7 (36%) patients in clinical stage IV and 12 (63%) in early stage I-II. The lungs were the most frequent extranodal organ involved. B symptoms were present in 9 (47%) patients. All our patients received as first line chemotherapy the regimen ABVD, the disease status before salvage induction chemotherapy with CGEV was: 9 (47%) patients with refractory disease and 10 (53%) patients were in relapse. The median number of cycles administrated was 4 (1-4). Only 14 patients received the total planned courses.The overall response to the CGEV regimen was 78%, of these, 6 (42.8%) patients achieved complete response and 5 (35.7%) partial response.Ten patients underwent autologous stem cell mobilization, obtaining an adequate CD34+ cell collection in all the patients. The median number of CD34+ cell was 9.08 x 106/kg (2.1-5.60 x 106/kg) with a median of 1 apheresis procedure.Hematologic grade 3 and 4 toxicity developed in 11 (59%) patients, no grade 4 extra-hematologic toxicity was observed. There were 3 treatment-related infections. Four patients died, 2 due to septic shock, and 2 with disease progression.Interpretation and conclusions:We describe a similar overall response rate of 78% with CGEV regimen compared with the 81% reported with IGEV regimen, it is less expensive and can be used in relapsed or refractory patients with HL, as salvage regimen before autologous stem cell transplantation. DisclosuresNo relevant conflicts of interest to declare.

Efficacy and Toxicity of Nucleoside Analogs in Patients with Hairy Cell Leukemia Treated Outside Clinical Trials

INTRODUCTION. Hairy cell leukemia (HCL) is a rare indolent B-cell malignancy, mainly characterized by peripheral cytopenias and splenomegaly. The current standard of treatment for HCL are Nucleoside Analogs (NA) cladribine and pentostatin, which produce remarkably high remission rates and durable responses. Aim of this study was to evaluate efficacy, short- and long-term toxicity of NA in HCL pts treated outside clinical trials.PATIENTS AND METHODS. We retrospectively analyzed 86 HCL patients (pts) treated with NA between 1996 and 2015 in two Hematologic Centers in Italy. The study was conducted in accordance to the Helsinki Declaration of 1964, as revised in 2000. Cladribine and pentostatin were administered according to standard schedules. Response criteria published by Jones et al. (Br J Haematol 2012) were retrospectively applied. Molecular assessment of BRAF-V600E mutation before and after NA therapy using quantitative real-time polymerase chain reaction (qRT-PCR)-based allelic discrimination assay (sensitivity 0.1%) was performed in 10 pts.RESULTS. The median follow-up of pts (71 males and 15 females, median age 53 years) was 5.8 years (range 0.5-28). During the disease course, 86 pts were treated with NA (cladribine n=76, 88%; pentostatin n=10, 12%); 59 pts received NA front-line (cladribine in 56/59 pts, 95%). Among the other 27 pts, receiving NA as second or subsequent line of therapy, 25 had been previously treated with interferon. Median time from diagnosis to the first NA was 3.3 months (range 0-315). Hematological toxicity was observed in 53 of 77 evaluable pts (69%), and was not significantly different with cladribine (72%) or with pentostatin (37%) (p=0.1). Grade 3-4 neutropenia, anemia and thrombocytopenia were observed in 50 (65%), 7 (9%) and 7 (9%) pts respectively. Extra-hematological toxicity was reported in 48 of 79 evaluable pts (61%). The incidence of extra-hematological toxicity with cladribine (63%) and pentostatin (37%) was not statistically different (p=0.2). Grade 3-4 febrile neutropenia was observed in 24 pts (30%); 9 pts (11%) had grade 3-4 infections; 4 pts (5%) had grade 3-4 skin toxicity, 1 pt (1%) had grade 3 hepatic toxicity. Four of 86 pts (5%) developed a second malignancy (prostatic adenocarcinoma n=2, colon adenocarcinoma n=1, diffuse large B cell lymphoma n=1). The median time from NA to second malignancy was 58 months (range 49-111). Four of 86 pts (5%) developed a skin cancer (basal-cell carcinoma n=3, squamous cell carcinoma n=1), after a median time of 59 months (range 16-126). Response was assessed at a median time of 3 months after the end of therapy. Overall Response Rate (ORR) and Complete Remission (CR) Rate were respectively 93% and 63% in the entire cohort, and 98% and 72% in pts treated with NA front-line. The allelic burden of BRAF before and after therapy with NA was available in 10 cases; none of the pts in clinical CR after NA achieved a complete molecular response (Table 1). The median Progression-Free Survival (PFS) for pts treated with NA frontline was 6.5 years. There was a trend toward a longer PFS in pts receiving NA as first-line therapy as compared to those treated in second or subsequent lines (p=0.05). PFS curves according to type of NA and line of therapy are shown in Figure 1. The 5- and 10-year Overall Survival (OS) rates were 96% (95% CI: 85% - 99%) and 90% (95% CI 76%-96%) respectively. OS was similar in pts treated with cladribine orpentostatin (p=0.49).CONCLUSIONS. This study shows that: i) NA are associated with an acceptable toxicity, neutropenia and febrile neutropenia being the main complications of therapy; ii) timing of response assessment may account for a CR rate that is slightly lower than reported in the literature, confirming the importance of waiting at least 4 months for response evaluation as recommended by current guidelines; iii) the persistence of molecular disease also in pts achieving a clinical CR supports the implementation of consolidation strategies aimed at eradicating minimal residual disease to prolong disease-free survival.Table 1BRAF allelic burden before and after therapyPatientAge (years)SexLine of TherapyAllelic Burden (%)Clinical ResponsePre- Post-133F121,80,1CR236M25,40,4CR339M124,20,7CR454M110,80,3PR542F1441,2CR653F17,90,2NV756M16,50,3CR854M112,20,2CR932M135,89,5PR1038M254,412,2PR [Display omitted] DisclosuresArcaini:Gilead: Consultancy, Other: Advisory Board; Celgene: Consultancy, Other: Advisory Board; Roche: Consultancy, Other: Advisory Board.

Long-Term Follow-up in Very Elderly Patients with Chronic Myeloid Leukemia Treated with Imatinib Frontline

In the current clinical practice, imatinib is widely used also in very elderly patients with chronic myeloid leukemia (CML) at different doses based on concomitant diseases and physician' judgment. However, data on long-term follow-up of these patients are still lacking. To address this issue, we revised in our retrospective database 233 CML patients aged ≥ 75 years and treated with imatinib frontline in 34 italian hematological centers from 2/2002 to 7/2014. Median age at diagnosis was 78.4 years [interquartile range (IQR) 76.3 - 81.3], there were 113 males (48.5%) and 120 females (51.5%), median WBC, Hb and PLT counts were 45.0 x 109/l (IQR 29.4 - 83.4), 12,4 g/dl (IQR 11.0 - 13.6) and 375 x 109/l (IQR 238 - 680), respectively. Sokal Risk at diagnosis was low in 1 patient (0.4%), intermediate in 149 (67.4%), high in 71 (32.2%) and not evaluable in 12. One or more concomitant diseases requiring specific treatments were present in 225/233 patients (96.5%). Median interval from diagnosis to imatinib start was 0.7 month (IQR 0.2 - 1.4): the initial imatinib dose was 400 mg/day in 161 patients (69.1%), 300 mg/day in 57 (24.5%) and < 300 mg/day in 15 (6.4%). According to WHO, a grade 3 - 4 hematological and extra-hematological toxicity was reported in 44 (18.8%) and 41 (17.6%) patients, respectively. As to cumulative response, 13 patients (5.6%) discontinued IM due to early toxicity, 4 (1.7%) were resistant and 2 (0.8%) died from unrelated cause early after IM initiation: the remaining 214 patients (91.9%) achieved a complete haematological response (CHR). Among these 214 patients in CHR, 13 refused any other karyotipic or molecular evaluation, 23 achieved CHR only and 178 (76.4% of all 233 patients) achieved a cytogenetic response (CyR), which was partial in 16 patients and complete (CCyR) in 162 (69.5% of all 233 patients). In addition, among the 162 patients in CCyR, 125 (53.6% of all 233 patients) achieved a molecular response (MolR) (ratio < 0.1). A blastic phase occurred in 11 patients (4.7%). After a median follow-up from imatinib start of 45.0 months (IQR 22.3 - 72.0), 70 patients have died (9 from disease progression and 61 from unrelated causes), 16 patients were lost to follow-up and 147 are still alive (115 of them still in treatment with imatinib): 5-year event-free survival (EFS) and overall survival (OS) were 51.4% (CI95% 43.9 - 58.9) and 68.5% (CI95% 61.2 - 75.8), respectively. At univariate analysis, only the initial dose of imatinib (400 vs ≤ 300, p=0.03) was a significant predictive factor for CCyR achievement while only PLT count ≤ 500 x 109/l (p=0.031) was a significant predictive factor for MolR achievement. At multivariate analysis for EFS, achievement of a MolR (OR 0.25, 95%CI 0.14 - 0.43, p<0.001), achievement of a CCyR (OR 0.40, 95%CI 0.23 - 0.67, p=0.001) and spleen enlargement (OR 1.56, 95%CI 1.01 - 2.41, p=0.042) were independent prognostic factors; at multivariate analysis for OS, achievement of a MolR (OR 0.30, 95%CI 0.18 - 0.49, p<0.001), age < 80 yrs (OR 0.53, 95%CI 0.33 - 0.86, p=0.011) and male gender (OR 1.80, 95%CI 1.11 - 2.91, p=0.016) were independent prognostic factors. In conclusion, the long term follow-up of very elderly CML patients who started imatinib is very good and justify any effort to treat these patients with standard doses, in order to achieve cytogenetic and molecular responses as in younger subjects. DisclosuresCastagnetti:BMS: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; ARIAD: Consultancy, Honoraria. Tiribelli:Ariad Pharmaceuticals: Consultancy, Speakers Bureau; Novartis Farma: Consultancy, Speakers Bureau; Bristol Myers Squibb: Consultancy, Speakers Bureau. Gugliotta:BMS: Honoraria; Novartis: Honoraria. Abruzzese:BMS, Novartis, Pfizer, Ariad: Consultancy.

Metronomic Chemotherapy Is Effective and Well Tolerated in Relapsed/Refractory Elderly Patients with Aggressive B- and T-Cell Lymphomas

BACKGROUNDElderly patients with Relapsed/Refractory (R/R) aggressive Large B-cell lymphoma (LBCL) and Peripheral T-cell lymphomas (PTCL), are commonly treated with intravenous conventional chemotherapies, which are often poorly tolerated and of short-lasting efficacy. Therefore only few fit-elderly patients might undergo intensive treatments with curative intent. Metronomic chemoterapy (MTN-CHT) is a new way of administering old drugs at low doses with only short chemotherapy free intervals. MTN-CHT may be combined with new targeted molecules, immunotherapies and radiotherapy. Although very few reports on MTN-CHT in LBCL and PTCL have been published existing data suggest that these lymphomas might respond to this approach. AIMWe aimed at demonstrating the efficacy and safety of MTN-CHT in a retrospective series of elderly patients with LBCL and PTCL, unfit for conventional treatments. PATIENTS AND TREATMENTSFrom October 2008 up to May 2015 we treated elderly patients with R/R LBCL, Follicular Lymphoma(FL) and PTCL with MTN-CHT based regimen. Eligible patients should have given written informed consent, have a Performance Status=0-3, a life expection >2 months, be able to take oral therapy and have a care-giver. We used three different MTN schedules1] Provecip; 2] Vinblastine+Endoxan+Etoposide+Prednisone (VEED) and in the last two years an all-oral schedule 3] Navelbine+Endoxan+Etoposide+Prednisone (DE-VEC). All three schedules of MTN-CHT consisted of an induction phase of six months followed by a maintenance phase administered until progression or excessive toxicity. Rituximab was added to the induction phase for those patients characterized by CD20 expression. Thrombosis prophylaxis was carried out with aspirin or LMWH.RESULTS Patients featuresLBCL=21; PTCL=7, FL=3; Age=77y (median, range 62-90), Previous CHT=2 (median, range 0-5) refractory to last CHT= 43%. MTN-CHT: 8 pts were treated with schedule 1], 8 pts with schedule 2] and 15 pts with schedule 3]. Outcome: in aggressive B and T-cell lymphomas (n=28pts) with all schedules Overall Response Rate = 62%, Complete Remission rate = 36%; Progression Free Survival = 8 months, Median Duration of Response (DOR)= 10 months. Overall Response Rate and Complete Remission in the subset treated with the all-oral DE-VEC schedule were 66% and 50% respectively. Serious adverse events: Extra hematologic toxicity grade 3-4: pulmonary embolism in 1pts; hematological toxicity of grade 3-4 and/or neutropenic infections in 6 patients 5 of whom had >2 previous conventional chemotherapies. The use of DE-VEC all-oral schedule reduced the number and the durations of day-hospital admissions.CONCLUSIONAlthough our series is limited, these results suggest that MTN-CHT in elderly patients with R/R LBCL, PTCL and FL might achieve favorable results in terms of activity, toxicity and costs due to hospital admissions. With MTN-CHT most of the patients did not need G-CSF. Notably, patients who had had >2 lines of chemotherapies may be at very high risk of prolonged cytopenia and infections during MTN-CHT. Since the all-oral DE-VEC schedule was particularly manageable and active we believe that this combination deserve further investigation in aggressive lymphomas. DisclosuresNo relevant conflicts of interest to declare.

Bendamustine-Bortezomib-Desametasone (BVD) in the Management of Relapsed and Refractory Multiple Myeloma : A REAL-Life Experience

Introduction:Bendamustine is a bifunctional alkylating agent, with low toxicity, proved to be effective in relapsed, refractory and in new diagnosed Multiple Myeloma (MM).It has been evaluated efficacy and tolerance of Bendamustine, in combination with bortezomib-dexametasone (BVD) in patients with relapsed and refractory MM (rrMM), whose prognosis is particularly severe. A regional retrospective real-life analysis of patients with rrMM who had been treated with BVD as salvage therapy has been performed.Methods:35 patients (19 M/16 F), with rrMM, median age at diagnosis 57 years (r. 36-82), median age at start of treatment 62 years (r.37-83) treated with several lines of treatments (median 6, r. 2-11), every refractory to all the drugs previously received (also Bortezomib), received BVD (Bendamustine 90mg/sqm days 1,2; Bortezomib 1.3mg/sqm days 1,4,8,11, Desametasone 20mg days 1,2,4,5,8,9,11,12, Pegfilgrastim day +4) every 28 days, until progression.ISS was equally distributed, and cytogenetic was evaluable in 9 patients, and in particular one del13q and one t(11;14). All the patients had previously been treated with schedule containing bortezomib and IMIDs, 90% of them with melphalan, 77% with cyclophosphamide, 34% with antracyclines and 30% had also received radiotherapy. 58% of them had undergone at least to a single auSCT. All patients were relapsed and refractory to last therapies received before BVD.Results:Bendamustine was well tolerated, with grade 3 transfusion-dependent anemia in 29% of patients, and 41% grade 3 neutropenia (no ospedalization was required, no septic shocks were observed). No severe extrahematologic toxicity was observed, only grade 1 gastrointestinal side effect (nausea), treated by common antiemetic drugs.According to IMWG, after a median follow-up of 9 months (r.2-36), ORR was 54% (1 CR, 1 VGPR, 9 PR, 8 MR) with 7 PD and 9 patients in SD, which can be considered as an impressive result in this subset of rrMM patients. In particular, for 4 patients, BVD was, after having achieved a PR, a bridge to second auSCT, and for one patient a bridge to auSCT.Median OS from diagnosis was 61.4 months (range 6-151), median OS from start of Bendamustine was 7.2 months (range 2-36).Conclusion:BVD has shown significant efficacy (ORR 54%) in a particular severe setting of patients, relapsed and refractory to all avaiable therapeutic resources, and in particular cases it could be considered as a bridge to a second autologous or allogenic BMT. DisclosuresNo relevant conflicts of interest to declare.

Lenalidomide in Combination with Bendamustine for Patients with Chemorefractory Hodgkin Lymphoma: Final Results of the Leben Multicenter Phase 1/2 Study

BackgroundImproving strategies for patients (pts) with relapsed/refractory (R/R) Hodgkin lymphoma (HL) who fail stem cell transplantation (SCT) or are unsuitable for the procedure remains an essential need. Lenalidomide and bendamustine are active and well tolerated as single agents in recurrent HL, with overall response rates (ORR) of 30% to 53% [Fenhinger, 2012; Corazzelli, 2012; Moskowitz, 2012].These agents independently frame different targets on tumor and microenvironment cells and may cooperate to override disturbed immunologic pathways and circumvent drug resistance in HL. In a Bayesian, multi-center, open label phase 1/2 study, we investigated for safety and efficacy the combination of continuous lenalidomide with weekly bendamustine (ClinicalTrials.gov # NTC01412307).MethodsThe study aimed at defining the optimal daily dose of continuous lenalidomide (10, 15, 20 or 25 mg) as combined, in a 28-day cycle, to weekly fixed-dose bendamustine (60 mg/m2; d 1, 8, 15). The dose-finding algorithm proceeded in cohorts of 3 pts, based on anticipated efficacy and toxicity pairs of probability (Thall & Cook, Biometrics 2004). Trade-offs between response [Cheson 2007 criteria] and dose-limiting toxicity [CTCv3.0 grade (G) >3 lasting >2 weeks] were assessed after 2 cycles (day +56) and pts were planned to receive up to 6 total courses, unless progression or unacceptable toxicity occurred. ORR and progression-free survival (PFS) were additional endpoints.ResultsThirty-six pts (69% male) with a median age of 31 yrs (r 19-75) were enrolled. The median number of prior therapies was 4 (r 1-9) and the median time from upfront treatment was 24 mo.s (r 7-118). Twenty-six pts (72%) had primary refractory disease after ABVD, 16 pts (44%) failed prior SCT [single (n=7) or tandem (n=3) ASCT, tandem ASCT/alloSCT (n=6)]. Fifteen pts (42%) had previously received a median of 5 cycles (r 2-8) of brentuximab vedotin (BV) and 3 pts were already given bendamustine (>3 courses). Overall, 23 pts (64%) were refractory to most recent therapy. Eff/Tox trade-offs at cycle 2 showed that 73% of pts had response w/o toxicity, 19% had no response w/o toxicity, 6% had response with toxicity and 2% had no response with toxicity. With such Eff/Tox profiles, the study algorithm did not prompt any dose escalation for lenalidomide after the first 18 pts and the initial dose level (10 mg) was adopted for the expansion phase. A total of 156 LeBen cycles were administered, and pts received a median of 4 courses (r 1-6). Overall, 16 cycles were delayed due to G3/G4 thrombocytopenia (n=6), G4 neutropenia (n=3), G3 pneumonia (n=3), G3 respiratory infection (n=2), G2 phlebitis (n=1), G2 supraventricular arrhythmia (n=1). Two patients discontinued treatment, while in PR and CR after 4 courses, due to protracted (>2 weeks) thrombocytopenia. No G4 extra-hematological toxicity was observed. The complete response (CR) rate was 44% (16/36) with an ORR of 75% (27/36; 95% CI, 59-86). Notably, substantial CR and PR rates were achieved after LeBen regardless of primary refractoriness, SCT and BV failure (Table). Most CRs (14/16) were obtained within the first 4 cycles; 6 responders (4 CRs and 2 PRs) underwent SCT. Median PFS was 3.2 mo.s (r 1.5-5.4) for pts with progressive (PD) or stable disease (SD) and 11.4 mo.s (r 4-31) for those achieving CR/PR. Median overall survival for the entire cohort was 24 mo.s. Overall, complete responders (including 6 pts consolidated with SCT) had a 2-year disease-free survival of 41% (median, 14.3 mo.s).ConclusionsThe innovative schedule of the Leben combination is safe, yields high response rates in heavily pretreated and primary refractory HL pts, including SCT and BV failures, and steps over the 'single agent' activity of its components. Due to its immunomodulatory potential the Leben platform is amenable to further upgrading through lenalidomide maintenance, combination with immune checkpoint inhibitors and BV.Table 1Efficacy resultsResponsesno. (%)All ptsRefractory to upfront therapyRefractory to most recent therapyFailure after SCTFailure after ASCTFailure after AlloSCTFailure after BVFailure after SCT and BVFailure after bendamustineNo BV(n=36)(n=26)(n=23)(n=16)(n=10)(n= 6)(n=15)(n=8)(n=3)(n=21)CR16 (44)11 (42)8 (35)8 (50)6 (60)2 (33)5 (33)3 (37)011PR11894224207SD2221011111PD7543215222CR+PR27 (75)19 (73)17 (74)12 (75)8 (80)4 (66)9 (60)5 (62)018 (86) DisclosuresPinto:Takeda, Celgene, Roche, TEVA: Honoraria; Takeda: Research Funding. Zinzani:Takeda: Membership on an entity's Board of Directors or advisory committees; J&J: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees.

Chelation efficacy and erythroid response during deferasirox treatment in patients with myeloproliferative neoplasms in fibrotic phase.

At present, very few data are available on deferasirox (DFX) in the treatment of patients with Philadelphia-negative myeloproliferative neoplasms in fibrotic phase (FP-MPN) and transfusion dependence. To address this issue, a retrospective analysis of 28 patients (22 male and 6 female) with FP-MPN and iron overload secondary to transfusion dependence was performed, based on patients enrolled in the database of our regional cooperative group who received treatment with DFX. DFX was started after a median interval from diagnosis of 12.8months (IR 7.1-43.1) with median ferritin values of 1415ng/mL (IR 1168-1768). Extra-hematological toxicity was reported in 16 of 28 patients (57.1%), but only two patients discontinued treatment due to toxicity. Among 26 patients evaluable for response (≥6months of treatment), after a median treatment period of 15.4months (IR 8.1-22.3), 11 patients (42.3%) achieved a stable and consistent reduction in ferritin levels <1000ng/mL. As for hematological improvement, 6 of 26 patients (23%) showed a persistent (>3months) rise of Hb levels >1.5g/dL, with disappearance of transfusion dependence in four cases. Treatment with DFX is feasible and effective in FP-MPN with iron overload. Moreover, in this setting, an erythroid response can occur in a significant proportion of patients.