EHA 2014 N. 18 comunicazioni su Bendamustina 2 comunicazioni orali A. Tedeschi (Niguarda, MI) BR Waldenstrom S. Gandolfi (Humanitas, MI) BEGEV 11 posters e 5 solo per pubblicazione N. 3 comunicazioni su DepoCyte 1 poster e 2 solo per pubblicazione

CLL, effetti collaterali FCR

Treatment related mortality CLL10: Tolerability AE, CTC grade 3-5 FCR BR P value Overall 90.8% 78.5% <0.001 Haematotoxicity 90.0% 66.9% Neutropenia 81.7% 56.8% Thrombocytopenia 21.5% 14.4 0.03 Infections 39.0% 25.4% 0.001 Infections in elderly 47.4% 26.5% 0.002 Treatment related mortality 3.9% (n=11) 2.1% (n=6) NS 561 patients were included in the study, 282 (50.3%) were randomised to the FCR and 279 (49.7%) to the BR arm. Median observation time was 27.9 months. 395 (70.4%) of all patients developed an infection. A total of 1050 infections were reported and 26.2% were defined as severe (CTC grade 3-5). When comparing the different treatment arms significantly more patients treated with FCR developed an infection (53.2 vs. 46.8%, p=0.034) and infections were more severe (29.8 vs. 21.3%, p=0.002). The average number of infections in all affected patients was 2.6. Median time from registration to onset was 4.6 months in the FCR-group compared to 5.0 months in the BR-group. Late infections occurred significantly more in the FCR-treated patients after initial response (23.8 vs. 10.7%, p<0.000) and final restaging (19.8 vs. 10.8%, p=0.008). The causative pathogen was identified as bacterial in 15.7%, as viral in 14.8%, as fungal in 2%, and as other in 2.3%. The pathogen was unknown in 66.8%. Viral infections were significantly more common in patients treated with FCR (20.8% vs. 12.3%, p=0.007). 13.9% of all infections were classified as fever of unknown origin, followed by pneumonia in 8.9%, and bacteremia in 3%. Severe pneumonia was more frequently observed in patients treated with FCR (32 vs. 17, p=0.027). Antibiotic treatment was administered in 76.1% of all documented infections, followed by antiviral, and antifungal treatment in 15.3, and 4.6% respectively. G-CSF was administered in 85 (8.3%) cases and was significantly more frequently given with FCR treatment (10.8 vs. 4.8%, p=0.001). Inpatient treatment was necessary in 141 and intensive care treatment in 12 patients, there was no significant differences in both treatment arms. Six patients in the BR arm and seven patients in the FCR arm died due to treatment related infectious complications. Pneumonias and sepsis were the reason for death in five patients each; one patient each died because of neutropenic colitis, hepatitis B and progressive multifocal leukencephalopathy. Interval: 1st cycle until 3 months after final staging Eichhorst B et al. Abstract at ASH 2013

Infezioni nello studio CLL10 Infezioni in 395 pazienti (70.4%) 1050 infezioni, 26.2 % severe (CTC grade 3-5) FCR BR P value Infezioni 74.5% 66.3% 0.03 Infezioni G 3-5 29.8% 21.3% 0.002 Infezioni virali 20.8% 12.3% 0.007 Infezioni fatali 3.9% (n=6) 2.1% (n=5) NS 561 patients were included in the study, 282 (50.3%) were randomised to the FCR and 279 (49.7%) to the BR arm. Median observation time was 27.9 months. 395 (70.4%) of all patients developed an infection. A total of 1050 infections were reported and 26.2% were defined as severe (CTC grade 3-5). When comparing the different treatment arms significantly more patients treated with FCR developed an infection (53.2 vs. 46.8%, p=0.034) and infections were more severe (29.8 vs. 21.3%, p=0.002). The average number of infections in all affected patients was 2.6. Median time from registration to onset was 4.6 months in the FCR-group compared to 5.0 months in the BR-group. Late infections occurred significantly more in the FCR-treated patients after initial response (23.8 vs. 10.7%, p<0.000) and final restaging (19.8 vs. 10.8%, p=0.008). The causative pathogen was identified as bacterial in 15.7%, as viral in 14.8%, as fungal in 2%, and as other in 2.3%. The pathogen was unknown in 66.8%. Viral infections were significantly more common in patients treated with FCR (20.8% vs. 12.3%, p=0.007). 13.9% of all infections were classified as fever of unknown origin, followed by pneumonia in 8.9%, and bacteremia in 3%. Severe pneumonia was more frequently observed in patients treated with FCR (32 vs. 17, p=0.027). Antibiotic treatment was administered in 76.1% of all documented infections, followed by antiviral, and antifungal treatment in 15.3, and 4.6% respectively. G-CSF was administered in 85 (8.3%) cases and was significantly more frequently given with FCR treatment (10.8 vs. 4.8%, p=0.001). Inpatient treatment was necessary in 141 and intensive care treatment in 12 patients, there was no significant differences in both treatment arms. Six patients in the BR arm and seven patients in the FCR arm died due to treatment related infectious complications. Pneumonias and sepsis were the reason for death in five patients each; one patient each died because of neutropenic colitis, hepatitis B and progressive multifocal leukencephalopathy. Langerbeins et al, EHA Congress 2014, P237

Infezioni FCR vs BR nello studio CLL10 Infections CTC grade 3/4/5   total FCR BR p value overall 32,3% 39,0% 25,4% 0,001 bacterial 1,3% 1,8% 0,7% ns fungal 0,5% 1,1% 0,0% pneumonia 8,8% 11,5% 6,1% 0,03 viral 4,9% 6,5% 3,2% pathogen unspecified 22,8% 27,2% 18,4% 0,01 561 patients were included in the study, 282 (50.3%) were randomised to the FCR and 279 (49.7%) to the BR arm. Median observation time was 27.9 months. 395 (70.4%) of all patients developed an infection. A total of 1050 infections were reported and 26.2% were defined as severe (CTC grade 3-5). When comparing the different treatment arms significantly more patients treated with FCR developed an infection (53.2 vs. 46.8%, p=0.034) and infections were more severe (29.8 vs. 21.3%, p=0.002). The average number of infections in all affected patients was 2.6. Median time from registration to onset was 4.6 months in the FCR-group compared to 5.0 months in the BR-group. Late infections occurred significantly more in the FCR-treated patients after initial response (23.8 vs. 10.7%, p<0.000) and final restaging (19.8 vs. 10.8%, p=0.008). The causative pathogen was identified as bacterial in 15.7%, as viral in 14.8%, as fungal in 2%, and as other in 2.3%. The pathogen was unknown in 66.8%. Viral infections were significantly more common in patients treated with FCR (20.8% vs. 12.3%, p=0.007). 13.9% of all infections were classified as fever of unknown origin, followed by pneumonia in 8.9%, and bacteremia in 3%. Severe pneumonia was more frequently observed in patients treated with FCR (32 vs. 17, p=0.027). Antibiotic treatment was administered in 76.1% of all documented infections, followed by antiviral, and antifungal treatment in 15.3, and 4.6% respectively. G-CSF was administered in 85 (8.3%) cases and was significantly more frequently given with FCR treatment (10.8 vs. 4.8%, p=0.001). Inpatient treatment was necessary in 141 and intensive care treatment in 12 patients, there was no significant differences in both treatment arms. Six patients in the BR arm and seven patients in the FCR arm died due to treatment related infectious complications. Pneumonias and sepsis were the reason for death in five patients each; one patient each died because of neutropenic colitis, hepatitis B and progressive multifocal leukencephalopathy. Langerbeins et al, EHA Congress 2014, P237

CLL10 Study: FCR VS BR in FrontLine Infections: Incidence by time * * * Cycle 1-3 Cycle 4-6 IR to FR FR to FU3 * p < 0.005 IR=Initial response; FR= final restaging Langerbeins et al, EHA Congress 2014, P237

Late Onset Neutropenia (LON): complicazione frequente dopo FCR Pazienti: 104 pz (66% CLL), età mediana 66 44 naive, 60 (58%) prec. chemioRX N. cicli FCR mediana 4 (1-6) Trattamento Neutropenia G3-4 43% • Neutropenia febbrile 20% Follow-up • LON 29% • Insorgenza dopo FCR 95 gg (53–326) 57% se G-CSF durante FCR 43% 19% Methods: We performed a retrospective analysis of 104 consecutive patients (pts) who received FCR treatment across 2 major cancer centres between 01/2004 and 11/2012, in order to determine the incidence, clinical consequence and risk factor for development of neutropenic complications (a) during therapy, and (b) in the first year after treatment completion. Eight-six pts received follow-up at their primary treatment center, with a minimum of 3 complete blood count over the 12 month study period. LON was defined as grade III-IV neutropenia (G3-4N) developing at least four weeks after cessation of therapy. Severe prolonged cytopenias are defined as grade III-IV cytopenias persisting for >4 weeks post completion of treatment.   Results: DURING THERAPY: the median age of the 104 pts (71M, 33F) was 66 years (range: 40-83). 69 received FCR for CLL; 35 for low-grade non-Hodgkin lymphomas. 44 previously untreated and 60 had prior chemotherapy [median 2 (range 1 – 6) regimens]. The median number of FCR cycles received was 4 (range: 1-6), and 16 pts received maintenance rituximab. G3-4N occurred in (43%), and febrile neutropenia in 20% of pts (5.8% per cycle). ONE YEAR POST THERAPY: Of the 86 pts assessable, LON was documented in 25 (29%) after a median of 95 (range 53-326) days from treatment cessation. The median LON neutrophil count was 0.4 x 109/L (range: 0.0-0.9). LON was associated with substantial morbidity: 28% of pts were hospitalized for neutropenic complications and 32% were administered antibiotics and G-CSF. There was no significant association between the risk of LON development and age, ECOG, disease subtype, previous therapy, number of FCR cycles, maintenance rituximab, baseline hemoglobin / neutrophil / platelet or baseline creatinine. However, there was a positive association between LON and the occurrence of G3-4N during treatment: of those pts who developed G3-4N during therapy (n=35), LON developed in 15 (43%; p=0.017 compared with 19% in pts without G3-4N, figure); this risk of LON rises to 57% for pts who developed G3-4N and received GCSF support. Among pts who did not develop G3-4N during treatment, female sex emerged as the dominant risk factor for LON (33% risk, vs 13% for males, p=0.07). Prolonged severe cytopenias occurred in 20 pts and similarly was more common in women (p<0.001) and those with grade 3-4N during treatment (p-0.005).  Summary/Conclusion: Neutropenic complications, particularly LON, is an under-recognized and poorly reported complication of FCR. LON in pts receiving FCR is associated with high morbidity and frequent hospitalization. Pts who develop G3-4N during FCR chemotherapy are at high risk of subsequent LON, particularly if their chemotherapy was supported using GCSF. Our results demonstrate that the onset of G3-4N during FCR chemotherapy identifies pts at high risk for late neutropenic complications, and sound a cautionary note regarding the use of GCSF support during FCR therapy. Ho K et al, EHA 2014 P238

Bendamustina nella Leucemia Linfatica Cronica

CLL, I linea: Studio retrospettivo multic. italiano RISULTATI Pazienti 66 pz > 65 aa (età mediana: 72 anni) Binet A/B/C: 17%/42%/41% Alteraz genetiche (55 pz): del11q 23.6%, del 17p 3.6%, IGHV non mutato 47.8% Mediana cicli: n 5.4 Risposte, % ORR 86.3 CR 31.8 PR 54.5 Fischer, 2012 ORR 88% CR 23% OS a 27 mesi 90.5% Trattamento Bendamustina 90 mg/m2 gg 2 e 3 Rituximab 375-500 mg/m2 g 1 Tossicità Ematologica G 3-4: 36.4% Non ematologica G 1-3: 50% ogni 28 giorni per 6 cicli A 2 anni: PFS 79% OS 89.6% Laurenti et al, EHA 2014

CLL, I linea: Studio retrospettivo multic. italiano RISULTATI Pazienti 118 pz (età mediana: 71 anni) Binet C: 28% Alteraz genetiche (valutate in 78/118 pz): del11q 10.3%, del 17p 6.4% pz CrCr < 70 ml/min :46% pz Mediana cicli: n 4 Risposte, % ORR 96 CR 69 PR 27 SD 4 Trattamento Bendamustina 90 (68%) -70 mg/m2 gg 2 e 3 Rituximab 375-500 mg/m2 g 1 Tossicità G 3-4 Neutropenia 16.1% Trombocitopenia 27.1% Anemia 16.1% Infezioni severe 6.8% ogni 28 giorni per 6 cicli Follow up (mediana 8 mesi): PFS a due anni 87% OS a due anni 80% Gentile et al, EHA 2014

CLL, I linea: Studio prospettico multic. tedesco RISULTATI Pazienti (2011-2013) 263 pz (età mediana: 73 anni) 63% > 70 anni Binet A/B/C: 21%/44%/31% Mediana cicli: n 6 Mediana dose: 174 mg/m2 per ciclo Discontinuazione: 6% Risposte, % ORR 89 CR 38.6 PR 50.6 Trattamento BR 90% B 7% Altre combinazioni 3% Tossicità AE più comune: neutro/leucopenia 25% (tutti i gradi) AE G 3/4 : 14% pz 1 exitus (sepsi) Bruch et al, EHA 2014

Bendamustina nei Linfomi non-Hodgkin indolenti

Linfoma Follicolare, I linea: Protocollo rituximab, bendamustine, mitoxantrone RBM risultati 70 (92%) hanno completato TX Pazienti 76 pazienti > 65 aa, “fit” Età mediana: 71 anni Istologia: grado I, II, IIIa FLIPI ad alto rischio 60% BCL-2/IgH + 51% dopo induzione, % dopo consolidam. % ORR 95 94 CR 42 78 PR 53 16 Trattamento Bendamustina 90 mg/m2 gg 1 e 2 Rituximab 375 mg/m2 g 1 Mitoxantrone 8 mg/m2 g 1 per 4 cicli Rituximab (consolidamento) (375 mg/m2 1 x 4 sett) Tossicità Neutropenia G3-G4: 18% cicli Infezioni severe: 6 pz (7.9%) Neutropenia febbrile 8 pz (10.5%) Boccomini et al, EHA 2014

R-BM induction plus rituximab consolidation in elderly de novo advanced stage follicular lymphoma Follow-up mediana 31 mesi PFS a 2 anni: 88% OS a 2 anni: 95% OS, overall survival; PFS, progression-free survival Boccomini et al. EHA 2014 Abstract P438

Waldenstrom, terapia di salvataggio Studio retrospettivo multicentrico italiano RISULTATI Risposte, % ORR 85 CR 7 VGPR 17 PR 55 Pazienti 71 pz Età mediana: 72 anni Mediana prec. trattamenti : 2 (1-5) 34% refrattari Trattamento Bendamustina 70 (n. 26)-90 (n.45) mg/m2 gg 1 e 2 Rituximab 375 mg/m2 g 1 ogni 28 giorni per 6 cicli 6 cicli di terapia in 47 pz (66%) Interruzione per tossicità: 10 pz (14%) Tossicità Neutropenia G3-G4: 36% Febbre nnd: 14 (14%) Infezioni G3-G5: 5 (7%) (1 exitus) Tedeschi et al EHA 2014

Waldenstrom, terapia di salvataggio Studio retrospettivo multicentrico italiano Follow-up (mediana 19 mesi): 11/57 (19.5%) progressioni 1 exitus Event Free Survival Overall Survival 57 (81%) 14 (19%) Tedeschi et al EHA 2014

Waldenstrom, terapie di salvataggio 71 2 (1-5) 85% 79% 14% 19 m NR Tedeschi et al EHA 2014

Linfoma Follicolare, I linea: Rituximab sc vs iv Studio Sabrina RISULTATI Pazienti 410 pz con LF grado I, II, IIIa R sc, % R iv, % ORR 83.4 84.4 CR/CRu 32.7 31.7 Trattamento CHOP (64%) o CVP (36%) Rituximab sc o Rituximab iv + mantenimento Risposte complete simili a studio BRIGHT (25% !!) Davies et al, EHA 2014

I.V. vs S.C. rituximab plus chemotherapy in first-line follicular lymphoma: Phase III trial Safety The majority of AEs were grade ≤2 in severity (1469/1651 AEs [90%] in the RSC arm; 1225/1386 AEs [88%] in the RIV arm) AEs Rituximab S.C. n, (%) Rituximab I.V. All 184 (93) 194 (92) Infections 20 (10) 16 (8) Febrile neutropenia 11 (6) 9 (4) Administration-related reactions 93 (47) 70 (33) Patients with at least one grade ≥3 AE 96 (49) 99 (47) Patients with ≥1 SAE 57 (29) 55(26) Safety: The majority of AEs were grade ≤2 in severity (1469/1651 AEs [90%] in the RSC arm; 1225/1386 AEs [88%] in the RIV arm). The incidence of patients with at least one grade ≥3 AE was similar between RSC (96/197, 49%) and RIV (99/210, 47%). Serious AEs (SAEs) were reported in 57 patients (29%) RSC and 55 patients (26%) RIV, respectively. Infections were the most frequently reported SAEs (20/197 [10%] SC; 16/210 [8%] IV) followed by febrile neutropenia (11/197 [6%] SC; 9/210 [4%] IV). Other common haematological AEs were neutropenia and anaemia (both ≤5% of patients in each group). Administration-related reactions occurred in 93 (47%) RSC patients and 70 (33%) RIV patients and were predominantly grade 1 or 2. The difference was mainly due to grade 1 injection site erythema (10% vs 0%) which was anticipated following the change in route of administration. AEs, adverse events; n, number of patients; SAE, severe adverse event Davies et al. EHA 2014 Abstract S652

Bendamustina nel Linfomi di Hodgkin

Linfoma Hodgkin, terapia di salvataggio : Protocollo LEBEN Pazienti 17 pz HL refrattario dopo ASCT (n. 7), allo-T (n. 5) o terapia salvataggio (n.5) Mediana prec. terapie: 4 Brentuximab prec. 5 pz RISULTATI Mediana cicli: n 5 Risposte dopo 4 cicli, % ORR 80% CR 53% Trattamento Bendamustina 60 mg/m2 gg 1, 8 e 15 Lenalidomide (dose-finding: 10-25 mg, finale 10 mg daily) Tossicità Grado 3-4 Neutropenia: 44% Trombocitopenia 24% Linfopenia 34% Diarrea 3% Rash 3% ogni 28 giorni per 6 cicli PFS mediana: 8.7 mesi Corazzelli et al ASCO 2014

Linfoma di Hodgkin, mobilizzazione: Protocollo BEGEV Pazienti 40 pz HL R/R RISULTATI 37 pz valutabili Mobilizzazione in 36 (97.3%) Mediana raccolta: 8,6x106 CD34+/Kg Successivo ASCT: 67% Recovery (mediana): neutrofili g 10, piastrine g 12 Trattamento Bendamustina 90 mg/m2 gg 2 e 3 Gemcitabina 800 mg/m2 gg 1 e 4 Vinorelbina 25 mg/m2 g 1 Raccolta cellule staminali G-CSF da g 7 fino a raccolta CD34+ Raccolta PBSC: cicli 1 o 3 Tossicità non/ematologica: Grado 1-2 limitata, nessun exitus Gandolfi et al, EHA 2014

Condizionamento con Bendamustina

Condizionamento: Studio BeEAM RISULTATI Pazienti: 43 pz, età mediana 47 28 NHL + 15 HL; mal. R/R Blood 2011 Follow up 18 mesi: 81% in CR Desease Free Survival (DFS) influenzata da malattia (NHL vs HL) e status (chemo-sens. vs -resistante) Trattamento Bendamustina 200 mg/m2 gg -7 and -6 • Aracytin 400 mg/m2 da gg -5 a -2 • Etoposide 200 mg/m2 da gg -5 a -2 • Melphalan 140 mg/m2 gg -1 • ASCT giorno 0 EBMT 2014 Follow up mediano 41 mesi: 72% dei pazienti ancora in CR PFS a 3 anni 75% DFS influenzata solo da status e non dal tipo di malattia End point primario: EFS a 36 mesi Visani et al, EBMT 2014

Condizionamento Studio BeEAM-2 RISULTATI 27 pz valutabili Pazienti: 37/88 pz Età mediana 56 anni 32 DLBCL, 5 FL grado IIIB; mal R/R Post-trapianto CR 81.5% PR: 7.5% Non responder: 11% Mortalità T-R: 2.7% Trattamento Bendamustina 200 mg/m2 gg -7 and -6 • Aracytin 400 mg/m2 da gg -5 a -2 • Etoposide 200 mg/m2 da gg -5 a -2 • Melphalan 140 mg/m2 gg -1 • ASCT giorno 0 Tossicità 21.6% febbre nnd 51% infezioni End point primario: CR ad 1 anno (tra 55% e 70%) Follow up mediano 9 mesi: 79.1% ancora in CR Visani et al, EHA 2014

Dati in real life mono/multicentrici - Levact

Autore Provenienza Istologia Linea di terapia N pz Trattamento Italiani Buquicchio Barletta NHL R/R e I linea 33 BR Merchionne Bari DLBCL R/R 19 Lucania Napoli CLL 24 Gozzetti Pistoia I linea e R/R 26 Cerchione MM BVD/BDL/BD Ricciuti Pescara HL 10 B Rigacci Toscana I linea 72 BR, B Europei Poddubnaya Russia iNHL 42 B+mantenim. Hernández-Sánchez Spagna 18 BVD/BP Caers Belgio 20 Zagoskina 36 Hagberg Norvegia iNHL + MCL 116

Depocyte

R-HDS + terapia IT + ASCT nei linfomi aggressivi e coinvolgimento SNC Pazienti 40 pz, Età mediana 59 DLBCL 34 pz, 4 blastoidi, 3 MCL CNS inv.: 17 esordio, 23 relapse RISULTATI ASCT in 20 (50%) ORR 60% (CR 58%) Exitus n. 4 (10%) G4 neutropenia 90% cicli G4 thrombocytopenia 76% G4 anemia 8% Febrile neutropenia 26% Terapia MTX 3.5 g/m2 d1, AraC 2 g/m2  x 2 d2-3: x 2 R-HDS (Cyclophosphamide 7 g/m2 d1; AraC 2 g/m2 x 2 d 22-25; Etoposide 2 g/m2 d 43) BCNU-thiotepa conditioning DepoCyte 50 mg IT x 4 Rituximab 375 mg/mq x 8 Follow up (mediana 36 mesi): 17 pz vivi, 16 in remissione 2-yr PFS 40±8%. 2-yr OS: 41±8% ( 64±11% dopo ASCT) ASCT Ferreri et al, EHA 2014

® ® ® ® @ @ £ ®: Rituximab £: Leukapheresis @: Depocyte Phase I: HD-MTX + HD-araC (2 courses) @ ® ® CR, PR SD, PD CCR, CR, PR, SD CCR, CR, PR ® ® Phase III: HD-araC £ Phase II: HD-CTX @ Phase IV: HD-VP16 Phase VI: WBRT + boost Phase V: Conditioning CR, PR WBRT 40 Gy + Boost 10 Gy PD Off study SD, PD ®: Rituximab @: Depocyte £: Leukapheresis Ferreri et al, EHA 2014 30

CNS Relapse of Aggressive NHL Studio fase II di ChemioT HD, CNS-directed + ASCT Mortalità 3% RR dopo induzione: 74% OS > 30 mesi 2-year OS 63% RR dopo ASCT: 71% Korfel A, et al Hematologica 2013; 98(3)

Profilassi Aracnoidite con co-somministrazione DepoCyte - desametasone intratecale RISULTATI Pazienti 54 pz Età mediana 55 DLBCL 25 pz, leuc. linfoblastica 13 pz , Linf. Follic. 4 pz, leuc. mieloblastica 4 pz, MCL 2 pz, Richter 2 pz, Burkitt 2 pz , Linf. T 2 pz Mediana somministrazioni IT: 2 (1-5) Tossicità grade 3 in 3 pazienti: Emicrania ortostatica dopo la I somministrazione, non pervenuta dopo la II somministraz. Emicrania dopo la I somministraz., trattamento interrotto Emicrania dopo la II e IV somministraz. , ipertensione intracranica (reversibile) Profilassi LM: DepoCyte 50 mg IT + Dexametasone 4 mg IT + Dexametasone 20 mg iv, g 1 Follow up (mediana 10.4 mesi): nessun caso di LM De la Fuente et al, EHA 2014