ALBERT

Beschreibung: Previously, we reported a study on efficacy and toxicity of cladribine (2-CdA) + prednisone (P) compared with chlorambucil (Chl) + P in previously untreated patients with progressive or symptomatic chronic lymphocytic leukemia (CLL) in a randomized multicenter trial (Blood2000, 96, 2723). Of 229 patients enrolled, 126 received 2-CdA+P and 103 received Chl+P. Here, we present the long-term follow-up and the results of subsequent treatment in refractory or relapsed patients. Patients with non responsive (NR) disease or with progression after 3 courses of 2-CdA + P or Chl+P or who relapsed earlier then 12 months after completing the treatment were switched to an alternative arm. Patients who relapsed later than 12 months from first remission (late relapse) were retreated with the same schedule that induced previous response. In 50 patients, non-responsive or with early relapse, treated originally with Chl+P who received 2-CdA+P as second line, complete response (CR) was achieved in 12 (24%) and overall response (OR) in 32 (64%). Twenty eight patients originally treated with 2-CdA+P received Chl+P and CR and OR was obtained in 1 (3,6%) and in 6 (21.4%), respectively (p=0.002 for both arms). Thirty three patients with late relapse were retreated with 2-CdA+P and 19 patients were retreated with Chl+P. OR (CR) was 54.6% (6.1%) and 47.4% (15.8%), respectively (p=0.34). The third line treatment was CHOP in both arms. Twenty seven patients from 2-CdA+P group and 37 patients from Chl+P group were treated with CHOP and only one patient responded. Median survival was 3.3 and 3.75 years, respectively (p=0.63). Secondary neoplasms were observed in 8 (6.4%) patients treated with 2-CdA+P and in 4 (3.9%) treated with Chl+P as first line treatment (p=0.6). Death rates have been similar in patients treated originally with 2-CdA+P 82 (64.6%) and Chl+P 69 (66.4%) (p=0.8). In conclusion, cladribine is significantly more effective as a second line treatment than chlorambucil. Both agents are similarly effective in retreatment of late relapsed patients. CHOP is of no value in patients previously treated with 2-CdA + P and with Chl + P. There is no significant difference in median survival of patients treated initially with Chl + P and 2-CdA + P.

Beschreibung: Accelerated phase marks the onset of advanced rapidly progressive chronic myelogenous leukaemia (CML) and generally leads finally to a fatal blast crisis (BC) within 6 months. Gleevec (imatinib mesylate) as a potent tyrosine kinase inhibitor has demonstrated significant activity in chronic phase (CP) of CML. Because of the observed activity and favorable tolerability of Gleevec and because of the limited treatment options available to these patients we have introduced Gleevec in CML patients meeting rigorous criteria for acceleration and blast crisis phase of CML. PATIENTS: MALE - 31 and FEMALE - 20 were eligible for inclusion in this study if they were at least 18 years old and had a diagnosis of Ph+ CML (AP; BC) confirmed by cytology, histology, cytogenetic and molecular analyses. Characteristics CML patients (AP-accelerated phase; BC-blast crisis phase) is showed in table 1. Table 1- Demographics, Disease History and Characteristics of CML Patients. 1 Duration time of CML-yr 3.8 (1–4.5) 3.7 (0.7–5.1) Prior therapy -n(%) 100% 100% combined Chemotherapy 10 (33) 18 (86) BMT 2 (6.6) 0 Sokal’s score 〉0.8 16 (53) 15 (71) PLT (x 109/L) 100.0–300.0 11 (37) 8 (38) 〉300.0 15 (50) 4 (19) Blasts in peripheral blood (%) median 9 34 range 4–20 31–80 Blasts in bone marrow (%) range 10–25 32–78 HGB (g%) median 6.24 6.12 range 5.0–9.4 4.4–10.0 Gleevec dosage AP BC 300mg: n (%) 1 (3.3) 1 (4.8%) 400 mg: n (%) 4 (13.3) 1 (4.8) 600–800 mg: n (%) 25 (83.4) 19 (90.4) Duration of treatment (months) AP BC median 31.64 40.0 range 1–98 0.5–91 Patients received Gleevec 300–800 mg orally daily (table 2). Clinical evaluation of Gleevec therapy was determined by the rate of sustained haematological response (lasting 〉= 4 weeks) The results of Gleevec therapy are showed in table 2. Table 2 - Haematologic Response in Patients with AP & BC Phase after Gleevec Treatment Response AP BC 2 CHR 25 (83.3%) 4 (19.0%) Cytogenetic response Major : 5 (16.7%) 1 (4.8%) CCR 2 (6.7%) 0 PCR 3 (10.0%) 1 (4.8%) Minimal 11 (36.7%) 1.4.8%) No response 9 (30%) 18 (85.6%) BMT performed 5 (16.7%) 2 (9.6%) after Gleevec therapy (months) 6–12 7–13 The most often observed side effects were irst few months ( neutropenia, thrombocytopenia, weakness, bone and muscles pain, headache, nausea, vomiting, diarrhoea, legs’ oedema, deaths (6.3% – 27.3%). Conclusions: Imatinib as a single agent is well tolerated and has substantial activity in the accelerated phase of CML. The overall response rate in these cases was 83%. Imatinib as a single agent is well tolerated and has substantial activity in the accelerated phase of CML. The overall response rate in these cases was 83%. Imatinib as a single agent is well tolerated and has substantial activity in the accelerated phase of CML. The overall response rate in these cases was 83%. 5 pts. out of these 30 patients are still in the chronic phase after 10 to 32 months of follow-up. In 4 ( 19%) out of 21 patients with BC the improvement after Gleevec therapy was short and transient mainly due to advanced stage of disease.

Beschreibung: Purine nucleoside analogues, cladribine(2-CdA) and fludarabine (FA), especially combined with cyclophosphamide (CY) are potent cytotoxic drugs for the treatment of chronic lymphocytic leukemia (CLL). In this randomized study we aimed to establish whether combination of 2-CdA plus CY (CC) with FA plus (FC) provide similar benefit to previously untreated patients with CLL. The trial was started in January 2004 and the recruitment was ended in May 2007. The study primary endpoints were overall response (OR) and complete response (CR). The secondary endpoints included progression free survival (PFS), overall survival (OS), minimal residual disease negativity (MRD/-/) and treatment related toxicity. Eligible patients were randomly assigned to receive 6 courses of either 2-CdA 0.12 mg/kg/d i.v. + CY 250 mg/m2/d i.v. or FA 25 mg/m2/d i.v. + CY 250 mg/m2/d, both combinations for 3 consecutive days. The treatment response and toxicity were evaluated according to NCI-WG guidelines. MRD was evaluated in patients with CR using four-color flow cytometry assay. There were no significant difference in the rates of OR, CR, MRD negativity, grade 3/4 neutropenia, thrombocytopenia and infections. PFS and OS were also similar in both groups. In conclusion, CC and FC regimens are similarly active and toxic in previously untreated CLL, however trend of longer OS in CC group is observed. Characteristic CC arm FC arm P value Pts enrolled 212 211 - Pts evaluated 184 187 - No of courses (median, range) 6 (2–6) 5 (2–6) 0.56 OR (%) 163 (88.6) 159 (85.0) 0.31 CR (%) 86 (46.7) 91 (48.7) 0.43 MRD/–/ (%) 33 (68.8) 44 (72.1) 0.70 PFS (median, years) 2.195 2.361 0.86 Thrombocytopania gr 3/4 (%) 23 (12.6) 22 (11.6) 0.77 Neutropenia gr 3/4 (%) 39 (21.4) 43 (22.8) 0.76 Infection gr 3/4 (%) 53 (29.1) 54 (28.6) 0.91 OS (median, years) 4.066 2.531 0.10 Death (%) 37 (20.2) 53 (27.9) -

Beschreibung: The efficacy and toxicity of cladribine (2-CdA) + cyclophsphamide (CY) - CC versus fludarabine (FA) + CY - FC were compared in previously untreated chronic lymphocytic leukemia (CLL) patients. The study was started in January 2004. Eligible patients were asigned to either 2-CdA 0,12mg/kg/d and CY 250mg/m2/d for 3 consecutive days or FA 25mg/m2/d and CY 250mg/m2/d also for 3 days. Courses were repeated at 28 days intervals or longer if myelosupression and/or infection developes for a maximum 6 courses. The response and toxicity criteria were those recommended by NCI SWG. Minimal residual disease (MRD) was evaluated by flow cytometry if complete response (CR) was achieved. As shown in the table, there were no significant differences in the rates of overall response (OR), CR, grade 3/4 thrombocytopenia, neutropenia and infections between the programmes. MRD negativity was obtained in 4 patients in CC arm and in 6 patients in FC arm (p=0.69). The death rate was similar in both groups, 2 (3.2%) and 6 (8.2%), respectively (p=0.19). The therapy related mortality was not observed. In conclusion, CC and FC programmes seem to have similar efficacy and toxicity in previously untreated CLL patients. The results of the interim analysis of PALG CLL3 trial justify continuation of this study. Treatment Pts enrolled Pts evaluated OR (%) CR (%) Thrombocytopenia Neutropenia Infections CC 96 63 57 (90.5) 20 (31.7) 8 (12.7) 15 (23.8) 26 (41.3) FC 100 73 62 (84.9) 25 (34.3) 6 (8.2) 17 (23.3) 20 (27.4) p value 0.24 0.45 0.27 0.53 0.06

Beschreibung: Abstract 1115 Poster Board I-137 Introduction Nilotinib, a potent and highly selective BCR-ABL kinase inhibitor, is approved for the treatment of patients (pts) with Philadelphia chromosome-positive chronic myelogeneous leukemia (Ph+ CML) in chronic phase (CML-CP) or accelerated phase (CML-AP) who are resistant or intolerant to prior therapy, including imatinib. The ENACT study is a Phase IIIb, open-label, multicenter study that evaluated the efficacy and safety of nilotinib in adult pts with imatinib-resistant or intolerant CML in a clinical practice setting outside of a registration program. It is the largest single source of efficacy and safety information of any available tyrosine kinase inhibitor (TKI) in CML. Data from ENACT are used to characterize the patterns and management of adverse events (AEs) in nilotinib pts with imatinib-resistant or -intolerant CML-CP or -AP. Methods Pts received nilotinib 400 mg twice daily. Safety assessments included monitoring for all AEs and cardiac procedures. The first occurrence of the following AEs were selected on the basis of the following criteria: 1) the most frequently reported hematologic or biochemical laboratory abnormalities; or 2) identified by participating investigators as AEs of interest that may lead to study drug discontinuation: thrombocytopenia, neutropenia, hyperglycaemia, elevated lipase, elevated amylase, hyperbilirubinaemia, elevated alanine transaminase (ALT), and elevated aspartate transaminase (AST). There were no differences observed between the pattern of management between AEs suspected and regardless of study drug relationship as well as all grades vs. grade 3/4. For this reason this analysis covers management of grade 3/4 AEs suspected of study-drug relationship including duration and subsequent management. The following actions taken were reported by the treating physicians: study drug dose adjusted or temporarily interrupted, non-drug therapy given, no action taken, study drug permanently discontinued, concomitant medication taken or hospitalization/ prolonged hospitalization. More than one action was allowed to be selected. Results The AEs experienced by 1,603 pts (1,422 CP and 181 AP) were generally identified during nilotinib treatment and lasted for short durations. The number of the grade 3 and 4 AEs in CP and AP, median time from start of treatment and median duration are reported in Table. For all included AEs, the overall most common action taken for the first occurrence was dose adjustment or temporary interruption with the exception of hyperglycaemia which was most often managed by treatment with concomitant medications (8/11 of hyperglycaemia AEs in CP and 1/2 in AP). In the majority of the biochemical abnormalities other than hyperglycaemia there was no additional action taken. 49/308 (16%) events of thrombocytopenia in CP pts (9 in AP) were managed by non-drug therapy. 31/204 (15%) events of neutropenia in CP pts were managed by concomitant medication (6/33 events in AP). Permanent discontinuation of study drug was infrequently observed (number of pts in CP; AP): thrombocytopenia (25; 7), neutropenia (15; 2), hyperglycaemia (1; 0), elevated lipase (3; 0), elevated amylase (0; no pts), hyperbilirubinaemia (2; 0), elevated ALT (3; 0), and elevated AST (1; 0). Conclusions Based on a large cohort of 1,603 nilotinib pts with CML-CP and CML-AP, nilotinib is well-tolerated. Most study drug-related grade 3/4 AEs could be managed by temporary treatment interruption or dose adjustment, such that permanent discontinuation of study drug due to AEs was infrequent. The only events requiring concomitant medication administration or non-drug therapy were thrombocytopenia, neutropenia, hyperglycaemia and hyperbilirubinaemia. The AE profile observed was predictable and similar to that seen in registration trial. Disclosures le Coutre: Novartis: Honoraria, Research Funding; BMS: Honoraria. Ceglarek:Novartis Pharmaceuticals: Honoraria. Turkina:Novartis Pharmaceuticals: Honoraria. Kim:Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis Pharma: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Wyeth: Research Funding. Shen:Novartis Pharmaceuticals: Honoraria. Smith:Novartis Pharmaceuticals: Honoraria. Rizzieri:Novartis Pharma: Honoraria, Research Funding, Speakers Bureau. Szczudlo:Novartis: Employment. Berton:Novartis Pharmaceuticals: Employment. Wang:Novartis Pharmaceuticals: Employment. Dial:Novartis Pharmaceuticals: Research Funding. Nicolini:Novartis Pharma: Consultancy, Honoraria, Research Funding, Speakers Bureau; Bristol Myers Squibb: Consultancy, Honoraria, Research Funding, Speakers Bureau; Chemgenex: Honoraria, Speakers Bureau.

Beschreibung: Abstract 2201 Poster Board II-178 Introduction: Nilotinib, a potent and highly selective BCR-ABL tyrosine kinase inhibitor (TKI), is approved for the treatment of patients (pts) with Philadelphia chromosome-positive chronic myelogeneous leukemia (Ph+ CML) in chronic phase (CP) and accelerated phase (AP) who are resistant or intolerant to prior therapy, including imatinib. The ENACT study is a Phase IIIb, open-label, multicenter study that evaluated the efficacy and safety of nilotinib 400 mg twice daily in 1,422 pts with CP who were resistant and/or intolerant to imatinib. It is the largest single source of efficacy and safety information of any available TKI in CML. Study results are presented for all CP pts as well as 2 subpopulations: (1) 2nd-line pts who received imatinib as the only prior CML therapy with no prior exposure to other therapy including interferon (IFN), busulfan and ara-c; and (2) pts with 6- and 12-month suboptimal cytogenetic response (SoR) to prior imatinib therapy. Methods: In addition to all CP pts, ENACT study results are presented for 2 subpopulations, defined as follows. (1) Pts who received nilotinib as 2nd-line therapy received only imatinib (hydroxycarbamide was allowed) prior to nilotinib. Pts with any other therapy, including interferon, busulfan and ara-c were excluded. (2) Pts with 6- or 12-month cytogenetic SoR to imatinib were identified as: a) received imatinib as 1st-line therapy within 12 months of CML diagnosis; b) did not have imatinib resistance; and c) met ELN criteria for cytogenetic SoR (

Beschreibung: Abstract 3286 Poster Board III-1 Introduction: Nilotinib, a potent and highly selective BCR-ABL kinase inhibitor, is approved for the treatment of patients (pts) with Philadelphia chromosome-positive chronic myelogeneous leukemia (Ph+ CML) in chronic phase (CML-CP) and accelerated phase (CML-AP) who are resistant or intolerant to prior therapy including imatinib. The ENACT study is a Phase IIIb, open-label, multicenter study that evaluated the efficacy and safety of nilotinib in adult pts with imatinib-resistant or intolerant CML in a clinical practice setting outside of a registration program. It is the largest single source of efficacy and safety information of any available tyrosine kinase inhibitor (TKI) in CML, particularly among the elderly. Methods: The present is a sub-analysis of the ENACT study on the efficacy and safety of 400 mg twice daily nilotinib in elderly (aged =60 years) pts initiating treatment in CML-CP who were resistant and/or intolerant to imatinib. Results: Of the 1,422 CML-CP pts enrolled in the ENACT study between January 2006 and October 2008, 452 (32%) were elderly (=60 years) at study initiation and 165 (37%) of these pts were =70 years [10 (2%) were =80 years]. Countries that enrolled =20 elderly pts include France, Italy, USA, Germany, UK, Spain, Canada, and Brazil. At study initiation, elderly pts had longer median durations of CML (5 years (

Beschreibung: The purpose of the study was to evaluate response, duration of response, and toxicity of fludarabine (F), mitoxantrone (M), and dexamethason (D) (FMD) in patients (pts) with relapsed or refractory low-grade non-Hodgkin lymphoma (LGNHL). 26 pts with advanced relapsed/refractory LGNHL exposed to previous chemotherapy (CHT) received 3–6 monthly cycles of FMD. The median age was 60 years (range 34–73), included 13 male (50%) and 13 female (50 %). The regimen consisted of F (25 mg/m2 i.v., day 1–3), M (10 mg/m2 i.v., day 1) and D (20 mg p.o., day 1–5). Parameters analyzed included response, toxicity and infection rates, number of previous CHT lines, performance status (ECOG), Ann Arbor scale, LDH, International Prognostic Index score, freedom from progression (FFP) and overall survival (OS). In total 78 cycles of FMD was administered. This induced 25% complete and 37,5% partial response, with a total response rate of 62,5%. After 14 months of the median follow-up of the pts remaining alive, median FFP was 11 months and median OS has not been achieved yet. Out of 78 administered cycles 16 (20%) were associated with toxicity, including 8 (10%) severe infections despite prophylaxis and 6 (8%) grade III/IV neutropenias. In addition, one case of grade III/IV thrombocytopenia and acute noninflammatory renal dysfunction were observed. Toxicity rate was not correlated with the number of previous CHT lines or ECOG, but IPI 〉2 was significant factor predictive for FMD-related toxicity (p=.037). Shorter OS was observed for the pts with ECOG〉1 (p=.049), IPI〉2 (p=.005) and FMD-related toxicity (p=.036). FMD is an active regimen for relapsed and refractory LGNHL. Toxicity rate is substantial and seems to predict survival.

Beschreibung: 2-Chlorodeoxyadenosine (2-CdA, Cladribine) was used in patients with advanced, low-grade lymphomas (Lymphoplasmacytoid, Centroblastic/centrocytic, Centrocytic, Lymphocytic) resistant to conventional therapy. There was conducted a trial of 2-CdA group versus control group (patients treated different chemotherapy: Chlorambucil, COP, CHOP) in 85 patients. There were 47 men and 38 women with median age of 55 years were treated. Forty five patients with low-grade lymphomas were given 2-CdA at 0.1 mg/kg/d as a 7–5 day continuous infusion every 4–6 weeks. A total number of courses was different (2–7), median of three courses per patient, of 2-CdA were administered. All patients were evaluable for toxicity and for response. The results of overall response for 2-CdA group and control group are in table 1. Table 1- The results of overall response for 2-CdA group and control group 2-CdA Group Control Group P CR (%) 16.7 10.8 p〉0.5 PR (%) 28.3 43.2 p〉0.5 Overall (%) 45.0 54.0 p〉0.5 The results of 2-CdA therapy are showed in tabel 2. Table 2 - The results of 2-CdA therapy in low grade NHL patients. 2-CdA First line therapy II–III line therapy P Numbers of pts. 15.0 30.0 CR (%) 15.2 15.4 p〉0.05 PR (%) 30.3 30.8 p〉0.05 Overall (%) 45.5 46.2 p〉0.05 The results of 2-CdA therapy LG NHL patients (I-6pts; II-7pts.; III-25pts.; IV-7 pts.) concerned with clinical stage are showed below: Clinical Stage-CR (%) I-50 II-42.9 III-12 IV-14.3 P〉0.05 Clinical Stage-PR (%) I-33.3 II-42.9 III-40.0 IV-28.6 P〉0.05 Toxicity, in particular opportunistic infections (〈 or = grade 2, 35.6–48.4% in 2-CdA group v 31.6–64.7% in chemotherapy treated group; P〉0.05) and myelosuppression (〈 or = grade 2 leucopenia, 31.1% in 2-CdA group v 25.0% in chemotherapy treated group, P〉0.05 and thrombocytopenia 0–II grade WHO), were more frequent in 2-CdA group (II–III line therapy). The median response duration was 12 months (range, 3 to 44+). I observed less death numbers in 2-CdA first line patients than II–III line 2-CdA group (P=.00132). Conclusions : There was no statistical significant difference in frequency overall response (CR+PR) between 2-CdA group and chemotherapy treated group. 2-CdA therapy as a consecutive line caused an increase in mortality risk in contrast to the first line therapy. 2-CdA therapy as II–III line therapy allowed to receive complete remission in 9.4% previously treated low grade non Hodkin’s lymphoma patients.

Beschreibung: The aim of the study was to determine the efficacy and toxicity of cladribine alone (2-CdA) and in combination with cyclophosphamide - CY (CC) or CY and mitoxantrone - MIT (CMC) in previously untreated patients with progressive or symptomatic chronic lymphocytic leukemia in a randomized, multicenter study. 2-CdA was given at a dose of 0.12 mg/kg/d in 2 h I.V. infusion for 5 consecutive days in monotherapy and for 3 days in combination. In CC and CMC programmes cyclophosphamide was administered at a dose of 650 mg/m2 I.V. on day 1 and additionally mitoxantrone 10 mg/m2 I.V. on day 1 in CMC. Courses were repeated at 28 day intervals or longer if myelosuppression and/or infection developed, for a maximum of 6 courses. The response criteria were those recommended by NCI sponsored Working Group. Minimal residual disease (MRD) were evaluated by flow cytometry if CR was achieved. In conclusion, the results of our study indicate that 2-CdA combined with CY or CY+MIT as first line therapy give higher CR rate than 2-CdA alone. However, CMC is more toxic than 2-CdA or CC. We recommend CC combination for further studies. Treatment 2-CdA CC CMC p value Entered pts 167 169 163 Evaluated pts 143 152 139 CR 37 (25.9%) 43 (28.3%) 55 (39.6%) 0.03 OR 106 (74.1%) 125 (82.2%) 110 (79.1%) 0.2 MRD 15 (46.9%) 22 (82.2%) 25 (56.8%) 0.7 Median OR duration (years) 1.67 1.81 1.43 0.1 Relapse 48 (45.3%) 45 (29.6%) 43 (30.9%) 0.2 AIHA 10 (7.0%) 10 (6.6%) 5 (3.6%) 0.4 Thrombocytopenia grIII/IV 25 (17.5%) 25 (16.4%) 32 (23.0%) 0.3 Neutropenia grIII/IV 27 (18.9%) 43 (28.3%) 52 (37.4%)