ALBERT

Description: Key Points INTERIM treatment affects cytogenetic and molecular response, but not the outcome. No patients treated with INTERIM progressed to accelerated or blast phase.

Description: Abstract 4446 Life expectancy of CML patients has greatly improved in tyrosine-kynase inhibitor (TKI) era, but still some questions remain about the management of suboptimal responders (SR) to imatinib standard dose. This group of patients appears to be heterogeneous, with significant differences in terms of event-free survival between cytogenetic SR and molecular SR (Alvarado et al, Cancer 2009) European Leukemia Net (ELN) recommendations did not clarify those differences and there isn't a clear agreement on SR: maintaining imatinib at standard or higher dose or switching to another TKI are all considered acceptable options (Baccarani et al, JCO 2009). We retrospectively analyzed 63 CML patients, diagnosed in chronic phase between 1988 and 2011, SR to imatinib 400 mg/d, treated according to the 3 different ELN options. Fifty-two patients received imatinib front line and 11 had been previously treated with an interferon based therapy. Sokal score, evaluable in 44 patients, was high in 7, intermediate in 24 and low in 12, respectively. Twenty-five patients were cytogenetic SR and 38 molecular SR. The median follow-up from diagnosis was 76 months (range 10–292). At suboptimal response detection 47 patients (74%) continued imatinib 400 mg/d (30 of them afterword switched to high dose imatinib or new TKI), 12 patients (19%) increased imatinib dose to 600 mg/d (7) or 800 mg/d (5) (8 of them later changed TKI) and only 4 patients switched immediately to new TKI. Twenty-three percent of the 47 patients who continued imatinib 400 mg/d obtained a stable complete cytogenetic response (CCyR) and major molecolar response (MMR) while 27% underwent to a failure. Globally thirty-tree SR patients increased imatinib dose, 36% at suboptimal response detection and 64% after a median of further 12 months of standard dose treatment (range 3–50): 48% of them obtained a durable CCyR and MMR. Twenty-six evaluable patients switched to new TKI (9 to nilotinib and 17 to dasatinib), 13 after high dose imatinib: 62% of the patients achieved a stable CCgR and MMR. Both high dose imatinib and new TKI were significantly more effective in achieving CCyR and MMR than maintaining imatinib 400 mg/d (p

Description: Background. Bortezomib, an inhibitor of the proteasome, is effective in relapsed mantle cell lymphoma (MCL) and indolent lymphomas and it is synergistic with Rituximab to enhance apoptosis and NFkB depletion. On these basis, the FIL conducted a phase II multicenter study aimed to evaluate safety and efficacy of Bortezomib in association with Rituximab in relapsed/refractory non-follicular Lymphoma (Linfocytic, LL and Marginal Zone Lymphoma, MZL) and MCL, not eligible to high dose chemotherapy with stem cell transplantation. Patients and methods. The study was a prospective single arm phase II trial, designed on Simon two-stage Optimal Design. Primary end-point was to obtain an Overall Response Rate (ORR) 〉 40%. The aim of this analysis is to evaluate long term follow-up of Bortezomib and Rituximab combination. A central histological revision was planned in all the patients at the enrollment. Inclusion criteria were: 18-75 years, relapsed/refractory LL, MZL, MCL after 1-4 lines. Treatment schedule was: one course of 1.6 mg/sqm Bortezomib weekly in combination with standard 375 mg/sqm Rituximab on days 1, 8, 15, 22 followed by two courses of four weekly intravenous bolus of Bortezomib alone; patients with complete (CR), partial remission and stable disease at the intermediate evaluation were planned to be given three further courses with the same schedule. Results. From September 2006 to March 2008, 55 patients were enrolled and six were excluded at central histological revision. Clinical characteristics were: median age 68 (50-74); 16 (33%) LL, 8 (16%) MZL, 25 (51%) MCL; 42 (86%) stage III/IV; 33 (67%) bone marrow involvement. Median number of previous treatments was 2 (range 1-7); 34 (69%) were Rituximab pretreated; 21 (43%) had refractory disease. Thirty (61%) patients completed the treatment and 233 courses were delivered (median: 4.7 courses/patient); 19 (39%) patients did not because of no response in 13, adverse events in five, with only one toxic death due to interstitial pneumonia. ORR was 53% (CR 26.5%); no response was seen in 43% and 4% were not evaluable for response. ORRs by clinical subgroup were: LL 37%, MZL 50%, MCL 64%; Rituximab pretreated 62%, Rituximab naïve 33%; relapsed 64% and refractory 38%. With a median follow-up of 85 months, median Overall Survival (OS) was 61.5 months (95%CI: 35.0-81.5), with 5-years OS 51% (95% CI: 36-65) and median Progression Free Survival (PFS) was 8.9 months (95%CI: 5.3-18.3), with 5-years PFS 16% (95% CI: 7-28%). Five-years PFS by histology was: 12% (95% CI: 2-31) for LL, 17% (95% CI: 5-34) for MCL and 19% (95% CI: 11-53) for MZL. PFS rates were not different between Rituximab pretreated versus naïve nor international prognostic index 1-2 versus 3-4-5 nor refractory versus relapsed. By number of previous therapies, 5-years PFS for 1 previous therapy versus 2 versus 3 or more was: 24%, 14% and 13%, respectively, p=0.36. Conclusions. Weekly infusion of Bortezomib in combination with Rituximab is effective in relapsed/refractory indolent and MCL and represents a treatment option in this setting of patients. Disclosures No relevant conflicts of interest to declare.

Description: Background and rationale In chronic myeloid leukemia (CML) about half of patients (pts) achieving a deep and stable molecular response (MR) with tyrosine kinase inhibitors (TKIs) may discontinue TKI treatment without disease recurrence. As such, treatment free remission (TFR) has become an ambitious goal of treatment. Given the evidence that deepness and duration of molecular response are necessary but not sufficient requisites for a successful TFR, additional biological criteria to possibly identify more and better CML patients suitable for an efficacious discontinuation are today focus of research in CML. Leukemia stem cells (LSCs) are supposed to be the reservoir of disease. We first showed in a cross-sectional study including 112 pts in TFR for a median of 31 months (mos) that residual circulating CD34+/CD38-/CD26+ CML-specific LSCs were still detectable in the majority of CML pts despite stable and deep molecular response. This evidence suggested that the level of BCR-ABL transcript only may not reflect the actual residual CML LSCs burden and that there could be a "threshold" of LSCs predicting a successful TFR. Aims To further study the behavior of residual LSCs during TKI discontinuation we designed a prospective multicentered study (AIRC IG 20133 study) in which we monitored circulating CD26+ LSCs in CML pts from the time of TKI discontinuation until molecular relapse. Methods CML pts meeting the current molecular criteria for TKI withdrawal entered this multicenter study. At TKI stop (baseline) and at +1, +2, +3, +6, + 12 mos after discontinuation and at any time if molecular relapse, CML pts were evaluated for peripheral blood number of CD34+/CD38-/CD26+ LSCs by centralized flow-cytometry analysis and for BCR-ABL transcript level by standard (IS) quantitative RT-PCR assay. Results 49 consecutive CML pts were enrolled in the study so far. Pts characteristics at diagnosis, type of TKI, disease response and treatment duration before discontinuation are shown in Tab. 1. After a median time of 7 mos since TKI stop (range 1-24), 13/49 (26.5%) pts lost their molecular response and restarted TKI treatment. Median time to relapse after discontinuation was 4 mos (range 2-7). 36/49 (73.4%) pts are still in TFR after a median time of 7.5 mos (range 1-24). If considering a cut-off of 6 mos from discontinuation as the period with higher risk of relapse, 14/36 pts actually in TFR have discontinued treatment for ≤ 6 mos (range 1-6) while 22/36 pts are in TFR for a median of 10 mos (range 7-24). Regarding residual CML LSCs evaluation, at baseline 23/49 (46%) pts had still measurable circulating CD26+LSCs with a median number of 0.0204µ/L (range 0.0077-0.1197), while 26/49 (54%) had no detectable CD26+ LCSs. Considering the small number of molecular relapses no statistical difference in number of residual CD26+ LSCs at time of discontinuation was shown between pts losing vs maintaining TFR (13 pts median CD26+ LSC 0.0237/µ/L, range 0-0.1197 and 36 pts median CD26+ LSCs 0.0204/µ/L, range 0-0.1039, respectively). However, the number of pts with undetectable CD26+ LSCs at baseline was 6/13 (45%) and 20/36 (55%) in the two subgroups, respectively. Considering subsequent time points, the 13 relapsed pts showed a small yet progressive increase of residual CD26+ LSCs number until molecular relapse, while the 36 pts in TFR showed a fluctuation of CD26+ cells number. However, Kendall rank correlation coefficient, Mood test and bi-linear relation model of the whole cohort showed no correlation between BCR-ABL/ABLIS ratio and number of residual CD26+ LSCs either at baseline or at each time points after discontinuation, thus confirming our previous observations. Conclusions Yet very preliminary our results showed that CD26+ LSCs are detectable at time of TKI discontinuation and during TFR. Moreover, at least for the observation median time of the study (7.5 mos) the persistence of "fluctuating" values of residual CD26+ LSCs do not hamper the possibility to maintain a stable TFR. Due to the short follow up and the small number of molecular relapsed pts we could not find a threshold of CD26+ LSCs predictive of TFR loss. Our data may suggest other factors then LSCs "burden" to play an active role in controlling disease recurrence. Additional studies evaluating CD26+ LSCs ability to modulate the immune system through a variable expression of immune response inhibitory molecules and through their interactions with effectors cells are ongoing. Table Disclosures Bocchia: Novartis: Honoraria; Incyte: Honoraria; BMS: Honoraria. Pregno:Bristol Myers Squibb: Honoraria; Incyte: Consultancy, Honoraria; Novartis: Honoraria; Pfizer: Honoraria. Abruzzese:Incyte: Consultancy; Novartis: Consultancy; Pfizer: Consultancy; BMS: Consultancy. Crugnola:Novartis: Honoraria; Incyte: Honoraria. Iurlo:Pfizer: Honoraria; BMS: Honoraria; Incyte: Honoraria; Novartis: Honoraria. Galimberti:Roche: Speakers Bureau; Celgene: Speakers Bureau; Novartis: Speakers Bureau. Liberati:Bristol & Mayer: Honoraria; Takeda: Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria; Servier: Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte: Consultancy; Amgen: Membership on an entity's Board of Directors or advisory committees; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria.

Description: Abstract 3375 Introduction. Telomere are effective sensors of cell integrity and their accelerated shortening is a marker of genetic and/or proliferative stress in several tissues including the hematopoietic compartment. Severe telomere attrition has been indeed observed in aplastic anemia and post-transplant setting. Little is currently known on the genetic integrity of Ph-negative hematopoietic cells (HCs) repopulating the bone marrow (BM) after successful chronic myeloid leukemia (CML) treatment. We thus decided to verify whether severe telomere shortening might occur in this setting and to assess whether its presence might correlate to genetic and functional impairment of Ph-negative hematopoiesis. Patients and methods. We investigated 81 CML patients with persistent (≥12 months) complete cytogenetic remission (CCyR). Median age was 62 years (23-88), M/F ratio was 1.5. Median time from diagnosis and CCyR were 4 years (1-18) and 3 years (1-12) respectively. 15 patients had acquired cytogenetic abnormalities (CA) (del7: 4 patients, +8: 5 patients, del5q: 2 patients, del or +Y: 2 patients, other CA: 2 patients). Telomere length (TL) analysis was performed by Southern Blotting on polymorphonucleates (PMN) and on monocyte-depleted PBMC (MD-PBMC) to monitor both the myeloid and lymphoid compartments. As control group we analyzed 76 age-matched healthy donors. Prospective follow-up monitoring of TL was performed on 56 CML patients with a median time of 22 months from the first determination (range 12–20). Results. PMN (but not MD-PBMC) from CML patients showed a major erosion of their telomeric DNA (median loss 1294 bp p

Description: Abstract 2196 Poster Board II-173 BACKGROUND: Imatinib (IM) 400 mg daily is the standard treatment for Chronic Myeloid Leukemia (CML) in early chronic phase (ECP). The European LeukemiaNet (ELN) recommendations were designed to help identify ECP CML patients responding poorly to front-line IM, suggesting, at given time points, when the treatment strategy should be changed (”failure”), or when “the long-term outcome of the treatment would not likely be as favourable” (“suboptimal response”). Suboptimal response is a “grey zone”: the patient may still have substantial benefit from continuing IM, but other therapies should be considered. AIM: To assess the outcome of “failure” and “suboptimal responders” Philadelphia-positive (Ph+) CML patients in a large multicentric, nationwide experience. METHODS: Between January 2004 and April 2007, 559 patients were enrolled in an observational study and in 2 independent intervention studies of the GIMEMA CML WP (Clin Trials Gov. NCT00514488 and NCT00510926). Response monitoring was based on conventional cytogenetic examination of bone marrow cell metaphases every 6 months and RT Q-PCR evaluations of blood cells after 3, 6, 12 months, and every 6 months thereafter. Definitions: major molecular response (MMR): BCR-ABL/ABL ratio 〈 0,1%IS; failure (according to ELN criteria): no hematologic response (HR) at 3 months, no complete HR (CHR) at 6 months, no cytogenetic response (CgR) at 6 months, no partial CgR (PCgR) at 1 year, no complete CgR (CCgR) at 18 months, loss CHR or CCgR, progression or death; suboptimal response (according to ELN criteria): no CHR at 3 months, no PCgR at 6 months, no CCgR at 12 months, no MMR at 18 months ; optimal response: non-suboptimal and non-failure at each time-point; event: failure or treatment discontinuation for any reason. All the calculations have been made according to the intention-to-treat principle. RESULTS: The patients who fitted the ELN criteria for failure had a significantly lower probability of subsequently achieving a CCgR and a MMR, and had a significantly lower overall survival (OS), failure-free survival (FFS) and event-free survival (EFS). The patients who fitted the ELN definitions of suboptimal response at 6 months (data not shown) and at 12 months (figure 1) had a significantly lower probability than “optimal” responders of subsequently achieving a CCgR and a MMR, and a significantly poorer FFS and EFS (figure 1), while the OS was not different in the two groups (90% and 95%, p= 0.35). CONCLUSIONS Our data confirms that suboptimal responders at 6 and at 12 months have a poorer outcome with respect to “optimal” responders, comparable to the outcome of failure patients. Acknowledgments: European LeukemiaNet, COFIN, University of Bologna and BolognAIL. Disclosures: No relevant conflicts of interest to declare.

Description: Abstract 2293 Background. Dasatinib is a tyrosine kinase inhibitor that has 325-fold greater in vitro activity against native BCR-ABL (breakpoint cluster region-Abelson leukemia virus) compared with imatinib and can overcome primary (intrinsic) and secondary (acquired) imatinib resistance. A phase III dose optimization study showed that in patients with chronic phase (CP) chronic myeloid leukaemia (CML), dasatinib at 100 mg once daily improved the safety profile while maintaining efficacy compared with the previously recommended dose of 70 mg twice-daily. Few data exist on the efficacy and safety of dasatinib in elderly CML patients. Aims. The aim of the study was to evaluate the impact of dose reduction on dasatinib efficacy. Methods. We revised 129 unselected pts with CP CML aged 〉60 yrs treated in 21 Italian haematological Institution, who received dasatinib after being resistant/intolerant to imatinib. Among this group 70 pts were given dasatinib at adjusted-dosage below the standard recommended dose of 100 mg daily for 〉 6 months. In relation to the dose modulation, patients were divide in 2 groups: group-a (21/70, 30%) received a starting dose of 20 mg daily dose excalated to the maximum tolerated dose of 70 mg daily; group-b (49/70=70%) received a starting dose of 100 mg daily, successively adhusted according to tolerance. Sokal score was evaluable for 59/70 patients (low for 16, intermediate for 28, high for 15). All patients were analyzed for haematological, cytogenetic and molecular response. Results. All patients were fully evaluable for response at a median FU time of 25 mos (range 0,7- 56,3 mos). Eight pts (11.4%) discontinued treatment due to intolerance. Response rates were 25,7% (18pts), 24.3% (17 pts), 15.7% (11 pts), 10% (7 pts), 12.8% (9 pts) for complete haematologic response (RHC), complete cytogenetic response (RCyC), major molecular response (RMolM), complete molecular response (RMolC), partial cytogenetic response (RCyP), respectively. Median Cumulative event free survival (EFS) and overall survival (OS) were 21.3 and 27.3 mos respectively. We did not observe any significative difference in term of response between group A and B receiving different doses. Interestingly, 3/9 patients in group A who had a transient loss of molecular response achieved major molecular response after dose escalation to 50 mg. Conclusions: Dasatinib given at a lower dose than currently recommended is still effective in elderly CML patients. However, more close molecular monitoring is advised when lower doses are prescribed. Studies in larger series are warranted to better define optimal dose and schedule of dasatinib in this frail patient population. Disclosures: Rosti: Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Bristol Myers Squibb: Honoraria, Speakers Bureau; Roche: Speakers Bureau.

Description: Defibrotide (DF) showed antithrombotic properties and remarkable activity in Multiple Myeloma (MM), without significant anticoagulant effects and bleeding risk. DF may abrogate tumor cells interaction with marrow stromal cells and enhance sensitivity to chemotherapy, thus improving activities of Melphalan, Prednisone and Thalidomide, while protecting against thrombotic state. We designed a multicenter phase I/II trial to define efficacy and safety of Melphalan, Prednisone, Thalidomide and DF (MPTD) in relapsed/refractory MM. The MPTD treatment consisted of 6 35-days cycles of oral melphalan (0.25 mg/Kg day 1–4), prednisone (1.5 mg/kg day 1–4), thalidomide (50–100 mg/day continuously), DF at 3 dose levels (17 mg/Kg iv or 2.4 g po D 1–4, 1.6 g po D 5–35; 34 mg/Kg iv or 4.8 g po D 1–4, 3.2 g po D 5–35; 51 mg/Kg iv or 7.2 g po D 1–4, 4.8 g po D 5–35), every 35 days, without deep vein thrombosis (DVT) prophylaxis. Safety was assessed by defining dose-limiting toxicity (DLT) and maximum tolerated dose (MTD). DLT was defined as the occurrence of febrile neutropenia, G4 neutropenia 〉1 week, any other G4 hematologic toxicity, or any 〉G3 non-hematologic toxicity. MTD was the dose level prior to that resulting in DLT. Efficacy was evaluated according to EBMT/IBMTR criteria. Twenty-four patients were enrolled between March and November 2006 and 19 patients completed at least 1 MPTD (median age 69, excluding primary refractory and/or patients receiving anticoagulation) and were evaluated for toxicity and response. Fourty-two percent of patients achieved at least partial response (PR) after a median of 3 cycles (including 16% very good PR), without significant differences among DF dose. The MTD was not reached. DLTs observed were not considered related to DF and included: G3 ileus (1st dose level) and acute myocardial infarction (AMI) in the 2nd. Toxicities ≥G3 consisted of neutropenia 47%, thrombocytopenia 10%, anemia 21%, whereas

Description: Introduction: The PET is mostly used in staging of NHL patients at diagnosis and as response assessment at the end of treatment. The evaluation by PET after few cycles of chemotherapy may be useful to predict chemosensitivity and then response, progression-free survival and overall survival in this subset of patients. In our study we introduced the PET in the mid-treatment evaluation (PET-2) of aggressive NHL disease. Patients and methods: From June 2004 to December 2006, 25 consecutive aggressive NHL patients were evaluated for this study: 17 males and 8 females respectively with median age of 49 years (range 21–67). We included: 18 Diffuse Large B Cell, 1 anaplastic, 2 mantle cell, and 4 follicular grade III NHL. Patients characteristics were: 11/25 bulky disease; 20/25 intermediate or high IPI risk; 3/25 stage II, 3/25 stage III and 19/25 stage IV. All patients were staged according to standard imaging procedures completed by PET at the diagnosis and at the end of treatment. After 2 or 4 cycles of Rituximab-CHOP-like chemotherapy PET-2 was repeated in all of them. Results: PET-2 demonstrated: 16/25 patients negative and 9/25 patients positive. The conventional and PET restaging performed at the end of treatment were 21/25 negative and 4/25 positive. Among the 16 patients PET-2 negative, 14/16 remained negative at the final PET evaluation and achieved CR, 2/16 became positive with demonstration of progression disease. Among the 9 patients PET-2 positive, 7/9 became negative with achievement of CR. The other 2/9 patients remained positive at the end of therapy: one of them was false positive because of parotid gland carcinoma without NHL involvement. Among 21/25 patients PET negative at the final evaluation, 20/25 patients remained in CR with a median follow-up of 18 months and only one patient negative at the PET-2 and at the final PET demonstrated disease progression. Finally, with a median follow-up of 18 months, FFS was 84% in all pts, 81% in PET-2 negative patients and 89% in PET-2 positive patients respectively. Conclusions: The PET is an important imaging technique for staging and end-treatment evaluation in lymphoma disease, because it can better define CR patients. In Hodgkin disease several studies demonstrated that the early evaluation by PET is a crucial prognostic factor to test chemosensitivity and then to predict favourable outcome. In our study the mid-evaluation of response by this procedure had not so clear predictive value of response assessment, because patients, even if positive at PET-2, can achieve CR at the end of treatment. More large studies are needed to determine the real impact of on-course PET as response assessment in aggressive NHL patients.

Description: Introduction: Elderly patients (pts) with FL do worse than younger ones and the aim of the treatment is usually palliation rather than cure. In order to outline a treatment plan specifically devised for elderly pts with a reduced amount of chemotherapy, we investigated the efficacy and safety of a brief chemo-immunotherapy FND plus Rituximab. Patients and methods: from March 1999 to March 2003, 80 elderly pts (age 〉60) with advanced stage FL at diagnosis were enrolled. Treatment plan was: 4 courses of FND (Fludarabine 25 mg/m2 days 1–3, Mitoxantrone 10 mg/m2 day 1 and Dexamethasone 20 mg days 1–3) followed by 4 Rituximab infusions at 375 mg/m2/week; pts in partial remission received 2 further FND and 2 Rituximab infusions. PCR molecular monitoring for the presence of IgH/Bcl2 and/or Ig heavy chain gene rearrangement was performed at the beginning of the treatment, after FND, after Rituximab and during follow-up time on bone marrow (BM) samples. Results: median age was 66 (range 60–78); 42 males and 38 females; 16% had stage II, 12% stage III and 72% stage IV disease; 61% had BM involvement; 41% had bulky disease and 24% were at high risk according to IPI score. PCR molecular analysis was performed in 46 pts at diagnosis: 63% were Bcl2 rearranged and 37% were not; IgH rearrangement was detected in 24% of Bcl2 negative pts. Up to date, 70 pts are evaluable. Overall response at the end of treatment was achieved in 63 pts (90%) with 58 pts (83%) in complete remission (CR) and 5 pts (7%) in partial remission (PR). Six pts (9%) did not respond and one patient (1%) died of neutropenic sepsis during a FND course. The addition of Rituximab allowed to increase CR rate from 44% (31 pts) after FND to 83% (58 pts); 73% of responding pts did so with a brief treatment program (4 FND + 4 Rituximab). Patients with adverse prognostic features at diagnosis responded as well as those with more favorable ones with no significant differences in CR rates: BM+ 89%, BM- 79%; low IPI 83%, high IPI 82%; Bulky+ 85%, Bulky- 79%; stage II 90%, III 87%, IV 84%. A thorough molecular analysis is ongoing; to date a molecular marker was detectable in 26 pts. After FND 9/26 pts (35%) did not show anymore BM molecular disease, while PCR negativity was achieved in 23/26 pts (88%) after Rituximab treatment. With a median follow-up of 30 months, 3-yr failure free survival was 50% for the whole series of pts. Failures were observed more frequently in PCR+ pts: all 3 PCR+ pts failed compared to only 7/23 PCR- pts (p=.01). The toxicity was mild with grade 3–4 neutropenia reported in 22% of FND courses, but only 3 pts developed grade 3–4 infections. The whole program was performed in an outpatient setting. Rituximab toxicity was as expected. Conclusions: a brief course of chemo-immunotherapy is able to achieve high clinical and molecular response rates in elderly pts with low toxicity. The sequential use of FND and Rituximab induces a CR rate 〉80% also in unfavorable subsets of pts. The achievement of PCR negative status correlates with a lower risk of failure.