ALBERT

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.

Description: Abstract 3434 Poster Board III-322 Introduction Fludarabine alone or in combination is considered the standard treatment for Chronic Lymphocytic Leukemia (CLL). A high response rate is usually observed following fludarabine, particularly if delivered together with rituximab. In spite of the high therapeutic efficacy, most patients subsequently relapse. For these patients there are no defined salvage treatments. Moreover, fludarabine-containing regimens may have some restrictions due to non-negligible side effects. In particular, there are some concerns in employing fludarabine first-line in patients with autoimmune hemolytic anemia (AHA) or with renal function impairment. In addition, fludarabine has been reported to compromise the capacity of progenitor cell mobilization. Thus, novel effective treatment approaches are needed, for the management of patients failing after fludarabine-based regimens and for those unfit to receive fludarabine first-line. A very effective salvage regimen for refractory/relapsed lymphoproliferative disorders is the DHAP combination. DHAP has been widely used in the rescue of both low-grade and high-grade lymphoma. However, its efficacy in CLL has not been verified yet. The main concern with DHAP is the well known renal toxicity of cisplatin. However, the use of the less toxic analog Oxaliplatin, might circumvent this problem. Indeed, recent reports have shown that the inclusion of oxaliplatin into the original DHAP regimen (Ox-DHA) markedly improves the tolerability and widens regimen applicability. Aim: To evaluate retrospectively feasibility and efficacy of the DHAP and Ox-DHA regimens in CLL and in other non-follicular low-grade lymphomas, in particular in Waldenström Macroglobulinemia (WM). Patients and Methods Between 2002 and 2008, 84 low-grade lymphoma patients received DHAP or Ox-DHA; their median age was 60 yrs. (range: 24-84), 58 were male; 70 patients had CLL with advanced stage (65 patients with Binet stage B and C) and 14 had WM. Thirty-eight patients were treated at first relapse, 27 at second or subsequent relapse, whereas 19 received the DHAP or Ox-DHA schedule as first-line treatment, in place of Fludarabine, due to: i. AHA (3 patients), ii. concomitant second malignancy (4 cases), iii. need of initial debulking, before a high-dose program with autograft. The original DHAP schedule requires hospitalization for three to five days; it includes: Cisplatin 100 mg/sqm on day 1, Cytarabine 2 g/sqm/b.i.d. every 12 hrs. on day 2, Dexamethasone 40 mg days 1-4. Ox-DHA can be delivered in the outpatient setting, compared to DHAP, there are two main modifications: Oxaliplatin 100 mg/sqm in two-hr i.v. infusion on day 1, and Cytarabine 2 g/sqm two doses delivered in two consecutive days (day 2 and day 3). Rituximab (375 mg/sqm) was added in 12 DHAP and 28 Ox-DHA courses. Patients aged over 70 yrs had variable dose reductions (25% to 50%). Results Ox-DHA had hematological toxicity analogous to that commonly observed with the original DHAP schedule; 11 patients required short hospitalization for severe infectious complications; 7 patients developed fever of unknown origin, 4 showed reversible peripheral neurotoxicity. The program was discontinued in four patients due to disease progression (3 patients) and AHA (1 case). There were no severe liver or renal toxicities. No toxic deaths were recorded. The overall response (OR) rate was 90%; in details, complete remission (CR), or very good partial remission (VGPR), was achieved in 41% of patients receiving DHAP without rituximab and 50% of those receiving DHAP supplemented with rituximab. In the Ox-DHA group, 50% of patients treated without rituximab and 75% of those treated with rituximab reached CR or VGPR. Among patients treated at diagnosis, overall 47% reached CR or VGPR and 42% reached partial remission (PR). The OR rate was unexpectedly high at 91% in patients treated for refractory/relapsed disease, with 66% of them achieving CR/VGPR (74% and 55% for patients at 1st and ≥ 2nd relapse, respectively) and 35% PR. Among 14 WM patients, 1 obtained a CR, 5 a VGPR, 6 a PR and 2 had a stable disease. Conclusions Dexamethasone, Cytarabine and Cisplatin or Oxaliplatin schedule is a well tolerated regimen, highly effective both front-line and in the rescue for relapsed/refractory disease in CLL and WM patients. Future clinical trials will define the real efficacy of the DHAP or Ox-DHA regimen in the management of CLL and WM patients. Disclosures No relevant conflicts of interest to declare.

Description: Abstract 1553 Background and Aim The number and type of lymphocytes and monocytes/macrophages detectable in the peripheral blood and the lymph nodes of patients with Hodgkin and non-Hodgkin lymphomas has been recently extensively investigated and interesting results indicate they may possibly affect the pathogenesis and prognosis of these diseases. Recent results indicate that the lymphocyte/monocyte ratio (LMR), when assessed at diagnosis by a simple automatic blood count, may predict the clinical outcome of diffuse large B cell lymphoma patients (DLBCL) treated with the R-CHOP chemotherapy program (Li Z-M et al.: PLoS ONE 7(7):2012). The main objective of our study was to evaluate whether: a) the prognostic value of LMR could be confirmed either in patients treated with CHOP and Rituximab (R-CHOP) as well as in those treated with CHOP alone and b) the LMR could improve the prognostic profile as defined by the International Prognostic Index (IPI). Patients and Methods We retrospectively reviewed the clinical outcome of 973 DLBCL patients treated (549 with R-CHOP) and regularly followed at our institutions from 1984 to 2012. The median age of this patients cohort was 61 years (range, 18–86), the Male/Female ratio 55% and the median follow up 44 months (range, 2 – 330). According to the IPI score, 61% of patients were in the low (0–2) risk group, while 39% were in the intermediate or high-risk groups (3–5). A receiver operating characteristic (ROC) curve analysis was used to illustrate in our data set the best cut off values of peripheral blood lymphocyte absolute count (ALC), monocyte absolute count (AMC) or LMR. The relationship between IPI and the LMR was analyzed by the Fisher exact test. Univariate analysis to evaluate differences between variables was performed by the log rank. A multivariate analysis was performed by Cox proportional-hazards models. Results A preliminary ROC curve analysis performed on all patients (treated with or without rituximab) failed to identify any meaningful relationship between Overall Survival (OS) and the ALC, the AMC or the LMR. However, when the same analysis was restricted to patients treated with R-CHOP, we could confirm not only the positive correlation between ALC and AMC and OS, but most importantly that a LMR value 〉2.6 is the most sensitive (70%) and specific (53%) cut off to predict the OS. Within the R-CHOP treated cohort (N=549), we further investigated the relationships between LMR and the most relevant clinical features measured at diagnosis. Patients with a LMR ≤ 2.6 (52%) had a worst ECOG PS (p= 0.000), a higher LDH level (P= 0.000), a higher IPI (p= 0.000) and more frequently they were male (p= 0.02) and had an advanced Ann Arbor disease stage (p= 0.002). On the contrary, no statistical correlation was observed with age and the presence of extranodal sites. The proportion of patients achieving a complete response or a very good partial response was 95% in patients with a LMR 〉2.6 and 87% for those with a LMR ≤ 2.6 (p=0.018). More interestingly, among patients failing to achieve CR the proportion of those with a LMR ≤ 2.6 was 79% as compared to 21% among those with a LMR 〉2.6. The Event Free Survival of patients with a LMR 〉2.6 was significantly better when compared to those with a LMR ≤ 2.6 (71% vs. 59% at 5 years, p= 0.01) while no difference was observed for the Disease Free Survival. By univariate and multivariate analysis we could show that, similarly to a high IPI, a LMR ≤ 2.6 strongly predict a poor OS (p= 0.0000) (Figure 1). In addition, we could demonstrate a strong interaction between IPI and LMR since patients with a high IPI and LMR ≤ 2.6 are characterized by a very poor prognosis when compared to all the others (p= 0.000). Conclusions Our results confirm that a LMR ≤ 2.6 when assessed at diagnosis by a simple automatic blood count is not only a strong predictor of poor survival but it may help to better define a very poor prognostic subgroup in R-CHOP treated DLBCL. This novel prognostic marker is irrelevant when applied to patients receiving chemotherapy alone, giving further support to the notion that lymphocytes and/or monocytes play a crucial role on the therapeutic activity of Rituximab. Disclosures: Rambaldi: Hoffman-La Roche: Consultancy, Honoraria. Ladetto:Hoffman-La Roche: Consultancy, Honoraria. Gianni:Hoffman-La Roche: Consultancy, Honoraria. Tarella:Hoffman-La Roche: Consultancy, Honoraria.

Description: Abstract 882 Background. Three consecutive trials have been performed in Italy over the last 18 years, to verify the efficacy of the use of High-Dose Sequential Chemotherapy (HDS) and autograft as first-line therapy for high-risk Follicular Lymphoma (FL)

Description: T-cell lymphomas represent a rare and heterogeneous group of non-Hodgkin lymphomas (NHLs) characterized by dismal prognosis. Current first line chemotherapeutic approaches have not significantly changed during the last 20 years, and several efforts have been made for early risk stratification of T-cell NHL patients with unsatisfactory results. Functional imaging with 2-deoxy-2-[fluorine-18]fluoro- D-glucose positron emission tomography scan (FGD-PET) has demonstrated improved outcome stratification and response evaluation in Hodgkin lymphoma and B-cell NHL, in comparison with computed tomography (CT) scan. Most T-cell lymphomas are FDG avid and FDG-PET is routinely used in clinical practice, however limited and conflicting data are available on the value of FDG-PET in response assessment at the end of treatment (FDG-PETend). With the aim of evaluating the prognostic value of FDG-PETend in T-cell lymphomas we performed a retrospective study evaluating all T-cell NHL patients treated at the European Institute of Oncology (IEO, Milan) over the past 20 years. Clinical data of all T-cell NHL patients treated at IEO from 1995 to 2015 were retrospectively collected. The back bone of first line therapy did not significantly change over time, being based on the administration of CHOP/CHOP-like chemotherapy eventually followed by treatment intensification with autologous stem cell transplantation (ASCT). Post first-line therapy FDG-PET scans were visually evaluated according to the criteria of the international Harmonization Project (positive vs negative). Ninety-eight consecutive patients (58 males, 40 females) with complete clinical data were considered in this analysis. FDG-PET was used for response evaluation starting from 2002, but only 18 patients considered in the present analysis were treated before 2002. Median age at diagnosis was 54 years (range 14-82). Fifty-two patients (53.1%) had Peripheral T-cell lymphomas not otherwise specified (PTCL-NOS), 23 (23.5%) had anaplastic large T-cell lymphoma (ALCL), 15 (15.3%) had acute lymphoblastic T-cell lymphoma (LAL-T), 8 (8.1%) had NK/T-cell lymphoma. Ten patients were diagnosed in stage I, 21 in stage II, 17 in stage III, 50 patients in stage IV. Thirty-two patients underwent ASCT during the study period. Median follow-up was 16 months (range 1-182). 42 patients were evaluated with FDG-PET at the end of first line therapy: 25 had negative (60%), and 17 (40%) positive PET scans. In 56 patients response was evaluated with CT scan only, and complete responses or complete responses unconfirmed (CR/CRu) were detected in 29 cases (51%). The 10-year progression free survival (PFS) and overall survival (OS) of the whole patient cohort were 22% and 32% respectively. To determine the prognostic value of FDG-PETend we first assessed the PFS of PET positive vs PET negative patients. Those patients who were PET positive at the end of treatment had a statistically inferior PFS compared to PET negative ones (5-year PFS: 29% vs 47% respectively; p

Description: Abstract 4640 Introduction. Lenalidomide is a novel therapeutic agent with immunomodulatory activity, that is clinically active in myelodysplastic syndrome and multiple myeloma. Recent clinical trials have shown that Lenalidomide may have clinical efficacy also in patients with Chronic Lymphocytic Leukemia (CLL). Studies so far reported have been carried out in patients with refractory or relapsed CLL. Besides its clinical efficacy, some concerns have been raised on the possible toxicity of Lenalidomide, with some unique effects, namely tumor flare reactions and tumor lysis syndrome, observed in CLL patients. A recent pilot study has been started at our Institution aimed to verify safety and efficacy of Lenalidomide given to control persistent minimal residual disease (MRD) in patients with CLL in 1st Complete Remission (CR). The selection of patients in 1st CR had a dual advantage: i. the possible use of Lenalidomide as single agent, without any other concurrent chemo-immunotherapeutic drugs that might interact in the clinical response; ii. the presence of low tumor burden, that allows to minimize the risk of severe side effects, in particular the risk of tumor lysis syndrome. So far, three patients have concluded the first year of Lenalidomide. Their clinical outcome, including treatment feasibility and monitoring of MRD, is here reported. Patients and treatment plans. Case # 1: male, aged 53 yrs. in 2002 when he had a diagnosis of B-CLL, with mutated IgH genes; he remained in watchful waiting (w/w) for two yrs., then he received a Fludarabine-based treatment supplemented with Rituximab, achieving CR in September 2005; he then received 2-yr. maintenance with Rituximab; since 2008 he was off-therapy in clinical CR; Case # 2: male, aged 59 yrs. in 2005 when he had a diagnosis of B-CLL, with mutated IgH genes; he remained in w/w for three yrs., then he received a Fludarabine-based treatment supplemented with Rituximab, achieving CR in May 2008; thereafter he was off-therapy in clinical CR; Case # 3: female, aged 38 yrs. in 2002 when she had a diagnosis of B-CLL, with un-mutated IgH genes and she received an induction treatment with Fludarabine supplemented with Rituximab, achieving CR in April 2003; she then received prolonged and intermittent maintenance treatments with Rituximab; since 2008 she was off-therapy in clinical CR. All these patients showed a slow though continuous increase of their clonal B-cell population, identified by cytofluorimetric analysis as CD19+/CD5+ve cells. Based on the increase of the MRD, the patients were placed under Lenalidomide, given at 15 mg/day for 3 weeks/month, until disease progression or discontinuation for severe toxicity. Aspirin at 100 mg. daily was added for thromboembolic prophylaxis. Lenalidomide administration was approved by the Italian National Agency of drugs (AIFA). Results. Presently, all three patients are under Lenalidomide since 12 consecutive months, according to the planned treatment. There have been no severe toxicities, in particular neither tumor flare nor symptoms related to tumor lysis have been recorded. So far, no patients showed clinical signs of disease progression. MRD has been carefully monitored by immunophenotypic analysis on both bone marrow and peripheral blood. In details, the CD19+/CD5+ve clonal B-cell population progressively decreased under Lenalidomide in two patients, with the following changes over 1 yr. before and 1 yr. after Lenalidomide, respectively: 5 to 66 cells/μ L before, then reduction to 12 cells/μ L, in case #1; 189 to 4,480 cells/μ L before, then reduction to 1,317 cells/μ L, in case #2; the clonal B-cell population is still growing (from 67 to 116 cells/μ L before, and then up to 497/μ L after Lenalidomide) in the third patient, with un-mutated B-CLL. A significant increase of the activated T-cell (CD3+/DR+) population has been observed in all three patients following Lenalidomide. Conclusions. This pilot study suggests that: i. Lenalidomide can be administered at 15 mg/day, 21 days/month, for over 1 yr. to patients with B-CLL in first CR, with reduced risks of severe side effects; ii. this schedule may be effective to control the expansion of the MRD in patients with B-CLL in clinical CR; iii. further studies on large series should be planned to verify in which patient subsets Lenalidomide might be offered, in order to reduce or even eliminate the MRD that usually persists in B-CLL patients following induction chemo-immunotherapy. Disclosures: Off Label Use: Lenalidomide in CLL in first CR to control MRD.

Description: Background. The assessment of nodal and extranodal involvement in Hodgkin’s (HL) and non-Hodgkin’s (NHL) lymphoma is mostly performed by Computed Tomography with i.v. iodinated contrast agent (CE-CT) and 18F-FDG Positron Emission Tomography (PET), along with bone marrow (BM) biopsy. Both CE-CT and 18F-FDG-PET require the delivery of considerable dose of ionizing radiation, that may be of concern given the increased risk of secondary malignancies in long surviving patients. Whole body Magnetic Resonance Imaging (Wb-MRI) is a novel and promising radiation-free technique and the development of Diffusion Weighted Imaging (DWI) has enhanced its diagnostic potential. At our Institution, Wb-MRI-DWI has been used as additional diagnostic tool in a series of lymphoma patients at disease onset. The diagnostic accuracy of the procedure is here reported. Patients and Methods. From February 2010 to October 2013, 41 patients underwent the Wb-MRI-DWI procedure, which was added to the standard procedures in order to further investigate possible bone, liver and kidney involvement. Median age of the patients was 49 yrs. (20-76), histological subtypes included 10 Diffuse Large B-Cell (DLB-CL), 13 Follicular (FL), 3 Mantle-cell (MCL), 1 Burkitt’s (BL) Lymphoma and 14 HL. All patients received the diagnostic procedures required for staging definition, including CE-CT, BM biopsy, and 18F-FDG-PET co-registered with low dose unenhanced CT. Nodal and extra-nodal sites were considered pathologic according to standard parameters employed for imaging technique evaluation. For the present analysis, the Gold Standard (GS) assessment was defined based on: i. the information obtained primarily by 18F-FDG PET-CT and secondary by CE-CT findings; ii. the BM histological examination; iii. the modifications before and after therapy for those lesions with discordant definition at diagnosis; iv. for few lesions, with uncertain definition at diagnosis a biopsy procedure was performed and histological data were considered true positive. Results. According to GS, among 1,025 nodal regions analyzed in 41 patients, 217 were judged positive for involvement by lymphoma. CE-CT had 22 false negative and 10 false positive errors, whereas Wb-MRI-DWI erroneously considered involved 6 nodes and failed in recognizing 17 localizations, mostly for misdiagnosed nodes in the mediastinum. There were no errors in nodal assessment by 18F-FDG PET-CT. A total of 458 extranodal sites were evaluated and 37 were considered positive. Compared to GS, 18F-FDG PET-CT had four false negative errors, i.e. no detection of BM (three cases) and spleen (one case) involvement; in addition, 18FDG PET-CT had two false positive results, due to presumed tonsil and BM involvement that were not confirmed on histological examination. CE-CT had 17 false negative errors mainly due to misdiagnosis of BM involvement in 13 out of 14 BM positive cases. Other false negative errors with CE-CT were lack of disease detection in the spleen (1 case), oropharyx (2 cases) and vulva (1 case). Wb-MRI-DWI was unable to detect the gastric involvement in one patient, while no false positive were recorded. The comparative analysis indicates that: i.18F-FDG PET-CT alone overstaged two patients (4.9%) (wrong involvement in BM and tonsil), two patients were understaged due to the failure in recognizing BM involvement; ii. CE-CT alone understaged 12 patients (29%), mainly due to low sensibility in detecting BM involvement; no patient was overstaged by CE-CT; iii. Wb-MRI-DWI alone, in spite of the 24 errors, mainly in nodal misdiagnosis, did not fail the final per-patient staging assessment. Wb-MRI-DWI proved to be the most reliable imaging technique for BM evaluation, with no misjudgment recorded, while 18F-FDG PET-TC was unable to correctly assess BM involvement in four patients and CE-CT in 13. Conclusion. The data indicate that Wb-MRI-DWI is a sensitive and specific imaging technique for malignant lymphoma evaluation. Compared to CE-CT, it detects additional disease that modify clinical stage in a significant percentage of patients, altering their management and outcome. Wb-MRI-DWI is also extremely effective in detecting BM involvement. Thanks to the lack of any radiation exposure and intravenous contrast agent injection, the results here reported further support the use of Wb-MRI-DWI in place of CE-CT for the staging and possibly the follow up monitoring of malignant lymphoma. Disclosures No relevant conflicts of interest to declare.