ALBERT

Description: The FL2000 study was undertaken to evaluate the combination of the anti-CD20 monoclonal antibody rituximab with chemotherapy plus interferon in the first-line treatment of follicular lymphoma patients with a high tumor burden. Patients were randomly assigned to receive either 12 courses of the chemotherapy regimen CHVP (cyclophosphamide, adriamycin, etoposide, and prednisolone) plus interferon-α2a (CHVP+I arm) over 18 months or 6 courses of the same chemotherapy regimen combined with 6 infusions of 375 mg/m2 rituximab and interferon for the same time period (R-CHVP+I arm). After a median follow-up of 5 years, event-free survival estimates were, respectively, 37% (95% confidence interval [CI], 29%-44%) and 53% (95% CI, 45%-60%) in the CHVP+I and R-CHVP+I arm (P = .001). Five-year overall survival estimates were not statistically different in the CHVP+I (79%; 95% CI, 72%-84%) and R-CHVP+I (84%; 95% CI, 78%-84%) arms. In a multivariate regression analysis, event-free survival was significantly influenced by both the Follicular Lymphoma International Prognostic Index score (hazard ratio = 2.08; 95% CI, 1.6%-2.8%) and the treatment arm (hazard ratio = 0.59; 95% CI, 0.44%-0.78%). With a 5-year follow-up, the combination of rituximab with CHVP+I provides superior disease control in follicular lymphoma patients despite a shorter duration of chemotherapy. This study's clinical trial was registered at the National Institutes of Health website as no. NCT00136552.

Description: Background: The efficacy of epoetin beta (E) is well documented in clinical trials in anemic cancer patients (pts). This study was conducted to assess E use, efficacy, safety and effect on quality of life in cancer pts, in usual practice. Methods: This prospective, multicenter, longitudinal, observational French study assessed a 4-month follow-up of informed consent cancer pts (including both solid tumors (ST) and non-myeloid hematological malignancies (H)) treated with E for chemotherapy-related anemia. Data were collected between January 2005 and March 2006. We only present here the results of the H subgroup. Results: Among 2809 pts, 675 had an H including 325 non-Hodgkin lymphoma (NHL), 181 multiple myeloma (MM) and 80 chronic lymphocytic leukemia (CLL). 52% of pts received their first line of chemotherapy, 24% their second one. At inclusion, Hb levels were distributed as follows: 〈 9 g/dl: 32%, [9–11[ g/dl, 56%, [11–13[ g/dl, 11%. At inclusion, endogenous erythropoietin rate was monitored for only 8% of pts, ferritin was available for 32%, transferrin saturation for 17% and reticulocytes for 24%. At initiation, pts received a median dose of 30000 U/week of E on a once weekly regimen schedule for 98% of pts. E was associated with iron supplementation in 20% of pts (1% IV). The mean Hb level increased from 10 g/dl [5 – 14] at baseline to 13 g/dl [7 – 17] in the entire cohort of H pts, from 10 g/dl [5 – 14] to 12 g/dl [7 – 16] in NHL pts, from 10 g/dl [6 – 13] to 13 g/dl [8 – 17] in MM pts and from 10 g/dl [6 – 13] to 13 g/dl [7 – 17] in CLL pts. Hb response rate (RR) was 56% (CI95: 51 – 61) in H pts, 53% (CI95: 46 – 60) in NHL pts, 57% (CI95: 48 – 66) in MM pts and 56% (CI95: 41 – 70) in CLL pts. 41% of patients were transfused at inclusion or during the study. Good performance status (PS≤1) (OR=1.6, CI95: 1.1–2.5), non platinum-based regimen (OR=2.4, CI95: 1.2–4.9) and iron supplementation (OR=2.6, CI95: 1.4–5.1) are identified both in univariate and multivariate analysis as predictive factors of Hb response. The mean of FACT score improved from 29 (CI95: 26–31) at initiation to 36 (CI95: 34–38) at the end of study (p

Description: Introduction: Clinical evolution of classical Hodgkin lymphoma (cHL) cannot be always predicted by clinical, biological or radiological parameters. Given the high treatment related morbidity of clinical trials it should be interesting to get other prognostic markers to predict cHL patients evolution. Some immunohistochemical (IHC) markers have been already published as prognostic in cHL but they are still matter to debate. We have tested 13 IHC markers in the LYSA H3/4 trial of cHL which compares patients with stage III to IV cHL in a phase III who were assigned to either doxorubicin, bleomycin, vinblastine and dacarbazine (ABVD, 8 courses) to bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine and prednisons (escBEACOPPx4 & BEACOPP x4) without radiation therapy, in order to determine if some of these markers could predict different progression free survival (PFS) or overall survival (OS). Methods: The H3/4 trial includes both high (n=549) and low risk (n=150) patients, and we obtained all biological data for 165 patients (106 high & 59 low risk). We performed 13 IHC markers (CD20, CD3, CD68, CD163, CD117, TiA1, FoxP3, ICOS, CD10, CXL13, PD1, PDL1 & EBER probe) on Tissue Micro Arrays (TMA) performed for these 165 patients. Most of these markers were evaluated on the micro-environment cells of the cHL (absolute number of cells stained when they are few or percentage of cells stained on TMA spots when they are numerous). For PDL1 and EBER, we evaluated the number of both micro-environmental cells and Reed-Sternberg (RS) cells stained with this antibody. The results of this IHC study were compared with the clinical data base of these patients. For each variable different cut-offs were studied on PFS and OS. Results: Patients characteristics were similar to those of the total population: median age (31 y), male sex (66%), nodular sclerosis histology (83.3%), stage IV (61%), B symptoms (73%), IPS〉2 (66%), bulky disease (26.5%), bone marrow involvement (16%). Half of the patients received ABVD or escBEACOPP. 82.4% achieved a CR/Cru at the end of treatment and we observed 23 relapses and 14 deaths with a five-year median follow up. IHC study revealed a marked expression of tumor associated macrophages (TAM) and lymphocytes markers but none of them were associated with PFS or OS by statistical evaluation. By contrast, we found that a low count of TiA1+ cells in cHL microenvironment (median ≤29)) and a high number of RS cells PDL1+ (=100)) were significantly associated in a multivariate analysis with a worse PFS (TiA1: HR;95% CI=5.33; [1.62;17.52] and PDL1: HR;95%CI = 5.01; [1.39;18.05]). We also found that the association of a higher number of PDL1 RS+ and TAM CD68+ was statistically significant in patients of the high group risk in multivariate analysis. EBER expression on RS cells or on micro-environmental cells was not statistically associated with PFS or OS. But, the association of a higher number of EBER RS+ cells and TAM CD68+ was statistically significant in both high or low risk groups. The association of EBER and CD68 on micro-environmental cells was not statistically significant. Conclusion: In this large and unselected series of advanced cHL, we do not find prognostic significance of TAM CD68/CD163+ nor of other lymphoid markers tested nor of EBER expression. But, we showed that a low count of TiA+ cells in the micro-environment of cHL and a high level of PDL1 RS+ cells expression cells are predictive of a worse PFS in this study. We found also that there is a significant association between the number of PDL1 RS+ cells and TAM CD68+ in the high risk group and between EBER RS+ and TAM CD68+ cells in both groups. These results suggest that IHC markers could be helpful to predict evolution in cHL patients. Disclosures Casasnovas: Roche: Consultancy; takeda: Consultancy; merck: Consultancy; MSD: Consultancy; Gilead Sciences: Consultancy; Janssen: Consultancy; Roche: Research Funding; Gilead Sciences: Research Funding; Roche: Honoraria; Takeda: Honoraria; Merck: Honoraria; MSD: Honoraria; Gilead Sciences: Honoraria; Janssen: Honoraria; Celgene: Honoraria. Coiffier:NOVARTIS: Membership on an entity's Board of Directors or advisory committees; CELGENE: Consultancy, Membership on an entity's Board of Directors or advisory committees; MORPHOSYS: Membership on an entity's Board of Directors or advisory committees; MUNDIPHARMA: Membership on an entity's Board of Directors or advisory committees; CELLTRION: Membership on an entity's Board of Directors or advisory committees.

Description: We previously reported a 93% CR rate in patients with Philadelphia positive acute lymphoblastic leukemias (Ph+ ALL) treated with an imatinib (Glivec®) based induction (DIV regimen) (Rea et al. Leukemia, 2006;20:400–3). We decided to further confirm these results in a larger prospective cohort of patients and to evaluate the combination of imatinib and Pegasys® for patients in CR not eligible for hematopoietic stem cell transplantation (HSCT). Patients not previously exposed to imatinib and with resistant or refractory Ph+ ALL, lymphoid blast crisis CML (LBC CML) or with de novo Ph+ ALL and aged over 55y were eligible. The DIV regimen consisted in one IV injection of vincristine 2 mg combined with 2 days of dexamethasone 40 mg PO repeated weekly for 4 weeks as induction and then monthly for 4 months as consolidation. Imatinib was administered at 800 mg per day during the induction period and at 600 mg/d continuously with 6 mercaptopurine during consolidation. Patients in CR not eligible for HSCT were allocated to maintenance therapy consisting in weekly SC injection of Pegasys® 45 μg and continuous administration of imatinib 400 mg per day for 2 years. 54 patients (median age 62y, 22 to 83) were included (22 resistant or refractory Ph+ ALL, 3 relapsed Ph+ ALL, 4 LBC CML and 25 elderly Ph+ ALL). The median follow up was 18 months. The overall CR rate after induction was 85%. 42 patients were eligible for post consolidation therapy: 18 patients received HSCT (10 allogenic HSCT including 9 out of the 15 patients aged under 55y and 8 autologous HSCT). 18 out of 24 patients (75%) without HSCT started the maintenance therapy. Reasons for not being in maintenance were relapse in one case, septic death in 3 cases and toxicity in 2 cases. The interval from CR to HSCT was 5.8 months in median (2.6 to 11.3). The medain interval from CR to maintenance was 5.4 months (5.2 to 6.7). The median survival of the transplanted group of patients was 29.9 months compared to 27.9 months for patients treated with the maintenance schedule (p=0,98). Six patients (33%) relapsed in the HSCT group and 7 (38.8%) in the maintenance group. Grade 2 to 4 neutropenia and/or thrombocytopenia were observed in 33% of cases during maintenance therapy leading to transient interruption of Pegasys® injections. Extra haematological grade 3 to 4 toxicities were infrequent (1 papillary oedema and two infections). We confirm here the high CR rate obtained in Ph+ acute lymphocytic leukemias with the DIV regimen, without the need of intensive chemotherapy. Maintenance therapy with Pegasys® and imatinib represents an alternative approach for patients not eligible for HSCT and was associated with a median survival of 27.9 months in this study.

Description: Conventional cytogenetics (CC) of B-cell lymphoproliferations remains difficult because of low mitotic in vitro activity of the leukemic cells. Therefore, mitogen stimulation of B-cells is required to analyze an adequate number of metaphases. Chromosome abnormalities using CC with TPA can be detected in up to 50% of chronic lymphocytic leukemia (CLL), but the development of FISH techniques has allowed the detection of selected chromosome abnormalities in more than 80% of CLL. However, FISH is restricted, since information is only available for the genes/loci for which probes are used. So, for a comprehensive genetic analysis, CC is essential because it provides an overview of all microscopically visible chromosome abnormalities important as prognostic factors. The use of the immunostimulatory CpG-oligonucleotide DSP30 to effectively induce cell cycle progression of CLL cells in vitro has been reported. This proliferation is markedly enhanced upon addition of Interleukine-2 to cultures. To our knowledge and to date, there has been no direct comparison of classical TPA versus DSP30+IL-2. DSP30+IL-2 stimulation has been successfully tested in CLL but no data are available for other lymphoproliferations. We cultured 132 B-cell lymphoproliferations (80 CLL and 52 other B-cell lymphoid neoplasms (BCLN)) in parallel, in presence of TPA or DSP30+IL-2. The objective of this study was to evaluate the suitability of DSP30+IL-2 as a routine B-cell mitogen for metaphase cytogenetics. CC successfully analyzed 94.9% of CLL and 98.1% of BCNL with more than 80% abnormal karyotypes. For CLL, failures of karyotypes were more frequent in cultures with DSP30+IL-2 (14%) than in those with TPA (4%). The rate of failures were similar for BCLN (6% versus 4%). For CLL, there were significantly fewer metaphases in DSP30+IL-2 than in TPA spreads (mean of 50 versus 72 metaphases per slide respectively, p=0.0007), as well as for BCLN (mean of 50 versus 71 metaphases per slide respectively, p=0.009). However, the proportion of abnormal metaphases was significantly higher in DSP30+IL-2 (mean of 59%) compared to TPA cultures (mean of 26%, p=0.00265) for CLL and for BCLN (mean of 57% versus 33%, p=0.0065). Stimulation with DSP30+IL-2 allowed to detect more abnormalities, more abnormal subclones and more complex karyotypes in CLL and in the majority of BCLN. Though FISH exploration using a large probe panel has yielded valuable results in lymphoproliferative diseases, it underestimates the heterogeneity of chromosomal aberrations. Complexity of chromosomal changes, recently associated to unfavorable outcomes, can only be assessed with CC. In conclusion, our results in both CLL and BCLN indicate that the immunostimulatory oligonucleotide DSP30 in combination with IL-2 is an easy and efficient stimulus in metaphase generation for routine chromosomal banding.

Description: Abstract 3378 Chronic Myelogenous Leukemia (CML) originates in the Philadelphia chromosome, a reciprocal translocation creating the fusion oncogene BCR-ABL. In 1–2% of CML cases, breakpoints fall outside the M-BCR gene on chromosome 22, leading to the synthesis of a variety of atypical BCR-ABL transcripts [shortened: e1a2 (m-BCR), e6a2, e8a2, b2a3 (e13a3), b3a3 (e14a3), or elongated transcripts: e19a2 (m-BCR)] and to the synthesis of different molecular weight BCR-ABL proteins that might have different tyrosine kinase activities. Thus, clinical phenotypes and BCR-ABL inhibition by tyrosine kinase inhibitors might be different and lead to different prognostic features. We retrospectively analysed at the national level, the clinical characteristics and the responses to imatinib (IM) of 63 patients with CML harbouring atypical BCR-ABL transcripts: 22 e1a2 [Group 1 (G1)], 20 e19a2 [Group 2 (G2)], 5 e8a2 [Group 3 (G3)], 4 e6a2 [Group 4 (G4)], 5 b2a3 [Group 5 (G5)], and 3 b3a3 [Group 6 (G6)] BCR-ABL transcripts. The general characteristics of the patients and their best response to IM are depicted in Table 1: Table 1 Group 1(e1a2) Group 2 (e19a2) Group 3 (e8a2) Group 4 (e6a2) Group 5 (b2a3) Group 6 (b3a3) n 22 20 5 8 5 3 M/F 7/15 6/14 4/1 4/4 5/0 0/3 Median age (years) 70 69 43 57 62 47 CP/AccP/MBC 20/0/2 17/1/2 5/0/0 4/1/3 4/1/0 2/1/0 Sokal (L/H/I/Ukn)* 6/8/2/4 1/3/9/4 3/1/0/1 1/2/1/0 1/2/0/1 0/2/0/0 Leukocytes (G/l, median) 60.85 28.3 55 28.4 93 82.4 Hemoglobin (g/dl, median) 12 10.2 11.7 10.95 11.1 10.2 Platelets (G/l, median) 303 848 253 259 167 363 Monocytes (G/l median) 4.8 0.8 2.34 0.05 1.08 0.825 Additional Clonal Abnormalities at diag (% of patients) 20 28 0 29 25 0 IM duration (median, years) 1.55 1.38 1.58 0.8 1.13 1.42 Interval Diagnosis-IM (median, years) 1.31 1.48 1 1.17 0.87 1.66 Best response to IM* No response 20 0 0 0 0 0 CHR (%) 13 32 0 0 0 0 Minor CyR (%) 47 0 0 0 0 0 PCyR (%) 0 10 20 10 25 67 CCyR (%) 13 32 60 50 0 0 MMR (%) 7 26 20 40 75 33 Follow-up since diag (median, years) 3.24 1.57 1.6 3.82 1.5 1.68 (CP states for Chronic phase, AccP for accelerated phase, MBC for myeloid blast crisis, L for Low, I for intermediate, H for High, Ukn for Unknown, * For CP patients only) Surprisingly, e1a2 and e19a2 transcripts seem significantly more frequent in females than in males conversely to typical BCR-ABL transcripts (p=0.01) and occurring more often in the elderly (p=0.05). The majority of the patients presented with typical cytological CML features, however, a significant monocytosis was observed in e1a2 and e8a2 atypical transcripts (p=0.0002). The median time on IM and the interval between diagnosis and IM were not statistically different between the 6 groups. Overall, there was no significant difference in the (hematologic, cytogenetic, molecular) responses to IM, but e1a2 transcripts seem less sensitive to this agent. The overall survival since diagnosis or since IM initiation was not different between atypical transcripts (p=0.55 and p=0.73 respectively), however, the progression-free survival (PFS) since diagnosis with e1a2 transcripts was significantly worse than for all other atypical transcripts (p=0.02) as shown in Figure 1: The PFS since IM initiation was somewhat worse for e1a2 transcripts, but close to significance (p=0.09), but the follow-up is not very long yet. Fifteen patients among 63 had second generation TKIs (TKI2), 7 in group 1, 3 in group 2, 1 in groups 3, 4, 5, and 2 in group 6. Only one patient (b3a3 transcript) developed a MBC being on IM. Two patients developed a T315I BCR-ABL mutation (1 e1a2, and 1 e6a2). Two patients got allo-transplanted (1 e1a2 alive and well at last follow-up, 1 e19 a2 died from GVHD). In conclusion, atypical BCR-ABL transcripts induce a particular molecular and subsequent clinical phenotypes, particularly e1a2 transcripts showing in this study poor prognosis features. The response of atypical BCR-ABL transcripts to IM might vary from that what it is for classical M-BCR transcripts, but a longer follow-up is needed. Disclosures: No relevant conflicts of interest to declare.

Description: Background. The FL2000 study evaluated the combination of the anti-CD20 monoclonal antibody rituximab with chemotherapy plus interferon in the first line treatment of follicular lymphoma patients. Methods. Untreated follicular lymphoma patients (n=359) presenting with a high tumor burden were randomly assigned to receive either 12 courses of the chemotherapy regimen CHVP (cyclophosphamide, adriamycin, etoposide and prednisolone) plus interferon-α2a (CHVP+I arm) over 18 months or 6 courses of the same chemotherapy regimen combined with 6 infusions of 375 mg/m2 of rituximab and interferon for the same time period (R-CHVP+I arm). The primary endpoint of the study was event free survival and all results are shown as intent to treat. Results. Six months after treatment initiation, 156 out of 183 (85%) and 164 out of 175 (94%) patients had a response to therapy in the CHVP+I and R-CHVP+I study arm, respectively (P=.009). At the end of the 18 months treatment period, 59% and 75% of the patients were respectively in CR or CRu in the CHVP+I and R-CHVP+I arm (P

Description: Our previous report concluded that an imatinib (Glivec®) based induction may be proposed as front line therapy in elderly patients (pts) with Philadelphia positive acute lymphocytic leukemia (Ph+ ALL) (Rea et al. Leukemia, 2006;20:400–3). We decided to test this hypothesis and to evaluate the value of maintenance therapy with Pegasys® and imatinib in a prospective study of pts aged over 55 years with de novo Ph+ ALL. The protocol consisted in IV injections of vincristine 2 mg combined with 2 days of dexamethasone 40 mg PO repeated weekly for 4 weeks as induction and then monthly for 4 months as consolidation. Imatinib was administered at 800 mg per day during the induction period and at 600 mg/d continuously with 6 mercaptopurine during consolidation. Pts in CR were allocated to maintenance with SC injections of Pegasys 45μg once a week and continuous administration of imatinib during 2 years. BCR-ABL analysis were performed in a centralized laboratory according to the ENL recommendations. 25 pts were included from May 2005 to July 2007. Median age was 68 years and sex ratio 0,92. After a median follow up of 13.2 months (1 to 27), median overall survival and DFS were not reached. The estimated proportion of pts alive and free of relapse at 18 months was 53.7%. The CR rate was 84%. Induction failures (n=4) were due to death in 3 cases and intolerance in 1 case. Extra haematological grade 2 to 4 adverse events during induction were mainly related to vincristine (ileus in 6 cases, neuropathy in 5 cases). Median duration of neutropenia (