Abstract 3426
Imatinib mesylate (IM) has shown remarkable efficacy for the treatment of Chronic Myeloid Leukemia (CML) patients (pts) in the chronic phase of the disease. However, while most ...individuals achieve an optimal response to conventional IM therapy, approximately 30% either fail IM or develop intolerance to the drug. Thus, there is a growing need for biological parameters predictive of IM response (at diagnosis or during the first months of therapy) in order to recognize pts with a more aggressive disease that should receive alternative treatments. We examined the outcomes of the first 193 CML pts accrued to the observational SCREEN (Sicily and Calabria CML REgional ENterprise) multicenter non-sponsored study, and analyzed the responses of this unselected population. Pts characteristics were as shown in Table 1. All subjects received IM 400 mg daily. Median follow-up was 26 months (range 3–60). Complete hematological (CHR), cytogenetic (CCyR) and major molecular responses (MMR) were rated according to the European Leukemia Net 2006 guidelines. Peripheral blood samples were used for BCR-ABL determination by quantitative real-time polymerase chain reaction according to the International standardized Scale (IS). To identify parameters predictive of IM response, pts were stratified according to clinical and molecular responses or BCR-ABL transcript levels at diagnosis and analyzed for their outcome on an intention to treat basis. At 12 months, cumulative incidences of CHRs, CCyRs and MMRs were 100%, 82% and 43%, respectively. At 24 months, incidences of CCyR and MMR increased to 87% and 67%. According to the ELN criteria, 121 pts (62%) achieved an optimal response; 36 pts (19%) had a suboptimal response; 32 pts (17%) failed IM because of either primary (20 pts) or secondary (12 pts) resistance. Only 4 pts (2%) were intolerant to IM. Kaplan-Meyer estimates for overall, progression-free, event-free and failure-free survival at 60 months were 99%, 96% 80% and 72%. When we clustered all subjects in optimal responders (ORs) and suboptimal/resistant (S/R) pts and correlated response to therapy with various molecular characteristics we found that the amount of BCR-ABLIS transcripts at diagnosis predicted response to IM. Indeed, the median amount of BCR-ABLIS at diagnosis displayed by patients that failed IM or achieved a suboptimal response was significantly higher (104.154IS) than that of patients obtaining an optimal response (53.478IS; p=0.000611). As WBC counts were not significantly different between ORs and S/R pts (p=0.2065), increased amounts of BCR-ABLIS transcripts were probably representative of the aggressiveness of the leukemic clone. We also observed that pts displaying >10% BCR-ABLIS after 3 or 6 months of IM had a significantly lower chance of achieving a CCyR compared to pts with BCR-ABLIS levels lower than 10% (p<0.001). IM is a highly effective and well-tolerated treatment for most chronic phase CML pts, producing high rates of CHR, CCyR and MMR. However, 35–40% of newly diagnosed CML pts will either fail IM or obtain a suboptimal response. High levels of BCR-ABLIS transcripts at diagnosis may allow the rapid identification of CML pts that are likely to fail IM or to achieve a suboptimal response. Furthermore, failing to achieve BCR-ABLIS transcript levels <10% after 3 or 6 months of IM treatment significantly reduces the probability of subsequently obtaining a CCyR.
Table 1Characterisitics of CML pts included in the SREEN studyAge (median yrs)54 (range 24–90)Sex (M/F)108/85WBC × 109/L (median)64.8 (range 3.4–718.0)Hb (g/dL)12.1 (range 7.5–17.0)PLT × 109/L (median)330.0 (range 67.0–1690.0)Organomegaly %58Sokal risk stratification %49 Low/36 Intermediate/15 HighPh+ % (diagnosis)96ACA % (diagnosis)7BCR-ABL transcript variants %38 e13a2/53 e14a2/9 otherBCR-ABLIS % (median at diagnosis)58.641
No relevant conflicts of interest to declare.
Abstract▪294▪This icon denotes a clinically relevant abstract
Rituximab plus fludarabine/cyclophosphamide (R-FC) is currently the standard of care for fit patients with untreated or relapsed CLL. ...However, patients with CLL are predominantly an elderly population and many of these patients may have comorbidities that make them less suitable to receive fludarabine-containing therapy. Chlorambucil-based treatments are frequently used for these patients despite the fact that clinical benefits are limited. There is a need for well-tolerated and more efficacious treatment regimens for these patients.
The ML21445 study evaluated the combination of rituximab and chlorambucil (R-chlorambucil) as first-line treatment for patients with CLL considered ineligible for treatment with the current standard of care, R-FC. Patients aged >65 years (or 60–65 years and ineligible for fludarabine) were treated with eight 28-day cycles of chlorambucil (8 mg/m2/day Days 1–7) with rituximab administered on Day 1 of cycle 3 (375 mg/m2) and cycles 4–8 (500 mg/m2). Patients with a response at the end of induction were randomized to rituximab maintenance therapy (375 mg/m2 every 8 weeks for 2 years) or observation. The induction phase of the study is complete while the maintenance phase is still ongoing. The overall response rate (ORR) in 85 patients who received at least one dose of rituximab during induction was 81.2% (n = 69) with 16.5% (n = 14) achieving a complete response (CR) and 2.4% (n = 2) a CR with incomplete bone marrow recovery (CRi). ORR and CR rates were similar across the different Binet stages (ORR: Binet A 86.4%, Binet B 79.6%, Binet C 78.6%) and age categories (ORR: 60–64 years 84.6%, 65–69 years 85.2%, 70–74 years 75.0%, ≥75 years 81.0%). Two of four patients aged ≥80 years responded to induction treatment. Logistic regression analysis revealed no correlation between known biological prognostic factors – CD38, cytogenetics, IGHV mutational status, ZAP-70, thymidine kinase, soluble CD23, and beta-2 microglobulin – and response to treatment. To further investigate possible factors influencing response, pre-treatment patterns of gene expression were analyzed in different patient subgroups. Material was available for 62 patients, including 16 with CR/CRi, 41 partial responders and 5 non-responders. In an exploratory analysis, mRNA expression was examined using Affymetrix® Human Genome U133 microarrays. This revealed marked differences in pre-treatment gene expression profiles between response groups. Non-responders showed a homogeneous gene expression signature involving up-modulation of transcripts involved in anti-apoptotic and pro-proliferative pathways, including K-ras and N-ras. CR/CRi patients also showed a homogeneous pattern of gene expression that was clearly distinct from non-responding patients, while patients with a partial response showed a more heterogeneous pattern of gene expression before treatment.
These initial findings reflect the heterogeneity of CLL and suggest that microarray analysis of gene expression may be useful in predicting response to R-chlorambucil in elderly patients with CLL.
Foa:Roche: Consultancy, Speakers Bureau. Cuneo:Roche: Consultancy, Speakers Bureau. Montillo:Roche: Membership on an entity's Board of Directors or advisory committees. Alietti:Roche: Employment. Runggaldier:Roche: Employment. Gamba:Roche Italia: Employment.
Abstract 1360
The arbitrary cut-off of 5000/μL chronic lymphocytic leukemia (CLL)-phenotype cells in peripheral blood is generally used to separate monoclonal B-cell lymphocytosis (MBL) from CLL. ...However, a major concern is the biological differentiation, if any, between MBL and CLL. We tried to address the issue therefore analyzing 261 Rai stage 0 patients enrolled in a Gruppo Italiano Studio Linfomi (GISL) prospective multicentre trial designed to validate biological parameters in early CLL as well as to assess the impact on clinical outcome of an early versus delayed policy of treatment with subcutaneous alemtuzumab in the high biological risk. In this cohort, biological characteristics of 105 (40.2%) patients who would be reclassified as MBL using the 2008 CLL diagnostic criteria were compared with those of the remaining 156 patients who had more than 5000/μL CLL-phenotype cells in peripheral blood and fulfilled diagnostic criteria of CLL.
Male to female ratio was similar for MBL and CLL (54/53 vs. 92/66, P=0.21) as was median age (58.18 vs 58.18, P=0.98). Median absolute number of cells with CLL phenotype in peripheral blood was 3120/μL (range,400-4959) in MBL and 9925/μL (range, 5020–110000) in CLL (P<0.0001). No difference in the CD38 status (P=0.48),ZAP-70 expression (P=0.29) or cytogenetic abnormalities as detected by FISH trisomy 12 (P=0.24); deletion 11q (P=0.68); del17p (P=0.09) was found between patients with MBL and CLL. The only feature differentiating CLL from MBL was represented by an excess of patients with unmutated IgVH disease in the former group (CLL,69.2% vs. MBL, 30.8%: P=0.04). In addition, patients with CLL had an about 2-fold risk of having IgVH germline status in comparison to patients with MBL (OR,1.80; 95% CI, 1.02–3.13; P=0.04). Since the arbitrary cut-off of 5000/μL CLL-phenotype cells in peripheral blood failed to identify a peculiar biological profile for either MBL or CLL, we wondered whether a different B-cell threshold based on disease clinical outcome better stratified patients according to biological risk. In an independent cohort including 818 Rai stage 0 patients registered in a GIMEMA (Gruppo Italiano Malattie EMatologiche Maligne dell'Adulto) database, we demonstrated that a count of 10000/ μL B-cells is the best lymphocyte threshold to predict time to first therapy (TFT). When this cut-off was applied to the GISL series we found that the distribution of main high-risk features CD38, P=0.83; trisomy 12,P=0.36; del11q,P=0.85; del17,P=0.37) was similar between patients with B-cell lymphocytes higher and lower than 10000/ μL. Only an excess of cases with unmutated IgVH (P=0.04) and slightly increase of ZAP-70 (P=0.06) characterized patients B-cell higher than 10000 μL. In conclusion, present data obtained from a prospective multicentre study indicate that biological characteristics of CLL are found also in MBL and there is no general predominance of good risk variables in MBL in comparison to CLL. This implies that MBL may not be considered a distinct disease but as an early stage of CLL.
Musto:Celgene: Honoraria; Janssen Cilag: Honoraria.
Abstract 2686
Poster Board II-662
Fludarabine in combination with cyclophosphamide (FC) plus rituximab (R) is an effective treatment for newly diagnosed as well as relapsed low-grade non-Hodgin's ...lymphoma (NHL). The role of maintenance treatment with R has been demonstrated in relapsed/resistant follicular NHL improving overall and progression-free survival. We investigated efficacy and safety of the chemo-immunotherapy FCR followed by rituximab maintenance treatment in patients with advanced untreated indolent B-cell non follicular lymphomas (INFL).
from July 2005 to May 2007, 47 pts whit untreated advanced stage INFL (23 lymphocytic, 20 limphoplasmacytic and 4 nodal marginal zone NHL) were enrolled by 10 IIL centres, in an open label, single arm, multicenter phase II study. Treatment plan was: 6 courses of FC (Fludarabine, 25 mg/m2 i.v. plus Cyclophosphamide, 250 mg/m2, days 2–4) every 28 days plus 8 doses of R (375 mg/m2 , day 1 every FC cycle and day 14 of cycles 4 and 5) followed by R maintenance (375 mg/m2 every two months for 4 doses). Prophylactic antibiotic treatment with cotrimoxazole (two tablets three times a week) and antifungal profilaxis with itraconazole was planned from the beginning of chemotherapy to three months later or until normalization of CD4 count. The primary endpoint of this study is the percentage of failure free patients after two years from the treatment start.
all the patients were evaluable for safety analysis and 46/47 pts were evaluable in terms of intention to treat analysis. Median age was 59 years (31–68) and M/F ratio was 28/18; stages II/III/IV were 2/2/44; B symptoms and splenomegaly were observed in 11 and 14 pts respectively; FLIPI scores were: 0–1 in 16 pts (34.8%), score 2 in 19 pts (41.3%) and score ≥ 3 in 11 pts (23.9%). Forty-one patients (87.2%) completed the planned therapeutic program; the remaining 6 patients stopped the treatment for SAE (4 pts) or for other reasons (2 pts) after 9 courses (1 pt), 8 (1 pt), 6 (2 pts), 3 (1 pt) and 1 (1 pt). Overall response at the end of treatment was 80.4% with 60.9% CR and 19.5% PR. One patient relapsed during maintenance phase. All the patients are still alive.
A total of 279 courses of FC were given to 47 patients. All the patients presented at least one toxic/adverse events (AE); 11 pts developed 12 serious AEs, but only 6 were related to therapy. Seventeen pts had to interrupt (4 pts), delay or reduce therapy. Three hundred twenty related AEs were registered: grade 1–2: 228 events; grade 3–4: 92 events. Among these last the most frequent was neutropenia: 30 pts presented 83 episodes whose grade 3–4 related to the therapy were 58. During maintenance phase, 4 episodes of neutropenia occurred (2 of grade 3–4). Sixteen pts presented 31 infective episodes; the most frequent were: 5 Herpes zoster infections, 5 pneumonia (1 mycotic) and 4 urinary tract infections.
in a series of INFL at diagnosis, FCR regimen is effective with a very high CR rate. The toxicity was acceptable and the schedule can be considered safe although the frequence of neutropenia and infective events require a close surveillance. The next year of follow-up will allow us to establish the failure free survival after two years from the treatment start.
Vitolo:Roche: Lecture fees. Morra:Roche: Lecture fees.
Abstract 4613
Biologic risk factors such as immunoglobulin variable heavy chain (IgVH) gene mutation status and CD38 and ZAP-70 expression levels, along with genomic aberrations, have been integrated ...in clinical prognostic evaluation of CLL. Additionaly, CLL subsets expressing a certain stereotyped B-cell receptors have also been indicated to share biological and clinical features.
We investigated, by FISH, the incidence of the major cytogenetic alterations (+12 and 13q14, 17p13, 11q23 deletions), their clinical implication and their relationship with prognostic biomarkers in 344 out of 384 Binet A CLLs enrolled in the prospective multicenter O-CLL1 GISL trial. Stereotypy subsets identification have been performed in 324 patients.
Molecular markers characterization and FISH protocols were previously reported (Cutrona et al. Haematologica, 2008; Fabris et al. Genes Chromosomes Cancer, 2008), while stereotyped subsets were defined according to Stamatopoulos et al (Blood, 2007) and Murray et al (Blood, 2008).
At least one abnormality was found in 225/344 (65.4%) cases. The most frequent abnormality was del(13q14), detected in 173 CLLs (50.3%) followed by +12 (44/344;12.8%) (one case harboring 17p13 deletion), del(17p13) (9/344, 2.6%) and del(11q23) (18/344, 5.2%). 13q14 deletion was found as a sole abnormality in 155 (45%) patients; in the remaining cases, it was combined with +12 (3 pts) and 17p13 (4 pts) or 11q23 deletions (11 pts). The 13q deletion was found as a monoallelic deletion in 139/173 (80.3%); the presence of a biallelic deletion (> 20% of interphase nuclei) was found in the remaining 34 cases. No acquisition of new cytogenetic aberrations was evidenced among the 13 CLLs developing progressive disease (range, 6 to 32 months; median, 20 months); in only one case, the proportion of nuclei with 17p13 and 13q14 deletions increased from the time of diagnosis (from 33% to 92%). Biomarkers data were available in all of the patients. CD38 percentages (mean value ± sem) were 7.9±1.3, 15.1±1.9, 51.7±5.5, 22.0±7.8,40.8±13.2, 39.8±7.3 for del(13q14), normal karyotype, +12, del(11q23), del(17p13) and multiple alterations, respectively (p<0.0001). The percentages of IgVH mutations significantly correlated with cytogenetic alterations; namely, 5.7±0.2 for cases with del(13q14), 4.7±0.4 for normal karyotype, 2.3±0.5 for +12, 0.05±0.05 for del(11q23), 2.0±1.1 for del(17p13) and 1.0±0.4 for multiple alterations (p<0.0001). Similarly, a significant correlation was found for ZAP-70 expression: namely 32.9±1.6 for cases with del(13q14), 38.5±2.1 for normal karyotype, 46.4±3.6 for +12, 67.0±8.3 for del(11q22), 41.0±12.8 for del(17p13) and 50.7±5.4 multiple alterations (p<0.0001). Cytogenetic abnormalities were clustered in 3 risk groups i.e. low del(13q14) and normal; intermediate (+12); and high risk 17p13 and 11q23 deletions and correlated with a scoring system in which patients were stratified in 4 different groups according to the absence or presence of 1, 2 or 3 biomarkers (Morabito et al., Br. J. Haematol., 2009). Notably, 166/175 cases scoring 0, gathered in the low FISH group, whereas 21/26 high FISH risk cases clustered in scoring 2–3 (p<0.0001). A significantly higher risk of starting treatment was found in high vs. intermediate (p=0.024) and low FISH risk (p=0.001) CLLs. Finally, stereotyped IgVH sequences were found in 108/324 (33%). Unfavorable stereotyped subsets (#1, #2, #3, #7 and #9) were significantly more frequent in CLLs with poor-prognostic aberrations (p=0.0203; RR=3.589).
Our data indicate that cytogenetic lesions predicting unfavorable prognosis show a relatively low incidence in newly diagnosed Binet stage A CLLs and are significantly associated with negative prognostic biomarkers predictive of disease progression. Our prospective study also confirms the prognostic value of risk FISH categories in predicting the time to the first treatment and revealed a higher rate of unfavorable stereotyped IgVH subsets in patients carrying poor-prognostic genomic aberrations. Finally, preliminary evidence in a limited number of cases indicates that the acquisition of new genetic abnormalities seem to be an infrequent event during disease progression.
No relevant conflicts of interest to declare.
Abstract 2423
Chronic lymphocytic leukemia (CLL) is characterized by an extremely variable clinical course. Mutational status of the immunoglobulin heavy-chain variable (IGHV) region defines two ...disease subsets with different prognosis. A fraction of CLL cases carries highly homologous B-cell receptors (BCR), i.e. characterized by non-random combinations of immunoglobulin heavy-chain variable (IGHV) genes and heavy-chain complementarity determining region-3 (HCDR3).
We performed sequence analysis to characterize IGHV regions in a panel of 1133 CLL patients investigated by a multicenter Italian study group. A total of 1148 rearrangements were identified; the analysis of stereotyped subsets was performed based on previously reported criteria (Messmer et al, J Exp Med 2004; Stamatopuolos et al, Blood 2007). Specifically, we compared all our sequences with those found in three different publicly available data sets (Stamatopoulos et al, Blood 2007; Murray et al, Blood 2008 and Rossi et al, 2009 Clin Cancer Res). In addition, a pairwise alignment within all sequences was performed in order to discover novel potential subsets (HCDR3 identity > 60%).
Based on the 2% cut-off used to discriminate between Mutated (M) and Unmutated (UM) cases, 777 sequences (67.59%) were classified as M, while 371 sequences (32.3%) as UM. The most represented IGHV genes within mutated cases were IGHV4-34 (104/118) and IGHV3-23 (85/96), whereas IGHV1-69 (97/112) was the most frequently used in the UM group. Interestingly, the IGHV3-21 gene, reported to be frequently expressed in CLL patients from Northern Europe, was present in only a small fraction of cases (24; 2.07%), confirming a previous finding reported by Ghia et al (Blood 2005) in a smaller panel. In our series, stereotyped HCDR3 sequences were found in 407/1148 (35.45%) patients, 177 of whom were M and 230 were UM cases. Overall, we observed that stereotyped sequences were significantly associated with UM IGHV status (Fisher's exact test, P<0.0001). Among the 407 stereotyped HCDR3 sequences, 345 belong to the clusters reported by Murray et al and 14 to those described by Rossi et al., 2009 Clin Cancer Res. The most frequent stereotyped subsets identified in our panel were #1 (35 cases), #7 (28 cases), #4 (24 cases), #3 and #9 (16 cases), #28 (13 cases), and #2 (12 cases), together with subsets #5, #8, #10, #12, #13, #16 and #22 (all ranging from 6 to 9 cases). Finally, we were able to identify by auto-matching analysis 48 sequences potentially specific for 23 novel putative stereotype subsets.
In our series we identified 407/1148 (35.45%) stereotyped HCDR3 sequences. The percentage was higher than that reported by Stamatopoulos et al and Murray et al. This discrepancy may partially be due to the different approach used in our analysis, namely the matching to a general data set including all published stereotyped subsets instead of the auto-matching performed by those Authors. We demonstrated a significant association between IGHV status and stereotyped sequences and confirmed the finding that #1 is the most frequent subset identified so far. Finally, we were able to identify a series of 23 novel putative subsets that will require further confirmation.
No relevant conflicts of interest to declare.
Abstract 2462
Two of the largest trials ever conducted in patients with chronic lymphocytic leukemia (CLL) have shown that the addition of rituximab to fludarabine plus cyclophosphamide (R-FC) ...significantly improves outcome. However, myelotoxicity and immunosuppression limit the use of this regimen in patients with impaired performance status and pre-existing co-morbidities, predominantly in the elderly. Chlorambucil (CLB) remains a first-line treatment option for such patients. The use of CLB in combination with R is thus an attractive therapeutic option in view of the potentially increased activity compared to CLB alone and the likely good tolerability. This study was designed to determine whether the R-CLB combination is feasible and beneficial as first-line treatment for elderly patients with CLL and to define the role of maintenance R.
Between October 2008 and January 2010, 97 elderly patients with untreated CD20+ CLL requiring therapy according to the IWCLL criteria were enrolled into the protocol. CLB treatment was administered every 28 days for up to 8 courses at a dose of 8 mg/m2/day p.o. on days 1–7 combined with 375 mg/m2 R for cycle 3 and 500 mg/m2 for cycles 4–8. Responsive patients were randomized to R maintenance (375 mg/m2 every 2 months for 2 years) versus observation. At baseline, blood samples were taken for FISH analysis, IgVH mutational status and expression of Zap-70 and CD38. Minimal residual disease (MRD) was planned to be evaluated on peripheral blood (PB) and bone marrow (BM) cells by four-color flow cytometry and, when required, by PCR. The primary endpoint was the overall response rate at the end of the induction phase defined according to the IWCLL 2008 on the intention-to-treat (ITT) population (all enrolled patients who received at least 1 dose of R). Secondary endpoints included the adverse event (AE) profile, progression-free and overall survival.
These are the data of the planned interim analysis based on the first 54 evaluable patients from 19 Italian centers, including tumor response at the end of the induction phase and safety. The median age of patients was 70.5 years (range 61–84): 14.8% were between 61 and 64, 31.5% between 65 and 69, 31.5% between 70 and 74, 16.7% between 75 and 79, and 5.6% were ≥80 years; thus, 53.8% of patients were over the age of 70; 70.4% were males; 25.9% were Binet stage A, 57.4% stage B and 16.7% stage C. The overall incidences of trisomy 12 and abnormalities of 13q, 11q23 and 17p13 were 24.5%, 52.8%, 20.8% and 5.7%, respectively; 7.5% of patients had p53 mutations. Of the 51/54 patients analyzed for the IgVH mutational status, 64.7% were unmutated; of the 53/54 patients studied, 39.6% were CD38+ and 71.7% were Zap-70+. The overall response rate on an ITT analysis was 81.4% (44/54 patients); a CR assessed by CT scan and trephine immunohistochemistry was found in 16.7% of cases (9 patients: 4 in Binet stage A, 3 in stage B and 2 in stage C), a CRi in 3.7% (2 patients), a nPR in 1.9% (1 patient) and a PR in 59.3% (32 patients). Eight of the 9 CR cases were investigated for MRD by flow cytometry and all proved positive: 6/8 had MRD levels <10−3 in the PB and 2/8 in the BM. A progressive disease was recorded in 2 patients (4%) and a stable disease in 2 (4%). Six patients (11%) were not evaluable for response: 1 investigator's decision, 2 AEs (1 R infusion-related reaction and 1 unrelated episode of dyspnea) and 3 SAEs (1 CLB-related anemia, 1 endometrial in situ carcinoma and 1 anaplastic oligoastrocytoma). Seven SAEs occurred in 7 patients during courses 3–8. Only 1 SAE was related to treatment (1 CLB-related anemia). The most common toxicities were neutropenia (31.5% of patients, 8.9% of cycles) and thrombocytopenia (14.8% of patients, 5.7% of cycles). Grade III-IV neutropenia was present in 16.7% of patients and in 3.8% of cycles. No grade III-IV infections occurred. A median of 85.4 R-CLB courses was administered with 85.1% of patients completing the planned treatment; 15.3% of cycles needed a CLB dose reduction (12.9% due to toxicity, mainly neutropenia and thrombocytopenia).
Overall, the results of the interim analysis indicate that R-CLB is active and well tolerated in elderly patients with previously untreated CLL.
Foa: Roche: Consultancy, Speakers Bureau. Montillo: Roche: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Runggaldier: Roche S.p.A. Monza: Employment. Gamba: Roche S.p.A. Monza: Employment.
BACKGROUND. The current study was conducted to asses the safety profile and clinical activity of rituximab in combination with fludarabine and cyclophosphamide in patients with recurrent follicular ...lymphoma (FL). METHODS. This study was a noncomparative, multicenter, phase II study. Between March 2000 and December 2002, 54 patients with recurrent FL were enrolled in the FC+R trial. Patients received fludarabine at a dose of 25 mg/m2 and cyclophosphamide at a dose of 300 mg/m2 daily for 3 consecutive days, every 3 weeks for 4 cycles. Rituximab was administered at a dose of 375 mg/m2 beginning 2 weeks after the first course of fludarabine and cyclophosphamide and then on Day 1 of each cycle thereafter. The planned treatment duration was 10 weeks. RESULTS. Overall, 92% of patients completed the planned therapy in 10 to 14 weeks and 74% achieved a complete response (CR). Among patients with BCL2-positive bone marrow, 86% obtained a molecular disease remission (MR). The median survival from treatment (SFT), the duration of disease remission (DR), and time to disease progression (TTP) had not been reached after a median follow-up of 45 months. Of the baseline characteristics, >2 previous treatments, BCL2-positive bone marrow, and low Follicular Lymphoma International Prognostic Index (FLIPI) score were found to be associated with better DR and/or TTP. Hematologic toxicity was transient and reversible, with the exception of 3 patients with severe and prolonged neutropenia. Three patients presented with infections, 1 of whom died of bronchopneumonia. CONCLUSIONS. The FC+R scheme, a nonanthracycline-containing regimen lasting up to 10 weeks, was found to be relatively well-tolerated and demonstrated significant antilymphoma activity with excellent clinical CR and molecular response rates. Cancer 2007.
BACKGROUND. It is unclear whether new treatment modalities have improved the survival of follicular lymphoma patients. Some data show that there has been no improvement in survival in the last 3 ...decades of the 20th century, whereas the results of recent retrospective studies suggest that evolving therapy has improved the outcome for follicular lymphoma patients. METHODS. To evaluate the impact of evolving therapies for follicular lymphoma, particularly the introduction of rituximab, the overall survival (OS), failure-free survival (FFS), and survival after recurrence (SAR) was analyzed in 438 advanced-stage follicular lymphoma patients enrolled in consecutive Gruppo Italiano Studio Linfomi (GISL) trials between 1988 and 2004. RESULTS. A stepwise improvement in FFS and a significant reduction in the hazard ratio was observed with succeeding studies. Cox regression analysis showed an improvement over time for OS, with a decline in the hazard ratio particularly evident in the group treated with rituximab. Furthermore, the SAR significantly improved in the group of patients treated with chemotherapy + rituximab. CONCLUSIONS. After adjusting for all parameters with an impact on FFS and OS, the results of multivariate analysis suggest that rituximab therapy has a favorable effect on the prognosis of follicular lymphoma. The data show that FFS and OS have significantly improved in advanced-stage follicular lymphoma patients treated on GISL protocols during the last 18 years. These improvements are related to evolving front-line and salvage therapies, particularly the introduction of rituximab in combination with chemotherapy. Cancer 2007.
Ematologia, Azienda Ospedaliera S. Giovanni Battista, Corso Bramante 88, 10126 Turin, Italy. uvitolo@molinette.piemonte.it
BACKGROUND AND OBJECTIVES: Poor prognosis diffuse large cell lymphoma (DLCL) ...responds poorly to standard chemotherapy. Randomized studies comparing high-dose chemotherapy with autologous stem-cell transplantation (ASCT) against standard chemotherapy have produced conflicting results. Dose-dense chemotherapy with granulocyte colony-stimulating factor (G-CSF) support seems to hold promise. The purpose of this multicenter, randomized trial was to compare failure-free and overall survival in patients with poor prognosis DLCL treated with high-dose sequential (HDS) chemotherapy followed by ASCT or an outpatient dose-dense chemotherapy regimen (MegaCEOP). DESIGN AND METHODS: Between 1996 and 2001, 130 DLCL patients, aged
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