R-CVP versus R-CHOP versus R-FM for the initial treatment of patients with advanced-stage follicular lmphoma: results of the FOLL05 trial conducted by the Fondazione Italiana Linfomi

PURPOSE Although rituximab (R) is commonly used for patients with advanced follicular lymphoma (FL) requiring treatment, the optimal associated chemotherapy regimen has yet to be clarified. PATIENTS AND METHODS We conducted an open-label, multicenter, randomized trial among adult patients with previously untreated stages II to IV FL to compare efficacy of eight doses of R associated with eight cycles of cyclophosphamide, vincristine, and prednisone (CVP) or six cycles of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) or six cycles of fludarabine and mitoxantrone (FM). The principal end point of the study was time to treatment failure (TTF). Results There were 534 patients enrolled onto the study. Overall response rates were 88%, 93%, and 91% for R-CVP, R-CHOP, and R-FM, respectively (P=.247). After a median follow-up of 34 months, 3-year TTFs were 46%, 62%, and 59% for the respective treatment groups (R-CHOP v R-CVP, P=.003; R-FM v R-CVP, P=.006; R-FM v R-CHOP, P=.763). Three-year progression-free survival (PFS) rates were 52%, 68%, and 63% (overall P=.011), respectively, and 3-year overall survival was 95% for the whole series. R-FM resulted in higher rates of grade 3 to 4 neutropenia (64%) compared with R-CVP (28%) and R-CHOP (50%; P< .001). Overall, 23 second malignancies were registered during follow-up: four in R-CVP, five in R-CHOP, and 14 in R-FM. CONCLUSION In this study, R-CHOP and R-FM were superior to R-CVP in terms of 3-year TTF and PFS. In addition, R-CHOP had a better risk-benefit ratio compared with R-FM

Differentiating chronic lymphocytic leukemia from monoclonal B-lymphocytosis according to clinical outcome: on behalf of the GIMEMA chronic lymphoproliferative diseases working group

BACKGROUND. Optimal lymphocyte parameters and thresholds for the diagnosis of chronic lymphocytic leukemia have been proposed by The National Cancer Institute sponsored Working Group and recently updated by the International Workshop on chronic lymphocytic leukemia. However, it is not clear how these criteria apply to patient management in daily clinical practice and whether the lymphocyte thresholds recommended truly predict clinical outcome in early chronic lymphocytic leukemia. DESIGN AND METHODS: For the purpose of this study, an observational database of the GIMEMA (Gruppo Italiano Malattie Ematologiche dell'Adulto) which included 1,158 patients with newly diagnosed Binet stage A chronic lymphocytic leukemia who were observed at different primary hematology centers during the period 1991-2000, was used. RESULTS: Among 818 consecutive chronic lymphocytic leukemia patients with Rai stage 0 (i.e. no palpable lymphadenopathy or hepatosplenomegaly) who had flow cytometry evaluations at the time of diagnosis and were included in a GIMEMA database, both absolute lymphocyte count and B-cell count were of a similar value in predicting time to first treatment as continuous variables (P<0.0001). Receiver operating characteristic analysis identified an absolute lymphocyte count of 11.5×10(9)/L and an absolute B-cell count of 10.0×10(9)/L as the best thresholds capable of identifying patients who will require treatment from those with stable disease. However, in a Cox's multivariate analysis only the B-cell count retained its discriminating power (P<0.0001) and the estimated rate of progression to chronic lymphocytic leukemia requiring treatment among subjects with a B-cell count less than 10.0×10(9)/L was approximately 2.3% per year (95% CI 2.1-2.5%) while it was 2-fold higher for patients with a B-cell count of 10.0×10(9)/L or over (i.e. 5.2% per year; 95% CI 4.9-5.5%). Finally, in this community-based patient cohort, the B-cell threshold defined by investigators at the Mayo Clinic (i.e. 11.0×10(9)/L) allowed patients to be divided into two subsets with a higher and lower likelihood of treatment (P<0.0001). CONCLUSIONS: Our results, based on a retrospective patients' cohort, provide a clear justification to retain the B-cell count as the reference gold standard of chronic lymphocytic leukemia diagnosis and imply that a count of 10×10(9)/L B cells is the best lymphocyte threshold to predict time to first treatment. The use of clinical outcome to distinguish chronic lymphocytic leukemia from other premalignant conditions, such as monoclonal B-cell lymphocytosis, is a pragmatic approach meeting the patients' need to minimize the psychological discomfort of receiving a diagnosis of leukemia when the risk of adverse clinical consequences is low

Introduction of Combined Chemotherapies Plus Rituximab (R) Has Improved Outcome of Previously Untreated and Relapsed Follicular Lymphoma (FL) Patients (pts)..

Some data suggest that there are been no improvement in survival of FL Pts in the last three decades of the 20th century. However that review ended in 1992, before the introduction of R treatment. Most recently reported data, show that evolving chemotherapies, including the incorporation of R has led to outcome improvement. Between 1994 and 2004, 344 Pts with FL were enrolled in different GISL Trials. For the purpose of this study we considered 270 Pts with similar characteristics enrolled in trials including or not R. The first group accounts for 176 naive Pts treated with Antracycline plus Fludarabine containing regimens (Cohort #1: 125 Pts) or plus R (Cohort #2: 51Pts). The second group accounts for 99 relapsed Pts treated with Antracycline plus Fludarabine containing regimens (Cohort #3: 40 Pts) or plus R (Cohort #4: 59 Pts). To evaluate the impact of the incorporation of R in front line and salvage therapies we assessed the patients OS, FFS, TTF, SAR in these different Cohorts of Pts. Descriptive analysis of prognostic features showed differences in the distribution among groups. To compensate for these variations we also performed Cox regression analysis. Previously Untreated patients. Regarding group #1 and #2 that enrolled Pts with clinical stage IIB, III and IV, FFS and OS according to treatment did not show any statistical differences. The univariate analysis of baseline clinical features showed an impact on OS and FFS for clinical stage, LDH level, involvement of more than 4 nodal sites and presence of extranodal involvement. The prevalence of this characteristics were higher in group #2 than group #1. Thus the FFS from group #2 vs. group #1 was adjusted for variation in prognostic features by Cox regression analysis, that shows a failure Hazard Radio reduction (HR) of 40 % in Pts who received R. Because of difference in follow up (FU) (49 months in Cohort #1 vs 21 months in Cohort #2), to evaluate differences in OS we utilized exact Log Rank test for unequal FU. So far, a trend exists for better OS in R treated patients, although the difference is not statistically significant. Relapsed Patients. Clinical characteristics were similar in the two Cohorts of pts. TTF was better in R treated Pts and the difference was statistically significant (66% vs. 53% at 3 yrs, p=0.023) The analysis of SAR demonstrated a better result for R Cohort with a statistically significant difference (88% vs. 68% at 3 yrs, p=0.022). OS according to treatment protocol, showed advantage for patients in R Cohort and the difference was statistically significant (92% vs. 70% at 5 yrs, p=0.004). Conclusion. In naïve patients our retrospective analysis showed a reduction of HR for FFS and a trend toward better OS in R treated Pts. In relapsed Pts all outcome parameters as OS, TTF and SAR had significant improvement in the Cohort treated with R. Although any conclusions between nonrandomized groups maybe subject to differences in observed and unobserved prognostic features, we believe that improvement have occurred in the management of FL Pts with the introduction of combined chemotherapy with R

Role of interferon-alpha administration after 2-deoxycoformycin in the treatment of hairy cell leukemia patients

BACKGROUND AND OBJECTIVE: Hairy cell leukemia (HCL) is a rare chronic B-cell lymphoproliferative disorder which is treated effectively by interferon-alpha (IFN-alpha), deoxycoformycin (DCF) and 2-clorodeoxyadenosine (2-CdA). As a third of patients treated with DCF do not achieve a complete remission (CR) and many of them tend to relapse, we evaluated the potential role of IFN-alpha, randomly administered after DCF, in increasing the number of patients attaining CR and/or duration of CR. METHODS: From March 1997 to December 2000, 167 previously untreated HCL patients, from 37 Italian institutions, were enrolled in the study. A total of 138 males and 29 females, with a median age of 55 yr were included in the study. All patients received six courses of DCF 4 mg/m(2) i.v. every other week and then two additional courses once a month. Complete and partial responders were randomly assigned to receive or not receive IFN-alpha at a dose of 3 MU s.c. three times a week for 6 months. RESULTS: Of the 167 patients enrolled in the study, 145 (86.8%) obtained a CR or a partial remission (PR) and were therefore suitable for randomization. One hundred and thirty-five patients were successively randomized to receive IFN-alpha (63 cases; arm A) or not (72 cases; arm B). Progression of disease was observed in eight (arm A) and 12 (arm B) patients with a median time of 27.8 and 26.9 months, respectively. As far as the improvement in response was concerned, no significant difference in the two subgroups was observed. In fact, five patients in arm A and six patients in arm B showing a good PR at the end of DCF therapy, subsequently attained a late CR. CONCLUSIONS: From our data there does not appear to be any significant role for IFN-alpha in improving the proportion and the duration of CR in HCL patients previously treated with DCF

Role of interferon-alpha administration after 2-deoxycoformycin in the treatment of hairy cell leukemia patients

Background and objective: Hairy cell leukemia (HCL) is a rare chronic B-cell lymphoproliferative disorder which is treated effectively by interferon-alpha (IFN-α), deoxycoformycin (DCF) and 2-clorodeoxyadenosine (2-CdA). As a third of patients treated with DCF do not achieve a complete remission (CR) and many of them tend to relapse, we evaluated the potential role of IFN-α, randomly administered after DCF, in increasing the number of patients attaining CR and/or duration of CR. Methods: From March 1997 to December 2000, 167 previously untreated HCL patients, from 37 Italian institutions, were enrolled in the study. A total of 138 males and 29 females, with a median age of 55 yr were included in the study. All patients received six courses of DCF 4 mg/m 2 i.v. every other week and then two additional courses once a month. Complete and partial responders were randomly assigned to receive or not receive IFN-α at a dose of 3 MU s.c. three times a week for 6 months. Results: Of the 167 patients enrolled in the study, 145 (86.8%) obtained a CR or a partial remission (PR) and were therefore suitable for randomization. One hundred and thirty-five patients were successively randomized to receive IFN-α (63 cases; arm A) or not (72 cases; arm B). Progression of disease was observed in eight (arm A) and 12 (arm B) patients with a median time of 27.8 and 26.9 months, respectively. As far as the improvement in response was concerned, no significant difference in the two subgroups was observed. In fact, five patients in arm A and six patients in arm B showing a good PR at the end of DCF therapy, subsequently attained a late CR. Conclusions: From our data there does not appear to be any significant role for IFN-α in improving the proportion and the duration of CR in HCL patients previously treated with DCF. © 2006 Blackwell Munksgaard

Phase II Study with Fludarabine and Cyclophosphamide Plus Rituximab (FC+R) in Relapsed Follicular Lymphoma Patients.

Both Cyclophsphamide (C) and Fludarabine (F) have individual anti-lymphoma activity and the combination Rituximab (R) + F has been shown to have a synergistic activity against resistant lymphoma cell lines in vitro. In march 2000, we started a Phase II multicenter clinical trial to test safety and efficacy of FC+R combination in patients with relapsed follicular lymphoma. We have recently completed the enrollment of 48 pts in the trial. Patients received 4 doses of R (375 mg/sqm/d) in combination with 4 cycles of F (30 mg/sqm/d for 3 days) and C (300mg/sqm/d for 3 days) every 28 days. Patients characteristic: 45% males, 55% females; median age: 62 years (range 44-71); stage IV 47% pts; Systemic Symptoms 8,5% pts; elevated LDH 15% pts. Rearrangement of BCL2 gene was evaluated with PCR in 38pts (79%) on bone marrow or peripheral blood mononucleated cells; 22 patients showed BCL2 rearrangement (58%). Medium number of previous chemotherapy regimens was 1,7 (range 1-4); median duration of last remission before registration into the trial was 12 months (range 1-68). Thirty-nine patients were available for evaluation at the time of current analysis. One patient did not complete therapy due to severe cytopenia. The response rate in the intent-to-treat analysis was 97%, with 74%, Complete Responses (CR) and 23% Partial Responses (PR). Out of 18 patients with molecular monitoring of disease before and after chemotherapy, 15 patients (83%) obtained molecular remission in the bone marrow (BM) .After a median follow-up of 12 months (1-25), median duration of remission was 13 months; twenty percent of patients were only recently registered into the trial and had a short follow-up (less than 4 months). Overall, 8 patients relapsed (21%). One patient died due to severe neutropenia occurred during chemoterapy; two patients died due to lymphoma progression. Complete responses are ongoing in 28 patients. As far as toxicity is concerned WHO grade III-IV leukopenia was observed in 10 patients, with 4 patients presentig a WHO grade IV granulocytopenia. WHO grade IV infections were observed in only one patient who had a pulmonary infection after third cycle. Non-ematologic toxicity was minimal. During follow up, one patient had a renal cell tumor and one patient had myelodisplasia, 3 and 6 months after the end of treatment, respectively. In conclusion the combination FC+R is associated with acceptable toxicity and with an excellent response rate in this group of heavily pre-treated patients with relapsed follicular lymphoma. Furhter follow-up is required to evaluate response duration and survival in the whole group of patients

Rituximab (R) in Combination with Fludarabine (F) and Cyclophosphamide (C) in Relapsed Follicular Lymphoma (FL) Patients (pts).Final Results of FC + R Phase II Trial by the GISL.

Blood (ASH Annual Meeting Abstracts) 2006 108: Abstract 2763\ua9 2006 American Society of HematologyThis Article Services Email this article to a friend Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Sacchi, S. Articles by Baldini, L. Search for Related Content PubMed Articles by Sacchi, S. Articles by Baldini, L. Social Bookmarking What's this? Poster Board #-Session: 941-II Rituximab (R) in Combination with Fludarabine (F) and Cyclophosphamide (C) in Relapsed Follicular Lymphoma (FL) Patients (pts).Final Results of FC + R Phase II Trial by the GISL. Stefano Sacchi, MD1, Samantha Pozzi, MD1,*, Raffaella Marcheselli, BS1,*, Stefano Luminari, MD1,*, Massimo Federico, MD1, Alessandra Tucci, MD2,*, Francesco Merli, MD3,*, Loretta Orsucci, MD4,*, Giulia Cervetti, MD5,*, Ubaldo Occhini, MD6,*, Marina Liberati, MD7,*, Vincenzo Callea, MD8,*, Maura Brugiatelli, MD9 and Luca Baldini, MD10,* 1 Dipartimento di Oncologia ed Ematologia, Universita di Modena, Modena, Italy; 2 Dipartimento di Medicina Interna, Ospedale, Brescia, Italy; 3 Dipartimento di Ematologia, Ospedale, Reggio Emilia, Italy; 4 Dipartimento di Ematologia, Ospedale, Torino, Italy; 5 Dipartimento di Ematologia, Universita di Pisa, Pisa, Italy; 6 Servizio di Ematologia, Ospedale, Arezzo, Italy; 7 Ist. Scienze Oncologiche, Universita di Perugia, Perugia, Italy; 8 Dipartimento di Ematologia, Ospedale, Reggio Calabria, Italy; 9 Divisione di Ematologia, Ospedale, Messina, Italy and 10 Dipartimento di Scienze Mediche, Universita di Milano, Milano, Italy . AbstractFifty-four Pts entered this trial between January 2000 and December 2002. Eligible Pts had histologic documentation of CD 20+ relapsed FL, according to the revised European/American Lymphoma classification, that required treatment, measurable lesion, and an ECOG performance status of 0 or 1. Pts were further required to be aged 18\u201370 years, and to have undergone < 3 previous lines of chemotherapy. Pts received FC + R chemoimmunotherapy consisting of F 25 mg/m2 and C 300 mg/m2/day for 3 consecutive days every 3 weeks for 4 cycles. R 375 mg/m2 I.V. infusion was administered starting 2 weeks following the first FC course and then on day 1 of each cycle thereafter. Clinical response were defined according to the International Working Group recommendations. BCL 2 analysis was performed by PCR assay. DR, TTP and OS were analyzed by Kaplan-Meier method. Cox analysis was used to analyse the association of baseline prognostic factors with response to treatment, DR,TTP and OS. The overall response rate for all 54 Pts by ITT analysis was 90%; forty Pts (74%), obtained complete responses. Progression occurred in 3 Pts ( 6% ) and 2 Pts dropped out of the trial: 1 for toxicity and 1 refused to start with therapy. A univariate analysis of baseline prognostic factors demonstrated that none of these factors predicted for response to treatment. There were 29 Pts out of 45 tested, positive for BCL 2 before therapy. Among these, 22 Pts were evaluated after treatment and 19 ( 86%) converted to BCL negativity. At last follow up (FU), 40 Pts were alive, 31 with ongoing response and 9 with progressive disease. The median DR, TTP and OS have not been reached after a median FU time of 45 months ( range, 1 to 74 months ). The median DR in the 49 Pts who have reached CR or PR was 35 months ( range, 6 to 70 months). None of the baseline prognostic characteristics was significantly related to DR. The median TTP in all 54 Pts, was 36 months ( range, 1 to 74 months ).BCL2 positivity and < 2 previous treatments were related with better TTP (p<0.05 ) OS rate at 4 years was 75%. Toxicity was evaluable in 52 Pts. The most common severe side effects were hematologic, and included 21 cases of neutropenia, 3 cases of thrombocytopenia and 2 cases of anemia. Infectious complications manifested in 3 Pts and 1 died for pneumonitis. Treatment delays of 1\u20133 weeks was necessary in 12 patients. The results of our trial have demonstrated that FC+R chemoimmunotherapy is active and relatively well tolerated. The OR rate of 90%, associated with an excellent molecular remission rate, and the mean DR of 35 months compares favourably with the results obtained in other trials in similar subset of patients and supports the use of an FC+R arm in future controlled trials

The Length of Treatment of Aggressive Non Hodgkin’s Lymphomas According to the International Prognostic Index Score. Some Lessons from the GISL LA03 Study.

In 1993 the Gruppo Italiano per lo Studio dei Linfomi (GISL) started a randomized 2x2 factorial study comparing a flexible versus fixed dosing schedule of two different antracycline-containing ProMACE-CytaBOM regimens, where the length of the treatment was modulated according to the IPI. Patients were randomly assigned to receive one of the following treatments: fixed ProME(Epidoxorubicin)CE-CytaBOM (PE-C); fixed ProMI(Idarubicin)CE-CytaBOM (PI-C); flexible PE-C; flexible PI-C. Epidoxorubicin (EPI) was used at the dose of 40 mg/sm IV and Idarubicin (IDA) at 8 mg/sm IV. In the flexible arms the doses of EPI or IDA were modified according to the following criteria: in absence of haematologic toxicity (i.e.WBC>4,000 and platelets>150,000) during the previous cycle increase the dose by 20%, in case of grade 1 toxicity, was increased the dose by 10%, in case of grade 2 toxicity administer the same dose, in case of grade 3-4 toxicity decrease the dose by 10%.After four courses of ProMACE-CytaBOM, remitters patients with low or low-intermediate IPI (low risk) were planned to receive 2 additional courses whereas those with intermediate-high or high IPI(high risk)were planned to receive 4 additional courses of chemotherapy. Between July 1993 and June 1997, 356 patients with advanced aggressive NHL were registered for the study. After randomization 11 patients were excluded for lacking inclusion criteria. Five out of remaining 345 patients withdrawn from the study before the first assessment of response. The remaining 340 patients, 246 at low and 94 at high risk, were assessed for response. The relative dose intensity of EPI and IDA was 0.91 and 0.88 in the fixed and 1.00 and 1.01 in flexible arms, respectively. At the end of induction chemotherapy 208 patients(61%)achieved a CR, and 59(17%)a PR. The CR rate was 70% and 48% for patients at low and high risk(P = 0.000), whereas no differences emerged between patients treated with fixed or flexible PC(P = 0.894) and EPI or IDA containing PC(P = 0.144). With radiotherapy(10 patients) or other different salvage treatments(11 patients), 21 additional patients reached a CR. In conclusion 229 patients (65% of all eligible and 67% of assessable patients) enrolled in the trial achieved a CR.During follow-up 77 relapses(34%) were recorded, with a 5-year relapse-free survival rate of 65%. The relapse rate was similar in patients treated with fixed or flexible PC(P=0.339), EPI or IDA containing PC(P=0.335), and in patients at low or high risk (P=0.507). After a median follow-up of 57 months (84 months for patients alive), 59% patients were estimated to be alive at 5 years. The 5-year estimated survival rates were 60% and 58% for flexible and fixed P-C (P=0.915), 61% and 57% for EPI and IDA (P=0,325), and 66% and 40% for patients at low and high risk (P = 0.000) respectively.The mature results of our study suggest that 6 courses of fixed or flexible PE-C or PI-C can determine a promising success rate in patients with advanced aggressive NHL and low or low intermediate IPI, whereas the same regimens are less effective in patients with intermediate or high IPI, even if 2 additional courses are delivered. Moreover, given that in the latter group of patients most failures were observed during the first 4 courses of therapy, we suggest that innovative approaches should be considered up-front

The length of treatment of aggressive non-Hodgkin's lymphomas established according to the international prognostic index score : long-term results of the GISL LA03 study

OBJECTIVES: To compare two different schedules of two different anthracycline-containing regimens, where length of treatment is modulated according to the international prognostic index (IPI) in patients with aggressive non-Hodgkin's Lymphoma (NHL). METHODS: In 1993 the Gruppo Italiano per lo Studio dei Linfomi (GISL) started a randomized 2 x 2 factorial phase III clinical trial for patients with newly diagnosed aggressive NHL comparing ProME(Epidoxorubicin)CE-CytaBOM (PE-C) to ProMI(Idarubicin)CE-CytaBOM (PI-C) and a fixed to a flexible treatment schedule where anthracycline dose was to be modulated according to observed hematological toxicity. Patients with low or low-intermediate IPI (IPI 0-2) and those with intermediate-high or high IPI (IPI 3-5) should receive six or eight courses, respectively. Involved-field radiotherapy was allowed for patients with initial bulky disease or with residual masses. RESULTS: Three hundred and fifty-six patients were registered into the study and randomized. Patients were well balanced among the four study arms in terms of clinical characteristics and prognostic factors. Three hundred and forty-five patients were available for evaluation of study endpoints. At the end of induction therapy complete remission rate was 61%, 5-year failure-free survival (FFS) rate was 40% and 5-year overall survival (OS) rate was 59%; no differences were observed according to treatment arms. Patients in the flexible arm received higher dose intensity of anthracycline (P < 0.001) with no apparent increase in toxicity. However, the flexible schedule was not superior to the fixed one. Patients with IPI 3-5 showed lower response rates (45% vs. 67%: P < 0.0001) and lower 5-year FFS (29% vs. 45%: P < 0.0001) compared to those with IPI 0-2. CONCLUSIONS: six courses of fixed or flexible PE-C or PI-C can determine a promising success rate in patients with advanced aggressive NHL with IPI 0-2, whereas the same regimens are less effective in patients with IPI 3-5, even if two additional courses are delivered. For the latter group of patients innovative approaches are warranted