FLIPI Score Research Articles

Risk and Clinical Implications of Transformation of Follicular Lymphoma (FL) to Diffuse Large Cell B-Cell Lymphoma (tFL).

Between 1971 and 2000, 330 consecutive adults (176M/154F) with newly diagnosed FL were referred to St Bartholomew's Hospital. The median age was 55 (range 23–90) years; 50 Stage I, 47 Stage II, 56 Stage III, 177 Stage IV. The FLIPI score was ‘low': 38%, ‘intermediate': 27%, ‘high': 35%, with 111 missing observations (LDH or number of nodal sites). 100 patients are still alive, 230 having died between 6 months and 30 years, the causes of death being: disease 106, treatment-related complications 37, other malignancy 30, cardiac disease 20, ‘other' 18, unknown 19. With expectant management if appropriate and intervention with irradiation, chemotherapy or immunotherapy at times of progression, the response rate was 84% at 1st treatment, declining to 43% at fifth, with duration of remission declining correspondingly. With a strict policy of documenting histology at each progression, a repeat biopsy rate of 70% was achieved. tFL has occurred in 89/330 cases between diagnosis and 16 years, in 25/330 (8%) whilst being managed expectantly or during first therapy and at a relatively constant rate at 2nd, 3rd, 4th and 5th progression, (17%, 16%, 15%, 14% respectively). To date, no patients have transformed after 16 years, with 41 patients ‘at risk' between 16 and 35 years (Figure 1), 18 in continuous first remission and 23 having had a recurrence of FL. On univariate analysis, risk of transformation is higher with high FLIPI score (p= .009) and advanced stage (p= .02) at presentation. Survival of patients is shorter in whom transformation occurs (p= .0003). Median survival from transformation was 1.3 years, and correlated with ‘stage' (p= .008) and LDH (p= .03) at the time of transformation, but not with time from diagnosis to transformation. These observations highlight the significance of transformation of FL to t-FL, demonstrating its major clinical importance. The actuarial prediction is that transformation will occur in at least 50% of patients overall with a very poor prognosis for the majority. The ‘time to transformation curve' supports the hypothesis that there may be two distinct populations of patients who develop FL, one in which transformation is programmed to occur and one in which it is not. [Display omitted]

Clinical Outcome of Low Grade Non Hodgkin's Lymphoma Patients with Bone Marrow Involvement Detected by Flow Cytometry Alone.

Bone marrow (BM) involvement in low grade NHL patients results in stage IV clinical classification and has a negative impact on survival. Standard practice includes morphologic examination of BM biopsy at diagnosis. In many institutions flow cytometry (FC) is also routinely performed on BM aspirates accompanying respective biopsies. FC is believed to increase the sensitivity of the morphologic analysis by detecting occult lymphoma cells evading the pathologist's eyes. However, the prevalence of such finding and especially its clinical significance are largely unknown. In our institute BM biopsies of NHL patients conducted after 1993 were routinely accompanied by BM aspirates with FC analysis. We retrospectively reviewed the charts of all low grade NHL patients (small lymphocytic lymphoma, follicular small cleaved cell NHL, follicular mixed small and large cell, marginal zone B-cell lymphoma, mantle cell lymphoma and Waldenstrom macroglobulinemia) diagnosed or followed at the Hematology Unit (1994–2004), who had undergone BM biopsies and aspirates as part of their diagnostic workup or before treatment. FC results were considered positive if they showed either a ratio of immunoglobulin light chain expression of kappa: lambda >3:1 or lambda: kappa >2:1 in at least 2% of the gated population. Cell analysis included: CD5 versus CD19, CD20 versus CD10, and kappa light chain versus lambda light chain occasionally with the addition of CD19 or CD20. Lymphoma involving BM by morphology was found in the biopsies of 43 patients (61.4%) (BM+ group). Of the remaining 1 patient had inconclusive results and 26 patients had normal BM biopsies. Of these 27 patients the FC analysis was positive in 9 patients (BM-FC+ group) and negative in 18 (BM-FC- group). We could not compare the groups using FLIPI or IPI scores as a whole since both include the stage as one of the five summed parameters while BM involvement was different by definition between the groups. However, the groups had similar parameters that are prognostically important and are part of the FLIPI scoring system including age, hemoglobin and LDH levels and also the number of involved extranodal sites. Splenic involvement and number of involved nodal sites were higher in BM+ and BM-FC+ groups than in BM-FC- group. Significant differences in disease progression as indicated by time-to-treatment were observed. The median treatment-free period was shorter in the BM+ and BM-FC+ groups (1 month and 4 months, respectively) as compared with the BM-FC- group (31 months) (log rank test p=0.0195). BM-FC- patients had significantly longer survival time than BM+ and BM-FC+ groups. Median survival time was not reached for the BM-FC- patients while in the BM+ and BM-FC+ groups median survival times were 129 and 89 months respectively with no significant difference between them. (Log rank test=0.029 for the difference between BM-FC- and the two other groups). We conclude that the outcome of low grade NHL patients found to have malignant cells by FC analysis while their BM morphology is normal is the same as that of patients with histological involvement. This may imply that patients with localized disease who have BM involvement by FC should be regarded as advanced stage disease.

Time to Treatment Failure (TTF) and FLIPI Correlate Well with Survival and Are Independent Variables in Stage IV Indolent Follicular Lymphomas (IFL).

BACKGROUND: The FLIPI score has been shown to predict survival in FL pts. Previous studies have suggested that type of treatment, and quality of response may not affect survival in pts with stage IV IFL. We address here the significance of TTF and quality of response as prognostic factors for survival in stage IV IFL.METHODS: We reviewed the records of 580 pts with stage IV IFL treated from 1972- to 2002 with anthracycline containing regimens +/− rituximab. Demographics: male 51%, age 60 28%, Hgb<12 17%, high LDH 23%, 5 or more nodal groups 66%, BM+ 93%, FLIPI 3 or more 76%.RESULTS: With a median f/up of 7 yearsResponse<PR (n=17)PR (n=86)CR (n=477)% dead887434Median OS (mos)19*56*185*TTF<1yr (n=60)1–2yr (n=88)>2yr (n=432)% dead855333Median OS (mos)25*76*191**p=0.001% ORR (% CR)TTF (mos)Median OS (yrs)FLIPI<3 (n=151)98 (89)8420.5FLIPI≥3 (n=429)96 (80)4410Regression analysis for survival showed that both TTF and FLIPI correlated well with survival and were independent of each other (p<0.00001).CONCLUSION: As expected, FLIPI <3 correlated with longer survival in IFL treated with anthracycline containing regimens. Interestingly, achievement of CR, longer response duration as measured by TTF also correlated with longer survival.

Updated Results from a Phase II Study of Galiximab (Anti-CD80) in Combination with Rituximab for Relapsed or Refractory, Follicular NHL.

Galiximab is a PRIMATIZED®, anti-CD80, monoclonal antibody with human IgG1 constant regions and macaque variable regions. CD80 is an immune costimulatory molecule that is constitutively expressed on the surface of follicular lymphomas. Modest single-agent clinical activity was demonstrated in a Phase I study in relapsed or refractory, follicular NHL (ORR=11%). Preclinical data show that galiximab + rituximab may be more effective than either antibody alone. Here we report updated results from the Phase II part of a multicenter study (Study 114–21) evaluating galiximab + rituximab for relapsed or refractory, follicular NHL. Patients (pts) were administered galiximab (500 mg/m2 qwk x 4) concurrently with a standard course of rituximab (375 mg/m2 qwk x 4). Rituximab-refractory pts (no response or a response with TTP<6 months) were excluded. Study objectives were to evaluate safety, PK, and efficacy. Sixty-four pts received treatment. The median follow up is 14.5 months. Mean age at study entry was 59 yrs. The majority of pts (88%) were Stage III/IV, and FLIPI risk groups were distributed as good (27%), intermediate (39%), or poor (34%). All pts had received at least 1 prior lymphoma therapy; 42% were rituximab naïve. Galiximab infusions were delivered over 1 hr and were well tolerated. No DLTs were reported. Sixty-one (95%) pts experienced study-related AEs; the most common were lymphopenia (44%), leucopenia (38%), fatigue (38%), neutropenia (23%), and chills (23%). IWRC was used to evaluate response. An ORR of 64% was demonstrated: 17% CR, 14% CRu, and 33% PR. The median PFS was 12.1 months. Univariate analysis showed no correlation between response and baseline characteristics, although there was a trend for fewer responses in pts with elevated LDH, poor FLIPI score, and Grade III follicular histology. Cmax and AUC values were dose-proportional, with a mean serum half-life of 13 to 24 days. These results were retrospectively compared with 3 historical Biogen Idec studies of follicular NHL pts treated with a standard course of rituximab monotherapy. Baseline characteristics were similar; however, there was a higher incidence of rituximab-naïve pts in the rituximab monotherapy group (77%) compared with galiximab + rituximab (42%). The toxicity profiles for the 2 groups were similar. The median PFS was longer in the galiximab + rituximab group (12.1 mo.) than in the historical rituximab monotherapy group (9.4 mo.). These results suggest that galiximab can be safely combined with a standard course of rituximab and produce promising response rates and PFS. The toxicity profile and PFS with this combination compared favorably with historical rituximab monotherapy studies. A Phase III, randomized study is planned.

Phase II Trial of Abbreviated CHOP-Rituximab Followed by 90Y Ibritumomab Tiuxetan (Zevalin) and Rituximab in Patients with Previously-Untreated Follicular Non-Hodgkin Lymphoma (NHL).

Background: CHOP-rituximab (CHOP-R) and radioimmunotherapy (RIT) have demonstrated efficacy in the treatment of follicular NHL. The combination of these agents as initial therapy is a novel strategy which has been previously reported with promising results (Hainsworth et al. Proc ASCO. 2005; 23,Abstract 6577). We report the safety and efficacy of this approach in a single-institution, non-randomized, phase II trial with abbreviated CHOP-R followed by Zevalin and rituximab. The rationale for following Zevalin with additional rituximab includes the potential beneficial effect of extended therapy and the possible vaccinal effect (Cartron et al. Blood. 2004; 104,2635).Methods: Eligible patients have CD20 positive follicular NHL, Grade 1–3, Stage II-IV, no prior treatment with monoclonal antibody or chemotherapy, and symptomatic disease. CHOP-R is first given in standard doses every 21 days for 3 cycles. Four weeks after the last dose of CHOP-R, patients receive the Zevalin regimen. One week after the therapeutic Zevalin dose, patients receive rituximab 375 mg/m2 IV weekly for 4 doses. Bone marrow examination and fusion PET-CT scans were performed at baseline, after CHOP-R, and 12 weeks after RIT. For this study, a complete remission required both functional imaging with positron emission tomography (PET) scanning showing no areas of FDG-avidity and the International Working Group criteria including CT scanning.Results: At the planned interim analysis after accrual of 19 patients, 8 patients have completed therapy and follow-up studies and are fully evaluable. For these 8 patients with follicular NHL, two were Grade 1, three were Grade 2, and three were Grade 3. Half had Stage III disease and half had Stage IV. The median age was 59 (range 45–77). Two patients had a FLIPI score of 1 (low risk), four patients had a score of 2 (intermediate risk), and two patients had a score of 3 (poor risk). The overall response rate after 3 cycles of CHOP-R was 75% with a CR in 2 of these 8 patients (25%). After treatment with Zevalin and rituximab, 7 of 8 (87.5%) achieved a CR (CR/CRu with negative PET scan). During treatment with CHOP-R, 2 patients had Grade 3/4 neutropenia, and 1 patient had Grade 4 hyperglycemia. After treatment with Zevalin, 4 patients developed Grade 3/4 thrombocytopenia, and 4 patients developed Grade 3/4 neutropenia. During the Zevalin phase, there were no episodes of neutropenic fever.Conclusions: Three cycles of CHOP-R followed by Zevalin and rituximab is effective in inducing a CR (CR/CRu) in previously-untreated patients with follicular NHL, decreases exposure to anthracyclines, and is a promising regimen for initial therapy. In this trial, the CR rate of 25% after CHOP-R increased to 87.5% after treatment with Zevalin and rituximab. Functional imaging with fusion PET-CT may be a more sensitive technique than CT scanning in determining residual tumor. This trial continues to accrue patients, and additional time is needed to determine the duration of response and time to next therapy.

Safety and Efficacy of Fludarabine Plus Mitoxantrone (FM) Followed by Yttrium-90 (90Y) Ibritumomab Tiuxetan (Zevalin®) and Maintenance Rituximab in Intermediate- to High-Risk Newly Diagnosed and Relapsed Follicular Non-Hodgkin's Lymphoma (NHL).

Background: The combination of fludarabine and mitoxantrone (FM) as a frontline therapy for advanced follicular lymphoma has been shown to result in higher complete response rates when compared with standard-dose CHOP. We assessed the safety and efficacy of FM followed by 90Y ibritumomab tiuxetan (IT) and maintenance rituximab in previously untreated or relapsed follicular NHL.Patients and methods: Patients with newly diagnosed stage II-IV low-grade NHL and an intermediate-high or high IPI, as well as those with relapsed low-grade or transformed disease, were initially eligible. The protocol was later amended to include patients with follicular NHL with an intermediate or high FLIPI. Adult patients were required to have an expected survival of at least 3 months, a performance status ≤2, and adequate bone marrow function (ANC 1500/mm3, platelets 100,000/mm3), liver, and renal function. Exclusion criteria included impaired bone marrow reserve, history of failed stem cell collection, and prior radioimmunotherapy. Initial treatment consisted of 4 cycles of FM (mitoxantrone 12 mg/m2 on day 1, fludarabine 25 mg/m2 on days 1–3 of each 28-day cycle). After restaging, complete and partial responders with ≤25% bone marrow involvement proceeded to the IT therapeutic regimen. Partial responders with >25% bone marrow involvement received 2 additional cycles of FN before IT. The 90Y IT dose (0.3 or 0.4 mCi/kg) was adjusted according to the patient's platelet count. Maintenance rituximab (375 mg/m2 × 4) was scheduled for every 6 months over 2 years.Results: Twelve patients have been enrolled, including 5 with relapsed disease. The median age was 57 years (range, 38–67), and 5 were male. All patients presented with grade 1–3 follicular NHL; most had stage IV disease and lymphomatous bone marrow involvement (10/12). The median FLIPI score was 2 (range, 1–4). Patients with relapsed disease had received prior CVP (3/5) or FMR (2/5). In those with relapsed NHL, hematologic toxicities were grade 3 or 4 neutropenia (4/5), grade 3 thrombocytopenia (2/5), and grade 3 anemia (2/5) with FN. Four did not proceed to 90Y IT (1 had progressive disease, 1 had >25% bone marrow involvement, 1 had myelosuppression, and 1 went on to transplant). The patient, who later received 90Y IT, had a partial response but relapsed at 9 months. Four patients with newly diagnosed disease were assessable for safety and response. The incidence of grade 3 or 4 neutropenia, thrombocytopenia, and anemia with chemotherapy were 75%, 50%, and 50%, respectively, in these patients. All 4 patients went on to receive 90Y IT; platelet, ANC, and hemoglobin nadirs occurred at 5–8 weeks following 90Y IT, and were reversible. Partial responses were achieved after 4–6 cycles of FN in all cases. One patient converted to a complete response after 90Y IT; another 2 patients were PET-negative after radioimmunotherapy. As of yet, no patients have gone on to rituximab maintenance. The remaining patient relapsed at 6 months.Conclusions: This preliminary data suggests that FM followed by the 90Y ibritumomab tiuxetan therapeutic regimen is highly effective in patients with untreated follicular lymphoma. This combination, however, may be too toxic for patients with relapsed disease, especially if they have been treated with prior fludarabine.

Correlation of the FLIPI score for follicular lymphoma with period of diagnosis and type of treatment

ObjectivesFollicular lymphoma (FL) is generally considered an indolent disorder but a significant subset of patients shows a worse outcome. Aim of this study was to validate the FLIPI score in an independent series of follicular lymphoma patients and to correlate prognostic categories with the period of diagnosis and the use of anthracycline. MethodsWe evaluated the clinical characteristics, prognostic stratification, and outcome of 338 patients with follicular lymphoma consecutively diagnosed and followed at our Institution between 1975 and 2002. ResultsThe distribution of patients within the prognostic categories of the IPI and FLIPI score, while confirming the indolent outcome of follicular lymphoma, shows that a subset of patients has a worse prognosis. With the IPI score, 62% of patients are in the low risk, 26% in the low-intermediate, and 12% in the high (high-intermediate+high) risk group. With the FLIPI score, 48% of patients are categorized as low risk, 31% as intermediate risk, and 21% as poor risk. With the IPI score, median OS is 17.3 years for the low risk; 6.3 for the intermediate risk, and 5.2 years for the high risk group (p=0.0004). With the FLIPI system, median OS is 15.5 years for the low risk, 8.3 years for the intermediate risk, and 5.2 for the poor risk group (p=0.0002). Prognostic scores were calculated also after dividing patients according to the time of diagnosis: in three periods (before 1987, between 1988 and 1997, and from 1998), as well as in two periods (before and after 1998). In all the periods studied survival of patients classified according to IPI and FLIPI categories was significantly different. ConclusionThis study shows in an independent series that the FLIPI score is a reproducible prognostic index of clinical utility for the initial assessment of patients with follicular lymphoma.

Rituximab Added αIFN+CHVP Improves the Outcome of Follicular Lymphoma Patients with a High Tumor Burden: to First Analysis of the GELA-GOELAMS FL-2000 Randomized Trial in 359 Patients.

The monoclonal anti-CD20 antibody rituximab has been shown to induce a high response rate in follicular lymphoma patients and to improve the outcome when associated with CVP or CHOP in newly diagnosed patients. Rituximab synergy with αIFN has also been established in experimental and clinical studies. In order to investigate the benefit of rituximab when added to the classical association of αIFN with CHVP (cyclophosphamide 600 mg/m2, doxorubicin 25 mg/m2, etoposide 100 mg/m2 on day 1 and prednisone 40 mg/m2 day 1–5), the intergroup GELA-GOELAMS FL-2000 trial was initiated. Inclusion criteria consisted in untreated histologically proven stage II-IV follicular lymphoma (any grade) patients (18–75 years) with a high tumor burden consisting in the presence of at least one of the following criteria: B symptoms presence; ECOG PS≥1; LDH>normal value; β2-microglobulin≥3 mg/L; largest tumor≥7cm; three distinct nodes≥3cm; serous effusion, compression or symptomatic splenomegaly). Treatment in arm A consisted in CHVP (6 monthly courses + 6 courses every 2 months) associated with αIFN-2a (4.5 MU [reduced at 3 MU > 70 years] 3 times a week) for 18 months and in arm B in 6 monthly courses of CHVP associated with 18 months of αIFN-2a combined with 6 infusions of 375 mg/m2 rituximab (Day 1 and 8 course 3 & 4 ; day 1 courses 5 & 6). Patients were evaluated for response at 6 months and 18 months and followed every 3 months. From 05/2000 until 05/2002, 359 eligible patients were included (Arm A 175 pts and Arm B 184 pts) with the following characteristics: M/F =1; median age =60 years [25–75]; ECOG>1 =8%; B symptoms =27%; AA stage>II =87%; bone marrow involvement =58%; β2−m≥3mg/L =31%; LDH>N =37%; Hb≤12g/dL =18%; the FLIPI score was ≥3 in 56% of patients. This first analysis of all patients demonstrated a significant improvement of response to therapy in arm B as compared to arm A, both at 6 months [CR+CRru 49% vs. 76%; PR 36% vs. 18%; stable, progression or death 15% vs. 6%; respectively (P<.0001)] and at 18 months [CR+CRu 79% vs. 63%; PR 5% vs. 10%; stable, progression or death 17% vs. 27%; respectively (P=.004)]. With a median follow-up of 30 months, the median EFS was not reached in both arms and 104 patients presented an event. In the control arm, estimated 2.5 years EFS is of 62% versus 78% in arm B (P=.003). In conclusion, this first analysis indicate that 1) the control arm reproduces earlier results with the same regimen 2) rituximab associated with α-IFN+CHVP induces a higher response rate in high tumor burden FL patients; 3) rituximab addition to αIFN+CHVP allows to reduce the number of CHVP chemotherapy cycles and 4) this rituximab association with αIFN+CHVP results in a marked improvement of event-free survival comparing favorably to the control arm or to other rituximab+chemotherapy combinations.