Prolonged disease‐free survival and overall survival with CVP alternating with fludarabine in advanced follicular lymphoma
Authors: Weiyun Z. Ai, Holbrook E. K. Kohrt, John Timmerman, Jimmy Hwang, Frank J. Hsu, Debra D. Czerwinski, Behnaz Taidi, Ronald Levy
Journal: American Journal of Hematology (2011)

Cyclophosphamide and fludarabine are highly active in treating follicular lymphoma (FL). However, many cyclophosphamide and fludarabine combination regimens, although highly effective, exhibited severe infectious toxicities including toxic death [ 1-7]. We designed a novel sequential regimen consisting of CVP (cyclophosphamide 400 mg/m2 PO d1-5, vincristine 2 mg d1, prednisone 100 mg/m2 d1-5) alternating with fludarabine (25 mg/m2 IV d1–5) as induction chemotherapy for idiotype vaccination, with a goal of obtaining a higher quality of tumor debulking before vaccination. Herein, we report the safety and efficacy of this regimen. Thirty-four consecutive untreated patients with FL received this regimen. Toxicities were modest with no severe infections or toxic deaths. Complete response/unconfirmed complete response (CR/CRu) was achieved in 18 patients (53%) and PR in 38%. At a median follow-up of 12 years, overall survival (OS), event-free survival (EFS), time to progression (TTP), and disease free survival (DFS) were 85, 37, 38, and 70%, respectively. Among a cohort of historical controls with similar characteristics receiving CVP, the CR rate was 34%, 12-year OS, EFS, TTP, and DFS were 64, 20, 21, and 37%, respectively. Thus, CVP/F exhibited favorable safety profile while maintaining the excellent efficacy of combining cyclophosphamide and fludarabine and warrants further evaluation in combination with rituximab. FL, the second most common subtype of non-Hodgkin's lymphoma (NHL) in Western countries, comprises 22% of NHLs [ 8]. Even though the survival of patients with FL has improved in the past decade, a great majority of patients with FL do eventually succumb to the disease. Thus, there is an unmet need to develop new and effective regimens for FL. As FL is primarily a disease of the elderly, the safety profile of new regimens is of great importance in clinical practice. Both alkylating agents and purine analogs are highly active in FL [ 9, 10], which make them attractive agents for a combination chemotherapy regimen. Various combinations of fludarabine and cyclophosphamide have been tested in clinical trials [ 1-7]. Although a high level of activity was observed in both untreated patients and patients with relapsed low-grade lymphoma, nonhematologic toxicity, especially infectious complications, hampered wide acceptance of these very effective regimens. Thus, it is imperative to optimize the dosing and schedule of a cyclophosphamide and fludarabine combination regimen to improve its safety profile while maintaining its high activity. It was hypothesized that a higher quality of tumor debulking before idiotype vaccination may lead to enhanced antitumor immune responses. Thus, we designed a novel sequential combination regimen, CVP alternating with fludarabine (CVP/F) as induction chemotherapy for idiotype vaccination. The primary endpoint of the study was the rate of generating idiotype-specific immune responses. When compared with our historical experience using CVP as induction chemotherapy for idiotype vaccination, CVP/F generated a lower rate of tumor-specific T-cell immune response with a similar rate of antibody response (data not shown). Despite of unfavorable impact of CVP/F on generating anti-idiotype immune responses, CVP/F exhibited excellent efficacy in cytoreduction with a favorable safety profile. Herein, we report a retrospective and unplanned analysis of the chemotherapeutic effect of this novel regimen. From August 1994 to January 1996, 34 consecutive patients with advanced-stage FL who required treatment judged by their treating physicians received CVP/F as the first-line therapy. One hundred and eleven contemporaneous patients treated with CVP (1990–2000 inclusive) in our institution were selected as a reference population as described in Methods. Of note, the accrual period for CVP bracketed that for CVP/F without overlap. The patient characteristics of the study and the reference cohorts are described in Table I. The median age at diagnosis was 45 years for the study cohort and 47 years for the reference cohort. When categorized according to FLIPI [ 11], the majority of the patients in both cohorts had intermediate risk. The percentage of high risk patients was 12% in the CVP/F group and 21% in the CVP group. Of known single prognostic factors, the percentage of patients in the CVP/F versus CVP groups with unfavorable prognostic factors were as follows: 79% versus 74% had involvement in more than four nodal areas, 6% versus 9% had abnormal LDH, 12% versus 9% had B symptoms, and 3% and 11% patients had abnormal hemoglobin. Ninety-four and sixty-nine percent of patients in the CVP/F and CVP groups, respectively, received idiotype vaccination following the induction chemotherapy. The median follow-up for living patients was 12 (range: 9.9–13.2) and 9 (range: 1.5–15.7) years for the study and reference cohorts, respectively. It should be noted that given the retrospective nature of this study, the comparison between CVP/F with CVP was not performed in a randomized fashion, thus, has its intrinsic limitations. With regard to the toxicity of CVP/F, all patients in the CVP/F cohort completed planned treatment. Prophylactic antibiotics were not permitted. Nonhematologic toxicities were uncommon. Two patients developed varicella-zoster virus reactivations, but no other opportunistic infections were reported. Moderate hematologic toxicities were observed, with grade 1/2 and 3/4 neutropenia seen in 11% and 13% of cycles of CVP treatment, respectively. In comparison with CVP, hematologic toxicities were more modest with fludarabine, with 14.3% and 1.9% of cycles resulting in grade 1/2 and grade 3 neutropenia, respectively; and 13.3% of cycles causing grade 1/2 thrombocytopenia. Among 117 cycles of CVP and 116 cycles of fludarabine delivered, seven episodes of neutropenic fevers occurred, which were evenly distributed between CVP and fludarabine cycles. G-CSF was given only when patients developed neutropenic fevers or had treatment delay due to grade 2 or greater leucopenia. Based on these criteria, 25 of 34 (74%) patients required G-CSF during their treatment. Twenty-eight percent of the CVP and 19.6% fludarabine cycles were associated with treatment delays because of hematologic toxicity defined by the study. No acute toxic deaths were observed. Two patients died of second malignancy in the CVP/F cohort, which were possibly related to chemotherapy; one from colon cancer, the other from AML, 8 and 5 years after chemotherapy, respectively. Clinical outcomes of patients treated with CVP/F compared with our historical control cohort received CVP are described in Table I and displayed in Figure 1. The CR and overall response rates (ORR) were 53 and 91% for the CVP/F group and 34 and 93% for the CVP group. At a median follow-up of 12 years for the CVP/F group, 12-year OS, EFS, TTP, and DFS were 85, 37, 38, and 70%, respectively. In comparison, the 12-year OS, EFS, TTP, and DFS observed in the CVP group were 64, 20, 21, and 37%, respectively. Comparing CVP/F with CVP, median OS was not reached versus 15.2 years (95% CI = 15.24–10.40) with a P value of 0.033; median EFS was 2.66 years (95% CI = 1.63–1.97) versus 1.80 years (95% CI = 1.17–2.48) with a P value of 0.0479; median TTP was 5.54 years (95% CI = 1.97–2.93) versus 2.33 years (95% CI = 1.80–3.10) with a P value of 0.0316, and media DFS was not reached versus 4.80 years (95% CI = 3.11–3.94) with a P value of 0.0294 (Table I). Outcomes after treatment with CVP/F or CVP as initial therapy for advanced follicular lymphoma. Kaplan–Meier estimates of OS (A), EFS (B), TTP (C), and DFS (D) in patients treated with CVP/F or CVP. (E) described Kaplan–Meier estimates of DFS in vaccinated patients only. Both CVP and CVP/F were used as induction chemotherapy for customized tumor idiotype vaccines in our institution. To receive vaccination, patients had to achieve at least a PR to induction therapy with no disease progression before customized vaccine was produced, which generally took 6 months. In this study, a higher percentage of patients in the CVP/F group proceeded to vaccination, reflecting the higher response rate and more durable remission achieved by CVP/F when compared with CVP (Table I). Given that we could not discern the potential contribution of idiotype vaccination to the outcomes of induction chemotherapy, we performed subgroup analysis on vaccinated patients. In vaccinated patients, DFS in the CVP/F group (n = 18) remained superior to that in the CVP group (n = 36) (Fig. 1E). Additionally, the trend of improvement in TTP and EFS favoring CVP/F remained; however, the P values were no longer significant, possibly because of a small number of patients and/or events in each group. Similarly, OS was not significantly different in vaccinated patients from CVP/F and CVP groups (data not shown). To improve the outcome of FL, there are continued unmet needs to develop safe and effective regimens. Sequential administration of CVP and fludaraine (CVP/F) generated a high response rate and durable remission. More importantly, in contrast to previously reported cyclophosphamide and fludarabine concurrent regimens, our alternating regimen was well tolerated with no toxic deaths or severe opportunistic infections, even without prophylactic antibiotics or preemptive growth factor support. CVP/F compares favorably to historical experiences with CVP from our institution as well as from others (Table II) [ 2-4, 12-15]. It appears to generate a higher CR rate and a “deeper response” as evidenced by a superior DFS (Table I and Fig. 1D). Consistent with our observation, a high quality response with CF (cyclophosphamide and fludarabine) was also observed in the ECOG/CALGB intergroup E1496 trial, where newly diagnosed patients with FL randomized to CVP versus CF followed up by second randomization of rituximab maintenance versus observation in nonprogressing patients [ 4]. In this study, more than 90% of patients treated with CF randomized to maintenance achieved protocol-defined minimal residual disease compared with 64% of patients treated with CVP. Additionally, our CVP/F compares favorably with other cyclophosphamide and fludarabine (CF) concurrent regimens in CR and ORR rates without prohibitive infectious complications occurred in many of those studies (Table II). For instance, the largest study (n = 115), ECOG 1496 described above, reported 12 deaths (10%) in patients treated with CF, with 9 due to infection. This result led to early closure of the CF arm [ 4]. The favorable safety profile of CVP/F may be due to the fact that the accumulative dose of fludarabine was only a half of the dose as in concurrent FC combination regimens. In line with our results, a FC sequential regimen appeared to be highly effective but less toxic than FC concurrent regimens in CLL [ 16]. In summary, CVP alternating with fludarabine is highly active for FL with a favorable safety profile. Our long-term follow-up afforded us to observe the durability of CRs and survival benefit of CVP/F comparing with CVP. These features, along with a favorable toxicity profile, make CVP/F an exciting addition to the therapeutic repertoire for FL, thus CVP/F merits further exploration in combination with rituximab. From August 1994 to January 1996 at Stanford University, 34 consecutive patients with untreated stage III or IV follicular B-cell lymphoma who required treatment in the opinion of their treating physicians received CVP/F as an induction regimen. All patients had signed a consent form, approved by the Institutional Review Board of Stanford University. For the purpose of comparison, we selected a reference population from the Stanford Lymphoma Database. The reference population included patients with newly diagnosed advanced stage follicular B-cell lymphoma, who required treatment judged by their physicians and were treated with CVP as the first-line chemotherapy at Stanford University from 1990 to 2000 (inclusive). One hundred and eleven patients met the criteria and were included in the current analysis. Of note, the accrual period for CVP bracketed that for CVP/F without overlap. The planned treatment consisted of cytoreduction with CVP alternating with single agent fludarabine. Patients were treated with CVP as described by Bagely et al. [ 12], utilizing cyclophosphamide 400 mg/m2 PO qd × 5, vincristine 1.4 mg/m2 IV capped at 2 mg, and prednisone 100 mg/m2 po qd × 5, alternating with fludarabine (25 mg/m2 qd × 5) every 21 days for two cycles beyond best response (maximum of eight cycles). The schedule for dose reduction was as follows: the doses of cyclophosphamide or fludarabine were reduced by 25% for grade 1 leukopenia or thrombocytopenia (WBC 3000–3500, or platelets 75,000–100,000). The treatment was delayed for 1 week for grade 2 leukopenia or thrombocytopenia (WBC was 2000–2900, or platelets 50,000–75,000). G-CSF was given if febrile neutropenia or treatment delay had occurred in the previous cycle. Treatment response was evaluated using standard criteria [ 17]. Patients were evaluated after four cycles of treatment and then every two cycles with maximum of eight cycles. For patients with initial bone marrow involvement by the tumor, those who had resolution of all clinical and radiographic evidence of disease, but did not have repeat bone marrow evaluation at the end of treatment, were scored as partial responders (n = 1 for the CVP/F group and n = 3 for the CVP group). After the completion of therapy, patients were followed up at Stanford or by their local oncologists, who then communicate the follow-up status with Stanford physicians. Both patients treated with CVP/F and CVP were followed up by the same group of physicians (Dr. Levy and associates) in the same fashion. OS was calculated from the date of the first treatment to the last follow-up or death and described by Kaplan–Meier method. EFS was defined as the interval between the initiation of chemotherapy to disease progression, relapse, second-line treatment for intolerability or inadequate response (less than a partial response), or death from any cause. Additional efficacy endpoints included response rates, TTP (interval between first chemotherapy to progression, relapse after response, or death from any cause) and disease-free survival (DFS: interval between response and relapse or death in patients who achieved CR/CRu to induction chemotherapy). OS, EFS, TTP, and DFS were examined by Kaplan–Meier method (PRISM, GraphPad software, San Diego, CA). Adverse events were graded according to NCI Common Terminology Criteria for Adverse Events, version 3.0. W.A. is a Lymphoma Research Foundation Fellow and a recipient of the American Society of Clinical Oncology Young Investigator Award. R.L. is an American Cancer Society Clinical Oncology Research Professor. W. Z. Ai*, H. E. K. Kohrt , J. Timmerman , J. Hwang§, F. J. Hsu¶, D. Czerwinski , B. Taidi , R. Levy , * Department of Medicine, Division of Hematology and Oncology, University of California, San Francisco, California, Department of Medicine, Division of Medical Oncology, Stanford University School of Medicine, Stanford, California, Department of Medicine, Division of Hematology and Oncology, University of California, Los Angeles, California, § Biostatistics and Computational Biology Core, University of California, San Francisco, California, ¶ Genzyme Corporation, Clinical Research, 55 Cambridge Parkway, Cambridge, Massachusetts.