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Keywords:

  • cladribine;
  • low-grade B-cell non-Hodgkin lymphoma;
  • treatment response;
  • progression-free survival;
  • overall survival;
  • international prognostic index

Abstract

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES

BACKGROUND.

The objective of this study was to compare the efficacy of 3 regimens, cladribine alone, cladribine and cyclophosphamide combination, or cyclophosphamide, vincristine, and prednisone combination in previously untreated patients with low-grade B-cell non-Hodgkin lymphoma (LGNHL).

METHODS.

For this 3-arm, phase 3 study, 197 patients were randomly allocated to receive 6 monthly courses of cladribine alone, cladribine and cyclophosphamide combination, or cyclophosphamide, vincristine, and prednisone combination. Patients for whom all clinical data were available and 162 patients who completed scheduled chemotherapy were analyzed for the endpoints of this study.

RESULTS.

Compared with cyclophosphamide, vincristine, and prednisone combination regimen, cladribine alone or cladribine and cyclophosphamide combination induced higher probability of overall response (odds ratio [OR] = 4.0; 95% confidence interval [CI], 1.7–9,3; P = .002, and OR = 8.5; 95% CI, 3.2–22.7; P < .0001, respectively), complete remission (OR = 5.8; 95% CI, 1.8–18.5; P = .003; and OR = 14; 95% CI, 4.4–44; P < .0001, respectively), progression-free survival (log-rank test P < .0001), but not overall survival. After incorporating the International Prognostic Index in multivariate analysis, treatment with cladribine-containing regimens remained an independent prognostic factor for progression-free survival (χ2 = 35.94; hazard ratio = 2.38; P < .0002). Incidences of infections were similar in the randomized groups, whereas cladribine and cyclophosphamide combination, but not cladribine alone, induced more frequent neutropenia, anemia, and thrombocytopenia compared with cyclophosphamide, vincristine, and prednisone combination (P < .05 for each). This resulted in a higher frequency of prolongation of intervals between cladribine and cyclophosphamide combination and cyclophosphamide, vincristine, and prednisone combination cycles (P < .05), but dose reductions due to hematological or other toxicity did not differ significantly in cladribine alone, cladribine and cyclophosphamide combination, and cyclophosphamide, vincristine, and prednisone combination groups.

CONCLUSIONS.

For patients with LGNHL, first-line cladribine alone or cladribine and cyclophosphamide combination regimens both provided similar treatment responses, acceptable toxicity, and better response rates than cyclophosphamide, vincristine, and prednisone combination. Cancer 2008. © 2008 American Cancer Society.

Low grade B-cell non-Hodgkin lymphomas (LGNHL) are a heterogenous group of entities with different clinical presentations and treatment outcomes depending on histopathological diagnosis. The initial disease presentation often shows advanced disease stage and continuous relapse pattern. Although their clinical course is indolent and median overall survival varies from 5 to 10 years from diagnosis, LGNHL are incurable in the vast majority of cases. As disease relapse is a part of LGNHL nature, establishing treatment options that lead to better therapy response rates and longer progression-free survival remains the main goal of clinical trials in this group of patients.

Previous clinical studies have shown no benefit from up-front treatment with alkylating agents in asymptomatic patients without massive local involvement. Once chemotherapy was indicated, the most commonly applied first-line treatments were chlorambucil or cyclophosphamide, with or without vincristine and prednisone (cyclophosphamide, vincristine, and prednisone combination). The incorporation of doxorubicin and/or radiotherapy into cyclophosphamide, vincristine, and prednisone combination showed no benefit in terms of disease outcome, although toxicity was significantly higher. However, a subset of patients with LGNHL who received more intensive combination chemotherapy might have experienced improved disease control and survival.1–3

The phase 1 and 2 clinical trials that used purine analogs in the first-line therapy of patients with LGNHL revealed response rates and progression-free survival rates comparable to or higher than the above-mentioned treatments, with especially high activity in small lymphocytic lymphoma and chronic lymphocytic leukemia. However, toxicity, including myelosuppression and increased susceptibility to infections, was more pronounced than with standard chemotherapy.4–9

Several studies that compared cyclophosphamide, vincristine, and prednisone combination to fludarabine-containing regimens were conducted in LGNHL, but cladribine use in first-line chemotherapy was not sufficiently documented in phase 3 studies. Thus, to establish the role of cladribine-containing regimens in this setting, including follicular lymphoma, lymphoplasmacytic lymphoma, marginal-zone lymphoma, and small lymphocytic lymphoma, we designed this prospective, randomized, phase 3 study. Importantly, the study protocol was launched before rituximab had become widely available and before studies of maintenance immunotherapy in follicular lymphoma were conducted. This allowed us to enroll rituximab-naive patients and to treat them with chemotherapy alone.

MATERIALS AND METHODS

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES

Criteria for Eligibility

A phase 3, prospective, randomized trial was conducted to compare efficacy and toxicity of cladribine alone, cladribine combined with cyclophosphamide, and cyclophosphamide, vincristine, and prednisone combination in previously untreated patients with LGNHL, including follicular lymphoma, lymphoplasmacytic lymphoma, marginal-zone lymphoma, and small lymphocytic lymphoma. All 17 participating centers cooperate within the Polish Lymphoma Research Group. Patients were required to be older than 18 years of age and to have a 3-month or greater life expectancy. Central nervous system involvement, human immunodeficiency virus infection, previous chemotherapy or radiotherapy, other malignancy, pregnancy, inappropriate organ function, or patient noncompliance were exclusion criteria. The study protocol met the regulatory authorities' requirements. All participants gave informed, written consent, and their confidentiality was preserved in accordance with the Polish regulations for studies on human subjects.

Staging Studies

Pathological confirmation of the diagnosis of LGNHL and clinical history were available in every case. Histological diagnoses were established according to the World Health Organization (WHO) classification. The initial medical evaluation comprised a complete history and physical examination, chest radiographic examination, computed tomographic scan of the chest, abdomen, and pelvis, and laboratory tests including complete blood count, bilirubin, alanine and asparagine phosphatase, lactate dehydrogenase (LDH), β2-microglobulin, uric acid, creatinine, and protein level with electrophoresis. The extent of disease and presence of systemic symptoms (B symptoms) were categorized according to the Ann Arbor classification, and performance status was assessed by using Eastern Cooperative Oncology Group (ECOG) criteria. Treatment outcome was assessed according to criteria established by the International Workshop to Standardize Response Criteria for Non-Hodgkin Lymphomas.10

Randomization and Treatment Schedule

Between July 1, 2000 and June 30, 2005, 197 patients were randomized to treatment with 6 cycles of either cladribine alone (0.12 mg/kg 2-hours infusion intravenously [iv] on Days 1 to 5 every 28 days) or cladribine and cyclophosphamide combination (cladribine, 0.12 mg/kg 2-hours infusion iv on Days 1 to 5; cyclophosphamide, 800 mg/m2 bolus iv on Day 1 every 28 days), or cyclophosphamide, vincristine, and prednisone combination (cyclophosphamide, 800 mg/m2 bolus iv on Day 1; vincristine 1.4 mg/m2 bolus iv on Day 1; prednisone 45 mg/m2 orally on Days 1 to 4 every 21 days). Patients were centrally randomized by using facsimile confirmation.

Three weeks after completion of the third cycle of chemotherapy, staging was repeated to assess response and, thus, subsequent therapy. When complete remission, unconfirmed complete remission, partial remission, or stable disease was observed, 3 additional cycles were administered. Only when progressive disease occurred at the time of a restaging procedure, then the choice of second-line chemotherapy was made by centers for each patient individually.

On Day 1 of each cycle, neutrophil and platelet counts must have exceeded 1.5 × 109/L and 50 × 109/L, respectively. If these values were not reached, then chemotherapy interval prolongation was allowed up to 4 additional weeks. If at 8 weeks after the previous cycle these parameters were not achieved, then further modifications were performed individually according to clinical indications. After administration of vincristine, if neuropathy was observed, then a dose reduction of 50% or replacement by an adequate dose of vinblastine was allowed. Follow-up phase was based on local guidelines with at least 1 follow-up visit every 3 months. In any case of disease progression or death, referral to an appropriate coordinating center was mandatory. Patients who prematurely terminated the study for any cause, including withdrawal of consent, histopathological diagnosis, protocol violation, or clinical indications, were excluded from further analysis.

Endpoints

The study was aimed to assess treatment outcome and toxicity. The primary endpoint was progression-free survival calculated from either the onset of treatment until disease progression or last follow-up evaluation. The overall response rates, including complete remission, unconfirmed complete remission, partial remission, and overall survival, as well as grade 3-4 hematological and nonhematological toxicities were secondary endpoints. Overall survival was measured as the time between the beginning of treatment and death from any cause or the date of the last follow-up evaluation. Standard WHO criteria were used for evaluation of chemotherapy-induced toxicities. Adverse events, observed at each course, with at least WHO grade 3 were recorded by using detailed case report forms. Incidences of chemotherapy dose reductions and/or prolongation of intervals between cycles were also recorded.

Sample Size

The original planned sample size was calculated to detect a 20% difference in the proportion of patients remaining free from disease progression at 18 months, in favor of any of the cladribine-containing regimens. This was determined, by consensus among the participating investigators, to be a clinically relevant improvement in outcome before the era of rituximab. Accordingly, with α = .05 and β = .2, 70 patients were required in each group (total study sample of 210) within a plan to accrue patients over a 3-year period.

Statistical Analysis

Statistical analyses of categorical data were conducted using χ2 or Fisher exact tests and continuous variables were analyzed with Student t or Wilcoxon tests. Logistic regression was used to estimate the influence of the 3 treatment regimens on response rates. Actuarial survival data were analyzed according to the method of Kaplan and Meier and compared by using the log-rank test. A multivariate regression analysis with the Cox proportional hazard model was used to adjust the effect of the cladribine-containing regimens for potential independent prognostic factors. Statistical tests with P < .05 were considered significant. All reported P values were 2-sided. Statistical analysis was performed by using SPSS (version 14.0; SPSS, Chicago, Ill) and Statistica (version 7; StatSoft, Tulsa, Okla) software.

RESULTS

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES

A total of 197 patients from 17 institutions of the Polish Lymphoma Research Group were enrolled onto the study between July 1, 2000 and June 30, 2005. Accrual was slower than expected, mostly because of the introduction of rituximab into clinical practice in Poland, but analysis after longer follow-up suggested that a sufficient number of events had occurred to allow assessment of progression-free survival. Of 197 randomized patients, 24 were further excluded from final analysis, including 9 for inappropriate histology on pathology center review, 8 for withdrawn consent, and 7 for protocol violation. In addition, for 11 patients, data were not complete at the time of final analysis performed July 1, 2006. Finally, 162 patients who completed all 6 cycles of scheduled chemotherapy and for whom all clinical data were available were analyzed for endpoints of the study. Patients' demographic and baseline clinical characteristics were similar among randomized groups (Table 1).

Table 1. Baseline Comparison of Clinical Characteristics of 162 Patients With Low Grade Non-Hodgkin Lymphoma According to Randomized Treatment Groups
CharacteristicWhole groupTreatment arms
CdA*CCdACOP
No. of patients(%)n = 58(%)n = 59(%)n = 45(%)
  • *

    CdA, cladribine 0.12mg/kg 2-hour infusion intravenously (iv) on Days 1 to 5 every 28 days.

  • CCdA, cladribine 0.12mg/kg 2-hour infusion iv on Days 1 to 5 and cyclophosphamide 800 mg/m2 bolus iv on Day 1 every 28 days.

  • COP, cyclophosphamide 800 mg/m2 bolus iv on Day 1, vincristine 1.4 mg/m2 bolus iv on Day 1, and prednisone 45 mg/m2 orally on Days 1 to 4 every 21 days.

Age, y        
 <6071(43.8)27(46.6)28(47.5)16(35.6)
 ≥6091(56.2)31(53.4)31(52.5)29(64.4)
Sex        
 Men90(55.6)28(48.3)34(57.6)28(62.2)
 Women72(44.4)30(51.7)25(42.4)17(37.8)
ECOG        
 <2152(93.8)53(91.4)57(96.6)42(93.3)
 ≥210(6.2)5(8.6)2(3.4)3(6.6)
Ann Arbor        
 I,II21(13)6(10.3)8(13.6)7(15.6)
 III,IV141(87)52(89.7)51(86.4)38(84.4)
LDH        
 ≤1 x upper normal limit95(58.6)38(65.5)31(52.5)26(57.8)
 >1 x upper normal limit67(41.4)20(34.5)28(47.5)19(42.2)
Extranodal sites        
 <271(43.8)23(39.7)26(44.1)22(51.1)
 ≥291(56.2)35(60.3)33(55.9)23(48.9)
Histopathological subtypes        
 Lymphocytic56(34.6)19(32.8)21(35.6)16(35.5)
 Lymphoplasmacytic12(7.4)6(10.4)3(5.1)3(6.7)
 Marginal40(24.7)17(29.3)10(16.9)13(28.9)
 Follicular46(28.4)14(24.1)22(37.3)10(22.2)
 Low grade B-cell not #specified8(4.9)2(3.4)3(5.1)3(6.7)
International Prognostic Index        
 0–130(18.5)11(19.0)9(15.3)10(22.2)
 246(28.4)15(25.9)18(30.5)13(29.0)
 353(32.7)21(36.1)21(35.6)11(24.4)
 4–553(20.4)11(19.0)11(18.6)11(24.4)

Interim analysis performed on July 1, 2004 included 105 of 165 (63.6%) randomized patients who had completed at least 6 cycles of scheduled chemotherapy. Of 105 analyzed patients, 38 (36.2%) were diagnosed with small lymphocytic lymphoma, 8 (7.6%) with lymphoplasmacytic lymphoma, 22 (21%) with marginal-zone lymphoma, 33 (31.4%) with follicular lymphoma, and 4 (3.8%) with not otherwise specified B-cell LGNHL. Randomization produced comparable groups, including International Prognostic Index prognostic factors. Compared with cladribine alone and cladribine and cyclophosphamide combination, cyclophosphamide, vincristine, and prednisone combination induced lower overall response rates (75%, 85%, 51%, respectively; χ2P < .005), including complete remission and unconfirmed complete remission rates (43%, 62.5%, 5.5%, respectively; χ2P < .001). With a median follow-up of 10 months, median progression-free survival was superior in patients who were receiving cladribine-containing regimens (8, 11, and 6 months, respectively; χ2 = 15.1; log-rank P < .001). No difference in median overall survival was detected (9, 12, and 7 months, respectively; χ2 = 1.15; log-rank P = .56). In conclusion, we found that first-line chemotherapy with cladribine alone and cladribine and cyclophosphamide combination regimens both provided similar response rates, progression-free survival, and overall survival, and better results than cyclophosphamide, vincristine, and prednisone combination. This has resulted in discontinuation of accrual into the cyclophosphamide, vincristine, and prednisone combination group July 1, 2004 and further recruitment into cladribine alone and cladribine and cyclophosphamide combination arms through June 30, 2005.

The final analysis of 162 patients, performed July 1, 2006, comprised 56 (34.6%) patients with small lymphocytic lymphoma, 12 (7.4%) with lymphoplasmacytic lymphoma, 40 (24.7%) with marginal-zone lymphoma, 46 (28.4%) with follicular lymphoma, and 8 (4.9%) with not otherwise specified B-cell LGNHL. Randomization provided comparable groups, including International Prognostic Index variables. The imbalances in sample sizes resulted from discontinuation of accrual in the cyclophosphamide, vincristine, and prednisone combination group since the interim analysis (Table 1). Of 162 patients, 59 (36.4%) patients achieved complete remission or unconfirmed complete remission, 59 (36.4%) achieved partial remission, and 44 (27.2%) achieved stable disease or progressive disease. The detailed treatment response after 6 courses of chemotherapy by randomized group is listed in Table 2. Compared with cyclophosphamide, vincristine, and prednisone combination, cladribine alone or cladribine and cyclophosphamide combination was associated with a higher probability of overall response achievement in univariate logistic regression analysis (OR = 4.0; 95% confidence interval [CI], 1.7-9.3; P = .002, and OR = 8.5; 95% CI, 3.2–22.7; P < .0001, respectively). The probability of complete remission and unconfirmed complete remission achievement was also significantly higher in patients who were treated with cladribine alone or cladribine and cyclophosphamide combination regimen compared with those receiving cyclophosphamide, vincristine, and prednisone combination (OR = 5.8; 95% CI, 1.8–18.5; P = .003, and OR = 14; 95% CI, 4.4–44; P < .0001, respectively). Of 162 patients, 83 (51%) patients experienced disease progression, and 37 (23%) patients died. With a median follow-up of the patients remaining alive at 36 months, progression-free survival was longer in patients who were receiving cladribine alone or cladribine and cyclophosphamide combination than in those treated with cyclophosphamide, vincristine, and prednisone combination, but no difference in overall survival was detected among randomized groups (Fig. 1, Table 3). Compared with the entire group of 162 randomized patients, similar results in treatment response rates, progression-free survival, and overall survival were observed in different histological subtypes of LGNHL, including small lymphocytic lymphoma (n = 56), follicular lymphoma (n = 46), and marginal-zone lymphoma (n = 40) (data not shown).

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Figure 1. Progression free survival (A) and overall survival (B) of 162 patients with low grade non-Hodgkin lymphoma by randomized group. The initial number of patients at risk was 58 (35.8%) for CdA (cladribine alone), 59 (36.4%) for CCdA (cladribine and cyclophosphamide combination), and 45 (27.8%) for COP (cyclophosphamide, vincristine, prednisone combination). P denotes the log-rank test value; ns, not significant.

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Table 2. Treatment Response After 6 Courses of Chemotherapy by Randomized Group
Treatment responseCdA* n = 58CCdA, n = 59COP, n = 45P CdA/CCdA vs COPP CdA vs CCdA
No.(%, 95% CI)No.(%, 95% CI)No.(%, 95% CI)
  • *

    CdA, cladribine 0.12mg/kg 2-hour infusion intravenously (iv) on Days 1 to 5 every 28 days.

  • CCdA, cladribine 0.12mg/kg 2-hour infusion iv on Days 1 to 5 and cyclophosphamide 800 mg/m2 bolus iv on Day 1 every 28 days.

  • COP, cyclophosphamide 800 mg/m2 bolus iv on Day 1, vincristine 1.4 mg/m2 bolus iv on Day 1 and prednisone 45 mg/m2 orally on Days 1 to 4 every 21 days.

  • §

    ns, not significant.

Complete remission13(22.4, 12–33%)27(45.8, 33–58%)3(6.7, 0–14%)<.0001.01
Unconfirmed complete remission8(13.8, 5–23%)7(11.9, 4–20%)1(2.2, 0–6%).04ns
Partial remission24(41.4, 29–54%)18(30.5, 19–42%)17(37.8, 24–52%)ns§ns
Stable disease8(13.8, 5–23%)4(6.7, 0–13%)10(22.2, 10–34%).07ns
Progressive disease5(8.6, 1–16%)3(5.1, 0–11%)14(31.1, 17–45%)<.0001ns
Table 3. Probability of Progression-free and Overall Survival at 3 Years by Randomized Treatment Group
TreatmentNo. of patients% PFS (95% CI)P*No. of patients% OS (95% CI)P*
  • PFS indicates progression-free survival; CI, confidence interval; OS, overall survival; ns, not significant.

  • *

    P denotes the log-rank test value of the whole model (CdA versus CCdA versus COP) and CdA versus CCdA (below).

  • CdA, cladribine 0.12mg/kg 2-hours infusion intravenously (iv) on Days 1 to 5 every 28 days.

  • CCdA, cladribine 0.12mg/kg 2-hours infusion iv on Days 1 to 5 and cyclophosphamide 800 mg/m2 bolus iv on Day 1 every 28 days.

  • §

    COP, cyclophosphamide 800 mg/m2 bolus iv on Day 1, vincristine 1.4 mg/m2 bolus iv on Day 1 and prednisone 45 mg/m2 orally on Days 1 to 4 every 21 days.

CdA5848.3 (32–65)<.00015876.4 (62–87)ns
CCdA5961.2 (46–74).25977.0 (63–86)1.0
COP§4521.8 (12–37)4575.8 (61–86)

To evaluate the importance of cladribine-containing regimens on LGNHL outcome, a multivariate regression analysis was performed. The Cox model was tested by introducing the cladribine alone or cladribine and cyclophosphamide combination treatment status along with prognostic variables of the International Prognostic Index, ie, age (60 years of age or older), Ann Arbor disease stage (I–II or III–IV), ECOG performance status (0–1 or 2–4), serum activity of LDH (normal or above upper normal limit), and number of extranodal sites of disease (0–1 or >1). After incorporating the International Prognostic Index (0–1 vs 2–3 vs 4–5 adverse factors) in multivariate analysis, treatment with the cladribine-containing regimens remained an independent prognostic factor for longer progression-free survival (χ2 = 35.94; HR = 2.38; P < .0002) (Table 4).

Table 4. Factors Independently Prognostic of Progression-free Survival
FactorβSEHRP
  • β indicates regression coefficient; SE, standard error of β; HR, hazard ratio; IPI, International Prognostic Index.

  • *

    CdA, cladribine 0.12mg/kg 2-hour infusion intravenously (iv) on Days 1 to 5 every 28 days or CCdA, cladribine 0.12mg/kg 2-hour infusion iv on Days 1 to 5 and cyclophosphamide 800 mg/m2 bolus iv on Day 1 every 28 days.

CdA or CCdA*0.8660.2272.38<.0002
IPI risk group0.8600.1962.36<.0001

Percentages of patients with at least grade 3 adverse events observed within 6 courses of initial chemotherapy by randomized group are reported in Table 5. No patients experienced nausea, vomiting, alopecia, renal, hepatic, cardiac, pulmonary, or neurological toxicity attributable to chemotherapy. Incidences of infections were similar among randomized groups, whereas cladribine and cyclophosphamide combination, but not cladribine alone, induced more frequent peripheral cytopenias compared with cyclophosphamide, vincristine, and prednisone combination, including 36% (95% CI, 24% to 48%) versus 7% (95% CI, 0% to 14%) for neutropenia, 10% (95% CI, 2% to 18%) versus 0% for anemia, and 15% (95% CI, 6% to 24%) versus 0% for thrombocytopenia (χ2P < .05 for each). This resulted in a higher frequency of prolongation of intervals between cladribine and cyclophosphamide combination (37.3%; 95% CI, 25% to 50%) and cyclophosphamide, vincristine, and prednisone combination (13.3%; 95% CI, 3% to 23%) (χ2P < .05). The frequency of delay to the next cycle of cladribine alone (24%) did not differ significantly from the cladribine and cyclophosphamide combination or cyclophosphamide, vincristine, and prednisone combination arms. Dose reductions due to hematological or other toxicities did not differ significantly among cladribine alone, cladribine and cyclophosphamide combination, and cyclophosphamide, vincristine, and prednisone combination (12%, 20.3%, and 6.6%, respectively).

Table 5. Percentages of Patients With at Least Grade 3 Adverse Events Observed Within the First 6 Courses of Chemotherapy by Randomized Group
Adverse eventCdA,* n = 58CCdA, n = 59COP, n = 45
No. of patients (%, 95% CI)No. of patients (%, 95% CI)No. of patients (%, 95% CI)
  • *

    CdA, cladribine 0.12mg/kg 2-hour infusion intravenously (iv) on Days 1 to 5 every 28 days.

  • CCdA, cladribine 0.12mg/kg 2-hour infusion iv on Days 1 to 5 and cyclophosphamide 800 mg/m2 bolus iv on Day 1 every 28 days.

  • COP, cyclophosphamide 800 mg/m2 bolus iv on Day 1, vincristine 1.4 mg/m2 bolus iv on Day 1 and prednisone 45 mg/m2 orally on Days 1 to 4 every 21 days.

Neutropenia10 (17%, 7–27%)21 (36%, 24–48%)3 (7%, 0–14%)
Anemia2 (3%, 1–7%)6 (10%, 2–18%)0 (0)
Thrombocytopenia3 (5%, 0–11%)9 (15%, 6–24%)0 (0)
Infections7 (12%, 4–20%)7 (12%, 4–21%)7 (15%, 5–25%)

DISCUSSION

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES

The choice of the initial treatment for a given patient with LGNHL is controversial and should be directed toward obtaining the highest remission rate of longest duration while restricting morbidity and cost without compromising salvage treatment efficacy.11–13 Purine analogs are unique among conventional antimetabolites as they are cytotoxic to both resting and proliferating lymphocytes. This property confers their advantage over standard therapies in the treatment of malignancies with low-growth fractions, such as LGNHL. In relapsed LGNHL, fludarabine induced a slightly longer progression-free survival compared with cyclophosphamide, vincristine, and prednisone combination, but no differences in response rates or median overall survival between the 2 treatment groups were observed.14 In contrast, the efficacy of fludarabine combinations, especially in relapsed or refractory LGNHL, has been demonstrated with impressive remission rates of 70% to 100%.15–17 Similar results with cladribine alone on previously untreated and relapsed chronic lymphocytic leukemia patients have been published.7, 8

To our knowledge, this prospective, controlled trial that compared the efficacy and toxicity of cladribine-containing regimens and cyclophosphamide, vincristine, and prednisone combination in previously untreated patients with LGNHL is the only study reported in the literature so far. Considering treatment response, our results show that first-line cladribine alone or cladribine and cyclophosphamide combination regimens both provided close response rates and similar progression-free survival, clearly superior to cyclophosphamide, vincristine, and prednisone combination. This was observed since the interim analysis of this trial and caused the cessation of accrual in the cyclophosphamide, vincristine, and prednisone combination arm thereafter.18 This decision appeared reliable both from statistical and ethical viewpoints. Importantly, our findings were similar to those of previously published phase 2 trials that evaluated initial treatment with cladribine alone in patients with LGNHL.6, 9

In the trial comparing fludarabine with CVP, no benefit regarding time to treatment failure was observed, even with significantly improved complete remission rates in the fludarabine arm.4 Other phase 2 studies in untreated patients indicated fludarabine complete remission rates of 37% to 47% and overall response ratios up to 65%, which is consistent with our results in the cladribine alone arm.5, 19 Higher overall response rates and complete remission rates of cladribine alone-treated and cladribine and cyclophosphamide combination-treated patients can be partly explained by differences in the distribution of histopathological entities in our cohort. Follicular lymphoma represents 40% to 60% of LGNHL and 15% to 30% of all lymphomas and, thus, is 1 of the most frequent lymphoma subtypes that have an increasing incidence in western countries.20 In contrast, follicular lymphoma occurs in only 8% of newly diagnosed LGNHL in Poland, as demonstrated by the National Cancer Registry and population-based survey performed in the southern part of Poland.21

As in many other comparative studies, the differences in remission rates and even prolonged progression-free survival, did not create differences in overall survival. This is not surprising because, whatever the randomization group, a majority of included patients received second-line and even subsequent treatments over the course of their disease, obscuring the interpretation of survival curves. Similar conclusions have been outlined in other prospective studies.4, 5, 7, 8

Recent clinical trials have convincingly demonstrated that combined immunochemotherapy is superior to conventional chemotherapy and should be considered a standard approach in first-line, including both induction and maintenance, therapy.22–25 Regardless of the final results of phase 3 primary rituximab maintenance (PRIMA) trial that addressed the most effective chemoimmunotherapy of LGNHL (R-CHOP, R-cyclophosphamide, vincristine, and prednisone combination, R-MCP, and R-CHVP-IFN), it can be anticipated that similar improvements in outcomes will be associated when combining rituximab with cladribine or cladribine and cyclophosphamide combination. In a prospective study of recurrent LGNHL, a similar combined approach consisting of rituximab, fludarabine, cyclophosphamide, and mitoxantrone (R-FCM) resulted not only in significantly improved response rates and prolonged progression-free survival, but also, more importantly, improved overall survival.26 In addition, high activity of cladribine alone or cladribine and cyclophosphamide combination and rituximab has also been observed.27, 28

Although purine analogs are generally well tolerated, and their toxicity profile seems comparable to other regimens, both fludarabine and cladribine are associated with immunosuppression, and physicians should be aware of an increased risk of opportunistic infections.27 The therapeutic strategy adopted in this study was aimed at minimizing the potential for cumulative myelosuppression and immunosuppression. Accordingly, the maximal number of cladribine courses was limited to 6, and therapy was discontinued when there was significant protracted myelosuppression or a lack of ongoing response to treatment. In fact, we observed increased hematological toxicity in the cladribine-containing regimens arms compared with cyclophosphamide, vincristine, and prednisone combination, particularly in the cladribine and cyclophosphamide combination arm. This resulted in a higher frequency of prolongation of intervals between cladribine and cyclophosphamide combination cycles, but dose reductions due to hematological or other toxicities as well as incidences of infections did not differ significantly among randomized groups. The latter could be related to the finding that cladribine-containing regimens were administered to previously untreated patients, whereas increased incidence of infectious complications associated with purine analogs were mostly observed in heavily pretreated individuals.29 Nevertheless, when compared with other chemotherapeutic protocols, purine analog-based therapies display some disadvantages in a first-line treatment setting. Particularly, their cumulative stem cell toxic effect has to be considered if an autologous stem-cell transplantation is planned.30, 31

In conclusion, selection of a chemotherapy regimen to be combined with immunotherapy in first-line therapy of LGNHL still remains an open question. Once settled, the decision must consider not only the quality of remission and its duration but also early and delayed safety profiles. New insights into the underlying biology of different histological subtypes of LGNHL and broader use of established and new prognostic and/or predictive factors are anticipated to help guide therapy for individual patients. Our study demonstrates that cladribine-containing regimens are acceptable candidates for further chemoimmunotherapy studies in this setting.

REFERENCES

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES
  • 1
    Peterson BA,Petroni GR,Frizzera G, et al. Prolonged single-agent versus combination chemotherapy in indolent follicular lymphomas: a study of the cancer and leukemia group B. J Clin Oncol. 2003; 21: 515.
  • 2
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