Autografting

A phase II trial of rituximab as adjuvant to intensive sequential chemotherapy in patients under 60 years with untreated poor-prognosis diffuse large B-cell lymphoma

Abstract

The potential benefit of rituximab as adjuvant to high-dose therapy (HDT) has been investigated in patients under 60 years with poor-risk (age-adjusted international prognostic index at 2–3) CD20+ diffuse large B-cell lymphoma (DLBCL). The treatment consisted of four cycles of high-dose CEOP (cyclophosphamide, epirubicin, vincristine, prednisone), plus etoposide and cisplatin during the two last cycles. Peripheral blood stem cells were collected after cycle 1, and reinfused after cycles 3 and 4. Four weekly rituximab infusions were subsequently delivered. Among the 36 patients included, 30 could complete chemotherapy schedule, and 24/36 received rituximab. A complete response occured in 26/36 patients (72%). With a median follow-up of 30 months, the estimated 5-year overall survival (OS) and event-free survival (EFS) rates (mean±s.d.) were 65±16 and 63±15%, respectively. For the 24 patients who received both chemotherapy and rituximab, the estimated 5-year OS and EFS rates were 86±14 and 82±15%. These data suggest that rituximab after HDT is feasible. Both complete remission rate and survival curves compare favorably with the poor outcome usually observed in high-risk DLBCL patients managed with HDT without rituximab.

Introduction

According to the World Heath Organization (WHO) classification of tumours of haematopoietic and lymphoid tissues, diffuse large B-cell lymphomas (DLBCL) account for 30–40% of adult non-Hodgkin's lymphoma (NHL) in Western countries.1 Among patients with DLBCL, 30–40% present with poor-prognosis factors at diagnosis with an intermediate- or high-risk international prognosis index (IPI) score.2

Several randomized phase III studies have reported that high-dose therapy (HDT) followed by autologous stem cell transplantation could be of benefit in terms of freedom from progression in higher risk patients younger than 60 years.3, 4 Thus, HDT benefits patients at higher risk who achieve complete remission (CR) after induction treatment in the LNH87-2 trial.5 More recently, the Groupe Ouest-Est des Leucémies et des Autres Maladies du Sang reported a cooperative randomized trial comparing HDT plus autologous stem cell support (ASCS) with the standard CHOP regimen in patients up to the age of 60 years with disseminated aggressive lymphoma. The results suggested that HDT plus ASCS is superior to CHOP with an estimated 5-year event-free survival (EFS) at 55%.6

The use of up-front HDT induction instead of consolidative HDT was also tested and seemed to improve survival in poor-risk patients.7, 8, 9 Since 1992, we and others have developed investigational trials, where HDT supported by both hematopoietic growth factors (HGF) and peripheral blood stem cells (PBSC) was used as front-line treatment in patients under 60 years with poor-risk aggressive NHL. These regimens differ from HDT plus ASCS as consolidation treatment by the concept of dose intensity (DI), which was well known to be an independant prognostic factor of cure. We could report a 5-year overall survival (OS) and EFS at 51 and 42%, respectively. We concluded that multiple cycles of high-dose CHOP supported by both HGF and PBSC could cure half of poor-risk NHL patients who have nearly 70% risk of dying of their disease when treated with standard CHOP regimen.10, 11

However, such an issue remains confusing as recent meta-analysis data failed to show an improvement in EFS or OS for patients undergoing early autologous.12

Whatever the chemotherapy schedule used, 30–40% of high-risk NHL patients still remain refractory to treatment or relapse from their disease. These results were all reported before the introduction of rituximab, a chimeric anti-CD20 monoclonal antibody. Rituximab was initially used alone in patients with relapsed or refractory CD20+ DLBCL, and responses could be observed in 30–40% of patients.13 The benefit of the association chemotherapy plus rituximab as front-line treatment in CD20+ DLBCL patients was therefore evaluated.

To date, there are three large phase III trials that clearly demonstrate superior survival for patients with DLBCL treated with chemotherapy plus rituximab over those treated with chemotherapy alone. The GELA study clearly showed that addition of rituximab to the CHOP regimen increases CR rate and prolongs survival in elderly patients with CD20+ DLBCL.14 The ECOG study conducted in a similar population of elderly patients also showed an advantage to associate rituximab to CHOP chemotherapy with a significant improvement in both OS and progression-free survival.15 Chemotherapy plus rituximab is also effective in patients under 60 years with CD20+ DLBCL as recently demonstrated in the Mabthera International Trial. However, this trial was conducted in favorable DLBCL patients as only low-risk and low-intermediate-risk patients were included.16

Since 1999, we have conducted a phase II clinical trial with front-line intensive sequential chemotherapy (ISC) followed by rituximab consolidation in patients under 60 years with poor-prognosis DLBCL (R-ISC 98 trial). We report here the results of 36 patients included in the study.

Patients and methods

Patients

From August 1999 to December 2002, 36 patients were eligible for the R-ISC 98 clinical trial. Inclusion criteria were as follows: age between 18 and 60 years; a diffuse large cell lymphoma according to the WHO classification; and at least two adverse prognostic factors from the age-adjusted IPI (Aa-IPI). Patients with previous cancer and comorbid disease that could interfere with the chemotherapy/immunotherapy regimen were excluded. Patients had to be free of any previous treatment. They all underwent physical examination, whole-body computer tomography scan, bone marrow biopsy and lumbar puncture. Patients were informed of the investigational nature of the study and informed consent was required in accordance with institutional guidelines.

Treatment (Figure 1)

The R-ISC 98 protocol consisted of four cycles of high-dose CEOP delivered at 3-week intervals. The first two cycles (C1, C2) included cyclophosphamide (Cy) at 6000 mg/m2 day (d) 1 (4000 mg/m2 at C2), epirubicin (Epi) at 120 mg/m2 d1, vincristine (Vcr) at 1.4 mg/m2 d1 and prednisone (Pred) at 2 mg/kg/d from d1 to d5. The last two cycles (C3 and C4) used the same drugs with 6000 mg/m2 of Cy, 120 mg/m2 of Epi and 1.4 mg/m2 of Vcr at d1, and 2 mg/kg/d of Pred from d1 to d5. Cycles 3 and 4 also included etoposide at 250 mg/m2 at d1 and d2, and cisplatin at 100 mg/m2 at d1. G-CSF was given from d6 to d12 after each cycle, and cytapheresis were performed after cycle 1. PBSC were infused at d4 after cycles 3 and 4. The projected duration of chemotherapy in R-ISC 98 regimen was 12 weeks, with a planned DI of 1833 mg/m2/week for Cy and 40 mg/m2/week for Epi. Rituximab was planned to be delivered between 4 and 6 weeks after cycle 4, and patients were scheduled to receive 4 weekly infusions of rituximab 375 mg/m2.

Figure 1
figure1

Design of treatment in the R-ISC 98 trial.

Criteria of response

CR was defined as the disappearance of all detectable clinical and radiographic evidence of disease, disappearance of all disease-related symptoms and normalization of biochemical abnormalities assigned to NHL. Unconfirmed CR (CRu) includes patients in CR with residual lymph node mass greater than 1.5 cm in greater transverse diameter that has regressed by more than 75% in the sum of the products of the greatest diameters, or with indeterminate bone marrow. No CR/CRu defined all other situations (partial response, stable disease or progressive disease).17

Statistical methods

The stopping date was set at 1 December 2004. The primary end point of the study was a 3-year EFS of at least 60%, in comparison with the 42% EFS rate observed in our historical series. The secondary end points were OS and response rate. EFS was calculated from the date of diagnosis to the date of progression, relapse or death. OS rates were measured from the date of diagnosis to the date of death. Assessment of response was performed after rituximab, or at any time after stopping treatment. All analyses were performed on an intent-to-treat basis. Survival rates were estimated using the Kaplan and Meïer method. Survival rates are presented with their 95% confidence intervals (95% CI).

Results

Patients characteristics (Table 1)

The R-ISC 98 patients characteristics are listed in Table 1. There were 36 patients with a median age of 42 years (range, 20–59). Thirty-four patients (94%) had a CD20+ DLBCL, whereas two patients presented with null anaplastic large cell lymphoma (ALCL). The Aa-IPI score was at 2 for 23 patients and 3 for 13 patients. The more frequent extranodal localizations were: bone marrow (33%), gastrointestinal tract (20%), bone (16%) and lung (13%). Seven stage IV patients (28%) had two or more extranodal localizations.

Table 1 R-ISC 98 trial, patients characteristics (N=36)

Treatment delivery and toxicity (Tables 2 and 3)

Six patients did not receive the complete chemotherapy regimen because of toxic death (one), disease-related death (one), medical decision (one), patient decision (one) and progressive disease (two). The median chemotherapy duration for the whole population was 13 weeks (range, 12–16). The median DI was 37 mg/m2/week (range, 28–45) for Epi and 1677 mg/m2/week (range, 838–2308) for Cy, with a relative DI (received dose/projected dose) at 92 and 91%, respectively.

Table 2 R-ISC 98 trial, delivery of chemotherapy and rituximab
Table 3 R-ISC 98 trial, hematological toxicity

Collection of PBSC was performed for 33 patients, with a median number of two apheresis per patient (range, 1–3). Thirty-one patients were infused with a cellular product containing a median value of 17 × 106 CD34+ cells/kg (range, 6–107). This dose was split so that patients received approximately 8 × 106 cells/kg with each of the last two cycles.

Among the 30 patients who completed the total schedule of chemotherapy, 24 received the 4 weekly planned infusions of rituximab. Rituximab was initiated after a median duration of 33 days (range, 23–43) lasting the fourth cycle of chemotherapy. Rituximab was not delivered in six patients: progressive disease (two), nul ALCL (two), disease-related death (one) and severe infusional reaction (one).

Toxicity of R-ISC 98 regimen was mostly hematological (Table 3). A grade 4 neutropenia occurred in 100% of patients, and 32/36 needed rehospitalization for intravenous antibiotics treatment. The median duration of rehospitalization was 18 days (range, 4–30) and concerned the whole procedure of treatment. A total of 82 serious adverse events (SAE) were reported to the data management center, with a median of four SAE per patient (range, 1–4). One patient developed a severe rituximab infusional reaction during the first perfusion, and did not receive the subsequent doses.

Response and survival

A complete response (CR+CRu) was achieved in 26/36 patients (72%). Six patients were refractory to treatment and they all died within 4 months. Three patients were in partial response of whom two could achieve a CR after salvage treatment. One patient experienced a fatal lysis syndrome after cycle 1 and was not evaluable for response. With a median follow-up of 30 months (range, 22–64), the estimated 5-year OS rate was 65% (95% CI: 52–84), and the estimated 5-year EFS rate was 63% (95% CI: 50–81) for all patients assessed on an intent-to-treat basis (Figure 2). For patients in response after treatment, the estimated 5-year disease-free survival (DFS) rate was 78% (95% CI: 66–95).

Figure 2
figure2

Survivals observed in the R-ISC 98 trial according to an intent-to-treat basis: overall survival [——]; event-free survival [– –]; disease-free survival [- - -].

Twenty-four patients could receive both chemotherapy and rituximab, 22 were in CR+Cru and two in PR. Four patients (17%) relapsed. With a median follow-up of 30 months (range, 22–60), the estimated 5-year OS and EFS rates in this group were 86% (95% CI: 72–100), and 82% (95% CI: 68–99), respectively (Figure 3).

Figure 3
figure3

Survivals observed for the 24 patients who received both chemotherapy and rituximab in the R-ISC 98 trial: overall survival [- - -]; event-free survival [——].

Discussion

The R-ISC 98 was designed as a phase II study to assess the role of both DI of chemotherapy and rituximab consolidation in order to reduce relapse rate in poor-risk DLBCL, with a primary end point of a 3-year EFS at 60%.

This clinical trial was conducted as a continuum of two previous ISC trials, ISC 92 and ISC 95. Both ISC 92 and ISC 95 trials concerned patients under 60 years with aggressive NHL and high-intermediate and high-risk international prognostic index. With a median follow-up of 7 years among surviving patients, the results of the ISC 92 and ISC 95 trials can be considered complete, with an OS rate ranging between 50 and 55%, and an EFS rate ranging between 45 and 50%. Although the follow-up remains short in the R-ISC 98 trial, the estimated 5-year OS and EFS rates are at 65 and 63%, respectively. This result is in accordance with the primary end point of the study. The R-ISC 98 regimen was feasible with 83% of patients completing the chemotherapeutic schedule. Chemotherapy delivery was optimal, with a relative DI of Epi and Cy at 92 and 91%, respectively. When comparing the R-ISC 98 trial and previous ISC trials, the median DI was similar for anthracyclins, whereas there was a 1.2-fold increase of the Cy DI. However and despite a correct administration of chemotherapy, no significant advantage of R-ISC 98 regimen over ISC 92 or ISC 95 regimen was observed. In fact, the comparison of survivals between the 36 patients of the R-ISC 98 trial and our historical series (ISC 92 and ISC 95) shows no statistically significant difference, either for OS (P=0.98) or EFS (P=0.92). This lack of difference supposes that HDT with stem-cell support among high-risk NHL patients has its limits including both feasability and efficacy. Our data suggest that there could be a maximal effective dose of chemotherapy in patients with poor-risk aggressive NHL.

The R-ISC 98 trial was designed as a combination of high-dose chemotherapy and immunotherapy to reduce the 30–40% failure rate observed when chemotherapy was used alone. The intent-to-treat analysis did not show any advantage to use rituximab after chemotherapy in patients with aggressive DLBCL. This could be owing to the design of the trial. In fact, rituximab was not associated to chemotherapy as front-line treatment, but delayed.

There are few reports in the literature concerning feasability and efficacy of rituximab and HDT as front-line treatment in young patients with high-intermediate-risk and high-risk DLBCL. Rituximab as adjuvant to HDT and autologous stem-cell transplantation was evaluated in a recent phase II trial including 35 patients with various NHL subtypes (DLBCL, transformed lymphoma, mantle cell). Patients in first remission as well as refractory and relapsed patients were included. The authors concluded that rituximab is feasible after HDT without serious adverse consequences. The ability of rituximab to inhibit the minimal residual disease was highlighted by the excellent outcome of this series with a 2-year OS and EFS rates at 88 and 83%, respectively.18 More recently, Zanni et al.19 reported the results of a prospective multicenter phase II study of rituximab-supplemented high-dose sequential chemotherapy with autograft in high-risk DLBCL patients. This study enrolled 91 patients and the results showed an 80% of CR rate with a 4,3-year OS and EFS projections at 80 and 74%, respectively. Milpied et al.20 also reported the results of a prospective pilot trial testing front-line high-dose chemotherapy combined with rituximab for young adults with high-risk DLBCL. Among the 42 patients enrolled in the study, the treatment was completed in 30 patients with a CR rate at 64% and a 2-year probability of OS and EFS at 79 and 59%, respectively. In contrast to our study, rituximab was combined to chemotherapy in these two trials. The authors concluded that simultaneous use of rituximab and high-dose chemotherapy is feasible. Nevertheless, both CR rate and survival curve projections compare favorably with the poor outcome usually observed in high-risk DLBCL patients managed with chemotherapy without rituximab.

Finally, there is no available phase II or phase III trial including a large cohort of young patients with poor-risk DLBCL receiving both rituximab and HDT as front-line treatment to date. The main conclusion of our study remains that rituximab as adjuvant to HDT is feasible with no unexpected toxicity. When added to intensive chemotherapy, rituximab does not seem to improve the outcome of high-risk patients. However, our results as others are too preliminary, and althought no conclusion could be assessed, this is still encouraging comparing to standard pre-rituximab therapy. Moreover, HDT may need to be re-evaluated with regard to the results obtained with less toxic approaches as dose-dense R-CHOP every 14 days.

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Coso, D., Sebban, C., Boulat, O. et al. A phase II trial of rituximab as adjuvant to intensive sequential chemotherapy in patients under 60 years with untreated poor-prognosis diffuse large B-cell lymphoma. Bone Marrow Transplant 38, 217–222 (2006). https://doi.org/10.1038/sj.bmt.1705414

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Keywords

  • aggressive lymphoma
  • high-dose chemotherapy
  • rituximab
  • survival

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