RIBOMUSTIN Powder for solution for infusion Ref.[50298] Active ingredients: Bendamustine

Pharmacotherapeutic group: Antineoplastic agents, alkylating agents
ATC code: L01AA09

Mechanism of Action

Bendamustine hydrochloride is an alkylating antitumour agent with unique activity. The antineoplastic and cytocidal effect of bendamustine hydrochloride is based essentially on a cross-linking of DNA single and double strands by alkylation. As a result, DNA matrix functions and DNA synthesis and repair are impaired. Bendamustine is active against both quiescent and dividing cells.

The active substance revealed no or very low cross-resistance in human tumour cell lines with different resistance mechanisms.

The exact mechanism of action of bendamustine remains unknown.

Clinical trials

Chronic Lymphocytic Lymphoma

The safety and efficacy of RIBOMUSTIN were evaluated in an open-label, randomised, controlled multicenter trial (02CLLIII) comparing RIBOMUSTIN to chlorambucil. The trial was conducted in 319 previously-untreated patients with Binet Stage B or C CLL requiring treatment. Need-to-treat criteria included hematopoietic insufficiency, B-symptoms, rapidly progressive disease or risk of complications from bulky lymphadenopathy. Patients with autoimmune hemolytic anemia or autoimmune thrombocytopaenia, Richter’s syndrome, or transformation to prolymphocytic leukemia were excluded from the study.

The patient populations in the RIBOMUSTIN and chlorambucil treatment groups were balanced with regard to the following baseline characteristics: age (median 63 vs. 66 years), gender (63% vs. 61% male), Binet stage (72% vs. 71% Binet B), lymphadenopathy (79% vs. 82%), enlarged spleen (77% vs. 78%), enlarged liver (49% vs. 45%), hypercellular bone marrow (80% vs. 73%), lymphocyte count (mean 68.9 × 10⁹/L vs. 62.4 × 10⁹/L). Ninety percent of patients in both treatment groups had immuno-phenotypic confirmation of CLL (CD5, CD23 and either CD19 or CD20 or both).

Patients were randomly assigned to receive either RIBOMUSTIN at 100 mg/m², administered intravenously over a period of 30 minutes on Days 1 and 2 or chlorambucil at 0.8 mg/kg (Broca’s normal weight) administered orally on Days 1 and 15 of each 28-day cycle.

Efficacy endpoints of objective response rate and progression-free survival were calculated using a pre-specified algorithm based on NCI working group criteria for CLL.

The results of this open-label randomised study demonstrated a higher rate of overall response and a longer progression-free survival for RIBOMUSTIN compared to chlorambucil (see Table 10). Survival data are not mature.

Table 10. Efficacy data for CLL reported in study 02CLLIII:

CI = confidence interval
^* CLL response was valued as CR when all of the following criteria were met for at least 8 weeks after first response was observed:

• Enlarged lymph nodes are no longer detectable by palpation (X-ray or ultrasound are optional);
• Absence of hepatomegaly or splenomegaly, confirmed by palpation. CT and ultrasound were optional;
• No disease symptoms (B-symptoms);
• Blood counts:
  • Lymohocytes ≤4.0 × 10⁹/L
  • Neutrophils ≥1.5 × 10⁹/L
  • Platelets >100 × 10⁹/L
  • Hemoglobin > 11 g/dL (without blood transfusion)
• Bone marrow biopsy (histology and cytology) was to be performed 8 weeks after meeting the above criteria. The bone marrow had to be at least normocellular for age, with less than 30% lymphocytes.

^** nPR was defined as described for CR with lymphocyte being less than 30% in the bone marrow sample but still showing focal infiltration.
^† PR was defined as ≥50% decrease in peripheral blood lymphocyte count from the pretreatment baseline value, and either ≥50% reduction of enlarged lymph nodes (total of affected lymph nodes), or 50% reduction of hepatomegaly and/or spelomegaly, as well as one of the following haematologic improvements: neutrophils ≥ 1.5 × 109/L or 50% improvement over baseline, platelets >100 × 109/L or 50% improvement over baseline, haemoglobin >11g/dL or 50% improvement over baseline without transfusions, for a period of at least 8 weeks.
^†† PFS was defined as time from randomization to progression or relapse after inter-current remission or death from any cause.

Progression free survival based upon the Independent Committee Response Assessment (ICRA) criteria by treatment group in the follow-up report (ITT analysis) in Study 02CLLIII is shown in Figure 1.

Figure 1. Progression-Free Survival:

Previously Untreated Advanced Indolent Non-Hodgkin’s Lymphoma (NHL) and Mantle Cell Lymphoma (MCL)

The safety and efficacy of RIBOMUSTIN in previously untreated advanced indolent NHL and MCL have been assessed in a Phase III trial.

The NHL1-2003 study is a prospective phase III, multicentre, randomised (1:1), non-inferiority, open-label clinical study of 549 patients, conducted to determine that RIBOMUSTIN (90 mg/m²) in combination with rituximab 375 mg/m² is non-inferior to CHOP (cycles every 3 weeks of cyclophosphamide 750 mg/m², doxorubicin 50 mg/m², and vincristine 1.4 mg/m² on day 1, and prednisone 100 mg/day for 5 days) plus rituximab 375 mg/m². Rituximab was administered in both treatment arms on day 1 of each cycle. Treatment was administered for a maximum of 6 cycles. Baseline demographics and patient characteristics are summarized in Table 11.

Table 11. Summary of Baseline Patient and Disease Characteristics in the NHL1-2003 Study:

Data are median (range), n (), or n/N ().
B-R=bendamustine plus rituximab; R-CHOP=CHOP plus rituximab; LDH=lactate dehyrogenase; IPI=International Prognostic Index; FLIPI-Folicular Lymphoma International Prognostic Index.
^* Waldenström macroglobulinaemia.

A significant benefit for progression-free survival was shown with B-R vs. R-CHOP for all histological subtypes except for marginal-zone lymphoma (see Figure 2).

Figure 2: Progression-free survival in histological subtypes of follicular lymphoma (A), mantlecell lymphoma (B), marginal-zone lymphoma (C), and Walderstrom’s macrglobulinaemia (D):

B-R=bendamustine plus rituximab; R-CHOP=Chop plus rituximab

The improvement in progression-free survival with B-R was independent of age, concentration of lactate dehydrohgenase (LDH), and FLIPI score (Table 12). Overall survival did not differ between the two treatment groups.

The rate of overall response did not differ between the treatment groups (93% for B-R vs. 91% for R-CHOP); however the rate of complete response was significantly increased in patients in the B-R group (104 [40%] vs. 76 [30%]; p=0.021).

Table 12: Exploratory subgroup analysis to assess the PFS benefit of B-R vs. R-CHOP:

PFS=progression-free survival; LDH=lactate dehydrogenase; FLIPI=Follicular Lymphoma International Prognostic Index; HR=hazard ratio.

Relapsed / Refractory NHL

The efficacy of RIBOMUSTIN was evaluated in a single arm study (SDX-105-03) of 100 patients with indolent B-cell NHL that had progressed during or within six months of treatment with rituximab or a rituximab-containing regimen. Patients were included if they relapsed within 6 months of either the first dose (monotherapy) or last dose (maintenance regimen or combination therapy) of rituximab. All patients received RIBOMUSTIN intravenously at a dose of 120 mg/m², on Days 1 and 2 of a 21-day treatment cycle. Patients were treated for up to 8 cycles.

The median age was 60 years, 65% were male, and 95% had a baseline WHO performance status of 0 or 1. Major tumour subtypes were follicular lymphoma (62%), diffuse small lymphocytic lymphoma (21%), and marginal zone lymphoma (16%). Ninety-nine percent of patients had received previous chemotherapy, 91% of patients had received previous alkylator therapy, and 97% of patients had relapsed within 6 months of either the first dose (monotherapy) or last dose (maintenance regimen or combination therapy) of rituximab. Efficacy was based on the assessments by a blinded independent review committee (IRC) and included overall response rate (complete response + complete response unconfirmed + partial response) and duration of response (DR) as summarized in Table 13.

Table 13. Efficacy data for progressing NHL* reported in study SDX-105-03:

CI = confidence interval
^* IRC assessment was based on modified International Working Group response criteria (IWG-RC). Modifications to IWG-RC specified that a persistently positive bone marrow in patients who met all other criteria for CR would be scored as PR. Bone marrow sample lengths were not required to be ≥20 mm.

Progression-free survival (PFS), a secondary endpoint in this study, was comparable across all patient groups defined by baseline characteristics (Table 14). The median PFS was 72 weeks in patients without previous alkylator therapy, and 51 weeks in patients who were sensitive to the previous alkylator therapy or chemotherapy. In the patients who had received previous radioimmunotherapy, the PFS was 53 weeks. Disease characteristics at baseline (FLIPI risk category, number of lymph nodal sites, or bulky disease) did not markedly affect duration of PFS.

Table 14. Progression-Free Survival by Baseline Characteristics:

CI = confidence interval; NA = not applicable