This is the second article in a 4-part series on bendamustine. This article discusses the efficacy of bendamustine for patients with chronic lymphocytic leukemia (CLL) and non-Hodgkin lymphoma (NHL) in the registration studies cited in the US product labeling.1 Subsequent articles in this series will discuss the safety of bendamustine and describe ongoing clinical investigations of the agent.
Chronic Lymphocytic Leukemia
CLL, the most common form of leukemia in Europe and North America, is a disorder in which morphologically mature but immunologically less mature lymphocytes accumulate in the blood, bone marrow, and lymphatic tissues.2 According to the American Cancer Society, an estimated 15,680 new cases of CLL will occur in 2013 (9720 in men and 5960 in women), and 4580 people will die of the disease.3
The American Cancer Society estimates that the 5-year relative survival rate for patients with CLL is 82%.3 However, the clinical course of patients with CLL is heterogeneous, with some patients experiencing rapid disease progression and others living for decades without requiring treatment. The clinical staging systems developed by Rai et al4 and Binet et al5 are used to classify patient stage and predict survival (Table 1).
For many years, alkylating agents, especially chlorambucil, were considered the drugs of choice for first-line treatment of CLL.9 More recently, first-line treatment is frequently conducted with chlorambucil, fludarabine, or fludarabine plus cyclophosphamide, either alone or in combination with rituximab.10 Studies have shown significantly higher response rates, longer duration of remission, and longer progression-free survival (PFS) rates in patients treated initially with fludarabine than in those treated with chlorambucil.11,12 However, the median survival times did not differ among the patients treated with fludarabine and chlorambucil.
Table 1
Bendamustine in CLL
On March 20, 2008, the FDA approved bendamustine hydrochloride (Treanda), an alkylating agent administered IV, for the treatment of patients with CLL. As the basis for its approval, the FDA used the results of a randomized, open-label, parallel-group, multicenter trial comparing bendamustine with chlorambucil as first-line treatment for previously untreated patients with advanced CLL.1,10 Because of this, the US product label points out that efficacy relative to first-line therapies other than chlorambucil has not been established.1 Chlorambucil was chosen as the comparator for this study because it was approved for first-line use in CLL in all participating countries when the pivotal trial was planned in 2001.
The trial was conducted in 301 patients (153 on bendamustine and 148 on chlorambucil) with Binet stage B or C (Rai stages I-IV) CLL requiring treatment.1
Need-to-treat criteria included1:
- Hematopoietic insufficiency
- B symptoms (such as weight loss of 10% or more, drenching night sweats, extreme fatigue, or unexplained fever of 100.5°F or higher)
- Rapidly progressive disease
- Risk of complications from bulky lymphadenopathy
Exclusion criteria included1:
- Autoimmune hemolytic anemia
- Autoimmune thrombocytopenia
- Richter’s syndrome
- Transformation to prolymphocytic leukemia
Patients were randomly assigned to receive either bendamustine 100 mg/m2 IV on days 1 and 2 every 28 days or chlorambucil 0.8 mg/kg (Broca’s normal weight) orally on days 1 and 15 every 28 days (Figure 1).1 Up to 6 cycles were administered to each patient.
The patient populations in the bendamustine and chlorambucil treatment groups were balanced with regard to baseline characteristics, as shown in Table 2. Ninety percent of patients in both treatment groups had immunophenotypic confirmation of CLL (CD5, CD23, and either CD19, CD20, or both).1
Figure 1
Table 2
Efficacy Results
A National Cancer Institute (NCI)-sponsored working group had formulated standardized guidelines in 1996 for criteria related to response to be used in clinical trials in CLL.13 The efficacy analyses were based on this NCI-sponsored working group’s criteria, as follows1:
- Overall response rate (ORR) included patients with a best response of complete response (CR), nodular partial response (nPR), and partial response (PR) (ORR = CR + nPR + PR)
- CR was defined as peripheral lymphocyte count ≤4.0 × 109/L, neutrophils ≥1.5 × 109/L, platelets >100 × 109/L, hemoglobin >11.0 g/dL without transfusions, absence of palpable hepatosplenomegaly, lymph nodes ≤1.5 cm, <30% lymphocytes without nodularity in at least a normocellular bone marrow, and absence of B symptoms. The clinical and laboratory criteria were required to be maintained for a period of at least 56 days
- nPR was defined as described for CR with the exception that the bone marrow biopsy shows persistent nodules
- PR was defined as ≥50% decrease in peripheral lymphocyte count from the pretreatment baseline value, and either ≥50% reduction in lymphadenopathy, or ≥50% reduction in the size of spleen or liver, as well as 1 of the following hematologic improvements: neutrophils ≥1.5 × 109/L or 50% improvement over baseline, platelets >100 × 109/L or 50% improvement over baseline, hemoglobin >11.0 g/dL or 50% improvement over baseline without transfusions, for a period of at least 56 days
ORR was higher in patients in the bendamustine treatment group compared with those in the chlorambucil group (Figure 2). In the bendamustine group, an ORR of 59% (90 of 153 patients) was achieved, with 73 of 153 (48%) achieving a PR, 4 of 153 (3%) an nPR, and 13 of 153 (8%) a CR, while in the chlorambucil group an ORR of 26% (38 of 148 patients) was achieved, with 37 of 148 (25%) achieving a PR, 0 patients an nPR, and 1 of 148 (<1%) a CR.1
The median PFS (defined as time from randomization to progression or death from any cause) was 18 months (95% CI, 11.7-23.5) for bendamustine versus 6 months (95% CI, 5.6-8.6) for chlorambucil (hazard ratio 0.27; 95% CI, 0.17-0.43; P<.0001).1 Survival data were not mature. Kaplan-Meier estimates of PFS comparing the bendamustine and chlorambucil treatment groups are shown in Figure 3.1
Figure 2
Figure 3
B-Cell Non-Hodgkin Lymphoma
According to the American Cancer Society, 69,740 new cases of NHL (both B-cell and T-cell) are expected (37,600 in men and 32,140 in women) in 2013, and 19,020 people will die of these diseases.3 The subtypes of NHL are characterized in 2 ways14:
- By the type of cells (B cells, T cells, or natural killer cells) they affect
- By how rapidly or slowly the disease progresses: indolent (slow growing) or aggressive (fast growing)
B-cell lymphomas make up most (about 85%) of NHLs in the United States.15,16 B-cell lymphomas with indolent histologies, and their relative incidences, include14: - Follicular lymphoma (22% of all NHL)
- Mucosa-associated lymphatic tissue lymphoma (7.5% of all NHL)
- Small cell lymphocytic lymphoma/CLL (7% of all NHL)
- Lymphoplasmacytic lymphoma and Waldenström macroglobulinemia (<2% of all NHL)
- Nodal marginal zone B-cell lymphoma (<2% of all NHL)
Treatment of indolent NHL depends on the histology and stage of the disease. The stages of NHL are listed in Table 3.14 Because indolent NHL is often asymptomatic in early stages, it is generally advanced (stage III or IV) at the time of detection.
Over the past decade, the addition of rituximab, an anti-CD20 monoclonal antibody, to conventional chemotherapy has revolutionized the treatment of B-cell malignancies. Studies have established rituximab as a viable treatment option in patients with relapsed or refractory indolent NHL,17 and treatment guidelines from the National Comprehensive Cancer Network now recommend a rituximab-based regimen as initial therapy for patients with B-cell lymphoma.18 However, patients tend to become refractory to rituximab over time. In addition, patients with indolent B-cell lymphoma who are treated with rituximab-chemotherapy combinations often develop rituximab resistance, so innovative treatments were sought for this rituximab-refractory patient population.19
Table 3
Figure 4
Table 4
Figure 5
Bendamustine in Indolent B-Cell Non-Hodgkin Lymphoma
On October 31, 2008, the FDA approved bendamustine for the treatment of patients with indolent B-cell NHL that has progressed during or within 6 months of treatment with rituximab or a rituximab-containing regimen.1 As the basis for its approval, the FDA used the results of a single-arm study of 100 patients with indolent B-cell NHL who had progressed during or within 6 months of treatment with rituximab or a rituximab-containing regimen.19 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 bendamustine IV over 60 to 120 minutes 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 (Figure 4).1,19
Seventy-six percent of patients had advanced-stage disease at enrollment, and the median number of prior chemotherapy regimens was 2 (range, 0-6 regimens).19 The baseline patient demographics and disease characteristics are shown in Table 4.1,19 Ninety-seven percent of patients had relapsed within 6 months of either the first dose (monotherapy) or last dose (maintenance regimen or combination therapy) of rituximab.1
Efficacy Results
Efficacy was assessed by a blinded independent review committee using the modified International Working Group response criteria (IWG-RC) for NHL.20 Modifications to the 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. The end points were defined as follows:
- ORR was defined as the proportion of patients who achieved as their best response a CR, an unconfirmed CR (CRu), and a partial response (PR)
- Duration of response was defined as the time from the first documentation of response until disease progression, death, or change of therapy
In this population of patients with B-cell NHL who were previously treated with and resistant to rituximab-containing regimens, an ORR of 74% (74 of 100 patients) was achieved with bendamustine monotherapy, with 57 of 100 (57%) achieving a PR, 4 of 100 (4%) a CRu, and 13 of 100 (13%) a CR (Figure 5).1
In addition, single-agent bendamustine provided durable responses that lasted a median of 9.2 months.1
Part 3 in the Series
The next article in this series will discuss the safety data in patients with CLL and NHL reported in the registration studies cited in the bendamustine US product labeling.
References
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