A closer look at Bendamustine in CLL

Have I been too hard on Bendamustine? This alkylating agent is more than 30 years old and was discovered in communist East Germany, where it has been used for all that time. It has now been introduced to the West as if it were a new drug with all the attendant costs. What made me cross about it was the randomized clinical trial which compared it to chlorambucil. There seemed to me to be some chicanery involved in the trial. The median progression-free survival in the chlorambucil arm was only 8.8 months which compared with the almost 2 years that we found in LEF CLL4. The explanation was clear; they had used a smaller dose of chlorambucil; but more than that they had concealed how much smaller. The LRF CLL4 trial had used 70mg per sq m per month, whereas the bendamustine trial had used 0.8 mg/kg twice monthly. Hidden in the methods section and not spotted by anyone except me was the fact that this was not actual weight, but 'ideal weight'. I am sure that everyone is aware that most people's ideal weight is less than their actual weight and this would therefore have led to relative uderdosing.

Still, I should not remain in a huff about it but try and look objectively at whether it is a good drug for its target diseases. I therefore turn to a new review of Bendamustine published in a supplement to Seminars in Hematology, by Rummel and Gregory (2011, 48:S24-S36). A word of caution - Supplements to major journals seldom have such a high standard of peer-review and may indeed have been paid for by the Pharmaceutical industry.

The first point they make is that rituximab sensitizes CD20+ B-cell lymphoma lines to chemotherapy-induced apoptosis in vitro. This includes Bendamustine induced killing as well as a variety of other agents. It is also important to make the point at this stage that Bendamustine is not a simple alkylating agent. As I have written before it does have other useful properties, though the fancied resemblance of its chemical structure to fludarabine does not mean that it behaves like a mixture of alkylating agent and purine analog. Those claims have not been born out by experimental data.

The earliest study of bendamustine as a single agent in CLL was a phase II study of 23 patients (10 relapsed or refractory, 13 untreated) with a total dose of 250-300 mg/sq m every month. The overall response rate was 75% with 36% CRs. At this dose it was myelotoxic with 51% Grade 3/4 leukopenia and 3 deaths from sepsis. Four subsequent phase I/II studies with doses ranging from 140 to 300 mg/sq m/month had response rates between 56 and 93% (overall 69%) and CR rates between 7 and 29% (overall 14%).

The optimum dose depends on how much previous treatment has been given. Treatment naive patients can safely receive 200mg/sq m/m whereas those who are heavily pretreated especially those who have had previous fludarabine should receive no more than 140 mg/sq m/m. Nevertheless the first randomised phase 2 study in previously treated patients (who had mainly had chlorambucil) received 200mg/sq m/m. This was compared with fludarabine 125 mg/sq m/m. In this study Bendamuctin outperformed fludarabine (ORR 78% v 65%; CRR 29% v 10%; PFS 83 weeks ve 64 weeks) but grade 3/4 leukopenia was worse in the Bendamustine arm, though not the infection rate.

The same dose of Bendamustine was used for treatment naive patients in the pivotal study used for FDA approval (this was the comparison with chlorambucil that I have already referred to). The overall response rate was 68% (31% CR) and the PFS was 54 months v 8.8 months. The rate of infection was approximately three times as great in the Bendamustine arm which reflected the much higher grade 3/4 hematological toxicity (40% v 19%).

There have also been trials of Bendamustine in combination. A trial of escalating dose of Bendamustine (80 to 240 mg) with mitozantrone (8 to 10 mg) had an overall response rate of 86% (CR 27%) but even at 150 mg the grade 3/4 neutropenia was 89% suggesting that a smaller dose is required for previously treated patients. A phase 1/2 of Bendamustine 160, mitozantrone 10 and rituximab 375 was tested in 54 patients with various B cell tumors. Treatment was continued only until there was an objective response. Among 21 patients with CLL 95% got an objective response (the majority within 2 cycles). The CR rate was 23%.

Subsequently there has been a German phase 2 study of Bendamustine 140 + rituximab 375-500 in 81 patients with relapsed/refractory patients. Only 12% got grade 3/4 nutropenia, but 3 died of infection. The response rate was 77% (14.5% CR). Significantly there was a 44% response rate in del 17p patients and a 78% response rate in fludarabine refractory patients. However we are still waiting for response duration and late complications of this trial.

A similar study in 117 previously untreated patients uses a slightly higher dose of Bendamustine (180 mg/sq m/m) with the same dose of rituximab. The ORR was 91% (31% CR) with 76% still in remission at 18 months. Three of seven patients with del 17p had a PR. Grade 3/4 neutropenia was present in 6.5% of cycles and grade 3/4 infections in 5% of cycles though 2 patients died of infection.

There are ongoing phase III studies of this regimen compared with FCR in 550 previously untreated patients in Germany and another comparison of BR with CHL-R in 600 previously untreated patients. At MD Anderson there is a FBR trial in previously treated patients and several other studies of combinations of Bendamustine with rituximab, ofatumumab and alemtuzumab.

There is preclinical evidence of synergy between Bendamustine and Fludarabine.

So in summary, despite my misgivings about how Bendamustine has been brought to the market, it does seem to have an advantage over standard alkylating agents in producing rather more CRs and a higher response rate. Dosing is crucial, however, The haematological toxicity is much higher than is seen with chlorambucil. Some years ago there was a trial of chlorambucil in Yugoslavia, which pushed the drug to toxic levels and produced results that were superior to those of fludarabine. This may be what we are seing with Bendamustine. In previously treated patients the maximum tolerated dose is 140 mg/sq m/month and in untreated patients it is 200 mg/ sq m/month. In combinations with other chemothereutic drugs this should be reduced.

It does have some activity in del 17p disease but there are better options and it should certainly not be first choice.

Bendamustine has to be given iv which is a disadvantage over chlorambucil, cyclphosphamide and fludarabine.