Friday, November 25, 2011

New treatment for DLCBL.

For a long time it has been accepted wisdom that R-CHOP is as good as anything else for diffuse large cell lymphoma. More intensified regimens are possible, but a meta-analysis of some years ago found no advantage for them.

In today's Lancet there is a paper from France reporting a trial that suggests that this is no longer true. Here is the abstract:

We did an open-label randomised trial comparing dose-intensive rituximab, doxorubicin, cyclophosphamide, vindesine, bleomycin, and prednisone (R-ACVBP) with subsequent consolidation versus standard rituximab, doxorubicin, cyclophosphamide, vincristine, and prednisone (R-CHOP). Random assignment was done with a computer-assisted randomisation-allocation sequence with a block size of four. Patients were aged 18–59 years with untreated diffuse large B-cell lymphoma and an age-adjusted international prognostic index equal to 1. Our primary endpoint was event-free survival. Our analyses of efficacy and safety were of the intention-to-treat population. This study is registered with, number NCT00140595.

One patient withdrew consent before treatment and 54 did not complete treatment. After a median follow-up of 44 months, our 3-year estimate of event-free survival was 81% (95% CI 75–86) in the R-ACVBP group and 67% (59–73) in the R-CHOP group (hazard ratio [HR] 0·56, 95% CI 0·38–0·83; p=0·0035). 3-year estimates of progression-free survival (87% [95% CI, 81–91] vs 73% [66–79]; HR 0·48 [0·30–0·76]; p=0·0015) and overall survival (92% [87–95] vs 84% [77–89]; HR 0·44 [0·28–0·81]; p=0·0071) were also increased in the R-ACVBP group. 82 (42%) of 196 patients in the R-ACVBP group experienced a serious adverse event compared with 28 (15%) of 183 in the R-CHOP group. Grade 3–4 haematological toxic effects were more common in the R-ACVBP group, with a higher proportion of patients experiencing a febrile neutropenic episode (38% [75 of 196] vs 9% [16 of 183).

Compared with standard R-CHOP, intensified immunochemotherapy with R-ACVBP significantly improves survival of patients aged 18–59 years with diffuse large B-cell lymphoma with low-intermediate risk according to the International Prognostic Index. Haematological toxic effects of the intensive regimen were raised but manageable.

Here is an editorial from Julie Vose on the trial

In The Lancet, Christian Récher and colleagues report the findings of their randomised trial of dose-intense chemo therapy with rituximab, doxorubicin,
cyclo phos pha mide, vindesine, bleomycin, and pred nisone (R-ACVBP) versus rituximab, cyclophosphamide, doxo rubicin, vincristine, and prednisone

379 patients aged 18–59 years with diffuse large B-cell lymphoma and an age-adjusted International Prognostic Index of 1 were randomly assigned to receive either dose-intense chemotherapy with four cycles of R-ACVBP with a subsequent sequential consolidation with two cycles of methotrexate and calcium folinate rescue, four cycles of rituximab with etoposide and ifosfamide, and two cycles of cytarabine or to receive eight cycles of R-CHOP at intervals of 21 days. On the basis of previous studies in this population of patients, 3-year event-free survival would be expected to range from 70% to 80%.3 The study by Récher and colleagues had a 3-year event-free survival of 67% (95% CI 59–73) in the R-CHOP group, which seems slightly low.

In terms of the trial’s primary endpoint, event-free survival, there was an advantage to R-ACVBP versus R-CHOP (hazard ratio 0·56, 95% CI 0·38–0·83, p=0·0035). The dose-intense R-ACVBP regimen with sequential consolidation has an expected higher rate of toxic effects, with significantly increased haematological toxic effects over R-CHOP identified in this and previous trials. Also, the additional chemotherapeutic drugs, higher haemopoietic growth factor use, and higher neutropenic fever rate would lead to higher health-care resource consumption. Therefore, this dose-intense regimen should only be used in patients in whom the expected relapse rate is sufficient to justify the higher toxic effects and cost profile.

Possible risk stratification factors for the use of more dose-intense treatments include: International Prognostic Index, bulky disease, gene expression profiling results (eg, activated B cell v germinal centre B cell), oncogenic profile (eg, MYC positive or so-called double hit lymphomas), or interim PET positivity. Clinical features, such as International Prognostic Index or bulky disease, are the easiest to use in clinical practice. However, more biologically relevant assays, such as genetic profiles, interim PET, or a combination approach, might be more accurate in predicting which patients are at higher risk. Once patients at higher risk are identified by biologically relevant assays or procedures, future study designs will address the use of these biological prognostic factors for direction of treatment by dose intensification or pathway-directed drugs.

Some of the newer pathway-directed drugs seem to be less toxic and, if earlier-phase studies show that they can be combined with standard chemotherapy, this might represent a more directed treatment for patients at higher risk. Examples of drugs tested in this manner include lenalidomide, bortezomib, or drugs directed at
the B-cell signalling pathway. In the meantime, who should receive dose-intensified
treatment? Récher and colleagues report convincing evidence that patients younger than 59 years with an International Prognostic Index of 1, who can tolerate the
additional toxic effects of R-ACVBP with consolidation, do have a better 3-year event-free survival. Unfortunately, some of the drugs in the regimen are not available in all countries and testing of substitute drugs or modifications would be needed. Furthermore, a direct comparison of other dose-intensive chemo therapy regimens such as a dose-adjusted regimen of rituximab, etoposide, vincristine,
cyclophosphamide, and doxorubicin (R-EPOCH) versus the R-ACVBP regimen is needed, pending the results of the present R-CHOP versus dose-adjusted R-EPOCH protocol being done by the United States Cooperative Group Mechanism (registered with, number NCT00118209). Although we continue to identify subsets of patients at higher risk, further international clinical trials are needed to assess the best individualised approach to treatment for these patients.

Of course for CLL patients, we have to question whether the standard treatment for Richter syndrome should remain R-CHOP, but I fear that patients with Richter Syndrome may not be able to withstand this intensity of treatment.

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