Best therapy for primary amyloidosis, a not-yet-solved question

We read with interest the paper from Dispenzieri et al¹  in the May 15, 2004, issue of Blood on a case-match-control study comparing overall survival of 63 primary amyloidosis (AL) patients undergoing transplantation with 63 patients not undergoing transplantation. In contrast, we do not agree with J. Mehta when he wrote, in the accompanying editorial, that “The data from the Mayo Clinic and Boston University are impressive enough to make a prospective, randomised study of high-versus conventional-dose therapy in amyloidosis scientifically unattractive and practically impossible.”

In their paper, Dispenzieri et al compared the survival of amyloidosis patients who received high-dose therapy in the Mayo Clinic in the late 1980s and early 1990s with the survival of matched control patients who were treated by various therapeutic regimens, mainly melphalan and prednisone (MP), but also colchicine and vitamin E, in the early 1980s. From our point of view this study only supports the fact that for selected AL patients, in a center with a great experience, intensive treatment with stem cell support is better that treatments used in the control group. The authors themselves are much more careful than Mehta in their conclusions.

We considered 4 years ago that a prospective randomized comparison of intensive and conventional treatment was needed to solve the issue of the respective merits of both therapeutic strategies in the different risk-groups of AL patients. We thought at this time, as Mehta does, that to compare intensive treatment with MP was unattractive and we choose, as conventional treatment, an association of melphalan and high-dose dexamethasone (M-Dex: melphalan 10 mg/m² and dexamethasone 40 mg for 4 days each month up to 18 months), hypothesizing that this regimen could provide more frequent and more rapid hematological responses than MP, with subsequent improvement in involved organ function and survival.

The results of a close regimen (same schedule and dose for dexamethasone, melphalan 0.22 mg/kg instead of 10 mg/m,² treatment up to 9 months) was recently reported in Blood by Palladini et al,³  with a response rate much higher than the one known with MP, 67% of patients achieving a hematological response and 33% a complete remission, versus 28% overall responses for MP.⁴  Functional improvement of the organs involved was observed in 48% of treated patients. This good efficacy seems to have a positive impact on survival and to compare favorably with the one reported after high-dose therapy with stem cell support.⁵ 

Our experience with M-Dex is similar, with a good response rate, which is probably a little bit lower than with high-dose therapy but with fewer treatment-related deaths, especially in a multicentric setting. Moreover, responses with M-Dex can be very rapid, with a complete response after 1 course for some patients, and most responses occurring before 6 months.

Thus, in contrast to Mehta, we believe that benefit/risk ratios of high-dose versus an effective conventional therapy like M-Dex must be compared in a randomized fashion in patients with primary amyloidosis. In our randomized trial, which is ongoing, M-Dex is compared to a high-dose regimen using melphalan (200 or 140 mg/m², depending on age and clinical status) supported with autologous blood stem cells previously collected after mobilization with granulocyte colony-stimulating factor (G-CSF) alone. More than 80 of the 100 patients planned have been included already in 25 centers, demonstrating that such a study is realizable. We hope that it will be completed at the end of this year and will help to solve the still-persisting issue of dose intensity in AL.