Response: Re: High-Dose Chemotherapy with Autotransplantation in AL Amyloidosis: A Flawed Meta-analysis

Abstract

The primary claim put forward by Dr. Mehta et al. is that there is “reliable” evidence that autologous stem cell transplantation is superior to conventional chemotherapy. Any reasonable observer would conclude with the main findings of our systematic review that there is a paucity of reliable data on the efficacy of autologous stem cell transplantation in AL amyloidosis, and this is precisely the conclusion of our manuscript [1Mhaskar R. Kumar A. Behera M. Kharfan-Dabaja M.A. Djulbegovic B. Role of high-dose chemotherapy and autologous hematopoietic cell transplantation in primary systemic amyloidosis: a systematic review.Biol Blood Marrow Transplant. 2009; 15: 893-902Abstract Full Text Full Text PDF PubMed Scopus (40) Google Scholar].Dr. Mehta's main critique relate to omission of an article by Dispenzieri et al. [2Dispenzieri A. Kyle R.A. Lacy M.Q. et al.Superior survival in primary systemic amyloidosis patients undergoing peripheral blood stem cell transplantation: a case-control study.Blood. 2004; 103: 3960-3963Crossref PubMed Scopus (216) Google Scholar] from the systematic review, and inclusion of this article would have somehow changed the findings. Unfortunately, Mehta and colleagues did not read the inclusion criteria of the systematic review attentively. The study by Dispenzieri et al. [2Dispenzieri A. Kyle R.A. Lacy M.Q. et al.Superior survival in primary systemic amyloidosis patients undergoing peripheral blood stem cell transplantation: a case-control study.Blood. 2004; 103: 3960-3963Crossref PubMed Scopus (216) Google Scholar] is a retrospective study as stated in the first sentence of the Methods section. The inclusion criteria of this systematic review [1Mhaskar R. Kumar A. Behera M. Kharfan-Dabaja M.A. Djulbegovic B. Role of high-dose chemotherapy and autologous hematopoietic cell transplantation in primary systemic amyloidosis: a systematic review.Biol Blood Marrow Transplant. 2009; 15: 893-902Abstract Full Text Full Text PDF PubMed Scopus (40) Google Scholar] clearly mentions inclusion of prospective studies only. Nevertheless, for the sake of academic discussion, even if we included retrospective case-controlled studies, we would not know which of the studies published by Dispenzieri et al. are to be included. In 2001, Dispenzieri et al. [3Dispenzieri A. Lacy M.Q. Kyle R.A. et al.Eligibility for hematopoietic stem-cell transplantation for primary systemic amyloidosis is a favorable prognostic factor for survival.J Clin Oncol. 2001; 19: 3350-3356PubMed Google Scholar] published a study concluding that there is no difference in outcomes between conventional chemotherapy and autologous stem-cell transplantation. Using essentially the same population of amyloid patients but different selection criteria for controls, in 2004, the authors reported that autologous stem cell transplant might be superior [2Dispenzieri A. Kyle R.A. Lacy M.Q. et al.Superior survival in primary systemic amyloidosis patients undergoing peripheral blood stem cell transplantation: a case-control study.Blood. 2004; 103: 3960-3963Crossref PubMed Scopus (216) Google Scholar]. Additionally, in both the articles Dispenzieri et al. [2Dispenzieri A. Kyle R.A. Lacy M.Q. et al.Superior survival in primary systemic amyloidosis patients undergoing peripheral blood stem cell transplantation: a case-control study.Blood. 2004; 103: 3960-3963Crossref PubMed Scopus (216) Google Scholar, 3Dispenzieri A. Lacy M.Q. Kyle R.A. et al.Eligibility for hematopoietic stem-cell transplantation for primary systemic amyloidosis is a favorable prognostic factor for survival.J Clin Oncol. 2001; 19: 3350-3356PubMed Google Scholar] called for randomized-controlled trials to definitively address the role of transplant in AL amyloidosis as the correct methodologic approach to settle differences highlighted in variety of nonrandomized controlled trials. Consequently, we are puzzled by this apparent reversal of this stand, as expressed in the letter by Dr. Mehta and colleagues.Mehta et al. further state that, centers in France [4Jaccard A. Moreau P. Leblond V. et al.High-dose melphalan versus melphalan plus dexamethasone for AL amyloidosis.N Engl J Med. 2007; 357: 1083-1093Crossref PubMed Scopus (427) Google Scholar] have limited experience in treating primary AL amyloidosis, and in his opinion that is the main reason for high treatment-related mortality [4Jaccard A. Moreau P. Leblond V. et al.High-dose melphalan versus melphalan plus dexamethasone for AL amyloidosis.N Engl J Med. 2007; 357: 1083-1093Crossref PubMed Scopus (427) Google Scholar] while claiming the superiority of the specialized centers in treating primary systemic AL amyloidosis. The proclaimed superiority of the specialized centers can be equally explained by selection bias, as these centers may treat selective group of patients (ie, good-risk patients) as originally pointed out by Dispenizeri et al. [3Dispenzieri A. Lacy M.Q. Kyle R.A. et al.Eligibility for hematopoietic stem-cell transplantation for primary systemic amyloidosis is a favorable prognostic factor for survival.J Clin Oncol. 2001; 19: 3350-3356PubMed Google Scholar]. Therefore, if indeed, the specialized centers have better outcomes with autologous transplantation in comparison with other centers, the onus of proving such claim rests with physicians practicing in such centers (eg, by undertaking an RCT to test this hypothesis).In another incidence of misstatement of facts, Dr. Mehta and colleagues refer to a meta-analysis published in the Journal of the National Cancer Institute as “erroneous” without referring to the author's reply, which highlights the lack of basic understanding of the meta-analytic techniques [5Kumar A. Mohamed K.-D. Djulbegovic B. Response: Re: Single versus tandem autotransplantation in myeloma: a call for the retraction of a flawed meta-analysis.J Natl Cancer Inst. 2009; (in press)PubMed Google Scholar]. Of note, the editorial board of Journal of the National Cancer Institute extensively reviewed the manuscript and reached a decision that the meta-analysis was properly performed, and thus we strongly believe represents important addition to the existing knowledge on treatment of patients with multiple myeloma [5Kumar A. Mohamed K.-D. Djulbegovic B. Response: Re: Single versus tandem autotransplantation in myeloma: a call for the retraction of a flawed meta-analysis.J Natl Cancer Inst. 2009; (in press)PubMed Google Scholar, 6Kumar A. Kharfan-Dabaja M.A. Glasmacher A. Djulbegovic B. Tandem versus single autologous hematopoietic cell transplantation for the treatment of multiple myeloma: a systematic review and meta-analysis.J Natl Cancer Inst. 2009; 101: 100-106Crossref PubMed Scopus (97) Google Scholar].In summary, critique of our article by Dr. Mehta et al. [1Mhaskar R. Kumar A. Behera M. Kharfan-Dabaja M.A. Djulbegovic B. Role of high-dose chemotherapy and autologous hematopoietic cell transplantation in primary systemic amyloidosis: a systematic review.Biol Blood Marrow Transplant. 2009; 15: 893-902Abstract Full Text Full Text PDF PubMed Scopus (40) Google Scholar] is compromised by poor understanding of the hierarchy of evidence and how reliable data are generated in clinical research. The key message our systematic review highlights is the absence of good methodological quality data on the efficacy of autologous transplantation in AL amyloidosis, and the urgent need for adequately powered and good methodological quality RCTs to conclusively address the issue related to the efficacy of autologous transplantation for AL amyloidosis. We cannot understand how any researcher with even a minimum understanding of the principles of evidence-based medicine would conclude otherwise. We understand that Mehta and colleagues do not agree with the results of our meta-analyses [1Mhaskar R. Kumar A. Behera M. Kharfan-Dabaja M.A. Djulbegovic B. Role of high-dose chemotherapy and autologous hematopoietic cell transplantation in primary systemic amyloidosis: a systematic review.Biol Blood Marrow Transplant. 2009; 15: 893-902Abstract Full Text Full Text PDF PubMed Scopus (40) Google Scholar, 6Kumar A. Kharfan-Dabaja M.A. Glasmacher A. Djulbegovic B. Tandem versus single autologous hematopoietic cell transplantation for the treatment of multiple myeloma: a systematic review and meta-analysis.J Natl Cancer Inst. 2009; 101: 100-106Crossref PubMed Scopus (97) Google Scholar]. However, we hope that in the future critiques will be based on true scientific merit rather than distorted attacks using unreasonable language. The primary claim put forward by Dr. Mehta et al. is that there is “reliable” evidence that autologous stem cell transplantation is superior to conventional chemotherapy. Any reasonable observer would conclude with the main findings of our systematic review that there is a paucity of reliable data on the efficacy of autologous stem cell transplantation in AL amyloidosis, and this is precisely the conclusion of our manuscript [1Mhaskar R. Kumar A. Behera M. Kharfan-Dabaja M.A. Djulbegovic B. Role of high-dose chemotherapy and autologous hematopoietic cell transplantation in primary systemic amyloidosis: a systematic review.Biol Blood Marrow Transplant. 2009; 15: 893-902Abstract Full Text Full Text PDF PubMed Scopus (40) Google Scholar]. Dr. Mehta's main critique relate to omission of an article by Dispenzieri et al. [2Dispenzieri A. Kyle R.A. Lacy M.Q. et al.Superior survival in primary systemic amyloidosis patients undergoing peripheral blood stem cell transplantation: a case-control study.Blood. 2004; 103: 3960-3963Crossref PubMed Scopus (216) Google Scholar] from the systematic review, and inclusion of this article would have somehow changed the findings. Unfortunately, Mehta and colleagues did not read the inclusion criteria of the systematic review attentively. The study by Dispenzieri et al. [2Dispenzieri A. Kyle R.A. Lacy M.Q. et al.Superior survival in primary systemic amyloidosis patients undergoing peripheral blood stem cell transplantation: a case-control study.Blood. 2004; 103: 3960-3963Crossref PubMed Scopus (216) Google Scholar] is a retrospective study as stated in the first sentence of the Methods section. The inclusion criteria of this systematic review [1Mhaskar R. Kumar A. Behera M. Kharfan-Dabaja M.A. Djulbegovic B. Role of high-dose chemotherapy and autologous hematopoietic cell transplantation in primary systemic amyloidosis: a systematic review.Biol Blood Marrow Transplant. 2009; 15: 893-902Abstract Full Text Full Text PDF PubMed Scopus (40) Google Scholar] clearly mentions inclusion of prospective studies only. Nevertheless, for the sake of academic discussion, even if we included retrospective case-controlled studies, we would not know which of the studies published by Dispenzieri et al. are to be included. In 2001, Dispenzieri et al. [3Dispenzieri A. Lacy M.Q. Kyle R.A. et al.Eligibility for hematopoietic stem-cell transplantation for primary systemic amyloidosis is a favorable prognostic factor for survival.J Clin Oncol. 2001; 19: 3350-3356PubMed Google Scholar] published a study concluding that there is no difference in outcomes between conventional chemotherapy and autologous stem-cell transplantation. Using essentially the same population of amyloid patients but different selection criteria for controls, in 2004, the authors reported that autologous stem cell transplant might be superior [2Dispenzieri A. Kyle R.A. Lacy M.Q. et al.Superior survival in primary systemic amyloidosis patients undergoing peripheral blood stem cell transplantation: a case-control study.Blood. 2004; 103: 3960-3963Crossref PubMed Scopus (216) Google Scholar]. Additionally, in both the articles Dispenzieri et al. [2Dispenzieri A. Kyle R.A. Lacy M.Q. et al.Superior survival in primary systemic amyloidosis patients undergoing peripheral blood stem cell transplantation: a case-control study.Blood. 2004; 103: 3960-3963Crossref PubMed Scopus (216) Google Scholar, 3Dispenzieri A. Lacy M.Q. Kyle R.A. et al.Eligibility for hematopoietic stem-cell transplantation for primary systemic amyloidosis is a favorable prognostic factor for survival.J Clin Oncol. 2001; 19: 3350-3356PubMed Google Scholar] called for randomized-controlled trials to definitively address the role of transplant in AL amyloidosis as the correct methodologic approach to settle differences highlighted in variety of nonrandomized controlled trials. Consequently, we are puzzled by this apparent reversal of this stand, as expressed in the letter by Dr. Mehta and colleagues. Mehta et al. further state that, centers in France [4Jaccard A. Moreau P. Leblond V. et al.High-dose melphalan versus melphalan plus dexamethasone for AL amyloidosis.N Engl J Med. 2007; 357: 1083-1093Crossref PubMed Scopus (427) Google Scholar] have limited experience in treating primary AL amyloidosis, and in his opinion that is the main reason for high treatment-related mortality [4Jaccard A. Moreau P. Leblond V. et al.High-dose melphalan versus melphalan plus dexamethasone for AL amyloidosis.N Engl J Med. 2007; 357: 1083-1093Crossref PubMed Scopus (427) Google Scholar] while claiming the superiority of the specialized centers in treating primary systemic AL amyloidosis. The proclaimed superiority of the specialized centers can be equally explained by selection bias, as these centers may treat selective group of patients (ie, good-risk patients) as originally pointed out by Dispenizeri et al. [3Dispenzieri A. Lacy M.Q. Kyle R.A. et al.Eligibility for hematopoietic stem-cell transplantation for primary systemic amyloidosis is a favorable prognostic factor for survival.J Clin Oncol. 2001; 19: 3350-3356PubMed Google Scholar]. Therefore, if indeed, the specialized centers have better outcomes with autologous transplantation in comparison with other centers, the onus of proving such claim rests with physicians practicing in such centers (eg, by undertaking an RCT to test this hypothesis). In another incidence of misstatement of facts, Dr. Mehta and colleagues refer to a meta-analysis published in the Journal of the National Cancer Institute as “erroneous” without referring to the author's reply, which highlights the lack of basic understanding of the meta-analytic techniques [5Kumar A. Mohamed K.-D. Djulbegovic B. Response: Re: Single versus tandem autotransplantation in myeloma: a call for the retraction of a flawed meta-analysis.J Natl Cancer Inst. 2009; (in press)PubMed Google Scholar]. Of note, the editorial board of Journal of the National Cancer Institute extensively reviewed the manuscript and reached a decision that the meta-analysis was properly performed, and thus we strongly believe represents important addition to the existing knowledge on treatment of patients with multiple myeloma [5Kumar A. Mohamed K.-D. Djulbegovic B. Response: Re: Single versus tandem autotransplantation in myeloma: a call for the retraction of a flawed meta-analysis.J Natl Cancer Inst. 2009; (in press)PubMed Google Scholar, 6Kumar A. Kharfan-Dabaja M.A. Glasmacher A. Djulbegovic B. Tandem versus single autologous hematopoietic cell transplantation for the treatment of multiple myeloma: a systematic review and meta-analysis.J Natl Cancer Inst. 2009; 101: 100-106Crossref PubMed Scopus (97) Google Scholar]. In summary, critique of our article by Dr. Mehta et al. [1Mhaskar R. Kumar A. Behera M. Kharfan-Dabaja M.A. Djulbegovic B. Role of high-dose chemotherapy and autologous hematopoietic cell transplantation in primary systemic amyloidosis: a systematic review.Biol Blood Marrow Transplant. 2009; 15: 893-902Abstract Full Text Full Text PDF PubMed Scopus (40) Google Scholar] is compromised by poor understanding of the hierarchy of evidence and how reliable data are generated in clinical research. The key message our systematic review highlights is the absence of good methodological quality data on the efficacy of autologous transplantation in AL amyloidosis, and the urgent need for adequately powered and good methodological quality RCTs to conclusively address the issue related to the efficacy of autologous transplantation for AL amyloidosis. We cannot understand how any researcher with even a minimum understanding of the principles of evidence-based medicine would conclude otherwise. We understand that Mehta and colleagues do not agree with the results of our meta-analyses [1Mhaskar R. Kumar A. Behera M. Kharfan-Dabaja M.A. Djulbegovic B. Role of high-dose chemotherapy and autologous hematopoietic cell transplantation in primary systemic amyloidosis: a systematic review.Biol Blood Marrow Transplant. 2009; 15: 893-902Abstract Full Text Full Text PDF PubMed Scopus (40) Google Scholar, 6Kumar A. Kharfan-Dabaja M.A. Glasmacher A. Djulbegovic B. Tandem versus single autologous hematopoietic cell transplantation for the treatment of multiple myeloma: a systematic review and meta-analysis.J Natl Cancer Inst. 2009; 101: 100-106Crossref PubMed Scopus (97) Google Scholar]. However, we hope that in the future critiques will be based on true scientific merit rather than distorted attacks using unreasonable language. High-Dose Chemotherapy with Autotransplantation in AL Amyloidosis: A Flawed Meta-analysisBiology of Blood and Marrow TransplantationVol. 16Issue 1PreviewThe conclusions of the meta-analysis by Mhaskar et al. [1] evaluating high-dose chemotherapy with autotransplantation in immunoglobulin light chain amyloidosis are compromised by the omission of a key publication [2] and flawed analytical techniques. The meta-analysis included 1 prospective randomized study of 100 patients and 2 nonrandomized studies containing a total of 49 patients. The pooled results of these 3 studies showed superior overall survival (OS) with conventional chemotherapy (CC) compared to autologous hematopoietic stem cell transplantation (AHSCT) (hazard ratio 1.79; P=.018). Full-Text PDF Open Archive