|Year : 2008 | Volume
| Issue : 1 | Page : 49-52
Long-term outcome of patients with AL amyloidosis treated with high-dose melphalan and stem cell transplantation
Aarti Gupta, Lalit Kumar
Department of Medical Oncology, Institute Rotary Cancer Hospital, All India Institute of Medical Sciences, New Delhi-110029, India
|Date of Web Publication||30-May-2009|
Department of Medical Oncology, Institute Rotary Cancer Hospital, All India Institute of Medical Sciences, New Delhi-110029
Source of Support: None, Conflict of Interest: None
|How to cite this article:|
Gupta A, Kumar L. Long-term outcome of patients with AL amyloidosis treated with high-dose melphalan and stem cell transplantation. Indian J Med Paediatr Oncol 2008;29:49-52
|How to cite this URL:|
Gupta A, Kumar L. Long-term outcome of patients with AL amyloidosis treated with high-dose melphalan and stem cell transplantation. Indian J Med Paediatr Oncol [serial online] 2008 [cited 2020 Oct 23];29:49-52. Available from: https://www.ijmpo.org/text.asp?2008/29/1/49/51445
| Summary|| |
Primary systemic amyloidosis results due to deposition of clonal immunoglobulin light chains in various organs resulting in organ failure and subsequent death. Melphalan and Prednisolone has been the standard first line therapy until late 1990's when aggressive treatment with high dose chemotherapy (HDT) followed by peripheral blood stem cell transplantation (PBSCT) showed higher response rate and improved overall survival.  In the present study  , authors at Boston Medical Center, USA studied the longterm outcome of HDT followed by PBSCT.
Between July 1994-July1997, 80 patients with a median age of 56 years (range, 29 to 71) diagnosed to have primary systemic amyloidosis and SWOG (South Western Oncology Group) performance status of 1 (0 to 3) entered the study. 48% had cardiac involvement and on an average two organs (range=1-5) were involved with amyloid. All patients met eligibility criteria  : confirmed tissue diagnosis of amyloidosis, clear evidence of clonal plasma cell dyscrasia, age > 18 years, performance status (SWOG 0-2), cardiac function >40%, pulmonary function (O 2 saturation >=95% on room air), hemodynamic stability (baseline systolic blood pressure >=90 mm Hg). Patients on peritoneal or hemodialysis for renal failure were not excluded if they met eligibility criteria. Stem cell mobilization was done with G-CSF (granulocyte colony stimulating factor) and HDT included intravenous melphalan (100-200 mg/m 2 ) followed by stem cell transplant 24-72 hours after completion of chemotherapy. Response evaluation included-hematological assessment and was defined as absence of monoclonal protein in serum and urine by immunofixation electrophoresis together with a bone marrow biopsy showing less than 5% plasma cells without clonal dominance of k or l light chain isotypes and was done at end of one year. Transplant related mortality (TRM) was defined as death within 100 days of transplant including mobilization and collection days. 17 patients could not be evaluated as they died within 1 st year of study (14% due to transplant related mortality and 8% due to disease per se). Statistical analysis of survival was done using Kaplan-Meier method.
Among 63 evaluable patients, 32 (51%) achieved complete hematological response (CHR) with a relapse rate of 34% within 2.5 years and survival at 10 years being 53% in this subgroup. Median survival has not reached yet. Relapses occurred in 34% within 2.5 years and were treated with second line therapy. 31 (49%) patients who did not achieve hematological CR formed the other subgroup and had median survival of 50 months and probability of survival at 10 years being 6%. The survival at 10 years in both these subgroups was statistically significant (p<0.001). The median survival was higher (p=0.20) in the patients receiving full dose melphalan (200 mg / m 2 ) versus modified dose.
In patients who achieved CR, 15/32 (47%) have died compared to mortality rate of 97% (30 of 31) in patients who did not achieve CR. Causes of death in the subgroup achieving CHR were progressive disease (n=6), therapy related myelodysplastic syndrome and acute myelogenous leukemia (n=1), solid tumours (n=2) and organ dysfunction despite CHR (n=6).
Overall, the median survival for these 80 patients was 57 months and long-term survival beyond 10 years was achieved in 18 patients (23%) of which 17 belonged to group who achieved CHR and 1 belonged to the non CHR group. Thus, achievement of complete hematologic remission following high dose chemotherapy and stem cell transplantation was the most powerful predictor of long term survival.
| Comments|| |
Kyle et al  in a randomized study first demonstrated the superiority of melphalan (M) and prednisolone (P) in the treatment of primary systemic amyloidosis. Promising results of HDT/PBSCT in myeloma and ability to reverse the disease process formed the basis for its therapeutic option in primary systemic amyloidosis. The earliest pilot study was published in 1996  , which included a cohort of 5 patients followed by expanded series5 of 25 patients and since, then many more pilot and prospective studies have been published. However, many controversies have reined regarding high dose therapy (HDT) mainly because of selection bias and high transplant related mortality. Though a number of studies ,,,,,,,,,, have shown benefits but follow up was short.
PBSCT results in improved performance status and quality of life in survivors by (i) reduction in monoclonal proteins (ii) regression of amyloid deposition from organs (iii) significant symptomatic response (iv) improved overall survival. However, high transplant related mortality in SCT ranges from 6.5% to 26% mainly due to (i) poor performance status (ii) advanced cardiac involvement& poor ejection fraction (iii) more number of organs involved (iv) age more than 70 years (v) dialysis dependent renal failure (vi) history of gastrointestinal bleeding. Other issues like pretransplant chemotherapy regimens and the choice between chemotherapy versus HDT still remains unclear.
Among carefully selected patients, the results of PBSCT are encouraging. Present study in this regard confirms these observations. Patients who achieved CHR post PBSCT had higher survival at 10 years follow up. 17 out of 32 patients (53%) are alive from this subgroup. These results are consistent with a study from UK  , which shows estimated survival of 59% for those who survived day +100 post transplant and were in CR post-PBSCT with a follow up of more than 8 years. In the present study, among patients who did not achieve CHR, estimated survival at 10 years was 6%. [Table 1] describes important studies on high dose chemo and PBSCT for AL amyloidosis.
Transplant related mortality is the major complication in HDT, which is as high as 10-20% in single centre studies and more in multicentric studies. Mortality was higher in early 90's compared to late 1990's. In the present study though the patients underwent transplant in early 90's, transplant related mortality (14%) was less than contemporary candidates mainly because of adoption of more stringent eligibility criteria for selection of candidates and it being a single centre study. The causes of death for transplant related mortality include multi-organ failure, GI bleeding, hypotension, cardiac arrythmias.
Review of transplant studies supports the author's conclusion that transplant definitely induces hematological and organ response and improves overall and median survival. Long term outcome is high in patients who achieve CHR. More than 2 organs involvement with amyloid, advanced cardiac disease, non achievement of hematological remission are important factors affecting survival and outcome negatively. However, more stringent criteria need to be adopted to lessen the transplant related mortality.
| References|| |
|1.||Kyle RA, Gertz MA, Greipp PR et al. A trial of three regimens for primary amyloidosis: colchicine alone, melphalan and prednisone, and melphalan, prednisone, and colchicines. N Engl J Med. 1997;336:1202-7. |
|2.||Sanchorwala V, Skinner M, Quillen K. Long-term outcome of patients with AL amyloidosis treated with high-dose melphalan and stem-cell transplantation. Blood 2007;110:3561-3. |
|3.||Sanchorawala V, Wright DG, Seldin DC et al. An overview of the use of high-dose melphalan with autologous stem cell transplantation for the treatment of AL amyloidosis. Bone Marrow Transplant 2001;28:637-42. |
|4.||Comenzo RL, Vosburgh E, Simms et al. Doseintensive melphalan with blood stem cell support for the treatment of AL amyloidosis: one-year follow-up in five patients. Blood 1996;88:2801-6. |
|5.||Comenzo RL, Vosburgh E, Falk RH. Dose-intensive melphalan with blood stem-cell support for the treatment of AL (amyloid light-chain) amyloidosis: survival and responses in 25 patients. Blood 1998;91:3662-70. |
|6.||Gertz MA, Lacy MQ, Dispenzieri A et al. Stem cell transplantation for the management of primary systemic amyloidosis. Am J Med. 2002;113:549-55. |
|7.||Dispenzieri A, Kyle RA, Lacy MQ et al. Superior survival in primary systemic amyloidosis patients undergoing peripheral blood stem cell transplantation: a case-control study. Blood 2004;103:3960-3. |
|8.||Skinner M, Sanchorawala V, Seldin DC et al. Highdose melphalan and autologous stem-cell transplantation in patients with AL amyloidosis: an 8-year study. Ann Intern Med. 2004;140:85-93. |
|9.||Porrata LF, Gertz MA, Litzow MR et al. Clin Cancer Res. Early lymphocyte recovery predicts superior survival after autologous hematopoietic stem cell transplantation for patients with primary systemic amyloidosis. Clin Cancer Res 2005;11:1210-8. |
|10.||Leung N, Leung TR, Cha SS et al. Excessive fluid accumulation during stem cell mobilization: a novel prognostic factor of first-year survival after stem cell transplantation in AL amyloidosis patients. Blood 2005;106:3353-7. |
|11.||Seldin DC, Anderson JJ, Skinner M et al. Successful treatment of AL amyloidosis with high-dose melphalan and autologous stem cell transplantation in patients over age 65. Blood 2006;108:3945-7. |
|12.||Goodman HJ, Gillmore JD, Lachmann HJ et al. Outcome of autologous stem cell transplantation for AL amyloidosis in the UK. Br J Haematol. 2006;134:417-25. |
|13.||Perfetti V, Siena S, Palladini G et al. Long-term results of a risk-adapted approach to melphalan conditioning in autologous peripheral blood stem cell transplantation for primary (AL) amyloidosis. Haematologica 2006;91:1635-43. |
|14.||Perz JB, Rahemtulla A, Giles C et al. Long-term outcome of high-dose melphalan and autologous stem cell transplantation for AL amyloidosis. Bone Marrow Transplant 2006;37:937-43. |
|15.||Vesole DH, Pιrez WS, Akasheh M et al. High-dose therapy and autologous hematopoietic stem cell transplantation for patients with primary systemic amyloidosis: a Center for International Blood and Marrow Transplant Research Study. Mayo Clin Proc. 2006;81:880-8. |