Improvement of Long-Term Survival after High-Dose Melphalan in Patients with Light Chain Amyloidosis Responding to Induction Chemotherapy.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 3334-3334 ◽  
Author(s):  
Anja Mangatter ◽  
Stefan O Schoenland ◽  
Marion Hansberg ◽  
Tilmann Bochtler ◽  
Sascha Dietrich ◽  
...  
Keyword(s):  
Stem Cell ◽  
Induction Chemotherapy ◽  
Light Chain ◽  
Long Term Results ◽  
High Dose ◽  
Al Amyloidosis ◽  
Karnofsky Performance Score ◽  
Organ Response ◽  
High Dose Melphalan

Abstract Introduction: High-dose melphalan (HDM) with autologous hematopoietic stem cell transplantation (SCT) is an effective treatment for patients (pts) with systemic light chain (AL) amyloidosis. The goal is to achieve complete remission (CR) of the underlying clonal plasma cell disorder which leads to organ response and prolongs overall survival (OS). Most centers use granulocyte colony-stimulating factor (G-CSF) to mobilize stem cells and proceed directly to SCT. However, it is not well investigated whether induction chemotherapy (IC) prior to HDM might improve the long-term results of this intensive treatment approach (Perz et al., BJH 2004; Sanchorawala et al, BMT 2004). Patients and methods: We performed a retrospective analysis in 100 AL amyloidosis pts transplanted in our centre since 1998. 94 pts received HDM as part of an upfront treatment. Major eligibility criteria were cardiac disease < NYHA stage III and performance status (PS) < 3. Median age of pts at SCT was 57 years (range 35–69 years). Fifty-five pts received a median of 2 IC cycles using VAD-like chemotherapy or pulsed high-dose dexamethasone within two prospective clinical trials. In 93 pts stem cell collection was performed after mobilization chemotherapy. Due to age >65 years or reduced PS (Karnofsky performance score <80%) the HDM dosage was reduced from 200 to 140 mg/m2 in 16 pts. HDM dosage was adapted to impaired renal function (creatinine clearance <60 ml/min to 85%, <45 ml/min to 75%, <30 ml/min to 70%, in dialysis pts to 50%) in 27 pts. Hematological remission (HR: CR or partial remission (PR)) and organ response were evaluated using Consensus Criteria (Gertz et al. Am J Hematol 2005). Results: Median follow-up since stem cell mobilization is 28 months (range 10–126). Transplant-related mortality was very low with 3% and could be reduced significantly since 2004 (1998 – 2004 vs 2005 – 2007, 7% vs. 0%, p=0.05). Median OS has not been reached. CR after HDM was achieved in 42/95 evaluable pts (44%) and PR in 35%. This resulted in an improved OS for HR pts (CR vs. PR vs. SD: median OS not reached vs. 88 vs. 22 months, respectively, p<0.001, Figure 1a). HR post SCT led to organ response in 40/92 evaluable pts (43%) and stabilization of organ function in 47% of pts. Of the 55 pts with IC 23 pts (42%) had achieved HR at SCT. Patients with IC had a higher CR rate after HDM (58% vs 29%, p<0.01). Consecutively, pts with HR at SCT showed an increased CR rate post HDM (70% vs 33%, p<0.005). This resulted in a significant prolonged OS (median not reached vs. 5 years, p<0.0001, Figure 1b). Pts receiving full-dose HDM had a longer OS (p=0.02) as well. Conclusion: Patients with AL amyloidosis who respond to pre-transplant IC have an excellent prognosis after HDM. This finding facilitates identification of those patients who particularly benefit from SCT and warrant prospective studies with new and more effective drugs for induction therapy to confirm and even improve these promising results. Figure Figure

scholarly journals Outcome of AL amyloidosis after high-dose melphalan and autologous stem cell transplantation: long-term results in a series of 421 patients

Blood ◽  
2011 ◽  
Vol 118 (16) ◽  
pp. 4346-4352 ◽  
Author(s):  
Maria Teresa Cibeira ◽  
Vaishali Sanchorawala ◽  
David C. Seldin ◽  
Karen Quillen ◽  
John L. Berk ◽  
...  
Keyword(s):  
Stem Cell ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Autologous Stem Cell Transplantation ◽  
Complete Response ◽  
Long Term Results ◽  
High Dose ◽  
Al Amyloidosis ◽  
Organ Response ◽  
High Dose Melphalan

Abstract Previous studies have suggested that, in patients with AL amyloidosis treated with high-dose melphalan and autologous stem-cell transplantation (HDM/SCT), the greatest benefit is seen in those patients achieving a hematologic complete response (CR). We analyzed a series of 421 consecutive patients treated with HDM/SCT at a single referral center and compared outcomes for patients with and without CR. Treatment-related mortality was 11.4% overall (5.6% in the last 5 years). By intention-to-treat analysis, the CR rate was 34% and the median event-free survival (EFS) and overall survival (OS) were 2.6 and 6.3 years, respectively. Eighty-one patients died within the first year after HDM/SCT and were not evaluable for hematologic and organ response. Of 340 evaluable patients, 43% achieved CR and 78% of them experienced an organ response. For CR patients, median EFS and OS were 8.3 and 13.2 years, respectively. Among the 195 patients who did not obtain CR, 52% achieved an organ response, and their median EFS and OS were 2 and 5.9 years, respectively. Thus, treatment of selected AL patients with HDM/SCT resulted in a high organ response rate and long OS, even for those patients who did not achieve CR.

Short and long-term outcome of treatment with high-dose melphalan and stem cell transplantation for multiple myeloma-associated AL amyloidosis

2009 ◽  
Vol 89 (6) ◽  
pp. 579-584 ◽  
Author(s):  
Saulius Girnius ◽  
David C. Seldin ◽  
Martha Skinner ◽  
Kathleen T. Finn ◽  
Karen Quillen ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Stem Cell ◽  
Stem Cell Transplantation ◽  
High Dose ◽  
Al Amyloidosis ◽  
Term Outcome ◽  
Long Term Outcome ◽  
Short And Long Term ◽  
High Dose Melphalan

High Dose Melphalan with Autologous Stem Cell Transplantation Overcomes Poor Prognosis of Primary Amyloidosis

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 1350-1350
Author(s):  
Simrit Parmar ◽  
Mubeen Khan ◽  
Gabriela Rondon ◽  
Nina Shah ◽  
Qaiser Bashir ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Stem Cell ◽  
Plasma Cells ◽  
High Dose ◽  
Al Amyloidosis ◽  
Hematologic Response ◽  
Bone Marrow Plasma ◽  
Organ Response ◽  
High Dose Melphalan

Abstract Abstract 1350 Background: Systemic Primary AL Amyloidosis is a rare but potentially fatal disease resulting from tissue deposits of amyloid fibrils derived from monoclonal immunoglobulin light chains. High-dose melphalan followed by autologous hematopoietic stem cell transplant (auto HCT) is associated with hematologic and organ responses and improved survival. Methods: In this retrospective analysis we identified 46 patients with primary AL amyloidosis who received auto HCT between 01/1998 to 05/2010 at MDACC. Organ responses were determined using Amyloidosis Consensus Criteria. Results: The median age at auto HSCT was 56 years (34-74) where 61% were males and 35% were older than 60 years of age. 61% had lambda light chain restriction and only 4% had cytogenetic abnormalities. Disease characteristics are summarized in Table 1. The median time from diagnosis to auto HCT was 6.6 months (2.2-29.4 months). 22 pts (47.8%) had one organ, 19 pts (41.3%) had 2 organ and 4 pts (8.7%) had 3 organ involvement. 11 pts (23.9%) had heart and 35 pts (76.1%) had kidney involvement. The median follow up from the time of diagnosis was 22.4 months and from time of auto HCT was 16.7 months. High dose Melphalan dose was 200mg/m2 in 24 pts (52%) and 140mg/m2 in 22 (47.8%). There were 4 early deaths and 4 pts whose follow up was less than 3 months and their response was not assessed. Out of the 38 evaluable patients, the post-transplant organ responses were as follows ≥PR 25(66%), ≥stable disease 35(92%) (Table2). The hematologic responses were: CR=5 (13%), ≥VGPR=10(26%), ≥PR=26 (68%), ≥SD=37(97%). One patient had progressive disease. There was a correlation between organ response and hematologic response (chi square;p<10-3). The day-100 treatment related mortality (TRM) was 8.7% and 1-yr TRM was 13%. The median progression-free (PFS) and overall survival (OS) from auto HCT was 73.8 months and not reached (from transplant). The median PFS and OS from diagnosis were 93 months and 59.8 months respectively. In multivariate analysis, heart involvement (p=0.01), female sex (p=0.011), age ≥60 years (p=0.002), bone marrow plasma cells≥10% (p=0.043) and Beta-2 microglobulin>3.5mg/l (p=0.02) were associated with poor OS. Improved OS correlated with organ response (52.6 vs 11.4 months; p=0.01) and hematologic response (52.6 vs.6.1months; p=0.002). Hemoglobin <10 g/dl (p=0.047), bone marrow plasma cells≥10% (p=0.043) and age≥60 years (p=0.075) were associated with shorter PFS. Hematologc response (p=0.48) and organ response (p=0.12) were not associated with improved PFS. Conclusion: In this analysis the outcome of patients with primary systemic AL amyloidosis was durable with auto HCT with acceptable mortality risk and improved survival. Disclosures: No relevant conflicts of interest to declare.

Early Serum Free Light Chain Responses Following High-Dose Melphalan and Stem Cell Transplantation for AL Amyloidosis Predict Treatment Outcomes.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 1160-1160
Author(s):  
Vaishali Sanchorawala ◽  
Daniel G. Wright ◽  
Karen Quillen ◽  
Catherine Fisher ◽  
Martha Skinner ◽  
...  
Keyword(s):  
Stem Cell ◽  
Treatment Outcomes ◽  
Light Chain ◽  
Free Light Chain ◽  
High Dose ◽  
Al Amyloidosis ◽  
Serum Free ◽  
Serum Free Light Chain ◽  
Treatment Responses ◽  
High Dose Melphalan

Abstract AL amyloidosis is caused by a clonal plasma cell dyscrasia and characterized by widespread, progressive deposition of amyloid fibrils derived from monoclonal Ig light chains, leading to multisystem organ failure and death. Aggressive treatment of AL amyloidosis with high-dose melphalan followed by autologous stem cell transplant (HDM/SCT) can induce hematologic and clinical remissions and extend survival. Several approaches have been used to define hematologic responses following HDM/SCT and other forms of treatment. The standard definition of a hematologic complete response (CR) that we have used requires that there be no evidence of a persistent monoclonal gammopathy by immunofixation electrophoresis (IFE) of serum and urine proteins, or of a persistent plasmacytosis or plasma cell clonality in a bone marrow biopsy by immunohistochemistry. Others have defined hematologic responses according to reductions in free light chain (FLC) measurements. Treatment responses as defined by both criteria correlate with survival and clinical improvement following HDM/SCT. We have carried out a prospective analysis of HDM/SCT treatment outcomes for patients with AL amyloidosis to determine the extent to which early FLC responses within weeks of treatment predict hematologic CR, as defined by our standard criteria. Serum free light chain concentrations (FLC) were measured by a sensitive nephelometric immunoassay in 31 patients with AL amyloidosis, between 2003–2005, 1–3 weeks after treatment with HDM/SCT. Hematologic responses, as defined by standard criteria, as well as FLC responses were subsequently determined at 3, 6 and 12 months. Serum FLC levels or κ/λ FLC ratios were abnormal and informative in 28 patients (90%) prior to HDM/SCT, and these patients were included in subsequent analyses. Twenty patients (71%) achieved normalization of abnormal serum FLC levels or ratios within 1–3 weeks of undergoing HDM/SCT. Of these 20 patients, 13 patients (65%) subsequently achieved a hematologic CR as defined by standard criteria, while 7 (35%) did not, within 3 months following HDM/SCT. In contrast, none of the 8 patients with no demonstrable FLC response within 1–3 weeks of HDM/SCT, were found to have achieved a hematologic CR subsequently. In conclusion, meaningful quantitative FLC responses (or lack of response) can be detected within weeks following HDM/SCT treatment that predict hematologic responses, as defined subsequently by standard criteria based on IFE and marrow studies (p=0.0018 by chi square analysis). Moreover, a lack of an early FLC response predicts for hematologic non-CR. We anticipate that prospective studies of FLC responses in HDM/SCT and other clinical trials for AL amyloidosis will eventually lead to more rapid assessment of treatment responses that will guide therapeutic decisions.

Durable Responses to Lenalidomide (Revlimid®) in Patients with AL Amyloidosis: Follow Up of a Phase II Trial.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 192-192 ◽  
Author(s):  
David C. Seldin ◽  
Michael Rosenzweig ◽  
Kathleen T. Finn ◽  
Salli Fennessey ◽  
Anthony Shelton ◽  
...  
Keyword(s):  
Long Term Results ◽  
Plasma Cell Dyscrasia ◽  
High Dose ◽  
Al Amyloidosis ◽  
Treatment Protocols ◽  
Results Of Treatment ◽  
Kaplan Meier ◽  
High Dose Melphalan

Abstract AL amyloidosis is a clonal plasma cell dyscrasia in which misfolded immunoglobulin light chains deposit in tissues and produce organ failure and death. Untreated, median survival is short. Melphalan-based regimens can produce hematologic remissions and improvement in organ function; more than 20% of patients treated with high dose melphalan and autologous stem cell transplantation (HDM/SCT) have survived more than 10 years (Blood, in press). The combination of lenalidomide and dexamethasone can also produce partial and complete hematologic responses (Blood2007;109:492–496). Here we report on remission duration and long-term results of treatment in the original 34 patients and an additional 9 patients, with median follow up of 26.5 m. The median age of the 43 patients was 64 (range, 44–84), 70% were male, 67% were lambda isotype, 46% had multi-organ involvement, and 42% had cardiac involvement. 90% had received prior melphalan-based therapy; in 60% this was HDM/SCT. 14% of patients had received thalidomide and 5%, bortezomib. 10% had no prior treatment. Patients were begun at 15 mg lenalidomide per day for 21 days per month; the median tolerated dose was 10 mg. The response rate was 60% (24% CR, 36% PR); an additional 15% of patients had minor responses. Of the 8 patients who achieved a CR, 6 occurred at 3–6 months of treatment, but 2 were late (18m, 19m). 7 of 8 are alive; one died of cardiac allograft rejection. 3 of 8 have relapsed. 5 of 8 maintain remissions for 6–30 m, of which 4 of 8 continue in CR off therapy for 6–21m. Kaplan-Meier survival for all 43 patients is shown. 7 of 8 patients achieving CR had significant proteinuria: in 2 patients (29%), proteinuria resolved (2 g to 120 mg, 8.8 g to 140 mg); in 3 (43%) it improved by 50% or more; and in 2 there has been no change. Thus, lenalidomide can produce beneficial hematologic and organ responses in AL amyloidosis patients, and remissions can be durable off therapy. Further trials should be done to determine how and when to incorporate lenalidomide into treatment protocols for AL amyloidosis. Figure Figure

Long Term Results of High-Dose Melphalan and Autologous Stem Cell Transplantation in Non-Amyloid Monoclonal Immunoglobulin Deposition Disorders.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 4356-4356
Author(s):  
Saulius Girnius ◽  
David C. Seldin ◽  
Karen Quillen ◽  
Kathleen T. Finn ◽  
Nancy T. Andrea ◽  
...  
Keyword(s):  
Stem Cell ◽  
Stem Cell Transplantation ◽  
Creatinine Clearance ◽  
Light Chain ◽  
Total Protein ◽  
High Dose ◽  
Monoclonal Immunoglobulin ◽  
Protein Excretion ◽  
High Dose Melphalan

Abstract Abstract 4356 Monoclonal Immunoglobulin Deposition Disorder (MIDD) is a plasma cell dyscrasia in which whole immunoglobulins or heavy or light chain subunits form non-fibrillar deposits in various tissues, causing organ dysfunction. Several studies have previously reported that high dose melphalan and autologous stem cell transplantation (HDM/SCT) is safe and effective at achieving a complete hematologic response in this disease, but long term data is sparse. Hematological complete response is defined as normalization of serum free light chain ratio and concentration, bone marrow exam with less than 5% plasma cells, and absence of monoclonal gammopathy in serum and urine by immunofixation electrophoresis. Between 2003 and 2008, ten patients with MIDD were treated with HDM/SCT at a dose of 200mg/m2 (n=6) or 100-140 mg/m2 (n=4) depending upon age and clinical status and were assessed for hematologic responses and improvements in organ function at 3-6 and 12 months, and annually thereafter. The median age was 45 years (range, 34 to 70); all but one patient were male. Six patients had kappa clonal predominance and four patients had lambda clonal predominance. All ten patients had renal involvement, two were on dialysis and one had undergone a renal transplant. Two patients also had extrarenal manifestations with cardiac involvement. The median creatinine clearance was 26 mL/min (range 20 to 100) and the median 24 hour urine total protein excretion was 4,037 mg (range, 458 to 15,632). Peripheral blood stem cells were collected after GCSF mobilization and a median of 6.9 ×106 CD34cells/kg were collected. There was no treatment related mortality within 100 days of SCT. One patient developed end stage renal disease during the peri-transplant period. Of the seven patients who have had follow-up of at least a year, five (71%) achieved a complete hematological response (CR) and two (29%) had a partial hematological response. One patient died six months after HDM/SCT due to progressive disease. Clinical and organ responses were also evident after HDM/SCT in 5 out of 7 patients. The median creatinine clearance was 42 mL/min (range, 38-55) and the median 24 hour urine total protein excretion was 179 mg (range, 150 to 349) at 2 years after treatment. Of the five patients with hematologic CR, 3 (60%) have relapsed at a median of 3 years (range, 2-3). Two of the 5 patients continue to have hematologic CRs at four and six years after HDM/SCT. In summary, HDM/SCT in MIDD often results in hematological CRs, as well as an improvement in renal function. However, the 5-year relapse rate is high. This group of patients may benefit from maintenance anti-plasma cell therapy. Disclosures: No relevant conflicts of interest to declare.

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