92: Longterm Follow-Up of Patients with Systemic AL Amyloidosis Treated with High-Dose Melphalan after Induction and Mobilization Chemotherapy

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.

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

Blood ◽

10.1182/blood.v110.11.192.192 ◽

2007 ◽

Vol 110 (11) ◽

pp. 192-192 ◽

Cited By ~ 1

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

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Long Term Follow up of the Combination of Bortezomib with Dexamethasone as Initial Treatment for AL Amyloidosis

Blood ◽

10.1182/blood.v116.21.3048.3048 ◽

2010 ◽

Vol 116 (21) ◽

pp. 3048-3048

Author(s):

Efstathios Kastritis ◽

Maria Roussou ◽

Magdalini Migkou ◽

Maria Gavriatopoulou ◽

Constantinos Pamboukas ◽

...

Keyword(s):

Initial Treatment ◽

Cardiac Amyloidosis ◽

Cardiac Involvement ◽

High Dose ◽

Al Amyloidosis ◽

Long Term Follow Up ◽

Organ Response ◽

High Dose Melphalan

Abstract Abstract 3048 Until recently, patients with AL amyloidosis had limited treatment options, especially those who were not candidates for high dose therapy, those with severe cardiac involvement or patients who relapsed after initial treatment or never responded to first line alkylators with steroids. Bortezomib (B) with dexamethasone (D) has shown significant activity in patients with AL amyloidosis in patients who relapsed or even those who were refractory to initial treatment. We and others have presented data indicating that BD is active in newly diagnosed patients with AL, inducing responses rapidly but also associated with high rates of complete responses. However, data about long-term follow-up of these patients are limited. Thus, we updated a series of 24, previously untreated patients who received frontline BD. In all patients, treatment started with B at a dose of 1.3 mg/m2 on days 1, 4, 8 & 11 and D was given for 4 consecutive days at a dose of 40 mg per day (days 1–4), every 21 days for up to 6 cycles. The median age of these patients was 70 years (range 42–82) and 46% were males. The median number of involved organs was 2; heart was involved in 83% and kidneys in 63%. Fifty-seven percent were Mayo stage II and 26% were Mayo stage III while 67% had impaired ECOG performance status ≥ 2. The first patient started treatment with BD on September 2005. A median of 5 cycles of BD was given (range 1–6) and 57% of patients received the planned 6 cycles. On intent to treat and according to criteria published by Gertz et al in 2005, 77% of patients achieved a hematologic response including 36% with a hematologic CR. Most of the responses occurred after the first cycle of BD (median time to first response <1 month), while a median of two cycles of BD was needed for CR (median time to CR was 42 days, range 21–84). In 54% of patients an organ response was recorded: 47% of patients with a cardiac involvement achieved a cardiac response and 77% had a reduction of NTproBNP ≥ 30% (which was at least 300 pg/ml), while 60% of patients with a kidney involvement achieved an organ response. Three patients received high dose melphalan with autologous stem cell transplant (HDM-ASCT) after they had completed 6 cycles of BD, 2 while in CR and one in PR. All these 3 patients had achieved organ responses before ASCT. The median follow up for all patients is 31 months. Thirteen patients (54%) have died; most of them due to complications of cardiac amyloidosis and the median survival is estimated to exceed 36 months (patients who underwent ASCT were censored at the time of HDM). Baseline NT-proBNP was the most significant factor independently associated with survival. There were no differences in the baseline characteristics of patients who achieved CR compared to those who achieved a PR as best hematologic response. The median follow up for patients who achieved a CR is 31 months (range 2–55 months). One patient died early due to complications of cardiac amyloidosis, while she had achieved a CR. Among the rest of the patients who achieved a CR but did not receive HDM, all remain alive and without progression for a median of 32 months. Similarly none of the patients who received HDM has relapsed. Among patients who achieved a PR as their best response, 4 (50%) have relapsed and the median progression free survival (PFS) for these patients is 9 months and their median survival is 34 months. In conclusion, BD induces high rates of CRs, in unselected, patients with previously untreated AL amyloidosis, most of whom had features of advanced disease and elevated cardiobiomarkers. i.e. patients that may be excluded form clinical trials. The severity of cardiac involvement remains the most important prognostic factor despite the rapid responses and the high rates of hematologic CRs. It is also of interest to note that CRs may persist even in patients who did not receive any alkylating agents or consolidation with high dose melphalan. A CR is associated with improved survival and should be the primary goal of treatment in patients with AL. Our data indicate that primary treatment with bortezomib based regimens should be evaluated in a phase III trial. Disclosures: Dimopoulos: Ortho-Biotech: Honoraria; Celgene: Honoraria; Millennium: Honoraria.

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Induction Therapy with Bortezomib and Dexamethasone Followed By Autologous Stem Cell Transplantation for Systemic Light Chain Amyloidosis: Our Experience

Blood ◽

10.1182/blood.v124.21.5907.5907 ◽

2014 ◽

Vol 124 (21) ◽

pp. 5907-5907

Author(s):

Sandeep Jain ◽

Luciano J Costa ◽

Robert K Stuart ◽

Saurabh Chhabra ◽

Alice Mims ◽

...

Keyword(s):

Stem Cell ◽

Cardiac Involvement ◽

Stem Cell Transplant ◽

Patient Characteristics ◽

Autologous Stem Cell Transplant ◽

High Dose ◽

Al Amyloidosis ◽

Cell Transplant ◽

High Dose Melphalan

Abstract Introduction: The optimal treatment approach for systemic AL amyloidosis remains unclear. Autologous stem cell transplant (ASCT) is the only modality associated with long term survival, but failure to show survival benefit in randomized clinical trial raises doubts about its efficacy 1, 2. Outcomes after ASCT are better in patients who achieve complete hematologic response after the ASCT3. One report has shown improved outcomes with combining one dose of the proteasome inhibitor bortezomib with high dose melphalan as part of conditioning regimen 4. Preliminary data from a recent study suggest that the outcome of treating AL amyloidosis with two cycles of bortezomib and dexamethasone followed by ASCT was superior to the outcome of the ASCT alone5. We describe our experience with giving 4-6 cycles of bortezomib and dexamethasone induction prior to high dose melphalan and ASCT in patients with systemic AL amyloidosis. Patients and methods: We included all patients who underwent autologous transplant for symptomatic systemic AL amyloidosis at our institution from October 2010 till June 2014. Five patients were included in the analysis and patient characteristics are described in table 1. All patient received 4 -6 cycles of induction with bortezomib and dexamethasone followed by autologous stem cell transplant using high dose melphalan (200 mg/m2). One patient also received six cycles of lenalidomide and dexamethasone prior to bortezomib based induction for lack of response. Hematologic and organ response were assessed using the definitions from the 10th International symposium on Amyloid and Amyloidosis. Overall survival was calculated by Kaplan Meyer’s method using Graphpad Prism 6.0 software. Results: There was no transplant related mortality. After median follow up of 13 months (12-25 months) all patient are alive. Toxicities from the ASCT were mostly cytopenias in the immediate post-transplant period which were managed as per the standard of care. Two patients achieved hematological complete response while one more had very good partial response and other two achieved partial response. Of the four patients with nephrotic range proteinuria, two patients had > 95% reduction in proteinuria, one had > 75% reduction in proteinuria and another patient had > 50% reduction in proteinuria. One patient had Liver involvement with elevated alkaline phosphatase which normalized post-transplant (table 2). The responses were maintained on last follow up and none of the patient had hematological or organ relapses. Discussion: Bortezomib alone and in combination with steroids has shown efficacy in AL amyloidosis, but its role in induction prior to high dose melphalan/ASCT to help achieve deeper hematological response is unknown. Our experience shows that this combination may be highly efficacious without significant toxicity. Limitations of our study include the small number of patients and absence of any patients with cardiac involvement, which is a worse prognostic marker. We conclude that the bortezomib and dexamethasone induction followed by high dose melphalan/ASCT for AL amyloidosis should be studied in prospective trials. Table 1.Patient Characteristics n=5Age, years 51.2 (44-62)Race (Caucasian)4 (80%)Gender ( female)3 (60%)Cardiac involvement 0 (0)Renal involvement 4 (80%)Serum creatinine ≥ 2.5 0 (0)Organ involvement ≥21 (20%)BM plasma cells > 10%1 (20%)Hgb ≤ 10 g/dl0 (0)LVEF <50%0 (0)Induction therapy Bortezomib/dexamethasone only4 (80%)Lenalidomide/dexamethasone + Bortezomib/dexamethasone1 (20%) Table 2. Outcomes n=5 Baseline After ASCT Hematologic response n=5 M protein 0.772 gm/dl 0.096 gm/dl 2 CR, 1 VGPR, 2 PR Renal response n=4 24 hours proteinuria 3.13 gm 0.432 gm 2 > 95% reduction, 1 >75% reduction, 1 >50 % reduction. Liver response n=1 Alkaline phosphatase 700 IU/L 62 IU/L Disclosures No relevant conflicts of interest to declare.

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Safety and efficacy of risk-adapted cyclophosphamide, thalidomide, and dexamethasone in systemic AL amyloidosis

Blood ◽

10.1182/blood-2006-07-035352 ◽

2006 ◽

Vol 109 (2) ◽

pp. 457-464 ◽

Cited By ~ 153

Author(s):

Ashutosh D. Wechalekar ◽

Hugh J. B. Goodman ◽

Helen J. Lachmann ◽

Mark Offer ◽

Philip N. Hawkins ◽

...

Keyword(s):

Randomized Study ◽

High Dose ◽

Al Amyloidosis ◽

Prior Therapy ◽

Oral Regimen ◽

Risk Patients ◽

High Dose Melphalan ◽

Treatment Related Mortality ◽

Related Mortality

AbstractHigh-dose melphalan with stem-cell transplantation is believed to be the most effective treatment for systemic light-chain (AL) amyloidosis, but many patients are ineligible because of the extent of their disease, and treatment-related mortality (TRM) remains substantial. We report the use of a risk-adapted oral regimen of cyclophosphamide, thalidomide, and dexamethasone (CTD) or attenuated CTD (CTDa) in 75 patients with advanced AL amyloidosis, including 44 patients with clonal relapse after prior therapy. Fifty-one (68%) patients received CTD and 24 (32%) received CTDa. A hematologic response occurred in 48 (74%) of 65 evaluable patients, including complete responses in 14 (21%) and partial responses in 34 (53%) cases. Median estimated overall survival (OS) from commencement of treatment was 41 months, and from diagnosis median was not reached with a median follow-up of 22 months. Three-year estimated OS was 100% and 82% among complete and partial hematologic responders, respectively. Toxicity necessitating cessation of therapy occurred in 8% and was at least grade 2 in 52% of patients. TRM was 4%. The clonal response rates to CTD reported here are higher than any previously reported nontransplantation regimen in AL amyloidosis, and risk adaptation allows its use in poorer risk patients. CTD merits prospective randomized study.

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Induction Therapy with Bortezomib and Dexamethasone and Conditioning with High-Dose Melphalan and Bortezomib Followed By Autologous Stem Cell Transplantation for AL Amyloidosis: Long Term Follow-up Analysis

Blood ◽

10.1182/blood-2018-99-111551 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 4616-4616

Author(s):

Vishal K Gupta ◽

Dina Brauneis ◽

Anthony C Shelton ◽

Karen Quillen ◽

John Mark Sloan ◽

...

Keyword(s):

Clinical Trial ◽

Median Time ◽

Progression Free Survival ◽

High Dose ◽

Al Amyloidosis ◽

Biochemical Relapse ◽

Renal Progression ◽

High Dose Melphalan

Abstract In light-chain (AL) amyloidosis, the depth of hematologic response has been shown to be associated with improved survival and organ responses. Bortezomib has been shown to be efficacious in achieving hematologic responses in AL amyloidosis. We conducted a trial utilizing bortezomib with dexamethasone for induction, bortezomib with high-dose melphalan (B-HDM) for conditioning, followed by stem cell transplantation for AL amyloidosis (Clinicaltrials.gov Identifier NCT01083316). The results of this clinical trial with a median follow-up of 36 months have been reported previously (Sanchorawala et al., 2015). We, here in, report the long-term results of this clinical trial, conducted from Jan 2010 to Aug 2013 with a median follow-up of 77.3 months (range, 55.4 to 100.1). The objectives of this follow-up report were to describe long-term survival, hematologic response and relapse rates, progression free survival and median time to organ response for patients treated on this clinical trial. As reported in the prior publication, patients received 2 cycles of induction with bortezomib 1.3mg/m2 and dexamethasone 20mg on day 1, 4, 8, 11 every 21 days followed by conditioning regimen of bortezomib 1mg/m2on day -6, -3, +1, +4 and HDM at 140-200mg/m2 in two divided doses on days -2 and -1 with transplantation of >2.5 x 106 autologous CD34+ cells/kg on day 0. Thirty-five patients were enrolled. Hematologic complete responses (CR) and very good partial responses (VGPR) were noted in 27/27 (100%) of assessable patients at 6 months and in 26/26 (100%) at 1 year following SCT. By intention-to-treat analysis, hematologic CR and VGPR were achieved by 27/35 (77%) at 6 months and 26/35 (74%) at 1 year following SCT. Hematologic relapse was defined as recurrence of a monoclonal protein on serum or urine IFE and/or abnormality of serum free light chain assay corresponding to their original clone. In contrast, biochemical relapse was defined as hematologic relapse without the progression of organ parameters. Renal progression was defined as 50% increase of 24-hour urine protein to >1g/day or 25% worsening of serum creatinine or creatinine clearance and cardiac progression was defined as NT-proBNP progression (>30% and >300 ng/mL increase), cTn progression (>30%) or LVEF progression (≥ 10% decrease). Of the 27 patients who achieved a hematologic CR or VGPR at 6 months, 4 patients had hematologic relapse at a median of 42.3 months (range, 34.5-63.0), 1 patient had organ (renal) progression despite maintaining a hematologic VGPR at 37 months and 4 had biochemical relapse at a median of 53 months (range, 49-79). Immunomodulatory agents and proteasome inhibitors were used in 2 and 3 patients with relapse, respectively. None of the patients with biochemical relapse required additional anti-plasma cell directed treatment at the time of last follow-up (median follow-up of 12.5 months; range, 7-44). Of the four who had hematologic relapse, two patients had achieved a VGPR at 6 months, and two had achieved a CR at 6 months. The median overall survival and progression-free survival are not yet reached (Figure). Eight deaths occurred in the follow up period. Two of these occurred in patients who did not proceed to SCT. Three occurred within 100 days of SCT. Three occurred in the subsequent follow-up period at 10.4, 55.0, and 80.1 months following enrollment attributed to worsening cardiac and renal function due to relapse of AL amyloidosis. The median time to renal response, defined as a 30% reduction in 24-hour urine protein in those with a baseline level of proteinuria over 0.5 g/24 hr, and in the absence of a worsening of estimated glomerular filtration rate by 25%, was 12 months (range, 6-24). The median time to cardiac response, defined as a reduction of B-type natriuretic peptide level by 30% with a baseline level greater than 100 pg/mL, was 6 months (range, 6-24). There were two cases of biopsy proven autologous graft-vs-host disease during periSCT period, and both these patients are alive and maintain a hematologic CR. In conclusion, incorporating bortezomib into induction and conditioning yielded durable hematologic responses of AL amyloidosis with corresponding cardiac and renal responses, and prolonged survival. This clinical trial was partly supported by Takeda Oncology. Figure. Figure. Disclosures Sloan: Stemline Therapeutics: Consultancy.

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Safety and Efficacy of Once Weekly Subcutaneous Bortezomib in Advanced Stage AL Amyloidosis

Blood ◽

10.1182/blood.v124.21.4753.4753 ◽

2014 ◽

Vol 124 (21) ◽

pp. 4753-4753 ◽

Cited By ~ 1

Author(s):

Naresh Bumma ◽

Frederic J. Reu ◽

Christy Samaras ◽

Hien K. Duong ◽

Mitchell R. Smith ◽

...

Keyword(s):

Cardiac Toxicity ◽

Cardiac Risk ◽

High Dose ◽

Al Amyloidosis ◽

Hematologic Response ◽

Staging Systems ◽

Plasma Cell Disorder ◽

High Dose Melphalan ◽

Cell Disorder

Abstract Background: Intravenous bortezomib (BTZ) based therapy is effective for AL amyloidosis, although cardiac toxicity is a concern in advanced stage patients (pts). Survival in AL amyloidosis is dependent on hematologic and cardiac organ response emphasizing the need for safe and effective treatments. Staging systems to identify high cardiac risk pts developed by Dispenzieri et al JCO 22.18 (2004): 3751-3757 and revised by Kumar et al JCO 30.9 (2012): 989-995 can be used to guide therapy. Since January 2011, our institutional preference has been to treat plasma cell disorder patients with subcutaneous (SC) once weekly BTZ and have eliminated requirement for intravenous hydration. Considering the historically poor outcome of high cardiac risk AL amyloid pts with conventional therapy, we did not exclude them from weekly SC bortezomib and report safety and efficacy data here. Methods: After IRB approval, we reviewed our plasma cell disorder registry and identified 40 pts with AL amyloidosis who received weekly SC BTZ as initial therapy between January 2011 and June 2014. Review of the electronic medical record was used to confirm details of BTZ based regimens, response to treatment according to consensus criteria (Palladini et al. JCO (2012): 4541-4549.), and adverse events including neuropathy and cardiac toxicity graded via the NCI CTCAE version 4.0. We ascribed advanced cardiac stage to pts who were stage 3 by the 2004 staging and 3 and 4 by the 2012 staging. Six pts were excluded from hematologic response assessment as the difference between the involved and uninvolved free light chains was less than 50 mg/L at baseline. Results: Out of the 34 evaluable pts, 18 (53%) and 23 (68%) were found to be advanced cardiac stage by the respective staging systems and 1 of these pts died of ventricular tachycardia arrest about 8 hours after initial 1 mg/m2 bortezomib dose with 8 mg of dexamethasone. Additional toxicity included grade 4 ventricular tachycardia in 1 patient after the fifth cycle of BTZ although not in close relation to the BTZ dose. Neurologic toxicity attributed to BTZ was seen in 4 pts (10%) with 3 grade 1 and 1 grade 3. Six deaths occurred in SC BTZ treated pts and all were in advanced cardiac stage pts. Two advanced cardiac stage pts successfully underwent high dose melphalan and autologous stem cell transplant. Hematologic responses are listed in the tables. All patients received corticosteroid. Table 1Hematologic response with weekly SQ BTZ in cardiac risk stage 3 disease (as per 2004 staging) Alkylating agent Hematologic response (median follow up: 13 months)VGPR or betterPartial responseNo response / deathYes ( N=9)33%22%44%No ( N=9)55%22%22% Table 2 Hematologic response with weekly SQ BTZ in stage 3/4 disease (as per 2012 staging) Alkylating agent Hematologic response (median follow up 13 months) VGPR or better Partial response No response / death Yes (N=12) 42% 17% 42% No (N=11) 64% 27% 9% Discussion: Only 2 pts experienced cardiac toxicity and 1 was in close temporal relation to the BTZ dose but resulted in death. The responses seen with weekly SC BTZ in advanced cardiac stage AL amyloidosis are reasonably consistent with those seen with intravenous dosing although small patient numbers limit this comparison. Hematologic response in pts treated with BTZ and corticosteroid alone can support a response adapted therapeutic approach. Two advanced cardiac stage pts were able to undergo high dose melphalan after improvement in their cardiac status with BTZ based therapy. Once weekly SC BTZ based therapy was safe and effective treatment for AL amyloidosis even in high cardiac risk pts. Disclosures No relevant conflicts of interest to declare.

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High Dose Melphalan and Autologous Stem Cell Transplantation In Light Chain and Light and Heavy Chain Deposition Disease: Hematologic and Renal Outcomes.

Blood ◽

10.1182/blood.v116.21.4597.4597 ◽

2010 ◽

Vol 116 (21) ◽

pp. 4597-4597

Author(s):

David Telio ◽

John Shepherd ◽

Donna L. Forrest ◽

Michael J. Barnett ◽

Thomas J. Nevill ◽

...

Keyword(s):

Stem Cell ◽

Renal Disease ◽

Light Chain ◽

High Dose ◽

Al Amyloidosis ◽

Renal Response ◽

Deposition Disease ◽

Stage Renal Disease ◽

High Dose Melphalan

Abstract Abstract 4597 Introduction: Light chain deposition disease (LCDD) and light and heavy chain deposition disease (LHCDD) are plasma cell disorders characterized by pathologic aggregation and deposition of immunoglobulin components in tissues leading to organ dysfunction. Reported outcomes with conventional chemotherapy include high rates of end stage renal disease and death. High dose melphalan followed by autologous stem cell transplantation (ASCT) has been employed in an attempt to improve outcomes, but few published data are available to support this practice. Methods: We conducted a retrospective review of all patients within our institutional database treated with ASCT for LCDD or LHCDD. Diagnosis was based in all cases upon renal biopsy. Associated multiple myeloma (MM) was diagnosed if bone marrow plasma cells were > 10% with concomitant anemia, hypercalcemia or lytic bone disease. Filgrastim was used for peripheral blood stem cell mobilization. All patients received melphalan conditioning at a reduced dose of 140 mg/m2 (due to renal dysfunction) with the exception of one patient who received melphalan 200 mg/m2. Response to treatment was adapted from the International Consensus Criteria (Gertz et al. 2005) designed for use in AL amyloidosis except that bone marrow biopsies were not performed to confirm complete hematologic remission. A renal response was considered to have been reached if proteinura decreased from 50% of baseline with stable creatinine or if creatinine decreased by 50% from its peak value. Results: We identified eight patients (7 LCDD, 1 LHCDD) treated with ASCT between August 2006 and November 2009. The median age at diagnosis was 48 years (range 40–62). Two patients had associated MM. All patients had come to medical attention as a consequence of renal dysfunction. The median serum creatinine at presentation was 192 μ mol/L (119-444) with two patients meeting criteria for nephrotic syndrome and a third having anasarca with nephritic syndrome. No patients were found to have associated AL amyloidosis, myeloma cast nephropathy, or extrarenal LCDD. Left ventricular ejection fraction was normal in all patients and none had evidence of cardiac infiltration. Kappa light chain restriction was present in seven patients with lambda light chain restriction in the eighth. Median kappa FLC level at diagnosis was 528 mg/L (range 42–1290, normal 3.3–19.4). Induction therapy consisted of dexamethasone in five patients and dexamethasone with bortezomib in two patients; one patient proceeded directly to ASCT without induction therapy. At the time of ASCT, the median serum creatinine was 183 μ mol/L (122-298). Stem cell mobilization was uncomplicated and ASCT was tolerated with no treatment related deaths or requirement for ICU admission. Significant toxicities included engraftment syndrome requiring steroids (2), bacteremia (2), sepsis with hypotension (1), pneumonia (1), grade 3 mucositis (1) and edema requiring ultrafiltration (1). One patient with a pre-ASCT creatinine of 298 μ mol/L went on to develop end stage renal disease and dialysis dependence two months after ASCT. Hematologic response was CR in two, PR in four, and not assessable in two patients due to insufficiently elevated baseline M-protein quantity for response determination. Seven patients had a renal response. After a median follow up from ASCT of 18 months (1-39 months), only one patient had experienced disease progression with increasing kappa FLC level. With the exception of the one dialysis dependent patient, no patients had symptoms related to renal disease at last follow up. Conclusion: In selected patients with LCDD and LHCDD, high dose melphalan with ASCT produced a high rate of hematologic and renal response with acceptable toxicity. Longer follow up is needed to assess the durability of response. Disclosures: No relevant conflicts of interest to declare.

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High Dose Melphalan Followed By Autologous Stem Cell Transplant in AL Amyloidosis: a Single-Center Experience

Blood ◽

10.1182/blood.v124.21.5909.5909 ◽

2014 ◽

Vol 124 (21) ◽

pp. 5909-5909

Author(s):

Mariella D'Adda ◽

Francesca Schieppati ◽

Samantha Ferrari ◽

Claudia Crippa ◽

Annalisa Peli ◽

...

Keyword(s):

Cardiac Troponin ◽

Stem Cell Transplant ◽

Troponin T ◽

Autologous Stem Cell Transplant ◽

High Dose ◽

Al Amyloidosis ◽

Cell Transplant ◽

Single Center Experience ◽

High Dose Melphalan

Abstract INTRODUCTION: high-dose melphalan (HDM) followed by autologous stem cell transplant (ASCT) has been routinely used as a treatment option for systemic light chain AL amyloisosis since the first report in mid-1990s. The high treatment-related mortality (death before post-transplant day 100) reported in literature (11-40% in different papers) has decreased over the last years with the improvement in patient selection. Particularly, in the largest Mayo Clinic series of 422 subjects, patients with cardiac troponin-T < 0.06 ng/L and NT-proBNP < 5000 ng/L had TRM < 1%; besides, patients achieving hematologic complete response/very good partial remission (CR/VGPR) had superior overall survival than those achieving hematologic partial response (PR) and no response. Here we report our single-center experience of 14 ASCT performed in 10 patients between 2007 and 2014. PATIENTS AND METHODS: the median age at the time of ASCT was 58 years (range 44-68). Five patients had 2 or more involved organs. All 10 patients had: normal troponin-I value, NT-proBNP < 5000 ng/L, PS 0-1, cardiac ejection fraction over 50%, CO diffusion capacity over 50%; only one had creatinine clearance < 50 ml/min. Three patients collected stem cells after cyclophosphamide (1,5 g/m^2), the others after G-CSF alone. Four patients proceeded directly to ASCT after diagnosis, 3 received CyBorD and 3 other induction regimen (5 patients were non responders and 1 was in hematologic PR after “induction therapy” before HDM). Patients received melphalan 200 mg/m^2 (9 ASCT) or dose adjusted HDM (100-140 mg/m^2, 5 ASCT), depending on clinical decision. Four patients received double ASCT. RESULTS: median follow up is 48 months (range 0,5-80); all patients were alive at the last visit. Of nine evaluable patients (1 patient too early), overall hematologic and organ response rate after ASCT were 78% and 45%. Only 1 of 4 patients with double ASCT improved response after the second course (this patient maintains a hematologic CR without organ involvement after 80 months of follow up). Median hospitalization for ASCT was 24 days (range 17-45), without any threatening-life side effect. Six of 9 evaluable patients needed a 2ndline therapy for progressive disease after a median follow up of 24 months (range 13-52): 4 of them had achieved hematologic PR after ASCT, 1 patient achieved hematologic VGPR and 1 had no hematologic response. Three patients are in follow up without other therapy after ASCT (2 hematologic CR and 1 non response). CONCLUSION: HDM followed by ASCT is a very effective treatment option in AL-amyloidosis, which may be effective even in patients non responding to first-line treatment with non myeloablative drugs. According to the data of the literature, our experience suggests that a careful selection of patients is critical for good outcomes and that particular cardiac biomarkers (cardiac troponin-T < 0.06 ng/L and NT-proBNP < 5000 ng/L) are useful to guide the choice of therapy. Furthermore, consolidation therapy (IMiDs and proteasome inhibitors) should be considered for patients who do not obtain at least a VGPR/CR after HDM. Disclosures No relevant conflicts of interest to declare.

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