A European Collaborative Study of Treatment Outcomes In 428 Patients with Systemic AL Amyloidosis

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 988-988 ◽  
Author(s):  
Ashutosh D Wechalekar ◽  
Efstathios Kastritis ◽  
Giampaolo Merlini ◽  
Philip N Hawkins ◽  
Meletios A. Dimopoulos ◽  
...  
Keyword(s):  
Cardiac Amyloidosis ◽  
Cardiac Involvement ◽  
Median Number ◽  
Cardiac Response ◽  
Al Amyloidosis ◽  
Line Treatment ◽  
End Of Treatment ◽  
Significant Difference ◽  
Organ Response

Abstract Abstract 988 The treatment of patients with systemic AL amyloidosis remains challenging. Cyclical combination chemotherapy is used in majority of patients but a report that I.V. melphalan-dexamethasone may not overcome the poor prognosis for cardiac amyloidosis (Deitrich S et al, Blood, 116, 2010) has fuelled the controversy about best front line treatment. We report outcomes of 428 patients treated with oral cyclophosphamide thalidomide dexamethasone (CTD), oral melphalan dexamethasone (M-dex), bortezomib dexamethasone with or without an alkylator (BD), cyclophosphamide-lenalidomide-dexamethasone (CLD) or stem cell transplant (ASCT) as first line treatment for systemic AL amyloidosis assessed at three large European amyloid centres in London (UK), Pavia (Italy) and Athens (Greece) between 2003–2010. Patients with a full baseline data set were included in the study. Clonal and organ responses were defined according to the international amyloidosis consensus statement (Gertz et al 2005) and responses were assessed at 6 months or at the end of treatment. dFLC (difference between involved and uninvolved free light chain (FLC)) was used to assess the absolute FLC change after treatment. 204 (48%) received M-dex, 155 (36%) received CTD, 13 (3%) received ASCT, 28 (7%) received BD and 25 (6%) received CLD. The median number of cycles received was 5 for all regimens. 257 (60%) had cardiac involvement, 325 (76%) had renal and 59 (14%) had liver involvement. Cardiac involvement by regime was: BD 75%, CLD 68%, M-dex 65%, CTD 45% and ASCT 23%. 30 (7%) died within six months of diagnosis. The median number of organ involved was 2 (range 1–5) with ECOG performance status ≥2 in 123 (28%). 98 (23%) patients achieved a complete response (CR), 175 (41%) achieved a partial response (PR) and 125 (29%) did not respond to treatment. A haematological CR/PR was seen, respectively, in 22%/41% treated with CTD, 26%/44% with M-dex, 23%/46% with ASCT, 39%/42% with BD and 4%/44% with CLD. There was significantly greater reduction in dFLC after BD (median reduction 91% over starting value) compared to CTD (median 81%; p = 0.006), M-Dex (median 83%; p = 0.004) and CLD (median 72%; p = 0.03). There was no significant difference in the median dFLC reduction between patients treated with CTD and M-Dex. 100/325 (30%) had a renal organ response, 17/59 (29%) had a hepatic response and 24/257 (9%) had a cardiac response, and 61 (16%) had a cardiac response by NT-proBNP criteria. The organ and NT-proBNP responses respectively were highest in the cohort treated with BD (53% and 32%) followed by CTD (38% and 12%), ASCT (30%), M-dex (23% and 19%) and CLD (12% and nil). CTD achieved significantly better organ responses compared to M-dex (p=0.0024). At median follow up of 29 months, median overall survival (OS) for the whole cohort has not been reached with 2, 3 and 4 year estimated survival of 75%, 65% and 61%, respectively. When patients with cardiac involvement were considered, those achieving a CR have not reached median OS with an estimated 3 year survival of 89%, those with PR had an estimated median OS of 50 months and the non-responders had a median OS of 21 months. Detailed comparison by Mayo stage will be presented. There was no significant difference in the OS of patients treated with CTD or M-Dex (as compared directly or by centre). In summary, outcome of patients with AL amyloidosis across three major European centres appears comparable. BD treatment achieves significantly lower end of treatment dFLC values compared to CTD, M-dex, ASCT or CLD – which importantly translates into an organ response in over half of all patients receiving BD compared to a third of those treated with CTD and quarter of those with M-dex and further follow up may yet reveal survival differences. Organ responses appear significantly better with CTD compared to M-dex – possibly due to more rapid response to CTD since the end of treatment dFLC values are not significantly different - although this does not translate into a survival advantage. Depth of clonal response appears to be directly linked to improvement in survival of patients with cardiac amyloidosis (including in patients treated with CTD and M-dex) and organ response in general. This study supports the rational for doing urgent phase III studies confirming benefits of bortezomib combination chemotherapy for upfront treatment in AL amyloidosis and the benefit of rapid deep clonal responses in cardiac amyloidosis irrespective of the regimen. Disclosures: Off Label Use: Thalidomide, bortezomib, lenalidomide. Dimopoulos:Celgene: Honoraria; Othro Boitech: Honoraria.

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

Blood ◽  
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.

Abnormal NT-ProBNP in AL Amyloidosis Patients without Cardiac Involvement at Diagnosis - A Predictor of Subsequent Cardiac Involvement.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 1500-1500
Author(s):  
Ashutosh D. Wechalekar ◽  
Helen J. Lachmann ◽  
Julian D. Gillmore ◽  
Philip N. Hawkins
Keyword(s):  
Cardiac Amyloidosis ◽  
Cardiac Involvement ◽  
Myocardial Dysfunction ◽  
Posterior Wall ◽  
Left Ventricular ◽  
Al Amyloidosis ◽  
International Consensus ◽  
Cardiac Amyloid ◽  
Significant Difference

Abstract Cardiac involvement in AL amyloidosis is associated with a poor prognosis and greatly increased treatment related morbidity and mortality, and regression of cardiac amyloid deposits is extraordinarily slow following chemotherapy that suppresses the underlying aberrant light chain production. Diagnosis of cardiac amyloidosis is normally made by echocardiography, by which time significant diastolic dysfunction has usually developed. Atrial natriuretic peptides (ANP, BNP and its N-terminal fragment NT-ProBNP) are useful in early diagnosis of myocardial dysfunction. Serum NT-ProBNP concentration has been reported to be a promising marker of cardiac dysfunction in AL amyloidosis, and patients with normal NT-ProBNP values at diagnosis have superior outcomes. We report here the outcome of patients attending the UK National Amyloidosis Centre (NAC) who had elevated NT-ProBNP at diagnosis of AL amyloidosis but who did not have accompanying evidence of cardiac involvement using conventional consensus criteria. To exclude the confounding effect of renal failure which is associated with substantial elevation of NT-ProBNP, we studied patients with serum creatinine &lt;150 μmol/L and creatinine clearance of &gt;50ml/min at diagnosis in whom there was less than 10% change in renal function after treatment. AL type amyloidosis was confirmed in all patients histologically with corroborating genetic studies to robustly exclude hereditary amyloidosis as indicated. Organ involvement and responses/progression were defined according to recent international consensus criteria (Gertz et al 2005). 102 patients who had no evidence of cardiac involvement by these conventional parameters and who otherwise conformed with our study criteria were identified. Median creatinine was 87 μmol/L (44–128), albumin 33g/L (10–65), bilirubin 7 μmol/L (1–65) and alkaline phosphatase 89 units/L (36–2649). The median interventricular septal and left ventricular posterior wall thickness was 9 mm (7–11 mm). 62 (61%) patients had NT-ProBNP ≤ 35pMol/L at diagnosis while 40 (39%) had NT-ProBNP of &gt;35 pMol/L. There was no significant difference in the baseline characteristics of either group. 5 patients in each group did not respond to the initial chemotherapy (p=0.46). With median follow-up of 60 months, 19/40 (47%) of patients with NT-ProBNP &gt;35pMol/L at diagnosis developed evidence of cardiac involvement compared to only 6/62 (10%) of whose baseline NT-ProBNP was ≤ 35 pMol/L (p&lt;0.001). The Kaplan-Meier estimated median overall survival has not been reached for either group but the estimated 7 year survival was significantly better in the group with NT-ProBNP of ≤35pMol/L compared to those with greater values (92% vs. 82%, p=0.03). In conclusion, these preliminary findings suggest that patients who have elevated NT-ProBNP concentration but no conventional evidence of cardiac involvement at diagnosis of AL amyloid appear to be at greater risk of developing cardiac amyloidosis during follow-up, and have a poorer prognosis. It reasonable to speculate that such patients have early cardiac involvement at diagnosis that cannot be identified by conventional non-invasive methods, and that their risk of subsequently developing clinically significant cardiac amyloidosis may be reduced by striving to achieve complete remission of their underling clonal plasma cell disease.

scholarly journals Cardiac involvement Is Underdiagnosed in Patients with Biopsy-Proven Systemic AL Amyloidosis

2016 ◽  
Vol 6 ◽  
Author(s):  
Haoyi Zheng ◽  
Amitabha Mazumder ◽  
Stuart Katz
Keyword(s):  
Clinical Diagnosis ◽  
Cardiac Amyloidosis ◽  
Cardiac Involvement ◽  
Clinical Care ◽  
Response To Therapy ◽  
Cardiac Response ◽  
Al Amyloidosis ◽  
Limited Data ◽  
Nccn Guidelines

<p><strong>Background</strong>: Clinical recognition of cardiac involvement and cardiac response to therapy is an important element of clinical care in patients with AL amyloidosis. The new criteria including NT-proBNP, troponin, and echocardiography for assessment of cardiac involvement in patients with systemic AL amyloidosis were proposed in 2004, but there are limited data on the utilization of these in clinical practice</p><p><strong>Methods</strong>: We retrospectively reviewed the clinical data of 28 patients with AL amyloidosis. Clinical diagnosis of cardiac amyloidosis was based on medical record documentation of symptomatic heart failure without other causes. Then we use the criteria from the current NCCN Guidelines to reassess cardiac involvement.</p><p><strong>Results</strong>: 14 cases (50%) had clinical diagnosis of cardiac amyloidosis at the time of diagnosis and also met the NCCN criteria. An additional 6 cases without clinical diagnosis of cardiac amyloidosis met the NCCN criteria. In total, 20 patients (71.4%) met the NCCN criteria for cardiac involvement. No routine follow-up testing with echocardiography and biomarkers was documented during treatment for any of the patients.</p>

Difference of Treatment Outcomes in AL Amyloidosis and Multiple Myeloma with / without Translocation (11;14)

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 4224-4224 ◽  
Author(s):  
Kenshi Suzuki ◽  
Miho Kasuga ◽  
Kanji Miyazaki ◽  
Sohsuke Meshitsuka ◽  
Yu ABE ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Overall Survival ◽  
Chromosome Aberration ◽  
The Other ◽  
Cardiac Response ◽  
Al Amyloidosis ◽  
Positive Group ◽  
Other Hand ◽  
Significant Difference ◽  
Organ Response

Abstract Introduction AL amyloidosis (AL) is characterized by the deposition of immunoglobulin light chains as amyloid fibrils accumulated in different organs. Translocation (11;14) (t(11;14)) is seen in about half of AL patients, but the clinical significance is still unknown. So our study has focused on the chromosome aberration of t(11;14). We report the relationship between the chromosome aberration and the organ response, the organ involvement which greatly influence prognosis of AL patients. Furthermore, we examined the prognosis and treatment response to compare t(11;14) influences of AL with t(11;14) influences of multiple myeloma (MM). Patients and Methods We analyzed in AL and symptomatic MM patients have t(11;14) using fluorescence in situ hybridization from January 2010 to December 2014 in Japanese Red Cross Medical Center. We examined the overall survival and the therapy response rate. In addition, we compared t(11;14)-positive and negative in AL and MM respectively. Besides, we investigated the involved organ parts and the organ response with melphalan and dexamethasone (MD) therapy in AL. Outcome was assessed based on remission after three months and one year. Remissions were determined according to consensus criteria in 2011 for AL and IMWG uniform criteria for MM. Survival distribution of OS was estimated using the Kaplan-Meier method and compared using the log-rank test. Data between t(11;14)-positive and negative were compared with the Mann-Whitney U test or X2 test. The statistical analysis was performed using IBM SPSS statistics ver.23. Results Among 27 patients with AL, 9 cases were t(11;14)-positive patients (age median, 64yr; range, 37-80), and 13 out of 46 were positive in MM (age median, 64yr; range, 34-86). (excluded complication of both AL and MM cases) In AL cases, the t(11;14)-positive group tended to shorter overall survival (OS) than negative cases. On the other hand, in the patients with MM, positive group tended to superior OS to negative (AL: P=0.442(Fig.1A), MM: P=0.327(Fig.1B)). Compared with t(11;14)-negative AL group, t(11;14) positive group was tended to have much organ involved numbers of amyloid protein (67% v 34%; P=0.109) and much cardiac involvement patients (67% v 39%; P=0.171). On the other hand, there were little cardiac and renal response in both t(11;14)-positive and negative with MD therapy after 3 months (heartF17% v 0% P=0.462/renalF0% v 0%). In MM patients, ORR after 3 months were 67% and 79% in t(11;14)-positive and negative cases respectively (P=0.386). That after 1 year were 78% and 74% respectively (P=0.889). Conclusion t(11;14) is important prognostic factor and showed conflict prognosis between AL and MM. From this investigation, the importance of connecting the chromosome abnormality every disease was shown. In addition, our investigation recognized tendencies that the amyloid involvement rate to the heart was high, and the cardiac response with MD therapy were low in AL t(11;14)-positive group. As these results, we thought that t(11;14)-positive AL patients' OS were shortened. The significant difference did not appear in this examination while these tendencies were clearly accepted in little number of patient cases. Further investigation using rather number of patient samples is needed. In conclusion, the cardiac amyloid involvement is high in the AL t(11;14)-positive group, and the cardiac response by MD therapy is low. We should have doubt eyes of the amyloid involvement to the heart in AL t(11;14)-positive patients, and have the posture that can support cardiac amyloidosis immediately. In addition, breakthrough new treatments are expected urgently for AL patients. Figure 1. Figure 1. Disclosures No relevant conflicts of interest to declare.

scholarly journals Hematologic Responses and Cardiac Organ Improvement in Patients with Heavily Pretreated Cardiac Immunoglobulin Light Chain (AL) Amyloidosis Receiving Daratumumab

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 4525-4525 ◽  
Author(s):  
Gregory Kaufman ◽  
Ronald Witteles ◽  
Matthew Wheeler ◽  
Patricia Ulloa ◽  
Marie Lugtu ◽  
...  
Keyword(s):  
Light Chain ◽  
Research Funding ◽  
Cardiac Involvement ◽  
Cardiac Response ◽  
Al Amyloidosis ◽  
Immunoglobulin Light Chain ◽  
Prior Therapy ◽  
Hematologic Response ◽  
Heavily Pretreated ◽  
Organ Response

Abstract Introduction: In immunoglobulin light chain (AL) amyloidosis, cardiac involvement is the primary cause of premature death. Light chain suppression, with therapies targeting the underlying plasma cell clone producing amyloidogenic free light chains, has been difficult to achieve in a relapsed/refractory disease setting. Hematologic response is required to obtain a cardiac organ response, which is predictive of survival and is an important, if not primary, therapeutic goal. We have previously reported rapid and favorable hematologic response rates with the monoclonal anti-CD38 antibody daratumumab in a cohort of heavily pretreated relapsed/refractory AL patients. The aim of this study was to evaluate cardiac organ response following light chain suppressive therapy with daratumumab in patients with relapsed/refractory AL. Materials & Methods:Consecutive patients with biopsy-proven AL and cardiac involvement, followed at the Stanford University Amyloid Center, who received daratumumab were retrospectively evaluated for hematologic and cardiac organ response. In accordance with IRB approval, demographic and clinical information was obtained from medical records. Hematologic and cardiac organ response criteria were defined per consensus guidelines in AL (Comenzo et al, Leukemia 2012). Results: Twelve patients with previously treated AL with cardiac involvement received a median of 12 doses (range 5-18) of single agent daratumumab. The antibody was given intravenously at 16 mg/kg weekly for 8 weeks, followed by every other week infusion for 8 doses and then monthly infusions. The median patient age was 67 and 75% of patients were male. The median number of lines of prior therapy was 3; notably, none of the patients had previously achieved a hematologic complete response to prior therapy including high dose melphalan and autologous stem cell transplant in 2 patients. Ten of 12 patients (83%) achieved a partial hematologic response or better with daratumumab (3 complete responses (25%), 3 very good partial responses (25%), and 4 partial responses (33%)). Median NT-pro BNP was 2516 pg/mL prior to daratumumab therapy. Of all 12 treated patients, seven patients were evaluable for cardiac response based on baseline NT-proBNP >650 ng/L. Of these, 3 patients achieved a cardiac organ response by NT-pro BNP criteria (>30% reduction and >300 ng/l decrease). Two patients had cardiac progression by NT-pro BNP criteria (no echocardiographic progression was observed) despite hematologic response with one patient discontinuing therapy to pursue hospice care. Infusion reactions were observed in 8/12 patients with only 1 grade 3 infusion reaction. Conclusions: Daratumumab yielded rapid and significant hematologic responses in our retrospective single institution cohort of heavily pretreated AL patients. At a median daratumumab duration of therapy of only 4 months, evidence of cardiac organ improvement was observed. Daratumumab represents a well tolerated and exceptionally promising new treatment for patients with AL amyloidosis; larger prospective trials to evaluate this agent are warranted. Disclosures Liedtke: Takeda: Consultancy, Research Funding; Prothena: Consultancy, Research Funding; Celgene: Research Funding; Amgen: Consultancy, Research Funding; Novartis: Research Funding; Gilead: Research Funding; Pfizer: Consultancy, Research Funding.

scholarly journals Free Light Chain Burden and Elevated Alkaline Phosphatase Identify Patients with Non-Cardiac AL Amyloidosis with Poor Outcome

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 3361-3361
Author(s):  
Giovanni Palladini ◽  
Paolo Milani ◽  
Andrea Foli ◽  
Giampaolo Merlini
Keyword(s):  
Alkaline Phosphatase ◽  
Partial Response ◽  
Cause Of Death ◽  
Cardiac Amyloidosis ◽  
Cardiac Involvement ◽  
Stage I ◽  
Liver Involvement ◽  
Al Amyloidosis ◽  
Heart Involvement

Abstract Background. The prognosis of patients with AL amyloidosis is mainly driven by the severity of heart involvement. Cardiac amyloidosis is being extensively studied, and accurate staging systems have been developed to identify patients with different degrees of heart dysfunction who are candidates for different treatment approaches. However, little is known on the outcome of patients without heart involvement who are generally considered low-risk. In the present study we evaluated factors affecting survival of patients with non-cardiac AL amyloidosis. Patients and Methods. The subjects (n=135) without cardiac involvement (NT-proBNP <332 ng/L and mean left ventricular wall thickness at echocardiography £12 mm) and with normal troponin (Mayo Clinic stage I) were selected form the prospectively maintained database including 748 consecutive, previously untreated patients with AL amyloidosis diagnosed at our center between 2004 and 2012. Results. Median age was 61 years (range 39-80 years). Involved organs were kidney (111, 82%); with median (range) proteinuria 7.2 g/24h (0.5-23.5 g/24h) and creatinine 1.1 mg/dL (0.5-4.4 mg/dL); soft tissues (21, 16%); liver (18, 13%), with median alkaline phosphatase (ALP) 2.3 times the upper reference limit (range 1.6-7.5 times u.r.l.); peripheral nervous system (13, 10%); gastrointestinal (GI) tract (10, 7%). One hundred seven patients (79%) had more than one organ involved. Median (range) bone marrow plasma cell infiltrate was 10% (2-29%) and dFLC (difference between involved and uninvolved free light chains) 70 mg/L (0-5721 mg/dL). Fifty-two patients (38%) were treated with melphalan / dexamethasone (MDex), 42 (31%) with bortezomib-based regimens, 14 (10%) underwent stem cell transplant (ASCT), 13 (10%) received thalidomide-based regimens, and the remaining patients received treatment for IgM clones or high-dose dexamethasone alone. After a median follow-up of living patients of 51 months, 23 patients (17%) died. Survival at 5 years was 82%. Twelve patients (52%) died a cardiac death (heart failure in 8 cases, sudden death in 4), after having developed cardiac involvement. All of them had baseline dFLC >100 mg/L. In these subjects the median NT-proBNP concentration at last assessment was 2401 ng/L, with a median 1646% increase compared to baseline. Of them 7 had failed to respond to frontline therapy, and the remaining had progressed after an initial partial response (PR, 3 cases) or very good partial response (VGPR, 2 cases). Eight patients (35%) died of liver failure. Six satisfied the criteria for liver involvement at baseline, and 2 developed hepatic amyloidosis during the follow-up, but had elevated ALP at baseline (1.3 and 1.4 times the u.r.l., respectively). Among them, 5 were non-responders to first-line therapy, and 3 had relapsed after PR (1) and VGPR (2). One patient died due to GI bleeding during ASCT. In the remaining 2 patients the causes of death were not directly related to the disease: myelodysplasia (5.9 years after having achieved VGPR with 6 cycles of MDex), and colorectal cancer (6.5 years after diagnosis). Only the two deaths that were not disease-related occurred in patients who presented with normal ALP and dFLC <100 mg/L (Figure). Elevated ALP (HR 5.11, P<0.001) and dFLC (HR 4.79, P<0.001) were independent prognostic factors at multivariate analysis. Conclusion. This is the first study specifically addressing the outcome of patients with non-cardiac AL amyloidosis. Cardiac dysfunction after development of heart involvement remains the first cause of death also in patients who do not have cardiac involvement at diagnosis. Notably, fatal cardiac amyloidosis occurred only in patients in whom dFLC was >100 mg/L at diagnosis. Progressive liver involvement emerges as a significant cause of death in Stage I AL patients, and is predicted by elevated ALP. Patients with non-cardiac AL who have high dFLC and/or ALP should be treated aggressively to prevent the onset of terminal organ damage. Figure Figure. Survival of patients with non-cardiac AL amyloidosis according to baseline dFLC and alkaline phosphatase Disclosures Merlini: Millennium Takeda: Honoraria.

Efficacy of Bortezomib/Cyclophosphamide/Dexamethasone (VCD) Chemotherapy In Naive Patients with High Risk Cardiac Light Chain Amyloidosis (Mayo Clinic stage III)

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 5126-5126
Author(s):  
Arnaud Jaccard ◽  
Murielle Roussel ◽  
Anne Banos ◽  
David Lavergne ◽  
Jacques Ninet ◽  
...  
Keyword(s):  
High Risk ◽  
Mayo Clinic ◽  
Poor Prognosis ◽  
Cardiac Amyloidosis ◽  
Median Number ◽  
Stage Iii ◽  
Hematological Toxicity ◽  
Al Amyloidosis ◽  
Hematological Response

Abstract Abstract 5126 Purpose: Severe cardiac involvement is known to confer a poor prognosis in patients with AL amyloidosis. High-dose chemotherapy is not an option for these patients and melphalan/dexamethasone (M-Dex) therapy is not able to overcome this poor prognosis (Dietrich et al, 2010). Bortezomib (Bb) is known to induce rapid hematological response in amyloidosis and its association with cyclophosphamide and dexamethasone is proven to be highly active and effective in multiple myeloma. (Reeder, Leukemia 2009). We therefore proposed to use this regimen for patients with high-risk cardiac amyloidosis as defined by Mayo Clinic stage III, treated among the French network for amyloidosis. Patients and Method: We retrospectively evaluated 13 patients with systemic AL amyloidosis, classified as Mayo Clinic stage III cardiac amyloidosis based on their elevated cardiac biomarkers NT-proBNP and troponine-T values treated with VCD as first line treatment in 5 centres. To reduce toxicity in these frail patients Bb was administered once weekly with a usual dosage of 1.3 mg/m2 on days 1, 8, 15 and 22 in a 5 week schedule. Dexamethasone was given the day of Bb administration and the day after, 10 or 20 mg depending on patient age and performans status; cyclophosphamide, 300 mg/m2, max 500 mg, was given orally at days 1, 8 and 15. The new criteria defined at the international amyloidosis meeting in Roma in April 2010 were used to define the hematological response. Result: There were 7 women and 6 men, median age was 69 (55–81). Median NT-proBNP was 12325 ng/L (1036–66000) and median troponine-T was 0, 11 mg/mL (0.04–0.61). The median number of involved organ was 2 (1–5). Median difference between pathologic and normal FLC (dFLC) was 281 mg/L (82–2976). Height patients had a renal involvement. Median follow up of the entire cohort is 3.0 months (0–8), only 1 patients died, during ongoing VCD, probably from cardiac arrest. Median number of cycle was 3 (1–6). Height patients had a free light chain (FLC) measurement after 1 to 3 cycles (median 3) and all achieved an hematological response (4 CRs (50%), 3 PRs (37.5 %) and 1 VGPR (12.5 %) defined as a dFLC below 40 mg. The median dFLC of these 8 pts was 278 (137–3759) at diagnosis and 17.9 (0.6–298) at evaluation. We observed non-hematological toxicity in 5 patients, sepsis in 1, non fatal cardiac decompensation in 2, diarrhoea in 1 and bowel obstruction in 1. No neuropathy or hematological toxicity was observed. Therapy was stopped before the planned 6 – 8 cycles in 2 patients due to patient choice in 1 case and to clinician choice in 1 patient in CR. Therapy is still ongoing in 8 patients. Conclusion: The retrospective nature, small sample size and short follow-up limit this study (which should be updated for the meeting), but the impressive hematological response rate (CR-VGPR = 62.5%) obtained very rapidly, the low toxicity profile and the excellent OS with only 1 death in these very severe cohort of naive patients with Mayo stage III (median OS 3.5 months, Dispenzieri et al, 2004) already justify a prospective phase II trial using this regimen in Mayo stage III pts. Disclosures: Jaccard: Janssen: Honoraria, Research Funding.

Abstract 18297: Clinical and Prognostic Utility of Cardiac Magnetic Resonance Imaging in Multiple Myeloma Patients With Suspected Amyloidosis

Circulation ◽  
2014 ◽  
Vol 130 (suppl_2) ◽  
Author(s):  
Sabha Bhatti ◽  
Evan Watts ◽  
Fahd Syed ◽  
Abdul Hakeem
Keyword(s):  
Magnetic Resonance Imaging ◽  
Multiple Myeloma ◽  
Cardiac Mri ◽  
Cardiac Amyloidosis ◽  
Cardiac Involvement ◽  
Al Amyloidosis ◽  
Resonance Imaging ◽  
Prognostic Utility

Background: Upto 30% of patients with multiple myeloma have AL amyloidosis and cardiac involvement is associated with worse outcomes in these patients. Traditional screening modalities including EKG, echocardiography and biomarkers have limited value. The aim of this study was to evaluate the role of “screening” cardiac MRI in a large multiple myeloma population at a large specialized referral center. Methods & Results: 164 consecutive patients with multiple myeloma who underwent cardiac MRI between 6/2005 and 10/2011 were enrolled in this study. Primary endpoint was all cause death. Clinical, EKG, echocardiographic, biomarker and MRI predictors for death were analyzed. Mean age of population was 63+10 years, 40% females and 16% African Americans. 30% of the population had MRI evidence of cardiac involvement. There were 26 patients who had biopsy proven systemic amyloidosis, of whom 62% showed cardiac involvement on MRI. 81% patients with confirmed cardiac amyloidosis on endomyocardial biopsy had typical MR pattern of cardiac involvement. During a median follow up period of 702 days (mean 1019 (950) days), there were 59 deaths (36%). Amyloid pattern on cardiac MRI (OR 2.19), elevated BNP and increased LV wall thickness on MRI were significant predictors of mortality . (All p<0.05) Conclusions: This is the largest study to date evaluating the role of cardiac MRI in multiple myeloma patients with suspected cardiac amyloidosis. Cardiac MRI is a clinically robust tool for risk stratification of this subset of patients.

scholarly journals The Pattern of Organ Responses Varies in Patients with Systemic Light-Chain Amyloidosis and Heart or Kidney or Heart and Kidney Involvement Who Achieve Deep Hematologic Responses

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 2715-2715
Author(s):  
Diana Zhang ◽  
Danai Dima ◽  
Mumtu Lalla ◽  
Denis Toskic ◽  
Ping Zhou ◽  
...  
Keyword(s):  
Research Funding ◽  
Cardiac Involvement ◽  
Response Rate ◽  
Renal Involvement ◽  
Post Treatment ◽  
Cardiac Response ◽  
Renal Response ◽  
Kidney Involvement ◽  
Significant Difference ◽  
Organ Response

Abstract Introduction: In systemic light-chain amyloidosis (AL) aberrant clonal free immunoglobulin light chains (FLC) misfold and deposit in vital organs causing severe dysfunction (Nat Rev Dis Primers 2018;4:38). With anti-plasma cell therapy that reduces or eliminates the involved FLC (iFLC), defined organ responses can occur (N Engl J Med 2021;385:46, Blood Rev 2019;37:100581, Leukemia 2017;31:136, Blood 2014;124:2325). We asked whether the timing of individual organ responses may be influenced by the number of organs involved at diagnosis; therefore we evaluated the pattern of responses in patients with the two most commonly involved organs (heart, kidney) who achieved deep hematologic responses to therapy (CR=complete response, VGPR=very good partial response)(J Clin Oncol 2012;30:4541). We examined whether the rate of and time to organ response varied in patients with only heart or kidney or heart and kidney involvement, and whether the depth of hematologic response impacted the pattern of organ response. Methods: We performed a retrospective analysis AL patients diagnosed by tissue biopsy between 2007-2019 who had heart and/or kidney involvement at diagnosis and achieved hematologic CR/VGPR with treatment. Mann-Whitney was used to compare rates of organ responses and log-rank tests were applied to compare times to organ response among the subgroups as well as overall survival (OS) differences based on iFLC responses and on organ responses. Results were considered to be significant if two-sided P-value was less than or equal to 0.05. Results: We identified 111 patients with a median age of 62.5 years (range, 40-80) who met these criteria, 65 of whom (59%) were male. Cardiac involvement only was present in 34 (30.6%), renal involvement only in 31 (28.0%), and both cardiac and renal involvement in 46 (41.4%). Table 1 highlights patient characteristics. The median OS for the entire cohort was 112 months (95% CI 100-NA). The overall cardiac response rate was 62.5%, with a median time to response of 8 months (range, 1-73 months). Overall renal response rate was 67.1% with a median time to response of 10 months (range, 1-57 months). Log-rank analysis showed a significant difference in the OS based on post treatment iFLC levels (&lt;10 vs. 10-20 vs. &gt;20 mg/L) as we have previously described (Am J Hematol 2021;96:E20). Patients with kidney involvement only had significantly improved overall survival (OS) compared to those with cardiac involvement only (p=0.05), as expected. However, there was no difference in the OS of patients with cardiac only vs. cardiac and renal involvement (p=0.58), while there was a trend towards shorter OS in patients with cardiac and renal vs renal (p=0.09). The lower iFLC levels achieved post-treatment influenced cardiac response rate (p=0.07), and significantly impacted renal response rate (p&lt;0.01). For patients with cardiac involvement, iFLC responses did not have a significant impact on time to cardiac response, whereas for patients with renal involvement, faster responses were noted in those achieving lower iFLC levels (p=0.017) (Figure 1). There was no significant difference in time to cardiac response between patients with cardiac only vs. cardiac and renal involvement (p=0.93) whereas patients with renal only vs cardiac and renal involvement had a faster time to renal response (medians 14 (range, 10-29) vs 43 (13-not reached) months, p=0.018) (Figure 2). Conclusion: In AL patients with renal involvement who achieve CR/VGPR with treatment, post-treatment iFLC levels and co-presence of cardiac involvement play significant roles in the timing of renal responses. In AL patients with cardiac involvement who achieve CR/VGPR, post-treatment iFLC levels but not the co-presence of renal involvement influences the rate of cardiac response but neither influences the timing. These differences may be due to organ-specific factors such as proteomic adaptations or relative iFLC toxicity or complex cardio-renal hormonal interactions. Further hypothesis-driven study of these differences is warranted in this era of new and effective anti-plasma cell therapies. Figure 1 Figure 1. Disclosures Comenzo: Prothena Biosciences: Consultancy, Research Funding; Karyopharm: Research Funding; Takeda: Research Funding; Unum: Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi-Aventis: Membership on an entity's Board of Directors or advisory committees; Caelum: Consultancy, Research Funding; Janssen: Patents & Royalties: WO2016187546A1, Research Funding.

scholarly journals Efficacy and Tolerability of Daratumumab in Heavily Pretreated AL Amyloidosis: A Systematic Review

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 2025-2025 ◽  
Author(s):  
Muhammad Aadil Rahman ◽  
Ali Younas Khan ◽  
Awais Ijaz ◽  
Muhammad Junaid Tariq ◽  
Muhammad Usman ◽  
...  
Keyword(s):  
Heart Failure ◽  
Partial Response ◽  
Light Chain ◽  
Cardiac Amyloidosis ◽  
Cardiac Involvement ◽  
Renal Involvement ◽  
Renal Amyloidosis ◽  
Al Amyloidosis ◽  
Heavily Pretreated ◽  
Organ Response

Abstract Introduction Light chain (AL) amyloidosis is a low burden plasma cell disorder, characterized by deposition of misfolded lambda or kappa light chains. Kidney dysfunction is present in almost two-thirds of patients at the time of initial presentation, followed by diastolic heart failure in about 50% of cases, which is responsible for 75% of deaths in these patients. Autologous stem cell transplant (auto-SCT) remains the gold standard for the management of AL amyloidosis but is often impractical to perform by virtue of patients' age, medical comorbidities including cardiac involvement. Methods We conducted a literature search using three databases (PubMed, Embase,Web of Science). Our search strategy included MeSH terms and key words such as AL amyloidosis, daratumumab and darzalex from date of inception to March 2018. After excluding duplicates, reviews and non-relevant articles, we selected eight studies, including two case reports, two phase II prospective trials and four retrospective trials. Results Data on 129 patients was included, there ages ranged from 43-83 years. Median number of prior therapies were 3 (range: 2-6), 106 (82%) received proteasome inhibitor (bortezomib) based therapy, and 69 (53.5%) received immunomodulatory (lenalidomide) based therapy. Another 41 (32%) received high dose melphalan (HDM) followed by auto-SCT. The time from the diagnosis of AL to the start of daratumumab therapy varied from 0.7-150 months. Eighty-nine (69%) patients had cardiac and 64 (49.6%) patients had renal involvement. A total of 114 (88%) patients received a daratumumab dose of 16 mg/kg weekly for 8 weeks followed by every 2 weeks for the next 8 weeks. A total of 104 patients were evaluable for hematological response, assessed by improvement in free light chain (FLC) levels. Daratumamab achieved an impressive overall response rate (ORR) of 72% (n=75). Complete remission (CR) in 15 (14%) of patients, very good partial response (VGPR) in 44 (42%) and a partial response (PR) in 16 (15%) of patients was noted. Thirty-four patients with cardiac involvement and 26 patients with renal amyloidosis were assessed for organ response across four studies. Thirteen (38%) patients with cardiac amyloidosis demonstrated an improvement in N-terminal pro brain natriuretic peptide (NT-proBNP) levels. Ten (38%) patients with renal involvement responded according to consensus criteria [Palladini et al 2014] for organ response. Another two had improvement in serum creatinine levels. Among the 129 patients treated with daratumumab for AL amyloidosis, 36 (32%) reported infusion related reactions (IRR). Most were mild (grade 1-2). Daratumumab infusion was well tolerated in patients with cardiac (n=54) and renal involvement (n=48). Only one patient needed adjustment in his diuretic dose, another one developed decompensated heart failure and one died due to progression of cardiac disease. Seven patients had worsening of their NT-proBNP levels. Similarly, no dose adjustments were required for patients with renal amyloidosis and one patient tolerated daratumumab infusion at a GFR<20 mL/min without any complications. Conclusion Daratumumab monotherapy is associated with deep and prompt hematological responses in patients with heavily pretreated AL amyloidosis, at the standard dosing regimens used for multiple myeloma, with a favorable safety profile. Furthermore, daratumumab performed well in patients with cardiac amyloidosis even though there is an increased risk of volume overload and infusion related morbidity. Given the high incidence of peripheral neuropathy with bortezomib, cardiotoxicity with carfilzomib based regimens in amyloidosis patients, daratumumab appears to be a suitable alternative. It has already been approved for relapsed amyloidosis (AL) patients in the European Union. Currently, it is being investigated as monotherapy for AL amyloidosis in phase 2 trials (NCT02841033 and NCT02816476) and in combination with bortezomib, cytoxin and dexamethasone (VCd) in a phase III trial (NCT03201965). Disclosures No relevant conflicts of interest to declare.

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