High-Dose Melphalan and Stem Cell Transplantation for Patients with AL Amyloidosis and Cardiac Involvement

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 2043-2043
Author(s):  
Saulius Girnius ◽  
David C Seldin ◽  
Karen Quillen ◽  
Nancy T Andrea ◽  
John Mark Sloan ◽  
...  
Keyword(s):  
Overall Survival ◽  
Cardiac Involvement ◽  
Troponin I ◽  
Performance Status ◽  
Stage I ◽  
Stage Iii ◽  
High Dose ◽  
Al Amyloidosis ◽  
Cardiac Biomarker ◽  
High Dose Melphalan

Abstract Abstract 2043 Treatment of AL amyloidosis (AL) with high dose melphalan and autologous stem cell transplant (HDM/SCT) results in a high rate of durable complete hematologic responses associated with clinical responses and improvement in survival. However, patients with cardiac involvement are at increased risk of treatment-related mortality (TRM). Recently, cardiac biomarkers, B-type natriuretic peptide (BNP) and troponins, have been used to predict survival for AL amyloidosis patients, including those undergoing treatment with HDM/SCT. Here we report on treatment-related mortality (TRM), overall survival, and time to next treatment (progression) and hematologic responses in patients with AL amyloidosis and cardiac involvement, stratified by cardiac biomarker stage, treated with HDM/SCT. Eligibility for HDM/SCT was based upon strict functional and clinical criteria rather than upon staging based upon biomarkers, and required a Zubrod performance status <2, NYHA heart failure class < III, left ventricular ejection fraction (LVEF) >40%, and adequate cardiopulmonary reserve at a stair climb. Cardiopulmonary exercise testing was also used for some patients. Cardiac involvement was determined by electrocardiographic and echocardiographic abnormalities, as defined by Consensus Opinion of the 10th Symposium on Amyloid and Amyloidosis. A cardiac risk assessment or “cardiac staging” system incorporating biomarkers was used, with patients assigned to stage I (normal biomarkers, BNP < 100 pg/mL and troponin I < 0.1 ng/mL), II (one elevated biomarker) or III (both biomarkers elevated). Between 1/2008 and 10/2010, 35 patients with AL amyloidosis and cardiac involvement were treated with HDM/SCT. The median age was 58 years (range, 41–72). There were 17 males (49%) and 29 (83%) with lambda clonal plasma cell dyscrasia. All but one patient had multi-organ involvement and 80% (n=28) had renal involvement. Eleven percent (n=4) patients had cardiac biomarker stage I disease, 31% (n=11) had stage II disease, and 57% (n=20) had stage III disease. The median troponin I level was 0.121 ng/mL (range, 0.006 – 0.523), and the median BNP was 224 pg/mL (range, 18–923). The median interventricular septal thickness was 13 mm (range, 9–18) and the median LVEF was 60% (range, 40–70). Peripheral blood stem cells were mobilized using G-CSF alone at 10–16 m/kg/day for 3–4 days. The total dose of melphalan, administered over two consecutive days, depending on age, severity of cardiac disease and performance status. Forty % (n=14) received 200 mg/m2 HDM and 60% (n=21) received 140 mg/m2 HDM. TRM, defined as deaths within 100 days of SCT, occurred in 3 patients (9%), all cardiac stage III (3/20, 15% of the stage III patients); patients with cardiac stage I or II did not have any TRM. This compares to a TRM of 3% (n=1/30) in patients without cardiac involvement who were treated with HDM/SCT during the same time period (Fisher's exact test, p=0.6177). There were two additional deaths during the first year after HDM/SCT, one with cardiac stage II disease and one with stage III disease. Three-year overall survival for combined Stage I and II disease was 93%, for Stage III it was 76%, and for the cohort without cardiac involvement it was 96% (p=0.08). Three-year progression free survival for combined Stage I and II disease was 69%, for Stage III it was 45%, and without cardiac involvement it was 69% (p=0.0424). Median overall survival and progression free survivals have not been reached, with a median follow-up for 21 months. By intention-to-treat analysis, 23% (n=8) of patients achieved a hematologic complete response (CR) and 46% (n=16) a partial response (PR) at 1 year following HDM/SCT. Thirty % (n=11) required additional treatment by one year following HDM/SCT. While the cardiac biomarker stage III group clearly encompasses patients at high risk of early mortality from disease and complications of treatment, for patients that meet functional criteria for HDM/SCT, this therapeutic modality may offer the potential for effective treatment for selected stage III patients. Disclosures: No relevant conflicts of interest to declare.

Pulsed Low Dose Intravenous Melphalan in Patients with AL Amyloidosis, Ineligible for Aggressive Treatment with High-Dose Melphalan and Stem Cell Transplantation.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 2393-2393
Author(s):  
Vaishali Sanchorawala ◽  
David C. Seldin ◽  
Daniel G. Wright ◽  
Martha Skinner ◽  
Kathleen T. Finn ◽  
...  
Keyword(s):  
Stem Cell ◽  
Light Chain ◽  
Low Dose ◽  
Cardiac Involvement ◽  
Performance Status ◽  
Left Ventricular Ejection ◽  
High Dose ◽  
Al Amyloidosis ◽  
Aggressive Treatment ◽  
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. However, not all patients are able to tolerate HDM/SCT, particularly those with severe multisystem disease. Consequently, we investigated an alternative treatment regimen consisting of pulsed low-dose intravenous melphalan (LDM) for a series of patients considered ineligible for HDM/SCT because of severe cardiac involvement and poor performance status. LDM was administered at 17.5–25 mg/m2 every 4–6 weeks for 3–4 cycles depending upon patients’ clinical condition, renal function and performance status. Growth factor support was used with each cycle, and the dose of melphalan was reduced by 20% for white blood cell counts &lt;500/mm3 and/or platelet count &lt;20,000/mm3 during any treatment cycle. Changes in serum free light chain (FLC) levels, as well as toxicity and survival were evaluated. Fifteen patients with AL amyloidosis (11 males, 4 females; median age 55, range 47–69) were treated with this regimen between July 2002 and January 2004. Light chain isotypes were l in 11 cases and k in 4. All patients had clinically significant cardiac involvement with NYHA class III/IV congestive heart failure and/or left ventricular ejection fraction ≤ 45%, and/or ≥ 2 organ systems involved. The median number of LDM cycles given was 3 (maximum; 4), and 3 patients received only 1 cycle. Serum FLC levels were available before and after treatment in 10 patients. Eight of these patients (80%) achieved a &gt; 50% reduction in FLC levels, and 2 (20%) achieved normal FLC levels. One patient achieved a 20–25% reduction in the FLC, and 3 experienced no reduction. Of the15 patients treated, 2 patients survive 6 and 24 months after treatment, while 13 have died (median survival, 2 months; range, 0–10 months). Ten patients (67%) died within 35 days of initiating treatment. Transient myelosuppression was the major treatment-related toxicity with neutrophil and platelet nadirs occurring 12–16 days after melphalan infusions. There was 1 death from sepsis during treatment-induced myelosuppression. In summary, pulsed low-dose intravenous melphalan (LDM) was found to induce hematologic responses in most patients who could be evaluated. However, extended survival ≥ 2 years was observed in only 1 of the 15 patients with severe amyloidosis who were studied. Nonetheless, this regimen may benefit healthier patients, particularly those with less severe cardiac involvement, who are otherwise ineligible or unable to receive HDM/SCT.

Weekly Combination Chemotherapy with Cyclophosphamide, Bortezomib and Dexamethasone (CyBorD) for Newly Diagnosed Patients with Advanced Cardiac Disease Due to Systemic AL Amyloidosis

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 5139-5139
Author(s):  
Furha I. Cossor ◽  
Adam Boruchov ◽  
Michael Danso ◽  
Michael Edward Lee ◽  
Ayan Patel ◽  
...  
Keyword(s):  
Standard Therapy ◽  
Cardiac Involvement ◽  
Troponin I ◽  
Single Agent ◽  
Left Ventricular ◽  
Stage Iii ◽  
Al Amyloidosis ◽  
Cell Transplant ◽  
Newly Diagnosed ◽  
Hematologic Response

Abstract Abstract 5139 The treatment of systemic AL amyloidosis (AL) with advanced cardiac involvement (cardiac biomarker stage III) at diagnosis remains challenging and unsatisfactory. Median survival with melphalan and dexamethasone (MDex) in stage III patients is about 10 months from diagnosis with one quarter of patients dying within 3 months of starting therapy (BJH 2008;143:369; Blood 2010;116:522). Bortezomib has been shown to be the most active single agent in the treatment of AL (Blood 2011;118:865) and, when incorporated into CyBorD, clinical studies have shown a > 90% hematologic response rate in both myeloma and in AL (Blood 2010;115:3416; Leukemia 2009;23:1337; Amyloid 2010;17(S1):171a). In addition, bortezomib has been shown to have limited cardiac toxicity and no arrhythmogenicity in patients with AL and cardiac involvement (QJM 2011 published online July 13, 2011). Based on these data we have used CyBorD as initial standard therapy in patients with newly diagnosed systemic AL amyloidosis with advanced (stage III) cardiac involvement who are ineligible for stem cell transplant or clinical trials. We now retrospectively report the outcomes in the 11 consecutive stage III patients who have been treated thus far with CyBorD as initial standard therapy (6F, 5M). Patients were a median of 57 years old (range, 44–74) with median brain natriuretic peptide (BNP) of 709 (145–1490), troponin I of 0.29 (0.11–0.77), involved free light chains of 322mg/L (101–4325) and marrow plasma cells of 20% (4–41%). Median left ventricular (LV) ejection fraction and LV wall thickness (average of IVSd+LVPWd) by echocardiogram were 52% (35–70%) and 1.7cm (1.2–2.1) respectively. Patients received CyBorD on a 35-day cycle on days 1, 8, 15 and 22 with cyclophosphamide (300mg/m2) and dexamethasone (20 or 40mg flat dose) given orally or IV and bortezomib (1.3mg/m2) given IV or subcutaneously. Routine prophylactics included acyclovir, fluconazole and omeprazole. Patients have received a median of 4 cycles (1–8). Of the 11 patients, 2 died suddenly at 1 and 5 months, and 9 are alive with a median follow up of 8 months (3–15). Three patients experienced worsening congestive heart failure requiring hospitalization, medication adjustments and in 1 case pericardiocentesis. The gastrointestinal (GI) side-effects of bloating and constipation were common and usually manageable although 1 patient stopped therapy after 2 cycles because of lower GI bleeding. Of 10 patients evaluable for hematologic response, 8 responded (1 CR, 4 VGPR, 3 PR) (response criteria from Blood 2010;116:586a) and 2 had no response. Median time to response was 1 cycle (1–3). Thus far, there have been 4 patients (2 VGPR, 2 PR) who within months of starting therapy have had BNP reductions of 40% to 76% of baseline (median BNP reduction of 434pg/ml (282–712)). In conclusion, these retrospective data are encouraging and hopefully will spur the development of phase II and III trials in newly diagnosed patients with advanced cardiac involvement due to AL. Disclosures: Off Label Use: Pentostatin and Extracorporeal photopheresis are not FDA approved for conditioning prior to allogeneic transplant.

Autologous stem cell transplantation (ASCT) in AL amyloidosis: Feasibility outside national amyloidosis referral centers and proposal for simpler pre-transplant staging

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 17545-17545
Author(s):  
N. Jain ◽  
M. Pasquini ◽  
M. Paul ◽  
P. Hari
Keyword(s):  
Multiple Myeloma ◽  
Stem Cell ◽  
Hospital Stay ◽  
Stage I ◽  
High Dose ◽  
Al Amyloidosis ◽  
Cell Transplant ◽  
Safe Procedure ◽  
Hematological Response ◽  
High Dose Melphalan

17545 Background: Single center data from national amyloidosis referral centers suggest that high dose melphalan based ASCT is an effective upfront treatment strategy for AL amyloidosis. Absence of published randomized control trials, referral bias and center experience make generalizability of this data difficult since data from outside of major referrals centers is limited. Pre-transplant staging is complicated by the profusion of articles describing various adverse risk factors. Methods: Retrospective review of bone marrow transplant database at our institution was conducted. All patients with AL amyloidosis who underwent ASCT were included in the study. We stratified patients based on International Staging System (ISS) for multiple myeloma. Organ and hematological response were assessed using 2005 consensus guidelines. Results: 13 patients (6 males) underwent ASCT for AL amyloidosis with risk adapted high dose melphalan dosing (melphalan mg/m2 100 (n = 1), 150 (n = 8) and 200 (n = 4)). Median age of the patient population was 53 years (range 31–75 years). Organ involvement was as follows - single organ = 6, 2 organs = 4 and 3 organs = 3. 4 patients had cardiac amyloidosis. 100 day transplant related mortality (TRM) was 15.3%. Overall survival was 84 % (95 % CI 51–96%) @ 1 yr and 75% (95% CI 38–91%) @ 2 yrs. Median follow up was 18 months. No deaths were observed >17 months post-transplant. 45 % patients had organ response. Complete hematological response was observed in 45 % patients. Mean duration of peri-transplant hospital stay for ISS stage I, II and III were 20.5 days (n = 2), 23.3 days (n = 9) and 29 days (n = 1) respectively. Number of deaths observed in ISS stage I, II and III were 0 (0/2), 2 (2/9) and 1 (1/1) respectively. Conclusions: Autologous stem cell transplant (ASCT) for AL amyloidosis is a feasible, effective and safe procedure outside of major national referral centers. Pretransplant stratification of amyloidosis patients using ISS for multiple myeloma indicated a trend towards longer peri-transplant hospital stay and mortality with increasing ISS stage. This hypothesis needs to be tested in larger studies. No significant financial relationships to disclose.

scholarly journals Safety and efficacy of high-dose melphalan and auto-SCT in patients with AL amyloidosis and cardiac involvement

2013 ◽  
Vol 49 (3) ◽  
pp. 434-439 ◽  
Author(s):  
S Girnius ◽  
D C Seldin ◽  
H K Meier-Ewert ◽  
J M Sloan ◽  
K Quillen ◽  
...  
Keyword(s):  
Cardiac Involvement ◽  
High Dose ◽  
Al Amyloidosis ◽  
Safety And Efficacy ◽  
High Dose Melphalan

scholarly journals Exploration of the Appropriate NT-Probnp Level for AL Amyloidosis Staging

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 3777-3777
Author(s):  
Hana Kim ◽  
Darae Kim ◽  
Jinoh Choi ◽  
Eunseok Jeon ◽  
Jung Eun Lee ◽  
...  
Keyword(s):  
Overall Survival ◽  
Mayo Clinic ◽  
Medical Center ◽  
Stage Iv ◽  
Stage I ◽  
Stage Ii ◽  
Stage Iii ◽  
Al Amyloidosis ◽  
School Of Medicine ◽  
Staging Systems

Abstract Exploration of the Appropriate NT-proBNP Level for AL Amyloidosis Staging Hana Kim, MD 1, Darae Kim, MD, PhD 2, Jin-Oh Choi, MD, PhD 2, Eun-Seok Jeon, MD, PhD 2, Jung Eun Lee, MD, PhD 3, Ju-Hong Min, MD, PhD 4, Joon Young Choi, MD, PhD 5, Jung-Sun Kim, MD, PhD 6, Seok Jin Kim, MD, PhD 1, Kihyun Kim, MD, PhD 1 1 Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea 2 Division of Cardiology, Department of Medicine, Heart Vascular Stroke Institute, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea 3 Division of Nephrology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea 4 Department of Neurology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea 5 Department of Nuclear Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea 6 Department of Pathology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea The most important factor affecting prognosis of systemic light chain (AL) amyloidosis is severity of cardiac damage. For this reason, cardiac biomarkers are used in European 2015 and Mayo clinic 2012, two representative staging systems for AL amyloidosis. Since the NT-proBNP levels of the existing AL amyloidosis staging systems are different, we tried to find the appropriate NT-proBNP level in our 16-year AL amyloidosis patient cohort. Newly diagnoded AL amylodosis patients between August 2004 and July 2020 were included in this study (n=401). Patients who did not have laboratory results for staging had been exclude (n=86). Among them, 86 patients of stage III and 145 patients of stage IV patients (according to Mayo clinic 2012 stage) were analyzed (n=231). Of the 231 stage III, IV patients, 25, 82, 47, and 77 patients were classified as a group of NT-proBNP ≤1800, 1800 &lt; NT-proBNP ≤5000, 5000&lt; NT-proBNP ≤8000, and NT-proBNP &gt;8000 (ng/L), respectively. The characteristics and overall survival of each group were investigated through statistical analysis. Age at diagnosis (p=0.016), ECOG (p=0.046), serum creatinine(p=0.001), and Estimated glomerular filtration rate (eGFR) (p=0.003) had statistically significant differences in the groups divided by the NT-proBNP criteria. With 54.4 months of median follow up, the overall survivals analyzed by Mayo clinic 2012 were stage I: not reached, stage II: 49.6 months, stage III: 46.8 months, and stage IV: 11.9months, respectively. As a result of European 2015 analysis, stage I: not reached, stage II: 65.9 months, stage IIIa: 41.4 months, stage IIIb: 4.3 months.) In our analysis according to NT-proBNP (ng/L) in stage III and IV patients, the overall survival of NT-proBNP ≤1800 group has not yet been reached. The median OS of group 1,800&lt;NT-proBNP ≤5000, 5000&lt; NT-proBNP ≤8000, and NT-proBNP &gt;8000 were 54.8 months, 11.9 months, and 4.5 months, respectively (p &lt;0.001). The Kaplan-Meier's curve for OS had a clear difference at NT-proBNP 5000 value. On the basis of NT-proBNP, the OS of less than 5000 group was 62 months, and the OS of 5000 or more group was 5.9 months. In analysis of factors affecting the OS, statistically significant results were age at diagnosis (p = 0.018), ECOG (p = 0.002), and NT-proBNP 5000 ng/L or higher (p &lt; 0.001). The dFLC included in the Mayo clinic 2012 was found to have a statistically insignificant on the overall survival (p=0.584). Although disease stage is important in predicting the prognosis of AL amyloidosis, it was revealed that NT-proBNP is the most important factor in predicting survival prognosis. In this study we confirmed that AL amyloid patients with high NT-proBNP of &gt;5000 ng/L may have particularly poor survival rate. When staging AL amyloidosis, it can be considered based on NT-proBNP 5000 ng/L level. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

Tandem Cycle High-Dose Melphalan and Busulfan/Cyclophosphamide Followed by Maintenance Interferon Alpha-2 (IF) with or without Thalidomide (Thal) Is Associated with High Complete and Very Good Partial Response Rates, Improved Progression-Free, and Overall Survival.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 3089-3089
Author(s):  
George Somlo ◽  
Dajun Qian ◽  
Firoozeh Sahebi ◽  
Neil Martin Kogut ◽  
Roberto Rodriguez ◽  
...  
Keyword(s):  
Overall Survival ◽  
Radiation Therapy ◽  
Karnofsky Performance Status ◽  
Performance Status ◽  
Concomitant Administration ◽  
Entire Group ◽  
High Dose ◽  
Day Range ◽  
High Dose Melphalan ◽  
To Receive

Abstract Tandem cycle high-dose melphalan (Mel) followed by Mel +/− total body radiation therapy improves progression-free (PFS) and overall survival (OS) in comparison to single cycle Mel, but is associated with 3% treatment-related mortality (TRM). We tested a new tandem regimen (THDCT) followed by maintenance therapy in order to lower TRM, while enhancing efficacy. Between 5/94 and 8/04, 114 patients (pts) were enrolled on 2 sequential studies. First, pts received Mel 150 mg/m2 [cycle 1 (C1)], oral busulfan (bu 16 mg/kg; 46 pts), and cyclophosphamide 120 mg/kg (Cy; C2); the next cohort received the same THDCT but bu was given intravenously (i.v. 12.8 mg/kg; 68 pts). All pts were to receive maintenance IF 3 million units/m2 given subcutaneously, 3 times/week. Pts participating on the 2nd study were to receive thal together with IF provided that they were not in CR at 6 months post-THDCT. Peripheral blood progenitor cell mobilization consisted of G-CSF 10 microgram/kg to procure 4 x 106 CD34+ cells/kg without (first 46 pts) or with Cy 1.5 g/m2 (last 68 pts). Pts ≤65 years, with responsive or stable MM, with <40% marrow involvement, with a creatinine clearance of 70 cc/min and Karnofsky performance status of 70% were enrolled. Median age was 52 years (range: 29–65); 70% of pts were diagnosed with stage III MM, and 4 pts presented with plasma cell leukemia; 40% received prior radiation therapy. Pts received a median of 1(1–3) induction chemotherapy regimens; the median time from diagnosis to THDCT was 8 months (range: 2–73); 89% of pts received both C-s at a median of 76 days (range, 29–134). Among the first 46 pts (treated with oral bu) there were 7 cases of veno-occlusive disease (VOD): 3 were fatal, resulting in TRM of 7%. There were 8 cases of VOD in the 68 pt cohort treated with i.v. bu, one of whom died of multi-organ failure/sepsis (TRM:1.5%). Eighty nine percent of pts tolerated at least 1 million units/m2 of IF 2–3 times/week. Of pts receiving concomitant IF and thal (median dose of thal: 100 mg/day[range, 50–400]), only 7 pts tolerated both (median: 4 months; range: 1.6–18 months), 3 of whom converted to CR. At best response 44% pts were in CR and 12% achieved 90% reduction (very good partial remission (VGPR). For the entire group, 3-year PFS is 50% (95% CI, 40–59%) and OS is 71% (95%CI, 61–78%). Three-year PFS is 66% (95% CI 52–76%) vs. 29% (95% CI 16–42%) and OS is 87% (95% CI 76–93%) vs. 49% (95% CI 35–63%) favoring pts in CR and VGPR vs. all others. THDCT with Mel and i.v. bu /Cy and maintenance IF can be given safely, and may provide an alternative regimen to tandem Mel. Concomitant administration of IF and thal is not feasible. Thal should be used either in sequence or in lieu of IF as maintenance.

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.

European Collaborative Study of Treatment Outcomes in 347 Patients with Systemic AL Amyloidosis with Mayo Stage III Disease

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 995-995 ◽  
Author(s):  
Ashutosh Wechalekar ◽  
Stefan O Schonland ◽  
Efstathios Kastritis ◽  
Philip N Hawkins ◽  
Meletios A. Dimopoulos ◽  
...  
Keyword(s):  
Risk Factors ◽  
Overall Survival ◽  
Clinical Trials ◽  
High Risk ◽  
Cardiac Involvement ◽  
Staging System ◽  
Stage Iii ◽  
Al Amyloidosis ◽  
High Risk Factors ◽  
Intent To Treat

Abstract Abstract 995 N-terminal fragment of BNP (NT-proBNP) and cardiac troponin –T (TnT) or I (TnI) form a useful staging system in AL amyloidosis and poor outcomes have been reported in stage III patients treated before routine use of novel agents. These patients are routinely excluded from clinical trials and prospective outcome data is limited but recent studies suggest that some such patients may have better outcomes. We report the outcomes of 347 patients with Mayo stage III AL amyloidosis seen at the amyloid centres in London (UK), Pavia (Italy), Heidelberg (Germany) and Athens (Greece). Organ involvement and responses are defined according to 2005 amyloidosis consensus criteria. Presenting features were [n (%)/median (range)]: cardiac, renal and liver involvement in 338 (97%), 216 (62%) and 77 (22%) respectively, NT-proBNP 9106 ng/L (379–216187); TnI – 0.18 ng/ml (0.1–12); TnT −0.09 ng/ml (0.04–8.2) and IVS 15 mm (7–24). Treatments given were: Bortezomib combinations - 23 (7%), MDex - 150 (43%), thalidomide combinations - 96 (28%), lenalidomide combinations - 13 (4%). 30 (8%) were deemed too ill for treatment or died prior to treatment initiation. Only 37% completed the planned treatment course. The haematological responses on an intention to treat basis were seen in (Overall response rate/complete response (CR)/partial response (PR))(n(%)): MDex – 63(42%)/24 (16%)/39 (26%); Thalidomide combinations 31(32%)/11(12%)/20(21%), bortezomib combinations 10(43%)/6 (23%)/4 (17%), lenalidomide combination 5(38%)/0(0%)/5(38%). The median overall survival (OS) was 7.1 mos. The overall survival at 12 months from response evaluation was 74% for CR, 52% for PR and 18% for NR and from diagnosis was (median): CR – 59 mo, PR 28 mo, NR 10 mo and not assessable for response 2.9 mos. Stage III patients without echocardiographic evidence of cardiac involvement had excellent outcomes with 80% estimated 2 year OS. Using best fit cut-off, in multivariate model (including NT-proBNP., systolic blood pressure (SBP), ejection fraction, NYHA, ECOG, dFLC, LV wall thickness), NT-proBNP > 8000 ng/L (HR 2.3; p <0.0001) and SBP < 100 mm of Hg (HR 1.6; p<0.0001) were the only independent predictors of poor outcome. Using NT-proBNP >8000 ng/L and SPB <100 mm of Hg as high risk criteria, stage III patients can be further subdivided based on presence of none, one or two criteria with OS of 25 mo, 6 mo and 3 mo respectively. Using these criteria, on intent to treat basis, OS by CR/PR/NR was: no high risk factors – median not reached/69 mo/7 mo and one high risk factor - 59 mo/23 mo/4 mos respectively and too few patients for patients with two high risk factors making comparison unreliable. In conclusion, outcomes amyloidosis patients with stage III disease remain poor. However, stage III patients are heterogeneous and combination of NT-proBNP and SBP can usefully sub-classify these patients. Patients with abnormal biomarkers just due to renal failure in absence of cardiac involvement should be excluded from the current Mayo staging system. Although, treatment responses of stage III patients, on intent to treat basis, are poor with all regimes, it is encouraging that haematological responses improve outcomes and patients who achieve a CR have best outcomes. Clinical trials are urgently needed in patients with stage III disease to confirm these findings and define optimal treatment options. Disclosures: No relevant conflicts of interest to declare.

B Type Natriuretic Peptide (BNP) Less Than 200 Pg/Ml Represents Good Candidate For High Dose Melphalan and Predicts Longer Survival In Systemic Light Chain Amyloidosis

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 5523-5523
Author(s):  
Toshiaki Hayashi ◽  
Hiroshi Ikeda ◽  
Yuka Aoki ◽  
Yumiko Maruyama ◽  
Tadao Ishida ◽  
...  
Keyword(s):  
Diastolic Function ◽  
Natriuretic Peptide ◽  
Light Chain ◽  
Contractile Function ◽  
Performance Status ◽  
Conditioning Regimen ◽  
High Dose ◽  
Al Amyloidosis ◽  
Organ Response ◽  
High Dose Melphalan

Abstract Background High dose melphalan with autologous stem cell transplantation (ASCT) is a standard treatment for eligible patients with systemic light chain (AL) amyloidosis. Treatment-related mortality (TRM) of ASCT for AL amyloidosis was previously reported being as high as 40%; however, risk-adapted melphalan dosing reduced TRM to about 10% or less in experienced institutes. Several ways to determine the dose of melphalan have been proposed. They were focusing on organ failures especially cardiac dysfunction shown by ejection fraction (EF). EF represents contractile function of the heart; however, in AL amyloidosis, EF is known to be maintained until late stage whereas diastolic function is damaged earlier. We here present the outcomes of AL patients who received ASCT following risk-adapted melphalan with our criteria including B type natriuretic peptide (BNP) which is a practical marker for diastolic function of the heart and less affected by the renal function than NT-proBNP. Patients and Methods A total of 12 patients with primary systemic AL amyloidosis treated with HD-Mel with ASCT at Sapporo Medical University Hospital between 2004 and 2012 were evaluated. Patients with age older than 65 years, poor performance status or severe organ dysfunction were determined not to eligible for ASCT. The dose of melphalan for conditioning regimen was modified due to patients' condition. A dose of 200 mg/m2 was administered to patients in performance status (ECOG) 0 or 1, number of organ involvement 2 or less, serum creatinine <1.5 mg/dl, EF >50%, and BNP <200 pg/ml; otherwise 140 mg/m2. Hematological response (HR) and organ response (OR) were evaluated according to the Consensus Opinion from the 10th International Symposium on Amyloid and Amyloidosis. The Kaplan-Meier method was used to estimate event-free survival (EFS) and overall survival (OS); both of them were measured from the day of ASCT. Results Twelve patients were included in this study, 4 were women. The median age at transplantation was 54 years (range, 32 - 65 years). Involvement of 1 organ was present in 1 patient (8.3%), 2 organs were involved in 8, and 3 or more organs in the remaining 3. Ten patients had a lambda monoclonal protein, and the median percentage of plasma cells in the bone marrow was 2.5% (range, 0.2% - 9.6%). No patients received treatment before HDM/ASCT, except 2 patients treated high-dose dexamethasone or 1 course of VAD regimen before referring to our hospital. Six patients received 200 mg/m2 of melphalan and remaining six received reduced dose based on the criteria in Patient and Methods. Notably, it was possible to screen patients with only the value of BNP; i.e., all the patients who received 140 mg/m2 of melphalan by the criteria had a high level (more than 200 pg/ml) of BNP. The median time from diagnosis of AL to ASCT was 95 days (range, 47 to 195 days). The median number of CD34-positive cells infused was 3.55 x106/kg, and all patients were engrafted. The hematologic CR was achieved in 5 patients and PR in 2. The organ response was observed in 2 patients who achieved hematologic CR. The median EFS of all patients was 21.1 months (range, 3.4 to 70.8 months), and median OS was 21.1 months (range, 3.4 to 112.5 months). EFS and OS were significantly longer for patients who received 200 mg/m2 of melphalan that are same with patients who had BNP less than 200 pg/ml, compared with a lower dose of melphalan and higher level of BNP (EFS: 15.0 months vs not reached, p=0.0166; OS: 15.0 months vs not reached, p=0.0166). No TRM was observed. Conclusions AL patients with less than 200 pg/ml of BNP can be safely performed HD-Mel with ASCT and expected longer survival. Disclosures: No relevant conflicts of interest to declare.

Sign in / Sign up

Export Citation Format

Share Document