Organ Response Rates Research Articles

Phase II Trial of Cyclophosphamide, Lenalidomide and Dexamethasone (CYCLO-LEN-DEX) for Previously Untreated Patients with Light-Chain Amyloidosis (AL)

Background: Treatment with oral melphalan and dexamethasone has been adopted as the standard of care for newly diagnosed patients with immunoglobulin light chain (AL) amyloidosis not eligible for high-dose melphalan and stem cell transplantation (HDM/SCT). However, new treatment options are still needed for this patient population.Aim: Based on the activity of IMiDs® immunomodulatory drugs in relapsed/refractory AL amyloidosis, we designed a multicenter prospective, phase II trial with lenalidomide, dexamethasone and cyclophosphamide for newly diagnosed patients not eligible for autologous transplant.Patients and methods: The main inclusion criteria were newly diagnosed AL amyloidosis confirmed by biopsy, significant organ involvement, cardiac ejection fraction over 50%, serum creatinine below 3 mg/dL, and not being eligible for autologous transplant. Treatment schedule consisted of 6 cycles of lenalidomide at 15 mg orally (po) on days 1 to 21, dexamethasone at 20 mg po on days 1 to 4 and 9 to 12, and cyclophosphamide at 300 mg/m2 intravenously (iv) on days 1 and 8 every 28 days, followed by 6 more cycles of lenalidomide at the same dose, dexamethasone at 20 mg po on days 1 to 4 and cyclophosphamide 300 mg/m2 iv on day 1. After these 12 cycles, maintenance with lenalidomide (10 mg po on days 1 to 21) and dexamethasone (20 mg po on days 1 to 4) was planned for three additional years or until discontinuation due to intolerance or disease progression. All patients received prophylaxis of thromboembolic events with oral aspirin (100 mg po daily) or subcutaneous low-molecular-weight heparin. The primary endpoint was hematologic response. Diagnosis of AL amyloidosis, definition of organ involvement and response criteria followed the Consensus Opinion from the Xth International Symposium on Amyloid and Amyloidosis (Gertz et al, Am J Hematol 2005), adding the very good partial response category included in the recently reported criteria (Palladini et al, J Clin Oncol 2012). Assessments of response were performed at the beginning of each cycle during the treatment period and every 3 months during the maintenance phase.Results: From September 2010 to December 2012, 28 patients were enrolled in the study. Twenty-three patients had cardiac involvement, with cardiac stage 3 in 14 of them. The overall hematologic response rate was 46%, including 7 patients (25%) with complete response, 5 patients (18%) with very good partial response and 1 patient (3%) with partial response. The organ response rate was 46% and was only observed among patients who achieved hematologic response. The organ response was reached in 10 (43%) of the 23 patients with renal involvement and 6 (26%) of the 23 patients with cardiac involvement. In 4 patients lenalidomide was reduced or discontinued due to toxicity. A therapy-related serious adverse event was reported in 6 patients. No significant cytopenias and no second primary malignancies (SPM) were observed. So far, 11 patients remain on the study. Seventeen (60%) have been discontinued mostly due to death secondary to cardiac or renal AL-related late events (8 patients), progression or lack of response (4), and toxicity (3). After a median follow up of 24 months, the median PFS and OS have not been reached, being significantly longer in responders. The estimated probability of PFS and OS for responders was 92% at 34 months. In contrast, the median PFS and OS for non-responders were only 1.9 and 2.4 months, respectively. Finally, according to Mayo Clinic risk stratification based on cardiac biomarkers, median OS for patients with stage I-II has not been reached (the 2-year estimate was 100%), and was 2.2 months for stage III (p <0.001; Figure 1).Conclusions: Our results support the efficacy and safety of the combination lenalidomide, dexamethasone and cyclophosphamide as a new treatment option for patients with AL amyloidosis not eligible for ASCT, without the risk of neuropathy associated with bortezomib-based therapies. However, this regimen should be preferably used when the organ function is still preserved since patients with advanced stage disease, particularly those with severe cardiac involvement, are unlikely to benefit. [Display omitted] DisclosuresBlade:Janssen, Celgene and Onyx: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding. Off Label Use: Lenalidomide. First-line therapy in combination for AL amyloidosis.. Oriol:Janssen and Celgene: Honoraria. Lahuerta:Celgene: Honoraria; Janssen: Honoraria. Mateos:Celgene: Honoraria, Membership on an entity’s Board of Directors or advisory committees. de la Rubia:Janssen and Celgene: Honoraria, Membership on an entity’s Board of Directors or advisory committees. Fernandez de Larrea:Janssen and Celgene: Honoraria, Membership on an entity’s Board of Directors or advisory committees. San Miguel:Celgene: Honoraria, Membership on an entity’s Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity’s Board of Directors or advisory committees; Onyx: Honoraria, Membership on an entity’s Board of Directors or advisory committees; Millenium: Honoraria, Membership on an entity’s Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity’s Board of Directors or advisory committees. Cibeira:Janssen and Celgene: Honoraria.

Induction Bortezomib in AL Amyloidosis Followed By High Dose Melphalan and Autologous Stem Cell Transplantation: A Single Institution Retrospective Study

High-dose melphalan (HDM) followed by autologous stem cell transplant (ASCT) for light chain amyloidosis (AL) was performed in 31 patients at Oregon Health and Science University between 2005 and 2012. Fifteen patients had cardiac involvement. Patients received melphalan 200 mg/m(2) or dose-adjusted HDM (100-140 mg/m(2)) depending on high risk features. Thirteen patients proceeded directly to ASCT after diagnosis, 12 patients received a bortezomib-containing regimen, and 6 received a variety of other induction regimens. The day 100 treatment-related mortality was 9.6%. Overall hematologic (ORR) and organ response rates (OR) in the whole cohort after ASCT were 77% and 58%. ORR and OR in the bortezomib pretreated group were 92% and 75% vs. 69% and 54% in the group that received no pretreatment. The median time to maximum hematologic response after ASCT was reduced in the group that received bortezomib induction (3 vs. 14 months). Overall cardiac response rate was 60%; 100% in patients pretreated with bortezomib and 43% in those without induction treatment. With a median follow-up of 2.9 years, the 3-year progression-free and overall survival rates in the entire cohort were 66% and 73% and in those with cardiac involvement, 73% and 80%. We observed that bortezomib-based induction is well tolerated in patients with and without cardiac involvement and suggest that this approach be studied in prospective multi-institutional trials.

Improved Stem Cell Transplant Related Mortality for AL Amyloidosis At a Single Transplant Center

Abstract 2016The role of AHSCT in AL amyloidosis is controversial. There is evidence that AHSCT offers long term disease control with high organ response rates, however, the only randomized phase III trial comparing transplant with conventional melphalan and dexamethasone therapy deemed transplant inferior. Better understanding of risk stratification for SCT candidacy has resulted in TRM rates are as low as 5.6% in some series. The goal of the current study was to evaluate the TRM rate for all consecutive patients who have undergone AHSCT for AL amyloidosis at institution. Special attention in evaluation of any detectable differences in TRM over the time period of this review was a major goal of this project.Retrospective review was performed of all patients with primary AL amyloidosis who have undergone AHSCT at our institution. The database captured patients from December 2001 and our study includes patients through February 2012. Patients who were diagnosed with secondary amyloidosis by the stem cell transplant service and/or referring oncologist were excluded. TRM was defined as death from any cause within 100 days post stem cell infusion. We then evaluated data from the entire cohort and divided it into two different time periods: 2001–2006 and 2007–2012.Thirty-nine patients had an initial AHSCT during the study period. Nine patients were enrolled in the SWOG 0115 trial which comprised tandem autoSCT using 100 mg/m2 of melphalan conditioning 3–6 months apart. Of those, 6/9 (66%) had both transplants. For purposes of this abstract we report on the data resulting from first transplantation only for patients in the SWOG 0115 trial. The median age at transplant for the entire cohort was 57.6 years old (39–74). Males represent 64% of the patients. Most of the patients had symptomatic involvement of one organ (48.7%) with 23% having more than 2 organs involved. There were 14 patients transplanted in the 2001–2006 period and 25 patients in the 2007–2012 period. Overall TRM for 2001–2012 was 5.1%. During the 2001–2006 period TRM was 14% (2/14 patients). No TRM occurred for patients transplanted from 2007–2012. Overall survival (OS) improved when separately comparing the two study periods. Overall survival was 64% at 3 years in the 2001–2006 cohort and 92% at 3 years in the 2007–2012 cohort.Patients in the 2007–2012 cohort include all patients enrolled to SWOG 0115. Sixty percent of patients reported for that period received <200mg/m2 melphalan for transplant conditioning. Eight of nine patients enrolled in SWOG 0115 received 100 mg/m2, one received 140mg/m2. Six patients treated on our institution’s standard amylodosis SCT protocol received 140mg/m2 conditioning. The remaining ten patients received 200mg/m2 melphalan. Patients in the 2007–2012 period were more likely to receive induction treatment prior to transplant with novel regimens (72% vs 21% p=0.003). In addition, these patients were more frequently diagnosed with amyloid cardiac involvement. For purposes of this abstract amyloid cardiac involvement is defined according to whether or not the SCT team concluded on the basis of history, physical examination and available ancillary data (including echocardiography) that the patient had amyloidotic cardiac disease (40% vs 14% p=0.15). All patients had echocardiography pre-AHSCT. The mean Inter Ventricular Septum (mIVS) thickness was 14.5 mm in the 2007–2012 period vs. 11.7 mm in the 2001–2006 one p=0.004.Univariate analysis of risk factors affecting improved OS identified year of transplant (>2006; p=0.03), number of treatments pre-transplant (>1; p=0.04), and time from diagnosis to transplant (>4mo; p=0.05) as factors associated with improved survival. Number of organs involved (>1; p=0.06) showed a trend towards worse survival.In conclusion, our single institution data demonstrates a reduction in TRM over the past 5 years. Reasons for improvement in TRM are under investigation and may include better risk stratification, better supportive care (including frequent hospitalization for cardiac monitoring in high-risk patients) and improvement in pre-AHSCT performance status for those patients receiving induction therapy with novel agents. [Display omitted] Disclosures:Holmberg:Millenium: Research Funding; Otsuka: Research Funding; Merck: Research Funding; Seattle Genetics: Research Funding; Sanofi: Research Funding.

Circulating B-cell activating factor level predicts clinical response of chronic graft-versus-host disease to extracorporeal photopheresis

AbstractExtracorporeal photopheresis (ECP) is an important therapeutic option in steroid-refractory chronic graft-versus-host disease (cGVHD). Few biomarkers predicting response exist. We measured serum B-cell activating factor (BAFF) in 46 cGVHD patients receiving ECP before and during treatment course. BAFF level at 1 month of ECP predicted 3- and 6-month skin disease response, with BAFF less than 4 ng/mL associated with significant skin improvement and complete resolution in 11 of 20 patients. High BAFF at 1-month ECP associated with a worsening median 6-month skin score and resolution in 1 of 10 patients. BAFF level at 3 months also predicted the likelihood of maintaining skin disease improvement at 6 months. BAFF level was not correlated directly with extracutaneous cGVHD response, although full cutaneous responders exhibited improved extracutaneous organ response rates compared with skin nonresponders (65% vs 35%). This study suggests that early BAFF measurement during ECP for cGVHD represents a potentially useful biomarker in prediction of treatment outcome.

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

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

Outcome of Patients with AL Amyloidosis Who Do Not Achieve Hematologic Complete Response After Treatment with High Dose Melphalan and Autologous Transplantation: Results In a Series of 421 Patients

AbstractAbstract 2394 Background:Treatment of AL amyloidosis with high-dose melphalan and autologous stem-cell transplantation (HDM/SCT) results in hematologic complete response (CR) in 40% of patients and a median survival of about 5 years. Hematologic CR is associated with improved organ function and long survival. Whether patients who fail to achieve CR have any benefit from HDM/SCT has not been examined in a large series of patients. OBJECTIVE: The aim of this study was to investigate the outcome of patients with AL who do not achieve a CR after HDM/SCT and assess the transplant-related mortality (TRM) at a single specialized referral center. DESIGN and PATIENTS: Retrospective analysis of 421 patients with AL amyloidosis treated with HDM/SCT (100 to 200 mg/m2) in the Amyloid Treatment and Research Program at Boston Medical Center between July 1994 and December 2008. The subgroup of patients who did not achieve a CR at 1 year after transplant was analyzed in detail to assess their outcome in terms of organ response, event-free survival (EFS) and overall survival (OS). The median follow-up was 4 years (range, 0 to 15.6) for the entire cohort and 6.3 years (range, 1 to 15.6 years) for surviving patients. RESULTS: Three hundred and forty patients out of 421 included in the study (81%) were evaluable for response at 1 year post-HDM/SCT. The CR rate among the 1-year survivors was 43% while 195 patients (57%) did not achieve a CR, defined as disappearance of all signs of monoclonal gammopathy and bone marrow plasmacytosis. By consensus criteria, organ response rate in the non-CR group was 53.3%, compared to 78.6% for CR-patients (p<0.0001). Hematologic and/or clinical progression was observed in 68% (133/195) of non-CR patients, with a median time to progression of 1.5 years (range, 0.13 to 11.3). More than half of these patients (68/133) received second line therapy with melphalan (4), thalidomide (21), bortezomib (8), lenalidomide (24), dexamethasone (8), a second HDM/SCT (2), and a reduced-intensity allogeneic SCT (1). Fifty (26%) of the non-CR patients are alive and clinically stable, although 12 of them received further treatment due to persistence of clonal disease without evidence of clinical/organ progression. Median EFS in the non-CR population was 2 years (CI95% 1.6–2.7), as compared with 8.3 years for patients in CR (p<0.0001). Outcome of non-CR patients in terms of event rate and EFS was not influenced by the light chain isotype. The OS was significantly longer for evaluable patients who achieved a CR compared with those who did not (13.2 versus 5.9 years, p<0.0001). The estimated probability of survival for patients in CR was 86% (CI95% 79–91%) at 5 years and 67% (CI95% 57–76%) at 10 years, while it was 58% (CI95% 50–65%) and 24% (CI95% 16–32%) at 5 and 10 years, respectively, for those who did not achieve CR. At the time of this analysis, 234 (55.5%) of the 421 patients have died, 81 (19.2%) of them within the first year after HDM/SCT. Transplant-related mortality was 11.4%, decreasing to 5.6% for the 124 patients who received HDM/SCT in the last 5 years, despite the fact that the patients' clinical characteristics were similar in the two time periods. CONCLUSIONS: Treatment of selected AL patients with HDM/SCT resulted in durable hematological responses, high organ response rate and a median OS of almost 6 years even in those who do not achieve a CR after HDM/SCT.Supported by NIH HL-68705 and Instituto de Salud Carlos III (grant CM07/00108). Disclosures:Sanchorawala: Celgene corp: Research Funding.

A Pilot Study of Melphalan, Lenalidomide and Dexamethasone In AL Amyloidosis: Interim Results

AbstractAbstract 1946 BackgroundAL amyloidosis is a clonal disorder of light-chain secreting plasma cells. The light chains deposit as beta-pleated sheets, resulting in significant hematologic and organ toxicity. A recent randomized trial failed to demonstrate superiority of myeloablative melphalan followed by autologous stem cell infusion over the less toxic oral melphalan and high-dose dexamethasone regimen (Jaccard, New Engl J Med 2007). Furthermore, chemotherapeutic options now often include lenalidomide; however, this agent has had limited evaluation in combination with melphalan and dexamethasone and has been hampered by high rates of toxicity at doses of 25mg/day. To assess whether combination therapy at reduced doses would be tolerable and effective, we conducted a single center prospective clinical trial of an oral three drug regimen consisting of melphalan, lenalidomide and dexamethasone (MLD) in AL amyloidosis. MethodsThe primary endpoint is evaluation of the safety and tolerability of MLD in patients with AL amyloidosis. The secondary endpoint is evaluation of the hematologic response rate, the relevant organ responses and the time to progression. Enrolled patients had a biopsy-proven diagnosis of AL amyloidosis with the presence of measurable disease. Exclusion criteria included absolute neutrophil count < 1000 cells/mm3, platelets < 75,000/mm3, creatinine clearance < 15 ml/min, an ECOG performance status > 3, and potential future candidacy for autologous stem cell transplant. There were no exclusions based on patients' cardiac function. Treatment consisted of a 28 day cycle of lenalidomide 10 mg days 1–21, melphalan 0.18 mg/kg days 1–4, and dexamethasone 40 mg weekly. Stepwise dose reductions were allowed for toxicity. Evaluation of hematologic response rate was via serum free kappa and lambda light chains and/or serum or urine immunofixation. Relevant organ responses were measured with 24-hour urine protein/serum creatinine for patients with renal amyloidosis, transthoracic echocardiogram, troponin-I and NT-BNP for patients with cardiac amyloidosis, and alkaline phosphatase for patients with hepatic amyloidosis. The trial has been expanded from the originally planned 15 patients to 25 patients given rapid enrollment; this report reflects an interim analysis of the first 12 patients. ResultsTwelve patients have been enrolled. One patient died prior to initiation of therapy, and thus was excluded from further evaluation. The median age of the remaining 11 patients was 65 years (range of 62–84). The median number of organs involved was 2 (range of 1–4). Ten patients had cardiac involvement, 3 patients had renal involvement, and 2 patients had hepatic involvement. Nine of the 11 patients (82%) were newly diagnosed. The mean number of cycles was 3 (range of 1–9 with a total of 36 cycles). A complete hematologic response (CHR) was seen in 3 patients, a partial hematologic response (PHR) was seen in 4 patients, and 3 patients exhibited stable disease, according to consensus criteria (Gertz, Am J of Hem 2005). One patient died during the first cycle and thus response to treatment was not evaluable. Toxicities included: grade 4 neutropenia in 1 patient and grade 3 anemia, thrombocytopenia, and infection in 3 patients. Seven of the 11 patients have died, all of whom had cardiac amyloidosis, of progressive heart failure or arrhythmias. Of these 7 patients, 2 exhibited a CHR and 3 had a PHR. Of the 9 evaluable patients with cardiac amyloidosis, 2 patients exhibited stable cardiac disease, while the other 7 patients had disease progression, primarily via a rising NT-BNP and Troponin-I. Of the 3 patients with renal involvement, 2 had organ disease progression and 1 patient had stable disease, and of the 2 patients with hepatic involvement, 1 had organ disease progression and 1 had stable disease, according to consensus criteria (Gertz, Am J of Hem 2005). ConclusionIn a patient cohort consisting primarily of newly diagnosed patients with advanced AL amyloidosis, MLD has promising complete and partial hematologic response rates. Hematologic and infectious toxicities remain significant even at reduced doses. Despite promising hematologic response rates, organ responses occur less frequently. Patients with cardiac amyloidosis, particularly those presenting with heart failure, continue to have poor overall prognosis. A larger trial is warranted to further assess drug toxicity and organ response rates. Disclosures:Witteles:Celgene: Research Funding. Witteles:Celgene: Research Funding. Liedtke:Celgene: Lecture fee, Research Funding. Schrier:Celgene: Research Funding. Off Label Use: Melphalan and Lenalidomide as therapy for AL amyloidosis.

Transplantation for Immunoglobulin Light Chain Amyloidosis. A Statistical Analysis of Factors Predicitng Outcome In Over 400 Patients

AbstractAbstract 3557 Introduction:Autologous stem cell transplantation for patients with amyloidosis results in high reported hematologic and organ response rates compared with conventional chemotherapy. Patients:Four-hundred and thirty-four patients have undergone transplantation between March 8, 1996, and April 13, 2010 Table 1. Clinical parameters seen in patients with amyloid are given in Table 2. The overall day-100 mortality seen in this group of patients is 44 of 434 patients (10%).Table 1Characteristics of Patients with Amyloidosis Prior to Autologous Stem Cell Transplant (n=434)NumberPercentage (%)Sex M/F259/17560Renal involvement30470Cardiac involvement21449Peripheral nerve involvement5412Liver involvement5914Autonomic involvement153CTS5412Tongue enlargement4410Number organs involved:120347216839>26314Table 2Laboratory Values in Patients with Amyloidosis (n=434)UnitsMedianInterquartile Range (IQR)Liver edge N=59cm BCM7(4–10)Albuming/dL2.7(1.9–3.3)Creatininemg/dL1.1(0.9–1.3)Cholesterolmg/dL241(185–336)Alkaline phosphataseU/L88(70–129)β2 Microglobulinmg/L2.59(2.08–3.04)24-hour urine total proteing/day3.68(0.28–7.45)% Marrow PC7(3–13)IVS septal thicknessmm12(10–14)EF%65(60–69)Ageyears57(51–63)Months from diagnosis to SCT4(3–7) Results:The most important determinant of outcome is stage defined by BNP and troponin levels. Figure 1 demonstrates the survival for patients for all 3 cardiac stages. Troponin <.035; NT-proBNP <332. Stage 1 both low, Stage 3 both elevated. The survival of all patients based on whether they achieved a complete response, a partial response (>50%), or no response was analyzed. Median survival has not been reached for the complete response group, is 107 months for the partial response group, and is 32 months for the no response group (p<0.0001). Figure 2, divides the patients at the median dFLC level of 13.5 mg/dL demonstrating that for patients with a higher level of free light chain, the median survival is 87.6 months and has not been reached for those with a lower level of free light chain. A proportional hazards model for variables that impact on survival was done in all patients, and the only relevant predictor of outcome was stage (p<0.0001). When the same analysis was performed using a landmark of 6 months, the only predictor of outcome was stage (p=0.0005). When best response was incorporated into the landmark model, it was the strongest predictor of survival. The amyloid stage predicted survival (p= 0.0005), and the best response to therapy (p <0.0001). When the same analysis was performed in the entire group of 434, stage and best response each remained significant (p<0.0001). [Display omitted] [Display omitted] Discussion:There is a high response rate associated with high-dose therapy that was not observed in the melphalan and prednisone era. For eligible patients who can be transplanted safely, high-dose melphalan is an effective therapy for many patients with amyloidosis. Best response and stage at diagnosis are the best predictors of overall survival. Disclosures:Lacy:Celgene: Research Funding. Dispenzieri:Celgene: Honoraria, Research Funding; Binding Site: Honoraria. Kumar:Celgene: Consultancy, Research Funding; Millennium: Research Funding; Merck: Consultancy, Research Funding; Novartis: Research Funding; Genzyme: Consultancy, Research Funding; Cephalon: Research Funding.

Autologous stem cell transplant for immunoglobulin light chain amyloidosis: a status report

High-dose chemotherapy for the management of immunoglobulin light chain amyloidosis remains an effective and viable treatment technique for selected patients with this disorder. We reviewed the medical records of 434 patients uniformly treated with high-dose chemotherapy and autologous stem cell transplant at Mayo Clinic, Rochester, Minnesota, between 8 March 1996 and 13 April 2010. Outcomes, engraftment, and predictors of early mortality were reviewed. Median survival has not been reached for the patients with a complete response, is 107 months for those with a partial response, and is 32 months for patients with no response (p < 0.001). The only predictor of survival was cardiac stage (p < 0.001). The hematologic response rate is predictive for organ response rates. Both hematologic and organ responses are associated with improved survival.

Lenalidomide in Combination with Melphalan and Dexamethasone in Patients with Newly-Diagnosed Light-Chain (AL)-Amyloidosis: a Multicenter Phase I/II Dose Escalation Study.

Abstract 427 Introduction:The combination of melphalan and dexamethasone (M-dex) is widely used in patients with newly diagnosed AL-amyloidosis, with hematologic and organ response rates of 50 and 40%, respectively (Jaccard, New Engl J Med 2007). Lenalidomide has also been evaluated, mainly in the relapse setting, and the initial dose of 25 mg/day was poorly tolerated. However, a 15 mg/day dose regimen was well tolerated and effective, with both hematologic and organ responses (Dispenzieri, Blood 2007 & Sanchorawala, Blood 2007). Combining M-dex with lenalidomide could increase the response rate but the toxicity of this regimen is still unknown. Thus we have initiated a multicenter single-arm open-label phase I/II dose escalation study of lenalidomide administered in combination with M-dex. Patients and methods:The primary endpoint was the incidence of dose limiting toxicities (DLT) during the first cycle of lenalidomide at a given dose level in order to determine the maximum tolerated dose (MTD). In addition to melphalan 0.18mg/kg/day from day 1-4 of each 28 day cycle and dexamethasone 40mg/day from day 1- 4 of each 28 day cycle, patients were successively exposed to escalating doses of lenalidomide (5, 10, 15 and 20 mg once daily on days 1–21 of a 28 day cycle). Nine cycles were planned at each dose level, according to safety and efficacy. DLT was defined using National Cancer Institute common toxicity criteria during the first 4 weeks of treatment (one cycle) as the following: at least grade 2 cardiac arrhythmia, at least grade 3 non hematologic toxicity, grade 4 neutropenia lasting >7 days or any other Grade 4 hematologic toxicity, or treatment delay due to toxicity that occurred during the first cycle. Organ involvement and the response to therapy were evaluated according to the international consensus guidelines (Gertz Am J Hem 2005). Results:From 03/2008 to 01/2009, 27 patients were enrolled. 1 patient withdrew consent after the first month of therapy and was thereafter lost to follow-up. No DLT was observed among the patients treated at 5 (3 patients), 10 (4 patients) and 15 mg lenalidomide/day (13 patients). 2 / 6 patients treated in cohort 4 at the dose of 20 mg lenalidomide/day experienced DLT, grade 4 hematologic toxicity and treatment delay due to toxicity; thus 15 mg lenalidomide/day, in combination with M-dex, was considered as the MTD. With a median follow-up of 12 months (7-17), 20/26 patients (77%) are alive. Six deaths were observed, due to progressive disease in 5 cases (median time from diagnosis 1 month, 1 to 3), or cholangiocarcinoma in 1 case (7 months after the diagnosis of AL-amyloidosis). Hematologic and organ responses were observed in 68 and 50% of the cases, respectively. At the reference date of Aug15th, 2009 none of the responding patients experienced progression, and all were able to receive 9 cycles according to the protocol.Conclusion: The recommended dose of lenalidomide in combination with M-dex in subjects with AL-amyloidosis previously untreated is 15 mg/day (days 1-21 of a 28 day cycle). Response and survival rates compare favourably with those achieved with M-dex alone. A prospective phase III trial comparing M-dex with M-dex lenalidomide should be valuable. Disclosures:Moreau:celgene: Speakers Bureau. Off Label Use: lenalidomide in combination with melphalan and dexamethasone in patients with AL-amyloidosis. Jaccard:celgene: Speakers Bureau. Salles:Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Alakl:Celgene: Employment. Harousseau:celgene: Speakers Bureau. Fermand:celgene: Speakers Bureau.

AL Amyloidosis Associated with IgM Monoclonal Protein: A Distinct Clinical Entity

IgM-associated AL amyloidosis is rare and may represent a distinct entity. Sixty (7%) of 868 consecutive AL patients referred to our center had an IgM monoclonal protein. They were significantly older than non-IgM patients (median, 67 years vs. 62 years), had a higher frequency of lymph-node involvement (25% vs. 2%) and significantly lower median proteinuria (1.2 g/24h vs. 3.4 g/24h), N-terminal pro-natriuretic peptide type-B (1177 ng/L vs. 2135 ng/L) and troponin I (0.02 ng/mL vs. 0.05 ng/mL). In IgM patients, κ light-chains were more frequent (42% vs. 23%) and the involved free light-chain concentration was lower (median 63 mg/L vs. 182 mg/L). Serum albumin and NT-proBNP were independent prognostic determinants. Response to treatment improved survival. The 14 patients who received melphalan/dexamethasone showed a 64% hematologic (complete remissions, 29%) and a 43% organ response rate. IgM-associated AL amyloidosis is a distinct entity, with less advanced organ dysfunction. Treatment with melphalan/dexamethasone might be effective in these patients.

Long Term Follow-up of Patients with Immunoglobulin Light Chain Amyloidosis Treated with Lenalidomide and Dexamethasone.

Background: Primary systemic amyloidosis (AL) is an incurable plasma cell disorder. Lenalidomide, especially in conjunction with dexamethasone, has been shown to be highly active in patients with multiple myeloma. We previously reported a hematologic response rate of 41% and an organ response rate of 23% among 22 AL patients treated with lenalidomide and on-demand dexamethasone (Dispenzieri et al, Blood 2007). Long term outcomes of AL patients treated with lenalidomide have not yet been described.Methods: Thirty-seven patients were treated on an IRB approved treatment trial with single agent lenalidomide, starting doses of 25 mg in 22 and reduced dose of 15 mg in the last 15. If progression within or no evidence of hematologic response after 3 cycles, dexamethasone was added. Patients were classified according to cardiac biomarker stage (cut-offs for serum troponin T <0.035 ng/ml and NT-proBNP <332 pg/ml–Stage I neither above cutoff; Stage III, both above cut-off; and Stage II, any one above cut-off). Survival estimates were done according to the methods of Kaplan and Meier.Results: Median age was 64 years (range 44–88), with 70% male. Sixty-five percent of patients were previously treated, and the median time from diagnosis to study entry was 8.9 months (range 0.4–237). The biomarker staging breakdown was: I, 16%; II, 43%; and III, 41%. As of 7/11/08, 5 patients remain on active therapy. The overall hematologic response rate was 43% (1 CR and 15 PR), with only one patient responding to single agent lenalidomide, and the overall organ response rate was 20%. If one excludes the 13 patients who did not complete 3 months of therapy and have the opportunity of having dexamethasone added to their program, the respective hematologic and organ response rates were 62% and 32%. With a median follow-up of 33.6 months (range 14.4–42), twenty-two patients (59%) have died, but only 2 had deaths possibly related to treatment. Median duration of response, progression free survival and overall survival were 31 months, 14.8 months (95%CI: 5.7–28.1), and 18.8 months (95%CI: 11.7-not reached), respectively. Overall survival from diagnosis was 48 months (95%CI: 21.6–153.6). As shown in Table below, outcomes were dependent on underlying risk stratification and ability to stay on therapy. High risk patients were more likely to drop out early and less likely to respond. High risk patients had shorter OSAll PatientsOutcomeStage IStage IIStage IIIpN61615Survival from enrollment, moNR18.8 (11.7–33.6)5.7 (3.2–18.3)0.01Survival from Diagnosis, moNR48.4 (20.4–62)21.1 (11.2–31.7)0.005Progression Free Survival, mo34.7 (33.7–NR)18.3 (6.2–28.1)4.4 (3–8.6)NSDrop out by cycle 4, %173160NSMedian # of cycles administered31630.04Time to response, mo6.2 (3.6–9.3)6.4 (5.2–NR)4.7 (3.8–NR)NSHematologic response rate, %8338270.05Organ response rate, %402013NSDuration of Response, moNR27.2 (13.6–NR)NRNSSubgroup analysis of patients receiving >3 cycles of therapy (i.e getting LenandDex)N5127Time on therapy, mo35.2810.5Hematologic Response Rate, %1005056Organ response rate, %502725Conclusions: Based on these data, single agent lenalidomide is not recommended for patients with AL; however, lenalidomide in combination with dexamethasone can be associated with good progression free and overall survival rates, even among patients with relapsed or refractory disease.

A Multicenter Phase I/II Dose Escalation Study of Lenalidomide in Combination with Melphalan and Dexamethasone in Subjects with Newly-Diagnosed Light-Chain (AL)-Amyloidosis.

A recent prospective randomized trial comparing standard-dose to high-dose melphalan in patients presenting with newly diagnosed AL-amyloidosis showed that oral melphalan-dexamethasone (M-dex) given monthly could be considered the current standard of care, with a median survival of 56 months (Jaccard, N Engl J Med 2007). The use of a combination of lenalidomide and dexamethasone has also been tested in patients with symptomatic AL-amyloidosis. The initial dose of lenalidomide at 25 mg/day was poorly tolerated. However, a 15 mg/day dose regimen was well tolerated and effective, with both hematologic and organ responses (Dispenzieri, Blood 2007 & Sanchorawala, Blood 2007). Combining M-dex with lenalidomide (M-dex-rev) could increase the response rate but the toxicity of this regimen is still unknown. Thus we have initiated a multicenter single-arm open-label phase I/II dose escalation study of lenalidomide administered in combination with M-dex. The primary endpoint was the incidence of dose limiting toxicities (DLT) during the first cycle of lenalidomide at a given dose level in order to determine the maximum tolerated dose (MTD). In addition to melphalan 0.18mg/kg/day from day 1–4 of each 28 day cycle and dexamethasone 40mg/day from day 1– 4 of each 28 day cycle, 3 cohorts of 3 subjects were successively exposed to escalating doses of lenalidomide (5, 10 and 15mg once daily on days 1–21 of a 28 day cycle). DLT was defined using National Cancer Institute (NCI) common toxicity criteria during the first 4 weeks of treatment (one cycle) as the following: at least grade 2 cardiac arrhythmia, at least grade 3 non hematologic toxicity, grade 4 neutropenia lasting >7 days or any other Grade 4 hematologic toxicity, or treatment delay due to toxicity that occurred during the first cycle. No DLT was observed among the first 3 patients treated at 5, 10 and 15 mg lenalidomide/day. 9 additional subjects will be enrolled at 15 mg/day to better define the safety profile and estimate the hematologic and organ response rate. Final results regarding both toxicity and efficacy will be presented during the meeting.

Risk‐adapted autologous stem cell transplantation with adjuvant dexamethasone ± thalidomide for systemic light‐chain amyloidosis: results of a phase II trial

High-dose melphalan (MEL) with autologous stem cell transplant (SCT) is an effective therapy for systemic AL amyloidosis (AL), but treatment-related mortality (TRM) has historically been high. We performed a phase II trial of risk-adapted SCT followed by adjuvant dexamethasone (dex) and thalidomide (thal) in an attempt to reduce TRM and improve response rates. Patients (n = 45) with newly diagnosed AL involving < or =2 organ systems were assigned to MEL 100, 140, or 200 mg/m(2) with SCT, based on age, renal function and cardiac involvement. Patients with persistent clonal plasma cell disease 3 months post-SCT received 9 months of adjuvant thal/dex (or dex if there was a history of deep vein thrombosis or neuropathy). Organ involvement was kidney (67%), heart (24%), liver/GI (22%) and peripheral nervous system (18%), with 31% having two organs involved. TRM was 4.4%. Thirty-one patients began adjuvant therapy, with 16 (52%) completing 9 months of treatment and 13 (42%) achieving an improvement in haematological response. By intention-to-treat, overall haematological response rate was 71% (36% complete response), with 44% having organ responses. With a median follow-up of 31 months, 2-year survival was 84% (95% confidence interval: 73%, 94%). Risk-adapted SCT with adjuvant thal/dex is feasible and results in low TRM and high haematological and organ response rates in AL patients.

Autologous stem cell transplantation and IgM amyloidosis

High dose chemotherapy (HDC) followed by autologous stem cell transplant (ASCT) is an accepted form of treatment for patients with AL amyloidosis. The purpose of the current study is to review the outcomes of IgM AL amyloidosis patients treated with high dose chemotherapy and autologous stem cell transplant and compare them to the outcomes of all AL amyloidosis subtypes treated similarly. We retrospectively reviewed the pretransplant characteristics, conditioning regimens and response to transplant of all twelve IgM AL amyloidosis patients who were transplanted at the Mayo Clinic between May 1999 and August 2005. Transplant related mortality was low at 8%. The overall hematologic response rate was 89%. The organ response rate was 67%. Overall median survival has not been reached as eleven patients are still alive. IgM AL amyloidosis patients appear to have similar outcomes after HDC and ASCT as other subtypes of AL amyloidosis suggesting that this therapy is an acceptable form of treatment for patients with IgM amyloidosis, and should be considered as a first line treatment option.

Adjuvant Dexamethasone (D) ± Thalidomide (T) Improves Hematologic and Organ Responses after Risk-Adapted High-Dose Melphalan with Autologous Stem Cell Transplant (SCT) for Patients with Systemic AL Amyloidosis (AL).

Risk-adapted dosing of melphalan (MEL) has been proposed as a means of reducing treatment-related mortality (TRM) in patients with AL undergoing SCT but recent retrospective studies show poorer response rates in patients receiving < 200mg/m2 of MEL (Ann Intern Med 2004; 140; BMT 2004; 34). We have prospectively studied a combined approach using risk-adapted MEL followed by adjuvant D ± T with the goals of achieving low TRM and optimal hematologic and organ response rates. To be eligible, patients with systemic AL with ≤ 2 organ systems involved and no advanced cardiac disease had to be untreated and diagnosed within 12 months of enrollment. Patients received MEL200, 140, or 100 mg/m2 with autologous SCT based on age, renal function, and cardiac involvement (Blood 2002; 99). Those not achieving a hematologic complete response (CR) at 3 months post-SCT were treated with 9 months of D (20mg/m2, 1–3 pulses monthly) + T (50–200mg nightly), or only D if they had prior DVT or neuropathy. Forty-five patients (51% men) enrolled, a median of 57 years old (range 34–73) and 2 months from diagnosis. Dominant organ involvement was renal in 58% (n=26), cardiac in 24% (n=11), and liver/GI or peripheral nervous system in 18% (n=8). A third (n=15) had 2 organ systems involved. Twenty-one percent (8/38) had elevated serum troponin I levels (>0.06ng/ml) and 53% (19/36) had elevated serum brain natriuretic peptide levels (>100pg/ml) at baseline. Dose-assignments were MEL200 (n=15), MEL140 (n=24) and MEL100 (n=6). TRM was 4.4% (2/45), with 6 patients out of hospital and well < 100 days post-SCT. At 3 months post-SCT, 63% of patients had hematologic responses (8 CR, 15 PR). Persistent clonal plasma cell disease was found in 29 patients; 1 refused and 2 were too ill for D+T, 17 received D+T and 9 D. Ten completed 9 months of adjuvant therapy, with 13 discontinuing and 3 still on therapy. Reasons for discontinuation were progressive disease (n=4), DVT/PE (n=2), RSV pneumonia (n=2), femoral avascular necrosis (n=1), anxiety (n=1) and intolerance (n=3). Thirty-five percent (9/26) on adjuvant therapy had improvements in hematologic response at 12 mos post-SCT, including 4 PR to CR (2 D+T, 2 D) and 5 stable disease (SD) to PR (3 D+T, 2 D). The hematologic response rate at 12 months was 79% (22/28; 9 CR, 13 PR) with no significant difference based on dose of MEL. Forty-six percent (13/28) had organ responses at 12 months, while 32% had stable and 21% worsened organ function. Only patients who achieved a hematologic response at 12 months had organ responses (59% (13/22) of PR/CR patients vs. 0% (0/6) with stable or progressive disease, p=0.01). With a median follow-up of 18 months (range 1–33), overall survival is 76% and median survival is not yet reached. In summary, risk-adapted MEL has a low TRM and adjuvant D±T can improve hematologic response in a third of patients with persistent clonal plasma cell disease post-SCT, albeit with moderate toxicity. Further study of such combined approaches in AL SCT patients is warranted.

Interim analysis of a phase II study of risk-adapted intravenous melphalan followed by adjuvant dexamethasone (D) and thalidomide (T) for newly diagnosed patients with systemic al amyloidosis (AL)

High-dose melphalan (M) with autologous stem cell transplant (ASCT) is effective therapy for AL, but treatment-related mortality (TRM) remains high, and hematologic complete responses (CR) occur in a minority of patients. In this study, we investigated whether a risk-adapted approach to intravenous (IV) M dosing could decrease TRM, and whether adjuvant D± T could improve hematologic and amyloid-involved organ response rates. Low-risk patients (1 or 2 major organs involved, no advanced cardiac disease) receive M 100, 140, or 200 mg/m2 with ASCT based on age, cardiac involvement, and renal function.

Low Dose Single Agent Thalidomide Is Tolerated in Patients with Primary Systemic Amyloidosis, but Responses Are Limited.

Background: Primary systemic amyloidosis (AL) is an incurable plasma cell dyscrasia with limited therapeutic options. Based on the observed 25 to 50% partial response rates in myeloma patients, thalidomide has been tried in patients with AL. Two reports (Dispenzieri et al, Amyloid 10:247; 2003; Seldin et al, Clinical Lymphoma 3:241; 2003) have demonstrated that standard dose, single agent thalidomide (≥ 200 mg per day) has a higher than expected rate of adverse events in AL patients without hematologic or organ response, potentially due to rapid patient attrition. We therefore performed a prospective clinical trial using low dose, single agent thalidomide in patients with AL.Methods: In August 2001, we began accrual to a phase II trial of low dose thalidomide for patients with AL. Eligibility included: age ≥ 18 years, creatinine <3mg/dL, total bilirubin < 3 mg/dL, ANC ≥ 1 x 10(9)/L, left ventricular ejection fraction of >45%, histochemical proof of amyloid and a monoclonal plasma cell dyscrasia, symptomatic organ involvement, and ability to supply informed consent. Patients were started with thalidomide 50 mg per day, with a dose escalation to a maximum dose of 400 mg per day over a 19 week period as tolerated. Patients were evaluated monthly by their physician. These office visits were staggered with telephone toxicity checks monthly by the primary investigator. The endpoint of the study was hematologic and organ response by 12 months.Results: Eighteen patients were treated. The median age was 66 years (range 43–83). Eight were male. Twenty-eight percent had an ECOG performance status of 2 or 3. Five patients (28%) had received no prior therapy. Five had received one prior regimen; 6, two prior; and 2, ≥ three. Three had received prior PBSCT. Sixteen patients had a monoclonal lambda plasma cell disorder; two, monoclonal kappa. Immunoglobulin heavy chains were IgG (n=9), IgM (n=5), IgA (n=1), and none (n=3). Twelve patients (67%) had cardiac involvement; twelve (67%) renal; two liver; two symptomatic gastrointestinal; one pulmonary; and two nerve involvement. Study participants had significant symptomatology at baseline with dyspnea (n=12), light-headedness (n=6), and edema (n=13). Median number of organs involved was 1, range (1 to 4). Median time on study drug was 5.6 months, range 0.7–24 months. Reasons for discontinuation included: progression, 7 (39%); 3 each (17%) for adverse events, death, and patient refusal; and other causes in 2. The median tolerated dose was 100 mg. There were no hematologic responses observed. The overall organ response rate was 11%. There was one renal response at 1 year and a gastrointestinal response at 3 months with 24 hour fecal fat changing from 21 to 8.7 grams. The most common adverse effects attributable to thalidomide were: constipation (78%), edema (44%), sinus bradycardia (17%), dyspnea (11%), and paresthesias (11%). Light-headedness, rising creatinine, thrombosis, infection, syncope, and rash was attributed to the thalidomide in 5.6% of patients.Conclusions: Low dose thalidomide is tolerable in this fragile group of patients, but as a single agent efficacy is limited. Further study of combination therapy of thalidomide and low dose dexamethasone may be warranted. A study using the next generation immune modulatory drug Revlimid is scheduled to open to accrual. Funded by NIH grant CA 91561 and Celgene.

Risk-Adapted Intravenous Melphalan Followed by Adjuvant Dexamethasone (D) and Thalidomide (T) for Newly Diagnosed Patients with Systemic AL Amyloidosis (AL): Interim Results of a Phase II Study.

High-dose melphalan (M) with autologous stem cell transplant (ASCT) is an effective therapy for AL, but treatment-related mortality (TRM) remains high, and hematologic complete responses (CR) occur in a minority of patients. In this study, we asked whether a risk-adapted approach to IV M dosing could decrease TRM, and whether adjuvant D +/− T could improve hematologic and amyloid-involved organ response rates. Other objectives of the trial are to study prospectively the prognostic significance of the serum free light chain (FLC), troponin I, and brain natriuretic peptide (BNP) assays. Newly diagnosed untreated AL patients are risk-stratified upon enrollment. Low-risk patients (1 or 2 major organs involved, no advanced cardiac disease) receive M 100, 140, or 200 mg/m2 with ASCT based on age, presence of cardiac involvement, and renal function. High-risk patients (≥3 organs involved or advanced cardiac disease) receive 2 cycles of M 40 mg/m2 without ASCT. Patients with persistent clonal plasma cell disease at 3 months receive 9 months of adjuvant D+T or D alone (if history of deep venous thrombosis or neuropathy). Since 9/02, 38 patients (median age=57.5 (range 34–73), 68% males) have enrolled. Median time from diagnosis to enrollment is 1.5 months (range 0.5 – 7). Organ involvement includes 13 (34%) cardiac, 24 (63%) renal (12 with renal only), 13 (34%) liver/GI tract, and 10 (26%) peripheral nervous system. Thirty-two (84%) had baseline elevated serum FLC with abnormal κ:λ ratio. Thirty-four patients have been treated--3 high-risk and 31 low-risk (5 at M 100, 16 at 140 and 10 at 200 mg/m2). Treatment-related mortality is 7.4% (2/27) with an additional 7 patients alive <100 days post-treatment. Six patients, including all 3 treated high-risk patients, have died of progressive disease (PD) a median of 5.5 months (range 4–17) after M. Of the 8 patients who died, 7 had symptomatic cardiac involvement. At 3 months, 22 low-risk patients are evaluable for hematologic response. Thirteen (59%) responded (4 CR, 9 PR) and 9 had stable disease. Of the 18 patients with persistent clonal disease, 9 began T (50 to 200 mg nightly) and D (1 to 3 four-day pulses monthly), 6 began D alone, and 3 had no adjuvant therapy (refused or too ill). Five patients completed 9 months of adjuvant therapy, and 2 remain on therapy, with 2 conversions from PR→CR (T+D, D), and 1 from SD→PR (D). Reasons for discontinuation were PD (n=4), pulmonary embolus (n=1), pneumonia (n=2), and intolerance (n=2). Eleven patients are evaluable at 12 months, with 10 (91%) responses (4 CR, 6 PR) and 1 PD (9%). Seven (77%) have objective improvement in amyloid-related organ function, 2 have stable and 2 worsened AL. Preliminary analysis of serum FLC data (n=23) shows an association between a persistently abnormal κ:λ ratio 3 months after treatment and an increased risk of death (RR=1.67, 95% CI=1.10–2.52, p=0.02). Analyses of the prognostic significance of serial troponin and BNP assays are ongoing. In conclusion, risk-adapted dosing of IV M in newly diagnosed AL patients has a low TRM. Adjuvant D +/− T is feasible, with toxicity leading to discontinuation in 33% (5/15) of patients, and with a benefit to date in 20% (3/15) of patients with persistent clonal plasma cell disease 3 months post ASCT, including induction of 2 hematologic CRs.

Autologous stem cell transplantation in primary systemic amyloidosis: the impact of selection criteria on outcome.

Autologous stem cell transplantation (ASCT) for primary systemic amyloidosis (AL) produces high hematologic and organ responses. However, treatment-related mortality remains high and reported series are subject to selection bias. In all, 48 of 80 amyloid patients referred to our center had AL in the absence of myeloma, 26 of these 48 were deemed transplant candidates and 20 actually underwent ASCT. Transplant-related mortality has fallen from 50 to 20% since January 1999 due to better patient selection and prophylactic measures. Intent-to-treat organ responses were renal (46%), cardiac (25%) and liver (50%). Organ responses in patients who survived transplantation were renal (75%), cardiac (40%) and liver (100%). The 3-year OS post-ASCT was 56% with improved outcome predicted by a better performance status (P=0.08), normal ALP (P=0.08), nephrotic syndrome (P=0.01) and the absence of severe hypotension (P=0.01). The 3-year OS for all referred patients was 44% and this was not significantly better for transplant candidates. Patients with significant hypotension (systolic blood pressure < or =90 mmHg) or poor performance status (ECOG >2) have an exceedingly high treatment-related mortality and should not be transplanted. For those undergoing ASCT, organ response rates appear promising, but conclusive evidence of improved survival for this select group of patients is still lacking and will require randomized trials.