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 <500/mm3 and/or platelet count <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 > 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.

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

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

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

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.

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.

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

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 5907-5907
Author(s):  
Sandeep Jain ◽  
Luciano J Costa ◽  
Robert K Stuart ◽  
Saurabh Chhabra ◽  
Alice Mims ◽  
...  
Keyword(s):  
Stem Cell ◽  
Cardiac Involvement ◽  
Stem Cell Transplant ◽  
Patient Characteristics ◽  
Autologous Stem Cell Transplant ◽  
High Dose ◽  
Al Amyloidosis ◽  
Cell Transplant ◽  
High Dose Melphalan

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

scholarly journals High-dose melphalan and peripheral blood stem cell transplantation for light-chain amyloidosis with cardiac involvement

Blood ◽  
2012 ◽  
Vol 119 (5) ◽  
pp. 1117-1122 ◽  
Author(s):  
Sumit Madan ◽  
Shaji K. Kumar ◽  
Angela Dispenzieri ◽  
Martha Q. Lacy ◽  
Suzanne R. Hayman ◽  
...  
Keyword(s):  
Stem Cell ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Light Chain ◽  
Cardiac Involvement ◽  
High Dose ◽  
Light Chain Amyloidosis ◽  
Reduced Dose ◽  
Organ Response ◽  
High Dose Melphalan

Abstract High-dose melphalan (HDM) plus stem cell transplantation is an effective treatment for light-chain amyloidosis (AL), but is associated with high treatment-related mortality in patients with cardiac involvement. We studied 187 patients with cardiac involvement with AL who underwent HDM between 1996 and 2008. The median age was 57 years and the median time from diagnosis to HDM was 3.6 months. Half of the patients received reduced-dose melphalan (100-160 mg/m2). The median overall survival (OS) was 66 months, 54 months from diagnosis and HDM, respectively, and 91 patients (49%) were alive at the last follow-up 52 months (median) from HDM. Thirty patients (16%) died within 100 days of transplantation; only low serum albumin predicted early deaths. Overall, hematologic response (HR) and cardiac responses were seen in 66% and 41% of patients, respectively. The median OS for patients with and without HR was not reached and 22 months, respectively (P < .01); and for those with any decrease and no decrease in N-terminal-pro-brain natriuretic peptide was not reached and 26 months, respectively (P < .01). In multivariate analysis of baseline factors, only reduced-dose melphalan predicted shorter OS. HDM is feasible in patients with cardiac amyloidosis, and achievement of HR and organ response is associated with improved survival.

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

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 4352-4352
Author(s):  
Saulius Girnius ◽  
Frank Tsai ◽  
David C. Seldin ◽  
Karen Quillen ◽  
Lisa Yanarella ◽  
...  
Keyword(s):  
Stem Cell ◽  
Stem Cell Transplantation ◽  
Light Chain ◽  
Predictive Value ◽  
Complete Response ◽  
High Dose ◽  
Al Amyloidosis ◽  
Serum Free ◽  
Serum Free Light Chain ◽  
High Dose Melphalan

Abstract Abstract 4352 AL amyloidosis is a clonal plasma cell dyscrasia which produces insoluble amyloid fibrils from Ig light chains, leading to multiorgan failure. High dose melphalan and autologous stem cell transplantation (HDM/SCT) can induce remission and extend survival, but response is assessed at 6 and 12 months. Serum free light chain (FLC) assays can improve detection of AL amyloidosis, have prognostic significance, and are routinely used to assess response to treatment. Serum half life of FLCs is only 2-6 hours, even with diminished glomerular filtration rates. In a small prospective series, we previously reported that FLC levels 1-3 weeks after HDM/SCT correlate with hematologic response at 1 year. This study was performed to confirm these results on a larger scale. A prospective analysis of patients with AL amyloidosis treated with HDM/SCT was performed to determine the extent to which early FLC responses predict hematologic complete response (CR). Exclusion criteria included initial normal FLC concentrations and ratios and chronic renal insufficiency (Cr>1.2 mg/dL) with a normal FLC ratio. Hematologic responses, as defined by standard traditional criteria, were determined at 6 and 12 months. Traditional criteria define hematologic CR as by normalization of bone marrow exam and absence of monoclonal gammopathy in urine and serum by immunofixation electrophoreses. Serum FLC concentrations were measured by a sensitive nephelometric analysis within 10 days and within 3 weeks of HDM/SCT. Complete response for serum FLC was defined as normalization of FLC concentration and ratio or normalization of the ratio in renal failure (Cr>1.2 mg/dL). Serum FLC levels or k/l FLC ratios were abnormal and informative in 124 patients (87%) prior to HDM/SCT, and these patients were included in subsequent analyses. One week after transplant, sensitivity of FLC to predict hematologic CR was 0.64, specificity was 0.67, positive predictive value (PPV) was 0.49, negative predictive value (NPV) was 0.79, positive likelihood ratio (LR) was 1.92, and negative LR was 0.54. For a >90% reduction in FLC, sensitivity to predict hematologic CR was 0.36, specificity was 0.86, PPV was 0.54, NPV was 0.75, positive LR was 2.59, and negative LR was 0.74. Two to three weeks after transplant, sensitivity of FLC CR to predict hematologic CR was 0.72, specificity was 0.74, PPV was 0.57, NPV was 0.85, positive LR was 2.78, and negative LR was 0.38. For a >90% reduction in FLC, sensitivity to predict hematologic CR was 0.34, specificity was 0.86, PPV was 0.52, NPV was 0.74, positive LR was 2.40, and negative LR was 0.77. Serum FLC concentrations within 3 weeks of HDM/SCT have poor predictive values and should not be used to predict hematologic CR. However, failure to reduce FLC concentrations by 90% has a somewhat higher negative predictive value and could be used to guide additional post-transplant management. Disclosures: No relevant conflicts of interest to declare.

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

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 4597-4597
Author(s):  
David Telio ◽  
John Shepherd ◽  
Donna L. Forrest ◽  
Michael J. Barnett ◽  
Thomas J. Nevill ◽  
...  
Keyword(s):  
Stem Cell ◽  
Renal Disease ◽  
Light Chain ◽  
High Dose ◽  
Al Amyloidosis ◽  
Renal Response ◽  
Deposition Disease ◽  
Stage Renal Disease ◽  
High Dose Melphalan

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

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

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

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

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