Treatment with Oral Melphalan and Dexamethasone of An Extended Patient Population with AL Amyloidosis.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 3889-3889 ◽  
Author(s):  
Giovanni Palladini ◽  
Paola Russo ◽  
Andrea Foli ◽  
Letizia Zenone Bragotti ◽  
Francesca Lavatelli ◽  
...  
Keyword(s):  
Multivariate Analysis ◽  
Nyha Class ◽  
Fluid Retention ◽  
Phase Iii ◽  
High Dose ◽  
Al Amyloidosis ◽  
Hematologic Response ◽  
Heart Involvement ◽  
Phase Iii Trials ◽  
Organ Response

Abstract Abstract 3889 Poster Board III-825 Oral melphalan and dexamethasone (MDex) has been adopted in many referral centers as standard therapy for AL amyloidosis, particularly in patients who are not eligible for high dose melphalan (M) and autologous stem cell transplant (ASCT). A randomized trial failed to demonstrate the superiority of ASCT over MDex, and phase III trials are being designed to compare MDex with regimens including new drugs. However, only few small series of patients treated with MDex have been published so far. We report the outcome of 126 consecutive patients with AL amyloidosis who received first line MDex between January 2004 and December 2007. All the patients who were not eligible for ASCT with high dose M, due to any of the following conditions: age >60 years, N terminal natriuretic peptide type B (NT-proBNP) >332 ng/L, troponin I (cTnI) >0.1 ng/mL, glomerular filtration rate (eGFR) ≤50 mL/min, were included. Patients were given M (0.22 mg/Kg, or 0.16 mg/Kg if eGFR was <30 mL/min) and Dex (40 mg, or 20 mg in case of fluid retention >3% of body weight or complex ventricular arrhythmias at 24 h Holter ECG) on days 1-4 q28 days for up to 9 cycles. Treatment was discontinued if complete remission (CR) or partial hematologic response (PR) plus organ response (OR) was reached after 6 cycles, or in case of lack of response after 3 cycles. The International Society for Amyloidosis (ISA) consensus criteria for hematologic and organ response and progression were used. Progression free survival (PFS) was defined as the time to death or hematologic or organ progression according to the ISA criteria. Response and progression of NT-proBNP were defined as 3300 ng/L and 330% modifications. The median number of organs involved was 2 (range 1-5), 92 patients (73%) had heart involvement, with New York Heart Association (NYHA) class ≥2 heart failure in 66 cases (60%) and 93 patients (74%) had renal involvement, with eGFR <30 mL/min in 9 (7%). Cardiac TnI was >0.1 ng/mL in 27 patients (22%) and NT-proBNP was >332 ng/L in 99 (79%). Twenty-four patients (19%) experienced severe, though non fatal, adverse events. The most common was fluid retention (12%), that was significantly associated with NYHA class (p=0.02) and cTnI concentration (p<0.001). Four patients (3%) died on treatment due to progressive cardiac amyloidosis. Hematologic response was reached in 78 subjects (62%), with 33 CRs (26%). Median time to response was 3.5 months (range 0.7-13.2 months). Forty-two patients (33%) achieved OR. The mLVW thickness decreased by at least 2 mm in 6 (6%) of the 92 patients with heart involvement, whereas NT-proBNP response was achieved in 32 patients (35%) and was associated with improvement of NYHA class. Forty-two patients (33%) died. The median follow-up of living patients was 3 years (range 1.1-5.4 years). Median overall survival (OS) was not reached. Median PFS was 2.5 years. The multivariate analysis including variables measured at presentation showed that only NT-proBNP was independently associated with OS and PFS (p <0.001). Hematologic response improved OS (median 22 months vs. not reached, p<0.001) and PFS (median 6 vs. 40 months, p<0.001), and CR gave an advantage in OS (70% vs. 100% surviving at 3 years, p<0.001) and PFS (median 30 months vs. not reached, p<0.001) over PR. Patients who obtained NT-proBNP response had longer OS (62% vs. 88% surviving at 3 years, p=0.005) and PFS (median 18 vs. 40 months, p=0.01). Progression of NT-proBNP identified patients with poor outcome among non responders (median OS 6 months vs. not reached, p=0.02; PFS 3 vs. 15 months, p=0.006) and among patients in PR (median OS 19 months vs. not reached, p=0.03; PFS 14 vs. 32 months, p=0.05). The multivariate analysis including variables measured 6 months after treatment initiation showed that only the absolute concentrations of involved free light chains (FLC) and NT-proBNP remaining after therapy independently affected survival (p <0.001). The FLC (62 mg/L) and NT-proBNP (3100 ng/L) cutoff best predicting survival after MDex were identified. Estimated OS at 3 years was 94% in patients with both NT-proBNP and FLC below the cutoff, 60% in subjects with 1 marker above the cutoff and 30% in those with both markers above the cutoff (p=0.001). Future efforts should be directed to improve the response rate and rapidity of response, while preserving treatment tolerability and feasibility. Phase III trials comparing MDex with MDex associated with new agents are being developed. Disclosures: No relevant conflicts of interest to declare.

A Phase II Trial of Cyclophosphamide, Lenalidomide and Dexamethasone (CLD) in Previously Treated Patients with AL Amyloidosis.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 2863-2863 ◽  
Author(s):  
Giovanni Palladini ◽  
Paola Russo ◽  
Letizia Zenone Bragotti ◽  
Andrea Foli ◽  
Francesco Musca ◽  
...  
Keyword(s):  
Heart Failure ◽  
Nyha Class ◽  
Previous Treatment ◽  
Fluid Retention ◽  
Al Amyloidosis ◽  
Hematologic Response ◽  
Significant Toxicity ◽  
Organ Response ◽  
Previously Treated Patients ◽  
Previously Treated

Abstract Abstract 2863 Poster Board II-839 Despite significant toxicity, thalidomide is effective in AL amyloidosis. A study of the United Kingdom National Amyloidosis Centre showed that the association of cyclophosphamide, thalidomide and dexamethasone produced a high hematologic response rate. Lenalidomide is a potent analogue of thalidomide and two independent phase II trials by the Mayo Clinic and the Boston groups demonstrated its activity, alone and in combination with dexamethasone, in AL amyloidosis. In both studies the dose of 25 mg/day, commonly used in multiple myeloma, showed significant toxicity. A lower dosage of 15 mg/day was generally better tolerated. In the present trial (NCT00607581) we evaluated the combination of cyclophosphamide, lenalidomide and dexamethasone (CLD) in previously treated patients with AL amyloidosis. Main exclusion criteria were overt multiple myeloma, having both N terminal natriuretic peptide type B (NT-proBNP) >332 ng/L and troponin I (cTnI) ≥0.1 ng/mL, New York Heart Association (NYHA) class 4 heart failure, glomerular filtration rate <30 mL/min, neutrophils <1500/mL, platelets <140000/mL, performance status >3. The patients received up to 9 cycles of C (500 mg on days 1, 8 and 15), L (15 mg on days 1-21), and D (40 mg on days 1, 8, 15 and 22) every 28 days. The protocol was amended to allow starting with D 20 mg in patients who presented with severe fluid retention (>3% of body weight). The patients received prophylactic aspirin (100 mg/day) and omeprazole (20 mg/day). Treatment was discontinued if complete remission or partial hematologic response plus organ response was reached after 6 cycles, or in case of lack of response after 3 cycles. Twenty patients were enrolled. Organ involvement was cardiac (60%), renal (80%), hepatic (25%) and nerve (20%). Median (range) NT-proBNP was 872 ng/L (62-2778 ng/L) and cTnI was 0.02 ng/mL (0-0.09 ng/mL). Eleven patients (55%) received 1 previous treatment line, 6 (30%) had 2 prior treatments and 3 patients (15%) underwent to 3 previous therapies. All the patients were exposed to melphalan, 5 (25%) to thalidomide and 3 (15%) to bortezomib. Twelve subjects (60%) were refractory to previous treatment and the remaining had relapsed. Twelve patients (60%) experienced severe adverse events (grade 3 in all cases): neutropenia in 6 cases (30%), fluid retention in 2 (10%), renal failure in 2 (10%), thrombocytopenia and rash in 1 patient (5%) each. Treatment was discontinued only in the patient who experienced skin rash. Fluid retention, though not severe, was common and D was reduced to 20 mg in 11 of the 18 patients who started with full dosage. Six patients (30%) required L dose reduction. Notably, NT-proBNP increased by at least 30% and 300 ng/L (median 220% and 2024 ng/L) in 14 patients (70%) after cycle 1. This increase occurred in all the 12 patients with heart involvement, was accompanied by an increase by at least 0.05 ng/mL in cTnI in 6 cases, was asymptomatic and was not associated with modifications in NYHA class, ejection fraction, creatinine, fluid retention, hematologic response and survival. Four patients (20%) died after a median of 8 months (range 6-11 months) due to heart failure (2) and sudden death (2). Median survival was not reached. With a median follow-up of 9 months, 8 patients (40%) obtained a hematologic response that was complete in 1 case (5%). Median time to response was 1.9 months (range 0.8-3.9 months). Organ response was reached in 3 patients (proteinuria in 2 cases and neuropathy in 1). Treatment with CLD proved effective in this cohort of heavily pretreated patients and warrants further investigation. Adverse events were frequent but not fatal and they could be managed by dose adjustments. Treatment with CLD causes an asymptomatic increase in cardiac biomarkers that should be considered when evaluating organ response. Disclosures: No relevant conflicts of interest to declare.

Baseline Serum Albumin and Proteinuria Predict Renal Response after Autologous Stem Cell Transplantation in AL Amyloidosis.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 1166-1166
Author(s):  
Nelson Leung ◽  
Angela Dispenzieri ◽  
Martha Q. Lacy ◽  
Mark R. Litzow ◽  
Shaji K. Kumar ◽  
...  
Keyword(s):  
Multivariate Analysis ◽  
Stem Cell ◽  
Stem Cell Transplantation ◽  
Light Chain ◽  
Al Amyloidosis ◽  
Baseline Serum ◽  
Monoclonal Protein ◽  
Renal Response ◽  
Hematologic Response ◽  
Organ Response

Abstract Introduction: High dose melphalan followed by autologous stem cell transplantation (ASCT) is an effective treatment for patients with light chain associated (AL) amyloidosis. Longer patient survival and higher rates of organ response have now been documented by multiple studies. However, predictors of organ response remain unknown. Previously, we have reported the benefits of renal response after ASCT in this population. This study was conducted to investigate the characteristics that would predict renal response after ASCT. Methods: The study was performed retrospectively on consecutive patients that underwent ASCT at our institution from March of 1996 to December of 2004. Exclusion criteria include baseline proteinuria &lt; 1 g/d, dialysis prior to ASCT and lack of laboratory data at follow up to determine renal response. Renal response was defined by &gt; 50% reduction in baseline proteinuria with &lt; 25% decline in renal function as measured by serum creatinine. Treatment related mortality and dialysis dependence prior to meeting criteria of response were viewed as treatment failures. Hematologic response was determined by 50% reduction of monoclonal protein (free light chain) or complete eradication if the monoclonal protein was too small to be quantified. Results: A total of 135 patients met criteria for study. Median age was 56.2 years at the time of transplant, 53.7% were male. Median baseline proteinuria and GFR were 6.4 g/d and 70 ml/min/1.73m2 respectively. Renal response was achieved in 35.6% of the patients while hematologic response was 71.1% in the 128 patients evaluated. Patient’s age, sex, albumin, GFR, proteinuria, conditioning regimen, and hematologic response were evaluated and the following were found to be associated with renal response: albumin (p = 0.001), proteinuria (p = 0.008), and hematologic response (p = 0.0002). The cutoff for albumin was found to be 1.6 mg/dl and proteinuria was 3.5 g/d. Multivariate analysis using a logistic regression model showed hematologic response and proteinuria to be independent predictors of renal response. The impact of proteinuria and hypoalbuminemia was then investigated together (Table 1). When combined, they were a better predictor then either one alone (Hazard ratio = 6.34 for combined, 3.43 for proteinuria, 3.32 for hypoalbuminemia). The combination was also a better independent predictor of renal response in the multivariate analysis. In this group of patients, renal response was associated with longer survival but hematologic response was not (p = 0.02). Discussion: Our study showed that besides hematologic response, baseline serum albumin and proteinuria are independent predictors of renal response in AL patients after ASCT. Hypoalbuminemia and nephrotic range proteinuria, both markers of the severity of renal disease, have strong negative impact on response. This implies that there may be a limit to the reversibility of organ damage even when hematologic response is achieved. This study also points out the importance of organ (renal) response in this disease as hematologic response alone did not predict long term outcome. Our results suggest ASCT should be done early for AL to insure optimal organ response and patient outcome. Table 1 The Effects of Hypoalbuminemia and Proteinuria on Renal Response after ASCT Hypoalbuminemia & Proteinuria No Renal Response Renal Response None 39.3% 60.7% One 66.2% 33.8% Both 81.8% 18.2%

High Dose Melphalan with Autologous Stem Cell Transplantation Overcomes Poor Prognosis of Primary Amyloidosis

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 1350-1350
Author(s):  
Simrit Parmar ◽  
Mubeen Khan ◽  
Gabriela Rondon ◽  
Nina Shah ◽  
Qaiser Bashir ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Stem Cell ◽  
Plasma Cells ◽  
High Dose ◽  
Al Amyloidosis ◽  
Hematologic Response ◽  
Bone Marrow Plasma ◽  
Organ Response ◽  
High Dose Melphalan

Abstract Abstract 1350 Background: Systemic Primary AL Amyloidosis is a rare but potentially fatal disease resulting from tissue deposits of amyloid fibrils derived from monoclonal immunoglobulin light chains. High-dose melphalan followed by autologous hematopoietic stem cell transplant (auto HCT) is associated with hematologic and organ responses and improved survival. Methods: In this retrospective analysis we identified 46 patients with primary AL amyloidosis who received auto HCT between 01/1998 to 05/2010 at MDACC. Organ responses were determined using Amyloidosis Consensus Criteria. Results: The median age at auto HSCT was 56 years (34-74) where 61% were males and 35% were older than 60 years of age. 61% had lambda light chain restriction and only 4% had cytogenetic abnormalities. Disease characteristics are summarized in Table 1. The median time from diagnosis to auto HCT was 6.6 months (2.2-29.4 months). 22 pts (47.8%) had one organ, 19 pts (41.3%) had 2 organ and 4 pts (8.7%) had 3 organ involvement. 11 pts (23.9%) had heart and 35 pts (76.1%) had kidney involvement. The median follow up from the time of diagnosis was 22.4 months and from time of auto HCT was 16.7 months. High dose Melphalan dose was 200mg/m2 in 24 pts (52%) and 140mg/m2 in 22 (47.8%). There were 4 early deaths and 4 pts whose follow up was less than 3 months and their response was not assessed. Out of the 38 evaluable patients, the post-transplant organ responses were as follows ≥PR 25(66%), ≥stable disease 35(92%) (Table2). The hematologic responses were: CR=5 (13%), ≥VGPR=10(26%), ≥PR=26 (68%), ≥SD=37(97%). One patient had progressive disease. There was a correlation between organ response and hematologic response (chi square;p<10-3). The day-100 treatment related mortality (TRM) was 8.7% and 1-yr TRM was 13%. The median progression-free (PFS) and overall survival (OS) from auto HCT was 73.8 months and not reached (from transplant). The median PFS and OS from diagnosis were 93 months and 59.8 months respectively. In multivariate analysis, heart involvement (p=0.01), female sex (p=0.011), age ≥60 years (p=0.002), bone marrow plasma cells≥10% (p=0.043) and Beta-2 microglobulin>3.5mg/l (p=0.02) were associated with poor OS. Improved OS correlated with organ response (52.6 vs 11.4 months; p=0.01) and hematologic response (52.6 vs.6.1months; p=0.002). Hemoglobin <10 g/dl (p=0.047), bone marrow plasma cells≥10% (p=0.043) and age≥60 years (p=0.075) were associated with shorter PFS. Hematologc response (p=0.48) and organ response (p=0.12) were not associated with improved PFS. Conclusion: In this analysis the outcome of patients with primary systemic AL amyloidosis was durable with auto HCT with acceptable mortality risk and improved survival. Disclosures: No relevant conflicts of interest to declare.

Treatment of Light Chain (AL) Amyloidosis and Light Chain Deposition Disease (LCDD) with the Combination of Bortezomib and Dexamethasone.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 191-191 ◽  
Author(s):  
Efstathios Kastritis ◽  
Athanasios Anagnostopoulos ◽  
Maria Roussou ◽  
Savvas Toumanidis ◽  
Constantinos Pamboukas ◽  
...  
Keyword(s):  
Median Time ◽  
Light Chain ◽  
Dose Adjustment ◽  
High Dose ◽  
Al Amyloidosis ◽  
Light Chain Deposition Disease ◽  
Hematologic Response ◽  
Organ Response ◽  
Light Chain Deposition

Abstract Background: Primary (AL) amyloidosis and light chain deposition disease (LCDD) are clonal plasma cells disorders characterized by deposition of either amyloid fibrils (in AL) or amorphous nodular non-congophilic deposits (in LCDD) derived from abnormal light chains, that cause failure of affected organs. Treatment of AL is based on steroids and standard dose or high dose melphalan with ASCT. Data on treatment of LCDD are limited. Bortezomib, a proteasome inhibitor, has significant activity in myeloma, which is enhanced by the addition of dexamethasone (BD) and can be given in myeloma patients with renal impairment. We evaluated this combination in patients with AL and LCDD. Methods: We treated consecutive patients with AL or LCDD with the combination of Bortezomib (1.3 mg/m2 days 1, 4, 8 and 11) and Dexamethasone (40 mg days 1–4), every 21 days, for up to 6 cycles. Dose modifications were made based on toxicity. Organ involvement and hematologic and organ response were assessed following standard criteria (Gertz et al, Am J Hematol 2005). Results: Since September 2005, 21 consecutive AL and 2 LCDD patients started treatment with BD. Eight patients (38%) had at least one prior therapy and 13 (62%) had ≥2 organs involved; kidneys and heart were affected in most patients. The majority had impaired performance status, high BNP values and 7 (33%) patients had creatinine&gt;2 mg/dl. Among the 21 AL patients, 2 are early for evaluation, 4 had non-measurable disease and 15 patients are evaluable: 13 (87%) responded (CR+PR) and 7 (47%) achieved hematologic CR. All 5 patients refractory to high dose DEXA had a hematologic response and 3 had a CR. Two of 3 AL patients with abnormal FLC ratio but involved FLC&lt;100 mg/L achieved normal FLC ratio. Both patients with LCDD responded- the patient who was refractory to VAD had a CR. Median time to hematologic response was 0.93 months; all responses occurred within 2 courses while all patients in hematologic CR maintain CR for a median of 10.5 months (range 4.6–21). So far, 6 (28%) AL patients had organ responses (3 renal and 3 cardiac) while 7 (44%) patients had a sustained &gt;50% reduction in BNP. Median time to organ response in AL patients was 4 months (range 2–8). In both LCDD patients albuminuria was reduced by more than 50%. Median follow-up for all patients and for living patients is 9.5 months (range 1–23) and 12 months (range 4–23) respectively. In an intention to treat basis 8 (38%) patients have progressed, including 3 AL patients (14%) who died while on treatment (with two of them at hematologic PR at the time of their death- one died before she was assessable for response). Five AL patients had either hematologic or organ progression at a median of 6.8 months after treatment initiation. Peripheral neuropathy, fatigue, peripheral edema, constipation and exacerbation of postural hypotension were managed with appropriate dose adjustment; however 10 (47%) patients were not able to receive the planned 6 courses. Conclusions: The combination of BD is feasible for patients with AL amyloidosis and LCDD. Most patients achieve rapid hematologic response and toxicity can be managed with close follow-up and appropriate dose adjustment. This treatment may be a valid option for patients with severe heart or kidney impairment who are not candidates for other therapies.

High-Dose Pomalidomide and Dexamethasone Induce Rapid Responses In Patients With AL Amyloidosis Exposed To Alkylators, Immune Modulatory Drugs, and Proteasome Inhibitors

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 288-288 ◽  
Author(s):  
Giovanni Palladini ◽  
Paolo Milani ◽  
Marta Vidus Rosin ◽  
Andrea Foli ◽  
Giampaolo Merlini
Keyword(s):  
Adverse Events ◽  
Proteasome Inhibitors ◽  
Median Number ◽  
Fluid Retention ◽  
Cardiac Response ◽  
High Dose ◽  
Al Amyloidosis ◽  
Cell Transplant ◽  
Heart Involvement ◽  
Rapid Responses

Abstract In the present trial (NCT01510613) we treated with the combination of pomalidomide and dexamethasone (PDex) 27 patients previously exposed to alkylators and bortezomib. All the patients were refractory to the last line of therapy performed. The median number of prior treatments was 2 (range: 1-7). Seven patients (26%) also received lenalidomide, 4 (15%) thalidomide, 3 (11%) ixazomib, 2 (7%) bendamustine, and six (22%) underwent autologous stem cell transplant. Pomalidomide was administered continuously in 28-day cycles. A standard 3 + 3 dose escalation scheme was adopted: since no dose limiting toxicity was observed in the first 3 patients treated with pomalidomide 2 mg/day, the remaining received 4 mg/day. Dexamethasone was administered at 40 mg weekly, and at 20 mg in 13 subjects who had baseline fluid retention >3% of body weight and / or repetitive ventricular arrhythmias at Holter electrocardiography. Prophylactic aspirin was also administered. Nineteen (68%) patients had heart involvement and 8 (29%) were stage 3. The kidney was involved in 11 patients (39%), the soft tissues in 5 (18%), and 4 subjects (14%) had peripheral neuropathy. The median number of PDex cycles performed was 3 (range: 1-9), and treatment is ongoing in 20 patients. Overall 18 patients (67%) experienced severe (grade 3-4) adverse events: neutropenia (8, 30%), fluid retention (7, 26%, all with heart involvement), infection (3, 11%), worsening neuropathy (2, 7%, all with peripheral nervous system involvement), and rash (2, 7%). Five patients (18%) discontinued treatment due to adverse events. Overall, 18 patients (67%) achieved a hematological response, with 5 (18%) very good partial responses. Importantly, the median times to first response and to best response were 1.1 and 3.0 months, respectively. Moreover, of the 7 patients previously exposed to lenalidomide 5 responded to pomalidomide, and the 3 patients who were refractory to ixazomib responded, indicating that pomalidomide can overcome resistance to other immune modulatory drugs and a second-generation proteasome inhibitor. As previously reported with other immune modulatory drugs, pomalidomide was associated with a median 116% increase in NT-proBNP during cycle 1, preventing the assessment of cardiac response according to current criteria. A renal response was achieved in 3 of the 11 patients (27%) with kidney involvement. With a median follow-up of 6 months, 1 patient died 5 months after enrollment due to heart failure. “High-dose” (4 mg/day) pomalidomide combined with dexamethasone induces a high rate of rapid responses in patients previously exposed to alkylators, other immune modulatory drugs, and proteasome inhibitors, representing a powerful and rapid rescue treatment in AL amyloidosis. Further studies are warranted to elucidate whether different dosing schedules based on high-dose induction followed by low-dose (2 mg/day) maintenance might retain the high response rates and rapid action, while improving tolerability. Disclosures: Off Label Use: Pomalidomide in AL amyloidosis. Merlini:Millennium-Takeda: Honoraria; Pfizer: Honoraria.

scholarly journals Stem-cell transplantation in multiple myeloma: how far have we come?

2019 ◽  
Vol 10 ◽  
pp. 204062071988811 ◽  
Author(s):  
Cinnie Y. Soekojo ◽  
Shaji K. Kumar
Keyword(s):  
Multiple Myeloma ◽  
Stem Cell ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Residual Disease ◽  
Phase Iii ◽  
Novel Agents ◽  
Optimal Timing ◽  
High Dose ◽  
Phase Iii Trials

High-dose therapy (HDT) and autologous stem-cell transplantation (ASCT) has historically been an essential part of multiple myeloma (MM) management since early studies demonstrated its efficacy in relapsed disease, and subsequent phase III trials demonstrated better responses and improved survival with this modality compared with standard chemotherapy. With further advances in the MM treatment landscape, including the development of potent novel agents, there has been an increasing debate around various aspects of ASCT, including the optimal timing, role of single versus tandem ASCT, and the practice of consolidation and maintenance therapy post-ASCT. Routine incorporation of the novel agents at each of the treatment phases, induction, consolidation when used, and maintenance has led to better responses as reflected by increasing rates of minimal residual disease (MRD) negativity, longer progression-free survival (PFS) with improvement in overall survival (OS) and in some of the trials. The phase III trials over the last decade have provided significant clarity on the current approach, and have raised important questions regarding the applicability of this modality in all patients. This review aims to summarize the latest literature in the field and discusses how these findings impact the practice of ASCT today.

scholarly journals Patients with light-chain amyloidosis and low free light-chain burden have distinct clinical features and outcome

Blood ◽  
2017 ◽  
Vol 130 (5) ◽  
pp. 625-631 ◽  
Author(s):  
Paolo Milani ◽  
Marco Basset ◽  
Francesca Russo ◽  
Andrea Foli ◽  
Giampaolo Merlini ◽  
...  
Keyword(s):  
Clinical Features ◽  
Light Chain ◽  
Free Light Chain ◽  
Al Amyloidosis ◽  
Renal Survival ◽  
Light Chain Amyloidosis ◽  
Hematologic Response ◽  
Heart Involvement ◽  
Key Points

Key PointsPatients with AL amyloidosis and low dFLC burden (<50 mg/L) have less severe heart involvement and better survival. These patients are evaluable for hematologic response with adapted criteria predicting improvement of overall and renal survival.

Outcome of Children with T-Cell Acute Lymphoblastic Leukemia (T-ALL) and Standard Risk (SR) Features: Results of CCG-1952, CCG-1991 and POG 9404.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 680-680 ◽  
Author(s):  
Yousif Matloub ◽  
B.L. Asselin ◽  
Linda C. Stork ◽  
Meenakshi Devidas ◽  
Harland Sather ◽  
...  
Keyword(s):  
T Cell ◽  
High Risk ◽  
Lymphoblastic Leukemia ◽  
Intensive Therapy ◽  
Phase Iii ◽  
High Dose ◽  
Phase Iii Trials ◽  
Cell Acute Lymphoblastic Leukemia ◽  
Intensified Chemotherapy ◽  
Standard Risk

Abstract Children with T-ALL have generally had a poorer prognosis than patients with precursor-B ALL. Patients with T-ALL are more likely than those with B-precursor ALL to be > 9 years and present with WBC > 50,000/ul, bulky lymphadenopathy and mediastinal mass. Since 1996, the former CCG has stratified protocol eligibility for patients with ALL based on NCI defined Standard Risk (SR = age between 1-9.99 years; WBC < 50,000/ul) or High Risk (HR) groups, regardless of immunophenotype. In contrast, the former POG has treated all T-cell patients on protocols separate from those for precursor-B ALL. This report compares the outcomes among children with T-cell ALL treated on recently completed or ongoing CCG and POG phase III trials for ALL. CCG-1952 enrolled 2176 eligible children with SR ALL between 1996 and 2000; 106 (5%) had T-cell immunophenotype. Treatment was a standard BFM regimen with prednisone and 2 phases of delayed intensification (DI) with a 2x2 randomization of IT methotrexate (MTX) v ITT and MP v TG. From June 2000 to March 2004, CCG-1991 has enrolled 1794 SR ALL patients: 80 (4%) had T-ALL. Treatment included a similar BFM backbone with substitution of dexamethasone and a 2x2 randomization between escalating IV v oral MTX and 1 v 2 DIs. POG-9404 (opened 1996; closed 2001) was developed exclusively for T-cell disease and enrolled 363 patients with T-ALL; 84 (23%) fit the NCI SR group criteria. On the latter protocol, patients received treatment similar to that developed by the Dana-Farber Leukemia Consortium for high risk B-precursor ALL, with randomization to ± 4 cycles of high dose MTX (5 Gm/m2) and leucovorin. All patients on 9404 received 1800 cGy prophylactic cranial radiation while CCG patients did not. Outcome for T-ALL on CCG-1952 is substantially worse than for B-precursor ALL, with 5 year event-free survival (EFS) of 73% compared to 82% (p = 0.007). Interim analysis of CCG-1991 also shows a significantly worse outcome for T-ALL compared to B-precursor ALL: 3y estimated EFS 78% v 90%, p = 0.0002. In contrast, estimated 5y EFS for patients with SR T-ALL on POG-9404 is 88% (90% on the superior high dose MTX regimen). Comparison of the SR v HR T-ALL patients treated on POG 9404 shows a significant advantage for the SR group (5y EFS of 90% v 75%, p < 0.004). This is in contrast to comparison of T-ALL patients on CCG-1952 (SR) v the concurrent CCG-1961 HR study where T-ALL patients have similar outcome (5y EFS 73% v 72%, p = 0.77). These data suggest that patients with T-ALL and SR features have better EFS when treated with more intensified chemotherapy regimens. Because early EFS for T-cell patients treated on CCG-1991 is worse than on POG 9404, the former study was closed to further accrual of patients with T-ALL. The COG ALL Committee is developing a study for exclusive enrollment of patients with T-ALL using intensive therapy based on the current COG HR ALL regimen, regardless of SR or HR features.

Impact of Holmium-DOTMP on Transplant Outcomes. Results of a Retrospective Single Institution Analysis.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 426-426
Author(s):  
Anna Christoforidou ◽  
Patricia Williams ◽  
Linda Roden ◽  
Ana Aleman ◽  
Donna Weber ◽  
...  
Keyword(s):  
Univariate Analysis ◽  
Conditioning Regimen ◽  
Patient Characteristics ◽  
Phase Iii ◽  
High Dose ◽  
Free Survival ◽  
Transplant Outcomes ◽  
Phase Iii Trials ◽  
Total Body ◽  
High Dose Melphalan

Abstract Background:166Holmium-DOTMP is a beta emitting radiophosphonate that localizes specifically to the bone surfaces and can deliver high dose radiation both to the bone and bone marrow. Phase I/II trials have shown feasibility and tolerability when combined with a standard conditioning regimen of melphalan with or without total-body irradiation (TBI) in pts with multiple myeloma (MM) undergoing autologous stem cell transplantation (SCT). Purpose: To define the potential impact of 166Holmium-DOTMP (HO) in combination with melphalan when compared to a standard conditioning regimen of melphalan 200 mg/m2 (M200) in MM patients undergoing auto SCT. Methods: We performed a retrospective review of transplant outcomes among patients with MM who received an auto SCT between 1/98-12/01 with either M200 or a melphalan-HO combination and were in a 1ry refractory or 1st remission consolidation state. Univariate analysis was performed for response, survival and event free survival. Results: 104 pts were identified. Patient characteristics are summarized in Table 1. In brief the HO group had a higher percentage of patients with IgA disease, otherwise there were no siginificant differences in prognostic factors among the groups. Transplant outcomes are summarized in Table 2. The HO group had a trend towards a higher conversion to CR rate (51% vs 32%) for all patients, (23% vs 12.5%) for 1ry refractory patients and similar OS rates and a higher NRM rate of 12% vs 3% when compared to MEL200. When the analysis was limited to patients receiving &lt;2400 mCi the HO group had a trend towards longer PFS (33 months vs 24 months) with no difference in NRM rates. The OS rate at 5 yrs was 54% for the HO group vs 43% for the MEL200 group, among the 21 patients in the HO group receiving &lt;2400 mCi the 5 yr OS was 61% (Figure 1). Conclusion: 166Holmium-DOTMP in combination with high dose melphalan can result in higher CR rates than melphalan 200 mg/m2 alone, when given in optimal doses (&lt;2400 mCi) the results seem to be superior and the toxicities are minimal. Targeted skeletal radiotherapy with 166Holmium-DOTMP in combination with melphalan 200 mg/m2 is safe and effective and should be further studied in Phase III trials in all patients with MM undergoing autologous SCT, based on these data other methods of targeted skeletal radiotherapy should also be pursued. Patient Characteristics HO &lt;2400 mCi HO ≥ 2400 mCi Melphalan 200 p MEL200 vs HO N 21 20 63 Median Age 52 (45–61) 53 (36–64) 55 (35–69) NS IgA Type 33% 40% 14% .03 Median B2M @ Dx 3.15 3.15 3.5 NS Durie Salmon III 43% 55% 67% NS Number with Δ13 0 0 3 NS CR/PR @ SCT 5%/57% 5%/70% 6%/68% NS 1ry Refractory 38% 25% 25% NS Transplant Outcomes HO &lt;2400 mCi HO ≥ 2400 mCi MEL200 MEL 200 vs HO ORR/CR conversion 95%/55% 90%/48% 92%/32% NS/.06 NRM 5% 20% 3% .07 Median OS NR 31 months 52 months NS Median EFS 30 months 23 months 19 months .3

Bortezomib with Dexamethasone in Newly Diagnosed Patients with Primary Systemic Light Chain Amyloidosis or Multiple Myeloma-Associated AL Amyloidosis

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 5036-5036 ◽  
Author(s):  
Beihui Huang ◽  
Juan Li ◽  
Junru Liu ◽  
Dong Zheng ◽  
Mei Chen ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Side Effects ◽  
Light Chain ◽  
Conflicts Of Interest ◽  
Complete Response ◽  
Al Amyloidosis ◽  
Newly Diagnosed ◽  
Hematologic Response ◽  
Best Response ◽  
Organ Response

Abstract Abstract 5036 Objective: To assess the efficacy and tolerability of bortezomib with dexamethasone for patients with primary systemic light chain (AL) amyloidosis or multiple myeloma-associated AL amyloidosis. Methods: Twelve newly diagnosed patients with primary systemic AL amyloidosis and six patient with multiple myeloma-associated AL amyloidosis were treated with a combination of bortezomib (1. 3 mg/m2 d1, 4, 8, 11) and dexamethasone (20 mg d1–4). Results: Sixteen patients was evaluable. 12/16 had a hematologic response and 6/16 (37. 5%) a hematologic complete response. Median cycles to response was 1 cycle and median cycles to best response was 2 cycles. In patients with primary AL amyloidosis, 8/10 (80. 0%) had a hematologic response and 5/10 (50. 0%) a hematologic complete response. In patients with myeloma-associated AL amyloidosis, 7/10 (70. 0%) had a hematologic response and 1/6 (16. 7%) a hematologic complete response. Twelve patients (75. 0%) had a response in at least one affected organ, in which 7 in patients with primary AL amyloidosis and 5 in myeloma-associated AL amyloidosis. Person correlation between hematologic response and organ response was 0. 667 (p=0. 005). Fatigue, diarrhea and infection were the most frequent side effects. Three patients developed herpes zoster and had to stop chemotherapy. Conclusions: VD produces rapid and high hematological responses in the majority of patients with newly diagnosed AL regardless of primary or associated with myeloma. It is well tolerated with few side effects. This treatment may be a valid option as first-line treatment for newly diagnosed patients with primary systemic AL amyloidosis and multiple myeloma-associated AL amyloidosis. Disclosures: No relevant conflicts of interest to declare.

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