Pre-Stem Cell Transplant Induction Therapy Does Not Affect Post-Transplant Survival In Light Chain (AL) Amyloidosis

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 370-370 ◽  
Author(s):  
Sumit Madan ◽  
Shaji Kumar ◽  
Martha Lacy ◽  
Angela Dispenzieri ◽  
Francis Buadi ◽  
...  
Keyword(s):  
Stem Cell ◽  
Induction Therapy ◽  
Light Chain ◽  
Research Funding ◽  
Rank Test ◽  
Al Amyloidosis ◽  
Cell Transplant ◽  
Exact Test ◽  
Post Transplant ◽  
Hematologic Response

Abstract Abstract 370 Background: Light chain (AL) amyloidosis is characterized by the deposition of amyloid derived from immunoglobulin light chains in various organs. Autologous peripheral blood stem cell transplantation (SCT) is a commonly used and effective treatment for AL. For patients (pts) undergoing this procedure, a proportion of pts receive treatment similar to induction therapy employed in pts with myeloma undergoing SCT. However, the significance of induction therapy and its impact on the overall survival (OS) in AL is unknown. We conducted this study to ascertain the role of pre-SCT therapy on the post-transplant outcomes in AL. Patients and methods: 435 pts with AL who underwent SCT at our institution between March 1996 and May 2010 form the study group. Groups were compared using Fisher's exact test or t-test, and survival was calculated using Kaplan Meier method. Survival curves were compared using log rank test. Result: The median (range) age of pts at the time of SCT was 57.4 years (26-75); 260 (60%) were males. The median (range) duration from AL diagnosis to SCT was 4 mos (1-87), and 284 (65%) pts were alive at the time of analysis. Melphalan 200/m2 (271 pts) or Mel/TBI (17 pts) was used for conditioning in 66% pts, whereas the remaining one-third had reduced doses of melphalan (100-160 mg/m2). The median OS for pts that received pre-SCT therapy (N=286) compared with those who did not (N=149) was 94.7 and 96.5 months, respectively (P=0.6) (Fig 1). Among the group of pts who underwent pre-SCT therapy and were evaluable for response, the median OS for those with a hematologic response (N=42) and no hematologic response (N=42) was 82.1 and 51 months (P=0.2), respectively (Fig 2). Conclusion: Our study demonstrates no difference in the OS of AL patients who received a pre-SCT therapy compared with those who received a SCT after their diagnosis of AL. In patients receiving pre-SCT therapy, there was a trend towards reduced OS among those with no hematologic response to pre-transplant therapy, but this difference was not significant. Disclosure: Kumar: Celgene: Consultancy, Research Funding; Millennium: Research Funding; Merck: Consultancy, Research Funding; Novartis: Research Funding; Genzyme: Consultancy, Research Funding; Cephalon: Research Funding. Dispenzieri:Celgene: Honoraria, Research Funding; Binding Site: Honoraria.

Depth of response prior to autologous stem cell transplantation to predict survival in light chain amyloidosis.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 8516-8516
Author(s):  
Iuliana Vaxman ◽  
M Hasib Sidiqi ◽  
Abdullah S. Al Saleh ◽  
Shaji Kumar ◽  
Eli Muchtar ◽  
...  
Keyword(s):  
Stem Cell ◽  
Partial Response ◽  
Induction Therapy ◽  
Light Chain ◽  
Multivariable Analysis ◽  
Al Amyloidosis ◽  
Prognostic Impact ◽  
Cell Transplant ◽  
Depth Of Response ◽  
The Impact

8516 Background: The role of induction therapy prior to autologous stem cell transplant (ASCT) in immunoglobulin light chain (AL) amyloidosis remains controversial. Data on the prognostic impact of response to induction in a transplanted cohort are lacking. The aim of this study was to assess the impact of response to induction therapy on survival in patients undergoing ASCT for AL amyloidosis. Methods: We conducted a retrospective study of all newly diagnosed AL amyloidosis patients who received induction prior to ASCT between January 2007 and August 2017 at Mayo Clinic, Rochester, Minnesota. Patients receiving only corticosteroids prior to transplant were excluded as were those with an involved light chain of less than 5 mg/dL (not measurable for response). Results: 134 patients met inclusion criteria. The median age at diagnosis was 60 (range 36-74) and 85 (63%) were men. The most commonly used induction regimen was proteasome inhibitor-based (73.1%, n=98). The overall response rate to induction was 83% (complete response 17%, very good partial response 30% and partial response 36%). With a median follow up of 56.5 months, the median PFS and OS was 48.5 months and not reached, respectively. Response depth to induction therapy was associated with improved PFS and OS and was independent of the bone marrow plasma cell percentage. The median PFS was not reached for patients achieving ≥VGPR prior to ASCT and 33.8 months for patient achieving PR or less (P=0.001). The median OS was longer in patients with deeper responses (not reached for patients achieving ≥VGPR vs. 128 months for patients achieving PR or less (P=0.02). On multivariable analysis, independent predictors of OS were melphalan conditioning dose (RR= 0.38; P=0.018) and depth of response prior to transplant (RR 2.52; P=0.039). Conclusions: Hematologic response prior to transplant predicts post-transplant outcomes in patients with AL amyloidosis. [Table: see text]

Serum Free Light Chain Responses after High-Dose Intravenous Melphalan and Autologous Stem Cell Transplantation for AL (Primary) Amyloidosis.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 942-942
Author(s):  
Vaishali Sanchorawala ◽  
Daniel G. Wright ◽  
Barbarajean Magnani ◽  
Martha Skinner ◽  
David C. Seldin
Keyword(s):  
Stem Cell ◽  
Plasma Cell ◽  
Light Chain ◽  
Free Light Chain ◽  
High Dose ◽  
Al Amyloidosis ◽  
Cell Transplant ◽  
Serum Free ◽  
Hematologic Response ◽  
Serum Free Light Chain

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 of plasma cell dyscrasias underlying AL amyloidosis following HDM/SCT and other forms of treatment. The 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 persistent plasmacytosis or plasma cell clonality in a bone marrow biopsy by immunohistochemistry. Others have defined hematologic response as a ≥ 50% reduction in free light chain (FLC) measurements. Hematologic responses by both criteria correlate with survival and clinical improvement following HDM/SCT. We have carried out a retrospective analysis of HDM/SCT treatment outcomes for patients with AL amyloidosis to determine the extent to which hematologic CR, by our standard criteria, correlates with FLC response. Serum free light chain concentrations (FLC) were measured by a sensitive nephelometric immunoassay in 67 patients with AL amyloidosis before and after treatment with HDM/SCT. After treatment with HDM/SCT, 27 patients (40%) achieved a CR by standard criteria. Of these 27 patients, 63% (n=17) demonstrated normalization of FLC levels and an improvement of ≥50% in FLC occurred in 100%. Of the 40 patients who did not achieve a CR, 25% (n=10) experienced normalization of FLC levels, and an improvement of ≥50% occurred in 78% (n=31), while only 5 patients (13%) experienced no significant change in FLC. The average improvement in FLC was 94% for patients who achieved a CR by standard criteria and 72% for those who did not (p=0.0001, t-test). Thus, HDM/SCT was found to induce improvements in FLC levels of ≥50% in the vast majority of AL amyloidosis patients treated with HDM/SCT (87%, or 58/67). These data indicate that a decrease in FLC of ≥50% is a substantially less stringent indicator of hematologic response than is CR, as defined by standard criteria. Nonetheless, these measures of hematologic response are complementary, since decreases in FLC can be detected earlier following treatment than changes in IFE and marrow studies required to determine CR.

scholarly journals Similar Survival with Deferred Versus Salvage Autologous Stem Cell Transplant in Light Chain Amyloidosis

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 4579-4579 ◽  
Author(s):  
Danny Luan ◽  
Koen Van Besien ◽  
Paul J Christos ◽  
Roger Pearse ◽  
Danielle Guarneri ◽  
...  
Keyword(s):  
Overall Survival ◽  
Stem Cell ◽  
Light Chain ◽  
Research Funding ◽  
Small Sample ◽  
Renal Amyloidosis ◽  
High Dose ◽  
Al Amyloidosis ◽  
Cell Transplant

Background: Light chain (AL) amyloidosis is characterized by deposition of misfolded monoclonal immunoglobulin light chains leading to organ dysfunction. AL amyloidosis has traditionally been treated with agents used in multiple myeloma, primarily alkylators, proteasome inhibitors (PIs), immunomodulatory agents (IMiDs), and high-dose melphalan/autologous stem cell transplantation (ASCT). A retrospective study comparing patients with AL amyloidosis who underwent ASCT as frontline therapy ('upfront ASCT') to those undergoing ASCT following induction ('deferred ASCT') revealed that deferred ASCT was associated with prolonged overall survival (OS) compared to upfront ASCT (Afrough et al, Biol Blood Marrow Transplant, 2018). Given the number of effective new therapies for AL amyloidosis, the potential to delay ASCT after one or more lines of therapy ('salvage ASCT') is feasible. To our knowledge, transplant outcomes of AL amyloidosis patients undergoing deferred vs salvage ASCT following at least one relapse have not been reported. A retrospective chart review was conducted to compare AL amyloidosis patients receiving deferred vs salvage ASCT for progression-free survival (PFS) and overall survival (OS). The study was approved by the Institutional Review Board at Weill Cornell Medical College. Methods: Twenty-four patients with AL amyloidosis who underwent deferred or salvage ASCT between 2000-2018 were included in the analysis. Patients who underwent upfront ASCT without induction chemotherapy were excluded. Demographics and clinical parameters were extracted from the electronic medical record. PFS was calculated from date of ASCT to first relapse and OS was calculated both from date of diagnosis and date of ASCT to death. Patients were censored if lost to follow-up prior to experiencing the relevant event. PFS as well as OS of patients who underwent deferred vs salvage ASCT were compared. Log-rank tests were used to statistically evaluate differences between Kaplan-Meier PFS/OS curves. Cox proportional hazards models were used to calculate hazard ratios (HR) using deferred ASCT as the reference treatment. Results: Among the 24 patients included in this analysis, 13 underwent deferred ASCT with 1 prior line of chemotherapy (e.g., induction), and 11 underwent salvage ASCT with a median of 3 prior lines (Table 1). Ten patients had cardiac amyloidosis, 15 had renal amyloidosis, and 6 had multi-organ involvement. Induction regimens received in the deferred group are included in Table 1. Neither PFS nor OS was significantly different between patients receiving deferred vs salvage ASCT. After median follow-up of 2.9 years, median PFS in patients who received deferred ASCT was 6.5 years and not reached in those who received salvage ASCT (P=0.47), with a HR of 1.74 (95% CI, 0.38-7.85) (Figure 1A). Median OS from date of ASCT was not reached in either group after a median follow-up of 2.8 years (P=0.52), with a HR of 2.16 (95% CI, 0.19-24.04) (Figure 1B). Similarly, median OS calculated from date of diagnosis was not significantly different between deferred vs salvage ASCT (P=0.79) (Figure 1C). Conclusions: In this cohort of 24 AL amyloidosis patients, no significant differences in PFS or OS were seen between patients undergoing deferred ASCT following induction vs salvage ASCT following multiple lines of therapy. Unlike the superior OS seen with deferred vs upfront ASCT, our findings show that either deferred or salvage ASCT may be associated with comparable outcomes and suggest similar OS despite timing of transplant. However, it is important to note the small sample size and that none of our patients received daratumumab-based regimens which may have improved PFS/OS in either or both groups. There were also small differences between groups in use of maintenance (1 vs 3 patients in the deferred and salvage groups, respectively) and proportion of patients receiving higher doses of melphalan 200mg/m2 vs 140 mg/m2 (69% vs 55% in deferred and salvage groups, respectively). Nevertheless, the lack of difference seen in PFS and OS between the two groups suggests that eventual hematologic relapse and organ progression with death occur at similar time intervals despite timing of ASCT. This speaks to the point that in newly diagnosed AL amyloidosis as well as later in the disease, achieving deep responses to prevent organ progression and death regardless of timing of ASCT remains an important treatment goal. Disclosures Van Besien: Miltenyi Biotec: Research Funding. Coleman:Kite Pharmaceuticals: Equity Ownership; Pharmacyclics: Speakers Bureau; Merck: Research Funding; Gilead, Bayer, Celgene: Consultancy, Research Funding, Speakers Bureau. Niesvizky:Takeda, Amgen, BMS, Janssen, Celgene: Consultancy, Research Funding. Rosenbaum:Janssen: Research Funding; Honoraria Akcea: Other: Accordant Health.

scholarly journals Increased Early Mortality after Fludarabine and Melphalan Conditioning with Peripheral Blood Grafts in Haploidentical SCT with Post-Transplant Cyclophosphamide

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 4496-4496 ◽  
Author(s):  
Luke Eastburg ◽  
David A. Russler-Germain ◽  
Ramzi Abboud ◽  
Peter Westervelt ◽  
John F. DiPersio ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Stem Cell ◽  
T Cell ◽  
Board Of Directors ◽  
Research Funding ◽  
Early Mortality ◽  
Cell Transplant ◽  
Advisory Committees ◽  
Post Transplant ◽  
Equity Ownership

The use of post-transplant cyclophosphamide (PTCy) in the context of haploidentical stem cell transplant (haplo-SCT) has led to drastically reduced rates of Graft-vs-Host (GvH) disease through selective depletion of highly allo-reactive donor T-cells. Early trials utilized a reduced-intensity Flu/Cy/TBI preparative regimen and bone marrow grafts; however, relapse rates remained relatively high (Luznik et al. BBMT. 2008). This led to the increased use of myeloablative (MA) regimens for haplo-SCT, which have been associated with decreased relapse rates (Bashey et al. J Clin Oncol. 2013). Most studies have used a MA total body irradiation (TBI) based regimen for haplo-SCT. Preparative regimens using fludarabine and melphalan (FluMel), with or without thiotepa, ATG, and/or low dose TBI have also been reported using bone marrow grafts. Reports on the safety and toxicity of FluMel in the haplo-SCT setting with PTCy and peripheral blood stem cell (PBSC) grafts are lacking. In this two-center retrospective analysis, the safety/toxicity of FluMel as conditioning for haplo-SCT was evaluated. We report increased early mortality and toxicity using standard FluMel conditioning and PBSC grafts for patients undergoing haplo-SCT with PTCy. 38 patients at the University of Rochester Medical Center and the Washington University School of Medicine underwent haplo-SCT with FluMel conditioning and PBSC grafts between 2015-2019. Outcomes were measured by retrospective chart review through July 2019. 34 patients (89.5%) received FluMel(140 mg/m2). Two patients received FluMel(100 mg/m2) and two patients received FluMel(140 mg/m2) + ATG. The median age at time of haplo-SCT was 60 years (range 21-73). 20 patients were transplanted for AML, eight for MDS, two for PMF, two for NHL, and five for other malignancies. The median Hematopoietic Cell Transplantation-specific Comorbidity Index (HCT-CI) score was 4 (≥3 indicates high risk). 11 patients had a history of prior stem cell transplant, and 16 patients had active disease prior to their haplo-SCT. Seven patients had sex mismatch with their stem cell donor. Median donor age was 42 (range 21-71). 20 patient deaths occurred by July 2019 with a median follow up of 244 days for surviving patients. Nine patients died before day +100 (D100, "early mortality"), with a D100 non-relapse mortality (NRM) rate of 24%. Median overall and relapse free survival (OS and RFS, respectively) were 197 days (95% CI 142-not reached) and 180 days (95% CI 141-not reached), respectively, for the entire cohort. The 1 year OS and NRM were 29% and 50%. The incidence of grades 2-4cytokine release syndrome (CRS) was 66%, and 52% of these patients were treated with tocilizumab. CRS was strongly associated with early mortality, with D100 NRM of 36% in patients with grade 2-4 CRS compared to 0% in those with grade 0-1. The incidence of acute kidney injury (AKI) was 64% in patients with grade 2-4 CRS, and 8% in those without (p < 0.001). 28% of patients with AKI required dialysis. Grade 2-4 CRS was seen in 54% of patients in remission prior to haplo-SCT and in 92% of those with active disease (p = 0.02). Of the 9 patients with early mortality, 89% had AKI, 44% needed dialysis, and 100% had grade 2-4 CRS, compared to 31%, 10%, and 55% in those without early mortality (p = 0.002, p = 0.02, p = 0.01). Early mortality was not significantly associated with age, HCT-CI score, second transplant, disease status at transplant, total dose of melphalan, volume overload/diuretic use, or post-transplant infection. In conclusion, we observed a very high rate of NRM with FluMel conditioning and PBSC grafts for haplo-SCT with PTCy. The pattern of toxicity was strongly associated with grade 2-4 CRS, AKI, and need for dialysis. These complications may be mediated by excessive inflammation in the context of allo-reactive donor T-cell over-activation. Consistent with this, multiple groups have shown that FluMel conditioning in haplo-SCT is safe when using bone marrow or T-cell depleted grafts. Based on our institutional experiences, we would discourage the use of FluMel as conditioning for haplo-SCT with PTCy with T-cell replete PBSC grafts. Alternative regimens or variations on melphalan-based regimens, such as fractionated melphalan dosing or inclusion of TBI may improve outcomes but further study and randomized controlled trials are needed. This study is limited in its retrospective design and sample size. Figure Disclosures DiPersio: WUGEN: Equity Ownership, Patents & Royalties, Research Funding; Karyopharm Therapeutics: Consultancy; Magenta Therapeutics: Equity Ownership; Celgene: Consultancy; Cellworks Group, Inc.: Membership on an entity's Board of Directors or advisory committees; NeoImmune Tech: Research Funding; Amphivena Therapeutics: Consultancy, Research Funding; Bioline Rx: Research Funding, Speakers Bureau; Macrogenics: Research Funding, Speakers Bureau; Incyte: Consultancy, Research Funding; RiverVest Venture Partners Arch Oncology: Consultancy, Membership on an entity's Board of Directors or advisory committees. Liesveld:Onconova: Other: Data safety monitoring board; Abbvie: Membership on an entity's Board of Directors or advisory committees.

scholarly journals Conventional Therapy for Amyloid Light-Chain Amyloidosis

2020 ◽  
Vol 143 (4) ◽  
pp. 365-372
Author(s):  
Paolo Milani ◽  
Giovanni Palladini
Keyword(s):  
Stem Cell ◽  
Plasma Cell ◽  
Light Chain ◽  
Cell Clone ◽  
Alkylating Agents ◽  
Proteasome Inhibitors ◽  
Response Rates ◽  
Al Amyloidosis ◽  
Cell Transplant ◽  
Conventional Chemotherapy

The vast majority of patients with light-chain (AL) amyloidosis are not eligible for stem cell transplant and are treated with conventional chemotherapy. Conventional regimens are based on various combinations of dexamethasone, alkylating agents, proteasome inhibitors, and immunomodulatory drugs. The choice of these regimens requires a careful risk stratification, based on the extent of amyloid organ involvement, comorbidities, and the characteristics of the amyloidogenic plasma cell clone. Most patients are treated upfront with bortezomib and dexamethasone combined with cyclophosphamide or melphalan. Cyclophosphamide does not compromise stem cell mobilization and harvest and is more manageable in renal failure. Melphalan can overcome the effect of t(11;14), which is associated with lower response rates and shorter survival in subjects treated with bortezomib and dexamethasone, or in combination with cyclophosphamide. Lenalidomide and pomalidomide are the mainstay of rescue treatment. They are effective in patients exposed to bortezomib, dexamethasone, and alkylators, but deep hematologic responses are rare. Ixazomib, alone or in combination with lenalidomide, increases the rate of complete responses in relapsed/refractory patients. Conventional chemotherapy regimens will represent the backbone for future combinations, particularly with anti-plasma-cell immunotherapy, that will further improve response rates and outcomes.

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%

Outcome of High Dose Melphalan with Autologous Hematopoietic Stem Cell Transplant In Myeloma Associated with AL Amyloidosis

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 2400-2400
Author(s):  
Simrit Parmar ◽  
Mubeen Khan ◽  
Gabriela Rondon ◽  
Nina Shah ◽  
Qaiser Bashir ◽  
...  
Keyword(s):  
Stem Cell ◽  
Hematopoietic Stem Cell ◽  
Research Funding ◽  
Hematopoietic Stem Cell Transplant ◽  
Stem Cell Transplant ◽  
High Dose ◽  
Al Amyloidosis ◽  
Cell Transplant ◽  
Hematopoietic Stem ◽  
High Dose Melphalan

Abstract Abstract 2400 Background: Approximately 10% of patients with multiple myeloma (MM) have clinically overt primary systemic light-chain (AL) amyloidosis, and about 30% have concurrent occult AL amyloidosis. The impact of concurrent AL amyloidosis on the prognosis of myeloma is not well known. High-dose melphalan followed by autologous hematopoietic stem cell transplant (auto HCT) has shown significant activity in both MM and AL amyloidosis. Methods: We performed a retrospective analysis of patients who had concurrent MM and AL amyloidosis and underwent auto HSCT with high dose Melphalan at MDACC between 01/1998 to 05/2010. We identified 41 patients with concurrent MM and AL amyloidosis. Patient characteristics are summarized in Table 1. Twenty -six patients had occult AL amyloid, while 15 had clinically overt disease. Results: Median age at auto HSCT was 56 years (39-77), 58.5% being male with median follow up of 58.7 months from the time of diagnosis and 42.5 months from auto HCT. The median time from diagnosis to auto HCT was 8.9 mos (2.7-102.4 mos). 39% had Salmon Durie Stage III disease and 36.6% had more than one involved site at the time of transplant.Cytogenetic abnormalities were detected in 24.4% of patients. Post transplant hematologic responses were as follows: ≥CR=10 (24%), ≥VGPR=16 (39%), >PR=33 (80.5%), ≥stable disease= 40 (97.6%). Among the patients with overt organ involvement, one had early death. Of the 15 evaluable patients, organ responses were scored using the published consensus guidelines for amyloidosis and were as follows: PR=5 (33.3%), ≥SD=7 (46.7%). No correlation was seen between organ response and hematologic response. The 100-day treatment related mortality (TRM) was 0 and 1-year TRM of 2.4% which is comparable to patients transplanted for MM alone at our center. The median progression-free (PFS) and overall survival (OS) from auto HCT were 33.8 and 58.3 months, respectively.The median PFS and OS from diagnosis were 49.8 and 96 mos, respectively. In multivariate analysis, creatinine ≥ 2mg/dl was associated with a shorter PFS (p=0.043) and hemoglobin <10g/dl showed a trend towards a shorter PFS (p=0.093). None of these variables (Hb <10g/dl, Age>60yrs, Creatinine≥2mg/dl, B2M >3.5mg/l, BM plasma cells>30%) emerged as significant predictors of OS. There was no significant difference in outcome between patients with occult or symptomatic AL amyloidosis for OS (p=0.24) or PFS (P=0.9) Conclusion: In this analysis the outcome of patients with concurrent MM and AL amyloidosis was comparable to patients with MM alone. We believe these patients are acceptable candidates for auto HCT. Disclosures: Shah: Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Millenium: Research Funding; Novartis: Research Funding. Weber: novartis-unpaid consultant: Consultancy; Merck- unpaid consultant: Consultancy; celgene- none for at least 2 years: Honoraria; millenium-none for 2 years: Honoraria; celgene, Millenium, Merck: Research Funding. Orlowski: Celgene: Consultancy, Research Funding; Millennium Pharmaceuticals, Inc.: Consultancy, Research Funding.

Outcomes and Treatments of Relapsed AL Amyloidosis Following Stem Cell Transplant

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 1858-1858 ◽  
Author(s):  
Rahma Warsame ◽  
Soo-Mee Bang ◽  
Shaji K. Kumar ◽  
Martha Q Lacy ◽  
Francis K Buadi ◽  
...  
Keyword(s):  
Stem Cell ◽  
Stem Cell Transplant ◽  
Plasma Cells ◽  
Conflicts Of Interest ◽  
Treatment Options ◽  
Autologous Stem Cell Transplant ◽  
Al Amyloidosis ◽  
Cell Transplant ◽  
Post Transplant

Abstract Abstract 1858 Systemic light chain amyloidosis (AL amyloidosis) is a condition where clonal plasma cells produce misfolded insoluble immunoglobulin light chains that deposit in various organs causing progressive organ dysfunction. Chemotherapy and autologous stem cell transplant (ASCT) when eligible is the standard treatment options for patients with AL amyloidosis. There are several studies who report long term outcomes of patient post ASCT. However, there is a paucity of literature describing the outcomes of patients who have received ASCT but have relapsed. We performed a retrospective study to assess the outcomes and treatment regimens employed following relapse after ASCT. Between 1996 and 2009, 410 patients received ASCT at the Mayo Clinic as first line therapy. Of those 410 patients 42 patients died within 3 months of transplant, 64 patients died without documented relapse, 158 patients were alive without documented progression, and 146 patients had documented progression. Those 146 patients are the subject of our study. The median time to hematologic relapse was 2 years (range: 0.2–15.5 years). At relapse, 59 patients were treated with IMiD based therapy, 36 with alkylator based therapy, 24 with bortezomib, 15 with steroids, and 5 with second ASCT. The respective hematologic response rates were 58%, 33%, 50%, 53%, and 60%. The remaining six patients were not evaluable for response for one other following reasons: organ transplants; no further therapy; inevaluable disease. With a median post relapse follow up of 3.6 years, the median overall survival (OS) from the first post ASCT relapse was 4.6 years. The median post transplant follow up was 6.1 years, the median OS for these patients was 7.3 years from the time of transplant. These data provide novel information about outcomes after SCT relapse, which should be useful not only for patients and doctors but also for investigators designing studies for salvage therapies post-transplant. Disclosures: No relevant conflicts of interest to declare.

Long-Term Outcomes of Patients with Systemic Light Chain Amyloidosis (AL) Treated At Diagnosis with Risk-Adapted Stem Cell Transplant and Consolidation with Novel Agents.

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 3150-3150 ◽  
Author(s):  
Raymond L. Comenzo ◽  
Daniel E Fein ◽  
Hani Hassoun ◽  
Christina Bello ◽  
Joanne F Chou ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Light Chain ◽  
Cumulative Incidence ◽  
Research Funding ◽  
Initial Therapy ◽  
Novel Agents ◽  
Cell Transplant ◽  
Advisory Committees ◽  
Hematologic Response

Abstract Abstract 3150 Background: AL is a plasma cell dyscrasia characterized by the pathologic production of monoclonal light chains which misfold, deposit in various organs, including the heart, and can cause early death. High dose melphalan with stem cell transplant (SCT) results in high hematologic response rates and is a standard treatment for eligible patients. Achieving a complete hematologic response (CR) to SCT results in extended event-free and overall survival (OS), up to 8 and 13 years respectively in one large series. (Blood 2011; 118:4346) We have studied the addition of novel agents as consolidation following risk-adapted SCT (RA-SCT) in order to improve hematologic response (HR) rates and therefore outcomes. (Br J Haem 2007;139:224; Amyloid 2010;17:80a) In this report we examine the long-term outcomes of patients who received initial therapy with RA-SCT followed by consolidation for hematologic response less than CR (HR < CR). Methods: We performed a retrospective study to assess the HR rates, incidence of hematologic progression and overall survival (OS) of AL patients enrolled at diagnosis on two consecutive phase II trials using RA-SCT with consolidation for HR < CR (NCT01527032 and NCT00458822). OS was calculated from date of transplant to date of death or last follow up. Median event free survival (EFS) and OS were estimated by the method of Kaplan Meier. Cumulative incidence function was used to estimate the incidence of progression and death. Results: Between 2002 and 2011, 83 patients were enrolled and underwent RA-SCT on these trials and, following RA-SCT, those with HR < CR received consolidation with thalidomide and dexamethasone (TD) in the first and bortezomib and dexamethasone (BD) in the second trial. Thirty-six patients had cardiac involvement (43%) and all patients had free light chain measurements employed to score hematologic response and progression using consensus criteria (Am J Hematol 2005;79:319; Blood 2010;116:1364a). The frequency of CR following SCT was 24% and increased to 48% with post-SCT consolidation. The CR rates increased at 1 year compared to 3 months post-SCT from 21% to 36% with TD and from 28% to 62% with BD. With a median follow up of 5.1 years, the EFS is 4.5 years (95% CI: 2.6 to not reached) and the OS of all patients has not been reached (Figure 1). Sixteen patients died prior to hematologic progression and 26 patients have progressed with a cumulative incidence of hematologic progression of 8%, 18%, and 29% at 1, 2 and 3 years, respectively (Figure 2). Thirty-one percent (8/26) of relapsed patients have not required second-line therapy while among those who have, 78% (14/18) have responded including 44% (8/18) with CR. The median OS following hematologic progression was 5 years (95% CI: 2.6–5.8). Conclusions: Half of the AL patients on initial therapy trials employing RA-SCT and consolidation for HR < CR achieved CR with 36% of pts on the TD and 62% on the BD consolidation trial in CR at 1 year post-SCT respectively. At 3 years post-SCT the cumulative incidence of relapse was 29% and a third of relapsed patients did not require therapy, likely due to the very sensitive serum free light chain assay that detects low level hematologic progression in the absence of organ progression. Almost 80% of patients requiring second-line therapy responded, over half with CR, and median OS after relapse was 5 years. These results indicate that initial therapy with RA-SCT and consolidation is an effective initial treatment strategy for patients with AL in the era of novel agents. With over 5 years of follow up the median OS has not been reached. Disclosures: Comenzo: Millennium Pharmaceuticals, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Off Label Use: Use of the investigational agent MLN9708, an oral proteasome inhibitor, in the treatment of relapsed or refractory light-chain amyloidosis. Hassoun:Millenium: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Research Funding. Giralt:Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Millenium: Membership on an entity's Board of Directors or advisory committees; Onyx: Membership on an entity's Board of Directors or advisory committees, Research Funding. Landau:Millenium: Membership on an entity's Board of Directors or advisory committees, Research Funding; Onyx: Research Funding.

Cyclophosphamide, Bortezomib and Dexamethasone (CyBorD) Induction Therapy For Newly Diagnosed Light Chain Amyloidosis

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 3231-3231 ◽  
Author(s):  
Donna E. Reece ◽  
Madeline Phillips ◽  
Beryl Chung ◽  
Christine I. Chen ◽  
Esther Masih-Khan ◽  
...  
Keyword(s):  
Stem Cell ◽  
Median Time ◽  
Induction Therapy ◽  
Light Chain ◽  
Research Funding ◽  
Primary Therapy ◽  
Newly Diagnosed ◽  
Organ Function ◽  
Light Chain Amyloidosis ◽  
Definitive Therapy

Abstract Previously, most younger and fit patients (pts) with light chain amyloidosis (AL) received upfront autologous stem cell transplantation (ASCT) -- without any preceding induction therapy-while older pts and/or those with significant organ dysfunction were given definitive therapy with oral melphalan + dexamethasone (mel + dex). Recently, bortezomib (btz) was shown to be effective in relapsed AL, and has increasingly been used earlier in the disease course. The CyBorD combination (weekly cyclophosphamide + btz + dex) is a highly effective induction regimen for newly diagnosed multiple myeloma pts, and has shown encouraging preliminary outcomes in AL. Over the last 2 years, we have been offering CyBorD induction to all newly diagnosed AL pts. CyBorD was either administered for: 1) 2-4 cycles to try to reduce the monoclonal plasma cell population while allowing time to arrange stem cell (SC) collection/transplant admission in eligible pts, or 2) 8 cycles to serve as primary therapy for transplant-ineligible pts; it was also hoped that some of these pts who responded to CyBorD might experience improved organ function over time and eventually be able to undergo SC collection and/or ASCT. In order to assess this approach, we retrospectively examined the relative efficacy of induction therapy with CyBorD compared to other btz-containing regimens and to mel + dex in AL pts. Methods Between 01/2009 and 06/2013, 43 pts with biopsy-confirmed AL were referred to Princess Margaret Cancer Centre and received induction therapy with ≥1 cycle of CyBorD (n=15), other btz therapies (n=10; btz alone in 2, btz + steroids in 6 and btz + mel + prednisone in 2), or mel + dex (n=18). CyBorD doses were individualized and consisted of weekly oral cyclophosphamide 300 mg/m2, bortezomib IV/SQ 1.3-1.5 mg/m2and dex 12-20 mg. Thirty-four pts are evaluable for hematologic (heme) responses; 4 had insufficient data, while 5 are too early to evaluate. Organ responses were assessed in 44 organ systems in 26 pts. Results Median age was 55 yrs (range 44-85). Organ involvement included cardiac in 65%, renal in 49% and ≥ 2 organs in 58%. Median troponin I level was <0.07 (range <0.07-1.57) and BNP 305.6 (range 212-1625.3). After induction, 22 pts (64.7%) achieved a heme response (≥ PR): 67%, 44%, and 75% in the CyBorD, btz-other, and mel + dex groups, respectively. Treatment with CyBorD yielded the highest percentage of ≥ VGPR (55.5%, compared with 22% in the btz-other and 31% in the mel + dex arms); corresponding CR rates were 11%, 22% and 6%, respectively. Median times to first/best heme responses for the 3 groups were 1.2/4.0 mos for CyBorD, 1.3/2.1 mos for btz-other, and 2.1/5.5 mos for mel + dex. Pts treated with CyBorD also experienced the highest percentage of organ improvement: 29% improvement in 21 evaluable organs, compared with 12.5% of 8 organs btz-other and 0% of 15 organs in the mel + dex group at the time of this analysis. The median time to first organ response was 3 mos for CyBorD and 0.9 mos for btz-other. Toxicities included peripheral neuropathy in 30% of those treated with CyBorD (gr 1/2 in 4 and gr 3 in 1 pt) vs 20% in those receiving btz-other (gr 1/2 in 1 and gr 3 in 1 pt) vs 0 with mel + dex. Among the mel + dex pts, 17% experienced gr 3/4 thrombocytopenia and 6% developed gr 3/4 neutropenia; 1 case of secondary AML was observed in this group. SCs have been collected in 15 pts (34.8%), including 9 who received CyBorD, 3 treated with btz-other and 3 treated with mel + dex. To date, 8 pts (18.6%) have undergone ASCT (5 after CyBorD and 3 after btz-other regimens). Twelve of 15 (80%) CyBorD pts are alive at a median of 10 mos (range 1-22), while 5/10 (50%) btz-other pts are surviving at a median of 7 mos (range 5-47) and 14/18 (77.7%) mel + dex pts are alive at a median of 25 mos (range 2-50) after starting induction therapy. Conclusions Treatment with CyBorD produced a high rate of ≥ VGPR, with a median time to first heme response of only 1.2 months; improvements in organ function, which typically occur later, were observed in a significant proportion of pts as well. CyBorD therefore compares favorably with mel + dex, and has the advantage of less myelosuppression and reliable SC collection. Longer follow-up is needed to determine the durability of remissions induced by CyBorD alone or followed by ASCT, as well as the number of initially transplant-ineligible pts who can eventually undergo this procedure if needed. Disclosures: Reece: Otsuka: Honoraria, Research Funding; BMS: Research Funding; Merck: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Millennium Pharmaceuticals: Research Funding; Celgene: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Onyx: Consultancy. Off Label Use: Use of bortezomib in light chain amyloidosis. Chen:Celgene Corporation: Consultancy, Honoraria, Research Funding. Tiedemann:Janssen: Honoraria; Celgene: Honoraria. Trudel:Celgene: Honoraria; GSK: Research Funding; Sanofi: Honoraria.

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