scholarly journals Efficacy of Newer Combinations and Fibril-Targeting for AL Amyloidosis: A Systematic Review of Transplant and Innovative Non-Transplant Therapies

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 5763-5763
Author(s):  
Shaunak Pandya ◽  
Nadia Carenina Nunes Cavalcante Parr ◽  
Muhammad Sardar ◽  
Christine Chiu ◽  
Maria Serafini ◽  
...  
Keyword(s):  
Stem Cell ◽  
Retrospective Studies ◽  
Stem Cell Transplant ◽  
Conflicts Of Interest ◽  
Progression Free Survival ◽  
Cochrane Library ◽  
Al Amyloidosis ◽  
Cell Transplant ◽  
Amyloid Protein ◽  
Novel Drugs

Abstract Background Light-chain (AL) amyloidosis is a multi-organ amyloid deposition disease caused by misfolded protein aggregation. Current treatments have improved overall (OS) and progression-free survival (PFS) but challenges remain in improving therapy with newer agents and targeting amyloid protein deposits with novel immunotherapy. We review the literature regarding efficacy of existing chemotherapy in AL amyloidosis and summarize non-FDA approved novel drugs and monoclonal antibodies (mAbs) in early phase clinical development. Methods We searched databases including Cochrane library, PubMed and ClinicalTrials.gov for all prospective and retrospective studies (As of 4/15/2018) with measured hematologic response rate (HR) in patients with AL amyloidosis since 2000. Inclusion criteria included all prospective and retrospective studies with melphalan-based treatments, bortezomib combinations including bortezomib, cyclophosphamide and dexamethasone (VCD), bortezomib and dexamethasone (VD) and immunotherapies. We included all studies with at least 5 or more patients and reported HR. Results From 918 studies, we selected 57 studies (2640 patients) evaluating HR with melphalan-based stem cell transplant (SCT) treatments and non-stem cell transplant treatments including melphalan and bortezomib combinations. Other agents included daratumumab (anti-CD38 mAb), and ixazomib (proteasome inhibitor). Mean aggregate HR reported from studies with melphalan-based SCT treatment (17 studies, n=587) was 67%. Mean aggregate HR from all non-transplant treatments (40 studies, n=2053) was 64%. Of the non-transplant treatments, HR for melphalan-based treatments (21 studies, n=1148) was 59% and varied as follows: melphalan + lenalidomide + dexamethasone (57%) and melphalan + dexamethasone (52%). Mean aggregated HR for non-transplant bortezomib-based treatment (17 studies, n=859) was 72% consisting of VD (69%) and VCD (76%). HR with Ixazomib (1 study) and Daratumumab (1 study) was 52% and 76% respectively. Other novel drugs currently being studied include 11-1F4 (chimeric fibril-reactive mAb), GSK2398852 and GSK2315698 (anti-serum amyloid protein mAbs), and NEOD001 (anti-circulating soluble and deposited aggregated amyloid mAb). Conclusion For AL amyloidosis, melphalan-based SCT has shown effectiveness while VD and VCD demonstrate effectiveness in non-transplant patients. Further studies are warranted to evaluate novel proteasome inhibitors (Ixazomib) and emerging immunotherapy with daratumumab. Current trials including amyloid protein and fibril targeting (circulating and tissue-fixed) with novel immunotherapy are innovative and may have higher clinical efficacy, but need further testing. Disclosures No relevant conflicts of interest to declare.

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.

scholarly journals Effect of Severe Hypoalbuminemia on Myelosuppression and Other Toxicities of High Dose Melphalan and Autologous Stem Cell Transplantation in AL Amyloidosis Patients

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 5906-5906
Author(s):  
Robert Meehan ◽  
David Seldin ◽  
John Mark Sloan ◽  
Karen Quillen ◽  
Dina Brauneis ◽  
...  
Keyword(s):  
Stem Cell ◽  
Median Time ◽  
Stem Cell Transplant ◽  
Conflicts Of Interest ◽  
Autologous Stem Cell Transplant ◽  
Albumin Level ◽  
High Dose ◽  
Al Amyloidosis ◽  
Cell Transplant ◽  
Peripheral Blood Stem Cells

Abstract Background: Treatment of AL amyloidosis with high dose intravenous melphalan followed by autologous stem cell transplant (HDM/SCT) is effective in inducing hematologic and clinical remissions associated with prolonged survival. The major toxicities are myelosuppression and GI side effects. Studies have shown that ~75% of melphalan in the blood is bound to plasma proteins, with ~25% free. We hypothesized that AL patients with severe nephrotic syndrome and profound hypoalbuminemia might have a higher fraction of free melphalan, a higher effective dose, and greater toxicity of treatment. Methods: Patients with AL amyloidosis and severe hypoalbuminemia, defined as serum albumin level of < 2 g/dL, treated from 2011 to 2013, were studied retrospectively. The stem cell transplant database was queried for dose of HDM, treatment-related complications, and days of neutrophil and platelet engraftment after SCT. Results: Of 71 patients with AL amyloidosis who underwent HDM/SCT between Jan 2011 and Dec 2013, 12 patients had severe hypoalbuminemia. Of these, 5 received full HDM at 200 mg/m2 and 7 received modified HDM at 140 mg/m2. All patients received GCSF mobilized peripheral blood stem cells following HDM, with a median stem cell dose of CD34+ cells 8.1 x 106/kg (range, 4.0 to 12.2). The median time to engraftment of neutrophils was 11 days, and not statistically different based upon melphalan dose. The median time to platelet engraftment was 13 days, and also did not differ significantly by dose. These times were similar to controls without severe hypoalbuminemia. Grade 4 toxicities were observed in 2 of 7 patients with modified HDM/SCT and 1 of 5 patients with full HDM/SCT. Conclusions: These data suggest that patients with severe hypoalbuminemia do not have more prolonged myelosuppression or increased non-hematologic toxicities compared to other patients. In this retrospective study, we did not measure free melphalan concentrations in the blood. However, these data suggest that patients with severe hypoalbuminemia do not require adjustment of melphalan dosing. Disclosures No relevant conflicts of interest to declare.

scholarly journals Sequential response-driven bortezomib-based therapy followed by autologous stem cell transplant in AL amyloidosis

2020 ◽  
Vol 4 (17) ◽  
pp. 4175-4179
Author(s):  
Marco Basset ◽  
Paolo Milani ◽  
Mario Nuvolone ◽  
Francesca Benigna ◽  
Lara Rodigari ◽  
...  
Keyword(s):  
Stem Cell ◽  
Partial Response ◽  
Stem Cell Transplant ◽  
Complete Response ◽  
Autologous Stem Cell Transplant ◽  
Survival Duration ◽  
Al Amyloidosis ◽  
Cell Transplant ◽  
Duration Of Response ◽  
Landmark Analyses

Abstract Autologous stem cell transplant (ASCT) is highly effective in selected patients with light chain (AL) amyloidosis. Bortezomib, preceding or following ASCT, improves responses. Satisfactory responses, including at least a partial response, very good partial response (VGPR) with organ response, or complete response, can be observed after induction therapy alone. We report 139 patients treated upfront with cyclophosphamide/bortezomib/dexamethasone (CyBorD), followed by ASCT only if response was unsatisfactory. Only 1 treatment-related death was observed. After CyBorD, hematologic response (HR) rate was 68% (VGPR or better, 51%), with 45% satisfactory responses. Transplant was performed in 55 (40%) subjects and resulted in an 80% HR rate (65% ≥ VGPR). Five-year survival was 86% and 84% in patients treated with ASCT or CyBorD alone, respectively (P = .438). Also, 6- and 12- month landmark analyses did not show differences in survival. Duration of response was not different in the 2 groups (60 vs 49 months; P = .670). Twenty-one (15%) patients with an unsatisfactory response to CyBorD could not undergo ASCT because of ineligibility or refusal; instead, they received rescue chemotherapy, with HR in 38% of cases and 51% 5-year survival. This sequential response-driven approach, offering ASCT to patients who do not attain satisfactory response to upfront CyBorD, is very safe and effective in AL amyloidosis.

Weekly Cyclophosphamide and Alternate Day Prednisone: An Effective, Convenient and Well Tolerated Treatment for Relapsed Multiple Myeloma Following Autologous Stem Cell Transplant.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 4917-4917
Author(s):  
A. Keith Stewart ◽  
Young Trieu ◽  
Suzanne Trudel ◽  
Greg Pond ◽  
Joseph Mikhael ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Stem Cell ◽  
Median Time ◽  
Stem Cell Transplant ◽  
Alkylating Agents ◽  
Progression Free Survival ◽  
Median Number ◽  
Autologous Stem Cell Transplant ◽  
Cell Transplant ◽  
Protein Reduction

Abstract Alkylating agents remain among the most potent therapies available for treatment of Multiple Myeloma (MM). Their use prior to, or following, autologous stem cell transplant (ASCT) is, however, compromised by concerns about stem cell quality and by myelosuppression limiting effective dose delivered. To address this concern we have studied a combination of cyclophosphamide 500 mg p.o. once weekly and prednisone 100 mg p.o. on alternate days in 66 patients requiring salvage therapy post-ASCT. Dose reductions were allowed for toxicity beginning at cycle 2. On an intent to treat basis, 66 patients received this regimen, however, 7 of these patients were not fully evaluable for response due to non-secretory disease. Of the 59 patients evaluable for response, the median time from transplant to treatment was 26.4 months (range, 6.0 to 66.6). The median time from post-transplant relapse to start of cyclophosphamide and prednisone (C/P) therapy was 1.4 months. The median number of therapies from time of diagnosis to C/P initiation was 2 (range, 1.0 to 5.0). At the date of analysis, treatment with C/P is ongoing in 12 (20.3%) patients, with a median duration of 3.6 months (range, 1.9 to 11.6). The 47 patients who have completed C/P therapy were treated for a median time of 5.5 months (range, 0.5 to 21.7). The reason for discontinuation among these 47 patients included disease progression (42.6% of patients discontinued), plateau disease (21.3%), receiving a second transplant (17.0%), toxicity (10.6%), or switched to another regimen (8.5%). A partial response (&gt;50% protein reduction) was obtained in 37.3% of patients, 18.6% attained minimal response (25–50% protein reduction), 33.8% patients stable disease, while 10.2% patients had progressed on treatment. The estimated median (95% CI) months of progression-free survival after start of C/P treatment is 14.9 (8.7, 21.7). Twenty-three (38.9%) of patients have relapsed after C/P treatment, a median (range) of 8.7 (0.5–65.7) months after start of C/P treatment. At 6 months 74.3% (95% C.I. 61.9% – 89.1%) of patients were progression-free with 28% (95% CI: 16.1–49.2%) progression free at two years. At time of analysis, 44 (74.6%) patients are still alive, with a median follow up of 10.6 months (range, 1.2 to 65.7) since the start of C/P therapy. Fifteen patients have died at a median 13.0 months (range, 1.4 to 61.7) since the time of C/P initiation. The median overall survival (95% C.I.) is estimated to be 35.9 months (24.2, NA). These results demonstrate that the combination of oral cyclophosphamide and prednisone is an effective (56% MR or PR), very well tolerated (10% discontinued due to toxicity) and convenient treatment as salvage MM therapy post-ASCT. The relative lack of myelosuppression allows for re-collection of stem cells and salvage transplant while retaining other active second line agents for later relapse. This regimen thus compares favorably with recent salvage therapeutics introduced in MM and is now being studied in combination with these newer active agents and in induction therapy.

Characteristics and Outcome of Patients with Acute Myeloid Leukemia (AML) Refractory to One Cycle of High Dose Cytarabine-Based Induction Chemotherapy.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 1038-1038
Author(s):  
Farhad Ravandi ◽  
Jorge Cortes ◽  
Stefan Faderl ◽  
Susan O'Brien ◽  
Guillermo Garcia-Manero ◽  
...  
Keyword(s):  
Stem Cell ◽  
Stem Cell Transplant ◽  
Conflicts Of Interest ◽  
Single Agent ◽  
Salvage Chemotherapy ◽  
High Dose ◽  
Cell Transplant ◽  
Refractory Disease ◽  
Allogeneic Stem Cell Transplant

Abstract Abstract 1038 Poster Board I-60 Background: Outcome of patients (pts) with AML refractory to initial induction is assumed to be poor but the available data is limited. Furthermore, pts refractory to standard dose cytarabine-based regimens may be salvaged with high dose ara-C (HiDaC, defined as daily ara-C dose ≥ 1 g/m2). Information on the outcome of pts refractory to initial HiDaC - based induction is more limited. Aim To better characterize predictors of poor response to HiDaC-based induction and to evaluate the outcome of pts refractory to such induction regimens. Methods: We identified pts treated with induction regimens containing HiDaC at the University of Texas – M D Anderson Cancer Center who did not achieve a compete remission (CR) after one cycle of induction. We examined their pre-treatment characteristics and compared them with similar pts achieving a CR. We also examined their response to salvage chemotherapy and outcome. Results: Among 1179 pts treated with HiDaC-based induction therapy from 1995 to 2009, 285 were primary refractory to one course of induction. Their median age was 59 (range, 18 - 85). Median pretreatment WBC was 9.0 × 109/L (range, 0.3 – 394 × 109/L). Cytogenetics included-5/-7/complex 101 (35%), diploid 85 (30%), other intermediate 98 (34%), favorable 1 (<1%). 165 (58%) pts had antecedent hematological disorder. Induction regimens used included HiDaC with anthracyclines (n=181, 64%), HiDaC with non-anthracycline chemotherapy (fludarabine, clofarabine, topotecan, and troxacitabine) (n=104, 36%) Pts with primary refractory disease were older (Median age 59 vs. 56; p=000004), more likely to have chromosome 5/7 or complex cytogenetic abnormalities (P=0.0001), more likely to have AHD (p=0.0001), and had a higher presentation WBC (P=0.036), but not a higher incidence of FLT3 mutations (p=0.85) than those achieving CR. Primary refractory disease was not more likely with non-anthracycline containing regimens than those with anthracyclines (p=0.58). Salvage chemotherapy included combination chemotherapy in 111 (39%)(non-ara-C regimen in 40, containing ara-C in 71), single agent chemotherapy in 64 (22%), allogeneic stem cell transplant in 22 (8%) and none in 88 (31%). Forty-three (15%) pts responded to salvage including 35 CR and 8 CRp. 114 (58%) pts were resistant and 35 (18%) died; 5 (3%) were lost to follow-up. With a median follow-up of 115 weeks (range 8 – 347 weeks) in pts responding to salvage, 21 pts (7%) were alive and in CR, for at least 6 months including 14 who underwent an allogeneic stem cell transplant (median overall survival for these 21 pts, 30 months; range, 13 to 87 months). Conclusions: Outcome of pts with disease refractory to HiDaC-based induction is poor. Alternative strategies are needed in these pts who are likely to be resistant to standard chemotherapy. Disclosures: No relevant conflicts of interest to declare.

Second Autologous Peripheral Blood Stem Cell Transplantation with High Dose Melphalan (HDM/SCT) in Patients Relapsing After An Initial Course of HDM/SCT for the Treatment of AL Amyloidosis.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 2318-2318
Author(s):  
Karen Quillen ◽  
David C. Seldin ◽  
Kathleen T. Finn ◽  
Vaishali Sanchorawala
Keyword(s):  
Stem Cell ◽  
Conflicts Of Interest ◽  
Plasma Cell Dyscrasia ◽  
High Dose ◽  
Time Interval ◽  
Al Amyloidosis ◽  
Clinical Relapse ◽  
Cell Transplant ◽  
Organ Function ◽  
High Dose Melphalan

Abstract Abstract 2318 Poster Board II-295 High-dose melphalan and autologous stem cell transplant (HDM/SCT) can induce complete hematologic responses (CR), defined as disappearance of the underlying monoclonal gammopathy from serum and urine by immunofixation electrophoresis, and of the clonal plasma cell dyscrasia by bone marrow immunohistochemistry, and extend survival in patients with AL amyloidosis. HDM/SCT results in a CR in 40% of patients, and leads to clinical improvements in organ function in >70% of those who achieve a CR. However, hematologic and clinical relapses occur in ∼8% of patients who initially achieve a CR. Tandem cycles of HDM/SCT, which are typically performed within 12 months of each other, have been shown to achieve a higher ultimate CR rate of >60%. Among patients who do not achieve a CR following a single cycle of HDM/SCT, 30% nonetheless experience improvement in organ function. However, in this latter group, clinical improvement is not durable. We designed a study to explore the feasibility, and efficacy, of a second cycle of HDM/SCT in patients who relapse after initially responding to a first cycle of HDM/SCT. Results: Eleven patients, median age 55 (range 39-62), M:F 7:4, who had achieved hematologic and clinical responses after an initial cycle of HDM/SCT, were treated with a second cycle of HDM/SCT when a hematologic and/or clinical relapse occurred after a median time interval of 34 months (range 12-63). Five patients underwent a second course of G-CSF mobilization and a mean of 5.1 million (range 3.4-7.6 million) CD34 cells/kg was collected in a median of 2 days; the other patients had cells saved from the first mobilization. Six patients received 200 mg/m2 HDM; 5 patients received modified high-dose HDM at 140 mg/m2. Engraftment occurred at a median of 10 days for neutrophils, and 12 days for platelets (two days without platelet transfusion support); this engraftment timing is similar to that following the initial transplants (10 days for neutrophils, 13 days for platelets). There was no treatment-related mortality, but toxicity was moderate; almost all patients (except one) experienced grade III/IV non-hematologic toxicities. Of the 11 patients, 3 achieved hematologic CR at one year; these patients are alive and in continuous remission at 2-6 yr after the second transplant, including one patient who received a subsequent renal transplant. Three patients died of progressive disease at 1-2 years after the second transplant. Five patients are alive at 1-3 years post second transplant, in partial remission. Conclusion: 27% (3/11) of patients with AL amyloidosis who experience a hematologic or clinical relapse after responding to initial HDM/SCT can achieve a hematologic CR with a second course of HDM/SCT. Disclosures: No relevant conflicts of interest to declare.

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.

Tandem Autologous Stem Cell Transplants (auto-auto) with or without Maintenance Therapy Versus Single Autologous Transplant Followed by HLA-Matched Sibling Non- Myeloablative Allogeneic Stem Cell Transplant (auto-allo) for Patients (pts) with High Risk (HR) Multiple Myeloma (MM): Results From the Blood and Marrow Transplant Clinical Trials Network (BMT-CTN) 0102 Trial

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 526-526 ◽  
Author(s):  
Edward A Stadtmauer ◽  
Amrita Krishnan ◽  
Marcelo C Pasquini ◽  
Marian Ewell ◽  
Edwin P Alyea ◽  
...  
Keyword(s):  
Stem Cell ◽  
High Risk ◽  
Stem Cell Transplant ◽  
Chronic Gvhd ◽  
Secondary Analysis ◽  
Progression Free Survival ◽  
Phase Iii ◽  
Cell Transplant ◽  
Primary Analysis ◽  
Hematopoietic Stem

Abstract Abstract 526 The prognosis of patients with high-risk myeloma (HR MM) continues to be dismal, despite the early incorporation of novel agents. Early phase trials of allogeneic hematopoietic stem cell transplant (alloHCT) suggest the possibility of an immunologic graft-versus-myeloma effect that might favorably affect survival. Less toxic reduced-intensity HCT preparative regimens now allow more widespread use of alloHCT in the MM population. BMT CTN 0102 is a phase III multicenter clinical trial that biologically assigned patients to either melphalan 200mg/m2 (MEL 200) auto-auto without (obs) or with 1 year of thalidomide and dexamethosone (ThalDex), or an auto-allo approach using MEL 200 followed by alloHCT using 2 Gy total body irradiation. Graft-versus-host disease (GVHD) prophylaxis was cyclosporine and mycophenolate mofetil. Patients were stratified by biological prognostic factors that were considered to be high risk at the time of the trial design: chromosome 13 deletions by metaphase karyotype and beta-2 microglobulin ≥4 mg/dl. The primary endpoint was 3-year progression free survival (PFS). Between December 2003 and March 2007, 710 patients from 43 US centers were enrolled, and 85 fulfilled the criteria of HR MM. Among them, 48 were assigned to auto-auto (24 Thal-Dex and 24 obs) and 37 to auto-allo. Groups differed in age (median 57 y and 51y, p=0.02) but were otherwise balanced. Compliance with second transplant was 65% for auto-auto and 78% for auto-allo. Compliance with ThalDex was poor, so the two auto-auto arms were pooled for the primary analysis. Three-year PFS was 33% (95% Confidence Interval (CI), 22–50%) and 40% (95% CI, 27–60%, p=0.74) and 3-year OS was 67% (95% CI, 54–82%) and 59% (95% CI, 49–78%, p=0.46) for auto-auto and auto-allo, respectively. Corresponding probabilities for 3-year progression/relapse was 53% and 33% (p=0.09), and 3 year treatment-related mortality was 8% and 20% (p=0.3). Among auto-allo patients, probabilities of grade 3–4 acute and chronic GVHD were 9% and 48%, respectively. Among the 59 (31 auto-auto, 28 auto-allo) patients who received second transplant, 3 year PFS was 35% and 46% (p=0.6). Disease response at day 56 after second transplant was 57% for very good partial response (VGPR) or better and 37% for complete response (CR) and near CR (nCR) in the auto-auto group; and 48% (VGPR or better) and 41% (CR+nCR) in the auto-allo group. In conclusion, this planned secondary analysis of a cohort of HR MM patients demonstrated equivalent 3-year PFS and OS for auto-auto and auto-allo in both intention-to-treat and as-treated analyses. However, trends in late PFS and time to progression/relapse suggest further follow-up is needed before final conclusions regarding the utility of auto-allo in this HR cohort can be made. Finally, this study shows the feasibility of an alloHCT approach for HR MM patients and may serve as a platform for future studies seeking to enhance graft-versus-myeloma effects. Disclosures: Stadtmauer: Celgene: Speakers Bureau. Krishnan:Celgene: Speakers Bureau. Qazilbash:Celgene: Speakers Bureau. Vesole:Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Giralt:Celgene: Honoraria, Speakers Bureau; Millenium: Honoraria, Speakers Bureau.

Tandem Autologous Stem Cell Transplantation in Chemorefractory Multiple Myeloma

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 4554-4554
Author(s):  
Catherine Garnett ◽  
Chrissy Giles ◽  
Osman Ahmed ◽  
Maialen Lasa ◽  
Holger W. Auner ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Overall Survival ◽  
Stem Cell ◽  
Stem Cell Transplantation ◽  
Stem Cell Transplant ◽  
Progression Free Survival ◽  
Autologous Stem Cell Transplant ◽  
Cell Transplant ◽  
Free Survival

Abstract Abstract 4554 High-dose chemotherapy followed by autologous stem cell transplantation (ASCT) is currently standard treatment for younger patients with multiple myeloma, resulting in improved survival and response rate compared to conventional chemotherapy. Disease relapse, however, remains almost inevitable and thus the role of two successive (tandem) autologous stem cell transplants has been evaluated in chemorefractory patients as a means of prolonging duration of disease response. We retrospectively analysed the results of nine patients with chemorefractory disease treated at a single UK institution who received tandem ASCT between January 1998 and February 2009. There were six men and three women. Median age at diagnosis was 56 years (range, 42–65 years). Paraprotein isotype was IgG in eight patients and IgA in one patient. Median serum paraprotein level was 41g/L (range 12–73g/L) at presentation. At time of 1st transplant six patients were in stable disease (SD) and three had evidence of progressive disease. Conditioning melphalan dose was 140mg/m2 in all but two patients who received 110mg/m2 and 200mg/m2. Median time between transplants was 3.7 months (range 2.3–6.4 months) with PR and SD being observed in 2/9 and 7/9 patients at time of 2nd transplant. None of the patients reached complete response (CR). One patient received melphalan 140mg/m2 prior to 2nd transplant. The remaining patients received melphalan 200mg/m2. Median follow up after tandem transplant was 54.3 months (range 15.6 –143.6 months). No treatment related mortality was reported. At the time of analysis, six patients were still alive and under follow up with an overall survival (OS) figure for the group of 52% at 10 years from diagnosis (Figure 1). Median progression free survival (PFS) was 20 months from 2nd transplant (range 6.7–62.6 months) (Figure 2). Tandem autologous stem cell transplant in chemorefractory patients has resulted in overall survival similar to autologous stem cell transplant in chemosensitive patients and should be considered in patients with chemorefractory disease. Figure 1: Overall survival from diagnosis in patients receiving tandem autologous stem cell transplant for multiple myeloma Figure 1:. Overall survival from diagnosis in patients receiving tandem autologous stem cell transplant for multiple myeloma Figure 2: Progression free survival following tandem transplant Figure 2:. Progression free survival following tandem transplant Disclosures: No relevant conflicts of interest to declare.

The Chemotherapy Regimen IVAC Is Highly Active for Multiply Relapsed and Refractory Hodgkin Lymphoma

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 4863-4863
Author(s):  
Catherine S. Diefenbach ◽  
David Kaminetzky ◽  
Shannon Andersen ◽  
Jane Chin ◽  
Barbara MacGregor-Cortelli ◽  
...  
Keyword(s):  
Stem Cell ◽  
Hodgkin Lymphoma ◽  
Stem Cell Transplant ◽  
Chemotherapy Regimen ◽  
Conflicts Of Interest ◽  
Combined Modality Therapy ◽  
Cell Transplant ◽  
Refractory Disease ◽  
Highly Active ◽  
Grade 3

Abstract Abstract 4863 Background: Hodgkin Lymphoma (HL) has a cure rate of 70% with chemotherapy or combined modality therapy. Despite this success, approximately 5–10% of patients have primary refractory disease, and 20–30% of patients will relapse after initial complete remission (CR). Second-line chemotherapy and autologous stem cell transplant (ASCT) approaches are curative for only 50% of patients with relapsed/refractory disease. Maximal cytoreduction prior to ASCT confers the greatest potential benefit, yet the current standard salvage chemotherapy regimens have a low CR rate despite a high overall response rate (ORR), and survival is poor for patients who relapse after ASCT. Allogeneic stem cell transplantation can induce durable remissions in some patients with relapsed and primary refractory HL; however the use of this modality is limited in part by the challenges of achieving adequate disease control prior to transplantation. Novel treatment platforms to maximally debulk these patients and allow them to proceed to successful transplantation are needed. Our group has treated multiply relapsed HL patients with the chemotherapy regimen of Ifosfamide, Etoposide, and Cytarabine (IVAC) and we report a retrospective chart review detailing our experience. Methods: Between January of 2011 and June of 2012, 4 patients with relapsed or primary refractory HL were treated with the chemotherapy regimen IVAC consisting of: Ifosfamide 1,500mg/m2 days 1–5; MESNA 1,500mg/m2 days 1–5, Etoposide 600mg/m2 days 1–5, and Cytarabine 2,000mg/m2 q 12hrs × 4 doses days 1–2 given every 21 days. All patients received growth factor support beginning 24hrs after completion of chemotherapy. All patients received prophylactic antifungal, antiviral, and PCP prophylaxis. Restaging PET/CT was performed after 2 cycles of therapy. All patients received 2 cycles of therapy prior to assessment for transplant. Results: Four patients have been treated to date on this regimen. The mean age of the 4 patients was 35.5 (range 32–43). All patients were male. All patients were heavily pre-treated with a mean of 8 prior chemotherapy regimens (range 7–9) including ICE (Ifosfamide, Carboplatin, Etoposide) and Brentuximab vedotin. Three of the 4 patients had prior stem cell transplant: autologous (n=2), allogneic with subsequent DLI (n=1). All patients tolerated the chemotherapy well. The most common significant adverse events were: grade 3 pneumonia (1/4 patient), grade 3 febrile neutropenia (1/4 patients), grade 3 neutropenia (4/4 patients), grade 3 anemia (4/4 patients), grade 3 thrombocytopenia (4/4 patients). All patients recovered to baseline before initiating cycle 2, and after the completion of therapy. Response was evaluated after 2 cycles of therapy in all patients. Three of 4 patients (75%) had a response giving an ORR rate of 75%. Two of the 3 responding patients had a CR giving a CR rate of 50%, 1 patient had a PR. Response duration was: 6 weeks (n=1), 3 months (n=1), 6 months (n=1). Conclusion: IVAC is highly active, even in heavily pre-treated HL patients, with an ORR of 75% and a CR rate of 50%. With close clinical monitoring hematologic and infectious toxicities were manageable in all patients. The regimen of IVAC may allow disease debulking for multiply relapsed HL patients prior to stem cell transplant. Prospective evaluation of this therapy is ongoing. Disclosures: No relevant conflicts of interest to declare.

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