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.

Feasibility of Second Autologous Peripheral Blood Stem Cell (PBSC) Collection Followed by a Second Cycle of High Dose Melphalan (HDM) in Patients Relapsing after an Initial Course of HDM for the Treatment of AL Amyloidosis.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 5226-5226 ◽  
Author(s):  
Karen Quillen ◽  
Daniel G. Wright ◽  
David C. Seldin ◽  
Martha Skinner ◽  
Karim Malek ◽  
...  
Keyword(s):  
Stem Cell ◽  
Plasma Cell Dyscrasia ◽  
High Dose ◽  
Time Interval ◽  
Al Amyloidosis ◽  
Clinical Relapse ◽  
Cell Transplant ◽  
Organ Function ◽  
High Dose Melphalan ◽  
Initial Cycle

Abstract 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 ~5% of patients who initially achieve a CR. Tandem cycles of HDM/SCT, for which sufficient PBSC collected during the initial cycle are saved for the second cycle of treatment, 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 improvements in organ function. However, in this latter group, clinical improvements are not durable. Because there is limited experience with second PBSC collections in patients who have undergone prior myeloablative chemotherapy and because of the potential benefits of repeated cycles of HDM/SCT, we designed a study to explore the feasibility, and efficacy, of a second PBSC mobilization and collection followed by a second cycle of HDM/SCT in patients who relapse after initially responding to a first cycle of HDM/SCT. Results: Five patients, median age 52 (range 43–59), M:F 1.5:1.0, 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 39 mo.(range 16–63 mo.). After G-CSF mobilization a mean of 5.2 million CD34 cells/kg was collected in a median of 3 days (range 2–4 days). The yields were not significantly different from those of the first cycle of HDM/SCT. Engraftment occurred at a median of 10 days for neutrophils, and 13 days for platelets (two days without platelet transfusion support); this engraftment timing is similar to that following initial transplants (11 and 12 days respectively). There was no treatment-related mortality, but toxicity was moderate; all patients experienced grade III/IV non-hematologic toxicities. For the 3 patients evaluable at 1 year, no hematologic CR was observed; these patients expired at 38, 37 and 15 mo. Two patients are alive at 5 and 11 mo. post transplant. Conclusion: Patients with AL amyloidosis who experience a hematologic or clinical relapse after responding to an initial course of HDM/SCT can successfully be re-mobilized, and undergo a second cycle of HDM/SCT, with prompt hematopoietic recovery. Clinical benefits of second cycles of HDM/SCT in this setting have yet to be determined. Patient data prior Rx CD34 yield #1/#2 (10E6 cells/kg) HDM #1/#2 (melphalan dose mg/m2) Days to WBC eng #1/#2 Days to PLT eng #1/#2 CR#1/CR#2 Survival (mo.) #1/#2 refer to first/second transplant 1 none 8.0/4.1 200/200 9/11 9/12 yes/no 38 2 M/P x2 8.8/7.7 200/200 11/10 12/34 no/no 37 3 VAD x3 7.9/4.6 200/140 11/10 17/13 no/no 15 4 M/P x2 5.9/6.2 200/200 9/9 12/24 no/? alive at 11 mo. 5 none 4.3/3.4 200/140 11/10 11/11 no/? alive at 5 mo.

Oral Cyclic Melphalan and Dexamethasone in the Treatment of Patients with AL Amyloidosis; Ineligible for High-Dose Melphalan and Stem Cell Transplantation.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 1883-1883
Author(s):  
Vaishali Sanchorawala ◽  
David C. Seldin ◽  
John Mark Sloan ◽  
John L. Berk ◽  
Martha Skinner
Keyword(s):  
Stem Cell ◽  
Cardiac Involvement ◽  
Conflicts Of Interest ◽  
Additional Treatment ◽  
Patient Choice ◽  
Plasma Cell Dyscrasia ◽  
High Dose ◽  
Al Amyloidosis ◽  
Cell Transplant

Abstract Abstract 1883 Poster Board I-906 AL amyloidosis is caused by a clonal plasma cell dyscrasia and is characterized by widespread, progressive amyloid deposition leading to multisystem organ failure and death. In this disease, amyloid protein deposits are derived from monoclonal immunoglobulin light chains. Aggressive treatment of AL amyloidosis with high dose intravenous melphalan followed by autologous stem cell transplant (HDM/SCT) is effective in inducing hematologic remission and clinical improvement. However, only selected patients with AL amyloidosis are eligible for HDM/SCT due to amyloid-associated organ dysfunction. Recently, several investigators have demonstrated the efficacy of treatment with oral cyclic melphalan and dexamethasone (Mel/Dex) in inducing hematologic responses and improving survival for patients with AL amyloidosis. We report on 70 patients with AL amyloidosis who were treated with oral Mel/Dex. Oral melphalan was administered at 0.22 mg/kg/day for D1-4 and dexamethasone at 20-40 mg one day per week and repeated every month. The median age was 65 years (range, 46-84) and the median number of organ system involvement was 3 (range, 1–6). Majority of the patients (n=31) had predominant cardiac involvement. The reasons to select this regimen of Mel/Dex rather than HDM/SCT included severe cardiac involvement (n=23), age > 75 years (n=6), patient choice (n=6), severe autonomic neuropathy (n=6), poor functional status (n=5), treatment started by local physicians (n=9), complications of stem cell mobilization and collection precluding HDM (n=5) and others (n=11). Patients received a median of 4 cycles of Mel/Dex, (range 1-13). Hematologic responses were not evaluable in 22 patients due to early death, toxicity or patients failing to return for follow-up. Of 48 evaluable patients, 7 patients (15%) achieved a complete hematologic response. Median survival for these 70 patients has not yet been reached with a median follow-up of 17 months. Overall survival is 60% at 3 years. Thirteen of these patients received additional treatment for their disease. In conclusion, oral cyclic melphalan and dexamethasone can lead to hematologic complete responses in 15% of patients and to improvement in survival for patients with AL amyloidosis, who are not eligible for HDM/SCT. Disclosures: 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.

Autologous stem cell transplantation (ASCT) in AL amyloidosis: Feasibility outside national amyloidosis referral centers and proposal for simpler pre-transplant staging

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 17545-17545
Author(s):  
N. Jain ◽  
M. Pasquini ◽  
M. Paul ◽  
P. Hari
Keyword(s):  
Multiple Myeloma ◽  
Stem Cell ◽  
Hospital Stay ◽  
Stage I ◽  
High Dose ◽  
Al Amyloidosis ◽  
Cell Transplant ◽  
Safe Procedure ◽  
Hematological Response ◽  
High Dose Melphalan

17545 Background: Single center data from national amyloidosis referral centers suggest that high dose melphalan based ASCT is an effective upfront treatment strategy for AL amyloidosis. Absence of published randomized control trials, referral bias and center experience make generalizability of this data difficult since data from outside of major referrals centers is limited. Pre-transplant staging is complicated by the profusion of articles describing various adverse risk factors. Methods: Retrospective review of bone marrow transplant database at our institution was conducted. All patients with AL amyloidosis who underwent ASCT were included in the study. We stratified patients based on International Staging System (ISS) for multiple myeloma. Organ and hematological response were assessed using 2005 consensus guidelines. Results: 13 patients (6 males) underwent ASCT for AL amyloidosis with risk adapted high dose melphalan dosing (melphalan mg/m2 100 (n = 1), 150 (n = 8) and 200 (n = 4)). Median age of the patient population was 53 years (range 31–75 years). Organ involvement was as follows - single organ = 6, 2 organs = 4 and 3 organs = 3. 4 patients had cardiac amyloidosis. 100 day transplant related mortality (TRM) was 15.3%. Overall survival was 84 % (95 % CI 51–96%) @ 1 yr and 75% (95% CI 38–91%) @ 2 yrs. Median follow up was 18 months. No deaths were observed >17 months post-transplant. 45 % patients had organ response. Complete hematological response was observed in 45 % patients. Mean duration of peri-transplant hospital stay for ISS stage I, II and III were 20.5 days (n = 2), 23.3 days (n = 9) and 29 days (n = 1) respectively. Number of deaths observed in ISS stage I, II and III were 0 (0/2), 2 (2/9) and 1 (1/1) respectively. Conclusions: Autologous stem cell transplant (ASCT) for AL amyloidosis is a feasible, effective and safe procedure outside of major national referral centers. Pretransplant stratification of amyloidosis patients using ISS for multiple myeloma indicated a trend towards longer peri-transplant hospital stay and mortality with increasing ISS stage. This hypothesis needs to be tested in larger studies. No significant financial relationships to disclose.

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

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

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

Treatment of AL Amyloidosis with Tandem Cycles of High Dose Melphalan and Autologous Stem Cell Transplantation: Final Analysis of a Prospective Trial.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 612-612
Author(s):  
Vaishali Sanchorawala ◽  
Daniel G. Wright ◽  
Karen Quillen ◽  
Laura M. Dember ◽  
John L. Berk ◽  
...  
Keyword(s):  
Stem Cell ◽  
Clinical Improvement ◽  
Plasma Cell ◽  
Initial Treatment ◽  
Performance Status ◽  
Prospective Trial ◽  
Plasma Cell Dyscrasia ◽  
High Dose ◽  
Al Amyloidosis ◽  
Cell Transplant

Abstract AL amyloidosis is caused by a clonal plasma cell dyscrasia and is characterized by widespread, progressive amyloid deposition leading to multisystem organ failure and death. In this disease, amyloid protein deposits are derived from monoclonal immunoglobulin light chains. Aggressive treatment of AL amyloidosis with high dose intravenous melphalan followed by autologous stem cell transplant (HDM/SCT) is effective in inducing hematologic remission and clinical improvement. Furthermore, we have observed in over 300 patients treated with HDM/SCT that achievement of a hematologic complete response (CR), i.e. disappearance of monoclonal gammopathy and clonal plasma cell dyscrasia, is a critical determinant of clinical improvement and prolonged survival. Because of the importance of hematologic CR in treatment outcome, we conducted a prospective trial to determine whether a second cycle of HDM/SCT would induce a hematologic CR in patients in whom the plasma cell dyscrasia persisted following initial treatment with HDM/SCT. Additional objectives of the trial were to determine the feasibility and tolerability of tandem cycles of HDM/SCT in AL amyloidosis. Eligibility for entry into the trial required evidence of plasma cell dyscrasia, age &lt; 65 years, ≤ 300 mg of prior oral melphalan, and minimal measures of performance status (SWOG ≤ 2) and cardiopulmonary function (LVEF &gt; 45%, DLCO &gt; 50%). Peripheral blood stem cells were collected by leukapheresis following G-CSF mobilization, with minimum yields of 7.5 x 106 CD34+ cells/kg required for participation in the trial. From 11/2000 to 6/2005, 62 patients, median age 55.5 (range 32–65), M: F ratio 1.8:1.0, were enrolled. Of the 62 patients enrolled, 9 (15%) were removed from the protocol either because of an inadequate stem cell collection (7) or because of complications during stem cell mobilization and collection that precluded treatment with HDM/SCT (2). Of the 53 patients who received the first cycle of 200 mg/m2 HDM, 4 patients died within 100 days of treatment (8%), and 27 (55%) were found to have achieved a hematologic CR 6 months after HDM/SCT. Of the 22 patients who did not achieve a CR after initial treatment, 17 patients received a second HDM/SCT with 140 mg/m2 of IV melphalan. Mortality within 100 days after this second treatment was 6% (1/17), while 27 % (4/15) of surviving patients achieved a hematologic CR by 6 months following the second cycle of HDM/SCT. Therefore, for the patients treated with one or two cycles of HDM/SCT on this study, the ultimate hematologic CR rate was 63% (31/49). With a median follow up of 38 months (range, 14–69 months), the median survival for all patients enrolled has not yet been reached. Moreover, improvements in amyloid related organ dysfunction, particularly in nephrotic syndrome, liver involvement, neuropathy and/or performance status, were evident in all patients who achieved a hematologic CR. In conclusion, tandem cycles of HDM/SCT are tolerable for selected patients with AL amyloidosis and can increase the proportion of patients who ultimately achieve a hematologic CR.

Myeloma with AL Amyloidosis: 10 Years Experience with Stem Cell Transplant.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 5112-5112 ◽  
Author(s):  
Leandro De Padua Silva ◽  
Donna Weber ◽  
Michael Wang ◽  
Eric Han ◽  
Floralyn Mendoza ◽  
...  
Keyword(s):  
Stem Cell ◽  
Stem Cell Transplant ◽  
Median Number ◽  
High Dose ◽  
Al Amyloidosis ◽  
Cell Transplant ◽  
Allogeneic Transplant ◽  
Hematopoietic Stem ◽  
High Dose Melphalan ◽  
Hematological Remission

Abstract Background: (AL) Amyloidosis is a rare and potentially fatal disease that involves deposition of light chain protein by a clonal plasma cell population. Treatment with high dose melphalan and autologous stem cell transplant (ASCT) can improve survival and reverse organ damage, but this treatment is associated with toxicity and mortality. We reviewed the outcome of patients with amyloidosis, who received hematopoietic stem cell transplant (HSCT) at our institution. Patients and Methods: The retrospective study analyzed 32 patients with AL Amyloidosis who underwent transplant between 1997–2006. There were 17 men and 15 women, with a medium age of 53 years (range 35–73 years). All patients had diagnostic criteria for multiple myeloma (MM) and had biopsy confirmed amyloidosis of at least one organ site. Six patients had at least 1 organ involved with AL amyloidosis (3 bone marrows, 2 subcutaneous and 1 kidney), 20 patients had 2 organs involved, while 6 patients had 3 or more organs affected. All received a median of 3 cycles of chemotherapy (range 0–13) before transplant. Twenty-eight patients underwent autologous transplant, while 4 had an allogeneic transplants (2 syngeneic and 2 siblings). The preparative regimens received in 28 patients were high dose melphalan (26 autologous and 2 syngeneic), 2 patients received Busulfan and Melphalan, 2 allogeneic transplant Fludarabine and Melphalan. Results: The median Charlson Comorbidities Index (CCI) was 3 (range 0–8). The median number of CD34+ cells infused was 4.85 x 106 cells/kg (range 1.43–7.82 cells/kg). The median time to neutrophil and platelet engraftment were 11 (range 2–21days) and 14 days (range2–41), respectively. 56% of patients developed moderate to severe gastrointestinal effects. Four patients underwent allogeneic transplant and 1 had acute and chronic graft vs host disease (GVHD). Twenty-one patients (65%) achieved a partial hematological remission (PR), and 5 patients (15%) achieved complete hematological remission (CR), with a total response hematological rate of 80%. The 100 day NRM was 3.2%. The median overall survival was (OS) 41 months (range 1–108), 7 patients died (4 relapsed and 3 infections) all 7 patients had CCI greater or equal to 4. Conclusion: Selected patients with MM and amyloidosis can benefit from high dose therapy with stem cell support including allogeneic transplantation. The high mortality seen in patients with CCI >4 suggests that this index could be useful in selecting patients for high dose chemotherapy.

scholarly journals Melphalan Based Regimens for Treatment of Newly Diagnosed Amyloidosis, Lessons from Clinical Literature: A Systematic Review

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 5561-5561
Author(s):  
Muhaddis Ejaz Ahmad ◽  
Muhammad Abdullah Yousaf ◽  
Abdul Rafae ◽  
Mustafa Nadeem Malik ◽  
Tariq Iqtidar Sadiq Syed ◽  
...  
Keyword(s):  
Stem Cell ◽  
Cochrane Library ◽  
High Dose ◽  
Al Amyloidosis ◽  
Cell Transplant ◽  
Newly Diagnosed ◽  
Group A ◽  
Group B ◽  
High Dose Melphalan ◽  
Combination Regimens

Introduction: Melphalan causes cross linkage between DNA, causes cytotoxicity in both dividing and non-dividing tumor cells. Our objective is to analyze and summarize the published literature for the efficacy of melphalan based regimen used for the treatment of newly diagnosed Amyloidosis (ND-AL). Methods: We performed a comprehensive literature search on articles following PRISMA guidelines. Beginning with articles published after June 2006, we used databases like PubMed, Embase, Clinicaltrials.gov, Cochrane Library and Web of Science. Total 649 articles were identified initially and after detailed screening, we finalized 10 studies involving 616 ND-AL patients. Results: Melphalan (M), Bortezomib (V) and dexamethasone (d)/prednisone (p): A retrospective study by Zhao et al., included 123 ND-AL patients (pts) were given M, V, and d. Overall hematological response (OHR) was 100% with complete response (CR) in 44% and partial response (PR) in 38.9% pts. Median overall survival (mOS) was 38 months (mo) and 3-yr survival ranged from 41-72%. Organ response (OR) was 25%. In a study by Lee et al., with 19 pts who received M, V, and p demonstrated OHR of 84% (Table 1). Melphalan (M) and dexamethasone (d): Sanchorawala et al. (n=70) reported patients treated with M and d showed OHR of 69%, with CR in 13% and PR in 25%. Similarly, a study by Lebovic et al. reported 40 pts who were given M, d. OHR was 58% and 13% pts showed CR (Table 1). High dose Melphalan/Stem Cell Transplant (HDM/SCT) with and without induction: In study by Cowan et al., (n=45) pts in group A (n=21) were given novel induction using agents like protease inhibitor (PI), cyclophosphamide, bortezomib and dexamethasone (CyBorD), Lenalidomide (L), dexamethasone (d) prior to high-dose melphalan (HDM). CR was observed in 50%, VGPR in 7% and PR in 7% pts. Group B (n=24) pts were given frontline HDM/SCT upfront. CR was observed in 28%, VGPR in 14% and PR in 14% pts. In a study by Scott et. al., 31 pts were categorized in 3 groups who received HDCT either with no induction, induction with V-based regimen and induction with other regimens including lenalidomide/dexamethasone (len/dex), melphalan/dexamethasone (mel/dex) and thalidomide/dexamethasone (Thal/dex). OHR in mel/dex cohort (n=3) was 67% (Table 1). In a study by Huang, X. et al., 56 pts were divided in two groups of 28 pts each. Pts in group A received Vd+HDM/SCT demonstrated CR in 67.9%, VGPR in 7.1%, PR in 10 .7 % and no response (NR) in 7.1 % pts. In group B, pts received with HDM/SCT upfront demonstrated CR in 35.7%, VGPR in 10.7%, PR in 2.1 % and no response NR in 21.4 % pts (Table 1). Randomized Standard dose Melphalan (SDM) versus HDM: In a study by Jaccard et al., there were two groups. The OHR was 68% in group A pts who were given SDM and high-dose dexamethasone (HD-dex) with CR in 31% and PR in 36% pts. The OHR was 67% in group B pts who were given HDM+ASCT with CR in 40% and PR in 25% pts (Table 1). Melphalan with Total body irradiaton (TBI): Vesole et al., reported 107 pts who were given M and TBI. OHR was 32% with CR in 16% and PR in 16% pts. mOS was 47.2 mo (Table 1). Melphalan (M), dexamethasone (d), Lenalidomide (L): In a clinical trial (NCT00890552) involving 25 pts M, d, and lenalidomide were give. CR, VGPR and PR were observed in 8%, 16% and 33%. 37.5% pts showed no-response (Table 1). Conclusion: Despite heterogeneity in the AL patient population and various regimens used in published literature, melphalan based regimens are very effective for treatment. Induction regimens and supportive care have evolved over the years. Novel combination regimens used for induction followed by HD-Melphalan consolidation along with careful selection of patients for high dose chemotherapy consolidation and stem cell transplantation in routine clinical practice is the best approach for personalized therapy selection for AL amyloidosis. Cytopenias of three cell lines are the major side effects reported with Mel therapy. Just like melphalan use for treatment of multiple myeloma in novel combination regimens, future randomized prospective trials are needed to better understand the efficacy and safety profile of melphalan based newer combination regimens for AL amyloidosis treatment. Disclosures Anwer: In-Cyte: Speakers Bureau; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees.

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.

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