Abstract
Autologous stem cell transplantation has been used in treatment for AL amyloidosis for over two decades and generally reserved for patients younger than 70 years of age. Herein we report on outcomes of ASCT in a cohort of patients with AL amyloidosis aged 70 years or older. Between August of 2002 and April of 2017, 34 patients aged 70 years or older, with biopsy proven AL amyloidosis, received an autologous stem cell transplant at the Mayo Clinic Rochester. 70% (n=24) of patients were transplanted within 6 months of diagnosis and 74% (n=25) received reduced intensity conditioning with melphalan <200mg/m2. 65% (n=22) of patients required hospitalization with a median duration of hospital admission of 8 days. Common reasons for hospitalization included fever or infection (14%), cardiac arrhythmia (14%), nutritional support (24%) and volume overload (19%). Overall response rate was 75% with a complete response seen in 25% of patients. Overall survival and progression free survival for the cohort were 66 months and 40 months respectively. One patient died within 100 days of transplant representing a 3% 100 day mortality rate. Autologous stem cell transplant is safe and efficacious in carefully screened patients aged 70 or above.
Introduction
Immunoglobulin light chain (AL) amyloidosis is a disorder driven by clonal plasma cells or B cells producing amyloidogenic light chain protein that deposits in various organs leading to organ dysfunction. Like multiple myeloma it is more common in the elderly, with a median age at presentation of 64.1,2 Autologous stem cell transplantation (ASCT)has been utilized in AL amyloidosis for over two decades and although early experience was marred by high rates of early mortality, advances in understanding of high risk features optimized selection criteria and have helped improve safety and efficacy of this therapy. Age has traditionally been a variable taken into consideration when selecting patients for ASCT, with cutoffs for transplant eligibility of 65 and 70 utilized variably in transplant centers around the world. In multiple myeloma, data has now emerged showing that ASCT can be safely delivered in patients aged 70 or older.3,4 Data on ASCT in patients with AL amyloidosis above the age of 65 is limited, with one early report suggesting myeloablative chemotherapy can be delivered without excess toxicity and similar efficacy.5 Herein we report on outcomes of ASCT in a cohort of patients with AL amyloidosis aged 70 years or older.
Methods
Between August of 2002 and April of 2017, 34 patients ≥ age 70 with biopsy proven AL amyloidosis, received an autologous stem cell transplant at the Mayo Clinic Rochester. We conducted a retrospective review of patient and disease characteristics as well as transplant related outcomes in this cohort. Risk stratification was according to the revised 2012 Mayo staging systems.6 Organ involvement was defined according to consensus criteria.7 Our current consensus guidelines on selection criteria for patients with AL amyloidosis undergoing ASCT, which include age 70 years or younger, Eastern Cooperative Oncology Group performance score ≤ 2, systolic blood pressure≥90 mmHg, troponin T≤0.06 ng/mL, creatinine clearance≥30 mL/min, New York Health Association functional class I or II, and no more than two organs significantly involved. As a transplant group we adhere strictly to these guidelines, however realize there may be situations where physician judgment allows for flexibility in inclusion for eligibility for transplant. The variable most dependent on physician assessment was physiologic age, and therefore we have transplanted a cohort of patients aged 70 or above who meet all other criteria for eligibility. Response was assessed at approximately 100 days post ASCT according to updated consensus criteria.8 Chart review was conducted to assess for complications post transplant. Data on primary indication for hospitalization and duration of hospitalization was collected on all patients. 100 day mortality was defined as death from any cause within 100 days of ASCT. Statistical analysis was performed on JMP software (SAS, Cary, NC). Survival analysis was performed using the Kaplan-Meier method. Overall survival (OS) was calculated from day zero of bone marrow transplant to death from any cause. Progression free survival was defined as time to hematological progression, assessed by consensus criteria, or time to reinitiation of therapy or death
Results
Baseline characteristics for all 34 patients are listed in Table 1, and were consistent for a population of patients with AL amyloidosis. Patients aged 70 or 71 accounted for 70% of the cohort. There was a slight male predominance and the common organs involved were cardiac and renal. 41% of patients had received chemotherapy prior to their ASCT. The hematopoietic stem cell transplantation specific comorbidity index (HCT-CI) was 0 in all but one patient who had a score of 3. Transplant related data is summarized in Table 2. The majority of patients (70%) were transplanted within 6 months of diagnosis. The majority of patients 25 (74%) received reduced intensity conditioning, 24 with melphalan 140mg/m2 and 1 patient with melphalan 100mg/m2. 16 (47%) of patients had a febrile episode with bacteremia confirmed in 10 patients. Stem cell transplantation at our center is routinely performed as an outpatient, with patients being hospitalized when deemed clinically necessary upon physician review. 65% of patients required hospitalization post transplant. The median duration of hospital admission was 8 days. Common reasons for hospitalization included fever or infection (14%), cardiac arrhythmia (14%), nutritional support (24%) and volume overload (19%). Overall response rate (patients achieving at least a partial response) was 75% with a complete response see in 25% of patients. OS and PFS for the cohort were 66 months and 40 months respectively, Figure 1. Conditioning dose did not predict OS or PFS (OS: median not reached for Melphalan 200 vs 66 months for Melphalan <200, p=0.59; PFS: median not reached for Melphalan 200 vs 37 months for Melphalan <200, p=0.11). However this analysis is limited by small numbers in each cohort. One patient died within 100 days of transplant representing a 3% 100 day mortality.
Table 1.
Baseline Characteristics.
| Characteristic | Patients (n=34) | Range |
|---|---|---|
| Age, years, n (%) | 71–75 | |
| 70 | 15 (44) | |
| 71 | 9 (26) | |
| 72 | 4 (12) | |
| 73 | 5 (14) | |
| 75 | 1 (3) | |
| Male, n (%) | 20 (59) | |
| Organs involved n(%) | ||
| Cardiac | 16 (47) | |
| Renal | 20 (59) | |
| Hepatic | 0 | |
| BMPCs, %, Median (IQR) | 7 (3–13) | |
| BMPCs ≥10% n(%) | 13 (39) | |
| Lambda Light Chain, % | 26 (87) | |
| Creatinine, Median, mg/dL (IQR) | 1 (0.9–1.3) | |
| Creatinine Clearance, Median, ml/min (IQR) | 67 (49–80) | |
| ALP, Median, U/L, (IQR) | 70 (61–89) | |
| NT-Pro BNP, Median, pg/ml (IQR) | 850 (411–2621) | |
| Troponin T, Median, ng/mL (IQR) | 0.01 (0.01–0.035) | |
| Ejection Fraction, Median, % (IQR) | 66 (62–69) | |
| dFLC, Median, mg/dL (IQR) | 8.5 (3.7–21.1) | |
| 24 hour urine protein, g (IQR) | 1.3 (0.2–5.1) | |
| Mayo Stage 2012 n(%) | ||
| I | 14 (44) | |
| II | 7 (22) | |
| III | 6 (19) | |
| IV | 5 (15) | |
| Missing | 2 | |
| Pretransplantation Chemotherapy n(%) | 14 (41) | |
| Corticosteroid only | 3 (21) | |
| IMiD based | 2 (14) | |
| Bortezomib based | 8 (57) | |
| Other | 1 (7) |
Abbreviations: IQR, interquartile range; BMPCs, bone marrow plasma cells; ALP, alkaline phosphatase; dFLC, difference between involved and uninvolved light chains; IMiD, immunomodulatory drug.
Table 2.
Transplant outcomes.
| Variable | Patients (n=34) |
|---|---|
| Timing of Transplant from Diagnosis n(%) | |
| <6 months | 24 (70) |
| ≥6 months | 10 (29) |
| Apheresis collections, median (range) | 2 (1–8) |
| Plerixafor use, n (%) | 8 (24) |
| CD34 stem cell dose, x10^6 cells/kg, median (IQR) | 4.61 (3.71–5.58) |
| Conditioning n(%) | |
| Melphalan 200mg/m2 | 9 (26) |
| Melphalan <200mg/m2 | 25 (74) |
| Days to Neutrophil Engraftment, median (IQR) | 14 (13–16) |
| Days to Platelet Engraftment, median (IQR) | 15 (14–17) |
| Febrile Episode, n(%) | 16 (47) |
| Bacteraemia, n(%) | 10 (29) |
| Hospitalisation, n (%) | 22 (65) |
| Fever/Infection | 3 (14) |
| Cardiac Arrhythmia | 3 (14) |
| Nutritional Support | 5 (24) |
| Volume overload | 4 (19) |
| Other | 7 (33) |
| Days in Hospital, median (IQR) | 8 (3–23) |
| 100 Day Mortality | 1 (3) |
| Hematologic response | |
| CR | 8 (25) |
| VGPR | 12 (38) |
| PR | 4 (13) |
| NR | 8 (25) |
Abbreviations; IQR, interquartile range; CR, complete response; VGPR, very good partial response; PR, partial response; NR, no response.
Figure 1. Survival post transplant.
Abbreviations; OS, overall survival; PFS, progression free survival.
Discussion
Our data show that ASCT can be safely delivered in selected patients with AL amyloidosis aged 70 or above. In addition, an overall response rate of 75% and a median overall survival of over 5 years in a population that generally has multiple competing risks for death, are encouraging. Early mortality has been a particular concern when considering ASCT for AL amyloidosis. The 100 day mortality of 3% in this cohort is comparable to the early mortality rate we have reported in our overall cohort of patients with AL amyloidosis receiving ASCT in recent years.9 The one early death in this cohort occurred 9 days post ASCT due to septic shock and multiorgan failure in the context of gram negative bacteremia, highlighting the need for vigilance when monitoring these patients in the post transplant setting. The hospitalization rate and nature of complications leading to hospitalization is consistent with what we see in our clinical practice in patients with AL amyloidosis receiving ASCT. The majority of patients received reduced intensity melphalan as conditioning. Whilst we generally try and avoid dose reduction, given improved outcomes in patients with full intensity conditioning, in patients aged 70 or above we often use reduced intensity conditioning in an attempt to reduce toxicity. 10
While acknowledging the retrospective nature of our study and our small and highly selected cohort of patients, we demonstrate that ASCT is efficacious and can be safely delivered in carefully screened patients aged 70 or above. An arbitrary cutoff for age should not be used to exclude patients from ASCT, rather careful assessment of patient co-morbidities and physiologic status is required by the treating physician.
Highlights.
Autologous stem cell transplantation can be safely performed in carefully selected patients aged 70 or older.
The overall response rate is 75% in this cohort.
Progression free and overall survival are encouraging for a population with competing risks for death.
Footnotes
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