Effect of Severe Hypoalbuminemia on Toxicity of High-Dose Melphalan and Autologous Stem Cell Transplantation in Patients with AL Amyloidosis

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ORIGINAL ARTICLE Effect of severe hypoalbuminemia on toxicity of high-dose melphalan and autologous stem cell transplantation in patients with AL amyloidosis

SY Lee1,2, RS Meehan2, DC Seldin1,2, JM Sloan1,2, K Quillen1,2, A Shelton1,2, D Brauneis1,2 and V Sanchorawala1,2

High-dose melphalan with stem cell transplantation (HDM/SCT) extends survival and induces hematologic and clinical responses in patients with light chain (AL) amyloidosis. Eighty percent of melphalan is bound to plasma proteins (60% albumin-bound). We hypothesized that patients with profound hypoalbuminemia have a greater free melphalan fraction and more toxicity. Patients with AL amyloidosis treated with HDM/SCT between 2011 and 2014 with severe hypoalbuminemia (SH), defined as serum albumin ⩽ 2 g/dL were studied retrospectively. Sixteen patients with SH were identified. Forty-one patients without severe hypoalbuminemia (WSH) treated between 2011 and 2012 served as control. The incidence of acute renal failure requiring hemodialysis was 25% among patients with SH, compared with 5% among patients WSH (P=0.05). Not all patients who needed dialysis required it long term; 6.25% for SH and 2.44% for WSH (P=0.49). The rates of grade 3 or 4 febrile neutropenia and gastrointestinal toxicities were not significantly different between the groups. Engraftment kinetics were similar for both groups. Grade 4 renal toxicity and grade 3 lightheadedness were more frequent in patients with SH undergoing HDM/SCT for AL amyloidosis. Further studies into the mechanism of increased renal toxicity in patients with SH are warranted.

Bone Marrow Transplantation (2016) 51, 1318–1322; doi:10.1038/bmt.2016.132; published online 16 May 2016

INTRODUCTION more treatment-related toxicity with respect to myelosuppression The amyloidoses are a group of diseases where insoluble toxic and gastrointestinal toxicities compared with patients without protein aggregates are deposited in tissues and vital organs.1 severe hypoalbuminemia (WSH). We hypothesized that patients Light-chain (AL) amyloidosis is the most common form of systemic with SH have decreased melphalan clearance, increased unbound amyloidosis, where the amyloidogenic protein is an Ig light chain drug levels and are therefore at higher risk of melphalan toxicity. or light chain fragment produced by a clonal population of plasma cells in the bone marrow.2 Eradicating the small plasma cell clone by chemotherapy can arrest damage and may result in improve- MATERIALS AND METHODS ment of the affected organs. One of the major advances in the treatment of AL amyloidosis is the utilization of high-dose Study design and participants melphalan with autologous hematopoietic stem cell transplanta- In this retrospective single center observational study, we analyzed tion (HDM/SCT). This approach to treatment has been shown to consecutive patients with AL amyloidosis and SH treated with HDM/SCT extend survival and to induce hematologic and clinical responses between January 2011 and December 2014 at the Boston Medical – Center (BMC). SH was defined as a serum albumin level of 2 g/dL or less in selected patients, even in those with cardiac involvement.3 7 fi prior to admission to the SCT program. Patient data were extracted from Melphalan, rst synthesized by Bergel and Stock in 1953, is a the stem cell transplant database and the hospital’s electronic medical fi non-cell-cycle speci c bifunctional (interstrand or intrastand) record. AL amyloidosis patients WSH treated with HDM/SCT between 8 alkylating agent. Most of this drug is eliminated by renal January 2011 and December 2012 were identified and served as excretion. Melphalan also undergoes spontaneous degradation control. Toxicities were graded according to the National Cancer to non-cytotoxic active metabolites, but this occurs to a much Institute Common Terminology Criteria for Adverse Events, version 4.0 smaller degree because of its binding to plasma proteins.9,10 (CTCAE v4). This study was approved by the BMC institutional review In vitro, melphalan is 60% bound to albumin.11 The kidneys board. All study subjects signed an informed consent in accordance to the are frequently involved in AL amyloidosis,12 with patients often Declaration of Helsinki. fi presenting with nephrotic syndrome.2 Severe hypoalbuminemia For the HDM/SCT procedure, all patients rst underwent stem cell mobilization with granulocyte colony-stimulating factor followed by stem (SH) from nephrotic syndrome may result in higher free melphalan cell collection. Afterwards, HDM, dosed at either 200 mg/m2 or 140 mg/m2, levels, and therefore increased toxicity. The most common was given intravenously over 2 days in equally divided doses (days − 3 toxicities of HDM include profound myelosuppression, nausea and − 2). Stem cell infusion was then performed on day 0. The HDM/SCT 8 and vomiting, mucositis, and diarrhea. procedure was performed in the outpatient setting. Patients underwent The objective of this study was to evaluate whether patients daily evaluations in the SCT clinic, and were admitted to the hematology with AL amyloidosis and SH treated with HDM/SCT experience inpatient service for complications.

1Amyloidosis Center, Boston University School of Medicine and Boston Medical Center, Boston, MA, USA and 2Section of Hematology/Oncology, Boston University School of Medicine and Boston Medical Center, Boston, MA, USA. Correspondence: Dr V Sanchorawala, Amyloidosis Center, Boston University School of Medicine and Boston Medical Center, 820 Harrison Avenue, FGH-1007, Boston, MA 02118, USA. E-mail: [email protected] Received 5 January 2016; revised 31 March 2016; accepted 6 April 2016; published online 16 May 2016 Hypoalbuminemia and melphalan toxicity in AL amyloidosis SY Lee et al 1319 Statistical analysis in the proportion of patients who had fever (4100.5 °F), required Fisher’s exact test was used to compare proportions. The Kruskal–Wallis IV antibiotics or required transfusions. More SH patients received rank sum test was used to compare means as the data did not follow a an albumin infusion (SH 81.25% vs WSH 24.39%; P=o0.01). normal distribution. A P value of o0.05 was considered statistically Patients in both groups had similar median days to neutrophil significant in this study. engraftment (SH 11 days vs WSH 10 days), and identical median days to platelet engraftment (13 days for both groups). RESULTS Peritransplantation toxicity Baseline characteristics All patients in both groups developed expected grade 4 Of the 84 patients with AL amyloidosis who underwent HDM/SCT cytopenias. The proportion of patients with any grade 3 or 4 between January 2011 and December 2014, 16 patients (19.05%) non-cytopenic adverse event during the peritransplantation with SH were identified. Forty-one patients WSH treated between period are listed in Table 3. A larger proportion of SH patients January 2011 and December 2012 served as control. Baseline (43.75%) had a grade 4 non-cytopenic adverse event compared characteristics, including age, sex, serum albumin level, creatinine with the control population (21.95%). However, the difference was clearance, proteinuria, cardiac biomarkers, hemoglobin and organ fi fi not statistically signi cant. There was no difference in the involvement are shown in Table 1. The only statistically signi cant proportion of patients who developed grade 3 non-cytopenic differences were seen in mean albumin levels and mean 24-h toxicities (68.75% of patients in the SH group and 82.93% in the proteinuria, with patients in the SH group with lower serum WSH group). albumin levels (1.71 g/dL vs 3.08 g/dL; Po0.01) and more proteinuria (10.09 g/d vs 5.04 g/d; Po0.01). fi In terms of organ involvement, as expected, all patients in the Speci c adverse events SH group had renal involvement, but a significant proportion The proportion of patients in each group with specific grade 4 and (73.17%) of WSH subjects had this as well (P=0.02). Cardiac 3 adverse events are listed in Tables 3 and 4, respectively. The involvement was the next most common, with about half of most common grade 4 toxicity in patients with SH was acute patients in both groups having been diagnosed with cardiac kidney injury (AKI). One quarter of SH patients developed AKI amyloid. Autonomic nervous system and peripheral nervous compared with 5% in WSH patients (P=0.05). All subjects with system involvement were similarly distributed between both grade 4 AKI underwent hemodialysis during the peritransplanta- groups. SH patients were about half as likely to have soft tissue tion period. However, only one patient in the SH group and one involvement compared with the WSH group, although this patient in the WSH group with grade 4 AKI needed long-term difference was not statistically significant. The numbers for other dialysis (6.25% vs 2.44% respectively, P=0.49). Grade 4 hyperur- organ involvement were small (hepatic, gastrointestinal, muscu- icemia was the second most prevalent grade 4 toxicity in SH loskeletal and pulmonary), and not statistically different between patients at 18.75%, compared with 5% in WSH patients, though the two groups. this is not a statistically significant difference. Grade 4 hypotension was the third most common (SH 12.50% vs WSH 4.88%; P=0.31). A higher (but not statistically significant) proportion of patients in Peritransplantation events WSH had grade 4 febrile neutropenia and infection. Peritransplantation events are listed in Table 2. There were no The only significantly different grade 3 peritransplantation fi signi cant differences in the mean number of CD34+ cells toxicity was lightheadedness, which occurred in 19% of SH administered, mean melphalan dose given, proportion of patients 2 patients compared with none in WSH patients (P=0.02). The most receiving the full 200 mg/m melphalan dose, proportion of common grade 3 adverse events in SH subjects were fatigue, pain, patients requiring hospital admission or the length of hospital stay diarrhea, hyponatremia, hypotension and increase in alkaline fi if admitted. There were also no statistically signi cant differences phosphatase levels.

Table 1. Baseline characteristics Hematologic and renal response The 6-month hematologic complete response rate was 18.75% in SH (n = 16) WSH P-value (n = 41) SH and 36.59% in WSH, but this difference was not statistically different (P=0.54). Hematologic complete response was defined 13 Median age (years) 59 59 according to the 2012 consensus criteria. 6-month renal Males (%) 56.25 53.66 1.00 response rates were similar between the groups (SH 18.75% vs Mean albumin (g/dL) 1.71 3.08 o0.01 WSH 20.00%; P=1.00), and was defined according to the system Mean CrCl (mL/min) 102.99 86.15 0.09 proposed by Palladini et al.14 Mean 24-h proteinuria (g) 10.09 5.04 o0.01 Mean B-type natriuretic peptide 162.44 177.10 0.67 (pg/mL) Mortality Mean troponin I (ng/mL) 0.063 0.068 0.52 All patients in both groups were alive at 30 days after HDM/SCT. Mean hemoglobin (g/dL) 13.53 13.16 0.30 The 100-day mortality rate was 0% in SH patients and 2.44% in Organ involved (%) WSH patients. Renal 100.00 73.17 0.02 Cardiac 56.25 53.66 1.00 Autonomic nervous system 25.00 21.95 1.00 DISCUSSION Peripheral nervous system 25.00 17.07 0.48 Soft tissue 12.50 31.71 0.19 This is the first study to compare the toxicity of HDM/SCT for AL Hepatic 0.00 7.32 0.55 amyloidosis in patients who have SH with those who do not. Gastrointestinal 0.00 4.88 1.00 About one out of every five patients who were treated between Musculoskeletal 0.00 4.88 1.00 January 2011 and December 2014 at our Amyloidosis Center Pulmonary 0.00 7.32 0.55 were identified as having SH, defined as having a pretransplant ⩽ Abbreviations: CrCl = creatinine clearance; SH = severe hypoalbuminemia; serum albumin of 2 g/dL. Our results show that patients with SH WSH = without severe hypoalbuminemia. do not have more prolonged myelosuppression. Furthermore, we demonstrated that a large proportion (43.75%) of subjects with SH

Table 2. Peritransplantation events

SH (n = 16) WSH (n = 41) P-value

Proportion receiving full melphalan dose 200 mg/m2 (%) 50.00 68.00 0.23 Mean melphalan dose (mg/m2) 170.00 180.98 0.23 Mean CD34+ cells × 106/kg administered 7.68 8.39 0.99 Admitted during peritransplantation period (%) 75.00 78.05 1.00 If admitted, mean days admitted 15.6 (n = 12) 9.7 (n = 32) 0.77 Fever T4100.5 F (%) 31.25 36.59 0.77 Required IV antibiotics (%) 43.75 56.10 0.56 Received PRBC transfusion (%) 43.75 56.10 0.56 Received platelet transfusion (%) 100.00 95.12 1.00 Received albumin infusion (%) 81.25 24.39 o0.01 Median days to neutrophil engraftment (days) 11 10 Median days to platelet engraftment (days) 13 13

Any non-cytopenic treatment toxicity Grade 4 toxicity (%) 43.75 21.95 0.11 Grade 3 toxicity (%) 68.75 82.93 0.29 Abbreviations: PRBC = packed red blood cell; SH = severe hypoalbuminemia; WSH = without severe hypoalbuminemia.

response or renal response rates, though there was a larger trend Table 3. Grade 4 toxicity towards a higher hematologic complete response rate in the Grade 4 toxicity (%) SH (n = 16) WSH (n = 41) P-value control group. We also found that 30- and 100-day mortality was not worse in patients with SH. AKI (requiring hemodialysis) 25.00 4.88 0.05 Only grade 4 AKI and grade 3 lightheadedness were statistically AKI (requiring long-term dialysis) 6.25 2.44 0.49 different between the two groups, with a higher proportion of SH CHF 6.25 0.00 0.28 patients suffering from these events. Grade 4 AKI is defined by the Febrile neutropenia 6.25 7.32 1.00 CTCAE v4 as an acute loss of renal function with life-threatening Hyperuricemia 18.75 4.88 0.13 consequences requiring dialysis. Grade 3 lightheadedness is Hypotension 12.50 4.88 0.31 fi Hypoxia 6.25 0.00 0.28 de ned as severe unsteadiness or sensation of movement limiting Infection 0.00 7.32 0.55 self-care activities of daily living. AKI was the most common grade 4 toxicity in patients with SH; a quarter of these patients required Abbreviations: AKI = acute kidney injury; CHF = congestive heart failure; initiation of hemodialysis during the peritransplantation period, SH = severe hypoalbuminemia; WSH = without severe hypoalbuminemia. compared with only 5% of patients in the control population. Remarkably, 75% of the SH patients who were initially dialyzed did not require long-term dialysis because of eventual recovery of Table 4. Grade 3 toxicity renal function. The incidence and outcomes of renal complications complicat- Grade 3 toxicity (%) SH (n = 16) WSH (n = 41) P-value ing HDM/SCT have previously been studied. Cornelison et al.15 reported low rates of renal toxicity with HDM/SCT in a cohort of 75 AKI 12.50 9.76 1.00 patients with renal amyloid involvement. Only 13% of subjects in Anorexia 12.50 7.32 0.61 – CHF 6.25 0.00 0.28 that study suffered from grade 2 3 renal toxicity, all of which was Delirium 12.50 0.00 0.08 reversible. However, neither the proportion of patients with SH Diarrhea 18.75 29.27 0.52 nor the dose of melphalan used were reported. The median Edema 12.50 9.76 1.00 pretransplant serum albumin level was 2.6 g/dL. Also, only 9% of Fatigue 25.00 34.15 0.75 patients had cardiac involvement.15 Fadia et al.16 found that Febrile neutropenia 6.25 4.88 1.00 peritransplantation acute renal failure occurred in 21% of 173 Hyponatremia 18.75 9.76 0.39 patients who received HDM/SCT between the years 1994 and Hypotension 18.75 17.07 1.00 2000 at our institution. Five percent required initiation of dialysis, Increase in alkaline phosphatase 18.75 7.32 0.33 Infection 0.00 7.32 0.55 which mirrors that of our WSH population. Of note, 46% of the Lightheadedness 18.75 0.00 0.02 patients with AKI, including almost half of those who had required Mucositis 0.00 9.76 0.57 dialysis eventually had recovery of renal function. The authors Nausea 0.00 19.51 0.09 found that bacteremia was the strongest risk factor for AKI. Other Pain 25.00 24.39 1.00 risk factors included underlying renal impairment and cardiac Stroke 0.00 4.88 1.00 disease. These factors do not explain the disparate renal toxicity in Syncope 0.00 9.76 0.57 our study as there were no major differences in febrile = = neutropenia, baseline renal function or cardiac involvement Abbreviations: AKI acute kidney injury; CHF congestive heart failure; 16 SH = severe hypoalbuminemia; WSH = without severe hypoalbuminemia. between our comparison groups. Fadia et al. did not report serum albumin levels, but the degree of proteinuria (4.4 g/24 h) was less severe compared with our SH patients (10.1 g/24 h). suffered from a grade 4 non-hematologic adverse event, double The most common known toxicities of HDM are profound the proportion of patients in the control (WSH) group. This myelosuppression, nausea and vomiting, diarrhea, and mucositis.8 difference was not statistically significant. Conversely, there was a All the patients in our study had expected grade 4 cytopenias. non-significant trend towards the control group having a higher However, none of our patients with SH suffered from grade 4 grade 3 non-hematologic toxicity event rate. There were no gastrointestinal toxicities. Gastrointestinal symptoms such as significant differences in the 6-month hematologic complete nausea, vomiting and diarrhea have previously been shown to

Bone Marrow Transplantation (2016) 1318 – 1322 © 2016 Macmillan Publishers Limited, part of Springer Nature. Hypoalbuminemia and melphalan toxicity in AL amyloidosis SY Lee et al 1321 be a common reason for admission post HDM/SCT.17 It is our insufficiency having more adverse effects.26 Although slightly practice to manage these gastrointestinal symptoms aggressively more patients with SH had renal amyloid involvement in our with IV fluids, antiemetics and antimotility agents. This may study, the creatinine clearance (by Cockroft Gault method) was explain our low rate of severe toxicity. None of our SH patients about 20% higher in this group compared with the control group, suffered from grade 3 or 4 mucositis either. All patients under- though the difference is not statistically significant. going HDM/SCT at our institution receive oral cryotherapy, which As plasma protein binding reduces the hydrolysis rate of this has been shown to decrease frequency and severity of oral drug, spontaneous degradation has a much smaller role in mucositis.18 The lack of mucositis in our patient population speaks melphalan elimination (o5%),27 which may not be the case in to the effectiveness of this strategy. SH. A study by Nath et al.9 looking at population pharmacokinetics Compared with the known common toxicities of HDM, grade 4 of melphalan in a group of 100 patients with multiple myeloma AKI and hypotension were in fact the more prevalent adverse found that hematocrit can also affect melphalan clearance. This events in our subjects with SH. This could be explained by the was thought to be a result of decreased melphalan binding to reduced oncotic pressure, decreased intravascular volume and proteins in the red cell membranes.28,29 However, Nath et al.9 did the inability of patients to maintain their usual intravascular not detect any significant associations between unbound physiology in the face of severely low serum albumin levels. It may melphalan clearance and pretransplant paraprotein, total protein, also be why this group of patients had more grade 3 light- transferrin or albumin levels. We are not able to draw any 19 headedness. Usberti et al. reported that nephrotic patients with conclusions from this report because the median albumin level in plasma albumin concentrations o1.7 g/dL have contraction of the patient population of this study was 3.7 g/dL, not low as in our the blood volume, along with compensatory hormonal mechan- patients. Also, the mean hemoglobin level in our two comparison isms to promote sodium retention. This means that severe groups was identical. nephrotic syndrome may be a risk factor for intravascular volume Despite the proposed pharmacokinetic/pharmacodynamic depletion and AKI, especially with any stress such as diuresis or differences in SH patients, no statistically significant difference in diarrhea. hematologic or renal response rates were seen. Bensinger et al.30 The SH group in our study were three times more likely to showed that a higher preparative melphalan dose may improve receive an albumin infusion during the peritransplantation period; response rates in myeloma; therefore, one could hypothesize that interestingly, this did not ameliorate the group’s propensity for higher free melphalan levels could improve response rates in AL hypotension or lightheadedness. Patients with amyloid involve- amyloidosis. The differences in free melphalan may not be ment of the cardiac or nervous system can also certainly suffer fi 20 signi cant enough to result in meaningful changes in response, from more orthostasis or hypotension. However, there were no and measuring free melphalan levels would be helpful. significant differences in the proportion of subjects with cardiac or In addition to what was discussed above, the retrospective autonomic nervous system involvement between the groups to nature and small sample size of this study are additional explain this disparate toxicity. limitations. Because of small sample size, trends toward significant Melphalan’s cytotoxic effects are related to its concentration 5 differences could have been missed. However, a prospective and duration of exposure. Therefore, the dose of melphalan randomized study would not be possible to answer our research received, unbound drug levels and rate of clearance of the drug question. To obtain larger sample size for our SH group, we had to can all affect the chance and severity of toxicity. Patients with review data from a longer time frame (years 2011 to 2014). The higher total and unbound melphalan exposure suffer from more 9 data for our control population were obtained from 2011 to 2012; severe gastrointestinal toxicity and long hospital admissions. owing to the small sample size of the SH group, increasing control Unbound drug exposure has been demonstrated to be a more group subjects would not offer additional statistical benefit. sensitive predictor of both efficacy and toxicity.9 Approximately 8 As far as we know, the standard procedure for HDM/SCT and 90% of the drug is bound to plasma proteins; in vitro studies peritransplantation supportive care had not changed during this show that melphalan is 60% bound to albumin and 20% bound to 11 fi time period. One of the strengths of this study is that it was based alpha1-glycoprotein. With such a signi cant amount of the drug on a relatively large study population for an uncommon disease, bound to albumin, SH could in theory result in higher free especially because we were studying a subset of patients with SH. melphalan levels and therefore more toxicity. Unfortunately, We are also fortunate to have detailed records from our stem cell one of the limitations of this study was that we were unable to transplant database. measure free melphalan levels. In conclusion, our study suggests that patients with SH All patients in our study received IV melphalan dosed at either receiving HDM/SCT may not require adjustment in melphalan 200 mg/m2 or 140 mg/m2. There were no significant differences in 2 dose for gastrointestinal toxicity, mucositis or hematologic the proportion of patients receiving the higher 200 mg/m toxicities, but patients should be informed of the higher risk of melphalan dose in either group, or the mean melphalan dose AKI. Biomarkers to predict AKI may be of value in future studies. received. Melphalan has been in use for decades for various SH was not associated with worse 30- or 100-day mortality. indications,21 and is primarily given intravenously because of its known inconsistent oral absorption.22 HDM given at 200 mg/m2 was first adopted by the Arkansas group for multiple myeloma. It CONFLICT OF INTEREST is now widely used as a preparative regimen for autologous stem The authors declare no conflict of interest. cell transplantation23 in multiple myeloma and AL amyloidosis. In multiple myeloma patients with renal failure, a lower melphalan dose of 140 mg/m2 may have similar efficacy to the gold standard ACKNOWLEDGEMENTS 2 24 2 dose of 200 mg/m . However, in AL amyloidosis, the 200 mg/m We gratefully acknowledge our colleagues in the Amyloidosis Center at the Boston has been associated with better survival as well as better University School of Medicine, and the Clinical Trials Office and staff of the Solomont 4 hematologic response rates compared with lower doses. Dose Center for Cancer and Blood Disorders at Boston Medical Center who assisted with adjustments of melphalan for age, renal function or in obese the multidisciplinary evaluation and treatment of these patients with amyloidosis. patients have not been standardized.25 Melphalan is removed by both renal excretion and spontaneous degradation to non-cytotoxic active mono- and di-hydroxy AUTHOR CONTRIBUTIONS metabolites.9,10 Renal function is the major determinant SYL and RSM collected and analyzed data, performed research and wrote the of melphalan clearance,9 with patients suffering from renal manuscript. DCS designed and performed research and edited manuscript. JMS,

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