Amyloid The Journal of Protein Folding Disorders
ISSN: 1350-6129 (Print) 1744-2818 (Online) Journal homepage: http://www.tandfonline.com/loi/iamy20
Plerixafor-augmented peripheral blood stem cell mobilization in AL amyloidosis with cardiac involvement: a case series Steve Y. Lee, Vaishali Sanchorawala, David C. Seldin, J. Mark Sloan, Nancy Andrea & Karen Quillen To cite this article: Steve Y. Lee, Vaishali Sanchorawala, David C. Seldin, J. Mark Sloan, Nancy Andrea & Karen Quillen (2014) Plerixafor-augmented peripheral blood stem cell mobilization in AL amyloidosis with cardiac involvement: a case series, Amyloid, 21:3, 149-153, DOI: 10.3109/13506129.2014.900486 To link to this article: http://dx.doi.org/10.3109/13506129.2014.900486
Published online: 29 Apr 2014.
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Date: 04 November 2016, At: 10:06
http://informahealthcare.com/amy ISSN: 1350-6129 (print), 1744-2818 (electronic) Amyloid, 2014; 21(3): 149–153 ! 2014 Informa UK Ltd. DOI: 10.3109/13506129.2014.900486
ORIGINAL ARTICLE
Plerixafor-augmented peripheral blood stem cell mobilization in AL amyloidosis with cardiac involvement: a case series Steve Y. Lee, Vaishali Sanchorawala, David C. Seldin, J. Mark Sloan, Nancy Andrea, and Karen Quillen Department of Medicine, Boston University Medical Center, Boston, MA, USA
Abstract
Keywords
Nearly half of AL amyloidosis patients have cardiac involvement, an independent predictor of poor prognosis. High-dose melphalan and autologous stem-cell transplantation (HDM/SCT) can induce complete hematologic responses and prolong survival in AL amyloidosis. Granulocyte colony-stimulating factor (G-CSF)-induced mobilization of peripheral blood stem cell (PBSC) in AL amyloidosis patients is associated with volume overload, arrhythmias and capillary leak syndrome. Plerixafor has a different mechanism of action and has non-overlapping toxicities with G-CSF. We describe our experience in five patients with AL amyloidosis and cardiac involvement who received plerixafor with G-CSF for PBSC mobilization. Median age was 56 years; two patients had undergone heart transplantation within the year prior to HDM/SCT. Three patients received plerixafor after an initial trial of mobilization with G-CSF alone. No patient had any significant toxicities during mobilization and PBSC collection. The median total yield of PBSCs collected was 5.9 106 CD34+ cells/kg; the median number of leukapheresis days was 2. Neutrophil engraftment after HDM/SCT occurred at a median of nine days, platelet engraftment at a median of 13 days. Plerixafor was effective and well tolerated when used upfront or as rescue for PBSC mobilization in AL amyloidosis patients with cardiac involvement.
Amyloidosis, autologous, heart failure, plerixafor (JM 3100), stem cells, transplantation History Received 4 December 2013 Revised 7 February 2014 Accepted 23 February 2014 Published online 29 April 2014
Abbreviations: FLC: free light chains; G-CSF: granulocyte colony-stimulating factor; HDM/SCT: high-dose melphalan and autologous stem cell transplantation; OHT: orthotopic heart transplantation; PBSC: peripheral blood stem cell
Introduction High-dose melphalan and autologous stem-cell transplantation (HDM/SCT) can induce complete hematologic responses and prolong survival in AL amyloidosis [1,2]. Up to 50% of AL amyloidosis patients have cardiac involvement, an independent predictor of poor clinical prognosis [3,4]. Cardiac biomarker elevation correlates with poor prognosis, and has been used to develop a staging system [5–8]. However, patients with cardiac involvement who successfully undergo HDM/SCT can have durable remissions and excellent survival [7,8]. At our institution, deaths during stem cell mobilization and collection accounted for 2% (11/522) treatment-related mortality during HDM/SCT; most of these were cardiac events [9]. Mortality up to 8% during mobilization with granulocyte colony-stimulating factor (G-CSF) has
been reported by Jaccard et al. [10]. High-dose G-CSF for peripheral blood stem cell (PBSC) mobilization in AL amyloidosis patients is associated with volume overload, arrhythmias, capillary leak syndrome, hypotension and hypoxia [11–13], even in patients without cardiac involvement. Plerixafor, a CXCR4 receptor antagonist, has well-established efficacy when used with G-CSF in PBSC mobilization in multiple myeloma and non-Hodgkin’s lymphoma [14,15]. There have been no reports of efficacy and tolerability of plerixafor mobilization in AL amyloidosis with cardiac involvement. We describe our experience in five patients with AL amyloidosis and cardiac involvement who received plerixafor with G-CSF for PBSC mobilization as upfront mobilization regimen or as an ‘‘on demand’’ regimen.
Methods Data review
Address for correspondence: Karen Quillen, M.D., 670 Albany St., 7/F, Boston, MA 02118, USA. Tel: +617 638 7828. Fax: 617 638 4556. E-mail: [email protected]
Electronic medical records of a single multidisciplinary amyloidosis referral center were reviewed in the time period between December 2010 and December 2012 to identify patients with AL amyloidosis and cardiac involvement who received plerixafor as part of HDM/SCT. Cardiac biomarker staging was performed according to standard criteria [5].
S. Y. Lee et al.
Hepatic (bilirubin) VGPR 6 month Febrile neutropenia, GI, hepatic (alkaline phos) Persistent disease at 22 months
0.9 5.7 2 200 5.7 9 12 7
45/F
1.1 5.9 2 140 5.9 11 13 9 X X 0.54 2.9 3 140 2.9 12 16 23
X GI, oral mucositis Died D+149
N/A 6.4 1 200 6.4 9 11 8 X
Weight gain (2%) X Weight gain (2%), myalgias X Weight gain (3%)
Weight gain (2%) Diarrhea N/A 15.7 2 140 10.4 9 17 9
X
II III
N/A N/A X X III II
59/F
X Sepsis, renal, hyperglycemia Complete remission at 30 months
56/M
N/A N/A X
This was a 57-year-old man with cardiac, renal and peripheral nerve involvement. Due to the severity of his cardiomyopathy, the patient was treated with orthotopic heart transplantation (OHT) followed by HDM/SCT, as published by Dey et al. [16]. Five months after OHT, azathioprine and valganciclovir were discontinued, atovaquone substituted for trimethoprim/ sulfamethoxazole, and immunosuppression was maintained with tacrolimus and prednisone during PBSC mobilization and HDM/SCT. The patient underwent standard G-CSF
Cardiac stage NHYA class CHF Heart transplant Upfront plerixafor Rescue plerixafor Mobilization AE (G-CSF) Plerixafor AE CD34+cells with G-CSF (106/kg) Total PBSC yield (106/kg CD34+cells) Total SCC days Melphalan dose PBSC infused Neutrophil engraftment Platelet engraftment # Input days to D +100 Arrhythmia CHF Other grade III–IV toxicities Outcome
Patient 1
57/M
We identified five patients with AL amyloidosis and cardiac involvement whose mobilization regimens included plerixafor. Three patients received plerixafor after inadequate mobilization with G-CSF alone; two were intentionally treated with plerixafor and G-CSF. Clinical data are summarized in Table 1.
Age/sex
Results
Table 1. Clinical summary of patients with AL amyloidosis and cardiac involvement who received plerixafor.
Two patients were felt to be at high risk for G-CSF toxicity, and underwent planned upfront mobilization with plerixafor (Genzyme, Cambridge, MA) in addition to G-CSF. For these patients, G-CSF was administered at 10 lg/kg in the morning on Days 1–5, with plerixafor 0.24 mg/kg (with dose adjustment for creatinine clearance) administered in the evening on Day 4, and leukapheresis on Day 5. Three patients received plerixafor after inadequate mobilization with G-CSF alone. In these patients, G-CSF was administered at 16 lg/kg on Days 1–3, with leukapheresis on Day 4. PBSCs yield 51.5 106 CD34+ cells/kg was considered inadequate. After a decision was made to add plerixafor, G-CSF was given at 10 lg/kg, followed by plerixafor 0.24 mg/kg in the evening, with an additional dose of G-CSF at 10 lg/kg the next morning, until the target CD34+ dose (2.5–5 106 CD34+ cells/kg) was achieved by subsequent leukapheresis. In both pathways, the typical duration between plerixafor dose and the initiation of apheresis was 11 h. Large volume leukapheresis was used routinely (duration of procedure set at 5 h). Patients received HDM at 140 or 200 mg/m2 as per institutional guidelines the following week, and 24–48 h later they were re-infused with PBSC. After stem-cell infusion, supportive care included G-CSF (300 or 480 lg/d), antiemetics, prophylactic antimicrobials (quinolone, fluconazole and acyclovir) and transfusions. Patients were evaluated daily in an outpatient setting and admitted for complications as needed. Hematologic complete response was defined as an absence of a monoclonal gammopathy by immunofixation in serum and urine, a normal bone marrow biopsy, and normal serum free light chains (FLC), if available [7,8].
53/M
Clinical protocol
Died D+224
Peritransplant morbidity and mortality was considered through Day +100 post transplant. Complications and deaths were categorized according to the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) v3.0 (2006). The study was approved by the Institutional Review Board of the Boston Medical Center in accordance with federal regulations.
X Weight gain (3%)
Amyloid, 2014; 21(3): 149–153
III II
150
DOI: 10.3109/13506129.2014.900486
mobilization with plerixafor rescue after inadequate initial apheresis yield. Patient 2 This was a 56-year-old man with cardiac, liver and soft tissue involvement by AL amyloidosis. The patient had previously been diagnosed with smoldering myeloma seven years prior and had been treated with intermittent pulse dexamethasone. A defibrillator had been implanted one month prior to mobilization for bifascicular block. After standard G-CSF mobilization, he underwent plerixafor rescue after inadequate yield complicated by fluid overload requiring administration of intravenous diuretics. The post-transplant course was notable for neutropenic fever, neutrophil engraftment on Day +11, a repeat G-CSF course for neutropenia associated with nonspecific abdominal pain from Days +17 to +20, and two episodes of non-sustained ventricular tachycardia. At the six-month post-transplant follow-up, a partial hematologic response was documented with persistent cardiac symptoms, and therapy with bortezomib and dexamethasone was planned. He died on Day +224 from large bowel obstruction and septic shock. Patient 3 This was a 59-year-old woman with cardiac, renal and soft tissue involvement by AL amyloidosis. The patient had undergone OHT nine months prior to HDM/SCT, complicated by acute cellular rejection after mycophenolate was discontinued in preparation for SCT, requiring pulse corticosteroids and addition of sirolimus to tacrolimus. Atovaquone was substituted for trimethoprim/sulfamethoxazole, and valganciclovir was discontinued just prior to PBSC mobilization. Upfront use of G-CSF and plerixafor achieved the target PBSC yield in one day. The post-transplant course was notable for nausea, grade III mucositis and grade III diarrhea. She was later hospitalized for colitis and cryptococcal sepsis, from which she expired at Day +149. Patient 4 This was a 53-year-old man with renal, cardiac and soft tissue involvement. The patient had been treated with bortezomib and dexamethasone twice weekly for four cycles ending three months prior to mobilization with minimal response in free light chains. He received planned mobilization with G-CSF and plerixafor upfront per protocol. Post-transplant course was notable for neutropenic fever and mucositis. He also had an asymptomatic run of non-sustained ventricular tachycardia, attributed to underlying cardiac disease. An increase in free light chains was noted at Day +56, for which he received additional chemotherapy with cyclophosphamide, bortezomib and dexamethasone for eight cycles and then lenalidomide, which continued at 22 months post transplant. Patient 5 This was a 45-year-old woman with AL amyloidosis and cardiac involvement. The patient underwent G-CSF mobilization with inadequate yield after first collection and
PBSC mobilization plerixafor cardiac amyloid AL
151
received plerixafor rescue. Post-transplant course was complicated by hyperbilirubinemia. At six months follow-up post SCT, she was in a very good partial hematologic remission (VGPR), defined as 540 mg/L difference between involved and uninvolved FLC [7,8]; however, she had moderately decreased systolic heart function by echocardiogram.
Discussion In this series of AL amyloidosis patients with cardiac involvement undergoing HDM/SCT, plerixafor was employed either upfront or as a rescue therapy in order to shorten the duration of mobilization and to improve the likelihood of safely achieving the target CD34+ yield within two days of leukapheresis, the median number of leukapheresis sessions at our center [17]. Even when effective, G-CSF-stimulated PBSC mobilization is complicated in patients with cardiac amyloidosis due to problems with fluid retention, hypotension and development of decompensated CHF. Patients with significant cardiac or renal dysfunction from amyloidosis, or severe hypoalbuminemia from nephrotic syndrome, are particularly sensitive to fluid overload [12]. Systemic capillary leak syndrome associated with G-CSF is well described, attributable to cytokine release from neutrophils and increased vascular permeability from endothelial damage [11]. These adverse effects from G-CSF during PBSC mobilization can be fatal in patients with AL amyloidosis [9,10,13]. Plerixafor mobilizes stem cells by antagonizing binding to the bone marrow niche and increasing chemotaxis of CD34+ cells [18,19]. When used in conjunction with G-CSF, plerixafor increases the yield of PBSCs collected compared with G-CSF alone. It has been approved by the US FDA and European Union for use with G-CSF in the mobilization of PBSCs in myeloma and non-Hodgkin’s lymphoma. Plerixafor is typically given the evening prior to apheresis for its synergistic effect with G-CSF [18]. The side effect profiles of plerixafor and G-CSF are non-overlapping; unique side effects (410%) of plerixafor are primarily gastrointestinal in nature, including nausea, vomiting, abdominal pain and diarrhea, or are otherwise non-specific, including nausea, fatigue, injection site reaction and headaches [20]. Rare (51%) but significant side effects include allergic reactions including anaphylaxis [20]. Only one instance of adverse effect attributable to plerixafor was observed in this series (diarrhea in patient 3). Weight gain and headache are commonly observed in AL amyloidosis patients receiving G-CSF alone for mobilization (see Table 1). Tumor cell mobilization is of concern in leukemia patients, but it is not routinely assessed in AL amyloidosis patients given the low plasma cell burden. The post-transplantation course of our series was notable for worsening fluid overload in three of five patients and asymptomatic arrhythmias noted on inpatient cardiac telemetry monitoring. One patient developed Escherichia coli sepsis and acute kidney injury, and two others experienced Grade III/IV gastrointestinal symptoms; none experienced an allergic reaction or anaphylaxis. Most recorded complications were not suspected to be related to
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plerixafor, but rather to the underlying amyloidosis and complications of high-dose chemotherapy, neutropenia and immunosuppression. Risk factors for poor mobilization are well described: a low peripheral blood CD34+ level is the best predictor of poor response; other factors include low platelet counts, extensive marrow involvement, advanced age, previous chemo/radiotherapy and previous lenalidomide. Most patients undergoing HDM/SCT at our institution do not have these risk factors for poor mobilization, and mobilize readily with growth factor alone, achieving the target PBSC yield after two consecutive leukapheresis days [17]. Upfront plerixafor was used in two patients who were at high risk of fluid overload and arrhythmia after initial experience with two patients who received plerixafor in the rescue setting. In the current series, neutrophil and platelet engraftment kinetics are comparable with those observed with G-CSFmobilized PBSCs [21]. Plerixafor has been reported to improve graft composition and shorten time to lymphocyte recovery after HSCT in AL amyloidosis patients with end-stage renal disease [22]. In prior studies, PBSC yields with upfront plerixafor were similar to those with rescue (or ‘‘just-in-time’’ or ‘‘demand’’) plerixafor [18]. The chief disadvantage of planned plerixafor use is drug cost [18]. In our series, the two patients given plerixafor upfront required only a single day of apheresis to achieve adequate yield, as opposed to three sessions (patient #1) when given as rescue therapy. Using cost estimates of G-CSF at $500/dose, plerixafor at $5700/dose, apheresis at $3570/day, and cryopreservation $4780/product [23], the cost of a three-day collection with G-CSF alone would be estimated at about $28 000, versus $16 500 with combined therapy and a one-day collection. Coupled with the high cost and morbidity of treating worsening heart failure that occurs with extended days of G-CSF mobilization, upfront combination plerixafor/G-CSF may be a very cost-effective option for patients with Stage II or III cardiac amyloidosis otherwise eligible for HDM/SCT. Overall, we have been encouraged by the efficacy and favorable side-effect profile of plerixafor-augmented PBSC mobilization in AL amyloidosis, and are in the process of developing institutional guidelines for this mobilization regimen. We are evaluating criteria such as upfront use in Stage III cardiac involvement, or patients who are receiving immunosuppression for OHT [16], and rescue use in other AL amyloidosis patients whose Day 1 leukapheresis yield is 51.0 106 CD34+ cells/kg [18].
Declaration of Interest This is original research article. It has not been previously published or submitted for publication elsewhere while under consideration. The authors declare no conflicts of interest.
References 1. Skinner M, Sanchorawala V, Seldin DC, Dember LM, Falk RH, Berk JL, Anderson JJ, et al. High-dose melphalan and autologous stem-cell transplantation in patients with AL amyloidosis: an 8-year study. Ann Intern Med 2004;140:85–93.
Amyloid, 2014; 21(3): 149–153
2. Cibeira MT, Sanchorawala V, Seldin DC, Quillen K, Berk JL, Dember LM, Segal A, et al. Outcome of AL amyloidosis after high-dose melphalan and autologous stem cell transplantation: long-term results in a series of 421 patients. Blood 2011;118: 4346–52. 3. Falk RH. Diagnosis and management of the cardiac amyloidoses. Circulation 2005;112:2047–60. 4. Meier-Ewert HK, Sanchorawala V, Berk JL, Ruberg FL. Cardiac amyloidosis: evolving approach to diagnosis and management. Curr Treat Options Cardiovasc Med 2011;13:528–42. 5. Dispenzieri A, Gertz MA, Kyle RA, Lacy MQ, Burritt MF, Therneau TM, McConnell JP, et al. Prognostication of survival using cardiac troponins and N-terminal pro-brain natriuretic peptide in patients with primary systemic amyloidosis undergoing peripheral blood stem cell transplantation. Blood 2004;104:1881–7. 6. Palladini G, Lavatelli F, Russo P, Perlini S, Perfetti V, Bosoni T, Obici L, et al. Circulating amyloidogenic free light chains and serum N-terminal natriuretic peptide type B decrease simultaneously in association with improvement of survival in AL. Blood 2006;107:3854–8. 7. Palladini G, Dispenzieri A, Gertz MA, Kumar S, Wechalekar A, Hawkins PN, Scho¨nland S, et al. New criteria for response to treatment in immunoglobulin light chain amyloidosis based on free light chain measurement and cardiac biomarkers: impact on survival outcomes. J Clin Oncol 2012;30:4541–9. 8. Girnius S, Seldin DC, Cibeira MT, Sanchorawala V. New hematologic response criteria predict survival in patients with immunoglobulin light chain amyloidosis treated with highdose melphalan and autologous stem-cell transplantation. J Clin Oncol 2013;31:2749–50. 9. Tsai SB, Seldin DC, Quillen K, Berk JL, Ruberg FL, Meier-Ewert H, Sloan JM, et al. High-dose melphalan and stem cell transplantation for patients with AL amyloidosis: trends in treatment-related mortality over the past 17 years at a single referral center. Blood 2012;120:4445–6. 10. Jaccard A, Moreau P, Leblond V, Leleu X, Benboubker L, Hermine O, Recher C, et al. High-dose melphalan versus melphalan plus dexamethasone for AL amyloidosis. N Engl J Med 2007;357: 1083–93. 11. Shinohara K. Systemic capillary leak syndrome caused by granulocyte colony-stimulating factor. Intern Med (Japan) 2011; 50:2259. 12. Roy V. Autologous stem cell transplant for AL amyloidosis. Bone Marrow Res 2012;2012:238961. 13. Comenzo RL, Gertz MA. Autologous stem cell transplantation for primary systemic amyloidosis. Blood 2002;99:4276–82. 14. DiPersio JF, Stadtmauer EA, Nademanee A, Micallef IN, Stiff PJ, Kaufman JL, Maziarz RT, et al. Plerixafor and G-CSF versus placebo and G-CSF to mobilize hematopoietic stem cells for autologous stem cell transplantation in patients with multiple myeloma. Blood 2009;113:5720–6. 15. Duarte RF, Shaw BE, Marı´n P, Kottaridis P, Ortiz M, Morante C, Delgado J, et al. Plerixafor plus granulocyte CSF can mobilize hematopoietic stem cells from multiple myeloma and lymphoma patients failing previous mobilization attempts: EU compassionate use data. Bone Marrow Transplant 2011;46:52–8. 16. Dey BR, Chung SS, Spitzer TR, Zheng H, Macgillivray TE, Seldin DC, McAfee S, et al. Cardiac transplantation followed by dose-intensive melphalan and autologous stem cell transplantation for AL amyloidosis and heart failure. Transplantation 2010;90: 905–11. 17. Quillen K, Seldin DC, Finn KT, Sanchorawala V. A second course of high-dose melphalan and auto-SCT for the treatment of relapsed AL amyloidosis. Bone Marrow Transplant 2011;46:976–80. 18. To LB, Levesque JP, Herbert KE. How I treat patients who mobilize hematopoietic stem cells poorly. Blood 2011;118:4530–40. 19. De Clercq E. The AMD3100 story: the path to the discovery of a stem cell mobilizer (Mozobil). Biochem Pharmacol 2009;77: 1655–64. 20. U.S. Food and Drug Administration. Highlights of prescribing information: Mozobil (plerixafor injection), solution for subcutaneous use. MedWatch The FDA Safety Information and Adverse Event Reporting Program. 2008. [updated 2013 Jun; cited 2013 Aug 27]. Available from: http://www.accessdata.fda.gov/ drugsatfda_docs/label/2013/022311s013lbl.pdf
DOI: 10.3109/13506129.2014.900486
21. Oran B, Malek K, Sanchorawala V, Wright DG, Quillen K, Finn KT, La Valley M, et al. Predictive factors for hematopoietic engraftment after autologous peripheral blood stem cell transplantation for AL amyloidosis. Bone Marrow Transplant 2005;35: 567–75. 22. Dunn D, Vikas P, Jagasia M, Savani BN. Plerixafor in AL amyloidosis: improved graft composition and faster lymphocyte
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recovery after auto-SCT in patient with end-stage renal-disease. Bone Marrow Transplant 2012;47:1136–7. 23. Li J, Hamilton E, Vaughn L, Graiser M, Renfroe H, Lechowicz MJ, Langston A, et al. Effectiveness and cost analysis of ‘‘just-in-time’’ salvage plerixafor administration in autologous transplant patients with poor stem cell mobilization kinetics. Transfusion 2011;51: 2175–82.
ISSN: 1350-6129 (Print) 1744-2818 (Online) Journal homepage: http://www.tandfonline.com/loi/iamy20
Plerixafor-augmented peripheral blood stem cell mobilization in AL amyloidosis with cardiac involvement: a case series Steve Y. Lee, Vaishali Sanchorawala, David C. Seldin, J. Mark Sloan, Nancy Andrea & Karen Quillen To cite this article: Steve Y. Lee, Vaishali Sanchorawala, David C. Seldin, J. Mark Sloan, Nancy Andrea & Karen Quillen (2014) Plerixafor-augmented peripheral blood stem cell mobilization in AL amyloidosis with cardiac involvement: a case series, Amyloid, 21:3, 149-153, DOI: 10.3109/13506129.2014.900486 To link to this article: http://dx.doi.org/10.3109/13506129.2014.900486
Published online: 29 Apr 2014.
Submit your article to this journal
Article views: 112
View related articles
View Crossmark data
Citing articles: 1 View citing articles
Full Terms & Conditions of access and use can be found at http://www.tandfonline.com/action/journalInformation?journalCode=iamy20 Download by: [University of Otago]
Date: 04 November 2016, At: 10:06
http://informahealthcare.com/amy ISSN: 1350-6129 (print), 1744-2818 (electronic) Amyloid, 2014; 21(3): 149–153 ! 2014 Informa UK Ltd. DOI: 10.3109/13506129.2014.900486
ORIGINAL ARTICLE
Plerixafor-augmented peripheral blood stem cell mobilization in AL amyloidosis with cardiac involvement: a case series Steve Y. Lee, Vaishali Sanchorawala, David C. Seldin, J. Mark Sloan, Nancy Andrea, and Karen Quillen Department of Medicine, Boston University Medical Center, Boston, MA, USA
Abstract
Keywords
Nearly half of AL amyloidosis patients have cardiac involvement, an independent predictor of poor prognosis. High-dose melphalan and autologous stem-cell transplantation (HDM/SCT) can induce complete hematologic responses and prolong survival in AL amyloidosis. Granulocyte colony-stimulating factor (G-CSF)-induced mobilization of peripheral blood stem cell (PBSC) in AL amyloidosis patients is associated with volume overload, arrhythmias and capillary leak syndrome. Plerixafor has a different mechanism of action and has non-overlapping toxicities with G-CSF. We describe our experience in five patients with AL amyloidosis and cardiac involvement who received plerixafor with G-CSF for PBSC mobilization. Median age was 56 years; two patients had undergone heart transplantation within the year prior to HDM/SCT. Three patients received plerixafor after an initial trial of mobilization with G-CSF alone. No patient had any significant toxicities during mobilization and PBSC collection. The median total yield of PBSCs collected was 5.9 106 CD34+ cells/kg; the median number of leukapheresis days was 2. Neutrophil engraftment after HDM/SCT occurred at a median of nine days, platelet engraftment at a median of 13 days. Plerixafor was effective and well tolerated when used upfront or as rescue for PBSC mobilization in AL amyloidosis patients with cardiac involvement.
Amyloidosis, autologous, heart failure, plerixafor (JM 3100), stem cells, transplantation History Received 4 December 2013 Revised 7 February 2014 Accepted 23 February 2014 Published online 29 April 2014
Abbreviations: FLC: free light chains; G-CSF: granulocyte colony-stimulating factor; HDM/SCT: high-dose melphalan and autologous stem cell transplantation; OHT: orthotopic heart transplantation; PBSC: peripheral blood stem cell
Introduction High-dose melphalan and autologous stem-cell transplantation (HDM/SCT) can induce complete hematologic responses and prolong survival in AL amyloidosis [1,2]. Up to 50% of AL amyloidosis patients have cardiac involvement, an independent predictor of poor clinical prognosis [3,4]. Cardiac biomarker elevation correlates with poor prognosis, and has been used to develop a staging system [5–8]. However, patients with cardiac involvement who successfully undergo HDM/SCT can have durable remissions and excellent survival [7,8]. At our institution, deaths during stem cell mobilization and collection accounted for 2% (11/522) treatment-related mortality during HDM/SCT; most of these were cardiac events [9]. Mortality up to 8% during mobilization with granulocyte colony-stimulating factor (G-CSF) has
been reported by Jaccard et al. [10]. High-dose G-CSF for peripheral blood stem cell (PBSC) mobilization in AL amyloidosis patients is associated with volume overload, arrhythmias, capillary leak syndrome, hypotension and hypoxia [11–13], even in patients without cardiac involvement. Plerixafor, a CXCR4 receptor antagonist, has well-established efficacy when used with G-CSF in PBSC mobilization in multiple myeloma and non-Hodgkin’s lymphoma [14,15]. There have been no reports of efficacy and tolerability of plerixafor mobilization in AL amyloidosis with cardiac involvement. We describe our experience in five patients with AL amyloidosis and cardiac involvement who received plerixafor with G-CSF for PBSC mobilization as upfront mobilization regimen or as an ‘‘on demand’’ regimen.
Methods Data review
Address for correspondence: Karen Quillen, M.D., 670 Albany St., 7/F, Boston, MA 02118, USA. Tel: +617 638 7828. Fax: 617 638 4556. E-mail: [email protected]
Electronic medical records of a single multidisciplinary amyloidosis referral center were reviewed in the time period between December 2010 and December 2012 to identify patients with AL amyloidosis and cardiac involvement who received plerixafor as part of HDM/SCT. Cardiac biomarker staging was performed according to standard criteria [5].
S. Y. Lee et al.
Hepatic (bilirubin) VGPR 6 month Febrile neutropenia, GI, hepatic (alkaline phos) Persistent disease at 22 months
0.9 5.7 2 200 5.7 9 12 7
45/F
1.1 5.9 2 140 5.9 11 13 9 X X 0.54 2.9 3 140 2.9 12 16 23
X GI, oral mucositis Died D+149
N/A 6.4 1 200 6.4 9 11 8 X
Weight gain (2%) X Weight gain (2%), myalgias X Weight gain (3%)
Weight gain (2%) Diarrhea N/A 15.7 2 140 10.4 9 17 9
X
II III
N/A N/A X X III II
59/F
X Sepsis, renal, hyperglycemia Complete remission at 30 months
56/M
N/A N/A X
This was a 57-year-old man with cardiac, renal and peripheral nerve involvement. Due to the severity of his cardiomyopathy, the patient was treated with orthotopic heart transplantation (OHT) followed by HDM/SCT, as published by Dey et al. [16]. Five months after OHT, azathioprine and valganciclovir were discontinued, atovaquone substituted for trimethoprim/ sulfamethoxazole, and immunosuppression was maintained with tacrolimus and prednisone during PBSC mobilization and HDM/SCT. The patient underwent standard G-CSF
Cardiac stage NHYA class CHF Heart transplant Upfront plerixafor Rescue plerixafor Mobilization AE (G-CSF) Plerixafor AE CD34+cells with G-CSF (106/kg) Total PBSC yield (106/kg CD34+cells) Total SCC days Melphalan dose PBSC infused Neutrophil engraftment Platelet engraftment # Input days to D +100 Arrhythmia CHF Other grade III–IV toxicities Outcome
Patient 1
57/M
We identified five patients with AL amyloidosis and cardiac involvement whose mobilization regimens included plerixafor. Three patients received plerixafor after inadequate mobilization with G-CSF alone; two were intentionally treated with plerixafor and G-CSF. Clinical data are summarized in Table 1.
Age/sex
Results
Table 1. Clinical summary of patients with AL amyloidosis and cardiac involvement who received plerixafor.
Two patients were felt to be at high risk for G-CSF toxicity, and underwent planned upfront mobilization with plerixafor (Genzyme, Cambridge, MA) in addition to G-CSF. For these patients, G-CSF was administered at 10 lg/kg in the morning on Days 1–5, with plerixafor 0.24 mg/kg (with dose adjustment for creatinine clearance) administered in the evening on Day 4, and leukapheresis on Day 5. Three patients received plerixafor after inadequate mobilization with G-CSF alone. In these patients, G-CSF was administered at 16 lg/kg on Days 1–3, with leukapheresis on Day 4. PBSCs yield 51.5 106 CD34+ cells/kg was considered inadequate. After a decision was made to add plerixafor, G-CSF was given at 10 lg/kg, followed by plerixafor 0.24 mg/kg in the evening, with an additional dose of G-CSF at 10 lg/kg the next morning, until the target CD34+ dose (2.5–5 106 CD34+ cells/kg) was achieved by subsequent leukapheresis. In both pathways, the typical duration between plerixafor dose and the initiation of apheresis was 11 h. Large volume leukapheresis was used routinely (duration of procedure set at 5 h). Patients received HDM at 140 or 200 mg/m2 as per institutional guidelines the following week, and 24–48 h later they were re-infused with PBSC. After stem-cell infusion, supportive care included G-CSF (300 or 480 lg/d), antiemetics, prophylactic antimicrobials (quinolone, fluconazole and acyclovir) and transfusions. Patients were evaluated daily in an outpatient setting and admitted for complications as needed. Hematologic complete response was defined as an absence of a monoclonal gammopathy by immunofixation in serum and urine, a normal bone marrow biopsy, and normal serum free light chains (FLC), if available [7,8].
53/M
Clinical protocol
Died D+224
Peritransplant morbidity and mortality was considered through Day +100 post transplant. Complications and deaths were categorized according to the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) v3.0 (2006). The study was approved by the Institutional Review Board of the Boston Medical Center in accordance with federal regulations.
X Weight gain (3%)
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mobilization with plerixafor rescue after inadequate initial apheresis yield. Patient 2 This was a 56-year-old man with cardiac, liver and soft tissue involvement by AL amyloidosis. The patient had previously been diagnosed with smoldering myeloma seven years prior and had been treated with intermittent pulse dexamethasone. A defibrillator had been implanted one month prior to mobilization for bifascicular block. After standard G-CSF mobilization, he underwent plerixafor rescue after inadequate yield complicated by fluid overload requiring administration of intravenous diuretics. The post-transplant course was notable for neutropenic fever, neutrophil engraftment on Day +11, a repeat G-CSF course for neutropenia associated with nonspecific abdominal pain from Days +17 to +20, and two episodes of non-sustained ventricular tachycardia. At the six-month post-transplant follow-up, a partial hematologic response was documented with persistent cardiac symptoms, and therapy with bortezomib and dexamethasone was planned. He died on Day +224 from large bowel obstruction and septic shock. Patient 3 This was a 59-year-old woman with cardiac, renal and soft tissue involvement by AL amyloidosis. The patient had undergone OHT nine months prior to HDM/SCT, complicated by acute cellular rejection after mycophenolate was discontinued in preparation for SCT, requiring pulse corticosteroids and addition of sirolimus to tacrolimus. Atovaquone was substituted for trimethoprim/sulfamethoxazole, and valganciclovir was discontinued just prior to PBSC mobilization. Upfront use of G-CSF and plerixafor achieved the target PBSC yield in one day. The post-transplant course was notable for nausea, grade III mucositis and grade III diarrhea. She was later hospitalized for colitis and cryptococcal sepsis, from which she expired at Day +149. Patient 4 This was a 53-year-old man with renal, cardiac and soft tissue involvement. The patient had been treated with bortezomib and dexamethasone twice weekly for four cycles ending three months prior to mobilization with minimal response in free light chains. He received planned mobilization with G-CSF and plerixafor upfront per protocol. Post-transplant course was notable for neutropenic fever and mucositis. He also had an asymptomatic run of non-sustained ventricular tachycardia, attributed to underlying cardiac disease. An increase in free light chains was noted at Day +56, for which he received additional chemotherapy with cyclophosphamide, bortezomib and dexamethasone for eight cycles and then lenalidomide, which continued at 22 months post transplant. Patient 5 This was a 45-year-old woman with AL amyloidosis and cardiac involvement. The patient underwent G-CSF mobilization with inadequate yield after first collection and
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received plerixafor rescue. Post-transplant course was complicated by hyperbilirubinemia. At six months follow-up post SCT, she was in a very good partial hematologic remission (VGPR), defined as 540 mg/L difference between involved and uninvolved FLC [7,8]; however, she had moderately decreased systolic heart function by echocardiogram.
Discussion In this series of AL amyloidosis patients with cardiac involvement undergoing HDM/SCT, plerixafor was employed either upfront or as a rescue therapy in order to shorten the duration of mobilization and to improve the likelihood of safely achieving the target CD34+ yield within two days of leukapheresis, the median number of leukapheresis sessions at our center [17]. Even when effective, G-CSF-stimulated PBSC mobilization is complicated in patients with cardiac amyloidosis due to problems with fluid retention, hypotension and development of decompensated CHF. Patients with significant cardiac or renal dysfunction from amyloidosis, or severe hypoalbuminemia from nephrotic syndrome, are particularly sensitive to fluid overload [12]. Systemic capillary leak syndrome associated with G-CSF is well described, attributable to cytokine release from neutrophils and increased vascular permeability from endothelial damage [11]. These adverse effects from G-CSF during PBSC mobilization can be fatal in patients with AL amyloidosis [9,10,13]. Plerixafor mobilizes stem cells by antagonizing binding to the bone marrow niche and increasing chemotaxis of CD34+ cells [18,19]. When used in conjunction with G-CSF, plerixafor increases the yield of PBSCs collected compared with G-CSF alone. It has been approved by the US FDA and European Union for use with G-CSF in the mobilization of PBSCs in myeloma and non-Hodgkin’s lymphoma. Plerixafor is typically given the evening prior to apheresis for its synergistic effect with G-CSF [18]. The side effect profiles of plerixafor and G-CSF are non-overlapping; unique side effects (410%) of plerixafor are primarily gastrointestinal in nature, including nausea, vomiting, abdominal pain and diarrhea, or are otherwise non-specific, including nausea, fatigue, injection site reaction and headaches [20]. Rare (51%) but significant side effects include allergic reactions including anaphylaxis [20]. Only one instance of adverse effect attributable to plerixafor was observed in this series (diarrhea in patient 3). Weight gain and headache are commonly observed in AL amyloidosis patients receiving G-CSF alone for mobilization (see Table 1). Tumor cell mobilization is of concern in leukemia patients, but it is not routinely assessed in AL amyloidosis patients given the low plasma cell burden. The post-transplantation course of our series was notable for worsening fluid overload in three of five patients and asymptomatic arrhythmias noted on inpatient cardiac telemetry monitoring. One patient developed Escherichia coli sepsis and acute kidney injury, and two others experienced Grade III/IV gastrointestinal symptoms; none experienced an allergic reaction or anaphylaxis. Most recorded complications were not suspected to be related to
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plerixafor, but rather to the underlying amyloidosis and complications of high-dose chemotherapy, neutropenia and immunosuppression. Risk factors for poor mobilization are well described: a low peripheral blood CD34+ level is the best predictor of poor response; other factors include low platelet counts, extensive marrow involvement, advanced age, previous chemo/radiotherapy and previous lenalidomide. Most patients undergoing HDM/SCT at our institution do not have these risk factors for poor mobilization, and mobilize readily with growth factor alone, achieving the target PBSC yield after two consecutive leukapheresis days [17]. Upfront plerixafor was used in two patients who were at high risk of fluid overload and arrhythmia after initial experience with two patients who received plerixafor in the rescue setting. In the current series, neutrophil and platelet engraftment kinetics are comparable with those observed with G-CSFmobilized PBSCs [21]. Plerixafor has been reported to improve graft composition and shorten time to lymphocyte recovery after HSCT in AL amyloidosis patients with end-stage renal disease [22]. In prior studies, PBSC yields with upfront plerixafor were similar to those with rescue (or ‘‘just-in-time’’ or ‘‘demand’’) plerixafor [18]. The chief disadvantage of planned plerixafor use is drug cost [18]. In our series, the two patients given plerixafor upfront required only a single day of apheresis to achieve adequate yield, as opposed to three sessions (patient #1) when given as rescue therapy. Using cost estimates of G-CSF at $500/dose, plerixafor at $5700/dose, apheresis at $3570/day, and cryopreservation $4780/product [23], the cost of a three-day collection with G-CSF alone would be estimated at about $28 000, versus $16 500 with combined therapy and a one-day collection. Coupled with the high cost and morbidity of treating worsening heart failure that occurs with extended days of G-CSF mobilization, upfront combination plerixafor/G-CSF may be a very cost-effective option for patients with Stage II or III cardiac amyloidosis otherwise eligible for HDM/SCT. Overall, we have been encouraged by the efficacy and favorable side-effect profile of plerixafor-augmented PBSC mobilization in AL amyloidosis, and are in the process of developing institutional guidelines for this mobilization regimen. We are evaluating criteria such as upfront use in Stage III cardiac involvement, or patients who are receiving immunosuppression for OHT [16], and rescue use in other AL amyloidosis patients whose Day 1 leukapheresis yield is 51.0 106 CD34+ cells/kg [18].
Declaration of Interest This is original research article. It has not been previously published or submitted for publication elsewhere while under consideration. The authors declare no conflicts of interest.
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