IMW 2013 Chiaki Nakaseko Department of Hematology, Chiba University Hospital, Chuo-ku, Chiba City, Chiba, Japan
Clinical Lymphoma, Myeloma & Leukemia Vol. 14, No. 1, 21-3
Autologous Stem Cell Transplantation for POEMS Syndrome Submitted: Dec 12, 2013; Accepted: Dec 12, 2013; Epub: Dec 22, 2013 Address for correspondence: Chiaki Nakaseko, Professor of Hematology, Department of Hematology, Chiba University Hospital 1-8-1 Inohana, Chuo-ku, Chiba, 260-8677, Japan E-mail contact: [email protected]
Table 1 Patient Characteristics Characteristic
Value
Gender Male Female
16 (70) 7 (30)
Age at ASCT (years) Median
52
Range
34-64
Interval to ASCT from diagnosis (mo) Median
9
Range
3e105
ECOG-PS at ASCT 0
12 (52)
3-4
11 (48) 20 (87)
IgA-l
11 (48)
IgG-l
8 (35)
IgG-l þ IgG-k History of previous therapies
POEMS syndrome is a rare plasma cell disorder characterized by polyneuropathy, organomegaly, endocrinopathy, M-protein, and skin changes associated with multiorgan involvement. The pathogenesis of POEMS syndrome is not well understood; however, overproduction of vascular endothelial growth factor (VEGF), probably secreted by plasma cells, has been considered responsible.1,2 Treatment was largely unsuccessful until the past decade.3,4 More recently, considerable progress has been made in interpreting the pathogenesis, clinical features, and diagnosis, and new treatment options have become available, including novel agents such as thalidomide, lenalidomide, and bortezomib, anti-VEGF antibody, and autologous stem cell transplantation (ASCT). ASCT has been reported to be a successful treatment strategy in patients < 65 years old. Jaccard et al5 reported the first case series of high-dose therapy and ASCT in patients with POEMS syndrome, in which 5 patients received high-dose melphalan (140-200 mg/m2) followed by ASCT. No deaths from drug toxicity occurred during mobilization or transplantation, and the neurologic symptoms and other manifestations of POEMS syndrome improved significantly, and all patients were alive and free of relapse after 36 months. In another study from the Mayo Clinic, 16 patients were treated with ASCT, and 14 evaluated patients achieved
0
1-2 Monoclonal proteins at diagnosis
Introduction
Figure 1 Efficiency of Stem Cell Mobilization in Patients With POEMS Syndrome. (A) Cyclophosphamide (CY) Plus Granulocyte Colony-Stimulating Factor (G-CSF). (B) G-CSF Alone
1 (4) 21 (91)
Number of previous regimens Median
2
Range
0-5
Types of previous treatment Thalidomide-based
15 (65)
Melphalan-based
7 (30)
Cyclophosphamide-based
3 (13)
Lenalidomide-based
1 (4)
Bortezomib-based
1 (4)
Bevacizumab
3 (13)
Intravenous immunoglobulin
5 (22)
Data presented as n (%), unless otherwise noted.
2152-2650/$ - see frontmatter ª 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.clml.2013.12.009
Clinical Lymphoma, Myeloma & Leukemia February 2014
- 21
ASCT for POEMS Syndrome Figure 2 Overall Survival (OS) and Progression-Free Survival (PFS) After Autologous Stem Cell Transplantation. (A) OS. (B) PFS. Progression was Defined as Elevated Vascular Endothelial Growth Factor Level (‡ 1000 pg/mL) and/or Clinical Relapse
substantial neurologic improvement or stabilization of neuropathic deficits, and 5 of 6 patients with a quantifiable serum M protein level achieved a hematologic complete response.6 Moreover, ASCT also improved organomegaly, extravascular volume overload, skin changes, and papilledema. However, ASCT was associated with a high risk of transplant-related toxicities in the early post-transplant period. Six patients (37.5%) were admitted to the intensive care unit, 5 required intubation and mechanical ventilation during mobilization and transplantation, and 1 (6.2%) died 115 days after ASCT. Recently, the long-term outcomes after ASCT for 59 patients with POEMS syndrome were reported by the same group and found that 92% of patients achieved clinical responses, and the most rapid responses were seen as soon as 100 days after transplantation.7 Maximal neurologic improvement was often not seen until 3 years afterward. After a median follow-up period of 45 months, 3 patients died, and the 5-year overall survival (OS) was 94%. One patient died, as mentioned, another died from relapse and disease progression 4 years after transplantation, and a third died of lymphoma unrelated to POEMS syndrome. Although 14 patients developed disease progression, most had hematologic, radiographic, or VEGF relapse, and only 1 patient had developed a clinical relapse. At our institution, 23 patients with POEMS syndrome have been treated with ASCT from 2004 to 2012.8-11 The patient characteristics are summarized in Table 1. The median age at ASCT was 52 years (range, 34-64), and the median interval from diagnosis to ASCT was 9 months. Regarding stem cell mobilization, the patients mobilized by cyclophosphamide plus granulocyte colonystimulating factor (G-CSF) achieved a greater number of CD34þ cells than those mobilized by G-CSF alone, although the proportion of poor mobilization was similar between the 2 groups (Fig. 1).12 Moreover, splenomegaly might be a predictive factor for poor mobilization. Three patients did not achieve sufficient peripheral blood stem cell mobilization, but the stem cells were successfully mobilized with plerixafor and G-CSF.13 Fifteen patients (65.2%) received thalidomide before ASCT, with significant improvements in serum VEGF levels and extravascular volume overload. Eleven patients presented with a poor performance status of 3 to 4 because
22
-
Clinical Lymphoma, Myeloma & Leukemia February 2014
of peripheral neuropathy. All patients achieved prompt engraftment after ASCT. Engraftment syndrome was observed in 5 patients (21.5%), but they all responded well to corticosteroid therapy. A complete hematologic response, defined by negative M-protein using immunofixation, was achieved in 65% of the patients. An improvement in clinical symptoms and a reduction in VEGF were observed in 22 patients (95.6%). No transplant-related death was observed. The overall neuropathy limitations score gradually and continuously improved after ASCT, and most of the patients became able to walk without support. Five patients experienced disease relapse. At a median observational period of 51 months, the 3- and 5-year OS and progression-free survival was 96% and 81% and 64.6% and 59.8%, respectively (Fig. 2). In conclusion, ASCT is an effective therapy for POEMS syndrome. With stabilization of the serum VEGF level with induction therapy, the transplant-related mortality was low and the periengraftment complications were manageable. However, a certain number of patients experienced disease relapse after ASCT. Therefore, all patients should be followed up carefully, and effective salvage strategies are required.
References 1. Watanabe O, Maruyama I, Arimura K, et al. Overproduction of vascular endothelial growth factor/vascular permeability factor is causative in Crow-Fukase (POEMS) syndrome. Muscle Nerve 1998; 21:1390-7. 2. Watanabe O, Arimura K, Kitajima I, Osame M, Maruyama I. Greatly raised vascular endothelial growth factor (VEGF) in POEMS syndrome. Lancet 1996; 347:702. 3. Kuwabara S, Hattori T, Shimoe Y, Kamitsukasa I. Long term melphalanprednisolone chemotherapy for POEMS syndrome. J Neurol Neurosurg Psychiatry 1997; 63:385-7. 4. Kuwabara S, Dispenzieri A, Arimura K, Misawa S, Nakaseko C. Treatment for POEMS (polyneuropathy, organomegaly, endocrinopathy, M-protein, and skin changes) syndrome. Cochrane Database System Rev 2012; 6: CD006828. 5. Jaccard A, Royer B, Bordessoule D, Brouet JC, Fermand JP. High-dose therapy and autologous blood stem cell transplantation in POEMS syndrome. Blood 2002; 99:3057-9. 6. Dispenzieri A, Moreno-Aspitia A, Suarez GA, et al. Peripheral blood stem cell transplantation in 16 patients with POEMS syndrome, and a review of the literature. Blood 2004; 104:3400-7. 7. D’Souza A, Lacy M, Gertz M, et al. Long-term outcomes after autologous stem cell transplantation for patients with POEMS syndrome (osteosclerotic myeloma): a single-center experience. Blood 2012; 120:56-62.
Chiaki Nakaseko 8. Kuwabara S, Misawa S, Kanai K, et al. Neurologic improvement after peripheral blood stem cell transplantation in POEMS syndrome. Neurology 2008; 71: 1691-5. 9. Kuwabara S, Misawa S, Kanai K, et al. Autologous peripheral blood stem cell transplantation for POEMS syndrome. Neurology 2006; 66:105-7. 10. Nakaseko C, Ohwada C, Shimizu N, et al. Long term outcomes of autologous stem cell transplantation for POEMS syndrome: a single center experience of 23 cases. Clin Lymphoma Myeloma Leuk 2013; 13:S46-7.
11. Nakaseko C. Autologous stem cell transplantation for POEMS syndrome. Clin Lymphoma Myeloma Leuk 2013; 13:S9-10. 12. Shimizu N, Nakaseko C, Sakaida E, et al. Factors associated with the efficiency of PBSC collection in POEMS syndrome patients undergoing autologous PBSC transplantation. Bone Marrow Transplant 2012; 47:1010-2. 13. Shimizu N, Sakaida E, Ohwada C, et al. Mobilization of PBSCs in poor mobilizers with POEMS syndrome using G-CSF with plerixafor. Bone Marrow Transplant 2012; 47:1587-8.
Clinical Lymphoma, Myeloma & Leukemia February 2014
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Clinical Lymphoma, Myeloma & Leukemia Vol. 14, No. 1, 21-3
Autologous Stem Cell Transplantation for POEMS Syndrome Submitted: Dec 12, 2013; Accepted: Dec 12, 2013; Epub: Dec 22, 2013 Address for correspondence: Chiaki Nakaseko, Professor of Hematology, Department of Hematology, Chiba University Hospital 1-8-1 Inohana, Chuo-ku, Chiba, 260-8677, Japan E-mail contact: [email protected]
Table 1 Patient Characteristics Characteristic
Value
Gender Male Female
16 (70) 7 (30)
Age at ASCT (years) Median
52
Range
34-64
Interval to ASCT from diagnosis (mo) Median
9
Range
3e105
ECOG-PS at ASCT 0
12 (52)
3-4
11 (48) 20 (87)
IgA-l
11 (48)
IgG-l
8 (35)
IgG-l þ IgG-k History of previous therapies
POEMS syndrome is a rare plasma cell disorder characterized by polyneuropathy, organomegaly, endocrinopathy, M-protein, and skin changes associated with multiorgan involvement. The pathogenesis of POEMS syndrome is not well understood; however, overproduction of vascular endothelial growth factor (VEGF), probably secreted by plasma cells, has been considered responsible.1,2 Treatment was largely unsuccessful until the past decade.3,4 More recently, considerable progress has been made in interpreting the pathogenesis, clinical features, and diagnosis, and new treatment options have become available, including novel agents such as thalidomide, lenalidomide, and bortezomib, anti-VEGF antibody, and autologous stem cell transplantation (ASCT). ASCT has been reported to be a successful treatment strategy in patients < 65 years old. Jaccard et al5 reported the first case series of high-dose therapy and ASCT in patients with POEMS syndrome, in which 5 patients received high-dose melphalan (140-200 mg/m2) followed by ASCT. No deaths from drug toxicity occurred during mobilization or transplantation, and the neurologic symptoms and other manifestations of POEMS syndrome improved significantly, and all patients were alive and free of relapse after 36 months. In another study from the Mayo Clinic, 16 patients were treated with ASCT, and 14 evaluated patients achieved
0
1-2 Monoclonal proteins at diagnosis
Introduction
Figure 1 Efficiency of Stem Cell Mobilization in Patients With POEMS Syndrome. (A) Cyclophosphamide (CY) Plus Granulocyte Colony-Stimulating Factor (G-CSF). (B) G-CSF Alone
1 (4) 21 (91)
Number of previous regimens Median
2
Range
0-5
Types of previous treatment Thalidomide-based
15 (65)
Melphalan-based
7 (30)
Cyclophosphamide-based
3 (13)
Lenalidomide-based
1 (4)
Bortezomib-based
1 (4)
Bevacizumab
3 (13)
Intravenous immunoglobulin
5 (22)
Data presented as n (%), unless otherwise noted.
2152-2650/$ - see frontmatter ª 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.clml.2013.12.009
Clinical Lymphoma, Myeloma & Leukemia February 2014
- 21
ASCT for POEMS Syndrome Figure 2 Overall Survival (OS) and Progression-Free Survival (PFS) After Autologous Stem Cell Transplantation. (A) OS. (B) PFS. Progression was Defined as Elevated Vascular Endothelial Growth Factor Level (‡ 1000 pg/mL) and/or Clinical Relapse
substantial neurologic improvement or stabilization of neuropathic deficits, and 5 of 6 patients with a quantifiable serum M protein level achieved a hematologic complete response.6 Moreover, ASCT also improved organomegaly, extravascular volume overload, skin changes, and papilledema. However, ASCT was associated with a high risk of transplant-related toxicities in the early post-transplant period. Six patients (37.5%) were admitted to the intensive care unit, 5 required intubation and mechanical ventilation during mobilization and transplantation, and 1 (6.2%) died 115 days after ASCT. Recently, the long-term outcomes after ASCT for 59 patients with POEMS syndrome were reported by the same group and found that 92% of patients achieved clinical responses, and the most rapid responses were seen as soon as 100 days after transplantation.7 Maximal neurologic improvement was often not seen until 3 years afterward. After a median follow-up period of 45 months, 3 patients died, and the 5-year overall survival (OS) was 94%. One patient died, as mentioned, another died from relapse and disease progression 4 years after transplantation, and a third died of lymphoma unrelated to POEMS syndrome. Although 14 patients developed disease progression, most had hematologic, radiographic, or VEGF relapse, and only 1 patient had developed a clinical relapse. At our institution, 23 patients with POEMS syndrome have been treated with ASCT from 2004 to 2012.8-11 The patient characteristics are summarized in Table 1. The median age at ASCT was 52 years (range, 34-64), and the median interval from diagnosis to ASCT was 9 months. Regarding stem cell mobilization, the patients mobilized by cyclophosphamide plus granulocyte colonystimulating factor (G-CSF) achieved a greater number of CD34þ cells than those mobilized by G-CSF alone, although the proportion of poor mobilization was similar between the 2 groups (Fig. 1).12 Moreover, splenomegaly might be a predictive factor for poor mobilization. Three patients did not achieve sufficient peripheral blood stem cell mobilization, but the stem cells were successfully mobilized with plerixafor and G-CSF.13 Fifteen patients (65.2%) received thalidomide before ASCT, with significant improvements in serum VEGF levels and extravascular volume overload. Eleven patients presented with a poor performance status of 3 to 4 because
22
-
Clinical Lymphoma, Myeloma & Leukemia February 2014
of peripheral neuropathy. All patients achieved prompt engraftment after ASCT. Engraftment syndrome was observed in 5 patients (21.5%), but they all responded well to corticosteroid therapy. A complete hematologic response, defined by negative M-protein using immunofixation, was achieved in 65% of the patients. An improvement in clinical symptoms and a reduction in VEGF were observed in 22 patients (95.6%). No transplant-related death was observed. The overall neuropathy limitations score gradually and continuously improved after ASCT, and most of the patients became able to walk without support. Five patients experienced disease relapse. At a median observational period of 51 months, the 3- and 5-year OS and progression-free survival was 96% and 81% and 64.6% and 59.8%, respectively (Fig. 2). In conclusion, ASCT is an effective therapy for POEMS syndrome. With stabilization of the serum VEGF level with induction therapy, the transplant-related mortality was low and the periengraftment complications were manageable. However, a certain number of patients experienced disease relapse after ASCT. Therefore, all patients should be followed up carefully, and effective salvage strategies are required.
References 1. Watanabe O, Maruyama I, Arimura K, et al. Overproduction of vascular endothelial growth factor/vascular permeability factor is causative in Crow-Fukase (POEMS) syndrome. Muscle Nerve 1998; 21:1390-7. 2. Watanabe O, Arimura K, Kitajima I, Osame M, Maruyama I. Greatly raised vascular endothelial growth factor (VEGF) in POEMS syndrome. Lancet 1996; 347:702. 3. Kuwabara S, Hattori T, Shimoe Y, Kamitsukasa I. Long term melphalanprednisolone chemotherapy for POEMS syndrome. J Neurol Neurosurg Psychiatry 1997; 63:385-7. 4. Kuwabara S, Dispenzieri A, Arimura K, Misawa S, Nakaseko C. Treatment for POEMS (polyneuropathy, organomegaly, endocrinopathy, M-protein, and skin changes) syndrome. Cochrane Database System Rev 2012; 6: CD006828. 5. Jaccard A, Royer B, Bordessoule D, Brouet JC, Fermand JP. High-dose therapy and autologous blood stem cell transplantation in POEMS syndrome. Blood 2002; 99:3057-9. 6. Dispenzieri A, Moreno-Aspitia A, Suarez GA, et al. Peripheral blood stem cell transplantation in 16 patients with POEMS syndrome, and a review of the literature. Blood 2004; 104:3400-7. 7. D’Souza A, Lacy M, Gertz M, et al. Long-term outcomes after autologous stem cell transplantation for patients with POEMS syndrome (osteosclerotic myeloma): a single-center experience. Blood 2012; 120:56-62.
Chiaki Nakaseko 8. Kuwabara S, Misawa S, Kanai K, et al. Neurologic improvement after peripheral blood stem cell transplantation in POEMS syndrome. Neurology 2008; 71: 1691-5. 9. Kuwabara S, Misawa S, Kanai K, et al. Autologous peripheral blood stem cell transplantation for POEMS syndrome. Neurology 2006; 66:105-7. 10. Nakaseko C, Ohwada C, Shimizu N, et al. Long term outcomes of autologous stem cell transplantation for POEMS syndrome: a single center experience of 23 cases. Clin Lymphoma Myeloma Leuk 2013; 13:S46-7.
11. Nakaseko C. Autologous stem cell transplantation for POEMS syndrome. Clin Lymphoma Myeloma Leuk 2013; 13:S9-10. 12. Shimizu N, Nakaseko C, Sakaida E, et al. Factors associated with the efficiency of PBSC collection in POEMS syndrome patients undergoing autologous PBSC transplantation. Bone Marrow Transplant 2012; 47:1010-2. 13. Shimizu N, Sakaida E, Ohwada C, et al. Mobilization of PBSCs in poor mobilizers with POEMS syndrome using G-CSF with plerixafor. Bone Marrow Transplant 2012; 47:1587-8.
Clinical Lymphoma, Myeloma & Leukemia February 2014
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