High-Dose Melphalan and Autologous Hematopoietic Stem Cell Transplantation in Primary Amyloidosis: Single-Center Results G. Charlinski, M. Ziarkiewicz, P. Boguradzki, E. Wiater, T. Torosian, J. Dwilewicz-Trojaczek, and W. Wiktor-Jedrzejczak* Medical University of Warsaw, Department of Hematology, Oncology and Internal Diseases, Warsaw, Poland
ABSTRACT Background. Systemic immunoglobulin light-chain amyloidosis (AL) is a plasma cell dyscrasia resulting in multisystem organ failure and death. Autologous hematopoietic stem-cell transplantation (ASCT) has been widely used to treat patients with AL. However, treatment-related mortality remains high and reported series are subject to selection bias. Methods. To define the role of patient selection in stem cell transplantation, we evaluated 24 consecutive AL patients transplanted at our center. Results. Complete hematologic response was achieved in all 20 patients surviving >100 days posttransplantation. The 1-year overall survival (OS) rate after ASCT was 78.5%. The 5- and 10-year progression-free and OS rates were 57% and 47%, respectively. Treatmentrelated deaths owing to cardiovascular problems occurred in 16% of cases. Conclusion. ASCT for AL amyloidosis can be safely performed in experienced transplantation centers, and increased risk is associated mainly with cardiovascular system involvement.
S
YSTEMIC IMMUNOGLOBULIN light-chain amyloidosis (AL) is a neoplastic disease belonging to plasma cell dyscrasias, which is characterized by a presence of malignant clone of plasma cells producing a pathologic protein, namely the immunoglobulin light chain or its fragment. Pathologic protein produces amyloid fibrils in the tissues adopting the structure of a beta sheet, and their deposition deteriorates function of involved tissues and organs [1]. AL is the most common form of systemic amyloidosis with the incidence of approximately 5e12 persons per million population per year and is associated with particularly poor outcome with median survival of 12 months [2,3]. High-dose melphalan (HDM) with subsequent autologous stem cell transplantation (ASCT) was introduced to the treatment of AL based on good results of this treatment modality in a more common plasma cell dyscrasia, namely, multiple myeloma. However, unlike in multiple myeloma treatment-related mortality remains high and varies depending on the treating center between 13% (in tertiary referral centers) and 43% [4e6]. Therefore despite the fact that hematologic and organ responses range between 16% and 67% and 25% and 60% of patients, respectively, and
median overall survival (OS) reaches 5 years [7] and that these results are better than in nontransplanted patients it is used only in 25% of them [4]. The aim of this analysis was to compare our results with previously published data to identify factors that might have contributed to the unfavorable outcome in some patients. PATIENTS AND METHODS Our retrospective analysis included 24 consecutive AL patients treated with HDM, administered intravenously (IV), with subsequent ASCT, at the Department of Haematology, Oncology and Internal Diseases, Medical University of Warsaw, between December 2001 and May 2013. The diagnosis of AL was made according to valid diagnostic criteria [8]. All obtained tissue specimens underwent Congo red staining as well as immunohistochemical staining. Patients with the diagnosis of smoldering or symptomatic plasma cell myeloma, as well as other lymphoproliferative diseases with concomitant AL, were excluded from the analysis. The study *Address correspondence to Wieslaw Wiktor-Jedrzejczak, MD, Professor of Medicine, 1a Banacha Street, 02-097 Warsaw, Poland. E-mail: [email protected]
ª 2014 by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710
0041-1345/14 http://dx.doi.org/10.1016/j.transproceed.2014.09.053
Transplantation Proceedings, 46, 2877e2881 (2014)
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group received no remission induction protocol before HDM/ASCT. The observation in the study was terminated on August 31, 2013. We included 24 consecutive AL patients in this retrospective analysis. There were 13 males and 11 females aged 30e68 years (median, 56). The clinical characteristic of the study group is presented in Table 1. At the time of qualification to HDM/ASCT, 20 of the 24 patients (83.5%) had Eastern Cooperative Oncology Group (ECOG) performance status of 1. In 12 patients (50%), single organ involvement was diagnosed, whereas another 12 patients (50%) had amyloid deposits in 2 organs. Renal involvement was detected in 13 patients (54%), macroglosia in 3 (12.5%), cardiac involvement in 3 (12.5%), hepatic involvement in 3 (12.5%), peripheral nervous system involvement in 2 (8.5%), gastrointestinal tract involvement in 2 (8.5%), and pulmonary amyloid deposits 1 (4.2%). Serum monoclonal light chain l was detected in 13 patients (53%) and serum monoclonal light chain k was found in 11 (47%). The median percentage of plasma cells in the bone marrow was 6% (range, 5%e17%). Before ASCT treatment, 1 patient (4.2%) required renal replacement therapy. In another patient, liver transplantation owing to AL-related hepatic insufficiency was performed before ASCT. The median time from the diagnosis of AL to ASCT was 3 months (range, 1e17). Stem cells were collected from the peripheral blood after mobilization using cyclophosphamide and granulocyte colony stimulating factor (G-CSF) in 17 patients and G-CSF alone in the dose of 2 5 mg/kg body weight (BW) in 7 patients. Conditioning Table 1. Patient Characteristics Characteristic
Patient, n (%) Sex, n (%) Male Female Age (y), median (range) Performance status ECOG, median (range) Mayo Clinic stage at diagnosis, n (%) I II III No. of organs involved, n (%) 1 2 % BM plasma cells, median (range) Light chain isotype, n (%)
k l Hemoglobin (g/dL), median (range) Creatinine (mg/dL), median (range) Albumin (g/dL), median (range) Alkaline phosphatase (U/L), median (range) NT-pro-BNP (pg/mL), median (range) Troponin-T (ng/mL), median (range) Interventricular septal thickness (mm), median (range) Dose of melphalan (mg/m2), n (%) 200 100e140 Treatment Auto-SCT Tandem auto-SCT
Value
24 (100) 13 11 56 1 18 10 3 5
(54) (46) (30e68) (0e3) (100) (55.5) (16.7) (27.8)
12 (50) 12 (50) 6 (65 years old. Overall, 16 patients (66.5%) received the full high dose of melphalan (200 mg/m2), 6 patients received the intermediate dose (140 mg/m2), and 2 patients received the low dose (100 mg/m2). Five patients (20.8%) underwent tandem ASCT; 2 received 2 cycles of melphalan 200 mg/m2, 2 received 2 cycles of melphalan 140 mg/m2, and 1 received the dose of 200 mg/m2, followed by a second cycle with 140 mg/m2.
Eligibility for Transplantation Eligibility criteria for ASCT in AL patients included age 20 G/L) was seen 13 days (median) after ASCT (range, 11e41). The most frequent nonhematologic serious adverse event (CTC AE grade 3 or 4) was oral mucositis, which was diagnosed in 12 patients (50%).
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11 patients (55%) with PR; 1 patient (5%) had stable disease and in another (5%) progressive disease was established. Response was analyzed separately in 5 patients who underwent tandem ASCT. After the second transplantation, in 2 patients response status was improved form PR to CR, whereas in the remaining 3 patients no improvement was noted in comparison with the results achieved after the first ASCT. Overall, in the entire evaluable group, irrespective of the number of HDM/ ASCT, 9 patients obtained CR (45%), 9 patients obtained PR (45%), 1 patient had stable disease (5%), and 1 patient had progression of disease (5%). Overall, median duration of response after HDM/ASCT was 26.5 months (range, 3e141). In the subgroup of complete responders, the median duration of response was 28 months (range, 3.5e141), whereas in the group with response
ABSTRACT Background. Systemic immunoglobulin light-chain amyloidosis (AL) is a plasma cell dyscrasia resulting in multisystem organ failure and death. Autologous hematopoietic stem-cell transplantation (ASCT) has been widely used to treat patients with AL. However, treatment-related mortality remains high and reported series are subject to selection bias. Methods. To define the role of patient selection in stem cell transplantation, we evaluated 24 consecutive AL patients transplanted at our center. Results. Complete hematologic response was achieved in all 20 patients surviving >100 days posttransplantation. The 1-year overall survival (OS) rate after ASCT was 78.5%. The 5- and 10-year progression-free and OS rates were 57% and 47%, respectively. Treatmentrelated deaths owing to cardiovascular problems occurred in 16% of cases. Conclusion. ASCT for AL amyloidosis can be safely performed in experienced transplantation centers, and increased risk is associated mainly with cardiovascular system involvement.
S
YSTEMIC IMMUNOGLOBULIN light-chain amyloidosis (AL) is a neoplastic disease belonging to plasma cell dyscrasias, which is characterized by a presence of malignant clone of plasma cells producing a pathologic protein, namely the immunoglobulin light chain or its fragment. Pathologic protein produces amyloid fibrils in the tissues adopting the structure of a beta sheet, and their deposition deteriorates function of involved tissues and organs [1]. AL is the most common form of systemic amyloidosis with the incidence of approximately 5e12 persons per million population per year and is associated with particularly poor outcome with median survival of 12 months [2,3]. High-dose melphalan (HDM) with subsequent autologous stem cell transplantation (ASCT) was introduced to the treatment of AL based on good results of this treatment modality in a more common plasma cell dyscrasia, namely, multiple myeloma. However, unlike in multiple myeloma treatment-related mortality remains high and varies depending on the treating center between 13% (in tertiary referral centers) and 43% [4e6]. Therefore despite the fact that hematologic and organ responses range between 16% and 67% and 25% and 60% of patients, respectively, and
median overall survival (OS) reaches 5 years [7] and that these results are better than in nontransplanted patients it is used only in 25% of them [4]. The aim of this analysis was to compare our results with previously published data to identify factors that might have contributed to the unfavorable outcome in some patients. PATIENTS AND METHODS Our retrospective analysis included 24 consecutive AL patients treated with HDM, administered intravenously (IV), with subsequent ASCT, at the Department of Haematology, Oncology and Internal Diseases, Medical University of Warsaw, between December 2001 and May 2013. The diagnosis of AL was made according to valid diagnostic criteria [8]. All obtained tissue specimens underwent Congo red staining as well as immunohistochemical staining. Patients with the diagnosis of smoldering or symptomatic plasma cell myeloma, as well as other lymphoproliferative diseases with concomitant AL, were excluded from the analysis. The study *Address correspondence to Wieslaw Wiktor-Jedrzejczak, MD, Professor of Medicine, 1a Banacha Street, 02-097 Warsaw, Poland. E-mail: [email protected]
ª 2014 by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710
0041-1345/14 http://dx.doi.org/10.1016/j.transproceed.2014.09.053
Transplantation Proceedings, 46, 2877e2881 (2014)
2877
2878
CHARLINSKI, ZIARKIEWICZ, BOGURADZKI ET AL
group received no remission induction protocol before HDM/ASCT. The observation in the study was terminated on August 31, 2013. We included 24 consecutive AL patients in this retrospective analysis. There were 13 males and 11 females aged 30e68 years (median, 56). The clinical characteristic of the study group is presented in Table 1. At the time of qualification to HDM/ASCT, 20 of the 24 patients (83.5%) had Eastern Cooperative Oncology Group (ECOG) performance status of 1. In 12 patients (50%), single organ involvement was diagnosed, whereas another 12 patients (50%) had amyloid deposits in 2 organs. Renal involvement was detected in 13 patients (54%), macroglosia in 3 (12.5%), cardiac involvement in 3 (12.5%), hepatic involvement in 3 (12.5%), peripheral nervous system involvement in 2 (8.5%), gastrointestinal tract involvement in 2 (8.5%), and pulmonary amyloid deposits 1 (4.2%). Serum monoclonal light chain l was detected in 13 patients (53%) and serum monoclonal light chain k was found in 11 (47%). The median percentage of plasma cells in the bone marrow was 6% (range, 5%e17%). Before ASCT treatment, 1 patient (4.2%) required renal replacement therapy. In another patient, liver transplantation owing to AL-related hepatic insufficiency was performed before ASCT. The median time from the diagnosis of AL to ASCT was 3 months (range, 1e17). Stem cells were collected from the peripheral blood after mobilization using cyclophosphamide and granulocyte colony stimulating factor (G-CSF) in 17 patients and G-CSF alone in the dose of 2 5 mg/kg body weight (BW) in 7 patients. Conditioning Table 1. Patient Characteristics Characteristic
Patient, n (%) Sex, n (%) Male Female Age (y), median (range) Performance status ECOG, median (range) Mayo Clinic stage at diagnosis, n (%) I II III No. of organs involved, n (%) 1 2 % BM plasma cells, median (range) Light chain isotype, n (%)
k l Hemoglobin (g/dL), median (range) Creatinine (mg/dL), median (range) Albumin (g/dL), median (range) Alkaline phosphatase (U/L), median (range) NT-pro-BNP (pg/mL), median (range) Troponin-T (ng/mL), median (range) Interventricular septal thickness (mm), median (range) Dose of melphalan (mg/m2), n (%) 200 100e140 Treatment Auto-SCT Tandem auto-SCT
Value
24 (100) 13 11 56 1 18 10 3 5
(54) (46) (30e68) (0e3) (100) (55.5) (16.7) (27.8)
12 (50) 12 (50) 6 (65 years old. Overall, 16 patients (66.5%) received the full high dose of melphalan (200 mg/m2), 6 patients received the intermediate dose (140 mg/m2), and 2 patients received the low dose (100 mg/m2). Five patients (20.8%) underwent tandem ASCT; 2 received 2 cycles of melphalan 200 mg/m2, 2 received 2 cycles of melphalan 140 mg/m2, and 1 received the dose of 200 mg/m2, followed by a second cycle with 140 mg/m2.
Eligibility for Transplantation Eligibility criteria for ASCT in AL patients included age 20 G/L) was seen 13 days (median) after ASCT (range, 11e41). The most frequent nonhematologic serious adverse event (CTC AE grade 3 or 4) was oral mucositis, which was diagnosed in 12 patients (50%).
2879
11 patients (55%) with PR; 1 patient (5%) had stable disease and in another (5%) progressive disease was established. Response was analyzed separately in 5 patients who underwent tandem ASCT. After the second transplantation, in 2 patients response status was improved form PR to CR, whereas in the remaining 3 patients no improvement was noted in comparison with the results achieved after the first ASCT. Overall, in the entire evaluable group, irrespective of the number of HDM/ ASCT, 9 patients obtained CR (45%), 9 patients obtained PR (45%), 1 patient had stable disease (5%), and 1 patient had progression of disease (5%). Overall, median duration of response after HDM/ASCT was 26.5 months (range, 3e141). In the subgroup of complete responders, the median duration of response was 28 months (range, 3.5e141), whereas in the group with response
