Abstract
Castleman disease (CD) is a rare lymphoproliferative disease characterized by diverse clinical and pathologic features. Due to its rarity, there are limited studies comparing currently available therapies. The role of autologous stem cell transplantation (ASCT) in CD has not yet been established. In this paper, we describe the clinical characteristics, treatment choices, and outcomes in 34 Mayo Clinic patients diagnosed with multicentric CD from July 1, 2003 to April 30, 2018. Eighteen patients (53%) also met the criteria for POEMS, including 14 with the osteosclerotic variant. The first-line treatments included: steroid monotherapy (4), cytotoxic chemotherapy (6), rituximab alone (8) or with chemotherapy (2), anti-IL6 treatment (3), and ASCT (10). The median follow-up was 4.8 (range: 0.1–15.2) years. The 5- and 10-year overall survival rates were 84% and 71%, respectively. Sixteen patients received high-dose chemotherapy followed by ASCT during their disease course. Among those, 14 had multicentric CD associated with POEMS. There were no transplant-related deaths. All patients had at least a partial response to ASCT, most of whom achieved a complete response. The favorable outcomes seen with ASCT in this cohort suggest that transplantation may have a role in multicentric CD, particularly for patients with multicentric CD associated with POEMS.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 401-410 |
| Number of pages | 10 |
| Journal | American journal of hematology |
| Volume | 97 |
| Issue number | 4 |
| DOIs | |
| State | Published - Apr 2022 |
ASJC Scopus subject areas
- Hematology
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Multicentric Castleman disease : A single center experience of treatment with a focus on autologous stem cell transplantation. / Abdallah, Nadine H.; Habermann, Thomas; Buadi, Francis K.; Gertz, Morie A.; Lacy, Martha Q.; Rajkumar, S. Vincent; Dingli, David; Go, Ronald S.; Hayman, Suzanne R.; Kumar, Shaji K.; Kourelis, Taxiarchis; Warsame, Rahma; Kapoor, Prashant; Muchtar, Eli; Hwa, Yi L.; Fonder, Amie L.; Hobbs, Miriam A.; Lin, Yi; Leung, Nelson; Binder, Moritz; Siddiqui, Mustaqeem A.; Kyle, Robert A.; Witzig, Thomas E.; Dispenzieri, Angela.
In: American journal of hematology, Vol. 97, No. 4, 04.2022, p. 401-410.Research output: Contribution to journal › Article › peer-review
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TY - JOUR
T1 - Multicentric Castleman disease
T2 - A single center experience of treatment with a focus on autologous stem cell transplantation
AU - Abdallah, Nadine H.
AU - Habermann, Thomas
AU - Buadi, Francis K.
AU - Gertz, Morie A.
AU - Lacy, Martha Q.
AU - Rajkumar, S. Vincent
AU - Dingli, David
AU - Go, Ronald S.
AU - Hayman, Suzanne R.
AU - Kumar, Shaji K.
AU - Kourelis, Taxiarchis
AU - Warsame, Rahma
AU - Kapoor, Prashant
AU - Muchtar, Eli
AU - Hwa, Yi L.
AU - Fonder, Amie L.
AU - Hobbs, Miriam A.
AU - Lin, Yi
AU - Leung, Nelson
AU - Binder, Moritz
AU - Siddiqui, Mustaqeem A.
AU - Kyle, Robert A.
AU - Witzig, Thomas E.
AU - Dispenzieri, Angela
N1 - Funding Information: is a principal investigator of research studies for which Mayo Clinic has received funding from AbbVie, Takeda, Sanofi, Janssen, Karyopharm, Glaxo SmithKline, Regeneron Pharmaceuticals, Ichnos Sciences, and Amgen. He has served on the Medical advisory board meetings of Sanofi, Pharmacyclics, BeiGene, Cellectar, GSK, X4, and Karyopharm. received research funding from Celgene, Millennium Pharmaceuticals, Pfizer, and Janssen and received a travel grant from Pfizer. served as a consultant for Millennium Pharmaceuticals and received honoraria from Celgene, Millennium Pharmaceuticals, Onyx Pharmaceuticals, Novartis, GlaxoSmithKline, Prothena, Ionis Pharmaceuticals, and Amgen. received research funding from Celgene. serves on an advisory board for Takeda Pharmaceuticals. served as a consultant for Celgene, Millennium Pharmaceuticals, Onyx Pharmaceuticals, Janssen, and Bristol‐Myers Squibb and received research funding from Celgene, Millennium Pharmaceuticals, Novartis, Onyx Pharmaceuticals, AbbVie, Janssen, and Bristol‐Myers Squibb. received honorarium from Janssen and consultation fee from Protego (fee paid to institution). The remaining authors declare no competing financial interests. P.K. A.D. M.A.G. M.Q.L. N.L. S.K.K. E.M. Funding Information: P.K. is a principal investigator of research studies for which Mayo Clinic has received funding from AbbVie, Takeda, Sanofi, Janssen, Karyopharm, Glaxo SmithKline, Regeneron Pharmaceuticals, Ichnos Sciences, and Amgen. He has served on the Medical advisory board meetings of Sanofi, Pharmacyclics, BeiGene, Cellectar, GSK, X4, and Karyopharm. A.D. received research funding from Celgene, Millennium Pharmaceuticals, Pfizer, and Janssen and received a travel grant from Pfizer. M.A.G. served as a consultant for Millennium Pharmaceuticals and received honoraria from Celgene, Millennium Pharmaceuticals, Onyx Pharmaceuticals, Novartis, GlaxoSmithKline, Prothena, Ionis Pharmaceuticals, and Amgen. M.Q.L. received research funding from Celgene. N.L. serves on an advisory board for Takeda Pharmaceuticals. S.K.K. served as a consultant for Celgene, Millennium Pharmaceuticals, Onyx Pharmaceuticals, Janssen, and Bristol-Myers Squibb and received research funding from Celgene, Millennium Pharmaceuticals, Novartis, Onyx Pharmaceuticals, AbbVie, Janssen, and Bristol-Myers Squibb. E.M. received honorarium from Janssen and consultation fee from Protego (fee paid to institution). The remaining authors declare no competing financial interests. MCD is a rare disease characterized by marked heterogeneity in clinical characteristics and outcomes. The cohort described in this paper, including 34 Mayo Clinic patients diagnosed with MCD over a period of 15 years, portrays the heterogeneity of this disease and of therapy. Nearly half of patients received ASCT as part of their therapy during the course of their disease. There was no transplant-related mortality, and both TTNT and OS were excellent. Most of the patients undergoing ASCT had coexistent POEMS syndrome; two patients did not. The clinical phenotype of MCD patients with and without POEMS syndrome features were as expected: by definition, patients with MCD and POEMS were more likely to present with peripheral neuropathy, endocrinopathy, skin changes, bone lesions, and extracellular volume overload compared to patients with MCD without POEMS and were more likely to have a monoclonal protein in the serum and/or urine. Although patients with MCD and POEMS had a higher rate of pulmonary hypertension, hepatomegaly, and splenomegaly, the differences were not statistically significant, which may be attributed to small sample size. We did not observe differences in histology between the two groups. Laboratory differences were also observed and were consistent with prior studies,18 where the MCD without POEMS group had lower hemoglobin concentration and platelet counts, but higher levels of inflammatory markers (although not statistically significant) compared to patients with MCD and POEMS. In addition, lower albumin and higher lactate dehydrogenase (LDH) levels were observed in this group. The heterogeneity in clinical characteristics was paralleled by an assortment of treatments, reflecting the paucity of comparative studies to guide management of this rare disease. Variability in the timing of treatment initiation and TTNT was also seen, with some patients not requiring treatment for several years from the first-line treatment. The treatment armamentarium has expanded in the last decade; in the Mayo Clinic/University of Nebraska study spanning the period before 2002, patients primarily received steroids and alkylator-based treatments; only one subject received rituximab in second-line setting. The changes in treatment over time are reflected in a recent study evaluating treatments and treatment responses in patients with POEMS and Castleman's from 2000 to 2018 in Japan; among 14 evaluable patients, 10 received thalidomide-based treatment in the first-line setting, and 6 underwent ASCT after proteasome inhibitor- or immunomodulatory-based induction, with responses achieved in the vast majority.19 The treatment used in the Mayo cohort included cytotoxic chemotherapy, proteasome inhibitors, immunomodulatory agents, rituximab (alone or in combination with chemotherapy), and IL-6 targeting treatments. Furthermore, ASCT was utilized in approximately 50% of patients with treatment data, mainly those with MCD and POEMS. All patients who underwent transplant achieved at least a PR to treatment and there were no deaths within 100 days of transplantation, and patients who underwent transplant in the first-line setting had a 5-year TTNT of 83%. We observed improved TTNT in patients who underwent ASCT in the frontline setting, but without significant improvement in OS, which may be due to the small sample size and/or inadequate follow-up. Although, we did not observe significant differences in performance status at diagnosis between patients who underwent ASCT and those who did not (p?=.93), the risk of selection bias, where more fit patients undergo transplant, cannot be excluded. ASCT is considered one of the treatment modalities in management of POEMS syndrome, with high rates of clinical, hematologic, and VEGF responses, significant improvement in neuropathy, and long progression-free survival reported in retrospective studies.15?17,19?21 There are no randomized controlled studies comparing upfront treatment with ASCT versus other regimens, but a retrospective study by Zhao et al. comparing upfront ASCT, melphalan and dexamethasone combination, and lenalidomide and dexamethasone combination among 347 patients with POEMS treated over a 17-year period showed that ASCT was associated with higher response and 5-year progression-free survival rates especially among medium-high risk patients.21 Although results from this and other retrospective studies may be confounded by selection bias with more fit patients and those with lower risk undergoing ASCT, favorable long-term outcomes reported in these studies suggest that ASCT should be considered in the upfront setting in eligible patients with disseminated bone marrow involvement albeit with close monitoring for periengraftment syndrome.14,22 The role of ASCT in MCD without POEMS has not yet been established, with only a few case reports and mostly after failure of other regimens. These are summarized in Table?4 and include six cases of ASCT and two cases of allogeneic stem cell transplant. Responses with ASCT appeared to be durable, ranging from 15+ to 50+ months. In the present study, we highlighted the clinical course of the two patients with MCD without POEMS who underwent transplant; one patient underwent ASCT as first-line treatment followed by maintenance chemotherapy and was still alive and in CR at the last follow-up 9.4?months from his transplant. The second patient who underwent transplant as salvage therapy achieved a PR was still alive by last follow-up 1.2 years from transplant. 1. VAP ? resolution of Sx and LN regression ? 6?m 2. CHOP alternating with etoposide, vindesine, doxorubicin and prednisolone ? 8 courses ? LN regression. Response lasted 1?m 3. ASCTa ? CR 16 weeks after treatment 1. Prednisone 80 mg/day ? significant response lasting 5?months 2. CVP ? 6?cycles ? CR lasting 5?m ? follicular mixed lymphoma 3. ASCTb ? CR 1. Double-filtration plasmapheresis twice monthly and oral daily cyclophosphamide and prednisolone ? response lasting 6?m 2. ASCTc ? CR 1. R-CVP 6?cycles? CR 2. Rituximab and vinblastine ? 2?months ? ASCTd consolidation 1. R-CHOP ? 3?cycles followed by weekly Ritux ? 4 ? NR 2. Steroids 3. Tocilizumab at 2-wk intervals ? 17 doses ? CR ? ASCTa consolidation 1. Rituximab ? 4 doses ? NR 2. R-CHOP ? 6 courses ? NR 3. Tocilizumab ? 12 doses ? consolidation ASCTa 1. Rituximab weekly ? 4?cycles ? CR lasting 18 months 2. Rituximab ? 4?cycles ? CR ? 21 months 3. R-CHOP ? 6?cycles ? CR ? 1?month 4. R-Dexa-BEAM ? 2?cycles (intent for ASCT consolidation) ? PD 5. Rituximab and tocilizumab ? Sx resolved but no radiologic response, then PD after 5?cycles 6. AlloSCTe from a matched-unrelated donor 1. CHOEP ? 3?cycles ? NR 2. Hyper-CVAD-B ? NR 3. COAP ? NR 4. VAD ? 2 ? CR lasting 6?m 5. VAD ? NR 6. Bortezomib and dexamethasone ? 2?cycles ? PR 7. Allo-HSCTf from HLA-matched unrelated donor 1. Partial resection of a mediastinal mass, prednisone and tocilizumab 2. Lenalidomide and dexamethasone ? NR 3. ASCTg and Pomalidomide and dexamethasone consolidation ? 9 ? PR Abbreviations: ASCT, transplant; BEAM, carmustine, etoposide, cytarabine and melphalan; CHOEP, cyclophosphamide, vincristine, methylprednisolone, and epirubicin; CHOP, cyclophosphamide, doxorubicin, vincristine and prednisone; COAP, cyclophosphamide, vincristine, methylprednisolone, and cytarabine; CR, complete remission; CVP, cytoxan, vincristine, prednisone; HV, hyaline vascular; Hyper-CVAD-B, high-dose methotrexate and cytarabine; LN, lymph node; MCV, multicentric Castleman's disease; NA, not available; NHL, non-Hodgkin's lymphoma; PCV, plasma cell variant, Sx, symptoms; TMA, thrombotic microangiopathy; VAD, vincristine, doxorubicin, and dexamethasone; VAP, Prednisolone 70 mg/day ? 5 weeks, then vincristine 2?mg/week ? 3 weeks, then doxorubicin 30 mg/week ? 3 weeks. Conditioning with Melphalan 200 mg/m2. Conditioning with total body radiation 1200 cGy, etoposide 60 mg/kg and cyclophosphamide 100 mg/kg. Conditioning with Melphalan 140 mg/m2. Conditioning with etoposide, thiotepa, cytosine arabinoside, cyclophosphamide, and melphalan. Reduced intensity conditioning with fludarabine, cyclophosphamide, total body irradiation, and antithymocyte globulin. Conditioning with Busulfan, etoposide, and smoustin. Conditioning with carmustine, etoposide, cytarabine, and melphalan. This study is limited by its retrospective nature, limited sample size due to the rarity of this disease, missing data for certain laboratory values and missing treatment-related data, heterogeneous follow-up, and data obtained over a long period over which treatments have changed. Despite these limitations, the findings in our study are important to enhance understanding of this rare disease and in providing our experience in treatment with contemporary regimens, especially ASCT where experience is limited. The favorable outcomes seen with ASCT in this cohort and in previous reports suggest that transplant may have a role in MCD, including patients with MCD associated with POEMS. In summary, in this paper, we described the clinical characteristics, treatments, and outcomes of patients with MCD over a 15-year period, during which ASCT was utilized in a subset of patients. MCD should be recognized as a heterogeneous disease, demanding an individualized treatment approach at present.8,13 With improvement in patient selection and outcomes with transplantation over the recent years, ASCT may be considered a major treatment option in patients with MCD, especially those with the POEMS-variant. Future studies are needed to clarify the optimal timing and ideal candidates for ASCT in MCD. All patients authorized use of their electronic medical records for research purposes. This is a retrospective descriptive study, including patients diagnosed histologically with MCD from July 1, 2003 to April 30, 2018. Patients were identified using a prospectively maintained database at Mayo Clinic, and additional clinical and laboratory data were obtained by review of electronic medical records. All patients authorized the use of their medical record data for research purposes. The study was approved by our Institutional Review Board. We collected data from the time of diagnosis on clinical characteristics, histology, common serum and urine tests, serum and urine protein electrophoresis and immunofixation, and serological tests for human immunodeficiency virus (HIV), hepatitis B, and hepatitis C infections. Serum testing for HHV-8 was done using quantitative real-time polymerase chain reaction. To determine HHV-8 status on tissue specimens, immunoperoxidase studies were performed on paraffin sections of lymph node specimens using antibodies directed against HHV-8. We also collected data, when applicable, for concurrent rheumatologic disorders and associated clonal plasma cell disorders including coexistent POEMS syndrome defined based on established criteria.15 For patients with available treatment information, we collected data on first-line and subsequent lines of treatment, including radiation therapy, corticosteroids or other immunosuppressive agents, cytotoxic chemotherapy, rituximab, IL-6 inhibitors (siltuximab, tocilizumab), and/or ASCT. All patients undergoing ASCT were conditioned with high-dose melphalan; one was conditioned with BEAM (carmustine, etoposide, cytarabine, and melphalan) chemotherapy. Response to treatment was reported as documented by the treating physician: stable disease (SD), progressive disease (PD), partial response (PR), or complete response (CR). For patients treated after 2018, treatment response was based on consensus criteria developed by the international working group in 2018.13 Prior to that, response assessments were based on the treating physician's judgment of the composite clinical, biochemical (inflammatory makers, organ function tests) and radiographic responses (lymph node size by positron emission tomography/computed tomography) or response in terms of the predominant disease manifestation. For patients with POEMS and iMCD, POEMS response criteria were utilized if this was the predominant disease manifestation, using laboratory (plasma vascular endothelial growth factor), hematologic (M-spike, bone marrow plasma cells, serum/urine electrophoresis/immunofixation), radiologic, neurologic, and/or organ-specific response criteria, where applicable.14 The time to next treatment (TTNT) was defined as the time from start of the first-line treatment to the time of start of the second-line treatment. Patients who had not started a subsequent line of treatment were censored at their last follow-up. Overall survival (OS) was defined as time from diagnosis to death of any cause; patients who were alive at the last follow-up were censored at their last contact. Survival curves were estimated using the Kaplan?Meier method. All statistical analysis was performed using the JMP Pro Software SAS, NC. Publisher Copyright: © 2022 Wiley Periodicals LLC.
PY - 2022/4
Y1 - 2022/4
N2 - Castleman disease (CD) is a rare lymphoproliferative disease characterized by diverse clinical and pathologic features. Due to its rarity, there are limited studies comparing currently available therapies. The role of autologous stem cell transplantation (ASCT) in CD has not yet been established. In this paper, we describe the clinical characteristics, treatment choices, and outcomes in 34 Mayo Clinic patients diagnosed with multicentric CD from July 1, 2003 to April 30, 2018. Eighteen patients (53%) also met the criteria for POEMS, including 14 with the osteosclerotic variant. The first-line treatments included: steroid monotherapy (4), cytotoxic chemotherapy (6), rituximab alone (8) or with chemotherapy (2), anti-IL6 treatment (3), and ASCT (10). The median follow-up was 4.8 (range: 0.1–15.2) years. The 5- and 10-year overall survival rates were 84% and 71%, respectively. Sixteen patients received high-dose chemotherapy followed by ASCT during their disease course. Among those, 14 had multicentric CD associated with POEMS. There were no transplant-related deaths. All patients had at least a partial response to ASCT, most of whom achieved a complete response. The favorable outcomes seen with ASCT in this cohort suggest that transplantation may have a role in multicentric CD, particularly for patients with multicentric CD associated with POEMS.
AB - Castleman disease (CD) is a rare lymphoproliferative disease characterized by diverse clinical and pathologic features. Due to its rarity, there are limited studies comparing currently available therapies. The role of autologous stem cell transplantation (ASCT) in CD has not yet been established. In this paper, we describe the clinical characteristics, treatment choices, and outcomes in 34 Mayo Clinic patients diagnosed with multicentric CD from July 1, 2003 to April 30, 2018. Eighteen patients (53%) also met the criteria for POEMS, including 14 with the osteosclerotic variant. The first-line treatments included: steroid monotherapy (4), cytotoxic chemotherapy (6), rituximab alone (8) or with chemotherapy (2), anti-IL6 treatment (3), and ASCT (10). The median follow-up was 4.8 (range: 0.1–15.2) years. The 5- and 10-year overall survival rates were 84% and 71%, respectively. Sixteen patients received high-dose chemotherapy followed by ASCT during their disease course. Among those, 14 had multicentric CD associated with POEMS. There were no transplant-related deaths. All patients had at least a partial response to ASCT, most of whom achieved a complete response. The favorable outcomes seen with ASCT in this cohort suggest that transplantation may have a role in multicentric CD, particularly for patients with multicentric CD associated with POEMS.
UR - http://www.scopus.com/inward/record.url?scp=85122854668&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85122854668&partnerID=8YFLogxK
U2 - 10.1002/ajh.26466
DO - 10.1002/ajh.26466
M3 - Article
C2 - 35015310
AN - SCOPUS:85122854668
VL - 97
SP - 401
EP - 410
JO - American Journal of Hematology
JF - American Journal of Hematology
SN - 0361-8609
IS - 4
ER -