Long‐term durable efficacy of autologous stem cell transplantation in POEMS syndrome

POEMS syndrome is a rare paraneoplastic phenomenon associated with underlying monoclonal plasma cell clones. The diagnosis is established with the presence of the following: (a) two mandatory major criteria (polyradiculoneuropathy, monoclonal gammopathy), (b) one other major criteria (sclerotic bone lesions, Castleman disease, high serum vascular endothelial growth factor [VEGF] levels) and, (c) one minor criteria (endocrinopathy, organomegaly, skin changes, papilledema, extravascular volume overload, and thrombocytosis/polycythemia).1 Due to its rarity, the standard of care is not well established in the management of the disease. Recently, multiple studies have reported on the durable responses with autologous hematopoietic stem cell transplantation (auto-HCT),2-8 which is accepted as standard treatment approach in eligible patients.9 We had previously reported on the role of auto-HCT in a smaller cohort of POEMS patients.10 Here, we present an updated analysis in a larger cohort of POEMS patients who were treated at our institution. We retrospectively collected data on POEMS patients who underwent auto-HCT at our institution between January 1999 and June 2018. Patients lost to follow-up were censored on the day of the last follow-up visit. Patients were evaluated for responses (hematologic, radiologic and clinical), toxicity, progression-free survival (PFS) and overall survival (OS). Hematologic response was defined by the International Myeloma Working Group (IMWG) criteria. Radiological data for bone lesions were assessed with bone surveys and Positron Emission Tomography/Computed Tomography scans. The improvement was defined by an improvement in performance status, subjective perception of neuropathy symptoms by patients, laboratory values, and physical examination findings. Toxicities were defined per the Common Terminology Criteria for Adverse Events version 4.0 (CTCAEv4.0). Sixteen patients (13 males, 3 females) with POEMS syndrome received a total of 17 auto-HCTs. One patient underwent auto-HCT twice for relapsed disease. The median age at auto-HCT was 48 years (range: 18-75). Patient characteristics are described in detail in Table 1 and Supporting Information Table S1. Among patients with available data (n = 7), the mean serum VEGF level pre-transplant was 389 pg/mL (268-1622). The median number of CD34+ stem cells collected was 3.43 × 106 cells/kg (range 1.73-6.5). Median follow-up among surviving patients is 52 months (5-120 months). One-year transplant-related mortality was 0%. Engraftment syndrome (ES) requiring corticosteroid use was seen in 1 (6%) patient only. The chemotherapy-related gastrointestinal toxicities were mostly graded 1 or 2. The other toxicities during immediate post-transplant period were febrile neutropenia (FN) in 5 (29%), pulmonary edema in 4 (24%), volume overload/leg edema in 4 (24%), congestive heart failure exacerbation in 2 (12%), skin rash in 2 (12%), superficial thrombophlebitis in 1 (6%), deep venous thrombosis/pulmonary embolism in 1 (6%), fungal pneumonia in 1 (6%), cardiovascular shock in 1 (6%), and transaminase elevation in 1 (6%). All patients fully recovered from the toxicities. Out of 17 auto-HCTs, seven patients received autologous stem cell infusion on an outpatient basis. Out of these seven patients, 4 needed in-patient hospitalization for management of toxicities (3 for FN, one for syncope). For the remaining 10 auto-HCTs, the median length of hospitalization was 18 days (range 12-37). Fourteen out of 16 patients are alive at last follow-up. One patient died 6 years after his auto-HCT secondary to gastrointestinal bleeding unrelated to his underlying disease, and the second patient died 11 years post-auto-HCT of unknown cause. The response rates, as per the IMWG criteria, were as follows: 5 (29.4%) complete responses, 2 (11.7%) very good partial response, and 5 (29.4%) partial responses. At the time of diagnosis, five patients had normal serum protein electrophoresis, and monoclonal gammopathy was detectable only by immunofixation (IFE). Among these five patients, four (23.5%) were persistent IFE positive post-transplant, but all showed clinical improvement and were labeled as “non-hematological” responders (Supporting Information Table S1). No patient received post-transplant maintenance therapy. The mean serum VEGF levels improved from 389 pg/mL before transplant to 35 pg/mL (31-86) post-transplant. All 16 patients had a complete or partial resolution of their clinical symptoms after auto-HCT as described in detail in Supporting Information Table S1. Importantly, a complete hematologic response was not required for significant clinical response. One patient had his neuropathy evaluated by electromyography/nerve conduction study 3 years post-transplant and abnormalities seen before transplant had completely resolved. One patient who received two separate transplants had symptom free remission for 4.5 years after his first auto-HCT. The second transplant resulted in partial resolution of clinical symptoms for a year, but his symptoms returned soon after that. The median PFS and OS have not been reached yet. Four-year PFS and OS rates for the entire cohort were 80.2% and 100%, respectively. Ten-year PFS and OS rates were 59.4% and 80%, respectively. In these updated results, we show an impressive OS, durable PFS, and significant improvement in symptoms in patients with POEMS syndrome who received an auto-HCT. Our data are consistent with previous literature reporting equally favorable outcomes in selected patients receiving auto-HCT (Supporting Information Table S2). The rate of ES in previous studies has varied from 12% to 37%, probably due to the different criteria used to define ES. The incidence of ES in our cohort was very low. The reason behind this is not clear. Previous reports had suggested that the use of cyclophosphamide mobilization can lower the ES rate.11, 12 However, in our cohort, only one patient had cyclophosphamide-based mobilization. The other toxicities related to autologous transplant were mostly manageable, and there was no transplant-related death in our cohort. Our case series adds to the growing literature supporting the use of auto-HCT in POEMS syndrome, which leads to durable responses, significant improvement in symptoms, and recovery of functional status. Further studies are needed to investigate the role of novel drugs such as anti-CD38 monoclonal antibodies, immunomodulatory drugs and proteasome inhibitors in combination with auto-HCT. Nothing to report. Table S1. Supplementary - Individual clinical presentation of each patient and clinical (subjective) and hematological responses. Table S2. Previous reports documenting responses to auto-HCT in patients with POEMS syndrome. Figure S1. Kaplan Meier curve representing PFS and OS of our cohort. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.