Coverage Policy Manual
Policy #: 2013036
Category: Medicine
Initiated: October 2013
Last Review: June 2018
  HDC & Autologous or Allogeneic Stem &/or Progenitor Cell Support- POEMS Syndrome

Description:
High-Dose Chemotherapy
High-dose chemotherapy (HDC) involves the administration of cytotoxic agents using doses several times greater than the standard therapeutic dose. In some cases, whole body or localized radiotherapy is also given and is included in the abbreviation HDC when applicable. The most significant adverse effect of HDC is marrow ablation. Thus, HDC is followed by infusion of hematopoietic stem cells to repopulate the bone marrow.
 
Typically, 1 course is given of HDC followed by stem-cell support (SCS). Two or more planned courses of HDC/SCS are referred to as “tandem” transplantation. Tandem transplants are typically administered at intervals of 2–6 months irrespective of the patient’s remission status but contingent on recovery from prior toxicity. Potential donors and sources of stem cells are described below.
 
Donor Types
 
Autologous - Autologous hematopoietic stem cells are harvested from patients prior to myeloablative therapy.
 
Syngeneic - Syngeneic hematopoietic stem cells are harvested from an identical twin. Their use is limited by the rarity of identical twins.
 
Allogeneic - Allogeneic hematopoietic stem cells are those harvested from a donor, after verifying the donor and recipient are well matched with respect to human leukocyte antigens (HLA). Allogeneic cells provide 2 theoretical advantages: the lack of tumor contamination associated with autologous stem cells, and the possibility of a beneficial graft-versus-tumor effect. Their disadvantage is the risk of graft-versus-host disease (GVHD), which increases with greater HLA disparity and recipient age.
 
Stem-Cell Sources
Hematopoietic stem cells can be collected from either the bone marrow or the peripheral blood of patients or donors. Stem cells may be harvested from the peripheral blood using a pheresis procedure. To increase the number of stem cells in the peripheral circulation (termed mobilization), patients providing autologous blood stem cells are pretreated with a course of chemotherapy or hematopoietic growth factors, or both. Donors providing allogeneic blood stem cells are mobilized with growth factors only.
 
Blood harvested from the umbilical cord and placenta shortly after delivery of neonates contains stem and progenitor cells. Although cord blood is an allogeneic source, these stem cells are antigenically naïve and apparently are associated with a lower incidence of GVHD.
 
POEMS Syndrome
POEMS syndrome (also known as osteosclerotic myeloma, Crow-Fukase syndrome, or Takasuki syndrome) is a rare, paraneoplastic disorder secondary to a plasma-cell dyscrasia (Dispenzieri, 2012; Dispenzieri, 2012). This complex, multiorgan disease was first described in 1938, but the acronym POEMS was coined in 1980, reflecting hallmark characteristics of the syndrome: polyneuropathy, organomegaly, endocrinopathy, M protein, and skin changes (Bardwick, 1980). No single test establishes the presence of POEMS syndrome. Its pathogenesis is undefined, although some evidence suggests it is mediated by imbalance of proinflammatory cytokines including interleukin-1β (IL-1β), IL-6, and tumor necrosis factor-α; vascular endothelial growth factor may also be involved (Dispenzieri, 2012; Dispenzieri, 2003). However, specific criteria have been established, and the syndrome may entail other findings in the constellation of signs and symptoms. Both major criteria and at least one of the minor criteria listed below are necessary for diagnosis (Dispenzieri, 2003).
 
Major Criteria:  
Polyneuropathy
Monoclonal plasma proliferative disorder
 
Minor Criteria:  
Sclerotic bone lesions
Castleman disease
Organomegaly (splenomegaly, hepatomegaly or lymphadenopathy)
Edema (edema, pleural effusion or ascites)
Endocrinopathy (adrenal, thyroid, pituitary, gonadal, parathyroid, pancreatic)
Skin changes (hyperpigmentation, hypertrichosis, plethora, hemangioma, white nails)
Papilledema
 
The prevalence of POEMS syndrome is unclear. A national survey in Japan showed a prevalence of about 0.3 per 100,000.(7) Other large series have been described in the United States (Dispenzieri, 2012; Dispenzieri, 2003; Dispenzieri, 2004) and in India (Singh, 2003). In general, patients with POEMS have a superior overall survival compared with that of MM, nearly 14 years in a large series from the Mayo Clinic (Dispenzieri, 2003). However, given the rarity of POEMS, no randomized controlled trials of therapies have been reported (Kuwabara, 2012). Numerous approaches have included ionizing radiation, plasmapheresis, intravenous immunoglobulin, interferon alfa, corticosteroids, alkylating agents, azathioprine, tamoxifen, transretinoic acid, and high-dose chemotherapy with autologous HSCT support (Dispenzieri, 2012; Dispenzieri, 2003). Optimal treatment involves eliminating the plasma cell clone, for example, by surgical excision or local radiation therapy for an isolated plasmacytoma, or systemic chemotherapy in patients with disseminated disease, such as medullary disease or multiple plasmacytomas. Given the underlying plasma cell dyscrasia of POEMS, newer approaches to MM, including bortezomib, lenalidomide, and thalidomide, are also under investigation (Dispenzieri, 2012; Dispenzieri, 2012).
 

Policy/
Coverage:
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
 
High dose chemotherapy with autologous bone marrow, stem cell, or progenitor cell support to treat disseminated POEMS syndrome meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes.
 
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
 
High dose chemotherapy with allogeneic bone marrow, stem cell, or progenitor cell support and tandem transplantations to treat POEMS syndrome do not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes.
 
For members with contracts without primary coverage criteria, high dose chemotherapy with allogeneic bone marrow, stem cell, or progenitor cell support and tandem transplantations to treat POEMS syndrome is considered investigational.  Investigational services are specific contract exclusions in most member benefit certificates of coverage.
 

Rationale:
A comprehensive source of information on treatment of POEMS is a Cochrane review that was published in 2012 (Kuwabara, 2012). The authors performed a broad literature search, including CENTRAL (2012, Issue 2), MEDLINE (January 1966 to February 2012), EMBASE (January 1980 to February 2012), and CINAHL Plus (January 1937 to February 2012). They identified no randomized controlled trials (RCTs), no quasi-RCTs, no historically controlled trials or trials with concurrent controls that met their study selection criteria. The Cochrane authors included 6 small series of patients (total n=57) who underwent autologous HSCT. Two-year survival rates ranged from 94-100%. The review authors indicated that if all published experience with autologous HSCT was pooled, transplant-related mortality would be 3 of 112 (2.7%). They caution that long-term outcomes with autologous HSCT have not been elucidated and require continuing study.
 
A second 2012 review article indicates case series suggest most patients achieve at least some neurologic and functional improvement using conditioning doses of melphalan ranging from 140 to 200 mg/m2  (Dispenzieri, 2012). Responses have been reported as durable but relapse occurs. Symptomatic progression has typically been reported as rare, with most progressions identified as rising vascular endothelial growth factor (VEGF) and radiographic. This author also reports that long-term outcomes with autologous HSCT are unclear given the sparse numbers. However, a single-center series published in 2012 from Mayo Clinic reported a 5-year OS of 94% and a PFS of 75% among 59 patients entered between 1999 and late 2011 (D’Souza, 2012).
 
National Comprehensive Cancer Network (NCCN) Practice Guidelines 2013
As of March 29, 2013, the NCCN has not proffered recommendations for the treatment of POEMS syndrome.
 
National Cancer Institute PDQ® Clinical Trial Database
A search of the National Cancer Institute’s online database of clinical trials on March 29, 2013 identified no clinical trials specifically addressing HSCT and a comparator in the treatment of POEMS syndrome.
 
Summary
No RCTs of hematopoietic stem-cell transplantation (HSCT) have been performed in patients with POEMS syndrome, nor is it likely such studies will ever be performed given the rarity of this condition. Available case reports and series are subject to selection bias and are heterogeneous with respect to treatment approaches and peri-transplant support. However, for autologous HSCT, a chain of indirect evidence suggests improved health outcomes, as several case studies have reported good clinical responses.
 
2014 Update
A literature search conducted through August 2014 did not reveal any new information that would prompt a change in the coverage statement. The key identified literature is summarized below.
 
The EBMT reported an analysis of 413 MM patients who received a related or unrelated RIC allogeneic HSCT for the treatment of relapse or disease progression after a prior autologous HSCT (Auner, 2013). Median age at RIC allogeneic HSCT was 54 years, and 45% of patients had undergone two or more prior autologous transplants. The median OS and PFS from the time of allogeneic transplantation for the entire population were about 25 and 10 months, respectively. Cumulative non-relapse mortality (NRM) at 1 year was about 22%. In a multivariate analysis, cytomegalovirus (CMV) seronegativity of both patient and donor was associated with significantly better PFS, OS and NRM. Patient-donor gender mismatch was associated with better PFS, fewer than two prior autologous transplants was associated with better OS, and shorter time from the first autologous HSCT to the RIC allogeneic HSCT was associated with lower NRM. These results suggest patient and donor CMV seronegativity represent key prognostic factors for outcome after RIC allogeneic HSCT for MM that relapses or progresses following one or more autologous transplants.
 
At 96 months in the EBMT trial, progression-free survival (PFS) and overall survival (OS) were 22% and
49% versus 12% (P = .027) and 36% (P = .030) with autologous/RIC-allogeneic and autologous HSCT, Respectively (Gahrton, 2013). The corresponding relapse/progression rate (RL) was 60% versus 82% (P = .0002). Nonrelapse mortality at 36 months was 13% versus 3% (P = .0004). In patients with the del(13) abnormality corresponding PFS and OS were 21% and 47% versus 5% (P = .026), and 31% (P = .154).43 Long-term outcome in patients with multiple myeloma was better with autologous/RIC-allogeneic HSCT as compared with autologous only and the autologous/RIC-allogeneic approach seemed to overcome the poor prognostic impact of del(13) observed after autologous transplantation.
 
The role of allogeneic HSCT remains controversial, in particular because of conflicting data from cooperative group trials, but also because of improvement in outcomes that have been observed with proteasome inhibitors, new immune modulatory agents, and the use of post-transplant maintenance therapy. These issues have recently been reviewed and summarized (Giralt, 2014; Giralt 2013).
 
Ongoing Clinical Trials
A search of the National Cancer Institute’s database of clinical trials identified the following Phase III trials
addressing HSCT and a comparator in the treatment of myeloma:
  • Second autologous HSCT versus low-dose consolidation therapy after relapse (NCT00747877)
  • Risk-adapted therapy (NCT00546988)
  • Tandem transplantation (NCT00670631)
  • Single autologous HSCT and maintenance versus tandem autologous HSCT and maintenance therapy (NCT01109004)
  •  Autologous versus allogeneic HSCT (Phase II/III; NCT00998270)
  •  Single versus tandem autologous HSCT (NCT01208766)
  • Conventional-dose induction therapy followed by maintenance versus high-dose therapy with autologous HSCT in the initial treatment of myeloma (NCT01191060)
  • Comparison of the drug combination of lenalidomide, bortezomib and dexamethasone with or without HSCT in newly diagnosed myeloma (NCT01208662).
 
A second recent series included 9 advanced POEMS syndrome patients, who had an Eastern Cooperative Oncology Group performance status score of 3 or 4, and were treated with high-dose melphalan therapy followed by autologous stem cell transplantation from 2004 to 2011 (Jang, 2014). Eight patients achieved an initial hematologic response, 4 of whom had complete responses. At a median follow-up of 44 months (range, 8-94 months), 7 patients were alive, with 3-year overall survival rate of 78%. There were no hematologic relapses in the survivors. One patient died of disease progression; the other died of pneumonia despite a hematologic response 3 months after autologous stem cell transplantation. All survivors achieved improvement in general performance status and in clinical response. The responses observed in these patients with advanced POEMS suggest it is a valid treatment option for such cases.
 
2015 Update
A literature search conducted through July 2015 did not reveal any new information that would prompt a change in the coverage statement.  
 
2017 Update
A literature search conducted using the Medline database through August 2017. There was no new information identified that would prompt a change in the coverage statement.
 
2018 Update
A literature search conducted using the MEDLINE database through May 2018 did not reveal any new information that would prompt a change in the coverage statement.
 
A 2017 review article by Autore et al evaluated potential mobilizing regimens for the collection of peripheral blood in patients with POEMS syndrome; reviewers also included a number of small studies evaluating the roles of vascular endothelial growth factor and lenalidomide in cases of POEMS syndrome (Autore, 2017). In 7 studies using high-dose melphalan followed by autologous HCT, clinical response rates ranged from 69.3% to 100%, and morbidity rates related to autologous HCT ranged from 21.7% to 42.9%. Four studies evaluating lenalidomide as a treatment of POEMS syndrome showed clinical response rates ranging from 78% to 100%, although the case series included were small. Reviewers reported mixed results on the use of granulocyte colony-stimulating factor with chemo-mobilization compared with granulocyte colony-stimulating factor alone in 11 case series, in which engraftment syndrome occurred in 11% to 37.5% of patients when reported.

CPT/HCPCS:
38240Hematopoietic progenitor cell (HPC); allogeneic transplantation per donor
38241Hematopoietic progenitor cell (HPC); autologous transplantation

References: Auner HW, Szydlo R, van Biezen A, et al.(2013) Reduced intensity-conditioned allogeneic stem cell transplantation for multiple myeloma relapsing or progressing after autologous transplantation: a study by the European Group for Blood and Marrow Transplantation. Bone Marrow Transplant. Nov 2013;48(11):1395-1400. PMID 23708704

Autore F, Innocenti I, Luigetti M, et al.(2017) Autologous peripheral blood stem cell transplantation and the role of lenalidomide in patients affected by poems syndrome. Hematol Oncol. Sep 15 2017. PMID 28913957

Bardwick PA, Zvaifler NJ, Gill GN et al.(1980) Plasma cell dyscrasia with polyneuropathy, organomegaly, endocrinopathy, M protein, and skin changes: the POEMS syndrome. Report on two cases and a review of the literature. Medicine (Baltimore) 1980; 59(4):311-22.

D'Souza A, Lacy M, Gertz M et al.(2012) Long-term outcomes after autologous stem cell transplantation for patients with POEMS syndrome (osteosclerotic myeloma): a single-center experience. Blood 2012; 120(1):56-62.

Dispenzieri A, Kyle RA, Lacy MQ et al.(2003) POEMS syndrome: definitions and long-term outcome. Blood 2003; 101(7):2496-506.

Dispenzieri A, Moreno-Aspitia A, Suarez GA et al.(2004) Peripheral blood stem cell transplantation in 16 patients with POEMS syndrome, and a review of the literature. Blood 2004; 104(10):3400-7.

Dispenzieri A.(2012) How I treat POEMS syndrome. Blood 2012; 119(24):5650-8.

Dispenzieri A.(2012) Long-term outcomes after autologous stem cell transplantation in patients with POEMS syndrome. Clin Adv Hematol Oncol 2012; 10(11):744-6.

Dispenzieri A.(2012) POEMS syndrome: update on diagnosis, risk-stratification, and management. Am J Hematol 2012; 87(8):804-14.

Gahrton G, Iacobelli S, Bjorkstrand B, et al.(2013) Autologous/reduced-intensity allogeneic stem cell transplantation vs autologous transplantation in multiple myeloma: long-term results of the EBMTNMAM2000 study. Blood. Jun 20 2013;121(25):5055-5063. PMID 23482933

Giralt S, Costa L, Schriber J, et al.(2014) Optimizing autologous stem cell mobilization strategies to improve patient outcomes: consensus guidelines and recommendations. Biol Blood Marrow Transplant. Mar 2014;20(3):295- 308. PMID 24141007

Jang IY, Yoon DH, Kim S, et al.(2014) Advanced POEMS syndrome treated with high-dose melphalan followed by autologous blood stem cell transplantation: a single-center experience. Blood Res. Mar 2014;49(1):42-48. PMID 24724066

Kuwabara S, Dispenzieri A, Arimura K et al.(2012) Treatment for POEMS (polyneuropathy, organomegaly, endocrinopathy, M-protein, and skin changes) syndrome. Cochrane Database Syst Rev 2012; 6:CD006828.

Nasu S, Misawa S, Sekiguchi Y et al.(2012) Different neurological and physiological profiles in POEMS syndrome and chronic inflammatory demyelinating polyneuropathy. J Neurol Neurosurg Psychiatry 2012; 83(5):476-9.

Singh D, Wadhwa J, Kumar L et al.(2003) POEMS syndrome: experience with fourteen cases. Leuk Lymphoma 2003; 44(10):1749-52.


Group specific policy will supersede this policy when applicable. This policy does not apply to the Wal-Mart Associates Group Health Plan participants or to the Tyson Group Health Plan participants.
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