Clinical Policy Title: Bone marrow transplant for children with hyper IgM disorder

Transcription

1 Clinical Policy Title: Bone marrow transplant for children with hyper IgM disorder Clinical Policy Number: Effective Date: July 1, 2016 Initial Review Date: April 20, 2016 Most Recent Review Date: April 19, 2017 Next Review Date: April 2018 Policy contains: Hyper IgM syndrome. CD40 mutation. CD40 ligand mutation. Related policies: CP# Bone marrow transplant ABOUT THIS POLICY: AmeriHealth Caritas Pennsylvania has developed clinical policies to assist with making coverage determinations. AmeriHealth Caritas Pennsylvania s clinical policies are based on guidelines from established industry sources, such as the Centers for Medicare & Medicaid Services (CMS), state regulatory agencies, the American Medical Association (AMA), medical specialty professional societies, and peer-reviewed professional literature. These clinical policies along with other sources, such as plan benefits and state and federal laws and regulatory requirements, including any state- or plan-specific definition of medically necessary, and the specific facts of the particular situation are considered by AmeriHealth Caritas Pennsylvania when making coverage determinations. In the event of conflict between this clinical policy and plan benefits and/or state or federal laws and/or regulatory requirements, the plan benefits and/or state and federal laws and/or regulatory requirements shall control. AmeriHealth Caritas Pennsylvania s clinical policies are for informational purposes only and not intended as medical advice or to direct treatment. Physicians and other health care providers are solely responsible for the treatment decisions for their patients. AmeriHealth Caritas Pennsylvania s clinical policies are reflective of evidence-based medicine at the time of review. As medical science evolves, AmeriHealth Caritas Pennsylvania will update its clinical policies as necessary. AmeriHealth Caritas Pennsylvania s clinical policies are not guarantees of payment. Coverage policy AmeriHealth Caritas Pennsylvania considers the use of bone marrow transplant for children with hyper IgM disorder to be clinically proven and, therefore, medically necessary. Limitations: None. Alternative covered services: None. Background 0

2 The hyper IgM syndrome is a rare, inherited immune deficiency disorder resulting from defects in the CD40 ligand (CD40L)/CD40-signaling pathway. It manifests clinically as a severe life-threatening infection due to defects in humoral and cell-mediated immunity (e.g., fungal infections, opportunistic infections, or bacterial infections). The diagnosis of hyper IgM syndrome is suggested by flow cytometry showing normal T-cell numbers in the presence of serum IgM that is elevated (or even normal) with reductions in serum IgG and IgA. Diagnosis is confirmed with genetic studies, which show mutation in either CD40 or CD40L. The X-linked hyper IgM disorder is the most frequent type, is caused by mutations in the CD40L gene, and is regarded as a combined T and B immunodeficiency. The long-term outcome of X-linked hyper-igm syndrome caused by mutations in CD40LG is poor, and the only curative treatment is hematopoietic stem cell transplantation (HSCT). Searches AmeriHealth Caritas Pennsylvania searched PubMed and the databases of: UK National Health Services Center for Reviews and Dissemination. Agency for Healthcare Research and Quality s National Guideline Clearinghouse and other evidence-based practice centers. The Centers for Medicare & Medicaid Services (CMS). We conducted searches on March 1, Search terms were: "CD40 (MeSH)," "CD40 ligand (MeSH)," and "hyper IgM syndrome." We included: Systematic reviews, which pool results from multiple studies to achieve larger sample sizes and greater precision of effect estimation than in smaller primary studies. Systematic reviews use predetermined transparent methods to minimize bias, effectively treating the review as a scientific endeavor, and are thus rated highest in evidence-grading hierarchies. Guidelines based on systematic reviews. Economic analyses, such as cost-effectiveness, and benefit or utility studies (but not simple cost studies), reporting both costs and outcomes sometimes referred to as efficiency studies which also rank near the top of evidence hierarchies. Findings A study (Al-Saud, 2015) retrospectively reviewed and analyzed data from five patients who received HSCT for hyper IgM disorder at King Faisal Specialist Hospital & Research Centre in Riyadh, Saudi Arabia, between 2005 and Five patients underwent HSCT from a human leukocyte antigen (HLA) matched sibling donor at a median age of 41 months (range, nine 72 months). The median time from diagnosis to transplantation was 30 months (range, five 58 months). The survival rate was 100 percent, with a 1

3 median follow-up of 69 months (range, months). Four patients showed complete immune recovery with positive CD40L expression in activated T-cells. The authors concluded that HSCT from an HLA-matched sibling donor is effective at treating hyper IgM disorder. A retrospective analysis (Allewelt, 2015) of seven patients who underwent allogeneic HSCT for hyper IgM disorder at Duke University Medical Center found that all patients are alive at a median follow-up of 9.7 years (range ) post-transplantation. The median age at transplant was 5.2 years (range ). None of the patients had active hepatic or pulmonary disease immediately prior to transplant, but all had a history of serious infections. Post-transplantation complications included veno-occlusive disease, hemorrhagic cystitis, adenoviremia, and cryptosporidium recurrence in one patient each. The authors concluded that allogeneic HSCT results in excellent survival and sustained immune reconstitution in patients with CD40L deficiency. A Japanese study (Mitsui-Sekinaka, 2015) retrospectively analyzed data from 56 patients with hyper IgM disorder, including 29 patients who received HSCT. The long-term survival rate was poor in those not undergoing HSCT (overall survival rate at 40 years of age, 28.2 percent). The overall survival rate of patients undergoing HSCT (n = 29) was significantly higher than that of those not undergoing HSCT (n = 27, P =.0231). Moreover, event-free and disease-free survival rates were significantly greater in patients 5 years old or younger at the time of transplantation (n = 14) than in older patients (n = 15). The authors concluded that HSCT improved the outcomes of patients with hyper IgM disorder and that an age of 5 years or younger was optimal for the timing of HSCT because persistent infections and severe organ damage were frequently observed in patients older than 6 years. A case study (Tsai, 2015) reported an 18-year-old male who was diagnosed initially with hypogammaglobulinemia in infancy, but developed repeated pneumonia, sepsis, cellulitis, perianal abscess, pericarditis, and bronchiectasis, despite regular intravenous immunoglobulin replacement therapy. The patient died at age 18 years due to pneumonia and tension pneumothorax. Post-mortem mutation analysis revealed CD40L gene mutation within Exon 5 at nucleotide position 476 (cdna 476G > A). This nonsense mutation predicted a tryptophan codon (TGG) change to a stop codon (TGA) at position 140 (W140X), preventing CD40L protein expression. Sequence analysis in the family confirmed a de novo mutation. A second case study (Tsai, 2015) of a 6-month-old male infant presented as Pneumocystis jiroveci pneumonia and acute respiratory distress syndrome. Gene analysis of the CD40L gene revealed G to C substitution in intron 4 (c G > C) and that the mother was a carrier. HSCT was arranged for the patient as therapeutic management in the second case. Wang (2014) retrospectively analyzed the clinical and molecular features of 20 Chinese patients diagnosed with hyper IgM disorder and followed up in hospitals affiliated to Shanghai Jiao Tong University School of Medicine from 1999 to The median onset age of these patients was 8.5 months (range: 20 days 21 months). Half of them had positive family histories, which helped identify them as sufferers from the disease. The most common symptoms were recurrent sinopulmonary 2

4 infections (18 patients, 90 percent), neutropenia (14 patients, 70 percent), oral ulcer (13 patients, 65 percent), and protracted diarrhea (13 patients, 65 percent). Six patients received HSCT and four of them had immune reconstructions and clinical remissions. Eighteen unique mutations in CD40L gene were identified, with 12 novel mutations. Another case study (Jasinska, 2013) gave an account of a boy with X-linked hyper IgM disorder and a novel Y172C mutation within his CD40LG gene. He presented with severe neutropenia. His bone marrow showed maturation arrest at the promyelocyte/myelocyte stage, typical of congenital neutropenia. The child suffered from life-threatening infections and required high doses of recombinant human granulocyte stimulating factor (rhg-csf), and a haploidentical HSCT was also successfully performed, leading to reconstitution of CD40L expression on activated CD4+ T cells (confirmed with flow cytometry six months after the procedure). Two low-dose T-cell add-backs were required to re-establish full donor chimerism and clear cytomegalovirus reactivation. Petrovic (2009) retrospectively analyzed the transplantation outcomes of 31 patients with primary immunodeficiency diseases treated at All Children's Hospital in Tampa, Florida. The hospital is affiliated with the University of South Florida. The primary immune diseases included severe combined immunodeficiency, Wiscott-Aldrich syndrome, X-linked hyper IgM syndrome, and chronic granulomatous disease. The age of the patients at the time of transplant ranged from 1 month to 19 years, and conditioning regimens varied based on the patients underlying disease. In 23 patients, the graft source was bone marrow, four patients received umbilical cord blood grafts, and four patients received peripheral blood stem cell grafts. Better survival rates were observed in patients transplanted at a younger age and with a history free of infections. The authors concluded that transplantation at an early age before significant infections, autoimmune manifestation, and malignant transformation have occurred is beneficial to survival. Policy updates: None. Summary of clinical evidence: Citation Al-Saud (2015) HSCT for hyper IgM syndrome due to CD40L defects: a single-center experience Content, Methods, Recommendations A study retrospectively reviewed and analyzed data from five patients who received HSCT for hyper IgM disorder at King Faisal Specialist Hospital & Research Centre in Riyadh, Saudi Arabia, between 2005 and Five patients underwent HSCT from an HLA-matched sibling donor at a median age of 41 months (range, nine 72 months). The median time from diagnosis to transplantation was 30 months (range, five 58 months). The survival rate was 100%, with a median follow-up of 69 months (range,

5 Allewelt (2015) HSCT for CD40L deficiency: single institution experience Mitsui-Sekinaka (2015) Clinical features and HSCTs for CD40L deficiency in Japan Tsai (2015) X-linked hyper IgM syndrome with CD40LG mutation: two case reports and literature review in Taiwanese patients. Wang (2014) Clinical features and months). Four patients showed complete immune recovery with positive CD40L expression in activated T cells. The authors concluded that HSCT from an HLA-matched sibling donor is effective at treating the disease. A retrospective analysis of seven patients who underwent allogeneic HSCT for hyper IgM disorder at Duke University Medical Center found that all patients are alive at a median follow-up of 9.7 years (range ) post-transplantation. Median age at transplant was 5.2 years (range ). None of the patients had active hepatic or pulmonary disease immediately prior to transplant, but all had a history of serious infections. Post-transplantation complications included veno-occlusive disease, hemorrhagic cystitis, adenoviremia, and cryptosporidium recurrence in one patient each. The authors concluded that allogeneic HSCT results in excellent survival and sustained immune reconstitution in patients with CD40L deficiency. Retrospective study analyzed data from 56 Japanese patients with X-linked hyper igm disorder, including 29 patients who received HSCT. The long-term survival rate was poor in those not undergoing HSCT (overall survival rate at 40 years of age, 28.2%). The overall survival rate of patients undergoing HSCT (n = 29) was significantly higher than that of those not undergoing HSCT (n = 27, P =.0231); moreover, event-free and disease-free survival rates were significantly greater in patients 5 years old or younger at the time of transplantation (n = 14) than in older patients (n = 15). The authors concluded that HSCT improved the outcomes of patients and that an age of 5 years or younger was optimal for the timing of HSCT because persistent infections and severe organ damage were frequently observed in patients older than 6 years. Case report of an 18-year-old male who was diagnosed initially with hypogammaglobulinemia in infancy, but developed repeated pneumonia, sepsis, cellulitis, perianal abscess, pericarditis, and bronchiectasis despite regular intravenous immunoglobulin replacement therapy. The patient died at age 18 years due to pneumonia and tension pneumothorax. Mutation analysis revealed CD40L gene mutation within Exon 5 at nucleotide position 476 (cdna 476G > A). A second case of a 6-month-old male infant presented as Pneumocystis jiroveci pneumonia and acute respiratory distress syndrome. Gene analysis of the CD40L gene revealed G to C substitution in Intron 4 (c G > C) and the mother was a carrier. HSCT was arranged in the second case. Study retrospectively analyzed the clinical and molecular features of 20 Chinese 4

6 genetic analysis of 20 Chinese patients with X- linked hyper IgM syndrome Wahadneh (2013) Mismatched related HSCT in primary immunodeficiency Jasinska (2013) Successful haploidentical PBSCT with subsequent T-cell addbacks in a boy with hyper IgM syndrome presenting as severe congenital neutropenia patients diagnosed and followed up in hospitals affiliated to Shanghai Jiao Tong University School of Medicine from 1999 to The median onset age of these patients was 8.5 months (range: 20 days 21 months). Half of them had positive family histories, with a shorter diagnosis lag. The most common symptoms were recurrent sinopulmonary infections (18 patients, 90%); neutropenia (14 patients, 70%); oral ulcer (13 patients, 65%); and protracted diarrhea (13 patients, 65%). Six patients received HSCT and four of them had immune reconstructions and clinical remissions. Eighteen unique mutations in CD40L gene were identified in these 20 patients from 19 unrelated families, with 12 novel mutations. Study retrospectively analyzed results of 10 patients with primary immunodeficiency (PID), severe combined immunodeficiency (SCID) (n = 7), hyper IgM syndrome (n = 1), and combined immunodeficiency (CID) (n = 2), who lacked a fully matched donor and underwent mismatched related HSCT during the period from 2008 to The median age at the time of transplantation ranged between three and 84 months (median 6.5 months). Peripheral blood stem cells (PBSCs) were used in all HSCTs. The mean value of the peripheral CD34+ cells infused was (6)/kg recipient weight. Patients received different conditioning protocols. All patients received anti graft versus host disease (GVHD) prophylaxis and all were engrafted. Mixed chimerism (5% 55%) was noticed. GVHD was observed in 50% of the patients. Post-transplant follow-up ranged from three weeks to 36 months (median 15 months). Five patients are still alive while one patient developed engraftment syndrome followed by graft slippage for which a second transplant with CD34+ stem cells (6)/kg recipient's weight was infused; however, the others died from sepsis and transplantrelated complications. Immune reconstitution was noticed in four patients. The authors concluded that HLA-haploidentical stem cell transplantation may be feasible, with appropriate GVHD prophylaxis, for patients with PID who lack a fully matched donor. Case study of a boy with X-linked hyper IgM disorder and a novel Y172C mutation within his CD40LG gene. The child presented with severe neutropenia as the dominating symptom, and the bone marrow showed maturation arrest at the promyelocyte/myelocyte stage, typical of congenital neutropenia. History was positive for multiple life-threatening infections and required high doses of rhg-csf, and a haploidentical HSCT was successfully performed, leading to reconstitution of CD40L expression on activated CD4+ T cells (as assessed with flow cytometry six months after the procedure). The authors concluded that alternative donor allogeneic HSCT may be effective in correcting the defect in X-linked hyper IgM disorder, and HSCT is not necessarily 5

7 limited to matched sibling donor transplantation. Petrovic (2009) HSCT for pediatric patients with primary immunodeficiency diseases at All Children's Hospital, University of South Florida Narrative review retrospectively analyzed the transplantation outcomes of 31 patients with PID treated at All Children's Hospital, University of South Florida, since its inception in The primary immune diseases included SCID, Wiscott-Aldrich syndrome, X-linked hyper IgM syndrome, and chronic granulomatous disease. The age of the patients at the time of transplant ranged from 1 month to 19 years, and conditioning regimens varied based on the patients underlying disease. In 23 patients, the graft source was bone marrow. Four patients received umbilical cord blood grafts and four patients received peripheral blood stem cell grafts. Better survival rates were observed in those patients transplanted at a younger age and free of infections. The authors concluded that transplantation at an early age before significant infections, autoimmune manifestation, and malignant transformation have occurred is beneficial. References Professional society guidelines/other: Stiehm RE, Ochs HD, Winkelstein JA. Immunologic Disorders in Infants and Children 5th edition. Philadelphia: Saunders, Peer-reviewed references: Al-Saud B, Al-Mousa H, Al-Ahmari A, et al. Hematopoietic stem cell transplant for hyper-igm syndrome due to CD40L defects: A single-center experience. Curr Opin Pediatr. 2001;13(6): Allewelt H, Martin PL, Szabolcs P, Chao N, Buckley R, Parikh S. Hematopoietic Stem Cell Transplantation for CD40 Ligand Deficiency: Single Institution Experience. Pediatr Blood Cancer. 2015;62(12); Durandy A, Peron S, Fischer A. Hyper-IgM syndromes. Curr Opin Rheumatol. 2006;18(4): Fernandes JF, Kerbauy FR, Ribeiro AA, et al. Allogeneic hematopoietic stem cell transplantation in children with primary immunodeficiencies: Hospital Israelita Albert Einstein experience. Einstein 2011;9(2): Fuleihan RL. The hyper IgM syndrome. Curr Allergy Asthma Rep. 2001;1(5): Hadzić N, Pagliuca A, Rela M. Correction of the hyper-igm syndrome after liver and bone marrow transplantation. N. Engl. J. Med. 2000:342(5);

8 Jasinska A1, Kalwak K, Trelinska J, et al. Successful haploidentical PBSCT with subsequent T-cell addbacks in a boy with HyperIgM syndrome presenting as severe congenital neutropenia. Pediatr Transplant Feb;17(1):E Kutukculer N, Aksoylar S, Kansoy S, Cetingul N, Notarangelo LD. Outcome of hematopoietic stem cell transplantation in hyper-igm syndrome caused by CD40 deficiency. J. Pediatr. 2003; 143 (1); Mitsui-Sekinaka K, Imai K, Sato H, et al. Clinical features and hematopoietic stem cell transplantations for CD40 ligand deficiency in Japan. J Allergy Clin Immunol Oct;136(4): Rezaei N, Notarangelo LD. Hematopoietic stem cell transplantation for hyper-igm syndromes. Pediatr Transplant. 2013:17(1); 1-2. Tsai HY, Yu HH, Chien YH, et al. X-linked hyper-igm syndrome with CD40LG mutation: two case reports and literature review in Taiwanese patients. J Microbiol Immunol Infect. 2015;48(1): Wang LL, Zhou W, Zhao W, et al. Clinical features and genetic analysis of 20 Chinese patients with X- linked hyper-igm syndrome. J Immunol Res. 2014;: Wahadneh AM, Bin Dahman HA, Abu Shukear ME, et al. Mismatched related hematopoietic stem cell transplantation in primary immunodeficiency. Saudi J Kidney Dis Transpl Nov;24(6): CMS National Coverage Determinations (NCDs): No NCDs identified as of the writing of this policy. Local Coverage Determinations (LCDs): No LCDs identified as of the writing of this policy. Commonly submitted codes Below are the most commonly submitted codes for the service(s)/item(s) subject to this policy. This is not an exhaustive list of codes. Providers are expected to consult the appropriate coding manuals and bill in accordance with those manuals. CPT Code Description Comment Hematopoietic progenitor cell (HPC); allogeneic transplantation per donor 7

9 ICD-10 Code Description Comment D80.5 Immunodeficiency with increased immunoglobulin M [IgM] HCPCS Level II N/A Description Comment 8