Management of Heavy Chain Diseases: The Challenges of Biologic Heterogeneity

January 15, 2014

In the absence of a clear understanding of the underlying biologic heterogeneity, the etiology of the different heavy chain diseases (HCDs) should be taken into consideration when treatment decisions are made. Extrapolation from related conditions, such as aggressive lymphomas (in γ-HCD) and CLL (in μ-HCD), suggests that novel and targeted therapies may be effective in the management of these rare diseases.

Heavy chain diseases (HCDs) pose significant challenges to clinicians, principally because of two cardinal features: they are very rare and the underlying molecular biology that distinguishes them from other B-cell neoplasms is unknown. Thus, definitive diagnosis of HCDs is commonly delayed and treatment uncertainties are universal. The 2008 World Health Organization (WHO) classification of lymphomas categorizes HCDs among the mature small B-cell neoplasms, along with the related entities chronic lymphocytic leukemia (CLL), hairy-cell leukemia (HCL), marginal zone lymphoma (MZL), and lymphoplasmacytic lymphoma (LPL). As outlined by Bianchi et al in this issue of ONCOLOGY,[1] HCDs are further subdivided into α (immunoglobulin A 1-2 [IgA1-2]), γ (immunoglobulin G 1-4 [IgG1-4]), and μ (immunoglobulin M [IgM]) subtypes, depending on the truncated heavy chain that is produced by the transformed cells.[2] Bianchi et al provide an in-depth review of the current understanding of the pathophysiology, clinical features, diagnosis, and treatment of heavy chain diseases. They detail the nature of the uniquely altered paraproteins and discuss the etiology of the malignant clone, including its relationship to other similar B-cell neoplasms such as MZL, LPL, and CLL. The etiology of HCDs remains unknown; however chronic antigen stimulation and somatic hypermutation have been postulated to play a role in some types of HCDs.[3,4] As discussed, α-HCD is associated with infections and γ-HCD is associated with numerous autoimmune disorders.[5] Structural and genomic analyses provide insight into the pathogenesis of HCDs, linking them to the synthesis of defective free heavy chains. In γ-HCD, a short normal variable (V) immunoglobulin genetic region is followed by a large deletion of the remainder of the V region and of CH1, and occasionally, of the CH2 domain.[6,7] In contrast, μ-HCD often contains normal constant regions, including the CH1 domain; can synthesize monoclonal free light chains unassociated with the μ heavy chain; and can be detectable in the urine or serum.[8,9] Cogne et al showed that CH1 is required for intracellular degradation of defective free heavy chains.[10] Heavy chain binding protein (BiP) binds to CH1 and targets it for degradation through the ubiquitin-proteasome pathway (UPP). The order of V or constant (C) deletions and the relationship of this order to pathogenesis are currently unknown.

The authors highlight the increasing use of novel therapies in HCDs, including monoclonal antibodies and proteasome inhibitors. Immunomodulatory agents and small-molecule inhibitors of the B-cell receptor pathway are currently changing the therapy of related B-cell neoplasms, and the underlying molecular mechanisms of HCDs may also prove susceptible to these agents. It is enticing for clinicians to consider treatment with novel agents when encountering patients with rare B-cell neoplasms such as HCDs.

The definitive diagnosis of a specific HCD requires a high index of suspicion and is established by electrophoresis and immunofixation of serum and urine in conjunction with immunohistologic analysis of the underlying malignant clone. Multiparameter flow cytometric analysis and heavy chain polymerase chain reaction can aid in the diagnosis and the establishment of B-cell clonality. An advanced method such as next-generation DNA/RNA sequencing could provide evidence of deletions, insertions, and in-frame mutations associated with HCDs, but the technique is not routinely used in this setting.

As we approach the goal of personalized medicine in all B-cell neoplasms, the investigation of molecular differentiation and signaling pathways that help define and differentiate morphologically related diseases has become paramount. Indeed, the MYD88 L265P activating mutation is a recurrent somatic mutation that helps clinicians to distinguish LPL from the morphologically similar MZL in more than 90% of cases.[11] MYD88 mutations can also be identified in the activated B-cell (ABC) subtype of diffuse large B-cell lymphoma (DLBCL), primary central nervous system (CNS) lymphoma, and mucosa-associated lymphoid tissue (MALT) lymphomas.[12-14] In addition to aiding in diagnostics, the identification of such recurrent mutations helps to establish subtypes of lymphoma that selectively respond to therapy. Interim results of a phase II trial of ibrutinib in relapsed/refractory DLBCL showed an overall response rate of 40% in ABC DLBCL, providing clinical support that chronic B-cell receptor signaling in this subtype is required for tumor cell survival.[15] In LPL, the presence of a MYD88 mutation also may predict for responsiveness to inhibition of Bruton tyrosine kinase.[16] Similar precision strategies may be applicable to HCDs if the pathogenesis were better elucidated.

As discussed by Bianchi et al, the rarity of HCDs and lack of standard treatment principles necessitate collaborative efforts focused on establishing prospective national and international registry databases for patient characterization, treatment outcomes, and follow-up. Molecular genetics studies, such as RNA and whole-exome sequencing, may lead to discovery of the underlying functional mechanisms of activation within HCDs, such as chronic immune system activation and B-cell receptor signaling.

In the absence of a clear understanding of the underlying biologic heterogeneity, the etiology of the different HCDs should be taken into consideration when treatment decisions are made. Extrapolation from related conditions, such as aggressive lymphomas (in γ-HCD) and CLL (in μ-HCD), suggests that novel and targeted therapies may be effective in the management of these rare diseases.

Financial Disclosure:The authors have no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.


1. Bianchi G, Anderson KC, Harris NL, Sohani AR. The heavy chain diseases: clinical and pathologic features. Oncology (Williston Park). 2014;28:45-53.

2. Jaffe ES. The 2008 WHO classification of lymphomas: implications for clinical practice and translational research. Hematology Am Soc Hematol Educ Program. 2009;523-31.

3. Goossens T, Klein U, Kuppers R. Frequent occurrence of deletions and duplications during somatic hypermutation: implications for oncogene translocations and heavy chain disease. Proc Natl Acad Sci U S A. 1998;95:2463-8.

4. Husby G, Blichfeldt P, Brinch L, et al. Chronic arthritis and gamma heavy chain disease: coincidence or pathogenic link? Scand J Rheumatol. 1998;27:257-64.

5. Wahner-Roedler DL, Witzig TE, Loehrer LL, Kyle RA. Gamma-heavy chain disease: review of 23 cases. Medicine (Baltimore). 2003;82:236-50.

6. Guglielmi P, Bakhshi A, Cogne M, et al. Multiple genomic defects result in an alternative RNA splice creating a human gamma H chain disease protein. J Immunol. 1988;141:1762-8.

7. Cooper SM, Franklin EC, Frangione B. Molecular defect in a gamma-2 heavy chain. Science. 1972;176:187-9.

8. Zucker-Franklin D, Franklin EC. Ultrastructural and immunofluorescence studies of the cells associated with mu-chain disease. Blood. 1971;37:257-71.

9. Cogne M, Aucouturier P, Brizard A, et al. Complete variable region deletion in a mu heavy chain disease protein (ROUL). Correlation with light chain secretion. Leuk Res. 1993;17:527-32.

10. Cogne M, Guglielmi P. Exon skipping without splice site mutation accounting for abnormal immunoglobulin chains in nonsecretory human myeloma. Eur J Immunol. 1993;23:1289-93.

11. Treon SP, Xu L, Yang G, et al. MYD88 L265P Somatic mutation in Waldenström’s macroglobulinemia. N Engl J Med. 2012;367:826-33.

12. Ngo VN, Young RM, Schmitz R, et al. Oncogenically active MYD88 mutations in human lymphoma. Nature. 2011;470:115-9.

13. Gonzalez-Aguilar A, Idbaih A, Boisselier B, et al. Recurrent mutations of MYD88 and TBL1XR1 in primary central nervous system lymphomas. Clin Cancer Res. 2012;18:5203-11.

14. Li Z-M, Rinaldi A, Cavalli A, et al. MYD88 somatic mutations in MALT lymphomas. Brit J Haematol. 2012;158:662-64.

15. Wilson WH, Gerecitano JF, Goy A, et al. The Bruton’s tyrosine kinase (BTK) inhibitor, ibrutinib (PCI-32765), has preferential activity in the ABC subtype of relapsed/refractory de novo diffuse large B-cell lymphoma (DLBCL): interim results of a multicenter, open-label, phase 2 study. ASH 54th Annual Meeting Abstracts. 2012;120:abstr 686.

16. Yang G, Zhou Y, Liu X, et al. A mutation in MYD88 (L265P) supports the survival of lymphoplasmacytic cells by activation of Bruton’s tyrosine kinase in Waldenstrom’s macroglobulinemia. Blood. 2013;122:1222-32.