SUMMARY and ACKNOWLEDGEMENT

Steven P. Treon - 1, Meletios Dimopoulos - 2, and Robert A. Kyle - 3

Department of Medical Oncology, Dana Farber Cancer Institute,

Department of Medicine, Harvard University, Boston MA 02115 USA - 1;

University of Athens, Athens, Greece2; and Mayo Clinic, Rochester MN - 3.

Reprint Requests:

Steven P. Treon MD, MA, PhD
Waldenstrom¹s Macroglobulinemia Program
Dana Farber Cancer Institute
LG100
44 Binney Street Boston MA 02115

Tel: (617) 632-2681 • Fax: (617) 632-4862
Email: steven_treon@dfci.harvard.edu

Nearly sixty years have passed since Jan Gosta Waldenstrom (Figure 1) first described two patients with oronasal bleeding, lymphadenopathy, anemia and thrombocytopenia, an elevated erythrocyte sedimentation rate, a high serum viscosity level, normal bone radiographs and a bone marrow demonstrating predominately lymphoid cells (1). These seminal observations provided the foundation for the widely recognized, though uncommon clinical diagnosis of Waldenstrom¹s macroglobulinemia (WM). Likely hampered by its uncommon presentation, estimated at 1.7 (for females) and 3.4 (for males) per million person-years at risk (2), WM remained a loosely defined clinical diagnosis which encompassed patients with an elevated serum IgM level and a monoclonal IgM gammopathy. Many interpretations of what was considered WM existed, which differed largely on the basis of arbitrarily established serum IgM level cutoffs, while no underlying histopathological diagnosis existed to provide a firm pathological basis for the disease. With improvements in the diagnosis of lymphoid malignancies introduced by successive pathological classification systems, a pathological accounting for patients with WM was attempted. The most recent of these classification schemes, the World Health Organization and (WHO) and Revised European and American Lymphoma (REAL) classifications attempted to define ³real² disease entities among the lymphoid neoplasms by reconciling morphological, immunophenotypic, genetic and clinical features (3,4). Within the WHO and REAL classification, WM was recognized as a clinical syndrome that largely corresponded to the ³real² disease entity of ³lymphoplasmatic lymphoma². Though the WHO and REAL classification systems provided a pathological basis to diagnose many patients with WM, they left open the possibility that patients with WM could have any of the recognized IgM secreting lymphoid neoplasms as their underlying diagnosis thereby hampering the conduct or interpretation of clinical trials involving WM patients. In view of the above, a consensus panel of experts focused on WM, was organized as part of the 2nd International Workshop on WM, which was held in Athens, Greece in September, 2002. Consensus Panel One, chaired by Drs. Meletios Dimopoulos (Greece) and Roger Owen (United Kingdom) was charged with formulating a clinicopathological definition for WM. The highlights of this consensus panel summary, as reported in the June 2003 issue of Seminars in Oncology was the recognition that WM represented a defined clinicopathological entity that was represented by the underlying pathological diagnosis of lymphoplasmacytic lymphoma, as defined by the WHO and REAL classification systems (5). Moreover, the consensus panel concluded that since the IgM ³macroglobulin² was a significant component of the morbidity of WM, the diagnosis of WM should be limited to patients with IgM secreting lymphoplasmacytic lymphoma, and that serum IgM levels, per se, should not form a a basis for establishing the diagnosis of WM. In addition to providing a clinicopathological definition for WM, Consensus Panel One formulated criteria to distinguish apart patients with an IgM monoloclonal gammopathy in whom there was no histological evidence for disease, thereby discerning the categories of ³IgM Monoclonal Gammopathy of Undetermined Significance (MGUS)², and IgM Related Disorders, the latter recognizing those patients in whom the IgM monoclonal antibody is pathologically relevant.

In the June 2003 issue of Seminars in Oncology, the recommendations of Consensus Panel Two, charged with identifying prognostic criteria and developing criteria to initiate therapy in WM are also presented (6). Co-chaired by Drs. Robert Kyle (United States) and Veronique Leblond (France), Consensus Panel Two identified serum beta 2 microglobulin and hemoglobin levels at the time of diagnosis as important prognostic determinants for overall survival in WM patients, though stressed that no data existed at this time to validate the use of these or other factors in deciding the initiation, or choice of treatment for a particular patient. Consensus Panel Two however considered that initiation of therapy was appropriate for patients who demonstrated a hemoglobin of <10 g/dL, or a platelet count of <100x109 /L due to marrow infiltration. Certain complications such as hyperviscosity syndrome, symptomatic sensorimotor peripheral neuropathy, systemic amyloidosis, renal insufficiency, or symptomatic cryoglobulinemia were also considered as potential indications for therapy.

The outcome of deliberations from Consensus Panel Three, charged with providing treatment recommendations in WM are presented in the June 2003 issue of Seminars in Oncology (7). Co-chaired by Drs. Morie Gertz (United States) and Steven Treon (United States), Consensus Panel Three considered that alkylating agents, nucleoside analogues, and the monoclonal antibody rituximab represented reasonable choices for the first line therapy of WM. The panel also recognized the paucity of randomized clinical trials in WM, and concluded that it was not possible to recommend the use of one first line agent over another, and that individual patient considerations including the presence of cytopenias, need for rapid disease control, age, and candidacy for autologous transplant therapy should be weighed in making the choice of a first line agent. The panel also considered options for the treatment of relapsed disease, and recommendations on the use of alternate first line agents, re-use of a first line agent, use of combination myelotoxic chemotherapy, and thalidomide as a single agent or in combination therapy. Importantly, Consensus Panel Three affirmed for eligible patients, a role for high dose chemotherapy with autologous peripheral blood cell transplantation in primary refractory or relapsed disease while stressing that allogeneic or ³non-myeloablative allogeneic² transplant procedures should be cautiously approached in view of the associated high mortality and/or morbidity risks, and ideally should be undertaken in context of a clinical trial.

A confounding factor for therapeutics trials in WM has been a lack of uniformity in the clinical response criteria used. Current response criteria for WM rely on various adaptations of low-grade non-Hodgkin¹s lymphoma and multiple myeloma response criteria thereby complicating interpretation and comparison of clinical trial outcomes. In the June 2003 issue of Seminars in Oncology, the recommendations of Consensus Panel Four, co-chaired by Drs. Donna Weber (United States) and Eva Kimby (Sweden) are summarized in which uniform response criteria are proposed for evaluating therapeutic responses in WM (8).

While the above consensus panel efforts represent a defining moment for the diagnosis and management of WM, considerable progress has also been made in characterizing and defining WM at the chromosomal and molecular level. These efforts, which were presented at the 2nd International Workshop on WM, are detailed in large part in reports appearing in the June 2003 issue of Seminars in Oncology. Highlights of these studies include the identification of 6q21 deletions in 42% of WM patients by Schop et al (9), whilst translocations involving the immunoglobulin heavy chain (IgH) which are typically present in IgM myeloma patients (10), were not found in WM (9,10). The latter finding may be particularly critical to differentiating patients with WM from those with IgM secreting multiple myeloma. Lastly, as reported in the June 2003 issue of Seminars in Oncology, the outcomes of studies by Pilarksi et al (12) and Sahota et al (13) using IgH VDJ sequencing in WM patients are reported. Their studies have helped characterize the clonal origin of the WM malignant cell to a post-germinal, but pre-immunoglobulin heavy chain switched mature IgM+ B-cell, which should greatly facilitate further studies aimed at identifying the oncogenetic event(s) which contribute to malignant transformation in WM.

Lastly, to facilitate the ongoing clinical and basic science progress into WM, a 3rd International Workshop on WM has been planned for October, 2004 in France.

Acknowledgements

Funding for the 2nd International Workshop on Waldenstrom¹s macroglobulinemia was made possible through unrestricted grants or gifts provided by Amgen Inc., Berlex Oncology Inc., the Dr. and Mrs. Peter Bing Fund at the Dana Farber Cancer Institute, Celgene Corporation, Genentech BioOncology Inc., IDEC Pharmaceuticals Inc., the International Waldenstrom¹s Macroglobulinemia Foundation, the Paul Mattis Family, the Research Fund for Waldenstrom¹s at the Dana Farber Cancer Institute, and the Research Fund for Waldenstrom¹s, Ltd. The 2nd International Workshop on Waldenstrom¹s macroglobulinemia was dedicated to the memories of Mrs. Delores M. Hermsdorf and Mr. Stephen Yates. Drs. Treon, Dimopoulos and Kyle served as the organizing chairs for the 2nd International Workshop. Dr. Treon served as the chair for the consensus panel organizing committee and is a recipient of an NIH Career Development Award for the study of WM and related plasma cell malignancies.

References

1. Waldenström J. Incipient myelomatosis or essential hyperglobulinemia with fibrinogenopenia ‹ a new syndrome? Acta Med Scand. 1944; 117:217-247.

2. Groves FD, Travis LB, Devesa SS, Ries LAG, and Fraumeni JF. Waldenstrom¹s macroglobulinemia. Incidence Patters in the Unites states, 1988-1994. cancer 1998; 82:1078-1081.

3. Harris NL, Jaffe ES, Stein H. A revised European-American classification of lymphoid neoplasms: a proposal from the International Lymphoma Study Group. Blood. 1994; 84:1361-1392.

4. Harris, NL, Jaffe ES, Diebold J, et al. World Health Organization classification of neoplastic diseases of the hematopoietic and lymphoid tissues: report of the Clinical Advisory Committee meeting- Airlie House, Virginia, November 1997. J Clin Oncol. 1999; 17:3835-3849.

5. Owen RG, Treon SP, Al-Katib A, Fonseca R, Greipp PR, McMaster ML, Morra E, Pangalis GA, San Miguel JF, Branagan AR, Dimopoulos MA. Clinicopathological definition of Waldenström¹s macroglobulinemia: Consensus Panel Recommendations from the Second International Workshop on Waldenström¹s macroglobulinemia. Sem Oncology 2003 (manuscript in press).

6. Kyle RA, Treon SP, Alexanian R, Barlogie B, Bjorkholm M, Dhodapkar M, Lister TA, Merlini G, Morel P, Stone M, Branagan AR, Leblond V. Prognostic markers and criteria to initiate therapy in Waldenstrom¹s macroglobulinemia: Consensus Panel Recommendations from the Second International Workshop on Waldenstrom¹s macroglobulinemia. Sem Oncology (manuscript in press).

7. Gertz M, Anagnostopoulos A, Anderson KC, Branagan AR, Coleman M, Frankel S, Giralt S, Levine T, Munshi N, Pestronk A, Rajkumar V, and Treon SP. Treatment Recommendations in Waldenstrom¹s macroglobulinemia: Consensus Panel Recommendations from the Second International Workshop on Waldenstrom¹s macroglobulinemia. Sem Oncology 2003 (manuscript in press).

8. Weber D, Treon SP, Emmanouilides C, Branagan AR, Byrd JC, Blade J, Kimby E. Uniform response criteria in Waldenstrom¹s Macroglobulinemia: Consensus Panel Recommendations from the Second International Workshop on Waldenstrom¹s Macroglobulinemia. Sem Oncology 2003 (manuscript in press).

9. Schop RFJ, Fonseca R. Genetics and cytogenetics of Waldenstrom macroglobulinemia. Sem Oncol 2003 (manuscript in press).

10. Avet-Loiseau H, Garand R, Lode L, Robillard N, Bataille R. 14q32 translocations discriminate IgM multiple myeloma from waldenstrom¹s macroglobulinemia. Sem Oncol 2003 (manuscript in press).

11. Kriangkum J, Taylor BJ, Mant MJ, Treon SP, Belch AR, Pilarski LM. The malignant clone in Waldenstrom¹s macroglobulinemia. Sem Oncology 2003 (manuscript in press).

12. Sahota SS, Forconi F, Ottensmeier CH, Stevenson FK. Origins of the malignant clone in typical Waldenstrom¹s macroglobulinemia. Sem Oncol 2003 (manuscript in press).

Figure 1. Dr. Jan Gosta Waldenstrom in 1944.