10.        Myeloma and Related Conditions

 

60                                                                                                            Myeloma and Related Conditions

 

10.3              Waldenström’s macroglobulinemia

 

10.3.1     General considerations  

The term Waldenström’s macroglobulinemia describes a clinical syndrome characterized by high levels of monoclonal IgM protein (macroglobulin), anemia, hepatosplenomegaly and symptoms related to hyperviscosity. Histologically the disease overlaps with lymphoplasmacytoid lymphoma/immunocytoma (kiel classification) and lymphoplasmacytic lymphoma (WHO classification).

 

Information on its natural history and prognosis is still limited and the decision to initiate therapy is generally individualized. A simple prognosis- based staging system which was proposed by the SWOG may give some guidance.

 

Prognosis-based staging system of the SWOG *

Stage       Risk group            Criteria                                            Therapy

A                low                  ß2M < 3mg/1 + HB ≥ 120 g/l       low probability of                

                                                                                                     requirement

B                medium           ß2M < 3mg/1 + HB < 120 g/l        generally required

C                medium           ß2M ≥ 3mg/1 + IgM ≥ 40 g/l         generally required

D                high                ß2M ≥ 3mg/1 + IgM < 40 g/l          generally required

*  Adapted from Dhodapkar et al (2001)

           

Plasmapheresis. Which reduces the amount of circulating IgM, and chemotherapy, which inhibits tumor growth have been the standard therapy for patients with symptomatic macroglobulinemia. Active chemotherapeutic agents include alkylating agents, especially chlorambucil, and nucleoside analogs such as fludarabine or cladribine, usually administered singly and in sequence. All patients sooner or later will develop resistance, however, if not refractory from the beginning. Limited trials with high-dose therapy and autologous stem cell transplantation, the monoclonal antibody rituximab or thalidomide have shown activity in some patients with chemoresistant disease.

 

            Literature: for review e.g.

*    DHODAPKAR et al, Blood 98 (2001): 41 – 48 (prognostic factors from U.S. intergroup trial SWOG S 9003)

      DIMOPOULOS et al, J. Clin. Oncol. 18 (2000): 214 – 226

      GERTZ, Leuk. Lymphoma 43 (2002): 1517 – 1526

 

10.3.2 First-line therapy

 

10.3.2.1Alkylating agents

Chlorambucil

Chlorambucil                  0.1 mg /kg/d or 0.3 mg/kg/d for 7 d every 6 wks for a

                                        Total of at least 6 months

 

Literature:

            DYLE et al. Br. J. Haematol. 108 (2000): 737 – 742

 

Or

 

Cyclophosphamide

Cyclophosphamide                 e.g.  200 mg  daily

 

Both with or without glucocorticoids

 

 

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10.3.2.2 Purine uncleoside analogs

            (Es[ecoally for rapid cytoreduction in patients with serious complications of the disease)

           

            Fludarabine

Fludarabine             25 – 30 mg / m2             i.v. (30 min inf)                     d 1 – 5

            To be repeated every 4 weeks (until maximum response plus 2 further cycles as consolidation)

           

            Literature:

DHODAPKAR et al, Blood 98 (2001): 41-48 (U.S. intergroup trials SWOG S9003 OWEN et al, Expert Opin. Pharmacother. 2 (2001): 945 – 952 (review )

            Or

           

            Cladribine

           

Cladribine              0.14 mg/kg                  i.v. (2 h inf)                        d 1 – 5

            To be repeated every 4 – 5 weeks. Cladribine can also be given subcutaneously.

 

            Literature:

                        BETTICHER et al, Br. J. Haematol. 99 (1997): 358 – 363 (s.c. administration)

                        LEWANDOWSKI et al, Med. Sci. Monit. 6 (2002): 740 – 745)

 

10.3.3 Salvage therapy

 

10.3.3.1 Purine nucleoside analogs

              Fludarabine

 

Fludarabine            25 mg/m2                  i.v. (30 min inf)                        d 1- 5

            To be repeated every 4 weeks (with a target of 6 courses)

 

            Literature:

LEBLOND et al, Blood 98 (2001): 2640 – 2644 (multicenter, randomized trial of fludarabine vs CAP in WM in first relapse or primary refractory disease)

 

10.3.3.2  Anti-CD 20 monoclonal antibody (Rituximab)

            Rituximab

 

Rituximab                  375 mg /m2                i.v.                              weekly x 4

 

Three months after completion of the first cycle, patients  without evidence of progressive disease receive repeat 4 – week courses . The first dose to be infused at an intial rate of 50 mg/h which can be  increased by 50 mg/h every 30 min to a maximum of 400 mg/h if no hypersensitivity or infusion –related events occur.

 

      Literature :

DIMPOULOS et al, J. Clin. Oncol. 20 (2002): 2327-2333 (pretreated and unpretreated patients)

 

10.3.3.3  Myeloablative therapy with stem cell rescue

 

Literature:

            ANAGNOSTOPOULOS et al, Bone Marrow Transplant. 27 (2001): 1027-

            1029

            DESIKAN et al, Br. J. Haematol. 105 (1999): 993-996