Introduction

Waldenstrom's macroglobulinaemia (WM) is a rare low-grade chronic B-cell lymphoproliferative disorder characterized by bone marrow infiltrates of lymphoplasmacytoid lymphocytes and a monoclonal IgM serum peak. The disease usually has a long natural history, with patients often surviving more than 5 years after the initial diagnosis.^{1, 2, 3}

WM, although not curable with conventional chemotherapy, is quite chemosensitive. Initial treatments, once patients are symptomatic from their disease, include alkylating agents such as chlorambucil and cyclophosphamide, nucleoside analogues (fludarabine or cladribine) and anti-CD 20 monoclonal antibodies. Overall response rate for chlorambucil and the nucleoside analogues are about 50 and 40–90% respectively.² Complete responses are rare and all patients who initially respond to induction chemotherapy will eventually relapse.^{2, 3}

High-dose chemotherapy followed by autologous stem cell transplantation (SCT) has been used in refractory or high-risk patients^{1, 4, 5, 6, 7, 8, 9} and is considered a reasonable treatment option.¹⁰ However, limitations for autologous stem cell transplant exist for patients with heavy marrow involvement including a difficulty in procuring autologous stem cells due to the use of purine analogues, multiple lines of prior chemotherapy and concerns of tumour cell contamination.³ Allogeneic SCT provides another treatment option. Published experience using allogeneic transplantation is limited but allogeneic stem cells provide the benefit of a graft free of contamination from WM.^{2, 3} In addition, a potential graft-versus-tumour effect has been well described in indolent non-Hodgkin's lymphoma and multiple myeloma^{3, 11} and reports have demonstrated the potential from a graft-versus-WM effect.^{8, 12, 13} We report the results of five allogeneic transplantations for WM at Princess Margaret Hospital in Toronto, Ontario, Canada.

Patients and methods

Data from one woman and four men diagnosed with WM, who underwent allogeneic SCT between 1998 and 2005, were retrospectively collected. The diagnosis of WM was based on the international working group formulation as described previously.¹⁴ The characteristics of all five patients who underwent allogeneic SCT are listed in Table 1. The median age of the five patients at transplant was 56 years (range 40–60) with a median interval between diagnosis and transplant of 3 years (range 1.5–7). Pre-transplant quantitative IgM levels obtained by nephelometry for patients 1–5 were 17.0, 28.3, 26.0, 1.67 and 33.2 g/l respectively. All patients were heavily pretreated but had chemosensitive relapses before transplant. None had received a prior autologous stem cell transplant.

Table 1 - Demographics of five patients who underwent allogeneic SCT for WM.

Full table

Transplantation characteristics

Four out of five patients received an HLA full matched sibling transplant with peripheral blood stem cells. One patient received a fully matched sibling bone marrow. All five received a fully myeloablative regimen. GVHD prophylaxis and engraftment data are listed in Table 1. All patients received intravenous busulphan (2.5 mg/kg on day –7 through to day 4) and cyclophosphamide (60 mg/kg on days –3 and –2).

Results

Engraftment and toxicity

The median time to stem cell engraftment based on a neutrophil count over 0.5 10⁹/l was 19 (range 16–23) days and a platelet count over 20 10⁹/l was 21 (range 11–28). Transplant-related toxicity early in the course of transplantation was acceptable and included mucositis (Bearman grade II, n=3) and culture-negative febrile neutropaenia (n=4).

Treatment-related mortality occurred in one patient. He was 55 years old and had the highest pre-transplant IgM level at 33.2 g/l. He had received four prior courses of chemotherapy, including bortezomib, and his best response to treatment had only been partial. He received stem cells from a fully matched sibling. This patient developed veno-occlusive disease (VOD) of the liver followed by multiple infections and acute GVHD of the liver and skin (grade 4). The patient died 2 months after the transplant from fulminant liver failure suspected to be from VOD and acute GVHD of the liver.

Response, graft-versus-host disease and post transplant course

Four out of four evaluable patients (100%) achieved a major response as defined in Dimopoulos et al.² All five transplanted patients developed acute GVHD (grade 2, n=4 and grade 4, n=1). In addition, of the four patients who survived beyond day 100 after transplantation, three patients experienced extensive chronic GVHD.

IgM levels decreased gradually after transplantation with a plateau achieved at 6, 12, 18 and 3 months after transplantation. There was association between flare of chronic GVHD and reduction of IgM level. As is shown in Figure 1, initial decrease in IgM monoclonal protein is seen following high-dose chemotherapy for three patients. No donor leucocyte infusions were given. Subsequent decreases in IgM values correlate temporally with symptomatic flares in GVHD, suggesting a graft-versus-WM effect.

Figure 1.

Serial change of IgM levels in cases 1–3 after allogeneic stem cell transplantation.

Full figure and legend (106K)

Outcome

With a median follow-up of 32 months (range 2–43), four patients are alive and free of disease progression at 33 months post transplant (range 12–43 months). One patient died at 2 months from fulminant liver failure due to VOD.

Discussion

Autologous stem cell transplant has been shown to be a feasible and reasonable option for patients with WM, with overall survivals in some reports approaching 79%.² Patients eligible for possible autologous SCT require planning early in the therapeutic regimen, as treatment with nucleoside analogues may impair stem cell collection.¹⁵ In some cases, bone marrow involvement with disease may limit the use of high-dose chemotherapy and autologous stem cell support.

Recent trials in WM have focused on the use of novel therapies that have been tested in multiple myeloma. Thalidomide, velcade and combinations of these agents have been studied and demonstrate reasonable activity with acceptable toxicity.^{16, 17, 18, 19} However, none of these strategies appear to provide the possibility of long-term disease control. WM is a rare lymphoproliferative disease, and published series on the use of allogeneic transplant have largely been single-institution retrospective reviews. In the most recent and largest series published to date, albeit a registry analysis, Anagnostopoulos et al.¹⁶ reviewed the results of 26 patients who received an allogeneic transplant. The overall survival was 40%; however, 58% of the patients received total body irradiation-based conditioning therapy.

Allografting has been shown to be curative for patients with relapsing indolent lymphoma, in large part related to a graft-versus-lymphoma effect.^{18, 20, 21, 22} A graft-versus-WM effect has previously been suggested.^{3, 23} Similar to the case report by Ueda et al.,²³ in which a reduction in abnormal cell counts in bone marrow and the disappearance of abnormal phenotypic cells occurred after a series of GVHD, as is shown in Figure 1, symptoms of GVHD temporally correlate with decreases in monoclonal protein values. Only one patient received steroids for treatment of the GVHD. Further evaluation of the graft-versus-tumour effect on WM is needed in the future, but the use of non-myeloablative SCT in patients with advanced disease is appealing. Non-myeloablative SCT techniques will make this treatment option available to patients over the age of 60, who represent the majority of cases. If data from non-myeloablative SCT in indolent lymphoma or myeloma may be extrapolated to WM, non-myeloablative SCT will reduce early treatment-related mortality and will allow for the possible exploitation of graft-versus-WM effect to improve disease response or prevent relapse. Further investigation into the possibility of allogeneic SCT earlier in the treatment of disease, especially in individuals with high-risk features (increased age, cytopaenias, low serum albumin level, high ₂-microglobulin level),¹⁴ is needed.

The paucity of data and clinical trials currently leaves the role of allogeneic stem cell transplant for WM undefined. In our series, five patients underwent allogeneic SCT. All were heavily pretreated. All patients received cyclophosphamide and busulphan as conditioning therapy before transplant. Our previous work in allogeneic transplant outcomes for follicular lymphoma using busulphan plus cyclophosphamide conditioning reported 89 and 79% overall survival at 1 and 5 years with six non-relapse mortality cases (6/37, 16%).²⁴ This conditioning uses a nonirradiation-based regimen, which possibly results in a decrease in tissue damage, and might ultimately contribute to a lower transplant-related mortality. Presently, however, there is no published evidence with respect to WM, to suggest superiority of one conditioning regimen over another. In this series, four patients are alive and disease free. Treatment-related mortality appears to be lower than current published reports.^{3, 19}

In conclusion, we have shown that allogeneic SCT is a feasible and efficacious option for treatment of relapsed WM. We have also suggested a graft-versus-WM effect and its potential in contributing to sustained disease resolution. Future clinical trials to further define the role of allogeneic SCT and graft-versus-WM are needed.

References

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