Lymphoplasmacytic lymphoma (LPL) is one of the least prevalent forms of lymphoma with an estimated relative frequency of 1.4% of all B-cell lymphomas.1 Waldenström’s macroglobulinaemia (WM) is defined as LPL with bone marrow involvement and an IgM monoclonal gammopathy.1 The median age of presentation is >65 years and treatment is indicated in symptomatic patients. Response rates to single-agent chemotherapy and combination chemotherapy/chemoimmunotherapy range between 26 and 92% and 55 and 94%, respectively.2, 3, 4, 5 Despite these respectable response rates, all patients eventually relapse.
For most patients, a non-intensive approach is entirely appropriate. Those of an older age will have limited capacity to tolerate intensive treatment or have low-risk disease with the likelihood of prolonged survival with sequential non-intensive therapy. For those of younger age with more aggressive disease, an adequate depth of response following conventional therapy is likely to be limited and fail to produce a significant improvement in survival. Such patients require special consideration such as autologous SCT (auto-SCT) in first response.
We have analysed our institution’s experience of auto-SCT in patients diagnosed with WM or LPL, which consisted of 16 patients (13 male) during the period 2002–2011. One unique feature of our study was the uniform nature of conditioning therapy as all received BEAM (Carmustine 300 mg/m2 on day −6, Cytarabine 200 mg/m2 on days −5 to −2, Etoposide 200 mg/m2 on days −5 to −2, Melphalan 140 mg/m2 on day −1, stem cell return on day 0), except one in whom Lomustine was substituted for Carmustine due to supply difficulties.
The primary end points were non-relapse mortality, PFS, OS and relapse risk. The definitions of response were applied according to the consensus criteria agreed at the VIth IWWM.6
Median age at diagnosis was 52 years (range 39–64) and at auto-SCT was 54.5 years (range 40–66). Thirteen patients had a diagnosis of WM and 3 had LPL. Fourteen patients had BM involvement at the time of diagnosis. The median time from diagnosis to transplantation was 13.5 months (range 9–108) and the median number of lines of chemotherapy prior to transplantation was 2 (range 1–4). All patients had received prior therapy with a Rituximab-containing regimen. Stem cell mobilisation was achieved successfully following a median of one attempt (range 1–3) with peripheral blood as the stem cell source. The median CD34 count was 2.7 × 106/kg (range 0.97–26.6 × 106/kg).
Disease assessment pre-transplantation showed nine patients had a PR, four patients had a very good PR (VGPR), two had a CR and one patient had progressive disease.
The median time of follow-up was 39 months (range 1–104). Fourteen patients were alive at 12 months post transplant. One patient died of a non-relapse cause at 16 days (pneumonia and oesophageal perforation) and the second patient died after relapsing 11 months post transplant. Response was assessed with IgM monoclonal gammopathy level, if present at diagnosis, and computed tomography scan if lymphadenopathy was present previously. Patients were monitored every month for 3 months and every 3 months thereafter using serial paraprotein measurements. BM biopsies were obtained at 3 and 6 months post transplant if involved previously. The best disease response following transplant was achieved at a median time of 5 months (range 1–7). Post transplant, six patients achieved CR (two were in CR pre-transplant, two were in PR and two had a VGPR pre-transplant) and five patients achieved a VGPR, including three patients who were in PR pre-transplant. In total, half the patient group improved their categorical response following auto-SCT (Table 1). Eight patients have since relapsed/progressed at a median time of 27 months post transplant (range 4–38), giving a relapse risk of 12% at 1 year and 42% at 4 years. OS at 1 year was 88 and 71% at 4 years (Figure 1). PFS was 81% at 1 year and 51% at 4 years.
Four patients have required further chemotherapy (including the patient who had progressive disease at the time of transplant). One patient had high-grade transformation and two patients proceeded to a reduced-intensity allogeneic haematopoietic SCT following salvage chemotherapy. No other secondary malignancies have been detected.
The majority of the reported data involving auto-SCT for WM has been examined in single-centre retrospective studies, although recently data from multicentre registries have been reported. The largest published analysis of 158 patients7 reported a non-relapse mortality of 3.8%, relapse rate of 52.1% at 5 years, PFS of 39.7% at 5 years and OS of 68.5% at 5 years. The study concluded that auto-SCT was a reasonable option in patients with high-risk or early relapse disease as it had low morbidity and mortality.
WM is a relatively chemosensitive disease in most patients and, previously, transplant was used primarily for patients who had relapsed or progressed following initial chemotherapy. More recently, it has been proposed as part of a frontline treatment strategy, particularly for high-risk patients.7, 8, 9 Regardless of the timing of the high-dose therapy and auto-SCT, patients should be assessed as to whether they are potential future auto-SCT candidates at the time of diagnosis, as this will influence the choice of first-line therapy offered.10
In our study, the median time to best response post transplant was 5 months (range 1–17) and Kyriakou et al.7 reported their best response was attained at a median of 3 months. It is likely that, as most patients may show their best response to treatment within 3–6 months of therapy, restaging at a time point more than 3 months post transplant may be preferable to accurately reflect the best response to transplantation.
In conclusion, there were no reported secondary malignancies in our patient group and there was a low level of toxicity associated with this treatment with an OS of 88% at 1 year post transplant, demonstrating that auto-SCT is a feasible option in patients with WM/LPL with acceptable toxicity, and improves the quality of the response in a significant proportion of patients.
Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H et al. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. IARC: Lyon, France, 2008.
Treon SP How I treat Waldenstrom macroglobulinemia. Blood 2009; 114: 2375–2385.
Tam C, Seymour JF, Brown M, Campbell P, Scarlett J, Underhill C et al. Early and late infectious consequences of adding rituximab to fludarabine and cyclophosphamide in patients with indolent lymphoid malignancies. Haematologica 2005; 90: 700–702.
Dimopoulos MA, Hamilos G, Efstathiou E, Siapkaras I, Matsouka C, Gika D et al. Treatment of Waldenstrom's macroglobulinemia with the combination of fludarabine and cyclophosphamide. Leukemia Lymphoma 2003; 44: 993–996.
Tamburini J, Levy V, Chaleteix C, Fermand JP, Delmer A, Stalniewicz L et al. Fludarabine plus cyclophosphamide in Waldenstrom's macroglobulinemia: results in 49 patients. Leukemia 2005; 19: 1831–1834.
Owen RG, Kyle RA, Stone MJ, Rawstron AC, Leblond V, Merlini G et al. Response assessment in Waldenstrom macroglobulinaemia: update from the VIth International Workshop. Br J Haematol 2013; 160: 171–176.
Kyriakou C, Canals C, Sibon D, Cahn JY, Kazmi M, Arcese W et al. High-dose therapy and autologous stem-cell transplantation in Waldenstrom macroglobulinemia: the Lymphoma Working Party of the European Group for Blood and Marrow Transplantation. J Clin Oncol 2010; 28: 2227–2232.
Caravita T, Siniscalchi A, Tendas A, Cupelli L, Dentamaro T, Natale G et al. High-dose therapy with autologous PBSC transplantation in the front-line treatment of Waldenstrom's macroglobulinemia. Bone Marrow Transplant 2009; 43: 587–588.
Usmani S, Sexton R, Crowley J, Barlogie B . Autologous stem cell transplantation as a care option in Waldenstrom's macroglobulinemia. Clin Lymphoma Myeloma Leuk 2011; 11: 139–142.
Dimopoulos MA, Gertz MA, Kastritis E, Garcia-Sanz R, Kimby EK, Leblond V et al. Update on treatment recommendations from the Fourth International Workshop on Waldenstrom's Macroglobulinemia. J Clin Oncol 2009; 27: 120–126.
The authors declare no conflict of interest.
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Annals of Hematology (2019)
Blood Cancer Journal (2018)
Best Practice & Research Clinical Haematology (2016)
The role of autologous and allogeneic stem cell transplantation in the management of indolent B-cell lymphoma