- © 2011 by American Society of Clinical Oncology
Complete Remission of Waldenström Macroglobulinemia With Azacitidine and Rituximab
- Corresponding author: Lukas Weiss, Muellner Hauptstrasse 48, 5020 Salzburg, Austria; e-mail: lu.weiss{at}salk.at.
A 78-year-old male patient was referred to our department because of persistent macrocytic and hyperchromic anemia and occasional night sweats. A full blood count showed hemoglobin 9.0 g/dL (mean corpuscular volume, 99.3 fL; mean corpuscular hemoglobin, 33.3 pg), leukocytes 4.2 × 109/L (neutrophils 1.9 × 109/L), and platelets 335 × 109/L. Circulating kappa clonal B cells with an immunophenotype of lymphoplasmacytic lymphoma were detected. Slight deficiencies in vitamin B12 (195.5 pg/mL) and folate (2.6 ng/mL) but no iron deficiency were evident. Bone marrow biopsy revealed infiltration by small-cell lymphoma composed of morphologically atypical lymphocytes, plasma cells, and plasmacytic lymphocytes, comprising 20% of marrow volume, with remaining hematopoiesis lacking any signs of dysplasia. Serum electrophoresis and immunofixation showed kappa clonal immunoglobulin M (IgM) paraproteinemia (IgM 3,580 mg/dL). Therefore, the diagnosis of Waldenström macroglobulinemia (WM) was established. Neither lymphadenopathy nor hepatosplenomegaly were present, and no association with hepatitis C infection or signs of hemolysis were found. The extent of bone marrow infiltration by lymphoma cells could not explain symptomatic anemia.1 Conventional cytogenetics of the bone marrow aspirate showed a complex karyotype (45-48, X, del (1)(q22), −6, +7, der(7)t(Y;7)(q12:q32)x2, −8, −11, −16, +18, +1∼3; Fig 1). Complex karyotypes have been described in 14% of WM patients2 but might, in retrospect, have been indicative of myelodysplastic syndrome (MDS) that has otherwise been undetected up to now. Despite replenishment of vitamin B12 and folate deficiencies, anemia increased, and the patient began to require transfusions. Because of inadequate erythropoietin levels (26.3 U/L), stimulation with recombinant erythropoietin 40,000 IU per week was initiated but showed no response.
Repeated examination of the bone marrow after 3 months showed clearly increased infiltration by lymphoma representing 50% to 60% of marrow volume with immunohistochemical expression of CD79a (predominantly), CD20, and VS38c (Fig 2). Furthermore, trilinear dysplasia and hypoplasia were detected with blasts focally exceeding 5% of nucleated cells by using immunohistochemistry (glycophorin A, CD61, MPOX, CD34, and c-kit; Fig 2). Hence, coexisting MDS, precisely refractory cytopenia with multilineage dysplasia in transition to refractory anemia with excess blasts I, was diagnosed.
Although anemia could not be clearly attributed to MDS or WM, we independently performed risk scoring and evaluation of therapy indication: transfusion-dependent anemia in WM represents a criterion for therapy indication3 as does MDS with an International Prognostic Scoring System (IPSS) score of intermediate 2 with bone marrow blasts of 5% and complex karyotype as well as chromosome 7 aberrations at first diagnosis.4 Risk stratification according to WHO classification–based Prognostic Scoring System (WPSS) at time of erythropoietin failure was high with 5 points,5 translating into an estimated median overall survival of 9 months and a cumulative risk of leukemic transformation at 2 years of 0.8.
Weighing the clinical significance of the respective diagnoses for the symptomatic patient, we deemed MDS to be the potentially more life-threatening condition. Advanced age and mild renal insufficiency were considered contraindications for intensive chemotherapy. Because of its reported efficacy in higher-risk MDS,6 azacitidine (AZA) was the treatment we chose. Therapy was initiated at a standard dosage of 75 mg/m2 subcutaneously for 7 days every 28 days. In the initial cycles, we observed a significant drop in monoclonal protein, and we therefore pursued AZA monotherapy despite few changes in transfusion requirements. After seven cycles, the patient had persistent anemia requiring transfusions every 3 to 4 weeks. Although paraproteinemia had declined substantially from IgM 3,580 mg/dL to 1,850 mg/dL, restaging examination of the bone marrow paradoxically demonstrated further increased infiltration by lymphoma with 70% to 80% of marrow volume. It seems that AZA monotherapy was able to suppress neoplastic IgM production without effective induction of apoptosis in lymphoma cells, as has previously been reported for other antineoplastic agents.7
We assumed that suppression of hematopoiesis by expanding lymphoma in the bone marrow might hinder clinical improvement by AZA. Therefore, we decided to continue AZA treatment in combination with the anti-CD20 antibody rituximab. The standard dosage of 375 mg/m2 intravenously was used weekly for 4 weeks and then every 4 weeks concomitant to AZA treatment. No dose modifications were performed since no additive or synergistic toxicity was suspected. During rituximab treatment, no IgM flare reaction was observed.
After completion of eight cycles of concomitant AZA and rituximab (AZA-R) treatment, hemoglobin levels exceeded 12 g/dL, paraproteinemia declined to IgM 31 mg/dL with a normal free light chain ratio (Fig 3; CR, complete remission), and bone marrow was free of lymphoma (Fig 2). Nevertheless, myelodysplastic changes of hematopoiesis were still observed in trephine biopsy, reflecting a persistent refractory cytopenia with multilineage dysplasia according to WHO criteria (Fig 2). AZA treatment was continued without rituximab thereafter, and negative immunofixation in serum and urine was accomplished only at 24 weeks after the end of rituximab treatment. This was confirmed 8 weeks later, representing complete remission according to current response criteria for WM.8 The delayed serologic remission of WM in contrast to early remission in bone marrow could be explained by the long half-life of circulating IgM.
Several studies9–13 have investigated rituximab monotherapy for the treatment of WM: in five different trials, 61 previously untreated patients and 99 patients with relapsed or refractory disease were treated with rituximab by using the standard dosage of 375 mg/m2 for four or eight cycles. No complete response could be observed although clinical activity was clearly evident. Nevertheless, rituximab represents an essential combination partner for chemoimmunotherapy of WM.1
There is only limited data on the effect of AZA in lymphoid neoplasms, but AZA has recently been described to exhibit dose-dependent cytotoxicity in WM cell lines as well as in primary WM cells.14 So far, there are no reports on AZA in the clinical practice of treating WM.
We believe that our patient could obtain complete remission of WM only by the combined activity of AZA and rituximab. Although initial AZA monotherapy could clearly reduce paraproteinemia, it did not result in measurable reduction of cellular tumor burden. Only the addition of rituximab could induce significant clinical response. In the light of the existing literature, we do not consider rituximab alone to confer the induction of complete remission.
A possible explanation for this additive or even synergistic effect might lie in the enhancement of immunologic effector mechanisms, leading to increased antineoplastic activity of rituximab. In a xenograft model for acute myeloid leukemia, AZA has been shown to enhance the activity of lintuzumab, a monoclonal antibody directed against CD33 expressed on leukemic cells.15 This effect has been attributed to an increase in antibody-dependent cellular cytotoxicity and phagocytic activities. Considering AZA's diverse modes of action, interference with downstream targets of rituximab signaling also seem probable.
Ongoing clinical trials are using AZA as a single agent or in combination with known therapeutics for the treatment of various lymphoid neoplasms. Since we have observed isolated paraprotein response without relevant control of tumor mass in our case, we believe that AZA in combination with rituximab may represent a superior therapeutic strategy for the exploration of AZA efficacy in clinical trials.
AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST
Although all authors completed the disclosure declaration, the following author(s) indicated a financial or other interest that is relevant to the subject matter under consideration in this article. Certain relationships marked with a “U” are those for which no compensation was received; those relationships marked with a “C” were compensated. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors.
Employment or Leadership Position: None Consultant or Advisory Role: Lisa Pleyer, Celgene (C); Alexander Egle, Celgene (C) Stock Ownership: None Honoraria: Lukas Weiss, Celgene; Lisa Pleyer, Celgene, Bristol-Myers Squibb, Novartis; Richard Greil, Roche, Celgene; Alexander Egle, Roche, Celgene Research Funding: Alexander Egle, Celgene Expert Testimony: None Other Remuneration: Lukas Weiss, Roche; Alexander Egle, Roche
