- Email: [email protected]
Activity of Rituximab Monotherapy in Refractory Splenic Marginal Zone Lymphoma Complicated with Autoimmune Hemolytic Anemia
Case Report Activity of Rituximab Monotherapy in Refractory Splenic Marginal Zone Lymphoma Complicated with Autoimmune Hemolytic Anemia Alberto Fabbri,1 Alessandro Gozzetti,1 Stefano Lazzi,2 Mariapia Lenoci,1 Alessandro D’Amuri,2 Lorenzo Leoncini,2 Francesco Lauria1
Abstract We describe the case of a 61-year-old patient with refractory splenic marginal zone lymphoma and secondary autoimmune hemolytic anemia, both successfully treated with rituximab. This case demonstrates that rituximab monotherapy might also be a valid therapeutic approach in marginal zone lymphoma and autoimmune hemolytic anemia after failure of first-line treatment. Maintenance therapy, although expensive, could be useful to improve event-free survival in patients with unfavorable clinical behavior.
Clinical Lymphoma & Myeloma, Vol. 6, No. 6, 496-499, 2006 Key words: B-cell lymphoma, CD20, Chemotherapy, Rituximab, Splenectomy
Introduction Rituximab, a human/murine chimeric monoclonal antibody against the B-cell surface antigen CD20, has become part of standard therapy for patients with B-cell malignancies and is currently under investigation for other indications. This antibody determines, after a high affinity and stable CD20 binding, a selective B-lymphocyte depletion by multiple mechanisms, including complement-dependent cytotoxicity, antibody-dependent cellular cytotoxicity, and induction of apoptosis, and eventually by sensitizing cells to the effects of cytotoxic drugs.1 The increasing evidence of a critical role of the B-cell in the pathogenesis of several autoimmune disorders led to the extension of the use of rituximab, alone or in combination with immunosuppressant drugs, with encouraging results in patients with severe primary and secondary refractory autoimmune diseases.2-5 Splenic marginal zone lymphoma (SMZL) is an indolent peripheral B-cell neoplasm frequently associated with monoclonal gammopathy, chronic viral diseases (mainly hepatitis C virus infection), and autoimmune disorders. The 1Division
of Hematology and Transplants of Human Pathology and Oncology Policlinico “S. Maria alle Scotte” and University of Siena, Italy 2Department
Submitted: Dec 5, 2005; Revised: Feb 10, 2006; Accepted: Mar 26, 2006 Address for correspondence: Alberto Fabbri, MD, Division of Hematology and Transplants, Policlinico “S. Maria alle Scotte,” University of Siena, Viale Bracci, 13, 53100 Siena, Italy Fax: 39-0577-586185; e-mail: [email protected]
disease is rare, slightly more common in women than in men, with a median age at diagnosis of > 60 years; it typically presents with marked splenomegaly, frequent bone marrow involvement, and, uncommonly, nodal involvement. Therapeutic options in symptomatic patients include splenectomy and chemotherapy alone or combined with anti-CD20 antibody; although benefits of splenectomy are observed in the majority of patients, chemotherapy often induces partial and short responses, although more recently, purine analogues and monoclonal antibodies appear more effective.6-10
Case Report In July 2002, a 61-year-old man presented with a 2-month history of fatigue, intermittent fever, and mild splenomegaly (4 cm from costal arch). White blood cell count was 6600/μL; hemoglobin level 10 g/dL; mean corpuscular volume 100 reticulocytes were 3.2%; and platelet count 174,000/μL. Differential count and blood smear examination did not show abnormalities. Significant serum laboratory tests showed a mild increase of lactate dehydrogenase (LDH; 600 IU/L), bilirubin (1.7 mg/dL, direct 0.5), uric acid (9 mg/dL), creatinine (1.7 mg/dL), and `2-microglobulin (2.7 mg/dL), whereas haptoglobin was markedly decreased (< 8 mg/dL), and serum immunofixation was negative. Chest radiographic examination was normal, and total abdomen ultrasound scan confirmed splenomegaly with 16.5-cm maximum diameter. Bone marrow biopsy results showed erythroid hyperplasia and mild lymphoid polyclonal infiltrates. A few weeks after first examination, direct and indirect antiglobulin
Electronic forwarding or copying is a violation of US and International Copyright Laws. Authorization to photocopy items for internal or personal use, or the internal or personal use of specific clients, is granted by CIG Media Group, LP, ISSN #1557-9190, provided the appropriate fee is paid directly to Copyright Clearance Center, 222 Rosewood Drive, Danvers, MA 01923 USA 978-750-8400.
496 • Clinical Lymphoma & Myeloma May 2006
Figure 1 Histologic Presentation of Spleen
Figure 2 Histology and Immunohistochemical Features Indicative of Marginal Zone Lymphoma Infiltration
A A
B B
C C
(A) Lymphoid infiltration of the red pulp of the spleen (magnification ×50). (B) The infiltration consists of small/medium–sized lymphoid cells with dispersed chromatin and abundant pale cytoplasm (magnification ×100). (C) The immunostaining for CD20 showed intense positivity (magnification ×100).
test results, initially reported as negative, became positive (panagglutinant immunoglobulin G), and hemoglobin level decreased to 6.5 g/dL, whereas LDH and bilirubin levels increased to 806 IU/L and 2.5 mg/dL, respectively (direct 1 mg/dL), finally leading to a diagnosis of acquired autoimmune hemolytic anemia. The patient started therapy with prednisone (1 mg/kg body weight), obtaining only a transient improvement of his clinical picture with temporary increase of hemoglobin level and disappearance of systemic symptoms. Therefore, the patient underwent splenectomy (September 2002). Histologic examination of the spleen showed an infiltration of the red pulp
(A) Bone marrow biopsy results showed a nodular and interstitial infiltration by small/medium sized lymphocytes with peripheral epithelioid nests (magnification ×50). (B) The same features at a high power magnification (×100). (C) Lymphoid infiltration is CD20+ and has a nodular and interstitial distribution (magnification ×50).
with invasion of the sinuses by small- to medium-sized cells with more dispersed chromatin and abundant pale cytoplasm that resembled marginal zone cells and were interspersed with transformed blasts (Figure 1). The tumor cells showed the following immunophenotypes: CD20+, CD79a+, CD3–, CD5–, CD23–, and cyclin D1–. Molecular studies using the BIOMED-2® primers showed evidence of immunoglobulin heavy chain gene rearrangement. DNA extracted from paraffin section was amplified using a polymerase chain reaction method in a Mastercycler® with different sets of primers: FR2A, FR2FS, FR2BM, and FR3BM. Polymerase chain reaction conditions
Clinical Lymphoma & Myeloma May 2006 • 497
Rituximab for Splenic Marginal Zone Lymphoma Figure 3 Complete Remission with Disappearance of Bone Marrow B-Cell Clonal Infiltration A
B
tomography scan did not show abnormalities, but, in contrast, bone marrow biopsy results documented a nodal interstitial infiltrate of small- to medium-sized lymphocytes with morphologic and immunohistochemical features indicative of marginal zone lymphoma infiltration (Figure 2). Because of these findings and the clinical behavior of the disease, a chemotherapy program (cyclophosphamide/vincristine/prednisone) was started but interrupted after 3 cycles for recurrence of hemolytic anemia and persistence of bone marrow infiltration. Therefore, we started immunotherapy with rituximab given each week at 375 mg/m2 for a total of 4 administrations. Treatment was very well tolerated, and we observed a continuous progressive improvement of the hematologic picture. A reassessment performed 1 month after therapy completion documented a complete remission with disappearance of bone marrow B-cell clonal infiltration (Figure 3). Because of persistent direct Coombs’ test positivity, we started a maintenance therapy with rituximab (4 bimonthly administrations at 375 mg/m2). Eighteen months after the last treatment, the patient is still in complete remission without signs of hemolysis, including Coombs’ test results, which became negative.
Discussion
C
Bone marrow biopsy results showed (A) a persistent lymphoid nodular infiltration, but (B) immunostaining was negative for the B-cell marker CD79a and strongly positive for the pan-T marker CD3. (C) Magnification ×50.
and primers have been described in detail elsewhere.11 A diagnosis of SMZL was therefore performed. Splenectomy determined a quick recovery of the patient’s general condition, normalization of hemoglobin, LDH, bilirubin, aptoglobin levels, and, once again, disappearance of systemic symptoms; a total-body computed tomography scan was negative, and for these reasons, we decided to adopt a “watch and wait” strategy. After 5 months, the patient presented again with intermittent febrile episodes, apparently not related to any infectious disease. Routine blood test results were normal, total body computed
498 • Clinical Lymphoma & Myeloma May 2006
Optimal treatment for SMZL is not yet clearly established. Most cases can be managed with a “watch and wait” policy until patients become symptomatic from massive splenomegaly with abdominal discomfort, peripheral cytopenias, and clinical symptoms. We described a case of SMZL with associated acquired autoimmune hemolytic anemia, refractory to conventional therapy and splenectomy, which, in contrast, exhibited a complete remission after rituximab treatment. Rituximab has already been proven effective in the treatment of SMZL and secondary autoimmune hemolytic anemia. In our case, unlike other reports, disappearance of all hemolysis signs and complete remission were achieved. Rituximab efficacy in chemotherapyresistant cases could be caused by the peculiar mechanisms of action, not influenced by p53 deletion and MDR expression, which are consistently associated with a poor outcome. Because results obtained in SMZL with monochemotherapy and polychemotherapy are often unsatisfactory, rituximab monotherapy could be proposed as first-line treatment in patients not eligible for splenectomy, or as second choice in patients with relapsed or chemotherapy-refractory disease8; moreover, rituximab could also be useful to treat residual disease after splenectomy. Previous experience of prolonged rituximab treatment in patients with low-grade non-Hodgkin’s lymphoma comes from different groups: Ghielmini et al reported an overall response rate of 46% in patients with pretreated follicular non-Hodgkin’s lymphoma; in particular, at a median follow-up of 35 months, the median event-free survival (EFS) was 16 months in the no further treatment arm versus 36 months in the prolonged maintenance treatment arm; Hainsworth et al treated 44 chemotherapy-naive patients with B-cell chronic lymphocytic leukemia/small lymphocytic lymphoma with an overall response rate of 51% and a 2-year EFS rate of 49%.12,13 Maintenance
Alberto Fabbri et al therapy, even if expensive, could be useful to improve results in terms of EFS and progression-free survival in patients with marginal zone lymphoma and unfavorable clinical behavior.
5.
Conclusion
6.
Because the neoplastic cells in marginal zone lymphoma have constant strong expression of the antigen CD20, rituximab monotherapy might exert a high activity and represent the elective treatment in patients considered not suitable for splenectomy or a chemotherapeutic approach. Moreover, this case confirms that rituximab is safe and also has considerable activity in refractory SMZL and autoimmune diseases. Further studies are needed to confirm the role of rituximab monotherapy in SMZL and its possible superiority compared with chemotherapy.
7.
References 1. Johnson P, Glennie M. The mechanism of action of rituximab in the elimination of tumor cells. Semin Oncol 2003; 30:3-8. 2. Chasemberg SA, Isemberg D. Anti-B cell therapy (rituximab) in the treatment of autoimmune diseases. Lupus 2005; 14:210-214. 3. Pitashny M, Shoenfeld Y. B cell depletion in autoimmune rheumatic diseases. Autoimmunity Rev 2005; 4:436-441. 4. Paydas S, Yavuz S, Disel U, et al. Successful rituximab therapy for hemo-
8. 9. 10. 11.
12.
13.
lytic anemia associated with relapsed splenic marginal zone lymphoma with leukemic phase. Leuk Lymphoma 2003; 44:2165-2166. Petit J, Clavo M, de Sevilla AF, et al. Refractory cold agglutinin-immunohaemolytic anemia associated to marginal zone lymphoma responding to rituximab. Hematol J 2003; 4:450-451. Thieblemont C, Felman P, Berger F, et al. Treatment of splenic marginal zone B-cell lymphoma: an analysis of 81 patients. Clin Lymphoma 2002; 3:41-47. Arcaini L, Orlandi E, Scotti M, et al. Combination of rituximab, cyclophosphamide, and vincristine induces complete hematologic remission of splenic marginal zone lymphoma. Clin Lymphoma 2004; 4:250-252. Oscier D, Owen R, Johnson S. Splenic marginal zone lymphoma. Blood Rev 2005; 19:39-51. Bertoni F, Zucca E. State of the art therapeutics: marginal-zone lymphoma. J Clin Oncol 2005; 23:6415-6420. Bennet M, Sharma K, Yegena S, et al. Rituximab monotherapy for splenic marginal zone lymphoma. Haematol 2005; 90:856-858. van Dongen JJ, Langerak AW, Bruggemann M, et al. Design and standardization of PCR primers and protocols for detection of clonal immunoglobulin and T-cell receptor gene recombination in suspect lymphoproliferations: report of the BIOMED-2 Concerted Action BMH4-CT98-3936. Leukemia 2003; 17:2257-2317. Ghielmini M, Schmitz S-F, Cogliatti SB, et al Prolonged treatment with rituximab in patients with follicular lymphoma significantly increases event-free survival and response duration compared with the standard weekly x 4 schedule. Blood 2004; 103:4416-4423. Hainsworth JD, Litchy S, Barton JH, et al. Single agent rituximab as first line and maintanance treatment for patients with chronic lymphocytic leukemia or small lymphocytic lymphoma: a phase II trial of the Minnie Pearl Cancer Research Network. J Clin Oncol 2003; 21:1746-5171.
Clinical Lymphoma & Myeloma May 2006 • 499
Abstract We describe the case of a 61-year-old patient with refractory splenic marginal zone lymphoma and secondary autoimmune hemolytic anemia, both successfully treated with rituximab. This case demonstrates that rituximab monotherapy might also be a valid therapeutic approach in marginal zone lymphoma and autoimmune hemolytic anemia after failure of first-line treatment. Maintenance therapy, although expensive, could be useful to improve event-free survival in patients with unfavorable clinical behavior.
Clinical Lymphoma & Myeloma, Vol. 6, No. 6, 496-499, 2006 Key words: B-cell lymphoma, CD20, Chemotherapy, Rituximab, Splenectomy
Introduction Rituximab, a human/murine chimeric monoclonal antibody against the B-cell surface antigen CD20, has become part of standard therapy for patients with B-cell malignancies and is currently under investigation for other indications. This antibody determines, after a high affinity and stable CD20 binding, a selective B-lymphocyte depletion by multiple mechanisms, including complement-dependent cytotoxicity, antibody-dependent cellular cytotoxicity, and induction of apoptosis, and eventually by sensitizing cells to the effects of cytotoxic drugs.1 The increasing evidence of a critical role of the B-cell in the pathogenesis of several autoimmune disorders led to the extension of the use of rituximab, alone or in combination with immunosuppressant drugs, with encouraging results in patients with severe primary and secondary refractory autoimmune diseases.2-5 Splenic marginal zone lymphoma (SMZL) is an indolent peripheral B-cell neoplasm frequently associated with monoclonal gammopathy, chronic viral diseases (mainly hepatitis C virus infection), and autoimmune disorders. The 1Division
of Hematology and Transplants of Human Pathology and Oncology Policlinico “S. Maria alle Scotte” and University of Siena, Italy 2Department
Submitted: Dec 5, 2005; Revised: Feb 10, 2006; Accepted: Mar 26, 2006 Address for correspondence: Alberto Fabbri, MD, Division of Hematology and Transplants, Policlinico “S. Maria alle Scotte,” University of Siena, Viale Bracci, 13, 53100 Siena, Italy Fax: 39-0577-586185; e-mail: [email protected]
disease is rare, slightly more common in women than in men, with a median age at diagnosis of > 60 years; it typically presents with marked splenomegaly, frequent bone marrow involvement, and, uncommonly, nodal involvement. Therapeutic options in symptomatic patients include splenectomy and chemotherapy alone or combined with anti-CD20 antibody; although benefits of splenectomy are observed in the majority of patients, chemotherapy often induces partial and short responses, although more recently, purine analogues and monoclonal antibodies appear more effective.6-10
Case Report In July 2002, a 61-year-old man presented with a 2-month history of fatigue, intermittent fever, and mild splenomegaly (4 cm from costal arch). White blood cell count was 6600/μL; hemoglobin level 10 g/dL; mean corpuscular volume 100 reticulocytes were 3.2%; and platelet count 174,000/μL. Differential count and blood smear examination did not show abnormalities. Significant serum laboratory tests showed a mild increase of lactate dehydrogenase (LDH; 600 IU/L), bilirubin (1.7 mg/dL, direct 0.5), uric acid (9 mg/dL), creatinine (1.7 mg/dL), and `2-microglobulin (2.7 mg/dL), whereas haptoglobin was markedly decreased (< 8 mg/dL), and serum immunofixation was negative. Chest radiographic examination was normal, and total abdomen ultrasound scan confirmed splenomegaly with 16.5-cm maximum diameter. Bone marrow biopsy results showed erythroid hyperplasia and mild lymphoid polyclonal infiltrates. A few weeks after first examination, direct and indirect antiglobulin
Electronic forwarding or copying is a violation of US and International Copyright Laws. Authorization to photocopy items for internal or personal use, or the internal or personal use of specific clients, is granted by CIG Media Group, LP, ISSN #1557-9190, provided the appropriate fee is paid directly to Copyright Clearance Center, 222 Rosewood Drive, Danvers, MA 01923 USA 978-750-8400.
496 • Clinical Lymphoma & Myeloma May 2006
Figure 1 Histologic Presentation of Spleen
Figure 2 Histology and Immunohistochemical Features Indicative of Marginal Zone Lymphoma Infiltration
A A
B B
C C
(A) Lymphoid infiltration of the red pulp of the spleen (magnification ×50). (B) The infiltration consists of small/medium–sized lymphoid cells with dispersed chromatin and abundant pale cytoplasm (magnification ×100). (C) The immunostaining for CD20 showed intense positivity (magnification ×100).
test results, initially reported as negative, became positive (panagglutinant immunoglobulin G), and hemoglobin level decreased to 6.5 g/dL, whereas LDH and bilirubin levels increased to 806 IU/L and 2.5 mg/dL, respectively (direct 1 mg/dL), finally leading to a diagnosis of acquired autoimmune hemolytic anemia. The patient started therapy with prednisone (1 mg/kg body weight), obtaining only a transient improvement of his clinical picture with temporary increase of hemoglobin level and disappearance of systemic symptoms. Therefore, the patient underwent splenectomy (September 2002). Histologic examination of the spleen showed an infiltration of the red pulp
(A) Bone marrow biopsy results showed a nodular and interstitial infiltration by small/medium sized lymphocytes with peripheral epithelioid nests (magnification ×50). (B) The same features at a high power magnification (×100). (C) Lymphoid infiltration is CD20+ and has a nodular and interstitial distribution (magnification ×50).
with invasion of the sinuses by small- to medium-sized cells with more dispersed chromatin and abundant pale cytoplasm that resembled marginal zone cells and were interspersed with transformed blasts (Figure 1). The tumor cells showed the following immunophenotypes: CD20+, CD79a+, CD3–, CD5–, CD23–, and cyclin D1–. Molecular studies using the BIOMED-2® primers showed evidence of immunoglobulin heavy chain gene rearrangement. DNA extracted from paraffin section was amplified using a polymerase chain reaction method in a Mastercycler® with different sets of primers: FR2A, FR2FS, FR2BM, and FR3BM. Polymerase chain reaction conditions
Clinical Lymphoma & Myeloma May 2006 • 497
Rituximab for Splenic Marginal Zone Lymphoma Figure 3 Complete Remission with Disappearance of Bone Marrow B-Cell Clonal Infiltration A
B
tomography scan did not show abnormalities, but, in contrast, bone marrow biopsy results documented a nodal interstitial infiltrate of small- to medium-sized lymphocytes with morphologic and immunohistochemical features indicative of marginal zone lymphoma infiltration (Figure 2). Because of these findings and the clinical behavior of the disease, a chemotherapy program (cyclophosphamide/vincristine/prednisone) was started but interrupted after 3 cycles for recurrence of hemolytic anemia and persistence of bone marrow infiltration. Therefore, we started immunotherapy with rituximab given each week at 375 mg/m2 for a total of 4 administrations. Treatment was very well tolerated, and we observed a continuous progressive improvement of the hematologic picture. A reassessment performed 1 month after therapy completion documented a complete remission with disappearance of bone marrow B-cell clonal infiltration (Figure 3). Because of persistent direct Coombs’ test positivity, we started a maintenance therapy with rituximab (4 bimonthly administrations at 375 mg/m2). Eighteen months after the last treatment, the patient is still in complete remission without signs of hemolysis, including Coombs’ test results, which became negative.
Discussion
C
Bone marrow biopsy results showed (A) a persistent lymphoid nodular infiltration, but (B) immunostaining was negative for the B-cell marker CD79a and strongly positive for the pan-T marker CD3. (C) Magnification ×50.
and primers have been described in detail elsewhere.11 A diagnosis of SMZL was therefore performed. Splenectomy determined a quick recovery of the patient’s general condition, normalization of hemoglobin, LDH, bilirubin, aptoglobin levels, and, once again, disappearance of systemic symptoms; a total-body computed tomography scan was negative, and for these reasons, we decided to adopt a “watch and wait” strategy. After 5 months, the patient presented again with intermittent febrile episodes, apparently not related to any infectious disease. Routine blood test results were normal, total body computed
498 • Clinical Lymphoma & Myeloma May 2006
Optimal treatment for SMZL is not yet clearly established. Most cases can be managed with a “watch and wait” policy until patients become symptomatic from massive splenomegaly with abdominal discomfort, peripheral cytopenias, and clinical symptoms. We described a case of SMZL with associated acquired autoimmune hemolytic anemia, refractory to conventional therapy and splenectomy, which, in contrast, exhibited a complete remission after rituximab treatment. Rituximab has already been proven effective in the treatment of SMZL and secondary autoimmune hemolytic anemia. In our case, unlike other reports, disappearance of all hemolysis signs and complete remission were achieved. Rituximab efficacy in chemotherapyresistant cases could be caused by the peculiar mechanisms of action, not influenced by p53 deletion and MDR expression, which are consistently associated with a poor outcome. Because results obtained in SMZL with monochemotherapy and polychemotherapy are often unsatisfactory, rituximab monotherapy could be proposed as first-line treatment in patients not eligible for splenectomy, or as second choice in patients with relapsed or chemotherapy-refractory disease8; moreover, rituximab could also be useful to treat residual disease after splenectomy. Previous experience of prolonged rituximab treatment in patients with low-grade non-Hodgkin’s lymphoma comes from different groups: Ghielmini et al reported an overall response rate of 46% in patients with pretreated follicular non-Hodgkin’s lymphoma; in particular, at a median follow-up of 35 months, the median event-free survival (EFS) was 16 months in the no further treatment arm versus 36 months in the prolonged maintenance treatment arm; Hainsworth et al treated 44 chemotherapy-naive patients with B-cell chronic lymphocytic leukemia/small lymphocytic lymphoma with an overall response rate of 51% and a 2-year EFS rate of 49%.12,13 Maintenance
Alberto Fabbri et al therapy, even if expensive, could be useful to improve results in terms of EFS and progression-free survival in patients with marginal zone lymphoma and unfavorable clinical behavior.
5.
Conclusion
6.
Because the neoplastic cells in marginal zone lymphoma have constant strong expression of the antigen CD20, rituximab monotherapy might exert a high activity and represent the elective treatment in patients considered not suitable for splenectomy or a chemotherapeutic approach. Moreover, this case confirms that rituximab is safe and also has considerable activity in refractory SMZL and autoimmune diseases. Further studies are needed to confirm the role of rituximab monotherapy in SMZL and its possible superiority compared with chemotherapy.
7.
References 1. Johnson P, Glennie M. The mechanism of action of rituximab in the elimination of tumor cells. Semin Oncol 2003; 30:3-8. 2. Chasemberg SA, Isemberg D. Anti-B cell therapy (rituximab) in the treatment of autoimmune diseases. Lupus 2005; 14:210-214. 3. Pitashny M, Shoenfeld Y. B cell depletion in autoimmune rheumatic diseases. Autoimmunity Rev 2005; 4:436-441. 4. Paydas S, Yavuz S, Disel U, et al. Successful rituximab therapy for hemo-
8. 9. 10. 11.
12.
13.
lytic anemia associated with relapsed splenic marginal zone lymphoma with leukemic phase. Leuk Lymphoma 2003; 44:2165-2166. Petit J, Clavo M, de Sevilla AF, et al. Refractory cold agglutinin-immunohaemolytic anemia associated to marginal zone lymphoma responding to rituximab. Hematol J 2003; 4:450-451. Thieblemont C, Felman P, Berger F, et al. Treatment of splenic marginal zone B-cell lymphoma: an analysis of 81 patients. Clin Lymphoma 2002; 3:41-47. Arcaini L, Orlandi E, Scotti M, et al. Combination of rituximab, cyclophosphamide, and vincristine induces complete hematologic remission of splenic marginal zone lymphoma. Clin Lymphoma 2004; 4:250-252. Oscier D, Owen R, Johnson S. Splenic marginal zone lymphoma. Blood Rev 2005; 19:39-51. Bertoni F, Zucca E. State of the art therapeutics: marginal-zone lymphoma. J Clin Oncol 2005; 23:6415-6420. Bennet M, Sharma K, Yegena S, et al. Rituximab monotherapy for splenic marginal zone lymphoma. Haematol 2005; 90:856-858. van Dongen JJ, Langerak AW, Bruggemann M, et al. Design and standardization of PCR primers and protocols for detection of clonal immunoglobulin and T-cell receptor gene recombination in suspect lymphoproliferations: report of the BIOMED-2 Concerted Action BMH4-CT98-3936. Leukemia 2003; 17:2257-2317. Ghielmini M, Schmitz S-F, Cogliatti SB, et al Prolonged treatment with rituximab in patients with follicular lymphoma significantly increases event-free survival and response duration compared with the standard weekly x 4 schedule. Blood 2004; 103:4416-4423. Hainsworth JD, Litchy S, Barton JH, et al. Single agent rituximab as first line and maintanance treatment for patients with chronic lymphocytic leukemia or small lymphocytic lymphoma: a phase II trial of the Minnie Pearl Cancer Research Network. J Clin Oncol 2003; 21:1746-5171.
Clinical Lymphoma & Myeloma May 2006 • 499