research paper
Outcomes in splenic marginal zone lymphoma: analysis of 107 patients treated in British Columbia
Katharine H. Xing,1 Amrit Kahlon,2 Brian F. Skinnider,3 Joseph M. Connors,4 Randy D. Gascoyne,3 Laurie H. Sehn,4 Kerry J. Savage,4 Graham W. Slack,3 Tamara N. Shenkier,4 Richard Klasa,4 Alina S. Gerrie4,5 and Diego Villa4 1
Department of Medical Oncology, British
Columbia Cancer Agency – Vancouver Island Centre, Victoria, 2Department of Hematology, Surrey Memorial Hospital, Surrey, 3Centre for Lymphoid Cancer and Department of Pathology, British Columbia Cancer Agency, 4Centre for Lymphoid Cancer and Department of Medical Oncology, British Columbia Cancer Agency, and 5
Leukemia/BMT Program of British Columbia,
Vancouver General Hospital, Vancouver, BC, Canada Received 13 November 2014; accepted for publication 1 January 2015 Correspondence: Katharine H. Xing, BC Cancer Agency – Vancouver Island Centre, 2410 Lee Avenue, Victoria, BC V8R 6V5, Canada. E-mail: [email protected] A preliminary analysis of the results reported
Summary Splenic marginal zone lymphoma (SMZL) accounts for less than 2% of all non-Hodgkin lymphomas. We identified 107 cases diagnosed with SMZL between 1985 and 2012 from the British Columbia Cancer Agency Centre for Lymphoid Cancer and Lymphoma Pathology Databases. Patient characteristics were: median age 67 years (range 30–88), male 40%, stage IV 98%, splenomegaly 93%, bone marrow involvement 96%, peripheral blood involvement 87%. As initial treatment, 52 underwent splenectomy (10 with chemotherapy), 38 chemotherapy alone (21 chemoimmunotherapy containing rituximab, 1 rituximab alone), two antivirals for hepatitis C, and 15 were only observed. The 10-year overall survival for first-line splenectomy versus chemotherapy was 61% and 42%, respectively [Hazard Ratio (HR) 048, 95% confidence interval (CI) 026–088, P = 0017]. The 10-year failure-free survival (FFS) after first-line splenectomy vs chemotherapy was 39% and 14%, respectively (HR 048, 95% CI 028–080, P = 0004). Among the 38 patients who received first-line chemotherapy, FFS was similar between those receiving rituximab (n = 22) and those who did not (n = 16) (HR 064, 95% CI 031–134, P = 0238). Fifteen patients transformed to aggressive lymphoma with median time to transformation of 35 years (range 6 months to 12 years) and the 10-year transformation rate was 18%. In conclusion, splenectomy remains a reasonable treatment for patients with SMZL. Keywords: splenic marginal zone lymphoma, splenectomy, rituximab, transformation, chemotherapy.
in this paper was presented at the 55th American Society of Hematology Annual Meeting, New Orleans LA, USA.
Splenic marginal zone lymphoma (SMZL) was first recognized as a provisional entity in the Revised European/American Lymphoma (REAL) classification (Harris et al, 1994). Subsequently, the 2008 World Health Organization (WHO) classification described 3 clinically and pathologically distinct subtypes of marginal zone lymphoma (MZL), namely extranodal MZL, splenic MZL and nodal MZL (Swerdlow et al, 2008). SMZL is an uncommon indolent lymphoma and accounts for less than 2% of all non-Hodgkin lymphomas (Armitage & Weisenburger, 1998). It is postulated to arise from marginal zone memory B cells of splenic origin, which surround and replace the splenic white pulp germinal centres and infiltrate the red pulp. Tumour cells express surface
First published online 02 December 2015 doi: 10.1111/bjh.13320
immunoglobulins (most commonly IgM but also IgD), B cell markers (CD19, CD20, CD22) and BCL2. Lack of CD5 helps to distinguish SMZL from chronic lymphocytic leukaemia and mantle cell lymphoma, while lack of CD103 and CD25 help to distinguish it from hairy cell leukaemia (Matutes et al, 1994, 2008). Patients with SMZL typically present with symptomatic splenomegaly, peripheral blood cytopenias or lymphocytosis with villous lymphocytes. Splenic hilar nodes and bone marrow are also commonly involved, but peripheral lymphadenopathy is rare (Armitage & Weisenburger, 1998; Berger et al, 2000). A monoclonal protein and autoimmune manifestations may be present in a third of patients (Berger et al, 2000). An associaª 2015 John Wiley & Sons Ltd British Journal of Haematology, 2015, 169, 520–527
Splenic Marginal Zone Lymphoma tion with hepatitis C infection has been reported, particularly in Southern Europe (Hermine et al, 2002; Arcaini et al, 2006). Patients with SMZL often have an indolent course with median life expectancy greater than 10 years. However, about a quarter of patients have a more aggressive course, with disease progression and death within the first few years after diagnosis (Arcaini et al, 2006). As with other indolent lymphomas, SMZL can develop transformation to high-grade lymphoma (Mulligan et al, 1991). The majority of patients with SMZL will require at least one treatment during their disease course. Given the rarity of this disease, most studies are retrospective institutional reviews and there is no standard initial therapy. Splenectomy has traditionally been the treatment of choice for patients with symptomatic splenomegaly, with the additional advantage that it allows for pathological confirmation of the diagnosis. Systemic therapy, including chemotherapy or chemoimmunotherapy and single agent rituximab, have been used as alternative strategies to splenectomy. In particular, single-agent rituximab may achieve high response rates (88–95%) with low toxicity (Tsimberidou et al, 2006; Bennett & Schechter, 2010; Kalpadakis et al, 2013). However, the optimal schedule for rituximab is not known, and there are no studies comparing splenectomy to rituximab and chemotherapy. We report the treatments and outcomes of 107 patients with SMZL treated in our institution over two decades.
Patients and methods All adult patients diagnosed with SZML between 1985 and 2012 were identified in the British Columbia Cancer Agency (BCCA) Lymphoid Cancer and Lymphoma Pathology Databases. Diagnoses were based on the 2008 WHO classification (Swerdlow et al, 2008). A BCCA haematopathologist reviewed 40 of the 59 available splenectomy specimens. The remaining 19 splenectomy specimens could not be obtained for review. Patient, disease, treatment and outcome data were obtained from these databases as well as paper and electronic health records. For each patient, all lines of treatment were recorded. As there was no formal provincial treatment policy for SMZL during the study period, individual treating physicians recommended the type and timing of treatments. The study was approved by the University of British Columbia and the BCCA Research Ethics Board.
Statistical analysis Overall survival (OS) was measured from date of diagnosis to date of death from any cause or last follow-up. Failurefree survival (FFS) was measured from the date of first therapy initiation to the date of lymphoma recurrence or progression, transformation, death or last follow-up. Failurefree survival calculations therefore exclude patients who were observed and never received treatment. Time to ª 2015 John Wiley & Sons Ltd British Journal of Haematology, 2015, 169, 520–527
transformation (TTT) was calculated from the date of diagnosis to the date of transformation to aggressive lymphoma. Baseline characteristics were compared between groups using the Pearson chi-square test. Survival was estimated using the Kaplan–Meier method and comparisons were made using the log rank test (Kaplan & Meier, 1958). Multivariate Cox proportional hazards regression was performed to evaluate the association between first-line treatment (splenectomy versus chemotherapy) and outcomes, adjusted for the following prognostic factors in patients with available data: age ≥60, Eastern Cooperative Oncology Group (ECOG) performance status ≥2, elevated lactate dehydrogenase (LDH), and haemoglobin 5 9 109/l Platelet count < 100 9 109/l Elevated LDH Hepatitis C positive Hepatitis B positive HIV positive
107 67 (30–88) 43/64 104/106 18/101 100/104 90/103 98/105 22/98 60/102 46/91 19/97 22/85 5/59 1/58 0/31
98 18 96 87 93 22 59 51 46 34 8 2 0
ECOG, Eastern Cooperative Oncology Group; LDH, lactate dehydrogenase; HIV, human immunodeficiency virus.
521
K. H. Xing et al splenomegaly (as defined by radiology, 93%), bone marrow involvement (96%) and peripheral blood lymphocytosis (87%). B symptoms were present in 18% patients, and 22% had ECOG performance status ≥2. Hepatitis C serology was positive in 5 of 59 patients with available data, Hepatitis B in 1 out of 58 patients, and human immunodeficiency virus in none out of 31 patients tested.
Initial treatment As part of initial treatment, 52 patients underwent splenectomy (10 immediately before or after chemotherapy) (Table I). Twelve of these patients underwent splenectomy after a median period of observation from diagnosis of 28 years (range: 6 months–63 years), while the other 40 underwent splenectomy shortly after diagnosis, with median time to splenectomy of 12 months (range: 0–4 months). Of the ten patients receiving chemotherapy along with splenectomy as first line therapy, three of the chemotherapy regimens contained rituximab [two received cyclophosphamide, doxorubicin, vincristine, prednisone and rituximab (CHOPR), one received fludarabine and rituximab (FR)] and 7 did not (two received a CHOP-like regimen, four received chlorambucil and one fludarabine). Thirty-eight patients received chemotherapy alone as initial treatment: 26 immediately after diagnosis and 12 after a median of 31 years (range: 3 months–85 years) of observation. Of these, 22 received various rituximab-containing chemotherapy regimens: 17 cyclophosphamide, vincristine, prednisone and rituximab (CVP-R), one cyclophosphamide and rituximab, three FR and one single agent rituximab. In total, 11 out of 22 received maintenance rituximab post-chemotherapy. Of the 16 patients who did not receive rituximab, seven received chlorambucil, three CVP, one
cladribine, four fludarabine, and one cyclophosphamide, fludarabine and prednisone. Two patients were treated with antiviral therapy against hepatitis C alone, which was not considered to be definitive therapy when calculating FFS. The remaining 15 patients were only observed and never required any treatment. Corticosteroids were temporarily used in two of these patients for management of cytopenias, although this was not considered to be definitive therapy. Table II shows that baseline characteristics were generally similar between patients initially treated with chemotherapy alone versus splenectomy, although there was a higher proportion of thrombocytopenia in the former group (31% vs. 8%, P = 0012). Compared to patients who received treatment with either chemotherapy and/or splenectomy, patients who were observed or received antiviral therapy had worse performance status (44% vs. 17%, P = 0017) and less frequent anaemia (24% vs. 66%, P = 0001).
Subsequent lines of treatment Of the 42 patients who underwent splenectomy alone as initial treatment, nine subsequently received chemotherapy at disease progression (eight received rituximab-containing chemotherapy, one had reduced intensity allogeneic transplant), one had excision of a soft tissue mass and one received targeted radiation and subsequent ibritumomab tiuxetan (Table III). Of the ten patients who received combined splenectomy and chemotherapy, five patients received subsequent chemotherapy (two with rituximab). Of the 38 patients who received chemotherapy alone as initial treatment, six subsequently received combined chemotherapy and splenectomy (one of these patients received an allogeneic transplant), one splenectomy alone,
Table II. Comparison of the characteristics of patients receiving initial splenectomy, chemotherapy and antiviral/observation. Fractions represent number of patients divided by number of patients with available data. Initial treatment
Characteristic Patients (n) Male sex Median age, years (range) B symptoms ECOG ≥ 2 Hb < 120 g/l Platelets < 100 9 109/l Lymphocytes >5 9 109/l Elevated LDH Bone marrow involvement Peripheral blood involvement
Splenectomy* (A) N (%)
Chemotherapy Alone (B) N (%)
Observation/Antivirals (C) N (%)
P-value (A vs. B)
P-value (A/B vs. C)
52 23 66 8/50 8/47 28/48 14/45 17/41 10/40 48/51 37/48
38 13 67 9/36 6/35 28/37 3/36 20/34 14/31 37/37 36/38
17 7 73 1/15 7/16 4/17 2/16 9/16 3/13 15/16 17/17
0338 0174 0301 0988 0095 0012 0134 0075 0133 0023
0928 0360 0221 0017 0001 0434 0615 0446 0587 0086
(44%) (30–86) (16%) (17%) (58%) (31%) (41%) (25%) (94%) (77%)
(34%) (32–85) (25%) (17%) (76%) (8%) (59%) (45%) (100%) (95%)
(41%) (50–88) (7%) (44%) (24%) (13%) (56%) (23%) (95%) (100%)
ECOG, Eastern Cooperative Oncology Group performance status; LDH, lactate dehydrogenase. *10/52 patients received splenectomy and chemotherapy.
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ª 2015 John Wiley & Sons Ltd British Journal of Haematology, 2015, 169, 520–527
Splenic Marginal Zone Lymphoma Table III. Initial and subsequent treatments of patients with Splenic Marginal Zone Lymphoma (SMZL). Initial treatment
Subsequent treatment for SMZL
Subsequent transformation N
Modality
N
Modality
N
Splenectomy
42
Chemotherapy Excision (soft tissue) Radiation No further treatment*
9 1 1 31
4
Splenectomy + chemotherapy
10 38 [22/38]
Hepatitis C anti-virals Observation alone
2 15
5 5 1 6 4 1 26 2 15
3
Chemotherapy [with Rituximab]
Chemotherapy No further treatment* Splenectomy Splenectomy + chemotherapy Chemotherapy Radiation No further treatment* No further treatment No further treatment
8
0 0
*No further treatment for SMZL (treatment for transformed disease not counted as subsequent treatment for SMZL).
four chemotherapy alone and one radiation therapy to the left orbit for localized disease progression. Neither of the two patients who received antivirals had further progression. Fifteen patients were observed for a median follow-up of 38 years (range: 5 days–106 years) and have not required any treatment to date, although one patient died 5 days after diagnosis from an acute myocardial infarction.
Survival outcomes With a median follow-up of 83 years (range: 23–248 years) for living patients, the 5- and 10-year OS for the entire cohort was 64% and 50%, respectively. The 5- and 10-year FFS after first-line treatment (for the 90 patients who received treatment) was 47% and 29%, respectively. The 5- and 10-year OS for the patients who had splenectomy as initial therapy (n = 52) was 77% and 61%, respectively; for those who had chemotherapy alone (n = 38), 55% and 42%, respectively; and for those who were observed or received antivirals (n = 17), 47% and 40%, respectively (P = 0010 for all three comparisons) (Fig 1). Patients who underwent splenectomy as part of their initial therapy (i.e., including ten who received chemotherapy) had an improved OS compared to those who received chemotherapy alone (HR 048, 95% CI 026–088, P = 0017) or observation (HR 037, 95% CI 017–082, P = 0014) as initial therapy. Overall survival was similar between patients who were initially observed or treated with chemotherapy (HR 042, 95% CI 064–289, P = 0419). There was no difference in OS between patients who received splenectomy in later lines of treatment (n = 9) (5- and 10-year OS, 44% and 33%, respectively) compared to those who were splenectomized as initial treatment (HR 214, 95% CI 085–537, P = 0106). ª 2015 John Wiley & Sons Ltd British Journal of Haematology, 2015, 169, 520–527
P = 0·010
Fig 1. Overall survival by initial treatment strategy (n = 107).
The 5- and 10-year FFS following first-line splenectomy (n = 52) was 58% and 39%, respectively; compared to 31% and 14%, respectively, for those who received chemotherapy (n = 30), (HR 048, 95% CI 028–080, P = 0004) (Fig 2). The median FFS post-splenectomy was 67 years, while the median FFS post-chemotherapy was 29 years. Among the 38 patients who received chemotherapy alone initially, there was no difference in FFS between those who received rituximab (n = 22) compared to those who did not (n = 16) (HR 064, 95% CI 031–134, P = 0238). A total of 53 patients died during follow-up. Twenty-seven of the deaths were from lymphoma (51%), and ten of these were from transformation to aggressive lymphoma. Other causes of death included: five infections (three of whom had prior splenectomies); five other malignancies (three lung cancer, one prostate cancer, one amyloidosis); four cardiovascular 523
K. H. Xing et al
P = 0·004
Fig 2. Failure-free survival by initial treatment strategy (n = 90).
Fig 3. Time to transformation (n = 107)
disease; seven miscellaneous causes (one each of pulmonary embolism, liver failure, renal failure, intracranial haemorrhage, gastrointestinal haemorrhage, pulmonary fibrosis and adult respiratory distress syndrome); and five unknown causes (but not lymphoma). Twenty-three (85%) of the 27 lymphomarelated deaths occurred within the first 4 years of diagnosis, while the remaining four patients died at 7, 10, 12, 17 years post-diagnosis.
the endpoint was restricted to deaths due to lymphoma, haemoglobin < 120 g/l, elevated LDH, age ≥ 60 years and ECOG performance status ≥2 were all found to be associated with decreased survival. (Table S1). Multivariate analyses for OS and FFS were performed in 70 patients receiving first-line splenectomy (n = 39) or chemotherapy (n = 31) who had complete prognostic factor data, including age, ECOG performance status, LDH and haemoglobin. Age ≥60 years (HR 272, 95% CI 122–605, P = 0014) and elevated LDH (HR 215, 95% CI 108–429, P = 0030), but not treatment (HR 062, 95% CI 030–127, P = 0194), were independently associated with worse OS. On the other hand, treatment was the only variable associated with FFS in multivariate analysis; patients treated with splenectomy experienced improved FFS compared to those receiving chemotherapy (HR 047, 95% CI 026–085, P = 0013).
Transformation to aggressive lymphoma A total of 15 patients (14%) experienced transformation to aggressive lymphoma with a median TTT of 35 years (range: 6 months to 12 years). These were all patients who had previously received splenectomy and/or chemotherapy for SMZL. The 5- and 10-year rates of transformation were 9% and 18%, respectively (Fig 3). Transformation was confirmed by biopsy in 11 patients (all of which were diffuse large B cell lymphoma [DLBCL]), and the remaining four were diagnosed based on clinical/laboratory findings (Al-Tourah et al, 2008). Nine received CHOP-like chemotherapy (seven with rituximab), one received radiation to the site of DLBCL transformation (thyroid), four received single-agent chemotherapy due to poor performance status and one had insufficient records. Ten died from transformed lymphoma, and five are alive to date (all of whom received CHOP-like chemotherapy). Median OS post-transformation was 84 months (range 0 to 8 years) and 5-year OS was 33%.
Prognosis In univariate analysis, age ≥60 years and ECOG performance status ≥2 were found to be associated with a significantly worse OS. No baseline patient characteristics were associated with worse FFS for treated patients or TTT. However, when 524
Discussion Over the course of almost three decades, patients with SMZL at our institution received a broad range of treatments at initial presentation and subsequent relapse. Observation, splenectomy and chemotherapy were the three most common treatment modalities. The majority of patients required at least one line of therapy during their disease course. Consistent with the indolent behaviour of SMZL, in our cohort the median OS was 10 years, and >15 years for the subset of patients who were able to undergo splenectomy as part of first-line therapy. Due to the retrospective nature of this study, treatment was not randomized and was subject to patient, disease and physician bias. For example, patients with indolent disease biology may have been initially observed. Those who received chemotherapy alone initially may have had a higher burden of disease, with trend toward higher LDH (P = 0075), more ª 2015 John Wiley & Sons Ltd British Journal of Haematology, 2015, 169, 520–527
Splenic Marginal Zone Lymphoma thrombocytopenia (P = 0012) and lower haemoglobin (P = 0095). Although one can speculate that patients chosen for splenectomy were probably fitter and healthier, other important clinical characteristics were similar, including sex, age, B symptoms and performance status. Splenectomy has traditionally been the treatment of choice for symptomatic patients with SMZL (Troussard et al, 1996; Parry-Jones et al, 2003; Thieblemont et al, 2003). Splenectomy offers immediate symptomatic relief from bulky splenomegaly, frequent improvement in cytopenias and an additional opportunity for pathological confirmation of the diagnosis. The median post-splenectomy FFS in our cohort was 67 years, consistent with other reports describing 4–8 years (Troussard et al, 1996; Thieblemont et al, 2003; Lenglet et al, 2014). Our data confirm that splenectomy continues to play an important role in the treatment of SMZL. Patients selected for splenectomy must have been fit enough to tolerate abdominal surgery under general anaesthesia as well as the ensuing immune suppression. One significant concern with splenectomy is the risk of infection from encapsulated organisms. Of note, it is BCCA policy to recommend immunization at least 2 weeks prior to splenectomy. Three of the 61 (5%) patients who underwent splenectomy in our series died from infectious complications, similar to the 4% rate reported in other series of splenectomy for SMZL (Lenglet et al, 2014). Prior to the rituximab era, splenectomy was found to improve OS compared to chlorambucil in retrospective series (Troussard et al, 1996; Parry-Jones et al, 2003). However, alkylating chemotherapy achieves modest response rates in SMZL (Parry-Jones et al, 2003; Iannitto et al, 2004). In contrast, single-agent rituximab is very active against SMZL, with high overall response rates (88% to 100%) including complete responses ranging from 43% to 79% (Tsimberidou et al, 2006; Bennett et al, 2008; Else et al, 2012; Kalpadakis et al, 2013). Purine analogues, especially when combined with rituximab, are also highly effective (Cervetti et al, 2013). In several retrospective series, rituximab-containing chemotherapy was reported to improve outcomes compared with splenectomy (Else et al, 2012; Kalpadakis et al, 2013), although there has been no randomized study to date. In our series, over half of the patients initially treated with chemotherapy received rituximab. There were no clinically significant differences in outcomes between those who received rituximab-containing regimens and those who did not. Compared to recent reports showing superior outcomes with rituximab as a single agent or in combination (Tsimberidou et al, 2006; Bennett et al, 2008; Else et al, 2012; Kalpadakis et al, 2013), this difference in results may be due to the relatively small number of patients studied, lack of treatment randomization and differences in regimen administered (there were various chemotherapy backbones and one patient received single-agent rituximab). It is important to identify the subgroup of patients who may experience a more aggressive disease course from the ª 2015 John Wiley & Sons Ltd British Journal of Haematology, 2015, 169, 520–527
outset. The Integruppo Italiano Linfomi prognostic model uses haemoglobin
Outcomes in splenic marginal zone lymphoma: analysis of 107 patients treated in British Columbia
Katharine H. Xing,1 Amrit Kahlon,2 Brian F. Skinnider,3 Joseph M. Connors,4 Randy D. Gascoyne,3 Laurie H. Sehn,4 Kerry J. Savage,4 Graham W. Slack,3 Tamara N. Shenkier,4 Richard Klasa,4 Alina S. Gerrie4,5 and Diego Villa4 1
Department of Medical Oncology, British
Columbia Cancer Agency – Vancouver Island Centre, Victoria, 2Department of Hematology, Surrey Memorial Hospital, Surrey, 3Centre for Lymphoid Cancer and Department of Pathology, British Columbia Cancer Agency, 4Centre for Lymphoid Cancer and Department of Medical Oncology, British Columbia Cancer Agency, and 5
Leukemia/BMT Program of British Columbia,
Vancouver General Hospital, Vancouver, BC, Canada Received 13 November 2014; accepted for publication 1 January 2015 Correspondence: Katharine H. Xing, BC Cancer Agency – Vancouver Island Centre, 2410 Lee Avenue, Victoria, BC V8R 6V5, Canada. E-mail: [email protected] A preliminary analysis of the results reported
Summary Splenic marginal zone lymphoma (SMZL) accounts for less than 2% of all non-Hodgkin lymphomas. We identified 107 cases diagnosed with SMZL between 1985 and 2012 from the British Columbia Cancer Agency Centre for Lymphoid Cancer and Lymphoma Pathology Databases. Patient characteristics were: median age 67 years (range 30–88), male 40%, stage IV 98%, splenomegaly 93%, bone marrow involvement 96%, peripheral blood involvement 87%. As initial treatment, 52 underwent splenectomy (10 with chemotherapy), 38 chemotherapy alone (21 chemoimmunotherapy containing rituximab, 1 rituximab alone), two antivirals for hepatitis C, and 15 were only observed. The 10-year overall survival for first-line splenectomy versus chemotherapy was 61% and 42%, respectively [Hazard Ratio (HR) 048, 95% confidence interval (CI) 026–088, P = 0017]. The 10-year failure-free survival (FFS) after first-line splenectomy vs chemotherapy was 39% and 14%, respectively (HR 048, 95% CI 028–080, P = 0004). Among the 38 patients who received first-line chemotherapy, FFS was similar between those receiving rituximab (n = 22) and those who did not (n = 16) (HR 064, 95% CI 031–134, P = 0238). Fifteen patients transformed to aggressive lymphoma with median time to transformation of 35 years (range 6 months to 12 years) and the 10-year transformation rate was 18%. In conclusion, splenectomy remains a reasonable treatment for patients with SMZL. Keywords: splenic marginal zone lymphoma, splenectomy, rituximab, transformation, chemotherapy.
in this paper was presented at the 55th American Society of Hematology Annual Meeting, New Orleans LA, USA.
Splenic marginal zone lymphoma (SMZL) was first recognized as a provisional entity in the Revised European/American Lymphoma (REAL) classification (Harris et al, 1994). Subsequently, the 2008 World Health Organization (WHO) classification described 3 clinically and pathologically distinct subtypes of marginal zone lymphoma (MZL), namely extranodal MZL, splenic MZL and nodal MZL (Swerdlow et al, 2008). SMZL is an uncommon indolent lymphoma and accounts for less than 2% of all non-Hodgkin lymphomas (Armitage & Weisenburger, 1998). It is postulated to arise from marginal zone memory B cells of splenic origin, which surround and replace the splenic white pulp germinal centres and infiltrate the red pulp. Tumour cells express surface
First published online 02 December 2015 doi: 10.1111/bjh.13320
immunoglobulins (most commonly IgM but also IgD), B cell markers (CD19, CD20, CD22) and BCL2. Lack of CD5 helps to distinguish SMZL from chronic lymphocytic leukaemia and mantle cell lymphoma, while lack of CD103 and CD25 help to distinguish it from hairy cell leukaemia (Matutes et al, 1994, 2008). Patients with SMZL typically present with symptomatic splenomegaly, peripheral blood cytopenias or lymphocytosis with villous lymphocytes. Splenic hilar nodes and bone marrow are also commonly involved, but peripheral lymphadenopathy is rare (Armitage & Weisenburger, 1998; Berger et al, 2000). A monoclonal protein and autoimmune manifestations may be present in a third of patients (Berger et al, 2000). An associaª 2015 John Wiley & Sons Ltd British Journal of Haematology, 2015, 169, 520–527
Splenic Marginal Zone Lymphoma tion with hepatitis C infection has been reported, particularly in Southern Europe (Hermine et al, 2002; Arcaini et al, 2006). Patients with SMZL often have an indolent course with median life expectancy greater than 10 years. However, about a quarter of patients have a more aggressive course, with disease progression and death within the first few years after diagnosis (Arcaini et al, 2006). As with other indolent lymphomas, SMZL can develop transformation to high-grade lymphoma (Mulligan et al, 1991). The majority of patients with SMZL will require at least one treatment during their disease course. Given the rarity of this disease, most studies are retrospective institutional reviews and there is no standard initial therapy. Splenectomy has traditionally been the treatment of choice for patients with symptomatic splenomegaly, with the additional advantage that it allows for pathological confirmation of the diagnosis. Systemic therapy, including chemotherapy or chemoimmunotherapy and single agent rituximab, have been used as alternative strategies to splenectomy. In particular, single-agent rituximab may achieve high response rates (88–95%) with low toxicity (Tsimberidou et al, 2006; Bennett & Schechter, 2010; Kalpadakis et al, 2013). However, the optimal schedule for rituximab is not known, and there are no studies comparing splenectomy to rituximab and chemotherapy. We report the treatments and outcomes of 107 patients with SMZL treated in our institution over two decades.
Patients and methods All adult patients diagnosed with SZML between 1985 and 2012 were identified in the British Columbia Cancer Agency (BCCA) Lymphoid Cancer and Lymphoma Pathology Databases. Diagnoses were based on the 2008 WHO classification (Swerdlow et al, 2008). A BCCA haematopathologist reviewed 40 of the 59 available splenectomy specimens. The remaining 19 splenectomy specimens could not be obtained for review. Patient, disease, treatment and outcome data were obtained from these databases as well as paper and electronic health records. For each patient, all lines of treatment were recorded. As there was no formal provincial treatment policy for SMZL during the study period, individual treating physicians recommended the type and timing of treatments. The study was approved by the University of British Columbia and the BCCA Research Ethics Board.
Statistical analysis Overall survival (OS) was measured from date of diagnosis to date of death from any cause or last follow-up. Failurefree survival (FFS) was measured from the date of first therapy initiation to the date of lymphoma recurrence or progression, transformation, death or last follow-up. Failurefree survival calculations therefore exclude patients who were observed and never received treatment. Time to ª 2015 John Wiley & Sons Ltd British Journal of Haematology, 2015, 169, 520–527
transformation (TTT) was calculated from the date of diagnosis to the date of transformation to aggressive lymphoma. Baseline characteristics were compared between groups using the Pearson chi-square test. Survival was estimated using the Kaplan–Meier method and comparisons were made using the log rank test (Kaplan & Meier, 1958). Multivariate Cox proportional hazards regression was performed to evaluate the association between first-line treatment (splenectomy versus chemotherapy) and outcomes, adjusted for the following prognostic factors in patients with available data: age ≥60, Eastern Cooperative Oncology Group (ECOG) performance status ≥2, elevated lactate dehydrogenase (LDH), and haemoglobin 5 9 109/l Platelet count < 100 9 109/l Elevated LDH Hepatitis C positive Hepatitis B positive HIV positive
107 67 (30–88) 43/64 104/106 18/101 100/104 90/103 98/105 22/98 60/102 46/91 19/97 22/85 5/59 1/58 0/31
98 18 96 87 93 22 59 51 46 34 8 2 0
ECOG, Eastern Cooperative Oncology Group; LDH, lactate dehydrogenase; HIV, human immunodeficiency virus.
521
K. H. Xing et al splenomegaly (as defined by radiology, 93%), bone marrow involvement (96%) and peripheral blood lymphocytosis (87%). B symptoms were present in 18% patients, and 22% had ECOG performance status ≥2. Hepatitis C serology was positive in 5 of 59 patients with available data, Hepatitis B in 1 out of 58 patients, and human immunodeficiency virus in none out of 31 patients tested.
Initial treatment As part of initial treatment, 52 patients underwent splenectomy (10 immediately before or after chemotherapy) (Table I). Twelve of these patients underwent splenectomy after a median period of observation from diagnosis of 28 years (range: 6 months–63 years), while the other 40 underwent splenectomy shortly after diagnosis, with median time to splenectomy of 12 months (range: 0–4 months). Of the ten patients receiving chemotherapy along with splenectomy as first line therapy, three of the chemotherapy regimens contained rituximab [two received cyclophosphamide, doxorubicin, vincristine, prednisone and rituximab (CHOPR), one received fludarabine and rituximab (FR)] and 7 did not (two received a CHOP-like regimen, four received chlorambucil and one fludarabine). Thirty-eight patients received chemotherapy alone as initial treatment: 26 immediately after diagnosis and 12 after a median of 31 years (range: 3 months–85 years) of observation. Of these, 22 received various rituximab-containing chemotherapy regimens: 17 cyclophosphamide, vincristine, prednisone and rituximab (CVP-R), one cyclophosphamide and rituximab, three FR and one single agent rituximab. In total, 11 out of 22 received maintenance rituximab post-chemotherapy. Of the 16 patients who did not receive rituximab, seven received chlorambucil, three CVP, one
cladribine, four fludarabine, and one cyclophosphamide, fludarabine and prednisone. Two patients were treated with antiviral therapy against hepatitis C alone, which was not considered to be definitive therapy when calculating FFS. The remaining 15 patients were only observed and never required any treatment. Corticosteroids were temporarily used in two of these patients for management of cytopenias, although this was not considered to be definitive therapy. Table II shows that baseline characteristics were generally similar between patients initially treated with chemotherapy alone versus splenectomy, although there was a higher proportion of thrombocytopenia in the former group (31% vs. 8%, P = 0012). Compared to patients who received treatment with either chemotherapy and/or splenectomy, patients who were observed or received antiviral therapy had worse performance status (44% vs. 17%, P = 0017) and less frequent anaemia (24% vs. 66%, P = 0001).
Subsequent lines of treatment Of the 42 patients who underwent splenectomy alone as initial treatment, nine subsequently received chemotherapy at disease progression (eight received rituximab-containing chemotherapy, one had reduced intensity allogeneic transplant), one had excision of a soft tissue mass and one received targeted radiation and subsequent ibritumomab tiuxetan (Table III). Of the ten patients who received combined splenectomy and chemotherapy, five patients received subsequent chemotherapy (two with rituximab). Of the 38 patients who received chemotherapy alone as initial treatment, six subsequently received combined chemotherapy and splenectomy (one of these patients received an allogeneic transplant), one splenectomy alone,
Table II. Comparison of the characteristics of patients receiving initial splenectomy, chemotherapy and antiviral/observation. Fractions represent number of patients divided by number of patients with available data. Initial treatment
Characteristic Patients (n) Male sex Median age, years (range) B symptoms ECOG ≥ 2 Hb < 120 g/l Platelets < 100 9 109/l Lymphocytes >5 9 109/l Elevated LDH Bone marrow involvement Peripheral blood involvement
Splenectomy* (A) N (%)
Chemotherapy Alone (B) N (%)
Observation/Antivirals (C) N (%)
P-value (A vs. B)
P-value (A/B vs. C)
52 23 66 8/50 8/47 28/48 14/45 17/41 10/40 48/51 37/48
38 13 67 9/36 6/35 28/37 3/36 20/34 14/31 37/37 36/38
17 7 73 1/15 7/16 4/17 2/16 9/16 3/13 15/16 17/17
0338 0174 0301 0988 0095 0012 0134 0075 0133 0023
0928 0360 0221 0017 0001 0434 0615 0446 0587 0086
(44%) (30–86) (16%) (17%) (58%) (31%) (41%) (25%) (94%) (77%)
(34%) (32–85) (25%) (17%) (76%) (8%) (59%) (45%) (100%) (95%)
(41%) (50–88) (7%) (44%) (24%) (13%) (56%) (23%) (95%) (100%)
ECOG, Eastern Cooperative Oncology Group performance status; LDH, lactate dehydrogenase. *10/52 patients received splenectomy and chemotherapy.
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Splenic Marginal Zone Lymphoma Table III. Initial and subsequent treatments of patients with Splenic Marginal Zone Lymphoma (SMZL). Initial treatment
Subsequent treatment for SMZL
Subsequent transformation N
Modality
N
Modality
N
Splenectomy
42
Chemotherapy Excision (soft tissue) Radiation No further treatment*
9 1 1 31
4
Splenectomy + chemotherapy
10 38 [22/38]
Hepatitis C anti-virals Observation alone
2 15
5 5 1 6 4 1 26 2 15
3
Chemotherapy [with Rituximab]
Chemotherapy No further treatment* Splenectomy Splenectomy + chemotherapy Chemotherapy Radiation No further treatment* No further treatment No further treatment
8
0 0
*No further treatment for SMZL (treatment for transformed disease not counted as subsequent treatment for SMZL).
four chemotherapy alone and one radiation therapy to the left orbit for localized disease progression. Neither of the two patients who received antivirals had further progression. Fifteen patients were observed for a median follow-up of 38 years (range: 5 days–106 years) and have not required any treatment to date, although one patient died 5 days after diagnosis from an acute myocardial infarction.
Survival outcomes With a median follow-up of 83 years (range: 23–248 years) for living patients, the 5- and 10-year OS for the entire cohort was 64% and 50%, respectively. The 5- and 10-year FFS after first-line treatment (for the 90 patients who received treatment) was 47% and 29%, respectively. The 5- and 10-year OS for the patients who had splenectomy as initial therapy (n = 52) was 77% and 61%, respectively; for those who had chemotherapy alone (n = 38), 55% and 42%, respectively; and for those who were observed or received antivirals (n = 17), 47% and 40%, respectively (P = 0010 for all three comparisons) (Fig 1). Patients who underwent splenectomy as part of their initial therapy (i.e., including ten who received chemotherapy) had an improved OS compared to those who received chemotherapy alone (HR 048, 95% CI 026–088, P = 0017) or observation (HR 037, 95% CI 017–082, P = 0014) as initial therapy. Overall survival was similar between patients who were initially observed or treated with chemotherapy (HR 042, 95% CI 064–289, P = 0419). There was no difference in OS between patients who received splenectomy in later lines of treatment (n = 9) (5- and 10-year OS, 44% and 33%, respectively) compared to those who were splenectomized as initial treatment (HR 214, 95% CI 085–537, P = 0106). ª 2015 John Wiley & Sons Ltd British Journal of Haematology, 2015, 169, 520–527
P = 0·010
Fig 1. Overall survival by initial treatment strategy (n = 107).
The 5- and 10-year FFS following first-line splenectomy (n = 52) was 58% and 39%, respectively; compared to 31% and 14%, respectively, for those who received chemotherapy (n = 30), (HR 048, 95% CI 028–080, P = 0004) (Fig 2). The median FFS post-splenectomy was 67 years, while the median FFS post-chemotherapy was 29 years. Among the 38 patients who received chemotherapy alone initially, there was no difference in FFS between those who received rituximab (n = 22) compared to those who did not (n = 16) (HR 064, 95% CI 031–134, P = 0238). A total of 53 patients died during follow-up. Twenty-seven of the deaths were from lymphoma (51%), and ten of these were from transformation to aggressive lymphoma. Other causes of death included: five infections (three of whom had prior splenectomies); five other malignancies (three lung cancer, one prostate cancer, one amyloidosis); four cardiovascular 523
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P = 0·004
Fig 2. Failure-free survival by initial treatment strategy (n = 90).
Fig 3. Time to transformation (n = 107)
disease; seven miscellaneous causes (one each of pulmonary embolism, liver failure, renal failure, intracranial haemorrhage, gastrointestinal haemorrhage, pulmonary fibrosis and adult respiratory distress syndrome); and five unknown causes (but not lymphoma). Twenty-three (85%) of the 27 lymphomarelated deaths occurred within the first 4 years of diagnosis, while the remaining four patients died at 7, 10, 12, 17 years post-diagnosis.
the endpoint was restricted to deaths due to lymphoma, haemoglobin < 120 g/l, elevated LDH, age ≥ 60 years and ECOG performance status ≥2 were all found to be associated with decreased survival. (Table S1). Multivariate analyses for OS and FFS were performed in 70 patients receiving first-line splenectomy (n = 39) or chemotherapy (n = 31) who had complete prognostic factor data, including age, ECOG performance status, LDH and haemoglobin. Age ≥60 years (HR 272, 95% CI 122–605, P = 0014) and elevated LDH (HR 215, 95% CI 108–429, P = 0030), but not treatment (HR 062, 95% CI 030–127, P = 0194), were independently associated with worse OS. On the other hand, treatment was the only variable associated with FFS in multivariate analysis; patients treated with splenectomy experienced improved FFS compared to those receiving chemotherapy (HR 047, 95% CI 026–085, P = 0013).
Transformation to aggressive lymphoma A total of 15 patients (14%) experienced transformation to aggressive lymphoma with a median TTT of 35 years (range: 6 months to 12 years). These were all patients who had previously received splenectomy and/or chemotherapy for SMZL. The 5- and 10-year rates of transformation were 9% and 18%, respectively (Fig 3). Transformation was confirmed by biopsy in 11 patients (all of which were diffuse large B cell lymphoma [DLBCL]), and the remaining four were diagnosed based on clinical/laboratory findings (Al-Tourah et al, 2008). Nine received CHOP-like chemotherapy (seven with rituximab), one received radiation to the site of DLBCL transformation (thyroid), four received single-agent chemotherapy due to poor performance status and one had insufficient records. Ten died from transformed lymphoma, and five are alive to date (all of whom received CHOP-like chemotherapy). Median OS post-transformation was 84 months (range 0 to 8 years) and 5-year OS was 33%.
Prognosis In univariate analysis, age ≥60 years and ECOG performance status ≥2 were found to be associated with a significantly worse OS. No baseline patient characteristics were associated with worse FFS for treated patients or TTT. However, when 524
Discussion Over the course of almost three decades, patients with SMZL at our institution received a broad range of treatments at initial presentation and subsequent relapse. Observation, splenectomy and chemotherapy were the three most common treatment modalities. The majority of patients required at least one line of therapy during their disease course. Consistent with the indolent behaviour of SMZL, in our cohort the median OS was 10 years, and >15 years for the subset of patients who were able to undergo splenectomy as part of first-line therapy. Due to the retrospective nature of this study, treatment was not randomized and was subject to patient, disease and physician bias. For example, patients with indolent disease biology may have been initially observed. Those who received chemotherapy alone initially may have had a higher burden of disease, with trend toward higher LDH (P = 0075), more ª 2015 John Wiley & Sons Ltd British Journal of Haematology, 2015, 169, 520–527
Splenic Marginal Zone Lymphoma thrombocytopenia (P = 0012) and lower haemoglobin (P = 0095). Although one can speculate that patients chosen for splenectomy were probably fitter and healthier, other important clinical characteristics were similar, including sex, age, B symptoms and performance status. Splenectomy has traditionally been the treatment of choice for symptomatic patients with SMZL (Troussard et al, 1996; Parry-Jones et al, 2003; Thieblemont et al, 2003). Splenectomy offers immediate symptomatic relief from bulky splenomegaly, frequent improvement in cytopenias and an additional opportunity for pathological confirmation of the diagnosis. The median post-splenectomy FFS in our cohort was 67 years, consistent with other reports describing 4–8 years (Troussard et al, 1996; Thieblemont et al, 2003; Lenglet et al, 2014). Our data confirm that splenectomy continues to play an important role in the treatment of SMZL. Patients selected for splenectomy must have been fit enough to tolerate abdominal surgery under general anaesthesia as well as the ensuing immune suppression. One significant concern with splenectomy is the risk of infection from encapsulated organisms. Of note, it is BCCA policy to recommend immunization at least 2 weeks prior to splenectomy. Three of the 61 (5%) patients who underwent splenectomy in our series died from infectious complications, similar to the 4% rate reported in other series of splenectomy for SMZL (Lenglet et al, 2014). Prior to the rituximab era, splenectomy was found to improve OS compared to chlorambucil in retrospective series (Troussard et al, 1996; Parry-Jones et al, 2003). However, alkylating chemotherapy achieves modest response rates in SMZL (Parry-Jones et al, 2003; Iannitto et al, 2004). In contrast, single-agent rituximab is very active against SMZL, with high overall response rates (88% to 100%) including complete responses ranging from 43% to 79% (Tsimberidou et al, 2006; Bennett et al, 2008; Else et al, 2012; Kalpadakis et al, 2013). Purine analogues, especially when combined with rituximab, are also highly effective (Cervetti et al, 2013). In several retrospective series, rituximab-containing chemotherapy was reported to improve outcomes compared with splenectomy (Else et al, 2012; Kalpadakis et al, 2013), although there has been no randomized study to date. In our series, over half of the patients initially treated with chemotherapy received rituximab. There were no clinically significant differences in outcomes between those who received rituximab-containing regimens and those who did not. Compared to recent reports showing superior outcomes with rituximab as a single agent or in combination (Tsimberidou et al, 2006; Bennett et al, 2008; Else et al, 2012; Kalpadakis et al, 2013), this difference in results may be due to the relatively small number of patients studied, lack of treatment randomization and differences in regimen administered (there were various chemotherapy backbones and one patient received single-agent rituximab). It is important to identify the subgroup of patients who may experience a more aggressive disease course from the ª 2015 John Wiley & Sons Ltd British Journal of Haematology, 2015, 169, 520–527
outset. The Integruppo Italiano Linfomi prognostic model uses haemoglobin
![[Splenic marginal zone lymphoma].](/assets/img/hold.png)
