Leukemia & Lymphoma, November 2014; 55(11): 2640–2642 © 2014 Informa UK, Ltd. ISSN: 1042-8194 print / 1029-2403 online DOI: 10.3109/10428194.2014.897703

LETTER TO THE EDITOR

Validation of the simplified prognostic score for splenic marginal zone lymphoma of the Splenic Marginal Zone Lymphoma Working Group Christina Kalpadakis1, Gerassimos A. Pangalis2, Maria K. Angelopoulou3, Sotirios Sachanas2, Flora Kontopidou4, Maria Moschogiannis2, Maria Ximeri1, Pantelis Tsirkinidis2, Xanthi Yiakoumis2, Helen A. Papadaki1 & Theodoros P. Vassilakopoulos3

Leuk Lymphoma Downloaded from informahealthcare.com by Michigan University on 11/01/14 For personal use only.

1Department of Hematology, Heraklion University Hospital, University of Crete, Heraklion, Greece, 2Department of Hematology,

Athens Medical Center – Psychikon Branch, Athens, Greece, 3Department of Hematology, University of Athens, Laikon General Hospital, Athens, Greece and 4Department of Hematology, Ippokrateion General Hospital, Athens, Greece

Splenic marginal zone lymphoma (SMZL) is a low grade B-cell lymphoma usually characterized by an indolent clinical course and long survival (median ⬎ 10 years) [1–3]. However, a significant proportion of patients, constituting almost 20% of SMZL, display a more aggressive clinical course with compromised survival [4]. Histologic transformation to diffuse large B-cell lymphoma is seen in fewer than 10% of patients and is associated with an adverse outcome, since survival after transformation is usually less than 2 years [4–6]. Several clinical and biological factors have been proposed for identifying prognostic subgroups in this lymphoma entity, but the results were not reproducible [4–12]. Recently, the SMZL Working Group (SMZLWG) proposed a prognostic index based on the combination of four factors: hemoglobin level, platelet count, elevated lactate dehydrogenase (LDH) and the presence of extrahilar lymphadenopathy (outside the splenic and hepatic hila) [13]. Hemoglobin level and platelet count were used as continuous variables to provide the best fit, which resulted in the following prognostic index: PI ⫽ 0.02 ⫻ hemoglobin (g/L) ⫹ 0.006 ⫻ platelet count (109/L) ⫺ 1 ⫻ LDH (1 when high, 0 when normal) ⫺ 1 ⫻ extrahilar lymphadenopathy (1 when present, 0 when absent) This stratification system allowed the separation of three risk groups with significantly different 5-year lymphoma specific survival (LSS). However, this formula is not practical for application in the routine clinical setting. For this purpose a simplified version was proposed based on the analysis of 550 patients [14]. The same four risk factors were used as in the initial prognostic system, but hemoglobin level and platelet count were not used as continuous variables. Instead, cut-off points of 9.5 g/dL for hemoglobin level and 80 ⫻ 109/L for platelet count were established. All

variables were considered to have the same statistical weight and were assigned the same value of 1 point each. The prognostic score was calculated as the sum of the four variables (0 or 1; range 0–4). Three risk groups were identified: low (A) for patients with 0 points, intermediate (B) for patients with 1 or 2 points and a high risk group (C) for patients with 3 or 4 points. Five-year LSS was significantly different among the three risk sgroups [14]. The aim of the present study was to evaluate the reproducibility of the simplified risk stratification score in a series of patients with SMZL diagnosed, treated and followed up in our departments. The Kaplan–Meier method was used to estimate survival and the log-rank test to compare survival curves. Among 122 patients with SMZL, 117 had complete data for all four variables and were included therefore in this analysis. In order to precisely identify any other disease localization besides the spleen, all patients underwent complete physical examination along with whole-body computed tomography (CT) scan. Table I presents a pairto-pair comparison of the main clinical characteristics between the studied population and the patients of the SMZLWG. The median age of the patients was 65 years (range, 41–91) with a slight female predominance (62/117 or 53%). Anemia and thrombocytopenia were present in 24/117 (21%) and 7/117 (6%), respectively. Serum LDH was elevated in 39% (46/117), while 23/117 (20%) of patients with SMZL had extrahilar lymphadenopathy at diagnosis. Among the 23 patients with extrahilar lymphadenopathy, the vast majority (17/23) presented intraabdominal lymph node enlargement, 2/23 had cervical lymphadenopathy, while axillary, femoral, iliac and mediastinal lymphadenopathy were present in one patient each. None of the patients presented bulky or generalized lymphadenopathy. According to the simplified prognostic score the stratification of our patients into the three risk groups was as

Correspondence: Christina Kalpadakis, Department of Hematology, Heraklion University Hospital, University of Crete, Heraklion, Greece. E-mail: [email protected] Received 22 January 2014; revised 13 February 2014; accepted 17 February 2014

2640

Letter to the Editor 2641

Leuk Lymphoma Downloaded from informahealthcare.com by Michigan University on 11/01/14 For personal use only.

Male Median age (range) Hb ⬍ 9.5 g/dl PLTs ⬍ 80 ⫻ 103/μL LDH ⬎ N Extrahilar lymphadenopathy Group A Group B Group C Treatment Watch and wait Splenectomy Rituximab Chemotherapy Immunochemotherapy Chemotherapy ⫹ splenectomy 5-Year lymphoma specific survival (%) Group A Group B Group C

SMZLWG, n (%)

55/117 (47%) 307/593 (52%) 65 (41–91) 64 (mean) 24/117 (21%) 79/550 (14%) 7/117 (6%) 67/550 (12%) 46/117 (39%) 210/550 (38%) 23/117 (20%) 180/550 (33%) 53 (45%) 198 (36%) 59 (51%) 311 (56%) 5 (4%) 41 (7.4%) 6 (5%) 26 (22%) 67 (57%) 15 (13%) 3 (3%) 0 96 90 60

161 (27%) 171 (29%) 1 114 (19%) 38 (6.5) 106 (18%) 95 87 68

SMZLWG, Splenic Marginal Zone Lymphoma Working Group; Hb, hemoglobin; PLTs, platelets; LDH, lactate dehydrogenase; N, normal.

follows: 53/117 (45%) were stratified into group A, 59/117 (51%) into group B and 5/117 (4%) into group C. Treatment differed among the three risk groups. Rituximab was given as first-line therapy in 70%, 54% and 60% of patients in groups A, B and C respectively, while 8% and 36% of patients with SMZL in groups A and B, respectively, underwent splenectomy. At the time of this analysis 25 deaths had been recorded (14 disease-related). The 5- and 10-year LSS and OS rates for all patients were 91% and 76% and 83% and 67%, respectively. The 5- and 10-year LSS was 96% and 91% for group A, 90% and 62% for group B and 60% at 5 years (but not applicable at 10 years due to shorter follow-up) for group C (p ⫽ 0.005) [Figure 1(a)]. The 5- and 10-year OS was 94% and 89% for group Α, 78% and 52% for group Β and 30% at 5 years (but not applicable at 10 years) for group C (p ⫽ 0.0003) [Figure 1(b)]. In pairwise comparisons of LSS, differences were statistically significant (A vs. C, p ⫽ 0.006; B vs. C, p ⫽ 0.02), except for the comparison between groups A and B, which was of marginal significance (p ⫽ 0.08). All pairwise differences were statistically significant with respect to OS (A vs. C, p ⫽ 0.0002; B vs. C, p ⫽ 0.008; A vs. B, p ⫽ 0.03). A comparison between the original data of the recently proposed simplified prognostic system of the SMZLWG and those reported here is shown in Table I. Actually there was a difference in LSS between groups A and B, though not statistically significant, most probably due to the relatively low number of patients included in our study in comparison to the original report of the SMZLWG. Moreover, the size of the high-risk group (C) remains very small and the confidence intervals of the corresponding survival rates are wide. The incorporation of additional factors or novel biological markers may improve the effective discrimination of patients with SMZL into sizeable risk groups with markedly

Lymphoma Specific Survival (%)

Characteristic

Present study, n (%)

(a) 100

Group A

90 80 70

Group B

Group C

60 50 40 30

Risk Groups A B C

20 10 0 0

5

Pts/died 5- and 10-yr LSS p 53/3 96% & 91% 59/9 90% & 62% 0.005 5/2 60% & NA

10

15

20

25

Time (years)

(b) 100 90 Group A

80 Overall Survival (%)

Table I. Comparison of the clinical characteristics between the present study and the SMZLWG pts.

70 60

Group B

50 Group C

40 30

Risk Groups

20 A B

10 C 0 0

5

Pts/died 5- and 10-yr OS p 53/6 94% & 89% 59/16 78% & 52% 0.0003 5/3 30% & NA

10

15

20

25

Time (years) Figure 1. (a) Lymphoma specific survival according to the three risk groups. (b) Overall survival according to the three risk groups.

different outcomes. In conclusion, our results confirm the applicability of the recently proposed simplified prognostic system of the SMZLWG in an independent series of 117 patients with SMZL.

Potential conflict of interest: Disclosure forms provided by the authors are available with the full text of this article at www.informahealthcare.com/lal.

References [1] Kalpadakis C, Pangalis GA , Angelopoulou MK, et al. Treatment of splenic marginal zone lymphoma with rituximab: progress report and comparison with splenectomy. Oncologist 2013;18: 190–197. [2] Kalpadakis C, Pangalis GA , Vassilakopoulos TP, et al. Treatment of splenic marginal zone lymphoma: should splenectomy be abandoned? Leuk Lymphoma 2014;55:1463–1470. [3] 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. [4] Chacon JI, Mollejo M, Munoz E, et al. Splenic marginal zone lymphoma: clinical characteristics and prognostic factors in a series of 60 patients. Blood 2002;100:1648–1654.

2642

C. Kalpadakis et al.

Leuk Lymphoma Downloaded from informahealthcare.com by Michigan University on 11/01/14 For personal use only.

[5] Troussard X, Valensi F, Duchayne E, et al. Splenic lymphoma with villous lymphocytes: clinical presentation, biology and prognostic factors in a series of 100 patients. Br J Haematol 1996;93:731–736. [6] Parry-Jones N, Matutes E, Gruszca-Westwood AM, et al. Prognostic features of splenic lymphoma with villous lymphocytes:a report on 129 patients. Br J Haematol 2003;120:759–764. [7] Arcaini L, Lazzarino M, Colombo N, et al. Splenic marginal zone lymphoma: a prognostic model for clinical use. Blood 2006;107:4643–4649. [8] Ruiz-Ballesteros E, Mollejo M, Rodriguez A , et al. Splenic marginal zone lymphoma: proposal of new diagnostic and prognostic markers identified after tissue and cDNA microarray analysis. Blood 2005;106:1831–1838. [9] Bikos V, Darzentas N, Hadzidimitriou A , et al. Over 30% of patients with splenic marginal zone lymphoma express the same immunoglobulin heavy variable gene: ontogenetic implications. Leukemia 2012;26:1638–1646. [10] Arcaini L, Paulli M, Boveri E, et al. Splenic and nodal marginal zone lymphomas are indolent disorders at high hepatitis C virus

seroprevalence with distinct presenting features but similar morphologic and phenotypic profiles. Cancer 2004;100:107–115. [11] Salido M, Baró C, Oscier D, et al. Cytogenetic aberrations and their prognostic value in a series of 330 splenic marginal zone B-cell lymphomas: a multicenter study of the Splenic B-Cell Lymphoma Group. Blood 2010;116:1479–1488. [12] Rossi D, Trifonov V, Fangazio M, et al. The coding genome of splenic marginal zone lymphoma: activation of NOTCH2 and other pathways regulating marginal zone development. J Exp Med 2012;209:1537–1551. [13] Montalban C, Arbraira V, Arcaini L, et al. Risk stratification for splenic marginal zone lymphoma based on haemoglobin concentration, platelet count, high lactate deydrogenase level and extrahilar lymphadenopathy: development and validation on 593 cases. Br J Haematol 2012;159:164–171. [14] Montalban C, Abraira V, Arcaini L, et al. Simplification of the risk stratification for splenic marginal zone lymphoma: a point-based score for practical use. Leuk Lymphoma 2014;55:929–931.