Research
Original Investigation
Improvement of Survival in Patients With Primary Cutaneous Diffuse Large B-Cell Lymphoma, Leg Type, in France Florent Grange, MD, PhD; Pascal Joly, MD, PhD; Coralie Barbe, MD; Martine Bagot, MD, PhD; Stéphane Dalle, MD, PhD; Saskia Ingen-Housz-Oro, MD; Eve Maubec, MD, PhD; Michel D’Incan, MD, PhD; Caroline Ram-Wolff, MD; Sophie Dalac, MD; Isabelle Templier, MD; Eric Esteve, MD; Gaëlle Quereux, MD, PhD; Laurent Machet, MD, PhD; Marion Leduc, MSc; Olivier Dereure, MD, PhD; Liliane Laroche, MD, PhD; Philippe Saiag, MD, PhD; Béatrice Vergier, MD, PhD; Marie Beylot-Barry, MD, PhD
IMPORTANCE Primary cutaneous diffuse large B-cell lymphoma, leg type (PCDLBCL-LT),
occurs in elderly patients and has been considered as a lymphoma with a poor prognosis, with estimated 5-year specific survival rates of approximately 50%. The hypothesis of an improvement in prognosis over time has not been studied. OBJECTIVES To evaluate this hypothesis in a large series of patients and investigate factors associated with prognosis as well as improvement in the prognosis. DESIGN, SETTING, AND PARTICIPANTS A retrospective multicenter study was conducted including dermatology departments belonging to the French Study Group on Cutaneous Lymphoma. Participants were 115 patients with PCDLBCL-LT diagnosed between 1988 and 2003 (period 1) or between 2004 and 2010 (period 2). MAIN OUTCOMES AND MEASURES Age, sex, period of diagnosis, number of skin lesions, tumor stage, tumor location (leg vs nonleg), lactate dehydrogenase level, type of therapy (with or without a combination of rituximab and polychemotherapy [PCT]), and outcome were recorded. Baseline characteristics and outcome were compared according to period of diagnosis and type of therapy. Prognosis factors were identified by univariate and multivariate survival analyses. RESULTS The mean age of the patients was 76.9 years, and 47% of the patients were older than 80 years. The 3- and 5-year specific survival rates improved between period 1 and period 2, from 55% to 74% and from 46% to 66%, respectively (P = .01). Patients had similar baseline characteristics during both periods, but rituximab-PCT regimens were administered to 88.5% of the patients in period 2 vs 16.7% in period 1 (P < .001). The 3- and 5-year specific survival rates were 80% and 74%, respectively, in patients who received a rituximab-PCT regimen compared with 48% and 38% in those who received less-intensive therapies. No significant difference was observed between both groups in age and baseline prognostic factors. In multivariate analysis, treatment without rituximab-PCT was the only adverse prognostic factor (odds ratio, 4.6 [95% CI, 2.4-9.1]; P < .001), whereas the number of skin lesions (P = .06) and location on the leg (P = .07) had only borderline significance. CONCLUSIONS AND RELEVANCE A major improvement in the survival of patients with PCDLBCL-LT has occurred over time in France, mainly as a result of the use of intensive rituximab-PCT regimens in most patients, including very elderly ones. Until further prospective clinical trials are conducted, such regimens should be considered as the standard of care in these patients. Author Affiliations: Author affiliations are listed at the end of this article.
JAMA Dermatol. 2014;150(5):535-541. doi:10.1001/jamadermatol.2013.7452 Published online March 19, 2014.
Corresponding Author: Florent Grange, MD, PhD, Department of Dermatology, Hôpital Robert Debré, avenue du général Koenig, 51092 Reims CEDEX, France ([email protected]).
535
Copyright 2014 American Medical Association. All rights reserved.
Downloaded From: http://archderm.jamanetwork.com/ by a Purdue University User on 05/19/2015
Research Original Investigation
Primary Cutaneous Diffuse B-Cell Lymphoma, Leg Type
P
rimary cutaneous diffuse large B-cell lymphoma, leg type (PCDLBCL-LT), was recognized as a unique entity in the World Health Organization/European Organization for Research and Treatment of Cancer classification of cutaneous lymphomas in 2005.1 This lymphoma is characterized clinically by its occurrence in elderly persons with a preferential (but not exclusive) leg localization and histologically by confluent sheets of medium to large cells with round nuclei typically positive for CD20, MUM-1, and BCL2 in the absence of t(14;18) translocation, which resembles the activated B-cell type of nodal diffuse large B-cell lymphomas (DLBCLs).1-7 In contrast with the more frequent other subtypes of cutaneous B-cell lymphomas (ie, primary cutaneous marginal zone B-cell lymphoma and primary cutaneous follicle center lymphoma), PCDLBCL-LT has a poor prognosis, with 5-year survival rates ranging from 41.0% to 73.1% in studies 4,6,8-11 and approximately 50% to 55% in most reviews.1,7,12,13 A combination of rituximab and the standard cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) regimen has been recognized as the standard therapy for patients with DLBCLs.14,15 Although PCDLBCL-LT is a specific disease entity occurring in older patients, this combination regimen was also used more frequently in this rare cutaneous lymphoma or replaced by less-intensive combinations of rituximab and polychemotherapy (PCT) in the oldest and/or frailest patients. In previous studies,16 we provided preliminary data suggesting an improvement of prognosis in patients with PCDLBCL-LT as a result of a combination of rituximab and PCT and/or other improvements in treatment management. At the outset of the present study, we hypothesized that specific survival of patients with PCDLBCL-LT had increased over time, and then investigated for factors associated with such an evolution, focusing on period of diagnosis and type of treatment.
Methods Patient Selection and Data Collection The study was approved by the institutional review board of Reims University Hospital, Reims, France. A retrospective review was carried out on cases of PCDLBCL-LT included in the registry of the French Study Group on Cutaneous Lymphoma (FSGCL) between January 1, 1988, and December 31, 2010. Inclusion criteria were (1) a histologic diagnosis of PCDLBCL-LT according to standard criteria1 as assessed by an expert panel of pathologists, (2) the absence of extracutaneous localization at diagnosis, and (3) available clinical data in the patient’s medical records. All medical records were reviewed. The following clinical characteristics at diagnosis were recorded: date of diagnosis, age, sex, performance status (ie, 0, asymptomatic; 1, symptomatic but completely ambulatory; 2, symptomatic, with 50% of the time spent in bed during the day; and 4, bedridden), anatomic site (head or neck, arm, anterior aspect of the trunk, posterior aspect of the trunk, or leg), number of skin lesions, TNM clinical category at diagnosis according to the International Society for Cutaneous Lymphomas/European Organization of Research and Treatment of Cancer classification,17 536
lactate dehydrogenase level, and B symptoms (ie, systemic symptoms including fever, sweats, and/or weight loss). According to date, 2 diagnosis periods were defined: from January 1, 1988, to December 31, 2003 (period 1), and from January 1, 2004, to December 31, 2010 (period 2). These 2 periods were a priori defined for comparison because we hypothesized that significant changes in management of the care of patients with PCDLBCL-LT progressively occurred from 2003 to 2004, with a possible effect on clinical outcome. Data on therapy included initial and subsequent therapies and whether the patient received rituximab-PCT at any time. For this purpose, the most intensive therapy received at any time was recorded, including rituximab-PCT with anthracycline (ie, standard or age-adapted rituximab-CHOP), rituximab-PCT without anthracycline, PCT (without rituximab and with or without anthracycline), and less-intensive therapies (including radiotherapy, corticosteroids, and/or single-agent chemotherapy, as well as rituximab alone). Follow-up data were recorded until December 31, 2011, including achievement of a complete response, cutaneous relapse, extracutaneous progression of the disease, final status, and date and cause of death. Causes of death were ascertained by physician members of the FSGCL who monitored patients in most cases and in some cases by questioning their general practitioners. The follow-up time ranged from 8 days to 159 months (mean, 39 months). Eighty-five patients (73.9%) were monitored until death, until the end point of the study, or for longer than 5 years; 30 patients (26.1%) were lost to follow-up after less than 5 years (range, 4.2-55.5 months).
Statistical Analysis Data are described using mean (SD) for quantitative variables and number and percentages for qualitative variables. Comparisons between subgroups of patients according to diagnosis period and type of therapy were performed using a χ2 test; Fisher exact test; 2-tailed, unpaired t test; or Wilcoxon ranksum test, as appropriate. Specific survival duration was calculated from diagnosis to date of disease-related death or censoring. Patients whose deaths were unrelated to lymphoma were considered censored. The survival curves according to period of diagnosis and type of treatment were established by the Kaplan-Meier method. Prognostic factors were identified by univariate analysis using the logrank test and by multivariate analysis using a Cox proportional hazards regression model. Factors significant at the 0.20 level in univariate analysis were included in a stepwise regression multivariate analysis with entry and removal limits set at 0.20. P < .05 was considered significant. Statistical analysis was performed using SAS, version 9.3 (SAS Institute, Inc).
Results Patients and Baseline Clinical Characteristics One hundred fifteen patients met the inclusion criteria. Sixty of these patients had been included in a previous study.4 Fiftyfour received the diagnosis of PCDLBCL-LT in period 1 and 61 received the diagnosis in period 2. The main characteristics of patients and baseline characteristics in the entire study group and according to the diagnosis period are reported in Table 1.
JAMA Dermatology May 2014 Volume 150, Number 5
Copyright 2014 American Medical Association. All rights reserved.
Downloaded From: http://archderm.jamanetwork.com/ by a Purdue University User on 05/19/2015
jamadermatology.com
Primary Cutaneous Diffuse B-Cell Lymphoma, Leg Type
Original Investigation Research
Table 1. Main Findings at Diagnosis and Follow-up Data in Entire Series and According to Period of Diagnosisa Characteristic Age, mean (SD) [range], y
Total (N = 115)
Period 1 (n = 54)
Period 2 (n = 61)
P Valueb
76.9 (10.8) [44-97]
75.9 (11.5) [44-93]
77.8 (10.2) [50-97]
.37
Age, y >70
87 (75.6)
40 (74.1)
47 (77.0)
.71
>80
54 (47.0)
24 (44.4)
30 (49.2)
.61
Sex Female
68 (59.1)
33 (61.1)
35 (57.4)
Male
47 (40.9)
21 (38.9)
26 (42.6)
T1N0M0
31 (27.4)
17 (32.1)
14 (23.3)
T2N0MO
58 (51.3)
26 (49.1)
32 (53.3)
T3N0MO
24 (22.3)
10 (18.8)
14 (23.4)
1
31 (27.2)
18 (33.3)
13 (21.7)
>1
83 (72.8)
36 (66.7)
47 (78.3)
Leg
91 (79.1)
39 (72.2)
52 (85.2)
Nonleg
24 (20.9)
15 (27.8)
9 (14.8)
0 or 1
68 (77.3)
27 (81.8)
41 (74.5)
2, 3, or 4
20 (22.7)
6 (18.2)
14 (25.5)
Normal
74 (69.2)
37 (74.0)
37 (64.9)
Abnormal
33 (30.8)
13 (26.0)
20 (35.1)
34 (29.6)
24 (44.4)
10 (16.4)
.001
2 (1.7)
1 (1.8)
1 (1.6)
.93
PCT
19 (16.5)
19 (35.2)
Rituximab-PCT
47 (40.9)
5 (9.3)
42 (68.9)
Original Investigation
Improvement of Survival in Patients With Primary Cutaneous Diffuse Large B-Cell Lymphoma, Leg Type, in France Florent Grange, MD, PhD; Pascal Joly, MD, PhD; Coralie Barbe, MD; Martine Bagot, MD, PhD; Stéphane Dalle, MD, PhD; Saskia Ingen-Housz-Oro, MD; Eve Maubec, MD, PhD; Michel D’Incan, MD, PhD; Caroline Ram-Wolff, MD; Sophie Dalac, MD; Isabelle Templier, MD; Eric Esteve, MD; Gaëlle Quereux, MD, PhD; Laurent Machet, MD, PhD; Marion Leduc, MSc; Olivier Dereure, MD, PhD; Liliane Laroche, MD, PhD; Philippe Saiag, MD, PhD; Béatrice Vergier, MD, PhD; Marie Beylot-Barry, MD, PhD
IMPORTANCE Primary cutaneous diffuse large B-cell lymphoma, leg type (PCDLBCL-LT),
occurs in elderly patients and has been considered as a lymphoma with a poor prognosis, with estimated 5-year specific survival rates of approximately 50%. The hypothesis of an improvement in prognosis over time has not been studied. OBJECTIVES To evaluate this hypothesis in a large series of patients and investigate factors associated with prognosis as well as improvement in the prognosis. DESIGN, SETTING, AND PARTICIPANTS A retrospective multicenter study was conducted including dermatology departments belonging to the French Study Group on Cutaneous Lymphoma. Participants were 115 patients with PCDLBCL-LT diagnosed between 1988 and 2003 (period 1) or between 2004 and 2010 (period 2). MAIN OUTCOMES AND MEASURES Age, sex, period of diagnosis, number of skin lesions, tumor stage, tumor location (leg vs nonleg), lactate dehydrogenase level, type of therapy (with or without a combination of rituximab and polychemotherapy [PCT]), and outcome were recorded. Baseline characteristics and outcome were compared according to period of diagnosis and type of therapy. Prognosis factors were identified by univariate and multivariate survival analyses. RESULTS The mean age of the patients was 76.9 years, and 47% of the patients were older than 80 years. The 3- and 5-year specific survival rates improved between period 1 and period 2, from 55% to 74% and from 46% to 66%, respectively (P = .01). Patients had similar baseline characteristics during both periods, but rituximab-PCT regimens were administered to 88.5% of the patients in period 2 vs 16.7% in period 1 (P < .001). The 3- and 5-year specific survival rates were 80% and 74%, respectively, in patients who received a rituximab-PCT regimen compared with 48% and 38% in those who received less-intensive therapies. No significant difference was observed between both groups in age and baseline prognostic factors. In multivariate analysis, treatment without rituximab-PCT was the only adverse prognostic factor (odds ratio, 4.6 [95% CI, 2.4-9.1]; P < .001), whereas the number of skin lesions (P = .06) and location on the leg (P = .07) had only borderline significance. CONCLUSIONS AND RELEVANCE A major improvement in the survival of patients with PCDLBCL-LT has occurred over time in France, mainly as a result of the use of intensive rituximab-PCT regimens in most patients, including very elderly ones. Until further prospective clinical trials are conducted, such regimens should be considered as the standard of care in these patients. Author Affiliations: Author affiliations are listed at the end of this article.
JAMA Dermatol. 2014;150(5):535-541. doi:10.1001/jamadermatol.2013.7452 Published online March 19, 2014.
Corresponding Author: Florent Grange, MD, PhD, Department of Dermatology, Hôpital Robert Debré, avenue du général Koenig, 51092 Reims CEDEX, France ([email protected]).
535
Copyright 2014 American Medical Association. All rights reserved.
Downloaded From: http://archderm.jamanetwork.com/ by a Purdue University User on 05/19/2015
Research Original Investigation
Primary Cutaneous Diffuse B-Cell Lymphoma, Leg Type
P
rimary cutaneous diffuse large B-cell lymphoma, leg type (PCDLBCL-LT), was recognized as a unique entity in the World Health Organization/European Organization for Research and Treatment of Cancer classification of cutaneous lymphomas in 2005.1 This lymphoma is characterized clinically by its occurrence in elderly persons with a preferential (but not exclusive) leg localization and histologically by confluent sheets of medium to large cells with round nuclei typically positive for CD20, MUM-1, and BCL2 in the absence of t(14;18) translocation, which resembles the activated B-cell type of nodal diffuse large B-cell lymphomas (DLBCLs).1-7 In contrast with the more frequent other subtypes of cutaneous B-cell lymphomas (ie, primary cutaneous marginal zone B-cell lymphoma and primary cutaneous follicle center lymphoma), PCDLBCL-LT has a poor prognosis, with 5-year survival rates ranging from 41.0% to 73.1% in studies 4,6,8-11 and approximately 50% to 55% in most reviews.1,7,12,13 A combination of rituximab and the standard cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) regimen has been recognized as the standard therapy for patients with DLBCLs.14,15 Although PCDLBCL-LT is a specific disease entity occurring in older patients, this combination regimen was also used more frequently in this rare cutaneous lymphoma or replaced by less-intensive combinations of rituximab and polychemotherapy (PCT) in the oldest and/or frailest patients. In previous studies,16 we provided preliminary data suggesting an improvement of prognosis in patients with PCDLBCL-LT as a result of a combination of rituximab and PCT and/or other improvements in treatment management. At the outset of the present study, we hypothesized that specific survival of patients with PCDLBCL-LT had increased over time, and then investigated for factors associated with such an evolution, focusing on period of diagnosis and type of treatment.
Methods Patient Selection and Data Collection The study was approved by the institutional review board of Reims University Hospital, Reims, France. A retrospective review was carried out on cases of PCDLBCL-LT included in the registry of the French Study Group on Cutaneous Lymphoma (FSGCL) between January 1, 1988, and December 31, 2010. Inclusion criteria were (1) a histologic diagnosis of PCDLBCL-LT according to standard criteria1 as assessed by an expert panel of pathologists, (2) the absence of extracutaneous localization at diagnosis, and (3) available clinical data in the patient’s medical records. All medical records were reviewed. The following clinical characteristics at diagnosis were recorded: date of diagnosis, age, sex, performance status (ie, 0, asymptomatic; 1, symptomatic but completely ambulatory; 2, symptomatic, with 50% of the time spent in bed during the day; and 4, bedridden), anatomic site (head or neck, arm, anterior aspect of the trunk, posterior aspect of the trunk, or leg), number of skin lesions, TNM clinical category at diagnosis according to the International Society for Cutaneous Lymphomas/European Organization of Research and Treatment of Cancer classification,17 536
lactate dehydrogenase level, and B symptoms (ie, systemic symptoms including fever, sweats, and/or weight loss). According to date, 2 diagnosis periods were defined: from January 1, 1988, to December 31, 2003 (period 1), and from January 1, 2004, to December 31, 2010 (period 2). These 2 periods were a priori defined for comparison because we hypothesized that significant changes in management of the care of patients with PCDLBCL-LT progressively occurred from 2003 to 2004, with a possible effect on clinical outcome. Data on therapy included initial and subsequent therapies and whether the patient received rituximab-PCT at any time. For this purpose, the most intensive therapy received at any time was recorded, including rituximab-PCT with anthracycline (ie, standard or age-adapted rituximab-CHOP), rituximab-PCT without anthracycline, PCT (without rituximab and with or without anthracycline), and less-intensive therapies (including radiotherapy, corticosteroids, and/or single-agent chemotherapy, as well as rituximab alone). Follow-up data were recorded until December 31, 2011, including achievement of a complete response, cutaneous relapse, extracutaneous progression of the disease, final status, and date and cause of death. Causes of death were ascertained by physician members of the FSGCL who monitored patients in most cases and in some cases by questioning their general practitioners. The follow-up time ranged from 8 days to 159 months (mean, 39 months). Eighty-five patients (73.9%) were monitored until death, until the end point of the study, or for longer than 5 years; 30 patients (26.1%) were lost to follow-up after less than 5 years (range, 4.2-55.5 months).
Statistical Analysis Data are described using mean (SD) for quantitative variables and number and percentages for qualitative variables. Comparisons between subgroups of patients according to diagnosis period and type of therapy were performed using a χ2 test; Fisher exact test; 2-tailed, unpaired t test; or Wilcoxon ranksum test, as appropriate. Specific survival duration was calculated from diagnosis to date of disease-related death or censoring. Patients whose deaths were unrelated to lymphoma were considered censored. The survival curves according to period of diagnosis and type of treatment were established by the Kaplan-Meier method. Prognostic factors were identified by univariate analysis using the logrank test and by multivariate analysis using a Cox proportional hazards regression model. Factors significant at the 0.20 level in univariate analysis were included in a stepwise regression multivariate analysis with entry and removal limits set at 0.20. P < .05 was considered significant. Statistical analysis was performed using SAS, version 9.3 (SAS Institute, Inc).
Results Patients and Baseline Clinical Characteristics One hundred fifteen patients met the inclusion criteria. Sixty of these patients had been included in a previous study.4 Fiftyfour received the diagnosis of PCDLBCL-LT in period 1 and 61 received the diagnosis in period 2. The main characteristics of patients and baseline characteristics in the entire study group and according to the diagnosis period are reported in Table 1.
JAMA Dermatology May 2014 Volume 150, Number 5
Copyright 2014 American Medical Association. All rights reserved.
Downloaded From: http://archderm.jamanetwork.com/ by a Purdue University User on 05/19/2015
jamadermatology.com
Primary Cutaneous Diffuse B-Cell Lymphoma, Leg Type
Original Investigation Research
Table 1. Main Findings at Diagnosis and Follow-up Data in Entire Series and According to Period of Diagnosisa Characteristic Age, mean (SD) [range], y
Total (N = 115)
Period 1 (n = 54)
Period 2 (n = 61)
P Valueb
76.9 (10.8) [44-97]
75.9 (11.5) [44-93]
77.8 (10.2) [50-97]
.37
Age, y >70
87 (75.6)
40 (74.1)
47 (77.0)
.71
>80
54 (47.0)
24 (44.4)
30 (49.2)
.61
Sex Female
68 (59.1)
33 (61.1)
35 (57.4)
Male
47 (40.9)
21 (38.9)
26 (42.6)
T1N0M0
31 (27.4)
17 (32.1)
14 (23.3)
T2N0MO
58 (51.3)
26 (49.1)
32 (53.3)
T3N0MO
24 (22.3)
10 (18.8)
14 (23.4)
1
31 (27.2)
18 (33.3)
13 (21.7)
>1
83 (72.8)
36 (66.7)
47 (78.3)
Leg
91 (79.1)
39 (72.2)
52 (85.2)
Nonleg
24 (20.9)
15 (27.8)
9 (14.8)
0 or 1
68 (77.3)
27 (81.8)
41 (74.5)
2, 3, or 4
20 (22.7)
6 (18.2)
14 (25.5)
Normal
74 (69.2)
37 (74.0)
37 (64.9)
Abnormal
33 (30.8)
13 (26.0)
20 (35.1)
34 (29.6)
24 (44.4)
10 (16.4)
.001
2 (1.7)
1 (1.8)
1 (1.6)
.93
PCT
19 (16.5)
19 (35.2)
Rituximab-PCT
47 (40.9)
5 (9.3)
42 (68.9)
