research paper
Autologous stem cell transplantation outcomes in elderly patients with B cell Non-Hodgkin Lymphoma
Satyen H. Gohil,1,2 Kirit M. Ardeshna,2 Jonathan M. Lambert,2 Martin A. Pule,1,2 Sajir Mohamedbhai,2 Andres Virchis,2 Emma C. Morris,2 David C. Linch,1,2 Kirsty J. Thomson2 and Karl S. Peggs1,2 1
Research Department of Haematology, Univer-
sity College London, and 2Department of Clinical Haematology, University College London Hospitals NHS Foundation Trusts, London, UK Received 14 March 2015; accepted for publication 20 May 2015 Correspondence: Dr Karl Peggs, Research Department of Harmatology, University College London Cancer Institute, 72 Huntley Street, London, WC1E 6DD, UK. E-Mail: [email protected]
Summary The precise role of autologous haematopoietic stem cell transplantation (ASCT) remains unclear in patients over 60 years of age. There is potential for increased procedural morbidity and mortality, and differences in disease biology that could impact outcomes. We performed a retrospective singlecentre review of 81 elderly B-cell Non-Hodgkin Lymphoma patients undergoing ASCT. Five-year overall survival (OS) and progression-free survival (PFS) was 547% and 491% respectively. Non-relapse mortality (NRM) at 100 days and 1 year was 13% and 25%, suggesting no major excess compared to younger cohorts. OS and PFS were significantly worse in those over 65 years compared to those aged 60–64 (476% vs. 577%, P = 00437, and 276% vs. 577%, P = 00052 at 5 years). This resulted largely from an increased relapse risk (RR) (538% vs. 301%, P = 00511) rather than excess NRM, and age remained independently significant for PFS on multivariate analyses [Hazard ratio 256 (135–484, P = 00052) for PFS and 189 (099–361, P = 0054) for OS]. Our data adds to the growing body of evidence demonstrating that ASCT can be an effective treatment strategy with an acceptable safety profile in selected elderly patients. Further evaluation of its overall benefit is warranted, however, in those over 65 years of age, as RR appears to be considerably higher. Keywords: lymphoma, transplantation, elderly.
Autologous haematopoietic stem cell transplantation (ASCT) is a standard treatment modality for patients with chemosensitive relapsed or refractory aggressive B-cell Non-Hodgkin Lymphoma (B-NHL), including those with diffuse large B-cell lymphoma (DLBCL) occurring either de novo or following transformation of indolent disease. ASCT is also widely employed in patients with relapsed follicular lymphoma (FL) and forms part of primary therapy in those with mantle cell lymphoma (MCL). Clinical practice in DLBCL is based on the results of a single randomized trial, together with multiple single institution and registry studies confirming similar outcomes following ASCT. Notably in the landmark PARMA trial, which included only patients with relapsed DLBCL (Philip et al, 1995), all patients were ≤60 years of age and none had received rituximab during induction or salvage. Outcomes in elderly patients (>60 years of age) are generally inferior to those in younger patients [higher non-relapse mortality (NRM), higher relapse risk and lower overall survival (OS) and event-free survival], although ª 2015 John Wiley & Sons Ltd British Journal of Haematology, 2015, 171, 197–204
this may relate more to attendant co-morbidities rather than age per se (Jantunen et al, 2008; Wildes et al, 2008). Nevertheless, outcomes of relapsed or refractory DLBCL in the elderly are generally unfavourable and it seems likely that ASCT may confer benefit in selected patients. Although response rates to salvage are lower in the rituximab era, outcomes following ASCT appear similar in chemo-sensitive patients (Smith et al, 2011; Moore et al, 2012; Mounier et al, 2012). For patients with MCL, the Nordic MCL2 trial demonstrated the benefit of ASCT in first remission (Geisler et al, 2008, 2012), whilst, for relapsed or refractory FL, the CUP (Chemotherapy with high-dose therapy followed by Unpurged stem-cell transplantation or high-dose therapy followed by Purged stem-cell transplantation) trial showed clear benefit for ASCT (Schouten et al, 2000). Both of these trials, however, excluded patients over the age of 65 years; the median age was 56 (range 32–65) years and 48 (range 29–64) years for the MCL-2 and CUP trials, respectively. Given that elderly patients, defined here as those above the age of
First published online 26 June 2015 doi: 10.1111/bjh.13561
S. H. Gohil et al 60 years, are underrepresented in these trials, the safety and efficacy of ASCT is not well established in this age group. We wished to better define the outcomes of this population in order to determine tolerability and efficacy, and provide further evidence to support current clinical practice recommendations.
Patients and methods We undertook a retrospective review of all patients over the age of 60 years who underwent a BEAM (carmustine, etoposide, cytarabine, melphalan) or LEAM (lomustine, etoposide, cytarabine, melphalan) conditioned ASCT between January 2000 and January 2012 at our institution and identified a total of 98 cases: 81 underwent ASCT for B-NHL, whilst the remainder were treated for Hodgkin Lymphoma or T-cell lymphomas. The average age was 63 (median 63; range 60–71) years; 67 were male and 31 were female. The average number of procedures per year in this cohort was 75 and this did not fluctuate significantly over the time course we reviewed. The data was locked and analysed in August 2014.
Statistical analyses Survival analyses were performed using the Kaplan–Meier time-to-event method. Overall Survival was defined as the time from the date of transplant to death from any cause.
Progression-free survival (PFS) was defined as the date of transplant to the date of documented progression/relapse or death from any cause. Comparison of survival curves was performed using the log-rank method. Non-relapse mortality and relapse incidence were calculated by cumulative incidence analyses. Non-relapse mortality was the time to death without relapse, with relapse as the competing risk, and relapse incidence was the time to relapse, with death without relapse as the competing risk. Comparison of cumulative incidence curves was performed by the method of Fine and Gray (1999). The multivariate analyses were performed using the Cox proportional hazards model. All statistical analyses were performed using NCSS software (Number Cruncher Statistical System, Kaysville, UT, USA) except for the Fine and Gray analyses, which were performed in R (The R Project for Statistical Computing, http://www.r-project.org). P < 005 was considered statistically significant.
Patient Selection & Conditioning regimen BEAM consisted of carmustine 300 mg/m2 on day 6, cytarabine 200 mg/m2 bd iv on days 5 to 2, etopside 200 mg/m2 od on days 5 to 2 and melphalan 140 mg/m2 on day 1 with stem cell return the next day. For LEAM conditioning, Lomustine (200 mg/m2) was used due to lack of availability of carmustine. Patients were discussed at a multi-disciplinary meeting to ensure a consensus decision to proceed to ASCT. Patients were screened to ensure satisfac-
Table I. Patient characteristics.
Male/ Female
Median Time from diagnosis (years)
19/10
1 19
Median age (Range), years
Remission prior to ASCT
Rituximab prior to ASCT
Complete Remission at 100 d
16
62 (60–70)
1st–7 2nd–20 3rd–1 Unknown– 1
59%
76%
11/8
14
63 (60-71)
89%
89%
19
17/2
13
64 (60-69) 625 (61-68)
1st–11 2nd–3 3rd–4 1st–13 2nd–3 1st–4 2nd–9 3rd–1 1st–1 2nd–8 1st–6 2nd–2
89%
100%
100%
100%
N/A
78%
N/A
100%
Diagnosis
n
High Grade B-NHL DLBCL B-NHL NOS Plasmablastic lymphoma T-cell rich B-NHL High grade B-NHL transformed from low grade disease Mantle cell lymphoma Follicular lymphoma
29 20 6 2
14
12/2
20
Hodgkin lymphoma T-cell lymphoma
9
6/3
20
8
2/6
089
65 (63-68) 62 (60-64)
ASCT, autologous stem cell transplantation; B-NHL, B-cell non-Hodgkin lymphoma; DLBCL, diffuse large B cell lymphoma; NOS, not otherwise specified; N/A, not applicable.
198
ª 2015 John Wiley & Sons Ltd British Journal of Haematology, 2015, 171, 197–204
Autologous Transplantation in Elderly Patients with NHL tory organ function prior to commencement of conditioning therapy.
Overall survival
(A) 1·00 0·75
Supportive care medications
0·50
Patients received conditioning chemotherapy as inpatients or in ambulatory care and were admitted when clinically indicated. Red cell transfusions were given when haemoglobin levels fell to < 80 g/l unless there were prior cardiac issues necessitating a higher transfusion requirement. Platelets were transfused when the platelet count was
Autologous stem cell transplantation outcomes in elderly patients with B cell Non-Hodgkin Lymphoma
Satyen H. Gohil,1,2 Kirit M. Ardeshna,2 Jonathan M. Lambert,2 Martin A. Pule,1,2 Sajir Mohamedbhai,2 Andres Virchis,2 Emma C. Morris,2 David C. Linch,1,2 Kirsty J. Thomson2 and Karl S. Peggs1,2 1
Research Department of Haematology, Univer-
sity College London, and 2Department of Clinical Haematology, University College London Hospitals NHS Foundation Trusts, London, UK Received 14 March 2015; accepted for publication 20 May 2015 Correspondence: Dr Karl Peggs, Research Department of Harmatology, University College London Cancer Institute, 72 Huntley Street, London, WC1E 6DD, UK. E-Mail: [email protected]
Summary The precise role of autologous haematopoietic stem cell transplantation (ASCT) remains unclear in patients over 60 years of age. There is potential for increased procedural morbidity and mortality, and differences in disease biology that could impact outcomes. We performed a retrospective singlecentre review of 81 elderly B-cell Non-Hodgkin Lymphoma patients undergoing ASCT. Five-year overall survival (OS) and progression-free survival (PFS) was 547% and 491% respectively. Non-relapse mortality (NRM) at 100 days and 1 year was 13% and 25%, suggesting no major excess compared to younger cohorts. OS and PFS were significantly worse in those over 65 years compared to those aged 60–64 (476% vs. 577%, P = 00437, and 276% vs. 577%, P = 00052 at 5 years). This resulted largely from an increased relapse risk (RR) (538% vs. 301%, P = 00511) rather than excess NRM, and age remained independently significant for PFS on multivariate analyses [Hazard ratio 256 (135–484, P = 00052) for PFS and 189 (099–361, P = 0054) for OS]. Our data adds to the growing body of evidence demonstrating that ASCT can be an effective treatment strategy with an acceptable safety profile in selected elderly patients. Further evaluation of its overall benefit is warranted, however, in those over 65 years of age, as RR appears to be considerably higher. Keywords: lymphoma, transplantation, elderly.
Autologous haematopoietic stem cell transplantation (ASCT) is a standard treatment modality for patients with chemosensitive relapsed or refractory aggressive B-cell Non-Hodgkin Lymphoma (B-NHL), including those with diffuse large B-cell lymphoma (DLBCL) occurring either de novo or following transformation of indolent disease. ASCT is also widely employed in patients with relapsed follicular lymphoma (FL) and forms part of primary therapy in those with mantle cell lymphoma (MCL). Clinical practice in DLBCL is based on the results of a single randomized trial, together with multiple single institution and registry studies confirming similar outcomes following ASCT. Notably in the landmark PARMA trial, which included only patients with relapsed DLBCL (Philip et al, 1995), all patients were ≤60 years of age and none had received rituximab during induction or salvage. Outcomes in elderly patients (>60 years of age) are generally inferior to those in younger patients [higher non-relapse mortality (NRM), higher relapse risk and lower overall survival (OS) and event-free survival], although ª 2015 John Wiley & Sons Ltd British Journal of Haematology, 2015, 171, 197–204
this may relate more to attendant co-morbidities rather than age per se (Jantunen et al, 2008; Wildes et al, 2008). Nevertheless, outcomes of relapsed or refractory DLBCL in the elderly are generally unfavourable and it seems likely that ASCT may confer benefit in selected patients. Although response rates to salvage are lower in the rituximab era, outcomes following ASCT appear similar in chemo-sensitive patients (Smith et al, 2011; Moore et al, 2012; Mounier et al, 2012). For patients with MCL, the Nordic MCL2 trial demonstrated the benefit of ASCT in first remission (Geisler et al, 2008, 2012), whilst, for relapsed or refractory FL, the CUP (Chemotherapy with high-dose therapy followed by Unpurged stem-cell transplantation or high-dose therapy followed by Purged stem-cell transplantation) trial showed clear benefit for ASCT (Schouten et al, 2000). Both of these trials, however, excluded patients over the age of 65 years; the median age was 56 (range 32–65) years and 48 (range 29–64) years for the MCL-2 and CUP trials, respectively. Given that elderly patients, defined here as those above the age of
First published online 26 June 2015 doi: 10.1111/bjh.13561
S. H. Gohil et al 60 years, are underrepresented in these trials, the safety and efficacy of ASCT is not well established in this age group. We wished to better define the outcomes of this population in order to determine tolerability and efficacy, and provide further evidence to support current clinical practice recommendations.
Patients and methods We undertook a retrospective review of all patients over the age of 60 years who underwent a BEAM (carmustine, etoposide, cytarabine, melphalan) or LEAM (lomustine, etoposide, cytarabine, melphalan) conditioned ASCT between January 2000 and January 2012 at our institution and identified a total of 98 cases: 81 underwent ASCT for B-NHL, whilst the remainder were treated for Hodgkin Lymphoma or T-cell lymphomas. The average age was 63 (median 63; range 60–71) years; 67 were male and 31 were female. The average number of procedures per year in this cohort was 75 and this did not fluctuate significantly over the time course we reviewed. The data was locked and analysed in August 2014.
Statistical analyses Survival analyses were performed using the Kaplan–Meier time-to-event method. Overall Survival was defined as the time from the date of transplant to death from any cause.
Progression-free survival (PFS) was defined as the date of transplant to the date of documented progression/relapse or death from any cause. Comparison of survival curves was performed using the log-rank method. Non-relapse mortality and relapse incidence were calculated by cumulative incidence analyses. Non-relapse mortality was the time to death without relapse, with relapse as the competing risk, and relapse incidence was the time to relapse, with death without relapse as the competing risk. Comparison of cumulative incidence curves was performed by the method of Fine and Gray (1999). The multivariate analyses were performed using the Cox proportional hazards model. All statistical analyses were performed using NCSS software (Number Cruncher Statistical System, Kaysville, UT, USA) except for the Fine and Gray analyses, which were performed in R (The R Project for Statistical Computing, http://www.r-project.org). P < 005 was considered statistically significant.
Patient Selection & Conditioning regimen BEAM consisted of carmustine 300 mg/m2 on day 6, cytarabine 200 mg/m2 bd iv on days 5 to 2, etopside 200 mg/m2 od on days 5 to 2 and melphalan 140 mg/m2 on day 1 with stem cell return the next day. For LEAM conditioning, Lomustine (200 mg/m2) was used due to lack of availability of carmustine. Patients were discussed at a multi-disciplinary meeting to ensure a consensus decision to proceed to ASCT. Patients were screened to ensure satisfac-
Table I. Patient characteristics.
Male/ Female
Median Time from diagnosis (years)
19/10
1 19
Median age (Range), years
Remission prior to ASCT
Rituximab prior to ASCT
Complete Remission at 100 d
16
62 (60–70)
1st–7 2nd–20 3rd–1 Unknown– 1
59%
76%
11/8
14
63 (60-71)
89%
89%
19
17/2
13
64 (60-69) 625 (61-68)
1st–11 2nd–3 3rd–4 1st–13 2nd–3 1st–4 2nd–9 3rd–1 1st–1 2nd–8 1st–6 2nd–2
89%
100%
100%
100%
N/A
78%
N/A
100%
Diagnosis
n
High Grade B-NHL DLBCL B-NHL NOS Plasmablastic lymphoma T-cell rich B-NHL High grade B-NHL transformed from low grade disease Mantle cell lymphoma Follicular lymphoma
29 20 6 2
14
12/2
20
Hodgkin lymphoma T-cell lymphoma
9
6/3
20
8
2/6
089
65 (63-68) 62 (60-64)
ASCT, autologous stem cell transplantation; B-NHL, B-cell non-Hodgkin lymphoma; DLBCL, diffuse large B cell lymphoma; NOS, not otherwise specified; N/A, not applicable.
198
ª 2015 John Wiley & Sons Ltd British Journal of Haematology, 2015, 171, 197–204
Autologous Transplantation in Elderly Patients with NHL tory organ function prior to commencement of conditioning therapy.
Overall survival
(A) 1·00 0·75
Supportive care medications
0·50
Patients received conditioning chemotherapy as inpatients or in ambulatory care and were admitted when clinically indicated. Red cell transfusions were given when haemoglobin levels fell to < 80 g/l unless there were prior cardiac issues necessitating a higher transfusion requirement. Platelets were transfused when the platelet count was
