Comorbidities, Not Age, Impact Outcomes in Autologous Stem Cell Transplant for Relapsed Non-Hodgkin Lymphoma

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Comorbidities, Not Age, Impact Outcomes in

Autologous Stem Cell Transplant for Relapsed

Non-Hodgkin Lymphoma

Tanya M. Wildes,1Kristan M. Augustin,1Diane Sempek,1Qin Jean Zhang,1Ravi Vij,1 John F. Dipersio,1Steven M. Devine2

1Washington University School of Medicine, St. Louis, Missouri and2The Ohio State University, Columbus, Ohio

Correspondence and reprint requests: Tanya M. Wildes, M.D., Washington University School of Medicine, 660 South Euclid Avenue, Campus Box 8007, St. Louis, MO 63110 (e-mail:twildes@im.wustl.edu).

Received March 3, 2008; accepted May 5, 2008 ABSTRACT

High-dose chemotherapy followed by autologous peripheral blood stem cell transplantation is a widely applied treatment for advanced non-Hodgkin lymphoma (NHL), but few studies have analyzed the tolerability and out-comes in older patients compared with younger patients treated in a homogeneous manner. We retrospectively reviewed 152 consecutive patients who underwent autologous stem cell transplantation (ASCT) following BEAM conditioning (carmustine, etoposide, cytarabine, and melphalan) for NHL from January 2000 through August 2004 at our institution. We compared 59 patients age $60 years and 93 patients age \60 years. Support-ive care was identical for all patients. The frequency of comorbidities was similar between both groups. CD341 cell doses, days to neutrophil recovery, and days to platelet count .20,000/mm3were similar in younger and older patients, although days to platelet count .50,000/mm3were longer in the older patients (median 30.0 days versus 22.5 days, P 5 .01). Patients over the age of 60 were more likely to develop grade III/IV mucositis than their younger counterparts (37.7% versus17.4%, P 5 .0063). Otherwise, the frequency of other grade III/IV toxicities were similar between younger and older patients. Treatment-related mortality (TRM) was sim-ilar between older and younger patients (8.5% versus 5.4%, P 5 .45). Although age was not associated with TRM, the Charlson Comorbidity Index Score was significantly correlated with TRM (P 5 .03). Median disease-free survival was similar between older and younger patients (21.8 months versus 29.9 months, P 5 .93), as was overall survival (OS) (47.7 months versus 62.5 months, P 5 .20). After controlling for age, the Charlson Comorbidity Index Score influenced OS [P 5 .013]. Overall, our cohort of patients with NHL over the age of 60 who under-went ASCT following BEAM conditioning experienced toxicities and survival similar to their younger counter-parts. Comorbidities significantly influenced TRM and OS in this retrospective cohort. Future study should focus on improving tolerability of conditioning and careful prospective evaluation of comorbidities and their association with outcomes.

Ó 2008 American Society for Blood and Marrow Transplantation

KEY WORDS

Non-Hodgkin lymphoma  Elderly  Comorbidity  High-dose chemotherapy  Autologous stem cell transplantation

INTRODUCTION

Although autologous stem cell transplantation (ASCT) following high-dose chemotherapy is a widely utilized strategy for relapsed non-Hodgkin lymphoma (NHL), few studies have examined the tolerability and efficacy in patients over the age of 60. Prior studies ex-amining the use of autologous transplant in the elderly are limited in their current applicability by small sam-ple size, the use of bone marrow rather than mobilized

peripheral blood stem cells, inclusion of multiple un-derlying malignancies, and an array of conditioning regimens. Early studies of autologous bone marrow transplants in older patients found transplant-related mortality rates as high as 28% in patients over the age of 50[1], or even as high as 60% in a cohort of patients over the age of 55 who received total-body irradiation (TBI)[2]. More recent studies evaluating only peripheral blood stem cell transplants have found

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lower mortality rates (0%-11% in patients over the age of 60[3-13]). Some studies have shown higher rates of mucositis [11], infectious complications [14], and cardiac toxicity[13]in older patients. Overall, the tol-erability and efficacy of high-dose chemotherapy (HDT) and ASCT for NHL in patients over 60 has not been well characterized. We therefore undertook a retrospective review of all patients who underwent ASCT for NHL following an identical BEAM condi-tioning and supportive care strategy between January 2000 and August 2004.

METHODS

With the approval of the institutional review board, we retrospectively identified 152 consecutive patients who underwent ASCT for NHL at a single institution following BEAM conditioning between January 1, 2000 and August 31, 2004 from the Wash-ington University School of Medicine Bone Marrow Transplant database.

All patients underwent peripheral blood stem cell harvest via tunneled pheresis catheter following cyto-kine or chemomobilization. The goal number of CD341 cells collected was 2.5  106 cells/kg. The pheresis laboratory database provided data regarding stem cell mobilization. Conditioning for all patients consisted of: carmustine 450 mg/m2until April 2003 (97 patients), at which time the institutional protocol was changed, and the carmustine dose was decreased to 300 mg/m2(55 patients) on day 28, etoposide 100 mg/m2every 12 hours (total 200 mg/m2/day) on day 27 through day 24, cytarabine 100 mg/m2 every 12 hours (total 200 mg/m2/day) on day 27 through day 24, and melphalan 140 mg/m2 on day 23, fol-lowed by 2 rest days. On the day of transplant, cryopre-served stem cell products were warmed to 37C and infused per protocol. Patients received growth factor support with colony stimulating factors and other sup-portive care per institutional standards.

The medical records were reviewed for laboratory results and comorbid medical conditions. Toxicities were graded retrospectively using the NCI Common Toxicity Criteria v3.0. Days to neutrophil recovery (absolute neutrophil count [ANC] .500/mm3) and platelet recovery (platelet count .20,000/mm3 and 50,000/mm3, without transfusion) were calculated from date of transplant. If the patient survived to neu-trophil recovery, days of neutropenic fevers were cal-culated from date of transplant. All Gram-negative bacteremias and fungemias were considered patho-genic. When nonpathogenic Gram-positive bacteria were cultured, they were considered pathogenic if more than 1 blood culture was positive. Creatinine clearance was calculated using the Cockcroft-Gault method [15], and the serum creatinine, weight, and height at the time of initiation of conditioning; where

ideal body weight and actual body weight differed sig-nificantly, the lower estimated creatinine clearance was utilized. The Charlson Comorbidity Index (CCI)

[16,17]was calculated from known medical history at the time of admission for stem cell transplant, inclusive of the diagnosis of NHL.

Disease-free survival (DFS) was defined as the time from transplant to recurrence or death from any cause. Overall survival (OS) was defined as the time from transplant to death from any cause. Treatment-related mortality (TRM) was defined as death unrelated to re-lapse within the first 100 days following autologous stem cell transplant.

Statistical Analysis

DFS and OS rates were estimated by the Kaplan-Meier method. The log-rank test was used to examine potential differences in survival between age groups. In addition, multivariate Cox proportional hazards models were fitted to test independent effects after con-trolling for confounding covariates. Other statistical ap-proaches used for the analyses included Student’s t-test, Wilcoxon nonparametric test, c2 test, Fisher’s exact text, and Pearson or Spearman correlation test. The sig-nificance level used in the study was 0.05, and all tests were 2-sided. All statistical analyses were performed using SAS version 9.1 (SAS Institute Inc, Cary, NC). RESULTS

Baseline Characteristics

A total of 152 consecutive patients from a single in-stitution were included; 59 were age 60 or older (mean age 64.1 6 3.4, range: 60-73) and 93 were under age 60 (48.6 6 9.0, range: 21-59). In the older group, 42% of the patients were female, whereas 47% of the patients in the younger group were female. The mean CCI was similar between the 2 groups (2.6 6 0.8 in the older patients, 2.4 6 0.7 in the younger patients, P 5 .10).

Table 1details the baseline demographics, histology, and treatment history of the patients.

Mobilization

The number of pheresis sessions, number of stem cell products collected, and total CD341 counts did not differ between older and younger patients (Table 2). Similar numbers of patients underwent mobilization with cytokines only (89.8% in older patients versus 95.7% in younger, P 5 .15); the remainder either underwent chemotherapy-induced mobilization, cy-tokines in combination with chemotherapy, or others.

Engraftment

Overall, the older and younger cohorts had similar engraftment kinetics, with the exception of platelet re-covery. Older patients required a mean of 12.7 6 5.5

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days (range: 9-39) to achieve an absolute neutrophil count .500/mm3, whereas younger patients required 12.5 6 4.1 days (range: 9-38) (P 5 .81). Days to achiev-ing a platelet count of .20,000/mm3independent of transfusion were similar between the 2 groups (median 21.5 days [range: 7-219] in older patients versus 15.5 days [range 6-463] in younger patients, P 5 .69). How-ever, the older patient required a significantly longer time to recovery of platelet count to .50,000/mm3 (median 30.0 days [range: 13-561] versus 22.5 days in younger patients [range 12-104], P 5 .01).

Only 1 patient failed to recover his ANC and died on posttransplant day 45; he was in the younger cohort. Of the patients in the older cohort, 5.1% failed to recover their platelet count to .20,000/mm3, com-pared to 5.4% in the younger cohort (P 5 .94). Of the older patients, 10.2% failed to recover their platelet to .50,000/mm3, compared to 11.8% of the younger pa-tients (P 5 .75). Changes in carmustine dose instituted during the study period did not affect engraftment (data not shown).

Infectious Complications

The older and younger patients had similar rates of infectious complications during the posttransplant period. Older patients had a mean of 5.3 6 2.6 days (range: 1-13) of neutropenic fevers, whereas younger patients averaged 4.9 6 3.1 days (range: 0-19) (P 5

.38). Overall rates of documented bacteremia were similar (35.6% in older patients versus 24.7% in youn-ger patients, P 5 .15), as were rates of Gram-negative bacteremia (20.3% in older patients versus 12.9% in younger patients, P 5 .22) and Gram-positive bacter-emia (16.9% in older patients versus 12.9% in youn-ger, P 5 .49). Duration of intravenous antibiotic use was similar between older and younger patients (14.3 6 6.5 days [range: 6-38] versus 14.4 6 9.2 [range: 0-66], P 5 .92). Rates of documented fungemia (10.2% in older patients versus 4.3% in younger pa-tients, P 5 .15) and days of intravenous antifungal use (6.7 6 7.0 days [range: 0-31] versus 6.6 6 9.8 days [range: 0-67], P 5 .94) were statistically similar in each group. The incidence of Clostridium difficile-associated diarrhea was similar between the older and younger patients (16.9% versus 11.8%, P 5 .37). TRM and Morbidity

TRM was similar between older and younger pa-tients (8.5% versus 5.4%, P 5 .45). Although age .60 or \60 was not significantly associated with TRM, the score on the CCI significantly correlated with TRM (r 5 0.17, P 5 0.03).

Severe oral mucositis (OM) was more common in the older patients; a significantly larger proportion of older patients had $grade 3 OM (33.9% of patients $60 years versus 17.2% of patients \60 years, P 5 Table 1.Baseline Demographics, Histology, and Treatment History

Age $60 Years Age \60 Years P Value

Number of patients 59 93

Mean age in years: mean ± standard deviation (range) 64.1 ± 3.4 (60-73) 48.6 ± 9.0 (21-59)

Gender: frequency (percent) ..1

Female 25 (42%) 44 (47%)

Male 34 (58%) 49 (53%)

Histology: frequency (percent) ..1

Diffuse large B cell 36/59 (61%) 44/93(47%)

Follicular lymphoma 15/59 (25%) 26/93 (28%)

Mantle cell lymphoma 6/59 (10.2%) 6/93 (6.5%)

Anaplastic large cell lymphoma 1/59 (1.7%) 5/93 (5.4%)

Peripheral T cell lymphomas 1/59 (1.7%) 7/93 (7.5%)

Other high grade 0/59 (0%) 5/93 (5.4%)

Mean Charlson Comorbidity Index Score 2.6 ± 0.8 2.4 ± 0.7 .10

Number of pretranspant chemotherapy regimens: mean (range) 2.2 (1-4) 1.9 (1-3) .005

Prior fludarabine: frequency (percent) 4/59 (6.8%) 7/93 (7.5%) ..1

Chemosensitive at transplant: frequency (percent) 54/59 (91.5%) 88/93 (94.6%) ..1 Prior rituximab (in patients with B cell lymphomas): frequency (percent) 47/57 (82%) 55/79 (70%) ..1

Prior radiation therapy 11/59 (18.6%) 16/93 (17.2%) ..1

Table 2.Peripheral Blood Stem Cell Harvest

Patients $60 Years (Mean ± SD, Range) Patients \60 Years (Mean ± SD, Range) P Pheresis sessions 1.4 ± 0.6 (1-4) 1.2 ± 0.5 (1-3) .16 CD341cells 106/kg 3.5 ± 1.7 (1.7-10.6) 3.6 ± 1.8 (1.7-12.8) .68

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.0063). The severity of OM was significantly inversely related with creatinine clearance (r 5 20.17, P 5 .045). The frequency of other grade III/IV toxicities was similar between the 2 groups, detailed inFigure 1. When toxicities were analyzed for association with the CCI, there were no statistically significant correlations between CCI and mucositis (r 5 0.039, P 5 .64), nausea/vomiting (r 5 20.068, P 5 .41), diarrhea (r 5 .034, P 5 .69), or incidence of bacteremia (r 5 0.11, P 5 .17).

Duration of hospitalization and rates of readmis-sion did not differ between the older and younger pa-tients. Older patients had a mean duration of hospitalization from day of transplant of 16.2 6 5.6 days (range: 11-43), whereas younger patients stayed in the hospital 17.2 6 8.4 days following transplant (range: 10-56) (P 5 .45). Of the older patients 25.9% were readmitted within the first 100 days for various

complications, whereas 25.0% of the younger patients required readmission (P 5 .90).

DFS and OS

Lactate dehydrogenase (LDH) immediately prior to transplant did not predict risk of relapse (r 5 0.0011, P 5 .99). Aggressive versus indolent histology influenced neither DFS (P 5 .85) nor OS (P 5 .18). DFS was similar between older and younger patients (Figure 2) (P 5 .94). In the older patients, the median DFS was 21.8 months (95% Confidence Interval [CI] 10.5-43.3 months) versus 29.9 months (95% CI 21.8-36.3 months) in the younger patients. OS was also similar between patients over the age of 60 and those younger than 60 (Figure 3) (P 5 .20). The median OS in the older cohort was 47.7 months versus 62.5 months in the younger patients. We then analyzed the relation-ship between age as a continuous variable with DFS and 16.9% 10.2% 44.1% 8.5% 1.7% 10.2% 18.9% 24.5% 37.7% 18.3% 15.1% 39.8% 7.5% 1.1% 9.7% 14.1% 21.7% 17.4% 0.0% 5.0% 10.0% 15.0% 20.0% 25.0% 30.0% 35.0% 40.0% 45.0% 50.0% Tachyarrhythmias Required vasopressors Required PCA Required TPN for nutritional

support Nephrotoxicity (Grade III/IV) Hepatotoxicity (Grade III/IV) Nausea (Grade III/IV) Diarrhea (Grade III/IV) Mucositis (Grade III/IV)

Toxicities

Frequency

Age <60 years Age >60 years

* p=0.0063

All comparisons were not statistically significantly different unless noted. Figure 1.Frequency of grade III/IV toxicities.

DFS: Disease Free Survival

<60 years old >= 60 years old DFS Probability 0.0 0.2 0.4 0.6 0.8 1.0 Time in months 0 12 24 36 48 60 72 P=0.94 Figure 2.DFS.

OS: Overall Survival

<60 years old >= 60 years old OS Probability 0.0 0.2 0.4 0.6 0.8 1.0 Time in months 0 12 24 36 48 60 72 P=0.20 Figure 3.OS.

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OS. After adjusting for comorbidities, age had no signif-icant influence on DFS (P 5 .40) or OS (P 5 .059). After controlling for age, comorbidity was an independent in-fluential factor in both OS (P 5 .016) and DFS (P 5 .036). DISCUSSION

The present study demonstrates that autologous stem cell transplant following BEAM conditioning was efficacious and well tolerated in a cohort of patients over the age of 60.

In this study, age alone did not predict TRM, DFS, or OS in patients undergoing BEAM conditioning and ASCT for relapsed NHL. Admittedly, the patients who are eligible to proceed with HDT and ASCT are a select population, with preserved performance status and acceptable cardiac, pulmonary, hepatic, and renal function. Our results will not be applicable to patients who do not meet eligibility criteria to pro-ceed with ASCT. In addition, a number of clinical pre-dictors of outcome, including performance status and the International Prognostic Index score could not be reliably extracted from the medical record in this retro-spective series. Differences in the histology of NHL between the younger and older patients could also have obscured differences in outcomes.

Despite these limitations in the applicability of our findings, our results mirror what has been seen in the literature addressing autologous transplant in the era of peripheral blood stem cell transplant with improved supportive care [11,13,18]. The influence of comor-bidities on outcomes is receiving increasing attention. The CCI score, as opposed to age, influenced TRM, DFS, and OS in our study. A number of tools have been developed for predicting the impact of comorbid-ities on prognosis. The CCI[16,17], a weighted scale based on the relative risk of death attributable to a number of conditions, was utilized in this study given the reliability with which it can be applied retrospec-tively to a cohort. Monfardini et al.[19] created the MACE scale (Multidimensional Assessment for Can-cer in the Elderly), which incorporates a number of do-mains including comorbidities, symptoms, cognition, depression, physical function, and disability. A more comprehensive assessment of comorbidity, the Cumu-lative Illness Rating Scale-Geriatric (CIRS-G) [20], rates the severity of illness and correlates well with mortality, hospitalizations, and medication use [21]. However, when the CCI and CIRS-G were applied to a geriatric oncology population, comorbidity corre-lated poorly with functional status[22]. Because both comorbidity and functional status independently pre-dict survival in geriatric oncology patients [23], one should not be used as a surrogate for the other. Unfor-tunately, in this retrospective study, performance status of the patients could not be reliably extracted from the medical record to allow for analysis.

Another recently developed comorbidity index, the hematopoietic cell transplantation-specific comorbid-ity index (HCT-CI) is more comprehensive in its inclusion of comorbidities, and more tailored to co-morbidities unique to the hematopoietic stem cell transplantation population. It was initially developed in allogeneic stem cell transplant patients[24]. In a re-cent report, Sorror et al.[25]applied the HCT-CI to a cohort of patients who had undergone ASCT for re-lapsed lymphoma. The cohort included patients up to age 76. On multivariate analysis, comorbidities inde-pendently predicted nonrelapse mortality (NRM), OS, and relapse-free survival (RFS).

Peripheral blood stem cell mobilization was simi-lar between older and younger patients, with collection of similar numbers of CD341cells in similar numbers of pheresis sessions. Although this study represents a selected patient population who mobilized adequate stem cell numbers to proceed with high-dose therapy, previous studies have shown that elderly NHL patients are able to mobilize and harvest peripheral blood stem cells as successfully as their younger counterparts

[3,4,11,26]. Similarly, older multiple myeloma patients have been shown to mobilize peripheral blood stem cells as successfully as younger patients[27].

Although neutrophil engraftment and platelet count recovery to .20,000/mm3was similar between older and younger patients, there was a delay of plate-let count recovery to .50,000/mm3in older patients. This is not explained by differences in stem cell harvest or prior fludarabine exposure, as these were similar be-tween the 2 groups. The patients in the older group were more heavily pretreated, which could result in damage to the bone marrow microenvironment and the delay in platelet count recovery to .50,000/mm3 in older patients. An alternate explanation for this dif-ference may be found in the increasing evidence that aging affects the proliferative potential of hematopoi-etic stem cells [28], which could explain age-related differences in platelet recovery.

Overall, patients over the age of 60 tolerated BEAM conditioning as well as their younger counter-parts, with the exception of oral mucositis. Older patients were more likely to experience grade III/IV OM. This has been described previously[11]. Grade of OM was significantly inversely correlated with creatinine clearance (P 5 .0448). This relationship be-tween renal function and mucositis has been demon-strated in other studies. A recent analysis of patients with multiple myeloma undergoing ASCT explored risk factors for oral mucositis[29]. The conditioning regimen consisted of melphalan 200 mg/m2as a single dose, with reduction to 140 mg/m2for patients with creatinine .3 mg/dL. In that study, age did not inde-pendently predict severe mucositis. On multivariate logistic regression analysis, serum creatinine was sig-nificantly associated with the development of severe

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mucositis (odds ratio 1.58 [CI 1.08-2.13])[29]. Other studies have similarly shown a relationship between impaired renal function and severe mucositis in pa-tients with myeloma receiving melphalan conditioning for autologous stem cell transplant[30,31]. Although melphalan is predominantly eliminated by spontane-ous degradation, 13%-14% of melphalan is eliminated by renal excretion[32]. It could be hypothesized that increased drug exposure because of prolonged renal excretion results in more severe mucositis. However, a study of the pharmacokinetics of melphalan in the setting of high dose therapy for multiple myeloma concluded that creatinine clearance did not correlate with plasma melphalan clearance or plasma AUC

[33]. Similar studies in the setting of combination chemotherapy with BEAM have not been conducted. Although melphalan likely plays the most significant role in oral mucositis in the present study, cytarabine and etoposide may also be contributory.

High-dose therapy with autologous peripheral stem cell transplant remains the best chance for cure in many patients with relapsed NHL. Future studies could focus on improving the tolerability of high-dose chemotherapy. Several interventions have been utilized to decrease the incidence of mucositis. Cryo-therapy has been successfully employed to reduce the incidence of mucositis in multiple myeloma patients receiving high-dose melphalan [34,35]. Amifostine decreased the incidence of grade III/IV mucositis, the need for total parenteral nutrition, and opioid an-algesic use for mucositis compared to historic controls in a cohort of patients with advanced hematologic ma-lignancies who underwent TBI-based conditioning and ASCT[36]. In a prospective randomized trial of patients with multiple myeloma undergoing high-dose melphalan followed by ASCT, amifostine de-creased the incidence and severity of mucositis [37]. The recombinant human keratinocyte growth factor palifermin was studied in 212 patients with hema-tologic malignancies undergoing ASCT after condi-tioning with TBI, etoposide, and cyclophosphamide. The incidence of grade III/IV mucositis in patients who received palifermin was 64% compared to 98% in the placebo group; palifermin also reduced the dura-tion of mucositis and the severity of patient-reported symptoms [38]. Last, low-power laser therapy was studied in a randomized, placebo-controlled trial in 38 patients with hematologic malignancies who were undergoing either allogeneic or ASCT. Low-power laser therapy resulted in a lower severity and shorter duration of mucositis compared to placebo [39]. Thus, a number of potential interventions to reduce mucositis could be studied in a population of patients undergoing ASCT after BEAM conditioning. Further, the addition of targeted agents or radioimmunoconju-gates to the conditioning regimen may yield improved outcomes without incurring additional toxicity.

In summary, older patients with relapsed NHL overall tolerated high-dose therapy with BEAM condi-tioning and ASCT similar to their younger counter-parts, with the exception of more frequent severe mucositis and delayed recovery of platelet count to .50,000/mm3. Comorbid conditions were associated with higher TRM and lower OS in this retrospective cohort study. The decision to proceed with high-dose therapy and autologous transplant in an older patient should be individualized and incorporate a careful assessment of comorbidities, functional sta-tus, and renal function. Future studies prospectively evaluating the association between comorbidities and outcomes are warranted.

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