Results of a retrospective review of lymphoma patients aged ≥70 years and receiving autologous stem cell transplantation are presented. Safety and outcomes are described and clinical variables that may influence selection of patients for autologous stem cell transplantation are analyzed.
Keywords: Autologous stem cell transplantation, High‐dose chemotherapy, Lymphoma, Elderly
Abstract
Background.
High‐dose chemotherapy and autologous stem cell transplantation (ASCT) can offer durable remission in many patients with relapsed or high‐risk lymphoma. However, elderly patients are often not considered ASCT candidates based on age alone.
Subjects, Materials, and Methods.
A retrospective analysis of patients ≥70 years of age with a diagnosis of Hodgkin or non‐Hodgkin lymphoma receiving ASCT between 2000 and 2016 at two partner institutions was performed. Clinical data were extracted from institutional databases and individual medical records. Multivariate analysis was performed to examine the association of clinical variables with transplant outcomes.
Results.
One hundred seven patients were identified. Median age at transplant was 72 years (range, 70–79). The most common lymphoma subtype was diffuse large B‐cell (n = 63, 59%). Median time to neutrophil and platelet engraftment were 10 and 12 days, respectively. With a median follow‐up for survivors of 20 months following ASCT (range, 6 months to 13.1 years), estimates for 2‐year progression‐free survival and overall survival were 58% (95% confidence interval [CI], 48%–67%) and 65% (95% CI, 55%–74%), respectively. Two‐year estimate for relapse was 34% (95% CI, 25%–44%) and nonrelapse mortality (NRM) was 7% (95% CI, 3%–14%). Multivariate analysis showed that more recent date of transplant was associated with lower NRM. The Hematopoietic Cell Transplantation‐Comorbidity Index score was not predictive of NRM in this data set (high‐risk vs. low‐risk, hazard ratio 3.45, p = .065).
Conclusion.
Eligibility for ASCT should be an individualized decision, and age should not be an absolute contraindication to ASCT in healthy elderly patients with lymphoma.
Implications for Practice.
Although high‐dose chemotherapy and autologous stem cell transplantation (ASCT) can offer durable remission in many patients with relapsed or high‐risk lymphoma, elderly patients are often not considered candidates due to concern for excess toxicity and mortality. This retrospective study showed favorable transplant outcomes, including survival and toxicity, in a large cohort of lymphoma patients over 70 years of age who underwent ASCT. Eligibility for ASCT should be an individualized decision, and age should not be an absolute contraindication to ASCT in healthy elderly patients with lymphoma.
Introduction
High‐dose chemotherapy and autologous stem cell transplantation (ASCT) is a potentially curative therapeutic modality for patients with lymphoma. ASCT is considered the standard of care for chemotherapy‐sensitive relapsed Hodgkin [1] or non‐Hodgkin lymphoma [2], [3], [4], [5]. For patients with certain high‐risk lymphoma subtypes, ASCT is often incorporated into upfront consolidation [6], [7], [8].
Due to a concern for excess toxicity, early use of ASCT excluded patients over the age of 60–65 years. With advances in supportive care, ASCT‐associated morbidity and mortality has greatly improved. However, the notion that elderly patients should not be considered candidates for ASCT persists, withholding potentially curative therapy from a group of patients accounting for an increasing number of lymphoma cases. A growing body of evidence supports that ASCT is safe for carefully chosen healthy elderly patients. Some initial reports regarding the use of ASCT in patients >60 years of age reported higher rates of infectious complications and cardiovascular toxicity, resulting in higher rates of nonrelapse mortality (NRM) and inferior survival as compared with the nonelderly population [9], [10], [11], [12], [13], [14], [15]. Other studies did not observe significantly different outcomes by age category [16], [17], [18], [19], and have suggested that poorer outcomes may correlate more closely with comorbidities than with numerical age [16]. Recent studies have increasingly focused on older cohorts of patients (>65 and >70 years of age), but have been limited in sample size [14], [15], [17], [20].
We undertook this retrospective review of lymphoma patients ≥70 years of age receiving ASCT with the goal of describing safety and outcomes, as well as analyzing clinical variables that may influence selection of patients for ASCT.
Subjects, Materials, and Methods
This study was approved by the institutional review board at the Dana‐Farber/Harvard Cancer Center. We identified patients ≥70 years of age with a diagnosis of Hodgkin or non‐Hodgkin lymphoma who underwent ASCT between 2000 and 2016 at Massachusetts General Hospital Cancer Center and Dana‐Farber Brigham and Women's Cancer Center. Date of diagnosis, disease histology, type and number of prior chemotherapy regimens, and disease status at transplantation were recorded for each patient, using retrospective chart review. Complete remission (CR) was defined as the absence of radiological evidence of lymphoma on positron emission tomography, computed tomography, and/or magnetic resonance imaging. Partial remission (PR) was defined as ≥50% reduction in lymphoma mass as assessed by imaging. Patient comorbidities were assessed with the Hematopoietic Cell Transplantation Comorbidity Index (HCT‐CI) score [21]. HCT‐CI score was retrospectively calculated based on initial consult note, lab values, and diagnostic tests obtained prior to transplant (supplemental online Table 1). Patients were classified as low risk (HCT‐CI 0), intermediate risk (HCT‐CI 1–2), or high risk (HCT‐CI 3 or higher). Hematopoietic cell mobilization was performed using filgrastim, either alone or following chemotherapy, according to physician discretion. The minimum CD34+ cell target yield was 2 × 106 cells per kg. To our knowledge, no patients received maintenance therapy after ASCT. Data regarding relapse and death were obtained from the medical record and/or from the Social Security Death Index.
Statistical Analysis
We recorded number of days to engraftment of platelet count (≥20 × 109/L × 3 days) and neutrophil count (≥0.5 × 109/L × 3 days) for each patient, as well as toxicities including sepsis and organ failure both acutely (<100 days from transplant) and long‐term. Overall survival (OS) was calculated from the date of transplantation to death or censored at the time of last clinical evaluation. Progression‐free survival (PFS) was calculated from the date of transplantation to disease progression or death from any cause. Patients who were alive without disease recurrence or progression were censored at the time of last clinical evaluation. PFS and OS were estimated using the Kaplan‐Meier method. Cumulative incidence of NRM was calculated with relapse as the competing risk. Log‐rank test or Gray test was used for comparisons of time‐to‐event outcomes. Patient characteristics, including age, HCT‐CI score, disease histology, type of conditioning regimen, number of prior regimens, and disease status at transplantation, were analyzed for their association with OS or PFS (or NRM) using a Cox proportional hazards model (or competing risks regression model).
Results
Patient and ASCT Characteristics
One hundred nineteen patients were identified and 12 were excluded due to less than 6 months of follow‐up after ASCT. Characteristics of the 107 patients included in the analysis are summarized in Table 1. Median age at transplant was 72 (range, 70–79). Fifty‐nine patients were male and 48 were female. The most common lymphoma subtype was diffuse large B‐cell (n = 62, 58%). Additional subtypes included T‐cell (n = 18), mantle cell (n = 11), follicular (n = 7), classical Hodgkin lymphoma (n = 6), and primary central nervous system lymphoma (n = 3). The most commonly used conditioning regimens were CBV (cyclophosphamide, carmustine, etoposide; n = 44), BEAM (carmustine, etoposide, cytarabine, melphalan; n = 31), and busulfan/cyclophosphamide (n = 24). Twenty‐three patients received radiation as part of their pre‐ASCT therapy. Patients were characterized as low (n = 33), intermediate (n = 28), or high risk (n = 46) by HCT‐CI. The most common comorbidity in our patient population was moderate or severe lung disease (n = 55), followed by prior solid tumor (n = 19) and diabetes mellitus (n = 12).
Table 1. Patient and transplant characteristics.
Abbreviations: ASCT, autologous stem cell transplantation; BEAM, carmustine, etoposide, cytarabine, melphalan; CBV, cyclophosphamide, carmustine, etoposide; CNS, central nervous system; CR, complete remission; Gem/Bu/Mel, gemcitabine, busulfan, melphalan; ICE, ifosfamide, carboplatin, etoposide; PET, positron emission tomography; PR, partial remission; TBC, thiotepa, busulfan, cyclophosphamide.
The number of transplanted elderly patients increased over time, with 10 patients transplanted during 2000–2005, 34 patients transplanted during 2006–2010, and 63 patients transplanted during 2011–2016. There was no significant difference in HCT‐CI score between patients transplanted in these time periods. The majority of patients (84 of 107) had two or more chemotherapy regimens prior to ASCT. The most commonly administered salvage regimen was RICE (rituximab, ifosfamide, carboplatin, etoposide; n = 45). The majority of patients (n = 77) were in CR (CR1, n = 21; ≥CR2, n = 56), whereas 30 patients had partial remission or active disease at time of transplant. The median time from diagnosis to ASCT was 16 months (range, 4 months to 23 years), with 75 patients undergoing transplant >1 year after their initial diagnosis.
Transplant Outcomes
Table 2 summarizes transplant outcomes. Median time to neutrophil and platelet recovery was 10 (range, 8–27) and 12 (range, 6–42) days, respectively. Median length of inpatient hospital stay was 21 days (range, 16–83). The median follow‐up for survivors was 20 months (range, 6–157). The Kaplan‐Meier estimates for OS and PFS at 2 years was 65% (95% confidence interval [CI], 55%–74%) and 58% (95% CI, 47%–67%), respectively (Fig. 1). Relapse rate was 34% at 2 years (95% CI, 25%–44%). Of 53 patients who relapsed, 49 relapsed before 5 years, whereas 4 patients relapsed beyond 5 years after ASCT.
Table 2. Autologous stem cell transplantation outcomes.
Abbreviation: CI, confidence interval.
Figure 1.
Kaplan‐Meier curve depicting OS and PFS.
Abbreviations: OS, overall survival; PFS, progression‐free survival.
Toxicities and NRM
Toxicities and mortality events are summarized in Table 3. In addition to common side effects of neutropenic fever, gastrointestinal toxicity, and mucositis, 25 patients experienced infectious complications including bacteremia (n = 12), Clostridium difficile colitis (n = 4), pneumonia (n = 7), viral cystitis (n = 1), and cellulitis (n = 1). Twelve patients experienced peri‐ASCT neurologic symptoms including seizure (n = 3), delirium (n = 7), syncope (n = 1), and aphasia (n = 1). Acute kidney injury (n = 7), BCNU‐pneumonitis (n = 3), and liver injury (n = 2) were also observed. Three patients have developed treatment‐related myelodysplastic syndrome and acute myeloid leukemia following ASCT.
Table 3. Toxicities and mortality.
Abbreviation: AML, acute myeloid leukemia.
Three patients experienced early mortality in the first 100 days after ASCT. One patient had rapid disease progression and died on Day +57. Another developed treatment‐related acute myeloid leukemia as well as renal failure, and died on Day +61. The third developed sepsis and multi‐organ failure and died on Day +12. Of those with late mortality (after Day +100), 31 of 43 patients died due to relapsed or progressive disease. The cause of death for the other 12 patients included sepsis or infectious complications (n = 5), heart failure (n = 2), multi‐organ failure (n = 1), therapy‐related MDS (n = 1), and unknown reasons (n = 3). NRM was 5% at 1 year (95% CI, 2%–10%) and 7% at 2 years (95% CI, 3%–14%) for the entire cohort.
Multivariate Analysis
Results of multivariate analysis for clinical factors associated with PFS, OS, relapse, and NRM are summarized in Table 4. As expected, ASCT performed in CR1 was associated with superior PFS compared with patients with PR/active disease (hazard ratio [HR] 3.28, 95% CI, 1.21–8.92, p = .02), and showed a nonsignificant trend toward superior PFS compared with patients in ≥CR2 (HR 2.37, 95% CI, 0.9–6.26, p = .08). Additionally, ASCT with PR/active disease was associated with a higher risk for relapse when compared with the CR1 group (HR 5.09, 95% CI, 1.51–17.18, p = .0086), but not when compared with ≥CR2 cohort (HR 1.65, 95% CI, 0.85–3.24, p = .14). HCT‐CI score, age, and year of transplant did not impact relapse or PFS. No factors analyzed were found to be associated with OS. In the NRM model, ASCT performed in earlier years (2000–2010) was associated with higher risk for NRM than those transplanted in later years (2011–2016; HR 6.54, 95% CI, 1.37–31.31, p = .019). There was a trend toward a higher risk for NRM in patients with high‐risk HCT‐CI as compared with low‐risk patients, although this did not meet statistical significance (HR 3.45, 95% CI, 0.93–12.86, p = .065; Fig. 2).
Table 4. Multivariate analysis.
Values in bold indicate those meeting statistical significance (p < .05).
Abbreviations: CI, confidence interval; CR, complete response; HCT‐CI, hematopoietic cell transplantation comorbidity index; HR, hazard ratio; NRM, nonrelapse mortality; OS, overall survival; PFS, progression‐free survival; PR, partial response.
Figure 2.
Nonrelapse mortality following autologous stem cell transplantation according to HCT‐CI risk.
Abbreviation: HCT‐CI, Hematopoietic Cell Transplantation Comorbidity Index.
Discussion
We present outcomes for a large series of elderly lymphoma patients >70 years of age receiving ASCT. The 2‐year outcomes were promising, with OS and PFS of 65% (95% CI, 55%–74%) and 58% (95% CI, 47%–67%), respectively. Furthermore, 2‐year NRM was 7% (95% CI, 3%–14%), which, although higher than in younger cohorts, is acceptably low in this elderly population. Our results are generally consistent with prior reports in this age group and validate the use of ASCT in selected elderly patients with lymphoma [9], [10], [14], [15], [16], [17], [18], [19], [20], [22], [23], [24], [25], [26], [27] (Table 5).
Table 5. Previous reports of autologous stem cell transplantation for elderly lymphoma patients.
Abbreviations: d, day; DLBCL, diffuse large B‐cell lymphoma; NHL, non‐Hodgkin lymphoma; NR, not reported; NRM, nonrelapse mortality; OS, overall survival; PCNSL, primary central nervous system lymphoma; PFS, progression‐free survival; yr, year.
A major concern for elderly patients receiving ASCT is the risk for NRM. We further set out to characterize clinical factors that may help guide clinicians how to best select elderly patients fit for ASCT, especially in regard to NRM. Previously published studies of ASCT in elderly lymphoma patients have reported 100‐day NRM ranging from 4% to 18% (Table 5). A large European registry study of 463 patients with diffuse large B‐cell lymphoma aged ≥60 years found acceptable but inferior 100‐day NRM (4.4%), 3‐year PFS (51%), and 3‐year OS (60%) compared with patients under the age of 60 [23]. In multivariate analysis, the factors associated with greater NRM were age ≥60 years, multiple lines of chemotherapy prior to ASCT, poor performance status, and refractory disease [23]. In another experience of 484 patients who underwent ASCT over the age of 60 in Japan, there was no significant difference in NRM between age groups of 60–64 years, 65–69 years, and 70 years or older; in fact, 100‐day NRM for the oldest cohort of patients was only 5.2% [10]. Presence of B symptoms at diagnosis was predictive of greater risk of NRM on univariate analysis but not multivariate analysis, which did not reveal any significant predictors of risk of NRM [10]. In the largest published study of patients ≥70 years of age undergoing ASCT, which included 81 patients, toxicity outcomes were as acceptable as those reported in the population aged ≥60 years, with 100‐day NRM of 5.4%. In this study, as in ours, HCT‐CI score did not display prognostic impact on survival or toxicity outcomes [20].
In multivariate analysis, we found that ASCT performed in the recent years was associated with a lower risk for NRM (2000–2010 vs. 2011–2016, HR 6.54, 95% CI, 1.37–31.31, p = .019). We believe that this largely reflects improvements in medical practice, including advancements in infectious disease, intensive care unit medicine, and supportive care. The high‐dose chemotherapy regimens employed have remained stable over time. Better outcomes in the recent era may also be due to better selection of patients, which is difficult to characterize. It is noteworthy that there was no significant difference in HCT‐CI score comparing those transplanted in the past with more recent years.
In this series of patients, the risk of NRM did not significantly change with risk categories of HCT‐CI, although a trend toward higher NRM was seen when comparing high‐risk and low‐risk HCT‐CI cohorts. This may be because the data set is underpowered to detect the association between HCT‐CI and NRM seen in other studies. However, it also suggests that HCT‐CI may have some limitations in its application to elderly patients undergoing ASCT. Several prior studies in elderly lymphoma patients have similarly reported that HCT‐CI did not display prognostic impact [20], [26], or that HCT‐CI score predicted higher risk of toxicity but did not impact OS [19]. We noted a high proportion of patients (47 of 107, 44%) classified as high‐risk by HCT‐CI, and the median HCT‐CI score in our population was 2. Other studies have reported much lower comorbidity scores in elderly patients undergoing ASCT—in the study by Hermet, 73% of transplanted elderly patients had an HCT‐CI score of zero [20]; and in Hosing's 2008 study, only 36% had an HCT‐CI score >2 [19]. Several factors likely played a role in our patients’ higher HCT‐CI scores. In this analysis, we retrospectively scored HCT‐CI following extensive review of individual patient records, which may have led to identification of quiescent comorbidities that otherwise can be overlooked. For example, a significant proportion of our patients (19 of 107, 18%) were classified as high‐risk based on a history of prior solid tumor alone, most of which were remote localized cancers with questionable clinical relevance in the setting of ASCT.
The HCT‐CI score was initially developed in a younger cohort of patients undergoing allogeneic stem cell transplantation [21] and its applicability in an elderly population undergoing ASCT has not been well defined [20], [26]. A revised HCT‐CI for elderly patients, perhaps that de‐emphasizes comorbidities such as solid tumors, which become increasingly common with age, may be useful in evaluation of these patients for ASCT candidacy. The use of geriatric assessment tools and evaluation for impairment in activities of daily living might potentially help better evaluate physiologic age in older ASCT candidates [28]. Furthermore, pretransplant evaluations may be enhanced by consideration of emerging comorbid conditions, highlighted by a recent analysis that showed that clonal hematopoiesis of indeterminate potential, whose prevalence increases with age, is associated with inferior survival and increased risk of NRM after ASCT [29]. Ultimately, despite a high median HCT‐CI score, our population of elderly lymphoma patients undergoing ASCT had acceptably low NRM and favorable survival outcomes.
We acknowledge several limitations of our retrospective analysis. This study included a selected population of relatively fit elderly patients at only two centers, thus limiting the generalizability of our findings. In addition, we included patients with multiple disease and histological classifications, which limits the ability to perform more detailed analysis in regard to disease risk. Given the different treatment approaches to specific lymphoma subtypes, future investigations examining the indications of ASCT in elderly patients according to disease subtype are important.
Conclusion
ASCT is safe and feasible in selected elderly lymphoma patients as consolidation for high‐risk disease or relapsed disease. Eligibility for ASCT should be an individualized decision, and age alone should not be an absolute contraindication. Additional tools are likely needed to help providers make appropriate decisions.
See http://www.TheOncologist.com for supplemental material available online.
Supplementary Material
Author Contributions
Conception/design: Lova Sun, Yi‐Bin Chen, Zachariah DeFilipp
Provision of study material or patients: Areej El‐Jawahri, Philippe Armand, Bimalangshu R. Dey, David C. Fisher, Eric D. Jacobsen, Caron A. Jacobson, Ann S. LaCasce, Steven L. McAfee, Thomas R. Spitzer, Yi‐Bin Chen, Zachariah DeFilipp
Collection and/or assembly of data: Lova Sun, Zachariah DeFilipp
Data analysis and interpretation: Lova Sun, Shuli Li, Areej El‐Jawahri, Yi‐Bin Chen, Zachariah DeFilipp,
Manuscript writing: Lova Sun, Zachariah DeFilipp
Final approval of manuscript: Lova Sun, Shuli Li, Areej El‐Jawahri, Philippe Armand, Bimalangshu R. Dey, David C. Fisher, Eric D. Jacobsen, Caron A. Jacobson, Ann S. LaCasce, Steven L. McAfee, Thomas R. Spitzer, Yi‐Bin Chen, Zachariah DeFilipp
Disclosures
Philippe Armand: Merck, Pfizer, Bristol‐Myers Squibb (C/A), Merck, Bristol‐Myers Squibb, Pfizer, Roche, Tensha, Sequenta, Affimed (RF); Caron A. Jacobsen: Kite Pharma, Bayer, Pfizer (C/A). The other authors indicated no financial relationships.
(C/A) Consulting/advisory relationship; (RF) Research funding; (E) Employment; (ET) Expert testimony; (H) Honoraria received; (OI) Ownership interests; (IP) Intellectual property rights/inventor/patent holder; (SAB) Scientific advisory board
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