Autologous hematopoietic stem cell transplantation for older ... - Nature

Bone Marrow Transplantation (2006) 37, 1017–1022 & 2006 Nature Publishing Group All rights reserved 0268-3369/06 $30.00

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ORIGINAL ARTICLE

Autologous hematopoietic stem cell transplantation for older patients with relapsed non-Hodgkin’s lymphoma FK Buadi, IN Micallef, SM Ansell, LF Porrata, A Dispenzieri, MA Elliot, DA Gastineau, MA Gertz, MQ Lacy, MR Litzow, A Tefferi and DJ Inwards Division of Hematology, Department of Internal Medicine, Mayo Clinic College of Medicine, Rochester, MN, USA

To evaluate autologous stem cell transplant (ASCT) in older patients with intermediate grade non-Hodgkin’s lymphoma (NHL), the Mayo Clinic Rochester BMT database was reviewed for all patients 60 years of age and older who received ASCT for NHL between September 1995 and February 2003. Factors evaluated included treatment-related mortality (TRM), event-free survival (EFS) and overall survival (OS). Ninety-three patients were identified, including twenty-four (26%) over the age of 70 years. Treatment-related mortality (5.4%) was not significantly different when compared to a younger cohort (2.2%). At a median follow-up of 14 months (0.6–87.6 months), the estimated median survival is 25 months (95% confidence interval (CI) 12–38) in the older group compared to 56 months (95% CI 37–75) (P ¼ 0.037) in the younger group. The estimated 4-year EFS was 38% for the older group compared to 42% in the younger cohort (P ¼ 0.1). By multivariate analysis, the only factor found to influence survival in the older group was ageadjusted International Prognostic Index at relapse, 0–1 better than 2–3 (P ¼ 0.03). Autologous stem-cell transplant can be safely performed in patients 60 years or older with chemotherapy sensitive relapsed or first partial remission NHL. The outcome may not be different from that of younger patients in terms of TRM and EFS. Bone Marrow Transplantation (2006) 37, 1017–1022. doi:10.1038/sj.bmt.1705371; published online 24 April 2006 Keywords: autologous; transplant; lymphoma

Introduction In 2003, an estimated 53 400 new cases of non-Hodgkin’s lymphoma (NHL) will be diagnosed in the United States, with 54% older than 65 years.1,2 As demonstrated by the International Prognostic Index (IPI), age above 60 years is

Correspondence: Dr DJ Inwards, Division of Hematology, Department of Internal Medicine, Mayo Clinic College of Medicine, 200 First Street SW, Rochester, MN 55905, USA. E-mail: [email protected] Received 4 March 2005; revised 14 February 2006; accepted 13 March 2006; published online 24 April 2006

a poor prognostic factor for survival, and patients older than 60 years are less likely to be cured of their disease, even when treated with combination chemotherapy similar to that used for younger individuals.3 The literature suggests that lymphoma in the elderly may be more aggressive and resistant to therapy than in the younger population.4–6 Even with the higher complete response (CR) rate of 76% using the new regimen of cyclophosphamide, doxorubicin, vincristine, prednisone and rituximab (R-CHOP), the 2-year event-free survival (EFS) was only 57% showing that many of these patients will relapse and require some form of salvage chemotherapy.7 Using platinum-based salvage chemotherapy, CR rates of 30–50% may be achieved. Cure rate, however, is less than 10%,8,9 and hence other forms of therapy will be required to improve the outcome in these patients. The PARMA trial demonstrated that standard dose combination chemotherapy alone results in an inferior survival, compared to standard dose combination chemotherapy followed by high-dose therapy and autologous stem cell transplant (ASCT) for relapsed diffuse large B-cell lymphoma.10 However, this landmark study was restricted to patients less than 60 years of age, because of concerns of increased toxicity in older patients. Since the publication of the PARMA trial in 1995, there has been improvement in supportive care and better understanding of post-ASCT complications, making it reasonable to offer ASCT to selected older patients with hematologic malignancies. Although problems exist with stem cell mobilization, recent studies have shown the feasibility of ASCT in older patients with multiple myeloma.11,12 Similarly, a number of recent studies have demonstrated that ASCT can be safely carried out in older patients with NHL, with reasonable response rates, acceptable toxicity and minimal transplant-related mortality.13–17 These studies, while informative, were limited by their small size. We set out to examine the outcome of ASCT in a large group of older patients with NHL. We analyzed the results of ASCT in 93 patients age 60 years and older with NHL who received their transplant at Mayo Clinic in Rochester between September 1995 and February 2003. The purpose of this study was to determine overall survival (OS), EFS, treatment-related mortality (TRM), and to identify patient, disease or treatment-related variables that correlated with outcome.

Autologous stem cell transplant FK Buadi et al

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Materials and methods The Mayo Clinic Institutional Review Board approved this retrospective study. All NHL patients 60 years and older who received ASCT between September 1995 and February 2003 were included. Patients were eligible for transplant during this time period if they had relapsed, progressive or refractory intermediate or high-grade NHL. Patients with high-risk disease in first remission were also considered for transplant. In the case of those with relapsed or progressive disease (PD), sensitivity to a salvage regimen was a prerequisite to transplant; however, a few patients with refractory disease were offered ASCT. Adequate pulmonary, hepatic and cardiac function were necessary to be eligible for transplant. Ninety-three patients were identified from the database. During the same period, 178 patients below 60 years of age with NHL received ASCT at our institution. Similar hematopoietic progenitor cell mobilization methods, conditioning regimens and supportive care were given to all patients, regardless of age. All medical records were reviewed for retrieval of data. Lymphoma histology was classified according to the World Health Organization classification of neoplastic diseases of the hematopoietic and lymphoid tissue.18 Peripheral blood stem cells (PBSCs) were mobilized with granulocyte colonystimulating factor (G-CSF) or granulocyte–macrophage colony-stimulating factor (GM-CSF). Peripheral blood was the main source of stem cells, except in situations where patients had failed to mobilize adequate PBSCs, in which case a bone marrow harvest was utilized either in addition to PBSCs or instead of PBSCs. A suggested minimum PBSC dose of 2.0 10(6) CD34 þ cells/kg body weight was required to proceed to transplant without autologous bone marrow harvest.

Treatment Myeloablative chemotherapy consisted of the BEAM regimen (BCNU 300 mg/m2 over 2 h infusion on day 6, cytarabine 100 mg/m2 over 1 h infusion twice a day from day 5 to 2, etoposide 100 mg/m2 over 2 h infusion twice a day from days 5 to 2 and melphalan 140 mg/m2 over 1 h infusion on day 1) in all patients who were transplanted after April 1999. Between September 1995 and April 1999 BEAC was the standard regimen (BCNU 300 mg/m2 over 2 h infusion on day 8, etoposide 100 mg/ m2 over 2 h infusion twice a day from day 7 to 4, cytarabine 100 mg/m2 over 1 h infusion twice a day from day 7 to 4 and cyclophosphamide 35 mg/kg over 2 h infusion each day from day 7 to day 4). Autologous hematopoietic stem cells were infused through a central line on day 0. The median dose of stem cells infused was 3.1 10(6) CD34 þ cells/kg (1.3–14.9) for patients who received only PBSCs (n ¼ 69) and 2.6 10(8)NC/kg (1.2–3.0) for those who received only bone marrow (n ¼ 11). Thirteen patients received a combination of PBSC and bone marrow. Either G-CSF or GM-CSF was started on day þ 6 post transplant and continued until neutrophil engraftment. A combination of a quinolone and penicillin VK was used for antibacterial prophylaxis. Antifungal prophylaxis was with fluconazole. Bone Marrow Transplantation

Antifungal and antibacterial prophylaxis were started during conditioning and continued until neutrophil engraftment. Penicillin VK was continued for 1 year. Antiviral prophylaxis was routinely used until day þ 30 in patients with positive herpes simplex virus serology. Pneumocystis carinii prophylaxis with sulfamethoxazole/ trimethoprim was started during conditioning, but was discontinued before stem cell infusion and restarted after neutrophil and platelet engraftment to be continued until day 100. Neutropenic fever was treated with broadspectrum antibiotics. Leukocyte reduced irradiated packed red blood cells and platelets were transfused as required to keep the hemoglobulin above 8 g/dl and platelets greater than 10 10(9)/l. When possible, adjuvant external beam radiotherapy was initiated to sites of previous bulky disease or relapse sites that could be contained within reasonable sized involved fields at approximately day þ 60. Response to ASCT was determined on day þ 100 unless there was evidence of disease relapse before day þ 100 or the patient returned for post transplant adjuvant radiation, in which case restaging was performed before radiation therapy with subsequent restaging after completion of planned therapy. Following day þ 100, patients were evaluated quarterly by their primary hematologist and seen at Mayo Clinic at least yearly. No patient was lost to follow-up.

Statistical methods Neutrophil engraftment was defined as the first day of an absolute neutrophil count above 0.5 106/ml for three consecutive days. Platelet engraftment was defined as the first day of platelet count above 50 000 109/l and maintained for 1 week without platelet transfusion support. Tumor responses were classified as CR, complete response unconfirmed (CRu), partial response (PR), stable disease (SD) or PD according to the International Workshop criteria.19 An event was defined as a relapse, evidence of disease progression, or death, whatever the cause. The date of the first event was used in calculating the EFS. Treatment-related mortality was defined as death within 100 days of transplant without any evidence of disease progression. Performance status was defined according to the criteria of the Eastern Clinical Oncology Group (ECOG). Age-adjusted IPI was defined on the basis of performance status, lactate dehydrogenase and stage of disease. Both survival and disease-free survival were calculated from the day of transplant. Survival curves were generated using the method of Kaplan and Meier and compared using the two-sided log-rank analysis.20 Comparison between the older and younger groups for engraftment, TRM and stem cell dose were performed with the w2 or t-test. The Cox proportional hazard regression model was used to analyze the effect of the following potential prognostic variables on survival: age, sex, histology, age-adjusted IPI score, disease status at transplant, number of prior chemotherapy regimens and conditioning regimens.21 All statistical tests used a significance level of 0.05. All analyses were performed using SPSS for Windows, version 11.0 (SPSS, Chicago, IL, USA).


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Results Characteristics of the patients are presented in Table 1. Histology, age adjusted IPI, conditioning regimen and stem cell source were similar in both cohorts. There were 24 (26%) patients 70 years and older included in this study. Diffuse large B-cell lymphoma (DLBCL) was the predominant histology. The time to neutrophil and platelet engraftment, TRM, and survival were compared to those found in the younger cohort of patients transplanted during the same time interval. The results are depicted in Table 2. The median time to neutrophil engraftment was 13 days (range 9–33) for the older group and 13 days (range 9–69) for the younger group (P ¼ 0.77). Median time to platelet count of 50 000 109/l was 32 days (range 13–355) compared to 26 days (11–477) for the younger cohort (P ¼ 0.16). By day

Table 1

Characteristics of patients Patient characteristics before ASCT Ageo60 years AgeX60 years

No. of patients Median age at transplant (range) years

178 50 (18–59.6)

Sex (%) Male Female Disease status at transplant 1st CR 1st PR 2nd CR/PR 42nd CR/PR Refractory disease Histology (%) DLBCL Transformed/follicular Mantle cell T-cell Others

93 66 (60–76.5) Table 2 Comparison of engraftment, TRM, event-free and overall survival of the older and younger cohorts

— — — —

41 (44%) 28 (30%) 24 (26%)

106 (60%) 72 (40%)

75 (81%) 18 (19%)

Age groups 60–64 65–69 70+

þ 100, 68% of older patients had platelet counts greater than 50 000 109/l. There were 13 (14%) patients who never attained this benchmark; however, they were able to maintain an adequate platelet count of 420 000 without platelet transfusion support. Only three patients in the older cohort received a stem cell dose less than 2 106 CD34 cells/kg. Treatment-related mortality was 5.4% (95% confidence interval (CI): 0–15.6) in the older group and 2.2% (95% CI: 0–9.6) in the younger group (P ¼ 0.17). One patient in the older group died of sudden cardiac arrest 2 days after transplant; there was no evidence of disease progression at autopsy. One hundred-day all-cause mortality was 9% in the older group and 7.9% in the younger group. There have been 44 deaths at the time of this evaluation, the majority of which (75%) were related to relapsed/ progressive lymphoma (Table 3). There have been 6 (7%) documented secondary malignancies including two myelodysplastic syndromes, one adenocarcinoma of the colon and three cases of squamous cell carcinoma of the skin in the older group. The two patients with myelodysplastic syndrome died of their secondary malignancy at 50 months and 13 months post transplant without any evidence of lymphoma. The patient with adenocarcinoma of the colon

20 32 83 33 10

(11%) (18%) (47%) (18%) (6%)

5 6 50 29 3

(5%) (7%) (54%) (31%) (3%)

111 32 20 13 2

(62%) (18%) (11%) (7%) (1%)

57 24 6 4 2

(61%) (26%) (7%) (4%) (2%)

Ageo60 years AgeX60 years Significance (n ¼ 178) (n ¼ 93) Median days to neutrophil engraftment (range) Median days to platelet engraftment (range) Treatment-related mortality (%) Median EFS in months (95% CI) Median survival in months (95% CI)

103 (58%) 43 (24%) 32 (18%)

62 (67%) 17 (18%) 14 (15%)

Conditioning regimen (%) BEAC BEAM

71 (40%) 107 (60%)

29 (31%) 64 (69%)

Source of graft (%) PBSC BM Both

143 (80%) 19 (11%) 16 (9%)

69 (74%) 11 (12%) 13 (14%)

Abbreviations: ASCT ¼ autologous stem-cell transplant; BM ¼ bone marrow; DLBCL ¼ diffuse large B-cell lymphoma; CR ¼ complete response; IPI ¼ International Prognostic Index; PBSC ¼ peripheral blood stem cell; PR ¼ partial response.

13 (9–33)

P ¼ 0.77

26 (11–477)

32 (13–355)

P ¼ 0.16

4 (2.2%)

5 (5.4%)

P ¼ 0.17

23 (11–34)

13 (5–26)

P ¼ 0.1

56 (37–75)

25 (12–38)

P ¼ 0.037

Abbreviations: CI ¼ confidence interval; TRM ¼ treatment-related mortality.

Table 3 Age-adjusted IPI at relapse (%) 0–1 2–3 Unknown

13 (9–69)

survival;

Primary causes of death after transplant

Cause of death Recurrent/progressive lymphoma Sepsis Pulmonary aspergillosis secondary myelodysplastic syndrome Multi-organ failure Sudden cardiac arrest Diffuse alveolar hemorrhage Adenocarcinoma of colon Acute respiratory distress syndrome Motor vehicle accident Unknown Total

EFS ¼ event-free

No. of deaths No. of deaths o60 years (%) 460 years (%) 59 3 1 1

(86) (4) (1) (1)

33 3 1 2

(75) (7) (2) (5)

2 (3) — — — 2 (3) — 1 (1)

1 (2) 1 (2) 1 (2) 1 (2) — 1 (2) —

69

44

Bone Marrow Transplantation


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patients (o60 and X60 years) was performed looking at the effect of the following potential prognostic factors on EFS and OS: age, disease status at transplant, histology, stem cell source and IPI. The only factor that influenced both EFS (P ¼ 0.04) and OS (P ¼ 0.01) was stem cell source, with patients receiving a combination of PBSC and bone marrow doing worse than patients receiving PBSC or bone marrow alone. Further subanalysis was performed looking at patients with DLBCL and excluding all patients transplanted in first complete remission. There were 102 patients less than 60 years and 53 patients age 60 years and above. Univariate analysis comparing these two groups showed an estimated median EFS of 21 months (95% CI: 9–83) in the younger group compared to 9 months (95% CI: 6–50) in the older group (P ¼ 0.17). Overall survival was significantly different with an estimated median survival of 66 months (95% CI: 19–88) in the younger group and 18 months (95% CI: 10–50) in the older group (P ¼ 0.04).

1.0 Probability of event free survival

died at 3 months from vancomycin-resistant enterococcal peritonitis after surgery and was also in CR. Those with squamous cell carcinoma of the skin are still in remission of their lymphoma and have received curative therapy for their skin malignancy. Sixty-seven of the older patients had evidence of disease at the time of transplant; of these, 57 (85%) achieved CR or CRu after ASCT. Twenty-six patients were already in CR at the time of transplant. Overall, 83 (89%) were in CR or CRu after ASCT. Only 14 patients received consolidation radiation treatment after transplant. The CR/CRu rate after transplant in the younger group was 87%. The median follow-up was 12 months (range 0.6–79) for the older group and 17 months (range 0.6–87.6) for the younger group. The estimated median survival is 25 months (95% CI: 12–38) for the older patients and 56 months (95% CI: 37–75) for the younger patients. Although the difference was significant in a univariate analysis (P ¼ 0.037) (Figure 1), age was not a significant determinant of survival in a multivariate analysis. The median EFS was 13 months (95% CI: 4.7–21.5) in the older group. The estimated 4-year EFS is 38% for the older group compared to 42% in the younger cohort (P ¼ 0.1) (Figure 2). Within the older group, a Cox proportional hazard model was used to analyze the impact of the following potential prognostic variables on survival: age, histology, disease status at transplant, conditioning regimen, number of prior chemotherapy regimens, sex and age-adjusted IPI. The only pre-transplant factor, which influenced survival, was age-adjusted IPI. Survival duration was longer for patients with an age-adjusted IPI of 0–1 compared to 2–3 (P ¼ 0.03) Figure 3. This survival advantage was maintained in both univariate and multivariate analysis. Analysis of survival by age within the older group using groupings of 60–64, 65–69 and X70 years showed no differences (P ¼ 0.8). Twenty-four patients were 70 years of age or older. Their time to engraftment, TRM (12.5%) and OS were not statistically different from the results in those between 60 and 69 years of age. A multivariate analysis of all 271

0.8

0.6 Age < 60 yrs 0.4 Age .60 yrs P = 0.1

0.2

0.0 0

12

24

36

48

60

72

84

96

Time (months) Figure 2 Event-free survival by age.

1.0 1.0

Probability of survival

0.6 Age < 60 yrs 0.4 Age .60 yrs

Probability of survival

0.8 0.8

0.6 Age adjusted IPI 0 or 1 0.4 Age adjusted IPI 2 or 3

P =0.032

0.2 P = 0.037

0.2

0.0 0

0.0 0

12

24

36

48

60

Time (months) Figure 1

Overall survival by age.


72

84

12

24

96

36

48

60

72

Time (months) Figure 3 Overall survival in patients 60 years and older by age-adjusted International Prognostic Index.


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Discussion Conventional first-line chemotherapy can cure only 30– 50% of all newly diagnosed DLBCL.22–24 Thus a large number of patients will not experience a complete remission from initial therapy or will relapse and require further therapy. Currently, it is clear that ASCT for chemotherapysensitive relapsed aggressive NHL produces superior progression free and OS when compared to standard salvage chemotherapy and radiation therapy in patients less than 60 years of age.10 The benefits of ASCT are less certain in older patients. A few studies with small numbers of patients have suggested that ASCT in older patients may be superior to standard salvage regimens;13,15,25 however, this can only be confirmed by a prospective randomized trial. In the interim, larger retrospective series may be informative. Our retrospective study of 93 patients did show a high CR/ CRu rate of 89% after salvage chemotherapy and ASCT for older patients, compared to a CR/CRu rate of 87 % in younger patients, likely reflecting careful patient selection. The median survival of 25 months in the older patients was inferior to the median survival in the younger patients (56 months) (P ¼ 0.037). Subanalysis of patients with DLBCL, excluding patients transplanted in first complete remission, gave similar results. Surprisingly, we saw no evidence of any deterioration of survival data with increasing age among those undergoing transplant beyond the age of 60 years, despite the inclusion of patients beyond age 75 years. The estimated 4-year EFS of 38% in the older patients was not significantly different from the rate of 42% in the younger cohort (P ¼ 0.1). The estimated 4-year OS was 38% in the older patients compared to 54% in the younger cohort (P ¼ 0.037). Despite the high complete response rate, a third of our patients died of progressive or relapsed lymphoma despite ASCT. This parallels the experience in younger patients in that failure to achieve disease control is the primary cause of failure of ASCT for relapsed NHL. Our patient selection criteria did ensure that a larger proportion of the older patients had chemotherapy sensitive disease; it, however, also resulted in a high percentage of patients with transformed follicular lymphoma, as transplant was favored for this subset of patients. The latter population may have a worse prognosis than de novo relapsed aggressive NHL. In our study, TRM was not significantly higher in patients X60 years (5.4%) than in the younger cohort (2.2%) (P ¼ 0.17). This appears lower than the 8–22% TRM reported in this age group in the literature.12,15,17 Although the TRM and EFS were similar in both age groups, the OS was better for the younger group. This is likely due to the younger patients being able to tolerate further salvage therapy after relapse following ASCT. Nine patients in the younger cohort are in complete remission after salvage chemotherapy on relapse after transplant. The median days to neutrophil engraftment were no different in patients 60 years and older (13 days) than in the younger patients, which may partly explain the lack of difference in TRM. It is likely that the careful selection of older patients on the part of referring physicians, transplant physicians and patients themselves also contributed to the low TRM in our study. Although the time to platelet engraftment was

somewhat longer (32 days) in the older patients, this did not result in any catastrophic bleeding. As there was no significant difference between the young and old in the number of CD34 þ cells infused, the slight delay in platelet engraftment must be explained on a basis other than the apparent stem cell dose. It should be noted that the time to platelet engraftment in our study is longer than what is reported in the literature. This is because our definition of platelet engraftment of 50 000 109/l is different from the 20 000 109/l used in most publications. This benchmark was used because most of our patients received platelet transfusion for catheter removal if the platelet count was less than 50 000 109/l. Thus, it was difficult to apply the standard definition of 20 000 without transfusion for 7 days. Most patients did attain a platelet count of 50 000 109/l and were platelet transfusion independent. The ability of age-adjusted IPI at initial diagnosis to separate patients with aggressive NHL into prognostic groups has been clearly documented.3 We were able to determine that the age-adjusted IPI at the time of relapse was predictive for survival post-ASCT in patients X60 years of age, with those with a low age-adjusted IPI doing better. This may potentially be used to identify patients at higher risk for relapse, who may be candidates for new therapeutic approaches. There have been two cases of therapy-related myelodysplastic syndrome (2%) to date in this population, far lower than the 12% reported by Micallef et al.,26 although the latter study had total body irradiation as part of the conditioning regimen. Given the short median follow-up of only 12 months, it is likely there will be more cases over time. Both patients, however, died of therapy-related myelodysplastic syndrome confirming the poor prognosis of this complication after ASCT. This study of 93 patients between the ages of 60 and 77 years demonstrates that ASCT can be performed in selected older patients with aggressive NHL with acceptable TRM and morbidity. Although OS appears to be inferior to that achieved in younger populations, the results appear superior to what would be expected with salvage chemotherapy alone in this setting.

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