Autologous SCT is a potentially curative procedure for patients with relapsed lymphoma (NHL). We analyzed the outcomes of 34 patients ⩾60 years old, including eight patients ⩾70 years old, who received BU and CY and SCT for NHL. Patients received BU 0.8 mg/kg i.v. (n=25) or 1 mg/kg p.o. (n=9) q 6 h × 14 doses and CY 60 mg/kg i.v. q day × 2 days. The median age was 66 (range, 60–78) years. Twenty-two patients had large cell, 10 follicular and two-mantle cell lymphoma. Fifteen patients were in a second or greater CR and 19 patients were in a PR. The median days to ANC >500/μl and platelet count >50 000/μl were 10 and 13 days respectively. The 100-day transplant-related mortality was 0%. Toxicities included interstitial lung disease (n=2), seizures in a patient with CNS lymphoma (n=1), mild veno-occlusive disease (n=2), and transient atrial fibrillation (n=4). With a median follow-up of 40 months, the 2-year overall survival and PFS were 67 and 54% respectively. BU/CY is a well-tolerated conditioning regimen for older patients with NHL. Age alone should not be used as an exclusion criterion for autologous SCT.
More than 55 000 patients are diagnosed with non-Hodgkin's lymphoma (NHL) in the United States each year. More than 60% of these cases occur in patients who are 60 years or older. The incidence of NHL is increasing and the largest increase in incidence occurs in patients more than 60 years of age, who may have a poorer prognosis.1, 2 About 50–70% of older patients with large-cell lymphoma achieve a complete response with upfront combination chemotherapy regimens including the combination of CY, adriamycin, vincristine and prednisone (CHOP).3 Adding rituximab (R) to CHOP in patients aged more than 60 years has increased the 3-year disease-free survival from 46% with CHOP alone to 53% with R- CHOP.4
High-dose chemotherapy followed by autologous SCT has been shown to be potentially curative for patients who relapse after initial chemotherapy.5 SCT in second or third CR was established as a standard of care by the Parma trial in patients between 18 and 60 years of age with intermediate or high-grade NHL. The study reported an event-free survival of 46% at 5 years in the transplantation group as compared with 12% in the group receiving chemotherapy without transplant.6
The safety and efficacy of SCT in NHL has been studied in patients between ages 60 and 70 years. One hundred-day mortality for patients between 60 and 70 years varies from 5 to 11% with an overall survival of 38–51%.7, 8, 9
Several conditioning regimens for SCT have been described in older patients with NHL.7, 8, 10 The BEAM regimen incorporates carmustine, etoposide, cytarabine and melphalan and has been associated with a treatment-related mortality of 9% in older patients.9 CY, BCNU and etoposide has also been extensively used and is associated with cardiac toxicity.11 The regimen of BU and CY has been described extensively in several patient groups as a conditioning regimen for both autologous and allogeneic SCT for the treatment of hematologic malignancies.12, 13, 14, 15 The efficacy and side effects of this regimen have not been extensively studied in patients more than 60 years of age with NHL undergoing SCT, and there are little data on the outcomes of patients greater than 70 years old.
In this retrospective study, we present the outcomes of 34 patients aged 60 and older, including eight patients aged 70 years and over receiving SCT for relapsed NHL after conditioning with a modified BU and CY-conditioning regimen.
Materials and methods
We treated 34 NHL patients 60 years or older with a modified BU and CY-conditioning regimen followed by autologous SCT. Patients underwent autologous SCT between December 1995 and March 2007. All patients were treated at Massachusetts General Hospital, and met standard transplant criteria including Eastern Cooperative Oncology Group performance status of 0 or 1, bilirubin <2.0, creatinine <2.0, a diffusion coefficient of carbon monoxide of more than 50% of the predicted value corrected for hemoglobin, and an echocardiogram with an ejection fraction of more than 50%. All patients gave informed consent before being enrolled on the protocol. All Massachusetts General Hospital patients with chemosensitive, relapsed lymphoma who met the eligibility criteria above were offered transplantation; the group, however, is a selected referral population who expressed interest in evaluation at a transplant center.
Histology of the NHL was recorded according to the World Health Organization Formulation. Disease was staged according to the Ann Arbor staging system. The state of the disease at the time of the SCT was defined as first, second or third remission (each being defined as partial or complete) or relapse. CR and PR were defined according to criteria outlined by the International Working Group.16 CR was defined as complete disappearance of all clinical and radiographic evidence of disease and disappearance of all disease-related symptoms. PR was defined as more than or equal to a 50% decrease in the sum of the products of the greatest diameter in the six largest nodes or nodules. Liver and spleen nodules were required to regress by at least 50% and the development of new disease sites was not allowed. Chemosensitivity was defined as either a CR or PR to the salvage chemotherapy administered before the harvest of stem cells.16, 17
Neutrophil engraftment was defined to occur on the first of 3 consecutive days with an ANC of 500/μl or greater. Platelet engraftment was defined as the achievement of an unsupported platelet count of more than or equal to 20 000/μl. Toxicities were defined according to the Seattle (Bearman) criteria.
All patients received the following BU/CY regimens. Before December 2000, patients received oral BU (nine patients) and after December 2000, patients received i.v. BU (25 patients). One patient received oral BU at 1 mg/kg every 6 hours for 16 doses starting on day –7 (total dose 16 mg/kg). All subsequent patients receiving oral BU received 1 mg/kg every 6 hours for 14 doses starting on day –7 (total dose 14 mg/kg). Oral BU was dosed at 50% between ideal and actual body weight for patients >20% above ideal body weight. Intravenous BU was dosed at 0.8 mg/kg every 6 hours starting on day –7 for 14 doses (total dose 11.2 mg/kg). Intravenous BU dosing was based on either actual or ideal body weight, whichever weight was less. Pharmacokinetic sampling was not performed. The lower dose of BU was used secondary to toxicities seen with the 16 mg/kg dose in older patients. All patients received CY 60 mg/kg daily on days –3 and –2 (total dose 120 mg/kg), given as a 120-minute infusion. CY was dosed at 50% between ideal and actual body weight for patients >20% above ideal body weight. All patients received standard supportive care, which included filgastrim (G-CSF) 5 mcg/kg i.v. daily until total white blood cell count was more than 5000/μl and viral, bacterial, fungal and PCP prophylaxis per institutional guidelines.18 Hydration and Mesna were provided to protect from the bladder toxicity of CY and patients received phenytoin as prophylaxis against seizures from BU.
Engraftment and survival times were measured starting from the day of stem cell infusion (day 0) and were estimated by the Kaplan–Meier method. Overall survival was defined as death owing to any cause and was censored at the last date of follow-up. PFS was defined as the time to relapse or death in the absence of disease progression, whereas patients who were still alive without relapse were censored at the last follow-up date. Time to relapse was defined as the time to relapse, whereas patients alive or dead without relapsing were censored at the latter of last follow-up or death date. The log–log transformation is applied to the survivor function to compute pointwise limits for the 95% confidence interval (CI) of survival outcomes. As the Kaplan–Meier estimator has zero standard error on account of no transplant-related deaths by day 100, the 95% CI for 100-day transplant-related mortality is obtained as a binomial exact interval with 5% probability in the right tail. The log-rank test was used to assess the survival difference between age groups. StatXact version 6.2 (Cytel Software Corp., Cambridge, MA, USA) was used to compute the exact P-value based on a two-sided hypothesis.
Thirty-four consecutive patients aged 60 years or older with relapsed NHL underwent SCT at Massachusetts General Hospital between December 1995 and March 2007 (Table 1). The median age of the patients was 66 years, with eight patients 70 years or older. The majority of patients had relapsed, chemotherapy-sensitive diffuse large cell lymphoma. Patients with refractory disease were excluded. Sixteen patients had stage III disease at diagnosis and seven patients had stage IV disease at diagnosis. Five patients had documented marrow involvement at the time of diagnosis. The median time from diagnosis to transplant was 29 months (range, 5 months to 21 years).
All patients received peripheral blood stem cell grafts. Three patients received bone marrow as well as peripheral blood stem cells. The median CD34+ count infused was 2.87 × 10 (6)/kg (range, 0.7–140 × 10 (6) CD34+cells/kg). All patients engrafted. The median time to ANC >500/μl was 10 (range, 8–29) days. The median time to unsupported platelet count >20 000/μl was 13 (range, 8–196) days.
The 100-day transplant-related mortality was 0% (95% CI 0–8%). There was one late transplant-related death from pneumonitis and diffuse alveolar hemorrhage on day 696 after transplant. Toxicities were graded according to the Seattle (Bearman) criteria and are shown in Table 2. Serious toxicities experienced included: interstitial lung disease (n=2 including patient described above), seizures in a patient with CNS lymphoma (n=1) and veno-occlusive disease which resolved (n=2). The two patients with veno-occlusive disease had both received oral BU, and veno-occlusive disease occurred on days 42 and 27 post transplant. No defibrotide was administered. One of the patients with veno-occlusive disease had severe hemorrhage and hypotension after liver biopsy and sustained a small myocardial infarction. She recovered fully. Four patients experienced transient atrial fibrillation.
Patients received a median of four red blood cell transfusions (range, 0–26 units) and 5 platelet transfusions (median 1–59) in the first 100 days post transplantation. At 100 days post transplantation, five patients were still transfusion-dependent. Median hospital stay was 20 days, with a range of 11–36 days. There were no ICU admissions during the transplant hospitalization.
There were six patients with bacteremia, one with vancomycin-resistant enterococcus, four with coagulase negative staphylococcal infection and one with a stomatococcus infection. The staphylococcal infections all occurred early in the patient's course, with positive blood cultures on days −7, 0, +2 and +3 after transplant. Three patients had clostridium difficile colitis, and one patient developed herpes zoster. Mucositis was severe in four patients who required total parenteral nutrition. There was one secondary malignancy reported during the period of follow-up; one patient developed breast cancer 5 years after transplant.
Relapse and survival
Seventeen patients have relapsed. Median time to relapse was 39 months (range, 72 days to 54 months). With a median follow-up of 40 months (range 5–125 months), the 2-year overall survival was 67% (95% CI 47–61%) (Figure 1) and 2-year PFS was 54% (95% CI: 35–69%) (Figure 2).
Patients 70 years and older
Eight patients 70 years and older were transplanted. One hundred-day transplant-related mortality rate was 0% (95% CI: 0–31%). With a median follow-up of 48 months, seven of eight patients were alive and four were progression-free. Grade 3 and 4 toxicities for patients 70 years of age and older are summarized in Table 2. Significant toxicities for these older patients included one patient with engraftment syndrome and one patient with atrial fibrillation. Overall and PFS for patients 70 years and older are illustrated in Figures 3 and 4. They were not significantly different from the overall (P=0.35) and progression-free survivals (P=0.44) for patients younger than 70 years.
The standard of care for patients with intermediate and high-grade NHL is upfront chemotherapy with R-CHOP.3, 4 Patients in chemotherapy-sensitive relapse have improved survival with autologous SCT.5, 6 Several studies have been published in an attempt to discern the optimal conditioning regimen before stem cell infusion. These have included BCNU or TBI combined with etoposide and CY, TBI with etoposide and CY, carmustine, cytarabine, CY and etoposide (BEAC), or BCNU, etoposide, ara-c and melphalan (BEAM).19, 20, 21, 22 Disease-free survival probabilities of 28–60% have been reported after autologous transplantation using these regimens. No randomized studies have compared these conditioning regimens. Recently, rituximab has been added to either mobilization regimens, or post transplantation regimens to reduce the risk of relapse23, 24 We selected a reduced dose of BU based on toxicities observed with the 16 mg/kg oral BU dose in older patients. The lower total dose of BU used in this study—14 mg/kg orally or 11.2 mg/kg intravenously was evaluated by the AIDS Malignancy Consortium and found to be well-tolerated in 20 patients with human immunodeficiency virus-associated NHL or Hodgkin's lymphoma.25
Advanced age is an independent risk factor for recurrent NHL; thus a higher percentage of older patients will be candidates for autologous SCT.10 Advances in supportive care such as the introduction of peripheral blood stem cell grafts, growth factors, antibiotic prophylaxis, transfusion support and mucositis prevention have reduced the toxicity of transplantation. There are no conclusive data to recommend one conditioning regimen over another in this population.7, 8, 9, 26 We have demonstrated that a modified BU and CY regimen in selected patients ⩾60 years of age is well tolerated. The dose of BU has been reduced to 14 doses of 0.8 mg/kg i.v. as per our institutional practice for patients more than the age of 50 years. Limitations of this study include the small sample size, variety of lymphoma histologies and retrospective nature.
The low transplant-related mortality and the rates of overall and progression-free survival (67 and 54%) in our patient population are comparable to those reported previously. Bitran et al report a 4-year disease-free survival of 44% in 11 patients aged 65–78 years. The 100-day transplant-related mortality was 9%.9 The Mayo clinic series reported an event-free survival of 38% in 93 patients, 60–76 years old, who received SCT for NHL after conditioning with BEAC or BEAM. Transplant-related mortality was 5%.7 A lower age-adjusted International Prognostic Index (IPI) at relapse was the only predictive factor for survival.7, 27 Differences in progression-free survival may be attributable to patient selection; our patients were all transplanted in PR or CR and all had chemosensitive disease.
BU and CY was very well tolerated in our patient population. There were no deaths within 100 days of transplant and one death attributed to interstitial pneumonitis after 100 days. Side effects from CY and BU were similar to those reported in younger patients receiving full dose BU, who have been reported to have a 3.1% transplant-related mortality.28 Four patients experienced transient atrial fibrillation, which may be related to CY-conditioning.29 Patients over age 55 receiving CY-based conditioning regimens have been reported to experience a decrease in cardiac output, suggesting that high-dose CY in older patients may be associated with cardiac toxicity.30
There are little published data on the outcomes of autologous SCT for patients more than the age of 70 years. Yet, these patients represent over 30% of patients with lymphoma who would be potential candidates for transplantation. BU and CY were effective and tolerated well in selected patients more than the age of 70 years. Carefully selected older lymphoma patients with a good performance status should not be denied potentially curative stem cell transplant therapy. Further studies comparing conditioning regimens in older patients are warranted.
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Yusuf, R., Dey, B., Yeap, B. et al. Autologous SCT with a dose-reduced BU and CY regimen in older patients with non-Hodgkin's lymphoma. Bone Marrow Transplant 43, 37–42 (2009) doi:10.1038/bmt.2008.298
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