Scholarly article on topic 'High-dose myeloablative therapy and autologous peripheral blood progenitor cell transplantation for elderly patients (greater than 65 years of age) with relapsed large cell lymphoma'

High-dose myeloablative therapy and autologous peripheral blood progenitor cell transplantation for elderly patients (greater than 65 years of age) with relapsed large cell lymphoma Academic research paper on "Clinical medicine"

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Abstract of research paper on Clinical medicine, author of scientific article — Jacob D Bitran, Leonard Klein, Doreen Link, Jane Kosirog-Glowacki, Cynthia Stewart, et al.

Abstract Eleven elderly patients (older than 65 years) with relapsed large cell lymphoma were treated with high-dose myeloablative therapy and autologous peripheral blood progenitor cell support (ABMT). All 11 patients were in sensitive relapse at the time of ABMT. Treatment-related mortality was 9%. Median CD34 cell collection was 4.8 × 106 cells/kg. Median time to hematologic recovery was 11 days for granulocytes (range, 9 to 16 days) and 18 days for platelets (range, 14 to 42 days). Nine of 11 patients (81%) achieved a complete response following ABMT. Median time to treatment failure was 17 months. The 4-year disease-free and overall survival is projected to be 44%. When compared with a cohort of patients under age 65 years with sensitive relapsed large cell lymphoma treated with ABMT during the same time interval, disease-free and overall survival are comparable. ABMT is feasible, tolerable, and effective in elderly patients with relapsed large cell lymphoma with disease-free survival rates comparable to younger patients.

Academic research paper on topic "High-dose myeloablative therapy and autologous peripheral blood progenitor cell transplantation for elderly patients (greater than 65 years of age) with relapsed large cell lymphoma"

Biology of Blood and Marrow Transplantation 9:383-388 (2003) © 2003 American Society for Blood and Marrow Transplantation l083-879l/03/0906-0004$30.00/0 doi:l0.l0l6/Sl083-879l(03)00099-5

High-Dose Myeloablative Therapy and Autologous Peripheral Blood Progenitor Cell Transplantation for Elderly Patients (Greater than 65 Years of Age) with Relapsed Large Cell Lymphoma

Jacob D. Bitran, Leonard Klein, Doreen Link, Jane Kosirog-Glowacki, Cynthia Stewart, David Raack, Pat Sheahan, Josephine Lisowski, Josie Rowen

Departments of Medicine, Division of Hematology/Oncology, Section of Adult Bone Marrow Transplantation, Nursing, and Pharmacy, Lutheran General Hospital, Park Ridge, Illinois

Correspondence and reprint requests: Jacob D. Bitran, MD, Lutheran General Hospital Cancer Care Center, 1700 Luther Lane, Park Ridge, IL 60068 (e-mail: jbitran@oncmed.net).

Received January 24, 2003; accepted March 21, 2003

ABSTRACT

Eleven elderly patients (older than 65 years) with relapsed large cell lymphoma were treated with high-dose myeloablative therapy and autologous peripheral blood progenitor cell support (ABMT). All 11 patients were in sensitive relapse at the time of ABMT. Treatment-related mortality was 9%. Median CD34 cell collection was 4.8 X 106 cells/kg. Median time to hematologic recovery was 11 days for granulocytes (range, 9 to 16 days) and 18 days for platelets (range, 14 to 42 days). Nine of 11 patients (81%) achieved a complete response following ABMT. Median time to treatment failure was 17 months. The 4-year disease-free and overall survival is projected to be 44%. When compared with a cohort of patients under age 65 years with sensitive relapsed large cell lymphoma treated with ABMT during the same time interval, disease-free and overall survival are comparable. ABMT is feasible, tolerable, and effective in elderly patients with relapsed large cell lymphoma with disease-free survival rates comparable to younger patients. © 2003 American Society for Blood and Marrow Transplantation

KEY WORDS

Large cell lymphoma • Elderly • Bone marrow transplantation

High-dose myeloablative chemoradiotherapy or chemotherapy with autologous hematopoietic progenitor cell support (ABMT) is potentially curative for patients with intermediate-grade or high-grade non-Hodgkin's lymphoma who are either induction failures or who relapse after initial chemotherapy. However, most published series [1-3] have restricted this procedure to patients less than 60 years of age because of the potential poor tolerance of older patients to this procedure. More recent studies [4-10] have reported the outcome of this approach in patients over the age of 60 years with acceptable toxicities. These published studies [4-10] have reported on a total of 159 patients

INTRODUCTION

over the age of 60 years who were treated with ABMT. Of these 159 patients, 134 patients had relapsed or refractory lymphoma treated with ABMT. Among these 134 patients with lymphoma treated with ABMT, at least 16 were older than 65 years. Thus, the database in the elderly (65 years or older) is limited. The purpose of this communication is to report the outcomes of our series of consecutive patients over the age of 65 years with relapsed malignant lymphoma, diffuse large cell type (LCL), and to expand the existing database in the elderly.

PATIENTS AND METHODS

Presented in part at the American Society of Hematology Meeting, Orlando, Florida, December 7-11, 2001.

Between January 1, 1995 and June 1, 2002, we treated 11 consecutive patients 65 years of age or older with relapsed B-cell LCL with high-dose myeloabla-

Table 1. Patient Characteristics

Patient Initial Time to

No. Sex/Age Therapy Response Relapse (mo)

1 M/66 mBACOD CR 66

2 M/66 CHOP CR 15

3 F/66 CHOP CR 46

4 F/66 CHOP CR 23

5 F/65 CHOP CR 24

6 F/71 CHOP CR 15

7 M/65 CHOP CR 18

8 F/71 CHOP CR 18

9 M/78 CNOP CR 15

10 M/76 CHOP CR 18

11 M/72 CHOP CR 64

Abbreviations: mBACOD, methotrexate, bleomycin, doxorubicin, cyclophosphamide, vincristine, and dexamethasone; CHOP, cyclophosphamide, doxorubicin, vincristine, and prednisone; CR, complete response.

tive chemoradiotherapy or chemotherapy with autologous peripheral blood progenitor cell support (PBPC) at our institution (Lutheran General Hospital, Cancer Care Center, Park Ridge, IL). These 11 patients were screened and selected from a cohort of 57 patients over the age of 65 years with relapsed LCL during this time period. The 46 patients who did not undergo high-dose myeloablative chemotherapy or chemoradiotherapy were excluded for the following reasons: poor performance status (18 patients), failure to achieve a response to salvage chemotherapy (13 patients), patient refusal (8 patients), and failure to meet criteria for high-dose myeloablative therapy (7 patients). Patient characteristics at the time of highdose myeloablative therapy with PBPC support are shown in Table 1. The international prognostic index for all 11 patients at presentation and at relapse was low-intermediate. The prior chemotherapy regimens included cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) (9 patients); cyclophosphamide, mitoxantrone, vincristine, prednisone (CNOP); and methotrexate, bleomycin, doxorubicin, cyclo-phosphamide, vincristine, dexamethasone (mBACOD) (1 patient each). All 11 patients relapsed from a complete response (CR) to prior chemotherapy. All 11 patients met criteria for myeloablative therapy as previously published [11], and were in sensitive relapse before high-dose myeloablative therapy. The salvage regimens used to induce (at the very least) a partial response included: ifosfamide, carboplatin, etoposide (ICE; 5 patients) [12]; mesna, ifosfamide, mitoxantrone, etoposide (MINE; 2 patients) [13]; dexa-methasone, high-dose cytarabine, and cisplatin (DHAP; 2 patients) [14]; and etoposide, methylpred-nisolone, cytarabine, and cisplatin (ESHAP; 2 patients) [15]. The number of cycles of salvage therapy administered was 2 to 3. At the conclusion of salvage therapy before PBPC mobilization there were 2 patients in CR and 9 patients in partial response.

Informed consent for both PBPC mobilization and high-dose myeloablative therapy was obtained in all 11 patients before proceeding with PBPC mobilization. The informed consent allowed for patient data collection.

Apheresis, Peripheral Blood Progenitor Cell Mobilization and Collection

Subsequent to the documentation of either CR or partial response to salvage therapy, all patients underwent placement of a VasCath (Bard, Salt Lake City, UT) or Neostar (Horizon, Manchester, GA) catheter in the superior vena cava and underwent PBPC mobilization by using high-dose cyclophosphamide 4 g/m2 intravenously day 1 and etoposide 200 mg/m2 intravenous piggyback (IVPB) days 1, 2, and 3, with filigrastim 10 ^g/kg starting on day 4. The apheresis procedure was carried out by methods previously described [11]. The apheresis procedure commenced when the peripheral blood CD34 count was close to or exceeded 20 cells/^L. The procedure was completed when a minimum of 2 X 106 CD34+ cells/kg were collected.

Conditioning Regimens (High-Dose Myeloablative Therapy)

All patients were admitted to the inpatient unit to receive high-dose myeloablative therapy. The conditioning regimens used consisted of fractionated total body irradiation (TBI) 1.2 Gy twice daily on days —8 to —5, etoposide 60 mg/kg intravenously/or syringe pump on day —4, and cyclophosphamide 100 mg/kg IVPB on day —2 in the first 6 patients [16]. In an attempt to ameliorate the toxicities from TBI, the BEAM regimen (carmustine 300 mg/m2 intravenously on day —6, etoposide 200 mg/m2 IVPB over 2 hours (daily for 4 doses) on days —5 to —2, cytarabine 200 mg/m2 IVPB over 60 minutes every 12 hours for 8 doses on days —5 to —2, and melphalan 140 mg/m2 IVPB over 15 minutes on day — 1) was used in the last

5 patients [17].

Supportive Care

Following completion of the conditioning regimen, all patients received the collected and cyropre-served PBPC product on day 0. Prophylactic antibiotics were started on day —1 and consisted of oral valacyclovir 500g every 12 hours, oral ciprofloxacin 500 mg every 12 hours, oral cephalexin 500 mg every

6 hours, and oral fluconazole 400 mg daily. Prophylactic antibiotics were continued until hematologic recovery or until the onset of febrile neutropenia, at which point they were discontinued. At the onset of febrile neutropenia, patients were pan-cultured and intravenous broad-spectrum antibiotics were started that included cefepime ± vancomycin, (and, on occa-

Table 2. ABMT Outcomes

Patient Conditioning Day ANC Day Platelets

No. Regimen > 500 > 20,000 Response DFS (yrs) Survival (yrs)

1 Cy/TBI/VP 16 30 NE 0.15 0.15

2 Cy/TBI/VP 12 14 CR 6.0* 6.0*

3 Cy/TBI/VP 11 17 CR 5.5* 5.5*

4 Cy/TBI/VP 16 28 NR 0.5 0.5

5 Cy/TBI/VP 11 18 CR 1.25 3.0

6 Cy/TBI/VP 10 12 CR 2.0* 2.0*

7 BEAM 9 17 CR 2.3* 2.3*

8 BEAM 12 19 CR 1.0* 1.0*

9 BEAM 10 18 CR 0.5 0.5

10 BEAM 12 42 CR 0.5 0.5

11 BEAM 11 18 CR 0.5* 0.5*

Abbreviations: DFS, disease-free survival; Cy, cyclophosphamide; TBI, total body irradiation; VP, etoposide; BEAM, carmustine/ etoposide/cytarabine/melphalan; NE, not evaluable; CR, complete response; NR, no response. *Alive.

sion amphotericin B); filgrastim 5 ^g/kg subcutaneous was started on day 0 and continued until the absolute neutrophil count (ANC) exceeded 1500 cells/^L for 3 consecutive days, at which point filgrastim was discontinued. Irradiated, leukocyte-depleted packed red blood cells were transfused in patients when the hemoglobin fell to less than 8 g/dL in patients without any history of underlying heart disease. The threshold for red cell transfusion was 9 g/dL in patients with a history of heart disease. Single-donor leukocyte-depleted platelet packs were transfused when the platelet count fell to less than 10 000 cells/^L; in patients with active bleeding, single-donor platelets packs were used to maintain a platelet count of 50 000 cells/^L. Patients were placed on a low-bacteria diet and total parenteral nutrition was instituted if caloric intake fell to less than 1000 calories per day. Patients were encouraged to ambulate and exercise in their rooms using either a treadmill or exercise bicycles for at least a total of 30 minutes per day [18].

Toxicity Grading of the Conditioning Regimen

Toxicities were graded according to the National Cancer Institute-Bone Marrow Transplantation tox-icity scores.

Discharge Criteria and Follow-Up

Patients were discharged when the following criteria were met: (1) ANC >1500 cells/^L for 3 consecutive days; (2) platelets >20 000 cells/^L; (3) oral caloric intake >1000 calories per day; and (4) ability to provide self-care.

Once discharged, patients were followed in the ambulatory setting. Response to ABMT was determined at about day 100 by repeat computed tomography of the chest, abdomen, and pelvis, and more recently by computed tomography and positron emission tomography scans. Patients were seen for follow-up once every 2 months for the first year follow-

ing day 100, then once every 3 months for the next 24 months, then once every 6 months until 60 months. During those visits, a history and physical examination was conducted along with a complete blood count and comprehensive metabolic panel.

Follow-up computed tomography and positron emission tomography scans were performed routinely once every 6 months for the first 36 months and yearly thereafter unless symptoms or physical signs suggesting recurrent LCL developed, at which time restaging was carried out.

Survival, Disease-Free Survival, and Comparison to Patients <60 Years

Disease-free survival was measured from day 0 until relapse or death. Survival was measured from day 0 until death from any cause. The survival and disease-free survival of these 11 patients was compared with a cohort of patients under age 65 years treated during the same time period. These were patients with sensitive-relapse LCL treated with TBI, etoposide, and cyclophosphamide [16] or the BEAM regimen [17] in those patients who had received prior radiotherapy. This cohort consisted of 78 patients (45 men, 33 women). Of these 78 patients, 55 received TBI, etoposide, and cyclophosphamide and 23 received BEAM.

RESULTS

Median PBPC collection was 4.6 X 106 CD34+ cells/kg (range, 2.5 to 10 X 106 cells/kg). The median number of apheresis performed to yield this collection was 2 (range, 1-4). The results are shown in Table 2. Median time to hematologic recovery (ANC >500 cells/^L) was 11 days for granulocytes and 18 days for platelets (platelets > 20 000 cells/^L). There was 1 patient who died within the first 100 days; patient number 1 (Table 2) was a 65-year-old man who died from a hemophilus influenza pneumonia that precip-

Figure 1. Disease-free survival (DFS) of 11 elderly patients with relapsed LCL treated with high-dose myeloablative therapy and ABMT. Median disease-free survival is 17 months and the projected 4-year disease-free survival is 44 months.

itated adult respiratory distress syndrome and death on day +45. Thus, the treatment-related mortality was 9%. The average length of stay was 25 days (range, 21-54 days). The average in-patient hospital charge was $39,800 (range, $23,500-115,000).

Of the 11 patients treated, 10 of whom were alive on day +100, there were 9 CRs and 1 no response. The CR rate was 81%.

Treatment-related toxicities included: grade 2 mucositis (9 patients), grade 3 mucositis (2 patients, both of whom received TBI), grade 2 diarrhea (10 patients), grade 3 diarrhea (1 patient who received TBI). There were 7 episodes of febrile neutropenia. One patient who received BEAM developed grade 3 proctitis with rectal bleeding and 1 patient developed atrial fibrillation with a rapid ventricular response and hypotension. The severest toxicities (grade 3) were seen most frequently in the 6 patients receiving TBI, etoposide, and cyclophosphamide.

Currently, 6 patients are alive (as shown in Table 2). The 4 patients who died after day 100 did so from relapsed LCL. Median disease-free survival is 17

months and the projected disease-free survival at 4 years is 44% (Figure 1). Median survival is 34 months and the projected survival at 4 years is 44%.

The results of these 11 patients were compared with those of a cohort of 78 patients under age 65 years treated during the same time period and are shown in Table 3. At 3 and 4 years the results are remarkably similar.

DISCUSSION

The treatment of elderly patients with malignant lymphoma, diffuse, LCL has come under increasing attention in part because of an aging population and in part because of the absolute increase in the incidence of LCL. The use of multidrug chemotherapy, such as the CHOP regimen, in the elderly can yield long-term curative results but the toxicities can be substantial when compared with younger patients. In an attempt to improve the cure rate of CHOP alone in the elderly, a prospective, randomized study was con-

Table 3. Comparison of Disease-Free Survival, Overall Survival, and 100-day Treatment-Related Mortality for Patients with Sensitive Relapse LCL Over Age 65 Years to Those Less than 65 Years

Relapse LCL > 65 years, n = 11 Relapsed LCL < 65 years, n = 78

Year DFS OS TRM DFS OS TRM

1 67% 67% 9% 74% 81% 2.5%

2 44% 67% - 51% 72% -

3 44% 44% - 47% 62% -

4 44% 44% - 47% 53% -

Abbreviations: DFS, disease-free survival; OS, overall survival; TRM, treatment-related mortality.

Table 4. Results of ABMT for the Treatment of Relapse LCL in the Elderly Study No. > 60 yrs No. > 65 yrs Regimen Response DFS (yrs)

Stamatoullas4 13 4 BEAM 2/4 CR 0.16 & 1.2+

Moreau5 14 3 BEAM 1/3 CR 2.0+

Mazza6 19 6 BEAM/BuMel 3/6 1.33

de la Rubria8 4 Unknown BEAM/CyTBI not stated not known

Jantunen7 17 Unknown BEAM/BEAC not stated >1.3

Gopal9 45 Unknown BuMelTT not stated 1.0

CyTBI/CyTBIVP

Oliveri10 14 Unknown BEAM/BuCy 5/14 not known

Current Series 11 11 BEAM/CyTBI 9/11 CR 1.5

TOTAL 139 24 15/24 CR 1.5 yrs

Abbreviations: BuMel, busulfan and melphlan; CyTBI, cyclophosphamide and total body irradiation; BEAC, carmustine, etoposide, cytarabine, cyclophosphamide; CyTBIVP, cyclophosphamide, total body irradiation, and etoposide; BuMelTT, busulfan, melphalan, and thiotepa.

ducted that compared rituximab and CHOP with the standard CHOP regimen. The results of this study established the superiority of rituximab and CHOP over CHOP alone in patients older than 60 years of age [19]. Thus, the treatment of choice in a newly diagnosed elderly patient with LCL is rituximab and CHOP.

When elderly patients with LCL relapse, the treatment approach has typically been to use palliative measures rather than proceed with potentially curative ABMT because of the perception than elderly patients would tolerate the procedure poorly with excessive morbidity and mortality. The first published report on ABMT in the elderly was by Stamatoullas et al [4]. In this pilot study, 13 patients over the age of 60 with relapsed lymphoma were treated with the BEAM regimen and ABMT. There were no treatment-related deaths, and toxicities were relatively mild (none more severe than grade 2). The major causes of morbidity were infections. The subsequent published reports by Moreau et al. [5], Mazza et al. [6], Jantunen et al. [7], de la Rubia et al. [8], Gopal et al. [9], and Oliveri et al. [10] confirmed the pilot study of Stamatoullas et al. [4] and further demonstrated the ability of elderly patients to tolerate ABMT. A summary of the aforementioned published series and the current series are shown in Table 4. As shown in both Tables 3 and 4, the results in elderly patients very much parallel the published results in younger patients; namely, a CR rate of 60%, a median survival of 1.5 years, and (in our series) a projected 4-year disease-free survival of 44%. The toxicities we observed included mucositis, diarrhea, proctitis with rectal bleeding, and in 1 patient atrial fibrillation and hypotension. All these toxicities were manageable. The 1 treatment-related death occurred as a consequence of hemophilus influenza pneumonia and acute respiratory distress syndrome.

In summary, myeloablative therapy and ABMT is an effective mode of therapy in good performance status elderly patients with relapsed LCL and should be considered part of the therapeutic armamentarium.

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