Introduction

A significant proportion of patients who develop Hodgkin's disease (HD) or aggressive non-Hodgkin's lymphoma (NHL), can be cured with conventional therapy. However, patients who have primary refractory disease or who relapse after systemic chemotherapy are only rarely cured with any form of salvage therapy [1,2]. High-dose chemoradiotherapy followed by autologous stem cell transplantation has improved the outlook for those patients and in select groups may yield a 35% -40% chance of cure [3-5]. While autologous stem cell transplantation is associated with an increased morbidity and mortality, patient selection using clinical criteria with prognostic value such as sensitivity of the tumor to salvage therapy, tumor burden at entry, and overall performance status may result in lower rates of toxicity. In addition, comparisons between trials using different prospective regimens may identify ones that are relatively less toxic. Sixty patients who underwent autologous transplantation for relapsed or refractory HD or NHL are described in this report and analyzed retrospectively to determine whether their disease status on entry could predict the outcome from transplantation. Since more than 90% of these patients received an identical regimen consisting of carmustine, etoposide, cytosine arabinoside, and cyclophosphamide as preparative chemotherapy, the efficacy and toxicity of this regimen is also retrospectively evaluated.

Patients and Methods

Between November 1988 and April 1991, 60 patients with relapsed or refractory HD or aggressive NHL underwent marrow or peripheral stem cell transplants at the University of Rochester Medical Center, Rochester, New York. Most patients were treated pretransplant with one or more courses of dexamethasone, cytosine arabinoside, and cisplatinum (OHAP) [6]. Patients included 21 women and 39 men; these underwent marrow transplant (51) or peripheral stem cell transplant (9) at a median age of 39 years (range 9-64). Thirty patients had HO and 30 had aggressive NHL. Based on pre-transplant clinical and radiological evaluation, 35 patients (18 HD, 17 NHL) were defined as having minimal disease (all disease areas <- 2 cm), and 25 patients (12 HO, 13 NHL) were defined as having bulky disease areas (at least one area >2 cm). Of the 60 patients in this series, 55 received the BEAC conditioning regimen: carmustine (300 mg/m²) on day -7; etoposide (lOO mg/m² bid) on days -6, -5, -4, -3; cytosine arabinoside (lOO mg/m² q 12 h) on days -6, -5, -4, -3, and cyclophosphamide (35 fig/kg) on days -6, -5, -4, -3. Five patients received total body irradiation (TBI). On day 0, 51 patients received unpurged autologous marrow, with a median of 1.4 times 108 NBC/kg, and 9 patients received autologous blood stem cells, with a median of 7.5 time 108 NBC/kg. Survival curves are based on the actual survival. An event is defined as death from any cause, disease relapse, or progression.

Fig. la, b. All patients: Hodgkin's disease and non-Hodgkin's lymphoma (n=60). a Event-free survival (EFS) and overall survival ( OS) .b Effect of pretransplant disease status on EFS

Results

Survival

Sixty patients underwent autologous transplant for HO and NHL. The overall event free survival for these 60 patients is shown in Figure la. The event-free survival was further analyzed according to whether the patients entered with minimal or bulky disease, and the results of this are shown in Figure lb, where it is clear that there was a very significant difference based on disease state at autotransplantation (80% vs. 20 %). Figure 2a demonstrates the overall and event-free survival for the 30 patients with HO and Figure 2b demonstrates the event-free survival according to disease status at entry. A significant difference is noted, and, furthermore, all the treatment-related deaths occurred in the bulky disease group. Similar results are shown in Figure 3 for the 30 patients transplanted for NHL.

Fig. 3a, b. Patients with Hodgkin's disease (n=30). a Event-free survival (EFS) and overall survival ( OS) .b Effect of pretransplant disease status on EFS

Characteristics of Engraftment

The median time to reach a neutrophil count of 100/µ1 for 2 consecutive days was 16 days (8-43), whereas the median time to reach 500 neutrophils/µl for 2 consecutive days was 23 days (9-51). The unsupported platelet count of 50000/µ1 was reached at a median of 22 days (range 13-825).

Table I. Severe or life-threatening nonhematological toxicity (n = 60)

Toxicity

The data on nonhematological toxicity are summarized in Table 1. I t should be noted that of the nine patients who succumbed to cardiopulmonary toxicity, eight had bulky disease on entry. Overall mortality was 10/60 (17% ) : 8/25 (32% ) in patients with bulky disease and 2/35 ( 6 % ) in those with minimal disease .

Discussion

It appears clear from the above data, that patients entering transplant with "bulky" disease are more likely to succumb to complications of therapy or suffer early relapse. In contrast, those patients with minimal disease had a very low overall mortality as well as a low early relapse rate. It is likely that a significant proportion of patients who entered the study with minimal disease will be long-term survivors. The BEAC chemotherapy regimen was very well tolerated in this patient population, but was associated with a significant risk of cardiopulmonary toxicity in those patients entering with "bulky" disease. Only 3% of patients died from sepsis (both due to fungal etiologies) , and there was no severe (ECOG grade 3 or 4) hepatic toxicity or mucositis. Additional follow-up is clearly needed as it is obvious that with time these results cannot be maintained. Nevertheless, at this stage of the trial, the results compare very favorably with other published reports and appear to confirm the benefit that autologous stem cell transplantation may confer on patients with relapsed or refractory Hodgkin's disease or non-Hodgkin's lymphoma. Nonetheless, it is clear that additional approaches are needed to improve efficacy and reduce the toxicity of autotransplantation for patients with bulky disease at the time of transplantation.

References

1. Rosenberg SA (1987) Autologous bone marrow transplant in non-Hodgkin's lymphoma. N Engl J Med 316:1541-1542
2. Hagemeister FB (1988) Management of relapsing Hodgkin's disease. In: Fuller L et al. (eds) Hodgkin's disease and non-Hodgkin's lymphoma in adults and children. Raven, New York, pp 285-302
3. Philip T, Armitage JO, Spitzer G et al. (1987) High-dose therapy and autologous bone marrow transplantation after failure of conventional chemotherapy in adults with high-grade non-Hodgkin's Iymhoma. N Engl J Med 316:1493-1498
4. Kessinger A, Nademanee A, Forman SJ, Armitage JO (1990) Autologous bone marrow transplantation for Hodgkin's lymphoma. Hematol Oncol Clin North Am 4:577-587
5. Jagannath S, Armitage JO, Dicke KA et al. (1989) Prognostic factors for response and survival after high-dose cyclophosphamide, carmustine, etoposide with autologous bone marrow transplantation for relapsed Hodgkin's disease. Blood 7: 179-185
6. Velasquez WD, Cabanillas F, Salvador Pet al. (1988) Effective salvage therapy for lymphoma with cisplatinum combination with high-dose ara-C and dexamethasone (DHAP). Blood 71:117-122