Rescue Treatment with Mesna, Ifosfamide, Novantrone and Etoposide (MINE) for Relapsed non-Hodgkin’s Lymphoma
H. Attarian MD, J. Raafat MD
Modarres Hospital, Cancer Institute, Tehran, Iran
Background
and Objective- High-dose chemotherapy with stem
cell rescue has emerged as the treatment of choice for
patients with refractory and relapsed non-Hodgkin’s
lymphoma (NHL). To evaluate the efficacy and toxicity of
a novel chemotherapy regimen with mesna, Ifosfamide
novantrone and etoposide (MINE) in patients with relapsed
NHL previously treated with adriamycin-based regimens.
Methods-Forty-six patients with
relapsed NHL were treated in this study. The median age
was 42 years (range 13-65). Twenty-eight patients (60.8%)
had high grade, 10 (21.7%) had low grade and the rest had
intermediate grade lymphoma. The program utilized cyclic
administration of ifosfamide 1.33 gm/m2
day 1-3, mesna 1.33 gm/m2 day
1-3, etoposide 100 mg/m2 day
1-3, novantrone 12 mg/m2 day 1.
Cycles were repeated every 3 weeks for 6 cycles. Mean
while, adequate hydration was also provided.
Results-The overall response rate was
65.2% (30 patients). Complete response was achieved in
30.4% (14 patients) and a partial response in 34.8%. The
median survival period was 7 months. Grade III
neutropenia was seen in 10 patients (21.7%) and grade IV
in 1 patient who died of treatment-related toxicity.
Conclusion-MINE combination is an
effective and well tolerated treatment for patients with
relapsed NHL who have no chance for bone marrow
transplantation.
Keywords · Relapsed non-Hodgkin’s lymphoma (NHL) · aggressive chemotherapy · MINE · salvage chemotherapy
Introduction
Non-Hodgkin’s lymphoma (NHL) includes a diverse group of malignancies with many different modes of presentation and treatment options. It is generally agreed that patients with refractory and relapsed NHL after first-line therapy (CHOP) have a poor prognosis.1,2
High-dose chemotherapy with stem cell rescue has emerged as the treatment of choice for patients with refractory and relapsed NHL. However, the optimal timing of transplantation remains an issue of controversy.3
Although combination chemotherapy has improved the prognosis of patients with NHL, durable remissions after a salvage regimen for relapsed NHL are rarely observed. Conventional salvage regimens such as dexamethasone, cytarabin and cisplatin (DHAP) etopside, prednisolone, cytarabin, cisplatin (ESAP) confer complete remission (CR) ranging from 10% to 37%, but the 2-year survival rates are only about 25%.5,7
Regarding the lack of sufficient transplantation centers in Iran, the only option for relapsed NHL is aggressive chemotherapy. Therefore, we conducted a prospective trial to determine the role of salvage chemotherapy in Iranian patients with relapsed NHL.
Patients and Methods
Between August 1995 and February 1998, in three oncology centers in Iran, a total of 46 patients with relapsed NHL who had been previously treated with doxorubicin-containing regimens (CHOP) were enrolled into this trial. The diagnosis and histologic subtype of NHL was based on biopsy results at the onset of disease and patients were classified according to the working formulation.
An accurate clinical re-staging for confirming the relapse included physical examination; routine blood analysis; lactate dehyrogenase (LDH) level; renal and hepatic function tests; chest X-ray; chest, abdomen and pelvic CT scanning; ultrasound of liver and spleen; and bone marrow biopsy if indicated.
At the end of the designated program, the patients were checked again to evaluate the response. The treatment scheme consisted of ifosfamide 1.33 gm/m2 day 1-3, mesna 1.33 gm/m2 day 1-3, etopside 100 mg/m2 day 1-3, and novantrone 12 mg/m2 day 1. Therapy was repeated every 3 to 4 weeks in accordance with the extent of neutropenia and continued for six courses on patients responding to treatment. All patients were admitted to hospital for 3 days during each cycle of MINE chemotherapy. Adequate hydration was provided,and empirical broad-spectrum antibiotics were started if clinically indicated.
Results
A total of 46 patients were enrolled in this study, 28 men and 18 women, with a median age of 42 years (range 13-65). Twenty eight patients had high grade, 8 had intermediate grade, and 10 had low grade NHL. Only 27 of the 46 patients completed the planned 6 cycles of MINE chemotherapy. The rate of response to treatment was evaluated when 4 cycles of MINE regimen were given. Of the 46 patients, 14 (30.4%) had complete remission and 16 patients (34.8%) achieved a partial response, providing an overall response rate of 65.2%. Another 16 patients (34.8%) were primary-resistant.
A single fatal toxic event occurred on a patient who developed severe respiratory infection and septic shock after chemotherapy.
The median survival period was 7 months after completing the courses of chemotherapy. Five out of the 14 patients who achieved complete remission were disease-free after 13 months of treatment. Myelosuppression was the major side effect of treatment, resulting in 11 neutropenic febrile episodes from a total of 168 courses. Grade III neutropenia was seen in 10 patients (21.7%) and grade IV was seen only in one patient.
Discussion
Patients who do not attain complete remission with initial therapy or relapse in a later time, need additional therapy for their NHL. The prognosis is poor for patients with NHL who have a relapse after a CR, regardless of whether any further treatment is given. The most important prognostic factor is the duration of remission. Second complete remission occurs however, after further treatment with combination chemotherapy and 10% of patients survive for a long period.
Cures with high-dose chemotherapy and autologous bone marrow transplantation were first reported by Applebaum et al.3 However, if patients are candidates for high-dose chemotherapy and transplantation, they should be offered such therapy as it becomes the golden standard as compared to conventional salvage therapy. In the Parma trial3, patients with relapsed chemotherapy-sensitive aggressive NHL were randomized to receive either additional salvage chemotherapy or high-dose chemotherapy and autologous bone marrow transplantation. In this trial results showed that 46% of patients in the transplant arm were alive and disease-free 5 years after therapy as compared to only 12% in the salvage chemotherapy arm.3 For patients who are not transplant candidates (almost all relapsed NHL in Iran), there are many different salvage chemotherapy regimens reported to have some limited results. Some of the most popular regimens are CDE: cyclophosphamide, doxorubicin, etoposide; ESHAP: etoposide, cytarabine, cisplatin, prednisone, (± bleomycin). These regimens have shown a CR rates of 20% to 40%. However, the long-term failure-free survival rates are only 5% to 15% in most published series.4,5,6,7
The rates of mortality from toxic effects and morbidity were higher in the transplantation group than in the conventional treatment group. Since we did not select patients who were optimally suited for salvage chemotherapy, our results were disappointing. Furthermore, 5 out of 14 patients who achieved CR were still alive at the time of reporting these results (18 months from start of treatment).1,3
Overall, MINE regimen was well-tolerated and proved to be an effective palliative therapy for patients with NHL after relapse, particularly for the patients who do not have a chance to be transplanted.
MINE regimen may also be considered for
initial therapy in selected patients who cannot tolerate doxorubicin-containing regimens.
References