CASE REPORTS
Aggressive Non-Hodgkin's Lymphoma - therapeutic considerations of pre rituximab era
Carmino Antônio de Souza
Lymphomas have been known as one of the most responsive malignancies to chemotherapy. They are frequently subdivided on Hodgkin's Disease (HD) and Non-Hodgkin's Lymphoma (NHL). Lymphomas are heterogeneous clonal malignancies that have been classified in different ways. For the REAL classification, each disease is defined as a different entity based on the morphology integration, immunephenotypic and genetics aspects, clinical behavior and the original cell. Most patients with localized disease, stage I and II (Ann Arbor Classification), cure with conventional doses of chemotherapy (CTX) or CTX + radiotherapy (RTX) - 75% of 5 years disease-free-survival (DFS). Those with advanced disease (stage III and IV) have less favorable results, the complete remission rate (RR) is nearly 50%, but only 2/3 of the patients will be free of disease. The long term DFS for these patients is around 40 to 50% with polichemotherapy. Regimens with antracyclines, specifically CHOP (cyclophosphamide (CY), doxorubicin, vincristine, e prednisone), have been the main approach for aggressive lymphomas since 1970. 70 to 80% of the patients will respond to CHOP. The long term cure rate with CHOP is around 35% and there are no evidences that second and third generation regimens are more efficient. FISHER, in 1993 did not find difference in the survival and response rates comparing CHOP, m-BACOD, Promace-Cytabom and MACOP-B, although the CHOP protocol was cheapest and less toxic. GORDON, SERTOLI e COOPER also did not show that regimens like m-BACOD, MACOP-B, e ProMACE-MOPP, have better results than CHOP on the treatment of intermediate and high grade lymphomas. It is generally accepted that patients with intermediate and high grade lymphomas that relapse after initial therapy have a reserved prognostic and the additional chemotherapy rarely induces a second long term remission. Relapses of lymphoma will occur in 40% of the cases, after induction therapy; refractory disease is seen in 10 to 20% of the patients. Rescue therapy with CTX including cytostatic agents, normally not used as first line therapy was introduced as an attempt to rescue these patients. Salvage therapy with chemotherapy regimens like DHAP (dexamethasone, cytarabine, cisplatin); ESHAP (etoposide phosphate, methylprednisolone, cytarabine, cisplatine); IMVP-16 (mesna, ifosfamida, metrotrexate, etoposide phosphate) gives complete remission rates ranging from 10 to 37%, but 2-years survival of 25%. A review of approximately 700 young patients with advanced diffuse large cells lymphoma, treated with rescue chemotherapy in 29 different trials, showed a 2-years DFS lower than 5%. In 1987, PHILIP said that the experience acquired with Burkitt Lymphoma showed that these lymphomas still could be responsive to CTX with intensified doses. The combination of large dose CTX and rescue with bone marrow autologous transplant was considered promissory. This multi-institutional study included 100 patients with primarily refractory lymphomas, with sensitive or resistant relapse. The DFS was 0% at the primarily refractory group, 14% at the resistant relapsed group, and 36% at the sensitive relapsed group.
The Role of the Autologous Transplant
The objective of the high dose therapy with support of bone marrow autologous transplantation or peripheral progenitor cells is to overcome the resistant tumor cell, through cytotoxic drugs in mieloablative dosage. Several clinical studies with relapsed or refractory aggressive lymphomas have been done using high dose CTX and rescue with bone marrow autologous transplant or peripheral blood progenitor cells (PBPC). These studies demonstrate benefits with patients with chemo sensitive disease. Most studies used BEAM protocol as induction and PBPC infusion as rescue. The global survival rates, for 2 to 5 years, ranged from 60% to 30%. 2-years and 5-years DFS ranged from 51% to 27% and the event-free- survival ranged from 48% to 26%. These studies presented mortality rates associated with the procedure, ranging from 2.5% to 15% and this still shows high relapse rates after transplantation (35% to 57%). Some controlled, prospective and randomized studies compared the ASCT results and conventional CTX as rescue therapeutic at "slow" responders, with no significant differences in terms of survival rates. In 1995, PHILIP proved the superiority of the ASCT strategy as compared with DHAP protocol, for chemo sensitive patients, as a rescue therapy. The authors demonstrated survival rates of 53% for ASCT and 32% for DHAP rescue (p=0.038).
Prognostic Factors
Many prognostic factors has been identified, and associated to the treatment used for lymphomas. In 1993, the International Non-Hodgkin's Lymphoma Prognostic Factors Project proposed a system of international prognostic index (IPI). It was studied the clinical characteristics of 3,273 patients with large cells, immunoblastic and mixed diffuse lymphoma, treated with doxorubicin regimens. The risk factors considered independent and adjusted by the age were: lactic dehidrogenase (LDH), "Performance Status" (according WHO) and stages III and IV (Ann Arbor) (SHIPP et al, 1993). This classification system is extremely helpful for a better therapeutic indication, following the disease risk. The IPI divides patients at diagnosis in four risk groups: low, intermediate-low, high-intermediate, and high, with global survival rates projected, in 5 years, from 73%, 51%, 43% e 26%, respectively, independent of age. For patients with less than 60 years, survival rates of 83%, 69%, 46%, e 32%, respectively. For patients with more than 60, the global survival rates were 56%, 44%, 37%, and 21%. The increased experience with the autologous transplant for the Non-Hodgkin's lymphomas treatment has identified prognostic factors for this therapeutic modality result. These factors are useful in determining the transplant situation, as so the selection of the patients that will benefit most with the procedure. The sensitivity to treatment before the transplant is the most important factor associated with the transplant results, for relapsed or refractory aggressive lymphomas patients. In 1987, PHILIP demonstrated the importance of autologous transplant as salvage treatment of aggressive Non-Hodgkin's lymphomas. Patients with sensitive relapsed tumors have significantly higher survival rates than those with resistant (3-years DFS 36% vs. 14%; p<0.003). The complete remission with initial CTX was the most important factor for the result after the transplant (3-years DFS, 30% vs. 0%; p<0.001). Another important prognostic factor is associated with the previous treatment extension. In 1993, VOSE demonstrated that patients receiving more than three CTX schemas before the transplant have worst results, in terms of global response and survival rates. Other adverse prognostic factors include high LDH levels, number of extra-nodal disease and presence of bulky tumor masses.
Publication Dates
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Publication in this collection
06 Jan 2006 -
Date of issue
Oct 2005
