Results of CAV regimen (CCNU, Melphalan, and VP-16) as third-line salvage therapy for Hodgkin's disease

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1 Annals of Oncology : 47-4, 994. O 994 Kluwer Academic Publishers. Primed in the Netherlands. Original article Results of CAV regimen (CCNU, Melphalan, and VP-6) as third-line salvage therapy for Hodgkin's disease E. Brusamolino, E. Orlandi, A. Canevari, E. Morra, G. Castelli, E. P. Alessandrino, G. Pagnucco, P. Bernasconi, C. Astori, M. Lazzarino & C. Bernasconi Cattedra di Ematologia, Universitd di Pavia, Divisione di Ematologia, Policlinico San Matteo IRCCS, Pavia, Italy Summary Background: A prospective study was conducted to assess the efficacy and toxicity of a salvage regimen consisting of CCNU, Melphalan, and VP-6 (CAV) given at 8-day intervals in patients with Hodgkin's disease (HD) relapsing after primary therapy or refractory to the alternating MOPP/ ABVD regimen. Patients and methods: This study included 8 patients (median age: 4 years), with resistant or relapsing HD. Primary therapy had consisted of alternating MOPP/ABVD (8) or MOPP alone (9); 8 of patients were relapsing from prior complete remission (CR) while 6 had resistant disease. Extranodal disease was present in and B-symptoms in 7 of patients; one-fifth had bulky disease and/or bone marrow involvement. The CAV was used as first salvage in half of the patients. Results: Complete remission was obtained in patients (9); unfavorable factors for CR in univariate analysis were the presence of bulky disease and the failure to achieve CR with prior therapy. Nine patients ( of remitters) have Introduction Prospective studies in Hodgkin's disease (HD) have indicated that to 0 of patients with advanced disease do not obtain complete remission from their initial chemotherapy (CT) and that 0 to 0 of complete remitters relapse in the first three years after treatment [-4]. In patients resistant to MOPP utilized as first-line chemotherapy, several second-line non-cross-resistant regimens are available, with a cure rate of about [-7]. In patients resistant to alternating MOPP and ABVD (or congeners), third-line protocols have been devised, (mostly including nitrosourea and podophyllotoxin derivatives); however, their efficacy is much less satisfactory, with a CR rate ranging from to 0 of total [8-]; the best results obtained so far with third-line conventional CT in this setting consist of about 0 prolonged complete remissions [9]; altogether, the clinical experience is limited and the curative potential is highly questionable [,4]. subsequently relapsed with a -month median duration of CR. The -year overall survival after CAV was with an 8-month median survival; significant differences in survival were found according to the extent of disease, the presence of B-symptoms and the HD status (prior sensitive or resistant disease, first or subsequent relapse). Seven patients are longterm remitters (), and one of them has been given highdose chemotherapy and autologous bone marrow transplantation at relapse after CAV. The CAV toxicity was mostly hematological; severe pancytopenia occurred in six cases with two cases of fatal infections and one of fatal hemorrhage. Conclusion: CAV therapy was moderately effective as third-line salvage in patients with HD resistant to alternating MOPP/ABVD or previously given two different regimens for relapse; the toxicity was mostly hematological and supportive therapy was needed in one-third of the patients. Key words: CAV chemotherapy, resistant Hodgkin's disease, salvage therapy As far as relapses are concerned, the likelihood of effecting a durable second-line remission has been correlated with the duration of the first CR; reinduction with MOPP was used to salvage patients after first relapse and a significantly higher rate of second remission was obtained in those whose first remission had lasted more than months []. Further experience suggested that any regimen given in this setting of laterelapse patients has a higher probability of response, of durable second remission and survival than in the patients whose initial remission has been shorter than one year [6,]. Myeloablative high-dose chemotherapy with autologous bone marrow (ABMT) and/or peripheral stem cell transplantation is being used as potentially curative therapy in relapsing and resistant Hodgkin's disease; only about of patients undergoing this aggressive approach have any potential for long-term disease control or cure [8]. Data from various studies have indicated that factors such as drug sensitivity at relapse, disease burden, performance status and number of

2 48 prior regimens have significant effect on the long-term benefit [9-]. In this paper, we present the results obtained with a third-line combination CT including CCNU, Melphalan, and VP-6 (CAV) in patients with Hodgkin's disease relapsing after primary therapy or refractory to the alternating MOPP/ABVD regimen. This analysis would define the boundary of conventional salvage CT in patients who have already received at least two prior regimens (alternating or in sequence) and would provide a control to which high-dose therapy regimens could be compared. Patients and methods Patient characteristics Between 98 and 989, 8 patients with resistant or relapsing Hodgkin's disease entered this study; the main patient characteristics are listed in Table. The median age at the initiation of CAV chemotherapy was 4 years; male sex and nodular sclerosis histology were predominant, accounting for 7 and of all cases, respectively. Extranodal disease was present in and B symptoms in 7 of patients; one-fifth of the entire group had bulky disease and/or bone marrow involvement; bulky disease was defined as evidence either of nodes >7 cm diameter or of a mediastinum/thorax ratio >0.. Table illustrates the type of therapy at diagnosis of HD, and the disease status at the initiation of CAV chemotherapy. All patients had been treated with MOPP and ABVD regimens before CAV; 47 (8) patients had received alternating MOPP/ABVD as primary therapy and had received ABVD or MOPP/ABVD as first salvage after MOPP alone as induction therapy. As far as disease status is concerned, 6 of patients were treated with CAV for their first relapse and for a subsequent relapse; 6 of patients had failed to achieve complete remission (resistant disease) after primary therapy. The median duration of the disease before CAV was 9 months (range: 4-8). The CAV regimen was utilized as first salvage regimen in 0 patients (); in the remaining patients, CAV was administered for multi- Table. Patient characteristics at the initiation of CAV. Characteristics TotaJ Sex Males Females Median age (years) Range Histology Lymphocyte prevalence Nodular sclerosis Mixed cellularity Lymphocyte depletion Unclassified B symptoms Sites of disease Nodal only Extranodal only Both Extent of disease Bulky > extranodal sites Bone marrow involvement No. of patients Table. Primary therapy and disease status at the initiation of CAV. Primary therapy MOPP MOPP/ABVD Disease status First relapse Multiple relapses Failure to achieve CR Median duration of disease before CAV (months) Range No. of patients ABVD adriamycin, bleomycin, vinblastine, dacarbazine; CEP - CCNU, etoposide, prednimustine; MOPP mechloretamine, vincristine, procarbazine, prednisone. pie relapses as subsequent salvage after MOPP (6 cases), ABVD (6 cases), MOPP/ABVD (4 cases) and ABVD/CEP ( cases). As of August 9, the median follow-up of survivors after CAV is months with a range from 6 to 6. The CAV regimen The CAV regimen consisted of CCNU 80 mg/m orally on day, melphalan (Alkeran*) mg/m orally on days through and VP- 6 (Vepesid*) 60 mg/m intravenously every hours on days through. The cycles were repeated at 8-day intervals; the drug doses were reduced by 0 for PMN < 9 /L and /or platelet count <7 x lo'/l; CCNU was permanently reduced for severe anemia (Hb < 8 g/dl). Treatment with CAV was continued for 6-8 cycles or until disease progression. Assessment of response and toxlcity The anatomic extent of the disease before CAV therapy was evaluated according to conventional staging procedures including chest X-rays, chest and abdomen computerized axial tomography scan, hematological and chemical profiles and bone marrow biopsies. Repeated measurements of tumor were carried out after the first three cycles of therapy and at the end of the program; CR was defined as the disappearance of all symptoms and measurable lesions and partial response as a reduction of 0 or more in the longest perpendicular diameter of all sites of measurable disease. Toxicity was evaluated according to the WHO criteria []. Statistics Overall and relapse-free survival and freedom from progression were calculated with the product-limit method. Univariate analysis for the influence of clinical factors on CR rate was performed with the Fisher's exact test, and the differences between survival actuarial curves were analyzed with the log-rank test. The following independent variables were included into the analysis: age, systemic symptoms, extranodal involvement, bulky disease, bone marrow status at the initiation of CAV, the response after primary therapy, and the duration of the first remission. Results Efficacy Complete remission was obtained in patients (9) and partial response in (9), with an overall

3 response rate of 48 of total; the median number of cycles necessary to achieve CR was four; the actual percentage of the optimal dose administered (relative dose-intensity) was 70 for CCNU, 7 for VP-6 and 8 for melphalan. The efficacy of CAV according to pretreatment variables is illustrated in Table. In univariate analysis, factors adversely affecting the CR rate were the presence of bulky disease (p ) and the failure to achieve CR with prior therapy (resistant disease; p = 0.04). The -year overall survival for the entire group after the initiation of CAV therapy was and the median survival was 8 months (Fig. A). Log-rank analysis revealed significant differences in the overall survival between patients with nodal or extranodal involvement (p - 0.0), bulky or non-bulky disease (p ), with or without B symptoms (p ) and between those who had achieved CR after primary therapy (sensitive disease) and those who had not (resistant disease; p = 0.04). The -year relapse-free survival and freedom from progression (Fig. IB) after CAV were 40 and 0, respectively. Among complete remitters, nine have subsequently relapsed, with a median CR duration of months, and two have died of acute nonlymphocytic leukemia, with no evidence of disease. Four relapsing patients were eventually treated with high-dose chemotherapy followed by autologous bone marrow transplantation; one of them is in continuous complete remission after months and two are alive with stable disease (data now shown). So far, seven patients ( of the entire group) have no evidence of disease after a median 6 months from remission (two for more than two years: and 90 months, respectively); six patients were salvaged by CAV alone and one by additional ABMT. Toxicity and causes of death The toxicity of CAV chemotherapy is illustrated in Table 4. Hematological toxicity was dose-limiting; 9 and of patients had grade -4 leukopenia and/or Table. Results of CAV chemotherapy according to pretreatment variables. Features Total Nodal disease Extranodal disease Non-bulky disease Bulky disease No symptoms B-symptoms CR after primary therapy Resistant disease OS - overall survival. No. of CR Fisher test p-value ns ns yr OS Log-rank p-value Proportion months Total 6 AJrve fig.. A) Actuarial survival of the entire group from the initiation of CAV therapy. B) Actuarial freedom from progression of patients responding to CAV therapy. Table 4. Toxicity of CAV chemotherapy. Type of toxicity (WHO grading) Leukopenia 4 Thrombocytopenia 4 Anemia (grade ) with negative BM Severe hemorrhage Gastrointestinal Infectious episodes Life-threatening infections No. of patients BM - bone marrow; WHO World Health Organization thrombocytopenia, respectively; severe neutropenia required the use of the hematopoietic factor G-CSF in seven patients for a median duration of 6 days. Admission into hospital was required in patients for infectious episodes and in 8 for platelet transfusions; grade anemia with negative bone marrow occurred in 8

4 40 patients ( of total); these patients required periodical packed red cell transfusions (median: units/ month). Severe and prolonged pancytopenia was documented in six cases, with five episodes of life-threatening infections (two were fatal) and one lethal gastrointestinal hemorrhage. To date, 4 of 8 patients (74) have died; of those, 6 (84) had disease progression with organ failure, three (7) developed acute non-lymphocytic leukemia (two were in complete remission) two had fatal infections (sepsis from Pseudomonas aeruginosa and Aspergillus fumigatus, respectively), and two died of hemorrhage and of unrelated complications, respectively. Among the patients who developed acute non-lymphocytic leukemia, two had been given CAV as first salvage therapy after alternating MOPP/ABVD and one had been given different regimens including alkylating agents and nitrosourea derivatives; the time intervals from the diagnosis of HD to acute leukemia were 0, and 60 months, respectively. Discussion The CAV (CCNU, Melphalan, VP-6) combination chemotherapy, developed at our institution in 98, has been used as salvage therapy in 8 patients with resistant or relapsing Hodgkin's disease. The majority of cases (6) had failed to achieve complete remission after alternating MOPP/ABVD or MOPP alone, and had relapsed more than once before the initiation of CAV therapy; only a small minority of patients (6) were administered CAV therapy at their first relapse. The overall complete remission rate after CAV was 9; the -year overall survival and freedom from progression were and 0, respectively, and long-term remitters represent of the entire group. A significantly unfavorable influence on CR and survival rate was observed for extranodal and/or bulky disease, for B symptoms and for refractoriness to prior chemotherapy. The results of this study are similar to those obtained by others with third-line chemotherapy programs, mostly containing VP-6 and CCNU [8, 4-6]. In particular, they compare well with the results of CAVP regimen incorporating the same drugs as CAV plus prednisone [] and of MIME therapy [] which produced a CR rate, with a median survival for all patients of 0 weeks. The acute toxicity of CAV therapy was not negligible, in particular with respect to the hematological effects; CCNU was reduced on several occasions for drug-induced anemia and prolonged pancytopenia, and supportive therapy with red cell transfusions and/or hematopoietic growth factors was to be given. Infectious episodes (mild to severe) occurred in 4 of cases and were life-threatening in 9 (infections were the cause of death in two instances). A leukemogenic risk after lomustine therapy in Hodgkin's disease has been observed [7, 8]; of concern, was the fact that three patients in our series died of acute myeloid leukemia, two of whom were in complete remission after CAV chemotherapy. The efficacy of salvage regimens in HD is contingent on several factors [9] including the performance status, B symptoms, the time elapsed since primary treatment (more or less than months) and the sensitivity to prior therapy. This has been demonstrated by the ABVD [] and MTME [] studies and confirmed by our previous experience with CAV therapy []. In this study, a prognostically unfavorable circumstance was represented by the fact that a large majority of patients had been resistant to prior chemotherapy (namely, the alternating MOPP/ABVD regimen); indeed, the refractoriness to prior therapy adversely affected the achievement of complete remission and the overall survival. Additional factors that have a negative impact on results of salvage therapy in HD are the presence of extranodal or bulky disease [, 6, ] and the occurrence of multiple prior relapses []; in this study, of patients had multiple relapses before CAV and had extranodal disease ( had bone marrow involvement); the bulkiness of disease was the single most negative determinant of response and survival after CAV. Acute toxicity and treatment-related leukemia further lowered the probability of cure after CAV; likewise, in the NCI experience [], the low probability of cure after conventional-dose salvage combination chemotherapy in patients relapsing with Hodgkin's disease, was heavily influenced by the development of secondary acute leukemias. To improve on the results of conventional salvage CT, high-dose chemotherapy with autologous bone marrow or peripheral stem-cell transplantation has been extensively studied in the clinical setting of relapsed or refractory HD [9-]. A variety of highdose programs have been used including CBV [9,, ], BEAM [0, 6], total body irradiation (TBI) + high-dose cyclophosphamide [], TBI + high-dose cyclophosphamide and busulphan [] and total lymphoid irradiation + high-dose cyclophosphamide and VP-6 [0]. Complete remission rates higher than 0 have been obtained in the different series, with continuous disease-free survivals ranging from [] to [0], and toxic death rates ranging from 7 [] to 4 [] of patients. Such wide variability in the results of high-dose salvage chemotherapy in Hodgkin's disease is dependent on patient selection factors more than on the intrinsic efficacy of the different regimens; the comparison between the different studies is puzzling because of the interplay of several different factors including the timing of high-dose CT, the type and duration of previous chemotherapy and the patient performance status. The overall results of ABMT in relapsing or resistant Hodgkin's disease have recently been reviewed [4, 40] and decision analysis models have been created to determine the optimal

5 salvage strategy and the most cost-effective approach [4]. Dose-intensive chemotherapy approaches have also been used without autologous bone marrow transplantation; in a study of young patients with refractory HD, results comparable to those of ABMT, with less toxicity, have been obtained after high-dose chemotherapy alone [4]. Disappointingly, the higher dose-intensity, does not always translate into an improvement of overall response and of clinical outcome; a recent association of high-dose cytarabine and mitoxantrone yielded a low CR rate, with high hematopoietic toxicity and infection risk [4]; the use of hematopoietic growth factors (GM-CSF and G-CSF) as adjunct to shorten the neutropenia after high-dose chemotherapy and to lower the drug-related toxicity is being evaluated [44, 4]. In conclusion, the CAV therapy proved moderately effective as a third-line salvage regimen in heavily pretreated patients with Hodgkin's disease, mostly resistant to alternating MOPP/ABVD or previously given two different CT regimens for prior relapse; the hematologjcal toxicity required supportive therapy in about one-third of the patients. The analysis of third-line salvage therapies such as CAV in Hodgkin's disease may provide a standard to which new high-dose programs, with or without autologous bone marrow reconstitution, can be compared. A reliable conclusion about the role of conventional-dose CT versus high-dose CT as salvage therapy in Hodgkin's disease can only be provided by a randomized study, with patient stratification for the main prognostic factors. References. Longo DL, Young RC, Wesley M et al. Twenty years of MOPP therapy for Hodgkin's disease. J Clin Oncol 986; 4: Bonadonna G, Santoro A, Gianni M et al. 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