Meta-analysis to evaluate the role of interferon in follicular lymphoma.

PURPOSE: To determine whether interferon (IFN) -alpha2, when given with or following chemotherapy, influences response rate, remission duration, and survival in newly diagnosed patients with follicular lymphoma. PATIENTS AND METHODS: Ten phase III studies evaluating the role of IFN-alpha2 in 1,922 newly diagnosed patients with follicular lymphoma were analyzed. Updated individual patient data were used to perform meta-analyses for response, survival, and remission duration. RESULTS: The addition of IFN-alpha2 to initial chemotherapy did not significantly influence response rate. An overall meta-analysis for survival showed a significant difference in favor of IFN-alpha2, but also showed significant heterogeneity between studies. Further analyses were carried out in order to explain this heterogeneity, and to define the circumstances in which IFN-alpha2 prolonged survival. The survival advantage was seen when IFN-alpha2 was given: (1) in conjunction with relatively intensive initial chemotherapy (2P = .00005), (2) at a dose >/= 5 million units (2P = .000002), (3) at a cumulative dose >/= 36 million units per month (2P = .000008), and (4) with chemotherapy rather than as maintenance therapy (P = .004). With regard to remission duration, there was also a significant difference in favor of IFN-alpha2, irrespective of the intensity of chemotherapy used, IFN dose, or whether IFN was given as a maintenance strategy or with chemotherapy. CONCLUSION: When given in the context of relatively intensive initial chemotherapy, and at a dose >/= 5 million units (>/= 36 x 10(6) units per month), IFN-alpha2 prolongs survival and remission duration in patients with follicular lymphoma.

MACOP-B versus ProMACE-MOPP in the treatment of advanced diffuse non-Hodgkin's lymphoma: results of a prospective randomized trial by the non-Hodgkin's Lymphoma Cooperative Study Group.

PURPOSE: The aim of our study was to compare in a multicentric randomized trial two regimens widely used in the treatment of advanced-stage intermediate- to high-grade non-Hodgkin's lymphoma and to assess whether a third-generation regimen (methotrexate with leucovorin, doxorubicin, cyclophosphamide, vincristine, prednisone, and bleomycin [MACOP-B]) was superior to a second-generation regimen (procarbazine, methotrexate with leucovorin, doxorubicin, cyclophosphamide, and etoposide [ProMACE-MOPP]). PATIENTS AND METHODS: Between January 1987 and August 1991, 221 patients with diffuse intermediate- to high-grade non-Hodgkin's lymphoma (Working Formulation groups F, G, H, and K), stage II bulky (> 10 cm), III, or IV, were randomized by the Non-Hodgkin's Lymphoma Cooperative Study Group (NHLCSG) to receive ProMACE-MOPP for six cycles or MACOP-B for 12 weeks. Survival, progression-free survival, and disease-free survival were determined, and multivariate analysis of prognostic factors was performed. RESULTS: In the two groups of patients, there was no significant difference in terms of complete remission (CR) rate (49.1% with ProMACE-MOPP and 52.3% with MACOP-B), 3-year overall survival rate (45.2% with PROMACE-MOPP and 52.3% with MACOP-B), and 3-year progression-free survival rate (36.4% with ProMACE-MOPP and 36.1% with MACOP-B). In terms of toxicity, no significantly greater toxicity occurred in either arm. Overall toxicity was acceptable. The most frequent side effects were grade II through IV leukopenia, infection, mucositis, and anemia. Treatment-related deaths were equally distributed. CONCLUSION: No significant differences in terms of efficacy and/or toxicity between ProMACE-MOPP and MACOP-B are evident. These results are consistent with recent randomized trials showing that the new-generation aggressive regimens are no better than previous ones.

VACOP-B versus VACOP-B plus autologous bone marrow transplantation for advanced diffuse non-Hodgkin's lymphoma: results of a prospective randomized trial by the non-Hodgkin's Lymphoma Cooperative Study Group.

PURPOSE: The aim of this multicenter randomized study was to compare conventional therapy with conventional plus high-dose therapy (HDT) and autologous bone marrow transplantation (ABMT) as front-line treatment for poor-prognosis non-Hodgkin's lymphoma (NHL). PATIENTS AND METHODS: Between October 1991 and June 1995, 124 patients, aged 15 to 60 years, with diffuse intermediate- to high-grade NHL (Working Formulation criteria), stages II bulky (> or = 10 cm), III, or IV were enrolled. Sixty-one patients were randomized to receive etoposide, doxorubicin, cyclophosphamide, vincristine, prednisone, and bleomycin (VACOP-B) for 12 weeks and cisplatin, cytarabine, and dexamethasone (DHAP) as a salvage regimen (arm A), and 63 to receive VACOP-B for 12 weeks plus HDT and ABMT (Arm B). RESULTS: There was no significant difference in terms of complete remissions (CRS) in the two groups: 75% in arm A, and 73% in arm B. The median follow-up observation time was 42 months. The 6-year survival probability was 65% in both arms. There was no difference in disease-free survival (DFS) or progression-free survival (PFS) between the two groups. DFS was 60% and 80% (P = .1) and PFS was 48% and 60% (P = .4) for arms A and B, respectively. Procedure feasibility was the major problem. In arm B, 29% of enrolled patients did not undergo HDT and ABMT. A statistical improvement in terms of DFS (P = .008) and a favorable trend in terms of PFS (P = .08) for intermediate-/high- plus high-risk group patients assigned to HDT and ABMT was observed. CONCLUSION: In this study, conventional chemotherapy followed by HDT and ABMT as front-line therapy seems no more successful than conventional treatment in terms of overall results. However, our results suggest that controlled studies of HDT plus ABMT should be proposed for higher risk patients.

Different mechanisms of activation of proliferating CD3+ cells in patients with lymphoproliferative disease of granular lymphocytes.

To investigate the role of p55 and p75 chains of interleukin-2 receptor (IL-2R) on the activation of granular lymphocytes (GL) in patients with lymphoproliferative disease of granular lymphocytes (LDGL), the cells obtained from 11 LDGL patients (belonging to the CD3+ group) were studied for (a) the surface expression and (b) mRNA transcripts of the p55 and p75 IL-2R after activation with anti-CD3 monoclonal antibody (mAb) or interleukin-2 (IL-2). The effects of mAbs specifically blocking the p55 and p75 IL-2R on the generation of proliferative and cytotoxic functions were studied following anti-CD3 mAb stimulation. A significant difference was observed in the expression of p55 and p75 antigens on LDGL cells under resting conditions: a low number of p55 IL-2R+ (mean 1.2 +/- 0.4%) and high values of p75 IL-2R+ cells (54.9 +/- 7.4%). Accordingly, a barely detectable message for the p55 IL-2R and a strong signal for the p75 IL-2R mRNA were demonstrated. Following activation with anti-CD3 or IL-2, different patterns of IL-2R expression were observed. Anti-CD3 mAb induced an increase in the expression of the p55 IL-2R both at the mRNA and antigen level, whereas the p75 values remained consistently raised. In contrast, IL-2 induced the expression of p55 IL-2R mRNA associated with only a slight expression of this antigen. This finding was associated with a decrease in the cell expression of the p75 IL-2R, whereas the amount of p75 mRNA was unchanged. Both anti-CD3 mAb and IL-2 induced cell proliferation and cytotoxicity against the K-562 target cells. Anti-p55 IL-2R mAb did not affect the cytotoxic activity mediated by anti-CD3, but it markedly inhibited cell proliferation. Anti-p75 mAb did not inhibit either lytic function or cell proliferation mediated by anti-CD3 mAb, suggesting that only the high affinity IL-2R (p55 plus p75) is involved in anti-CD3 mediated cell activation in LDGL patients. This mechanism is different from that responsible for the IL-2 activation of CD3+ GL in LDGL patients, which is achieved through the p75 IL-2R alone. These results provide new insights into the pathophysiology of proliferating GL in LDGL patients and may also contribute to further characterization of the normal CD3+ GL population.

Autologous bone marrow transplantation for adult advanced stage lymphoblastic lymphoma in first CR. A study of the NHLCSG.

Fourty successive adult patients with lymphoblastic lymphoma entered a study of sequential chemotherapy consisting of an intensive LSA-L2-type protocol to induce first complete remission. Twenty-one patients in first CR (median age 24 years, range 15-43), after receiving a conditioning regimen consisting of cyclophosphamide and total body irradiation, underwent autologous bone marrow transplantation. At this time fourteen patients are alive and well 5-72 months post-transplant (median follow-up 58 months) with an actuarial disease free survival of 66%. These early results suggest that high-dose chemoradiotherapy followed by autologous bone marrow transplantation may improve long-term disease free survival in advanced stage adult lymphoblastic lymphoma.

ProMACE-MOPP vs MACOP-B in high grade non-Hodgkin's lymphomas: a randomised study in a multicenter cooperative study group (NHLCSG).

From January '85 to April '87, 81 patients (pts) with diffuse intermediate and high-grade non-Hodgkin's lymphomas were treated with the ProMace/MOPP protocol in a large Italian Cooperative Study Group (NHLCSG). Criteria for entry into the study included: no prior therapy, stage III-IV or stage II with bulky disease and/or B-symptoms, age below 65. 79 pts were evaluable for response. Almost all pts received six courses of chemotherapy, plus radiotherapy on bulky disease. 53 pts (67%) achieved complete remission (CR), 7 (9%) partial remission (PR), 4 (5%) were considered stable disease (SD) and 15 (19%) progression disease (PD) with 5 of them died early during treatment. The actuarial overall survival (OS) and disease free survival (DFS) are respectively 54% at 61 mos and 62% at 41 mos. The median follow-up from the end of therapy is 56 mos (range 40-68). Until now 20 pts (38%) relapsed on a median time of 8 mos (range 2-21) from CR. These data allowed to us to consider this regimen as effective as the third generation protocols also taking into account the multicenter basis of this study. With the aim to evaluate the impact of the third generation regimen on the outcome of these pts, a randomized study has been performed comparing ProMACE-MOPP with the third generation regimens MACOP-B. Therefore, from 1988 up to now, 206 pts with similar clinical and histological characteristics, have been enrolled in the two arms. No differences in terms of CR and DFS have been registered between the two treatments, with roughly the same toxicity. An analysis of prognostic factors in the larger series of pts treated with ProMACE-MOPP in the first and in the second study (167 pts) was performed. On these basis it seems reasonable that our next step would be to candidate these poor prognosis pts to a new therapeutic strategy which included the use of ABMT and/or PBSC transplantation as first line.

Human lymphoblastoid interferon for hairy cell leukemia: results from the Italian Cooperative Group.

Since April 1985, 82 patients with HCL entered a multicenter study using lymphoblastoid alpha-interferon; 51 (including 15 who failed splenectomy and 24 with substantial splenomegaly) enrolled before April 1986 are evaluated in this study. The patients were treated with 3 mega units daily subcutaneously until complete or partial response and were thereafter randomly allocated to a maintenance regime of 3 mega units/week or to observation only. Ten cases had a complete response, 18 a partial response, and 15 a minimal response. Two patients had no response, two interrupted therapy due to major toxicity (toxic hepatitis and thrombocytopenia), six died before completing 1 month of therapy of sepsis, and two died of myocardial infarction. In the two groups of splenectomized and nonsplenectomized patients the mean time to hemoglobin recovery was 8.5 and 6.5 weeks, respectively, the neutrophil count recovery was 6.5 and 9.3 weeks, and the time to platelet count recovery was 4.0 and 5.4 weeks, respectively. No significant differences in recovery time and response rate were observed between the two groups. In 31 out of 32 patients with substantial splenomegaly the spleen became either inpalpable (18) or significantly smaller (13). This study confirms the responsiveness of HCL to IFN in nonsplenectomized patients with high tumor burdens and is therefore recommended as a first-line therapy.

Mobilization/transplantation of peripheral blood progenitor cells for aggressive non-Hodgkin's lymphoma with marrow involvement.

Thirty-five aggressive non-Hodgkin's lymphomas (NHL) with marrow involvement received high-dose cyclophosphamide (7 g/m2) and G-CSF in order to collect peripheral blood progenitor cells (PBPC). Fourteen patients were in partial remission, 16 patients were in relapse ('sensitive', 12; 'resistant', 4) and five patients were refractory to conventional treatment. A good yield of PBPC was obtained in 30 patients, while a low number of CD34+ cells and of CFU-GM was seen in two cases. Two patients entered progression and one patient died. Thirty patients underwent PBPC autografting. Twenty-nine out of 35 (83%) patients entered complete remission (CR). Two patients died in CR of infection following marrow aplasia 3 and 6 months after autografting. At 3 years the probability of survival and disease-free survival (DFS) are 62 and 51%, respectively.

Randomized study of chlorambucil (CB) compared to interferon (alfa-2b) combined with CB in low-grade non-Hodgkin's lymphoma: an interim report of a randomized study. Non-Hodgkin's Lymphoma Cooperative Study Group.

Alpha interferon has shown initial promise in the treatment of low-grade non-Hodgkin's lymphoma (NHL), especially with the nodular form of the disease. The present study enrolled 70 NHL patients who received either chlorambucil (CB; 10 mg/day) or CB plus interferon alfa-2b (5 million units (MU)/m2 subcutaneously three times a week). Among 63 evaluable patients, similar response rates (62.1% and 64.7% respectively) were recorded for the treatment arms. In patients receiving no maintenance therapy, those who received interferon alfa-2b during the induction phase showed a favourable trend in terms of incidence of relapse compared to those who had received chlorambucil alone. During maintenance therapy with interferon alfa-2b, no significant differences in the occurrence of relapse have yet been seen compared to patients on no maintenance therapy. A longer observation period is needed to make a definitive conclusion about the usefulness of interferon maintenance therapy and to evaluate further the effects of the combined schedule of chlorambucil and interferon induction on the duration of remission.

One year follow-up study of T-cell subsets and incidence of seropositivity for HTLV-I and HTLV-III antibodies in patients treated "on demand" or sporadically with clotting concentrates.

A 1-year follow-up study of the T-cell subset abnormalities was carried out in 16 severe haemophilia A patients, treated "on demand" with an average amount of 500 U/kg/yr of factor VIII concentrate (group A) and in 15 mild haemophiliacs or von Willebrand patients treated only sporadically with less than 3000 U of factor VIII and no longer exposed to any other blood component in the 2 years preceding the beginning of the study (group B). In group A, 50% and 70% of patients showed a reduced or inverted T 4/T 8 ratio, respectively, at the beginning and at the end of follow-up. These values were of 30% and 20% in patients of group B, suggesting a long-lasting effect of concentrate therapy on T-cell subsets. The low T 4/T 8 ratio was mainly due to an increase of suppressor cells. None of the patients was found positive for anti HTLV-I, whereas 3 patients, all belonging to the group A, showed antibodies against HTLV-III. Thus, in these patients, HTLV-III seems not to be the only cause of low T 4/T 8 ratio.

Should alpha interferon be used as primary treatment for hairy cell leukemia? Italian Cooperative Group for Hairy Cell Leukemia.

To answer the question of whether interferon (IFN) should replace splenectomy, we reviewed the Italian HCL Registry: the records of 450 patients with hairy cell leukemia (HCL), seen from 1975 to 1988 were analysed. Of these, 321 were considered for the study: 231 had been splenectomized, 46 of them receiving subsequently IFN and 90 patients had IFN as initial therapy. Patients treated with splenectomy showed different survival according to Jansen and Hermans' staging system, which identified two risk groups: stage 1 and stages 2 and 3, p = 0.0329. On the contrary, patients treated with IFN did not show significantly different survival according to stage. By the comparison of stage 1 patients, either treated with splenectomy or with IFN, no statistical difference in survival was registered. Different survivals emerged for patients stage 2 + 3, which improved when treated with IFN, p = 0.0324. The median failure free survival (FFS) after splenectomy resulted in 89 months versus 33 months after IFN. In conclusion, splenectomy still remains the primary therapy for HCL patients stage 1. For high risk patients, stages 2 and 3, IFN should be adopted as first line therapy, improving substantially the survival. The short duration of response to IFN suggests a sequential combination of the two treatments for this group of patients, IFN reducing tumor mass quite safely and splenectomy assuring long lasting stable disease.

Release of natural killer cytotoxic factor in patients with lymphoproliferative disease of granular lymphocytes.

To further investigate the mechanisms accounting for defective natural killer (NK) activity observed in the majority of patients with lymphoproliferative disease of granular lymphocytes (LDGL), we have studied the generation of natural killer cytotoxic factor (NKCF) from peripheral blood lymphocytes recovered from twelve LDGL patients. On the basis of their cytotoxic activity against the K-562 target cells, cases under study were separated in two groups. Cells from five patients, referred to as NK+, were found to exhibit high levels of NK-cell mediated cytotoxicity; cells from seven patients, referred to as NK-, despite their ability to bind to the K-562 targets, displayed a defective NK function. The coculture of cells from NK+ patients with NK sensitive K-562 cells triggered a significantly higher production of NKCF with respect to NK- patients (p less than 0.001 at 1:2 dilution). Using phytohemagglutinin (PHA) as the NKCF stimulator, differences between the groups were not significant, due to a recovery of NKCF generation in NK- patients. Furthermore, a consistent lectin (PHA) dependent cellular cytotoxicity (LDCC) was exhibited by both groups of patients. The addition of gamma-interferon (IFN-gamma) or interleukin-2 (IL-2) during NKCF generation did not significantly modify the production of this factor. Our data point out that (a) NKCF is involved in the lytic activity of LDGL patients' cells, (b) a constitutional impairment in the generation of NKCF is not present in NK- patients, since recovery of lytic function occurs after PHA stimulation, and (c) IL-2 and IFN-gamma do not play a relevant role in triggering NKCF production when added during the generation of this factor. These studies help to clarify the factors involved in the cytotoxic machinery of LDGL patients' cells, suggesting that the defect of the cytotoxic function observed in some LDGL patients could lie at the level of target recognition.

Autologous bone marrow transplantation for advanced stage adult lymphoblastic lymphoma in first complete remission. A pilot study of the non-Hodgkin's Lymphoma Co-operative Study Group (NHLCSG).

Twenty successive adult patients with lymphoblastic lymphoma entered a study of sequential chemotherapy consisting of an intensive LSA2-L2-type protocol to induce first complete remission. Twelve patients in first CR (median age 22 years, range 15-43), after receiving a conditioning regimen consisting of cyclophosphamide and total body irradiation, underwent autologous bone marrow transplantation. Of these 12 patients at diagnosis, one was in stage III and 11 in stage IV; 11 showed mediastinal and seven showed bone marrow involvement. The transplant procedure was well tolerated and no treatment-induced deaths occurred. At this time nine patients are alive and well 25-44 months post-transplant (median follow-up 36 months) with an actuarial disease-free survival of 75%. These early results suggest that high-dose chemoradiotherapy followed by autologous bone marrow transplantation may improve long-term disease-free survival in advanced stage adult lymphoblastic lymphoma. In order to draw definite conclusions, however, a larger and randomized study is needed.

Recurrent chromosomal aberrations in peripheral T-cell lymphoma.

Histological, immunological, and cytogenetic analysis of the same neoplastic tissues have been performed on seven patients with peripheral T-cell lymphomas (PTCL). Clonal chromosomal abnormalities in five cases are reported. The most common chromosomal aberration, observed in four patients, is a rearrangement of chromosome 14 with a breakpoint in q11.2. Aberrations of chromosome 8 also occurred in four patients, three of whom had an extra 8q. The data indicate that breakpoints of malignant diseases affecting similar cell types might cluster to specific chromosomal regions, which can be helpful in recognition and classification of PTCL.

The rationale of therapy with mitoxantrone in non-Hodgkin's lymphoma. The Non-Hodgkin's Lymphoma Co-operative Study Group, (NHLCSG) Italy.

In order to evaluate the role of Mitoxantrone in the therapy of non-Hodgkin's lymphoma (NHL) (intermediate-high grade malignancy) a series of successive phase II-III studies were performed in a multicenter cooperative group. The first phase II study consisted of Mitoxantrone alone administered at 14 mg/m2 i.v. on day 1 and repeated every 3 weeks for six times. Fifteen refractory or relapsed patients (pts) entered the study, and an overall response of 54% (CR 4 pts, PR 4 pts) was obtained. 7 pts progressed or remained stable disease (NR). The second phase II consisted of Mitoxantrone in combination with Etoposide and Prednisone (VeMP). Twenty pts were treated and a complete remission (CR) of 50% with 1 partial remission (PR) were obtained with an overall response of 55%. The third phase II study consisted of 13 pts with refractory or relapsed disease treated with Mitoxantrone, Cis-platinum, Etoposide and Prednisone (CEMP); an overall response of 62% was obtained with an acceptable toxicity. This was not superior to other conventional salvage regimens. On this background a phase III study with VEMP (Etoposide, Cyclophosphamide, Mitoxantrone, Prednisone) was started as first line therapy for pts presenting one or more of following criteria: Performance Status (P.S.) 2-3, aggressive histology at stage I-IIE or advanced stage in old pts, low grade histology with B-symptoms stage in III-IV, age over 65 years. Until now 64 pts entered this study.(ABSTRACT TRUNCATED AT 250 WORDS)

Does the Therapy According to Stage Improve Response and Survival in Multiple Myeloma Patients?

The records of 104 patients (1972-80) with Multiple Myeloma (MM) were reviewed and a staging system was used dividing patients into Low Risk (LR) and High Risk (HR) groups, according to individual factors. Serum-calcium and serum creatinine, haemoglobin and the percentage of bone marrow plasma cells (BMPC), at the time of diagnosis, had predictive value on survival. This group of patients had already received treatment independent of these risk categories. Subsequently during 1980 to 1988, 114 evaluable patients with MM entered a prospective study using two treatment regimens according to that same staging system: LR patients were treated with Melphalan + Prednisone (MP) and HR patients with Vincristine, Melphalan, Cyclophosphamide and Prednisone (VMCP) for a minimum of six cycles. In the event of no response to the initial therapy given, a more aggressive regimen was then used: VMCP for LR patients and VAP or BAP (Vincristine or BCNU, Adriamycin, Prednisone) for the HR group for six to twelve cycles. The rate of response for Low and High Risk category was 42% and 73%, respectively. The median duration of response to initial therapy was 19 months for LR and 11 months for HR patients. Furthermore therapy chosen according to stage resulted in an improvement in survival compared to the earlier 1972-80 series. This was particularly significant for HR patients who benefited by an obvious decrease in the number of early deaths, due to progression of disease, when the combined regimens were used. The study indicates that therapy according to risk categories seems to be a worthwhile approach, MP being an appropriate initial treatment for LR while combination chemotherapy may be better for HR patients.

Long term results of interferon treatment in hairy cell leukemia. Italian Cooperative Group of Hairy Cell Leukemia (ICGHCL).

Eighty nine of 104 patients with hairy cell leukemia (HCL), enrolled between 1985 and 1987 in a multicenter prospective study on human lymphoblastoid IFN alpha-n1, were evaluable for long-term follow-up. The induction treatment, 3 MU/mq daily for a median of 5.7 months, produced a response of 93%, complete+partial response (CR+PR) = 80%, minor (MR) = 13%. Neither prior splenectomy nor pre-treatment variables were associated with the rate of response to IFN. However maintenance treatment of 3 MU/mq weekly given randomly had a slightly significant effect on failure free survival (FFS). Of the 43 patients who relapsed, 31/36 (86%) obtained a new response with IFN. No differences in FFS were recorded between first and second response. At the third induction 7/11 patients were treated again with IFN, 4/7 obtaining some response, but the FFS was significantly worse. The overall survival is still 85%. We conclude that (1) IFN should be used as chronic uninterrupted treatment for HCL, (2) reduced dosage is sufficient to prolong the disease free status and (3) continuous lymphoblastoid IFN administration seems not to be associated with the development of resistance to retreatment.

Treatment of Early Stage Hodgkin's Disease According to Risk Factors.

Between January 1981 and December 1987, 95 patients with stage IA (34 patients), IIA (42 patients) and stage IIB (19 patients) Hodgkin's disease (HD) were evaluated in our institution. Thirty patients defined as "high risk" because of either bulky mediastinal disease, systemic symptoms or both were treated with combined modality therapy (CMT). The remaining 65 patients considered as "standard risk" because they presented at diagnosis without any known adverse prognostic factor, received radiotherapy (RT) only. The median follow-up was 39 months. The complete remission (CR) rate was 97% (92/95). The actuarial 3 year overall (OS) and disease free survival (DFS) were 93% and 72% respectively with no differences between the two groups of patients. All 65 "standard risk" patients achieved CR; thirteen (20%) relapsed after a median time of 22 months. Twenty seven of 30 "high risk" patients (90%) achieved CR and six of them (22%) had early relapses. No severe pancytopenia episodes or life-threatening complications occurred during therapy. As far as the risk of second neoplasms is concerned, we observed only a single case of acute non lymphoblastic leukemia 48 months after the completion of CMT. These results indicate that in unfavourable early stage HD, CMT is effective with a probability of more than a 70% DFS 3 years after therapy with an acceptable acute and late toxicity. Patients without "high" risk factors showed the expected response after RT. About 60% of the patients who failed RT could be salvaged by chemotherapy (CT) while refractory cases or patients who relapsed after CMT did poorly with a third line chemotherapeutic regimen. Therefore alternative therapeutic approaches including high dose CT followed by autologous bone marrow transplantation should be considered for this subset of patients.

Cemp, a mitoxantrone containing combination, in the treatment of intermediate and high grade non-hodgkin's lymphoma: an effective and non toxic therapeutic alternative for adult and elderly patients.

Here we report the results of a randomised multicenter phase III clinical trial which assesses the therapeutic efficacy and tolerability of a chemotherapy protocol CEMP (cyclophosphamide, etoposide, mitoxantrone and prednisone) in adult and elderly patients with advanced intermediate and high-grade NHL. Between October 1991 and October 1995, 139 patients, aged 55 to 79 years, with diffuse intermediate and high-grade lymphoma, were enrolled. A considerable percentage of patients had clinically aggressive disease: 32.4% had systemic symptoms, 79% had stage III or IV disease, 33.8% had bone marrow involvement, 46% had splenic involvement and 42.5% had increased values of serum lactate dehydrogenate. Complete remission was achieved in 70 of the 139 patients (51.9%) and PR in 12 (16.6%) with an overall response of 68.5%. The overall response survival rate at 6 years was 39%, whereas DFS rate was 48.7% and PFS rate was 28.5%. At four years 49% of the patients were still in CR. Dividing the patients in two groups, under and over 65 years of age, we obtained the same results as far as overall response is concerned. No toxic deaths occurred, neither cardiac, renal nor liver complications happened. CEMP regimen is an effective and safe protocol with good results in elderly people, well comparable to those achieved in younger ones.

Mobilization/transplantation of peripheral blood progenitor cells for aggressive non-Hodgkin's lymphoma with marrow involvement.

Thirty-five aggressive non-Hodgkin's lymphomas (NHL) with marrow involvement received high-dose cyclophosphamide (7 g/m2) and G-CSF in order to collect peripheral blood progenitor cells (PBPC). Fourteen patients were in partial remission, 16 patients were in relapse ("sensitive", 12; "resistant", 4) and 5 patients were in refractory to conventional treatment. A good yield of PBPC was obtained in 30 patients, while a low number of CD34+ cells and of CFU-GM was seen in two cases. Two patients entered progression and one patient died. Thirty patients underwent PBPC autografting. Twenty-nine out of 35 (83%) patients entered complete remission (CR). Two patients died in CR of infection following marrow aplasia 3 and 6 months after autografting. At 3 years the probability of survival and disease-free survival (DFS) are of 62% and 51% respectively.