Sandro Nati

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-Hodgkins 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.

Reduced intensity conditioning for allograft after cytoreductive autograft in metastatic breast cancer

The benefits of allografting noted in some malignant diseases might be safely extended to metastatic breast cancer by a combination of cytoreduction with high-dose chemotherapy (HDT) and autologous stem-cell transplant (ASCT) with graft-versus-tumour effect mediated by transplanted donor immune cells with nonmyeloablative allografting (reduced intensity conditioning transplantation, RICT). 17 patients with heavily pretreated disease were given tandem transplants. 13 patients sustained donor engraftment. Three had partial remission after HDT and ASCT and complete remission after RICT; they achieved full chimerism and all developed graft-versus-host disease (GVHD) before regression of cancer. Another patient did not respond to HDT and ASCT but had partial remission after RICT, giving an overall response rate of 24%. Five patients had grade II or higher acute GVHD and five had extensive chronic GVHD. No non-relapse-related deaths occurred during the first 100 days. Five patients (29%) were alive 90-2160 days (median 1320) after RICT. This two-step approach is feasible in patients with metastatic breast cancer.

Massive chemotherapy with non-frozen autologous bone marrow transplantation in 13 cases of refractory Hodgkin's disease

A group of 13 patients with advanced, diffuse Hodgkins disease, poorly responding to the most widely employed primary chemotherapy regimens, were treated with massive chemotherapy (MCH) followed by rescue with non-frozen autologous bone marrow infusion (ABMT). Complete remission (CR) was obtained in 8/13 patients (61.5%) and partial remission in two. Hematopoietic recovery occurred in 12 cases. These preliminary results would seem to indicate that MCH with non-frozen ABMT may be successfully used in patients with resistant or relapsed Hodgkins disease.

4-Demethoxydaunorubicin (Idarubicin) in refractory or relapsed acute leukemias. A pilot study

Twenty‐five adults with previously treated acute leukemia were treated with 4‐demethoxydaunorubicin (Idarubicin) with a daily dose of 8 mg/m2 for 3 days intravenously. Complete remission was achieved in 3 of 18 patients with acute nonlymphoblastic leukemia (ANLL) and 2 of 6 with lymphoblastic leukemia. Complete remissions were observed in two of eight ANLL patients refractory to cytarabine, anthracycline, and m‐Amsa (amsacrine), indicating a lack of cross‐resistance between these drugs and Idarubicin. The median duration of remission was 8 weeks. The main major toxicity of Idarubicin therapy, severe myelosuppression, cannot be considered a toxic effect because it was desired in this case list. Our preliminary results indicate that Idarubicin has significant activity against refractory adult acute leukemia.

Twelve Years Experience with High-Dose Therapy and Autologous Stem Cell Transplantation for High-Risk Hodgkin's Disease Patients in First Remission After MOPP/ABVD Chemotherapy

High-dose therapy followed by autografting can cure patients with aggressive Hodgkins disease (HD) refractory or with early relapse to first-line combination chemotherapy. On the other hand, the eradication of the disease is rarely achieved in heavily pretreated patients. It has been suggested that patients with HD with very high risk characteristics at diagnosis, often relapse despite appropriate therapy with 7-8 drugs combination. Thus it seems to us that such patients are potential candidates for early autografting during first remission. Twelve years ago, we initiated a pilot study to investigate whether patients with very high risk characteristics, would benefit from early autografting. The application of early autografting was compared with our historical group of patients in complete remission after receiving MOPP/ABVD, who had the same negative prognostic characteristics, refused autografting and who did not receive other treatment after achieving complete remission. Among the 22 consecutive patients entered into the pilot study and autografted, 18 are alive and 17 (77%) remain alive in unmaintained remission at a median of 86 months. One patient (4%) died of interstitial pneumonitis in the transplantation group. Only 8/24 (33%) patients, who did not receive an autograft, are currently alive and disease free at a median of 89 months. In conclusion, the early application of autografting appears to improve the outcome in patients with very high risk HD who achieved remission with MOPP/ABVD.

First line Fludarabine treatment of symptomatic chronic lymphoproliferative diseases: clinical results and molecular analysis of minimal residual disease

Abstract: Fludarabine (25 mg/m2 for 5 d, every 4 wk, for 6 courses) was administered as first line therapy in 32 symptomatic chronic lymphoproliferative diseases. All CLL patients achieved at least partial response (5 CR, 2 nPR, 9 PR) but 44% of patients relapsed. In LG‐NHLs response and relapse rate were similar. Haematological toxicity was low. VDJ rearrangement PCR analysis was performed on marrow samples at diagnosis and at the time of response evaluation. In the 3 patients who underwent high dose therapy with peripheral blood progenitor cell rescue analysis was also performed on apheresis samples and on marrow samples at the end of the procedure. Clonal VDJ rearrangement was always evident after Fludarabine therapy even in those patients who achieved histological and immunophenotypic complete remission, whereas it disappeared in 2 of 3 patients who underwent HDT. Our data confirm that Fludarabine monotherapy can reduce the neoplastic mass to a subclinical level and suggest the possibility that high dose therapy might produce true complete remission.

High-dose chemotherapy and non-frozen autologous bone marrow transplantation in relapsed advanced lymphomas or those resistant to conventional chemotherapy

Ten patients with advanced, diffuse Hodgkins and non‐Hodgkins lymphomas responding poorly to the most widely employed primary chemotherapy regimens were treated with a high‐dose chemotherapy (HDC) followed by rescue with non‐frozen autologous bone marrow infusion (ABMT). Complete remission (CR) was obtained in seven of ten patients (70%) and partial remission in two. Hemopoietic recovery occurred in nine cases. These preliminary results appear to indicate that HDC and non‐frozen ABMT may be successfully used in patients with resistant or relapsed lymphomas.

Amifostine (WR-2721), a cytoprotective agent during high-dose cyclophosphamide treatment of non-Hodgkin's lymphomas: a phase II study

Clinical trials indicate that amifostine may confer protection on various normal tissues without attenuating anti-tumor response. When administered prior to chemotherapy or radiotherapy, it may provide a broad spectrum of cytoprotection including against alkylating drugs. The mechanism of protection resides in the metabolism at normal tissue site by membrane-bound alkaline phosphatase. Toxicity of this drug is moderate with hypotension, nausea and vomiting, and hypocalcemia being observed. We report a phase II study using amifostine as a protective drug against high-dose cyclophosphamide (HDCY) (7 g/m2), used to mobilize peripheral blood progenitor cells (PBPC) and to reduce tumor burden. We enrolled 29 patients, 22 (75. 9%) affected by aggressive and 7 (24.1%) by indolent non-Hodgkins lymphoma (NHL), who were submitted to 58 infusions of amifostine and compared them with a historical group (33 patients) affected by aggressive NHL and treated with VACOP-B followed by HDCY. The most important results in favor of amifostine were the reduction of intensity of cardiac, pulmonary and hepatic toxicity, and a significant reduction of frequency and severity of mucositis (P = 0. 04). None of the 29 patients died in the protected group, while in the historical group 2/33 patients died because of cardiac or pulmonary toxicity and 2 patients stopped therapy due to toxicity. Amifostine did not prevent the aplastic phase following HDCY. PBPC collection and hematological recovery were adequate in both groups. The number of CFU-GM (colony-forming units-granulocyte/macrophage) colonies and mononuclear cells in the apheresis products was significantly higher in the amifostine group (P = 0.02 and 0.01, respectively). Side effects were mild and easily controlled. We conclude that amifostine protection should be useful in HDCY to protect normal tissues, with acceptable side effects.

Alpha-interferon as induction and maintenance therapy in hairy cell leukemia:a long-term follow-up analysis

Abstract: Although in recent years the use of purine analogues has increased the percentage of long‐term complete response the effect on overall survival of HCL patients is not yet clear. This study aimed to evaluate the long‐term outcome (mean follow up of 92 months) of sixty‐four patients receiving IFN as first‐line therapy. IFN was well tolerated and effective. The overall response rate was 91% (PR 65%, CR 13%, GPR 13%). Forty‐one patients (63%) received IFN 3 MU/wk as maintenance therapy. The 10‐yr projected survival rate of responding patients (CR and GPR 100%; PR 95%) and non responders (SD, PD 80%) clearly shows that type of response does not affect survival. Patients receiving IFN maintenance had a statistically higher PFS than those who did not (p<0.01). This study shows that IFN is still one of the standard therapies for this disease, that achieving CR has no primary relevance for the control of the disease, and that good utilization of therapeutic resources may assure HCL patients a survival rate comparable to that of a normal, healthy population.

Rituximab is effective for extensive steroid-refractory chronic graft-vs.-host-disease.

Chronic graft-vs.-host disease (cGVHD) is the most common cause of late morbidity and mortality after allografting. Patients who fail to respond to steroid-based therapy have poor outcome [1]. There is now mounting evidence implicating B cells in the pathophysiology of cGVHD. Antibodies to Y chromosome-encoded minor histocompatibility antigens are generated after sex-mismatched allogeneic transplantation [2], and the presence of these antibodies has been correlated with the occurrence of cGVHD and a decreased risk of relapse [3]. This finding generates the hypothesis that specific anti-Bcell therapy may be effective therapy for cGVHD. The efficacy of anti-B-cell therapy using the monoclonal anti-CD20 antibody Rituximab for cGVHD has been reported [4 – 8]. Recently, 21 patients with cGVHD were treated by Cutter et al. [9] with 38 cycles of rituximab; the clinical response rate was 70%, including two patients with complete remission. These responses were durable through one year after therapy. Unfortunately, the responses were limited to patients with cutaneous and musculoskeletal manifestations. Here, we describe a patient with extensive liver and gastrointestinal cGVHD combined with severe thrombocytopenia, refractory to cyclosporine, highdose prednisolone and high-dose immunoglobulins who obtained a complete resolution after rituximab. A 28-year-old male presented with bulky mediastinal mass. After a diagnosis of CD20þ diffuse large B-cell non-Hodgkin’s lymphoma was made, the patient received two cycles of conventional chemotherapy (R-CHOP, MACOP-B) with no clinical response. The patient was then treated with highdose therapy (BEAM protocol) and autografting. A positron emission tomography (PET)/computed tomography (CT) scan 2 months after high-dose therapy/autografting showed a 50% decrease in the mediastinal mass. Thirteen months after diagnosis, he received reduced intensity conditioning for allografting fludarabine (30 mg/m for 3 days) and melphalan (70 mg/m for 1 day). Filgrastimmobilized peripheral blood progenitor cells from an HLA-matched sister were harvested and infused into the patient. Prophylaxis against GVHD consisted of cyclosporine and methotrexate. There was prompt hematologic reconstitution after transplantation. On day 28, the patient developed grade III aGVHD with maculopapular rash of the upper torso and diarrhea. Methylprednisolone 10 mg/kg (up to 15 mg/kg) was administered daily. The patient had a good response to steroid therapy in the skin lesions but not in gastrointestinal symptoms. Bone marrow aspirate on day 35 showed full donor chimerism confirmed by polymerase chain reaction of microsatellite markers. On day 100, he developed progressive xerostomia with lichenoid changes of the oral mucosa; subsequently, he experienced complications including coagulase-negative staphylococcal septicemia, cytomagalovirus reactivation, thrombotic trombocytopenic purpura (TTP)-like syndrome, and aspergillus pneumonia. These events were effectively treated with antibiotic, antiviral, plasmaspheresis, and liposomal amphotericin therapies. On day 130,