Allogeneic hemopoietic stem cell transplantation in solid tumors.

The existence of a graft versus tumor (GVT) effect of donor-derived T cells after allogeneic hematopoietic stem cell transplantation is well established as a critical component for the success of the procedure in several hematologic malignancies. Although it has been suggested that a GVT effect might also be generated in patients affected by refractory solid tumors, the morbidity of conventional allogeneic hematopoietic stem cell transplantation has limited its investigation in these diseases. Recently introduced allogeneic nonmyeloablative regimens have greatly decreased morbidity and mortality related to transplants which retain a powerful GVT. On this basis, it has become possible to explore the existence of alloreactivity toward solid tumors. The present article reviews the early clinical results of this novel immunotherapeutic approach for solid tumors.

Idarubicin in patients with diffuse large cell lymphomas: a randomized trial comparing VACOP-B (A = doxorubicin) vs VICOP-B (I = idarubicin).

BACKGROUND AND OBJECTIVE: Idarubicin is an effective drug in acute leukemia but its use in non-Hodgkin lymphomas (NHLs) is not yet well established. We evaluated its efficacy in patients with diffuse large cell lymphoma (DLCL) by means of a randomized trial comparing two 12-week regimens (VACOP-B and VICOP-B) which differed only in the anthracycline drug used (doxorubicin vs idarubicin). METHODS: From January 1992 to December 1994, 104 patients aged less than 65 years with de novo advanced stage DLCL were enrolled. Fifty-two patients were treated with VACOP-B (doxorubicin 50 mg/sqm) and 52 with VICOP-B (idarubicin initially 8 mg/sqm and thereafter 10 mg/sqm). RESULTS: Clinical characteristics of the two groups were not significantly different. One HBsAg+ patient died of hepatic necrosis in the VICOP-B arm, and severe (WHO grade > 2) toxicities occurred in 7 patients treated with VACOP-B and in 5 treated with VICOP-B; the only significant difference was for mucositis (p = 0.02). Complete remission (CR) was obtained in 79% of patients receiving VACOP-B and in 56% (idarubicin 8 mg/sqm) and 75% (idarubicin 10 mg/sqm) of those in the VICOP-B group (p = n.s.). Prognostic factors that negatively affected CR were advanced stage in VACOP, bone marrow infiltration in both schedules. At a median follow-up of two years, overall survival (67% VACOP and 61% VICOP) and disease-free survival (65% and 67%, respectively) were not significantly different. INTERPRETATION AND CONCLUSIONS: Idarubicin is slightly less toxic than doxorubicin; at a dose of 10 mg/sqm the former is easily tolerated and shows the same efficacy as doxorubicin in the treatment of DLCL.

Combined modality treatment with a weekly brief chemotherapy (ACOP-B) followed by locoregional radiotherapy in localized-stage intermediate- to high-grade non-Hodgkin's lymphoma.

BACKGROUND: A cooperative study was undertaken to evaluate the efficacy and toxicity of a very brief course of chemotherapy followed by locoregional radiotherapy in patients with localized-stage intermediate- to high-grade non-Hodgkin's lymphoma (NHL). PATIENTS AND METHOD: From January 1988 to November 1994, 84 patients with localized stages IA and IIA intermediate- to high-grade NHL underwent a combined modality treatment. All patients underwent a six-week chemotherapy regimen, ACOP-B (doxorubicin 50 mg/sqm and cyclophosphamide 350 mg/sqm on weeks 1, 3, 5; vincristine 1.4 mg/sqm and bleomycin 10 mg/sqm on weeks 2, 4, 6; prednisone 50 mg p.o. daily throughout the first two weeks and thereafter every other day), followed by locoregional radiotherapy (36 Gy). RESULTS: The median age was 58 years, with 35% older than 65 years; 52 patients had stage I and 32 stage II; 39 patients had extranodal +/- nodal involvement, and 4 had testicular involvement. Treatment was well tolerated, with only 38% suffering from mild mucositis and no toxic deaths. Seventy-nine patients achieved CR after ACOP-B and 83 at the end of the program. With a median follow-up of four years, relapse-free survival was 79% with 15 relapses (93% disseminated). Two patients with testis lymphoma had CNS relapses. Overall survival was 90% at four years. CONCLUSION: This combined program is effective and probably curative in localized stage intermediate- to high-grade NHL, with low toxicity, also in elderly people. Patients with NHL of the testis, as primary site, require CNS prophylaxis due to the high likelihood of CNS relapse.

Results of a low aggressivity chemotherapy regimen (CVP/CEB) in elderly Hodgkin's disease patients.

BACKGROUND: Hodgkin's disease (HD) after the age of 65 years is uncommon and there are no published data on chemotherapy regimens devised for elderly HD patients. PATIENTS AND METHODS: From 1990 to 1993, 25 elderly HD patients were treated with the CVP/CEB regimen: chlorambucil 6 mg/sqm p.o. days 1 through 7, vinblastine 6 mg/sqm i.v. on day 1, procarbazine 100 mg/sqm p.o. days 1 through 7, prednisone 30 mg/sqm p.o. days 1 through 7, cyclophosphamide 500 mg./sqm i.v. day 15, etoposide 70 mg/sqm i.v. day 15, bleomycin 10 mg/sqm i.v. day 15. Each course was repeated every 4 weeks. Stage I and II patients were treated with 3 courses followed by involved field radiotherapy, while more advanced stage patients received 6 courses and radiotherapy was limited to bulky areas. The results of the CVP/CEB regimen are retrospectively compared to those of 74 elderly patients treated between 1982 and 1989 and subdivided into the following 2 groups: 32 patients treated according to the same therapy used at that time in younger patients, and 42 patients given alternative low aggressivity or palliative treatment. RESULTS: CVP/CEB is a well-tolerated regimen, with only 1 (4%) toxic death and 2 (8%) protocol violations/interruptions. The CVP/CEB complete remission rate (73%) compares favorably with our previous groups of patients, mainly because of the lower toxic death rate. However, the CVP/CEB relapse-free survival rate is lower than that of patients treated with more aggressive conventional regimens (47% vs. 77%, p < 0.02). The CVP/CEB overall survival and event-free survival rates are 55% and 32%, respectively, and they are not statistically different from those of patients treated before 1990. CONCLUSIONS: CVP/CEB is a well-tolerated low toxicity regimen with a high CR rate. The relapse rate is high and event-free survival is comparable to that of patients treated conventionally. Our results suggest the need for individualized treatment criteria for older patients with HD.

The treatment of elderly patients with aggressive non-Hodgkin's lymphomas: feasibility and efficacy of an intensive multidrug regimen.

The results of a prospective trial of an 8 week treatment for elderly patients with advanced intermediate-high grade NHL are reported. Our aim was to reduce general toxicity without losing an antilymphoma effect. For this reason the use of growth factor was studied. We also analysed the behavior of different histological groups (E + F vs G + H). From November 1991 to November 1993 100 patients older than 65 years with combination intermediate-high grade advanced stage NHL were treated with the P-VEBEC regimen, an original including epirubicin 50 mg/sqm, cyclophosphamide 300 mg/sqm and etoposide 100 mg/sqm on weeks 1, 3, 5, 7; vinblastine 5 mg/sqm and bleomycin 5 mg/sqm on weeks 2, 4, 6, 8; prednisone 50 mg/sqm/day per os in the first two weeks and thereafter every other day .46 pts received rG-CSF 5 micrograms/Kg/day throughout the treatment starting on day 2 of every week for 4 consecutive days. Twenty eight pts had B symptoms, 41 had bulky disease, 37 LDH levels above normal, 50 stage IV patients and 30 had bone marrow involvement. Sixty two percent achieved a complete remission (CR). Adverse prognostic factors for CR were E and F histology, stage IV disease, bone marrow infiltration, serum LDH levels above normal, international Prognostic Index (I.I.) intermediate-high and high risk categories and relative dose intensity (RDI) less than 0.80. Severe toxicity was rarely recorded and only one toxic death was observed. With a median follow-up of 33 months OS, DFS and EFS were 44%, 60% and 30% respectively. EFS was influenced by stage, BM involvement, level of LDH and I.I. intermediate-high and high risks. The 52 patients with DLCL (diffuse large cell lymphomas--G + H according to WF) did better with a higher CR, OS, DFS and EFS rates, than the other WF subtypes. In conclusion P-VEBEC is a feasible combination to use in elderly patients, mainly in DLCL. The use of rG-CSF improves the RDI. A RDI > 0.80 could play a role in improving the outcome, especially in patients with adverse prognostic factors. For other subgroups another schedule is probably justified.

Probability of cure in elderly Hodgkin's disease patients.

BACKGROUND: Elderly Hodgkin's disease patients have a poor prognosis. The question arises whether these patients need aggressive treatment or a palliative strategy. So far, as a consequence of the scarcity of trials designed for them, useful information can be obtained only by retrospective analyses. METHODS: We retrospectively studied clinical data from 567 patients recorded from 1982 to 1989 in the Piemonte Hodgkin's Disease Register (PHDR). The 65 patients over 65 years of age were compared to younger ones. We analyzed the role of disease independently of confounding variables, mainly inadequacy of staging and/or treatment, comorbidity and toxicity. RESULTS: In the elderly comorbidity was as high as 35%. Forty elderly patients (60%) entered a suboptimal plan with a low degree of aggressivity, which was different from the usual PHDR protocol. Elderly patients also had a high proportion of subsequent protocol interruptions (25%). Chemotherapy dose intensity was negatively affected by advanced age (p < 0.01 after both 3 and 6 courses of chemotherapy). Toxic deaths were significantly higher in elderly patients than in younger ones (14% vs 1%; p < 0.05). CR rates, overall survival (OS), disease-specific survival (DSS) and event free survival (EFS) were all significantly influenced by age (p < 0.01). Relapse-free survival (RFS) in patients achieving CR did not differ according to age class (77% vs 60%; p = ns). RFS was better in elderly patients entering the PHDR protocols than in those following an alternative plan (75% vs 54%; p = 0.04); however, elderly patients treated according to PHDR guidelines showed a higher incidence of toxic deaths than those treated less aggressively (23% vs 8%). The two groups had similar EFS (36% vs 24%; p = ns). CONCLUSIONS: Elderly patients who achieve CR can have good RFS and cure is possible, but the toxic cost of conventional strategies is unacceptable and selected strategies still must be found.

Malignant lymphoproliferative disorders in liver cirrhosis.

BACKGROUND: Lymphoproliferative disorders in patients with liver cirrhosis, although uncommon, have been reported in at least 49 cases. Some authors have suggested that the association between chronic liver disease and lymphoma is not coincidental, that immune mechanisms may be pathogenetically involved. PATIENTS AND METHODS: In the present study we calculated the incidence rate of lymphoproliferative disorders in 334 liver cirrhosis patients (201 males, mean age 59 +/- 12; 133 females, mean age 61 +/- 11) treated at the Gastroenterology Department of the Mauriziano Hospital in Turin from January 1987 to September 1990. RESULTS: We diagnosed 12 lymphoproliferative disorders, corresponding to an incidence of 9.56/1,000 person-years, a figure much higher than expected on the basis of the incidence rate registered in the Turin general population. Six of the 12 lymphoproliferative disorders were non-Hodgkin's lymphomas of the stomach, a proportion by far exceeding expectation. CONCLUSIONS: Our data support the hypothesis that the association between chronic liver disease and lymphoproliferative disorders is not just coincidental, and suggest that liver cirrhosis might be considered an immunological disturbance which entails an increased risk of developing lymphoproliferative disorders. Mechanisms causing lymphoproliferative disorders to develop in the course of chronic liver disease have been hypothesized.

[Liver cirrhosis and lymphoproliferative diseases: coincidence or association?]. / Cirrosi epatica e malattie linfoproliferative: coincidenza o associazione?

The development of lymphoproliferative disorders in association with a chronic liver disease, although uncommon has been documented in several reports and a review of the available literature yielded a total of 34 cases. It has been suggested that this association is probably not a fortuitous coincidence and several mechanisms explaining the development of lymphoproliferative diseases in the course of liver disease have been offered. We have evaluated the annual cumulative incidence of such an association in the specific population of patients with liver cirrhosis (N.:344) admitted to our Department of Gastroenterology, Mauriziano Hospital, in Turin, within 3.5 years, from January 1987 to June 1990: it resulted to be 9.56/1,000 subjects per year. This figure is much higher than the annual incidence registered in Turin within the years 1985-87 for the same lymphoproliferative disease, 39.6/100,000 inhabitants. Our data add value to the hypothesis that this association is not incidental and suggest that chronic liver disease should be added to the list of the pathological conditions with immunological disturbances associated with lymphoproliferative disorders.

[The lymphocytogram in recurrent aphthous stomatitis. The etiopathogenic aspects]. / Il linfocitogramma nelle stomatiti aftose ricorrenti. Considerazioni eziopatogenetiche.

The paper studies the distribution of circulating lymphocytic phenotypes in 20 cases of recurrent aphthous stomatitis. The statistical analysis of data, together with that found in 40 normal subjects, reveals the selective immunoactivation of cytotoxic T lymphocytes and NK cells similar to that found during the course of acute viral diseases. In etiopathogenetic terms, results should therefore be considered as a possible demonstration of the viropathic genesis of this disease.

Mitoxantrone, etoposide, cisplatin and dexamethasone (MEPD) as salvage chemotherapy in resistant non-Hodgkin's lymphoma.

BACKGROUND: An effective second-line treatment for intermediate and high grade non-Hodgkin's lymphoma is greatly needed since 30% of patients do not achieved complete remission (CR) and another 20% to 30% of the CRs will eventually relapse. METHODS: A four-drug combination with Mitoxantrone, Etoposide, Cisplatin and Dexamethasone (MEPD) was devised for the treatment of patients with relapsing or refractory non-Hodgkin's lymphoma (NHL). So far 22 patients with intermediate or high grade NHL have entered the study. All patients were previously treated with doxorubicin based regimens. RESULTS: Seven patients obtained a complete remission (CR), 3 a partial remission (PR), 4 a minor response (MR) and 8 were treatment failures (F). Thus, an overall response rate of 45% has been achieved. To date three of the complete responders have relapsed at 3, 6 and 15 months. Four patients are still in CR at +2, +4, +9 and +17 months, respectively. Patients with relapsing lymphoma responded better than those with primary refractory disease. Myelosuppression was the most frequent side effect, nevertheless there were no severe infections. CONCLUSIONS: These preliminary results suggest the effectiveness of MEPD as salvage chemotherapy in resistant NHL and warrant further clinical studies.

Phenotypical characterization of lymphocyte recirculating subsets in patients undergoing splenectomy for trauma.

The spleen is a peripheral lymphatic organ where lymphocytes stop for long time during their circulation. We studied the peripheral blood lymphocyte subsets both in 30 subjects splenectomized for trauma and in 30 healthy, non splenectomized, subjects. The phenotypical characterization of lymphocyte subpopulations was performed employing monoclonal antibodies by direct immunofluorescence assays with single and double labelling. Comparing the results, we put in evidence, in splenectomized patients, an increase in all the lymphocyte subsets but one (L. G.L. Leu7+). The CD8+ population showed the major increase according with its large representation in the splenic tissue. Splenectomy induces a change in lymphocyte recirculating pool because of the loss of an important anatomical site of migration. This reduction of lymphocyte recirculating capacity can be related to a decreased efficiency in immunocompetence. In fact, many Authors showed that splenectomy is associated with several anomalies of both humoral and cellular immune response. In contrast with this, our group of splenectomized patients doesn't reveal a greater incidence of infections. We conclude that splenectomy realizes a new anatomical situation where the reduction of lymphocyte recirculating capacity can be related to a decreased statistical efficiency in immunocompetence.

Severe platelet dysfunction in a patient with autoantibodies against membrane glycoproteins IIb-IIIa.

A young women affected by Hodgkin's disease developed chronic autoimmune thrombocytopenic purpura. Splenectomy induced normalization of her platelet count, but hemorrhagic symptoms did not disappear. The patient's platelets did not aggregate in response to collagen and ADP and the IgG fraction of the patient's plasma induced the same defect in normal platelets. The women's IgG recognized glycoproteins IIb and IIIa of normal platelet membranes. Prednisone therapy induced the disappearance of bleeding symptoms and the normalization of platelet aggregation.

[Platelet aggregation and resistance to osmotic shock of platelet concentrates obtained by discontinuous-flow cell separation with the surge pump technic]. / Aggregazione piastrinica e resistenza allo shock osmotico di concentrati piastrinici ottenuti mediante separatore cellulare a flusso discontinuo con la tecnica "surge pump".

We studied the ultrastructural morphology and function of platelets collected by apheresis procedure with discontinuous flow using the Surge Pump Technique. The platelet concentrates obtained by this technique are free of erythrocyte and lymphocyte contamination. The platelet morphology as well as the platelet aggregation induced by ADP, adrenaline and collagen of platelet concentrates were similar to those observed in PRP before the apheresis. The response to the hypotonic shock of platelet concentrates was also normal, indicating membrane integrity and good platelet metabolism. These results show that platelet concentrates obtained by the Surge Pump Technique maintain their haemostatic effects and may be infused in thrombocitopenic patients, reducing the risk of alloimmunization related to the presence of erythrocytes and lymphocytes.