Teodoro Chisesi

The lymphoproliferative disease of granular lymphocytes. A heterogeneous disorder ranging from indolent to aggressive conditions

A multiparameter analysis, which included the evaluation of clinical features, cell morphology, karyo‐type, phenotypic and functional immunologic findings, and T‐cell receptor beta‐chain configuration was performed on 34 patients with lymphoproliferative disease of granular lymphocytes (LDGL). The two‐fold aim of the study was to identify the most useful tools that would more accurately characterize these patients and to deal with the problem of classifying these lymphoproliferative disorders. The data presented in this article suggest that a single parameter may not be sufficient to define the nature of the proliferating cells or to predict the clinical course of the disease and prognosis for the patient. The use of a multiparameter approach, however, may reach this goal, thus providing important prognostic and therapeutic information. Our study supports the concept that lymphoproliferative disease of granular lymphocytes is a heterogeneous disorder that ranges from indolent and possibly reactive conditions to the manifestation of aggressive malignancies.

ABVD Versus Modified Stanford V Versus MOPPEBVCAD With Optional and Limited Radiotherapy in Intermediate- and Advanced-Stage Hodgkin's Lymphoma: Final Results of a Multicenter Randomized Trial by the Intergruppo Italiano Linfomi

PURPOSE In this multicenter, prospective, randomized clinical trial on advanced Hodgkins lymphoma (HL), the efficacy and toxicity of two chemotherapy regimens, doxorubicin, vinblastine, mechlorethamine, vincristine, bleomycin, etoposide, and prednisone (Stanford V) and mechlorethamine, vincristine, procarbazine, prednisone, epidoxirubicin, bleomycin, vinblastine, lomustine, doxorubicin, and vindesine (MOPPEBVCAD), were compared with doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) as standard therapy to select which regimen would best support a reduced radiotherapy program, which was limited to < or = two sites of either previous bulky or partially remitting disease (a modification of the original Stanford program). PATIENTS AND METHODS Three hundred fifty-five patients with stage IIB, III, or IV HL were randomly assigned. Three hundred thirty-four patients were assessable for the study and received six cycles of ABVD (n = 122), three cycles of Stanford V (n = 107), or six cycles of MOPPEBVCAD (n = 106); radiotherapy was administered to 76, 71, and 50 patients in these three arms, respectively. RESULTS The complete response rates for ABVD, Stanford V, and MOPPEBVCAD were 89%, 76% and 94%, respectively; 5-year failure-free survival (FFS) and progression-free survival rates were 78%, 54%, 81% and 85%, 73%, and 94%, respectively (P < .01 for comparison of Stanford V with the other two regimens). Corresponding 5-year overall survival rates were 90%, 82%, and 89% for ABVD, Stanford V, and MOPPEBVCAD, respectively. Stanford V was more myelotoxic than ABVD but less myelotoxic than MOPPEBVCAD, which had larger reductions in the prescribed drug doses. CONCLUSION When associated with conditioned and limited (not adjuvant) radiotherapy, ABVD and MOPPEBVCAD were superior to Stanford V chemotherapy in terms of response rate and FFS and progression-free survival. Patients were irradiated less often after MOPPEBVCAD, but this regimen was more toxic. ABVD is still the best choice when it is combined with optional, limited irradiation.

Positron emission tomography in the staging of patients with Hodgkin's lymphoma. A prospective multicentric study by the Intergruppo Italiano Linfomi.

In this prospective multicentric study, we investigated the contribution of positron emission tomography (PET) scanning to the staging of Hodgkin’s lymphoma (HL) by computed tomography (CT) and attempted to determine whether it has any impact on therapeutic approach. One hundred eighty six consecutive patients with HL from six Italian centers were enrolled in this study. They were staged with conventional methods; 2-[fluorine-18]fluoro-2-deoxy-d-glucose PET scanning were prospectively compared to CT. CT and FDG-PET stages were concordant in 156 patients (84%) and discordant in 30 patients (16%). PET stage in comparison to CT stage was higher in 27 patients (14%) and lower in 3 patients (1%). The programmed treatment strategy was modified in 11 out of 30 patients (37%) after the definition of final stage. If we considered the 123 CT staged patients with localized stage, ten patients (8%) with a change of stage from localized to advanced after PET evaluation were treated with different strategy. FDG-PET was shown to be a relevant, non-invasive method that supplements conventional procedures and should therefore be used routinely to stage HL, particularly in early stage patients, where a change in stage may modify disease management.

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-Hodgkins 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-Hodgkins lymphoma (Working Formulation groups F, G, H, and K), stage II bulky (> 10 cm), III, or IV, were randomized by the Non-Hodgkins 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.

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

Alpha interferon has shown initial promise in the treatment of low-grade non-Hodgkins 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.

Long-Term Follow-Up Analysis of HD9601 Trial Comparing ABVD Versus Stanford V Versus MOPP/EBV/CAD in Patients With Newly Diagnosed Advanced-Stage Hodgkin's Lymphoma: A Study From the Intergruppo Italiano Linfomi

PURPOSE The Intergruppo Italiano Linfomi HD9601 trial compared doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) versus doxorubicin, vinblastine, mechloretamine, vincristine, bleomycin, etoposide, and prednisone (Stanford V [StV]) versus the combination of mechlorethamine, vincristine, procarbazine, prednisone (MOPP) with epidoxorubicin, bleomycin, vinblastine (EBV), lomustine, doxorubicin, and vindesine (CAD) (MOPP/EBV/CAD [MEC]) for the initial treatment of advanced-stage Hodgkins lymphoma to select which regimen would best support a reduced radiotherapy program (limited to two or fewer sites of either previous bulky or partially remitting disease). Superiority of ABVD and MEC to StV was demonstrated. We report analysis of long-term outcome and toxicity. PATIENTS AND METHODS Patients with stage IIB, III, or IV were randomly assigned among six cycles of ABVD, three cycles of StV, and six cycles of MEC; radiotherapy was administered in 76, 71, and 50 patients in the three arms, respectively. RESULTS Currently, the median follow-up is 86 months; in the prolonged observation period, eight additional failures, including two relapses, both in the StV arm, and six additional deaths in complete response were recorded. The 10-year overall survival rates were 87%, 80%, and 78% for ABVD, MEC, and StV, respectively (P = .4). The 10-year failure-free survival was 75%, 74%, and 49% in the ABVD, MEC, and StV arms, respectively (P < .001). The 10-year disease-free survival of patients treated or not with radiotherapy (RT) showed no difference for ABVD or MEC (85% v 80% and 93% v 68%), and a statistically significant difference for StV (76% v 33%; P = .004). No significant long-term toxicity was recorded. CONCLUSION The long-term analysis confirmed ABVD and MEC superiority to StV. The use of RT after StV was established as mandatory. ABVD is still to be considered as the standard treatment with a good balance between efficacy and toxicity.

Evaluation of serum levels of soluble interleukin-2 receptor in patients with chronic lymphoproliferative disorders of T-lymphocytes

Serum levels of soluble interleukin‐2 receptor (sIL‐2R) have been evaluated in 33 patients with chronic lymphoproliferative disorders of T‐lymphocytes, including 12 T‐helper phenotype chronic lymphocytic leukemias (Th‐CLL) and 21 lymphoproliferative diseases of granular lymphocytes (LDGL). All Th‐CLL cases were negative for antibodies against type I human T‐leukemia virus (HTLV‐I). Serum levels of sIL‐2R were significantly increased in patients with Th‐CLL with respect to controls (P < 0.02) and this increase was related to the clinical course of the disease. In fact, patients with rapidly progressive disease (mean survival, 11.6 ± 3 months) showed significantly higher concentrations of sIL‐2R than patients with less aggressive disease (mean survival, 39.5 ± 5 months) (16,223 U/ml ± 5612 versus 1447 U/ml ± 817; P < 0.05). A significant positive correlation was found between sIL‐2R concentrations and the number of CD4‐positive cells (r = 0.64; P < 0.05). These data point to the possible use of sIL‐2R levels as a marker of active malignancy in patients with Th‐CLL. Patients with LDGL showed increased sIL‐2R values (721 U/ml ± 112) with respect to controls (334 U/ml ± 28; P < 0.005). However, the sIL‐2R levels were lower than those detected in Th‐CLL patients (P < 0.05). Among the different correlations the authors tried to establish, the only observed difference was found between serum sIL‐2R levels in the group of CD3+ LDGL patients with respect to CD3‐ LDGL cases (P < 0.05).

Clonally expanded CD3+, CD4-, CD8- cells bearing the α β or the γ δ T-cell receptor in patients with the lymphoproliferative disease of granular lymphocytes

Abstract Among 60 retrospectively assessed patients with the lymphoproliferative disease of granular lymphocytes (LDGL), lymphocytes from only 2 patients had the CD3+, CD4−, CD8− phenotype, rarely observed in normal peripheral blood lymphocytes (about 3%). In this paper we report a detailed study of lymphocytes isolated from these two patients. The cells from patients 1 had the CD3+, CD4−, CD8−, WT31−, βF1−, TCRδ1+, TiγA−, BB3+, CD7+, CD16−, CD57+ phenotype, while cells from patient 2 had a phenotype even more rarely observed on normal lymphocytes: CD3+, CD4−, CD8−, WT31+, βF1+, TCRδ1−, CD7+, CD16−, CD57+. Thus, in only the first case the cells expressed the γ δ T-cell receptor (TCR) on the membrane, while the cells from the second case had the α β TCR. Genetic studies showed that in case 1 the TCR γ gene was rearranged and the β chain gene configuration was germline; the TCR mRNA was of normal size for the γ chain, while that of the β chain was truncated. Case 2 had the β and the γ genes of the TCR rearranged, but only the α and β mRNA were expressed. In agreement with these findings, the δ chain gene of the TCR was rearranged in case 1 and was deleted in case 2. Cytotoxic activity was absent in cells from case 1 and low in case 2; in the latter, the lytic activity could be up-regulated following incubation with IL-2 or an anti-CD3 monoclonal antibody. Our study indicates that CD3+, CD4−, CD8− lymphocytes are rarely expanded in patients with LDGL. The detection of a lymphoproliferative disease of a CD3+, CD4−, CD8−, α β+ cell may contribute to a better characterization of this novel lymphocytic subpopulation.

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.

High-Risk Fludarabine-Pretreated B-Cell Chronic Lymphocytic Leukemia's High Response Rate Following Sequential DHAP and Alemtuzumab Administration Though in Absence of Molecular Remission

B-CLL patients with resistant/relapsed disease or adverse prognostic factors at presentation are suitable for alternative treatments. In the present pilot study we investigated a novel intensive chemo-immunotherapy approach for high-risk, fludarabine pretreated patients. Ten patients with resistant/relapsed, advanced stage B-CLL were included. Age was 37–60 yr (median 53). All but one had an unmutated IgVH status. The treatment schedule included debulking with two DHAP courses followed by alemtuzumab (30 mg, eight doses), followed by peripheral blood progenitor cell (PBPC) mobilization with intermediate/high-dose cyclophosphamide and by autografting after high-dose mitoxantrone+L-Pam. The DHAP-alemtuzumab combination was highly effective. Eight patients out of 10 responded to DHAP, with a single complete remission. Following alemtuzumab. the number of overall responses increased to nine, and the complete remissions to five. After alemtuzumab PB double-positive clonal CD5+/CD19+ lymphocytes dropped, with median purification rate 99.95%. Owing to poor PBPC mobilization, only five patients underwent autografting, and three of these experienced post-graft recurrence. The six patients entering complete remission were free of disease 3–23 mo after study entry, and three of them were still in remission at 3,7, and 22 mo. However, molecular evaluation regularly revealed persistence of minimal residual disease, both in all PBPC collections tested and in post-treatment follow-up samples. The use of DHAP/alemtuzumab appears useful to re-induce disease remission in relapsed/refractory. high-risk B-CLL patients. However, the addition of autograft was not usually feasible and of questionable clinical use. Other strategies should thus be considered for remission maintenance.