Primary effusion lymphoma in two HIV-negative patients successfully treated with pleurodesis as first-line therapy.

Primary effusion lymphoma (PEL) is a rare non-Hodgkin's lymphoma (NHL) mostly occurring in HIV-positive patients. It is characterized by the development of effusion in one or more body cavities, with no tumor masses and a positive human herpes virus-8 (HHV8) status. It has a poor survival profile and no optimal treatment is yet defined. We report two HIV-negative, HHV8-positive patients with PEL of the pleural cavity who achieved a durable remission after pleurodesis with bleomycin and no systemic therapy. We also perform a review of the relevant literature regarding the clinical data, treatment, and survival of PEL in HIV-negative patients.

Rituximab monotherapy is highly effective in splenic marginal zone lymphoma.

Splenectomy has traditionally been considered as a standard first line treatment for splenic marginal zone lymphoma (SMZL) conferring a survival advantage over chemotherapy. However it carries significant complications, especially in elderly patients. The purpose of this retrospective study was to report our experience on the efficacy of Rituximab as first line treatment in 16 consecutive SMZL patients, diagnosed in our department. The diagnosis was established using standard criteria. Patients' median age was 57 years (range, 48-78). Prior to treatment initiation all patients had splenomegaly, nine had anemia, five lymphocytosis, five neutropenia and six thrombocytopenia. Rituximab was administered at a dose of 375 mg/m2/week for 6 consecutive weeks. The overall response rate was 100%. After treatment, all patients had a complete resolution of splenomegaly along with restoration of their blood counts. Eleven patients (69%) achieved a CR, three (19%) unconfirmed CR and two (12%) a PR. Among the complete responders seven patients had also a molecular remission. The median time to clinical response was 3 weeks (range, 2-6). Rituximab maintenance was given to 12 patients. Eleven of them had no evidence of disease progression after a median follow-up time of 28.5 months (range, 14-36), while two out of four patients who did not receive maintenance, relapsed 7 and 24 months after the completion of induction treatment. Median follow-up time for the entire series was 29.5 months (range, 15-81). No deaths were recorded during the follow-up period. Therapy was well tolerated. The present study demonstrates that rituximab is an effective treatment for SMZL and could be considered as a substitute or alternative to splenectomy.

beta(2)-microglobulin in Hodgkin's lymphoma: prognostic significance in patients treated with ABVD or equivalent regimens.

PURPOSE: Serum beta-2 microglobulin (sbeta(2)m) is an established prognostic factor for several lymphoproliferative disorders. Because its significance in Hodgkin's lymphoma (HL) is controversial, we determined sbeta(2)m levels in pretreatment serum samples of patients with HL in order to elucidate its prognostic value in this condition. PATIENTS AND METHODS: Pretreatment sbeta(2)m levels were determined in 379 HL patients who were treated with ABVD or equivalent regimens with or without radiotherapy (RT), using a radioimmunoassay (upper normal limit 2.4 mg/l). Sbeta(2)m levels were correlated with several clinical and laboratory parameters. RESULTS: Elevated sbeta(2)m levels were detected in 138/379 (36%) patients and correlated with all clinical and laboratory baseline features except gender, lung involvement and mediastinal bulk. They also correlated with serum soluble CD30 and interleukin-10 levels. The 8-year failure-free survival (FFS) was 78 -/+ 4% for patients with normal versus 65 -/+ 7% for patients with elevated sbeta(2)m levels (p=0.003). The corresponding rates among early-stage patients were 83 -/+ 53% versus 71 -/+ 9% (p=0.003), while for advanced stages they were 70 -/+ 6% versus 64 -/+ 8% (p=0.54). In multivariate analysis of the whole patient population elevation of sbeta(2)m levels was not predictive of FFS, but it was strongly predictive among early-stage patients. The 8-year overall survival (OS) rates were 91 -/+ 3% for patients with normal versus 59 -/+ 11% (p <0,0001) for patients with elevated sbeta(2)m levels, while unrelated mortality at 8 years was 1 -/+ 1% versus 27 -/+ 12% (p<0.0001). CONCLUSION: Our data suggest that sbeta(2)m levels may be a potent prognostic factor for FFS in patients with early stage HL treated with ABVD and equivalent regimens. Their effect on OS is confounded by the higher unrelated mortality in patients with elevated baseline sbeta(2)m levels, probably due to the strong association between sbeta(2)m and older age.

Retinoblastoma gene product and P21 (WAF1, CIP1) protein expression in non Hodgkin's lymphomas: a multivariate survival analysis.

We evaluated immunohistochemically the expression of two negative regulators of the cell cycle, namely retinoblastoma gene product (pRb) and WAF1/Cip1 gene product (p21), in paraffin sections from 93 patients with non-Hodgkin's lymphomas (NHL) and related it to clinicopathological parameters, proliferative fraction, p53 expression and survival. Patients were followed until death (n=33) or for an average of 52 months (60-160). Rb labelling index (LI) increased with malignancy grade and proliferative activity but was unrelated to other clinicopathological parameters. In 33% of cases, especially those of the aggressive groups, we observed diminished pRb expression (i.e. low pRb/Ki-67 ratio). p21 expression on the other hand correlated only with histological grade, Rb LI and p53 LI. In multivariate analysis, Rb LI was a negative predictor of disease-free survival but was linked to a higher probability of complete response. However, diminished pRb expression as well as p21 expression were not statistically significant prognostic indicators. Our results suggest that pRb as a cell cycle related molecule may play an important role in determining prognosis and therapeutic response in NHL patients.

Primary lung involvement in Waldenström's macroglobulinaemia: report of two cases and review of the literature.

Pulmonary involvement in Waldenström's macroglobulinaemia (WM) occurs in 3-5% of cases, but lung involvement without bone marrow infiltration is extremely rare. We report 2 patients who presented with bilateral consolidations on chest X-ray and non-specific symptoms and were treated for a long period of time for pulmonary infections until the diagnosis was made by open lung biopsy. Both patients presented high monoclonal IgM in the serum and one also had blood lymphoplasmacytosis. Trephine bone biopsy and bone marrow smears were normal and there was no other site of involvement. Along with the presentation of our patients, we review the literature, discuss some of the possible underlying mechanisms and raise the attention of clinicians to this rare manifestation of the disease.

Serum interleukin-10 levels are an independent prognostic factor for patients with Hodgkin's lymphoma.

BACKGROUND AND OBJECTIVES: Interleukin-10 (IL-10) is a pleiotropic cytokine which increases bcl-2 levels and protects cells from steroid or doxorubicin-induced apoptosis. Hodgkin and Reed-Sternberg (HRS) cells bear functional IL-10 receptors. Thus serum IL-10 (sIL-10) might inhibit apoptosis in HRS cells, which could occur as a result of either chemotherapy or the crippled immunoglobulin genes. DESIGN AND METHODS: We determined sIL-10 levels in 122 patients with Hodgkin's lymphoma (HL), treated with ABVD or equivalent regimens with or without radiotherapy, and correlated them with presenting clinical and laboratory features, as well as failure-free survival (FFS) and overall survival. RESULTS: Elevated sIL-10 levels ( > or = 10 pg/mL) were detected in 55 patients (45%), and were correlated with advanced stage and elevated serum b2-microglobulin levels. At 7 years FFS was 85% vs. 63% for patients with normal vs. elevated sIL-10 levels, respectively (p=0.01); overall survival was 97% vs. 73% (p=0.005). Multivariate analysis with Cox's proportional hazards model demonstrated that elevated sIL-10 levels were the strongest independent predictor of FFS, and were also associated with inferior overall survival. INTERPRETATION AND CONCLUSIONS: We conclude that sIL-10 levels are elevated in 45% of patients with HL, and are associated with inferior FFS and overall survival, independently of other established prognostic factors.

Waldenström's macroglobulinemia: clinical course and prognostic factors in 60 patients. Experience from a single hematology unit.

Waldenström's macroglobulinemia (WM) is a lymphoplasmacytic lymphoma characterized by the presence in patients' serum of an IgM monoclonal component. We report on our experience with 60 WM patients, focusing on their clinical findings, response to treatment, and the possible identification of prognostic factors. Of these patients, 70% presented with fatigue, and lymphadenopathy was observed in 22%, splenomegaly in 18%, hepatomegaly in 13%, and extranodal site of involvement in 6%. Bleeding tendency was seen in 17%, infections in 17%, hyperviscosity syndrome in 12%, and cardiac failure in 25% of the patients. The median of IgM levels was 30 g/l with hypoalbuminemia in 20% of cases, hypogammaglobulinemia in 27%, polyclonal hypergammaglobulinemia in 15%, kappa light-chain restriction in 78%, and Bence-Jones proteinuria in 54%. Anemia was frequent (85%), followed by leukocytosis (18%), lymphocytosis (12%), leukopenia (10%), and thrombocytopenia (10%). Cryoglobulinemia and autoimmune hemolytic anemia were encountered in 5%. In all cases but two, bone marrow was involved. Of 50 patients initially treated with intermittent oral chlorambucil, 46 (92%) responded. Median overall survival was 108 months. Factors associated with adverse prognosis were age > or =65 years (p=0.06), presence of lymphadenopathy (p=0.06), bone marrow infiltration > or =50% (p=0.007), international prognostic index (IPI) > or =3 (p=0.0001), and Morel's scoring system (p=0.04). Concluding, we found in this series of WM patients that chlorambucil is an effective treatment and that the parameters of age, lymphadenopathy, percentage of bone marrow infiltration, IPI, and Morel's scoring system carry prognostic significance.

Prognostic factors in advanced stage Hodgkin's lymphoma: the significance of the number of involved anatomic sites.

BACKGROUND: Advanced Hodgkin's lymphoma (HL) is curable by conventional chemotherapy in 60--70% of patients. The pretreatment identification of a sizeable subgroup of patients with sufficiently low failure-free survival (FFS) to be eligible for investigational treatment is necessary. OBJECTIVES: To determine the prognostic significance of the number of involved sites (NIS) in patients with advanced HL and its relationship to the International Prognostic Score (IPS). METHODS: A retrospective review of patients with advanced HL, defined as Ann Arbor stage (AAS) IB, IIB, III or IV, treated with anthracycline-based regimens. The end-point was FFS. RESULTS: We identified 277 patients with a median age of 32 yr (14--78), 57% of whom were males. AAS was I in 4% of patients, II in 29%, III in 38% and IV in 29%. B-symptoms were recorded in 81%. Most patients had nodular sclerosis (64%) and mixed cellularity (26%) histology. IPS was greater-than-or-equals 3 in 44% of 242 evaluable patients. The NIS was greater-than-or-equals 5 in 32% of the patients and 20% of all patients had both greater-than-or-equals 5 involved sites and IPS greater-than-or-equals 3. The 10-yr FFS was 67%, being 76% vs. 50% for patients with less-than-or-equals 4 vs. greater-than-or-equals 5 involved sites (P < 0.0001). The NIS (greater-than-or-equal 5), AAS IV and anemia were independent predictors of FFS in multivariate analysis. The NIS remained significant along with IPS, when the latter was included in the analysis. Patients with greater-than-or-equals 5 involved sites and IPS greater-than-or-equals 3 had 10-yr FFS overall, and relapse-free survival of 41%, 45% and 49%, respectively. CONCLUSIONS: The NIS was associated with FFS in advanced HL, was independent of IPS, and led to the identification of a sizeable subgroup of patients with 10-yr FFS of approximately 40%. This factor should be evaluated during the development of prognostic systems.

EBVD combination chemotherapy plus low dose involved field radiation is a highly effective treatment modality for early stage Hodgkin's disease.

To evaluate the efficacy of EBVD combination chemotherapy followed by low dose (LD) involved field (IF) radiation therapy (RT) in patients with clinical stage (CS) I-IIA Hodgkin's disease (HD), we analyzed 148 patients treated in our Unit from March 1988 to November 1995. EBVD consisted of Epirubicine 40 mg/m2, Bleomycin 10 mg/m2, Vinblastine 6 mg/m2 and Dacarbazine 300 mg. All drugs were administered i.v. at days 1 and 15, every 4 weeks, for a total of 4-6 cycles. LDIF RT (24-32 Gy) was scheduled for patients with complete response (CR) or >90% reduction of tumor load, after EBVD. Patients with stable or progressive disease (SD, PD) after EBVDx3 or poor compliance to the regimen received mantle or inverted Y RT at standard dose. The median follow-up of patients currently alive was 71.5 months. 129 patients achieved a CR after EBVD and 10 a >90% reduction of tumor load, for a post-CT response rate of 94%. Eight patients had SD after EBVDx3 and one had a partial response with poor compliance. All 9 patients received mantle or inverted Y RT and 8/9 achieved a CR. Nine patients relapsed at a median of 7 months from the end of treatment. At 10 years, FFS was 90% and overall survival 95%. Six patients have died so far; 5 of HD and one of stroke. One patient developed a diffuse large cell lymphoma 48 months after the diagnosis of HD. We conclude that EBVD followed by LDIF RT is a highly effective regimen for patients with CS I-IIA HD. Longer follow up is required to assess the risk of secondary malignancies, especially solid tumors.

Correction of disease related anaemia of B-chronic lymphoproliferative disorders by recombinant human erythropoietin: maintenance is necessary to sustain response.

Thirty three B-chronic lymphoproliferative disorder (B-CLD) patients [22 with B-chronic lymphocytic leukemia (B-CLL), 5 with small lymphocytic lymphoma (SLL) and 6 with lymphoplasmacytic lymphoma (LPL)] with anaemia (Ht <32%) of no other cause but their disease, received recombinant human erythropoietin (r-HuEPO). The treatment protocol provided r-HuEPO in a dose of 150 U/kg s.c. thrice weekly for 3 mo. After 1.5 mo of r-HuEPO administration, if response was not satisfactory, r-HuEPO dose escalation was utilised by giving incremental doses of 50 U/kg more than the previous dose up to a maximum dose of 300 U/kg tiw. After maximal response, half of the responding patients discontinued therapy, while the other half received maintenance therapy at a dose of 150 U/kg s.c./w. Oral iron was given throughout the study. Pretreatment EPO levels were determined in all patients. A complete response (CR) was defined when Ht was >38% and a partial response (PR) when there was an increase of the Ht >6% from the initial value was achieved. Sixteen of the 22 B-CLL patients had Rai stage III disease and 6 stage IV, with a median duration of anaemia 27 months (6-38); twelve of them were receiving chlorambucil while the rest were on no treatment. Of the SLL and LPL group, 4 patients had Ann Arbor stage III disease and 7 stage IV with a median duration of anaemia 24 months (5-36); 8 patients were on chlorambucil. Complete response was achieved in 50% of the B-CLL group and 54% of the SLL and LPL group, with an overall response rate of 77% and 81% respectively. All patients on maintenance therapy had a continuous response, while all patients, in whom rHuEPO was discontinued, relapsed. No correlation was found between patients: with low or high pretreatment serum EPO levels; those receiving concomitant therapy or not; those with B-symptoms or not; those with a non-diffuse or diffuse bone marrow infiltration pattern; and with splenomegaly or not. Life quality was significantly improved and no major side effects were encountered. We conclude from our study that r-HuEPO is very effective in correcting disease-related anaemia in B-CLD, resulting in down-staging of Rai stage III patients and that maintenance therapy is necessary. Whether the correction of anaemia improves patients' overall survival, still remains to be seen.

Adhesion molecules in B-chronic lymphoproliferative disorders.

In B-chronic lymphoproliferative disorders (B-CLD) adhesion molecules (AM) have been investigated in order to explain the variable biologic behavior and dissemination patterns and to assess their contribution to the differential diagnosis and prognosis of these diseases. The main AM studied either by immunohistochemistry on lymph node sections or by flow cytometry in blood and bone marrow specimens are L-selectin, CD11a/CD18 (LFA-1), CD54 (ICAM-1), CD44 (HCAM), CD11c/CD18 (gp150/95), and CD49d/CD29 (VLA-4). Among B-CLD, hairy-cell leukemia (HCL) and follicular lymphoma (FL) show a uniform AM expression pattern. Thus, HCL is characterized by high CD54, CD44, VLA-4, CD11c, and CD18 and by low or absent CD11a and L-selectin, whereas FL confined to the lymph nodes is characterized by high CD11a, CD18, and CD54 expression. Diffuse growth and dissemination of FL is associated with alteration in the AM profile. Mantle-cell lymphoma (MCL) seems to be characterized by low or absent L-selectin and CD11c and high CD54 expression, especially compared with B-chronic lymphocytic leukemia (B-CLL). B-CLL is the most heterogeneous among all B-CLD with respect to AM expression. In general, low LFA-1 and CD54, high L-selectin and CD44, and variable CD11c characterize B-CLL. Cases with splenomegaly as their prominent feature bear high CD11a, CD18, CD29, and CD11c on the surface of the leukemic cells. Small lymphocytic lymphoma (SLL) shares the same AM phenotype with B-CLL, with the possible exception of LFA-1, which is strongly expressed on SLL cells. LFA-1 and CD54 are more frequently positive in lymphoplasmacytic lymphoma (LPL) as compared with B-CLL. Splenic lymphoma with villous lymphocytes differs from B-CLL by its high LFA-1, VLA-4, and CD54 and low L-selectin expression, whereas its high LFA-1 positivity can differentiate it from HCL. Surface and soluble AM have been investigated as possible prognostic markers in these diseases. Conflicting data exist concerning the prognostic significance of surface AM. However, high soluble (s)CD44 and CD54 levels in B-CLL and non-Hodgkin's lymphomas (NHL) are considered as adverse prognostic factors.