Walter Feremans

Arsenic Trioxide in Patients With Myelodysplastic Syndromes: A Phase II Multicenter Study

PURPOSE Evaluation of the safety and efficacy of arsenic trioxide in patients with myelodysplastic syndromes (MDS). PATIENTS AND METHODS MDS patients diagnosed according to standard French-American-British criteria received a loading dose of 0.3 mg/kg per day of arsenic trioxide for 5 days followed by a maintenance dose of 0.25 mg/kg arsenic trioxide twice weekly for 15 weeks. Patients were divided into two cohorts: lower-risk MDS (International Prognostic Scoring System risk category low or intermediate 1) and higher-risk MDS (International Prognostic Scoring System risk category intermediate 2 or high). Modified International Working Group criteria were used for response evaluation. RESULTS Of 115 patients enrolled and treated in the study, 67% of patients were transfusion dependent at baseline; median age was 68 years. Most treatment-related adverse events were mild to moderate. The overall rate of hematologic improvement (intent-to-treat) was 24 (19%) of 115, including one complete and one partial response in the higher-risk cohort. The hematologic response rates were 13 (26%) of 50 and 11 (17%) of 64 in patients with lower-risk and higher-risk MDS, respectively. Major responses were observed in all three hematologic lineages; 16% of RBC transfusion-dependent patients and 29% of platelet transfusion-dependent patients became transfusion independent. At data cut off, the median response duration was 3.4 months, with responses ongoing in nine patients. CONCLUSION Arsenic trioxide treatment consisting of an initial loading dose followed by maintenance therapy has moderate activity in MDS, inducing hematologic responses in both lower- and higher-risk patients. This activity combined with a manageable adverse effect profile warrants the additional study of arsenic trioxide, particularly in combination therapy, for the treatment of patients with MDS.

Subcutaneous panniculitis-like T-cell lymphoma: further evidence for a distinct neoplasm originating from large granular lymphocytes of T/NK phenotype

We report the case of a 20 year‐old caucasian woman who presented a primary subcutaneous panniculitis‐like T‐cell lymphoma (SPTCL) as an invasive tumor of the chest wall. Herein, the neoplastic cells were found to express a CD3+CD8+ phenotype but also displayed variably the natural killer (NK)‐associated antigens CD56 and CD57 as well as granzyme B. On cytological examination, these cells showed a large granular lymphocyte (LGL)‐like morphology with presence of azurophilic granules in their cytoplasm. Electron dense and membrane bound granules like those found in cytotoxic T lymphocytes (CTL) were also demonstrated by electron microscopy. Neither rearrangement of the T‐cell receptor subunits nor Epstein‐Barr virus (EBV) genome was observed at the molecular level. The LGL‐like features of the neoplastic cells found in this case and the presence of NK‐associated antigens provide additional support to the cytotoxic derivation of most SPTCL.

Post-transplant lymphoproliferative disorders after lung transplantation: first-line treatment with rituximab may induce complete remission.

Abstract: Background: Post‐transplant lymphoproliferative disorders (PTLD) are potentially lethal complications of solid organ transplantation. We, here, report on our experience with rituximab, an anti‐CD20 monoclonal antibody, as first‐line treatment for PTLD in six lung transplant recipients.

IgM lambda cytoplasmic crystals in three cases of immunocytoma: a clinical, cytochemical, and ultrastructural study.

Endoplasmic reticulum-associated crystals were seen in 1-10% of the bone-marrow lymphocytes and in the lymphocytes of the peripheral blood in three cases of immunocytoma. Their crystalline nature and their location in the cisternae of the rough endoplasmic reticulum was proved by ultrastructural study. IgM lambda in the crystals was demonstrated by fluorescent and peroxidase-labelled antibody methods. The crystals did not stain with the PAS reaction, suggesting that the immunoglobulin was not bound to a carbohydrate group. A defect in glucosyltransferase activity with failure to modify the immunoglobulins could explain the absence of the PAS reaction and the accumulation of immunoglobulin in crystalline before reaching the Golgi region.

Second primary tumors and immune phenomena after fludarabine or 2-chloro-2'-deoxyadenosine treatment.

The purine nucleoside analogs fludarabine and 2-chloro-2′-deoxyadenosine display substantial activity in the treatment of various chronic lymphoproliferative disorders. Their major toxicities are primarily immunosuppression and myelosuppression. The profound influence of these drugs on the immune system has raised questions as to the emergence of secondary neoplasms or auto-immune disorders after their use. Based on a literature review and on personal observations, this article reviews the potential clinical importance of these concerns.

Genetically identical twin transplantation for chronic lymphocytic leukemia

We identified 19 persons with B-cell chronic lymphocytic leukemia (CLL) who received genetically identical twin blood cell or bone marrow transplants after high-dose conditioning. Ten are alive (eight disease-free) with a median follow-up of 89 months (range, 31–171 months); 5-year relapse rate was 50% (95% confidence interval (CI), 26–73%). Estimated 5-year survival and disease-free survival were 61% (95% CI, 37–82%) and 45% (95% CI, 23–68%). In two of four patients tested at 12 and 21 months by polymerase chain reaction no evidence of residual CLL was detected post-transplant. In one recipient who relapsed at 6 years, molecular studies showed a different CLL clone from that detected pretransplant. This clone was subsequently identified in the donor suggesting transfer of occult leukemia at the time of transplant. Genetically identical twin transplants can result in long-term disease-free survival and molecular remissions, these data suggest the potential for CLL control in the absence of allogeneic graft-versus-leukemia effect. The case of leukemia transfer indicates the need for careful evaluation of donors prior to graft collection.

Bone marrow scintigraphy in breast cancer.

Bone marrow scintigrams (BMS) have been performed in 101 women with histologically proven breast cancer (36 stage IV among them at the time of the first investigation, follow-up examinations available in 41, disease evolution observed in 17). They have been compared to conventional bone scintigram (CBS) as well as to radiological, clinical, biological and follow-up data obtained in the same patients. Only three (7.4%) out of the 41 patients with radiologically or/and histologically proven skeletal metastasis had normal BMS and 33 had corresponding bone marrow scintigraphic defects (BMS ++). On the other hand, only three patients of the 32 with normal BMS had documented skeletal abnormalities. Abnormal bone marrow extension, observed in 61.4% of the patients (62/101), seems to represent a reaction of the reticulo-endothelial system to the disease dissemination - even microscopic - and, as such, to have prognostic implications. As BMS demonstrated skeletal invasion earlier or more precisely than CBS in ten cases, the technique appears of value and of interest in breast cancer management.

Dexamethasone compared to prednisolone for adults with acute lymphoblastic leukemia or lymphoblastic lymphoma: final results of the ALL-4 randomized, phase III trial of the EORTC Leukemia Group

Background Corticosteroids are a standard component of the treatment of acute lymphoblastic leukemia and lymphoblastic lymphoma. Our aim was to determine whether dexamethasone results in a better outcome than prednisolone. Design and Methods Adult patients with acute lymphoblastic leukemia or lymphoblastic lymphoma were randomized to receive, as part of their induction therapy on days 1–8 and 15–22, either dexamethasone 8 mg/m2 or prednisolone 60 mg/m2. Those who reached complete remission were given two courses of consolidation therapy with high-dose cytarabine and mitoxantrone and methotrexate and asparaginase. Subsequently patients younger than 50 years, with a suitable donor, were to undergo allogeneic stem cell transplantation, whereas the others were planned to receive either an autologous stem cell transplant or high-dose maintenance chemotherapy with prophylactic central nervous system irradiation. Randomization was done with a minimization technique. The primary endpoint was event-free survival and the analyses was conducted on an intention-to-treat basis. Results Between August 1995 and October 2003, 325 patients between 15 to 72 years of age were randomized to receive either dexamethasone (163 patients) or prednisolone (162 patients). After induction and the course of first consolidation therapy, 131 (80.4%) patients in the dexamethasone group and 124 (76.5%) in the prednisolone group achieved complete remission. No significant difference was observed between the two treatment groups with regards to 6-year event-free survival rates (±SE) which were 25.9% (3.6%) and 28.7% (3.5%) in the dexamethasone and prednisolone groups, respectively (P=0.82, hazard ratio 0.97; 95% confidence interval, 0.75–1.25). Disease-free survival after complete remission was also similar in the dexamethasone and prednisolone groups, the 6-year rates being 32.3% and 37.5%, respectively (hazard ratio 1.03; 95% confidence interval 0.76–1.40). The 6-year cumulative incidences of relapse were 49.8% and 53.5% (Gray’s test: P=0.30) while the 6-year cumulative incidences of death were 18% and 9% (Gray’s test: P=0.07). Conclusions In the ALL-4 trial in adult patients with acute lymphoblastic leukemia or lymphoblastic lymphoma, treatment with dexamethasone did not show any advantage over treatment with prednisolone.

ALPHA-INTERFERON THERAPY IN REFRACTORY ANGIOIMMUNO-BLASTIC LYMPHADENOPATHY

To the Editor: Angioimmunoblastic lymphadenopathy is a rare disorder first described by Frizzera (1) in 1974. A very extensive review of the disease was carried out in 1985 (2) . Except for cases of spontaneous remission, the clinical evolution is generally severe despite chemotherapy, with a median survival of about 18 months. Recently, the analysis of the beta chain of the T-cell receptor indicates that a monoclonal T-cell proliferation is present in more than 85% of cases of angioimmunoblastic lymphadenopathy (3, 4). We report here the case of a 67-yr-old man who presented in January 1985 with weight loss, arthralgia of the hands, night sweats, fever, cough and skin rash. 3 months later, he developed generalized lymphadenopathies, splenomegaly and purpura. His biological picture was: E.S.R.111 mm/h, W.B.C. 1486O/pl, apolyclonal hypergammaglobulinemia and a positive Coombs test. Axillary lymph-node biopsy was performed and exhibited the typical pattern of angioimmunoblastic lymphadenopathy. The histological diagnosis was confirmed by Pr. J . Diebold (Paris). A bone marrow aspiration was normal. The clinical evolution was unfavourable despite 60 mg prednisolone/d for 2 months. The patient then received a CVP chemotherapy that was accompanied by a complete clinical and biological resolution, with correction of the thrombocytopenia. After 5 cycles, a recurrence of all the constitutional symptoms required another course of chemotherapy (CHOP 6 cycles) and the patient entered a new complete remission. He remained free of symptoms with no maintenance treatment for 6 months. Then a second recurrence was characterized by fever, rash, splenomegaly, a slight axillary lymphadenopathy, presence of circulating atypical lymphocytes, but absence of thrombocytopenia, a negative Coombs test and a normal bone marrow aspiration. The disease became resistant to corticoids, cyclophosphamide and teniposide and his clinical condition rapidly worsened. Therapy with interferon alpha 2-b (Schering) 5 x lo6 I.U. SC 3 times a week was begun. After 2 wk, the lymphadenopathy, the constitutional symptoms and the splenomegaly had disappeared. His general condition improved but the platelet count dropped gradually to 30 OOO/pI. Interferon therapy was interrupted because of pancytopenia after 2 months. At this time, bone-marrow aspiration showed an aplastic pattern without immunoblasts or other abnormal cells. The platelet count increased after 6 wk without treatment and the patient was again in clinical remission. The mode of action of alpha-interferon in haematologic malignancies is composite: direct antiproliferative effects, immunomodulatory activities and inhibition of oncogene expression (5). The role of antiviral activity remain to be elucidated in light of virological investigations focused on HTLV-I, HTLV-I1 and the new isolate HBLV (6). In the present case, a hypothetical mechanism centred on oncogene expression seems to us to be attractive. Indeed, the use of low doses of interferon does not favour direct antiproliferative activity. Moreover, the modulation of c-fos oncogene expression by alphainterferon is well known in hairy-cell leukaemia (7) and we found very striking the recent study (8) concerning abnormalities of N-ras and c-fos oncogenes expression in angioimmunoblastic lymphadenopathy, which may be corrected by cyclophosphamide.

Phase II trial of CPT-11 in myelodysplastic syndromes with excess of marrow blasts

CPT-11 is an antineoplastic agent which acts as a specific inhibitor of DNA topisomerase 1 and has a broad spectrum of activity in solid tumors. Very few studies have evaluated the activity of CPT-11 in hematological malignancies. We conducted a phase II trial of CPT-11 in 26 patients with high-risk MDS (RAEB 1: n = 4; RAEB 2: n = 9; MDS having progressed to AML: n = 10; CMML: n = 3) who could not receive anthracycline/cytarabine intensive chemotherapy. Induction therapy consisted of four courses of CPT-11 given intravenously at 200 mg/m2 every 2 weeks. Patient characteristics were: median age, 71 (range 51–77); sex, (M/F), 21/5, median % marrow blasts cells, 13.5 (range 7–52). Cytogenetics according to IPSS were: low-risk n = 13, intermediate-risk n = 6, high-risk n = 3, failure or not done n = 4. Six patients stopped treatment after only one or two courses of CPT-11 due to severe infection (n = 2), progressive disease (n = 3), acute lysis syndrome with renal failure (n = 1). In the 20 patients who received at least three cycles of CPT-11, complete remission was achieved in one case, partial remission in four cases, and hematological improvement in three cases with an overall response rate of 33% in the 26 patients. Duration of response was short (median 4 months, range 1–6 months) and median survival was 8 months (range 1–23 months). Digestive toxicity (diarrhea) occurred in 26/89 (29%) courses, but was mild (grade 1, 20% courses; grade 2 or 3, 9% courses). Hematological toxicity was difficult to assess in non-responders because of initial pancytopenia, but all the patients who responded had grade 3/4 hematological toxicity associated with grade ⩾2 infection requiring hospitalization in 18% of the courses. No other major toxicity was observed. Thus CPT-11 has an interesting activity in MDS with excess of blasts; toxicity is easily managed and most patients can be treated in the out-clinic setting. These results suggest that further evaluation of CPT-11 in MDS is warranted.