G. Bos

A randomized phase 3 study on the effect of thalidomide combined with adriamycin, dexamethasone, and high-dose melphalan, followed by thalidomide maintenance in patients with multiple myeloma

The phase 3 trial HOVON-50 was designed to evaluate the effect of thalidomide during induction treatment and as maintenance in patients with multiple myeloma who were transplant candidates. A total of 556 patients was randomly assigned to arm A: 3 cycles of vincristine, adriamycin, and dexamethasone, or to arm B: thalidomide 200 mg orally, days 1 to 28 plus adriamycin and dexamethasone. After induction therapy and stem cell mobilization, patients were to receive high-dose melphalan, 200 mg/m(2), followed by maintenance with alpha-interferon (arm A) or thalidomide 50 mg daily (arm B). Thalidomide significantly improved overall response rate as well as quality of the response before and after high dose melphalan. Best overall response rate on protocol was 88% and 79% (P = .005), at least very good partial remission 66% and 54% (P = .005), and complete remission 31% and 23% (P = .04), respectively, in favor of the thalidomide arm. Thalidomide also significantly improved event-free survival from median 22 months to 34 months (P < .001), and prolonged progression free from median 25 months to 34 months (P < .001). Median survival was longer in the thalidomide arm, 73 versus 60 months; however, this difference was not significant (P = .77). Patients randomized to thalidomide had strongly reduced survival after relapse. This trial was registered on www.controlled-trials.com as ISRCTN06413384.

Thalidomide in induction treatment increases the very good partial response rate before and after high-dose therapy in previously untreated multiple myeloma

Thalidomide as part of initial treatment of multiple myeloma improves pre- and post-transplant response by increasing the proportion of patients achieving a very good partial response. In the prospective phase 3 HOVON-50/GMMG-HD3 trial, patients randomized to TAD (thalidomide, doxorubicin, dexamethasone) had a significantly higher response rate (at least PR) after induction compared with patients randomized to VAD (vincristine, adriamycin, dexamethasone, 72% vs. 54%, p<0.001). Complete remission (CR) and very good partial remission (VGPR) were also higher after TAD. After High Dose melphalan 200mg/m2 response was comparable in both arms, 76% and 79% respectively. However, CR plus VGPR were significantly higher in the patients randomized to TAD (49% vs. 32%, p<0.001). CTC grade 3–4 adverse events were similar in both arms.

For which patients with aggressive non-Hodgkin's lymphoma is prophylaxis for central nervous system disease mandatory?

PURPOSE Data of a multicenter study in non-Hodgkins lymphoma (NHL) by the Dutch Hovon Group were reanalyzed to assess the risk of relapse in the central nervous system (CNS) related to the international risk index for NHL. In addition we assessed the risk for CNS disease in relation to the presence of bone marrow localisation at presentation. DESIGN We focused our analysis on those patients reaching a complete remission (CR). Two hundred eighty-six patients (histological subtypes D-H Working Formulation) and with stages II-IV were analyzed. One hundred ninety-three (67%) patients reached a CR. RESULTS Relapse occurred in 78 patients of whom 10 patients with concomitant or isolated CNS disease. According to the international risk index the following observations were made: low risk (n = 38) nine out of 34 CR relapsed, none had CNS involvement; low-intermediate risk (n = 115) 27 out of 83 CR relapsed, three had CNS involvement; high-intermediate risk (n = 110) 37 out of 68 CR relapsed, six had CNS involvement; high risk (n = 22) four out of seven CR relapsed, one had CNS involvement. Two out of 10 developed isolated CNS disease and eight out of 10 patients developed CNS disease with systemic relapse. CONCLUSION Our data show that the number of CNS relapses after CR is relatively low (10 out of 193 = 5%), with an increasing incidence in the high-risk groups according to the international risk index. The occurrence of CNS relapse seems to be related to the risk of systemic relapse after CR. No subgroup could be discriminated in which prophylactic treatment would be of substantial benefit.

Negative sural nerve biopsy in neurolymphomatosis.

Abstract Patients with non-Hodgkin’s lymphoma occasionally develop widespread invasion of peripheral nerves by tumor cells or neurolymphomatosis (NL). Clinically this usually results in asymmetrical, progressive, and painful polyneuropathy. Diagnosis rests on the identification of tumor cells in peripheral nerves. To avoid false-negative biopsy findings in patients with malignant lymphomatous infiltration of peripheral nerves it has been recommended to biopsy clinically involved nerves. We present two patients with histologically confirmed NL in whom sural the nerve biopsy finding was negative despite clinical and neurophysiological evidence of involvement of the sural nerve a. The clinical features of NL are reviewed. Some patients with neurolyphomatosis have only focal or proximal involvement of nerves, requiring the biopsy of an affected part of these nerves. Magnetic resonance imaging may be useful in identifying affected nerves.

Extramedullary relapses after allogeneic non-myeloablative stem cell transplantation in multiple myeloma patients do not negatively affect treatment outcome.

Recent literature suggests that after non-myeloablative allogeneic (NMA) stem cell transplantation (SCT), the incidence of extramedullary (EM) relapse in multiple myeloma (MM) patients is increased and that these relapses have a poor prognosis. However, numbers on incidence and treatment outcome are scarce. We collected data from 54 relapsed MM patients from a total group of 172 treated with sequential autologous and allogeneic NMA SCT at seven transplantation centres. There were 43 (79.6%) systemic relapses, including 6 with concurrent EM localisation. Five patients had a local EM relapse only. Six patients relapsed with only bone involvement. Patients with deletion of chromosome 13 had a higher incidence of EM relapse (30.8 versus 5.6%, P=0.06). EM relapses were treated with donor lymphocyte infusion, radiotherapy, or chemotherapy, especially with novel agents. The response rate was 45.5%, which was not different when compared to patients without EM disease (54.1%). Overall survival and progression-free survival were not significantly different in patients with EM disease, when compared to those without EM disease. In conclusion, the incidence of relapse with EM disease following allogeneic NMA SCT was 20.4%. There was no negative impact of EM relapse on response rate, overall survival and progression-free survival.

Bortezomib before and after high-dose therapy in myeloma: long-term results from the phase III HOVON-65/GMMG-HD4 trial

The Dutch-Belgian Cooperative Trial Group for Hematology Oncology Group-65/German-speaking Myeloma Multicenter Group-HD4 (HOVON-65/GMMG-HD4) phase III trial compared bortezomib (BTZ) before and after high-dose melphalan and autologous stem cell transplantation (HDM, PAD arm) compared with classical cytotoxic agents prior and thalidomide after HDM (VAD arm) in multiple myeloma (MM) patients aged 18–65 years. Here, the long-term follow-up and data on second primary malignancies (SPM) are presented. After a median follow-up of 96 months, progression-free survival (censored at allogeneic transplantation, PFS) remained significantly prolonged in the PAD versus VAD arm (hazard ratio (HR)=0.76, 95% confidence interval (95% CI) of 0.65–0.89, P=0.001). Overall survival (OS) was similar in the PAD versus VAD arm (HR=0.89, 95% CI: 0.74–1.08, P=0.24). The incidence of SPM were similar between the two arms (7% each, P=0.73). The negative prognostic effects of the cytogenetic aberration deletion 17p13 (clone size ⩾10%) and renal impairment at baseline (serum creatinine >2 mg dl−1) on PFS and OS remained abrogated in the PAD but not VAD arm. OS from first relapse/progression was similar between the study arms (HR=1.02, P=0.85). In conclusion, the survival benefit with BTZ induction/maintenance compared with classical cytotoxic agents and thalidomide maintenance is maintained without an increased risk of SPM.

Erythropoietin induced visual hallucinations after bone marrow transplantation.

Sirs: Seizures are a known neurological side effect of treatment with recombinant human erythropoietin (rhu-EPO), which usually occur during abrupt periods of hypertension in uremic patients [3, 9]. Often these seizures are preceded by headache and visual disturbances [9]. These features resemble the clinical characteristics of the recently described posterior leukoencephalopathy syndrome (PLS). This syndrome is characterized by visual disturbances, headache, hypertension, and seizures; neuroimaging usually shows white matter abnormalities, predominantly in the occipital lobes and to a lesser extent in the parietal and paraventricular regions and in the cerebellar hemispheres. PLS is observed in a variety of diseases such as eclampsia and acute hypertensive encephalopathy and after treatment with several drugs, including cyclosporin and tacrilomus [1, 8, 10, 14]. Visual hallucinations have also been reported as a side effect of rhuEPO treatment [15]. We report an rhu-EPO treated bone marrow transplant patient who developed visual hallucinations associated with PLS. A 45-year-old woman developed non-Hodgkins lymphoma in 1987, for which she received chemotherapy. Relapses in 1989, 1993, and 1994 were treated with chemotherapy. The last relapse was treated with dexamethasone, high-dose cytosine arabinoside and cisplatin; this chemotherapy was complicated by nephrotoxicity. She then developed a myelodysplastic syndrome with monosomy of chromosome 7, probably as a late effect of chemotherapy. In May 1996 she underwent a matched unrelated bone marrow transplant but remained pancytopenic, with a severe thrombocytopenia and anemia. After this procedure she developed another episode with renal insufficiency (creatinine clearance 15 ml/min). A graft-versus-host reaction was treated with cyclosporin and prednisone. On 26 November she received a second bone marrow donation but nevertheless remained dependent on thrombocyte and erythrocyte transfusions. At that time her creatinine clearance was 20 ml/min. Following discontinuation of cyclosporin the subcutaneous administration of 4000 U rhu-EPO per day was started on 8 January 1997; the dose was lowered to 2000 U after an increase in hemocrit to 0.45 on 16 January (Table 1). Comedication consisted of prednisone, diflucan, domperidone, tramadol, cisapride, cefpodoxim and oxazepam. On 28 January she developed headache, and for the first time an elevation in blood pressure was noted (170/120 mmHg). Nifedipine was started, and the next morning (29 January) her diastolic blood pressure was lowered to 95 mmHg. Later that day her blood pressure increased again 120 mmHg diastolic. On that afternoon she saw multiple televisions and black dots although she realized these were not real. This epsiode lasted aproximately 5 min. The neurological examination shortly afterwards was normal, although at times it appeared as if she had visual field deficits. T2-weighted magnetic resonance imaging (Fig.1) showed increased signal predominantly in the occipital white matter of both hemisperes but also in the periventricular white matter and in the cerebellar hemisphere. Electroencephalography showed occipital slowing without epileptic discharges. The rhu-EPO was discontinued, and she received phenytoin and nifedipine. In the next 2 days her blood pressure varied between 130/85 and 150/120 mmHg. On 30 January she had another episode with visual hallucinations. Thereafter her blood pressure normalized, and no further episodes of visual hallucinations occurred. Results of magnetic resonance imaging 2 weeks later were normal (Fig.2). Our patient had visual hallucinations in combination with hypertension after administration of rhu-EPO, with full recovery after discontinuation of rhu-EPO. This case shows that rhu-EPO is another potential cause of the posterior leukoencephalopathy sydrome after bone marrow transplantation. The visual hallucinations and headache were the first symptoms of a threatening encephalopathy. Magnetic resonance imaging showed the characteristic lesions of PLS, and this patient, as well as those with visual hallucinations during cyclosporin treatment, show that hallucinations in these paLETTER TO THE EDITORS J Neurol (1999) 246 :614–616

A046 HOVON-50 Final Analysis of Thalidomide Combined with Adriamycin, Dexamethasone, and HDM

Patient characteristics were as follows: 27 men, 14 women; median age, 61 years (range, 41-70 years); isotype (21 IgG, 12 IgA, 6 light chain only, 2 nonsecretory); and Durie-Salmon stage (31 stage III, 8 stage II, 2 stage I). Thirty-four patients who were at least 18 months from HDT were compared with a control group that received the same induction (VAD/ZDex) and HDT but without any thalidomide maintenance at our institution. CDT treated and control groups had similar disease isotype, Durie-Salmon stage, and response to HDT after 3 months. Results: Median duration of CDT consolidation was 4 months (range, 1-6 months). Cyclophosphamide dose was reduced in 20 (49%) patients because of grade 2 neutropenia. Median thalidomide dose was 100 mg daily. Fifteen (37%) patients developed grade 1 neuropathy. Two (5%) patients withdrew because of adverse side effects. There were no incidences of febrile neutropenia or DVT. Median follow-up from HDT is 31 months (range, 8-54 months) in CDT-treated patients and 42 months (range, 19-102 months) in the control group. CDT consolidation improved depth of response to HDT. VGPR/CR rate was increased from 33% (11 patients) at 3 months following HDT to 55% (18 patients) at 12 months. No improvement in depth of response was seen in the control group. Median PFS was longer in CDT treated patients (24 months vs. 17 months control group; P = .02). Conclusion: CDT consolidation following HDT is safe and well tolerated and improves depth of response.