A rapidly destructive amyloid arthropathy associated with myeloma.

Amyloid arthropathy is a known complication of multiple myeloma. Clinically, it can be confused with RA with a symmetrical swelling of small and large joints. However, radiologically it can produce bone cysts, but it is said to be distinguished from RA by preservation or even widening of the joint space. We describe a 53-year-old man with myeloma who developed a rapidly destructive rare form of amyloid arthropathy within months of his hematologic diagnosis. The myeloma was aggressive and only partially responsive to treatment; this may have influenced the severity of the joint disease. The arthritis had minimal improvement with the chemotherapy. Intraarticular injections with depot corticosteroids gave some symptomatic relief. Two other unusual features were an unexplained inflammatory arthritis of an elbow with associated soft tissue calcification. If other causes are excluded, amyloidosis may account for a more destructive arthritis than is generally recognized.

Autoimmune haemolysis in patients with B-CLL treated with chlorodeoxyadenosine (CDA).

We have treated 19 B-chronic lymphocytic leukaemia (B-CLL) patients with CDA (Leustat, Janssen-Cilag). Four patients developed severe autoimmune haemolytic anaemia, and 2 of these had severe reticulocytopenia due to red cell aplasia/hypoplasia. Two patients died as a complication of the haemolysis one during the primary episode, with a clinical course suggestive of transfusion associated graft-versus-host disease (taGVHD), and one following a relapse of haemolysis. The onset of haemolysis occurs within 4 cycles of CDA therapy and is temporally related to the T-lymphocyte nadir induced by CDA. The presence of a positive DAT prior to therapy in 3 of 4 patients developing haemolysis suggests that the CDA induced T-lymphocytopenia may exacerbate the tendency of certain CLL patients to autoimmune haemolysis.

Severe intravascular hemolysis due to autoantibodies stimulated by blood transfusion.

Autoantibodies may cause severe hemolytic anemia, but only rarely are they the cause of a hemolytic transfusion reaction due to the destruction of transfused allogeneic blood. In two patients, autoantibody was detected shortly after blood transfusion. The first case was a D-negative patient who produced an autoanti-Ce and subsequently developed hemoglobinuria and hyperbilirubinemia. The second case was a patient who developed an autoanti-Wrb that caused severe hemolysis that resulted in death.

Effect of anti-APO1 on spontaneous apoptosis of B cells in chronic lymphocytic leukaemia: the role of bcl-2 and interleukin 4.

The cell surface protein apolipoprotein 1 (APO1) is expressed on various cell types including malignant lymphoid cells. Triggering of APO1 protein with antibody (Ab) induces apoptosis in APO1-expressing cells. We examined the effect of anti (alpha) APO1 Ab on spontaneous apoptosis (SA) and bcl-2 expression in B cell chronic lymphocytic leukaemia (B-CLL) in vitro. We also investigated the anti-apoptotic activity of interleukin 4 (IL4) on the aAPO1-induced apoptosis in B-CLL cells. Although expression of APO1 on B-CLL cells was not detectable by immunofluorescence, alpha APO1 Ab induced apoptosis in these cells. At 24 hours in culture the number of apoptotic cells was increased by a mean percentage (%) of 27% (range: 21-38) in only half of the cases studied. But in all twelve cases studied, at 48 hours alpha APO1 increased SA by a mean of 72% (range: 26-114) (P < .001) and at 72 hours, the mean % increase was 69% (range: 31-96) in 6/7 cases (P < .001). This effect was alpha APO1 concentration dependent. Interleukin 4 significantly protected B-CLL cells against alpha APO1-induced apoptosis by a mean of 53% (range: 28-76) (P < .001). This protection was specific to IL4 and it was significantly reduced or abolished with alpha IL4 Ab. Expression of bcl-2 protein in untreated cultures was not significantly different from that of the alpha APO1-treated cells; the mean equivalent of soluble fluorochrome (MESF) (range) was 4.9 (3.0-6.8) and 5.2 (3.5-6.0) respectively (P > 0.2). In fresh B-CLL cells the MESF (range) was 4.5 (2.4-6.6). Thus alpha APO1 Ab induced apoptosis in B-CLL cells by a pathway that is independent of bcl-2 expression and partially blocked by IL4.

Fludarabine-related autoimmune haemolytic anaemia in patients with chronic lymphocytic leukaemia.

We have treated 52 patients with chronic lymphocytic leukaemia (CLL) with fludarabine; 12 developed severe autoimmune haemolysis. Only three had a previous history of haemolytic anaemia. Six out of eight patients retreated with fludarabine after control of their haemolysis developed an exacerbation of the haemolytic anaemia. The cause of autoimmune phenomena in CLL is not known, but our findings reinforce the view that they are caused by a disturbance in immunoregulatory T cells. Fludarabine is a known suppressor of T-cell function.

Granisetron in the prevention of irradiation-induced emesis.

A double-blind double-dummy, comparative study was carried out in 30 patients receiving highly emetogenic fast dose rate, single fraction total body irradiation prior to bone marrow transplantation. Patients were randomised into one of two groups, receiving either granisetron, a specific 5-HT3 antagonist or a combination of metoclopramide, dexamethasone phosphate and lorazepam to assess the comparative efficacy of the two regimens in the control of irradiation-induced nausea and vomiting. After 24 h eight patient (53%) treated with granisetron showed a complete response compared with two patients (13%) in the comparator group. The control of vomiting by granisetron, over both 24 h and 7-day periods (P = 0.001 and P = 0.004), was significantly better than that seen with the comparator and required significantly fewer rescue doses. The safety profiles in the two groups appeared similar, with the exception that granisetron produced less drowsiness than the comparator.

Interleukin-5 (IL-5) increases spontaneous apoptosis of B-cell chronic lymphocytic leukemia cells in vitro independently of bcl-2 expression and is inhibited by IL-4.

During hematopoiesis, viability factors that suppress apoptosis are required throughout the differentiation process. Some of these factors may also function as growth factors. Interleukin-5 (IL-5) is recognized as a growth factor in hematopoiesis. We examined the involvement of IL-5 as a viability factor of B-CLL in vitro. In 13 B-CLL cases studied, IL-5 at 20 U/mL increased spontaneous apoptosis by a mean percentage of 53% (range, 20% to 129%) (P < .05) after 2 days in culture. On the third day, the mean percentage increase was 37% (range, 18% to 50%). In all cases, IL-4 protected B-CLL cells against IL-5-induced apoptosis by a mean percentage of 47% (range, 18% to 81%) (P < .001). This protection was specific to IL-4 and it was reduced with anti-IL-4 antibody. In addition, expression of bcl-2 protein in untreated cultures was not significantly different from that of the IL-5-treated cells; mean equivalent of soluble fluorochrome (MESF) was 5.2 (range, 3.0 to 6.8) and 4.9 (range, 3.0 to 6.3), respectively (P > .2). In freshly isolated B-CLL cells, the MESF was 4.5 (range, 2.4 to 6.6). These results show that IL-5 induced apoptosis in B-CLL cells by a pathway that is independent of bcl-2 expression. IL-4 partially protects against this effect.

Understanding the mechanism of cure of acute myeloid leukemia by allogeneic bone marrow transplantation: toward the application of interleukin-2 in autologous bone marrow transplantation.

Analysis of the results of different methods of post remission therapy in acute myeloid leukemia (AML) has been used to study their impact on outcome, with a particular emphasis on antileukemic effects by contrasting the risk of relapse. We have compared consolidation chemotherapy (CT), autologous bone marrow transplantation (ABMT) with and without subsequent interleukin-2 (IL-2) and allogeneic bone marrow transplantation (BMT). Additionally we have studied the immunological consequences of each of these maneuvers with particular regard to the cellular components having proven or suspected antileukemic properties and the secondary cytokines released by these cells in vitro and in vivo.

Donor-specific bone marrow infusion after orthotopic liver transplantation.

Donor-specific bone marrow infusion after organ grafting can induce tolerance in animals. In this randomised controlled study we show it has no benefit in patients undergoing liver transplantation. Of 25 patients, 9 received bone marrow 5 days after a 10 day course of antithymocyte globulin. Immunosuppression was maintained with cyclosporin only. An average of 3.0 rejection episodes per patient was seen in the bone marrow group compared to 3.1 in the controls. Chimerism was not found in peripheral blood or bone marrow of recipients using erythrocyte antigen markers, PCR for donor class II DNA or Y-probe in-situ hybridisation in one female recipient of male liver and bone marrow.

Incidence of cataracts after single fraction total body irradiation: the role of steroids and graft versus host disease.

Eighty-eight patients who received single fraction total body irradiation (sfTBI) as part of their conditioning for allogeneic BMT have been evaluated for the risk of cataract formation. Thirty-eight (43%) have developed cataracts; 11 required surgery. With 9.5-13.6 years follow-up (median 10.7 years), all 12 recipients of unmanipulated marrow allografts have developed cataracts; the actuarial risk of needing surgery was 32 (+/- 18%, 95% confidence intervals (CI)). Ten of these 12 required high-dose steroids (prednisolone > 1 mg/kg/day) for the treatment of GVHD. Seventy-six patients received T cell-depleted allografts; 14 of 76 required post-transplant immunosuppression with high-dose steroids. With 1-9.4 years follow-up (median 5 years), the actuarial risk of cataract formation in T cell-depleted allograft recipients is 72% (+/- 52% CI), the actuarial risk for needing surgery is 20% (+/- 9% CI). Recipients of sfTBI and non-T cell-depleted allografts had a significantly greater risk of developing cataracts (p = 0.003, long rank test) and of needing surgery (p < 0.05, log rank test) than patients receiving T cell-depleted BM. Cataracts occurred more frequently in patients requiring post-transplant immunosuppression with steroids (relative risk 2.12, p < 0.01 log rank test).

Progress in the diagnosis and management of aspergillosis in bone marrow transplantation: 13 years' experience.

Over 13 years, we have seen 16 cases of proven invasive aspergillosis in 446 bone marrow transplant recipients, an incidence of 3.6%. The incidence of infection is low in patients with uncomplicated allogeneic or autologous bone-marrow transplants (< 2% and 0, respectively). Of the 16 episodes following transplantation, 10 occurred in patients with late transplant complications who were no longer in protective isolation. In patients who had focal pulmonary lesions (as diagnosed by computed tomographic scanning), culture of bronchoalveolar lavage (BAL) fluid was not an effective diagnostic procedure. In diffuse pulmonary disease due to Aspergillus, culture of BAL fluid had a sensitivity of 100%. Aspergillus species were isolated from an additional six patients who had no evidence of invasive aspergillosis. Graft rejection was a significant predisposing factor for the development of invasive aspergillosis (P < .001, log-rank test), and in our hospital, these patients now receive intravenous amphotericin B as prophylaxis. None of the six patients whose chest roentgenograms showed abnormalities before transplantation and who underwent surgical resection as part of the treatment for invasive aspergillosis developed recurrent infection.

Plasma soluble interleukin 2 receptor levels in patients with malignant lymphoma are correlated with disease activity but not cellular immunosuppression.

Studies of peripheral blood lymphocytes (PBL) and plasma from patients with malignant lymphoma [Hodgkin's disease (HD) and non Hodgkin's lymphoma (NHL)] show that plasma soluble interleukin 2 receptor (sIL2R) levels are closely linked with disease status [normal volunteers (n = 15) 402 +/- 158 u/ml; patients with Hodgkin's disease in remission (n = 4) 525 +/- 195 u/ml or with active disease (n = 11) 3026 +/- 1602 u/ml (p < 0.001); patients with non Hodgkin's lymphoma in remission (n = 6) 462 +/- 202 u/ml, active disease (n = 15) 2713 +/- 1755 u/ml, (p < 0.001)] but no correlation between sIL2R and the inhibition of interleukin 2 (IL2) generated cytotoxicity for the cell line K562. In only 1 of 15 patient plasma samples studied was there a dose dependent inhibition of IL2 generated cell killing. In a further patient, IL2 generated K562 killing was inhibited at all doses (500-3000 brmp units/ml); treatment of this plasma with anti-Interleukin 4 (alpha IL4) had no effect on the potent inhibitory activity of the plasma. Plasma sIL2R levels were markedly elevated in patients receiving IL2 in vivo (pre treatment 520 +/- 170 IU/ml, during treatment 5578 +/- 2564 IU/ml, p = 0.05). The aetiology of immunosuppression in patients with lymphoma appears to be multi-factorial; although sIL2R correlates with disease activity it does not appear to directly mediate immunosuppression in most patients with malignant lymphoma.

Immunotherapy with interleukin 2 after ABMT in AML.

Myeloablative chemo (+/- radio) therapy and rescue with ABMT has been used as final consolidation therapy in 18 patients with AML in first remission. In seven (6 autologous, 1 syngeneic) marrow reinfusion was followed by iv IL-2. One patient, who commenced IL-2 4 days after BMT, died from pulmonary oedema due to the capillary leak syndrome. Thereafter, treatment with IL-2 was delayed until the platelet count reached 30 x 10(9)/l. All patients developed reversible hypotension (treated with infusion of colloid), but treatment was otherwise well tolerated. With 21-58 months (median 32 months) from the time of ABMT there has been one relapse (actuarial risk 17%, 95% confidence intervals (CI) 3-31%). The disease-free survival is 71% (95% CI 38-100%). Eleven patients with comparable remission induction and consolidation therapy, and an identical interval between diagnosis and ABMT (5-11 months, median 6 months) received an autograft without immunotherapy. With 24-45 months (median 29 months) follow-up the actuarial disease-free survival is 36% (95% CI 8-64%), the actuarial relapse risk is 54% (95% CI 18-90%). We conclude that immunotherapy given after ABMT to patients with AML in first remission when the platelet count exceeds 30 x 10(9)/l is safe and may induce an immunological environment which results in the elimination of residual leukaemia.

Failure of purged autologous bone marrow transplantation in high risk acute lymphoblastic leukaemia in first complete remission.

Patients in first remission of acute lymphoblastic leukaemia (ALL) considered to be at high risk of relapse were offered autologous bone marrow transplantation (ABMT) using purged marrow as a therapeutic alternative to cranial irradiation and maintenance chemotherapy. Twenty-seven bone marrows taken in remission, were purged using monoclonal antibodies (anti CD7 for T lineage and anti CD10 and/or anti CD19 for B lineage leukaemias) plus rabbit complement. Retrospective analysis of 19 purged marrows by immunophenotyping or immunoglobulin gene rearrangement studies demonstrated no evidence of disease. Engraftment was seen in 26 of the patients. No correlation was found between the numbers of infused nucleated cells or colony forming units-granulocyte-macrophage (CFU-GM) and subsequent engraftment kinetics. The actuarial disease-free survival (DFS) is 32% at 7 years (median follow-up 3.4 years). There were two transplant related deaths (actuarial risk 8%); the main cause of treatment failure has been disease recurrence with an overall actuarial risk of 67%; 76% for T-ALL (five of nine), 62% for common ALL (five of 10), two of five pre B and none of three patients with B-ALL. In these 27 high risk patients in vitro purging of remission marrow as part of ABMT appears not to improve patient outcome, although confirmation of this would require a randomized trial.