Lucille Wood

Intravenous gammaglobulin has no advantages over oral corticosteroids as primary therapy for adults with immune thrombocytopenia: A prospective randomized clinical trial

Symptomatic immune thrombocytopenia in adults is potentially lethal, and, when conventionally treated with oral corticosteroid agents, approximately two thirds of patients will have some response in platelet count, but this is seldom durable. Since cytotoxic drugs are of limited benefit at this stage, splenectomy becomes necessary in 70% of patients. Intravenous gammaglobulin has been advocated as an alternative to prednisone as the primary form of treatment. A prospective, randomized comparison was carried out between oral prednisone (1 mg/kg/day; group 1; n = 17), high-dose intravenous gammaglobulin (400 mg/kg on days 1 through 5; group 2; n = 13), or a combination of both agents given on the same schedule (group 3; n = 13). The groups were well matched clinically and hematologically. No mortality occurred after initiating therapy, but one patient experienced a cerebrovascular accident. Response, defined as a platelet count greater than 50 x 10(9)/L, was achieved in 82%, 54%, and 92% of patients in groups 1, 2, and 3, respectively, but was only significant between groups 2 and 3 (P = 0.0365). The median times to peak platelet counts were 8.5 days (range 7 to 21 days), 7 (range 5 to 10 days), and 7 (range 3 to 23 days), respectively. Although there was a trend in favor of the steroid-administered groups, relapse was not significantly different, which occurred at a median of 184, 32, and 76 days, respectively, nor was the average time to splenectomy different at 339, 59, and 98 days, respectively. At a minimum of 2 years of follow-up, 5 of 17 in group 1, 2 of 13 in group 2, and 1 of 13 in group 3 had achieved platelet counts of greater than 100 x 10(9)/L and, therefore, did not require splenectomy. In contrast, where this indication was present for failure to respond, 8 of 12 (67%) in group 1, 4 of 8 (50%) in group 2, and 9 of 12 (75%) in group 3 remain in complete remission. Significantly more patients in group 2 than group 3 experienced a relapse (P = 0.0365). It is concluded that in previously untreated adults with symptomatic immune thrombocytopenia, gammaglobulin offers no advantage over conventional corticosteroid administration as the primary form of therapy. Additionally, more intense immunosuppression, resulting from the use of both agents combined, is no better than single agent corticosteroid agents and appears to be an unnecessary and unwarranted expense.

Cyclosporin A in the treatment of severe acute aplastic anaemia

Summary. Twelve consecutive adults with severe acute aplastic anaemia, not having a bone marrow transplantation option, were prospectively randomized to receive either cyclosporin A alone or an equivalent amount of this immunosuppressive agent in combination with antilymphocyte serum. The minimum follow‐up is 36 months, with half the patients developing nephrotoxicity, which was easily reversible in all but one. No response could be attributed to either regimen. Cyclosporin A does not appear to have a place as primary form of treatment for adults with severe acute aplastic anaemia, either on its own or in combination with antilymphocyte serum.

The treatment of tumors by the induction of anemia and irradiation in hyperbaric oxygen

Because increased effects have been achieved when murine tumors are irradiated after a period of hypoxia and because of anecdotal clinical experiences of an improved result after irradiation of previously anemic patients in hyperbaric oxygen, the relationship between irradiation and increased survival was investigated in seventy‐two patients with advanced head and neck or cervical cancer. Anemia was achieved by means of a two‐stage isovolemic venesection maintained for seventy‐two hours, hemoglobin was returned to a normal level, and treatment in hyperbaric oxygen was started. Marked tumor shrinkage after the induction of anemia and before radiotherapy was seen and was probably disease, site, and hemoglobin level related. As a result, a possible new approach to cancer therapy is suggested. After completion of therapy, the 1‐year disease‐free survival for patients with head and neck and cervical cancer was not improved, but the 21‐month survival for cervical cancer was improved. Further studies are strongly urged.

Treatment of Adult Acute Lymphoblastic Leukaemia

Eighty-five consecutive patients with acute lymphoblastic leukaemia (ALL), having a median age of 24 years (range 10-69 years), underwent induction and consolidation chemotherapy with weekly parenteral vincristine, Adriamycin, l-asparaginase and daily oral prednisone (VAAP), followed by standard (CNS) prophylaxis. Maintenance therapy was given for 3 years and consisted of daily 6-mercaptopurine, weekly methotrexate and monthly intrathecal therapy, with drug intensification comprising either vincristine, Adriamycin and l-asparaginase (VAA) or cyclophosphamide, vincristine, cytosine arabinoside and prednisone (COAP). Complete remission (CR) was obtained in 59 patients (69%) and only the French-American-British (FAB) L1 morphology was a significant predictive factor (P = 0.048). Twenty-three patients failed to achieve CR and of these 12 had primary drug resistance. Median follow-up is currently 260 weeks, median predicted survival of all patients is 58 weeks and for those who achieved CR it is 104 weeks. Median duration of CR is 70 weeks. Of the prognostic factors for survival, only FAB L1 subtype was significant. Bone marrow relapses occurred in 29 patients, and of these 9 (31%) achieved CR. There has been CNS relapse in two patients and both have died. Eleven patients continue in CR off therapy, with a median of 152 weeks. This regimen is effective, with acceptable toxicity, and a number of patients are potentially cured. The incidence of resistant and relapsing disease is an argument for further intensifying both induction and postinduction therapy.

Plasma exchange for homozygous familial hypercholesterolaemia: the Cape Town experience.

Homozygous familial hypercholesterolaemia (FH) is a rare disorder having a greater frequency in populations with founder effects for the mutations in low density lipoprotein (LDL) receptors. It is characterized by early signs of cholesterol infiltrates with premature coronary artery disease and does not respond to conventional lipid-lowering therapy. Plasma exchange is an established mode of treatment which improves the biochemical abnormality and may allow reversal of the physical manifestations as well as favourably influencing the clinical course of the disease. The efficacy, safety and tolerability of this procedure is confirmed by our experience over the 15 years following the previous report. In a subset of these patients who have residual LDL receptor activity, further lowering of the plasma cholesterol concentration was achieved by adding simvastatin, an hydroxy-methylglutaryl coenzyme A reductase inhibitor. It is concluded that this combined approach may be of benefit in selected cases of homozygous FH undergoing regular plasmapheresis.

The comparison of gammaglobulin to steroids in treating adult immune thrombocytopenia

SummarySymptomatic immune thrombocytopenia is a life-threatening situation which is conventionally treated in the adult with prednisone, although subsequent splenectomy is frequently unavoidable. Recently, high-dose intravenous gammaglobulin has been reported to be an effective alternative option, particularly in children. To determine the role of this agent in adults a controlled prospective trial has been undertaken. Previously untreated patients with immune thrombocytopenia were randomised to compare oral prednisone (1 mg/kg/day: Group 1: n=13) to high-dose intravenous gammaglobulin (400 mg/kg on days 1 through 5: Group 2: n=7), or a combination of both agents given on the same schedule (Group 3: n=12). The time from diagnosis to commencement of treatment, initial platelet counts, age and sex were comparable in the three groups. At this interim analysis there has been no mortality, but one patient has suffered a cerebrovascular accident. Objective response, defined as a platelet count greater than 50×109/l, was achieved in a median of 5, 5 and 3 days, whereas the time taken to reach peak counts were 9, 5 and 7 days, respectively. The relapse rates, percentage of patients subsequently requiring splenectomy for control of symptomatic bleeding and the postoperative course was comparable between the three groups. These data, although preliminary, re-emphasize differences between the paediatric and adult forms of immune thrombocytopenia and also suggest in the latter patients a need for caution before advocating replacement of prednisone by gammaglobulin as the primary form of treatment.

INTERFKRON RESPONSE IN B‐CELL PROLYMPHOCYTE LEUKAEMIA

Prolymphocytic leukaemia is a well-defined clinical and haematologic entity in which there is generally a poor response to therapy with alkylating agents or corticosteroids. and median survival tends to be short (Galton ef a]. 19 74). Phenotypically. 85% of the neoplasms are of B-cell lineage (Schroff et al. 1982) and have features reminiscent of hairycell leukaemia in that both tumours arise relatively late in Bcell maturation (Jansen et (11. 1 Y 82 ), have strong immunoglobulin staining and express surface antigens recognized by the monoclonal antibody FMC7 (Melovt N I , 1984, 1985). In view of these similarities and the response in hairy-cell leukaemia obtained when patients are treated with alpha-interferon (Quesada et 01. 1984). a similar therapeutic approach was attempted in a patient with B-cell prolymphocytic leukaemia; a durable haematologic and clinical response is reported. A 66-year-old female presented with a 3-month history of anorexia. weight loss, and discomfort in the left upper quadrant of her abdomen. The remainder of her history was not contributory. Physical examination was unremarkable apart from an enlarged spleen palpable 6 cm below the left costal margin. Initial haemoglobin was 1 3 g/dl. with normal red cell indices, total white cell count 58.2 x IOY/l, of which 84% were typical prolymphocytes (Owens et al. 19 84). and a platelet count of 104 x 1 Oy/l. Bone marrow aspiration and trephine biopsy were of normal cellularity. but haematopoietic reserve was estimated to be less than 1 5 % due to a dense diffuse interstitial infiltrate of typical prolymphocytes. Biochemical profile. including protein electrophoresis and immunoglobulin levels, was normal. The cells expressed combined IgM (65%) and IgD ( 5 5%). with monoclonal kappa light chain (8 3%,) and lambda light chains (4%) (normal ratio 2-3 : 1 ). Surface immunoglobulin was intensely fluorescent, rosette formation with sheep red cells was 16% (normal j.O-SOO/,) and with mouse erythrocytes less than 1% (normal 1-1 5%). 1% T-cells were demonstrated with specific monoclonal antibodies. The patient elected not to undergo splenectomy and was commenced on recombinant alpha-interferon (F. Hoffman-la Roche & Co. I,td. Basle. Switzerland) on a schedule of 100 x 10” units/m2 intravenously once a month and a subcutaneous dose of 10 x 1 Oh/m’ three times a week. This schedule was well tolerated, without side effects. Although the white count continued to average 6 0 x 10Y/l a peak level of 1 3 6 x lOY/ l was recorded; splenomegaly, however, increased rapidly to extend 2 0 c m below the left costal margin, and there was further decrease in appetite now associated with vomiting and worsening left upper quadrant discomfort. with sharp pain over the spleen. Troublesome oedema developed in her legs and lymph nodes became palpable for the first time in the left axilla. The haemoglobin fell to 9 .5 g/dl and red cell transfusion became necessary. Platelets dropped to 80 x 109/1 and easy bruising became apparent on the legs. A small amount of fresh red blood was passed rectally and on examination this was shown to be due to the development of haemorrhoids. one of which had prolapsed. In view of her deterioration the patient elected to discontinue alpha-interferon and underwent a n uncomplicated splenectomy in October 1984. Histologically, the spleen showed characteristic features of prolymphocytic leukaemia and cell phenotyping was the same as that from peripheral blood and marrow. Modest improvement occurred in her haematology. with haemoglobin stabilizing a t approximately 11 g/dl, white count between 50 and 70 x IOY/l, with 86% circulating prolymphocytes and platelet count over 300 x 1OY/1. However, there was no parallel clinical benefit and, because of increasing lymphadenopathy, dependent oedema and further weight loss, the patient requested recommencement of recombinant alpha-interferon. On the identical schedule to that used previously. side effects were again not encountered and within 2 months there was dramatic clinical improvement, with resolution of lymphadenopathy, return of appetite, weight gain, and at 9 6 weeks of follow-up her Karnofsky rating increased from 60% to 80% and then reached 100%. The patient required no further red cell transfusions, total white count varied between 5 and 10 x 10y/l. and prolymphocytes between 20% and 50% (Fig 1 ). Biochemical profile remained normal. Serial bone marrow aspiration and trephine biopsy showed steady improvement and in April 1986 haematopoietic reserve was in excess of 50% and prolymphocytes were now predominantly in aggregates with only limited interstitial infiltration evident. In view ofthe good response interferon was discontinued in February 1986 and the patient remains clinically and haematologically completely well. This case illustrates a response to recombinant alphainterferon in a patient with B-cell prolymphocytic leukaemia. suggesting that it is of value in a tumour that usually responds poorly to conventional cytotoxic chemotherapy. Three observations appear pertinent. Firstly, prior to splenectomy the alpha-interferon was without effect and the patient deteriorated clinically and haematologically. Secondly. even at the relatively high doses used, interferon was well tolerated and without side effects. Thirdly, splenectomy was associated with modest improvement in haematologic values but continuing symptomatic deterioration, increasing lymphadenopathy and no reduction in tumour bulk gauged on white cell and differential count or involvement of bone marrow on trephine biopsy. However, while a late effect of splenectomy cannot be discounted, the dramatic response that followed

Treatment of acute lymphoblastic leukaemia (ALL)

Abstract: Forty‐six consecutive patients with acute lymphoblastic leukaemia (ALL), having a median age of 23 years (range 14 to 64), underwent induction and consolidation chemotherapy with weekly parenteral vincristine, adriamycin, 1‐asparaginase and daily oral prednisone (VAAP), followed by standard central nervous system (CNS) prophylaxis. Maintenance therapy was given for 3 years and consisted of daily 6‐mercaptopurine, weekly methotrexate, and monthly intrathecal chemotherapy, with drug intensification comprising either vincristine, adriamycin and 1‐asparaginase (VAA) or cyclophosphamide, vincristine, cytosine arabinoside and prednisone (COAP). Complete remission (CR) was achieved in 36 patients (78%) and only the FAB L1 morphology was a significant predictive factor (Chi‐squared = 3.91: p < 0.05). Eight of the 10 non‐responders had significant drug resistance and 3 deaths were associated with marrow hypoplasia. Median follow‐up is 52 months. Median duration of CR is 28 months, median survival of all patients is 16 months, and for those who achieved CR is 44 months. There was no difference between the two maintenance arms. Significant prognostic factors for survival are French‐American‐British (FAB) subtype, in which the L1 is better than L2 (p = 0.05), and age (p = 0.035). Nineteen patients have experienced medullary relapse and 7 (37%) achieved subsequent CR; this is durable in a single patient who underwent allogeneic bone marrow transplantation. Eight patients (17%) had CNS disease at diagnosis; 5 achieved CR and 1 is alive and disease‐free at 65 + months. There has been 1 CNS relapse. These results demonstrate that prolonged remissions and survival can be achieved with this protocol and many patients possibly cured. The level of toxicity is acceptable and the pattern of induction failure indicates that a margin exists for intensifying chemotherapy and thereby possibly further improving results.

A risk-to-benefit analysis for central venous catheters

Reliable venous access is an important consideration in the management of the cancer patient, where long-term intravenous therapy is needed. A single institution retrospective analysis of 205 catheter placements allowed comparison of different lines and techniques. This experience shows that surgical introduction under general anaesthetic of a double-lumen, 12 gauge, silastic catheter in the superior vena cava, via the internal jugular vein and using a 15 cm anterior chest wall tunnel, resulted in longest survival, fewest infections, and enjoyed a high patient acceptability. A substantial cost-saving, particularly in antibiotic usage, was observed as a result of the improved technique.

Pure red cell aplasia. Stable complete remission following antilymphocyte globulin administration.

A 25‐yr‐old woman with idiopathic pure red cell aplasia achieved complete remission following a single 5‐day course of antilymphocyte globulin at a dose of 50 mg/kg daily by intravenous injection as initial and sole therapy. Apart from transient arthralgia and asymptomatic thrombocytopenia there were no side effects. At 2 yr, the patient has normal peripheral blood, bone marrow and in vitro culture studies. This approach offers an alternative to conventional immunosuppressive therapy where there is evidence of an underlying immune disorder.