Intranasal amphotericin B reduces the frequency of invasive aspergillosis in neutropenic patients.

PURPOSE: To retrospectively study the prophylaxis of invasive aspergillosis in neutropenic patients and to relate the frequency of this fungal disease to any causal or modifying factors that could be identified. PATIENTS AND METHODS: Between 1977 and 1988, 130 patients underwent 158 intensive treatment episodes to control acute leukemia, lymphoma, and aplastic anemia, and the frequency of complicating aspergillus infection was determined. RESULTS: Proven invasive aspergillus infections occurred in 22 cases, 12 of which were fatal. Invasive aspergillosis was suspected in a further 16 cases and all these patients recovered with amphotericin B treatment. Colonization by Aspergillus in the absence of clinically significant infection was seen in 31 treatment episodes. Invasive aspergillosis involved mainly the upper and lower respiratory tract and skin. Control of the infection was closely related to the control of the underlying disease, with subsequent return of normal marrow function and resolution of neutropenia. The incidence of aspergillus infection has decreased dramatically since 1985, most probably due to the introduction of intranasal amphotericin B. This occurred despite the persistence of aspergillus spores in the hematology ward air during the 1986 to 1988 period. CONCLUSION: Intranasal aerosolized amphotericin B may protect against invasive aspergillosis, even when neutropenic patients are cared for in conventional wards without HEPA filtration.

Busulphan/cyclophosphamide conditioning for bone marrow transplantation may lead to failure of hair regrowth.

Following the introduction of bulsulphan and cyclophosphamide (BUCY) conditioning in our unit in 1987, a number of patients noted incomplete scalp hair regrowth following bone marrow transplantation (BMT). Between August 1987 and May 1989, 22 patients had undergone allogeneic or autologous BMT in our unit and we recalled for detailed assessment the 14 who were alive and well at least 6 months post grafting. Six patients had experienced incomplete hair regrowth of varying severity 7-27 months following BMT. All those affected had received BUCY conditioning and the four most severely affected were allogeneic BMT recipients. No patient had received any post-BMT chemotherapy or radiation. None of the patients had evidence of graft-versus-host disease. No laboratory test abnormalities distinguished the affected from the unaffected patients. Despite the relatively small number of patients, our results suggest that BUCY has caused permanent damage to the hair follicles of the affected patients. Prolonged alopecia may markedly impair the quality of life for long-term survivors of BMT and this unexpected complication also has significant medicolegal implications.

Complex karyotypic evolution in B-cell chronic lymphocytic leukemia.

Cytogenetic analysis at diagnosis in a female patient with chronic B-cell leukemia showed a single abnormal clone with a 4p+ abnormality, 46,XX, -4, +der(4)t(4;?)(p16;?). Six additional clones evolved from this clone during the following 4 1/2 years and showed 3p+, 4p-, and 11q- chromosomes in addition to the 4p+ abnormality. Immunoglobulin heavy chain gene rearrangement studies showed two rearranged bands and a faint germline band. Following splenectomy, a strong germline and faint rearranged bands were seen, suggesting that the majority of cells were normal, whereas cytogenetic studies showed that the karyotypically abnormal cells were still present. The combination of cytogenetic and Ig gene rearrangement studies provides detailed information regarding the number of circulating normal and leukemic cells.

Cytogenetic studies of acute promyelocytic leukemia.

Translocation t(15;17) is reported in bone marrow cells from six of seven patients with active acute promyelocytic leukemia (APL). One patient who showed t(15;17) at final relapse did not show it in directly prepared or cultured cells taken from a previous relapse. Bone marrow samples from two patients showed only cells with a normal karyotype in the direct preparation, whereas more than 60% of cells cultured for 24 hr showed t(15;17). R-Banding, G-banding, and an attempt at high-resolution banding indicated the break points t(15;17)(q24;21) for one of our patients.

Chromosome abnormalities in chronic lymphocytic leukemia revealed by cytochalasin B and Epstein-Barr virus.

Peripheral blood lymphocytes from eight patients with chronic lymphocytic leukemia (CLL) were cultured with Epstein Barr virus (EBV) and cytochalasin B. All eight cytochalasin B cultures had analyzable metaphases whereas only six of the EBV cultures were successful. Furthermore, the number of abnormal metaphases and the mitotic indices were greater in the cytochalasin B cultures than in the EBV cultures. Trisomy 12, alone or in combination with other abnormalities, was the most frequent cytogenetic finding. Structural abnormalities of chromosomes #6 and #14 were also found. Cytochalasin B appears to be an effective mitogen for demonstrating abnormal metaphases in patients with CLL.

Trisomy 10 in acute myeloid leukemia: three new cases.

Trisomy 10 is a rare nonrandom cytogenetic abnormality found in association with acute myeloid leukemia (AML). The hematological and clinical features associated with this finding have not yet been clearly defined. A literature review revealed 13 cases of trisomy 10 in AML, some reported as a minority component of a more comprehensive AML study and therefore lacking a full description of both clinical and hematological features. We present a summary of these reports and add three new cases to the literature.

Characterization of the C-MYC amplicon in a case of acute myeloid leukemia with double minute chromosomes.

We have characterized the double minute chromosomes in a case of acute myeloid leukemia (AML). Southern blot analysis showed that the C-MYC was amplified. Further analysis with probes located both 3' and 5' of MYC indicated that the amplicon was at least 700 kb in size, extending from the papilloma virus integration site situated 500 kb 5' of MYC to the PVT gene located 280 kb 3' of MYC. This appears to be the largest MYC-containing amplicon in human leukemia.

Nonrandom cytogenetic changes in New Zealand patients with acute myeloid leukemia.

Bone marrow clones with abnormal chromosomes were observed in 56% of 66 patients with forms of acute myeloid leukemia [French-American-British (FAB) M1-M6]. Acute myeloblastic leukemia (AML, M1 and M2) was the most common form, and 65% of these patients showed chromosomal abnormalities compared with 41% of patients with acute myelomonocytic leukemia (AMMoL, M4). The recognized nonrandom chromosomal abnormalities found were trisomy 8, monosomy 5 or 7, trisomy 1q, t(6;9), t(8;21), t(15;17), and abnormalities in 17q. There was also a strong involvement of chromosome No. 11: Abnormalities were found in eight patients when their leukemia was diagnosed and in a further three patients during the course of karyotypic evolution. Six of these patients had AMMoL or AMoL. Complex or multiple clones were found in 37% of AML patients at diagnosis. Our AML patients had a reduced frequency of abnormalities in chromosome No. 5 or 7 and an increased frequency of abnormalities in chromosome No. 8 compared with studies reported in other countries (p = 0.01). This difference suggests that in New Zealand AML might be caused by factors different from those operating in more industrialized centers.

Invasive aspergillosis in severely neutropenic patients over 18 years: impact of intranasal amphotericin B and HEPA filtration.

The impact of intranasal amphotericin B and high-efficiency particulate air (HEPA) filtration on the incidence of invasive aspergillosis was reviewed in patients from 1977 to 1994 undergoing intensive chemotherapy. Overall, the incidence of proven invasive aspergillosis was reduced from 24.4% (1977-1984) to 7.1% (1985-1991) (P < 0.001) following the introduction of intranasal prophylaxis, but when probable cases of aspergillosis were included and lymphoma cases excluded, there was no change in incidence. Following the introduction of HEPA filtration, patient exposure to aspergillus spores as measured by air sampling was markedly reduced and there were no new cases of invasive aspergillosis. HEPA filtration proved effective in reducing invasive aspergillosis and has allowed increasingly aggressive treatment regimens to be introduced.

Hemorrhagic lymphadenopathy as a presenting feature of primary al amyloidosis.

Lymphadenopathy associated with hemorrhage as a presenting feature of primary (AL) amyloidosis has not previously been described. We report two such cases one of whom had an acquired factor X and IX deficiency. The clinical presentations were characterized by sudden spontaneous enlargement of lymph nodes followed by partial regression. In both cases significant delay in diagnosis, and hence treatment, occurred due to the mode of presentation. One patient died with rapidly progressive disease but the other has had an excellent response to therapy with high-dose melphalan (HDM, 200 mg/m2) and peripheral blood stem cell rescue. AL amyloid should be considered in all patients presenting with hemorrhagic lymphadenopathy.

De novo mutation of the platelet glycoprotein Ib alpha gene in a patient with pseudo-von Willebrand disease.

Pseudo (or platelet-type)- von Willebrand disease (vWD) is a very rare autosomal dominant bleeding disorder caused by an abnormal hyper-responsiveness of the platelet membrane glycoprotein (GP) Ib/IX complex, the receptor for von Willebrand factor. We found a heterozygous missense mutation in the GPIb alpha gene in a sporadic case with pseudo-vWD: Met (ATG) to Val (GTG) at residue 239. The mutation was not detected in either parent. Investigation of three variable number of tandem repeat loci, D1S80 (MCT118), vWA and D17S5 (YNZ22), confirmed paternity and the de novo origin of the mutation. Furthermore, we have shown by the TaqI polymorphism analysis, which is located downstream of the GPIb alpha gene, that the mutation occurred in the maternal allele. This is the first description of de novo mutation occurred in pseudo-vWD and/or platelet GPIb alpha gene.

Danazol therapy in haemophilia.

Three patients with severe haemophilia A and one patient with moderately severe Christmas disease were given danazol and placebo in a double blind cross over trial to study the effects on haemostatic variables and bleeding tendency. In each case there was a shortening of the activated partial thromboplastin time (APTT) and euglobulin clot lysis time (ECLT) during danazol therapy but factor VIII and IX levels did not show any consistent change and there was no improvement in the bleeding tendency.

The peripheral blood picture in thyrotoxicosis.

The haematological results of 200 patients with uncomplicated thyrotoxicosis is reviewed. Although more than half of the patients showed a normal blood picture, several abnormalities were detected. In 37 percent of patients the erythrocytes showed microcytosis, and 8.5 percent were mildly anaemic. An absolute lymphocytosis was found in 11 percent and neutropenia was present in 2.5 percent of patients. The prevalence of treated pernicious anaemia was 1.5 percent.

The costs and benefits of bone marrow transplantation.

The average direct costs of performing a bone marrow transplant (BMT), including the subsequent year, was found to be NZ$27,074 for 43 consecutive transplants. In 29 BMTs a full two year period of follow up was available and a quality of life analysis was carried out on these patients. It was calculated that 59 quality adjusted life years (QALYs) had been gained by the BMT procedure at the time of analysis. By combining these two analyses the cost of each QALY gained by BMT is NZ$13,272. The relatively low cost of BMT is partly due to the extremely low annual costs in second and subsequent years post BMT. In our patients this cost amounted to $195 per year. The costs and benefits of BMT compare very favourably with other complex medical procedures.

Aplastic anaemia in Christchurch Hospital 1979-89.

We have reviewed the records of all patients referred to our departments with aplastic anaemia during the 11 years from 1979 to 1989. Of the 22 patients identified, 19 fulfilled the standard criteria for severe aplastic anaemia. There were 11 females and 11 males. Their mean age was 35 (range 2-85 years). Five cases followed exposure to drugs known to cause aplastic anaemia and one had a recent history of viral hepatitis. A variety of treatments were used. Four patients received an allogeneic bone marrow transplant (BMT) from matched sibling donors and two of these were alive and well 65 and 120 months post BMT. Antithymocyte globulin (ATG) treatment has been followed by lasting complete remission in two of the six patients treated and a partial response was seen in one other patient. Cyclosporin therapy was associated with unmaintained complete remission in one of the three patients given this drug after ATG had failed. The remaining 13 patients received only supportive care with or without androgens and six (46%) had early recovery of bone marrow function with lasting complete remission. These patients illustrate some of the therapeutic options available for aplastic anaemia.

Right atrial catheters for long-term venous access.

Thirty-two Hickman central venous catheters were placed in patients suffering mainly from blood disorders. The catheters remained in situ for an average of 64 days. In 20 patients the catheters were removed either because they were no longer needed (14) or at death (6). In five patients they are still in position. Complications in seven patients led to the catheter being removed and these included four patients with catheter related sepsis. The use of these catheters allows safe long-term access to the venous circulation even in the neutropenic, immunosuppressed patient.

Bone marrow transplantation for severe aplastic anaemia.

An eight-year-old girl with severe acquired aplastic anaemia received a bone marrow transplant from her 11-year-old brother. The bone marrow graft is firmly established, but the patient has mild chronic graft versus host disease affecting liver and skin. The indications for bone marrow transplantation in aplastic anaemia are discussed.

Allogeneic bone marrow transplantation at Christchurch 1979-1985.

Twelve bone marrow transplants have been carried out at Christchurch since 1979 in five patients with aplastic anaemia and seven with acute leukaemia. Five patients are currently alive at 77, 69, 63, 45, and seven months post-transplant. Acute and chronic graft versus host disease have been major problems and its clinical features and management are described. Long term follow-up data is presented on the four patients currently alive at between three to six years post-transplant. The practical problems we have experienced by carrying out bone marrow transplants without special funding have been considerable and the implications of this are discussed.

Bone marrow transplantation for acute leukaemia and severe marrow aplasia: an analysis of five patients.

Five patients, three with severe aplasia and two with acute leukaemia have been treated by bone marrow transplantation (BMT). Four are alive and well with excellent graft function. One showed engraftment but died of acute graft-versus-host disease (GVH); this patient and his donor were hepatitis B antigen positive. Three show evidence of mild chronic GVH, two patients requiring control by immunosuppressive therapy. Bone marrow transplantation (BMT) has now become an established method of treatment in severe aplasia and in acute leukaemia and our results serve to emphasise this. The clinical and organisational problems associated with BMT are discussed.

Treatment of hairy cell leukaemia with recombinant alpha interferon.

Eleven patients with progressive hairy cell leukaemia (three nonsplenectomised) were treated with recombinant alpha-2 interferon (Intron-A or Roferon-A) subcutaneously three times per week at a dosage of 3 x 10(6) units. Ten patients completed at least ten weeks of therapy and could be evaluated; one patient died of haemorrhage from severe thrombocytopenia after only three weeks treatment. Nine of the ten patients responded and all of these are regarded as good partial remissions (normalisation of all blood parameters but still discernible hairy cells in the marrow). Responding patients have all been followed for a median of two years and in one case 3 1/2 years since commencement of therapy. The patients are all transfusion independent and free of infection. We conclude that alpha-2 interferon therapy for progressive hairy cell leukaemia is effective therapy in both splenectomised and nonsplenectomised patients.