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Recombinant human interferon (IFN) alpha-2b in chronic myelogenous leukaemia: dose dependency of response and frequency of neutralizing anti-interferon antibodies

Summary. Twenty‐seven patients with Philadelphia chromosome positive chronic myelogenous leukaemia in the chronic phase were treated with low doses of recombinant interferon (IFN) alpha‐2b. Ten patients entered a complete and six a partial haematologic remission with a median duration of 5·8 and 9·1 months respectively. Five minor cytogenetic responses were observed. These results are inferior compared to other studies with higher interferon‐doses. Fever was an acute side effect after injection of IFN, limb pains and fatigue occurred protractedly. Haematologic side effects, nonspecific EEG changes, weight loss, and development of pulmonary infiltrates were observed in later periods of the treatment. Eight patients developed neutralizing anti‐IFN antibodies after 4·2–20·4 months (median 12·8 months). Anti‐IFN antibodies were associated with relapse or refractoriness to IFN treatment: five out of nine patients with rising WBC after initial fall had antibodies, while four did not. Two out of four patients with primary non‐response had IFN‐antibodies. These results may indicate a serious problem in the long‐term treatment of CML with recombinant interferon.

Aerosol amphotericin B inhalations for prevention of invasive pulmonary aspergillosis in neutropenic cancer patients

To determine the value of aerosol amphotericin B inhalations for prevention of invasive pulmonary aspergillosis (IPA), we initiated a prospective randomized multicenter trial. The scheduled intent-to-treat interim analysis included 115 patients (30%) with prolonged neutropenia after chemotherapy for acute myeloid leukemia, acute lymphoblastic leukemia/high-grade non-Hodgkins lymphoma, or solid tumors undergoing autologous stem cell transplantation. Sixty-five patients had been randomized to receive prophylactic aerosol amphotericin B inhalations at a dose of 10 mg twice daily (group A); for the remaining 50 patients no aerosol amphotericin B prophylaxis was used (group B). No serious side effects from amphotericin B inhalations occurred, but coughing (54%), bad taste (51%), and nausea (37%) caused early cessation of aerosol amphotericin B prophylaxis in 23% (15/65) of courses. In group A, the incidence of proven, probable, or possible IPA was 5% (3/65) as compared with 12% (6/50) in group B (p>0.05). Microbiologically documented bacterial pneumonias were observed in 5/65 (8%) patients in group A and in 1/50 (2%) patients in group B (p>0.05). Thus, no reduction in incidence of IPA from use of prophylactic aerosol amphotericin B inhalations was found in this interim analysis. As there were no serious side effects from aerosol amphotericin B prophylaxis, accrual in the study will continue for a total of 380 patients.

Three T-cell epitopes within the C-terminal 265 amino acids of the matrix protein pp65 of human cytomegalovirus recognized by human lymphocytes

Although a T‐cell response in human cytomegalovirus (HCMV)‐immune individuals exists against the most abundantly expressed protein pp65 of the virus matrix, less is known about the determinants that evoke this response. The aim of the study was to identify regions within HCMV pp65 (ppUL83) that contain sequences for the cellular immune response by the use of three recombinant overlapping β‐galactosidase pp65 fusion proteins (C74, C35, and C47), covering the C‐terminal 265 amino acids of the entire pp65 sequence. Two T‐cell epitope determinants were recognized by human lymphocytes of healthy, HCMV‐seropositive, human leukocyte antigen (HLA)‐typed individuals. One T‐cell determinant (amino acids [aa] 303–388) was localized in the mid‐region of the entire pp65 sequence and a second T‐cell determinant (aa 477–561) within the C‐terminal region. By fine mapping with synthetic hexadecamer peptides three T‐cell epitopes were identified within these two regions: P10‐I (aa 361–376) in the mid‐region, P3‐II (aa) 485–499), and P6‐II (aa 509–524) in the C‐terminal region. Inhibition studies with monoclonal antibodies to HLA class I or class II revealed a class I restricted response to peptides P10‐I or P6‐II, respectively. P10‐I responders shared the HLA‐DR11 allele and P6‐II responders the ‐DR3 allele. Therefore, these T‐cell epitopes of HCMV pp65 might be presented in association with particular HLA class II alleles. J. Med. Virol. 52:68–76, 1997.

Meropenem monotherapy versus combination therapy with ceftazidime and amikacin for empirical treatment of febrile neutropenic patients

Abstractu2002Infections remain the major cause of morbidity and mortality among neutropenic cancer patients. The current study addresses the question whether monotherapy with the new broad-spectrum carbapenem meropenem exhibits efficacy comparable to that of the standard combination therapy with ceftazidime and amikacin for empirical treatment of febrile neutropenic patients. Seventy-one patients with hematological malignancies (55%) or solid tumors (45%), neutropenia <500/μl, and fever <38.5u200au200a°C were randomly assigned to either meropenem (1u2009g every 8u2009h) or ceftazidime (2u2009g every 8u2009h) and amikacin (15u2009mg/kg/day) intravenously. Meropenem (n=34) and ceftazidime/amikacin (n=37) were equivalent with respect to the clinical response at 72u2009h (62% versus 68%) (p<0.05) and at the end of unmodified therapy (59% versus 62%). Gram-positive bacteremia responded poorly in the meropenem and ceftazidime/amikacin group (29% versus 25%), whereas all gram-negative bacteremias responded except for one in the meropenem group caused by Pseudomonas aeruginosa. All patients survived to 72u2009h. One patient in each group died of gram-positive sepsis resistant to study medication. No significant side effects occurred in any regimen. This study suggests that meropenem monotherapy might be as effective as combination therapy with ceftazidime and amikacin for the empirical treatment of febrile neutropenic patients.

Interventional Antimicrobial Strategy in Febrile Neutropenic Patients

In a prospective, randomized multicenter trial of the Paul Ehrlich society different concepts for sequential empirical antimicrobial strategy for the treatment of patients with neutropenia

Treatment with natural human interferon alpha of a CML-patient with antibodies to recombinant interferon alpha-2 b

SummaryA patient with Philadelphia-chromosome positive chronic myelogenous leukemia developed interferon antibodies on treatment with recombinant interferon alpha-2 b. Clinically this event corresponded with progressive disease. No cross-reactivity of antibodies with human leukocyte interferon was found by Western blot. Treatment was switched to human leukocyte interferon with an obvious clinical effect: WBC was reduced and platelet count stabilized, but the effect was transient and no hematologic remission was achieved. Human leukocyte interferon may be an alternative in CML-patients with neutralizing antibodies to recombinant interferon alpha.

Prednimustine and mitoxantrone (PmM) in patients with low-grade malignant non-Hodgkin's lymphoma (NHL), chronic lymphocytic leukemia (CLL), and prolymphocytic leukemia (PLL)

SummaryThirty-five patients with a mean age of 60.6 years (44–78 years, 22 male, 13 female) with advanced low-grade non-Hodgkins lymphoma (NHL), chronic lymphocytic leukemia (CLL), or prolymphocytic leukemia (PLL) were treated every 4 weeks with prednimustine 100 mg/m2 p.o. d 1-d 5 and mitoxantrone 8 mg/m2 i.v. d 1 and d 2. Seven patients had CLL, one lymphocytic NHL, two PLL, 13 immunocytoma, nine centroblastic/ centrocytic NHL, and three centrocytic NHL. Twentyfive patients were pretreated. The subjective toxicity of the treatment was mild, with no WHO grade-3 alopecia, polyneuropathy, cardiotoxicity, mucositis, nausea, or vomiting. Hematologic side effects with WHO grade-4 granulopenia and thrombopenia were experienced by 26% and 23% of the patients, respectively. The overall response rate (CR + PR) was 72% for lymphoma patients and 37% for CLL patients, with a median remission duration of 14.6 months. The maximum response was achieved after a median of two treatment courses. Prednimustine with mitoxantrone is a subjectively well tolerated treatment for low-grade malignant NHL, to be further evaluated in phase-III studies. The regimen may shorten the duration of treatment, saving time-consuming outpatient visits and costs.

Five-day 4′-(9-acridinylamino)methanesulphon-m-anisidide and intermediate-dose cytosine arabinoside in high-risk relapsing or refractory acute myeloid leukemia

SummaryTwenty-two patients with acute myeloid leukemia (AML), having a median age of 48.3 years (range 26–70; 10 male, 12 female), were treated with 4′-(9-acridinylamino)methanesulphon-m-anisidide (m-AMSA) 100 mg/m2 and cytosine arabinoside (AraC) 2×1000 mg/m2 i.v. on days 1–5. There were 2 M1, 8 M2, 9 M4, 2 M4 Eo, and 1 M5a. Of these, 12 achieved a complete remission, 3 a partial remission and 6 did not respond. The median remission duration was 9.0 months and the median overall survival 8.1 months. Side-effects of induction consisted mainly of haematological toxicity and infections with a median duration of WHO-grade-4 granulopenia and thrombopenia of 20 and 28 days respectively. Organ toxicity was mild with mucositis and cutaneous and liver toxicity being experienced by only a few patients. There was one treatment-related death. Five-day m-AMSA and intermediate-dose AraC is an easy-to-handle condensed treatment schedule with tolerable toxicity. Its effectiveness in relapsed and refractory AML is comparable to combinations of high-dose AraC with m-AMSA, anthracyclines or etoposide.

Results and Prognosis of Acute Non-Lymphocytic Leukemia in Adults

Between 1977-87, 319 patients with AML were admitted to Hannover Medical School. At all 41 of these patients were not treated (median duration of survival 0.6 months). Among the 278 treated patients, there was a CR rate of 53.6%, the median duration of remission was 10.1 months and the median duration of survival 7.0 months. The patients with FAB-classification M4-M5 had a worse prognosis than those with M1-M3. Patients under 50 years of age had a significant higher remission rate and survival time than those over 50 years. In the last 10 years, the remission rate rose from 37.3% to 61.0% (p = 0.1776). There was a rise in median duration of survival from 5.9 months (1977-79) to 8.0 months (1984-85) (p less than 0.001). The median remission time decreased from 15.8 months (1977-79) to 12.0 months (1984-85) (p less than 0.001). After the first reinduction therapy, the remission rate (46.6%), duration of remission (5.3 months), and duration of survival (4.1 months) was lower than after primary therapy. After the second reinduction therapy the CR rate was 69.2%, and the remission time 2.9 months. The CR rate after the third reinduction therapy was 22.2%.

Analysis of Variable Number of Tandem Repeats Reveals Differences Between Leukemic Cells and Remission Phase Leukocytes

It is commonly accepted that the transformation of cells and the development of acute leukemia is the result of an accumulation of somatic changes of cellular DNA. The appropriate methodology to monitor genomic changes depends on the nature and extent of the alterations. The gain or loss of whole chromosomes or parts thereof, as well as gross chromosomal translocations, insertions, deletions, and other rearrangements, is readily detectable by routine cytogenetic investigations [1]. To demonstrate minor somatic changes (ranging from micro-insertions or -deletions to point mutations), direct DNA analyses are mandatory. Hence southern blotting and hybridization experiments using singlecopy probes were usually applied (with or without DNA-amplification by PCR). Despite the enormous potential of such probes, the information is limited to a minute spot in the vast “desert” of the genome. And normally, unknown alterations will escape detection. In order to overcome this shortcoming to some extent, multilocus probes, as introduced by Jeffreys et al. (1985) [2], were used for the simultaneous monitoring of many DNA loci, distributed over the chromosomal complement. A second relevant criterion is the number of alleles existing in each of the DNA loci. Several of these probes have considerable individualization potential, thus yielding “fingerprint” pattern.