Ingemar Winqvist

A Combination of Granulocvte Colonv- Stimulating Factor and Erythiopoietin may Synergistically Improve the Anaemia in Patients with Myelodysplastic Syndromes

In an attempt to obtain a synergistic effect on the hemoglobin levels in anaemic patients with myelodysplastic syndromes (MDS), granulocyte colony-stimulating factor (G-CSF) and erythropoietin (epo) were combined in a clinical phase II trial. Twenty-two patients with MDS were included in the study. G-CSF was given alone for six weeks and then in combination with epo for the following twelve weeks. Eight (38%) of 21 evaluable patients showed a significant increase in hemoglobin. One patient with a previous response and subsequent failure to epo alone improved after the addition of G-CSF. Responses were more frequent in patients with less advanced pancytopenia, lower endogenous levels of serum-epo and in those with ring sideroblasts in the bone marrow. The response frequency of 38% is higher than in any study of epo as monotherapy. Moreover, patients with ring sideroblasts, who respond poorly to epo alone, showed a response rate of 60%. Our findings suggest a synergistic in vivo effect of granulocyte-CSF and erythropoietin in patients with myelodysplastic syndromes.

Treatment of myelodysplastic syndromes with retinoic acid and 1α-hydroxy-vitamin D3 in combination with low-dose ara-C is not superior to ara-C alone. Results from a randomized study

Abstract: 63 evaluable patients with myelodysplastic syndromes (MDS) and 15 with acute myelogenous leukemia (AML) were randomized between low‐dose ara‐C (arm A) and low dose ara‐C in combination with 13‐cis‐retinoic acid (13‐CRA) and 1α‐hydroxy‐vitamin D3 (1α D3) (arm B). 69 patients were evaluable and 18 (26.1%) responded to therapy. The addition of 13‐CRA and 1α D3 had no positive influence on survival of the patients, remission rates or duration of remissions. 12/27 patients in arm A and 6/29 patients in arm B progressed from MDS to AML during the course of the study (p = 0.0527). Arm B gave significantly more side‐effects than arm A (p = 0.005). Therapeutic effects of 13‐CRA and 1α D3 on MDS is not supported by this study. However, an inhibiting effect on AML development in some MDS subgroups cannot be excluded.

Therapeutic effects of low‐dose cytosine arabinoside, alpha‐interferon, 1α‐hydroxyvitamin D3 and retinoic acid in acute leukemia and myelodysplastic syndromes

62 evaluable patients with myelodysplastic syndromes (MDS) or acute leukemia were treated with different combinations of low dose ara‐C, α‐interferon (IFN), 1α‐hydroxyvitamin D3 (vit D3) and retinoic acid. The aim was to study the efficacy and toxicity of each combination. The overall rate was 44%. Of these, 50% responded favorably to the combination of IFN, vit D3 and retinoic acid (IDR), which was comparable to the response rate of 43% for low‐dose ara‐C. The results of the IDR treatment may be explained by additive or synergistic effects between the separate drugs in the combination. Ara‐C and IDR treatment was generally well‐tolerated but interferon gave more side effects than any other drug used in the study. Evaluation of the full combination of ara‐C, IFN, vit D3 and retinoic acid was not possible because of toxicity. Marrow hypoplasia was infrequent (5/27 patients) in cases responding favorably to treatment. Complete remissions were not longer than partial remissions or significant responses.

Fulminant Course of Infectious Mononucleosis with Virus-associated Hemophagocytic Syndrome

A fatal case of infectious mononucleosis due to serologically verified Epstein-Barr virus infection in a previously healthy 30-year-old man is presented. The clinical course was characterized by severe prostration, persistently high spiking fever, and continuous development of enlarged lymph nodes. Hematologic examination revealed peripheral leukopenia and thrombocytopenia, and in the bone marrow an increased number of benign histiocytes showed marked hemophagocytosis. At autopsy abnormal lymphoid infiltrates were present in several tissues. The pathogenesis of this infection-associated hemophagocytic syndrome is discussed in terms of the possibility of an impaired immune response to infectious agents.

Bernard-Soulier syndrome in two Swedish families: effect of DDAVP on bleeding time.

Abstract:  We present 2 patients with Bernard‐Soulier syndrome from two different families. The parents of one of the patients were found to have had common ancestors in the 17th century. The platelet membrane content of glycoprotein (GP)Ib was measured in the patients and their first‐degree relatives with an ELISA technique based on monoclonal antibodies. Both patients had very low levels of GPIb. In one of the families the heterozygotes had reduced expression of GPIb but in the other the obligate heterozygotes had normal values, suggesting that the molecular pathology differs between the two families. In both patients, bleeding time was shortened by infusion of DDAVP (1‐deamino‐8‐D‐arginine vasopressin), although it was not completely normalised. DDAVP may be of some therapeutic value in cases of Bernard‐Soulier syndrome.

Variations of Cationic Proteins from Eosinophil Leukocytes in Food Intolerance and Allergic Rhinitis

Challenge tests were performed in patients with food intolerance and allergic rhinitis to evaluate the usefulness of measurement of the eosinophil cationic protein (ECP) of serum to distinguish different allergic reactions. In one group of patients with food intolerance symptom‐induced challenge resulted in a marked decrease of serum‐ECP. The number of blood eosinophils decreased simultaneously in some but not all of these patients. In another group of patients with food intolerance serum‐ECP displayed peak‐like increases followed by a decrease. The decrease in serum‐ECP may reflect that consumption of ECP is a result of idiosyncrasy in the target organ. In allergic rhinitis some patients showed an initial peak–like increase of serum–ECP, which was abolished by pretreatment with disodiumcromoglycate but not by pretreatment with antihistamine. Similar results have previously been demonstrated for allergic asthma. The difference obtained in serum‐ECP upon challenge in typical reagin‐mediated allergy and food intolerance may indicate that the latter is not reagin‐mediated. However, the interpretation of data is difficult because of lack of knowledge regarding the turnover in the circulation of ECP.

A pilot study of piperacillin and ciprofloxacin as initial therapy for fever in severely neutropenic leukemia patients

We studied the efficacy of piperacillin and ciprofloxacin as initial parenteral therapy in 41 adult patients with leukemia who developed 47 febrile episodes during severe neutropenia following chemotherapy. 40 patients (98%) survived their febrile episode(s), whereas 1 patient died of infection. When assessed at 72 h after initiation of treatment (early evaluation), 24/47 episodes (51%) had been successfully treated. These 24 favourable responses were seen in 15/24 (63%) microbiologically documented infections and 9/19 (47%) fever of unknown origin (FUO). At the resolution of fever (late evaluation) 46 episodes were evaluable, and 28 (61%) had responded successfully to piperacillin and ciprofloxacin. Successful treatment was most frequently observed in microbiologically defined infections, 18/23 (78%). Three of 5 (60%) Gram-positive, 11/12 (92%) Gram-negative and 1 of 2 mixed bacteremias were successfully treated. In contrast, only 10/19 (53%) FUO and none of 4 clinically defined infections had responded. Thus, this pilot study indicates that piperacillin and ciprofloxacin may be a safe and effective combination for the treatment of febrile episodes in severely neutropenic leukemia patients, which merits further investigation in randomized trials.

Effect of zinc and other cations on the release of the eosinophil cationic protein.

The eosinophil cationic protein, ECP, is a unique eosinophil granule constituent, which is released extracellularly after exposure of the eosinophils to a non-phagocytosable surface such as complement-coated Sephadex beads. The ECP is released to some extent even in the absence of Ca2+ and Mg2+, though both these cations augment the release reaction tested alone, and an optimal release is observed only in the presence of 2 mmol/l Ca2+ and 2 mmol/l Mg2+ in the medium. Zn2+ at concentrations from 0.25-4.0 mmol/l inhibited the release of ECP in a dose-dependent fashion, with or without Ca2+ and Mg2+ in the medium. Mn2+ had dual effects, stimulating the ECP release in the absence of Mg2+ and Ca2+, and inhibiting the release in the presence of these cations. Li1+ caused minor inhibition of ECP release, but only in the absence of Ca2+ and Mg2+. The inhibitory effect of Zn2+ was immediate and reversible after washing of the cells, suggesting that the inhibition is due to interaction with the plasma membrane functions.

MEPERIDINE (PETHIDIN) TO CONTROL SHAKING CHILLS AND FEVER ASSOCIATED WITH NON-HEMOLYTIC TRANSFUSION REACTIONS

To the editor: Febrile, non-hemolytic transfusion reactions may be due to sensitivity to leukocytes and platelets, bacterial contamination and unidentifiable mechanisms. Bacterial contamination is an uncommon complication since the introduction of disposable plastic blood bags. Transfusion-induced sepsis nowadays occurs especially following platelet transfusion, probably because platelets have to be stored at room temperature. This complication is rare and if septicemia does occur following blood transfusion, it is most frequently secondary to catheter-related thrombophlebitis. The other febrile, non-hemolytic transfusion reactions cannot equal the immediate hemolytic variety but are certainly more common. They accounted earlier for more than a third of all transfusion reactions and occurred in about 2% of all transfusions (1). They result from sensitivity to leukocyte and platelet antigens. Since sensitization is a prerequisite for this reaction, it occurs in patients who have had previous transfusions or have been pregnant. The interaction between leukocytes, platelets and antibodies directed against them leads to release of endogenous pyrogens (interleukin1) from neutrophils and other cells. Endogenous pyrogens act on the hypothalamic area and cause the set-point of the hypothalamic thermostat to rise. The resultant elevation of body temperature may be mediated by prostaglandins. The finding that specific prostaglandin antagonists do not prevent this fever reaction suggests that there are other (fever) mediators. Alteration of the thermoregulatory set-point with opioid agonists has been described in rats, reflecting a role of opioid receptors, and possibly endogenous opioids, in thermoregulatory control (2). to ted control shaking with non-hemolytic

Autologous del(20q)-positive erythroid progenitor cells, re-emerging after DLI treatment of an MDS patient relapsing after allo-SCT, can provide a normal peripheral red blood cell count

Summary:A 54-year-old RhD-negative male with del(20q)-positive myelodysplastic syndrome was transplanted with bone marrow from an HLA-identical RhD-positive sibling donor. Cytogenetic relapse was detected 21 months after stem cell transplantation (SCT), with reappearance of the original del(20q)-positive clone and reversion to recipient RhD-negative blood group. The patient received sequential donor lymphocyte infusions (DLIs), resulting in mild graft-versus-host disease and pure red cell aplasia. At 2 years post DLI, the patient remains in a stable condition, despite a dominance of recipient-derived erythro- and granulopoiesis originating in del(20q)-carrying progenitor cells. We conclude that reappearance of autologous erythropoiesis, upon relapse after allogeneic SCT, may be predictive of erythropenia after DLI and that re-emerging autologous del(20q)-positive erythropoiesis post DLI can provide a normal peripheral red blood cell count. Furthermore, in patients relapsing after blood-group-mismatched transplantation, a possible reversion to recipient blood group should be considered prior to blood transfusion or DLI.