Paul A. Chervenick

Human Blood Monocytes: Stimulators of Granulocyte and Mononuclear Colony Formation in vitro

Human blood monocytes in a feeder layer or by use for conditioning medium produced a colony-stimulating factor capable of stimulating the in vitro growth of colonies of granulocytes and mononuclear cells from human and murine marrow. Lymphocytes and neutrophils did not stimulate colony formation, and medium conditioned by neutrophils was inhibitory. This suggests that the monocyte may control granulocyte proliferation and maturation.

Human Leukemic Cells: In vitro Growth of Colonies Containing the Philadelphia (Ph1) Chromosome

Human leukemic cells with a marker (Philadelphia; Ph1) chromosome gave rise to granulocytic and mononuclear cell colonies when grown in vitro. All metaphases from a single colony were either Ph1 positive or Ph1 negative. No colonies contained a mixed cell population. This suggests that leukemic and normal cells exist simultaneously and that in vitro colonies are clonal in origin.

Bone marrow colonies, stimulation in vitro by supernatant from incubated human blood cells.

A substance which stimulates growth of granulocytic and mononuclear cell colonies from mouse and human bone marrow was produced by incubated human blood cells. It is resistant to heat and freezing and is not dialyzable. Intact irradiated and unirradiated cells had very little activity, and sonically disrupted cells had no activity. The addition of plasma or sonically disrupted cells to the cell supernatant decreased its activity.

Corneal Toxicity with Systemic Cytarabine

Three patients with leukemia developed corneal toxicity while receiving high doses (3 g/m2) of systemic cytarabine. Symptoms began five to seven days after initiation of treatment with high doses of systemic cytarabine and consisted of ocular pain, tearing, foreign-body sensation, photophobia, and blurred vision. All three patients developed bilateral conjunctival hyperemia and fine corneal epithelial opacities and refractile microcysts that were more numerous in the central than in the peripheral cornea. The symptoms disappeared without treatment in approximately one week. The corneal changes we observed with high doses of systemic cytarabine resembled descriptions of corneal toxicity from topical cytarabine and were probably secondary to inhibition of DNA synthesis in the corneal epithelium.

Prediction of response of patients with acute nonlymphocytic leukaemia to remission induction therapy: use of clinical measurements

Two hundred patients with acute nonlymphocytic leukaemia received remission induction therapy consisting of cytosine arabinoside and an anthracycline antibiotic. Analysis of the pretherapy characteristics of the patients demonstrated that patient age was the most important factor in determining whether or not the patient would survive remission induction therapy. Assessment of the characteristics of the bone marrow after 6 d of therapy permitted the recognition of patients who were likely to fail to enter remission because of persistent leukaemia. Taken together, these observations demonstrate that it is possible to identify patients for whom conventional chemotherapy is not likely to be of benefit either because it is too intensive or because it is not intensive enough to produce a complete remission.

Use of the day 6 bone marrow to alter remission induction therapy in patients with acute myeloid leukaemia: a leukemia intergroup study

Summary. Patients with acute myeloid leukaemia who fail to show substantial bone marrow cytoreduction by day 6 of induction therapy enter complete remission (CR) less frequently than patients with good bone marrow leukaemic cytoreduction. The objective of the current study was to determine whether an increase in the intensity of therapy on days 8, 9 and 10 (‘augmentation’ of remission induction therapy) for patients with poor bone marrow cytoreduction detected in the day 6 bone marrow could improve the complete remission rate without increasing the number of toxic deaths. Patients from six centres were entered and treated with standard dose ara‐C for 7 or 10 d and an anthracycline for the first 3 d. Patients aged less than 60 years and with > 30% bone marrow biopsy cellularity or > 10% abnormal cells on the aspirate obtained 6 d after the start of therapy were augmented with cytosine arabinoside 3 g/m2 every 12 h on days 8, 9 and 10. Therapy was augmented in 116 of the 252 patients <60 years. There was a highly statistically significant difference between augmented and nonaugmented patients (P<0.001) for the per cent biopsy cellularity and per cent abnormal cells in the day 6 marrow. The CR rate for augmented patients was 69% and for nonaugmented patients 60% suggesting that augmentation therapy abrogated the prognostic significance of more extensive residual leukaemia in the day 6 bone marrow. The results suggest that augmentation of remission induction for patients with poor bone marrow cytoreduction detected 6 d after initiation of therapy, may salvage patients who are destined to fail remission induction because of resistant disease without producing excessive toxicity.

Lithium Effects on Granulopoiesis in Mice Following Cytotoxic Chemotherapy

Recent clinical studies have suggested that administration of lithium may modify the duration of neutropenia in patients receiving chemotherapy for treatment of acute leukemia (Stein et al., 1978) and solid tumors (Stein et al., 1977; Lyman et al., 1978). Fehir and Rossof (1978) reported similar effects of lithium in dogs following administration of cyclophosphamide. The mechanisms by which lithium increases blood neutrophil concentrations are not completely understood. Neutrophilia is associated with increased marrow neutrophil production (Malloy et al., 1978; Rothstein et al., 1978), increased neutrophil progenitor cells (CFU-C) (Tisman et al., 1973; Joyce and Chervenick, 1979) and enhanced release of colony stimulating activity (CSA) (Joyce and Chervenick, 1975; Harker et al., 1977). The present studies describe changes in hematopoiesis during daily administration of lithium chloride (Li) to normal mice and report enhanced recovery of granulopoiesis following administration of cytotoxic drugs.

Effects of hypoxia on megakaryocytopoiesis and granulopoiesis

Previous studies have reported that exposure of mice to hypoxic conditions results in a decrease in blood platelets. To further explore the effect of hypoxia on megakaryocytopoiesis, megakaryocytes and their progenitor cells (CFU‐M) were studied in hypoxic mice. Mice were exposed to hypoxia by enclosure in cages covered with dimethyl‐silicone rubber membranes for up to 10 d. At various times during the hypoxic and ex‐hypoxic periods the total megakaryocytes and CFU‐M were determined in the humerus and spleen. CFU‐M were assayed in the soft gel colony forming assay using pokeweed mitogen‐stimulated spleen cell conditioned medium (PWCM) as a source of colony stimulating activity. After 10 d of hypoxia, packed red cell volume (PRCV) increased to 148% of control levels and blood platelets decreased to 40% of controls. Total megakaryocytes and CFU‐M per humerus decreased to 18% and 50% of controls respectively. 4 d into the ex‐hypoxic phase, PRCV was still increased at 128% of controls while marrow megakaryocytes and CFU‐M increased to normal levels. Platelet recovery was somewhat slower, returning to normal by d 6. In contrast to the findings in the marrow, total spleen megakaryocytes and CFU‐M increased to about 3‐ and 5‐fold of control levels respectively by 6 d of hypoxia. During the exhypoxic phase, CFU‐M decreased to normal on d 4, followed by a rebound of 3‐fold control values on d 8. Spleen megakaryocytes decreased more slowly, returning to normal by d 10. A marked granulocytosis was observed during the hypoxic phase. Changes in granulocytes and granulocyte‐macrophage progenitor cells (CFU‐GM) in marrow and spleen were similar to those observed for megakaryocytes and CFU‐M. The results indicate that the thrombocytopenia of hypoxia is due to a decrease in production of marrow megakaryocytes and CFU‐M and is not offset by a simultaneous increase in spleen megakaryocytopoiesis.

Spontaneous Remission in Chronic Lymphocytic Leukemia

Excerpt Although spontaneous remissions have been reported to occur in leukemia (1-3) and many other types of cancer (4), rarely have such remissions been observed in chronic lymphocytic leukemia (...

The Effect of Lithium on Release of Granulocyte Colony Stimulating Activity in Vitro

Blood neutrophil concentration increases when lithium carbonate (Li) is given to hematologically normal subjects (O’Connell, 1970; Shopsin and Friedman, 1971). Recent reports (Hammond and Dale, 1979) have suggested that Li may increase blood neutrophils in gray collie dogs with cyclic hematopoiesis and may attenuate the neutropenia induced by cyto-toxic chemotherapy (Stein et al., 1977; Fehir and Rossof, 1977; Lyman et al., 1978; Joyce and Chervenick, 1979). Following reports (Tisman et al., 1973) that lithium enhances granulocyte production in vitro and increases release of colony stimulating activity (CSA) (Joyce and Chervenick, 1975a), Rothstein et al., (1978) demonstrated increased granulocyte production and expanded blood granulocyte pools in psychiatric patients receiving Li. Malloy et al., (1978) studied normal subjects given Li and found increased marrow neutrophils and neutrophil progenitor cells and increased levels of urinary CSA. Increased levels of urine CSA have been reported in patients with Felty’s syndrome given Li (Gupta et al., 1976) and addition of Li to media conditioned by murine lung tissue has been demonstrated to enhance release of CSA (Harker et ah, 1977). Blood monocytes and mitogen stimulated lymphocytes are major sources of CSA in man (Chervenick and LoBuglio, 1972; Cline and Golde, 1974). The increased release of CSA from leukocytes in the presence of Li forms the basis of this report.