David Jendiroba

Treatment of neutropenia-related fungal infections with granulocyte colony-stimulating factor-elicited white blood cell transfusions: a pilot study.

Neutropenia-related fungal infections can be life-threatening despite antifungal therapy. We evaluated the role of recombinant granulocyte colony-stimulating factor (rG-CSF)-elicited white blood cell (WBC) transfusions in patients with neutropenia-related fungal infections. Adult patients with hematologic malignancies, absolute neutrophil counts (ANC) <500/μl and fungal infections refractory to amphotericin b, received daily transfusions of rg-csf-elicited and irradiated wbc transfusions from related donors. donors received 5 μg/kg/day of rg-csf subcutaneously. donors achieved a mean anc of 29.4 × 103 per microliter. The mean yield of neutrophils per transfusion was 41 × 109 (range, 10–116). Fifteen patients received a median of eight transfusions (range, 3–16). Fourteen patients had received rG-CSF for a median of 12 days. The median ANC baseline was 20/μl. Eleven patients had favorable responses and eight of them remained free of infection 3 weeks after therapy. Favorable responses occurred among patients with better Zubrod performance status (median, 3 vs 4) and shorter duration of both profound neutropenia (median, 15 vs 25 days) and active infection (median, 8 vs 17 days). The mean 1- and 24-h post-transfusion ANCs were 594/μl (range, 98–1472/μl) and 396/μl (range, 50–1475/μl), respectively. Adverse reactions were observed in nine of 35 donors and in the recipients of six of 130 transfusions. rG-CSF-elicited WBC transfusions may be a safe and promising approach for treating neutropenia-related fungal infections.

Evaluation and comparison of three mobilization methods for the collection of granulocytes

BACKGROUND: Cancer chemotherapeutic regimens have become more potent and myeloablative. As a consequence, morbidity and mortality due to opportunistic infections have become a major challenge. The provision of adequate doses of viable granulocytes has thus become an important approach for circumventing the problem. A schedule for collecting therapeutic numbers of cells with minimal donor toxicity has yet to be established.

Increased CD38 expression is associated with favorable prognosis in adult acute leukemia

CD38 is expressed in acute lymphoblastic leukemia (ALL) and acute myelogenous leukemia (AML) blasts and its prognostic significance is unknown. We investigated CD38 expression in 304 AML and 138 ALL patients. CD38 was lower in AML-M3 compared to other FAB subtypes (5% vs. 41%; P < 0.001), but was similar among ALL subtypes (56.6%; P = 0.69). Ph + ALL and AML with t(15; 17) patients showed lower CD38 expression than the other cytogenetic groups. Overall survival favored AML and ALL patients with higher CD38 levels. Multivariate analysis revealed CD38 expression to be an independent outcome predictor in AML, but not in ALL.

Effective cytotoxicity against human leukemias and chemotherapy-resistant leukemia cell lines by N-N-dimethylsphingosine

We evaluated the cytotoxicity of dimethylsphingosine (DMS) against four human leukemia cell lines: two acute (HL60 and a multi-drug resistance MDR-positive derivative HL60-dox) and two blast crisis chronic myelogenous leukemias (JFP1, from a treatment refractory patient and K562), and against blasts isolated from 11 leukemia patients. Cell line viability decreased proportionally to DMS concentration and treatment time (P<0.001). HL60-dox and JFP1 were the most sensitive, indicating DMS efficacy against human leukemia MDR. Importantly, leukemia samples showed a similar sensitivity to DMS as that of the cell lines, firstly demonstrating PKC-independent sphingolipid activity against fresh human tumor specimens. DMS-based chemotherapy may improve leukemia treatment.

Dexrazoxane in combination with anthracyclines lead to a synergistic cytotoxic response in acute myelogenous leukemia cell lines

In an attempt to improve current therapeutic strategies for acute myelogenous leukemia (AML), we studied the effects of a commercially available drug, dexrazoxane (DEX), which protects against anthracycline-induced cardiotoxicity. The rationale was that DEX would permit higher doses of cardiotoxic drugs to be given. The drug itself may have therapeutic potential as well. Finally, there are concerns that the drug may, as a protective agent, diminish the effectiveness of various chemotherapeutics. To help resolve the question about potential drug antagonism, we undertook a series of in vitro analyses of DEX and various combinations with anthracyclines and other agents. Colony-forming assays were used to evaluate stem-cell renewal of myeloid cells in vitro, and median-effect analysis was used to evaluate antagonism, synergism, and additivity. The anthracyclines doxorubicin, daunorubicin, and idarubicin were individually combined with DEX to study in vitro effects in leukemic myeloid cell lines. In the hope, we could extend the findings to non-anthracyclines, etoposide and cytosine arabinoside were also evaluated in combination with DEX using the same in vitro model and method. We found that the effects of DEX in combination with any of the anthracyclines were schedule dependent. The antitumor effect was greater for each combination than for any anthracycline alone except when DEX was administered 24h before doxorubicin or daunorubicin. These data were corroborated through median-effect analysis. Etoposide in combination with DEX was synergistic for all combinations and schedules, and the combination of cytosine arabinoside and DEX was effective depending on the schedule used. DEX appears to be a promising drug in the treatment of AML and warrants further clinical study involving novel drug combinations.

High incidence of monosomy 18 in lymphoid malignancies that have bone marrow and peripheral blood involvement

We studied the incidence of numerical chromosome 18 abnormalities in 107 patients with lymphoid malignancies by fluorescence in situ hybridization (FISH) using a directly conjugated centromeric probe for chromosome 18. Samples were obtained by fine needle aspiration of diseased nodes, bone marrows or peripheral blood. Monosomy 18 was more common in chronic lymphocytic leukemia (43%), small lymphocytic lymphoma (28%), and follicular lymphomas (12.5%) than in diffuse lymphomas (5.3%; p < 0.01). Monosomy 18 was detected in 9.7-17.1% of the cells in non-Hodgkins lymphoma (NHL) (background, 5.4%; 99% CI, 4.2%-6.6%) and in 8%-16.7% (median, 10%) of the cells in (CLL) (background, 3.4%; 99% CI, 2.5%-4.3%). All patients with monosomy 18 were found to have bone marrow involvement. Of all untreated patients who had disease involving the bone marrow, 32% were found to have monosomy 18. Trisomy 18 was detected in 3.6%-48.2% of the cells in NHL (background, 0.9%; 99% CI, 0.2%-1.6%) and was most common in diffuse large-cell lymphoma (34%) and follicular lymphomas (31%). None of the patients with small lymphocytic lymphoma or chronic lymphocytic leukemia had trisomy 18. There was no correlation between trisomy 18 and response to treatment or clinical presentation. In this study, monosomy 18 was observed frequently in patients with lymphoid malignancies that involve the bone marrow and peripheral blood. Our data suggest that important gene(s) located on chromosome 18 may be involved in homing of the malignant lymphocytes to the bone marrow and peripheral blood.

Chromosome X numerical abnormalities in patients with Non-Hodgkin's Lymphoma: A study of 59 patients using fluorescence in situ hybridization

Chromosome X numerical abnormalities are frequently observed in non-Hodgkins lymphoma (NHL), with an incidence of 3% to 14% for chromosomal loss and 7% to 33% for chromosomal gain. Because sex chromosome numerical abnormalities are thought to be due to aging, little information is known about their relation to gender, therapy, and prognosis. Therefore, to determine the incidence and clinical relevance of this abnormality in NHL, we studied specimens from 59 NHL patients (31 men and 28 women) by fluorescence in situ hybridization (FISH) using a directly conjugated centromeric probe for chromosome X. The median age for the entire group was 52 years (range, 31-88 years). All specimens were obtained by fine-needle aspiration of diseased lymph nodes. Sex-matched lymphocytes from benign hyperplastic lymph nodes were used as controls. The overall incidence of chromosome X numerical abnormalities was 49.2%. Female patients had a higher overall incidence than males (76% vs. 24%; p < 0.001). The median percentage of cells involved in this abnormality in each specimen was 5.2%. There was no statistically significant difference in the incidence in previously treated than untreated patients (53.1% vs. 44.4%; p < 0.75) and in intermediate-grade NHL than low-grade NHL (61.1% vs. 50%; p < 0.75). There was a trend towards a higher incidence of chromosome X loss in older patients. While the difference in the incidence of chromosome X abnormalities observed between women and men may be due to the difference in the normal copy numbers of this chromosome in each sex group, this abnormality remained higher than any other autosomal chromosome abnormality in NHL previously evaluated by FISH. We conclude that, although FISH detected a high incidence of chromosome X numerical abnormalities and that females had a higher incidence than males, only a small percentage of the cells were involved, suggesting that this abnormality is most likely a secondary genetic defect that is not important in the pathogenesis of NHL.

The Use of Hematopoietic Growth Factors for Recruitment of Leukocytes for Transfusion

Neutropenia and its related opportunistic infections have always been a concern, particularly in patients undergoing chemotherapy. Neutropenic infection is a leading cause of morbidity and mortality in patients who undergo chemotherapy. Improvement in antibiotic therapies as well as increased use of hematopoietic growth factors provide wider margins of safety for the use of higher doses of chemotherapy, with some regimens approaching marrow transplantation ablative potency. While the supportive use of growth factors and improved antibiotics have advanced cancer treatment, they have not, even in combination, provided enough support to counterbalance deeper peaks of neutropenia and prolonged nadirs caused by the more aggressive chemotherapy strategies. As a consequence, fewer cycles of chemotherapy, nowadays, induce longer periods of marrow aplasia with consequently longer recovery periods.