Recombinant human granulocyte-macrophage colony-stimulating factor ameliorates zidovudine-induced neutropenia in patients with acquired immunodeficiency syndrome (AIDS)/AIDS-related complex.

To evaluate the effect of recombinant granulocyte-macrophage colony-stimulating factor (GM-CSF) on patients with acquired immunodeficiency syndrome (AIDS) or AIDS-related complex (ARC) who were intolerant to zidovudine because of neutropenia, we performed a randomized, open-label study in which patients were assigned to one of two groups. Zidovudine was discontinued in group A patients before instituting GM-CSF treatment and was restarted in a graduated fashion over 4 weeks. Group B patients continued on full-dose (1,200 mg/d) zidovudine therapy while beginning GM-CSF therapy. A total of 17 patients were entered, eight in group A and nine in group B. Five of eight patients in group A and seven of nine in group B had a history of Pneumocystis carinii pneumonia (PCP). All were homosexual males, except one female in group A who was the sex partner of a bisexual male with AIDS. All patients had neutropenia (absolute neutrophil count [ANC] less than 1,000/microL) while taking full-dose zidovudine. The mean CD4 (+/- SD) lymphocyte level was 37 (+/- 29)/microL and 39 (+/- 44)/microL in groups A and B, respectively. After randomization, patients were begun on subcutaneous GM-CSF at a dose of 1.0 microgram/kg/d. Patients in group A received 2 weeks of daily GM-CSF, at which time zidovudine was restarted if the ANC was greater than 1,000/microL; if the ANC was less than 1,000/microL, the dose of GM-CSF was increased to 3.0 micrograms/kg, and at 2-week intervals either zidovudine was restarted or the dose of GM-CSF was increased to 5 micrograms/kg and then 10 micrograms/kg, to maintain the ANC greater than 1,000/microL. Group B patients received full-dose zidovudine concurrently with GM-CSF administration. The dose of GM-CSF was increased every 2 weeks if necessary to keep the ANC greater than 1,000/microL while maintaining full-dose zidovudine therapy. Patients in each group showed an increase in total white blood cell (WBC) count. Neutrophils and eosinophils were responsible for the majority of this increase. Patients in group A had a more rapid increase in WBC than those in group B; however, by week 8, the WBC in each group was essentially equal. Viral replication as measured by human immunodeficiency virus (HIV) p24 antigen (Ag) was decreased in four patients in each group, increased in one patient in each group, and remained unchanged in the remainder. The ability to culture virus from peripheral blood mononuclear cells was not changed by the regimen. The major toxicities of the regimen were fever and malaise.(ABSTRACT TRUNCATED AT 400 WORDS)     

Combined therapy with recombinant granulocyte colony-stimulating factor and erythropoietin decreases hematologic toxicity from zidovudine.

Twenty-two patients with acquired immunodeficiency syndrome (AIDS) or severe AIDS-related complex and multilineage hematopoietic defects were treated with recombinant granulocyte colony-stimulating factor (G-CSF) and erythropoietin (EPO) in a phase I/II trial. All patients were neutropenic and anemic after withdrawal of all bone marrow-suppressive drugs. Daily, G-CSF was subcutaneously self-administered until an absolute neutrophil count (ANC) greater than 6,000/microL was achieved and maintained for 2 weeks. Subcutaneous EPO was added to the regimen and the dose increased until an increase of 15 g/L of hemoglobin was observed. Groups of patients were administered increasing doses of zidovudine to determine their tolerance. G-CSF and EPO therapy was continued with dose modification to maintain an ANC greater than 1,500/microL and hemoglobin greater than 100 g/L. The dose of zidovudine was not altered. All 22 patients responded to G-CSF with a mean 10-fold increase in neutrophils occurring in less than 2 weeks. Significant increases in CD4 and CD8 cell number, lymphocyte proliferative response, and bone marrow cellularity were seen. EPO therapy increased hemoglobin in all 20 evaluable patients within 8 weeks. Sixteen patients received 1,000 mg and four patients received 1,500 mg of zidovudine per day. The reinstitution of zidovudine resulted in a decline in reticulocytes and hemoglobin and the reappearance of transfusion requirements in eight of the 20 patients, six of whom had the study medications stopped. No patient had the study medications stopped because of neutropenia or thrombocytopenia. Toxicities were mild and did not require dose modifications. Limiting dilution plasma and lymphocyte co-cultures for HIV as well as serum p24 antigen levels did not change significantly during G-CSF or combined G-CSF and EPO therapy. HIV p24 antigen decreased significantly with zidovudine therapy. Opportunistic infections occurred in 14 patients but were successfully treated with myelosuppressive antimicrobial agents, including ganciclovir, without the development of neutropenia. These results suggest that combined therapy with G-CSF and EPO may improve the neutropenia and anemia of AIDS. Combined therapy may allow the resumption of full-dose zidovudine in most patients intolerant of the hematologic effects of zidovudine without apparent alteration of HIV expression or the efficacy of zidovudine.     

Use of oral mucosal neutrophil counts to detect the onset and resolution of profound neutropenia following high-dose myelosuppressive chemotherapy

Severe neutropenia following cytotoxic, anti-cancer chemotherapy is well-known to be associated with an increased risk of infections that may be life-threatening, particularly if not treated immediately. Consequently, serial measurements of neutrophil counts in peripheral blood are done routinely following the administration of high-dose myelosuppressive chemotherapy in order to monitor the onset, severity, and duration of iatrogenic neutropenia. We have studied a non-invasive method of quantifying neutrophils recoverable from the oral mucosa, a normal tissue site of neutrophil turnover, as an alternative approach for monitoring severe, chemotherapy-induced neutropenia. This method is based on the quantification of fluorochrome-stained neutrophils present in timed mouthwash specimens. Blood neutrophil (ANC) and mucosal neutrophil counts (MNC) were measured repeatedly in 23 patients who had been treated with dose-intensive chemotherapy for a variety of indications. All 23 patients developed profound neutropenia (ANC < 100/mm3), and 19 developed neutropenic fever (>101 degrees F) during the 2 weeks following treatment. Nadirs of neutropenia defined by MNC were significantly less prolonged than those defined by the ANC. Furthermore, the onset and resolution of neutropenic fever coincided more precisely with nadirs of neutropenia defined by the MNC than with those defined by the ANC. Our findings indicate that oral mucosal neutrophil counts predict the timing of clinical events associated with neutropenia (e.g., the onset and resolution of fever) with significantly greater accuracy than blood neutrophil counts.     

A comparison of therapeutic schedules for administering granulocyte colony-stimulating factor to nonhuman primates after high-dose chemotherapy.

Granulocyte colony-stimulating factor (G-CSF) has been shown to be effective in clinical trials for reducing the period of neutropenia after chemotherapy. In this study, we compared the timing for initiating G-CSF administration after chemotherapy with the duration of neutropenia and hematopoietic regeneration. Nonhuman primates treated with high-dose chemotherapy (mechloroethamine, 1.5 mg/kg, intravenously) and not administered G-CSF therapy experienced 8 days of neutropenia (absolute neutrophil count [ANC] less than 1,000/mm3) and had an ANC nadir of 124 +/- 64/mm3 at day 7. Monkeys receiving G-CSF (5 micrograms/kg/d, subcutaneously) began treatment on either days 1, 3, 5, or 7 after chemotherapy. Monkeys treated with G-CSF had an earlier ANC recovery and the number of days with an ANC less than 500/mm3 and ANC less than 1,000/mm3 was reduced by approximately 50% in all treatment strategies. All G-CSF-treated animals, irrespective of the time that G-CSF was initiated, reached an ANC of 10,000/mm3 on day 13 +/- 1 day after chemotherapy. These results demonstrated that the duration of G-CSF therapy was almost twice as long for monkeys treated on day 1 as it was for monkeys that received therapy beginning on day 7. A comparison of the results for all treated monkeys identified a distinct difference in the responses of monkeys treated on day 1 from that of animals treated with G-CSF at later times. G-CSF initiated 1 day after chemotherapy led to an earlier onset of neutropenia and a more rapid and augmented recovery of myeloid progenitor cells in the peripheral blood when compared with control and delayed therapy groups. This study demonstrates that neutropenia due to a single dose of mechloroethamine can be equally reduced with both early and delayed initiation of G-CSF. Further, initiating G-CSF therapy after 7 days required approximately 50% less days of therapy to reach an appropriate termination point. The applicability of these findings to other chemotherapy regimens and for repeated cycles is uncertain and needs to be further evaluated. This is a US government work. There are no restrictions on its use.     

Blood neutrophil increment after a single injection of rhG-CSF or rhGM-CSF correlates with marrow cellularity and may predict the grade of neutropenia after chemotherapy

Summary. The grade of neutropenia after chemotherapy seems to be correlated to the bone marrow cellularity as judged by biopsies. Prolonged blood neutropenia after sequential chemotherapy reduces dose intensity and increases the risk of severe infections. A predictive non-invasive test for marrow cellularity is needed in the attempt to predict chemotherapy-induced blood neutropenia.
Thirty-one patients with haematological disorders were studied with measurements of blood absolute neutrophil counts (ANC) 24 h after a single subcutaneous injection of recombinant human granulocyte colony stimulating factor (rhG-CSF) or granulocyte-macrophage CSF (rhGM-CSF). Before cytokine administration all patients had bone marrow biopsies performed.
The median increase in blood ANC 24 h after cytokine administration was 15·9 × 10⁹/l (range 3·7–34·2) in 18 patients with normo- or hypercellular marrows and only 0·4 × 10⁹/l (range 0·0–11·2) in 13 patients with hypocellular marrows ( P <0·00001). An increase in ANC or more than 5 × 10⁹/l was predictive for normo- or hypercellular bone marrows with a sensitivity and specificity of 94% and 84%, respectively.
A subsequent pilot study in selected patients with prolonged neutropenia was performed. The ANC increment in 12 cases before chemotherapy correlated to the grade of neutropenia and may predict the risk of febrile neutropenia.
It is suggested that blood responsiveness to myeloid growth factors correlates with marrow cellularity and may identify outpatients with risk for severe neutropenia after cyclic chemotherapy.     

Circulating granulocyte colony-stimulating factor (G-CSF) levels after allogeneic and autologous bone marrow transplantation: endogenous G-CSF production correlates with myeloid engraftment.

Myeloid engraftment after bone marrow transplantation (BMT) is influenced by a number of variables, including cytoreductive chemoradiotherapy, genetic disparity, number of reinfused committed myeloid progenitor cells, healthy microenvironment, and the presence of hematopoietic growth factors. Granulocyte colony-stimulating factor (G-CSF) stimulates proliferation of myeloid progenitor cells and enhances myeloid engraftment after BMT. We investigated the temporal relationship between endogenous G-CSF production and myeloid engraftment in both children and adults after allogeneic (ALLO) and autologous (AUTO) BMT. Circulating endogenous G-CSF levels ranged between 0 and 2552 pg/mL. The correlation coefficient between circulating serum G-CSF levels and the peripheral absolute neutrophil count (ANC) was r = -.875 (P less than .001). The endogenous serum G-CSF level was highest during the first week after BMT, when the ANC was less than or equal to 200/microL (699 +/- 82.3 pg/mL) (P less than .001). Both children and adults demonstrated a similar inverse relationship between circulating G-CSF level and degree of neutropenia. One patient failed to engraft after AUTO BMT and also failed to generate any endogenous G-CSF production. Lastly, once the serum G-CSF level decreased to less than 200 pg/mL, a mean of 6.1 +/- 0.9 days elapsed before the ANC was greater than or equal to 500/microL for 2 consecutive days. This study demonstrates that endogenous G-CSF production is associated with myeloid engraftment in both children and adults after AUTO and ALLO BMT and that the rate of increase and decrease in endogenous G-CSF may be predictive of either failure to engraft or duration of neutropenia.     

Ganciclovir-related neutropenia after preemptive therapy for cytomegalovirus infection: comparison between cord blood and bone marrow transplantation

We studied ganciclovir (GCV)-related neutropenia after preemptive therapy for cytomegalovirus infection: 9 of 17 (53%) cord blood transplantation (CBT) patients and 18 of 20 (90%) bone marrow transplantation (BMT) patients developed GCV-related neutropenia with an absolute neutrophil count (ANC) of less than 1000/l. Among the patients who did not receive granulocyte colony-stimulating factor, 2 (13%) and 1 (7%) CBT patients, and 10 (56%) and 8 (44%) BMT patients, developed neutropenia with an ANC of less than 500 and 250/l, respectively. The incidences of neutropenia in patients with an ANC of less than 1000, 500, and 250/l were significantly lower after CBT in comparison with BMT. Two BMT patients, but no CBT patients, developed neutropenic fever, and both patients recovered after antibiotic therapy. In CBT patients, a creatinine clearance rate of less than 50 ml/min and an absence of steroid therapy were associated with a greater incidence of GCV-related neutropenia. No risk factors for GCV-related neutropenia were found in BMT patients. These results suggest that GCV may be less toxic to myeloid progenitor cells from cord blood than those from bone marrow.     

Hematopoietic growth factors for graft failure after bone marrow transplantation: a randomized trial of granulocyte-macrophage colony- stimulating factor (GM-CSF) versus sequential GM-CSF plus granulocyte- CSF

Delay in hematologic recovery after bone marrow transplantation (BMT) can extend and amplify the risks of infection and hemorrhage, compromise patients' survival, and increase the duration and cost of hospitalization. Because current studies suggest that granulocyte- macrophage (GM) colony-stimulating factor (CSF) may potentiate the sensitivity of hematopoietic progenitor cells to G-CSF, we performed a prospective, randomized trial comparing GM-CSF (250 micrograms/m2/d x 14 days) versus sequential GM-CSF x 7 days followed by G-CSF (5 micrograms/kg/d x 7 days) as treatment for primary or secondary graft failure after BMT. Eligibility criteria included failure to achieve a white blood cell (WBC) count > or = 100/microL by day +21 or > or = 300/microL by day +28, no absolute neutrophil count (ANC) > or = 200/microL by day +28, or secondary sustained neutropenia after initial engraftment. Forty-seven patients were enrolled: 23 received GM-CSF (10 unrelated, 8 related allogeneic, and 5 autologous), and 24 received GM- CSF followed by G-CSF (12 unrelated, 7 related allogeneic, and 5 autologous). For patients receiving GM-CSF alone, neutrophil recovery (ANC > or = 500/microL) occurred between 2 and 61 days (median, 8 days) after therapy, while those receiving GM-CSF+G-CSF recovered at a similar rate of 1 to 36 days (median, 6 days; P = .39). Recovery to red blood cell (RBC) transfusion independence was slow, occurring 6 to 250 days (median, 35 days) after enrollment with no significant difference between the two treatment groups (GM-CSF: median, 30 days; GM-CSF+G- CSF; median, 42 days; P = .24). Similarly, platelet transfusion independence was delayed until 4 to 249 days (median, 32 days) after enrollment, with no difference between the two treatment groups (GM- CSF: median, 28 days; GM-CSF+G-CSF: median, 42 days; P = .38). Recovery times were not different between patients with unrelated donors and those with related donors or autologous transplant recipients. Survival at 100 days after enrollment was superior after treatment with GM-CSF alone. Only 1 of 23 patients treated with GM-CSF died versus 7 of 24 treated with GM-CSF+G-CSF who died 16 to 84 days (median, 38 days) after enrollment, yielding Kaplan-Meier 100-day survival estimates of 96% +/- 8% for GM-CSF versus 71% +/- 18% for GM-CSF+G-CSF (P = .026). These data suggest that sequential growth factor therapy with GM-CSF followed by G-CSF offers no advantage over GM-CSF alone in accelerating trilineage hematopoiesis or preventing lethal complications in patients with poor graft function after BMT.(ABSTRACT TRUNCATED AT 400 WORDS)     

Neutrophil recovery in elderly breast cancer patients receiving adjuvant anthracycline-containing chemotherapy with pegfilgrastim support

Shortening duration of chemotherapy-induced neutropenia may reduce risk of infection and aid subsequent chemotherapy delivery. Cycle 1 neutrophil recovery was evaluated in 59 elderly women with breast cancer receiving adjuvant FEC100 (5-fluorouracil 500 mg/m², epirubicin 100 mg/m² and cyclophosphamide 500 mg/m²) and randomized to pegfilgrastim primary prophylaxis (PP) from cycle 1, or secondary prophylaxis (SP, i.e., subsequent to a neutropenic event [no G-CSF in cycle 1]). In cycle 1, grade 4 neutropenia occurred in 77% (PP; N = 30) and 72% (SP; N = 29). Duration of grade 3-4 neutropenia was shorter with pegfilgrastim than without. Mean absolute neutrophil count (ANC) recovered above 1.0 × 10⁹/L by day 9 (pegfilgrastim) versus days 16-18 (without). At last observation (≥day 14 ± 2), no PP patient had ANC <1.0 × 10⁹/L versus approximately 25% of those receiving no pegfilgrastim. In conclusion, cycle 1 pegfilgrastim improved recovery from severe neutropenia in elderly breast cancer patients receiving adjuvant FEC100.     

Sequential administration of recombinant human interleukin-3 and granulocyte-macrophage colony-stimulating factor after autologous bone marrow transplantation for malignant lymphoma: a phase I/II multicenter study

Preclinical studies of recombinant human interleukin-3 (rhIL-3) and granulocyte-macrophage colony-stimulating factor (rhGM-CSF) have shown enhancement of multilineage hematopoiesis when administered sequentially. This study was designed to evaluate the safety, tolerability, and biologic effects of sequential administration of rhIL- 3 and rhGM-CSF after marrow ablative cytotoxic therapy and autologous bone marrow transplantation (ABMT) for patients with malignant lymphoma. Thirty-seven patients (20 patients with non-Hodgkin's lymphoma and 17 patients with Hodgkin's disease) received one of four different treatment regimens before ABMT. Patients were entered in one of four study groups to receive rhIL-3 (2.5 or 5.0 micrograms/kg/day) administered by subcutaneous injection for either 5 or 10 days starting 4 hours after the marrow infusion. Twenty-four hours after the last dose of rhIL-3, rhGM-CSF (250 micrograms/m2/d as a 2-hour intravenous infusion) administration was initiated. rhGM-CSF was administered daily until the absolute neutrophil count (ANC) was > or = 1,500/microL for 3 consecutive days or until day 27 posttransplant. The most frequent adverse events in the trial included nausea, fever, diarrhea, mucositis, vomiting, rash, edema, chills, abdominal pain, and tachycardia. Three patients were removed from the study because of chest, skeletal, and abdominal pain felt to be probably related to study drug. Four patients died during the study period because of complications unrelated to either rhIL-3 or rhGM-CSF. The median time to recovery of neutrophils (ANC > or = 500/microL) and platelets (platelet count > or = 20,000/microL) was 14 and 15 days, respectively. There were fewer days of platelet transfusions than seen in historical control groups using rhGM-CSF, rhG-CSF, or rhIL-3 alone. In addition, there were fewer days of red blood cell transfusions compared with historical controls using no cytokines or rhGM-CSF. These data indicate that the sequential administration of rhIL-3 and rhGM-CSF after ABMT is safe and generally well-tolerated and results in rapid recovery of multilineage hematopoiesis.     

Clinical evaluation of recombinant human G-CSF in children with cancer]

Recombinant human granulocyte colony-stimulating factor (rG-CSF), produced by Chinese hamster ovary cells, was administered in 69 chemotherapy-induced neutropenic pediatric patients (pts) with malignant tumors. Each pt received two cycles of the same chemotherapy and had neutropenia with absolute neutrophil counts (ANC) less than 500/microliter in the first cycle. Initiating 72 hours after termination of chemotherapy in the second cycle, rG-CSF (2 micrograms/kg/day) was given subcutaneously or intravenously to each pt for 10 days. rG-CSF significantly increased ANC at nadir; 72 +/- 14 vs. 206 +/- 40/microliter (data in the first cycle vs. data in the second cycle, respectively), and reduced the period of neutropenia with ANC less than 500/microliter; 9.7 +/- 0.6 vs. 5.1 +/- 0.6 days, and the period for restoration to ANC greater than or equal to 1,000/microliter after initiation of chemotherapy; 25.5 +/- 0.6 vs 17.5 +/- 0.9 days. rG-CSF did not affect other components of peripheral blood. The number of days with fever greater than or equal to 38 degrees C was significantly reduced by rG-CSF treatment. Neck pain and lumbago were observed in one pt, pollakisuria in one pt, and elevation of the serum levels of LDH and uric acid in one pt, however these were mild to moderate, transient, and resolved without any specific treatment. We concluded that rG-CSF was effective in neutropenia induced by intensive chemotherapy for malignant tumors without any serious side effects.     

Recovery from neutropenia can be predicted by the immature reticulocyte fraction several days before neutrophil recovery in autologous stem cell transplant recipients

The duration of neutropenia (absolute neutrophil count (ANC) < or = 100/microl) identifies cancer patients at risk for infection. A test that precedes ANC > or = 100/microl would be of clinical value. The immature reticulocyte fraction (IRF) reflects erythroid engraftment and hence a recovering marrow. We evaluated the IRF as predictor of marrow recovery among 90 myeloma patients undergoing their first and second (75 patients) melphalan-based autologous stem cell transplantation (Mel-ASCT). The time to IRF doubling (IRF-D) preceded ANC > or = 100/microl in 99% of patients after the first Mel-ASCT by (mean+/-s.d.) 4.23+/-1.96 days and in 97% of the patients after the second Mel-ASCT by 4.11+/-1.95 days. We validated these findings in a group of 117 myeloma patients and 99 patients with various disorders undergoing ASCT with different conditioning regimens. We also compared the time to hypophosphatemia and to absolute monocyte count > or = 100/microl to the time to ANC > or = 100/microl. These markers were reached prior to this ANC end point in 55 and 25% of patients but were almost always preceded by IRF-D. We conclude that the IRF-D is a simple, inexpensive and widely available test that can predict marrow recovery several days before ANC> or = 100/microl.     

Comparable kinetics of myeloablation between fludarabine/full-dose busulfan and fludarabine/melphalan conditioning regimens in allogeneic peripheral blood stem cell transplantation

Fludarabine was utilized in the conditioning regimen of 30 adult patients undergoing an allogeneic hematopoietic stem cell transplant. In 18 patients it was combined with full-dose busulfan (FluBu) as a myeloablative regimen and in 12 cases with melphalan (FluMel) as a reduced intensity conditioning (RIC) regimen. Patients in the FluBu group were younger than in the FluMel group (P=0.03). Of 30 patients, 24 received peripheral blood stem cells (PBSC) whereas six patients in the FluBu group received bone marrow cells. The hematological toxicity of each regimen was evaluated by analyzing the kinetics of the neutropenia induced by preparative regimens and the time to recovery of the absolute neutrophils count (ANC) and platelets post transplantation. In PBSC transplants, the median day of severe neutropenia (<500 ANC/microl) occurred on day +6 after the FluBu regimen and on day +3 after FluMel (P=ns), whereas both groups had a duration of severe neutropenia of 9 days and a comparable time for ANC and platelet engraftment. Extra-hematological toxicities were also comparable in the two groups. These findings suggest that the hematological and extra-hematological toxicities induced by fludarabine/full-dose i.v. busulfan are similar to those induced by a standard RIC regimen such as fludarabine/melphalan.     

Leucocyte transfusions from rhG-CSF or prednisolone stimulated donors for treatment of severe infections in immunocompromised neutropenic patients

Sepsis in profound neutropenia after chemotherapy is associated with high mortality despite appropriate antibacterial or antifungal treatment. In a prospective phase I/II study we evaluated the feasability and efficacy of leucocyte transfusions (LT) in patients with malignancies or haematological disorders who were suffering from severe bacterial or fungal infection during therapy-related bone marrow aplasia. 30 patients with severe neutropenia and clinical signs of life-threatening sepsis not responding to adequate treatment, received LT from rhG-CSF-stimulated family donors or from prednisolone-primed volunteers. A total of 301 LT were administered. The median number of LT per patient was seven (range three to 65), the median duration of LT treatment was 8 d (range 2-35). The white cell count (WBC), absolute neutrophil count (ANC) and lymphocyte count of the concentrates from rhG-CSF-stimulated donors were significantly higher than those from prednisolone-primed volunteers (P = 0.0001). Despite the critical condition of the patients, LT were generally well tolerated. Only 39 (12.9%) LT were associated with adverse reactions. The transfusion of leucocytes collected by continuous flow leukapheresis from both rhG-CSF and prednisolone stimulated donors resulted in a measurable increment of the peripheral leucocyte and ANC counts in our patients. On day 100 after the first LT, 20/30 patients were alive with complete clearance of the infection.     

Treatment of myelodysplastic syndrome with low-dose human granulocyte colony-stimulating factor: a multicenter study

The objective of this study was to determine the hematopoietic effects and toxicity of low-dose granulocyte colony-stimulating factor (G-CSF) in myelodysplastic syndrome (MDS) patients with neutropenia. Recombinant human G-CSF (Lenograstim) was administered by daily subcutaneous injection with an initial dosage of 0.5 microg/kg per day for 2 weeks. Patients not responding to the initial dosage received the escalated dosage, 1 to 2 microg/kg per day for 2 weeks. Eligibility criteria were the following: French-American-British disease classification subtype refractory anemia (RA), refractory anemia with ringed sideroblasts (RARS), or refractory anemia with excess blasts (RAEB) with an absolute neutrophil count (ANC) of <1.5 x 10(9)/L. Criteria indicating response to treatment were ANC of >1.5 x 10(9)/L and doubling of ANC on at least 2 occasions. Thirty-two MDS patients were recruited from 6 university hospitals. Eighteen patients had RA, 4 had RARS, and 10 had RAEB. Median age was 56.4 years (range, 28-87 years). Twenty-six patients (81.2%) had an increase in ANC from a median of 0.94+/-0.35 x 10(9)/L to 4.24+/-3.78 x 10(9)/L.Three of 6 patients who did not respond to the initial dosage responded to the escalated dosage of 1 microg/kg per day. Eighteen (81.8%) of 22 patients with RA or RARS responded compared with 8 (80%) of 10 patients with RAEB. The response rates in patients with ANCs of <0.5 x 10(9)/L. 0.5 to <1.0 x 10(9)/L, and 1.0 to 1.5 x 10(9)/L were 80%, 70%, and 88.2%, respectively. The side effects were minimal. No significant changes in hemoglobin levels or platelet counts were observed. In conclusion, low-dose G-CSF administered by subcutaneous injection is well tolerated and effective in improving neutropenia in MDS patients.     

Outlook in oral and cutaneous Kaposi's sarcoma

We looked at survival of 138 patients with HIV-1-associated Kaposi's sarcoma. Patients with lesions of the oral mucosa had a higher death rate (risk ratio 3.4 [95% CI 1.6-7.1]; p=0.001) than those having exclusively cutaneous manifestations of the disease. Patients with oral Kaposi's sarcoma and a CD4 cell count of at least 150/microL had a similar mortality risk to patients with the cutaneous disease but CD4 cell concentration of no more than 150/microL. Thus, oral Kaposi's sarcoma is an important prognostic marker, at least for patients who do not receive triple antiretroviral therapy.     

In vivo administration of recombinant human granulocyte/macrophage colony-stimulating factor in acute lymphoblastic leukemia patients receiving purged autografts [see comments]

Based on the recent reports that recombinant human granulocyte/macrophage colony-stimulating factor (rhGM-CSF) accelerates the rate of engraftment in a variety of autologous bone marrow transplantation settings, we have investigated its effects on hematopoietic recovery of patients with acute lymphoblastic leukemia (ALL) undergoing autologous bone marrow transplantation. Our studies, which involved 25 autologous ALL recipients who received rhGM-CSF and 27 controls similar for disease status (remission or relapse) and disease type (B- or T-lineage) differed from previous studies in one important aspect: the bone marrows were purged with 4- hydroperoxcyclophosphamide (4HC) and anti-T or anti-B-cell lineage- specific antibodies before transplantation. Such treatments frequently lead to a reduction in the CFU-GM content of the transplanted marrow. Eighteen of 25 patients completed the entire course of rhGM-CSF. Of the 16 patients who received greater than or equal to 64 micrograms/M2/d for at least eight days, there were five patients who had an apparent rhGM-CSF response and 11 patients who did not respond. Of the parameters analyzed, only the number of CFU-GM progenitor cells infused per kilogram was significantly associated with an rhGM-CSF response. All patients receiving greater than or equal to 1.2 x 10(4) CFU-GM progenitors per kilogram achieved an absolute neutrophil count (ANC) greater than or equal to 1,000/microL by day 21 and had a greater than 50% decrement in ANC within 48 to 72 hours of discontinuing rhGM-CSF, as contrasted to none of the patients receiving less than or equal to 7.2 x 10(3) CFU-GM progenitors per kilogram.(ABSTRACT TRUNCATED AT 250 WORDS)     

A retrospective study of neutropenia in HIV disease

In aiming to define the characteristics of HIV-infected subjects developing neutropenia and describe the causes, features and effects of neutropenia we undertook a retrospective study in a dedicated HIV unit in London, UK. Two hundred and forty-four patients with documented neutropenia, defined as absolute neutrophil count (ANC) < 1,000/mm3, during a 12-month period were studied. First neutropenia occurred at a median CD4 count of 30 cells/mm3. Low CD4 count was associated with longer episodes of neutropenia with a more profound nadir. Two-thirds of episodes lasted less than 2 weeks. ANC nadir was < 500 cells/mm3 in 45% of episodes. Infections were most frequent in patients with profound but brief neutropenic episodes. Neutropenia was generally mild, short-lived and associated with late-stage disease. However, profound neutropenia did develop suddenly in some patients with no prior history of neutropenia (in 13% first neutropenic ANC recorded was < or =500 cells/mm3), and at CD4 count > 200 cells/mm3. Most patients were receiving multiple myelosuppressive therapies. Infection was associated with brief, profound neutropenia.     

Treatment of severe neutropenia due to Felty's syndrome or systemic lupus erythematosus with granulocyte colony-stimulating factor.

OBJECTIVES: To examine the efficacy and safety of recombinant human granulocyte colony-stimulating factor (rhG-CSF) and recombinant human granulocyte-macrophage colony-stimulating factor (rhGM-CSF) for the treatment of severe neutropenia due to Felty's syndrome (FS) or systemic lupus erythematosus (SLE). METHODS: Eight patients with absolute neutrophil counts (ANC) below 1,000/microL attributable to FS (n = 4) or SLE (n = 4) were treated with rhG-CSF. The hematologic and clinical response as well as side effects were recorded. In addition, reports on the use of rhG-CSF/rhGM-CSF in FS and SLE retrieved from the English language literature were analyzed. RESULTS: RhG-CSF effectively corrected neutropenia due to FS and SLE in seven of the current eight patients. In 54 of 55 FS and SLE patients retrieved from the literature, G-CSF or GM-CSF, respectively, proved to be effective at elevating the neutrophil count, which was often associated with improvement of infectious complications. The neutrophil count often declined again when growth factor treatment was stopped but generally stabilized at a level that exceeded the pretreatment count. Side effects included rare cases of thrombocytopenia, arthralgias, and development of cutaneous leukocytoclastic vasculitis. Side effects were dose dependent and resolved when treatment was discontinued. One of our own patients and 17 previously reported patients continued to benefit from long-term administration of rhG-CSF over periods of more than 40 months. CONCLUSIONS: RhG-CSF is an effective and generally well-tolerated treatment for neutropenia due to FS or SLE. Exacerbation of the underlying rheumatic condition due to G-CSF appears to be rare if G-CSF is administered at the lowest dose effective at elevating the ANC above 1,000/microL.     

Severe congenital neutropenia

Severe congenital neutropenia (CN) includes a variety of hematologic disorders characterized by severe neutropenia, with absolute neutrophil counts (ANC) below 0.5 x 10(9)/L, and associated with severe systemic bacterial infections from early infancy. One subtype of CN, Kostmann syndrome, is an autosomal recessive disorder, characterized histopathologically by early-stage maturation arrest of myeloid differentiation. CN with similar clinical features occurs as an autosomal dominant disorder and many sporadic cases also have been reported. This genetic heterogeneity suggests that several pathophysiological mechanisms may lead to this common clinical phenotype. Recent studies on the genetic bases of CN have detected inherited or spontaneous point mutations in the neutrophil elastase gene (ELA 2) in about 60% to 80% of patients and, less commonly, mutations in other genes. Acquisition of additional genetic defects during the course of the disease, for example, granulocyte colony-stimulating factor (G-CSF) receptor gene mutations and cytogenetic aberrations, indicates an underlying genetic instability as a common feature for all congenital neutropenia subtypes. Data on more than 600 patients with CN collected by the Severe Chronic Neutropenia International Registry (SCNIR) demonstrate that, regardless of the particular CN subtype, more than 95% of these patients respond to recombinant human (rHu)G-CSF with ANCs that can be maintained above 1.0 x 10(9)/L. Adverse events include mild splenomegaly, osteoporosis, and malignant transformation into myelodysplasia (MDS)/leukemia. If and how G-CSF treatment impacts on these adverse events is not fully understood. In recent analyses the influence of the G-CSF dose required to achieve neutrophil response (ANC >1,000/microL) in the risk of developing acute myeloid leukemia (AML) has been reported. Hematopoietic stem cell transplantation (HSCT) is still the only treatment available for patients who are refractory to G-CSF treatment.