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The correlation between duration and severity of neutropenia and incidence of serious

infection is well established. Administration of rGM-CSF to bone marrow transplant

recipients is aimed at reducing morbidity in the early post-transplant period by shortening
the duration of agranulocytosis. Intravenous administration of rGM-CSF up to 16 µg/kg/day
(approximately 640 µg/m2/day) is well tolerated, and when begun within 24 hours of
autologous marrow infusion produces the earlier appearance of > 0.5 × 109/L neutrophils in
the peripheral circulation as compared with historical controls. Early studies indicate that
treated patients have a lower incidence of culture-proven bacteraemia, and recent reports,
some preliminary, of placebo-controlled and randomised trials confirm that patients with
nonHodgkin's lymphoma or acute lymphocytic leukaemia who receive rGM-CSF 250
µg/m2 by daily 2-hour infusion for 21 days or more post transplantation, have significant
reductions in duration of infectious episodes, antibiotic administration and hospitalisation.
More limited data support a similar acceleration of neutrophil recovery in allogeneic bone
marrow transplant recipients treated with rGM-CSF, with no apparent effect on the
incidence or severity of graft-versus-host disease. rGM-CSF is less effective in patients in
whom progenitor cell numbers are reduced by chemical purging of the marrow whether
administered immediately after marrow infusion or when used as salvage therapy in
patients with graft failure. A substantial proportion of patients with failure of autologous or
allogeneic bone marrow grafts respond to prompt administration of rGM-CSF after
diagnosis of graft failure, with an increase in absolute neutrophil count and bone marrow
cellularity. In 1 study of 37 such patients, overall survival was significantly improved
compared with historical controls. rGM-CSF increases the number of progenitor cells in
peripheral circulation and, either alone or in combination with cyclophosphamide, facilitates
the harvest of stem cells by apheresis for subsequent transplantation. Similar to the effect
seen after myeloablative therapy and marrow transplantation, rGM-CSF accelerates
neutrophil recovery following cytoreductive chemotherapy in patients with
nonhaematological malignancies. Less frequent and less severe mucositis was also
observed in rGM-CSF-treated versus control patients in several studies. Importantly,
adjunctive use of rGM-CSF facilitated delivery of planned cycles of high or escalated doses
of antineoplastic drugs although the value of such chemotherapy regimens remains to be
proven. There has been no evidence to date that rGM-CSF increases the rate of relapse of
patients with haematological malignancies when administered after myeloablative therapy
and bone marrow transplantation or, in patients with acute myelogenous leukaemia, after
induction therapy. Use of rGM-CSF to recruit quiescent leukaemic blast cells into S phase
prior to chemotherapy is under investigation. rGM-CSF has been investigated in various
disorders of haematopoiesis. A substantial number of adults and children with refractory
aplastic anaemia respond to treatment with increases in bone marrow cellularity and
peripheral blood granulocyte count; however, the response is generally not sustained after
withdrawal of rGM-CSF. Elevation of neutrophil counts may not occur in patients with long-
standing and severe aplasia; however, beneficial stimulation of macrophage function may
still occur. Generally, rGM-CSF induces eosinophilia without correcting the neutropenia in
patients with congenital neutropenic conditions. In myelodysplasia, rGM-CSF is capable of
increasing the neutrophil count in a proportion of patients for the duration of administration.
Caution is appropriate in administering this drug to patients with high (> 14% blasts) initial
leukaemic burdens or with chronic myelomonocytic leukaemia in view of the potential for
rGM-CSF to stimulate the leukaemic clone and precipitate acute leukaemia. Despite this
concern, encouraging preliminary results from a trial with rGM-CSF (3 µg/kg/day by
subcutaneous injection) and observation-only treatment groups suggest that, after > 6
months, the rate of transformation to acute leukaemia is similar in both groups but that
rGM-CSF recipients have a sustained increase in neutrophil counts and an associated
reduction in infection rate. rGM-CSF 1 to 5 µg/kg/day by subcutaneous injection
ameliorates leucopenia associated with HIV infection and corrects zidovudine
(azidothymidine)-induced neutropenia without affecting the disease course as determined
by p24 antigen levels, CD4: CD8 ratios and recovery of HIV from mononuclear cells.
Similar dosages ameliorate myelosuppression induced by ganciclovir in the treatment of
AIDS-associated cytomegalovirus retinitis and by the combination of zidovudine and
interferon-α in treating Kaposi's sarcoma. A trilineage response to rGM-CSF has been seen
occasionally (e.g. some children with aplastic anaemia and some patients with
myelodysplasia). Disease-or drug-induced anaemia or thrombocytopenia is generally not
improved; however, both significant increases and decreases in platelet count have been
reported, and the effect of rGM-CSF on megakaryocytosis and splenic phagocyte function
require clarification. The combination of rGM-CSF with other recombinant colony-
stimulating factors to expand the lineages stimulated is an exciting future possibility.
At clinically useful dosages rGM-CSF is generally well tolerated. Limited comparison with
placebo suggests that the type and incidence of adverse reactions reported are generally
similar in both groups with the possible exception of slightly higher incidences of diarrhoea,
asthenia, rash and malaise. However, reports from noncomparative and open-label trials
indicate that mild to moderate flu-like symptoms (myalgias, bone pain, fatigue and
headache) are common with rGM-CSF. Management of patients in whom this agent is
indicated may be complicated by rGM-CSF-induced fever and, rarely, by a capillary leak
syndrome causing fluid retention and potentially peripheral oedema, pericardial or pleural
effusions which necessitate drug withdrawal. Also reported are rash (particularly at sites of
subcutaneous injection), and occasional incidents of central venous catheter thrombosis.
The occasional report of respiratory distress has led to the recommendation that respiratory
symptoms be monitored and caution exercised in patients with preexisting lung disease.
The approved (USA) dosage of yeast-derived rGM-CSF (sargramostim) for myeloid
reconstitution after autologous bone marrow transplantation is 250 µg/m2 by daily 2-hour
intravenous infusions, beginning 2 to 4 hours after marrow infusion and continued for 21
days. For management of bone marrow transplantation failure or delayed engraftment, the
approved (USA) dosage of yeast-derived rGM-CSF is 250 µg/m2/day by 2-hour intravenous
infusion. Treatment should be continued for 14 days and, if clinically indicated, may be
repeated after 7 days off therapy. A third 14-day course of rGM-CSF at the increased
dosage of 500 µg/m2/day by 2-hour infusion may be administered after a further 7 days off
therapy. Further dose escalation in non-responding patients is unlikely to be of benefit.
rGM-CSF has also been successfully administered by continuous intravenous infusion and
by subcutaneous injection, including self-administration of long term therapy by the
subcutaneous route. The optimal route for administration, dose and duration of therapy for
indications other than autologous bone marrow transplantation and failure or delay of
engraftment have not been established.