G-CSF with Autologous Marrow Transplantation


Recombinant growth factors are being tested intensively in order to modify the hematopoietic toxicity of high-dose therapies associated with protracted absolute neutropenia. High-dose cyclophosphamide (Cytoxan) 6 mg/m², carmustine (BCNU) 300 mg/m², and etoposide (VP-16) 750 mg/m² (CBV therapy) with autologous bone marrow transplantation (ABMT) has been shown to be very effective therapy in relapsed Hodgkin's disease [3, 4, 7]. Complete response (CR) was achieved in 45% of the patients, 75 %) of these enduring on to more than 5 years. The major toxicity of this potentially curative therapy is related to fevers and infections during the neutropenic phase. Most patients (>90 %) ) suffer from febrile episodes during the period of neutropenia, approximately one-quarter of patients have clinical symptoms or radiological changes consistent with pneumonia, a third or more documented bacteremia, and approximately one-quarter suffered from severe mucositis [3, 4]. CBV therapy is an important high-dose therapy to study the impact of recombinant growth factors on toxicity. In our first study we selected G-CSF because of its relatively restricted proliferative action to neutrophilic granulocytes alone, without any known in vivo induction of eosinophilia. We initially performed a phase II study employing G-CSF by a 30 minute blous infusion at a dose of 60 µ/kg per day beginning 24 h after marrow reinfusion in 18 patients with Hodgkin's disease who received CBV therapy [9, 101 and sequently by continuous infusion over a range of doses, including even greater doses in another 21 patients.

Table 1. Haematopoietic recovery: bolus infusion

From Table 1 it is obvious that the difference in recovery to an absolute neutrophil count (ANC) of 1000/µ1 is remarkably faster, 14 days, with G-CSF than control patients. Recovery to 500 ANC is impressive, 9 days faster, but to lOO ANC recovery is only 4 days faster. These patterns of recovery are identical to the best recoveries of other studies using either G, or GM-CSF after autologous marrow transplantation [1,5] .However, the febrile episodes were not significantly decreased and days febrile marginally different. There is a drop to below 100/µ1 ANC on days 8-10 following the initiation of chemotherapy, 2 days after ABM infusion and arise to > 100/µ1 neutrophils on days 19-21 after chemotherapy. Therefore, despite use of recombinant growth factors there is still an absolute neutropenic period ( <lOO neutrophils/µl) of approximately 7-10 days. Toxicity is related to complications occurring during the absolute neutropenic interval. The frequency of febrile episodes in patients receiving G-CSF remains unchanged (95 % ) .The onset of fever frequently (95% ) occurs during the first 5- 7 days of absolute neutropenia.
Recombinant growth factors hasten neutrophil recovery over that of ABM alone. But, growth factor accelerates predominately the terminal part of neutrophil recovery and this is not necessarily enough to modify the
morbidity, mortality or cost of ABMT in the majority of patients. There continues to be approximately 7 days of absolute
neutropenia ( < 100/µ1) even with growth factor support. The difference in neutrophil emergence in the tissues and saliva between controls and growth factor treated patients may be even less than the 4 days difference to lOO granulocytes.



Growth Factor-Mobilized Peripheral Blood Cells and the Absolute Neutropenia

To enhance recovery even further we and others have proposed that it is probably necessary to infuse significantly higher numbers of progenitor cells [2, 11] .However, does peripheral blood really enhance neutrophil recovery over that achievable with the use of ABM alone or ABM with recombinant growth factor? Studies reported by us in abstract form and to be published suggest that neutrophil recovery is not improved compared to either our data with G-CSF and ABM or those of other studies using GM-CSF. The clinical study that we refer to evaluated the effects of peripheral blood stem cells collected following chemotherapy and GM-CSF and added to ABM and GM-CSF. The major question was does the addition of peripheral blood collected in such a fashion and added to ABM and GM-CSF further diminish the duration of neutropenia? To optimize the collection of peripheral blood we followed the basic concept of Gianna et al. [2]. Patients received a priming dose of doxorubicin 50 mg/m² by continuous infusion (CI) over 48 hand cyclophosphamide 3 g/m² IVon day 1. On day 4, they were started an GM-CSF by Clover four hours at 0.6 mg/m² per day, which continued if tolerated through day 18 or until white blood cell count (WBC) reached 20 000, at which time the dose was halved (0.3,0.15, and 0.075 mg/m² per day) each day as long as the WBC count was < 20000/µ1. On day 18, all GM-CSF was ceased. Peripheral stem cell storage by apheresis was performed on consecutive weekdays until a minimum of 4 times 10high 8 mononuclear cells/kg had been collected. After marrow and peripheral blood stroage, the patients then received CVP in the doses described below. We administered two courses of high-dose therapy. For each course of therapy we administered cyclophosphamide 1.5 gm/m² per day times 3 (days 1-3), etoposide (VP-16) 400 mg/m² per day times 3 (days 1-3), and cisplatinum 55 mg/m² per day times 3 (days 1-3). On the fifth day ofeach cycle of CVP, patients received GM-CSF at a dose of 0.6 mg/m² as a 4-h IV infusion until an absolute neutrophil count of 1500 µI was maintained for 2 consecutive days. The dose was halved daily till the absolute neutrophils remained >1000. If absolute neutrophils fell below 1000 during the tapering off of GM-CSF, the dose was doubled daily until absolute neutrophils were >1000 for two consecutive days at which time they were tapered as described above. On the sixth day of cycle 1 CVp, one-half of the stored bone marrow was infused. On the sixth day of cycle 2 CVP, the remaining half of the bone marrow plus all the peripheral blood stem cells were infused. Patients received a second cycle of therapy commencing as soon as hematologic recovery had occurred ( defined as granulocyte count > 1000/µ1 and platelet count >lOO OOO/µI), and reversible non-hematologic toxicity had returned to baseline. Distinct from other studies patients were not isolated. In this way the contribution of peripheral blood to hematopoietic recovery over that of marrow and GM-CSF alone could be determined.We concluded that peripheral blood infusion did not enhance granulocyte recovery, or reduce febrile episodes, days febrile or documented infections. However, there was a reduction in the numer of platelet transfusions during the second cycle (from five to two) and enhanced early platelet recovery (11) .

Conclusions

Recombinant growth factors following transfusion of ABM and/or peripheral blood cells apheresed following recombinant growth factors with or without preceding chemotherapy have contributed in modest ways to hematopoietic recovery. Patients with exceptionally prolonged recovery following marrow infusion may benefit the most from addition of peripheral blood cells. Peripheral blood collected during the early phase of recovery from cytotoxic chemotherapy with high-numbers of colony-forming units-granulocyte/macrophage (CFU-GM) does cause earlier neutrophil recovery than ABM but is not necessarily faster than ABM with recombinant growth factor. Platelet recovery is enhanced. However, these are highly selected patients and the ability to enhance recovery in heavily pretreated patients not necessarily proven. Efforts to develop more effective methods to further enhance hematopoietic recovery are still needed.

References

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