Phase I/II trial of recombinant human granulocyte-macrophage colony-stimulating factor following allogeneic bone marrow transplantation

Forty-seven patients with hematologic neoplasia received recombinant human granulocyte-macrophage colony-stimulating factor (rhGM-CSF) by daily 2-hour infusion following allogeneic bone marrow transplantation from HLA-identical sibling donors in a phase I-II dose-escalation trial. Dose levels ranged from 30 to 500 micrograms/m2/d. At doses at or below 250 micrograms/m2/d, toxicity felt to be caused by rhGM-CSF was negligible. However, three of five patients treated with 500 micrograms/m2/d had unacceptable side effects caused by rhGM-CSF. Two different graft-versus-host disease (GVHD) prophylactic regimens were administered. Twenty-seven evaluable patients were administered regimens that did not contain methotrexate (MTX) (Group I) and reached an absolute neutrophil count of 1,000/microL by a median of day 14. In contrast, 18 patients who received GVHD prophylactic regimens containing MTX (Group II) reached an absolute neutrophil count of 1,000/microL on a median of day 20. Patients in Group I had fewer febrile days and, of those discharged, had shorter initial hospitalizations than patients in Group II. The overall incidence of severe acute GVHD (grade 2 or greater) in the rhGM-CSF-treated patients was 28% and was similar to that in historical "good risk" patients who did not receive rhGM-CSF. These preliminary data suggest rhGM-CSF is unlikely to exacerbate GVHD in HLA-identical sibling donor transplants and indicate the need for randomized trials of rhGM-CSF in allogeneic marrow transplant patients.     

Long-term follow-up of patients who received recombinant human granulocyte-macrophage colony stimulating factor after autologous bone marrow transplantation for lymphoid malignancy

Twenty-seven patients with lymphoid neoplasia who underwent autologous bone marrow transplant (BMT) and who had received recombinant human granulocyte-macrophage colony stimulating factor (rhGM-CSF) were followed in order to examine the potential long-term consequences of rhGM-CSF. rhGM-CSF (15-240 micrograms/m2/day) was given daily either for 14 or 21 days after marrow infusion. All surviving patients who remained in remission had stable marrow graft function. The actuarial survival rate was 45% and the relapse incidence was 50% at a median of 774 days after autologous BMT. These findings suggest that treatment with rhGM-CSF does not have profound adverse long-term consequences.     

Use of recombinant human granulocyte-macrophage colony-stimulating factor in autologous marrow transplantation for lymphoid malignancies

The use of recombinant human granulocyte-macrophage colony-stimulating factor (rhGM-CSF) following autologous marrow transplantation for lymphoid malignancies was explored in a phase I/II dose escalation study. rhGM-CSF given as a 2-hour infusion daily for 14 days was well tolerated at doses up to 240 micrograms/m2/day. When compared with 86 disease-matched and treatment-matched historical controls, patients receiving greater than or equal to 60 micrograms/m2/day rhGM-CSF recovered neutrophil and platelet counts more rapidly, had fewer days with fever, and were discharged from the hospital sooner.     

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)     

Recombinant human granulocyte-macrophage colony-stimulating factor accelerates engraftment kinetics after allogeneic bone marrow transplantation for childhood acute lymphoblastic leukemia

BACKGROUND AND OBJECTIVE: The use of recombinant human granulocyte-macrophage stimulating factor (rhGM-CSF) has been shown to be well-tolerated and to reduce post-transplantation morbidity in adults undergoing HLA-identical allogeneic bone marrow transplantation (BMT). There is however, limited experience in children. DESIGN AND METHODS: We performed a prospective, comparative multicenter trial using rhGM-CSF after allogeneic BMT in children with acute lymphoblastic leukemia (ALL). The study comprised 24 patients with ALL who received rhGM-CSF and 22 patients with ALL who did not receive rhGM-CSF. There were no statistically significant differences in the demographic characteristics between the rhGM-CSF-treated and untreated groups. rhGM-CSF was given at a dose of 10 micrograms/kg/day infusion over 4 hours from day +1 until +28 or until the absolute neutrophil count (ANC) was > or = 1 x 10(9)/L. All patients received HLA-identical sibling marrow and cyclosporine alone for graft-versus-host disease (GvHD) prophylaxis. The number of cells infused was similar in both groups. A software program (Statview 4.0, Abacus Concept, Inc., Berkeley, CA, USA) was used for statistical analysis. RESULTS: The median of days to achieve ANC > or = 0.5 x 10(9)/L was shorter in the rhGM-CSF-treated patients (14 days vs 18.5 days; p < 0.0001). Patients who received rhGM-CSF had a lower incidence of grade III-IV mucositis. The duration of hospital stay was significantly shorter in patients who received rhGM-CSF (31 days vs 45 days; p < 0.005). No differences in GvHD severity, relapse or survival were observed. At the dose and schedule used in the present study, rhGM-CSF was well-tolerated and no side effects were observed. INTERPRETATIONS AND CONCLUSIONS: rhGM-CSF at a dose of 10 micrograms/kg/day in children with ALL undergoing allogeneic BMT is well tolerated, accelerates neutrophil and platelet engraftment, reduces the intensity and severity of mucositis and permits a more rapid discharge from hospital.     

Phase I trial of recombinant human macrophage colony-stimulating factor in patients with invasive fungal infections

A phase I dose escalation trial of recombinant human macrophage colony- stimulating factor (rhM-CSF) in combination with conventional antifungal therapy was conducted in 24 marrow transplant recipients with invasive fungal infection. Daily doses ranged from 100 to 2,000 micrograms/m2/d. Toxicity, such as constitutional symptoms, directly ascribed to rhM-CSF was not observed; however, transient, dose-related thrombocytopenia was observed. Patients who received 2,000 micrograms/m2/d of rhM-CSF had a mean reduction in platelet count of 61,000/mm3 during the rhM-CSF infusion period, which was significant when compared with patients who received lower doses of rhM-CSF (P = .008). Fourteen of the 16 patients who received rhM-CSF after undergoing allogeneic bone marrow transplantation had no change in the severity of graft-versus-host disease (GVHD) while receiving rhM-CSF. One had an increase in the severity of GVHD and one had a decrease. There were no effects on neutrophil, monocyte, or lymphocyte counts. Six patients had resolution of their infections, 12 were not evaluable for response, and six did not respond. Ten patients survived 100 days after initiation of rhM-CSF and 14 died. Further trials with rhM-CSF to assess antifungal activity are indicated.     

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.     

Allogeneic stem cell transplantation reduces disease progression compared to autologous transplantation in patients with multiple myeloma

This study compares the probability of disease progression, progression-free survival, and overall survival between patients undergoing an allogeneic or autologous transplant for multiple myeloma using an identical preparative regimen. Patients received a preparative regimen of TBI, busulfan, and cyclophosphamide followed by an allogeneic or autologous transplant. In the allogeneic group (n = 21), six patients received bone marrow and 15 received G-CSF mobilized PBSC; all autologous patients (n = 35) received PBSC mobilized with cyclophosphamide and G-CSF. Allogeneic donors were HLA-identical (n = 20) or one-antigen mismatched (n = 1) siblings. Graft-versus-host disease (GVHD) prophylaxis consisted of tacrolimus (n = 10), tacrolimus/methotrexate (n = 6), cyclosporine/methotrexate (n = 4), or cyclosporine (n = 1). The groups were evenly matched for gender, pretransplant therapy, disease status at time of transplant, myeloma subtype, and time from diagnosis to transplant. The median age was significantly lower in the allogeneic group (48 vs 55 years, P < 0.01). In the allogeneic group the probabilities of developing acute GVHD grade II-IV and chronic GVHD were 55% and 82%, respectively. The Kaplan-Meier probability of disease progression was significantly lower in the allogeneic group (11% vs 64%, P < 0.001) compared to the autologous group. Although progression-free (60% vs 30%, P = 0.19) and overall survival at 2 years (60% vs 42%, P = 0.39) favored the allogeneic group, this did not reach statistical significance. Within the allogeneic transplant group, patients age 50 years or under had a 3-year overall survival significantly higher when compared to older patients (79% vs 29%, P = 0.03). Using identical preparative regimens, allogeneic transplantation reduced disease progression compared to autologous transplantation for myeloma. This suggests that allogeneic transplantation induces a graft-versus-myeloma (GVM) effect.     

Second allogeneic hematopoietic stem cell transplantation as treatment for leukemia relapsing following a first transplant

We report 27 patients with relapsed acute or chronic leukemia who underwent a second hematopoietic stem cell transplant (HSCT) from a related or unrelated donor. Seventeen patients were diagnosed with acute myelogenous leukemia (AML), six with acute lymphocytic leukemia (ALL) and four with chronic myeloid leukemia (CML). Ages ranged from 22 to 49 years (median 37); 13 patients were female and 14 male. Relapse was diagnosed between 1 and 45 months after the first HSCT. Sixteen patients who relapsed had received an autologous transplant initially and 11 an allogeneic transplant. Ten patients relapsed within 6 months and 17 patients later than 6 months. Chemotherapy was used as reinduction for relapse after HSCT in 16 patients who had received an autologous transplant and in three who had received an allogeneic transplant, since the latter did not respond to reduction of immunosuppression to induce a graft-versus-leukemia (GVL) reaction. Five of these 19 patients (26%) achieved complete remission (CR), seven patients did not respond to chemotherapy and seven achieved a partial remission (PR). The stem cell source for the second HSCT included bone marrow (n = 12) and PBSC (n = 4) from genotypically identical unrelated donors, PBSC (n = 7) and bone marrow (n = 3) from related donors. Currently eight of the 27 patients are alive and disease-free after the second HSCT. One patient is alive and disease-free after two allogeneic transplants (day +1538), eight patients, who relapsed after an autologous transplant followed by an allogeneic transplant (days +248 to +1140), acute myeloid leukaemia (n = 6) and chronic myeloid leukemia (n = 2) are alive and disease-free. The overall disease-free survival is 30% (8/27). The overall disease-free survival of autologous transplant patients subsequently undergoing an allogeneic transplant is 43% (P = 0.049). It is suggested that a second HSCT is possible for patients with leukemia relapse following the first autologous transplant. A second transplant might also be offered to patients relapsing after the first allogeneic HSCT. Bone Marrow Transplantation (2000) 25, 41-45.     

Prospective comparative trial of autologous versus allogeneic bone marrow transplantation in patients with non-Hodgkin's lymphoma

A prospective comparative trial of allogeneic versus autologous bone marrow transplant (BMT) was conducted. Sixty-six consecutive patients (median age, 41; range, 15 to 60; female:male ratio = 21:45) entered this clinical trial. Priority for allogeneic BMT was given to patients who were 55 or younger and had a major histocompatibility complex- matched or 1-antigen-disparate sibling donor. Autologous BMT was offered to all other patients whose age was 60 or younger. Patients who had no sibling donor and who had BM involvement at the time of evaluation were not eligible. Thirty-one patients received an allograft, and 35 patients received an autograft. Thirteen patients received a BM graft purged with 4-hydroperoxycyclophosphamide because of previous BM involvement. Patients who had previous radiation to the thoracic and/or abdominal areas of more than 20 Gy received a preparative regimen consisting of cyclophosphamide (1,800 mg/m2/d for 4 days), VP-16 (200 mg/m2 every 12 hours for 8 doses), and 1,3-bis(2- chloroethyl)-1-nitrosourea (600 mg/m2 as 1 dose). Other patients received cyclophosphamide 1,800 mg/m2/d for 4 days followed by total body irradiation of 12 Gy administered as a single daily fraction over 4 days. With a median follow-up of 14 months, the progression-free survival (PFS) for autograft and allograft recipients was 24% +/- 8% (+/- SE) and 47% +/- 9%, respectively, (P = .21). However, the probability of disease progression was significantly higher in the autologous group (69% +/- 9%) than in the allogeneic group (20% +/- 10%; P = .001). When other confounding prognostic factors were adjusted in the multivariate analysis, chemosensitive disease and allograft were found to have a significant favorable influence on probability of disease progression (P = .03 and .003), but only chemosensitive disease had a significant influence on the PFS (P < .002). Our results suggest the existence of graft-versus-lymphoma effect and also support the rationale of using immunotherapy after autologous BMT. Allogeneic BMT should be preferable to autologous BMT in younger patients with lymphoma.     

Recombinant human granulocyte-macrophage colony-stimulating factor accelerates neutrophil and monocyte recovery after allogeneic T-cell-depleted bone marrow transplantation.

In a prospective randomized study, five European transplant centers compared recombinant human granulocyte-macrophage colony-stimulating factor (rhGM-CSF; mammalian glycosylated) with placebo. rhGM-CSF was administered in a dose of 8 micrograms glycoprotein (5.5 micrograms protein)/kg/d, as a continuous intravenous (IV) infusion for 14 days, starting 3 hours after bone marrow infusion. Fifty-seven patients entered and completed the study. Median age of the recipients was 34 years (range, 17 to 51 y). All donors were HLA-identical, MLC-nonreactive siblings. Marrow grafts were depleted of T lymphocytes either by counterflow centrifugation (n = 42) or by immunological methods (n = 15). Twenty-nine patients received rhGM-CSF and 28 patients placebo. The leukocyte count and the absolute neutrophil count were significantly higher in the rhGM-CSF-treated group from day +9 to day +14 after bone marrow transplantation (BMT). This was also true for the monocyte count from day +12 to day +21. Early neutrophil (greater than 0.1 and greater than 0.3 x 10(9)/L) and early leukocyte (greater than 0.3 and greater than 0.5 x 10(9)/L) recovery was significantly faster for the patients given GM-CSF. The incidences of graft-versus-host disease (GVHD) and transplant-related mortality were not different in both groups. However, the number of bronchopneumonias was significantly lower in the rhGM-CSF-treated group (P = .03). Long-term follow-up showed a trend to better overall disease-free survival at 2 years and a trend to a lower relapse risk in patients treated with rhGM-CSF. This study shows that rhGM-CSF significantly increases neutrophil and monocyte counts during periods of 6 to 10 days in the second and third week after BMT. This shortened period until myeloid cell recovery after transplantation resulted in a decreased number of pneumonias, without an increase in incidence of GVHD or relapse.     

Recombinant human granulocyte-macrophage colony-stimulating factor in combination with standard induction chemotherapy in de novo acute myeloid leukemia

Based on in vitro data suggesting that recombinant human granulocyte-macrophage colony-stimulating factor (rhGM-CSF) is capable of stimulating acute myeloid leukemia (AML) blast cells to become more sensitive to cell-cycle-specific drugs we conducted a phase I/II study in de novo AML patients (pts). rhGM-CSF (250 micrograms/m2/d, continuous intravenous infusion) was administered in 18 pts suffering from de novo AML in combination with standard induction chemotherapy (3 + 7 = daunorubicin 45 mg/m2 days 1 through 3, cytosine-arabinoside [Ara-C] 200 mg/m2 continuous infusion days 1 through 7). GM-CSF was started 48 or 24 hours before chemotherapy (prephase) in 14 pts. In four pts with high white blood cell counts (WBC) rhGM-CSF was started after chemotherapy-induced cell reduction (WBC less than 30,000/mm3). During prephase GM-CSF induced an increase in neutrophil and blast cell counts in 13 of 14 and 10 of 14 pts, respectively. In vivo recruitment of leukemic cells into drug-sensitive phases of the cell cycle could be demonstrated by multiparameter cell-cycle analyses in peripheral blood (n = 7) and bone marrow (n = 4) specimens. On day 14, complete aplasia was evident in 17 of 18 pts. GM-CSF was administered until recovery from chemotherapy-induced myelosuppression (absolute neutrophil counts, [ANC] greater than 500/mm3). Fifteen pts (83%) achieved complete remission, 12 did so with one cycle. A shorter duration of neutropenia was evident in these pts compared with historical controls (n = 39), (ANC greater than 500/mm3, day 22.5 +/- 3.4 v 25.2 +/- 3.7, P less than .05). Three pts achieved complete remission after a second cycle (same combination of rhGM-CSF and 3 + 7). Two pts died during bone marrow aplasia because of invasive pulmonary aspergillosis. Clinical side effects possibly related to GM-CSF, mainly fever, diarrhea, and weight gain were mild and tolerable (World Health Organization toxicity grade less than or equal to 2). Together, rhGM-CSF recruits kinetically quiescient AML cells in vivo to enter drug-sensitive phases of the cell cycle and promotes early myeloid recovery from aplasia after exposure to standard induction chemotherapy for AML.     

GM-CSF accelerates neutrophil recovery after autologous bone marrow transplantation for Hodgkin's disease

Thirty-one patients with resistant Hodgkin's disease were treated by an identical high dose chemotherapy regimen and autologous bone marrow transplantation. Twelve of these patients received recombinant human granulocyte/macrophage colony stimulating factor (rh GM-CSF) in a phase I/II study. rh GM-CSF was administered by continuous infusion into an indwelling central venous catheter for 3-21 days at doses of 100-400 micrograms/m2/day. The patients receiving rh GM-CSF did not differ significantly from those who did not receive growth factor with regard to age, previous therapy or number of bone marrow cells infused. rh GM-CSF resulted in more rapid neutrophil regeneration, the average time to achieve a neutrophil count of greater than or equal to 0.5 x 10(9)/l being 17.5 days compared to 24.9 days in the control group (p less than 0.01). Platelet recovery was very varied and not accelerated by rh GM-CSF. Patients receiving rh GM-CSF had a similar infection rate (58% vs 68% in the control group), similar number of febrile days (5.0 vs 4.7 days) and similar period of hospitalization to the control group (30.1 vs 30.2 days). Randomized controlled trials are now required to define the clinical value of rh GM-CSF in the setting of autologous bone marrow transplantation.     

Influence of mobilized peripheral blood cells on the hematopoietic recovery by autologous marrow and recombinant human granulocyte-macrophage colony-stimulating factor after high-dose cyclophosphamide, etoposide, and cisplatin.

Peripheral blood cells (PBC) can hasten hematopoietic recovery after high-dose chemotherapy. To determine if PBC apheresed after mobilization further enhance hematopoietic recovery over that achieved with autologous bone marrow (ABM) and recombinant human granulocyte-macrophage colony-stimulating factor (rhGM-CSF), 14 patients with metastatic solid tumors were supported by ABM and rhGM-CSF during the first course of high doses of cyclophosphamide, etoposide, and cisplatin (CVP) and 11 of these 14 patients by mobilized PBC with ABM and rhGM-CSF during the second CVP. Each patient served as his or her own control. Identical doses of CVP were administered in both courses: cyclophosphamide 5.25 g/m2, etoposide 1,200 mg/m2, and cisplatin 165 to 180 mg/m2. PBC were collected on day 10 after mobilization with cyclophosphamide (3 g/m2) intravenously (IV) on day 1, doxorubicin (50 mg/m2) as a continuous IV infusion over 48 hours starting day 2, and rhGM-CSF as a daily 4-hour IV infusion starting day 4 at 0.6 mg/m2 for 14 days. Comparing recovery in the 11 patients to receive two cycles of therapy, the median days to an absolute neutrophil count of 0.1 x 10(9)/L and 0.5 x 10(9)/L were not statistically significant between the two courses; neither was there a difference in the incidence of fever and bacteremia. The median number of days to platelet count of 0.02 x 10(12)/L unmaintained by platelet transfusion was 20 from marrow infusion for course 1 and 16 for course 2 (P = .059). The median number of days to a platelet count of 0.05 x 10(12)/L was significantly shortened: 24 and 19 days for courses 1 and 2, respectively (P = .045). Patients who received PBC required fewer number of platelet transfusions. Extramedullary toxicities were not different between the groups. Our finding of enhanced early recovery of platelets and reduced platelet transfusion requirement is in concordance with other studies.     

Phase II trial of recombinant human granulocyte-macrophage colony-stimulating factor in patients undergoing allogeneic bone marrow transplantation from unrelated donors.

The safety and possible efficacy of recombinant human granulocyte-macrophage colony-stimulating factor (rhGM-CSF) were evaluated in 40 consecutive patients who received transplants from unrelated donors. rhGM-CSF was administered by 2-hour daily intravenous infusion from day 0 to day 20 or day 27 after the marrow infusion. These patients were compared with 78 historical patients who received transplants from unrelated donors who did not receive rhGM-CSF. The rhGM-CSF-treated patients were older (P = .037) and were treated less frequently in laminar air flow rooms (P = .005) than were control patients. However, the rhGM-CSF-treated group had a higher proportion of "good risk" patients with chronic myelogenous leukemia in chronic phase (P = .006) than did the comparison group (P = .017), rendering comparisons of transplant-related complications not meaningful. rhGM-CSF was well tolerated and did not adversely increase the incidence of graft rejection or increase the incidence and severity of acute graft-versus-host disease. The median day the absolute neutrophil count reached 500/mm3 in patients who received rhGM-CSF was day 21, which was not different from that of historical patients. Nevertheless, the numbers of febrile days and septicemic episodes within the first 28 days in patients who received rhGM-CSF were less than in historical patients. The probability of nonrelapse mortality at 1 year in patients who received rhGM-CSF was 22%. In view of the retrospective nature of the control group, we cannot conclusively determine whether rhGM-CSF administration was beneficial. A prospective, randomized controlled study of rhGM-CSF is required to confirm these suggestive data.     

High-dose cytosine arabinoside, total body irradiation and marrow transplantation for advanced malignant lymphoma

Twenty-four patients with advanced malignant lymphoma including Hodgkin's disease (HD, n = 1), intermediate grade non-Hodgkin's lymphoma (IGL, n = 12) and high-grade non-Hodgkin's lymphoma (HGL, n = 11) were prepared for syngeneic (n = 2), allogeneic (n = 11) or autologous (n = 11) marrow transplantation with cytosine arabinoside, 3 g/m2 every 12h for 12 doses (HDAC) and total body irradiation, 200 cGy daily for 6 days (TBI) to determine toxicity and efficacy. Eight patients (33%) died from early regimen related toxicity and all eight had a Karnofsky performance score less than or equal to 80 at the start of treatment. The actuarial probability of disease-free survival was 17% with a 65% probability of relapse at 4 years after transplantation. Four patients are surviving 2-4 years post-transplant, three transplanted for IGL and one for HD. None of the patients transplanted for HGL survived. The result of this phase II study suggests that HDAC followed by TBI and marrow infusion offers no apparent advantage over cyclophosphamide + TBI for patients with relapsed advanced malignant lymphoma. Earlier transplantation currently is the only demonstrated method of achieving better results.     

Results of induction and consolidation treatment with intermediate and high-dose cytosine arabinoside and m-Amsa of patients with poor-risk acute myelogenous leukaemia

50 patients (aged 18-58 years) with acute myelogenous leukaemia after a preleukaemic phase (n = 14), acute myelogenous leukaemia that previously failed to respond to conventional chemotherapy (n = 9) or relapsed disease (n = 27) were given remission induction therapy consisting of cytosine arabinoside (1 g/m2 q 12 h x 12) and m-Amsa (115 mg/m2 for 1 or 3 days). Overall, 27 patients (54%) achieved complete remission. The complete remission rate for patients with acute myelogenous leukaemia after a preleukaemic phase (7/14) and those with primary refractory or relapsed leukaemia (20/36) seems superior to that obtained with conventional remission-induction therapy. 12 patients received 1-3 courses of consolidation chemotherapy with cytosine arabinoside (3 g/m2 q 12 h x 8) and m-Amsa (115 mg/m2 for 1 d). 3 of them subsequently underwent autologous bone marrow transplantation. The median duration of remission for the remaining 9 patients was 8 months. 11 patients did not receive consolidation therapy; their median duration of remission was 3 months. The difference between the two groups was not significant. 4 patients underwent allogeneic bone marrow transplantation after achievement of complete remission. The impact of high-dose cytosine arabinoside consolidation chemotherapy on poor-risk acute myelogenous leukaemia remains unclear.     

Colony-stimulating activity in the serum of patients with hemopoietic malignancies after intensive chemotherapy/radiotherapy: its augmentation by GM-CSF in vivo and interleukin 4 in vitro.

Colony-stimulating activity (CSA) in the serum of patients with hematological malignancies increased substantially after intensive therapy with cyclophosphamide/busulfan, cyclophosphamide/total body irradiation, or melphalan/total body irradiation. This was not dependent on patients receiving allogeneic bone marrow transplantation (ABMT) or autologous bone marrow rescue (ABMR). In 44 of 62 patients CSA was maximum approximately 7 days after chemotherapy/radiotherapy, whereas in 18 of 62 patients CSA was maximum between 9 and 20 days after therapy and decreased thereafter. The time course of CSA was not dependent on disease and was not affected by recombinant human granulocyte-macrophage colony-stimulating factor (rhGM-CSF) given as a continuous infusion for 14 days after therapy; however, serum from patients receiving rhGM-CSF produced significantly more colonies from donor bone marrow than serum from patients who did not receive the cytokine (p = 0.013). Despite the early peak in CSA in the majority of patients, there was no correlation between the time at which CSA was maximum and the return of patients' neutrophils to 500/microliters. Recombinant human interleukin 4 (IL-4) increased the number of granulocyte-macrophage colony-forming unit colonies, principally granulocyte colony-forming unit colonies, from normal bone marrow exposed to patients' serum after intensive therapy and antibody to GM-CSF reduced colony numbers. The results suggest that after intensive therapy granulocyte colony-stimulating factor (G-CSF) as well as GM-CSF is released into the serum and, in addition to acting directly with G-CSF, IL-4 may stimulate mononuclear cells to produce and/or release G-CSF.     

Treatment of refractory aplastic anemia with recombinant human granulocyte-macrophage-colony-stimulating factor

Fifteen patients with refractory aplastic anemia or agranulocytosis received treatment with recombinant human granulocyte-macrophage-colony-stimulating factor (rhGM-CSF) in doses from 4 to 64 micrograms/kg/d by continuous intravenous (IV) infusion. Ten of 11 evaluable patients with aplastic anemia had substantial increments in granulocytes, monocytes, and eosinophils associated with myeloid and eosinophilic hyperplasia in the bone marrow. Patients with pretreatment granulocytes greater than 0.3 x 10(9)/L had greater increments in circulating myeloid cells than patients with more severe granulocytopenia. Only one patient had improvement in erythrocytes and platelets. Blood counts fell to baseline after rhGM-CSF treatment was discontinued. Doses up to 16 micrograms/kg/d were relatively well tolerated in the absence of extreme leukocytosis. Fatigue and myalgia were common. Three patients developed pulmonary infiltrates that resolved with discontinuation of treatment. Patients tended to have recurrent inflammation in previously diseased tissues. These data indicate that rhGM-CSF will increase circulating granulocytes, monocytes, and eosinophils in patients with refractory aplastic anemia. Further studies are necessary to determine if rhGM-CSF treatment will reduce morbidity or improve survival.     

Is treatment intensification by adding etoposide and carboplatin to fractionated total body irradiation and melphalan acceptable in children with solid tumors with respect to toxicity?

Conventional chemotherapy results in high mortality rates in patients with solid tumors involving the bones or the bone marrow. High dose melphalan (MEL) with or without total body irradiation followed by bone marrow transplantation (BMT) has prolonged survival, but curative potential has remained disappointing. In order to improve survival 20 children with generalized or relapsed solid tumors (neuroblastoma, peripheral neuroectodermal tumor, Ewing's sarcoma, rhabdomyosarcoma) underwent autologous (n = 16) or allogeneic (n = 4) BMT. The myeloablative regimen consisted of 12 Gy fractionated total body irradiation (FTBI) and high dose MEL. In 12 of these patients this regimen was intensified by giving 60 mg/kg etoposide (1800 mg/m2 VP), and 1.5 g/m2 carboplatin (CBDCA) was added in seven of these 12 patients. The intensification of FTBI and MEL by adding VP and CBDCA was followed by acceptable toxicity. Acute liver toxicity in 15/20 patients (75%) and acute renal toxicity in 17/20 patients (85%) did not exceed WHO grade 1. The use of the conditioning regimen FTBI-MEL-VP-CBDCA during first chemotherapy response is a promising approach in treatment of children suffering from generalized solid tumors.