stimulating factor following allogeneic bone marrow ...

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Abbreviations: plt, platelet; T, temperature; (+), still alive; NR, not reached; CMV, cytomegalovirus; VOD, venoocclusive disease; RSV, respiratory. *The grade is ...
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1991 77: 2065-2071

Phase I/II trial of recombinant human granulocyte-macrophage colonystimulating factor following allogeneic bone marrow transplantation J Nemunaitis, CD Buckner, FR Appelbaum, CS Higano, M Mori, J Bianco, C Epstein, J Lipani, J Hansen and R Storb

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Phase 1/11 Trial of Recombinant Human Granulocyte-Macrophage Colony-Stimulating Factor Following Allogeneic Bone Marrow Transplantation By John Nemunaitis, C. Dean Buckner, Frederick R. Appelbaum, Celestia S.Higano, Matomi Mori, James Bianco, Carol Epstein, John Lipani, John Hansen, Rainer Storb, E. Donnall Thomas, and Jack W. Singer 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 1-11 dose-escalation trial. Dose levels ranged from 30 to 500 kg/m2/d. At doses at or below 250 kg/m2/d, toxicity felt to be caused by rhGM-CSF was negligible. However, three of five patients treated with 500 Fglm’ld 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 neutrophilcount of I,OOO/pL 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 1,00O/~L 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-CSFtreated patients was 28% and was similar to that in historical “good risk” patients who did not receive rhGM-CSF. These preliminarydata suggest rhGM-CSF is unlikely to exacerbate GVHD in HLA-identicalsibling donor transplantsand indicate the need for randomized trials of rhGM-CSF in allogeneic marrow transplant patients. 0 1991 by The American Society of Hematology.

P

in the probability of relapse compared with historical control patients“ (unpublished data). The present study was designed to determine the safety and efficacy of rhGM-CSF in patients with hematologic malignancies who receive allogeneic BMT from HLAmatched, sibling donors. Because the toxicity of methotrexate (MTX), a drug used for GVHD prophylaxis, is greatest for rapidly cycling cells, there was concern that concurrent rhGM-CSF might adversely affect hematopoietic reconstitution. Therefore, two independent rhGM-CSF dose escalations were performed; one for patients treated without MTX (Group I), and the other for patients who received MTX-containing GVHD prophylactic regimens (Group 11).

HASE 1/11 CLINICAL TRIALS with recombinant human granulocyte-macrophage colony-stimulating factor (rhGM-CSF) in patients after autologous marrow infusion have yielded encouraging results. Enhancement of neutrophil and platelet recovery with minimal _toxic l,OOO/pL

Day plt Indep.

No. Days T 2 38°C Day 0-28

Maximum Bilirubin Day 0-28

Maximum Creatinine Day 0-28

Day of Discharge

1.8 f 1.4 1.5 1.6 + 1.1 1.3 .497t

262 13 24 37 + 17 33 .003t,.166*

2.2 2 1.9 1.6 .447t 2.1 f 1.9 1.4 .480t

36 ? 19 31 ,001t, .023* 39 -t 13 36 .234t,.169*

Study Group No MTX (n = 27) MTX (n = 18)

+

Mean SD Median Mean Median P value

6+4 5.0 10 2 5 11 .007t

16+ 9 14 21 + 3 20 .001*

17+ 1 1 23 21 f 5 23 .328*

5+5 4 11 + 6 9.0 .OO2t

8 2 10

Mean f SD Median P value* Mean 2 SD Median P value§

8+5 7 .127t 12 + 5 12 .158t

21 + 8 19 ,0017" 25 + 6 24 .0052*

38 2 31 21 .803* 30 + 25 20 .396*

10 2 6 9.0 .0015t 10 f 7 8.0 .291t

8 + 12

5.0 5+8 3.0 .483t

Historical Group No MTX (n = 50) MTX (n = 43)

3.1 .958t 728 4.8 .058t

The study group is patients who received rhGM-CSF (Groups I and 11, excluding unevaluable patients 5437 and 5347).The historical group is historical patients who did not receive rhGM-CSF" (CML or ANL in first remission). Median values based on Kaplan Meier estimates. Abbreviations: Day plt. indep., day of last platelet transfusion; SD, standard deviation; mean values based on patients who achieved stated events. *P value based on Kaplan Meier Wilcoxon analysis. t P value based on Wilcoxon Rank Sum comparing patients who achievedthe stated event. *P value when compared with No MTX patients who received rhGM-CSF. §P value compared with MTX patients who received rhGM-CSF.

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RHGM-CSFFOLLOWING ALLOGENEIC BMT

either venoocclusive disease of the liver or severe mucositis. The median number of days required to reach an ANC of l,OOO/pL was 20 in these patients, which is identical to the value for those who received all four doses of MTX. Six Group I patients (UPNs 4931,4962,5029,5073,5338, and 5456) did not receive total body irradiation (TBI). The median day to reach an ANC greater than 1,00O/pLwasday 11, compared with day 14 in the same group of patients who received TBI. Four Group I1 patients (UPNs 5143, 5300, 5327, and 5253) also did not receive TBI. The median day to reach an ANC greater than l,OOO/pLwas day 26, compared with day 20 in the patients who received TBI. These differences were not significant. Fever and infection. Patients in Group I had fewer febrile days (temperature greater than 38°C) than those in Group 11. Ten (37%) of the Group I patients and none of the Group I1 patients had 1 or less febrile days (see Table 2). There were four minor and one lethal infection in the Group 1 patients. Four of 28 (14%) had single positive blood cultures within the first 28 days. UPN 4962 had a coagulase-negative staphylococcus isolated on day 15, UPN 5437 grew Escherichia coli from a culture on day 8, UPN 4931 grew acinetobacter on day 10, and UPN 5375 had Candida tropicalis on day 3. UPN 4982 died ofpseudomonas pneumonia on day 17. Two of the Group I patients resolved severe infections that preexisted the BMT. UPNs 4868 and 5056 had histologically proven hepatic and splenic candidiasis before BMT. Both received continuous amphotericin therapy and were transplanted despite the active fungal disease due to their high-risk neoplasia. In both, the hepatic and splenic abscesses resolved by computed tomographic (CT) scan by day 21. Four (22%) of the Group I1 patients had significant septicemia. UPN 5014 had a blood culture isolate of Pseudomonas maltifilia on day 17, UPN 5269 had Candida parasilopsis isolated on days 7 and 13, and UPNs 5253 and 5374 had persistent coagulase-negative staphylococcus isolates beginning on days 14 and 4, respectively. Overall, of the nine patients who developed significant infection, seven did so before reaching an ANC greater than l,OOO/pL. A marginally significant positive association between number of days with temperature greater than 38°C and the number of days with ANC less than lOO/pL was Found (P = -054, regression analysis). However, the day to reach an ANC greater than l,OOO/pL was not significantly associatedwith the number of febrile days (P = 301). Incidence of G W D . The severity and initial day of detection of acute GVHD are shown in Table 2. Fourteen (55%) of the patients in Group I and 10 (55%) of the patients in Group I1 developed acute GVHD. The incidence of severe acute GVHD (grade I1 or greater) was 29% in Group I, (95% confidence interval [CI] = 11% to 47%) and 29% (95% CI = 7% to 51%) in Group 11. Seven of the patients (UPNs 4966, 4983, 5037, 5056, 5205, 5374, and 5256) met the criteria for grade I1 GVHD solely on the basis of a skin rash over more than 50% of their bodies. The rashes resolved with corticosteroid therapy in all seven. None of the 45 patients developed multiorgan GVHD during, or within 1 week of, discontinuing rhGM-CSF,

although five patients (four in Group I and one in Group 11) later developed multiorgan GVHD grade I11 to IV (Table 2). Four received antithymocyte globulin; two responded (UPNs 4807 and 5094) and two died (UPNs 4868 and 5269). UPN 5047 responded to corticosteroid therapy and did not require antithymocyte globulin. Toxicity. Twelve patients received fewer than the planned 21 doses of rhGM-CSF. However, rhGM-CSF was discontinued in only one patient as a result of toxicity (UPN 5347). All patients, except two (UPNs 5347 and 5437) received more than 14 doses of rhGM-CSF therapy. Toxicity at doses less than 259 ~~.g/m~ld are s h w n in Table 4. Three patients (UPNs 4982, 5073, and 5137) developed renal failure in association with venoocclusive disease of the liver and one (UPN 5253) in association with sepsis. None of these episodes were felt to be related to rhGMCSF. Five patients received rhGM-CSF at a dose of 500 pg/mZ/d. Toxicity is shown in Table 4. UPN 5347 required discontinuation of rhGM-CSF as a result of severe chest burning, bone pain, and tachycardia within 30 minutes of starting the infusion. The symptoms completely resolved within 2 hours after discontinuation of rhGM-CSF. UPN 5327 required a 50% reduction in dose of rhGM-CSF for severe chest/bone pains. UPN 5338 also developed bone pain, but elected to continue full-dose therapy. However, on the last day of therapy he developed an interstitial pneumonitis of unknown etiology and required bronchial intubation. All three patients required narcotics for pain relief. Two other patients (UPNs 5299 and 5300) received rhGM-CSF at 500 pg/m2/dwithout toxicity. Initial hospital discharge. Nine of 28 (32%) patients in Group I and 3 of 18 (17%) patients in Group I1 died during their initial hospitalization. The median day of discharge of all patients by Kaplan/Meier Wilcoxon analysis was not different between the two groups (P = .166). However, when only patients who were discharged were analyzed, patients in Group I had shorter initial hospitalizations than patients in Group I1 (P = .003, Wilcoxon rank sum test). The number of days the ANC was less than 100 correlated with the day of discharge (P = .044, stratified generalized Wilcoxon test), and the number of days the temperature was greater than 38°C also correlated with the day of discharge (P = .008, stratified generalized Wilcoxon test). Survivallrelupse. There were no differences in the survival or relapse rates between the two groups of patients treated with rhGM-CSF. Ten (35%) in Group I died before day 100 and six additional patients (UPNs 4966,4943,5068, Table 4. Presumed Toxicity to rhGM-CSF Not Attributed to Other BMT-Related Complications Percent of Patients

s 250 pglm2 Toxicity

(n = 42)

500 pg/m2 (n = 5) ~~

Nauseakomiting Rash Bone/chest pain Pulmonary infiltrates Abbreviation: n, number of patients.

7 12 12 7

40 20 60

20

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5134,5287, and 5229) relapsed before day 100 (Table 2). In Group 11, three (17%) patients died and one patient relapsed (Table 2) before day 100. Two (UPNs 5068 and 5287) of the 12 (17%) patients transplanted for a myeloid malignancy relapsed before day 100. Causes of death are shown in Table 2. The probability of survival by Kaplan Meier analysis to day 100 was 64% (0.44% to 0.84%, 95% CI) in Group I patients and was 83% (0.65% to loo%, 95% CI) in Group I1 patients. DISCUSSION

The goal of this study was to determine if rhGM-CSF could be administered safely to allogeneic BMT patients. As observed in prior trials in autologous BMT patients, allogeneic BMT patients had few side effects from rhGMCSF at doses up to 250 pg/m’/d. However, at the 500 pg/m’ dose level, three of five patients developed significant, but transient and non-life-threatening toxicities. Therefore, the maximum tolerated dose of rhGM-CSF was determined to be 250 pg/m2/d and all subsequent patients were treated at that dose. The patients who received CyA and prednisone as GVHD prophylaxis and who were treated at the lowest dose level of rhGM-CSF tested, 30 pglm’ld, reached an ANC of l,OOO/pL on a mean of day 13 (median day 12). Increasing doses of rhGM-CSF did not appear to further accelerate engraftment. The median day of reaching an ANC of 1,OOOlpL of all patients in Group I was day 14. These values can be compared with a published series of “good-risk” patients with CML in chronic phase and ANL in first remission who received CyA alone for GVHD prophylaxis and did not receive rhGM-CSF.” The median day to reach an ANC of l,OOO/pL in these patients was day 19. Studies in autologous BMT patients indicate that doses of rhGM-CSF 260 pg/mZ/d are required for sufficient biologic activity.’ However, early neutrophil recovery was observed at 30 pg/mZ/d in this study. Theoretically, stem cells from allogeneic marrow donors that have not been exposed to prior chemotherapy andlor radiotherapy may be better able to respond to growth factors than progenitor cells from autologous donors. Thus, it appears probable that rhGM-CSF shortened the neutropenic period in patients who received CyA and prednisone for GVHD prophylaxis. Consistent with this finding, the patients who were administered CyA and prednisone as GVHD prophylaxis and were treated with rhGM-CSF had significantly fewer febrile days and were discharged a mean of 11 days earlier than patients who received MTX. Despite a less impressive effect with rhGM-CSF on neutrophil recovery and the number of febrile days in patients receiving MTX, the low incidence of significant infection was the same in both

groups. Studies in patients requiring MTX for prophylaxis of acute GVHD who have a high incidence of infectionrelated mortality (ie, unrelated BMT patient^)'^ may be indicated. Fifty percent of the rhGM-CSF patients in Group I1 did not reach an ANC of l,OOO/pL until day 20, a value similar to the published value in CyA and MTX-treated patients who did not receive rhGM-CSF.” Deletion of day 11 MTX in five rhGM-CSF-treated patients did not increase their rate of engraftment. Thus, administration of rhGM-CSF concurrently with MTX did not have a deleterious effect on graft function when compared with historical patients who did not receive rhGM-CSF. However, rhGM-CSF did not accelerate engraftment as rapidly in these patients. The apparent reduced effectiveness of rhGM-CSF in patients who received MTX may be caused by an increase in the cytotoxic effect of MTX on early myeloid cells stimulated to cycle rapidly by rhGM-CSF. There were no differences in the incidence or severity of GVHD between the two groups of rhGM-CSF-treated patients. The incidence of severe (grade 11-IV) GVHD in rhGM-CSF-treated patients, regardless of their GVHD prophylactic regimen, was lower than that reported for CyA alone (50%) and similar to patients who received CyA and MTX (30%) in a recent controlled study.” In the present study, the overall incidence of grade I1 or greater GVHD during the first 60 days was 28%. Only 16% of the patients developed grade I1 GVHD before day 28 and all responded to steroid therapy. Multisystem GVHD was not observed until after day 28, when the effects of rhGM-CSF were no longer likely to be present. The low incidence of severe GHVD in these patients suggests that rhGM-CSF does not exacerbate GVHD. Two other hematopoietic growth factors that have undergone Phase 1-11 trials in allografted patients, human M-CSF and rhG-CSF, also did not appear to increase GVHD.l4.l5 We conclude from the present data that rhGM-CSF is well tolerated at a dose of 250 pg/m’/d, that it is unlikely to increase the incidence or severity of acute GVHD, and that it does not adversely affect hematopoietic reconstitution even in patients receiving concurrent MTX. Randomized, controlled trials are indicated to determine whether rhGMCSF significantly affects transplant-related toxicities and if survival can be improved while decreasing the BMTassociated morbidity. ACKNOWLEDGMENT

The authors acknowledge to Kathleen Shannon-Dorcey and Kathy Lilleby for patient monitoring, Pam Jones for excellent data management, and Carol Crittendon and Walley Meyers for assistance with data analysis.

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Anderson D, Cosman D, Andrews RG, Bernstein ID, Urdal DL: Interleukin-3, GM-CSF, and G-CSF receptor expression on cell lines and primary leukemia cells: Receptor heterogeneity and relationship to growth factor responsiveness. Blood 74:56,1989 4. Dinarello CA, Cannon JG, Mier JW, et al: Multiple biological activities of human recombinant interleukin 1. J Clin Invest 77:1734,1986 5. Moore RN, Oppenheim JJ, Farrar JJ, Carter CS Jr, Waheed A, Shadduck R K Production of lymphocyte-activating factor (interleukin 1) by macrophages activated with colony-stimulating factors. J Immunol 125:1302,1980 6. Wing EJ, Magee DM, Whiteside TL, Kaplan SS, Shadduck R: Recombinant human granulocyte/macrophage colony-stimulating factor enhances monocyte cytotoxicity and secretion of tumor necrosis factor-a and interferon in cancer patients. Blood 73:643, 1989 7. Ho AD, Haas R, Wulf G, Knauf W, Erhardt R, Heilig B, Kurbling M, Schulz G, Hunstein W: Activation of lymphocytes induced by recombinant human granulocyte-macrophage colonystimulating factor in patients with malignant lymphoma. Blood 75:203,1990 8. Blazar BR, Widmer MB, Soderling CCB, Urdal DL, Gillis S, Robison LL, Valera D A Augmentation of donor bone marrow engraftment in histoincompatible murine recipients by granulocytemacrophage colony-stimulating factor. Blood 71:320,1988 9. Blazar BR, Widmer MB, Soderling CB, Gillis S, Vallera D A Enhanced survival but reduced engraftment in murine recipients of recombinant granulocyte/macrophage colony-stimulating factor fol-

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