Clinical and Pharmacologie Effects of High Dose Single Agent Busulfan with Autologous Bone Marrow Support in the Treatment of Solid Tumors W

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[CANCER RESEARCH 47, 6402-6406, December 1, 1987) Clinical and Pharmacologie Effects of High Dose Single Agent Busulfan with Autologous Bone Marrow Support in the Treatment of Solid Tumors W. P. Peters,1 W. David Henner, L. B. Grochow, G. Olsen, S. Edwards, H. Stanbuck, A. Stuart, J. Gockerman, J. Moore, R. C. Bast, Jr., H. F. Seigler, and O. M. Colvin Bone Marrow Transplant Program, Department of Medicine [W. P. P., G. O., H. S., A. S., J. C., J. M.], Department of Surgery [H. F. S.], Duke University Medical Center, Durham, North Carolina; Department of Pharmacology, Dana Farber Cancer Institute, Boston, Massachusetts [W. D. H.]; and the Division of Pharmacology, Johns Hopkins Hospital, Baltimore, Maryland /L. B. G., O. M. C.]

ABSTRACT gous bone marrow support in patients with resistant solid tumor malignancies. In addition, the urinary excretion rate of muta A Phase I-II clinical trial of high dose single agent busulfan (16-20 genic metabolites and effects on DNA structure were studied. ntg/kg) administered over a 4-day period was undertaken. Pharmacoki- netic measurements reveal that steady state total plasma busulfan levels between 2 and 10 MMwere achieved by the second day and maintained MATERIALS AND METHODS through the remaining treatment period. Urinary excretion of mutagenic activity monitored by the Salmonella mutagenesis assay persisted for up Patient Population to 48 h following the last dose of busulfan. The treatment showed Six patients with measurable metastatic melanoma or hepatocellular specificity for myelocytic precursorsas evidenced by selective depression carcinoma were treated with two-dose escalations of busulfan (Table of granulocytes with relative sparing of lymphocytic elements, and by 1). No patient had evidence of bone or bone marrow involvement with differences in DNA damage as measured by a nucleoid sedimentation assay. Dose limiting toxicity was mucositis, anorexia, and hepatic toxic- tumor at the time of marrow harvest or evidence of central nervous system metastatic disease. Two patients each had received prior chemo ity. Transient autoimmune disorders were observed in three of the six patients. Partial responses were seen in two of five patients with mela therapy or local radiotherapy; all except one had visceral disease. Pretherapy evaluation included physical examination, liver chemistries, noma, but these lasted for only 2 and 3 months. High dose busulfan pulmonary function testing including DLCO, and lymphocyte subset represents an alkylating agent with marked myelocytic selectivity and analysis. may be useful for inclusion in intensive combination regimens. Treatment Protocol

INTRODUCTION Bone marrow was aspirated from bilateral posterior iliac crests under general anesthesia using 12-guage modified Rosenthal needles and The administered dose is a major prognostic factor in effec anticoagulated with heparin and TC-199 (GIBCO, Grand Island, NY). tive therapeutic regimens for both solid tumors and leukemias Buffy coat concentration was performed using a Cobe 2991 cell washer (1). Because the major dose-limiting toxicity of many anticancer and cryopreserved in 10% dimethyl sulfoxide and 20% autologous agents is myelosuppression, attempts have been made to amel plasma. A mean of 1.58 x 10*cells/kg were cryopreserved. All patients iorate this toxicity by bone marrow infusions from autologous, had double-lumen silastic catheters inserted. Patients were treated in syngeneic, or allogeneic sources (2, 3). This technique has private rooms with access via reverse isolation and provided a low permitted modest dose escalations (2-15 times) before dose- bacterial, low fungal content diet. Busulfan was administered over 4 days (day â€”6to day â€”3)in 16 limiting nonmyelosuppressive toxicities occurred (4), as well as improvements in objective response rates in resistant solid doses given orally every 6 h. The first two patients received each 1 mg/ tumors (5-7). However, these responses have, in general, been kg dose as commercially available pills, either whole or crushed. Sub sequent patients received doses as gelatin capsules prepared from bulk partial and not durable, emphasizing the need for more effective busulfan (Burroughs-Wellcome, Ltd., Research Triangle Park, NC). agents. Perphenazine was used as the sole antiemetic; steroids or barbiturates Busulfan is an alkylating agent of the alkyl alkane sulfonate were not administered during chemotherapy to any patient because of class which is widely used in the treatment of chronic myelo- possible effects on alkylating agent pharmocokinetics. Two days follow genous leukemia. However, clinical trials in solid tumors at ing completion of chemotherapy, autologous bone marrow was rapidly standard doses have been limited (8). Trials of high dose busul thawed and i.v. infused. Toxicity and response are reported from day fan and cyclophosphamide with allogenic bone marrow trans of marrow infusion. Red blood cells were transfused for a hematocrit less than 42% (11), and platelets transfused to maintain a platelet count plantation in the treatment of acute leukemia have demon above 20,000/mm3. strated that substantial dose escalation in the administered dose of busulfan can be achieved before dose-limiting mucositis is Salmonella Mutagenesis Assay encountered (9), and that the therapeutic efficacy is equivalent, if not superior to cyclophosphamide and total body irradiation Tester strain TA 100 was obtained from Dr. Bruce Ames. Urine as a preparative regimen (10). The maximum tolerated dose of specimens from initiation of treatment until the time of bone marrow infusion were filter sterilized (0.22 firn; Millipore, Waltham, MA) and busulfan as a single agent with bone marrow support has not stored frozen at -70Â°C.The urine was diluted 1 to 250, and 0.3 cc of been established, nor its efficacy at high doses in solid tumors. urine mixed with 0.1 cc overnight culture of TA 100 as previously The present trial was undertaken to establish the maximum described (12, 13). After 72 h of incubation at 37Â°Ccolonies were tolerated dose, toxicity, and pharmacology of busulfan as a counted and corrected for spontaneous reversion frequency. single agent and to evaluate the hematological, antitumor, and immunosuppressive effects of high dose busulfan with autolo- Nucleoid Sedimentation Assay

Received 12/15/86; revised 8/11/87; accepted 9/10/87. Sedimentation of the nuclei of lymphocytes and buffy coat cells The costs of publication of this article were defrayed in part by the payment derived from patients treated with busulfan were performed as previ of page charges. This article must therefore be hereby marked advertisement in ously described (14, 15). Lymphocytes were prepared from whole blood accordance with 18 U.S.C. Section 1734 solely to indicate this fact. 1To whom requests for reprints should be addressed, at Duke University by sedimentation through Ficoll-Hypaque (LSM), and cryopreserved Medical Center, P. O. Box 3961. Durham, NC 27710. with 20% autologous plasma and 10% dimethyl sulfoxide until use. 6402

Table 1 Patient characteristics (cm2)Response*NR volume

treatment therapy for dose maximum Patient1 number6 mÃ©tastases"XRTNone (mg/kg)16 (days)10372Initial0.9 response0.2 (I if 23 7 28 F Melanoma Skin, lungs 16 NR 13.428.7 4.5(14) 32 48 M Melanoma Liver, lungs BOLD, DBD, XRT 16 NE 5.0 (9) 4 35 50 MFMDiagnosisMelanomaMelanoma Nodes, mediastinum DBDNoneNoneBusulfan 162020TumorPR 12.5 4.2 (67) 56Unique 3640Age(yr)264430SexM MelanomaHepatomaSitesNodesPelvicmassLiverPrior PRNRDuration 300.0 98.3 (20) 21.4 3.2 (20) 258.0At 280.0 (35) " XRT, radiation therapy; BOLD, bleomycin, vincristine, lomustine. dacarbazine; DBD, dibromodulcitol. * NR, no response; NE, not Ã©valuable;PR,partial response. ' Day from bone marrow reinfusion of maximum response is given in parentheses.

Unity coat cell collections were obtained from 10 cc of peripheral blood centrifuged in a RC-3B HB-4 rotor at 2000 rpm for 10 min and cryopreserved in a similar manner. Lymphocytes obtained in this man ner were thawed at 37'C, washed with media containing 20% fetal calf serum. Buffy coat cells were rapidly thawed at 37Â°Candapplied directly to the sucrose gradient described below. Rapid processing and layering of the BC2 preparations was essential to obtaining reproducibility with granulocyte preparations. Lymphocytes or BC specimens obtained as Z above were directly applied to a 14-ml 15-30% sucrose gradient con taining 30 Mg/ml ethidium bromide (Sigma Chemical Co., St. Louis, MO) overlayed with buffer containing 0.1% Triton-X-100, 2.0 M so dium chloride and Tris-HCl, pH 8.0. After lysis for 15 min at room -5 10 15 20 25 30 temperature, the cells were sedimented through the sucrose gradient and AH-627 (Sorvall) rotor, 25,000 rpm for 120 min (lymphocytes) or Dty From Marrow Relnfuilon 45 min (BC). The distance sedimented by nucleoids was directly mea sured via short-wave IV fluorescence, and compared to sedimentation of a pretreatment sample.

Pharmacokinetics

Plasma samples were obtained from three patients via indwelling venous catheters in heparinized tubes (Vacutainer) at 0, 30 m, 60 m, 90m, 120m, and 240m after the first, 5th, 9th, and 13th doses. U _J Samples were centrifuged and 5 ml was frozen and shipped on dry ice to Baltimore (L. B. G., M. C.) and Boston (W. D. H.) for analysis. Plasma concentrations were measured using two independent methods described elsewhere (16).3 Concentrations were fit to a one-compart ment model with first order absorption adjusted for multiple dosing 10 15 20 25 30 using PCNonlin (Statistical Consultants, Lexington. KY) for the analy DÂ«yFrom Marrow Reinfiiiion sis done in Baltimore and using MLAB (National Cancer Institute, Fig. 1. I. median absolute polymorphonuclear cell (PMN) count following Division of Research Resources) for the analysis done via Boston high dose busulfan from the day of bone marrow reinfusion; I!, median absolute methodology. lymphocyte count (ALC) following high dose busulfan from the day of bone marrow reinfusion. Toxicity Immunological Toxicity. The median absolute lymphocyte count re Acute Toxicity. There were no complications in the marrow harvest mained unchanged throughout therapy (Fig. Ã¬li).Further, measurement ing and reinfusion procedure. Administration of the busulfan was of T-cell subsets by fluorescence-activated cell sorting revealed no uneventful. Two patients experienced minor episodes of nausea and significant change in the number of T4, T8, la, Bl, T3, or Tl 1 positive vomiting which did not require readministration of drug. No seizures lymphocytes or the T4/T8 ratio at any time following therapy. This occurred during drug administration. Two patients (UTN 7 and 35) finding is in marked contrast to our experience with high dose combi developed unexplained acute pain at the sites of tumor shortly after nation alkylating agent regimens where there is a decrease in T4 and drug administration which resolved after several days. Hematological Effects. Severe myelosuppression (Polymorphonu- Bl positive cells, an increase in T8 and la positive cells and an inversion clear cell < 100/mm') followed administration of busulfan at both dose of T4/T8 ratio which develops soon after therapy and persists for 6 to 12 months (17). escalations. The median polymorphonuclear cell count following ad Three patients developed unusual "immunological syndromes" fol ministration of high dose busulfan and autologous bone marrow rein- lowing therapy. One patient (UTN 6) developed a heliotrope rash and fusion is shown in Fig. \A. Severe granulocytopenia resolved by a a severe sero-negative arthritis requiring transient steroid therapy 20 median 16 days from marrow reinfusion. No dose effect on leukopenia days following bone marrow infusion. This patient also developed was seen between the two dose escalations examined. antiplatelet antibodies. A second patient (UTN 7) developed antigran- Fever was seen during neutropenia in all patients; however, no blood ulocyte and antiplatelet antibodies and required steroid treatment for 2 cultures were positive. Three patients developed oral candidiasis and weeks to reverse neutropenia. A third patient (UTN 30) developed one patient developed a fatal systemic infection with Candida albicans. chronic active hepatitis beginning 18 days from marrow infusion which Viral infections were not documented. resolved over 2 months without specific therapy. In this case, antimi- 2The abbreviation used is: BC. bufTycoat. tochondrial and anti-smooth muscle sÃ©rologieswerenegative. 3L. B. Growchow, unpublished data. B-Cell function appeared intact with patients retaining the ability to 6403

Downloaded from cancerres.aacrjournals.org on October 1, 2021. © 1987 American Association for Cancer Research. BUSULFAN WITH AUTOLOGOUS BONE MARROW IN SOLID TUMORS mount antibody response against Herpes and cytomegalovirus antigens TOTAL PLASMA BUSULFAN LEVELS following therapy. Sensitivities to specific challenge antigens were not tested. Nonhematological Toxicity. Dose-limiting toxicity in the trial was a diffuse mucositis with accompanying diarrhea (Table 2). The mucositis was more severe at 20 mg/kg, requiring narcotic administration for pain and precluding oral food intake for more than 2 weeks. Frequent diarrhea also accompanied the mucositis and all patients required i.v. fluid supplementation. While nausea and vomiting was not a feature of the acute drug administration, five of six patients subsequently devel oped nausea, vomiting, and accompanying profound anorexia of more than 2 weeks. All patients developed hyperbilirubinemia greater than 2.0 mg/dl Course with half of the patients developing jaundice with bilirubin in excess of Course 5 5.0 mg/dl. Hepatic biopsy in one patient showed chronic active hepa Course 9 titis. At autopsy 6 months later, there was tumor present but resolution Course 13 of the liver active hepatitis. Autopsy in a second patient demonstrated hepatic candidiasis but no evidence of drug toxicity. I 2 Time (hoursl Pulmonary symptoms or toxicity were not encountered. Pulmonary function testing including diffusing capacity for carbon monoxide and Fig. 2. Total plasma busulfan levels measured following the first, fifth, ninth, and thirteenth dose of busulfan at 16 mg/kg. Plasma levels were monitored using arterial blood gases before and after therapy were not significantly the Boston method described in "Materials and Methods." different in four Ã©valuablepatients. Response. Two patients with melanoma achieved a partial response of 2 and 3 months' duration. Five patients demonstrated evidence of Table 3 Peak plasma busulfan levels (tig/ml) following high dose single agent treatment tumor regression by measurement of tumor volumes (Table 1); however, these were frequently transient and therefore not qualifying as partial methodDoseno.15913Dayno.-6-5-4-3UTNÂ°354.77ND3.115.91UTN365.048.358.158.15UTN409.705.116.485.11BaltimoreBoston methodUTN354.02ND3.665.81UTN363.786.066.345.77UTN408.827.768.946.95 responses. All patients had evidence of regrowth of tumor by 4 months following treatment. Pharmacokinetics. Pharmacokinetic measurement by two independ ent methods indicated that the oral absorption of busulfan was consist ent both in an individual patient and among several patients evaluated. Fig. 2 shows that steady state plasma levels of between 2 and 8 Â¿IM ' UTN, unique treatment number. ND, not determined. were achieved by the second day of treatment and maintained through out the remainder of the treatment course. The daily peak plasma level of busulfan achieved was similar among several evaluated patients I50r (Table 3) with good correlation between samples analyzed by the two different analytic methods. Salmonella Mutagenesis Assay. Urinary excretion of mutagenic me-

Table 2 Toxicity following high dose busulfan Ã©valuable ConditionInfectious (no./no.)6/60/63/6

Fever Fever + culture 050 Candida Oral SystemicNumber 1/6%100 17

Pulmonary Restrictive Physiology 0/5

Gastrointestinal -4 -2 0 Nausea/vomiting 5/6 83 Day From Marro* Reinfusion Diarrhea 5/6 83 Fig. 3. Urinary excretion of mutagenic activity monitored by the Salmonella Stomatitis/esophagitis 6/6 100 mutagenesis assay. Number of revertan! colonies above background from 0.25- Anorexia 4/6 67 ml filter sterilized urine obtained versus the day from bone marrow infusion is plotted. Symbols, serial samples on individual patients. HepaticBili >2Bili >5VODÂ°Chronic tabolites was monitored using the Salmonella mutagenesis assay (13, 14). Excretion of mutagenic activity was seen from days -5 to â€”2(Fig. hepatitisNeurologicalSeizuresDermatologica!RashImmunologicalLupusactive 3). However, by the time of bone marrow infusion urinary levels of mutagenic activity had returned to baseline. In one patient (UTN 40) treated at 20 mg/kg urinary mutagenic activity was noted until day -1, suggesting a limited margin of safety in the timing of bone marrow infusion. Nucleoid Body Assay. DNA strand breaks of lymphocytes from patients before and after treatment (Fig. 4) were unchanged as moni syndromeAntigranulocyte tored by sedimentation of the nucleoid in neutral sucrose gradients AbAntiplatelet AbChronic whereas strand breaks and damage to the huffy coat DNA increased hepatitis6/63/60/61/60/63/61/61/61/61/61005001705017171717*active progressively following each day of busulfan treatment. The differential VOD, venoocclusive disease. effect on lymphocytes and granulocytes was not seen in nucleoids obtained from patients treated with cyclophosphamide, cisplatin, and 6404

membranes and proteins, and that because immune function is otherwise unaltered, cell surface alkylated products might be immunogenic, leading to the development of the transient immunological syndromes. An alternative explanation for the noted immunological syndromes would be modification of spe cific subpopulations of lymphocytes which were not detected by the reagents used. That such immune syndromes have not been observed when busulfan is administered in combination with the immunosuppressive agent cyclophosphamide (10) is consistent with the possibility that these effects are immuno- logically mediated. Busulfan has been widely used at conventional dosage for the treatment of chronic myelogenous leukemia (18). At does sim ilar to those employed in this study, busulfan has been used

-4 -3 -2 successfully as a component of preparative regimens in alloge- Day From Marro* Infusion neic bone marrow transplantation for acute and chronic leuke Fig. 4. Relative segmentation compared to pretreatment sample of nucleoids mia (10). Animal experimentation with busulfan and di mollivi- derived from lymphocytes of patients treated with high dose busulfan (â€¢.â€¢,A, myleran, a dimethylated derivate of busulfan, suggests that *), buffy coat cells (>80% polymorphonuclear leukocyte) (D, A, O) of patients treated with high dose busulfan, and lymphocytes (O) from 25 patients treated these agents produce a selective granulocytopenia with little with high dose cyclophosphamide. cisplatin, and carmustine. Results are ex effect on cellular or humoral immune function (19). Further, pressed as percentage of central distance migrated compared to pretreatment control. Day â€”6sample is prior to treatment and days are expressed relative to the marrow suppressive and therapeutic effects of busulfan and bone marrow infusion. dimethylmyleran were shown to be relatively independent of the proliferative state of the marrow (20, 21). This property is carmustine where alteration of sedimentation of nucleoids from both attractive for the selection of agents for autologous marrow lymphocytes and buffy coat cells following treatment was consistently transplantation efforts as most solid tumors have a low growth observed. fraction. Further, many of the complications of high dose therapy are related to the immunosuppressive properties of the therapeutic regimens. Since immunosuppression is not required DISCUSSION for high dose chemotherapy using autologous or syngeneic The dose response effect of antitumor agents is steep for both transplants, agents lacking immunosuppressive effects may pro neoplastic and normal tissues. However, various antitumor vide a therapeutic advantage. agents vary substantially in the targets of their nonmyelosup- Analysis of sedimentation of the nucleoid from lymphocytes pressive toxicities. The observations reported here suggest that and granulocytes in high salt, neutral sucrose gradients shows busulfan at 16-20 mg/kg possesses selectivity for myelocytic that less damage occurs to lymphocyte DNA after in vivo and megakaryocytic hematopoietic precursors. While profound busulfan exposure. Whether this difference is due to more myelosuppression accompanied busulfan administration, little effective repair or to differences in transport require further effect was seen on lymphocyte numbers and subsets. analysis. Consistent absorption of drug with steady state plasma levels Busulfan demonstrates efficacy in several solid tumor animal (2-10 fiM) was seen after multiple drug doses in the same screens (22, 23). Recent experimental data suggests that busul patient and among several patients (Table 3). This pharmaco fan at transplant doses is effective in the treatment of B16 melanoma.4 However, few trials of the activity of busulfan in logical consistency is of major importance in assessing the value of an intensively administered oral antineoplastic agent. human solid tumors have been reported (reviewed in Ref. 8). Dose-limiting toxicity in this trial was mucositis and an Even though administered at doses approximately 100 times orexia. The maximum tolerated dose of busulfan in combina standard doses as in this study, busulfan produced limited tion with cyclophosphamide has been demonstrated to be 16 therapeutic results as a single agent in melanoma. Two patients mg/kg. This study shows the maximum tolerated dose without developed temporary partial responses and evidence of transient cyclophosphamide to be 16 mg/kg confirming the nono verlap tumor volume regression (50%) was seen in five of six (83%). ping toxicity of these agents. Hepatic toxicity manifested as Kaiser has demonstrated that the therapeutic efficacy of busul unexplained hyperbilirubinemia also accompanies busulfan ad fan in P388 leukemia is highly dependent upon its temporal ministration. Busulfan, being an orally administered agent sub administration with other agents. Alteration of the schedule of ject to first-pass hepatic clearance, perhaps partially accounts administration may also affect toxicity and antitumor effect. for this observation. The transient immunological syndromes accompanying bu ACKNOWLEDGMENTS sulfan administration are unexplained. No significant pertur bation of lymphocyte numbers or phenotype were noted al We would like to acknowledge the help of the nurses, physicians, though specific immune responses were not tested. While an- and support teams of the Bone Marrow Transplant Program in the tigranulocyte (one patient) and antiplatelet antibodies (two completion of these studies, and the excellent administrative support patients) were demonstrated, no other specific or nonspecific of Pat Wood and data management of B. W. Blackburn. antibodies were found. Despite multiple-platelet transfusions in other patients, neither lymphocytotoxic nor antiplatelet an REFERENCES tibodies developed. Chronic active hepatitis and a seronegative lupus-like syndrome also occurred. These immunological syn 1. Frei, E., HI, and Canellos G. P. Dose: a critical factor in cancer chemotherapy. Am. J. Med., 69: 585-594, 1980. dromes were transient and the mechanism remains unex plained. It might be speculated that because busulfan alkylates 4 H. Kaiser, personal communication. 6405

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Downloaded from cancerres.aacrjournals.org on October 1, 2021. © 1987 American Association for Cancer Research. Clinical and Pharmacologic Effects of High Dose Single Agent Busulfan with Autologous Bone Marrow Support in the Treatment of Solid Tumors

W. P. Peters, W. David Henner, L. B. Grochow, et al.

Cancer Res 1987;47:6402-6406.

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