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THE PHARMACOLOGY OF INTENSIVE CYCLOPHOSPHAMIDE, CISPLATIN AND BCNU (CPA/CDDP/BCNU) IN PATIENTS WITH BREAST CANCER. Roy B. Jones, Steven Matthes, Christopher Dufton, Scott I. Bearman, Salomon M. Stemmer, Susan Meyers, and Elizabeth J. Shpall. Combinations of alkylating agents in intensive doses with autologous bone marrow support (ABMS) are commonly used to treat advanced adult solid tumors, particularly breast and ovarian cancer. These drugs are usually administered in the maximally tolerated doses adjusted for weight or body surface area. The specific drug combinations and schedule of administration often lack firm scientific or clinical rationale, and, with rare exception, no further individualization of dose is ever done. In an attempt to lend further rationale to these treatments, we embarked on a program of comprehensive pharmacokinetic (PK) monitoring of the CPA/cDDP/BCNU regimen. The major goals of this program were: 1) Description of the PK variability of the regimen 2) Definition of pharmacodynamic (PD) correlations of this PK variability 3) Development of predictive methods for the PK of each drug in each patient to allow individualized drug dosing. 4) Testing the impact of individualized dosing on patient outcomes. BACKGROUND AND SIGNIFICANCE The use of PK measurements to direct drug dosing is common in medicine. Antibiotics, neurotropic agents, and immunosuppressants exemplify classes of drugs where therapeutic drug monitoring is routinely performed. The goal of this activity is to optimize the therapeutic index of the drug by optimally balancing toxicity and therapeutic effect through dosage individualization. Several hypotheses underlie these programs: 1) Important variability in drug PK exists between patients in spite of standardized drug dosing 2) This variability should correlate with toxic or therapeutic outcome, preferably both. 3) Correction of this variability should be possible using therapeutic drug monitoring, and should improve the therapeutic index of the drug (regimen). It is ironic that therapeutic drug monitoring is almost never used in anticancer therapy. Antineoplastic agents have the narrowest therapeutic index of any class of drugs and are the most common class of drugs to produce fatal toxicity in routine use. The only antineoplastic agent frequently monitored is methotrexate, ironically a drug where a "rescue" compound (leucovorin) is available. There are important deterrents to antineoplastic drug monitoring. Most 124 SIXTH INTERNATIONAL SYMPOSIUM ON AUTOLOGOUS BONE MARROW TRANSPLANTATION
agents are given intermittently in multiple drug regimens, thus preventing repetitive refinement of dose by multiple dose monitoring over time as done with many oral agents. More accurate modeling of PK is thus required than the usual "random blood level" or "peak and trough" strategy used in most instances to obtain adequate accuracy of dose adjustment. For drugs other than methotrexate, validated drug assays for monitoring (having standardized precision, reproducibility, biologic relevance, and rapid result availability) are often unavailable. These topics are discussed in greater detail elsewhere 111 . In the field of high-dose chemotherapy with autologous hematopoietic cell support (HrXVAHCS), antineoplastic drug monitoring might have maximal justification. Sporadic life-threatening and fatal toxicities are seen, and conventional prognostic factor analysis poorly defines patients likely to achieve multiyear tumor-free survival. It is reasonable to hypothesize that variability in drug exposure might affect toxic and therapeutic outcome in this setting. Only limited investigations in this area have been reported. Ayash et al. treated patients with advanced breast cancer with high-dose cyclophosphamide, carboplatin, and thiotepa (CPA/CBDCA/TT) and demonstrated that CPA PK correlated with both risk of cardiotoxicity and probability of progression-free survival 121 . Jones, et al treated similar patients with CPA/cDDP/BCNU and correlated the risk of acute pulmonary injury with BCNU PK 131 . Groshow et al. treated patients with high-dose busulfan and cyclophosphamide (Bu/Cy) and correlated the risk of hepatic veno-occlusive disease (VOD) with BU PK 141 . Importantly, in subsequent studies she demonstrated that PK-directed dose adjustment of BU could be used to reduce the incidence of VOD 151 . With this background, we proposed to perform a comprehensive PK/PD study of the CPA/cDDP/BCNU regimen. This high-dose regimen is frequently used in patients with breast cancer and its use is the subject of an NCI high-priority intergroup trial in patients with St II breast cancer involving 10 or more axillary lymph nodes. Preliminary data justifying this trial was generated at Duke University, and showed that 72% of treated patients are projected to remain progression-free survivors 5 years following treatment 161 . Comparable patients treated with conventional chemotherapy have a progression-free survival of 30% in many series. The potency of this regimen and the likelihood of its expanded use in the future added justification to this investigation. The doses and schedule of CPA/cDDP/BCNU are shown below: Day -6 -5 -4 -3 -2 -1 0 +1 CPA + + + 1875 mg/m 2 /day cDDP 55 mg/m < > 2 /day BCNU 600 mg/m + 2 <strong>Marrow</strong> + Sam INTERNATIONAL SYMPOSIUM ON AUTOLOGOUS BONE MARROW TRANSPLANTATION 125
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Autologous Bone Marrow Transplantat
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CONTENTS nviAum TMLHTA'I OTT! 7 A l
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AUTOLOGOUS BONE MARROW TRANSPLANTAT
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TREATMENT OF NONSMALL CELL LUNG CAN
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SUMMARY OF THE NON HODGKIN LYMPHOMA
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Session I: Leukemia
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TRIAL PROGRESS The trial opened in
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Table 1. Achievement of Second Remi
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ALLOGENEIC VERSUS AUTOLOGOUS BONE M
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pts). The other 56 pts are too earl
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Figure 1 EORTC-GIMEMA AML 8 A EORTC
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PATIENTS AND METHODS Patients The B
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Thus, as the results of some ongoin
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COMPARISON OF INTENSIVE CONSOLIDATI
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over, 13 pts who had received ICC1
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Session II: Future Directions
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in a previous report 3 . Analysis a
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Engraftment of granulocyte, monocyt
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0.2 - 0.1 - ABMT with mAb purging f
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ENHANCED REGENERATION OF NATURAL KI
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RESULTS The in vivo immune effects
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16. Rizzoli V, Mangoni L, Carlo-Ste
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hydroperoxycyclophosphamide (4HC)-t
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survival in patients undergoing ABM
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IMMUNOTHERAPY OF AML AFTER ABMT - S
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Otherwise toxicity was mild to mode
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Therapy. Amsterdam Elsevier 1987;89
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200 IL6 in serum 44 SIXTH INTERNATI
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sodes), fewer days of i.v. antibiot
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Session III: Myeloma
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trary, in case of adequate collecti
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tion is considered, and all the mor
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Table 3: Cost effectiveness of high
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Session W: Lymphoma
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METHODS Selection of patients and t
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marrow treatment. Am J Med 85:829,1
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HIGH DOSE THERAPY WITH HEMATOPOIETI
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in TC 19 medium (Flobio), with an h
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progression for a long time after A
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Table 2. STATUS AT GRAFT Remission
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IL Figura 3 70 SIXTH INTERNATIONAL
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( 5 ) lowed by ABMT than refractory
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74 Figure 4 Low grade lymphoma - pr
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(range 15-55); 68 males and 32 fema
Page 100 and 101: our experience, this has a seven-ye
Page 102 and 103: 30. Colombat P, Gorin NC, Lemonnier
Page 104 and 105: 82 OVERALL SURUIWL from ABUT (accor
Page 107 and 108: PROGNOSTIC FACTORS IN ADVANCED STAG
Page 109 and 110: REFERENCES 1. Chopra R, Mc Millan A
Page 111 and 112: lished data to attempt to assess th
Page 113 and 114: 1992;10:175-7. 3. McMillan A, Golds
Page 115 and 116: B. DAILY DAY AGENT DOSE -7 -6 -5 -4
Page 117 and 118: cohort with HR treated with BEC-2 i
Page 119 and 120: p R 0 P O R T I 0 N 1 0.9 0.8 0.7 0
Page 121 and 122: TABLE 3. TOXICITY BEC TAVe TMJ as 2
Page 123 and 124: ies. 10 Longer blood half-lives hav
Page 125 and 126: agents have been developed cautious
Page 127 and 128: Table 1. Radioisotopes for RIT. Pur
Page 129 and 130: The treatment criterion in this stu
Page 131 and 132: more than 80% of the cases. Patient
Page 133 and 134: Disease Free Survival 800 Time •
Page 135: Session VI: Breast Cancer
Page 138 and 139: achieved a complete remission survi
Page 140 and 141: acil, vincristine, prednisone (CMFV
Page 142 and 143: t: 3 en a in S « J •S •> c ai
Page 144 and 145: LONG TERM FOLLOW UP OF POOR PROGNOS
Page 146 and 147: tors both for progression-free surv
Page 148 and 149: 222 INDUCTION PHASE ESTROGEN RECEPT
Page 152 and 153: PK VARIABILITY OF CPA/CDDP/BCNU Whe
Page 154 and 155: 5. Groshow LB, Piantadosi S, Santos
Page 157 and 158: - Tn'üTiifi'.m'jii.'yjKJiHtyiwiT T
Page 159 and 160: normal CD34+ progenitor cells
Page 161 and 162: sequence analysis of the human haem
Page 163 and 164: Bielefeld, FRG) or control medium w
Page 165 and 166: 3. Koeffler HP, and Golde DW: Chron
Page 167 and 168: ply infected with supernatants from
Page 169 and 170: controls must be carefully matched
Page 171 and 172: Fig. IB: GPI isozyme analysis of 2
Page 173 and 174: PROCESSING OF STEM CELLS FOR TRANSP
Page 175 and 176: in progress using marker genes to l
Page 177 and 178: Table 1. Factors Affecting Quality
Page 179: Figure 2 .2 A Refractory/Relapsed L
Page 183 and 184: HIGH DOSE CHEMOTHERAPY IN GERM CELL
Page 185 and 186: carboplatin and etoposide with auto
Page 187 and 188: HIGH DOSE THERAPY IN GERM CELL TUMO
Page 189 and 190: Confusing data come out from early
Page 191: Session Mill: Lung Cancer
Page 194 and 195: Of the 14 limited stage patients in
Page 196 and 197: esponses with persistent nodular di
Page 198 and 199: hanced, detection of initial failur
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Cellules. Bull Cancer 1987;74:587-5
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30 36 42 48 54 60 66 72 78 84 12 18
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Table 2: Toxicity of CBP Regimen fo
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TREATMENT OF NONSMALL CELL LUNG CAN
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Table 1. Combination Chemotherapy R
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Table 6. Hematological Data of the
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ence in survival among the three hi
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Session IX: Ovarian Cancer
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lymph node involvement or parenchym
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higher frequencies of neurotoxicity
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12. Ovarian Cancer Meta-Analysis Pr
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Table 2. Randomized Trials Employin
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BONE MARROW TRANSPLANTATION FOR OVA
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1). Data from the survey was combin
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carboplatinum and ifosfamide. The s
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Session X: Sarcoma
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ated doses in a recent Pediatric On
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cytokines to reduce hospitalization
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TABLE 2 Dose Escalation Schedule Do
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CHRONIC MYELOGENOUS LEUKEMIA WITH B
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DISCUSSION In this study, the use o
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AUTOGRAFTING IN CHRONIC MYELOID LEU
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Table 1 Remission Deaths Graft Hema
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16 (800 mg/m2 per day for two conse
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Session XII: CNS
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1.2 Description of the study The tr
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3. Conclusion In conclusion, treatm
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3. Conclusion Hematological toxicit
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Session XIII: Peripheral Stem Cells
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Crouse, 1992). In the present repor
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with no evidence of systemic diseas
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Administration of rhSCF at doses of
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In summary, the ligand for c-kit ha
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AUTOGRAFTING WITH G-CSF-MOBILIZED B
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cells and CD34+ cells observed in t
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6. Brugger W, Bross K, Frisch J, et
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100 -l Collection Efficiency Figure
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MATERIALS AND METHODS PATIENTS. Pat
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None of the patients included in ar
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9. Aurer I, Ribas A, Gale RP. What
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246 o 0.6 b 0.1 B1 Figure 2 p = 0.0
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AUTOLOGOUS BONE MARROW TRANSPLANTAT
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SUMMARY OF THE NON HODGKIN LYMPHOMA
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SUMMARY: AUTOLOGOUS MARROW TRANSPLA
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mor. The obverse of this coin is po
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treated at Memorial Hospital in New
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Contributors and Participants Tause
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Leonard Kalman, Hematology/Oncology
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D.R. Sutherland, Oncology Research,
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