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86 Mafosfamide Purging in Leukemia dose-response curve was too steep to select appropriate drug doses to work with. Others have made similar observations, and the inverse relation between mafosfamide cytotoxicity to progenitor cells and the RBC contamination responsible for nonspecific binding and diversion of the drug from the primary target is now well established. Our preliminary studies also showed a wide range of sensitivity among patients; further, a few patients tested sequentially (data not shown) revealed an increasing resistance to the drug that developed in parallel with disease progression. When we started the clinical trial, these observations prompted us to study each patient's sensitivity to mafosfamide immediately before marrow collection to select the incubation dosage rather than using a constant amount—hence, we used the PIT. As in our preliminary studies, the PIT showed considerable variations among patients in response to identical drug concentrations, which suggested that adjusting the dose for individuals might be appropriate. Because we could not directly evaluate the tumor log-cell kill and because the biological importance of cells detected in the CFCI-L assay is unknown, we decided to define the incubation dose of mafosfamide for marrow as the highest possible dose that would spare enough normal stem cells to ensure consistent engraftment. A residual amount of 5% ± 5% CFCl-GM in the cleansed marrow was considered a safe margin beyond which further cytotoxicity would not be measurable, at least by conventional laboratory means. With this definition, doses of mafosfamide ranging from 50 ug to 140 ug/2 x 10 7 buffy coat cells were necessary. Since we initiated our program, other investigators have reported similar individual variations in sensitivity to mafosfamide both in animal progenitor cell populations (8) and in human leukemic and lymphoid cells (9). Our long-term culture studies indicated that even marrows totally depleted of CFCl-GM still retained a self-regenerating ability. Although they confirmed the higher resistance of early progenitors to CY derivatives, as suggested by initial preliminary reports of successful autologous engraftment in humans with marrow deprived of CFCl-GM (10), these studies also showed that the selfrenewal capacity was proportional to the surviving fraction of CFCl-GM in the sample initially placed in culture, which reassured us in our intention not to go below the threshold of 5% residual CFCl-GM in the cleansed marrow. Fifty of 52 patients in our study experienced engraftment, although they received, as predicted, very low numbers of CFCl-GM. We can draw some conclusions. First, mafosfamide can be used to cleanse the marrow of patients with acute leukemia. Because patients show a wide range of sensitivity to the drug, we believe that individual dosage adjustment is an option, the clinical relevance of which must be tested further. Second, the differences in kinetics of hematopoietic recovery suggest that the engraftment potential has been altered more severely in ANLL than in ALL, which may reflect both the intensity of the in vitro treatment and the intrinsic fragility of the stem cell pool in ANLL.
Mafosfamide Purging in Leukemia 87 ACKNOWLEDGMENT The authors are indebted to C. Baillou, M. C. Giarratana, and D. Bardinet for their expert technical assistance, and to J. Lallier for preparing the manuscript. REFERENCES 1. Sharkis S, Santos GW, Colvin M. Blood 1980:55:521. 2. Douay L, Gorin NC, Gerota L, Najman A, Duhamel G. Exp Hematol 1982;10(Suppl 12):113. 3. Chang UA, TilUE, McCulloch EA. J Cell Physiol 1980; 102:217. 4. Pike BL, Robinson WA. J Cell Physiol 1970;76:77. 5. Iscove NN, Sieber F. Exp Hematol 1975;3:32. 6. Dexter RM, Allen TD, Lajtha LG. J Cell Physiol 1977;91:335. 7. Herve P, Cahn JY, Plouvier E, Flesch M, Tamayo E, Leconte des Floris R. Invest New Drugs 1984;2:245. 8. Hagenbeek A, Martens ACM. Invest New Drugs 1984;2:237. 9. Osieka R, Pannenbacker P, Schmidt CG. Invest New Drugs 1984;2:161. 10. Kaizer H, Stuart RK, Brookmeyer R, Beschorner WE, Braine HG, Burns WH, Fuller DJ, Korbling M, Mangan KF, Saral R, Sensenbrenner L, Shadduck RK, Shende AC, Tutschka PJ, Yeager AM, Zinkham WH, Colvin OM, Santos GW. Blood 1985;65:1504.
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Autologous Bone Marrow Transplantat
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To our colleagues, Drs. R. Lee Clar
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via ABMT Autologous Bone Marrow Tra
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X ABMT Pharmacological Manipulation
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XII ABMT C. INTERNATIONAL RANDOMIZE
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xiu ABMT Session IV - Breast Cancer
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xui ABMT Panel Discussion: Session
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xuiii ABMT Effect of Interleukin 2
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Acknowledgments The publication of
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AML in First Remission 5 performed
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AML in First Remission 7 than 50% o
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10 BAVC + ABMT in Patients With AML
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BAVC + ABMT in Patients With AML in
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14 BAVC + ABMTin Patients With AML
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16 Purged ABMT in CR of Acute Leuke
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24 First-Remission Autograft forAML
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Transplantation in CRI AML 33 DISCU
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Page 70 and 71: 46 ABMTin CRI RESULTS The AML inves
Page 73 and 74: Leukemia: First Remission K A. Dick
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Magnetic Separation of Marrow Cells
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*r r- r» u. >>• O S ^ CO ai a> C
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Magnetic Separation of Marrow Cells
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4-Hydroperoxycyclophosphamide and V
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Chemopurging 145 incubation, the ce
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Chemopurging 147 To date, four pati
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Chemopurging 149 4-HC + VCR IC75 AM
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Decontaminating Bone Marrow With Me
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Merocyanine 540 Marrow Decontaminat
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Merocyanine 540 Marrow Decontaminat
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CALLA-Negative Clonogenic Cultures
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CALLA-Negatiœ Clonogenic BCell ALL
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CALLA-Negative Clonogenic BCell ALL
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164 Acetaldophosphamide Ex Vivo Che
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766 Acetaldophosphamide Ex Vivo Che
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168 Acetaldophosphamide Ex Viuo Che
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Detecting Residual Disease in Bone
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178 Pharmacological Manipulation an
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ID. Chronic Myelogenous Leukemia
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190 CML Chronic Phase Autografting
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196 CML Blast Crisis Autografting e
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Autologous Transplantation of Phila
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Autografting in Chronic Granulocyti
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Autografting in Chronic Granulocyti
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206 Panel Discussion: Session ID DR
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Natural History of Relapsed Hodgkin
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ABMT in Hodgkin's Disease 211 50%.
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ABMTin Hodgkin, 's Disease 213 (62%
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ABMT in Hodgkin's Disease 215 LLLLL
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Updated Results of CBV and Autologo
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CBV and ABMT in Hodgkin's Disease 2
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CBV and ABMT in Hodgkin 's Disease
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224 Chemotherapy and ABMT in Hodgki
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226 Chemotherapy and ABMTin Hodgkin
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232 ABMT for Advanced Hodgkin's Dis
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234 ABMTfor Advanced Hodgkin's Dise
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Hodgkin's Disease J. O. Armitage an
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Panel Discussion: Session IIA 239 D
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IIB. Non-Hodgkin's Lymphoma
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244 Salvage Chemotherapy for Lympho
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246 Salvage Chemotherapy for Lympho
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ABMT in Burkitt's Lymphoma 251 Tabl
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ABMT in Burkitt's Lymphoma 253 medi
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ABMT in Burkitt's Lymphoma 255 Heal
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ABMT in Burkitt's Lymphoma 257 •
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ABMT in Burkitt's Lymphoma 259 init
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ABMT in Burkitt's Lymphoma 261 11.
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264 Myeloma Biology and Therapy hig
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266 Myeloma Biology and Therapy mon
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265 Myeloma Biology and Therapy 5.
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270 BMT in Relapsed Diffuse Large C
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276 Transplantation for Malignant L
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Optimum Timing of Autologous Bone M
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ABMT Timing in Lymphoma 281 PATIENT
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3 o + + + + o LO T— T— LO co Tf
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ABMT Timing in Lymphoma 285 RESULTS
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co co I I I I I I I I I I 2 2 2 CD
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ABMT Timing in Lymphoma 289 Median
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ABMT Timing in Lymphoma 291 in a mi
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ABMT Timing in Lymphoma 293 Develop
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ABMT Timing in Lymphoma 295 53. Sto
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298 Treatment Strategies for NHL PA
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300 Treatment Strategies for NHL 10
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302 Treatment Strategies for NHL 2)
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304 Treatment Strategies for NHL al
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306 Treatment Strategies for NHL 31
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308 Panel Discussion: Session IIB m
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IIC. International Randomized Study
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314 Proposed International Adult Ly
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International Randomized Trial in N
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International NHL Trial 337 dispari
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International NHL Trial 339 cannot
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International NHL Trial 341 ORGANIZ
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Lymphoma T. Philip and G. Spitzer,
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IID. Purging and Detection
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348 Chemoimmunoseparation of T Lymp
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350 Chemoimmunoseparation of T Lymp
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352 Burkitt's Lymphoma Purging Assa
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354 Burkitts Lymphoma Purging Assay
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356 Burkitt's Lymphoma Purging Assa
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358 Burkitts Lymphoma Purging Assay
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360 Purging Methods in Burkitt's Ly
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366 Leukemia Cell Sensitivity to Im
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368 Leukemia Cell Sensitivity to Im
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370 Leukemia Cell Sensitiuity to Im
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372 Panel Discussion: Session IID D
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ABMTfor Neuroblastoma 377 sedimenta
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ABMT for Neuroblastoma 379 EX VIVO
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ABMTfor Neuroblastoma 381 PATIENTS
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Repeated High-Dose Chemotherapy Fol
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ABMT in Metastatic Neuroblastoma 38
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ABMT in Metastatic neuroblastoma 39
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394 Clnpurged ABMTfor Neuroblastoma
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396 Unpurged ABMTfor Neuroblastoma
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398 Unpurged ABMTfor Neuroblastoma
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ENSG 1—Randomized Study of High-D
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High-Dose Melphalan in Neuroblastom
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High-Dose Melphalan in Neuroblastom
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408 ABMTin 65 Patients With Neurobl
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410 ABMT in 65 Patients With. Neuro
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416 ABMTin 65 Patients With neurobl
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A Single Institution's Experience o
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ABMT in Neuroblastoma 421 procedure
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ABMT in Neuroblastoma 423 therapies
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426 Purged Marrow Engraftment in Ne
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Digital Image Analysis System for D
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Digital Image Analysis System 435 d
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Digital Image Analysis System 437 c
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Digital Image Analysis System 439 C
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Digital Image Analysis System 441 1
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444 Immune-magnetic Purging ofBurki
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450 Panel Discussion: Session III W
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452 Panel Discussion: Session III e
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High-Dose Chemotherapy Intensificat
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High-Dose Chemotherapy and ABMT in
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466 Treatment Strategies in Breast
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10 CO 0) I- m c o a. a. 3 W ? o k_
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476 Phase I and II Studies of Alkyl
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482 High-Dose Therapy and ABMT in B
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484 High-Dose Therapy and ABMT in B
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486 Immunodetection of Breast Carci
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ABMTfor Breast Cancer 491 only adju
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ABMT for Breast Cancer 493 Table 3.
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ABMTfor Breast Cancer 495 4. Eder J
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498 Occult Breast Cancer Cells in M
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504 Panel Discussion: Session IV DR
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506 Panel Discussion: Session IV a
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Detection of Bone Marrow Metastases
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Tumor Cell Detection 511 Two separa
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Tumor Cell Detection 513 immunofluo
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516 Etoposide and Cisplatin for Lun
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Lung Cancer G. Spitzer and H. Lazar
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Panel Discussion: Session V 525 com
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Panel Discussion: Session V 527 col
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Treatment of Advanced Melanoma With
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ABMT in Melanoma 533 Table 1. Three
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ABMT in Melanoma 535 mg/m 2 ). The
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Melanoma/ Sarcoma/ Carcinoma R. Ben
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Panel Discussion: Session VI 539 re
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VII. Brain Cancer
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544 Carmustine and ABMT for Maligna
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546 Carmustine and ABMTfor Malignan
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Pilot Study of High-Dose Carmustine
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High-Dose Carmustine and Transplant
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High-Dose Chemotherapy With Autolog
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High-Dose Therapy of CNS Gliomas Ta
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High-Dose Therapy of CHS Gliomas 56
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High-Dose Therapy of CHS Gliomas 56
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566 Panel Discussion: Session VII A
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VIII. New Regimens
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572 Clinical Intensification Regime
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574 Clinical Intensification Regime
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Clinical Intensification Regimens f
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Clinical Intensification Regimens f
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High-Dose Busulfan and Cyclophospha
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Busulfan + Cyclophosphamide in Chil
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The Intensive Use of Carmustine Wit
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Intensive Use ofCarmustine 591 6. P
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594 BEAM: Cytoreductive Regimen for
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596 BEAM: Cytoreductiue Regimen for
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602 Total Body Irradiation, Cytarab
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604 Total Body Irradiation, Cytarab
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606 Panel Discussion: Session VIII
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Herpesvirus Infections After Autolo
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Herpesvirus Infections 611 Table 2.
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Herpesvirus Infections 613 contrast
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616 Peripheral Stem Cell Transplant
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CO ^ CO COi-t'ycOi-T-CO O E « to T
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fc CD rr ^ O < c E + o — ce S O O
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o E ra o CD .Q Û ra co CL o E o 15
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634 Toxic Deaths in ABMT PATIENTS A
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636 Toxic Deaths in ABMT Table 2. D
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638 Toxic Deaths in ABMT defined an
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640 Infectious Complications ofABMT
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Infectious Complications of Autolog
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Infections in ABMT 649 Table 1. ABM
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Infections in ABMT 651 herpes simpl
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Newer Antibiotic Regimens in Cancer
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Antibiotics in Cancer Patients 655
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Antibiotics in Cancer Patients 657
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660 Amphotericin B for Neutropenic
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662 Amphotericin B for Neutropenie
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664 Amphotericin B for Neutropenie
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666 IVIg in ABMT in autologous tran
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668 IVlg in ABMT 25. Neiman PE, Ree
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670 Natural Killer Cells and Transp
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672 Natural Killer Cells and Transp
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Autologous Transplantation of Circu
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678 Transplantation of Circulating
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Restoration of Hematopoietic Functi
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Peripheral Stem Cell Transplants 68
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Peripheral Stem Cell Transplants 68
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688 Peripheral Blood Stem Cell Tran
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694 Bronchoscopy in Marrow Transpla
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696 Bronchoscopy in Marrow Transpla
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698 T Lymphocyte CFU After ABMT cer
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700 T Lymphocyte CFCI After ABMT RE
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702 T Lymphocyte CFU After ABMT CMV
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Supportive Therapy H. Vriesendorp a
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X. Molecular Biology
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770 Human ADA in Monkeys years in a
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7/2 Human ADA in Monkeys supernatan
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714 Human ADA in Monkeys Number of
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776 Human ADA in Monkeys primate ma
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718 Electric Field-Mediated DMA Tra
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720 Electric Field-Mediated DNA Tra
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Aberrant Gene Expression in Acute M
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+ z + + + les •ras a z E i ü (0
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Aberrant Gene Expression in AML 727
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Aberrant Gene Expression in AML 729
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732 Clonal Detection of Remission p
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734 Clonal Detection of Remission K
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736 Clonal Detection of Remission 3
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Summary D. W. van Bekkum Attempts t
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Summary 741 T cell-depleted bone ma
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Summary 743 hybridization technique
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Summary 745 GENETIC THERAPY The las
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748 Concluding Remarks time of the
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750 Contributors and Participants F
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754 Contributors and Participants P
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756 Contributors and Participants A
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758 Contributors and Participants P
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762 Contributors and Participants H
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764 Contributors and Participants A
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766 Contributors and Participants G
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770 Contributors and Participants S
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772 Contributors and Participants C
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776 Contributors and Participants D
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