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Rational Approaches to the Treatment of Leukemia * H. D. Preisler Haematology and Blood Transfusion Vol. 26 <strong>Modern</strong> Trends in Human Leukemia IV Edited by Neth, Gallo, Graf, Mannweiler, Winkler © Springer-Verlag Berlin Heidelberg 1981 A. Introduction Advances in the treatment of acute myelocytic leukemia (AML) have largely resulted from empirical drug trials in man. Such trials have led to the recognition of drug combinations which pro du ce remissions in more than onehalf of the patients who are under 70 years of age (Yates et al. 1973; Preisler et al. 1977; Rees et al. 1977; Jacquillat et al. 1976). While intensive remission induction therapy will produ ce complete hematologic remissions in as many as 75 % of the patients, large numbers of leukemic cells must persist in the patients who enter remission, since the disease recurs in the majority of patients less than 1 1 /2 years after remission is induced. The selection of a treatment regimen on the basis of the regimen having produced a high remission rate in a majority of patients (75 %, for example) also mandates that this particular regimen is not appropriate for the patients who do not enter remission (25 %-45 % ofpatients). Clearly, for this group of individuals the use of a different treatment regimen would have been preferable. In the Department of Medical Oncology at Roswellj Park Memorial Institute we have been approaching these problems on a twotrack basis. On the one hand we have continued to treat patients empirically using our clinical observations to dictate our therapeutic approach. To this end 3 years ago we initiated a treatment program designed to deliver intensive chemotherapy to patients already in remission to reduce and perhaps ablate the * This study was supported by U.S.P.H.S. Grants CA-5834, CA-24162 and ACS Grant CH-168 leukemic cells remaining in patients who entered complete remission (Preisler et al. 1980, to be published a). At the same time we began to study the factors which determined response to therapy, so that we would be able to determine in advance the appropriate chemotherapeutic regimen for individual patients (Rusturn and Preisler 1979a; Preisler, to be published; Preisler et al. 1979b). This paper represents a progress report on our studies. B. Empirical Clinical Studies The therapeutic regimen (P970701) illustrated in Fig. la has been used to treat all patients of less than 70 years of age with AML since June 1977 (Preisler et al., to be published a). The regimen illustrated in Fig. 1b (P950501) was used to treat patients between 1975 and 1977 (Preisler et al. 1979b). Table 1 compares the remission induction efficacy of the two regimens. Given the number of patients studied, there is no significant difference in the overall induction efficacy of the two regimens. Figure 2 compares the duration of remission for three groups of patients: those treated with P950501, those treated with P970701, and a subgroup of patients induced into remission on P970701 but who did not receive the consolidation or maintenance portions of P970701 because their private physicians feIt that intensive postremission therapy was not indicated. Comparison of the life table plots for remission duration of the three groups of patients demonstrates a highly statistically significant (P
DAYS 1 5 10 15 20 25 30 35 , I I I , I I I I I I I I , I I I I I I I I I I' I I I I , I I I I ! INDUCTION 000 *11 I1I1 I I l\f * CONSOLIDATION -l-~ 1:. ...... '00 1 I -t-l-t 'I I I I I , , "or * GEBe ·H-!t E!wlE~wl7 - - - - I I 1 .4- ':2 ." ia" - - - - - -- - - .1 :oI1 .... _ ..... MAINTENANCE @ t·"""""·"··"" ...•..."""...·,,,,·,,, •••••••••• WEEKS 1 e 5 10 a + + ~ D Prednisene 150mg/m 2 PO + VCR 2 mg/m 2 IV -V Adri.mycin 30ma/m 2 IV I-+-+-t Ar.-C 100mg/.rr{ IV . lo6&'0o;I Ar s-C 100 mg:tm SQ b,d o Daunorllbicin 45mg~/d CptS.>60yrs .. 30mg/m >,d ... Bone Marrow ES Cylexan 500mQlm 2 IV • MeGAG 300m~2 IM 2 ".tllIlII ..... 6-Thioguanine 100 mlJlm PO @ Immunization RDllSSION III)UCl'ION ®( WEEKS MEt m ITIIII]] AAA t AAA t ~ ~ ME. amm DOD rnnm DDD WEEKS I I 4 fffiB @ t @ Q!!J illIß] ARA-Co- I.nfusion 7 m REKI.;SION CONSOLlDATION mm AM - Adriamycin J days mm ARA-C x 10 doses - S daya ®
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Haematology and Blood Transfusion 2
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Dr. Rolf Neth, Universitäts-Kinder
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Participants of the Meeting Aaronso
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Kurth, R, Friedrich-Miescher-Labora
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Wilsede Scholarship Holders (Grante
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Preface Gut ist eine Lehrart, wo ma
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Personal and scientific discussion
Page 15 and 16: Acknowledgement We should like to t
Page 17 and 18: Wilsede, June 21 1978 Memorial Trib
Page 19 and 20: limiting benign lymphoproliferative
Page 21 and 22: this most unlikely, however (for re
Page 23 and 24: longer subject to the same control
Page 25 and 26: Bregula U, Wiener F, Harris H (1971
Page 27 and 28: fresh lymph node biopsies from ten
Page 29 and 30: Fig. 3. Binucleate mitosis in an ob
Page 31 and 32: y Fig. 4. Schematic diagram of post
Page 33 and 34: than that among patients with Stage
Page 35 and 36: Tests of binding affinity, agglutin
Page 37 and 38: N Engl J Med 297: 963-968 - Green I
Page 39 and 40: Clinical Aspects
Page 41 and 42: "ring chromosome". "Mar" is marker,
Page 43 and 44: 191 chromosomally abnormal patients
Page 45 and 46: tumors of both African and non-Afri
Page 47 and 48: Haematology and Blood Transfusion V
Page 49 and 50: Retrospective group 26/93 evolved l
Page 53 and 54: Treatment
Page 55 and 56: advantage in terms of duration of f
Page 57 and 58: leukaemia. An analysis of 168 patie
Page 59 and 60: 11. Treatment Program Chemotherapy
Page 61 and 62: efractory congestive heart failure
Page 63 and 64: period (Sequence II) was gene rally
Page 65: children with a multiple drug proto
Page 69 and 70: Biologically Drug Outcome fit" sens
Page 71 and 72: may counterbalance the potential be
Page 73 and 74: Ht (0--0) 50 40 30 20 10 0 Platelet
Page 75 and 76: 10 7 ,-----------------------------
Page 77 and 78: 11. Haematological and Biochemical
Page 79 and 80: 0\ 0\ INTERFERON ... 10 3 rl E "'
Page 83 and 84: ("pre-B" phenotype) has been descri
Page 85 and 86: human bone marrow cells exhibit the
Page 87 and 88: 10 9.,0 MBKCC .. .,4 B prot:oool 1'
Page 89 and 90: demann W, Büehner T, Arlin Z, Gee
Page 91 and 92: -...l 00 a-tLDRENS CAt«:ER S TU>Y
Page 93 and 94: prognostic characteristics under in
Page 95 and 96: significantly higher in HR} (14.5%,
Page 97 and 98: normal or elevated immunoglobulin l
Page 99 and 100: References Andreeff M, Darzynkiewic
Page 101 and 102: R GROUP 1 ( 1970 - 1971 ) 17 PTS. R
Page 103 and 104: Table 3. Influence of initial featu
Page 105 and 106: LIJ (f) a.. < -1 LIJ Q: u. 0 >- I-
Page 109 and 110: me nt indicated that additional the
Page 111 and 112: 42:2123-2134 - Chessells JM, Cornbl
Page 113 and 114: Baum et al. 1979). This study was b
Page 115 and 116: 1. 0 '--'1--" 0.9 e: o .- VI VI E C
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e: o e: 1. 0 ,.--...-- 1'"'\ ......
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In conclusion, we can state that th
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Haematology and Blood Transfnsion V
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INDUCTION VCR + PRED + ASNASE (wk 3
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SCHED.INT 1 MTX • ! Adria MTX •
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~ looh---------ooooc>----o---c>----
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Consoll- Irra .tlon t) .tlon Indu
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Highrisk Standard risk Table 1. Cli
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Cumulo/ive comp/el9 remission 1.0 .
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10° 8 = 6 ö 4 Non T Cell .~ :ö
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Haematology and Blood Transfusion V
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% SURVIVAL 100 ~ ~II 0 80 60 40 - -
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a) Percentage of donor cell mitoses
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Table 5. Results of bone marrow tra
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...... w N Table 7. Clinical result
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agent had to be added and that in t
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C. Chronic Myelogenous Leukemia The
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Patients with a suitable donor rece
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No. Recurrent Leukaemia Other death
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followed by dialysis against isoton
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HS, HL- Heme >_ 40 0 HS I ;:. =====
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knowing at present. These genes may
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esistance to antifolates. In Vitro
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a DNA probe specific for the gene t
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translocation between chromosomes 9
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Table 1. Subdivision of 1827 Myelo-
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NORMAL CELL ®
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some change of the primary type, in
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F. Transformation of Mouse Bone Mar
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were carried out with 3H-MTX in the
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the lysozyme cDNA prepared from ovi
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et al. 1976). The BJAB cellline in
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dalton bands corresponding to light
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1979). The EBV-carrying cell lines
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producer lines (DAUDI and P3HR-1),
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G, Giovanella B, Westman A, Stehlin
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Dc;bt CT + i J.I9 Raji; 1. i .. 100
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c. Discussion During infectious mon
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C. Nonepisomal Viral DNA We have us
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A 260 3.0 A B 1670 70 N2 2.0 c: E .
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vivo. Nature 260:302-306 - Kirk JTO
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Fig. 1. a Polyacrylamide gelelectro
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1979). The lymphocyte subpopulation
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lysin 0 antigens are found, and mix
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Pope JH (1978) Long-term T cell-med
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Charaeteristie Morphologie maturati
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after TPA-induction (Table 3). The
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PA (1978) Reactivity of a rabbit an
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Blood Monocyte. B lood Monocytes 1-
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and nonhistone proteins can serve a
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The findings of the evaluation of s
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Fig. 3. Tumor grawth of L 428 cells
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Cell biological and Immunological A
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consideration. Sanel (1973) obtaine
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endotoxin serum, were used. A parti
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monocytic leukemia cell line in cul
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B. Isolation, Characterization and
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don al hemopathies generally displa
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nitors. Blood Cells 6:595-607 - Min
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\I) ....I ....I IU Jl 200 r 100 90
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their haemopoietic cells' ability t
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normal normal ALL ALL ALL persons p
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64.5 { V)
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References Biermann E, Neth R, Gros
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ehambers, the growth pattern observ
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References Anderssen LC, 10kinen M,
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REH CELL UNE TO CALLb~Ö ~q~ V.M. c
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the macrophage series in which the
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Table 1. Production of factor depen
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Table 1. Characteristics of the adh
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Fig. 3. A human marrow culture at 6
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300 250 • HYPERPROLIFERATIVE PATT
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Fig. 9. Nonadherent population from
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The cobblestone areas were often no
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L (1976) Induction of colony format
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B. Materials and Methods J. Tissue
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Fig. 2. Ultrastructural appearance
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Page 307 and 308:
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Table 1. Monoclonal antibody reacti
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al. 1979; Janossy et al. 1979) is e
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to which this is an exact replica o
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inger JL (1976) Distribution of la-
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I region antigens were found to be
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have been reported to be present on
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V. FunctionalAssays Assays for PHA
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Functional studies of UCHT1 separat
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40 ,...... (5 L.. C o u 30 .9 ~ .~
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with immunohistochemieal methods (L
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can be dissected by cloning. Utiliz
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Table 1. Origin and marker profile
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complete identity of gp 100 from no
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Table 1. Reaction of single anti se
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media. Following 24-h incubation, c
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nonleukemic eells (Greaves 1979). L
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Fig. 2. Cytocentrifuged smears of b
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Modification of amino-groups of hum
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disturb this balance in the directi
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The majority of human blood lymphoc
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of the EBV infected B cells. Howeve
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and immunoglobulins. J Immunol 120:
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" K 10 • j ~ ALL RNlL AL wtfh les
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tion akuter Leukämiezellen in "spo
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D. Results and Discussion J. Acute
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selectively responsive to different
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l1J ~ 100 ~ Q. ::) l1J Z 0 ~ z >- .
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Table 2. Growth inhibition of S49 e
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Reverse Infectious ASC/2X1Q6 transc
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munized animals to 1316 tumor cells
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Fig. 3. Expression of retroviral gp
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pg70. J Exp Med 143: 151-166 - McGr
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Table 1. Expression of tumor antige
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Virological and Molecularbiological
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Table 1. Oncogenic properties of re
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also Fig. 1). It followed that the
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whether this sequence is related to
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zed in infected cells argue that th
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a specific viral transforming prote
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detect viral RNA as the only charac
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Eisen H (1980) Myeloproliferate vir
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p,60- -34K - 1 2 3 4 Fig. 1. In vit
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.. p - • a'T ... I .t'l Fig. 4. D
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Fig. 2. Photomicrographs of NY68 in
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DEAE (o(lJmn 'liI GI -2 2 o e s 1
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vity was deterrnined. For endogenou
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pr 180 - - - P 12/15 - A B c D E F
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85,- 66- -27 - -66 40- 27- -1'9 19-
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= 0.5 o E Q. o ILI 0.4 (J) « ILI .
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Table 1. Oncogenic potential of avi
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100 III GI c: o "8 80 > w
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Expt. No. Infecting virus Proportio
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Haematology and Blood 'fransfusion
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sequences, provided its gag portion
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77:3009-3013 - Hu SSF, Moscoviei C,
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RI 2.2 md and Hind III 2.6 md leuke
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RELATIONSHIP OF ENDOGENOUS AND EXOG
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E ........ E Cl. U E :::l .... Q) (
Page 447 and 448:
References Astrin S (1978) Endogeno
Page 449 and 450:
the same animal were examined (e.g.
Page 451 and 452:
I) 'IQ a \0 - CL -- Fig. 2. Restrie
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~ ..................... ~ Cell 3' 5
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a :Sa,C! + . ~ 111 i' ( " '~ .J. b
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Table 1 Sampie Tissue TS fragment"
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a b Sac I / rep ._-_.-_ K J nl rep
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Haematology and Blood 'fiansfusion
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Osteopetrosis and osteosarcomas occ
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Lymphoma cellline Table 1. T and B
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Table 2. In vivo growth and oneogen
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Page 471 and 472:
Table 1. Transforming aetivity of c
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Table 3. Transformation aetivity of
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- Shoemaker C, Goff S, Gilboa E, Pa
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indieate a shifting of target eell
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Table 2. Expression of Jl and Sourc
Page 481 and 482:
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~ i ,..1---------,,':::::::::::::::
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fragment of pBR322 DNA, a 3.0-kbp S
Page 487 and 488:
Mak TW (1979) Proc Natl Acad Sci US
Page 489 and 490:
Table 1. Transformation of 3T3 cell
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inserts in the genome of rapidly tr
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pulations, it seemed likely that th
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contains antigens which react with
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le of reacting in sensitive radioim
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gic approach. In: Hiatt HH, Watson
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12 Eco R [ Fig. 1. Hybridization pa
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10 - '1~ )( -~ S:! E A U I o 1 2
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Haematology and Blood 'fransfusion
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cultures. These cells did not conta
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indication of malignant T-cells in
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Fig. 3. Thin-section electron micro
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Table 3. Lack of detectable related
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J. HTLV Was Present in the Primary
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specific signals into nonspecific s
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Table 2. Distribution of HTLV-relat
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u 10 ~ 20 ~ :c 30 a 40 o Fig. 1. Ki
Page 529 and 530:
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SSV TrS-gp labeled effectively with
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60 HFF/SSV cDNA CELL RNAs: 0 HF/SSV
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Antisera a Table 1. Immunofluoresce
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Haematology and Blood 'ftansfusion
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y competition RIA yielded virtually
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SiS'V' gp70: ANTIGEN, ANTI BODY, IM
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type-C virus p30 antigen in cells f
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c. Results The fractionated whole-b
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induced antibodies as well as exper
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- Fig. la-f. Retravirus particles p
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eplication of infecting murine leuk
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immunodeficiency, multic10nal lymph
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Bovine leukemia --, proteins of 499
Page 561 and 562:
Human T- cell - -, characterization
Page 563 and 564:
RNA -, of tumor virus 439 Rous sarc
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Haematology andBlood Transfusion Su
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