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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 Different Therapy Protocols for High Risk and Standard Risk ALL in Childhood F. Zintl, W. Plenert, andJ. Hermann Children with aeute lymphoeytie leukemia ean be apparently eured today. The subclassification of ALL in ehildhood as "high risk" and "standard risk" ALL by means of a determination of immunologie and clinical parameters is of inereasing importanee. This classification could become the basis for a risk-oriented individual therapy. We present here the eurrent results attained in the treatment of ehildhood ALL by our Pediatrie Hematology and Oneology working group involving 13 treatment centers of the German Demoeratie Republie. A. Patients and Methods I. StudylV From January 1976 to December 1977 111 previously untreated patients were entered in this study. The outline of therapy is shown in Fig. 1. There were two different treatment groups based upon the presence or absence of high risk factors at the time of diagnosis. The criteria for high risk factors were defined as: 1. Leukocyte count above 20,000 cells/mm3, 2. Age under 2 years and over 10 years, 3. Mediastinal mass, 4. Generalized enlargement of lymph nodes or enlargement of one or more lymph nodes by 3 cm or more, 5. Tumor of other organs, 6. Enlargement of liver or spleen by 5 cm or more, and 7. CNS leukemia at diagnosis. In the presence of one or more high risk criteria the patients received a consolidation therapy with Ara-C and L-asparaginase. Of the 111 patients 67 were classified as high risk and 44 as standard risk patients. As CNS prevention therapy - regardless of their prognostic factors - all children received combined intrathecal injections of methotrexate and prednisolone during induction therapy, early in remission, and periodically throughout the continuation treatment. In addition, 41 patients received preventive cranial irradiation (2400 rad telecobalt) and 68 received intrathecal application of macrocolloidal radiogold (198 Au, 2,5 mCi) (Metz et al. 1977). 11. Study V and LSA 2 L 2 Protocol As of January 1978 treatment was given by two other protocols: study V (Fig. 2) for standard risk patients and LSA2~ protocol for high risk patients (Fig. 3). This latter group also included children with non-Hodgkin lymphomas who had 25 % or more tumor cells in the bone marrow. In this study high risk criteria differed from the previous study and was limited to: 1. Leukocyte counts 50,000 per cu mm and more, 2. Mediastinal mass, 3. T -ALL (blast cells form spontaneous rosettes with sheep erythrocytes and/or give a positive re action with antithymocyte serum), 4. Positive acid phosphatase reaction of the blast cells, and 5. CNS leukemia at diagnosis. IH. Statistical Analysis The results of each of the three studies were analysed as of 31 December 1979 and the statistical analysis was performed according to the life table method of Cutler and Ederer (1958). B. ResuIts I. StudylV Table 1 depicts the clinical course of the 111 patients entered on study IV. As shown in Fig. 4, no statistieal differenee eould be deteeted in 115
Consoll- Irra .tlon t) .tlon Induction Puls 'HAu i. th or Irradation I MTX '2 mglm 2 + PrH. 12 mglm 2 ~ ~~ •• ~ . Puls I ~ ... .. .: ~ DHR25mg/m2ASP1OOfXJUlm2 ... ::... ! ! ! ! IIII! ! ~~ VCR 1,smglm 2 ARA-C 3OOmglm 2 NTX 20mglm 2 lW"k p. o. Cl.. ... • • • • Y??? ? • LI..LLLLL.LLI ~ • WM$4I r;:":":'r."~-----' C:>·:>····::] DXM Imglm2p.o. I-NP25mgIm2DXM I-NP 50mglm2Id.p.o. DXH [ 1 1 1 1 1 .1 1 1 I I 1 I Days 0 1 27 35 13 11 97 lOS 119 733 "1 767 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 I W .. ks 7 2 3 " 5 I 1 e 9 70 11 72 13 " 75 16 71 78 79 20 27 22 23 ') Consolidation only (or high risk pati.nts Fig. 1. Outline of therapy for study IV (1976-77) the outcome of standard and high risk patients entered on study IV. At 3 years the cumulative complete remission rate was 0.56 + 0.1lfor the standard risk group and 0.44+0.07 for the high risk group. Thirty nine patients are still receiving chemotherapy and in 15 treatment has recently been stopped (median time off therapy was 3 months). 11. Study V and LSA 2 L 2 Protocol New treatment programs were introduced in 1978 with the objective of improving these results. The LSA 2 L 2 protocol developed by Wollner et al. (1976) for patients with non Hodgkin lymphoma was used for a newly defined group of high risk patients as described R.m. Induction Irradat/on I Puls L....J Puls I I • •••• • MTX 72mglrn2+Pr~. 72mglm 2 ;. th. DHR 25mglm 2 L-ASP 10000 Ulm 2 T T T T I I I I T 1 1 1 97 1 70S I 119 733 Days 0 1 27 35 11 1 I 1 1 I I I i i i I WHlrs I 2 3 " 5 I 1 I 9 10 " 12 13 '" 15 " 11 11 19 20 Fig. 2. Outline of therapy for study V (1978-79) 116
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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
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Acknowledgement We should like to t
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Wilsede, June 21 1978 Memorial Trib
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limiting benign lymphoproliferative
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this most unlikely, however (for re
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longer subject to the same control
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Bregula U, Wiener F, Harris H (1971
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fresh lymph node biopsies from ten
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Fig. 3. Binucleate mitosis in an ob
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y Fig. 4. Schematic diagram of post
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than that among patients with Stage
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Tests of binding affinity, agglutin
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N Engl J Med 297: 963-968 - Green I
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Clinical Aspects
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"ring chromosome". "Mar" is marker,
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191 chromosomally abnormal patients
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tumors of both African and non-Afri
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Haematology and Blood Transfusion V
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Retrospective group 26/93 evolved l
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Treatment
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advantage in terms of duration of f
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leukaemia. An analysis of 168 patie
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11. Treatment Program Chemotherapy
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efractory congestive heart failure
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period (Sequence II) was gene rally
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children with a multiple drug proto
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DAYS 1 5 10 15 20 25 30 35 , I I I
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Biologically Drug Outcome fit" sens
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may counterbalance the potential be
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Ht (0--0) 50 40 30 20 10 0 Platelet
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10 7 ,-----------------------------
Page 77 and 78: 11. Haematological and Biochemical
Page 79 and 80: 0\ 0\ INTERFERON ... 10 3 rl E "'
Page 81 and 82: Haematology and Blood Transfusion V
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
Page 117 and 118: e: o e: 1. 0 ,.--...-- 1'"'\ ......
Page 119 and 120: In conclusion, we can state that th
Page 121 and 122: Haematology and Blood Transfnsion V
Page 123 and 124: INDUCTION VCR + PRED + ASNASE (wk 3
Page 125 and 126: SCHED.INT 1 MTX • ! Adria MTX •
Page 127: ~ looh---------ooooc>----o---c>----
Page 131 and 132: Highrisk Standard risk Table 1. Cli
Page 133 and 134: Cumulo/ive comp/el9 remission 1.0 .
Page 135 and 136: 10° 8 = 6 ö 4 Non T Cell .~ :ö
Page 139 and 140: % SURVIVAL 100 ~ ~II 0 80 60 40 - -
Page 141 and 142: a) Percentage of donor cell mitoses
Page 143 and 144: Table 5. Results of bone marrow tra
Page 145 and 146: ...... w N Table 7. Clinical result
Page 147 and 148: agent had to be added and that in t
Page 151 and 152: C. Chronic Myelogenous Leukemia The
Page 153 and 154: Patients with a suitable donor rece
Page 155 and 156: No. Recurrent Leukaemia Other death
Page 157 and 158: followed by dialysis against isoton
Page 161 and 162: HS, HL- Heme >_ 40 0 HS I ;:. =====
Page 165 and 166: knowing at present. These genes may
Page 167 and 168: esistance to antifolates. In Vitro
Page 169 and 170: a DNA probe specific for the gene t
Page 171 and 172: translocation between chromosomes 9
Page 173 and 174: Table 1. Subdivision of 1827 Myelo-
Page 175 and 176: NORMAL CELL ®
Page 177 and 178: 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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Haematology and Blood Transfnsion V
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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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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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Haematology and Blood Transfnsion V
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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
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the same animal were examined (e.g.
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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
Page 463 and 464:
Osteopetrosis and osteosarcomas occ
Page 465 and 466:
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
Page 475 and 476:
- Shoemaker C, Goff S, Gilboa E, Pa
Page 477 and 478:
indieate a shifting of target eell
Page 479 and 480:
Table 2. Expression of Jl and Sourc
Page 481 and 482:
Page 483 and 484:
~ i ,..1---------,,':::::::::::::::
Page 485 and 486:
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
Page 519 and 520:
Table 3. Lack of detectable related
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J. HTLV Was Present in the Primary
Page 523 and 524:
specific signals into nonspecific s
Page 525 and 526:
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:
Page 531 and 532:
SSV TrS-gp labeled effectively with
Page 533 and 534:
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60 HFF/SSV cDNA CELL RNAs: 0 HF/SSV
Page 537 and 538:
Antisera a Table 1. Immunofluoresce
Page 539 and 540:
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
Page 547 and 548:
c. Results The fractionated whole-b
Page 549 and 550:
induced antibodies as well as exper
Page 551 and 552:
- Fig. la-f. Retravirus particles p
Page 553 and 554:
eplication of infecting murine leuk
Page 555 and 556:
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immunodeficiency, multic10nal lymph
Page 559 and 560:
Bovine leukemia --, proteins of 499
Page 561 and 562:
Human T- cell - -, characterization
Page 563 and 564:
RNA -, of tumor virus 439 Rous sarc
Page 565 and 566:
Haematology andBlood Transfusion Su
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