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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 T -Cell Acute Lymphoblastic Leukemia in Children S. E. Sallan Newer chemotherapeutic and support programs have resulted in survival of approximately 40%-50% of children with acute lymphoblastic leukemia ( ALL) (Sallan et al. 1980; George et al. 1979; Haghbin 1977). It is likely that children who fail conventional therapy programs represent sub sets of patients whose disease is biologically distinct, and, as such, require different therapeutic strategies. Approximately 15%-20% of children with ALL have lymphoblasts with surface receptors for sheep erythrocytes or T -cell antigens. In a treatment program at our institution patients with T-cell disease had a median disease-free survivalof 12 months compared to 47 months for those with non-T-cell disease (P=0.0004) (Fig. 1) (Sallan et al. 1980). The majority of relapses in the T -cell population occurred at extramedullary sites, whereas nearly all of the non-T -cell patients relapsed in the bone marrow. When it became apparent that patients with T-cell disease enjoyed a less than 20% disease-free survival, a new treatment strategy was designed. A. Tbe Rationale for T -cell ALL Tberapy The treatment program reported herein entails three major differences from conventional ALL regimens: (1) the inclusion of chemotherapeutic agents that are more selective for T -cells; (2) special attention to extramedullary sites; and (3) thymectomy. Frei and his co-workers (1974) have demonstra ted that the most commonly used antileukemic agents, methotrexate and 6-mercaptopurine, are less cytotoxic in experimental murine T -cellieukemias, such as AKR leukemia, than are drugs such as cyclophosphamide and cytosine arabinoside (Ara-C). Extrapolations from these experimental systems suggested that the treatment of human T -cellieukemia might be facilitated by the incorporation of drugs active in the AKR system. Therefore, we chose to treat with cyclophosphamide, Ara-C, and adriamycin as weIl as vincristine and prednisone (see schema, Fig. 2). Because the majority of relapses in patients with T -cell ALL occurred in extramedullary sites (Sallan 1980), our T -cell ALL treatment program attempted to intensify therapy to the testes and central nervous system (CNS). Other investigators have demonstrated that prophylactic testicular irradiation can prevent the occurrence of testicular relapse (Nesbit et al. 1980). Thus, we irradiate both testes of all male T -cell ALL patients to 2400 rad. Although cranial irradiation and intrathecal methotrexate provide relatively good CNS "prophylaxis" (Green et al. 1980), at our institution the majority of failures of this mode of therapy have been T -cell patients. To strengthen CNS therapy we added intermittent high-dose, systemic Ara-C given in a 120 h continuous infusions. Pharmacokinetic studies of continuous infusion of Ara-C suggest that cytotoxic levels of drug can be attained in the cerebrospinal fluid shortly after the institution of the infusion and remain at therapeutic doses throughout the duration of the infusion (Weinstein et al. 1978). The rationale for thymectomy is based primarily on experimental evidence from AKR systems. It has been shown that the addition of thymectomy to cytotoxic therapy with cyclophosphamide prolonged survival in AKR mice when compared to treatment with cyclophosphamide alone (Athanasiou et al. 1978). In addition, we hypothesized that 121
10° 8 = 6 ö 4 Non T Cell .~ :ö c ..c 0 L.- a... 2 X X T CeU 10- 1 0~--:'::10:---2~0----::3':-0 ---'-4o:----:'::5o:--:--6~0----:7~0--8:.L.0--- Months Fig. 1. T-eell and Non-Teell leukemia disease free survival lymphocytes may be continuously transformed in the thymus by hormonal factors secreted by thymic epithelial cells. Although high dose radiation therapy could ablate the thymic epithelial cells, it would do so at the cost of added toxicity to both the esophagus and heart when it was used concurrently with adriamycin. Therefore, we chose to ablate the thymus by total thymectomy. B. Preliminary Results Since March 1977 17 patients with immunologically proven T -cell ALL have been entered onto the T -cell protocol, 12 from our institution and 5 from Yale-New Haven Medical Center. Two patients died during induction of sepsis and pneumonitis. Of the 15 patients who entered complete remission, 3 have relapsed. Vincristine 1.5mg I M2 i.v. push (max 2.0mg I Prednisone 40 mg/M2/d p.o. (divided doses I Vincristine 2.0mgl M2 i.v. push (max 2.0mg I Adriamycin 45 mg I M2 i.v. push Cyclophosphamide 500 mg 1M2 i.v. drip Predni sone 120 mg I M 2 1 d p.O. X 5 days Methotrexate 12 mg 1M2 l.l (max 12mgl Cronial irradiation - 2400 rads Testicular irradiation - 2400 rads Induction and CNS ProP.Dylaxis Week 1 2 3 4 5 6 7 B 9 Oay 8 15 22 29 tlThymectomyl t Toper t WH Vincristine 2.0mg 1M2 Lv. push (max 2.0mgl Cyclophosphamide 500 mg/W d i.v. push Cytosine arabinaside 200 mg I M2 continuous i.v. infusion Prednisolone 120 mg I M2 Id i.v. push Vincristine 2.0mg 1M2 i.v. push (max 2.0mgl Adriamycin 45mg/M2 Lv. push Cyclophosphamide 500 mg 1M2 i.v. push Prednisone 120 mg/W/d p.O. Week Intensification and Treatment in Remission 12 13 14 15 16 17 18 19 20 21 t t t ItUHI WH Fig. 2. Schema for treatment of T -eellieukemia 122 t t t WH t t t tHH t
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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 ,-----------------------------
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11. Haematological and Biochemical
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0\ 0\ INTERFERON ... 10 3 rl E "'
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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 107 and 108: Haematology and Blood Transfusion V
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 and 128: ~ looh---------ooooc>----o---c>----
Page 129 and 130: Consoll- Irra .tlon t) .tlon Indu
Page 131 and 132: Highrisk Standard risk Table 1. Cli
Page 133: Cumulo/ive comp/el9 remission 1.0 .
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
Page 181 and 182: 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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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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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
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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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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---------,,':::::::::::::::
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
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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
Page 547 and 548:
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
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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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