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883 ,ral ew ion 1: 3 Tl: mal ma ho,63Jiofol,urg 1potox- 3ty. hyl- P'o- :bml rchir Up.act3 iors. :cent Antinges 3hod WiO- ienic >wing HA. hemI. 4th Am I nocy- 'ancer Arch < BL. i:1 3 918). ladia. 1-8. - I The New England Journal of Medicine Official Organ of The Slassachusetts Medical Society Goodwill .\I. Stewart. S1.D. President \\-illiam B. SLunier. 1I.D. Charles S. Amorosino, Jr. E.recufiae 1i'cr-presiilenl E.rccufzce Secretap PUBLISHED Lb'EEKLY BY THE CO>lMl7TEEO N PIXILICATIOSS O F THE s[.4SSACHUSElTS h1EDICAL SOCIETY Samuel K. Stewart, 1I.D., Chairman it C. Ayres. 1 l . D . \Yilliarn H. Sweet, ll.D.. D.Sc. nk E. Bixby. Jr.. S1.D. , , 111 I . Sandson. X1.D. Robert E. Tranquada, M.D. Percv W.Ll'adman. 11.D. .Arnold S. Relman. 1I.D., EDITOR 1 l a r c i a h g e l l . 4I.D.. DEPUTY EDITOR Edwin Jk'. Salzman, M.D., DEPUTY EDITOR . ~ S S O C ~ A T EEDITORS j m c F. Desforges. 1,L.D. Sorrnan K. Hollenberg. S1.D.. Ph.D. Ku1i;tld A. 1lalt. M . D . Morton S. Swartz, 41.D. Franklin H. Epstein, M.D. Francis D. 11oore. .\l.D., BOOK REVIEWEDITOR John C . Bailar. 111, l l . D . . STATISTICAL COSSLLT.AST John K.Iglehart, SPECIAL CORRESPOXDEXT Joseph J . Elia. j r . . S ~ A N A G OEFRED~TORIAOLPERATIONS Emily S. Boro, DIRECTOR OF COPY E D ~ T I S G %dene A. Thayer, EDITORIAL OFFIC.E\l.AsACER EDITORlnL BOARD Richard H. Egdahl. S1.D. John T. Harrinqton. S1.D. l<olwrtJ. &layer. M.D. Homayoun Kazemi. M.D. ti,.-:iiethJ. Rothman. Dr.P.h. I\ I. Bloch, 1I.D. Kenneth 11cIntosh. 11.D. David C. Nathan. L1.D. I' CXabresi. S1.D. Lawrence G. Raisz. lI.D. \;.,III V. Chohanian. 11.D. Thomas .J. Ryan. M.D. Samuel A. Latt, SLD., Ph.D. Frederick Bowes, 111. DIRECTOR OF Pusl.lsHrxc OPERATIONS Ronald H. Brown, ~ I A N A G OEFR. ~ D V E R T I S I S G 8: L~ARKETISC IViIliarn H. Paise, X ~ A N A C E ROF PRODUCTION 8; DlSTRIBCTlOX 11ilton C. Paige. Jr.. CONSLLTAXT \I'ECTIYE authors should consult "Information Ibr Authors." which in the first issue ofevervvolume and may heobtained from rhc Journal I.ES with oriqinal material are accepted for consideration with the ~ ~ ~ ~ I ~ ~ ' \ t . iiihiadri. neqxcepr for abstracts. no part of the data has bren publ\hd.or will lic submitted for publication elsewhere. lietore appearing here. yn PIRT o f this publication mav be reproduced or transmitted in any form ,'llhnui written permission. \f.*rERiAL printed in the Journal is covered by copyright. TheJournal docs i " ~ t tiold itself responsible for statements made by any contributor. ~ T I C E Sshould be scnt at least 30 days belbre publication date. \L.THIlIIGH all adverrisinq material acccpred is expected to conform to ethi' medical standards. acceptance docs not imply endorsement bv theJouma1. 1 docs not stock reprints. and reprints of the MGH USA: 355 per year [interns, residents S35 per vear: . . 3 0 per ycarj. Canada ( U . S . funds o n l v ) : 365 per vear linterns. ii 545 per w a r ; students 540 per year). M a i l checks to Subscription l"\~:wnis,P.O. Box 4772. Boston, 11.4 @?I?. E o t l n R i A L OFFICES: IO Shattuck SI.. Boston. M A 021 15. ~ i ' s t ~ e AsNsD SUBSCRIPTION OFFICES1:440 Main St.. Waltham. .\LA 0??5+. CHRONIC MYELOCYTIC (MULTIPOTENT-STEM-CELL) LEUKEMIA CHRONIC myelocytic leukemia is a disease in which biomedical research efforts have paid substantial dividends in recent years. Both laboratory and clinical investigators have found that this disease, first described as "splenic leukemia" over 100 years ago, contains some important lessons for the astute observer. An early, notable example of the value of careful laboratory observation was the demonstration of the Philadelphia (Ph') chromosome in patients with this disease.' Subsequent cytogenetic analyses using banding 'techniques demonstrated that in most cases of chronic myelocytic leukemia. the Ph chromosome arises from a balanced translocation between the long arms of chromosomes 9 and 22, with break points in bands q3-k and q l 1 , respectively.' Studies using molecular probes3 now suggest that a cellular gene, termed c-abl, which is structurally related to the murine Abelsonleukemia-virus-transforming gene, u-abl, is Located in the fragment translocated from chromosome 9 to chromosome 22. Several laboratory groups are currently investiqating a mechanism by which chromosomal translocation could be associated with activation of a cellular gene or genes capable of inducing malignant transformation - e.g., c-ab1 or andther oncogene. Chromosomal studies have paid further dividends by demonstrating that all the various cell lines involved in the disease (granulocytic, erythrocytic, megakaryocytic, and lymphocytic) contain the characteristic chromosome. These data strongly suggest that all the malignant cells in chronic myelocytic leukemia are derived from a single multipotent-stem-cell clone. Further evidence that the disease arises from a single clone is supported by studies of glucose-&phosphate dehydrogenase isoenzymes." The nature of the clonal abnormality or abnormalities in chronic myelocytic leukemia has been of great interest to recent investigators. Studies demonstrating the involvement of lymphocytes in the disease have greatly aided this analysis. Early evidence implicating lymphocytes came from data indicating that progression of the disease resulted in blast crises that often had lymphoid morphology. The B-lymphocyte lineage of some lymphoid blast crises was demonstrated in studies indicating that the malignant cell contained immunoglobulin mu heavy chains in the cellular cytoplasm; these cells were thus characteristic of pre-B lymphocyte^.',^ Not all lymphoid blast crises showed evidence of cytoplasmic immunoglobulin, however, and thus the possibility existed that cells could be arrested at an even earlier stage of B-lymphocyte development. Studies of the structure of DNA have been extremely useful for analysis of these early steps in B-cell development. They indicate that rearrangement of immunoglobulin genes precedes immunoglobulin synthesis in B-lymphocyte maturation; an arrest in early B-lineage differentiation is observed in most cases of acute lymphoblastic leukemia.' T h e results f PLAINTIFF'S EXHIBIT I T H E KEW ENGLAND JOURNAL OF MEDICINE Oct. 6,1983 appear to be very similar in chronic myelocytic leukemia, as reported in the elegant study of Bakhshi et al. in this issue of the Journal.' Their studies of DNA rearrangement in immunoglobulin genes indicate that the vast majority of lymphoid blast crises of chronic myelocytic leukemia involve cells of B-cell lineage. Together with data from another group,' the work of Bakhshi et al. demonstrates that additional subclones at various levels of B-cell maturation may evolve during the course of the disease. T h e origin of these clones within clones remains unknown. The demonstration that the major clone in chronic myelocytic leukemia involves cells capable of lymphocytic, granulocytic, and erythrocytic differentiation has led to the conclusion that the transformation event occurs at a very early multipotent-stem-cell level. This conclusion has several theoretical and practical implications. It appears that arrested maturation does not necessarily occur at the level of the transformed cell, since transformed cells can produce ver). mature progeny, such as granulocytes. The therapeutic implications of the multipotent-stem-cell hypothesis are illustrated by studies using intensive chemotherapy, which demonstrate the difficulty in eliminating the abnormal clone. There are probably only very subtle differences between normal multipotent stem cells and the multipotent stem cells in chronic myelocytic leukemia"; therefore, it has been difficult to eradicate the leukemic population selectively, without causing major destruction of normal stem cells. This problem has been circumvented by giving the patient intensive chemoradiotherapy followed by allogeneic-bone-marrow' transplantation. 11*'' Current in\.estigations are directed at the appropriate timing of transplantation in the course of the disease, comparisons of various intensive treatment regimens, and the importance of matching donor with recipient. I am hopeful that the rate of progress in identifying the pathogenesis of chronic myelocytic (multipotentstem-cell) leukemia will continue to accelerate in the coming years. An understanding of the origin of the 9;22 translocation and the relation of this translocation to genes located at the break points will be important. Further therapeutic success in this formerly fatal disease is likely to be achieved with allogeneic-marrow transplantation and other innovative treatment methods. Continued cooperation of the laboratory and clinical investigator will be essential in this process. University of Minnesota Minneapolis. MN 55455 JOHN H . KERSEYM, .D. REFERENCES 1. Nowell FC. Hungerford DA. A minute chromosome in human chronic granulocytic leukemia. Science 1960. 132:1497. 2. Rowley JD. Ph'-positivc leukaemia. including chronic myelogenous Ieu- kaemia. Clin Haematol 1980: 955-86. 3. de Klein A. Geum van Kcssel A. Grosveld G , et al. A cellular oncogene is translocated to the Philadelphia chromosome in chronic myelocytic leukaemia. Nature 1982; 300:765-7. 4. Fialkow PJ. Jacobson W. Papayannopulou TH. Chronic myelocytic leukemia: clonal origin in a stem cell common IO the granulocyte. erythmyte. platelet and monocyte/macrophage. Am J Med 1977: 63:11530. 5. LeBien TW.HozierJ. Minowada I. Keney JH. Origin of chronic myelocytic leukemia in a precursor of pre-B lymphocytes. N Engl J Med 1979; 301 :144-7 6. Vogler LB, Crist WM. Vinson PC.Sarrif A. Branain MG, Coleman MS. Philadelphiachromosome-positivepre-B-cell leukemia presenting as blast crisis of chronic myelogenous leukemia. Blood 1979; 54:1164-70. 7 . Korsmeyer SJ. Arnold A, Bakhshi A , et al. Immunoglobulin gene rearrangement and cell surface antigen expression in acute lymphocytic leukemias of T cell and B cell precursor origins. J Clin Invest 1983; 7 I :30l- 13. 8 . Bakhshi A, Minowada J. Arnold A. et al. Lymphoid blast crises of chronic myelogenous leukemia represent stages in the development of B-cell precursors. N Engl J Med 1983; 309:826-31. 9. Ford AM. Molgaard HV. Greaves MF. et al. Immunoglobulin gene organisation and expression in haemopoietic stem cell leukaemia. EMBO J 1983: 2:997-1001. IO. Goto T. Nishikori M. Arlin Z, et al. Growth characteristics of leukemia an< normal hematopoietic cells in PH' + chronic myelogenous leukemia anr effects of intensive treatment. Blood 1982; 59793-808. 1 I , McGlave PB. Arthur DC,Kim M. et al. Successful allogeneic bone-mar- row transplantation for patients in the accelerated phase of chronic granulccytic leukaemia. Lancet 1982; 2:625-7. 12. Clift RA.Buckner CD. Thomas ED. et al. Treatmentof chronic granulocyic leukaemia in chronic phase by allogeneic marrow uansplantation. Lancet 1982; 2621-3. EDITORIAL RETROSPECTIVE SERUM ACID PHOSPHATASE AND SCREENING FOR CARCINOMA OF THE PROSTATE IN 1977 Foti et al.' described a new radioimmunoassay for prostatic acid phosphatase in patients with carcinoma of the prostate, including a large number with disease in Stages A and B. ( I n Stage A, foci of tumor are found incidentally at prostatectomy for prrsumed benign obstruction. Stage B refers to biops) proved intracapsular tumor, usually detected by rectal examination and without evidence of metastases.) The previously available colorimetric or enzymatic assays for acid phosphatase had yielded values within normal limits in patients with localized prostatic cancer, but Foti el al. reported increased levels found by radioimmunoassay in 33 per cent of patients with Stage A disease and 78 per cent ofpatients with Stage B. I n an accompanying editorial' I expressed the hope that if the sensitivity of the test were confirmed, it might pe mit the use of radioimmunoassay for mass screenir 2 and detection of prostatic cancer in the curable stages. Six years later, it is now clear that the radioimmunoassay did not and indeed could not live up to that hope. The two reasons for that outcome are worth reviewing. The first and more instructive reason was analyzed by Carroll3 and by Watson and Tang,4 who pointed out that in the original results of Foti el al., the specificity of only 94 per cent (204 negative tests among 217 patients without cancer of the prostate) undermini i the potential of the test for screening purposes. T1.r reported elevation of prostatic acid phosphatase 111 2 of 36 patients with benign prostatic hypertroph\ was particularly noteworthy. Nearly all men over 5 have some degree of benign prostatic hypertroph\. but no more than 1 in 100 has clinically impol- VOI. 3 I . tant level least I mPh Vati0: benig cance Th meas test. from repor over levels *P that \. clinic' dle bi remai screer but M trophi dresse noma patien obtain phospi my foi Fleish: creasec gery. a prosta patien Wcer prostai add pt occult &ted and th. Stage i group mately The hitiall! Stage P clinical tien& 1 ken pr hphProsta ti adQu 13 per c studies! Pelvic 1. 'ation ( localize, Qent af. ht edi ar1y-st' 'umber 'Y used I L