Acta med. scand. Vol. 193, pp. 257-258, 1973

Editorial

FROM BAD TO WORSE?

Treatment and Leukemogenesis

It has long been known that patients with poly- cythemia Vera (PV) who have been treated with 32P may develop acute blast cell leukemia. Inter- estingly enough this has been interpreted in dif- ferent ways. One very extensive and careful sta- tistical analysis has led to the conclusion that the leukemia is the result of the ionizing radia- tion. Another critical study concerns the develop- ment of acute myeloic leukemia (AML) as part of the “natural” history of PV. These authors maintain that a patient who lives long enough runs a considerable risk of dying from this “complication” and that patients live longer when treated with 32P. It has been maintained that we should treat our patients with Mylerana instead, but this is perhaps not a logical conclusion as a number of patients with chronic myeloic leu- kemia (CML), who respond well initially to such treatment, finally develop AML and die.

There are a few facts that are relevant in this connection. After treatment with 32P for PV and with Myleranm for CML, acute blast cell leu- kemia is not rare. Patients, who were treated in Great Britain for ankylosing spondylarthritis with X-rays to the spine developed significantly more AML (but never acute lymphatic leukemia) than untreated normals. Among the survivors of the atomic bomb in Hiroshima the same result was established-only an increase in myeloic leu- kemia was observed.

During the last years a number of observations have been made in patients with myeloma who were treated with cytostatic drugs, chiefly with Melphalana, and developed AML (so-called mono- myeloblastic). The first was the already classical case of Osserman with maximal lysozymuria and monocytic leukemic proliferation (6). A great

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number (20-25) of such cases are now known. It had not been observed previously that myeloma cases develop AML even if it may be possible that some instances of so-called plasma cell leukemia were in reality blast cell leukemias. I t seems difficult to imagine why a plasmo- cytoma should develop into a blast cell leukemia of monocytic type. Still more far-fetched is this explanation in a number of recent observations. Catovsky and Galton (2) have described a case of chronic lymphocytic leukemia (CLL) treated with chlorambucil for 40 months. He then devel- oped unquestionable monomyeloblastic leukemia with maximal lysozymuria and died. It is well established that lymphocytes do not produce lyso- zyme, and acute lymphoblastic anemia after CLL is extremely rare-many say non-existent. That this patient switched over from a lymphocytic pro- liferation or had a superimposed monomyelo- blastic malignancy is therefore remarkable. There are now a number of other observations of a similar kind. Macroglobulinemia (chlorambucil or Melphalana) into blast cell leukemia or erythro- leukemia is another lymphatic disease with this complication. Also patients with carcinoma (from lung or ovary) have died from acute leukemia after treatment with only Thiotepaa and no ir- radiation. Some patients have also been treated with cyclophosphamide, but they were also ex- posed to radiation and the effect of the drug is therefore difficult to assess (3).

In summary it may be said that a number of therapeutic agents-ionizing radiation (X-rays, 3*P), Melphalanm, chlorambucil, busulphan, Thio- tepaa-have been used for a considerable time in patients who have developed acute leukemia later.

Acta med. scand. 193

258 Editorial

An interesting paper in the present issue of this journal treats the question of cytogenetic studies in conditions where we know that acute blast cell leukemia occurs with increased fre- quency as a final event. The reader will find much food for thought in this paper. One of the great difficulties in such studies is the fact that we do not know how long the preleukemia period has lasted before we have enough symptoms to make a clinical diagnosis. There is, however, one very diagnostic “marker” for myeloic leukemia in the karyotypic picture. This is a small extra chromosome split off from the normal 22 accord- ing to the latest investigations (the reader may consult Caspersson’s excellent review of these subjects). This extra chromosome is called the Philadelphia chromosome and patients who carry it are said to bz Ph’. Recent work also on mye- loma indicates that there is a premyeloma stage with only y-globulin changes before visible mye- loma comes to the surface. A recent number of the Lancet contains a very interesting study (1) regarding this “subterraneous” existence of leu- kemia before it emerges with clearcut symptoms. A patient was followed for over 5 years with a low percentage of the Philadelphia chromosome in his bone marrow cells. On some occasions he had slight leukocytosis but otherwise no symp- toms of blood disease until he suddenly fell ill with blast cell leukemia. At this stag: the marrow contained 90 % PhC cells. These facts are interest- ing in themselves, but still more important is the finding that another person had a mosaic of two different karyotypes XXY and X Y (normal). This means that two different cell lines could be distinguished and the question arose whether the

Ph chromosome was present only in one of them. As a matter of Pact it was only found in the normal XY cells. This must mean that non-leu- kemic and leukemic cells may exist together in the same organism (5). Whether or not this has a bearing on Fialkow’s findings that normal donor cells became leukemic on transplantation into a leukemic recipient (4) cannot be discussed here. This is an interesting problem of great practicaI importance when judging the feasibility of trans- planting normal marrow to leukemic subjects.

The problem of malignancy after irradiation and after administration of cytostatic drugs has both practical and theoretical applications in an- other field. Persons with transplanted organs, who are under immunosuppression with anti- metabolites-usually ImureIB (azathi0prine)- suf- fer a certain risk in this respect. It is possible that the development of malignant lymphoma, usually reticulum cell sarcoma, in these cases is more related to immunosuppression than to active “lymphomogenesis”.

Only continued observations will give an an- swer to the problem.

REFERENCES

1 . Canellos, G. P. & Whang-Peng, J.: Lancet 2: 1227,

2. Catovsky, D. & Galton, D.: Lancet 1: 478, 1971. 3. Editorial: Lancet 1: 70, 1971. 4. Fialkow, P. J. et al.: Lanczt 1: 251, 1971. 5 . Fitzgerald et al.: Brit. J. hzmat. 21: 473, 1971. 6. Osserman, E. F. & Lawlor, D. P.: J. exp. Med. 124:

1972.

921, 1966.

Jan G . Waldenstrorn

Acta med. scand. 193