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Few cases of Ph-positive CML have been reported in which a long-term remission occurred without treatment.9,10,11 We describe a patient with Ph-positive CML who entered a lengthy remission, with a normal karyotype and no evidence of the BCR-ABL gene, without any therapy.
Case Report
A 45-year-old man was referred to our hospital for evaluation of leukocytosis in January 1985. Three months previously, he had reported tarry stools. A peptic ulcer was diagnosed and treated with intravenous cimetidine. At that time, leukocytosis, thrombocytosis, and anemia were detected. A bone marrow aspirate showed marked myeloid hyperplasia. Cytogenetic analysis revealed Ph-positive cells in the bone marrow, and a diagnosis of CML was made. During the next month the leukocyte count decreased to 14,400 per cubic millimeter, but it subsequently gradually increased to 31,800 per cubic millimeter before admission to our hospital.
Physical examination on admission revealed anemia and mild hepatosplenomegaly. A complete blood count again showed leukocytosis and thrombocytosis. The neutrophil alkaline phosphatase score was 94 (normal range, 170 to 335). Plasma histamine and prostaglandin E concentrations were within the normal range. An endoscopic examination revealed an ulcer scar in the duodenal bulb.
Regular follow-up, without chemotherapy, was planned for the patient. In February 1985, the hepatosplenomegaly disappeared. The leukocyte count and platelet count returned to normal in April 1985. As of January 30, 1996, the patient had been well, without any signs of recurrence, for 11 years. Blood counts since June 30, 1994, have been normal. Table 1 summarizes the hematologic values.
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Chromosome preparations were made from bone marrow cells, as described previously,12 and mounted on slides, which were then subjected to G and Q banding. Abnormal karyotypes were classified according to the International System for Human Cytogenetic Nomenclature.13
RNA was extracted from the bone marrow cells14 and reverse-transcribed to amplify the chimeric BCR-ABL complementary DNA (cDNA) with PCR.15 Southern blot analysis with a 1.3-kb 5'-BCR probe was performed as previously described,16 with genomic DNA extracted from the marrow cells.
Results
Table 1 shows the results of eight chromosomal analyses carried out over a period of 10 years. All marrow cells in metaphase were Ph-positive on the first (November 8, 1984) and second (January 30, 1985) examinations. The abnormality was apparently due to a reciprocal translocation between chromosomes 9 and 22, giving a karyotype of 46,XY,t(9;22)(q34;q11) (data not shown). The proportion of Ph-positive cells in the marrow was decreased in July 1985, and no Ph-positive cells were detected in February 1987. Thereafter, all metaphases examined showed a normal karyotype.
Reverse-transcription PCR was expected to yield a chimeric product of 446 bp, a 371-bp fragment of the major BCR-ABL region, a 472-bp fragment of the minor BCR-ABL region, and a 253-bp fragment of ABL (which was used as an internal standard). However, no rearrangements of the 3' or 5' ends of the BCR gene were detectable by Southern blot analysis (data not shown), and chimeric cDNA was not found by reverse-transcription PCR in the bone marrow cells obtained on August 10, 1993 (Figure 1A and Figure 1B), and June 30, 1994. No DNA or RNA from the bone marrow cells containing Ph-positive cells was available for analysis.
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measured in July 1985 was within the normal range (<4 IU per milliliter), and the level of interferon- produced by peripheral-blood mononuclear cells was also normal (1600 IU per milliliter). Discussion
The striking feature of this case is the disappearance of Ph-positive cells from the marrow without any treatment. To our knowledge, only three other cases of hematologic and cytogenetic regression without chemotherapy have been reported.9,10,11 In two of those cases, however, the remission was incomplete. Overt leukemia subsequently developed in one patient, with 100 percent Ph-positive marrow cells; in the other, a small percentage of Ph-positive cells persisted in the marrow.10 The third patient, who was followed for four years, was similar to ours.11 All Ph-positive cells disappeared from his blood, and Southern blot analysis revealed no rearrangements of BCR in the marrow cells.
In our patient, the absence of the chimeric BCR-ABL gene in bone marrow cells was demonstrated by Southern blot analysis and reverse-transcription PCR after the disappearance of cells. Because molecular analysis was not done before the disappearance of these cells, we cannot exclude the possibility that our patient may have had a unique breakpoint in the BCR gene that influenced his remission. However, the possibility of a relation between a BCR breakpoint and the duration of the chronic phase of CML is controversial.17
Transient spontaneous regression of acute nonlymphocytic leukemia in adults is a rare event that is generally associated with pyogenic bacterial infection and lasts only weeks to months.18 In such cases, intrinsic cytokines, such as interferons, may have a role. However, our patient had no febrile episodes after the onset of the disease and did not receive interferon therapy. An influence of intrinsic interferon- on his clinical course seems unlikely, since the serum interferon- level and the level of interferon- produced by mononuclear cells were normal in July 1985. The mechanism of the spontaneous remission in our case, as in most other examples of spontaneous regression of neoplasms, is unknown.
We are indebted to Yasunobu Yokoyama, Ph.D. (Special Reference Laboratory, Tokyo, Japan), for cytogenetic analysis; to Kyoko Kato, Ph.D. (Special Reference Laboratory), for the molecular analysis of the BCR gene; and to Mr. Yuzo Tsuda for his excellent technical assistance.
Source Information
From the Third Department of Internal Medicine (M. Musashi, J.T., Y.G., S.M., Y.S., M. Morioka, K.S., M.A., and T. Miyazaki) and the Department of Microbiology (T. Minagawa), Hokkaido University School of Medicine; and the Chromosome Research Unit, Faculty of Science, Hokkaido University (S.A., T.Y.) — both in Sapporo, Japan.
Address reprint requests to Dr. Musashi at the Third Department of Internal Medicine, Hokkaido University school of Medicine, Kita 15, Nishi 7, Kita-ku, Sapporo 060, Japan.
References
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X174 digested with HaeIII. No chimeric BCR-ABL products were detected.