A 44-year-old man suffering from cytogenetically and molecularly proven Philadelphia translocation-positive chronic myelogenous leukemia in chronic phase was treated with busulfan for 18 months and studied during a follow-up period of 13 years. Hematologically and cytogenetically, he attained a continuing complete remission, although at one point (9.5 years) at least, after attaining complete remission molecular analysis indicated the presence of minimal residual disease

Geurts van Kessel, A.H.M. (Ad)

Haanen, C. (C.)

Hagemeÿer, A. (A.)

Mandigers, C.

Mensink, E.J.B.M. (Ewald)

Plas, D. (D.) van der

Witte, T. de

Erasmus University Digital Repository

C. M. P. W. Mandigers 7 E. J. B. M. Mensink 7 C. Haanen 7T. de Witte (Y)University Hospital Nijmegen, 544 Department of Hematology,P. O. Box 9101, NL-6500 HB Nijmegen, The NetherlandsA. Geurts van KesselUniversity Hospital Nijmegen, Department ofAnthropogenetica, The NetherlandsD. C. van der Plas 7 A. HagemeÿerDepartment of Cell Biology and Genetics, Erasmus UniversityRotterdam, The NetherlandsAnn Hematol (1996) 72 :371–373 Q Springer-Verlag 1996CASE REPORTC. M. P. W. Mandigers 7 E. J. B. M. MensinkA. Geurts van Kessel 7 D. C. van der PlasC. Haanen 7 A. Hagemeÿer 7 T. de WitteA long-lasting, complete hematologic and cytogeneticremission of chronic myelogenous leukemia after treatmentwith busulfan aloneReceived: 27 October 1995 / Accepted: 27 February 1996Abstract A 44-year-old man suffering from cytogeneti-cally and molecularly proven Philadelphia transloca-tion-positive chronic myelogenous leukemia in chronicphase was treated with busulfan for 18 months andstudied during a follow-up period of 13 years. Hemato-logically and cytogenetically, he attained a continuingcomplete remission, although at one point (9.5 years) atleast, after attaining complete remission molecularanalysis indicated the presence of minimal residual dis-ease.Key words Busulfan 7 Chronic myelogenousleukemia 7 Cytogenetic 7 Minimal residual disease 7Polymerase chain reactionIntroductionThe clinical course of chronic myelogenous leukemia(CML) is characterized by a chronic phase lasting foran average of 3 years, followed by an accelerated phaseand a blastic transformation. Survival after transforma-tion is dismal and usually less than 3 months. Cytogen-etic and molecular techniques have elucidated some pa-thophysiological mechanisms in CML, including thePhiladelphia translocation (Phb). Generally, standardtreatment of CML is not capable of eliminating thePhb-positive clone and is therefore considered pallia-tive, but not curative. Recently, therapies have beendevised aiming at the eradication of the Phb-positivecell clone, a phenomenon designated Phb conversion.We present a patient with a very unusual hematologic,cytogenetic, and molecular course of CML after mildfirst-line oral therapy only.Case reportIn August 1982, a 44-year-old man, known to have nephrolithia-sis, presented to the urologist with pain in his flank. He had noother complaints. Routine blood analysis revealed a leukocytosis.Physical examination was normal; the spleen was not palpable. Acomplete blood cell count revealed a hemoglobin of 8.8 mmol/l,hematocrit of 0.45 l/l, platelet count of 145!109/l, white bloodcell count of 74!109/l with 1% myeloblasts, 1% promyelocytes,17% myelocytes, 9% metamyelocytes, 16% bands, 38% seg-mented neutrophils, 1% eosinophils, 3% basophils, 7% lympho-cytes, and 7% monocytes. The value of lactate dehydrogenasewas 486 units/l (normal ~330 units/l). Further chemical examina-tion of peripheral blood was normal. The leukocyte alkalinephosphatase score was unexpectedly elevated (1095/100 cells); itwas absent at subsequent sampling. Slight hepatosplenomegalywas found on technetium scintigraphy.Bone marrow morphology showed a predominance of myelo-poiesis (myelopoiesis :erythropoiesisp25 :1) and 5% myeloblasts.Cytogenetic analysis of the bone marrow revealed the presence ofthe Philadelphia chromosome in three of three metaphases, andin one of these metaphases inversion of chromosome 7 was seen.The diagnosis of Phb-positive chronic myelogenous leukemia inchronic phase was made. The Sokal index was 0.8 [12].Before treatment, peripheral stem cells were collected by con-tinuous-flow leukapheresis and cryopreserved to be used as stemcell rescue after intensive chemotherapy in case an accelerated orblastic phase should occur [3]. Cytogenetic analysis of these he-matopoietic progenitor cells showed the Philadelphia chromo-some in 20 of 20 metaphases, as well as an additional inversion ofchromosome 7 in nine metaphases. Molecular analysis of thesehematopoietic progenitor cells was performed 7.5 years later andrevealed the presence of a hybrid breakpoint cluster region–Abelson (BCR-ABL) messenger ribonucleic acid (mRNA) of theb2a2 type. The method used has a sensitivity of detecting onemalignant cell derived from CML cell line k562 in 105 normalcells.The patient was treated with busulfan orally in gradually de-creasing doses for 18 months with a total amount of 686 mg. Theperipheral blood cell count normalized after 6 months’ treatmentand remained normal during the follow-up period of 13 years af-ter diagnosis. No aplastic phase occurred during or after busulfan372Fig. 1 Therapy (a) and values of leukocytes (b) and platelets (c)in peripheral blood during follow-up of patienttherapy (Fig. 1). Bone marrow morphology normalized 4.5 yearsafter diagnosis and remained normal up to the most recent sam-pling, 11.5 years after diagnosis.Sequential cytogenetic and molecular analysis of blood andbone marrow samples collected 4–13 years after diagnosis showedthe almost complete conversion to a Phb-negative status (Table1). Molecular analysis was performed using the Southern blottechnique in the beginning and later on reverse polymerase chainreaction, as described before [2]. The detection of BCR-ABLmRNA was only weakly positive in March 1992. Repeated testinggave the same weakly positive result. This indicates that the num-ber of BCR-ABL mRNA molecules was then at the detection lev-el of the test, suggesting a low expression of the hybrid BCR-ABL ongogene.DiscussionChronic myelogenous leukemia is a myeloproliferativedisorder associated with the Philadelphia chromosomein more than 90% of patients. As a result of the Phila-delphia translocation, the ABL oncogene is transferredfrom chromosome 9 (band 34) onto the BCR gene onchromosome 22 (band 11), where it encodes a chimericBCR-ABL mRNA transcript resulting in a BCR-ABLfusion protein thought to be responsible for the leu-kemic transformation [4].In the literature several therapeutic options for pa-tients with CML are recommended [1, 6–9, 13]. Themedian survival of untreated patients is about 31months. Symptoms of chronic-phase CML can usuallybe controlled with oral busulfan or hydroxyurea, whichprolong the median survival to about 45 or 58 months,respectively [9]. After a remission of CML has beenachieved with busulfan, the bone marrow usually re-mains Phb positive, although a few Phb-negative remis-sions have been reported following busulfan-inducedaplasia [8, 10]. Intensive combination chemotherapyprolongs the median survival of chronic-phase CMLpatients to about 57 months and results in cytogeneticremission in up to a quarter of the patients. The mediansurvival of patients with chronic-phase CML is length-ened to 72 months by treatment with interferon-alpha,which leads to (partial) cytogenetic remission in 30% ofcases. At present, the only curative option is allogeneicbone marrow transplantation, which is the treatment ofchoice especially in young patients with CML inchronic phase; it results in suppression of Phb-positivecells in 100% and in a 3-year disease-free survival rateof about 63%. A close correlation exists between disap-pearance of Phb and hematologic remission.The long-lasting, practically complete Phb conver-sion of this patient is exceptional because it occurredafter a mild oral chemotherapy regimen without an epi-sode of bone marrow aplasia. The calculated Sokal in-dex of 0.8 indicates an intermediate relative risk of dy-ing, which is more than one may expect in this patient[12].The Philadelphia translocation at diagnosis was cy-togenetically and molecularly documented, in contrastto other reports [5, 11]. Moreover, an additional aspe-cific cytogenetic abnormality, the inversion of chromo-some 7, was documented in bone marrow and apheresismaterial at diagnosis. After treatment molecular studiesshowed a weakly positive signal of BCR-ABL mRNAat the detection level of the PCR technique on one oc-casion. Apparently, the growth potential of the leu-kemic clone has up to now been in equilibrium withthat of the normal hematopoietic progenitor cells. Animmunological suppression of the leukemic clone for atleast 3 years cannot be excluded. Similar observationshave been made only after allogeneic bone marrowtransplantation [14].373Table 1 Sequential cytogenetic and molecular analyses of apheresis material, bone marrow, and peripheral blood of our patient (AMapheresis material, BM bone marrow, PB peripheral blood, mBCR major breakpoint cluster region, SB Southern blot)Date(month/year)Material Cytogenetic analysis Molecular analysisNumber ofmetaphasesKaryotype Technique Result(breakpoint)09/1982 BM 3 46,xy,t(9;22) [2]/46,xy,t(9;22),inv(7) [1]AM 20 46,xy,t(9;22) [11]/46,xy,t(9;22),inv(7) [9]AM SB Positive (mBCR)AM RT-PCR Positive (b2a2)11/1986 BM 6 46,xy01/1987 BM 38 46,xy09/1989 BM RT-PCR Negative03/1992 BM 21 46,xyBM RT-PCR Weakly pos (b2a2)PB RT-PCR Negative02/1994 BM RT-PCR NegativePB RT-PCR Negative02/1995 PB RT-PCR NegativeAcknowledgements Part of this work was supported by theDutch Cancer Foundation. We thank Ellen Linders for perform-ing the BCR-ABL PCR assay.References1. 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A long-lasting, complete hematologic and cytogenetic remission of chronic myelogenous leukemia after treatment with busulfan alone

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A long-lasting, complete hematologic and cytogenetic remission of chronic myelogenous leukemia after treatment with busulfan alone

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