A 25-year-old male developed lymphoid blast crisis (BC) of chronic myelogenous leukemia (CML) more than 11 years after receiving an allogeneic bone ...
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Case reports Lymphoid blast crisis of chronic myelogenous leukemia occurring more than 11 years after receiving an allogeneic bone marrow transplant for chronic myelogenous leukemia in myeloid blast crisis at onset K Fukuno1,2, H Tsurumi2, T Yamada1, M Oyama1, T Matsuyama3, S Terakura4, Y Kodera4 and H Moriwaki2 1 Department of Internal Medicine, Kisogawa Hospital, Aichi, Japan; 2First Department of Internal Medicine, Gifu University School of Medicine, Gifu, Japan; 3Department of Pediatrics, Japanese Red Cross Nagoya First Hospital, Nagoya, Japan; and 4Department of Internal Medicine, Japanese Red Cross Nagoya First Hospital, Nagoya, Japan
Summary: A 25-year-old male developed lymphoid blast crisis (BC) of chronic myelogenous leukemia (CML) more than 11 years after receiving an allogeneic bone marrow transplant (alloBMT) for CML with myeloid BC at presentation from his HLA-identical brother. The lymphoid BC of CML probably occurred without a preceding chronic phase of CML. This case illustrates the difficulties involved in determining the appropriate length of followup after alloBMT. Bone Marrow Transplantation (2003) 31, 211–213. doi:10.1038/sj.bmt.1703820 Keywords: chronic myelogenous leukemia; bone marrow transplant; late relapse; lymphoid blast crisis; acute lymphoblastic leukemia
The incidence of recurrent leukemia more than 10 years after allogeneic bone marrow transplant (alloBMT) is very low. The pathogenesis of late relapse after alloBMT remains unknown. Cytogenetic evolution or oncogene alternations may be related to a failure of the graftversus-leukemia (GVL) effect. An early diagnosis of late relapse and countermeasures such as donor leukocyte infusion (DLI) are required. We describe a patient who relapsed with lymphoid blast crisis (BC) of chronic myelogenous leukemia (CML) more than 11 years after alloBMT for CML in myeloid BC at presentation.
Case report A 12-year-old male was admitted to our hospital with nasal bleeding in March 1987. Peripheral blood analysis revealed: hemoglobin, 11.1 g/dl; platelet count, 111 109/l and white
Correspondence: Dr H Moriwaki, First Department of Internal Medicine, Gifu University School of Medicine, 40 Tsukasa-machi, Gifu 5008705, Japan Received 16 November 2001; accepted 12 April 2002
blood cell count, 150 109/l. Bone marrow findings supported a diagnosis of myeloid BC of CML (Table 1). Treatment with busulfan and 6-mercaptopurine brought him into chronic phase (CP) of CML. In December 1988, he received an alloBMT for CP CML from his HLAidentical brother. The conditioning regimen consisted of busulfan 16 mg/kg orally and melphalan 180 mg/m2 intravenously. Methotrexate for prophylaxis of graft-versushost disease was discontinued by day 53 and the patient was followed for 4 years post-alloBMT. The patient had been well for over 11 years until March 2000, when he was readmitted to our hospital with nasal bleeding. Laboratory findings were as follows: white blood cell count, 3.7 109/l with 10% blasts; hemoglobin, 12.3 g/ dl and platelet count, 3.0 109/l. Terminal deoxynucleotidyl transferase was negative. Bone marrow findings suggested recurrent CML in lymphoid BC or de novo acute lymphoblastic leukemia (ALL) (Table 1). A FISH study was 71.6% positive (normal range o4.3%) for the bcr–abl fusion transcript. Both major and minor bcr–abl fusion transcripts were detected by reverse-transcription polymerase chain reaction (RT–PCR). The patient achieved complete remission (CR) on day 27 after the first half of reinduction chemotherapy, consisting of enocitabine, daunorubicin, 6-mercaptopurine, adriamycin, prednisolone, and vincristine. Cytogenetic analysis revealed that the Philadelphia (Ph1) chromosome had disappeared. The second half of reinduction chemotherapy, consisting of asparaginase and cyclophosphamide, was started from day 30. On day 43, the bcr–abl fusion transcript was 2.6% positive according to the FISH study, but obviously positive by RT-PCR. A short tandem repeat (STR) sequence marker on chromosome 18 that differed between donor and recipient was used to quantify mixed chimerism (Figure 1a–d). The ratio of recipient to donor cells calculated from electropherograms obtained from bone marrow smears at relapse in lymphoid BC of CML was 32%, suggesting that the leukemia cell was induced by host cell (Figure 1c). The ratio of recipient to donor cells in the peripheral blood on day 9 after reinduction chemotherapy, when blast cells had disappeared, was 0 with 90% confidence (Figure 1d).
Leukemia 11 years after alloBMT K Fukuno et al
212 Table 1
Bone marrow findings
Date Disease state Blast Promyelocyte MPO activity of the blast cells Immunophenotyping of the blast cells Chromosome
Short tandem repeat
March 1987 Myeloid BC of CML at onset
March 2000 Lymphoid BC of CML at relapse postBMT
25.5% 21.6% Positive Not done 46, XY, der (9) inv (9) (p11q13) t (9; 22) (q34;q11), der (22) t (9; 22)
66.5% 0.0% Negative CD10, 98.3%; CD13, 65.1%; CD19, 98.5%; CD20, 1.3%; CD33, 19.8%; CD34, 97.7%; HLA-DR, 96% 46, XY, der (9) inv (9) (p11q13) t (9; 22) (q34; q11), der (22) t (9; 22) in the five metaphases 46, XY, inv (9) (p11q13) in the 15 metaphases
Recipient’s original pattern
Mixed chimerism suggesting host cell leukemia
Abbreviations: BC, blast crisis; CML, chronic myelogenous leukemia; BMT, bone marrow transplant; MPO, myeloperoxidase.
Figure 1 Electropherograms for quantitative analysis of mixed chimerism using STR markers on chromosome 18. (a) Donor sample. (b) Recipient sample before first BMT (December, 1988), showing recipient’s original pattern. (c) Bone marrow sample at relapse post-BMT in lymphoid blast crisis of chronic myelogenous leukemia (8 March 2000), showing mixed chimerism. (d) Peripheral blood sample on day 9 after reinduction chemotherapy post-BMT, showing donor pattern.
The patient relapsed after the second course of consolidation chemotherapy. In December 2000, he received a second alloBMT from an HLA-identical unrelated donor, but then died of pneumonia and sepsis on day 4.
Discussion In diagnosing leukemia after alloBMT, the origin of the leukemic cells has to be determined in order to select an Bone Marrow Transplantation
appropriate therapeutic approach. The relative incidence of donor cell leukemia (DCL) and secondary leukemia increases with time after alloBMT. Five patients are considered to have developed DCL after alloBMT for CML.1 The leukemia (March 2000) was confirmed to be host cell leukemia by using STR sequences markers. A few primary leukemic cells that survived conditioning chemotherapy and escaped the GVL effect might have induced leukemic relapse, although chromosomal analysis did not identify any additional cytogenetic evolution such as trisomy 8 or an extra Ph1 chromosome. An immunophenotypic switch of the blast cells from myeloid at onset to lymphoid lineage at relapse postalloBMT might be related to oncogene alternations such as homozygous deletions of p16 tumor suppressor gene on chromosome 9p21 associated with lymphoid BC of CML.2,3 Electrophoresis identified fewer minor than major bcr– abl fusion transcripts at the time of lymphoid BC of CML. Although the p190 bcr–abl fusion transcript may correlate with transformation into BC of CML,4 Morgan et al5 described that its acquisition does not play a significant role in the generation of BC of CML. Lichty et al6 found that 35 of 67 patients with CML coexpressed p190 and p210, possibly because of alternative splicing. van Rhee et al7 frequently found p190 bcr–abl fusion transcripts at a low level in leukemias positive for p210 bcr–abl fusion transcripts including ALL. Therefore, the presence of this transcript is probably of no pathogenetic significance. Besides these hypotheses, the sensitivity of bcr–abl-positive stem cells to conditioning chemotherapy or the GVL effect have to be studied. This case illustrates the difficulties involved in determining the appropriate length of follow up after alloBMT. Radich et al8 described that PCR assay of the bcr–abl fusion transcript 6–12 months after BMT for CML is an independent predictor of subsequent relapse. However, minimal residual disease (MRD) in CML patients after alloBMT is not necessarily associated with relapse. van Rhee et al9 reported that two of the 19 patients with CML in first CP transplanted from HLA-identical sibling donors in remission for over 10 years had molecular evidence of persisting leukemic cells. The GVL effect may suppress persisting leukemic clones. A few CML patients with MRD will probably proceed to late relapse. To our knowledge, the longest period from alloBMT for CML to relapse is 14
Leukemia 11 years after alloBMT K Fukuno et al
years.10 CML patients who had increasing or persistently high bcr–abl fusion transcripts after alloBMT were likely to relapse.11 To identify patients at high risk of relapse in whom an established intervention such as DLI may be able to avert relapse,12 persisting or recurrent evidence of leukemia at the molecular level should be monitored by quantitative PCR for the bcr–abl fusion transcript. Although the patient had not been followed up between 4 and 11 years post-alloBMT, the lymphoid BC of CML after first alloBMT probably occurred without a preceding CP since the ratio of recipient to donor cells in quantitative analysis of mixed chimerism using STR sequences markers on day 9 after reinduction chemotherapy was already 0%. Further studies are required to elucidate the pathogenesis of late relapse after alloBMT.
References 1 Cooley LD, Sears DA, Udden MM et al. Donor cell leukemia: report of a case occurring 11 years after allogeneic bone marrow transplantation and review of the literature. Am J Hematol 2000; 63: 46–53. 2 Sill H, Goldman JM, Cross NC. Homozygous deletions of the p16 tumor-suppressor gene are associated with lymphoid transformation of chronic myeloid leukemia. Blood 1995; 85: 2013–2016. 3 Serra A, Gottardi E, Della Ragione F et al. Involvement of the cyclin-dependent kinase-4 inhibitor (CDKN2) gene in the pathogenesis of lymphoid blast crisis of chronic myelogenous leukaemia. Br J Haematol 1995; 91: 625–629.
213 4 Dhingra K, Talpaz M, Kantarjian H et al. Appearance of acute leukemia-associated p190 bcr–abl in chronic myelogenous leukemia may correlate with disease progression. Leukemia 1991; 5: 191–195. 5 Morgan GJ, Hernandez A, Chan LC et al. The role of alternative splicing patterns of BCR/ABL transcripts in the generation of the blast crisis of chronic myeloid leukaemia. Br J Haematol 1990; 76: 33–38. 6 Lichty BD, Keating A, Callum J et al. Expression of p210 and p190 bcr–abl due to alternative splicing in chronic myelogenous leukaemia. Br J Haematol 1998; 103: 711–715. 7 van Rhee F, Hochhaus A, Lin F et al. p190 bcr–abl mRNA is expressed at low levels in p210-positive chronic myeloid and acute lymphoblastic leukemias. Blood 1996; 87: 5213–5217. 8 Radich JP, Gehly G, Gooley T et al. Polymerase chain reaction detection of the bcr–abl fusion transcript after allogeneic marrow transplantation for chronic myeloid leukemia: results and implications in 346 patients. Blood 1995; 85: 2632–2638. 9 van Rhee F, Lin F, Cross NCP et al. Detection of residual leukemia more than 10 years after allogeneic bone marrow transplantation for chronic myelogenous leukaemia. Bone Marrow Transplant 1994; 14: 609–612. 10 Yong ASM, Goldman JM. Relapse of chronic myeloid leukaemia 14 years after allogeneic bone marrow transplantation. Bone Marrow Transplant 1999; 23: 827–828. 11 Lin F, van Rhee F, Goldman JM, Cross NCP. Kinetics of increasing bcr–abl transcript numbers in chronic myeloid leukemia patients who relapse after bone marrow transplantation. Blood 1996; 87: 4473–4478. 12 Kolb HJ, Schattenberg A, Goldman JM et al. Graft-versusleukemia effect of donor lymphocyte transfusions in marrow grafted patients. Blood 1995; 86: 2041–2050.
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