Bone Marrow Transplantation (2006) 37, 897–898 & 2006 Nature Publishing Group All rights reserved 0268-3369/06 $30.00
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LETTER TO THE EDITOR
Granulocytic sarcoma and subsequent acute leukemia recurrence with different biologic characteristics 5 years after allogeneic bone marrow transplantation for acute myeloid leukemia Bone Marrow Transplantation (2006) 37, 897–898. doi:10.1038/sj.bmt.1705344; published online 20 March 2006
A 25-year-old male with good cytogenetic risk and aberrant phenotype acute myeloid leukemia (AML) received an allogeneic transplantation from an HLA-matched sibling after an ablative conditioning regimen, achieving complete remission (CR) and full donor chimerism. He remained in CR for 2 years until a localized mammarian relapse occurred. This was treated by surgical excision. A PCR on bone marrow (BM) showed full donor chimerism. Two years later, he had a second localized relapse (inguinal adenopathy) again in the presence of full donor chimerism, and this was treated by excision alone. One year later, the patient suffered a new relapse as granulocytic sarcoma, with different characteristics compared to the initial phenotype. This was treated by radiotherapy and two fludarabine-based polychemotherapy schemes, and he received a second allograft from the same donor. Disease was refractory to treatment and the patient died of systemic aspergillosis. In February 1998, a 25-year-old male presented with pancytopenia; BM aspirate and peripheral blood (PB) smears showed infiltration of 91% mieloperoxidase (MPO)- and alpha naphtyl esterase (a-NE)-negative blastic cells. Karyotype was 46XY, t(8,21) and molecular assays showed AML1-ETO expression. Immunophenotype was CD7 þ , HLA-DR þ , CD34 þ , CD33 þ and CD13 þ . Diagnosis of AML, FAB classification M0, with a good cytogenetic risk but aberrant phenotype was made. Chest and back X-ray, abdomen and soft tissue sonogram were negative. The patient was treated with a chemotherapy induction scheme 3 þ 7 (idarubicine 12 mg/m2, days 1–3 and cytarabine 150 mg/m2, days 1–7) obtaining hematological CR but with persistence of minimal residual disease (MRD). Then, he achieved molecular CR after a consolidation scheme 3 þ 3 þ 5 (idarubicine 12 mg/m2 once daily on days 1–3; cytarabine 200 mg/m2 once daily on days 1–5 and etoposide 150 mg/m2 once daily on days 1–3). Next, he underwent an allogeneic BMT from a sibling donor (38-year-old female, ABO-matched, Rh mismatched, CMV positive) after conditioning regimen with busulfan (4 mg/kg p.o. in divided doses daily for 4 days, total dose 16 mg/kg) and cyclophosphamide (60 mg/kg in divided doses daily on days 5 and 6, total dose 120 mg/kg).
Cyclosporine and methotrexate (15 mg/m2 day 1, 10 mg/m2 days 3 and 6) were administered for GVHD prophylaxis. A total of 2.46 106 unmanipulated peripheral CD34 þ cells/kg were reinfused. Engraftment occurred at day þ 15. The patient maintained hematological and molecular CR with full donor chimerism until May 2000, when he presented a mammary gland nodule. Biopsy documented an AML relapse with the same features as those presented at diagnosis including AML1-ETO expression. Bone marrow aspirate was negative for blasts infiltration and AML1-ETO expression, and PCR analysis showed full donor chimerism. Soft tissue and abdominal sonogram were negative for any localization. In April 2002, a second relapse occurred, again as an AML1-ETO-positive granulocytic sarcoma, localized on the left leg. Bone marrow analysis confirmed molecular CR and full donor chimerism. Even this time, there were no other disease localizations and the lesion was treated with surgical excision. In March 2003, he experienced a new lesion in the same area as in the second relapse. Biopsy showed myeloid blast infiltration again. Biological characteristics were different: AML1-ETO was not detected, MPO was positive and c-kit was hyperexpressed by reverse transcriptase-PCR assays. Donor DNA percentage amounted to 69%; BM samples did not show blasts infiltration and full chimerism was present. The patient was then treated with local RT (total dose 40 cGy) and STI-571 400 mg daily (based on c-kit expression). Six months later, he presented with extensive lymphedema of left leg and scrotum. Doppler sonogram was negative for venous thrombosis. Abdominal nuclear magnetic resonance showed a bulky mass pressing on the iliac veins and ureter. Biopsy showed AML-ETO-negative granulocytic sarcoma. At this time, blasts infiltrated BM, karyotype was complex (88–91 chromosomes) and MPO (10%) and a-NE (80%) were positive; donor chimerism decreased to only 18%. Blood smears showed peripheral blastosis (50%). The patient was treated with new induction scheme (FLANG: fludarabine 10 mg/m2 daily on days 1–3; cytarabine 1000 mg/m2 daily on days 1–3 and novantrone 10 mg/m2 daily on days 1–3). Clinical condition improved, with decreased edema, but any hematological response was achieved, and soon lymphedema increased. A new polychemotherapy (FLAG: fludarabine 30 mg/m2 daily on days 1–5; cytarabine 2000 mg/m2 daily on days 1–5 and idarubicine 8 mg/m2 daily on days 1–3) was started after
Letter to the Editor
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which the patient underwent reinfusion of 2.19 106 CD34 þ donor marrow cells. During neutropenia, he developed fever, which was refractory to antibiotics. Bronco-alveolar aspiration showed the presence of aspergillus flavus. A CT scan confirmed the presence of a pulmonary nodule. Patient died of septic shock, 6 years after diagnosis and BMT. Our patient had a good-risk leukemia according to karyotype, but considering phenotypic aberration and donor availability, a transplant was performed. He did not develop acute GVHD and a full donor chimerism on marrow was achieved. He suffered three relapses as granulocytic sarcoma without BM or PB involvement: two of them showed the biological pattern of diagnosis, whereas the last one had different characteristics; owing to chronic GVHD presence at relapse, a donor lymphocyte infusion was not performed. Isolated relapse has already been observed after BMT1 and this suggests that GVL on leukemic cells present in (or migrating to) peripheral tissues may be less relevant than graft versus hematopoiesis or that its action may be more prevalent in BM than other sites. Moreover, a full chimerism status may not be predictive of absence of MRD and it does not appear to protect from extramedullary relapse.2 In the last relapse, the biological characteristics were different, showing a near-tetraploid leukemia clone. It may suggest a parallel extramedullary leukemic development independent of the AML-ETO1-positive clone. The t(8,21) clone was sensitive to both chemotherapy and the immunological effect of GVL after transplant, whereas the new clone was completely resistant, as shown by disease progression, diffusion and marrow involvement. Probably, the worst clone evolved over time with a new mutation, giving it proliferative advantage. Other cases of neartetraploid acute leukemia have been described in association with t(8;21),3,4 CD7 expression,5 such as in our patient, and granulocytic sarcoma.6 This suggests a biological relationship and a possible ‘natural’ evolution of this clone. The disappearance of AML/ETO rearrangement in the new clone could suggest that a ‘pre-leukemic’ clone without this translocation was persistent in the patient and the ‘second hitch’ was different in the final relapse compared to the original disease. If this is the case, our report confirms the hypothesis of the multi-step pathogenesis of AML and suggests that the translocation 8;21 is a final evolution of a
Bone Marrow Transplantation
clone that is particularly exposed to further mutations. Finally, this case confirms the poor prognosis of relapse after BMT and suggests the use of an aggressive approach also in a localized relapse, such as a granulocytic sarcoma.
Acknowledgements We thank Alison Frank for revising our manuscript.
M Pelosini, E Benedetti, S Galimberti, F Caracciolo, M Petrini, R Fazzi, F Andreazzoli and F Papineschi Hematology and Bone Marrow Transplantation Unit, Department of Oncology, Transplantation and New Technology in Medicine, University of Pisa, Pisa, Italy E-mail:
[email protected]
References 1 Ismail OK, Berksoy S, Semra P, Banu K. Granulocytic sarcoma of the heart: extramedullary relapse of acute myeloblastic leukemia after allogeneic stem cell transplantation successfully treated by chemotherapy alone. Leuk Lymphoma 2005; 46: 1081–1084. 2 Galimberti S, Benedetti E, Morabito F, Petrini I, Battola B, Papineschi F. Different gamma/delta T clones sustain GVM and GVH effects in multiple myeloma patients after non myeloablative transplantation. Leuk Res 2006; 30: 529–535. 3 Xiao Z, Liu S, Liu X, Yu M, Hao Y. Tetraploidy or neartetraploidy clones with double 8;21 translocation: a nonrandom additional anomaly of acute myeloid leukemia with t(8;21)(q22;q22). Haematologica 2005; 90: 413–414. 4 Xue Y, He J, Wang Y, Guo Y, Xie X, He Y. Secondary nearpentaploidy and/or near-tetraploidy characterized by the duplication of 8;21 translocation in the M2 subtype of acute myeloid leukemia. Int J Hematol 2000; 71: 359–365. 5 Yamamoto K, Nagata K, Kida A, Tsurukubo Y, Hamaguchi H. CD7+ near-tetraploid acute myeloblastic leukemia M2 with double t(8;21)(q22;q22) translocations and Aml1/ETO rearrangements detected by fluorescence in situ hybridization analysis. Int J Hematol 2001; 74: 316–321. 6 Au WY, Ma SK, Chan AC, Liang R, Lam CC, Kwong YL. Near tetraploidy in three cases of acute myeloid leukemia associated with mediastinal granulocytic sarcoma. Cancer Genet Cytogenet 1998; 102: 50–53.
