Secondary acute myeloid leukemia after double autologous hematopoietic stem cell transplantation for peripheral T-cell non-Hodgkin’s lymphoma: a case report

Introduction
Therapy-related acute myeloid leukemia (t-AML) after either conventional-dose regimens or high-dose chemotherapy (HD) followed by autologous hematopoietic stem cell transplantation (AHSCT) for non-Hodgkin’s lymphoma (NHL) is an important problem. The risk of t-AML is varied and it is thought to be higher after HD-AHSCT as compared to the risk after standard therapy [1].

Case report
A 46-year-old female was admitted to our hospital in June 2000 because of a 2-month history of increasing weakness and night sweats. On physical examination a general lymphadenopathy and hepatosplenomegaly were present. Ultrasonography revealed enlarged lymph nodes in the abdomen. The chest X-ray was normal. The histopathological examination of a node surgically taken from her neck revealed peripheral T-cell NHL. Bone marrow was occupied by lymphoma cells in 50%. The white blood cell count (WBC) was elevated – 23.7 x 10⁹/l with 80% of segmented neutrophils in differential. The biochemical tests were normal except for lactate dehydrogenase (LDH – 555 IU). The clinical stage was determined as IV and IPI was 3. A combination chemotherapy was started and after 6 cycles of CHOP, the patient achieved a complete remission (CR). The first autologous bone marrow transplantation (ABMT) was performed in December 2000 using carmustine (BCNU), cyclophosphamide (CTX) and etoposide (VP-16) (CBV regimen for consolidation). The bone marrow was harvested after G-CSF administration for 3 days at 0.9 mg. CR remained for 3 months. The first relapse occurred in February 2001, with lymph node involvement at primary localization. The WBC count was elevated with predominance of mature neutrophils. Bone marrow was disease-free. The patient was given cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP 2x) and CHOP with bleomycin (3x) with CR2 in May 2001. The second autologous peripheral blood stem cell transplantation (PBSCT) was performed in September 2001, after stem cell mobilization with ifosfamide, etoposide and epirubicin (IVE regimen). Conditioning consisted of total body irradiation (TBI) and cyclophosphamide. One year later a second relapse occurred with a general lymphadenopathy and enlargement of lymph nodes in mediastinum. The WBC count was again markedly increased but this time the immature granulocytic cells (promyelocytes and myelocytes) were present. The cytogenetic analysis did not reveal chromosome Philadelphia. BCR/ABL oncogene was negative. She was administered cyclophosphamide, mitoxantrone, vincristine and prednisone (CMOP 4x) and vinblastine with prednisone (5x) with CR3 in June 2003. Three months later the patient was referred to our hospital in a poor general condition, with fever up to 40 degrees and clinical symptoms of pneumonia. There were no enlarged lymph nodes. The WBC count varied from 108 up to 300 x 10⁹/l with 70% of myelomonoblasts. Surface-marker immunophenotyping of the leukemia cells showed positive results for CD13, CD15, CD33, CD34, CD117, CD133 and HLA-DR. There were no metaphases and chromosomal analysis could not be performed. Taking into consideration the results obtained from cytological and cytochemical exams and the expression of antigens on leukemic cells, we diagnosed AML (M4 FAB). She did not respond to chemotherapy and died of myocardial infarction in October 2003. On autopsy there was no evidence of lymphoma.

Discussion
Therapy-related AML is usually resistant to chemotherapy and has a very poor prognosis [1]. Up to 10% of NHL patients treated with either conventional-dose chemotherapy or HD-AHSCT may develop secondary malignancies within 10 years [2]. The median time from AHSCT to onset of t-AML is reported to be 31 to 44 months [3], but in almost 30% of patients that period is shorter and malignancy occurs within 12 months or earlier [1]. An analysis performed by Krishnan et al. on 612 patients with NHL who had undergone HD-AHSCT revealed priming with etoposide for stem cell collection to be associated with an increased risk of t-AML [4]. Most studies underscore the influence of high-dose alkylating agents and topoisomerase II inhibitors on the occurrence of secondary malignancies. An increased risk of developing t-AML is also found for conditioning with total body irradiation at doses 13.2 Grey [5].

The total doses of chemotherapeutic agents given to our patient were as follows: cyclophosphamide – 30400 mg, ifosfamide – 30000 mg, etoposide – 5000 mg, doxorubicin – 1000 mg, vincristine – 30 mg, bleomycin – 45 mg, mitoxantrone – 80 mg, vinblastine – 120 mg, cytarabine – 680 mg and carmustine – 700 mg. Accumulation of high-dose etoposide together with alkylating drugs, TBI used as conditioning and age of over 40 years at the time of AHSCT might be related to the onset of secondary AML in that case. It was proven that exposure to topoisomerase II inhibitors is associated with monocytic (M4 and M5) phenotype of acute leukemia. It is also likely that growth-factor therapy used routinely in our patient may facilitate the selection of aberrant progenitors [4, 6].
Taking into consideration the whole disease course we noticed that the elevated WBC count (varied between 20 and 30 x 10⁹/l) persisted during the whole observation. It dropped after chemotherapy and then it was gradually increasing, being elevated before the next cycle. At diagnosis we noted the prevalence of segmented cells, but then the increased proportion of immature granulocytes was present in peripheral blood and bone marrow. We assume it may reflect an abnormal immune response that is due to a variety of cytokines as it was described for Hodgkin’s lymphoma [7]. The coexistence of lymphoma with chronic neutrophilic leukemia is less likely.
References
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Kroll S. Treatment-related myelodysplasia and acute leukemia
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4. Krishnan A, Bhatia S, Slovak ML, et al. Predictors of therapy-related leukemia and myelodysplasia following autologous transplantation for lymphoma: an assessment of risk factors. Blood 2000; 95 (5): 1588-93.
5. Metayer C, Curtis RE, Vose J, et al. Myelodysplastic syndrome and acute myeloid leukemia after autotransplantation for lymphoma: a multicenter case-control study. Blood 2003; 101 (5): 2015-23.
6. Deeg HJ, Socie G. Malignancies after hematopoietic stem cell transplantation: many questions, some answers. Blood 1998; 91 (6): 1833-44.
7. Skinnider BF, Mak TW. The role of cytokines in classical Hodgkin lymphoma. Blood 2002; 99 (12): 4283-97.
Correspondence
dr med. Grzegorz Helbig
Klinika Hematologii i Transplantacji Szpiku
Śląska Akademia Medyczna
ul. Reymonta 8
40-029 Katowice
tel. +48 32 259 12 81
fax +48 32 255 49 85
e-mail: ghelbig@tlen.pl