Secondary Logo

Journal Logo

Non-AIDS-defining hematological malignancies in HIV-infected patients: an epidemiological study in Japan

Hagiwara, Shotaroa; Yotsumoto, Mihokob; Odawara, Takashic; Ajisawa, Atsushid; Uehira, Tomokoe; Nagai, Hirokazuf; Tanuma, Junkog; Okada, Seijih

doi: 10.1097/QAD.0b013e32835a5a7a
Epidemiology and Social: CONCISE COMMUNICATION

Objective: To clarify the incidence and clinical outcomes of non-AIDS-defining hematological malignancies (NADHMs), excluding non-Hodgkin's lymphomas, in HIV-infected patients.

Design: A nationwide epidemiological study was conducted to evaluate the incidence and clinical outcomes of NADHMs.

Methods: Questionnaires were sent to 429 regional AIDS centers and 497 educational hospitals certified by the Japanese Society of Hematology. Data from 511 institutes were obtained.

Results: From 1991 to 2010, 47 patients with NADHMs were detected (median age, 42.0 years; male, 93.6%). The median CD4-positive T-cell count was 255/μl, and the median duration from the diagnosis of HIV infection to development of hematological malignancy was 28.0 months. Most patients with acute leukemia were treated with standard induction chemotherapy. Complete remission rates and median overall survival periods for acute myeloblastic leukemia (AML) and acute lymphoblastic leukemia (ALL) were 70.0 and 85.7% and 13 and 16 months, respectively. Three of four patients with chronic-phase chronic myeloid leukemia (CML-CP) were well controlled with imatinib. Five patients (2 AML, 1 ALL, 1 accelerated-phase CML, and 1 myeloma) were treated with autologous or allogeneic stem-cell transplantation. Comparison of patients over the two periods (1991–2000 and 2001–2009) revealed a 4.5-fold increase in the incidence of hematological malignancies.

Conclusion: The incidence of NADHMs has increased in the past decade. The prognosis of these patients was similar to that of HIV-negative patients; therefore, standard chemotherapy may be a feasible treatment option for HIV-infected patients with hematological malignancies.

aDivision of Hematology, Department of Internal medicine, National Medical Center for Global Health and Medicine

bDepartment of Laboratory Medicine, Tokyo Medical University

cDepartment of Infectious Diseases and Applied Immunology, The Institute of Medical Science, The University of Tokyo

dDivision of Infectious Disease, Tokyo Metropolitan Cancer and Infectious Diseases Center Komagome Hospital, Tokyo

eDepartment of Infectious Diseases, National Hospital Organization OsakaNational Hospital, Osaka

fDepartment of Hematology, National Hospital Organization Nagoya Medical Center, Nagoya

gAIDS Clinical Center, National Medical Center for Global Health and Medicine, Tokyo

hCenter for AIDS Research, Kumamoto University, Kumamoto, Japan.

Correspondence to Shotaro Hagiwara, MD, Grad Dip Clin Epid, PhD, Division of Hematology, Department of Internal Medicine, National Medical Center for Global Health and Medicine, 1–21–1 Toyama, Shinjuku, Tokyo 162–8655, Japan. Tel: +81 3 3202 7181; fax: +81 3 3207 1038; e-mail:

Received 1 June, 2012

Revised 4 September, 2012

Accepted 12 September, 2012

Back to Top | Article Outline


By the end of 2010, a total of 12 648 cases of HIV infection and 5799 cases of AIDS were reported in Japan [1]. The prevalence of HIV infection is estimated to be less than 0.1% [1]. However, the number of newly reported HIV-infected individuals has gradually increased, and the estimated number now ranges from 6300 to 10 000[1]. Most of the HIV-infected population in Japan is men [2]. The morbidity and incidence of infections has decreased as the introduction of highly active antiretroviral therapy (ART). The incidence of AIDS-defining malignancies has also decreased [3,4].

Although the incidence of AIDS-related non-Hodgkin's lymphoma (NHL) is decreasing, other hematological malignancies such as acute myeloid leukemia (AML), Hodgkin's lymphoma, and chronic myeloid leukemia (CML) are often reported. We conducted a nationwide epidemiological study to evaluate the incidence and clinical outcomes of non-AIDS-defining hematological malignancies (NADHMs), excluding NHL, in HIV-infected patients.

Back to Top | Article Outline


Most HIV-infected patients are followed in regional AIDS centers, and educational hospitals for hematologists cover most patients with hematological malignancies in Japan.

Questionnaires were sent to 429 regional AIDS centers, namely specialty clinical institutes for AIDS in each region certified by the Ministry of Health, Labor, and Welfare, and 497 educational hospitals certified by the Japanese Society of Hematology, namely training institutes for hematologists (207 of these institutions overlapped); in total, both the types of institutes will cover almost all the patients with HIV-related hematological malignancies in Japan. These institutes were requested to report all cases of hematological malignancies between 1991 and 2010, excluding NHL, in HIV-infected patients. We conducted a two-step inquiry. In the first step, all the institutes were required to answer the experience of NADHMs; if yes, the questionnaire was sent. The questionnaire included the date of diagnosis, subtype classification, chromosomal analysis, age, sex, CD4 count at the time of diagnosis, overall survival, treatment, response to treatment, date of relapse, and duration of ART.

Epidemiological data for HIV were acquired from the Joint United Nations program on HIV/AIDS (UNAIDS) [1]. The estimated size of the HIV-infected population in Japan was also based on the data from UNAIDS [1]. Data on AIDS and HIV estimates in Japan were available from 1990 to 2009. We calculated the crude incidence of NADHM from 1991 to 2009. Patient background and clinical data were analyzed using SPSS version 18.0 (IBM Japan, Inc., Tokyo, Japan).

Back to Top | Article Outline


Responses were obtained from 511 institutes (response rate, 71.1%).

Back to Top | Article Outline

Patient characteristics

From 1991 to 2010, 47 patients with NADHMs were reported by 21 institutes, including 19 patients with Hodgkin's lymphoma, 13 with AML, seven with acute lymphoblastic leukemia (ALL), four with CML [three chronic phase (CML-CP) and one accelerated phase (CML-AP)], two with multiple myeloma, one with chronic lymphoid leukemia (CLL), and one with myelodysplastic syndrome–refractory anemia with excess blast one. The median age of the patients was 42.0 years (range, 21–70 years), with 93.6% being male. The median CD4-positive T-cell count was 255/μl (range, 1–1371/μl), and the median HIV viral load was 55 copies/ml. The median duration from the diagnosis of HIV infection to development of hematological malignancy was 28.0 months (range, 0–204 months) (Table 1). Prior to diagnosis, 68.1% patients were treated with ART (mean duration, 27.2 months) and 51.1% had AIDS. The median observation period after the diagnosis of NADHMs was 20.0 months (range, 0–140 months).

Table 1

Table 1

Back to Top | Article Outline

Subtypes of leukemia/lymphoma and cytogenetic abnormalities

Varying numbers of subtypes of AML were identified as follows: FAB-M1, M2, M3, M4, and M5. Four of the 13 patients with AML exhibited a normal karyotype; three exhibited recurrent cytogenetic abnormalities such as t(8;21), t(15;17), and inv(16);and three exhibited complex karyotypic abnormalities. Four of the seven patients with AML possessed Burkitt leukemia/lymphoma-type cytogenetic abnormalities such as t(8;14) or t(8;22). Three of the four patients with CML and 1patient with ALL possessed the Philadelphia (Ph1) chromosome (Ph1-ALL).

In 19 patients with Hodgkin's lymphoma, mixed-cellularity classical Hodgkin's lymphoma was the most common subtype (68%). Immunostaining revealed that 89% of the patients were positive for Epstein–Barr virus.

Back to Top | Article Outline

Treatments and outcomes

Most patients with AML and ALL received standard combination chemotherapy (such as cytarabine + daunorubicin and L-asparaginase + adriamycin, vincristine, prednisolone, cyclophosphamide), and the response rates for AML and ALL were 70.0 and 85.7%, respectively. However, the relapse rates for AML and ALL were 62.5 and 50%, respectively. The median overall survival (OS) period was 13 and 16 months for AML and ALL, respectively. The symptoms of three of the four patients with CML-CP were well controlled with imatinib. Four patients (2 AML, 1 Ph1-ALL, and 1 CML-AP) were treated with allogeneic stem cell transplantation. One patient died because of acute graft-versus-host disease; however, three survived for more than 4 years. One patient with multiple myeloma was treated with autologous stem-cell transplantation without serious toxicity. Sixteen of the 19 patients with Hodgkin's lymphoma were treated with a combination of adriamycin, bleomycin, vinblastine, and dacarbazine or with radiation therapy. Eighty percent achieved complete remission. Details of treatments and outcomes of Hodgkin's lymphoma was described in another report [5].

Back to Top | Article Outline

Epidemiological analysis

There is an upward trend in the number of patients with NADHMs and the estimated number of HIV-infected patients [1] (Fig. 1). The estimated incidence of total NADHMs, Hodgkin's lymphoma, AML, ALL, and chronic leukemia (CLL, CML) was 32.6 (minimum–maximum, 27.2–41.3), 12.7(10.6–16.1), 8.0(6.6–10.1), 5.6 (4.6–7.1), and 4.0(3.3–5.0)/100 000 persons per year, respectively, between 1991 and 2009. The estimated crude incidence of total NADHMs increased 4.5-fold (4.3–5.4) from 1991–2000 to 2001–2009.

Fig. 1

Fig. 1

Back to Top | Article Outline


The present study aimed to clarify the epidemiological status of NADHMs in Japan. Our results showed an estimated crude incidence rate of leukemia (CLL, CML, ALL and AML) of 17.6 (14.5–22.2)/100 000 persons per year in estimated HIV-infected individuals in Japan, which is 2.2-fold higher than that of leukemia (ICD10, C91–95) in the general population [6]. In addition, the estimated incidence of NADHMs has increased 4.5-fold (4.3–5.4) over the past decade.

The introduction of ART has improved the immunological status of HIV-infected individuals and reduced the incidence of AIDS-defining malignancies; however, the incidence of non-AIDS-defining malignancies is increasing. Several studies on non-AIDS-defining solid tumors suggest that aging; concomitant viral infection, such as that with Epstein–Barr virus, human papilloma virus, hepatitis C virus, and hepatitis B virus; low CD4 T-cell count with long-term immune suppression; and smoking are the possible causes of cancer [7–10]. However, the reason for the increased incidence of NADHMs remains unknown.

Recent developments in ART and supportive therapy for HIV-infected patients help facilitate long-term survival. Generally, aging is a key factor in carcinogenesis. In this study, we found that the mean age of patients with NADHMs was 49.3 years and that more than 30% were more than 60 years old, which is consistent with overall cancer trend.

Immune suppression is thought to be a risk factor for non-AIDS-defining malignancies. Krishnan et al.[9] analyzed prospective data of 3158 ART-naïve HIV-infected individuals and found that a recent low CD4 T-cell count is associated with non-AIDS-defining malignancies. In the present study, more than half of the patients with NADHMs had prior AIDS and their median CD4 T-cell count was less than 200/μl, suggesting that a low CD4 T-cell count is common in patients with NADHMs and may be one of the risk factors.

Uncontrolled HIV viral load is considered to be a risk factor for both AIDS-defining and non-AIDS-defining malignancies [11,12], and HIV itself may play a role in the onset of cancer. The regulatory proteins Tat and Vpr, which are encoded by the HIV genome, may contribute to oncogenesis [13,14]. However, a study by the AIDS Therapy Evaluation in the Netherlands (ATHENA) cohort showed no significant effect of viremiaon non-AIDS-defining malignancies [15]. In the present study, the HIV viral load was well controlled in more than 50% patients. Careful discussion is required to assess the association between carcinogenesis and HIV infection.

Before being diagnosed with NADHMs, the majority of patients were treated with ART, with the median duration of treatment being less than 1 year. Antiretroviral drugs can affect hematopoiesis, and zidovudine-containing regimens induce myelosuppression and possibly carcinogenesis [16]. Even when the duration of exposure to ART is short, its contribution to the development of NADHMs cannot be excluded.

We found that HIV-infected patients suffered from a variety of hematological malignancies, with a spectrum of NADHMs similar to that of HIV-negative patients. Cytogenetic analysis revealed typical chromosomal abnormalities of both acute and chronic leukemia. Moreover, adverse karyotypic abnormalities such as complex karyotype and/or monosomy, seven in AML and Burkitt-type karyotypes in ALL were often present. In three patients with AML with adverse karyotype, the duration of ART was more than 24 months. Long-term exposure to ART may cause therapy-related cytogenetic abnormalities.

In the present study, most patients with acute leukemia were treated with standard combination chemotherapy, and no deaths due to therapy were observed. Therapy appeared to be well tolerated, and the remission rate was similar to that of HIV-negative patients. In retrospective analysis, Sutton et al.[17] reported no deaths related to treatment of HIV-related AML in France, with a remission rate of 73.3%. Long-lasting remission of leukemia is rare in HIV-infected patients [18]. In the present study, more than 50% of the patients relapsed or represented primary refractory cases. However, two patients with AML and two with ALL continued in complete remission for more than 5 years. In the study by Sutton et al.[17], the estimated 5-year OS of 18 patients with AML was 19.9%, with a median survival period of 11 months [18]. There are several case reports of HIV-infected patients who have undergone stem-cell transplantation [19–21]. Five patients were found in our survey; however; only one death related to this therapy was observed. We conclude that stem-cell transplantation appears to be a feasible treatment for selected patients.

To summarize, a nationwide epidemiological study in Japan revealed that HIV-infected patients are at high risk for hematological malignancies, and the incidence of these malignancies has increased in the past decade. The prognosis of HIV-infected patients was similar to that of HIV-negative patients. Standard chemotherapy may be a feasible treatment option for HIV-infected patients with hematological malignancies. Further study focusing on the mechanism of carcinogenesis in HIV-infected individuals is required.

Back to Top | Article Outline


We are grateful to the following people for their contribution to this study: Dr Takeshi Fujii, The University of Tokyo, The Institute of Medical Science; Dr Satoshi Higasa, Hyogo College of Medicine; Dr Haruko Tashiro, Teikyo University School of Medicine; Dr Akifumi Takaori, Graduate School of Medicine, Kyoto University; Dr Kiyonori Takada, Ehime University Graduate School of Medicine; Dr Takuya Komeno, Mito Medical Center; Dr Naoki Kurita, Faculty of Medicine, University of Tsukuba; Dr Tomiko Ryu, Social Insurance Chuo General Hospital; Dr Hideki Akiyama, Tokyo Metropolitan Cancer and Infectious Disease Center Komagome Hospital; Dr Michihiro Hidaka, National Hospital Organization Kumamoto Medical Center; Dr Yuko Fujikawa, Saku Central Hospital; Dr Shun-ichi Maeda, Hachinohe City Hospital; Dr Kiyoshi Kitano, National Hospital Organization Matsumoto Medical Center; Dr Nobuyoshi Arima, Kitano Hospital; Dr Kenji Uno, Nara Medical University; Dr Toshiki Iwai, Japanese Red Cross Kyoto Daiichi Hospital; Dr Sadamu Okada, St Luke's International Hospital; and Dr Igen Hongo, Japanese Red Cross Musashino Hospital.

This study was supported by a Health and Labour Sciences Research Grant from the Ministry of Health, Labour, and Welfare of Japan (Grant number: H22-AIDS-002).

Back to Top | Article Outline

Conflicts of interest

The authors have no conflicts of interest.

Back to Top | Article Outline


1. UNAIDS. Report on the Global AIDS Epidemic-2010. [Accessed on 23 November 2010].
2. Committee of AIDS Trends, Ministry of Health, Labour and Welfare. Trend of AIDS incidence in Japan, Annual Report. Tokyo, Japan: Ministry of Health, Labour and Welfare; 2011.
3. Polesel J, Clifford GM, Rickenbach M, Dal Maso L, Battegay M, Bouchardy C, et al. Non-Hodgkin lymphoma incidence in the Swiss HIV Cohort Study before and after highly active antiretroviral therapy. AIDS 2008; 22:301–306.
4. Biggar RJ, Jaffe ES, Goedert JJ, Chaturvedi A, Pfeiffer R, Engels EA. Hodgkin lymphoma and immunodeficiency in persons with HIV/AIDS. Blood 2006; 108:3786–3791.
5. Yotsumoto M, Hagiwara S, Ajisawa A, Tanuma J, Uehira T, Nagai H, et al. Clinical characteristics of human immunodeficiency virus-associated Hodgkin lymphoma patients in Japan. Int J Hematol 2012; 96:247–253.
6. Matsuda T, Marugame T, Kamo KI, Katanoda K, Ajiki W, Sobue T. Cancer Incidence and incidence rates in Japan in 2006: based on data from 15 Population-based cancer registries in the monitoring of cancer incidence in Japan (MCIJ) project. Jpn J Clin Oncol 2012; 42:139–147.
7. Kirk GD, Merlo CA. HIV infection in the etiology of lung cancer: confounding, causality, and consequences. Proc Am Thorac Soc 2011; 8:326–332.
8. Shiels MS, Cole SR, Kirk GD, Poole C. A meta-analysis of the incidence of non-AIDS cancers in HIV-infected individuals. J Acquir Immune Defic Syndr 2009; 52:611–622.
9. Krishnan S, Schouten JT, Jacobson DL, Benson CA, Collier AC, Koletar SL, et al. Incidence of non-AIDS-defining cancer in antiretroviral treatment-naive subjects after antiretroviral treatment initiation: an ACTG longitudinal linked randomized trials analysis. Oncology 2011; 80:42–49.
10. Hu J, Ludgate L. HIV-HBV and HIV-HCV coinfection and liver cancer development. Cancer Treat Res 2007; 133:241–252.
11. Ferry T, Raffi F, Collin-Filleul F, Dupon M, Dellamonica P, Waldner A, et al. Uncontrolled viral replication as a risk factor for non-AIDS severe clinical events in HIV-infected patients on long-term antiretroviral therapy: APROCO/COPILOTE (ANRS CO8) cohort study. J Acquir Immune Defic Syndr 2009; 51:407–415.
12. Zoufaly A, Stellbrink HJ, Heiden MA, Kollan C, Hoffmann C, van Lunzen J, et al. Cumulative HIV viremia during highly active antiretroviral therapy is a strong predictor of AIDS-related lymphoma. J Infect Dis 2009; 200:79–87.
13. Nakai-Murakami C, Minemoto Y, Ishizaka Y. Vpr-induced DNA double-strand breaks: molecular mechanism and biological relevance. Curr HIV Res 2009; 7:109–113.
14. De Falco G, Bellan C, Lazzi S, Claudio P, La Sala D, Cinti C, et al. Interaction between HIV-1 Tat and pRb2/p130: a possible mechanism in the pathogenesis of AIDS-related neoplasms. Oncogene 2003; 22:6214–6219.
15. Kesselring A, Gras L, Smit C, van Twillert G, Verbon A, de Wolf F, et al. Immunodeficiency as a risk factor for non-AIDS-defining malignancies in HIV-1-infected patients receiving combination antiretroviral therapy. Clin Infect Dis 2011; 52:1458–1465.
16. Ayers KM, Clive D, Tucker WE Jr, Hajian G, de Miranda P. Nonclinical toxicology studies with zidovudine: genetic toxicity tests and carcinogenicity bioassays in mice and rats. Fundam Appl Toxicol 1996; 32:148–158.
17. Sutton L, Guenel P, Tanguy ML, Rio B, Dhedin N, Casassus P, et al. Acute myeloid leukaemia in human immunodeficiency virus-infected adults: epidemiology, treatment feasibility and outcome. Br J Haematol 2001; 112:900–908.
18. Aboulafia DM, Meneses M, Ginsberg S, Siegel MS, Howard WW, Dezube BJ. Acute myeloid leukemia in patients infected with HIV-1. AIDS 2002; 16:865–876.
19. Tomonari A, Takahashi S, Shimohakamada Y, Ooi J, Takasugi K, Ohno N, et al. Unrelated cord blood transplantation for a human immunodeficiency virus-1-seropositive patient with acute lymphoblastic leukemia. Bone Marrow Transplant 2005; 36:261–262.
20. Sora F, Antinori A, Piccirillo N, De Luca A, Chiusolo P, Cingolani A, et al. Highly active antiretroviral therapy and allogeneic CD34(+) peripheral blood progenitor cells transplantation in an HIV/HCV coinfected patient with acute myeloid leukemia. Exp Hematol 2002; 30:279–284.
21. Oka Y, Tashiro H, Mizutani-Noguchi M, Koga I, Sugao T, Shirasaki R, et al. Successful unrelated bone marrow transplantation for a human immunodeficiency virus type-1-seropositive acute myelogenous leukemia patient following HAART. Int J Hematol 2010; 91:140–145.

epidemiological study; HIV; leukemia; lymphoma; non-AIDS-defining hematological malignancy

© 2013 Lippincott Williams & Wilkins, Inc.