Leukemia & Lymphoma, June 2011; 52(S2): 38–42
Purine analog toxicity in patients with hairy cell leukemia
TAMAR TADMOR Hematology–Oncology Unit, Bnai-Zion Medical Center, Haifa, Israel
Abstract The introduction of cladribine and pentostatin for the treatment of hairy cell leukemia (HCL) has dramatically altered the natural history of the disease, and a single course of cladribine given as a subcutaneous injection for 7 days induces complete remission in the majority of patients. A systematic evaluation of the immediate and long-term side effects induced by purine analogs reveals that most of the available information relates to fludarabine, and mostly refers to the use of this agent in the treatment of indolent lymphoproliferative disorders (LPDs) and and chronic lymphocytic leukemia (CLL). Surprisingly, although purine analogs have been used for more than 30 years in the treatment of HCL, there are still not many reports on the toxicity of pentostatin and cladribine other than the early therapy-induced toxicity encountered in the initial management of patients. Only a few studies have evaluated the long-term adverse effects of purine analogs on the immune system or stem cell toxicity, and most of these are not very recent. In addition, the issue of the prevalence of secondary malignancy linked with the therapy of HCL still remains controversial. In this review the available data on cladribine and pentostatin toxicity in the treatment of HCL are summarized, emphasizing immune suppression, stem cell toxicity, and possible correlation with the development of second malignancy. Other rare toxicities are also described, and the special conditions that need to be taken into account when starting treatment for patients with HCL are also considered.
Keywords: Hairy cell leukemia, purine analogs, stem cell toxity, second malignancy Introduction
A variety of different intrinsic immune abnormalities have been identified in the past in untreated patients with hairy cell leukemia (HCL) prior to receiving therapy [1–6]. This pre-existing immune deficiency status will be further complicated after therapy with purine analogs, a category of drugs that are well known for their immunosuppressive effects. In order to understand more clearly what the immune defects induced by pentosatatin and cladribine are, the pre- existing immune aberrations that are characteristi- cally encountered in patients with HCL at the time of diagnosis and before therapy are first summarized in Table I. Thereafter the issues relating to immuno- deficiencies induced by the purine analogs are addressed.
Immune suppression induced by pentostatin
Pentostatin causes irreversible inhibition of adeno- sine deaminase (ADA), an enzyme found in the highest concentrations in lymphoid cells. T cells have
higher levels of ADA enzyme than B cells, which is the reason for the undesirable T cell immune- suppression after the use of the drug. The biological effects of ADA deficiency on the immune system are profound, and it is well recognized that children with congenital absence of ADA develop atrophy of their lymphoid tissues and combined immune deficiency syndrome. Although pentostatin achieves high rates of complete remission (CR) in HCL and was the first purine analog used in HCL, introduced as early as 1979 by the Ohio State group, only a very few studies evaluated the effect of the drug on the immune system in patients with HCL [7–12]. In 1989, Urba et al. reported a detailed investiga-
tion of the immune function in 13 patients with HCL receiving pentostatin alone or pentostatin followed by interferon a (IFNa) [7]. The initial numbers of
CD4þ and CD8þ cells at the time of HCL presentation were seen to be within normal limits in most patients. However, subsequent treatment with the purine analog resulted in lymphopenia,
decreasing especially the numbers of CD4þ and CD8þ lymphocytes to such a critical level that all
Correspondence: Tamar Tadmor, Bnai-Zion Medical Center, Golomb 47 Street, Haifa, Israel 31048. Tel: þ97248359407. Fax: þ97248359962. E-mail:
Tamar.tadmor@b-zion.org.il
ISSN 1042-8194 print/ISSN 1029-2403 online 2011 Informa UK, Ltd. DOI: 10.3109/10428194.2011.565097
Page 1 |
Page 2 |
Page 3 |
Page 4 |
Page 5 |
Page 6 |
Page 7 |
Page 8 |
Page 9 |
Page 10 |
Page 11 |
Page 12 |
Page 13 |
Page 14 |
Page 15 |
Page 16 |
Page 17 |
Page 18 |
Page 19 |
Page 20 |
Page 21 |
Page 22 |
Page 23 |
Page 24 |
Page 25 |
Page 26 |
Page 27 |
Page 28 |
Page 29 |
Page 30 |
Page 31 |
Page 32 |
Page 33 |
Page 34 |
Page 35 |
Page 36 |
Page 37 |
Page 38 |
Page 39 |
Page 40 |
Page 41 |
Page 42 |
Page 43 |
Page 44 |
Page 45 |
Page 46 |
Page 47 |
Page 48 |
Page 49 |
Page 50 |
Page 51 |
Page 52 |
Page 53 |
Page 54 |
Page 55 |
Page 56 |
Page 57 |
Page 58 |
Page 59 |
Page 60 |
Page 61 |
Page 62 |
Page 63 |
Page 64 |
Page 65 |
Page 66 |
Page 67 |
Page 68 |
Page 69 |
Page 70 |
Page 71 |
Page 72 |
Page 73 |
Page 74 |
Page 75 |
Page 76 |
Page 77 |
Page 78 |
Page 79 |
Page 80 |
Page 81 |
Page 82 |
Page 83 |
Page 84 |
Page 85 |
Page 86 |
Page 87 |
Page 88 |
Page 89 |
Page 90 |
Page 91 |
Page 92 |
Page 93 |
Page 94 |
Page 95 |
Page 96 |
Page 97 |
Page 98 |
Page 99 |
Page 100 |
Page 101 |
Page 102 |
Page 103 |
Page 104 |
Page 105 |
Page 106 |
Page 107 |
Page 108 |
Page 109 |
Page 110 |
Page 111 |
Page 112 |
Page 113 |
Page 114 |
Page 115 |
Page 116 |
Page 117 |
Page 118 |
Page 119 |
Page 120 |
Page 121 |
Page 122