40
T. Tadmor
lymphocytes reached a nadir of 92/mL (normal: 270– 1600/mL), but at a median period of 23 months after
therapy CD8þ counts were not significantly different from the baseline levels recorded before therapy [10].
Although a similar degree of CD4þ lymphocytopenia is known to be associated with a markedly enhanced risk of opportunistic infections, none of these patients reported major infectious episodes [10]. Juliusson et al. [11] characterized an extensive set of lymphocyte markers by flow cytometry, at different time points of treatment with cladribine. Analyses were performed in 75 patients with HCL before therapy, at the time of nadir, after 3 and 6 months, and after 1 and 2 years. In addition to enhanced T cell depletion, they also evaluated the effect of this agent on B cells, and showed that that the decrease in
the numbers of CD20þB cells lasted for 1–2 years [11]. However CD23þB cells reconstituted faster, and CD10þB cells were already seen in the bone marrow at the end of therapy, indicative of regenera-
tion of progenitor B cells early after therapy [11]. Another study by Schirmer et al. evaluated eluted T cells and NK cells from patients after treatment for HCL with cladribine and showed that impaired NK cell function and high soluble interleukin-2 receptor (sIL-2R) serum levels, evident in active disease, returned to normal limits within 2 months of therapy [12]. In summary, after therapy with both pentostatin and cladribine, there is significant impairment in the
T cell pool, particularly of CD4þ cells.Opportunistic infections tend to occur very early after therapy when patients are neutropenic, but are relatively rare despite the low CD4 numbers. Prolonged B cell depletion is also observed while the number and function of NK cells, granulocytes, and monocytes return to normal after treatment. Therefore it is evident that both these agents are not selective for HCL cells alone but clearly affect normal leukocytes and other cells of the immune system.
Secondary malignancy in hairy cell leukemia: possible correlation with purine analogs
Data on this topic are controversial and complex. Treatment with purine analogs for patients with HCL appears to be associated with an increased risk of secondary cancer as reported in some, but not all studies [13–18]. Some reports showed an increased incidence of solid tumors, while others described increases in hematopoietic malignancies. Revision of biopsies in some reports revealed some cases of HCL misdiagnosed as lymphoma, myeloma, and lymphoid leukemia. Accordingly it is indeed possible that in some of these cases, residual HCL disease may have been wrongly interpreted as a secondary lymphoproliferative disorder (LPD). Furthermore, another limitation of these studies relates to the fact that most of the reports describe small patient cohorts with a short median follow-up. In addition, different centers used different purine analogs and at different dosages, with or without IFNa, while some patients included underwent splenectomy and others not. All the above make interpretation of prevalence data difficult and more complex. Another important issue to be considered in these patients relates to whether there is an inherent predisposition to second cancers, probably due to immune dysfunction associated with HCL [13–18]. A summary of selected studies analyzing the
correlation of second malignancy in patients with HCL treated with purine analogs and their conclu- sions is presented in Table II.
Stem cell toxicity due to purine analog treatment
Manifestations of stem cell toxicity including diffi- culties in stem cell mobilization have started to emerge in patients with chronic lymphocytic leuke-
Table II. Correlation of second malignancy in patients with HCL treated with purine analogs. No. of pts with
Number of pts;
Authors Au et al.
Flinn et al.
Hisada et al. Else et al.
Ref. period of follow-up Therapy used
[16] 117 pts; 20 years 65 IFNa; 23 splenectomy; 24 pentostatin; 67 cladribine
Cheson et al. [17] 979 pts; 52 months Cladribine [15] 154 pts; 9.3 years Pentostatin
Federico et al. [13] 1022 pts; 6.1 years IFNa/splenctomy; 39 purine analogs
[14] 3104 pts; 6.5 years Not specified [18] 233 pts; 16 years 188 pentostatin; 45 cladribine 31 pts HCL, hairy cell leukemia; pts, patients; IFNa
2nd tumors; median time for their diagnosis
21 pts; 40 months 52 pts; 11.7 months
25 pts; 4.1 years 54 pts
Increased incidence of secondary tumors?
Yes (but-not related to therapy)
Yes (requires additional evaluation)
No
No (small no. of pts treated with purine analogs)
Yes No
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