HCL Meeting 2010
mia (CLL) treated with purine analogs, mostly due to therapy with fludarabine. A recent study in CLL showed that there may be a problem in stem cell harvesting in cladribine treated patients [19]; how- ever, this is not really an issue here as stem cell collection is not performed for HCL considering that bone marrow transplant is not part of the therapeutic repertoire for this disease. Only sporadic case reports of myelodysplastic
syndromes/acute myeloid leukemia (MDS/AML) have been reported after therapy with purine analogs for HCL [20,21]. A total of 11 reported cases of MDS/leukemia have been described in the literature, five of which were after purine analog treatment. New data are emerging on secondary MDS/AML in patients with LPDs after treatment with fludarabine- containing regimens, but this is not relevant in HCL [22]. In this respect, further investigation is still needed, and it is possible that cytogenetic studies may need to be performed earlier after therapy with purine analogs, in order to identify specific chromo- somal aberrations as evident in secondary leukemias after alkylating agents and etoposide, particularly in patients who show more prolonged cytopenias after therapy. There is a an unexpectedly relatively high
incidence of hypoplastic/aplastic foci seen in bone marrow biopsies in patients with HCL in remission following therapy with cladribine, and the duration of this finding and the possible reversibility of this phenomenon still need further evaluation [23,24].
Purine analogs: rarer toxicities and other aspects to be considered
Other toxicities related to treatment with purine analogs have been reported. Some of these side effects are more frequent when these drugs are used to treat other diseases and for other indications, such as for CLL in which there is tumor lysis syndrome, and renal failure. Although these are not patients with HCL, there is still a need for the treating hemato-oncologist to be aware of these potential therapeutic complications associated with the use of purine analogs.
Neurotoxicity
Neurotoxicity was reported in about 15% of patients treated with purine analogs, especially with a high dose of pentostatin. This side effect was less evident when a reduced dose (4 mg/m2) was used. The mechanism of this neurotoxicity is still unknown, but it can present as leg pains, is mostly mild, and is usually reversible.
Pregnancy
The literature regarding the impact of both cladribine and pentostatin on ovarian function is still very sparse and almost non-existent. In 2004, Orlowski described a successful pregnancy after cladribine therapy for HCL. However, despite the fact that HCL is rarer in young women than in men, they still require guidance about the drug and its possible effects on ovarian function, and information regard- ing the potential benefits of using gonadotropin releasing hormone (GnRH) analogs before receiving therapy with purine analogs [25].
Elderly patients
It is still unclear whether older patients who need to be treated for HCL require special considerations in the choice of therapy or dose reduction.
Conclusions
. Prolonged T cell immune suppression occurs after purine analog administration and is
most impressive in CD4þ lymphocytes with a median time for CD4 reconstitution of up to 40 months.
. Opportunistic infections tend to occur very early after therapy and at the time of severe neutrope- nia, while infectious episodes due to lymphopenia
are relatively rare despite the low CD4þ T cell numbers.
. There is probably no true increased incidence of second tumors in patients treated with purine analogs for HCL, but this debate continues and this still remains an open issue.
. Novel therapy utilizing immunotoxins and mono- clonal antibodies, which do not target T cells, is probably less immunosuppressive than therapy with purin analogs.
. A better understanding of the immune defects encountered in untreated patients with HCL, as well as those occurring in patients treated with purine analogs, could translate into an improved approach for patients with HCL and may eventually result in a better clinical outcome for them.
. Currently there is no documented evidence of stem cell toxicity due to purine analogs given in the treatment of HCL.
. How best to treat patients in special clinical settings, such as the elderly or pregnant women, is still an open issue, and clinical trials are required to address these issues in the elderly at least.
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