4 M. S. Tallman & A. Polliack
approximately 3 months, again with a single 7-day exposed to purine nucleoside analogues, the re-
infusion. Subsequently, long-term follow-up studies sponse rate to Rituximab varied between 13 and
confirm the durability of these CRs [36–40]. Ten- 53%. Several studies have combined purine nucleo-
year disease-free (or relapse-free) and overall survi- side analogues with Rituximab [60,61]. In the study
vals are higher than 90%. by Else et al., eight patients received either con-
current (six patients) or sequential (two patients)
2-CdA combined with Pentostatin or 2-CdA alone
2-Deoxycoformycin
combined with Rituximab. All eight patients re-
The revolution actually began with the first report in sponded and seven of the eight (87.5%) achieved
1981 of the effectiveness of the adenosine deaminase remission and with minimal toxicity. All patients
inhibitor 2-deoxycoformycine (2-DCF) led by the achieving CR had no evidence of minimal residual
group from Ohio State University [41–46]. Subse- disease. At a follow-up of 29-months, only one
quently, long-term follow-up studies revealed patient had developed recurrent disease and the
10-year survival rates of 90% or more [47–51]. estimated 2-year recurrence rate was 20%. Interest-
Investigators from the Royal Marsden Hospital in the ingly, Ravandi et al. [62] at the MD Anderson
United Kingdom retrospectively reviewed a series of Cancer Center administered weekly Rituximab for 8
patients treated with either 2-DCF or 2-CdA. weeks following Cladribine in 13 patients with HCL
Remission rates were very high, 81% for 2-DCF (11 newly diagnosed). This was an attempt to
and 82% for 2-CDA. The relapse rates at 5 and 10 eradicate minimal residual disease (MRD) [63–65].
years were 24% and 42%, respectively, for 2-DCF Among patients who achieved remission, MRD,
and 33% and 48%, respectively, for 2-CdA. Overall according to consensus primer polymerase chain
survival at 10 years was 96% and 100%, respectively. reaction (PCR) or flow cytometry, was eradicated in
Analysis of disease-free survival shows no plateau 92%. The importance of eradicating MRD in HCL
with either agent in this report. This has not in the long-term is unclear.
discouraged or deterred clinicians because of the Most exciting has been the development of yet
high CR rates and their durability with very modest another non-chemotherapeutic agent. Kreitman et al.
toxicity. [66,67] at the NIH have reported the dramatic
Although it is not clear whether one of the two efficacy of an immunotoxin formed by the fusion of
purine nucleoside analogues leads to a better out- an anti-CD22 antibody linked to a truncated exotoxin
come than the other, the short duration and ease of from the bacteria Pseudomonas (exotoxin A). Among
administration with minimal toxicity of 2-CdA has 16 patients who had failed purine nucleoside analo-
made this a popular choice. A number of investiga- gues, 11 achieved CR and 2 a partial remission. At the
tors have reported alternative doses, schedules and time of publication of these 16 patients, the median
routes of administration of 2-CdA; however, other follow-up was 16 months and 3 of 11 patients who
than the 5-day 2-h bolus infusion schedule and 7-day achieved a CR had relapsed and were retreated and all
continuous infusion schedule originally described three achieved a second CR. In the largest series
remains the most commonly used [52–55]. Remark- published, 36 patients, a CR rate after one cycle of
ably, the purine analogues are equally effective in this agent was 25% which improved to 47% with
patients with newly diagnosed as well as advanced multiple cycles. Several patients developed reversible
disease, in patients with large tumor burdens, and in grade III hemolytic-uremic syndrome and four
patients resistant to one purine analogue when patients (11%) developed neutralizing antibodies
treated with the other [15,56]. These observations which prevented retreatment [68].
are again extraordinary in the treatment of malignant Yet a newer immunoconjugate, HA22, is in
disease. clinical trials and differs from BL22 by mutations
in heavy chains CDR3 and shows increased cyto-
toxicity [69].
Immunoconjugates
Summary and future directions
In the 1990s, therapeutic strategies returned to non-
chemotherapeutic approaches. Since most patients The milestones in the development of effective
with HCL express the antigen CD20 and the anti- treatment for HCL weave a story of success
CD20 monoclonal antibody Rituximab proved so (Figure 1). Although it’s etiology and pathogenesis
effective in patients with other B-cell lymphoproli- are still a mystery, the disease is now readily
ferative disorders, several groups investigated this treatable, if not curable, with purine analogues. The
agent and reported modest activity of Rituximab in majority of patients enjoy many years of prolonged
HCL [57–59]. Among patients who were previously clinical and hematological remission, despite the fact
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