Combination therapies in HCL 19
recurrent chromosomal translocations [6]. The most treatments with PAs to reduce cytopenias and/
interesting and unique feature of HCL is the or infection-related comorbidity or mortality that
expression of multiple immunoglobulin isotypes on remain high at the onset of disease and in the first
the surface of tumor cells with no evidence of month from the start of PAs. In the pre-growth
subpopulations [7]. We have hypothesized that factors era, a pilot study of the Eastern Cooperative
multiple isotype expression occurs at the time prior Oncology Group (ECOG) was successfully designed
to deletion recombination when activation-induced to improve peripheral blood cell counts prior to a PA
cytidine deaminase and sterile ‘I’ transcripts are by administering IFN-a prior to pentostatin in
expressed [8]. These events together with different patients with an active infection at the time of
tiers of mutations of the expressed IGHV genes and treatment. The rationale of this approach was to
low levels of intraclonal heterogeneity in the majority combine the effective antineoplastic and immuno-
of the cases, lack of the memory B-cell marker CD27, modulating activities of IFN-a. Recombinant IFN-a
and other features suggest an origin different from a was administered 3610
6
IU s.c.63/week for 3
memory B-cell [9]. months prior to pentostatin 4 mg/m
2
i.v. every 2
After its first description by Bouroncle et al., HCL weeks for a maximum of 12 months in 34 patients.
had a long period of different unsatisfactory treat- The overall response rate was 94% (76% CR, 18%
ments till the early 1980s, when the effect of PR). One patient resolved a Mycobacterium avium
Interferon-alfa (IFN-a) was described [1,10]. In infection while receiving IFN-a without specific
1984, Spiers reported the dramatic results achieved antimycobacterial therapy and a CR was achieved
with pentostatin in two patients with HCL [11]. after pentostatin. Three febrile episodes and non-
These results were then confirmed and updated by disseminated herpes zoster were observed during the
other investigators, with overall response rates495% pentostatin phase of treatment. Overall, the sequen-
[12]. Three years later Piro et al. published the signif- tial administration of IFN-a and pentostatin resulted
icant impact of cladribine (2-chlorodeoxyadenosine) in a significantly low infection rate.
that determined a CR in 11 out of 12 patients with
almost no adverse effects [13]. In 1989, in Laguna
Combination treatments to improve CR rates
Niguel HCL Workshop, the extraordinary results
with cladribine were extended to 148 patients (85% Therapies designed to improve CR rates include the
CR rate and 12% PR) and only two patients subse- combinations of PAs with rituximab. The rationale to
quently experienced relapse [13]. Since then, several improve CR rates was that CR are expected to have a
other studies documented durable responses with longer disease-free survival [15–17], and rituximab
either compounds that also showed no cross-resis- appeared highly effective only if given at doses that
tance and significant effect in relapsed patients too are able to saturate the residual tumor cells [18,19].
[14]. However, patients with HCL can relapse after At MD Anderson, Ravandi et al. treated 13 patients
single agent purine analog (PA) treatments. Thus, in with newly diagnosed HCL (n¼11) or after failure of
the last 10 years, the efforts of clinicians have been one prior chemotherapy (n¼2) with cladribine given
dedicated to find combination therapies to improve at 5.6 mg/m
2
intravenously daily for 5 days followed
long-term outcome in HCL. by 8 weekly doses of rituximab (375 mg/m
2
) [16]. All
patients achieved a CR and minimal residual disease
(MRD) assessed by polymerase chain reaction
Objectives of combination treatments in hairy
(PCR) or flow cytometry was eradicated in 11
cell leukemia
(92%) of 12 and in 12 (92%) of 13 of patients,
Combination treatments have been used or pro- respectively. These data showed a very high rate of
posed for different purposes in HCL: (i) to reduce MRD eradication in HCL. However, PAs themselves
acute toxicity; (ii) to improve CR rate; (iii) to can determine complete eradication of disease with-
overcome resistance/refractoriness; (iv) to prolong out requiring rituximab, that is expensive and may
disease-free survival (DFS); and (v) to prolong not be needed in all patients with HCL in first line.
overall survival. Thus, it will be relevant to identify the disease
characteristics that may suggest the benefit of such
additional therapy.
Combination treatments to reduce acute toxicity
Agents currently used in clinical practice in combi-
Combination treatments to overcome resistance/
nation with PAs to reduce acute toxicity include
refractoriness
erythroid and myeloid growth factors (epoetins,
granulocyte-colony stimulating factors, etc). These A small but significant (10%) proportion of HCLs
are often used prior, during, or after induction are poor responders to PAs and up to 5% have
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