20 F. Lauria & F. Forconi
become totally resistant [12]. Since the advent of CHOP and pulsed vincristine doses. Only after
MoAbs that can have synergistic effects with PAs, it has splenic irradiation and Campath the patient obtained
become relevant to identify parameters that predict a persistent and durable remission. At our institution
response and/or event-free survival. The clinical (in collaboration with Dr. L. Rigacci, Hematology
parameters have been investigated to some extent Department, Florence), we tested the efficacy of
[20,21]. However, with the exception of anemia and fludarabine–Campath combination in a patient with
thrombocytopenia at diagnosis and/or quality of HCL with p53 dysfunctional mutation. This patient
response that can predict disease-free survival [21], had scored refractory to cladribine, rituximab, and
there is no consensus on prognostic parameters in pentostatin. Immediately after splenectomy the
HCL. At the University of Siena, we have committed to patient experienced a rapid progression with massive
identifying clinical and molecular parameters able to hyperleukocytosis (4150610
3
HCs/mL) and was
predict response and event-free survival after treatment given fludarabine and Campath for 3 consecutive
with cladribine [22]. Within the clinical parameters days monthly for four times. After 6 months from the
leukocytosis and splenomegaly appear to be the most termination of the treatment the patient was in CR at
important. Most interestingly, we are verifying the last follow-up.
status of tumor immunoglobulin heavy chain variable
(IGHV) genes and p53 dysfunction by mutation as
Combination treatments to prolong relapse or disease-free
two molecular parameters that are able to predict
survival
response to cladribine [22].
Combined treatment strategies will need to be Currently, there are no studies that have demon-
tested in the patients resistant to PAs. There are strated that combination treatments will prolong
currently two clinical trials that are investigating the relapse-free survival in HCL. However, it is very
effect of 2CdA either followed by rituximab (phase reasonable to think that the improved quality of
2 NCT00412594 protocol) or with ‘‘simultaneous response with MRD eradication by means of
or delayed’’ rituximab (phase 2 NCT00781235 rituximab and PA combinations will prolong dis-
protocol). Also the effects of new immunotoxin ease-free survival. The beneficial effect of MRD
conjugates alone or in combination with PAs are eradication was described in patients receiving either
being intensively investigated at NCI by Kreitman cladribine or pentostatin [17,26]. Tallman et al.
[23] in relapsed/resistant patients. Ongoing proto- observed that while only 50% patients with MRD
cols at NCI include those with anti-CD22 BL-22 relapsed, only 6% without MRD relapsed, indicating
(NCT00074048 protocol), or with anti-CD25 that the presence of MRD was associated with an
LMB-2 (NCT00337311) or with CAT immuno- increased risk of relapse [17]. Similarly, Catovsky’s
toxins (NCT00462189). group at Royal Marsden Hospital (RMH) has
At our institution, we have had the chance to test continuously confirmed that achievement of a CR
the efficacy and toxicity of cladribine given ‘con- is a very important parameter that predicts a longer
comitantly’ with rituximab in a case of HCL with treatment-free interval than achievement of a PR
unmutated tumor IGHV gene that had relapsed [21]. In the last report by the RMH group it was also
several times and had scored resistant to a number of observed with us that patients receiving rituximab
lines with PAs or rituximab given as single-agents combined with either cladribine or pentostatin were
[24]. After this first experience that resulted in the associated with high frequencies of MRD eradication
eradication of MRD, we have now collated the and rapid attainment of plateau in the disease-free
results of six additional relapsed/resistant patients survival curve [21]. Twelve patients with recurrent
(median 2 prior lines, range 1–10), of whom two had disease were re-treated at second or subsequent lines of
already received rituximab alone with no beneficial therapy with either PA plus 3–8 doses of rituximab,
response prior to the combination [18]. After given either concurrently (n¼9) or sequentially
concomitant cladribine plus rituximab, all patients (n¼3). Each had received up to nine (median 2) prior
obtained a CR and only one scored MRD positive by therapies, including splenectomy and IFN-a.Mosthad
PCR. Toxicity was also rare and 1 out of 6 patients shown poor responses to previous PAs (CR rate: 37%)
experienced a grade 3 ocular Varicella Zoster and/or short relapse-free survival (median 2.5 years).
reactivation. At a median follow-up of 2 years (range 0.5–5), the
Other combination therapies used to revert refrac- results appeared better than in those retreated with a
toriness to treatment are anecdotical. Sasaki et al. PA alone. The only partial responder relapsed after 10
reported the excellent effect of splenic irradiation months and subsequently died of HCL. The other 11
followed by anti-CD52 Mab-Campath in a variant patients attained a CR, with no evidence of MRD
case of CD25 negative HCL [25]. This patient was assessed by immunohistochemistry, and all currently
resistant to cladribine, pentostatin, rituximab, IFN-a, remain in remission.
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