H e m a t o lo g y E d u c a t io n - European Hematology Association

16 th Congress of the European Hematology Association
low hematological toxicity rate, this regimen seems
very promising for relapse treatment of the elderly. 47
Similar data were obtained by the same group evaluating
the FC regimen with a different dosing regimen
using 15 mg/m 2 of fludarabine and 200 mg/m 2 of
cyclophosphamide for 4 consecutive days. 48 Again clinical
toxicity in 20 elderly patients with refractory CLL
was mild and the response rates were favorable.
However, multicentre trials will have to show if dosereduced
FC combination with or without antibodies are
feasible in elderly CLL patients with reduced physical
fitness and relevant comorbidity burden.
Another phase II trial evaluated the combination of
bendamustine plus rituximab in relapsed setting. 49
Bendamustine was administered in a dose of 70 mg/m²
for 2 days combined with rituximab 375 mg/m² on
cycle 1 and 500 mg/m² on cycles two to six. Twenty
nine of the 78 patients (37%) were 70 years or older.
The overall response rate among all patients was 59%,
including 9% CRs. 49 Response rates in patients above
the age of 70 years were comparable to those with
younger age. Though data on comorbidity burden using
the CIRS were not assessed within this trial, the combination
bendamustine and rituximab appears to be a
good relapse treatment option in elderly CLL patients.
However, in relapse situation bone marrow recovery
may be significantly reduced in comorbid patients of
higher age. Therefore, treatment regimens with very
mild myelotoxicity are warranted for this group. More
recently, the anti CD20-antibody ofatumumab has been
approved for treatment of refractory CLL based on the
interim analysis of a trial, including 138 patients refractory
to fludarabine and alemtuzumab (FA-ref; n=59) or
refractory to fludarabine with bulky lymphadenopathy
(BF-ref; n=79). 37 The ORR was 58% for the FA-ref group
and 47% for the BF-ref group and median time to progression
was 5.7 and 5.9 months, respectively. Beside
some usually mild infusion-related adverse events at the
first application of ofatumumab, the main toxicities
were infections and neutropenia. 37 High dose methylprednisolone
(HDMP, 1 g/m 2 for five days) in combination
with rituximab (375 mg/m 2 weekly for 4 weeks)
has also proven to be effective in patients with
advanced, fludarabine resistant CLL showing an overall
response rates of 93% and a complete remission rate of
36% in a small trial including 14 patients. 50 The median
time-to-progression was 15 months and the median
time-to-next treatment was 22 months. Treatment was
well tolerated and serious adverse events were rare. 50
However, if the relapse or progression occurs at least
12 months after a monotherapy or 24 months after
chemo immunotherapy, first line regimen might be
repeated in the relapse setting. 51
Disturbances of the immune system
Most of the patients develop a severe immune defect
during the course of their disease. The immune defects
are both quantitative and qualitative and are associated
with an impaired humoral and cellular immune
response. More than 70% of CLL patients develop
severe hypogammaglobulinemia, 52 which correlates
with an increased risk of microbiological infections. The
Figure 1. Classification of treatment goal by geriatric assessment. 74
use of prophylactic intravenous immunoglobulin may
reduce the incidence of less severe infections, 53 but does
not have an impact on overall survival. 54 Because even a
low-dose treatment with intravenous immunoglobulin
is not a cost effective way to prevent infection in CLL
patients, only selected patients with a very high risk of
bacterial infection should receive immunoglobulin substitution.
55
Regarding the use of antibiotic prophylaxis no standard
guidelines for CLL patients independent from their
physical fitness or age exist. There is no clear evidence to
use routine application of anti-infectives in first line therapy
of younger patients 56 with the exception of pneumocystis
jiroveci prophylaxis during prolonged neutropenia
and CMV prophylaxis during alemtuzumab administration.
However, some advocate the use of antiviral prophylaxis
in elderly CLL patients, because high rates of
infectious complications may occur especially with
purine analogue-based combination therapies. 46
Pneumococcal and seasonal influenza vaccines are generally
used in CLL patients, though response to vaccination
may be suboptimal. Elderly CLL patients have probably
lower response rates to vaccination as demonstrated by
one study showing a negative correlation between higher
age and response to haemophilus vaccine. 57 Therefore,
vaccination in early stage CLL should be considered,
because adequate antibody response was more frequent
in patients with lower stage CLL. 58
Besides infectious complications autoimmune diseases
may occur as an expression of the immune defect
as well. Special attention should be paid to the appearance
of autoimmune hemolytic anemia (AIHA) and
autoimmune thrombocytopenia (AITP) that occur in 4–
11% of CLL patients. 59-61 Prognosis of CLL patients with
AIHA has been significantly improved during the past
decades, which is mainly due to improved diagnostic
procedures and to more treatment options in relapse of
autoimmune cytopenia. 61,62 Though there are no special
recommendations for treatment of autoimmune cytopenias
in elderly patients, the first line treatment of choice
in these patients should be the use of corticosteroids
such as in younger patients. Besides high dose immuno -
globulines, cyclophosphamide, cyclosporine or other
immune suppressive medication, the antibody rituximab
represents an alternative treatment option in the
relapse situation of AIHA or AITP. 63
| 108 | Hematology Education: the education programme for the annual congress of the European Hematology Association | 2011; 5(1)