The focus of this panel discussion, led by Dr.
Julie Vose, was management of infectious complications associated
with therapies with pentostatin (Nipent) alone or in combination with
other agents in patients with low-grade lymphomas. The number of
studies in this area is limited, and the general consensus was that
further studies are needed before any definitive treatment
recommendations can be made. The panel considered the use and the
optimal schedule of prophylaxis in combined therapies with
pentostatin. Panelists discussed use of several agents that would
target specific infectious complications and use of hematopoietic
growth factors for neutropenia. They further explored the
effectiveness of new combinations of pentostatin with biologic agents.
Julie Vose, MD: One of the problems associated with therapies
with pentostatin, in particular those administered in combination
with other agents, is infection. We really do not know what the
appropriate prophylaxis is for these therapies. Does anyone want to
discuss the problem of herpes, Pneumocystis carinii, cytomegalovirus,
the effects of other agents, and the monitoring of these patients for
infection and prophylaxis?
Fernando Cabanillas, MD: In terms of prophylaxis, I think if
we are going to provide any at all, we have to focus on opportunistic
infections. Herpes zoster is a major problem, but as far as I know,
there is no consistency in using prophylactic valacyclovir (Valtrex).
The period for which you would have to use valacyclovir would be
extremely long. Since these infections can develop at any time, you
are going to have continual use of the drugs. If you start treating
herpes zoster early enough, you generally get a good response.
Its not as serious a problem as P. carinii would be,
although prophylaxis for P. carinii would be much easier. When
we use fludarabine (Fludara), we initiate prophylaxis with
trimethoprim/sulfamethoxazole, one double-strength tablet twice per
day on Saturdays and Sundays. Since we started to do that, we
havent had any cases of P. carinii.
Dr. Vose: I associate varicella zoster with patients who have
undergone autologous transplant. They seem to develop it about 4 to 6
months after the transplant. Its difficult to provide
prophylaxis to patients for that long a period, although I understand
that in Europe they treat patients prophylactically for 1 year after
transplant. Is that really time and cost effective?
Susan OBrien, MD: I think varicella zoster is a major
issue, particularly in chronic lymphocytic leukemia. However, most of
the data derive from transplant cases where patients were provided
prophylaxis for up to 6 months. There are a few randomized trials
comparing no prophylaxis to prophylaxis with acyclovir (Zovirax) for
6 months after autologous transplant. These are older studies that
showed a markedly reduced incidence of varicella zoster during the
time acyclovir was administered. However, in the 6 months after
prophylaxis ended, patients who didnt develop varicella zoster
in the first 6 months developed it in the second 6 months. We know
that in chronic lymphocytic leukemia, the CD4 counts are depressed
for a long time but we do not have solid answers at this point in time.
Dr. Vose: Are there other agents or biologics that might be
effectively combined with pentostatin?
Francine Foss, MD: I have been thinking a lot about the
combination of interferon and pentostatin. Was the higher response
rate we saw related to the combination and, if so, could that be
reworked to use lower-dose interferon? One of the studies that I was
proposing was to use the same dose of pentostatin with intermittent
low-dose interferon (3 to 6 million U IV 3 times per week) in
patients with cutaneous T-cell lymphoma. Unlike the results reported
by Dr. Razelle Kurzrock at M. D. Anderson Cancer Center (Houston), we
saw responses in mycosis fungoides patients. Im not really sure
what the difference is between Dr. Kurzocks study and our
study, but I dont think its related to the dose. It may
be related to the fact that we use interferon along with pentostatin.
When looking across all studies, it seems as though we conducted one
of the only studies where we saw clear-cut responses in mycosis
fungoides patients with skin involvement.
Dr. Vose: I am somewhat concerned about the combination of
rituximab (Rituxan) with pentostatin, because with no B cells and no
T cells, there is little left of the immune system. Im
concerned about infectious complications.
Robert Drapkin, MD: Yes, infections are expected, as seen in
several protocols using pentostatin and other agents. Thus, consider
prophylaxis for viral diseases, valacyclovir for herpes zoster,
trimethoprim/sulfamethoxazole for Pneumocystis, and even
growth factors should these patients become neutropenic.
Dr. Cabanillas: The point that you mentioned is a valid one,
and we were concerned when we started using the combination of
fludarabine/Novantrone/dexamethasone (FND) plus rituximab because we
would be suppressing both the T-cell and B-cell immune systems.
However, we have not seen any opportunistic infections that we did
not see with FND alone. The addition of rituximab seems to be
extremely well tolerated. We have been using this regimen for over a
year, and we have not really seen any untoward side effects. For some
reason, although it suppresses B cells for a long time, patients
treated with rituximab usually do not have problems.
Hypergammaglobulinemia occurs in about 15% of cases, supposedly
because it does not affect plasma cells, which do not express CD20.
It also does not affect early B cells, which eventually are able to
repopulate the peripheral blood.
Question: I had a question about Sézary syndrome. One
of the things that I didnt hear much about was cell-surface
markers. Is CD26 or CD45 differentially expressed on these cells? Is
there a clue there, or will other flow cytometry data explain why
pentostatin works better in Sézary syndrome?
Nam Dang, MD, PhD: I dont think there are any data
available on CD26 or CD45 expression. In a study by Italian
researchers, they found CD26 being expressed in 10% to 15% of cases
diagnosed as mycosis fungoides, but it could have been advanced-stage
Question: There are some studies that have combined interferon
with retinoids in certain T-cell disorders, and some positive effects
have been seen. The questions are, do we know how a drug like all-trans-retinoic
acid (ATRA [Vesanoid]) affects CD26, and would it be possible that
ATRA with pentostatin could be synergistic in T-cell disorders?
Dr. Dang: We really have no data on the retinoids and CD26
expression. What we do know is that if you activate T cells by a
variety of means, CD26 expression goes up. The theory is that if we
have access to drugs that can increase the expression of CD26 on the
cell surface, as well as ADA expression, perhaps retinoids in
combination with pentostatin could enhance these effects. However,
this is all theoretical right now, and there is nothing clinical that
we know at this point.