HOUSTONSupportive care for patients undergoing allogeneic
hematopoietic stem cell transplantation presents a series of
challenges, from regimen-related toxicity to chronic
graft-versus-host disease (GVHD), said Daniel Couriel, MD, assistant
professor of blood and marrow transplantation, M.D. Anderson Cancer
Center.
Dr. Couriel discussed current transplant management strategies at
Medical Oncology: A Comprehensive Review, an oncology
board review sponsored by M.D. Anderson.
The potential complications associ-ated with stem cell
transplantation can be viewed in terms of regimen-related toxicities,
graft failure, infectious complications, and acute or chronic GVHD,
Dr. Couriel said. These complications occur within a general time
frame that begins at day 0 (the day of the stem cell infusion) and
continues beyond day 100 (the cutoff point used to distinguish acute
vs chronic GVHD).
The earliest problems are directly related to the chemotherapy or
radiotherapy regimen, Dr. Couriel said. Gastrointestinal toxicity,
such as mucositis, is common. Among genitourinary complications,
hemorrhagic cystitis is still a problem, he noted, and is often
related to adenovirus or polyomavirus infections.
Cardiotoxicityhemorrhagic carditis or myocarditisis rare
today, he said, as more radiotherapy regimens now rely on
fractionated dosages instead of total body irradiation.
Veno-occlusive disease is another potential regimen-related
complication. The problem typically arises within 30 days of the
transplant, most often between day 7 and day 21. Symptoms include
jaundice, hepatomegaly and right-upper-quadrant pain, and ascites or
weight gain.
Factors that predispose a patient to veno-occlusive disease are high
SGOT, active infection, total body irradiation, and chemotherapy
regimens including oral busulfan (Myleran) (less often, IV busulfan),
carmustine (BCNU), or mitomycin C (Mutamycin).
Anecdotal evidence suggests that prostaglandin E2 along with tissue
plasminogen activator (TPA) may be effective against veno-occlusive
disease, Dr. Couriel said, but the approach is by no means standard
of care.
Idiopathic Interstitial Pneumonia
Idiopathic interstitial pneumonia is a serious complication with a
mortality of approximately 50%. Patients can develop it up to 6
months after transplant, but the problem usually arises between day
30 and day 90. The risk increases with age, prior radiotherapy, and
preexisting lung disease.
The term idiopathic is relative, Dr. Couriel
said. A lot of the idiopathic part has to do with the fact that
10 or 15 years ago, we lacked the diagnostic capacity that we have
now. Today, probably only about 5% to 10% of patients with bilateral
pulmonary infiltrates dont have a diagnosis.
Because idiopathic interstitial pneumonia is more common among
patients receiving total body irradiation, he added, many of the
early cases probably could have been classified as radiation
pneumonitis.
Diffuse alveolar hemorrhage also is better recognized todayand
may explain another large portion of the idiopathic
cases. At M.D. Anderson, any bleeding in the lungs is
considered to be diffuse alveolar hemorrhage, Dr. Couriel said.
Total body irradiation and infection (both fungal and viral)
probably account for most cases.
Graft Failure
Graft failure, of course, is often a devastating complication.
We usually think about graft failure when the neutrophil count
has not gone beyond 500 in a consistent way after day 25 or day
30, Dr. Couriel said. It is most often immune
mediatedgraft rejectionbut we rarely find the
exact etiology.
Some of the factors that can lead to graft rejection are persistence
of host T cells (not as common with todays preparatory
regimens) and, in heavily transfused patients, post-transfusion
alloim-munization (host lymphocytotoxic antibodies). Immune-mediated
problems are more common when the transplant involves greater HLA
disparity or HLA class I disparity, especially HLA-C.
Non-immune-mediated causes of graft failure include stem cell damage,
viral infections, and drug toxicity. Theres a long list
of drugs that can lead to graft failure, Dr. Couriel said.
One of the most common is ganciclovir [Cytovene], which we use
for cytomegalovirus prophylaxis.
He noted that graft failure has a very high mortalityover 90%.
You can try growth factors. If theres no response, you
have to reinfusebut to reinfuse, you have to immunosuppress.
Its a very bad situation, he said.
Infection a Long-Term Concern
Infection is a significant, long-term concern among transplant
recipients, Dr. Couriel said. Supportive care includes prophylaxis
for bacteria, fungi, Pneumocystis carinii pneumonia (PCP), and
viruses.
Penicillin or norfloxacin (Noroxin) typically is given to prevent
bacterial infections until engraftment occurs, he said.
Prophylaxis for fungal infectionswith fluconazole (Diflucan) or
itra-conazole (Sporanox), or liposomal amphotericin B (Abelcet)
is started 5 days before transplantation and continues to day 100.
To prevent PCP, trimethoprim/sulfamethoxazole (Bactrim and others) is
started 8 days before infusion, then stopped 2 days before transplant
(because of concerns about myelosup-pression in the postconditioning,
post-infusion period). It is then started again after engraftment.
Bactrim prophylaxis continues for 6 months to 1 year.
Cytomegalovirus (CMV) prophylaxis consists of using only seronegative
blood products or leukocyte filters in seronegative patients.
Seropositive recipients can receive primary prophylaxis
with ganciclovir at the time of engraftmenta controversial
practiceor the more accepted preemptive treatment
with ganciclovir when the virus reactivates.
At M.D. Anderson, ganciclovir is started when a viral protein
associated with reactivation is detected in the blooda practice
that has significantly reduced CMV mortality, Dr. Couriel said.
Acute GVHD
GVHD is a major complication in allogeneic stem cell transplants.
Predisposing factors include HLA disparity, advancing age, gender
mismatch (female-to-male transplants, in part because the graft
recognizes the Y chromosome as foreign), donor parity, CMV infection,
type of graft (umbilical cord, peripheral blood stem cell, or T
cell-depleted graft), and, for chronic GVHD, a history of acute GVHD.
The risk of developing acute GVHD after an allogeneic stem cell
transplant ranges from 10% to 100%, depending on the conditioning
regimen, predisposing factors, and the degree of graft manipulation.
We tell our patients that with an unmanipulated HLA-matched
graft, the risk of any degree of GVHD is 30% to 40%, Dr.
Couriel said.
The severity of acute GVHD is based on the extent and degree of
target organ involvementskin, gut, and liver. Standard
prophylaxis has been cyclosporine (Neoral, Sandimmune) or tacrolimus
(Prograf) plus methotrexate. Four or five years ago, cyclosporine
plus prednisone was used, Dr. Couriel noted, but M.D. Anderson
prefers to use tacrolimus plus prednisone.
Established acute GVHD is treated with methylprednisolone (while
continuing cyclosporine or tacrolimus). Steroid-refractory patients,
who have a mortality of more than 50%, are given antithy-mocyte
globulin (Atgam) or experimental immunomodulating agents.
Chronic GVHD
Chronic GVHD is defined as GVHD that persists after day 100a
demarcation that is really arbitrary, he said.
Classically, every organ site is involved, Dr. Couriel
said. And chronic GVHD appears to be a different disease from
acute GVHD. It is more the result of persistent autoimmune attack,
and, in a way, it mimics autoimmune diseases like systemic lupus
erythematosus and scleroderma.
The clinical manifestations of chronic GVHD, he said, can include
lichenoid and sclerodermal skin rashes; oral lichenoid changes, dry
mouth, and altered taste; dry eyes and corneal erosions; anorexia,
nausea, and chronic diarrhea; liver dysfunction; musculoskeletal
con-tractures and arthritis; and repeated infections.
Treatment is immunosuppression, primarily with methylprednisolone and
tacrolimus or, for localized skin or mouth involvement, topical
steroids.
The specific treatment approach depends on the nature of the
diseasede novo (no history of acute GVHD), progressive, or
relapsing; clinical vs subclinical; extensive vs limited; high-risk
(platelets less than 100,000) vs low-risk; and early vs late
complications.
