Allogeneic Stem Cell Transplants: Supportive Care Is Key

HOUSTON—Supportive 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.

Cardiotoxicity—hemorrhagic carditis or myocarditis—is 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 don’t 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 today—and 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 mediated—graft ‘rejection’—but 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 today’s 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. “There’s 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 mortality—over 90%. “You can try growth factors. If there’s no response, you have to reinfuse—but to reinfuse, you have to immunosuppress. It’s 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 infections—with 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 engraftment—a controversial practice—or 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 blood—a 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 involvement—skin, 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 100—a 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 disease—de 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.