Management of Relapse
Despite the intensity of the preparative regimen, some patients relapse after receiving an allogeneic BMT. For patients with CML, withdrawal of immunosuppression to allow for an augmented graft-vs-tumor effect sometimes leads to remission. Other patients with CML may respond to post-transplant interferon or reintroduction of drugs such as imatinib or dasatinib, or nilotinib, which appears to be a useful approach. Intriguingly, infusion of donor lymphoid cells (DLI) into patients with CML is an effective means of inducing hematologic and cytogenetic responses in those who have relapsed after transplant; this approach has led to complete and durable remissions.
Some patients with AML have responded to either DLI or the combination of chemotherapy and donor stem cells. Hypomethylating agents (5-azacitidine, decitabine) have been studied as treatment of prevention of post-HCT AML relapses. Patients with acute lymphoblastic leukemia have had the lowest response rate to DLI. However, novel immunotherapeutic approaches using bi-specific T-cell engagers (BiTE) or CD19-specific chimeric antigen receptor (CD19 CAR) T cells showed highly promising results even in the cases of post-HCT relapses.
Patients with relapsed lymphoma or leukemia after autologous HCT and patients in whom myelodysplasia develops after autologous HCT (therapy-related MDS) can sometimes be successfully treated with reduced-intensity allogeneic transplant to restore normal hematopoiesis and cure the MDS.
Second Malignancy After HCT
Patients who undergo transplant are at risk for developing a second cancer. For those who undergo autologous transplant, particularly for treatment of lymphoma and Hodgkin lymphoma, the most common cancer is myelodysplasia/AML, which occurs in up to 10% of patients, usually within 3 to 7 years after transplant.
Risk factors for the development of myelodysplasia/AML after transplant include the number of prior chemotherapy and radiation therapy treatments; specific drugs, such as alkylating agents or topoisomerase inhibitors; difficulty in mobilizing stem cells; persistent cytopenias after transplant; and use of total body irradiation in the transplant preparative regimen. All patients should undergo cytogenetic screening of the marrow before stem cell collection and should be followed up for this complication after recovery from transplant.
Patients who undergo either autologous or allogeneic transplant are also at risk for the development of solid tumors up to 20 years after transplant. The risk is greater in patients who receive an allogeneic transplant. The most common tumors are related to the skin, but both common (breast, lung, and colon) and less common (sarcoma) tumors have been seen. As part of their long-term follow-up, all patients require screening for this complication to diagnose the cancer in its earliest stage.
Additional Long-Term Effects
Given the increasing numbers of patients who are long-term survivors of allogeneic transplant, both primary care physicians and medical oncologists are seeing patients with chronic GVHD as part of their practice. Thus, recognition of the manifestations of chronic GVHD and its complications are an important component of long-term care, as well as close coordination with the transplant unit for their management. Chronic GVHD may evolve from acute GVHD that develops early after transplant, but it may also occur after resolution of acute GVHD or it may occur without prior acute GVHD, often after a patient has returned to his or her primary care physician.
Common manifestations include lichenoid changes of the skin and mucous membrane, vitiligo, periorbital hyperpigmentation, odynophagia, nail dysplasia, keratoconjunctivitis, xerostomia, alopecia and, most important, susceptibility to infection. Hence, there is the need for prevention strategies as well as immunizations as previously mentioned. In women, vaginal strictures and dyspareunia can be the presenting features, and some patients may present with polyserositis, bronchiolitis obliterans, and malabsorption. All of these problems warrant discussion with a transplant team, and all patients who undergo transplant should have early and consistent oral care, with involvement of a dentist, to prevent caries.
Most patients with chronic GVHD require therapy with corticosteroids, often in association with tacrolimus or other medications. Thus, the sequelae of long-term corticosteroid use, including diabetes, lipid abnormalities, increase in blood pressure, skin changes, muscle atrophy, gastritis, pancreatitis, and psychological effects, are important components of care. Unlike acute GVHD, organ injury due to chronic GVHD may be very slow to resolve, necessitating long courses of treatment. In addition, tapering of immunosuppression may result in a flare requiring another course of treatment, so that the ultimate management and resolution of GVHD may occur over a period of years. The most important aspect of care is preventing infection. Patients with chronic GVHD are especially susceptible to reactivation of CMV, herpes simplex virus, and varicella-zoster virus infection; recurrent sinusitis or bronchitis; and Pneumocystis infection, and they require ongoing prevention therapy, as previously described. Although all patients should undergo re-vaccination, patients with chronic GVHD may not respond as well, and particular attention must be paid to these infections. Live vaccines, such as measles, mumps, and rubella, are not administered until 2 years after HCT in the absence of chronic GVHD and immunosuppressive therapy. Family members should receive routine vaccines, including influenza vaccine, and patients should avoid contact with children who received oral polio virus vaccine for about a month after vaccination.
Hypothyroidism is common after HCT, occurring in about a quarter of patients, particularly after total body irradiation. Thyroid adenomas and carcinomas may occur at rates higher than expected. In general, adrenal and pituitary function are not affected, although patients who receive corticosteroids long-term may have secondary hypoadrenalism and may require testing or even replacement therapy in the setting of decreased adrenal reserve.
Gonadal dysfunction is very common after transplant, especially if the patient received high-dose chemotherapy and radiation. Most men have relatively normal testosterone and luteinizing hormone levels, but when these levels are low, they should have replacement therapy, usually through the use of an androgen patch or testosterone injections. Women typically are anovulatory and have high levels of follicle-stimulating hormone and luteinizing hormone, and young women should receive replacement therapy. Infertility is not a universal consequence of transplant.
Increasingly, osteoporosis is a recognized problem in patients who have undergone HCT, and it often is a process begun even before transplant, likely due to the direct effect of hematologic cancers as well as their treatment. Thus, all patients require periodic bone density evaluations and adequate attention to both vitamin D and calcium replacement or, in some cases, the use of a bisphosphonate.
Avascular necrosis may occur in up to 5% of patients and is usually related to the use of corticosteroids and radiation. The hips are most commonly affected, but ankles and shoulders have also been involved and successful joint replacement has been performed.