cognitive impairment [65], and can be considered with auto‐transplant survivors. Geriatric assessments should be considered to identify patients with subclinical cognitive dysfunction. With a lack of prospective data and guidelines on geriatric assessment in this population, however, further studies are needed to identify patients who would benefit and optimal time‐points of geriatric assessments.
Special Considerations in Lymphoma and Myeloma
Late effects in lymphoma and MM deserve special consideration given specific chemotherapeutic agents patients receive prior to AHSCT which may affect long‐term outcomes, and the fact that they represent the most common indications for AHSCT in adults. Patients with HL who receive bleomycin as a part of initial chemotherapy are at an increased risk of bleomycin pulmonary toxicity [9]. Since bleomycin‐induced pulmonary fibrosis can occur several months after the drug is administered, close monitoring for pulmonary symptoms and periodic PFTs should be performed in HL AHSCT survivors who had prior exposure to bleomycin. Risk factors for bleomycin pulmonary toxicity include older age, use of ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine) as initial chemotherapy, and G‐CSF (granulocyte‐colony stimulating factor) use [9]. In patients with high‐risk HL undergoing salvage AHSCT, who subsequently receive consolidation with brentuximab vedotin, long‐term peripheral neuropathy can be seen in a minority of patients [66]. Prolonged use of rituximab as a maintenance therapy after auto‐transplant can lead to hypogammaglobulinemia and increased infection rate [67,68].
The number of transplants performed for MM has been steadily rising in the last decade [1,69]. Late effects after AHSCT for myeloma are frequently also affected by the continuous therapy that patients undergo even after transplant until end‐of life, which makes it challenging to separate exposures when considering late effects. The association between MM and secondary myeloid neoplasms (AML +MDS) has been well‐described before the era of novel agents [70–72]. Among currently used anti‐myeloma agents, convincing evidence for an increased risk of secondary malignancies exists for oral melphalan and lenalidomide [70,73,74]. Notably, the incremental risk of developing secondary malignancies with AHSCT in MM is unclear. A CIBMTR study on MM patients undergoing AHSCT between 1990 and 2010 did not find an increased overall risk of second malignancies [75]. However, subgroup analysis on specific tumor types showed increased risk of AML (SIR 5.2) and melanoma (SIR 3.6). Since a large proportion of these patients had pre‐ and/or posttransplant exposure to stem cell‐toxic agents, it remains unclear whether transplant is to blame for subsequent second cancers. Risk factors for t‐MN after AHSCT in MM are older age, male sex, obesity, and duration of alkylating agent‐based chemotherapy prior to transplant [75,76]. Since transplant‐eligible MM patients are known to have a high incidence of CHIP (~30%) [77], long‐term follow‐up is needed to assess whether CHIP can be a predictor of subsequent myeloid neoplasms in this population.
Patients with MM can progress after transplant with new renal dysfunction. Furthermore, other etiologies like development of AL amyloidosis, toxicities of anti‐myeloma therapy (e.g. carfilzomib, bisphosphonates), or kidney injury from monoclonal gammopathy of renal significance (e.g. cryoglobulinemic glomerulonephritis) can lead to renal failure. Carfilzomib, a second‐generation proteasome inhibitor, which is often used for posttransplant relapse in MM can lead to cardiopulmonary toxicity, including congestive heart failure, arrhythmias, and pulmonary hypertension [78]. The incidence of salvage second auto‐transplant in MM is also rising in the past decade [79]. Hence, careful assessment of pretransplant exposure profile is important to identify patients at a high risk of systemic late effects. Long‐term administration of steroids in MM can lead to several downstream complications, including steroid‐induced hyperglycemia, adrenal insufficiency, osteoporosis and avascular necrosis, increased risk of infections, and premature cataracts. Notably, patients with AL amyloidosis may have renal dysfunction at baseline. However, after achieving a deep hematologic response post‐AHSCT in AL amyloidosis with kidney involvement, subsequent kidney transplantation can lead to excellent long‐term survival in carefully selected patients [80].
Conclusion
With an increasing knowledge on the incidence and risk‐factors of late effects in the context of specific diseases, steps should be taken to initiate survivorship planning right from diagnosis and develop a treatment plan that will help minimize late adverse effects in AHSCT survivors. AHSCT survivors have a lower adherence to age‐ and sex‐specific preventative care guidelines compared to allogeneic‐transplant survivors [81]. Since these patients are cared for by a diverse group of physicians including transplant and cellular therapy physicians, non‐transplant hematologist/oncologists, primary care physicians, and subspecialists, communication between care teams and development of patient‐centric models will enable better monitoring and management of late effects in this growing population.
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