Case Challenges

A 72-year-old man develops engraftment syndrome after autologous HSCT

This case focuses on a 72-year-old man with a medical history significant for multiple myeloma, diagnosed 2 years prior.

He started myeloma therapy with lenalidomide (Revlimid, Celgene), bortezomib (Velcade, Millennium) and dexamethasone, and he underwent five cycles.

Autologous stem cell transplantation was planned. He underwent stem cell mobilization with filgrastim (Neupogen, Amgen) 10 mcg/kg subcutaneous injection daily for 5 days, as well as a single 240-mcg/kg subcutaneous dose of plerixafor (Mozobil, Genzyme) on day 5.

Tim McCarthy, MD 

Tim McCarthy

He was admitted to the bone marrow transplant unit and underwent pretransplant conditioning with melphalan 140 mg/m2. His post-transplant course progressed well until he began to develop fevers on day 7.

He was started on vancomycin and ceftazidime without an obvious source of infection. Given continued fevers on day 9, antibiotic coverage was broadened to vancomycin and doripenem (Doribax, Janssen Pharmaceuticals). On the morning of day 10, the patient developed hypotension and decreased urine output. He was aggressively hydrated with normal saline, and his hypotension improved.

Also on day 10, a mildly erythematous maculopapular rash developed on his abdomen and back. This constellation of symptoms was deemed consistent with engraftment syndrome and correlated with count recovery. IV methylprednisolone 0.5 mg/kg twice daily was started for this while broad-spectrum antibiotic coverage continued.

After the patient received aggressive IV hydration on day 10 for hypotension, he had several clinical indicators of fluid overload, including elevated brain natriuretic peptide levels and increased oxygen requirement. This required aggressive diuresis.

A chest X-ray at that time showed bibasilar opacities, small left pleural effusion and mild pulmonary edema. The patient developed atrial fibrillation with rapid ventricular response and hypotension on day 11 and was transferred to the ICU for closer monitoring. He developed hypotension-induced acute tubular necrosis with renal failure, which required intermittent hemodialysis for about 4 weeks.

During his hospitalization, he also developed a deep vein thrombosis in the left saphenofemoral vein junction and cytomegalovirus (CMV) viremia, which was treated with ganciclovir and severe deconditioning. He was ultimately tapered off of steroids and remained in normal sinus rhythm, but his CMV was not undetectable. He was discharged to acute inpatient rehab on day 89 post-transplant.

Discussion

Engraftment syndrome, a complication of hematopoietic stem cell transplantation (HSCT), appears to be becoming more common.

There are several definitions for engraftment syndrome. Broadly, it has been defined as presence of noninfectious fever plus skin rash that occurs in the early neutrophil recovery phase after HSCT. Diarrhea is common, whereas hepatic dysfunction, pulmonary infiltrates, transient encephalopathy and capillary leak syndrome are less common.

The reported frequency of diffuse opacities on chest radiograph ranges from 11% to 37%. Weight gain, edema, ascites and hypoalbuminemia also may be accompanying signs. Complications may range from mild and self-limiting to serious.

Although the pathogenesis is not entirely understood, it is related to the release of proinflammatory cytokines, including interleukin-1 and tumor necrosis factor-alpha.

Incidence and risk factors

Due to the lack of a clear definition, reports of incidence have varied from 7% to as high as 59%. Reported risk factors include underlying disease, the type of chemotherapy used in the conditioning regimen, the number of cycles of previous chemotherapy, previous radiotherapy, the number of cells infused and earlier engraftment.

A chart review by Maiolino and colleagues defined the final diagnostic criteria for engraftment syndrome as noninfectious fever plus any of the following: skin rash, pulmonary infiltrates or diarrhea. Using this definition, they reported an engraftment syndrome incidence of 20%.

Multiple studies have evaluated potential risk factors for engraftment syndrome. In the review by Maiolino and colleagues, multivariate analysis showed the single risk factor for engraftment syndrome was diagnosis other than Hodgkin’s disease (OR=6.17; 95% CI, 1.38-27.78).

Cornell and colleagues published a review in which multivariate analysis showed age older than 60 years (HR=1.71; 95% CI, 1.12-2.62) and transplantation for multiple myeloma (HR=2.8; 95% CI, 1.6-4.9) were associated with increased risk for engraftment syndrome. When stratified for myeloma patients only, age older than 60 years (HR=1.8; 95% CI, 1.13-2.87), as well as prior treatment with both lenalidomide and bortezomib (HR=1.83; 95% CI, 1.11-3.04) were associated with increased incidence of engraftment syndrome.

Their review also showed lack of exposure to cyclophosphamide from either chemomobilization or as a component of the pretransplantation therapeutic regimen increased engraftment syndrome risk (HR=3.05; 95% CI, 1.91-4.87). They concluded pretransplantation exposure of multiple myeloma patients to novel immunomodulatory agents and lack of exposure to cyclophosphamide significantly affects subsequent risk for developing engraftment syndrome.

The above findings are of particular interest in this case, as the patient appeared to be at high risk for developing engraftment syndrome based on his disease, age, prior chemotherapy exposure with lenalidomide and bortezomib, and lack of cyclophosphamide.

Treatment and prevention

Engraftment syndrome often is self-limited.

Empiric antibiotics are frequently given and appropriate cultures are collected. Systemic glucocorticoids often are administered, although the optimal dose and duration of glucocorticoid therapy is not known. Reported dose ranges are prednisone 0.5 mg/kg to 10 mg/kg per day, and methylprednisolone 1 mg/kg every 12 hours.

There is typically a rapid defervescence after administration of glucocorticoids, which may then be tapered, usually for 7 to 10 days.

Conclusion

This case demonstrates an example of engraftment syndrome in a patient post-autologous stem cell transplant for multiple myeloma.

As we seek to better define and understand engraftment syndrome, as well as risk factors, patients who are at a higher risk for engraftment syndrome may be identified. This could lead to considerations for preventive measures, including alternative induction regimens or prophylactic measures such as early use of glucocorticoids.

References:

Carreras E. Bone Marrow Transplant. 2010;45:1417-1422.

Cornell RF. Biol Blood Marrow Transplant. 2013;19:1368-1373.

Maiolino A. Bone Marrow Transplant. 2003;31:393-397.

For more information:

Tim McCarthy, MD, is a fellow in hematology and oncology at the University of North Carolina at Chapel Hill. He can be reached at Physicians Office Building, 170 Manning Drive, Third floor, CB# 7305, Chapel Hill, NC 27599.

Disclosure: McCarthy reports no relevant financial disclosures.

This case focuses on a 72-year-old man with a medical history significant for multiple myeloma, diagnosed 2 years prior.

He started myeloma therapy with lenalidomide (Revlimid, Celgene), bortezomib (Velcade, Millennium) and dexamethasone, and he underwent five cycles.

Autologous stem cell transplantation was planned. He underwent stem cell mobilization with filgrastim (Neupogen, Amgen) 10 mcg/kg subcutaneous injection daily for 5 days, as well as a single 240-mcg/kg subcutaneous dose of plerixafor (Mozobil, Genzyme) on day 5.

Tim McCarthy, MD 

Tim McCarthy

He was admitted to the bone marrow transplant unit and underwent pretransplant conditioning with melphalan 140 mg/m2. His post-transplant course progressed well until he began to develop fevers on day 7.

He was started on vancomycin and ceftazidime without an obvious source of infection. Given continued fevers on day 9, antibiotic coverage was broadened to vancomycin and doripenem (Doribax, Janssen Pharmaceuticals). On the morning of day 10, the patient developed hypotension and decreased urine output. He was aggressively hydrated with normal saline, and his hypotension improved.

Also on day 10, a mildly erythematous maculopapular rash developed on his abdomen and back. This constellation of symptoms was deemed consistent with engraftment syndrome and correlated with count recovery. IV methylprednisolone 0.5 mg/kg twice daily was started for this while broad-spectrum antibiotic coverage continued.

After the patient received aggressive IV hydration on day 10 for hypotension, he had several clinical indicators of fluid overload, including elevated brain natriuretic peptide levels and increased oxygen requirement. This required aggressive diuresis.

A chest X-ray at that time showed bibasilar opacities, small left pleural effusion and mild pulmonary edema. The patient developed atrial fibrillation with rapid ventricular response and hypotension on day 11 and was transferred to the ICU for closer monitoring. He developed hypotension-induced acute tubular necrosis with renal failure, which required intermittent hemodialysis for about 4 weeks.

During his hospitalization, he also developed a deep vein thrombosis in the left saphenofemoral vein junction and cytomegalovirus (CMV) viremia, which was treated with ganciclovir and severe deconditioning. He was ultimately tapered off of steroids and remained in normal sinus rhythm, but his CMV was not undetectable. He was discharged to acute inpatient rehab on day 89 post-transplant.

Discussion

Engraftment syndrome, a complication of hematopoietic stem cell transplantation (HSCT), appears to be becoming more common.

There are several definitions for engraftment syndrome. Broadly, it has been defined as presence of noninfectious fever plus skin rash that occurs in the early neutrophil recovery phase after HSCT. Diarrhea is common, whereas hepatic dysfunction, pulmonary infiltrates, transient encephalopathy and capillary leak syndrome are less common.

The reported frequency of diffuse opacities on chest radiograph ranges from 11% to 37%. Weight gain, edema, ascites and hypoalbuminemia also may be accompanying signs. Complications may range from mild and self-limiting to serious.

Although the pathogenesis is not entirely understood, it is related to the release of proinflammatory cytokines, including interleukin-1 and tumor necrosis factor-alpha.

Incidence and risk factors

Due to the lack of a clear definition, reports of incidence have varied from 7% to as high as 59%. Reported risk factors include underlying disease, the type of chemotherapy used in the conditioning regimen, the number of cycles of previous chemotherapy, previous radiotherapy, the number of cells infused and earlier engraftment.

A chart review by Maiolino and colleagues defined the final diagnostic criteria for engraftment syndrome as noninfectious fever plus any of the following: skin rash, pulmonary infiltrates or diarrhea. Using this definition, they reported an engraftment syndrome incidence of 20%.

Multiple studies have evaluated potential risk factors for engraftment syndrome. In the review by Maiolino and colleagues, multivariate analysis showed the single risk factor for engraftment syndrome was diagnosis other than Hodgkin’s disease (OR=6.17; 95% CI, 1.38-27.78).

Cornell and colleagues published a review in which multivariate analysis showed age older than 60 years (HR=1.71; 95% CI, 1.12-2.62) and transplantation for multiple myeloma (HR=2.8; 95% CI, 1.6-4.9) were associated with increased risk for engraftment syndrome. When stratified for myeloma patients only, age older than 60 years (HR=1.8; 95% CI, 1.13-2.87), as well as prior treatment with both lenalidomide and bortezomib (HR=1.83; 95% CI, 1.11-3.04) were associated with increased incidence of engraftment syndrome.

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Their review also showed lack of exposure to cyclophosphamide from either chemomobilization or as a component of the pretransplantation therapeutic regimen increased engraftment syndrome risk (HR=3.05; 95% CI, 1.91-4.87). They concluded pretransplantation exposure of multiple myeloma patients to novel immunomodulatory agents and lack of exposure to cyclophosphamide significantly affects subsequent risk for developing engraftment syndrome.

The above findings are of particular interest in this case, as the patient appeared to be at high risk for developing engraftment syndrome based on his disease, age, prior chemotherapy exposure with lenalidomide and bortezomib, and lack of cyclophosphamide.

Treatment and prevention

Engraftment syndrome often is self-limited.

Empiric antibiotics are frequently given and appropriate cultures are collected. Systemic glucocorticoids often are administered, although the optimal dose and duration of glucocorticoid therapy is not known. Reported dose ranges are prednisone 0.5 mg/kg to 10 mg/kg per day, and methylprednisolone 1 mg/kg every 12 hours.

There is typically a rapid defervescence after administration of glucocorticoids, which may then be tapered, usually for 7 to 10 days.

Conclusion

This case demonstrates an example of engraftment syndrome in a patient post-autologous stem cell transplant for multiple myeloma.

As we seek to better define and understand engraftment syndrome, as well as risk factors, patients who are at a higher risk for engraftment syndrome may be identified. This could lead to considerations for preventive measures, including alternative induction regimens or prophylactic measures such as early use of glucocorticoids.

References:

Carreras E. Bone Marrow Transplant. 2010;45:1417-1422.

Cornell RF. Biol Blood Marrow Transplant. 2013;19:1368-1373.

Maiolino A. Bone Marrow Transplant. 2003;31:393-397.

For more information:

Tim McCarthy, MD, is a fellow in hematology and oncology at the University of North Carolina at Chapel Hill. He can be reached at Physicians Office Building, 170 Manning Drive, Third floor, CB# 7305, Chapel Hill, NC 27599.

Disclosure: McCarthy reports no relevant financial disclosures.