Case Challenges

Sirolimus-associated thrombotic microangiopathy develops after allogeneic transplant

A 47-year-old black man with a history of multiple myeloma underwent autologous stem cell transplant in 2004, followed by an allogeneic 10 of 10 matched sibling-donor transplant in March 2005.

The patient’s post-transplant course has been complicated by a predominantly localized chronic graft-versus-host disease (GVHD) involving his eyes and mouth, as well as some pulmonary involvement, and he has required several courses of systemic corticosteroids. He began a course of rituximab (Rituxan, Genentech/Idec Pharmaceuticals) therapy, which he completed in 2010. For these issues, he has been treated with steroids, tacrolimus, sirolimus, hydroxychloroquine (discontinued at time of presentation of this case) and mycophenolate mofetil (also discontinued).

He was in his usual state of health until the week before admission, when he developed epistaxis and was noted to have 103,000 platelets/mcL, a creatinine of 3.4 mg/dL and a hemoglobin level that had fallen from 13 g/dL to 10.9 g/dL.

Tim McCarthy, MD 

Tim McCarthy

He was admitted for the treatment of what appeared to be microangiopathic hemolytic anemia. His peripheral blood smear at the time showed a moderate number of schistocytes. In addition, he was noted to have declining platelet counts and worsening anemia, as well as rising LDH, suggesting the presence of a thrombotic microangiopathy (TMA).

At the time of admission, he was on GVHD prophylaxis with tacrolimus and sirolimus, which were then stopped due to concern for drug-associated TMA.

His platelet count nadired at 21,000 platelets/mcL and his lactate dehydrogenase (LDH) peaked at 5,535 U/L on day 3 of admission. Plasma exchange (PLEX) was initiated. With PLEX, his LDH fell to 752 U/L with a platelet count that peaked at 200,000 platelets/mcL. He received 5 days of PLEX, and renal function and platelet counts continued to improve. The patient was initiated on rituximab before discharge, and the first of four weekly doses was given before discharge. His creatinine fell at discharge to 
1.78 mg/dL.

Discussion

This case gives an example of TMA and some of its associated challenges in diagnosis and treatment.

The initial concern in this case was for TMA associated with drugs (sirolimus and tacrolimus) vs. thrombotic thrombocytopenic purpura (TTP).

The patient’s case was not typical for transplant-associated TMA, given the long duration since his transplant. In this case, the patient had undergone both an autologous stem cell transplant in 2004 followed by an allogeneic stem cell transplant in 2005. Since then, he has had chronic GVHD treated with tacrolimus, sirolimus and, most recently, prednisone.

He presented with symptomatic thrombocytopenia and anemia, with evidence of TMA on his blood smear and lab values. He also had primarily end-organ damage associated with renal failure, which is more typical of bone marrow transplant or drug-associated TMA than idiopathic TTP.

TMA is a syndrome of microangiopathic hemolytic anemia, thrombocytopenia and renal dysfunction, although the exact definition varies in various published studies of the syndrome.

The etiology of TMA in hematopoietic stem cell transplant (HSCT) is unclear, although it may be related to endothelial injury related to chemotherapy and activated T cells — GVHD usually accompanies — followed by a trigger such as viral infection.

It has been reported that initiating events are likely to be multifactorial, with possible contributors including drugs, fully ablative conditioning regimens, GVHD, and angioinvasive fungal or viral infections. A recent case series looking at the increased incidence of TMA with combined tacrolimus- and sirolimus-based GVHD regimens identified three potential risk factors after multivariate analysis. Day 14 serum sirolimus level >9.9 ng/mL, presence of previous grade 2 to 4 acute GVHD, and fully myeloablative conditioning all predicted increased incidence of TMA. This did not necessarily fit the clinical picture that the above patient presented with; however, it did not exclude this etiology.

Treatment of TMA

Treatment of TMA remains difficult. Patients ultimately diagnosed with TMA often are critically ill and have other post-HSCT complications, such as GVHD.

The management of TMA is typically supportive, along with aggressive management of other transplant-associated complications.

Given the known association between TMA and calcineurin inhibitors and sirolimus, these drugs are commonly discontinued or administered in reduced doses. Withdrawal of these drugs may be difficult, given their use in treating and preventing GVHD. Potential alternative treatments that have been suggested for GVHD include glucocorticoids, mycophenolate mofetil and anti-thymocyte globulin.

PLEX has not been shown to be of definitive benefit, and it is not typically used in the treatment of transplant-associated TMA. Although there is a clear role for PLEX in treatment of TTP, reports have suggested that there is no improvement in survival when treating patients with TMA. Based on this, the current consensus statement from the committee of the NHLBI’s clinical trials network is that the universal use of post-transplant PLEX for TMA is not standard of care.

In this case, the patient received PLEX and showed overall clinical improvement, including improvement in renal function, platelet count and LDH values. As previously mentioned, his case was not typical for post-transplant TMA, given the time out from transplant (7 years). Because of this, the differential diagnosis included idiopathic TTP (related to ADAMTS13 deficiency).

This patient was at high risk for immune dysfunction, given his transplant and chronic GVHD with suppressive treatments, which could lead to autoimmune disease such as this. An ADAMTS13 level was checked and ultimately was equivocal, as it was decreased at 46%. Although this is not as low as typically present in TTP, often less than 5%, acquired TTP may show a large range of ADAMTS13 levels.

Based on American Society for Apheresis guidelines, bone marrow transplantation-associated TMA is a category III indication for PLEX, meaning the optimum role of apheresis is not clear. TTP, however, is a category I indication for PLEX and should be part of first-line therapy. Given this patient’s clinical picture, it was deemed reasonable to begin a series of PLEX procedures daily with a defined endpoint to evaluate clinical improvement in the patient’s condition.

This case demonstrates some of the clinical difficulties encountered when facing a case of potential TMA. Identifying the underlying cause or trigger may help guide treatment decisions.

There have been numerous reports of the combination of calcineurin inhibitors in conjunction with sirolimus increasing the risk for TMA, and it was ultimately felt to have contributed to this patient’s presentation. Although not first line of care, this patient ultimately appeared to benefit from a course of PLEX.

References:

Cutler C. Biol Blood Marrow Transplant. 2005;11:551-557.

Kojouri K. Curr Opin Oncol. 2007;19:148-154.

Shayani S. Biol Blood Marrow Transplant. 2013;19:298-304.

For more information:

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

Disclosure: McCarthy reports no relevant 
financial disclosures.

A 47-year-old black man with a history of multiple myeloma underwent autologous stem cell transplant in 2004, followed by an allogeneic 10 of 10 matched sibling-donor transplant in March 2005.

The patient’s post-transplant course has been complicated by a predominantly localized chronic graft-versus-host disease (GVHD) involving his eyes and mouth, as well as some pulmonary involvement, and he has required several courses of systemic corticosteroids. He began a course of rituximab (Rituxan, Genentech/Idec Pharmaceuticals) therapy, which he completed in 2010. For these issues, he has been treated with steroids, tacrolimus, sirolimus, hydroxychloroquine (discontinued at time of presentation of this case) and mycophenolate mofetil (also discontinued).

He was in his usual state of health until the week before admission, when he developed epistaxis and was noted to have 103,000 platelets/mcL, a creatinine of 3.4 mg/dL and a hemoglobin level that had fallen from 13 g/dL to 10.9 g/dL.

Tim McCarthy, MD 

Tim McCarthy

He was admitted for the treatment of what appeared to be microangiopathic hemolytic anemia. His peripheral blood smear at the time showed a moderate number of schistocytes. In addition, he was noted to have declining platelet counts and worsening anemia, as well as rising LDH, suggesting the presence of a thrombotic microangiopathy (TMA).

At the time of admission, he was on GVHD prophylaxis with tacrolimus and sirolimus, which were then stopped due to concern for drug-associated TMA.

His platelet count nadired at 21,000 platelets/mcL and his lactate dehydrogenase (LDH) peaked at 5,535 U/L on day 3 of admission. Plasma exchange (PLEX) was initiated. With PLEX, his LDH fell to 752 U/L with a platelet count that peaked at 200,000 platelets/mcL. He received 5 days of PLEX, and renal function and platelet counts continued to improve. The patient was initiated on rituximab before discharge, and the first of four weekly doses was given before discharge. His creatinine fell at discharge to 
1.78 mg/dL.

Discussion

This case gives an example of TMA and some of its associated challenges in diagnosis and treatment.

The initial concern in this case was for TMA associated with drugs (sirolimus and tacrolimus) vs. thrombotic thrombocytopenic purpura (TTP).

The patient’s case was not typical for transplant-associated TMA, given the long duration since his transplant. In this case, the patient had undergone both an autologous stem cell transplant in 2004 followed by an allogeneic stem cell transplant in 2005. Since then, he has had chronic GVHD treated with tacrolimus, sirolimus and, most recently, prednisone.

He presented with symptomatic thrombocytopenia and anemia, with evidence of TMA on his blood smear and lab values. He also had primarily end-organ damage associated with renal failure, which is more typical of bone marrow transplant or drug-associated TMA than idiopathic TTP.

TMA is a syndrome of microangiopathic hemolytic anemia, thrombocytopenia and renal dysfunction, although the exact definition varies in various published studies of the syndrome.

The etiology of TMA in hematopoietic stem cell transplant (HSCT) is unclear, although it may be related to endothelial injury related to chemotherapy and activated T cells — GVHD usually accompanies — followed by a trigger such as viral infection.

It has been reported that initiating events are likely to be multifactorial, with possible contributors including drugs, fully ablative conditioning regimens, GVHD, and angioinvasive fungal or viral infections. A recent case series looking at the increased incidence of TMA with combined tacrolimus- and sirolimus-based GVHD regimens identified three potential risk factors after multivariate analysis. Day 14 serum sirolimus level >9.9 ng/mL, presence of previous grade 2 to 4 acute GVHD, and fully myeloablative conditioning all predicted increased incidence of TMA. This did not necessarily fit the clinical picture that the above patient presented with; however, it did not exclude this etiology.

Treatment of TMA

Treatment of TMA remains difficult. Patients ultimately diagnosed with TMA often are critically ill and have other post-HSCT complications, such as GVHD.

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The management of TMA is typically supportive, along with aggressive management of other transplant-associated complications.

Given the known association between TMA and calcineurin inhibitors and sirolimus, these drugs are commonly discontinued or administered in reduced doses. Withdrawal of these drugs may be difficult, given their use in treating and preventing GVHD. Potential alternative treatments that have been suggested for GVHD include glucocorticoids, mycophenolate mofetil and anti-thymocyte globulin.

PLEX has not been shown to be of definitive benefit, and it is not typically used in the treatment of transplant-associated TMA. Although there is a clear role for PLEX in treatment of TTP, reports have suggested that there is no improvement in survival when treating patients with TMA. Based on this, the current consensus statement from the committee of the NHLBI’s clinical trials network is that the universal use of post-transplant PLEX for TMA is not standard of care.

In this case, the patient received PLEX and showed overall clinical improvement, including improvement in renal function, platelet count and LDH values. As previously mentioned, his case was not typical for post-transplant TMA, given the time out from transplant (7 years). Because of this, the differential diagnosis included idiopathic TTP (related to ADAMTS13 deficiency).

This patient was at high risk for immune dysfunction, given his transplant and chronic GVHD with suppressive treatments, which could lead to autoimmune disease such as this. An ADAMTS13 level was checked and ultimately was equivocal, as it was decreased at 46%. Although this is not as low as typically present in TTP, often less than 5%, acquired TTP may show a large range of ADAMTS13 levels.

Based on American Society for Apheresis guidelines, bone marrow transplantation-associated TMA is a category III indication for PLEX, meaning the optimum role of apheresis is not clear. TTP, however, is a category I indication for PLEX and should be part of first-line therapy. Given this patient’s clinical picture, it was deemed reasonable to begin a series of PLEX procedures daily with a defined endpoint to evaluate clinical improvement in the patient’s condition.

This case demonstrates some of the clinical difficulties encountered when facing a case of potential TMA. Identifying the underlying cause or trigger may help guide treatment decisions.

There have been numerous reports of the combination of calcineurin inhibitors in conjunction with sirolimus increasing the risk for TMA, and it was ultimately felt to have contributed to this patient’s presentation. Although not first line of care, this patient ultimately appeared to benefit from a course of PLEX.

References:

Cutler C. Biol Blood Marrow Transplant. 2005;11:551-557.

Kojouri K. Curr Opin Oncol. 2007;19:148-154.

Shayani S. Biol Blood Marrow Transplant. 2013;19:298-304.

For more information:

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

Disclosure: McCarthy reports no relevant 
financial disclosures.

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