Kristen Kelley, MD

INTRODUCTION: Methylene blue (MB) has recently gained traction as an adjunctive therapy in the management of vasoplegia. Due to risk of inducing oxidative hemolysis its use should be avoided in patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency Although rare, drug induced oxidative hemolysis can still occur in patients without G6PD deficiency. In this report, we describe a case of severe oxidative hemolysis in a G6PD sufficient adult following administration of a large dose of MB.

CASE REPORT: A 78-year-old male with a history of coronary artery disease was admitted for coronary artery bypass graft surgery. Patient underwent surgery without any major complications. Post operatively however he developed severe shock refractory to multiple vasopressors and inotropes. A presumptive diagnosis of vasoplegia was made for which the patient was given multiple boluses of MB. Hemodynamics improved thus the patient was started on a MB infusion. Approximately 24 hours later the patient was noted to have an acute drop in his hemoglobin from 9.9 to 8.0 g/dl. He was transfused multiple units of blood with only transient improvements in his hemoglobin. Physical exam and imaging revealed no evidence of bleeding. Additional workup was notable for an LDH of 7222 U/L and an elevated bilirubin raising concern for hemolytic anemia.

Review of his peripheral smear was notable for the presence of numerous bite cells. A diagnosis of oxidative hemolytic anemia secondary to MB administration was made. MB infusion was discontinued and within 48 hours the patient’s LDH normalized and hemoglobin had stabilized. A quantitative G6PD test ordered during the acute hemolytic period and was reported as normal. Due to the possibility of a falsely normal result in the setting of active hemolysis, G6PD testing was repeated two months following discharge and was also normal.

CONCLUSIONS: Methylene blue can be a lifesaving medication in the setting of severe vasoplegia. However, clinicians should be aware of the possibility of inducing severe oxidative hemolytic anemia even in G6PD sufficient patients when giving this agent in large doses. Management of oxidative hemolysis secondary to MB is supportive care with prompt discontinuation resulting in resolution of hemolysis.

INTRODUCTION: Methylene blue (MB) has recently gained traction as an adjunctive therapy in the management of vasoplegia. Due to risk of inducing oxidative hemolysis its use should be avoided in patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency Although rare, drug induced oxidative hemolysis can still occur in patients without G6PD deficiency. In this report, we describe a case of severe oxidative hemolysis in a G6PD sufficient adult following administration of a large dose of MB.

CASE REPORT: A 78-year-old male with a history of coronary artery disease was admitted for coronary artery bypass graft surgery. Patient underwent surgery without any major complications. Post operatively however he developed severe shock refractory to multiple vasopressors and inotropes. A presumptive diagnosis of vasoplegia was made for which the patient was given multiple boluses of MB. Hemodynamics improved thus the patient was started on a MB infusion. Approximately 24 hours later the patient was noted to have an acute drop in his hemoglobin from 9.9 to 8.0 g/dl. He was transfused multiple units of blood with only transient improvements in his hemoglobin. Physical exam and imaging revealed no evidence of bleeding. Additional workup was notable for an LDH of 7222 U/L and an elevated bilirubin raising concern for hemolytic anemia.

Review of his peripheral smear was notable for the presence of numerous bite cells. A diagnosis of oxidative hemolytic anemia secondary to MB administration was made. MB infusion was discontinued and within 48 hours the patient’s LDH normalized and hemoglobin had stabilized. A quantitative G6PD test ordered during the acute hemolytic period and was reported as normal. Due to the possibility of a falsely normal result in the setting of active hemolysis, G6PD testing was repeated two months following discharge and was also normal.

CONCLUSIONS: Methylene blue can be a lifesaving medication in the setting of severe vasoplegia. However, clinicians should be aware of the possibility of inducing severe oxidative hemolytic anemia even in G6PD sufficient patients when giving this agent in large doses. Management of oxidative hemolysis secondary to MB is supportive care with prompt discontinuation resulting in resolution of hemolysis.

INTRODUCTION: Methylene blue (MB) has recently gained traction as an adjunctive therapy in the management of vasoplegia. Due to risk of inducing oxidative hemolysis its use should be avoided in patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency Although rare, drug induced oxidative hemolysis can still occur in patients without G6PD deficiency. In this report, we describe a case of severe oxidative hemolysis in a G6PD sufficient adult following administration of a large dose of MB.

CASE REPORT: A 78-year-old male with a history of coronary artery disease was admitted for coronary artery bypass graft surgery. Patient underwent surgery without any major complications. Post operatively however he developed severe shock refractory to multiple vasopressors and inotropes. A presumptive diagnosis of vasoplegia was made for which the patient was given multiple boluses of MB. Hemodynamics improved thus the patient was started on a MB infusion. Approximately 24 hours later the patient was noted to have an acute drop in his hemoglobin from 9.9 to 8.0 g/dl. He was transfused multiple units of blood with only transient improvements in his hemoglobin. Physical exam and imaging revealed no evidence of bleeding. Additional workup was notable for an LDH of 7222 U/L and an elevated bilirubin raising concern for hemolytic anemia.

Review of his peripheral smear was notable for the presence of numerous bite cells. A diagnosis of oxidative hemolytic anemia secondary to MB administration was made. MB infusion was discontinued and within 48 hours the patient’s LDH normalized and hemoglobin had stabilized. A quantitative G6PD test ordered during the acute hemolytic period and was reported as normal. Due to the possibility of a falsely normal result in the setting of active hemolysis, G6PD testing was repeated two months following discharge and was also normal.

CONCLUSIONS: Methylene blue can be a lifesaving medication in the setting of severe vasoplegia. However, clinicians should be aware of the possibility of inducing severe oxidative hemolytic anemia even in G6PD sufficient patients when giving this agent in large doses. Management of oxidative hemolysis secondary to MB is supportive care with prompt discontinuation resulting in resolution of hemolysis.

CASE REPORT: A male smoker aged 51 years with denovo metastatic NSCLC was treated with first-line chemoimmunotherapy. After 4 cycles, an EML4-ALK fusion was identified. At time of disease progression, alectinib 600mg BID was started after an 8-week washout period. Within 2 weeks, he developed a pruritic rash covering 90% of his BSA that required hospitalization and IV steroids. Biopsy confirmed a spongiotic and interface dermatitis with eosinophils consistent with a drug eruption. Rash was reported as an adverse event in the ALEX trial in 17% of patients treated with front-line alectinib but grade 3 rash was reported in only 1%.

A literature search demonstrated successful case reports of alectinib de-sensitization and thus a de-sensitization protocol was devised. Alectinib was started at 150mg daily and increased to 300mg BID over 2 weeks. His rash worsened resulting in a drug hold, treatment with oral prednisone, and a dose reduction to 300mg daily. The dose was increased to 300mg/450mg over 1 week when he developed painful mouth erosions. This resulted in a second dose hold and reduction to 300mg BID. After 2 weeks, alectinib was discontinued due to worsening rash with a plan to switch to an alternate ALK TKI, a strategy which has been successfully reported in the literature. Lorlatinib 100mg was recommended given phase 2 data demonstrating very low rates of rash (5% grade 1-2 and < 1% grade 3). While he did experience a facial rash within 2 weeks, a dose hold or reduction was not required. Nonetheless, lorlatinib was discontinued after 4 weeks due to other intolerable side effects and hypertriglyceridemia

DISCUSSION: Pembrolizumab has a terminal half-life of 22 days with steady state reached at 16 weeks with every 3-week dosing. It is therefore possible that prior exposure to pembrolizumab exacerbated the cutaneous toxicity of alectinib in this case. Multiple studies have shown that combining immunotherapy with alectinib leads to substantially more adverse events.

CONCLUSION: In patients with alectinib hypersensitivity, a de-sensitization protocol can be attempted. If hypersensitivity recurs, switching to an alternate ALK TKI is warranted. However, if immunotherapy has been previously administered without time for adequate washout, no TKI therapy may be tolerable.

CASE REPORT: A male smoker aged 51 years with denovo metastatic NSCLC was treated with first-line chemoimmunotherapy. After 4 cycles, an EML4-ALK fusion was identified. At time of disease progression, alectinib 600mg BID was started after an 8-week washout period. Within 2 weeks, he developed a pruritic rash covering 90% of his BSA that required hospitalization and IV steroids. Biopsy confirmed a spongiotic and interface dermatitis with eosinophils consistent with a drug eruption. Rash was reported as an adverse event in the ALEX trial in 17% of patients treated with front-line alectinib but grade 3 rash was reported in only 1%.

A literature search demonstrated successful case reports of alectinib de-sensitization and thus a de-sensitization protocol was devised. Alectinib was started at 150mg daily and increased to 300mg BID over 2 weeks. His rash worsened resulting in a drug hold, treatment with oral prednisone, and a dose reduction to 300mg daily. The dose was increased to 300mg/450mg over 1 week when he developed painful mouth erosions. This resulted in a second dose hold and reduction to 300mg BID. After 2 weeks, alectinib was discontinued due to worsening rash with a plan to switch to an alternate ALK TKI, a strategy which has been successfully reported in the literature. Lorlatinib 100mg was recommended given phase 2 data demonstrating very low rates of rash (5% grade 1-2 and < 1% grade 3). While he did experience a facial rash within 2 weeks, a dose hold or reduction was not required. Nonetheless, lorlatinib was discontinued after 4 weeks due to other intolerable side effects and hypertriglyceridemia

DISCUSSION: Pembrolizumab has a terminal half-life of 22 days with steady state reached at 16 weeks with every 3-week dosing. It is therefore possible that prior exposure to pembrolizumab exacerbated the cutaneous toxicity of alectinib in this case. Multiple studies have shown that combining immunotherapy with alectinib leads to substantially more adverse events.

CONCLUSION: In patients with alectinib hypersensitivity, a de-sensitization protocol can be attempted. If hypersensitivity recurs, switching to an alternate ALK TKI is warranted. However, if immunotherapy has been previously administered without time for adequate washout, no TKI therapy may be tolerable.

CASE REPORT: A male smoker aged 51 years with denovo metastatic NSCLC was treated with first-line chemoimmunotherapy. After 4 cycles, an EML4-ALK fusion was identified. At time of disease progression, alectinib 600mg BID was started after an 8-week washout period. Within 2 weeks, he developed a pruritic rash covering 90% of his BSA that required hospitalization and IV steroids. Biopsy confirmed a spongiotic and interface dermatitis with eosinophils consistent with a drug eruption. Rash was reported as an adverse event in the ALEX trial in 17% of patients treated with front-line alectinib but grade 3 rash was reported in only 1%.

A literature search demonstrated successful case reports of alectinib de-sensitization and thus a de-sensitization protocol was devised. Alectinib was started at 150mg daily and increased to 300mg BID over 2 weeks. His rash worsened resulting in a drug hold, treatment with oral prednisone, and a dose reduction to 300mg daily. The dose was increased to 300mg/450mg over 1 week when he developed painful mouth erosions. This resulted in a second dose hold and reduction to 300mg BID. After 2 weeks, alectinib was discontinued due to worsening rash with a plan to switch to an alternate ALK TKI, a strategy which has been successfully reported in the literature. Lorlatinib 100mg was recommended given phase 2 data demonstrating very low rates of rash (5% grade 1-2 and < 1% grade 3). While he did experience a facial rash within 2 weeks, a dose hold or reduction was not required. Nonetheless, lorlatinib was discontinued after 4 weeks due to other intolerable side effects and hypertriglyceridemia

DISCUSSION: Pembrolizumab has a terminal half-life of 22 days with steady state reached at 16 weeks with every 3-week dosing. It is therefore possible that prior exposure to pembrolizumab exacerbated the cutaneous toxicity of alectinib in this case. Multiple studies have shown that combining immunotherapy with alectinib leads to substantially more adverse events.

CONCLUSION: In patients with alectinib hypersensitivity, a de-sensitization protocol can be attempted. If hypersensitivity recurs, switching to an alternate ALK TKI is warranted. However, if immunotherapy has been previously administered without time for adequate washout, no TKI therapy may be tolerable.