Article

The Diagnosis: Lymphomatoid Papulosis

At the time of the initial visit, a punch biopsy was performed on the posterior shoulder girdle. Histopathology revealed mild epidermal spongiosis and acanthosis with associated parakeratosis and a dermal lymphocytic infiltrate with extravasated erythrocytes consistent with pityriasis rosea (Figure 1). Two weeks after the biopsy, the patient returned for suture removal and to discuss the biopsy results. The patient reported more evolving lesions despite completing the prescribed course of dicloxacillin. At this time, physical examination revealed the persistence of several reddishbrown papules along with new nodular lesions on the arms and thighs, some with central ulceration and crusting (Figure 2). A second biopsy of a nodular lesion on the right distal forearm was performed at this visit along with a superficial tissue culture, which was negative for bacterial or fungal elements. The biopsy revealed an atypical CD30⁺ lymphoid proliferation (Figure 3). These cells were strongly PD-L1 positive and also positive for CD3, CD4, and granzyme-B. Ki67 showed a high proliferation rate, and T-cell gene rearrangement studies were positive. Given these histologic findings and the clinical context of rapidly evolving skin lesions from small papules to nodular skin tumors, a diagnosis of lymphomatoid papulosis (LyP) was established.

Because of the notable pathologic discordance between the 2 biopsy specimens, re-evaluation of the initial specimen was requested. The initial biopsy was subsequently found to be CD30⁺ with an identical peak on gene rearrangement studies as the second biopsy, further validating the diagnosis of LyP (Figure 4). Our patient was offered low-dose methotrexate therapy but declined the treatment plan, as the skin lesions had begun to resolve.

Lymphomatoid papulosis is a chronic CD30⁺ lymphoproliferative disorder with a characteristic recurrent and self-remitting disease course.^1,2 Although it typically has a benign clinical course, it is histologically malignant and considered a low-grade variant of cutaneous T-cell lymphoma. ^2,3 The classic clinical presentation of LyP involves the presence of reddish-brown papules and nodules typically measuring less than 2.0 cm, which may show evidence of central ulceration, hemorrhage, necrosis, and/or crust formation.^1-5 It is characteristic that a patient may present with these skin lesions in different stages of evolution and that biopsies of these lesions may reflect different histologic features depending on the age of the lesion, making a definitive diagnosis more difficult to obtain if not clinically correlated.^1,2 Any part of the body may be involved; however, there appears to be a predilection for the trunk and extremities in most cases.^1-3,5 The skin eruptions usually are asymptomatic, but pruritus is a commonly associated concern.^1,2,4,5

Lymphomatoid papulosis can have a localized, clustered, or generalized distribution pattern and typically will spontaneously regress without treatment within 3 to 12 weeks of symptom onset.^2,3 Lymphomatoid papulosis has a slight male predominance with a male to female ratio of 1.5:1. It occurs most commonly between 35 and 45 years of age, though it can present at any age. The overall duration of the disease can range from months to decades.^2,3 Lymphomatoid papulosis makes up approximately 15% of all cutaneous T-cell lymphomas.^2,3 Although the overall prognosis is excellent, patients with LyP are at an increased risk of developing cutaneous or systemic lymphoma, most commonly mycosis fungoides, anaplastic large cell lymphoma, or Hodgkin lymphoma.^1-3 This increased lifelong risk is the reason that patients with LyP must be followed long-term every 6 to 12 months for surveillance of emerging malignancy.^1,2,6

The pathogenesis of LyP remains unknown. Some have hypothesized a possible viral trigger; however, there is insufficient data to support this theory.^2,6 A diagnostic hallmark of LyP is its CD30 positivity, which is a known marker for T-cell activation.6 The spontaneous regression of skin lesions that is characteristic of LyP is believed to involve the interactions between CD30 and its ligand (CD30L), which may contribute to apoptosis of neoplastic T cells.^2,3,6 With regards to the possible mechanisms contributing to tumor progression in LyP, a mutation in the transforming growth factor β receptor gene on CD30+ tumor cells within LyP lesions may allow for these cells to evade growth regulation and progress to lymphoma.^2,6 A large percentage of LyP biopsy specimens show evidence of T-cell receptor gene monoclonal rearrangement, which can aid in establishing a diagnosis.^1,2

The histologic features of LyP can vary greatly depending on the age of the lesion sampled.^1,2 Histologic subtypes of LyP have been established, with type A being the most common (approximately 75% of cases), displaying a wedge-shaped infiltrate of scattered or clustered, large, atypical CD30+ T cells.^1,2 Types B through E vary in histologic features, with the exception that all subtypes contain a CD30+ lymphocytic infiltrate.^2,3

Treatment of LyP depends on the symptom/disease burden that the patient is experiencing. For patients with a limited number of nonscarring skin lesions in areas that are not cosmetically sensitive, observation is recommended. ^1-3 For symptomatic patients with an extensive number of lesions, particularly those that may be scarring and/or in cosmetically sensitive areas, low-dose oral methotrexate therapy is considered first-line treatment.^1-4 A methotrexate dose of 5 to 20 mg weekly can be effective in reducing the number and severity of lesions, with duration of treatment depending on clinical response.^1,2 For patients who have contraindications to or who cannot tolerate oral methotrexate, phototherapy using psoralen plus UVA twice weekly for 6 to 8 weeks is another treatment option.^1,2 Topical corticosteroids also can be used in children or for patients experiencing substantial pruritus.^1,2,4 Oral or topical retinoids, topical carmustine or mechlorethamine, and brentuximab (an anti-CD30 monoclonal antibody) are all alternative therapies that have shown some beneficial effects.^1,2 In the event that any of the skin lesions do not spontaneously regress within a 3- to 12-week time frame, surgical excision or radiotherapy can be performed on those lesions.²

Primary cutaneous anaplastic large cell lymphoma (C-ALCL) is another CD30+ lymphoproliferative disorder with overlapping clinical and histopathological features of LyP. Recurrent crops of multiple lesions favor a diagnosis of LyP, whereas solitary lesions favor C-ALCL; however, multifocal C-ALCL cases may occur.² Mycosis fungoides is the most common type of cutaneous T-cell lymphoma that characteristically presents in a patch, plaque, tumor progression. Although mycosis fungoides eventually may transform into a CD30⁺ lymphoma, our patient did not display the characteristic clinical progression to suggest this diagnosis. Pityriasis lichenoides et varioliformis acuta and pityriasis lichenoides chronica also fall into the spectrum of clonal T-cell cutaneous disorders that more commonly affect the pediatric population. Pityriasis lichenoides et varioliformis acuta has a marked CD8⁺ lymphocyte infiltrate, whereas pityriasis lichenoides chronica has more CD4⁺ lymphocytes. These disorders typically do not stain positive for CD30.²

All patients with a diagnosis of LyP should maintain lifelong, regular, 6- to 12-month follow-up visits to monitor disease status and screen for any evidence of developing malignancy.^1,2,6 A thorough review of clinical history, complete skin examination, and physical examination with a particular focus on detection of lymphadenopathy and hepatosplenomegaly should be included at every followup visit.1 Systemic symptoms such as fever, night sweats, or weight loss are not typical features of LyP; therefore, patients who begin to develop these symptoms should be promptly evaluated for systemic lymphoma.¹

The Diagnosis: Lymphomatoid Papulosis

At the time of the initial visit, a punch biopsy was performed on the posterior shoulder girdle. Histopathology revealed mild epidermal spongiosis and acanthosis with associated parakeratosis and a dermal lymphocytic infiltrate with extravasated erythrocytes consistent with pityriasis rosea (Figure 1). Two weeks after the biopsy, the patient returned for suture removal and to discuss the biopsy results. The patient reported more evolving lesions despite completing the prescribed course of dicloxacillin. At this time, physical examination revealed the persistence of several reddishbrown papules along with new nodular lesions on the arms and thighs, some with central ulceration and crusting (Figure 2). A second biopsy of a nodular lesion on the right distal forearm was performed at this visit along with a superficial tissue culture, which was negative for bacterial or fungal elements. The biopsy revealed an atypical CD30⁺ lymphoid proliferation (Figure 3). These cells were strongly PD-L1 positive and also positive for CD3, CD4, and granzyme-B. Ki67 showed a high proliferation rate, and T-cell gene rearrangement studies were positive. Given these histologic findings and the clinical context of rapidly evolving skin lesions from small papules to nodular skin tumors, a diagnosis of lymphomatoid papulosis (LyP) was established.

Because of the notable pathologic discordance between the 2 biopsy specimens, re-evaluation of the initial specimen was requested. The initial biopsy was subsequently found to be CD30⁺ with an identical peak on gene rearrangement studies as the second biopsy, further validating the diagnosis of LyP (Figure 4). Our patient was offered low-dose methotrexate therapy but declined the treatment plan, as the skin lesions had begun to resolve.

Lymphomatoid papulosis is a chronic CD30⁺ lymphoproliferative disorder with a characteristic recurrent and self-remitting disease course.^1,2 Although it typically has a benign clinical course, it is histologically malignant and considered a low-grade variant of cutaneous T-cell lymphoma. ^2,3 The classic clinical presentation of LyP involves the presence of reddish-brown papules and nodules typically measuring less than 2.0 cm, which may show evidence of central ulceration, hemorrhage, necrosis, and/or crust formation.^1-5 It is characteristic that a patient may present with these skin lesions in different stages of evolution and that biopsies of these lesions may reflect different histologic features depending on the age of the lesion, making a definitive diagnosis more difficult to obtain if not clinically correlated.^1,2 Any part of the body may be involved; however, there appears to be a predilection for the trunk and extremities in most cases.^1-3,5 The skin eruptions usually are asymptomatic, but pruritus is a commonly associated concern.^1,2,4,5

Lymphomatoid papulosis can have a localized, clustered, or generalized distribution pattern and typically will spontaneously regress without treatment within 3 to 12 weeks of symptom onset.^2,3 Lymphomatoid papulosis has a slight male predominance with a male to female ratio of 1.5:1. It occurs most commonly between 35 and 45 years of age, though it can present at any age. The overall duration of the disease can range from months to decades.^2,3 Lymphomatoid papulosis makes up approximately 15% of all cutaneous T-cell lymphomas.^2,3 Although the overall prognosis is excellent, patients with LyP are at an increased risk of developing cutaneous or systemic lymphoma, most commonly mycosis fungoides, anaplastic large cell lymphoma, or Hodgkin lymphoma.^1-3 This increased lifelong risk is the reason that patients with LyP must be followed long-term every 6 to 12 months for surveillance of emerging malignancy.^1,2,6

The pathogenesis of LyP remains unknown. Some have hypothesized a possible viral trigger; however, there is insufficient data to support this theory.^2,6 A diagnostic hallmark of LyP is its CD30 positivity, which is a known marker for T-cell activation.6 The spontaneous regression of skin lesions that is characteristic of LyP is believed to involve the interactions between CD30 and its ligand (CD30L), which may contribute to apoptosis of neoplastic T cells.^2,3,6 With regards to the possible mechanisms contributing to tumor progression in LyP, a mutation in the transforming growth factor β receptor gene on CD30+ tumor cells within LyP lesions may allow for these cells to evade growth regulation and progress to lymphoma.^2,6 A large percentage of LyP biopsy specimens show evidence of T-cell receptor gene monoclonal rearrangement, which can aid in establishing a diagnosis.^1,2

The histologic features of LyP can vary greatly depending on the age of the lesion sampled.^1,2 Histologic subtypes of LyP have been established, with type A being the most common (approximately 75% of cases), displaying a wedge-shaped infiltrate of scattered or clustered, large, atypical CD30+ T cells.^1,2 Types B through E vary in histologic features, with the exception that all subtypes contain a CD30+ lymphocytic infiltrate.^2,3

Treatment of LyP depends on the symptom/disease burden that the patient is experiencing. For patients with a limited number of nonscarring skin lesions in areas that are not cosmetically sensitive, observation is recommended. ^1-3 For symptomatic patients with an extensive number of lesions, particularly those that may be scarring and/or in cosmetically sensitive areas, low-dose oral methotrexate therapy is considered first-line treatment.^1-4 A methotrexate dose of 5 to 20 mg weekly can be effective in reducing the number and severity of lesions, with duration of treatment depending on clinical response.^1,2 For patients who have contraindications to or who cannot tolerate oral methotrexate, phototherapy using psoralen plus UVA twice weekly for 6 to 8 weeks is another treatment option.^1,2 Topical corticosteroids also can be used in children or for patients experiencing substantial pruritus.^1,2,4 Oral or topical retinoids, topical carmustine or mechlorethamine, and brentuximab (an anti-CD30 monoclonal antibody) are all alternative therapies that have shown some beneficial effects.^1,2 In the event that any of the skin lesions do not spontaneously regress within a 3- to 12-week time frame, surgical excision or radiotherapy can be performed on those lesions.²

Primary cutaneous anaplastic large cell lymphoma (C-ALCL) is another CD30+ lymphoproliferative disorder with overlapping clinical and histopathological features of LyP. Recurrent crops of multiple lesions favor a diagnosis of LyP, whereas solitary lesions favor C-ALCL; however, multifocal C-ALCL cases may occur.² Mycosis fungoides is the most common type of cutaneous T-cell lymphoma that characteristically presents in a patch, plaque, tumor progression. Although mycosis fungoides eventually may transform into a CD30⁺ lymphoma, our patient did not display the characteristic clinical progression to suggest this diagnosis. Pityriasis lichenoides et varioliformis acuta and pityriasis lichenoides chronica also fall into the spectrum of clonal T-cell cutaneous disorders that more commonly affect the pediatric population. Pityriasis lichenoides et varioliformis acuta has a marked CD8⁺ lymphocyte infiltrate, whereas pityriasis lichenoides chronica has more CD4⁺ lymphocytes. These disorders typically do not stain positive for CD30.²

All patients with a diagnosis of LyP should maintain lifelong, regular, 6- to 12-month follow-up visits to monitor disease status and screen for any evidence of developing malignancy.^1,2,6 A thorough review of clinical history, complete skin examination, and physical examination with a particular focus on detection of lymphadenopathy and hepatosplenomegaly should be included at every followup visit.1 Systemic symptoms such as fever, night sweats, or weight loss are not typical features of LyP; therefore, patients who begin to develop these symptoms should be promptly evaluated for systemic lymphoma.¹

The Diagnosis: Lymphomatoid Papulosis

At the time of the initial visit, a punch biopsy was performed on the posterior shoulder girdle. Histopathology revealed mild epidermal spongiosis and acanthosis with associated parakeratosis and a dermal lymphocytic infiltrate with extravasated erythrocytes consistent with pityriasis rosea (Figure 1). Two weeks after the biopsy, the patient returned for suture removal and to discuss the biopsy results. The patient reported more evolving lesions despite completing the prescribed course of dicloxacillin. At this time, physical examination revealed the persistence of several reddishbrown papules along with new nodular lesions on the arms and thighs, some with central ulceration and crusting (Figure 2). A second biopsy of a nodular lesion on the right distal forearm was performed at this visit along with a superficial tissue culture, which was negative for bacterial or fungal elements. The biopsy revealed an atypical CD30⁺ lymphoid proliferation (Figure 3). These cells were strongly PD-L1 positive and also positive for CD3, CD4, and granzyme-B. Ki67 showed a high proliferation rate, and T-cell gene rearrangement studies were positive. Given these histologic findings and the clinical context of rapidly evolving skin lesions from small papules to nodular skin tumors, a diagnosis of lymphomatoid papulosis (LyP) was established.

Because of the notable pathologic discordance between the 2 biopsy specimens, re-evaluation of the initial specimen was requested. The initial biopsy was subsequently found to be CD30⁺ with an identical peak on gene rearrangement studies as the second biopsy, further validating the diagnosis of LyP (Figure 4). Our patient was offered low-dose methotrexate therapy but declined the treatment plan, as the skin lesions had begun to resolve.

Lymphomatoid papulosis is a chronic CD30⁺ lymphoproliferative disorder with a characteristic recurrent and self-remitting disease course.^1,2 Although it typically has a benign clinical course, it is histologically malignant and considered a low-grade variant of cutaneous T-cell lymphoma. ^2,3 The classic clinical presentation of LyP involves the presence of reddish-brown papules and nodules typically measuring less than 2.0 cm, which may show evidence of central ulceration, hemorrhage, necrosis, and/or crust formation.^1-5 It is characteristic that a patient may present with these skin lesions in different stages of evolution and that biopsies of these lesions may reflect different histologic features depending on the age of the lesion, making a definitive diagnosis more difficult to obtain if not clinically correlated.^1,2 Any part of the body may be involved; however, there appears to be a predilection for the trunk and extremities in most cases.^1-3,5 The skin eruptions usually are asymptomatic, but pruritus is a commonly associated concern.^1,2,4,5

Lymphomatoid papulosis can have a localized, clustered, or generalized distribution pattern and typically will spontaneously regress without treatment within 3 to 12 weeks of symptom onset.^2,3 Lymphomatoid papulosis has a slight male predominance with a male to female ratio of 1.5:1. It occurs most commonly between 35 and 45 years of age, though it can present at any age. The overall duration of the disease can range from months to decades.^2,3 Lymphomatoid papulosis makes up approximately 15% of all cutaneous T-cell lymphomas.^2,3 Although the overall prognosis is excellent, patients with LyP are at an increased risk of developing cutaneous or systemic lymphoma, most commonly mycosis fungoides, anaplastic large cell lymphoma, or Hodgkin lymphoma.^1-3 This increased lifelong risk is the reason that patients with LyP must be followed long-term every 6 to 12 months for surveillance of emerging malignancy.^1,2,6

The pathogenesis of LyP remains unknown. Some have hypothesized a possible viral trigger; however, there is insufficient data to support this theory.^2,6 A diagnostic hallmark of LyP is its CD30 positivity, which is a known marker for T-cell activation.6 The spontaneous regression of skin lesions that is characteristic of LyP is believed to involve the interactions between CD30 and its ligand (CD30L), which may contribute to apoptosis of neoplastic T cells.^2,3,6 With regards to the possible mechanisms contributing to tumor progression in LyP, a mutation in the transforming growth factor β receptor gene on CD30+ tumor cells within LyP lesions may allow for these cells to evade growth regulation and progress to lymphoma.^2,6 A large percentage of LyP biopsy specimens show evidence of T-cell receptor gene monoclonal rearrangement, which can aid in establishing a diagnosis.^1,2

The histologic features of LyP can vary greatly depending on the age of the lesion sampled.^1,2 Histologic subtypes of LyP have been established, with type A being the most common (approximately 75% of cases), displaying a wedge-shaped infiltrate of scattered or clustered, large, atypical CD30+ T cells.^1,2 Types B through E vary in histologic features, with the exception that all subtypes contain a CD30+ lymphocytic infiltrate.^2,3

Treatment of LyP depends on the symptom/disease burden that the patient is experiencing. For patients with a limited number of nonscarring skin lesions in areas that are not cosmetically sensitive, observation is recommended. ^1-3 For symptomatic patients with an extensive number of lesions, particularly those that may be scarring and/or in cosmetically sensitive areas, low-dose oral methotrexate therapy is considered first-line treatment.^1-4 A methotrexate dose of 5 to 20 mg weekly can be effective in reducing the number and severity of lesions, with duration of treatment depending on clinical response.^1,2 For patients who have contraindications to or who cannot tolerate oral methotrexate, phototherapy using psoralen plus UVA twice weekly for 6 to 8 weeks is another treatment option.^1,2 Topical corticosteroids also can be used in children or for patients experiencing substantial pruritus.^1,2,4 Oral or topical retinoids, topical carmustine or mechlorethamine, and brentuximab (an anti-CD30 monoclonal antibody) are all alternative therapies that have shown some beneficial effects.^1,2 In the event that any of the skin lesions do not spontaneously regress within a 3- to 12-week time frame, surgical excision or radiotherapy can be performed on those lesions.²

Primary cutaneous anaplastic large cell lymphoma (C-ALCL) is another CD30+ lymphoproliferative disorder with overlapping clinical and histopathological features of LyP. Recurrent crops of multiple lesions favor a diagnosis of LyP, whereas solitary lesions favor C-ALCL; however, multifocal C-ALCL cases may occur.² Mycosis fungoides is the most common type of cutaneous T-cell lymphoma that characteristically presents in a patch, plaque, tumor progression. Although mycosis fungoides eventually may transform into a CD30⁺ lymphoma, our patient did not display the characteristic clinical progression to suggest this diagnosis. Pityriasis lichenoides et varioliformis acuta and pityriasis lichenoides chronica also fall into the spectrum of clonal T-cell cutaneous disorders that more commonly affect the pediatric population. Pityriasis lichenoides et varioliformis acuta has a marked CD8⁺ lymphocyte infiltrate, whereas pityriasis lichenoides chronica has more CD4⁺ lymphocytes. These disorders typically do not stain positive for CD30.²

All patients with a diagnosis of LyP should maintain lifelong, regular, 6- to 12-month follow-up visits to monitor disease status and screen for any evidence of developing malignancy.^1,2,6 A thorough review of clinical history, complete skin examination, and physical examination with a particular focus on detection of lymphadenopathy and hepatosplenomegaly should be included at every followup visit.1 Systemic symptoms such as fever, night sweats, or weight loss are not typical features of LyP; therefore, patients who begin to develop these symptoms should be promptly evaluated for systemic lymphoma.¹

Liver transplantation cures both HCC and the underlying cirrhosis; however, tumor progression while the patient is on the waiting list is an ongoing concern. Couillard and colleagues reported a retrospective study of 88 patients with HCC who underwent percutaneous microwave ablation for 141 tumors while on the liver transplant list. The median follow-up was 61 months. Seventy-one patients (80.7%) underwent liver transplantation after a median wait time of 8.5 months. No tumor seeding was identified. Seventeen patients (19.3%) were removed from the waitlist, four (4.5%) of whom because of tumor progression outside of the Milan criteria. A total of five of 71 (7.0%) patients had posttransplant recurrence of HCC and all died during this time. The 5-year overall survival (OS) following liver transplantation was 76.7% and the disease-specific survival after transplantation was 89.6%. The authors concluded that microwave ablation is a safe and effective treatment that bridges patients to successful transplantation.

Radiation segmentectomy is performed by the administration of radioactive yttrium (⁹⁰Y)-bound microspheres transarterially to the segment of liver containing an unresected tumor. Kim and colleagues described the results of a prospective trial that evaluated the efficacy of radiation segmentectomy with curative intent in patients with Child-Pugh score A–B7 and small (< 3 cm), unresectable HCC, where the tumors were in a location unsuitable for ablation. Of the 44 individuals assessed for eligibility, 29 patients were included in the study. A complete response was observed in 24 (83%) patients, and a partial response was observed in 5 (17%) patients. All patients had an initial objective tumor response, and 26 (90%) had a sustained complete response during 24 months of clinical follow-up. The treatment was well tolerated, with four (14%) patients having grade 3 leukopenia and two (7%) having grade 3 thrombocytopenia. The authors concluded that radiation segmentectomy should be investigated further as a potentially curative option for patients with HCC.

Portal vein thrombosis (PVT) has been considered a contraindication to transarterial chemoembolization (TACE) due to the concern for inadvertent liver ischemia if the hepatic artery becomes obstructed. Several studies have demonstrated that this risk is low. Stereotactic body radiation therapy (SBRT) is used to effectively target HCC (especially when there is a portal vein tumor) while minimizing collateral damage to the liver. Zhang and colleagues performed a meta-analysis of nine studies totaling 938 patients who had HCC with tumor PVT. Of those, 483 received either SBRT or TACE, and 455 were treated with both TACE and SBRT. There were 255 events reported in the monotherapy groups and 174 events in the combination groups. Following statistical analyses of all available data, the authors concluded that SBRT plus TACE yielded significantly higher 1-year OS (RR [relative risk] 1.52; 95% CI 1.33-1.74), 2-year OS (RR 2.00; 95% CI 1.48-2.70), and a lower progressive disease rate (RR 0.45; 95% CI 0.26-0.79) than monotherapy. The combination treatment was both safe and effective.

Liver transplantation cures both HCC and the underlying cirrhosis; however, tumor progression while the patient is on the waiting list is an ongoing concern. Couillard and colleagues reported a retrospective study of 88 patients with HCC who underwent percutaneous microwave ablation for 141 tumors while on the liver transplant list. The median follow-up was 61 months. Seventy-one patients (80.7%) underwent liver transplantation after a median wait time of 8.5 months. No tumor seeding was identified. Seventeen patients (19.3%) were removed from the waitlist, four (4.5%) of whom because of tumor progression outside of the Milan criteria. A total of five of 71 (7.0%) patients had posttransplant recurrence of HCC and all died during this time. The 5-year overall survival (OS) following liver transplantation was 76.7% and the disease-specific survival after transplantation was 89.6%. The authors concluded that microwave ablation is a safe and effective treatment that bridges patients to successful transplantation.

Radiation segmentectomy is performed by the administration of radioactive yttrium (⁹⁰Y)-bound microspheres transarterially to the segment of liver containing an unresected tumor. Kim and colleagues described the results of a prospective trial that evaluated the efficacy of radiation segmentectomy with curative intent in patients with Child-Pugh score A–B7 and small (< 3 cm), unresectable HCC, where the tumors were in a location unsuitable for ablation. Of the 44 individuals assessed for eligibility, 29 patients were included in the study. A complete response was observed in 24 (83%) patients, and a partial response was observed in 5 (17%) patients. All patients had an initial objective tumor response, and 26 (90%) had a sustained complete response during 24 months of clinical follow-up. The treatment was well tolerated, with four (14%) patients having grade 3 leukopenia and two (7%) having grade 3 thrombocytopenia. The authors concluded that radiation segmentectomy should be investigated further as a potentially curative option for patients with HCC.

Portal vein thrombosis (PVT) has been considered a contraindication to transarterial chemoembolization (TACE) due to the concern for inadvertent liver ischemia if the hepatic artery becomes obstructed. Several studies have demonstrated that this risk is low. Stereotactic body radiation therapy (SBRT) is used to effectively target HCC (especially when there is a portal vein tumor) while minimizing collateral damage to the liver. Zhang and colleagues performed a meta-analysis of nine studies totaling 938 patients who had HCC with tumor PVT. Of those, 483 received either SBRT or TACE, and 455 were treated with both TACE and SBRT. There were 255 events reported in the monotherapy groups and 174 events in the combination groups. Following statistical analyses of all available data, the authors concluded that SBRT plus TACE yielded significantly higher 1-year OS (RR [relative risk] 1.52; 95% CI 1.33-1.74), 2-year OS (RR 2.00; 95% CI 1.48-2.70), and a lower progressive disease rate (RR 0.45; 95% CI 0.26-0.79) than monotherapy. The combination treatment was both safe and effective.

Liver transplantation cures both HCC and the underlying cirrhosis; however, tumor progression while the patient is on the waiting list is an ongoing concern. Couillard and colleagues reported a retrospective study of 88 patients with HCC who underwent percutaneous microwave ablation for 141 tumors while on the liver transplant list. The median follow-up was 61 months. Seventy-one patients (80.7%) underwent liver transplantation after a median wait time of 8.5 months. No tumor seeding was identified. Seventeen patients (19.3%) were removed from the waitlist, four (4.5%) of whom because of tumor progression outside of the Milan criteria. A total of five of 71 (7.0%) patients had posttransplant recurrence of HCC and all died during this time. The 5-year overall survival (OS) following liver transplantation was 76.7% and the disease-specific survival after transplantation was 89.6%. The authors concluded that microwave ablation is a safe and effective treatment that bridges patients to successful transplantation.

Radiation segmentectomy is performed by the administration of radioactive yttrium (⁹⁰Y)-bound microspheres transarterially to the segment of liver containing an unresected tumor. Kim and colleagues described the results of a prospective trial that evaluated the efficacy of radiation segmentectomy with curative intent in patients with Child-Pugh score A–B7 and small (< 3 cm), unresectable HCC, where the tumors were in a location unsuitable for ablation. Of the 44 individuals assessed for eligibility, 29 patients were included in the study. A complete response was observed in 24 (83%) patients, and a partial response was observed in 5 (17%) patients. All patients had an initial objective tumor response, and 26 (90%) had a sustained complete response during 24 months of clinical follow-up. The treatment was well tolerated, with four (14%) patients having grade 3 leukopenia and two (7%) having grade 3 thrombocytopenia. The authors concluded that radiation segmentectomy should be investigated further as a potentially curative option for patients with HCC.

Portal vein thrombosis (PVT) has been considered a contraindication to transarterial chemoembolization (TACE) due to the concern for inadvertent liver ischemia if the hepatic artery becomes obstructed. Several studies have demonstrated that this risk is low. Stereotactic body radiation therapy (SBRT) is used to effectively target HCC (especially when there is a portal vein tumor) while minimizing collateral damage to the liver. Zhang and colleagues performed a meta-analysis of nine studies totaling 938 patients who had HCC with tumor PVT. Of those, 483 received either SBRT or TACE, and 455 were treated with both TACE and SBRT. There were 255 events reported in the monotherapy groups and 174 events in the combination groups. Following statistical analyses of all available data, the authors concluded that SBRT plus TACE yielded significantly higher 1-year OS (RR [relative risk] 1.52; 95% CI 1.33-1.74), 2-year OS (RR 2.00; 95% CI 1.48-2.70), and a lower progressive disease rate (RR 0.45; 95% CI 0.26-0.79) than monotherapy. The combination treatment was both safe and effective.

Liver transplantation cures both HCC and the underlying cirrhosis; however, tumor progression while the patient is on the waiting list is an ongoing concern. Couillard and colleagues reported a retrospective study of 88 patients with HCC who underwent percutaneous microwave ablation for 141 tumors while on the liver transplant list. The median follow-up was 61 months. Seventy-one patients (80.7%) underwent liver transplantation after a median wait time of 8.5 months. No tumor seeding was identified. Seventeen patients (19.3%) were removed from the waitlist, four (4.5%) of whom because of tumor progression outside of the Milan criteria. A total of five of 71 (7.0%) patients had posttransplant recurrence of HCC and all died during this time. The 5-year overall survival (OS) following liver transplantation was 76.7% and the disease-specific survival after transplantation was 89.6%. The authors concluded that microwave ablation is a safe and effective treatment that bridges patients to successful transplantation.

Radiation segmentectomy is performed by the administration of radioactive yttrium (⁹⁰Y)-bound microspheres transarterially to the segment of liver containing an unresected tumor. Kim and colleagues described the results of a prospective trial that evaluated the efficacy of radiation segmentectomy with curative intent in patients with Child-Pugh score A–B7 and small (< 3 cm), unresectable HCC, where the tumors were in a location unsuitable for ablation. Of the 44 individuals assessed for eligibility, 29 patients were included in the study. A complete response was observed in 24 (83%) patients, and a partial response was observed in 5 (17%) patients. All patients had an initial objective tumor response, and 26 (90%) had a sustained complete response during 24 months of clinical follow-up. The treatment was well tolerated, with four (14%) patients having grade 3 leukopenia and two (7%) having grade 3 thrombocytopenia. The authors concluded that radiation segmentectomy should be investigated further as a potentially curative option for patients with HCC.

Portal vein thrombosis (PVT) has been considered a contraindication to transarterial chemoembolization (TACE) due to the concern for inadvertent liver ischemia if the hepatic artery becomes obstructed. Several studies have demonstrated that this risk is low. Stereotactic body radiation therapy (SBRT) is used to effectively target HCC (especially when there is a portal vein tumor) while minimizing collateral damage to the liver. Zhang and colleagues performed a meta-analysis of nine studies totaling 938 patients who had HCC with tumor PVT. Of those, 483 received either SBRT or TACE, and 455 were treated with both TACE and SBRT. There were 255 events reported in the monotherapy groups and 174 events in the combination groups. Following statistical analyses of all available data, the authors concluded that SBRT plus TACE yielded significantly higher 1-year OS (RR [relative risk] 1.52; 95% CI 1.33-1.74), 2-year OS (RR 2.00; 95% CI 1.48-2.70), and a lower progressive disease rate (RR 0.45; 95% CI 0.26-0.79) than monotherapy. The combination treatment was both safe and effective.

Liver transplantation cures both HCC and the underlying cirrhosis; however, tumor progression while the patient is on the waiting list is an ongoing concern. Couillard and colleagues reported a retrospective study of 88 patients with HCC who underwent percutaneous microwave ablation for 141 tumors while on the liver transplant list. The median follow-up was 61 months. Seventy-one patients (80.7%) underwent liver transplantation after a median wait time of 8.5 months. No tumor seeding was identified. Seventeen patients (19.3%) were removed from the waitlist, four (4.5%) of whom because of tumor progression outside of the Milan criteria. A total of five of 71 (7.0%) patients had posttransplant recurrence of HCC and all died during this time. The 5-year overall survival (OS) following liver transplantation was 76.7% and the disease-specific survival after transplantation was 89.6%. The authors concluded that microwave ablation is a safe and effective treatment that bridges patients to successful transplantation.

Radiation segmentectomy is performed by the administration of radioactive yttrium (⁹⁰Y)-bound microspheres transarterially to the segment of liver containing an unresected tumor. Kim and colleagues described the results of a prospective trial that evaluated the efficacy of radiation segmentectomy with curative intent in patients with Child-Pugh score A–B7 and small (< 3 cm), unresectable HCC, where the tumors were in a location unsuitable for ablation. Of the 44 individuals assessed for eligibility, 29 patients were included in the study. A complete response was observed in 24 (83%) patients, and a partial response was observed in 5 (17%) patients. All patients had an initial objective tumor response, and 26 (90%) had a sustained complete response during 24 months of clinical follow-up. The treatment was well tolerated, with four (14%) patients having grade 3 leukopenia and two (7%) having grade 3 thrombocytopenia. The authors concluded that radiation segmentectomy should be investigated further as a potentially curative option for patients with HCC.

Portal vein thrombosis (PVT) has been considered a contraindication to transarterial chemoembolization (TACE) due to the concern for inadvertent liver ischemia if the hepatic artery becomes obstructed. Several studies have demonstrated that this risk is low. Stereotactic body radiation therapy (SBRT) is used to effectively target HCC (especially when there is a portal vein tumor) while minimizing collateral damage to the liver. Zhang and colleagues performed a meta-analysis of nine studies totaling 938 patients who had HCC with tumor PVT. Of those, 483 received either SBRT or TACE, and 455 were treated with both TACE and SBRT. There were 255 events reported in the monotherapy groups and 174 events in the combination groups. Following statistical analyses of all available data, the authors concluded that SBRT plus TACE yielded significantly higher 1-year OS (RR [relative risk] 1.52; 95% CI 1.33-1.74), 2-year OS (RR 2.00; 95% CI 1.48-2.70), and a lower progressive disease rate (RR 0.45; 95% CI 0.26-0.79) than monotherapy. The combination treatment was both safe and effective.

Liver transplantation cures both HCC and the underlying cirrhosis; however, tumor progression while the patient is on the waiting list is an ongoing concern. Couillard and colleagues reported a retrospective study of 88 patients with HCC who underwent percutaneous microwave ablation for 141 tumors while on the liver transplant list. The median follow-up was 61 months. Seventy-one patients (80.7%) underwent liver transplantation after a median wait time of 8.5 months. No tumor seeding was identified. Seventeen patients (19.3%) were removed from the waitlist, four (4.5%) of whom because of tumor progression outside of the Milan criteria. A total of five of 71 (7.0%) patients had posttransplant recurrence of HCC and all died during this time. The 5-year overall survival (OS) following liver transplantation was 76.7% and the disease-specific survival after transplantation was 89.6%. The authors concluded that microwave ablation is a safe and effective treatment that bridges patients to successful transplantation.

Radiation segmentectomy is performed by the administration of radioactive yttrium (⁹⁰Y)-bound microspheres transarterially to the segment of liver containing an unresected tumor. Kim and colleagues described the results of a prospective trial that evaluated the efficacy of radiation segmentectomy with curative intent in patients with Child-Pugh score A–B7 and small (< 3 cm), unresectable HCC, where the tumors were in a location unsuitable for ablation. Of the 44 individuals assessed for eligibility, 29 patients were included in the study. A complete response was observed in 24 (83%) patients, and a partial response was observed in 5 (17%) patients. All patients had an initial objective tumor response, and 26 (90%) had a sustained complete response during 24 months of clinical follow-up. The treatment was well tolerated, with four (14%) patients having grade 3 leukopenia and two (7%) having grade 3 thrombocytopenia. The authors concluded that radiation segmentectomy should be investigated further as a potentially curative option for patients with HCC.

Portal vein thrombosis (PVT) has been considered a contraindication to transarterial chemoembolization (TACE) due to the concern for inadvertent liver ischemia if the hepatic artery becomes obstructed. Several studies have demonstrated that this risk is low. Stereotactic body radiation therapy (SBRT) is used to effectively target HCC (especially when there is a portal vein tumor) while minimizing collateral damage to the liver. Zhang and colleagues performed a meta-analysis of nine studies totaling 938 patients who had HCC with tumor PVT. Of those, 483 received either SBRT or TACE, and 455 were treated with both TACE and SBRT. There were 255 events reported in the monotherapy groups and 174 events in the combination groups. Following statistical analyses of all available data, the authors concluded that SBRT plus TACE yielded significantly higher 1-year OS (RR [relative risk] 1.52; 95% CI 1.33-1.74), 2-year OS (RR 2.00; 95% CI 1.48-2.70), and a lower progressive disease rate (RR 0.45; 95% CI 0.26-0.79) than monotherapy. The combination treatment was both safe and effective.

First, Blauvelt and colleagues presented findings from the ongoing LIBERTY AD PED-OLE open-label extension study, including 294 adolescents with moderate to severe AD who participated in previous dupilumab trials. Patients received a maintenance dose of 300 mg dupilumab every 4 weeks, which was increased to a weight-based every-other-week regimen if there was inadequate clinical response to every-4-week dosing. They found that 81.2% of patients achieved an Eczema Area and Severity Index (EASI-75) response at week 52 with every-4-week dosing, and 51.9% of patients at week 48 after switching to every-2-week doing. These results indicate that some adolescents may be able to maintain clinical efficacy with monthly dosing, while others may require every-2-week dosing. Of note, no new safety signals emerged during the study and most adverse events were mild to moderate.

Two more studies were published showing real-world effectiveness and safety of dupilumab. Eichenfield and colleagues performed a retrospective, observational study of the effectiveness of dupilumab after 4 months of treatment using data from national electronic medical records in adults with moderate-to-severe AD. They found that most patients achieved at least a one-grade (81.8%) or two-grade (62.8%) improvement of their Investigator's Global Assessment (IGA) scores, with 42.8% achieving IGA scores of 0/1 (clear/minimal). There were also significant improvements in itch and lesional extent. The results were remarkably similar to those observed in the phase 3 clinical trial program of dupilumab in adults with moderate-to-severe AD.

Bagel and colleagues published baseline characteristics of patients enrolled in the ongoing PROSE longitudinal real-world registry of dupilumab use in adults with moderate-to-severe AD. Almost half of the patients (49.5%) previously received systemic medications, including 41.0% with systemic corticosteroids, 16.8% with nonsteroidal systemic therapies, such as cyclosporine and methotrexate, and 10.2% with phototherapy. This result indicates that many medical professionals are not using dupilumab as a first-line systemic therapy, despite its established record on safety and efficacy. It appears that many clinicians prefer a short-term treatment regimen, such as systemic corticosteroids, prior to initiating long-term treatment with dupilumab. However, short-term treatment approaches are not ideal for this chronic and often lifelong disease. It is important that clinicians develop appropriate long-term treatment approaches for atopic dermatitis in general, regardless of any specific therapy.

On a different research note, my research group just published the results of a longitudinal dermatology practice–based study of depressive symptoms in 695 adults with AD over time.¹ We found that approximately half of the patients experienced fluctuating severity of depressive symptoms, and 45.65% experienced persistent severity of depression. Severity of AD lesions and itch were the strongest predictors of more severe symptoms of depression. Perhaps most fascinating about this research was that symptoms of depression improved dramatically in a very large subset of patients who experienced reduced AD severity with standard-of-care treatment. These results highlight the broader impacts of AD on mental health, which were recently recognized by the American Academy of Dermatology's guideline update on AD comorbidities.² Moreover, our study demonstrated that many of these mental health impacts were modifiable with optimized AD therapy.

Additional References

1.         Chatrath S, Lei D, Yousaf M, et al. vc Longitudinal course and predictors of depressive symptoms in atopic dermatitis. J Am Acad Dermatol. 2022 (May 9). Doi: 10.1016/j.jaad.2022.04.061

2.         Davis DMR, Drucker AM, Alikhan A, et al. American Academy of Dermatology Guidelines: Awareness of comorbidities associated with atopic dermatitis in adults. J Am Acad Dermatol. 2022;86:1335-1336.e18. Doi: 10.1016/j.jaad.2022.01.009

First, Blauvelt and colleagues presented findings from the ongoing LIBERTY AD PED-OLE open-label extension study, including 294 adolescents with moderate to severe AD who participated in previous dupilumab trials. Patients received a maintenance dose of 300 mg dupilumab every 4 weeks, which was increased to a weight-based every-other-week regimen if there was inadequate clinical response to every-4-week dosing. They found that 81.2% of patients achieved an Eczema Area and Severity Index (EASI-75) response at week 52 with every-4-week dosing, and 51.9% of patients at week 48 after switching to every-2-week doing. These results indicate that some adolescents may be able to maintain clinical efficacy with monthly dosing, while others may require every-2-week dosing. Of note, no new safety signals emerged during the study and most adverse events were mild to moderate.

Two more studies were published showing real-world effectiveness and safety of dupilumab. Eichenfield and colleagues performed a retrospective, observational study of the effectiveness of dupilumab after 4 months of treatment using data from national electronic medical records in adults with moderate-to-severe AD. They found that most patients achieved at least a one-grade (81.8%) or two-grade (62.8%) improvement of their Investigator's Global Assessment (IGA) scores, with 42.8% achieving IGA scores of 0/1 (clear/minimal). There were also significant improvements in itch and lesional extent. The results were remarkably similar to those observed in the phase 3 clinical trial program of dupilumab in adults with moderate-to-severe AD.

Bagel and colleagues published baseline characteristics of patients enrolled in the ongoing PROSE longitudinal real-world registry of dupilumab use in adults with moderate-to-severe AD. Almost half of the patients (49.5%) previously received systemic medications, including 41.0% with systemic corticosteroids, 16.8% with nonsteroidal systemic therapies, such as cyclosporine and methotrexate, and 10.2% with phototherapy. This result indicates that many medical professionals are not using dupilumab as a first-line systemic therapy, despite its established record on safety and efficacy. It appears that many clinicians prefer a short-term treatment regimen, such as systemic corticosteroids, prior to initiating long-term treatment with dupilumab. However, short-term treatment approaches are not ideal for this chronic and often lifelong disease. It is important that clinicians develop appropriate long-term treatment approaches for atopic dermatitis in general, regardless of any specific therapy.

On a different research note, my research group just published the results of a longitudinal dermatology practice–based study of depressive symptoms in 695 adults with AD over time.¹ We found that approximately half of the patients experienced fluctuating severity of depressive symptoms, and 45.65% experienced persistent severity of depression. Severity of AD lesions and itch were the strongest predictors of more severe symptoms of depression. Perhaps most fascinating about this research was that symptoms of depression improved dramatically in a very large subset of patients who experienced reduced AD severity with standard-of-care treatment. These results highlight the broader impacts of AD on mental health, which were recently recognized by the American Academy of Dermatology's guideline update on AD comorbidities.² Moreover, our study demonstrated that many of these mental health impacts were modifiable with optimized AD therapy.

Additional References

1.         Chatrath S, Lei D, Yousaf M, et al. vc Longitudinal course and predictors of depressive symptoms in atopic dermatitis. J Am Acad Dermatol. 2022 (May 9). Doi: 10.1016/j.jaad.2022.04.061

2.         Davis DMR, Drucker AM, Alikhan A, et al. American Academy of Dermatology Guidelines: Awareness of comorbidities associated with atopic dermatitis in adults. J Am Acad Dermatol. 2022;86:1335-1336.e18. Doi: 10.1016/j.jaad.2022.01.009

First, Blauvelt and colleagues presented findings from the ongoing LIBERTY AD PED-OLE open-label extension study, including 294 adolescents with moderate to severe AD who participated in previous dupilumab trials. Patients received a maintenance dose of 300 mg dupilumab every 4 weeks, which was increased to a weight-based every-other-week regimen if there was inadequate clinical response to every-4-week dosing. They found that 81.2% of patients achieved an Eczema Area and Severity Index (EASI-75) response at week 52 with every-4-week dosing, and 51.9% of patients at week 48 after switching to every-2-week doing. These results indicate that some adolescents may be able to maintain clinical efficacy with monthly dosing, while others may require every-2-week dosing. Of note, no new safety signals emerged during the study and most adverse events were mild to moderate.

Two more studies were published showing real-world effectiveness and safety of dupilumab. Eichenfield and colleagues performed a retrospective, observational study of the effectiveness of dupilumab after 4 months of treatment using data from national electronic medical records in adults with moderate-to-severe AD. They found that most patients achieved at least a one-grade (81.8%) or two-grade (62.8%) improvement of their Investigator's Global Assessment (IGA) scores, with 42.8% achieving IGA scores of 0/1 (clear/minimal). There were also significant improvements in itch and lesional extent. The results were remarkably similar to those observed in the phase 3 clinical trial program of dupilumab in adults with moderate-to-severe AD.

Bagel and colleagues published baseline characteristics of patients enrolled in the ongoing PROSE longitudinal real-world registry of dupilumab use in adults with moderate-to-severe AD. Almost half of the patients (49.5%) previously received systemic medications, including 41.0% with systemic corticosteroids, 16.8% with nonsteroidal systemic therapies, such as cyclosporine and methotrexate, and 10.2% with phototherapy. This result indicates that many medical professionals are not using dupilumab as a first-line systemic therapy, despite its established record on safety and efficacy. It appears that many clinicians prefer a short-term treatment regimen, such as systemic corticosteroids, prior to initiating long-term treatment with dupilumab. However, short-term treatment approaches are not ideal for this chronic and often lifelong disease. It is important that clinicians develop appropriate long-term treatment approaches for atopic dermatitis in general, regardless of any specific therapy.

On a different research note, my research group just published the results of a longitudinal dermatology practice–based study of depressive symptoms in 695 adults with AD over time.¹ We found that approximately half of the patients experienced fluctuating severity of depressive symptoms, and 45.65% experienced persistent severity of depression. Severity of AD lesions and itch were the strongest predictors of more severe symptoms of depression. Perhaps most fascinating about this research was that symptoms of depression improved dramatically in a very large subset of patients who experienced reduced AD severity with standard-of-care treatment. These results highlight the broader impacts of AD on mental health, which were recently recognized by the American Academy of Dermatology's guideline update on AD comorbidities.² Moreover, our study demonstrated that many of these mental health impacts were modifiable with optimized AD therapy.

Additional References

1.         Chatrath S, Lei D, Yousaf M, et al. vc Longitudinal course and predictors of depressive symptoms in atopic dermatitis. J Am Acad Dermatol. 2022 (May 9). Doi: 10.1016/j.jaad.2022.04.061

2.         Davis DMR, Drucker AM, Alikhan A, et al. American Academy of Dermatology Guidelines: Awareness of comorbidities associated with atopic dermatitis in adults. J Am Acad Dermatol. 2022;86:1335-1336.e18. Doi: 10.1016/j.jaad.2022.01.009

Dr Ann Partridge from the Dana-Farber Cancer Institute in Boston, Massachusetts, highlights important new data in early breast cancer presented at American Society of Clinical Oncology (ASCO) 2022. 

Dr Partridge begins with promising results from the NeoSTAR study, which looked at the use of the novel antibody-drug conjugate (ADC) sacituzumab govitecan in the neoadjuvant setting. This is the first trial of an ADC in patients with triple-negative breast cancer (TNBC) and demonstrated single-agent efficacy in localized TNBC. 

Next, Dr Partridge discusses the 8-year post-trial follow-up of the ASTRRA study, which randomly assigned patients to 5 years of tamoxifen or 5 years of tamoxifen plus 2 years of ovarian suppression. The findings demonstrated consistent survival advantage and suggest that adding ovarian function suppression to tamoxifen should be considered for those who remain in a premenopausal state or resume ovarian function after chemotherapy. 

Looking to potential new biomarkers for risk recurrence, Dr Partridge reports on provocative data from the CHiRP study. The investigators looked at the use of circulating tumor DNA to identify minimal residual disease and predict clinical outcomes in high-risk, early-stage HR+ breast cancer. Although additional research is needed, Dr Partridge is encouraged that in the near future, the use of circulating DNA technology will help guide therapeutic decisions in early breast cancer. 

--

Ann H. Partridge, MD, MPH, Professor of Medicine; Vice Chair of Medical Oncology, Department of Breast Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 

Ann H. Partridge, MD, MPH, has disclosed no relevant financial relationships. 

Dr Ann Partridge from the Dana-Farber Cancer Institute in Boston, Massachusetts, highlights important new data in early breast cancer presented at American Society of Clinical Oncology (ASCO) 2022. 

Dr Partridge begins with promising results from the NeoSTAR study, which looked at the use of the novel antibody-drug conjugate (ADC) sacituzumab govitecan in the neoadjuvant setting. This is the first trial of an ADC in patients with triple-negative breast cancer (TNBC) and demonstrated single-agent efficacy in localized TNBC. 

Next, Dr Partridge discusses the 8-year post-trial follow-up of the ASTRRA study, which randomly assigned patients to 5 years of tamoxifen or 5 years of tamoxifen plus 2 years of ovarian suppression. The findings demonstrated consistent survival advantage and suggest that adding ovarian function suppression to tamoxifen should be considered for those who remain in a premenopausal state or resume ovarian function after chemotherapy. 

Looking to potential new biomarkers for risk recurrence, Dr Partridge reports on provocative data from the CHiRP study. The investigators looked at the use of circulating tumor DNA to identify minimal residual disease and predict clinical outcomes in high-risk, early-stage HR+ breast cancer. Although additional research is needed, Dr Partridge is encouraged that in the near future, the use of circulating DNA technology will help guide therapeutic decisions in early breast cancer. 

--

Ann H. Partridge, MD, MPH, Professor of Medicine; Vice Chair of Medical Oncology, Department of Breast Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 

Ann H. Partridge, MD, MPH, has disclosed no relevant financial relationships. 

Dr Ann Partridge from the Dana-Farber Cancer Institute in Boston, Massachusetts, highlights important new data in early breast cancer presented at American Society of Clinical Oncology (ASCO) 2022. 

Dr Partridge begins with promising results from the NeoSTAR study, which looked at the use of the novel antibody-drug conjugate (ADC) sacituzumab govitecan in the neoadjuvant setting. This is the first trial of an ADC in patients with triple-negative breast cancer (TNBC) and demonstrated single-agent efficacy in localized TNBC. 

Next, Dr Partridge discusses the 8-year post-trial follow-up of the ASTRRA study, which randomly assigned patients to 5 years of tamoxifen or 5 years of tamoxifen plus 2 years of ovarian suppression. The findings demonstrated consistent survival advantage and suggest that adding ovarian function suppression to tamoxifen should be considered for those who remain in a premenopausal state or resume ovarian function after chemotherapy. 

Looking to potential new biomarkers for risk recurrence, Dr Partridge reports on provocative data from the CHiRP study. The investigators looked at the use of circulating tumor DNA to identify minimal residual disease and predict clinical outcomes in high-risk, early-stage HR+ breast cancer. Although additional research is needed, Dr Partridge is encouraged that in the near future, the use of circulating DNA technology will help guide therapeutic decisions in early breast cancer. 

--

Ann H. Partridge, MD, MPH, Professor of Medicine; Vice Chair of Medical Oncology, Department of Breast Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 

Ann H. Partridge, MD, MPH, has disclosed no relevant financial relationships. 

Dr Harold J. Burstein, from the Dana-Farber Cancer Institute in Boston, Massachusetts, reports on important abstracts in the management of metastatic breast cancer from the 2022 American Society of Clinical Oncology (ASCO) annual meeting. 

Dr Burstein first highlights results from the NRG-BR002 trial, a randomized phase 2 study comparing standard therapy vs standard therapy in combination with focal stereotactic radiation treatment for oligometastatic disease in up to four sites. Investigators reported no impact on progression-free or overall survival.  

Exciting results from the DESTINY-Breast04 trial were a "showstopper," according to Dr Burstein. Investigators reported prolonged progression-free survival and overall survival in patients with HER2-low unresectable and/or metastatic disease with the use of the antibody-drug conjugate trastuzumab deruxtecan compared with physicians' choice of standard single-agent chemotherapy, advancing a new treatment option for the large subset of patients with HER2-low disease. 

Next, Dr Burstein discusses results from the TROPiCS-02 trial, which compared another antibody-drug conjugate, sacituzumab govitecan, with standard chemotherapy in patients with ER+/HER- breast cancer. A statistically significant benefit was reported, although the progression-free survival at just 6 weeks was relatively modest. 

Finally, Dr Burstein reports on interesting data from the MAINTAIN study, a phase 2 randomized trial looking at maintenance CDK4/6 inhibition after progression on initial treatment. Results suggest that switching endocrine therapy and continuing treatment with CDK4/6 inhibitor ribociclib beyond progression may be of clinical value to patients.

--

Harold J. Burstein, MD, PhD, Professor, Department of Medicine, Harvard Medical School; Medical Oncologist, Dana-Farber Cancer Institute, Brigham & Women's Hospital, Boston, Massachusetts 

Harold J. Burstein, MD, PhD, has disclosed no relevant financial relationships. 

Dr Harold J. Burstein, from the Dana-Farber Cancer Institute in Boston, Massachusetts, reports on important abstracts in the management of metastatic breast cancer from the 2022 American Society of Clinical Oncology (ASCO) annual meeting. 

Dr Burstein first highlights results from the NRG-BR002 trial, a randomized phase 2 study comparing standard therapy vs standard therapy in combination with focal stereotactic radiation treatment for oligometastatic disease in up to four sites. Investigators reported no impact on progression-free or overall survival.  

Exciting results from the DESTINY-Breast04 trial were a "showstopper," according to Dr Burstein. Investigators reported prolonged progression-free survival and overall survival in patients with HER2-low unresectable and/or metastatic disease with the use of the antibody-drug conjugate trastuzumab deruxtecan compared with physicians' choice of standard single-agent chemotherapy, advancing a new treatment option for the large subset of patients with HER2-low disease. 

Next, Dr Burstein discusses results from the TROPiCS-02 trial, which compared another antibody-drug conjugate, sacituzumab govitecan, with standard chemotherapy in patients with ER+/HER- breast cancer. A statistically significant benefit was reported, although the progression-free survival at just 6 weeks was relatively modest. 

Finally, Dr Burstein reports on interesting data from the MAINTAIN study, a phase 2 randomized trial looking at maintenance CDK4/6 inhibition after progression on initial treatment. Results suggest that switching endocrine therapy and continuing treatment with CDK4/6 inhibitor ribociclib beyond progression may be of clinical value to patients.

--

Harold J. Burstein, MD, PhD, Professor, Department of Medicine, Harvard Medical School; Medical Oncologist, Dana-Farber Cancer Institute, Brigham & Women's Hospital, Boston, Massachusetts 

Harold J. Burstein, MD, PhD, has disclosed no relevant financial relationships. 

Dr Harold J. Burstein, from the Dana-Farber Cancer Institute in Boston, Massachusetts, reports on important abstracts in the management of metastatic breast cancer from the 2022 American Society of Clinical Oncology (ASCO) annual meeting. 

Dr Burstein first highlights results from the NRG-BR002 trial, a randomized phase 2 study comparing standard therapy vs standard therapy in combination with focal stereotactic radiation treatment for oligometastatic disease in up to four sites. Investigators reported no impact on progression-free or overall survival.  

Exciting results from the DESTINY-Breast04 trial were a "showstopper," according to Dr Burstein. Investigators reported prolonged progression-free survival and overall survival in patients with HER2-low unresectable and/or metastatic disease with the use of the antibody-drug conjugate trastuzumab deruxtecan compared with physicians' choice of standard single-agent chemotherapy, advancing a new treatment option for the large subset of patients with HER2-low disease. 

Next, Dr Burstein discusses results from the TROPiCS-02 trial, which compared another antibody-drug conjugate, sacituzumab govitecan, with standard chemotherapy in patients with ER+/HER- breast cancer. A statistically significant benefit was reported, although the progression-free survival at just 6 weeks was relatively modest. 

Finally, Dr Burstein reports on interesting data from the MAINTAIN study, a phase 2 randomized trial looking at maintenance CDK4/6 inhibition after progression on initial treatment. Results suggest that switching endocrine therapy and continuing treatment with CDK4/6 inhibitor ribociclib beyond progression may be of clinical value to patients.

--

Harold J. Burstein, MD, PhD, Professor, Department of Medicine, Harvard Medical School; Medical Oncologist, Dana-Farber Cancer Institute, Brigham & Women's Hospital, Boston, Massachusetts 

Harold J. Burstein, MD, PhD, has disclosed no relevant financial relationships. 

Cardiologist Martha Gulati, from the American Society for Preventive Cardiology, offers insight on the key findings in diabetes and heart disease presented at the 2022 annual meeting of the American College of Cardiology.  

First, Dr Gulati shares updates from the SCORED trial, which looked at SGLT2 inhibitors and cardiovascular and renal event reduction in patients with type 2 diabetes and chronic kidney disease.  

Next, she shares insight on CHAP, an important study about chronic hypertension in pregnancy. Researchers found that more aggressive blood pressure control reduced adverse pregnancy outcomes.  

She then discusses the SuperWIN trial, which looked at various types of educational interventions regarding heart-healthy diet provided in supermarkets. The goal of this study was to assess adherence to the DASH diet.  

Dr Gulati closes her report with the PROMPT-HF trial, which aimed at improving the use of guideline-directed medical therapy in outpatients with heart failure. 

--

President, American Society for Preventive Cardiology, Jacksonville, Florida 

Martha Gulati, MD, has disclosed no relevant financial relationships. 

Cardiologist Martha Gulati, from the American Society for Preventive Cardiology, offers insight on the key findings in diabetes and heart disease presented at the 2022 annual meeting of the American College of Cardiology.  

First, Dr Gulati shares updates from the SCORED trial, which looked at SGLT2 inhibitors and cardiovascular and renal event reduction in patients with type 2 diabetes and chronic kidney disease.  

Next, she shares insight on CHAP, an important study about chronic hypertension in pregnancy. Researchers found that more aggressive blood pressure control reduced adverse pregnancy outcomes.  

She then discusses the SuperWIN trial, which looked at various types of educational interventions regarding heart-healthy diet provided in supermarkets. The goal of this study was to assess adherence to the DASH diet.  

Dr Gulati closes her report with the PROMPT-HF trial, which aimed at improving the use of guideline-directed medical therapy in outpatients with heart failure. 

--

President, American Society for Preventive Cardiology, Jacksonville, Florida 

Martha Gulati, MD, has disclosed no relevant financial relationships. 

Cardiologist Martha Gulati, from the American Society for Preventive Cardiology, offers insight on the key findings in diabetes and heart disease presented at the 2022 annual meeting of the American College of Cardiology.  

First, Dr Gulati shares updates from the SCORED trial, which looked at SGLT2 inhibitors and cardiovascular and renal event reduction in patients with type 2 diabetes and chronic kidney disease.  

Next, she shares insight on CHAP, an important study about chronic hypertension in pregnancy. Researchers found that more aggressive blood pressure control reduced adverse pregnancy outcomes.  

She then discusses the SuperWIN trial, which looked at various types of educational interventions regarding heart-healthy diet provided in supermarkets. The goal of this study was to assess adherence to the DASH diet.  

Dr Gulati closes her report with the PROMPT-HF trial, which aimed at improving the use of guideline-directed medical therapy in outpatients with heart failure. 

--

President, American Society for Preventive Cardiology, Jacksonville, Florida 

Martha Gulati, MD, has disclosed no relevant financial relationships. 

As a class of drugs, proteasome inhibitors are known to rarely cause drug-induced thrombotic microangiopathy (DITMA). In particular, carfilzomib is a second-generation, irreversible proteasome inhibitor approved for the treatment of relapsed, refractory multiple myeloma (MM) in combination with other therapeutic agents.¹ Although generally well tolerated, carfilzomib has been associated with serious adverse events such as cardiovascular toxicity and DITMA.^2-4 Thrombotic microangiopathy (TMA) is a life-threatening disorder characterized by thrombocytopenia, microangiopathic hemolytic anemia, and end-organ damage.⁵ Its occurrence secondary to carfilzomib has been reported only rarely in clinical trials of MM, and the most effective management of the disorder as well as the concurrent risk factors that contribute to its development remain incompletely understood.^6,7 As a result, given both the expanding use of carfilzomib in practice and the morbidity of TMA, descriptions of carfilzomib-induced TMA from the real-world setting continue to provide important contributions to our understanding of the disorder.

At our US Department of Veterans Affairs (VA) medical center, 2 patients developed severe carfilzomib-induced TMA within days of one another. The presentation of simultaneous cases was highly unexpected and offered the unique opportunity to compare clinical features in real time. Here, we describe our 2 cases in detail, review their presentations and management in the context of the prior literature, and discuss potential insights gained into the disease.

Case Presentation

Case 1

A 78-year-old male patient was diagnosed with monoclonal gammopathy of undetermined significance in 2012 that progressed to Revised International Staging System stage II IgG-κ MM in 2016 due to worsening anemia with a hemoglobin level < 10 g/dL (Table 1). He was treated initially with 8 cycles of first-line bortezomib, lenalidomide, and dexamethasone, to which he achieved a partial response with > 50% reduction in serum M-protein. He then received 3 cycles of maintenance bortezomib until relapse, at which time he was switched to second-line therapy consisting of carfilzomib 20 mg/m² on days 1 and 2 and 56 mg/m² on days 8, 9, 15, and 16 for cycle 1, followed by 56 mg/m² on days 1, 2, 8, 9, 15, and 16 for subsequent cycles plus dexamethasone 20 mg twice weekly every 28 days.

After the patient received cycle 3, day 1 of carfilzomib, he developed subjective fevers, chills, and diarrhea. He missed his day 2 infusion and instead presented to the VA emergency department, where his vital signs were stable and laboratory tests were notable for the following levels: leukocytosis of20.3 K/µL (91.7% neutrophils), hemoglobin 12.4 g/dL (prior 13.5 g/dL), platelet count 171 K/µL, and creatinine 1.39 mg/dL (prior 1.13 g/dL). A chest X-ray demonstrated diffuse bilateral opacities concerning for edema vs infection, and he was started empirically on vancomycin, piperacillin-tazobactam, and azithromycin. His outpatient medications, which included acyclovir, aspirin, finasteride, oxybutynin, ranitidine, omega-3 fatty acids, fish oil, vitamin D, and senna, were continued as indicated.

On hospital day 2, the patient’s platelet count dropped to 81 K/µL and creatinine level rose to 1.78 mg/dL. He developed dark urine (urinalysis [UA] 3+ blood, 6-11 red blood cells per high power field [RBC/HPF]) and had laboratory tests suggestive of hemolysis, including lactic dehydrogenase (LDH) > 1,200 IU/L (reference range, 60-250 IU/L), haptoglobin < 30 mg/dL (reference range, 44-215 mg/dL), total bilirubin 3.2 mg/dL (reference range, 0.2-1.3 mg/dL; indirect bilirubin, 2.6 mg/dL), and a peripheral blood smear demonstrating moderate microangiopathy (Figure 1).

Case 2

A 59-year-old male patient, diagnosed in 2013 with ISS stage I IgG-κ MM after presenting with compression fractures, completed 8 cycles of cyclophosphamide, bortezomib, and dexamethasone before undergoing autologous hematopoietic stem cell transplantation with complete response (Table 1). He subsequently received single-agent maintenance bortezomib until relapse nearly 2 years later, at which time he started second-line carfilzomib 20 mg/m² on days 1 and 2 and 27 mg/m² on days 8, 9, 15, and 16 for cycle 1, followed by 27 mg/m² on days 8, 9, 15, and 16 for cycles 2 to 8, lenalidomide 25 mg on days 1 to 21, and dexamethasone 40 mg weekly every 28 days. Serum free light chain levels normalized after 9 cycles, and he subsequently began maintenance carfilzomib 70 mg/m² on days 1 and 15 plus lenalidomide 10 mg on days 1 to 21 every 28 days.

On the morning before admission, the patient received C6D17 of maintenance carfilzomib, which had been delayed from day 15 because of the holiday. Later that evening, he developed nausea, vomiting, and fever of 101.3 °F. He presented to the VA emergency department and was tachycardic (108 beats per minute) and hypotensive (86/55 mm Hg). Laboratory tests were notable for hemoglobin level 9.9 g/dL (prior 11.6 g/dL), platelet count 270 K/µL, and creatinine level 1.86 mg/dL (prior 1.12 mg/dL). A respiratory viral panel was positive for influenza A, and antimicrobial agents were eventually broadened to piperacillin-tazobactam, azithromycin, and oseltamivir. His outpatient medications, which included acyclovir, zoledronic acid, sulfamethoxazole/trimethoprim, aspirin, amlodipine, atorvastatin, omeprazole, zolpidem, calcium, vitamin D, loratadine, ascorbic acid, and prochlorperazine, were continued as indicated.

On hospital day 2, the patient’s platelet count declined from 211 to 57 K/µL. He developed tea-colored urine (UA 2+ blood, 0-2 RBC/HPF) and had laboratory tests suggestive of hemolysis, including LDH 910 IU/L (reference range, 60-250 IU/L), total bilirubin 3.3 mg/dL (reference range, 0.2-1.3 mg/dL; no direct or indirect available), and a peripheral blood smear demonstrating moderate microangiopathy. Although haptoglobin level was normal at this time (206 mg/dL; reference range, 44-215 mg/dL), it decreased to 42 mg/dL by the following day. Additional workup included a negative direct Coombs and a DIC panel showing elevated fibrinogen (596 mg/dL; reference range, 200-400 mg/dL) and mildly elevated INR (1.16). Blood cultures remained negative, and a 22-pathogen GI PCR panel identified no viral or bacterial pathogens, including E coli O157:H7. C3 (114 mg/dL; reference range, 90-180 mg/dL) and C4 (40 mg/dL; reference range, 16-47 mg/dL) complement levels were both normal.

Based on these findings, empiric treatment was started with plasma exchange and pulse-dosed steroids. The patient received 3 cycles of plasma exchange until the results of the ADAMTS13 activity ruled out TTP (63% enzyme activity). Over the next 6 days, his platelet count reached a nadir of 6 K/µL and creatinine level peaked at 10.36 mg/dL, necessitating the initiation of hemodialysis. Given severe renal insufficiency, a diagnosis of atypical HUS was again considered, and eculizumab 900 mg was administered on days 9 and 16 with stabilization of renal function. By the time of discharge on day 17, the patient’s creatinine level had decreased to 4.17 mg/dL and platelet count was 164 K/µL. Creatinine level normalized to 1.02 mg/dL by day 72.

Outpatient genetic testing through the BloodCenter of Wisconsin Diagnostic Laboratories was negative for gene mutations associated with atypical HUS. Approximately 1 month after discharge, the patient resumed maintenance lenalidomide alone without reinitiation of proteasome inhibitor therapy.

Discussion

In this case series, we describe the uncommon drug-related adverse event of TMA occurring in 2 patients with MM after receiving carfilzomib. Although the incidence of TMA disorders is low, reaching up to 2.8% in patients receiving carfilzomib plus cyclophosphamide and dexamethasone in the phase 2 CARDAMON trial, our experience suggests that a high index of suspicion for carfilzomib-induced TMA is warranted in the real-world setting.⁸ TMA syndromes, including TTP, HUS, and DITMA, are characterized by microvascular endothelial injury and thrombosis leading to thrombocytopenia and microangiopathic hemolytic anemia.^5,9 Several drug culprits of DITMA are recognized, including quinine, gemcitabine, tacrolimus, and proteasome inhibitors (bortezomib, carfilzomib, ixazomib).^10-12 In a real-world series of patients receiving proteasome inhibitor therapy, either carfilzomib (n=8) or bortezomib (n=3), common clinical features of DITMA included thrombocytopenia, microangiopathic hemolytic anemia, gastrointestinal symptoms, and renal insufficiency with or without a need for hemodialysis.² Although DITMA has been described primarily as an early event, its occurrence after 12 months of proteasome inhibitor therapy has also been reported, both in this series and elsewhere, thereby suggesting an ongoing risk for DITMA throughout the duration of carfilzomib treatment.^2,13

The diagnosis of DITMA can be challenging given its nonspecific symptoms that overlap with other TMA syndromes. Previous studies have proposed that for a drug to be associated with DITMA, there should be: (1) evidence of clinical and/or pathologic findings of TMA; (2) exclusion of alternative causes of TMA; (3) no other new drug exposures other than the suspected culprit medication; and (4) a lack of recurrence of TMA in absence of the drug.¹⁰ In the case of patients with MM, other causes of TMA have also been described, including the underlying plasma cell disorder itself and stem cell transplantation.¹⁴ In the 2 cases we have described, these alternative causes were considered unlikely given that only 1 patient underwent transplantation remotely and neither had a previous history of TMA secondary to their disease. With respect to other TMA syndromes, ADAMTS13 levels > 10% and negative stool studies for E coli O157:H7 suggested against TTP or typical HUS, respectively. No other drug culprits were identified, and the close timing between the receipt of carfilzomib and symptom onset supported a causal relationship.

Because specific therapies are lacking, management of DITMA has traditionally included drug discontinuation and supportive care for end-organ injury.⁵ The terminal complement inhibitor, eculizumab, improves hematologic abnormalities and renal function in patients with atypical HUS but its use for treating patients with DITMA is not standard.¹⁵ Therefore, the decision to administer eculizumab to our 2 patients was driven by their severe renal insufficiency without improvement after plasma exchange, which suggested a phenotype similar to atypical HUS. After administration of eculizumab, renal function stabilized and then gradually improved over weeks to months, a time course similar to that described in cases of patients with DITMA secondary to other anticancer therapies treated with eculizumab.¹⁶ Although these results suggest a potential role for eculizumab in proteasome inhibitor–induced TMA, distinguishing the benefit of eculizumab over drug discontinuation alone remains challenging, and well-designed prospective investigations are needed.

Conclusions

DITMA is a known risk of proteasome inhibitors and is listed as a safety warning in the prescribing information for bortezomib, carfilzomib, and ixazomib.¹² Given the overall rarity of this adverse event, the simultaneous presentation of our 2 cases was unexpected and underscores the need for heightened awareness in clinical practice. In addition, while no underlying complement mutations were identified, eculizumab was used in both cases to successfully stabilize renal function. Further research investigating the efficacy of eculizumab and the role of complement activation in proteasome inhibitor–induced TMA will be valuable.

Acknowledgments

The authors would like to thank the patients whose histories are reported in this manuscript as well as the physicians and staff who provided care during the hospitalizations and beyond. We also thank Oscar Silva, MD, PhD, for his assistance in reviewing and formatting the peripheral blood smear images.

As a class of drugs, proteasome inhibitors are known to rarely cause drug-induced thrombotic microangiopathy (DITMA). In particular, carfilzomib is a second-generation, irreversible proteasome inhibitor approved for the treatment of relapsed, refractory multiple myeloma (MM) in combination with other therapeutic agents.¹ Although generally well tolerated, carfilzomib has been associated with serious adverse events such as cardiovascular toxicity and DITMA.^2-4 Thrombotic microangiopathy (TMA) is a life-threatening disorder characterized by thrombocytopenia, microangiopathic hemolytic anemia, and end-organ damage.⁵ Its occurrence secondary to carfilzomib has been reported only rarely in clinical trials of MM, and the most effective management of the disorder as well as the concurrent risk factors that contribute to its development remain incompletely understood.^6,7 As a result, given both the expanding use of carfilzomib in practice and the morbidity of TMA, descriptions of carfilzomib-induced TMA from the real-world setting continue to provide important contributions to our understanding of the disorder.

At our US Department of Veterans Affairs (VA) medical center, 2 patients developed severe carfilzomib-induced TMA within days of one another. The presentation of simultaneous cases was highly unexpected and offered the unique opportunity to compare clinical features in real time. Here, we describe our 2 cases in detail, review their presentations and management in the context of the prior literature, and discuss potential insights gained into the disease.

Case Presentation

Case 1

A 78-year-old male patient was diagnosed with monoclonal gammopathy of undetermined significance in 2012 that progressed to Revised International Staging System stage II IgG-κ MM in 2016 due to worsening anemia with a hemoglobin level < 10 g/dL (Table 1). He was treated initially with 8 cycles of first-line bortezomib, lenalidomide, and dexamethasone, to which he achieved a partial response with > 50% reduction in serum M-protein. He then received 3 cycles of maintenance bortezomib until relapse, at which time he was switched to second-line therapy consisting of carfilzomib 20 mg/m² on days 1 and 2 and 56 mg/m² on days 8, 9, 15, and 16 for cycle 1, followed by 56 mg/m² on days 1, 2, 8, 9, 15, and 16 for subsequent cycles plus dexamethasone 20 mg twice weekly every 28 days.

After the patient received cycle 3, day 1 of carfilzomib, he developed subjective fevers, chills, and diarrhea. He missed his day 2 infusion and instead presented to the VA emergency department, where his vital signs were stable and laboratory tests were notable for the following levels: leukocytosis of20.3 K/µL (91.7% neutrophils), hemoglobin 12.4 g/dL (prior 13.5 g/dL), platelet count 171 K/µL, and creatinine 1.39 mg/dL (prior 1.13 g/dL). A chest X-ray demonstrated diffuse bilateral opacities concerning for edema vs infection, and he was started empirically on vancomycin, piperacillin-tazobactam, and azithromycin. His outpatient medications, which included acyclovir, aspirin, finasteride, oxybutynin, ranitidine, omega-3 fatty acids, fish oil, vitamin D, and senna, were continued as indicated.

On hospital day 2, the patient’s platelet count dropped to 81 K/µL and creatinine level rose to 1.78 mg/dL. He developed dark urine (urinalysis [UA] 3+ blood, 6-11 red blood cells per high power field [RBC/HPF]) and had laboratory tests suggestive of hemolysis, including lactic dehydrogenase (LDH) > 1,200 IU/L (reference range, 60-250 IU/L), haptoglobin < 30 mg/dL (reference range, 44-215 mg/dL), total bilirubin 3.2 mg/dL (reference range, 0.2-1.3 mg/dL; indirect bilirubin, 2.6 mg/dL), and a peripheral blood smear demonstrating moderate microangiopathy (Figure 1).

Case 2

A 59-year-old male patient, diagnosed in 2013 with ISS stage I IgG-κ MM after presenting with compression fractures, completed 8 cycles of cyclophosphamide, bortezomib, and dexamethasone before undergoing autologous hematopoietic stem cell transplantation with complete response (Table 1). He subsequently received single-agent maintenance bortezomib until relapse nearly 2 years later, at which time he started second-line carfilzomib 20 mg/m² on days 1 and 2 and 27 mg/m² on days 8, 9, 15, and 16 for cycle 1, followed by 27 mg/m² on days 8, 9, 15, and 16 for cycles 2 to 8, lenalidomide 25 mg on days 1 to 21, and dexamethasone 40 mg weekly every 28 days. Serum free light chain levels normalized after 9 cycles, and he subsequently began maintenance carfilzomib 70 mg/m² on days 1 and 15 plus lenalidomide 10 mg on days 1 to 21 every 28 days.

On the morning before admission, the patient received C6D17 of maintenance carfilzomib, which had been delayed from day 15 because of the holiday. Later that evening, he developed nausea, vomiting, and fever of 101.3 °F. He presented to the VA emergency department and was tachycardic (108 beats per minute) and hypotensive (86/55 mm Hg). Laboratory tests were notable for hemoglobin level 9.9 g/dL (prior 11.6 g/dL), platelet count 270 K/µL, and creatinine level 1.86 mg/dL (prior 1.12 mg/dL). A respiratory viral panel was positive for influenza A, and antimicrobial agents were eventually broadened to piperacillin-tazobactam, azithromycin, and oseltamivir. His outpatient medications, which included acyclovir, zoledronic acid, sulfamethoxazole/trimethoprim, aspirin, amlodipine, atorvastatin, omeprazole, zolpidem, calcium, vitamin D, loratadine, ascorbic acid, and prochlorperazine, were continued as indicated.

On hospital day 2, the patient’s platelet count declined from 211 to 57 K/µL. He developed tea-colored urine (UA 2+ blood, 0-2 RBC/HPF) and had laboratory tests suggestive of hemolysis, including LDH 910 IU/L (reference range, 60-250 IU/L), total bilirubin 3.3 mg/dL (reference range, 0.2-1.3 mg/dL; no direct or indirect available), and a peripheral blood smear demonstrating moderate microangiopathy. Although haptoglobin level was normal at this time (206 mg/dL; reference range, 44-215 mg/dL), it decreased to 42 mg/dL by the following day. Additional workup included a negative direct Coombs and a DIC panel showing elevated fibrinogen (596 mg/dL; reference range, 200-400 mg/dL) and mildly elevated INR (1.16). Blood cultures remained negative, and a 22-pathogen GI PCR panel identified no viral or bacterial pathogens, including E coli O157:H7. C3 (114 mg/dL; reference range, 90-180 mg/dL) and C4 (40 mg/dL; reference range, 16-47 mg/dL) complement levels were both normal.

Based on these findings, empiric treatment was started with plasma exchange and pulse-dosed steroids. The patient received 3 cycles of plasma exchange until the results of the ADAMTS13 activity ruled out TTP (63% enzyme activity). Over the next 6 days, his platelet count reached a nadir of 6 K/µL and creatinine level peaked at 10.36 mg/dL, necessitating the initiation of hemodialysis. Given severe renal insufficiency, a diagnosis of atypical HUS was again considered, and eculizumab 900 mg was administered on days 9 and 16 with stabilization of renal function. By the time of discharge on day 17, the patient’s creatinine level had decreased to 4.17 mg/dL and platelet count was 164 K/µL. Creatinine level normalized to 1.02 mg/dL by day 72.

Outpatient genetic testing through the BloodCenter of Wisconsin Diagnostic Laboratories was negative for gene mutations associated with atypical HUS. Approximately 1 month after discharge, the patient resumed maintenance lenalidomide alone without reinitiation of proteasome inhibitor therapy.

Discussion

In this case series, we describe the uncommon drug-related adverse event of TMA occurring in 2 patients with MM after receiving carfilzomib. Although the incidence of TMA disorders is low, reaching up to 2.8% in patients receiving carfilzomib plus cyclophosphamide and dexamethasone in the phase 2 CARDAMON trial, our experience suggests that a high index of suspicion for carfilzomib-induced TMA is warranted in the real-world setting.⁸ TMA syndromes, including TTP, HUS, and DITMA, are characterized by microvascular endothelial injury and thrombosis leading to thrombocytopenia and microangiopathic hemolytic anemia.^5,9 Several drug culprits of DITMA are recognized, including quinine, gemcitabine, tacrolimus, and proteasome inhibitors (bortezomib, carfilzomib, ixazomib).^10-12 In a real-world series of patients receiving proteasome inhibitor therapy, either carfilzomib (n=8) or bortezomib (n=3), common clinical features of DITMA included thrombocytopenia, microangiopathic hemolytic anemia, gastrointestinal symptoms, and renal insufficiency with or without a need for hemodialysis.² Although DITMA has been described primarily as an early event, its occurrence after 12 months of proteasome inhibitor therapy has also been reported, both in this series and elsewhere, thereby suggesting an ongoing risk for DITMA throughout the duration of carfilzomib treatment.^2,13

The diagnosis of DITMA can be challenging given its nonspecific symptoms that overlap with other TMA syndromes. Previous studies have proposed that for a drug to be associated with DITMA, there should be: (1) evidence of clinical and/or pathologic findings of TMA; (2) exclusion of alternative causes of TMA; (3) no other new drug exposures other than the suspected culprit medication; and (4) a lack of recurrence of TMA in absence of the drug.¹⁰ In the case of patients with MM, other causes of TMA have also been described, including the underlying plasma cell disorder itself and stem cell transplantation.¹⁴ In the 2 cases we have described, these alternative causes were considered unlikely given that only 1 patient underwent transplantation remotely and neither had a previous history of TMA secondary to their disease. With respect to other TMA syndromes, ADAMTS13 levels > 10% and negative stool studies for E coli O157:H7 suggested against TTP or typical HUS, respectively. No other drug culprits were identified, and the close timing between the receipt of carfilzomib and symptom onset supported a causal relationship.

Because specific therapies are lacking, management of DITMA has traditionally included drug discontinuation and supportive care for end-organ injury.⁵ The terminal complement inhibitor, eculizumab, improves hematologic abnormalities and renal function in patients with atypical HUS but its use for treating patients with DITMA is not standard.¹⁵ Therefore, the decision to administer eculizumab to our 2 patients was driven by their severe renal insufficiency without improvement after plasma exchange, which suggested a phenotype similar to atypical HUS. After administration of eculizumab, renal function stabilized and then gradually improved over weeks to months, a time course similar to that described in cases of patients with DITMA secondary to other anticancer therapies treated with eculizumab.¹⁶ Although these results suggest a potential role for eculizumab in proteasome inhibitor–induced TMA, distinguishing the benefit of eculizumab over drug discontinuation alone remains challenging, and well-designed prospective investigations are needed.

Conclusions

DITMA is a known risk of proteasome inhibitors and is listed as a safety warning in the prescribing information for bortezomib, carfilzomib, and ixazomib.¹² Given the overall rarity of this adverse event, the simultaneous presentation of our 2 cases was unexpected and underscores the need for heightened awareness in clinical practice. In addition, while no underlying complement mutations were identified, eculizumab was used in both cases to successfully stabilize renal function. Further research investigating the efficacy of eculizumab and the role of complement activation in proteasome inhibitor–induced TMA will be valuable.

Acknowledgments

The authors would like to thank the patients whose histories are reported in this manuscript as well as the physicians and staff who provided care during the hospitalizations and beyond. We also thank Oscar Silva, MD, PhD, for his assistance in reviewing and formatting the peripheral blood smear images.

As a class of drugs, proteasome inhibitors are known to rarely cause drug-induced thrombotic microangiopathy (DITMA). In particular, carfilzomib is a second-generation, irreversible proteasome inhibitor approved for the treatment of relapsed, refractory multiple myeloma (MM) in combination with other therapeutic agents.¹ Although generally well tolerated, carfilzomib has been associated with serious adverse events such as cardiovascular toxicity and DITMA.^2-4 Thrombotic microangiopathy (TMA) is a life-threatening disorder characterized by thrombocytopenia, microangiopathic hemolytic anemia, and end-organ damage.⁵ Its occurrence secondary to carfilzomib has been reported only rarely in clinical trials of MM, and the most effective management of the disorder as well as the concurrent risk factors that contribute to its development remain incompletely understood.^6,7 As a result, given both the expanding use of carfilzomib in practice and the morbidity of TMA, descriptions of carfilzomib-induced TMA from the real-world setting continue to provide important contributions to our understanding of the disorder.

At our US Department of Veterans Affairs (VA) medical center, 2 patients developed severe carfilzomib-induced TMA within days of one another. The presentation of simultaneous cases was highly unexpected and offered the unique opportunity to compare clinical features in real time. Here, we describe our 2 cases in detail, review their presentations and management in the context of the prior literature, and discuss potential insights gained into the disease.

Case Presentation

Case 1

A 78-year-old male patient was diagnosed with monoclonal gammopathy of undetermined significance in 2012 that progressed to Revised International Staging System stage II IgG-κ MM in 2016 due to worsening anemia with a hemoglobin level < 10 g/dL (Table 1). He was treated initially with 8 cycles of first-line bortezomib, lenalidomide, and dexamethasone, to which he achieved a partial response with > 50% reduction in serum M-protein. He then received 3 cycles of maintenance bortezomib until relapse, at which time he was switched to second-line therapy consisting of carfilzomib 20 mg/m² on days 1 and 2 and 56 mg/m² on days 8, 9, 15, and 16 for cycle 1, followed by 56 mg/m² on days 1, 2, 8, 9, 15, and 16 for subsequent cycles plus dexamethasone 20 mg twice weekly every 28 days.

After the patient received cycle 3, day 1 of carfilzomib, he developed subjective fevers, chills, and diarrhea. He missed his day 2 infusion and instead presented to the VA emergency department, where his vital signs were stable and laboratory tests were notable for the following levels: leukocytosis of20.3 K/µL (91.7% neutrophils), hemoglobin 12.4 g/dL (prior 13.5 g/dL), platelet count 171 K/µL, and creatinine 1.39 mg/dL (prior 1.13 g/dL). A chest X-ray demonstrated diffuse bilateral opacities concerning for edema vs infection, and he was started empirically on vancomycin, piperacillin-tazobactam, and azithromycin. His outpatient medications, which included acyclovir, aspirin, finasteride, oxybutynin, ranitidine, omega-3 fatty acids, fish oil, vitamin D, and senna, were continued as indicated.

On hospital day 2, the patient’s platelet count dropped to 81 K/µL and creatinine level rose to 1.78 mg/dL. He developed dark urine (urinalysis [UA] 3+ blood, 6-11 red blood cells per high power field [RBC/HPF]) and had laboratory tests suggestive of hemolysis, including lactic dehydrogenase (LDH) > 1,200 IU/L (reference range, 60-250 IU/L), haptoglobin < 30 mg/dL (reference range, 44-215 mg/dL), total bilirubin 3.2 mg/dL (reference range, 0.2-1.3 mg/dL; indirect bilirubin, 2.6 mg/dL), and a peripheral blood smear demonstrating moderate microangiopathy (Figure 1).

Case 2

A 59-year-old male patient, diagnosed in 2013 with ISS stage I IgG-κ MM after presenting with compression fractures, completed 8 cycles of cyclophosphamide, bortezomib, and dexamethasone before undergoing autologous hematopoietic stem cell transplantation with complete response (Table 1). He subsequently received single-agent maintenance bortezomib until relapse nearly 2 years later, at which time he started second-line carfilzomib 20 mg/m² on days 1 and 2 and 27 mg/m² on days 8, 9, 15, and 16 for cycle 1, followed by 27 mg/m² on days 8, 9, 15, and 16 for cycles 2 to 8, lenalidomide 25 mg on days 1 to 21, and dexamethasone 40 mg weekly every 28 days. Serum free light chain levels normalized after 9 cycles, and he subsequently began maintenance carfilzomib 70 mg/m² on days 1 and 15 plus lenalidomide 10 mg on days 1 to 21 every 28 days.

On the morning before admission, the patient received C6D17 of maintenance carfilzomib, which had been delayed from day 15 because of the holiday. Later that evening, he developed nausea, vomiting, and fever of 101.3 °F. He presented to the VA emergency department and was tachycardic (108 beats per minute) and hypotensive (86/55 mm Hg). Laboratory tests were notable for hemoglobin level 9.9 g/dL (prior 11.6 g/dL), platelet count 270 K/µL, and creatinine level 1.86 mg/dL (prior 1.12 mg/dL). A respiratory viral panel was positive for influenza A, and antimicrobial agents were eventually broadened to piperacillin-tazobactam, azithromycin, and oseltamivir. His outpatient medications, which included acyclovir, zoledronic acid, sulfamethoxazole/trimethoprim, aspirin, amlodipine, atorvastatin, omeprazole, zolpidem, calcium, vitamin D, loratadine, ascorbic acid, and prochlorperazine, were continued as indicated.

On hospital day 2, the patient’s platelet count declined from 211 to 57 K/µL. He developed tea-colored urine (UA 2+ blood, 0-2 RBC/HPF) and had laboratory tests suggestive of hemolysis, including LDH 910 IU/L (reference range, 60-250 IU/L), total bilirubin 3.3 mg/dL (reference range, 0.2-1.3 mg/dL; no direct or indirect available), and a peripheral blood smear demonstrating moderate microangiopathy. Although haptoglobin level was normal at this time (206 mg/dL; reference range, 44-215 mg/dL), it decreased to 42 mg/dL by the following day. Additional workup included a negative direct Coombs and a DIC panel showing elevated fibrinogen (596 mg/dL; reference range, 200-400 mg/dL) and mildly elevated INR (1.16). Blood cultures remained negative, and a 22-pathogen GI PCR panel identified no viral or bacterial pathogens, including E coli O157:H7. C3 (114 mg/dL; reference range, 90-180 mg/dL) and C4 (40 mg/dL; reference range, 16-47 mg/dL) complement levels were both normal.

Based on these findings, empiric treatment was started with plasma exchange and pulse-dosed steroids. The patient received 3 cycles of plasma exchange until the results of the ADAMTS13 activity ruled out TTP (63% enzyme activity). Over the next 6 days, his platelet count reached a nadir of 6 K/µL and creatinine level peaked at 10.36 mg/dL, necessitating the initiation of hemodialysis. Given severe renal insufficiency, a diagnosis of atypical HUS was again considered, and eculizumab 900 mg was administered on days 9 and 16 with stabilization of renal function. By the time of discharge on day 17, the patient’s creatinine level had decreased to 4.17 mg/dL and platelet count was 164 K/µL. Creatinine level normalized to 1.02 mg/dL by day 72.

Outpatient genetic testing through the BloodCenter of Wisconsin Diagnostic Laboratories was negative for gene mutations associated with atypical HUS. Approximately 1 month after discharge, the patient resumed maintenance lenalidomide alone without reinitiation of proteasome inhibitor therapy.

Discussion

In this case series, we describe the uncommon drug-related adverse event of TMA occurring in 2 patients with MM after receiving carfilzomib. Although the incidence of TMA disorders is low, reaching up to 2.8% in patients receiving carfilzomib plus cyclophosphamide and dexamethasone in the phase 2 CARDAMON trial, our experience suggests that a high index of suspicion for carfilzomib-induced TMA is warranted in the real-world setting.⁸ TMA syndromes, including TTP, HUS, and DITMA, are characterized by microvascular endothelial injury and thrombosis leading to thrombocytopenia and microangiopathic hemolytic anemia.^5,9 Several drug culprits of DITMA are recognized, including quinine, gemcitabine, tacrolimus, and proteasome inhibitors (bortezomib, carfilzomib, ixazomib).^10-12 In a real-world series of patients receiving proteasome inhibitor therapy, either carfilzomib (n=8) or bortezomib (n=3), common clinical features of DITMA included thrombocytopenia, microangiopathic hemolytic anemia, gastrointestinal symptoms, and renal insufficiency with or without a need for hemodialysis.² Although DITMA has been described primarily as an early event, its occurrence after 12 months of proteasome inhibitor therapy has also been reported, both in this series and elsewhere, thereby suggesting an ongoing risk for DITMA throughout the duration of carfilzomib treatment.^2,13

The diagnosis of DITMA can be challenging given its nonspecific symptoms that overlap with other TMA syndromes. Previous studies have proposed that for a drug to be associated with DITMA, there should be: (1) evidence of clinical and/or pathologic findings of TMA; (2) exclusion of alternative causes of TMA; (3) no other new drug exposures other than the suspected culprit medication; and (4) a lack of recurrence of TMA in absence of the drug.¹⁰ In the case of patients with MM, other causes of TMA have also been described, including the underlying plasma cell disorder itself and stem cell transplantation.¹⁴ In the 2 cases we have described, these alternative causes were considered unlikely given that only 1 patient underwent transplantation remotely and neither had a previous history of TMA secondary to their disease. With respect to other TMA syndromes, ADAMTS13 levels > 10% and negative stool studies for E coli O157:H7 suggested against TTP or typical HUS, respectively. No other drug culprits were identified, and the close timing between the receipt of carfilzomib and symptom onset supported a causal relationship.

Because specific therapies are lacking, management of DITMA has traditionally included drug discontinuation and supportive care for end-organ injury.⁵ The terminal complement inhibitor, eculizumab, improves hematologic abnormalities and renal function in patients with atypical HUS but its use for treating patients with DITMA is not standard.¹⁵ Therefore, the decision to administer eculizumab to our 2 patients was driven by their severe renal insufficiency without improvement after plasma exchange, which suggested a phenotype similar to atypical HUS. After administration of eculizumab, renal function stabilized and then gradually improved over weeks to months, a time course similar to that described in cases of patients with DITMA secondary to other anticancer therapies treated with eculizumab.¹⁶ Although these results suggest a potential role for eculizumab in proteasome inhibitor–induced TMA, distinguishing the benefit of eculizumab over drug discontinuation alone remains challenging, and well-designed prospective investigations are needed.

Conclusions

DITMA is a known risk of proteasome inhibitors and is listed as a safety warning in the prescribing information for bortezomib, carfilzomib, and ixazomib.¹² Given the overall rarity of this adverse event, the simultaneous presentation of our 2 cases was unexpected and underscores the need for heightened awareness in clinical practice. In addition, while no underlying complement mutations were identified, eculizumab was used in both cases to successfully stabilize renal function. Further research investigating the efficacy of eculizumab and the role of complement activation in proteasome inhibitor–induced TMA will be valuable.

Acknowledgments

The authors would like to thank the patients whose histories are reported in this manuscript as well as the physicians and staff who provided care during the hospitalizations and beyond. We also thank Oscar Silva, MD, PhD, for his assistance in reviewing and formatting the peripheral blood smear images.

Dr George Grunberger, of Wayne State University School of Medicine in Detroit, Michigan, discusses key takeaways on the use of insulin in adults with type 2 diabetes from the 2022 American Diabetes Association Scientific Sessions, held June 3-7 in New Orleans, Louisiana. 

Dr Grunberger highlights presentations that address three challenges among insulin users: cost, hypoglycemia, and the high treatment burden of daily injections. 

On cost, Dr Grunberger reports on a study of Basaglar, a follow-on biologic approved to reference Lantus insulin. After 1 year, Basaglar demonstrated comparable A1c lowering and adverse events, higher adherence, and lower cost. 

Next, on hypoglycemia, Dr Grunberger cites the GRADE trial, which examined adding insulin glargine or the sulfonylurea glimepiride to patients taking metformin. The incidence of severe hypoglycemia proved to be lower in the insulin glargine group. 

Finally, Dr Grunberger reported on studies that explored progress in the development of weekly insulin, with an eye toward decreasing treatment burden. 

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George Grunberger, MD, Chairman, Grunberger Diabetes Institute, Bloomfield Hills; Clinical Professor, Department of Internal Medicine and Molecular Medicine & Genetics, Wayne State University School of Medicine, Detroit, Michigan; Professor, Department of Internal Medicine, Oakland University William Beaumont School of Medicine, Rochester, Michigan 

George Grunberger, MD, has disclosed the following relevant financial relationships:  

Serve(d) as a director, officer, partner, employee, advisor, consultant, or trustee for: Nevro; Lifescan  

Serve(d) as a speaker or a member of a speakers bureau for: Eli Lilly; Novo Nordisk 

Dr George Grunberger, of Wayne State University School of Medicine in Detroit, Michigan, discusses key takeaways on the use of insulin in adults with type 2 diabetes from the 2022 American Diabetes Association Scientific Sessions, held June 3-7 in New Orleans, Louisiana. 

Dr Grunberger highlights presentations that address three challenges among insulin users: cost, hypoglycemia, and the high treatment burden of daily injections. 

On cost, Dr Grunberger reports on a study of Basaglar, a follow-on biologic approved to reference Lantus insulin. After 1 year, Basaglar demonstrated comparable A1c lowering and adverse events, higher adherence, and lower cost. 

Next, on hypoglycemia, Dr Grunberger cites the GRADE trial, which examined adding insulin glargine or the sulfonylurea glimepiride to patients taking metformin. The incidence of severe hypoglycemia proved to be lower in the insulin glargine group. 

Finally, Dr Grunberger reported on studies that explored progress in the development of weekly insulin, with an eye toward decreasing treatment burden. 

--

George Grunberger, MD, Chairman, Grunberger Diabetes Institute, Bloomfield Hills; Clinical Professor, Department of Internal Medicine and Molecular Medicine & Genetics, Wayne State University School of Medicine, Detroit, Michigan; Professor, Department of Internal Medicine, Oakland University William Beaumont School of Medicine, Rochester, Michigan 

George Grunberger, MD, has disclosed the following relevant financial relationships:  

Serve(d) as a director, officer, partner, employee, advisor, consultant, or trustee for: Nevro; Lifescan  

Serve(d) as a speaker or a member of a speakers bureau for: Eli Lilly; Novo Nordisk 

Dr George Grunberger, of Wayne State University School of Medicine in Detroit, Michigan, discusses key takeaways on the use of insulin in adults with type 2 diabetes from the 2022 American Diabetes Association Scientific Sessions, held June 3-7 in New Orleans, Louisiana. 

Dr Grunberger highlights presentations that address three challenges among insulin users: cost, hypoglycemia, and the high treatment burden of daily injections. 

On cost, Dr Grunberger reports on a study of Basaglar, a follow-on biologic approved to reference Lantus insulin. After 1 year, Basaglar demonstrated comparable A1c lowering and adverse events, higher adherence, and lower cost. 

Next, on hypoglycemia, Dr Grunberger cites the GRADE trial, which examined adding insulin glargine or the sulfonylurea glimepiride to patients taking metformin. The incidence of severe hypoglycemia proved to be lower in the insulin glargine group. 

Finally, Dr Grunberger reported on studies that explored progress in the development of weekly insulin, with an eye toward decreasing treatment burden. 

--

George Grunberger, MD, Chairman, Grunberger Diabetes Institute, Bloomfield Hills; Clinical Professor, Department of Internal Medicine and Molecular Medicine & Genetics, Wayne State University School of Medicine, Detroit, Michigan; Professor, Department of Internal Medicine, Oakland University William Beaumont School of Medicine, Rochester, Michigan 

George Grunberger, MD, has disclosed the following relevant financial relationships:  

Serve(d) as a director, officer, partner, employee, advisor, consultant, or trustee for: Nevro; Lifescan  

Serve(d) as a speaker or a member of a speakers bureau for: Eli Lilly; Novo Nordisk 

New guidelines and key studies in glycemic control from the 2022 annual meeting of the American Diabetes Association (ADA) are highlighted by Dr Ildiko Lingvay, from the University of Texas Southwestern Medical Center.  

Dr Lingvay opens by reporting on forthcoming guidelines by the ADA in joint partnership with the European Association for the Study of Diabetes (EASD) on the treatment of hyperglycemia in type 2 diabetes. This consensus paper, she says, will endorse a holistic, person-centered approach to managing type 2 diabetes. The finalized paper will be presented at the EASD annual meeting in Stockholm in September 2022. Next, Dr Lingvay discusses the yearly update to the ADA Standards of Medical Care in Diabetes, which include the benefits of finerenone, the benefits of SGLT2 inhibitors on heart failure and renal outcomes, and the endorsement of the updated eGFR calculator, which omits patient race from calculations.   

She then looks at the SURMOUNT-1 study, a phase 3 trial investigating tirzepatide, a dual GLP/GLP-1 receptor agonist, for the treatment of obesity. In addition to a demonstration of substantial weight loss, the study indicated that tirzepatide provided impressive glucose-lowering benefit. 

Dr Lingvay also examines post hoc data from the STEP 1 and 4 trials showing that semaglutide, compared with placebo, reduced the risk for type 2 diabetes in patients with obesity by approximately 60%, regardless of their baseline glycemic status.  

Finally, Dr Lingvay discusses a novel triple GIP, GLP-1, and glucagon receptor agonist called LY3437943, currently in phase 1 trials, which demonstrated promising glycemic and body weight lowering efficacy after a short 12-week trial.  

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Ildiko Lingvay, MD, MPH, Professor, Department of Internal Medicine, Department of Population and Data Sciences, University of Texas Southwestern Medical Center, Dallas, Texas 

Ildiko Lingvay, MD, MPH, has disclosed the following relevant financial relationships: 

Received income in an amount equal to or greater than $250 from: NovoNordisk; Sanofi; Eli Lilly; AstraZeneca; Target Pharma; Boehringer Ingelheim; Intercept; Merck; Janssen; Intarcia; Merck  

Received research grant from: NovoNordisk; Mylan; Sanofi; Merck; Pfizer; Boehringer Ingelheim 

New guidelines and key studies in glycemic control from the 2022 annual meeting of the American Diabetes Association (ADA) are highlighted by Dr Ildiko Lingvay, from the University of Texas Southwestern Medical Center.  

Dr Lingvay opens by reporting on forthcoming guidelines by the ADA in joint partnership with the European Association for the Study of Diabetes (EASD) on the treatment of hyperglycemia in type 2 diabetes. This consensus paper, she says, will endorse a holistic, person-centered approach to managing type 2 diabetes. The finalized paper will be presented at the EASD annual meeting in Stockholm in September 2022. Next, Dr Lingvay discusses the yearly update to the ADA Standards of Medical Care in Diabetes, which include the benefits of finerenone, the benefits of SGLT2 inhibitors on heart failure and renal outcomes, and the endorsement of the updated eGFR calculator, which omits patient race from calculations.   

She then looks at the SURMOUNT-1 study, a phase 3 trial investigating tirzepatide, a dual GLP/GLP-1 receptor agonist, for the treatment of obesity. In addition to a demonstration of substantial weight loss, the study indicated that tirzepatide provided impressive glucose-lowering benefit. 

Dr Lingvay also examines post hoc data from the STEP 1 and 4 trials showing that semaglutide, compared with placebo, reduced the risk for type 2 diabetes in patients with obesity by approximately 60%, regardless of their baseline glycemic status.  

Finally, Dr Lingvay discusses a novel triple GIP, GLP-1, and glucagon receptor agonist called LY3437943, currently in phase 1 trials, which demonstrated promising glycemic and body weight lowering efficacy after a short 12-week trial.  

--

Ildiko Lingvay, MD, MPH, Professor, Department of Internal Medicine, Department of Population and Data Sciences, University of Texas Southwestern Medical Center, Dallas, Texas 

Ildiko Lingvay, MD, MPH, has disclosed the following relevant financial relationships: 

Received income in an amount equal to or greater than $250 from: NovoNordisk; Sanofi; Eli Lilly; AstraZeneca; Target Pharma; Boehringer Ingelheim; Intercept; Merck; Janssen; Intarcia; Merck  

Received research grant from: NovoNordisk; Mylan; Sanofi; Merck; Pfizer; Boehringer Ingelheim 

New guidelines and key studies in glycemic control from the 2022 annual meeting of the American Diabetes Association (ADA) are highlighted by Dr Ildiko Lingvay, from the University of Texas Southwestern Medical Center.  

Dr Lingvay opens by reporting on forthcoming guidelines by the ADA in joint partnership with the European Association for the Study of Diabetes (EASD) on the treatment of hyperglycemia in type 2 diabetes. This consensus paper, she says, will endorse a holistic, person-centered approach to managing type 2 diabetes. The finalized paper will be presented at the EASD annual meeting in Stockholm in September 2022. Next, Dr Lingvay discusses the yearly update to the ADA Standards of Medical Care in Diabetes, which include the benefits of finerenone, the benefits of SGLT2 inhibitors on heart failure and renal outcomes, and the endorsement of the updated eGFR calculator, which omits patient race from calculations.   

She then looks at the SURMOUNT-1 study, a phase 3 trial investigating tirzepatide, a dual GLP/GLP-1 receptor agonist, for the treatment of obesity. In addition to a demonstration of substantial weight loss, the study indicated that tirzepatide provided impressive glucose-lowering benefit. 

Dr Lingvay also examines post hoc data from the STEP 1 and 4 trials showing that semaglutide, compared with placebo, reduced the risk for type 2 diabetes in patients with obesity by approximately 60%, regardless of their baseline glycemic status.  

Finally, Dr Lingvay discusses a novel triple GIP, GLP-1, and glucagon receptor agonist called LY3437943, currently in phase 1 trials, which demonstrated promising glycemic and body weight lowering efficacy after a short 12-week trial.  

--

Ildiko Lingvay, MD, MPH, Professor, Department of Internal Medicine, Department of Population and Data Sciences, University of Texas Southwestern Medical Center, Dallas, Texas 

Ildiko Lingvay, MD, MPH, has disclosed the following relevant financial relationships: 

Received income in an amount equal to or greater than $250 from: NovoNordisk; Sanofi; Eli Lilly; AstraZeneca; Target Pharma; Boehringer Ingelheim; Intercept; Merck; Janssen; Intarcia; Merck  

Received research grant from: NovoNordisk; Mylan; Sanofi; Merck; Pfizer; Boehringer Ingelheim