Article

The areas of hair loss and different length hairs in a patient with otherwise normal-density hair was consistent with a diagnosis of trichotillomania. The physician initially thought the patient had a “fade” hairstyle, but then observed him twirling his hair. Further queries confirmed a history of hair pulling (trichotillomania) and ingesting the hair (trichophagia).

In adulthood, trichotillomania affects females about 4 times more than males, although in childhood, the sex distribution appears about equal.¹ The typical age of onset is between 10 to 13 years. Several mental health conditions are associated with trichotillomania, such as major depressive disorder, anxiety disorders, and substance use disorder, with trichotillomania generally preceding these comorbid disorders. It is important to rule out obsessive compulsive disorder and consider body dysmorphic disorder when making a diagnosis of trichotillomania.¹

It is common to see androgenetic alopecia precipitated by hormone therapy in FTM individuals. This would usually cause thinning of the hair rather than the irregular hair lengths and pattern seen in this patient. Tinea capitis is also part of the differential diagnosis in a case such as this. It can be diagnosed by potassium hydroxide (KOH) preparations in the setting of friable and broken hair shafts (and sometimes erythema and inflammation).

Patients with trichotillomania may have hair with blunt or tapered ends; hair may also look like uneven stubble.² The scalp is the most commonly involved site (72.8%), followed by eyebrows (50.7%), and the pubic region (50.7%).¹ Useful diagnostic clues include an unusual shape of the affected area, accessible location, and a changing pattern from visit to visit.² If trichotillomania is suspected, it might be useful to ask about hair-playing activities, such as twirling or twisting, or playing with the ends of eyelashes or eyebrows.²

Unwanted medical consequences of trichotillomania include skin damage (if sharp instruments are used for hair pulling), and the formation of gastrointestinal trichobezoars (hairballs) if trichophagia is present. Trichobezoars that cause bowel obstructions may need surgical intervention.¹

Behavioral therapy is the first-line treatment for trichotillomania in all age groups.^1,3 Treating any coexisting mental health disorders is also essential. There are currently no FDA-approved medications for treatment; however, there is evidence that N-acetylcysteine may be useful in treating adults with trichotillomania and other repetitive skin disorders.³ Antipsychotics and cannabinoid agonists also may be beneficial.¹

This patient was continued on his current lithium, naltrexone, and bupropion regimen (rather than adding additional psychiatric medicines) as he was doing better than his previous baseline. He was advised to continue with his cognitive behavioral therapy. His hormone replacement therapy also was continued because it was not thought to be contributory. He was provided with education about symptoms of trichobezoar and red flag symptoms (eg, worsening nausea, vomiting, abdominal pain) that would necessitate emergency follow-up. His GERD symptoms were thought not to be related to his trichophagia. He was scheduled to follow up for routine primary care in 6 months.

‌

Photo courtesy of Daniel Stulberg, MD. Text courtesy of Sarasawati Keeni, MD, and Daniel Stulberg, MD, FAAFP, Department of Family and Community Medicine, Western Michigan University Homer Stryker, MD School of Medicine, Kalamazoo.

The areas of hair loss and different length hairs in a patient with otherwise normal-density hair was consistent with a diagnosis of trichotillomania. The physician initially thought the patient had a “fade” hairstyle, but then observed him twirling his hair. Further queries confirmed a history of hair pulling (trichotillomania) and ingesting the hair (trichophagia).

In adulthood, trichotillomania affects females about 4 times more than males, although in childhood, the sex distribution appears about equal.¹ The typical age of onset is between 10 to 13 years. Several mental health conditions are associated with trichotillomania, such as major depressive disorder, anxiety disorders, and substance use disorder, with trichotillomania generally preceding these comorbid disorders. It is important to rule out obsessive compulsive disorder and consider body dysmorphic disorder when making a diagnosis of trichotillomania.¹

It is common to see androgenetic alopecia precipitated by hormone therapy in FTM individuals. This would usually cause thinning of the hair rather than the irregular hair lengths and pattern seen in this patient. Tinea capitis is also part of the differential diagnosis in a case such as this. It can be diagnosed by potassium hydroxide (KOH) preparations in the setting of friable and broken hair shafts (and sometimes erythema and inflammation).

Patients with trichotillomania may have hair with blunt or tapered ends; hair may also look like uneven stubble.² The scalp is the most commonly involved site (72.8%), followed by eyebrows (50.7%), and the pubic region (50.7%).¹ Useful diagnostic clues include an unusual shape of the affected area, accessible location, and a changing pattern from visit to visit.² If trichotillomania is suspected, it might be useful to ask about hair-playing activities, such as twirling or twisting, or playing with the ends of eyelashes or eyebrows.²

Unwanted medical consequences of trichotillomania include skin damage (if sharp instruments are used for hair pulling), and the formation of gastrointestinal trichobezoars (hairballs) if trichophagia is present. Trichobezoars that cause bowel obstructions may need surgical intervention.¹

Behavioral therapy is the first-line treatment for trichotillomania in all age groups.^1,3 Treating any coexisting mental health disorders is also essential. There are currently no FDA-approved medications for treatment; however, there is evidence that N-acetylcysteine may be useful in treating adults with trichotillomania and other repetitive skin disorders.³ Antipsychotics and cannabinoid agonists also may be beneficial.¹

This patient was continued on his current lithium, naltrexone, and bupropion regimen (rather than adding additional psychiatric medicines) as he was doing better than his previous baseline. He was advised to continue with his cognitive behavioral therapy. His hormone replacement therapy also was continued because it was not thought to be contributory. He was provided with education about symptoms of trichobezoar and red flag symptoms (eg, worsening nausea, vomiting, abdominal pain) that would necessitate emergency follow-up. His GERD symptoms were thought not to be related to his trichophagia. He was scheduled to follow up for routine primary care in 6 months.

‌

Photo courtesy of Daniel Stulberg, MD. Text courtesy of Sarasawati Keeni, MD, and Daniel Stulberg, MD, FAAFP, Department of Family and Community Medicine, Western Michigan University Homer Stryker, MD School of Medicine, Kalamazoo.

The areas of hair loss and different length hairs in a patient with otherwise normal-density hair was consistent with a diagnosis of trichotillomania. The physician initially thought the patient had a “fade” hairstyle, but then observed him twirling his hair. Further queries confirmed a history of hair pulling (trichotillomania) and ingesting the hair (trichophagia).

In adulthood, trichotillomania affects females about 4 times more than males, although in childhood, the sex distribution appears about equal.¹ The typical age of onset is between 10 to 13 years. Several mental health conditions are associated with trichotillomania, such as major depressive disorder, anxiety disorders, and substance use disorder, with trichotillomania generally preceding these comorbid disorders. It is important to rule out obsessive compulsive disorder and consider body dysmorphic disorder when making a diagnosis of trichotillomania.¹

It is common to see androgenetic alopecia precipitated by hormone therapy in FTM individuals. This would usually cause thinning of the hair rather than the irregular hair lengths and pattern seen in this patient. Tinea capitis is also part of the differential diagnosis in a case such as this. It can be diagnosed by potassium hydroxide (KOH) preparations in the setting of friable and broken hair shafts (and sometimes erythema and inflammation).

Patients with trichotillomania may have hair with blunt or tapered ends; hair may also look like uneven stubble.² The scalp is the most commonly involved site (72.8%), followed by eyebrows (50.7%), and the pubic region (50.7%).¹ Useful diagnostic clues include an unusual shape of the affected area, accessible location, and a changing pattern from visit to visit.² If trichotillomania is suspected, it might be useful to ask about hair-playing activities, such as twirling or twisting, or playing with the ends of eyelashes or eyebrows.²

Unwanted medical consequences of trichotillomania include skin damage (if sharp instruments are used for hair pulling), and the formation of gastrointestinal trichobezoars (hairballs) if trichophagia is present. Trichobezoars that cause bowel obstructions may need surgical intervention.¹

Behavioral therapy is the first-line treatment for trichotillomania in all age groups.^1,3 Treating any coexisting mental health disorders is also essential. There are currently no FDA-approved medications for treatment; however, there is evidence that N-acetylcysteine may be useful in treating adults with trichotillomania and other repetitive skin disorders.³ Antipsychotics and cannabinoid agonists also may be beneficial.¹

This patient was continued on his current lithium, naltrexone, and bupropion regimen (rather than adding additional psychiatric medicines) as he was doing better than his previous baseline. He was advised to continue with his cognitive behavioral therapy. His hormone replacement therapy also was continued because it was not thought to be contributory. He was provided with education about symptoms of trichobezoar and red flag symptoms (eg, worsening nausea, vomiting, abdominal pain) that would necessitate emergency follow-up. His GERD symptoms were thought not to be related to his trichophagia. He was scheduled to follow up for routine primary care in 6 months.

‌

Photo courtesy of Daniel Stulberg, MD. Text courtesy of Sarasawati Keeni, MD, and Daniel Stulberg, MD, FAAFP, Department of Family and Community Medicine, Western Michigan University Homer Stryker, MD School of Medicine, Kalamazoo.

The Diagnosis: Hypopigmented Mycosis Fungoides

Histopathology showed an atypical lymphoid infiltrate with expanded cytoplasm and hyperchromatic nuclei of irregular contours in the dermoepidermal junction (Figure 1). Immunohistochemical stains of atypical lymphocytes demonstrated the presence of CD3, CD8, and CD5, as well as the absence of CD7 and CD4 lymphocytes (Figure 2). The T-cell γ rearrangement showed polyclonal lymphocytes with 5% tumor cells. The histologic and clinical findings along with our patient’s medical history led to a diagnosis of stage IA (<10% body surface area involvement) hypopigmented mycosis fungoides (hMF).¹ Our patient was treated with triamcinolone cream 0.1%; she noted an improvement in her symptoms at 2-month follow-up.

Hypopigmented MF is an uncommon manifestation of MF with unknown prevalence and incidence rates. Mycosis fungoides is considered the most common subtype of cutaneous T-cell lymphoma that classically presents as a chronic, indolent, hypopigmented or depigmented macule or patch, commonly with scaling, in sunprotected areas such as the trunk and proximal arms and legs. It predominantly affects younger adults with darker skin tones and may be present in the pediatric population within the first decade of life.¹ Classically, MF affects White patients aged 55 to 60 years. Disease progression is slow, with an incidence rate of 10% of tumor or extracutaneous involvement in the early stages of disease. A lack of specificity on the clinical and histopathologic findings in the initial stage often contributes to the diagnostic delay of hMF. As seen in our patient, this disease can be misdiagnosed as tinea versicolor, postinflammatory hypopigmentation, vitiligo, pityriasis alba, subcutaneous lupus erythematosus, or Hansen disease due to prolonged hypopigmented lesions.² The clinical findings and histopathologic results including immunohistochemistry confirmed the diagnosis of hMF and ruled out pityriasis alba, postinflammatory hypopigmentation, subcutaneous lupus erythematosus, and vitiligo.

The etiology and pathophysiology of hMF are not fully understood; however, it is hypothesized that melanocyte degeneration, abnormal melanogenesis, and disturbance of melanosome transfer result from the clonal expansion of T helper memory cells. T-cell dyscrasia has been reported to evolve into hMF during etanercept therapy.³ Clinically, hMF presents as hypopigmented papulosquamous, eczematous, or erythrodermic patches, plaques, and tumors with poorly defined atrophied borders. Multiple biopsies of steroid-naive lesions are needed for the diagnosis, as the initial hMF histologic finding cannot be specific for diagnostic confirmation. Common histopathologic findings include a bandlike lymphocytic infiltrate with epidermotropism, intraepidermal nests of atypical cells, or cerebriform nuclei lymphocytes on hematoxylin and eosin staining. In comparison to classical MF epidermotropism, CD4− and CD8+ atypical cells aid in the diagnosis of hMF. Although hMF carries a good prognosis and a benign clinical course,⁴ full-body computed tomography or positron emission tomography/computed tomography as well as laboratory analysis for lactate dehydrogenase should be pursued if lymphadenopathy, systemic symptoms, or advancedstage hMF are present.

Treatment of hMF depends on the disease stage. Psoralen plus UVA and narrowband UVB can be utilized for the initial stages with a relatively fast response and remission of lesions as early as the first 2 months of treatment. In addition to phototherapy, stage IA to IIA mycosis fungoides with localized skin lesions can benefit from topical steroids, topical retinoids, imiquimod, nitrogen mustard, and carmustine. For advanced stages of mycosis fungoides, combination therapy consisting of psoralen plus UVA with an oral retinoid, interferon alfa, and systemic chemotherapy commonly are prescribed. Maintenance therapy is used for prolonging remission; however, long-term phototherapy is not recommended due to the risk for skin cancer. Unfortunately, hMF requires long-term treatment due to its waxing and waning course, and recurrence may occur after complete resolution.⁵

The Diagnosis: Hypopigmented Mycosis Fungoides

Histopathology showed an atypical lymphoid infiltrate with expanded cytoplasm and hyperchromatic nuclei of irregular contours in the dermoepidermal junction (Figure 1). Immunohistochemical stains of atypical lymphocytes demonstrated the presence of CD3, CD8, and CD5, as well as the absence of CD7 and CD4 lymphocytes (Figure 2). The T-cell γ rearrangement showed polyclonal lymphocytes with 5% tumor cells. The histologic and clinical findings along with our patient’s medical history led to a diagnosis of stage IA (<10% body surface area involvement) hypopigmented mycosis fungoides (hMF).¹ Our patient was treated with triamcinolone cream 0.1%; she noted an improvement in her symptoms at 2-month follow-up.

Hypopigmented MF is an uncommon manifestation of MF with unknown prevalence and incidence rates. Mycosis fungoides is considered the most common subtype of cutaneous T-cell lymphoma that classically presents as a chronic, indolent, hypopigmented or depigmented macule or patch, commonly with scaling, in sunprotected areas such as the trunk and proximal arms and legs. It predominantly affects younger adults with darker skin tones and may be present in the pediatric population within the first decade of life.¹ Classically, MF affects White patients aged 55 to 60 years. Disease progression is slow, with an incidence rate of 10% of tumor or extracutaneous involvement in the early stages of disease. A lack of specificity on the clinical and histopathologic findings in the initial stage often contributes to the diagnostic delay of hMF. As seen in our patient, this disease can be misdiagnosed as tinea versicolor, postinflammatory hypopigmentation, vitiligo, pityriasis alba, subcutaneous lupus erythematosus, or Hansen disease due to prolonged hypopigmented lesions.² The clinical findings and histopathologic results including immunohistochemistry confirmed the diagnosis of hMF and ruled out pityriasis alba, postinflammatory hypopigmentation, subcutaneous lupus erythematosus, and vitiligo.

The etiology and pathophysiology of hMF are not fully understood; however, it is hypothesized that melanocyte degeneration, abnormal melanogenesis, and disturbance of melanosome transfer result from the clonal expansion of T helper memory cells. T-cell dyscrasia has been reported to evolve into hMF during etanercept therapy.³ Clinically, hMF presents as hypopigmented papulosquamous, eczematous, or erythrodermic patches, plaques, and tumors with poorly defined atrophied borders. Multiple biopsies of steroid-naive lesions are needed for the diagnosis, as the initial hMF histologic finding cannot be specific for diagnostic confirmation. Common histopathologic findings include a bandlike lymphocytic infiltrate with epidermotropism, intraepidermal nests of atypical cells, or cerebriform nuclei lymphocytes on hematoxylin and eosin staining. In comparison to classical MF epidermotropism, CD4− and CD8+ atypical cells aid in the diagnosis of hMF. Although hMF carries a good prognosis and a benign clinical course,⁴ full-body computed tomography or positron emission tomography/computed tomography as well as laboratory analysis for lactate dehydrogenase should be pursued if lymphadenopathy, systemic symptoms, or advancedstage hMF are present.

Treatment of hMF depends on the disease stage. Psoralen plus UVA and narrowband UVB can be utilized for the initial stages with a relatively fast response and remission of lesions as early as the first 2 months of treatment. In addition to phototherapy, stage IA to IIA mycosis fungoides with localized skin lesions can benefit from topical steroids, topical retinoids, imiquimod, nitrogen mustard, and carmustine. For advanced stages of mycosis fungoides, combination therapy consisting of psoralen plus UVA with an oral retinoid, interferon alfa, and systemic chemotherapy commonly are prescribed. Maintenance therapy is used for prolonging remission; however, long-term phototherapy is not recommended due to the risk for skin cancer. Unfortunately, hMF requires long-term treatment due to its waxing and waning course, and recurrence may occur after complete resolution.⁵

The Diagnosis: Hypopigmented Mycosis Fungoides

Histopathology showed an atypical lymphoid infiltrate with expanded cytoplasm and hyperchromatic nuclei of irregular contours in the dermoepidermal junction (Figure 1). Immunohistochemical stains of atypical lymphocytes demonstrated the presence of CD3, CD8, and CD5, as well as the absence of CD7 and CD4 lymphocytes (Figure 2). The T-cell γ rearrangement showed polyclonal lymphocytes with 5% tumor cells. The histologic and clinical findings along with our patient’s medical history led to a diagnosis of stage IA (<10% body surface area involvement) hypopigmented mycosis fungoides (hMF).¹ Our patient was treated with triamcinolone cream 0.1%; she noted an improvement in her symptoms at 2-month follow-up.

Hypopigmented MF is an uncommon manifestation of MF with unknown prevalence and incidence rates. Mycosis fungoides is considered the most common subtype of cutaneous T-cell lymphoma that classically presents as a chronic, indolent, hypopigmented or depigmented macule or patch, commonly with scaling, in sunprotected areas such as the trunk and proximal arms and legs. It predominantly affects younger adults with darker skin tones and may be present in the pediatric population within the first decade of life.¹ Classically, MF affects White patients aged 55 to 60 years. Disease progression is slow, with an incidence rate of 10% of tumor or extracutaneous involvement in the early stages of disease. A lack of specificity on the clinical and histopathologic findings in the initial stage often contributes to the diagnostic delay of hMF. As seen in our patient, this disease can be misdiagnosed as tinea versicolor, postinflammatory hypopigmentation, vitiligo, pityriasis alba, subcutaneous lupus erythematosus, or Hansen disease due to prolonged hypopigmented lesions.² The clinical findings and histopathologic results including immunohistochemistry confirmed the diagnosis of hMF and ruled out pityriasis alba, postinflammatory hypopigmentation, subcutaneous lupus erythematosus, and vitiligo.

The etiology and pathophysiology of hMF are not fully understood; however, it is hypothesized that melanocyte degeneration, abnormal melanogenesis, and disturbance of melanosome transfer result from the clonal expansion of T helper memory cells. T-cell dyscrasia has been reported to evolve into hMF during etanercept therapy.³ Clinically, hMF presents as hypopigmented papulosquamous, eczematous, or erythrodermic patches, plaques, and tumors with poorly defined atrophied borders. Multiple biopsies of steroid-naive lesions are needed for the diagnosis, as the initial hMF histologic finding cannot be specific for diagnostic confirmation. Common histopathologic findings include a bandlike lymphocytic infiltrate with epidermotropism, intraepidermal nests of atypical cells, or cerebriform nuclei lymphocytes on hematoxylin and eosin staining. In comparison to classical MF epidermotropism, CD4− and CD8+ atypical cells aid in the diagnosis of hMF. Although hMF carries a good prognosis and a benign clinical course,⁴ full-body computed tomography or positron emission tomography/computed tomography as well as laboratory analysis for lactate dehydrogenase should be pursued if lymphadenopathy, systemic symptoms, or advancedstage hMF are present.

Treatment of hMF depends on the disease stage. Psoralen plus UVA and narrowband UVB can be utilized for the initial stages with a relatively fast response and remission of lesions as early as the first 2 months of treatment. In addition to phototherapy, stage IA to IIA mycosis fungoides with localized skin lesions can benefit from topical steroids, topical retinoids, imiquimod, nitrogen mustard, and carmustine. For advanced stages of mycosis fungoides, combination therapy consisting of psoralen plus UVA with an oral retinoid, interferon alfa, and systemic chemotherapy commonly are prescribed. Maintenance therapy is used for prolonging remission; however, long-term phototherapy is not recommended due to the risk for skin cancer. Unfortunately, hMF requires long-term treatment due to its waxing and waning course, and recurrence may occur after complete resolution.⁵

The neoadjuvant setting provides a favorable environment to study de-escalation approaches as treatment response (via pathologic complete response [pCR] assessment) can be used as a surrogate marker for outcome. Studies have shown the effect of HER2-enriched subtype and high ERBB2 expression on pCR rates after receipt of a chemotherapy-free, dual HER2-targeted regimen.² The prospective, multicenter, neoadjuvant phase 2 WSG-TP-II trial randomly assigned 207 patients with HR+/HER2+ early breast cancer to 12 weeks of endocrine therapy (ET)–trastuzumab-pertuzumab vs paclitaxel-trastuzumab-pertuzumab. The pCR rate was inferior in the ET arm compared with the paclitaxel arm (23.7% vs 56.4%; odds ratio 0.24; 95% CI 0.12-0.46; P < .001). In addition, an immunohistochemistry ERBB2 score of 3 or higher and ERBB2-enriched subtype were predictors of higher pCR rates in both arms (Gluz et al). This study not only supports a deescalated chemotherapy neoadjuvant strategy of paclitaxel + dual HER2 blockade but also suggests that a portion of patients may potentially be spared chemotherapy with very good results. The role of biomarkers is integral to patient selection for these approaches, and the evaluation of response in real-time will allow for the tailoring of therapy to achieve the best outcome.

Systemic staging for locally advanced breast cancer (LABC) is important for informing prognosis as well as aiding in development of an appropriate treatment plan for patients. The PETABC study included 369 patients with LABC (TNM stage III or IIB [T3N0]) with random assignment to ¹⁸F-labeled fluorodeoxyglucose PET-CT or conventional staging (bone scan, CT of chest/abdomen/pelvis), and was designed to assess the rate of upstaging with each imaging modality and effect on treatment (Dayes et al). In the PET-CT group, 23% (N = 43) of patients were upstaged to stage IV compared with 11% (N = 21) in the conventional-staging group (absolute difference 12.3%; 95% CI 3.9-19.9; P = .002). Fewer patients in the PET-CT group received combined modality treatment vs those patients in the conventional staging group (81% vs 89.2%; P = .03). These results support the consideration of PET-CT as a staging tool for LABC, and this is reflected in various clinical guidelines. Furthermore, the evolving role of other imaging techniques such as ¹⁸F-fluoroestradiol (18F-FES) PET-CT in detection of metastatic lesions related to estrogen receptor–positive breast cancer³ will continue to advance the field of imaging.

Additional References

1. Rugo HS, Lerebours F, Ciruelos E, et al. Alpelisib plus fulvestrant in PIK3CA-mutated, hormone receptor-positive advanced breast cancer after a CDK4/6 inhibitor (BYLieve): One cohort of a phase 2, multicentre, open-label, non-comparative study. Lancet Oncol. 2021;22:489-498. doi: 10.1016/S1470-2045(21)00034-6. Erratum in: Lancet Oncol. 2021;22(5):e184. doi: 10.1016/S1470-2045(21)00194-7
2. Prat A, Pascual T, De Angelis C, et al. HER2-enriched subtype and ERBB2 expression in HER2-positive breast cancer treated with dual HER2 blockade. J Natl Cancer Inst. 2020;112:46-54. doi: 10.1093/jnci/djz042
3. Ulaner GA, Jhaveri K, Chandarlapaty S, et al. Head-to-head evaluation of ¹⁸F-FES and ¹⁸F-FDG PET/CT in metastatic invasive lobular breast cancer. J Nucl Med. 2021;62:326-331. doi: 10.2967/jnumed.120.247882

The neoadjuvant setting provides a favorable environment to study de-escalation approaches as treatment response (via pathologic complete response [pCR] assessment) can be used as a surrogate marker for outcome. Studies have shown the effect of HER2-enriched subtype and high ERBB2 expression on pCR rates after receipt of a chemotherapy-free, dual HER2-targeted regimen.² The prospective, multicenter, neoadjuvant phase 2 WSG-TP-II trial randomly assigned 207 patients with HR+/HER2+ early breast cancer to 12 weeks of endocrine therapy (ET)–trastuzumab-pertuzumab vs paclitaxel-trastuzumab-pertuzumab. The pCR rate was inferior in the ET arm compared with the paclitaxel arm (23.7% vs 56.4%; odds ratio 0.24; 95% CI 0.12-0.46; P < .001). In addition, an immunohistochemistry ERBB2 score of 3 or higher and ERBB2-enriched subtype were predictors of higher pCR rates in both arms (Gluz et al). This study not only supports a deescalated chemotherapy neoadjuvant strategy of paclitaxel + dual HER2 blockade but also suggests that a portion of patients may potentially be spared chemotherapy with very good results. The role of biomarkers is integral to patient selection for these approaches, and the evaluation of response in real-time will allow for the tailoring of therapy to achieve the best outcome.

Systemic staging for locally advanced breast cancer (LABC) is important for informing prognosis as well as aiding in development of an appropriate treatment plan for patients. The PETABC study included 369 patients with LABC (TNM stage III or IIB [T3N0]) with random assignment to ¹⁸F-labeled fluorodeoxyglucose PET-CT or conventional staging (bone scan, CT of chest/abdomen/pelvis), and was designed to assess the rate of upstaging with each imaging modality and effect on treatment (Dayes et al). In the PET-CT group, 23% (N = 43) of patients were upstaged to stage IV compared with 11% (N = 21) in the conventional-staging group (absolute difference 12.3%; 95% CI 3.9-19.9; P = .002). Fewer patients in the PET-CT group received combined modality treatment vs those patients in the conventional staging group (81% vs 89.2%; P = .03). These results support the consideration of PET-CT as a staging tool for LABC, and this is reflected in various clinical guidelines. Furthermore, the evolving role of other imaging techniques such as ¹⁸F-fluoroestradiol (18F-FES) PET-CT in detection of metastatic lesions related to estrogen receptor–positive breast cancer³ will continue to advance the field of imaging.

Additional References

1. Rugo HS, Lerebours F, Ciruelos E, et al. Alpelisib plus fulvestrant in PIK3CA-mutated, hormone receptor-positive advanced breast cancer after a CDK4/6 inhibitor (BYLieve): One cohort of a phase 2, multicentre, open-label, non-comparative study. Lancet Oncol. 2021;22:489-498. doi: 10.1016/S1470-2045(21)00034-6. Erratum in: Lancet Oncol. 2021;22(5):e184. doi: 10.1016/S1470-2045(21)00194-7
2. Prat A, Pascual T, De Angelis C, et al. HER2-enriched subtype and ERBB2 expression in HER2-positive breast cancer treated with dual HER2 blockade. J Natl Cancer Inst. 2020;112:46-54. doi: 10.1093/jnci/djz042
3. Ulaner GA, Jhaveri K, Chandarlapaty S, et al. Head-to-head evaluation of ¹⁸F-FES and ¹⁸F-FDG PET/CT in metastatic invasive lobular breast cancer. J Nucl Med. 2021;62:326-331. doi: 10.2967/jnumed.120.247882

The neoadjuvant setting provides a favorable environment to study de-escalation approaches as treatment response (via pathologic complete response [pCR] assessment) can be used as a surrogate marker for outcome. Studies have shown the effect of HER2-enriched subtype and high ERBB2 expression on pCR rates after receipt of a chemotherapy-free, dual HER2-targeted regimen.² The prospective, multicenter, neoadjuvant phase 2 WSG-TP-II trial randomly assigned 207 patients with HR+/HER2+ early breast cancer to 12 weeks of endocrine therapy (ET)–trastuzumab-pertuzumab vs paclitaxel-trastuzumab-pertuzumab. The pCR rate was inferior in the ET arm compared with the paclitaxel arm (23.7% vs 56.4%; odds ratio 0.24; 95% CI 0.12-0.46; P < .001). In addition, an immunohistochemistry ERBB2 score of 3 or higher and ERBB2-enriched subtype were predictors of higher pCR rates in both arms (Gluz et al). This study not only supports a deescalated chemotherapy neoadjuvant strategy of paclitaxel + dual HER2 blockade but also suggests that a portion of patients may potentially be spared chemotherapy with very good results. The role of biomarkers is integral to patient selection for these approaches, and the evaluation of response in real-time will allow for the tailoring of therapy to achieve the best outcome.

Systemic staging for locally advanced breast cancer (LABC) is important for informing prognosis as well as aiding in development of an appropriate treatment plan for patients. The PETABC study included 369 patients with LABC (TNM stage III or IIB [T3N0]) with random assignment to ¹⁸F-labeled fluorodeoxyglucose PET-CT or conventional staging (bone scan, CT of chest/abdomen/pelvis), and was designed to assess the rate of upstaging with each imaging modality and effect on treatment (Dayes et al). In the PET-CT group, 23% (N = 43) of patients were upstaged to stage IV compared with 11% (N = 21) in the conventional-staging group (absolute difference 12.3%; 95% CI 3.9-19.9; P = .002). Fewer patients in the PET-CT group received combined modality treatment vs those patients in the conventional staging group (81% vs 89.2%; P = .03). These results support the consideration of PET-CT as a staging tool for LABC, and this is reflected in various clinical guidelines. Furthermore, the evolving role of other imaging techniques such as ¹⁸F-fluoroestradiol (18F-FES) PET-CT in detection of metastatic lesions related to estrogen receptor–positive breast cancer³ will continue to advance the field of imaging.

Additional References

1. Rugo HS, Lerebours F, Ciruelos E, et al. Alpelisib plus fulvestrant in PIK3CA-mutated, hormone receptor-positive advanced breast cancer after a CDK4/6 inhibitor (BYLieve): One cohort of a phase 2, multicentre, open-label, non-comparative study. Lancet Oncol. 2021;22:489-498. doi: 10.1016/S1470-2045(21)00034-6. Erratum in: Lancet Oncol. 2021;22(5):e184. doi: 10.1016/S1470-2045(21)00194-7
2. Prat A, Pascual T, De Angelis C, et al. HER2-enriched subtype and ERBB2 expression in HER2-positive breast cancer treated with dual HER2 blockade. J Natl Cancer Inst. 2020;112:46-54. doi: 10.1093/jnci/djz042
3. Ulaner GA, Jhaveri K, Chandarlapaty S, et al. Head-to-head evaluation of ¹⁸F-FES and ¹⁸F-FDG PET/CT in metastatic invasive lobular breast cancer. J Nucl Med. 2021;62:326-331. doi: 10.2967/jnumed.120.247882

Small-cell lung cancer (SCLC) occurs almost exclusively in cigarette smokers. Veterans are particularly vulnerable to SCLC because of their prevalent smoking history and exposures to carcinogens, including Agent Orange. 

SCLC is characterized by the early development of widespread metastases, including liver, bone, and brain. 

Unlike, non–-small cell lung cancer, which has seen great improvement in survival from the introduction of immunotherapy and targeted agents, there has been relatively little improvement in SCLC. 

Patients generally are classified into limited- and extensive-stage disease, but platinum-based chemotherapy is almost always the standard first-line treatment. Unfortunately, most patients relapse within a year. 

In this ReCAP, Dr Shadia Jalal, of Indiana University Melvin and Bren Simon Comprehensive Cancer Center, discusses second-line treatment options for SCLC patients who relapse after chemotherapy. She also discusses four subtypes of SCLC categorized on the basis of specific transcription regulators, which may offer the potential of targeted therapies for this patient population.  

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Shadia Jalal, MD, Associate Professor of Medicine, Physician, Indiana University Melvin and Bren Simon Comprehensive Cancer Center, Indianapolis, Indiana 

Shadia Jalal, MD, has disclosed no relevant financial relationships. 

Small-cell lung cancer (SCLC) occurs almost exclusively in cigarette smokers. Veterans are particularly vulnerable to SCLC because of their prevalent smoking history and exposures to carcinogens, including Agent Orange. 

SCLC is characterized by the early development of widespread metastases, including liver, bone, and brain. 

Unlike, non–-small cell lung cancer, which has seen great improvement in survival from the introduction of immunotherapy and targeted agents, there has been relatively little improvement in SCLC. 

Patients generally are classified into limited- and extensive-stage disease, but platinum-based chemotherapy is almost always the standard first-line treatment. Unfortunately, most patients relapse within a year. 

In this ReCAP, Dr Shadia Jalal, of Indiana University Melvin and Bren Simon Comprehensive Cancer Center, discusses second-line treatment options for SCLC patients who relapse after chemotherapy. She also discusses four subtypes of SCLC categorized on the basis of specific transcription regulators, which may offer the potential of targeted therapies for this patient population.  

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Shadia Jalal, MD, Associate Professor of Medicine, Physician, Indiana University Melvin and Bren Simon Comprehensive Cancer Center, Indianapolis, Indiana 

Shadia Jalal, MD, has disclosed no relevant financial relationships. 

Small-cell lung cancer (SCLC) occurs almost exclusively in cigarette smokers. Veterans are particularly vulnerable to SCLC because of their prevalent smoking history and exposures to carcinogens, including Agent Orange. 

SCLC is characterized by the early development of widespread metastases, including liver, bone, and brain. 

Unlike, non–-small cell lung cancer, which has seen great improvement in survival from the introduction of immunotherapy and targeted agents, there has been relatively little improvement in SCLC. 

Patients generally are classified into limited- and extensive-stage disease, but platinum-based chemotherapy is almost always the standard first-line treatment. Unfortunately, most patients relapse within a year. 

In this ReCAP, Dr Shadia Jalal, of Indiana University Melvin and Bren Simon Comprehensive Cancer Center, discusses second-line treatment options for SCLC patients who relapse after chemotherapy. She also discusses four subtypes of SCLC categorized on the basis of specific transcription regulators, which may offer the potential of targeted therapies for this patient population.  

--

Shadia Jalal, MD, Associate Professor of Medicine, Physician, Indiana University Melvin and Bren Simon Comprehensive Cancer Center, Indianapolis, Indiana 

Shadia Jalal, MD, has disclosed no relevant financial relationships. 

Incidence peaks in children aged 1-4 years, decreasing thereafter. Cases are highest among Native American/Alaskan Native and Hispanic children, and higher in White than Black children.⁴ ALL is seen more in patients with certain inherited conditions, including Down syndrome, ataxia telangiectasia, neurofibromatosis type 1, and Bloom syndrome.¹

Treatment advances have improved remission rates and outcomes for patients. However, relapse is still a leading cause of death for patients of all ages.⁶ Prompt diagnosis and care are important to optimize outcomes, as treatment delay is associated with poorer survival.⁷

Pathophysiology

In ALL, abnormal, immature lymphocytes and progenitor B cells/T cells proliferate uncontrollably and eventually replace healthy cells in bone marrow and the lymphatic system. The loss of healthy cells leads to classic symptoms of cytopenia, splenomegaly, and hepatomegaly.¹ B cells and T cells are descended from lymphoid stem cells (and are transformed by germline or somatic mutation into pathogenic cells, leading to symptom development and bone marrow dysfunction. Most pediatric patients have extensive bone marrow involvement at diagnosis, with > 25% blast cells in marrow (defined as M3 disease).⁴

Presentation

Patients usually present with signs and symptoms that are related to disease-associated anemia, thrombocytopenia, or neutropenia; these signs and symptoms may include fatigue or weakness, pale skin, bleeding or bruising easily, fever or infection, joint or extremity pain, B-cell symptoms such as night sweats or unintentional weight loss, and splenomegaly or hepatomegaly. Central nervous system (CNS) symptoms can include stroke-like symptoms due to leukemic cell invasion of CNS vasculature or neuropathies related to increased intracranial pressure. Sometimes, children may present with no symptoms other than joint or extremity pain.^1,3,8

Classification

ALL is classified by whether it derives from B-cell or T-cell progenitor cells and, within these, by typical genetic alterations (Table 1).^3,9-15 Some cytogenetics are associated with risk assessment as well. Well-identified B-ALL subtypes include Philadelphia (Ph) chromosome-positive, hyper- and hypodiploidy, and KMT2A rearranged, while newer classifications include Ph-like ALL and B-lymphoblastic leukemia with iAMP21. Provisional T-ALL subtypes include early T-cell precursor lymphoblastic leukemia and natural killer cell lymphoblastic leukemia.³

B-cell lineage is present in 88% of pediatric and 75%-80% of adult disease. T-ALL is found in about 12% of pediatric patients and 25% of adults.^3,8 Familial syndromes associated with ALL are present in about 4% of pediatric patients, including autosomal dominant germline mutations in RUNX1 (T-cell ALL), ETV6 (B-ALL), PAX5 (B-ALL), IKZF1 (B-ALL and T-ALL), and TP53 (low-hypodiploid ALL).³ If a known-familial genotype is identified, families should be referred for genetic counseling and further testing if needed. If germline mutation is suspected, early identification is important; hereditary ALL can influence treatment choice and use of allogeneic transplantation or radiation.³

A third classification crucial to guiding treatment is Ph-positive vs Ph-negative or Ph-like, the latter strongly associated with abnormal B-cell development due to deletions in related genes.^3,16 About 3% to 5% of pediatric patients and 25% of adults have Ph-positive ALL.¹⁷ The remission failure rate among pediatric patients treated with chemotherapy was 11% in one study, vs 2%-3% among patients with Ph-negative ALL.¹⁰

Diagnosis and Risk Stratification

Diagnosis is based on presentation and molecular features, requiring demonstration of ≥ 20% lymphoblasts in bone marrow biopsy or aspirate or ≥ 1,000 circulating lymphoblasts/mL in peripheral blood. Testing can include immunophenotyping using flow cytometry, molecular characterization of baseline leukemic clone, morphology using hematoxylin and eosin staining and Wright/Giemsa staining, and karyotyping.^1,3 CNS involvement is assessed using a lumbar spinal tap.¹

Risk stratification is based on molecular features (eg, high- and low-risk mutations, Table 1),^3,9-15 which are assessed using fluorescence in-situ hybridization, broad-panel next-generation sequencing, and reverse-transcriptase polymerase chain reaction of bone marrow or peripheral blood.³ Other risk factors include age, CNS involvement, white blood cell (WBC) count, and response to initial induction or consolidation therapy.³

Pediatric patients are assigned standard or high risk based on factors identified by the Children’s Oncology Group and National Comprehensive Cancer Network (NCCN). Patients
aged 1 to < 10 years with WBC < 50 × 109/L are considered standard risk, and all others are considered high risk. Patients with ALL before age 1 have very high risk. All pediatric patients with T-ALL are considered high risk.³ Ph-positive, Ph-like, hypoploidy, failure to achieve remission with induction, and extramedullary disease are high-risk factors as well, whereas hyperploidy and certain mutations convey low risk.³

Newer treatment strategies for initial ALL diagnosis include targeted therapies. One goal of targeted therapy is avoidance of long-term toxicity, leading to improved survival outcomes. Well-studied targeted therapies include the tyrosine kinase inhibitors used in first-line and subsequent treatment of Ph-positive ALL.³

Treatment Options in Relapsed/Refractory ALL

The initial treatment goal is complete remission (CR) defined as minimal residual disease (MRD) < 0.01% on flow cytometry (Table 2).³ Prognosis is dependent on time and location of relapse. Early relapse (< 18 months from diagnosis) predicts poor survival. Relapse in bone marrow is associated with poorer prognosis than relapse in CNS.^11-18 Where possible, consolidation with allogeneic hematopoietic cell transplantation improves survival for patients with early relapse.⁶ Three approaches have advanced treatment options for relapsed/refractory (R/R) B-ALL, all based around common cell markers seen in B-ALL.

The CD22-directed antibody-drug conjugate inotuzumab ozogamicin is approved for adults with R/R B-ALL. In clinical trials, a higher percentage of patients had results below the MRD threshold, and longer progression-free survival and OS compared with standard care.^19,20

Blinatumomab is a bispecific T-cell engager that binds to CD19 on the surface of B-ALL cells and to CD3 on T cells to trigger apoptosis.²¹ It was first approved for R/R ALL in adults or children, and is also now approved for treatment in remission with MRD ≥ 0.1%. Patients must demonstrate CD19-positive disease to qualify.^15-22 For R/R ALL, blinatumomab improves OS and CR rates compared with standard chemotherapy.²³

The use of CAR T-cell therapies has expanded greatly with increasing knowledge about their efficacy and safety. In R/R ALL, tisagenlecleucel (tisa-gen) is approved for treatment of patients aged ≤ 25 years, and brexucabtagene autoleucel (brexucel) is approved for treatment of adults.^3,24,25 Patients undergoing the CAR T-cell process have apheresis to collect T cells, which are then manufactured before being reinfused into the patient. Depending on local capabilities, the time between T-cell harvest and reinfusion can extend to weeks.^3,26,27 Cytoreduction with CAR T-cell therapy can allow previously ineligible patients (due to bulky disease) to undergo transplant. Patients treated in key clinical trials with tisa-gen or brexu-cel achieved high overall remission rates and improved event-free survival and OS rates compared with historical experience.^25,28,29 Important toxicities with CAR T-cell therapy are cytokine release syndrome (CRS) and neurotoxicity, which can develop rapidly. NCCN recommends hospitalizing patients at the first sign of either adverse event. Patients can be managed with tocilizumab or steroids for low-grade CRS or steroids for neurotoxicity. The Society for Immunotherapy of Cancer, American Society of Clinical Oncology, and NCCN have guidelines on management of toxicities related to CAR T-cell therapy as well as management of symptoms and other adverse effects of CRS.^5,23,24

Programs also incorporate telemedicine for symptom monitoring and follow-up.^32-34 Centers providing CAR T-cell therapy must have a certified Risk Evaluation and Mitigation Strategy (REMS), which ensures adherence to specific guidelines for administration, adverse event management, and patient education.^35,36 Overcoming technical, social, and financial barriers to CAR T-cell therapy is an ongoing challenge of great interest.³⁷

R/R T-Cell Precursor ALL

Patients with R/R T-ALL have poor prognosis, partly due to limited treatment options. Nelarabine, a nucleoside analog, is the only approved treatment for R/R T-ALL, but has increasingly been used in first-line therapy added to multiagent chemotherapy as a consolidation and maintenance approach to pediatric disease.^3,38,39 Four-year DSF in pediatric patients with newly diagnosed T-ALL undergoing treatment incorporating nelarabine was 88.9%.³⁹ Treatment is associated with grade ≥ 3 neurotoxicity in > 10% of patients, and can include CNS toxicity as well as neuropathy.³

In a recently completed phase 2 trial (NCT03384654), daratumumab was added to standard chemotherapy (vincristine, prednisone, PEG-asparaginase, doxorubicin) for R/R T-ALL in pediatric (ages 1-17 years) and young adult patients (age ≥ 18 years).⁴⁰ Among 24 pediatric patients, CR was 41.7% and overall response rate (ORR; ORR = CR + CRi) was 83% after 1 cycle of treatment. Ten (41.7%) pediatric patients achieved MRD-negative status as well. ORR was 60% in the 5 older patients. All pediatric patients had at least 1 grade ≥ 3 toxicity, but none of the adverse events led to discontinuation.⁴⁰

Success in achieving MRD-negative responses in patients treated for R/R ALL has increased interest in using targeted therapies for newly diagnosed patients. Recommended treatment approaches are summarized in Table 3.³

Long-Term Follow-Up and Survivorship

A study of > 500 pediatric patients followed for an average 23 years reassuringly found low prevalence of adverse outcomes related to disease or treatment. Major adverse outcomes such as death due to late relapse; secondary malignancy; or development of osteoporosis, cataracts, and diminished functional status were infrequent.⁴¹ Most prevalent were growth effects (short stature or growth hormone insufficiency), likely related to certain treatment approaches.⁴¹ Guidelines for long-term follow-up of pediatric patients are available from the Children’s Oncology Group.⁴²

A 2017 systematic review concluded that the quality of life for survivors is diminished upon treatment, and persistently over time for some patients.⁴³ In contrast, a 2022 comparison of long-term survivors (median 20.5 years since diagnosis) of pediatric ALL with healthy controls found that survivors had better quality of life in some domains, including general health, vitality, and mental health.⁴⁴ Smaller percentages of survivors rated themselves happiest about sleep quality, absence of pain, and physical abilities.⁴⁴

As therapy patterns and options evolve, continued follow-up is important to ensure patients derive optimal benefit from treatment and post-treatment life.

Click to read more from 2023 Rare Diseases Report: Cancers

Incidence peaks in children aged 1-4 years, decreasing thereafter. Cases are highest among Native American/Alaskan Native and Hispanic children, and higher in White than Black children.⁴ ALL is seen more in patients with certain inherited conditions, including Down syndrome, ataxia telangiectasia, neurofibromatosis type 1, and Bloom syndrome.¹

Treatment advances have improved remission rates and outcomes for patients. However, relapse is still a leading cause of death for patients of all ages.⁶ Prompt diagnosis and care are important to optimize outcomes, as treatment delay is associated with poorer survival.⁷

Pathophysiology

In ALL, abnormal, immature lymphocytes and progenitor B cells/T cells proliferate uncontrollably and eventually replace healthy cells in bone marrow and the lymphatic system. The loss of healthy cells leads to classic symptoms of cytopenia, splenomegaly, and hepatomegaly.¹ B cells and T cells are descended from lymphoid stem cells (and are transformed by germline or somatic mutation into pathogenic cells, leading to symptom development and bone marrow dysfunction. Most pediatric patients have extensive bone marrow involvement at diagnosis, with > 25% blast cells in marrow (defined as M3 disease).⁴

Presentation

Patients usually present with signs and symptoms that are related to disease-associated anemia, thrombocytopenia, or neutropenia; these signs and symptoms may include fatigue or weakness, pale skin, bleeding or bruising easily, fever or infection, joint or extremity pain, B-cell symptoms such as night sweats or unintentional weight loss, and splenomegaly or hepatomegaly. Central nervous system (CNS) symptoms can include stroke-like symptoms due to leukemic cell invasion of CNS vasculature or neuropathies related to increased intracranial pressure. Sometimes, children may present with no symptoms other than joint or extremity pain.^1,3,8

Classification

ALL is classified by whether it derives from B-cell or T-cell progenitor cells and, within these, by typical genetic alterations (Table 1).^3,9-15 Some cytogenetics are associated with risk assessment as well. Well-identified B-ALL subtypes include Philadelphia (Ph) chromosome-positive, hyper- and hypodiploidy, and KMT2A rearranged, while newer classifications include Ph-like ALL and B-lymphoblastic leukemia with iAMP21. Provisional T-ALL subtypes include early T-cell precursor lymphoblastic leukemia and natural killer cell lymphoblastic leukemia.³

B-cell lineage is present in 88% of pediatric and 75%-80% of adult disease. T-ALL is found in about 12% of pediatric patients and 25% of adults.^3,8 Familial syndromes associated with ALL are present in about 4% of pediatric patients, including autosomal dominant germline mutations in RUNX1 (T-cell ALL), ETV6 (B-ALL), PAX5 (B-ALL), IKZF1 (B-ALL and T-ALL), and TP53 (low-hypodiploid ALL).³ If a known-familial genotype is identified, families should be referred for genetic counseling and further testing if needed. If germline mutation is suspected, early identification is important; hereditary ALL can influence treatment choice and use of allogeneic transplantation or radiation.³

A third classification crucial to guiding treatment is Ph-positive vs Ph-negative or Ph-like, the latter strongly associated with abnormal B-cell development due to deletions in related genes.^3,16 About 3% to 5% of pediatric patients and 25% of adults have Ph-positive ALL.¹⁷ The remission failure rate among pediatric patients treated with chemotherapy was 11% in one study, vs 2%-3% among patients with Ph-negative ALL.¹⁰

Diagnosis and Risk Stratification

Diagnosis is based on presentation and molecular features, requiring demonstration of ≥ 20% lymphoblasts in bone marrow biopsy or aspirate or ≥ 1,000 circulating lymphoblasts/mL in peripheral blood. Testing can include immunophenotyping using flow cytometry, molecular characterization of baseline leukemic clone, morphology using hematoxylin and eosin staining and Wright/Giemsa staining, and karyotyping.^1,3 CNS involvement is assessed using a lumbar spinal tap.¹

Risk stratification is based on molecular features (eg, high- and low-risk mutations, Table 1),^3,9-15 which are assessed using fluorescence in-situ hybridization, broad-panel next-generation sequencing, and reverse-transcriptase polymerase chain reaction of bone marrow or peripheral blood.³ Other risk factors include age, CNS involvement, white blood cell (WBC) count, and response to initial induction or consolidation therapy.³

Pediatric patients are assigned standard or high risk based on factors identified by the Children’s Oncology Group and National Comprehensive Cancer Network (NCCN). Patients
aged 1 to < 10 years with WBC < 50 × 109/L are considered standard risk, and all others are considered high risk. Patients with ALL before age 1 have very high risk. All pediatric patients with T-ALL are considered high risk.³ Ph-positive, Ph-like, hypoploidy, failure to achieve remission with induction, and extramedullary disease are high-risk factors as well, whereas hyperploidy and certain mutations convey low risk.³

Newer treatment strategies for initial ALL diagnosis include targeted therapies. One goal of targeted therapy is avoidance of long-term toxicity, leading to improved survival outcomes. Well-studied targeted therapies include the tyrosine kinase inhibitors used in first-line and subsequent treatment of Ph-positive ALL.³

Treatment Options in Relapsed/Refractory ALL

The initial treatment goal is complete remission (CR) defined as minimal residual disease (MRD) < 0.01% on flow cytometry (Table 2).³ Prognosis is dependent on time and location of relapse. Early relapse (< 18 months from diagnosis) predicts poor survival. Relapse in bone marrow is associated with poorer prognosis than relapse in CNS.^11-18 Where possible, consolidation with allogeneic hematopoietic cell transplantation improves survival for patients with early relapse.⁶ Three approaches have advanced treatment options for relapsed/refractory (R/R) B-ALL, all based around common cell markers seen in B-ALL.

The CD22-directed antibody-drug conjugate inotuzumab ozogamicin is approved for adults with R/R B-ALL. In clinical trials, a higher percentage of patients had results below the MRD threshold, and longer progression-free survival and OS compared with standard care.^19,20

Blinatumomab is a bispecific T-cell engager that binds to CD19 on the surface of B-ALL cells and to CD3 on T cells to trigger apoptosis.²¹ It was first approved for R/R ALL in adults or children, and is also now approved for treatment in remission with MRD ≥ 0.1%. Patients must demonstrate CD19-positive disease to qualify.^15-22 For R/R ALL, blinatumomab improves OS and CR rates compared with standard chemotherapy.²³

The use of CAR T-cell therapies has expanded greatly with increasing knowledge about their efficacy and safety. In R/R ALL, tisagenlecleucel (tisa-gen) is approved for treatment of patients aged ≤ 25 years, and brexucabtagene autoleucel (brexucel) is approved for treatment of adults.^3,24,25 Patients undergoing the CAR T-cell process have apheresis to collect T cells, which are then manufactured before being reinfused into the patient. Depending on local capabilities, the time between T-cell harvest and reinfusion can extend to weeks.^3,26,27 Cytoreduction with CAR T-cell therapy can allow previously ineligible patients (due to bulky disease) to undergo transplant. Patients treated in key clinical trials with tisa-gen or brexu-cel achieved high overall remission rates and improved event-free survival and OS rates compared with historical experience.^25,28,29 Important toxicities with CAR T-cell therapy are cytokine release syndrome (CRS) and neurotoxicity, which can develop rapidly. NCCN recommends hospitalizing patients at the first sign of either adverse event. Patients can be managed with tocilizumab or steroids for low-grade CRS or steroids for neurotoxicity. The Society for Immunotherapy of Cancer, American Society of Clinical Oncology, and NCCN have guidelines on management of toxicities related to CAR T-cell therapy as well as management of symptoms and other adverse effects of CRS.^5,23,24

Programs also incorporate telemedicine for symptom monitoring and follow-up.^32-34 Centers providing CAR T-cell therapy must have a certified Risk Evaluation and Mitigation Strategy (REMS), which ensures adherence to specific guidelines for administration, adverse event management, and patient education.^35,36 Overcoming technical, social, and financial barriers to CAR T-cell therapy is an ongoing challenge of great interest.³⁷

R/R T-Cell Precursor ALL

Patients with R/R T-ALL have poor prognosis, partly due to limited treatment options. Nelarabine, a nucleoside analog, is the only approved treatment for R/R T-ALL, but has increasingly been used in first-line therapy added to multiagent chemotherapy as a consolidation and maintenance approach to pediatric disease.^3,38,39 Four-year DSF in pediatric patients with newly diagnosed T-ALL undergoing treatment incorporating nelarabine was 88.9%.³⁹ Treatment is associated with grade ≥ 3 neurotoxicity in > 10% of patients, and can include CNS toxicity as well as neuropathy.³

In a recently completed phase 2 trial (NCT03384654), daratumumab was added to standard chemotherapy (vincristine, prednisone, PEG-asparaginase, doxorubicin) for R/R T-ALL in pediatric (ages 1-17 years) and young adult patients (age ≥ 18 years).⁴⁰ Among 24 pediatric patients, CR was 41.7% and overall response rate (ORR; ORR = CR + CRi) was 83% after 1 cycle of treatment. Ten (41.7%) pediatric patients achieved MRD-negative status as well. ORR was 60% in the 5 older patients. All pediatric patients had at least 1 grade ≥ 3 toxicity, but none of the adverse events led to discontinuation.⁴⁰

Success in achieving MRD-negative responses in patients treated for R/R ALL has increased interest in using targeted therapies for newly diagnosed patients. Recommended treatment approaches are summarized in Table 3.³

Long-Term Follow-Up and Survivorship

A study of > 500 pediatric patients followed for an average 23 years reassuringly found low prevalence of adverse outcomes related to disease or treatment. Major adverse outcomes such as death due to late relapse; secondary malignancy; or development of osteoporosis, cataracts, and diminished functional status were infrequent.⁴¹ Most prevalent were growth effects (short stature or growth hormone insufficiency), likely related to certain treatment approaches.⁴¹ Guidelines for long-term follow-up of pediatric patients are available from the Children’s Oncology Group.⁴²

A 2017 systematic review concluded that the quality of life for survivors is diminished upon treatment, and persistently over time for some patients.⁴³ In contrast, a 2022 comparison of long-term survivors (median 20.5 years since diagnosis) of pediatric ALL with healthy controls found that survivors had better quality of life in some domains, including general health, vitality, and mental health.⁴⁴ Smaller percentages of survivors rated themselves happiest about sleep quality, absence of pain, and physical abilities.⁴⁴

As therapy patterns and options evolve, continued follow-up is important to ensure patients derive optimal benefit from treatment and post-treatment life.

Click to read more from 2023 Rare Diseases Report: Cancers

Incidence peaks in children aged 1-4 years, decreasing thereafter. Cases are highest among Native American/Alaskan Native and Hispanic children, and higher in White than Black children.⁴ ALL is seen more in patients with certain inherited conditions, including Down syndrome, ataxia telangiectasia, neurofibromatosis type 1, and Bloom syndrome.¹

Treatment advances have improved remission rates and outcomes for patients. However, relapse is still a leading cause of death for patients of all ages.⁶ Prompt diagnosis and care are important to optimize outcomes, as treatment delay is associated with poorer survival.⁷

Pathophysiology

In ALL, abnormal, immature lymphocytes and progenitor B cells/T cells proliferate uncontrollably and eventually replace healthy cells in bone marrow and the lymphatic system. The loss of healthy cells leads to classic symptoms of cytopenia, splenomegaly, and hepatomegaly.¹ B cells and T cells are descended from lymphoid stem cells (and are transformed by germline or somatic mutation into pathogenic cells, leading to symptom development and bone marrow dysfunction. Most pediatric patients have extensive bone marrow involvement at diagnosis, with > 25% blast cells in marrow (defined as M3 disease).⁴

Presentation

Patients usually present with signs and symptoms that are related to disease-associated anemia, thrombocytopenia, or neutropenia; these signs and symptoms may include fatigue or weakness, pale skin, bleeding or bruising easily, fever or infection, joint or extremity pain, B-cell symptoms such as night sweats or unintentional weight loss, and splenomegaly or hepatomegaly. Central nervous system (CNS) symptoms can include stroke-like symptoms due to leukemic cell invasion of CNS vasculature or neuropathies related to increased intracranial pressure. Sometimes, children may present with no symptoms other than joint or extremity pain.^1,3,8

Classification

ALL is classified by whether it derives from B-cell or T-cell progenitor cells and, within these, by typical genetic alterations (Table 1).^3,9-15 Some cytogenetics are associated with risk assessment as well. Well-identified B-ALL subtypes include Philadelphia (Ph) chromosome-positive, hyper- and hypodiploidy, and KMT2A rearranged, while newer classifications include Ph-like ALL and B-lymphoblastic leukemia with iAMP21. Provisional T-ALL subtypes include early T-cell precursor lymphoblastic leukemia and natural killer cell lymphoblastic leukemia.³

B-cell lineage is present in 88% of pediatric and 75%-80% of adult disease. T-ALL is found in about 12% of pediatric patients and 25% of adults.^3,8 Familial syndromes associated with ALL are present in about 4% of pediatric patients, including autosomal dominant germline mutations in RUNX1 (T-cell ALL), ETV6 (B-ALL), PAX5 (B-ALL), IKZF1 (B-ALL and T-ALL), and TP53 (low-hypodiploid ALL).³ If a known-familial genotype is identified, families should be referred for genetic counseling and further testing if needed. If germline mutation is suspected, early identification is important; hereditary ALL can influence treatment choice and use of allogeneic transplantation or radiation.³

A third classification crucial to guiding treatment is Ph-positive vs Ph-negative or Ph-like, the latter strongly associated with abnormal B-cell development due to deletions in related genes.^3,16 About 3% to 5% of pediatric patients and 25% of adults have Ph-positive ALL.¹⁷ The remission failure rate among pediatric patients treated with chemotherapy was 11% in one study, vs 2%-3% among patients with Ph-negative ALL.¹⁰

Diagnosis and Risk Stratification

Diagnosis is based on presentation and molecular features, requiring demonstration of ≥ 20% lymphoblasts in bone marrow biopsy or aspirate or ≥ 1,000 circulating lymphoblasts/mL in peripheral blood. Testing can include immunophenotyping using flow cytometry, molecular characterization of baseline leukemic clone, morphology using hematoxylin and eosin staining and Wright/Giemsa staining, and karyotyping.^1,3 CNS involvement is assessed using a lumbar spinal tap.¹

Risk stratification is based on molecular features (eg, high- and low-risk mutations, Table 1),^3,9-15 which are assessed using fluorescence in-situ hybridization, broad-panel next-generation sequencing, and reverse-transcriptase polymerase chain reaction of bone marrow or peripheral blood.³ Other risk factors include age, CNS involvement, white blood cell (WBC) count, and response to initial induction or consolidation therapy.³

Pediatric patients are assigned standard or high risk based on factors identified by the Children’s Oncology Group and National Comprehensive Cancer Network (NCCN). Patients
aged 1 to < 10 years with WBC < 50 × 109/L are considered standard risk, and all others are considered high risk. Patients with ALL before age 1 have very high risk. All pediatric patients with T-ALL are considered high risk.³ Ph-positive, Ph-like, hypoploidy, failure to achieve remission with induction, and extramedullary disease are high-risk factors as well, whereas hyperploidy and certain mutations convey low risk.³

Newer treatment strategies for initial ALL diagnosis include targeted therapies. One goal of targeted therapy is avoidance of long-term toxicity, leading to improved survival outcomes. Well-studied targeted therapies include the tyrosine kinase inhibitors used in first-line and subsequent treatment of Ph-positive ALL.³

Treatment Options in Relapsed/Refractory ALL

The initial treatment goal is complete remission (CR) defined as minimal residual disease (MRD) < 0.01% on flow cytometry (Table 2).³ Prognosis is dependent on time and location of relapse. Early relapse (< 18 months from diagnosis) predicts poor survival. Relapse in bone marrow is associated with poorer prognosis than relapse in CNS.^11-18 Where possible, consolidation with allogeneic hematopoietic cell transplantation improves survival for patients with early relapse.⁶ Three approaches have advanced treatment options for relapsed/refractory (R/R) B-ALL, all based around common cell markers seen in B-ALL.

The CD22-directed antibody-drug conjugate inotuzumab ozogamicin is approved for adults with R/R B-ALL. In clinical trials, a higher percentage of patients had results below the MRD threshold, and longer progression-free survival and OS compared with standard care.^19,20

Blinatumomab is a bispecific T-cell engager that binds to CD19 on the surface of B-ALL cells and to CD3 on T cells to trigger apoptosis.²¹ It was first approved for R/R ALL in adults or children, and is also now approved for treatment in remission with MRD ≥ 0.1%. Patients must demonstrate CD19-positive disease to qualify.^15-22 For R/R ALL, blinatumomab improves OS and CR rates compared with standard chemotherapy.²³

The use of CAR T-cell therapies has expanded greatly with increasing knowledge about their efficacy and safety. In R/R ALL, tisagenlecleucel (tisa-gen) is approved for treatment of patients aged ≤ 25 years, and brexucabtagene autoleucel (brexucel) is approved for treatment of adults.^3,24,25 Patients undergoing the CAR T-cell process have apheresis to collect T cells, which are then manufactured before being reinfused into the patient. Depending on local capabilities, the time between T-cell harvest and reinfusion can extend to weeks.^3,26,27 Cytoreduction with CAR T-cell therapy can allow previously ineligible patients (due to bulky disease) to undergo transplant. Patients treated in key clinical trials with tisa-gen or brexu-cel achieved high overall remission rates and improved event-free survival and OS rates compared with historical experience.^25,28,29 Important toxicities with CAR T-cell therapy are cytokine release syndrome (CRS) and neurotoxicity, which can develop rapidly. NCCN recommends hospitalizing patients at the first sign of either adverse event. Patients can be managed with tocilizumab or steroids for low-grade CRS or steroids for neurotoxicity. The Society for Immunotherapy of Cancer, American Society of Clinical Oncology, and NCCN have guidelines on management of toxicities related to CAR T-cell therapy as well as management of symptoms and other adverse effects of CRS.^5,23,24

Programs also incorporate telemedicine for symptom monitoring and follow-up.^32-34 Centers providing CAR T-cell therapy must have a certified Risk Evaluation and Mitigation Strategy (REMS), which ensures adherence to specific guidelines for administration, adverse event management, and patient education.^35,36 Overcoming technical, social, and financial barriers to CAR T-cell therapy is an ongoing challenge of great interest.³⁷

R/R T-Cell Precursor ALL

Patients with R/R T-ALL have poor prognosis, partly due to limited treatment options. Nelarabine, a nucleoside analog, is the only approved treatment for R/R T-ALL, but has increasingly been used in first-line therapy added to multiagent chemotherapy as a consolidation and maintenance approach to pediatric disease.^3,38,39 Four-year DSF in pediatric patients with newly diagnosed T-ALL undergoing treatment incorporating nelarabine was 88.9%.³⁹ Treatment is associated with grade ≥ 3 neurotoxicity in > 10% of patients, and can include CNS toxicity as well as neuropathy.³

In a recently completed phase 2 trial (NCT03384654), daratumumab was added to standard chemotherapy (vincristine, prednisone, PEG-asparaginase, doxorubicin) for R/R T-ALL in pediatric (ages 1-17 years) and young adult patients (age ≥ 18 years).⁴⁰ Among 24 pediatric patients, CR was 41.7% and overall response rate (ORR; ORR = CR + CRi) was 83% after 1 cycle of treatment. Ten (41.7%) pediatric patients achieved MRD-negative status as well. ORR was 60% in the 5 older patients. All pediatric patients had at least 1 grade ≥ 3 toxicity, but none of the adverse events led to discontinuation.⁴⁰

Success in achieving MRD-negative responses in patients treated for R/R ALL has increased interest in using targeted therapies for newly diagnosed patients. Recommended treatment approaches are summarized in Table 3.³

Long-Term Follow-Up and Survivorship

A study of > 500 pediatric patients followed for an average 23 years reassuringly found low prevalence of adverse outcomes related to disease or treatment. Major adverse outcomes such as death due to late relapse; secondary malignancy; or development of osteoporosis, cataracts, and diminished functional status were infrequent.⁴¹ Most prevalent were growth effects (short stature or growth hormone insufficiency), likely related to certain treatment approaches.⁴¹ Guidelines for long-term follow-up of pediatric patients are available from the Children’s Oncology Group.⁴²

A 2017 systematic review concluded that the quality of life for survivors is diminished upon treatment, and persistently over time for some patients.⁴³ In contrast, a 2022 comparison of long-term survivors (median 20.5 years since diagnosis) of pediatric ALL with healthy controls found that survivors had better quality of life in some domains, including general health, vitality, and mental health.⁴⁴ Smaller percentages of survivors rated themselves happiest about sleep quality, absence of pain, and physical abilities.⁴⁴

As therapy patterns and options evolve, continued follow-up is important to ensure patients derive optimal benefit from treatment and post-treatment life.

Click to read more from 2023 Rare Diseases Report: Cancers

Within the last 40 years, younger fit patients have benefited from intensive chemotherapy regimens for acute myeloid leukemia (AML) with improved survival, and the possibility of long-term disease-free survival (DFS) (“cure”).¹ Older patients are often considered too unfit for standard curative treatment with intensive induction chemotherapy followed by consolidation chemotherapy, allogeneic hematopoietic cell transplantation (allo-HCT), or both.^2-4 Higher induction mortality and poor overall survival (OS) are associated with worse performance status, organ impairment, significant comorbidities, and declining cognitive function, all of which are more common with advancing age. Although the suggested criteria for determining unfitness have not been validated (Table 1), they can provide guidance in clinical practice.^2-5

The National Comprehensive Cancer Network (NCCN) panel recommends the consideration of a patient’s performance status and comorbid conditions in addition to their age to determine a patient’s fitness for intensive induction therapy.⁶ Adverse disease features should also be considered, because disease biology may make intensive chemotherapy futile or inappropriate. For example, the mutational driver tumor protein p53 (TP53) appears at a higher frequency in older adults than younger adults and is associated with dismal outcomes even with intensive chemotherapy. Likewise, the spliceosome and chromatin modifier gene mutations are more common in older patients with AML and confer a worse OS with intensive therapy.^6,7 Older unfit patients faced a difficult decision: proceed with intensive therapy with some possibility of long-term survival but risk of early mortality and significant toxicity, or opt for supportive care and palliative chemotherapy, such as the hypomethylating agents (HMAs) or low-dose cytarabine, with much shorter survival.

Guidelines for Treating Older Unfit Patients

Evidence-based guidelines for managing older adults with newly diagnosed AML were developed by the American Society of Hematology in 2020; however, these guidelines were released prior to the results of several clinical trials involving older patients with AML (Table 2).⁸ In 2022, the European LeukemiaNet (ELN) recommendations were updated to include new therapeutic agents that target specific mutations in genes such as tyrosine kinase 3 (FLT3), isocitrate dehydrogenase 1 (IDH1), isocitrate dehydrogenase 2 (IDH2), and B-cell lymphoma 2 (BCL2). Given the important effects of genetic aberrations on disease phenotype, treatment options, and outcomes, screening for genetic aberrations at diagnosis is now essential.⁹

The potential for clonal evolution leading to new actionable targets that were not present at diagnosis highlights the importance of reevaluation of genetic aberrations throughout clinical progression. Actionable targets can include mutations in IDH1/IDH2, FLT3-internal tandem duplication or FLT3 tyrosine kinase domain.⁹

Treatment Landscape

Since 2018, several therapeutic agents have been added to the treatment armamentarium that can induce longer-term complete remission (CR) for older unfit patients with newly diagnosed AML (Table 2).⁴ 

Management of Primary AML With Less Intensive Induction Therapy

VIALE-A established a new standard of care for older unfit patients by demonstrating the benefit of adding the BCL2 inhibitor venetoclax (VEN) to azacitidine (AZA).2 VIALE-A demonstrated that the rate of CR plus CR with partial hematologic recovery (CRi) was 65% for VEN plus AZA and 18% for AZA. Most remissions in the AZA/VEN arm occurred rapidly in the first 2 cycles. The median survival improved from 9.6 months with AZA to 14.7 months with AZA/VEN. An improvement in survival with VEN and low-dose cytarabine also emerged in a 6-month post hoc analysis of the VIALE-C trial.¹⁰ Various other trials examining targeted therapies on specific mutations have provided mixed results in the front-line setting.^13,14,18 It is important to note that a recent systematic review found that 12% to 25% of patients who were unfit for intensive therapy were successfully bridged to HCT.¹⁹

Management of Postremission Response

Patients with a longer duration of first remission have demonstrated better survival outcomes.¹⁵ Two trials have examined postremission therapy in the setting of prior intensive therapy. HOVON97 enrolled older patients who achieved CR/CRi after 2 cycles of intensive therapy to receive either AZA postremission or no further treatment. The proportion of patients with DFS at 12 months was greater in the AZA maintenance group than in the observation group (64% vs 42%), but significant DFS improvement did not translate into improved OS.²⁰ QUAZAR AML-001 demonstrated that OS was longer for older patients receiving maintenance therapy with CC-486 (a non-bioequivalent oral formulation of AZA) vs placebo (24.7 vs 14.8 months).¹⁵ CC-486 was FDA-approved for maintenance therapy after intensive induction with or without consolidation in patients who are not candidates for allo-HCT. However, limited evidence exists specifically for postremission therapy in unfit patients who have received less intensive therapy. Continuation of the lower intensive therapy is recommended until disease progression.⁶ No data are available to support the use of oral AZA therapy alone for maintenance of remission following HMA/VEN-induced remissions.

Management of Relapsed and Refractory AML

Nearly 50% of patients with AML experience relapse and up to 40% may be refractory.¹⁹ Importantly, patients who were considered fit for intensive therapy may not remain so with relapsed or refractory AML (r/rAML), so patients should be evaluated for fitness for an intensive salvage regimen. Similar to assessing fitness for induction therapy, no standard definition of fitness exists for r/rAML.¹⁹

Disease control is the goal for patients with r/rAML who are unfit for intensive salvage therapy; however, treatment options remain limited and prognosis is poor.¹⁹ Depending on the patient’s cytogenetic profile, management can include HMA with or without VEN, glasdegib with LDAC, gilteritinib, ivosidenib or enasidenib, or gemtuzumab ozogamicin.⁹ Only a few studies have been published involving the r/rAML population not eligible for intensive salvage regimen, and guidelines are needed for this population.¹⁹ Thus, the ELN recommends that clinical trial enrollment be considered for patients with r/rAML.⁹

Management of Secondary AML or High-risk AML

Compared with de novo AML, both secondary AML (sAML) and therapy-related AML (tAML) have been associated with inferior outcomes. Factors that influence poor outcomes can include older age, comorbidities, persistent malignant disease or relapse of primary malignancy, treatment-induced depletion of hematopoietic reserves and/or prolonged myelosuppression, and genetic abnormalities, such as TP53 mutations.²¹

CPX-351 is a dual drug that contains cytarabine and daunorubicin.^9,22 An open-label study (NCT01696084) compared CPX-351 with conventional cytarabine and daunorubicin (induction and consolidation therapy) in older patients (aged 60-75 years) with newly diagnosed high-risk/sAML who were considered fit for intensive therapy. The OS for CPX-351 was longer (9.56 vs 5.95 months) and the safety profiles were similar between the treatment groups.²³ Patients achieving CR/CRi received up to 2 cycles of consolidation with CPX-351. An exploratory analysis of this subgroup revealed median OS was longer with CPX-351 consolidation (25.43 vs 8.53 months).²² Patients with TP53 mutations had poor treatment outcomes regardless of treatment arm, whereas patients with sAML-type mutations including spliceosome and chromatin modifier genes had longer OS with CPX-351 therapy.²⁴ The 5-year results of this trial indicate that the survival benefit of CPX-351 was maintained.²⁵ However, data from a retrospective review involving 136 patients with either sAML or AML with myelodysplasia-related changes revealed no difference in survival outcomes between patients treated with either HMA/VEN or CPX-351.²⁶

Case Study: Elderly Woman With Newly Diagnosed AML

In 2018, Ms. W, age 69 years, was diagnosed with seropositive, non-erosive rheumatoid arthritis; she began methotrexate 17.5 mg per week split dosing in conjunction with oral folic acid 2 mg/d with varying doses based on symptoms. Her comorbidities included recurrent episodes of diverticulitis, hypertension, hypothyroidism, obstructive sleep apnea, and gastrointestinal reflux disease. On February 4, 2021, her methotrexate was increased to 20 mg and required intermittent prednisone tapers for flares. In November 2021, a blood test revealed she had a decreased white blood cell (WBC) count at 1.8 K/μL, and her methotrexate dose was decreased to 15 mg weekly. Despite the dose reduction, she had grade 3 neutropenia and anemia (WBC: 0.7 K/μL; HGB:10.5 g/dL) with a normal platelet count (PLT: 165,000/μL). Methotrexate was discontinued and leucovorin was initiated. She then had only modest improvement in her lab values and peripheral blood blasts. 

On March 17, 2022, she underwent a bone marrow biopsy and aspirate, which resulted in a diagnosis of AML. She had 55% blasts in a 90% cellular bone marrow with mild reticulin fibrosis and numerous circulating blasts. She was classified as having AML without maturation (FAB AML-M1). Flow cytometry detected a phenotypically abnormal population with CD45 expression and side scatter/forward scatter features of small-to-medium sized blasts, accounting for 23% of total cells. The chromosome analysis demonstrated a normal female karyotype in all 19 available metaphases. Polymerase chain reaction analysis was negative for FLT3-ITD, FLT3-TKD, and NPM1 mutations and positive for an IDH1 R132C missense mutation. The myeloid gene panel identified only a single pathogenic variant, IDH1 R132C (variant allele frequency [VAF] 21.2%), and a variant of unknown significance DNMT3A A575P (VAF 25.7%).

Noting that she does not have favorable risk features, we discussed treatment options. Although she is a candidate for curative therapy, the patient was not interested in pursuing allo-HCT. Her history of diverticulitis is concerning for tolerating intensive chemotherapy. In addition, her immunosuppressive therapy increases her risk for opportunistic infections. Based on the available data from the AGILE and VIALE studies and associated potential adverse reactions, she opted for starting treatment with AZA and IVO.

On March 31, 2022, she began receiving AZA 75 mg/m² intravenous (IV) once daily days 1-7 and oral IVO 500 mg once daily continuously. She has received 12 cycles and has not needed transfusion. She has not had febrile neutropenia or symptoms of differentiation syndrome. On March 24, 2023, she underwent laparoscopic cholecystectomy, because an ultrasound revealed cholelithiasis, abnormal gallbladder wall thickening, and pericholecystic fluid. She was discharged home the following day and is continuing with AZA/ivosidenib.

Click to read more from 2023 Rare Diseases Report: Cancers

Within the last 40 years, younger fit patients have benefited from intensive chemotherapy regimens for acute myeloid leukemia (AML) with improved survival, and the possibility of long-term disease-free survival (DFS) (“cure”).¹ Older patients are often considered too unfit for standard curative treatment with intensive induction chemotherapy followed by consolidation chemotherapy, allogeneic hematopoietic cell transplantation (allo-HCT), or both.^2-4 Higher induction mortality and poor overall survival (OS) are associated with worse performance status, organ impairment, significant comorbidities, and declining cognitive function, all of which are more common with advancing age. Although the suggested criteria for determining unfitness have not been validated (Table 1), they can provide guidance in clinical practice.^2-5

The National Comprehensive Cancer Network (NCCN) panel recommends the consideration of a patient’s performance status and comorbid conditions in addition to their age to determine a patient’s fitness for intensive induction therapy.⁶ Adverse disease features should also be considered, because disease biology may make intensive chemotherapy futile or inappropriate. For example, the mutational driver tumor protein p53 (TP53) appears at a higher frequency in older adults than younger adults and is associated with dismal outcomes even with intensive chemotherapy. Likewise, the spliceosome and chromatin modifier gene mutations are more common in older patients with AML and confer a worse OS with intensive therapy.^6,7 Older unfit patients faced a difficult decision: proceed with intensive therapy with some possibility of long-term survival but risk of early mortality and significant toxicity, or opt for supportive care and palliative chemotherapy, such as the hypomethylating agents (HMAs) or low-dose cytarabine, with much shorter survival.

Guidelines for Treating Older Unfit Patients

Evidence-based guidelines for managing older adults with newly diagnosed AML were developed by the American Society of Hematology in 2020; however, these guidelines were released prior to the results of several clinical trials involving older patients with AML (Table 2).⁸ In 2022, the European LeukemiaNet (ELN) recommendations were updated to include new therapeutic agents that target specific mutations in genes such as tyrosine kinase 3 (FLT3), isocitrate dehydrogenase 1 (IDH1), isocitrate dehydrogenase 2 (IDH2), and B-cell lymphoma 2 (BCL2). Given the important effects of genetic aberrations on disease phenotype, treatment options, and outcomes, screening for genetic aberrations at diagnosis is now essential.⁹

The potential for clonal evolution leading to new actionable targets that were not present at diagnosis highlights the importance of reevaluation of genetic aberrations throughout clinical progression. Actionable targets can include mutations in IDH1/IDH2, FLT3-internal tandem duplication or FLT3 tyrosine kinase domain.⁹

Treatment Landscape

Since 2018, several therapeutic agents have been added to the treatment armamentarium that can induce longer-term complete remission (CR) for older unfit patients with newly diagnosed AML (Table 2).⁴ 

Management of Primary AML With Less Intensive Induction Therapy

VIALE-A established a new standard of care for older unfit patients by demonstrating the benefit of adding the BCL2 inhibitor venetoclax (VEN) to azacitidine (AZA).2 VIALE-A demonstrated that the rate of CR plus CR with partial hematologic recovery (CRi) was 65% for VEN plus AZA and 18% for AZA. Most remissions in the AZA/VEN arm occurred rapidly in the first 2 cycles. The median survival improved from 9.6 months with AZA to 14.7 months with AZA/VEN. An improvement in survival with VEN and low-dose cytarabine also emerged in a 6-month post hoc analysis of the VIALE-C trial.¹⁰ Various other trials examining targeted therapies on specific mutations have provided mixed results in the front-line setting.^13,14,18 It is important to note that a recent systematic review found that 12% to 25% of patients who were unfit for intensive therapy were successfully bridged to HCT.¹⁹

Management of Postremission Response

Patients with a longer duration of first remission have demonstrated better survival outcomes.¹⁵ Two trials have examined postremission therapy in the setting of prior intensive therapy. HOVON97 enrolled older patients who achieved CR/CRi after 2 cycles of intensive therapy to receive either AZA postremission or no further treatment. The proportion of patients with DFS at 12 months was greater in the AZA maintenance group than in the observation group (64% vs 42%), but significant DFS improvement did not translate into improved OS.²⁰ QUAZAR AML-001 demonstrated that OS was longer for older patients receiving maintenance therapy with CC-486 (a non-bioequivalent oral formulation of AZA) vs placebo (24.7 vs 14.8 months).¹⁵ CC-486 was FDA-approved for maintenance therapy after intensive induction with or without consolidation in patients who are not candidates for allo-HCT. However, limited evidence exists specifically for postremission therapy in unfit patients who have received less intensive therapy. Continuation of the lower intensive therapy is recommended until disease progression.⁶ No data are available to support the use of oral AZA therapy alone for maintenance of remission following HMA/VEN-induced remissions.

Management of Relapsed and Refractory AML

Nearly 50% of patients with AML experience relapse and up to 40% may be refractory.¹⁹ Importantly, patients who were considered fit for intensive therapy may not remain so with relapsed or refractory AML (r/rAML), so patients should be evaluated for fitness for an intensive salvage regimen. Similar to assessing fitness for induction therapy, no standard definition of fitness exists for r/rAML.¹⁹

Disease control is the goal for patients with r/rAML who are unfit for intensive salvage therapy; however, treatment options remain limited and prognosis is poor.¹⁹ Depending on the patient’s cytogenetic profile, management can include HMA with or without VEN, glasdegib with LDAC, gilteritinib, ivosidenib or enasidenib, or gemtuzumab ozogamicin.⁹ Only a few studies have been published involving the r/rAML population not eligible for intensive salvage regimen, and guidelines are needed for this population.¹⁹ Thus, the ELN recommends that clinical trial enrollment be considered for patients with r/rAML.⁹

Management of Secondary AML or High-risk AML

Compared with de novo AML, both secondary AML (sAML) and therapy-related AML (tAML) have been associated with inferior outcomes. Factors that influence poor outcomes can include older age, comorbidities, persistent malignant disease or relapse of primary malignancy, treatment-induced depletion of hematopoietic reserves and/or prolonged myelosuppression, and genetic abnormalities, such as TP53 mutations.²¹

CPX-351 is a dual drug that contains cytarabine and daunorubicin.^9,22 An open-label study (NCT01696084) compared CPX-351 with conventional cytarabine and daunorubicin (induction and consolidation therapy) in older patients (aged 60-75 years) with newly diagnosed high-risk/sAML who were considered fit for intensive therapy. The OS for CPX-351 was longer (9.56 vs 5.95 months) and the safety profiles were similar between the treatment groups.²³ Patients achieving CR/CRi received up to 2 cycles of consolidation with CPX-351. An exploratory analysis of this subgroup revealed median OS was longer with CPX-351 consolidation (25.43 vs 8.53 months).²² Patients with TP53 mutations had poor treatment outcomes regardless of treatment arm, whereas patients with sAML-type mutations including spliceosome and chromatin modifier genes had longer OS with CPX-351 therapy.²⁴ The 5-year results of this trial indicate that the survival benefit of CPX-351 was maintained.²⁵ However, data from a retrospective review involving 136 patients with either sAML or AML with myelodysplasia-related changes revealed no difference in survival outcomes between patients treated with either HMA/VEN or CPX-351.²⁶

Case Study: Elderly Woman With Newly Diagnosed AML

In 2018, Ms. W, age 69 years, was diagnosed with seropositive, non-erosive rheumatoid arthritis; she began methotrexate 17.5 mg per week split dosing in conjunction with oral folic acid 2 mg/d with varying doses based on symptoms. Her comorbidities included recurrent episodes of diverticulitis, hypertension, hypothyroidism, obstructive sleep apnea, and gastrointestinal reflux disease. On February 4, 2021, her methotrexate was increased to 20 mg and required intermittent prednisone tapers for flares. In November 2021, a blood test revealed she had a decreased white blood cell (WBC) count at 1.8 K/μL, and her methotrexate dose was decreased to 15 mg weekly. Despite the dose reduction, she had grade 3 neutropenia and anemia (WBC: 0.7 K/μL; HGB:10.5 g/dL) with a normal platelet count (PLT: 165,000/μL). Methotrexate was discontinued and leucovorin was initiated. She then had only modest improvement in her lab values and peripheral blood blasts. 

On March 17, 2022, she underwent a bone marrow biopsy and aspirate, which resulted in a diagnosis of AML. She had 55% blasts in a 90% cellular bone marrow with mild reticulin fibrosis and numerous circulating blasts. She was classified as having AML without maturation (FAB AML-M1). Flow cytometry detected a phenotypically abnormal population with CD45 expression and side scatter/forward scatter features of small-to-medium sized blasts, accounting for 23% of total cells. The chromosome analysis demonstrated a normal female karyotype in all 19 available metaphases. Polymerase chain reaction analysis was negative for FLT3-ITD, FLT3-TKD, and NPM1 mutations and positive for an IDH1 R132C missense mutation. The myeloid gene panel identified only a single pathogenic variant, IDH1 R132C (variant allele frequency [VAF] 21.2%), and a variant of unknown significance DNMT3A A575P (VAF 25.7%).

Noting that she does not have favorable risk features, we discussed treatment options. Although she is a candidate for curative therapy, the patient was not interested in pursuing allo-HCT. Her history of diverticulitis is concerning for tolerating intensive chemotherapy. In addition, her immunosuppressive therapy increases her risk for opportunistic infections. Based on the available data from the AGILE and VIALE studies and associated potential adverse reactions, she opted for starting treatment with AZA and IVO.

On March 31, 2022, she began receiving AZA 75 mg/m² intravenous (IV) once daily days 1-7 and oral IVO 500 mg once daily continuously. She has received 12 cycles and has not needed transfusion. She has not had febrile neutropenia or symptoms of differentiation syndrome. On March 24, 2023, she underwent laparoscopic cholecystectomy, because an ultrasound revealed cholelithiasis, abnormal gallbladder wall thickening, and pericholecystic fluid. She was discharged home the following day and is continuing with AZA/ivosidenib.

Click to read more from 2023 Rare Diseases Report: Cancers

Within the last 40 years, younger fit patients have benefited from intensive chemotherapy regimens for acute myeloid leukemia (AML) with improved survival, and the possibility of long-term disease-free survival (DFS) (“cure”).¹ Older patients are often considered too unfit for standard curative treatment with intensive induction chemotherapy followed by consolidation chemotherapy, allogeneic hematopoietic cell transplantation (allo-HCT), or both.^2-4 Higher induction mortality and poor overall survival (OS) are associated with worse performance status, organ impairment, significant comorbidities, and declining cognitive function, all of which are more common with advancing age. Although the suggested criteria for determining unfitness have not been validated (Table 1), they can provide guidance in clinical practice.^2-5

The National Comprehensive Cancer Network (NCCN) panel recommends the consideration of a patient’s performance status and comorbid conditions in addition to their age to determine a patient’s fitness for intensive induction therapy.⁶ Adverse disease features should also be considered, because disease biology may make intensive chemotherapy futile or inappropriate. For example, the mutational driver tumor protein p53 (TP53) appears at a higher frequency in older adults than younger adults and is associated with dismal outcomes even with intensive chemotherapy. Likewise, the spliceosome and chromatin modifier gene mutations are more common in older patients with AML and confer a worse OS with intensive therapy.^6,7 Older unfit patients faced a difficult decision: proceed with intensive therapy with some possibility of long-term survival but risk of early mortality and significant toxicity, or opt for supportive care and palliative chemotherapy, such as the hypomethylating agents (HMAs) or low-dose cytarabine, with much shorter survival.

Guidelines for Treating Older Unfit Patients

Evidence-based guidelines for managing older adults with newly diagnosed AML were developed by the American Society of Hematology in 2020; however, these guidelines were released prior to the results of several clinical trials involving older patients with AML (Table 2).⁸ In 2022, the European LeukemiaNet (ELN) recommendations were updated to include new therapeutic agents that target specific mutations in genes such as tyrosine kinase 3 (FLT3), isocitrate dehydrogenase 1 (IDH1), isocitrate dehydrogenase 2 (IDH2), and B-cell lymphoma 2 (BCL2). Given the important effects of genetic aberrations on disease phenotype, treatment options, and outcomes, screening for genetic aberrations at diagnosis is now essential.⁹

The potential for clonal evolution leading to new actionable targets that were not present at diagnosis highlights the importance of reevaluation of genetic aberrations throughout clinical progression. Actionable targets can include mutations in IDH1/IDH2, FLT3-internal tandem duplication or FLT3 tyrosine kinase domain.⁹

Treatment Landscape

Since 2018, several therapeutic agents have been added to the treatment armamentarium that can induce longer-term complete remission (CR) for older unfit patients with newly diagnosed AML (Table 2).⁴ 

Management of Primary AML With Less Intensive Induction Therapy

VIALE-A established a new standard of care for older unfit patients by demonstrating the benefit of adding the BCL2 inhibitor venetoclax (VEN) to azacitidine (AZA).2 VIALE-A demonstrated that the rate of CR plus CR with partial hematologic recovery (CRi) was 65% for VEN plus AZA and 18% for AZA. Most remissions in the AZA/VEN arm occurred rapidly in the first 2 cycles. The median survival improved from 9.6 months with AZA to 14.7 months with AZA/VEN. An improvement in survival with VEN and low-dose cytarabine also emerged in a 6-month post hoc analysis of the VIALE-C trial.¹⁰ Various other trials examining targeted therapies on specific mutations have provided mixed results in the front-line setting.^13,14,18 It is important to note that a recent systematic review found that 12% to 25% of patients who were unfit for intensive therapy were successfully bridged to HCT.¹⁹

Management of Postremission Response

Patients with a longer duration of first remission have demonstrated better survival outcomes.¹⁵ Two trials have examined postremission therapy in the setting of prior intensive therapy. HOVON97 enrolled older patients who achieved CR/CRi after 2 cycles of intensive therapy to receive either AZA postremission or no further treatment. The proportion of patients with DFS at 12 months was greater in the AZA maintenance group than in the observation group (64% vs 42%), but significant DFS improvement did not translate into improved OS.²⁰ QUAZAR AML-001 demonstrated that OS was longer for older patients receiving maintenance therapy with CC-486 (a non-bioequivalent oral formulation of AZA) vs placebo (24.7 vs 14.8 months).¹⁵ CC-486 was FDA-approved for maintenance therapy after intensive induction with or without consolidation in patients who are not candidates for allo-HCT. However, limited evidence exists specifically for postremission therapy in unfit patients who have received less intensive therapy. Continuation of the lower intensive therapy is recommended until disease progression.⁶ No data are available to support the use of oral AZA therapy alone for maintenance of remission following HMA/VEN-induced remissions.

Management of Relapsed and Refractory AML

Nearly 50% of patients with AML experience relapse and up to 40% may be refractory.¹⁹ Importantly, patients who were considered fit for intensive therapy may not remain so with relapsed or refractory AML (r/rAML), so patients should be evaluated for fitness for an intensive salvage regimen. Similar to assessing fitness for induction therapy, no standard definition of fitness exists for r/rAML.¹⁹

Disease control is the goal for patients with r/rAML who are unfit for intensive salvage therapy; however, treatment options remain limited and prognosis is poor.¹⁹ Depending on the patient’s cytogenetic profile, management can include HMA with or without VEN, glasdegib with LDAC, gilteritinib, ivosidenib or enasidenib, or gemtuzumab ozogamicin.⁹ Only a few studies have been published involving the r/rAML population not eligible for intensive salvage regimen, and guidelines are needed for this population.¹⁹ Thus, the ELN recommends that clinical trial enrollment be considered for patients with r/rAML.⁹

Management of Secondary AML or High-risk AML

Compared with de novo AML, both secondary AML (sAML) and therapy-related AML (tAML) have been associated with inferior outcomes. Factors that influence poor outcomes can include older age, comorbidities, persistent malignant disease or relapse of primary malignancy, treatment-induced depletion of hematopoietic reserves and/or prolonged myelosuppression, and genetic abnormalities, such as TP53 mutations.²¹

CPX-351 is a dual drug that contains cytarabine and daunorubicin.^9,22 An open-label study (NCT01696084) compared CPX-351 with conventional cytarabine and daunorubicin (induction and consolidation therapy) in older patients (aged 60-75 years) with newly diagnosed high-risk/sAML who were considered fit for intensive therapy. The OS for CPX-351 was longer (9.56 vs 5.95 months) and the safety profiles were similar between the treatment groups.²³ Patients achieving CR/CRi received up to 2 cycles of consolidation with CPX-351. An exploratory analysis of this subgroup revealed median OS was longer with CPX-351 consolidation (25.43 vs 8.53 months).²² Patients with TP53 mutations had poor treatment outcomes regardless of treatment arm, whereas patients with sAML-type mutations including spliceosome and chromatin modifier genes had longer OS with CPX-351 therapy.²⁴ The 5-year results of this trial indicate that the survival benefit of CPX-351 was maintained.²⁵ However, data from a retrospective review involving 136 patients with either sAML or AML with myelodysplasia-related changes revealed no difference in survival outcomes between patients treated with either HMA/VEN or CPX-351.²⁶

Case Study: Elderly Woman With Newly Diagnosed AML

In 2018, Ms. W, age 69 years, was diagnosed with seropositive, non-erosive rheumatoid arthritis; she began methotrexate 17.5 mg per week split dosing in conjunction with oral folic acid 2 mg/d with varying doses based on symptoms. Her comorbidities included recurrent episodes of diverticulitis, hypertension, hypothyroidism, obstructive sleep apnea, and gastrointestinal reflux disease. On February 4, 2021, her methotrexate was increased to 20 mg and required intermittent prednisone tapers for flares. In November 2021, a blood test revealed she had a decreased white blood cell (WBC) count at 1.8 K/μL, and her methotrexate dose was decreased to 15 mg weekly. Despite the dose reduction, she had grade 3 neutropenia and anemia (WBC: 0.7 K/μL; HGB:10.5 g/dL) with a normal platelet count (PLT: 165,000/μL). Methotrexate was discontinued and leucovorin was initiated. She then had only modest improvement in her lab values and peripheral blood blasts. 

On March 17, 2022, she underwent a bone marrow biopsy and aspirate, which resulted in a diagnosis of AML. She had 55% blasts in a 90% cellular bone marrow with mild reticulin fibrosis and numerous circulating blasts. She was classified as having AML without maturation (FAB AML-M1). Flow cytometry detected a phenotypically abnormal population with CD45 expression and side scatter/forward scatter features of small-to-medium sized blasts, accounting for 23% of total cells. The chromosome analysis demonstrated a normal female karyotype in all 19 available metaphases. Polymerase chain reaction analysis was negative for FLT3-ITD, FLT3-TKD, and NPM1 mutations and positive for an IDH1 R132C missense mutation. The myeloid gene panel identified only a single pathogenic variant, IDH1 R132C (variant allele frequency [VAF] 21.2%), and a variant of unknown significance DNMT3A A575P (VAF 25.7%).

Noting that she does not have favorable risk features, we discussed treatment options. Although she is a candidate for curative therapy, the patient was not interested in pursuing allo-HCT. Her history of diverticulitis is concerning for tolerating intensive chemotherapy. In addition, her immunosuppressive therapy increases her risk for opportunistic infections. Based on the available data from the AGILE and VIALE studies and associated potential adverse reactions, she opted for starting treatment with AZA and IVO.

On March 31, 2022, she began receiving AZA 75 mg/m² intravenous (IV) once daily days 1-7 and oral IVO 500 mg once daily continuously. She has received 12 cycles and has not needed transfusion. She has not had febrile neutropenia or symptoms of differentiation syndrome. On March 24, 2023, she underwent laparoscopic cholecystectomy, because an ultrasound revealed cholelithiasis, abnormal gallbladder wall thickening, and pericholecystic fluid. She was discharged home the following day and is continuing with AZA/ivosidenib.

Click to read more from 2023 Rare Diseases Report: Cancers

Pathophysiology

HCL develops from activated, mature memory B-cells that, in most cases, have the acquired mutation in BRAF V600E, which is present in 80% to 90% of patients with classic HCL.^1,3,5 BRAF is an integral part of the RAS-BRAF-MEK-ERK cellular pathway that transmits growth factor signals from the cell surface to the nucleus to regulate cell growth and proliferation.⁶ Mutated BRAF V600E continuously activates BRAF kinase and downstream signaling, resulting in enhanced HCL cell survival and unchecked proliferation.³

Variant HCL (HCLv) is a separate, more virulent disease that lacks BRAF V600E mutation and CD25 expression on flow cytometry.^1,7-9 Patients with HCLv have a worse prognosis and poor responses to front-line purine analogs, and a higher proportion of these patients carry the unmutated immunoglobulin heavy chain variable (IGHV) gene (54% vs 17% in HCL).^1,10,11 About 30% to 50% have wild-type BRAF and activating mutations in MAP2K1, which encodes aberrant MEK downstream of BRAF.^10,12

Most patients with HCL have somatic mutations in the IGHV gene.^3,13,14 Patients with unmutated IGHV4-34 and wildtype BRAF have an aggressive form of the disease, even if the HCL cells express CD25 as in classic HCL.^1,15 HCL in patients with unmutated IGHV is often refractory to purine analogs and these patients have poor prognosis and rapid progression.¹⁶ Other identified mutations include CDKN1B in HCL and MAP2K1 and CCNC3 in HCLv.²

Signs and Symptoms

In many cases, HCL is asymptomatic, and diagnosed when pancytopenia, monocytopenia, and leukopenia are discovered on unrelated blood work.^2,3,11 Monocytopenia is a specific presentation of HCL, but not HCLv.¹¹ Typical systemic symptoms include unexplained weight loss and extreme fatigue (80%).^1,3 Other symptoms can include fever, recurrent infections, night sweats, splenomegaly and related pain or abdominal fullness, hepatomegaly, and bleeding or bruising due to thrombocytopenia.^1,3 Splenomegaly is associated with advanced disease.¹¹

Up to 30% of patients may present with autoimmune disorders such as vasculitis or psoriasis. Although skin involvement is rare with HCL, 10% to 12% of patients will have dermatologic symptoms either due to recurrent infection or autoimmune reactions.^1,2 Skin reactions include localized or generalized maculopapular rash, pyoderma gangrenosum (which may be severe), and recurrent bacterial or viral skin infections.¹⁷

Diagnosis

After complete history and physical examination, a diagnosis of HCL is usually made based on flow cytometry for immunophenotyping and molecular testing for BRAF V600E (Table 1).^2,17

Disease-related fibrosis may impede bone marrow aspiration, and trephine biopsy should be done to make the diagnosis.¹¹ On morphologic examination, HCL cells are small- to medium-sized, with round, oval, or indented, well-defined nuclei. Cytoplasm is pale blue, and cells have small cytoplasmic projections (Figure 1).^2,18

©Getty Images/Kateryna Kon/Science Photo Library

On flow cytometry, HCL is positive for B-cell antigens (CD19, CD20, CD22), as well as antigens specific to the disease (CD11c, CD25, CD103, CD123), and by immunohistochemistry (IHC) for cyclin D1 and annexin-A1. CD20, CD123, and CD200 are bright in HCL. The presence of T-cell marker CD103 on B-cells indicates HCL.^1-3 HCLv, in contrast, is positive for CD11c and CD103, but usually negative for CD25, CD123, and annexin-A1.^2,19

BRAF V600E mutation can be identified using droplet digital polymerase chain reaction (PCR), next-generation molecular sequencing, or IHC with a VE1 stain.^3,11 IHC for CD20, annexin-1, and VE1 establish the diagnosis, but also are useful in determining the extent to which leukemic cells have infiltrated bone marrow.¹¹

Differential diagnosis of HCL includes HCL variants, splenic marginal zone lymphoma, and splenic diffuse red pulp small B-cell lymphoma.^7,11

Indications for Treatment and Criteria for Response

Over time, about 90% of patients with HCL will require treatment. However, not all such patients will require urgent or immediate treatment, and some can be managed with observation and close monitoring.^1,11 The indications for initiating treatment generally are systemic symptoms and significant pancytopenia (Table 2).^2,11

The optimal response with treatment of HCL is complete response (CR) without minimal residual disease (MRD-free), which minimizes the risk for relapse.^1,11 Hematologic and molecular response is assessed using peripheral blood samples; physical examination, ultrasound, computed tomography, or magnetic resonance imaging is used to determine response in lymph nodes, spleen, or liver.¹ MRD-free is defined by the absence of HCL cells by the chosen method (IHC, flow cytometry, or PCR).²⁰ Bone marrow aspirate flow cytometry is the most sensitive standard test for MRD detection.¹Table 3 summarizes response criteria for HCL.^2,11

Initial Treatment of HCL

The purine nucleoside analogs (PNAs) cladribine (± rituximab) and pentostatin are widely recommended for initial treatment.^1,2,11 As monotherapy, cladribine and pentostatin are considered similarly effective, with CR in 70% to 90% of patients and durations of response > 10 years.¹ Adding the anti-CD20 monoclonal antibody rituximab in 8 weekly doses starting the first day of front-line cladribine (CDAR) improves remission, MRD-free rates, and duration of response (94% MRD-free at 96 months), with minimal added toxicity.²¹ Rituximab is often added 4 weeks after cladribine, which offers more convenience, an equally high CR rate of 100%, and a 76% MRD-free rate at 3 months.¹¹ Bone marrow biopsy should be delayed for 4 to 6 months to allow a full response to develop with cladribine.^1,11

Daily (intravenous or subcutaneous) and weekly cladribine are equally safe and effective.^2,11 Pentostatin is administered intravenously every 2 weeks for 3 to 6 months, allowing time for hematologic recovery between doses.^1,11 Patient factors to consider when choosing treatment include baseline neutropenia, patient preference, and comorbidities.

Toxicities of PNAs include neutropenia and fever, which typically occur during the first month of treatment and are more frequent in patients with baseline severe neutropenia; T-cell recovery may take years.¹ CDAR is associated with higher transient thrombocytopenia, but faster platelet and neutrophil recovery at 4 weeks than cladribine alone.²¹ Both therapies are immunosuppressive. Patients should be evaluated for existing infections and watched for new infections during treatment. Control of active infection prior to treatment initiation is required.^11,23

Patients with confirmed BRAF V600E mutation are candidates for vemurafenib if they are unable to tolerate a PNA, have an active infection, or would like effective vaccinations.^2,23-25

Treatment at Relapse

At suspected HCL relapse, patients should be evaluated to determine whether cytopenia is due to recurrent disease or lingering effects from prior treatment. Use of successive flow cytometry over time can clarify whether symptoms are related to disease and need interventional treatment, or will resolve with additional time.¹

Patients who have an HCL relapse after initial therapy with cladribine or pentostatin may be candidates for re-treatment with the same or alternate PNA plus rituximab.² Rituximab
monotherapy has been used for patients unable to tolerate PNA but yields CR rates as low as 13%.²⁶ Repeated courses of PNA therapy yield lower rates and durations of response with each course.^1,2

For patients with primary refractory disease (less than CR with initial therapy) or relapse within 2 years of initial therapy, treatment with the BRAF V600E inhibitor vemurafenib off-label, with or without rituximab, is an option.^2,5 In HCL, vemurafenib for patients with relapsed or refractory disease achieved CR in 35% and 42% in 2 small trials (N = 54). Relapse-free survival among people with CR was 19 months in 1 of the trials.²⁷ Vemurafenib plus rituximab achieved CR in 87% of patients with relapsed or refractory HCL, and an MRD-free CR rate of 57%. Among patients with CR, 85% were relapse-free at a median follow-up of 34 months.⁵ Treatment with vemurafenib is not myelotoxic—an advantage for HCL patients. Adverse effects with vemurafenib are often manageable with dose reductions, if needed. A specific concern with vemurafenib is the potential development of secondary skin cancers.^5,27,28

Novel Targeted Options and Recommended Use

Promising alternatives for patients with relapsed or refractory HCL include combined BRAF and MEK inhibitors and the Bruton tyrosine kinase (BTK) inhibitor ibrutinib. The concept of BRAF/MEK inhibition was validated in studies with BRAF-mutated melanoma, in which dabrafenib plus trametinib (the MEK inhibitor) improved overall survival (OS) with less toxicity and better quality of life than vemurafenib.^1,29 In a phase 2 trial in HCL, dabrafenib monotherapy demonstrated an overall response rate (ORR) of 80%, including 30% CR.³⁰ In a subsequent phase 2 trial, dabrafenib combined with trametinib was evaluated in refractory or late relapsed HCL. Among 55 enrolled patients, objective response rate was 89%, including 65.5% CR. Nine of 36 patients with CR were MRD-free. Among responding patients, duration of response was 97.7% at 24 months.³¹ The most common grade ≥ 3 toxicities were hyperglycemia, pyrexia, neutropenia, and pneumonia. Secondary skin cancers were seen in about 5% of patients.³¹

BRAF/MEK inhibitor combinations in HCL offer effective therapy with less myelosuppression than PNAs, making them useful for patients with or at risk for infection.²³ Their use in HCL is off-label, as they currently are approved for treatment of BRAF-mutated melanoma and some other tumors.³² A study of encorafenib (a BRAF inhibitor) combined with binimetinib (a MEK inhibitor) is ongoing (Table 4).³²

Ibrutinib interrupts B-cell receptor signaling to stop tumor cell growth. In a phase 2 trial, patients with relapsed or refractory HCL or HCLv were treated with once-daily oral ibrutinib. Best ORR was 54% (19% CR; 3% MRD-free). Despite the low CR rate, 3-year progression-free survival with ibrutinib was 73% and OS was 85%. Treatment was well-tolerated; cytopenia (including 22% grade ≥ 3 thrombocytopenia and neutropenia) and diarrhea were frequent toxicities.³³

Moxetumomab pasudotox is a novel CD22-targeted antibody fused with protein toxin that interrupts protein synthesis in tumor cells.¹ As treatment, it was studied in a phase 3 trial of relapsed HCL in heavily pretreated patients, and achieved a CR rate of 41%, including 36% durable CR.³⁴ Although FDA-approved for relapsed or refractory HCL, the drug is being discontinued due to business decisions, not safety or efficacy concerns.² It is notable that many types of B-cell lymphoma also express CD22.³⁵

Enrollment in a clinical trial to study possible treatment advances is recommended by the National Comprehensive Cancer Network (NCCN) at first and subsequent relapses of HCL for appropriate patients.² Figure 2 summarizes an approach to treatment choice and sequencing for patients with HCL.

Supportive Care

Patients being treated for HCL should have supportive care to manage adverse effects of their disease. Such care includes prophylaxis against herpes virus if CD4+ T cells < 200 cells/μL and other prophylactic vaccinations to hepatitis B virus, COVID-19 and Influenza. Patients with neutropeni may require broad-spectrum antibacterial prophylaxis or neutrophil growth factors if neutropenic fever develops. Blood product support is recommended if needed.² Assessment of anti-COVID-19 antibodies is recommended to optimize immunity, particularly prior to beginning anti-CD20 antibody therapy like rituximab.²³

Unmet Needs

Despite improvements in response and survival with newer therapies, not all patients with HCL benefit from these advances. Unmet needs are finding optimal treatment for patients with HCLv, despite some success with MEK inhibitors, and for patients with BRAF mutations other than V600E, who have few options beyond PNAs and rituximab.

Click to read more from 2023 Rare Diseases Report: Cancers

Pathophysiology

HCL develops from activated, mature memory B-cells that, in most cases, have the acquired mutation in BRAF V600E, which is present in 80% to 90% of patients with classic HCL.^1,3,5 BRAF is an integral part of the RAS-BRAF-MEK-ERK cellular pathway that transmits growth factor signals from the cell surface to the nucleus to regulate cell growth and proliferation.⁶ Mutated BRAF V600E continuously activates BRAF kinase and downstream signaling, resulting in enhanced HCL cell survival and unchecked proliferation.³

Variant HCL (HCLv) is a separate, more virulent disease that lacks BRAF V600E mutation and CD25 expression on flow cytometry.^1,7-9 Patients with HCLv have a worse prognosis and poor responses to front-line purine analogs, and a higher proportion of these patients carry the unmutated immunoglobulin heavy chain variable (IGHV) gene (54% vs 17% in HCL).^1,10,11 About 30% to 50% have wild-type BRAF and activating mutations in MAP2K1, which encodes aberrant MEK downstream of BRAF.^10,12

Most patients with HCL have somatic mutations in the IGHV gene.^3,13,14 Patients with unmutated IGHV4-34 and wildtype BRAF have an aggressive form of the disease, even if the HCL cells express CD25 as in classic HCL.^1,15 HCL in patients with unmutated IGHV is often refractory to purine analogs and these patients have poor prognosis and rapid progression.¹⁶ Other identified mutations include CDKN1B in HCL and MAP2K1 and CCNC3 in HCLv.²

Signs and Symptoms

In many cases, HCL is asymptomatic, and diagnosed when pancytopenia, monocytopenia, and leukopenia are discovered on unrelated blood work.^2,3,11 Monocytopenia is a specific presentation of HCL, but not HCLv.¹¹ Typical systemic symptoms include unexplained weight loss and extreme fatigue (80%).^1,3 Other symptoms can include fever, recurrent infections, night sweats, splenomegaly and related pain or abdominal fullness, hepatomegaly, and bleeding or bruising due to thrombocytopenia.^1,3 Splenomegaly is associated with advanced disease.¹¹

Up to 30% of patients may present with autoimmune disorders such as vasculitis or psoriasis. Although skin involvement is rare with HCL, 10% to 12% of patients will have dermatologic symptoms either due to recurrent infection or autoimmune reactions.^1,2 Skin reactions include localized or generalized maculopapular rash, pyoderma gangrenosum (which may be severe), and recurrent bacterial or viral skin infections.¹⁷

Diagnosis

After complete history and physical examination, a diagnosis of HCL is usually made based on flow cytometry for immunophenotyping and molecular testing for BRAF V600E (Table 1).^2,17

Disease-related fibrosis may impede bone marrow aspiration, and trephine biopsy should be done to make the diagnosis.¹¹ On morphologic examination, HCL cells are small- to medium-sized, with round, oval, or indented, well-defined nuclei. Cytoplasm is pale blue, and cells have small cytoplasmic projections (Figure 1).^2,18

©Getty Images/Kateryna Kon/Science Photo Library

On flow cytometry, HCL is positive for B-cell antigens (CD19, CD20, CD22), as well as antigens specific to the disease (CD11c, CD25, CD103, CD123), and by immunohistochemistry (IHC) for cyclin D1 and annexin-A1. CD20, CD123, and CD200 are bright in HCL. The presence of T-cell marker CD103 on B-cells indicates HCL.^1-3 HCLv, in contrast, is positive for CD11c and CD103, but usually negative for CD25, CD123, and annexin-A1.^2,19

BRAF V600E mutation can be identified using droplet digital polymerase chain reaction (PCR), next-generation molecular sequencing, or IHC with a VE1 stain.^3,11 IHC for CD20, annexin-1, and VE1 establish the diagnosis, but also are useful in determining the extent to which leukemic cells have infiltrated bone marrow.¹¹

Differential diagnosis of HCL includes HCL variants, splenic marginal zone lymphoma, and splenic diffuse red pulp small B-cell lymphoma.^7,11

Indications for Treatment and Criteria for Response

Over time, about 90% of patients with HCL will require treatment. However, not all such patients will require urgent or immediate treatment, and some can be managed with observation and close monitoring.^1,11 The indications for initiating treatment generally are systemic symptoms and significant pancytopenia (Table 2).^2,11

The optimal response with treatment of HCL is complete response (CR) without minimal residual disease (MRD-free), which minimizes the risk for relapse.^1,11 Hematologic and molecular response is assessed using peripheral blood samples; physical examination, ultrasound, computed tomography, or magnetic resonance imaging is used to determine response in lymph nodes, spleen, or liver.¹ MRD-free is defined by the absence of HCL cells by the chosen method (IHC, flow cytometry, or PCR).²⁰ Bone marrow aspirate flow cytometry is the most sensitive standard test for MRD detection.¹Table 3 summarizes response criteria for HCL.^2,11

Initial Treatment of HCL

The purine nucleoside analogs (PNAs) cladribine (± rituximab) and pentostatin are widely recommended for initial treatment.^1,2,11 As monotherapy, cladribine and pentostatin are considered similarly effective, with CR in 70% to 90% of patients and durations of response > 10 years.¹ Adding the anti-CD20 monoclonal antibody rituximab in 8 weekly doses starting the first day of front-line cladribine (CDAR) improves remission, MRD-free rates, and duration of response (94% MRD-free at 96 months), with minimal added toxicity.²¹ Rituximab is often added 4 weeks after cladribine, which offers more convenience, an equally high CR rate of 100%, and a 76% MRD-free rate at 3 months.¹¹ Bone marrow biopsy should be delayed for 4 to 6 months to allow a full response to develop with cladribine.^1,11

Daily (intravenous or subcutaneous) and weekly cladribine are equally safe and effective.^2,11 Pentostatin is administered intravenously every 2 weeks for 3 to 6 months, allowing time for hematologic recovery between doses.^1,11 Patient factors to consider when choosing treatment include baseline neutropenia, patient preference, and comorbidities.

Toxicities of PNAs include neutropenia and fever, which typically occur during the first month of treatment and are more frequent in patients with baseline severe neutropenia; T-cell recovery may take years.¹ CDAR is associated with higher transient thrombocytopenia, but faster platelet and neutrophil recovery at 4 weeks than cladribine alone.²¹ Both therapies are immunosuppressive. Patients should be evaluated for existing infections and watched for new infections during treatment. Control of active infection prior to treatment initiation is required.^11,23

Patients with confirmed BRAF V600E mutation are candidates for vemurafenib if they are unable to tolerate a PNA, have an active infection, or would like effective vaccinations.^2,23-25

Treatment at Relapse

At suspected HCL relapse, patients should be evaluated to determine whether cytopenia is due to recurrent disease or lingering effects from prior treatment. Use of successive flow cytometry over time can clarify whether symptoms are related to disease and need interventional treatment, or will resolve with additional time.¹

Patients who have an HCL relapse after initial therapy with cladribine or pentostatin may be candidates for re-treatment with the same or alternate PNA plus rituximab.² Rituximab
monotherapy has been used for patients unable to tolerate PNA but yields CR rates as low as 13%.²⁶ Repeated courses of PNA therapy yield lower rates and durations of response with each course.^1,2

For patients with primary refractory disease (less than CR with initial therapy) or relapse within 2 years of initial therapy, treatment with the BRAF V600E inhibitor vemurafenib off-label, with or without rituximab, is an option.^2,5 In HCL, vemurafenib for patients with relapsed or refractory disease achieved CR in 35% and 42% in 2 small trials (N = 54). Relapse-free survival among people with CR was 19 months in 1 of the trials.²⁷ Vemurafenib plus rituximab achieved CR in 87% of patients with relapsed or refractory HCL, and an MRD-free CR rate of 57%. Among patients with CR, 85% were relapse-free at a median follow-up of 34 months.⁵ Treatment with vemurafenib is not myelotoxic—an advantage for HCL patients. Adverse effects with vemurafenib are often manageable with dose reductions, if needed. A specific concern with vemurafenib is the potential development of secondary skin cancers.^5,27,28

Novel Targeted Options and Recommended Use

Promising alternatives for patients with relapsed or refractory HCL include combined BRAF and MEK inhibitors and the Bruton tyrosine kinase (BTK) inhibitor ibrutinib. The concept of BRAF/MEK inhibition was validated in studies with BRAF-mutated melanoma, in which dabrafenib plus trametinib (the MEK inhibitor) improved overall survival (OS) with less toxicity and better quality of life than vemurafenib.^1,29 In a phase 2 trial in HCL, dabrafenib monotherapy demonstrated an overall response rate (ORR) of 80%, including 30% CR.³⁰ In a subsequent phase 2 trial, dabrafenib combined with trametinib was evaluated in refractory or late relapsed HCL. Among 55 enrolled patients, objective response rate was 89%, including 65.5% CR. Nine of 36 patients with CR were MRD-free. Among responding patients, duration of response was 97.7% at 24 months.³¹ The most common grade ≥ 3 toxicities were hyperglycemia, pyrexia, neutropenia, and pneumonia. Secondary skin cancers were seen in about 5% of patients.³¹

BRAF/MEK inhibitor combinations in HCL offer effective therapy with less myelosuppression than PNAs, making them useful for patients with or at risk for infection.²³ Their use in HCL is off-label, as they currently are approved for treatment of BRAF-mutated melanoma and some other tumors.³² A study of encorafenib (a BRAF inhibitor) combined with binimetinib (a MEK inhibitor) is ongoing (Table 4).³²

Ibrutinib interrupts B-cell receptor signaling to stop tumor cell growth. In a phase 2 trial, patients with relapsed or refractory HCL or HCLv were treated with once-daily oral ibrutinib. Best ORR was 54% (19% CR; 3% MRD-free). Despite the low CR rate, 3-year progression-free survival with ibrutinib was 73% and OS was 85%. Treatment was well-tolerated; cytopenia (including 22% grade ≥ 3 thrombocytopenia and neutropenia) and diarrhea were frequent toxicities.³³

Moxetumomab pasudotox is a novel CD22-targeted antibody fused with protein toxin that interrupts protein synthesis in tumor cells.¹ As treatment, it was studied in a phase 3 trial of relapsed HCL in heavily pretreated patients, and achieved a CR rate of 41%, including 36% durable CR.³⁴ Although FDA-approved for relapsed or refractory HCL, the drug is being discontinued due to business decisions, not safety or efficacy concerns.² It is notable that many types of B-cell lymphoma also express CD22.³⁵

Enrollment in a clinical trial to study possible treatment advances is recommended by the National Comprehensive Cancer Network (NCCN) at first and subsequent relapses of HCL for appropriate patients.² Figure 2 summarizes an approach to treatment choice and sequencing for patients with HCL.

Supportive Care

Patients being treated for HCL should have supportive care to manage adverse effects of their disease. Such care includes prophylaxis against herpes virus if CD4+ T cells < 200 cells/μL and other prophylactic vaccinations to hepatitis B virus, COVID-19 and Influenza. Patients with neutropeni may require broad-spectrum antibacterial prophylaxis or neutrophil growth factors if neutropenic fever develops. Blood product support is recommended if needed.² Assessment of anti-COVID-19 antibodies is recommended to optimize immunity, particularly prior to beginning anti-CD20 antibody therapy like rituximab.²³

Unmet Needs

Despite improvements in response and survival with newer therapies, not all patients with HCL benefit from these advances. Unmet needs are finding optimal treatment for patients with HCLv, despite some success with MEK inhibitors, and for patients with BRAF mutations other than V600E, who have few options beyond PNAs and rituximab.

Click to read more from 2023 Rare Diseases Report: Cancers

Pathophysiology

HCL develops from activated, mature memory B-cells that, in most cases, have the acquired mutation in BRAF V600E, which is present in 80% to 90% of patients with classic HCL.^1,3,5 BRAF is an integral part of the RAS-BRAF-MEK-ERK cellular pathway that transmits growth factor signals from the cell surface to the nucleus to regulate cell growth and proliferation.⁶ Mutated BRAF V600E continuously activates BRAF kinase and downstream signaling, resulting in enhanced HCL cell survival and unchecked proliferation.³

Variant HCL (HCLv) is a separate, more virulent disease that lacks BRAF V600E mutation and CD25 expression on flow cytometry.^1,7-9 Patients with HCLv have a worse prognosis and poor responses to front-line purine analogs, and a higher proportion of these patients carry the unmutated immunoglobulin heavy chain variable (IGHV) gene (54% vs 17% in HCL).^1,10,11 About 30% to 50% have wild-type BRAF and activating mutations in MAP2K1, which encodes aberrant MEK downstream of BRAF.^10,12

Most patients with HCL have somatic mutations in the IGHV gene.^3,13,14 Patients with unmutated IGHV4-34 and wildtype BRAF have an aggressive form of the disease, even if the HCL cells express CD25 as in classic HCL.^1,15 HCL in patients with unmutated IGHV is often refractory to purine analogs and these patients have poor prognosis and rapid progression.¹⁶ Other identified mutations include CDKN1B in HCL and MAP2K1 and CCNC3 in HCLv.²

Signs and Symptoms

In many cases, HCL is asymptomatic, and diagnosed when pancytopenia, monocytopenia, and leukopenia are discovered on unrelated blood work.^2,3,11 Monocytopenia is a specific presentation of HCL, but not HCLv.¹¹ Typical systemic symptoms include unexplained weight loss and extreme fatigue (80%).^1,3 Other symptoms can include fever, recurrent infections, night sweats, splenomegaly and related pain or abdominal fullness, hepatomegaly, and bleeding or bruising due to thrombocytopenia.^1,3 Splenomegaly is associated with advanced disease.¹¹

Up to 30% of patients may present with autoimmune disorders such as vasculitis or psoriasis. Although skin involvement is rare with HCL, 10% to 12% of patients will have dermatologic symptoms either due to recurrent infection or autoimmune reactions.^1,2 Skin reactions include localized or generalized maculopapular rash, pyoderma gangrenosum (which may be severe), and recurrent bacterial or viral skin infections.¹⁷

Diagnosis

After complete history and physical examination, a diagnosis of HCL is usually made based on flow cytometry for immunophenotyping and molecular testing for BRAF V600E (Table 1).^2,17

Disease-related fibrosis may impede bone marrow aspiration, and trephine biopsy should be done to make the diagnosis.¹¹ On morphologic examination, HCL cells are small- to medium-sized, with round, oval, or indented, well-defined nuclei. Cytoplasm is pale blue, and cells have small cytoplasmic projections (Figure 1).^2,18

©Getty Images/Kateryna Kon/Science Photo Library

On flow cytometry, HCL is positive for B-cell antigens (CD19, CD20, CD22), as well as antigens specific to the disease (CD11c, CD25, CD103, CD123), and by immunohistochemistry (IHC) for cyclin D1 and annexin-A1. CD20, CD123, and CD200 are bright in HCL. The presence of T-cell marker CD103 on B-cells indicates HCL.^1-3 HCLv, in contrast, is positive for CD11c and CD103, but usually negative for CD25, CD123, and annexin-A1.^2,19

BRAF V600E mutation can be identified using droplet digital polymerase chain reaction (PCR), next-generation molecular sequencing, or IHC with a VE1 stain.^3,11 IHC for CD20, annexin-1, and VE1 establish the diagnosis, but also are useful in determining the extent to which leukemic cells have infiltrated bone marrow.¹¹

Differential diagnosis of HCL includes HCL variants, splenic marginal zone lymphoma, and splenic diffuse red pulp small B-cell lymphoma.^7,11

Indications for Treatment and Criteria for Response

Over time, about 90% of patients with HCL will require treatment. However, not all such patients will require urgent or immediate treatment, and some can be managed with observation and close monitoring.^1,11 The indications for initiating treatment generally are systemic symptoms and significant pancytopenia (Table 2).^2,11

The optimal response with treatment of HCL is complete response (CR) without minimal residual disease (MRD-free), which minimizes the risk for relapse.^1,11 Hematologic and molecular response is assessed using peripheral blood samples; physical examination, ultrasound, computed tomography, or magnetic resonance imaging is used to determine response in lymph nodes, spleen, or liver.¹ MRD-free is defined by the absence of HCL cells by the chosen method (IHC, flow cytometry, or PCR).²⁰ Bone marrow aspirate flow cytometry is the most sensitive standard test for MRD detection.¹Table 3 summarizes response criteria for HCL.^2,11

Initial Treatment of HCL

The purine nucleoside analogs (PNAs) cladribine (± rituximab) and pentostatin are widely recommended for initial treatment.^1,2,11 As monotherapy, cladribine and pentostatin are considered similarly effective, with CR in 70% to 90% of patients and durations of response > 10 years.¹ Adding the anti-CD20 monoclonal antibody rituximab in 8 weekly doses starting the first day of front-line cladribine (CDAR) improves remission, MRD-free rates, and duration of response (94% MRD-free at 96 months), with minimal added toxicity.²¹ Rituximab is often added 4 weeks after cladribine, which offers more convenience, an equally high CR rate of 100%, and a 76% MRD-free rate at 3 months.¹¹ Bone marrow biopsy should be delayed for 4 to 6 months to allow a full response to develop with cladribine.^1,11

Daily (intravenous or subcutaneous) and weekly cladribine are equally safe and effective.^2,11 Pentostatin is administered intravenously every 2 weeks for 3 to 6 months, allowing time for hematologic recovery between doses.^1,11 Patient factors to consider when choosing treatment include baseline neutropenia, patient preference, and comorbidities.

Toxicities of PNAs include neutropenia and fever, which typically occur during the first month of treatment and are more frequent in patients with baseline severe neutropenia; T-cell recovery may take years.¹ CDAR is associated with higher transient thrombocytopenia, but faster platelet and neutrophil recovery at 4 weeks than cladribine alone.²¹ Both therapies are immunosuppressive. Patients should be evaluated for existing infections and watched for new infections during treatment. Control of active infection prior to treatment initiation is required.^11,23

Patients with confirmed BRAF V600E mutation are candidates for vemurafenib if they are unable to tolerate a PNA, have an active infection, or would like effective vaccinations.^2,23-25

Treatment at Relapse

At suspected HCL relapse, patients should be evaluated to determine whether cytopenia is due to recurrent disease or lingering effects from prior treatment. Use of successive flow cytometry over time can clarify whether symptoms are related to disease and need interventional treatment, or will resolve with additional time.¹

Patients who have an HCL relapse after initial therapy with cladribine or pentostatin may be candidates for re-treatment with the same or alternate PNA plus rituximab.² Rituximab
monotherapy has been used for patients unable to tolerate PNA but yields CR rates as low as 13%.²⁶ Repeated courses of PNA therapy yield lower rates and durations of response with each course.^1,2

For patients with primary refractory disease (less than CR with initial therapy) or relapse within 2 years of initial therapy, treatment with the BRAF V600E inhibitor vemurafenib off-label, with or without rituximab, is an option.^2,5 In HCL, vemurafenib for patients with relapsed or refractory disease achieved CR in 35% and 42% in 2 small trials (N = 54). Relapse-free survival among people with CR was 19 months in 1 of the trials.²⁷ Vemurafenib plus rituximab achieved CR in 87% of patients with relapsed or refractory HCL, and an MRD-free CR rate of 57%. Among patients with CR, 85% were relapse-free at a median follow-up of 34 months.⁵ Treatment with vemurafenib is not myelotoxic—an advantage for HCL patients. Adverse effects with vemurafenib are often manageable with dose reductions, if needed. A specific concern with vemurafenib is the potential development of secondary skin cancers.^5,27,28

Novel Targeted Options and Recommended Use

Promising alternatives for patients with relapsed or refractory HCL include combined BRAF and MEK inhibitors and the Bruton tyrosine kinase (BTK) inhibitor ibrutinib. The concept of BRAF/MEK inhibition was validated in studies with BRAF-mutated melanoma, in which dabrafenib plus trametinib (the MEK inhibitor) improved overall survival (OS) with less toxicity and better quality of life than vemurafenib.^1,29 In a phase 2 trial in HCL, dabrafenib monotherapy demonstrated an overall response rate (ORR) of 80%, including 30% CR.³⁰ In a subsequent phase 2 trial, dabrafenib combined with trametinib was evaluated in refractory or late relapsed HCL. Among 55 enrolled patients, objective response rate was 89%, including 65.5% CR. Nine of 36 patients with CR were MRD-free. Among responding patients, duration of response was 97.7% at 24 months.³¹ The most common grade ≥ 3 toxicities were hyperglycemia, pyrexia, neutropenia, and pneumonia. Secondary skin cancers were seen in about 5% of patients.³¹

BRAF/MEK inhibitor combinations in HCL offer effective therapy with less myelosuppression than PNAs, making them useful for patients with or at risk for infection.²³ Their use in HCL is off-label, as they currently are approved for treatment of BRAF-mutated melanoma and some other tumors.³² A study of encorafenib (a BRAF inhibitor) combined with binimetinib (a MEK inhibitor) is ongoing (Table 4).³²

Ibrutinib interrupts B-cell receptor signaling to stop tumor cell growth. In a phase 2 trial, patients with relapsed or refractory HCL or HCLv were treated with once-daily oral ibrutinib. Best ORR was 54% (19% CR; 3% MRD-free). Despite the low CR rate, 3-year progression-free survival with ibrutinib was 73% and OS was 85%. Treatment was well-tolerated; cytopenia (including 22% grade ≥ 3 thrombocytopenia and neutropenia) and diarrhea were frequent toxicities.³³

Moxetumomab pasudotox is a novel CD22-targeted antibody fused with protein toxin that interrupts protein synthesis in tumor cells.¹ As treatment, it was studied in a phase 3 trial of relapsed HCL in heavily pretreated patients, and achieved a CR rate of 41%, including 36% durable CR.³⁴ Although FDA-approved for relapsed or refractory HCL, the drug is being discontinued due to business decisions, not safety or efficacy concerns.² It is notable that many types of B-cell lymphoma also express CD22.³⁵

Enrollment in a clinical trial to study possible treatment advances is recommended by the National Comprehensive Cancer Network (NCCN) at first and subsequent relapses of HCL for appropriate patients.² Figure 2 summarizes an approach to treatment choice and sequencing for patients with HCL.

Supportive Care

Patients being treated for HCL should have supportive care to manage adverse effects of their disease. Such care includes prophylaxis against herpes virus if CD4+ T cells < 200 cells/μL and other prophylactic vaccinations to hepatitis B virus, COVID-19 and Influenza. Patients with neutropeni may require broad-spectrum antibacterial prophylaxis or neutrophil growth factors if neutropenic fever develops. Blood product support is recommended if needed.² Assessment of anti-COVID-19 antibodies is recommended to optimize immunity, particularly prior to beginning anti-CD20 antibody therapy like rituximab.²³

Unmet Needs

Despite improvements in response and survival with newer therapies, not all patients with HCL benefit from these advances. Unmet needs are finding optimal treatment for patients with HCLv, despite some success with MEK inhibitors, and for patients with BRAF mutations other than V600E, who have few options beyond PNAs and rituximab.

Click to read more from 2023 Rare Diseases Report: Cancers

Mortality from TC has been decreasing since the 1970s due to cisplatin-based chemotherapy regimens^2,3; TC is among the most curable of solid neoplasms, with a 5-year relative survival rate of 95%.^2-4 Thus, the focus of research has shifted from optimizing treatments for improved survival to decreasing treatment-related, long-term adverse events (AEs).⁵

New Modifications in Risk Assessment and Prognostication

The widely accepted risk stratification model in use today was first developed in 1997 by the International Germ Cell Cancer Collaborative Group (IGCCCG) after studying data on patients with seminoma and NSGCTs.⁶ The original classification categorized metastatic NSGCTs as having good, intermediate, or poor prognosis based on levels of alpha-fetoprotein (AFP), human chorionic gonadotropin (hCG), lactate dehydrogenase (LDH), and the presence of nonpulmonary visceral metastases (NPVM). Primary mediastinal NSGCTs were classified as having poor prognosis regardless of the other factors.⁶ Metastatic seminoma GCTs were categorized as having good or intermediate prognosis based on the occurrence of brain, liver, or bone metastasis.⁷

Using contemporary data from more than 12,000 patients with metastatic GCTs who received either cisplatin or etoposide, the IGCCCG model was updated in 2021. For seminoma GCTs, 5-year progression-free survival (PFS) and 5-year overall survival (OS) were extended for both good and intermediate prognostic groups.⁷ LDH remained the most significant prognostic factor for determining good prognosis however, patients with LDH above 2.5× upper limit of normal (ULN) before chemotherapy had worse survival probabilities than patients with LDH at 2.5× ULN or lower. The survival probabilities for patients with otherwise good prognosis with LDH of more than 2.5× ULN were like those for patients with intermediate prognosis.⁷ Thus, using LDH of more than 2.5× ULN has revealed a subgroup with significantly worse outcomes within the “good” prognostic group.^7,8

For NSGCTs, 5-year PFS rates did not differ from the original IGCCCG for good and intermediate prognostic groups; however, the 2021 update revealed an improved PFS for the poor prognostic group. The 2021 update also demonstrated that 5-year OS rates improved for each group, and further confirmed that the 2 most important prognostic factors for NSGCT were the presence of NPVM and the presence of a mediastinal primary tumor. The update added 2 new adverse prognostic variables: age and metastases. Risk of progression increases 25% with every decade-of-life increase, and 66% with the presence of lung metastases. The LDH groups were reduced to a single cutoff at 2.5× ULN for NSGCTs.⁸

Primary and Subsequent Treatments for TC

Guideline-directed first-line and subsequent treatments for seminomas and NSGCTs have been developed by several organizations, including the National Comprehensive Cancer Network, IGCCCG, and the American Urological Association (see Figure 1 and 2). An analysis of the most used treatments was performed using the National Cancer Database.² Most patients underwent orchiectomy without chemotherapy or radiation for both stage I seminomas (78%) and NSGCTs (57%). For stage II and III seminomas, most patients underwent surgery with chemotherapy (66% and 68%, respectively). Nearly half of patients with stage II NSGCTs were treated with surgery and chemotherapy (49%), and a third were treated with retroperitoneal lymph node dissection (RPLND) in addition to surgery and chemotherapy. Surgery with chemotherapy was used for 55% of stage III NSGCTs; other treatments included surgery combined with chemotherapy and RPLND (19%), and chemotherapy with or without radiation (20%).² However, nearly 30% of patients with TC do not receive guideline-directed therapy, including inappropriate imaging and overtreatment; and nonguideline–directed therapy has been independently associated with risk of relapse.^12,13

TC Survivorship

The trend of improved OS after treatment for metastatic GCTs highlights a need to focus on survivorship. The 10-year survival rate for TC post-treatment is 95%.¹⁴ Latest estimates suggest there are more than 300,000 TC survivors in the United States,² accounting for approximately 4% of all US male cancer survivors.¹⁴ With longer-term survival, however, comes the risk for long-term complications from cancer treatments. For example, circulating platinum has been detected in the plasma of men up to 28 years after undergoing cisplatin-based chemotherapy for TC.¹⁵ Increasing levels of residual serum platinum have also been shown to correlate with severity of neurotoxicity between 5 and 20 years after treatment.¹⁶

A significant concern with cancer treatment is the development of second malignant neoplasms (SMNs).^14,17 The relative risk of the development of SMNs depends on whetherradiation therapy or chemotherapy, or both, was used as the primary treatment. Patients who received either radiation therapy or chemotherapy are at increased risk for leukemia and solid cancers, including gastrointestinal cancers. For patients treated with cisplatin, a significant dose-response relationship between cumulative dose and leukemic risk has been reported.¹⁴

Other concerns are increased non-TC mortality and SMN mortality. Hellesnes et al examined cause-specific, non-TC mortality using a population-based cohort in Norway.¹⁸ They determined that the overall 25-year, non-TC mortality risk was 13.7% (95% CI, 12.5-14.9) for patients who previously had TC vs 11.3% for patients who never had TC. The highest mortality rates were reported for patients who had radiation (19%) or platinum-based chemotherapy plus radiation (18.4%); the lowest mortality rate was reported for patients who had received platinum-based chemotherapy only (9.5%). Patients with the highest non-TC mortality risk were fewer than 20 years post-cancer diagnosis. Non-TC mortality excess ranged from 23% to 40% for patients with a prior TC diagnosis, and a significant 1.43- to 3.24-fold increase in SMN mortality emerged after treatment with platinum-based chemotherapy or radiation therapy, or both.¹⁹ Awareness of the increased premature mortality risk is crucial for both TC survivors and their care providers.¹⁸

Quality of life for TC survivors appears to be affected by the presence of long-term treatment-related AEs.¹⁸ The relative risk of developing cardiovascular disease increases after treatment with chemotherapy. Raynaud phenomenon resulting from bleomycin-induced vascular damage developed within 4 to 12 months after chemotherapy for 18.7% to 39% of TC survivors.^14,19 Bleomycin may also cause pulmonary toxicity. Pulmonary surgery, tobacco use of ≥ 20 pack-years, and a cumulative cisplatin dose of > 850 mg are risk factors for late  bleomycin-associated pulmonary toxicity.¹⁴

Other late-developing toxicities resulting from cisplatin treatment include ototoxicity, neurotoxicity, nephrotoxicity, chronic fatigue, and hypogonadism.^14,19 Nearly 1 in 5 North American survivors treated with cisplatin reported severe-to-profound hearing loss within a median of 4.3 years. The extent of hearing loss has been directly associated with the increase in cumulative cisplatin dose. Peripheral neurotoxicity after cisplatin-based chemotherapy is reported to be as high as 40%.¹⁴ Chronic cancer-related fatigue can range from 15% to 27%, and has been associated with peripheral neuropathy, low testosterone levels, low physical activity, anxiety, and depression. Post-treatment hypogonadism ranges from 11% to 16%.^14,17,20,21

Psychosocial issues are also of concern. Mild-to-moderate psychological distress with diagnosis and survivorship has been reported.¹⁷ Anxiety and depression are higher in TC survivors than in the general population. Variables associated with clinically significant anxiety include younger age and shorter time from diagnosis; whereas feeling helpless/hopeless, having less social support, having a higher number of physical symptoms, and having children are factors associated with higher levels of depression. A moderate-to-high level of fear of recurrence has also been reported.¹⁷

Recent Clinical Trials in Stage II Disease

Stage II disease has been the focus of current research to reduce treatment-related toxicities and limit longer-term complications. While few phase 3 clinical trials are ongoing (see Table), the results of several phase 2 trials have been reported recently.^22-24

PRIMETEST was a single-arm, single-center, phase 2 study examining the efficacy and surgical safety of primary RPLND for stage II disease.²² Participants underwent either open or robot-assisted unilateral RPLND for stage IIA or B seminoma. No adjuvant treatment was permitted. Of the 33 participants, 9 presented initially with clinical stage II disease (27%) and 24 (73%) had recurrence during active surveillance. Five of the 24 had 1 cycle of carboplatin prior to progressing to stage II. With a median follow-up of 32 months, the study did not meet its primary endpoint of PFS at 36 months. After 32 months, 10 recurrences (30%) were detected, yielding a PFS rate of 70%. All 10 patients with recurrence received chemotherapy and were alive without evidence of disease at the time of publication. This study demonstrates that RPLND may be appropriate for select patients; however, criteria for selecting patients to receive only RPLND need to be clearly defined.²²

The SEMS (surgery in early metastatic seminoma) trial was a single-arm, international, phase 2 study of RPLND as first-line treatment for early metastatic seminoma with isolated retroperitoneal lymphadenopathy between 1 and 3 cm (stage II).²³ With a median follow-up of 24 months, OS was 100% and 2-year recurrence-free survival was 87%. Recurrence rate was 18% (10 recurrences) with a median time to recurrence of 8 months. Short-term complications occurred in 7 patients (13%), and no patients reported long-term complications. The authors suggested that RPLND is a therapeutic option for first-line treatment in early metastatic seminoma.²³

SAKK 01/10 was a single-arm, international, phase 2 study examining the de-escalation of treatment to potentially avoid toxic effects for patients with either stage IIA or stage IIB seminoma.²⁴ Treatment included carboplatin (area under the curve [AUC] 7 mg/mL/min) followed 3 weeks later with involvednode radiotherapy (30 Gy in 15 fractions for stage IIA and 36 Gy in 18 fractions for stage IIB). The study did not meet its primary endpoint of PFS of 95% at 3 years. Grade ≥ 3 treatment-related AEs (TRAEs) included neutropenia (4%), thrombocytopenia (3%), and vomiting (1%). No treatment-related deaths and no late TRAEs were reported. One case of transient creatinine increase was reported as a serious AE, and second primary tumors were reported in 4 participants. Although the primary endpoint was not met, long-term AEs continue to be recorded for potentially up to 20 years. The favorable efficacy and toxicity profile observed in the deescalation combination treatment warrants further study.²⁴

Emerging Trends and Future Directions for TC Treatment

Although the outlook for most newly diagnosed patients with TC is promising, especially for those diagnosed with early-stage disease and good prognosis advanced disease, treatment challenges remain. Between 10% and 20% of patients will have a relapse of TC after initially achieving a complete remission. Most patients will have a relapse within 2 years of initial treatment, but a small subgroup will have a relapse more than 5 years after therapy. Most recurrences occur in the retroperitoneum and lungs and require definitive therapy using chemotherapy and surgical resection.²¹

Patients with platinum-refractory disease may still achiev long-term remission with salvage therapy of surgery, conventional-dose chemotherapy, or high-dose chemotherapy with autologous stem cell transplantation; however, these treatments will fail for some patients, resulting in poor prognosis. Targeted therapy for TC has not produced meaningful benefits for this population with refractory disease, and the optimal treatment for this group of patients with TC remains to be determined.²¹

Although current guidelines recommend determining the levels of AFP, hCG, and LDH for clinical staging, treatment monitoring, and follow-up, limitations exist with their usage.⁹ The assays for these markers have low sensitivity and lack specificity; about half of all GCTs express only 1 of the 3 biomarkers, and seminomas lack AFP expression.^7,25,26 Further research is needed on LDH. An emerging group of patients with LDH below 2.5× ULN may be candidates for de-escalatio strategies to reduce treatment burden, while inferior outcomes remain for patients with either good prognosis seminoma and elevated LDH, or intermediate prognosis seminoma.⁷

Other biomarkers, such as miRNA371a-3p and PD-L1, are being investigated; miRNA371a-3p has been shown to have prognostic significance. The results of this assay can be informative for both seminomas and NSGCTs.²⁶ However, the protocol for quantification and implementation still needs to be determined.²⁷

Click to read more from 2023 Rare Diseases Report: Cancers

Mortality from TC has been decreasing since the 1970s due to cisplatin-based chemotherapy regimens^2,3; TC is among the most curable of solid neoplasms, with a 5-year relative survival rate of 95%.^2-4 Thus, the focus of research has shifted from optimizing treatments for improved survival to decreasing treatment-related, long-term adverse events (AEs).⁵

New Modifications in Risk Assessment and Prognostication

The widely accepted risk stratification model in use today was first developed in 1997 by the International Germ Cell Cancer Collaborative Group (IGCCCG) after studying data on patients with seminoma and NSGCTs.⁶ The original classification categorized metastatic NSGCTs as having good, intermediate, or poor prognosis based on levels of alpha-fetoprotein (AFP), human chorionic gonadotropin (hCG), lactate dehydrogenase (LDH), and the presence of nonpulmonary visceral metastases (NPVM). Primary mediastinal NSGCTs were classified as having poor prognosis regardless of the other factors.⁶ Metastatic seminoma GCTs were categorized as having good or intermediate prognosis based on the occurrence of brain, liver, or bone metastasis.⁷

Using contemporary data from more than 12,000 patients with metastatic GCTs who received either cisplatin or etoposide, the IGCCCG model was updated in 2021. For seminoma GCTs, 5-year progression-free survival (PFS) and 5-year overall survival (OS) were extended for both good and intermediate prognostic groups.⁷ LDH remained the most significant prognostic factor for determining good prognosis however, patients with LDH above 2.5× upper limit of normal (ULN) before chemotherapy had worse survival probabilities than patients with LDH at 2.5× ULN or lower. The survival probabilities for patients with otherwise good prognosis with LDH of more than 2.5× ULN were like those for patients with intermediate prognosis.⁷ Thus, using LDH of more than 2.5× ULN has revealed a subgroup with significantly worse outcomes within the “good” prognostic group.^7,8

For NSGCTs, 5-year PFS rates did not differ from the original IGCCCG for good and intermediate prognostic groups; however, the 2021 update revealed an improved PFS for the poor prognostic group. The 2021 update also demonstrated that 5-year OS rates improved for each group, and further confirmed that the 2 most important prognostic factors for NSGCT were the presence of NPVM and the presence of a mediastinal primary tumor. The update added 2 new adverse prognostic variables: age and metastases. Risk of progression increases 25% with every decade-of-life increase, and 66% with the presence of lung metastases. The LDH groups were reduced to a single cutoff at 2.5× ULN for NSGCTs.⁸

Primary and Subsequent Treatments for TC

Guideline-directed first-line and subsequent treatments for seminomas and NSGCTs have been developed by several organizations, including the National Comprehensive Cancer Network, IGCCCG, and the American Urological Association (see Figure 1 and 2). An analysis of the most used treatments was performed using the National Cancer Database.² Most patients underwent orchiectomy without chemotherapy or radiation for both stage I seminomas (78%) and NSGCTs (57%). For stage II and III seminomas, most patients underwent surgery with chemotherapy (66% and 68%, respectively). Nearly half of patients with stage II NSGCTs were treated with surgery and chemotherapy (49%), and a third were treated with retroperitoneal lymph node dissection (RPLND) in addition to surgery and chemotherapy. Surgery with chemotherapy was used for 55% of stage III NSGCTs; other treatments included surgery combined with chemotherapy and RPLND (19%), and chemotherapy with or without radiation (20%).² However, nearly 30% of patients with TC do not receive guideline-directed therapy, including inappropriate imaging and overtreatment; and nonguideline–directed therapy has been independently associated with risk of relapse.^12,13

TC Survivorship

The trend of improved OS after treatment for metastatic GCTs highlights a need to focus on survivorship. The 10-year survival rate for TC post-treatment is 95%.¹⁴ Latest estimates suggest there are more than 300,000 TC survivors in the United States,² accounting for approximately 4% of all US male cancer survivors.¹⁴ With longer-term survival, however, comes the risk for long-term complications from cancer treatments. For example, circulating platinum has been detected in the plasma of men up to 28 years after undergoing cisplatin-based chemotherapy for TC.¹⁵ Increasing levels of residual serum platinum have also been shown to correlate with severity of neurotoxicity between 5 and 20 years after treatment.¹⁶

A significant concern with cancer treatment is the development of second malignant neoplasms (SMNs).^14,17 The relative risk of the development of SMNs depends on whetherradiation therapy or chemotherapy, or both, was used as the primary treatment. Patients who received either radiation therapy or chemotherapy are at increased risk for leukemia and solid cancers, including gastrointestinal cancers. For patients treated with cisplatin, a significant dose-response relationship between cumulative dose and leukemic risk has been reported.¹⁴

Other concerns are increased non-TC mortality and SMN mortality. Hellesnes et al examined cause-specific, non-TC mortality using a population-based cohort in Norway.¹⁸ They determined that the overall 25-year, non-TC mortality risk was 13.7% (95% CI, 12.5-14.9) for patients who previously had TC vs 11.3% for patients who never had TC. The highest mortality rates were reported for patients who had radiation (19%) or platinum-based chemotherapy plus radiation (18.4%); the lowest mortality rate was reported for patients who had received platinum-based chemotherapy only (9.5%). Patients with the highest non-TC mortality risk were fewer than 20 years post-cancer diagnosis. Non-TC mortality excess ranged from 23% to 40% for patients with a prior TC diagnosis, and a significant 1.43- to 3.24-fold increase in SMN mortality emerged after treatment with platinum-based chemotherapy or radiation therapy, or both.¹⁹ Awareness of the increased premature mortality risk is crucial for both TC survivors and their care providers.¹⁸

Quality of life for TC survivors appears to be affected by the presence of long-term treatment-related AEs.¹⁸ The relative risk of developing cardiovascular disease increases after treatment with chemotherapy. Raynaud phenomenon resulting from bleomycin-induced vascular damage developed within 4 to 12 months after chemotherapy for 18.7% to 39% of TC survivors.^14,19 Bleomycin may also cause pulmonary toxicity. Pulmonary surgery, tobacco use of ≥ 20 pack-years, and a cumulative cisplatin dose of > 850 mg are risk factors for late  bleomycin-associated pulmonary toxicity.¹⁴

Other late-developing toxicities resulting from cisplatin treatment include ototoxicity, neurotoxicity, nephrotoxicity, chronic fatigue, and hypogonadism.^14,19 Nearly 1 in 5 North American survivors treated with cisplatin reported severe-to-profound hearing loss within a median of 4.3 years. The extent of hearing loss has been directly associated with the increase in cumulative cisplatin dose. Peripheral neurotoxicity after cisplatin-based chemotherapy is reported to be as high as 40%.¹⁴ Chronic cancer-related fatigue can range from 15% to 27%, and has been associated with peripheral neuropathy, low testosterone levels, low physical activity, anxiety, and depression. Post-treatment hypogonadism ranges from 11% to 16%.^14,17,20,21

Psychosocial issues are also of concern. Mild-to-moderate psychological distress with diagnosis and survivorship has been reported.¹⁷ Anxiety and depression are higher in TC survivors than in the general population. Variables associated with clinically significant anxiety include younger age and shorter time from diagnosis; whereas feeling helpless/hopeless, having less social support, having a higher number of physical symptoms, and having children are factors associated with higher levels of depression. A moderate-to-high level of fear of recurrence has also been reported.¹⁷

Recent Clinical Trials in Stage II Disease

Stage II disease has been the focus of current research to reduce treatment-related toxicities and limit longer-term complications. While few phase 3 clinical trials are ongoing (see Table), the results of several phase 2 trials have been reported recently.^22-24

PRIMETEST was a single-arm, single-center, phase 2 study examining the efficacy and surgical safety of primary RPLND for stage II disease.²² Participants underwent either open or robot-assisted unilateral RPLND for stage IIA or B seminoma. No adjuvant treatment was permitted. Of the 33 participants, 9 presented initially with clinical stage II disease (27%) and 24 (73%) had recurrence during active surveillance. Five of the 24 had 1 cycle of carboplatin prior to progressing to stage II. With a median follow-up of 32 months, the study did not meet its primary endpoint of PFS at 36 months. After 32 months, 10 recurrences (30%) were detected, yielding a PFS rate of 70%. All 10 patients with recurrence received chemotherapy and were alive without evidence of disease at the time of publication. This study demonstrates that RPLND may be appropriate for select patients; however, criteria for selecting patients to receive only RPLND need to be clearly defined.²²

The SEMS (surgery in early metastatic seminoma) trial was a single-arm, international, phase 2 study of RPLND as first-line treatment for early metastatic seminoma with isolated retroperitoneal lymphadenopathy between 1 and 3 cm (stage II).²³ With a median follow-up of 24 months, OS was 100% and 2-year recurrence-free survival was 87%. Recurrence rate was 18% (10 recurrences) with a median time to recurrence of 8 months. Short-term complications occurred in 7 patients (13%), and no patients reported long-term complications. The authors suggested that RPLND is a therapeutic option for first-line treatment in early metastatic seminoma.²³

SAKK 01/10 was a single-arm, international, phase 2 study examining the de-escalation of treatment to potentially avoid toxic effects for patients with either stage IIA or stage IIB seminoma.²⁴ Treatment included carboplatin (area under the curve [AUC] 7 mg/mL/min) followed 3 weeks later with involvednode radiotherapy (30 Gy in 15 fractions for stage IIA and 36 Gy in 18 fractions for stage IIB). The study did not meet its primary endpoint of PFS of 95% at 3 years. Grade ≥ 3 treatment-related AEs (TRAEs) included neutropenia (4%), thrombocytopenia (3%), and vomiting (1%). No treatment-related deaths and no late TRAEs were reported. One case of transient creatinine increase was reported as a serious AE, and second primary tumors were reported in 4 participants. Although the primary endpoint was not met, long-term AEs continue to be recorded for potentially up to 20 years. The favorable efficacy and toxicity profile observed in the deescalation combination treatment warrants further study.²⁴

Emerging Trends and Future Directions for TC Treatment

Although the outlook for most newly diagnosed patients with TC is promising, especially for those diagnosed with early-stage disease and good prognosis advanced disease, treatment challenges remain. Between 10% and 20% of patients will have a relapse of TC after initially achieving a complete remission. Most patients will have a relapse within 2 years of initial treatment, but a small subgroup will have a relapse more than 5 years after therapy. Most recurrences occur in the retroperitoneum and lungs and require definitive therapy using chemotherapy and surgical resection.²¹

Patients with platinum-refractory disease may still achiev long-term remission with salvage therapy of surgery, conventional-dose chemotherapy, or high-dose chemotherapy with autologous stem cell transplantation; however, these treatments will fail for some patients, resulting in poor prognosis. Targeted therapy for TC has not produced meaningful benefits for this population with refractory disease, and the optimal treatment for this group of patients with TC remains to be determined.²¹

Although current guidelines recommend determining the levels of AFP, hCG, and LDH for clinical staging, treatment monitoring, and follow-up, limitations exist with their usage.⁹ The assays for these markers have low sensitivity and lack specificity; about half of all GCTs express only 1 of the 3 biomarkers, and seminomas lack AFP expression.^7,25,26 Further research is needed on LDH. An emerging group of patients with LDH below 2.5× ULN may be candidates for de-escalatio strategies to reduce treatment burden, while inferior outcomes remain for patients with either good prognosis seminoma and elevated LDH, or intermediate prognosis seminoma.⁷

Other biomarkers, such as miRNA371a-3p and PD-L1, are being investigated; miRNA371a-3p has been shown to have prognostic significance. The results of this assay can be informative for both seminomas and NSGCTs.²⁶ However, the protocol for quantification and implementation still needs to be determined.²⁷

Click to read more from 2023 Rare Diseases Report: Cancers

Mortality from TC has been decreasing since the 1970s due to cisplatin-based chemotherapy regimens^2,3; TC is among the most curable of solid neoplasms, with a 5-year relative survival rate of 95%.^2-4 Thus, the focus of research has shifted from optimizing treatments for improved survival to decreasing treatment-related, long-term adverse events (AEs).⁵

New Modifications in Risk Assessment and Prognostication

The widely accepted risk stratification model in use today was first developed in 1997 by the International Germ Cell Cancer Collaborative Group (IGCCCG) after studying data on patients with seminoma and NSGCTs.⁶ The original classification categorized metastatic NSGCTs as having good, intermediate, or poor prognosis based on levels of alpha-fetoprotein (AFP), human chorionic gonadotropin (hCG), lactate dehydrogenase (LDH), and the presence of nonpulmonary visceral metastases (NPVM). Primary mediastinal NSGCTs were classified as having poor prognosis regardless of the other factors.⁶ Metastatic seminoma GCTs were categorized as having good or intermediate prognosis based on the occurrence of brain, liver, or bone metastasis.⁷

Using contemporary data from more than 12,000 patients with metastatic GCTs who received either cisplatin or etoposide, the IGCCCG model was updated in 2021. For seminoma GCTs, 5-year progression-free survival (PFS) and 5-year overall survival (OS) were extended for both good and intermediate prognostic groups.⁷ LDH remained the most significant prognostic factor for determining good prognosis however, patients with LDH above 2.5× upper limit of normal (ULN) before chemotherapy had worse survival probabilities than patients with LDH at 2.5× ULN or lower. The survival probabilities for patients with otherwise good prognosis with LDH of more than 2.5× ULN were like those for patients with intermediate prognosis.⁷ Thus, using LDH of more than 2.5× ULN has revealed a subgroup with significantly worse outcomes within the “good” prognostic group.^7,8

For NSGCTs, 5-year PFS rates did not differ from the original IGCCCG for good and intermediate prognostic groups; however, the 2021 update revealed an improved PFS for the poor prognostic group. The 2021 update also demonstrated that 5-year OS rates improved for each group, and further confirmed that the 2 most important prognostic factors for NSGCT were the presence of NPVM and the presence of a mediastinal primary tumor. The update added 2 new adverse prognostic variables: age and metastases. Risk of progression increases 25% with every decade-of-life increase, and 66% with the presence of lung metastases. The LDH groups were reduced to a single cutoff at 2.5× ULN for NSGCTs.⁸

Primary and Subsequent Treatments for TC

Guideline-directed first-line and subsequent treatments for seminomas and NSGCTs have been developed by several organizations, including the National Comprehensive Cancer Network, IGCCCG, and the American Urological Association (see Figure 1 and 2). An analysis of the most used treatments was performed using the National Cancer Database.² Most patients underwent orchiectomy without chemotherapy or radiation for both stage I seminomas (78%) and NSGCTs (57%). For stage II and III seminomas, most patients underwent surgery with chemotherapy (66% and 68%, respectively). Nearly half of patients with stage II NSGCTs were treated with surgery and chemotherapy (49%), and a third were treated with retroperitoneal lymph node dissection (RPLND) in addition to surgery and chemotherapy. Surgery with chemotherapy was used for 55% of stage III NSGCTs; other treatments included surgery combined with chemotherapy and RPLND (19%), and chemotherapy with or without radiation (20%).² However, nearly 30% of patients with TC do not receive guideline-directed therapy, including inappropriate imaging and overtreatment; and nonguideline–directed therapy has been independently associated with risk of relapse.^12,13

TC Survivorship

The trend of improved OS after treatment for metastatic GCTs highlights a need to focus on survivorship. The 10-year survival rate for TC post-treatment is 95%.¹⁴ Latest estimates suggest there are more than 300,000 TC survivors in the United States,² accounting for approximately 4% of all US male cancer survivors.¹⁴ With longer-term survival, however, comes the risk for long-term complications from cancer treatments. For example, circulating platinum has been detected in the plasma of men up to 28 years after undergoing cisplatin-based chemotherapy for TC.¹⁵ Increasing levels of residual serum platinum have also been shown to correlate with severity of neurotoxicity between 5 and 20 years after treatment.¹⁶

A significant concern with cancer treatment is the development of second malignant neoplasms (SMNs).^14,17 The relative risk of the development of SMNs depends on whetherradiation therapy or chemotherapy, or both, was used as the primary treatment. Patients who received either radiation therapy or chemotherapy are at increased risk for leukemia and solid cancers, including gastrointestinal cancers. For patients treated with cisplatin, a significant dose-response relationship between cumulative dose and leukemic risk has been reported.¹⁴

Other concerns are increased non-TC mortality and SMN mortality. Hellesnes et al examined cause-specific, non-TC mortality using a population-based cohort in Norway.¹⁸ They determined that the overall 25-year, non-TC mortality risk was 13.7% (95% CI, 12.5-14.9) for patients who previously had TC vs 11.3% for patients who never had TC. The highest mortality rates were reported for patients who had radiation (19%) or platinum-based chemotherapy plus radiation (18.4%); the lowest mortality rate was reported for patients who had received platinum-based chemotherapy only (9.5%). Patients with the highest non-TC mortality risk were fewer than 20 years post-cancer diagnosis. Non-TC mortality excess ranged from 23% to 40% for patients with a prior TC diagnosis, and a significant 1.43- to 3.24-fold increase in SMN mortality emerged after treatment with platinum-based chemotherapy or radiation therapy, or both.¹⁹ Awareness of the increased premature mortality risk is crucial for both TC survivors and their care providers.¹⁸

Quality of life for TC survivors appears to be affected by the presence of long-term treatment-related AEs.¹⁸ The relative risk of developing cardiovascular disease increases after treatment with chemotherapy. Raynaud phenomenon resulting from bleomycin-induced vascular damage developed within 4 to 12 months after chemotherapy for 18.7% to 39% of TC survivors.^14,19 Bleomycin may also cause pulmonary toxicity. Pulmonary surgery, tobacco use of ≥ 20 pack-years, and a cumulative cisplatin dose of > 850 mg are risk factors for late  bleomycin-associated pulmonary toxicity.¹⁴

Other late-developing toxicities resulting from cisplatin treatment include ototoxicity, neurotoxicity, nephrotoxicity, chronic fatigue, and hypogonadism.^14,19 Nearly 1 in 5 North American survivors treated with cisplatin reported severe-to-profound hearing loss within a median of 4.3 years. The extent of hearing loss has been directly associated with the increase in cumulative cisplatin dose. Peripheral neurotoxicity after cisplatin-based chemotherapy is reported to be as high as 40%.¹⁴ Chronic cancer-related fatigue can range from 15% to 27%, and has been associated with peripheral neuropathy, low testosterone levels, low physical activity, anxiety, and depression. Post-treatment hypogonadism ranges from 11% to 16%.^14,17,20,21

Psychosocial issues are also of concern. Mild-to-moderate psychological distress with diagnosis and survivorship has been reported.¹⁷ Anxiety and depression are higher in TC survivors than in the general population. Variables associated with clinically significant anxiety include younger age and shorter time from diagnosis; whereas feeling helpless/hopeless, having less social support, having a higher number of physical symptoms, and having children are factors associated with higher levels of depression. A moderate-to-high level of fear of recurrence has also been reported.¹⁷

Recent Clinical Trials in Stage II Disease

Stage II disease has been the focus of current research to reduce treatment-related toxicities and limit longer-term complications. While few phase 3 clinical trials are ongoing (see Table), the results of several phase 2 trials have been reported recently.^22-24

PRIMETEST was a single-arm, single-center, phase 2 study examining the efficacy and surgical safety of primary RPLND for stage II disease.²² Participants underwent either open or robot-assisted unilateral RPLND for stage IIA or B seminoma. No adjuvant treatment was permitted. Of the 33 participants, 9 presented initially with clinical stage II disease (27%) and 24 (73%) had recurrence during active surveillance. Five of the 24 had 1 cycle of carboplatin prior to progressing to stage II. With a median follow-up of 32 months, the study did not meet its primary endpoint of PFS at 36 months. After 32 months, 10 recurrences (30%) were detected, yielding a PFS rate of 70%. All 10 patients with recurrence received chemotherapy and were alive without evidence of disease at the time of publication. This study demonstrates that RPLND may be appropriate for select patients; however, criteria for selecting patients to receive only RPLND need to be clearly defined.²²

The SEMS (surgery in early metastatic seminoma) trial was a single-arm, international, phase 2 study of RPLND as first-line treatment for early metastatic seminoma with isolated retroperitoneal lymphadenopathy between 1 and 3 cm (stage II).²³ With a median follow-up of 24 months, OS was 100% and 2-year recurrence-free survival was 87%. Recurrence rate was 18% (10 recurrences) with a median time to recurrence of 8 months. Short-term complications occurred in 7 patients (13%), and no patients reported long-term complications. The authors suggested that RPLND is a therapeutic option for first-line treatment in early metastatic seminoma.²³

SAKK 01/10 was a single-arm, international, phase 2 study examining the de-escalation of treatment to potentially avoid toxic effects for patients with either stage IIA or stage IIB seminoma.²⁴ Treatment included carboplatin (area under the curve [AUC] 7 mg/mL/min) followed 3 weeks later with involvednode radiotherapy (30 Gy in 15 fractions for stage IIA and 36 Gy in 18 fractions for stage IIB). The study did not meet its primary endpoint of PFS of 95% at 3 years. Grade ≥ 3 treatment-related AEs (TRAEs) included neutropenia (4%), thrombocytopenia (3%), and vomiting (1%). No treatment-related deaths and no late TRAEs were reported. One case of transient creatinine increase was reported as a serious AE, and second primary tumors were reported in 4 participants. Although the primary endpoint was not met, long-term AEs continue to be recorded for potentially up to 20 years. The favorable efficacy and toxicity profile observed in the deescalation combination treatment warrants further study.²⁴

Emerging Trends and Future Directions for TC Treatment

Although the outlook for most newly diagnosed patients with TC is promising, especially for those diagnosed with early-stage disease and good prognosis advanced disease, treatment challenges remain. Between 10% and 20% of patients will have a relapse of TC after initially achieving a complete remission. Most patients will have a relapse within 2 years of initial treatment, but a small subgroup will have a relapse more than 5 years after therapy. Most recurrences occur in the retroperitoneum and lungs and require definitive therapy using chemotherapy and surgical resection.²¹

Patients with platinum-refractory disease may still achiev long-term remission with salvage therapy of surgery, conventional-dose chemotherapy, or high-dose chemotherapy with autologous stem cell transplantation; however, these treatments will fail for some patients, resulting in poor prognosis. Targeted therapy for TC has not produced meaningful benefits for this population with refractory disease, and the optimal treatment for this group of patients with TC remains to be determined.²¹

Although current guidelines recommend determining the levels of AFP, hCG, and LDH for clinical staging, treatment monitoring, and follow-up, limitations exist with their usage.⁹ The assays for these markers have low sensitivity and lack specificity; about half of all GCTs express only 1 of the 3 biomarkers, and seminomas lack AFP expression.^7,25,26 Further research is needed on LDH. An emerging group of patients with LDH below 2.5× ULN may be candidates for de-escalatio strategies to reduce treatment burden, while inferior outcomes remain for patients with either good prognosis seminoma and elevated LDH, or intermediate prognosis seminoma.⁷

Other biomarkers, such as miRNA371a-3p and PD-L1, are being investigated; miRNA371a-3p has been shown to have prognostic significance. The results of this assay can be informative for both seminomas and NSGCTs.²⁶ However, the protocol for quantification and implementation still needs to be determined.²⁷

Click to read more from 2023 Rare Diseases Report: Cancers