Dear Editor Ruxolitinib is an oral target small molecule inhibitor of Janus kinase (JAK) 1 and 2 approved for the treatment of myelofibrosis (MF) and polycythemia vera (PV) patients [1]. A significant improvement in spleen dimension and constitutional symptoms in MF have been reported [2]. Long-term findings from the COMFORT-II study, a phase 3 trial of ruxolitinib versus best available therapy (BAT) for MF, have indicated an increased risk of newly diagnosed non-melanoma skin cancer (basal cell carcinoma [BCC] and squamous cell carcinoma [SCC]) in 17.1% of patient in the ruxolitinib arm and in only 2.7% of patients on the BAT arm [3]. It has been reported that cutaneous malignancies developing in patients on ruxolitinib therapy exhibit a more aggressive and metastatic profile [4–6]. We hereby report a case of combined treatment of cemiplimab and ruxolitinib for a relapsed and advanced non-melanoma skin cancer in a MF patient. In 2009, a 72-year-old man was diagnosed as having a secondary MF in a JAK2-positive PV treated with hydroxyurea for 5 years. In March 2015, due to constitutional symptoms and increased splenomegaly, he started treatment with ruxolitinib, initially at a reduced dose of 5-mg BID because of a baseline anemia. Two years later, considering the improvement in the hemoglobin levels, ruxolitinib was increased to 15 mg daily. A complete control of splenomegaly and resolution of associated symptoms was obtained without the need of transfusion support. After 13 months of ruxolitinib treatment, the patient presented a BCC on the right temporal region with squamous cell differentiation and well-defined margins that was treated with local surgery. About 2 years later, he reported two new lesions and the pathologic xamination revealed an invasive and ulcerated SCC with evident keratinization and well-differentiated lesion on the right jowl (Broder I), while a medium histologic differentiation was detected on the left jowl (Broder II) associated with a Bowen carcinoma (squamous cell carcinoma In situ (SCCS)/Bowen’s Disease). Both lesions showed clear excision borders. During 2019, 4 years after the start of ruxolitinib, the patient developed multiple skin lesions in different regions: right temple, forehead, right and left cheek bones, and nose, treated by surgical resection. Histologic analyses of the cutaneous biopsies were all consistent with a SCC characterized by a variable degree of infiltration and differentiation. No evidence of lymph node involvement was shown by post-surgical neck ultrasound. A few months later, an ulcerated lesion recurred on his nose and right zygomatic area and a further surgical resection was carried out. A diagnosis of relapsed SCC was made by histological analysis that showed a deep margin involvement by tumor cells; thus, a radical eradication could not be performed. At this time, a MRI revealed a 15 × 22 × 22 mm solid lesion in the right asofacial angle ulcerated on the cutaneous plan, with an involvement of deep structures (subcutaneous fat, muscle, bone, and cartilage). In consideration of the advanced cutaneous SCC, the advanced age and multiple concomitant comorbidities (including a secondary MF), the patient was considered not eligible for a massive surgical approach but only for palliative radiation. Cemiplimab, a checkpoint inhibitor directed against programmed death 1 (PD-1) receptor, was considered, taking into account the possible association with ruxolitinib. In November 2019, the patient started intravenous administration of cemiplimab every 3 weeks associated with ruxolitinib treatment which was continued at a decreased dose of 10 mg daily. At present, after 6 months (7 cycles) of cemiplimab, the patient has achieved a partial clinical response for the SCC and ruxolitinib has never been discontinued due to adverse events or cumulative ematologic toxicities. The lesion has almost disappeared from the superficial cutaneous plan (Fig. 1), and after 5 years of ruxolitinib, the MF is stable with an optimal control of constitutional symptoms and of the spleen volume. An increased occurrence of skin cancers such as keratoacanthomas and SCC has also been described following long-term hydroxyurea treatment [7, 8]. Our elderly patient developed a SCC during treatment with ruxolitinib, but he had been treated earlier for several years with hydroxyurea: therefore, a iatrogenic pathogenesis cannot be excluded as the cause of the SCC [4, 5]. SCC is the second most common skin cancer in the world and compared with BCC, it has a greater invasive behavior and metastatic propensity. Some cutaneous areas of localization (scalp, forehead, ears, nose, and lips), tumor size, and level of structure invasion are correlated with a high risk of metastasis and tumor recurrence. Thus, due to its more aggressive nature, an appropriate surgical excision is crucial [9]. Advanced cutaneous SCC is a life-threatening condition especially for patients not eligible for curative surgery or radiation. Recently, a novel immunotherapy approach with cemiplimab, a potent high-affinity monoclonal antibody directed against programmed death 1 (PD-1) receptor [10], has been approved by the Food and Drug Administration (FDA) as single agent for the treatment of adult patients with metastatic or locally advanced SCC who are not candidate for curative surgery or curative radiation [11]. In a phase 1 study of cemiplimab, objective and durable responses in a patient with advanced and metastatic cutaneous SCC were reported [12]. Migden et al. [13, 14] reported a consistent response rate in the phase 1 and 2 studies of patients with locally advanced or metastatic cutaneous SCC treated with cemiplimab. These data suggest that cases with advanced cutaneous SCC, ineligible for an intensive approach, may respond to immunotherapy with a checkpoint inhibitor such as cemiplimab which has shown an important antitumor activity and an acceptable safety profile with adverse events that are similar to those seen with other PD-1 inhibitors [13, 14]. Few data are available on the co-administration of ruxolitinib and PD-1/PD-L1 checkpoint inhibitors. Debureaux et al. [15] reported the promising effect of the association between ruxolitinib and nivolumab in a patient with MF and diffuse Merkel cell carcinoma who achieved a complete clinical and metabolic response after four cycles of nivolumab. Due to the important response observed, the authors hypothesized that the PD-1/PDL-1 pathway and JAK2 could constitute complementary therapeutic targets and that the combination of nivolumab and ruxolitinib might be synergistic [15], despite a T-lymphocyte reduction induced by the JAK2 inhibitor that could result in a potential loss of efficacy of nivolumab [16]. As suggested by our case, the combination of ruxolitinib and checkpoint inhibitors, even in an elderly patient with multiple comorbidities and a 10-year history of a hematologic malignancy, can be safe and effective for both diseases. Due to the increased risk of cutaneous malignancies among patients on ruxolitinib treatment, a routine skin examination should periodically carry out [4, 5]. Considering the large use of this drug in MF and PV patients, and the increased risk of skin cancers, further investigations are necessary to conclusively investigate the association of the two drugs that may in the near future become more frequent.

Management of myelofibrosis and concomitant advanced cutaneous squamous cell carcinoma with ruxolitinib associated with cemiplimab / Di Prima, A.; Botticelli, A.; Scalzulli, E.; Colafigli, G.; Pepe, S.; Lisi, C.; Marchetti, P.; Martelli, M.; Foa, R.; Breccia, M.. - In: ANNALS OF HEMATOLOGY. - ISSN 0939-5555. - (2020). [10.1007/s00277-020-04236-7]

Management of myelofibrosis and concomitant advanced cutaneous squamous cell carcinoma with ruxolitinib associated with cemiplimab

Scalzulli E.;Colafigli G.;Pepe S.;Lisi C.;Martelli M.;Foa R.;Breccia M.
2020

Abstract

Dear Editor Ruxolitinib is an oral target small molecule inhibitor of Janus kinase (JAK) 1 and 2 approved for the treatment of myelofibrosis (MF) and polycythemia vera (PV) patients [1]. A significant improvement in spleen dimension and constitutional symptoms in MF have been reported [2]. Long-term findings from the COMFORT-II study, a phase 3 trial of ruxolitinib versus best available therapy (BAT) for MF, have indicated an increased risk of newly diagnosed non-melanoma skin cancer (basal cell carcinoma [BCC] and squamous cell carcinoma [SCC]) in 17.1% of patient in the ruxolitinib arm and in only 2.7% of patients on the BAT arm [3]. It has been reported that cutaneous malignancies developing in patients on ruxolitinib therapy exhibit a more aggressive and metastatic profile [4–6]. We hereby report a case of combined treatment of cemiplimab and ruxolitinib for a relapsed and advanced non-melanoma skin cancer in a MF patient. In 2009, a 72-year-old man was diagnosed as having a secondary MF in a JAK2-positive PV treated with hydroxyurea for 5 years. In March 2015, due to constitutional symptoms and increased splenomegaly, he started treatment with ruxolitinib, initially at a reduced dose of 5-mg BID because of a baseline anemia. Two years later, considering the improvement in the hemoglobin levels, ruxolitinib was increased to 15 mg daily. A complete control of splenomegaly and resolution of associated symptoms was obtained without the need of transfusion support. After 13 months of ruxolitinib treatment, the patient presented a BCC on the right temporal region with squamous cell differentiation and well-defined margins that was treated with local surgery. About 2 years later, he reported two new lesions and the pathologic xamination revealed an invasive and ulcerated SCC with evident keratinization and well-differentiated lesion on the right jowl (Broder I), while a medium histologic differentiation was detected on the left jowl (Broder II) associated with a Bowen carcinoma (squamous cell carcinoma In situ (SCCS)/Bowen’s Disease). Both lesions showed clear excision borders. During 2019, 4 years after the start of ruxolitinib, the patient developed multiple skin lesions in different regions: right temple, forehead, right and left cheek bones, and nose, treated by surgical resection. Histologic analyses of the cutaneous biopsies were all consistent with a SCC characterized by a variable degree of infiltration and differentiation. No evidence of lymph node involvement was shown by post-surgical neck ultrasound. A few months later, an ulcerated lesion recurred on his nose and right zygomatic area and a further surgical resection was carried out. A diagnosis of relapsed SCC was made by histological analysis that showed a deep margin involvement by tumor cells; thus, a radical eradication could not be performed. At this time, a MRI revealed a 15 × 22 × 22 mm solid lesion in the right asofacial angle ulcerated on the cutaneous plan, with an involvement of deep structures (subcutaneous fat, muscle, bone, and cartilage). In consideration of the advanced cutaneous SCC, the advanced age and multiple concomitant comorbidities (including a secondary MF), the patient was considered not eligible for a massive surgical approach but only for palliative radiation. Cemiplimab, a checkpoint inhibitor directed against programmed death 1 (PD-1) receptor, was considered, taking into account the possible association with ruxolitinib. In November 2019, the patient started intravenous administration of cemiplimab every 3 weeks associated with ruxolitinib treatment which was continued at a decreased dose of 10 mg daily. At present, after 6 months (7 cycles) of cemiplimab, the patient has achieved a partial clinical response for the SCC and ruxolitinib has never been discontinued due to adverse events or cumulative ematologic toxicities. The lesion has almost disappeared from the superficial cutaneous plan (Fig. 1), and after 5 years of ruxolitinib, the MF is stable with an optimal control of constitutional symptoms and of the spleen volume. An increased occurrence of skin cancers such as keratoacanthomas and SCC has also been described following long-term hydroxyurea treatment [7, 8]. Our elderly patient developed a SCC during treatment with ruxolitinib, but he had been treated earlier for several years with hydroxyurea: therefore, a iatrogenic pathogenesis cannot be excluded as the cause of the SCC [4, 5]. SCC is the second most common skin cancer in the world and compared with BCC, it has a greater invasive behavior and metastatic propensity. Some cutaneous areas of localization (scalp, forehead, ears, nose, and lips), tumor size, and level of structure invasion are correlated with a high risk of metastasis and tumor recurrence. Thus, due to its more aggressive nature, an appropriate surgical excision is crucial [9]. Advanced cutaneous SCC is a life-threatening condition especially for patients not eligible for curative surgery or radiation. Recently, a novel immunotherapy approach with cemiplimab, a potent high-affinity monoclonal antibody directed against programmed death 1 (PD-1) receptor [10], has been approved by the Food and Drug Administration (FDA) as single agent for the treatment of adult patients with metastatic or locally advanced SCC who are not candidate for curative surgery or curative radiation [11]. In a phase 1 study of cemiplimab, objective and durable responses in a patient with advanced and metastatic cutaneous SCC were reported [12]. Migden et al. [13, 14] reported a consistent response rate in the phase 1 and 2 studies of patients with locally advanced or metastatic cutaneous SCC treated with cemiplimab. These data suggest that cases with advanced cutaneous SCC, ineligible for an intensive approach, may respond to immunotherapy with a checkpoint inhibitor such as cemiplimab which has shown an important antitumor activity and an acceptable safety profile with adverse events that are similar to those seen with other PD-1 inhibitors [13, 14]. Few data are available on the co-administration of ruxolitinib and PD-1/PD-L1 checkpoint inhibitors. Debureaux et al. [15] reported the promising effect of the association between ruxolitinib and nivolumab in a patient with MF and diffuse Merkel cell carcinoma who achieved a complete clinical and metabolic response after four cycles of nivolumab. Due to the important response observed, the authors hypothesized that the PD-1/PDL-1 pathway and JAK2 could constitute complementary therapeutic targets and that the combination of nivolumab and ruxolitinib might be synergistic [15], despite a T-lymphocyte reduction induced by the JAK2 inhibitor that could result in a potential loss of efficacy of nivolumab [16]. As suggested by our case, the combination of ruxolitinib and checkpoint inhibitors, even in an elderly patient with multiple comorbidities and a 10-year history of a hematologic malignancy, can be safe and effective for both diseases. Due to the increased risk of cutaneous malignancies among patients on ruxolitinib treatment, a routine skin examination should periodically carry out [4, 5]. Considering the large use of this drug in MF and PV patients, and the increased risk of skin cancers, further investigations are necessary to conclusively investigate the association of the two drugs that may in the near future become more frequent.
2020
myelofibrosis; cutaneous squamous cell carcinoma;
01 Pubblicazione su rivista::01a Articolo in rivista
Management of myelofibrosis and concomitant advanced cutaneous squamous cell carcinoma with ruxolitinib associated with cemiplimab / Di Prima, A.; Botticelli, A.; Scalzulli, E.; Colafigli, G.; Pepe, S.; Lisi, C.; Marchetti, P.; Martelli, M.; Foa, R.; Breccia, M.. - In: ANNALS OF HEMATOLOGY. - ISSN 0939-5555. - (2020). [10.1007/s00277-020-04236-7]
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11573/1462884
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