Update in Diagnosis and Management of Primary Cutaneous B-Cell Lymphomas

Amanda Krenitsky; Skylar Klager; Leigh Hatch; Carlos Sarriera-Lazaro; Pei Ling Chen; Lucia Seminario-Vidal

Am J Clin Dermatol. 2022;23(5):689-706.

Abstract and Introduction

Abstract

Primary cutaneous lymphomas are a rare group of diseases, with an estimated incidence of 0.5–1 case per 100,000 people per year. Primary cutaneous B-cell lymphomas (pCBCLs) represent 25–30% of all primary cutaneous lymphomas. There are three main subtypes of pCBCL: primary cutaneous marginal zone lymphoma, primary cutaneous follicle center lymphoma, and primary cutaneous diffuse large B-cell lymphoma, leg type. Cutaneous B-cell lymphomas have a broad spectrum of clinical presentations, which makes diagnostic and therapeutic strategies challenging. To date, treatment recommendations for cutaneous B-cell lymphomas have been largely based on small retrospective studies and institutional experience. Recently, the pharmacotherapeutic landscape has expanded to include drugs that may modify the underlying disease pathology of pCBCLs, representing new therapeutic modalities for this rare group of diseases. Novel therapies used for other systemic B-cell lymphomas show promise for the treatment of pCBCLs and are being increasingly considered. These new therapies are divided into five main groups: monoclonal antibodies, immune checkpoint inhibitors, small-molecule inhibitors, bispecific T-cell engaging, and chimeric antigen receptor T cell. In this review, we discuss the clinical, histopathological, molecular, and cytogenetic features of the most common pCBCL subtypes with a focus on current and innovative therapeutic developments in their management. These emerging treatment strategies for B-cell lymphomas and cutaneous B-cell lymphomas may represent novel first-line options for the management of these rare diseases.

Introduction

Primary cutaneous B-cell lymphomas (pCBCLs) constitute a heterogeneous group of extra-nodal B-cell non-Hodgkin lymphomas (B-NHLs). Defined as being present only in the skin at the time of diagnosis, pCBCLs are a rare entity, representing only 25–30% of all primary cutaneous lymphomas.^[1] Incidence is estimated at < 1 per 100,000 persons/year and increases with age.^[2]

The 2018 update of the World Health Organization-European Organization for Research and Treatment of Cancer classifies pCBCL into three major subtypes: primary cutaneous marginal zone lymphoma (PCMZL), primary cutaneous follicle center lymphoma (PCFCL), and primary cutaneous diffuse large B-cell lymphoma, leg type (PCDLBCL, LT). Primary cutaneous follicle center lymphoma and PCMZL portend an indolent clinical course with 5-year survival rates of over 90% and up to 98%, whereas PCDLBCL, LT is a more aggressive variant with associated 5-year survival between 20 and 70%.^[3] Intravascular large B-cell lymphoma is a rare and aggressive subtype of large B-cell lymphoma with a 3-year survival rate of 56% in patients with only cutaneous manifestations and 22% in those with disseminated disease. Primary cutaneous diffuse large B-cell lymphoma not otherwise specified, and Epstein–Barr virus-positive mucocutaneous ulcer are very rare pCBCL subtypes. Primary cutaneous diffuse large B-cell lymphoma not otherwise specified has a 5-year survival around 90% and Epstein–Barr virus-positive mucocutaneous ulcer portends an indolent self-limited course.^[1,2,4]

An accurate pathologic diagnosis of the subtype is the most important first step in the management of pCBCLs. Basic clinicopathologic evaluation is the same for each subtype, although some further evaluation may be useful in certain circumstances to clarify a particular diagnosis. To appropriately confirm the diagnosis of pCBCL, systemic involvement must be ruled out. As such, a thorough work-up is necessary and includes a detailed history and physical examination, tissue sampling, molecular studies, and laboratory studies. Cytogenetics and flow cytometry of the blood and/or lesional tissue are helpful in certain conditions^[5–7]

Management of pCBCL is complex and requires coordination of a multidisciplinary care team comprising dermatologists, pathologists, hematology-oncologists, and radiation oncologists. There is a scarcity of large randomized trials in pCBCL, and current therapeutic guidelines are based on small retrospective studies.^[3,8–10] This review aims to describe the pathophysiological, epidemiological, clinicopathological, immunohistochemical, molecular, and cytogenetic features of the most common pCBCL subtypes with a focus on current and innovative therapeutic developments in their management.

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Table 1. Innovative therapeutic approaches in primary cutaneous B-cell lymphomas
Author	Indication	Target	Intervention	Route	Dose and frequency	Study design	n	ORR (%)	CR (%)	PFS (months)	Side effects
Monoclonal antibodies
Galanina et al. [79]	rrDLBCL	CD20	Ofatumumab	IV	1000 mg weekly × 8 weeks	II	11	18	0	2	Diarrhea, anorexia, hyponatremia, fatigue
Rosenbaum et al. [80]	FL	CD20	Ofatumumab	IV	1000 mg/week × 4 doses followed by 1 dose/8 weeks × 4 doses	III	36	84	16	1.9	Lymphopenia, anemia, thrombocytopenia, neutropenia, leukocytosis, pain, fatigue, dyspnea, insomnia, nausea, hyperglycemia, hyponatremia, infection
Moore et al. [108]	rrPCDLBCL-LT	CD20 (+CD40, +BTK)	Rituximab (+ lenalidomide + ibrutinib)	IV, PO	Ibrutinib 560 mg daily, lenalidomide 20 mg days 1–21/month, rituximab 375 mg/m²/month	CS	2	100	100	ND	Fatigue, neutropenia, rash
de Vos et al. [88]	rrDLBCL	CD40	Dacetuzumab	IV	Dose-escalation to 8 mg/kg/week × 5 weeks, then 8 mg/kg/week × 4 weeks	II	46	9	4	1.2	Fatigue, headache, chills, fever, nausea, DVT, lymphopenia, neutropenia, thrombocytopenia, reversible ocular event
Salles et al. [89]	rrDLBCL	C19 (+ proteasome)	Tafasitamib (+ lenalidomide)	IV, PO	Tafasitamib 12 mg/kg and lenalidomide 25 mg/day up to 12, 28-day cycles	II	81	54	32	16.2	Neutropenia, thrombocytopenia, pneumonia, febrile neutropenia, pulmonary embolism, bronchitis, atrial fibrillation, congestive cardiac failure
Bispecific T-cell engager antibodies
Viardot et al. [91]	rrDLBCL	CD19/CD3	Blinatumomab	IV	112 mcg/day for 2 cycles (8 weeks + 4 weeks)	II	21	43	19	3.7	Tremor, pyrexia, fatigue, edema, thrombocytopenia, pneumonia, diarrhea, leukopenia
Coyle et al. [93]	rrB-NHL	CD19/CD3	Blinatumomab	IV	9 mcg/day for 7 days, 28 mcg/day for 7 days, 112 mcg/day for 42 days	II	41	37	22	2.5	Back pain, pyrexia, headache, tremor, peripheral edema, neutropenia, anemia, confusion, aphasia
Katz et al. [94]	DLBCL	CD19/CD3	Blinatumomab	IV	9 mcg/day for 7 days, 28 mcg/day for 7 days, 112 mcg/day for 42 days	II	28	89	ND	ND	Neurotoxicity, neutropenia, neurologic events
Poh et al. [95]	rrB-NHL	CD19/CD3 (+ proteasome)	Blinatumomab (+ lenalidomide)	IV, PO	Blinatumomab 9 mcg/day to 112 mcg/day days 1–56 and lenalidomide 10 or 20 mg/day days 29–49	I	12	83	50	8.3	Lymphopenia, hypophosphatemia, hyponatremia, neurotoxicity
Schuster et al. [96]	rrB-NHL	CD20/CD3	Mosunetuzumab	IV	1/2/60 mg (step-up days 1, 8, 15) cycle 1, then fixed dose day 1 of each subsequent 21-day cycle	I/Ib	218	43.8	25	ND	Cytokine release syndrome, headache, insomnia, dizziness
Immune checkpoint inhibitors
Tuscano et al. [103]	rrB-NHL	CTLA-4 (+ CD20)	Ipilimumab (+ rituximab)	IV	Rituximab 375/m², ipilimumab 3 mg/kg on day 1 and every 3 weeks × 4 doses	I	33	2	6	2.6	Neutropenia, skin infection, diarrhea, abdominal pain, dyspnea, maculopapular rash
Ansell et al. [129]	rrB-NHL	CTLA-4	Ipilimumab	IV	3 mg/kg then 1 mg/kg/month × 3 months, then 2 mg/kg × 4 months	I	18	11	ND	16	Fatigue, diarrhea, abdominal pain, thrombocytopenia
Di Raimondo et al. [102]	rrPCDLBCL, LT	PD1 (+ CD20, + proteasome)	Pembrolizumab (+ rituximab, + lenalidomide)	IV, PO	Rituximab 375 mg/m² × 4 weeks, lenalidomide 10 mg/day 1–21, pembrolizumab 200 mg × 2 cycles	CR*	1	100	100	ND	Neutropenia, pneumonia
Small-molecule inhibitors
Gupta et al. [81]	PCDLBCL, LT	BTK	Ibrutinib	PO	560 mg/day	CR*	1	100	100	ND	N/A
Leonard et al. [130]	rrB-NHL	Proteasome (+ CD20)	Lenalidomide (+ rituximab)	PO, IV	Lenalidomide 20 mg/day days 1–21, rituximab 375 mg/m² every 7 days, then once/week × 5 cycles	III	178	78	34	39.4	Neutropenia, diarrhea, constipation, cough, fatigue, pyrexia
Beylot-Barry et al. [106]	rrPCDLBCL, LT	Proteasome	Lenalidomide	PO	25 mg/day days 1–21 of 28-day cycle × 12 cycles	II	19	26.3	4.9	19.4	Thrombocytopenia, neutropenia, anemia, asthenia, diarrhea, constipation, neuropathy, skin rash, atrial fibrillation, death
Crump et al. [109]	DLBCL	PKCβ	Enzastaurin	PO	500 mg/day × 3 years	III	758	80	ND	ND	Chromaturia, QTc prolongation, diarrhea, feces discoloration
Forero-Torres et al. [110]	rrB-NHL	PI3Kδ	Parsaclisib	PO	5–45 mg/day dose escalation, 20 and 30 mg/day dose expansion	I/II	72	20–100	0–44	ND	Diarrhea/colitis, nausea, fatigue, rash, pyrexia, hypotension, sepsis
Davids et al. [110,112]	rrB-NHL	Bcl-2	Venetoclax	PO	200–1200 mg/day dose escalation	I	106	44	14/106	6	Anemia, neutropenia, thrombocytopenia
CAR-T
Bao et al. [120]	rrDLBCL	Anti-CD19 CAR-T	IM19 CAR-T	IV	3 × 10⁶/kg cells once	I	5	75	50	ND	Cytopenia, transient aphasia
Neelapu et al. [118]	rrDLBCL	CD19 CAR-T	Axicabtagene-ciloleucel	IV	2 × 10⁶/kg cells once	II	111	82	54	5.8	Neutropenia, anemia, thrombocytopenia, cytokine release syndrome, neurologic events
Schuster et al. [117]	rrDLBCL	CD19 CAR-T	Tisagenlecleucel	IV	Mean 11 × 10⁸ cells total	II	93	52	54	5.8	Cytokine release syndrome, anemia, pyrexia, neutropenia, thrombocytopenia, leukopenia, diarrhea
Cao et al. [122]	rrDLBCL	CD19 CAR-T (+ PD-1)	CD19 CAR-T (+ nivolumab)	IV	Median 8 × 10⁶/kg cells total	NA	11	81.8	45.4	6	Cytopenia fever, fatigue, nausea, neurotoxicity

B-NHL B-cell non-Hodgkin lymphoma, BTK Bruton tyrosine kinase, CAR-T chimeric antigen receptor T cells, CR complete remission, CR* case report, CS case series, DLBCL diffuse large B-cell lymphoma, DVT deep vein thrombosis, FL follicular lymphoma, IV intravenous, ORR overall response rate, PCDLBCL-LT primary cutaneous diffuse large B-cell lymphoma, leg type, PFS progression-free survival, PO oral, QTc corrected QT, rr relapsed/refractory, rrB-NHL relapsed, refractory B-cell non-Hodgkin lymphoma

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Update in Diagnosis and Management of Primary Cutaneous B-Cell Lymphomas

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