Clinical Remission of Primary Aggressive CD8+ Cutaneous T-Cell Lymphoma After Pralatrexate Infusion | Dermatology | JAMA Dermatology | JAMA Network
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The Cutting Edge
March 2014

Clinical Remission of Primary Aggressive CD8+ Cutaneous T-Cell Lymphoma After Pralatrexate Infusion

Author Affiliations
  • 1Department of Dermatology and Cutaneous Surgery, Miller School of Medicine University of Miami, Miami, Florida
  • 2Florida Academic Dermatology Centers, Miami, Florida
  • 3Broward Health, Broward General Medical Center, Miami, Florida
JAMA Dermatol. 2014;150(3):320-322. doi:10.1001/jamadermatol.2013.8647

Primary aggressive CD8+ cutaneous T-cell lymphoma (CTCL) is a rare, rapidly progressive peripheral cutaneous malignant condition. The rapid progression is accompanied by a dismal prognosis, despite attempts to treat with multiple treatment regiments. Herein, we report a case of primary aggressive CD8+ CTCL that successfully responded to pralatrexate.

Report of a Case

A white male patient in his 60s developed pruritic and painful plaques over his upper body. His medical history included Wegner granulomatosis, which was successfully treated with cyclophosphamide in 2006. He took no medications daily and denied any drug allergies.

A drug-related cutaneous eruption was considered at the initial evaluation, and sequential courses of corticosteroids and antibiotics for secondary impetiginization were prescribed. Biopsy specimens were sent for hematoxylin-eosin staining and direct immunofluorescence. Hematoxylin-eosin staining revealed mild epidermal spongiosis with focal vacuolar alteration along the dermoepidermal junction, dyskeratotic cells, focal exocytosis of lymphocytes, extravasated erythrocytes and superficial polymorphous infiltrate, parakeratosis, and intracorneal neutrophils. Immunostains showed a CD3+ population with a 1:1 ratio of CD4 and CD8+ cells. Results from direct immunofluorescence were negative. Overall, findings favored an acute interface inflammatory process.

The eruption progressed over months into erosions and ulcers with tumors (Figure 1) involving oral mucosa but sparing palms and soles. Repeated biopsies for hematoxylin-eosin staining and direct immunofluorescence ruled out a pemphigus-related disorder. The patient also appeared clinically septic and complained of malaise, anorexia, and severe pain in the skin. He was admitted for sepsis at a local hospital, underwent fluid resuscitation, and received intravenous antibiotics. Repeated biopsies showed an upper dermal bandlike CD8-predominant lymphocytic infiltrate associated with papillary dermal fibrosis and focal epidermotropism with atypia. Immunostains showed an inverted ratio of CD4 to CD8 (1:1-2), with mild decreases in CD7 and CD3 levels, and few epidermotropic CD30+ cells. CD56 and granzyme B stained mononuclear cells, but there was no CD57 staining. Insufficient tissue precluded T-cell rearrangement studies. Although our differential included Mucha-Habermann disease, clinicopathologic correlation favored primary aggressive CD8+ cutaneous T-cell lymphoma (CTCL)—specifically, the patient did not develop fever until months later; cutaneous lesions did not resolve spontaneously; several tumors developed on the skin; and arthritis, hemoptysis, or gastrointestinal tract bleeding were absent; however, oral mucosa was affected.

Figure 1.  Before Treatment
Before Treatment

An initially pruritic eruption on the upper chest progressed to multiple painful ulcerated and eroded plaques, many with yellow crust.

Findings from flow cytometry showed no evidence of lymphoproliferative disorder, and a positron emission tomography–computer tomography (PET/CT) scan demonstrated skin involvement without nodal or visceral involvement.

Therapeutic Challenge

The challenge was to identify a treatment that might offer a chance of remission.


Traditionally, advanced CTCL has been treated with CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone), with disappointing results. The track record with primary aggressive CD8+ CTCL has been just as dismal. With no good therapeutic options, the patient’s deteriorating clinical course convinced our team to consider the new systemic chemotherapeutic pralatrexate (Folotyn, Allos Therapeutics). He received a 30-mg/m2 infusion of pralatrexate after folate and cyanocobalamin supplementation. Following the infusion, the patient developed numerous new ulcers over approximately 80% of his body surface area. The face and scalp were minimally affected, though the lower lip developed a hemorrhagic ulceration. The patient also developed neutropenia (absolute neutrophil count of 0.0/μL [normal >1500/μL]) and fever (39.0°C). These findings mirrored commonly reported Grade 3 and 4 adverse events, eg, thrombocytopenia (32%), mucosal inflammation (21%), neutropenia (20%), and anemia (17%) associated with a 30-mg/m2 infusion.1

The patient was then transferred to the inpatient dermatology service at University of Miami Hospital to provide specialized cutaneous care. On arrival, the patient was given broad-spectrum antibiotics for neutropenic fever and daily filgrastim (Neupogen; Amgen Inc) injections, and he was encased in nonstick sheets with a warming blanket and covered with silver sulfadiazine paste (Silvadene cream [Hoechst Marion Roussel] mixed 1:1 with talcum powder) twice a day. Nursing left any dried paste that remained in place and reapplied paste to areas that showed visible denuded skin. A feeding tube was placed for hyperalimentation, with 2 calories per mL and advanced to 80 mL/h over 48 hours. Additional free water was given and adjusted based on daily laboratory values. This approach was adapted from the University of Miami’s protocol for toxic epidermolytic necrosis.

After the patient stabilized clinically, we obtained biopsy specimens from healing skin and persistent ulcerations to determine whether the patient had benefitted from pralatrexate therapy. These biopsy results were negative for CTCL, and weekly pralatrexate infusions were restarted at a reduced dose (15 mg/m2) because of the severe adverse effects. The patient continued folate and cyanocobalamin supplementation. Because the patient experienced significant mucositis, we administered leucovorin calcium, 50 mg, every 6 hours for 6 doses starting 24 hours after pralatrexate infusion.

In total, 6 pralatrexate infusions were given (a single 30-mg/m2 dose followed by five 15-mg/m2 doses). The patient’s skin continued to heal with supportive care and hyperalimentation. One month after discharge, 2 additional biopsy specimens of persistent ulcerations were read as negative for CTCL. At 7 months, the patient denied any new lesions and has received 2 additional 6-week infusion cycles of 15-mg/m2 pralatrexate without incident (Figure 2). Currently, he is being monitored with clinical skin examinations and serial PET/CT scans for any hypermetabolic foci. There is no plan for further therapy unless new lesions are identified.

Figure 2.  After Treatment
After Treatment

Seven months after his initial cycle of pralatrexate and aggressive supportive care, the patient’s skin showed mild erythema and hyperpigmentation. Two biopsy skin specimens were negative for malignancy.


Primary aggressive CD8+ CTCL is a recently recognized entity characterized by rapid progression over weeks to months of widespread tumors and/or plaques with painful ulceration of the skin, commonly with mucosal involvement.2 Unlike classically indolent CTCL, metastasis is extranodal (lung, testis, central nervous system, and oral), and patients are often ill appearing. Despite dramatic clinical findings, diagnosis relies on histologic analysis to confirm, with hematoxylin-eosin demonstrating lymphocyte epidermotropism with nodular or diffuse T-cell infiltrate. While occasionally adnexal involvement, angiocentricity/angioinvasion, spongiosis or blistering, necrotic keratinocytes, and deep infiltration are seen, immunohistochemistry identifies a CD8+ and CD4 population of T-cells cells with a high proliferation index (Ki-67) and CD2/CD7+. T-cell receptor gene rearrangements can also be performed. To stage a patient, PET/CT can identify often-reported early and distant metastases. Prognosis appears similar to stage IV melanoma, with 18% survival at 5 years, unlike mycosis fungoides, which is approximately 88%.3

Few therapies in managing primary aggressive CD8+ CTCL have had much success. Traditional therapies used in treating CD4+ CTCL, such as topical corticosteroids, chemotherapy, psoralen-UV-A, interferon alfa-2b, and photopheresis, are ineffective.1 Bexarotene has been reported to stabilize more “indolent” cases that clinically progressed over a year or received concurrent total skin electron beam therapy. There is 1 case of allogeneic transplant resulting in remission after 17 months follow-up.4

Pralatrexate represents one of several potentially useful therapies for CD8+ CTCL, including histone deacetylase inhibitors (eg, romidepsin).5 Developed for refractory peripheral T-cell lymphomas, pralatrexate is a novel antineoplastic folate analogue that leverages fetal oncoprotein RFC-1 to enter the cell. Compared with methotrexate, pralatrexate is more than 10-fold more efficient and toxic to cells in in vivo studies.6 In patients with CD4+ CTCL, a recent phase 1 trial concluded that 15 mg/m2 per week for 3 to 4 weeks was appropriate.7

This case represents, to our knowledge, the first reported use of pralatrexate in this condition. Our case report has demonstrated clinical remission and opens the door for treatment of this devastating disease. Further studies are warranted.

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Article Information

Accepted for Publication: September 14, 2013.

Corresponding Author: Francisco A. Kerdel, MD, Florida Academic Dermatology Centers, The University of Miami Hospital, 1400 NW 12th Ave, Ste 4, Miami, FL 33136 (

Published Online: January 22, 2014. doi:10.1001/jamadermatol.2013.8647.

Conflict of Interest Disclosures: Dr Kerdel received honoraria from Amgen, Abbott, and Janssen and received grants from Amgen, Abbott, Pfizer, Eli Lilly, Celgene, Stiefel, and Novartis.

Additional Contributions: We are indebted to Carlos H. Nousari, MD, Sadegh Amini, MD, and Carlos A. Vidal, MD, who were also involved in the care of this patient.

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