Brentuximab vedotin update and the #MeToo saga of the Reed-Sternberg cell
By Warren R. Heymann, MD
Jan. 1, 2018
Dorothy Reed (1874-1964) was matriculated as one of the first female medical students at Johns Hopkins School of Medicine, graduating fifth in her class in 1900. She described her experiences as unflattering by a number of inappropriate comments routinely made in the presence of female students. She considered leaving medicine after attending a lecture by an otolaryngologist who repeatedly compared nasal erectile tissue to the corpus spongiosum of the penis. Her stick-to-itiveness allowed her to secure a coveted medical internship under the tutelage of William Osler; male classmates unsuccessfully tried to convince her to give up her spot to a man. She switched to pathology in 1901 and within one year she described what is now known as the Reed-Sternberg cell of Hodgkin disease (HD). Carl Sternberg independently described the cell, however, his hypothesis was that HD was secondary to chronic tuberculous inflammation. Dr. Reed’s studies allowed her to reach a different conclusion – that HD was a malignant lymphoma, with tuberculosis occurring secondarily. Despite this seminal discovery, published in 1902, she was not promoted to a teaching appointment in the department, although her immediate male predecessor in the fellowship advanced without having performed any research. She left for New York to train in pediatrics. In 1906, she married Charles Elwood Mendenhall, Professor of Physics at the University of Wisconsin, taking a professional hiatus for next 8 years to raise her children. Motivated by the loss of her firstborn daughter, she returned to work, having an impactful career studying the epidemiology of infant mortality. (1,2)
Harassment aside, more than a century later, numerous studies, including those by the American Association of Medical Colleges (AAMC), have demonstrated sex-based differences in advancement, leadership, productivity, and salary in academic medicine. Although gaps in rate of promotion and productivity in academic dermatology have closed, important differences persist (3)
BV is indicated for treatment of patients with: 1) Classical Hodgkin lymphoma (HL) after failure of autologous hematopoietic stem cell transplantation (auto-HSCT) or after failure of at least two prior multi-agent chemotherapy regimens in patients who are not auto-HSCT candidates; 2) Classical HL at high risk of relapse or progression as post-auto-HSCT consolidation; and 3) Systemic anaplastic large cell lymphoma (sALCL) after failure of at least one prior multi-agent chemotherapy regimen. (4)
CD 30 is a cell membrane glycoprotein belonging to the tumor necrosis factor receptor family, serving as a marker of lymphocyte activation. (5) BV is an antibody-drug conjugate that brings the antimicrotubule agent monomethyl auristatin E into CD30-expressing cells. The standard dosing of BV is 1.8 mg/kg every 3 weeks. There is a trend to lower the dose, as well as prolong treatment intervals, to diminish adverse reactions such as peripheral neuropathy, without loss of efficacy. (6)
In their review of 10 publications that met their inclusion criteria, Enos et al found 61 patients with CD30+ transformed MF and seven with primary cutaneous anaplastic large cell lymphoma (PC-ALCL). The mean age at BV initiation was 60.8 years, and 4.1 therapies were attempted prior to BV administration. The overall response rate was 67.7% (100% – PC-ALCL; 63.9% – MF), with 16.2% of patients experiencing complete response (100% – PC-ALCL; 6.6% – MF). Mean time to clinical response was 5.3 and 9.3 weeks for PC-ALCL and MF, respectively. Mean response duration for patients with PC-ALCL was 7.6 and 7.8 months for MF. Peripheral neuropathy (57.2%) and fatigue (35.6%) were the most commonly reported adverse effects. (5)
Lewis et al studied 12 patients with lymphomatoid papulosis (LyP, 8 men and 4 women; median age, 46 years) who responded to BV – 7 exhibited a complete response. Time to response was 3 weeks in all patients. The median duration of response was 20 weeks (range, 6-103 weeks). For 5 patients who relapsed, the median time to relapse was 12 weeks (range, 6-41 weeks). One patient who relapsed was retreated and has remained in partial response for more than 23 months. Grade 1 to 2 neuropathy occurred in 10 patients but resolved in 5. Adverse events of grade 3 or higher were neutropenia (n = 2) and dizziness/vertigo (n = 1). Three patients withdrew owing to adverse events. The authors concluded that BV is effective in treating LyP, but its use should be reserved for patients with truly severe and refractory to standard treatments for LyP (steroids, methotrexate, or phototherapy). More research is needed to optimize its dosing to minimize adverse events, such as peripheral neuropathy. (7)
Prince et al, in an international, open-label, randomized, phase 3, multicenter trial, evaluated adult patients with CD30-positive mycosis fungoides or primary cutaneous anaplastic large-cell lymphoma who had been previously treated. Patients were randomly assigned (1:1) to receive intravenous BV 1·8 mg/kg once every 3 weeks, for up to 16 3-week cycles, or physician’s choice (oral methotrexate 5-50 mg once per week or oral bexarotene 300 mg/m2 once per day) for up to 48 weeks. At a median follow-up of 22·9 months, the proportion of patients achieving an objective global response lasting at least 4 months was 56·3% (36 of 64 patients) with BV versus 12·5% (eight of 64) with physician’s choice. Significant improvement in objective response lasting at least 4 months was seen with BV versus physician’s choice of methotrexate or bexarotene. The authors concluded that these data provide compelling evidence favoring BV over methotrexate or bexarotene for the treatment of relapsed or refractory CD30-positive cutaneous T-cell lymphoma.
The use of BV in lymphoproliferative disease is expanding. It has even been successful in CD30 negative cases, such as in the case of a man with stage IIB mycosis fungoides. Its effectiveness in this case could hinge on the fact that standard assays may be insufficiently sensitive to detect the minimum CD30 expression required to respond to BV; it could also be due to a bystander effect of vedotin killing neighboring malignant cells. (9)
In conclusion, the advances of therapy utilizing targeted therapy such as BV, are based on the observations of a true medical pioneer, Dorothy Reed. I suspect that she would be proud of the accomplishments of the past century, but the first to acknowledge that neither optimal lymphoma therapy nor the deserved place of women in academia has been reached.
1. Terezakis S. Dorothy Reed Mendenhall: Expressions of a pioneer in Hodgkin disease. Int J Radiat Oncol Biol Phys 2015; 92:8-10.
2. Zwitter M, et al Dorothy Reed and Hodgkin’s disease: A reflection after a century. Int J Radiation Oncology Biol Phys 2002; 53: 366-75.
3. Sadeghpour M, et al. Role of sex in academic dermatology: Results from a national survey. Arch Dermatol 2012; 148: 809-14.
4. Package insert ADCETRIS® (brentuximab vedotin)
5. Enos TH, et al. Brentuximab vedotin in CD30+ primary cutaneous T-cell lymphomas: A review and analysis of existing data. Int J Dermatol 2017; 56: 1400-5.
6. Stranzenbach R, et al. Bretuximab vedotin in CD30+ cutaneous lymphoma: How do we treat, how shall we treat? A review of the literature. Br J Dermatol 2017 Jul 13 [Epub ahead of print]
7. Lewis DJ, et al. Brentuximab vedotin for patients with refractory lymphomatoid papulosis. JAMA Dermatol 2017; 153: 1302-6.
8. Prince HM, et al. Brentuximab vedotin or physician’s choice in CD30-positive cutaneous T-cell lymphoma (ALANZA): An international, open-label, randomised, phase 3 multicentre trial. Lancet 2017; 390: 555-66.
9. Zhang C, et al. Treatment of CD30-negative refractory mycosis fungoides with brentuximab vedotin. JAMA Dermatol 2017 Nov 22 [Epub ahead of print].
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