Mycosis fungoides

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Mycosis fungoides

Pierluigi Porcu and Henry K. Wong

Evidence Levels:  A Double-blind study  B Clinical trial ≥ 20 subjects  C Clinical trial < 20 subjects  D Series ≥ 5 subjects  E Anecdotal case reports

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Mycosis fungoides (MF) is the most common subtype of cutaneous T-cell lymphoma (CTCL), a heterogeneous group of extranodal non-Hodgkin lymphomas (NHL) of the skin, which includes Sézary syndrome (SS) and CD30-positive lymphoproliferative disorders. The identity of the T-cell subset and the immune compartment (blood, skin, or lymph nodes) targeted by the transforming event in most CTCLs are not known; however, the tumor cell in MF is a mature, CD45RO+, CD4+, CLA+, skin-homing, memory T cell. Functional studies of this T-cell subset in patient samples have provided insight into the pathogenesis and clinical aspects of MF. Decreased production of IFN-γ and IL-12, upregulation of inhibitory molecules such as CTLA4 and PD1, and diminished T-cell immune repertoire, contribute to an increased risk of infections and of secondary malignancies. Selective skin trafficking, mediated by the chemokine receptors CCR4 and CCR10, makes the skin the dominant site of disease across all stages of MF, even though tumor cells are almost always present in the blood and the lymph nodes. Finally, in advanced stage MF, complex chromosomal abnormalities, unresponsiveness to growth-inhibitory signals, and defective apoptosis drive MF’s transformation into a highly aggressive malignancy.

MF accounts for 65–75% of all CTCL cases. MF usually presents in the sixth decade, but can affect all ages, and is more common in males and Blacks, where it may also have a more aggressive behavior. The age-adjusted incidence rates for CTCL in the US have ranged from 4 to 6.4/million person-years, but for 1998–2002 they were up to 9.6/million person-years. The current best estimate for the number of new MF cases in the US is about 3000 per year. Prevalence is much higher owing to the long survival.

Incidence of cutaneous T-cell lymphoma in the United States, 1973–2002.

Criscione VD, Weinstock MA. Arch Dermatol 2007; 143: 854–9.

These papers provide an updated view of the changing epidemiological landscape of cutaneous lymphoma (CL) in the US using the SEER database, a program of the National Cancer Institute (NCI) that collects cancer incidence and survival data from population-based registries covering approximately 28% of the US population. The incidence of CL has increased in the last decade, due in part to improved diagnosis. Inconsistencies in classification and diagnostic criteria remain a limitation in studies spanning several decades, but population-based studies are key to better understand these disorders. Incidence rates vary markedly by race and sex, supporting the notion that cutaneous lymphomas include distinct disease entities.

Diagnosis and staging

An effective treatment strategy depends on making an accurate diagnosis, which in early stage MF can be very challenging. The key diagnostic finding is epidermal invasion by atypical lymphoid cells with a convoluted ‘cerebriform’ nucleus, in the proper clinical context. The International Society for Cutaneous Lymphomas (ISCL) has developed consensus standards for diagnosis, grounded on clinical, pathologic, and immunophenotypic criteria. While not perfect, these criteria should be used to increase concordance in clinical practice. Often, multiple visits and skin biopsies are needed during the evolution of MF before the distinctive histologic features develop and the ISCL criteria are reached.

Once diagnosis is confirmed, determining the clinical stage is crucial. As in other malignancies, staging aims at defining the specific sites of involvement and the overall disease burden, drives the management strategy, and predicts outcomes. The current staging system for MF (and SS) is the product of a joint effort of the ISCL and the European Organisation for Research and Treatment of Cancer (EORTC). This system includes assessment of the peripheral blood compartment, hence TNMB. The ISCL/EORTC staging system requires the integration of clinical findings and laboratory assays, such as flow cytometry and T-cell receptor (TCR) gene rearrangement analysis. Based on this classification, for treatment decisions and discussion of survival, patients can be divided into ‘early stage’ (IA–IIA), or ‘advanced stage’ (IIB–IVB).

Revisions to the staging and classification of mycosis fungoides and Sézary syndrome: a proposal of the International Society for Cutaneous Lymphomas (ISCL) and the cutaneous lymphoma task force of the European Organization of Research and Treatment of Cancer (EORTC).

Olsen E, Vonderheid E, Pimpinelli N, Willemze R, Kim Y, Knobler R, et al. Blood 2007; 110: 1713–22.

These two papers provide an updated consensus approach to the diagnosis of early stage MF and the clinical staging classification of MF/SS. The papers explicitly focus on MF/SS and exclude other types of CTCL and the cutaneous B-cell lymphomas (CBCLs), which are staged differently. A prospective, multi-institutional validation of the ISCL criteria was planned, but has not yet been completed. However, several retrospective studies of the applicability of these criteria have been published and they support the validity of the ISCL/EORTC classification across different patient populations. The two largest studies (Agar et al., Talpur et al.) are discussed below.

Natural history

MF is typically an indolent disease, with a slow and predictable progression, which can very often be inferred by the behavior and evolution of the lesions in the skin. While many patients with MF can be treated without systemic therapy, and enjoy a normal lifespan, a significant subset experiences incomplete clearance of skin lesions, progression to more advanced stages, and significant disease-specific morbidity and mortality. Long term outcome studies based on large patient populations are required to estimate true rates of disease relapse, progression, transformation, and survival.

Survival outcomes and prognostic factors in mycosis fungoides/Sézary syndrome: validation of the revised International Society for Cutaneous Lymphomas/European Organisation for Research and Treatment of Cancer staging proposal.

Agar NS, Wedgeworth E, Crichton S, Mitchell TJ, Cox M, Ferreira S, et al. J Clin Oncol 2010; 28: 4730–9.

This paper presents data on a multicenter cohort of 1502 CTCL patients observed over a 30-year period (1980–2009) and classified per ISCL/EORTC criteria. The large size of the cohort and the long term follow-up allowed a better estimate of rates of progression (34%) and disease-specific mortality (26%). These rates suggest that, in the long term, the morbidity and mortality of MF/SS may be greater than expected. In particular, the rate of progression in patients with stage IA and IB at 20 years may be higher than previously recognized (18% and 47%, respectively). Furthermore, a significant difference in survival and progression was noted for patients with early-stage disease having patches alone (T1a/T2a) compared with those having patches and plaques (T1b/T2b). Multivariate analysis also showed that advanced skin (T) stage, presence of the tumor clone in the blood (B0b), increased LDH, and folliculotropic MF were independent predictors of survival and progression.

Long-term outcomes of 1263 patients with mycosis fungoides and Sézary syndrome from 1982 to 2009.

Talpur R, Singh L, Daulat S, Liu P, Seyfer S, Trynosky T, et al. Clin Cancer Res 2012; 18: 5051–60.

Another recent large outcome study based on a cohort of 1263 MF/SS patients at the MD Anderson Cancer Center between 1982 and 2009. The mean age at diagnosis (~55 years) and the fraction of patients with early stage (~71%) was almost identical to the study by Agar et al. Rates of disease progression for early stage patients (12%), and disease-specific mortality for the entire cohort (8.1%) were lower than those observed by Agar et al. The median overall survival was ~24 years and the median progression-free survival was 16 years. Risk factors associated with progression or deaths were advanced age, plaque stage, LDH, and tumor area.

Second lymphomas and other malignant neoplasms in patients with mycosis fungoides and Sézary syndrome: evidence from population-based and clinical cohorts.

Huang KP, Weinstock MA, Clarke CA, McMillan A, Hoppe RT, Kim YH. Arch Dermatol 2007; 143: 45–50.

Patients with MF/SS have an increased risk of second malignancies. This study analyzed Stanford (1973–2001) and SEER-9 registry data (1984–2001), for a cumulative population of >2200 patients and estimated relative risk for various malignancies, excluding non-melanoma skin cancers. A higher relative risk for all malignancies was observed in the SEER-9 but not the Stanford cohort. However, in both cohorts there was a very significant increase in the risk of Hodgkin lymphoma. The risk of non-Hodgkin lymphoma was increased in the SEER-9 cohort. The cumulative incidence of second malignancies in the Stanford cohort was estimated to be 10% at 8.6 years. Therefore, updated SEER (population based) and Stanford (clinic based) data confirm earlier findings of increased risk of lymphoma in patients with MF/SS.

Management strategies

Patients with MF should ideally be managed by a multidisciplinary team including a dermatologist, a medical oncologist, a pathologist familiar with skin lymphoma, and a radiation oncologist. The availability of nursing staff with expertise in dealing with skin malignancies is also desirable. This approach minimizes the risk of management errors and has been shown to increase patient satisfaction. An initial consultation at a comprehensive cancer center with an experienced cutaneous lymphoma team should be strongly considered. Finally, optimal patient support and education are paramount for an effective treatment strategy in MF, and all new patients should be encouraged to contact patient advocacy organizations that provide those resources.

The objectives of treatment depend on the stage of the patient at diagnosis. For patients presenting with early stage MF (IA–IIA), the goals are to control symptoms, to clear all visible disease in the skin, to slow or prevent progression, and to minimize distress, costs, and side effects. Avoidance of therapies with immune suppressive effects is a key objective. In a few patients, this can be achieved with minimal topical therapy. In most patients, however, this will require a coordinated effort and a sequence of skin-directed treatments to induce, and then maintain, a response. Finally, in some patients this objective will only be achieved with combinations of skin-directed and systemic therapies.

With the many modalities now available for skin-directed and systemic therapy, there is often more than one option for disease management, and the strategy chosen for each individual patient may depend on the availability and accessibility of specific treatments. The goal is to initiate a treatment plan that the patient can adhere to reliably. Whether cure is achievable in early stage MF remains to be determined as the duration of complete clinical clearance in the skin varies and long term follow-up is often lacking. While occasional patients do not have recurrence of the disease after 5-10 years, or longer, in most cases the disease recurs. The lesions may reappear in the skin as patches or plaques and are often responsive again to skin-directed treatments. Re-institution of treatments that were previously effective is a wise and effective approach in early stage MF and is currently recommended by the National Comprehensive Center Network (NCCN).

For patients with advanced stage MF (IIB–IVB) the goal of therapy is to induce remission, avoid any further reduction of immune competence, and prevent infections. Inability to realize these goals is likely to result in disease progression, severe morbidity, and death. In these patients, treatment decisions are complex, and effective options for therapy are limited. Patients with SS are particularly challenging, due to drug resistance, intractable pruritus, greater risk of infections, and difficulty with venous access.

A look at the National Comprehensive Cancer Network guidelines for cutaneous lymphomas.

Porcu P. Clin Lymph Myelom Leuk 2010; 10(Suppl 2): S109–11.

These two articles stress the importance of a multidisciplinary approach in the management of MF/SS and the general strategy of gradual escalation of systemic therapy, starting with biologics, and leaving cytotoxic drugs for later. In addition, the strategy of ‘looping back’ is integral to the NCCN guidelines. Disease relapse or progression in MF/SS does not necessarily imply advancement to a higher stage (i.e., from T1 to T2, or T3). Rather, patients who start with T1 disease and achieve remission may relapse back to T1 disease. In that case, resuming the treatment initially adopted may be more appropriate (loop back), rather than switching to more aggressive therapies.

Specific investigations

The diagnostic work-up and initial clinical assessment in patients with MF can be complex. In the US, the NCCN produces guidelines for the diagnosis and therapy of MF and SS. The NCCN guidelines represent the annually updated consensus view of a panel of experts that includes dermatologists, medical oncologists, radiation oncologists, and pathologists. The NCCN guidelines suggest a combination of essential and non-essential investigations, which the treating physician can select as clinically indicated:

Many of the clinical assessment tools and laboratory investigations were recently reviewed and integrated into new clinical end points and response criteria for MF, through a collaborative effort of the ISCL, EORTC, and the United States Cutaneous Lymphoma Consortium (USCLC).

Review of the treatment of mycosis fungoides and Sézary syndrome: a stage-based approach.

Horwitz SM, Olsen EA, Duvic M, Porcu P, Kim YH. J Natl Compr Cancer Netw 2008; 6: 436–42.

The NCCN is a non-profit alliance of 21 NCI-designated Comprehensive Cancer Centers in the US. The NCCN releases evidence-based clinical practice guidelines in oncology. The MF/SS guidelines were developed by a multidisciplinary panel, which included oncologists and dermatologists. The NCCN MF/SS guidelines are based on the principle of gradual, sequential escalation of therapy. For patients with early-stage disease (IA–IIA), initial treatment with skin-directed therapies is preferred, and many patients never require systemic therapy. For patients with refractory or advanced-stage disease (≥IIB), biologic therapies are often the first choice, whereas chemotherapy is reserved for later. Many therapies can be repeated several times, and maintenance and tapering strategies are encouraged.

First-line therapies

Early stage (IA–IIA)  
image Emollients E
image Topical corticosteroids B
image UVB or PUVA B
image Topical chemotherapy B
image Local radiotherapy B
image Topical bexarotene and other retinoids B

In stage I MF, response may occasionally be achieved with emollients, but often potent topical corticosteroids are necessary. Other skin-directed therapy may be as effective as monotherapy and each can be tried sequentially. These include topical chemotherapy, retinoids, or phototherapy. Phototherapy (UVB, UVA) or photochemotherapy (PUVA) is very effective. In poorly responsive disease, combination treatment with topical and phototherapy may yield greater response. As disease stage advances, treatment strategy should change to reflect the disease velocity and burden.

In stage II MF, achieving a complete clinical response is a higher priority based on reduced survival of patients in this group, thus combining a systemic therapy with skin directed therapy is necessary. Many patients will respond to combinations of topical treatment as before with NB-UVB or PUVA. The addition of a systemic agent is beneficial in regimens such as PUVA plus retinoids or PUVA plus interferon-α2a. Local radiotherapy is very effective at controlling persistent plaques or tumors, and total skin electron beam (TSEB) therapy is a good option when skin involvement is widespread and refractory to other approaches. Topical chemotherapy (nitrogen mustard) may still be effective.

Long-term follow-up of patients with early-stage cutaneous T-cell lymphoma who achieved complete remission with psoralen plus UV-A monotherapy.

Querfeld C, Rosen ST, Kuzel TM, Kirby KA, Roenigk Jr. HH, Prinz BM, Guitart J. Arch Dermatol 2005; 14: 305–11.

This is a single center analysis of 66 patients with early stage MF (IA–IIA) who achieved long-term complete remission with PUVA phototherapy between 1979 and 1995. Of these, 33 maintained CR for an average of 84 months, and 33 relapsed with a median disease-free interval of 39 months. The long-term survival rates at 5, 10, and 15 years were 94%, 82%, and 82%, respectively, in patients with stage IA, and 80%, 69%, and 58% in patients with stage IB/IIA. The major complication from PUVA was that 1/3 of the patients developed signs of chronic photodamage and secondary cutaneous malignancies.

Narrowband UVB and psoralen-UVA in the treatment of early-stage mycosis fungoides: a retrospective study.

Diederen PV, van Weelden H, Sanders CJ, Toonstra J, van Vloten WA. J Am Acad Dermatol 2003; 48: 215–19.

Retrospective study in 56 patients with early-stage MF (stage IA–IB) comparing NB-UVB and PUVA in regard to response, relapse-free interval, and irradiation dose. A total of 21 patients received NB-UVB and 35 received PUVA. NB-UVB led to complete remission in 17/21 patients (81%), partial remission in 4/21 (19%). None had progressive disease. PUVA led to complete remission in 25/35 patients (71%), partial remission in 10 of 35 (29%). None showed progressive disease. The mean relapse-free interval for patients treated with NB-UVB was 24.5 months (range, 2–66 months) and for PUVA was 22.8 months (range, 1–43 months). Thus NB-UVB therapy for early stage MF is an effective modality, which can be considered first. If there is progression or no response one can switch to PUVA therapy.

Monochromatic excimer light (308 nm) in patch-stage IA mycosis fungoides.

Mori M, Campolmi P, Mavilia L, Rossi R, Cappugi P, Pimpinelli N. J Am Acad Dermatol 2004; 50: 943–5.

A 308 nm monochromatic excimer in the narrowband wavelength has been shown to be effective for patch stage IA MF. The authors treated seven patch lesions in four patients with unequivocal clinicopathologic diagnosis of MF. All lesions achieved clinical and histologic complete remission. The number of weekly sessions varied from four to 11 (mean 6.5; median 5.5). The total UVB 308-nm irradiation dose ranged from 5 to 9.3 J/cm2 (mean 7.1 J/cm2; median 7 J/cm2). All lesions remained in stable complete remission after a follow-up of 3 to 28 months. No remarkable side effects were reported. Other preliminary results suggest that monochromatic excimer light phototherapy is a useful treatment modality in limited patch/plaque MF.

Treatment of patch and plaque stage mycosis fungoides with imiquimod 5% cream.

Deeths MJ, Chapman JT, Dellavalle RP, Zeng C, Aeling JL. J Am Acad Dermatol 2005; 52: 275–80.

This paper supports the concept that tumor immunity plays a role in management of MF and topical treatments to boost interferon may be an approach. This paper shows the safety and efficacy of topical imiquimod in patch and plaque stage MF in six patients, stage IA to IIB, treated with topical imiquimod 5% cream three times per week for 12 weeks. The authors biopsied pre- and post-treatment, and up to four additional treated lesions were monitored for 16 weeks. There was a 50% response with histologic clearance of disease in index lesions. Irritation at the application site was seen in patients responding to treatment, thus imiquimod may be valuable in patients who have refractory patch or plaque MF lesions.

Treatment of early-stage mycosis fungoides with twice-weekly applications of mechlorethamine and topical corticosteroids: a prospective study.

de Quatrebarbes J, Estève E, Bagot M, Bernard P, Beylot-Barry M, Delaunay M, et al. Arch Dermatol 2005; 141: 1117–20.

This article shows the efficacy of reduced frequency application of mechloretamine.

Advanced stage (IIB–IVB)  
image Oral bexarotene and other retinoids B
image Interferons B
image Denileukin diftitox B
image Extracorporeal photopheresis B
image Low-dose methotrexate B
image PUVA ± retinoids B
image PUVA ± interferons B

Due to the natural history of MF, with multiple relapses and gradual progression over many years, by the time patients have developed advanced stage (IIB–IVB) they are likely to have been exposed to combined skin-directed and systemic therapy, most frequently interferons and bexarotene. Thus, very few patients with advanced stage MF are systemic therapy naïve and the concept of ‘first-line’ versus ‘second-line’ choice may not easily apply. In most cases, progression is subtle and does not occur en bloc. Patients have a gradation of skin lesions, exhibiting differential response to the ongoing therapy. The initial management of advanced stage MF often focuses on strategies aimed at buttressing the existing treatment plan, rather than drastically changing direction. Skin-directed therapy is generally continued, because most patients have areas of persistent patch/plaque disease that need to be optimally controlled. Likewise, systemic drugs in use at the time of progression may be continued if there is evidence of residual activity and they are well tolerated.

Older front-line drugs (bexarotene, interferons), shown to be effective in advanced stage MF, are now being used in the treatment of earlier stages, in combination with skin-directed therapies, and newer drugs (vorinostat, romidepsin) are being introduced as primary choices in patients who progress from early to advanced stage, resistant disease. The drug denileukin diftitox is no longer available from the manufacturer in the US, although a new formulation may become available in the future.

Patients with SS may be stage III–IVB. For patients with low tumor burden extracorporeal photopheresis (ECP) can be effective, although durable complete responses are not common and its effect on survival is unclear. More frequently, patients with SS require combined modality therapy with bexarotene, interferons, and ECP. Chemotherapy should rarely be used in the management of SS.

In stage IV MF outcomes are generally poor, regardless of the treatment. Incomplete response and quick relapses following treatment are the rule. CHOP and similar chemotherapy regimens can be used for patients who need rapid debulking, followed by more effective long term strategies, such as allogeneic hematopoietic stem cell transplant. Local radiotherapy is useful for bulky nodal disease and symptomatic skin lesions. Effective palliation requires consideration of symptoms such as nausea, constipation, pain, anorexia, infections, pruritus, and depression.

Comparison of pegylated interferon α−2b plus psoralen PUVA versus standard interferon α−2a plus PUVA in patients with cutaneous T-cell lymphoma.

Hüsken AC, Tsianakas A, Hensen P, Nashan D, et al. J Eur Acad Dermatol Venereol 2012; 26: 71–8.

This small (17 patients) retrospective study attempted a comparison of the safety and efficacy pegylated IFN-α2b (1.5 µg/kg weekly) versus standard IFN-α2a (9 MIU three times a week) in combination with PUVA. Myelosuppression and liver toxicity were more frequent with pegylated IFN-α2b, whereas fatigue and other adverse events leading to discontinuation were more frequent with standard IFN-α2a. The response rate in the pegylated IFN-α2b plus PUVA group appeared to be higher. This is one of the few studies that reports outcomes with pegylated IFN-α2b in CTCL.

Predictors of response to extracorporeal photopheresis in advanced mycosis fungoides and Sézary syndrome.

McGirt LY, Thoburn C, Hess A, Vonderheid EC. Photodermatol Photoimmunol Photomed 2010; 26: 182–291.

The paper by Olsen et al. is the most exhaustive, evidence-based, summary of all the available treatment options for SS ever published. Extracorporeal photopheresis (ECP), a procedure that treats pheresed blood with a photoactive agent, was FDA approved in 1988 as a medical device for the treatment of CTCL. ECP is generally safe and well tolerated and should be considered for all patients with SS. Treatment is delivered every 2 to 4 weeks, with responses typically seen at 3 to 6 months. Oral bexarotene and interferons should be combined with ECP in all but cases where the peripheral blood burden of Sézary cells is minimal. The paper by Raphael et al. reports the outcomes of therapy in 98 patients with SS according to ISCL/EORTC criteria over a 25-year period. Patients were treated with at least 3 months of extracorporeal photopheresis and one or more systemic agents. A total of 73 patients had significant improvement with multimodality therapy: 30% had complete response, with clearing of all disease. Lower CD4/CD8 ratio, median percentage of CD4+/CD26− and CD4+/CD7− cells at baseline predicted for complete response. The article by Zic reviews the evidence for the use of ECP in CTCL and the evolution of the ECP technique, which is now available with continuous flow technology.

Second-line therapies

Early stage (IA–IIA)
image Retinoids plus PUVA B
image Interferons B
image Total skin electron beam radiotherapy B
image Oral bexarotene B
image Low-dose methotrexate B
Advanced stage (IIB–IVB)
image Total skin electron beam radiotherapy B
image Vorinostat B
image Depsipeptide B
image Alemtuzumab B
image Liposomal doxorubicin B
image Gemcitabine B
image Pralatrexate B
image Purine analogs B

image

Phase II multi-institutional trial of the histone deacetylase inhibitor romidepsin as monotherapy for patients with CTCL.

Piekarz RL, Frye R, Turner M, Wright JJ, Allen SL, Kirschbaum MH, et al. J Clin Oncol 2009; 27: 5410–17.

Vorinostat and romidepsin are two recently approved histone deacetylase inhibitors (HDACi), a promising class of new cancer drugs. Vorinostat, an oral agent, was approved in the US in 2006 and romidepsin, an intraveneous agent, was approved in 2009 for the treatment of relapsed/refractory CTCL. These agents modulate chromatin condensation and were developed with the goal of correcting abnormal gene expression in cancer cells. They affect multiple cell functions, including proliferation, apoptosis, and angiogenesis. A subset of T-cell lymphomas, including MF and SS, appear to be particularly sensitive to HDACi. While not as myelosuppressive as conventional chemotherapy, HDACi may have some immune suppressive effects. The pivotal study supporting approval of vorinostat (Olsen et al.) was an open-label phase II trial that enrolled 74 patients with stage >IB CTCL who had failed two systemic therapies (one of which must have been bexarotene). Patients received vorinostat 400 mg daily, with dose reductions for toxicity. The response rate, assessed by the Severity-Weighted Assessment Tool (SWAT), was 30%, and the median response duration was ~6 months. In a second study (Duvic et al.) a similar population of CTCL patients received vorinostat at various dosing schedules. For the 13 patients who received a dose of 400 mg/day the response rate was 31%. In both studies the most common toxicities were diarrhea, fatigue, nausea, anorexia, thrombocytopenia, hyperglycemia, and proteinuria. Romidepsin was approved based on two phase II trials (Whittaker et al., Piekartz et al.) that enrolled a total of 167 patients with relapsed or refractory CTCL. Romidepsin was administered as a 4-hour intravenous infusion at 14 mg/m2 on days 1, 8, and 15 of a 28-day cycle. The average number of cycles received by the patients was four, and the median number of doses was 12. In both trials, the overall response rate was 34%, the complete response rate was 6%, and the median duration of response was >12 months. One of the studies (Whittaker et al.) included pruritus assessment, with 43% of the patients experiencing ‘clinically significant’ improvement. The most common adverse effects were fatigue, nausea, vomiting, anorexia, and thrombocytopenia. Although EKG changes were common, no serious cardiac events were observed.

Low-dose intermittent alemtuzumab in the treatment of Sézary syndrome: clinical and immunologic findings in 14 patients.

Bernengo MG, Quaglino P, Comessatti A, Ortoncelli M, Novelli M, Lisa F, et al. Haematologica 2007; 92: 784–94.

Alemtuzumab (campath-1H) is a humanized monoclonal antibody that targets CD52, a molecule expressed on almost all leukocytes. The drug is approved in the US for the treatment of refractory chronic lymphocytic leukemia (CLL), but it appears to have activity also in T-cell lymphoma and leukemia. Alemtuzumab is considered standard front-line therapy for T-cell prolymphocytic leukemia (T-PLL), and is often successfully used in SS. The phase II study by Querfeld et al. specifically investigated the activity of alemtuzumab in patients with erythrodermic CTCL (including SS). Ten patients received alemtuzumab intravenously using an escalating dose regimen with a final dose of 30 mg three times weekly for 4 weeks followed by subcutaneous administration for 8 weeks. Nine patients were treated with only the SC or IV dosing. The overall response rate was 84%, with nine (47%) complete and seven (37%) partial remissions. The median follow-up was 24 months. Median survival was 41 months whereas median PFS was 6 months. Toxicities included myelosuppression and infections, but most were moderate and transient. Bernengo et al. studied a lower dose, intermittent schedule with the goal of avoiding excessive toxicity. The drug, given subcutaneously, was held once circulating Sézary cells fell below a certain threshold and resumed when the Sézary cell count increased. This approach appears to be safer, but it needs to be compared with the conventional schedule for efficacy.

Third-line therapies

image Clinical trials  
image Topical bexarotene gel and other retinoids B
image Single-agent chemotherapy B
image Combination chemotherapy B
image Allogeneic bone marrow transplantation B
image Liposomal doxorubicin B
image Gemcitabine B
image Pralatrexate C
image Purine analogs B

Total skin electron beam and non-myeloablative allogeneic hematopoietic stem-cell transplantation in advanced mycosis fungoides and Sézary syndrome.

Duvic M, Donato M, Dabaja B, Richmond H, Singh L, Wei W, et al. J Clin Oncol 2010; 28: 2365–72.

Allogeneic hematopoietic stem cell transplantation (HSCT) is an aggressive treatment modality that leverages the anti-tumor immune effect of the allograft, or ‘graft versus lymphoma’ (GVL) effect. The efficacy of GVL has been validated, and patients with advanced stage, refractory CTCL are alive today because of it. However, even with a highly compatible donor, allogeneic HSCT is associated with a very significant mortality (up to 30%). Therefore, selecting the best time window, remission-inducing therapy, and conditioning regimen for patients with refractory CTCL is a very difficult task. Since refractory CTCL is often insensitive to chemotherapy, radiation has been considered an alternative way for disease control before transplantation. Duvic et al. studied the use of TSEBR in the preparatory regimen for allogeneic HSCT. Nineteen patients with heavily pretreated, advanced CTCL, median age 50 years, received TSEBR followed by fludarabine, melphalan and allogeneic HSCT (2001–2008). GVHD prophylaxis was with tacrolimus and methotrexate. Fifteen patients achieved full donor chimerism. Twelve had acute GVHD, and 12 chronic GVHD. Four patients died in remission from complications and two died from progressive disease. Five of eight patients who relapsed regained complete response with reduced immunosuppression or donor lymphocyte infusions. Eleven patients were in complete remission, with median follow-up of 19 months.

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