Follow-up of patients with mycosis fungoides after interferon α2b treatment failure.

INTRODUCTION: Treatment of T cell cutaneous lymphoma( CTCL) is a controversial subject and the effectiveness of treatment is still low. AIM: Report of single center experience of management CTCL after progression after first line treatment.
MATERIAL AND METHODS: We present 41 patients with CTCL, 29 received interferon α2b in first line, and 12 of them received second line therapy.
RESULTS: Overall response rate for second line therapy was 60%.
CONCLUSIONS: Results of the follow-up of patients with mycosis fungoides after interferon α2b treatment failure with the literature review and discussion.

Introduction

Treatment of T-cell lymphomas is a controversial subject as there is no established effective treatment and the results of the standard CHOP (cycloposphamide, oncovin, doxorubicin, prednisone)-like chemotherapy are unsatisfactory, especially with regard to the progress that has been made in the treatment of B-cell lymphomas in recent years since the introduction of rituximab [1].

There is no consensus either regarding standard therapy for primary cutaneous T-cell lymphomas. It is a group of rare conditions with a small number of reports on the methods of treatment, especially after the failure of local therapy. Knowledge of this topic is limited due to the lack of major studies on this issue.

Until recently, the number of drugs dedicated to the treatment of these disorders was very limited and irrespective of the treatment line consisted of the same options. Treatment of mycosis fungoides (MF) consisted primarily of psoralen phototherapy (PUVA)-therapy [2, 3], total skin electron beam radiation therapy for stages I–III [4-6] and extracorporeal photopheresis when Sezary's syndrome (SS) developed [7, 8].

Interferon α2b is still a well-established first-line systemic treatment option [9-11]. Subsequent treatment lines include bexarotene [12-15], cytotoxic agents such as low dose methotrexate [9, 16, 17], liposomal doxorubicin or gemcitabine [18, 19]. Multidrug regimens are not recommended due to the increased risk of infectious events in this group of patients with extensive skin barrier damage.

It is worth mentioning that most recommendations are based on experts’ opinions and consensus rather than data from clinical trials [20-22]. ESMO guidelines for primary cutaneous lymphomas recommend PUVA-therapy combined with interferon or bexarotene in patients who failed to respond to local therapy modalities. In cases of further disease progression, usage of gemcitabine, liposomal doxorubicin or histone deacetylase inhibitors (HDAC) inhibitors is suggested [20, 23]. For young patients, allogeneic hematopoietic stem cell transplantation is an option; there is no standard method of conditioning the regimen that should be applied. For SS, extracorporeal photopheresis is recommended with the expected rate of partial responses of 30–80% and 14–25% of complete remissions. Similar recommendations were published by the Polish Lymphoma Research Group [20, 23].

Recently a number of novel agents have been developed. Histone deacetylase inhibitors are potent drugs both in MF and SS. There are currently four drugs in this group – vorinostat, romidepsin [24, 25], panobinostat [26] and belinostat [27-29]. Vorinostat (Zolinza) and romidepsin (Istodax) were first to be registered by the Food and Drug Administration (FDA) in the treatment of the refractory and recurrent form of MF/SS [24]. Other drugs are currently subject of research in numerous conditions other than T-cell lymphomas, like Hodgkin's lymphoma or multiple myeloma. The European Medicines Agency (EMA) has not yet registered any of those agents.

The investigated agents include zanolimumab (HuMax-CD4), a fully humanized anti-CD4 antibody. Zanolimumab produces an objective response rate as high as 50% and the risk of secondary infections, including cytomegalovirus reactivation, is lower than in the case of alemtuzumab [30].

Another novel drug is pralatrexate – antifolate, methotrexate analog, that interferes with dihydrofolate reductase and subsequently leads to cell death. Based on the results of the PROPEL study, it was approved by the FDA in 2009 for patients with relapsed or refractory PTCL. Pralatrexate has not been approved by the EMA [31, 32].

Ongoing clinical trials investigate other novel agents – retinoids like tazarotene, antiangiogenic drugs – lenalidomide (Revlimid) [33], selective immunosuppressive agent for T-cells–Forodesine (BCX-1777) [34], synthetic oligonucleotides and toll-like receptor antagonists [35].

Known agents like temozolomide, oral derivative of dacarbazine, are also being investigated – in the phase II trial conducted on 26 patients, overall response rate (ORR) was 27% with overall survival 24 months [36, 37]. Another novel agent is C-Beta kinase inhibitor – enzastaurin; 25 patients were recruited in the clinical trial and benefited from treatment mainly in the form of relief of itching; progression-free survival was 78 days [38].

The object of the studies is also immunotoxins – denileukin diffitox, diphtheria toxin and interleukin-2 conjugate, already approved by the FDA [39]. In the phase III placebo-controlled trial on 144 patients, ORR was 44%, including 10% of complete remissions and 34% of partial remissions. The effect was dose-dependent – the group who received a dose of 18 mg/kg/day had ORR of 49% compared to 34% ORR in a group who received 9 mg/kg/day. Progression-free survival was significant – more than 2 years.

There are also attempts to combine novel drugs like denileukin diffitox with bexarotene or HDACs, which in theory should result in an increased number of receptors for interleukin-2 [40].

All those reports give reasons to hope that therapeutic options for this group of patients will expand, which is of up most importance given the chronic course of disease severely impairing quality of life.

Aim

The aim of this paper is to report a single-center experience of patient management after disease progression after the first line treatment with interferon α2b.

Material and methods

Forty-one patients with mycosis fungoides treated in the Oncology Center in Bydgoszcz of whom 29 received interferon α2b as the first line of treatment. The stages of disease ranged from IB to III. Their median age was 51 (range: 37–75 years).

In 12 cases, the disease subsequently progressed after median time of 38 months. In this cohort, 1 to 5 subsequent lines of systemic therapy was introduced.

The 2nd line treatment included chemotherapy alone (gemcitabine, n = 1 patient) or with concurrent use of interferon (either methotrexate or doxorubicin, n = 7 patients), bexarotene (n = 2 patients), pralatrexate (n = 1 patient) or corticosteroid therapy (n = 1 patient). The 3rd line of treatment included histone deacetylase inhibitors – romidepsin, vorinostat (n = 2 patients), doxorubicin (n = 1 patient) and gemcitabine (n = 3 patients). The fourth (n = 4 patients) and fifth (n = 3 patients) line consisted of the same drugs as in the 2nd and 3rd line. One patient received allogeneic hematopoietic cell transplantation (HCT), as a 4th line, from a matched related donor after radiation-based conditioning regimen – total body and total skin irradiation.

To sum up, methotrexate was chosen as a treatment option 5 times, liposomal doxorubicin – 6, gemcitabine – 5, bexarotene – 2, and other drugs were used in individual patients.

Because of the existing differences concerning approved indications and complex reimbursement policies we decided to present a method of obtaining used agents in the form of a Table 1.

Table 1

Source of the drug access

Drug name	Method of obtaining
Methotrexate	Reimbursement
Liposomal/pegylated doxorubicin	Drug not reimbursedRequest to the national health provider
Gemcitabine	Drug not reimbursedRequest to the national health provider
Bexarotene	Drug not reimbursedRequest to the national health provider
Prednisone	Reimbursement
Pralatrexate	Clinical trial
HDACs:
Romidepsin	Donation
Vorinostat	Import

Results

Second-line treatment results – progression-free survival was 5.37 months. The objective response rate was 67% (complete remission (CR) = 0; partial remission (PR) = 8; stabilisation disease (SD) = 3; progression disease (PD) = 1). Third-line treatment results – progression free survival (PFS) was 6.06 months, ORR = 50% (CR = 0, PR = 4, SD = 2).

Forth-line treatment results (excluding the patient treated with alloHCT) – PFS = 3.6 months. The probability of the overall survival (OS) at 5 years was 64%. Tables 2 and 3 present detailed treatment information.

Table 2

Detailed treatment plan in particular patients

Age [years]	Stage	1st line treatment duration [months]	Best response	2nd line	Response to 2nd line	3rd line	Response to 3rd line
65	III	38	PR	Bexarotene	SD	Gemcitabine	SD
55	III	3	SD	INF + MTX	SD	Vorinostat	SD
37	III	16	PR	INF + MTX	SD	DOX	PR
48	III	22	PR	Gemcitabine	PR	Romidepsin	PR
65	III	25	CR	Pralatrexate	PR
53	III	17	PR	INF + MTX	PR
49	III	40	PR	INF + PRED	PR
62	III	18	SD	INF + DOX	PR
45	III	6	SD	INF + MTX	PR
75	III	5	SD	INF + MTX	PD
49	III	10	PR	INF + DOX	PR	INF + GEM	PR
47	III	48	PR	Bexarotene	PR	INF + GEM	PR

Table 3

Detailed treatment plan in particular patients

Age [years]	Stage	1st line treatment duration [months]	Best response	4th line	Response to 4th line	5th line	Response to 5th line
65	III	38	PR	DOX	SD	MTX	SD
55	III	3	SD	GEM + INF	SD	DOX	SD
37	III	16	PR	alloHCT + TBI + TSI	CR
48	III	22	PR
65	III	25	CR
53	III	17	PR	RTH	PD	DOX	SD
49	III	40	PR
62	III	18	SD
45	III	6	SD
75	III	5	SD
49	III	10	PR
47	III	48	PR

The best treatment result was obtained in the patient in whom allogeneic hematopoietic stem cell transplantation was performed – the patient received complete and long-lasting remission – a result not possible to be achieved by chemotherapy. Combined usage of liposomal doxorubicin and interferon prior to the alloHCT procedure resulted in regression of skin lesions and served as induction phase treatment. One of the patients treated with romidepsin was also qualified to the alloHCT procedure, but treatment had to be canceled due to active HBV infection. Both mentioned patients are young people with no other severe comorbidities.

Analyzing the rest of patients, it should be noted that the longest clinical benefit period was observed in 2 patients treated with bexarotene in the second-line treatment (12 and 9 months, respectively).

Each subsequent line of treatment was associated with lower efficacy. Incorporating novel agents into clinical practice was associated with a clear improvement in the efficiency and thus better prognosis.

Discussion

Primary cutaneous T-cell lymphomas are still an unresolved clinical problem. It is a group of chronic diseases severely impairing quality of life, even in the early stages of the disease. It is therefore always symptomatic disease that requires treatment.

There are numerous novel treatment options and even though they are not completely effective, they mark the progress that has been made in caring for that group of patients. Those novel modalities include both systemic agents as well as new radiotherapy techniques.

Clinical and cost-effectiveness analyses of every new modality should take into account that it is a rare disease affecting patients in their productive age and otherwise able to work. Unfortunately, most of publications lack that kind of economic analysis.

In Poland, drugs other than methotrexate that are recommended by the Polish Lymphoma Research Group in second-line treatment are not reimbursed; they can only be used after obtaining special consent of the national health provider [23]. The procedure of requesting for individual reimbursement will no longer be continued and access to drugs like gemcitabine, liposomal doxorubicin or bexarotene will not be possible [41].

Interferon is a valuable treatment option, but the disease inevitably progresses [9–11, 42]. Allogeneic hematopoietic stem cell transplantation is a promising therapeutic modality, but is dedicated to a limited group of young and otherwise healthy patients [43, 44].

Presented results show that good clinical effects can be achieved when relatively aggressive treatment is applied, like alloHCT. Currently there is an ongoing trial by Polish Lymphoma Research Group (PLRG) regarding the value of alloHCT preceded by radiation-based conditioning inpatients whose disease progressed after one systemic treatment line.

Extracorporeal photopheresis is not available in Poland [7, 45, 46]. Access to radiotherapy, both total skin electron beam therapy (TSEB) and helical to motherapy, is limited. It is therefore critical to have access to at least one systemic agent that could be used after interferon treatment failure [47, 48].

Conclusions

Presented results and cited literature indicate that the use of several lines of treatment results in improved quality of life and disease regression that can last for many months. It should be noted that in most cases, initiation of the next line of treatment after failure of the previous one was usually delayed by formal proceedings required to obtain the drug. By the time of approval of novel agents like romidepsin or pralatrexate by the European Medicines Agency (EMA), usage of liposomal doxorubicin or gemcitabine in combination with interferon seems to be a reasonable treatment option especially for patients not eligible for the allotransplantation procedure. Proposed treatment is recommended by PLRG and should be reimbursed by the national health provider.