Does preemptive leucovorin use compromise the efficacy of pralatrexate in CTCL?
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P7010 Does preemptive leucovorin use compromise the efficacy of pralatrexate in CTCL? Sara Story, MD, University of Pittsburgh Medical Center, Pittsburgh, PA, United States; Larisa Geskin, MD, University of Pittsburgh Medical Center, Pittsburgh, PA, United States Pralatrexate (PDX) is a novel FDA-approved antifolate for the treatment of relapsed/refractory peripheral T-cell lymphoma (PTCL) and transformed mycosis fungoides (T-MF). During the pivotal phase II clinical trial (‘‘PROPEL’’), patients received 30 mg/m 2 weekly infusions for 6 out of 7 weeks (1 cycle) with an overall response rate of 29%. Symptomatic mucositis was the most common treatment- related adverse event (AE) affecting more than 70% of the patients, in 22% it was the dose limiting toxicity. PDX was designed to have a higher affinity for the reduced folate carrier (RFC) and the folylpolyglutamate synthetase enzyme (FPGS) and, therefore, more selective accumulation in cells than other antifolate agents includ- ing methotrexate (MTX). In some cell cultures (but not all) PDX was found to be up to 100 times more potent in terms of cell killing. Because of this increased uptake and prolonged intracellular activity, 30 mg/m 2 of PDX may be akin to ;300 mg/m 2 or more of MTX at the cellular level. At high doses of MTX, leucovorin (LV) rescue is the standard of care and prevents side effects while preserving efficacy. In PDX therapy, however, LVis recommended only for overdose and has not been studied for use preemptively to alleviate AEs. In our clinical experience the vast majority of cutaneous T-cell lymphoma (CTCL) patients on PDX develop significant mucositis which often leads to dose reduction or discontinuation of treatment. The mecha- nism of action of LV bypasses the antifolate blocked dihydrofolate reductase enzyme (DHFR) as it is not dependent on the DHFR to participate in ‘‘one carbon’’ reactions for DNA synthesis. As a whole, studies of other antifolates in combination with LV have had mixed results in determining any compromise in efficacy due to LV use. Efficacy of PDX after LV administration may be related to several factors including timing of a subsequent PDX infusion, route of administration, dosage, and form of LV given. All of these effect the intracellular accumulation of LV and therefore the effect it can have on the efficacy of PDX. We report the use of LV in 3 CTCL patients treated with PDX without compromise of efficacy while essentially eliminating mucositis and other AEs. Though our clinical experience is not sufficient to generalize overall efficacy of the PDX-LV combination it is enough to recommend further randomized clinical trials to evaluate this combination in CTCL as well as other malignancies. Commercial support: None identified. P6489 Elucidating the molecular pathogenesis of cutaneous T-cell lymphoma Ivan Litvinov, MD, PhD, McGill University Health Center, Montreal, Quebec, Canada; Denis Sasseville, MD, McGill University Health Center, Montreal, Quebec, Canada; Thomas Kupper, MD, Harvard University, Boston, MA, United States; Youwen Zhou, MD, PhD, University of British Columbia, Vancouver, British Columbia, Canada Cutaneous T-cell lymphoma (CTCL) is the most common lymphoma of the skin. Unfortunately, the molecular pathogenesis of this disease remains poorly under- stood. While the disease is indolent in the majority of patients, in 10% to 20% of cases it progresses towards advanced stages, where it exhibits high morbidity and mortality. Current, cutting edge clinical tests are not able to identify stage I patients, who are at risk of progression. Previously, we performed a microarray and RT-PCR analyses of lesional skin from a cohort of CTCL patients in order to identify novel molecular prognostic markers. In the current work, we test the expression of number of putative tumor suppressor genes in 42 early stage CTCL, 21 benign inflammatory dermatoses and 6 normal skin samples by RT-PCR and correlate our findings with 6 years of clinical follow up in CTCL patients. These findings reveal that BCL7A (B-cell CLL/lymphoma 7A) , DLEU1 (deleted in lymphocytic leukemia 1) and CDKN1C (cyclin-dependent kinase inhibitor 1C) are expressed in all inflam- matory dermatoses and normal skin samples, but such expression is often lost in CTCL. The observed loss of expression of the above genes correlates with an aggressive disease course in stage I CTCL patients based on KaplaneMeier disease progression analysis. Our findings combined with previous reports provide clinical confirmation for the importance of the above described putative tumor suppressor genes in CTCL and suggest that their loss or downregulation is an early event that may be associated with poor disease outcome. Commercial support: None identified. P6621 Epidemiologic and clinical features of cutaneous T-cell lymphoma in a Mediterranean population Deysy Elizabeth Cieza-D ıaz, MD, Hospital General Universitario Gregorio Mara~ n on, Madrid, Spain; Carmen Ceballos-Rodr ıguez, MD, Hospital General Universitario Gregorio Mara~ n on, Madrid, Spain; Isabel Longo-Imedio, MD, PhD, Hospital General Universitario Gregorio Mara~ n on, Madrid, Spain; Javier Men arguez-Palanca, MD, PhD, Hospital General Universitario Gregorio Mara~ n on, Madrid, Spain; Ricardo Su arez-Fern andez, MD, PhD, Hospital General Universitario Gregorio Mara~ n on, Madrid, Spain; Ver onica Parra-Blanco, MD, Hospital General Universitario Gregorio Mara~ n on, Madrid, Spain Background: Primary cutaneous lymphomas represent the second most common group of extranodal non-Hodgkin lymphomas and cutaneous T-cell lymphomas comprise 70% to 80% of them. The frequency of each type differs depending on the geographic area, race and sex. Objective: To characterize the epidemiologic and clinical features of adult patients diagnosed of cutaneous T-cell lymphomas between January 2000 and June 2010 from a reference population of approximately 700,000 inhabitants. Methods: We carried out a retrospective study based on the pathology reports of cutaneous T-cell lymphoma in a target area served by one community hospital, one University Hospital and over 10 dermatology outpatient clinics of the public health care system. All the clinical charts were reviewed and the lymphomas were classified according to the joint WHO-EORTC classification. Results: A total of 53 patients were diagnosed of cutaneous T-cell lymphoma, 54.7% were diagnosed between 2002 and 2005, yielding an incidence rate at least twice higher (2/100,000 inhabitants) than most reported series except in Arab popula- tions. The most common subtype was mycosis fungoides and its variants that represented 68% of the total and 5% belonged to provisional entities. The median age at the time of diagnosis was 51.6 years for the whole group of cutaneous T-cell lymphomas and 49.2 years for mycosis fungoides, which is significantly younger than the reported age in most series (over 57 years) except in Arab populations ( \50 years). Mycosis fungoides was slightly more frequent in males (5:4) in contrast with the male predominance reported in most series (2:1) except in some studies from Arab populations. The percentage of patients diagnosed in early stages (IA-IIA) is close to 95% which might be explained by the absence of referral bias but is also similar to the proportion described in Arab populations compared to the majority of reports. The definitive diagnosis required an average of two biopsies and 71.7% and 43.4% of the patients had another previous clinical and histologic diagnosis, respectively. Conclusion: The incidence rate, sex distribution, age, and stage at diagnosis of mycosis fungoides is more similar to that observed in Arab populations compared to other Mediterranean populations. We speculate that the strong Arab ancestry in Spain might partially explain our findings. Commercial support: None identified. P6970 EpsteineBarr virus-associated hydroa vacciniformeelike cutaneous lym- phoma and NK/T-cell lymphoma Julio Cesar Jasso Olivares, MD, Instituto Nacional de Ciencias Medicas y Nutricion Salvador Zubiran, Mexico City, Mexico; Judith Dominguez-Cherit, MD, Instituto Nacional de Ciencias Medicas y Nutricion Salvador Zubiran, Mexico City, Mexico; Linda Garcia Hidalgo, MD, Instituto Nacional de Ciencias Medicas y Nutricion Salvador Zubiran, Mexico City, Mexico Background: Hydroa vacciniforme (HV) is a rare, chronic skin disease. It occurs mainly in young children and presents itself with papulovesicles on the sun exposed- areas. Skin vesicles often heal with a small pox-like scar, generally, HV tends to regress spontaneously at the end of the puberty. Recently, a group of patients with severe HV-like eruptions and systemic symptoms, hepatosplenomegaly and lymphoproliferative disorders like NK/T lymphomas have been reported in Asia and South America. Although no causative factor have been found, nowadays, those diseases are associated with latent EpsteineBarr virus (EBV) infection, from evidence that the cutaneous lesions contains EBV DNA sequences and a consider- able number of infiltrating T cells with EBV-encoded small nuclear RNA (EBER). Case report:We report a case of a 32-year-old woman who was brought to our hospital because of a recurrent left facial edema, erythem, pox-like scars and a papulovesicular disorder of 4 years’ duration (Fig 1). She also had fever, nasal obstruction, cervical adenopathies and lose weight. One punch biopsy was performed and blood cell count, LDH, liver and renal test with normal value result. A CT scan report cervical adenopathies, turbinate involve and splenomegaly. Hystopathologic skin biopsy and inmunohistochemical reported: extranodal NK/T lymphoma, nasal type CD 56 + , EBER + , TIA + . Chemotherapy with methotrexate and L-asparginase was initiated with improvement of skin changes. Conclusions: Actually lymphoproliferative disorders associated with EBV infection comprise hydroa vacciniformeelike cutaneous lymphoma, including NK/T lym- phoma, aggressive neoplasia with a poor prognostic because of a high rate of resistance to conventional chemotherapy. It is unknown how can latent infection causes a proliferating lymphoma, nevertheless, it has been proven, that individual with genetic chromosomal abnormalities in the 6q region decrease immune tolerance and increase cellular proliferation. Treatments with L-asparginase have demonstrated to extend overall survival in patients with NK/T lymphoma. Commercial support: None identified. APRIL 2013 JAM ACAD DERMATOL AB145
Transcript of Does preemptive leucovorin use compromise the efficacy of pralatrexate in CTCL?
P7010Does preemptive leucovorin use compromise the efficacy of pralatrexatein CTCL?
Sara Story, MD, University of Pittsburgh Medical Center, Pittsburgh, PA, UnitedStates; Larisa Geskin, MD, University of Pittsburgh Medical Center, Pittsburgh,PA, United States
Pralatrexate (PDX) is a novel FDA-approved antifolate for the treatment ofrelapsed/refractory peripheral T-cell lymphoma (PTCL) and transformed mycosisfungoides (T-MF). During the pivotal phase II clinical trial (‘‘PROPEL’’), patientsreceived 30 mg/m2 weekly infusions for 6 out of 7 weeks (1 cycle) with an overallresponse rate of 29%. Symptomatic mucositis was the most common treatment-related adverse event (AE) affecting more than 70% of the patients, in 22% it was thedose limiting toxicity. PDX was designed to have a higher affinity for the reducedfolate carrier (RFC) and the folylpolyglutamate synthetase enzyme (FPGS) and,therefore, more selective accumulation in cells than other antifolate agents includ-ing methotrexate (MTX). In some cell cultures (but not all) PDX was found to be upto 100 times more potent in terms of cell killing. Because of this increased uptakeand prolonged intracellular activity, 30 mg/m2 of PDX may be akin to ;300 mg/m2
or more of MTX at the cellular level. At high doses of MTX, leucovorin (LV) rescue isthe standard of care and prevents side effects while preserving efficacy. In PDXtherapy, however, LV is recommended only for overdose and has not been studiedfor use preemptively to alleviate AEs. In our clinical experience the vast majority ofcutaneous T-cell lymphoma (CTCL) patients on PDX develop significant mucositiswhich often leads to dose reduction or discontinuation of treatment. The mecha-nism of action of LV bypasses the antifolate blocked dihydrofolate reductase enzyme(DHFR) as it is not dependent on the DHFR to participate in ‘‘one carbon’’ reactionsfor DNA synthesis. As a whole, studies of other antifolates in combination with LVhave had mixed results in determining any compromise in efficacy due to LV use.Efficacy of PDX after LV administration may be related to several factors includingtiming of a subsequent PDX infusion, route of administration, dosage, and form of LVgiven. All of these effect the intracellular accumulation of LVand therefore the effectit can have on the efficacy of PDX.We report the use of LV in 3 CTCL patients treatedwith PDX without compromise of efficacy while essentially eliminating mucositisand other AEs. Though our clinical experience is not sufficient to generalize overallefficacy of the PDX-LV combination it is enough to recommend further randomizedclinical trials to evaluate this combination in CTCL as well as other malignancies.
APRIL 20
cial support: None identified.
CommerP6489Elucidating the molecular pathogenesis of cutaneous T-cell lymphoma
Ivan Litvinov, MD, PhD, McGill University Health Center, Montreal, Quebec,Canada; Denis Sasseville, MD, McGill University Health Center, Montreal,Quebec, Canada; Thomas Kupper, MD, Harvard University, Boston, MA, UnitedStates; Youwen Zhou, MD, PhD, University of British Columbia, Vancouver,British Columbia, Canada
Cutaneous T-cell lymphoma (CTCL) is the most common lymphoma of the skin.Unfortunately, the molecular pathogenesis of this disease remains poorly under-stood.While the disease is indolent in themajority of patients, in 10% to 20% of casesit progresses towards advanced stages, where it exhibits high morbidity andmortality. Current, cutting edge clinical tests are not able to identify stage I patients,who are at risk of progression. Previously, we performed a microarray and RT-PCRanalyses of lesional skin from a cohort of CTCL patients in order to identify novelmolecular prognostic markers. In the current work, we test the expression ofnumber of putative tumor suppressor genes in 42 early stage CTCL, 21 benigninflammatory dermatoses and 6 normal skin samples by RT-PCR and correlate ourfindings with 6 years of clinical follow up in CTCL patients. These findings revealthat BCL7A (B-cell CLL/lymphoma 7A) , DLEU1 (deleted in lymphocytic leukemia 1)and CDKN1C (cyclin-dependent kinase inhibitor 1C) are expressed in all inflam-matory dermatoses and normal skin samples, but such expression is often lost inCTCL. The observed loss of expression of the above genes correlates with anaggressive disease course in stage I CTCL patients based on KaplaneMeier diseaseprogression analysis. Our findings combined with previous reports provide clinicalconfirmation for the importance of the above described putative tumor suppressorgenes in CTCL and suggest that their loss or downregulation is an early event thatmay be associated with poor disease outcome.
cial support: None identified.
Commer13
P6621Epidemiologic and clinical features of cutaneous T-cell lymphoma in aMediterranean population
Deysy Elizabeth Cieza-D�ıaz, MD, Hospital General Universitario GregorioMara~n�on, Madrid, Spain; Carmen Ceballos-Rodr�ıguez, MD, Hospital GeneralUniversitario Gregorio Mara~n�on, Madrid, Spain; Isabel Longo-Imedio, MD, PhD,Hospital General Universitario Gregorio Mara~n�on, Madrid, Spain; JavierMen�arguez-Palanca, MD, PhD, Hospital General Universitario GregorioMara~n�on, Madrid, Spain; Ricardo Su�arez-Fern�andez, MD, PhD, Hospital GeneralUniversitario Gregorio Mara~n�on, Madrid, Spain; Ver�onica Parra-Blanco, MD,Hospital General Universitario Gregorio Mara~n�on, Madrid, Spain
Background: Primary cutaneous lymphomas represent the second most commongroup of extranodal non-Hodgkin lymphomas and cutaneous T-cell lymphomascomprise 70% to 80% of them. The frequency of each type differs depending on thegeographic area, race and sex.
Objective: To characterize the epidemiologic and clinical features of adult patientsdiagnosed of cutaneous T-cell lymphomas between January 2000 and June 2010from a reference population of approximately 700,000 inhabitants.
Methods: We carried out a retrospective study based on the pathology reports ofcutaneous T-cell lymphoma in a target area served by one community hospital, oneUniversity Hospital and over 10 dermatology outpatient clinics of the public healthcare system. All the clinical chartswere reviewed and the lymphomaswere classifiedaccording to the joint WHO-EORTC classification.
Results: A total of 53 patients were diagnosed of cutaneous T-cell lymphoma, 54.7%were diagnosed between 2002 and 2005, yielding an incidence rate at least twicehigher (2/100,000 inhabitants) than most reported series except in Arab popula-tions. The most common subtype was mycosis fungoides and its variants thatrepresented 68% of the total and 5% belonged to provisional entities. The medianage at the time of diagnosis was 51.6 years for the whole group of cutaneous T-celllymphomas and 49.2 years for mycosis fungoides, which is significantly youngerthan the reported age inmost series (over 57 years) except in Arab populations (\50years). Mycosis fungoides was slightly more frequent in males (5:4) in contrast withthe male predominance reported in most series (2:1) except in some studies fromArab populations. The percentage of patients diagnosed in early stages (IA-IIA) isclose to 95% which might be explained by the absence of referral bias but is alsosimilar to the proportion described in Arab populations compared to the majority ofreports. The definitive diagnosis required an average of two biopsies and 71.7% and43.4% of the patients had another previous clinical and histologic diagnosis,respectively.
Conclusion: The incidence rate, sex distribution, age, and stage at diagnosis ofmycosis fungoides is more similar to that observed in Arab populations compared toother Mediterranean populations. We speculate that the strong Arab ancestry inSpain might partially explain our findings.
cial support: None identified.
CommerP6970EpsteineBarr virus-associated hydroa vacciniformeelike cutaneous lym-phoma and NK/T-cell lymphoma
Julio Cesar Jasso Olivares, MD, Instituto Nacional de Ciencias Medicas yNutricion Salvador Zubiran, Mexico City, Mexico; Judith Dominguez-Cherit,MD, Instituto Nacional de Ciencias Medicas y Nutricion Salvador Zubiran, MexicoCity, Mexico; Linda Garcia Hidalgo, MD, Instituto Nacional de Ciencias Medicas yNutricion Salvador Zubiran, Mexico City, Mexico
Background: Hydroa vacciniforme (HV) is a rare, chronic skin disease. It occursmainly in young children and presents itself with papulovesicles on the sun exposed-areas. Skin vesicles often heal with a small pox-like scar, generally, HV tends toregress spontaneously at the end of the puberty. Recently, a group of patients withsevere HV-like eruptions and systemic symptoms, hepatosplenomegaly andlymphoproliferative disorders like NK/T lymphomas have been reported in Asiaand South America. Although no causative factor have been found, nowadays, thosediseases are associated with latent EpsteineBarr virus (EBV) infection, fromevidence that the cutaneous lesions contains EBV DNA sequences and a consider-able number of infiltrating T cells with EBV-encoded small nuclear RNA (EBER).
Case report:We report a case of a 32-year-old woman who was brought to ourhospital because of a recurrent left facial edema, erythem, pox-like scars and apapulovesicular disorder of 4 years’ duration (Fig 1). She also had fever, nasalobstruction, cervical adenopathies and lose weight. One punch biopsy wasperformed and blood cell count, LDH, liver and renal test with normal value result.A CT scan report cervical adenopathies, turbinate involve and splenomegaly.Hystopathologic skin biopsy and inmunohistochemical reported: extranodal NK/Tlymphoma, nasal type CD 56+, EBER+, TIA+. Chemotherapy with methotrexate andL-asparginase was initiated with improvement of skin changes.
Conclusions: Actually lymphoproliferative disorders associated with EBV infectioncomprise hydroa vacciniformeelike cutaneous lymphoma, including NK/T lym-phoma, aggressive neoplasia with a poor prognostic because of a high rate ofresistance to conventional chemotherapy. It is unknown how can latent infectioncauses a proliferating lymphoma, nevertheless, it has been proven, that individualwith genetic chromosomal abnormalities in the 6q region decrease immunetolerance and increase cellular proliferation. Treatments with L-asparginase havedemonstrated to extend overall survival in patients with NK/T lymphoma.
cial support: None identified.
CommerJ AM ACAD DERMATOL AB145
