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Rituximab plus liposomal pegylated doxorubicin in the treatment of primary cutaneous B-cell lymphomas
European Journal of Haematology
Abstract
Background:
In primary cutaneous B-cell lymphomas (PCBCL), radiotherapy - or surgery in a minority of cases - is the first-line treatment in follicle center lymphoma (PCFCL) and marginal zone B-cell lymphoma (PCMZL). Conversely, patients with multifocal skin involvement or relapsed/refractory disease deserve a systemic chemotherapy. In diffuse large B-cell lymphoma, leg type (PCLBCL-LT), due its poorer outcome, cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP)-like regimens are the most commonly used frontline, although hard to propose in elderly patients. In this regard, the association of rituximab (R) and pegylated liposomal doxorubicin (PLD) can be considered a promising, alternative approach.
Aims:
Based on the favorable results reported with R and PLD in several recent trials, we decided to test efficacy and safety of this combination.
Methods:
Twelve patients with PCBCL were treated with R plus PLD, and 7 had relapsed disease. Treatment plan consisted of 2 monthly cycles of R 375 mg/m(2) and PLD 20 mg/m(2) day 1;15, followed (in responders) by two cycles given only at day 1. All patients received prophylactic pyridoxine to prevent palmar-plantar erythrodysesthesia (PPE).
Results:
Ten of 12 patients had a response (eight complete; two partial), remarkably 2/3 with PCLBCL-LT. Two patients did not respond (one progressive disease, PD, and one stable disease). Three patients died after a median follow-up of 56 months, two patients due to PD, and 1 due to a second neoplasm. Two out of 10 responders relapsed after 31 and 32 months, respectively. Hematological toxicity was negligible (one case of grade 2 neutropenia), as well as extra-hematological toxicity (two cases of grade 2 PPE).
Conclusions:
These preliminary data suggest that R-PLD is effective and well tolerated in all subsets of PCBCL and may be offered frontline in indolent cases unsuitable for radiotherapy or surgery as well as in more aggressive cases with contraindications to CHOP-like regimens.
... Although secondary cutaneous cases originating from extracutaneous sites were included in some reports, one RCT 177 and three cohort studies 154,178,179 for MALT lymphoma were found. ...
... The descriptive studies include seven case series studies and one published work review; the latter consisting of 32 case reports, and 60 case series or retrospective cohort studies. 145,147,154,[161][162][163]179,180 In this review, the response and relapse rates for patients who received multi-agent immunochemotherapy were 92% and 9%, respectively, and for patients who received single-agent rituximab and/or radiation or surgical excision 82% and 56%, respectively. 145 OS, PFS, AE and response duration were unclear. ...
Since the publication of the Japanese “Guidelines for the management of cutaneous lymphomas” in 2011, the World Health Organization (WHO) classification of hematolymphoid neoplasms and the WHO–European Organisation for Research and Treatment of Cancer classification for primary cutaneous lymphomas were updated and a number of novel systemic drugs for cutaneous T‐cell lymphoma had been approved in Japan. In 2020, we revised the Japanese guidelines for the management of cutaneous lymphomas with consideration of the recent advances in the understanding of the pathophysiology and classification of cutaneous lymphomas together with the update of treatment strategies reflecting the advent of novel drugs. In addition to a brief explanation of epidemiology, diagnosis, staging system, prognosis and management of each subtype of cutaneous lymphomas, the recommendations for nine clinical questions regarding treatment options that can vary even among experts are also described. A systematic review process and determination of recommendations in answer to each clinical question have been performed in accordance with the Grading of Recommendations, Assessment, Development and Evaluation scheme by a multidisciplinary expert panel consisting of dermatologists, a hematologist and a radiation oncologist. In this article, we present the outlines of the revised Japanese “Guidelines for the management of cutaneous lymphomas”.
... 141 Pegylated liposomal doxorubicin used successfully in the treatment of PCTCL in a dose from 20 mg/ m 2 to 40 mg/m 2 , administered intravenously and repeated every 2 to 4 weeks, may be considered an alternative for the treatment of PCBCL having been used alone or in combination with rituximab, with appreciable response rates, good tolerance and low hematological toxicity. [137][138][139] A study in which 5 patients with PCBCL (1 with PCMZL and 4 with PCLBCL-leg-type) with disseminated skin lesions) were treated with pegylated liposomal doxorubicin at a dose of 20 mg/m 2 showed CR in 100% of cases. 137 In follow-up, one patient died with disease progression and 4 patients maintained CR after 5, 52, 63 and 69 months, respectively. ...
... Two patients relapsed at 31 and 32 months, respectively. 138 A relatively common side effect associated with the administration of liposomal doxorubicin, which may also arise with other chemotherapy regimens, is the palmoplantar erythrodysesthesia, also known as "hand-foot-syndrome", which is characterized by painful acral (palmoplantar) erythema. [170][171][172] Coldness during administration of chemotherapy, topical application of high potency corticosteroids and prophylactic administration of pyridoxine orally are some of the recommended measures to control the associated symptoms. ...
Primary cutaneous B-cell lymphomas are a heterogeneous group of mature B-cells neoplasms with tropism for the skin, whose biology and clinical course differ significantly from the equivalent nodal lymphomas. The most indolent forms comprise the primary cutaneous marginal zone and follicle center B-cell lymphomas that despite the excellent prognosis have cutaneous recurrences very commonly. The most aggressive forms include the primary cutaneous large B-cell lymphomas, consisting in two major groups: the leg type, with poor prognosis, and others, the latter representing a heterogeneous group of lymphomas from which specific entities are supposed to be individualized over time, such as intravascular large B-cell lymphomas. Treatment may include surgical excision, radiotherapy, antibiotics, corticosteroids, interferon, monoclonal antibodies and chemotherapy, depending on the type of lymphoma and on the type and location of the skin lesions. In subtypes with good prognosis is contraindicated overtreatment and in those associated with a worse prognosis the recommended therapy relies on CHOP-like regimens associated with rituximab, assisted or not with local radiotherapy. We review the primary cutaneous B-cell lymphomas, remembering the diagnostic criteria, differential diagnosis, classification, and prognostic factors and presenting the available therapies.
... Of these 12 patients (four with PCFCL, five with PCMZL, and three with PCDLBCL, LT), the overall response rate (ORR) was 66% with one patient achieving a CR, one with a partial response, and one with progressive disease. Minimal side effects were noted with no dose interruptions required [73]. ...
Primary cutaneous lymphomas are a rare group of diseases, with an estimated incidence of 0.5–1 case per 100,000 people per year. Primary cutaneous B-cell lymphomas (pCBCLs) represent 25–30% of all primary cutaneous lymphomas. There are three main subtypes of pCBCL: primary cutaneous marginal zone lymphoma, primary cutaneous follicle center lymphoma, and primary cutaneous diffuse large B-cell lymphoma, leg type. Cutaneous B-cell lymphomas have a broad spectrum of clinical presentations, which makes diagnostic and therapeutic strategies challenging. To date, treatment recommendations for cutaneous B-cell lymphomas have been largely based on small retrospective studies and institutional experience. Recently, the pharmacotherapeutic landscape has expanded to include drugs that may modify the underlying disease pathology of pCBCLs, representing new therapeutic modalities for this rare group of diseases. Novel therapies used for other systemic B-cell lymphomas show promise for the treatment of pCBCLs and are being increasingly considered. These new therapies are divided into five main groups: monoclonal antibodies, immune checkpoint inhibitors, small-molecule inhibitors, bispecific T-cell engaging, and chimeric antigen receptor T cell. In this review, we discuss the clinical, histopathological, molecular, and cytogenetic features of the most common pCBCL subtypes with a focus on current and innovative therapeutic developments in their management. These emerging treatment strategies for B-cell lymphomas and cutaneous B-cell lymphomas may represent novel first-line options for the management of these rare diseases.
... With a median follow-up of 56 months, the ORR of PCDLBCL, LT patients was 66% including 33% of complete and 33% of partial responses. The median time to best response was two months (ranging from one to four months) with a good safety profile: only grade 2 AEs were observed (neutropenia and palmar-plantar erythrodysesthesia) [75]. New combination treatments with rituximab need to be explored. ...
Primary cutaneous B-cell lymphomas are rare entities that develop primarily in the skin. They constitute a heterogeneous group that represents around a quarter of primary cutaneous lymphomas. The 2018 update of the World Health Organization-European Organization for Research and Treatment of Cancer (WHO-EORTC) classification differentiates primary cutaneous marginal zone lymphoma and primary cutaneous follicle center lymphoma with an indolent course from primary cutaneous diffuse large B-cell lymphoma, leg type with an aggressive behavior. The broad spectrum of clinical presentations and the disease course marked by frequent relapses are diagnostic and therapeutic challenges. The classification of these diseases has been refined in recent years, which allows to better define their immunopathogenesis and specific management. In the present article, we review the main clinico-biological characteristics and the current therapeutic options of these three main subsets. Based on the recent therapeutic advances in nodal B-cell lymphomas, we focus on the development of novel treatment options applicable to primary cutaneous B-cell lymphomas, including targeted therapies, combination treatments and immunotherapeutic approaches, and cover basic, translational and clinical aspects aiming to improve the treatment of cutaneous B-cell lymphomas.
... On the other hand patients with PCDLBCL-LT are typically elderly, with multiple comorbidities and impaired organ function, which limits therapeutic options in relapsing/refractory cases. The association of rituximab with pegylated liposomal doxorubicin may be an alternative and safer approach and there are preliminary data indicating that this approach is effective and well-tolerated in more aggressive cases with contraindications to CHOP-like regimens (11). ...
... The liposomal pegylated formulation increases specificity and uptake by the skin. 64 PLD applied to PCBCL was first reported in a prospective phase II clinical trial of monotherapy. 65 Of the 5 patients in the trial, 1 patient was diagnosed with PCMZL and 4 patients had widespread PCDLBCL-LT. ...
Primary cutaneous B-cell lymphomas are a group of diseases with indolent and aggressive behavior. The goal of the initial workup is to evaluate for systemic involvement, provide adequate staging, and guide therapy. Histopathological studies are a critical part of the workup for classification of these lymphomas because they are similar to their nodal counterparts. There are limited data for treatment guidelines, and thus, therapy differs among institutions. Overall, localized therapies are preferred for indolent types and chemotherapy or immunotherapy for the aggressive forms.
... Recently, ultralow dose radiation with 4 Gy to the orbit in two 2-Gy doses has been shown to be curative in a majority of patients, while maintaining local control in those who ultimately require the current standard dose of 24 Gy [17]. Relapses occur in 25-29% of patients after standard treatment, Ocul Oncol Pathol 2019;5:147-152 DOI: 10.1159/000491381 and, as long as there is no further evidence of systemic involvement or spread at the time of recurrence, further radiation can be utilized [18]. Systemic treatment with chemotherapy is reserved for patients with extensive or diffuse disease or extracutaneous spread. ...
Primary cutaneous follicle center lymphoma (PCFCL) is a unique entity that represents up to 11% of all cutaneous lymphomas. PCFCL is associated with an indolent course and excellent 5-year survival rates, but can progress to secondary systemic involvement if left untreated. Histopathologic features of PCFCL can vary depending on the size, duration, and clinical stage of the lesion, making diagnosis somewhat challenging. Here, we present a case of a 50-year-old woman with an eyelid lesion that was initially classified as an inflamed cyst based on biopsy, but 1 year later, was determined to be PCFCL after repeat biopsy revealed different histology. In light of the recent changes to the WHO classification of lymphoid neoplasms, we review the unique clinical and histopathologic features of PCFCL that distinguish it from other more aggressive forms of cutaneous lymphoma in terms of course, prognosis, and management.
... Es wurden initial gute Ergebnisse erzielt, allerdings kam es zu einer hohen Rate von Rezidiven [33,34]. Weiterhin kommen als zweite Therapieoption Doxorubicin oder Gemcitabin, ggf. in Kombination mit Rituximab infrage [34,35]. ...
Zu den kutanen B‑Zell-Lymphomen mit intermediärer/schlechter Prognose werden das primär kutane diffus-großzellige B‑Zell-Lymphom (PCBLT), das Epstein-Barr-Virus (EBV)-positive diffus-großzellige B‑Zell-Lymphom, nicht weiter spezifiziert (EBV+ DLBCL, NOS) sowie das primär kutane intravaskuläre großzellige B‑Zell-Lymphom (PCIVLBL) gezählt. Eine Abgrenzung zu indolenten kutanen B‑Zell-Lymphomen ist sowohl klinisch als auch histologisch nicht immer einfach, aber vital für den Patienten. In den letzten Jahren wurden erhebliche Prognoseverbesserungen erzielt, insbesondere beim diffus-großzelligen B‑Zell-Lymphom durch den Einsatz von kombinierter Immuntherapie/Polychemotherapie wie R (Rituximab)-CHOP (Cyclophosphamid, Adriamycin, Oncovin, Prednison). Die Entscheidung für das therapeutische Vorgehen muss individuell getroffen werden, möglichst im Rahmen einer interdisziplinären Tumorkonferenz. Immunseneszenz spielt bei älteren Individuen mit EBV+ DLBCL, NOS eine Rolle in der Pathogenese. Die Prognose ist ungünstiger als die des EBV-negativen PCBLT, wobei dies insbesondere bei älteren Patienten zu beobachten ist. Bei einem Drittel der Patienten mit PCIVLBL kommt es im Verlauf zu einer systemischen Manifestation. Ein nodaler Befall ist eher selten. Die Symptome können je nach betroffenem Organsystem vielfältig sein. Aufgrund der Seltenheit der Erkrankung existieren keine evidenzbasierten Therapieempfehlungen. Das EBV-positive mukokutane Ulkus ist eine neue provisorische Kategorie in der aktuellen WHO-Klassifikation für lymphatische Neoplasien. Es wurde vom EBV+ DLBCL, NOS abgegrenzt aufgrund seines selbstlimitierenden Verlaufs und guten Ansprechens auf konservative Maßnahmen.
... Beyond the recommended -and evidence-based -first-line treatment with R-CHOP, there are no uniform recommendations for second-line treatment of DLBCL-LT in the event of recalcitrant or recurrent lesions. Due to the limited data available in this regard, recommended options most likely include liposomal pegylated doxorubicin or gemcitabine, possibly in combination with rituximab [18,37,38]. In addition, there are case reports on the successful use of lenalidomide or isolated limb perfusion with melphalan [39,40]. ...
Zusammenfassung
Primär kutane B‐Zell‐Lymphome (PCBCL) beschreiben reifzellige lymphoproliferative Erkrankungen der B‐Zell‐Reihe, die primär die Haut betreffen. Die Biologie und der klinische Verlauf der einzelnen PCBCL‐Subtypen variieren untereinander stark und unterscheiden sich grundsätzlich von primär nodalen und systemischen B‐Zell‐Lymphomen. Primär kutane Marginalzonenlymphome (PCMZL) und primäre kutane follikuläre Keimzentrumslymphome (PCFCL) werden auf Grund ihres unkomplizierten Verlaufs und ihrer exzellenten Prognose zu den indolenten PCBCL gezählt. Demgegenüber stellen die diffus großzelligen B‐Zell‐Lymphome, hauptsächlich vom Beintyp (DLBCL, LT) die aggressiveren PCBCL‐Varianten mit schlechterer Prognose dar. Für die Ausbreitungsdiagnostik und die Therapieentscheidung sind eine genaue histologische und immunhistochemische Klassifizierung sowie der Ausschluss einer systemischen Beteiligung in Abgrenzung zu nodalen oder systemischen Lymphomen notwendig. Die Diagnostik sollte dabei durch molekularbiologische Untersuchungen unterstützt werden. Therapeutisch stehen für die indolenten PCBCL primär operative und radioonkologische Maßnahmen im Vordergrund sowie eine Systemtherapie mit dem CD20‐Antikörper Rituximab bei disseminiertem Befall. Die aggressiveren Varianten sollten in erster Linie mit Kombinationen aus Rituximab und Polychemotherapieschemata wie z. B. dem CHOP‐Schema oder Modifikationen davon behandelt werden. Auf Grund der in allen seinen Einzelheiten noch nicht vollständig verstandenen Pathogenese und Biologie sowie des begrenzten Therapiespektrums der PCBCL besteht hier, speziell beim DLBCL, LT, noch erheblicher Forschungsbedarf.
... Beyond the recommended -and evidence-based -first-line treatment with R-CHOP, there are no uniform recommendations for second-line treatment of DLBCL-LT in the event of recalcitrant or recurrent lesions. Due to the limited data available in this regard, recommended options most likely include liposomal pegylated doxorubicin or gemcitabine, possibly in combination with rituximab [18,37,38]. In addition, there are case reports on the successful use of lenalidomide or isolated limb perfusion with melphalan [39,40]. ...
Cutaneous B-cell lymphomas (CBCLs) comprise a group of mature lymphoproliferative B-cell disorders that primarily affect the skin. Characterized by great biological and clinical variability among its various subtypes, CBCLs fundamentally differ from primary nodal or systemic B-cell lymphomas. Given their uncomplicated course and excellent prognosis, lymphoma classifications rank primary cutaneous marginal zone lymphoma (PCMZL) and primary cutaneous follicle center lymphoma (PCFCL) as indolent CBCLs. By contrast, diffuse large B-cell lymphoma, leg type (DLBCL-LT) in particular, represent more aggressive lymphoma variants associated with a poorer prognosis. Therapeutic decisions and diagnostic procedures are based on the exact histological and immunohistochemical classification as well as the exclusion of systemic involvement and thus differentiation from nodal and systemic lymphomas. In this context, the diagnostic workup should also include molecular biology methods. Primary therapeutic options for indolent CBCL lesions include surgery and radiation therapy, as well as systemic treatment with rituximab (anti-CD20 antibody) in case of dissemination. More aggressive CBCLs usually require a combination of rituximab and polychemotherapy, primarily the CHOP regimen or modifications thereof. Given that the pathogenesis and biology of CBCLs has not been conclusively elucidated, and given the limited therapeutic armamentarium available, there is great need for comprehensive research, especially with respect to DLBCL-LT.
... DOX leads to DNA double strand breaks, which affects the cell cycle control, DNA repair and cell death. It is broadly used in the chemotherapeutic regimen of many malignancies, such as small cell lung cancer, breast cancer and lymphoma [22][23][24]. In other tumors, such as ovarian cancer and hepatic cancer, the inhibition activity of the PI3K or NF-κB pathways can enhance the sensitivity of the chemo- and reversing the state of multidrug resistance of chemo-resistance to DOX in hepatic cancer, breast cancer and neuroblastoma via PI3K and NF-κB [28][29][30]. ...
Metadherin (MTDH) is highly expressed in many tumors and is involved in the proliferation, metastasis and drug resistance of tumor cells by regulating multiple signaling pathways. Our previous studies demonstrated that MTDH is overexpressed in diffuse large B cell lymphoma (DLBCL) and involved in apoptosis resistance, in part, via Wnt signaling. Here, we investigated the role of MTDH in the chemo-sensitivity of DLBCL. The study was performed in the DLBCL cell line LY8 to investigate the relationship between MTDH expression and doxorubicin (DOX) sensitivity in DLBCL. A MTDH interference model was developed in LY8 cells by transfected with lentivirus which is carrying MTDH interference sequence. Western blot was used to detect the protein expression. A CCK-8 assay was used to evaluate cell proliferation. The results showed that DOX treatment had no effect on the intracellular MTDH expression of LY8 cells. The proliferation of LY8 cells was inhibited after MTDH interference. MTDH interference increased the DOX sensitivity in the LY8 cell lines. The results suggested that MTDH is a potential therapeutic target in DLBCL, and it cooperates with DOX in treatment of DLBCL.
Primary cutaneous B-cell lymphomas (PCBCLs) are lymphoproliferative disorders that appear on the skin without evidence of extracutaneous manifestations at the time of diagnosis. There is a lack of evidence-based guidelines for their clinical management due to the availability of very few large scale studies and controlled clinical trials. Here we present and discuss a series of major unmet clinical needs (UCNs) in the management of PCBCLs by a panel of 16 experts involved in research and clinical practice of PCBCL. The Panel produced recommendations on the appropriateness of the clinical decisions concerning the identified clinical needs and proposed research for improving the knowledge needed to solve them. Recommendations and proposals were achieved by multiple-step formalized procedures to reach a consensus after a comprehensive analysis of the scientific literature. Recommendations and proposals lay in the domain of classification uncertainties of PCBCL, optimization of diagnosis, optimization of prognosis, optimization of staging and critical issues on therapeutic strategies with particular focus on new treatments. These recommendations are intended for use not only by experts but above all by dermatologists and hematologists with limited experience in the field of PCBCLs as well as general practitioners.
Primary cutaneous B-cell lymphomas (CBCL) are a heterogeneous group of B-cell lymphomas without evidence of extracutaneous disease at the time of diagnosis. The 2022 World Health Organization classification of mature lymphoid neoplasms differentiates the indolent primary cutaneous marginal zone lymphoproliferative disorder, primary cutaneous follicle center lymphoma and Epstein-Barr virus-positive mucocutaneous ulcer, from the more aggressive primary cutaneous diffuse large B-cell lymphoma, leg-type and intravascular large B-cell lymphoma. The new updates in the 2022 classification are based on recent scientific advances in the understanding and characterization of these entities. This article aims to review the main clinical, cellular and molecular features of the five CBCL subsets along with their management and treatment. The exponentially growing evidence for new treatment options for systemic B-cell lymphomas raises expectations for the field of CBCL as well. However, specific prospective high quality research on CBCL is still crucial to further define their management and update international guidelines.
Introduction
early-stage follicular lymphoma (FL) is characterized by good prognosis and can be cured with involved-field radiotherapy (IF-RT) in most cases. PET scan is a milestone of diagnostic work-up, with the aim of identifying a truly-localized disease; however, staging in most of the studies was without PET.
Areas covered
we have searched in MEDLINE (inclusive dates 1994-2020) data about localized FL management. While high-quality evidence is lacking, current guidelines recommend IFRT or involved-site RT as first-line treatment in limited stages FL. Since a significant proportion of disease relapse occurred in non-irradiated areas, it has been hypothesized that occult disease could be present at diagnosis and could persist after RT, contributing to relapse. Available treatment options include watch-and-wait, chemotherapy, RT plus chemo- or chemo-immunotherapy and RT combined with rituximab (R).
Expert opinion
RT combined with chemotherapy could increase PFS, but a clear OS benefit is lacking and toxic effects could be unacceptable. A promising strategy is represented by R combined with IF-RT, with low relapse rate outside the radiation fields and without the toxicity reported with chemotherapy. The study of prognostic factors in PET-staged patients, the reduction of RT fields and doses and a response-adapted strategy represent new perspectives to investigate.
We report on a 74-year-old man with a cutaneous B-cell follicle center lymphoma, which was treated upfront with systemic rituximab and suffered several local relapses. The first of the local recurrences, 10 months after completion of treatment, was characterized by a dense T-cell infiltrate that obscured a minor population of B-cell lymphoma cells, suggesting a second primary cutaneous T-cell lymphoma. This represents a previously not reported diagnostic pitfall and underscores the importance of performing sequential biopsies when dealing with lymphoma recurrences in this setting.
Data on clinical features, treatment, and outcome of pediatric marginal zone lymphoma (MZL) is still limited. MZL represent a B-NHL subtype which clearly differs from aggressive B-NHL with respect to clinical presentation and the need of treatment intensity. Three subtypes of MZL are defined with nodal MZL (nMZL), extranodal MZL (enMZL), and splenic MZL. The latter subtype is rare in children and adolescents. Nodal MZL occur most commonly in healthy male adolescents and present with limited stage disease. Extra nodal MZL are also most common in the adolescent age group with a less prominent male predominance compared with nMZL. An association with infectious agents, inflammation, autoimmune diseases, and immunodeficiency is observed in enMZL. One third of patients presents with advanced stage of disease. For both nMZL and enMZL, the prognosis is excellent with limited treatment for the vast majority of patients.
Kutane Lymphome sind überwiegend Erkrankungen des älteren und alten Menschen. Ihr Management erfordert eine stadiengerechte Therapie, d. h. frühe Stadien und indolente Formen können im allgemeinen mit lokalen Therapien behandelt werden, während spätere Stadien und aggressivere Varianten eine systemische Therapie erfordern. Explizite Therapieempfehlungen speziell für geriatrische Patienten existieren auf Grund der Seltenheit der Erkrankung und mangelnde durch vergleichende Studien belegte Evidenz nicht. Dabei besteht gerade für diese Patientengruppe ein erhöhtes Risiko, da ein hohes Alter einen negativen prognostischen Marker für kutane T-Zell-Lymphome darstellt und sich aggressivere B-Zell-Lymphome auch fast ausschließlich bei hochbetagten Patienten entwickeln. Trotz mangelnder altersspezifischer Therapieempfehlung muss die Therapieentscheidung bei geriatrischen Patienten häufig sehr individuell getroffen werden, da viele Kontraindikationen und Komorbiditäten speziell im höheren Patientenalter das Erstlinientherapiespektrum einschränken und ein Ausweichen auf alternative Optionen notwendig machen.
Primär kutane B-Zell-Lymphome (primary cutaneous B-cell lymphomas: PCBCL) stellen extranodale Non-Hodgkin-Lymphome reifer B-Lymphozyten dar, die die Haut als Zielorgan haben und dort proliferieren. Sie zeigen eine große Bandbreite klinischer und histologischer Erscheinungsformen. Ca. 22 % der kutanen Lymphome (cutaneous lymphomas: CL) entfallen auf kutane B-Zell-Lymphome (cutaneous B-cell lymphomas: CBCL), 73 % auf kutane T-Zell-Lymphome (cutaneous T-cell lymphomas: CTCL) und < 10 % werden seltenen Formen von CL zugeordnet. Die Inzidenz der CL ist weiterhin zunehmend und wird basierend auf den Daten aus den USA auf eine Neuerkrankung pro Jahr und 100 000 Einwohner geschätzt.
Die Diagnose eines PCBCL erfolgt in der Regel anhand klinischer und histologischer bzw. immunhistologischer Untersuchungen. Nicht immer jedoch erlauben diese Untersuchungen eine zweifelsfreie Diagnose. Vor allem frühe Stadien eines PCBCL ähneln sowohl klinisch als auch histologisch oft benignen entzündlichen Hauterkrankungen. Aufgrund der Heterogenität der PCBCL mit unterschiedlicher biologischer Potenz, die von einem indolenten Verlauf bis hin zu einem fatalen Verlauf reicht, ist eine eindeutige Diagnosestellung unabdingbar. Hier spielt insbesondere die Dermatohistologie, in Kombination mit der Immunhistologie und Molekularbiologie, eine entscheidende Rolle.
Hintergrund
Kutane Lymphome stellen sowohl für den Grundlagenforscher als auch für den Kliniker eine besondere Herausforderung dar, da ihre kausale Pathogenese noch weitgehend ungeklärt ist, was die Entwicklung kausal kurativer Therapieansätze erschwert.
Diagnose
Zur Diagnosestellung ist eine komplexe Kombination aus Klinik, Histologie, Immunhistologie und Molekularbiologie notwendig. Die exakte Diagnose ist bedeutsam für den Patienten und den behandelnden Arzt, da die verschiedenen Hautlymphome sehr unterschiedliche Prognosen und Verläufe haben, die bedeutsam für die Therapieauswahl sind.
Therapie
Da bislang keine kurativen Therapien existieren, ist im Verlauf einer Hautlymphomerkrankung selbst unter Therapie häufig ein Wiederaufflammen der Erkrankung zu verzeichnen. Dies macht Therapieumstellungen notwendig, sodass viele Patienten im Verlauf ihrer Erkrankung zahlreiche Therapien durchlaufen. Die etablierten Therapieformen bedürfen häufig aufgrund ihres Nebenwirkungsprofils engmaschiger Kontrollen sowie Erfahrung und speziellen Wissens im Umgang mit den entsprechenden Substanzen. Anhand konkreter und komplexerer Fälle werden in diesem Beitrag allgemeine und praxisrelevante Aspekte des mitunter schwierigen Managements kutaner Lymphome dargestellt.
PURPOSE
Mycosis fungoides (MF) is the most common primary cutaneous T-cell lymphoma. There is a need for multicenter trials involving defined patient populations using rigorous assessment criteria. We have investigated pegylated liposomal doxorubicin (PLD) in a clearly defined patient population with advanced MF.
PATIENTS AND METHODS
Eligible patients had stage IIB, IVA, or IVB MF, refractory or recurrent after at least two previous systemic therapies. Patients were registered to receive a maximum of six cycles of PLD 20 mg/m(2) on days 1 and 15, every 28 days (one cycle). The primary end point was response rate (RR). RESULTS:
three (6.1%) experienced CCRs, and 17 (34.7%) experienced PRs. A 50% or greater reduction of cutaneous manifestations was observed in 26 (60.5%) of 43 assessable patients. Two early deaths were reported, resulting from related cardiovascular toxicity and disease progression. The lower limit of the one-sided 90% CI for RR was 31.2%. Median time to progression and median duration of response were 7.4 and 6 months, respectively.
CONCLUSION
PLD has an acceptable safety profile in patients with advanced MF. The efficacy of PLD seems promising.
Primary cutaneous B-cell lymphoma (PCBCL) is a heterogeneous group of rare clonal B-cell lymphoproliferative disorders with distinct clinicopathologic features from more common nodal B-cell lymphomas.
We performed a systematic review of the relevant literature in the MEDLINE database and analyzed laboratory and clinical data. This review discusses the three most common types of PCBCL: primary cutaneous marginal zone lymphoma (PCMZL), primary cutaneous follicle-center lymphoma (PCFCL), and primary cutaneous diffuse large B-cell lymphoma, leg type (PCDLBCL, LT).
Skin biopsies with histology, immunohistochemistry, and molecular clonality studies are essential for a correct diagnosis of cutaneous B-cell lymphoma. Comprehensive lymphoma staging with laboratory and imaging studies and bone marrow aspiration and biopsy are important for determining the prognosis and differentiation of PCBCL from secondary skin involvement with systemic B-cell lymphomas. PCMZL and PCFCL are low-grade PCBCLs, with an estimated 5-year disease-specific survival rate of greater than 95%. Surgical excision or focal radiation therapy is sufficient to control stages T1 and T2 disease. Rituximab monotherapy is frequently used for patients with stage T3 disease. PCDLBCL, LT is an intermediate-grade B-cell lymphoma, with a 5-year disease-specific survival rate of approximately 50%. An anthracycline-based chemotherapy regimen with rituximab is usually required as initial therapy to improve outcomes.
In less than a decade, significant progress has been made in our understanding of PCBCL. Novel classification, staging, and prognostic systems have resulted in more accurate diagnosis and prognosis. Although no randomized prospective studies have been conducted in PCBCL, therapies derived from systemic B-cell lymphomas have shown promising results.
The efficacy of systemic polychemotherapy in the treatment of primary cutaneous B-cell lymphomas (CBCL) or T-cell lymphomas (CTCL) is still controversial. A series of 81 patients (46 primary CBCL and 35 CTCL) were treated with COP or CHOP regimens. In primary CBCL, the overall objective response rate (RR) was 98%, with an 89% CR rate and a 33% relapse-rate. Five-year disease-free survival was 70%, 5-year survival 97%. Patients with leg or widespread lesions showed a higher relapse-rate (55% vs 26%) than those with trunk or head lesions. The overall objective RR was 40% in CTCL patients, with a 23% CR rate; median response duration was 5.7 months, median survival 19 months. The results confirm both the good prognosis of primary CBCL and the efficacy of polychemotherapy. CHOP regimen is to be preferred to COP in as much as it reduces relapse rates. Conversely, there are no indications for the use of COP/CHOP regimens as first-line chemotherapy in CTCL patients.
Clinical investigations have shown prognostic heterogeneity within the non-Hodgkin's lymphomas (NHLs) according to histology, but few descriptive studies have considered NHLs by subgroup. Our purpose is to assess the demographic patterns and any notable increases in population-based rates of different histologic subgroups of NHL.
Using data collected by the Surveillance, Epidemiology, and End Results Program of the National Cancer Institute, we calculated incidence rates for the major clinicopathologic categories of NHL by age, race, sex, geographic area, and time period.
Among the 60 057 NHL cases diagnosed during the period from 1978 through 1995, total incidence (per 100 000 person-years) was 17.1 and 11.5 among white males and females, respectively, and 12.6 and 7.4 among black males and females, respectively. However, rates for follicular NHLs were two to three times greater among whites than among blacks, with little sex variation. Blacks demonstrated much higher incidence than whites for peripheral T-cell NHL, with the incidence rates higher in males than in females. For other NHL subgroups, the incidence rates for persons less than 60 years of age were generally higher among males than among females, with little racial difference; at older ages, the rates were higher among whites than among blacks, with little sex difference. High-grade NHL was the most rapidly rising subtype, particularly among males. Follicular NHL increased more rapidly in black males than in the other three race/sex groups. Overall, the broad categories of small lymphocytic, follicular, diffuse, high-grade, and peripheral T-cell NHL emerged as distinct entities with specific age, sex, racial, temporal, and geographic variations in rates.
Findings from our large, population-based study reveal differing demographic patterns and incidence trends according to histologic group. Future descriptive and analytic investigations should evaluate NHL risks according to subtype, as defined by histology and new classification criteria.
Most primary cutaneous B-cell lymphomas have an excellent prognosis. However, primary cutaneous large B-cell lymphomas (PCLBCLs) of the leg have been recognized as a distinct entity with a poorer prognosis in the European Organization for Research and Treatment of Cancer (EORTC) classification. This distinction on the basis of site has been debated. Our aim was to identify independent prognostic factors in a large European multicenter series of PCLBCL.
The clinical and histologic data of 145 patients with PCLBCL were evaluated. According to the EORTC classification, 48 patients had a PCLBCL of the leg and 97 had a primary cutaneous follicle center-cell lymphoma (PCFCCL). Data from both groups were compared. Univariate and multivariate analyses of specific survival were performed using a Cox proportional hazards model.
Compared with PCFCCL, PCLBCL-leg were characterized by an older age of onset, a more recent history of skin lesions, a more frequent predominance of tumor cells with round nuclei and positive bcl-2 staining, and a poorer 5-year disease-specific survival rate (52% v 94%; P <.0001). Univariate survival analysis in the entire study group showed that older age, a more recent onset of skin lesions, the location on the leg, multiple skin lesions, and the round-cell morphology were significantly related to death. In multivariate analysis, the round-cell morphology (P <.0001), the location on the leg (P =.002), and multiple skin lesions (P =.01) remained independent prognostic factors. The round-cell morphology was an adverse prognostic factor both in PCLBCL-leg and in PCFCCL, whereas multiple skin lesions were associated with a poor prognosis only in patients with PCLBCL-leg.
With site, morphology, and number of tumors taken into account, guidelines for the management of PCLBCL are presented.
The standard treatment for patients with diffuse large-B-cell lymphoma is cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP). Rituximab, a chimeric monoclonal antibody against the CD20 B-cell antigen, has therapeutic activity in diffuse large-B-cell lymphoma. We conducted a randomized trial to compare CHOP chemotherapy plus rituximab with CHOP alone in elderly patients with diffuse large-B-cell lymphoma.
Previously untreated patients with diffuse large-B-cell lymphoma, 60 to 80 years old, were randomly assigned to receive either eight cycles of CHOP every three weeks (197 patients) or eight cycles of CHOP plus rituximab given on day 1 of each cycle (202 patients).
The rate of complete response was significantly higher in the group that received CHOP plus rituximab than in the group that received CHOP alone (76 percent vs. 63 percent, P=0.005). With a median follow-up of two years, event-free and overall survival times were significantly higher in the CHOP-plus-rituximab group (P<0.001 and P=0.007, respectively). The addition of rituximab to standard CHOP chemotherapy significantly reduced the risk of treatment failure and death (risk ratios, 0.58 [95 percent confidence interval, 0.44 to 0.77] and 0.64 [0.45 to 0.89], respectively). Clinically relevant toxicity was not significantly greater with CHOP plus rituximab.
The addition of rituximab to the CHOP regimen increases the complete-response rate and prolongs event-free and overall survival in elderly patients with diffuse large-B-cell lymphoma, without a clinically significant increase in toxicity.
To determine the relationship between the WHO and European Organization for Research and Treatment of Cancer (EORTC) pathologic classifications for primary cutaneous B-cell lymphoma (CBCL) and the implication of this relationship on initial treatment.
Patients with primary CBCL treated with radiotherapy were identified retrospectively. Initial biopsy specimens were reviewed by two dermatopathologists and classified according to the EORTC and WHO systems. Primary outcomes were recurrence-free and overall survival.
Thirty-four patients were identified; initial biopsy specimens were adequate for classification in 32 patients. Four different composite histopathologic subtypes of lymphoma were identified: 53% (17 of 32) follicle center cell by EORTC and diffuse large B-cell by WHO (FCC/DLB), 25% (eight of 32) follicle center cell by EORTC and follicular by WHO (FCC/Fol), 13% (four of 32) marginal zone by EORTC and WHO (MZ/MZ), and 9% (three of 32) large B-cell of the leg by EORTC and diffuse large B-cell by WHO (Leg/DLB). Five-year relapse-free survival ranged from 62% to 73% for FCC/DLB, FCC/Fol, and MZ/MZ but was 33% for Leg/DLB (P =.6). Five-year overall survival was 100% for FCC/DLB, FCC/Fol, and MZ/MZ but was 67% for Leg/DLB (P =.07). At 5 years, 21% of all patients had developed extracutaneous disease.
Two-thirds of primary cutaneous FCC lymphomas by EORTC criteria satisfy WHO criteria for DLB lymphoma. Unlike DLB lymphoma presenting in nodal or noncutaneous sites, these lesions are associated with an indolent course and may be treated with local radiotherapy alone.
The combination of cyclophosphamide, vincristine, and prednisone (CVP) is one of several standard treatment options for advanced follicular lymphoma. This, like similar chemotherapeutic regimens, induces response rates of 60% to 80%, with a median response duration of under 2 years. Rituximab, a chimeric monoclonal antibody against CD20, is active in follicular lymphoma, both as monotherapy and in combination with chemotherapy. Previously untreated patients with stages III to IV follicular lymphoma were randomly assigned to receive either 8 cycles of CVP plus rituximab (R-CVP; n = 162) or CVP (n = 159). Overall and complete response rates were 81% and 41% in the R-CVP arm versus 57% and 10% in the CVP arm, respectively (P < .0001). At a median follow-up of 30 months, patients treated with R-CVP had a very significantly prolonged time to progression (median 32 months versus 15 months for CVP; P < .0001). Median time to treatment failure was 27 months in patients receiving R-CVP and 7 months in the CVP arm (P < .0001). Rituximab did not add significantly to the toxicity of CVP. The addition of rituximab to the CVP regimen significantly improves the clinical outcome in patients with previously untreated advanced follicular lymphoma, without increased toxicity.
In this review, the different types of liposome used in medicine, in particular in the field of antitumor therapy, are focalised, emphasizing their structures, pharmacological action, pharmacokinetics and biodistribution, toxicity profiles and in the main clinical applications. The first-generation liposomes (conventional liposomes) comprised a liposome-containing amphotericin B, Ambisome, and Myocet, doxorubicin-containing liposome used in clinical trials to treat metastatic breast cancer. The last generation liposomes were pegylated liposomal doxorubicin (Caelix), called "stealth liposomes" because of their ability to evade interception by the immune system, characterized by very long-circulation half-life, favourable pharmacokinetic behaviour and specific accumulation in tumor tissues.
Primary cutaneous lymphomas are currently classified by the European Organization for Research and Treatment of Cancer (EORTC) classification or the World Health Organization (WHO) classification, but both systems have shortcomings. In particular, differences in the classification of cutaneous T-cell lymphomas other than mycosis fungoides, Sezary syndrome, and the group of primary cutaneous CD30+ lymphoproliferative disorders and the classification and terminology of different types of cutaneous B-cell lymphomas have resulted in considerable debate and confusion. During recent consensus meetings representatives of both systems reached agreement on a new classification, which is now called the WHO-EORTC classification. In this paper we describe the characteristic features of the different primary cutaneous lymphomas and other hematologic neoplasms frequently presenting in the skin, and discuss differences with the previous classification schemes. In addition, the relative frequency and survival data of 1905 patients with primary cutaneous lymphomas derived from Dutch and Austrian registries for primary cutaneous lymphomas are presented to illustrate the clinical significance of this new classification.
Phase 2 studies suggest that the monoclonal antibody rituximab may improve the prognosis of patients with follicular lymphoma (FL) when it is added to chemotherapy. In the current study, 428 patients with untreated, advanced-stage FL were randomly assigned for therapy with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) alone (n = 205) or CHOP combined with rituximab (R-CHOP) (n = 223). R-CHOP reduced the relative risk for treatment failure by 60% and significantly prolonged the time to treatment failure (P < .001). In addition, a significantly higher overall response rate (96% vs 90%; P = .011) and a prolonged duration of remission (P = .001) were achieved. In spite of a relatively short observation time, these beneficial effects even translated to superior overall survival (P = .016), with 6 deaths in the R-CHOP group compared with 17 deaths in the CHOP group within the first 3 years. The predominant treatment-related adverse effect was myelosuppression. Severe granulocytopenia was more frequently observed after R-CHOP (63% vs 53%; P = .01). However, severe infections were rare and of similar frequency after R-CHOP and CHOP (5% and 7%). Hence, adding rituximab to CHOP significantly improves the outcome for patients with previously untreated advanced-stage FL and does not induce major adverse effects.
The role of rituximab in combination with different CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone)-like chemotherapy regimens in young patients with good-prognosis diffuse large-B-cell lymphoma remains to be defined. We aimed to compare CHOP-like chemotherapy and rituximab with CHOP-like chemotherapy alone in these patients.
824 patients who were from 18 countries; aged 18-60 years; and who had no risk factors or one risk factor according to age-adjusted International Prognostic Index (IPI), stage II-IV disease, or stage I disease with bulk were enrolled. These patients were randomly assigned to six cycles of CHOP-like chemotherapy and rituximab (n=413) or to six cycles of CHOP-like chemotherapy alone (n=411). Bulky and extranodal sites received additional radiotherapy. The primary endpoint was event-free survival; secondary endpoints were response, progression under therapy, progression-free survival, overall survival, and frequency of toxic effects. Analyses were done by intention to treat and per protocol. This trial is registered at http://www.clinicaltrials.gov, NCT 00064116.
After a median follow-up of 34 months (range 0.03-61), patients assigned chemotherapy and rituximab had increased 3-year event-free survival compared with those assigned chemotherapy alone (79% [95% CI 75-83] vs 59% [54-64]; difference between groups 20% [13-27], log-rank p<0.0001), and had increased 3-year overall survival (93% [90-95] vs 84% [80-88]; difference between groups 9% [3-13], log-rank p=0.0001). Event-free survival was affected by treatment group, presence of bulky disease, and age-adjusted IPI: after chemotherapy and rituximab, a favourable subgroup (ie, IPI=0, no bulk) could be defined from a less-favourable subgroup (ie, IPI=1 or bulk, or both). Groups did not differ in the frequency of adverse events.
Rituximab added to six cycles of CHOP is an effective treatment for young patients with good-prognosis diffuse large-B-cell lymphoma. The definition of two prognostic subgroups allows for a more refined therapeutic approach for these patients.
In the article by Olsen et al entitled “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),” which appeared in the September 15, 2007, issue of Blood (Volume 110:1713–1722), the sentence on page 1717, first column, should read, “Conversely, the Dutch system uses the diameter (> 7.5 μm) of the nuclei of cerebriform mononuclear cells to define abnormal (neoplastic) cells, and if present, this constitutes early involvement (Grade 2).⁵⁸” This is in accord with what is written in Table 5.
• © 2008 by The American Society of Hematology
The monoclonal antibody rituximab directed against the B-cell antigen CD20 has been approved for the treatment of B-cell lymphomas and maintenance therapy in follicular lymphomas more than a decade ago. However, median follow-up in case series of intravenous rituximab therapy in primary cutaneous B-cell lymphomas (CBCL) lasts only up to three years. We retrospectively analyzed a cohort of CBCL patients treated with rituximab to gain more information on the long-term.
Eighteen patients, treated intravenously with rituximab for a primary cutaneous B-cell lymphoma (follicle center lymphoma (PCFCL), n=11; diffuse large B-cell lymphoma, leg type (PCLBCL, leg type), n=5; marginal zone B-cell lymphoma (PCMZL), n=2) were included. Response rate (RR), time to relapse (TTR), and course of disease after treatment were analysed.
The overall RR was 89% (16/18 patients). Within the median follow-up time of 52 months, 81% (13/16) of patients experienced a relapse; the median TTR was 25 months. Duration of remission lasted significantly shorter in patients presenting with generalized skin lesions at start of therapy. Both non-responding patients suffered from PCLBCL, leg type with extracutaneous manifestations. In responders neither severe adverse events nor occurrence of extracutaneous dissemination or nodal lymphomas were observed during follow-up.
Therapy with rituximab is effective and safe for the treatment of PCFCL, but relapses, in particular in patients with generalized skin involvement, are commonly observed. However, all relapses responded well to treatment and therefore maintenance therapy does not seem to be indicated. Patients with PCLBCL, leg type should receive chemotherapy in addition to rituximab. This article is protected by copyright. All rights reserved.
Background and Design:
Primary cutaneous follicular center cell lymphomas represent a distinct type of cutaneous B-cell lymphoma, clinically characterized by localized skin lesions on the head or trunk and an excellent prognosis. Histologically similar lymphomas may occur on the legs. The clinical behavior of this group is still undefined, and controversy exists whether these lymphomas should be classified as follicular center cell lymphoma or B-immunoblastic lymphoma. We reviewed the clinical, histologic, and follow-up data of 18 patients with primary cutaneous large B-cell lymphoma of the legs.
Disease overview:
Approximately one-fourth of cutaneous lymphomas are B-cell derived and are generally classified into three distinct subgroups: primary cutaneous follicle center lymphoma (PCFCL), primary cutaneous marginal zone lymphoma (PCMZL), and primary cutaneous diffuse large B-cell lymphoma, leg type (PCDLBCL, LT).
Diagnosis:
DIAGNOSIS and disease classification is based on histologic review and immunohistochemical staining of an appropriate skin biopsy. Pathologic review and an appropriate staging evaluation are necessary to distinguish primary cutaneous B-cell lymphomas from systemic B-cell lymphomas with secondary skin involvement. Risk-stratification: Disease histology remains the most important prognostic determinant. Both PCFCL and PCMZL are indolent lymphomas that infrequently disseminate to extracutaneous sites and are associated with 5-year survival rates that exceed 95%. In contrast, PCDLBCL, LT is an aggressive lymphoma with an inferior prognosis.
Risk-adapted therapy:
PCFCL and PCMZL patients with solitary or relatively few skin lesions may be affectively managed with local radiation therapy. While single-agent rituximab may be employed for patients with more widespread skin involvement, multiagent chemotherapy is rarely appropriate. In contrast, management of patients with PCDLBCL, LT is comparable to the management of patients with systemic DLBCL.
Cutaneous B-cell lymphomas (CBCL) are the second most common form of primary cutaneous lymphomas. The cutaneous follicle center lymphoma and the cutaneous marginal zone lymphoma (extranodal MALT type lymphoma) account for the vast majority of CBCL and manifest with nodules. These two lymphoma entities have an indolent, slowly progressive course and an excellent prognosis despite a high rate of recurrences. In contrast, cutaneous diffuse large B-cell lymphoma, leg type, and other rare forms of CBCL display an impaired prognosis and therefore require to be treated with multiagent chemotherapy and anti-CD20 monoclonal antibodies in most cases. Clinico-pathologic correlation, histology with immunohistochemical profile and genotyping as well as staging examinations are crucial diagnostic elements in the work-up of CBCL.
Because of high single-agent activity and modest toxicity, we hypothesized the combination of gemcitabine (G), vinorelbine (V), and pegylated liposomal doxorubicin (D) would be an effective salvage therapy for Hodgkin's lymphoma (HL).
A total of 91 patients participated. GVD was administered on days 1 and 8 every 21 days at doses of G 1000 mg/m(2), V 20 mg/m(2), and D 15 mg/m(2) for transplant-naive patients, and G 800 mg/m(2), V 15 mg/m(2), and D 10 mg/m(2) for post-transplant patients.
The dose-limiting toxicity was mucositis for the transplant-naive patients and febrile neutropenia for post-transplant patients. The overall response rate (RR) for all patients was 70% [95% confidence interval (CI) 59.8, 79.7], with 19% complete remissions. The 4-year event-free and overall survival rates in transplant-naive patients treated with GVD followed by autologous transplant were 52% (95% CI 0.34, 0.68) and 70% (95% CI 0.49, 0.84), and in the patients in whom prior transplant failed, these were 10% (95% CI 0.03, 0.22) and 34% (95% CI 0.17, 0.52), respectively.
GVD is a well-tolerated, active regimen for relapsed HL with results similar to those reported for more toxic regimens. High RRs in patients in whom prior transplant failed confirms this regimen's activity even in heavily pretreated patients.
Data on early lesions of primary cutaneous follicle center lymphoma (PCFCL), diffuse type are very limited.
We sought to elucidate the early clinicopathologic features of PCFCL, diffuse type.
Clinical, histologic, immunohistologic, molecular, and fluorescence in situ hybridization data from 24 patients with early lesions of PCFCL, diffuse type (male:female = 19:5; median age: 57 years) were determined.
Lesions consisted mostly of solitary or clustered papules and small nodules located on the trunk (21 cases), arm (two cases), and scalp (one case). In 3 patients small papules were located at a distance from the main affected area. All biopsy specimens from early lesions showed aggregates of medium and large centrocytes admixed with small lymphocytes without formation of clear-cut lymph follicles. Staining for Bcl-2 was positive in only 7 cases, one revealing also a rearranged BCL2 signal by fluorescence in situ hybridization. Data on treatment and follow-up were available for 22 patients. At last examination 13 patients were in complete remission (median follow-up: 60 months), 6 were alive with skin disease alone (median follow-up: 60 months), two were alive with skin disease and bone-marrow or lymph node involvement, respectively, and one died of unrelated causes while in complete remission.
The retrospective study and the fact that patients were treated at different institutions are limitations.
Early lesions of PCFCL, diffuse type present with characteristic clinicopathologic features. Dermatologists should be alert particularly to the early clinical manifestations of this lymphoma and to the presence of small, inconspicuous lesions at a distance from the main affected area in order to plan treatment properly.
Primary cutaneous diffuse large B-cell lymphoma leg type (PCDLBCL-LT) is a rare type of lymphoma, of poor prognosis, which affects elderly people. Rituximab is an anti-CD20 monoclonal antibody and has demonstrated its efficiency in the treatment of nodal lymphomas. Rituximab with polychemotherapy has been reported in PCDLBCL-LT with a good response but many adverse effects. We evaluated the risk-benefit ratio of treatment with single-agent rituximab in a retrospective study on 8 patients with PCDLBCL-LT treated with rituximab. The main evaluation clinical endpoint was the rate of objective responses to the treatment. The secondary endpoints were the adverse effects, disease-free survival and overall survival. After 4 courses of single-agent rituximab, 75% of objective responses were achieved. 100% of patients relapsed (median disease-free survival: 5.25 months, median follow-up: 17.7 months). The tolerance was excellent with one adverse event (Grade I). Rituximab monotherapy induces a rate of objective responses which is less than rituximab with polychemotherapy, with no lasting therapeutic response. The tolerance of rituximab monotherapy is higher than rituximab with polychemotherapy. The risk-benefit ratio is a bit lower but rituximab is well tolerated and may be useful for short term palliative treatment.
Primary cutaneous marginal zone B-cell lymphoma (PCMZL) is included in the group of extranodal marginal zone B-cell lymphoma involving mucosal sites. Many evidences suggest that chronic antigen stimulation is a key-player in its pathogenesis. While Helicobacter pylori seems not to be implicated in PCMZL, Borrelia Burgdorferi's role is still matter of debate since the results are discordant between European and North American/Asian countries. However Borrelia subspecies are different between the studied areas and this difference could be a confounding factor. Then ubiquitous candidate antigen is still missing. Beyond these discrepancies the treatment of diffuse PCMZL has been recently improved. If local therapies (surgery, radiation) are the gold standard for localized disease, rituximab can also be considered as an alternative for disseminated or plurifocal PCMZL.
The therapy of advanced, relapsed or refractory primary cutaneous lymphomas is often unsatisfactory. Recent data indicate a favourable pharmacokynetic, pharmacodynamic and toxicity profile of pegylated liposomal doxorubicin (Peg-Doxo) in primary cutaneous T-cell lymphomas, while in primary cutaneous B-cell lymphomas (PCBCLs), the drug efficacy has never been assessed so far.
We performed a prospective phase II pilot clinical trial of Peg-Doxo monotherapy (20 mg/m(2)) in PCBCLs. One patient had a marginal zone B-cell lymphoma and four were affected by diffuse large B-cell lymphoma-leg type, all with widespread nodular lesions.
All the patients achieved a complete response (CR = 100%) in a short period of time (median 3 months), even when pretreated with radio-chemotherapy. Two experienced a relapse. At follow-up, one patient died for progressive disease; four are in CR after 5, 52, 63 and 69 months. As concerning the toxicity profile, the treatment was well-tolerated, no one decreased or delayed the dose. The haematological toxicity was mild with only one case of grade III neutropenia; a patient showed a grade I neurotoxicity. Dermatological toxicity, in particular the palmar-plantar erythrodysesthesia, did not occurred, probably because of both the low dosages of Peg-Doxo monotherapy and the oral prophylaxis with pyridoxine.
In spite of the small number of patients, it emerges that monochemotherapy with Peg-Doxo has a significantly high clinical activity and a good safety profile in PCBCLs, even in aggressive forms, compared with other therapeutic regimens, which are completely reviewed. It suggests the need of further investigations in this field.
We have carried out a retrospective analysis to evaluate the therapeutic value of the anti-CD20 antibody rituximab in 16 consecutive patients with primary cutaneous CD20+ B-cell lymphomas.
Sixteen patients (4 females, 12 males) with a median age of 54 years received systemic therapy with rituximab 375 mg/m(2) once weekly for four or six consecutive weeks. Eleven patients had primary cutaneous follicle center cell lymphoma and five patients had a primary cutaneous marginal zone B-cell lymphoma.
Of the 16 patients with PCBCL, 14 patients (87.5%) achieved complete remission (CR). In two patients, partial remission was obtained and additional focal radiotherapy was applied, which resulted in final CR. Five to 14 (35%) patients with CR relapsed, in an interval between 6 and 37 months. There were no severe side-effects.
On the basis of our results, single-agent treatment with i.v. rituximab appears to be feasible and safe and results in a high rate of durable remissions. Judging from our data, it appears to be an attractive treatment option and should be directly compared with local radiotherapy.
In this study the clinical characteristics and follow-up data of nineteen patients with a diffuse large cell lymphoma of follicular center cell (B cell) origin, with only skin lesions at presentation, are reported. Sixteen of nineteen patients came to us with localized nodules or tumors, preferentially on the trunk, scalp, and lower legs. Remarkably, eight of eleven patients with disease confined to a limited area on the trunk had a history of slowly progressive papular lesions that had been present for 1 to 20 years prior to the development of rapidly growing skin tumors. Initial treatment, generally radiotherapy and/or polychemotherapy, resulted in complete remissions in seventeen of nineteen patients. Only three patients developed extracutaneous disease, whereas two other patients had recurrent disease in the skin at sites distant from the original skin lesions. Excluding three patients who had just finished initial treatment at the time of writing, twelve of sixteen patients were currently alive and in complete remission with a median survival of 44 months. Four patients died, three of whom were elderly women who had skin tumors on the lower legs when first seen. These results suggest that patients with a primary cutaneous large cell lymphoma of follicular center cell origin with disease confined to the trunk of scalp have a very favorable prognosis.
Primary cutaneous follicular center cell lymphomas represent a distinct type of cutaneous B-cell lymphoma, clinically characterized by localized skin lesions on the head or trunk and an excellent prognosis. Histologically similar lymphomas may occur on the legs. The clinical behavior of this group is still undefined, and controversy exists whether these lymphomas should be classified as follicular center cell lymphoma or B-immunoblastic lymphoma. We reviewed the clinical, histologic, and follow-up data of 18 patients with primary cutaneous large B-cell lymphoma of the legs.
Primary cutaneous large B-cell lymphoma of the legs generally occurred in elderly patients (median age at diagnosis, 76 years), in particular women (male-female ratio, 7:2), and preferentially affected the lower legs (14 of 18 patients). Radiotherapy and/or systemic polychemotherapy resulted in complete remissions in 16 of 17 patients. Follow-up data demonstrated estimated 2- and 5-year survival rates of 77% and 58%, respectively. Histologic evaluation showed diffuse dermal infiltrates with variable proportions of centroblasts (large noncleaved cells), large centrocytes (large cleaved cells), and B immunoblasts. Seventeen of 18 patients were diagnosed as having primary cutaneous follicular center cell lymphoma; only 1 patient, whose histologic examination showed more than 30% immunoblasts, was diagnosed as having B-immunoblastic lymphoma.
Primary cutaneous large B-cell lymphoma of the legs is a distinct clinicopathologic entity that mainly affects elderly patients and has an intermediate prognosis. Although most cases have a follicular center cell origin, primary cutaneous large B-cell lymphoma is proposed as the most appropriate term for this type of cutaneous lymphoma.
Primary cutaneous lymphomas represent a heterogeneous group of T- and B-cell lymphomas that show considerable variation in histology, phenotype, and prognosis. Recently, the European Organization for Research and Treatment of Cancer (EORTC) Cutaneous Lymphoma Project Group has reached consensus on a new classification for this group of diseases. The EORTC classification for primary cutaneous lymphomas is based on a combination of clinical, histologic, and immunophenotypic criteria, and thus contains well-defined disease entities rather than histologic subgroups. In addition, this new classification contains a number of provisional entities, which may display characteristic histologic features, but are not yet well defined clinically. These provisional entities account for less than 5% of all primary cutaneous lymphomas. In this report the basic principles of this new classification, as well as the characteristic features of the different disease entities, are described. In addition, survival data of 626 patients with primary cutaneous lymphomas derived from the registry of the Dutch Cutaneous Lymphoma Working Group, illustrating the clinical validity of this new classification, are presented.
This is a case report of a woman who had chronic lymphedema on one leg and who developed a primary cutaneous large B-cell lymphoma of the leg at that site. She received radiotherapy and did not show any systemic involvement thereafter. Other neoplasms may appear in a clinical setting of chronic lymphedema, namely, lymphangiosarcoma (Stewart-Treves), melanoma, and metastatic carcinoma. There are four other reports in the English literature of cutaneous lymphoma arising in an extremity with chronic lymphedema.
To record the profile of toxic effects of polyethylene glycol-coated liposomal doxorubicin hydrochloride (Doxil) to the skin, and to evaluate whether the long circulation pattern and enhanced accumulation of liposomes in specific skin sites will result in any unique presentations.
Patients were accrued in the frame of dose-range-finding studies that examine the toxic effects and antitumor activity of Doxil therapy in metastatic breast and prostate cancers. All patients receiving Doxil were instructed to report any skin eruption or discomfort. Skin examination was performed on a regular basis at every cycle of Doxil therapy and after specific complaints.
Outpatient day care unit of the oncology institute of a secondary-referral medical center.
Sixty patients (45 women and 15 men).
A basic severity scale of I through IV was adopted for toxic effects to the skin, based on National Cancer Institute common toxicity criteria.
The following 4 patterns of skin eruptions were encountered: hand-foot syndrome (n = 24), diffuse follicular rash (n = 6), intertrigolike eruption (n = 5), and new formation of melanotic macules (n = 3). Another major toxic effect of Doxil was stomatitis, which was found to be the dose-limiting factor for the maximal single dose. Alopecia and extravasation injuries did not occur.
The profile of toxic effects of Doxil to the skin reflects its unique pharmacokinetics and tissue distribution. These skin reactions vary significantly from those associated with doxorubicin in non-liposome-encapsulated form.
Monoclonal antibody IDEC-C2B8 (rituximab) has been shown to be highly effective in the treatment of non-Hodgkin's lymphomas (NHL). The present study was designed to investigate relationships between the efficacy of IDEC-C2B8 and expression of CD20, presence of complement, and effects of differently acting chemotherapeutic agents used in lymphoma treatment (doxorubicin, mitoxantrone, cladribine, bendamustine).
DOHH-2, WSU-NHL and Raji lymphoma cell lines and ex vivo cells from patients with chronic lymphocytic leukemia (CLL) (n=17) and leukemic B-cell lymphomas (n=9) were studied. Additionally, the effect of interleukin (IL)-2, IL-4, IL-6, IL-13, granulocyte/macrophage colony-stimulating factor (GM-CSF) and tumor necrosis factor (TNF)alpha on expression of CD20 molecules per cell was determined.
We demonstrate that 10 mg/mL rituximab saturated 80-95% of CD20 molecules per cell in all tested lymphoma samples. Although rituximab induced only a minor increase of apoptosis, combinations of rituximab with different cytotoxic drugs significantly decreased the IC(30)- and IC(50) dosages of the chemotherapeutic agents necessary for induction of apoptosis irrespective of addition of complement, demonstrating a chemosensitizing effect of rituximab in combination with cytotoxic drugs in the neoplastic lymphocytes. This effect seemed to be independent of the percentage of saturated CD20 molecules. After addition of caspase inhibitors to the cell lines incubated with rituximab and cytotoxic agents, caspase-7 and -8 were found, by Western blotting, to be the executioner caspases, possibly explaining the rituximab-sensitized apoptosis. Preincubation of lymphoma cells with cytokines did not alter the expression of CD20; IL-2 and IL-4 even decreased the rate of apoptosis.
We conclude that rituximab sensitizes lymphoma cells to the effect of differently acting cytotoxic drugs used in lymphoma treatment, that this effect does not require complement, and that caspase-7 and -8 may represent the main executioner caspases in chemosensitization by rituximab.
Anthracyclines remain as the best drugs in the treatment of patients with aggressive malignant lymphoma in combination with other cytotoxic drugs. However, dose escalation is poorly tolerated and acute and late cardiac toxicity has limited the use of these compounds. Pegylated liposomal doxorubicin has been proven to be useful in some malignancies, without the presence of acute cardiac toxicity and with a good response rate in patients with relapsed/refractory lymphomas. We report the first study of this drug in combination chemotherapy in patients with previously untreated aggressive malignant lymphoma.
Twenty consecutive patients with diagnosis of diffuse large-B-cell lymphoma, age <18 yr to <70 yr, without previous treatment, HIV-negative high and high-intermediate clinical risks were treated with the CHOP-Bleo regimen at standard doses, using pegylated-liposomal doxorubicin instead of doxorubicin, at 25 mg/m2 (3 patients), 30 mg/m2 (3 patients), and 35 mg/m2 (14 patients).
Complete response was achieved in 17 cases (85%), with failure in 3 patients (15%). At a median followup of 18.1 mo, relapse has not been observed. Two patients died secondary to tumor progression. Toxicity was mild, only three episodes of granulocytopenia grade I were observed, and no mucositis, thrombocytopenia, or granulocitopenia grade >2 was observed. Erythrodisestesias grade II was observed in one case and grade I in two cases. Cardiac function was normal before and 12 mo after chemotherapy. Pegylated liposomal doxorubicin appear as an promising drug in the treatment of patients with aggressive malignant lymphoma.
The purpose of this study was to determine the objective response rate, median duration of response, time to disease progression, and survival time and to evaluate the safety of pegylated liposomal doxorubicin in previously treated patients with low-grade non-Hodgkin's lymphoma. Thirty-two patients with low-grade non-Hodgkin's lymphoma were treated and analyzed. Pegylated liposomal doxorubicin 30 mg/m2 was administered intravenously as a single dose on day 1 of each 3-week cycle. Patients had an Eastern Cooperative Oncology Group performance status of 0-1 and had stage II-IV disease. The median baseline left ventricular ejection fraction was 60%, and the median age was 68 years. In 29 evaluable patients, there were 3 (10%) complete responses, 6 (21%) partial responses, 11 (38%) patients with stable disease, and 9 (31%) with progressive disease. The median number of cycles was 4 (range, 1-22 cycles). The median duration of response (complete response plus partial response) was 11.0 months (range, 2.3-37.0 months). The estimated median time to progression was 5.6 months (range, 1.1-40.5 months) and the estimated median survival was 29.6 months (range, 3.9-41.6 months). Treatment-related toxicities grade = 3 included neutropenia (25%) and palmoplantar erythrodysesthesia (9%). Only 1 clinically significant cardiac toxicity was observed. There were 17 deaths; none were treatment related. Single-agent pegylated liposomal doxorubicin 30 mg/m2 every 3 weeks, is associated with antitumor activity in the treatment of low-grade non-Hodgkin's lymphoma, as shown by an objective response of 31%, and produced no significant cardiac or hematologic toxicity. Based on these results, pegylated liposomal doxorubicin should be further evaluated in combination with other agents in low-grade non-Hodgkin's lymphoma.
Pegylated liposomal doxorubicin (doxorubicin HCl liposome injection; Doxil® or Caelyx®) is a liposomal formulation of doxorubicin, reducing uptake by the reticulo-endothelial system due to the attachment of polyethylene glycol polymers to a lipid anchor and stably retaining drug as a result of liposomal entrapment via an ammonium sulfate chemical gradient. These features result in a pharmacokinetic profile characterised by an extended circulation time and a reduced volume of distribution, thereby promoting tumour uptake.
Preclinical studies demonstrated one- or two-phase plasma concentration-time profiles. Most of the drug is cleared with an elimination half-life of 20–30 hours. The volume of distribution is close to the blood volume, and the area under the concentration-time curve (AUC) is increased at least 60-fold compared with free doxorubicin. Studies of tissue distribution indicated preferential accumulation into various implanted tumours and human tumour xenografts, with an enhancement of drug concentrations in the tumour when compared with free drug.
Clinical studies of pegylated liposomal doxorubicin in humans have included patients with AIDS-related Kaposi’s sarcoma (ARKS) and with a variety of solid tumours, including ovarian, breast and prostate carcinomas. The pharmacokinetic profile in humans at doses between 10 and 80 mg/m2 is similar to that in animals, with one or two distribution phases: an initial phase with a half-life of 1–3 hours and a second phase with a half-life of 30–90 hours. The AUC after a dose of 50 mg/m2 is approximately 300-fold greater than that with free drug. Clearance and volume of distribution are drastically reduced (at least 250-fold and 60-fold, respectively). Preliminary observations indicate that utilising the distinct pharmacokinetic parameters of pegylated liposomal doxorubicin in dose scheduling is an attractive possibility.
In agreement with the preclinical findings, the ability of pegylated liposomes to extravasate through the leaky vasculature of tumours, as well as their extended circulation time, results in enhanced delivery of liposomal drug and/or radiotracers to the tumour site in cancer patients. There is evidence of selective tumour uptake in malignant effusions, ARKS skin lesions and a variety of solid tumours.
The toxicity profile of pegylated liposomal doxorubicin is characterised by dose-limiting mucosal and cutaneous toxicities, mild myelosuppression, decreased cardiotoxicity compared with free doxorubicin and minimal alopecia. The mucocutaneous toxicities are dose-limiting per injection; however, the reduced cardiotoxicity allows a larger cumulative dose than that acceptable for free doxorubicin.
Thus, pegylated liposomal doxorubicin represents a new class of chemotherapy delivery system that may significantly improve the therapeutic index of doxorubicin.
Effects of multiple injections of liposomal doxorubicin on pharmacokinetics, therapeutic outcome, and toxicity were studied in mice using different dosing schedules and dose intensities. Biodistribution of doxorubicin to the cutaneous tissues of mice (skin and paws) and to orthotopically implanted mammary tumors (4T1) was examined. Weekly intravenous administration of pegylated (STEALTH) liposomal doxorubicin (SL-DXR) at a dose of 9 mg/kg (every week x 4 doses) resulted in accumulation of doxorubicin in cutaneous tissues of mice and development of lesions resembling palmar-plantar erythrodysesthesia (PPE). Lengthening the dose interval to every 2 weeks x 4 doses reduced the accumulation of doxorubicin and lowered the incidence of PPE-like lesions. A dose interval of every 4 weeks x 4 resulted in complete clearance of doxorubicin from tissues between subsequent doses and a negligible incidence of PPE-like lesions. Doses of 9 mg/kg SL-DXR given at every week x 2 or every 2 weeks x 2 had similar therapeutic activities, whereas prolonging the dose interval to every 4 weeks x 2 reduced therapeutic activity. Pharmacokinetics, biodistribution, and therapeutic activity were studied in tumor-bearing mice for three dose schedules having the same dose intensity (4.5 mg/kg every 3 days x 4, 9 mg/kg every week x 2, or 18 mg/kg every 2 weeks x 1). For these schedules, larger doses administered less often tended to be superior therapeutically to smaller doses given more often. These data provide the first pharmacokinetic measurements of doxorubicin concentrations in cutaneous tissues and tumors with repeat administration of liposomal formulations, and they provide a useful model for the study of factors leading to PPE in humans.
In single center studies and case reports, it was shown that pegylated liposomal doxorubicin (PEG-DOXO) was effective as second-line therapy for patients with cutaneous T-cell lymphoma (CTCL). The objective of this study was to evaluate the efficacy and toxicity of single-agent PEG-DOXO as second-line chemotherapy in patients with CTCL.
A retrospective, multicenter study was performed evaluating 34 patients (31 male patients and 3 female patients). Twenty-seven patients received PEG-DOXO 20 mg/m(2), 5 patients received PEG-DOXO 20-30 mg/m(2), and 2 patients received PEG-DOXO 40 mg/m(2). PEG-DOXO was administered intravenously every 2 weeks in 6 patients, every 2-3 weeks in 4 patients, and every 4 weeks in 23 patients. One patient received only a single course of PEG-DOXO. Outcomes were evaluated, and adverse effects were recorded.
Thirty-four patients received at least 1 cycle of PEG-DOXO. Disease was classified as mycosis fungoides in 28 patients, mycosis fungoides with follicular mucinosis in 2 patients, small or medium-sized pleomorphic CTCL in 2 patients, Sèzary syndrome in 1 patient, and CD30 positive CTCL in 1 patient. Fifteen patients achieved a complete response (CR), including patients who achieved a CR and patients who achieved a CR defined by clinical criteria only with no biopsy (CRu), and 15 patients achieved a partial response (PR), resulting in a response rate (CRs, CRus, and PRs) of 88.2%. Two patients dropped out: one patient after a single PEG-DOXO infusion because of Grade 3 capillary leakage syndrome and one patient after two cycles because of a suicide attempt that was not related to treatment or to CTCL. All other patients received at least four cycles of PEG-DOXO. Overall survival was 17.8 months +/- 10.5 months (n = 33 patients), event-free survival was 12.0 months +/- 9.5 months, and disease-free survival was 13.3 +/- 10.5 months (n = 16 patients). Adverse effects were seen in 14 of 34 patients (41.2%); they were temporary and generally mild. Only 6 patients had Grade 3 or 4 adverse effects.
This multicenter study provided evidence of high efficacy of PEG-DOXO monotherapy with a low rate of severe adverse effects compared with other chemotherapy protocols in patients with CTCL.
Clostridia are anaerobic Gram-positive bacilli that can be isolated from the soil and the intestinal tract of humans. These microorganisms are recognized as the cause of devastating soft tissue infections, such as cellulitis, myositis, and gas gangrene. However, such bacteria may also be involved in various postoperative orthopedic infections, including prosthetic joint infection. We present three clinical cases of clostridial orthopedic infection and review the related medical literature.
Rituximab is a genetically engineered antibody directed against the CD20 antigen. Intravenous administration of rituximab has been used for the treatment of patients with low-, intermediate-, and high-grade B-cell non-Hodgkin's lymphomas and is a registered treatment modality for this indication. Treatment of primary cutaneous B-cell lymphoma (CBCL) with intralesionally or systemically administered rituximab has been described only in a few cases.
Our purpose was to assess the efficacy of rituximab in the treatment of CBCL.
We performed a retrospective study on 9 patients with CBCL who were treated with intralesional or systemic administration of rituximab.
Two patients treated with systemic rituximab achieved complete remission. Complete remission could be observed in 6 of 7 patients after 1 to 8 cycles of intralesional treatment with rituximab. In one patient one of two lesions showed a partial remission after 4 cycles of treatment, whereas the second showed complete remission. A local recurrence was observed in one patient after 27 months of follow-up and in two patients recurrences developed at other body sites after 12 and 14 months of follow-up. No severe side effect occurred except for slight pain during intralesional injection.
Rituximab therapy is a well-tolerated and effective treatment for primary CBCL. In comparison to intravenous administration, intralesional application of the drug allows the use of lower dosages. Intralesional therapy with rituximab deserves further investigation and comparison to systemic administration of the drug in controlled multicenter studies.
Previous studies have shown that pegylated liposomal doxorubicin (LD) is effective in the treatment of relapsing or recalcitrant cutaneous T-cell lymphoma.
To evaluate the activity and toxicity of LD in patients with stage IVB mycosis fungoides (MF).
In this retrospective study, we evaluated outcomes and recorded adverse effects in 10 patients with MF (seven men and three women) with extracutaneous involvement. Patients were treated with LD 20 mg m(-2) administered intravenously every 4 weeks.
All patients received at least two cycles of LD, three patients received four cycles and one patient received six cycles. Three patients (30%) had a partial response and two patients had stable disease. Grade 1-2 leucopenia occurred in three of the 10 patients, and grade 4 leucopenia in one. Three patients had grade 2 palmoplantar erythrodysaesthesia.
This study demonstrates that LD is beneficial in terms of activity and toxicity in stage IVB MF. These observations should be verified in larger studies.
Background:
Primary cutaneous B-cell lymphomas (PCBCLs) are characterized by restriction to the skin and a variable but mostly favourable prognosis. Since 1997 the recombinant, chimeric anti-CD20 antibody rituximab has been used in patients suffering from non-Hodgkin's B-cell lymphomas. Different studies have shown that the effectiveness and safety in the treatment of patients with low-grade follicular lymphoma is comparable to or even higher than the standard CHOP chemotherapy. So far it has been unclear whether an extended duration of therapy leads to a benefit for the patients with PCBCL.
Objectives:
To evaluate the objective response rate, time to progression, remission quality and histological changes and to compare our data with the literature.
Patients/methods:
Ten patients with PCBCL [eight with follicle centre cell lymphoma (FCCL), one with marginal zone lymphoma (MZL) and one with diffuse large B-cell lymphoma of the leg (DLBCL)] were treated by intravenous application of a chimeric antibody against the CD20 transmembrane antigen (rituximab) with a dosage of eight cycles, 375 mg m(-2) body surface, weekly.
Results:
The treatment regimen resulted in clinical overall response in 9 of 10 patients, in particular there were seven complete responses (70%) plus two partial responses (20%). The median duration of remission (durable remission, DR) is 23 months (4-30 months) to date. Histological assessment of responses in four patients showed no tumour-specific infiltration. In two patients histology revealed a residual infiltration and in one patient an increasing infiltration. In two patients no histology was taken after treatment; one patient developed a new lesion. No severe side-effects occurred. Observed side-effects were two bacterial infections, two patients with shivering during infusion, one patient with sweating for months and one patient with persisting itching. As expected the B-cell count in peripheral blood was depressed in all patients after infusion.
Conclusions:
Intravenous therapy with eight cycles of the anti-CD20 antibody rituximab is a non-toxic and effective treatment for a subset of patients with PCBCL (relapsed, aggressive entity, old patients, multiple lesions) with a long DR.
Primary cutaneous B-cell lymphomas include extranodal marginal zone B-cell lymphoma, follicular lymphoma, large B-cell lymphoma, and, rarely, mantle cell lymphoma. Our purpose in conducting this review was to determine the clinical and behavioral characteristics of primary cutaneous B-cell lymphomas, their relationship to infectious triggers, and therapeutic response. We conducted a retrospective chart review of 23 adult patients presenting to the dermatology clinic at M. D. Anderson Cancer Center with primary cutaneous B-cell lymphoma between January 1999 and May 2003. Primary cutaneous B-cell lymphomas generally present on the head and neck, with the trunk and extremities afflicted to a lesser extent. Patients were found to have serologic evidence of prior infection with Borrelia burgdorferi (n = 10), Helicobacter pylori (n = 5), and Epstein-Barr virus (n = 6). Overall, treatment of primary cutaneous B-cell lymphoma should involve multiple modalities; however, specific treatment aimed at concurrent or suspected infection, particularly B burgdorferi, is a helpful adjunct and may achieve complete remission in a small subset of patients.
Primary cutaneous marginal zone B-cell lymphoma (PCMZL) is a low-grade B-cell lymphoma that originates in the skin, with no evidence of extracutaneous disease. Studies focusing on the optimal treatment of PCMZL have not been published thus far. We describe 50 patients with PCMZL to further characterize clinical characteristics and outcome and, in particular, to evaluate our current therapeutic approach.
The majority of the patients (36/50 [72%]) presented with multifocal skin lesions, and 14 patients (28%) presented with solitary or localized lesions. The initial treatment of patients with solitary lesions consisted of radiotherapy or excision, whereas patients with multifocal lesions received a variety of initial treatments, most commonly radiotherapy and chlorambucil therapy. Cutaneous relapses developed in 19 (48%) of 40 patients who had complete remission and were more common in patients with multifocal disease. After a median period of follow-up of 36 months, 2 patients developed extracutaneous disease, but none of the patients died of lymphoma.
Patients with PCMZL who have solitary lesions can be treated effectively with radiotherapy or excision. For patients with PCMZL who have multifocal lesions, chlorambucil therapy and radiotherapy are suitable therapeutic options. In case of cutaneous relapses, the beneficial effects of treatment should carefully be weighed against the potential adverse effects.
Primary cutaneous B-cell lymphomas (PCBCLs) are a distinct group of primary cutaneous lymphomas with few and conflicting data on their prognostic factors.
The study group included 467 patients with PCBCL who were referred, treated, and observed in 11 Italian centers (the Italian Study Group for Cutaneous Lymphomas) during a 24-year period (1980 to 2003). All of the patients were reclassified according to the WHO-European Organisation for Research and Treatment of Cancer (EORTC) classification.
Follicle center lymphoma (FCL) accounted for 56.7% of occurrences, followed by marginal-zone B-cell lymphoma (MZL; 31.4%); diffuse large B-cell lymphoma (DLBCL), leg type, was reported in 10.9% of patients. Radiotherapy was the first-line treatment in 52.5% of patients and chemotherapy was the first-line treatment in 24.8% of patients. The complete response rate was 91.9% and the relapse rate was 46.7%. The 5- and 10-year overall survival (OS) rates were 94% and 85%, respectively. Compared with FCL/MZL, DLBCL, leg type, was characterized by statistically significant lower complete response rates, higher incidence of multiple cutaneous relapses and extracutaneous spreading, shorter time to progression, and shorter OS rates. The only variable with independent prognostic significance on the OS was the clinicopathologic diagnosis according to the WHO-EORTC classification (DLBCL, leg-type, showed a significantly worse prognosis v FCL and MZL; P < .001), whereas the only variable with independent prognostic significance on disease-free survival was the presence of a single cutaneous lesion (P = .001).
Our study identifies a possible PCBCL subclassification and the extent of cutaneous involvement as the two most relevant prognostic factors in PCBCL. These data can be considered reasonably as the clinical background for an appropriate management strategy.
Primary cutaneous marginal zone lymphomas (pcMZL) belong to the primary cutaneous B-cell lymphoma (pCBCL) group. They are characterized by their restriction to the skin and a high likelihood of recurrence after various treatment modalities. First-line therapy consists of surgery and radiotherapy. These therapies may not always be indicated in young patients or in patients with pCBCL located in the face, where surgery or radiotherapy may leave disfiguring scars or radioderma. Eight patients with pcMZL were treated with intra-lesional injections of 3 million units of recombinant IFNalpha2a three times per week. The patients either did not want to undergo or did not qualify for surgical excision or radiotherapy due to inappropriate localization or age. All patients experienced complete tumor regression after a mean of 8.5 weeks (range 3 - 20). Two patients relapsed 4 and 12 months after treatment, respectively, but tumor regression was repeated after additional cycles of intra-lesional IFNalpha2a. All other patients remained free of disease. Thus, intra-lesional IFNalpha2a may represent a valuable alternative to surgery and radiotherapy as first-line treatment of pcMZL.
Primary cutaneous marginal zone lymphoma (PCMZL) is an indolent disease. Treatment options include excision, local irradiation, interferon-alpha or chemotherapy. We present two patients with PCMZL and multiple skin lesions successfully treated with intralesional administration of the anti-CD20 monoclonal antibody rituximab. The first presented with four red skin lesions and the second with two. Biopsy of the largest lesion revealed marginal zone B-cell lymphoma in both patients. There was no evidence of systemic involvement in either patient. Both patients were treated with intralesional rituximab for 18 consecutive weeks. Skin lesions gradually regressed. Apart from mild local pain during the injection, no other adverse effects were observed. In conclusion, rituximab can be safely administered intralesionally in patients with PCMZL and can produce disease remission.
Background:
Rituximab (MabThera); Roche, Basel, Switzerland; an anti-CD20 chimeric monoclonal antibody) has been shown to have significant activity in nodal B-cell lymphomas, with few associated adverse effects. Its efficacy and safety were first demonstrated in the treatment of systemic B-cell lymphomas. Intravenous and subsequently intralesional administration of rituximab have also been reported to be effective and well tolerated in cutaneous B-cell lymphoma (CBCL). The comparative efficacy of intravenous vs. intralesional rituximab in CBCL is not known.
Objectives:
To evaluate the objective response rate, relapse rate, time to progression, and tolerance in patients with CBCL treated with intravenous or intralesional rituximab.
Methods:
Eight patients with multiple primary CBCL (four follicle centre lymphoma and four marginal zone lymphoma) were treated with intralesional rituximab (six patients; 10-30 mg per lesion, three times weekly for one or two cycles at a 4-week interval) or intravenous rituximab (two patients; 375 mg m(-2) once weekly for four consecutive weeks).
Results:
Complete clinical remission was obtained in all cases. The two patients treated intravenously did not relapse during a follow-up period of 18-24 months. Four of six patients treated intralesionally presented a relapse of new lesions at another site within a mean of 6 months after treatment. The injected lesions did not, however, recur. New lesions also responded to another cycle of intralesional rituximab. Tolerance to treatment was very good in both treatment groups.
Conclusions:
Rituximab therapy of CBCL appears to have a potential advantage in cases where lesions are localized in sites that are difficult to treat with radiotherapy or surgery and in which secondary scarring or alopecia is likely. Intralesional injections of rituximab allow the use of considerably smaller doses compared with intravenous treatment, with similar response rates and tolerance. However, within a 12-month follow-up period, relapse of CBCL with new lesions at distinct sites was frequently observed after intralesional treatment.
Palmar-plantar erythrodysesthesia (PPE), also called hand-foot syndrome or hand-to-foot syndrome, is a distinctive and relatively frequent dermatologic toxic reaction associated with certain chemotherapeutic agents. Pegylated liposomal doxorubicin (PLD), a long-circulating formulation of doxorubicin in which doxorubicin hydrochloride is encapsulated within pegylated liposomes, is approved to treat patients with metastatic breast cancer, advanced ovarian cancer, and acquired immunodeficiency syndrome-related Kaposi's sarcoma. The incidence of PPE is increased in patients receiving PLD compared with conventional doxorubicin. In studies that utilized the currently approved dose of PLD (50 mg/m(2) every 4 weeks), approximately 50% of all patients receiving PLD experienced PPE, and approximately 20% experienced grade 3 PPE. The pathophysiology of PPE, as it occurs with any drug with which it is associated, is not well understood. Studies evaluating the development of PPE specifically associated with PLD have not fully elucidated the mechanism; however, data support the roles of drug excretion in sweat and local pressure as contributors. When PPE develops, clinical interventions with respect to altering PLD administration include dose reduction, less frequent dosing, and ultimately, drug withdrawal with several consequences on treatment efficacy. This article will review the available data regarding the etiology and potential management strategies of PPE associated with PLD.