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DIAGNOSTIC AND THERAPEUTIC BURNING QUESTIONSON LYMPHOPROLIFERATIVE DISEASES
Rieti 27-29 Ottobre 2006
DALLA CHEMIOTERAPIADALLA CHEMIOTERAPIAAGLI ANTICORPI MONOCLONALI,AGLI ANTICORPI MONOCLONALI,
AGLI INIBITORI TIROSINCHINASICIAGLI INIBITORI TIROSINCHINASICINEL TRATTAMENTO DEI LINFOMINEL TRATTAMENTO DEI LINFOMI
A CELLULE T PERIFERICHEA CELLULE T PERIFERICHE
Lorenzo FalchiUniversità degli Studi di Perugia
Sez. di Medicina Interna e Scienze Oncologiche
LINFOMI A CELLULE T PERIFERICHE
CLASSIFICAZIONE W.H.O. / EORTC
LINFOMI A CELLULE T PERIFERICHE
CARATTERI GENERALI
Rappresentano il 10-15% di tutti i LNH nel Mondo Occidentale;
Condividono una origine post-timica del clone neoplastico;
Mostrano un ampio spettro di variabilità morfologico-immunofenotipica;
Mostrano nella maggior parte dei casi un comportamento aggressivo (eccezioni: cALCL; MF) in assenza di un preciso correlato morfologico-biologico-clinico
LINFOMI A CELLULE T PERIFERICHE
BURNING QUESTIONS!
La comprensione della biologiaLa comprensione della biologiae la definizione di una ottimale strategia terapeuticae la definizione di una ottimale strategia terapeutica
è stata per i linfomi a cellule T periferiche (PTCL)è stata per i linfomi a cellule T periferiche (PTCL)meno ben sviluppata ed è quindi meno evoluta,meno ben sviluppata ed è quindi meno evoluta,
rispetto a quanto si è verificato per i LNH a cellule B per:rispetto a quanto si è verificato per i LNH a cellule B per:
RARITÀ MODALITÀ DI CONDUZIONE DEGLI
STUDI CLINICIETEROGENEITÀ
LINFOMI A CELLULE T PERIFERICHE
Valore prognostico del fenotipo T-cellulare
Numerosi ampli studi hanno recentemente dimostrato che il fenotipo T-cellulare ha DI PER Sil fenotipo T-cellulare ha DI PER SÈ È un impatto un impatto negativo sulla sopravvivenza globale dei pazientinegativo sulla sopravvivenza globale dei pazienti
Studi precedenti, privi di adeguati strumenti classificativi, avevano indicato una prognosi equivalente per i pazienti con LNH B- e T cellulare
ETEROGENEITETEROGENEITÀÀANCHE PROGNOSTICA!ANCHE PROGNOSTICA!
L’inclusione di sottotipi a prognosi più favorevole (i.e. ALCL) nel gruppo dei PTCL può aver sottostimato il reale comportamento clinicodella maggior parte di questi linfomi.
LINFOMI A CELLULE T PERIFERICHE
BURNING QUESTIONS!
““There is no reason to expect that the same drugs There is no reason to expect that the same drugs would be optimal for patients withwould be optimal for patients with
peripheral T-cell lymphoma – or that all subtypes peripheral T-cell lymphoma – or that all subtypes of peripheral T-cell lymphoma would benefitof peripheral T-cell lymphoma would benefit
from the same drugs.”from the same drugs.”
J.O. Armitage et al. Ann Oncol. 2004 15: 1447-9 (Editorial)
LINFOMI A CELLULE T PERIFERICHE
TERAPIA DI PRIMA LINEA
NON NON ÈÈ STATO ANCORA INDIVIDUATO UN REGIME TERAPEUTICO STATO ANCORA INDIVIDUATO UN REGIME TERAPEUTICO CHE POSSA CONSIDERARSI IL “GOLDEN STANDARD”CHE POSSA CONSIDERARSI IL “GOLDEN STANDARD”
PER IL TRATTAMENTO PRIMARIO DEI PTCLsPER IL TRATTAMENTO PRIMARIO DEI PTCLs
CHOP e CHOP-like: terapia di scelta nella maggior parte dei pazienti con PTCL di nuova diagnosi, ma risultati uniformemente non soddisfacenti
Regimi chemoterapici più intensivi non chiaramente superiori vs. schema CHOP
Alcuni sottotipi istologici di PTCL mostrano un comportamento biologico-clinico peculiare e necessitano di strategie terapeutiche differenziate
Ruolo dell’AUTO- e dell’ALLOtrapianto: non ancora stabilito
Necessità di scores prognostici con potere discriminativo maggiore vs. IPI?
LINFOMI A CELLULE T PERIFERICHE
TERAPIA DI PRIMA LINEA
NON NON ÈÈ STATO ANCORA INDIVIDUATO UN REGIME TERAPEUTICO STATO ANCORA INDIVIDUATO UN REGIME TERAPEUTICO CHE POSSA CONSIDERARSI IL “GOLDEN STANDARD”CHE POSSA CONSIDERARSI IL “GOLDEN STANDARD”
PER IL TRATTAMENTO PRIMARIO DEI PTCLsPER IL TRATTAMENTO PRIMARIO DEI PTCLs
CHOP e CHOP-like: terapia di scelta nella maggior parte dei pazienti con PTCL di nuova diagnosi, ma risultati uniformemente non soddisfacenti
Regimi chemoterapici più intensivi non chiaramente superiori vs. schema CHOP
Alcuni sottotipi istologici di PTCL mostrano un comportamento biologico-clinico peculiare e necessitano di strategie terapeutiche differenziate
Ruolo dell’AUTO- e dell’ALLOtrapianto: non ancora stabilito
Necessità di scores prognostici con potere discriminativo maggiore vs. IPI?
Peripheral T-cell lymphomas: Initial features, natural history, and prognostic factors in a series of 174 patients diagnosed according to the R.E.A.L. Classification
A. Lopez-Guillermo et al. Ann Oncol. 1998; 9: 849-855.
Overall survival of the 174 patients with PTCL included in the present series.
38% (95% CI: 28-48)
LINFOMI A CELLULE T PERIFERICHE
TERAPIA DI PRIMA LINEA
NON NON ÈÈ STATO ANCORA INDIVIDUATO UN REGIME TERAPEUTICO STATO ANCORA INDIVIDUATO UN REGIME TERAPEUTICO CHE POSSA CONSIDERARSI IL “GOLDEN STANDARD”CHE POSSA CONSIDERARSI IL “GOLDEN STANDARD”
PER IL TRATTAMENTO PRIMARIO DEI PTCLsPER IL TRATTAMENTO PRIMARIO DEI PTCLs
Regimi chemoterapici più intensivi non chiaramente superiori vs. schema CHOP
CHOP e CHOP-like: terapia di scelta nella maggior parte dei pazienti con PTCL di nuova diagnosi, ma risultati uniformemente non soddisfacenti
Alcuni sottotipi istologici di PTCL mostrano un comportamento biologico-clinico peculiare e necessitano di strategie terapeutiche differenziate
Ruolo dell’AUTO- e dell’ALLOtrapianto: non ancora stabilito
Necessità di scores prognostici con potere discriminativo maggiore vs. IPI?
LINFOMI A CELLULE T PERIFERICHE
TERAPIA DI PRIMA LINEA
NON NON ÈÈ STATO ANCORA INDIVIDUATO UN REGIME TERAPEUTICO STATO ANCORA INDIVIDUATO UN REGIME TERAPEUTICO CHE POSSA CONSIDERARSI IL “GOLDEN STANDARD”CHE POSSA CONSIDERARSI IL “GOLDEN STANDARD”
PER IL TRATTAMENTO PRIMARIO DEI PTCLsPER IL TRATTAMENTO PRIMARIO DEI PTCLs
Alcuni sottotipi istologici di PTCL mostrano un comportamento biologico-clinico peculiare e necessitano di strategie terapeutiche differenziate
CHOP e CHOP-like: terapia di scelta nella maggior parte dei pazienti con PTCL di nuova diagnosi, ma risultati uniformemente non soddisfacenti
Regimi chemoterapici più intensivi non chiaramente superiori vs. schema CHOP
Ruolo dell’AUTO- e dell’ALLOtrapianto: non ancora stabilito
Necessità di scores prognostici con potere discriminativo maggiore vs. IPI?
Survival of T-cell/null cell anaplastic large cell lymphoma (ALCL) patients by anaplastic lymphoma kinase (ALK) expression.
Randy D. Gascoyne et al. Blood. 1999; Vol 93, No 11: 3913-3921
Prognostic Significance of Anaplastic Lymphoma Kinase (ALK) Protein Expression in Adults With Anaplastic Large Cell Lymphoma
ALK+
ALK-
Prognostic Significance of Anaplastic Lymphoma Kinase (ALK) Protein Expression in Adults With Anaplastic Large Cell Lymphoma
Randy D. Gascoyne et al. Blood. 1999; Vol 93, No 11: 3913-3921
Very few data are available concerning the clinical and pathological features that are useful for predicting outcome in ALCL.
Interpretation of these data is further confounded by the lack of precise criteria to distinguish primary cutaneous ALCL from systemic ALCL.
Even less is known about the prognostic significance of NPM-ALK/p80 protein expression.
Although three reports have suggested that NPMALK/p801 cases of ALCL are associated with a younger median age at diagnosis and an improved survival, no treatment details were provided and, more importantly, these studies did not perform multivariate analysis.
BURNING QUESTIONS:BURNING QUESTIONS:
LINFOMI A CELLULE T PERIFERICHE
TERAPIA DI PRIMA LINEA
NON NON ÈÈ STATO ANCORA INDIVIDUATO UN REGIME TERAPEUTICO STATO ANCORA INDIVIDUATO UN REGIME TERAPEUTICO CHE POSSA CONSIDERARSI IL “GOLDEN STANDARD”CHE POSSA CONSIDERARSI IL “GOLDEN STANDARD”
PER IL TRATTAMENTO PRIMARIO DEI PTCLsPER IL TRATTAMENTO PRIMARIO DEI PTCLs
Ruolo dell’AUTO- e dell’ALLOtrapianto: non ancora stabilito
CHOP e CHOP-like: terapia di scelta nella maggior parte dei pazienti con PTCL di nuova diagnosi, ma risultati uniformemente non soddisfacenti
Regimi chemoterapici più intensivi non chiaramente superiori vs. schema CHOP
Alcuni sottotipi istologici di PTCL mostrano un comportamento biologico-clinico peculiare e necessitano di strategie terapeutiche differenziate
Necessità di scores prognostici con potere discriminativo maggiore vs. IPI?
LINFOMI A CELLULE T PERIFERICHE
TERAPIA DI PRIMA LINEA
NON NON ÈÈ STATO ANCORA INDIVIDUATO UN REGIME TERAPEUTICO STATO ANCORA INDIVIDUATO UN REGIME TERAPEUTICO CHE POSSA CONSIDERARSI IL “GOLDEN STANDARD”CHE POSSA CONSIDERARSI IL “GOLDEN STANDARD”
PER IL TRATTAMENTO PRIMARIO DEI PTCLsPER IL TRATTAMENTO PRIMARIO DEI PTCLs
Ruolo dell’AUTO- e dell’ALLOtrapianto: non ancora stabilito
CHOP e CHOP-like: terapia di scelta nella maggior parte dei pazienti con PTCL di nuova diagnosi, ma risultati uniformemente non soddisfacenti
Regimi chemoterapici più intensivi non chiaramente superiori vs. schema CHOP
Alcuni sottotipi istologici di PTCL mostrano un comportamento biologico-clinico peculiare e necessitano di strategie terapeutiche differenziate
Necessità di scores prognostici con potere discriminativo maggiore vs. IPI?
LINFOMI A CELLULE T PERIFERICHE
BURNING QUESTIONS!
““There is no reason to expect that the same drugs There is no reason to expect that the same drugs would be optimal for patients withwould be optimal for patients with
peripheral T-cell lymphoma – or that all subtypes peripheral T-cell lymphoma – or that all subtypes of peripheral T-cell lymphoma would benefitof peripheral T-cell lymphoma would benefit
from the same drugs.”from the same drugs.”
J.O. Armitage et al. Ann Oncol 15: 1447-9 (Editorial)
LINFOMI A CELLULE T PERIFERICHE
TERAPIA DI PRIMA LINEA
NON NON ÈÈ STATO ANCORA INDIVIDUATO UN REGIME TERAPEUTICO STATO ANCORA INDIVIDUATO UN REGIME TERAPEUTICO CHE POSSA CONSIDERARSI IL “GOLDEN STANDARD”CHE POSSA CONSIDERARSI IL “GOLDEN STANDARD”
PER IL TRATTAMENTO PRIMARIO DEI PTCLsPER IL TRATTAMENTO PRIMARIO DEI PTCLs
CHOP e CHOP-like: terapia di scelta nella maggior parte dei pazienti con PTCL di nuova diagnosi, ma risultati uniformemente non soddisfacenti
Regimi chemoterapici più intensivi non chiaramente superiori vs. schema CHOP
Alcuni sottotipi istologici di PTCL mostrano un comportamento biologico-clinico peculiare e necessitano di strategie terapeutiche differenziate
Ruolo dell’AUTO- e dell’ALLOtrapianto: non ancora stabilito
Necessità di scores prognostici con potere discriminativo maggiore vs. IPI?
NECESSITA’ DI NUOVI APPROCCI TERAPEUTICI!
LINFOMI A CELLULE T PERIFERICHE
NUOVI APPROCCI TERAPEUTICI
Analoghi nucleosidici
Immunotossine
HDACi
IMMUNOTERAPIA• Gemcitabina
• Ara-G
• Denileukin difitox
• Depsipeptide
• Anti-CD25 (radiolabeled)
• Alemtuzumab
• Alemtuzumab + CT
• SGN30
• MDX-060
• 5F11
• KM2760-AntiCCR4
• Pentostatina
Author Drug Mech. of action Outcome
LINFOMI A CELLULE T PERIFERICHE
ANALOGHI NUCLEOSIDICI
Schedule
Sallah gemcitabine Nucleoside analog, pyridine anti-metab: non-specific DNA synthesis inhibition
IV, 1200 mg/ms; D1, 8, 15 every28 days; 2-4 cy
ORR: 60%
Pt n.
10(4 PTCLs)
Myron 506U78 Pro-drug of Ara-G (deoxyguanosine analog): toxic toT-cells
IV, 1,5 gr/ms;D1, 3, 5 every21 days 2-8 cy
19(8 PTCLs)
ORR: 10,5%,15 pts dead, median OS: 3m
Tsimberidou(MDACC)
pentostatin inhibits adenosine deaminase
42(4 PTCLs +1 ATLL)
3 Ds every 3 W.1) 0: 5.0 mg/m2; 2) -1: 3.75 g/m2; 3) -2: 2.8 mg/m2; 4) +1: 6.25 g/m2
ORR: 100%2ys OS: 53%
Author Drug Mechanism of action Outcome
LINFOMI A CELLULE T PERIFERICHE
IMMUNOTOSSINE
SchedulePt n.
Dang Denileukin difitox*
Targets tumor cells expressing IL-2R
18 μg/Kg/day X5 days every 3W; up to 8 cy
14(7 CD25+, 7 CD25-)*
** CD25-positivity defined as 10% or more of tumor cells expressing detectable CD25
ORR: 50%(CR 14%, PR 36%)
*fusion protein combining the enzimatically active domain of diphteria toxin and the full-lenght sequence of IL-2.
Author Drug Mechanism of action Outcome
INIBITORI DELLE HDAC
SchedulePt n.
Piekarz Depsipeptide Inhibitor of histone deacetylation; differentiating agent
19 14 mg/ms; 4 h inf; D 1, 8, 15 every 28 days
Phase II; ORR: 26%
Author Drug Mechanism of action Outcome
LINFOMI A CELLULE T PERIFERICHE
IMMUNOTERAPIA
SchedulePt n.
Waldmann Anti-CD25 yttrium-90 labeled
18 (16 evaluable)
Anti-Tac binds to IL-2Rα, preventing interaction with IL-2*
IV injection; phase I study: dose escalation**;phase II: 10 mCi 90Y anti-Tac per cycle
**Start at 5 mCi, increase by 5 mCi every cycle until MTD
ORR: 56%
*Resting normal T cells, B cells and monocytes do not display IL-2Rα. In contrast, this receptor subunitis expressed by a proportion of the abnormal cells in certain forms of leukemia and lymphoma
Forero-Torres
Anti-CD30 Chimeric mAb which recognizes the CD30 Ag
5 (ALCL) IV, 6 mg/Kg weekly
ORR: 33%Well tolerated
Ansell Anti-CD30 Fully human anti-CD30 IgG1k mAb
IV injection; phase I study:dose escalation;phase II: 10-15 mg/Kg weekly for 4 cy
ORR: 33%Well tolerated
5 (ALCL)
Ishida KM2760 Defucosylated chimeric anti CCR4; ADCC
Cell lines, primary tumor cells
Preclinical studies
Alemtuzumab is a humanized immunoglobulin G1 (IgG1; CDR grafted) anti-CD52 monoclonal antibody that binds to the cell membrane of more than 95% of all normal human blood lymphocytes, as well as to most B- and T-cell lymphomas.
CD52 is a nonmodulating antigen which is expressed at high density on > 95% of all normal and malignant B and T lymphocytes, monocytes and macrophages, but not on hemopoietic stem cells.
Alemtuzumab
In vitro: complement-mediated lysis, antibody-dependent cell cytotoxicity (ADCC) and apoptosis. It is unclear which of these mechanisms is most important for the therapeutic activity of this antibody in vivo.
Malignant T cells appear to express extraordinarily high numbers of CD52 cell surface molecules (approximately 500 000 molecules per lymphocyte). Thus, T-cell lymphomas, including PTLs, may be particularly suitable for therapy with alemtuzumab
A pilot study of alemtuzumab (anti-CD52 monoclonal antibody) therapy for patients with relapsed or chemotherapy-refractory peripheral T-cell lymphomas
Gunilla Enblad, Blood. 2004;103: 2920-2924
Responses were obtained at all tumor sites, including lymph nodes
Alemtuzumab may have high antitumor activity in PTL. The rate of remissions in this heavily pretreated, poor-prognosis group of patients is promising.
However, the infectious (5 patients dying from infectious complications) and hematologic (more pronounced than in previous alemtuzumab studies in B-CLL, T-PLL, and MF/SS) toxicity observed was unacceptably high, leading to an early closure of the study. after 14 of the planned 25 patients had been enrolled
CONCLUSIONS I:CONCLUSIONS I:
Alemtuzumab, in combination with the emerging availability of technologiesthat help restore T-cell functions and numbers (i.e. antibodies to CD3 and CD28), may hopefully enhance the safety of CD52-targeted therapy in forthcoming clinical trials.
Alternatively, lower dosages of alemtuzumab could be explored to improve the safety of alemtuzumab therapy in PTL patients.
Further studies with alemtuzumab in PTL are warranted in patients with less advanced disease and earlier in the disease course.
A pilot study of alemtuzumab (anti-CD52 monoclonal antibody) therapy for patients with relapsed or chemotherapy-refractory peripheral T-cell lymphomas
Gunilla Enblad, Blood. 2004;103: 2920-2924
CONCLUSIONS II:CONCLUSIONS II:
The safety and efficacy of alemtuzumab as a component of first-line therapy for PTL also needs to be investigated.
Preliminary observations of a phase II study of reduced-dose alemtuzumab treatment in patients with pretreated T-cell lymphoma
ORR: 60%, 2 (20%) CR, and 4 (40%) PR.
The median duration of response was 7 months (range: 2-10).
No grade 3-4 anemia/ neutropenia/ thrombocytopenia.
Response rates are broadly in line with those achieved utilizing conventional alemtuzumab schedules.
Alemtuzumab at lower doses increases safety while maintaining effectiveness.
Escalating dosage: 3 mg d 1; 10 mg d 3; then 10 mg, 3 times a week, for a maximum of 4 weeks.
RESULTS AND CONCLUSIONS:
Pier Luigi Zinzani, haematologica 2005; 90:702-703
Reduced intensity conditioning and allogeneic stem cell transplantation after salvage therapy integrating alemtuzumab for patients with relapsed peripheral T-cell non-Hodgkin’s lymphoma
GG Wulf. Bone Marrow Transplantation (2005) 36, 271–273.
Reduced intensity conditioning and allogeneic stem cell transplantation after salvage therapy integrating alemtuzumab for patients with relapsed peripheral T-cell non-Hodgkin’s lymphoma
Combining anti-CD52 antibody therapy with chemotherapy in peripheral T-NHL appears feasible.
As for the efficacy of alemtuzumab against T-NHL in this setting, no firm conclusions can be drawn: may help patients with T-NHL to achieve PR prior to definitive HDS followed by SCT?
CONCLUSIONS:CONCLUSIONS:
LINFOMI A CELLULE T PERIFERICHE
PROSPETTIVE FUTURE - 1
The comparison of peripheral T-cell lymphoma with normal samples revealed a subset of 17 and 35 significantly differentially expressed genes between all peripheral T-cell lymphoma tumors and normal T lymphocytes or reactive lymph nodes, respectively
Some of these genes represented immune response proteins, and some of them could represent tumoral markers characterizing T-cell ymphomas.
LINFOMI A CELLULE T PERIFERICHE
DIREZIONI FUTURE - 1
On the basis of genes that are differentially expressed between lymphoblastic T-cell lymphoma and peripheral T-cell lymphoma tumors, we identified genes related with NF-KB signaling pathway, both proteins necessary for the activation of this factor as could be some interleukin receptors such us IL2RB, LTB, tumor necrosis factor-induced proteins, PRKCD, RELB, or MAP3K14 (NIK), or genes that are targets of the transcriptional activity of NF-B such as VCAM1, BIRC3, JUNB, or MMP9.
B Martinez-Delgado Clin Cancer Res, 10, 4971–4982, 2004
As a whole, we found that NF-B pathway is not activated in lymphoblastic T-cell lymphomas, although it seems to be hyperactivated in peripheral T-cell lymphoma tumors.
LINFOMI A CELLULE T PERIFERICHE
DIREZIONI FUTURE - 2
Gene expression profiling identifies molecular subgroups among nodal peripheral t-cell lymphomas
• PTCLUS divided into the three subgroups:
U1: expression of cyclin D2 and few reactive cells
U2: with some overlap with U1 but also associated with overexpression of genes involved in T-cell activation and apoptosis including NF-κB1 and BCL2;
U3 (including the previously defined “Lennert’s lymphoma”): overexpression of histiocytic markers in addition to genes involved in the IFNγ/JAK/STAT pathway.
B. Ballester
LINFOMI A CELLULE T PERIFERICHE
Gene expression analysis of peripheral t-cell lymphoma not otherwise specified reveals the existence of two subgroups related to different cellular counterparts
Comparison with the gene expression profiles of purified normal T-cell subpopulations, shows that PTCLUS cells are more related to activated T cells, both CD4+ and CD8+.
Of interest was overexpression of PDGFRA, confirmed by IHC, which may be a potential therapeutic target.
P. Piccaluga
DIREZIONI FUTURE - 3
Expression of platelet-derived growth factor receptor in peripheral T-cell lymphoma not otherwise specified
Platelet-derived growth factor (PDGF) induces mitosis in fibroblasts, smooth-muscle cells (wound healing) and other cells.
BACKGROUND:
In addition to its role in autocrine growth stimulation of tumor cells, PDGF has also been suggested to regulate tumor stroma fibroblasts and tumor angiogenesis
Ever since the discovery 20 years ago that the transforming retroviral v-sis oncogene is derived from the platelet-derived growth factor (PDGF) B chain gene, PDGF signaling has been an interesting target for cancer treatment.
in several tumours, aberrant PDGF or PDGFR signalling constitutively activates a cell-signalling cascade.
Moreover, inhibition of PDGFR activity can lead to tumour regression.
BACKGROUND:
Expression of platelet-derived growth factor receptor in peripheral T-cell lymphoma not otherwise specified
Gene expression profile of 17 patients with peripheral T-cell lymphoma not otherwise specified and 15 samples of purified T lymphocytes from healthy donors
Genes differentially expressed in healthy and neoplastic samples.
PDGFRα was overexpressed by four fold in peripheral T-cell lymphoma not otherwise specified.
Pier Paolo Piccaluga et al. Lancet Oncol 2005; 6: 440
Expression of platelet-derived growth factor receptor in peripheral T-cell lymphoma not otherwise specified
On immunoalkaline-phosphatase staining, neoplastic cells showed that the cytoplasm of all tested cases were positive for PDFGR.
Because PDGFR is a potential target for imatinib, our findings might have important pathogenetic and clinical implications.
We then searched tissue samples for presence of PDGFRα by applying a polyclonal antibody to tissue microarrays containing samples from the 17 patients who had gene-expression profiling
Gene expression profile of 17 patients with peripheral T-cell lymphoma not otherwise specified and 15 samples of purified T lymphocytes from healthy donors
Pier Paolo Piccaluga et al. Lancet Oncol 2005; 6: 440
Expression of platelet-derived growth factor receptor in peripheral T-cell lymphoma not otherwise specified
TK inhibitor
The points of intervention of PDGF receptor signaling.
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