Annual Meeting Proceedings Part 1 - American Society of Clinical ...
Annual Meeting Proceedings Part 1 - American Society of Clinical ...
Annual Meeting Proceedings Part 1 - American Society of Clinical ...
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136s Central Nervous System Tumors<br />
2085 General Poster Session (Board #17H), Sat, 1:15 PM-5:15 PM<br />
The role <strong>of</strong> fluorescence-guided surgical resection in the combined treatment<br />
<strong>of</strong> malignant glioma. Presenting Author: Carmine Maria Carapella,<br />
Neurosurgery, Cancer Institute Regina Elena, Roma, Italy<br />
Background: Malignant glioma represents a relevant therapeutic issue and<br />
the value <strong>of</strong> extensive surgical resection remains debated; recent evidence<br />
suggests that radical removal is associated with better survival. An<br />
interesting tool for identifying tumor tissue and increasing the extent <strong>of</strong><br />
surgery is represented by fluorescence-guided resection, taking advantage<br />
<strong>of</strong> metabolic and structural changes induced by a natural precursor <strong>of</strong> heme<br />
biosynthetic pathway, 5-amino-levulinic acid (ALA). Methods: The present<br />
experience is related to 32 patients affected by malignant glioma (18 newly<br />
diagnosed: 16 glioblastoma (GBM), 2 anaplastic oligodendroglioma; and<br />
14 recurrent GBM) eligible for fluorescence-guided resection, operated on<br />
in our Institute since fall <strong>of</strong> 2009. All patients underwent preoperative and<br />
early postoperative MRI, showing contrast enhancing lesions. An oral dose<br />
<strong>of</strong> 20 mg 5-ALA /kg bw was administered to each patient. Microsurgical<br />
resection was performed by an operating microscope enabled to visualize<br />
the fluorescence. All the patients, as first line treatment, have been<br />
submitted to radiotherapy and chemotherapy; second and in some cases<br />
third line treatments were utilized in recurrent cases. The patients<br />
follow-up ranged from 2 years to 6 months. Results: In more than 90% <strong>of</strong><br />
patients tumor tissue showed intraoperative red fluorescence; mainly in<br />
recurrent GBM, when MRI documented heterogeneous lesions with enhancing<br />
areas mixed with non enhancing gliotic scars, fluorescence-guided<br />
surgery allowed a better definition <strong>of</strong> active tumor, with net margins from<br />
perilesional “healthy” brain. Early postoperative MRI confirmed gross total<br />
resection without contrast enhancement in 80 % <strong>of</strong> patients. In the present<br />
experience the procedure did not determine any relevant additional<br />
neurological deficit. Considering overall survival <strong>of</strong> recurrent patients we<br />
obtained a median extension <strong>of</strong> at least 9.0 months (3 – 16� months).<br />
Conclusions: Fluorescence-guided surgery improves tumor detection and<br />
allows extended resection <strong>of</strong> malignant glioma, without any relevant impact<br />
on neurological status, resulting helpful mainly in the recurrent setting with<br />
a consistent effect on overall survival.<br />
2087 General Poster Session (Board #18B), Sat, 1:15 PM-5:15 PM<br />
Correlation <strong>of</strong> survival with tumor antigen expression in patients with newly<br />
diagnosed glioblastoma receiving a multi-epitope pulsed dendritic cell<br />
vaccine. Presenting Author: Surasak Phuphanich, Neuro-Oncology Program,<br />
Cedars-Sinai Medical Center, Los Angeles, CA<br />
Background: This study evaluated the safety and immune responses to an<br />
autologous dendritic cell vaccine pulsed with class I peptides from tumor<br />
associated antigens (TAA) expressed on gliomas and overexpressed in their<br />
cancer stem cell population (ICT-107). These TAA epitodes AIM-2. TRP-2,<br />
HER2 and AIM-2, are also overexpressed on glioblastoma multiforme<br />
(GBM) cancer stem cells. Methods: TAA epitopes included HER2, TRP-2,<br />
gp100, MAGE-1, IL13R�2, and AIM-2. HLA-A1 and/or HLA-A2 positive<br />
glioblastoma (GBM) patients with gross total resection were eligible.<br />
Mononuclear cells from leukapheresis were differentiated into dendritic<br />
cells, pulsed with TAA peptides, and administered intradermally three<br />
times at two-week intervals in the axilla region after a standard treatment<br />
with concurrent temozolomide (TMZ) and radiation therapy for newly<br />
diagnosed (ND-GBM). Results: Twenty-one patients were enrolled with 17<br />
ND-GBM and three recurrent GBM patients and one brainstem glioma.<br />
Immune response data on 15 newly diagnosed patients showed 33%<br />
responders. TAA expression by qRT-PCR showed all patient tumors<br />
expressed at least three TAA with 75% expressing all six. Correlations <strong>of</strong><br />
increased PFS and quantitative expression <strong>of</strong> MAGE1, AIM-2, gp100 and<br />
HER2 were observed. A decrease or absence <strong>of</strong> CD133 expression was seen<br />
in five patients who underwent a second resection. As <strong>of</strong> February 1, 2012,<br />
six <strong>of</strong> 16 ND-GBM patients showed no evidence <strong>of</strong> tumor recurrence<br />
(44-63 months). Median progressive free survival (PFS) in newly diagnosed<br />
patients was 16.9 months with a two-year PFS rate was 43.8%<br />
(95%CI,19.8-66.0 ). The median overall survival rate (OS) was 38.4<br />
months and a two-year OS was 80.3% (95%CI,58.6-96.7). Conclusions:<br />
Expression <strong>of</strong> four ICT-107 targeted antigens in the pre-vaccine tumors<br />
correlated with prolonged overall survival and PFS in ND-GBM patients.<br />
The goal <strong>of</strong> targeting tumor antigens highly expressed on glioblastoma<br />
cancer stem cells is supported by the observation <strong>of</strong> decreased or absent<br />
CD133 expression in the recurrent areas <strong>of</strong> gadolinium-enhanced tumor.<br />
2086 General Poster Session (Board #18A), Sat, 1:15 PM-5:15 PM<br />
An investigator-initiated monocentric phase I dose escalation trial <strong>of</strong><br />
temsirolimus and irinotecan (TEMIR) in patients with relapsing glioblastoma<br />
multiforme (reGBM). Presenting Author: Max E. Scheulen, Department<br />
<strong>of</strong> Medical Oncology, West German Cancer Center, University <strong>of</strong><br />
Duisburg-Essen, University Hospital Essen, Essen, Germany<br />
Background: Deregulation <strong>of</strong> the PI3K/AKT pathway has been preclinically<br />
involved in the pathophysiology <strong>of</strong> GBM. The mammalian target <strong>of</strong><br />
rapamycin (mTOR) is an important downstream mediator <strong>of</strong> PI3K/AKT<br />
signalling. The mTOR-inhibitor temsirolimus (Tem) achieves significant<br />
drug levels in brain. Thus, Tem may be effectively combined with irinotecan<br />
(Iri) which has shown promising results in combination with bevacizumab<br />
in patients (pts) with reGBM refractory to temozolomide (Tmz) in phase II.<br />
Exposure to Tem as well as Iri is substantially reduced in pts receiving<br />
CYP3A4 enzyme-inducing anticonvulsants (CYP3A4-Ind). Methods: TEMIR<br />
is a phase I trial <strong>of</strong> escalating doses <strong>of</strong> Tem in combination with Iri in pts<br />
with reGBM refractory to Tmz depending on the cotreatment with CYP3A4-<br />
Ind. In pts without CYP3A4-Ind dose escalation <strong>of</strong> Tem was performed<br />
according to the “3�3 protocol” from 15 via 20 to 25 mg iv wkly together<br />
with 85 mg/m2 Iri iv wkly. In pts with CYP3A4-Ind the doses <strong>of</strong> Tem were<br />
30, 40 and 50 mg iv wkly together with 170 mg/m2 Iri iv wkly, respectively.<br />
The determination <strong>of</strong> the pharmacokinetics (PK) <strong>of</strong> Tem and its influence<br />
on the PK <strong>of</strong> Iri and its active metabolite SN38 was performed by validated<br />
RP-HPLC methods with fluorescence detection. Results: Up to now, 14 pts<br />
[4 female and 10 male, median age 47 yrs (range 41-65 yrs), 9 without and<br />
5 with CYP3A4-Ind] have been treated. All 9 pts without CYP3A4-Ind (3<br />
pts on 15, 20 and 25 mg Tem each) are evaluable for safety with only mild<br />
toxicity [highest CTC-grade �2 (gr) per pt]: diarrhea 4 (gr2) and 1 (gr3),<br />
neutropenia 1 (gr3), thrombopenia 1 (gr2), anemia 1 (gr2), pneumonia 2<br />
(gr2), rash 1 (gr2). PK parameters <strong>of</strong> Iri and SN38 were in agreement with<br />
previously published studies and there was no significant effect <strong>of</strong> 15 to 25<br />
mg Tem combined with 85 mg/m2 Iri on the PK <strong>of</strong> Iri and SN38. In 7 pts<br />
evaluable for efficacy there was no remission (RECIST) and median time to<br />
symptomatic and/or MRT progression was 10 wks (7, 9�, 10, 10�, 11,<br />
15, 20 wks). Conclusions: The combination <strong>of</strong> Tem in standard dose <strong>of</strong> 25<br />
mg iv wkly with 85 mg/m2 Iri wkly is safe in pts with reGBM without<br />
CYP3A4-Ind. Tem has no significant effect on the PK <strong>of</strong> Iri and SN38.<br />
2089 General Poster Session (Board #18D), Sat, 1:15 PM-5:15 PM<br />
High-dose chemotherapy (HDC) followed by autologous stem cell transplant<br />
(ASCT) for recurrent/progressive CNS lymphoma. Presenting Author:<br />
Mary Roberta Welch, Memorial Sloan-Kettering Cancer Center, New York,<br />
NY<br />
Background: In two reports by Soussain et al, promising efficacy was<br />
observed in recurrent primary CNS lymphoma with induction cytarabine/<br />
VP-16 (CYVE) followed by HDC-ASCT (busulfan, thiotepa and cyclophosphamide<br />
[BTC]), but significant toxicity, mainly from CYVE, has limited<br />
widespread use. We report our experience with HDC-ASCT with alternative<br />
induction regimens. Methods: Retrospective review <strong>of</strong> pts with recurrent/<br />
refractory non-Hodgkin lymphoma (NHL) with CNS involvement treated<br />
with HDC-ASCT (2000-present). Results: Seventeen pts met inclusion<br />
criteria: med age� 58 (41-65); 9 were women; med KPS prior to<br />
transplant� 90 (range 70-100). At initial presentation, 10 had primary<br />
CNS lymphoma (ocular: 1); 7 had systemic NHL without CNS involvement;<br />
1 had both systemic and CNS disease. Pts had been heavily pre-treated.<br />
Among those with PCNSL, high dose MTX was used in all pts and WBRT in<br />
4. Two pts had received a previous HDC-ASCT. Among systemic NHL pts,<br />
various regimens were used, mostly R-CHOP(4), but also R-EPOCH (1),<br />
CVP (1), ICE (1) and CODOX-M (1). At CNS recurrence, pts received various<br />
induction regimens prior to HD-ASCT: high-dose methotrexate (MTX)based<br />
chemotherapy (N� 13), cytarabine-based regimens (N�2), and<br />
other (N� 2). All pts achieved a CR or near CR prior to HDC-ASCT.<br />
Harvesting was obtained with G-CSF alone in 9 pts; 8 required plerixafor.<br />
Two pts failed mobilization N�15 received HDC-ASCT. The HDC consisted<br />
<strong>of</strong> BTC (N�13); 1 received BEAM and 1 received reduced intensity<br />
fludarabine, melphalan and alemtuzumab. Eight pts experienced a grade<br />
III or IV toxicity – most commonly fatigue, febrile neutropenia, and<br />
infection. One previously transplanted pt died from sepsis. With a med<br />
follow-up <strong>of</strong> 11 months, post-transplant med-PFS has not been reached.<br />
The 12m PFS was 92% (95% CI 56-98). Because no patient has<br />
progressed, the OS was identical to PFS. Conclusions: HDC-ASCT was a<br />
highly effective salvage approach in this population <strong>of</strong> recurrent/refractory<br />
CNS lymphoma. To reduce the risk <strong>of</strong> harvesting failure at the time <strong>of</strong><br />
recurrence, harvesting stem cells at the time <strong>of</strong> initial treatment could be<br />
considered in pts with high risk for relapse.<br />
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