Multicenter phase I/II trial of encorafenib with and without binimetinib in combination with nivolumab and low-dose ipilimumab in metastatic BRAF-mutant melanoma.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. TPS9596-TPS9596
Author(s):  
Max Jameson-Lee ◽  
Patrick Alexander Ott ◽  
Jason J. Luke ◽  
Michael A. Postow ◽  
Andrew Stewart Poklepovic
Keyword(s):  
Targeted Therapy ◽  
T Cell ◽  
High Risk ◽  
Brain Metastases ◽  
Phase I ◽  
Liver Metastases ◽  
Metastatic Melanoma ◽  
Quadruple Therapy ◽  
Mek Inhibition ◽  
Braf Mutant

TPS9596 Background: Targeted therapy (BRAF + MEK inhibitors) and immunotherapy (anti-PD1 + anti-CTLA4) have improved overall survival for metastatic or unresectable BRAFV600E/Kmutant melanoma. Whereas targeted therapy has a high response rate, immunotherapy may deliver longer term disease control for a larger number of patients. Despite these treatments, patients with high risk metastatic melanoma such as those with brain or liver metastases, elevated lactate dehydrogenase (LDH) and bulky disease have inferior treatment outcomes with current therapies. A BRAF+MEK+PDL1 regimen has recently emerged however the role for this treatment remains unclear. Several recent trials combining MEK inhibition and immunotherapy have failed possibly because MEK inhibition can compromise T cell activation. Meanwhile the addition of CTLA4 blockade to PD1 inhibition appears to disproportionately benefit patients with non-T cell-inflamed tumors and potentially high-risk disease. For patients with high risk BRAF-mutant metastatic melanoma, further investigation of BRAF/MEK targeted and PD-1/CTLA-4 directed immunotherapy combination strategies remains a priority. Methods: This is an open label, multi-site, Phase 1/2 study of encorafenib (Enco) +/- binimetinib (Bini) + nivolumab (Nivo) + ipilimumab (Ipi) for the treatment of patients with unresectable or metastatic BRAF-mutated melanoma in high-risk cohorts (NCT04655157). An initial regimen confirming Phase I approach will be pursued on two schedules concurrently, with patients accruing equally to each group. Group 1 will receive 3mg/kg Nivo, and 1 mg/kg Ipi and 300mg Enco (12 participants, triple therapy) and Group 2 will receive 3mg/kg Nivo and 1mg/kg Ipi and 450mg Enco and 45mg Bini, (12 participants, quadruple therapy). Dose limiting toxicity (DLT) will be evaluated weeks 1-6. A recommended Phase II regimen (RP2R) [either triple or quadruple therapy] will be carried forward into two high risk metastatic disease cohort expansions of 30 participants each. Cohort 1 will include patients with symptomatic brain metastases, while cohort 2 will include patients with elevated LDH as well as either liver metastases OR bulky visceral disease (sum of longest diameters > 44mm). Patients meeting criteria for cohorts 1 and 2 will be placed in cohort 1. Patients with symptomatic brain metastases will be included with an ECOG up to 2 and on ≤ 4mg of dexamethasone or equivalent. Continuous Bayesian toxicity monitoring will be used throughout to monitor DLT. Pre and on-treatment tumor biopsies will assess changes in the tumor microenvironment while peripheral blood ctDNA and T cell Ki67% changes will assess early response and immune activation during triplet and quadruplet therapy. Clinical trial information: NCT04655157.

A Phase I Study Of Myeloablative Radioimmunotherapy Using Iodine-131 Anti-CD45 Antibody Followed By Autologous Stem Cell Transplantation For High-Risk B-Cell and T-Cell Non-Hodgkin Lymphoma and Hodgkin Lymphoma

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 3333-3333 ◽  
Author(s):  
Ryan D. Cassaday ◽  
Oliver W. Press ◽  
John M. Pagel ◽  
Joseph G. Rajendran ◽  
Theodore A. Gooley ◽  
...  
Keyword(s):  
Stem Cell ◽  
T Cell ◽  
High Risk ◽  
Phase I ◽  
B Cell ◽  
Hodgkin Lymphoma ◽  
Dose Escalation ◽  
Absorbed Dose ◽  
High Dose ◽  
Normal Organ

Abstract Background High-dose therapy and autologous stem cell transplant (ASCT) remains the standard of care for many high-risk/relapsed B-cell non-Hodgkin lymphomas (B-NHL), T-cell NHL (T-NHL) and classical Hodgkin lymphoma (HL), yet most will not achieve sustained remissions. High-dose anti-CD20 radioimmunotherapy (RIT) and ASCT has been successfully employed to address this challenge in B-NHL, yet relapse still occurs potentially due to blockade of target sites by circulating rituximab (R). RIT options are limited for patients with T-NHL and HL. Preclinical data indicate that targeting the panhematopoietic antigen CD45 with RIT can successfully circumvent R blocking in B-NHL and target a variety of T-NHL histologies (Gopal, 2008 & 2009). We thus performed a phase I trial using high-dose anti-CD45 RIT and ASCT for B-NHL, T-NHL, and HL. Methods Patients were ≥18 years old with relapsed, refractory, or high-risk B-NHL, T-NHL, or HL and had acceptable organ function with an ECOG performance status of 0-1 and no detectible human anti-mouse antibodies. They could not have received ≥20 Gy of prior radiation (RT) to critical organs or prior ASCT within 1 year, or prior allogeneic transplant at any time. All patients first received anti-CD45 antibody (BC8) trace-labeled with 131I followed by gamma camera imaging to evaluate biodistribution and estimate organ-specific absorbed doses. Patients then received 131I-BC8 at an absorbed dose determined by the following: Patients with prior RT >20 Gy or prior ASCT started at 10 Gy to the dose-limiting normal organ (Arm A), while others started dose escalation at 20 Gy (Arm B). Subsequent dose escalation/de-escalation followed a two-stage approach (Storer, 2001). ASCT occurred after sufficient radiation decay, and G-CSF was started on day 1. Dose limiting toxicity (DLT) was determined by Bearman grade III/IV events. The primary objective was to estimate the maximum tolerated dose, defined as that yielding a DLT rate of 25%. Responses were scored using standard criteria (Cheson, 2007). Results Between August 2009 and March 2013, 15 patients were treated. Median age was 62 years (range 20-71); stage III/IV = 11 (73%); median prior regimens = 3 (range 2-12), including 1 prior ASCT; chemorefractory disease (i.e., <PR to the most recent chemotherapy) = 8 (53%); histologies were HL (n = 6), B-NHL (n = 6), and T-NHL (n = 3; see Table). The mean administered 131I activity was 646 mCi (range 344-1064 mCi; 23.9 GBq, range 12.7-39.4 GBq). The liver was the dose-limiting normal organ in 12 patients (2.41-3.98 cGy/mCi). The absorbed dose was escalated to 14 Gy for patients in Arm A (n = 3) and 30 Gy in Arm B (n = 12). Neutrophil (>500/μl) and platelet (>20 K/μl) engraftment occurred a median of 8 (range 10-20) and 12 (range 8-26) days after ASCT, respectively. No DLTs, non-relapse deaths, or non-hematologic toxicities > NCI-CTCAE v3 grade 3 have been observed. Currently, 11 (73%) patients are alive and 7 (47%) are progression-free with a median follow-up of 12 months. Seven (54%) of 13 patients with measurable disease at enrollment had objective disease responses, including 3 of 3 with T-NHL, 3 of 6 with HL, and 1 of 1 with follicular lymphoma (FL; see Table). Conclusion Myeloablative doses of 131I targeted to CD45 are safe and feasible in patients with lymphoma, with no DLTs observed after delivery of up to 30 Gy to the liver. Objective disease responses in heavily-treated B-NHL, T-NHL, and HL were observed. This work has led to current studies using yttrium-90 as the therapeutic radionuclide (given its longer beta pathlength and absence of gamma emission) in anti-CD45 RIT for lymphoma. Disclosures: No relevant conflicts of interest to declare.

Initial experience with combined BRAF and MEK inhibition with stereotactic radiosurgery for BRAF mutant melanoma brain metastases

2016 ◽  
Vol 26 (4) ◽  
pp. 382-386 ◽  
Author(s):  
Bindiya G. Patel ◽  
Kamran A. Ahmed ◽  
Peter A.S. Johnstone ◽  
Hsiang-Hsuan Michael Yu ◽  
Arnold B. Etame
Keyword(s):  
Brain Metastases ◽  
Stereotactic Radiosurgery ◽  
Initial Experience ◽  
Mek Inhibition ◽  
Melanoma Brain Metastases ◽  
Braf Mutant

scholarly journals A Phase I Study Evaluating the Safety and Persistence of Allorestricted WT1-TCR Gene Modified Autologous T Cells in Patients with High-Risk Myeloid Malignancies Unsuitable for Allogeneic Stem Cell Transplantation

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 1367-1367
Author(s):  
Emma C Morris ◽  
Rita Tendeiro-Rego ◽  
Rachel Richardson ◽  
Thomas A Fox ◽  
Francesca Sillito ◽  
...  
Keyword(s):  
T Cells ◽  
Stem Cell ◽  
T Cell ◽  
High Risk ◽  
Phase I ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
Post Infusion ◽  
Equity Ownership ◽  
Acute Myeloid

Background:Patients with acute myeloid leukemia (AML), myelodysplasia (MDS) or tyrosine kinase inhibitor resistant chronic myeloid leukemia (CML) who are unsuitable for consolidative allogeneic stem cell transplantation (alloSCT) have high relapse rates following chemotherapy. Wilms' tumor 1 (WT1) is highly expressed in the majority of acute myeloid leukemias (AML) and in many subtypes of myelodysplasia (MDS) as well as other hematological and solid tumors. WT1 is an intracellular antigen, which makes it difficult to target using current Chimeric Antigen Receptor (CAR)-T cell technologies. The use of genetically modified T cells expressing WT1-specific α/β T cell receptors can re-direct T cell specificity via the recognition of intracellular peptides presented by MHC molecules on the malignant cell surface. Phase I clinical trials of WT1-TCR gene-modified T cells have been conducted in the settings of relapsed disease and post-alloSCT and preliminary data suggests this treatment approach is safe and potentially clinically effective in these cohorts (Tawara et al. Blood. 2017;130(18):1985-94; Chapuis et al, Nat Med. 2019;25(7):1064-72). Methods:We report a phase I/II safety and dose escalation study evaluating WT1-TCR gene-modified autologous T cells in HLA-A*0201 positive patients with AML, MDS and CML, unsuitable for alloSCT (NCT02550535) (Fig 1A). Patient T cells were harvested by leucapheresis and transduced with a retroviral vector construct encoding the codon optimised variable and constant a and bchains of the human pWT126-specific TCR separated by a self-cleaving 2A sequence (Fig 1B). Bulk transduced T cells were analysed by flow cytometry (CD3, CD8 and Vb2.1) prior to infusion and at regular intervals post-infusion. A quantitative PCR assay was developed to identify WT1-TCR expressing T cells in the peripheral blood post infusion. Patients received minimal conditioning with fludarabine and methylprednisolone prior to transfer of transduced T cells. All subjects were followed for a minimum of 12 months or until death. Results:A total of 10 patients (6 AML, 3 MDS and 1 TKI- resistant CML) were recruited. The mean age was 71.3 years (range 64-75) and all had high risk disease (by cytogenetic or clinical criteria). All AML patients were in complete morphological remission at the time of trial entry, whilst MDS patients had ≤ 15% blasts on bone marrow examination. All 10 patients received the gene-modified T cells in dose escalation cohorts (seven patients received £2x107/kg and three patients received £1x108/kg bulk WT1 TCR transduced cells). No adverse events directly attributable to the investigational product were recorded apart from one possible cytokine release syndrome, which was managed without tociluzimab. Transferred T cells demonstrated in vivoproliferation commensurate with maintenance of functional capacity despite ex vivo manipulation (Fig 1C and 1D). The TCR-transduced T cells were detectable in all patients at 28 days and in 7 patients persisted throughout the study period (Fig 1E). All 6 AML patients were alive at last follow up (median 12 months; range 7-12.8 months). The 3 patients with MDS had a median survival of 3 months (range 2.1-3.96 months) post T cell infusion. 2 died from progressive disease and one from other causes. 2 patients discontinued the study early due to disease progression. Conclusions: This is the second reported phase I/II clinical trial of autologous WT1-TCR gene-modified T cells for treatment of AML and MDS in a high-risk cohort of patients not suitable for alloSCT. We have shown that the WT1-TCR T cells demonstrated a strong safety profile without detectable on-target, off-tumour toxicity and no severe adverse events in the ten patients treated. An important cause of treatment failure for adoptive cellular therapies is the lack of persistence of transferred T cells leading to loss of disease specific effects. We demonstrated that autologous WT1-TCR T cells proliferated in vivoand persisted for many months. Recent work within our group (in press) has shown that TCRs modified to include key framework residues, show increased TCR expression and functional improvement. These modifications could be incorporated into future studies to improve efficacy. This data supports the rationale for a larger, phase II trial of WT1-TCR T cells in myeloid malignancies in patients for whom alloSCT is not appropriate, in order to assess clinical efficacy. Figure 1 Disclosures Morris: Quell Therapeutics: Consultancy, Other: Scientific Founder,stock; Orchard Therapeutics: Consultancy. Qasim:CellMedica: Research Funding; Bellicum: Research Funding; UCLB: Other: revenue share eligibility; Autolus: Equity Ownership; Orchard Therapeutics: Equity Ownership; Servier: Research Funding. Mount:Gamma Delta Therapeutics: Employment. Inman:Cellmedica: Employment. Gunter:Cellmedica: Employment. Stauss:Cell Medica: Other: I have stock; Quell Therapeutics: Consultancy, Other: I have stock.

A phase I/II trial of BKM120 combined with vemurafenib (PLX4032) in BRAFV600E/k mutant advanced melanoma.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. TPS8602-TPS8602
Author(s):  
Andrea Kantor ◽  
Adil Daud ◽  
Pamela N. Munster ◽  
Roth Ea ◽  
Alain Patrick Algazi
Keyword(s):  
Phase I ◽  
Metastatic Melanoma ◽  
Phase Ii ◽  
Primary Endpoint ◽  
Braf Inhibitors ◽  
Safety And Efficacy ◽  
Pten Loss ◽  
Pi3k Activation ◽  
Melanoma Patients ◽  
Braf Mutant

TPS8602 Background: Vemurafenib induces transient objective responses in half of BRAFV600E mutant melanoma patients and a median PFS of 5.3 months (NEJM. 2011;364:2507-2516). BRAF mutations are not sufficient to cause melanoma, but the combination of BRAFV600E mutation and PTEN loss is sufficient to recapitulate the malignant melanoma phenotype in vivo (Nat. Genet. 2009;41:544-552). PTEN loss and PI3K activation are common in BRAF mutant metastatic melanoma, and PI3K activation has been implicated as a cause acquired resistance to BRAF inhibitors (Cancer Cell. 2010;18:683-695). This phase I/II study is the first trial to test the safety and efficacy of combining a potent BRAF inhibitor, vemurafenib, with a potent PI3K inhibitor, BKM120, in patients with metastatic BRAF mutant melanoma. Methods: Design: Phase I patients receive a single dose of oral BKM120 (d -7) then vemurafenib twice daily with BKM120 daily (starting on c1d1). PK analysis is performed for BKM120 alone and for both drugs in combination. Doses of both drugs will be escalated in 3+3 scheme. Phase II patients receive continuous dosing of vemurafenib twice daily and BKM120 daily. Serial biopsies for PD and mRNA expression analyses are required for patients with visible or palpable tumors. Reimaging will be performed every 8 weeks.Eligibility: This study is enrolling BRAFV600E/K mutant metastatic melanoma patients with no prior exposure to BRAF inhibitors or PI3K inhibitors, ECOG PS ≥ 2 and adequate organ function. Endpoints: The primary endpoint for phase 1 is the recommended phase 2 dose of the combination. The primary endpoint for phase II is the 6 month PFS rate. Secondary endpoints include median PFS and OS. Baseline PTEN expression and changes is pS6 protein levels will be examined as predictors of efficacy, and changes in gene expression profiles will be assessed. Summary: This is the first trial examining the safety and efficacy of combined BRAF/PI3K inhibition in BRAF mutant melanoma patients.

Relapse-free survial and target identification to enhance response with neoadjuvant and adjuvant dabrafenib + trametinib (D+T) treatment compared to standard-of-care (SOC) surgery in patients (pts) with high-risk resectable BRAF-mutant metastatic melanoma.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 9587-9587 ◽  
Author(s):  
Jennifer Ann Wargo ◽  
Rodabe Navroze Amaria ◽  
Peter A. Prieto ◽  
Miles Cameron Andrews ◽  
Michael T. Tetzlaff ◽  
...  
Keyword(s):  
Clinical Trial ◽  
High Risk ◽  
Metastatic Melanoma ◽  
Response Rate ◽  
Mapk Pathway ◽  
Pathologic Complete Response ◽  
Stage Iv ◽  
Complete Response ◽  
Stage Iiib ◽  
Braf Mutant

9587 Background: Targeted and immune therapies have dramatically improved outcomes in stage IV metastatic melanoma pts. These agents are now being tested in earlier-stage disease. SOC surgery for high-risk resectable melanoma (AJCC stage IIIB/IIIC), with or without adjuvant therapy, is associated with a high risk of relapse (~70%). We hypothesized that neoadjuvant (neo) + adjuvant treatment with D+T improves RFS in these pts. Longitudinally collected biospecimens from pts receiving this treatment were analyzed to identify candidate strategies to further improve outcomes. Methods: A prospective single-institution randomized clinical trial (NCT02231775) was conducted in BRAF-mutant pts with resectable Stage IIIB/C or oligometastatic stage IV melanoma. Pts were randomized 1:2 to SOC (Arm A) versus neo + adjuvant D+T (Arm B; 8 wks neo + 44 wks adjuvant). The primary endpoint was RFS. Tumor biopsies were collected at baseline, week 3, and at surgery for molecular and immune profiling (whole exome sequencing, gene expression profiling, IHC, flow cytometry). Results: 21 of a planned 84 patients were enrolled (Arm A = 7, Arm B = 14). Arms were well balanced for standard prognostic factors, and toxicity was manageable. RECIST response rate with neo D+T was 77%, and the pathologic complete response rate (pCR) was 58%. First interim analysis revealed significantly improved RFS in the D+T arm over SOC (HR 62.5, p < 0.0001), leading to early closure to enrollment. Pts with a pCR at surgery had significantly improved RFS versus pts without pCR (p = 0.04) on neo D+T. Tumor profiling revealed incomplete MAPK pathway blockade and higher levels of CD8+ T cells expressing immunomodulators Tim-3 and Lag-3 in pts who did not achieve a pCR. Conclusions: Neo + adjuvant D+T is associated with a high pCR rate and markedly improved RFS over SOC in pts with high-risk resectable BRAF-mutant metastatic melanoma. pCR at surgery is associated with improved RFS. Tumor analyses reveal candidate targets for testing in future trials to enhance responses to neo D+T. Clinical trial information: NCT02231775.

Phase I Study of Adoptive T-Cell Therapy Using Antigen-Specific CD8+ T Cells for the Treatment of Patients With Metastatic Melanoma

2006 ◽  
Vol 24 (31) ◽  
pp. 5060-5069 ◽  
Author(s):  
Andreas Mackensen ◽  
Norbert Meidenbauer ◽  
Sandra Vogl ◽  
Monika Laumer ◽  
Jana Berger ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Adverse Effects ◽  
Phase I ◽  
Metastatic Melanoma ◽  
Adoptive Transfer ◽  
Phase I Study ◽  
Low Grade ◽  
Melanoma Patients

Purpose The adoptive transfer of in vitro generated tumor antigen-specific cytotoxic T lymphocytes (CTL) provides a promising approach to the immunotherapy of cancer. A phase I study was conducted to test the feasibility, safety, and survival of adoptively transferred Melan-A–specific CTL lines in melanoma patients. Patients and Methods Eleven HLA-A2+ patients with metastatic melanoma received at least three intravenous infusions of Melan-A–specific CTL at 2-week intervals. CTL were generated by four rounds of in vitro stimulation of purified CD8+ peripheral blood lymphocytes with autologous dendritic cells pulsed with an HLA-A2 binding Melan-A peptide. Each T-cell infusion was accompanied by a 6-day course of low-dose interleukin-2. Results A total of 52 T-cell infusions were administered, averaging 2.1 × 108 Melan-A–specific CTL per infusion. Clinical adverse effects were mild and consisted of chills and low-grade fever in seven of 11 patients. Clinical and immunologic responses revealed an antitumor response in three of 11 patients (one complete regression, one partial regression, one mixed response), an elevated frequency of circulating Melan-A tetramer+ T cells up to 2 weeks in all the patients with a maximal frequency of 2% of total CD8+ T cells, an increase in eosinophils to up to 50% in seven of 11 patients, and a selective loss of Melan-A expression in lymph node metastases in two evaluated patients after T-cell transfer. Conclusion Our data indicate that the adoptive transfer of antigen-specific T cells in melanoma patients can induce clinical tumor-specific immune responses without major adverse effects.

scholarly journals Correlation between early 18F-FDG PET/CT response to BRAF and MEK inhibition and survival in patients with BRAF-mutant metastatic melanoma

2016 ◽  
Vol 37 (2) ◽  
pp. 122-128 ◽  
Author(s):  
Ronald J. Schmitt ◽  
Sarah M. Kreidler ◽  
Deborah H. Glueck ◽  
Rodabe N. Amaria ◽  
Rene Gonzalez ◽  
...  
Keyword(s):  
Metastatic Melanoma ◽  
Fdg Pet ◽  
Mek Inhibition ◽  
Pet Ct ◽  
18F Fdg ◽  
Fdg Pet Ct ◽  
Braf Mutant

Phase I Trial of Prophylactic Rituximab for the Prevention of Post Transplant Epstein-Barr Related Lymphoproliferative Disease (EBV-PTLD) Following T Cell Depleted (TCD) Unrelated or HLA-Mismatched Related Hematopoietic Cell Transplantation (HCT): Efficacy, Toxicity, and Effect on Subsequent B Cell Reconstitution

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 1971-1971 ◽  
Author(s):  
Trudy N Small ◽  
Nancy A. Kernan ◽  
Ann A. Jakubowski ◽  
Molly A Knowles ◽  
James W Young ◽  
...  
Keyword(s):  
T Cell ◽  
B Cells ◽  
High Risk ◽  
Phase I ◽  
B Cell ◽  
Specific Antibody ◽  
Cd4 Count ◽  
Normal Numbers ◽  
Cell Dysfunction ◽  
Ebv Viremia

Abstract Abstract 1971 Rituximab, a chimeric IgG1 kappa monoclonal antibody against the pan-B cell marker CD20, has proven effective in treating B cell malignancies, including EBV-PTLD. To determine its potential role in prevention of EBV-PTLD, 25 patients were enrolled on a prospective IRB approved trial (11/1/03-2/1/07) of monthly rituximab (375 mg/m2/dose, maximum 6 doses), starting 30–45 days after a TCD unrelated (n=23) or HLA-mismatched HCT (n=2). Eligibility included EBV seropositive patient, negative hepatitis B surface antigen, ANC >1500 cells/uL, remission, and negative plasma EBV PCR at baseline. Per protocol, rituximab was stopped prior to 6 doses in patients who achieved a circulating CD4 count >200 cells/ul, at which time their risk of EBV-PTLD was considered minimal. The median patient age (range) was 22.0 (8.0-68.0) years. Patients underwent transplantation for acute leukemia (n=18), CML (n=2), NHL (n=2), MDS (n=2), or Fanconi anemia/AML (n=1). Only two patients developed fever and chills, without respiratory distress or hypotension, within the first hour of their initial infusions, which proved to be due to coincidental line infections for which both were treated and recovered uneventfully. Both patients refused further rituximab. Six patients received all 6 planned doses; 5 patients received fewer than 6 doses due to recovery of CD4 count >200 cells/ul before the planned 3rd (n=4) or 5th dose (n=1). The remaining 12 patients received 1 (n=2), 2 (n=4), 3 (n=2), or 4 doses (n=4), due to persistent neutropenia (<1500 cells/ul) >45d after the prior rituximab dose (n=4), recurrent disease (n=2), prolonged parainfluenza upper respiratory tract infection (n=1), secondary graft failure (n=1), abnormal LFTs of unclear etiology (n=1), GVHD requiring phase I therapy (n=1), aseptic meningitis (n=1) attributed to intravenous gammaglobulin, or pneumococcal sepsis (n=1). At a median follow-up of 5.8 (4.4-5.7) years, 16 of 25 patients are alive, 13 disease-free. Five patients died of recurrent hematologic malignancy, three of GVHD, and one of non-alcoholic steatohepatitis. Of the 25 patients accrued to the protocol, none developed EBV viremia or EBV-PTLD, compared to 23% (p<0.01) and 7%, respectively of patients (n=95) not given prophylactic rituximab following a TCD unrelated or HLA –mismatched related donor performed during the same time period. Despite recovery of normal numbers of CD20+ B cells at a median of 8.4 months post rituximab, 5 of 13 recipients of prophylactic rituximab have had prolonged hypogammaglobulinemia, a paucity of memory switched (CD27+ IgD-) B cells, and no specific antibody responses persisting at least 4 years from their last dose of rituximab. B cell dysfunction did not correlate with the number of doses of prophylactic rituximab administered. To estimate how frequently persistent B cell dysfunction occurs following rituximab treatment, serum immunoglobulin levels +/− specific antibody production was assessed in an additional 44 patients who received rituximab following TCD unrelated or HLA-mismatched related HCTs for the treatment of EBV viremia, EBV-PTLD, autoimmune cytopenias, or as prophylaxis against recurrent EBV (-) B-cell NHL, or EBV-LPD. Patients received a median of 4 doses of rituximab at a dose of 375 mg/m2 given weekly in most patients. Despite recovery of normal numbers of circulating B cells in all 44 patients, 10 patients have had prolonged hypogammaglobulinemia (>18 months), including 6 patients who remain on monthly IVIG a median of 40 (25–66) months following rituximab. In this cohort, 30 patients were immunized with a series TDAP, PCV7 or PCV13, HIB, and/or inactivated polio vaccines. Following the third vaccine, 13 patients (43%) failed to respond to any vaccine, 6 patients (20%) had incomplete responses, and 11 patients (37%) responded to all vaccines administered. Lack of vaccine response was associated with a paucity of memory switched B cells. This study demonstrates the effectiveness of rituximab in preventing EBV viremia in high risk recipients of a T cell depleted HCT. It also suggests that rituximab affects B cell function long-term, despite quantitative, but not necessarily qualitative recovery of B cells. Further studies investigating the minimal number of rituximab doses required to prevent EBV viremia/EBV-PTLD in high risk patients and the mechanism of prolonged B cell impairment following its use are needed. Disclosures: Off Label Use: Rituximab for the prevention of EBV-LPD post HCT. Papadopoulos:Biogen-Idec: Membership on an entity's Board of Directors or advisory committees, family member on board of Biogen-Idec who receives royalties from Hoffman La-Roche.

Gamma knife stereotactic radio-surgery and BRAF inhibition in metastatic melanoma.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 9088-9088
Author(s):  
Melissa Wilson ◽  
John Y Lee ◽  
Michelle Alonso-Basanta ◽  
Wei Xu ◽  
Suzanne McGettigan ◽  
...  
Keyword(s):  
Brain Metastases ◽  
Metastatic Melanoma ◽  
Gamma Knife ◽  
Median Survival ◽  
Progression Free Survival ◽  
Term Survival ◽  
Prior Therapy ◽  
Braf Inhibition ◽  
Braf Mutant

9088 Background: Gamma knife radio-surgery (GK) is an effective approach to treating brain metastases in patients with metastatic melanoma. BRAF inhibition with vemurafenib produces a median progression free survival (PFS) of 7 months, but low central spinal fluid penetration may limit its effectiveness in patients who develop brain metastases. We report long term follow-up of patients with BRAF mutant melanoma treated with vemurafenib and GK. Methods: Demographics and clinical outcomes were characterized for 18 BRAF mutant melanoma patients with brain metastases treated between 2007 and 2012 with GK and with vemurafenib (vem) for >1 month. Results: The median age at starting vem was 51 yrs (range 34-76). 61% of the patients were women. Patients were treated with a median of 1 prior therapy (range 0-3). 7/18 patients (39%) had brain involvement prior to starting vem. 16/18 patients (89%) had stage M1c disease at the time of starting vem. Patients were treated with vem for a median of 8.4 months (range 2.1 to 27 months), had a median survival of 15.7 months after starting vem (range 4.2-29.4), and a median survival after GK of 7.8 months (range 1.2-21.1). Patients underwent GK to a median of 3 lesions (range 1-6). In total, 8/18 patients (44%) were treated with WBRT. 7/18 patients underwent craniotomies, 2 of which were for progression in lesions treated with GK, and 4 of which were also among the patients treated with WBRT. In 7/18 patients treated with GK for new brain progression after starting vem, vem was continued after GK for a median duration of 4.1 months (range 1.3 to 15.8). In these 7 patients that had vem and GK and continued vem, the median overall survival after starting vem was 19.9 months (range 6.7 to 29.3). Of these 7 patients, 4 required whole brain radiation therapy (WBRT); 3 have not required any additional brain directed therapy, including 2 patients who continue on vemurafenib at the time of analysis. 5/18 patients were treated with more than 1 round of GK, 3 of which were subsequently treated with WBRT. Conclusions: Despite the brain being a common site of progression on vemurafenib therapy, long term survival can be achieved in some cases by continuing vem after GK therapy.

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