Search

Stimulatory antiplatelet derived growth factor receptor α (PDGFRA) antibodies have been associated with extensive chronic graft-versus-host disease (cGVHD). We performed a phase 1 dose escalation trial of imatinib in corticosteroid-dependent/refractory cGVHD to assess the safety of imatinib and test the hypothesis that abrogation of PDGFRA signaling can ameliorate the manifestations of cGVHD. Fifteen patients were enrolled. Mean follow-up time was 56.6 weeks (range, 18-82.4 weeks). Imatinib 400 mg daily was associated with more frequent moderate to life-threatening adverse events than 200 mg daily. The main adverse events were nausea, edema, confusion, diarrhea, liver function test elevation, fatigue, and myalgia. The overall response rate was 40% (6 of 15). The treatment failure rate was 40% (6 of 15). Twenty percent (3 of 15) of subjects had stable disease. Of 4 subjects with phospho-PDGFRA and phospho-PDGFRB immunohistochemistry studies before and after treatment, inhibition of phosphorylation was observed in 3 but correlated with response in one. Anti-PDGFRA antibodies were observed in 7 of 11 evaluable subjects but correlated with clinical activity in 4. We conclude that cGVHD responds to imatinib through multiple pathways that may include PDGFRA signal transduction. This study is registered at www.clinicaltrials.gov as #NCT00760981.

Positive interim positron emission tomography (PET) scans are thought to be associated with inferior outcomes in diffuse large B-cell lymphoma. In the E3404 diffuse large B-cell lymphoma study, PET scans at baseline and after 3 cycles of rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone were centrally reviewed by a single reader. To determine the reproducibility of interim PET interpretation, an expert panel of 3 external nuclear medicine physicians visually scored baseline and interim PET scans independently and were blinded to clinical information. The binary Eastern Cooperative Oncology Group (ECOG) study criteria were based on modifications of the Harmonization Criteria; the London criteria were also applied. Of 38 interim scans, agreement was complete in 68% and 71% by ECOG and London criteria, respectively. The range of PET+ interim scans was 16% to 34% (P = not significant) by reviewer. Moderate consistency of reviews was observed: κ statistic = 0.445 using ECOG criteria, and κ statistic = 0.502 using London criteria. These data, showing only moderate reproducibility among nuclear medicine experts, indicate the need to standardize PET interpretation in research and practice. This trial was registered at www.clinicaltrials.gov as #NCT00274924.

Abstract 2686 Background: Nodular lymphocyte predominant Hodgkin lymphoma (NLPHL) is a rare subtype of HL (∼5%). This unique clinical entity is characterized by an indolent clinical course and unlike classical HL late relapses may occur. Standard treatment depends on stage and includes radiation therapy (RT) and/or chemotherapy which can be associated with an increased risk of treatment related late effects warranting investigation of other active agents. The malignant cells of NLPHL universally express CD20, therefore therapy with rituximab (R), the monoclonal anti-CD20 antibody, is a targeted option. We report our experience with R as front-line treatment for patients with NLPHL. Methods: Patients with newly diagnosed NLPHL and measurable disease were treated with R at 375 mg/m2 administered weekly × 4 or, after protocol amendment (February 2003) with R followed by 4 doses of R maintenance (RM) administered every 6 months for 2 years. Restaging studies were performed at 1, 3 and 6 months and then every 6 months until progression. All pathology was centrally reviewed. Results: Nineteen patients were enrolled between May 1999 and September 2006. The median age at treatment was 45 years (range 17–63), stage I (n=6), stage II (n=7), stage III (n=6). Ten patients were treated with R alone and 9 with R+RM. The median follow-up for R patients is 8.8 years (5–11.4) and for R+RM patients is 5 years (2.5–7.6). At the end of induction therapy with R alone, the overall response rate was 100% [complete response (CR) (n=10), CR unconfirmed (n=2) and partial response (n=7)]. The median progression free survival (PFS) for patients treated with R alone and R+RM is 50 months and 67 months, respectively (p=0.7; log rank test) and median overall survival (OS) not reached. The median follow up for patients without progressive disease at the time of this analysis was 6.9 years (range 2.5–11.5). The estimated PFS at 5 years is 51.7%, [95% CI 33.2–80.4] and at 10 years 35.4% [95% CI 17.7–70.8]. There was no difference in median PFS between patients with stages I-II versus III (5.6 years and 4.15 years respectively, p=0.58 [log rank test]). The estimated OS at 5 years is 93.3%, [95% CI 81.5–100] and 10 years 76% [95% CI 55.4–100]. Ten patients progressed (5 treated with R alone, 5 treated with R+RM) of whom 6 transformed to an aggressive B cell lymphoma (biopsy proven) at a median of 4.2 years [range 0.9–8]. Five of the 6 transformed patients had abdominal disease at initial diagnosis (stage III, n=4). Three patients died (2 aggressive NHL, 1 unknown). Conclusion: Rituximab is an active single agent in the treatment of newly diagnosed NLPHL with a median PFS of 5.6 years. R+ RM resulted in a non-significant increase in PFS compared to R alone. In this series, abdominal involvement was associated with transformation to an aggressive B cell lymphoma underscoring the need for biopsy at relapse. These results demonstrate a pattern of late relapse following rituximab, at least as great as the historical data with RT or RT + CT. Although R alone achieved proof of concept for a targeted therapy, its use should remain investigational as primary therapy of NLPHL. Disclosures: Advani: Genentech Inc.: Membership on an entity's Board of Directors or advisory committees, Research Funding. Off Label Use: Rituximab. Anti-CD20 agent that targets CD20 on NLPHL cells. Horning:Genentech: Employment, Equity Ownership.

Abstract 2320 The therapeutic potential of imatinib in chronic graft-versus-host disease (cGVHD) is thought to derive from abrogation of the agonistic effects of anti-PDGFRA antibodies (APA) previously identified in patients with extensive cGVHD. Here, we update outcomes from a 15 subject phase 1 dose escalation trial of imatinib for steroid dependent cGVHD and provide correlation with APA measurements. We also determine the prevalence of APA in 120 allo-HCT patients and their donors demonstrating that donor and pre transplant plasma sample APA measurements predict for cGVHD. Methods. All trial subjects had extensive steroid dependent cGVHD previously treated with ≥2 agents. Steroid dependence was defined as progressive cGVHD refractory to prednisone ≥0.5 mg/kg/d for ≥ 1 month or cGVHD requiring prednisone ≥0.25 mg/kg/d for ≥ 3 months. Subjects were treated with imatinib for ≥ 6 months starting at 200 mg daily with dose escalation to 400 mg after 4 weeks as tolerated and if a complete response did not occur. Steroids and one other immunosuppressant were allowed. Steroids were tapered as tolerated and other immunosuppressant dosing remained constant. The primary endpoint was safety and tolerability measured by CTCAE v. 3.0 criteria through 6 months. Secondary endpoints were graded according to the Hopkins' scale for cGVHD assessment, change in daily prednisone requirement, and change in symptom burden measured by the Lee cGVHD scale. APA in pre-imatinib plasma samples were detected by immunoblot with the extracellular PDGFRA domain (56 kDa) and confirmed by ELISA. Subsequently, 120 consecutive allo-HCT patients with available donor, pre- and 1 year post transplant plasma samples were tested for APA by ELISA. Results. Median age was 46 years (20-68). Mean time to study enrollment from transplant was 5.1 years and from cGVHD diagnosis 4.1 years. The clinical trial completed accrual on 8/4/09. Imatinib was escalated in 12/15 subjects. Grade 2–3 adverse events (AEs) possibly or probably related to imatinib occurred in 8/12 subjects receiving imatinib 400 mg daily; 5 of these subjects were subsequently dose reduced. Grade 2–3 AEs possibly or probably related to imatinib occurred in 4/15 subjects receiving imatinib 200 mg daily; we concluded this dose to be well tolerated. Subjects were evaluable for clinical responses after 6 months of therapy. Four subjects were non-evaluable: one subject died secondary to H1N1 infection induced respiratory failure, one subject experienced grade 3 vascular thrombosis and was removed from the study, and two subjects withdrew consent before 6 months. Of 11 clinically evaluable subjects, 3 experienced a major response, 4 experienced a minor response, 2 had stable disease, and 2 experienced progressive disease. Median follow-up was 56.6 weeks (19.1-76.1). We measured APA in order to directly assess PDGFRA as a relevant imatinib target. APA were detected by immunoblotting in 7/11 evaluable subjects: 4 experienced a major or minor response, 2 had stable disease, and 1 experienced progressive disease. APA were not detected in 4/11 evaluable subjects: 2 experienced a major or minor response, 1 had stable disease, and 1 experienced progressive disease. The small sample size precluded interpretation of the significance of APA relative to clinical outcome. Therefore, we extended our APA analysis and measured donor, pre, and 1 year post transplant plasma samples from 120 consecutive allo-HCT patients to determine the clinically relevant APA frequency. Pre transplant and donor APA ELISA measurements ≥ OD 2.0 (absorption at 405 nm) were associated with development of extensive cGVHD (see figure, relative risk=2.23, CI=1.71-2.90). Positive and negative predictive value of this assay for extensive cGVHD was 93% and 58%. Sensitivity and specificity were 24% and 98%. APA measurements in samples 1 year after transplant did not associate with extensive cGVHD (relative risk=0.51, CI=0.09-2.8) explaining the inability of APA to predict response to imatinib in our clinical trial. Conclusions. 1) The response rate of cGVHD to imatinib was 64% warranting further phase 2 studies using 200 mg daily. 2) Pre transplant and donor APA measurements predict for the development of extensive cGVHD. Our APA ELISA may be utilized to improve patient selection in cGVHD prophylaxis trials and to improve donor selection. Disclosures: Off Label Use: imatinib for cGVHD. Miklos: Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.

Abstract 3304 Poster Board III-192 Introduction Anti-PDGFRA antibodies (APA) are associated with cGVHD and are hypothesized to stimulate PDGFRA signal transduction resulting in collagen deposition (Svegliati et al. Blood 2007). Imatinib inhibits PDGFRA activation and may reduce clinical manifestations in patients with cGVHD. We conducted a phase 1 dose escalation trial of imatinib in steroid dependent cGVHD and correlated response with measurements of APA. Patients and Methods All 15 subjects had extensive steroid dependent NIH defined cGVHD previously treated with ≥ 2 agents. Median age was 46 years (20-68). Mean time to study enrollment from transplant was 5.1 years and from cGVHD diagnosis was 4.1 years. Steroid dependence was defined as progressive cGVHD refractory to prednisone ≥ 0.5 mg/kg/d for ≥ 1 month or cGVHD requiring prednisone ≥ 0.25 mg/kg/d for ≥ 3 months. Subjects were treated with imatinib for 6 months starting at 200 mg daily with dose escalation to 400 mg after 4 weeks as tolerated and if a complete response did not occur. Steroids and one other immunosuppressant were allowed. Steroids were tapered as tolerated while other immunosuppressant dosing remained constant during the trial. The primary endpoint was safety and tolerability measured by CTCAE v. 3.0 criteria. Secondary endpoints were clinical response, change in daily prednisone requirement, and rate of treatment failure. Clinical assessment by medical providers, change in musculoskeletal function measured by grip strength and joint range of motion, and patient reported symptom burden measured by the Lee cGVHD scale were recorded. Treatment failure (TF) was defined as discontinuation of imatinib due to intolerance or cGVHD progression requiring new therapy. Imatinib was considered safe if no deaths or life threatening adverse events (CTCAE ≥ Grade 4) could be attributed to it. A ≥ 25% response rate was considered promising and worthy of phase 2 investigation. APA were detected by ELISA and immunoblotting against the extracellular PDGFRA domain. Results The study began on 9/24/08 and completed accrual on 8/4/09. Among the 14 subjects evaluable for safety and tolerability, 9 were dose escalated to 400 mg. 3/9 did not tolerate the increased dose and were dose reduced. All but 1 subject tolerated 200 mg. Possibly related grade 1-2 adverse events included edema (10), nausea (7), fatigue (6), LFT elevation (6), diarrhea (4), muscle cramping (4), confusion (3), flatulence (3), fever (2) and LDH elevation, vomiting, weight loss, erythema, heartburn, tachycardia, hypertension, and headache (1 each). Grade 3-4 adverse events were muscle cramping and pulmonary infiltrates (1 each at 400 mg) and vascular insufficiency (1 at 200 mg). One subject on prednisone, cyclosporine, and imatinib 200 mg experienced respiratory failure due to H1N1 infection and died at 16 weeks. 8/15 subjects have completed ≥ 6 months of therapy and are evaluable for clinical response. Seven of these subjects were dose escalated after an average of 87 days (28-160) of treatment at 200 mg. Responses by Hopkins criteria (HC, Jacobsohn et al. JCO 2007) were first observed at the 200 mg dose level in 6 subjects at an average of 47 days (27-110). Response was observed at 400 mg but not 200 mg in 1 subject. One subject failed to respond to both 200 and 400 mg. Some early responses were not durable. Evaluation by HC at 6 months demonstrated 1 major response, 4 minor responses, and 3 progressive disease. Evaluation by NIH criteria (Filipovich et al. BBMT 2005) at 6 months demonstrated 2 partial responses, 3 non-responses, and 3 treatment failures. Musculoskeletal function was improved in 3, unchanged in 3, and worse in 2 subjects. Patient reported Lee cGVHD symptom burden (Lee et al. BBMT 2002) was rated as improved in 2, unchanged in 3, and worse in 3. On average, the daily weight adjusted steroid dose decreased by 20%. APA were detected pre-treatment in 3/8 fully evaluable subjects. Two achieved minor responses, but the 3rd experienced early progression and was censored. Of the 5 cases without detected APA, 1 had a major response, 2 had minor responses, and 2 had disease progression. Conclusions Imatinib at 200 and 400 mg is safe and appears to be effective in some cGVHD patients. Tolerability is decreased at 400 mg. APA are present in some but not all imatinib responders, suggesting that imatinib exerts its effects through mechanisms in addition to abrogation of PDGFRA signal transduction. Further phase 2 investigation is warranted. Disclosures Chen: Novartis: Research Funding. Off Label Use: Imatinib for chronic graft versus host disease. Otani:Novartis: Research Funding. Miklos:Novartis: Research Funding.

Background: Positive interim PET scans have been associated with inferior outcomes in DLBCL treated with chemotherapy, alone or with rituximab. In the ECOG 3404 study for bulky and advanced DLBCL, PET scans at baseline and after 3 R-CHOP are centrally reviewed by a single reader; those with positive scans cross-over to R-ICE after 4 R-CHOP, whereas those with negative scans continue on R-CHOP. The primary endpoint of E3404 is progression-free survival. To determine the reproducibility of interim PET scan interpretation, we convened an expert panel. Methods: Three external nuclear medicine physicians visually scored baseline and interim PET scans independently and blinded to other clinical information or outcome. ECOG study criteria were binary (0,1) based on residual disease in initially involved sites with uptake greater than the liver. London criteria were on a scale of 0–5, where 4–5 was positive, based on increased uptake relative to the liver. Overall scores and agreement among experts were evaluated for both criteria, with application of the kappa statistic to correct for chance. Results: Using the ECOG criteria, external reviewers were in complete agreement in 68% of 38 interim scans and completely agreed with the central review in the same 68% cases. Agreement among the experts was 71% employing the London criteria in these cases. The range of PET+ interim scans by reviewer was 16.8% to 34.2% (p=NS) by both ECOG and London criteria. The kappa statistic for overall pairwise correlation between readers was 0.445 (0.396–0.533) using ECOG and 0.502 (0.396–0.630) using London criteria – indicating moderate consistency. Areas of disagreement often, but not exclusively, related to bone disease, the shape and focality of residual uptake, splenic disease, and rare scans without CT-fusion. Conclusions: These data show that visual criteria, either ECOG or London in this series, for interim PET results are moderately reproducible among individual nuclear medicine experts. Our finding of variability among experts indicates the need for caution in interpreting interim PET results in studies and in practice. Review of all E3404 cases is planned after accrual is completed (projected 12/08). Other ongoing studies evaluating interim PET after 1–3 cycles of therapy, the application of quantitative criteria, and consensus panels may provide further valuable information.

The peripheral T cell lymphomas (PTCL) are uncommon malignancies that typically carry a worse prognosis than the B cell non-Hodgkins lymphomas. There is no uniform standard therapy for PTCL, and AHCT is often offered at relapse or as consolidation in first remission due to the inherently poor prognoses. We conducted a retrospective review of patients who underwent AHCT for PTCL from 1989 to 2006 at Stanford, excluding mycosis fungoides and lymphoblastic lymphoma. Fifty-eight cases were identified: systemic anaplastic large cell (ALCL, n=18), PTCL unspecified (NOS, n=17), angioimmunoblastic (AITL, n=9), nasal type extranodal NK/T (nNK/T, n=7), primary cutaneous anaplastic large cell (n=5), hepatosplenic (n=2), and adult T cell lymphoma/leukemia (n=1). The median age at AHCT was 45 years (range 18–73), and 57% were male. The graft source was mobilized peripheral blood HC in 86% and bone marrow in 14%. The graft was T cell purged in 86% of cases. The conditioning regimen was high dose cyclophosphamide, carmustine, and etoposide in 83% of cases with the rest receiving total body irradiation, carmustine, and etoposide. Fifteen patients were transplanted in first complete or partial response (CR/PR1); 32 in second or beyond CR or PR (CR/PR2+); and 11 with primary refractory disease (REF). The PTCL subtypes transplanted in CR1 (n=12) and PR1 (n=3) included nNK/T (5), AITL (4), NOS (2), hepatosplenic (2), and ALCL (2). Multiple regimens were required to achieve first response in 5 patients. Only one ALK+ (anaplastic lymphoma kinase) ALCL pt was transplanted in CR/PR1 and required 3 induction regimens. The median follow up was 5 years (yr) (range 1–12). For all subjects, five yr overall survival (OS) was 49% and 5 yr progression free survival (PFS) was 24%. Disease status at AHCT had a strong impact on PFS (p=.004) and OS (p=0.06). Five yr PFS was 51%, 17%, and 0%, respectively, and the PFS curve appeared to plateau at 5 yrs. Corresponding OS at 5 yrs for the CR/PR1, CR/PR2+, and REF patients were 76%, 41%, and 36%, respectively. The number of prior regimens and achievement of CR at day +90 post AHCT were also significant factors for PFS by univariate analysis. Age, bone marrow involvement, B symptoms, stage, and histology were not significant for PFS or OS. By multivariate analysis, CR at day +90 remained a highly significant factor for both PFS and OS (p

The IPSS, created for evaluating clinical outcomes of MDS patients with IMRAW data combined from seven large risk-based studies, has been validated through multiple studies of MDS patients and has been proven useful in clinical decision-making. To determine whether the depth of cytopenias (in addition to their number) could further refine the prognostic ability of the IPSS, we evaluated this parameter in the 815 patients from the IMRAW database and assessed their correlation to patients’overall survival (OS) and risk of evolution to acute myeloid leukemia (AML). Univariate analyses of platelet (plt), hemoglobin (Hb), and absolute neutrophil count (ANC) depth levels were correlated with IPSS risk groups, FAB categories [refined as: RA, RARS, RAEB-1, RAEB-2, RAEB-T, CMML, del(5q) alone], cytogenetic groups, bone marrow blast percent (%), and age groups (≤60, >60 years).Our results showed that all cytopenic categories had statistically significant rank correlations with IPSS and marrow blast % (Tables 1 & 2, Kendall rank coefficient τ, p10 | 43 | 4.9 | 5.6 | 63 | 41 | 28 | 7 | Table 1 | Plt(X1000/ μl) | Marrow Blast %(%pts)τ=-0.16 | |:--------------:| --------------------------- | ----- | | | 10 | 49 | 39 | 31 | 22 | Table 2