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PurposeTo evaluate the impact of the addition of bortezomib to rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) on outcomes in previously untreated patients with non–germinal center B-cell–like (non-GCB) diffuse large B-cell lymphoma (DLBCL).Patients and MethodsAfter real-time determination of non-GCB DLBCL using the Hans immunohistochemistry algorithm, 206 patients were randomly assigned (1:1; stratified by International Prognostic Index [IPI] score) to six 21-day cycles of standard R-CHOP alone or R-CHOP plus bortezomib 1.3 mg/m2intravenously on days 1 and 4 (VR-CHOP). The primary end point, progression-free survival (PFS), was evaluated in 183 patients with centrally confirmed non-GCB DLBCL who received one or more doses of study drug (91 R-CHOP, 92 VR-CHOP).ResultsAfter a median follow-up of 34 months, with 25% (R-CHOP) and 18% (VR-CHOP) of patients having had PFS events, the hazard ratio (HR) for PFS was 0.73 (90% CI, 0.43 to 1.24) with VR-CHOP ( P = .611). Two-year PFS rates were 77.6% with R-CHOP and 82.0% with VR-CHOP; they were 65.1% versus 72.4% in patients with high-intermediate/high IPI (HR, 0.67; 90% CI, 0.34 to 1.29), and 90.0% versus 88.9% (HR, 0.85; 90% CI, 0.35 to 2.10) in patients with low/low-intermediate IPI. Overall response rate with R-CHOP and VR-CHOP was 98% and 96%, respectively. The overall survival HR was 0.75 (90% CI, 0.38 to 1.45); 2-year survival rates were 88.4% and 93.0%, respectively. In the safety population (100 R-CHOP and 101 VR-CHOP patients), grade ≥ 3 adverse events included neutropenia (53% v 49%), thrombocytopenia (13% v 29%), anemia (7% v 15%), leukopenia (26% v 25%), and neuropathy (1% v 5%).ConclusionOutcomes for newly diagnosed, prospectively enrolled patients with non-GCB DLBCL were more favorable than expected with R-CHOP and were not significantly improved by adding bortezomib.

Prospective data are needed to ascertain the impact of iron chelation therapy in patients with myelodysplastic syndromes. The present 5-year prospective registry analysis was conducted to compare clinical outcomes between chelated and nonchelated patients with lower-risk myelodysplastic syndromes and transfusional iron overload. In an interim analysis at 24 months, we previously reported that chelation therapy was associated with longer median overall survival and a tendency toward longer leukemia-free survival and fewer cardiac events. In the present report, we detail findings from the final analysis at 5 years. We confirm, at the conclusion of this 5-year, prospective, non-interventional study, that overall survival was significantly longer in patients who received iron chelation therapy vs those who did not. Causes of death in the overall population were predominantly myelodysplastic syndromes/acute myeloid leukemia followed by cardiac disease. Time to progression to acute myeloid leukemia was also significantly longer in patients receiving chelation therapy, and significantly fewer patients progressed to leukemia vs those not receiving chelation therapy. Limitations of the study include a potential for clinical bias, as patients with longer predicted survival may have been chosen for chelation therapy, the differences present in concomitant conditions at baseline, and the possibility that some high-risk patients were not identified due to limited cytogenetic classification.

3516 Background: The purpose of this study was to quantify different molecules of TIME including T cells, macrophages, and immune checkpoint proteins (ICPs), and determine their association with clinical outcomes and treatment benefit in pts enrolled in C-08, which tested the efficacy of adding bev to 5-fluoruracil+leucovorin+oxaliplatin. Our pre-specified, NCTN-CCSC approved primary objective hypothesized that pts with more CD8 cells would have a better prognosis and receive benefit from bev. Methods: Tissue microarrays were used to assess TIME of 1,509 C-08 pts using m-IF and the Vectra Pathology System. Three m-IF panels were used to quantitatively assess T cells (CD3, CD8, CD45RO, FOXP3), macrophages (CD68, CD163), and ICPs (PD-1, PD-L1, CTLA4, TIM3, LAG3, OX40) in stromal and tumor (panCK) regions. The primary objective was to determine the association between overall survival (OS) and high (top 3rd) v low CD8 expression in both stromal and tumor regions. All markers were tested for associations with OS and recurrence-free interval (RFI) and with bev prediction using Cox models and median cut points. Results: Based on our pre-specified analysis, pts with high CD8 cells had better OS, HR=0.66 (95%CI: 0.49-0.88), p=0.005 but pts with high CD8 cells did not receive bev benefit. All T cells and double stained CD8/PD-1 were associated with better RFI. CD3, CD8, CD68, PD-1, PD-L1, and LAG3 cells were associated with better OS. PD-1 and CD8/PD-1 were associated with RFI in pts with deficient mismatch repair (dMMR) and proficient (p)MMR but TIM3, CD3/CD45RO and CD163 were only associated with RFI in dMMR. Association of CD8 cells with bev benefit (RFI) was seen in dMMR pts, HR 0.27 (95% CI: 0.1-0.73), p=.01 and OS, HR=0.27, (95% CI: 0.12-0.64), p=0.0028 but there was no significant interaction. Single staining CD8, PD-1, and double staining CD8/PD-1 cells were associated with bev benefit in dMMR pts but with bev harm in pMMR pts. However, pts with tumors having >1% of PD-1 and PD-L1 cells (n=197 including 76 dMMR, 100 pMMR, and 21 unknown), received significant bev benefit (int p=.0056). Conclusions: CD8 cells were associated with better OS but were not associated with bev benefit. All T cells and PD-1, PD-L1, and LAG3 cells, were associated with better prognosis in the entire cohort but when pts were stratified for MMR status differences in their association with prognosis and bev benefit emerged. PD-1, CD8, and CD8/PD-1 cells were associated with bev harm in pMMR but bev benefit in dMMR. A significant interaction for the association of high % PD-1 and PD-L1 with bev benefit regardless of MMR status may be a chance finding. However, VEGF has immunosuppressive effects and bev may block these effects in tumors with high PD-L1 and PD-1, regardless of MMR status. NCT: 00096278 PA DOH, U10CA-180868, -180822, -196067, Genentech, Sanofi; NSABP. Clinical trial information: 00096278.

This 5-year, prospective registry enrolled 600 lower-risk MDS patients (pts) with transfusional iron overload. Clinical outcomes were compared between chelated and nonchelated pts. At baseline, cardiovascular comorbidities were more common in non-chelated pts, and MDS therapy was more common in chelated pts. At 24 months, chelation was associated with longer median overall survival (52.2 months vs. 104.4 months; p

Preclinical studies have established the pharmacologic advantages of liposomal anthracyclines, including pharmacokinetic profiles after bolus dosing that resemble continuous infusion of conventional anthracyclines, increased drug concentrations in tumor cells compared with the surrounding tissues, and reduced toxicity relative to conventional anthracycline treatment. Based on these studies, many phase I and phase II clinical trials were conducted to assess the safety and potential activity of liposomal anthracyclines in the management of both solid and hematologic tumors. These studies provided valuable insight into the safety of pegylated liposomal doxorubicin (Doxil/Caelyx [PLD]), nonpegylated liposomal doxorubicin (Myocet [NPLD]), and liposomal daunorubicin (DaunoXome [DNX]) over a range of doses, either as single-agent therapy or in combination with other cytotoxic agents. Other liposomal anthracyclines in development may be well tolerated but their activity remains to be elucidated by clinical trials. The available data also suggest that liposomal anthracyclines have activity not only against tumor types with known sensitivity to conventional anthracyclines, but also potentially for tumors that are typically anthracycline-resistant. Despite the availability of clinical data from a wide variety of tumor types and patient populations, further studies of liposomal anthracycline therapy are needed to fully establish their safety, efficacy, and dosing in the treatment of these patients.

7523 Background: Bendamustine (B) + rituximab (R; BR) is a commonly used 1L treatment for CLL. The CLL10 study reported an ORR of 96% and CR of 31% with BR. Obinutuzumab (GA101; G) is a glycoengineered, type II anti-CD20 monoclonal antibody. A randomized Phase III trial in 1L CLL pts showed that G significantly improved PFS and CR rate compared with R, when used in combination with chlorambucil (Goede 2014). B + G (BG) was evaluated in a subgroup of CLL pts in the GREEN study (Stilgenbauer 2015). We present results of a Phase II study (NCT02320487) evaluating the efficacy and safety of BG as 1L treatment for CLL pts. Methods: 102 pts with previously untreated CLL received BG, consisting of 6 cycles of G (cycle [C] 1: 100mg day (D) 1, 900mg D2, 1000mg D8 and D15; C2–6: 1000mg D1) and B (90mg/m2: C1, D2 and D3; C2–6, D1 and D2). Each cycle was 28 days. Primary endpoint was CR assessed using iwCLL criteria. Secondary endpoints included ORR, PFS, OS, and MRD. Median follow-up at the time of analysis was 11.0 months. Results: Median pt age was 61 yrs (range 35–90); 68.6% were male; 44.1% had Rai stage 3–4. For evaluated pts, IgVH status was 32.9% mutated and 67.1% unmutated. The incidences of trisomy 12, normal cytogenetics, and deletions of 13q, 11q, and 17p were 23.4%, 37.5%, 17.2%, 15.6%, and 6.3%, respectively. Investigator-assessed CR rate was 49.0% (95% CI 39.0–59.1) and ORR was 89.2% (95% CI 81.5–94.5) after 6 cycles. MRD negativity (MRD-) in blood, as measured by 4-color flow cytometry, was achieved in 42.7% of pts at the end of induction response assessment and in 75.5% of pts at any time following treatment. MRD- in bone marrow (BM) was 60.8% in pts with BM samples. The most common AEs (all grades [Gr]) were infusion reactions (72.5%), nausea (52.0%), pyrexia (36.3%), neutropenia (34.3%), fatigue (34.3%), constipation (26.5%), and rash (26.5%). The most common Gr 3–4 AE was neutropenia (26.5%). Incidence of Gr 3–4 infections was 11.8%. Incidence of TLS was 4.9% (all Gr 3). Three pts died; none were deemed related to study treatment or CLL by investigators. Conclusions: BG is an effective regimen for 1L treatment of CLL pts, inducing a high CR rate after 6 cycles of therapy. No unexpected safety signals were observed. Clinical trial information: NCT02320487.

Background Addition of bortezomib to R-CHOP (VR-CHOP) may overcome the less favorable prognosis of non-GCB subtype lymphoma (Ruan et al. JCO 2011). We report results of a prospective open-label, randomized, phase 2 study evaluating the efficacy and safety of frontline R-CHOP vs VR-CHOP in pts with non-GCB DLBCL. Methods Adult pts with previously untreated non-GCB DLBCL who had ≥1 site of measurable disease, ECOG performance status 0-2, and adequate hematologic, hepatic, and renal function were eligible. Confirmation of non-GCB subtype using the Hans immunohistochemical (IHC) algorithm was required. Hans IHC non-GCB testing was performed in real time at a central US laboratory (48-72 hr turnaround from arrival of FFPE sample). Several centers demonstrated consistent scoring with the central laboratory and were permitted to enroll pts based on local non-GCB subtyping, with retrospective central laboratory confirmation. All pts received 6 cycles of standard R-CHOP in 21-d cycles (rituximab 375 mg/m2, cyclophosphamide 750 mg/m2, doxorubicin 50 mg/m2, vincristine 1.4 mg/m2 [max 2 mg], all IV on d 1, and prednisone 100 mg PO on d 1-5). In the VR-CHOP arm, pts also received bortezomib 1.3 mg/m2 IV on d 1 and 4 of each cycle. Follow-up was every 3 mos for up to 2 yrs after enrollment of the last pt. The primary endpoint was progression-free survival (PFS). Secondary endpoints included: overall survival (OS), overall response rate (ORR) and complete response (CR) rate after cycles 2 and 6, and safety. Response/disease progression were investigator-assessed by CT and FDG-PET scan at the end of cycles 2 and 6, and in follow up per 2007 Revised Response Criteria for Malignant Lymphoma. Adverse events (AEs) were graded by NCI-CTCAE v3.0. Sample size (n=~190) was determined to provide 80% power to detect an improvement in 2-yr PFS from 62% with R-CHOP (Fu et al. JCO 2008) to 77% (1-sided log rank; significance level 0.05). Here we present preliminary findings (data cut-off: Jun 2015). Results 206 pts were randomized at 69 sites; of these, 183 (91 R-CHOP, 92 VR-CHOP) had centrally confirmed non-GCB DLBCL and received ≥1 dose of study drug (modified intent-to-treat population). 86% (R-CHOP) and 85% (VR-CHOP) of pts completed study treatment per protocol. 60% of pts received study drug within 4 wks after tumor sample collection. Baseline characteristics were (R-CHOP vs VR-CHOP): male 58% vs 49%; median age 62 vs 65 yrs (>65 yrs 44% vs 46%); AJCC stage III/IV disease 73% vs 72%; extranodal disease 46% vs 52%; bone marrow involvement 11% vs 14%; IPI low/low-int/high-int/high 24/25/38/12% vs 26/28/33/13%. After a median follow-up of 31.5 mos, 2-yr PFS was 77% vs 82% (HR 0.77; 90% CI: 0.45, 1.30; p=0.70). In pts with high-int/high IPI, 2 yr PFS was 64% vs 72% (HR 0.66; 90% CI: 0.34, 1.28; p=0.294), whereas in pts with low/low-int IPI the HR was 1.13 (90% CI: 0.46, 2.75; p=0.821). At data cut-off, 15% and 11% of pts in the R-CHOP and VR-CHOP arms had died (HR: 0.65; 90% CI: 0.32, 1.29); median OS was not estimable in either arm and 2 yr OS rates were 80% vs 82%. In pts with high-int/high IPI, 2 yr OS rates were 79% (R-CHOP) vs 92% (VR-CHOP); in pts with low/low-int IPI, 2-yr OS rates were 98% in both arms. In 86 R-CHOP and 90 VR-CHOP response-evaluable pts, ORRs were 98% vs 92% (52% vs 54% CR). After 2 yrs, 73% of R-CHOP pts and 76% of VR-CHOP pts had not yet received a subsequent anti-lymphoma therapy. The safety population comprised 100 R-CHOP and 101 VR-CHOP pts. In both arms, pts received a median of 6 cycles of therapy (range 1-6). In the R-CHOP and VR-CHOP arms, 71% and 79% of pts had a G≥3 AE, and 31% and 34% had serious AEs, and 55% and 68% reported drug-related G≥3 AEs, the most common of which were neutropenia (34% vs 28%) and thrombocytopenia (8% vs 20%).G≥3 peripheral neuropathy rates were 1% (R-CHOP) and 5% (VR-CHOP). Conclusions These preliminary data suggest no significant efficacy advantage with the addition of bortezomib to R-CHOP in pts with previously untreated non-GCB DLBCL. This may be due to lack of bortezomib effect, time required for Hans IHC testing, IHC missclassification, or pt selection (R-CHOP alone pts had better outcomes/lower event rate than expected). These results have important implications for upcoming studies of new therapeutic strategies in DLBCL that target pt subsets based on cell of origin. Disclosures Kolibaba: Pharmacyclics: Research Funding; Seattle Genetics: Research Funding; TG Therapeutics: Research Funding; Cell Therapeutics: Research Funding; Celgene: Research Funding; Amgen: Research Funding; Amgen: Research Funding; Acerta: Research Funding; Gilead: Consultancy, Honoraria, Research Funding; Genentech: Research Funding; Novartis: Research Funding; GSK: Research Funding; Janssen: Research Funding. Tulpule:Millennium Pharmaceuticals Inc.: Research Funding. Flinn:Cephalon, Inc; Teva Pharmaceutical Industries Ltd; Genentech, inc; Gilead: Research Funding. Flowers:Janssen: Research Funding; Infinity Pharmaceuticals: Research Funding; Janssen: Research Funding; Onyx Pharmaceuticals: Research Funding; Acerta: Research Funding; Millennium/Takeda: Research Funding; Spectrum: Research Funding; Onyx Pharmaceuticals: Research Funding; Gilead Sciences: Research Funding; Pharmacyclics: Research Funding; Gilead Sciences: Research Funding; Acerta: Research Funding; Seattle Genetics: Consultancy; Pharmacyclics: Research Funding; Millennium/Takeda: Research Funding; AbbVie: Research Funding; Infinity Pharmaceuticals: Research Funding; Seattle Genetics: Consultancy; OptumRx: Consultancy; AbbVie: Research Funding; Genentech: Research Funding; Celegene: Other: Unpaid consultant, Research Funding; OptumRx: Consultancy; Genentech: Research Funding; Celegene: Other: Unpaid consultant, Research Funding; Spectrum: Research Funding. Papish:Genentech: Speakers Bureau; Pfizer: Speakers Bureau; Genomic Health: Speakers Bureau; Novartis: Speakers Bureau. Venugopal:Genentech: Research Funding; Celgene: Research Funding. Hajdenberg:Gilead: Speakers Bureau; AbbVie: Speakers Bureau; Incyte: Speakers Bureau; Novartis: Speakers Bureau; Celgene: Speakers Bureau; Janssen: Speakers Bureau; Idera Pharmaceuticals: Research Funding. Mulligan:Millennium Pharmaceuticals, Inc., Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment. Neuwirth:Millennium Pharmaceuticals, Inc., Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment. Suryanarayan:Millennium Pharmaceuticals, Inc., Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment. Esseltine:Takeda Pharmaceuticals, Inc.: Equity Ownership; Millennium Pharmaceuticals, Inc., Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment; Johnson & Johnson: Equity Ownership.

Introduction: We prospectively collected data from lower-risk patients (pts) with MDS in an ongoing US registry in order to assess the association between chelation and clinical outcomes. In addition, we evaluated the association between chelation and overall survival (OS). Here we report outcomes at 5 years. Methods: The registry enrolled 600 pts from 107 US centers. Pts were ≥18 years old with lower-risk MDS (WHO, FAB, and/or IPSS criteria) and transfusional iron overload (serum ferritin ≥1000 µg/L and/or ≥20 packed red blood cell units and/or ≥6 units every 12 weeks). Pts were analyzed by iron chelation status; ie, had never been chelated or had ever used iron chelation, and a subgroup of the latter group—pts with ≥6 mo of chelation. Pts were evaluated every 6 mo for 5 years or until death with respect to characteristics, survival, disease status, comorbidities, cause of death, and MDS therapy. Results: 600 pts (median age, 76 years [range, 21-99], 346 [57.8%] male, 519 [86.6%] Caucasian) were evaluated. IPSS status was similar across chelation groups. Chelated pts (n=271) had a greater median number of lifetime units transfused at the time of enrollment vs nonchelated pts (n=328): 38.5 vs 20.0. At baseline, cardiac and vascular comorbidities (CVC) were significantly higher in nonchelated vs chelated pts (52.4% vs 34.3% [P OS from diagnosis of MDS and time to acute myeloid leukemia (AML) were significantly greater in the chelated vs nonchelated pts (P Patients with ≥6 mo of chelation had numerically fewer deaths in the registry, numerically greater OS, time to death, and time to AML transformation vs pts who had any chelation (Table). Conclusions: Limitations of these analyses include variation in time from diagnosis, duration of chelation, impact of pt clinical status on decision to chelate, and optional conduct of clinical assessments. Nonetheless, the results after 5 years of follow-up of lower-risk pts with MDS suggest iron chelation therapy is associated with improved OS and longer time to AML transformation. Causation has not been established. Abstract 1350. TABLE. Characteristics of Patients Nonchelated, Chelated, and Chelated ≥6 Months Nonchelated n=328 Chelated n=271 Chelated ≥6 Months n=202 Time to death, median (min/max) mo 47.8 (43.4, 53.1) 88.0 (78.4, 103.0) *P Disclosures Paley: Novartis Pharma: Employment. Esposito:Novartis Pharma: Employment. McNamara:Novartis Pharmaceuticals Corporation: Employment. Garcia-Manero:Novartis Pharma: Research Funding.

8559 Background: The role of local pathologists in promoting patient (pt) accrual and evaluating eligibility criteria involving a complicated immunohistochemical (IHC) algorithm has rarely been investigated. The phase II PYRAMID trial (NCT00931918) is assessing R-CHOP ± bortezomib for newly diagnosed pts with non-germinal-center B-cell (non-GCB) subtype DLBCL. In this trial, local pathologists were encouraged to perform DLBCL subtyping at the point of biopsy, identify suitable pts for the trial, and facilitate accrual. Methods: Determination of GCB vs non-GCB subtype is per the Hans method, an algorithm based on IHC for CD10, BCL-6, and IRF4/MUM1. In stage 1, pathologists demonstrated IHC subtyping proficiency by evaluating a tissue microarray (TMA) of 12 DLBCL cases; those with ≥80% of samples in agreement with central lab results were certified for determining trial eligibility. In stage 2, to broaden participation, pathologist certification occurred via teleconference outlining trial eligibility criteria, tissue subtyping requirements, and determining pathologists’ experience with the Hans method. Results: 182 pathologists have been certified for local subtyping, 50 via TMA and 132 by teleconference. 66/88 active study sites have ≥1 certified pathologist. Only 1 of the 10 top enrolling sites lacks a certified pathologist. 52% (84/162) of pts have been enrolled based on local pathologist subtyping prior to central lab confirmation. Discordance with central lab results occurred in 9/84 cases (11%). Enrollment rates pre- and post-local pathologist certification were 0.053 and 0.096 pts/site/month; an improvement of 81%. Trial accrual correlates with the presence of a certified local pathologist (p=0.0026). The rate of ineligible GCB cases sent for central lab testing was lower from sites with a certified pathologist (23% [69/299 cases] vs 38% [40/106 cases] for sites without). Conclusions: Engagement of local pathologists in trials requiring pathology selection can significantly improve accrual. This study demonstrates the effectiveness of various training modalities in improving selection by local pathologists using a complex IHC algorithm. Clinical trial information: NCT00931918.

7096 Background: The objective was to evaluate the types, frequency and adherence of molecular tests utilized in patients (pts) with CML-CP who initiated 1st-line TKI therapy in the community practice (prac) setting. Methods: A retrospective study of newly diagnosed CML-CP pts; initiating 1st-line TKI during 06/2007 and 03/2011, with ≥18-mo follow-up was conducted. Data was collected from iKnowMed, various local & national labs to evaluate whether qRT-PCR test results was reported in International Scale (IS) or not (non-IS). The proportion (prop) of pts tested for molecular response in 3-mo intervals was tallied. Results: The study identified 189 pts (mean age 57 yrs, 53% male), 15% had no cytogenetic (cyto, FISH included) or molecular test (MT) recorded during 1st-line TKI therapy. The median number of MT was 6 (range: 1-28). In 3-mo intervals, the prop of pts tested for cyto responses were: 0-3 mos (24%), 3-6 mos (21%), 6-9 mos (24%), 9-12 mos (22%), 12-15 mos (10%), and 15-18 mos (7%). The prop of pts had MT in the 3-mo intervals were: 34%, 47%, 54%, 47%, 51% , and 55%. Regional patterns show the Northeast (defined by U.S. census regions) had a higher prop of pts for MT at almost all of these intervals. The number of physicians seeing CML pts correlated with the prop of pts monitored at each interval. Of the 1,226 MT ordered, 25% were reported on IS, 9% were unknown and 69% were on non-IS (Data reported: 48% log reduction, 45% BRC-ABL%, 7% other). Labs in the Midwest report on IS most often (61%), followed by the Northeast, Western (29% for both), and the South (13%). As the prac size increased, so did the utilization of IS. Conclusions: A low prop of CML pts were monitored for cyto and molecular responses. Only a quarter of the MT results were reported in IS. These results suggest gaps in CML management that could be closed with effective educational programs stressing the importance of monitoring and using IS reporting labs.

7122 Background: Many patients (pts) with lower-risk myelodysplastic syndromes (MDS) require chronic red blood cell transfusions for symptomatic anemia, which can result in iron overload. We present a 36-month interim analysis of a 5-year US registry that prospectively collected data on clinical events and survival in chelated vs non-chelated, transfused, lower-risk MDS pts. Methods: This multicenter, non-interventional registry enrolled 600 pts ≥18 yr old with lower-risk MDS (WHO, FAB, and/or IPSS risk stratification criteria) and transfusional iron overload (serum ferritin ≥1,000 ng/mL and/or ≥20 packed red blood cell units and/or ≥6 units every 12 wks). The chelated group included pts who had received any chelation. Results: Median age was 76 yr (range, 21–99), 57.8% were male, and risk status was 38.6% IPSS low risk and 61.4% IPSS INT-1 risk. Baseline demographics and IPSS risk status were similar between groups, although transfusion burden trended higher in chelated pts. As of April 30, 2012, 169 pts continued on the registry, and 431 discontinued (345 died, 57.5%; 61 lost to follow-up, 10.2%; and 25 other, 4.2%). In all, 264 pts (44%) received chelation therapy; 200 had ≥6 mos chelation. Overall survival (OS) and time to acute myeloid leukemia (AML) transformation were significantly longer, and the percentage of deaths was significantly lower, in chelated ≥6 mos vs non-chelated pts (P

International Working Group criteria, overall response rate (ORR) was 58% (15/26pts): 5 pts (19%) achieved complete remission (CR), while 10pts (39%) showed an hematologic improvement (HI). 11/26pts (42%) maintained a stable disease (SD). Generally the drug was very well tolerated. The most commonly reported hematologic toxicities were neutropenia (55%) and thrombocytopenia (20%). 4/30pts (13%) died during treatment. The median duration of response was 5 months (range 1–14 months). Surprisingly, 3/15 patients (2 CR and 1 HI erythroid) showed a long duration of response (11, 13 and 14 months, respectively), still ongoing, after discontinuation of AZA. Preliminary data on the lipid signalling pathways suggested a direct correlation between the demethylating effect on PI-PLC-beta1 and responsiveness to treatment. Conclusion: Our study shows that AZA low-dose schedule may be a feasible and effective treatment for low-risk MDS pts and may induce durable responses. Despite AZA safety, extreme caution is needed in pts with age-related comorbidities and/or with severe neutropenia or thrombocytopenia, especially in low-risk MDS. Furthermore, PIPLC-b1 demethylation and gene expression could represent a new biological marker to predict the clinical response to AZA.

18 patients with metastatic or recurrent bronchogenic carcinoma and one patient with a squamous cell carcinoma of the trachea were treated with a combination of CCNU, hexamethylmelamine and methotrexate. Objective remissions were observed in 3/19 (16%): 1 complete, 1 partial (greater than 50%) and 1 incomplete (less than 50%). However, the patient with the complete response was the only drug death, on day 21. Remission duration in the other two patients was 3 and 9+ months respectively. One patient with oat cell carcinoma experienced no tumor progression for 5 months. This combination resulted in severe gastrointestinal toxicity in 5/19, severe thrombopenia in 12/19 and severe neutropenia in 6/19. We conclude that the combination as used here resulted in no increased clinical effectiveness and proved to be quite toxic.

Two cases of disseminated atypical tuberculosis are presented in which the infection anteceded by over four years the development of acute granulocytic leukemia on one and Hodgkin's Disease in the other patient. The presence of disseminated atypical mycobacteriosis in the absence of a clearcut underlying illness suggests a "preneoplastic state." It should alert the clinician to the possibility of a neoplastic disorder which may not become clinically manifest for several years.

Forty patients with various types of myeloproliferative disorders were evaluated immunologically. Serum immunoglobulin levels were within the normal range in most patients and no monoclonal gammopathies were detected. Serum C'3 levels were decreased in 19 of 40 (48%) patients. The response of peripheral blood lymphocytes to phytohemagglutinin was decreased in 26 of 40 (65%) and to pokeweed mitogen in 18 of 28 (64%) patients studied. Lymphocytes from patients with polycythemia vera were least affected. Unstimulated lymphocytes from some patients demonstrated markedly increased thymidine uptake activity. Despite the diminished mitogenic response, only 2 of 33 patients (6%) were anergic by intradermal skin testing. There was no association between depressed lymphocyte response and recent chemotherapy except in chronic myelogenous leukemia where 6 of 8 patients were receiving cytotoxic therapy when studied. These observations suggest that most of our patients with myeloproliferative disorders have abnormal cellular responses in vitro, but that delayed hypersensitivity and humoral responses are minimally affected.

Fifty-six patients with advanced metastatic carcinoma of the breast, melanoma and lymphoma were treated with the new vinca alkaloid vindesine in a prospective Phase II study. The dose was 3 mg/M2 by I.V. bolus once a week for a minimum of two doses. Patients who failed to respond to four I.V. doses were treated with 48-h intravenous infusions at a dose of 1.5 mg/M2 per 24 h. Of the 26 evaluable patients with breast cancer, there were only two incomplete responses and four patients who experienced stabilization of disease. Of the 12 evaluable patients with melanoma, no responses were seen with four patients experiencing stabilization of disease. Of the 11 patients with non-Hodgkin's lymphomas, there was one complete remission which persisted for 26 months and two partial remissions. No additional responses were seen when the mode of administration was changed to 48-h infusion in three patients with breast cancer, five patients with melanoma and one patient with lymphoma. Significant toxicities included neutropenia in 24 patients and nausea and vomiting in two patients. There were no drug related deaths. Previously reported experience with vindesine in these tumors is reviewed as well.

21 patients with metastatic breast cancer, refractory to conventional agents, were treated with a combination of BCNU, vincristine, mitomycin-C and prednisone given every 4 weeks. Only three of the nineteen (15.8%) evaluable patients were observed to have a partial remission, whereas four experienced stabilization of tumor. The sites which responded included skin lesions in two patients and a pleural effusion in 1 patient. This combination resulted in moderate to severe thrombocytopenia in five patients, but was otherwise well tolerated. This pilot study therefore suggests that these four agents in the schedule and doses given do not appear to be superior to any of these agents used singly for advanced, refractory breast cancer.

The records of 177 patients with small cell carcinoma of the lung were reviewed to determine parameters associated with brain metastases. Complete autopsy, including examination of the brain, was done in each case. Of the 70 cases of brain metastases, only two patients (3%) were aged 70 years or more as compared with 19 (18%) aged 70 years or more who did not have brain metastases. Patients with brain metastases had a longer median survival as compared with those without brain metastases. Patients with brain metastases had involvement of the thyroid and kidney more frequently (23% and 34%, respectively) compared with patients without brain metastases (8% and 13%). Thus, patients who have brain metastases tend to (1) be less than 70 years of age; (2) have a longer survival; and (3) have a higher incidence of metastases to the thyroid and kidney. ( JAMA 242:2084-2086, 1979)

Excerpt We have recently seen a 63-year-old man with mixed cell Hodgkin's disease who has been receiving multiple agent chemotherapy for difficult-to-control retroperitoneal disease. One of the age...

Excerpt Tamoxifen is a nonsteroidal antiestrogen currently used primarily in the treatment of patients with hormone-receptor-positive breast cancer (1). Its major advantage over other hormonal agen...

In Reply.— The main point of Dr Mira's letter is that patients with small cell carcinoma of the lung have a greater tendency to have brain metastases develop with increasing length of survival. We agree with this statement and expressed this in our article. Our article states that the present aggressive regimens may result in an improved survival and, therefore, an increase in the incidence of brain metastases. This hypothesis was based on our finding that those patients who lived longer had an increased incidence of brain metastases. We then quoted Hansen who had similar findings and conclusions. Perhaps instead of stating that "patients who developed brain metastases had a longer survival," any misinterpretation could have been prevented if we had simply stated that those patients who survived longer had a greater tendency to have the development of brain metastases. We do agree with the comments by Dr Mira on

• Pyrimethamine, a folate antagonist similar to methotrexate without known hepatotoxicity in man, was administered orally, once a week, to seven patients with severe, long-standing psoriasis. Four patients obtained a good to excellent response; a fifth withdrew from the study early after a partial response; a sixth had minimal response to high doses, and the seventh was withdrawn due to a probable drug-induced hepatotoxic reaction. Hepatotoxic reaction was suspected in another patient with abnormal liver biopsy and liver function test results. Two patients experienced severe gastrointestinal toxic reactions and two developed significant thrombocytopenia, which resolved after oral treatment with folic acid or discontinuation of the drug. These did not recur at lower doses. Pyrimethamine appears to be effective in severe psoriasis, but offers no advantage, and several disadvantages over methotrexate. Pyrimethamine is probably hepatotoxic. It should be used with caution in patients with liver disease or impaired renal function; pretreatment liver biopsy is recommended. ( Arch Dermatol 113:172-174, 1977)

To the Editor.— We appreciated the comments by Okin and Brandstetter (243:2154, 1980) in respect to our study on small cell carcinoma of the lung (242:2084, 1979). They reviewed their data and obtained different results. We agree with their comment that the observed differences could be secondary to a different patient population. Only 24% of their patients had brain metastases develop. This is much lower than that which is reported in the literature, with some authors reporting an incidence as high as 65% in patients on whom autopsies were performed. 1 If the incidence were truly 24%, then prophylactic cranial irradiation (PCI) would be difficult to justify in this tumor. In their letter they state that their longer mean survival of 5.75 months for those patients with brain metastases vs 3.5 months for those without brain metastases was not statistically significant. They commented that this was similar to our mean

Teardrop-shaped erythrocytes (TD) are frequently observed in the peripheral blood of patients with agnogenic myeloid metaplasia (AMM). These deformed cells may result from the myelofibrosis or the extramedullary hematopoiesis in the spleen. To determine the influence of the spleen on TD formation, we reviewed the presplenectomy (pre-S) and postsplenectomy (post-S) peripheral blood smears from 13 patients with AMM. The splenectomy was performed for a variety of reasons, including symptomatic hypersplenism or splenomegaly. The average number of TDs per 1,000 RBCs in the pre-S smears was 42 (range, 15 to 112 TDs), compared with 11 TDs in the post-S smears (range, 6 to 20 TDs) (P= (Arch Intern Med137:380-381, 1977)