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In contrast to that in children, pharmacokinetic, pharmacodynamic, and safety information on pegaspargase in adults is very limited. We administered a single intravenous dose of pegaspargase (2000 IU/m2) as part of a standard frontline induction regimen to 25 adults with newly diagnosed acute lymphoblastic leukemia (ALL), and obtained serum samples on several time points. The population mean peak serum concentration of asparaginase enzymatic activity was 1 IU/mL, the elimination half-life was 7 days, and the volume of distribution was 2.43 L/m2. After the single dose, asparagine deamination was complete in all patients after 2 hours, and in 100%, 81%, and 44% on days 14, 21, and 28, respectively. A pharmocodynamic correlation model showed minimal enzymatic activity of 0.2 IU/mL for optimal asparagine depletion. The kinetic posthoc analyses demonstrated enzymatic activity for 3 weeks or more. One patient developed neutralizing antiasparaginase antibodies on day 22 after administration. Pegaspargase was well tolerated, with few grade 3/4 side effects. No allergic reactions or pancreatitis were observed. In adults aged 55 years or younger, pegaspargase produces a long duration of asparagine depletion and can be given intravenously, with a safety profile that is similar to equivalent multiple doses of intramuscular Escherichia coli asparaginase.

In this issue of Blood , some of the controversies surrounding optimal therapy for patients with AIDS-related lymphoma (ARL) are now clarified by the analyses of Barta et al.[1][1] ![Figure][2] OS for ARL patients treated with rituximab-containing regimens vs those treated with regimens that

Bone marrow involvement is reported in approximately 25% of patients with newly diagnosed acquired immunodeficiency syndrome–related lymphoma (ARL). Studied were 291 patients with ARL, diagnosed and treated at one medical center between 1984 and 1998. Clinical, immunologic, and pathologic characteristics of patients with bone marrow involvement were compared with those of patients without marrow involvement. Bone marrow involvement was present in 55 patients (19%). Small noncleaved lymphoma was diagnosed in 38% of the entire group and was the most common pathologic subtype in patients with bone marrow involvement (55% versus 34%;P = .008). Analysis of complete blood counts revealed a median hemoglobin level of 10.6 g/dL in both marrow-positive and marrow-negative groups. In contrast, a platelet count lower than 100 000/μL was more common in patients with bone marrow involvement (27% versus 11%; P = .02). Patients with marrow involvement were more likely to have leptomeningeal (cerebrospinal fluid [CSF]) lymphoma than patients whose marrows were uninvolved (24% versus 7%; P

Background: Value is defined as health outcomes achieved per dollar spent. While risk-stratified AL HCT survival estimates are made possible by the Stem Cell Therapeutic Outcomes Database (SCTOD), an assessment of healthcare value is not possible as they do not include cost adjustments based upon clinical risk. We report a risk-based cost analysis, modeled on AL pts undergoing HCT at our institution that can potentially serve as a simple, statistically significant risk-based comparison tool. Methods: All AL pts who underwent HCT at City of Hope between 1/1/2010 and 12/31/2014 were included. Detailed data were captured from multiple electronic record sources in our database. Total direct costs were assessed for each pt from 14 days prior to 100 days post HCT. Categorical data were tested for associations by Chi-square; continuous data that were normally distributed were tested by T-test, while non-normal data were tested by Wilcoxon rank sum test. Univariate and multivariable logistic regression models were used to identify predictors associated with HCT costs ≥ median and ≥ 80th percentile. Univariate and multivariable Cox proportional hazards regression were used to identify predictors of overall survival (OS). All p-values were 2-sided with alpha level of 0.05. Results: This analysis included 389 pts (AML 352; ALL 37); median age was 52.5 years (yr) [range 1-74; 107 (27.5%) age ≥ 60]; 48% were female. At the time of HCT 204 (52%) were in 1st complete remission [CR], 87 (22%) in 1st relapse (rel)/2nd CR, and 98 (25%) >2nd CR/Induction Failure [IF]; ECOG performance status was ≥1 in 29.5% and Sorrer comorbidity score ≥1 in 56%. 214 (55%) and 175 (45%) received myeloablative (MAC) or reduced intensity (RIC) conditioning regimen, respectively; 231 (59%) had matched unrelated donor [MUD] or mismatched related donor (MRD) HCT. Graft-versus-host prophylactic (GVHD) regimen consisted of tacrolimus/sirolimus for 80% pts. 207 pts were enrolled on a therapeutic intervention trials and 121 had Medicare and/or Medicaid (Medi-Cal) as payer. Median follow-up was 12.9 months. The estimated 1- yr unadjusted OS for the entire group post-HCT was 71% (95% CI 66%-75%), 80% (74%-85%) for pts in 1st CR, 68% (57%-77%) for pts in 1st rel/2nd CR, and 56% (45%-65%) for pts >2nd CR/ IF. OS was similar for sibling matched and MUD/MRD transplants (1-yr OS 73% vs. 70%). In a multivariable analyses, disease status, MUD/MRD donor, MAC regimen, GVHD prophylaxis other than tacrolimus/sirolimus, ECOG ≥1, and Medicare and/or Medicaid as payer significantly predicted for cost ≥ median (Figure1A). Using Akaike Information Criterion (AIC) scores, donor type and disease status at HCT were found to be more informative variables with regard to higher cost of HCT. Disease status, MUD/MRD, MAC regimen, Medicare and/or Medicaid as payer and ECOG ≥1 also significantly predicted cost ≥ 80th percentile (Figure1B). In a multivariable analysis for OS (Figure 1C) , only >2nd CR/IF and HCT cost exceeding median had significantly higher hazard of death. Of note, despite reaching statistical significance in univariate analysis age, cytogenetics, treatment on protocol, and Sorrer score lost significance in adjusted higher costs and OS multivariable models. Conclusions: Our data suggest that: 1. Higher levels of care complexity drive higher costs, 2. Patients with more advanced disease status and inferior performance status have higher costs, 3. Statistically significant drivers of higher care costs are predictable prior to HCT. These risk factors are easily abstractable from medical records and provide prospective, equitably comparisons of risk-based costs between transplant centers. These data compliment the outcomes data available from the SCTOD and may enable providers and payers to make meaningful value comparisons between transplant centers. They may also help establish alternative models for payer contracting that include consideration of clinical risk-stratification. Of note, given the favorable survival outcomes of pts with higher cost-risk features (i.e., advanced disease status at HCT and MUD/MRD), the higher care costs associated with effective care of higher complexity pts are justified. While validation of this model is necessary using large payer or multi-institutional databases, we propose that similar clinical-economic models can be created for pts with other blood cancers requiring high complexity care. Figure 1 Figure 1. Figure 2 Figure 2. Figure 3 Figure 3. Disclosures Forman: Mustang Therpapeutics: Other: Construct licensed by City of Hope.

Over time, the epidemiologic and demographic characteristics of AIDS have changed in the United States, while the use of highly active antiretroviral therapy has changed the natural history of the disease. The goal of the study was to ascertain any changes in the epidemiologic, immunologic, pathologic, or clinical characteristics of AIDS-related lymphoma (ARL) over the course of the AIDS epidemic. Records of 369 patients with ARL diagnosed or treated at a single institution from 1982 through 1998 were reviewed. Single institutional data were compared to population-based data from the County of Los Angeles. Significant changes in the demographic profile of patients with newly diagnosed ARL have occurred, with the later time intervals associated with a higher prevalence in women (P = .25), in Latino/Hispanic individuals (P

Over time, the epidemiologic and demographic characteristics of AIDS have changed in the United States, while the use of highly active antiretroviral therapy has changed the natural history of the disease. The goal of the study was to ascertain any changes in the epidemiologic, immunologic, pathologic, or clinical characteristics of AIDS-related lymphoma (ARL) over the course of the AIDS epidemic. Records of 369 patients with ARL diagnosed or treated at a single institution from 1982 through 1998 were reviewed. Single institutional data were compared to population-based data from the County of Los Angeles. Significant changes in the demographic profile of patients with newly diagnosed ARL have occurred, with the later time intervals associated with a higher prevalence in women (P = .25), in Latino/Hispanic individuals (P

A high frequency (24%) of acute promyelocytic leukemia (APL) was noted among acute myelocytic leukemia (AML) cases at the Los Angeles County-University of Southern California (LAC-USC) Medical Center, in comparison with the expected frequency of 5% to 15%. Because of the high proportion of Latinos in this center, we questioned if APL is more common in this ethnic group. The proportion of APL among the 80 AML patients of Latino origin was significantly higher (30; 37.5%) when compared with the 62 non-Latinos (4; 6.5%) (P = .00001). In an attempt to verify this finding on a larger group of patients, we analyzed 276 pathologically verified cases of AML in patients aged 30 to 69 years from the entire County of Los Angeles, registered on an ongoing population-based epidemiologic study of AML. APL was more frequent among the 47 Latinos (24.3%) than in the 229 non-Latinos (8.3%) (P = .0075). APL is seen in younger patients with AML, but Latino AML patients also had a higher frequency of APL after accounting for their younger age (age-adjusted odds ratio for APL among Latinos in LAC-USC Medical Center, 9.4 [95% confidence interval (CI) 2.9, 30] P = .0002; among Latinos in the population-based study, 3.0 [95% CI 1.3 to 6.9] P = .01). The different ethnic distribution of AML was found to be due to a higher proportion of APL cases per se, and not to a lower proportion of any other French-American-British subtype (P = .0004). These results, from two different populations of AML patients, indicate that Latinos with AML have a higher likelihood of the APL subtype of disease, which may suggest a genetic predisposition to APL and/or exposure to distinct environmental factor(s).

The role of zidovudine and other antiretroviral agents in the pathogenesis of acquired immunodeficiency syndrome (AIDS)-related lymphomas has been somewhat controversial. In an attempt to elucidate the precise role of antiretroviral agents in the subsequent development of AIDS-related lymphoma, we performed a population-based, case-control study of human immunodeficiency virus (HIV)-seropositive patients with intermediate- or high-grade lymphoma in Los Angeles County, California, in which information regarding use of antiretroviral medications was ascertained. Diagnostic biopsy material was reviewed to confirm intermediate-or high-grade lymphoma. A structured interview, conducted with all cases and controls, included information about use of zidovudine and other antiretroviral agents. A total of 112 HIV-infected homosexual/bisexual men with lymphoma were matched to 112 homosexual/bisexual men with asymptomatic HIV infection; 49 of the lymphoma cases were also matched to 49 additional controls with AIDS, as defined by conditions other than lymphoma. Positive histories of zidovudine use were reported by 44 (39%) lymphoma cases, 24 (21%) asymptomatic HIV controls, and 21 (42%) AIDS controls. The average duration of zidovudine use up to 12 months before lymphoma diagnosis was 19.0 +/- 13.0 months (mean +/- SD) for the lymphoma cases, 12.6 +/- 10.5 months for the asymptomatic controls, and 11.0 +/- 7.1 months for the AIDS controls. When comparing the 49 HIV-positive lymphoma cases with their 49 matched AIDS controls, all of whom were diagnosed with AIDS during the same time period, the matched relative odds of lymphoma associated with prior use of zidovudine was 0.43 (95% confidence interval [CI] = 0.17 to 1.12). In comparing all 112 lymphoma cases with 49 AIDS controls, the unmatched relative odds of lymphoma associated with zidovudine use was 0.93 (95% confidence interval = 0.47 to 1.83). One lymphoma case and no AIDS control cases had a history of didanosine use; no lymphoma case or AIDS control cases had taken zalcitabine. We conclude that zidovudine is not associated with an increased risk of development of lymphoma among HIV-infected homosexual or bisexual men.

Lymphoproliferations associated with Epstein-Barr virus (EBV) commonly arise in settings of immune dysfunction, including human immunodeficiency virus (HIV) infection. In this study, EBV was associated with 39 of 59 (66%) HIV-related systemic lymphomas. Unlike the lymphoproliferations that arise in the setting of transplantation, the HIV-related lymphomas were monoclonal, as evaluated by Ig heavy chain rearrangements and EBV termini analysis, and associated (40%) with c-MYC rearrangements. Furthermore, analysis of multiple lymphoma tissues from one autopsy showed evidence that a single lymphoma clone was responsible for dissemination. The latent EBV nuclear antigen (EBNA- 1) transcripts detected in the HIV-related lymphomas were characteristic of the pattern found in Burkitt lymphoma (g1 EBNA1) and not in transplant-related lymphoproliferations. However, unlike Burkitt lymphoma, EBV latent membrane-associated protein (LMP) transcripts were also detected, thereby constituting an EBV expression pattern (g1 EBNA1+, LMP+) not previously observed in B-cell lymphomas. These findings demonstrate a high frequency of EBV-associated lymphomas in the setting of HIV infection that are distinct from the lymphoproliferations that arise during iatrogenic transplant-associated immuno-suppression or in the general population. However, it is also apparent that HIV-related lymphomas are biologically heterogeneous, which may reflect the multiple mechanisms or steps necessary for eventual malignant transformation.

Individuals infected with the human immunodeficiency virus (HIV) have an increased incidence of high-grade B-cell lymphoma. In many instances, these lymphomas contain Epstein-Barr viral (EBV) genomes. To investigate the role of EBV in development of HIV-related lymphoma, benign fixed lymph node biopsies from normal individuals and HIV- infected individuals with persistent generalized lymphadenopathy (PGL) were analyzed for EBV sequences by polymerase chain reaction and in situ DNA hybridization techniques. EBV DNA was not detected in any of 16 benign lymph node biopsies from normal individuals, but could be detected from 13 of 35 PGL biopsies. The EBV-infected cells were present in both follicular and interfollicular areas and in both small and large lymphoid cells. The presence of detectable amounts of EBV DNA in the 13 PGL biopsies was associated with an increased incidence of concurrent lymphoma at another site (n = 3) or development of lymphoma in time (n = 2). In contrast, only 1 of 22 individuals with EBV- negative PGL biopsies developed lymphoma in time (P less than .05). EBV was detected in all five lymphomas in which tissue was available for subsequent analysis, including the lymphoma that developed in the individual without EBV in his previous PGL biopsy. These findings support the hypothesis that EBV plays a role in development of some HIV- related lymphomas. Detectable EBV lymphoproliferations occur in a few PGL biopsies and are associated with a significant risk of EBV DNA- positive non-Hodgkin's lymphoma.

This is a phase 2 study to assess the role of tumor histogenesis (subtype), fluorodeoxyglucose positron emission tomography (FDG-PET), and short-course etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin with dose-dense rituximab (SC-EPOCH-RR) in newly diagnosed HIV-associated CD20+ diffuse large B-cell lymphoma. Patients received a minimum of 3 and a maximum of 6 cycles with 1 cycle beyond stable radiographic and FDG-PET scans. Overall, 79% of patients received 3 cycles. Combination antiretroviral therapy was suspended before and resumed after therapy. Thirty-three enrolled patients had a median age of 42 years (range, 9-61 years), and 76% had a high-intermediate or high age-adjusted international prognostic index. At 5 years median follow-up, progression-free and overall survival were 84% and 68%, respectively. There were no treatment-related deaths or new opportunistic infections during treatment, and patients had sustained CD4 cell count recovery and HIV viral control after treatment. FDG-PET after 2 cycles had an excellent negative but poor positive predictive value. Tumor histogenesis was the only characteristic associated with lymphoma-specific outcome with 95% of germinal center B-cell (GCB) versus 44% of non-GCB diffuse large B-cell lymphoma (DLBCL) progression-free at 5 years. SC-EPOCH-RR is highly effective and less immunosuppressive with shorter duration therapy compared with standard strategies. However, new therapeutic advances are needed for non-GCB DLBCL, which remains the important cause of lymphoma-specific death. This trial was registered at www.clinicaltrials.gov as NCT000019253.

Background: ABT-263 is a novel small molecule Bcl-2 family protein inhibitor that binds with high affinity (Ki ≤ 1 nM) to multiple antiapoptotic Bcl-2 family proteins including Bcl-XL, Bcl-2, Bcl-w, and Bcl-B. ABT-263 displays potent mechanism-based cytotoxicity (EC50 ≤ 1 mM) against human tumor cell lines derived from lymphoid malignancies and small cell lung cancer (SCLC). Pre-clinical experiments on primary patient derived chronic lymphocytic leukemia (CLL) samples with ABT-737, a first generation Bcl-2 family protein inhibitor, induced robust, concentration-dependent apoptosis. The anticipated ABT-263 associated toxicities are mechanism based, in particular, Bcl-XL mediated decrease in circulating platelet survival, Bcl-w mediated testicular toxicity, and Bcl-2 mediated effects on lymphocytes. ABT-263 is currently being investigated in 3 Phase 1/2a studies in patients with lymphoid malignancies, SCLC/solid tumors, and CLL. Methods: In this Phase 1/2a study of ABT-263 in subjects with lymphoid malignancies, the Phase 1 dose escalation portion of the study was designed to determine the maximum tolerated dose (MTD), dose limiting toxicity (DLT), and recommended Phase 2 dose (RPTD). For each 21-day cycle, subjects receive ABT-263 orally QD for 14 consecutive days followed by 7 days off drug. Pharmacokinetic (PK) assessment was performed at study initiation and on Day 14 of drug dosing. The Phase 2a portion of the study will evaluate ABT-263 at the RPTD in up to 40 subjects with follicular and aggressive NHL to obtain additional safety information and a preliminary assessment of efficacy. Results: Currently 17 subjects have been enrolled in the lymphoma study. Three subjects completed each of the 10, 20, 40, and 80 mg cohorts enrolled thus far. A Grade 3 DLT (URI resulting in hospitalization treated with antibiotics) occurred in the 160 mg cohort, thus the cohort was expanded to 6. Two patients with bulky SLL/CLL in the 40 and 160 mg cohorts had 95% and 64% tumor reductions after cycles 4 and 2, respectively, and continue on treatment. The PK profile of ABT-263 appeared to be linear between the 10 mg and 160 mg dose levels. The average terminal half-life of ABT-263 varied between 14 and 25 hours across all dose levels. ABT-263 reduced the platelet level in a dose-dependent manner. One subject experienced a Grade 3 thrombocytopenia (platelets 45K/uL) on C1D14, 4 hours post-dosing with 80 mg, resolving 8 hours post-dosing to a platelet count of 162 K/uL. The decreased platelet count did not result in any medical sequelae. Conclusions: ABT-263 is a novel, orally bioavailable and active small molecule Bcl-2 family protein inhibitor that has shown preliminary evidence of activity in lymphoid malignancies.

Comment on Biggar et al, page [3786][1] Highly active antiretroviral therapy (HAART) has resulted in a stunning decrease in all AIDS-related illnesses, with one apparent exception: Hodgkin lymphoma (HL). Biggar and colleagues, linking data from national AIDS and cancer registries in the United

Introduction: Arsenic trioxide (ATO) has demonstrated efficacy in acute promyelocytic leukemia (APL), inducing complete remissions (CR) in 85% of relapsed patients. On the other hand, ATO alone has no activity in non-APL AML. Although this difference could be explained by degradation of the APL specific PML/RAR fusion protein, ATO has shown to be active against APL cells by mechanisms that are independent of this gene rearrangement. ATO-induced apoptosis correlates inversely with intracellular concentrations of reduced glutathione (GSH) via generation of reactive oxygen species (ie, cells with high concentrations of GSH are more resistant to ATO). APL cells were found to have low levels of GSH compared to non-AML cells. Agents that reduce intracellular GSH, such as ascorbic acid (AA), increase ATO-induced apoptosis and can overcome resistance to ATO in non-APL AML cell lines; AA alone has no activity in these cells. Thus, the combination of ATO and AA was evaluated in patients with non-APL AML. Methods: ATO (0.25 mg/kg/d) was administrated intravenously over 1–4 hours with intravenous AA (1g/d, given 30 minutes after ATO) for five days/week (five days on/2 days off) for five weeks (25 doses=one cycle). These doses were based on a phase I/II trial of ATO + AA in patients with multiple myeloma (Behalis et al Clin Cancer Res8:3658, 2002). Responding patients received an additional consolidation cycle of 25 doses followed by maintenance including ATO + AA two weeks of every month for 4 cycles. Patients who failed to respond after two cycles were considered treatment failures. Results: Eleven patients, aged 36–84 years (median: 66 years), were enrolled: 5 had relapsed after chemotherapy; and 6 elderly, aged 66–84, (including 5 with antecedent MDS), were previously untreated. One patient was discontinued prematurely because of QT prolongation. Major response was seen in 3 (27%) pts: CR or CRp in 2 patients and decrease in bone marrow blasts to 500 msec), anorexia, fatigue, sensory neuropathy, elevated bilirubin (n=1 each). One responding patient developed shortness of breath with severe hypoxemia, reminiscent of the APL differentiation syndrome, which responded immediately to dexamethasone. Conclusion: ATO + AA can have anti-leukemic activity in poor risk non-APL AML with much less toxicity than chemotherapy, especially in previously untreated patients. Most relapsed patients did not respond to ATO +AA, suggesting that chemotherapy can induce resistance to this combination. Further studies are needed to explore the potential of ATO +AA as a front-line therapy instead of intensive chemotherapy in elderly patients with non-APL AML.

BACKGROUND: ATN-224 is an orally available, small molecule containing molybdenum (Mo) that specifically binds copper. ATN-224 inhibits multiple signaling pathways important to angiogenesis and tumor growth such as pathways mediated by growth factors, including vascular endothelial growth and epidermal growth factors and signaling molecules such as protein kinase B (PKB/Akt) and nuclear factor kappa B. ATN-224 exerts these effects through the inhibition of the enzyme copper-zinc superoxide dismutase (SOD1) in endothelial and tumor cells. Activity has been seen in a variety of animal tumor models including bortezomib-resistant myeloma. METHODS: Adult pts with recurrent or refractory hematologic malignanies or for which no standard therapy exists were enrolled. Pts had to have adequate performance status (PS 0–2) and have adequate hematologic and organ function. Pts were monitored for safety and efficacy and blood samples for pharmacokinetic and biomarker determinations were taken at specified intervals. At least 3 pts were to be enrolled at each dose level starting at 120 mg/day. Pts who left the study prior to 28 days for reasons other than toxicity were to be replaced. If 1 pt developed dose-limiting toxicity (DLT) as defined by the protocol, the cohort was to be expanded to up to 6 pts. Maximum tolerated dose (MTD) was defined as the highest dose where no more than 1 of 6 pts had DLT. Dose adjustments were made on the basis of toxicity and serum ceruloplasmin (Cp), a surrogate marker for total body copper. Pts received a loading dose for 2 weeks and then doses were titrated to keep Cp between 5 and 15 mg/dL. RESULTS: 17 pts (53% female), ages 43–79 (mean 63), with PS 0 or 1 were entered. 8 pts had myeloma, 5 leukemia, 3 lymphoma, and 1 myelodysplastic syndrome. Because of rapid progression in 5 pts who were replaced and 1 DLT (Grade [Gr] 4 neutropenia, Gr 3 anemia), 11 pts were entered in the 1st cohort. With information from a companion study in pts with solid tumors, the dose for the next cohort was increased to 300 mg. 1 of 6 pts had DLT (Gr 4 neutropenia). No further cohorts were entered as 300 mg/day was determined as MTD from the companion study. Pts who received long-acting antacids were found to have higher Mo concentrations than those without, so the protocol was amended to require all pts to receive daily antacid. Dose-dependent inhibition of SOD in red blood cells (a surrogate tissue for tumor) was observed. Major adverse events included reversible Gr 4 neutropenia, Gr 3 anemia, and Gr 3 thrombocytopenia. Gr 3 fatigue, which was DLT in the solid tumor study, was not observed in this trial. Mild to moderate symptoms such as gastrointestinal disorders, headache and lightheadedness were also observed. There were no responses but 1 pt with leukemia had stable disease for 5 months and a pt with myeloma had stable disease for 4.5 months. CONCLUSION: ATN-224, an antiangiogenesis and antitumor agent with a novel mechanism of action, has manageable, reversible toxicity. The dose recommended for Phase II studies is 300 mg/day with dose adjustment starting at 2 weeks to maintain Cp at 5–15 mg/dL.

Introduction: Large randomized trials in pediatric ALL show that multiple doses of E.Coli asparaginase (ASP) given throughout post remission phase are associated with improved outcome. ASP is routinely incorporated into most front line adult ALL protocols. PEG-asparaginase (PEG-ASP) is E.coli ASP, which is linked to polyethylene glycol reducing the risk of hypersensitivity reactions and prolonging the half life compared to the native forms. In children multiple doses of PEG-ASP produce less neutralizing antibodies than equivalent doses of native E. coli ASP with similar toxicity (Avramis Blood 99:1986Avramis Blood 99:2002). Information on PEG-ASP in adults is very limited. In a previous study we showed that in adult ALL, a single IV dose of PEG-ASP given at induction produces a long duration of serum ASP enzymatic activity and concomitant asparagine depletion with similar toxicity to equivalent multiple doses of E.coli ASP. We currently report in adults the pharmacokinetics (PK), antibody production and toxicity of multiple doses of PEG-ASP given throughout the treatment of patients with newly diagnosed previously untreated ALL. Methods: We used a modified augmented BFM ALL protocol consisting of 8 cycles of multi-agent chemotherapy followed by maintenance. PEG-ASP (2000 U/m2/dose) is given IV once on day 15 of the following cycles (total 6 doses): induction phase I (cycle 1), induction phase II (cycle 2), two cycles of consolidation (cycles 3 and 6), and two cycles of delayed re-induction (cycles 5 and 8). Serum samples were taken weekly for three weeks for ASP enzymatic activity after PEG-ASP dosing in induction phase 1 (dose 1) and in delayed re-inductions I and II (doses 4 and 6, respectively). Results: 18 patients aged 19–57 (median 28) years with newly diagnosed ALL (precursor B cell - 14, T -4) were studied. All 18 patients (100%) achieved a CR after induction phase I. Six patients discontinued the protocol because of undergoing allogeneic stem-cell transplantation. The number of doses of PEG-ASP was: all 6 doses- 4 pts, 4-3 pts., 2–5 pts., 1– 6 pts. Total number of doses was 52. T ½ was 7±4.7 days (n=18) after the fist dose increasing to 11.9±5.9 days (n=11) after dose 4 and 6. In the first cycle the AUC and MRT were lower while the Vd, Vdss and total clearance (Clt) were higher compared to the subsequent cycles. The change in PK parameters over time is most likely due to Michaelis-Menten (M-M) rate-limiting step on the elimination of the drug. Peak serum levels did not change significantly between the cycles. Anti-ASP antibodies were not detected in any patient-cycles. Grade 3/4 toxicities were hyperbilirubinemia - 3 pts (3 doses), elevated liver enzymes - 10 pts (13 doses), hyperglycemia - 7 pts (10 doses), allergy, pancreatitis, neuropathy, and fatigue - 1 pt (1 dose) each. All toxicities were reversible. We saw no pattern of increasing toxicity in subsequent doses of PEG-ASP. Only two patients had relapsed (median follow up of 15 months). Conclusion: multiple doses of PEG-ASP can be given IV to adults (age

ABT-510 is a potent nonapeptide that mimics the antiangiogenic activity of the endogenous protein, thrombospondin-1. Dogs with spontaneous lymphoma showed a response rate of 17% (4/23). In 2 phase 1 studies in patients with solid tumors, ABT-510 was tolerated at doses up to 260 mg per day. Doses ≥20 mg daily exceeded the pharmacokinetic target of 100 ng/mL for >3 hours. 67 patients with relapsed or refractory lymphoma were randomized to receive ABT-510 10 mg or 100 mg twice daily (BID) by subcutaneous injection. The 10 mg BID arm was discontinued after 15 patients were enrolled to consolidate recruitment to the higher dose. The primary endpoint was tumor response; secondary endpoints included progression-free survival (PFS) and overall survival. Tumor progression was evaluated every 8 weeks by the Cheson criteria; safety was evaluated every 4 weeks. 6 of the 67 patients remain on active therapy. Data are available for 56 patients (32M/24F); the median age is 63 years (range 22–87), and the baseline ECOG Performance Score for all patients ranges from 0–2. All patients were heavily pretreated, with a median of 5 prior treatments (range 1–11). There are 3 partial responses, all in the 100 mg dose group in non-Hodgkins lymphoma (NHL) patients. PFS data are as follows: Patient Group N 6-month PFS % (90 % CI) 12 month PFS % (90 % CI) All 56 41 (28, 53) 17 (3, 31) 10 mg BID 15 34 (11, 56) 0 100 mg BID 38 48 (33, 64) 24 (8, 41) Hodgkins 11 29 (3, 55) 0 NHL 45 44 (30, 58) 22 (4, 40) Aggressive 17 29 (9, 49) 0 Indolent 27 51 (33, 70) 36 (16, 56) The most frequent adverse events (AEs) were asthenia (39%), injection site reaction (39%), diarrhea (24%), and anorexia (20%). 19% of patients had Grade 3–4 AEs considered related to ABT-510: anemia (4), thrombocytopenia (2), asthenia, chest pain, hemorrhage, gastrointestinal hemorrhage, leukopenia, and hypercalcemia (1 each). Correlative analyses of circulating endothelial cell data are pending. Based on these preliminary data, ABT-510 appears well-tolerated with biological activity in heavily pretreated patients with lymphoma. Study of ABT-510 in combination with immunotherapy or standard chemotherapy is warranted.

Noscapine is an alkaloid derived from opium, which lacks sedative, euphoric, analgesic or respiratory depressant properties. Antitumor activity of Noscapine has been demonstrated both in vivo, against human lymphoid tumor cells, and in vitro, in human tumors implanted in athymic mice. Noscapine induces conformational changes in tubulin, which results in altered microtubule assembly. In this Phase I trial, cohorts of subjects with relapsed/refractory non-Hodgkin’s lymphoma (NHL) or chronic lymphocytic leukemia (CLL/SLL) were treated at three different dose levels of total daily doses of 1 g, 2 g, and 3 g. At each dose level the drug was administered orally on a three times a day schedule. The total duration of treatment was 49 days. Results: Twelve subjects with a median age of 65 years (range 38–71) have been accrued. Four subjects had CLL/SLL, 2 had mantle cell lymphoma, one had follicular grade III, 4 had DLC, and one had lymphoplasmacytic low grade lymphoma. 10 subjects are evaluable for response. Partial response was seen in 1 subject with follicular grade III disease. The duration of this PR is 56+ months. Stable disease was seen in a case of mantle cell lymphoma (duration 30 days) and a case of DLC (duration 77 days). The remaining 7 subjects had progression of disease. Noscapine has been well tolerated, with no grade 3 or 4 hematological toxicities. One grade 3 neurotoxicity consisting of depressed level of consciousness was experienced at the 3 g dose level. We conclude that a larger study of Noscapine is warranted to evaluate the efficacy of the compound in patients with lymphoma. The oral formulation, suggestion of efficacy and relative lack of toxicity make Noscapine an attractive candidate for further study.

Mantle cell lymphoma is an aggressive B cell tumor, with a median survival of approximately 3 years, despite treatment. While intensive therapy may be curative in some patients, the median age at diagnosis is in the 60’s, and such therapy is not always feasible. We developed a regimen of fludarabine, mitoxantrone and rituximab, comprised of fludarabine, 25 mg/m2, IV on days 1–3; mitoxantrone, 10mg/m2, IV on day 1, every 28 days for 6 cycles, along with rituximab, 375 mg/m2 given on day 1, of cycles 2 through 6, and then given alone for 3 weekly doses as cycle 7. To date, 14 male and 7 female patients with a median age of 60 years (range 41–87) have been accrued. Five patients (24 %) relapsed from prior systemic chemotherapy including stem cell transplantation in 1. All but 1 patient had either stage III (n=2) or stage IV disease (n=20). Sites of extranodal disease included bone marrow in 15 (71%), pleural effusions in 5 (24 %), and GI tract involvement in 3 (14 %) patients. Eight patients (38 %) had an intermediate or high IPI score. B symptoms were present in 7. On pathologic assessment, no patient had blastoid morphology. Cyclin D1 was expressed in 19 of 21 tissues tested. Treatment has been well tolerated; the most common side effect was transient grade 3 or 4 neutropenia reported in 17 (81 %) patients; transient grade 3 or 4 thrombocytopenia in 3 patients; and anemia observed in 6 patients. No grade 3 or 4 non-hematologic toxicity has been reported. Of 20 evaluable patients, complete remissions (CR) have been documented in 18 (90 %). The median duration of complete remission is 17.4 months (range 1.1–29.9). Thirteen patients have relapsed after 1.1 to 29.9 months in CR. All 20 of the evaluable patients remain alive after a median follow-up of 16.4+ mos (range 1.0–39.6+). Combination therapy with fludarabine, mitoxantrone, and rituxan is a well tolerated regimen and is highly active in patients with both newly diagnosed and relapsed mantle cell lymphoma. While relapse is seen in the majority, the regimen is capable of inducing CR in 90 % and can be used safely in elderly patients and those who have relapsed or are not eligible for stem cell transplant.

PEL is a rare B-cell neoplasm characterized by a preferential involvement of fluid-filled body spaces, consistent infection of the tumor clone by human herpesvirus type-8 (HHV-8) and a close relationship with underlying immunodeficiency status of the host. The International Extranodal Lymphoma Study Group (IELSG) coordinated a retrospective survey involving 15 international institutions to determine the clinico-pathological features and patterns of outcome of PEL. Fourty-three patients (38 males and 5 females) were registered. Median age at diagnosis was 59 years (range 27–102). In 23 (53%) patients an associated human immunodeficiency virus (HIV) infection was reported, in one case the diagnosis of PEL was made after a solid organ transplantation, in two patients other immunodeficiency conditions were present. The tumor HHV-8 infection was demonstrated in 35 out of the 39 tested cases, Epstein-Barr virus infection in 13 of 30 cases. CD4 count was lower than 200/μl in 18 of the 25 cases in whom the data was available. An ECOG perfomance status score ≥ 2 was observed in 29 patients and the presence of B-symptoms in 20 patients. Serum LDH was elevated in 21 of the 39 tested patients. In 4 patients nodal involvement at diagnosis was reported, in 4 cases at least one extranodal site of localization other than serous cavities was present. A low/low-intermediate risk score according to International Prognostic Index was reported in 10 cases, an intermediate-high/high risk score in 29 cases. Twenty-one patients received systemic chemotherapy, in 17 cases an anthracycline-based regimen. Intrapleural cidofovir was administered in 3 patients. Twelve HIV+ patients received highly active anti-retroviral therapy (HAART), four of them as single therapy. Among the 39 patients for whom adequate follow-up data were available, median overall survival was 6.7 months, median cause-specific survival was 13.6 months and median progression-free survival was 8.3 months. Interestingly, cases of tumor complete regression after implementation of the sole HAART, after intrapleural administration of cidofovir or without any treatment were reported. Our data confirm the poor prognosis of PEL but suggest a possible heterogeneity of this entity with respect to its biological and clinical features. A review of the pathological, phenotypical and virological features is forthcoming to validate these preliminary results.

Introduction: While intensive chemotherapy is recommended for the treatment of non-HIV related small non-cleaved cell lymphoma (SNC), optimal treatment of AIDS-related SNC is unknown, as previous studies in patients (pts) with AIDS-related lymphoma have not considered differences in histologic characteristics. The purpose of this retrospective study was to compare the clinical characteristics and outcome of AIDS-related SNC with those of diffuse large cell/immunoblastic lymphoma (DLCL), in the pre-HAART and post-HAART eras. Methods: We reviewed the data on 135 HIV infected pts with SNC and 227 HIV + pts with DLCL seen at our institution from 1982 to January 2004. ALL other histologic subtypes were excluded. All cases were reviewed by one expert hematopathologist (BNN). As highly active antiretroviral therapy (HAART) first became available to us in 1996, pre-HAART and post-HAART periods were defined as before and after 1996. Results: There were 117 cases of SNC (45%) and 143 cases of DLCL in the pre-HAART era vs 18 SNC (18%) and 84 DLCL in the post-HAART era (p Demographics, HIV Characteristics, Treatment and Overall Survival SNC n=135 (%) DLCL n=227 (%) p value Median Age 39 38 0.09 Median LDH 323 267 0.16 Stage III/IV 109 (80.7) 155 (68.3) 0.31 Median CD4 121 67 0.07 History of OI 47 (35.6) 90 (39.6) 0.28 BM involvement 38 (28.1) 26 (11.5) Conclusions: (1) Bone marrow, kidney and liver involvement are more common in AIDS-related SNC versus DLCL (2) SNC is statistically less common in the post-HAART era than pre-HAART (3) After CHOP or m-BACOD, OS was similar for both histologic subtypes in the pre-HAART era. (4) After CHOP or m-BACOD in the post-HAART era, OS of pts with AIDS related SNC is significantly shorter than that for pts with DLCL, suggesting that the current practice of using a uniform regimen for both histologic subtypes should be reviewed.

Background: Thrombocytopenia is a common condition among HIV-infected individuals, however its significance is unclear, particularly among women. Two previous studies, one consisting mostly of men (Sullivan PS, et al. J Acquir Immune Defic Syndr.1997;14:374–379) and one of hemophiliacs (Ehmann WC, et al. Am J Hematol.1997; 54:296–300), have suggested that low platelet count is associated with decreased survival. Methods: The Women’s Interagency HIV Study (WIHS) is a long-term prospective cohort study of HIV-infected women and HIV-negative women that is being conducted at six urban sites across the United States. 1,990 HIV-infected women and 553 HIV-negative women are included in this report. These women are seen every six months; the median follow-up time is 7.5 years. We conducted extensive multivariate analysis using both generalized estimating equations and Cox proportional hazards models in order to determine the predictors of thrombocytopenia and the role of platelet count in mortality among women being followed as part of this study. Results: At baseline, 15% of HIV-positive women were thrombocytopenic versus 1.6% of HIV-negative women (p Conclusions: (1) Thrombocytopenia is associated with HIV infection (p

Introduction: Arsenic trioxide (ATO) is an exceptionally active drug in acute promyelocytic leukemia (APL), inducing complete remissions in 85% of relapsed patients. ATO also has clinical activity in myelodysplastic syndrome (MDS). In non-APL AML cells lines, ATO induces apoptosis in vitro; however, in a small study of 11 non-APL AML patients, ATO showed no activity (Parmer et al Leuk Res28:090, 2004). In some types of cancer cells, ATO-induced apoptosis has been shown to correlate inversely with the level of intracellular reduced glutathione (GSH) via generation of reactive oxygen species; cells with high concentrations of GSH are more resistant to ATO. Ascorbic acid (AA) increases apoptosis and overcomes resistance to ATO in multiple myeloma, non-APL AML and other cell lines by reducing intracellular GSH levels. AA alone has no activity in these cells. We therefore conducted a clinical trial in patients with non-APL AML combining ATO and AA. Methods: ATO at a dose of 0.25 mg/kg is administrated intravenously over 1–3 hour with 1 gram of intravenous AA given within 30 minutes daily for five days a week (five days on/2 days off) for five weeks (25 doses - one cycle). These doses were based on a phase I/II trial of ATO+AA in patients with multiple myeloma (Behalis et al Clin Cancer Res8:3658, 2002)). Responding patients receive an additional consolidation cycle of 25 doses followed by maintenance of two weeks of every month of ATO+ AA for 4 cycles. Patients who fail to respond after two cycles are considered treatment failures. Results: Seven patients have so far enrolled: three (aged 36,52,59) had relapsed after chemotherapy, and four aged 66–84 (median 70), never received chemotherapy. For these untreated patients ATO+AA was given as front line treatment. In three of the four previously untreated patients the number of bone marrow blasts dropped from > 40% to < 5% (2 pts. after 1 cycle; 1 pt. after 2 cycles) At the time of this report only one of the responding patients received more than one cycle and had improvement in the peripheral blood counts. The three patients, who failed chemotherapy, did not respond to ATO+AA (one patient received only one cycle). Despite the high doses of ATO, higher than used in APL and MDS, the combination was very well tolerated with grade 3 toxicity in one patient only (sensory neuropathy). One responding patient developed shortness of breath with severe hypoxemia, reminiscent of the APL differentiation syndrome, which responded immediately to dexamethasone. Conclusion: These preliminary results in patients with non-APL AML suggest that: (1) AA +ATO has anti-leukemia activity in untreated non-APL AML patients with minimal toxicity; (2) more than one cycle is probably needed to achieve a response in the peripheral blood counts; (3) in non-APL AML, ATO can cause the so called “differentiation syndrome” which should be anticipated and treated early. If confirmed in additional patients, ATO+AA might be a less toxic alternative upfront approach to intensive chemotherapy in elderly patients with non-APL AML.

Background: Anemia is common in patients (pts) infected with the Human Immunodeficiency Virus (HIV). In these pts, anemia is associated with diminished quality of life (QoL) and is an independent prognostic factor for mortality. Aranesp® (darbepoetin-alfa) is a recombinant erythropoiesis-stimulating protein with extended serum half-life allowing for less frequent dosing than conventional recombinant erythropoietin. We studied Aranesp® in anemic HIV-positive pts to evaluate safety, hemoglobin (Hgb) response, and quality of life (QoL). Methods: Entry criteria included HIV infection, Hgb < 11.5 g/dL, and adequate renal and liver function. Patients with anemia due to bleeding, malignancy, B12, folate, or iron deficiency were excluded. Aranesp® 3.0 mg/kg was given sc every 2 weeks (Q2W) for 24 weeks. Treatment response was defined as Hgb increase of ≥ 1.5 g/dL from baseline sustained for ≥ 4 weeks duration at any time during the study. If no response by wk 8, Aranesp® was escalated to 5.0 μg/kg. Results: Thirteen female and 10 male pts have been enrolled to date. Median age was 43 years (range 27–67), median entry Hgb was 10.6 g/dL (range 8.6–11.5), and median CD4 count was 197 cells/mm3 (range 29–821). Nine (39%) pts had a prior clinical AIDS-defining illness or opportunistic infection, 19 (87%) pts received concurrent HAART therapy; 11 (58%) were receiving a zidovudine- containing regimen with either combivir (n=6) or trizivir (n=5). Aranesp® was well tolerated. The only treatment-associated side effect was mild pain at the injection site. Pts who received ≥ 8 wks of Aranesp® were analyzed (n=20). 17 of the 20 pts (85%) had a Hgb response (median duration 12+ weeks [range 4+ to 22+]). One of these pts required a dose escalation. Evaluation of change in QoL using a Linear Analog Scale in 20 evaluable patients showed a mean improvement in energy level (+23.2 mm), activity level (+19.8 mm) and overall QoL (+15.5 mm) over the first 8 wks of treatment. Conclusions: In HIV-infected pts with anemia, Aranesp® at a dose of 3.0 mg/kg Q2W is well tolerated, is associated with a Hgb response in the majority of pts, effectively maintains Hgb levels, and improves QoL. Further work is on-going.

HIV infected patients may be at increased risk for VTE, as shown by case reports, and a recent retrospective, longitudinal medical record review of approximately 42,000 HIV-infected individuals (Sullivan, 2000). There is a well documented association between acute and chronic inflammation and activation of the hemostatic system. Inflammatory cytokines such as TNF alpha, IL-1 and IL-6 have been shown to activate coagulation via the Tissue Factor pathway. Inflammation can also result in a decrease in functional Protein S, and in an increase in Factor VIII coagulant protein. We hypothesized that the inflammatory state associated with more advanced HIV disease would be associated with hemostatic activation, and clinical development of VTE over time. Methods: We assayed plasma for factor VIII activity levels, functional protein S activity, presence of lupus anticoagulant, and C reactive protein levels in a group of 96 HIV infected women and 50 HIV negative women from the Women’s Interagency HIV Study (WIHS). All assays were performed blinded to subjects HIV status. This cross sectional sample of WIHS participants from the Los Angeles site were studied at their second study visit (1994-5). The sample was selected to represent the following groups: (1) History of clinical AIDS, CD 4< 200; (2) CD4 < 200, no clinical AIDS; (3) HIV positive, CD4 > 200; HIV-negative. Pts were excluded if they were taking any hormones or contraceptives; had been pregnant within 6 weeks of study; had any acute, active infection at the time of study visit. Hemostatic data were correlated with HIV viral load, CD4 cell count, history of clinical AIDS, history of anti-retroviral and other medication use, and levels of serum and plasma C reactive protein (CRP). Results are depicted below for median (inter-quartile range) values, adjusted for age: Group Protein S Factor VIII Serum CRP# 1. Clinical AIDS, CD4 < 200 46* (40,65) 212* (174,253) 2.0 (0.5,4.8) 2. No Clinical AIDS, CD4 < 200 62^ (55,67) 196+ (150, 234) 0.8 (0.7,2.7) 3. HIV+, No Clinical AIDS, CD4 > 200 67.5 (59,83) 154^ (111,202) 0.9 (0.4, 3.3) 4. HIV Negative 75.5 (66,85) 116.5 (97,154) 1.85 (0.8, 5.1) Models were adjusted for age. Groups are significantly different from HIV negative participants (group 4) at the indicated p-values, determined using Scheffe adjustment * p ^p + p # CRP Medians are not significantly different for the different groups. No patient or control was found to have a positive assay for the Lupus anticoagulant. We conclude: (1) Increasing progression of HIV disease, from asymptomatic, to immunologic (CD 4< 200) and then clinical AIDS, is associated with progressive increase in factor VIII activity, and decrease in functional protein S; (2) This progressive hemostatic changes were not associated with elevated CRP levels, suggesting that IL-6 is not involved in this process; (3) An increase in VTE is biologically plausible in the setting of HIV infection; (4) Further prospective study is warranted to determine the full range of hemostatic abnormalities associated with HIV, and to determine any correlation between these abnormalities and development of VTE in time.

Within the Lukes-Collins classification system of malignant lymphoma, a tumor of large transformed lymphocytes, termed immunoblastic sarcoma (IBS), is described. This morphological type would have been included within the “histiocytic” category of Rappaport. Immunoblastic sarcoma may be of B-lymphocytic or T-lymphocytic origin. Since differences or similarities of these two variants have not yet been described, we reviewed the case histories of 35 such patients, all of whom had immunologic marker studies performed. Nineteen patients had T-cell IBS (T-IBS), whereas 16 had B-cell IBS (B-IBS). Median age for both groups was approximately 50 yr. A history of prior immune disorder was found in 31% of B-IBS and 16% of T-IBS cases. Prior lymphoproliferative malignancy was noted in 21% of T-IBS and 13% of B-IBS patients. All T- IBS patients first presented because of lymphadenopathy, whereas 56% of B-IBS cases initially presented because of extranodal disease. Systemic “B” symptoms were common in both. Similarly, most patients had widespread disease (stage III or IV) at diagnosis. Clinically suspected hepatic (p = 0.05) and retroperitoneal node (p = 0.01) involvement were more often found in T-IBS. Forty-one percent of T-IBS patients demonstrated polyclonal hypergammaglobulinemia, a finding seen in no B- IBS patient (p = 0.02). Although not statistically significant because of small numbers of patients, data on therapy and survival suggest that IBS of B-cell type may be successfully treated with aggressive, multiagent chemotherapy, while alternative approaches appear warranted in T-cell disease.

Evidence suggests that the “la-like” or antigen is a differentiation marker that is expressed on early human hematopoietic precursor cells, but is absent on their mature progeny. The eosinophil precursor cell (CFU-EO) is distinct from the granulocyte-monocyte colon-forming cell (CFU-C). We provide data that indicate that the ia antigen is expressed on the human eosinophil colony-forming cells and is absent on mature eosinophils. All CFU-EO were inhibited in the presence of rabbit la antiserum at a titer of 1:30. Cytotoxicity was complement-dependent. The metamyelocytic eosinophil and more mature eosinophil forms did not express the la antigen.

To clarify the clinicopathologic characteristics of Coombs' positivity in Hodgkin's disease, the records of 71 cases were reviewed. The direct Coombs test was positive in seven. Mean age of the seven was 22 yr (range 11–33). All were males. All had extensive disease (pathologic stage III or IV) and six had systemic (B) symptoms. Four had mixed cellularity; three had nodular sclerosis. The positive Coombs test was detected at original diagnosis in three and at time of relapse in four. Although all were anemic, only three had evidence of overt hemolysis. The antibody responsible for Coombs positivity was characterized in three and fulfilled the criteria for IgG anti-It. The presence of a positive direct Coombs test in the patient with Hodgkin's disease suggests active and advanced disease. The presence of IgG anti-It may represent a unique antibody in the Coombs-positive hemolytic anemia associated with Hodgkin's disease.

Fifteen adult patients with biopsy-proven convoluted T-lymphoblastic lymphoma were treated with an aggressive regimen, modified from the LSA2-L2 protocol used for childhood lymphoma. The treatment schema consisted of induction phase, including cyclophosphamide, vincristine, prednisone, adriamycin, and 2000 rads to mediastinum, as well as intrathecal methotrexate. Consolidation phase included cytosine arabinoside, 6-thioguanine, L-asparaginase, and CCNU, along with cranial irradiation and further intrathecal methotrexate. Maintenance consisted of cyclical chemotherapy and intrathecal methotrexate, continuing for a total of 3 yr. Median age in the group was 25 yr (range 16–73). There were 8 males and 7 females. At diagnosis, 9 patients had mediastinal involvement, and 9 had bone marrow involvement. Five of these demonstrated malignant cells in the peripheral blood. Complete clinical response was attained in 11 patients. Three patients achieved partial response. Four complete responders have relapsed, 1 in the central nervous system at 6 mo. and 1 in nodal sites at 3 mo, 1 in multiple sites at 24 mo. and 1 in bone marrow at 42 mo while off all chemotherapy for 6 mos. At this time, median survival of all patients is 28.3 mo. and median relapse-free survival is 21 mo. The median survival for complete responders in excess of 71 mo. while the median relapse-free survival for this group is 41 mo.

Fulminant bacterial sepsis has been described in patients with Hodgkin disease who have undergone splenectomy for staging purposes. The organisms commonly associated with sepsis in this setting include Streptococcus pneumoniae and Haemophilus influenzae. Polyvalent pneumococcal vaccine (Merck) has recently been licensed and has been suggested for use in patients with Hodgkin disease who are at risk for postsplenectomy sepsis. We administered 14-valent pneumococcal vaccine to 24 patients with Hodgkin disease and 24 normal controls, and measured antibody response to 13 antigens at time of immunization and at 3 wk and 3 mo following immunization. Our results indicate that patients who have been previously treated for Hodgkin disease, with chemotherapy, radiotherapy, or both, have severe impairment of antibody response. Untreated patients, however, respond in a manner similar to normal controls.

Eight patients with cutaneous T cell lymphomas (CTCL) and five with various other T cell malignancies were treated with mouse monoclonal antibody (MoAb) T101. Doses of 1 to 500 mg were administered weekly over a two-hour period and resulted in one complete remission (convoluted T cell lymphoma) and one partial remission (CTCL). Remission duration was 6 weeks and 3 months, respectively. Frequent toxicities were pruritus, hives, flushing, and shortness of breath. Supraventricular arrhythmias and blood pressure instability were also observed. Complete targeting of peripheral blood T cells was achieved with 1 mg of MoAb in the nonleukemic patients (WBC less than 10,000/microL), and free, bioavailable antibody was present at the next (10-mg) dose level. Even higher doses resulted in substantial antibody excess that persisted for as long as 6 weeks. Serum concentrations of MoAb decreased with increasing number of peripheral blood T cells, and 25 to 35 mg of T101 were required for induction of antibody excess in leukemic patients. Excess antibody induced antigenic modulation, which was of consequence only if MoAb excess persisted to the next treatment. In the original treatment, the rapidly administered MoAb was able to target and remove peripheral blood T cells before the development of antigenic modulation. Antimouse antibodies developed in three patients. Their presence rendered further therapy ineffective and was associated with an anaphylactic reaction in one patient. Development of these antibodies could not be predicted by lymphoproliferative assays. In these assays, however, the T101 protein strongly stimulated the mononuclear cells of the patient who reached the only complete remission of this trial. Immunologic stimulation by the MoAb thus might have played a role in this patient's antitumor response. In summary, therapy with MoAb T101 was specific but only modestly efficacious. Rapid infusion of nonmodulating doses of antibody provided excellent targeting and removal of peripheral blood T cells and might be a valid approach in future trials with immunoconjugated T101.