Superior Failure-free Survival Research Articles

Comparison of Hematopoietic Stem Cell Transplantation and Repeated Immunosuppressive Therapy As Second-Line Treatment for Relapsed/Refractory Severe Aplastic Anemia

The optimal treatment for patients with severe aplastic anemia (SAA) who fail or have relapse after an initial course of immunosuppressive therapy (IST) has not been established. We conducted a retrospective study to compare the effectiveness of allogeneic hematopoietic stem cell transplantation (allo-HSCT) (n = 36) with repeated IST (n = 33) as salvage therapy for relapsed/refractory SAA between 2007 and 2022. In the repeated IST group, patients were treated with antithymocyte globulin (ATG) (n = 16) or high-dose cyclophosphamide (HD-CTX) (n = 17). The overall response rate was 42.4% at 6 months, and 60.6% at 12 months. In the HSCT group, 6 were matched sibling donor (MSD), 7 were matched unrelated donor (MUD), and 23 were haploidentical donor (HID). All patients achieved neutrophil engraftment and no primary graft failure was observed. The rate of platelet engraftment was 88.9%, with a median time of 16 days. The cumulative incidences of grade II-IV, III-IV acute GVHD was 36.1% ± 0.7%, 13.9% ± 0.3% at day +100, and chronic GVHD was 36.2% ± 0.7% at 5 years. Compared with IST, HSCT recipients showed much higher hematologic recovery rate at 3-, 6- and 12-months post treatment (63.9%, 83.3% and 86.1%, respectively, P < 0.001). The estimated 5-year overall survival (OS) (79.8% ± 6.8% vs. 80.0% ± 7.3%, p = 0.957) were similar; however, the estimated 5-year failure-free survival (FFS) was significantly better in the HSCT group (79.8% ± 6.8% vs. 55.2% ± 9.2%, p = 0.049). In multivariate analysis, age ≤ 35 years at salvage HSCT was the only favorable factor for OS and FFS ( p = 0.019, 95% CI 0.019-0.706). These results suggest that HSCT and repeated IST are both effective for refractory/relapsed SAA in the salvage setting. Considering the superior FFS in the HSCT cohort, especially in younger patients (age ≤ 35 years), we recommend HSCT instead of a second IST for these patients.

Propensity Score Matching Analysis Comparing the Efficacy and Steroid Tapering Benefit of Extracorporeal Photopheresis to Best Available Therapy in Third-Line or Beyond Treatment for Chronic GvHD

Graft-versus host disease (GVHD) is one of the major limitations to allogeneic hematopoietic stem cell transplantation (HCT). Although corticosteroids with calcineurin inhibitors are established first line-therapy for chronic graft-versus-host disease (cGVHD), approximately one-half of cGVHD patients are refractory to corticosteroid therapy. The goal of the present study was to compare treatment outcomes of patients treated with extracorporeal photopheresis (ECP) and best available therapy (BAT) as third-line or beyond treatment for cGVHD. Using propensity score matching (PSM), treatment outcomes were compared between ECP-treated patients (n=74) and a historical cohort of cGVHD patients treated with BAT (n=132). By adjusting for unbalanced risk factors between the groups, including GVHD severity at the start of therapy, acute GVHD history, and baseline corticosteroid dose, 62 patients were balanced and selected for PSM. In the PSM cohort, the ECP group showed a 12-month failure-free survival (FFS) rate of 70.1% versus 32.5% in the BAT group (P < .0001; hazard rate [HR], .214), and 93.1% 12 months' overall survival (OS) rate of 93.1% versus 68.1% in the BAT group (P=.0249; HR, .3811); multivariate analysis confirmed ECP's superior FFS and OS compared with BAT. Generalized linear model analysis showed faster tapering of corticosteroids and higher rates of prednisone discontinuation in the ECP versus BAT PSM groups in the first 6 months. The ECP group also had a higher percentage of prednisone discontinuation, by 6% at month 0, by 14.9% at month 3, and by 22.5% at month 6. The current study demonstrates superior FFS, OS, and steroid tapering efficacy for ECP compared with BAT as third-line therapy or beyond in cGVHD patients.

Comparison of Hematopoietic Stem Cell Transplantation and Immunosuppressive Therapy for Patients with Severe Hepatitis-Associated Aplastic Anemia

Background：Hepatitis-associated aplastic anemia (HAAA) is known as a rare variant of acquired aplastic anemia, characterized by a syndrome of bone marrow failure following the development of hepatitis. Immunosuppressive therapy (IST) or hematopoietic stem cell transplantation (HSCT) could provide lifesaving opportunities for severe HAAA patients. However, to date, no cohort has characterized treatment outcome and long-term survival between those patients receiving IST and HSCT. In this study, we aim to retrospectively evaluate the outcome of these two therapies for severe HAAA in China. Methods: Patients consecutively diagnosed as severe HAAA between August 2008 and Jan 2021 were enrolled in this study. The definition of severe HAAA is that severe aplastic anemia developed within three months after documented hepatitis. The enrollments were patients who received HSCT or IST as a first-line treatment. Patients with HSCT were conditioned as described previously with cyclophosphamide (Cy, 120-150 mg/kg, divided doses on days -6 to -2), and rabbit ATG (Thymoglobulin®, Genzyme, Cambridge, MA) (2.5mg/kg once i.v. daily on days -6 to -2) or p-ALG (Anti-lymphocyte Immunoglobulin®, Wuhan Institute of Biological Products Co., Ltd., China) (20mg/kg once i.v. daily on days -6 to -2), Fludarabine 150 mg/m2 i.v.in divided doses on days -6 to -2, with or without Busulfan (Bu, 0.8 mg/kg four times i.v. daily on days -7 and -6). IST consisted of both rabbit ATG (rATG) (3~3.75mg/kg once i.v. daily on 5 days), porcine antilymphocyte globulin (pALG)(20mg/kg once i.v. daily on 5 days), combined with a six-month course of cyclosporine (3mg per kilogram per day orally, with adjustment of the dose to maintain a blood level between 200 and 400 ng per milliliter). Probabilities of overall survival (OS), failure-free survival (FFS), and treatment-related-mortality (TRM) were calculated by Kaplan-Meier method. Results and Discussion: This study retrospectively included 94 consecutive HAAA patients, including 68 patients underwent HSCT and 26 patients receiving IST. The IST and HSCT groups were similar with respect to age and gender ratio. The median follow up were 1752 (±153.62, 95%CI 1450.90~2053.10) days, and 2648 (±321.41, 95%CI 2018.05-3277.96) days among alive patients in the IST and HSCT group, respectively. In HSCT group, all patients achieved neutrophil engraftment. No primary or secondary graft failures (GF) was documented. Compared with patients receiving alternative donor HSCT (n=11), patients in matched sibling donor HSCT (MSD-HSCT) group (n=15) had a significant lower cumulative incidence of acute graft versus host disease (aGVHD) (20±10.33% vs 56.4±15.47%, p=0.048), and lower incidence of cytomegalovirus (CMV) reactivation group (72.73% vs 13.33%, p=0.004). No clinical significance of chronic graft versus host disease (cGVHD) incidence group (43.4±18.85% vs 50±35.4%, p=0.78) and bacterial/fungus infection (26.67% vs 36.36%, p=0.683) was found between MSD-HSCT group and alternative donor-HSCT. Attributable causes of death were pneumonias and severe infection in patients receiving HSCT. In IST group, the hematology response rate to treatment evaluated at 3m, 6m and 12m was 27.68%, 52.94%, and 60.23%, respectively. There were thirteen patients were non-evaluable, including six patients transferred to perform HSCT, two patients were diagnosed MDS/AML transformation and one patient relapsed. The 5-year overall survival (OS) and failure-free survival (FFS) rate was 85.5±4.44% (95% CI, 0.772, 0.946) and 69.6± 5.35% (95% CI, 0.599,0.809) of all enrolled HAAA patients, respectively (Figure 1). For patients receiving different therapy, the 5-year OS rates were 92.86 ± 6.88% in MSD-HSCT group, 72.7± 13.43% in alternative donor-HSCT, and 84.1 ± 7.28% in the IST group (P = 0.56). Otherwise, the 5-year estimated FFS rate was 56.0± 11.51% in the IST group, compared with 92.86 ± 6.88% in the MSD-HSCT group and 72.7± 13.43% in alternative donor-HSCT group (P = 0.10). The cumulative incidence of treatment-related-mortality (TRM) of MSD-HSCT, alternative-HSCT and IST was 7.1±6.9% (95% CI, 80.30-100), 27.3±13.4% (95% CI, 50.60-100), 14±5.54% % (95% CI, 7.58-97.6) (p=0.22), respectively. Even there was no difference between the HSCT and IST groups in OS, MSD-HSCT group still showed superior FFS. Patients receiving alternative donor HSCT, and IST showed comparable OS and FFS. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

High Failure-Free Survival after Unrelated Donor Peripheral Blood Stem Cell Transplantation in Pediatric Severe Aplastic Anemia

The use of alternative donor peripheral blood stem cell transplantation (PBSCT) has increased in recent years. In this study, we analyzed the effect of stem cell source and HLA disparity on outcomes in pediatric patients with severe aplastic anemia (SAA). A total of 134 patients who underwent HSCT with nonmyeloablative conditioning between 2006 and 2020 were enrolled and classified into 3 groups: HLA-matched bone marrow transplantation (M-BMT; n = 24), HLA-matched PBSCT (M-PBSCT; n = 66), and HLA-mismatched PBSCT (MM-PBSCT; n = 44). Significantly higher stem cell doses were obtained for PBSCT than for BMT. A total of 13 patients experienced secondary graft failure (GF), with a cumulative incidence (CI) of 10.0%. HLA-mismatched PBSCT and a very severe degree of disease significantly decreased the incidence of secondary GF. The CI of grade II-IV acute graft-versus-host disease (GVHD) was significantly higher in PBSCT than in BMT, but the CI of grade III-IV acute GVHD and CI of chronic GVHD requiring systemic treatment did not increase in PBSCT. The estimated 5-year overall survival (OS), failure-free survival (FFS), and GVHD-free failure-free survival (GFFS) of the total cohort were 93.0%, 89.5%, and 77.5%, respectively. The most favorable FFS was observed in the MM-PBSCT group (97.6%; P = .03), whereas OS and GFFS were similar across the 3 groups. In multivariate analysis, HLA mismatch and short time from diagnosis to transplantation were associated with superior FFS. Unrelated donor PBSCT with low-intensity SAA conditioning showed favorable outcomes in terms of low rate of secondary GF, higher FFS, and manageable GVHD regardless of HLA compatibility. Our findings suggest the feasibility of PBSCT from unrelated donors, resulting in the possible expansion of the donor pool in transplantation for pediatric SAA. © 2021 American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc.

Propensity Score Matching Analysis Comparing Ruxolitinib Vs Historical Controls in 2 nd Line or Beyond Treatment for Chronic Gvhd after Therapy Failure

Propensity Score Matching Analysis Comparing Ruxolitinib Vs Historical Controls in 2 nd Line or Beyond Treatment for Chronic Gvhd after Therapy Failure

Propensity Score Matching Analysis Comparing Extracorporeal Photopheresis (ECP) Vs Best Available Therapy in Third Line or Later Treatment of Chronic Graft-Versus-Host Disease (cGVHD)

*DB and DK contributed to the work equallyBackgroundProspective randomized controlled data comparing extracorporeal photopheresis (ECP) to other treatments for chronic graft vs host disease (cGvHD) as third-line or later therapy are limited, despite its clinical benefit observed in patients (pts) who failed ≥ 2 lines of previous therapy. Our single-center experience has reported promising results, including 68.3% failure-free survival (FFS) and 85.9% overall survival (OS) at 12 months in 75 heavily pre-treated cGvHD pts treated with ECP (ASH 2021 Abstract ID 152640).The present study compared outcomes, using propensity-score matching (PSM), between ECP (“ECP group”, n=74) and a historical cohort treated with best available therapy (BAT) as third-line or later treatment from 2007 to 2021 (“BAT group”, n=132). Statistical endpoints such as FFS and OS, as well as steroid dose reduction were evaluated instead of overall response due to limited response assessment data available from retrospective chart review.Patients and methodsThe BAT group received MMF (n=71, 53.8%), prednisone (n=37, 28.0%), prednisone/cyclosporine (n=7, 5.3%), rituximab (n=7, 5.3%), and others (n=10, 7.6%). There was an imbalance in characteristics between the two groups, as expected; the ECP group had more pts with severe cGVHD (91.1% vs 20.5%; p<0.001), fewer with a previous history of acute GVHD (aGvHD: 60.8% vs 78.0%; p=0.008), and fewer on a prednisone dose ≥0.5mg/kg/day (37.8% vs. 90.5%; p<0.001). PSM analysis was applied to adjust risk factors imbalanced between groups, including cGVHD grade (mild/moderate vs severe), aGVHD history, and baseline prednisone dose (<0.5 vs. ≥ 0.5 mg/kg/day). A total of 54 pts (27 case-control pairs) were selected via PSM within 0.2 of a calliper difference, resulting in the balancing of risk factors between groups: cGVHD severity (p=0.941), aGVHD history (p=0.75) and prednisone dose ≥ 0.5 mg/kg/day (p=0.788).FFS and OS were calculated from the day of starting ECP or BAT, and were compared using Cox's hazard model. Daily prednisone dose at months 0, 3 and 6 were calculated divided by body weight (kg), and the proportions of pts on prednisone ≤ 0, 0.1, 0.2 and 0.5mg/kg/day were compared.ResultsIn the overall cohort (n=206), with a median 29 months of follow-up, 114 treatment failures (55.3%) occurred. While the non-relapse mortality (NRM) was similar in both groups, the ECP group showed a lower rate of resistance requiring therapy switch. Failure was noted in 27 ECP pts (36.4%) due to causes including resistance/intolerance requiring a switch to other therapy (n=15; 20.3%), NRM (n=11, 14.8%), and relapse (n=1; 1.4%), while 87 failures (65.9%) were noted in BAT pts due to resistance requiring a switch to other therapy (n=63; 47.7%), NRM (n=7; 5.3%), and relapse (n=17; 12.9%).In the overall cohort, the 12-month FFS was 68.3% and 32.0% in ECP and BAT groups (p<0.0001; Fig 1A), while OS was 86.2% and 82.2% in ECP and BAT groups, respectively (p=0.333; Fig 1B). In the PSM cohort (n=54), the ECP group showed a survival benefit at 12 months: FFS was 65.8% in the ECP group vs. 30.5% in the BAT group (p=0.00226; Fig 2A), and OS was 76.6% in the ECP group vs. 67.1% in the BAT group (p=0.0977; Fig 2B).Multivariate analysis in the PSM cohort confirmed that ECP was superior to BAT for FFS (p=0.024, HR 0.317 [0.117-0.859]) when adjusted for other risk factors including cGVHD severity, aGvHD history, age, HCT-CI score and prednisone dose ≤0.5mg/kg/day.Prednisone doses were gradually reduced over time; the median doses of prednisone at months 0, 3, and 6 were 0.35, 0.22 and 0.11 mg/kg/day, respectively, in the ECP group vs. 0.96, 0.24 and 0.19mg/kg/day in the BAT group. ECP also showed better kinetics of steroid dose reduction over time; the proportions of pts who discontinued prednisone at months 0, 3 and 6 were 16.2, 17.6% and 32.4% in ECP group vs. 0.8%, 0% and 2.5% in BAT group (Fig 3). The differences in the proportion of pts (delta) who discontinued prednisone in the ECP vs. BAT groups were 15.4%, 17.6% and 29.9% at 0, 3, and 6 months, respectively.ConclusionIn the current study using PSM analysis, use of ECP was associated with a superior FFS to BAT when used as third-line or later therapy in cGVHD patients who failed at least 2 lines of previous therapy. Use of ECP also allowed for better steroid tapering in comparison to BAT. [Display omitted] DisclosuresPatriquin: Alexion: Consultancy, Honoraria, Speakers Bureau; BioCryst Pharmaceuticals: Honoraria; AstraZeneca: Consultancy, Honoraria, Speakers Bureau; Apellis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Honoraria. Law: Novartis: Consultancy; Actinium Pharmaceuticals: Research Funding. Lipton: Bristol Myers Squibb, Ariad, Pfizer, Novartis: Consultancy, Research Funding. Mattsson: MattssonAB medical: Current Employment, Current holder of individual stocks in a privately-held company. Kim: Novartis: Consultancy, Honoraria, Research Funding; Paladin: Consultancy, Honoraria, Research Funding; Bristol-Meier Squibb: Research Funding; Pfizer: Honoraria.

Identification of good and poor prognosis HPV associated oropharyngeal cancer based on CD103 immune cell expression in patients treated with cetuximab and radiotherapy on TROG 12.01 and De-ESCALaTE randomized trials.

109 Background: Trials in human papilloma virus associated oropharyngeal squamous cell carcinoma (HPVOPSCC), substituting cetuximab (CETUX) for cisplatin (CIS) with radiotherapy (RT), resulted in decreased efficacy without improved toxicity or symptom burden. We reported that high intratumoral immune cell (ITIC) CD103 expression (&gt; 30%), a marker of tissue-resident memory T cells, is associated with better prognosis in unselected patients with HPVOPSCC treated with CIS/RT. In this study our aim was to determine whether low risk HPVOPSCC patients treated with CETUX/RT with high CD103 have a superior prognosis. Methods: TROG 12.01 and De-ESCALaTE are randomised multicentre trials that compared 70Gy RT/CETUX with 70Gy RT/CIS (weekly in TROG 12.01, 3-weekly in De-ESCALaTE) in patients with HPVOPSCC, low risk by Ang criteria: AJCC 7th Stage III (excluding T1-2N1) or stage IV (excluding N2b-c if smoking history &gt; 10 pack years and/or distant metastases). In TROG 12.01 T4 and/or N3 patients were also excluded. Eligible patients required tumor samples available for immune cell quantification on immunohistochemistry. Data from the two trials were pooled, with analyses performed in eligible randomised patients who commenced treatment. The primary endpoint was failure-free survival (FFS) in patients receiving CETUX/ RT comparing CD103 ITIC &gt; 30% (high) vs. &lt; 30% (low). High/low CD103 were compared using Cox model adjusting for age, stage and trial. Results: Samples for CD103 testing were available in 159/182 patients on TROG 12.01 and 145/334 on De-ESCALaTE. ITIC CD103 expression was high in 26% of patients. The median follow-up was 3.2 years. The 3 -year failure-free survival rates in patients treated with CETUX/RT were 92% (95% CI: 78-97%) in high CD103 and 74% (95% CI: 64-82%) in low CD103, adjusted HR 0.25 (95% CI: 0.14-0.44); p &lt; 0.001. The 3 -year overall survival (OS) in patients treated with CETUX/RT were 100% in high CD103 and 86% (95% CI: 76-92%) in low CD103, p &lt; 0.001. Superior FFS in the high CD103 group was independent of stage. In patients treated with CIS/RT there was no significant difference in FFS (3-year 86% in high CD103 and 90% in low CD103; p = 0.55) or in OS (3-year 100% in high CD103 and 95% in low CD103; p = 0.14). The increase in failures in the low CD103 patients treated with CETUX/RT was evenly split between distant and locoregional failures. Conclusions: ITIC CD103 separates CETUX/RT treated low risk HPVOPSCC into excellent and poor prognosis subgroups. In a low risk population CIS/RT achieves excellent outcomes in both high and low ITIC CD103 groups. The high ITIC CD103 population is a rational target for future de-intensification trials.

Comparative efficacy of docetaxel versus novel hormonal agent in de novo metastatic hormone-sensitive prostate cancer: Real-world data curated by deidentified chart abstraction.

e17047 Background: The addition of docetaxel or a novel hormonal agent (NHA), such as abiraterone acetate or enzalutamide, has become standard of care for mHSPC, but prospective data for comparative efficacy remains limited. Clinical variables abstracted through natural language processing of free text from patient charts can provide real-world data to answer important clinical questions. Methods: Using an innovative data abstraction process, we retrospectively identified men with de novo mHSPC within deidentified charts from the Mount Sinai Health System treated with either docetaxel or a NHA between January 1, 2014 and April 30, 2019. Dates were chosen to reflect the timeline for which these therapeutic agents received regulatory approval for mHSPC, but also to allow sufficient clinical follow up after treatment initiation. Primary outcome of failure-free survival (FFS), defined as the time to next treatment, was assessed using the Kaplan-Meier method and multivariable Cox proportional hazards models. We additionally performed multivariable analysis to evaluate the prognostic significance of post-treatment PSA nadir on FFS. Results: A total of 94 de novo mHSPC patients that received either docetaxel or an NHA were identified using proprietary Sema4 data abstraction process: 52 received docetaxel, 42 received an NHA. Use of an upfront NHA in mHSPC was associated with a significantly longer FFS compared to docetaxel (20.7 vs. 10.1 months, p = 0.023). While NHAs were associated with a significantly longer FFS than docetaxel in patients with high metastatic burden of disease (25.12 vs. 9.63 months, p = 0.014), this was not observed in low-volume disease (20.71 vs. 26.5 months, p = 0.9). In multivariable model analysis adjusting for age, baseline PSA, and metastasis burden, docetaxel remains independently associated with worse FFS compared to NHA (HR 1.96, 95% CI 1.12−3.45, p = 0.019). Irrespective of docetaxel or NHA use, lower post-treatment PSA nadir levels were associated with improved FFS (58.95 vs. 11.57 vs. 9.4 months for PSA ≤0.2, 0.2-0.4, &gt; 0.4ng/ml, respectively; p &lt; 0.001). Conclusions: Clinical variables abstracted from deidentified clinical documentation can efficiently provide relevant and reliable data upon which clinical research can be based. Comparative analysis of real-world data demonstrates superior FFS in de novo mHSPC treated with a NHA as compared to docetaxel. The depth of PSA response holds prognostic value for mHSPC outcomes, regardless of treatment used.

Patterns of relapse for children with localized intracranial ependymoma.

We examined patterns of relapse and prognostic factors in children with intracranial ependymoma. Records of 82 children diagnosed with localized intracranial ependymoma were reviewed. 52% first presented to our institution after relapse. Median age at initial diagnosis was 4years (range 0-18years). Gender was 55% male. Initial tumor location was infratentorial in 71% and supratentorial in 29%. Histology was WHO Grade II in 32% and Grade III in 68%. As part of definitive management, 99% had surgery, 70% received RT (26% 2D/3D-conformal RT[CRT], 22% intensity-modulated RT [IMRT], 22% proton), and 37% received chemotherapy. Median follow-up was 4.6years (range 0.2-32.9). Overall, 74% of patients relapsed (50% local, 17% distant, 7% local + distant) at a median 1.5 (range 0.1-17.5) years. Five-year OS and FFS for patients presenting prior to relapse are 70% (95% confidence interval [CI], 50-83%) and 48% (95% CI 30-64%), respectively. On log-rank, superior overall survival (OS) was demonstrated for gross total resection (p = 0.03). Superior failure-free survival (FFS) was demonstrated for age < 5years (p = 0.04). No difference in OS or FFS was found between 2D/3D-CRT versus IMRT/proton (p > 0.05). On multivariate analysis, age ≤ 5 was independently associated with a lower risk of death and failure versus older patients (p < 0.05). Contrary to previous reports, young age may not be a poor prognostic factor in patients who can tolerate intensive treatment. Future studies examining patients stratified by clinical and molecular attributes are warranted.

Adherence to Treatment, Response and Patterns of Failure in Pediatric Parameningeal Rhabdomyosarcoma: Experience From a Tertiary Cancer Care Center From India.

The study was aimed at evaluating adherence to treatment protocol and outcome in pediatric parameningeal rhabdomyosarcoma (PM-RMS). We analyzed the characteristics, treatment administered, outcomes and patterns of failure of pediatric PM-RMS, who were treated with multimodality therapy between January 2005 and December 2013.Univariate and multivariate analysis (MVA) was completed to evaluate the impact of various prognostic factors. Thirty-seven patients were treated at our institution. Majority of them had the primary disease in paranasal sinuses (n=13). Majority of the patients belonged to group III (n=30) and stage III (n=24). The overall response rate to treatment was 52.5% (n=21). At a mean follow-up of 19.1 months, 23 patients developed disease progression. The actuarial rates of failure-free survival and overall survival (OS) at 2 years were 40% and 67.5%, respectively. Patients who received >20 weeks of intended chemotherapy schedule (P=0.02) and had complete response to first-line treatment (P=0.0004) were found to have superior failure-free survival on MVA. Complete response was the lone determinant of superior OS on MVA (P=0.006). Majority of patients with PM-RMS present with advanced stage disease. Response to first-line treatment is a significant predictor of superior progression-free survival and OS in these patients.

Outcomes in Adolescents and Young Adults (AYA) with Hodgkin Lymphoma (HL) Treated on US Cooperative Group Protocols: An Adult Intergroup (E2496) and Children's Oncology Group (COG AHOD0031) Comparative Analysis

▪Introduction: There is no clear consensus regarding the optimal therapeutic approach for AYAs with HL. Prior registry data showed that HL AYA patients treated with ABVD had similar outcomes to their older counterparts (Foltz JCO 2006). However, SEER data have suggested that advances in HL survival among AYAs may be less robust compared with older populations (Bleyer NCI 2006). We sought to examine AYA patients treated on two recent, randomized pediatric and adult North American HL clinical trials (i.e., 17-21 years; the age group of those typically eligible for both pediatric- and adult-based HL clinical trials) by comparing outcomes of different age cohorts within E2496 as well as across the two different studies.Methods: We examined characteristics and outcomes of 114 newly diagnosed AYA HL patients aged 17-21 years treated on E2496 (ABVD vs. Stanford V [SV] chemotherapy, Gordon JCO 2013) trial and compared the failure free survival (FFS) and overall survival (OS) with patients ages >21 years. In addition, we compared presenting features, planned treatment, FFS, and OS of these ECOG AYA patients with 391 newly diagnosed AYA HL patients between ages 17-21 years treated on the COG AHOD0031 (ABVE-PC backbone, Friedman JCO 2014). Unstratified and stratified log-rank tests as well as propensity score analysis were utilized to compare differences in patient outcomes.Results: In E2496, the 5-year FFS and OS rates for AYAs were 68% and 89%, respectively, with significant variations identified by patient age (see Table). There was no FFS difference between ECOG AYAs treated with ABVD vs. SV (P =0.66). However, FFS in AYAs were inferior to those ages 21 to 44 years in E2496 (P =0.005; see Figure, sections A and B). Interestingly, AYA outcomes on E2496 appeared more similar to patients aged 45-59 years. In examining COG and E2496 AYA patient characteristics, there was no significant difference in sex, race, or histology. Due in part to trial design differences, a larger proportion of E2496 AYAs were stage III or IV vs. COG AYAs (63% vs. 29%, P <0.001) and had B symptoms (63% vs. 27%, P <0.001); fewer E2496 patients had bulk disease (33% vs. 77%, P <0.001). There was no significant difference in presentation with extralymphatic disease, anemia, or hypoalbuminemia. In terms of therapy, more COG AYAs received radiotherapy (76% vs. 66%, P =0.03), though in smaller doses (21 Gy vs. 36 Gy). In each group, 3 AYAs developed a second cancer. The 5-year FFS and OS for AYAs on the COG study were 80% and 97%, respectively (see Figure, sections C and D). For survival comparison across studies, COG AYAs appeared to have superior FFS compared with E2496AYAs (P =0.001). In stratified multivariable analyses (controlled for stage, anemia, and bulk), E2496 AYAs appeared to have worse FFS compared with COG AYAs in all strata except among the subgroup of patients with stage I/II without anemia. Furthermore, propensity score analysis with patients exactly matched on stage, anemia, and bulk disease confirmed the inferior FFS for E2496 AYAs compared with COG AYAs (P =0.004). Moreover, the AYA survival disparity across studies persisted after additional covariates were incorporated into the propensity score (i.e., age, gender, B symptoms, and hypoalbuminemia; P =0.026).Conclusions: AYA HL patients treated on E2496 had inferior outcomes compared with older patients (i.e., ages 22 to 44 years) treated within the same study, for unclear reasons, as well as to similarly matched AYA patients treated on COG AHOD0031. These outcomes may result from treatment regimen differences or dose-intensity, differing patient populations or risk profiles, biology, and/or other factors. Prospective examination of these issues in AYA HL patients is warranted.Table 1Survival Outcomes Within E2496 by Age.PFS3-yr5-yrP17-2170%68%0.00521-4479%76%45-5968%68%>=6056%48%OSP17-2193%89%<.000121-4496%93%45-5979%76%>=6070%58% [Display omitted] DisclosuresSmith:Pharmacyclics: Consultancy; Celgene: Consultancy. Advani:Seattle Genetics, Inc.: Research Funding; Genetech: Consultancy. Horning:Genentech: Employment. Shah:Seattle Genetics: Research Funding; Rosetta Genomics: Other: Grant support; Acetylon: Other: Advisory board; Plexus Communications: Honoraria; Pharmacyclics: Speakers Bureau; Spectrum: Other: Advisory board, Speakers Bureau; Bayer: Honoraria; Celgene: Other: Advisory board, Speakers Bureau; DeBartolo Institute for personalized medicine: Other: Grant support. Connors:Roche: Research Funding; Seattle Genetics: Research Funding. Leonard:Weill Cornell Medical College: Employment; Genentech: Consultancy; Medimmune: Consultancy; AstraZeneca: Consultancy; Spectrum: Consultancy; Boehringer Ingelheim: Consultancy; Vertex: Consultancy; ProNAI: Consultancy; Biotest: Consultancy; Seattle Genetics: Consultancy; Pfizer: Consultancy; Mirati Therapeutics: Consultancy; Gilead: Consultancy; Novartis: Consultancy. Gordon:Northwestern University: Employment; Dr Leo I. Gordon: Patents & Royalties: Patent for gold nanoparticles pending.

Rituximab Followed by Involved Fields Radiotherapy (IF-RT) in Stage I-II Follicular Lymphoma (FL): Long Term Results,

Abstract 3699 Background:Radiotherapy is considered the standard approach in stage I-II non bulky FL but no consensus of the required radiation field has been reached and failure-free survival (FFS) reported ranged between 41 to 49%. Published randomized trials failed to demonstrate the superiority of non adriamycin-containing regimens plus RT over RT alone and only one single arm study with COP-B plus IF-RT reported superior FFS (73%) however complicated by an high rate of treatment related toxicity. Since the monoclonal anti CD-20 antibody Rituximab has shown to be effective in systemic therapy of FL as primary treatment as well at relapse, the combination of the anti-CD20 Rituximab with IF-RT may be considered a valid approach, allowing an effective systemic disease control while sparing the toxicity of chemotherapy. We reported here the long-term outcome of a series of stage I-II FL pts treated front-line with Rituximab followed by IF-RT. Patients and Methods: From July 1999 to April 2009, 36 consecutive stage I-II FL WHO grade I-II, have been enrolled in this phase II study and treated with 4 weekly doses of Rituximab followed by IF-RT. Median age: 49 yrs (range 34–82), M/F: 20/16; FLIPI 0–1: 36; Bulky:0. BM PCR analysis to detect minimal residual disease (MRD) was carried out in 25 pts with a molecular probe: PCR+/PCR-: 10/15. Treatment consisted of 4 weekly doses of Rituximab (375 mg/sqm) followed by external bean RT on involved fields. Median radiation dose was 30.6 Gy, (range 20–40). Results: Rituximab followed by IF-RT was well tolerated without any additional toxicity. All but one pts reached a complete remission (CR). With a median follow-up of 7 years (range: 2–12), 34 pts are alive and 24 in continuous complete remission. Of the 12 relapsed pts, 6 were PCR+ versus 4 PCR- at baseline BM analysis; 2 pts had no molecular probe. Two smokers pts died of lung cancer at 3 and 4 years after immuno-radiotherapy. The OS and FFS were 94% and 67% respectively. These results compare favorably with those observed in similar historical control group treated at our Institution with IF-RT alone (OS:87%,FFS:46.8%). Conclusion: Rituximab followed by IF-RT is a well tolerated and effective front-line treatment for limited stage FL. Long-term results are comparable to those reported for non-anthracycline-containing chemo-radiotherapy and higher when compared to radiotherapy alone, making Rituximab-IF-RT a potential option as initial therapy of limited stage FL. Disclosures:No relevant conflicts of interest to declare.

The Baseline PET SUV Correlates Better with Clinical Outcome Than the Post-Therapy PET Scan in Previously Untreated Patients with Histologically Aggressive Non-Hodgkin Lymphoma (NHL)

The FDG-PET/CT scan has become a standard tool in management of NHL. Failure to achieve an early metabolic CR (mCR) has been previously associated with a poor outcome and is considered as an adverse prognostic feature. Most studies which have supported this finding have used standard CHOP+/−R therapy or included a small or histologically heterogeneous population. As more effective therapies are introduced, some proven prognostic factors will lose relevance. We designed a prospective study to answer the following questions: 1- is the PET scan still capable of predicting outcome with the newer dose dense CHOP−R? 2) Is a very early PET, one week after the first chemotherapy (W1 PET) as good or better as the traditional 3rd course PET scan (C3 PET)? We have entered 55 pts, of which 40 were frontline previously untreated histologically aggressive NHL (35 DLCL, 5 FLCL) and 15 previously treated recurrent NHL (9 DLCL, 3 transformed DLCL, 2 PTCL, 1 high grade NOS). Treatment consisted of CHOP-R in all pts (dose dense in 38/40). A baseline PET was performed and followed by a W1 PET and a C3 PET. Median follow up is 20 mos. IPI was ≥2 in 20/55 (37%). The failure free survival (FFS) at 24 months was 85% for previously untreated pts and 35% for previously treated. For previously untreated pts, median baseline SUVmax= 20.5 (5.6–66.6) and one week after the first course (W1 PET), median SUVmax dropped to 2.6 and by C3 PET the median was 0. We examined the correlation between baseline PET, W1 PET and C3 PET with clinical outcome in previously untreated pts and found that the best correlation was with the baseline PET (figure). [Display omitted] Table 1 shows that the W1 PET as well as the C3 PET failed to correlate with outcome in previously untreated pts. Those who achieved mCR (defined as SUV<4) on the W1 PET or C3 PET didn't have a significantly superior FFS than those who didn't reach mCR. Other cut-off points including SUV<3 and <2 gave similar results. IPI, although showing a trend for correlation with FFS in previously untreated pts, was not significantly associated with outcome: IPI <3 had FFS= 87% vs. ≥3 = 82%, P=0.62. For the 15 cases with recurrent aggressive NHL, the FFS was 100% for those whose W1 PET SUV<4 versus 13% for those with SUV≥4 (P=.013). For those with baseline SUV ≥12 it was 52% vs 0% for SUV <12. For previously treated pts with IPI <3 the 2 yr FFS= 50% vs 0% for those with IPI≥3.Conclusions- for previously untreated pts: a- Striking improvements in PET are seen as early as 1 week after chemotherapy and improved further by C3 PET, but their correlation with the clinical outcome was poor and only the baseline PET SUV correlated well with outcome. b-Those with an SUV below the typical range for DLCL (i.e. <12) were the only ones who relapsed. c- IPI was not significantly associated with outcome. For previously treated pts both the baseline and the W1 PET were predictive of outcome. IPI also correlated with outcome. A possible explanation for these unexpected findings in the frontline group is that traditional prognostic factors might have changed with the introduction of the more effective dose dense CHOP-R regimen. Our FFS of 85% is better than expected for the traditional 21 day CHOP-R. This erosion of traditional prognostic factors might also be reflected by the lack of correlation between the traditional IPI and clinical outcome. For previously treated pts where the impact of treatment is not as prominent, the post treatment PET and IPI still hold as prognostic factors. These findings might not necessarily apply to other histologies or to other treatments.Table 1:W1PET SUVmaxN%FFS 24 mos.P value<4.02483%≥4.01690%0.68C3PET SUV max<4.03583%≥4.03100%0.59

Survival Analysis of Anaplastic Large Cell Lymphoma, Systemic and Cutaneous-Types: Report from the International T-Cell Lymphoma Project.

The WHO (World Health) Organization Classification recognizes two distinct subtypes of anaplastic large cell lymphoma: Primary systemic and Primary cutaneous types, which have differences in immunophenotype, genetics, and clinical behavior. It is now known that approximately 60% of systemic ALCLs express the anaplastic lymphoma kinase (ALK) protein (ALK-pos) and have a significantly superior survival to ALK-neg cases. Since ALK-neg ALCL appear to have a prognosis similar to peripheral T-cell lymphoma unspecified (PTCL-U), it has been suggested that they should be classified as PTCL-U. Herein, we report the clinical features of newly diagnosed systemic and cutaneous ALCL from the International T-cell Lymphoma Study Group.Materials and Methods: 186 cases of ALCL were identified by the WHO disease definitions: systemic ALCL 163 (88%) (ALK-pos 91 (56%), 72(44%) ALK-neg), and 23 (17%) cutaneous ALCL (cut ALCL). The median age of ALK-pos, ALK-neg and cut ALCL was 32, 57.5 and 54, respectively. There was a male predominance for all subtypes. Most cases of systemic ALCL presented with stage III or IV disease (64% ALK-pos, 58% ALK-neg) and in contrast, 87% of cut ALCL had localized disease. The majority of patients with systemic ALCL were treated with CHOP-type chemotherapy. Most patients with cut ALCL (91%) received additional therapy: 13 (62%) CHOP-type chemotherapy, 11(52%) chemoradiation, 4 (19%) radiation alone.Results: The 5y failure free survival (FFS) and overall survival (OS) was superior for ALK-pos ALCL (70.5% and 58%) compared to ALK-neg ALCL (49% and 36%) (p=.022 and p=.014 for FFS and OS, respectively). Comparison of ALK-pos (n=16) and ALK-neg ALCL (n=23) patients with limited stage disease (defined as stage I or II, no B symptoms and non-bulky) failed to demonstrate a significant difference in FFS (p=.54) or OS (p=.21). Both ALK-pos and ALK-neg ALCL had a superior FFS (ALK-pos p< .001; ALK-neg p=.012) and OS (ALK-pos p<.001; ALK-neg p=.032) than PTCL-U. In contrast to PTCL-U, an apparent plateau was observed on the FFS curve for ALK-neg ALCL. For cut ALCL, the 5y FFS and OS was 90% and 57%, superior to systemic ALCL. The administration of chemotherapy did not appear to impact outcome in patients with cut ALCL (p=.64). Among the prognostic factors analyzed, the international prognostic index (IPI) was the most effective for defining risk categories in ALK-neg ALCL. For ALK-pos ALCL both the IPI and anemia (Hb < 11.0 g/L) were effective in risk-group stratification in multivariate analysis.Conclusions: Similar to prior reports, ALK-pos ALCL has a superior outcome to ALK-neg ALCL. For limited stage patients, this survival difference is not apparent, suggesting that a small subgroup of patients with ALK-neg ALCL may have a more favorable prognosis, similar to ALK-pos ALCL. The IPI is effective in both ALK-neg and ALK-pos ALCL at risk stratification. Finally, contrary to prior reports, ALK-neg ALCL patients appear to have a superior outcome to PTCL-U and an apparent plateau in the FFS curve. These results suggest that ALK-neg ALCL should still be distinguished from both ALK-pos ALCL and PTCL-U.

Very Early Post-Treatment PET/CT Scan Performed One Week after First Chemotherapy Course Compared Against the Standard PET after Third Course in Histologically Aggressive Lymphoma (NHL).

The FDG-PET/CT scan has become a standard tool in the management of NHL. Failure to achieve an early metabolic CR (mCR) is associated with a poor outcome and this information can be used to modify subsequent management. However, several issues still need to be resolved, including: 1-What is the best time to perform a post-treatment PET scan? Is very early (i.e. 1 week) after the first chemotherapy superior to the traditional 3rd course PET scan? 2-What criteria can we use to define mCR? Is there an SUV threshold on the very early PET scan that best defines mCR? In order to answer these questions we designed a study in which patients with histologically aggressive NHLs had 3 sequential PET scans: 1st one at baseline, a 2nd one on week 1 after the 1st course of chemotherapy (W1 PET) and the 3rd one after course 3 of chemotherapy (C3 PET). We have entered 32 patients of which 30 are currently assessable. Histologies were: DLCL=26, FLCL=4. IPI was ≥2 in 69%. At baseline, median SUVmax=17.14 (range 5.6–47.1). In the 30 cases who had a W1 PET, the mean SUVmax dropped to 4.4 (0.7–21.3, corrected for background). In the 24 who have completed their C3 PET the mean SUVmax was 1.55 (0–15.2) and only 6 patients had an SUV >0: 0.9, 3.7, 3.9, 5.1, 8.3, 15.2. We then examined the correlation between the SUVmax of W1 PET with SUVmax of C3 PET. 24 cases have already had both a W1 PET and a C3 PET. Table 1 shows that the W1 PET correlated well with 17 (71%) of the 24 C3 PETs. All 14 who achieved SUVmax <4.0 on W1 PET had an SUVmax <4.0 on C3 PET (all of the latter achieved SUVs <1.0). However, of 10 cases who failed to attain SUVmax <4.0 on W1 PET, 7 went on to achieve SUVmax <4.0 on C3 PET, and 2 of these 7 relapsed. For the purpose of determining the best SUV cut-off that can be used to define mCR, we examined the failure free survival (FFS) at various cut-offs ranging from 0 to 8.0 for both W1 PETs and C3 PETs. The best cut-off for both W1 PET and C3 PET was observed at 4.0 (table 2). We thus defined mCR as a post-treatment SUVmax <4.0. Those who achieved mCR on the W1 PET had a significantly superior FFS (Kaplan-Meier method) than those who didn't reach mCR (table 2). The results for the C3 PET didn't reach statistical significance (table 2).Conclusions: 1- Striking improvements in the PET scan are seen as early as 1 week after the first chemotherapy course. 2-The results of the W1 PET anticipated correctly 71% of C3 PET results. 3- Patients who attained an SUVmax <4.0 on the W1 PET had a remarkably superior outcome than those with SUV max ≥4.0 and was associated with a 91% FFS. Thus an SUV cut-off of <4.0 at W1 PET can be used to define mCR. This finding should be confirmed in an independent set of patients. 4- The W1 PET is more sensitive and specific than the C3 PET and is preferable to the C3 PET in predicting clinical outcome.Correlation of W1PET SUVmax With C3PET SUVmaxW1PET SUVmaxNC3PET SUVmax<4.0C3PET SUVmax≥4.0<4.014140≥4.01073Correlation of W1PET SUVmax and C3PET SUVmax With OutcomeW1PET SUVmaxN%FFS 8 mos.P value<4.01891%≥4.0120%.01C3PET SUVmax<4.02173%≥4.0367%.19

Pooled analysis of phase II window studies in children with contemporary high-risk metastatic rhabdomyosarcoma: a report from the Soft Tissue Sarcoma Committee of the Children's Oncology Group.

The Soft Tissue Sarcoma Committee of the Children's Oncology Group has conducted five upfront window trials in patients with newly diagnosed metastatic rhabdomyosarcoma to identify promising new treatment agents. This pooled analysis identified a total of 420 patients (115 from Intergroup Rhabdomyosarcoma Study III [IRS-III] and 305 from the five window trials). We assessed window therapy response rate, failure-free survival (FFS), and overall survival (OS). Response rates (complete + partial response) assessed at week 6 of window therapy ranged from 41% to 55% and did not predict FFS (P = .073) or OS (P = .31). FFS was influenced by trial (P = .048); patients enrolled onto IRS-III and the ifosfamide/etoposide and ifosfamide/doxorubicin trials fared best. When grouped and compared with topoisomerase I poison trials, ifosfamide/topoisomerase II inhibitor trials had superior FFS (P = .013). However, there was no difference in survival. Upfront phase II window trials can efficiently provide robust estimates of activity for new agents and combinations in newly diagnosed patients with high-risk rhabdomyosarcoma. Our data indicate that, for some phase II window trials, the risk of treatment failure may be increased but that the trend towards lower survival for some of the window trials compared with IRS-III is not statistically significant. Window nonresponders did not suffer worse FFS or OS than patients who responded to window therapy. Finally, these results provide a rationale for incorporating ifosfamide, etoposide, doxorubicin, and topoisomerase I poisons in future trials of high-risk metastatic rhabdomyosarcoma.

Eicosanoid modulation in advanced non-small cell lung cancer (NSCLC): CALGB 30203

7025 Background: Increased expression of eicosanoids have been associated with adverse prognosis. Specific inhibitors of key enzymes of two eicosanoid pathways, COX-2 (celecoxib) and 5-LOX (zileuton) have been developed. In vitro, the addition of these inhibitors have demonstrated enhancement of cytotoxic chemotherapy. We hypothesized that the addition of eicosanoid inhibitors to standard chemotherapy of carboplatin (C) and gemcitabine (G) could improve outcome in advanced NSCLC. Methods: Patients (pts) with stage IIIb (pleural effusion)/stage IV NSCLC, PS 0–2, no prior therapy were eligible. All pts received up to six cycles of C AUC 5.5 d1 + G (1000 mg/m2) d1,8. Pts were randomized to three arms: A: Celecoxib (CEL) 400 mg po bid. B: Zileuton (Z) 600 mg qid po, C: CEL and Z at the same doses. CEL and Z were begun on the first day of therapy and continued until progression. In this randomized phase II trial, the objective was to demonstrate a 50% failure free survival (FFS) at 9 months. Serum and tissue samples were required. Results: Between 12/05/03 and 9/30/04, 140 pts were entered and 136 were eligible and treated (A: 44, B: 47, C: 45). M: 86, F: 50; PS 0,1,2 = 38,85,13. Toxicity was primarily hematologic with approximately 70% grade 3/4 toxicity on each arm. Response and survival with 95% CI (see table ). Arm C has superior FFS when compared to combined Arms A+B (p =.054, unstratified log rank test), however, this benefit decreases when adjusted for baseline PS (0 vs, 1,2) and stage (IIIB vs. IV) in a Cox model, p=.15, 2-sided Wald test. There was no difference in terms of OS (p=.96). Serum and tissue were submitted for &gt;90%. Analysis of COX-2 and 5-LOX expression are pending. Conclusions: 1. The combination of C/G + eicosanoid modulators was well tolerated. 2. The trend towards improved FFS in Arm C is intriguing, however, did not achieve the primary endpoint. 3. Correlative studies which may be able to identify pts likely to benefit from this approach are in progress. [Table: see text] [Table: see text]

High-dose chemotherapy and autologous hematopoietic stem-cell transplantation for aggressive non-Hodgkin's lymphoma.

To evaluate clinical and tumor characteristics in patients receiving high-dose chemotherapy and autologous peripheral stem-cell transplantation (PSCT) or bone marrow transplantation (ABMT) for relapsed or primary refractory non-Hodgkin's lymphoma (NHL). One hundred fifty-eight patients with NHL received high-dose chemotherapy and ABMT or PSCT. A multivariate analysis of characteristics was performed for comparison of the long-term failure-free survival (FFS) rate. Using a multivariate analysis, a prognostic model was constructed with patients in the good-prognosis group being those without a mass > or = 10 cm at the time of transplant, and no more than one of the following characteristics: three or more prior chemotherapy regimens, lactate dehydrogenase (LDH) level above normal, and chemotherapy resistance. Patients in the poor-prognosis group had a mass > or = 10 cm, or two of the other characteristics noted. The poor-prognosis group had a 3-year FFS rate of 10%, compared with a 45% 3-year FFS in the good-prognosis group (P < .001). Within the prognostic groups, there was no difference in the 3-year FFS rate of the poor-prognosis patients who received ABMT versus PSCT (10% v 12%; not significant). However, in the good-prognosis group, patients who received ABMT had a 3-year FFS rate of 32%, compared with 70% for those who received PSCT (P < .008). This prognostic model can identify patients with good and poor prognoses following high-dose chemotherapy and ABMT or PSCT for aggressive NHL. In good-prognosis patients, those who received PSCT had a superior FFS rate.

Is there an effective salvage therapy for advanced Hodgkin's disease?

The availability of increasing numbers of active agents has led to the development of a succession of regimens for use as alternative and second-line therapy following relapse from or refractoriness to MOPP (mechlorethamine/vincristine/procarbazine/prednisone) or its variants. ABVD (doxorubicin/bleomycin/vinblastine/dacarbazine) has been the most widely used and has been considered non-cross-resistant. Other programs containing the nitrosourea lomustine have been used with results similar to those with ABVD. A relatively small fraction of relapsed patients remain failure free at 5 years (about 20% to 30%) despite a 30% to 60% second-line complete response (CR) rate. The few randomized trials (Cancer and Leukemia Group B [CALGB], European Organization for Research and Treatment of Cancer) evaluable to assess the efficacy of alternating MOPP/ABVD compared with MOPP alone have shown a small but significant advantage in freedom from progression and/or survival favoring the complex regimens over MOPP. The CALGB trial (8251) included a third arm of ABVD alone. The ABVD and MOPP/ABVD arms had a higher CR rate and superior failure-free survival (FFS) than did MOPP, but have thus far shown no difference between ABVD and alternating MOPP/ABVD, suggesting that full doses of a single regimen are equivalent to the more complex multidrug regimen. The next step in the CALGB program was to attempt to improve ABVD. The substitution of etoposide, an active single agent, for dacarbazine and bleomycin in ABVD resulted in a new regimen, EVA (etoposide/vinblastine/doxorubicin). This program has already demonstrated a 66% response rate in MOPP-resistant/relapsed patients (CALGB 8751).(ABSTRACT TRUNCATED AT 250 WORDS)