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#6095 TRANSGENIC INDUCTION OF EPITHELIAL SENESCENCE PROMOTES RENAL FIBROSIS INDEPENDENT OF INJURY

Abstract Background and Aims Chronic Kidney Disease (CKD) affects over 850 million people worldwide. Progressive renal fibrosis is a hallmark of CKD, irrespective of the initiating aetiology. Any episode of acute kidney injury (AKI) significantly increases the risk of development of CKD, even after apparent complete resolution of the initiating injury. This risk is exacerbated by age and pre-existing CKD. This implies that factors persist within damaged/aging kidneys which drive functional loss, impair complete repair and promote on-going fibrosis. Senescent cells (SCs) are metabolically active, permanently growth arrested cells produced in response to stress and DNA damage. SCs accumulate with age and persist at the sites of previous disease and injury. Their depletion in animal models is safe and extends organ function and healthspan. We have shown that pharmacological SC depletion in kidneys significantly improves kidney function and reduces fibrosis post injury. However, models of renal injury induce changes in multiple cell lineages, and pharmacological depletion is non-specific both in terms of cell lineage (i.e. epithelial vs mesenchymal vs leukocyte) and characteristics of senescent cell (i.e. acute vs chronic, primary vs secondary). We hypothesised that induction of epithelial senescence in the absence of other renal injuries is sufficient to initiate renal fibrosis. We developed a transgenic mouse allowing selective senescence induction in renal epithelia in the absence of injury, with tdTomato labelling of induced cells. Method By crossing existing strains, we produced a triple transgenic Pax8creERT2/mdm2flfl/tdTOMLSL mouse allowing conditional senescence induction by tamoxifen via mdm2 deletion in Pax8 expressing renal epithelia, alongside TdTomato expression. Levels of renal fibrosis, p21cip1 and TdTomato induction were quantified by picrosirius red staining, immunofluorescence and flow cytometry, with downstream image analysis on QuPath 0.3.2. CDKN1A gene expression was quantified by qPCR. Results Examination of kidneys and livers from young mice ± tamoxifen demonstrated that tdTomato induction was tissue specific and restricted to renal epithelia (Fig 1A-C). Administration of Tamoxifen resulted in increased expression of tdTomato and CDKN1A expression at day 7 in transgenic but not in WT mice. (Fig. 1C, 2 A-F). We observed a rapid induction of fibrosis in the first 7 days after tamoxifen induction in both young (Fig. 3A,C) and old mice (Fig 3C). This persists to day 42 (Fig. 3B). This demonstrated that epithelial senescence alone was sufficient to induce renal fibrosis in young mice, and exacerbate fibrosis in old mice. Further studies assessed the longer-term impact of acute senescence induction, with fibrosis stabilising in both young and old mice at 6 weeks post induction (Fig. 3D). Conclusion Using a novel transgenic mouse line, we demonstrate for the first time that induction of renal epithelial senescence in the absence of injury is sufficient to induce renal fibrosis in the early aftermath of SC induction. The evolution and/or clearance of senescent cells over time is the focus of on-going study and will be presented at the ERA.

THE "FLARE-UP PHENOMENON": NEW ONSET OF DISTANT DERMATITIS DURING PATCH TESTING

<h3>Introduction</h3> Allergic contact dermatitis is common, affecting ∼20% of adults, and is often evaluated via diagnostic patch testing.[1] In rare cases, patch testing may result in worsening of pre-existing dermatitis, but development of de novo lesions is unusual.[2] <h3>Case Description</h3> In 2018, a 46-year-old woman experienced severe, bilateral eyelid swelling with intense itching and skin cracking, along with an eczematous rash on her chest and hands. Inpatient workup revealed no infectious/rheumatologic cause, and patient was diagnosed with contact dermatitis from an unknown trigger. After a period of remission, in 2021 patient again developed bilateral eyelid rash without involvement of the hands or chest. Following treatment with topical steroids, eyelid rash resolved. Epicutaneous patch testing was performed (T.R.U.E. TEST). 36h after patch test placement, patient experienced, rapid intensification of eczematous lesions around the eyelids, as well as new onset of rash on the dorsa of her hands, which had been unaffected prior to patch testing (Figure 1). 72h read was positive to colophony and fragrance mix (+1). Systemic and topical corticosteroids were prescribed for presumed flare-up phenomenon, with subsequent resolution of periorbital and hand rash. <h3>Discussion</h3> While generally well-tolerated, diagnostic patch testing has been associated with the "flare-up" phenomenon, worsening pre-existing eczema—and, in this case, leading to the development of de novo lesions.[3] Flare-up is more common in polysensitized patients, as was seen in our case.[2] The mechanism of the "flare-up phenomenon" is poorly understood, but is believed to involve reactivation of memory T cells at previous sites of disease.[3]

Bvgp: A Novel Protocol for Hodgkin's with Excellent Response, Minimal Acute Toxicities and Reduced Risk of Late Effects

Pediatric and Young Adult Hodgkin lymphoma (HL) has a five-year survival rate over 90%. The downside is use of chemotherapy with a lifetime risk of cardiac deaths, second malignancies, pulmonary disease and infertility. Because of effective salvage therapy, ultimate outcomes may be improved by using effective but less toxic initial therapy. To this end, we have piloted a regimen in low and intermediate risk HL using agents not known to be associated with significant late effects. The BVG regimen {bortezomib 1.3 mg/m2 IV day 1,4,8,11; vinorelbine (25 mg/m2 IV day 1,8); gemcitabine (1000 mg/m2 IV day 1,8) every 21 days} was derived from BIGEV [Ding 2009] with elimination of ifosfamide, etoposide and prednisone. Initial use was to consolidate 3 patients after ABVE-PC. Subsequently we treated 5 newly diagnosed patients with non-bulk stage IIA (n=4) or IIB (n=1) HD. Two received BVG and 3 received BVGP with the addition of prednisone (20 mg/m2/dose PO BID x 11 days). Nausea was mild and controlled with 5HT3 antagonists and scopolamine patch. Pegfilgrastim was not necessary due the high absolute neutrophil count nadir (median 1.16 & minimum 0.56 x 109/L). There were no episodes of febrile neutropenia, infections or need for transfusions. There were no significant abnormalities in electrolytes, renal or liver function tests. No patients had any hair loss. One patient developed sensory neuropathy, after dose 8 of bortezomib, that responded to gabapentin and a switch to subcutaneous administration. Newly diagnosed patients were all PET negative after 1 or 2 cycles and remained PET negative at the end of four cycles of therapy. Status of the five newly diagnosed patients ages 10 to 18 is: one is still on therapy; three in remission at 158, 312, 1015 days; one relapsed at 861 days in previous disease sites. This retrospective chart review was approved by Children's Minnesota IRB. For each patient an in depth discussion was held on the benefits and risks of BVGP vs. standard therapy. The chief barrier to use of the protocol was insurance coverage for bortezomib in patients under the age of 18. We hope this abstract will provide early evidence to allow expansion of this pilot experience leading to a randomized trial comparing BVGP with current chemotherapy for low and intermediate Young Adult and Pediatric HL. DisclosuresNo relevant conflicts of interest to declare.

Impact of Radicality Versus Timing of Surgery in Patients with Advanced Ovarian Cancer (Stage III C) Undergoing CRS and HIPEC-a Retrospective Study by INDEPSO.

HIPEC in addition to interval CRS has shown a survival benefit of 12months compared to CRS alone. However, there are many controversial issues pertaining to CRS itself which should be addressed first. To compare NACT and primary CRS approaches when CRS is categorized according to the extent of resection. To evaluate the feasibility of performing HIPEC at these two time points. A retrospective analysis of patients with stage III C ovarian cancer undergoing primary and interval CRS + HIPEC was performed. The surgical approach for interval CRS was classified as (1) resection of sites of residual disease alone or (2) resection of sites involved before NACT. The morphological response was divided into different categories, and surgeons had to state what they consider residual disease and what they do not. From January 2013 to December 2017, 54 patients were included (18-primary; 36-interval). Median PCI 11 vs 6.5 (p = 0.07); CC-0 was obtained in 77.7%. Three surgeons resected previously involved sites; three sites of residual disease only. All surgeons resected areas of scarring. Twenty percent patients had residual disease in "normal-looking" peritoneum. Morbidity (p = 0.09), median OS (p = 0.71), and median DFS (p = 0.54) were similar in the two groups. Early recurrence occurred in 50% with resection of residual disease alone compared to 16.6% when previous disease sites were resected (p = 0.07). Interval CRS should be performed to resect sites involved prior to NACT and not just sites of residual disease. HIPEC can be performed in both primary/interval settings with acceptable morbidity.

Likelihood of Bone Recurrence in Prior Sites of Metastasis in Patients With High-Risk Neuroblastoma

Despite recent improvements in outcomes, 40% of children with high-risk neuroblastoma will experience relapse, facing a guarded prognosis for long-term cure. Whether recurrences are at new sites or sites of original disease may guide decision making during initial therapy. Eligible patients were retrospectively identified from institutional databases at first metastatic relapse of high-risk neuroblastoma. Included patients had disease involving metaiodobenzylguanidine (MIBG)-avid metastatic sites at diagnosis and first relapse, achieved a complete or partial response with no more than one residual MIBG-avid site before first relapse, and received no total body irradiation or therapy with (131)I-MIBG before first relapse. Anatomically defined metastatic sites were tracked from diagnosis through first relapse to determine tendency of disease to recur at previously involved versus uninvolved sites and to assess whether this pattern was influenced by site irradiation. Of 159 MIBG-avid metastatic sites identified among 43 patients at first relapse, 131 (82.4%) overlapped anatomically with the set of 525 sites present at diagnosis. This distribution was similar for bone sites, but patterns of relapse were more varied for the smaller subset of soft tissue metastases. Among all metastatic sites at diagnosis in our subsequently relapsed patient cohort, only 3 of 19 irradiated sites (15.8%) recurred as compared with 128 of 506 (25.3%) unirradiated sites. Metastatic bone relapse in neuroblastoma usually occurs at anatomic sites of previous disease. Metastatic sites identified at diagnosis that did not receive radiation during frontline therapy appeared to have a higher risk of involvement at first relapse relative to previously irradiated metastatic sites. These observations support the current paradigm of irradiating metastases that persist after induction chemotherapy in high-risk patients. Furthermore, they raise the hypothesis that metastatic sites appearing to clear with induction chemotherapy may also benefit from radiotherapeutic treatment modalities (external beam radiation or (131)I-MIBG).

Young Adults Aged 18 to 30 Years with Hodgkin Lymphoma Can Tolerate a Modified Version of the Combined Modality German Paediatric HD95 Protocol with Minimal Neurotoxicity and Excellent Outcome. Results of the UK NCRN 18–30 Study (CRUK/08/012)

AbstractAbstract 1621The outcome for children with Hodgkin’s Lymphoma treated using the German-Austrian paediatric risk-adapted combined modality regimen appears superior to that of adults treated with ABVD +/− radiotherapy. Whether this is related to the superiority of the therapy or a biological difference in the disease in the different age groups is unclear. As a preliminary step to try and compare these regimens directly we enrolled 47 patients between 18 and 30 years of age (median 23y range 18–30) recruited from 8 centres across the UK onto the 18–30 study which used a modified version of the HD95 protocol. Patients were allocated to one of three treatment groups according to stage TG1=1A, 1B, 2A (n=16), TG2=2AE, 2B, 3A (n=11) TG3=2BE, 3AE, 3BE, 3B, 4A, 4B (n=20). Patients in TG1 received 2 cycles of OEPA (vincristine 1.5mg/m2 iv d1,d8,d15 (capped at 2mg/dose), etoposide 125mg/m2 iv d1–5, adriamycin 40mg/m2 iv d1 & 15, prednisolone 60mg/m2 po d1–15). Patients in TG2 received 2xOEPA and 2 xCOPP (cyclophosphamide 500mg/m2 iv d1 and 8 vincristine 1.5mg/m2 iv d1,8 (capped 2mg/dose) procarbazine 100mg/m2 po d1–15, prednisolone 40mg/m2 po d1–15). Patients in TG3 received OEPAx2 and COPPx4. All patients (except those in TG1 who were in CR by CT and PET criteria) went on to receive involved site radiotherapy to all sites of previous disease. The dose of radiotherapy was 20Gy for patients in CR and VGPR (>75% reduction) by CT criteria with areas of residual abnormality on scan >50ml receiving a 30Gy boost. Patients with a PR (50–75% reduction) received the same doses if they were PET negative however those who were PET positive received 30Gy to all sites of previous disease. The schedule of vinca alkaloids in HD95 is compressed with those in TG3 receiving 16 doses of vincristine 1.5mg/m2 (max 2mg) given over 6 months compared with 16 doses of vinblastine 6mg/m2 given over 8 months in ABVD. In view of this and the increase in vinca alkaloid related neurotoxicity with age the primary endpoint of this study was to establish the level of neurotoxicity using this paediatric regimen in young adults. 45 patients (23 male) completed therapy. 1 patient was withdrawn after a hypersensitivity reaction to etoposide on d1 OEPA1 and 1 patient withdrew consent prior to starting therapy. Worst neurotoxicity grade was recorded as: 0 (n=8), 1 (n=17), 2 (n=16) 3 (n=4 [with 2 motor in TG1 &TG2, 1 sensory inTG2, 1 ileus inTG3). In 3 of the 4 patients with severe neurotoxicity vincristine was converted to vinblastine 6mg/m2 according to protocol. No progression of the neuropathy was seen and patients were able to complete their scheduled therapy. In one case (TG2) vincristine was omitted in the final cycle. Neurotoxicity grade at last FU was 0 (n=34) 1 (n=8) 2 (n=3). All 4 cases of grade 3 neurotoxicity reverted to grade 0. Seven patients with grade 2 neuropathy had adjustments made to the dose or type of vinca alkaloid at the request of the physician. Current grade of neuropathy at last FU in these 7 patients:0 (n=4) 1 (n=2) 2 (n=1). There were 8 episodes of febrile neutropenia. Other grade 3 toxicities included diarrhoea (n=2), vomiting (n=3), mucositis (n=3), abdominal pain (n=3) and thrombosis (n=2). Bone/joint pain was seen in 4 patients. Two patients (both TG3) have developed proven osteonecrosis. All 45 patients who completed the chemotherapy achieved a CR or PR. Four did not require radiotherapy, 36 required 20Gy and 5 required 30Gy as a baseline dose to previously involved sites. The median follow up to date is 18 months. Four patients have progressed (1=TG2, 3=TG3) giving a 2yr PFS of 89%. All patients are currently alive. Quality of life data has been collected and assessments of late effects are ongoing. In conclusion, young adults aged 18–30 can tolerate a modified HD95 protocol with a minority of patients experiencing grade 3 neurotoxicity which is reversible when adjustments are made. Outcome with this regimen (which contains only 160mg/m2of adriamycin and no bleomycin) seems encouraging and this (or a more up to date German Austrian Paediatric protocol e.g.with dacarbazine replacing procarbazine in an attempt to spare fertility and omission of radiotherapy based on PET scan after OEPA) warrants testing against ABVD in this age group. Disclosures:No relevant conflicts of interest to declare.

Involved field radiation therapy following high dose chemotherapy and autologous stem cell transplant benefits local control and survival in refractory or recurrent Hodgkin lymphoma

Background and purposePatients with recurrent or primary refractory Hodgkin lymphoma (HL) treated with high dose chemotherapy (HDT) and autologous stem cell transplant (ASCT) commonly relapse post-ASCT in previous disease sites. We sought to evaluate involved field radiation therapy (IFRT) following ASCT and patterns of recurrence, overall survival (OS), and disease specific survival (DSS). Methods and materialsBetween May 1993 and October 2003, 62 (n=66) evaluable patients with refractory/relapsed HL underwent HDT followed by ASCT. Thirty-two (52%) patients received IFRT following transplant. Survival was calculated from the day of hematopoietic stem cell infusion. ResultsMedian follow-up was 2.3years (range 0.03–11.56). Estimated 3-year OS (p=0.05) and DSS (p=0.08) were 69.6% and 82.1% with IFRT and 40% and 57.6% without IFRT on univariate analysis. B-symptoms were adverse on univariate (p=0.007) and multivariate (p=0.01) analysis. HL patients who received IFRT following ASCT had improved local control in areas of previously recurrent disease (p=0.03). ConclusionOS and DSS showed marginal benefit at 3years. Given the retrospective nature of our study and attendant selection bias that can be both positive and negative, a future prospective study is warranted to better understand the value of IFRT in the transplant setting.

Role of 18FDG-PET/CT in detecting relapse during follow-up of patients with Hodgkin’s lymphoma

The role of 18FDG-PET/CT during follow-up of patients affected by Hodgkin's lymphoma (HL) in complete remission after treatment is not fully elucidated, since a wide use of 18F fluorodeoxyglucose positron emission tomography/computed tomography (18FDG-PET/CT) in this setting could be limited by a relative high rate of false-positive results. Herein, we summarize a retrospective analysis of 27 patients with Hodgkin's lymphoma in complete remission after the first-line (n = 20) or salvage (n = 7) therapy receiving serial 18FDG-PET/CT scans during follow-up. Out of 165 scans, 13 were suspected for relapse, which was confirmed in seven patients. All relapses were correctly identified by 18FDG-PET/CT positivity, with a 100% sensitivity; false-positive rate was 46% and negative predictive value was 100%. True-positive findings were mostly associated with multiple sites, subdiaphragmatic involvement, and/or previous sites of disease. According to our results, we conclude that performing routine PET/CT scan during follow-up of those patients who are at high risk of relapse would be advisable, although caution must be adopted when interpreting PET/CT results due to the relatively high rate of false-positive findings. If FDG abnormal uptake is present at multiple nodal sites, subdiaphragmatic lymph nodes, or previous sites of disease, histological verification of PET abnormal findings is warranted.

18F-FDG PET/CT for Monitoring the Response of Lymphoma to Radioimmunotherapy

We retrospectively evaluated 18F-FDG PET/CT for monitoring the response of non-Hodgkin's lymphoma to radioimmunotherapy. A total of 33 clinical patients received 131I-tositumomab (n=23) or 90Y-ibritumomab tiuxetan (n=10) and underwent 18F-FDG PET/CT scans before radioimmunotherapy and at 12 wk after radioimmunotherapy. A third scan was performed on 13 patients at 24 wk after radioimmunotherapy, 12 of whom did not receive interval therapy. Tumor metabolic activity was assessed before and after radioimmunotherapy visually and quantitatively by lean maximum standardized uptake value (SUVlean max). Response was assessed by the International Workshop Criteria (IWC) and Revised IWC, which includes 18F-FDG PET (IWC-PET). Mean SUVlean max decreased from baseline in 244 target lesions 12 wk after radioimmunotherapy (from 6.51+/-4.05 to 3.94+/-4.41; P<0.01), regardless of response at 12 wk after radioimmunotherapy (P<or=0.02). After radioimmunotherapy, SUVlean max was lower for responders than for nonresponders (P<or=0.01). Median percentage change in SUVlean max of target lesions per patient was -51% (-95% to 97%). No significant difference in decline in SUVlean max between patients who received 131I-tositumomab and those who received 90Y-ibritumomab tiuxetan was demonstrated (-31%+/-51% vs. -47%+/-46%; P=0.38). Patients with greater than a 52% decline in SUVlean max tended toward longer survival (P=0.09) than those with lesser declines. The 12-wk overall response rate to radioimmunotherapy based on IWC was 42% (14/33); complete response rate was 15% (5/33). Eleven of 12 patients with progression at 12 wk had new disease sites, and in 4 patients, new disease sites were the only sites of progression. Of 108 lesions evaluated at 12 and 24 wk after radioimmunotherapy, 49 resolved at 12 wk and remained resolved at 24 wk, 17 gradually declined in SUV over 24 wk, and 37 initially decreased at 12 wk but increased at 24 wk. PET showed disease progression at 24 wk in 10 of 13 patients; 7 patients had new lesions and 1 was reclassified from partial response to complete response. In non-Hodgkin's lymphoma, 18F-FDG uptake in tumors typically drops significantly after radioimmunotherapy. A continued decline in tumor SUVlean max between 12 and 24 wk without additional therapy can occur, suggesting a need for delayed-response assessment. In patients who progress after radioimmunotherapy, new sites of disease commonly develop, rather than recurrence or progression at previous disease sites. Large declines in 18F-FDG uptake tend to be seen in those with the longest progression-free survival.

Involved Field Radiation Therapy Following Autologous Stem Cell Rescue for Hodgkin and Non-Hodgkin Lymphoma - Is It Efficacious?.

Introduction: Patients with recurrent or refractory Hodgkin (HL) and non-Hodgkin lymphoma (NHL) treated with high dose chemotherapy and autologous stem-cell rescue (ASCR) commonly relapse (post-ASCR) (70–90%) in sites of previous disease. Although adjuvant involved field radiation therapy (IFRT) to sites of previous recurrence might be expected to enhance local control, translation of this into improved disease-free (DFS) or overall survival (OS) is controversial. We sought to evaluate IFRT following ASCR in terms of patterns of recurrence, OS and DFS.Methods and Materials: All 281 patients with recurrent or refractory HL and NHL who underwent ASCR between 5/92 and 7/03 were analyzed. Disease stratification at the time of transplant included HL, 24%, aggressive NHL (ANHL) 62%, and indolent NHL (INHL) 14%. Most, 46% underwent ASCR after 1st relapse, 18% after 2nd relapse, 4% after 3rd relapse and 26% had refractory disease at ASCR. IFRT was administered to 129 patients (46%). Physician and patient choice determined which patients received IFRT. Dose ranged from 20–36 Gy depending on response to salvage therapy before ASCR and the presence of visible imaging abnormalities following ASCR. For end point analysis 39 patients (14%) including 11 HL, 23 ANHL, and 5 INHL had insufficient data and were excluded.Results: Mean follow-up was 3 years (.3 – 12). The median age at ASCR was 45 years (8 – 73). Male to female ratio was 1.3:1. Thirty five percent of patients had prior RT. On univariate analysis, OS and DFS following IFRT for ANHL was superior (or approached this statistically) at 5 years. For HL, improved OS approached significance, whereas DFS did not despite an apparent benefit by disease-free percentages. IFRT appears to be disadvantageous in INHL, but patient numbers were very small. OS and DFS at 5 years are in the table.Survival Table5-year OS (%)5-year DFS (%)HLWith IFRT6279Without IFRT3768p-value.07.41Aggressive NHLWith IFRT5765Without IFRT3749p-value.02.07Indolent HNLWith IFRT5067Without IFRT8588p-value.06.30On multivariate analysis, for ANHL, IFRT was protective (p = .002, Hazard Ratio = 0.39) and bulky disease was adverse (p = .04, HR = 2.04). For HL, an advantage of IFRT did not reach statistical significance (p = .63, HR = .8). For INHL, IFRT was associated with an inferior outcome (p = .23, HR = 4.9).Conclusion: Recognizing that bias exists in patient selection for IFRT post-ASCR (in both directions), a survival benefit appears to exist for patients with ANHL, and potentially for those with HL. The absence of a difference in DFS may relate to relapses in other sites or competing events with censored data. Longer follow-up or larger patient numbers are necessary to confirm a long- term improvement. INHL did not benefit from IFRT as might be expected since this group is more likely to have occult disseminated, chemotherapy insensitive disease. Determination of specific patterns of disease recurrence is in progress.

Patterns and Timing of Initial Relapse in Patients with Hodgkin's and Non-Hodgkin's Lymphoma.

Purpose/Objective: To evaluate patterns of recurrence in patients with Hodgkin's (HL) and non-Hodgkin's lymphoma (NHL) who subsequently undergo autologous stem cell transplant (ASCT). In this population that has declared itself as high risk, we evaluated time to and sites of relapse relative to initial sites of disease and radiation therapy (RT). This information might enhance understanding of the natural history of these diseases in the setting of modern therapy, influence treatment strategies, and assist in screening decisions.Materials/Method: We analyzed the records of all 281 consecutive patients with refractory or recurrent HL and NHL (indolent and aggressive, as defined at initial diagnosis) who underwent ASCT in our center between 5/92–7/03. Patients were initially diagnosed between 1979–2003 at a median age of 44 years (8–70). 25 patients were unevaluable due to insufficient data, and 68 patients were excluded from analysis because their disease was refractory to initial and salvage therapy. HL patients were segregated according to initial staging (I/II vs. III/IV).Results: Early stage HL patients relapsed at a median of 2.0 years (0.5–10.3) with 87% relapsing in initial disease site(s); 13% (95% CI 3.8–30.1%) relapsed only in new sites. Advanced stage HL patients relapsed at a median of 1.4 years (0.6–10.5) with 96% relapsing in initial site(s); 4% (95% CI 0.1–21.9%) relapsed only in new sites. Indolent histology NHL patients relapsed at a median of 2.1 years (0.5–14.9) with 83% relapsing in initial site(s); 17% (95% CI 7.3–32.8%) relapsed only in new sites. Aggressive histology NHL patients relapsed at a median of 1.0 year (0.3–8.0) with 64% relapsing in initial site(s); 36% (95% CI 26.2–46.2%) relapsed only in new sites. For early stage HD patients, recurrences were predominantly local, and uniformly so in those unirradiated. For all other groups, fewer patients were irradiated than unirradiated and local recurrences predominated regardless of therapy.Conclusions: Almost all patients with HL who relapse and subsequently undergo ASCT initially recur in previous disease sites. Although patients with aggressive histology NHL are more likely to relapse in new sites than patients with indolent NHL, local recurrences predominate in both groups. The median time to recurrence is brief (1–2.1 years). In a population defined by recurrent disease, it is expected that relapses will occur in irradiated sites. Relative protection by RT of local recurrence cannot be determined until all patients, regardless of relapse status, are analyzed. However, these data support an emphasis on local control and suggest that the frequency of screening be most rapid in the early post-therapy years.Comparison of Site(s) of Relapse to Site(s) of Initial PresentationHLNHLEarly (n=30)Adv. (n=23)Ind. (n=40)Agg. (n=95)Characteristic%%%%New Site(s)1341836Previous site(s) only63616044Previous site(s) + new site(s)23352320CharacteristicnnnnRadiated patients relapsing in previous site(s)15/196/65/720/34Unradiated patients relapsing in previous site(s)11/1116/1726/3342/61

An Outpatient Salvage Approach for Advanced Lymphoma Incorporating Stratification and Dose-Escalation.

We have previously demonstrated significant anti-lymphoma activity using an outpatient-based salvage approach comprising vinorelbine and gemcitabine with an overall response (CR + PR) rate of 55%. We now report the results of a planned interim analysis of a similar outpatient approach for both non-Hodgkin's lymphoma (NHL) and Hodgkin's lymphoma (HL) but incorporating patient stratification and treatment escalation. Patients were stratified into Group 1 (G1 - good risk - first relapse following durable first remission - follicular NHL>12 months, all other NHL sub-types and HL>6 months); Group 2 (G2 - poor risk - primary refractory, second or subsequent relapse, or non-durable first remission); or Group 3 (G3 - post-transplant - relapse following any form of stem cell transplant therapy). Two chemotherapy regimens were evaluated. VGF (vinorelbine 25mg/sqm days 1 and 8, gemcitabine 1000mg/sqm days 1 and 8, pegfilgrastim 6mg SC day 9); F-GIV (same as VGF but with ifosfamide 3000mg/sqm day 1 with mesna uroepithelial protection). G1 and G3 commenced therapy with VGF and G2 with F-GIV. Following 2 cycles of therapy all patients were restaged. Any patients demonstrating disease progression were removed from trial. Responsive patients (>50% reduction in all previous sites of disease and gallium and/or FDG-PET negativity where baseline positivity was demonstrated) received 2 further cycles of the same therapy, the remainder ‘escalated' therapy with F-GIV (G1 and G3) or IVAC (G2) (inpatient treatment with ifosfamide, VP-16 and Ara-C). A planned total of 90 patients were accrued between December 2002 and December 2004. Here we report on the first 88 patients (G1 = 26, G2 = 50, G3 = 12) with a median age of 57 years (range, 17–78). Diagnoses at entry were HL, n = 16 (nodular sclerosing = 13, mixed cellularity = 3) and NHL, n = 72 (diffuse large cell = 41, follicular = 16, others = 15). So far G1 and G2 have received 79 and 138 cycles of VGF and F-GIV, respectively, with grades 3/4 neutropenia or thrombocytopenia occurring in 24% and 18% (VGF) and 62% and 49% (F-GIV) of patients, respectively. Significant non-haematological toxicities were uncommon. Febrile neutropenia, hospital admission, treatment delay or dose-reductions occurred with 4%, 19%, 4%, 1% and 17%, 34%, 9%, 9% of VGF and F-GIV cycles, respectively. The 12 post-transplant patients (G3) have received 28 and 8 cycles of VGF and F-GIV, respectively, with no unexpected toxicities. Based on published standardised response criteria overall response (CR + Cru + PR) on an intention-to-treat basis after 2 to 4 cycles of treatment is 54% (CR 29%) (77% and 42% for G1 and G2, respectively). Diffuse large cell NHL patients have demonstrated response rates of 67% and 17% for G1 and G2 patients, respectively. Based on this planned interim analysis we conclude that both VGF and F-GIV can be safely administered on an outpatient basis and show activity against advanced lymphoma.

18F-FDG PET in malignant lymphoma: significance of positive findings

The aim of this study was to evaluate the significance of increased uptake of 18F-fluorodeoxyglucose (FDG) in patients with malignant lymphoma (ML) studied by positron emission tomography (PET). A total of 1,120 consecutive scans carried out in 848 patients were reviewed; all patients had a diagnosis of ML [574 non-Hodgkin's lymphoma (NHL) and 274 Hodgkin's disease (HD)] and were studied at completion of therapy, for suspected recurrence or during follow-up. PET was carried out after intravenous injection of 370 MBq of 18F-FDG; images were recorded after 60-90 min. Patients were selected whose reports indicated areas of increased FDG uptake. PET findings were considered positive for lymphomatous localisation when uptake occurred at sites of previous disease, in asymmetrical lymph nodes or in nodes unlikely to be affected by inflammation (mediastinal, except for hilar, and abdominal). PET findings were adjudged negative for neoplastic localisations in the following instances: physiological uptake (urinary, muscular, thymic or gastrointestinal in patients without MALT), symmetrical nodal uptake, uptake in lesions unrelated to lymphoma that had already been identified by other imaging methods at the time of PET scan, uptake at sites atypical for lymphoma, very low uptake and non-focal uptake. PET findings were compared with the results of other diagnostic procedures (including CT and ultrasound), biopsy findings and follow-up data. Overall, 354 scans (in 256 patients) showed increased FDG uptake (244 scans in NHL and 110 in HD): in 286 cases, FDG uptake was considered pathological and indicative of ML, in 41 cases the findings were described as uncertain or equivocal and in 37 cases, FDG uptake was considered unrelated to ML (in ten scans, concurrent findings of abnormal FDG uptake attributed to ML and uptake assigned to other causes were obtained) . Of the 286 patients with positive PET findings, 274 (95.8%) were found to have residual or recurrent ML (i.e. true positives). Four of the 41 patients with inconclusive findings turned out to have ML, while in 13 patients, pathological processes other than ML could be identified as the cause of FDG uptake. ML was excluded in all patients with findings reported as non-pathological (100% true-negative rate). Therefore, the false-positive rate in our series was about 5%. The main cause of increased FDG uptake mimicking ML was inflammation. Our data confirm that 18F-FDG-PET has very high but not absolute specificity for ML. As already suggested, increased FDG uptake may also be observed in patients without active disease; in most cases, however, non-pathological FDG accumulation is properly identified. Less frequently, inconclusive scans are encountered; these cases are usually caused by inflammation, which subsequently resolves.

Patterns of recurrence after high-dose chemotherapy with autologous stem cell transplantation for refractory lymphoma

6659 Background: High-dose therapy (HDT) with or without total body irradiation followed by autologous stem cell transplantation (ASCT) is a therapeutic option for patients with relapsed or refractory to initial treatment for lymphoma. However, there are relatively few reports regarding outcome following recurrence after HDT therapy. In order to investigate outcome of the HDT, the patterns of recurrence and survival were analyzed. Methods: A total of 61 patients were treated with HDT followed by ASCT between Feb. 1991 and Dec. 2001. In this study, we investigated patterns of relapse and the factor especially bone marrow involvement at time of diagnosis. Results: Fifty-four patients were aggressive lymphoma, 4 were high-grade lymphoma, and 3 were low-grade lymphoma. Involved-field radiotherapy was added to sites of disease, if the sites were indicated after HDT. Median length of follow-up was 70 (24–156) months. Fifty-nine patients were assessable. Forty nine of 59 (83%) patients had complete response or continued CR, and 25 of 49 (51%) patients relapsed at median time of 20.5 (1.4–124.9) months after ASCT. Twelve of 25 patients (48%) relapsed 2 years after HDT. Seventeen of 25 patients (68%) presented with recurrence at previous sites of disease, five patients (20%) at new sites, and three patients (12%) at both previous and new sites. The length of 50% survival of the relapsed patients was 20.7 months. The Kaplan-Meier estimate of patients alive 5 years after recurrence was 13%. We analyzed relapse pattern according to bone marrow involvement. The results were shown in the table. The relapse patterns and survival after HDT followed by ASCT were identical in both groups. Conclusions: The HDT followed by ASCT might be able to save some group of refractory lymphoma patients regardless of bone marrow involvement. No significant financial relationships to disclose.

Patterns of recurrence after high-dose chemotherapy with autologous stem cell transplantation for refractory lymphoma

6659 Background: High-dose therapy (HDT) with or without total body irradiation followed by autologous stem cell transplantation (ASCT) is a therapeutic option for patients with relapsed or refractory to initial treatment for lymphoma. However, there are relatively few reports regarding outcome following recurrence after HDT therapy. In order to investigate outcome of the HDT, the patterns of recurrence and survival were analyzed. Methods: A total of 61 patients were treated with HDT followed by ASCT between Feb. 1991 and Dec. 2001. In this study, we investigated patterns of relapse and the factor especially bone marrow involvement at time of diagnosis. Results: Fifty-four patients were aggressive lymphoma, 4 were high-grade lymphoma, and 3 were low-grade lymphoma. Involved-field radiotherapy was added to sites of disease, if the sites were indicated after HDT. Median length of follow-up was 70 (24–156) months. Fifty-nine patients were assessable. Forty nine of 59 (83%) patients had complete response or continued CR, and 25 of 49 (51%) patients relapsed at median time of 20.5 (1.4–124.9) months after ASCT. Twelve of 25 patients (48%) relapsed 2 years after HDT. Seventeen of 25 patients (68%) presented with recurrence at previous sites of disease, five patients (20%) at new sites, and three patients (12%) at both previous and new sites. The length of 50% survival of the relapsed patients was 20.7 months. The Kaplan-Meier estimate of patients alive 5 years after recurrence was 13%. We analyzed relapse pattern according to bone marrow involvement. The results were shown in the table. The relapse patterns and survival after HDT followed by ASCT were identical in both groups. Conclusions: The HDT followed by ASCT might be able to save some group of refractory lymphoma patients regardless of bone marrow involvement. No significant financial relationships to disclose.

Patterns of relapse and subsequent management following high-dose chemotherapy with autologous haematopoietic support in relapsed or refractory Hodgkin's lymphoma: A two centre study

High-dose chemotherapy has an established role in recurrent or refractory Hodgkin's lymphoma (HL) although a significant proportion of patients subsequently relapse. This manuscript describes the clinical characteristics of such patients and documents their further management at two major UK cancer centres. Between 1987 and 1996 one hundred patients with recurrent or refractory HL received high-dose chemotherapy (HDCT) with autologous haematopoietic rescue. All had recurred within 12 months of initial therapy or had two or more recurrences. With a median follow-up of 2 years, 56 patients are currently progression-free. There were six treatment-related deaths. One patient died of pneumonia in remission. Thirty-seven patients have relapsed, intrapulmonary disease being seen for the first time in 53% and recurrence at previous sites of disease in 81%. Following recurrence, therapy was determined by circumstances: either one agent at a time was used (single sequential approach) or multiagent chemotherapy was chosen. There was a survival advantage for those who achieved a symptomatic response (13 vs. 4 months median, P = 0.0001). A trend towards longer survival was seen for those whose disease recurred beyond six months following high-dose chemotherapy and in those who received combination chemotherapy. These results confirm that HDCT with autologous haematopoietic support is inadequate for about half the patients who receive it for high-risk HL. Relapse in the site of prior disease is the most likely pattern with intrapulmonary disease for the first time occurring frequently. It is possible to administer further chemotherapy after failure of HDCT, and both objective as well as subjective benefit can be achieved. A few patients appear to get long-term benefit from further treatment.

Patterns of Outcome Following Recurrence After Myeloablative Therapy With Autologous Bone Marrow Transplantation for Follicular Lymphoma

To assess the patterns of recurrence, management, and survival following recurrence after myeloablative therapy with autologous bone marrow transplantation (ABMT) in patients with follicular lymphoma (FL). Between June 1985 and October 1995, 99 patients with FL received cyclophosphamide and total-body irradiation with ABMT as consolidation of second or subsequent remission. Median length of follow-up was 5 1/2 years, and 33 patients developed recurrent lymphoma a median of 14 months after ABMT. In 26 patients, the recurrence was overt; in seven, it was detected on surveillance investigation. Twenty-six patients presented with recurrence at previous sites of disease. Twenty-two patients (67%) had FL at the time of recurrence; in 11 (33%), there was evidence of transformation to diffuse large B-cell lymphoma. Eight patients were managed expectantly; five were alive 21 to 53 months later. Twenty-five patients have required treatment to date; eight remained alive 6 months to 10 years later, and five were in remission. The Kaplan-Meier estimate of patients alive 5 years after recurrence is 45% (95% confidence interval, 27% to 62%). In univariate and multivariate analyses, survival after recurrence and overall survival after diagnosis were similar to those of a historical control group who received conventional treatment, before the introduction of myeloablative therapy (adjusted hazard ratio [HR], 1.56, P = .3, and HR, 1.34, P = .4, respectively). The survival pattern of patients with FL following recurrence after myeloablative therapy and ABMT suggests that this treatment does not compromise outcome in patients in whom it fails, reflecting the survival pattern of the disease when treated conventionally.

Favorable prognosis after late relapse of hodgkin's disease

Most relapses of Hodgkin's disease (HD) occur within the first 2 years after diagnosis, but they may develop after a longer observation period. The aim of this study was to define the incidence, clinical course, and prognostic factors for late relapse (LR) of Hodgkin's disease. For this purpose, the authors defined LR as relapse that occurred in patients who achieved a complete remission that lasted a minimum of 24 months. During the years 1974-1994, 375 patients with newly diagnosed HD were treated at out institution. Of these patients, 223 remained free of disease for at least 2 years. In addition, 26 patients had been in complete remission for a minimum of 24 months after salvage treatment. Thus, 249 patients were identified as being at risk of LR, and they were the study subjects. The median age was 29 years. Fifty-nine percent of the patients had early stage disease (Stage I/II), and 48% underwent staging laparotomy. Ninety patients presented B symptoms at diagnosis, and 87 had bulky disease. Treatment consisted of radiotherapy for 68 patients, chemotherapy for 68, and combined modality therapy for 113. With a median follow-up of 125 months (range, 22-287 months), the authors observed LR in 25 patients (10%). The estimated relapse rate at 15 years was 13.4%. Relapse occurred after a median disease free interval of 45 months (range, 25-113 months), and it involved sites of previous disease in 70% of the patients. Age > 30 years and treatment with radiotherapy alone were the only significant independent predictors for an increased risk of LR. At a median of 79 months (range, 6-168 months) after therapy for LR, 20 patients were still alive and free of disease (1 of them after rescue treatment for second relapse), and 5 had died (3 of HD, 2 of second tumor). The estimated overall survival (OS) after LR was 82% at 8 years. OS was not significantly different for LR patients than for those who did not relapse. The actual incidence of LR emphasizes the need for continuous follow-up of patients treated for HD. LR, if properly managed with conventional therapy, does not compromise survival.

Tumor Cell Contamination of Bone Marrow Harvest Products: Clinical Consequences in a Cohort of Advanced-Stage Breast Cancer Patients Undergoing High-Dose Chemotherapy

Patients undergoing high-dose chemotherapy (HDC) with autologous stem cell rescue (ASCR) may have tumor cells inadvertently infused if their stem cell product is tumor contaminated. We used an immunocytochemical (ICC) method to analyze 31 histologically negative bone marrow (BM) specimens taken from women with advanced-stage breast cancer at the time of BM harvest before HDC. All 31 patients were treated on one of three consecutive HDC protocols and received BM or BM and peripheral stem cells (PSC) as ASCR. Six of 26 evaluable patients had ICC-detectable contaminating tumor cells in their BM harvests. These 6 patients had a trend toward decreased overall survival compared with those patients without ICC-detectable tumor cells (17 months median versus 25+ months, p = 0.11, log rank test for those patients achieving complete response, CR, from HDC). The sites of relapse in the ICC-positive and ICC-negative groups were not notably different when analyzed for new sites versus previous sites of disease. Therefore, our retrospective analysis of a small cohort of patients suggests that the infusion of tumor cells in breast cancer patients undergoing HDC may confer a poor prognosis. Relapse patterns however suggest failure both in new sites and in sites of previous disease. Additional studies in expanded patient populations are needed to explore further the role of tumor cell infusion in ASCR and the possible clinical benefits of tumor cell removal procedures.

Patterns of failure following total body irradiation and bone marrow transplantation with or without a radiotherapy boost for advanced neuroblastoma

To evaluate the patterns of failure and outcome of patients undergoing high-dose chemotherapy, total body irradiation (TBI), and bone marrow transplantation (BMT) for advanced/relapsed pediatric neuroblastoma, with emphasis on the impact of a radiotherapy boost to primary and metastatic sites. Between May 1986 and June 1993, 26 patients with advanced neuroblastoma underwent high-dose chemotherapy and TBI followed by BMT at our institution. The majority of patients were over the age of 2 years (73%) and were Stage IV at diagnosis (81%). Multiple metastatic sites were involved including bone (17), bone marrow (15), distant nodes (11), liver (5), lung (4) and brain (1). Twenty patients (77%) received cyclophosphamide (50 mg/kg x 4 days) and TBI as consolidation therapy. TBI was delivered to a total dose of 12 Gy given in 2 Gy twice daily (b.i.d.) fractions over the 3 days preceding bone marrow infusion. A local radiotherapy boost of 8-24 Gy was given to 13 out of 26 patients (50%) to the primary and/or metastatic sites immediately prior to or following induction chemotherapy according to physician judgement. Sites not amenable to a radiotherapy boost included the bone marrow, diffuse/bilateral lung involvement, and multiple bone metastases (> four sites). The actuarial overall survival of the 26 patients was 40.4% at 3 and 5 years, with a progression-free survival at 5 years of 38.5%. Six patients died of transplant-related toxicity (23%). The use of cyclophosphamide as high-dose consolidation chemotherapy was significantly better than other multidrug regimens used in terms of overall survival (p < 0.0001) and progression-free survival (p = 0.0004). The presence of liver involvement prior to BMT was a significant adverse prognostic factor by multivariate analysis. Of the 20 patients surviving the transplant, 10 (50%) underwent a local radiotherapy boost. The patterns of failure were as follows: 3 out of 10 "boost" patients failed overall, none in previous (old) sites of disease only, 1 in new sites only, and 2 in old and new sites; 6 out of 10 "no boost" patients failed overall, 4 in old sites only, none in new sites only, and 2 in old and new sites. There was a trend toward improved 5-year progression-free survival in patients surviving the transplant that received a boost (68% vs. 33%, p = 0.24). A failure analysis was also performed for each of the 59 initially involved sites, of which the majority (64%) were amenable to a radiotherapy boost. Overall, there is a trend toward less failure in sites amenable to a radiotherapy boost that were irradiated (1 out of 10) vs. those not irradiated (6 out of 28). Failure in the liver occurred in three out of four of the patients with liver involvement that did not receive boost radiotherapy, whereas all seven patients with distant nodal involvement were controlled without a boost. Long-term sequelae include learning difficulties (2), cataract formation (1), and hearing loss (2). Sequelae attributable to a radiotherapy boost occurred in only one patient who received whole brain radiotherapy and developed a cataract and learning difficulties. We have found an actuarial 5-year survival rate of 40.4% for patients with advanced neuroblastoma treated with BMT, which compares favorably with results of other published series. Disease recurrence following BMT was most common in previous sites of disease. The majority (64%) of these sites were amenable to a radiotherapy boost. An analysis of failure suggests that a low-dose radiotherapy boost improves control of these sites.