Long-term Disease-free Survival In Patients Research Articles

Durable remission related to CAR-T persistence in R/R B-ALL and long-term persistence potential of prime CAR-T

CD19-targeted chimeric antigen receptor T lymphocytes (CAR-T) has demonstrated a high proportion of complete remission in the treatment of relapsed refractory acute B cell lymphoblastic leukemia (r/r B-ALL). It is of great clinical significance to explore which factors will impact long-term disease-free survival of patients with r/r B-ALL after CAR-T therapy without bridging bone marrow transplantation. Our study found that, in patients with r/r B-ALL without bridging transplantation, the patients' age; infusion dosage; whether they had undergone allo-stem cell transplantation before CAR-T therapy, using CD-19-targeted or CD19/CD22-dual-targeted CAR-T; whether there is fusion gene; tumor burden before therapy; and comorbidity had no significant relationship with their long-term disease-free survival. We found only that CAR-T persistence was highly correlated with patients' long-term disease-free survival. So, we further profiled CAR-T cells using single-cell sequencing and found that there is a specific Tcell subset that may be associated with the long-term persistence of CAR-T. Finally, according to the single-cell sequencing results, we established cell production process named PrimeCAR, which shared common signaling pathways with the Tcell subset identified. In the preliminary clinical study, prime CAR-Ts yield good persistence in peripheral blood of patients with B-ALL and lymphoma, without observing grade 2 or higher cytokine release syndrome.

Disease-free survival does not differ according to fertility preservation technique for young women with breast cancer

To study whether fertility preservation strategies using ovarian stimulation or without using it impact long-term disease-free survival of patients with breast cancer. Retrospective bicentric cohort study. Two university hospitals. In this study, 740 women with breast cancer, aged 18-43 years, who received primary fertility preservation between 2013 and 2019 after a diagnosis of localized breast cancer were included. Overall, 328 patients underwent at least 1 ovarian stimulation cycle (STIM group) and 412 had a technique without hormonal administration (no STIM group). Disease-free survival and overall survival up to May 2021 were compared between the 2 groups by log-rank test. Cox proportional-hazard regression model was used for multivariable analyses. Out of the 740 women who underwent fertility preservation, follow-up data were available for 269 women in the STIM group (82%) and 330 (80%) in the no STIM group. Kaplan-Meier estimates of disease-free survival at 4 years were 87.9% (82.8%-92.2%) and 83.1% (78.4%-87.3%) in the STIM and no STIM groups, respectively. After adjustment on prognostic parameters, no significant difference in breast cancer recurrence rate was observed between the STIM and no STIM groups (hazard ratios, 0.83 [0.64-1.08]). Kaplan-Meier estimate of overall survival at 4 years was 97.6% (95.3%-99.2%) and 93.6% (90.9%-95.9%) in the STIM and no STIM groups, respectively. Overall survival was higher in the STIM group than no STIM group (log-rank test). After adjustment on prognostic parameters, the risk of death remained significantly lower in the STIM group (Hazard Ratio, 0.55 [0.35-0.85]). In our cohort, STIM for fertility preservation in breast cancer did not significantly impact disease-free survival but was associated with higher overall survival. The disease-free survival and overall survival of young patients with breast cancer were not impacted by fertility preservation techniques irrespective of the timing of chemotherapy (neoadjuvant or adjuvant) and the use of ovarian stimulation. Nevertheless, because death and recurrence were rare events, these results should be taken with caution.

Paediatric thyroidectomy: When and why? A 25-year institutional experience

ObjectiveThyroidectomy in paediatric patients is relatively uncommon. In this study, we reviewed our experience of thyroidectomy in children and identified risk factors associated with postoperative complications. MethodsWe performed a retrospective analysis of paediatric patients who had thyroidectomy in our institution between April 1995 and January 2021. Demographic data, preoperative cytological findings, indications of surgery, surgical complications and histological results were analysed. ResultsA total of 87 paediatric patients with 92 thyroidectomy were identified. The indications for surgery were Graves’ disease refractory to medical treatments (40.2%), benign thyroid nodules or multinodular goitre (26.4%), thyroid carcinoma (23.0%) and multiple endocrine neoplasm type 2A syndrome (10.3%). Patients presented with thyroid nodules or cervical lymph nodes had a 43.9% risk of malignancy.66 total thyroidectomy were done with median operation time of 134 min(102–170), while 26 hemi-thyroidectomy were performed (Right side 12/92, Left side 14/92) with median operation time of 65 min(49–102). The median postoperative hospital stay was 2 days(1–4). Intraoperative neck dissection (p = 0.003), drain insertion (p = 0.001) and hypocalcaemia requiring medical treatment (p = 0.004) were associated with longer hospital stay.The median follow-up was 11.3 years (3.0–16.8). 32% patients had immediate postoperative hypocalcaemia and 8% patients had permanent hypoparathyroidism. Transient vocal cord palsy was found in 3 patients(3%) and all resolved within 5-month time upon reassessment direct laryngoscopy. The use of intraoperative recurrent laryngeal nerve monitoring was associated with less vocal cord palsy (p = 0.022).The median disease-free survival was 13.7 years(7.4–17.7) for patients operated for well-differentiated thyroid carcinoma(WDTC). amongst the 9 patients who had prophylactic total thyroidectomy for MEN2A syndrome, 44% were found to have medullary thyroid microcarcinomas on pathology. ConclusionsSurgical management of paediatric thyroid disease can be complex. Postoperative hypocalcaemia and vocal cord palsy were usually transient after total thyroidectomy. The use of intraoperative recurrent laryngeal nerve monitoring had resulted in less vocal cord palsy. Long-term disease-free survival of patients with thyroid cancer had been achieved with multi-disciplinary management in our centre.Level of Evidence: Retrospective Comparative Study; Level III

Outcomes of Allogeneic Hematopoietic Cell Transplantation in T Cell Prolymphocytic Leukemia: A Contemporary Analysis from the Center for International Blood and Marrow Transplant Research

T cell prolymphocytic leukemia (T-PLL) is a rare, aggressive malignancy with limited treatment options and poor long-term survival. Previous studies of allogeneic hematopoietic cell transplantation (alloHCT) for T-PLL are limited by small numbers, and descriptions of patient and transplantation characteristics and outcomes after alloHCT are sparse. In this study, we evaluated outcomes of alloHCT in patients with T-PLL and attempted to identify predictors of post-transplantation relapse and survival. We conducted an analysis of data using the Center for International Blood and Marrow Transplant Research database on 266 patients with T-PLL who underwent alloHCT between 2008 and 2018. The 4-year rates of overall survival (OS), disease-free survival (DFS), relapse, and treatment-related mortality (TRM) were 30.0% (95% confidence interval [CI], 23.8% to 36.5%), 25.7% (95% CI, 20% to 32%), 41.9% (95% CI, 35.5% to 48.4%), and 32.4% (95% CI, 26.4% to 38.6%), respectively. In multivariable analyses, 3 variables were associated with inferior OS: receipt of a myeloablative conditioning (MAC) regimen (hazard ratio [HR], 2.18; P < .0001), age >60 years (HR,1.61; P=.0053), and suboptimal performance status, defined by Karnofsky Performance Status (KPS) <90 (HR,1.53; P=.0073). Receipt of an MAC regimen also was associated with increased TRM (HR,3.31; P < .0001), an elevated cumulative incidence of grade II-IV acute graft-versus-host disease (HR,2.94; P=.0011), and inferior DFS (HR,1.86; P=.0004). Conditioning intensity was not associated with relapse; however, stable disease/progression was correlated with increased risk of relapse (HR,2.13; P=.0072). Both in vivo T cell depletion (TCD) as part of conditioning and KPS <90 were associated with worse TRM and inferior DFS. Receipt of total body irradiation had no significant effect on OS, DFS, or TRM. Our data show that reduced-intensity conditioning without in vivo TCD (ie, without antithymocyte globulin or alemtuzumab) before alloHCT was associated with long-term DFS in patients with T-PLL who were age ≤60 years or who had a KPS>90 or chemosensitive disease.

CD200R1 Distinguishes Uncommitted Precursors from Functionally Mature NK Cells within the Human Tonsil Stage 4A NK Cell Population

Natural killer (NK) cells are cytotoxic innate lymphoid cells (ILCs) whose development and anti-tumor functions can be critical for the successful treatment and long-term disease-free survival of patients with hematologic malignancies. In humans, NK cells derive from bone marrow resident hematopoietic progenitor cells that traffic to secondary lymphoid tissues (SLTs) where they complete their terminal differentiation and maturation through a series of developmental stages before returning to the blood as mature NK cells. Although major stages of human NK cell development in SLTs have been clearly defined according to the differential surface expression of CD34, CD117, CD94, NKp80, CD16, and CD57 among lineage antigen (Lin) negative lymphocytes, continued investigation has revealed additional phenotypic and functional heterogeneity at each developmental stage. Through extensive ex vivo single-cell RNA sequencing and flow cytometry analyses we have identified two subsets of tonsil-resident Lin -CD34 -CD117 +/-CD94 +NKp80 -CD16 -CD57 - stage 4A NK cells. These two subsets differ in their expression of the inhibitory receptor, CD200R1, which is not expressed by mature NK cells in the peripheral blood from healthy individuals. The majority of stage 4A cells expressed high amounts of surface CD200R1, which correlated with low gene and undetectable protein expression of intracellular cytolytic granules (perforin and granzymes A, B, K, and M), killer immunoglobulin-like receptors (KIRs), and transcription factors required for terminal NK cell maturation (EOMES, T-BET). In addition, upon ex vivo stimulation with phorbol 12-myristate 13-acetate (PMA) and ionomycin, CD200R1 + stage 4A NKDIs did not produce interferon-gamma (IFN-g), a hallmark feature of mature NK cells. In contrast, many CD200R1 - stage 4A cells constitutively expressed perforin, granzymes, EOMES, and/or T-BET; many expressed KIRs; and many produced IFN-g upon ex vivo stimulation. Furthermore, the frequency of KIR + cells among CD200R1 - stage 4A cells was significantly higher than that among autologous tonsil stage 4B NK cells (Lin -CD34 -CD117 +/-CD94 +NKp80 +CD16 -CD57 -) (20.8 ± 1.65 vs. 8.12 ± 1.66; p < 0.01; n = 14), suggesting that as a population CD200R1 - stage 4A cells are potentially out of sequence in terms of the linear NK cell developmental pathway. Based on these ex vivo findings, we hypothesized that CD200R1 + stage 4A cells represent NK cell precursors, whereas the CD200R1 - stage 4A population contains more mature NK cells that lack NKp80, CD16, and CD57. To further address this hypothesis and to determine their ex vivo potentials for NK cell and non-NK ILC differentiation, we cultured CD200R1 + and CD200R1 - stage 4A cells in vitro in the presence of OP9-DL1 stroma and recombinant human IL-7 and IL-15, conditions previously shown to support all human ILC and NK cell subset differentiation. Under these conditions, both stage 4A populations generated NKp80 + NK cells in bulk and single-cell clonal assays, whereas neither population gave rise to ILC2s (CD294 +) which precede stage 4A NK cells in the developmental scheme. However, while the majority of cultures derived from CD200R1 + stage 4A clones contained ILC3s (CD94 -NKp44 +), significantly fewer clones from CD200R1 - stage 4A cells produced ILC3s (7 of 26 CD200R1 - clones vs. 20 of 23 CD200R1 + clones; p = 0.000587). Moreover, none of the CD200R1 - stage 4A-derived clonal cultures that contained KIR + NK cells contained ILC3s, suggesting that the majority of CD200R1 - stage 4A cells are lineage committed NK cells. Collectively, these data further characterize the heterogeneity of the human tonsil stage 4A NK cell population and identify CD200R1 as a marker distinguishing uncommitted precursor cells from a minor population of cells with otherwise mature NK-associated phenotype and function. In light of the role of CD200R1 in regulating lymphocyte functions in the setting of cancer, further research is warranted to determine its potential role(s) in regulating human NK cell development. DisclosuresBlachly: KITE: Consultancy, Honoraria; INNATE: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria; AstraZeneca: Consultancy, Honoraria.

A retrospective international study on primary extranodal marginal zone lymphoma of the lung (BALT lymphoma) on behalf of International Extranodal Lymphoma Study Group (IELSG).

Primary lymphoma of the lung is a rare entity. Clinical features, optimal treatment, role of surgery and outcomes are not well defined, and the follow-up is variable in published data. Clinical data of 205 patients who were confirmed to have bronchus mucosa-associated lymphoid tissue lymphoma from December 1986 to December 2011 in 17 different centres worldwide were evaluated. Fifty-five per cent of the patients were female. The median age at diagnosis was 62 (range 28-88) years. Only 9% had a history of exposure to toxic substances, while about 45% of the patients had a history of smoking. Ten per cent of the patients had autoimmune disease at presentation, and 19% patients had a reported preexisting lung disease. Treatment modalities included surgery alone in 63 patients (30%), radiotherapy in 3 (2%), antibiotics in 1 (1%) and systemic treatment in 128 (62%). Patients receiving a local approach, mainly surgical resection, experienced significantly improved progression-free survival (p = 0.003) versus those receiving a systemic treatment. There were no other significant differences among treatment modalities. The survival data confirm the indolent nature of the disease. Local therapy (surgery or radiotherapy) results in long-term disease-free survival for patients with localized disease. Systemic treatment, including alkylating-containing regimens, can be reserved to patients in relapse after incomplete surgical excision or for patients with advanced disease. Copyright © 2015 John Wiley & Sons, Ltd.

611TiP - Adjuvant Regorafenib (Reg) in Stage Iv Colorectal Cancer (Crc) After Curative Treatment of Liver Metastases: a Phase III Randomized, Placebo (Pbo)-Controlled Trial (Coast)

ABSTRACT Background: Complete resection and pre-/peri-/post-operative chemotherapy are the standard of care for patients with stage IV CRC and resectable metastases confined to the liver. Despite this treatment approach, long-term disease-free survival of patients with resected liver metastases is poor. The oral multikinase inhibitor REG significantly improved overall survival (OS) in patients with metastatic CRC that had progressed after all standard therapies (CORRECT study; HR 0.77; one-sided p = 0.0052; Lancet 2013). COAST will evaluate the efficacy and safety of REG vs PBO in patients with CRC after curative resection of liver metastases and completion of planned chemotherapy. Trial design: This double-blind, PBO-controlled, multicenter, phase III study (ClinicalTrials.gov identifier NCT01939223) will randomize patients (n = 750 planned) 1 : 1 to treatment with oral REG 160 mg or PBO once daily in 4-week cycles of 3 weeks on, 1 week off treatment. Doses of study drug may be delayed or reduced to manage clinically significant drug-related toxicities. Treatment will continue for 2 years or until recurrence of CRC, death, intolerable toxicity, or patient/investigator decision to stop. Inclusion criteria include age ≥18 years, stage IV CRC, pathology-proven complete resection of liver metastases, and ECOG performance status 0 or 1. Patients must have completed adjuvant, neoadjuvant, or perioperative chemotherapy. Randomization will be stratified by number of preoperative liver metastases ( 6 months), and time since last surgery for any CRC lesion (≤6 months vs >6 months). The primary endpoint is disease-free survival (DFS), assessed by the investigator using computed tomography or magnetic resonance imaging. Secondary endpoints include OS, health-related quality of life, and biomarker evaluations. Analyses will be performed when approximately 317 DFS events are observed, at which time the study will have 90% power to detect a 50% improvement in median DFS. The first patient entered the study in February 2014 and the estimated primary completion date is March 2018.Previously presented at WCGI 2014 abstract number: 749 (to be presented at WCGI 2014 as a poster presentation). Disclosure: A. Grothey: has the following financial disclosures: Advisory board: Bayer Corporate sponsored research: Bayer, Genentech, Eisai, Pfizer, ImClone, Daiichi; T. Yoshino: has the following financial disclosures: Corporate sponsored research: Daiichi Sankyo, Taiho, Bayer, Eli Lilly, Pfizer, Chugai, and Yakult; J. Zalcberg: has the following financial disclosures: Advisory board: Bayer, Roche Research and travel support, expert testimony: Bayer, Roche; D.J. Sargent: has the following financial disclosures: Advisory board: Bayer, Roche Corporate sponsored research: Roche, Celgene; M. Choti: has the following financial disclosures: Research consultant: Bristol Myers Squibb; M. Rutstein: has the following financial disclosures: Employment: Bayer HealthCare; L. Cupit: has the following financial disclosures: Employment: Bayer; I. Kuss: has the following financial disclosures: Employment: Bayer Pharma AG; E. Van Cutsem: has the following financial disclosures: Corporate sponsored research: Bayer . All other authors have declared no conflicts of interest.

Perspectives on using des-γ-carboxyprothrombin (DCP) as a serum biomarker: facilitating early detection of hepatocellular carcinoma in China.

Hepatocellular carcinoma (HCC) is the second leading cause of cancer-related deaths in China. Evidence has shown that surgical resection and liver transplantation may offer the best potential for treating HCC but are only available to patients whose tumors are detected early. Over the past few decades, although a series of measures for standardized management of HCC has been implemented in China, most patients with HCC in China still present with advanced-stage disease, thus strategies to screen for and diagnose HCC at an earlier stage are urgently needed in China when curable interventions can be offered to achieve long-term disease-free survival for patients with HCC. In China, the serum biomarker α-fetoprotein (AFP) is considered a useful and feasible tool for HCC screening and early diagnosis. However, the sensitivity and specificity of AFP vary widely, and the total AFP is not always specific, especially when HCC is in its early stages. Globally, numerous studies have reported that the combination of des-γ-carboxyprothrombin (DCP) and AFP may have a higher sensitivity than AFP alone, and suggested DCP could also be used to assess the progression of HCC. However, DCP has not been approved in China until now. Differ from most of Western countries, people with HBV infection are the largest population at risk of developing HCC China. In order to assess the screening and diagnostic value of DCP in Chinese patients with HCC, a first large-scale, multi-center study was launched in China in 2012, results showed that DCP can help to detect HCC in its early stages and facilitate definitive treatment. The clinical use of DCP is urgently needed to facilitate early detection of HCC in China.

Synergistic induction of cancer cell death and reduction of clonogenic resistance by cisplatin and FK228

Human urinary bladder cancer is the fifth most common cancer in the United States, and the long-term disease-free survival in patients is still suboptimal with current chemotherapeutic regimens. Development of effective chemotherapeutic regimens is crucial to decrease the morbidity and mortality of this cancer. The goal of this study was to investigate the effectiveness of FK228 in increasing cisplatin’s ability to induce bladder cancer cell death and reduce drug resistance. Our study revealed that FK228 combined with cisplatin synergistically induced cell death and reduced clonogenic survival of human urinary bladder cancer cells. The Erk-Nox pathway played an important role in mediating signals highly increased by this combined treatment to induce significantly-elevated levels of reactive oxygen species, leading to substantially-induced caspase activation and synergistically-increased death in cancer cells. Cisplatin was able to enhance the ability of FK228 to significantly reduce glutathione, indicating a novel activity of combined FK228 and cisplatin in reducing drug resistance. The ability of combined FK228 and cisplatin to synergistically induce cell death and reduce clonogenic survival was also applicable to colon cancer cells. Hence, combined use of FK228 with cisplatin should be considered in development of therapeutic strategies to control urinary bladder cancer and other cancer development and recurrence.

Guidelines on the diagnosis, investigation and management of chronic lymphocytic leukaemia

Royal Bournemouth Hospital, Bournemouth, 2 Royal Marsden Hospital, London, 3 Southampton General Hospital, Southampton, Cardiff and Vale NHS Trust, Cardiff Cambridge University Hospitals NHS Foundation Trust, Cambridge UK; St. James's Institute of Oncology, Leeds, Christie Hospital NHS Trust, Manchester Royal Marsden Hospital London; Heart of England NHS Foundataion Trust, Birmingham; 10 Royal Liverpool University Hospital, Liverpool; Churchill Hospital, Headington, Oxford, Norfolk and Norwich University Hospital, Norwich

PO-14 Preoperative D-dimer levels predict long-term disease-free survival in patients with curatively intended resection for stage III colorectal cancer: a prospective cohort study

PO-14 Preoperative D-dimer levels predict long-term disease-free survival in patients with curatively intended resection for stage III colorectal cancer: a prospective cohort study

Long-Term Disease-Free Survival of Patients with AML Relapse After T-Cell-Depleted Allogeneic Stem Cell Transplantation by Re-Induction Therapy and Subsequent Interferon-Boosted Donor Lymphocyte Infusion

Abstract 3064Relapse of AML after allogeneic stem cell transplantation (alloSCT) has a very poor prognosis. Salvage re-induction chemotherapy leads to clinical remissions in a substantial number of patients, but these remissions tend to be of short duration. In contrast, donor lymphocyte infusions (DLI) have the potential to effect long-lasting remissions, but the interval of several weeks to months that is required to develop a DLI-induced anti-leukemia response may prevent efficient control of a highly proliferative leukemia. In addition, a high tumor burden may suppress the immune response. In contrast, the combination of efficient cytoreduction by chemotherapy with DLI administered in rapid succession under circumstances favoring the development of an early and profound immune response might have the potential to eradicate otherwise resistant leukemia cells. We therefore adopted an institutional therapeutic strategy for relapsed myeloid leukemia post-allogeneic SCT based on administration of DLI at the anticipated end of the neutropenic phase after salvage re-induction chemotherapy. At this time point, the high prevalence of a pro-inflammatory milieu should favor the induction of the immune response, and an expected state of lymphopenia should promote the expansion of infused T cells by homeostatic proliferation. If 3 weeks after DLI no graft versus host disease (GvHD) was observed, the potential anti-leukemia immune response was further amplified by treatment with interferon- α (IFN- α) until GvHD occurred.Between January 2000 and December 2009 44 patients with relapsed myeloid malignancy after alloSCT were treated at our hospital. Pre-transplant diagnoses were AML n=40, CMML n=1 and MDS n=3. Median time from SCT to relapse was 187 days. Median follow-up after relapse was 3.1 years. 5 patients had a smouldering relapse (<10% bone marrow blasts) and 39 patients had an overt relapse.Of 39 patients with overt relapse, 7 patients (18%) did not receive re-induction therapy due to poor performance status (n=5) or patient choice (n=2). 32 patients received remission-induction therapy consisting of gemtuzumab ozogamycin (n=9), cytosine arabinoside-containing chemotherapy (n=17), or both (n=6). Following this treatment, 7 of 32 patients had rapidly progressive disease during induction therapy (n=6) or died due to toxicity (n=1) and did not receive DLI.The remaining 25 patients received DLI at a dose of 5.0×10 ^6 CD3+ cells/kg for related and 2.5×10 ^6 CD3+ cells/kg for unrelated donors 3 weeks after the start of remission-induction therapy. In 16 of these patients DLI was boosted with IFN- α 3.0×10 ^6 IE once daily. This strategy resulted in acute GvHD in 17 of 25 patients (n=8 grade 1–2, n=9 grade 3–4). At 6 weeks after DLI, 16 patients had reached CR, 5 patients had failed to reach CR (2 with GvHD) and 4 suffered treatment-related mortality (3 with GvHD). Of the 16 patients in CR, 4 had no signs of GvHD and developed a second relapse during the follow-up period. Only 3 of 12 patients in CR with signs of acute GvHD at 6 weeks after DLI developed a second relapse. In total, 9 of 17 patients (53%) with acute GvHD after DLI had long term survival versus none without acute GvHD. During follow-up, 8 patients developed chronic GvHD (n=4 limited, n=4 extensive).Finally, 5 patients with an early detected smouldering relapse received DLI, which was boosted with IFN- α in 2 patients, without salvage re-induction therapy. All 5 patients developed GvHD (n=2 grade 1–2, n=3 grade 3–4) and 3 patients achieved a CR of whom 1 patient died from GvHD.Our results indicate that treatment of relapsed AML after alloSCT with salvage re-induction therapy followed by DLI at the end of the neutropenic phase during minimal residual disease, with additional boosting of the immune response with IFN- α, can result in long-term disease-free survival. Disclosures:Off Label Use: Interferon: DLI-boosting.

Treatment of therapy-related myeloid neoplasms with high-dose cytarabine/mitoxantrone followed by hematopoietic stem cell transplant

Few clinical protocols have focused on patients with therapy-related myeloid neoplasms (t-MN). Therefore, we enrolled 32 patients with previously untreated t-MN on a clinical trial testing the effectiveness of a unified induction regimen of high-dose cytarabine and mitoxantrone. The complete remission (CR) rate was 66% (95% CI 47–81%) and the partial remission (PR) rate was 16% (95% CI 5–33%), for an overall response rate of 82%. Day 30 treatment mortality was 9% (3/32), and the most serious induction toxicity was cardiac dysfunction. Among the patients with CR, 13 (62%) received consolidation therapy using an allogeneic hematopoietic cell transplant (HCT), four (21%) received an autologous HCT, and three (16%) received further chemotherapy. We observed long-term disease-free survival in patients who received all three types of consolidation therapy. The remission induction of high-dose cytarabine and mitoxantrone for t-MN is a well-tolerated efficacious combination, which allows aggressive consolidation and long-term disease-free survival.

Long-term disease-free survival of patients with primary cardiac lymphoma treated with systemic chemotherapy and radiotherapy

Primary cardiac lymphoma (PCL) is a rare disease entity with only a few reported cases in Korea. In this paper, we report a case of PCL in a 59-year-old man presenting with chest pain. Diffuse large B-cell lymphoma was diagnosed through a cardiac catheterization-assisted percutaneous endomyocardial biopsy, and there was no evidence of extracardiac involvement of the lymphoma.The patient had a complete clinical response after systemic chemotherapy with a rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone (R-CHOP) regimen and additional post-chemotherapeutic radiation therapy. The patient experienced a long-term disease-free survival of over 4 years. However, he received coronary artery bypass graft surgery due to an acute myocardial infarction that occurred 3 years after the completion of the radiation therapy. Although the addition of radiation therapy to the treatment is thought to decrease the risk of relapse in patients with PCL, a careful and thorough consideration of the potential complications of radiation therapy, particularly with respect to cardiac complications, should be considered.

DAPK2 and PIM1 Are Myeloma-Associated Antigens That Elicit Coordinated B and T Cell Immunity After Syngeneic HSCT.

Abstract 2445Poster Board II-422Syngeneic hematopoietic stem cell transplantation (HSCT) can produce long-term disease-free survival in patients with hematologic malignancies, including multiple myeloma (MM). Because donor and host are genotypically identical in this setting, allo-immunity is absent and curative responses may result from donor-derived immune responses against tumor-associated antigens. We recently described potent, antigen-specific humoral immune responses arising after myeloablative syngeneic HSCT in an HLA-A2 positive patient with MM who achieved sustained molecular remission lasting over 3 years. Two target antigens of this response, DAPK2 and PIM1, were identified by serologic screening of a recombinant protein array consisting of the expressed products of 8000 open reading frames. Both proteins elicited antigen-specific antibody responses after HSCT that peaked around 3 months post-HSCT and gradually waned thereafter; prior to HSCT these antibody responses were low to undetectable. DAPK2 is a serine-threonine kinase involved in pro-apoptotic signaling, while PIM1 is an oncogene with known associations to B cell malignancies. By Western blot, both proteins demonstrate enriched protein expression in primary myeloma bone marrow compared to normal hematopoietic tissues.In the current studies, we determined whether antibody responses to DAPK2 and PIM1 were coordinated with T cell immunity against the same proteins following HSCT in this patient. As this patient was HLA-A2 positive, we used established MHC class I peptide binding algorithms to predict candidate peptide epitopes derived from PIM1 and DAPK2. We identified 23 9-mer peptides derived from DAPK2 and PIM1, all with high binding rank scores. All peptides were confirmed to bind to HLA-A2 using T2 binding assays. Ex vivo stimulation of fresh patient PBMC obtained ∼2.5 years post-HSCT with candidate peptides revealed 2 peptides, DAPK2156–164 (MLLDKNIPI) and PIM1191-199 (ALLKDTVYT) that elicited strong interferon-γ (IFNγ) secretion consistent with recall responses to these antigens. By IFNγ ELISpot, DAPK2- and PIM1-specific T cells recognized HLA-A2-positive myeloma cell lines MC/CAR and IM9, but not A2-negative OPM1 and NCI4929 lines. T cell recognition was mediated by CD8+ effector cells and was effectively blocked by the MHC class I blocking antibody w6/32. These studies indicate that the predicted peptides are naturally processed and presented by myeloma cells. When tested against CD138+ sorted primary MM marrow cells by IFNγ ELISpot, DAPK2-specific T cells and PIM1-specific T cells recognized 3 of 5 and 1 of 5 A2-positive primary tumor samples, respectively. Neither A2-negative CD138+ tumor samples nor A2-positive normal marrow elicited reactivity from antigen-specific T cells. These data demonstrate that PIM1 and DAPK2 are MM-associated antigens that commonly generate processed epitopes on malignant MM cells. Both proteins elicited coordinated B and T cell immunity in a MM patient who achieved sustained molecular remission after syngeneic HSCT. These data suggest that donor-derived MM-specific adaptive immunity contributes to disease regression following syngeneic HSCT for MM. As PIM1 and DAPK2 represent immunogenic tumor-associated antigens and not allo-antigens, these may be attractive targets for immunotherapy directed at MM outside of the context of allogeneic HSCT. Disclosures:No relevant conflicts of interest to declare.

Role of hematopoietic stem cell transplant in the management of follicular lymphoma.

Despite decades of published data regarding the application of autologous and allogeneic stem cell transplant in patients with follicular lymphoma, there remain no uniform indications for its use in this disease. Autologous transplant has been shown to lead to longer progression-free survival times in randomized trials when compared with postremission interferon-based chemoimmunotherapy. However, the development of rituximab and its use in frontline, salvage, and maintenance therapy complicates the decision to pursue autologous transplant, a modality developed prior to the advent of anti-CD20 monoclonal antibodies. Allogeneic transplant offers the advantages of lymphoma-free grafts and the immunologic graft-versus-lymphoma effect. These factors may confer the possibility of long-term remission, though historically they have been accompanied by high rates of upfront morbidity and mortality, especially in heavily pretreated patients with a poor performance status or chemotherapy-refractory disease. Advances in patient selection, human leukocyte antigen (HLA) matching, conditioning regimens, and supportive care have reduced transplant-related mortality and the incidence of graft-versus-host disease. Recently published data focus on the incorporation of rituximab and radioimmunoconjugates prior to, during, and following autologous transplant. Furthermore, reduced-intensity allogeneic stem cell transplantation has increasingly been used for relapsed follicular lymphoma patients with comorbidities or advanced age. Several recent reports suggest that reduced-intensity regimens may provide a high likelihood of long-term disease-free survival for patients up to 70 years of age with a good performance status, chemotherapy-sensitive disease, and HLA-matched sibling donors. Such patients with relapsed disease should be referred to a transplant center that can enroll them in one of the forthcoming clinical trials that aim to confirm these outcomes.

The Perioperative Period is an Underutilized Window of Therapeutic Opportunity in Patients With Colorectal Cancer

In this review, we address the underlying mechanisms by which surgery augments metastases outgrowth and how these insights can be used to develop perioperative therapeutic strategies for prevention of tumor recurrence. Surgical removal of the primary tumor provides the best chance of long-term disease-free survival for patients with colorectal cancer (CRC). Unfortunately, a significant part of CRC patients will develop metastases, even after successful resection of the primary tumor. Paradoxically, it is now becoming clear that surgery itself contributes to development of both local recurrences and distant metastases. Data for this review were identified by searches of PubMed and references from relevant articles using the search terms "surgery," "CRC," and "metastases." Surgical trauma and concomitant wound-healing processes induce local and systemic changes, including impairment of tissue integrity and production of inflammatory mediators and angiogenic factors. This can lead to immune suppression and enhanced growth or adhesion of tumor cells, all of which increase the chance of exfoliated tumor cells developing into secondary malignancies. Because surgery remains the appropriate and necessary means of treatment for most CRC patients, new adjuvant therapeutic strategies that prevent tumor recurrence after surgery need to be explored since the perioperative therapeutic window of opportunity offers promising means of improving patient outcome but is unfortunately underutilized.

Autologous stem cell transplantation in the treatment of Hodgkin's disease

High-dose chemotherapy with autologous stem cell transplantation (ASCT) has shown to produce long-term disease-free survival in patients with chemotherapy-sensitive Hodgkin disease. The aim of the study was to evaluate efficacy of ASCT in the treatment of Hodgkin's disease. Between May 1997 and September 2008, 34 patients with Hodgkin's disease in median age of 25 (range 16-60) years, underwent ASCT. Autologous SCT were performed as consolidation therapy in one poor-risk patients with complete response (CR) and in 10 patients in partial remission (PR) after induction chemotherapy (32.5%), for chemosensitive relapse (CSR 1 and CSR 2) in 47% patients and in 20.5% patients with chemoresistant disease (CRD). All except one patient were in stage III/IV, extranodal site of disease had 24 patients and bulky disease had 10 patients. All the patients received a uniform preparatory regimen (BEAM). An overall response was achieved in 30 of 32 evaluated patients, with 62.5% in CR and 31.25% in PR. After applying radiotherapy, two patients with PR after ASCT reached CR. Median follow-up was 15.5 months (range 3-133 months). The probability of overall survival (OS) and progression-free survival (PFS) at a 3-year period for all patients was 51.9 % and 48.9%, respectively. For 22 patients in CR after ASCT, a 3-year DFS was 66.5%. Estimates of 2.5-year survival were 14.3%, 61.9% and 100% for CRD, CSR and for patients with CR/PR, respectively (p < 0.01). However, when patients undergoing consolidation were analyzed separately from those in CSR, no significant difference in OS and PFS was observed according to the disease status at ASCT. In univariate analysis for OS, PFS i DFS, extranodal site of disease and disease bulk had no predictive value. Twelve patients died. The main cause of death was Hodgkin's disease. Transplant-related mortality was 3.1%. One patient with CRD developed secondary acute myeloid leukemia and died 28 months after the transplantation. Autologous SCT is efficient as consolidation therapy in high-risk patients and in chemosensitive relapse, but it has no benefit in patients with chemoresistant disease.

Novel Myeloma-Associated Antigens Revealed in the Context of Successful Syngeneic Hematopoietic Stem Cell Transplantation

Syngeneic hematopoietic stem cell transplantation (HSCT) can produce long-term disease-free survival in patients with hematologic malignancies including multiple myeloma (MM). Since donor and host are genotypically identical in this setting, allo-immunity is absent and curative responses may result from donor-derived immune responses against tumor-associated antigens. Our previous studies suggest that B cell responses play a role in successful graft-versus-tumor responses, and their identification may accelerate the discovery of targets of coordinated T cell immunity. To identify graft-versus- myeloma target antigens, we performed a detailed analysis of the humoral immune response in an HLA-A2+ patient with MM who underwent myeloablative syngeneic HSCT and achieved molecular remission now lasting more than 2 years. We probed high-density protein microarrays consisting of ~8000 expressed open reading frames with plasma obtained before and at 3, 6, 12, and 16 months after HSCT. Bioinformatic analysis identified 6 unique candidate antigens that elicited significantly increased post- HSCT antibody reactivity compared to pre-HSCT plasma, plasma from the patient's stem cell donor, and plasma from 2 age-, sex-, and parity-matched normal controls. Two patterns of antibody reactivity were observed: early responses directed at DAPK2, PIM1, and PRKCB1 peaking at 3 months post-HSCT; and late responses to C1orf116, PDGFRB, and RELA proteins arising at 1 year post-HSCT. By antigen-specific ELISA, positive antibody responses against 4 antigens (DAPK2, PDGFRB, PIM1, PRKCB1) were detected in patients with untreated MM (1/10, 1/10, 1/10, and 2/10, respectively), MM patients with durable responses after autologous transplant (1/10, 1/10, 1/10, and 2/10) and patients with monoclonal gammopathy of unknown significance (3/10, 1/10, 0/10, and 1/10, respectively), but not in 10 normal donors. Moreover, 4 of 6 patients achieving durable remission after allo-HSCT each demonstrated antibody responses against 1 to 3 of the 4 candidate antigens. These antibody responses developed in temporal association with clinical responses. Gene expression analysis using Affymetrix U133Plus 2.0 microarrays revealed high expression of 3 of 6 antigens (PIM1, PRKCB1, RELA) in CD138+-selected MM bone marrow samples (n=152). Using quantitative real-time PCR with gene-specific primers and probes, all 6 antigens had detectable expression in MM bone marrow (>95% tumor). Notably, DAPK2 and PIM1 show higher expression in MM bone marrow compared to normal PBMC (p=−0.008, and 0.056, respectively; exact Wilcoxon rank sum test). To determine whether patients develop specific T cell responses against these antigens in vivo, fresh patient PBMC were stimulated ex vivo with a series of peptides derived from PIM1 and DAPK2 that were consensually predicted to be strong HLA-A2 binders by the IEDB class I, NetMHC, and MHC-I peptide energy binding prediction servers. One peptide, DAPK2156–164 (MLLDKNIPI) elicited strong interferon-gamma secretion after two stimulations consistent with a recall response to this antigen. Ongoing work will further characterize T cell responses against DAPK2 in other serologically reactive post-HSCT MM patients, and will assess T cell responses against PIM1. We conclude that antigens identified by serologic screening after syngeneic HSCT are common myeloma-associated targets in vivo and can elicit coordinated T cell responses. The outlined studies will elucidate the potential of these promising antigens as novel immunogens for targeted immunotherapy.

Non‐myeloablative allogeneic haematopoietic cell transplantation for relapsed diffuse large B‐cell lymphoma: a multicentre experience

Patients with relapsed diffuse large B-cell lymphoma (DLBCL) who have failed or are ineligible for autologous haematopoietic cell transplantation (HCT) have a poor prognosis. We examined the outcomes of non-myeloablative allogeneic HCT in this setting. Thirty-one patients with DLBCL and one patient with Burkitt lymphoma received allogeneic HCT following 2 Gy total body irradiation with or without fludarabine. Median age was 52 years. Twenty-four patients (75%) had undergone prior autologous HCT. Disease status at HCT was complete response (14/32, 44%), partial response (9/32, 28%), or refractory (9/32, 28%). Cumulative incidences of acute graft-versus-host disease (GVHD) grades II-IV, grades III-IV, and chronic GVHD were 53%, 19%, and 47% respectively. With a median follow-up of 45 months, 3-year estimated overall (OS) and progression-free survival (PFS) was 45% and 35% respectively. Three-year cumulative incidences of relapse and non-relapse mortality were 41% and 25% respectively. In multivariate models, chemosensitive disease and receipt of >or=4 lines of treatment before HCT were associated with better OS. Patients with chemosensitive disease had 3-year OS and PFS of 56% and 43% respectively. Non-myeloablative allogeneic HCT can produce long-term disease-free survival in patients with chemosensitive relapsed DLBCL who have failed or are ineligible for autologous HCT.