Cyclophosphamide, Adriamycin, Vincristine, Prednisone Research Articles

PP2A Inhibitor LB100 Enhances the Sensitivity of NPM-ALK+ALCL to Crizotinib and Reverses the Resistance of ALCL to Crizotinib

Anaplastic large cell lymphoma (ALCL) is a rare and aggressive non-Hodgkin's lymphoma commonly discovered in children and adolescents. Despite the high remission rates in ALCL achieved by conventional chemotherapy based on conventional CHOP (cyclophosphamide, adriamycin, vincristine, prednisone), relapse and drug resistance occur in more than 40% of patients. The clinical use of the ALK inhibitor crizotinib in most relapsed refractory NPM-ALK+ ALCL in recent years has demonstrated effective treatment, but crizotinib resistance and intolerance due to the corresponding side effects still occur in 30% of cases. This urgently requires us to find new treatments to enhance the sensitivity of crizotinib as well as to overcome the resistance of crizotinib in ALCL. PP2A has been considered a tumor suppressor gene in the past, but with better understanding, it is two-sided, playing different roles in various types of tumors. In addition, it has been found that PP2A is closely related to drug sensitivity and resistance. LB100, a novel water-soluble PP2A inhibitor, is gaining attention because of its significantly higher safety profile than traditional PP2A inhibitors. It has potent effects on tumor inhibition and could increase tumor sensitivity to radiotherapy. In this study, we first established a crizotinib-resistant NPM-ALK+ ALCL cell model by exposing a highly sensitive NPM-ALK-positive ALCL cell line to continuously increasing doses of crizotinib until resistance developed. The PP2A inhibitor LB100 was then applied to normal and resistant cell lines to explore changes in their biological activity. We found that LB100 significantly inhibited the viability of normal and drug-resistant ALCL cell lines and was more sensitive in drug-resistant lines. In addition, a combination of LB100 and crizotinib was applied in normal and resistant cell lines to analyze the effect of LB100 on sensitization to crizotinib and reversal of drug resistance. LB100 significantly enhanced the killing effect of crizotinib in normal tumor cell lines and partially reverses crizotinib resistance in resistant lines. Western blot and immunofluorescence showed that LB100 leads to increased cellular G1 phase block by increasing cellular DNA damage, which in turn enhances the sensitivity of crizotinib. The above experiments showed that LB100, as an effective inhibitor of PP2A, can significantly increase the effect of crizotinib against normal NPM-ALK+ ALCL, inhibit the growth of crizotinib-resistant strains, and partially restore the sensitivity of crizotinib, which is expected to be a new therapeutic tool for ALCL. In addition, simultaneous targeting of PP2A and ALK has a very high potential in overcoming ALK inhibitor resistance in ALCL and could be a new therapeutic strategy to overcome drug resistance.

Outcomes in Advanced-Stage Plasmablastic Lymphoma

Introduction: Plasmablastic lymphoma (PBL) is a rare subtype of non-Hodgkin B-cell lymphoma (NHL), often characterized by immunoblastic morphology and plasmacytic immunophenotype. PBL was initially described in HIV-positive patients (pts) and is now often diagnosed in post-transplant and HIV-negative pts with other immunodeficiency. Pts with limited stage disease treated with induction chemotherapy and consolidative radiotherapy have a good prognosis; however, pts with advanced stage have poor outcome. Previously studied treatment regimens vary and include CHOP (cyclophosphamide, Adriamycin, vincristine, prednisone), HyperCVAD (cyclophosphamide, vincristine, Adriamycin, dexamethasone alternating with methotrexate and cytarabine), and DA-EPOCH (etoposide, vincristine, cyclophosphamide, Adriamycin, prednisone) with or without radiation and autologous stem cell transplant, with no current standard therapy, largely due to the rarity of PBL.Methods: We conducted a retrospective analysis of pts diagnosed with PBL between April 2003 and August 2020 to describe outcomes for pts treated at our center over the past 2 decades. We hope to use this to improve outcomes with novel therapies in the future. We evaluated the baseline demographics, stage, therapy, response rate, progression-free survival (PFS) and overall survival (OS). We used descriptive statistics including mean, standard deviation, median, and range for continuous variables, and frequency counts and percentages for categorical variables. Best response and its 95% exact confidence interval were calculated. Kaplan-Meier method was used to estimate the time-to-event endpoints including progression free survival, and overall survival.Results: 39 pts with PBL were identified, with a median age of 51 years (range 27-91). 16 were HIV+, and 5 were on immunosuppression for autoimmune disease (2), infectious hepatitis (2), or liver transplant (1); the other 18 had no apparent immunosuppression other than advanced age (defined as 70 years and older) in 13. Among those with HIV, 14 were on antiretroviral therapy at time of diagnosis of PBL. The median CD4 count was 140 (range 15-391) and 5 patients had an active viral load. 24 pts were EBV/EBER positive. 6 pts had stage III disease and 33 had stage IV disease. The primary sites of disease included head and neck (13), lymph node (7), gastrointestinal tract (6), other soft tissue (3), abdomen (3), breast (2), gynecologic (2), skin (2), and bone (1). The median LDH was 629 IU/L (313-618). A serum protein electrophoresis was checked in 21 pts and the median was 1.4 g/dL (range 0.2-2.6 g/dL, normal = 0). A beta 2 microglobulin was checked in 28 pts and the median was 3.95 (range 2.55-10.4, normal =0.8 to 2.3 mg/L). The median Ki-67 proliferation index was 85%, and the PBL cells were invariably CD20 negative. 12 cases showed MYC overexpression; 2 had MYC rearrangement by FISH.32 pts received systemic therapy and were evaluable with 2 median lines of treatment (range 1-6). First line therapy included Hyper-CVAD (n=7), CHOP (n=3), EPOCH (n=19), and other (n=3). The antimyeloma therapy, bortezomib, a proteasome inhibitor, was added to EPOCH for 4 patients or used with dexamethasone in one pt, while the CD38 antibody daratumumab was added to hypercytoxan for the first cycle of an elderly pt with poor performance status (PS). He responded well with improvement in his PS, and subsequently completed 5 cycles of DA-EPOCH and remains in CR. After first line therapy, 59% pts achieved complete response, 13% partial response, and 9% stable disease. 20 pts received intrathecal chemotherapy, 9 pts received radiation, and 8 pts underwent autologous stem cell transplantation (7 as consolidation and 1 at relapse). Please see figure for PFS and OS based on different treatment modalities. Median PFS and OS were 21 and 35.2 months, respectively. Median follow up time was 25.85 months.Conclusions: The majority of our pts (87%) with advanced stage PBL were immunocompromised with HIV (16), requiring immunosuppression (5), or elderly (13). Despite a 56% CR rate with induction, 69% of patients relapsed. Median PFS was less than 2 years and OS was less than 3 years. The dismal outcomes of pts with PBL suggests that this rare and aggressive subtype of NHL with plasmacytic differentiation requires further evaluation with therapies against plasma cell directed antigens such as CD38, BCMA or SLAMF7.*S Lee & C Dillard contributed equally. [Display omitted] DisclosuresSteiner: BMS: Research Funding; Seattle Genetics: Research Funding; Rafael Pharmaceuticals: Research Funding. Loghavi: Abbvie: Current equity holder in publicly-traded company; Curio Sciences: Honoraria; Gerson Lehrman Group: Consultancy; Guidepoint: Consultancy; Peerview: Honoraria; Qualworld: Consultancy. Ahmed: Seagen: Research Funding; Tessa Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: Research Funding; Xencor: Research Funding. Patel: Pfizer: Consultancy; Janssen: Consultancy, Research Funding; BMS Celgene: Consultancy, Research Funding; Oncopeptides: Consultancy.

Honoring Emil J. Freireich: A Visionary Medical Cancer Researcher-March 21, 1927-February 1, 2021.

![][1] Dr. Emil Freireich at MD Anderson in 2018, in conversation with Lauren Gobert, a leukemia physician assistant who had childhood acute lymphoblastic leukemia cured by combination therapy developed as a result of Dr. Freireich's research. Emil J, Freireich, a founding father of

Hematopoietic Cell Transplantation and Adoptive Cell Therapy in Peripheral T Cell Lymphoma.

Peripheral T cell lymphomas (PTCLs) are a heterogeneous group of diseases and represent approximately 10-15% of all non-Hodgkin lymphomas. Multiagent chemotherapy with a CHOP (cyclophosphamide, adriamycin, vincristine, prednisone)-like regimen is the current standard of care in the frontline setting, but outcomes for PTCL patients generally remain poor. Strategies used to improve survival and reduce the risk of relapse in PTCL patients include autologous hematopoietic cell transplant (autoHCT) and allogeneic HCT (alloHCT). Due to the relative rarity of these diseases, the evidence supporting the use of autoHCT and alloHCT is based on retrospective and single-arm prospective studies. Novel targeted therapies are now being incorporated into the treatment of PTCL, and they may play important roles in improving upon current standards of care. Herein, we summarize the evidence supporting HCT for the treatment of the most common PTCL histologic subtypes and highlight novel treatment strategies aimed at improving outcomes for these patients, including cutting-edge approaches using chimeric antigen receptor T cells (CAR-T). Given recent improvements in OS and PFS in CD30+ PTCL using the drug-antibody conjugate brentuximab vedotin (BV), new questions arise regarding the impact of BV on consolidative autoHCT, and its role as a maintenance therapy. Multiple histone deacetylase inhibitors (HDACis) have been approved for the treatment of relapsed/refractory PTCL, and these agents are being incorporated into HCT approaches, both in the frontline and maintenance settings. Early data incorporating these agents into novel conditioning regimens have been reported, and emerging evidence from recent trials suggests that CART cell therapies may prove effective in relapsed/refractory PTCL. The recommended treatment strategy in non-ALK+ PTCL remains induction with a CHOP-like regimen followed by consolidative autoHCT in first remission. In the relapsed/refractory setting, salvage chemotherapy followed by HCT (autoHCT or alloHCT depending on histologic subtype and HCT history) offers the only potential for cure or long-term remission. Ample room for improvement remains in the treatment of patients with PTCL, and novel treatment strategies incorporating targeted agents and CAR-T therapy may help to address the unmet needs of this patient population.

Clinical analysis of 14 cases of rare non-Hodgkin lymphoma in children

Objective To analyze the clinical characteristics and prognosis of 4 rare types of non-Hodgkin lymphoma(NHL) in children, and to discuss the progress in treatment. Methods Clinical data of 14 patients with rare types of NHL at Shanghai Children's Medical Center, Shanghai Jiaotong University School of Medicine between January 2004 and December 2014 were retrospectively analyzed, and their clinical features, treatment and prognosis were discussed. Results Fourteen cases were reported including 6 subcutaneous panniculitis-like T-cell lymphoma(SPTCL), 3 hydroa vacciniforme-like cutaneous lymphoma(HVLL), 2 pediatric follicular lymphoma(PFL) and 3 extranodal NK/T-cell lymphoma, and nasal type(ENKTL). Ten patients (71.4%) primarily presented with skin lesions and underwent a long course of illness before they were finally diagnosed (the median was 10 months), 71.4%(10/14 cases) of them associated with fever and 50.0%(7/14 cases) with liver and spleen enlargement, and no evidence of central nervous system (CNS) and bone marrow (BM) involvement was observed, while 28.6% patients (4/14 cases) had more than two lines' abnormalities in peripheral blood examination.Since there were no standard treatment guidelines, most patients received CHOP (Cyclophosphamide+ Adriamycin+ Vincristine+ Prednisone) and/or mature B-cell NHL-like therapy, and 50.0%(7/14 cases) of them received interferon therapy in addition, while 1 patient received allogeneic hematopoietic stem cell transplantation after recurrence.The complete remission was achieved in 71.4%(10/14 cases) of all the patients.Two of them died, 3 lost follow-up, and 1 relapsed.The 3-year overall survi-val and event free survival rates were 0.84 and 0.57, respectively, after a median follow-up of 26 months (range 12-64 months). Conclusions Pediatric rare types of NHL show atypical clinical manifestation, low incidence of CNS/BM infiltration and long course.It is hard to make pathological diagnosis and differentiation.It is also inappropriate to apply the commonly used staging system to these rare types of NHL.No standard treatment has been found by now.SPTCL, HVLL and PFL have relatively good outcomes when treated with mature B-cell NHL-type therapy plus interferon therapy. Key words: Subcutaneous panniculitis-like T-cell lymphoma; Hydroa vacciniforme-like cutaneous lymphoma; Pediatric follicular lymphoma; Extranodal NK/T-cell lymphoma, nasal type; Child

Intensified chemo-immunotherapy with or without stem cell transplantation in newly diagnosed patients with peripheral T-cell lymphoma

Peripheral T-cell lymphomas (PTCLs) receiving conventional treatment have a poor clinical outcome. We conducted a phase II study to evaluate the feasibility and efficacy of chemo-immunotherapy in young (⩽60 years old, Clin A study) and elderly (>60 and < or =75 years old, Clin B study) patients with newly diagnosed PTCL. Clin A patients (n=61) received two courses of CHOP (cyclophosphamide, adriamycin, vincristine, prednisone)-21 with alemtuzumab (AL, 30 mg) followed by two courses of high-dose chemotherapy. On the basis of donor availability, patients in response received allogeneic (allo) or autologous (auto) stem cell transplantation (SCT). Clin B patients (n=25) received six courses of CHOP-21 and AL (10 mg). Clin A responding patients were 38 of 61 (62%) and received alloSCT (n=23) or autoSCT (n=14); one complete remission (CR) patient was not transplanted. At a median follow-up of 40 months, the 4-year overall survival (OS), progression-free survival (PFS) and disease-free survival (DFS) rates were 49, 44 and 65%, respectively. In Clin B study, the response rate was 72%. At a median follow-up of 48 months, the 4-year OS, PFS and DFS rates were 31, 26 and 44%, respectively. In conclusion, front-line alloSCT or autoSCT is effective in prolonging DFS in young patients; AL in elderly improved response with no survival benefit.

Poor Concordance among Nine Immunohistochemistry Classifiers of Cell-of-Origin for Diffuse Large B-Cell Lymphoma: Implications for Therapeutic Strategies

The opportunity to improve therapeutic choices on the basis of molecular features of the tumor cells is on the horizon in diffuse large B-cell lymphoma (DLBCL). Agents such as bortezomib exhibit selective activity against the poor outcome activated B-cell type (ABC) DLBCL. In order for targeted therapies to succeed in this disease, robust strategies that segregate patients into molecular groups with high reliability are needed. Although molecular studies are considered gold standard, several immunohistochemistry (IHC) algorithms have been published that claim to be able to stratify patients according to their cell-of-origin and to be relevant for patient outcome. However, results are poorly reproducible by independent groups. We investigated nine IHC algorithms for molecular classification in a dataset of DLBCL diagnostic biopsies, incorporating immunostaining for CD10, BCL6, BCL2, MUM1, FOXP1, GCET1, and LMO2. IHC profiles were assessed and agreed among three expert observers. A consensus matrix based on all scoring combinations and the number of subjects for each combination allowed us to assess reliability. The survival impact of individual markers and classifiers was evaluated using Kaplan-Meier curves and the log-rank test. The concordance in patient's classification across the different algorithms was low. Only 4% of the tumors have been classified as germinal center B-cell type (GCB) and 21% as ABC/non-GCB by all methods. None of the algorithms provided prognostic information in the R-CHOP (rituximab plus cyclophosphamide-adriamycin-vincristine-prednisone)-treated cohort. Further work is required to standardize IHC algorithms for DLBCL cell-of-origin classification for these to be considered reliable alternatives to molecular-based methods to be used for clinical decisions.

Plasmablastic Lymphoma: 28 Patient Single Institution Experience

IntroductionPlasmablastic lymphoma (PBL) is a rare, aggressive subtype of non-Hodgkin lymphoma. Published data are predominantly in the form of case reports and small retrospective case series. Initial reports of PBL were described in HIV positive patients (pts) with disease in the oral cavity, and in pts after organ transplantation on immunosuppressive therapy. The natural history may have evolved recently, with case reports of PBL in immunocompetent patients. There is no established standard of care therapy, though HIV positive pts benefit from initiation of anti-retroviral therapy, tend to respond to chemotherapy, have historically been associated with CD20 expression, and have increased overall survival rates compared with HIV negative pts with PBL. We now describe our experience in pts with PBL who received treatment at the University of Texas MD Anderson Cancer Center (UTMDACC). MethodsWe conducted a retrospective analysis of pts diagnosed with PBL between August 2000 and August 2012. We evaluated the baseline demographics, stage, therapy, response rate, progression-free survival (PFS) and overall survival (OS). Results28 pts (males n=23) with PBL were identified, with a median age of 51 (range 26-81). 10 patients had a diagnosis of HIV, and 15 were EBV positive. 7 pts had stage I disease, 2 had stage II, 1 had stage III and 18 had stage IV disease. The primary site of disease in the 7 pts with stage I disease was: 2 in the maxillary sinus, 2 in the nasal cavity, and 1 each in the colon, testicle, and lower jaw. 2 pts with stage II disease had primary sites in bowel and tonsils. 7/17 (41%) of HIV negative pts and 2/10 (20%) of HIV positive pts had stage I/II disease.The median LDH was 492 IU/L (313-618), median Ki-67 proliferation index was 85%, and all pathological samples were CD20 negative. Median follow up was 16 months (1-120). 27 pts received systemic therapy (1 pt elected hospice care). PBL was an initial cancer diagnosis for 25 pts who received the following as first line therapy: Hyper-CVAD (cyclophosphamide, vincristine, Adriamycin, dexamethasone alternating with methotrexate and cytarabine) (n=10), CHOP (cyclophosphamide, Adriamycin, vincristine, prednisone) (n=7), modified CVAD, 2 with EPOCH (etoposide, vincristine, cyclophosphamide, Adriamycin, prednisone) (n=4), bortezomib/dexamethasone (n=1), and the DeAngelis protocol (methotrexate, vincristine, procarbazine, with intrathecal methotrexate) (n=1) for CNS involvement. 2 pts had prior therapy for diagnosis of diffuse large B-cell lymphoma (DLBCL) and chronic lymphocytic leukemia (CLL) prior to diagnosis of PBL. The first pt with DLBCL was treated with Rituximab-hyper-CVAD 6 years earlier, and gemcitabine/oxaliplatin for the diagnosis of PBL. The second pt had CLL which underwent Richter's transformation to PBL, and was treated with hyper-CVXD (cyclophosphamide, vincristine, liposomal daunorubicin and dexamethasone). 1 pt underwent auto-stem cell transplant, while 8 pts received localized radiation (5 for consolidation and 3 for palliative therapy); 5/7 pts with stage I disease received consolidation with involved field radiation. After first line therapy, 20/27 patients (74%) achieved complete response, 5/27 (19%) partial response, and 2/27 (7%) stable disease. Median PFS and OS were 24.1 and 28.8 months, respectively. 5 year PFS and OS were 40% and 38%, respectively. Early stage disease (stage I or II) and younger age at diagnosis (less than 40 years old) were associated with improved survival. 5 year PFS for stage I/II pts was 90%. Conclusion41% of HIV negative pts had stage I/II disease. Early stage PBL pts who received combined chemotherapy followed by radiotherapy achieved a good PFS of 90% at 5 years. PBL consistently lacked CD20 expression irrespective of HIV status. PBL can be seen in both HIV+ and HIV– patients with overall 40% long term survival. [Display omitted] [Display omitted] Disclosures:Qazilbash:Otsuka Pharmaceuticals: Research Funding. Fanale:Seattle Genetics, Inc.: Advisory/scientific board membership and travel expenses Other, Consultancy, Honoraria, Research Funding. Orlowski:Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene Corporation: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Millenium Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Onyx Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Resverlogix: Research Funding; Genentech: Honoraria, Membership on an entity's Board of Directors or advisory committees; Array Biopharma: Honoraria, Membership on an entity's Board of Directors or advisory committees; Merck: Membership on an entity's Board of Directors or advisory committees.

Survival Signals and Targets for Therapy in Breast Implant–Associated ALK−Anaplastic Large Cell Lymphoma

Anaplastic lymphoma kinase (ALK)-negative, T-cell, anaplastic, non-Hodgkin lymphoma (T-ALCL) in patients with textured saline and silicone breast implants is a recently recognized clinical entity for which the etiology and optimal treatment remain unknown. Using three newly established model cell lines from patient biopsy specimens, designated T-cell breast lymphoma (TLBR)-1 to -3, we characterized the phenotype and function of these tumors to identify mechanisms of cell survival and potential therapeutic targets. Cytogenetics revealed chromosomal atypia with partial or complete trisomy and absence of the NPM-ALK (2;5) translocation. Phenotypic characterization showed strong positivity for CD30, CD71, T-cell CD2/5/7, and antigen presentation (HLA-DR, CD80, CD86) markers, and interleukin (IL)-2 (CD25, CD122) and IL-6 receptors. Studies of these model cell lines showed strong activation of STAT3 signaling, likely related to autocrine production of IL-6 and decreased SHP-1. STAT3 inhibition, directly or by recovery of SHP-1, and cyclophosphamide-Adriamycin-vincristine-prednisone (CHOP) chemotherapy reagents, effectively kill cells of all three TLBR models in vitro and may be pursued as therapies for patients with breast implant-associated T-ALCLs. The TLBR cell lines closely resemble the primary breast implant-associated lymphomas from which they were derived and as such provide valuable preclinical models to study their unique biology.

BCL2 Predicts Survival in Germinal Center B-cell–like Diffuse Large B-cell Lymphoma Treated with CHOP-like Therapy and Rituximab

We have previously shown the prognostic significance of BCL2 expression in the activated B-cell-like diffuse large B-cell lymphoma (ABC-DLBCL) patients treated with cyclophosphamide-Adriamycin-vincristine-prednisone (CHOP) or CHOP-like therapy. However, after the inclusion of rituximab (R) in the CHOP regimen, several conflicting observations about the prognostic value of BCL2 expression have been reported. We evaluated the R-CHOP cohort of 221 DLBCL cases with gene expression profiling data. BCL2 protein (n = 169), mRNA (n = 221) expression, and t(14;18) (n = 144) were correlated with clinical outcome. The CHOP cohort (n = 181) was used for comparative analysis. BCL2 protein expression has significant impact on overall survival (OS) and event-free survival (EFS) in DLBCL (OS, P = 0.009; EFS, P = 0.001) and GCB-DLBCL (OS, P = 0.03; EFS, P = 0.002) but not in ABC-DLBCL in the R-CHOP cohort. The survival differences for EFS in GCB-DLBCL were still observed in multivariate analysis. At the mRNA level, this correlation was observed in EFS in DLBCL (P = 0.006), but only a trend was observed in GCB-DLBCL (P = 0.09). The t(14;18) was detected in 34% of GCB-DLBCL but was not associated with significant differences in survival. Gene enrichment analysis identified significant enrichment of the DLBCL "stromal-1" signatures and hypoxia-inducible factor 1 (HIF1-α) signature in BCL2(-)GCB-DLBCL, whereas T(FH) cell signatures were enriched in BCL2(+)GCB-DLBCL. The prognostic significance of BCL2 has changed after inclusion of rituximab in the treatment protocol and is observed in the GCB-DLBCL rather than the ABC-DLBCL. Although rituximab has benefited patients in both DLBCL subgroups, the BCL2(+)GCB-DLBCL seems to receive less benefit from this treatment and may require other novel therapeutic intervention.

Partners In Health Generalist/Specialist Twinning: A Health Delivery Model Used in Treating Childhood Lymphoma in Rural Rwanda,

Abstract 4222In the developed world approximately 80% of children with lymphoma can be cured. As global health initiatives have broadened to address noncommunicable diseases the approach to cancer care for children in resource poor settings becomes of increasing concern. Traditional models of tertiary care provision will not be applicable as there is not an adequate number of existing pediatricians subspecializing in oncology to provide for the world’s children. At Rwinkwavu, a Partners In Health (PIH) supported government district hospital in rural Rwanda, a small cohort of children with lymphoma have received therapy over the past 4 years using a unique approach to care delivery. Each case is managed by a team consisting of a Rwandan physician with no specialty training, a Rwandan nurse coordinator focused on oncology patients, a Rwanda-based US trained pediatrician and a US- based pediatric oncologist. Biopsies and radiologic staging studies were obtained in Rwanda but all pathologic diagnoses were made at Brigham and Women’s Hospital, a Harvard teaching hospital, through a formal arrangement. A treatment plan for each patient was formulated with the consulting pediatric oncologist and a road map was generated. Chemotherapy was administered by nurses in the Rwinkwavu pediatric ward under the daily supervision of the local generalist and with the support of the pediatrician. Blood counts and broad spectrum antibiotics were available but blood cultures could not be performed. If radiation therapy was required patients were transported to Uganda for the treatments. Ten patients aged 3–15 (median age 9.5 years) have been treated using this approach. 5 (50%) have completed therapy - Hodgkin’s Disease (HD) n =2, HIV-associated large cell lymphoma (HIV LCL) n =2, Burkitt’s Lymphoma (BL) n=1. They received either CHOP (cyclophosphamide, adriamycin, vincristine, prednisone), n=3 or ABVD (adriamycin, bleomycin, vincristine, dacarbazine), n=1; 1 patient with Stage 1 Lymphocyte Predominant HD is being observed without adjuvant therapy after complete surgical excision. All 5 have no evidence of disease recurrence 4 months - 4 years following completion of therapy (median = 14 months). 2 patients are currently on therapy (recurrent HD, HIV LCL) and are in remission. 2 patients succumbed to treatment complications (HD- died from cardiomyopathy, BL- died from transverse myelopathy) and 1 patient (BL) died of progressive disease while receiving chemotherapy. We can not determine the number of pediatric patients with lymphoma who died before a diagnosis was made or before receiving appropriate therapy. In the developing world lymphoma is one of the most common oncologic diseases in children. These data suggest that chemotherapy can be administered with curative intent to a subset of these patients in the setting of a confirmed pathological diagnosis. This approach provides a platform for models of care that rely on local physicians acting in concert with trained consultants from the developed countries to deliver subspeciality care in resource poor settings. Disclosures:No relevant conflicts of interest to declare.

Primary cutaneous diffuse large B cell lymphoma, leg type

Address for Correspondence: Ankit Shrivastav, MD, 242, Ajc Bose Road 700020 Kolkata, India Tel: +919883252055 E-mail: ankit.med@gmail.com A 55-year-old male presented with a superficial mass over the right leg that had gradually progressed over the last month. The lesion was pruritic and painful. It was firm, indurated, shiny, erythematous, and raised on the surface (Figure 1). There was no lymphadenopathy or hepatosplenomegaly. All routine parameters including bone marrow biopsy were normal. An incision biopsy was taken from the lesion, which revealed superficial and deep perivascular, nodular and interstitial, bottom-heavy infiltrate comprised predominantly of lymphocytes, which showed a marked crush artifact (Figures 2-4). There were some preserved lymphocytes with enlarged, slightly hyperchromatic nuclei with basophilic nuclei. The epidermis and adnexal structures were spared. Immunological staining revealed a predominance of CD20positive B-cells, which were bcl-2-positive. A diagnosis of primary cutaneous diffuse large B-cell lymphoma, leg type was made. The patient was treated with the cyclophosphamide, adriamycin, vincristine, prednisone (CHOP) regimen. Rituximab was not added to the regimen as the patient could not afford it. He did not respond to the treatment and was lost to follow-up.

Protocol for the Examination of Specimens From Patients With Non-Hodgkin Lymphoma/Lymphoid Neoplasms

Jerry W. Hussong, MD,DDS; DanielA.Arber, MD;Kyle T. Bradley,MD,MS;Michael S. Brown,MD;Chung-Che (Jeff) Chang,MD,PhD; Monica E. de Baca, MD; David W. Ellis, MBBS, FRCPA; Kathryn Foucar, MD; Eric D. Hsi, MD; Elaine S. Jaffe, MD; Michael Lill, MB, BS, FRACP, FRCPA; Stephen P. McClure, MD; L. Jeffrey Medeiros, MD; Sherrie L. Perkins, MD, PhD; for the Members of the Cancer Committee, College of American Pathologists

Superior Antitumor Activity of SAR3419 to Rituximab in Xenograft Models for Non-Hodgkin's Lymphoma

To investigate the activity of SAR3419, a novel humanized anti-CD19 antibody (huB4), conjugated to a cytotoxic maytansine derivative N(2)'-deacetyl-N(2)'-(4-mercapto-4-methyl-1-oxopentyl) maytansine, in preclinical xenograft models for non-Hodgkin's lymphoma. Antitumor activity of SAR3419 was assessed as a single agent and in comparison with conventional therapies using a subcutaneous model for diffuse large B-cell lymphoma (WSU-DLCL2) and a systemic model for follicular small cleaved cell lymphoma (WSU-FSCCL) in mice with severe combined immune deficiency. Our results showed that in these chemotherapy-resistant models, SAR3419 was more effective than CHOP (cyclophosphamide-Adriamycin-vincristine-prednisone) regimen or rituximab. Only treatment with SAR3419 led to survival of the whole group of animals to the end of the experiment (150-155 days) in both models. Higher doses of SAR3419 (15 and 30 mg/kg) were more effective than lower dose of 7.5 mg/kg. The immunoconjugation was necessary because neither huB4 nor DM4 alone had significant activity. Treatment with rituximab resulted in antitumor activity in both models comparable with the low dose of SAR3419. Cyclophosphamide-Adriamycin-vincristine-prednisone alone showed modest activity in both models. Necropsy and tissue staining in the WSU-FSCCL systemic model revealed that all deaths featured leptomeningeal lymphoma in the control and treated groups. Interestingly, some of the animals that survived to the end of the experiment and seemed healthy at time of euthanasia did show microscopic evidence of lymphoma. Overall, SAR3419 is a very active immunotoxin in preclinical models for human B-cell lymphoma and holds promise as a novel and well-tolerated therapy in B-cell non-Hodgkin's lymphoma.

CNS events in elderly patients with aggressive lymphoma treated with modern chemotherapy (CHOP-14) with or without rituximab: an analysis of patients treated in the RICOVER-60 trial of the German High-Grade Non-Hodgkin Lymphoma Study Group (DSHNHL)

AbstractOne thousand two hundred twenty-two patients treated in the Rituximab with CHOP over age 60 years (RICOVER-60) trial were examined for central nervous system (CNS) disease developing during first-line therapy or after a complete or partial remission had been achieved. Patients received 6 or 8 courses of CHOP (cyclophosphamide, adriamycin, vincristine, prednisone) administered every 2 weeks (CHOP-14) with or without rituximab. CNS prophylaxis for patients with involvement of bone marrow, testes, upper neck, or head consisted of intrathecal (i.th.) methotrexate (days 1 and 5 of first 2 courses). Fifty-eight cases of lymphoma in the CNS were observed (36/609 patients in the CHOP-14 and 22/608 patients in the arituximab–CHOP-14 [R-CHOP–14] arm). The estimated 2-year incidence of CNS disease was 6.9% (confidence interval [CI] 4.5; 9.3) after CHOP-14 and 4.1% (CI 2.3; 5.9) after R-CHOP–14. R-CHOP reduced the relative risk for CNS disease to 0.58 (95% CI 0.3; 1.0, P = .046). Cox regression analysis identified “involvement of more than 1 extranodal site” and “B-symptoms” as significant risk factors for CNS disease. Patients treated with R-CHOP–14 did not show any benefit from i.th. methotrexate. We conclude that elderly patients with aggressive CD20-positive lymphoma show a significantly lower incidence of CNS disease if treated with R-CHOP–14 instead of CHOP-14. Intrathecal methotrexate has no role in preventing CNS disease for patients treated with combined immunochemotherapy (R-CHOP–14)—with the possible exception of patients with testicular involvement. The original clinical trials are registered on www.clinicaltrials.gov as NCT000052936.

381: Echocardiography on neonates exposed to anthracycline therapy in utero for maternal cancer

UTERO FOR MATERNAL CANCER ELYCE CARDONICK, ANIQA USMANI, SADIA GHAFFAR, DENNIS WOOD, MARC LEVINE, Robert Wood Johnson University, OBGYN, Camden, New Jersey, Cooper University Hospital, OBGYN, Camden, New Jersey, Thomas Jefferson University, Philadelphia, Pennsylvania, Robert Wood Johnson University, pediatric cardiology, camden, New Jersey OBJECTIVE: To evaluate the cardiac function of neonates exposed to anthracyclines in utero. STUDY DESIGN: This was an observational study. Pregnant women diagnosed with cancer who underwent anthracycline based chemotherapy and delivered a liveborn infant after 24 weeks, were offered enrollment. Patients provided written consent to obtain doses and dates of chemotherapy treatment. Due to the known cardiotoxicity of anthracyclines in pediatric and adult populations, echocardiograms were offered to all newborns exposed as fetuses. Women chose to perform this echocardiogram locally or at the institution of the primary investigator. RESULTS: This is the largest report of echocardiograms performed in neonates exposed to chemotherapy in utero. Twenty one neonates participated. Women were treatment for Hodgkin’s Disease with ABVD (Adriamycin/BleomycinVincristine/Dacarbazine) for Hodgkin=s Disease (n 3), CHOP (Cyclophosphamide/ Adriamycin/Vincristine/Prednisone) for NonHodgkin=s Lymphoma (n 1), and Adriamycin/Cytoxan for breast cancer (n 17). There were no cases of exposure to epirubicin or idarubicin. Mean dosage of Adriamycin was 54.3mg/m2 / 10. Baseline fetal cardiac evaluation was normal prior to starting chemotherapy.Neonatal echocardiograms were performed at a mean age of 13 / 27months, with children ranging in age from 3 days of life to 9.75 years. LV dimensions, RV wall, IVS and LV posterior wall thickness measurements were within normal limits for age and BSA. Mean shortening fraction was 41 / 10%. (normal 33 / 3%). In all 21, AV and semilunar valves were normal. Great arteries were normal in 20/21, with one case of a small pulmonary artery fistula. Patent foramen ovale was noted in 6 cases, all in children less than 2.5 months of age. No additional structural or any functional heart defects were diagnosed in any of these children. CONCLUSION: Cardiac function appears to be preserved in neonates exposed to adriamycin chemotherapy in utero. Any toxicity effects on fetal myocytes were not evident in postnatal echocardiograms.

Antibody Therapy in Aggressive Lymphomas

The aggressive lymphomas are potentially curable. The natural history of certain aggressive lymphomas has been altered by monoclonal antibody therapy. Targeted monoclonal antibody therapy to the CD20 antigen has altered the outcome of patients with diffuse large B-cell lymphoma in patients of all ages. Anti-CD20-based radioimmunoconjugates are being evaluated as radioimmunotherapy approaches in patients who have relapsed and in stem cell transplant settings. Antibody-directed therapy to the B-cell-specific antigen CD22 are ongoing. New approaches include different CD20 antibodies and an antibody to the CD40 antigen, which is a member of the tumor necrosis factor (TNF) receptor family, which is expressed on B-cells. Antibody therapy has been incorporated into CHOP (cyclophosphamide, adriamycin, vincristine, prednisone) therapy and other regimens such as EPOCH (etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin) and HyperCVAD (cyclophosphamide, vincristine, adriamycin, dexamethasone). Single-agent anti-CD20 therapy is active in the post-transplantation lymphoproliferative disorders. T-cell antibodies are under evaluation in a number of T-cell lymphoproliferative disorders. Targeted therapy has changed the natural history of a number of aggressive non-Hodgkin lymphomas. This review will describe the contributions of antibody therapies to the treatment of these diseases.

The Humanized Anti-CD40 Antibody, SGN-40, Promotes Apoptosis Signaling and Is Effective in Combination with Standard Therapies in Lymphoma Xenograft Models.

CD40 is a TNF receptor family member that is expressed on B cells and by a wide variety of transformed cells including non-Hodgkin's lymphoma (NHL), multiple myeloma, and various solid tumors. The humanized anti-CD40 antibody, SGN-40, is a partial agonist that induces apoptosis as well as mediates ADCC against CD40+ NHL B cell lines, contributing to in vivo antitumor activity observed in human lymphoma xenograft models. The current study demonstrates the ability of SGN-40 to initiate multiple signaling cascades upon ligation of CD40 on NHL cell lines. SGN-40 was shown to activate the stress-induced p38 MAP kinase and pro-survival pathways including NF-κB, p42/44 MAP kinase and, to a lesser extent, AKT. Consistent with the apoptosis-inducing activity of SGN-40, cleavage of caspase-3 and its downstream substrate poly (ADP-ribose) polymerase was detected in NHL cell lines. SGN-40 signaling was qualitatively similar to that mediated by trimeric recombinant human CD40 ligand (rhCD40L). However, the overall magnitude of signaling was lower with SGN-40 compared to rhCD40L, consistent with the partial agonistic properties of SGN-40. In addition, constitutive phospho-AKT levels, a key pro-survival signal, were found to be very low in most high-grade lymphoma cell lines and primary NHL specimens, in contrast to the high levels reported in carcinomas. Low AKT activity may bias lymphoma cells toward apoptosis in response to SGN-40 signaling. To augment SGN-40-induced cell killing, in vitro combination studies with chemotherapeutics have been performed using the Ramos, RL, and HT NHL lines. We now report that SGN-40 has additive activity when combined with cisplatin, melphalan, or mitoxantrone and is synergistic with bleomycin. Furthermore, in vivo activity of combination therapy has been demonstrated in a subcutaneous Ramos lymphoma xenograft model. While tumor growth was delayed by either CHOP (cyclophosphamide, adriamycin, vincristine, prednisone) or SGN-40 alone, the combination of SGN-40 and CHOP was significantly more active. Our results suggest that SGN-40 can be combined with standard lymphoma therapies resulting in improved therapeutic efficacy, and provide a rationale for combination clinical trials involving SGN-40. The molecular mechanisms through which standard chemotherapeutic agents enhance SGN-40-mediated cell killing in target lymphoma B cells are currently being investigated.

A Prospective Randomized Study of Chop Versus Chop Plus Alpha-2B Interferon in Patients with Intermediate and High Grade Non-Hodgkin's Lymphoma: The International Oncology Study Group NHL1 Study

The addition of a brief alpha interferon regimen to each CHOP induction cycle, plus one year of alpha interferon thrice weekly maintenance therapy, has no early effect on response rates or survival in patients with Intermediate or High grade cell NHL.Background: The CHOP (Cyclophosphamide, Adriamycin, Vincristine, Prednisone) regimen is the most widely used first-line therapy for patients with Intermediate or High Grade (IG/HG) non-Hodgkin's lymphoma (NHL). Alpha 2b interferon (INF) enhances response rates and improves survival in low-grade NHL. The International Oncology Study Group (IOSG) conducted a prospective randomized study comparing CHOP alone or combined with INF in patients with IG/HG-NHL. The primary study aim was to compare the objective response rates in these patient cohorts. Patients and Methods: Patients with a confirmed diagnosis of measurable NHL of International Working Formulation (IWF) groups D to H histology were randomized to receive CHOP alone or CHOP with 5Mu INF SC for 5 days on days 22 to 26 of each 28 day cycle with INF 5 million units (Mu) given three times per week sub-cutaneously for 52 weeks in those patients who responded to CHOP plus INF. Results: The overall response rates were equivalent in both groups: CHOP alone (214 patients) 81% (complete 55%, partial 26%); CHOP plus INF (221 patients) 80% (complete 54%, partial 26%). At 36 months, the actuarial survival rate was equivalent in both groups. Conclusions: There is no apparent early advantage in terms of response or survival conferred by adding the study INF regimen to CHOP therapy for patients with IG/HG-NHL.

The Treatment of Malignant Histiocytosis

Twenty-four consecutive cases of malignant histiocytosis (MH) treated at Stanford Medical Center between 1973 and 1983 have been reviewed. Most patients presented with systemic symptoms (91%) and advanced disease (stage IV, 80%). Multiple organ involvement was common. In six cases, pathologic tissue was further characterized by frozen section immune histochemistry, using a panel of monoclonal antibodies known to react with monocytes and macrophages, as well as a variety of hematopoietic cells. One case expressed a mature monocyte/macrophage phenotype; three cases were considered null cell or primitive lesions; and two cases were identified as probable T cell lymphomas. Seven patients underwent splenectomy. Two patients died prior to any treatment. Twenty-two patients were treated with CHOP (cyclophosphamide, Adriamycin, vincristine, prednisone) +/- bleomycin (B), +/- midcycle high-dose methotrexate (HD-MTX) with leucovorin rescue. Seven patients received prophylactic intrathecal MTX. Of 22 evaluable patients, there was a 68% complete response rate (CR), a 23% partial response rate (PR), and a 9% no response rate (NR). Median duration of CR was 30+ months; median duration of PR was 2.4 months. Median survival for patients attaining a CR has not been reached v 3 months for the PR and NR groups. For all 24 patients, median survival was 2 years, with a 5-year actuarial survival of 40%. Multivariate analysis revealed that a platelet count less than 150,000 (P Cox = .005) and the dose of drug delivered (P Cox = .057) were the most important prognostic factors. Prophylactic intrathecal MTX therapy and splenectomy did not influence survival. Although MH is an aggressive disease with a poor prognosis, it is potentially curable. Systematic and aggressive treatment should further improve the outcome.