Multiagent Systemic Chemotherapy Research Articles

Clinical characteristics and outcomes of patients with Hodgkin lymphoma with central nervous system involvement: An international multicenter collaboration.

Central nervous system (CNS) involvement is rare in patients with Hodgkin lymphoma (HL). Thus, the clinical features and outcomes are not well described. Cases of histologically confirmed CNS HL diagnosed between 1995 and 2015 were retrospectively identified in institutional (n = 7), national (n = 2), and cooperative group (n = 1) databases. We screened 30,781 patients with HL in our combined databases and identified 21 patients meeting eligibility criteria, an estimated frequency of 0.07%. CNS involvement was present at initial diagnosis in 10 patients (48%) and a feature of relapsed/refractory disease in 11 (52%). Among these 11 patients, the median time from initial diagnosis of HL to development of CNS involvement was 1.9 years (range 0.4-6.6) and the median number of prior lines of therapy was 2 (range 1-7). Altogether, treatments included radiation, multiagent systemic chemotherapy, combined modality therapy, and subtotal resection. The overall response rate was 65%. After a median follow-up of 3.6 years (range 0.8-13.2) from diagnosis of CNS HL, the median PFS and OS were 7.6 and 29 months, respectively. CNS involvement as a feature of relapsed/refractory disease was adversely prognostic for both PFS and OS; however, four patients remain alive and free of relapse at 7-78 months follow-up. CNS involvement in HL is exceedingly rare and has a distinct clinical presentation with predilection for parenchymal lesions with dural extension. Around one-quarter of patients, mostly with CNS involvement at initial HL diagnosis, experience prolonged disease-free survival. Am. J. Hematol. 91:894-899, 2016. © 2016 Wiley Periodicals, Inc.

Does solitary- and organ-confined metastasectomy really improve survival in advanced urologic malignancies?

The role of metastasectomy on survival in advanced/urologic malignancies still remains unclear. Renal cell carcinoma (RCC) is the most common solid tumor within the kidney. 25-30 % of patients have metastases at manifestation. Urothelial carcinoma (UC) consists of bladder carcinoma, upper urinary tract urothelial cell carcinoma and urethral carcinoma. Bladder cancer is the ninth most common cancer worldwide. Half of patients with muscle invasive bladder cancer have lymph node or distant metastases. In metastatic disease first-line treatment is multi-agent platinum-based systemic chemotherapy. Testicular cancer is the most common cancer in men between the age of 15 and 35. Testicular tumors represent excellent oncologic outcomes. Prostate cancer is the most common solid tumor in Europe. Surgical resection of metastases can be considered as a treatment choice in advanced/metastatic urologic malignancies to improve survival rates, particularly in RCC and UC. Metastasectomy can be suggested in conjunction with effective chemotherapy if complete resection is possible. Solitary metastasectomy can represent better survival rates compared to multiple metastasectomy even if multiple metastases confined to single organ. Site of metastases is one of the main determinants of successful metastasectomy such as lung metastasectomy in urothelial cell carcinoma and liver metastasectomy in RCC may lead to better oncologic outcomes. Due to the lack of the relevant data it is not possible to make an evidence-based recommendation on the role of metastasectomy for solitary-/organ-confined metastases of prostate cancer, testicular cancer and penile cancer.

Outcome in pediatric acute lymphoblastic leukemia in children and adolescents using contemporary protocols of chemotherapy – experience of a single Pediatric Hematology-Oncology Center

The authors studied the outcome of a cohort of pediatric acute lymphoblastic leukemia (ALL) patients (33 children and adolescence) diagnosed and treated conforming to modern Chemotherapy Protocols (ALL ICBFM 2002, Interfant 06) in a single Center – Pediatric Clinic, Fundeni Clinical Institute, Bucharest, Romania. They analyzed the factors which determine the prognosis and the outcome of these patients in the course of multi-agent systemic chemotherapy to stand at the base of these Protocols: initial age, initial leukocyte count, blasts immunophenotype, cytogenetic and molecular abnormalities, initial response to cortisone, risk groups, time to obtain the complet remission, etc. Among the factors they discussed, a great value was proven to have the minimal residual disease (MRD) determination in certain check points of Protocols and revaluation of patients risk conforming to MRD values. Using the modern Protocols and continuously watching the evolution on therapy enable the authors to obtain results close to those of European and North American Pediatric Hematology Oncology Centers: OS 90.9% by 40 Mo and EFS 72.7% at the end of the same period of time.

PTH-312 5 year results of radical resection and hipec for colorectal cancer peritoneal metastases

Introduction Peritoneal metastases complicate 10 to 30% of patients with colorectal cancer. 1 Peritoneal carcinomatosis is traditionally associated with palliative care and a life expectancy measured in months. 2 Modern multiagent systemic chemotherapy prolongs survival in such cases to 18 months but many patients (60%) fail to complete the course due to side effects. Cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) are effective treatments for advanced colorectal cancer with peritoneal metastases allowing median survival of up to 62 months and 5 year survival in excess of 40%. 3 These modalities are being employed in Ninewells Hospital in Dundee, since 2009. Method Prospectively collected data from consecutive colorectal cancer patients with peritoneal metastases undergoing CRS and HIPEC. Patients were selected at multi-disciplinary meeting if expected peritoneal cancer index was less than 20 in abscence of significant comorbidities. Staging included CT chest abdomen and pelvis, PET scan and selected patients underwent a pre-operative staging laparoscopy to confirm disease extent. Following resection of all macroscopically visible disease the abdomen is closed and perfused with heated oxaliplatin and synchronous intravenous 5FU according to the Villejuif protocol. Patients are routinely admitted to ICU for at least 24 h. Results Since August2009,43 patients with colorectal cancer peritoneal metastases have been treated with a mean age of 55 years (20 to 78) and a median hospital stay of 24 days. 40% of patients experienced complications post operatively (23% Clavien-Dindo 3 and 4) 3 patients had a return to theatre (left colonic ischaemia, small bowel fistula, wound dehiscence). Most complicaitons were managed percutaneously with radiologically placed drains. There were no deaths. The median peritoneal cancer index was 19 (last 8 cases:12). Multi-visceral resections accounted for 68% of the cases, 53% had isolated peritoneal metastases whilst 47% had been treated for synchronous or metachronous liver metastatic disease. Completeness of cytoreduction (R0) was achieved in 98% (1 patient). Median survival at 12 months is 79%, 18 months 69%, 48% at 24 months and 37% at 60 months. Conclusion Radical resection and HIPEC for colorectal cancer peritoneal metastases are safe in selected patients and long term survival is possible even in the presence of liver metastatic disease. Disclosure of interest None Declared. References Jayne DG. Br J Surg. 2002;89:1545–1550 Chu DZ. Cancer 1989; 63 :364–367 Elias D. J Clin Oncol. 2009;27(5)

18-Year-Old Woman with an Embryonal Rhabdomyosarcoma of the Uterus in Statu Nascendi.

Background: We report a case of an 18-year-old woman with an embryonal rhabdomyosarcoma in statu nascendi. Case: A fist-sized embryonal rhabdomyosarcoma of the uterus filling the vaginal vault was diagnosed in an adolescent with virgo intacta suffering from therapy resistant vaginal discharge, bleeding and bulging mass for six months. Further imaging revealed one suspicious pelvine lymph node. Excision of the tumour including the intracervical stalk was performed and followed by systemic multiagent chemotherapy. PET-CT scan presented a complete response after the third cycle. Histological complete response was shown by laparoscopic dissection of regional pelvic lymph nodes and curettage. Conclusion: Uterine Rhabdomyosarcoma should be considered as differential diagnosis of therapy resistant vaginal flour and bleeding in young women. Fertility-sparing therapy is possible in selected exceptional cases.

Treatment of young children with CNS-primitive neuroectodermal tumors/pineoblastomas in the prospective multicenter trial HIT 2000 using different chemotherapy regimens and radiotherapy

Especially in young children, primitive neuroectodermal tumors of the central nervous system (CNS-PNET) and pineoblastomas are associated with an unfavorable outcome, and only a few prospective trials have been conducted thus far. From January 2001 through January 2005, 17 eligible children aged <4 years with CNS-PNET not otherwise specified (n = 8), ependymoblastoma (n = 1), or pineoblastoma (n = 8) confirmed by central review were prospectively treated in the trial HIT 2000. In nonmetastatic disease (n = 11), up to 5 postoperative cycles of HIT-SKK systemic multiagent chemotherapy (8 months duration), followed by craniospinal radiotherapy (CSI), were given. In metastatic disease (M1-M3, n = 6), treatment consisted of a shorter induction chemotherapy (2-3 months) with carboplatin and etoposide, followed by tandem high-dose chemotherapy (HDCT) in case of good response to induction. During induction and HDCT, patients received intraventricular methotrexate. CSI was applied to all patients with poor response to induction or residual disease after HDCT and was optional for patients with residual disease before HDCT. Five-year event-free survival and overall survival rates ± standard error for all eligible patients were 24% ± 10% and 40% ± 12%, respectively (median follow-up of survivors: 8.3 years). Only one patient with nonmetastatic disease remained free of relapse/progressive disease during induction. Three of 6 patients with metastatic disease responded to induction and received tandem-HDCT, followed by preventive CSI, and remain in continuous complete remission. Short intensive induction chemotherapy followed by tandem-HDCT in young children with CNS-PNET/pineoblastomas seems to be superior to the prolonged and less intensive induction regimen.

Cutaneous CD30‐positive lymphoproliferative disorders with CD8 expression: a clinicopathologic study of 21 cases

Lymphomatoid papulosis (LyP) and cutaneous anaplastic large cell lymphoma (ALCL) belong to the spectrum of cutaneous CD30+ lymphoproliferative disorders, an indolent form of T-cell lymphoproliferative disease. We reviewed 21 cases of CD30+ lymphoproliferative lesions expressing cytotoxic profile (CD8+). Seven cases of cutaneous ALCL, 2 cases of systemic ALCL involving the skin, and 12 cases of LyP. The cases of LyP were predominated by small lymphocytes exhibiting a prominent epidermotropic pattern consistent with either type B or type D LyP. Four cases showed co-expression of CD56. The ALCL cases included myxoid features, pseudoepitheliomatous change, and an intravascular component. In all cases that were primary in the skin an indolent clinical course was seen while one patient with systemic myxoid ALCL is in remission following systemic multiagent chemotherapy. The paucity of other neutrophils and eosinophils and concomitant granulomatous inflammation were distinctive features in cases of type B and type D LyP. CD30 and CD45 Ro positivity and a clinical course typical of LyP were useful differentiating features from an aggressive cytotoxic CD8+ T cell lymphoma. In all cases that were primary in the skin an indolent clinical course was observed. CD30 and CD45 Ro positivity and a clinical course typical of LyP were useful in preventing a misdiagnosis of an aggressive cytotoxic CD8+ T cell lymphoma.

Pilot study of systemic and intrathecal mafosfamide followed by conformal radiation for infants with intracranial central nervous system tumors: a pediatric brain tumor consortium study (PBTC-001)

A pilot study to investigate the feasibility of the addition of intrathecal (IT) mafosfamide to a regimen of concomitant multi-agent systemic chemotherapy followed by conformal radiation therapy (RT) for children <3 years with newly diagnosed embryonal CNS tumors was performed. Ninety-three newly diagnosed infants and children (<3 years) with embryonal CNS tumors were enrolled. Twenty weeks of systemic multi-agent chemotherapy commenced within 35 days of surgery. Patients without CSF flow obstruction (n = 71) received IT mafosfamide (14 mg) with chemotherapy. Localized (M(0)) patients with SD or better subsequently received RT followed by 20 additional weeks of chemotherapy. Second look surgery was encouraged prior to RT if there was an incomplete surgical resection at diagnosis. 71 evaluable patients with normal CSF flow received IT Mafosfamide with systemic chemotherapy; patients with M + disease were removed from protocol therapy at 20 weeks and those with PD at the time of progression. One and 5-year progression free survival (PFS) and overall survival (OS) for the cohort of 71 evaluable patients were 52 ± 6.5 % and 33 ± 13 %, and 67 ± 6.2 % and 51 ± 11 %, respectively. The 1-year Progression Free Survival (PFS) for M0 patients with medulloblastoma (MB, n = 20), supratentorial primitive neuroectodermal tumor (PNET, n = 9), and atypical teratoid rhabdoid tumor (ATRT, n = 12) was 80 ± 7 %, 67 ± 15 % and 27 ± 13 % and 5-year PFS was 65 ± 19 %, 37 ± 29 %, and 0 ± 0 %, respectively. The addition of IT mafosfamide to systemic chemotherapy in infants with embryonal CNS tumors was feasible. The PFS for M0 patients appears comparable to or better than most prior historical comparisons and was excellent for those receiving conformal radiotherapy.

Impact of platelet count in women with advanced ovarian cancer receiving adjuvant multi-agent systemic chemotherapy

Impact of platelet count in women with advanced ovarian cancer receiving adjuvant multi-agent systemic chemotherapy

Superselective ophthalmic artery infusion of melphalan for intraocular retinoblastoma: preliminary results from 140 treatments

To report our experience in superselective ophthalmic artery infusion of melphalan (SOAIM) for intraocular retinoblastoma. From June 2008 to October 2010, 38 patients (18 women, 20 men; age range at first treatment, 7 months to 22 years) with 41 eyes with retinoblastoma were scheduled for SOAIM, for 17 newly diagnosed retinoblastomas Tumour, Node and Metastasis (TNM) 7th Edition 1a (n = 1), 1b (n = 1), 2a (n = 7), 2b (n = 4) and 3a (n = 4) and 24 retinoblastomas with partial remission/relapse TNM 7th Edition 1b (n = 13), 2a (n = 1) and 2b (n = 10). Eight patients (ten eyes) have been treated by SOAIM alone. Follow-up was 6-27 months in 28 patients (30 eyes). Ophthalmic artery cannulation failed in two patients. Thirty-six patients underwent 140 treatments by internal (n = 112) or external (n = 28) carotid arteries. No major procedural complications occurred. Two patients have been lost to follow-up. Remaining 34 patients (37 eyes) had no metastatic disease. Four patients suffered permanent ocular complications: chorioretinal dystrophy (n = 2), ptosis (n = 1) and strabismus/exotropia (n = 1). Eight (22%) eyes in eight (24%) patients underwent enucleation: 7/16 (43%) newly diagnosed retinoblastomas and 1/22 (4.5%) retinoblastomas undergoing partial remission/relapse. For all treated eyes, Kaplan-Meier eye enucleation-free rates (K-M) were 85.4% (95% CI, 73.3-97.5%), 74.4% (95% CI, 57-91.8%) and still stable at 6, 12 months and 2 years, respectively. For eyes with partial remission/relapse, and eyes at presentation, K-M at 2 years were 95.5% (95% CI, 86.9-100%) and 45.6% (95% CI, 16.6-74.6%), respectively. Superselective ophthalmic artery infusion of melphalan was safe and powerful, especially following other therapies. Superselective ophthalmic artery infusion of melphalan should be added to focal therapies spectrum. In selected cases, melphalan should be combined with other chemotherapeutic agents.

A comparison of the outcomes of neoadjuvant and adjuvant chemotherapy for clinical T2‐T4aN0‐N2M0 bladder cancer

Despite evidence supporting perioperative chemotherapy, few randomized studies compare neoadjuvant and adjuvant chemotherapy for bladder cancer. Consequently, the standard of care regarding the timing of chemotherapy for locally advanced bladder cancer remains controversial. We compared patient outcomes following neoadjuvant or adjuvant systemic chemotherapy for cT2-T4aN0-N2M0 bladder cancer. In a retrospective review of a single institutional database from 1988 through 2009, we identified patients receiving neoadjuvant or adjuvant multiagent platinum-based systemic chemotherapy for locally advanced bladder cancer. Survival analysis was performed comparing disease-specific survival (DSS) and overall survival (OS). A total of 146 patients received systemic perioperative chemotherapy (73 neoadjuvant, 73 adjuvant). Of these, 84% (122/146) received cisplatin-based chemotherapy compared with carboplatin-based chemotherapy (24/146, 16.4%). Most patients receiving cisplatin-based chemotherapy were treated with methotrexate/vinblastine/adriamycin/cisplatin (79/122, 64.8%), whereas the remaining patients received gemcitabine/cisplatin (GC) (43/122, 35.2%). In multivariable analysis, there was no significant difference in DSS (P = .46) or OS (P = .76) between neoadjuvant or adjuvant chemotherapy groups. There was statistically significant improvement in DSS when patients received neoadjuvant GC rather than adjuvant GC (P = .049, hazard ratio, 10.6; 95% confidence interval, 1.01-112.2). In this study, there was no statistically significant difference in OS and DSS between patients receiving neoadjuvant versus adjuvant systemic platinum-based chemotherapy for locally advanced bladder cancer. In addition, there was no significant difference between neoadjuvant and adjuvant cisplatin- or carboplatin-based chemotherapy. Chemotherapy sequence relative to surgery appeared less important than whether or not a patient actually received perioperative chemotherapy.

Treatment of young children with localized medulloblastoma by chemotherapy alone: Results of the prospective, multicenter trial HIT 2000 confirming the prognostic impact of histology

This study was designed to confirm the previously observed favorable survival rates and prognostic factors in young children with nonmetastatic medulloblastoma (MB) treated with postoperative chemotherapy alone. Patients who received a diagnosis during the period January 2001 through December 2005 and who were aged <4 years received 3 cycles of postoperative systemic multiagent chemotherapy and intraventricular methotrexate. In cases of complete remission, treatment was terminated after 2 additional cycles of chemotherapy. Otherwise, secondary surgery, radiotherapy, and consolidation chemotherapy were recommended. At a median follow-up of 4.5 years, the 5-year event-free survival (EFS) and overall survival (OS) rates (± standard error) for 45 patients (median age, 2.5 years) were 57% ± 8% and 80% ± 6%, respectively. Nineteen patients with desmoplastic/nodular MB variants had better 5-year EFS and OS rates (90% ± 7% and 100% ± 0%, respectively) than did 23 patients with classic MB (30% ± 11% and 68% ± 10%, respectively; P < .001 for EFS; P = .008 for OS). Five-year EFS and OS rates for 3 children with anaplastic MB were 33% ± 27%. Desmoplastic/nodular histology was an independent prognostic factor for EFS. Twenty-nine of 30 patients without postoperative residual tumor remained in continuous complete remission. Our results confirm that histology of MB variants is a strong prognostic factor in this age group. Sustained tumor control can be achieved by this chemotherapy regimen in young children with desmoplastic/nodular MB variants. For children with non-desmoplastic/nonnodular MB variants, for which predominantly local relapses lead to less favorable survival rates, local radiotherapy has been introduced after chemotherapy since 2006.

Subdural hematomas in patients with Philadelphia chromosome-positive acute lymphoblastic leukemia receiving imatinib mesylate in conjunction with multi-agent chemotherapy.

6579 Background: Imatinib mesylate (IM) and other tyrosine kinase inhibitors that inhibit BCR-ABL have revolutionized the treatment of chronic myelogenous leukemia and also improved Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL) outcomes. BCR-ABL inhibitors are generally well tolerated, but both IM and dasatinib induce platelet dysfunction, which is of particular concern in the setting of thrombocytopenia in ALL patients. Three Ph+ ALL patients receiving IM in conjunction with systemic and intrathecal (IT) chemotherapy at the University of Maryland Greenebaum Cancer Center (UMGCC) developed subdural hematomas (SDH). We sought to define risk factors for SDH. Methods: Charts were reviewed for SDH risk factors, including thrombocytopenia, coagulopathy, lumbar punctures and meningeal leukemia, and SDH incidence was compared in Ph+ and Ph- ALL patients receiving multi-agent systemic and IT chemotherapy with and without IM, respectively, at UMGCC from 2007 through 2010. Results: Three Ph+ ALL patients developed SDH during treatment courses 1, 3, and 3, respectively. SDH was unilateral in two patients and bilateral in one. All were thrombocytopenic and had undergone repeated lumbar punctures, but none was coagulopathic nor had meningeal leukemia. SDH was treated with burr hole surgery in two patients, and conservatively in one. One patient died of resistant leukemia and one of post-transplant complications, while the third is alive and in remission 26 months after diagnosis and 22 months after SDH. SDH incidence was significantly higher in Ph+ compared to Ph- ALL patients receiving treatment with and without IM, respectively (3 of 10 vs. 0 of 22; p<0.05). Conclusions: Our data suggest that IM is a risk factor for SDH, likely due to IM-induced platelet dysfunction, and that patients with Ph+ ALL receiving IM, and likely dasatinib, in conjunction with systemic and IT chemotherapy may be at increased risk of SDH and should be closely monitored for subtle manifestations of this serious complication.

Abstract 3463: Treatment of young children with localized medulloblastoma by chemotherapy alone: Final results of the prospective multicenter trial HIT 2000 confirming the prognostic impact of histology

Abstract Background: This study was designed to confirm the previously observed favorable survival rates and prognostic factors in young children with non-metastatic medulloblastoma (MB) treated by postoperative chemotherapy alone. Methods: Patients diagnosed between January 2001 and December 2005 and younger than 4 years received three cycles of postoperative systemic multiagent chemotherapy and intraventricular methotrexate. In case of complete remission, treatment was terminated after two additional cycles of chemotherapy. Otherwise secondary surgery, radiotherapy and consolidation chemotherapy were recommended. Results: The 5-year event-free survival (EFS) and overall survival (OS) (±SE) rates of 45 patients were 57 ± 8% and 80 ± 6% (median follow-up: 4.5 years, median age: 2.5 years). Nineteen patients with desmoplastic / nodular MB variants had better EFS and OS (5-year rates: 90 ± 7% and 100 ± 0%) compared to 23 patients with classic MB (30 ± 11% and 68 ± 10%; p&amp;lt; 0.001 for EFS, p=0.008 for OS). Five-year EFS and OS rates of 3 children with anaplastic MB were 33 ± 27%. Desmoplastic / nodular histology was an independent prognostic factor for EFS. Twenty-nine of 30 (97%) patients without postoperative residual tumor remained in continuous complete remission. Conclusions: Our results confirm histology of MB variants as a strong prognostic factor in this age-group. Sustained tumor control and favorable survival rates can be achieved by this chemotherapy regimen in young children with desmoplastic / nodular MB variants. For children with non-desmoplastic / non-nodular MB variants, where predominantly local relapses lead to less favorable survival rates, local radiotherapy has been introduced after chemotherapy since 2006. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3463. doi:10.1158/1538-7445.AM2011-3463

Cutaneous T cell Lymphoma (Mycosis Fungoides)

An adult male presented with history of long standing scaly cutaneous lesions, progressed to multiple ulceronodular lesions on back of arm, front of thigh as shown in figure. Histopathology of lesion revealed non-Hodgkins lymphoma(CD4 +v)-Mycosis Fungoides His TNM stage was stage III-T3N1M0. Patient needed systemic multiagent chemotherapy to palliate his advanced disease. JMS 2010;13(2):72

Pralatrexate Is An Effective Treatment for Heavily Pretreated Patients with Relapsed/Refractory Transformed Mycosis Fungoides (tMF)

AbstractAbstract 1762 Background:Cutaneous T-cell lymphoma, which includes mycosis fungoides (MF) and the Sézary Syndrome, is an indolent T-cell lymphoma. Large-cell transformation (tMF) is a well-defined histopathological disease that is distinguished from primarily cutaneous MF by the presence of large cells that exceed 25% of total lymphoid infiltrate (Barberio et al. Br J Dermatol 2007; 157:284-9) and occurs in 11% to 23% of cases. tMF represents a significantly poorer prognostic subset of MF patients with median overall survival of 12 to 22 months from the time of diagnosis of large-cell transformation (Arulogun et al. Blood 2008; 112:3082-7). There is no standard therapy for tMF and most patients are treated with multiagent systemic chemotherapy regimens. Because of its poor outcome similar to that of aggressive peripheral T-cell lymphomas (PTCLs), tMF patients were included in PROPEL, the pivotal study that led to the accelerated approval of pralatrexate (FOLOTYN®) in the United States for the treatment of relapsed or refractory PTCL. Methods:Of 109 evaluable patients in the PROPEL trial, 12 patients had histologically confirmed tMF. All patients received pralatrexate at a dose of 30 mg/m2 weekly for 6 weeks in a 7 week cycle. Results:Of the 12 patients with tMF, the median age was 56.5 years. The median number of prior therapies was 6.5 (range 1 to 12), and 5 patients (42%) received ≥5 prior systemic regimens. The majority of patients had received prior multiagent chemotherapy, including cyclophosphamide/doxorubicin/vincristine/prednisone (CHOP) or CHOP-based therapy in 67% of patients and other multiagent regimens in 17% of patients. Only 1 of 12 patients had a response to their most recent prior chemotherapy regimen. The objective response rate (ORR) to pralatrexate in this group of refractory tMF using International Workshop Criteria based on investigator assessment, was 58%. Consistent with the overall study population, the ORR by independent central review was 25%. The difference in ORR between independent central review and investigator assessment for tMF is mainly due to challenges with photodocumentation of response assessment of cutaneous lesions. The 12 patients with tMF received a median of 10 doses of pralatrexate and remained on treatment for a median of 89 days. The median response duration was 4.4 months and median PFS was 5.3 months, per investigator assessment. The median survival in this group of patients was 13 months. Mucosal inflammation was reported in 7 patients (58%) including 1 patient with grade 3. Grade 4 adverse events (AEs) were fatigue (1 patient) and thrombocytopenia (1 patient). Overall, patients with tMF were able to tolerate full-dose pralatrexate treatment, with no patients discontinuing due to an AE. Conclusions:Pralatrexate demonstrated significant activity in the 12 refractory tMF patients enrolled in the PROPEL trial with an investigator assessed response rate of 58%. Pralatrexate should be considered as a treatment option for patients with tMF. Disclosures:Foss:Allos Therapeutics, Inc.: Consultancy, Speaker. Horwitz:Allos Therapeutics, Inc.: Consultancy, Research Funding. Pinter-Brown:Allos Therapeutics, Inc.: Consultancy. Goy:Allos Therapeutics, Inc.: Consultancy, Honoraria. Pro:Allos Therapeutics, Inc.: Research Funding. Savage:Allos Therapeutics, Inc.: Consultancy, Honoraria. Shustov:Allos Therapeutics, Inc.: Honoraria, Research Funding. Zain:Allos Therapeutics, Inc. : Speakers Bureau. Koutsoukos:Allos Therapeutics, Inc.: Employment. Fruchtman:Allos Therapeutics, Inc.: Employment. O'Connor:Allos Therapeutics, Inc.: Research Funding.

Clinicopathological Features of Nodular Sclerosis-Type Classical Hodgkin Lymphoma In the Elderly: Multicenter Study of Hodgkin Lymphoma In Japan

AbstractAbstract 2677 Background:Classical Hodgkin lymphoma (CHL), which is characterized by the presence of Hodgkin and Reed Sternberg (H-RS) cells in a background of non-neoplastic inflammatory cells, is divided into four histological subgroups, nodular sclerosis (NSCHL), mixed cellularity (MCCHL), lymphocyte-rich, and lymphocyte depletion. While NSCHL in young adults is characterized by a mediastinal mass and good prognosis, the clinicopathological characteristics of NSCHL in the elderly (NSCHL-e) remain uncertain. Patients and methods:Enrolled patients were diagnosed with CHL between 1986 and 2006 as part of the Hodgkin Lymphoma's Multicenter Study Group. To better characterize NSCHL-e, we compared the clinicopathological profiles of 84 NSCHL-e patients aged 50 or over with 237 NSCHL-y patients aged 49 or younger and 302 with MCCHL. Results:The total of 743 CHL patients consisted of 496 men and 247 women with a median age of 48 years (range, 15– 89 years). The pathological diagnoses were NSCHL in 324 patients (43%) and MCCHL in 303 (41%). NSCHL patients showed a bimodal age distribution, with an initial peak in their 20s and a second small peak in their 60s. We categorized the former as NSCHL-y (49 or younger) and the latter as NSCHL-e (50 and over). NSCHL-e patients were characterized by male predominance and a more advanced clinical stage (53%) than NSCHL-y. Immunophenotypically, H-RS cells had the prototypic immunophenotype of CD15+ CD30+ and Pax5+. NSCHL-e cases showed a significantly higher rate of CD20 (24%) than NSCHL-y (8%, P = 0.001). Furthermore, H-RS cells in 29 of 75 (39%) patients with NSCHL-e were positive for EBV RNA transcripts by in situ hybridization, whereas only 7% of NSCHL-y cases were EBER-positive (P < 0.0001) (Table). Regarding NSCHL-e and MCCHL, no significant difference between these patients was seen in clinical characteristics. Immunophenotypically, NSCHL-e patients showed significantly higher rates for CD3 and TIA-1, while MCCHL patients showed higher EBV positivity (75%). Fifty-five of 63 patients received systemic multi-agent chemotherapy as first-line treatment, consisting of doxorubicin, bleomycin, vinblastine, and dacarbacin (ABVD) in 38 patients; CHOP in 8; C-MOPP in 8; and BEACOPP in 1. Overall, 51 patients responded to first-line treatment, 39 with complete response and 12 with partial response. Disease-specific survival of NSCHL-e was poorer than that of NSCHL-y (P < 0.001) but similar to that of MCCHL (P = 0.43) (Figure). Conclusion:NSCHL-e is characterized by an unfavorable prognosis and different clinicopathological features to NSCHL-y, which is considered as typical NSCHL. A number of cases of NSCHL-e might have been associated with MCCHL, with most being EBV-positive. These results suggest the limitations of current histological subgroupings for CHL. [Display omitted] Disclosures:Matsushita:Pfizer CO.: Membership on an entity's Board of Directors or advisory committees, Research Funding; Baxter Co.: Membership on an entity's Board of Directors or advisory committees, Research Funding.

Tumor Microenvironment In Nodular Lymphocyte Predominant Hodgkin Lymphoma (NLPHL) Influences Occurrence of Relapses and Progression to Large Cell Lymphoma

AbstractAbstract 2684NLPHL accounts for 6.5% of all Hodgkin lymphoma cases in the West. It is characterized by a nodular or a nodular & diffuse proliferation of scattered large atypical CD20+ neoplastic B-cells referred to as lymphocyte predominant (LP) cells and typically associated with small lymphocytes mainly of B-cell type. Patients with NLPHL typically have an indolent clinical course but can frequently relapse. Progression to a higher grade lymphoma, notably T-cell/Histiocyte rich B-cell lymphoma (T/HRBCL) has been described in a relatively small number of cases. Because of its rarity, limited information is available about the role of non-neoplastic lymphocytes in NLPHL. Some studies suggest that NLPHL with T-cell rich background may behave differently than the conventional type with predominance of B-cells within the nodules. The purpose of this study was to evaluate outcomes of differential tumor microenvironment namely B-cell versus T-cell rich in patients with NLPHL. We document the clinicopathologic profiles of 29 patients with biopsy proven NLPHL, consisting of 22 male & 7 female, median age 26 years (range, 13–80 years). All patients had lymphoadenopathy & 2 cases showed extranodal involvement in addition to nodal disease. Two patients had a bulky mass, and three had stage 4 disease at presentation. The pathological diagnoses was reviewed and confirmed by an expert hematopathologist in all 29 cases. The LP cells in all cases had a prototypic immunophenotype of CD20+, CD79a+, PU.1+, Bcl-6+, CD15− CD30− & Fascin−. T/HRBCL was excluded as all cases demonstrated preservation of follicular dendritic meshwork by CD21 staining. The meshwork was expanded in 20 cases & in 9 cases it was partially disrupted evincing an irregular architectural pattern. Epstein-Barr Virus encoded RNA by in situ hybridization was negative in 8/8 cases tested. 27/29 patients received systemic multi-agent chemotherapy consisting of: doxorubicin, bleomycin, vinblastine, and dacarbacin (ABVD), 24 patients; cyclophosphamide, doxorubicin, vincristin, and prednisone (CHOP), 2 patients; Rituximab + CHOP (R-CHOP), 1 patient. 9/29 (31%) cases underwent autologous stem cell transplant. One patient in stage 2A refused therapy and one patient (stage 3A) developed significantly decreased cardiac ejection fraction following initial 2 cycles of ABVD. Both of these cases did not have adequate follow-up information available. Results:Twelve of the 29 cases (42%) were designated as having T-cell rich background population, whereas 17 (58%) were considered as conventional variant with a vast predominance of non-neoplastic small lymphocytes being B-cells. A few of the cases seemed to show admixture of both B-cells & T-cells. Comparing T-cell rich & B-cell rich background NLPHL no significant differences were detected in clinical parameters: age, sex, and stage at presentation, absolute lymphocyte count, LDH & Hb. All 27 (100%) patients in this study responded to first-line treatment: 23 with complete response & 4 with partial response. 13/27 (48%) had relapse/s. Five cases had more than one relapses. No patient died within a clinical follow-up period ranging from 18 to 84 months. When the overall survival (OS) of T-cell rich NLPHL was compared with the conventional variant there was no statistical significance between the two groups (log rank p= 0.1206). However, comparison of relapse rate showed that cases with T-cell rich background had higher relapse rate as well as greater incidence of multiple relapses as compared to B-cell rich type of NLPHL even after adjusting for the type of treatment received (log rank p= 0.003). Moreover, 2/12 (17%) T-cell rich NLPHL cases showed transformation to a high grade lymphoma (both T/HRBCL) at the time of recurrence. These findings suggest that in NLPHL a tumor microenvironment rich in T-cells rather than B-cells is characterized by an unfavorable clinical course although OS appears to be similar. These cases perhaps represent a distinctive clinicopathologic variant within the framework of NLPHL. Lately, the term ‘NLPHL with nodules resembling T/HRBCL’ has been used to express the immunobiological overlap between these two entities. It is possible that such cases could be regarded as “intermediate lymphomas” treading between NLPHL and T/HRLBCL. Further studies using gene array profiling analysis may help clarify the molecular differences between these closely related entities. Disclosures:No relevant conflicts of interest to declare.

Incorporation of ANTI-HHV-8 Agents as Targeted Therapy for the Treatment of HIV-Associated Primary Effusion Lymphoma.

Abstract 4768 BackgroundPrimary effusion lymphoma (PEL) is a non-Hodgkin lymphoma (NHL) which comprises 4% of all AIDS-related lymphomas. PEL has a predilection for body cavities, causing pleural and pericardial effusions and ascites, but may present as masses. EBV is present in PEL cells in 80% of cases, but HHV-8 infection in PEL cells is required for the diagnosis (dx). Historically, treatment encompassed approaches including intracavitary antiretroviral medications (ARV) or chemotherapeutic agents, single or multi-agent systemic chemotherapy, and systemic ARVs, but median survival in case series using these approaches was only 6 months (mo). Treatment with multi-agent chemotherapy and highly active ARV therapy (HAART) yields good outcome in other HIV-NHL with survival approaching that of the HIV-negative population, but gives unknown survival rates in PEL. Recent consideration has been given to targeted therapy directed against HHV-8 infection with antiviral agents, with encouraging outcomes reported in the literature, particularly the HHV-8 associated syndromes Kaposi Sarcoma (KS) and Multicentric Castleman's Disease. We report on 5 patients (pts) diagnosed with PEL and treated at St. Paul's Hospital, 2 of whom are receiving valganciclovir (VGCV) therapy directed against HHV-8 infection of PEL cells. MethodsWe conducted a retrospective review of pts with a tissue dx of PEL since 2004. PEL data was collected from the clinical charts and HIV-related data from the BC Centre for Excellence in HIV/AIDS (CFE) database. A literature search was performed to capture prior studies of anti-HHV-8 medications used to treat PEL. ResultsThe median age at PEL diagnosis was 60 (range 48-68) years (y); gender was: male, n=4; and female, n=1. 2 pts had a history of KS. The median CD4 count at PEL dx was 230 (50-560) cells/ml, 1 pt had a CD4 count of 50 cells/ml and all others were ≥210 cells/ml; median HIV viral load (VL; reported in 4) was 81 (35-176,600) copies/ml. The median time from HIV dx to PEL dx was 6 (0-21) y and from initiation of HAART to PEL dx 1 (0-11) y. Clinical PEL presentation was: pleural effusions, n=4; pericardial effusion, n=2; ascites, n=1; associated mass, n=1; mass without effusions, n=1. PEL treatment was: CHOP + HAART, n=2; CHOP + HAART + VGCV, n=1; HAART + VGCF, n=1; supportive care, n=1. 2 pts receiving CHOP and HAART are both in complete remission (CR) at 8 and 57 months (mo) from PEL dx. 2 pts diagnosed since December 2008 are receiving VGCV and HAART, and 1 of these pts is receiving CHOP with good tolerance (the other pt declined cytotoxic chemotherapy). Of 3 pts receiving CHOP, there was 1 episode of febrile neutropenia (FN) in 1 pt and 5 episodes of FN and 3 clinical infections in a second pt. The same pt had profound anemia and thrombocytopenia requiring transfusion support; this pt did not receive VGCV. 1 pt receiving VGCV with HAART and CHOP required G-CSF support but did not develop FN or clinical infection. 1 pt presented with a poor performance status, received supportive care only and died within one mo of PEL dx; all others are alive at 4, 8, 14 and 57 months from PEL dx. A literature review identified 2 reports of pts with PEL receiving systemic cidofovir (CDFV) directed against HHV-8. One pt with a CD4 count of 72 cells/ml and an HIV-VL of 75,000 copies/ml received unspecified systemic chemotherapy, HAART and intravenous (IV) CDFV followed by VGCV and is in CR at 68 mo from PEL dx. A second pt with a CD4 of 498 cells/ml (HIV-VL not reported) received HAART, IV cidofovir and interferon and is in CR at 28 mo. ConclusionsPEL treatment has focused on optimization of HIV control with HAART and lymphoma control with chemotherapy, however, antiviral medications as targeted therapy directed against HHV-8 infection of PEL cells may be used without undue toxicity and possibly with success. PEL generally involves latent HHV-8 infection, which is theoretically not susceptible to antiviral medications, but there are reports in the literature of encouraging results achieved by combining agents to induce lytic infection (including chemotherapeutic agents) with anti-herpes virus therapy. Our review indicates good tolerance of VGCV with HAART ± CHOP chemotherapy, and that with newer treatment approaches, pts may live longer than the 6 mo median survival previously reported. To our knowledge, our pts receiving VGCV are the third and fourth pts reported receiving anti-HHV-8 therapy as treatment for PEL. Disclosures:Off Label Use This presentation discusses the use of valganciclovir in the treatment of HHV-8 associated primary effusion lymphoma..

Cytotoxic Molecule (CM)-Positive Classical Hodgkin Lymphoma: a Clinicopathologic Study in Comparison with Nodal Peripheral T-Cell Lymphoma of Not Otherwise Specified Type Possessing CM Expression.

Abstract 1549Poster Board I-572Classical Hodgkin lymphoma (CHL) is characterized by Hodgkin and Reed Sternberg (H-RS) cells, which are B-cell origin in many cases. Recently, we highlighted an adverse prognostic significance of cytotoxic molecule (CM) expression among CHL patients (Asano N, et al. J Clin Oncol. 2006). However, the clinical characteristics of CM-positive CHL still remain controversial. We here document the clinicopathologic profiles of 35 patients with CM-positive CHL, consisting of 23 men and 12 women with a median age of 50 years (range, 16 - 84 years). All patients had lymphoadenopathy, and 14 cases showed mediastinal involvement at presentation. Physical findings included hepatomegaly and splenomegaly in six and five patients, respectively. Four patients had a bulky mass, and nine showed stage IV disease. As for laboratory data, four patients had elevated white blood cell counts (greater than 15.0 × 103/mm3). Anemia (hemoglobin level; less than 10.5 g/dl) was also present in six patients. The pathological diagnoses were nodular sclerosis type (NS) in 22 cases and mixed cellularity (MC) in 12 cases. The H-RS cells of CM-positive CHL had a prototypic immunophenotype of CD15+ CD30+ and Fascin+. All of the cases completely lacked CD20 positivity on H-RS cells, while the expression of CD3e and CD45RO was found in 2 and 1, respectively. The H-RS cells were further positive for EBV RNA transcripts in 14 of 32 (44%) cases studied by in situ hybridization method. All except three cases were negative for Pax5. A clonal TCR-g chain gene arrangement was undetected in any of the cases with successful amplification of control GAPDH DNA by PCR analysis. No cases show B-cell clonality. 27 of 35 patients received systemic multi-agent chemotherapy consisting of first-line treatment regimens as follows: doxorubicin, bleomycin, vinblastine, and dacarbacin (ABVD) (22 patients); cyclophosphamide, doxorubicin, vincristin, and prednisone (CHOP) (2 patients); two with C-MOPP; and one BEACOPP regimens. Three patients died within 6 months, before completing induction treatment because of disease progression. Overall, 22 patients responded to first-line treatment: 13 with complete response and 9 with partial response. 13 of them had relapses, and 8 died with a clinical course ranging from 7 to 142 months. Effective therapeutic approaches should be explored for CM-positive CHL patients, who resist standard treatment for CHL. Comparing CM-positive nodal peripheral T-cell lymphomas of not otherwise specified type (PTCL-N)(n=55) with CM-positive CHL(n=35), no significant differences were detected in clinical parameters except for the frequency of elevated lactate dehydrogenase level in CM-positive PTCL-N. Immunophenotypically, CM-positive CHL cases showed significantly higher rates for CD15, CD30, and Fascin expression, while CM-positive PTCL-N cases showed significantly higher CD3e, CD8, CD45RO, and CXCR3 positivity. The survival curve of CM-positive CHL showed poorer prognosis than that of CM-negative CHL (P = .0002) and better than that of CM-positive PTCL-N (P = .002) (Figure). These findings suggest that CM-positive CHL is characterized by an unfavorable clinical feature, although their histologic and phenotypic features are more suggestive of CHL. Moreover, one case in CM-positive CHL had presented the skin lesion as a CD30-positive lymphoproliferative disorder or an ALK-negative anaplastic large cell lymphoma (ALCL) at the time of recurrence. These findings suggest that CM-positive CHL represent a distinct variant form based on clinicopathologic and phenotypic traits beyond the framework of CHL. Significant overlaps in biologic and morphologic features has been identified in CHL and non-Hodgkin lymphoma. CM-positive CHL cases may be ‘intermediate lymphoma‘ between CHL and PTCL or ALK-negative ALCL. Further studies, including array CGH profiling analysis are needed to clarify the origin of CM-positive CHL. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.