Cycles Of Multiagent Chemotherapy Research Articles

Predictors of surgical complications in surger y of disseminated skull base tumors

Post-surgical complications are rather important, and, perhaps, more significant factors determining the efficiency of the provided treatment together with the natural oncological disease course, accompanying pathology, and peculiarities of the adjuvant therapy. The decrease in the frequency and severity of these complications, revealing of modifiable and non-modifiable risk factors, their prevention and reduction are definitely of scientific and practical interest. The aim of the work is the search for predictors of post-surgical complications in the patients with disseminated malignant skull base tumors. The retro-prospective single-center cohort study based on the analysis of the results of surgical treatment of 161 patients with such neoplasms was carried out. The study covered the patients at the age of 19–84 years, with the average age of 55 years (statistical deviation: +\- 1.2). There were 78 women and 83 men. Accordingly, the sex distribution was 1:1.064. The pre-surgical radical radiotherapy was made for 43 patients (26.71 %); 21 patients (13.04 %) underwent one or several cycles of multiagent chemotherapy. Morphologically, there were 16 different types of tumors, among which the epithelial tumors 40.37 % (n=65) prevailed: epidermoid cancer — 16.15 % (n=26), sinonasal cancer — 8.07 % (n=13), and acinic cell carcinoma 5.59 % (n=9). Sarcomas were diagnosed in 12 patients (7.45 %). The study results demonstrate the lack of particular statistically substantiated symptoms or clinical factors — predictors, individually and independently affecting the unfavorable results of the surgical treatment of the patients with disseminated malignant skull base tumors. On the contrary, the syndromological combination of local, general and organizational problems definitely influences the surgery result significantly, while not all mathematically predicted combinations can be formalized into some clinical equivalent.

Effect of Postreinduction Therapy Consolidation With Blinatumomab vs Chemotherapy on Disease-Free Survival in Children, Adolescents, and Young Adults With First Relapse of B-Cell Acute Lymphoblastic Leukemia

Standard chemotherapy for first relapse of B-cell acute lymphoblastic leukemia (B-ALL) in children, adolescents, and young adults is associated with high rates of severe toxicities, subsequent relapse, and death, especially for patients with early relapse (high risk) or late relapse with residual disease after reinduction chemotherapy (intermediate risk). Blinatumomab, a bispecific CD3 to CD19 T cell-engaging antibody construct, is efficacious in relapsed/refractory B-ALL and has a favorable toxicity profile. To determine whether substituting blinatumomab for intensive chemotherapy in consolidation therapy would improve survival in children, adolescents, and young adults with high- and intermediate-risk first relapse of B-ALL. This trial was a randomized phase 3 clinical trial conducted by the Children's Oncology Group at 155 hospitals in the US, Canada, Australia, and New Zealand with enrollment from December 2014 to September 2019 and follow-up until September 30, 2020. Eligible patients included those aged 1 to 30 years with B-ALL first relapse, excluding those with Down syndrome, Philadelphia chromosome-positive ALL, prior hematopoietic stem cell transplant, or prior blinatumomab treatment (n = 669). All patients received a 4-week reinduction chemotherapy course, followed by randomized assignment to receive 2 cycles of blinatumomab (n = 105) or 2 cycles of multiagent chemotherapy (n = 103), each followed by transplant. The primary end point was disease-free survival and the secondary end point was overall survival, both from the time of randomization. The threshold for statistical significance was set at a 1-sided P <.025. Among 208 randomized patients (median age, 9 years; 97 [47%] females), 118 (57%) completed the randomized therapy. Randomization was terminated at the recommendation of the data and safety monitoring committee without meeting stopping rules for efficacy or futility; at that point, 80 of 131 planned events occurred. With 2.9 years of median follow-up, 2-year disease-free survival was 54.4% for the blinatumomab group vs 39.0% for the chemotherapy group (hazard ratio for disease progression or mortality, 0.70 [95% CI, 0.47-1.03]); 1-sided P = .03). Two-year overall survival was 71.3% for the blinatumomab group vs 58.4% for the chemotherapy group (hazard ratio for mortality, 0.62 [95% CI, 0.39-0.98]; 1-sided P = .02). Rates of notable serious adverse events included infection (15%), febrile neutropenia (5%), sepsis (2%), and mucositis (1%) for the blinatumomab group and infection (65%), febrile neutropenia (58%), sepsis (27%), and mucositis (28%) for the chemotherapy group. Among children, adolescents, and young adults with high- and intermediate-risk first relapse of B-ALL, postreinduction treatment with blinatumomab compared with chemotherapy, followed by transplant, did not result in a statistically significant difference in disease-free survival. However, study interpretation is limited by early termination with possible underpowering for the primary end point. ClinicalTrials.gov Identifier: NCT02101853.

GCT-70. INTRACRANIAL GROWING TERATOMA SYNDROME IN CHILDREN

Germ cell tumors account for less than 5% of all intracranial malignancies in children. Intracranial growing teratoma syndrome (GTS) is a rare pathophysiologic process characterized by growth of mature teratoma elements of a non-germinomatous germ cell tumor (NGGCT) during or following treatment with chemotherapy, in addition to normalization of or declining AFP/βHCG of the cerebral spinal fluid (CSF)/serum. A 13-year-old male presented with headache, emesis, and diplopia. MRI of the brain/spine revealed a localized 3.1 x 3.1 x 3.2 cm pineal tumor. Biopsy confirmed NGGCT (germinoma, immature and mature teratoma). Serum AFP (227ng/ul) and βHCG (12 IU/L) and CSF AFP (21ng/ul) and βHCG (31 IU/L) were elevated. Prior to cycle two of chemotherapy, he developed unstable gait and moderate hearing loss. Repeat MRI brain demonstrated tumor enlargement (4.4 x 5.2 x 5.1 cm) and obstructive hydrocephalus, although serum AFP/βHCG had normalized. Gross total resection of tumor confirmed GTS, without residual immature/malignant elements. Following six cycles of multiagent chemotherapy (carboplatin, etoposide, ifosfamide) and proton beam craniospinal irradiation (36 Gy with 18 Gy boost), he remains free of disease at eleven months since diagnosis. The pathogenesis of GTS remains unclear. Care must be taken to avoid misdiagnosing GTS as progressive NGGCT, as treatment and prognosis differ significantly. Second-look surgery, with a goal of complete resection, should be considered in cases of NGGCT when residual tumor grows during or following therapy, as this may represent GTS. Although histologically benign, GTS can be fatal. In patients with GTS, complete resection is usually curative.

Gestational Trophoblastic Neoplasia

Introduction: Gestational trophoblastic neoplasia (GTN) account for less than 1% of cancers of the female reproductive system. Nearly 50% of gestational choriocarcinomas are seen after molar pregnancies. About 25% after abortions or ectopic pregnancy and another 25% after a normal pregnancy. FIGO staging and prognostic scoring index of modified WHO classification is used. Serum β-HCG assay is an important factor in the diagnosis and management of GTN. It is a sensitive tumour marker for GTN and its level is directly related to the number of viable tumour cells. Serial measurement of β-hCG levels is useful for follow-up of women diagnosed with complete or partial mole. An increasing level or plateauing of serum β-hCG is diagnostic of invasive disease which can be invasive mole or choriocarcinoma. Case Report: Patient A-was a 22 year old lady, para1, two year old child which was a normal delivery. She was asymptomatic and reported to the hospital for missed periods. Urine pregnancy test was positive. Ultrasound scan did not find any pregnancy. Beta HCG levels were very high. Then MRI was done which showed no abnormality, other than a bulky uterus. Curettage was done and the report came as trophoblastic tissue seen with possibility of choriocarcinoma. This patient was given 2 cycles of methotrexate with folinic acid after which the patient was lost to follow up. Patient B-was a 27 year old lady, para1, three year old child delivered by caesarean section. She also gave history of two subsequent abortions. She presented with menorrhagia and on examination a cervical polyp was detected. The polyp was resected and sent for histo-pathology and the report suggested choriocarcinoma. Her beta HCG was 30,000. This patient was given three cycles of multi-agent chemotherapy, MAC (Methotrexate, Actinomycin-D and Cyclophosphamide) regime and responded to treatment. Discussion: The main stay of treatment is chemotherapy. Mostly single agent chemotherapy is used methotrexate being the drug of choice. Methotrexate in the dose of 0.4 mg/kg IM or IV daily for 5 days, appears to be the most effective treatment protocol. Another widely used regimen is using folinic acid along with methotrexate. Some of the more commonly used multiagent chemotherapy combinations are – MAC, EMA-CO, EMA-EP, VBP and BEP. Conclusion: GTN can be treated with appropriate chemotherapy and supportive management, after correct staging and scoring of the disease. They are also the most curable of all cancers in women.

“Bilateral Ureteral Diffuse Large B-Cell Lymphoma” from the Diagnosis to the Management: A Unique Case to be Reported and Review of Literature

We are reporting a rare case of bilateral ureteral Non-Hodgkin's lymphoma. A 55-year-old male patient was presented with bilateral loin pain, oliguria and high serum creatinine (8 mg/dl). Non contrast computed tomography revealed bilateral hydroureteronephrosis down to bilateral upper lumbar ureteral soft tissue masses. Drainage of the kidneys by fixation of bilateral indwelling ureteral stents was done. Evaluation of the patient by magnetic resonance imaging revealed bilateral enhancing proximal ureteral lesions. Bilateral diagnostic ureteroscopy revealed bilateral fleshy lesions in the upper lumbar ureter from which was retrieved. The biopsy was positive for poorly differentiated urothelial carcinoma. The patient was managed by right nephroureterectomy. Histopathological evaluation of the radical specimen was highly suspicious for lymphoma. Immunohistochemistry analysis confirmed the presence of diffuse large B-cell lymphoma. The patient received three cycles of multi-agent chemotherapy. Complete remission of the left ureteral lesion was confirmed by magnetic resonance imaging and diagnostic ureteroscopy.

Hodgkin lymphoma in elderly patients.

We aim to summarize the current knowledge on the treatment of elderly Hodgkin lymphoma patients with a focus on evidence from clinical trials and novel drugs. For elderly Hodgkin lymphoma patients above 60 years without precluding comorbidities a curative treatment approach is warranted. Early favorable stage patients should receive two cycles of multiagent chemotherapy followed by 20 Gy localized radiotherapy. Early unfavorable stage patients should receive four cycles of multiagent chemotherapy followed by 30 Gy localized radiotherapy. For advanced stage patients six cycles of multiagent chemotherapy can be recommended and should be followed by localized radiotherapy on residual disease manifestations. Relapsed or refractory patients should be treated in an individually tailored approach that considers both the patient's objectives and comorbidities. The antibody-drug conjugate brentuximab vedotin is a very effective option for elderly patients with a high response rate albeit limited durability. Anti-programed cell death protein 1 antibodies might also be effective in elderly Hodgkin lymphoma patients with a mechanism of action distinct from chemotherapy. In conclusion, the goal of treatment in newly diagnosed elderly Hodgkin lymphoma patients is curative whenever possible and prospective and retrospective evidence has shown that this is feasible for all disease stages with a variety of multiagent chemotherapy regimen. Relapsed and refractory elderly Hodgkin lymphoma patients can mostly only be treated with the goal of palliation. However, it remains to be seen if novel substances and new combination regimen are able to change that.

Nodular lymphocyte-predominant Hodgkin lymphoma: a unique disease deserving unique management.

Nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL) is a rare lymphoma entity with an incidence of 0.1 to 0.2/100 000/y. Compared with the more common subtypes of classical Hodgkin lymphoma, NLPHL is characterized by distinct pathological and clinical features. Histologically, the disease-defining lymphocyte predominant cells consistently express CD20 but lack CD30. Clinically, NLPHL mostly has a rather indolent course, and patients usually are diagnosed in early stages. The prognosis of early-stage NLPHL is excellent, with progression-free survival and overall survival rates exceeding 90% after involved-field radiotherapy (IF-RT) alone (stage IA) or combined modality treatment consisting of a brief chemotherapy with 2 cycles of ABVD (doxorubicin, bleomycin, vinblastine, dacarbazine) chemotherapy followed by IF-RT (early stages other than stage IA). In contrast, patients with advanced disease at diagnosis tend to relapse either with NLPHL histology or with histological transformation into aggressive B-cell non-Hodgkin lymphoma despite more aggressive first-line treatment with 6 to 8 cycles of multiagent chemotherapy. However, even NLPHL patients with multiple relapses successfully respond to salvage therapy in many cases. Salvage therapies range from single-agent anti-CD20 antibody treatment to high-dose chemotherapy followed by autologous stem cell transplantation. Treatment at disease recurrence should be chosen on the basis of various factors, including histology at relapse, time to relapse, extent of disease at relapse, and prior treatment. Because death among NLPHL patients is more often caused by therapy-related late effects than lymphoma-related complications, optimizing the risk-benefit ratio of treatment by decreasing toxicity whenever possible is the major goal of clinical research in this disease.

Umbilical Cord Blood Transplant Patients At High Risk Of Graft Rejection Achieve Early Full Donor Chimerism When 300cGy Is Used In The Reduced Intensity Conditioning Regimen

BackgroundWhile delayed or failed engraftment following reduced intensity conditioning (RIC) umbilical cord blood transplant (UCBT) now occurs less frequently than initially reported, it continues to be higher than in the conventional donor setting. It has been shown that patients who have had a prior autologous transplant or who have received chemotherapy within 4 months of UCBT have an increased incidence of sustained donor engraftment compared with those without this prior therapy (98% vs 64%) (Barker et al ASH abstract 2003). The standard measure of engraftment following UCBT is neutrophil recovery to > 500 x 3 days. However, there has recently been established a possible correlation between time to neutrophil engraftment and early full donor chimerism after UCBT (Avery S et al BMT 2012). Herein, we conducted an RIC UCBT trial in which patients were assigned to one of two treatment regimens based on their risk of graft failure. In addition to evaluating sustained donor engraftment characterized by time to neutrophil recovery, we also sought to assess the achievement of full donor chimerism at Day +28 post-transplant in patients pre-determined to be high versus low risk of graft failure. MethodsForty-eight patients median age 59 years (range 25 - 73) and comorbidity index = 3 (range 0 - 8) with high risk hematologic malignancies received an RIC regimen containing cyclophosphamide 50mg/kg on Day -6, fludarabine 40mg/m2 Day -6 to -2 (dose reduced to 35mg/m2 for creatinine clearance < 70), and either 200 cGy TBI (Arm 1 = low risk of graft failure) or 300 cGy TBI (Arm 2 = high risk of graft failure) on Day -1. High risk for graft failure was defined as “receiving < 2 cycles of multiagent chemotherapy or no multiagent chemotherapy within the 3 months prior to UCBT.” Low risk for graft failure was defined as “having received a prior autologous transplant within 12 months or ≥ 2 cycles of multiagent chemotherapy with at least one cycle of therapy within the 3 months prior to UCBT.” Patients on both arms received GVHD prophylaxis with cyclosporine from Day -1 to Day +180 and mycopheolate mofeteil 1 gram every 8 hours until Day +40. Forty-seven of 48 patients received 2 UCB units (one patient received a single UCB) with a median TNC/kg of 4.05 x 107 and a post-thaw median CD34+cells/kg of 1.75 x 105. UCB grafts (98%) were 1-2 HLA antigen mismatched with the recipient. Twenty-six patients were assigned to Arm 1 and 22 patients were assigned to Arm 2. Bone marrow and peripheral blood chimerism assessment were performed at approximately Day +28 and Day +80. The blood was flow sorted in the clinical hematopathology lab into defined lineage subsets. Wilcoxon rank-sum test was used to compare the 2 groups. ResultsAll evaluable patients engrafted (n = 46). Patients on Arm 1 achieved neutrophil recovery (ANC > 500 x 3 days) at a median of 12 days (range 6 - 38) versus 23 days (range 7- 46) in patients on Arm 2 (p = 0.01). Day +28 chimerism values were evaluable for 23 patients on Arm 1 and 20 patients on Arm 2. Median chimerism in the CD3+ compartment was 100% (57 - 100) and 100% (0 - 100) on Arm 1 and Arm 2 respectively (p = 0.58). Median chimerism in the CD33+compartment was 98% (15 - 100) and 100% (44-100) on Arm 1 and Arm 2 respectively (p =0.26). Median chimerism in the bone marrow was 98% (15 - 100) and 100% (4 - 100) on Arm 1 and Arm 2 respectively (p = 0.84). This was maintained at Day +80. Acute graft versus host disease (GVHD) grades II - IV was seen in 84% (n = 21) and 68% (n = 15) of patients on Arm 1 and 2 respectively with 5% and 12% grade III-IV GVHD in the respective arms. Chronic GVHD was seen in 40% of patients on Arm 1 (8 mild, 2 moderate) and 23% on Arm 2 (3 mild, 1 moderate, 1 severe). Overall survival at 1 year in Arm 1 was 43% (95% CI: 22-62%) and Arm 2 was 46% (95% CI: 20-69%). ConclusionsThe goal of this RIC UCBT study was to assess engraftment rates by neutrophil recovery and Day +28 chimerism in patients at low versus high risk of graft rejection. Although time to neutrophil recovery was significantly faster in patients with low risk of graft failure, patients at high risk of rejection achieved a similar incidence of full donor chimerism at Day +28 as those with low risk of graft rejection. Using Day +28 chimerism as a measure of engraftment, patients deemed high risk of graft failure achieved early engraftment with UCBT following an RIC conditioning regimen containing 300cGy TBI. Disclosures:No relevant conflicts of interest to declare.

Pharmacokinetics-Based Modification of Intravenous Pegylated Asparaginase Dosing in the Context of a “Pediatric-inspired” Protocol in Adults with Newly Diagnosed Acute Lymphoblastic Leukemia (ALL)

AbstractAbstract 1495Prolonged Asparaginase (ASP) use is standard in all pediatric ALL regimens. In adults ASP is either not used or given for much shorter duration. Recently, several adult ALL protocols adopted pediatric regimens, with long duration of ASP, mostly E. coli, with better outcomes than historically reported. However, optimal implementation of pediatric regimens to adults, especially ASP dosing, has not been studied, considering its potential higher toxicity. We report the results of an ALL protocol adopted from pediatrics, modified by using the long acting pegaspargase (PEG-ASP) with a pharmacokinetics-based dosing strategy, intended for adults with newly diagnosed ALL. Methods:We adopted the augmented BFM pediatric protocol (Nachman NEJM 1998) replacing the native E. coli ASP with 6 doses of PEG-ASP. Pediatric and most pediatric-inspired adult protocols use 2,500 u/m2 PEG-ASP at 2 week intervals. Based on our PEG-ASP adult PK and PD data (Douer Blood 2007), the dose was reduced to 2,000 u/m2IV, at intervals no shorter than 4 weeks. Other modifications include 1) Each PEG-ASP dose, having a very long activity (2–4 weeks), was synchronized with the time of myelosuppressive drugs so that there anticipated different serious toxicities are less likely to coincide. 2) Replaced escalated MTX dosing plus E.coli ASP with 4 fixed high doses of MTX, timing PEG-ASP to avoid its overlapping long enzymatic activity with MTX activity. 3) hydrocortisone pre-medication and steroids for 7–14 days after each PEG-ASP dose to prevent allergic reactions. The protocol included 8 cycles of multi-agent chemotherapy, 2-year maintenance and IT MTX CNS prophylaxis. PEG-ASP was given intravenously (IV) once on day 15–17 of induction phase I (cycle 1), induction phase II (cycle 2), two cycles of consolidation (# 3 & 6), and two cycles of delayed re-induction (# 5 & 8). Results:Between July 2004 and July 2009, 51 (17 women) adults with newly diagnosed previously untreated ALL were enrolled in 2 USC affiliated hospitals. Patient characteristics include: median age - 33 (range18–57) yrs, precursor B cell - 46, T cell-5, Ph+ 11, and median WBC-14,500 (range 800-512, 000)/dL. Total number of PEG-ASP doses was: all 6 doses - 23 pts, 4 doses- 1 pt., 3– 7 pts. 2–9 pts, 1–11pts. Twenty eight (55%) pts. did not complete 6 PEG-ASP doses due to: allogeneic HSCT −8 pts, refusal −1pt., induction failure – 2pts, death in CR −3 pts., relapse- 4 pts; and PEG-ASP related toxicities: 11 (21%) pts: including pancreatitis −7pts, allergy −3 pts, DVT-1 pt (one pt. had pancreatitis and later transplanted). Among 51 pts PEG-ASP related grade 3/4 toxicities were: anaphylaxis-2 pts.(4%); pancreatitis-7 (14%) pts.; thrombosis-8(16%) (5 catheter-related); transaminitis −33(65%); high bilirubin −22 (43%); hyperglycemia-17(33%); high triglycerides −8(16%); fatigue-4(8%). Table I shows the rates of ASP related toxicities in 173 doses. All toxicities were reversible without any PEG-ASP-related deaths. Outcome data is shown in Table 2.Table 1:Rate of ASP Related Grade 3 /4 Toxicities in 173 DosesToxicityPancreatitis5%Allergy3%DVT5%Bleeding<1%Transaminitis36%High bilirubin14%Hyperglycemia20%High triglycerides27%Fatigue3%Neuropathy1%Vomiting1%Nausea2%Table 2OutcomesAll PatientsPh -Number5140CR, No (%)49 (96%)39 (98%)CR at 4 wks, No (%)48 (98%)39 (100%)OS*51%58%DFS*58%58%OS Standard risk73% (n=17)OS High risk**40% (n=34)OS No HSCT55% (n=42)DFS No HSCT58% (n=40)*At 7 years,**High Risk: Ph+, t(4;11), WBC B cell >35,000/dL, T cell > 100,000/dL, age > 30 yrs, CR in < 4 weeks (Goldstone Blood 2009).Median follow up – 44 monthsNeutralizing antibodies measured in 247 serum samples from 34 pts. (33, 11 & 10 pts. after PEG-ASP doses # 1, 4, and 6 respectively) were detected in 1 patient Conclusion:Our rational modification of a pediatric protocol, in adult ALL (age <57 years), is feasible, has very high CR rate (98% by 4 weeks), 58% 7-years DFS, even without HSCT, and in line with reported results of other pediatric-inspired regimens. PEG-ASP toxicities were common but mostly manageable and reversible. Our study suggests the that standard PEG-ASP adult dose can be reduced to 2,000 u/m2 IV at intervals no less than 4 weeks without impairing overall outcome. Steroids may reduce clinical allergies, without masking silent neutralizing antibody formation. The concepts of this study, especially PEG-ASP dosing, could be applied in future ALL protocols. Disclosures:Douer:Sigma Tau: Research Funding, Speakers Bureau. Avramis:Sigma Tau: Consultancy.

Umbilical Cord Blood Transplantation in Patients with Hematological Malignancies Using a Non-ATG Containing Reduced Intensity Preparative Regimen

Abstract 1943▪▪This icon denotes a clinically relevant abstractReduced intensity conditioning (RIC) regimens in umbilical cord blood transplant (UCBT) are increasingly utilized for older patients (pts) and those with comorbidities. However, the optimal conditioning regimen has not yet been established and remains a significant challenge of this therapeutic approach. Incorporation of ATG into the conditioning regimen is thought to decrease the incidence of graft rejection, but it is associated with high incidence of infusion associated reactions and serum sickness, delayed T cell recovery, increased infections and higher risk of EBV post-transplant lymphoproliferative disorder (PTLD). We report the results of a non-ATG containing RIC regimen, in which ATG is replaced with a higher dose of TBI in pts considered to be at higher risk of graft failure.All pts received fludarabine (40mg/m2/day) from day −6 to day −2 and cyclophosphamide (50mg/kg) on day −6. Pts who had received a previous autologous transplant within 12 months or ≥ 2 cycles of multiagent chemotherapy with at least one cycle of therapy within the 3 months previous to UCBT received a single fraction of 200cGy TBI on day −1. All other pts were considered at higher risk of graft rejection and received a single fraction of 300cGy of TBI on day −1. GVHD prophylaxis began on day −3 and consisted of cyclosporine A (CSA) and mycophenolate mofetyl (MMF). CSA was continued until at least day +100 and then tapered 10% per week starting on day +101 and discontinued no sooner than 6 months post-transplant. The duration of MMF was prolonged, with initiation of a taper on day+40 post transplant and then in the absence of GVHD, tapered by 12% per week and discontinued after day + 96.Thirty pts underwent double UCBT at 3 transplant centers using this protocol between February 2006 and January 2011. Median age and weight of the pts were 60 (range, 24–73) years and 78 (range, 55–141) kg, respectively. Disease status included AML-CR1 (n=11) and CR2 (n=5), ALL-CR2 (n=1) and refractory ALL (n=2), biphenotypic leukemia in 1st CR (n=1), MDS (n=1), relapsed/ refractory Hodgkin lymphoma (n=3), transformed DLBCL (n=1), primary PTCL (n=1) and very high grade B cell lymphoblastic lymphoma in 2nd CR (n=1). Nine pts (30%) had failed prior hematopoietic cell transplantation (HCT), of which 5 were auto, 3 were allo and 1 both auto and allo transplant. All pts received 2 cord blood units to achieve the required cryopreserved cell dose of 3.0×107 TNC/kg. The median cell doses infused were 4.92 × 107 (range, 3.12–8.3) TNC/kg and 0.26×106 (range, 0.02–2.85) CD34+ cells/kg. Among the 60 infused units, HLA matching was 6/6 in 3% (n=1), 5/6 in 30% (n=9) and 4/6 in 67% (n=20) of the pts. Twenty-two pts (73%) received 2GY and 8 (27%) received 3Gy of TBI. The median number of prior treatments and comorbidity score were 3 (range, 0–8) and 3 (range, 1–8), respectively. The median follow up was 183 days (range, 132 to 1303 days).Neutrophils engraftment occurred in all pts at a median of 13 (range, 6 to 40) days and platelet (PLT) engraftment (>50×109/L ) occurred at a median of 32 (range, 23 to 42) days, respectively. There was only one case of secondary graft rejection and no cases of primary graft rejection. The cumulative incidence of acute GVHD grade II-IV and III-IV were 60% and 24%, respectively; the cumulative incidence of chronic GVHD was 18%. Day 100 NRM was 17%. At one year, NRM, OS and PFS were 29%, 53% and 45%, respectively. Causes of death included relapse (n=6), multi-organ failure (n=2), sepsis (n=1), diffuse alveolar hemorrhage (n=1), necrotizing hemorrhagic meningitis (n=1), leukoencephalopathy (n=1) and intracranial bleed (n=1).There were no cases of CMV disease or PTLD. On multivariate analysis, only neutrophil and platelet engraftment were associated with mortality, with hazard ratios of 0.07 (95%, CI 0.009–0.61), p=0.01) and 0.11 (95%, CI 0.03–0.41, p=0.0009), respectively. Other variables, such as age, number of previous regimens, presence of minimal residual disease prior to transplant, dose of TBI (3Gy vs 2Gy), high-risk disease, comorbidity score and acute GVHD grade II-IV were not statistically significantly associated with poorer survival.In summary, results of this study to date demonstrate that this non-ATG containing conditioning regimen, with intensified immunosuppression and increased dose of TBI, provides a low incidence of graft rejection without increasing toxicity or the incidence of chronic GVHD. [Display omitted] Disclosures:No relevant conflicts of interest to declare.

Pilot Induction Regimen Incorporating Pharmacokinetically Guided Topotecan for Treatment of Newly Diagnosed High-Risk Neuroblastoma: A Children's Oncology Group Study

To assess the feasibility of adding dose-intensive topotecan and cyclophosphamide to induction therapy for newly diagnosed high-risk neuroblastoma (HRNB). Enrolled patients received two cycles of topotecan (approximately 1.2 mg/m(2)/d) and cyclophosphamide (400 mg/m(2)/d) for 5 days followed by four cycles of multiagent chemotherapy (Memorial Sloan-Kettering Cancer Center [MSKCC] regimen). Pharmacokinetically guided topotecan dosing (target systemic exposure with area under the curve of 50 to 70 ng/mL/hr) was performed. Peripheral-blood stem cell (PBSC) harvest and surgical resection of residual primary tumor occurred after cycles 2 and 5, respectively. Patients achieving at least a partial response received myeloablative chemotherapy with PBSC rescue and radiation to the presurgical primary tumor volume. Oral 13-cis-retinoic acid maintenance therapy was administered twice daily for 14 days in six 28-day cycles. Thirty-one patients were enrolled onto the study. No deaths related to toxicity or dose-limiting toxicities occurred during induction. Mucositis rarely occurred after topotecan cycles (9.7%) in contrast to 30% after MSKCC cycles. Thirty patients underwent PBSC collection with median 31.1 × 10(6) CD34+ cells/kg (range, 1.8 to 541.8 × 10(6) CD34+ cells/kg), all negative for tumor contamination by immunocytochemical analysis. Targeted topotecan systemic exposure was achieved in 26 (84%) of 31 patients. At the end of induction, 26 patients (84%) had tumor response and one patient had progressive disease. In the overall cohort, 3-year event-free and overall survival were 37.8% ± 9.4% and 57.1% ± 9.4%, respectively. This pilot induction regimen was well tolerated with expected and reversible toxicities. These data support investigation of efficacy in a phase III clinical trial for newly diagnosed HRNB.

Ovarian Yolk Sac Tumor Associated With Major Fibrosarcoma Component in a 13-year-old Girl

We are presenting a case of a 13-year-old girl with a chief complaint of lower abdominal pain. A computed tomographic scan showed a 10-cm right ovarian mass. The serologic testing showed high alpha-fetoprotein level. The patient underwent a right adnexectomy and an omentectomy. The final diagnosis was a yolk sac tumor with a major (95%) fibrosarcoma component, based on morphology and further confirmed by an extensive panel of immunohistochemistry. Postoperatively, the alpha-fetoprotein level dropped to normal. The patient completed 7 cycles of multiagent chemotherapy with cisplatin without major complications. At her 7-month follow-up, the patient still remains disease free. To our knowledge, our case is the first of its kind in the literature to document yolk sac tumor associated with fibrosarcoma in a teenage female. Owing to the rarity of this entity, the prognosis of this patient is widely unknown and it is yet still to be seen.

Multiple Doses of Intravenous Pegylated Asparaginase with a “Pediatric-like” Protocol in Adults with Newly Diagnosed Acute Lymphoblastic Leukemia (ALL): Toxicity, Clinical Outcome and Low Rate of Anti Asparaginase Antibody Formation.

Abstract 3082Poster Board III-19Several, large randomized multi-agent trials, in pediatric ALL have shown that prolonged use of asparaginase (ASP) during remission resulted in better outcomes. Adequate serum asparagine depletion from ASP administration has been suggested to have a therapeutic impact. Historically, adult ALL regimens use less, shorter or no ASP compared to pediatrics, as the drug is considered more toxic. However, a recent Adult ALL study (Huguet et al, JCO 27:911, 2009), suggested an improved outcome (EFS 55%, OS 60%) using a “pediatric-inspired” protocol, which included longer duration and higher cumulative doses of E-coli ASP. PEG-asparaginase (PEG-ASP) is a modified E.coli ASP with a longer half life, resulting in sustained asparagine depletion. PEG-ASP is also considered to be less allergogenic, and in children causes fewer clinical hypersensitivity reactions and lower rate of anti-ASP neutralizing antibodies (“silent” hypersensitivity i.e. antibodies without clinical hypersensitivity) than the native E. coli ASP. We report, the use of multiple doses (up to 6) of PEG-ASP, given throughout the induction and the post-remission phases in a “pediatric-like” protocol, to newly diagnosed adult ALL. We also determined the rate of anti-ASP neutralizing antibody formation throughout our study; currently these rates are unknown in adults. MethodsThe backbone of our protocol is an augmented BFM pediatric ALL regimen consisting of 8 cycles of multi-agent chemotherapy, followed by two year maintenance. PEG-ASP (2000 U/m2/dose) is given intravenously (IV) once on day 15 of the following cycles (total 6 doses): induction phase I (cycle 1), induction phase II (cycle 2), two cycles of consolidation (cycles 3 and 6), and two cycles of delayed re-induction (cycles 5 and 8). Steroids are always given before and for at least 7 (dexamethasone) or 14 (prednisone) days after the PEG-ASP dose depending on the treatment cycle. Since December 2006 Ph+ patients receive imatinib 600mg/daily. Results46 patients, aged 18-57 (median 33) years, precursor B cell - 41, T cell-5, Ph+ 11, were studied. Median WBC at diagnosis - 14,500/cumm (range 1,900-512,000). CR rate: 44(96%) pts (43 after induction phase I). So far the total number of PEG-ASP doses given was 160: 6-16 pts, 5- 3pts 3- 6 pts., 2-10 pts., 1-11 pts. Eighteen patients could not complete all doses of PEG-ASP: allogeneic SCT -8, refusal -1, pancreatitis -5 (one pt. had pancreatitis and SCT), anaphylaxis -2, DVT-1. Two additional patients died in CR from neutropenic sepsis. Patients with elevated liver enzymes, high bilirubin, DVT (except for one pt.) or hyperglycemia continued on the study. Number of pts. with PEG-ASP related grade 3/4 toxicities (at least once of each): anaphylaxis -2 (4%) (one additional patient a had grade 2 rash); pancreatitis 6 (13%) (one pt. after last dose); thrombosis- 5 (11%) with 4 of the 5 catheter-related in upper extremity; elevated liver enzymes -30 (64%); hyperbilrubinema - 11 (24%); hyperglycemia - 12 (26 %); hypertriglyceridemia -3 (7%); fatigue-5 (11%). All toxicities were reversible. Neutralizing antibodies were measured in 247 serum samples from 34 patients (33, 11 and 10 pts. after PEG-ASP doses # 1, 4, and 6 respectively). An antibody was detected in only ONE patient (after dose #1); he had PEG-ASP related rash. We confirmed the very long half life of PEG-ASP: 7 ±4.7 days after the fist dose increasing to 11.9±5.9 days after dose 4 and 6. Peak serum levels did not change significantly between the cycles. Four year EFS, OS and CIR were 59%, 64% and 32%, respectively. The 16 patients who received all 6 doses of PEG-ASP (no BMT) had a 4 year EFS of 85% (only 3 relapsed at 19, 28, 55 months). ConclusionThis study suggests that multiple IV dosing with the long acting PEG-ASP is feasible in replacing the native E.coli asparaginase in the context of “pediatric-inspired” ALL protocols in adults (age <57 years), maintaining their reported favorable outcomes, adding convenience with less frequent dosing, and acceptable toxicity. Multiple doses of PEG-ASP given IV (in conjunction with steroids) to adults, is associated with a low rate of clinical hypersensitivity reactions and neutralizing antibody formation. The very low rate, so far, of “silent” hypersensitivity in adults, suggests that PEG-ASP can be continued IV, with less concern for drug inactivation. Such approach may benefit adults with ALL. DisclosuresDouer:Enzon Pharmaceuticals: Honoraria, Research Funding, Speakers Bureau.

Negative Interim FDG-PET Scan Is Predictive of Superior Outcome in T Cell Lymphoma.

Abstract 1956Poster Board I-979 Background:Fluoro-deoxy-glucose positron emission tomography (FDG-PET) is a required staging study for diffuse large B-cell lymphoma and Hodgkin lymphoma. Numerous studies have demonstrated that FDG-PET performed after one to four cycles of multiagent chemotherapy (interim restaging) is predictive of outcome, with relapse rates much higher in patients with positive FDG-PET scans at interim restaging. The prognostic role of FDG-PET in T-cell lymphoma however is unclear and has yet to be well defined. Small retrospective studies have demonstrated FDG-PET avidity of T-cell lymphoma. Our experience confirms that the great majority of patients with mature T or NK lymphomas have FDG-PET avid disease. We hypothesized that the interim FDG-PET (int FDG-PET) may have prognostic importance in patients with T-cell lymphomas as they do in diffuse large B-cell lymphoma and Hodgkin lymphoma. Methods:We reviewed our T-cell lymphoma database to identify patients with mature T or NK lymphomas who had FDG-PET scans as part of complete staging at initial diagnosis as well as repeat PET imaging as part of restaging. Inclusion criteria required FDG-PET avid disease at baseline and treatment administered with curative intent. Results:We reviewed fifty four patients who met the above criteria. Histologies were as follows: peripheral T-cell lymphoma NOS (N=18), angioimmunoblastic T-cell lymphoma (N=5), anaplastic large cell lymphoma ALK-1- (N=15), anaplastic large cell lymphoma ALK-1+ (N=3), and other subtypes (N=13). Patients received a variety of initial chemotherapy regimens including CHOP (N=18), EPOCH (N=6), CHOP/ICE (N=20) or other treatments provided with curative intent. Twenty two patients were consolidated with high dose therapy and either autologous (N=18), or allogeneic (N=4) SCT. Fifty nine percent were PET negative at interim restaging (32/54), 7.4% were positive (4/54), 22 % were not available (12/54), and 11% had equivocal scans (6/54). Median follow up was 17 months. Median PFS for the entire group was 15 months. Median OS for the entire group was 40 months. The median OS of patients with negative int FDG-PET has not been reached, compared to the OS of patients with positive int FDG-PET of 10.2 months (p<.001). Patients with equivocal int FDG-PET had a median OS of 62 months, which was statistically superior to patients with positive int FDG-PET (p=.02). There was no significant difference in median OS in patients with negative versus equivocal int FDG-PET. Similar to what was observed in OS, the median PFS of patients with negative int FDG-PET has not yet been reached, compared to the PFS of patients with a positive int FDG-PET of 4.8 months (p=<.001). Patients with equivocal int FDG-PET had a statistically improved PFS of 16 months when compared to those with a positive int FDG-PET (p<.01). Patients with equivocal int FDG-PET had similar outcomes to patients with a negative int FDG-PET, and superior to those with a positive int FDG-PET, whose results were very poor. Conclusions:In this dataset, interim PET scans are strongly predictive of outcome. Patients with negative int FDG-PET enjoyed significantly longer remissions and better overall survival. Patients with negative int FDG-PET were more likely to receive consolidative therapy, which may contribute to their superior outcomes. This may be a potentially confounding factor. Nonetheless, achievement of a negative int FDG-PET appears to be a reliable predictor of outcome in patients with T-cell lymphomas and may have similar prognostic importance in these patients as they do in diffuse large B-cell lymphoma and Hodgkin lymphoma. It is reasonable to consider int FDG-PET in the restaging of patients with T-cell lymphomas. Disclosures:Zelenetz:Millenium Advisory board: Membership on an entity's Board of Directors or advisory committees. Horwitz:Allos Therapeutics, Inc: Consultancy, Research Funding.

Clonal B‐cell population in a reactive lymph node in acquired immunodeficiency syndrome

A 40-year-old female, HIV positive, stage C, since 4 years, complained of a right cervical lymph node swelling. Two years before, the patient had been diagnosed with follicular B-cell non-Hodgkin lymphoma (FL); she had been treated with four cycles of multiagent chemotherapy plus rituximab, the last cycle being administered 10 months before coming to our attention. An ultrasound (US) guided fine-needle cytology (FNC) showed an atypical lymphoid cell proliferation. The phenotype evidenced by flow cytometry (FC) analysis was D5: 10%, CD19: 49%, CD23: 10%, FMC7: 0%, CD10: 40%, CD10/19: 40%, lambda light chain 40%, kappa light chain 0%. FDG-positron emission tomography (PET/CT) scan showed positivity in the corresponding cervical area. Since low LDH values and a reduced lymph node size were observed, the lymph node was therefore excised; the histology revealed a reactive hyperplastic lymph node with florid follicular pattern. A subsequent PCR analysis, performed on DNA extracted from a whole histological section, did not evidence IgH rearrangement. The patient is currently undergoing strict clinical and instrumental follow-up, including PET every 3 months; after 13 months, she is alive without recurrence of lymphoma. Clonal B-cell populations in non-lymphomatous processes have been described in mucosa-associated lymphoid cell populations and reactive lymph nodes, and are considered non-malignant, antigen driven, proliferations of B-lymphocytes determined by an abnormal response to bacterial or viral antigen stimulation. The present case occurred in an HIV patient and was clinically complex because of the patient's history of FL. This experience suggests much attention in the evaluation of radiological, cytological, and FC data and in clinical correlation in patients suffering from autoimmune or immunodeficiency syndromes.

Pediatric radical abdominal trachelectomy for anaplastic embryonal rhabdomyosarcoma of the uterine cervix: an alternative to radical hysterectomy

Rhabdomyosarcoma arising in the female genital tract carries 5-year survival in excess of 80%, but lifelong infertility may be a consequence of local control strategies. We present the technique and outcome for a fertility-sparing, radical abdominal trachelectomy in a 12-year-old girl with anaplastic, embryonal rhabdomyosarcoma involving the uterine cervix. The patient had presented to our center after the piecemeal resection of a uterine cervical mass; because of concern about microscopic residual disease, we classified her as group II-A according to the Intergroup Rhabdomyosarcoma Study system. Staging studies excluded the presence of distant disease. The patient received 4 cycles of multiagent chemotherapy and then underwent radical abdominal trachelectomy, with removal of the uterine cervix, parametria, vaginal cuff, and regional lymph nodes. Microscopically, the specimen showed treatment effect and no residual tumor. Regional nodes were negative. Radical abdominal trachelectomy, which has not been previously reported for rhabdomyosarcoma, has appeared to secure local disease control in this case while preserving the patient's future fertility potential. In properly selected cases of rhabdomyosarcoma of the uterine cervix, where involvement of the uterus proper is not present, radical abdominal trachelectomy may be an attractive fertility-sparing alternative to radical hysterectomy.

Sustained and Prolonged Asparagine Depletion by Multiple Doses of Intravenous Pegylated Asparaginase in the Treatment of Adults with Newly Diagnosed Acute Lymphoblastic Leukemia.

The better outcome in pediatric ALL may not be solely related to the biology of the disease. Adult regimens are less intensive than used in children and include less, shorter or no use of asparaginase; the drug is often considered more toxic than in children. However, adequate serum asparagine depletion was shown to be associated with improved overall outcome. Further in several, multi-agent, large pediatric randomized trials, longer administration of asparaginase in the post remission phase and more sustained asparagine depletion resulted in better outcome. PEG-asparaginase (PEG-ASP) is a modified E.coli ASP, with less hypersensitivity reactions and longer half-life. In adults a single IV dose of PEG-ASP during induction produces long duration of asparagine depletion of up to 4 weeks, t½ = 7 days, with similar toxicity to equivalent multiple doses of E.coli ASP (Douer et al Blood 19:2744,2007). We now report the use of multiple doses of PEGASP, given during induction and throughout the post-remission phases in order to produce prolonged and sustained asparagine depletion in the context of an intensified pediatric protocol, in newly diagnosed, treatment naïve, adult ALL. Sustained asparaginase activity after the short acting E.coli ASP, can be impaired by development of neutralizing anti – asparaginase antibodies. We therefore measured the asparaginase enzymatic activity in a cohort of our patients who received PEG-ASP which in children was shown to be associated with less antibody formation (Avramis et al Blood 2002; 99:1986).Methods: The backbone of our protocol is an augmented BFM pediatric ALL regimen consisting of 8 cycles of multi-agent chemotherapy, followed by maintenance. PEG-ASP (2000 U/m2/dose) is given IV once on day 15 of the following cycles (total 6 doses): induction phase I (cycle 1), induction phase II (cycle 2), two cycles of consolidation (cycles 3 and 6), and two cycles of delayed re-induction (cycles 5 and 8). Since December 2006, Ph+ patients receive imatinib 600mg/daily. Asparaginase enzymatic activity was measured in samples obtained before and after PEG-ASP doses in cycles 1, 5 and 8.Results: 41 patients, aged 19–57 (median 33) years, with precursor B cell – 36, T cell-5, Ph+ 9, were studied. Median WBC at diagnosis - 15,900/cumm (range 1,900–512,000). CR rate: 37 (95%) pts. all after induction phase I. To date 15 patients received all 6 doses of PEG-ASP, having completed all consolidation cycles. The other patients are still being treated. So far the number of PEG-ASP doses given is: 6(15pts), 3(6 pts), 2(7 pts), 1(13 pts) Fifteen patients could not continue the protocol for: allogeneic stem-cell transplantation (8), refusal (1), pancreatitis (5), grade 3 DVT(1). Two additional patients died in CR from neutropenic sepsis. Patients with elevated liver enzymes, high bilirubin, or hyperglycemia continued on the study. Total number of PEG-ASP doses was 135. No pt had an allergic reaction. The number of pts with grade 3/4 toxicities during PEG-ASP cycles were: elevated liver enzymes 24 (59%), hyperbilrubinema 8 (20%), hyperglycemia 12 (29 %), pancreatitis 6(15%), fatigue 4(10%), hypertriglyceridemia 3 (7%), catheter thrombosis- 4 (10%), neuropathy-1. All toxicities were reversible. With a median follow up of 18 months, EFS at 3 and 4 yrs is 68 % (Ph- patients 74%) and CIR is 23%. Asparaginase enzymatic activity after each dose was very long in a cohort of 19 pts with a population average of t½ = 10.99 days (peak concentration 0.88 IU/ml). All 74 specimens analyzed from this cohort of patients had significant asparaginase activity after each PEG-ASP dose, highly suggesting that none of the patients analyzed had developed neutralizing anti asparaginase antibodies. Additional patients with enzymatic measurements will be presentedConclusions: Multiple doses of PEG-ASP IV in adults (ages 19–57 years) provide prolonged and sustained asparagine depletion and no apparent drug inactivating by antibody formation. In combination with an intensified BFM-based protocol this pediatriclike strategy is feasible, without allergic reactions, and with acceptable toxicity. Although the follow up is relatively short the EFS appears to be high. Such approach may benefit adults with ALL

A Dose Intensified Pediatric-Like Regimen Using Multiple Doses of Intravenous Pegylated Asparaginase in Adults with Newly Diagnosed Acute Lymphoblastic Leukemia.

Introduction: Recent studies have suggested that more intensive pediatric regimens may improve the outcome of adults with ALL. In particular, higher dose of asparaginase (ASP) are often used in pediatric ALL protocols than in adults. Large randomized pediatric ALL trials have shown that multiple doses of E.Coli ASP given throughout the post remission phase are associated with improved outcome. PEG-asparaginase (PEG-ASP) is a modified formulation of E.coli ASP, with lower risk of hypersensitivity reactions and prolonged half life. Data on PEG-ASP in adults is limited. In a previous study we showed in adult ALL patients that a single IV dose of PEG-ASP given during induction produces a long duration of asparagine depletion (up to 3-4 weeks) with similar toxicity to equivalent multiple doses of E.coli ASP (Douer et al Blood 19:2744, 2007). We currently report in adults the use of multiple doses of PEG-ASP given throughout the treatment course of patients with newly diagnosed previously untreated ALL as part of an intensive pediatric regimen.Methods: The therapeutic backbone of this protocol is based on an augmented BFM pediatric ALL protocol consisting of 8 cycles of multi-agent chemotherapy, followed by maintenance. PEG-ASP (2000 U/m2/dose) is given IV once on day 15 of the following cycles (total 6 doses): induction phase I (cycle 1), induction phase II (cycle 2), two cycles of consolidation (cycles 3 and 6), and two cycles of delayed re-induction (cycles 5 and 8).Results: 34 patients aged 19–57 (median 33) years with newly diagnosed ALL (precursor B cell - 29, T cell-5, Ph+ 7) were studied. Median WBC at diagnosis was 21,000/cumm (range 1,900–512,000). Thirty three patients (97%) achieved a CR after induction phase I. Eight (26%) patients discontinued the protocol because of undergoing allogeneic stem-cell transplantation. Other reasons for not completing all PEG-ASP doses are: relapse -3 pts., death in CR from neutropenic sepsis-2 pts., pancreatitis -4 pts. To date six patients received all 6 doses of PEG-ASP havingcompleted all consolidation cycles. The other patients are still being treated. So far the number of PEG-ASP doses given is: 6-6pts, 5-1 pt., 4-3 pts., 3-5 pts., 2-7 pts., 1-12 pts. Total number of doses was 94. Grade 3/4 toxicities during cycles after PEG-ASP was given were: elevated liver enzymes - 18/34 (53%) pts (25 doses), hyperbilrubinema - 7/34 (21%) pts (7 doses), hyperglycemia - 11/34 (32%) pts (13 doses), pancreatitis 4/34 (12%) pts, fatigue 3/34 (9%) pts, hypertriglyceridemia-2/34 (6%) pts, neuropathy, catheter thrombosis-1/34 pt each; no allergic reactions. All toxicities were reversible. In 20 patients anti-asparaginase antibodies were assayed and none were found. With a median follow up of 15 months event free survival at 3 yrs is 61%.Conclusion: Administration of multiple doses of PEG-ASP IV to adults (ages19–57 years) in an intensified BFM-based pediatric-like strategy is feasible and provides long term asparagine depletion. Such approach may benefit adults with ALL.

Pediatric Hodgkin Lymphoma: Maximizing Efficacy and Minimizing Toxicity

Historically, both adult and childhood Hodgkin lymphoma (HL) were treated with full-dose (35-45 Gy) extended-field radiation therapy (RT). Although this treatment was the first to produce reliable disease control, the resulting late toxicity led pediatric oncologists to pioneer the use of combined chemotherapy and low-dose (15-25 Gy) involved-field RT for all stages of HL. Currently, standard treatment of childhood HL is risk adapted; those with favorable risk disease typically receive 2 to 4 cycles of multi-agent chemotherapy with low-dose IFRT, whereas those with higher-risk disease receive more intensive chemotherapy before IFRT. This approach produces long-term survival rates >90% while limiting exposure to anthracyclines, alkylators, and radiation to normal tissues. In contrast to adult HL, IFRT remains an important component of the treatment of advanced-stage HL in pediatric patients. Current clinical trials for children with HL aim to further segregate patients into risk strata such that those who are highly curable can receive less toxic therapy, whereas high-risk patients can receive augmented therapy. Response-adapted therapy, in which overall treatment intensity is modified according to the initial response to chemotherapy, is emerging as a potential means of further reducing therapy for some while maintaining high cure rates. The challenge is to refine therapy in a rare disease in which long-time intervals are necessary to observe an adequate number of events (treatment failure or late effects) to answer judicious questions.

The Pharmacokinetics, Safety and Lack of Antibody Production from Multiple Doses of Intravenous Pegylated Asparaginase in Adults with Newly Diagnosed Acute Lymphoblastic Leukemia.

Introduction: Large randomized trials in pediatric ALL show that multiple doses of E.Coli asparaginase (ASP) given throughout post remission phase are associated with improved outcome. ASP is routinely incorporated into most front line adult ALL protocols. PEG-asparaginase (PEG-ASP) is E.coli ASP, which is linked to polyethylene glycol reducing the risk of hypersensitivity reactions and prolonging the half life compared to the native forms. In children multiple doses of PEG-ASP produce less neutralizing antibodies than equivalent doses of native E. coli ASP with similar toxicity (Avramis Blood 99:1986Avramis Blood 99:2002). Information on PEG-ASP in adults is very limited. In a previous study we showed that in adult ALL, a single IV dose of PEG-ASP given at induction produces a long duration of serum ASP enzymatic activity and concomitant asparagine depletion with similar toxicity to equivalent multiple doses of E.coli ASP. We currently report in adults the pharmacokinetics (PK), antibody production and toxicity of multiple doses of PEG-ASP given throughout the treatment of patients with newly diagnosed previously untreated ALL.Methods: We used a modified augmented BFM ALL protocol consisting of 8 cycles of multi-agent chemotherapy followed by maintenance. PEG-ASP (2000 U/m2/dose) is given IV once on day 15 of the following cycles (total 6 doses): induction phase I (cycle 1), induction phase II (cycle 2), two cycles of consolidation (cycles 3 and 6), and two cycles of delayed re-induction (cycles 5 and 8). Serum samples were taken weekly for three weeks for ASP enzymatic activity after PEG-ASP dosing in induction phase 1 (dose 1) and in delayed re-inductions I and II (doses 4 and 6, respectively).Results: 18 patients aged 19–57 (median 28) years with newly diagnosed ALL (precursor B cell - 14, T -4) were studied. All 18 patients (100%) achieved a CR after induction phase I. Six patients discontinued the protocol because of undergoing allogeneic stem-cell transplantation. The number of doses of PEG-ASP was: all 6 doses- 4 pts, 4-3 pts., 2–5 pts., 1– 6 pts. Total number of doses was 52. T ½ was 7±4.7 days (n=18) after the fist dose increasing to 11.9±5.9 days (n=11) after dose 4 and 6. In the first cycle the AUC and MRT were lower while the Vd, Vdss and total clearance (Clt) were higher compared to the subsequent cycles. The change in PK parameters over time is most likely due to Michaelis-Menten (M-M) rate-limiting step on the elimination of the drug. Peak serum levels did not change significantly between the cycles. Anti-ASP antibodies were not detected in any patient-cycles. Grade 3/4 toxicities were hyperbilirubinemia - 3 pts (3 doses), elevated liver enzymes - 10 pts (13 doses), hyperglycemia - 7 pts (10 doses), allergy, pancreatitis, neuropathy, and fatigue - 1 pt (1 dose) each. All toxicities were reversible. We saw no pattern of increasing toxicity in subsequent doses of PEG-ASP. Only two patients had relapsed (median follow up of 15 months).Conclusion: multiple doses of PEG-ASP can be given IV to adults (age<57 years) and provide a very long duration of post remission ASP enzymatic activity. The M-M kinetics suggest that multiple doses of PEG-ASP lead to gradually increasing trough levels resulting in longer depletion of asparagine and glutamine levels and possibly better clinical activity, without being associated with increased toxicity or neutralizing antibody production.