bluuebunny/crossref_metadata_2025 huggingface dataset:
Phase II study of R-CHOP with GM-CSF cytokine support for elderly patients with untreated diffuse large B-cell lymphoma (DLBCL): A Wisconsin Oncology Network study
Authors: Kahl B. S. , Go R. S. , Rodrigues G. , Sanchez F. A. , Saphner T. J. , Werndli J. E. , Kirkpatrick H. M. , Longo W. L.
Published: March 2020

7566

Background: According to mature data from the GELA study, approximately 55% of elderly patients with DLBCL will be cured with R-CHOP. We hypothesized that sargramostim (GM-CSF), added to R-CHOP may potentiate the efficacy of rituximab by upregulating tumor cell CD20 expression and by augmenting antibody dependent cellular cytotoxicity (ADCC). Methods: Patients > 60 years old with untreated stage I-IV DLBCL were eligible if they had PS ≤ 2, measurable disease, adequate organ function, and provided informed consent. R-CHOP for 6–8 cycles was given every 21 days with GM-CSF given subcutaneously at a dose of 250 mg/m2 days 3–10 of each cycle. The primary endpoint was to estimate the CR/CRu rate. Secondary endpoints included estimates of the ORR, EFS, and OS. Results: Thirty-eight/forty patients have been enrolled to date and data are available for 36. One patient is too early and another was deemed ineligible after centralized pathology review. Baseline characteristics include median age 72 (range 61–86), 25% PS 0, 44% PS 1, 31% PS 2, 80% stage III/IV, 56% elevated LDH, 8% IPI 0–1, 25% IPI 2, 36% IPI 3, 31% IPI 4–5. Thirteen/thirty-six (36%) patients did not complete 6 cycles of protocol therapy, 8 due to intolerance of R-CHOP and 5 due to intolerance of GM-CSF. By intent-to-treat analysis, 17/36 patients achieved CR/CRu (47%) and 9/36 achieved PR (25%) for an ORR of 72%. No patients progressed while on study and all non-responders were deemed so secondary to inability to complete protocol therapy. The median follow-up time for surviving patients is 19 months. Considering inability to complete protocol therapy as an event, the 2-year EFS is 38%, the 2-year PFS is 56%, and the 2-year OS is 74%. Conclusions: Any benefit that may be conferred by GM-CSF is likely to be offset by toxicity and intolerance, with 14% of patients in this series unable to complete GM-CSF therapy. Additionally, R-CHOP is more toxic in elderly patients than is commonly appreciated with, 22% of patients unable to complete 6 cycles. Despite recent advances, DLBCL in the elderly remains a difficult problem and new approaches to therapy must be developed.

[Table: see text]
Idiotype vaccine therapy of follicular lymphoma in first remission: Association of t(14;18) and disease free survival in a phase II cohort
Authors: Gause B. L. , Neelapu S. S. , Cohen C. M. , Katz L. M. , Watson T. , Stergiou A. M. , Kwak L. W.
Published: March 2020

7582

Background: A single-arm Phase 2 study (Nature Med 5:1171–7,1999), evaluated the ability of tumor-specific idiotype (Id) conjugated to keyhole limpet hemocyanin (KLH) administered with granulocyte-monocyte colony-stimulating factor - GM-CSF (BiovaxID vaccine) to induce complete remission (CR) and molecular remission (MR) in follicular NHL patients in first CR after chemotherapy. We reported (ASH 2005, Abstr 2441) that at 9.2 years follow-up, disease free survival (DFS) and overall survival (OS) were 45% and 95%, respectively; median DFS was 8.0 years. Previous studies indicated that the t(14;18) chromosomal translocation is associated with follicular NHL. We tested the hypothesis that absence of t(14;18) in peripheral blood (PB) of patients after Id vaccination is predictive of DFS. Methods: A 20-patient cohort in first CR treated with the vaccine was evaluated. t(14;18)- (MR) is defined as <1 t(14;18)+ cell in 105 cells using PCR of the MBR breakpoint cluster on DNA from tumor biopsies or PB. Of the 20 patients, 11 had t(14;18)+ tumors and PB before chemotherapy. Following chemotherapy all 11 patients continued to have t(14;18)+ PB despite being in CR. However, at 1 month following final vaccine treatment, 8 of these patients had converted to t(14;18)- . In this ad hoc analysis, the proportion of patients remaining in DFS was stratified by t(14;18) status; Kaplan-Meier analysis compared median DFS of patients across t(14;18) status following vaccination. Results: At median follow-up of 9.2 years, 55% of patients had clinically relapsed. Although not statistically significant, of the 17 patients t(14;18)- post-vaccine, only 47.1% had clinically relapsed while 100% of the 3 t(14;18)+ patients had relapsed [Chi-square test; P=0.089]. Median DFS in t(14;18)+ patients was 60 months (5.0 years) and had not yet been reached in t(14;18)- patients at 91 months (7.6 years) [Log-rank test; P=0.069]. Conclusions: These data show a possible association between t(14;18) negativity following vaccine and prolonged DFS. Additional follow-up on these patients is needed, as well as similar analyses in other cohorts, to further explore this association.

[Table: see text]
R-CHOP-14 in patients with diffuse large-B-cell lymphoma (DLBCL) younger than 70 years: A multicentric and prospective study
Authors: Rueda A. , Sabin P. , Rifá J. , Llanos M. , Gómez-Codina J. , Lobo F. , García-Arroyo R. , Herrero J. , Provencio M. , Jara C.
Published: March 2020

7592

Background: Several studies have shown that the addition of rituximab (R) to CHOP (cyclophosphamide, doxorubicin, vincristine, prednisona), or shortening the interval between cycles of chemotherapy to two weeks, improves survival of patients with DLBCL. These studies prompted our group (GOTEL) to evaluate in a prospective study, the feasibility and efficacy of R-CHOP-14 in patients (pts) with DLBCL. Methods: Patients (younger than 70 years) with stage II bulky, III or IV DLBCL, and no significant co-morbidities were included in the study. R was administered on day 1 before chemotherapy. R-CHOP was recycled every 14 days. No antimicrobial prophylaxis was administered. All pts received filgrastim (5 μg/kg) from day +3 to +10. Pts received 6 cycles if CR was achieved after 3 cycles; those in PR, and those pts with bone marrow disease at diagnosis, received 8 cycles. Involved field radiation therapy was permitted for pts with stage II bulky disease. Results: From May 2002 to august 2004, 77 pts were included. Median age was 54 years (range, 15–70); 55 patients were younger than 60 years. According to the age adjusted International Prognostic Index (aaIPI), 13 pts (17%) had low risk disease, 27 pts (35%) low-intermediate risk, 29 pts (38%) high-intermediate risk, and 8 pts (10%) high risk disease. Grade 3–4 toxicity occurred as follow: neutropenia in 15 pts (19%), anaemia in 7 pts (9%), thrombocytopenia in 4 pts (5%), mucositis in 4 pts (5%) and peripheral neurotoxicity in 4 pts (5%). Ten pts were hospitalized (febrile neutropenia: 8 cases, one case of gastric perforation and one pulmonary embolism). After therapy, 61 pts (79%) achieved a CR/CRu (C.I. 95%: 57%-90%) and 14 pts (18%) a PR. 2 pts (3%) had refractory disease. With a median follow-up of 20 months, progression-free and overall survival at 24 months were 68% and 87%, respectively. Conclusions: Administration of R-CHOP-14 (with filgrastim support) is feasible and effective in patients younger than 70 years.

[Table: see text]
Primary ocular adnexal MALT lymphoma (POAML): A long-term follow up study of 114 patients (pts)
Authors: Tanimoto K. , Kaneko A. , Suzuki S. , Sekiguchi N. , Watanabe T. , Kobayashi Y. , Kagami Y. , Maeshima A. M. , Matsuno Y. , Tobinai K.
Published: March 2020

7593

Background: Although POAML is a recently recognized distinct entity, its natural history, prognostic factors, behavior of progression and death, and standard initial management have not been fully elucidated. Methods: 114 pts with a histologically verified POAML treated at our institution between 1970 and 2003 were retrospectively analyzed. Results: With a median follow-up duration of 5.7 years (0.6–34.0), estimated overall survival (OS) rate and progression-free survival (PFS) rate at 10 years was 89% and 57%, respectively. Older pts (>60) showed significantly worse OS (p=0.002). However, other clinical factors did not affect significantly OS or PFS. 13 (11%) pts died, but only 3 (3%) due to progressive lymphoma. 31 (27%) pts progressed, 7(6%) at systemic diseases, 8 (7%) at contra lateral sites, and 16 (14%) at the same sites, and only 2 (2%) transformed high-grade lymphoma. All 8 pts who progressed at contra lateral sites were limited to those who had involved initially in the orbit (p=0.036) and their time to progression was significantly longer (p=0.039). Pts who received initially radiation-containing therapy were superior in PFS but not OS than those initially treated with other modalities (p=0.016 and 0.091, respectively). Moreover, when we compared the outcomes of no initial therapy cohort and immediate therapy cohort, there was no significant difference in OS and PFS (p=0.499 and 0.073, respectively). Conclusions: The majority of pts with POAML showed the behaviors of very indolent diseases, and only age was significant prognostic factor. Our preliminary observation suggesting that no initial therapy is an acceptable approach for selected pts (Ann Oncol 2006;17:135–40) was further confirmed in this study for all cohorts. Considering the possible heterogeneity of POAML among initial sites suggested by the present study and the genetic heterogeneity revealed by our previous study (Blood 2005;106:289a), further investigations on POAML are warranted.

No significant financial relationships to disclose.
Treatment of primary CNS lymphoma with induction high-dose methotrexate, temozolomide, rituximab followed by consolidation cytarabine/etoposide: A pilot study with biomarker analysis
Authors: Issa S. , Hwang J. , Karch J. , Fridlyand J. , Prados M. , Batchelor T. , Aldape K. , Haqq C. , Damon L. , Rubenstein J.
Published: March 2020

7595

Background: There is currently no consensus on the optimal treatment for patients diagnosed with primary CNS lymphoma (PCNSL). Between 2001–2004, UCSF PCNSL patients were treated with combination high-dose methotrexate, temozolomide, rituximab (MTR) as induction therapy. Patients in CR with this regimen were treated with high-dose cytarabine plus etoposide as consolidation. The purposes of this study were: (1) Pilot analysis to determine the safety and efficacy of intensive methotrexate-based induction therapy followed by high-dose consolidation with elimination of whole brain irradiation; (2) Analysis of molecular markers in PCNSL which predict sensitivity to chemotherapy and outcome. Methods: 21 untreated, CD20 +, immunocompetent PCNSL patients were treated with combination methotrexate (8 gm/m²), temozolomide (150 mg/m²/day)and rituximab (375 mg/m²). Patients in CR received consolidation cytarabine (2 g/ m² x 8 doses) plus etoposide (40 mg/kg over 96 hours). IHC analysis of potential biomarkers predictive of outcome was performed on paraffin sections from these patients. Candidate markers for validation were selected by gene expression analysis of an independent, multicenter dataset of 20 cases. Results: Mean age was 58.6 y (range 40–81). Median KPS was 60. MTR and cytarabine/etoposide consolidation was well-tolerated with no treatment-related mortality or evidence for neurotoxicity. One case of post-remission cytopenia occurred after consolidation and resolved spontaneously. Eleven patients (52.4%) attained CR with induction; eight received consolidation; three patients in CR deferred consolidation. Median PFS was 11.5 months. Median OS for all 21 patients has not yet been reached with median follow-up of 27.5 months. Expression of the apoptotic regulator DAP-1 by lymphoma cells as determined by IHC was associated with improved PFS (p<0.028) and OS (p<0.021). Conclusions: Combination MTR followed by intensive consolidation appears to be well tolerated in PCNSL. PFS appears at least similar to regimens that contain whole brain irradiation. A larger phase II study has been initiated to evaluate this regimen in a multicenter setting.

[Table: see text]
Prediction of survival using absolute lymphocyte count for newly diagnosed patients with multiple myeloma
Authors: Ege H. , Gertz M. , Markovic S. N. , Lacy M. Q. , Dispenzieri A. , Hayman S. R. , Kumar S. K. , Litzow M. R. , Gastineau D. A. , Porrata L. F.
Published: March 2020

7605

Background: In the setting of autologous stem cell transplantation (ASCT) in multiple myeloma (MM), it has been shown that peripheral blood absolute lymphocyte count (ALC) on day 15 is an independent prognostic factor for clinical outcomes. Recently the International Staging System (ISS) for MM has been developed as a simple staging system to assess survival in newly diagnosed MM patients. The role of ALC on survival in newly diagnosed MM patients is unknown. Methods: Between 1994 and 2002, 1,835 consecutive MM patients were evaluated at the Mayo Clinic, Rochester. Of these patients, we retrospectively analyzed 584 MM patients that were originally diagnosed and followed at the Mayo Clinic. The primary end point was to assess the role of ALC at the time of MM diagnosis on overall survival (OS). OS was measured from the date of diagnosis to time of death or last follow-up. ALC was analyzed as a continuous variable and dichotomized based on finding the optimal cut point based on the log-rank statistic. ALC was then compared to the ISS. Results: The median age of the cohort was 67 years (range: 29–94 years), including 234 females and 350 males. The median follow-up was 32 months (range: 1–136 months). The median ALC at diagnosis was 1.2 x 109/L (range: 0.12–5.44 x 109/L). ALC, as a continuos variables was identified as a prognostic factor for OS (HR= 0.466, 95%CI= 0.396–0.547, p < 0.0001). MM patients with an ALC ≥ 1.3 x 109/L experienced a superior OS compared with MM patients with an ALC < 1.3 x 109/L (55.5 months versus 22.6 months, p< 0.0001). In the multivariate analysis, ALC was independent prognostic factor when compared to the ISS (HR = 0.580, 95%CI=0.518–0.647, p< 0.0001). Conclusions: Our study shows that ALC at diagnosis for MM is an independent prognostic factor for OS, suggesting how the host immune status plays a critical role in the survival of patients with MM.

No significant financial relationships to disclose.
Update of melphalan 280 mg/m2 plus amifostine cytoprotection before autologous stem cell transplantation as part of initial therapy in multiple myeloma patients
Authors: Reece D. E. , Flomenberg N. , Badros A. , Phillips G. L. , Filicko J. , Howard D. S. , Meisenberg B. , Rapoport A. , Vesole D. H.
Published: March 2020

7608

Background: Autologous stem cell transplantation (ASCT) using melphalan 200 mg/m2 is a standard part of inital therapy in younger multiple myeloma (MM) patients (pts). We have previously reported an augmented regimen of melphalan 280 mg/m2 with the cytoprotectant agent amifostine (AF) to try to improve the anti-tumor response without increased mucosal toxicity (The Hematol J 2003; 4[suppl]: S207). We now update our experience with this regimen. Methods: Pts without disease progression and adequate organ function (creatinine clearance at least 60 cc/min) were eligible. Pts were treated as part of phase I-II trials approved by each center’s institutional review board. AF 740 mg/m2 was given IV over 5–15 min 24 hr and 15 min prior to melphalan 280 mg/m2 (infused over 15 min). Blood stem cells were reinfused 24 hrs later. The primary endpoint was response rate at day 100. Regimen-related toxicity using the Seattle criteria, progression-free (PFS) and overall survival (OS) were also assessed. Results: 24 pts were transplanted between 5/99–7/02. Median age was 50 (32–65) yrs; 1 pt had primary amyloidosis; median beta2-microglobulin level at diagnosis was 1.98 (0.88–11.80) mg/L. Prior therapy included VAD in 14, dexamethasone alone in 7 plus other regimens in 7. Day 100 responses compared with with pre-ASCT values included CR in 11, near CR (immunofixation positivity only) in 1, VGPR (greater than 90% reduction in serum M protein) in 3, PR in 5 and stable disease in 3. Maximum grade of mucositis was 2 (5 pts); no grade 3 or 4 toxicity was seen. The median day of ANC recovery to 0.5 x 109/L and median day of last platelet transfusion were 11 (6–16) and 10 (7–32), respectively. 4 received thalidomide (1 briefly), while 1 was treated with maintenance alpha interferon after day 100. Median follow-up is 52 (9–72) mos. 7 pts are alive without progression, including 5 in CR and 2 in PR. 16 have progressed at a median of 15 (7–36) mos post-ASCT. 8 have died from MM (7) or lung cancer (1). The 4 yr actuarial PFS is 28% (95% C.I. 34–76%) and OS 58% (95% C.I.11–47%). Conclusions: 1) Melphalan 280 mg/m2 with AF is well-tolerated; 2) the CR + nCR + VGPR rate of 62% warrants further evaluation, perhaps as part of tandem transplants or in conjuction with novel agents.

[Table: see text]
Development of neuropathy in patients (pts) with multiple myeloma (MM) treated with thalidomide (thal)—Patterns of occurrence and the role of electrophysiologic monitoring
Authors: Mileshkin L. R. , Stark R. , Day B. , Seymour J. F. , Zeldis J. B. , Prince H. M.
Published: March 2020

7618

Background: Given new treatment options for pts with MM, physicians are faced with the dilemma of how best to sequence these drugs in order to optimize efficacy and toxicity. Peripheral neuropathy frequently limits the duration of treatment (Rx) with thal. In this study we assessed the utility of serial nerve electrophysiological studies (NES) to detect the onset of neuropathy, and assessed the time course of occurrence and possible clinical and Rx-related predictive factors. Methods: 75 pts with relapsed/refractory MM were enrolled in a multi-centre trial of thal. In addition to clinical assessment, pts underwent sensory and motor NES at baseline and every 3 months in order to identify neuropathy. We examined the value of baseline and serial NES for development of neuropathy, with time to development of neuropathy according to clinical or NES criteria compared using Kaplan-Meier analysis. Differences between pt and Rx-related variables were compared using a Mann-Whitney U-test or a Fisher’s exact test. Results: Thirty nine percent had some NES abnormalities at baseline. Pts were treated with thal at a median dose intensity of 373 mg/day and followed for a median of 18 months (range 6–26). Thirty-one of the 75 pts (41%) developed neuropathy during thal Rx, with 11 (15%) ceasing thal due to neuropathy. The actuarial incidence of any neuropathy increased from 38% at 6 months to 73% at 12 months with 81% of responding pts developing this complication. The use of NES did not reliably predict the imminent development of clinical neuropathy requiring cessation of thal. Nor were pt age, gender or type of prior therapy (ie vincristine) predictive. Development of neuropathy was related to duration of thal exposure with a median time of 268 days thal in those who developed neuropathy compared to 89 days in those who did not (p = 0.0001). Cumulative dose or dose intensity received were not predictive. Conclusions: The majority of pts will develop peripheral neuropathy given sufficient length of thal Rx and to minimize the risk of neurotoxicity, therapy should be limited to less than six months. NES monitoring provides no clear benefit over careful clinical evaluation for the development of clinically significant neuropathy.

[Table: see text]
Correlation of bone marrow angiogenesis and response to thalidomide dexamethasone in multiple myeloma
Authors: Kumar S. , Greipp P. R. , Haug J. L. , Gertz M. A. , Blood E. , Rajkumar S. V.
Published: March 2020

7621

Background: Thalidomide (Thal) in combination with dexamethasone (Dex) is an effective therapy for myeloma (MM). Though initially evaluated in MM because of its anti-angiogenic properties, it is not clear how much this contribute to its anti-MM effects. We examined whether the degree of angiogenesis influences response to Thal + Dex, as well as effect of therapy on marrow angiogenesis. We also examined whether expression of angiogenic cytokines by MM cells affect response to therapy. Methods: A total of 207 pts with newly diagnosed MM were randomized on the ECOG phase III trial (E1A00) to either Thal-Dex or Dex alone. Bone marrow microvessel density (MVD) was determined on 88 pts at diagnosis and at 4 mos after therapy in 25 pts. Expression of fibroblast growth factor (FGF) and vascular endothelial growth factor (VEGF) by MM cells was determined by RTPCR on 60 pts at diagnosis and on 22 pts at 4 mos. In addition, the percentage of marrow PCs in apoptosis was determined at diagnosis and 4 mos in 43 pts. A decrease in the serum M protein by 50% or in its absence, a decrease in urine M protein by 50% was considered a response. Results: The median BM MVD at diagnosis was 33 (3–118), and was similar in the pts responding to therapy (36.4) and in the non responders (45.4). We also separately looked at those receiving the combination vs. Dex alone, and did not find any correlation. The expression of FGF and VEGF in the PCs did not predict response to therapy with either the combination or Dex. Among the 17 responding pts, MVD decreased by a mean of 12 compared to an increase in the mean MVD of 3 among the non responders (P = NS). There was no significant correlation between the level of FGF or VEGF expression and the marrow MVD. There was no correlation between the percentage of myeloma cells in apoptosis at baseline and response to therapy. Conclusion: While the anti-angiogenic activity of Thal may play a role in its anti-myeloma effect, baseline MVD or tumor cell expression of angiogenic cytokines do not predict resistance or response to Thal-Dex or Dex alone. The findings here confirm previous observations that marrow angiogenesis is not related to the degree of secretion of angiogenic cytokines by individual cells, but rather the cumulative effect of the tumor mass.

No significant financial relationships to disclose.
Visual complications in childhood cancer survivors: A Childhood Cancer Survivor Study report
Authors: Whelan K. , Mertens A. , Castleberry R. , Mitby P. , Kawashima T. , Sklar C. , Packer R. , Waterbor J. , Blatt J. , Robison L.
Published: March 2020

9006

Background: The Childhood Cancer Survivor Study (CCSS) is an NIH funded project (U01-CA 55727) designed to study the effects of childhood cancer treatment on long- term survivors. Previous studies have found associations between certain cancer therapies and visual complications. Methods: The CCSS is a retrospective cohort study investigating health outcomes of long-term survivors (> 5 years) diagnosed and treated between 1970 and 1986 compared to a randomly selected sibling cohort. Questionnaires were completed by 14,362 survivors of childhood cancer and 3,901 sibling controls. Analysis determined the first occurrence of 8 visual conditions in 3 time periods: during therapy, end of therapy to 5 years post diagnosis, and greater than or equal to 5 years post diagnosis. Multivariate analyses, adjusting for current age and gender, determined the relative risks (RR) and 95% confidence interval (CI) of visual conditions by treatment exposure. Results: Survivors had statistically significant increases in the RR of cataracts, glaucoma, legal blindness, double vision, retinal condition, and dry eyes, across all time periods, when compared to siblings. During the time period of 5 or more years post-diagnosis, statistically significant positive associations were present for cataracts and other head radiation, craniospinal radiation, total body radiation, and prednisone; glaucoma and craniospinal radiation; double vision and craniospinal radiation; legally blind and other head radiation and craniospinal radiation; and dry eyes and other head radiation, total body radiation, and dexamethasone. There were no statistically significant associations between treatment factors and retinal conditions. Conclusions: Childhood cancer survivors are at risk of developing visual complications and treatment related factors are important determinants of this risk. Follow-up is needed to evaluate the impact of visual conditions on quality of life.

[Table: see text]

No significant financial relationships to disclose.
Prognostic significance of myeloid associated antigen expression in childhood acute lymphoblastic leukemia in Peru
Authors: García J. L. , Wachtel A. E. , Pérez C. , Marcial J. , Dyer R. , Doimi F.
Published: March 2020

9030

Background: The prognostic significance of coexpression of myeloid antigens in pediatric patients with acute lymphoblastic leukemia (ALL) has been reported by several authors, with a frequency that has ranged widely. All of these authors are from developed countries, the aim of this study is to evaluate the prognostic significance of these antigens in childhood ALL in a developing country. Methods: We retrospectively reviewed 729 newly diagnosed patients with ALL under 14 years of age, who had a bone marrow flow cytometry performed at our institution, between 1996–2002. Clinical data and treatment outcomes were reviewed and compared between patients with ALL who expressed myeloid antigens and those who did not using chi-square test. Results: 729 medical charts were studied, 81.6% of them were B-common, 8.2% were pro-B, 8.2% were T-cell and 2.1% were pre-B ALL patients. Overall frequency of myeloid antigen expression was 36.6%. The most frequent specific antigens found were: CD13, 15.5%; CD15, 6.0% and CD33, 4.5%. Evaluating the B-common ALL patients the presence of myeloid antigens rises to 43%. Patients who had coexpression of myeloid antigens had a relapse rate (any site) of 49.2% while 36.3% who had no coexpression had a relapse (p=0.001). There has also been statistical significance in bone marrow response on day 14 of induction with 64.9% having less than 5% blasts in the group without coexpression and 46.4% in the group with coexpression (p<0.0001). Conclusions: The present retrospective review shows the presence of associated myeloid antigens in our ALL patients in 36.6%. We have shown that it is an adverse prognostic factor for childhood ALL in a developing country, unlike reports from other centers in developed countries.

No significant financial relationships to disclose.
RISK-adapted treatment of Burkitt’s lymphomas in childern
Authors: Mohran T. Z. , Ebeed E. N.
Published: March 2020

9034

Background and Purpose: Various treatment regimens have been implemented in an attempt to improveDFS of children with B cell lymphoma. We evaluates the treatment results of children with stage I, II III Burkitt’s lymphoma at 2 centers in Egypt. Patients and Methods: Patient recruitment in this open non-randomized study occurred from July 1998 to Dec 2002 . 97 patients with pathologically proven Burkitt’s lymphoma stage I to III were diagnosed . All patients were subjected to history, clinical examination, CSF, bone marrow and radiological evaluation. Patients with stage IV were excluded from. Patients with stage I and II received 4 cycles of (A→B→A→B), while patients with stage III received 8 cycles of (A→B→A→B→A→B→A→B). Intrathecals were given during the first 4 cycles. Cycle A was formed of cyclophosphamide, adriamycin, vincristine, cytosine arabinoside, plus intrathecal MTX and cytosine arabinoside. Cycle B was formed of ifosfamide, vepeside, methotrexate, vincristine and intrathecal cytosine arabinoside and mtx. Results: Patients was 97, their age ranged between 2 and 18, theirmean age was 8.6 and median was 8 years.The male to female ratio was 3.8:1. The primary site was the abdomen in 49 patients (50%), peripheral lymph node enlargement was encountered in 38 patients (39.1%). Jaw involvement occurred in 7 patients (7.2%). Two patients (2%) presented with Tonsilar mass and only one patient presented with mass at inner canthus (1%). Patients were staged according to St. Jude staging system. Patient distribution was as follows: Stage I, 18 (18.6%); stage II, 31 (32%); stage III, 48 (49.5%). In August 2003, 90 patients were in continuous complete remission with a follow up period ranged between 8 months and 53 months and a median 39 months. The projected 3 years DFS for the whole group was 93.8%±2.5%. Correlation between DFS and LDH was significant (P=0.01) while correlation with age, sex and stage was insignificant. Conclusions: Treatment result with the prescribed protocol is extremely good. The outcome of non advanced Burkitt’s lymphoma in rural areas of Egypt is comparable to all studies in developed countries. High dose methotrexate is not a must to improve survival of stage I-III Burkitt’s lymphoma. Initial serum LDH level is an important prognostic factor. Key words: Childhood, Burkitt’s lymph.

No significant financial relationships to disclose.
Radiotherapy plus concomitant and adjuvant temozolamide for newly diagnosed pediatric high-grade astrocytoma
Authors: Abdel Wahab M. M. , El-Hosseini H. , Eezz El-Arab L. R.
Published: March 2020

9042

Background: to evaluate the potential survival advantage of adding temozolamide (TMZ) concomitantly and adjuvant to radiotherapy (RT) as regard time to progression (TTP) and overall survival in addition to its safety and tolerability in pediatric high grade astrocytomas. Methods: A total of 29 pediatric patients newly diagnosed, histologically proven glioblastoma multiforme (GBM) or anaplastic astreocytoma (AA) were randomized, to radiotherapy alone (14 patients) or radiotherapy and concomitant (TMZ) 150mg/m2/d for 5 days every 28 days followed by up to 6 cycels of adjuvant TMZ (15 patients). Results: The median time to progression was significantly prolonged in patients treated with RT/TMZ compared to those treated with RT alone (14 months Vs 7 months respectively) (P<0.05). The median overall survival in the combined treatment Vs monotherapy was 23 months and 13 months respectively (P<0.01). Non hematologic adverse events were similar between both groups while grade 3 & 4 hematologic toxicities occurred in 20% only of the RT/TMZ arm (2 patients experienced grade 3 thrombocytopenia and 1 patient developed grade 4 neutropenia). Conclusions: This study demonstrate a significant survival benefit for the addition of TMZ to treatment of pediatric patients with high grade astrocytpoma and it’s safety, well tolerability which allows it to be given concurrently with RT, followed by additional adjuvant cycles.

No significant financial relationships to disclose.
Palliative radiotherapy in pediatric malignancies
Authors: Bhasker S. , Turaka A. , Mohanti B. K. , Bajpai V.
Published: March 2020

9050

Background: To evaluate the role of palliative radiotherapy in the management of incurable pediatric malignancies. Methods: Records of 40 pediatric patients treated between Jan’ 2003 and Nov’ 2005 were reviewed and analyzed retrospectively. All of theses 40 children received palliative external beam radiotherapy for symptom control. Palliative radiotherapy was given either as single modality or in addition to surgery, chemotherapy and symptom relief drugs. Information recorded for each patient included age, sex, and extent of disease, histological types, symptomatology, treatment methods and symptom relief. Results: There were 28 boys and 12 girls in the age group of 1 to 18 years, with a median age of 14 years (range of 1–18 years). Predominant symptoms were swelling with or without pain, bleeding, and weakness of limbs. The median duration of symptoms was 90 days (range of 4–50 days). The diagnosis of these children varied with different histologies, most in the group of malignant round cell tumors (11), retinoblastoma (4), neuroblastoma (4), AML with chloromas (3), Ewing’s sarcoma (4). All patients presented with advanced stages of disease. Out of 40 patients 18 (45%) had disseminated disease at presentation. Nine patients underwent surgery while 32 patients received chemotherapy and all but two patients received symptom relief drugs in addition to palliative radiotherapy. The various dose schedules were either 5 Gy or 8 Gy for single fraction treatment while the dose schedules for fractionated radiotherapy ranged from 20 Gy in 5 fractions to 30 Gy in 10 fractions. Four patients showed complete resolution, 20 patients showed good, while 15 patients had little, 1did not have any relief in their symptoms. At the completion of multimodality treatment, 18 patients had partial response, 8 patients had progressive disease, 8 had stable disease and two patients had complete response. The disease status of 4 patients could not be known. Conclusions: The role of radiotherapy as palliative modality in children with locally advanced lesions provides better symptom relief in combination with other modalities of treatment.

No significant financial relationships to disclose.
Feasibility and acute toxicities of outpatient ifosfamide infusions in children and adolescents with cancer
Authors: Macedo C. R. , Nogueira P. K. , Ginani V. C. , Gouveia R. V. , Petrilli A. S.
Published: March 2020

9055

Background: Ifosfamide (IFO) is very effective and widely used in pediatric oncology protocols. Patients are usually admitted to receive IFO infusions due to potential urological and neurological complications. The current study was conducted to assess the feasibility of outpatient IFO infusions in children and adolescents with cancer, the compliance of the patients and their parents, and the acute toxicities in this setting. Methods: All patients with newly diagnosed solid tumors included in protocols with at least three cycles of IFO/mesna were eligible for this study. IFO was administered I.V. over one hour. Doses varied according to the underlying malignancy and protocol from 2.5–3.0g/m2/day × 3 days to 2.7g/m2/day × 5 days. Three doses of mesna were administered intravenously in the outpatient clinic at 75% of the IFO dose divided on hours 0, 3 and 6 and a fourth dose of mesna was given as oral tablets at home 12 hours after IFO. Hydration was 2L/m2 I.V. over 5 hours in the hospital, followed by another 1L/m2 P.O. at home. Kidney function was assessed before, during, and after treatment through glomerular filtration rate; sodium, magnesium, calcium, uric acid renal excretions; urinary phosphate threshold and retinol-binding protein. Results: From November 2003 to August 2005, 30 patients received a total of 160 IFO cycles. Compliance was 100%. The incidence of grades 3 and 4 toxicities in all IFO cycles was: gastrointestinal 15%, leucopenia 92%, neutropenia 88%, thrombocytopenia 29%, hepatotoxicity 3%, and genitourinary 7%. No patient had gross hematuria, neurotoxicity or had to be admitted for chemotherapy. One third of the patients developed subclinical tubular nephropathy. Conclusions: Ambulatory infusion of IFO is safe and toxicities are comparable to the expected with inpatient administration.

No significant financial relationships to disclose.
Clinical utility of FDG-PET for evaluation of the viability in post-chemotherapeutic residual lesions in pediatric solid tumors
Authors: Hosono A. , Makimoto A. , Tsuji N. , Kawamoto H. , Watanabe A. , Tateishi U. , Terauchi T.
Published: March 2020

9067

Background: Exact evaluation of viability in post-chemotherapeutic residual lesions in patients with solid tumors should allow us to select the appropriate therapeutic options. F-18 fluorodeoxyglucose position emission tomography (FDG-PET) is one of the promising modality to evaluate it without invasive procedure. Methods: The cohort is a total of 14 patients with pediatric solid tumors (rhabdomyosarcoma 7, Ewing sarcoma 4, Wilms tumor 2 and neuroblastoma 1), which are either newly diagnosed or newly relapsed between January 2005 and December 2005. A total of 15 residual tumors from the 14 patients after chemotherapy underwent 51 FDG-PET scans. Seven residual tumors out of 6 patients, who were newly diagnosed, and another 8 tumors out of 8 patients, who were relapsed, were evaluated after induction or reinduction chemotherapy. Parameters of FDG-PET were assessed by area of FDG uptake and standardized uptake values (SUV). Results of FDG-PET were compared either with histological examination of the residual tumors (n=11) or with the clinical status 6-month after the last FDG-PET (n=4) in order to judge whether the findings of FDG-PET were true or false. Results: Three of 15 residual lesions showed increased SUV, while 12 lesions obtained negative SUV. Three lesions with positive SUV consisted of 2 true-positive and 1 false-positive lesions. Among twelve lesions were negative SUV, 11 lesions were true-negative, and 1 was false-negative. The sensitivity and specificity of FDG-PET in predicting the viability of residual lesions were 66% and 91%, respectively. A lesion of rhabdomyosarcoma which obtained negative SUV in FDG-PET histological showed viable cells. A lesion of another rhabdomyosarcoma which showed positive SUV was evaluated as inflammatory lesion. Conclusions: Although FDG-PET showed excellent sensitivity and fair specificity in predicting the viability of residual lesions in patients with pediatric solid tumors, possibility of false-negativity should give us a caution not to rely on FDG-PET to judge the termination of therapy.

No significant financial relationships to disclose.
A multicenter phase 2 consortium (P2C) study of the mTOR inhibitor CCI-779 in advanced soft tissue sarcomas (STS)
Authors: Okuno S. H. , Mahoney M. R. , Bailey H. H. , Adkins D. R. , Maples W. J. , Ettinger D. , Fitch T. R. , Bot B. M. , Erlichman C. E.
Published: March 2020

9504

Background: CCI-779 inhibits the mammalian target of rapamycin (mTOR), a Ser/Thr kinase involved with the initiation of mRNA translation, showing growth inhibition in many tumor cell types. The primary goal was to evaluate the confirmed response rate (RR) of CCI-779 in advanced STS. Methods: Eligibility included pts ≥ 18 yrs, measurable advanced STS, PS 0–2, adequate laboratory function (including Chol ≤ 350 mg/dL and TG ≤ 400 mg/dL), no prior chemo for advanced disease (adjuvant chemo allowed), and no brain metastases. Following premedication with an antihistamine, CCI-779 was given intravenously at 25 mg over 30 minutes on days 1, 8, 15, and 22, repeated q 4 wks. A total 50 pts were to be enrolled, if there were 2 responses at the time of an interim analysis conducted on the initial 20 patients. Pre- and post-treatment blood was collected to evaluate p70S6 kinase, S6 phosphorylation, inhibition of mTOR, and sirolimus levels. Pre-treatment paraffin-embedded tumor tissue was used to evaluate immunohistochemistry markers (including, EFGR, c-Myc, Her2, 4EBP1). Results: 41 eligible pts (18 male, median age 62 yrs with range 28–79) were enrolled from 11/04 to 9/05. 71% presented with high grade tumors. Histologic subtypes include: malignant fibrous histiocytoma (MFH) (7), sarcoma NOS (9), fibrosarcoma NOS (3), liposarcoma NOS (5), leiomyosarcoma (8), endometrial stromal (1), synovial (1), hemangio/angiosarcoma (2), hemangiopericytoma NOS (1), and neurofibrosarcoma (1). 42% (16/38) evaluable pts had Gr 3+ events at least possibly related to CCI-779, 1 of which was Gr 4 hyperglycemia (see table). One pt having extremity fibrosarcoma, achieved a PR after 2 cycles lasting at least 36 weeks. Twenty-eight pts have progressed and 10 have died. Estimated median time to progression is 2 months (95% CI 1.8–3.5). Conclusions: Despite an acceptable toxicity profile, CCI-779 failed to demonstrate promising activity in pts with advanced STS. Results of the correlative studies are pending. Supported by N01 CM17104.

[Table: see text]

No significant financial relationships to disclose.
Role of palliative chemotherapy in advanced soft tissue sarcoma: Retrospective analysis of 488 patients
Authors: Karavasilis V. , Seddon B. , Al-Muderis O. , Ashley S. , Judson I.
Published: March 2020

9520

Background: Advanced soft tissue sarcomas (aSTS) represent an incurable clinical entity of poor prognosis, in which chemotherapy is frequently viewed as relatively ineffective. We aimed to review the efficacy of palliative chemotherapy and investigate prognostic factors in a large group of patients treated on routine palliative protocols. Methods: Patients with STS who had first line chemotherapy for advanced and/or metastatic disease between 1991 and 2005 were identified from the Royal Marsden Hospital’s sarcoma database. Patients with Ewing’s sarcoma, rhabdomyosarcoma, desmoplastic small round cell tumour and GIST were excluded from the study. Patients who were treated elsewhere more than 1 year before they come to our hospital were also excluded. Results: 488 patients (242M/286F) fulfilled the criteria. Median age at the time of treatment was 50 years (range 19–79). The main tumour types were leiomyosarcomas (35%) synovial sarcoma (13%), liposarcoma (10%) and malignant fibrous histiocytoma (10%). The majority of patients (83%) received chemotherapy for metastatic disease. 71% of patients had single organ involvement and 29% had multiple disease sites. Lung was the most common site of metastasis (56%). 54% were treated with single agent chemotherapy. Response rate to chemotherapy was 33% (53% for synovial sarcoma); 22% achieved stable disease for a median duration of 8 months; 45% progressed through chemotherapy. Median time to progression was 3 months, duration of response 9 months and post treatment survival (OS) 12 months. In multivariate analysis, age <60, liposarcoma and synovial histology were found as positive and bone involvement as negative independent prognostic factors. Patients treated with combination chemotherapy experienced longer survival (11 vs 14 months OS; p=0.001). Conclusions: This retrospective study of standard palliative chemotherapy in unselected patients with aSTS shows that more than half of patients benefit from treatment, indicating that this is a worthwhile treatment option. Synovial sarcoma and liposarcoma represent the most chemosensitive sarcoma subtypes. Nevertheless, continuing search for new agents is strongly warranted to improve the survival of these patients.

No significant financial relationships to disclose.
A phase I trial of doxorubicin and flavopiridol in soft tissue sarcoma
Authors: D’Adamo D. R. , Scheu K. , Singer S. , Schwartz G. K. , Maki R. G.
Published: March 2020

9523

Background: Flavopiridol, a potent cyclin dependent kinase inhibitor, has been shown in vitro to enhance doxorubicin induced apoptosis. Using the BWH dediffentiated liposarcoma xenograft model we have shown that sequential therapy with doxorubicin (D) followed 1 hour later by flavopiridol (F) is superior to doxorubicin alone (p=0.006). Single agent flavopiridol was also active in this xenograft model, but less so than the combination. Methods: We have commenced an ongoing phase I study of the combination of D and F on the basis of this preclinical data in soft tissue sarcoma with fixed dose D (60 mg/m2), followed 1 hour later by escalating doses of F (40–70 mg/m2) administered over one hour, every 3 weeks. Standard phase I eligibility criteria apply. No prior anthracycline therapy is allowed. At 300 mg/m2 D, dexrazoxane is added to D F. Patients with responsive or stable disease after cumulative D dose of 600mg/m2 can receive single agent flavopiridol. Results: Median characteristics of 7 evaluable patients: age 52 (31–65), KPS 80% (70–90), 3 males / 4 females, 0 prior regimens (range 0–2). The combination has been well-tolerated, with no dose limiting toxicity (DLT) yet. There has been 1 grade 3 bleed in the setting of progressive disease and 1 grade 4 neutropenia without fever. Grade 1 and 2 diarrhea, related to flavopiridol have been observed. Pharmacokinetic (PK) studies are ongoing. We have observed no partial responses (PR). Prolonged stable disease (SD) has been seen in 3 patients for 6, 6 and 11 months. Two patients with SD have liposarcoma. One patient with liposarcoma continues on single agent flavopiridol with stable disease after having reached the prescribed limit of D of 600 mg/m2. Conclusions: The combination of doxorubicin and flavopiridol is safe, with no unexpected toxicities. Disease stabilization in STS has been observed. This appears to be an encouraging combination in liposarcoma and is consistent with our preclinical model. Flavopiridol dose escalation is continuing.

No significant financial relationships to disclose.
Familial gastrointestinal stromal tumor with homo-/hemizygous kit exon 11 deletion: Genotypic, histopathologic, radiographic, and therapeutic findings
Authors: Kleinbaum E. P. , Chen L. L. , Lazar A. , Strong L. , Zhang W. , Choi H. , Benjamin R. , Patel S. , Trent J. C.
Published: March 2020

9527

Background: Germ-line mutations in the kit receptor tyrosine kinase gene have been described in families with a propensity to develop gastrointestinal stromal tumor (GIST). We describe a large kindred with multiple individuals with GIST and describe the genotype, clinical presentation, radiographic imaging, surgical findings, imatinib-sensitivity, and histopathologic appearance. Patients and Methods: A large kindred with multiple GISTs were identified after the proband patient was referred to our institution. The history of each affected and unaffected family member was obtained in person or via telephone. A medical questionnaire was sent to family members and appropriate medical records, tumor tissue and radiographic imaging was obtained. Histopathologic specimens from four of the family members with GIST was obtained, the diagnosis confirmed and three specimens were used to sequence kit exon 9, 11, 13, 15 and 17. Results: Fifteen members were identified in this family with histopathologic diagnosis of GIST or probable GIST. Surgical findings revealed multiple tumors arising from the submucosa of the small intestine. Histopathology revealed microscopic proliferation of the myenteric plexus with areas of microscopic tumor nodularity. Four patients in this kindred were treated with imatinib and had radiographic and clinical evidence of therapeutic benefit. A deletion of codon 579 in exon 11 of the kit gene was identified in tumor and normal tissue of this family. Evaluation of one GIST revealed loss of heterozygosity in kit exon 11 suggesting a homozygous mutation or loss of the wild-type locus. Conclusion: This study describes a kindred with a propensity to develop GIST in association with hyperpigmentation and melanocytic nevi, but not dysphagia. The germline deletion of codon 579 appears to confer proliferation and nodularity of the myenteric plexus, synchronous tumors at presentation, a metastatic phenotype, and in vivo sensitivivity to imatinib therapy.

No significant financial relationships to disclose.