James P. O'Brien

Ifosfamide, carboplatin, and etoposide: a highly effective cytoreduction and peripheral-blood progenitor-cell mobilization regimen for transplant-eligible patients with non-Hodgkin's lymphoma.

PURPOSE To evaluate a chemotherapy regimen that consisted of ifosfamide administered as an infusion with bolus carboplatin, and etoposide (ICE) supported by granulocyte colony-stimulating factor (G-CSF) for cytoreduction and stem-cell mobilization in transplant-eligible patients with primary refractory or relapsed non-Hodgkins lymphoma (NHL). PATIENTS AND METHODS One hundred sixty-three transplant-eligible patients with relapsed or primary refractory NHL were treated from October 1993 to December 1997 with ICE chemotherapy at Memorial Sloan-Kettering Cancer Center. Administration of three cycles of ICE chemotherapy was planned at 2-week intervals. Peripheral-blood progenitor cells were collected after cycle 3, and all patients who achieved a partial response (PR) or complete response (CR) to ICE chemotherapy were eligible to proceed to transplantation. Event-free and overall survival, ICE-related toxicity, and the number of CD34(+) cells collected after treatment with ICE and G-CSF were evaluated. RESULTS All 163 patients were assessable for response, and there was no treatment-related mortality. A major response (CR/PR) was evident in 108 patients (66.3%); 89% of the responding patients underwent successful transplantation. Patient who underwent transplantation and achieved a CR to ICE had a superior overall survival to that of patients who achieved a PR (65% v 30%; P =.003). The median number of CD34(+) cells/kg collected was 8.4 x 10(6). The dose-limiting toxicity of ICE was hematologic, with 29.4% of patients developing grade 3/4 thrombocytopenia. There were minimal nonhematologic side effects. CONCLUSION ICE chemotherapy, with ifosfamide administered as a 24-hour infusion to decrease CNS side effects, and the substitution of carboplatin for cisplatin to minimize nephrotoxicity, is a very effective cytoreduction and mobilization regimen in patients with NHL. Furthermore, the quality of the clinical response to ICE predicts for posttransplant outcome.

Accelerated hyperfractionated total-lymphoid irradiation, high-dose chemotherapy, and autologous bone marrow transplantation for refractory and relapsing patients with Hodgkin's disease.

PURPOSE To evaluate the feasibility and therapeutic effect of accelerated hyperfractionated total-lymphoid irradiation (TLI), high-dose chemotherapy, and autologous bone marrow transplantation (AuBMT) in patients with relapsing or chemotherapy-resistant Hodgkins disease (HD). PATIENTS AND METHODS Forty-seven patients with HD who either relapsed after chemotherapy (n = 19), or failed to respond (n = 28) to at least two regimens of combination chemotherapy were studied. No patient received prior radiation therapy (RT). Treatment started with reinduction with standard-dose chemotherapy, followed by involved-field irradiation (15 Gy) to areas of relapsed or persistent disease and TLI (20.04 Gy given in 1.67 Gy fractions three times per day for 4 days). Subsequently, patients received etoposide and high-dose cyclophosphamide, followed by infusion of unpurged autologous bone marrow. All surviving patients had a minimum follow-up duration of 1 year. The median follow-up duration for survivors was 40+ months, and the maximum follow-up duration was 80+ months. RESULTS Of the 47 patients treated, eight (17%) died of toxicity during the peritransplant period. Twenty-nine of the remaining 39 assessable patients (74%) attained a complete response (CR), while 10 remained with residual disease and progressed early after AuBMT. Four of the CR patients (14%) relapsed and 25 patients remained alive and free of disease. The actuarial disease-free survival (DFS) rate for the entire group at 6.5 years was 50%. Patients who received the protocol for relapsing HD had a significantly better DFS rate (79%) compared with patients treated for continuous refractory disease (DFS, 33%; P < .03). CONCLUSION Previously unirradiated patients with relapsing or chemotherapy-resistant HD who have exhausted conventional chemotherapy may still respond to an aggressive therapeutic approach consisting of accelerated hyperfractionated TLI, high-dose chemotherapy, and AuBMT rescue. This program offers a potential for long-term DFS to approximately one half of patients who would otherwise have a dismal prognosis with standard-dose salvage therapy.

Chemosensitive epidural spinal cord disease in non-Hodgkins lymphoma

Epidural spinal cord disease (ESCD), an infrequent complication of systemic non-Hodgkins lymphoma (NHL), can occur at diagnosis or at relapse, and is usually treated with radiotherapy, or infrequently surgical decompression. We retrospectively analyzed 140 patients with intermediate-grade NHL (IG-NHL) who were treated on a dose-intense protocol using doxorubicin, vincristine, and high-dose cyclophosphamide (NHL-15). There were seven episodes of ESCD in six (4.3%) patients. Five episodes were asymptomatic at presentation; one patient had back pain, leg numbness, and tingling; and one had radicular pain and mild leg weakness. None had malignant cells in the CSF. One patient received high-dose dexamethasone after laminectomy for diagnostic biopsy; otherwise, dexamethasone was used only as an anti-emetic prior to chemotherapy. Patients who developed ESCD at diagnosis received the planned course of NHL-15 chemotherapy as treatment for ESCD, and those treated with NHL-15 who developed ESCD at relapse were given a regimen containing ifosfamide, carboplatin, and etoposide (ICE). After chemotherapy alone, five of seven episodes showed radiographic resolution of ESCD and improvement of neurologic deficits. One patient received consolidation radiotherapy (2,700 cGy) to the spine after ICE for relapsed ESCD and had a complete response. One patient had progression of systemic lymphoma and ESCD despite chemotherapy. These data suggest that chemotherapy may be effective as initial treatment of ESCD in IG-NHL and may reduce the potential complications of spinal surgery and radiotherapy. NEUROLOGY 1996;46: 1543-1547

Somatostatin-Receptor imaging in lymphoma

Patients with Hodgkins or non-Hodgkins lymphoma are staged for treatment based on the extent of known disease involvement and the histopathologic grading of the disease. Radiological techniques, including computed tomography, usually depend on estimates of lymph node enlargement and mass effects as the criterion for disease involvement. Lymphomatous tissue obtained at surgery has shown high-density somatostatin receptors. Several groups have evaluated the utility of 111In-DTPA-pentetreotide (Octreoscan, Mallinckrodt, St. Louis, MO) to detect lymphomatous tissue for more accurate staging of patients with lymphoma. The procedure is safe; both Hodgkins and non-Hodgkins disease involvement is identified. The results, however, have not been uniformly predictive of disease involvement. Consequently, the routine use of this technique in place of currently used anatomic imaging methods is not recommended at this time. The significance of detecting somatostatin receptors in vivo in patients with malignant lymphoma requires further study.

INITIAL CLINICAL EXPERIENCE WITH COMPUTER-CONTROLLED CONFORMAL RADIOTHERAPY OF THE PROSTATE USING A 50-MEV MEDICAL MICROTRON

PURPOSE We have described previously a model for delivering computer-controlled radiation treatments. We report here on the implementation and first years clinical experience with such treatments using a 50 MeV medical microtron. METHODS AND MATERIALS The microtron is equipped with a multileaf collimator and is capable of setting up and treating a sequence of fixed fields called segments, under computer control. An external computer derives machine parameters for the segments from a three-dimensional treatment planning system, transfers them to the microtron control computer, checks the machine settings before allowing dose delivery to begin, and records the treatment. We describe the patient treatment methodology, portal film acquisition, electronic portal imaging, and quality assurance. RESULTS Patient treatments began in July 1992, comprising six-segment conformal treatments of the prostate. Using the recorded treatment data, the system performance has been examined and compared to other treatment machines. The average treatment time is 10 min, of which 4 min is for computer-controlled setup and irradiation; the remaining time is for patient positioning and checking of clearances. Long-term reproducibility of computer-controlled setup of the gantry and multileaf position is better than 0.5 degrees and 1 mm, respectively. Termination due to a machine fault has occurred in 5.5% of treatments, improving to 2.5% in recent months. CONCLUSION Our initial experience indicates that computer-controlled segmental therapy can be performed reliably on a routine basis. Treatment times with the microtron are significantly shorter than with conventional linacs, and setup accuracy is consistent with that needed for conformal therapy. We believe that treatment times can be further improved through software upgrades and integration of electronic portal imaging.

Granulocyte-Colony Stimulating Factor (G-CSF) May Improve Disease Outcome in Elderly Patients with Diffuse Large Cell Lymphoma (DLCL) Treated with CHOP Chemotherapy

Advanced age is an adverse prognostic factor in patients with DLCL. CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) has frequent dose-limiting toxicities, including myelosuppression. We retrospectively reviewed 50 consecutive patients >60 years of age (median age 72) with B-cell DLCL who received CHOP with G-CSF. Patients received CHOP (median 6 cycles) at three-week intervals. G-CSF was given following all cycles of chemotherapy (“prophylactic G-CSF”) in 28 of 50 patients, and following an episode of febrile neutropenia and thereafter in 19 patients, according to ASCO guidelines. Dose intensity, treatment delays, episodes of febrile neutropenia, complete response (CR) rate, disease-free survival, time-to-treatment failure, and overall survival were all analyzed according to the age-adjusted International Prognostic Index (aaIPI). The actual dose intensity for cyclophosphamide was 225.9 mg/m2/week and 0.90, respectively and for doxorubicin was 14.9 mg/m2/week (90% of ideal CHOP dosing for both drugs)., Median followup was 4 years for the patients still living. Treatment delays and episodes of febrile neutropenia were less frequent among patients receiving G-CSF with all cycles of CHOP. The CR rates were 100%, 81%, 85%, and 36% for the low, low-intermediate, high-intermediate, and high aaIPI risk groups, respectively. The 5-year actuarial relapse-free and overall survival for our patients were comparable to that of the cohort ≤60 years of age and superior to the >60 years of age cohort used to establish the aaIPI. With optimization of CHOP dosing, advanced age may not be an adverse prognostic factor for patients with DLCL. The routine use of G-CSF in elderly patients with DLCL should be further investigated.

CHOP with High Dose Cyclophosphamide Consolidation versus CHOP Alone as Initial Therapy for Advanced Stage, Indolent Non-Hodgkin's Lymphomas

The role of high dose therapy, including autologous stem cell transplantation (ASCT) in indolent non-Hodgkins lymphomas remains controversial. We evaluated a dose intense regimen of CHOP induction followed by high dose cyclophosphamide consolidation (CHOP-HC) versus CHOP alone in a prospective comparison to assess intensified therapy without ASCT. Twenty-five patients with previously untreated advanced stage indolent NHL were enrolled: follicular lymphoma, grade 1 (11 patients) and grade 2 (8 patients); small lymphocytic lymphoma (5 patients); and lymphoplasmacytic lymphoma (1 patient). All patients were treated as clinically indicated. The median age was 47 years (21-70). There were 15 males, and 10 females. Three patients had intra-abdominal stage II, 2 patients with stage III, and 20 patients with stage IV disease. All patients received induction with CHOP for 4 cycles (weeks 1,4,7,10): cyclophosphamide 750 mg/m 2 IV, doxorubicin 50 mg/m 2 IV, vincristine 1.4 mg/m 2 IV (2 mg capped dose) and prednisone 100 mg PO × 5 days. Following induction, responding patients were given consolidation with either high dose cyclophosphamide @ 3 gm/m 2 IV for 3 doses with G-CSF (weeks 13,15,17) or 2 additional cycles of CHOP (weeks 13,16), stratified by stage and bulk of disease. The overall response rate to CHOP was 92% (3 CR, 8 PR) and to CHOP-HC was 93% (4 CR, 8 PR). The overall response, complete response and partial response rates were comparable in both arms. Median progression free survival for CHOP was 15.9 and 23.0 months for CHOP-HC. At 74.3 months median follow-up, all patients in the CHOP arm have recurred; 3 patients in the CHOP-HC arm (3 CR) have not recurred. The median overall survival has not been reached (at 5 years, 77% OS for CHOP-HC versus 83% OS for CHOP alone]. Greater hematologic toxicity was observed with CHOP-HC resulting in an increased number of hospitalizations for sepsis. There were no treatment-related deaths. No myelodysplasia or acute leukemia has been seen to date. With no obvious improvement in CR and with greater hematologic toxicity than CHOP, CHOP-HC is not recommended for treatment of indolent non-Hodgkins lymphomas.

Abstract 58: Local intratumoral treatment with anti-mesothelin Immunotoxins overcomes resistance to anti-CTLA-4 therapy

Background: SS1P and RG7787 are immunotoxins composed of anti-mesothelin antibody fused to a fragment from pseudomonas exotoxin A. We previously observed delayed tumor responses in patients treated with SS1P leading us to hypothesis that immunotoxins can provoke anti-tumor immunity. We hypothesize that intra-tumoral injection of SS1P or RG7787 will produce immunologic death and convert living tumors to a source of antigens and boost the therapeutic effect of immune check point blockade. Method: A BALB/c breast cancer cell line was transfected with human mesothelin (66C14-M) and grown in BALB/c mice transgenic for human mesothelin. SS1P or RG7787 was injected directly into established tumors (80-100 mm3) and anti-CTLA-4 administered IP. Results: We observed total tumor regressions in 23 out of 38 mice (60%) treated with anti-CTLA-4 and either RG7787 or SS1P. No cure was achieved when the drugs were given as a monotherapy supporting the case for synergic anti-tumor activity. Pathologic evaluation of regressing tumors showed a massive inflammation of admixed eosinophils and mononuclear cells located in a collar surrounding the tumors. Tumor regression was associated with increased number of CD8+ cells and was blocked when CD8+ cells were depleted by an antibody. In addition, cured mice were resistant to re-implantation of 66C14 cells not expressing mesothelin indicating that a long-term anti-tumor immunity was formed. To determine if pathogen associated molecular patterns contributed to the response, we combined anti-CTLA-4 with an inactive RG7787 and observed a major reduction in anti-tumor activity (P Conclusions: We suggest that injecting immunotoxins into tumors is a useful approach to boost the activity of anti-CTLA-4. Based on the synergistic anti-tumor effect demonstrated in this study we believe that there is a strong rational to explore such combination therapies in patients. Citation Format: Yasmin Leshem, Xiu-fen Liu, Tapan Bera, Masaki Terabe, Jay A. Berzofsky, Birgit Bossenmaier, Gerhard Niederfellner, James O9Brien, Yoram Reiter, Ira Pastan. Local intratumoral treatment with anti-mesothelin Immunotoxins overcomes resistance to anti-CTLA-4 therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 58. doi:10.1158/1538-7445.AM2017-58

A phase 2 trial of lenvatinib (E7080) in advanced, progressive, radioiodine-refractory, differentiated thyroid cancer: A clinical outcomes and biomarker assessment: Phase 2 Study of Lenvatinib in RR-DTC

Lenvatinib is an oral, multitargeted tyrosine kinase inhibitor of the vascular endothelial growth factor receptors 1 through 3 (VEGFR1‐VEGFR3), fibroblast growth factor receptors 1 through 4 (FGFR1‐FGFR4), platelet‐derived growth factor receptor α (PDGFRα), ret proto‐oncogene (RET), and v‐kit Hardy‐Zuckerman 4 feline sarcoma viral oncogene homolog (KIT) signaling networks implicated in tumor angiogenesis. Positive phase 1 results in solid tumors prompted a phase 2 trial in patients with advanced, radioiodine‐refractory, differentiated thyroid cancer (RR‐DTC).

Molecular profiling of melanoma tumor biopsies to identify a response signature to the multi-RTK inhibitor, E7080.

8595 Background: E7080 is an oral TKI targeting VEGFR1-3, FGFR1-4, PDGFRβ, RET and KIT, which affects tumor cell proliferation and tumor vascularization in laboratory models. Tumor response (RECIST) and prolonged disease stabilization (> 6 months) were observed in melanoma patients treated in phase I. The present study sought to identify predictive genomic/proteomic signatures. METHODS 25 patients with metastatic melanoma received E7080 10mg twice daily continuously. Biopsy of accessible lesions was performed pre-treatment D1 and on D22 post-treatment. The patient responses were: 2 PR, 14 SD > 3 months, 1 SD > 2 months and 5 PD (3 patients non evaluable). Tumor biopsies (D1 and D22) were frozen and preserved for sectioning. Melanoma cells and tumor infiltrating vasculature (IHC CD31+) were separately collected by laser capture micro-dissection for profiling from ~ 5,000 cells on Affymetrix U133+2 microarrays and from ~30,000 cells via a gel electrophoretic-tryptic digest-LC/MS/ MS method. RESULTS From 25 patient samples, 22 D1 samples yielded quality melanoma mRNA samples for hybridization and analyses used data from ~24,000 RMA-normalized probes. The genomic data was analyzed using Students T-test based on clinical benefit (=PR or SD ≥ 6 months); regression analysis for the continuous measure of tumor shrinkage and by Cox proportional regression based on PFS. The analysis identified genes encoding elements of the target RTK signaling pathways. At the intersection of the regression analyses was a set of 46 genes correlating with the observed clinical response. CONCLUSIONS A small set of genes in melanoma cells may potentially be used to predict clinical response in melanoma patients to E7080. The list will be refined based on on-going proteomic analysis of melanoma cells, gene expression data from the tumor vasculature and genotyping for melanoma-associated mutations from these same tumors. These will be tested for their predictive value in an ongoing Ph2 trial.