John M. Goldberg

Childhood T-Cell Acute Lymphoblastic Leukemia: The Dana-Farber Cancer Institute Acute Lymphoblastic Leukemia Consortium Experience

PURPOSE T-cell acute lymphoblastic leukemia (T-ALL) accounts for 10% to 15% of newly diagnosed cases of childhood acute lymphoblastic leukemia (ALL). Historically, T-ALL patients have had a worse prognosis than other ALL patients. PATIENTS AND METHODS We reviewed the outcomes of 125 patients with T-ALL treated on Dana-Farber Cancer Institute (DFCI) ALL Consortium trials between 1981 and 1995. Therapy included four- or five-agent remission induction; consolidation therapy with doxorubicin, vincristine, corticosteroid, mercaptopurine, and weekly high-dose asparaginase; and cranial radiation. T-ALL patients were treated the same as high-risk B-progenitor ALL patients. Fifteen patients with T-cell lymphoblastic lymphoma were also treated with the same high-risk regimen between 1981 and 2000. RESULTS The 5-year event-free survival (EFS) rate for T-ALL patients was 75% +/- 4%. Fourteen of 15 patients with T-cell lymphoblastic lymphoma were long-term survivors. There was no significant difference in EFS comparing patients with T-ALL and B-progenitor ALL (P =.56), although T-ALL patients had significantly higher rates of induction failure (P <.0001), and central nervous system (CNS) relapse (P =.02). The median time to relapse in T-ALL patients was 1.2 years versus 2.5 years in B-progenitor ALL patients (P =.001). There were no pretreatment characteristics associated with worse prognosis in patients with T-ALL. CONCLUSION T-ALL patients fared as well as B-progenitor patients on DFCI ALL Consortium protocols. Patients with T-ALL remain at increased risk for induction failure, early relapse, and isolated CNS relapse. Future studies should focus on the identification of and treatment for T-ALL patients at high risk for treatment failure.

Recommendations for the Use of WBC Growth Factors: American Society of Clinical Oncology Clinical Practice Guideline Update

PURPOSE To update the 2006 American Society of Clinical Oncology guideline on the use of hematopoietic colony-stimulating factors (CSFs). METHODS The American Society of Clinical Oncology convened an Update Committee and conducted a systematic review of randomized clinical trials, meta-analyses, and systematic reviews from October 2005 through September 2014. Guideline recommendations were based on the review of the evidence by the Update Committee. RESULTS Changes to previous recommendations include the addition of tbo-filgrastim and filgrastim-sndz, moderation of the recommendation regarding routine use of CSFs in older patients with diffuse aggressive lymphoma, and addition of recommendations against routine dose-dense chemotherapy in lymphoma and in favor of high-dose-intensity chemotherapy in urothelial cancer. The Update Committee did not address recommendations regarding use of CSFs in acute myeloid leukemia or myelodysplastic syndromes in adults. RECOMMENDATIONS Prophylactic use of CSFs to reduce the risk of febrile neutropenia is warranted when the risk of febrile neutropenia is approximately 20% or higher and no other equally effective and safe regimen that does not require CSFs is available. Primary prophylaxis is recommended for the prevention of febrile neutropenia in patients who are at high risk on the basis of age, medical history, disease characteristics, and myelotoxicity of the chemotherapy regimen. Dose-dense regimens that require CSFs should only be used within an appropriately designed clinical trial or if supported by convincing efficacy data. Current recommendations for the management of patients exposed to lethal doses of total-body radiotherapy, but not doses high enough to lead to certain death as a result of injury to other organs, include the prompt administration of CSFs.

Tivantinib (ARQ 197), a selective inhibitor of MET, in patients with microphthalmia transcription factor-associated tumors: results of a multicenter phase 2 trial.

Microphthalmia transcription factor (MITF)‐associated (MiT) tumors are a family of rare malignancies, including alveolar soft part sarcoma (ASPS), clear cell sarcoma (CCS), and translocation‐associated renal cell carcinoma (tRCC) that have dysregulated expression of oncogenic MITF family proteins. The MET receptor tyrosine kinase gene is transcriptionally activated by MITF family proteins, making MET a potential therapeutic target for MiT tumors. This study assessed the activity of tivantinib (ARQ 197), a selective MET inhibitor, in patients with MiT‐associated tumors.

Active immunotherapy using dendritic cells in the treatment of glioblastoma multiforme

OBJECTIVE Glioblastoma multiforme, the most common malignant brain tumor still has a dismal prognosis with conventional treatment. Therefore, it is necessary to explore new and/or adjuvant treatment options to improve patient outcomes. Active immunotherapy is a new area of research that may be a successful treatment option. The focus is on vaccines that consist of antigen presenting cells (APCs) loaded with tumor antigen. We have conducted a systematic review of prospective studies, case reports and clinical trials. The goal of this study was to examine the efficacy and safety in terms of complications, median overall survival (OS), progression free survival (PFS) and quality of life. METHODS A PubMed search was performed to include all relevant studies that reported the characteristics, outcomes and complications of patients with GBM treated with active immunotherapy using dendritic cells. Reported parameters were immune response, radiological findings, median PFS and median OS. Complications were categorized based on association with the craniotomy or with the vaccine itself. RESULTS A total of 21 studies with 403 patients were included in our review. Vaccination with dendritic cells (DCs) loaded with autologous tumor cells resulted in increased median OS in patients with recurrent GBM (71.6-138.0 wks) as well as those newly diagnosed (65.0-230.4 wks) compared to average survival of 58.4 wks. CONCLUSIONS Active immunotherapy, specifically with autologous DCs loaded with autologous tumor cells, seems to have the potential of increasing median OS and prolonged tumor PFS with minimal complications. Larger clinical trials are needed to show the potential benefits of active immunotherapy.

Management of colorectal carcinoma in children and young adults.

Colorectal Carcinoma (CRC) is rare in patients less than 20 years of age. Although presenting symptoms are similar to adults, this diagnosis is rarely considered in the initial differential diagnosis of young patients. We will review what is published about the incidence, epidemiology, and clinical presentation of CRC in children, adolescents and young adults. Because of its rarity in this age group, few pediatric oncologists will have experience with CRC, and clinical trials will rarely be available. The treatment of CRC in adults is evolving rapidly and consultation with medical oncologists experience in treating adults with CRC is essential to develop the best treatment plan for a young patient diagnosed with CRC.

Extended Progression-Free Survival in Two Patients With Alveolar Soft Part Sarcoma Exposed to Tivantinib

Introduction Alveolar soft part sarcoma (ASPS) is a rare malignancy that tends to strike young adults and adolescents. It has an unusual clinical behavior; it is somewhat indolent, with slow progression, and yet is incurable once metastasized. Patients with ASPS often present with extensive metastatic disease, frequently involving the lungs and sometimes the brain. On the basis of functional data linking the characteristic translocation found in ASPS, ASPL-TFE3, to upregulation of expression of the MET receptor tyrosine kinase, we proposed to conduct a clinical trial of tivantinib, an orally available, selective inhibitor of MET, for patients with ASPS and other cancers with expression of MET. This was a phase II study with response as the primary outcome (A Phase II Study of ARQ 197 in Patients With Microphthalmia Transcription Factor Associated Tumors). Herein we report two young patients from this trial who have continued on therapy for more than 3 years each, with stable disease and minimal adverse effects, despite metastases at study entry. During the time of the trial, the study dose of tivantinib was increased from 120 mg twice a day to 360 mg twice a day, on the basis of ongoing parallel pharmacokinetic studies. The study was Institutional Review Board approved at each institution where these patients were treated. The consent process for these minors included obtaining the appropriate assent from the patient and informed consent from the parents.

Biologic Activity of Autologous, Granulocyte–Macrophage Colony-Stimulating Factor Secreting Alveolar Soft-Part Sarcoma and Clear Cell Sarcoma Vaccines

Purpose: Alveolar soft-part sarcoma (ASPS) and clear cell sarcoma (CCS) are rare mesenchymal malignancies driven by chromosomal translocations that activate members of the microphthalmia transcription factor (MITF) family. However, in contrast to malignant melanoma, little is known about their immunogenicity. To learn more about the host response to ASPS and CCS, we conducted a phase I clinical trial of vaccination with irradiated, autologous sarcoma cells engineered by adenoviral-mediated gene transfer to secrete granulocyte–macrophage colony-stimulating factor (GM-CSF). Experimental Design: Metastatic tumors from ASPS and CCS patients were resected, processed to single-cell suspensions, transduced with a replication-defective adenoviral vector encoding GM-CSF, and irradiated. Immunizations were administered subcutaneously and intradermally weekly three times and then every other week. Results: Vaccines were successfully manufactured for 11 of the 12 enrolled patients. Eleven subjects received from three to 13 immunizations. Toxicities were restricted to grade 1–2 skin reactions at inoculation sites. Vaccination elicited local dendritic cell infiltrates and stimulated T cell–mediated delayed-type hypersensitivity reactions to irradiated, autologous tumor cells. Antibody responses to tissue-type plasminogen activator (tTPA) and angiopoietins-1/2 were detected. Tumor biopsies showed programmed death-1 (PD-1)–positive CD8+ T cells in association with PD ligand-1 (PD-L1)–expressing sarcoma cells. No tumor regressions were observed. Conclusions: Vaccination with irradiated, GM-CSF–secreting autologous sarcoma cell vaccines is feasible, safe, and biologically active. Concurrent targeting of angiogenic cytokines and antagonism of the PD-1–negative regulatory pathway might intensify immune-mediated tumor destruction. Clin Cancer Res; 21(14); 3178–86. ©2015 AACR.

Cardiac Failure 30 Years after Treatment Containing Anthracycline for Childhood Acute Lymphoblastic Leukemia

In 1977, a 5-year-old girl diagnosed with acute lymphoblastic leukemia was treated on Dana-Farber Cancer Institute Childhood Acute Lymphoblastic Leukemia Protocol 77-01, receiving a cumulative doxorubicin dose of 465 mg/m2, cranial radiation, and other drugs. After being in continuous complete remission for 34 months, she developed heart failure and was treated with digoxin and furosemide. At 16 years of age, she was diagnosed and treated for dilated cardiomyopathy. Over the years, she continued to have bouts of heart failure, which became less responsive to treatment. At 36 years of age, she received a heart transplant. Six months later, she stopped taking her medications and suffered a sudden cardiac death.

Dendritic cell vaccine for recurrent high-grade gliomas in pediatric and adult subjects: clinical trial protocol.

BACKGROUND Although there have been significant advances in understanding the basic pathogenesis of glioblastoma multiforme, the median survival of patients has changed little in the past 25 years. Recent studies have suggested that immune modulation through dendritic cell (DC) vaccines may stimulate the immune system against tumor antigens and potentially increase survival. OBJECTIVE To determine whether the use of adjuvant vaccination with autologous DCs (matured in situ after being loaded with tumor cell lysate derived from autologous refractory gliomas) is safe, feasible, and beneficial for adult and pediatric patients with recurrent high-grade gliomas. METHODS The study design is a single-center, nonrandomized, open phase I clinical trial. A total of 20 patients with malignant gliomas will be enrolled preoperatively over 2 years. Patients will be given adjuvant vaccination with autologous DCs loaded with tumor lysate after maximal safe surgical resection. EXPECTED OUTCOMES Using topical imiquimod before vaccination, it is anticipated that the immune response in vaccinated patients and potentially Overall survival will be greater than that demonstrated in the literature. We anticipate that there will be minimal side effects (minor dermatitis) associated with this treatment. DISCUSSION In the current trial, we assess immune response, safety, and survival using a novel vaccine protocol developed in Belgium that seems to markedly increase survival of certain subjects. Nevertheless, larger randomized clinical studies need to be performed to evaluate fully the efficacy of this therapy for both recurrent and newly diagnosed glioblastoma.

Pediatric phase I trial of oral sorafenib and topotecan in refractory or recurrent pediatric solid malignancies

Targeted kinase inhibitors and camptothecins have shown preclinical and clinical activity in several cancers. This trial evaluated the maximum tolerated dose (MTD) and dose‐limiting toxicities of sorafenib and topotecan administered orally in pediatric patients with relapsed solid tumors. Sorafenib was administered twice daily and topotecan once daily on days 1–5 and 8–12 of each 28‐day course. The study utilized a standard 3 + 3 dose escalation design. Three dose levels (DL) were evaluated: (1) sorafenib 150 mg/m2 and topotecan 1 mg/m2; (2) sorafenib 150 mg/m2 and topotecan 1.4 mg/m2; and (3) sorafenib 200 mg/m2 and topotecan 1.4 mg/m2. Pharmacokinetics were ascertained and treatment response assessed. Thirteen patients were enrolled. DL2 was the determined MTD. Grade 4 thrombocytopenia delaying therapy for >7 days was observed in one of six patients on DL2, and grade 4 neutropenia that delayed therapy in two of three patients on DL3. A patient with preexisting cardiac failure controlled with medication developed a transient drop in the left ventricular ejection fraction that improved when sorafenib was withheld. Sorafenib exposure with or without topotecan was comparable, and the concentration‐time profiles for topotecan alone and in combination with sorafenib were similar. One objective response was noted in a patient with fibromatosis. We determined MTD to be sorafenib 150 mg/m2 twice daily orally on days 1–28 combined with topotecan 1.4 mg/m2 once daily on days 1–5 and 8–12. While these doses are 1 DL below the MTD of the agents individually, pharmacokinetic studies suggested adequate drug exposure without drug interactions. The combination had limited activity in the population studied.