Raymond A. Kempf

Adjuvant immunotherapy of resected, intermediate-thickness, node-negative melanoma with an allogeneic tumor vaccine: Overall results of a randomized trial of the Southwest Oncology Group

PURPOSE Patients with clinically negative nodes constitute over 85% of new melanoma cases. There is no adjuvant therapy for intermediate-thickness, node-negative melanoma patients. PATIENTS AND METHODS The Southwest Oncology Group conducted a randomized phase III trial of an allogeneic melanoma vaccine for 2 years versus observation in patients with intermediate-thickness (1.5 to 4.0 mm or Clarks level IV if thickness unknown), clinically or pathologically node-negative melanoma (T3N0M0). RESULTS Six hundred eighty-nine patients were accrued over 4.5 years; 89 patients (13%) were ineligible. Surgical node staging was performed in 24%, the remainder were clinical N0. Thirteen eligible patients refused assigned treatment: seven on the observation arm and six on the vaccine arm. Most vaccine patients experienced mild to moderate local toxicity, but 26 (9%) experienced grade 3 toxicity. After a median follow-up of 5.6 years, there were 107 events (tumor recurrences or deaths) among the 300 eligible patients randomized to vaccine compared with 114 among the 300 eligible patients randomized to observation (hazard ratio, 0.92; Cox-adjusted P(2) = 0.51). There was no difference in vaccine efficacy among patients with tumors < or = 3 mm or > 3 mm. CONCLUSION This represents one of the largest randomized, controlled trials of adjuvant vaccine therapy in human cancer reported to date. Compliance with randomization was excellent, with only 2% refusing assigned therapy. There is no evidence of improved disease-free survival among patients randomized to receive vaccine, although the power to detect a small but clinically significant difference was low. Future investigations of adjuvant vaccine approaches for patients with intermediate-thickness melanoma should involve larger numbers of patients and ideally should include sentinel node biopsy staging.

Adjuvant Immunotherapy of Resected, Intermediate-Thickness, Node-Negative Melanoma With an Allogeneic Tumor Vaccine: Impact of HLA Class I Antigen Expression on Outcome

PURPOSE An association between expression of > or = two of five HLA class I antigens (HLA-A2, HLA-A28, HLA-B44, HLA-B45, and HLA-C3; collectively called M5) and response to an allogeneic melanoma vaccine (Melacine; Corixa Corporation, Seattle, WA) has been described in stage IV melanoma. This study investigated whether class I antigen expression impacted relapse-free survival (RFS) after adjuvant therapy with this vaccine. PATIENTS AND METHODS We performed class I (HLA-A, HLA-B, and HLA-C) serotyping on patients enrolled onto Southwest Oncology Group Trial 9035, a randomized, observation-controlled, phase III trial of adjuvant Melacine. All patients had clinically node-negative cutaneous melanoma (1.5 to 4.0 mm). Interactions between treatment and class I antigen expression were tested. Analyses involved all serotyped patients and were adjusted for tumor thickness, method of nodal staging, sex, ulceration, and primary tumor site. RESULTS HLA typing was performed on 553 (80%) of the 689 enrolled patients (294 vaccinated and 259 observed). Expression of > or = two M5 antigens was associated with a superior vaccine treatment effect. Among patients who matched > or = two of the M5, the 97 vaccine-treated patients had improved RFS compared with the 78 observation patients (5-year relapse-free survival, 83% v 59%; P =.0002). The major components of this effect were contributed by HLA-A2 and HLA-C3. Among those who were HLA-A2-positive and/or HLA-C3-positive, the 5-year RFS for vaccinated patients was 77%, compared with 64% for observation (P =.004). There was no impact of HLA-A2 and/or HLA-C3 expression among observation patients. CONCLUSION This prospective analysis indicates a highly significant benefit of adjuvant therapy with Melacine among patients expressing > or = two of the M5 class I antigens, validating a prior observation in stage IV disease. HLA-A2 and HLA-C3 contributed most to this effect. Processed melanoma peptides found in Melacine may be presented by HLA-A2 and HLA-C3 and play a role in preventing relapse in vaccinated patients.

Kaposi's sarcoma in homosexual men: an immunohistochemical study.

A recent outbreak of disseminated Kaposis sarcoma has been recognized in homosexual men in New York, San Francisco, and Los Angeles. Biopsy specimens of skin lesions were obtained from nine of these homosexual men in Los Angeles and San Francisco. T lymphocyte subset antigens, factor VIII-related antigen, and HLA-Dr antigen were evaluated in situ in frozen sections using immunoperoxidase technics. Factor VIII-related antigen and HLA-Dr antigen were present on tumor cells, supporting a vascular endothelial origin of this neoplasm. Langerhans cells and T lymphocytes were present in numbers similar to that of normal skin in skin specimens from seven patients with Kaposis sarcoma with visceral dissemination, but were increased in specimens from two patients with only cutaneous involvement.

Cytogenetic aberrations and DNA ploidy in soft tissue sarcoma: A southwest oncology group study

We performed cytogenetic analysis and determined DNA content by flow cytometry (FCM) on freshly disaggregated tumor biopsies from 45 patients with soft tissue sarcomas (STS). Cytogenetically aberrant clones characterized 30 (67%) tumors, with the remaining 15 yielding normal karyotypes with or without nonclonal aberrations. No tumors with multiple unrelated clones were observed. Among the 30 tumors with clonally abnormal karyotypes, 21 (70%) had near-diploid stemlines, six were near-triploid and three were near-tetraploid. Ten of the clonally aberrant tumors contained nonrandom chromosomal translocations characteristic of histologic subtypes. Overrepresentation of chromosomes 7 and 8 were common numerical aberrations. Structural aberrations most often involved chromosomes 1, 7, 9, 12, and 14. Clustering of breaks in 9p resulting in partial loss of the short arm was frequent. Unstable aberrations including rings, dicentrics, large markers, small numbers of double minutes, and telomeric associations were seen in nine tumors. With FCM, 27 (60%) tumors had aneuploid DNA content and 18 (40%) were DNA diploid. Of those 18 DNA diploid tumors, 11 showed clonal karyotypic aberrations. In addition, apparent discrepancies between the results of the cytogenetics and FCM with respect to ploidy pattern were seen in 13 samples; 11 had DNA content in the peritriploid to peritetraploid range but the corresponding karyotype was normal or near-diploid. When the findings of the cytogenetics and DNA content analyses were combined, an abnormal cell population by one or both methods was detected in 38 (84%) tumors. The concurrent application of standard cytogenetics and DNA ploidy by FCM provide complementary information confirming a high incidence of genetic alterations in STS.

Significant impact of HLA class I allele expression on outcome in melanoma patients treated with an allogeneic melanoma cell lysate vaccine. Final analysis of SWOG-9035

7501 Background: SWOG-9035 compared 2 years of an allogeneic melanoma lysate (Melacine™) to observation in patients (pts) with stage II melanoma 1.5-4.0 mm thick. We also analyzed the effects of expression of certain HLA antigens (≥2 of HLA-A2, A28, B44, B45, C3 - called M5 - or either HLA-A2 and or C3). Now we report the mature overall survival (OS) analysis as planned. METHODS Primary analyses were conducted on the eligible pt population (intent to treat, ITT) using a Cox model adjusted for stratification and recognized prognostic factors. HLA analyses were [Formula: see text], involved all typed pts and were adjusted for stratification and prognostic factors. RESULTS In total, 689 pts were entered over 4.5 years (598 eligible). Median follow-up time is 7.8 years (maximum 10.9 years). Ninety-one patients are ineligible, mostly (n=75) by pathology (tumor too thin or too thick). For the ITT analysis, the 5-year OS for the observation arm is 77% and for the vaccine arm is 81% (p=.98). For all randomized pts, the 5-year OS for the observation arm is 76% and for the vaccine arm is 82% (p=.49). We HLA typed 553 of the total 689 pts enrolled (80% of the total). There was a significant interaction of M5 status (≥2 vs 0-1) and treatment (p=.02). Among pts with 2 or more of the M5, 5-year OS for vaccine pts is 93% and for observation pts is 74% (p=.009). Among patients with 0-1 of the M5, 5-year OS for vaccine pts is 83% and for observation pts is 82% (p=.68). The interaction remained significant when only HLA A2/C3 status was considered (A2+ and/or C3+ vs A2- and C3-, p=.004). In the A2+ and/or C3+ group, 5-year OS for vaccine pts is 90% and for observation pts is 76% (p=.007). In the A2- and C3- group, 5-year OS for vaccine pts is 80% and for observation pts is 84% (p=.16). CONCLUSION There was no significant benefit of vaccine therapy overall, but this prospective analysis indicates significant survival benefit of vaccine therapy among early-stage melanoma pts expressing ≥2 of the M5 alleles. HLA-A2 and C3 were the predominant alleles contributing to this effect. A prospective confirmatory trial in pts expressing HLA-A2 and/or HLA-C3 is planned. No significant financial relationships to disclose.

Phase II study of low dose cyclophosphamide and intravenous interleukin-2 in metastatic renal cancer.

Thirteen patients with metastatic renal cancer were treated in a phase II trial with interleukin-2, 21.6 million IU/m2 intravenously daily for five days on two consecutive weeks, starting 3 days after the administration of low dose cyclophosphamide 350 mg/m2 intravenously. Treatment cycles were repeated every 21 days. No responses were seen (95% Confidence Interval: 0–22%). The most common toxicities were fever, fatigue, hypotension, nausea/emesis, and myalgia/arthralgia. There were 11 episodes of Grade III toxicity including Grade III hypotension in 7 patients. Because of the significant toxicity and the lack of observed response, the study was discontinued. Cyclophosphamide and interleukin-2 at the dose and schedule used in this study has considerable toxicity and is unlikely to improve on response rates previously seen with other IL-2-based regimens in metastatic renal cancer.

Ensuring Timely Completion of Type and Screen Testing and the Verification of ABO/Rh Status for Elective Surgical Patients

CONTEXT A blood bank can provide compatible blood for an elective surgical procedure, provided a blood sample is received by the laboratory with sufficient time to allow pretransfusion testing and acquire enough compatible red blood cell units. With the push for same-day admission surgical procedures, a patients pretransfusion blood sample is often collected the morning of surgery. However, if blood is needed, compatible units might not be immediately available. OBJECTIVE To define and improve the process of completing presurgical/preadmission type and screen testing and verifying the ABO/Rh status of scheduled surgical patients before they receive a transfusion. STUDY DESIGN A list of surgical procedures that might necessitate blood transfusion was created. A checklist was used to ensure that the preoperative clinic nurse collects a baseline pretransfusion blood sample for type and screen testing from patients scheduled for a listed procedure. A new pretransfusion specimen was received on the day of surgery, if needed, so that a current specimen would be available for compatibility testing and to verify the accuracy of the patients ABO/Rh status in case blood was requested. RESULTS During the 1-year study period, 666 patients qualified for baseline type and screen testing. Cholecystectomy was the most commonly scheduled surgery. In 99% of cases, a baseline type and screen specimen was received in the laboratory at least 1 day before surgery. The interval between the preoperative clinic visit and date of surgery varied from same day (6 patients) to 3 months. CONCLUSION Timely receipt of a presurgical specimen for type and screen testing and verification of a patients ABO/Rh status can be ensured when clinical services collaborate and when the hospital blood utilization committee provides oversight to improve compliance.

Evaluation of fludarabine phosphate in malignant melanoma

Twenty-seven evaluable patients with advanced malignant melanoma received fludarabine phosphate in a daily × 5 injection. Initial dosing was based on the presence of previous radiation therapy. There was no response seen in these patients despite appropriate dose escalation. Myelosuppression occurred without significant sequelae.

Limb salvage surgery for bone and soft tissue sarcoma. A phase II pathologic study of preoperative intraarterial cisplatin

Preoperative therapy has been tested as part of limb salvage therapy for localized bone and soft tissue sarcoma of the extremities. The activity of cisplatin (CDDP) by intraarterial (IA) infusion was evaluated in 40 cases of which 36 were evaluable for response. All patients had high‐grade sarcomas. All but 3 patients received 3 or 4 courses (24 patients received 4 courses) of CDDP at a dosage of 120 to 150 mg/m2 given over 6 hours every 2 weeks by IA infusion. Patients younger than 18 years of age received the higher dose of CDDP. Treatment was well tolerated with combination antiemetics. One patient experienced severe hearing loss with the first cycle of the higher CDDP dose. Pathologic evaluation of resected osteosarcoma showed a favorable response (90% or greater necrosis) in 8 of 20 evaluable cases and in 3 of 4 patients with malignant fibrous histiocytoma (MFH) of bone (without osteoid). In soft tissue sarcomas, minimal (50% to 89%) necrosis was seen in two of nine cases and none had 90% or greater necrosis. Patients received postoperative chemotherapy based on pathologic response, but the value of this postoperative adjuvant therapy requires further follow‐up and is uncertain in this small study. IA CDDP can often cause significant tumor necrosis in patients with bone sarcomas, whereas soft tissue sarcomas are less sensitive to this therapy.

Adjuvant Vaccine Immunotherapy of Resected, Clinically Node-Negative Melanoma: Long-term Outcome and Impact of HLA Class I Antigen Expression on Overall Survival

A final report of trial S9035 by Carson and colleagues indicates a significant overall benefit from the lysed adjuvant vaccine melacrine for patients with stage II to IV melanoma with HLA A2 and/or HLA Cw3 serotypes, implicating interactions between HLA haplotype and clinical outcome. Associations between HLA class I antigen expression and the efficacy of a melanoma vaccine (Melacine; Corixa Corp.) were initially described in stage IV melanoma. Similar associations were observed in S9035, a phase III adjuvant trial evaluating Melacine for 2 years compared with observation in patients with stage II melanoma. This report provides long-term results. The effects of treatment on relapse-free survival (RFS) and overall survival (OS) were evaluated, and prespecified analyses investigated associations between treatment and HLA expression. Multivariable analyses were adjusted for tumor thickness, ulceration and site, method of nodal staging, and sex. P = 0.01 was considered statistically significant in subset analyses to account for multiple comparisons. For the entire study population of 689 patients, there were no significant differences in RFS or OS by treatment arm. HLA serotyping was performed on 553 (80%) patients (vaccine, 294; observation, 259). Among the subpopulation with HLA-A2 and/or HLA-Cw3 serotype, vaccine arm patients (n = 178) had marginally improved RFS (adjusted P = 0.02) and significantly improved OS compared with observation arm patients (n = 145), with 10-year OS of 75% and 63%, respectively [hazard ratio (HR), 0.62; 99% confidence interval (CI), 0.37–1.02; P = 0.01]. There was no impact of HLA-A2 and/or HLA-Cw3 expression on observation arm patients. An analysis of mature data from S9035 indicates a significant OS benefit from adjuvant vaccine therapy for patients with HLA-A2– and/or HLA-Cw3–expressing melanoma. The possibility of interactions between HLA type and outcome should be considered in future immunotherapy trials. Further investigations of melanoma-associated antigens present in Melacine and presented by HLA-A2 and HLA-Cw3 may be warranted. Cancer Immunol Res; 2(10); 981–7. ©2014 AACR.