Chemoimmunotherapy In Patients Research Articles

Cenersen, An Antisense Inhibitor of p53, in Combination with Fludarabine, Cyclophosphamide, and Rituximab Shows Clinical Activity in High Risk CLL.

Abstract 3430Poster Board III-318 Background and SignificanceChronic lymphocytic leukemia (CLL) is a malignant B cell lymphoproliferative disorder characterized by the clonal expansion and accumulation of CD5+ B cells. CLL is quite heterogeneous in clinical behavior, where some patients remain asymptomatic and require no therapy for many years, whereas other patients follow an aggressive clinical course with early need for therapy and short overall survival. Those patients with somatic deletions and / or mutations of p53, a central mediator of cell cycle control, apoptosis, and a potent tumor suppressor, follow the most aggressive clinical courses of all patients with CLL. Furthermore, these patients tend to be refractory to conventional CLL chemotherapy regimens, and therefore novel therapeutic approaches are needed. Cenersen (Eleos Inc.) is a 20-mer antisense molecule and binds to a coding region of exon 10 in p53 mRNA and has been shown in vitro to increase apoptosis in lymphoma cell lines. We hypothesize that the addition of cenersen to chemo-immunotherapy will enhance leukemic cell apoptosis and thus increase chemotherapy sensitivity in vivo for patients with aggressive CLL. Here we report early clinical responses to cenersen in combination with FCR chemo-immunotherapy at a planned interim analysis for efficacy and safety after enrollment of 17 patients. MethodsWe have undertaken a clinical trial at Duke University Medical Center of cenersen in combination with chemo-immunotherapy for patients with CLL or SLL (ClinicalTrials.gov identifier: NCT00636155). Patients with relapsed CLL or previously untreated patients with a deletion or mutation of p53 requiring therapy were enrolled. Cenersen was administered at 2.4 mg/kg/day as a continuous infusion over 24 hours starting on day 1 and ending on day 4. Fludarabine was administered daily at 25 mg/m2 on days 2 through 4, cyclophosphamide was administered daily at 250 mg/m2 on days 2 through 4, and rituximab was administered at 375 mg/m2 on day 2. Cycles were repeated every 28 days for a maximum of 6 cycles. The primary outcome measure was the overall response rate (complete and partial responses by iwCLL response criteria), and secondary outcome measures included progression free survival, event free survival and overall survival. All patients received growth factor support as well as prophylaxis with acyclovir and trimethoprim / sulfamethoxazole. Interphase cytogenetics and sequencing analysis for somatic mutations of p53 was performed in all patients. ResultsTo date, 17 patients have been enrolled to a protocol-defined interim analysis of efficacy and safety. Of the enrolled patients, 1 was previously untreated, and the remaining 16 were relapsed (median number of prior therapies 4, range 1 - 8). Among previously treated patients, the mean response duration of the most recent prior regimen was 2 months. 15 of 16 had previously received fludarabine and 14 of 16 patients had previously received rituximab. 10 of 16 patients tested showed 17p deletions by FISH. Among the 14 patients tested to date, 8 showed somatic mutations in p53 by sequence analysis, of these, 6 showed both deletion of 17p as well as somatic mutation of p53. Of the 17 patients enrolled, 14 are evaluable for response: 1 patient has not yet received 3 cycles of therapy and 2 patients voluntarily discontinued trial participation. To date, 5 patients show a partial response by iwCLL criteria, including 2 patients who have concluded all therapy and show a partial response with incomplete hematologic recovery (PRi) with no detectable CLL B cells by flow cytometry analysis of bone marrow aspirate. One of these patients has subsequently undergone allogeneic stem cell transplantation. The remainder of the patients had stable disease (SD), though 3 were removed from study prior to the completion of 3 cycles for inadequate response as determined by the treating physician. There have been 4 episodes of febrile neutropenia, and there have been no toxicities specifically attributed to cenersen. ConclusionsWe have observed encouraging clinical responses to the combination of cenersen with FCR chemo-immunotherapy among a group of extensively pretreated patients with high risk genetic features. There does not appear to be any excess toxicity associated with the investigational agent. The results to date suggest that there may be therapeutic benefit to p53-targeted therapies in high risk CLL. This study will be continued to full accrual. DisclosuresLanasa:Genentech: Membership on an entity's Board of Directors or advisory committees. Off Label Use: Rituximab, in combination with fludarabine and cyclophosphamide, for the treatment of CLL. Cook:Eleos: Employment. Rizzieri:Eleos: Research Funding.

Pretreatment angiogenic cytokines predict response to chemoimmunotherapy in patients with chronic lymphocytic leukaemia

Serum levels of pro-[vascular endothelial growth factor (VEGF)] and anti-[thrombospondin-1 (TSP)] angiogenic cytokines were prospectively measured in a phase II trial of chemoimmunotherapy (CIT) for chronic lymphocytic leukaemia (CLL) patients (n = 56). Pretreatment VEGF levels were lower among patients who achieved complete remission (CR) or nodular partial remission (nPR) relative to those with partial remission (PR) or stable/progressive disease (median 122.0 pg/ml vs. 246.8 pg/ml; P = 0.03). VEGF:TSP ratio was lower (anti-angiogenic phenotype) among patients who achieved CR/nPR. The pretreatment VEGF:TSP ratio also correlated with overall survival (P = 0.008). A pro-angiogenic profile appears associated with diminished response and inferior survival in CLL patients receiving CIT.

A phase I–II study of the histone deacetylase inhibitor valproic acid plus chemoimmunotherapy in patients with advanced melanoma

We explored in a phase I/II clinical trial the combination of valproic acid (VPA), a clinically available histone deacetylase inhibitor, with standard chemoimmunotherapy in patients with advanced melanoma, to evaluate its clinical activity, to correlate the clinical response with the biological activity of VPA and to assess toxicity. Patients were treated initially with VPA alone for 6 weeks. The inhibition of the target in non-tumour peripheral blood cells (taken as a potential surrogate marker) was measured periodically, and valproate dosing adjusted with the attempt to reach a measurable inhibition. After the treatment with valproate alone, dacarbazine plus interferon-α was started in combination with valproate. Twenty-nine eligible patients started taking valproate and 18 received chemoimmunotherapy and are assessable for response. We observed one complete response, two partial remissions and three disease stabilisations lasting longer than 24 weeks. With the higher valproate dosages needed to reach a measurable inhibition of the target, we observed an increase of side effects in those patients who received chemoimmunotherapy. The combination of VPA and chemoimmunotherapy did not produce results overtly superior to standard therapy in patients with advanced melanoma and toxicity was not negligible, casting some doubts on the clinical use of VPA in this setting (at least in the administration schedule adopted).

Bendamustine/mitoxantrone/rituximab: a short remission induction chemoimmunotherapy for elderly patients with relapsed or refractory chronic lymphocytic leukemia

We have evaluated all outpatients with relapsed or refractory chronic lymphocytic leukemia (CLL) who were treated withbendamustine/mitoxantrone/rituximab (BMR) between May 1999 and December 2008. Treatment consisted ofbendamustine 90 mg/m2 on day 1 + 2, Mitoxantrone 6 mg/m2 on day 1, and Rituximab 375 mg/m2 on day 8, 15,22 + 29. Thirty-nine patients (19 males, 20 females) received BMR with a median age of 69 years (46–81). Nineteen patients(49%) were above 70 years and 13 patients (33%) were 75 years or above. Performance score ranged between 0 and 2. Themedian number of previous therapies was 2 (1–4). Therapy was tolerated well with two observed therapy-associatedhospitalizations. A reversible grade 3 or 4 hematotoxicity was seen in 30 patients (77%). Other reversible grade 3 or 4toxicities were seen in two patients (5%). The overall response rate was 92% (10% complete remission, 82% partialremission). Median time to next CLL-therapy was 13 months (0–69). We conclude that BMR is a short and effectiveoutpatient chemoimmunotherapy for patients with relapsed or refractory CLL, which can be used safely in elderly patients.

Plasma Alemtuzumab Levels at End of Treatment Correlate with Response and Response Duration in Patients with CLL Receiving Treatment for Residual Disease.

We conducted a phase II trial with alemtuzumab self-administered, subcutaneously (SQ) to eliminate residual disease after chemotherapy or chemoimmunotherapy for patients (pts) who were in partial remission (PR) or pts in complete remission (CR) with 2-color flow cytometry evidence of disease. Pts received alemtuzumab SQ 3mg, 10mg, 30mg on days 1,2,3 then 30mg thrice weekly for a total of 12 doses, including rampup. After the 12th dose, pts with residual disease could receive a second course of 12 additional doses. Responding pts were pts in PR who converted to nodular PR (NPR) or CR by NCI-WG ‘96 criteria or pts in CR who remained in CR and had no evidence of disease by 2-color flow cytometry. There were 26 pts enrolled in PR, 5 pts in CR. 7 pts received a second course of alemtuzumab. End of treatment plasma alemtuzumab levels were measured by a flow cytometry-based assay (Rebello and Hale, J Immunol Methods, 2002). The response rate in the intent-to-treat population was 74%. We retrospectively evaluated patients’ bone marrow for minimal residual disease by 4-color flow cytometry. A disappointing 18% of pts evaluated was MRD-negative in bone marrow by this method. Responding pts had mean plasma alemtuzumab level of 8μg/ml verses 3μg/ml for non-responders (p=.003). The median plasma alemtuzumab level for responders was 6μg/ml. Responders with end of treatment plasma alemtuzumab level greater than 6μg/ml had a significantly longer median response duration of 21.2 months versus 8.9 months for pts with less than 6μg/ml (p=.048). End of treatment plasma alemtuzumab level correlated with response to treatment and response duration for patients treated with alemtuzumab SQ. Future studies to optimize dose and schedule for alemtuzumab SQ as treatment for CLL, including for residual disease, should include measurement of end of treatment plasma alemtuzumab levels and evaluation of bone marrow for minimal residual disease by 4-color flow cytometry. Furthermore, consideration of these results should be given to optimize the effective duration of treatment with alemtuzumab SQ.

Alemtuzumab and Rituximab Combination Therapy for Patients with Untreated CLL – a Phase II Trial.

Despite the availability of multiple therapeutic regimens, without a stem cell transplant, chronic lymphocytic leukemia (CLL) remains an incurable disease. A dramatic response rate with intensive chemo-immunotherapy in patients with CLL is frequently associated with irreversible long term consequences to the bone marrow, limiting further therapeutic options. For this reason we have initiated a clinical trial combining Rituximab (RIT) and Alemtuzumab (ALEM), two monoclonal antibodies with established activity and side effects profiles, as an initial therapy for patients with CLL requiring intervention.Methods: Data is available on 20 out of 21 enrolled patients. Therapy duration is 18 weeks. Subcutaneous (SQ) ALEM dose escalation: 3 mg - 10 mg - 30 mg on days 1, 3, 5, followed by the 30 mg Monday, Wednesday and Friday for 17 weeks. RIT at a dose of 375 mg/m2/dose IV is administered every other week staring on the 3d week for 8 doses. All patients received PCP, herpes virus, and fungal prophylaxis as well as CMV viral DNA monitoring. Responses were based on NCI-WG 1996 criteria; however, lymphadenopathy and organomegaly were also assessed by serial CT scans. Minimal residual disease (MRD) was measured in peripheral blood and bone marrow aspirate using flow cytometry for CD19+/CD5+/CD23 lymphocytes.Patients' characteristics: Since September 2005, 21 patients have been enrolled and 20 completed the therapy. All patients met ECOG criteria for requiring treatment. Median age was 54 years (28 – 74) with 12 males and 8 females; 19 Caucasian and 1 African American. The median time from the diagnosis to treatment was 21.5 months (2–144 months). Clinical stage (Rai) was I in 2 patients, II in 8 patients, III in 4, and IV in 6 patients. Median β2 microglobulin was 3.23 (0.34–15.3). Median WBC was 56 x109/L (17.4 – 157.6), Hgb 12.6 g/dL (10 – 14.7), and platelet count 172 x 109/L (66 – 307). Cytogenetic analysis, by FISH panel, was 13q- in 7, trisomy 12 in 6, and 13q-/11q- in 3, 11q- in 1, 11q-/p53/13q- in 1, and 13q-/11q-/6q- in 1 patient. Half of the patients were Zap70+ and 3 patients were CD38+. Mutational analysis is pending.Results: Based on the NCI-WG 1996 criteria, 15 patients (75%) achieved CR, 3 patients (15%) achieved PR, and 2 patients (10%) had stable disease. With utilization of CT scans responses were: 8 CR (40%), 9 PR (45%), and 3 SD (15%). At the completion of the study 14 patients (70%) had no evidence of MRD by flow cytometry. Median duration of the response has not been reached with a median follow-up of 20 months (1–31+). All 5 patients with 11q- achieved CR based on the NCI-WG 96 criteria. Three patients (15%) required alternative therapy for the disease progression at 4, 24, and 27 months after the completion of study.Six patients (30%), all of whom were baseline CMV IgG+, had CMV reactivation by PCR. Two of them developed symptom of malaise and required hospitalization, none suffered organ involvement, and all of them cleared the infection with valgancyclovir administration. One patient suffered neutropenic fever requiring empiric antibiotic therapy followed by Clostridium difficile and adenovirus infections. No other serious infectious complications were documented.All patients developed grade 1–2 skin rash at the site of ALEM injection after the 1st dose of 3mg only; none required intervention. All patients developed grade 3–4 lymphopenia; neutropenia: grade 2 in 3, grade 3 in 5, and grade 4 in 3 patients; anemia: grade 1 in 9, grade 2 in 2 patients; thrombocytopenia: grade 1 in 8, grade 2 in 4, and grade 3 in 3 patients.Seven patients have not achieved full T cell recovery (CD4 >200) by 1, 4, 5, 7, 12, and 18 months. The other 13 patients achieved T cell recovery by 1 (n=2), 4 (n=2), 6 (n=1), 7 (n=2), 9 (n=1), 10 (n=1), 15 (n=1), 16 (n=2), and 22 months. All of the patients who suffered CMV reactivation achieved faster T cell recovery than those who did not (median time 5 vs. 22 months). Two patients developed clinically significant autoimmune hemolytic anemia and none suffered Richter's transformation. No death occurred.Discussion: Combination of ALEM and RIT is well tolerated and active regimen for patients with CLL and may represent a viable alternative to the combination chemotherapy.

Study of IL-2 receptor expression after chemoimmunotherapy in patients treated for metastatic malignant melanoma.

Using flow cytometry, cellular IL-2 receptors were studied before and following chemoimmunotherapy combination in 20 patients with metastatic malignant melanoma (MMM). Patients received cisplatin (100 mg/m2) at days 1 and 28, recombinant IL-2 by continuous infusion from days 3 to 6, 17 to 21, 31 to 34, and 45 to 49. Interferon-alpha (IFN-alpha) was given subcutaneously three times weekly. In terms of clinical response, we observed 55% objective response (complete: 15%). When pretreatment blood samples were compared with those of healthy donors, we did not observe any change in low (alpha chain) and high affinity receptor (alpha + beta) expression. In contrast, intermediate affinity p75 (beta chain) expression was decreased significantly (P < or = 0.0001) in MMM patients. During treatment, we found a dramatic increase of beta chain as well as high affinity (alpha + beta) expression in responding patients, as soon as IL-2 therapy began. Furthermore, the increase of beta chain expression was limited to natural killer (NK) cells (CD56+). In non-responding patients, on the other hand, increase of both receptors was seen only at day 31. These data suggest the involvement of beta chain expression in the mechanism of cell activation after chemoimmunotherapy. Moreover, this early beta chain expression is correlated with the clinical response to chemoimmunotherapy.

Y-90 Ibritumomab Tiuxetan as Consolidation Following Three Cycles of Fludarabine-Cyclophosphamide-Rituximab Chemoimmunotherapy in Patients with Relapsed Follicular, Indolent or Mantle-Cell Lymphoma: A Prospective “Dose”-Finding Study.

BACKGROUND: Tumed sequential treatment with fludarabine/cyclophosphamide/rituximab (FC-R) followed by Y-90 ibritumomab tiuxetan (IT) radioimmunotherapy may improve progression-free survival in patients (pts) with CD20+ NHL. However, even unpretreated pts submitted to four to six cycles of a fludarabine-containing combination and then IT at an Y-90 activity of 15 MBq/kg will experience severe prolonged, transfusion-dependent and only partially reversible pancytopenia, thus limiting its use in a non-curative setting (Jurczak et al., ASH 2005).AIM: We report on a trial including anthracycline-pretreated pts with relapsing CD20+ lymphoma > age 50 and unsuitable for myeloablative treatment. These received 3 cycles of FC-R. If at least stable disease was achieved and neutrophil as well as platelet counts had normalized (2.5 vz. 150/nl) within 8 weeks, this was immediately followed by IT at 11 or 15 MBq/kg Y-90 activity. Primary endpoint was the rate of dose-limiting toxic events (DLT) induced by consolidation IT as a function of Y activity employed. DLT was defined as NIH-CTC grade 4 neutropenia or thrombocytopenia for > 14 days or non-hematological toxicity of > grade 2 for > 7 days. Per level of activity, a maximum of 1 DLT episode occurring in two cohorts of 3 pts was considered acceptable.RESULTS: We recruited 21 patients into the trial (10 follicular, 9 mantle cell, 2 other). Median age was 70 years, all were stage III/IV and median no. of pretreatments was 1 (range 1 to 3). 9 had marrow involvement (< 25%), and 7 elevated LDH. 8 pts went off treatment before IT, mostly because of persistent cytopenia or progression. 13 received IT. Pt characteristics in this subcohort were comparable to the baseline cohort. Hematologic nadirs occurred at median 6 weeks post-IT. Median ANC nadir was 0.45/nl, with 1 pt in the 11 MBq and 2 in the 15 MBq activity level sustaining grade 4 neutropenia of > 2 weeks duration. Median PLT nadir was 26/nl. Grade 4 thrombocytopenia was found in only 1 pt at the 15 MBq level (duration 10 days) who did not require transfusion. Median ANC and PLT counts normalized by week 12, one showing persistent otherwise unexplained thrombocytopenia. Non-hematological toxicitiy including fever or infections was rare and < grade 3. No correlation was found with extent/type of pretreatment, baseline cell counts or presence of marrow involvement. With median 8 months follow-up, 1 has so far improved remission status to CR, and 1 pt in stable disease and 1 in PR before IT have progressed.CONCLUSIONS: In order to avoid neutropenia grade 4 of > 2 weeks duration, IT following 3 cycles of FC-R should be performed at an Y activity level of 11 MBq/kg. Nevertheless, the possibly higher incidence of prolonged severe neutropenia following IT at 15 MBq does not translate into a higher rate of infections or persistence of neutropenia and may therefore be regarded safe.

A Phase I study of thalidomide, Capecitabine and temozolomide in advanced cancer

Aim: To develop a novel oral antiangiogenic and immunomodulatory chemotherapy regimen against advanced cancers. Methods: Patients were enrolled in cohorts of 3 or 6 in a standard phase I design. Thalidomide 100 mg was kept stable for all cohorts. If well tolerated after 1 week, capecitabine and temozolomide (TCT) fixed-dose were given daily without rest and escalated one at a time until dose limiting toxicity (DLT) occurred. If no DLT occurred within 28 days (1 cycle), the subsequent group was enrolled into the next dose level. Results: Twenty-three adult patients with objective documentation of progressive metastatic cancer after a median of 2 therapies (range 0-4) received TCT in this study. Based on DLT within the first 28 days, the MTD of daily TCT therapy was thalidomide 100 mg, capecitabine 2000 mg and temozolomide 100 mg. With long-term treatment, majority of the patients required dose interruptions due to fatigue, hand-foot syndrome, and neutropenia. A dose level consisting of daily thalidomide and 3-weeks-on 1-week-off capecitabine and temozolomide was implemented and administered to six patients without DLT. Out of 23 subjects, 4 (17%) achieved a partial response (renal, gastric, prostate 2), and 4 patients (17%) had stable disease (renal, colon, pancreas 2), adding to a clinical benefit of 34%. Conclusions: TCT is an effective palliative oral chemo-immunotherapy for patients with advanced cancer. The recommended dose for phase II trial is thalidomide 100 mg daily without a break, capecitabine 2000 mg and temozolomide 100 mg daily three-weeks on and one-week off.

Chemoimmunotherapy with dacarbazine, cisplatin, interferon-alpha2b and interleukin-2 versus two cycles of dacarbazine followed by chemoimmunotherapy in patients with metastatic melanoma: A randomised phase II study of the European Organization for Research and Treatment of Cancer Melanoma Group

Background Chemoimmunotherapy for patients with metastatic melanoma is associated with high toxicity, and only a subset of patients will benefit. This randomised phase II study was performed with the primary objective of exploring whether two cycles of dacarbazine monotherapy could select the subset of patients that would benefit most from more intensive chemoimmunotherapy. Patients and methods Patients with metastatic melanoma were randomised to either receive chemoimmunotherapy with dacarbazine, cisplatin, interferon-alpha and interleukin-2 (arm A) or initial treatment with two cycles of dacarbazine monotherapy followed irrespective of response by the same 4-drug regimen of chemoimmunotherapy (arm B). Chemoimmunotherapy was continued in the absence of disease progression for a maximum of four cycles. Primary end-point was the disease stabilisation rate. Results A total of 93 patients were randomised, and 89 patients were eligible. Disease stabilisation (complete/partial response or stable disease) was achieved in 19 patients (42.2%) in arm A and 9 patients (20.5%) in arm B. In arm B 32 of the 44 patients continued chemoimmunotherapy after two cycles of dacarbazine. Of 20 patients with progressive disease (PD) after two cycles of dacarbazine in arm B, only 2 patients achieved an objective response. Median overall survival (OS) in arms A and B was 10.5 months and 9.5 months, respectively. Conclusions Despite a lower initial stabilisation rate, the strategy of starting with 2 courses of DTIC prior to a 4-drug regimen led to comparable median overall survival. Only few transient responses were achieved with the 4-drug regimen in patients with disease progression on DTIC, suggesting frequent cross resistance. Two cycles of dacarbazine monotherapy cannot be recommended to select patients for more intensive chemoimmunotherapy.

A phase I study of thalidomide, capecitabine and temozolomide (TCT) in advanced cancer

13122 Background: The aim is to develop a novel oral immuno-chemotherapy regimen against advanced cancers. Methods: Patients were enrolled in cohorts of 3 or 6 in a standard phase I design. Thalidomide 100 mg was kept stable for all cohorts. If well tolerated after 1 week, capecitabine and temozolomide (TCT) were given daily without rest and escalated one at a time until dose limiting toxicity (DLT) occurred. If no DLT occurred within 28 days (1 cycle), the following group was enrolled into the next dose level. Results: Twenty-three patients with advanced cancers have been treated in this study. All patients have been evaluated for toxicity and response. Eighty cycles of TCT have been administered (1–13 cycles/patient). Patient characteristics: Median age 59 (31–79), PS ECOG 1 (0–2). Type of cancer: renal (7), bladder (2), pancreatic (2), prostate (2), colon (2), and lung, gastric, synovial sarcoma, angiosarcoma, anal, nasopharyngeal, breast, esophageal (1 each). Prior to TCT, all patients had objective documentation of progressive metastatic disease after a median of 2 therapies (range 0–4). Objective response: Four subjects (17%) achieved partial response (renal 1, gastric 1, prostate 2), and 4 patients (17%) had stable disease (renal 1, colon 1, pancreas 2), adding to a clinical benefit of 34%. Toxicity: Treatment was well tolerated. Common toxicities included grade 3 thromboses 17%; and grade 1–2: hand-foot syndrome, fatigue, sensory neuropathy, nausea, vomiting, and neutropenia. Based on DLT within the first 28 days, the MTD of daily TCT therapy was thalidomide 100 mg, capecitabine 2000 mg and temozolomide 100 mg. With long-term treatment, majority of the patients required dose interruptions due to fatigue, hand-foot syndrome, and neutropenia. Dose level 2.5 was implemented: daily thalidomide and 3-weeks-on 1-week-off capecitabine and temozolomide. Six patients were treated at dose level 2.5 without toxicities. Conclusions: TCT is an effective palliative oral chemo-immunotherapy for patients with advanced cancer. The recommended dose for a phase II trial is dose level 2.5, including thalidomide 100 mg daily, capecitabine 2000 mg/day and temozolomide 100 mg/day three-weeks on and one-week off regimen. [Table: see text]

Retrospective study of uveal melanoma

To report the results of a retrospective study carried out at the 1st Department of Ophthalmology of Semmelweis University, Budapest, among patients treated for ocular melanoma. Clinical data of the patients, histopathological characteristics of the tumours and follow-up results are reported. Retrospective review of patients' charts, histopathological data and statistical analysis of collected data. From 120 patients treated by enucleation or exenteration for uveal melanoma, 22 had died by the end of the study. The medium survival after operation was 34.0+/-25.4 months, the majority of deaths occurred within three years following surgery. Statistically significant relationship was demonstrated between extraocular extension of the tumour and death, and between epithelioid cell tumours and death. Most large tumours involved the ciliary body, the prognosis of these tumours tended to be worse than for those infiltrating only the choroid, but the difference was not statistically significant. Uveal melanoma almost exclusively gives haematogenous metastases, liver metastases being the most frequent; rarely lung metastases are also reported. Since extraocular extension and epithelioid tumours carry a very poor prognosis, the possibility of providing adjuvant chemo-immunotherapy for patients harbouring these tumours should be entertained, even if liver metastases are not demonstrated at the time of diagnosis.

Bendamustine/Mitoxantrone/Rituximab (BMR): A Very Effective, Well Tolerated Outpatient Chemoimmunotherapy for Relapsed and Refractory CD20-positive Indolent Malignancies. Final Results of a Pilot Study

We have developed a new chemoimmunotherapy for patients with relapsed or refractory CD20-positive indolent lymphomas and CLL by combining the chemotherapeutic agents Bendamustine (B) and Mitoxantrone (M) with the monoclonal antibody Rituximab. Treatment consisted of (B): 90 mg/m2 (80 mg/m2 in CLL) day 1 + 2, (M): 10 mg/m2 day 1 and (R): 375 mg/m2 day 8,15,22 and 29. BM was repeated 3 times starting on day 36, thereafter every 4 weeks. The maximal therapy consisted of 1 × BMR followed by 5 × BM. We have treated 54 patients with BMR. Median age was 68 years (36 - 82). Disease distribution was as follows: 21 B-CLL, 1 B-PLL, 8 lymphoplasmacytic, 14 follicular, 2 mantle cell, 2 marginal zone, 6 secondary high grade. Median number of previous treatments was 2 (1 - 7). ORR was 96% with 41% CR and 55% PR. Median time to progression is 17 months in CLL and has not been reached in indolent lymphomas with a median observation time of 27 months (3 - 60 + ). The time to next antilymphoma treatment is prolonged significantly by BMR. No therapy associated death or hospitalization occurred within the study period. BMR is a well tolerated very effective outpatient treatment for relapsed and refractory CD20-positive indolent lymphomas and CLL.

Chemo-immunotherapy in patients with malignant melanoma

U.O.A. of Medical Oncology, San Gennaro Hospital, ‘Federico II’ University, Chair of Oncological Surgery, Naples, Italy

Clinical effects of chemoimmunotherapy for patients with peritoneal carcinomatosis

The present study was undertaken to determine whether chemoimmunotherapy using activated killer cells is better than chemotherapy alone for cancer patients with peritoneal carcinomatosis. Thirty-one cancer patients received adoptive immunotherapy by activated killer cells and chemotherapy by anticancer drugs selected by a chemosensitivity test (chemoimmunotherapy group), and another 31 cancer patients received chemotherapy (chemotherapy group). The regimen of chemotherapy was determined by the results of a chemosensitivity test in both groups. The clinical effects including response rate and survival were assessed. Five patients (16.1%) achieved complete response (CR), and 17 patients (54.8%) partial response (PR) in the chemoimmunotherapy group (response rate: 22/31 patients = 71.0%), whereas 4 patients (12.9%) achieved CR, and 5 patients (16.1%) PR in the chemotherapy group (response rate: 9/31 patients = 29.0%). The response rate was higher in chemoimmunotherapy group than in chemotherapy group (p<0.05). However, no difference was observed in survival between the two groups. Therefore, it is necessary to develop methods to induce more potent killer cells for adoptive immunotherapy.

Ex vivo activated memory T-lymphocytes as adoptive cellular therapy of human soft-tissue sarcoma targets with potentiation by cis-diamminedichloroplatinum(II).

Autolymphocyte therapy (ALT) is tumor-specific, adoptive cellular therapy of neoplastic disease using nonspecific ex vivo activation of autologous peripheral blood lymphocytes (PBL), which are composed primarily of memory T-cells (ALT-cells) and are active in patients with metastatic renal cell carcinoma and melanoma. Ex vivo pretreatment of tumor target cells with certain chemotherapeutic agents can enhance susceptibility to lysis by antitumor lymphocytes. To determine if cis-diamminedichloroplatinum(II) (CDDP) enhances ex vivo antitumor cytotoxicity of ALT-cells and if this lysis is mediated by T- and/or NK-cells and is human leukocyte antigen (HLA)-restricted, human soft tissue sarcoma (STS) target cells were derived from primary and metastatic surgical specimens and were incubated with and without CDDP. ALT-cells were prepared from autologous PBL obtained prior to surgery. Primary (PSTS) and metastatic (MSTS) target cells from each group were labelled with chromium 51 (51Cr) and used as targets for ALT-cells, CD45-depleted ALT-cells, CD56 (NK)-depleted ALT-cells, and PBL in a standard (4-hour) and delayed (18-hour) 51Cr release assay. Interferon-gamma (IFN-gamma) release was measured as an indication of antitumor effect and recognition by the noncytolytic lymphocytes in ALT-cells. Primary tumor target cells incubated in CDDP showed enhanced lysis as measured by the 51Cr release assay compared to non-CDDP-treated controls. Metastatic tumor target cells showed less lysis than the primary targets, although this was enhanced by pretreating metastatic tumor targets with CDDP. Lysis of all tumor targets was significantly greater when ALT-cells were used as the effector cells rather than PBL. Depletion of memory T-cells abrogated ex vivo lysis. Depletion of NK cells (CD56+) affected ex vivo lysis of autologous targets during the 4-hour but not the 18-hour assay. Ex vivo ALT-cell lysis and IFN-gamma release against only the autologous tumor targets confirmed tumor-specificity in one patient. Restriction of ALT-cell lysis and IFN-gamma release against HLA-A2+ autologous and one allogeneic HLA-A2+ STS tumor target, but not other non-STS targets, was demonstrated in another patient. These data suggest that CDDP may help render STS susceptible to tumor-specific, immune-mediated attack and that the combination of ALT and CDDP may lead to effective tumor-specific chemoimmunotherapy in patients with metastatic STS.

Chemo-immunotherapy in patients with metastatic melanoma using sequential treatment with decarbazine and recombinant human interleukin-2: evaluation of hematologic and immunologic parameters and correlation with clinical response

We have treated 18 patients with metastatic malignant melanoma (MM) with high-dose IL-2 administered by continuous iv infusion in combination with dacarbazine (DTIC), and correlated the clinical response with various hematologic and immunologic parameters. Two regimens differing in the sequence of treatment were employed, and 1–6 treatment cycles were given, depending on patient response. Two patients had a complete response (CR, 46+m, 14m), two patients a partial response (PR, 16m,6m), one a minimal response and four had a stable disease lasting 2–7 months, thus the response rate (CR+PR) was 22%. None of the following parameters, tested prior to initiation of the therapy and 1–2 days after termination of each course of IL-2, correlated with the clinical response: WBC counts (total and differential), levels of blood CD4 and CD8 T cells, NK cells, monocytes and B cells, production of IL-1 and IL-1 inhibitor by monocytes, responsiveness to 3 mitogens, NK/LAK cell activity, and serum levels of IL-1α, IL-2, soluble IL-2 receptor, and TNFα. The only prognostic parameter was the greater increase in the level of IL-2 receptor (Tac)-bearing lymphocytes in the responding patients after 1–3 cycles of IL-2. The data suggests that non-specific immune parameters have no prognostic value for patients undergoing IL-2-based immunotherapy.

Randomized Phase III Trial of Chemoimmunotherapy in Patients with Previously Untreated Stages III and IV Suboptimal Disease Ovarian Cancer

Between 1979 and 1984, 98 patients considered to have stage III epithelial type ovarian cancer and optimal surgical resections (i.e., less than 2 cm residual tumor masses) were randomly assigned to treatment with 2 cm residual tumor masses) were randomly assigned to treatment with doxorubicin + cyclophosphamide + BCG (DC + BCG) vs doxorubicin + cyclophosphamide + cisplatin (DCP) vs. doxorubicin + cyclophosphamide + cisplatin + BCG (DCP + BCG). Seventeen (17%) were considered ineligible on the basis of formal histopathologic review. The pathologically proven complete response rates for DC + BCG, DCP, and DCP + BCG-treated patients were 20, 23, and 41%, respectively, and the median survival durations were 36.8, 48.2, and 57.4 months, respectively. Because of the relatively small sample size, definite conclusions concerning the response or survival impact of adding cisplatin to DC + BCG or BCG to DCP can not be drawn; nevertheless, all three groups of patients experienced prolonged survival durations with approximately 40% of all eligible patients alive at 5 years.

Randomized phase III trial of chemoimmunotherapy in patients with previously untreated stages III and IV suboptimal disease ovarian cancer: A Southwest Oncology Group study

Between 1979 and 1984, 185 fully evaluable patients with stage III or IV epithelial type ovarian cancer and suboptimal surgical resections were randomly assigned to treatment with doxorubicin + cyclophosphamide + BCG (DC + BCG) vs doxorubicin + cyclophosphamide + cisplatin (DCP) vs. doxorubicin + cyclophosphamide + cisplatin + BCG (DCP + BCG). Patients with measurable disease (119) were analyzed separately from those with nonmeasurable disease (66). In measurable disease patients the overall clinical complete plus partial response rates for DC + BCG, DCP, and DCP + BCG-treated patients were 36, 57, and 59%, respectively. Although there were no significant patient characteristic differences between the DCP and DCP + BCG treatment groups, the addition of cisplatin to the DC + BCG regimen resulted in significantly prolonged response ( P < 0.03) and survival ( P < 0.002) durations. To the contrary, the addition of BCG to the DCP regimen did not improve objective response rates or response or survival durations. For patients with non-measurable, suboptimal disease there were no significant differences between the three treatments with respect to response or survival parameters; however, patients in this disease category fared generally better than those with clinically measurable disease. We conclude that cisplatin adds significantly to the efficacy of DC + BCG, but BCG does not add to the efficacy of DCP in patients with measurable, stage III or IV disease.

Randomized phase III trial of chemoimmunotherapy in patients with previously untreated stage III, optimal disease ovarian cancer: A Southwest Oncology Group study

Between 1979 and 1984, 98 patients considered to have stage III epithelial type ovarian cancer and optimal surgical resections (i.e., < 2 cm residual tumor masses) were randomly assigned to treatment with doxorubicin + cyclophosphamide + BCG (DC + BCG) vs doxorubicin + cyclophosphamide + cisplatin (DCP) vs. doxorubicin + cyclophosphamide + cisplatin + BCG (DCP + BCG). Seventeen (17%) were considered ineligible on the basis of formal histopathologic review. The pathologically proven complete response rates for DC + BCG, DCP, and DCP + BCG-treated patients were 20, 23, and 41%, respectively, and the median survival durations were 36.8, 48.2, and 57.4 months, respectively. Because of the relatively small sample size, definite conclusions concerning the response or survival impact of adding cisplatin to DC + BCG or BCG to DCP can not be drawn; nevertheless, all three groups of patients experienced prolonged survival durations with approximately 40% of all eligible patients alive at 5 years.