Intensive single-agent mitoxantrone for metastatic breast cancer.

Twenty-seven women with metastatic breast cancer were treated with mitoxantrone as a single agent, with the use of an intensive dose-escalating schedule. Doses were given at 0.5 mg/m2/day as an iv injection for 3 consecutive days and then were escalated each month by 2.5 mg/m2/day until maximal tolerance was reached on the basis of hematologic or cardiac toxicity. No complete responses were demonstrated. Six patients (22%) had partial responses of 5.5 months' median duration. Four of 12 patients who had not received prior doxorubicin responded (33%), whereas two of 15 patients with previous doxorubicin exposure responded (13%). Cardiotoxicity, determined by serial radionuclide ventriculography, occurred in 10 patients (37%) at a mean total mitoxantrone dose of 83.0 mg/m2. Three of these 10 patients had no predisposing risk factors, four had received thoracic radiotherapy that might have involved the heart, and three had received prior doxorubicin without clinical toxicity. The failure of dose intensification to augment the response rate when compared to the response rates reported for less myelotoxic doses of the drug, in addition to the extent of cardiotoxicity noted, calls into question the value of dose intensification of mitoxantrone in the treatment of metastatic breast cancer.

Mitoxantrone, vincristine, and prednisone in adults with relapsed or primarily refractory acute lymphocytic leukemia and terminal deoxynucleotidyl transferase positive blastic phase chronic myelocytic leukemia.

A combination of mitoxantrone, vincristine, and prednisone was used to treat 19 patients with acute lymphocytic leukemia. Of these, 12 were patients with acute lymphoblastic leukemia (ALL) (9 in first relapse and 5 primarily refractory to standard induction therapy with daunorubicin, vincristine, and prednisone), 2 had a phenotypic ALL relapse after an initial diagnosis of acute myelocytic leukemia and 5 had terminal deoxynucleotidyl transferase positive blastic phase chronic myelogenous leukemia (BCML). Eight patients with ALL (and of these, four with primarily anthracycline resistant disease), and two with BCML achieved complete remission. Five patients died in induction (three ALL from sepsis and two BCML from bleeding), and five had progressive disease. Median duration of response was 5 months, with two primarily refractory ALL patients remaining in continuing complete remission at 28 and 31 months. Treatment was well tolerated, with minimal nausea and vomiting, and oral mucositis. Posttreatment transient hepatic dysfunction was seen in 80% of patients. Mitoxantrone, vincristine, and prednisone are an active combination for the treatment of relapsed or refractory ALL and of terminal deoxynucleotidyl transferase positive BCML. The finding that four of five primarily refractory ALL patients were induced in complete remission supports the contention that mitoxantrone and anthracyclines are not cross-resistant.

Mitoxantrone in patients with acute leukemia in relapse.

Twenty-six patients with acute leukemia in relapse were treated with mitoxantrone (dihydroxyanthracenedione dihydrochloride). The drug was given as a rapid i.v. infusion for 5 days, and doses were escalated from 8 mg/sq m daily for 5 days to 20 mg/sq m daily for 5 days. Five of 12 patients with acute lymphoblastic leukemia were induced into complete remission; one patient was induced into complete remission twice. The marrow response lasted from 3 to 50+ weeks. Among 12 patients with acute myelogenous leukemia, there was one complete and one partial remission, with response duration lasting 8 and 2 weeks. One patient with chronic myelogenous leukemia in blastic crisis also had a partial remission lasting 17 weeks. Remissions occurred at doses ranging from 8 to 14 mg/sq m daily for 5 days. All responders had been treated previously with anthracyclines. Drug-induced side effects included dose-limiting oral mucositis, sporadic nausea and vomiting, and transient elevations of the hepatic enzymes. Approximately one-third of the patients had septic complications during the myelosuppressive phase following treatment. We believe that mitoxantrone has definite utility in the treatment of acute leukemia in relapse.

Recombinant interleukin-2 by continuous infusion and adoptive transfer of recombinant interleukin-2-activated cells in patients with advanced cancer.

Twenty-five patients with disseminated cancer (nine with renal cell carcinoma, five with melanoma, three with Hodgkin's lymphoma and chronic myelocytic leukemia [CML], two with soft tissue sarcoma, one each with large-cell lymphoma, breast cancer, and colon cancer), 13 males and 12 females, aged 25 to 68, were treated with recombinant human interleukin-2 (rIL2) by continuous infusion and adoptive transfer of autologous lymphocytes activated in vitro with IL2. Patients underwent leukapheresis on days 1, 8, 15, and 22 of the treatment. Cells, bulk activated for 20 hours in serum-free culture medium with 1,000 U IL2/mL in transfusion transfer packs as culture vessels, were transfused the following day. The infusion of IL2 by continuous infusion for six days started immediately after each adoptive transfer for 4 weekly courses. The dose of IL2 was escalated weekly in each patient; starting doses of IL2 were also escalated in subsequent cohorts of patients until maximally tolerated doses were reached. Nine patients had objective tumor regressions (three with renal cell cancer, two with Hodgkin's lymphoma, and one each with melanoma, sarcoma, breast, and colon cancer). Six responses were partial, two were minor, and one was mixed. Responding patients were maintained with IL2 by continuous infusion for six days every 6 to 8 weeks, without adoptive cell transfer. The median duration of responses was 16 weeks (3 to 60 + weeks). Tumor regression was related to the dose of IL2 (greater than or equal to 3.4 x 10(6) U/m2/d for six days) and to the in vivo lymphoproliferative effects of the lymphokine, but not to the total number of cells adoptively transferred. Side effects of treatment were transient and quickly reversible. Renal, hepatic dysfunction, and dyspnea were directly related to the dose of IL2 and to lymphocytosis. Other toxicities were mild hypotension with mild fluid retention, oral mucositis, anemia, thrombocytopenia, fever, and fatigue.

Surgical treatment of spinal cord compression from epidural metastasis.

PURPOSE: A retrospective study of the results of neoplastic cord compression was undertaken to determine the effectiveness of surgical treatment and to assess quality of life in patients undergoing extensive procedures with potential morbidity. PATIENTS AND METHODS: Over a 5-year period (1989 to 1993), a total of 110 patients underwent surgery. Fifty-five patients (50%) had undergone prior treatment, including 47 (43%) who had failed to respond to prior irradiation (RT). Before surgery, 48 patients (44%) were nonambulatory, with severe paresis being present in 20. Surgery included staged anterior-posterior resections in 53 patients (48%), anterior resections in 33 (30%), and posterior resection in six (5%), all of whom required spinal instrumentation for reconstruction; only 18 patients underwent resection without instrumentation. RESULTS: Postoperatively, 90 patients (82%) were improved, both in terms of pain relief and ambulatory status. Fifty-three patients (48%) experienced postoperative complications, related statistically to the following three factors: age over 65 years, prior treatment, and presence of paraparesis. The overall median survival duration was 16 months, with 46% alive at 2 years. Apart from primary tumor, the presence of preoperative paraparesis had the most significant impact on survival. CONCLUSION: Our data suggest that the effective surgical treatment of neoplastic compression requires anterior-posterior resection in most patients to achieve the goal of total tumor resection, with the majority requiring instrumentation. Long-term survival is feasible in a subset of patients with this aggressive surgical approach.

Phase III trial of brief intensive treatment of adult acute lymphocytic leukemia comparing daunorubicin and mitoxantrone: a CALGB Study.

This paper reports a study of the Cancer and Leukemia Group B (CALGB) comparing daunorubicin (DNR) or mitoxantrone (DHAD) in induction followed by multidrug intensification over 8 months in adult patients with acute lymphocytic leukemia (ALL). A total of 164 newly diagnosed patients were randomly assigned to either DNR or DHAD plus vincristine, prednisone and methotrexate given intravenously (i.v.) and interthecally (i.t.). Patients received four more intensification courses of chemotherapy and then all therapy was stopped. Central nervous system (CNS) prophylaxis consisted of nine infusions of intermediate dose methotrexate (MTX) and intrathecal MTX. DHAD and DNR were equally effective in producing complete remissions (63 and 65%, respectively). The estimated median remission duration is 10.2 and 12.3 months for the DHAD and DNR arms, respectively (p = 0.56). This study was stopped earlier than planned when it became apparent that remission duration for both arms was shorter than seen in our prior study in which all patients received more than 1 year of maintenance therapy. The estimated median survival is 18.3 and 20.6 months for the DHAD and DNR arms, respectively (p = 0.90). Younger patients and patients with a pre-treatment white blood count of less than 30,000/microliters had a significantly longer remission duration and survival. Eleven per cent of patients who achieved a complete remission have had a CNS relapse to date, which is not different from the rate in our prior study using cranial irradiation and i.t. MTX, implying that intermediate dose MTX with i.t. MTX may be as effective as cranial irradiation and i.t. MTX. This study suggests that some form of maintenance chemotherapy is required for the eradication of residual leukemia cells.

An evaluation of combinations of diaziquone, etoposide and mitoxantrone in the treatment of adults with relapsed or refractory acute myeloid leukemia: results of 8722, a randomized phase II study conducted by Cancer and Leukemia Group B.

A phase II trial was conducted to determine which of the three possible two-drug combinations of diaziquone, etoposide and mitoxantrone was associated with the highest response rate in patients with relapsed or refractory acute myeloid leukemia (AML). Of the 167 patients (median age 55) with AML who entered the trial, 123 were in first relapse, 22 were in second relapse and 22 had failed to achieve complete remission (CR). CR rates were 30% for diaziquone and mitoxantrone, and 23% for the other two combinations (mitoxantrone/etoposide and diaziquone/etoposide), NS. Patients in first relapse had higher CR rates (40%) than other patients. Of the 166 patients who actually received treatment, 43 died before having either a CR or persistent leukemia. Non-hematologic toxicity was primarily mucosal with 24% of patients experiencing grade 3 or greater stomatitis on the two diaziquone arms, and 43% on the mitoxantrone/etoposide arm. The combination of diaziquone and mitoxantrone was selected for further testing in patients with AML.

Mitoxantrone and ara-C in previously treated patients with acute myelogenous leukemia.

Mitoxantrone is a synthetic aminoanthraquinone we have previously reported to be effective for patients with acute leukemia in relapse. We presently report the results of a trial of mitoxantrone in combination with cytosine arabinoside (ara-C) in patients with refractory or relapsed acute myelocytic leukemia (AML). Forty-nine patients, 24 males and 25 females, with a median age of 56, of whom 32 were in first relapse, four were in second relapse, and 13 had primarily refractory AML, were treated with mitoxantrone 10 mg/m2 daily for 3 days and ara-C 100 mg/m2 daily by continuous infusion for 7 days. Twenty patients (62.5%) with first relapse AML achieved M1 marrow, whereas only two of 13 patients with refractory AML did; none of four patients with more than one prior remission responded. Marrow recovery was observed in a median of 32 days. Remissions were maintained with monthly ara-C plus mitoxantrone alternating with ara-C plus 6-TG; median duration of remission was 8 months and two patients are in continuing remission at 8 and 16 months. Treatment was well tolerated, with minimal nausea and vomiting, diarrhea, drug-induced mucositis. Treatment-related cardiac toxicity was not observed. Transient hepatic dysfunction was observed in greater than 50% of courses. Mitoxantrone plus ara-C is an active combination with great promise for the therapy of previously untreated patients with AML.

Alterations of platelet function induced by interleukin-2.

We recently reported that thrombocytopenia and bleeding are often limiting effects of immunotherapy with interleukin-2 (IL-2). In order to understand the mechanisms that lead to this unexpected clinical toxicity, we studied the effects of IL-2 on in vitro platelet function. When platelet aggregation was studied using whole blood (impedance, electrical) aggregometry, inhibition of aggregation was detected within 1 min of the addition of exogenous IL-2 to whole blood. IL-2-induced platelet secretion was quantified by radioimmunoassay (RIA) of PF4, BTG, and TXB2 independent of the addition of an aggregating agonist (ADP). Platelet secretion and inhibition of aggregation were an indirect consequence of a cellular effect of IL-2 on mononuclear cells, since aggregation was normal when whole blood was depleted of mononuclear cells and its reconstitution with autologous mononuclear cells led to a cell concentration-dependent inhibitory effect of aggregation and release of alpha-granule components in the presence of IL-2. In order to understand the mechanism of platelet secretion mediated by IL-2-activated mononuclear cells, we quantified the release of eicosanoid products from cultures of mononuclear cells exposed to IL-2 and found a significant increase in TXB2. Our results indicate that platelet secretion, indirectly initiated by IL-2-activated cells, is followed by inhibition of aggregation. These findings may not only have important implications for the planning of clinical immunotherapy trials with IL-2, but may also provide a novel link for a better understanding of the relationships between the hemostatic and the immune systems.

Mitoxantrone as a single agent and in combination chemotherapy in patients with refractory acute leukemia.

A total of 47 patients with relapsed or primarily refractory leukemia were treated with mitoxantrone alone or in combination with vincristine sulfate and prednisone or cytarabine. Eligible patients included those with adequate renal and hepatic function, normal left ventricular ejection fraction, and those who had received previous treatment. When mitoxantrone was given alone in a once daily times five schedule, 5 of 12 acute lymphoblastic leukemia patients achieved complete remission; 4 of these patients had been refractory to reinduction and 1 to induction chemotherapy with anthracycline-containing treatments. Four of these patients had progressive disease, and three died during induction. Of 12 patients with acute myeloid leukemia, 1 had a complete remission, 1 had a partial remission, 8 had progressive disease, and 2 died during induction. Mitoxantrone was also found to be active in two patients in the blastic transformation of chronic myeloid leukemia with a response in one patient lasting 17 weeks. Combinations of mitoxantrone with vincristine sulfate and prednisone resulted in complete remission in four of nine acute lymphoblastic leukemia patients and one of four patients with Tdt-positive chronic myeloid leukemia in blast crisis. Three of these patients had not experienced a prior remission following anthracycline-containing treatments. Partial remission occurred in two of the acute lymphoblastic leukemia patients and one of the Tdt-positive chronic myeloid leukemia patients. Two of this latter group of patients died in induction. Treatment with mitoxantrone and cytarabine resulted in two acute myeloid leukemia patients achieving complete remission and one a partial remission; two patients had progressive disease, and one died in induction. No response was seen in a patient with Tdt-negative chronic myeloid leukemia after two courses of treatment. One patient with acute leukemia in the course of myelofibrosis died in induction. All the patients achieving complete remission are alive and have been in complete remission from 2 to 12 months. Side effects included mild nausea and vomiting in 9 of 13 patients treated with the mitoxantrone-vincristine sulfate-prednisone combination, and in 3 of 8 patients treated with the mitoxantrone-cytarabine combination. Other side effects of the combination treatments include drug-induced oral mucositis (of a lesser degree than with mitoxantrone alone), transient hepatic abnormalities, and infectious complications, such as sepsis, Candida sp colonization of the upper digestive tract, and soft tissue cellulitis, in a few patients.(ABSTRACT TRUNCATED AT 400 WORDS)

Thrombocytopenia during immunotherapy with interleukin-2 by constant infusion.

PURPOSE: To elucidate some of the possible mechanisms that lead to interleukin-2 (IL2)-induced thrombocytopenia. PATIENTS AND METHODS: We evaluated retrospectively the effects of immunotherapy with IL2 in 76 patients with disseminated cancer. The lymphokine was administered by constant infusion, daily for 6 days a week for 4 consecutive weeks. RESULTS: A significant decrease in platelet counts was seen after the first 6 days of therapy in all but two patients: 14 patients experienced grade 2 or 3 toxicity, 21 had grade 1 toxicity, and although the decrease in platelet counts could not be graded as toxicity in the remaining 41 patients, there was an average decrease of 32% from baseline platelet counts in 39 (p less than 0.0001). Thrombocytopenia appeared to be secondary to peripheral platelet destruction, since bone marrow biopsy specimens obtained during thrombocytopenia showed hyperplastic megakaryocytopoiesis. IL2 is inactivated by tubular resorption, and severity of thrombocytopenia was strongly correlated with IL2-induced renal dysfunction (p = 0.0004). Additionally, both renal dysfunction and thrombocytopenia were related to total dose of IL2 and were more pronounced in patients with worse baseline renal function and lower baseline platelet counts. The incidence of thrombocytopenia increased with subsequent IL2 therapy: life-threatening thrombocytopenia (less than 25,000/microL) was seen in nine of 57 patients, five of whom required transfusional platelet support. CONCLUSION: On the basis of preliminary observations, we hypothesize that thrombocytopenia induced by IL2 is caused by accelerated clearance of platelets by the reticuloendothelial system.

Pinocchio cells: morphologically atypical immunologically heterogeneous lymphocytes induced by treatment with interleukin 2.

We describe a novel cell type, the Pinocchio cell, that appears in the peripheral blood of all patients receiving treatment with interleukin 2, up to 20,000 cells/microliter. This cell is characterized by a prominent and granular proboscis with which it attaches to tumor cells and mediates tumor cell lysis. Pinocchio cells are immunologically heterogeneous and express antigens of both T and NK cells; Pinocchio cells are adherent in culture and are more cytolytic than non-adherent cells against NK-sensitive and resistant tumor cells. Incubation of normal whole human blood for 1 h induces Pinocchio morphology of mononuclear white blood cells.

Interleukin-2 plus chemotherapy for patients with metastatic melanoma.

We studied the activity of recombinant interleukin-2 (IL2) in combination with multiagent chemotherapy in the treatment of patients with disseminated malignant melanoma. Patients were randomized to receive the same dose of lymphokine by constant 24 h intravenous infusion (CI) or by subcutaneous bolus (SB) injection. Twenty-two patients, 18 males and four females with a median age of 44 years (range 32-73 years) were randomized to receive IL2 5 million units/m2 once daily by SB injection or by CI, 5 days/week for 2 weeks. All patients received a chemotherapy regimen consisting of lomustine (CCNU) 75 mg/m2 on day 14, bleomycin 10 units/day by CI for 5 days (days 14-19) and cisplatin 75 mg/m2 on day 19. Patients were retreated after a 3 week interval. There were four complete responses and one partial response in the CI arm and two partial responses in the SB arm. The median duration of response was 38 weeks (range 26-107 weeks). The median duration of survival was 6.7 months in non-responders and 11.1 months in responders. The overall response rate was 32%. Since responses were brief and all the responding patients progressed after a median of 38 weeks, the study was terminated before accrual goals were met.

Mitoxantrone, vincristine, and dexamethasone in patients with refractory lymphoma.

Twenty-seven patients with failed malignant lymphomas (19 with intermediate grade, 4 with low-grade, 3 with high-grade lymphomas, and 1 with Hodgkin's disease) who had failed a median of 3 prior multidrug regimens, all previously exposed to anthracyclines (median prior doxorubicin 360 mg/m2), were treated with a combination of mitoxantrone (M), vincristine (V), and dexamethasone (D) every 4 weeks. Mitoxantrone was given in a 3 times daily schedule (days 1-3), at doses between 5 and 10 mg/m2/day; vincristine, 2-mg total dose, was given on day 1 and day 8; dexamethasone, 20 mg/m2, was given on days 1-5. A total of 71 courses was administered; there were 4 complete responses (CR) and 14 partial responses (PR) (response rate 66%). At the highest doses, hematological toxicity was severe (5 patients died while pancytopenic); the nadir for WBC and platelets was on day 13, with a median hematological recovery on day 23. There were transient hepatic, renal, and oral toxicities; vincristine-related neuropathy was seen in 8 patients. All patients had normal prestudy cardiac function, as assessed by gated pool scans; follow-up scans showed a greater than 15% decrease of the left ventricular ejection fraction (LVEF) in 2 patients, without evidence of cardiac dysfunction. Although responses lasted a median of 10 weeks (range 4-37), our data indicate that mitoxantrone, at the doses and schedules used, is an effective drug in malignant, doxorubicin-resistant lymphomas. This observation warrants the use of mitoxantrone in the upfront treatment of malignant lymphoma.

Mitoxantrone and constant infusion etoposide for relapsed and refractory acute myelocytic leukemia.

In an effort to search for new, synergistic and non-cross-resistant antileukemic regimens, the Cancer and Leukemia Group B (CALGB) investigated the activity and toxicity of mitoxantrone in combination with etoposide for the reinduction of patients with relapsed or refractory acute myelocytic leukemia (AML). Mitoxantrone, 12 mg/m2 daily for 3 days, was combined with three dose levels of etoposide, 100, 150 and 200 mg/m2 daily by constant infusion for 5 days. There were 19 male and 13 female patients, with a median age of 46 (range, 21-74). Of these, nine were primarily refractory to daunorubicin and ara-C; 17 had one prior complete remission (CR), five had two prior CR, and one had three prior CR. Thirteen patients were entered at the first dose level, 11 were entered at the second, and eight at the third. All but one patient, whose death occurred within the first 2 days of treatment, are evaluable for toxicity. There were five CR (four at the first and one at the second dose level) and six partial remissions (PR) (three at the first dose level and three at the second). Unmaintained responses lasted 6-33 weeks. Median survival for all patients was 12.6 weeks. Anti-leukemic effects with severe marrow hypoplasia were observed in all patients; severe nausea and vomiting were seen in four. Severe mucositis, often indistinguishable from superimposed candidiasis, occurred in 40% of all patients; it was associated with dose-limiting esophagitis (three of seven evaluable patients) at the highest etoposide dose. Hepatic and renal dysfunction was severe in three patients; no treatment-related severe pulmonary or cardiac toxicity was observed. Posttreatment infectious complications were severe in 11 patients. In three cases, they were fatal--an incidence not dissimilar from that of other reinduction regimens in heavily pretreated patients. The regimen appears to be active; the combination of mitoxantrone, 12 mg/m2 daily for 3 days, with etoposide, 150 mg/m2/day for 5 days, by constant intravenous infusion is now being explored by the CALGB in a randomized phase II study against mitoxantrone plus diazoquinone and diazoquinone plus etoposide.

Immunotherapy with IL2 by constant infusion and weekly doxorubicin.

Twelve women and 7 men, median age 58 (range 17-74), with a diagnosis of non-small-cell lung cancer (11 patients), inflammatory breast cancer (5 patients), osteosarcoma (2 patients), and colon carcinoma (1 patient) were studied. Treatment consisted of four consecutive 6-day courses of infusional interleukin-2 (IL2); 9 patients were treated with 20 X 10(6) IU/m2/day and 10 patients received weekly dose increments of 50% until the maximally tolerated dose was reached. One day after each course was completed patients received doxorubicin, 30 mg/m2; infusional IL2 was resumed 24 h after receiving doxorubicin. Rebounds of lymphocytes with high spontaneous synthetic rates of DNA occurred one day after stopping the infusion, despite doxorubicin administration. The kinetics were not different from earlier trials using IL2 alone. Sequential lymphocyte analysis showed that helper (CD4) and suppressor (CD8) T-cell subsets increased after the first week of treatment and declined thereafter, whereas the proliferation of natural killer (NK) cells (CD16) progressed through the 4-week treatment unaffected by doxorubicin. Mean cytolytic ability induced by IL2 against NK-resistant tumors in vitro was higher in patients who had evidence of clinical tumor regression and therefore is prognostically valuable (p = .02). Three patients left the study prematurely. Five partial remissions and 2 minimal responses were seen in the remaining 16 patients, but they were short-lived. Of the responding patients, only one had failed prior doxorubicin-containing chemotherapy. Toxicities attributable to IL2 and doxorubicin were encountered, and were manageable at these doses. Our data suggest that doxorubicin did not have cytotoxic or suppressive effects on lymphokine-induced lymphocyte functions and that both treatment modalities in combination are worthy of further investigation since they exert distinct and compatible cytotoxic mechanisms and induced tumor regressions with acceptable toxicity in a group of patients with poorly responsive cancers.