Recombinant human erythropoietin therapy for anemic cancer patients on combination chemotherapy.

BACKGROUND: Patients with advanced cancer frequently experience clinically significant anemia, which is often exacerbated by myelosuppressive chemotherapy. Consistent with the anemia of chronic disease, studies have documented serum erythropoietin levels that are inappropriately low for the degree of anemia in cancer patients. Myelosuppressive chemotherapy impairs erythropoiesis, which may not fully recover between treatment cycles. Recombinant human erythropoietin (rHuEPO) has been used safely and effectively to treat anemia in AIDS patients receiving zidovudine (AZT) and in patients with chronic renal failure. PURPOSE: This study was designed to evaluate the clinical role of rHuEPO in reducing symptomatic anemia in patients with advanced cancer who were receiving myelosuppressive chemotherapy (excluding cisplatin). METHODS: We studied 153 anemic cancer patients receiving cyclic combination chemotherapy in a prospective multicenter, double-blind, placebo-controlled trial. The patients were randomly assigned to receive either rHuEPO (150 U/kg) or placebo subcutaneously three times a week for a maximum of 12 weeks or until the hematocrit level increased to 38%-40%. If the hematocrit reached this target level before 12 weeks, the rHuEPO dose could be reduced to maintain the hematocrit at that level for the duration of the study. Response to rHuEPO therapy was assessed by measuring changes in hematocrit level, transfusion requirements, and quality of life. Quality-of-life assessment was based on patients' responses to questionnaires before and after the courses of therapy. RESULTS: The increase in hematocrit in the rHuEPO-treated group compared with hematocrit in the placebo-treated group was statistically significant (P = .0001) as measured by percentage point of change from baseline to final evaluation, by an increase in hematocrit level of six percentage points or more unrelated to transfusion, and by a rise in hematocrit level to 38% or more unrelated to transfusion. There was a trend toward the reduction in mean units of blood transfused per patient during months 2 and 3 of therapy combined in rHuEPO-treated patients compared with placebo-treated patients (0.91 U versus 1.65 U; P = .056). In addition, rHuEPO-treated patients experienced a statistically significant improvement in energy level and ability to perform daily activities (P < or = .05). The two treatment groups showed no statistically significant differences in toxic effects except for increased incidence of diaphoresis (P < .05) and diarrhea (P = .05) in the rHuEPO-treated group. CONCLUSIONS: We conclude that rHuEPO is safe and effective for reversing anemia related to advanced cancer or to chemotherapy for cancer.

Phase II study of oral idarubicin in favorable histology non-Hodgkin's lymphoma.

Idarubicin, a new analogue of daunorubicin, was administered p.o. for 3 consecutive days every 3 weeks at a dose of 45 mg/m2 in 46 patients (45 eligible and evaluable) with previously treated, favorable histology, non-Hodgkin's lymphoma. Median clinical characteristics included an age of 66 years, a performance status of 1, and one prior chemotherapeutic regimen. Forty-one patients were relapsing from prior therapy, and 37 had stage IV disease. Patients with prior anthracycline therapy were excluded. Responses were observed in 58% of patients (10 complete and 16 partial), with a median duration of 6+ months (2-41+ months). Idarubicin was well tolerated. Nonhematological toxicities (nausea/vomiting, mucositis/diarrhea, alopecia, and anorexia) were observed in less than or equal to 50% of patients. Median hematological values during the first cycle include a WBC of 4100/mm3 and a platelet count of 147,000/mm3. With dose escalation, hematological toxicity was the dose-limiting toxicity. Symptomatic cardiac toxicity was not observed. Median values for the resting left ventricular ejection fraction during the course of therapy were 0.65 (initial) and 0.63 (final). Idarubicin in oral form is an active drug in previously treated patients with favorable histology non-Hodgkin's lymphoma.

Phase I-II study of epirubicin in multiple myeloma.

Forty patients with relapsed (26) or refractory (14) myeloma were treated with epirubicin of doses of 75, 90, 105, and 120 mg/m2 in groups of 6 or more patients to test for response, maximum tolerated dose, and toxicity. Thirteen patients had received prior doxorubicin and were included in the dose findings part of the study only. Staging was I (1), II (5), and III (34). Partial responses were seen in 5 patients (18.5%) (duration 1.5, 2, 2.5, 10, and 18 months) not previously treated with doxorubicin. No responses were seen in patients treated with prior anthracycline. Responses were not dependent upon dose level of epirubicin. Median nadir white blood cell count at the four-dose levels were 2,300, 1,000, 1,600, and 1,700/mm3 with median nadir granulocyte counts of 897, 720, 688, and 192/mm3. Fever/neutropenia was infrequently observed at the three lower dose levels but occurred in 6 of 10 patients at 120 mg/m2. Platelet nadirs were 110,000, 83,000, 169,000, and 42,000/mm3. Nonhematological toxicity was not dose dependent and included alopecia (100%), nausea/vomiting (40%), and stomatitis (25%). Six patients had greater than or equal to 0.10 changes in the resting ejection fraction with one patient developing congestive heart failure that responded to medical management. This patient had received prior doxorubicin and had a history of myocardial infarction. Epirubicin can produce remissions in patients with previously treated myeloma who have not received prior doxorubicin. Since the response rate was not enhanced at 120/m2 and since fever/neutropenia was seen regularly at this dose level, the recommended dose for further study is 105 mg/m2.

Phase I-II trial of high-dose epirubicin in patients with lymphoma.

High-dose doxorubicin has shown considerable activity in both previously treated and previously untreated patients with lymphoma. Because of the toxicities of doxorubicin at high dose, we elected to study a new anthracycline at doses comparable to doxorubicin at high dose, to assess response and toxicity. Epirubicin was administered at doses of 120 mg/m2, 150 mg/m2, and 180 mg/m2 every 3 weeks (maximum four doses) to groups of six patients with previously treated intermediate- and high-grade lymphoma. Sixteen of the patients had received significant prior therapy with an anthracycline and/or anthracenedione. At all dose levels, myelosuppression was severe, with median granulocyte nadirs less than 504/mm3. Hematological recovery occurred by day 21 at the 120 mg/m2 and 150 mg/m2 dose levels, allowing for the next cycle of therapy. However, at the 180 mg/m2 dose level, the majority of patients failed to have hematological recovery by the day of the next scheduled therapy. Forty-two % of patients (eight patients) had fever/neutropenia, and required antibiotics. One treatment-related septic death occurred (at 150 mg/m2). Alopecia (68%), fever immediately following treatment (63%), mild/moderate stomatitis (58%), and nausea/vomiting (53%) were the most common nonhematological toxicities. These toxicities were independent of the dose levels and were not dose limiting. A significant change (greater than or equal to 0.10) in the radionuclide ejection (EF) was seen in seven patients. The median of the entire group of patients fell from 0.63 to 0.56. No patient developed clinical or radiological evidence of congestive heart failure. A response rate of 58% (two complete responses, nine partial responses) was achieved with a median duration of 5 months (range, 1-15+). High-dose epirubicin can be successfully utilized in patients with previously treated lymphoma. The only dose-limiting toxicity observed at these dose levels was the lack of hematological recovery by day 21 with 180 mg/m2. Since epirubicin at high dose will be incorporated into high-dose anthracycline regimens in previously untreated patients utilizing a 3-week treatment cycle, 150-180 mg/m2 may be the maximally tolerated dose for such studies.

Phase II study of intravenous idarubicin in unfavorable non-Hodgkin's lymphoma.

Idarubicin, a new analogue of daunorubicin, was administered i.v. at a dose of 15 mg/m2 to 31 previously treated patients with unfavorable non-Hodgkin's lymphoma. Clinical characteristics included median age, 69 years; performance status, 1; and prior chemotherapeutic regimens, 1. Twenty of the patients were relapsing after prior therapy and 11 were refractory; 29 had received prior anthracycline or anthracenedione. Responses were observed in 43% of patient (3 complete remission and 10 partial remission) with a median duration of 10+ months (2-29+ months). Idarubicin was well tolerated with nonhematological toxicities (nausea/vomiting, mucositis, and anorexia) seen in less than 50% of patients. Median hematological values during the first cycle for this dosage included WBC, 1,300/mm3; platelets, 129,000/mm3; and hemoglobin, 10.9 mg/dl. With dose escalation, hematological toxicity was dose limiting. Symptomatic cardiac toxicity was observed in one patient who had received maximum dose doxorubicin and radiotherapy. Median values for the cardiac ejection fraction during the full course of therapy for the entire group of patients were 0.62 (initial) and 0.60 (final). Idarubicin in i.v. form is an active drug in previously treated patients with unfavorable non-Hodgkin's lymphoma.

Multicenter clinical trial of mitoxantrone in non-Hodgkin's lymphoma and Hodgkin's disease.

In this phase II multicenter trial, the efficacy and safety of mitoxantrone (Novantrone; Lederle Laboratories, Wayne, NJ) were evaluated in the treatment of 206 patients with relapsed non-Hodgkin's lymphoma (NHL) or Hodgkin's disease (HD) previously treated with other agents. Sixty-nine percent of the patients had received prior therapy with doxorubicin. The patients received 14 mg/m2 of mitoxantrone every 3 weeks. Nineteen (12%) of the NHL patients and two (7%) of the HD patients had complete responses (CRs). The combined CR and partial response (PR) rates were 37% (60 of 163) for NHL patients and 36% (10 of 28) for HD patients; the median duration of response was 323 days for NHL patients and 209 days for HD patients. The median survival times were 337 days for patients with NHL and 469 days for patients with HD. The median survival time for patients with low-grade NHL was 589 days compared with 298 days for patients with intermediate-grade NHL and 167 days for patients with high-grade NHL. The median time to treatment failure was 73 days for NHL patients and 98 days for HD patients. The major toxicity was myelosuppression, which was moderate and reversible. Nausea, vomiting, and alopecia were mild. There were two cases of congestive heart failure (CHF) considered related to treatment; both patients had received prior treatment with doxorubicin. In this group of heavily pretreated patients, mitoxantrone was effective and well tolerated. Responses were seen with mitoxantrone in patients who had relapsed after prior therapy with doxorubicin and in patients who had failed to respond to prior therapy with doxorubicin. Mitoxantrone should be evaluated in less heavily pretreated patients and should be considered for incorporation into combination chemotherapeutic regimens for the treatment of malignant lymphoma.

Improved prognosis of diffuse histiocytic and undifferentiated lymphoma by use of high dose methotrexate alternating with standard agents (M-BACOD).

A new combination chemotherapy program (M-BACOD) was administered to 101 patients with advanced diffuse histiocytic and diffuse undifferentiated lymphoma (DHL and DUL). High dose methotrexate (M) 3 g/m2 with leucovorin factor rescue was given on day 14 between cycles of bleomycin (B), adriamycin (A), cyclophosphamide (C), oncovin (O), and dexamethasone (D) administered every 3 weeks for 10 cycles. The complete remission rate (CR) was 72% in all 101 patients or 77% in 95 evaluable patients. The median follow-up is 3 yr 2 mo with one-third of CR patients followed beyond 4 yr. Twenty-six percent of CR patients have relapsed with a projected 5-yr survival rate of 80% (5-yr disease-free rate 65%). The overall survival of all 101 study patients reaches a plateau at 59% projected out to 5 yr. Patients with prior therapy had a significantly lower CR rate than those without prior treatment (p = 0.001); however, no other unfavorable prognostic characteristics could be identified. Relapse in the central nervous system CNS occurred in only 5.4% of CR patients. M-BACOD results in prolonged survival and possible cure in a high proportion of all patients with DHL and DUL.

Randomized multicenter trial of cytosine arabinoside with mitoxantrone or daunorubicin in previously untreated adult patients with acute nonlymphocytic leukemia (ANLL). Lederle Cooperative Group.

This phase III, randomized trial in previously untreated adults with ANLL compared mitoxantrone plus cytosine arabinoside with the CALGB "7 + 3" daunorubicin-based regimen. Two hundred evaluable patients (98 treated with the mitoxantrone-based regimen and 102 with the daunorubicin-based regimen) were included in the analysis of efficacy. The median age of the patients was 60 years. The induction regimen comprised cytosine arabinoside 100 mg/m2 by infusion daily for 7 days and mitoxantrone 12 mg/m2 or daunorubicin 45 mg/m2 daily for days 1-3. If needed, a second induction course was administered: cytosine arabinoside for 5 days and mitoxantrone or daunorubicin for 2 days. Postremission therapy consisted of two consolidation courses, identical to the second induction course. Sixty-three percent (62 of 98) of patients treated with mitoxantrone achieved complete remission (CR), compared to 53% (54 of 102) treated with daunorubicin. The median time to CR was 35 days in patients treated with mitoxantrone and 43 days for those treated with daunorubicin. Eighty-nine percent (55 of 62) of patients treated with mitoxantrone who entered complete remission achieved CR following one induction course, compared to 68% (37 of 54) of patients treated with daunorubicin who entered CR. The median duration of CR was 240 days in patients treated with mitoxantrone and 198 days in those treated with daunorubicin; the median length of survival was 328 days in patients who received mitoxantrone and 247 days in those who received daunorubicin. The toxicity profiles in patients treated with either of the two regimens were comparable in incidence and in severity. Patients treated with mitoxantrone required fewer median platelet units and were treated with fewer median days of intravenous antibiotics, compared to those who received daunorubicin. Mitoxantrone in combination with cytosine arabinoside is effective in previously untreated ANLL. complete remissions occur more frequently after a single induction course of the mitoxantrone-based regimen, compared to the standard Cancer and Acute Leukemia Group B regimen. This should be explored in further trials.

A randomized trial of high- vs standard-dose mitoxantrone with cytarabine in elderly patients with acute myeloid leukemia.

To evaluate the efficacy and tolerability of a high-dose mitoxantrone-based induction regimen without consolidation therapy in patients over age 60 with newly diagnosed acute myeloid leukemia (AML), 54 patients aged 60-83 were randomized to receive mitoxantrone, either 80 mg/m2 on day 2, or 12 mg/m2 on days 1-3 in addition to cytarabine, 3 g/m2 on days 1-5. Significant toxicity included mucositis, diarrhea, transient hyperbilirubinemia and cardiac events. No difference in toxicity was observed between the two dosage regimens. Overall, 27 patients achieved a complete remission (CR), 16/28 CR in the high-dose and 11/25 in the lower-dose group. Induction death occurred in 11 patients, three in the high-dose and eight in the low-dose arm. Actuarial median survival was 6 months for the low-dose and 9 months for the high-dose group, and the respective relapse-free survival is 3 and 5 months. The observed differences in outcome were not statistically significant. patients in both arms of this trial, who received no consolidation, appear to have response and survival rates equivalent to those of standard-dose induction with repetitive consolidation. This approach might offer elderly patients equivalent outcome with fewer days of treatment, presumably enhancing quality of life.

The m-BACOD combination chemotherapy regimen in the treatment of diffuse large cell lymphoma.

The m-BACOD regimen attempted to lower the dose of methotrexate in the M-BACOD (methotrexate, bleomycin, doxorubicin, cyclophosphamide, vincristine, dexamethasone) program. Between July 1981 and January 1985, 87 previously untreated or minimally treated patients with diffuse large cell lymphoma were treated with the m-BACOD regimen (methotrexate 200 mg/m2 on days 8 and 15, bleomycin 4.0 mg/m2 on day 1, doxorubicin 45 mg/m2 on day 1, cyclophosphamide 600 mg/m2 on day 1, vincristine 1.0 mg/m2 on day 1, and dexamethasone 6 mg/m2 on days 1 to 5; leucovorin was given 24 hours after methotrexate at 10 mg/m2 every six hours for eight doses orally). Of 86 evaluable patients, 59 (68.5%) had a complete remission (CR). Partial response was seen in 21 patients with six still surviving (5 to over 15 months). Of the seven patients who had no change, all have died. The median duration of follow-up for the entire series was 30 months (range, 2 to 61). Relapse from CR occurred in 15 of 59 (25%). Currently, 56 of 87 patients (64%) survive; all but 12 are in their first remission. Overall survival was 84% for those achieving an apparent CR. The major toxic effect of the m-BACOD regimen was myelosuppression with severe leukopenia and fever, which required hospitalization for about 33% of patients. Mucositis occurred in 39 patients; 19 had severe mucositis. No significant difference in overall survival was seen between the high-dose methotrexate M-BACOD and the low-dose m-BACOD regimens.

Absence of a specific chromosomal marker in essential thrombocythemia.

In 33 patients with essential thrombocythemia, a specific chromosomal abnormality ( 21q -) could not be confirmed. All patients in this series met rigid criteria for diagnosis of this myeloproliferative disorder.

Malignant lymphoma with genitourinary symptoms.

Two cases are reported of patients with widespread intra-abdominal malignant lymphoma who althoug they initially presented with urologic complaints had no evidence of direct genitourinary involvement. Transrectal biopsy established the diagnosis in both cases. This unusual presentation of lymphoma is discussed together with a review of urologic involvement. The necessity for accurate diagnosis is stressed since effective treatment with radiation and chemotherapy is available.

Phase II study of intravenous idarubicin in unfavorable non-Hodgkin's lymphoma.

Idarubicin, a new analogue of daunorubicin, was administered intravenously at a dose of 15 mg/m2 to 31 patients with previously treated patients with unfavorable non-Hodgkin's lymphoma. Clinical characteristics included median age 69 years, performance status 1, and prior chemotherapeutic regimens 1. Twenty of the patients were relapsing after prior therapy and 11 were refractory; 29 had received prior anthracycline or anthracenedione. Responses were observed in 43% of patient (3 CR and 10 PR) with a median duration of 10+ months (2-29+ months). Idarubicin was well tolerated with non-hematologic toxicities (nausea/vomiting, mucositis, and anorexia) seen in < 50% of patients. Median hematologic values during the first cycle for this dosage included WBC 1300/mm3, platelets 129,000/mm3, and hemoglobin 10.9 mg/dl. With dose escalation, hematologic toxicity was dose-limiting. Symptomatic cardiac toxicity was observed in one patient who had received maximum dose doxorubicin and radiotherapy. Median values for the cardiac ejection fraction during the full course of therapy for the entire group of patients were 0.62 (initial) and 0.60 (final). Idarubicin in intravenous form is an active drug in previously treated patients with unfavorable non-Hodgkin's lymphoma. Further studies employing idarubicin in non-Hodgkin's lymphoma should be considered. Cardiac function should be followed in trials utilizing anthracycline-type chemotherapeutic agents.

m-AMSA: phase II trial in advanced lymphoma and leukemia.

m-AMSA, an acridine dye derivative, has been utilized in 36 patients with advanced hematologic malignancies. In 22 patients with lymphoma receiving 120 mg/m2 every 3 weeks, 10(45%) have achieved remissions. Eight of these remissions have been partial. The median duration of remission in patients with lymphoma was 3 months (range 1-12+ months). In 11 patients with acute leukemia receiving m-AMSA, 40 mg/m2 t.i.d. for 5 days, three (27%) have achieved remissions. Two of the three remissions have been complete. All three remissions in patients with leukemia were sustained for 1 month. Two patients with myeloma and one patient with chronic lymphocytic leukemia failed to respond. The major toxicity of m-AMSA has been myelosuppression. The dose-limiting toxic effect in patients with lymphoma was neutropenia. Nausea and vomiting, alopecia, phlebitis, and hepatic dysfunction have been noted in a minority of patients. Phlebitis appeared to be prevented with heparin administration after m-AMSA infusion. One fatal arrhythmia occurred, apparently related to therapy. m-AMSA appears active in advanced leukemia and lymphoma. Further studies are merited, particularly in combination with known effective agents, in order to improve upon remission duration.

Combination chemotherapy for mycosis fungoides with cyclophosphamide, vincristine, methotrexate, and prednisone.

Seven patients with stage IV mycosis fungoides [TNM classification] have been treated with combination chemotherapy consisting of cyclophosphamide, vincristine, methotrexate, and prednisone [COMP]. A complete response rate of 57% was produced with an overall response of 100% in patients having limited prior steroid and/or chemotherapy. Complete responses range from 4+ to 20 months [median, 11 months]. Overall survival ranges from 2 to 40+ months [median, 12+ months]. The protocol was well tolerated except for one treatment-related death. Combination chemotherapy can produce effective remissions in patients with advanced mycosis fungoides. TNM classification should be considered in staging patients with mycosis fungoides for comparison of different treatment regimens.

Phase II study of aclarubicin in acute myeloblastic leukemia.

Aclarubicin is a new anthracycline antibiotic that produces substantially less cardiotoxicity in animals that does doxorubicin. Based upon prior Phase I and II trials in leukemia, a Phase II study in acute myeloblastic leukemia was developed to assess the response rate and toxicity in previously treated patients. Forty patients received aclarubicin 100 mg/m2 per day X 3 with repeated course on days 14-16 if marrow hypoplasia was not produced. Complete responses were achieved in 27.5% (11/40) with durations of 1.5, 2, 2, 2, 3, 3+, 4, 5+, 32+, 33+, and 34+ months. Toxic effects of this therapy included severe neutropenia and thrombocytopenia, nausea/vomiting, mucositis, and diarrhea. No patient developed significant changes in the left ventricular ejection fraction, as measured by radionuclide angiography, or any clinical cardiac symptoms. Alopecia was minimal. Aclarubicin can produce a significant response rate in previously treated patients with acute myeloblastic leukemia and should be considered for study in initial therapy.

5-azacytidine in refractory acute leukemia.

11 patients (aged 23--75 years) with refractory acute leukemia were treated at the Maine Medical Center with 5-Azacytidine, 150 mg/m2/day, by continuous infusion for 5 days every 2 weeks. Prior therapy included anthracycline/cytosine arabinoside protocols. Of the 8 patients with refractory de novo acute myelogenous leukemia, 6 achieved remission at an overall response rate of 75% (3 complete remission and 3 partial remission). An average of 1.67 courses was necessary to achieve a response. Remissions were not seen in blastic chronic myelogenous leukemia nor in acute leukemia secondary to cytotoxic drugs. Toxicity included myelosuppression, moderate nausea and vomiting, abnormal liver function tests, and neuromuscular symptoms. 5-Azacytidine by continuous infusion has significant activity in refractory acute myelogenous leukemia and should be considered for inclusion in primary remission induction therapy.