Treatment of relapsed or refractory acute myeloid leukemia with humanized anti-CD33 monoclonal antibody HuM195.

HuM195 is a humanized, unconjugated, anti-CD33 monoclonal antibody. Fifty adult patients with relapsed or refractory AML were randomized to receive HuM195 at a dose of 12 or 36 mg/m(2) by intravenous infusion over 4 h on days 1-4 and 15-18. Patients with stable or responding disease received two additional cycles on days 29-32 and 43-46. HuM195 was given as first salvage therapy in 24 patients and as second or subsequent salvage therapy in 26 patients. Pretreatment blast percentage in the marrow was between 5 and 30% in 20 patients with the others having blast counts greater than 30%. The median age of patients was 62 years (range 26-86) and CD33 was detected in 95% of patients for whom immunophenotyping was available. Of 49 evaluable patients, two complete and one partial remission were observed. All three responses were in patients treated at the 12 mg/m(2) dose level and all had baseline blast percentages less than 30%. Decreases in blast counts ranging from 30 to 74% were seen in nine additional patients. Infusion-related events of fever and chills occurred in the majority of patients and were generally mild and primarily related to the first dose of antibody. No hepatic, renal or cardiac toxicities were observed and other adverse events such as nausea, vomiting, mucositis and diarrhea were uncommon or felt to be unrelated to HuM195. In addition, anti-HuM195 responses were not detected. HuM195 as a single agent has minimal, but observable, anti-leukemic activity in patients with relapsed or refractory AML and activity is confined to patients with low burden disease. No significant differences in clinical efficacy or toxicity were seen between the two dose levels of antibody. HuM195 was well tolerated with infusion-related fevers and chills the predominant toxicities seen. Meaningful clinical efficacy of this unconjugated monoclonal antibody may be realized only in patients with minimal residual disease, or in combination with chemotherapy.

Excellent response to interferon therapy in a patient with hypereosinophilic syndrome and elevated serum immunoglobulin E levels

The hypereosinophilic syndrome (HES) is a heterogeneous disease characterized by sustained eosinophilia for a period of at least six months with evidence of organ involvement. Its manifestations range from a benign disorder not requiring any therapy to an aggressive, malignant variety refractory to common treatments. Diverse therapies have been used, including steroids, hydroxyurea, and chemotherapy, with variable responses. Recently alpha-interferon therapy has been shown effective in this disorder. Of the various prognostic factors, elevated serum immunoglobulin E (IgE) levels is considered among the most favorable, with most patients presenting with a [quot ]benign[quot ] disorder, not requiring therapy. We describe a patient presenting with an aggressive variant of HES despite having elevated IgE levels. The patient had a dramatic and lasting response to alpha-interferon

Simultaneous occurrence of Hodgkin's disease and chronic lymphocyte leukemia: a unique presentation.

Chronic lymphocytic leukemia (CLL) is a chronic, low-grade hematologic malignancy that can transform to a large cell non-Hodgkin's lymphoma (Richter's syndrome), which is associated with an unfavorable prognosis. A distinct Hodgkin's disease subgroup of lymphomatous CLL transformation has been well characterized. We describe a patient presenting with simultaneous manifestations of CLL and Hodgkin's disease. This patient is unique, presenting with separate sites of involvement of each disease within the same organ, in this case the bone marrow. The morphologic and immunohistochemical findings at diagnosis are correlated with the findings of the postmortem examination.

Simultaneous occurrence of Hodgkin's disease and chronic lymphocyte leukemia: a unique presentation

Chronic lymphocytic leukemia (CLL) is a chronic, low-grade hematologic malignancy that can transform to a large cell non-Hodgkin's lymphoma (Richter's syndrome), which is associated with an unfavorable prognosis. A distinct Hodgkin's disease subgroup of lymphomatous CLL transformation has been well characterized. We describe a patient presenting with simultaneous manifestations of CLL and Hodgkin's disease. This patient is unique, presenting with separate sites of involvement of each disease within the same organ, in this case the bone marrow. The morphologic and immunohistochemical findings at diagnosis are correlated with the findings of the postmortem examination

Excellent response to interferon therapy in a patient with hypereosinophilic syndrome and elevated serum immunoglobulin E levels.

The hypereosinophilic syndrome (HES) is a heterogeneous disease characterized by sustained eosinophilia for a period of at least six months with evidence of organ involvement. Its manifestations range from a benign disorder not requiring any therapy to an aggressive, malignant variety refractory to common treatments. Diverse therapies have been used, including steroids, hydroxyurea, and chemotherapy, with variable responses. Recently alpha-interferon therapy has been shown effective in this disorder. Of the various prognostic factors, elevated serum immunoglobulin E (IgE) levels is considered among the most favorable, with most patients presenting with a "benign" disorder, not requiring therapy. We describe a patient presenting with an aggressive variant of HES despite having elevated IgE levels. The patient had a dramatic and lasting response to alpha-interferon.

Long-term follow-up of three randomized trials comparing idarubicin and daunorubicin as induction therapies for patients with untreated acute myeloid leukemia.

BACKGROUND: Most clinical trials for acute leukemia have reported results after 2-3 years of follow-up. Comparisons between the original data and longer-term follow-up data may be of interest, particularly with regard to promising new therapies. METHODS: In 1996, survival data were updated from three prospective, randomized comparisons of idarubicin and daunorubicin that began in 1984 and 1985. These were trials of the Memorial Sloan-Kettering Cancer Center (MSKCC), the U.S. Multicenter Study Group, and the Southeastern Cancer Study Group (SEG). The original results of these trials were reported in 1991 and 1992. RESULTS: The original results of the SEG trial demonstrated no significant difference between idarubicin and daunorubicin. The updated survival analysis showed similar results. The MSKCC trial revealed a significant advantage of idarubicin compared with daunorubicin in both the original and the updated analyses. The U.S. Multicenter trial found a significant difference favoring idarubicin in the original analysis, but the difference was not significant in the updated analysis. CONCLUSIONS: It is essential that the median length of follow-up be clearly stated in any clinical trial. When the results obtained with a particularly promising new drug or procedure are presented early in the course of study (within 1-2 years), the investigators should strongly consider a repeat evaluation after an additional 3-5 years of follow-up.

Cardioprotection with dexrazoxane for doxorubicin-containing therapy in advanced breast cancer.

PURPOSE: To determine the cardioprotective effect of dexrazoxane (DZR) used in a doxorubicin-based combination therapy in advanced breast cancer. PATIENTS AND METHODS: Between November 1988 and January 1991, 534 patients with advanced breast cancer were randomized to two multicenter, double-blind studies (088001 and 088006). Patients received fluorouracil, doxorubicin, and cyclophosphamide (FAC) with either DZR (DZR-to-doxorubicin ratio, 10:1) or placebo (PLA) every 3 weeks and were monitored with serial multiplegated acquisition (MUGA) scans. RESULTS: The hazards ratio (HR) of PLA to DZR for a cardiac event, which was predefined ejection fraction changes or congestive heart failure (CHF), was 2.63 (95% confidence interval [CI], 1.61 to 4.27; P < .001) for 088001 and 2.00 (95% CI, 1.01 to 3.96; P = .038) for 088006. The objective response rates for 088001 were 46.8% for DZR and 60.5% for PLA, a difference of 14% (95% CI, -25% to -2%; P = .019), and for 088006 were 53.7% for DZR and 49.3% for PLA, a difference of 4% (95% CI, -13% to 22%; P = .63). Time to progression and survival were not significantly different between treatment arms in either study. Toxicities on the DZR arms included lower granulocyte and platelet counts at nadir (P = .009 and P = .004, respectively) and more pain on injection (P = .001), with no difference in the rates of fever, infection, or hemorrhage. CONCLUSION: DZR had a significant cardioprotective effect as measured by noninvasive testing and clinical CHF. One of the two studies (088001) showed a lower response rate with DZR, but time to progression and survival were not significantly different. DZR is the first agent shown to reduce cardiotoxicity from doxorubicin.

T-cell rich B-cell lymphoma masquerading as Hodgkin disease: excellent outcome to inadequate therapy

T-cell rich B-cell lymphomas (TCRBCL) are characterized as non-Hodgkin lymphomas with a minor population of malignant B-cells scattered among predominant, reactive T-lymphocytes. This entity can easily be confused with lymphocyte-predominant Hodgkin disease (HD-LP), resulting in inappropriate therapy and a poor outcome. Because of their similarity, the pathology of patients treated for HD-LP with an inadequate or short-lived response to therapy should always be reviewed by an expert hematopathologist. We describe the first reported patient in Puerto Rico with TCRBCL, originally diagnosed and treated as HD-LP. Although the patient received partial, substandard therapy for TCRBCL, an excellent prolonged complete response ensued, thus, giving further credence to the fact that malignant lymphomas and TCRBCL in particular, are a protean group of disorders which should be precisely and accurately classified before the proper therapeutic strategies can be outlined

T-cell rich B-cell lymphoma masquerading as Hodgkin disease: excellent outcome to inadequate therapy.

T-cell rich B-cell lymphomas (TCRBCL) are characterized as non-Hodgkin lymphomas with a minor population of malignant B-cells scattered among predominant, reactive T-lymphocytes. This entity can easily be confused with lymphocyte-predominant Hodgkin disease (HD-LP), resulting in inappropriate therapy and a poor outcome. Because of their similarity, the pathology of patients treated for HD-LP with an inadequate or short-lived response to therapy should always be reviewed by an expert hematopathologist. We describe the first reported patient in Puerto Rico with TCRBCL, originally diagnosed and treated as HD-LP. Although the patient received partial, substandard therapy for TCRBCL, an excellent prolonged complete response ensued, thus, giving further credence to the fact that malignant lymphomas and TCRBCL in particular, are a protean group of disorders which should be precisely and accurately classified before the proper therapeutic strategies can be outlined.

A phase III trial comparing idarubicin and daunorubicin in combination with cytarabine in acute myelogenous leukemia: a Southeastern Cancer Study Group Study.

PURPOSE: A randomized clinical trial was undertaken to compare the therapeutic effectiveness of idarubicin (IDR) to daunorubicin (DNR), and both were given in combination with cytarabine (CA) in acute myelogenous leukemic (AML) patients. PATIENTS AND METHODS: Newly diagnosed patients were given a daily infusion of CA (100 mg/m2) for 7 days and were assigned randomly to receive DNR (45 mg/m2) or IDR (12 mg/m2) daily for the first 3 days. Those patients who achieved a complete remission (CR) were given three consolidation courses that consisted of CA (100 mg/m2 intravenously [IV]) and thioguanine (TG; 100 mg/m2 orally) every 12 hours for 5 days and either DNR (50 mg/m2) or IDR (15 mg/m2) on the first day of each cycle. After consolidation, patients received late intensification, which consisted of the same drugs used for induction except that the CA was given for 5 days and the anthracycline for 2 days. Four courses were planned at 13-week intervals. RESULTS: The CR rates were 75 of 105 (71%) on the IDR arm and 65 of 113 (58%) on the DNR arm (P = .03). The median survival and median remission durations were 297 and 433 days, respectively, on the IDR arm. The median survival and median remission durations were 277 and 328 days, respectively, on the DNR arm. Six deaths occurred during late intensification, five on IDR and one on DNR; this approach was abandoned after 47 patients were entered. The median survival was significantly longer for patients who received late intensification. CONCLUSION: This trial demonstrated that IDR was more effective than DNR in remission induction in AML.

A phase III randomized study comparing cisplatin and fluorouracil as single agents and in combination for advanced squamous cell carcinoma of the head and neck.

PURPOSE: To determine whether combination chemotherapy is superior to single agents for recurrent/metastatic head and neck cancer, we compared the efficacy and toxicity of cisplatin (CP) and fluorouracil (5-FU), alone and in combination in a phase III trial. PATIENTS AND METHODS: Two hundred forty-nine patients with recurrent head and neck cancer were randomized to one of three treatments: CP (100 mg/m2) and 5-FU (1 g/m2 x 4), CP, or 5-FU every 3 weeks. RESULTS: The overall response rate to the combination (32%) was superior to that of CP (17%) or 5-FU (13%) (P = .035). Response was associated with good performance status (PS) but not with primary site, site of recurrence, histology, prior irradiation, or relative dose intensity. Median time to progression was less than 2.5 months, and there was no significant difference in median survival (5.7 months) among the groups. By multivariate analysis, patients with better PS and poorly differentiated tumors had superior survival. Hematologic toxicity and alopecia were worse in the combination arm. CONCLUSION: Although the response rate to the combination of CP plus 5-FU was superior to that achieved with single agents, survival did not improve.

Multicenter phase II trial of brequinar sodium in patients with advanced squamous-cell carcinoma of the head and neck.

A total of 19 patients with advanced squamous-cell carcinoma of the head and neck who had not previously been exposed to chemotherapy were treated with brequinar sodium as first-line chemotherapy. Brequinar was given intravenously at a median weekly dose of 1,200 mg/m2. The toxicity was moderate, with 7 patients (37%) experiencing grade 3 or 4 toxicity. In all, 16 patients who were evaluable for efficacy showed no objective response. We conclude that brequinar given at this dose and on this schedule has no significant activity in advanced squamous-cell carcinoma of the head and neck.

Postsurgical adjuvant chemotherapy with or without radiotherapy in women with breast cancer and positive axillary nodes: a South-Eastern Cancer Study Group (SEG) Trial.

In a prospective study of 622 women with breast cancer, those with one to three histologically positive axillary lymph nodes were randomised after mastectomy to receive cyclophosphamide 100 mg/m2 orally on days 1-14, methotrexate 40 mg/m2 intravenously on days 1 and 8, and fluorouracil 600 mg/m2 intravenously on days 1 and 8 every 28 days for six cycles (CMF x six), or for twelve cycles of the same chemotherapy (CMF x 12). Those with > or = four positive nodes were randomised to one of these two groups or to 5000 cGy of postmastectomy regional radiotherapy (RT) followed by six cycles of the same chemotherapy (RT + CMF x six). With about 10 years median follow-up, there was no significant difference in survival or disease-free survival among the three groups. There was evidence of decreased locoregional recurrence in patients with > or = four nodes who received RT + CMF x six (relative risk 0.53, P = 0.067). Multivariate analysis indicated that the presence of > or = four positive nodes (negatively) and the percentage of ideal (full) dose of CMF received (positively) were the strongest factors predictive of survival. This study shows no advantage for 12 over six cycles of CMF chemotherapy in women with breast cancer and positive axillary nodes. There was a suggestion of decreased locoregional recurrence but no improvement in survival with radiotherapy for women with > or = four positive nodes.

Carcinocythemia in a patient with rhabdomyosarcoma.

Solid tumor cells are rarely seen in peripheral blood smears. When this occurs the term carcinocythemia is used. This report describes an 18-year-old female who presented with a painless lump in the labia majora associated with pancytopenia. Tumor cells were identified in the peripheral blood smear and the bone marrow aspirate showed a predominant population of small round vacuolated primitive cells, many of which formed clumps of varying sizes. Biopsies of the vulvar mass and bone marrow were interpreted as alveolar rhabdomyosarcoma. Review of the literature revealed 12 previously reported cases in whom carcinocythemia had been documented; rhabdomyosarcoma was the specific cell type involved in only two of these. The median time between detection of the leukemic phase of the tumor and death was 8.5 weeks, reflecting the fact that carcinocythemia, when it occurs, represents the terminal event of the disease. To our knowledge, our case is the third well documented case of rhabdomyosarcoma in leukemic phase so far reported. The clinical evolution as well as the management of this patient will be described in detail along with a review of the pertinent available literature.

Concomitant cisplatin chemotherapy and radiotherapy in advanced mucosal squamous cell carcinoma of the head and neck. Long-term results of the Radiation Therapy Oncology Group study 81-17.

One hundred twenty-four eligible patients with advanced mucosal squamous cell carcinoma of the head and neck were entered into a pilot study of concomitant cisplatin (100 mg/m2 given every 3 weeks for three doses) and standard irradiation. The initial complete response (CR) was 71% with an additional two cases salvaged by surgery for an overall 73% CR. When no keratin was identified in the histologic specimen (41 patients) the CR was 90%. The nasopharynx showed the best CR (89%) among the sites. At 4 years after treatment, the estimated locoregional tumor control rate was 43% and the survival, 34%. When no keratin was present in the specimen, the estimated locoregional control of tumor was superior (56% versus 38% with keratin identified, P = 0.02) and the estimated survival was also superior (48% versus 26%, P = 0.008). Acute treatment-related toxicities included one death due to renal damage and two patients with life-threatening renal damage. The delivery of radiotherapy was not altered. Late toxicity included necrosis -3%, fibrosis -4%, and one fistula. The results of this study justify a randomized trial for the comparison of this combination of cisplatin and radiotherapy versus radiotherapy alone in advanced mucosal carcinomas of the head and neck.

Severe hemolysis and red cell fragmentation caused by the combination of a spectrin mutation with a thrombotic microangiopathy.

Two patients are described who presented with severe hemolysis and erythrocyte fragmentation. One patient had renal allograft rejection and disseminated intravascular coagulation, and the other had thrombotic thrombocytopenia purpura. The severity of hemolysis and the red cell abnormalities were considerably more profound than usually seen in patients with thrombotic microangiopathies. After evaluation of blood smears prepared before the onset of the disease and biochemical characterization of proteins of the red blood cell skeleton, a mutation of the skeletal protein spectrin, designated Sp alpha l/65, was identified. In the heterozygous form, this mutation manifests as mild, often asymptomatic, hereditary elliptocytosis. We conclude that in these two patients with thrombotic microangiopathy, the intrinsic red cell membrane instability resulting from the underlying skeletal defect aggravated the mechanical red cell fragmentation, producing morphological features similar to the severe hemolytic form of hereditary elliptocytosis or hereditary pyropoikilocytosis.

Concurrent radiotherapy and chemotherapy with cisplatin in inoperable squamous cell carcinoma of the head and neck. An RTOG Study.

In patients who have locally advanced and inoperable head and neck cancer, the achievement of initial local control (complete response) of the disease with initial definitive treatment with radiotherapy (RT) with or without chemotherapy, is an important prognostic factor for overall survival. Cisplatin 100 mg/M2-intravenously (IV) with hydration and mannitol diuresis was given every 3 weeks for three doses concurrently with definitive radiotherapy (followed by salvage surgery [if possible] for persistent disease) was activated by the Radiation Therapy Oncology Group (RTOG) in 1981. One hundred thirty-four patients were initially registered and 124 were eligible and analyzed for this report. Eighty-two percent of the patients had Stage IV disease and greater than 50% of the primary sites were in oropharynx (39%), nasopharynx (22%), and oral cavity (18%). Eighty-seven percent of the patients are known to have finished the planned RT greater than 6450 cGy and 60% received three courses of cisplatin. Overall, 60% finished the planned combined treatment. Complete response to initial treatment occurred in 69% and an additional one patient (1%) was rendered disease-free after radical node dissection. Severe toxicities were as follows: leukopenia, 11%; anemia, 8%; nausea and vomiting, 6%; stomatitis, 31%; and renal, 6%. One toxic death occurred when a nephrotoxic antibiotic was administered at the same time. All patients were evaluated for total disease and survival regardless of compliance to the treatment or the cause of death. At 1 year, an estimated 51% of the patients had their disease totally controlled and an estimated 66% were alive. Incidence of initial complete response by various patient characteristics also were analyzed. The authors concluded that the combination of cisplatin and radiotherapy is an effective and safe treatment in patients with advanced head and neck cancer and needs to be tested against radiotherapy alone.

A phase II trial of diaziquone in patients with head and neck cancer.

Diaziquone (AZQ) is a lipophilic alkylating agent which crosses the blood-brain barrier and has marked antitumor activity in a broad spectrum of murine tumor systems. Myelosuppression has been the dose-limiting toxicity in phase I trials. In this study 36 patients with head and neck cancer received diaziquone. Thirty-one of these patients (28 male, 3 female) were evaluable for efficacy. The initial starting dose was 7 mg/m2/day X 5 days i.v. repeated every 28 days. Because of the severe myelosuppression encountered in the first four patients, the starting dose was decreased by 20% to 5.5 mg/m2/day X 5 days repeated every 28 days. The majority of patients were considered to be good-risk patients as evidenced by performance status (80% 0-1 Zubrod) and prior therapy. Even with this dosage reduction, myelosuppression (especially thrombocytopenia) was again the dose-limiting toxicity with 25% of patients experiencing granulocyte and platelet nadirs below 1000/mm3 and 50,000/mm3 respectively. Thirty-five percent of patients required a subsequent dosage reduction of 20% prior to receiving a second course of therapy. There was one complete (CR), four partial (PR) and three minor (MR) responses. All but the CR were of relatively short duration (mean of 30 days). The patient with a CR has remained disease-free for nearly 3 years. In this group of patients the activity of diaziquone as a single agent at this dose and schedule (CR + PR + MR = 26%; CR + PR = 16%) is less than that of methotrexate, bleomycin, and cis-platinum but is encouraging. Further trials utilizing combinations are warranted.