A phase II trial of pirfenidone (5-methyl-1-phenyl-2-[1H]-pyridone), a novel anti-fibrosing agent, in myelofibrosis with myeloid metaplasia.

The anti-fibrotic and cytokine modulatory properties of pirfenidone suggest its usefulness in the treatment of myelofibrosis with myeloid metaplasia (MMM). In a prospective study, 28 patients with MMM were treated with oral pirfenidone. Twelve patients completed 1 year of therapy; 13 were withdrawn because of disease progression and three because of drug intolerance. Only one patient experienced a clinically relevant benefit with respect to anaemia and splenomegaly. The overall lack of clinical benefit correlated with no significant improvement in the bone marrow morphological features of the disease. We conclude that pirfenidone has no significant clinical or biological activity in MMM.

A long-term retrospective study of young women with essential thrombocythemia.

OBJECTIVE: To describe presenting clinical manifestations, long-term disease complications, prognostic indicators, and outcome of pregnancy for women younger than 50 years with essential thrombocythemia. PATIENTS AND METHODS: We retrospectively reviewed the records of all patients with essential thrombocythemia evaluated at Mayo Clinic, Rochester, Minn, between 1969 and 1991 and identified 74 young women (median age, 35 years; range, 18-48 years) with essential thrombocythemia. The diagnosis was based on previously established criteria. Median follow-up was 9.2 years (range, 0.2-26.2 years). RESULTS: Overall survival was similar to that of an age- and sex-matched control population. Thrombotic events (except superficial thrombophlebitis) occurred at and after diagnosis in 11 patients (15%) and 13 patients (18%), respectively. A history of thrombosis at diagnosis was significantly associated with recurrent thrombosis (P = .03). A platelet count higher than 1500 x 10(9)/L at diagnosis was significantly associated with gastrointestinal tract bleeding and subsequent development of venous (but not arterial) thrombosis (P = .04). Major hemorrhagic events occurred in only 3 patients (4%) after diagnosis. Only 1 patient developed acute leukemia. Thirty-four pregnancies occurred in 18 patients. Of these, 17 (50%) resulted in live births. Of the 17 patients with unsuccessful pregnancies, 14 had spontaneous abortions, 1 had an ectopic pregnancy, and 2 had elective abortions. Preconception platelet count, thrombotic history, or specific therapy was not useful in predicting pregnancy outcome. CONCLUSION: Young women with essential thrombocythemia can expect long survival with a low incidence of life-threatening thrombohemorrhagic complications or acute leukemia. There is an increased incidence of first-trimester miscarriages that may not be influenced by specific therapy.

Anemia after orchiectomy.

The decrease in testosterone production associated with bilateral orchiectomy may result in normocytic anemia in men. We sought to determine the effect of orchiectomy on hemoglobin concentration. Patients were evaluated at the Mayo Clinic in 1993 and 1994 and underwent bilateral orchiectomy for prostate carcinoma. All patients were seen by one of the staff urologists. Patients were included if they had a normal preoperative complete blood cell count and serum levels of creatinine, if they remained without disease progression (suppressed prostate-specific antigen level and no evidence of clinical progression on review), and if they had normal serum levels of creatinine and mean corpuscular volume during the follow-up period. The patients could have no other cause of anemia. The complete blood cell count, prostate-specific antigen level, and serum level of creatinine were determined preoperatively and at least once (>90 days) after orchiectomy. Sixty-four patients were included in the analysis (median age, 68 years). The median decrease in hemoglobin concentration was 1.2 g/dL after orchiectomy. There was a statistically significant difference in the hemoglobin concentration before orchiectomy compared with postoperative values at all the intervals studied, both by the paired group t-test and the Kruskal-Wallis test. There is a clinically and statistically significant decrease in hemoglobin concentration after orchiectomy. Knowledge of this phenomenon may prevent unnecessary diagnostic work-up in men with normocytic anemia after bilateral orchiectomy.

Treatment of acute myelogenous leukemia in the older patient with attenuated high-dose ara-C.

We have evaluated the activity and toxicity of cytosine arabinoside (ara-C; 750 mg/m2 intravenously given over 3 hours every 12 hours for 12 doses) to induce remission in older (median age, 73 years) newly diagnosed patients who had acute myelogenous leukemia (AML). A maximum of two cycles of induction were administered. Patients who achieved complete remission could receive three additional consolidation courses limited to 4 to 6 doses of ara-C every 12 hours, depending on marrow cellularity. Thirty patients were evaluable. Twenty-two patients had one or more unfavorable prognostic factors, including antecedent hematologic disorders (10), cytogenetic abnormalities (17), or hyperleucocytosis (5). Fourteen patients (47%) achieved complete remission. Four patients did not receive consolidation as planned because of medical contraindication or refusal, and three patients relapsed during consolidation. The median duration of complete remission was 326 days. Sixteen patients failed induction because of relative or absolute drug resistance in nine patients, or death in seven patients. Median survival for the entire group was 6 months. Toxicity was significant, with a median initial hospitalization of 29 days. These results are comparable to those reported in the literature and suggest that this regimen may be considered to be an alternative to an anthracycline-containing regimen.

Continuous infusion etoposide/carboplatin for treatment of refractory acute leukemia.

Etoposide (125 mg/m2/d) and carboplatin (200 mg/m2/d) were administered by continuous 5-day intravenous infusion to 10 patients with relapsed or refractory acute leukemia (7 ANLL, 1 ALL, 2 blast crisis of CGL). No complete or partial response was observed despite dose-limiting toxicity characterized by severe diarrhea in four patients and neutropenic colitis in two additional cases. We cannot recommend the present schedule of drug administration for the treatment of acute leukemia.

Myelodysplastic (preleukemia) syndromes: the bone marrow factory failure problem.

The myelodysplastic syndromes are a group of hematologic disorders that adversely affect the levels of hemoglobin, platelets, erythrocytes, and leukocytes. Although the cause of this syndrome is unknown, new diagnostic techniques have facilitated identification and classification of these diseases into five categories: refractory anemia (refractory cytopenia), refractory anemia with ringed sideroblasts, refractory anemia with excess blasts, refractory anemia with excess blasts in transformation, and chronic myelomonocytic leukemia. Cytogenetic abnormalities may be present in more than 55% of the patients. Symptomatic patients should be assessed relative to life-threatening versus non-life-threatening cytopenias and age. Management consists of primarily supportive measures, although certain approaches that are currently being used or under investigation, such as concomitant administration of erythropoietin and other growth factors, show promise for the future.

Outcome analysis of 34 pregnancies in women with essential thrombocythemia.

OBJECTIVE: To evaluate the clinical impact of essential thrombocythemia on the outcome of pregnancy or vice versa. DESIGN: A retrospective study. SETTING: All patients were seen at our tertiary referral center, and most were followed up by their local physicians. PATIENTS: From 1975 through 1991, 73 women younger than 50 years with essential thrombocythemia were seen at our institution. All patients were followed up through patient or physician contact. A detailed obstetric history, including peripartum complications and management, was obtained. RESULTS: Among the 73 women, 34 pregnancies occurred in 18 patients. There were two uncomplicated elective abortions and one ectopic pregnancy. Of the 31 other pregnancies, 17 (55%) resulted in live birth and 14 (45%) ended in spontaneous abortion (all but two in the first trimester). Abortion could not be predicted from history of disease complications before or during pregnancy or by the presence or absence of specific therapy during pregnancy. Preconception platelet counts in women whose pregnancies resulted in live birth were similar to those of women whose pregnancies ended in abortion. Other complications during pregnancy were rare. CONCLUSIONS: Patients with essential thrombocythemia have an increased risk of first-trimester abortion, which does not appear to be predictable or influenced by therapy. However, most patients are able to carry pregnancies to term with little or no risk of obstetric or thrombohemorrhagic complications during or after delivery. Overall, specific therapy during pregnancy did not appear to modify the clinical outcome, and the benefit of platelet apheresis during delivery could not be substantiated.

Acute lymphocytic leukemia in adults: a retrospective study and analysis of current management options.

OBJECTIVE: To examine current therapeutic modalities for acute lymphocytic leukemia (ALL) in adults, analyze prognostic variables, and offer treatment recommendations. DESIGN: We reviewed our experience with 90 adult patients with ALL examined at the Mayo Clinic between 1982 and 1992 and used it as a background for discussion of prognostic factors and management options in adult patients with ALL. MATERIAL AND METHODS: The pretreatment characteristics of patients, types of induction chemotherapy, and postremission treatment, including bone marrow transplantation (BMT), were analyzed for prognostic significance for each of three outcomes: complete remission (CR) rate, duration of CR, and overall survival of patients. RESULTS: Of the 90 study patients, 80 had received induction chemotherapy. Overall long-term survival for treated patients was 25%. None of the 10 patients younger than 18 years of age underwent BMT, and their long-term survival was 80%. Of the other 70 patients, who were 18 years old or older, 42 (60%) had a CR with induction chemotherapy. Of these 42 patients, 31 did not undergo BMT, and their long-term survival was less than 13%. BMT was done in six patients during a first CR (with 100% survival), in four during a later CR (with 50% survival), and in six with disease (with 17% survival). The median age of patients who received chemotherapy was 50 years (range, 19 to 87) and that of patients who underwent BMT was 34 years (range, 18 to 46). Overall, age was the only significant prognostic factor. CONCLUSION: With our application of current chemotherapy, the outcome in adult patients (18 years old or older) with ALL was dismal. The results were considerably better in patients younger than 18 years of age or in those who underwent BMT as post-remission therapy. Comprehensive assessment of our experience and that in the literature, however, did not resolve issues about current management. Participation of patients in comparative trials is critical for determining the best therapy for ALL in adults.

Issues in the diagnosis and management of essential thrombocythemia.

OBJECTIVE: To summarize the current trends in the diagnosis and management of essential thrombocythemia (ET) and to discuss the treatment of young and pregnant patients with ET. DESIGN: We review our experiences in the diagnosis and management of ET. MATERIAL AND METHODS: A definitive diagnosis of ET at initial examination is seldom possible because of the low incidences of associated clonal cytogenetic abnormalities and palpable splenomegaly. The criteria of the Polycythemia Vera Study Group for the diagnosis of ET are provided, as are the clinical and laboratory features that help to distinguish ET from reactive thrombocytosis. RESULTS: Patients with ET have an almost normal life expectancy if thrombohemorrhagic complications are controlled. Although a previous history of thrombosis is an established risk factor for further episodes, the adverse effects of extreme thrombocytosis and age are less well defined. Determining which patients require therapy is controversial. The management of young or pregnant patients necessitates special considerations. CONCLUSION: Until additional data become available, no strong recommendations can be given in support of or against specific therapy for asymptomatic young patients. We favor treatment in asymptomatic patients with cardiovascular risk factors but not in asymptomatic women who are pregnant or are of childbearing age.

Successful treatment of simultaneous pulmonary Pseudallescheria boydii and Aspergillus terreus infection with oral itraconazole.

Pseudallescheria boydii and Aspergillus terreus are unusual opportunistic fungal pathogens that are often resistant to chemotherapy with amphotericin B. We report a case of simultaneous invasive pulmonary infection with these organisms occurring in a bone marrow transplant recipient who was successfully treated with the oral azole itraconazole.

Hemorrhagic pleural effusion and pleural thickening as a complication of chronic lymphocytic leukemia.

We report a case of pleural thickening and hemothorax in a 56-year-old male with B-cell chronic lymphocytic leukemia (CLL). The association of this entity with CLL has not been previously reported. Awareness of this occurrence is essential to appropriate therapy for similar patients with CLL.

The 5q- syndrome: a single-institution study of 43 consecutive patients.

A favorable prognosis and a low rate of leukemic transformation has been attributed to the 5q- syndrome, a myelodysplastic syndrome (MDS) characterized by macrocytic anemia, hypolobulated micromegakaryocytic hyperplasia, and an interstitial deletion of chromosome 5. We examined the characteristics and outcome of 43 consecutive patients in our institution strictly defined by morphologic criteria and a solitary 5q- cytogenetic defect. The median age at diagnosis was 68 years, with a clear female predominance (7:3). Eighty percent of the patients were red blood cell transfusion-dependent at diagnosis and all untransfused patients had macrocytic indexes. In contrast, significant neutropenia or thrombocytopenia was rare. The French-American-British (FAB) class distributions were RA (72%), RARS (7%), RAEB (16%), and RAEB-IT (5%). At a median follow-up of 31 months, 56% of the patients survive, with a projected median survival of 63 months. The incidence of acute leukemia was 16% and was uniformly fatal. Clinical hemosiderosis occurred in 28% of the patients, resulting in two deaths. Neither survival nor the risk of leukemic transformation was predictable from initial clinical parameters, including FAB classification, Bournemouth score, and degree of aneuploidy. The lack of significant neutropenia and thrombocytopenia seemed to account for a very low incidence of infection and bleeding resulting in a prognosis equal or superior to historical patients with MDS. Therapeutic endeavors, including the use of corticosteroids, androgens, cis-retinoic acid, pyridoxine, and danazol, were largely unsuccessful.

Outcome of recipients of bone marrow transplants who require intensive-care unit support.

To determine the outcome and prognostic factors associated with bone marrow transplantation (BMT), we reviewed the clinical course of 35 adult recipients of such a transplant who were admitted to our intensive-care unit (ICU). This constituted 24% of patients who underwent BMT for treatment of hematologic disorders during the study period. The reasons for admission to the ICU were postsurgical care in 5, respiratory failure in 25, shock in 4, and renal failure in 1. The in-hospital mortality was 20% for the postsurgical patients and 87% for the others. None of the postsurgical patients required mechanical ventilation, whereas 90% of the others did, and the associated mortality was 93%. Infection was the cause of the respiratory failure in all but 3 of the 25 patients and was associated with 95% mortality. Complications that involved multiple organs increased the mortality to 100%. No significant differences were found in age, sex, type of BMT, serologic tests for cytomegalovirus, history of graft-versus-host disease, conditioning regimen for BMT, and duration of stay in the ICU and the hospital between survivors and nonsurvivors. The APACHE II (acute physiology and chronic health evaluation) prognostic scoring system underestimated mortality and had no correlation with the duration of stay in the ICU or the hospital. Vasopressors, total parenteral nutrition, and transfusion of blood components in the ICU had no influence on the outcome. Open-lung biopsy was helpful in making specific diagnoses, and pulmonary artery catheters were used in most patients to guide therapy but did not improve survival.(ABSTRACT TRUNCATED AT 250 WORDS)

Cytogenetic and molecular detection of residual leukemic cells after allogeneic bone marrow transplantation in chronic granulocytic leukemia.

Allogeneic bone marrow transplantation (BMT) is a therapeutic modality with a curative potential for chronic granulocytic leukemia. Approximately 20% of patients have a hematologic relapse after BMT. The frequency of cytogenetic or molecular relapse (or both), despite hematologic remission, is reportedly higher. We performed allogeneic BMT in 32 patients with chronic granulocytic leukemia by using unmanipulated donor marrow and a conditioning regimen that consisted of cyclophosphamide and total-body irradiation. Of these 32 patients, 23 had cytogenetic studies after BMT. Seven of these patients had cytogenetically detectable Philadelphia chromosomes some time after BMT, during hematologic remission. The Philadelphia chromosome was detected transiently in two patients, and the fraction of abnormal metaphases exceeded 25% in three patients. None of the patients with negative results of cytogenetic studies or with the presence of the Philadelphia chromosome in less than 25% of analyzed metaphases had a clinical relapse, whereas two of the three patients with more than 25% abnormal metaphases had clinical relapses. Our results suggest that the detection of more than 25% abnormal metaphases during cytogenetic studies for chronic granulocytic leukemia after BMT may imply an incipient clinical relapse. We review the current literature that discusses isolated cytogenetic or molecular relapses of chronic granulocytic leukemia after BMT.

Hemorrhagic cystitis complicating bone marrow transplantation.

Hemorrhagic cystitis is a potentially serious complication of high-dose cyclophosphamide therapy administered before bone marrow transplantation. As standard practice at our institution, patients who are scheduled to receive a bone marrow transplant are treated prophylactically with forced hydration and bladder irrigation. In an attempt to obviate the inconvenience of bladder irrigation, we conducted a feasibility trial of uroprophylaxis with mesna, which neutralizes the hepatic metabolite of cyclophosphamide that causes hemorrhagic cystitis. Of 97 patients who received standard prophylaxis, 4 had symptomatic hemorrhagic cystitis. In contrast, two of four consecutive patients who received mesna uroprophylaxis before allogeneic bone marrow transplantation had severe hemorrhagic cystitis for at least 2 weeks. Because of this suboptimal result, we resumed the use of bladder irrigation and forced hydration to minimize the risk of hemorrhagic cystitis.

Mayo Clinic experience with allogeneic and syngeneic bone marrow transplantation, 1982 through 1990.

Between April 1982 and July 1990, 101 patients underwent allogeneic or syngeneic bone marrow transplantation at the Mayo Clinic. This patient population consisted of 30 with acute nonlymphocytic leukemia, 25 with acute lymphoblastic leukemia, 29 with chronic granulocytic leukemia, and 17 with other diseases (aplastic anemia in 7, myelodysplastic syndrome in 5, and lymphoma in 5). The results achieved in our patients who underwent transplantation in first complete remission of both acute nonlymphocytic leukemia and acute lymphoblastic leukemia compare favorably with previously reported results. Only 1 of 15 patients (7%) with acute nonlymphocytic leukemia and 2 of 8 patients (25%) with acute lymphoblastic leukemia who underwent transplantation in first complete remission had a relapse. Thus, we recommend early bone marrow transplantation during initial complete remission for patients with either of these disorders who have adverse prognostic factors. In contrast, of 12 patients with either acute nonlymphocytic leukemia or acute lymphoblastic leukemia who underwent transplantation during relapse, 11 died within 6 months. Therefore, such patients should be offered new experimental treatments. Our patients with chronic granulocytic leukemia fared better when they underwent transplantation early during the course of their disease rather than during the accelerated or blast phase. Prospective studies are needed to determine the best approach in these patients.