Murray N. Silverstein

Prognostic effect of weight loss prior tochemotherapy in cancer patients

The prognostic effect of weight loss prior to chemotherapy was analyzedusing data from 3,047 patients enrolled in 12 chemotherapy protocols of the Eastern Cooperative Oncology Group. The frequency of weight loss ranged from 31 percent for favorable non-Hodgkins lymphoma to 87 percent in gastric cancer. Median survival was significantly shorter in nine protocols for the patients with weight loss compared to the patients with no weight loss. Chemotherapy response rates were lower in the patients with weight loss, but only in patients with breast cancer was this difference significant. Decreasing weight was correlated with decreasing performance status except for patients with pancreatic and gastric cancer. Within performance status categories, weight loss was associated with decreased median survival. The frequency of weight loss increased with increasing number of anatomic sites involved with metastases, but within categories of anatomic involvement, weight loss was associated with decreased median survival. These observations emphasize the prognostic effect of weight loss, especially in patients with a favorable performance status or a limited anatomic involvement with tumor.

Population-based incidence and survival figures in essential thrombocythemia and agnogenic myeloid metaplasia: an Olmsted County Study, 1976-1995.

To provide basic information about occurrence and outcome of essential thrombocythemia (ET) and agnogenic myeloid metaplasia (AMM), we used the Rochester Epidemiology Project medical record linkage system for residents of Olmsted County, Minnesota. We identified all residents who were diagnosed with ET or AMM from 1976 to 1995. Community inpatient and outpatient medical records were reviewed to verify the diagnosis of ET or AMM, and patients were followed passively through their medical records to determine the outcome after diagnosis. We identified 39 cases of ET and 21 of AMM, with age‐ and sex‐adjusted incidence rates of 2.53 and 1.46 cases/100,000 population annually, respectively. The respective median ages at diagnosis were 72 and 67 years. The female‐to‐male ratios were 1.8 and 1.6 for ET and AMM, respectively, and when adjusted for age, there was no difference in risk. The median follow‐up period was 62.9 months for ET and 33.2 months for AMM. Five‐ and 10‐year survivals were 74.4% and 61.3%, respectively, for ET and were significantly lower than expected for age‐matched controls ( P = 0.012). Prognosis was worse for AMM, with a median progression time of 7 months and a 3‐year survival of 52.4%. This was significantly worse than for age‐matched controls (P < 0.001). This study provides population‐based incidence and comparative survival figures in ET and AMM. Am. J. Hematol. 61:10–15, 1999.

Splenic irradiation for symptomatic splenomegaly associated with myelofibrosis with myeloid metaplasia

Twenty‐three patients who had myelofibrosis with myeloid metaplasia (MMM) were treated at our institution with 50 courses of splenic irradiation (SI) for symptomatic splenomegaly. The median dose of radiation per course was 277.5 cGy, administered in a median of 7.5 fractions. 8/23 patients received multiple courses of SI. Of 49 evaluable courses of SI, 46 (93.9%) resulted in an objective decrease in spleen size. The median duration of response was 6 months (range 1–41). Reduction in spleen size was associated with symptomatic relief in all patients. Overall median survival after SI was 22 months. Significant cytopenia occurred in 10 (43.5%) patients, or 16 (32%) of the 50 courses of SI. Prolonged, life‐threatening pancytopenia after a single course of SI occurred in six patients (26%), resulting in fatal sepsis or haemorrhage in three (13%). Nine patients underwent subsequent splenectomy; the perioperative mortality rate was 11%. One third of patients experienced postoperative intra‐abdominal haemorrhage necessitating surgical re‐exploration. SI can provide symptomatic relief and a reduction in spleen size in most MMM patients. The increased risk of postoperative bleeding in patients requiring subsequent splenectomy dictates against considering SI as an alternative to splenectomy for patients who are otherwise good surgical candidates.

A clinical update in polycythemia vera and essential thrombocythemia.

Polycythemia vera and essential thrombocythemia pose specific management issues that distinguish them from other chronic myeloproliferative disorders. They are associated with a better prognosis, as well as a variable risk of thrombohemorrhagic complications. In addition, essential thrombocythemia occurs comparatively more often in young people and women. Treatment strategies for patients with polycythemia vera and essential thrombocythemia must consider the possibility of long-term survival, morbidity from thrombotic complications, transformation into myelofibrosis with myeloid metaplasia or acute myeloid leukemia, and the effect of specific therapies on the incidence of leukemic transformation and on pregnancy. There is increasing concern about the possible leukemogenic effect of hydroxyurea. Newer therapeutic agents, including interferon alpha and anagrelide, are being used more often. Ongoing studies are reexamining the effects of low-dose aspirin in preventing thrombotic complications.

Essential Thrombocythemia in Young Adults

Essential thrombocythemia is typically a disorder of adults in the sixth or seventh decade of life and is characterized by frequent thrombohemorrhagic complications. In young patients, the optimal management of complications is controversial. We studied 56 young adults (33 female and 23 male patients) with a diagnosis of essential thrombocythemia. The mean duration of follow-up was 4.68 years. The mean platelet count at diagnosis was 1,328,000/mm3. Platelet aggregation studies in 21 patients demonstrated hypoaggregation to epinephrine; spontaneous platelet aggregation was present in 4. At diagnosis, 39 patients were asymptomatic, and thrombocytosis was discovered incidentally. Throughout follow-up (up to 20 years), 24 patients remained asymptomatic. Thrombotic complications developed in 24 patients; they were life-threatening in only 3. The most common vaso-occlusive symptoms were migraine headache (in 12 patients) and erythromelalgia (in 3). Minor hemorrhagic complications occurred in six patients, and none was life-threatening. Serious complications (one cerebral and two myocardial infarctions) occurred in three patients, all of whom recovered. Two deaths occurred, neither of which was attributable to essential thrombocythemia. The treatment regimens used were chemotherapy in 9 patients, antiaggregating agents in 7, radioactive phosphorus in 1, the newer platelet-lowering agent anagrelide in 10, and only observation in 29. No treatment-related acute leukemias developed. This series of young patients with essential thrombocythemia, the largest to date, demonstrates a low incidence of life-threatening complications and a favorable long-term prognosis. Therapeutic recommendations should remain conservative, and potential leukemogens should be avoided unless serious complications develop. Anagrelide may be useful in young patients with thrombocythemia who are symptomatic.

The effects of anagrelide on human megakaryocytopoiesis

Anagrelide, an inhibitor of platelet aggregation, decreases the number of platelets in normal subjects and in patients with myeloproliferative disorders. We describe studies aimed at discovering the general mechanism(s) by which anagrelide acts. We examined three hypotheses: (1) anagrelide shortens platelet survival, (2) anagrelide inhibits the proliferation of megakaryocytic‐committed progenitor cells (CFU‐M), and (3) anagrelide inhibits maturation of megakaryocytes. We observed that anagrelide did not shorten platelet survival. Proliferation of CFU‐M in vivo was not affected by anagrelide, although high concentrations of anagrelide inhibited CFU‐M in vitro. In‐vivo and in‐vitro anagrelide altered the maturation of megakaryocytes, causing a decrease in their size and changing other morphometric features. We conclude that anagrelide decreases the number of platelets primarily by interfering with the maturation of megakaryocytes.

Thymoma and cancer

Twenty‐one per cent (31 of 146) of patients who had thymoma and whose condition was followed for 20 years had a malignant lesion of a nonthymic tissue. In contrast, 8% (15 of 177) of patients who had a parathyroid adenoma had a malignant neoplasm of another tissue. A review of 1030 reported cases of thymoma showed that nonthymic malignant lesions had developed in 20% (7 of 35) of patients whose condition was followed for 5 years or more. The present study suggests that nonthymic malignancy with thymoma should be added to the list of conditions (myasthenia gravis, pure red cell aplasia, and immunoglobulin abnormalities) that generally is accepted in association with thymoma.

2-Chlorodeoxyadenosine treatment after splenectomy in patients who have myelofibrosis with myeloid metaplasia

2‐Chlorodeoxyadenosine (2‐CdA) is a purine nucleoside analogue with therapeutic activity in low‐grade lymphoproliferative disorders. In addition, 2‐CdA has a potent myelosuppressive effect, and it has been shown to be toxic to malignant myeloid cells both in vitro and in vivo. In this pilot study we treated nine patients who had advanced myelofibrosis with myeloid metaplasia (MMM) and progressive hepatomegaly or symptomatic thrombocytosis after therapeutic splenectomy. 2‐CdA was administered at 0.05–0.1 mg/kg/d for 7 d for one to five treatment cycles. A reduction in liver size associated with marked improvement in fatigue and control of thrombocytosis and leucocytosis was achieved in seven of the nine patients (78% response rate). In four of the seven responding patients the reduction in liver size was durable (4–28 months) and was associated with a decrease in serum alkaline phosphatase levels. However, no patient had improvement in anaemia, and two of the seven initially responding patients have since died of acute leukaemia or progressive disease. Improvement in bone marrow fibrosis was noted in two of five available post‐treatment marrow examinations. Toxicity was mainly myelosuppression, which was severe in two patients. 2‐CdA may be considered a palliative therapeutic agent after splenectomy in noncytopenic patients with MMM who have progressive hepatomegaly or extreme thrombocytosis.

High-dose cyclophosphamide. An effective treatment for advanced refractory multiple myeloma

The Eastern Cooperative Oncology Group evaluated cyclophosphamide 600 mg/m2 intravenously daily × 4 (total dose each cycle 2400 mg/m2) as an aggressive approach to the treatment of patients with advanced multiple myeloma. The overall objective response rate is 43%. This includes a 38% response rate for all previously treated patients and a 29% response rate for patients refractory to prior therapy with cyclophosphamide. The objective response duration was 3 months and the survival of responding patients 9 months. A subjective response rate of 63% was observed, characterized by effective pain relief and improved performance. Sixty‐nine percent of patients experienced leukocyte cell nadirs < 500/mm2 with a mean time to marrow recovery of 17 days. Thrombocytopenia was less severe but required platelet transfusion in 43% of patients. Bone marrow toxicity was encountered in all patients, and death in aplasia is a significant risk. Strict adherence to entry criteria, and a systematic plan for hospitalization for antibiotic and blood component support is required for treatment with this regimen.

Metastatic carcinoma simulating agnogenic myeloid metaplasia and myelofibrosis.

Eight patients with metastatic carcinoma with findings simulating agnogenic myeloid metaplasia and myelofibrosis are reported. All patients had a previous histologic diagnosis of carcinoma and complained of bone pain. All had leukoerythroblastic anemia and reticulocytosis. Splenomegaly, observed in 6 of the 8 patients, was striking in only 2. Bone marrow examination in 6 patients revealed fibrosis in all 6, and carcinoma cells were demonstrable in 4. Osseous roentgenographic changes, observed in all 8 patients, were lytic, blastic, or mixed. Clinical differentiation from agnogenic myeloid metaplasia may be difficult but is possible. Long survival after the onset of myeloid metaplasia with metastatic carcinoma may occur; 3 of our patients were living more than 2 years after onset of the disorder.