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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.

In a 20-year period, 223 patients (median age, 64.8 years) with myelofibrosis with myeloid metaplasia (MMM) had therapeutic splenectomy at our institution. Primary indications for surgery were transfusion-dependent anemia (45.3%), symptomatic splenomegaly (39. 0%), portal hypertension (10.8%), and severe thrombocytopenia (4.9%). Operative mortality and morbidity rates were 9% and 31%, respectively. The 203 survivors of surgery had a median postsplenectomy survival time (PSS) of 27 months (range, 0-155). Among preoperative variables, thrombocytopenia (platelet count less than 100 x 10(9/)L) and nonhypercellular bone marrow were identified as independent risk factors for decreased PSS. Durable remissions in constitutional symptoms, transfusion-dependent anemia, portal hypertension, and severe thrombocytopenia were achieved in 67%, 23%, 50%, and 0% of the patients, respectively. Histologic or cytogenetic features of bone marrow obtained before splenectomy did not predict a response in cytopenias. After splenectomy, substantial enlargement of the liver and marked thrombocytosis occurred in 16.1% and 22.0% of the patients, respectively. The thrombocytosis was associated with an increased risk of perioperative thrombosis and decreased PSS. The rate of blast transformation (BT) was 16.3%, and the risk of BT was higher in the presence of increased spleen mass and preoperative thrombocytopenia. However, the PSS of patients with BT was not significantly different from that of patients without BT. We conclude that presplenectomy thrombocytopenia in MMM may be a surrogate for advanced disease and is associated with an increased risk of BT and inferior PSS. However, the development of BT after splenectomy may not affect overall survival and does not undermine the palliative role of the procedure for the other indications.

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.

Essential thrombocythemia (ET), the most common of the chronic myeloproliferative disorders, is characterized by thrombotic and hemorrhagic complications. Thrombotic complications predominate, endangering especially the older population and those with prior history of thrombotic episodes. However, because the life expectancy of ET patients is generally of normal length, caution must be exercised in treating these patients, and the complications of treatment must be weighed against the complications of the disease. Historically, most drugs used in the treatment of ET, such as alkylating agents and radiophosphorus, were carcinogenic themselves. Even hydroxyurea has recently come under investigation for its long-term mutagenicity. The newest drug, anagrelide, approved in March 1997 specifically for ET, appears to be safe and well tolerated.

The clinical course in both polycythaemia vera (PV) and essential thrombocythaemia (ET) is characterized by significant thrombohaemorrhagic complications and variable risk of disease transformation into myeloid metaplasia with myelofibrosis or acute myeloid leukaemia. Randomized studies have shown that the risk of thrombosis was significantly reduced in ET with the use of hydroxyurea (HU) and in PV with the use of chlorambucil or 32P. However, the use of chlorambucil or 32P has been associated with an increased risk of leukaemic transformation. Subsequently, other studies have suggested that both HU and pipobroman may be less leukaemogenic and as effective as chlorambucil and 32P for preventing thrombosis in PV. However, the results from these prospective studies have raised concern that even HU and pipobroman may be associated with excess leukaemic events in both ET and PV. The recent introduction of anagrelide as a specific platelet-lowering agent, the demonstration of treatment efficacy with interferon-alpha, and the revived interest in using low-dose acetylsalicylic acid provide the opportunity to initiate prospective randomized studies incorporating these treatments.

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.

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.

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.

Among the chronic myeloproliferative disorders, polycythemia vera and essential thrombocythemia are unique because of their association with thrombohemorrhagic manifestations and their relatively indolent clinical course. Patients with essential thrombocythemia may not have a significant shortening of life-expectancy and most may not require specific therapy. However, patients with polycythemia vera have a significant risk of transformation of polycythemia vera into acute leukemia or postpolycythemic myelofibrosis (or both). 'High-risk-for-thrombosis' patients with either polycythemia vera or essential thrombocythemia require specific therapy with a platelet-lowering agent to prevent thrombotic complications. Currently, the standard agent used for this is hydroxyurea. However, its tetratogenic and leukemogenic potential has been of concern. As a result, new platelet-lowering agents are being evaluated in the treatment of polycythemia vera and essential thrombocythemia. Anagrelide and interferon alfa are two such agents and have been shown to be effective in reducing platelet counts in patients with chronic myeloproliferative disorders. The putative mechanism of action of these drugs, their specific activity in polycythemia vera and essential thrombocythemia, side-effect profile, and current indications are discussed herein.

Anagrelide is an oral imidazoquinazoline agent with an anti-cyclic AMP phosphodiesterase activity and inhibits platelet aggregation in both humans and animals. In addition, it has in humans a species-specific platelet-lowering activity observed at dose levels lower than those required to inhibit platelet aggregation. Because of this, the drug has been tested in patients with clonal thrombocytosis and has been shown to have potent platelet-reducing activity in essential thrombocythemia (ET) and related disorders. The mechanism of action may involve the drug's interference with megakaryocyte maturation. More than 90% of patients with ET respond to anagrelide regardless of the presence or absence of previous therapy. The responses are durable with a median maintenance dose of approximately 2 to 2.5 mg/day. Side effects are related mostly to the drug's direct vasodilating and positive inotropic effects and include headache, fluid retention, tachycardia, and arryhthmias. The place of anagrelide therapy in the current management of patients with ET is discussed.

Agnogenic myeloid metaplasia (AMM) carries the worst prognosis among the chronic myeloproliferative disorders. Substantial bone marrow fibrosis, extramedullary hematopoiesis, anemia and hepatosplenomegaly are the characteristic features of the disease. AMM is currently incurable and the available treatment agents are mostly palliative and do not prolong life. Two pathogenetic processes are responsible for the impaired hematopoiesis and the clinical manifestations. The primary disease process is a clonal hematopoietic stem cell disorder which results in chronic myeloproliferation and atypical megakaryocytic hyperplasia. The secondary process of bone marrow fibrosis is the result of non-clonal fibroblastic proliferation and hyperactivity induced by growth factors abnormally shed from clonal megakaryocytes. Therefore, experimental treatment strategies may be directed towards either one or both of these disease processes. This report summarizes the current management options and new therapeutic endeavours.

Comparison of results of red cell mass (RCM) measurement by 51Cr and 125I methods in 119 patients showed virtual equivalence. Both methods have an acceptable coefficient of variation (CV) that is < 5%. The 125I method is simpler and much less expensive. Unrealistically narrow "normal ranges" for RCM are likely to lead to misdiagnosis of polycythemia vera. Upper normal limits of 39 mL/kg (males) and 32 mL/kg (females) are consistent with originally published data in normal persons; use of these limits as criteria would reduce the risk of misdiagnosis. No cases of "stress erythrocytosis" or Gaisbock Syndrome were encountered among the 119 cases reviewed.

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.

To investigate the suggestion that the incidence of polycythemia vera has increased in recent decades, we ascertained secular trends in the incidence of polycythemia vera in Olmsted County, Minnesota, over the 55-year period, 1935-1989. The inpatient and outpatient medical records of all potential cases of polycythemia vera in Olmsted County residents were reviewed and the diagnostic criteria of the Polycythemia Vera Study Group were applied. We found no indication of an increase in the age- and sex-adjusted incidence of polycythemia vera, which averaged 1.9 per 100,000 person-years (95% C.I., 1.4-2.5) over the study period. Incidence rates increased with age, and age-adjusted incidence rates were greater for men (2.8 per 100,000 person-years; 95% C.I., 1.8-3.9) than for women (1.3 per 100,000 person-years; 95% C.I., 0.7-1.9), with the highest incidence rate (23.5 per 100,000 person-years) among men aged 70-79 years. Survival was reduced in this inception cohort of 50 cases, compared to that expected for individuals of like age and sex (P < 0.0001); median survival following diagnosis was 7.2 years.

Life-threatening portal hypertension (PHN) in patients with chronic myeloproliferative disorders may result from increased portal flow caused by marked splenomegaly or an increased resistance to portal flow from either a large vein thrombosis or an intrahepatic obstruction usually associated with agnogenic myeloid metaplasia (AMM). The former cause is correctable by splenectomy alone, whereas the latter requires portal-systemic shunt surgery. Few data exist regarding the outcome of portal-systemic shunt surgery in patients with AMM and intrahepatic obstruction. During the past 25 years, 13 patients with chronic myeloproliferative disorders underwent portal-systemic shunt surgery at our institution. The cause of PHN was intrahepatic obstruction in ten patients and hepatic vein thrombosis in three. Ten of the thirteen patients had AMM as initial diagnosis. Only one patient had intraoperative complications, and four patients had either sepsis or thrombosis during the postoperative period. Twelve patients survived the postoperative period and had a median postsurgical survival of 3 years (range, 0.25 to 19 years). The long-term complications of the operation were very few and included hepatic encephalopathy (one patient), portal vein thrombosis (one patient), and shunt occlusion (one patient). The procedure was successful in alleviating complications of PHN in all but one patient. Deterioration of hepatic function and subsequent hepatomegaly were unusual. Portal-systemic shunt surgery seems to be a useful option in patients with AMM and life-threatening PHN from intrahepatic obstruction.

1. If gastric acid is necessary for the absorption of dietary calcium, the total absence of gastric acid secretion that occurs in pernicious anaemia could result in bone loss. To investigate this, we measured calcium absorption and bone density in 21 postmenopausal women (ages 51-76 years) with pernicious anaemia and in 24 normal postmenopausal women (ages 51-79 years). 2. Relative to the normal women, in the women with pernicious anaemia the bone mineral density of the lumbar spine was decreased by 16% (P less than 0.001). 3. After adjustment for age and body weight, lumbar spine bone mineral density correlated with the serum concentration of group 1 pepsinogens (a group of proteins produced by the gastric fundus) (r = 0.61, P less than 0.01). 4. Despite achlorhydria, the women with pernicious anaemia had normal true fractional calcium absorption and normal serum levels of parathyroid hormone and 1,25-dihydroxyvitamin D. 5. We conclude that gastric acid is not required for the absorption of dietary calcium. Thus, the loss of cancellous bone must be caused by some mechanism yet to be identified.

Myeloid metaplasia associated with idiopathic myelofibrosis most commonly involves the reticuloendothelial organs, such as the spleen, liver and retroperitoneal lymph nodes. We report on a patient with myeloid metaplasia (extramedullary hematopoiesis) of the renal pelves, ureters and bladder. The pathogenesis, clinical characteristics, treatment and prognosis of this condition are discussed.

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.

Sogn hemoglobinopathy was identified in a young American woman and in a young American man of apparently unrelated families of Norwegian ancestry. Both persons were asymptomatic and without clinical or hematologic manifestations. Hemoglobin Sogn, beta(A11)14 Leu----Arg, is an unstable hemoglobin that may easily be mistaken for hemoglobin S, G, or D by alkaline hemoglobin electrophoresis. These are the first known instances of hemoglobin Sogn outside of Norway. Oxygen affinity is normal. Sogn hemoglobinopathy is an incidental finding that has no adverse implication for the health of heterozygotes.

The various myeloproliferative diseases have different symptoms, therapeutic problems, and prognoses. The most common of these disorders appears to be agnogenic myeloid metaplasia, which primarily affects older persons. The five-year survival rate at the Mayo Clinic for these patients is 58%, and the prognosis depends on the presence of symptoms, anemia, and thrombocytopenia and on the size of the liver. Androgen therapy is often necessary to control anemia, and splenectomy may be indicated.

The prognostic effect of weight loss prior to chemotherapy was analyzed using 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-Hodgkin's 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.

In an Eastern Cooperative Oncology Group non-Hodgkin's lymphoma clinical trial, 90 patients with Stage III or IV diffuse histiocytic lymphoma (DHL) were treated with one of four chemotherapy regimens. All patients were previously untreated with chemotherapy, and careful restaging was required to document responses. Each treatment included cyclophosphamide, vincristine and prednisone (COP) plus Adriamycin (COPA), BCNU (BCVP) or bleomycin (COPB and CPOB). The two bleomycin-containing regimens differed only in the schedule of drug administration. CPOB-treated patients received cyclophosphamide on day 1, prednisone on days 1 to 5 and vincristine and bleomycin on day 15 of each 21-day cycle. COPB-treated patients received the same four drugs in the same dosage; however, the schedule was changed so that vincristine and bleomycin were given on day 1. Treatment of responders was continued for 8 cycles. Those with a complete response (CR) were randomized to maintenance therapy with BCVP or no treatment. Treatment with CPOB yielded a CR rate of 55% compared to 25% for COPB (P = 0.07). In contrast to COPB, treatment with CPOB was associated with a significantly longer median duration of CR (26.5 versus 5.7 months; P less than 0.05) and median survival (27.7 versus 11.2 months; P less than 0.02). The CR rate was 31% for BCVP and 45% for COPA, and the median survivals were 10.7 months and 14.4 months, respectively. One half of the CPOB-treated patients who achieved CR remained alive in continuous CR after 30 to 72 months. No advantage for maintenance therapy was observed. Myelotoxicity was greater with CPOB than COPB, but comparable to COPA. This trial demonstrated that the results of treatment of DHL with COP plus bleomycin were strikingly dependent upon the schedule of administration of bleomycin and vincristine. Bleomycin effectively combined with COP, as in CPOB, yielded results comparable to those obtained when Adriamycin was added to COP. CPOB appears to be an effective treatment for DHL that should be considered as an alternative to other regimens, particularly for patients who cannot receive Adriamycin.

In studies to determine the optimal treatment for polycythemia vera, 431 previously untreated patients whose disease met established diagnostic criteria were entered into a prospective, randomized controlled trial between 1967 and 1974. Three treatment regimens were used: phlebotomy alone, chlorambucil supplemented by phlebotomy, or radioactive phosphorus supplemented by phlebotomy. Despite minor differences in age and sex, the three groups were comparable in initial hematocrit, white-cell and platelet counts, and disease-related symptoms. The median duration of follow-up is now more than 6 1/2 years. As of February 15, 1980, there were no statistically significant differences in survival among the groups. However, the risk of acute leukemia in patients given chlorambucil was 2.3 times that in patients given radioactive phosphorus and 13 times that in patients treated with phlebotomy alone. The increased incidence of leukemia during chlorambucil treatment is statistically significant (P less than or equal to 0.002); accordingly, the Polycythemia Vera Study Group has discontinued the use of chlorambucil in the treatment of polycythemia vera.

The onset of postpolycythemic myeoloid metaplasia or spent polycythemia has been recognized for many years. As the result of many different series, the development of postpolycythemic myeolid metaplasia might be expected in from 15%-20% of patients with postpolycythemia vera. It appears that an etiologic role for sodium phosphate 32P may exist in this evolutionary pattern. About 70% of patients with PPMM will have symptoms with the onset of the syndrome. The major mechanisms producing symptoms result from (1) anemia, (2) pressure from massive splenomegaly, and (3) bleeding problems. Iron deficiency is a frequent cause of anemia in patients with PPMM. The major mechanism of anemia in these patients, however, relates to ineffective erythropoiesis and shortened red cell survival. Androgen trials for ineffective erythropoiesis seem worthwhile, although data on this point is too limited to draw any firm conclusions. A steroid trial for those patients with major hemolytic episodes is indicated. In those patients in whom adrenal steroid therapy fails to control major hemolysis, a consideration for splenectomy exists. Pressure-related manifestations secondary to massive splenomegaly have been treated with radiation therapy and oral alkylators. Although there is data to document amelioration of painful symptoms with associated shrinking of the spleen, long-term control of this problem has not been forthcoming. Again, patients who are medical failures in control of pressure-related manifestations may be considered for splenectomy. Bleeding problems may arise with PPMM secondary to thrombocytopenia, thrombocythemia, or qualitative platelet dysfunction. Adrenal steroids have met with some success in improving platelet counts in patients with life-threatening thrombocytopenia. Those patients who are medical failures with adrenal steroids in terms of thrombocytopenia might be candidates for splenectomy. Control of thrombocythemia has been observed with oral alkylator therapy and chlorambucil may have a special role in managing this complication. Qualitative platelet defects leading to severe bleeding are best managed with fresh platelet transfusions. Patients with PPMM in contrast to patients with agnogenic myeoloid metaplasia have a more lethal syndrome and shortened survivorship. Causes of death in patients with PPMM include cardiac problems, transition to acute leukemia, hemorrhage, and infection.

Teardrop-shaped erythrocytes (TD) are frequently observed in the peripheral blood of patients with agnogenic myeloid metaplasia (AMM). These deformed cells may result from the myelofibrosis or the extramedullary hematopoiesis in the spleen. To determine the influence of the spleen on TD formation, we reviewed the presplenectomy (pre-S) and postsplenectomy (post-S) peripheral blood smears from 13 patients with AMM. The splenectomy was performed for a variety of reasons, including symptomatic hypersplenism or splenomegaly. The average number of TDs per 1,000 RBCs in the pre-S smears was 42 (range, 15 to 112 TDs), compared with 11 TDs in the post-S smears (range, 6 to 20 TDs)(P = less than .001). Only one of the 13 patients failed to exhibit this decrease in TDs post-S. There was no definite correlation between the number of TDs and the weight of the spleen removed at surgery, the interval since surgery, or age and sex of the patient. Based on this fourfold decrease in the number of TDs post-S, we conclude that the spleen in AMM play an important role in TD formation.

The Eastern Cooperative Oncology Group evaluated cyclophosphamide 600 mg/m2 intravenously daily X 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 less than 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.

Relative and absolute polycythemia can be differentiated by measuring red cell mass and plasma volume. Often no treatment is recommended for patients with relative polycythemia unless directed toward vascular complications; phlebotomy is definitely contraindicated. For patients with polycythemia vera, however, phlebotomy is used routinely to decrease blood viscosity, while myelosuppression is reserved for patients who are not relieved by phlebotomy alone. Secondary polycythemia is controlled by correcting the cause or by circumspect use of phlebotomy if the cause cannot be remedied.

Forty-two patients with advanced malignant lymphomas, all of whom had failed at least one prior course of chemotherapy, were treated with one of two new combination chemotherapy regimens to determine patient tolerability. Twenty-seven patients received regimen 1, after which this study was discontinued, and subsequently 15 additional patients were treated with regimen 2. Regimen 1 (BAP) consisted of BCNU and adriamycin administered iv on Day 1 and prednisone administered orally on Days 1--5 with cycles repeated at 21-day intervals. Regimen 2 (VAP) consisted of VP-16-213 given iv on Days 1 and 2, adriamycin given iv on Day 3, and prednisone given on Days 3--7 in a schedule designed to produce cell cycle synchronization; cycles were repeated at 21--28-day intervals. Both regimens were, in general, well tolerated. Reversible bone marrow depression was the major toxic reaction observed. Nine of 27 patients treated with regimen 1 and five of 15 patients treated with regimen 2 experienced objective tumor regressions. Tolerable dosage levels of both regimens have been defined for future clincial trials.

Anagrelide is a member of the imidazo (2,1-b) quinazolin-2-one series of compounds, with a powerful antiaggregating effect on platelets. During studies in humans, anagrelide in small doses has produced thrombocytopenia. We therefore evaluated it in the treatment of thrombocytosis, and to date, platelet levels in 15 of 17 patients with primary thrombocythemia, 2 patients with polycythemia vera and thrombocytosis, and 1 patient with chronic granulocytic leukemia and thrombocytosis have been well controlled with the use of this agent. Induction doses of 1.0 to 1.5 mg given orally every six hours have produced a decrease in the platelet count, starting on day 5 and reaching a normal level by day 12. Side effects of anagrelide have been minimal. Maintenance therapy with 1.5 to 4.0 mg a day has continued to control the platelet count in patients for up to 28 months. This new agent appears promising in the treatment of thrombocytosis in patients with chronic myeloproliferative disease.

A 52-year-old man with agnogenic myeloid metaplasia had a sudden onset of pain and bleeding from the left ear and an associated decrease in hearing acuity on that side. Examination revealed a friable mass that filled the middle ear and protruded through a perforated tympanic membrane. Special staining of a tissue specimen of the mass revealed myeloid metaplasia. Otorhinolaryngologists should be aware of the fact that the ear can be involved in hematopoietic disorders.

A clinical trial of ICRF-159 was done in patients with Hodgkin's disease and non-Hodgkin's lymphomas whose tumors had become resistant to conventional chemotherapy. Antitumor effect and toxicity were compared in patients who were randomly assigned to receive either a loading course or a weekly regimen. Among 82 evaluable cases, five of 39 (13%) treated with the loading course schedule and six of 43 (14%) treated with the weekly schedule experienced objective tumor regressions. Response duration tended to be brief (median, 7 weeks). Life-threatening myelosuppression was more frequent in patients receiving the loading course regimen. Survival was somewhat longer among patients receiving the weekly schedule (median survival, 24 versus 12 weeks; P = 0.04). ICRF-159 demonstrated definite but limited therapeutic activity in this population of patients with advanced malignant lymphomas. The weekly schedule was associated with fewer episodes of life-threatening toxicity and longer patient survival.

The Eastern Cooperative Oncology Group evaluated hexamethylmelamine in 89 patients with advanced refractory or relapsing multiple myeloma. Hexamethylmelamine was initially used as a single agent administered orally at 200 mg/m2/day for the first 3 weeks of each 4-week cycle. When this regimen proved to be ineffective, it was modified first by increasing the dose of hexamethylmelamine to 280 mg/m2/day and subsequently by adding prednisone at 75 mg for the first 7 days of each 28-day cycle. None of the 39 patients receiving hexamethylmelamine without prednisone had an objective response, while two patients had minimal objective improvement (25%-50% decrease in M protein with symptomatic improvement). Only 14% of these patients had objective or symptomatic response or both. In contrast, patients treated with hexamethylmelamine plus prednisone had a 22% objective response rate, with another 14% showing lesser degrees of objective improvement. Fifty-one percent of the patients treated with this regimen had either objective or symptomatic improvement or both. Severe (grade 3) toxicity was seen in nearly two-thirds of the patients on the higher-dose hexamethylmelamine regimens compared with 37% of the patients receiving low-dose hexamethylmelamine; however, in most instances this represented rapidly reversible cytopenias. Because all but one of the patients responding to hexamethylmelamine plus prednisone had experienced previous treatment failure on regimens containing prednisone in similar dose and schedules, it is unlikely that the responses are due to prednisone alone. Instead, this study suggests that the activity of hexamethylmelamine in multiple myeloma is dependent on the concomitant administration of prednisone and that the combination regimen appears to be synergistic.

We report two cases of sea-blue histiocyte syndrome in Thai siblings. The abnormal histiocytes were found in the bone marrow and liver of both patients, but none was found in the other members of the family. Cirrhosis and absence of axillary hair were present in both patients. One patient also had elephantiasis of the legs and Klinefelter's syndrome. Our studies support an autosomal recessive inheritance.

Chronic lymphocytic leukemia and chronic granulocytic leukemia vary considerably in their clinical features, laboratory findings, and therapy, but both generally have an ominous prognosis. Chemotherapy remains the mainstay of treatment in both disorders, with adjunctive measures to control complications such as anemia and splenomegaly. Immunotherapy for granulocytic leukemia is still under study but appears promising.

Primary thrombocythemia is typically a disease of older patients and frequently is associated with thrombosis and hemorrhage. Seven female and two male patients younger than 30 years were evaluated because of platelet counts exceeding 1 million/mm3. No hemorrhagic or thrombotic problems existed before diagnosis or developed during the follow-up period of 14 months to 10 years. Platelet function studies done in six of the nine patients showed absent aggregation with epinephrine and variable aggregation with adenosine diphosphate, as are seen in other chronic myeloproliferative states. One patient had spontaneous aggregation. Secondary causes of thrombocytosis were excluded. Only one patient received specific chemotherapy, which was given before 1973. Thus, thrombocythemia without a secondary cause appears to be much more benign in the young patient than in the older, and aggressive chemotherapy to lower the platelet count is not necessarily justified unless serious complications develop.