Splenic histopathological patterns in chronic myelomonocytic leukemia with clinical correlations: reinforcement of the heterogeneity of the syndrome

The syndrome of chronic myelomonocytic leukemia (CMML) includes a heterogeneous group of patients who exhibit both myelodysplastic and myeloproliferative clinicopathological features. Troublesome splenomegaly is uncommon in myelodysplastic syndrome (MDS), but when organomegaly occurs, this complication is more likely to be associated with myelodysplastic-myeloproliferative overlap syndromes such as CMML rather than "dysplasia-only" MDS types such as refractory anemia. We report a single-institution experience with splenectomy in CMML patients, including a detailed review of splenic histopathology. Twelve patients with CMML underwent splenectomy at the Mayo Clinic, primarily because of refractory thrombocytopenia and/or mechanical complications related to splenomegaly. Three of the 12 patients (25%) died as a direct result of surgery, and significant postoperative morbidity was seen in another 4 patients (33%). Thrombocytopenia improved in 4 of the 11 patients (36%) with low platelet counts before surgery. Three of the four responders had an abundance of CD68 (PGM1)-positive foamy histiocytes in the marginal zone surrounding the splenic white pulp-a pattern which can be seen in immune thrombocytopenia-and two of these three patients had thrombocytopenia out of proportion to the degree of anemia pre-operatively, suggestive of peripheral destruction of platelets. More consistent splenic pathological findings in the 12 patients included trilineage extramedullary hematopoiesis in splenic red pulp and expansion of splenic cords by a myelomonocytic infiltrate. This study underscores both the uniformity and diversity of splenic findings in CMML, highlights the potential dangers and benefits of splenectomy in this group, and suggests peripheral destruction of platelets as a mechanism contributing to thrombocytopenia in a subset of CMML patients.     

The forgotten myeloproliferative disorder: myeloid metaplasia

Myelofibrosis with myeloid metaplasia is a hematologic disorder currently classified with polycythemia vera and essential thrombocythemia as a chronic myeloproliferative disease. The median age at diagnosis is 60 years, and more than 90% of patients are diagnosed after age 40 years. Clinical manifestations include massive splenomegaly, progressive anemia, profound constitutional symptoms, and extramedullary hematopoiesis. The diagnosis is confirmed by bone marrow examination after other causes of myelofibrosis are ruled out. Median survival is 5 years and causes of death include leukemic transformation. Prognosis is adversely affected by the presence of anemia (hemoglobin <10 g/dl), leukopenia or leukocytosis (white blood cells >30,000/ micro l), circulating blasts, and hypercatabolic symptoms. Conventional treatment is palliative and does not improve survival. In this regard, androgen preparations, corticosteroids, and erythropoietin are useful for the treatment of disease-associated anemia. Symptomatic splenomegaly is best managed by cytoreductive therapy or surgical removal. Radiation therapy is most useful in the treatment of nonhepatosplenic extramedullary hematopoiesis. New treatment approaches include the use of thalidomide alone or in combination with prednisone and hematopoietic stem cell transplantation.     

Factors that influence platelet recovery after transfusion: resolving donor quality from ABO compatibility

BACKGROUND: A system was established to examine the extent to which the apheresis donor determines platelet recovery after transfusion, to measure the impact of ABO identity, and to predict outcome by evaluating the donor. STUDY DESIGN AND METHODS: The percentage of platelet recovery was measured after prophylactic transfusion of apheresis units divided from single donors to paired recipients with uncomplicated thrombocytopenia secondary to leukemia chemotherapy. Platelet microaggregation induced by citrate was measured at the time of apheresis. RESULTS: Platelet recoveries in paired recipients correlated strongly when both transfusions were ABO- identical. When one recipient was ABO-identical and the other was ABO-nonidentical, nonidentical transfusions yielded one-third the recovery of ABO-identical transfusions. In ABO-identical transfusions, platelet recovery in donors having microaggregates in the before-apheresis ACD sample was one-third that in donors without microaggregates. This difference was observed at 1 and 24 hours. Expression of P-selectin in the apheresis units at the time of transfusion correlated well with ACD microaggregates in the before-apheresis sample. CONCLUSION: When transfusions of platelets are ABO-identical, donor quality dominates recovery in circulation. Donor quality is predicted by a rapid and simple assay of citrate-induced microaggregation performed at the time of apheresis. When donor quality is factored out, ABO identity prevails.     

Treatment options for hydroxyurea‐refractory disease complications in myeloproliferative neoplasms: JAK2 inhibitors,radiotherapy, splenectomy and transjugular intrahepatic portosystemic shunt

Clinical care of patients with polycythemia vera, essential thrombocythemia and myelofibrosis (MF) requires not only a broad understanding of general treatment principles but also familiarity with the management of hydroxyurea‐refractory disease complications. The latter include progressive splenomegaly, symptomatic portal hypertension (e.g. ascites, variceal bleeding), pulmonary hypertension, bone pain, intractable pruritus, constitutional symptoms (e.g. fatigue, night sweats) and cachexia (i.e. loss of lean body mass, general ill health, poor appetite). Some of these symptoms are directly or indirectly related to extramedullary hematopoiesis (EMH) and others to proinflammatory cytokine excess. Results from recent clinical trials of JAK inhibitors suggest remarkable activity in MF‐associated constitutional symptoms, cachexia, pruritus and hydroxyurea‐refractory splenomegaly. Involved‐field radiotherapy is best utilized in the setting of EMH‐associated symptoms, including ascites, bone (extremity) pain and pulmonary hypertension. Splenectomy is indicated in the presence of drug‐refractory splenomegaly and frequent red cell transfusion requirement. Transjugular intrahepatic portosystemic shunt is used to alleviate symptoms of portal hypertension.     

Phase II study of dasatinib in Philadelphia chromosome-negative acute and chronic myeloid diseases, including systemic mastocytosis

PURPOSE: Molecular characterization of Philadelphia chromosome-negative (Ph-) chronic myeloproliferative disorders, such as systemic mastocytosis (SM), has provided a clear rationale for investigating novel targeted therapies. The tyrosine kinase (TK) inhibitor dasatinib is 325-fold more potent against Bcr-Abl TK than imatinib in vitro, significantly inhibiting wild-type KIT and platelet-derived growth factor receptor beta TKs, and is active against cells carrying the mutant KIT-D816V gene. EXPERIMENTAL DESIGN: In this phase 2, open-label study, the efficacy of dasatinib (140 mg/d) was investigated in 67 patients with various Ph- myeloid disorders, including SM (n = 33; 28 KIT-D816V positive). RESULTS: The overall response rate to dasatinib in patients with SM was 33%. Only two patients, one with SM-myelofibrosis and one with SM-chronic eosinophilic leukemia, achieved complete response (elimination of mastocytosis) lasting for 5 and 16 months, respectively. Both patients were negative for KIT-D816V mutation, had low tryptase levels, abnormal WBC counts, and anemia, and had failed prior therapy with erythropoietin. Additional nine SM patients had symptomatic response, lasting 3 to 18+ months. Complete responses were achieved in two other patients (acute myeloid leukemia and hypereosinophilic syndrome). No responses were observed among patients with myelodysplastic syndromes and primary myelofibrosis. The majority of adverse events were grade 1/2. CONCLUSION: These data show that dasatinib therapy may benefit a selected group of SM patients, primarily by improving their symptoms, but it does not eliminate the disease in the patients with KIT-D816V mutation.     

Intensive care unit support and Acute Physiology and Chronic Health Evaluation III performance in hematopoietic stem cell transplant recipients

OBJECTIVE: Hematopoietic stem cell transplant (HSCT) recipients admitted to the intensive care unit (ICU) have high mortality. The prognostic importance of peripheral blood stem cell source in critically ill HSCT recipients and the performance of Acute Physiology and Chronic Health Evaluation (APACHE) III have not been well studied. In a previous study, the hospital mortality rate of HSCT recipients admitted to our ICU was 77%. The objectives of this study were to describe the clinical course of HSCT recipients admitted to the ICU and to determine the performance of APACHE III in predicting their mortality. DESIGN: Retrospective cohort study. SETTING: Academic medical center. PATIENTS: HSCT recipients admitted to the ICU. MEASUREMENTS: Demographics, transplant type, stem cell source, APACHE II and III predicted mortality, development of sepsis and organ failure, use of mechanical ventilation, duration of hospital stay, and mortality. RESULTS: Ninety-four percent of the 112 HSCT recipients were white and 64% male. The mean APACHE II and III scores were 25 and 44, respectively. The APACHE II and III hospital predicted mortality rates were 44% and 42%, respectively. Mechanical ventilation was provided to 63%. Organ failure developed in 94% and sepsis in 62%. The ICU, hospital, and 30-day mortality rates were 33%, 46%, and 52%, respectively. Allogeneic transplant and higher APACHE III scores, but not bone marrow stem cell source, were associated with increased mortality. Invasive mechanical ventilation, vasoactive medication use, sepsis, and organ failure during patients' ICU course were also associated with increased mortality. The area under the receiver operating characteristic curve for APACHE III hospital mortality prediction was 0.704 (95% confidence interval, 0.610-0.786). For APACHE III hospital mortality prediction, the value of the Hosmer-Lemeshow statistic showed good model fit. CONCLUSIONS: Current mortality figures of HSCT recipients admitted to the ICU are better than previously reported. The APACHE III prognostic model has moderate discrimination and good calibration in predicting hospital mortality in these patients.     

How to interpret and pursue an abnormal prothrombin time, activated partial thromboplastin time, and bleeding time in adults

The prothrombin time (PT) and activated partial thromboplastin time (APTT) are among the most commonly ordered coagulation tests. In 2005, more than 140,000 PT and more than 95,000 APTT tests were performed at Mayo Clinic. The most common indications for ordering these tests include anticoagulant monitoring, initial evaluation of hemorrhage, and, although not generally indicated, routine preoperative screening. In addition, the bleeding time (BT) test, which is infrequently performed, is still available in certain institutions. Abnormal results from these tests (prolonged PT, APTT, and BT), especially from tests conducted for initial evaluation of hemorrhage or for preoperative screening, may pose a diagnostic dilemma to the nonhematologist. We review the essential factors affecting test results; provide a practical approach to the evaluation of a prolonged PT, APTT, and BT; and offer suggestions on which reflexive tests are appropriate and when to consider a subspecialty consultation.     

Durable responses to thalidomide-based drug therapy for myelofibrosis with myeloid metaplasia

OBJECTIVE: To present the results of a long-term analysis of 2 sequential phase 2 trials of thalidomide (alone or in combination) for palliation of myelofibrosis with myeloid metaplasia (MMM). PATIENTS AND METHODS: We analyzed (March 1999 to August 2003) initial and long-term outcomes from 36 patients with symptomatic MMM who had enrolled in either our thalidomide single-agent trial (n=15) or our trial of low-dose thalidomide (50 mg/d) combined with prednisone (n=21). RESULTS: Among the 36 study patients, 20 (56%) showed some improvement in their clinical course. Response rates for specific end points included improvements in anemia (15 of 36 [42%]), thrombocytopenia (10 of 13 [77%]), or splenomegaly (5 of 30 [17%]). The combination of low-dose thalidomide and prednisone, as opposed to single-agent thalidomide, was better tolerated and more efficacious. After a median follow-up of 25 months (range, 20-56 months), 10 of 36 patients (28%) showed an ongoing response, including 8 patients in whom protocol treatment has been discontinued for a median of 21 months (range, 16-31 months). Durable treatment responses were documented for only anemia and thrombocytopenia. Treatment response was not affected by the baseline status of bone marrow fibrosis, angiogenesis, osteosclerosis, cytogenetics, or circulating myeloid progenitor (CD34) cell count. Unusual drug effects, all reversible, included leukocytosis (8 patients) and/or thrombocytosis (6 patients). CONCLUSIONS: Thalidomide (alone or combined with prednisone) is an effective first-line treatment of symptomatic anemia or thrombocytopenia in MMM. Thalidomide-based therapy has the potential to produce durable responses in MMM-associated cytopenias, even after discontinuation of the drug.