Lawrence A. Solberg

Proposed criteria for the diagnosis of post-polycythemia vera and post-essential thrombocythemia myelofibrosis: a consensus statement from the international working group for myelofibrosis research and treatment

Proposed criteria for the diagnosis of post-polycythemia vera and post-essential thrombocythemia myelofibrosis: a consensus statement from the international working group for myelofibrosis research and treatment

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.

The ASH Choosing Wisely® Campaign: five hematologic tests and treatments to question

Choosing Wisely® is a medical stewardship and quality improvement initiative led by the American Board of Internal Medicine Foundation in collaboration with leading medical societies in the United States. The ASH is an active participant in the Choosing Wisely® project. Using an iterative process and an evidence-based method, ASH has identified 5 tests and treatments that in some circumstances are not well supported by evidence and which in certain cases involve a risk of adverse events and financial costs with low likelihood of benefit. The ASH Choosing Wisely® recommendations focus on avoiding liberal RBC transfusion, avoiding thrombophilia testing in adults in the setting of transient major thrombosis risk factors, avoiding inferior vena cava filter usage except in specified circumstances, avoiding the use of plasma or prothrombin complex concentrate in the nonemergent reversal of vitamin K antagonists, and limiting routine computed tomography surveillance after curative-intent treatment of non-Hodgkin lymphoma. We recommend that clinicians carefully consider anticipated benefits of the identified tests and treatments before performing them.

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.

Acute leukemia with abnormal thrombopoiesis and inversions of chromosome 3.

Abnormal thrombopoiesis has been described in acute leukemias associated with inv(3) (q21q26.2) or t(3;3)(q21;q26.2). We reviewed 13 patients seen at the Mayo Clinic since 1979 with inversions of chromosome 3 or related abnormalities; 12 acquired and one constitutional. The patient with the constitutional abnormality had an inv(3)(p21q29) and mild leukocytosis and thrombocytosis. Among the 12 patients with acquired abnormalities, five had inv(3) (q21q26.2), three had t(3;3)(q21;q26.2), one had del(3)(q12q21), one had ins(6;3) (p21;q21q26.2), one had inv(3)(p21q12), and one had r(3)(p?21q?21). Each of these patients developed acute leukemia; eight had antecedent myelodysplastic syndrome, eight presented with platelet counts greater than 100 x 10(3)/microliters, and six had atypical megakaryocytic hyperplasia. Five patients had ringed sideroblasts in their marrow, an antecedent refractory anemia with ringed sideroblasts, or erythroleukemia. Seven patients received chemotherapy but showed no response. From the time of chromosome study, the median duration of survival was 4 months. Our results suggest that 1) although abnormal megakaryocytopoiesis is observed in patients with inv(3)(q21q26.2), multiple hematopoietic lineages are also involved in the neoplastic process; 2) an antecedent myelodysplastic syndrome is common in acute leukemia with inv(3) or related abnormalities; 3) affected patients have a poor survival and are resistant to conventional chemotherapy; and 4) abnormal megakaryocytopoiesis in acute leukemia may also be associated with pericentric inversions of chromosome 3.

Acute Megakaryocytic Leukemia (M7) in Children

We analyzed the clinical and laboratory features of eight children (median age, 20 months; range, 13 months to 11 years) with acute megakaryocytic leukemia (M7) and compared the findings with those reported in the literature. The diagnosis was supported by ultrastructural examination for platelet peroxidase or immunophenotyping for glycoprotein IIb/IIIa or the von Willebrand factor protein. Two patients had Downs syndrome. Initial findings included anemia (in all patients), thrombocytopenia (in six), myelofibrosis (in three), lytic bone lesions (in two), and pronounced leukocytosis (in one). Stem cell culture studies of peripheral blood specimens revealed an aberrant phenotype of the megakaryocytes in one patient and reversal to a normal pattern after successful therapy. Remission was achieved in seven of the eight patients after aggressive chemotherapy, and four patients remained in remission 27 to 57 months after diagnosis. Three of these four patients underwent allogeneic bone marrow transplantation. M7 leukemia is not infrequent in children younger than 3 years of age, especially in those with Downs syndrome. The availability of monoclonal antibodies specific to restricted antigens of the megakaryocytic lineage has made the diagnosis of M7 leukemia both possible and practical.

The ASH Choosing Wisely®campaign: five hematologic tests and treatments to question

Choosing Wisely® is a medical stewardship and quality improvement initiative led by the American Board of Internal Medicine Foundation in collaboration with leading medical societies in the United States. The ASH is an active participant in the Choosing Wisely® project. Using an iterative process and an evidence-based method, ASH has identified 5 tests and treatments that in some circumstances are not well supported by evidence and which in certain cases involve a risk of adverse events and financial costs with low likelihood of benefit. The ASH Choosing Wisely® recommendations focus on avoiding liberal RBC transfusion, avoiding thrombophilia testing in adults in the setting of transient major thrombosis risk factors, avoiding inferior vena cava filter usage except in specified circumstances, avoiding the use of plasma or prothrombin complex concentrate in the nonemergent reversal of vitamin K antagonists, and limiting routine computed tomography surveillance after curative-intent treatment of non-Hodgkin lymphoma. We recommend that clinicians carefully consider anticipated benefits of the identified tests and treatments before performing them.

Prognostic significance of computed tomography of the brain in thrombotic thrombocytopenic purpura

We studied the prognostic value of computed tomography (CT) of the brain for neurologic morbidity in patients with thrombotic thrombocytopenic purpura. On review of Mayo Clinic records for 1975 through 1985, we found 32 patients with thrombotic thrombocytopenic purpura, 20 of whom had undergone CT of the brain during their hospitalization. Despite major neurologic symptoms and signs, normal CT findings were associated with complete neurologic recovery. Seventy percent of patients with normal results of CT of the brain recovered and had no neurologic deficits, whereas 80% of patients with CT abnormalities died or had permanent neurologic sequelae. A review of the literature supports these conclusions. Thus, we suggest that CT of the brain be done in any patient with thrombotic thrombocytopenic purpura and neurologic deficits. Regardless of the severity of neurologic involvement, normal CT findings should encourage continued vigorous treatment of the patient because a normal scan supports the possibility of full clinical recovery.

Veno-occlusive Disease of the Liver after Blood and Marrow Transplantation: Analysis of Pre- and Post-transplant Risk Factors Associated with Severity and Results of Therapy with Tissue Plasminogen Activator

We reviewed our blood and marrow transplantation (BMT) database from April 1982 to July 1996 and identified 111 of 474 patients with serum bilirubin concentration (SBR) ≥ 34 µ mol/l for two consecutive days within the first 20 days after related allogeneic or autologous BMT. Of the 111, 73 fulfilled the Seattle criteria for veno-occlusive disease of the liver (VOD) and had no other obvious cause for liver dysfunction. The patients were 16-60 years old (median, 39 years), and 41 were male (56%). Fourteen patients (19%) had autologous BMT, and 59 (81%) had allogeneic BMT. Twenty-eight (38%), 12 (16%), and 33 (45%) patients had severe, moderate, and mild VOD, respectively, by Seattle criteria. None of 23 patients with maximum (max) SBR ≥ 257 µ mol/l survived, all patients with max SBR ≤ 128 µ mol/l survived, and 7 of 15 patients (47%) with max SBR 128-257 µ mol/l survived. The only pre-transplantation risk factor predictive of severe VOD was advanced disease state (P =0.035), and the only transplant factors that predicted severe VOD were max SBR (P =0.01) and maximum blood urea level (P =0.03). Ten patients (all with creatinine levels ≥ 150 µ mol/l) were treated with tissue plasminogen activator; only two had a significant response and only one survived beyond day 120.

Refractory and Relapsing Multiple Myeloma Treated by Blood Stem Cell Transplantation

Between June 1989 and June 1992, 12 patients with advanced multiple myeloma underwent peripheral blood stem cell autotransplantation after high-dose chemotherapy and radiotherapy. The conditioning regimen included melphalan (140 mg/m2), high-dose cyclophosphamide (120 mg/kg), methylprednisolone (2 g daily x 7), and total body irradiation (9-12 Gy). Transplant morbidity included severe mucositis (n = 7) and acute renal failure (n = 2) related to infusion of the stem cells. Engraftment was delayed (n = 4) in this heavily pretreated population, and two patients had complete graft failure. Despite the advanced nature and chemotherapy-refractory state of their disease, 11 of 11 evaluable patients achieved an objective response. Six patients survived to leave the hospital, and four remain alive--one died of acute leukemia induced by prior melphalan exposure. Three of the four are relapse-free at a median of 24.9 months (range, 18-28 months). Some patients with advanced refractory multiple myeloma can achieve objective responses from highdose chemoradiotherapy with peripheral blood stem cell rescue. Harvesting peripheral blood stem cells from high-risk patients early in their disease for later use may decrease the risk of graft failure. Peripheral blood stem cell transplantation after high-dose chemotherapy and total body irradiation can produce durable responses in patients with advanced refractory myeloma.