Lenalidomide and prednisone for myelofibrosis: Eastern Cooperative Oncology Group (ECOG) phase 2 trial E4903.

A multicenter Eastern Cooperative Group (ECOG) phase 2 trial assessed whether adding prednisone to lenalidomide would improve previously reported responses in persons with myelofibrosis (MF). Forty-eight subjects with anemia (42 evaluable) received lenalidomide, 10 mg/d, with a 3-month low-dose prednisone taper. Ten subjects received 3 months, and 25 received 6 months of therapy. Myelosuppression was the main toxicity with 88% with ≥ grade 3 hematologic toxicity and 45% ≥ grade 3 nonhematologic toxicity. There were responses in 10 subjects (23%) using the International Working Group for Myelofibrosis Research and Treatment (IWG-MRT)-defined clinical improvement of anemia in 8 (19%) and/or decreased spleen size in 4 (10%). Serial bone marrow analysis showed no resolution of disease-related fibrosis or angiogenesis. With a median follow-up of 2.3 years, 23 subjects are alive. Lenali-domide and prednisone for myelofibro-sis evaluated through a multicentered-cooperative group mechanism is only modestly active and myelosuppre-sive. This study was registered at http://clinicaltrials.gov as NCT00227591.

Prognostically relevant breakdown of 123 patients with systemic mastocytosis associated with other myeloid malignancies.

The prognostic heterogeneity of the World Health Organization category of "systemic mastocytosis with associated clonal hematologic nonmast cell lineage disease" (SM-AHNMD) has not been systematically validated by primary data. Among 138 consecutive cases with SM-AHNMD, 123 (89%) had associated myeloid neoplasm: 55 (45%) myeloproliferative neoplasm (SM-MPN), 36 (29%) chronic myelomonocytic leukemia, 28 (23%) myelodysplastic syndrome (SM-MDS), and 4 (3%) acute leukemia. Of the myeloid subgroups, SM-MPN displayed a 2- to 3-fold better life expectancy (P = .003), whereas leukemic transformation was more frequent in SM-MDS (29%; P = .02). The presence of eosinophilia, although prevalent (34%), was prognostically neutral, and the overall results were not affected by exclusion of FIP1L1-PDGFRA-positive cases. We conclude that it is clinically more useful to consider specific entities, such as SM-MPN, systemic mastocytosis with chronic myelomonocytic leukemia, SM-MDS, and systemic mastocytosis with-acute leukemia, rather than their broad reference as SM-AHNMD.

Systemic mastocytosis in 342 consecutive adults: survival studies and prognostic factors.

Clinical phenotype in systemic mastocytosis (SM) is markedly variable, which complicates prognostication and decision making regarding the choice and timing of therapy. In a retrospective study of 342 consecutive adult patients with SM seen at the Mayo Clinic between 1976 and 2007, disease subdesignation according to the World Health Organization (WHO) proposal was indolent (ISM) in 159 (46%), with associated clonal hematologic non-mast cell lineage disease (SM-AHNMD) in 138 (40%), aggressive (ASM) in 41 (12%), and mast cell leukemia in 4 (1%). KITD816V was detected in bone marrow-derived DNA by allele-specific polymerase chain reaction (PCR) in 68% of 165 patients evaluated (ISM, 78%; ASM, 82%; SM-AHNMD, 60%; P = .03); JAK2V617F was detected in 4%, all in SM-AHNMD. Compared with those with nonindolent SM, life expectancy in ISM was superior and not significantly different from that of the age- and sex-matched US population. In addition, multivariable analysis identified advanced age, weight loss, anemia, thrombocytopenia, hypoalbuminemia, and excess bone marrow blasts as independent adverse prognostic factors for survival. The current study validates the prognostic relevance of the WHO subclassification of SM and provides additional information of value in terms of both risk stratification and interpretation of clinical presentation and laboratory results.

Cytoreductive therapy in 108 adults with systemic mastocytosis: Outcome analysis and response prediction during treatment with interferon-alpha, hydroxyurea, imatinib mesylate or 2-chlorodeoxyadenosine.

Cytoreductive therapy in systemic mastocytosis (SM) includes several drugs whose individual merit has not been well characterized. We retrospectively studied 108 Mayo Clinic patients who met the 2008 WHO diagnostic criteria for SM and received at least one cytoreductive drug. The numbers of patients who were evaluable for response to treatment with interferon-alpha with or without prednisone (IFN-alpha), hydroxyurea (HU), imatinib mesylate (IM) or 2-chlorodeoxyadenosine (2-CdA) were 40, 26, 22, and 22, respectively. The corresponding overall (major) response rates, according to recently published consensus criteria, were 53% (18%), 19% (0%), 18% (9%), and 55% (37%). The respective overall response rates in indolent SM, aggressive SM and SM associated with another clonal hematological nonmast cell lineage disease (SM-AHNMD) were 60%, 60%, 45% for IFN-alpha, 0, 0, 21% for HU, 14%, 50%, 9% for IM and 56%, 50%, 55% for 2-CdA. The absence of mast cell mediator release symptoms in IFN-alpha-treated patients and presence of circulating immature myeloid cells in 2-CdA-treated patients predicted inferior response. TET2 mutational status did not influence treatment response. Although the major response rates with these four cytoreductive agents were still suboptimal and HU was mainly used in patients with SM-AHNMD, the current study favors 2-CdA or IFN-alpha as first-line current therapy in SM and identifies patients who are likely to respond to such therapy.

Hematological manifestations of copper deficiency: a retrospective review.

Copper deficiency is an established cause of hematological abnormalities but is frequently misdiagnosed. Copper deficiency can present as a combination of hematological and neurological abnormalities and it may masquerade as a myelodysplastic syndrome. We reviewed the records of patients with hypocupremia and hematologic abnormalities identified between 1970 and 2005. Patients with hypocupremia unrelated to copper deficiency (e.g. Wilson's disease) were excluded. Forty patients with copper deficiency and hematological abnormalities were identified. Ten patients (25%) had undergone bariatric (weight reduction) surgery and an additional 14 patients (35%) had undergone surgery on the gastrointestinal tract, most commonly gastric resection. In 12 cases, no cause for copper deficiency was identified. Anemia and neutropenia were the most common hematologic abnormalities identified and the majority of the patients also had neurologic findings, most commonly due to myeloneuropathy. Abnormalities observed on bone marrow examination including vacuoles in myeloid precursors, iron-containing plasma cells, a decrease in granulocyte precursors and ring sideroblasts may be valuable clues to the diagnosis. Copper deficiency is an uncommon but very treatable cause of hematologic abnormalities.

Cytogenetic studies at diagnosis in polycythemia vera: clinical and JAK2V617F allele burden correlates.

The prognostic significance of cytogenetic findings at diagnosis in polycythemia vera (PV) was investigated in a retrospective series of 137 patients. Cytogenetics were normal in 117 patients (85%) and displayed a -Y abnormality in five patients (7% of male patients), and other chromosomal abnormalities in 15 patients (11%). The most frequent cytogenetic anomalies were trisomy 8 (n = 4), trisomy 9 (n = 2), deletion 20q (n = 2) and chromosomal 1 abnormalities (n = 2). Parameters that were significantly associated with abnormal cytogenetics included age > or = 60 yr (P = 0.02), but not JAK2V617F allele burden, thrombosis, hemorrhage, leukemic/fibrotic transformation, or survival. We conclude that cytogenetic anomalies occur infrequently at PV diagnosis and do not confer an adverse outcome.

20+ yr without leukemic or fibrotic transformation in essential thrombocythemia or polycythemia vera: predictors at diagnosis.

OBJECTIVES: The current study identified patients with either essential thrombocythemia (ET) or polycythemia vera (PV) who have survived for at least 20 yr without the development of either acute myeloid leukemia/myelodysplastic syndrome (AML/MDS) or myelofibrosis (MF) and compared their presenting features with those in whom these complications occurred in the first 10 yr of disease. METHODS: The study patients were selected from an institutional database of 1061 patients with either ET (n = 603) or PV (n = 458). In both instances, three distinct groups were delineated and their presenting features compared; group A included patients who have remained AML/MDS/MF free after a minimum follow-up of 20 yr; groups B and C included patients who developed either AML/MDS or MF, respectively, in the first decade of their disease. RESULTS: The respective number of patients who fulfilled the above-mentioned criteria for inclusion in groups A, B and C were 40, 12 and 8 for ET and 23, 18 and 12 for PV. In ET, compared with both groups B and C, group A displayed significantly fewer patients with less than normal hemoglobin level (P < 0.0001 and =0.02) or male sex (P = 0.005 and 0.05), respectively. On multivariable analysis, only anemia sustained its significance. A similar analysis in PV revealed an association between group B and leukocytosis using a leukocyte count threshold of either 10 or 15 x 10(9)/L (P = 0.02). CONCLUSION: The current study identifies PV patients with leukocytosis and ET patients with anemia as the most likely to undergo leukemic or fibrotic transformation.

Pruritus in polycythemia vera is associated with a lower risk of arterial thrombosis.

Among 418 patients with polycythemia vera seen at our institution and in whom pruritus history was recorded, the presence of pruritus at diagnosis was documented in 131 (31%) and its absence in 287 (69%). Pruritus was less frequently reported by smokers (12% vs. 24%; P = 0.004) and diabetics (5% vs. 11%; P = 0.04). The presence of pruritus was associated with a lower rate of arterial thrombosis, both at diagnosis (8% vs. 17%; P = 0.01) and during follow-up (16% vs. 30%; P = 0.003). Multivariable analysis revealed that these associations were independent of other risk factors for thrombosis. High JAK2V617F allele burden clustered with pruritus (P = 0.002) but did not affect thrombosis rates.

Plasmablastic cytomorphologic features in plasma cell neoplasms in immunocompetent patients are significantly associated with EBV.

Multiple myeloma (MM) is rarely associated with Epstein-Barr virus (EBV) irrespective of HIV status, in contrast with its morphologic mimic, plasmablastic lymphoma, which occurs mainly in immunocompromised patients with frequent EBV association. Among 58 consecutive immunocompetent patients, we found plasmablastic cytomorphologic features in 2 of 4 with plasmacytomas and 14 (26%) of 54 with MM. Of the tumors, 4 (7%; 1 plasmacytoma and 3 MMs) were EBV-encoded RNA (EBER)-positive with plasmablastic cytomorphologic features in 3. The patient with plasmacytoma was disease free for 75 months, and the remaining 3 patients with MM died at 15, 74, and 97 months, respectively; the median survival of patients with EBER- MM was 12 months. EBV+ tumors were associated with plasmablastic cytomorphologic features and high labeling indices. Rare EBER+ plasmablastic plasma cell tumors exist in immunocompetent patients. These tumors may have been driven by EBV to gain the plasmablastic cytomorphologic features and high proliferation fraction. A large cohort study is needed to clarify the prognostic impact of EBV on immunocompetent patients with MM.

Microcytosis in agnogenic myeloid metaplasia: prevalence and clinical correlates.

Microcytosis is a characteristic laboratory feature for both iron deficiency anemia and thalassemia. It is also infrequently seen in "anemia of chronic disease" that accompanies a spectrum of chronic conditions including rheumatoid arthritis, polymyalgia rheumatica, diabetes mellitus, connective tissue disease, and protracted infection. In addition, there is a well established but pathogenetically obscure association of microcytosis with Hodgkin's lymphoma, Castleman's disease, and renal cell carcinoma. In the current study, we show that microcytosis is a frequent laboratory feature in agnogenic myeloid metaplasia and investigate its clinical relevance in the particular setting.

B-cell chronic lymphocytic leukemia: correlation of clinical stages with angiogenic cytokine expression.

B-cell chronic lymphocytic leukemia (B-CLL) is characterized by the accumulation of non-cycling B cells in lymphatic and extralymphatic tissues. Earlier studies had validated that angiogenesis was increased in B-CLL. Increased serum concentrations of vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) connote a poor prognosis in early-stage B-CLL. Early progression is also related to transforming growth factor-beta (TGF-beta), which inhibits B-cell proliferation and immunoglobulin production. The authors investigated the expression of CD34, VEGF, bFGF, and TGF-beta and their receptors in different stages of B-CLL by analyzing bone marrow samples from 23 patients (11 with Rai stages 0-II; 12 with stages III or IV). TGF-beta2 was expressed more strongly in stages 0 to II than in stages III or IV (P=0.03). There was no significant difference in the intensity of CD34, TGF-beta1, VEGF, and bFGF and their receptors between stages 0 to II and stages III or IV. Staining showed bFGF expression to be stronger than VEGF expression (P=0.001). Results did not confirm an association between the intensity of angiogenesis and B-CLL stage. The expression of TGF-beta2 was stronger in early-stage disease and may help slow disease progression.

Nonhepatosplenic extramedullary hematopoiesis: associated diseases, pathology, clinical course, and treatment.

OBJECTIVE: To define associated clinical conditions, pathology, natural history, and treatment outcome of nonhepatosplenic extramedullary hematopoiesis (NHS-EMH). PATIENTS AND METHODS: We retrospectively reviewed the medical charts of all patients identified as having NHS-EMH from 1975 to 2002. Diagnosis was made by tissue biopsy, fine-needle aspiration biopsy, or radionuclide bone marrow scanning. RESULTS: We identified 27 patients with antemortem diagnosis of NHS-EMH. The most common associated condition and disease site were myelofibrosis with myeloid metaplasia (MMM) (in 18 patients [67%]) and the vertebral column (in 7 patients [26%]; all involving the thoracic region), respectively. At the time of diagnosis of NHS-EMH, concurrent splenic EMH (in 22 patients [82%]; 15 [56%] had undergone splenectomy) and red blood cell transfusion dependency (in 12 patients [44%]) were prevalent. Of the 27 patients, 9 (33%) required no specific therapy. Specific therapy was radiation (in 7 patients with a 71% response rate) and surgical excision (in 6 patients with a 67% response). Treatment-associated complications were limited to surgery. Radiation therapy was not used in the non-MMM group, but low-dose radiation therapy was used in the MMM group for paraspinal or intraspinal EMH (median dose, 1 Gy; range, 1-10 Gy), pleural or pulmonary disease (median dose, 1.25 Gy; range, 1.00-1.50 Gy), and abdominal or pelvic disease (median dose, 2.02 Gy; range, 150-4.50 Gy). Median survival after the diagnosis of NHS-EMH was 13 months in the MMM group and 21 months in the non-MMM group. CONCLUSIONS: This retrospective study suggests that NHS-EMH is rare, is often associated with MMM, and preferentially affects the thoracic spinal region. Asymptomatic disease may require no specific treatment, whereas symptomatic disease is best managed with low-dose radiation therapy.

2-Chlorodeoxyadenosine therapy for disseminated Langerhans cell histiocytosis.

OBJECTIVE: To evaluate the efficacy of 2-chlorodeoxyadenosine (2-CDA), a purine nucleoside analogue, in treating disseminated Langerhans cell histiocytosis (LCH). PATIENTS AND METHODS: We retrospectively reviewed the clinical records of 5 patients who were seen at our institution for histologically confirmed disseminated LCH, including 1 patient with central nervous system parenchymal involvement. These patients were treated consecutively with 2-CDA chemotherapy between December 1994 and January 2001. The patients ranged in age from 19 to 81 years, and the median pretreatment duration of disease was 23 months. Median follow-up after initiation of 2-CDA treatment was 33 months. 2-Chlorodeoxyadenosine was used as frontline therapy for 1 patient and as salvage therapy for the other patients. Patients generally received 0.7 mg/kg over 5 or 7 days; the median number of courses was 4. RESULTS: Complete responses were achieved in 3 patients, including the patient with central nervous system disease, which, to our knowledge, has not been described previously. Two other patients achieved partial responses. The overall response rate was 100%. Toxic effects consisted mainly of myelosuppression; 1 patient developed dermatomal herpes zoster infection. CONCLUSION: Our experience confirms the reported efficacy of 2-CDA in the treatment of LCH; however, the optimal timing and schedule of therapy remain to be determined.

Systemic mast cell disease without associated hematologic disorder: a combined retrospective and prospective study.

OBJECTIVE: To study clinicopathologic correlations and identify prognostically important variables in patients with systemic mast cell disease (SMCD) who have no associated hematologic disorders. PATIENTS AND METHODS: We identified 40 adult patients with SMCD without associated hematologic disorders. Clinical, laboratory, and bone marrow (BM) histologic findings at the time of referral were evaluated (November 1980-February 2001) for possible correlations with a history of aggressive systemic mastocytosis (retrospectively analyzed) as well as survival (prospectively analyzed). RESULTS: The median follow-up time from diagnosis was 108 months and from BM examination was 24 months. A history of aggressive systemic mastocytosis correlated significantly with increased BM mast cell (MC) content, unfavorable MC infiltration pattern, BM eosinophilia, and elevated serum alkaline phosphatase (SAP) level, but not with BM angiogenesis, reticulin fibrosis, or levels of MC mediators. Of these factors, increased BM MC content and elevated SAP level were also associated with shortened survival from time of referral. CONCLUSIONS: This study suggests that the BM MC burden, BM eosinophilia, and SAP level are prognostically important in SMCD without associated hematologic disorders. In contrast, BM angiogenesis, reticulin fibrosis, and levels of MC mediators showed no prognostic relevance.

Bone marrow immunohistochemical studies of angiogenic cytokines and their receptors in myelofibrosis with myeloid metaplasia.

Bone marrow specimens from 11 patients with myelofibrosis with myeloid metaplasia (MMM) and seven normal controls were studied immunohistochemically to determine expression of transforming growth factor beta (TGF-beta), platelet-derived growth factor (PDGF), vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF) and corresponding receptors. Staining distribution and intensity for TGF-beta, PDGF, VEGF, TGF-beta type II receptor, a receptor for PDGF, and receptors for VEGF and bFGF were similar in patients and controls. Bone marrow from 10 MMM patients showed increased TGF-beta type I receptor (TGF-betaRI) expression in small vessel endothelial cells. Eight patient specimens had bFGF overexpression in megakaryocytes. Increased microvessel density and decreased concentration of bFGF-staining stromal cells accompanied these changes. Microvascular TGF-betaRI upregulation and bFGF overexpression by megakaryocytes may cause bone marrow microenvironmental changes in MMM patients.

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.

Eosinophils are derived from the neoplastic clone in patients with systemic mastocytosis and eosinophilia.

Twenty to thirty-three percent of systemic mast cell disease (SMCD) patients have some degree of peripheral blood and/or bone marrow eosinophilia. While the clonality of SMCD was established by identification of the pathogenic c-kit Asp816 to Val (D816V) mutation in sorted cells of different hematopoietic lineages, this mutation has not previously been demonstrated in eosinophils from SMCD patients. In the current study, we demonstrate the D816V mutation in purified eosinophils from two patients with aggressive, eosinophilia-associated SMCD, thus proving that the eosinophils are clonal and not reactive in nature. The clinical implications of this finding are discussed.

Immunohistochemical studies of c-kit, transforming growth factor-beta, and basic fibroblast growth factor in mast cell disease.

In 58 patients with mast cell disease (MCD) and three with basophilic leukemia, bone marrow (54 cases) or skin tissue (four cases) was studied immunohistochemically for expression of Kit (c-kit protein), the different isomers of transforming growth factor-beta (TGF-beta), basic fibroblast growth factor (bFGF), and their respective receptors. Kit was expressed in all cases of MCD but in none of basophilic leukemia. Expression pattern of cytokines and their receptors was variable in systemic MCD with (SMCD-HD) or without (SMCD) associated hematologic disorder. However, type I TGF-beta receptor (TGFbeta1R) was not expressed in 30% of SMCD-HD patients or in patients with mast cell leukemia, but the remaining cases of MCD showed near uniform expression. The associated hematologic disorders in TGFbeta1R-negative cases of SMCD-HD were prognostically less favorable than those associated with TGFbeta1R-positive cases of SMCD-HD. The results confirm the diagnostic value of Kit immunohistochemistry in MCD and suggest a biologically relevant heterogeneity in TGFbeta1R expression among patients with SMCD-HD.

Bone marrow biopsies for the diagnosis of systemic mastocytosis: is one biopsy sufficient?

The medical records of 21 patients evaluated for mastocytosis and 2 patients seen for follow-up of known mastocytosis who underwent bilateral iliac crest aspirations and biopsies were reviewed retrospectively to determine whether mastocytosis could be confirmed in each of a patient's biopsy specimens. In 19 cases (83%), each biopsy specimen showed evidence of mastocytosis; however in 4 cases (17%), only 1 of 2 biopsy sites revealed mastocytosis. Compared with the 4 patients with only a unilateral positive biopsy result, the bilateral group had significantly higher urinary excretion of 11beta-prostaglandin F2alpha, higher serum tryptase levels, and higher serum calcitonin values, and a higher percentage had splenomegaly (37% [7/19] vs 0% [0/4]). The 2 groups could not be distinguished by the main initial symptom(s), presence of urticaria pigmentosa, or other laboratory findings (alkaline phosphatase, aspartate transaminase, or hemoglobin concentrations or total WBC, total eosinophil, or platelet counts). Bilateral biopsies might be useful for diagnosing early systemic mastocytosis or detecting minimal bone marrow involvement.