Kelty R. Baker

Donor cell leukemia : Report of a case occurring 11 years after allogeneic bone marrow transplantation and review of the literature

We report the case of a man with chronic myelocytic leukemia (CML) and a 46,XY,t(5;9;22) karyotype who developed acute myelocytic leukemia (AML) with a 45,X,t(8;21) karyotype 11 years after bone marrow transplantation (BMT) from his HLA‐matched sister. Fluorescent in situ hybridization (FISH) studies and molecular analysis using short tandem repeat (STR) sequences proved the new leukemia to be of donor cell origin. Donor cell leukemia (DCL) after BMT is rare. Our review of the literature found 15 cases following BMT for leukemia and 2 cases after BMT for benign hematological disorders. In fewer than half the reported cases were molecular studies available to confirm the cytogenetic evidence for DCL, and the longest previously reported interval between BMT and DCL was 6 years. Am. J. Hematol. 63:46–53, 2000.

Responses to human CD40 ligand/human interleukin-2 autologous cell vaccine in patients with B-cell chronic lymphocytic leukemia.

Purpose: Human CD40 ligand activates the malignant B-cell chronic lymphocytic leukemia cells and enhances their capacity to present tumor antigens. Human interleukin-2 further potentiates the immunogenicity of human CD40 ligand in preclinical murine models. Experimental Design: We prepared autologous B-cell chronic lymphocytic leukemia cells that expressed both human CD40 ligand (>90% positive) and human interleukin-2 (median secretion, 1,822 pg/mL/106 cells; range, 174-3,604 pg). Nine patients were enrolled in a phase I trial, receiving three to eight s.c. vaccinations. Results: Vaccinations were administered without evidence of significant local or systemic toxicity. A B-cell chronic lymphocytic leukemia–specific T-cell response was detected in seven patients. The mean frequencies of IFN-γ, granzyme-B, and IL-5 spot-forming cells were 1/1,230, 1/1,450, and 1/4,500, respectively, representing a 43- to 164-fold increase over the frequency before vaccine administration. Three patients produced leukemia-specific immunoglobulins. Three patients had >50% reduction in the size of affected lymph nodes. Nonetheless, the antitumor immune responses were observed only transiently once immunization ceased. High levels of circulating CD4+/CD25+/LAG-3+/FoxP-3+ immunoregulatory T cells were present before, during and after treatment and in vitro removal of these cells increased the antileukemic T-cell reactivity. Conclusions: These results suggest that immune responses to B-cell chronic lymphocytic leukemia can be obtained with human CD40 ligand/human interleukin-2–expressing s.c. vaccines but that these responses are transient. High levels of circulating regulatory T cells are present, and it will be of interest to see if their removal in vivo augments and prolongs the antitumor immune response.

Partial characterization of a unique mitogenic activity secreted by rat Sertoli cells.

Sertoli cell conditioned medium (SCCM) contains a potent mitogen, Sertoli cell secreted growth factor (SCSGF). A431 cells, derived from a human epidermoid carcinoma have provided an excellent model cell line for the study of this apparently unique activity secreted by rat Sertoli cells in vitro. Previously, it was shown that SCCM contained an epidermal growth factor (EGF)-like activity which was thought to be the mitogen for A431 cells. The present study showed that these two factors are distinct entities. The secretion of the EGF-like activity decreased with increasing number of culture days, while that of SCSGF and of another Sertoli cell specific protein, transferrin remained constant. The addition of SCCM stimulated whereas 2.5 ng/ml EGF inhibited the A431 cell growth. The proliferative response of A431 cells to a wide variety of growth factors and known Sertoli cell secretions was investigated. SCSGF was the only growth factor of known Sertoli cell secretions tested (transforming growth factors (TGF alpha, TGF beta), EGF, bombesin, fibroblast growth factor (FGF), platelet derived growth factor (PDGF), insulin-like growth factors 1 and 2 (IGF-1 and IGF-2), prostaglandins E-1 and E-2, insulin, transferrin and lactate) which stimulated A431 cell proliferation. SCSGF was mitogenic for A431 cells even in the presence of serum in the culture medium. The partially purified SCSGF was heat- and acid-stable, protease-sensitive with a molecular weight of 14,000. It did not bind to heparin or concanavalin A-Sepharose. The secretion of a mitogenic activity by the Sertoli cell which is different from other previously identified growth factors and which coincides with active spermatogenesis could have important implications in the regulation of spermatogenesis.

Current management of the myeloproliferative disorders: a case-based review.

CONTEXT Properly managed, the myeloproliferative disorders are generally compatible with prolonged survival. Challenges to the hematologist include knowing when and how best to intervene to prevent and manage complications. The cytoreductive agent of choice for these disorders is currently hydroxyurea, emerging from randomized trials beginning with those of the Polycythemia Vera Study Group. OBJECTIVE To examine the roles and shortcomings of interventions (including hydroxyurea, antiplatelet agents, anagrelide, interferon, thalidomide, alkylating agents, cell cytopheresis, erythropoietins, splenectomy, bone marrow transplantation, and imatinib) for myeloproliferative disorders. DATA SOURCES This report uses actual case histories to illustrate the roles and shortcomings of these interventions. CONCLUSIONS Beyond phlebotomy for polycythemia vera, patients with polycythemia vera and essential thrombocythemia can be stratified by their risk for thrombosis, which guides the institution of cytoreductive therapies. High-risk patients generally benefit from cytoreductive therapy, and hydroxyurea has emerged as the agent of choice, because alkylating agents (and P32) have high leukemogenic potentials. Anagrelide and interferon are second-line agents. The addition of low-dose aspirin is beneficial for most, helping to prevent arterial thrombotic complications. Therapy in any of these disorders should be tailored to the unique characteristics of the individual patient. With myelofibrosis, therapeutic options run the gamut from observation, erythropoietic stimulators, cytotoxic agents, splenectomy, and bone marrow transplantation. Thalidomide and imatinib have shown some utility. Future challenges are the refinement of individualized treatment strategies and the development of targeted therapies based on rapidly expanding understanding of the molecular perturbations in these disorders.

Fatal Paraneoplastic Systemic Leukocytoclastic Vasculitis as a Presenting Feature of Chronic Lymphocytic Leukemia

BACKGROUND The most common paraneoplastic vasculitis is leukocytoclastic vasculitis (LCV),(1) 75% of which are caused by hematological malignancies. Chronic lymphocytic leukemia (CLL) is associated with a multitude of auto-immune paraneoplastic syndromes. Data on LCV in association with CLL is restricted to isolated case reports,(3,4) none of which had systemic LCV. We present a unique case of fatal paraneoplastic, systemic LCV as an initial presentation of CLL in an elderly male with multiple co-morbidities. CASE A 71-year-old man presented with a palpable, symmetric, purpuric rash on the lower extremities and an absolute lymphocytosis (white blood cell count 26.9; 23% lymphocytes). His co-morbidities included coronary artery disease, congestive heart failure, and new critical aortic stenosis. Flow cytometry of peripheral blood demonstrated an abnormal population of B-cells, positive for CD5, CD19, and CD23, consistent with CLL. The skin biopsy specimen revealed neutrophilic inflammation in vessel walls indicative of LCV. Acute renal failure (creatinine 2 mg/dL), urinary red cell casts, and hypocomplementemia were concerning for a systemic vasculitis. The antinuclear antibody, cryoglobulin titer, antineutrophil cytoplasmic antibody, serum protein electrophoresis, viral serologies were negative. On hospital day 6, he developed acute hepatocellular injury and acute respiratory failure. Continuous veno-venous hemodialysis was begun for worsening acidemia and hyperkalemia. Two days later he became obtunded on hospital day 8 and had an elevated lactic acid level with generalized abdominal tenderness worrisome for bowel ischemia. The same day he needed intubation with cardiopulmonary resuscitation for a brief episode of asystole. Despite aggressive treatment with high-dose steroids and plasmapheresis, he suffered worsening renal failure and shock. His family sought withdrawal of care on hospital day 11. Autopsy revealed diffuse LCV of the stomach, distal ileum, integument and alveoli with petechial hemorrhages, fibrin thrombi, and gangrenous patchy necrosis. CONCLUSION Paraneoplastic LCV is a rare syndrome and seldom occurs in association with CLL. This is the first reported case of fatal systemic paraneoplastic LCV from B-cell CLL. Dermatologic involvement is universal with LCV, and may portend systemic disease. More data on its pathogenesis in CLL is warranted.

Laparoscopic splenectomy for chronic recurrent thrombotic thrombocytopenic purpura

&NA; Thrombotic thrombocytopenic purpura (TTP) is a serious hematologic disorder with a high rate of morbidity and mortality when it fails to go into remission. The primary treatment is total plasma exchange. The addition of corticosteroids, chemotherapeutic agents, or antiplatelet agents is of unproven benefit, and splenectomy has been offered as salvage therapy in refractory cases. We performed laparoscopic splenectomy (LS) on two patients with chronic refractory TTP. The early and late postoperative courses, including hematologic data, are presented here. The mean duration of surgery was 113 minutes and the mean estimated blood loss was 35 mL. Mean hospital stay was 1.5 days. The early postoperative platelet count showed an immediate rise in both patients. After 19 months and 16 months of follow‐up, respectively, both patients remain in remission without further episodes of TTP. Laparoscopic splenectomy is a safe and effective therapy for patients with chronic relapsing and refractory TTP. The inherent benefits of the minimally invasive approach, its low morbidity, short hospital stay, and faster recovery, are significant advantages for these patients.

Overt leukemic phase: an unusual presentation of angioimmunoblastic lymphoma

Peripheral blood dissemination has been described in various types of B- and T-cell non-Hodgkin lymphomas. The likelihood of leukemic dissemination differs according to the type of lymphoma. In some cases, a leukemic phase may be the only presentation of the underlying lymphoma and hence careful examination of the peripheral blood smear may suggest a clue to the underlying disease process. However, leukemic dissemination is usually not a feature of angioimmunoblastic T-cell lymphoma (AITL). We describe a case of a 64-year-old woman who presented to our hospital with overt peripheral blood involvement by AITL.

Quantitative Flow Cytometry Immunophenotypic Data in Myelodysplastic Syndromes (MDS)

Background: Recent studies using qualitative analysis of flow cytometry data have demonstrated various im- munophenotypic abnormalities associated with myelodysplastic syndromes (MDS). However, there are limited reports as- sessing the ability of quantitative immunophenotypic analysis to discriminate MDS from other cytopenic conditions. Design: Using flow cytometry, we studied 37 bone marrow specimens from 23 patients with MDS and 14 cytopenic pa- tients with non-clonal hematologic disorders. Samples were analyzed quantitatively for percentages of T-cells, B-cells, NK cells, granulocytes, monocytes, blasts, erythroid precursors, and plasma cells; CD4:CD8 ratio; % granulocyte subsets; % CD56+ monocytes; and % erythroid precursor subsets. Results: Quantitative analysis of immunophenotypic data in MDS patients compared to controls showed decreases in total granulocytes (p=0.037) and more mature subsets of CD11b + CD16 bright granulocytes (p=0.0046) and CD10 + granulocytes (p=0.022). MDS patients also showed a trending increase in subset percentage of CD56+monocytes (p=0.056). Using re- ceiver operating characteristic (ROC) analysis, cut-off values for these parameters favoring a diagnosis of MDS were identified as follows: total granulocytes 10%. Subsequently, a scoring system was proposed whereby a score of one was assigned for the presence of each quantitative abnormality. Using this system on the original study population, the pres- ence of at least two abnormalities (score 2) revealed optimal sensitivity (69.6%) and specificity (71.4%) for a diagnosis of MDS. Conclusion: These findings suggest that quantitative analysis of immunophenotypic data can be complementary to quali- tative interpretation. These data may be useful for distinguishing MDS from non-clonal cytopenic disorders and warrant prospective study in additional MDS patients.