Regression Of Splenomegaly Research Articles

Deficiency of Adenosine Deaminase 2 (DADA2) Presenting As Familial Hodgkin Lymphoma

Familial Hodgkin Lymphoma (HL) accounts for 4.5% of HL. Both genetic susceptibility and shared environmental factors can play a role. The usual presentation of HL is cervical lymphadenopathy/ mediastinal mass. Subdiaphragmatic presentation is rare and hepatosplenomegaly is associated with advanced HL.Adenosine deaminase 2 (ADA2) act as an outside extracellular growth factor for integrity of endothelial cells and in the development of certain immune cells. Deficiency of ADA2 (DADA2) is a recently described inborn error of immunity caused by biallelic mutations in adenosine deaminase 2 (ADA2) gene (formerly known as CECR1). It is an auto-inflammatory disorder with a spectrum of vascular, inflammatory, hematological and immunodeficiency phenotypes. The condition is inherited in an autosomal recessive pattern.The association of DADA2 with lymphoproliferation such asT-LGL like condition and ALPS like disease have been reported, however, HL has not previously been reported in DADA2.Herein we describe two siblings with DADA2 who presented with Hodgkin Lymphoma. The first patient is the third child of Saudi first degree related parents. He is known to have bronchial asthma on bronchodilators. At the age of 5 years, he was referred from primary care clinic for investigation of hepatosplenomegaly. He was otherwise well with growth along the fifth centile. His complete blood count (CBC) showed mild lymphopenia, other lab results including liver function tests were within normal. Few months later, he developed non-tender mobile cervical lymph nodes enlargement. Viral serology including EBV was negative based on PCR testing. Lymph node biopsy revealed the diagnosis of HL, mixed cellularity type, EBV negative (Figure 1). Whole exome analysis sequencing identified a homozygous variant in ADA2 gene c.1447_1451del. This variant has been confirmed by Sanger sequencing. Plasma assay of ADA2 enzyme activity revealed undetectable levels compatible with ADA2 deficiency.The patient started on prednisone 2 mg/kg/day, which showed good response in the form of being off blood support and regression of splenomegaly. Few months later, the course was complicated by recurrent infections. The patient remained stable for three years on small dose of prednisone, monthly IVIG due to hypogammaglobulinemia. Recently, etanercept was started to control disease progression.Nine months after the diagnosis of first patient, his younger brother who is known to have mild bronchial asthma on bronchodilators presented at the age of five years with hepatosplenomegaly and generalized lymphadenopathy. Lymph node biopsy revealed the diagnosis of classical HL, lymphocyte-rich subtype. Similar to his sibling, whole exome analysis identified the same mutation (a homozygous variant in ADA2 gene c.1447_1451del). This variant has been confirmed by Sanger sequencing and plasma level of ADA2 enzyme activity was undetectable. After the diagnosis of DADA2, screening for serum immunoglobulin levels showed hypogammaglobulinemia. The patient continues to be off treatment. Both patients were treated with chemotherapy with or without radiotherapy showing good response and they remained in remission at respectively and months after cessation of chemotherapy.This study is important for several reasons. First, this is the first report of HL in the context of DADA2. This again widens the clinical spectrum of DADA2. Interestingly, the boys presented two different forms of HL at the cellular level with no evidence of viral infection. The reported siblings presented with subdiaphragmatic diseases, which is uncommon in HL but in line with the sites of lymphoproliferation in DADA2. In addition, the age of presentation in the two siblings is uncommon in HL (less than 10 years).Second, we report an novel mutation in ADA2 gene. It creates a shift in the reading frame starting at codon Ser483. The new reading frame ends in a stop codon 4 positions downstream. This description and the description of the HL occurrence further expands the spectrum of DADA2. Our data, call for judicious exclusion of ADA2 deficiency in the HL patient with an aberrant course and additional symptoms / signs.In summary, we report familial HL in two patients with a novel deleterious mutation in ADA2 gene. This expands the spectrum of this disease to include cancer and should alert the hemato-oncologist to the possibility of DADA2 as an underlying diagnosis in HL. DisclosuresNo relevant conflicts of interest to declare.

A Rare Case Of Graves’ Disease With Splenomegaly And Pancytopenia

Introduction: Splenomegaly and pancytopenia are rare complications of Graves' disease with few reports in the literature about this association. The pathogenesis is unknown and immunological mechanisms seem to be involved. The possibility of hyperthyroidsm should always considered in patients with pancytopenia.
 Objective: Describe clinical case of association between Grave's disease, splenomegaly and pancytopenia.
 Method: This is a case report, obtained through data from medical records of a reference hospital located in the city of Juazeiro do Norte, Ceara, Brazil. Case report: Patient, 46 years old, female, sought treatment at a reference hospital with abdominal pain that started two days earlier, prevalent in mesogastric region and left hypochondrium very intense and recurrent, associated with significant consuptive syndrome ( loss of 10 Kg in 4 months), asthenia, dyspnea on minimum exertion, irritability and fine tremor in extremitie. SHe denied fever, palpitations, heat intolerance, skin ou eye changes. A diffuse thyroid enlargement with the presence of thrill and murmur, digital clubbing, fixed and bright look, light exophthalmos and splenomegaly about 6 cm below the left costal margin were abserved after physical examination. Ultrasound examination (USG) of the abdomen and CT scan showed moderate splenomegaly. Laboratory tests showed normocytic and normochromic anemia, leukocytosis and mild thrombocytopenia. Thyroid USG showed characteristic features of Graves' disease, a bone marrow biopsy revealed maturation preserved in all strains and lack of fibrosis and megakaryocytes present in normal number without atypia. treatment was set with propylthiouracil 300 mg a day and after the first revaluation after hospital discharge three weeks later a regression of splenomegaly has been observed.
 Conclusion: This case ilustrates the rare association between hyperthyroidism and splenomegaly with pancytopenia.

The Effect of Initial Molecular Profile on Response to Recombinant Interferon Alpha (rIFNα) Treatment in Early Myelofibrosis

IntroductionSuccessful treatment of early myelofibrosis (eMF), defined as patients (pts) with low or intermediate-1 (int-1) risk and ≥15% hematopoietic foci in the marrow biopsy, with rIFNα has been reported, but effects of driver and epigenetic mutations on outcomes were not considered. We now report results of our single center phase II study of 30 pts with primary (PM) or secondary (SMF) eMF, correlating the baseline molecular profile with response to rIFNα treatment.MethodsWe used WHO 2008 and IWG-MRT criteria for the diagnosis of PM and post-polycythemia vera MF (pPV MF) or post-essential thrombocythemia MF (pET MF), respectively. Prognosis was assessed using the Dynamic International Prognostic Scoring System (DIPSS). Response classifications were complete response (CR), partial response (PR), clinical improvement (CI), stable disease (SD), progressive disease (PD). Evaluation included history, examination, spleen size (cm below left costal margin), CBC and differential counts, routine chemistries, liver, renal, and thyroid function tests, marrow biopsy, cytogenetic and molecular genetic evaluations. Marrow specimens were stained routinely for morphology, reticulin, and collagen; fibrosis was graded using the European consensus system.JAK2, CALR and MPL mutations were detected and quantified by amplicon based next generation sequencing (NGS). NGS of 45 genes recurrently mutated in myeloid malignancies was performed on 25 of 30 baseline specimens, including ASXL1, IDH1/2, EZH2 and SRSF2, previously defined as high molecular risk (HMR) genes.Descriptive statistics were calculated and Fisher’s exact test used to explore the relationship between mutations and various results. Pts received either rIFNα-2b or peg-rIFNα-2a starting at a 5x105 to 1x106 units SC 3X wk or 45 to 90 mcg weekly, respectively; dose increase dependent upon tolerance and/or response.ResultsOf 96 pts with PM or SMF, 30 met study criteria, including 16 women and 14 men (med. dx age 58 yrs). Twenty-one had PM, 7 pPV MF, and 2 pET MF. Twenty-one pts were low risk, 9 int-1. Twenty-two were JAK2V617F(+), 6 CALR(+), and 2 MPL(+). All 7 pPV MF pts were JAK2(+). One pET MF was JAK2(+) and 1 CALR(+). Of PM pts, 14 were JAK2(+), 5 CALR(+), and 2 MPL(+).Med. rx duration has been 5.6 yrs and is ongoing. Clinical toxicity, grade 1 or 2, included mild depression, dry skin, cough, and myalgia. Hem. toxicity included anemia (grade 1-2: 17 pts), leukopenia (grade 1-2: 9 pts), and thrombocytopenia (grade 1-2: 10; grade 3: 2 pts). In these cases, rIFNα dose was temporarily reduced/interrupted until cytopenias resolved. One pt developed hyperthyroidism; treatment was discontinued.Of 30 pts, 2 (7%) had CR, 9 (30%) PR, 4 (13%) CI, 7 (23%) SD. Four (13%) had PD, and 4 (13%) died. Nine of 21 low risk pts had CR or PR, compared with 2 of 9 int-1. A small spleen at baseline was associated with better response in the absence of HMR abnormalities. Of 18 pts with slight or no splenomegaly, 11 had CR or PR, and of the non-responders, 2 had a HMR. Of 12 pts with significant or moderate splenomegaly, none had CR or PR, including 2 with a HMR. Follow up biopsies in 25 pts (83%) a reduction in reticulin fibrosis in 5, increase in 9, and stable in 10. Decrease in cellularity occurred in 12. There was no correlation between decrease in JAK2 allele burden, response, fibrosis, or spleen size.There was no correlation between driver mutations and response (Table). Pts with a HMR had worse responses; of 4 such pts, 0 responded, 1 remained stable, 1 progressed and 2 died. Specifically, pts with ASXL1 mutations seemed to do worse than those without it, although sample size precludes a definitive statement (p=0.19).ConclusionThis is the first study considering the effect of baseline mutation status on response to rIFNα treatment in eMF pts. 73% of pts improved or remained stable regardless of initial low or int-1 score or driver mutation, but spleen size and HMR adversely affected treatment response.Although baseline driver mutation status was not prognostically useful, a molecular profile should be obtained initially to identify HMR mutations, which negatively affect response to treatment including rIFNα. In 73% of selected cases, low dose rIFNα in eMF resulted in marrow reversion, regression of splenomegaly or disease stability with tolerable toxicity. Early treatment of MF with rIFNα in pts without HMR may prevent the development of marked splenomegaly, anemia, and florid myelofibrosis. [Display omitted] DisclosuresSilver:Incyte: Membership on an entity’s Board of Directors or advisory committees. Ritchie:Pfizer: Honoraria; Incyte: Speakers Bureau; Celgene: Speakers Bureau; Novartis: Honoraria, Research Funding; Arian: Speakers Bureau. Roboz:Agois: Consultancy; Amgen: Consultancy; Amphivena: Consultancy; Astex: Consultancy; AstraZeneca: Consultancy; Boehringer Ingelheim: Consultancy; Celator: Consultancy; Celgene: Consultancy; CTI Biopharma: Consultancy; Genoptix: Consultancy; Janssen Pharamaceuticals: Consultancy; Junno: Consultancy; MedImmune: Consultancy; MEI Pharma: Consultancy; Novartis: Consultancy; Onconova: Consultancy; Pfizer: Consultancy; • Roche Pharmaceuticals: Consultancy; Sunesis: Consultancy; Teva: Consultancy. Orazi:Novartis: Honoraria. Tam:Millennium Pharmaceuticals, Inc.: Consultancy. Cross:Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau.

Post-Transplant Lymphoproliferative Disorder after Autologous Hematopoietic Cell Transplantation for Hodgkin's Lymphoma

Post-transplant lymphoproliferative disorder is a very rare complication post autologous bone marrow transplant with few cases reported so far. We report a case of a child with history of classic Hodgkin's lymphoma, nodular sclerosis type, who was treated with autologous stem cell transplantation. Three months after the transplant, he developed bilateral cervical lymphadenopathy, splenomegaly, neutropenia and thrombocytopenia. Excisional biopsy of a left cervical lymph node revealed a post-transplant lymphoproliferative disorder. The morphological pattern of this post-transplant lymphoproliferative disorder was combined monomorphic and polymorphic, with plasmacytoid/plasmablastic differentiation expressing CD20 and CD79A. Kappa and lambda light chain immunohistochemistry stains showed a clear evidence of lambda light chain restriction. Immunohistochemistry stain and in situ hybridization for Latent membrane protein-1 were positive for Epstein-Barr virus. Polymerase chain reaction study revealed monoclonal B-cell proliferation with immunoglobulin heavy chain gene rearrangement. The patient was treated with prednisolone as 2 mg/kg/day over 2 weeks with tapering over the following 3 months. The white cell count recovered with regression of splenomegaly and cervical lymphadenopathy. On his last visit to the outpatient clinic, two years after the diagnosis of post-transplant lymphoproliferative disorder, he was in good health with normal laboratory parameters.

PET Positive Generalized Lymphadenopathy and Splenomegaly Following Interferon-alfa-2b Adjuvant Therapy for Melanoma

Interferon-alfa (IFN-alpha) is used in patients with various inflammatory and neoplastic disorders. We recently encountered fluorodeoxyglucose (FDG) uptake in generalized lymphadenopathy, splenomegaly, and the marrow in a patient receiving high dose interferon-alpha-2b (IFN-alpha) as adjuvant therapy for the treatment of malignant melanoma. Biopsy of an enlarged hypermetabolic axillary lymph node revealed only a reactive node. Discontinuation of IFN-alpha caused regression of splenomegaly and lymphadenopathy within 3 months.A marrow "hyperstimulation" pattern that can include the spleen is a well-recognized phenomenon on (fluorodeoxyglucose) FDG positron emission tomography/computed tomography (PET/CT) scans in patients receiving chemotherapeutic agents like interferon, though classically due to colony stimulating factors, but does not generally include lymphadenopathy. This case, which likely reflects an interferon-induced pseudolymphoma, highlights the importance of a drug history and clinical correlation for the proper interpretation of FDG PET/CT scans.

ULTRASOUND AND CLINICAL INVESTIGATION OF HEPATOSPLENIC SCHISTOSOMIASIS: EVALUATION OF SPLENOMEGALY AND LIVER FIBROSIS FOUR YEARS AFTER MASS CHEMOTHERAPY WITH OXAMNIQUINE

The course of hepatosplenic schistosomiasis after mass chemotherapy with oxamniquine has been rarely reported. We report the effect of treatment in patients with advanced schistosomiasis mansoni living in area of Brazil highly endemic for this disease. A total of 739 inhabitants of a village were subjected to clinical and abdominal ultrasound examinations and were treated with oxamniquine. We have identified 84 individuals with hepatosplenic schistosomiasis. Alcohol abuse was associated with periportal thickening. Four years after treatment, 42 of the 84 individuals were re-examined and regression of splenomegaly was observed in 59% and of periportal thickening in 32%. Our data indicate that mass chemotherapy can lead to reduction of schistosomiasis morbidity but a significant group of patients (68%) will not improve. The association with alcohol abuse should be further evaluated. Thickening of the gallbladder wall can be a useful predictor of no involution of liver fibrosis after treatment.

Successful therapy and regression of splenomegaly in a patient with myeloproliferative hypereosinophilic syndrome (MHES) treated with imatinib

Successful therapy and regression of splenomegaly in a patient with myeloproliferative hypereosinophilic syndrome (MHES) treated with imatinib

Allogeneic blood cell transplantation following reduced-intensity conditioning is effective therapy for older patients with myelofibrosis with myeloid metaplasia

Standard myeloablative conditioning prior to allogeneic hematopoietic stem cell (HSC) transplantation has been associated with significant toxicity in patients older than 45 years of age with myelofibrosis with myeloid metaplasia (MMM). We sought to evaluate the efficacy of a reduced-intensity conditioning regimen for allogeneic HSC transplantation in this setting. A regimen consisting of fludarabine (30 mg/m2 intravenously daily for 5 days) and melphalan (70 mg/m2 intravenously daily for 2 days) followed by transplantation of filgrastim-mobilized peripheral blood cells from HLA-identical siblings was administered to 4 older patients (median age, 56 years; range, 48-58 years) with advanced MMM. All patients achieved prompt neutrophil and platelet engraftment and have experienced a significant regression of splenomegaly and bone marrow fibrosis. All now have normal bone marrow cellularity. With a median follow-up of 13 months (range, 11-19 months), all 4 patients are alive with stable full-donor hematopoietic chimerism. These results support the feasibility and effectiveness of reduced-intensity conditioning prior to allogeneic HSC transplantation for older patients with advanced MMM.

The diagnosis of hairy cell leukemia can be established by flow cytometric analysis of peripheral blood, even in patients with low levels of circulating malignant cells.

The diagnosis of hairy cell leukemia (HCL) has traditionally been based on microscopic means. Immunophenotypic analysis of peripheral blood by flow cytometry is not widely recognized as a method for diagnosing HCL, perhaps due to the expectation of low yield of neoplastic cells in patients who are characteristically leukopenic. The abnormal coexpression of CD103, CD25, and intense CD11c and CD20 on monotypic, slightly large B-lymphocytes has previously been shown to be highly characteristic of HCL. We wished to determine if this pattern was valuable in the diagnosis of HCL in leukopenic patients with low levels of neoplastic cells in the peripheral blood. The abnormal immunophenotype above was observed in 25 peripheral blood specimens from patients with unexplained cytopenias or suspected lymphoproliferative processes. Ten of the 25 blood samples exhibited this abnormal phenotype in less than 5% of circulating leukocytes (ranging from <1% to 4%). All 10 patients had other manifestations of HCL, including cytopenias (mean white blood cell count, 1.8 x 10(3)/mm(3); hemoglobin, 11.0 gm/dl; platelets, 74 x 10(3)/mm(3)), splenomegaly, and typical bone marrow morphologic changes. Eight of the 10 patients achieved an excellent response to one course of 2-CDA, with significant improvement of cytopenias (mean white blood cell count: 5.3 x 10(3)/mm(3); hemoglobin: 14.4 g/dl; platelets: 181 x 10(3)/mm(3)) and regression of splenomegaly. One patient had a partial response to alpha interferon and a subsequent complete response to 2-CDA, and one died during treatment. In conclusion, flow cytometric immunophenotyping of peripheral blood is capable of detecting low levels of circulating malignant cells in HCL, even in leukopenic patients. As such, it can be a very useful, non-invasive tool in the diagnosis of this disorder.

Massive Splenomegaly and Epstein-Barr Virus-Associated Infectious Mononucleosis in a Patient With Gaucher Disease

Gaucher disease should be considered in the differential diagnosis of a patient with Epstein-Barr virus (EBV) infection who has unexplained or disproportionate splenomegaly. A previously asymptomatic adolescent with EBV-associated infectious mononucleosis and massive splenomegaly is described. He was found to have Gaucher disease on bone marrow biopsy, which was performed to exclude a hematologic malignancy. The diagnosis was confirmed by assay of beta-glucosidase enzyme activity. Regression of splenomegaly and improving hematologic indices. Patients with infectious mononucleosis and disproportionate organomegaly should be investigated to exclude a hematologic malignancy or an underlying storage disorder such as Gaucher disease.

Splenic irradiation in the palliation of patients with lymphoproliferative and myeloproliferative disorders.

Splenic irradiation is an accepted mode of treatment for palliation of hypersplenism and splenic pain for patients with lymphoproliferative or myeloproliferative disorders. However, results are conflicting regarding the duration of palliation and the toxicity associated with this treatment. Twenty-five patients with lymphoproliferative or myeloproliferative disorders were treated with splenic irradiation for palliation of splenomegaly and pain. The spleen was measured and pain and toxicity were assessed during radiation therapy. Splenomegaly and splenic pain decreased in 60 percent and 91 percent of patients, respectively. Radiation doses higher than 500 cGy appeared to be more effective than lower doses in reducing the spleen size in patients with chronic lymphocytic leukemia. Regression of splenomegaly and pain relief were maintained for less than one year and more than six months, respectively. Acute radiation toxicity resulted in the cessation of radiotherapy in two patients. Splenic irradiation is effective in the short-term palliation of splenomegaly and pain and may be most useful in the subset of patients with a life expectancy of less than one year. Terminally ill patients with splenomegaly secondary to lymphoproliferative or myeloproliferative disorders may benefit from splenic irradiation to minimize pain and pressure symptoms in addition to possible reduction of narcotic use.

Therapeutic leukapheresis

For the majority of leukemic patients, leukapheresis represents emergency treatment aimed at reducing the number of white blood cells and producing an immediate improvement in the clinical picture. We have shown that leukapheresis procedures performed for the therapy of leukocytosis in 4 patients with acute leukemia (2 myelocytic; 1 lymphocytic; 1 monoblastic) resulted in marked reduction in the white blood cell count and a considerable reduction in symptomatology. Repeat removal of white blood cells applied in 20 instances for patients with chronic myelocytic leukemia also produced a significant decrease in the cell count and relief of symptoms such as sweating, malaise, and pain due to splenomegaly. In chronic lymphocytic leukemia (31 patients), intensive and frequent leukapheresis procedures were followed by a marked fall in white blood cell count, regression of splenomegaly/ lymphadenopathy and resolution of many symptoms and signs induced by the large number of cells.

Portal obstruction in children. II. Results of surgical portosystemic shunts

Seventy-six children with portal vein obstruction underwent surgical portosystemic shunt, for severe gastrointestinal tract bleeding in 64 and for prophylactic purposes in 12. Endoscopy and angiography or both showed shunt patency in 70 children; thrombosis occurred in the remaining six. The mean age at successful shunt surgery was 6 years 10 months. Early postoperative assessment of shunt patency was judged from regression of splenomegaly and thrombocytopenia when splenectomy was not performed; when done, early postoperative ultrasonography correctly indicated the result. Significant regression of endoscopy was most often delayed postoperatively for up to six months. Children with a proved patent shunt did not have any further episodes of gastrointestinal tract bleeding, displayed no clinical signs of encephalopathy, and often exhibited a striking increase in growth velocity. These results strongly support the contention that a portosystemic shunt is the best treatment for portal vein obstruction after the first spontaneous bleeding episode, even in young children.

The Wiskott-Aldrich syndrome. Results of transfer factor therapy.

12 patients with Wiskott-Aldrich syndrome were treated with therapeutic doses of transfer factor in an attempt to induce cellular immunity. Clinical improvement was noted after transfer factor therapy in 7 of the 12 patients treated. Because this disease has a variable course and temporary spontaneous improvement can occur, the observed improvement cannot necessarily be attributed to the transfer factor. However, in two patients repeated remissions consistently followed transfer factor administration on repeated occasions. This included freedom from infections, regression of splenomegaly, and clearing of eczema. An unexpected finding was a decrease in bleeding in 3 of the 10 patients who had bleeding. Conversion of skin reactivity was obtained in all seven patients who clinically seemed to respond to transfer factor. In vitro studies performed after the administration of transfer factor demonstrated that the lymphocytes of the patients now produced migration inhibitory factor in response to appropriate test antigens, but did not undergo increased radioactive thymidine incorporation in response to the same antigens. A defect in the monocyte IgG receptors has been found in certain patients with the disease, and the current study shows that all patients with defective monocyte IgG receptors responded to transfer factor, whereas only one patient with normal receptors showed any response. This test may thus prove to be useful in predicting the results of transfer factor therapy in patients with Wiskott-Aldrich syndrome, although evaluation of a larger series of patients will be necessary to confirm this point. We conclude that cellular immunity can be induced, that there appears to be clinical benefit in certain patients with Wiskott-Aldrich syndrome by the use of transfer factor, and that this mode of therapy warrents trial in these patients and others with defects of cellular immunity.

A colchicine derivative in therapy of chronic myelocytic leukemia.

Desacetylmethylcolchicine decreased the leukocyte count and produced reduction or disappearance of immature cells in the peripheral blood in all of 14 patients with chronic myelocytic leukemia. These effects were usually accompanied by regression of splenomegaly and hepatomegaly, rise in hemoglobin concentration, and subjective improvement. A beneficial effect was also observed in some cases of blastic crisis. This drug appeared to have greater selectivity of action against cells of the granulocytic series than other antileukemic agents. Continuous adminstration proved necessary to maintain remission. Regulation of dosage was difficult; hematologic relapse occurred with suboptimal doses and toxic manifestations occurred with doses above the optimum. The drug's principal advantages are: prompt therapeutic action, possible effectiveness against myeloblastic proliferation, and rapid reversibility of its toxic effects.