Deborah Rund

Screening, prevention and treatment of viral hepatitis B reactivation in patients with haematological malignancies.

The prevalence of hepatitis B virus (HBV) infection in patients with haematological malignancies is increased compared with the general population worldwide. HBV reactivation is common following chemotherapy and is associated with a high mortality despite prompt anti‐viral treatment. HBV reactivation may necessitate interruption of chemotherapy with adverse prognostic consequences for the haematological disease. Chemotherapy‐induced immune suppression may lead to increased HBV replication. Immune reconstitution within the weeks and months following recovery from chemotherapy may be associated with a flare of hepatitis B manifested by hepatocellular injury. Risk factors associated with HBV reactivation include detectable hepatitis B surface antigen (HBsAg), HBV DNA, Hepatitis B e (HBeAg) antigen, antibodies to hepatitis B core antigen (anti‐HBc), treatment with corticosteroids, young age and male gender. Lamivudine is effective during HBV reactivation due to immune suppression. Clinical trials have demonstrated that pre‐emptive antiviral treatment with lamivudine is superior to deferred treatment. Current recommendations emphasise screening for HBV infection in all haematology patients, particularly prior to chemotherapy. Patients who are HBsAg positive or HBV DNA positive should receive pre‐emptive treatment with lamivudine before chemotherapy. The duration of lamivudine treatment may be prolonged commensurate with the degree of immunosuppression. HBV naïve patients should be immunised against hepatitis B, as should haematopoietic stem cell donors. In summary, overt and occult HBV pose a serious, but preventable, threat. Pre‐treatment screening of patients at risk should be practiced diligently by all clinicians that treat patients with malignancies.

G6PD Mediterranean accounts for the high prevalence of G6PD deficiency in Kurdish Jews

The Jews of Kurdistan are a small inbred population with a high incidence of β-thalassaemia and glucose-6-phosphate dehydrogenase (G6PD) deficiency. Recently, it was reported that the β-thalassaemia in this population shows an unusual mutational diversity; 13 different mutations were identified, of which 4 had not previously been observed in any other population. In contrast, we now report that the G6PD deficiency, which has the highest known incidence in the world, and which affects about 70% of males, is almost entirely attributable to a single widespread mutation, G6PD Mediterranean.

Management of chronic viral hepatitis in patients with thalassemia: recommendations from an international panel.

Chelation therapy with new drugs prevents cardiac damage and improves the survival of thalassemia patients. Liver diseases have emerged as a critical clinical issue. Chronic liver diseases play an important role in the prognosis of thalassemia patients because of the high frequency of viral infections and important role of the liver in regulating iron metabolism. Accurate assessment of liver iron overload is required to tailor iron chelation therapy. The diagnosis of hepatitis B virus- or hepatitis C virus-related chronic hepatitis is required to detect patients who have a high risk of developing liver complications and who may benefit by antiviral therapy. Moreover, clinical management of chronic liver disease in thalassemia patients is a team management issue requiring a multidisciplinary approach. The purposes of this paper are to summarize the knowledge on the epidemiology and the risks of transmission of viral infections, to analyze invasive and noninvasive methods for the diagnosis of chronic liver disease, to report the knowledge on clinical course of chronic viral hepatitis, and to suggest the management of antiviral therapy in thalassemia patients with chronic hepatitis B or C virus or cirrhosis.

Rapid detection of the common Mediterranean α-globin deletions/rearrangements using PCR

The most frequent molecular lesions causing α‐thalassemia are deletions of one or more α‐globin genes. Detection of these deletions generally requires genomic Southern analysis, which is cumbersome and time consuming. We have designed new sets of primers for PCR identification of the common Mediterranean α‐globin gene rearrangements, including the ‐α3.7 deletion and the αααanti3.7 triplication, the ‐α4.2 deletion, and the ‐‐Med allele. We have established reaction conditions that provide easily interpretable, unambiguous diagnoses. Some of the PCR reactions are multiplex, simultaneously identifying several genotypes, thus reducing the time and cost of screening and prenatal testing. The use of these methods should facilitate carrier screening and identification of couples at risk for α‐thalassemia. Am. J. Hematol. 58:306–310, 1998.

Therapy-related leukemia and myelodysplasia: evolving concepts of pathogenesis and treatment.

Abstract Therapy-related leukemia and therapy-related myelodysplasia (t-AML/MDS) are serious and increasingly frequent complications of cytotoxic chemotherapy and/or radiotherapy. Two syndromes can be distinguished, one of which has a long latency (5-7 years or more) and is seen following alkylating agents, frequently with an antecedent dysplastic phase. The other has a short latency period (1-3 years), no antecedent dysplastic phase, and is characteristically seen following topoisomerase II inhibitors. Chromosomal abnormalities can confirm t-leuk/MDS and are predictive of poor prognosis, particularly those involving gains and losses of chromosome 7. There is no standard therapy for t-AML/MDS. This review concentrates on the various treatment approaches for t-AML/MDS. Treatment can be aggressive, with curative intent, particularly for patients who are young with no end-organ damage from the prior malignancy or chemotherapy. Various chemotherapy regimens have been designed to overcome the chemoresistance which is generally characteristic of these syndromes. Bone marrow transplantation offers the best chance for cure, and both myeloablative and nonmyeloablative protocols have been designed. Low dose chemotherapy is an option for patients not able to withstand traditional curative regimens and supportive care is a legitimate option for elderly or infirm patients. Multicenter studies are urgently needed to provide data on which clearcut treatment guidelines can be based, taking into account the patients age, disease status and risk factors.

Diversity of α‐globin mutations and clinical presentation of α‐thalassemia in Israel

α‐Thalassemia is among the worlds most common single gene disorders, caused primarily by gene deletions. In Israel, where αo‐trait thalassemia is uncommon, it is of particular importance because of its phenotypic interactions with β‐thalassemia in hetero‐ and homozygotes. In a study of 232 individuals referred for molecular evaluation of anemia, 303 chromosomes carried α‐globin gene abnormalities; 6 gene rearrangements and 11 point mutations were identified. This unexpected heterogeneity is in part due to the many ethnic subgroups represented by these patients. Our findings include nine unique Israeli alleles, 3 of which are described here for the first time. An equal number of point mutations was found in the α2‐globin gene as compared to α1. A threonine deletion in codon 39 of the α1‐globin gene, found frequently in Arabs, is unique to Israel and probably represents one of several indigenous alleles. Among Arabs, point mutations were more frequent than large deletions. Surprisingly, in Ashkenazi Jews, who resided for many centuries in a nonmalarial environment, a single α‐globin gene deletion −α3.7 was found in many cases. The clinical presentation of individuals carrying two or more α‐globin lesions was highly variable. In general, the severity correlated inversely with the number of functional α‐globin genes. In some cases, impairment of two α‐globin genes by point mutations led to a thalassemia‐intermedia‐like picture which could be misdiagnosed as β‐thalassemia. We conclude that α‐thalassemia is phenotypically and genotypically more heterogeneous than previously recognized. DNA analysis is invaluable as it provides a specific diagnosis and enables reliable genetic counseling. Am. J. Hematol. 65:196–203, 2000.© 2000 Wiley‐Liss, Inc.

Polymorphisms in transporter and phase II metabolism genes as potential modifiers of the predisposition to and treatment outcome of de novo acute myeloid leukemia in Israeli ethnic groups

Drug metabolism/disposition and transporter genes may influence predisposition or prognosis of AML (acute myeloid leukemia) patients. We analyzed polymorphisms in 3 transporters and 4 drug metabolism genes in 293 Israeli individuals (112 AML patients and 181 controls). We analyzed: ABCC3 (MRP3) C-211T; ABCG2 (BCRP) C421A; CNT1 (SLC28A1) G565A and NAT1, NAT2, and GSTT1 and GSTM1 null alleles for influence on predisposition, as well as treatment response and survival. We found that the ABCC3 C-211T polymorphism and GSTM1 null genotype have adverse prognostic significance in AML. None of the other polymorphisms studied were found to influence either predisposition or prognosis in Israeli AML patients.

Severe infections in thalassaemic patients: prevalence and predisposing factors.

The incidence of infections among patients with thalassaemia and the role of risk factors for infection are uncertain. We studied the occurrence of infections necessitating hospitalisation in 92 homozygous β‐thalassaemia patients who had been followed longitudinally for decades, and investigated the role of potential risk factors for these infections. Pneumonia accounted for 26% of the infections and fever of unknown origin for 14%. Staphylococcus aureus was the major pathogen possibly related to injections associated with intensive chelation with deferoxamine. There was a significant increase in the rate of infection over time, notably after 15 years. Splenectomy correlated with the incidence of infection (P < 0·001) without being confounded by other variables and with highest frequencies of infections present after 10 years. A direct correlation between iron overload and infection was evident only before the initiation of iron‐chelating treatment (P < 0·01). Following initiation of deferoxamine, paradoxically, the infection rate increased (P = 0·046). The combination of splenectomy and deferoxamine treatment was associated with the highest adjusted infection rate. Parathyroid dysfunction and glucose‐6‐phosphate dehydrogenase deficiency were significantly associated with infection (P = 0·02 and P = 0·04 respectively). The infection rate in thalassaemia is affected mainly by the duration of the disease and is increased by splenectomy and, in the long term, by treatment with deferoxamine.

SEGMENTAL TESTICULAR INFARCTION DUE TO SICKLE CELL DISEASE

Testicular infarction not associated with torsion is rare and segmental infarction is even more rare. The causes of testicular infarction in adults include trauma, sequela of epididymo-orchitis, polycythemia, hypersensitive angiitis, intimal fibroplasia of the spermatic artery and idiopathic etiology.l.2 In most reported cases the diagnosis of testicular infarction was made several days after the onset of symptoms, and the testis was removed to rule out malignancy. We report a case of segmental infarction of a testis presenting as an acute scrotum in a patient with sickle cell anemia. The clinical and sonographic findings that developed during 18 hours of observation allowed insight into the pathogenesis of large vessel occlusion in patients with sickle cell anemia. CASE REPORT A 27-year-old man with homozygous sickle cell anemia presented to the emergency department with severe pain in the left testicle 6 hours in duration. Previous complications of sickle cell disease included acute chest crisis, splenic infarction, osteomyelitis of the left foot and recurrent hemolytic crises. However, the patient had been free of painful crises for the last 9 years. He was married and the father of l-yearold twins who were born after successful in vitro fertilization. The pain was not accompanied by urinary or gastrointestinal symptoms and there was no history of trauma to the testicles. Physical examination revealed a severely distressed patient with normal vital signs. The left hemiscrotum was slightly swollen, red and tender. It was difficult to differentiate the epididymis from the testis. Urinalysis showed 10 to 20 red blood cells per high power field, hemoglobin was 7.7 gm. (normal 14 to 18) and white blood count was 16,500/mm.3 (normal 4,000 to 10,000). Working diagnosis was testicular torsion and color Doppler ultrasonography was done. Both testes appeared normal in echo texture and arterial blood flow. Analgesics, oxygen supplementation and hydration were administered.

Polymorphisms in the human organic cation transporter and the multidrug resistance gene: correlation with imatinib levels and clinical course in patients with chronic myeloid leukemia

Abstract The optimal tyrosine kinase inhibitor for any individual patient with chronic myeloid leukemia (CML) is not predictable. Pharmacogenetic parameters and trough levels of imatinib (IM) have each been independently correlated with response. We therefore studied the human organic cation transporter (hOCT1) and multidrug resistance (MDR1) single nucleotide polymorphisms (SNPs) and correlated these with IM levels and major molecular response (MMR) (3-log reduction) in 84 patients with CML, the first such study performed in Caucasians. We studied MDR1 G2677T and C3435T, and for hOCT1, C480G and A1222G. IM levels varied significantly with dose (< or > 400 mg/day) (p = 0.038) and were significantly lower in 20 patients who lost MMR (p = 0.042). Adjusting for dose, trough IM levels were not significantly correlated with SNPs. Patients with MDR1 3435 TT had significantly longer times to MMR compared to CC/CT genotypes (p = 0.047). Genotypes did not predict treatment failure when controlling for IM levels. We conclude that IM levels, but not the SNPs studied here, determine IM failure.