Abraham Klepfish

Enhancing the action of rituximab in chronic lymphocytic leukemia by adding fresh frozen plasma: complement/rituximab interactions & clinical results in refractory CLL.

Many patients with chronic lymphocytic leukemia (CLL) develop progressive treatment‐resistant disease. Rituximab (RTX), a monoclonal antibody targeting CD20 on B lymphocytes and widely used in other indolent B‐cell neoplasms is less efficacious in CLL, possibly because of associated complement deficiencies. Initial in vitro and in vivo observations support the central role of complement in rituximab‐mediated loss of CD20+ cells in CLL. In an open trial conducted in outpatient hematology clinics in Israel and Greece, we examined whether providing complement by concurrent administration of fresh frozen plasma (FFP) would enhance the effect of RTX in CLL. Five patients with severe treatment‐resistant CLL were included in the trial. All had been previously treated with fludarabine, and three also failed treatment with RTX. Each patient was treated with two units of FFP followed with RTX 375 mg/m2 as a single agent, repeated every 1–2 weeks as needed. A rapid and dramatic clinical and laboratory response was achieved in all patients. Lymphocyte counts dropped markedly followed by shrinkage of lymph nodes and spleen and improvement of the anemia and thrombocytopenia. This could be maintained over 8 months (median) with additional cycles if necessary. Treatment was well tolerated in all cases. In conclusion, adding FFP to RTX may provide a useful therapeutic option in patients with advanced CLL resistant to treatment. Further studies are needed to confirm and study the efficacy of the FFP/RTX combination in advanced CLL, establish the mechanisms, and possibly extend its use to other B‐cell‐dependent pathologies, such as treatment‐refractory autoimmune diseases.

Serum immunoglobulin levels at diagnosis have no prognostic significance in stage A chronic lymphocytic leukemia: a study of 1113 cases from the Israeli CLL Study Group

Hypogammaglobulinemia, commonly encountered in chronic lymphocytic leukemia (CLL), is one of the main causes of morbidity and mortality; however, its prognostic significance in patients diagnosed in early stages of disease remains uncertain. The aim of this study was to evaluate the predictive power of hypogammaglobulinemia at Bonet stage A.

Survival trends among 1,325 patients with chronic lymphocytic leukemia seen over the past 40 years in Israel

In the light of recent data showing survival improvement of patients with chronic lymphocytic leukemia (CLL), we investigated clinical characteristics and survival patterns of patients with CLL over the last 40 years in Israel. Demographic and clinical data collected in the database of the Israeli CLL Study Group were analyzed. Of the 1,325 patients, 221 were diagnosed during the time period 1968–1989, 456 during 1990–1999, and 639 during 2000–2010. There was shift toward older age (median, 71 vs. 68 vs. 66 years) and a higher proportion of patients at Binet stage A at diagnosis (77.6% vs. 66.7% vs. 60.3%) in the more recent time periods. Median survival for the entire cohort was 10.9 years; 12.2 years for patients diagnosed at Binet stage A, 8.5 years for stage B, and 6.4 years for stage C patients. Older age, high‐beta 2‐microglobulin level, and expression of ZAP‐70 predicted shorter survival. There were no apparent changes over time regarding gender, age or different clinical stages. Young patients with Binet stage A had lower life expectancy than the general population; but, in older ages, the survival rates were comparable. There were increased proportions of CLL patients diagnosed in early stages, and, at older age, during the last decades, however, survival rates according to sex, age, or stage remained stable. CLL continues to be an incurable disease affecting survival even in patients diagnosed at early stages. Survival benefit shown in recent trials using chemoimmunotherapy has still to be proven in wider general practice. Am. J. Hematol. 86:985–992, 2011.

Acute Splenic Infarction at an Academic General Hospital Over 10 Years: Presentation, Etiology, and Outcome.

Supplemental Digital Content is available in the textAbstractFew case series provide a current, comprehensive, and detailed description of splenic infarction (SI), an uncommon condition.Retrospective chart review complemented by imaging evaluation and patient follow-up.All adult patients with a confirmed diagnosis of acute SI discharged over 10 years from a single academic center were studied. A systematic literature review was done to compile a complete list of SI etiologies.SI was found in 32 patients, 0.016% of admissions. Ages ranged from 18 to 86 (median 64) years. Cardiogenic emboli were the predominant etiology (20/32, 62.5%) and atrial fibrillation was frequent. Other patients had autoimmune disease (12.5%), associated infection (12.5%), or hematological malignancy (6%). Nine of the patients (28%) had been previously healthy or with no recognized morbidity predisposing to SI. In 5 of 9 hitherto silent antiphospholipid syndrome or mitral valve disease had been identified. Two remained cryptogenic. Most patients presented with abdominal pain (84%), often felt in the left upper quadrant or epigastrium. Associated symptoms, leukocytosis or increased serum lactate dehydrogenase occurred inconsistently (∼25% each). Chest X-ray showed suggestive Lt. supra-diaphragmatic findings in 22%. Thus, the typical predisposing factors and/or clinical presentation should suggest SI to the clinician and be followed by early imaging by computed tomography (CT), highly useful also in atypical presentations. Complications were rare and patients were discharged after 6.5 days (median) on anticoagulant treatment. The systematic literature review revealed an extensive list of conditions underlying SI. In some, SI may be the first and presenting manifestation.SI is a rare event but should be considered in predisposed patients or those with any combination of suggestive clinical features, especially abdominal pain CT evaluation is diagnostic and the outcome is good.

Evaluating the impact of age and disease on survival of chronic lymphocytic leukaemia patients by a new method

Background:  The impact of chronic lymphocytic leukaemia (CLL) on survival may be different in younger patients, but this remains controversial.

Never say never: unexpected herpes lymphadenitis

A 67-year-old man with no history of cancer developed asymptomatic bilateral cervical and axillary lymph node enlargement without organomegaly in 2003. Blood count and serum lactate dehydrogenase (LDH) at the time were normal, and imaging showed moderately enlarged abdominal and retroperitoneal lymph nodes. Bone marrow biopsy showed nodular infi ltrate with small B lymphocytes, and lymph node biopsy fi ndings were consistent with small lymphocytic lymphoma CD20+ stage IV. After further lymph node enlargement, we treated him with six cycles of rituximab, fl udarabine, and cyclophosphamide immunochemotherapy, with almost complete remission on imaging, which lasted 10 years. In June, 2013, follow-up imaging showed recurrent lymph node enlargement, mostly in the abdomen and pelvis, but we decided not to treat because he was asymptomatic. In January, 2014, the patient developed sudden onset deafness and was found to have a nasopharyngeal mass causing bilateral middle ear eff usions. Biopsy sample of this mass was consistent with recurrent small lymphocytic lymphoma without transformation. The eff usions were drained and he was treated with two cycles of modifi ed rituximab/chlorambucil regimen. However, in March, 2014, he developed worsening lymph node enlargement with associated malaise. On examination he had cervical lymphadenopathy with a non-tender, round, rubber-like 7 × 4 cm left-sided cervical mass. CT scan showed increasing lymph node enlargement with a prominent left cervical lymph node containing areas of necrosis. We suspected transformation of small lymphocytic lymphoma into a more malignant form (Richter’s transformation) and did an excision biopsy of the cervical mass. However, given his recent history of nasopharyngeal mass, absence of B symptoms, normal LDH concentrations, and the morphological heterogeneity of the lymphoid cells surrounding the necrotic areas on the lymph node sample (fi gure) we did a literature search, which yielded three notable and treatable infectious causes of lymphadenopathy and necrotic areas: tuberculosis, tularaemia, and herpes simplex virus (HSV) lymphadenitis. Virus reactivation is a known complication of B-cell depletion induced by the anti-CD20 monoclonal antibody rituximab. Immunohistochemical analysis of the biopsy using anti-HSV antibodies was strongly positive (fi gure). We started treatment with oral valacyclovir 1 g, three times daily, for 10 days. On the fi fth day, the size of the cervical mass was greatly reduced and the patient’s malaise had improved. We started ibrutinib, a Bruton’s tyrosine kinase inhibitor used in the treatment of malignant diseases of B cells. At last follow-up in October, 2014, the patient is still taking ibrutinib 420 mg daily and valacyclovir 1·5 g daily and remains asymptomatic. Rapidly progressive lymph node enlargement in patients with previous indolent lymphoproliferative disorder is a sign of transformation to a more aggressive form, such as Richter’s transformation, in most cases. HSV lymphadenitis is extremely rare, with fewer than 30 patients reported worldwide. More than half of these patients had an underlying haematological malignancy; other reported causes include chronic steroid use and common variable immunodefi ciency. A few patients had no predisposing condition. Indeed, of 286 biopsies of rapidly progressive lymph node enlargement in patients with lymphoid malignancies, an infectious cause was established in only 12 patients (3·9%) and HSV was found in three of these. Patients with chronic lymphocytic leukaemia and small lymphocytic lymphoma often have an increased susceptibility to viral infections, particularly with herpes virus. Rituximab treatment seems to be an important risk factor: in one series, 54% of patients with haematological malignancies treated with rituximab developed an infection, and 62 of 181 cases had viral infections.

Expression of interleukin-11 receptor in CD38-positive cells from patients with multiple myeloma.

Interleukin-11, a cytokine with multiple biological activities, has been shown to stimulate the proliferation and to support the long-term growth of human myeloma cell lines. Despite this, no expression of the interleukin-11α receptor has so far been demonstrated in myeloma cells. We have investigated the expression of interleukin-11α receptor and interleukin-11 at the level of mRNA and protein product in bone marrow mononuclear cells isolated from patients with multiple myeloma using reverse-transcriptase polymerase chain reaction and flow cytometry. The mRNA for interleukin-11α receptor and/or the corresponding protein were identified in 9 of 15 patients with multiple myeloma. In contrast, the interleukin-11 was not detected in any of the patients examined.