Ralph Cobcroft

Incidence and nature of CD20-negative relapses following rituximab therapy in aggressive B-cell non-Hodgkin's lymphoma: a retrospective review.

Summary. Re‐treatment with rituximab for B‐cell non‐Hodgkins lymphoma (NHL) relapsing after previous rituximab therapy has recently been shown to be clinically efficacious. Although the mechanism of resistance to rituximab re‐treatment in non‐responding patients is unknown, it is possible that loss of CD20 expression in the relapsed NHL could be important in some patients. We examined the incidence and nature of CD20 negative relapses following rituximab therapy in aggressive B‐cell NHL treated at our institution. Of a total of 18 patients who received rituximab, 13 have relapsed, with 10 patients subsequently undergoing repeat tissue biopsy. Six of these 10 patients (60%) were shown to have lost CD20 expression by either immunohistochemistry and/or flow cytometry. Furthermore, three of the six patients who relapsed with CD20‐negative NHL also suffered relapses at unusual anatomical sites. We conclude that loss of CD20 expression in aggressive B‐cell NHL relapsing post‐rituximab therapy is common. As such, repeat tissue biopsy should be undertaken to document CD20 expression by both flow cytometry and immunohistochemistry prior to considering repeated courses of rituximab in relapsed aggressive lymphomas.

Practical Considerations for the Measurement of Free Light Chains in Serum

BACKGROUND A new immunoassay for free light chain measurements has been reported to be useful for the diagnosis and monitoring of monoclonal light chain diseases and nonsecretory myeloma. We describe experience with and some potential pitfalls of the assay. METHODS The assay was assessed for precision, sample type and stability, recovery, and harmonization of results between two analyzers on which the reagents are used. Free-light-chain concentrations were measured in healthy individuals (to determine biological variation), patients with monoclonal gammopathy of undetermined significance, myeloma patients after autologous stem cell transplants, and patients with renal disease. RESULTS Analytical imprecision (CV) was 6-11% for kappa and lambda free-light-chain measurement and 16% for the calculated kappa/lambda ratio. Biological variation was generally insignificant compared with analytical variation. Despite the same reagent source, values were not completely harmonized between assay systems and may produce discordant free-light-chain ratios. In some patients with clinically stable myeloma, or post transplantation, or with monoclonal gammopathy of undetermined significance, free-light-chain concentration and ratio were within the population reference interval despite the presence of monoclonal intact immunoglobulin in serum. In other patients with monoclonal gammopathy of undetermined significance, values were abnormal although there was no clinical evidence of progression to multiple myeloma. CONCLUSIONS The use of free-light-chain measurements alone cannot differentiate some groups of patients with monoclonal gammopathy from healthy individuals. As with the introduction of any new test, it is essential that more scientific data about use of this assay in different subject groups are available so that results can be interpreted with clinical certainty.

High‐dose gamma‐globulin therapy in the reactive haemophagocytic syndrome

Summary. Reactive haemophagocytic syndrome (RHS) is a disorder characterized by systemic proliferation of non‐malignant histiocytes occuring most commonly in patients with pre‐existing immunological abnormalities or neoplasma. Patients, particularly those with immunosuppression, often have a rapidly progressive fatal course. Treatment is directed at the underlying disorder. In the absence of identifiable cause, the therapy is less satisfactory. We report here three cases of RHS successfully treated with high‐dose gamma‐globulin therapy. Two of the three patients were immunocompromised and the third occurred during pregnancy. The improvement occurred within 24–72 h and all patients recovered. High‐dose i.v. gamma‐globulin therapy may be beneficial in RHS.

Neutrophil dysplasia characterised by a pseudo-Pelger-Huet anomaly occurring with the use of mycophenolate mofetil and ganciclovir following renal transplantation: a report of five cases

Aim: The pseudo‐Pelger‐Huet (PH) anomaly has been associated with a variety of primary haematological disorders, infections and drugs. Recently, the development of dysgranulopoiesis characterised by a pseudo‐PH anomaly has been reported in two patients with the use of mycophenolate mofetil (MMF) in the setting of heart and/or lung transplantation. We present a further five cases of MMF‐related dysgranulopoiesis characterised by a pseudo‐PH anomaly occurring after renal transplantation. Methods: All patients were receiving standard immunosuppression protocols for renal transplantation, including a combination of MMF, steroids and either cyclosporin or tacrolimus. Oral ganciclovir was also used for cytomegalovirus prophylaxis in each case. Results: Development of dysplastic granulopoiesis occurred a median of 96 days (range 66‐196 days) after transplantation. Moderate or severe neutropaenia (<1.0 2 10 9 /l) developed in three cases, and appeared to be directly correlated with the percentage of circulating neutrophils present with dysplastic morphology. Resolution of dysgranulopoiesis occurred in all cases only after dose reduction and/or cessation of both MMF and ganciclovir. Conclusions: In our series, the observed dysplastic granulopoiesis appeared related to the combination of MMF and ganciclovir, rather than MMF alone. Further study is required to determine the exact incidence and pathogenesis of this pattern of bone marrow toxicity.

Patterns of failure with increasing intensification of induction chemotherapy for acute myeloid leukaemia

Patterns of failure were studied in two consecutive randomized trials of intensified induction therapy carried out by the Australian Leukaemia Study Group (ALSG) between 1984 and 1991 to determine the impact of dose intensification. Patients received standard dose cytarabine and daunorubicin (7‐3), 7‐3 plus etoposide (7‐3‐7) or 7‐3 plus high‐dose cytarabine (HIDAC‐3‐7) chemotherapy. Patients with FAB M3 morphology were excluded. Time to failure (TTF) was defined as the time from randomization to induction death or removal from study for non‐responders, or to relapse or death in complete response (CR) for complete responders. An estimated 86% of 470 de novo patients with acute myeloid leukaemia failed within 10 years of randomization, as a result of death in induction in 17% of the randomized patients, failure to achieve CR in a further 17%, relapse in 44% and death in CR in 8% of patients. An estimated 66% of patients failed as a result of refractory disease or relapse within that period (disease‐related failures). Multifactor analysis identified age and peripheral blast count as the most significant pretreatment factors associated with overall TTF. These factors, together with cytogenetics, were significantly associated with disease‐related failures. High‐dose cytarabine in induction significantly decreased the disease‐related failure rate as did allogeneic transplantation in first CR. The impact of high‐dose cytarabine did not depend on the cytogenetic risk group.

Molecular remission without blood product support using all-trans retinoic acid (ATRA) induction and combined arsenic trioxide/ATRA consolidation in a Jehovah's Witness with de novo acute promyelocytic leukaemia.

Arsenic trioxide has recently been used in the treatment of both relapsed and de novo acute promyelocytic leukaemia (APML). Molecular remissions have been attained using arsenic trioxide with minimal associated haematological toxicity, making protocols utilizing this drug an attractive option for Jehovahs Witnesses with APML. A 62‐year‐old female Jehovahs Witness with de novo APML was treated with all‐trans retinoic acid induction followed by combined arsenic trioxide/ATRA consolidation, and achieved molecular remission with minimal haematological toxicity and no blood product support.

Hemolytic uremic syndrome following taipan envenomation with response to plasmapheresis

Summary We report a case of hemolytic uremic syndrome (HUS) in a 33 year old male who was bitten by a taipan, with apparent massive envenomation. The microangiopathic hemolytic anemia (MAHA) and thrombocytopenic aspects of his HUS appeared to respond to plasmapheresis, but his anuric renal failure persisted. He also had prolonged severe muscular paralysis which gradually began to resolve over the course of two weeks. At this point he suffered a cardiac arrest sustaining severe and subsequently fatal hypoxic brain injury. This case raises the possibility that the taipan venom may have induced HUS by damaging the renal endothelium. His cardiac arrest was not apparently related to his HUS.Abbreviations: aPTT, activated partial thomboplastin time; DIC, disseminated intravascular coagulation; HUS, hemolytic uremic syndrome; MAHA, microangiopathic hemolytic anemia; PT, Prothrombic time; TTP, thrombotic thrombocytopenic purpura.

Sweet's Syndrome, Acute Leukemia, and t(3;5)

We report herein the case of a 36-year-old woman who was diagnosed as having Sweets syndrome 13 months prior to developing acute myeloid leukemia (FAB type M2). Her bone marrow karyotype was 46,XX,t(3;5)(q21;q31). Translocation t(3;5) has been reported in seven other cases of acute nonlymphocytic leukemia. None of these cases have been associated with Sweets syndrome.

Transient Severe Hypoplastic Anemia in Q Fever

&NA; A case of severe transient marrow hypoplasia as a complication of Q fever is described. This caused marked thrombocytopenia and anemia. The patient recovered fully over the period of 1 wk. The initial marrow showed severe hypoplasia. The subsequent regenerating marrow showed numerous epithelioid granulomas one of which had a characteristic fibrin ring.

Spur cell anemia (acanthocytosis) complicating idiopathic hemochromatosis.

&NA; A 65‐year‐old male developed a rapidly progressive disease characterized by severe hemolysis, with spur cells (acanthocytes) and liver disease. Autopsy findings were consistent with a diagnosis of idiopathic hemochromatosis. Investigation of the patients family uncovered four out of five first degree relatives with significantly raised serum ferritin levels. A sister had biopsy proven hemochromatosis. Spur cell anemia is a recognized, though rare, complication of alcoholic liver disease and indeed the patient had a regular alcohol intake of up to 50 g daily. Although the alcohol intake could have contributed to the formation of spur cells, the possible association with hemochromatosis should be considered. A diagnosis of hemochromatosis has important implications for family members.