Meghan A. Higman

Chronic graft versus host disease

The ability to cure increasing numbers of individuals for malignant and non‐malignant diseases with the use of stem cell transplantation has resulted in a growing number of long‐term survivors with unique medical issues. Chronic graft versus host disease (GvHD) continues to be a significant problem in the allogeneic stem cell transplant setting and, as we continue to use alternative stem cell sources and attempt to modulate the immune system to increase an anti‐tumour effect, we will probably see rising numbers of patients with this complication. The capacity to treat this problem and improve both the immediate quality of life as well as long‐term effects is imperative and requires the ability of haematologists/oncologists to identify chronic GvHD and its multi‐organ system presentations. We describe the risk factors for developing chronic GvHD, its presentation and the current treatment options for both initial therapy and secondary treatment.

Phase II Study of Pentostatin in Patients With Corticosteroid-Refractory Chronic Graft-Versus-Host Disease

PURPOSE Therapy for patients with chronic graft-versus-host disease (cGVHD) is based on prolonged immunosuppression with corticosteroids. There is no standard therapy for patients whose cGVHD does not resolve with corticosteroid treatment. Pentostatin, a potent inhibitor of adenosine deaminase, has activity in acute GVHD. We examined the toxicity and efficacy of pentostatin in a prospective phase II trial in corticosteroid-refractory cGVHD. PATIENTS AND METHODS Patients of any age were eligible. Patients received pentostatin 4 mg/m2 intravenously every 2 weeks for 12 doses, and continued therapy as long as benefit was documented. Corticosteroid taper was begun after three doses of pentostatin. Responses were graded in real time in the skin, mouth, and liver using objective response criteria. RESULTS Fifty-eight heavily pretreated (median, four prior regimens) patients (median age, 33 years) were enrolled. Results are shown as an intent-to-treat analysis. Of the 58 patients, a total of 32 (55%; 95% CI, 42% to 68%) had an objective response, as evaluated by use of a new grading scale. Infection was the most significant toxicity, with 11 grade 3 to 4 infectious events. The survival at 1 and 2 years was 78% (95% CI, 64% to 86%) and 70% (95% CI, 57% to 80%), with cGVHD with/without infection accounting for the majority of deaths. CONCLUSION Pentostatin has immunosuppressive effects that are currently being explored further for treatment of cGVHD.

Reversible leukoencephalopathy associated with re-infusion of DMSO preserved stem cells

We report a case of posterior reversible leuko- encephalopathy (PRL) following the infusion of dimethylsulfoxide (DMSO) cryopreserved autologous stem cells in the setting of myeloablative chemotherapy in a patient with recurrent Ewing’s sarcoma. Magnetic resonance (MR) imaging revealed white matter changes which resolved over the next 2 months. Bone Marrow Transplantation (2000) 26, 797–800.

Successful treatment of a child with late onset T‐cell post‐transplant lymphoproliferative disorder/lymphoma

We report a novel regimen for refractory post‐transplant T‐cell lymphoma (PTL). Our patient presented with non‐Epstein–Barr virus (EBV) related, T‐cell post‐transplant lymphoproliferative disease (PTLD) 3.5 years after liver transplantation. Initially diagnosed as polyclonal PTLD, the disease progressed to a monoclonal, T‐cell PTL that was refractory to several chemotherapy regimens but responded to a regimen consisting of fludarabine, cyclophosphamide, cytarabine, and alemtuzumab. Consolidation therapy included high‐dose chemotherapy, autologous hematopoietic stem cell rescue, and radiation therapy. She remains in remission 2.5 years later. T‐cell PTL is a rare disease with a poor prognosis; this regimen provides a novel, potentially curative approach for its treatment. Pediatr Blood Cancer 2008;50:667–670.

A clinical algorithm identifies high risk pediatric oncology and bone marrow transplant patients likely to benefit from treatment of adenoviral infection

Background Adenoviral infections cause morbidity and mortality in blood and marrow transplantation and pediatric oncology patients. Cidofovir is active against adenovirus, but must be used judiciously because of its nephrotoxicity and unclear indications. Therefore, before introducing cidofovir use during an adenoviral outbreak, we developed a clinical algorithm to distinguish low risk patients from those who merited cidofovir therapy because of significant adenoviral disease and high risk for death. Objective This study was conducted to determine whether the algorithm accurately predicted severe adenovirus disease and whether selective cidofovir treatment was beneficial. Study Design A retrospective analysis of a pediatric oncology/blood and marrow transplantation cohort prealgorithm and postalgorithm implementation was performed. Results Twenty patients with adenovirus infection were identified (14 high risk and 6 low risk). All low-risk patients cleared their infections without treatment. Before algorithm implementation, all untreated high-risk patients died, 4 out of 5 (80%), from adenoviral infection. In contrast, cidofovir reduced adenovirus-related mortality in the high-risk group postalgorithm implementation (9 patients treated, 1 patient died; RR 0.14, P<0.05) and all treated high-risk patients cleared their virus. Conclusions The clinical algorithm accurately identified patients at high risk for severe fatal adenoviral disease who would benefit from selective use of cidofovir.

Treatment of hepatitis‐associated aplastic anemia with high‐dose cyclophosphamide

Demonstrate that high‐dose cyclophosphamide (CY) is effective therapy for hepatitis‐associated aplastic anemia (HAA).

Pentostatin - pharmacology, immunology, and clinical effects in graft-versus-host disease

Pentostatin (deoxycoformycin), is one of a number of purine analogues. The drug was originally designed to mimic a form of severe combined immune deficiency, characterised by marked T lymphopenia but variable B cell function. Clinically, the drug has been used primarily to treat a rare type of leukaemia – hairy cell leukaemia. Recently, the drug has seen increasing attention as an immunosuppressant. This review will cover the basic pharmacology and immunological effects of pentostatin. The clinical use of this agent in prevention and treatment of graft-versus-host disease will be examined. Although many of these studies are ongoing, this agent has promise as a novel immunosuppressive agent with a new mechanism of action.

Misinterpretation of a Calvert-derived formula leading to carboplatin overdose in two children.

Carboplatin is currently recommended to be dosed according to renal function. In adults, dosing by the Calvert formula is based on evidence that carboplatin clearance closely parallels glomerular filtration rate. Several studies have attempted to validate the Calvert formula and its derivations in pediatrics, but no final consensus has been achieved. As a result, different versions of the original formula exist in the pediatric literature. Other factors may also contribute to confusion when applying the formula to young patients, including the manner in which renal function is measured and reported. We describe how misinterpretation of the Calvert formula resulted in carboplatin overdosing in 2 pediatric patients with high-risk neuroblastoma undergoing peripheral blood stem cell transplantation. Measures to avoid such errors have been instituted.

Bone Marrow Engraftment Analysis after Granulocyte Transfusion

We present the case of a 6-year-old male who received an allogeneic bone marrow transplant as part of treatment for acute lymphoblastic leukemia. The patient relapsed 5 months after transplantation and received additional chemotherapy. He acquired an angioinvasive fungal infection that required transfusion of granulocytes. Approximately 5 weeks after relapsing (181 days after transplant), a bone marrow specimen was taken for molecular engraftment analysis and flow cytometry to assess graft loss as well as residual disease. The engraftment results generated by the multiple short tandem repeat loci tested were inconsistent, and alleles were present at several loci that were of neither patient nor donor origin. An error in specimen identification was initially considered. Further investigation into the circumstances surrounding procurement of the patients bone marrow aspirate revealed that the patient had received a granulocyte transfusion approximately 10 hours before the bone marrow specimen was taken. In addition, morphological and flow cytometric analyses of the same bone marrow aspirate demonstrated a significant degree of peripheral blood contamination. We determined that the unknown alleles in the bone marrow engraftment specimen were derived from the donor of the transfused granulocytes. This case illustrates that white cell transfusion can lead to erroneous bone marrow engraftment results, particularly if only one microsatellite locus is used to monitor engraftment.

Phenotypic characterization of three temperature-sensitive mutations in the vaccinia virus early gene transcription initiation factor

Vaccinia virus gene D6R encodes the small subunit of the virion early gene transcription initiation factor. Three temperature-sensitive mutations have been mapped to this gene. The biochemical phenotype exhibited by each mutation was examined. All mutants displayed altered viral protein synthesis in pulse-labelling analyses at both the permissive and non-permissive temperatures. The onset of early protein synthesis was delayed, and the rate of early protein synthesis was reduced in each case. Furthermore the shut-off of both host and early protein synthesis was delayed. In pulse-chase experiments, the stability of the D6R protein in E93- or C46-infected cells was shown to be reduced at 40 degrees C relative to that at 31 degrees C. Early mRNA was quantified in cells at 2 h post-infection and shown to be reduced substantially. The ability of each mutant virus to support transcription in vitro was examined at both temperatures and, of the three mutants, only S4 transcription was shown to exhibit reversible temperature sensitivity.