Dana C. Matthews

Bone marrow transplantation for sickle cell disease

BACKGROUND We investigated the risks and benefits of allogeneic bone marrow transplantation in children with complications of sickle cell disease. METHODS Twenty-two children less than 16 years of age who had symptomatic sickle cell disease received marrow allografts from HLA-identical siblings between September 1991 and April 1995. The indications for transplantation included a history of stroke (n = 12), recurrent acute chest syndrome (n = 5), and recurrent painful crises (n = 5). Patients were prepared for transplantation with busulfan, cyclophosphamide, and antithymocyte globulin. RESULTS Twenty of the 22 patients survived, with a median follow-up of 23.9 months (range, 10.1 to 51.0), and 16 patients had stable engraftment of donor hematopoietic cells. In three patients the graft was rejected and sickle cell disease recurred; in a fourth patient graft rejection was accompanied by marrow aplasia. In 1 of the 16 patients with engraftment, there was stable mixed chimerism. Two patients died of central nervous system hemorrhage or graft-versus-host disease. Kaplan-Meier estimates of survival and event-free survival at four years were 91 percent and 73 percent, respectively. Among patients with a history of acute chest syndrome, lung function stabilized; among patients with prior central nervous system vasculopathy who had engraftment, stabilization of cerebrovascular disease was documented by magnetic resonance imaging. CONCLUSIONS Allogeneic stem-cell transplantation can be curative in young patients with symptomatic sickle cell disease.

Phase II trial of 131I-B1 (anti-CD20) antibody therapy with autologous stem cell transplantation for relapsed B cell lymphomas.

25 patients with relapsed B-cell lymphomas were evaluated with trace labelled doses (2.5 mg/kg, 185-370 MBq [5-10 mCi]) of 131I-labelled anti-CD20 (B1) antibody in a phase II trial. 22 patients achieved 131I-B1 biodistributions delivering higher doses of radiation to tumour sites than to normal organs and 21 of these were treated with therapeutic infusions of 131I-B1 (12.765-29.045 GBq) followed by autologous haemopoietic stem cell reinfusion. 18 of the 21 treated patients had objective responses, including 16 complete remissions. One patient died of progressive lymphoma and one died of sepsis. Analysis of our phase I and II trials with 131I-labelled B1 reveal a progression-free survival of 62% and an overall survival of 93% with a median follow-up of 2 years. 131I-anti-CD20 (B1) antibody therapy produces complete responses of long duration in most patients with relapsed B-cell lymphomas when given at maximally tolerated doses with autologous stem cell rescue.

Follow-up of relapsed B-cell lymphoma patients treated with iodine-131-labeled anti-CD20 antibody and autologous stem-cell rescue.

PURPOSE Radioimmunotherapy (RIT) is a promising treatment approach for B-cell lymphomas. This is our first opportunity to report long-term follow-up data and late toxicities in 29 patients treated with myeloablative doses of iodine-131-anti-CD20 antibody (anti-B1) and autologous stem-cell rescue. PATIENTS AND METHODS Trace-labeled biodistribution studies first determined the ability to deliver higher absorbed radiation doses to tumor sites than to lung, liver, or kidney at varying amounts of anti-B1 protein (0.35, 1.7, or 7 mg/kg). Twenty-nine patients received therapeutic infusions of single-agent (131)I-anti-B1, given at the protein dose found optimal in the biodistribution study, labeled with amounts of (131)I (280 to 785 mCi [10.4 to 29.0 GBq]) calculated to deliver specific absorbed radiation doses to the normal organs, followed by autologous stem-cell support. RESULTS Major responses occurred in 25 patients (86%), with 23 complete responses (CRs; 79%). The nonhematopoietic dose-limiting toxicity was reversible cardiopulmonary insufficiency, which occurred in two patients at RIT doses that delivered > or = 27 Gy to the lungs. With a median follow-up time of 42 months, the estimated overall and progression-free survival rates are 68% and 42%, respectively. Currently, 14 of 29 patients remain in unmaintained remissions that range from 27+ to 87+ months after RIT. Late toxicities have been uncommon except for elevated thyroid-stimulating hormone (TSH) levels found in approximately 60% of the subjects. Two patients developed second malignancies, but none have developed myelodysplasia (MDS). CONCLUSION Myeloablative (131)I-anti-B1 RIT is relatively well tolerated when given with autologous stem-cell support and often results in prolonged remission durations with few late toxicities.

Allogeneic hematopoietic cell transplantation after conditioning with 131I―anti-CD45 antibody plus fludarabine and low-dose total body irradiation for elderly patients with advanced acute myeloid leukemia or high-risk myelodysplastic syndrome

We conducted a study to estimate the maximum tolerated dose (MTD) of (131)I-anti-CD45 antibody (Ab; BC8) that can be combined with a standard reduced-intensity conditioning regimen before allogeneic hematopoietic cell transplantation. Fifty-eight patients older than 50 years with advanced acute myeloid leukemia (AML) or high-risk myelodysplastic syndrome (MDS) were treated with (131)I-BC8 Ab and fludarabine plus 2 Gy total body irradiation. Eighty-six percent of patients had AML or MDS with greater than 5% marrow blasts at the time of transplantation. Treatment produced a complete remission in all patients, and all had 100% donor-derived CD3(+) and CD33(+) cells in the blood by day 28 after the transplantation. The MTD of (131)I-BC8 Ab delivered to liver was estimated to be 24 Gy. Seven patients (12%) died of nonrelapse causes by day 100. The estimated probability of recurrent malignancy at 1 year is 40%, and the 1-year survival estimate is 41%. These results show that CD45-targeted radiotherapy can be safely combined with a reduced-intensity conditioning regimen to yield encouraging overall survival for older, high-risk patients with AML or MDS. This study was registered at www.clinicaltrials.gov as #NCT00008177.

Outcome of allogeneic bone marrow transplantation for children with advanced acute myeloid leukemia

Summary:Allogeneic bone marrow transplantation (BMT) may offer the only chance of cure for children with acute myeloid leukemia (AML) in second complete remission (CR2) or with relapsed disease, but the outcome of these patients has not been clearly defined. We conducted a retrospective study of 58 children, median age 7.4 years (range 0.8–17.3), who received matched related or unrelated BMT at our institution for AML in CR2 (n=12), in untreated first relapse (n=11) or with refractory disease (n=35), to identify risk factors associated with disease-free survival (DFS). Life threatening to fatal regimen-related toxicity was observed in 22% of patients. Estimates of DFS at 5 years (95% confidence interval) for patients in CR2, with untreated first relapse and refractory disease were 58% (27–80%), 36% (11–63%) and 9% (2–21%), respectively. Non-relapse mortality estimates were 0%, 27% (0–54%) and 17% (5–30%), and relapse estimates were 42% (14–70%), 36% (8–65%) and 74% (60–89%), respectively. Advanced disease phase and cytogenetic abnormalities at the time of transplantation were each associated with decreased DFS and increased relapse in multivariable regression models. Survival for children transplanted in CR2 or untreated first relapse is higher than that previously reported, but relapse remains the major cause of treatment failure regardless of disease stage.

Radiolabeled antibody therapy of human B cell lymphomas.

Modern chemotherapy regimens are capable of curing the majority of patients with newly diagnosed diffuse aggressive lymphomas1, but few patients with low-grade lymphomas or relapsed aggressive lymphomas can be cured with conventional therapy. High dose chemoradiotherapy in conjunction with marrow transplantation affords long term disease-free survival for approximately 25% of such patients2,3, but toxicity is formidable and post-transplant relapse and treatment-related complications result in the death of most such patients. Targeted radiotherapy using radiolabeled antibodies (RAb) offers a potentially effective new approach for refractory malignancies as demonstrated by a variety of animal and human studies4–13. In this report we summarize our experience administering radiolabeled anti-B cell antibodies to patients with refractory non-Hodgkin’s lymphomas in a phase I dose escalation trial.

Post therapy imaging in high dose I‐131 radioimmunotherapy patients

The biodistribution of a trace-labeled I-131 antibody is used to predict the biodistribution of a high dose I-131 antibody for therapy. Internal radiation dose estimates derived from the trace-labeled antibody have been used to determine the I-131 doses in a phase I escalating dose therapy trial for hematologic malignancy. To confirm the hypothesis that the distribution of a trace- and high-dose labeled antibodies are similar, both trace (7-11 mCi, 259-407 MBq) and high-dose (100-800 mCi, 3700-29600 MBq) I-131 radiolabeled antibody infusion were imaged in 12 patients who were treated for leukemia or lymphoma. With specialized imaging techniques using lead attenuation sheets, clearance data from organs were obtained from serial gamma camera images. Biological clearance half times of I-131 from both trace and therapy level doses were in agreement. An exception was a patient who developed human antimouse antibody before therapy, and subsequently had rapid clearance of the therapy dose. The method was feasible, yielded reproducible results, and provided critical data for relating therapy toxicity to radiation absorbed dose estimates.

Antithrombin concentrates use in children on extracorporeal membrane oxygenation: a retrospective cohort study.

Objective: To investigate whether receipt of any antithrombin concentrate improves laboratory and clinical outcomes in children undergoing extracorporeal membrane oxygenation for respiratory failure during their hospitalization compared with those who did not receive antithrombin. Design: Retrospective cohort study. Setting: Single, tertiary-care pediatric hospital. Patients: Sixty-four neonatal and pediatric patients who underwent extracorporeal membrane oxygenation for respiratory failure between January 2007 and September 2011. Intervention: Exposure to any antithrombin concentrate during their extracorporeal membrane oxygenation course compared with similar children who never received antithrombin concentrate. Measurements and Main Results: Thirty patients received at least one dose of antithrombin during their extracorporeal membrane oxygenation course and 34 patients did not receive any. The median age at admission was less than 1-month old. Age, duration of extracorporeal membrane oxygenation, or first antithrombin level did not differ significantly between the two cohorts. The mean plasma antithrombin level in those who never received antithrombin was 42.2% compared with 66% in those who received it. However, few levels reached the targeted antithrombin level of 120% and those who did fell back to deficient levels within an average of 6.8 hours. For those who received antithrombin concentrate, heparin infusion rates decreased by an average of 10.2 U/kg/hr for at least 12 hours following administration. No statistical differences were noted in the number of extracorporeal membrane oxygenation circuit changes, in vivo clots or hemorrhages, transfusion requirements, hospital or ICU length of stay, or in-hospital mortality. Conclusions: Intermittent, on-demand dosing of antithrombin concentrate in pediatric patients on extracorporeal membrane oxygenation for respiratory failure increased antithrombin levels, but not typically to the targeted level. Patients who received antithrombin concentrate also had decreased heparin requirements for at least 12 hours after dosing. However, no differences were noted in the measured clinical endpoints. A prospective, randomized study of this intervention may require different dosing strategies; such a study is warranted given the unproven efficacy of this costly product.

Successful unrelated donor cord blood transplantation for Glanzmann’s thrombasthenia

Kitko CL, Levine JE, Matthews DC, Carpenter PA. Successful unrelated donor cord blood transplantation for Glanzmann’s thrombasthenia.
Pediatr Transplantation 2011: 15: e42–e46.

Chronic Graft-versus-Host Disease: Pathogenesis, Diagnosis, Treatment, and Prognostic Factors

Chronic graft-versus-host disease (GVHD) and associated infections are major determinants of late morbidity and mortality in 25–50% of long-term survivors of allogeneic marrow transplantation [1]. With improving supportive care during transplant, broadening criteria for donor selection and expanding indications and numbers of centers for transplant, an increasing number of long-term survivors are reported [2–4]. For primary care hematologists and oncologists, recognizing and treating late complications is of increasing importance. The following reviews the pathogenesis, diagnosis, treatment and prognosis of chronic GVHD.