Acute radiation injury: contingency planning for triage, supportive care, and transplantation.

Evaluation and management of victims of exposure to myelosuppressive radiation in a military, terrorist, or accidental event is challenging. The hematopoietic syndrome with marrow suppression and pancytopenia follows intermediate intensity radiation exposure and as such produces a clinical syndrome similar to that after myelosuppressive chemotherapy or stem cell transplantation. Therefore, hematologists, oncologists, and transplantation physicians have the opportunity and challenge to plan for care of irradiation victims. Management of the hematopoietic syndrome, as a component of acute radiation sickness, requires understanding its manifestations and implementation of clinical biodosimetry to provide appropriate therapeutic support. Hematopoietic growth factors may be of value if administered early as a component of supportive care. Planning for urgent stem cell transplantation for those with intermediate- to high-dose radiation (4-10 Gy) may be required. Establishing contingency plans for triage, assessment, supportive care, and treatment resembles the development of phase II trials, with defined eligibilities, treatment plans, and incorporated data collection to assess results and plan further improvements in care. The hematology/oncology community is most suited to participate in such contingency planning, and the necessary elements for its success are reviewed.

A phase I/II study examining pentostatin, chlorambucil, and theophylline in patients with relapsed chronic lymphocytic leukemia and non-Hodgkin's lymphoma.

In an attempt to exploit bcl-2 overexpression and aberrant p53 function, two frequently encountered aberrations that predict marked treatment resistance and worse prognosis in patients with chronic lymphocytic leukemia (CLL) and non-Hodgkin's lymphoma (NHL), we combined theophylline, pentostatin, and chlorambucil at two dose levels (cohort I: 30 mg/m(2); cohort II: 20 mg/m(2)) on a 21-day cycle for up to six courses. We employed a phase I/II design to determine feasibility, define the maximum tolerated dose (MTD), and explore the impact of biologic modulation on response and time to progression (TTP) in 20 patients with relapsed or refractory CLL and NHL. Eight patients were enrolled in cohort I. They demonstrated a response rate (RR) of 28% and a 16.5-month TTP after receiving a median of two cycles. A 50% RR was observed in this cohort when patients with adverse histologies were excluded. Because of myelotoxicity, this dose level defined the MTD, and de-escalation occurred. All 12 patients in cohort II received 20 mg/m(2) chlorambucil. A 50% RR and an 18-month TTP were observed after a median of 5.5 cycles. An RR of 47% and a complete remission (CR) of 5% were observed for the entire group, although responses and TTP varied greatly by histology. Significant activity was observed in patients with B-cell CLL and follicular lymphoma (FL). RR and TTP for fludarabine-sensitive/naïve and fludarabine-refractory (FR) B-cell CLL patients were 66 vs 25% and 20 vs 8.5 months, respectively. Both FL patients responded (one with partial remission and one with CR), with a 22.5-monthly median TTP. For responding patients, median TTP and overall survival (OS) was 21 and 69 months, respectively, compared to a median TTP of 2 months and an OS of 13.5 months for nonresponders. The combination of pentostatin, chlorambucil, and theophylline is the active regimen in patients with FL and B-cell CLL.

Medical management of radiological casualties.

Victims of radiological terrorism events require prompt diagnosis and treatment of medical and surgical conditions as well as conditions related to radiation exposure. Hospital emergency personnel should triage victims using traditional medical and trauma criteria. Radiation dose can be estimated early post-event using rapid-sort, automated biodosimetry and clinical parameters such as the clinical history, the time to emesis (TE), and lymphocyte depletion kinetics. For TE < 2 h, the effective whole-body dose is at least 3 Gy. If TE < 1 h, the whole-body dose most probably exceeds 4 Gy. Lymphocyte depletion follows dose-dependent, first order kinetics after high-level gamma and criticality incidents. Patient radiation dose can be estimated very effectively from the medical history, serial lymphocyte counts, and TE, and subsequently confirmed with chromosome-aberration bioassay, the current gold standard. These data are effectively analyzed using the Armed Forces Radiobiology Research Institute Biodosimetry Assessment Tool. The medical management of patients with acute, moderate to severe radiation exposure (effective whole-body dose >3 Gy) should emphasize the rapid administration of colony stimulating factors. All of these compounds decrease the duration of radiation-induced neutropenia and stimulate neutrophil recovery, albeit with some variability, in patients who have received myelotoxic chemotherapy, and all have demonstrated benefit in irradiated animals. For those patients developing febrile radiation-induced neutropenia, adherence to the current Infectious Diseases Society of America guidelines for high-risk neutropenia is recommended.

Medical management of the acute radiation syndrome: recommendations of the Strategic National Stockpile Radiation Working Group.

Physicians, hospitals, and other health care facilities will assume the responsibility for aiding individuals injured by a terrorist act involving radioactive material. Scenarios have been developed for such acts that include a range of exposures resulting in few to many casualties. This consensus document was developed by the Strategic National Stockpile Radiation Working Group to provide a framework for physicians in internal medicine and the medical subspecialties to evaluate and manage large-scale radiation injuries. Individual radiation dose is assessed by determining the time to onset and severity of nausea and vomiting, decline in absolute lymphocyte count over several hours or days after exposure, and appearance of chromosome aberrations (including dicentrics and ring forms) in peripheral blood lymphocytes. Documentation of clinical signs and symptoms (affecting the hematopoietic, gastrointestinal, cerebrovascular, and cutaneous systems) over time is essential for triage of victims, selection of therapy, and assignment of prognosis. Recommendations based on radiation dose and physiologic response are made for treatment of the hematopoietic syndrome. Therapy includes treatment with hematopoietic cytokines; blood transfusion; and, in selected cases, stem-cell transplantation. Additional medical management based on the evolution of clinical signs and symptoms includes the use of antimicrobial agents (quinolones, antiviral therapy, and antifungal agents), antiemetic agents, and analgesic agents. Because of the strong psychological impact of a possible radiation exposure, psychosocial support will be required for those exposed, regardless of the dose, as well as for family and friends. Treatment of pregnant women must account for risk to the fetus. For terrorist or accidental events involving exposure to radioiodines, prophylaxis against malignant disease of the thyroid is also recommended, particularly for children and adolescents.

Thrombotic microangiopathy (TMA) and stroke due to human herpesvirus-6 (HHV-6) reactivation in an adult receiving high-dose melphalan with autologous peripheral stem cell transplantation.

We report an adult autologous stem cell transplant (ASCT) patient who developed transplant-associated thrombotic microangiopathy (TMA) due to human herpesvirus-6 (HHV-6) reactivation. A 58-year-old female with Stage IIIA IgGkappa multiple myeloma received a melphalan (200 mg/m2) ASCT with discharge home after resolution of ASCT-related toxicities. She presented on D+20 with dyspnea, rash, and fever to 105 degrees F, followed by worsening dyspnea, hypotension, and capillary leak. Mental status (MS) changes were noted on D+23, but head CT and EEG were unremarkable. On D+29, a generalized seizure occurred with decline in platelet count and haptoglobin. TMA was noted on peripheral blood smear and therapeutic plasma exchange (TPE) was initiated on D+31. Lumbar puncture (LP) revealed CSF protein 74 mg/dL and white blood count 7,000/mm3 with 74% lymphocytosis. TPE was continued without improvement in her MS or thrombocytopenia despite improvement in microangiopathy. An MRI of the brain showed a left hippocampus abnormality, and an EEG was consistent with encephalopathy. Serum polymerase chain regimen (PCR) was negative for CMV, HSV1, and HSV2 but was strongly positive for HHV-6. Repeat LP protein was 597 mg/dL. Foscarnet was initiated, and cerebrospinal fluid (CSF) PCR for HHV-6 revealed 1,400 DNA copies/mL. Her MS greatly improved within 48 hr of antiviral therapy, serum HHV-6 became negative, and TPE was tapered without recurrence of her TMA. TMA with HHV-6 reactivation is likely an underdiagnosed entity. Given its fulminant course and favorable response to therapy, HHV-6 reactivation should be considered a potential etiology in patients with TMA after ASCT.

The hematologist and radiation casualties.

Since the terrorist attack of September 11, 2001, preparation by the health care system for an act of terrorism has been mandated by leaders of governments. Scenarios for terrorist acts involving radioactive material have been identified, and approaches to management (based on past experience from atomic weapons detonations and radiation accidents) have been developed. Because of their experience in managing patients with profound cytopenia and/or marrow aplasia, hematologists will be asked to play a significant role in evaluating and treating victims of mass accidental or deliberate exposure to radiation. This review provides a framework for understanding how radiation levels are quantified, how radiation alters the function of hematopoietic (and nonhematopoietic) cells and tissues, and how victims receiving a significant radiation dose can be identified and managed. In Section I, Dr. Nicholas Dainiak reviews four components of the Acute Radiation Syndrome: the hematopoietic, neurovascular, gastrointestinal and cutaneous subsyndromes. Clinical signs and symptoms are discussed for exposed individuals at the time of initial presentation (the prodromal phase) and during their course of disease (the manifest illness). In Section II, he presents clinical and laboratory methods to assess radiation doses, including time to onset and severity of vomiting, rate of decline in absolute blood lymphocyte count and the appearance of chromosome aberrations such as dicentrics and ring forms. Potential scenarios of a radiation terrorist event are reviewed, and methods for initial clinical assessment, triage, and early management of the acute radiation syndrome and its component subsyndromes are summarized. In Section III, Dr. Jamie Waselenko reviews the hematopoietic syndrome, and presents guidelines for the use of cytokine therapy, antibiotics, and supportive care that have been developed by the Strategic National Pharmaceutical Stockpile Working Group. Results of preclinical and clinical growth factor therapy studies with G-CSF, GM-CSF, pegylated G-CSF, SCF, and IL-3 are summarized. When and how potassium iodide should be used after exposure to radioiodines is also reviewed. In Section IV, Dr. James Armitage describes a narrow "window" of 7 to 10 Gy where therapy with stem cell transplantation may be appropriate. Victims who are candidates for allotransplantation should not have major trauma or significant injury to other (nonhematopoietic) tissues. Rarely, victims may have an identical sibling or autologous stored marrow or blood stem cells, in which case the threshold for transplantation is 4 Gy. In Section V, Dr. Thomas MacVittie describes new directions for therapy, using cytokines such as IL-7, keratinocyte growth factor, and FLT-3. The potential for combinations of cytokines to enhance hematopoietic recovery is also reviewed.

Post-transplant interleukin-2 in patients with low-grade lymphoid neoplasms previously treated with fludarabine is limited by hematologic toxicity.

Given the favorable immunologic effects of IL-2 post transplant, we conducted a feasibility study examining rIL-2 1.0x106 IU/m2/day (SQ) beginning on D+14 post-transplant and continuing for 90 days in 12 patients with low-grade lymphoproliferative disorders. Prior to high-dose chemotherapy and autologous peripheral blood stem cell transplantation (HDCT), 11 patients underwent cytoreduction with fludarabine and cyclophosphamide (Flu/Cy); 11 were in complete remission (CR) and one was in partial remission at the time of HDCT. All 12 patients were in CR 90 days post-HDCT. At a median follow-up of 30 (range 3-44) months, seven patients (58%) remain in remission, four are alive with disease, and one has died of disease progression, resulting in an overall survival of 92%. Kaplan-Meier estimates of progression-free survival (PFS) for the group demonstrate a median of 31 (range 3-43) months. Five patients required rIL-2 cessation at 8-58 days after starting the therapy due to hematologic toxicity. These results are comparable to those achieved in other published bone marrow and peripheral blood stem cell transplantion (PBSCT) series without the addition of rIL-2. Furthermore, rIL-2 using this schedule following fludarabine-based cytoreduction was associated with excessive hematologic toxicity.