The global problem of early deaths in acute promyelocytic leukemia: A strategy to decrease induction mortality in the most curable leukemia.

Acute promyelocytic leukemia (APL) is a hyper-acute illness and presents with profound cytopenias in most patients and disseminated intravascular coagulation (DIC). Excellent treatment options are now available with drugs such as all-trans retinoic acid (ATRA), arsenic trioxide (ATO), anthracyclines and cytarabine. The outcome in APL has improved tremendously in the last 50years due to better understanding of the disease, development of effective targeted agents and improvement in supportive care. Carefully selected groups of patients treated in large multi-center trials on a protocol and in experienced centers have shown survival rates in excess of 85%. However population data and other studies show that approximately 30% of patients die during induction. This is an Institutional, national and global problem and remains a pressing and frustrating challenge in APL. While most APL experts are aware of the high rate of early deaths (ED), such awareness is not typically present among general hematologists and oncologists. Our area of focus over the last 7years has been the reduction of ED in both academic and community centers; as a result we have acquired substantial experience in APL induction. Two centers have implemented population-wide prospective trials; Brazil and Georgia/South Carolina, USA with improvement in the ED rate. Both centers used standardized guidelines along with consultative support and sharing of expertise which proved effective and helped to decrease ED. Induction mortality in APL is 30% or greater. We believe ED is largely preventable and population-wide survival can be improved. An effective strategy is to utilize a set of simplified treatment guidelines coupled with support from a group of experts during induction. Treating oncologists in both academic and community hospitals should receive aggressive education about ED and be encouraged to seek advice from a core group of established APL experts. This model could be implemented nationally to improve population-wide survival in this most curable leukemia.

Adult T-cell leukemia/lymphoma: a rare case in the USA and review of the literature.

Adult T-cell leukemia/lymphoma (ATLL), in its acute stage, is a uniformly fatal disease. ATLL is caused by the human T-cell lymphotropic virus I (HTLV-1), a retrovirus endemic in numerous areas throughout the world including Japan, the Caribbean, Central and South America and certain areas of the United States. Although the progression from HTLV-1 carrier status to ATLL occurs only rarely, ATLL is incurable and thus prevention of HTLV-1 transmission should be a primary goal. With the development of new anti-retroviral and monoclonal therapies, there exist potential cures or at least prolonged remissions for patients diagnosed with ATLL. We present a case of ATLL that, to our knowledge, is only the third reported case in Georgia. In addition, we present a brief review of the literature, including potential new treatment regimens that appear to have promise in the treatment of ATLL.

Leukemic leptomeningeal involvement in stage 0 and stage 1 chronic lymphocytic leukemia.

Central nervous system (CNS) involvement in early (Rai Stage 0 and Stage 1) chronic lymphocytic leukemia (CLL) is rare, with only five cases reported. We present the sixth reported case, a 77-year-old male with a 4 year history of Stage 0 CLL who presented with sudden onset of diplopia and headache. Workup revealed a leukemic involvement of his CNS and he responded well to treatment with intrathecal (IT) methotrexate. After his third IT treatment, he developed a change in his mental status, consistent with a chemotherapy induced encephalopathy, which was effectively treated with IT hydrocortisone. In addition to the case presentation, we review the previously reported cases in an effort to determine any characteristics common among the Stage 0/1 CLL patients with reported CNS involvement.

Tumor lysis syndrome in small cell lung cancer.

Tumor lysis syndrome, resulting from the abrupt release of intracellular ions into the blood stream due to sudden tumor cell death, is a serious complication of chemotherapy treatment. This syndrome occurs more frequently in hematologic malignancies and lymphomas. Its incidence in solid tumors is rare, but has a high mortality rate owing to the lack of prophylactic therapy to prevent this complication. We report a case of tumor lysis syndrome accompanied by death in a patient with extensive stage small cell lung cancer who was treated with cisplatin and etoposide, and review the risk factors associated with the syndrome in solid tumor patients who are likely to respond to chemotherapy.

Ototoxicity after high-dose chemotherapy with cyclophosphamide, thiotepa and carboplatin followed by stem cell transplantation in patients with breast cancer.

Our purpose was to determine the risk of ototoxicity in breast cancer patients receiving a myeloablative regimen consisting of cyclophosphamide 6000 mg/m2, thiotepa 500 mg/m2 and carboplatin 800 mg/m2 (CTCb) followed by stem cell transplantation. Fourteen consecutive patients with breast cancer were treated with high dose chemotherapy consisting of the CTCb regimen followed by stem cell transplantation. A pretransplant complete hearing study was obtained which consisted of hearing case history, audiometry and tympanometry. In addition, DPOAE (Distortion Product Otoaccoustic Emissions) was done to evaluate measurable changes in the cochlear (outer hair cell) functioning. Pre-transplant, all patients had no clinical evidence of hearing impairment and hearing studies were normal. Eleven patients had hearing studies and a telephone interview posttransplant. One patient was lost to follow-up and two patients died. One of the 11 patients tested had an abnormal post-transplant hearing study but none of them had clinically detectable hearing impairment. In our prospective study of breast cancer patients treated with the CTCb regimen, we did not observe clinically detectable hearing impairment in any of the patients tested.

Autoimmune thrombocytopenia following autologous hematopoietic cell transplantation: review of literature and treatment options.

Autoimmune thrombocytopenia after high-dose chemotherapy and autologous bone marrow/peripheral blood stem cell transplantation occurs infrequently and only six cases meeting the criteria have been reported in the literature. All six of these patients had either acute myelogenous leukemia (AML) or lymphoblastic lymphoma (LBL). Immune thrombocytopenia following autologous transplantation in solid tumors has not been reported. We report the first case of autoimmune thrombocytopenia after high-dose chemotherapy and peripheral blood stem cell transplantation in a patient with breast cancer. A review of the literature has been conducted and treatment options are discussed. In two patients the condition resolved with treatment and in a third patient it improved. Immune-mediated thrombocytopenia in the post-transplant period is one of the causes of a low platelet count. It should be recognized promptly and treated.

P-glycoprotein expression and multidrug resistance in cutaneous T-cell lymphoma.

Advanced-stage cutaneous T-cell lymphoma (CTCL) is generally resistant to standard chemotherapy. Because P-glycoprotein (P-gp) has been detected in other types of resistant solid tumors, leukemias, and lymphomas, we analyzed P-gp expression in CTCL. Twenty-seven patients with CTCL and circulating Sezary cells in the peripheral blood as observed on a peripheral smear treated at the Yale Photopheresis Center between 1987 and 1993 were identified. Twenty-five of these patients had skin biopsies evaluated for expression of P-gp using JSB-1 (Accurate Chemical), MRK-16 (gift of T. Tsuruo), and UIC-2 (gift of E. Metchner). P-gp expression was considered present if immunoreactivity was noted with two of the three antibodies. Eighteen of 25 patients (72%) evaluated exhibited expression. The patients were treated with various combinations of drugs consisting of topical and systemic steroids electron beam therapy, psoralens in combination with UV light A (PUVA), systemic chemotherapy, and photopheresis before testing the tissue for P-gp expression. Treatment with systemic chemotherapy in P-gp-positive patients produced responses in 3 and no responses in 11 patients (4 were lost to follow-up). Seven patients did not express P-gp: One patient responded to treatment, five did not respond, and one patient was lost to follow-up. These results demonstrate that P-gp is frequently expressed in CTCL. P-gp expression in our study was not a useful predictor of drug resistance.

Non-Hodgkin's lymphoma presenting as anasarca: probably mediated by tumor necrosis factor alpha (TNF-alpha).

Two patients presented with anasarca, fevers and sweats. Subsequent evaluation revealed aggressive lymphoproliferative disease. Both patients were treated with CHOP chemotherapy. One patient responded with spontaneous, vigorous diuresis and complete resolution of the edema. She relapsed two months later with recurrent edema that responded a second time to salvage chemotherapy. The second patient died of gram positive sepsis a week after diagnosis. As anasarca is an unusual presenting symptom of non-Hodgkin's lymphoma, we postulated that the malignant cells were secreting a cytokine that resulted in "vascular leakage" of fluid and development of diffuse edema. Several serum cytokine levels were tested. Both patients had elevated TNF-alpha levels, which could have been the cause of the edema; or there might be yet another unidentified mediator that was responsible for the anasarca. We report these two cases to bring to attention the unusual nature of this presentation.

Surgery for T4 breast carcinoma: implications for local control.

Despite increasing public awareness and widespread availability of mammography, many patients will present with locally advanced breast cancers. The role of surgery remains controversial. Between 1993 and 1998, 47 of 393 (11.9%) breast cancer patients presented with T4 (inflammatory or locally advanced) carcinoma. We reviewed multimodality management, clinical response to neoadjuvant therapy, perioperative course and complications, and local control. Forty-six women and one man were diagnosed with clinical T4 breast cancer. There were 24 white and 23 African-American patients. Mean age at presentation was 54.5 (range, 31-88) years. Twenty-three patients had clinical metastases to axillary nodes, and five had distant metastases at the time of diagnosis. For these women, intent was for personal hygiene and control of pain. Neoadjuvant chemotherapy was given for 34 of 47 (72%) with 25 of 34 (73.5%) having partial or complete clinical response. There was no response or progression of disease in 9 of 34(26.5%). Forty-six patients underwent radical or modified radical mastectomy, whereas a single patient underwent breast conservation treatment. Twelve required tissue transfer for wound coverage. Although eight developed minor wound complications (cellulitis/flap separation), there were no major wound complications. Pathologically negative margins were achieved in all but one patient. To date, five women have developed local recurrence in either the chest wall (three) or axilla (two). Average time to local recurrence was 7.8 months. There is no evidence of local failure in the remaining 87 per cent. Locally advanced breast cancer is a common occurrence in certain populations. Multimodality management remains the standard of care. Surgical resection may allow for successful local control and, in certain situations, long-term cure.

High-dose chemotherapy followed by reinfusion of a high number of CD34+ progenitor cells is frequently associated with development of fever in the postengraftment period.

Twenty-nine patients received high-dose chemotherapy and autologous stem cell transplantation from June 1997 to December 1998. The number of CD34+ cells reinfused was 2.4 x 10(6) to 69.0 x 10(6)/kg. Twelve patients developed a fever in the immediate postengraftment period. One patient had a documented infection that could account for the fever; a second patient had a rash and biopsy proven acute graft-versus-host disease (GvHD) that responded to steroids. In the other 10 patients (30%) there was no identifiable cause of the fever. One of these patients received 4.2 x 10(6) CD34+ cells/kg. The other nine received 22.0 x 10(6) to 69.0 x 10(6) CD34+ cells/kg. In our series of 29 patients, 9 of the 11 (82%) patients who received > 20 x 10(6) CD34+ cells/kg developed fever in the postengraftment period. There was a significant association between the number of CD34+ cells (<20 vs. >20 x 10(6)) and occurrence of fever (odds ratio = 76.5; p = 0.00005). Even though they engrafted promptly (7 to 9 days), the fever required evaluation for infection, blood cultures, antibiotic treatment, and observation. This required additional hospitalization of 1 to 7 days. These data suggest that a high number of CD34+ cells is frequently associated with post-engraftment fever and prolongation of the hospital stay. Should there be an upper limit in the number of reinfused CD34+ cells is a question that has to be addressed and possibly studied.

Cyclophosphamide, cytosine arabinoside and TBI as a conditioning regimen for allogeneic bone marrow transplantation in patients with leukemia.

This is a prospective study designed to determine the toxicity, efficacy and antileukemic effect of high-dose cytosine arabinoside (ara-C), cyclophosphamide and total body irradiation (TBI) as a myeloablative regimen prior to allogeneic bone marrow transplantation for patients with hematologic malignancies. Fifty-eight patients with hematologic malignancies were treated with cyclophosphamide, high-dose ara-C and total body irradiation (TBI) followed by allogeneic bone marrow transplantation. Fifty patients had good prognosis disease and eight had poor prognosis disease. Cyclosporine and short-course methotrexate were used for graft-versus-host disease (GVHD) prophylaxis. The conditioning regimen consisted of ara-C 3000 mg/m2 twice a day x six doses on days -7, -6, and -5; cyclophosphamide 1800 mg/m2 on days -4 and -3; and TBI 1400 cGy midline dose at 5 cGy/min in eight total fractions administered twice a day on days -4, -3, -2, and -1. The bone marrow was infused on day 0 (zero). Toxicity related to the conditioning regimen was comparable to that reported with other conditioning regimens, except for diarrhea which appears to be more frequent. The actuarial survival at 1 year was 69% (58-82) and at 5 years was 54% (42-69) with the numbers in parentheses representing the 95% confidence interval of the Kaplan-Meier estimate. After a median follow-up of 28 months, 31 of 58 (53%) patients are alive without evidence of disease. Only four of the 58 patients (7%) have relapsed. Cyclophosphamide, ara-C and TBI is a safe and effective myeloablative regimen for patients with leukemia. The overall relapse rate in our study was 7% with a median follow-up of 28 months and appears to be lower than relapse rates reported in other series. This is probably due to the added antileukemic effect of ara-C. This regimen should be compared with other myeloablative regimens in a controlled study.

Neutropenic infections in 100 patients with non-Hodgkin's lymphoma or Hodgkin's disease treated with high-dose BEAM chemotherapy and peripheral blood progenitor cell transplant: out-patient treatment is a viable option.

A retrospective analysis was performed on 100 patients with non-Hodgkin's lymphoma (NHL, n = 75) or Hodgkin's disease (HD, n = 25) who underwent peripheral blood progenitor cell transplant (PBPCT) following high-dose chemotherapy (HDCT) with BCNU, etoposide, cytarabine and melphalan (BEAM) between March 1994 and June 1997. Following PBPCT and until engraftment all patients received oral ciprofloxacin and fluconazole, patients with positive Herpes simplex virus serology received acyclovir and 91 patients received filgrastim. The median days of neutropenia and days to an absolute neutrophil count (ANC) >500/mm3 were 6 and 9, respectively. Febrile neutropenia occurred in 68 patients. Gram-positive bacteremia occurred in 14 patients. No gram-negative infections, invasive fungal infections, intensive care visits or deaths occurred during the period of neutropenia or in the first 30 days following transplant. In multivariate logistic regression the risk of development of any infection was associated only with the duration of neutropenia (P = 0.02) and the risk of bacteremia was associated only with the number of CD34+ cells infused (P = 0.046). Among 49 patients treated in the outpatient setting, 14 (28%) were never admitted. High-dose chemotherapy with BEAM supported by PBPCT, prophylactic antibiotics and filgrastim resulted in a low incidence of infections and no acute mortality. WBC engraftment occurred rapidly allowing for a predictable course during which lengthy hospital stays and amphotericin therapy could be avoided.

Assessment of pulmonary and cardiac function after high dose chemotherapy with BEAM and peripheral blood progenitor cell transplantation.

BACKGROUND: Limited information is available regarding the cardiac and pulmonary effects of high dose chemotherapy (HDCT) and autologous peripheral blood progenitor cell (PBPC) transplantation. METHODS: The authors evaluated cardiac and pulmonary function after BEAM (BCNU 300 mg/m2, etoposide 400 mg/m2/day x 3 days, cytosine arabinoside 200 mg/m2/day x 4 days, and melphalan 140 mg/m2), HDCT, and PBPC transplantation in 26 patients with non-Hodgkin's lymphoma or Hodgkin's disease. Therapy prior to BEAM included doxorubicin (25 patients), bleomycin (6 patients), and mediastinal irradiation (4 patients). All patients had pulmonary function tests (PFTs) and equilibrium radionuclide angiography before and at a median of 57 weeks after transplantation. RESULTS: Prior to high dose therapy, 8 patients had abnormal PFTs, including 6 with a diffusing capacity of the lung for carbon monoxide (DLCO) <70% of predicted value. At the time of reevaluation after HDCT, all patients included in the study were in complete remission, and none had received additional therapy after transplantation. At a median of 77 weeks after transplantation, none of the patients had cardiac or pulmonary symptoms. Moreover, there were no significant changes in total lung capacity, forced vital capacity, forced expiratory volume in 1 second/forced vital capacity, DLCO, or left ventricular ejection fraction values when compared with baseline studies. CONCLUSIONS: The authors concluded that HDCT with BEAM and PBPC transplantation did not result in significant cardiac or pulmonary toxicity, even in patients with borderline pretransplantation PFT values. Further studies of patients undergoing HDCT and PBPC transplantation are needed.

Reinstituting warfarin in patients who develop warfarin skin necrosis.

Skin necrosis is a rare but serious complication of oral anticoagulation with coumarin derivatives. Frequently, the necrosis can be extensive and may result in major morbidity and mortality. The majority of these patients require prolonged anticoagulation for life-threatening conditions such as deep various thrombosis and pulmonary embolism. Resuming oral anticoagulants in the face of skin necrosis is a difficult decision for both the patient and the physician. Because long-term heparin therapy is inconvenient and is associated with significant side effects, we reviewed the literature to find alternative treatment strategies. A Medline search was done, and all papers published in English since 1967 were reviewed. Of 58 cases with skin necrosis attributed to oral anticoagulants, oral anticoagulation was resumed in 7 patients with no resulting adverse effects. Warfarin is the most widely used coumarin derivative in the United States. Based on our review, we make recommendations for resuming warfarin in patients who have developed skin necrosis when the clinical condition absolutely requires prolonged anticoagulation.