Induction Chemotherapy For Acute Leukemia Research Articles

Herpes simplex virus pneumonia during standard induction chemotherapy for acute leukemia: case report and review of literature

Herpes simplex virus pneumonia during standard induction chemotherapy for acute leukemia: case report and review of literature

Incidence and prognostic value of respiratory events in acute leukemia.

Acute respiratory failure and infectious pneumonia are the major causes of death during induction chemotherapy of acute leukemia. However, the causes, incidence and prognostic value of all respiratory events (REs) occurring in this context have never been assessed prospectively. We recruited 65 consecutive patients with newly diagnosed acute leukemia into a 1-year prospective study (December 2000-November 2001) to evaluate the incidence and prognostic value of these events. REs were frequent: 38 were recorded in 30 patients. There was a significant relationship between REs and pre-existing respiratory disease and/or smoking. REs were caused by infection in 34% of cases, by an established cause other than infection in 42% and had an undetermined cause in 24%. Poor early outcome (death within 45 days of starting induction chemotherapy) in patients experiencing an RE was independently associated with a >25/min respiratory rate (P=0.003) and the nonachievement of complete remission (CR) (P<0.0001). Predictors of overall survival in the entire patient population were the absence of CR (P<0.0001), REs (P=0.02) and a > or =2 performance status (P=0.03). In conclusion, REs are frequent during induction chemotherapy of acute leukemia and represent an independent prognostic factor of poor outcome, regardless of their cause.

The chemokine CCL21 protects normal marrow progenitors from Ara-C cytotoxicity.

Chemokines are a family of small proteins that regulate leukocyte infiltration into inflamed tissue and play key roles in the pathogenesis of many diseases. Some chemokines can also reversibly inhibit the proliferation of hematopoietic progenitors. We have previously found that the chemokine CCL21 (Exodus-2/SLC/6Ckine/TCA4) is a potent inhibitor of the proliferation of normal hematopoietic progenitors. In this study we sought to determine whether this inhibition of proliferation could be therapeutically exploited by protecting normal marrow progenitors from the cytotoxicity of the S phase-active chemotherapeutic agent Ara-C. Untreated and CCL21-pretreated mice were given doses of Ara-C that are toxic to marrow myeloid progenitors. The recovery of these myeloid progenitors was analyzed by colony formation assays. It was found that pretreatment with small doses of CCL21 prevented the death of normal murine marrow progenitors from the toxic effects of Ara-C. The chemokine CCL21 may be able to prevent Ara-C myelosuppression during acute leukemia induction chemotherapy, and thereby decrease morbidity and mortality of such therapy, and shorten hospital stays.

Reflections on gut decontamination in hematology.

In Europe, but decontamination (GD) is largely used in the prophylaxis of bacterial infections in departments of oncohematology treating neutropenic patients, in particular those patients subject to profound (absolute neutrophil count (ANC) <100/mm3) and prolonged (>10 days) neutropenia, such as patients undergoing bone marrow allografting or induction chemotherapy for acute leukemia. Initially, treatment was in the form of non-absorbable antibiotics, but this has been partially superseded by quinolone-containing regimens, in particular in the centers participating in EORTC trials. In the last two EORTC trials comparing different regimens for the treatment of febrile neutropenia, 57-73% of the patients were receiving GD. A French epidemiologic study, performed prospectively and consecutively in 36 oncohematology centers, has recently shown that 45% of febrile neutropenic patients receive digestive decontamination (DD) at the onset of their first febrile episode. The value of GD has been the subject of much controversy. Numerous trials, some of which were controlled, were performed in neutropenic patients in the 1980s, prior to trials of GD in intensive care units, but did not lead to a consensus in the medical community of the value of GD. Moreover, GD is not, or is infrequently, used in the USA. Apart from trials involving the quinolones, very few studies have been published during the last 10 years. Despite this, policies have not changed greatly in the various centers. The CLIOH group has gathered the opinions of experts invited to a multidisciplinary meeting that took place in Paris in October 1996. The text that follows summarizes the reflections arising from this forum. It should be noted that this meeting was not designed to be a consensus conference, but rather to re-examine the correlation between the data in the literature and actual clinical practice and to highlight the main problems posed by DD in current oncohematology. The experts were separated into three working groups, each of which has drafted a report which appears in the text below.

The use of anti‐D to improve post‐transfusion platelet response: a randomized trial

Patients undergoing induction chemotherapy for acute leukaemia often become refractory to platelet transfusions. Increased clearance of transfused platelets due to alloimmune destruction has been identified as one of the primary mechanisms contributing to this refractory state. We performed a double-blind randomized trial to determine whether the administration of anti-D to Rh-positive individuals could prevent the refractory state and improve post-transfusion platelet response. Rh-positive patients with acute leukaemia undergoing induction chemotherapy and requiring platelet transfusions were allocated to weekly intravenous anti-D (20 micrograms/kg) or placebo. Platelets and red cell concentrates were administered according to standardized transfusion guidelines. Outcome measures included platelet transfusion utilization, red cell utilization, platelet recovery 18-24 h post-infusion, and the percentage of patients refractory to platelet transfusion. There were 43 patients studied: 21 received anti-D and 22 saline placebo. The mean number of platelet concentrates required per day of observation was 0.59 (SD 0.22) in the anti-D group and 0.61 (SD 0.22) in the placebo group, P = 0.86. No difference was detected between groups in terms of platelet recovery post-infusion, refractoriness to platelet transfusion or frequency of infection (P = 0.97). Red cell concentrate utilization was significantly increased in the anti-D group compared to the placebo group, 0.58 units per day versus 0.37 units per day respectively, P = 0.005. We conclude that the use of anti-D did not improve post-transfusion platelet response in Rh positive patients with acute leukaemia, but did result in an increased need for red cell transfusion.

Infections in patients with acute non-lymphocytic leukemia nursed with central or peripheral venous access.

Infections are a major problem in patients undergoing induction chemotherapy for acute leukemia. Granulocytopenia is the single most important risk factor, but the pattern of infecting organisms can change according to nursing facilities or bacterial and fungal prophylaxis. We reviewed the patterns and types of infections in 30 patients with acute non-lymphocytic leukemia. Eighty-nine periods of neutropenia following chemotherapy were evaluated: in 60 courses patients had central and in 29 had peripheral venous access. Almost all patients (97%) became febrile after the 1st course of therapy, but one-third remained apyretic after the fourth course (P = 0.002). In this series, the incidence of gram-positive, gram-negative and mycotic isolations were respectively 76%, 18% and 6%. The need for antimicrobic treatment varied in relation to the course of chemotherapy. We conclude that in acute non-lymphocytic leukemia the first neutropenic period following the onset of disease is the most critical regarding infectious problems. Both quinolonic prophylaxis and central venous access could be responsible for the microbiologic findings.

Aspergillosis in the immunocompromised: focus on treatment.

Invasive aspergillosis, mainly due to Aspergillus fumigatus and Aspergillus flavus, is one of the most common fatal infections in the immunocompromised host; 25%–40% of autopsy cases in hematologic malignancies have invasive aspergillosis, with more than 80% of them being unrecognized during life (Young et al. 1970). In the normal host, inhaledAspergillus conidia are first phagocytized by alveolar macrophages. Those which escape phagocytosis sporulate and grow into large branching septated hyphae, which can invade lung tissues, but usually they are destroyed by the tissue neutrophils. Therefore, the patients most susceptible to aspergillosis are those with profound and prolonged granulocytopenia, especially those undergoing induction chemotherapy for acute leukemia, intensive chemotherapy for lymphoma, or bone marrow transplantation (Table 1). Patients with defective neutrophil function, particularly those with chronic granulomatous disease, are also at great risk of aspergillosis, as well as those with impaired macrophage function, such those receiving immunosuppressive therapy for organ transplantation or high-dose corticosteroids for vasculitides or connective tissue diseases. Recently, aspergillosis has been reported increasingly among acquired immunodeficiency syndrome (AIDS) patients; traditional factor risks including neutropenia, hematologic malignancies, and corticosteroid therapy were present in the majority of these patients (Pursell et al. 1992).

Protein C and S levels in acute leukemia

Patients with acute leukemia undergoing remission induction chemotherapy occasionally develop venous thrombosis despite severe thrombocytopenia and in the absence of disseminated intravascular coagulation. This observation prompted us to study the levels of the naturally occurring anticoagulant proteins C and S prospectively in patients undergoing remission induction chemotherapy for acute leukemia. Plasma samples from 50 adult patients with acute leukemia (34 AML, 16 ALL) were analyzed for protein C antigen, functional protein C, immunologic total and free protein S as well as levels of C4b binding protein (C4bBP). Plasma levels of immunologic protein C were significantly lower in patients with active acute myelocytic leukemia (mean = 77.9) than in controls (mean = 123.6) or patients in remission (mean = 132). Functional protein C levels were also significantly lower in AML patients with active disease (mean = 58.5) than controls (mean = 95.5) or patients in remission (mean = 98.5). Patients with acute lymphocytic leukemia (ALL) had normal levels of immunologic and functional protein C. Although total protein S levels were normal in all patients studied, levels of free protein S were significantly decreased in patients with active AML (mean = 29.3) compared with patients in remission (mean = 42.0) or controls (mean = 42.4). In contrast, patients with ALL, both with active disease and in remission had normal free protein S levels. This decrease in free protein S seen in active AML was not associated with liver disease, white cell count or an increase in C4bBP. These findings provide a possible explanation for the occasional occurrence of venous thrombosis in patients with acute myelocytic leukemia.

A Pilot Study Using Intravenous Immunoglobulin for the Prevention of Infection During Remission Induction in Acute Leukaemia.

Overwhelming infections cause significant morbidity and mortality in the immunocompromised host. There is considerable in vitro and in vivo evidence that the immune deficient state which accompanies acute leukaemia, and, is exacerbated by intensive chemotherapy, contributes to the infection risk in these patients. The most easily documented and corrected is that of impaired humoral immunity. In order to study the clinical significance of the deficit a double blind, randomised, placebo controlled pilot study was set up designed to test the feasibility, efficacy and toxicity of using prophylactic intravenous immunoglobulin to prevent infective complications in this patient group. Patients received 150 mg/kg of Pentaglobin, an immunoglobulin preparation specifically enriched in IgM and IgA, on days 0, 10 and 20 of the chemotherapy regimes. There were no adverse side effects. Patients in the placebo group had a 25% fall in IgM level whilst IgG and IgA remained unchanged. The treatment group maintained a stable IgM and IgG concentration throughout but had a rise in IgA. There was no difference in the total number of septicaemic episodes in each group but the placebo group had an increased number of non Staphylococcal infections (P < 0.04). We conclude that intravenous Pentaglobin protects patients against a fall in IgM during induction chemotherapy for acute leukaemia and decreases the number of non Staphylococcal infections.

Empiric Treatment of Fungal Infections in the Neutropenic Host

Persistent fever that is refractory to broad-spectrum antibacterials is common in neutropenic patients undergoing induction chemotherapy of acute leukemia. Clinical experience suggests that many of these patients are infected with fungi. Until recently, data supporting the role of empiric antifungal therapy in this setting were limited to small groups of patients or postmortem reports. Evolving evidence in larger patient populations supports data from smaller series: febrile neutropenic patients who have failed to respond to a 4- to 7-day course of broad-spectrum antibacterials may benefit from the early initiation of antifungal therapy. Patients with fungal colonization or pulmonary infiltrates and adult patients who have not received previous fungal prophylaxis may especially benefit from the early use of antifungal drugs. Amphotericin B has been the "gold standard" for empiric antifungal therapy, although the newer azoles may be useful in certain situations.

Ketoconazole in the Prevention of Candidiasis in Patients With Cancer

A prospective, randomized, controlled, double-blind study was performed between 1982 and 1985 to assess the ability of ketoconazole to prevent fungal infections in selected patients with cancer. Fifty-six patients receiving induction chemotherapy for acute leukemia, autologous bone marrow transplant for refractory nonhematopoietic malignant neoplasms, multidrug chemotherapy for malignant lymphoma, or corticosteroids for brain metastases were randomized to receive either oral ketoconazole, 400 mg/d, or placebo and observed until leukopenia resolved or corticosteroid therapy was stopped. Oral candidiasis developed in eight (28%) of 29 patients receiving placebo compared with none of 27 receiving ketoconazole. However, ketoconazole failed to prevent Candida esophagitis and vulvovaginitis in two patients and one patient, respectively. Furthermore, prophylactic use of ketoconazole did not significantly alter the total number of hospital days, febrile days, or antibiotic days or the requirement for amphotericin B in patients with acute leukemia and autologous bone marrow transplant. Since oral candidiasis can be successfully managed by several different treatment modalities when it does occur, we do not think that the routine prophylactic use of ketoconazole is justified.

Oral herpes simplex infections in patients with leukemia

Thirty patients hospitalized for induction chemotherapy of acute leukemia were studied for incidence, severity, and clinical features of oral herpes simplex virus infections. In 50% of the patients with evidence of past herpes infection, recurrent oral herpes developed during the study. Herpes simplex virus was the major cause of oral mucosal lesions seen in patients with leukemia. A majority of the episodes involved multiple oral sites and caused large atypical lesions. All lesions healed after topical or intravenous acyclovir therapy. Herpes simplex infection should be ruled out in all cases of oral ulcers detected in patients being treated for leukemia.

Primary invasive aspergillosis of the hand

Primary invasive aspergillosis of the hand is an unusual manifestation of an opportunistic fungal infection that affects children who receive induction chemotherapy for acute leukemia. The surgeon should maintain a high index of suspicion when evaluating even the most innocuousappearing hand lesion in an immunocompromised patient. Early diagnosis, intravenous amphotericin B, and radical surgical debridement may prevent angioinvasion and subsequent fatal widespread dissemination.

急性白血病寛解導入療法に関する研究

急性白血病寛解導入療法に関する研究

Oral Trimethoprim/Sulfamethoxazole for Prevention of Bacterial Infection During the Induction Phase of Cancer Chemotherapy in Children

We conducted a randomized, double-blind, placebo-controlled study to evaluate the efficacy of oral trimethoprim/sulfamethoxazole (TMP/SMX) in the prevention of bacterial infections in children with cancer. Sixty-three patients with acute leukemia were studied during the induction phase of chemotherapy; 28 patients with solid tumors who were starting intensive chemotherapy were also enrolled and treated for 2 months. There was no significant difference in the frequency of febrile episodes between the 43 children receiving trimethoprim/sulfamethoxazole and the 48 receiving placebo. However, when the group of 74 children who experienced granulocytopenia (absolute granulocyte count less than 500/microL) was analyzed separately, significant reductions in the frequencies of confirmed bacteremia (2.6% v 20.0%, P = .02) and febrile episodes (35.9% v 65.7%, P = .01) were observed in the trimethoprim/sulfamethoxazole group. Furthermore, life table analysis showed that children with leukemia receiving trimethoprim/sulfamethoxazole had significantly more days without fever and without bacteremia. No benefits from prophylaxis were recognized in the subgroup with solid tumors. Although the frequency of oral thrush was greater (P = .02) in the trimethoprim/sulfamethoxazole group (25.6%) than in the placebo group (6.3%), invasive fungal infection did not occur. Although the mean duration of granulocytopenia was greater among those receiving trimethoprim/sulfamethoxazole (13.7 v 9.0 days, P = .05), this did not appear to increase the overall risk for bacterial infection. These data suggest that trimethoprim/sulfamethoxazole reduces the frequency of bacteremia and febrile episodes in granulocytopenic children undergoing induction chemotherapy for acute leukemia.

Prospective randomized trial of antibiotic prophylaxis in acute leukemia

Patients undergoing initial remission induction chemotherapy for acute leukemia in a protected environment unit were randomly assigned to parenteral antibiotic prophylaxis or oral and parenteral antibiotic prophylaxis. Complete remissions were obtained in 82 percent of the 45 patients receiving oral and parenteral antibiotic prophylaxis and 76 percent of the 41 patients receiving parenteral antibiotic prophylaxis. Approximately 20 percent of the patients in both groups have had a continuous complete remission for more than five years. The episodes of fever of unknown origin and major infection were significantly more common in patients receiving parenteral antibiotic prophylaxis, although the episodes of local infection were similar in both groups. The duration of remission and survival was similar in both groups. Hence, the oral and parenteral antibiotic regimen was more effective for infection prophylaxis, but had no effect on response to antileukemic chemotherapy.

急性白血病寛解導入療法に関する研究

The streptococcal preparation, OK-432, has been found to be a biological response modifier. The effects of OK-432 on autologous CFUs in mice and hematopoietic disorders induced by anti-leukemic agents (DNR: daunorubicin, ara-C: cytosine arabinoside, NCS: neocarzinostatin) were investigated in order to obtain information as to the possibility of its clinical application in induction chemotherapy for acute leukemia.OK-432 increased autologous CFUs in irradiated mice, suggesting that it acted hematopoietically on multipotent stem cells. In mice treated with DNR, OK-432 reduced neutropenia when it was given before and simultaneously with DNR. In mice pretreated with OK-432, the duration of neutropenia caused by ara-C tended to be prolonged. On the other hand, simultaneous administration of OK-432 with ara-C showed no significant differences as compared to ara-C alone.These results suggested that the simultaneous administration of OK-432 with chemotherapeutic agents might protect normal hematopoiesis during induction chemotherapy for acute leukemia in man.

急性白血病寛解導入療法に関する研究

急性白血病寛解導入療法に関する研究

Oral trimethoprim/sulfamethoxazole in attempt to prevent infection after induction chemotherapy for acute leukemia

The efficacy of orally administered trimethoprim/sulfamethoxazole for infection prevention following induction chemotherapy was evaluated in 43 patients with acute leukemia. Twenty patients were randomly assigned to treatment with trimethoprim/sulfamethoxazole during 20 episodes of profound granulocytopenia; 23 patients in the control group were followed through 25 granulocytopenic episodes. The incidences of superficial skin and overall infections were significantly tower in those patients with multiple relapses who received trimethoprim/sulfamethoxazole (p = 0.008); however, there was no difference between the groups in regard to days of fever, days of antibiotic administration, days of hospitalization, or gram-negative rod bacteremia. As a result of this study, this regimen cannot be unequivocally recommended for infection prevention in neutropenic patients with acute leukemia undergoing induction or reinduction chemotherapy.

Serial enzyme-linked immunosorbent assays for antibody to Candida antigens during induction chemotherapy for acute leukemia.

Two or more sera were collected from 68 adult patients who received a total of 100 courses of induction chemotherapy for acute leukemia. Sera were tested by ELISAs for antibody to candidal mannan and a major cytoplasmic antigen. Twenty episodes of induction chemotherapy were accompanied by invasive candidiasis of skin, esophagus, or deeper organs. Levels of antibody to mannan rose more than 2.75 times normal activity in nine of these episodes and were already above this level in all sera in two episodes. Levels of antibody to mannan exceeded 2.75 times normal in only two of the remaining episodes in which invasive candidiasis was not observed. An eightfold increase in antibody to mannan occurred at some point in five of the 20 episodes complicated by invasive candidiasis but in only one of the remaining 80 episodes. Antibody to the major cytoplasmic antigen was detected infrequently in sera from episodes complicated by invasive candidiasis. Further studies of precise serial measurements of antibody to mannan therefore appear warranted.