Induction Therapy For Acute Leukemia Research Articles

PB2261: LINEZOLID AS A SAFE ANTIMICROBIAL AGENT IN THROMBOCYTOPENIC PATIENTS UNDERGOING CHEMOTHERAPY FOR HEMATOLOGIC MALIGNANCIES

Background: Febrile neutropenia (FN) is a common event in patients undergoing high-dose chemotherapy (HD-CT) for hematologic malignancies. Linezolid (LZ) is the first-in-class oxazolidinone antimicrobial agent active against gram-positive bacteria, often administered during FN as treatment for hospital-acquired pneumonia, gram-positive bacteriemia and soft-skin tissue infection. LZ induced thrombocytopenia or delayed platelet recovery are adverse events of concern in patients receiving HD-CT. As of today, few data are available on the safety of LZ in this specific setting. Aims: To retrospectively analyze a cohort of thrombocytopenic patients treated with LZ for FN in a single center, evaluating bleeding risk and impact on PLT recovery time. Methods: The analysis included patients diagnosed with Acute Leukemia (AL), High Grade Lymphomas (HGL) and Multiple Myeloma (MM) treated at our institution, between 2016 and 2021, with LZ for a FN episode during induction chemotherapy or ASCT conditioning. To be enrolled, PLT count at the start of LZ therapy had to be < 50×109/L. Results: A total of 40 FN episodes treated with LZ were identified. 22 occurred during induction therapy for AL and 18 during ASCT conditioning regimens. The median PLT count at the start of LZ therapy was 19×109/L in both groups (range 5-49×109/L in the AL cohort, 5-35×109/L in the ASCT group), while the median treatment duration was 8 days in both groups (range 2-15 days in the AL cohort, 3-12 days in the ASCT cohort). Only one clinically relevant bleeding event was observed in the AL group, while 0 bleeding events were observed in the ASCT group. Resolution of infection (defined as fever resolution, normalization of CRP and blood culture negativization) after the introduction of LZ therapy was observed in 17 (77%) AL patients and 15 (83%) ASCT patients. In the AML group PLT recovery (defined as a stable PLT count ≥20×109/L without the need for PLT transfusion) was observed in 18 (81%) patients with a median time to recovery of 22 days from the start of the chemotherapeutic regimen (range 18-41). PLT recovery was observed in 10 (71%) ASCT patients with a median time to recovery of 35 days from the stem cell infusion (range 13-136). 4 out of 18 patients in the ASCT group started LZ therapy after PLT recovery, and 3 out of 18 patients in the same group died due to the infectious complication that prompted the start of LZ therapy. Median PLT recovery time was not significantly different between patients enrolled in this study and historical controls from our center (AML: median 20 days, p>0.1. ASCT: median 22.5 days, p>0.1). Summary/Conclusion: Our observations support the use of LZ in this setting, as only one relevant bleeding event was observed among the two groups, and no impact on PLT recovery time was noted after comparison with historical data. Our study suggests that LZ is a safe and effective antimicrobial therapy in patients undergoing HD-CT for hematological malignancies. This data needs to be prospectively confirmed in a larger cohort of patients in a multicenter study.

Outcomes in Obese Patients Undergoing Induction Therapy for Acute Leukemia

Obesity continues to be a growing concern in the United States. According to the guidelines published by ASCO in 2012, chemotherapy doses in this patient population should be calculated based on actual body weight. However, the guidelines do not provide guidance for chemotherapy dosing in patients with hematologic malignancies. We conducted a single-center retrospective chart review (from November 2012 to August 2016) to evaluate clinical outcomes in obese versus nonobese patients undergoing induction chemotherapy for newly diagnosed acute leukemia. All chemotherapy doses were calculated based on actual body weight. The primary outcome was rate of complete remission (CR) following induction chemotherapy. Secondary outcomes included time to absolute neutrophil count (ANC) and platelet recovery, the incidence of febrile neutropenia and clinical or microbiological infections, rate of early (0-15 days) and in-hospital mortality, and overall survival at 6 months. The rate of CR was similar between obese patients and non-obese patients diagnosed with AML (60% vs 61.9%; p=0.86) and ALL (87.5% vs 92.8%; p=0.31). Obese patients with AML were more likely to receive re-induction chemotherapy following 14-day bone marrow biopsy (53.3% vs 23.2%; p=0.019). There were no significant differences in secondary outcomes in either group when comparing obese versus non-obese patients. Obese patients with acute leukemia had similar rates of CR compared to non-obese patients following induction chemotherapy. While chemotherapy dosing based on actual body weight did not lead to excessive toxicity in these patients, continued research is needed to determine optimal dosing and long-term outcomes in this patient population. DisclosuresNo relevant conflicts of interest to declare.

Early detection of infectious complications during induction therapy for acute leukemia with serial C-reactive protein biomarker assessment

Febrile neutropenia (FN) and blood stream infections (BSI) are major complications of induction treatment for acute leukemia. We assessed the predictive utility of C-reactive protein (CRP), an acute phase reactant, for FN and BSI during induction. CRP levels and dynamics were analyzed in 138 consecutive patients. FN and BSI occurred in 110 (80.3%) and 10 (7.5%) patients, respectively. Median peak CRP level in the 24-hours preceding FN was 7.5 mg/dl (0.2–38.1) vs. median peak CRP level of 5.11 mg/dl (0.2–23.1, p = .009) in patients without FN. CRP levels preceding BSI were 13.1 mg/dl (6.9–27.9) vs. 6.3 mg/dl (0.16–38.14, p = .011). CRP increase prior to event (ΔCRP) was higher among patients with BSI vs. patients without BSI (p = .013). CRP was predictive for FN (p = .009) and BSI (p = .01) on ROC curve analysis and was also independently associated with FN on multivariate analysis. In conclusion, CRP is a sensitive biomarker that precedes FN and BSI.

Incidence of Invasive Fungal Infections in Acute Leukemia Patients Utilizing Micafungin Prophylaxis Compared to Second-Generation Azole Prophylaxis

Introduction/Background: Standard therapy for both acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL) is myelosuppressive, and patients are expected to be neutropenic for a prolonged period. Due to the high risk of infection, antimicrobial prophylaxis is warranted and should be continued throughout neutropenia. The incidence of documented invasive fungal infections ranges from 12 to 24% in patients with AML and approximately 6.5% in patients with ALL. Guidelines currently include posaconazole as a category 1 recommendation for antifungal prophylaxis, with echinocandins and other azole antifungals as category 2B. However, posaconazole can be subject to drug-drug interactions and can increase the risk of hepatotoxicity, both of which can be problematic in acute leukemia patients undergoing chemotherapy. For patients unable to receive posaconazole or another second-generation azole antifungal, micafungin is utilized. To our knowledge, there are no studies comparing second-generation azole antifungals to micafungin as prophylaxis in both AML and ALL during initial or relapsed/refractory induction therapy. The aim of this retrospective study is to compare the incidence of invasive fungal infections in patients with acute leukemia in the setting of micafungin or second-generation azole antifungal prophylaxis during initial and/or relapsed/refractory induction therapy at an academic medical center. Methods: Retrospective, single-center study from June 22, 2013 to June 22, 2018. Detailed chart reviews were performed by hand. Results: The incidence of invasive fungal infections within 100 days of chemotherapy was 11.2% in patients who received a second-generation azole and 2.7% in patients who received micafungin (P=0.7618). The incidence of invasive fungal infections within 100 days in patients who received a high intensity AML regimen was 11.2%, low intensity AML regimen 0.9%, and ALL regimen 1.8% (P=0.5378). The incidence of invasive fungal infections within 30 days of chemotherapy was 4.5% in patients who received a second-generation azole and 2.2% in patients who received micafungin (P=0.2447). The most common reason for micafungin prophylaxis was drug-drug interactions with standard ALL regimens that utilize vincristine. Of those with a documented fungal infection, 14 patients (6.3%) had a proven invasive fungal infection, and 17 patients (7.6%) had a probable/possible invasive fungal infection. The most common site of infection was in the chest (9.8%), followed by fungemia (2.2%). Other sites of infection include the brain, sinuses, liver/spleen, and skin. Beta-D-glucan was collected in 17 patients, and galactomannan antigen was collected in 26 patients. Three patients had a positive beta-D-glucan, and 1 patient had an indeterminate beta-D-glucan. Two patients had a positive galactomannan antigen. Fusarium species accounted for 4 positive cultures in patients. For those patients who did experience an invasive fungal infection, 23 out of the 31 patients (74.2%) were on posaconazole, 6 patients on micafungin (19.4%), and 2 on voriconazole (6.5%). Ten out of the 14 proven fungal infections (71.4%) occurred while on posaconazole prophylaxis, and 3 of these patients had posaconazole levels &lt;0.7 mcg/mL. Twenty-one patients (67.7%) with documented infections had a neutrophil nadir &lt; 0.1x109/L. The majority (93.5%) of those with breakthrough infections while on antifungal prophylaxis were switched to another antifungal. Conclusions: Micafungin is a reasonable alternative therapy for use in patients who are unable to receive second-generation azoles as antifungal prophylaxis during induction therapy for acute leukemia. Some invasive fungal infections occurred while patients had sub-therapeutic posaconazole levels, however others had breakthrough fungal infections with therapeutic levels. Our conclusions are limited by the small sample size and non-randomized, retrospective nature of this analysis. Disclosures Erba: Agios, Amgen, Astellas Pharma, Daiichi Sankyo, ImmunoGen, Janssen, Jazz Pharmaceuticals, Juno, Millennium, Seattle Genetics: Research Funding; Celgene, Incyte, Novartis: Speakers Bureau; Amgen, Celgene, Daiichi Sankyo, ImmunoGen, Incyte, Jazz Pharmaceuticals, Millennium, Novartis, Ono, Pfizer, Seattle Genetics, Sunesis: Consultancy. LeBlanc:Seattle Genetics: Consultancy, Research Funding; Astra Zeneca: Consultancy, Research Funding; AbbVie: Membership on an entity's Board of Directors or advisory committees; Agios: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; NINR/NIH: Research Funding; Jazz Pharmaceuticals: Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees; CareVive: Consultancy; American Cancer Society: Research Funding; Daiichi-Sankyo: Membership on an entity's Board of Directors or advisory committees; Helsinn: Consultancy; Medtronic: Membership on an entity's Board of Directors or advisory committees; Otsuka: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer Inc: Consultancy; Heron: Membership on an entity's Board of Directors or advisory committees; Duke University: Research Funding; Celgene: Honoraria; Flatiron: Consultancy. Rizzieri:AROG, Bayer, Celgene, Celltron, Mustang, Pfizer, Seattle Genetics, Stemline: Consultancy; Stemline: Research Funding; Celgene, Gilead, Seattle Genetics, Stemline: Other: Speaker; AbbVie, Agios, AROG, Bayer, Celgene, Gilead, Jazz, Novartis, Pfizer, Sanofi, Seattle Genetics, Stemline, Teva: Other: Advisory Board.

Outcomes in obese patients undergoing induction therapy for acute leukemia.

Obesity continues to be a growing epidemic in the United States. Guidelines published by American Society of Clinical Oncology in 2012 recommend dosing chemotherapy using actual body weight. However, the guidelines do not provide guidance for patients with hematologic malignancies. The objective of this study was to evaluate outcomes in obese patients undergoing induction chemotherapy for acute leukemia versus nonobese patients using actual body weight dosing. This single center retrospective chart review from November 2012 to August 2016 evaluated newly diagnosed leukemia patients who received induction chemotherapy dosed on actual body weight. The primary outcome was rate of complete remission following induction chemotherapy between obese patients versus nonobese patients. Secondary outcomes included time to absolute neutrophil count and platelet recovery, incidence of febrile neutropenia, clinical or microbiological infections, early (0-15 days) and in-hospital mortality, and overall survival at six months. Obese patients had similar rates of complete remission versus nonobese patients with acute myeloid leukemia (60% vs. 61.9%; p = 0.86) and acute lymphoblastic leukemia (87.5% vs. 92.8%; p = 0.31). Obese patients with acute myeloid leukemia were more likely to receive re-induction chemotherapy following 14-day bone marrow biopsy vs. nonobese patients (53.3% vs. 23.2%; p = 0.019). There were no significant differences in secondary outcomes in either group when comparing obese versus nonobese patients. Obese patients have similar rates of complete remission compared to nonobese patients following induction chemotherapy in acute leukemia. Continued research is needed to determine optimal dosing and long-term outcomes in this patient population.

Acute Leukemia Induction Related Mortality: 6-Y Experience of Saudi Tertiary Care Institute

Mortality during induction therapy for acute leukemia, is a multifactorial process resulting in early treatment failure. It had shown sharp decline in the past 20 years in the Western world compared with developing countries.

Ciprofloxacin prophylaxis delays initiation of broad-spectrum antibiotic therapy and reduces the overall use of antimicrobial agents during induction therapy for acute leukaemia: A single-centre study

Background Due to an outbreak of extended-spectrum β-lactamase (ESBL)-producing Escherichia coli and Klebsiella pneumoniae, the routine use of fluoroquinolone prophylaxis was questioned. As a result, this study was conducted with the aim to evaluate the impact of ciprofloxacin-prophylaxis on the use of broad-spectrum antibioctics and anti-mycotics. Methods A cohort of 139 consecutive patients with acute leukaemia treated with remission-inducing induction chemotherapy between 2004–2012 at the Department of Haematology in Uppsala University Hospital was analysed. Results Fifty-three patients (38%) received broad-spectrum antibiotics at the initiation of chemotherapy and were not eligible for prophylaxis. Of the remaining patients, the initiation of broad-spectrum antibiotics was delayed by 3 days in those receiving ciprofloxacin prophylaxis (n = 47) compared with those receiving no prophylaxis (n = 39). The median duration of systemic antibiotic treatment was 6 days shorter in patients receiving ciprofloxacin prophylaxis (12 vs 18 days; p = 0.0005) and the cumulative (total) median days on systemic antibiotic treatment was shortened by 8 days (15 vs 23 days, p = 0.0008). Piperacillin/tazobactam (p = 0.02), carbapenems (p = 0.05) and empiric broad-spectrum antifungals (p < 0.01) were used significantly less often when ciprofloxacin prophylaxis was given. Conclusions Ciprofloxacin prophylaxis delayed empiric therapy by 3 days and reduced overall antibiotic use in this study. These benefits must be evaluated vs the risks of development of resistant bacterial strains, making fluoroquinolone prophylaxis an open question for debate.

Influence of the Insertion Site on Central Venous Catheter Related Complications in Patients Undergoing Allogeneic Hematopoietic Cell Transplantation, High Dose Therapy or Induction Therapy for Acute Leukemia

Central venous catheters (CVCs) are extensively used in patients undergoing hematopoietic cell transplantation (HCT) or induction chemotherapy for acute leukemia. In these patients CVCs are placed routinely either via internal jugular (IJV) or subclavian veins (SCV). Several studies have compared rates of complications between both insertion sites, particularly in the intensive care unit setting. However, to our knowledge there are no data in the literature comparing the insertion sites IJV versus SCV in patients undergoing allogeneic HCT or high dose therapy for hematologic malignancies. Thus, it was the purpose of this study to analyze systematically complications of CVCs at the different insertion sites in these patients.Patients and methods: All consecutive patients who were treated in the unit for adult HCT at our institution from 01/2011 to 06/2013 were included into this retrospective analysis. Inclusion criterion was insertion of a CVC due to allogeneic HCT, autologous HCT or induction therapy for AML or ALL. 3-lumen standard CVCs (Arrow, Reading, PA) were placed after informed consent either via the IJV or the SCV. CVCs were inserted by experienced physicians after disinfection by 70% propanolol under full barrier precautions. The insertion site was chosen at the responsible physician´s own discretion. CVCs were covered by chlorhexidine gluconate impregnated dressings, either as transparent polyurethane (Tegaderm CHG, 3M, Saint Paul, MN) or as sponge dressing (Biopatch, Ethicon, Cincinnati, OH). No patient received a systemic antibiotic prophylaxis. Reasons for premature removal of CVCs were suspected or proven CVC-related blood stream infection (BSI), progression of local infections at the insertion site, or any other CVC related severe adverse event. End points of this study were local infections, fever, BSI, duration of catheterization per CVC, congestion of the CVC, thrombosis, pneumothorax and suspected or proven catheter related deaths.Results: During the study period 255 CVCs were placed in 170 consecutive patients [median age: 59 years (range 19-79), F: n=63; M: n=107] due to allogeneic HCT (65 patients, 101 insertions), autologous HCT (30 patients, 33 insertions) or induction therapy for AML or ALL (75 patients, 121 insertions). Underlying diseases were AML (n=102), ALL (n=9), MDS (n=15), MPN (n=4), lymphoma (n=21) or plasma cell neoplasia (n=19). Out of the 255 CVSs 155 (61%) were sited via the IJV and 100 (39%) via the SCV. Among the 101 CVCs in the allogeneic HCT group 60 (60%) were placed in the IJV and 41 (41%) in the SCV. The median duration of catheterization/per CVC for the entire group was 16 days (range 3-49, IJV: 17, SCV: 15 days, ns). The corresponding data for the allogeneic HCT group were 18 (IJV) and 17 day (SCV). The events fever or local infection occurred in 75% (45/60) of IJV- and in 95% (39/41) of SCV-CVCs (p=0.0084) in the allogeneic HCT group. Moreover, in SCV-CVCs these events arose significantly earlier (median time to event 7 vs. 10 days in the IJV (p=0.012). Focusing only on the event local infection the results were also superior for the IJV-CVCs: 28/60 (47%) vs. 29/41(71%) for SCV-CVCs (p=0.026). For the entire cohort of CVCs data were similar: The events fever or local infection occurred in 127/155 (82%) of IJV- and 95/100 (95%) of SCV-CVCs (p=0.025). Median time to these events were 8 (IJV) vs. 10 days (SCV, p=0.0009). For local infections alone the differences were even more pronounced: 81/155 (IJV: 52%) vs. 81/100 (SCV: 81%, p<0.0001). There were no significant differences in the frequency of BSI between the insertion sites [entire group: IJV 46/155 (30%), SCV 20/100 (20%); allogeneic HCT group: IJV 14/60 (23%), SCV 12/41 (29%)]. Thrombosis or pneumothorax occurred only once, both with SCV-CVCs. Congestion of CVCs occurred in 20% (31/155) IJV- and in 24% (24/100) of SCV-CVCs (ns), respectively. Data for allogeneic HCT were 25% (15/60) in IJV- and 27% (11/41) in SCV-CVCs (ns). Out of the entire cohort 10 patients (7 x allogeneic HCT, 3 x induction therapy) died with an inserted CVC. 5 of them died due to BSI and therefore potentially CVC-related (3 x IJV, 2 x SCV).Conclusions: In contrast to earlier studies on patients without hematologic malignancies these data demonstrate clearly that CVCs placed in the SCV are not superior. Moreover, local infections and fever occurred significantly earlier and more frequent in SCV-CVCs in patients undergoing allogeneic HCT. DisclosuresNo relevant conflicts of interest to declare.

Hyperglycemia increases the complicated infection and mortality rates during induction therapy in adult acute leukemia patients

ObjectiveTo determine the prevalence of hyperglycemia during induction therapy in adult patients with acute leukemia and its effect on complicated infections and mortality during the first 30 days of treatment. MethodsAn analysis was performed in a retrospective cohort of 280 adult patients aged 18 to 60 years with previously untreated acute leukemia who received induction chemotherapy from January 2000 to December 2009 at the Hemocentro de Pernambuco (HEMOPE), Brazil. Hyperglycemia was defined as the finding of at least one fasting glucose measurement > 100 mg/dL observed one week prior to induction therapy until 30 days after. The association between hyperglycemia and complicated infections, mortality and complete remission was evaluated using the Chi-square or Fisher's exact tests by the Statistical Package for Social Sciences (SPSS) in the R software package version 2.9.0. ResultsOne hundred and eighty-eight patients (67.1%) presented hyperglycemia at some moment during induction therapy. Eighty-two patients (29.3%) developed complicated infections. Infection-related mortality during the neutropenia period was 20.7% (58 patients). Mortality from other causes during the first 30 days after induction was 2.8%. Hyperglycemia increased the risk of complicated infections (OR 3.97; 95% confidence interval: 2.08 - 7.57; p-value < 0.001) and death (OR 3.55; 95% confidence interval: 1.77-7.12; p-value < 0.001) but did not increase the risk of fungal infections or decrease the probability of achieving complete remission. ConclusionThis study demonstrates an association between the presence of hyperglycemia and the development of complicated infections and death in adult patients during induction therapy for acute leukemia.

The Mean Fluorescence Intensities of Anti-HLA Antibodies Detected Using Micro-Bead Flow Cytometry Predict the Risk of Platelet Transfusion Refractoriness.

AbstractAbstract 2285 Background:HLA allo-immunized patients often receive matched platelets only after demonstrating platelet transfusion refractoriness (PTR). If further risk stratification was possible, high risk patients could be considered for pre-emptive HLA-matched platelets, cryopreserved autologous platelets, or possibly thrombopoietin analogues. Micro-bead flow cytometry is widely used to detect anti-HLA antibodies, and mean fluorescence intensities (MFI) obtained from these assays correlate with antibody titers. We asked whether MFIs could be used to stratify the risk of PTR among allo-immunized patients. Study design:We retrospectively identified 387 patients who received an autologous stem cell transplant or induction therapy for acute leukemia, between January 2005 and March 2012. All patients had a serum sample taken for HLA antibody assay within 6 weeks of commencing cellular blood product transfusions. No patient was scheduled to receive prophylactic HLA matched platelets. The primary endpoint was the development of PTR. To minimize the influence of sensitization occurring after screening, only outcomes during the first 2 weeks from commencing cellular blood product transfusions were considered. PTR was defined as having received ≥ 2 consecutive RDPLT transfusions associated with an 18–24h corrected count increment of < 2.5 at 18 – 24 hours.Antibody testing was performed using a micro-bead flow cytometry assay (Lifecodes LifeScreen Deluxe, with positive results confirmed by Lifecodes Class I ID assay, Gen-Probe Transplant Diagnostics, Stamford, CT) either during the treatment period, or on serum samples stored at −30°C. Mean fluorescence intensities (MFI) were acquired using a Luminex 100 analyzer (Luminex Corporation, Austin, TX), and analyzed using Lifecodes Quicktype v2.5.5 (Gen-Probe Transplant Diagnostics, Stamford, CT). We defined the predictor variable avgMFI to be the average MFI of the 7 individual beads in the assay, weighted by whether the presence of antibodies was confirmed or not: [Display omitted] where w = 1 if the presence of antibodies is confirmed, and 0 otherwise; and subscript i refers to the ith class I bead. Results:Antibodies were detected in 57 (14.7%) patients of whom 45 (78.9%) were female. A total of 1443 random donor platelet (RDPLT) transfusions (mean platelet count 2.4×1011/unit) were studied. Sixty six (17%) patients developed PTR, of whom 28 had detectable antibodies; 29 of 321 patients who did not develop PTR also tested positive. Among antibody positive patients, median avgMFI for refractory patients was 4589 versus 349 for patients who were not, Wilcoxon rank sum test P< 0.0001. (Figure 1). The area under the receiver operating characteristic curve for avgMFI as a predictor of PTR was 0.8633 (95% confidence interval: 0.7664 – 0.9602). [Display omitted] [Display omitted] Higher avgMFIs also correlated with a broader range of target antigens, likely due to increasingly avid binding to cross-reactive epitopes. (Spearman’s r = 0.7736 for correlation between avgMFI and panel reactive antibody percentages (cPRA), calculated in reference to the general American population, and used here as a surrogate for the range of antibody specificities). cPRA was >80% in 25/27 patients with avgMFI>1000, suggesting poor ability to discriminate among patients with moderate to high antibody titers, and was not an independent predictor of PTR. Hence, while the increased probability of encountering a cognate antigen on a RDPLT may partly explain the correlation between avgMFI and PTR, the avidity of binding, represented in vitro by the MFIs, appears to be a more significant determinant of risk.In conclusion, we provide evidence for the concept that PTR risk due to HLA allo-immunization is usefully predicted by the MFIs of antibodies detected using micro-bead flow cytometry. Our model allows cut-offs for identifying high risk patients to be based on the degree of risk acceptable in a given clinical situation. This should enable hematology units to develop risk-adapted strategies for supporting allo-immunized thrombocytopenic patients. Disclosures:No relevant conflicts of interest to declare.

Clinical experience with posaconazole prophylaxis – a retrospective analysis in a haematological unit

Invasive fungal infections (IFI) are major causes of death in high-risk haematological patients receiving induction therapy for acute leukaemia or intensified immunosuppression due to acute or chronic graft-vs.-host disease (GvHD) following allogeneic stem cell transplantation (SCT). Recently, two randomised studies showed the efficacy of a posaconazole prophylaxis (PP) in these patients to prevent IFI. This prompted the strong recommendation for the use of PP in national and international guidelines. As we started PP in our leukaemia and transplantation unit in summer 2007, we retrospectively analysed the impact of PP on the incidence of possible, probable or proven IFI in this group of patients. Incidence of IFI according to the revised EORTC criteria, published in 2008, was reviewed retrospectively in a group of high-risk patients treated in our unit 1 year before the start of PP compared with the same group in the following year with PP. First analysis was performed on an intention-to-treat basis comparing patients during 1 year of PP with the same group of patients in the year before the start of PP. In a second, deeper analysis, patients were grouped for fluconazole or posaconazole irrespective of the time period the prophylaxis was given. In a first intent-to-treat analysis, 56 patients were analysed in the period without PP (noPP) compared with 34 patients in the period with PP. Overall IFI rates (possible, probable and proven IFI) were reduced from 47% (noPP group) to 35% (PP group). In a second analysis, only patients receiving either fluconazole or PP were analysed, resulting in 29 patients in the noPP group and 36 patients in the PP group. There was a reduction in overall IFI in the PP group especially in the acute myeloid leukaemia (AML) induction patients, but this does not reach statistical significance because of low patient numbers. However, initiation of antifungal therapy was significantly less frequent in AML induction patients in the PP group compared with the noPP group. Unfortunately, this does not result in reduced mortality rates, as mortality in the PP group is higher (15% vs. 7%) than in noPP patients because of double the number of patients with severe GvHD in the PP group. Both breakthrough infections were documented in this subgroup of patients. Our data, collected in every day clinical practice, add further evidence to the advantage of a PP strategy in this group of high-risk patients. However, more data are urgently needed to assess the impact of PP on the incidence and pattern of fungal infections and the strategies to be used in patients with persisting fever and pulmonary infiltrates receiving PP, especially in the setting of SCT and GvHD.

Sagittal sinus thrombosis due to L-asparaginase

Cerebral Sinovenous Thrombosis (CSVT) is a serious complication of L-asparaginase chemotherapy for leukemia in children. Clinical features of headache, altered consciousness, focal neurological deficit, and seizures developing during or immediately after treatment with L-asparaginase should alert the treating physician to the possibility of CSVT. Immediate imaging of the brain should be done using CT and MRI and the veins should be visualized noninvasively by CT and MR venography. We report two children on induction therapy for acute leukemia who presented with seizures, headache, and altered consciousness. Venous infarcts with and without hemorrhage were seen on CT in one patient and the empty delta sign was seen after contrast injection; however, the early changes were missed by CT. MRI detected dural sinus thrombosis relatively earlier in another patient, while the CT findings were equivocal; in this patient, contrast-enhanced MRI showed the empty delta sign and MR venography confirmed absent flow in the superior sagittal sinus, which was diagnostic of sinus thrombosis. Rapid anticoagulation was started with heparin and maintained with warfarin. The child with a unilateral small nonhemorrhagic infarct made a complete recovery while the other, with bilateral hemorrhagic infarcts, did not survive. We stress the importance of early diagnosis of CSVT using CT and MRI in children with leukemia being treated with L-asparaginase; this will permit timely treatment.

Molecular target therapy – towards curative regimen: a 20-year experience in the treatment of acute promyelocytic leukemia (APL) in the Shanghai Institute of Hematology

Since the first description of acute promyelocytic leukemia (APL) in 1957 as the most malignant form of acute leukemia, several developments have paved the way to make this disease the most curable leukemia in adults and change the paradigm of cancer treatment. Therapy of APL was pioneered by Bernard et al in 1973 demonstrating a striking sensitivity to daunorubicin, probably related to significantly lower P-glycoprotein expression observed in APL cells compared to other subtypes of acute myeloid leukemia (AML). The incorporation of ATRA, a noncytotoxic differentiating agent that is regarded as the first differentiation therapy has changed dramatically the management, outcome, and prognosis of APL. ATRA was first introduced to clinical use for the treatment of APL in 1986. Since then, randomized studies in many centers around the world document a rising CR rate, a decrease in severe adverse effects, and a prolongation of remission duration. ATRA combined with anthracycline-based chemotherapy can achieve CR in 90–95% of patients with APL and cure the disease in 70–75% of the cases. Combination therapy with ATRA and chemotherapeutic agents should now be considered as a standard treatment of APL. Over the last decade, tremendous efforts have been made to elucidate the molecular genesis of APL, as well as the mechanism of action of ATRA. The mechanism of action of ATRA can be summarized as follows: 1. The binding of ATRA to RAR receptors causes degradation of PML-RARα protein through the ubiquitin-proteosome and caspase system, leading to restoration of terminal differentiation of promyelocytes; 2. Exposure of APL cells to ATRA in vitro or in vivo induces relocalization of PML and restores the normal structure of PODs; and 3. Under the action of ATRA, CoR is dissociated from the repressive complex, whereas CoA (coactivator) is recruited to the complex. As a result, the repression of transcriptional activation of target genes is relieved and the differentiation of promyelocytes is restored. Treatment of APL by arsenic compounds represents a successful example of apoptosis induction therapy of acute leukemia. As2O3 exerts dual effects on APL cells. Studies in vitro with NB4 cells showed that a higher concentration of As2O3 (0.5–1.0 μM) induced apoptosis with typical morphological changes, DNA laddering on agarose gel electrophoresis, appearance of an apoptotic peak on flow cytometric analysis, and increased expression of annexin V on the cell surface membrane. At lower concentrations, As2O3 can induce APL cells to partially differentiate along the granulocytic pathway. Synergistic effect of ATRA and As2O3 was confirmed by several research works in vivo and in vitro. The first clinical trial was completed by SIH in 2001. CR rate was same as ATRA or As2O3 alone, but the median day to CR was very short, only 26 days, and OS and DFS were much better than ATRA or As2O3 alone. Now timing and dose of As2O3 combined with ATRA in newly diagnosed APL patients need to be confirmed. Recently, several genetic and phenotypic characteristics of acute promyelocytic leukemia (APL) blasts have been demonstrated. These include the PML/RARα fusion and the transcription co-repressor complex recruited at the promoter of target genes by the hybrid protein, the intense and homogeneous expression of the CD33 antigen, and absence of multidrug resistance-related phenotype, a frequently mutated and constitutively activated FLT3 receptor. Such genotypic and phenotypic features are targeted by agents currently in use in front-line therapy or at relapse (i.e., retinoids, As2O3, anthracyclines and anti-CD33 monoclonal antibodies), and by novel agents that many find a place in future treatments such as histone deacetylase and FLT3 inhibitors.

Rater

e20678 Background: Management of neutropenic fever is based on risk stratification of the episode which helps in optimizing treatment. MASCC is the most commonly used for risk stratification Patients with a score of &gt; 21 were regarded as low risk; patients with a score of &lt;21 were regarded as high risk. We tried to validate the MASCC index for our ethnic population. Methods: Patients were recruited throughout a 12 month period. Inclusion criteria were diagnosis of hematolymphoid malignancy, neutropenic febrile episode secondary to chemotherapy or during induction therapy of acute leukemia and more than 18 years of age All patients were risk stratified, hospitalized and treated with broad-spectrum, empiric, intravenous antibiotic therapy until recovery or outcome of the event. The incidence of medical complications in both groups and death related to the neutropenic infection was recorded. The data was entered on SPSS software and MASCC criteria was analyzed for sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV). Results: A total of 81 febrile neutropenic episodes were included; 34 classified as low risk and 47 as high risk according to MASCC risk index score. The sensitivity, specificity, PPV, NPV and accuracy of MASCC risk index score were 45.5%, 40%, 11%, 82%, 40.7%. We subsequently analyzed the subset of Acute Myeloid Leukemia (AML) patients as they were the majority comprising of 62/81 episodes. The subset of AML patients risk stratified according to MASCC risk index showed sensitivity, specificity, PPV, NPV and accuracy of 71%, 25.5%, 11%, 87.5%, 31% respectively. Conclusions: In our patient group, the value of MASCC score is limited with poor sensitivity, specificity and PPV. This trend is also seen in the subset analysis of AML patients. The value of the MASCC index with the score of 21 as the cut-off between low risk and high risk seems limited in our patients and requires confirmation with larger set of patients. No significant financial relationships to disclose.

The platelet prophylactic transfusion trigger: when expectations meet reality

The platelet prophylactic transfusion trigger: when expectations meet reality

Treatment of Diffuse Alveolar Hemorrhage with Recombinant Factor VIIa in Patients with Hematologic Malignancies.

Diffuse alveolar hemorrhage (DAH) is a potentially life-threatening pulmonary complication in patients following hematopoietic stem-cell transplantation (HSCT) or acute leukemia induction therapy. This syndrome is associated with a high mortality rate. Current management strategies include high-dose steroids, platelet transfusions and mechanical ventilatory support to treat acute respiratory failure. Recombinant factor VIIa (rFVIIa) is approved for treatment of bleeding in patients with hemophilia A/B with inhibitors. A greater understanding of the mechanism by which rFVIIa restores hemostasis has become available; with the in-vitro evidence supporting that the thrombin burst achieved by rFVIIa is independent of the presence or binding to tissue factor. This insight has suggested a range of other potential clinical uses for the drug. We report our experience of using rFVIIa for the treatment of DAH in the setting of HSCT and acute leukemia induction therapy. We treated 5 episodes of DAH in 4 adult patients with hematologic malignancies. Two patients had undergone matched unrelated donor HSCT. Clinically, DAH was suspected because of progressive respiratory failure. DAH was confirmed by radiologic and bronchoscopic exams. All patients received high-dose steroids, broad-spectrum antibiotics and respiratory support, as indicated. Packed red cells and platelets were transfused to keep the hemoglobin above 8gm/dL and platelets above 50,000/μL. Patients received boluses of rFVIIa at 90mcg/kg, every 3-12 hrs. The dose of rFVIIa ranged from 7,200–28,000 mcg/day. All five episodes of DAH achieved clinicoradiologic improvement. No toxicity or adverse events were observed with rFVIIa use. Our experience indicates that rFVIIa might be an effective treatment option for patients with DAH, post-HSCT or acute leukemia induction therapy. The optimal dosing schedule in this clinical situation needs to be studied.Patient demographics and outcomesPatientDiagnosisPre-interventionrFVIIa used (microgms)PRBC/Platelet transfused (units)Clinical outcomeOWALL-MUD, BMT, day +758.8/12,00024000/d X 4days3/10100 Non-rebreather to 6L nasal cannula O2OWALL-MUD, BMT, day +808/8,00028000/d X 4 days6/14Ventilatory support to successful weaningCSRelapsed AML, S/P induction8.8/19,0008400/d X 2 days2/4O2 requirement decreasedLWCML blast crisis, S/P induction8.6/101,00010800/d X 2 days4/1Clinically no bleeding, decreased O2 requirementRBRelapsed ALL8.7/7,0007200/d X 1 day2/4Ventilatory support to successful weaning

What would Karl Landsteiner do? The ABO blood group and stem cell transplantation

ABO blood group antigens, of great importance in transplantation and transfusion, are present on virtually all cells, as well as in soluble form in plasma and body fluids. Naturally occurring plasma IgM and IgG antibodies against these antigens are ubiquitous. Nonetheless, the ABO blood group system is widely ignored by many transfusion services, except for purposes of red cell transfusion. We implemented a policy of transfusing only ABO identical platelets and red cells in patients undergoing stem cell transplantation or treatment for hematologic malignancies. Major bleeding episodes have occurred in about 5% of patients undergoing induction therapy for acute leukemia as compared with 15-20% in the literature. Overall survival times appear to be superior to that in historical cohorts. In 2002-2004, treatment-related mortality at 100 days in our Blood and Marrow Transplant Unit was 0.7% for autologous transplants (n=148), 13% for sibling allogeneic transplants (n=110), and 24% (n=62) for matched unrelated allogeneic transplants, suggesting that our approach is safe. We speculate that more rigorous efforts on the part of transfusion services to provide ABO identical blood components, and to remove incompatible supernatant plasma, when necessary, might yield reduced morbidity and mortality in patients undergoing stem cell transplantation.

Association of ABO-mismatched platelet transfusions with morbidity and mortality in cardiac surgery.

The transfusion of ABO-mismatched platelets has been associated with increased morbidity and mortality during induction therapy for acute leukemia and allogeneic progenitor cell transplantation. Reported here is a cohort study of 153 patients undergoing primary coronary artery bypass graft or coronary valve replacement surgery by two surgeons in one institution during 1997 and 1998. All statistics employed nonparametric two-sided tests (Mann-Whitney; Fisher's exact test). Patients receiving at least one ABO-mismatched pool of platelets had a significantly longer hospital stay, more days of fever, greater total hospital charges, and more RBC transfusions. Mortality, hours in the intensive care unit, days on antibiotics, and numbers of platelet transfusions were also greater in recipients of ABO-mismatched platelets, but these differences were of less statistical significance. When the analysis was restricted to the 139 patients who received no more than two pools of platelets, the trends for increased morbidity and mortality (8.6% vs. 1.9%; p = 0.10) in recipients of ABO-mismatched platelets persisted. The number of RBC transfusions required in this latter cohort was 50 percent greater (mean, 6.1 vs. 9.2; p = 0.02), despite the fact that the number of platelet transfusions given was similar (mean, 1.2 vs. 1.3 pools; p = 0.22). ABO-mismatched platelet transfusions are associated with unfavorable outcomes in cardiac surgery, a relationship that remains unexplained. As this association has been found in three cohort studies in various clinical settings, further investigation of this association is warranted.

Fatal disseminated infection by scedosporium prolificans during induction therapy for acute leukemia: a case report and literature review

We report a case of fatal disseminated fungal infection by Scedosporium prolificans which occurred in a patient with acute leukemia during induction chemotherapy. Rapid clinical deterioration despite high-dose empirical amphotericin B highlights both the pathogenicity of this fungus in immunocompromised hosts and its resistance to standard antifungal therapy.

How Long does it Take to Get a “Do not Resuscitate” Order?

Less than 50% of physicians know the resuscitation wishes of their patients and only a small fraction of patients have completed "do not resuscitate" (DNR) orders before death. One of the common reasons given by physicians is that the process of "getting a DNR" takes too long, and some authorities have suggested that additional reimbursement is needed. The purpose of this study is to assess how long the DNR education and consent process actually takes in practice. Our study group was a convenience sample of consecutive patients seen by experienced oncologists in a community and academic practice setting. Physicians were asked to record the time spent in DNR discussions with patients, the outcomes, and their comments. DNR orders were obtained on 16 of 22 patients with a single interview lasting a mean time of 16 minutes. Additional DNR orders were obtained on two more patients after a second interview of 6 patients, mean time 17.5 minutes. After a third interview of 4 patients, mean time 23 minutes, only 2 of 22 patients would not allow DNR orders. Of these two, one died intubated in the intensive care unit and the other underwent continued unsuccessful induction therapy for acute leukemia before dying. DNR orders can be obtained on nearly all patients within the time frame of an inpatient or outpatient visit. Time is not the main obstacle to DNR discussions, and additional reimbursement for additional time is not necessary. A small subset of patients continue to refuse DNR orders. Physician and patient reluctance to broach the subject may be a bigger impediment than time.