Stability in the cumulative incidence, severity and mortality of 101 cases of invasive mucormycosis in high-risk patients from 1995 to 2011: a comparison of eras immediately before and after the availability of voriconazole and echinocandin-amphotericin combination therapies.

As invasive mucormycosis (IM) numbers rise, clinicians suspect prior voriconazole worsens IM incidence and severity, and believe combination anti-fungal therapy improves IM survival. To compare the cumulative incidence (CI), severity and mortality of IM in eras immediately before and after the commercial availability of voriconazole all IM cases from 1995 to 2011 were analysed across four risk-groups (hematologic/oncologic malignancy (H/O), stem cell transplantation (SCT), solid organ transplantation (SOT) and other), and two eras, E1 (1995-2003) and E2, (2004-2011). Of 101 IM cases, (79 proven, 22 probable): 30 were in E1 (3.3/year) and 71 in E2 (8.9/year). Between eras, the proportion with H/O or SCT rose from 47% to 73%, while 'other' dropped from 33% to 11% (P = 0.036). Between eras, the CI of IM did not significantly increase in SCT (P = 0.27) or SOT (P = 0.30), and patterns of anatomic location (P = 0.122) and surgical debridement (P = 0.200) were similar. Significantly more patients received amphotericin-echinocandin combination therapy in E2 (31% vs. 5%, P = 0.01); however, 90-day survival did not improve (54% vs. 59%, P = 0.67). Since 2003, the rise of IM reflects increasing numbers at risk, not prior use of voriconazole. Frequent combination of anti-fungal therapy has not improved survival.

Therapy-related acute promyelocytic leukemia: observations relating to APL pathogenesis and therapy.

Therapy-related acute promyelocytic leukemia (t-APL) is a well-recognized form of APL for which the underlying etiology has been well characterized. The pathogenesis of de novo (dn-APL) remains unknown; but epidemiologic studies have consistently identified increased body mass index (BMI), younger age, and ethnicity as possible risk factors. We analyzed demographics, clinical features, and treatment responses in a contemporary series of 64 patients treated with all-trans-retinoic acid and anthracycline-based therapy to assess for differences in these two etiologically distinct patient groups. Compared with patients with t-APL (n = 11), those with dn-APL (n = 53) had a greater median BMI (31.33 vs. 28.48), incidence of obesity (60.4% vs. 27.3%) (P = 0.04), and history of hyperlipidemia (45.3% vs. 18.2%) (P = 0.01). Fewer t-APL than dn-APL patients achieved complete remission at 63.6% vs. 92.5% respectively (P = 0.008). This was the result of a higher induction mortality rate of 36.4% vs. 7.5% respectively (P = 0.008). No cases of leukemic resistance were seen in either group. Overall survival (OS) was inferior in t-APL compared with dn-APL at 51% vs. 84%, respectively (P < 0.005), primarily as a result of higher induction mortality. Relapse occurred in nine patients (16.1%) overall, but no relapses occurred in the t-APL cohort. Our observations provide further support for the hypothesis that abnormalities in lipid homeostasis may in some way be of pathogenic importance in dn-APL. Therapy-related APL is sensitive to standard therapy with no cases of resistance or relapse seen. The inferior OS of the t-APL was due to induction mortality, possibly reflecting prior therapy.

Cancer-associated microangiopathic hemolytic anemia with thrombocytopenia: an important diagnostic consideration.

BACKGROUND: Early initiation of plasma exchange (PE) allows more than 80% of patients with idiopathic thrombotic thrombocytopenic purpura (TTP), most commonly because of severe ADAMTS13 deficiency, to achieve remission and mandates urgency in diagnosis and therapy. Metastatic cancer may present with a microangiopathic hemolytic anemia with thrombocytopenia that is clinically similar to TTP but does not respond to PE. ADAMTS13 activity can be diagnostic but usually not immediately available. Recognition of cancer-associated microangiopathic hemolytic anemia with thrombocytopenia (CA-MHA) is paramount to avoid inappropriate PE therapy and delays in cancer-specific chemotherapy. OBJECTIVE: To identify distinguishing characteristics of CA-MHA and TTP to facilitate early recognition of CA-MHA. METHODS: In a retrospective cohort study, baseline clinical and laboratory data of consecutive adult patients with CA-MHA (n = 7) or autoimmune TTP (n = 7) from a registry of patients with clinically suspected acute TTP referred for PE were compared. RESULTS: The frequencies of bone pain and respiratory symptoms were significantly greater among patients with CA-MHA compared to patients with TTP; other baseline clinical and laboratory characteristics did not differ significantly between the two groups. Response to PE and mortality at day 30 were significantly worse for CA-MHA (14% and 71%, respectively) compared to patients with TTP (86% and 14%, respectively). CONCLUSIONS: Baseline clinical and laboratory characteristics largely do not distinguish acute CA-MHA from autoimmune acute TTP. While all suspected acute patients TTP should receive urgent PE, bone pain, respiratory symptoms, or inadequate PE response should prompt an early search for CA-MHA.

Acute leukemia in pregnancy: a single institution experience with 23 patients.

Management of acute leukemia during pregnancy presents a considerable challenge. Herein, we review our experience of 23 patients diagnosed with acute leukemia; during pregnancy at the Mayo Clinic between 1962 and 2016. Ten (43.4%), seven (30.4%), and six (26.2%) patients were diagnosed in first, second, and third trimester, respectively. In approximately, 50% (n = 11) therapeutic terminations or spontaneous abortions occurred. Fifty percent (2/4) of patients diagnosed during either first or second trimester who delayed chemotherapy by greater than one week died during induction therapy. Eleven patients received chemotherapy while pregnant which led to four fetal losses and seven deliveries (five full-term and two preterm deliveries). No congenital malformations were reported. Eighteen patients (78%) achieved complete remission. At a median follow up of 55 months, seven patients (30%) remain alive. In summary, we provide a comprehensive description of maternal and fetal outcomes and insight into management of acute leukemia during pregnancy.

Safety and feasibility of lower antithrombin replacement targets in adult patients with hematological malignancies receiving asparaginase therapy.

The optimal antithrombin(AT) activity parameters for replacement as thromboprophylaxis following asparaginase remains unclear. This single-center, retrospective study evaluated two sets of AT replacement thresholds and targets in adults receiving asparaginase-containing chemotherapy. AT supplementation adhered to institutional standards, which lowered the AT activity target from 100% to 80% in 6/2014. Ninety-two patients were evaluated. Cumulative thrombosis incidence was 16% at 6 months (95%CI:6.8-24.0, maximum follow-up 315 days) with similar incidence between the 80% and 100% target groups, 14% (2 of the 14) and 13% (10 of the 78), respectively, with a small non-Line-Related DVT incidence (3%). Most thrombotic events occurred during induction chemotherapy and demonstrated no associations with replacement target, cumulative days or cumulative area under AT activity target, number of asparaginase doses, or cumulative asparaginase dose. Median estimated AT replacement expenditure was $34,963USD (IQR $16,260USD to $79,319USD) per patient. Cost-effectiveness and optimization of AT replacement for thromboprophylaxis following asparaginase requires prospective evaluation.

Phase I and pharmacologic study of infusional topotecan and Carboplatin in relapsed and refractory acute leukemia.

PURPOSE: To assess the maximum tolerated dose, toxicities, pharmacokinetics, and antileukemic activity of topotecan and carboplatin in adults with recurrent or refractory acute leukemias. EXPERIMENTAL DESIGN: Patients received topotecan and carboplatin by 5-day continuous infusion at nine dose levels. Patients achieving a complete remission received up to two additional courses for consolidation. Plasma topotecan and ultrafilterable platinum were assayed on days 1 to 5. In addition, pretreatment levels of various polypeptides in leukemic cells were examined by immunoblotting to assess possible correlations with response. RESULTS: Fifty-one patients received a total of 69 courses of therapy. Dose-limiting toxicity consisted of grade 4/5 typhlitis and grade 3/4 mucositis after one course of therapy or grade 4 neutropenia and thrombocytopenia lasting >50 days when a second course was administered on day 21. Among 45 evaluable patients, there were 7 complete remissions, 2 partial remissions, 1 incomplete complete remission, and 1 reversion to chronic-phase chronic myelogenous leukemia. Topotecan steady-state plasma concentrations increased with dose. No accumulation of topotecan or ultrafilterable platinum occurred between days 1 and 5 of therapy. Leukemic cell levels of topoisomerase I, checkpoint kinase 1, checkpoint kinase 2, and Mcl-1 correlated with proliferating cell nuclear antigen but not with response. In contrast, low Bcl-2 expression correlated with response (P = 0.014, Mann-Whitney U test). CONCLUSIONS: The maximum tolerated dose was 1.6 mg/m(2)/d topotecan plus 150 mg/m(2)/d carboplatin. The complete remission rate in a heavily pretreated population was 16% (33% at the highest three dose levels). Responses seem to correlate with low pretreatment blast cell Bcl-2 expression.

Mitoxantrone, etoposide, and cytarabine with or without valspodar in patients with relapsed or refractory acute myeloid leukemia and high-risk myelodysplastic syndrome: a phase III trial (E2995).

PURPOSE: To determine whether adding the multidrug resistance gene-1 (MDR-1) modulator valspodar (PSC 833; Novartis Pharmaceuticals, Hanover, NJ) to chemotherapy provided clinical benefit to patients with poor-risk acute myeloid leukemia (AML) and high-risk myelodysplastic syndrome (MDS). PATIENTS AND METHODS: A phase III randomized study was performed using valspodar plus mitoxantrone, etoposide, and cytarabine (PSC-MEC; n=66) versus MEC (n=63) to treat patients with relapsed or refractory AML and high-risk MDS. RESULTS: For the PSC-MEC versus MEC arms, complete response (CR) was achieved in 17% versus 25% of patients, respectively (P=not significant). For patients who had not received prior intensive chemotherapy (ie, with secondary AML or high-risk MDS), the CR rate was increased--35% versus 15% for the remaining patients (P=.018); CR rates did not differ between treatment arms. The median disease-free survival in those achieving CR was similar in the two arms (10 versus 9.3 months) as was the patients' overall survival (4.6 versus 5.4 months). The CR rates in MDR+ (69% of patients) versus MDR- patients were similar for those receiving either chemotherapy regimen (16% versus 24%). The CR rate for unfavorable cytogenetic patients (45% of patients) was 13% compared to the remainder, 28% (P=.09). Population pharmacokinetic analysis demonstrated that the clearances of mitoxantrone and etoposide were decreased by 59% and 50%, respectively, supporting the empiric dose reductions in the PSC-MEC arm designed in anticipation of drug interactions between valspodar and the chemotherapeutic agents. CONCLUSION: CR rates and overall survival were not improved by using PSC-MEC compared to MEC chemotherapy alone in patients with poor-risk AML or high-risk MDS.

Primary Myelodysplastic Syndromes: The Mayo Clinic Experience With 1000 Patients.

OBJECTIVES: To share our 25 years of experience with patients with primary myelodysplastic syndromes (MDS) and to describe the natural history of the disease including presenting clinical and laboratory characteristics and long-term disease outcomes. PATIENTS AND METHODS: One thousand consecutive patients with primary MDS evaluated at Mayo Clinic between January 1, 1989, and May 1, 2014, were considered. The Revised International Prognostic Scoring System and other risk models were applied for risk stratification. Separate analyses were conducted for patients diagnosed before 2005 (n=531) and after 2005 (n=469). RESULTS: Eighty-five percent of patients were older than 60 years (median age, 72 years), with 69% being men. The median follow-up period was 27 months (range, 0-300 months), during which time 808 (81%) deaths and 129 (13%) leukemic transformations were documented. Median survival and leukemic transformation rates were similar in patients diagnosed before or after 2005, despite the significantly higher use of hypomethylating agents in the latter group: 33 months vs 28 months (P=.46) and 13% vs 10% (P=.92), respectively. Revised International Prognostic Scoring System risk distribution was similar in patients diagnosed before or after 2005 (P=.23): 17% were categorized as very low, 36% low, 21% intermediate, 15% high, and 11% very high risk, with a median survival of 72, 43, 24, 18, and 7 months, respectively (P<.001). We found Revised International Prognostic Scoring System cytogenetic risk categorization to be suboptimal in its performance, whereas contemporary prognostic models were broadly similar in their performance. CONCLUSION: The poor outcome in patients with MDS does not appear to have improved over time. Current risk stratification systems for MDS are not substantially different from each other. There is a dire need for drugs that are truly disease modifying and risk models that incorporate prognostically relevant mutations.

Neutropenic colitis after treatment of acute myelogenous leukemia with idarubicin and cytosine arabinoside.

OBJECTIVE: To determine the gastrointestinal toxic effects of idarubicin and cytosine arabinoside combination therapy in patients with newly diagnosed acute myelogenous leukemia (AML). PATIENTS AND METHODS: We performed a single-institution retrospective analysis of the incidence of neutropenic colitis in patients with newly diagnosed AML receiving idarubicin and cytosine arabinoside combination therapy. Using pharmacy records, we identified 78 patients who received idarubicin during the study period of January 1997 to September 1998 and who agreed to a review of their medical records. Patients with preexisting bowel conditions were excluded from this analysis. We used a strict definition of neutropenic colitis that included clinical findings (severe abdominal pain, diarrhea, hematochezia, and/or peritoneal signs) plus radiographic evidence of bowel inflammation in the absence of an identified bacterial pathogen. RESULTS: Of the 78 patients receiving idarubicin and cytosine arabinoside for treatment of AML, 65 were included in this study. We observed neutropenic colitis in 10 of these 65 AML patients. This complication was followed by sepsis in 3 patients and was the major cause of death in 4 of the 8 patients who died. CONCLUSION: This analysis suggests that neutropenic colitis is a frequent and serious complication of idarubicin and cytosine arabinoside treatment.

Histologic and immunohistochemical study of bone marrow monocytic nodules in 21 cases with myelodysplasia.

Previously, 4 cases of myelodysplastic syndrome were reported that had unusual, distinct monocytic nodules in bone marrow. The monocytic nodules, predominantly composed of monocytes with CD68+ immunostaining, had no or low expression of Ki-67 and topoisomerase II alpha. The purpose of the present study was to further define the associated clinical diseases, histologic features, and immunohistochemical characteristics of 21 such cases. Relevant hematopathologic slides of all cases were reviewed, and extensive immunohistochemical staining was performed. Most patients (15/21 [71%]) had monocytosis in the bone marrow, and chronic myelomonocytic leukemia was the most commonly associated clinical disease. In 4 patients, the monocytic nodules also were present in lymph node, spleen, or skin. Immunohistochemical staining results for the monocytes in the nodules were similar to those for plasmacytoid monocytes. Our study established that monocytic nodules can be present in myelodysplastic syndromes, myeloproliferative diseases, and acute myeloid leukemia; verified the monocytic lineage; and revealed the low proliferative state of these cells.

The prognostic significance of trisomy 8 in patients with acute myeloid leukemia.

Recent therapeutic outcomes for patients with acute myeloid leukemia and trisomy 8 (+8) who were seen at our institution were investigated. Complete remission was achieved in 85% with isolated +8, 100% with +8 and chromosomal abnormalities predictive of a favorable outcome, and 47% of patients with +8 and other, mostly complex chromosomal abnormalities. Median relapse-free and overall survivals in months were 5.5 and 12 (isolated +8), 20 and 25 (+8 and favorable karyotype), and 7.5 and 6 (+8 and unfavorable karyotype). Despite an encouraging rate of complete remission, the relapse-free and overall survivals for patients with isolated +8 were not significantly different from those of patients with +8 and unfavorable karyotypes. The presence of +8 did not appear to adversely affect the outcome of patients with favorable karyotypes.

Thromboembolism in adults with acute lymphoblastic leukemia during induction with L-asparaginase-containing multi-agent regimens: incidence, risk factors, and possible role of antithrombin.

Thromboembolism (TE) is a known complication of L-asparaginase (ASP) therapy of acute lymphoblastic leukemia (ALL), possibly attributable to reduced synthesis of natural anticoagulants, in particular antithrombin (AT). This retrospective single institution study was performed to determine the TE incidence among adults undergoing induction with contemporary, ASP-containing regimens. Ten of 54 (18.5%) consecutive adults developed symptomatic, objectively confirmed TE, at a median of 5.5 days after the first ASP dose. These were notable for CNS and upper extremity localization, varied significantly according to ALL immunophenotype (precursor B: 11% vs. T cell: 33%), without apparent effect of schedule or total dose of ASP. Median baseline AT level was 94% and fell to a nadir of 47% (P < 0.0001) during ASP therapy. Prophylactic AT had been given to 17 during ASP therapy. None of these developed TE vs. 10/37 (27%) without replacement (P = 0.021). These observations merit further study to gain insight into disease and/or therapy-specific pathogenesis of TE in this population and call for the prospective evaluation of appropriate prophylactic interventions.

Veno-occlusive disease of the liver after blood and marrow transplantation: analysis of pre- and post-transplant risk factors associated with severity and results of therapy with tissue plasminogen activator.

We reviewed our blood and marrow transplantation (BMT) database from April 1982 to July 1996 and identified 111 of 474 patients with serum bilirubin concentration (SBR) > or = 34 micromol/l for two consecutive days within the first 20 days after related allogeneic or autologous BMT. Of the 111, 73 fulfilled the Seattle criteria for veno-occlusive disease of the liver (VOD) and had no other obvious cause for liver dysfunction. The patients were 16-60 years old (median, 39 years), and 41 were male (56%). Fourteen patients (19%) had autologous BMT, and 59 (81%) had allogeneic BMT. Twenty-eight (38%), 12 (16%), and 33 (45%) patients had severe, moderate, and mild VOD, respectively, by Seattle criteria. None of 23 patients with maximum (max) SBR > or = 257 micromol/l survived, all patients with max SBR < or = 128 micromol/l survived, and 7 of 15 patients (47%) with max SBR 128-257 micromol/l survived. The only pre-transplantation risk factor predictive of severe VOD was advanced disease state (P = 0.035), and the only transplant factors that predicted severe VOD were max SBR (P = 0.01) and maximum blood urea level (P = 0.03). Ten patients (all with creatinine levels > or = 150 micromol/l) were treated with tissue plasminogen activator; only two had a significant response and only one survived beyond day 120.

Prognostic factors and outcomes of adults with hemophagocytic lymphohistiocytosis.

OBJECTIVE: To describe the prognostic factors and outcomes of adults with hemophagocytic lymphohistiocytosis (HLH), a rare disorder caused by pathologic activation of the immune system. PATIENTS AND METHODS: The study population consisted of a consecutive cohort of adult (age ≥18 years) patients treated at Mayo Clinic in Rochester, Minnesota, from January 1, 1996, through December 31, 2011, in whom a diagnosis of HLH was suspected and subsequently confirmed by retrospective review using the HLH-04 diagnostic criteria. RESULTS: Of 250 adult patients suspected of having HLH, 62 met the HLH-04 diagnostic criteria and were included in the final analysis. The median age was 49 years (range, 18-87 years), and 42 (68%) were male. The underlying cause of HLH was malignant tumor in 32 patients (52%), infection in 21 patients (34%), autoimmune disorder in 5 patients (8%), and idiopathic disease in 4 patients (6%). After a median follow-up of 42 months, 41 patients (66%) had died. The median overall survival of the entire cohort was 2.1 months. The median overall survival of patients with tumor-associated HLH was 1.4 months compared with 22.8 months for patients with non-tumor-associated HLH (P=.01). The presence of a malignant tumor and hypoalbuminemia were significant predictors of inferior survival on multivariate analysis. CONCLUSION: In this large series of adults with secondary HLH treated at a single tertiary care center, patients with low serum albumin levels and tumor-associated HLH had a markedly worse survival. Hemophagocytic lymphohistiocytosis remains elusive and challenging to clinicians who must maintain a high index of suspicion. The recent discovery of several novel diagnostic and therapeutic modalities may improve outcomes of adult patients with HLH.

Comparison of complication rates of Hickman(®) catheters versus peripherally inserted central catheters in patients with acute myeloid leukemia undergoing induction chemotherapy.

Central venous access devices (CVADs) are used for intravenous therapy in patients with hematological malignancies. There are limited data comparing catheter outcomes in patients with acute myeloid leukemia (AML) undergoing induction chemotherapy. A retrospective review comparing the incidence of early and late CVAD-associated complications and their effect on CVAD removal was performed in patients with AML undergoing induction chemotherapy between 2007 and 2011. Overall, 64 Hickman(®) catheters and 84 peripherally inserted central catheters (PICCs) were inserted. There was a trend toward increasing use of PICCs. The rate of CVAD occlusion was higher in PICCs compared to Hickman catheters (48.2% vs. 3.2%), for a rate of 20.43 vs. 1.25 per 1000 CVAD-days (p = 0.0001). There was no significant difference in the rates of CVAD-associated thrombosis, premature removal, blood stream infection (BSI) and CVAD-related BSI. Importantly, there was no significant difference in the rate of CVAD removal between Hickman catheters and PICCs for the duration that the CVADs were in place. The choice of type of CVAD inserted into patients with newly diagnosed AML will depend on ease of catheter placement, cost, perception of frequency and severity of complications, and clinician preference.