Durable Remissions with Ivosidenib in IDH1-Mutated Relapsed or Refractory AML.

BACKGROUND: Mutations in the gene encoding isocitrate dehydrogenase 1 ( IDH1) occur in 6 to 10% of patients with acute myeloid leukemia (AML). Ivosidenib (AG-120) is an oral, targeted, small-molecule inhibitor of mutant IDH1. METHODS: We conducted a phase 1 dose-escalation and dose-expansion study of ivosidenib monotherapy in IDH1-mutated AML. Safety and efficacy were assessed in all treated patients. The primary efficacy population included patients with relapsed or refractory AML receiving 500 mg of ivosidenib daily with at least 6 months of follow-up. RESULTS: Overall, 258 patients received ivosidenib and had safety outcomes assessed. Among patients with relapsed or refractory AML (179 patients), treatment-related adverse events of grade 3 or higher that occurred in at least 3 patients were prolongation of the QT interval (in 7.8% of the patients), the IDH differentiation syndrome (in 3.9%), anemia (in 2.2%), thrombocytopenia or a decrease in the platelet count (in 3.4%), and leukocytosis (in 1.7%). In the primary efficacy population (125 patients), the rate of complete remission or complete remission with partial hematologic recovery was 30.4% (95% confidence interval [CI], 22.5 to 39.3), the rate of complete remission was 21.6% (95% CI, 14.7 to 29.8), and the overall response rate was 41.6% (95% CI, 32.9 to 50.8). The median durations of these responses were 8.2 months (95% CI, 5.5 to 12.0), 9.3 months (95% CI, 5.6 to 18.3), and 6.5 months (95% CI, 4.6 to 9.3), respectively. Transfusion independence was attained in 29 of 84 patients (35%), and patients who had a response had fewer infections and febrile neutropenia episodes than those who did not have a response. Among 34 patients who had a complete remission or complete remission with partial hematologic recovery, 7 (21%) had no residual detectable IDH1 mutations on digital polymerase-chain-reaction assay. No preexisting co-occurring single gene mutation predicted clinical response or resistance to treatment. CONCLUSIONS: In patients with advanced IDH1-mutated relapsed or refractory AML, ivosidenib at a dose of 500 mg daily was associated with a low frequency of grade 3 or higher treatment-related adverse events and with transfusion independence, durable remissions, and molecular remissions in some patients with complete remission. (Funded by Agios Pharmaceuticals; ClinicalTrials.gov number, NCT02074839 .).

Allogeneic hematopoietic stem cell transplant overcomes the adverse survival effect of very high risk and unfavorable karyotype in myelofibrosis.

The prognostic importance of genetic information in primary myelofibrosis (PMF) was recently highlighted in a study of over 1000 cytogenetically-annotated patients; 5-year survival rates were 8% for very high risk (VHR), 27% "unfavorable" and 45% "favorable" karyotype. The current study addresses the practice-relevant question of whether or not allogeneic hematopoietic stem cell transplant (HCT) can overcome the detrimental survival effect of VHR or unfavorable karyotype. The study included 67 patients with PMF or secondary MF who received HCT at the Mayo Clinic and in whom pretransplant cytogenetic information was available. Dynamic international prognostic scoring system (DIPSS) risk distribution was 13% high, 66% intermediate-2 and 21% intermediate-1. Cytogenetic risk distribution was 11% VHR, 34% unfavorable and 55% favorable. At median post-HCT follow-up of 60 months for living patients (range 34-170), 28 (42%) deaths were recorded. Five-year survival was 62% and was not affected by VHR or unfavorable karyotype (P = .68). The salutary effect of HCT in patients with VHR or unfavorable karyotype was also apparent during analysis of a combined dataset that included a nontransplant cohort of 383 patients with PMF; multivariable analysis of the combined dataset (n = 450) resulted in HRs (95% CI) of 2.4 (1.6-3.6) for absence of transplant, 3.3 (2.2-4.8) for VHR karyotype, 1.6 (1.2-2.1) for unfavorable karyotype, 2.9 (2.0-4.2) for DIPSS high and 1.7 (1.4-2.2) for DIPSS intermediate-2. These observations were further confirmed by analysis of more stringently matched case-control subset cohorts and provide the evidence for the therapeutic preference of HCT in cytogenetically high risk patients with MF.

Cytogenetic Evolution in Myeloid Neoplasms at Relapse after Allogeneic Hematopoietic Cell Transplantation: Association with Previous Chemotherapy and Effect on Survival.

Cytogenetic evolution (CGE) in patients with myeloid neoplasms who relapsed after an allogeneic (allo) hematopoietic cell transplantation (HCT) has been evaluated by only few studies. The effect of the CGE on survival of relapsed allo-HCT recipients is not clear. The effect of previously received chemotherapy to induce CGE in this patient population has not been studied. The aims of our study are to (1) characterize the patterns of cytogenetic change in patients with myeloid neoplasms who relapsed after an allo-HCT, (2) evaluate the effect of CGE on survival, and (3) explore the association of CGE with previous chemotherapy (including the lines of salvage therapy, type of induction, and conditioning therapy). Of 49 patients with a myeloid malignancy (27 acute myeloid leukemia [AML], 19 myelodysplastic syndrome [MDS]/myeloproliferative neoplasm [MPN], and 3 chronic myelogenous leukemia) who relapsed after an allo-HCT, CGE was observed in 25 (51%), whereas 24 patients had unchanged cytogenetic findings at relapse. The CGE group carried more cytogenetic abnormalities at original diagnosis. The most frequent cytogenetic change was the acquisition of 3 or more new chromosomal abnormalities followed by acquisition of unbalanced abnormalities, aneuploidy, and emergence of apparently new clones unrelated to the original clone. The CGE cohort had higher proportion of MDS and MPN and fewer patients with de novo AML. Disease risk assessment category showed a trend to higher frequency of high-risk patients in the CGE group, though the difference was not statistically significant. Time from diagnosis to transplantation and time from transplantation to relapse were not different between the CGE and non-CGE groups. CGE and non-CGE cohorts had similar exposures to salvage therapy and to induction chemotherapy, as well as similar conditioning regimens; thus, no particular type of chemotherapy emerged as a predisposing factor to CGE. CGE was associated with significantly shortened post-transplantation and postrelapse survival when compared with those of the non-CGE group (P = .004 and P < .001, respectively). Our results underscore the significance of CGE in progression of myeloid malignancies after an allo-HCT.

Microbiologic yield of bronchoalveolar lavage specimens from stem cell transplant recipients.

PURPOSE: Stem cell transplant (SCT) recipients commonly undergo bronchoalveolar lavage (BAL) collection as an infectious pulmonary work-up. Previous studies report the utility and overall diagnostic yield of fiberoptic bronchoscopy with BAL in this vulnerable population, though none focused purely on microbiologic yield or made comparisons with less invasive means of pathogen detection. We sought to determine and elaborate on the microbiologic yield of BAL in SCT recipients, assess a correlation between BAL studies and less invasive means of pathogen detection, and assess the utility of repeating a BAL within 30 days. METHODS: Between January 1, 2009, and July 31, 2013, we reviewed medical records of 125 SCT recipients who underwent 179 BALs. In addition to demographic information and details pertaining to their SCT, a comprehensive review of their microbiologic data was performed and recorded. RESULTS: Our study showed an overall BAL microbiologic yield of 40%, despite 92% of patients receiving broad-spectrum antimicrobial therapy at the time of the BAL procedure. CONCLUSIONS: Although an initial BAL sample in this population provides crucial microbiologic information, repeating the procedure within 30 days may have minimal additional microbiologic yield. BAL continues to be an essential diagnostic tool in SCT recipients undergoing an infectious pulmonary work-up.

Reduced toxicity conditioning and allogeneic stem cell transplantation in adults using fludarabine, carmustine, melphalan, and antithymocyte globulin: outcomes depend on disease risk index but not age, comorbidity score, donor type, or human leukocyte antigen mismatch.

Although reduced-intensity conditioning has become standard of care for patients with hematologic malignancies undergoing allogeneic hematopoietic cell transplantation (HCT), the optimum regimen has yet to be defined, and may depend on pretransplantation patient- and/or disease-specific risk factors. We report here results in 100 adults, ages 18 to 69, with high-risk hematologic malignancy who received conditioning with fludarabine, carmustine, melphalan, and rabbit antithymocyte globulin (FBM-A). Outcomes were stratified using the disease risk index (DRI) as published by Armand et al. (Blood 2012;120:905-913). Median age was 56, and patients were ineligible for standard myeloablative conditioning because of age, organ dysfunction, or prior autologous HCT. Patients underwent transplantation for myeloid (acute myelogenous leukemia, n = 40; myelodysplastic syndrome, n = 24; myelofibrosis, n = 13; other myeloid, n = 2) or lymphoid (acute lymphoblastic leukemia, n = 8; non-Hodgkin lymphoma, n = 8; Hodgkin lymphoma, n = 4, chronic lymphocytic leukemia, n = 1) malignancy. Donors were related in 26 patients (22 matched, 4 mismatched at 1 antigen) and unrelated in 74 (mismatched at 1 or 2 HLA loci in 33); grafts were peripheral blood stem cells in 97 patients, bone marrow in 2, and double cord in 1. According to the DRI, 68 patients were classified as low (n = 1) or intermediate risk (n = 67), and 32 were classified as high (n = 28) or very high risk (n = 4). With a median follow-up of surviving patients of 18 months, the Kaplan-Meier estimate of overall survival at 2 years for patients in the low/intermediate risk group is 80%, compared with 66% in the high/very high group (P = .11). Two-year cumulative incidence of relapse and nonrelapse mortality in the low/intermediate group are 9.9% and 15%, versus 25% and 19% in the high/very high group (respective P values .07 and .81). The cumulative incidence of acute graft-versus-host (GVHD) grades III to IV at 100 days was 8.1%, and the incidence of National Institutes of Health-defined moderate to severe chronic GVHD was 22% at 2 years. No deaths were attributable to chronic GVHD. Survival was not influenced by age, hematopoietic comorbidity index score, donor type, donor gender, or presence of mismatch. We conclude that FBM-A is an effective and safe conditioning regimen for adults up to age 69 with hematologic malignancies who have low-, intermediate-, or high-risk scores according to the DRI.

Does microgranular variant morphology of acute promyelocytic leukemia independently predict a less favorable outcome compared with classical M3 APL? A joint study of the North American Intergroup and the PETHEMA Group.

Few studies have examined the outcome of large numbers of patients with the microgranular variant (M3V) of acute promyelocytic leukemia (APL) in the all-trans retinoic acid era. Here, the outcome of 155 patients treated with all-trans retinoic acid-based therapy on 3 clinical trials, North American Intergroup protocol I0129 and Programa para el Estudio de la Terapéutica en Hemopatía Maligna protocols LPA96 and LPA99, are reported. The complete remission rate for all 155 patients was 82%, compared with 89% for 748 patients with classical M3 disease. The incidence of the APL differentiation syndrome was 26%, compared with 25% for classical M3 patients, and the early death rate was 13.6% compared with 8.4% for patients with classical M3 morphology. With a median follow-up time among survivors of 7.6 years (range 3.6-14.5), the 5-year overall survival, disease-free survival, and cumulative incidence of relapse for patients with M3V were 70%, 73%, and 24%, respectively. With a median follow-up time among survivors of 7.6 years (range 0.6-14.3), the 5-year overall survival, disease-free survival, and cumulative incidence of relapse among patients with classical M3 morphology were 80% (P = .006 compared with M3V), 81% (P = .07), and 15% (P = .005), respectively. When outcomes were adjusted for the white blood cell count or the relapse risk score, none of these outcomes were significantly different between patients with M3V and classical M3 APL.

Clinical outcomes with low dose anti-thymocyte globulin in patients undergoing matched unrelated donor allogeneic hematopoietic cell transplantation.

Anti-thymocyte globulin (ATG) has been associated with decreased rates graft versus host disease (GVHD) but with a potential risk of increasing risk of infection and relapse. We retrospectively studied the impact of single dose low dose (2.5 mg/kg) ATG in patients undergoing allogenic hematopoietic cell transplantation (HCT) from 8/8 matched unrelated donors (MUD). Of the total 209 patients identified, 129 received ATG. At baseline, the ATG group had more intermediate and high disease risk index (DRI) (64.6% vs. 54.3%) (28.3% vs. 23.7%) p < .001, respectively, and who received reduced intensity or non-myeloablative conditioning (RIC) (69.0% vs. 47.5%, p .003). There was no significant difference in the overall survival (OS) HR = 1.3, 95% CI [0.99, 1.0], p = .350 or relapse-free survival (RFS) HR = 1.2, 95% CI [0.74, 1.8], p = .526 between the two groups. Patients receiving ATG had a lower incidence of chronic GVHD (cGVHD) (10.1% vs. 25%, p = .007) and less moderate to severe cGVHD (8.5% vs. 25%, p = .002). ATG was associated with a reduced incidence of moderate to severe cGVHD OR = 0.28, 95% CI [0.12, 0.61], p < .01. There was no difference in the incidence of Epstein-Barr Virus (EBV) or cytomegalovirus (CMV) reactivation, CMV disease, invasive fungal infection, or grade III-IV acute GVHD (aGVHD). Our study shows that low dose ATG results in similar OS and RFS with lower rates of cGVHD. Additional prospective studies are needed to confirm these findings.

Early post-transplantation factors predict survival outcomes in patients undergoing allogeneic hematopoietic cell transplantation for myelofibrosis.

Factors predicting allogeneic hematopoietic cell transplantation (HCT) outcomes in myelofibrosis in the early post-HCT period have not been defined thus far. We attempt to study such factors that can help identify patients at a higher risk of relapse or death. This retrospective study included 79 patients who underwent first HCT for myelofibrosis at three centers between 2005 and 2016. Univariate analysis showed that red blood cell (RBC) transfusion dependence (HR 9.02, 95% CI 4.0-20.35), platelet transfusion dependence (HR 8.17, 95%CI 3.83-17.37), 100% donor chimerism in CD33 + cells (HR 0.21, 95%CI 0.07-0.62), unfavorable molecular status (HR 4.41, 95%CI 1.87-10.39), normal spleen size (HR 0.42, 95%CI 0.19-0.94), grade ≥ 2 bone marrow fibrosis (vs. grade ≤ 1; HR 2.7, 95%CI 1.1-6.93) and poor graft function (HR 2.6, 95%CI 1.22-5.53) at day +100 were statistically significantly associated with relapse-free survival (RFS). RBC transfusion dependence and unfavorable molecular status were also statistically significant in the multivariate analysis. Patients in whom both of these factors were present had a significantly worse RFS when compared to those with one or none. While limited by a small sample size, we demonstrate the significance of transfusion dependence and molecular status at day +100 in predicting outcomes.

Comparison of reduced intensity conditioning regimens used in patients undergoing hematopoietic stem cell transplantation for myelofibrosis.

The aim of this study is to compare clinical outcomes of patients who underwent allogeneic stem cell transplantation (HCT) for myelofibrosis with reduced intensity conditioning (RIC) using either Busulfan Fludarabine (BuFlu), Fludarabine Bis-chlorethyl-nitroso-urea/ carmustine Melphalan (FBM) or Fludarabine Melphalan (FluMel) regimens. Sixty-one patients were identified who underwent HCT with one of these RIC regimens. Overall survival (OS) was not different in the 3 groups. However, 100% donor chimerism was seen in more frequently at day +30 and day +100 in patients who received FBM or FluMel than BuFlu, in both CD3 and CD33 fractions. For instance, 100% donor chimerism in CD33 fraction was present in 100% patients in FBM cohort, 90% in FluMel cohort while 44% in BuFlu cohort at day +100. Acute graft-versus host disease, grade 2-4 and grade 3-4, was not statistically different in the 3 groups (BuFlu 47 and 35%, FBM 68 and 27%, FluMel 68 and 46%; p = 0.31 and 0.45). Relapses and non-relapse mortality was also not statistically significantly different. Our study shows similar OS with these 3 RIC regimens in myelofibrosis; although donor chimerism at day +30 and day +100 was better in patients who received FBM and FluMel.

Single dose versus multiple doses of rituximab for preemptive therapy of Epstein-Barr virus reactivation after hematopoietic cell transplantation.

Epstein-Barr virus (EBV) reactivation is an unresolved medical issue after allogeneic hematopoietic stem cell transplantation (HSCT). Rituximab treatment is recommended for EBV reactivation after HSCT but the number of doses of rituximab to use is unclear. In this study, risk factors and outcomes of patients who needed 1 dose vs >1 doses of preemptive rituximab to clear EBV viremia were compared. A higher viral load was more likely to be associated with higher doses of rituximab. Patients whose EBV viremia cleared with 1 dose of rituximab were more likely to have a preceding reduction of immunosuppression. Overall survival (OS) in these 2 cohorts was not different (18.7 vs 26.6 months, respectively, p = .96). Since rituximab can have side effects and is fairly costly, a predictive model to determine the number of rituximab doses using viral load would be a useful and cost-effective manner to utilize rituximab for this indication.

Early fluctuations in busulfan levels with therapeutic dose monitoring during allogeneic stem cell transplantation: do they matter?

Therapeutic dose monitoring is widely adopted for determination of busulfan (Bu) dose for use as a conditioning regimen. However, while dose adjustments are being incorporated, transient fluctuations of Bu levels may occur. We aim to understand if these fluctuations affect clinical outcomes of these patients. We compared outcomes in patients in whom the absolute dose changes and fluctuation of AUC were ≥ median% versus < median%. Rates of sinusoidal obstructive syndrome, grades 2-4/grades 3-4 acute and chronic graft versus host disease were not different between the two cohorts. The Kaplan-Meier curves for overall survival showed no significant differences. Six patients required >50% dose adjustment and four had a fluctuation in AUC of >50%. One of these patients died of sinusoidal obstruction syndrome and two died of infections. In our study, the transient fluctuations in Bu levels did not affect clinical outcomes; hence obviating the need for test dose strategy.

Thrombotic microangiopathy after allogeneic blood and marrow transplantation is associated with dose-intensive myeloablative conditioning regimens, unrelated donor, and methylprednisolone T-cell depletion.

BACKGROUND: Allogeneic blood and marrow transplantation (BMT)-associated thrombotic microangiopathy (TM) contributes to transplant-related morbidity and mortality. This report examines the incidence of and risk factors for allogeneic BMT-associated TM in two patient cohorts treated before and after changes in myeloablative conditioning regimen intensity (high vs. standard intensity). METHODS: Cohort 1 includes 153 consecutive allogeneic BMT patients who underwent transplantation between April 1994 and October 1997 with an allogeneic BMT-associated TM crude incidence of 12%. Cohort 2 includes 75 consecutive allogeneic BMT patients who underwent transplantation from November 1997 to November 2000 with an allogeneic BMT-associated TM crude incidence of 1%. RESULTS: In cohort 1, matched unrelated donor transplant and methylprednisolone (MP) T-cell depletion (TCD) of donor bone marrow were significantly associated with allogeneic BMT-associated TM by univariate analysis; therefore, a logistic model incorporating these effects was constructed to calculate the expected number of allogeneic BMT-associated TM cases in cohort 2. Seven cases would have been expected, but only one was observed (P = 0.003; bayesian predictive test). The multivariate analysis of both cohorts yielded MP-TCD (P<0.001), high-intensity myeloablative conditioning regimens used in cohort 1 (P = 0.02), and matched unrelated donor (P = 0.03) as significant predictors of time to allogeneic BMT-associated TM. CONCLUSION: Avoidance of high-intensity conditioning regimens may decrease the incidence of allogeneic BMT-associated TM.

Massive hyperdiploidy and tetraploidy in acute myelocytic leukemia and myelodysplastic syndrome.

Massive hyperdiploidy (>50 chromosomes) and tetraploidy (4n) are rare cytogenetic abnormalities in myelocytic malignancies, and their significance is unknown. We report on 11 patients with acute myelocytic leukemia (AML) and two patients with a myelodysplastic syndrome (MDS) with massive hyperdiploidy (10 patients) or tetraploidy (3 patients) seen at our institution over a 12-year period. Eleven patients were male and two were female. Age range was 44-84 years (median, 70 years). Only one AML patient had a previous MDS, and no patient had therapy-related disease. One or more copies of chromosomes 8 and 19 were gained in eight patients each; other frequently gained chromosomes included 13, 15, and 21. Eight patients had structural abnormalities in addition to chromosome gain; del(5q) was most common (five patients). Eleven patients received induction chemotherapy, but only four achieved complete remission. Survival ranged from 1 to 22 months, with a median of 6 months. We conclude that massive hyperdiploidy and tetraploidy are infrequent abnormalities in AML and MDS, are seen primarily in de novo disease in older male patients and are associated with a low remission rate and short survival. Massive hyperdiploidy and tetraploidy define a prognostically unfavorable cytogenetic group in de novo AML.

Dynamics of leukemia stem-like cell extinction in acute promyelocytic leukemia.

Many tumors are believed to be maintained by a small number of cancer stem-like cells, where cure is thought to require eradication of this cell population. In this study, we investigated the dynamics of acute promyelocytic leukemia (APL) before and during therapy with regard to disease initiation, progression, and therapeutic response. This investigation used a mathematical model of hematopoiesis and a dataset derived from the North American Intergroup Study INT0129. The known phenotypic constraints of APL could be explained by a combination of differentiation blockade of PML-RARα-positive cells and suppression of normal hematopoiesis. All-trans retinoic acid (ATRA) neutralizes the differentiation block and decreases the proliferation rate of leukemic stem cells in vivo. Prolonged ATRA treatment after chemotherapy can cure patients with APL by eliminating the stem-like cell population over the course of approximately one year. To our knowledge, this study offers the first estimate of the average duration of therapy that is required to eliminate stem-like cancer cells from a human tumor, with the potential for the refinement of treatment strategies to better manage human malignancy.

Allogeneic stem cell transplantation for myeloproliferative neoplasm in blast phase.

The prognosis for patients with Philadelphia-negative myeloproliferative neoplasms (MPN) who evolve into acute myeloid leukemia (AML) or blast phase (MPN-BP) is extremely poor. Although allogeneic stem cell transplantation (allo-SCT) is considered potentially curative, very few patients have been reported who have undergone allo-SCT for MPN-BP; therefore the success rate remains unknown. In a retrospective review, we identified 13 patients with an MPN transformation to blast phase after a median 9 years (range 5 months to 30 years); 8 (median age 55) continued to allo-SCT within 6 months. Induction chemotherapy cleared blood/marrow blasts in 60% (6/10) (2 declined therapy, 1 had early death). At the time of allo-SCT, 5/8 patients were in complete remission (CR) of their leukemia or had returned to MPN chronic phase (CP), 2 had residual blood blasts and 1 was refractory with >5% marrow blasts. At follow-up (median 20.3 months), 6 patients are alive in CR of both their leukemia/MPN. All 5 patients in CR/CP at pre-allo-SCT remain alive in remission, while 2/3 with persistent blood/marrow blasts relapsed and expired. We conclude that MPN-BP can be cured by allo-SCT in a significant percentage of patients, but that adequate leukemic clearance prior to allo-SCT offers an optimal outcome.

Multicenter study of decitabine administered daily for 5 days every 4 weeks to adults with myelodysplastic syndromes: the alternative dosing for outpatient treatment (ADOPT) trial.

PURPOSE: Decitabine, a DNA-targeted hypomethylating agent, is approved by the United States Food and Drug Administration for treatment of patients with myelodysplastic syndromes (MDS) on a schedule of 15 mg/m(2) administered via intravenous (IV) infusion every 8 hours for 3 days. This study assessed the efficacy and safety of an alternative dosing regimen administered on an outpatient basis in academic and community-based practices. PATIENTS AND METHODS: Patients were treated with decitabine 20 mg/m(2) by IV infusion daily for 5 consecutive days every 4 weeks. Eligible patients were > or = 18 years of age and had MDS (de novo or secondary) of any French-American-British (FAB) subtype and an International Prognostic Scoring System (IPSS) score > or = 0.5. The primary end point was the overall response rate (ORR) by International Working Group (IWG 2006) criteria; secondary end points included cytogenetic responses, hematologic improvement (HI), response duration, survival, and safety. RESULTS: Ninety-nine patients were enrolled; the ORR was 32% (17 complete responses [CR] plus 15 marrow CRs [mCRs]), and the overall improvement rate was 51%, which included 18% HI. Similar response rates were observed in all FAB subtypes and IPSS risk categories. Among patients who improved, 82% demonstrated responses by the end of cycle 2. Among 33 patients assessable for a cytogenetic response, 17 (52%) experienced cytogenetic CR (n = 11) or partial response (n = 6). CONCLUSION: Decitabine given on a 5-day schedule provided meaningful clinical benefit for patients with MDS, with more than half demonstrating improvement. This suggests that decitabine can be administered in an outpatient setting with comparable efficacy and safety to the United States Food and Drug Administration-approved inpatient regimen.

Invasive filamentous fungal infections in allogeneic hematopoietic stem cell transplant recipients after recovery from neutropenia: clinical, radiologic, and pathologic characteristics.

Invasive filamentous fungal infection (IFFI) is an important cause of mortality in allogeneic hematopoietic stem cell transplant (HSCT) recipients. We reviewed 22 consecutive cases of IFFI in allogeneic HSCT recipients at Roswell Park Cancer Institute. IFFI was diagnosed after neutrophil recovery in 21 patients (95%). All had received corticosteroids within 1 month prior to IFFI diagnosis. Fourteen (64%) presented with dyspnea, and only 7 (32%) were febrile. Aspergillus species were isolated in 18 (82%) cases. Thirty day mortality after IFFI diagnosis was associated with a higher mean daily dose of corticosteroids (P=0.02) and receiving OKT3 (P=0.01) within 1 month prior to IFFI diagnosis and serum creatinine>2 mg/dl at the time of diagnosis (P=0.004). Histopathologic material from biopsy or autopsy was available in 15 patients (68%). In 8 (53%), the predominant lung histopathology was an acellular coagulative necrosis and hyphal angioinvasion was observed in some of these cases. These findings have generally been observed in neutropenic patients but not in non-neutropenic HSCT recipients. The predominance of coagulative necrosis in our series may reflect the high doses of corticosteroids used to treat graft-versus-host disease (GVHD), which may have disabled leukocyte trafficking and hyphal killing.

Advances in the management of acute promyelocytic leukemia and other hematologic malignancies with arsenic trioxide.

Acute promyelocytic leukemia (APL), once considered the most devastating subtype of acute myeloid leukemia, is now the most treatable of all subtypes as a result of intensive research into its molecular pathogenesis. This research has led to a rational approach to treatment in which the use of the differentiating agent all-trans-retinoic acid (ATRA) has proven to be effective first-line treatment for inducing complete remission. Arsenic trioxide (ATO) is currently used to treat relapsed disease, further enhancing survival rates in a patient population for which limited salvage options exist. This review discusses the molecular mechanisms responsible for development of APL and the evolution of treatment options over the last three decades, including the major advances using ATRA and ATO in the last 12 years. The mechanism of action of ATO is also described in view of this agent's potential for broader therapeutic application in a variety of hematologic malignancies.

Simvastatin-fluconazole causing rhabdomyolysis.

OBJECTIVE: To report a case of rhabdomyolysis after concomitant use of simvastatin, a commonly used hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase inhibitor, and fluconazole, an azole antifungal agent. CASE SUMMARY: An 83-year-old white man with a history of congestive heart failure and hyperlipidemia presented to the hospital 1 week following the addition of fluconazole to a medication regimen that included simvastatin 40 mg once daily. The patient had severe muscle weakness and a markedly elevated serum creatine kinase activity, which resolved following discontinuation of simvastatin and fluconazole. DISCUSSION: Rhabdomyolysis is a recognized adverse effect of HMG-CoA reductase inhibitors (statins), commonly caused by their interaction with other drugs, such as azole antifungals, that inhibit the cytochrome P450 isoenzyme family. An objective causality assessment revealed that the adverse drug event was probable. Although drug interactions have been described for combinations of other HMG-CoA reductase inhibitors and azole antifungals, rhabdomyolysis likely caused by the interaction between simvastatin and fluconazole has not yet been reported. This case reinforces the importance of being vigilant for drug interactions, particularly in connection with commonly prescribed medications such as statins. CONCLUSIONS: Patients receiving statins who have cancer may receive azole antifungals and other drugs that inhibit CYP3A4 during treatment, predisposing them to toxicity. These patients should therefore be monitored closely for drug interactions.