Chemotherapy For Acute Myelogenous Leukemia Research Articles

208. Clinical outcomes of empirical versus pre-emptive broad spectrum antifungal therapy in patients with acute myelogenous leukemia receiving antimold prophylaxis

Abstract Background Since antimold prophylaxis has been widely used in induction chemotherapy for acute myelogenous leukemia (AML), it should be re-evaluated whether broad spectrum antifungal therapy should be empirically used in prolonged febrile neutropenia. Therefore, we compared clinical outcomes of empirical versus pre-emptive antifungal therapy in patients with AML receiving antimold prophylaxis. Methods From September 2016 to December 2020, all adult AML patients (≥ 18 years) receiving antimold prophylaxis who had febrile neutropenia for ≥ 4 days during induction or re-induction chemotherapy at Seoul National University Hospital were retrospectively reviewed. They were classified into the empirical group (therapeutic broad spectrum antifungal agents had been used without evidence of invasive fungal infection [IFI]) or the pre-emptive group (antimold prophylaxis had been maintained until the emergence of IFI’s evidence). We compared clinical outcomes between the two groups after propensity score matching. Results A total of 229 chemotherapy episodes, 36 in the empirical group and 193 in the pre-emptive group, were analyzed. In the pre-emptive group, broad spectrum antifungal therapy was administered in 45 (23.3%) episodes. After 1:3 matching with age, gender, induction or re-induction chemotherapy, and worst qSOFA score at febrile neutropenia, incidence of proven or probable IFI (0/36 [0%] in the empirical group vs. 5/97 [5.2%] in the pre-emptive group, P=0.323) and all-cause mortality (3/36 [8.3%] in the empirical group vs. 4/97 [4.1%] in the pre-emptive group, P=0.388) were not different between the two groups. Conclusion Clinical outcomes of empirical versus pre-emptive broad spectrum antifungal therapy were comparable in patients with AML receiving antimold prophylaxis. Broad spectrum antifungal therapy could be delayed until the emergence of evidence of IFI, in the current era of antimold prophylaxis. Disclosures All Authors: No reported disclosures.

Case report: A rare case of TBL1XR1-RARB positive acute promyelocytic leukemia in child and review of the literature.

Some forms of acute myelogenous leukemia (AML) share typical morphological and immunophenotypic features of acute promyelocytic leukemia (APL) but are negative for promyelocytic leukemia-retinoic acid receptor alpha (PML-RARA) fusion. These forms of AML are known as variant APL. Some variants of APL present with retinoic acid receptor beta (RARB) fused or rearranged with partner genes. RARB-positive APL is very rare, resistant to all-trans retinoic acid (ATRA), and associated with poor prognosis. Here, we reported one case with TBL1XR1-RARB positive APL, featured by early onset and no apparent bleeding tendency or coagulation dysfunction. This patient was resistant to ATRA and arsenic trioxide (ATO), but was good responsive to conventional chemotherapy for AML. The case report was followed by a literature review.

Tailoring a physical activity intervention to older adults receiving intensive chemotherapy for acute myeloid leukemia (AML): One size does not fit all

Older adults are at risk for functional decline during acute myeloid leukemia (AML) therapy [ [1] Klepin H.D. Tooze J.A. Pardee T.S. et al. Effect of intensive chemotherapy on physical, cognitive, and emotional health of older adults with acute myeloid leukemia. J Am Geriatr Soc. 2016; 64: 1988-1995 Crossref PubMed Scopus (55) Google Scholar ]. While some survivors demonstrate resilience [ [2] Mohamedali H. Breunis H. Timilshina N. et al. Older age is associated with similar quality of life and physical function compared to younger age during intensive chemotherapy for acute myeloid leukemia. Leuk Res. 2012; 36: 1241-1248 Crossref PubMed Scopus (38) Google Scholar , [3] Timilshina N. Breunis H. Tomlinson G.A. et al. Long-term recovery of quality of life and physical function over three years in adult survivors of acute myeloid leukemia after intensive chemotherapy. Leukemia. 2019; 33: 15-25 Crossref Scopus (13) Google Scholar ], short-term declines in physical function can be dramatic during an induction hospitalization [ [1] Klepin H.D. Tooze J.A. Pardee T.S. et al. Effect of intensive chemotherapy on physical, cognitive, and emotional health of older adults with acute myeloid leukemia. J Am Geriatr Soc. 2016; 64: 1988-1995 Crossref PubMed Scopus (55) Google Scholar ]. Physical performance (measured by the Short Physical Performance Battery [SPPB]) is predictive of survival at the time of diagnosis [ [4] Klepin H.D. Geiger A.M. Tooze J.A. et al. Geriatric assessment predicts survival for older adults receiving induction chemotherapy for acute myelogenous leukemia. Blood. 2013; 121: 4287-4294 Crossref PubMed Scopus (254) Google Scholar ], declines during induction therapy [ [1] Klepin H.D. Tooze J.A. Pardee T.S. et al. Effect of intensive chemotherapy on physical, cognitive, and emotional health of older adults with acute myeloid leukemia. J Am Geriatr Soc. 2016; 64: 1988-1995 Crossref PubMed Scopus (55) Google Scholar ], and is associated with shorter survival when measured at the time of remission [ [5] Saad M. Loh K.P. Tooze J.A. et al. Geriatric assessment and survival among older adults receiving post-remission therapy for acute myeloid leukemia. Blood. 2020; 136: 2715-2719 Crossref PubMed Google Scholar ]. Interventions designed to maintain physical performance may enhance the quality of survivorship, eligibility for subsequent therapies, and could potentially improve survival [ 6 Alibhai S.M. Durbano S. Breunis H. et al. A phase II exercise randomized controlled trial for patients with acute myeloid leukemia undergoing induction chemotherapy. Leuk Res. 2015; (S0145-2126(15)30365-9) Crossref Scopus (39) Google Scholar , 7 Alibhai S.M. O’Neill S. Fisher-Schlombs K. et al. A pilot phase II RCT of a home-based exercise intervention for survivors of AML. Support Care Cancer. 2014; 22: 881-889 Crossref PubMed Scopus (33) Google Scholar , 8 Klepin H.D. Danhauer S.C. Tooze J.A. et al. Exercise for older adult inpatients with acute myelogenous leukemia: a pilot study. J Geriatr Oncol. 2011; 2: 11-17 Abstract Full Text Full Text PDF PubMed Scopus (50) Google Scholar , 9 Thomas R. Kenfield S.A. Yanagisawa Y. et al. Why exercise has a crucial role in cancer prevention, risk reduction and improved outcomes. Br Med Bull. 2021; 139: 100-119 Crossref Scopus (3) Google Scholar , 10 Ezzatvar Y. Ramírez-Vélez R. Sáez de Asteasu M.L. et al. Physical function and all-cause mortality in older adults diagnosed with cancer: a systematic review and meta-analysis. J Gerontol A Biol Sci Med Sci. 2021; 76: 1447-1453 Crossref Scopus (13) Google Scholar ].

Breakthrough Penile Mucormycosis in a Patient With Acute Myelogenous Leukemia on Posaconazole Prophylaxis

Abstract In patients with acute myelogenous leukemia, posaconazole prophylaxis has been shown to prevent deep invasive fungal infections, including mucormycosis. In the present case, posaconazole prophylaxis was initiated in a 58-year-old man undergoing induction chemotherapy for acute myelogenous leukemia. Three weeks after initiating chemotherapy, he developed a tender violaceous macule on the shaft of his penis. The initial differential included fixed drug eruption versus pyoderma gangrenosum. However, punch biopsy ultimately showed mucormycosis, and cultures grew Rhizopus species, despite therapeutic posaconazole trough. He was treated with intravenous amphotericin B and required right orchiectomy, penectomy, and hyperbaric oxygen therapy. Oral posaconazole was reinstituted after completion of amphotericin B course, and at 4 months follow-up, his penectomy site was fully healed. As demonstrated by the present case, not all mucormycoses are prevented by posaconazole prophylaxis. A high index of suspicion and early biopsy for prompt diagnosis are of critical importance in improving outcomes.

A Placebo-Controlled Study of Recombinant Human Granulocyte-Macrophage Colony-Stimulating Factor Administered During and After Induction Treatment for De Novo Acute Myelogenous Leukemia in Elderly Patients

The complete remission (CR) rate after intensive chemotherapy for acute myelogenous leukemia (AML) remains low in elderly patients, mainly because of a higher infectious mortality rate related to neutropenia and an increased incidence of adverse prognostic factors. Granulocyte-macrophage colony-stimulating factor (GM-CSF) has been shown to potentially recruit leukemic blasts into cell cycle and improve cytotoxic effects when given during chemotherapy, and to shorten the duration of neutropenia when administered after chemotherapy. Two hundred forty patients aged 55 to 75 years who had newly diagnosed AML were randomly assigned to receive placebo or Escherichia coli-derived GM-CSF (5 micrograms/kg/d by 6-hour intravenous infusion) starting during induction chemotherapy on day 1 and continued through and after chemotherapy until recovery of neutrophils, or evidence of regrowth of leukemia, or up to day 28. Induction chemotherapy consisted of idarubicin (8 mg/m2/d on days 1 to 5) and cytarabine (100 mg/m2/d on days 1 to 7). The study drug was not administered subsequent to the induction course. Patients who achieved a CR received continuous maintenance therapy for 1 year with four quarterly reinduction courses; in the 55- to 64-year age subgroup, patients were randomly assigned to receive or not a consolidation course before maintenance therapy. The CR rate was similar in the GM-CSF and placebo groups (63% and 60.5%, respectively; P = .79). The mortality, rate of resistant disease, and rate of regrowth of leukemia were also similar in both groups. The time to neutrophil recovery was shorter in patients who received GM-CSF (24 v 29 days; P = .0001), but the incidence and characteristics of infectious events were not different. The 2-year disease-free survival (DFS) rate was significantly improved in the GM-CSF group (48% v 21% in the placebo group; P = .003). This effect was highly significant in the cohort of patients aged 55 to 64, but only marginal in patients >/=65 years of age. There was a trend toward a longer overall survival (OS) in the GM-CSF group (P = .082). In summary, the administration of GM-CSF, concomitantly with chemotherapy and thereafter during induction course in AML, shortened the time to neutrophil recovery, but did not improve the CR rate in patients aged 55 to 75. Nonetheless, DFS and OS were significantly prolonged in patients aged 55 to 64 treated with GM-CSF. These results are promising and further evaluation of myeloid growth factors in AML is warranted.

Heme Oxygenase 1-Targeted Hybrid Nanoparticle for Chemo- and Immuno-Combination Therapy in Acute Myelogenous Leukemia.

Acute myelogenous leukemia (AML) is a fatal blood cancer with high patient mortality. Daunorubicin and cytarabine are first‐line chemotherapy for AML, with bone marrow transplantation in most cases. Recently, cancer immunotherapy has been challenged in AML and leukemia‐niche myeloid cells are promising targets for the AML immunotherapy. Heme oxygenase 1 (HO1) is an antioxidative and cytoprotective enzyme inducing chemo‐resistant AML and has been focused as an immune checkpoint molecule in tumor microenvironments. Herein, lipid‐polymer hybrid nanoparticle (hNP) is loaded with tin mesoporphyrin (SnMP), a HO1‐inhibitor, and non‐covalently modified with an engineered antibody for leukemic cell‐targeted delivery. HO1‐inhibiting T‐hNP (T‐hNP/SnMP) enhances chemo‐sensitivity in human leukemia cells. In a human AML‐bearing orthotopic mouse model, intravenously injected T‐hNP not only actively targets to human leukemia cells but passively targets to CD11b+ myeloid cells in a bone marrow niche. The T‐hNP/SnMP enhances the chemo‐therapeutic effect of daunorubicin and boosts immune response by reprogramming bone marrow myeloid cells resulting from the recruitment of the monocyte‐lineage and induction of inflammatory genes. The ex vivo study demonstrates an enhanced immune response of HO1‐inhibited bone marrow CD11b+ myeloid cells against apoptotic leukemia cells. Collectively, HO1‐inhibiting dual cell‐targeted T‐hNP/SnMP has a strong potential as a novel therapeutic in AML.

Cytotoxic chemotherapy for AML in adults

Genomics and novel molecularly targeted drugs for treating acute myelogenous leukemia (AML) are developing rapidly. To optimize the allocation of patients to the best possible treatment, we have to expedite test results of cytogenetic and molecular analyses for target mutations such as CBF and FLT3, since gene mutations are specifically associated with patient prognosis and therefore inform medical decision making. However, novel agents cannot completely eradicate AML because of the emergence of resistance to these agents; therefore, at the moment it is still necessary to combine cytotoxic treatment with novel agents. Hence, it becomes vital to understand how to stratify AML patients and subsequently treat the right patients with the right combination of cytotoxic treatments and novel agents.

116. Risk Factors and Clinical Outcomes of Carbapenem Non-Susceptible Gram-Negative Bacteremia in Patients with Acute Myelogenous Leukemia

BackgroundEarly administration of susceptible antibiotics is crucial in Gram-negative bacteremia (GNB), especially in immunocompromised patients. We aimed to explore risk factors and clinical outcomes of carbapenem non-susceptible (Carba-NS) GNB in patients with acute myelogenous leukemia (AML).MethodsCases of all GNB during induction or consolidation chemotherapy for AML in a 15-year period in a tertiary hospital were retrospectively reviewed. Independent risk factors for Carba-NS GNB were sought and its clinical outcomes were compared with those of carbapenem susceptible (Carba-S) GNB.ResultsAmong 485 GNB cases from 930 patients, 440 (91%) were Carba-S and 45 (9%) were Carba-NS GNB. Frequent Carba-NS isolates were Stenotrophomonas maltophilia (n = 23), Pseudomonas aeruginosa (n = 11), and Acinetobacter baumannii (n = 10). Independent risk factors for Carba-NS GNB were carbapenem use at the onset of GNB (aOR [95% CI], 78.6 [24.4–252.8]; P < 0.001), the isolation of imipenem-resistant A. baumannii in the prior 1 year (aOR [95% CI], 14.6 [2.7–79.9]; P = 0.002), time interval from chemotherapy to GNB ≥20 days (aOR [95% CI], 4.7 [1.7–13.1]; P = 0.003), and length of hospital stay ≥30 days (aOR [95% CI], 3.4 [1.3–9.1]; P = 0.013). Except breakthrough GNBs which occurred during carbapenem treatment, the frequency of Carba-NS GNB was 48% (19/40) in cases having ≥2 risk factors other than carbapenem use. 30-day overall mortality (Carba-NS, 36% vs. Carba-S, 6%; P < 0.001) and in-hospital mortality (Carba-NS, 47% vs. Carba-S, 9%; P < 0.001) were significantly higher in Carba-NS GNB.ConclusionCarba-NS GNB in AML patients was independently associated with the use of carbapenem, the past isolation of resistant organism, and late onset of GNB, and its clinical outcomes were poorer than those of Carba-S GNB. Carba-NS organisms should be considered for antibiotic selection in AML patients having these risk factors.Disclosures All authors: No reported disclosures.

Neutrophilic Eccrine Hidradenitis in a Primary CNS Lymphoma Patient Receiving High-Dose Chemotherap

Neutrophilic Eccrine Hidradenitis (NEH) is a rare inflammatory neutrophilic dermatosis that primarily affects eccrine sweat glands. Although it has been described in various malignancies and with therapeutic agents, it is most frequently associated with cytarabine-based induction chemotherapy for acute myelogenous leukemia. We report a rare case of NEH in a 63-year-old male with a medical history significant for primary CNS lymphoma. The patient was treated with high-dose thiotepa, busulfan, and cyclophosphamide (BuCy) followed by autologous stem cell transplantation, which was complicated by bacteremia and septic shock. Approximately three weeks after chemotherapy, he developed localized bright red, desquamating plaques on his bilateral outer hips, posterior upper thighs, and buttocks. Histological findings revealed neutrophils infiltrating and surrounding the eccrine glands accompanied by squamous syringometaplasia, apoptotic keratinocytes, and basovacuolar changes. This case serves to highlight that NEH should be considered in the differential diagnosis of erosive, erythematous plaques, especially in patients with lymphoproliferative tumors receiving high-dose chemotherapy, in order to provide appropriate clinical management.

Multiple Septic Emboli in the Skin, Lungs, and Brain due to Corynebacterium Striatum Bacteremia in a Patient with Acute Myelogenous Leukemia

A 29-year-old man developed fever after chemotherapy for acute myelogenous leukemia. Corynebacterium striatum was detected via blood culture, and antibacterial treatment with vancomycin started. In the course of treatment, papules of the skin, multiple nodular shadows of the lung, cerebral infarction, and subdural empyema appeared. A diagnosis of multiple septic emboli in the skin, lungs, and brain due to C. striatum bacteremia was made from the clinical course. The antibacterial treatment improved skin and pulmonary lesions. The subdural empyema was considered as a postoperative infection of burr-hole craniotomy. It improved by performing craniotomy twice with drainage and empiric antibiotic therapy. In our case, neutropenia was present as an immunodeficiency, which made bacteremia severe. There has not been reported a case of septic emboli of three lesions; skin, lung, and brain. C. striatum bacteremia may result in septic emboli and should immediately be treated with antibiotics.

1017. Impact of Enterococcal Bloodstream Infection on Mortality in Patients With Acute Myelogenous Leukemia

BackgroundThough enterococcal bloodstream infection (EBSI) is common in patients with acute myelogenous leukemia (AML), its impact on mortality requires further elucidation. Our objectives were to: (1) determine attributable mortality to EBSI and (2) compare overall, 1-year, relapse-related mortality (RRM), and treatment-related mortality (TRM) between AML patients with and without EBSI.MethodsThis was a retrospective cohort receiving intensive chemotherapy for AML from 2010 to 2015. EBSI was defined by _1 positive blood culture for E. faecium or faecalis and fever, hypotension, or chills. Attributable mortality to EBSI was defined by failure to achieve BSI Clearance (_1 negative culture _24 hr after last positive culture and defervescence) by the date of death. Student’s t-test was used to compare continuous variables, and C2 test was used for categorical variables. Kaplan–Meier was used for survival analyses (unadjusted), and P-values were computed by log-rank.ResultsThree hundred eight patients were identified during the study period: 80 with EBSI and 228 without EBSI. 5/80 patients died with EBSI (6%) although 4/5 patients had concurrent infections at the time of death (Clostridium difficile colitis, candidemia, proven invasive aspergillosis, and probable invasive fungal disease, respectively). There were no significant differences between overall and 1-year mortality (Table 1). In the survival analyses, EBSI did not significantly impact overall survival, 1-year mortality, RRM, and TRM (Figure 1). However, patients with vancomycin-resistant EBSI (VRE) trended toward increased overall mortality.ConclusionAttributable mortality to EBSI is uncommon (6%) in AML. Additionally, EBSI does not significantly impact mortality in this vulnerable patient population that already has very high rates of RRM and TRM. However, as EBSI inflicted 26% of patients over the course of this study period, further investigation is needed to elucidate the morbidity suffered from this common infection and identify potentially modifiable risk factors.Table 1.EBSIN = 80 (26%)No EBSIN = 228 (74%) P Age AML diagnosis (median years, IQR)63(51–69)61(50–69)0.93Overall mortality (%)63/73 (86)154/198 (77)0.12Time AML diagnosis to death (median years, IQR)220 (67–541)273 (62–582)0.16 Disclosures A. Sung, Merck: Grant Investigator, Grant recipient. Enterome: Grant Investigator, Grant recipient.

Outcome of empirical or targeted antifungal therapy after antifungal prophylaxis in febrile neutropenia.

Azole prophylaxis has been shown to be effective in preventing invasive fungal infections (IFIs) and increasing survival in patients with prolonged neutropenia after myelosuppressive chemotherapy for haematological malignancies. Similarly, empirical antifungal therapy for persistent neutropenic fever has been shown to reduce IFI-related mortality. However, to date, there is little information with regard to the outcome of patients who receive both strategies. Here, we present our retrospective data on three cohorts of patients receiving empirical or targeted antifungal therapy after different antifungal prophylaxis regimens. All records from patients who received myelosuppressive induction chemotherapy for acute myelogenous leukemia (AML) in our centre from 2004-2010 were analysed. From 2004-2006, itraconazole was used as antifungal prophylaxis; for the first 6months in 2007, local polyenes and from mid-2007 till 2010, posaconazole. Data of 315 courses of chemotherapy in 211 patients were analysed. Antifungal therapy (empirical or targeted, time point and antifungal agent at the physician's discretion) was initiated in 50/174 (29%), 7/18 (39%) and 34/123 courses (28%, p = 0.615) in the itra cohort, the cohort without systemic prophylaxis and the posa cohort, respectively, and was effective in 24/50 (48%), 5/7 (71%) and 22/34 courses (65%, p = 0.221), respectively. IFI occurred in 25/174 (14%), 4/18 (22%) and 16/123 (13%) courses, respectively (p = 0.580). IFI-related survival was not different in the three cohorts. Antifungal treatment in patients with AML who received azole prophylaxis resulted in the expected efficacy-importantly, prior posaconazole prophylaxis did not render subsequent antifungal treatment less effective than prior itraconazole prophylaxis.

Fatal Breakthrough Mucormycosis in an Acute Myelogenous Leukemia Patient while on Posaconazole Prophylaxis.

Posaconazole is a new oral triazole with broad-spectrum antifungal activity. Posaconazole has also shown a significant advantage of preventing invasive fungal infection compared to fluconazole or itraconazole in patients with prolonged neutropenia. Indeed, posaconazole has been commonly used for antifungal prophylaxis in patients undergoing remission induction chemotherapy for acute myelogenous leukemia or myelodysplastic syndrome. We experienced a case of fatal mucormycosis despite posaconazole prophylaxis. To our knowledge, this is the first reported case of fatal breakthrough mucormycosis in a patient receiving posaconazole prophylaxis during remission induction chemotherapy in Korea. This case demonstrated that breakthrough fungal infection can occurs in patients receiving posaconazole prophylaxis because of its limited activity against some mucorales.

The prognostic importance of polypharmacy in older adults treated for acute myelogenous leukemia (AML)

We retrospectively evaluated the prognostic significance of polypharmacy and inappropriate medication use among 150 patients >60 years of age receiving induction chemotherapy for acute myelogenous leukemia (AML). After adjustment for age and comorbidity, increased number of medications at diagnosis (≥4 versus ≤1) was associated with increased 30-day mortality (OR=9.98, 95% CI=1.18–84.13), lower odds of complete remission status (OR=0.20, 95% CI=0.06–0.65), and higher overall mortality (HR=2.13, 95% CI=1.15–3.92). Inappropriate medication use (classified according to Beers criteria) was not significantly associated with clinical outcomes. Polypharmacy warrants further study as a modifiable marker of vulnerability among older adults with AML.

Clinical effectiveness of posaconazole versus fluconazole as antifungal prophylaxis in hematology–oncology patients: a retrospective cohort study

In preventing invasive fungal disease (IFD) in patients with acute myelogenous leukemia (AML) or myelodysplastic syndrome (MDS), clinical trials demonstrated efficacy of posaconazole over fluconazole and itraconazole. However, effectiveness of posaconazole has not been investigated in the United States in real-world setting outside the environment of controlled clinical trial. We performed a single-center, retrospective cohort study of 130 evaluable patients ≥18 years of age admitted to Duke University Hospital between 2004 and 2010 who received either posaconazole or fluconazole as prophylaxis during first induction or first reinduction chemotherapy for AML or MDS. The primary endpoint was possible, probable, or definite breakthrough IFD. Baseline characteristics were well balanced between groups, except that posaconazole recipients received reinduction chemotherapy and cytarabine more frequently. IFD occurred in 17/65 (27.0%) in the fluconazole group and in 6/65 (9.2%) in the posaconazole group (P = 0.012). Definite/probable IFDs occurred in 7 (10.8%) and 0 patients (0%), respectively (P = 0.0013). In multivariate analysis, fluconazole prophylaxis and duration of neutropenia were predictors of IFD. Mortality was similar between groups. This study demonstrates superior effectiveness of posaconazole over fluconazole as prophylaxis of IFD in AML and MDS patients. Such superiority did not translate to reductions in 100-day all-cause mortality.

Development of myeloid sarcoma after long-term methotrexate use for rheumatoid arthritis

Myeloid sarcoma (MS) in the complete absence of bone marrow disease is an extremely rare phenomenon. We report the case of a 78-year-old woman with multiple subcutaneous lung and liver nodules, including mediastinal and peritoneal lymph node swelling, who had been receiving methotrexate (MTX) for 10 years for rheumatoid arthritis (RA). She was initially diagnosed with ALK-negative anaplastic large cell lymphoma. After one course of an anthracycline-containing regimen, pathologic cells were identified as CD68 (Kp-1)-positive with myeloid-lineage tumor cells and abnormal karyotypes with 8q21 and 21q22. Subsequent treatment was changed to acute myelogenous leukemia (AML) induction chemotherapy. Although the lesions were partially reduced in size following treatment for lymphoma, complete response (CR) was obtained only after AML chemotherapy. The patient remained in CR over 3 years after the last chemotherapy. This case may indicate an association between long-term MTX use and MS. An early diagnosis and adequate therapy may be important for improving survival outcomes in MS. This report demonstrates that CD68 staining is important for the differential diagnosis of MS and lymphoma. Careful follow-up is necessary for this patient, who may be the first case of MS after methotrexate use for RA.

The TPO/c-MPL Pathway in the Bone Marrow may Protect Leukemia Cells from Chemotherapy in AML Patients

Accumulating evidence indicates that the interaction of human LSCs (leukemic stem cells) with the hematopoietic microenvironment, mediated by the thrombopoietin (TPO)/c-MPL pathway, may be an underlying mechanism for resistance to cell cycle-dependent cytotoxic chemotherapy. However, the role of TPO/c-MPL signaling in AML (acute myelogenous leukemia) chemotherapy resistance hasn't been fully understood. The c-MPL and TPO levels in different AML samples were measured by flow cytometry and ELISA. We also assessed the TPO levels in the osteoblasts derived from bone mesenchymal stem cells (BMSCs). The survival rate of an AML cell line that had been co-cultured with different BMSC-derived osteoblasts was measured to determine the IC50 of an AML chemotherapy drug daunorubicin (DNR). The levels of TPO/c-MPL in the initial and relapse AML patients were significantly higher than that in the control (P < 0.05). The osteoblasts derived from AML patients' BMSCs secreted more TPO than the osteoblasts derived from normal control BMSCs (P < 0.05). A strong positive correlation between the TPO level and c-MPL expression was found in the bone marrow mononuclear cells of the relapse AML patients. More importantly, the IC50 of DNR in the HEL + AML-derived osteoblasts was the highest among all co-culture systems. High level of TPO/c-MPL signaling may protect LSCs from chemotherapy in AML. The effects of inhibition of the TPO/c-MPL pathway on enhancing the chemotherapy sensitivity of AML cells, and on their downstream effector molecules that direct the interactions between patient-derived blasts and leukemia repopulating cells need to be further studied.

Geriatric assessment predicts survival for older adults receiving induction chemotherapy for acute myelogenous leukemia

AbstractWe investigated the predictive value of geriatric assessment (GA) on overall survival (OS) for older adults with acute myelogenous leukemia (AML). Consecutive patients ≥ 60 years with newly diagnosed AML and planned intensive chemotherapy were enrolled at a single institution. Pretreatment GA included evaluation of cognition, depression, distress, physical function (PF) (self-reported and objectively measured), and comorbidity. Objective PF was assessed using the Short Physical Performance Battery (SPPB, timed 4-m walk, chair stands, standing balance) and grip strength. Cox proportional hazards models were fit for each GA measure as a predictor of OS. Among 74 patients, the mean age was 70 years, and 78.4% had an Eastern Cooperative Oncology Group (ECOG) score ≤ 1. OS was significantly shorter for participants who screened positive for impairment in cognition and objectively measured PF. Adjusting for age, gender, ECOG score, cytogenetic risk group, myelodysplastic syndrome, and hemoglobin, impaired cognition (Modified Mini-Mental State Exam < 77) and impaired objective PF (SPPB < 9) were associated with worse OS. GA methods, with a focus on cognitive and PF, improve risk stratification and may inform interventions to improve outcomes for older AML patients.

Abstract 1761: Extracellular telomeres can be detected in serum following cellular apoptosis in vitro and after chemotherapy in acute myelogenous leukemia (AML) patients.

Abstract Telomeres are repeated DNA sequences that cap the ends of each chromosome. Telomeres are temporally among the earliest genomic sequences to be degraded during apoptosis. We quantified telomeres in cell-free DNA (CF-DNA) in vitro and in vivo. CF-DNA was obtained by differential centrifugation of media or serum to remove intact cells and cellular debris. Telomere sequence in CF-DNA was measured with a quantitative PCR-based assay. We initially studied human breast cancer and brain cancer cell lines in vitro. We found that following treatment with doxorubicin, telomere sequences were rapidly detected in CF-DNA in the media (within 24-48 hours). We call these CF-DNA telomere sequences “extracellular telomeres” (ETs). ETs were preferentially secreted after chemotherapy. The telomere sequence molar fraction in the CF-DNA was up to 50,000-fold higher compared with other genomic sequences such as exons or structural DNA sequences such as alpha-satellite DNA. CF-DNA from the serum of 80 patients with a history of breast cancer and 40 normal female volunteers were analyzed. The patients with a history of metastatic breast cancer (n = 40) had 8-fold higher median value for ETs compared to those with a history of localized breast cancer (p=0.006). 20 normal women had ET levels similar to the local breast cancer patients. We thus hypothesized that the serum extracellular telomere assay could be used as a surrogate marker for in vivo apoptotic cell death. We collected sequential peripheral blood samples of newly diagnosed AML patients with a minimum peripheral circulating blast count of 2500/mm3 or more who received standard induction chemotherapy (anthracycline and cytarabine). These sequential peripheral blood samples were collected before, during and after standard chemotherapy at 12 hours interval for consecutive 21 days. The samples were immediately centrifuged to isolate CF DNA. Subsequently, ETs were quantitatively measured by qPCR telomere assay. In our preliminary data analysis of seven patients, we routinely observed two peaks of ETs about 10- fold higher than baseline that occurred about 2-3 and 4-6 days after initiating standard chemotherapy respectively. We conclude that 1) Telomere DNA is preferentially released from cancer cells in response to chemotherapy-induced apoptosis, 2) ETs can be detected and measured in normal patients and patients with a history of cancer, and 3) ETs are released after chemotherapy in AML patients. We are further investigating the relationship between ETs and other prognostic features in AML including initial white blood cell count, cytogenetics, disease free survival and overall survival. Citation Format: Amitkumar Mehta, Mallick Hossain, Christine Pressey, Johanna Tuomela, Varun Dhulipala, Sunil Rangarajan, Robert Crescentini, Arja Jukkola-Vuorinen, Katri Selander, David Graves, Kevin Harris, Uma Borate. Extracellular telomeres can be detected in serum following cellular apoptosis in vitro and after chemotherapy in acute myelogenous leukemia (AML) patients. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1761. doi:10.1158/1538-7445.AM2013-1761

A Most Unusual Passage Per Rectum

Question: A 60-year-old man with acute myelogenous leukemia (AML) in remission relapsed and was admitted for salvage chemotherapy. He received induction with methotrexate, epirubicin and cisplatin. During the course of treatment, he became hypotensive and tachycardic, prompting transfer to the intensive care unit. Septic shock was empirically treated with broad-spectrum antibiotics. His course was further complicated by persistent pancytopenia, atrial fibrillation with rapid ventricular response, disseminated intravascular coagulation and respiratory failure requiring mechanical ventilation. He developed abdominal distension, proximal small bowel dilation, and mesenteric edema by computed tomography without pneumoperitoneum. Subsequent radiographic studies over several days revealed no interval changes; conservative therapy with nasogastric tube suction and methylnaltrexone was given. Five days later, he had an episode of melena accompanied by passage rectally of a 15-cm tubular structure (Figure A). Within hours of this event, he developed multisystem organ failure and hypotension followed by asystolic cardiac arrest. The tubular structure was sent for pathologic review (Figure B). What is your diagnosis? See the Gastroenterology web site (www.gastrojournal.org) for more information on submitting your favorite image to Clinical Challenges and Images in GI. Pathologic review revealed necrotic mucosa with cross-section containing luminal debris (black arrow), necrotic epithelium (red arrow), bacterial colonies and calcifications (blue arrow), and underlying superficial muscularis (green arrow). The superficial muscularis was thought to represent either thickened muscularis mucosa or a superficial layer of muscularis propria (Figure B). The final pathologic diagnosis was consistent with a partial thickness colonic cast. Passage of a partial or full thickness colonic cast is an extremely rare event. It was first described by Speakman and Turnbull in 1984 after an abdominal aortic aneurysm resection.1Speakman M.J. Turnbull A.R. Passage of a colon ‘cast’ following resection of an abdominal aortic aneurysm.Br J Surg. 1984; 71: 935Crossref PubMed Scopus (22) Google Scholar Since then, approximately one dozen additional case reports have been published.2Erguney S. Yavuz N. Ersoy Y.E. et al.Passage of “colonic cast” after colorectal surgery: report of four cases and review of the literature.J Gastrointest Surg. 2007; 11: 1045-1051Crossref PubMed Scopus (15) Google Scholar The common theme among most reported cases has been intestinal ischemia after abdominal surgery—usually repair or resection of an abdominal aortic aneurysm.2Erguney S. Yavuz N. Ersoy Y.E. et al.Passage of “colonic cast” after colorectal surgery: report of four cases and review of the literature.J Gastrointest Surg. 2007; 11: 1045-1051Crossref PubMed Scopus (15) Google Scholar Other surgeries that have led to this serious complication include rectal resection, J-pouch formation, and Hartmann pouch reversal.2Erguney S. Yavuz N. Ersoy Y.E. et al.Passage of “colonic cast” after colorectal surgery: report of four cases and review of the literature.J Gastrointest Surg. 2007; 11: 1045-1051Crossref PubMed Scopus (15) Google Scholar Nonsurgical conditions associated with passage of a colonic cast include graft-versus-host-disease,3Al Ashgar H. Peedikayil M. Chaudhri N. et al.Defecation of a “colon cast” as a rare presentation of acute graft-versus-host disease.Ann Saudi Med. 2009; 29: 231-233Crossref PubMed Scopus (35) Google Scholar acute pancreatitis, and now salvage chemotherapy for AML. Appropriate suspicion should arise in critically ill patients who have undergone colorectal or abdominal aneurysm surgery or those with significant intestinal ischemia and critical illness; such settings may rarely herald passage of a colonic cast. Although passage is often a near-terminal event, resection of the ischemic segment in the appropriate clinical setting may be a life-saving measure.2Erguney S. Yavuz N. Ersoy Y.E. et al.Passage of “colonic cast” after colorectal surgery: report of four cases and review of the literature.J Gastrointest Surg. 2007; 11: 1045-1051Crossref PubMed Scopus (15) Google Scholar