George Yaghmour

Early mortality in acute myeloid leukemia

The Southwest Oncology Group (SWOG) described the expected early mortality rate (EMR) for patients with non-M3 AML by age enrolled in clinical trials, but it is unclear how generalizable this data is. We sought to compare SWOGs reported EMR to that of the general population by utilizing the case listing session of SEER 18 matched to the accrual periods of the SWOG studies. 26,272 patients were identified within SEER compared to 968 in the SWOG cohort with mortality data. The EMR was 26.7% (7022 events) in the SEER cohort versus 12.2% (116) in the SWOG cohort. The EMR was higher in the SEER cohort in every studied age group and definition of EMR. Stepwise logistic regression analysis identified increasing age, black race (OR 1.15, CI 1.03-1.29, p<0.01), and monocytic differentiation (OR 1.55, CI 1.27-1.89, p<0.01) as predictors of higher EMR. This study demonstrates that EMR in patients with non-M3 AML is higher in the general patient population than reported in SWOG clinical trials.

Genomic alterations in neuroendocrine cancers of the ovary

BackgroundAs we have previously reported, small cell carcinoma of the ovary (SCCO) is a rare, aggressive form of ovarian cancer associated with poor outcomes. In an effort to identify new treatment options, we utilized comprehensive genomic profiling to assess the potential for novel therapies in SCCO.MethodsPatients with SCCO, SCCO-HT (hypercalcemic type), neuroendocrine tumors of the ovary (NET-O), and small cell carcinoma of the lung (SCLC) profiled by Caris Life Sciences between 2007–2015 were identified. Tumors were assessed with up to 21 IHC stains, in situ hybridization of cMET, EGFR, HER2 and PIK3CA, and next-generation sequencing (NGS) as well as Sanger sequencing of selected genes.ResultsForty-six patients with SCCO (10 SCCO, 18 SCCO-HT, 18 NET-O) were identified as well as 58 patients with SCLC for comparison. Patients with SCCO and SCCO-HT were younger (median 42 years [range 12–75] and 26 years [range 8–40], respectively) than patients with NET-O 62 [range 13–76] or SCLC 66 [range 36–86]. SCCO patients were more likely to be metastatic (70 %) than SCCO-HT (50 %) or NET-O (33 %) patients, but at a similar rate to SCLC patients (65 %). PD1 expression varied across tumor type with SCCO (100 %), SCCO-HT (60 %), NET-O (33 %) vs SCLC (42 %). PDL1 expression also varied with SCCO (50 %), SCCO-HT (20 %), NET-O (33 %) and SCLC (0 %). No amplifications were identified in cMET, EGFR, or HER2 and only 1 was found in PIK3CA (NET-O). Actionable mutations were rare with 1 patient with SCCO having a BRCA2 mutation and 1 patient with NET-O having a PIK3CA mutation. No other actionable mutations were identified.ConclusionsNo recurrent actionable mutations or rearrangements were identified using this platform in SCCO. IHC patterns may help guide the use of chemotherapy in these rare tumors.

Comorbidities Drive Outcomes for Both Malignancy-Associated and Non–Malignancy-Associated Hemophagocytic Syndrome

BACKGROUND Secondary hemophagocytic syndrome (SHPS) is a syndrome that develops as a result of infection, autoimmunity, or underlying malignancy. We studied novel predictors of mortality among adults with SHPS. PATIENTS AND METHODS SHPS were identified from the Nationwide Inpatient Sample for 2009 to 2011 using International Classification of Diseases, 9th Revision, Clinical Modification (ICD-9-CM), codes. Charlson comorbidity index (CCI) was used for comorbidity assessment, excluding malignancy. Patient- and hospital-related factors on mortality were assessed by chi-square test or analysis of variance. P values were 2 sided, and the level of significance was .05. RESULTS A total of 276 patient hospitalizations with SHPS were identified. Forty-four had an associated malignancy, 38 (86%) of which were hematologic. Median age was 42 years (range, 18-89 years). A total of 66% (n = 182) had a CCI of 0, 13% (n = 27) had a CCI of 1, and 21% (n = 57) had a CCI of 2 or more. On bivariate analysis, inpatient mortality rate was significantly higher in malignancy-associated hemophagocytic syndrome (HPS) (odds ratio [OR], 2.07; P = .04), age ≥ 50 years (OR, 3.46; P < .01), CCI ≥ 2 (OR, 3.04; P < .01), and Medicare patients (OR, 2.32; P < .01). In multivariate analysis, CCI ≥ 2 remained an independent predictor of survival in the overall study cohort (OR, 3.52; 95% confidence interval, 1.51-8.18; P < .01). CONCLUSION Malignancy-associated HPS, CCI ≥ 2, age > 50 years, and Medicare patients were associated with a worse in-hospital mortality. In multivariate analysis, greater comorbidity burden appeared to be the single most important predictor of mortality. This suggests that outcomes for adults with HPS are predicated by the extent of organ dysfunction at diagnosis.

Under-recognition of hemophagocytic syndrome in United States' rural, non-teaching hospitals.

Hemophagocytic syndrome (HPS) is a rare clinical syndrome characterized by hyper-inflammation due to an excessive immune response with an aggressive disease course and life-threatening consequences. Familial HPS is an autosomal recessive disorder caused by various gene defects that usually presents in infants and children.[1–4] Acquired or secondary HPS (SHPS) can occur at any age but primarily arises in adults due to extreme immunologic activation, which can be triggered, by infections, autoimmune disorders, and malignancies, with leukemia and lymphoma being the most common.[5,6] This syndrome is highly fatal without prompt diagnosis and treatment, but its rarity and complex clinical picture often leads to a delayed or missed diagnosis. Epidemiologic data on SHPS in the adult population is sparse. We sought to define the characteristics of SHPS in different hospital settings as well as the mortality when associated with hematologic malignancies, solid tumors, and in patients without a reported malignancy. We obtained IRB approval to search the United States Nationwide Inpatient Sample (NIS) database for adult patients diagnosed with HPS.[7] Utilizing search parameters established by Johnson et al. [8], we identified all adult hospitalizations from 2009 to 2011 with the diagnosis of HPS based on International Classification of Diseases-9th revision, Clinical Modification (ICD-9-CM) code 288.4 combined with ICD-9-CM procedure code 41.31 for bone marrow biopsy to improve diagnostic accuracy. Patient characteristics included age at diagnosis, race, and gender. We identified the underlying conditions associated with each case (malignant vs non-malignant) as well as the inpatient mortality. Lastly, we assessed the distribution of cases by hospital teaching status (teaching versus non-teaching) and location (rural versus urban). Statistical analysis was done using STATA 13.0 (StataCorp LP, College Station, TX). All p values were two sided and the level of significance was 0.05. A total of 896 HPS cases were identified and 276 of those cases also had bone marrow biopsies. Of the 276 cases identified for analysis, 44 (16%) had a concomitant diagnosis of a malignancy. The median age at diagnosis was 42 years (range 18–89 years), and 43% (n1⁄4 114) of the cases were females. Of the 232 non-malignant HPS cases, related causes could only be identified for 37 patients: 1 HIV (1%), 3 histoplasmosis (1%), 12 systemic lupus erythematosus (4%), and 21 rheumatoid arthritis (7%). There were a total of 23,634,793 hospitalizations in the NIS from 2009 to 2011; 12,532,948 (53%) belonged to non-teaching hospitals and 11,101,845 (47%) belonged to teaching hospitals. Similarly, 2,867,148 (12%) belonged to rural hospitals and 20,767,645 (88%) belonged to urban hospitals. Among HPS cases, 90% (n1⁄4 248) belonged to teaching hospitals and 99% (n1⁄4 273) belonged to urban hospitals. Chi-squared test showed that cases of HPS were more likely to be diagnosed in a teaching hospital (p < 0.01) and urban hospitals (p< 0.01). Of the 44 cases with an underlying malignancy, 38 (86%) were associated with a hematological malignancy and 5 (11.3%) with a solid tumor. The tumor type was not specified for one patient. The in-hospital mortality for HPS with and without underlying malignancy was 29.6% (n1⁄4 13) and 14.2% (n1⁄4 33), respectively (p value 0.01) [Table 1]. Inpatient mortality was 29% (n1⁄4 11) for patients with an associated hematological malignancy and 40% (n1⁄4 2) for those with associated solid tumor. Comparison of outcomes between rural and urban hospitals and teaching and non-teaching hospitals was not feasible due to the skewing of case distributions. To better understand reasons for the concentration of HPS cases in urban centers, we explored referral patterns using the NIS ‘‘transfer out’’ variable, which was only available in 2010 and 2011. Data was available for two of the three cases diagnosed in rural hospitals, and neither case

How Center Volumes Affect Early Outcomes in Acute Myeloid Leukemia.

Early mortality (EM) is all too frequent during induction chemotherapy for acute myeloid leukemia. Older patients shoulder an undue amount of this burden as a result of the inherent biology of their disease and increased comorbidities. EM rates in academic centers have seen a sharp decline over the past 20 years; however, data from population-based registries show that EM rates for the general population have significantly lagged behind. In this review, we analyze the data available on EM in academic centers and the general population, explore recent improvements in supportive care and the use of predictive models, and finally investigate the relationship between case volume and complications during chemotherapy.

The presence of Philadelphia chromosome does not confer poor prognosis in adult pre-B acute lymphoblastic leukaemia in the tyrosine kinase inhibitor era - a surveillance, epidemiology, and end results database analysis

The BCR‐ABL1 fusion gene is caused by a translocation between chromosomes 9 and 22, resulting in an abnormal chromosome 22 (Philadelphia chromosome; Ph). Prior to the introduction of tyrosine kinase inhibitors (TKI), the presence of BCR‐ABL1 conferred a poor prognosis in patients with acute lymphoblastic leukaemia (ALL). We compared the survival of Ph+ and Ph−ALL during the period when TKIs were universally available in the US for Ph+ALL, using a Surveillance, Epidemiology, and End Results (SEER) Database analysis. A total of 2694 patients with pre‐B ALL (206 Ph+ALL; 2488 Ph−ALL) aged ≥18 years, who were diagnosed between 2010 and 2014, were identified in SEER registries. The median overall survival (OS) was 32 months in Ph+ALL (95% confidence interval [CI] 18 months‐not reached) and 27 months (95% CI 24–30 months) in Ph−ALL (Log‐rank test P‐value 0·34). Older age was associated with worse prognosis in both Ph+ALL and Ph−ALL. Age‐adjusted OS was inferior in Hispanics and African‐Americans compared to non‐Hispanic whites. Survival of pre‐B ALL shows continued improvement with time. Philadelphia chromosome status does not confer poor prognosis in pre‐B ALL in the TKI era: prognostic factors in pre‐B ALL should be re‐evaluated in the light of this finding.

Drug-Induced Aseptic Meningitis Associated With Intrathecal Trastuzumab

Objective: To report a case of drug-induced aseptic meningitis (DIAM) in a patient receiving intrathecal trastuzumab (ITT) for leptomeningeal carcinomatosis (LC) secondary to HER-2/neu positive breast cancer. Case Summary: A 43-year-old female with stage IV breast cancer presented with headache, parasthesias, and aphasia. Brain imaging suggested leptomeningeal enhancement. Adenocarcinoma cells were found on cerebrospinal fluid analysis, and infectious etiologies were excluded. The patient received 30 mg of ITT via Ommaya reservoir and suffered sudden neurologic deterioration within 2 hours. Given the sudden onset of clinical deterioration after ITT administration, it was determined that the patient had suffered from DIAM. The patient suffered progressive neurologic decline and was unable to care for herself any further. Discussion: Treatment for LC remains challenging due to limited clinical experience and the challenging location of the disease. ITT has been used in multiple reports without adverse events. A temporal relationship existed between ITT administration and significant neurologic deterioration, possibly related to DIAM. Our patient was not exposed to any more common causative agents of DIAM. Reasons for her lack of recovery are likely multifactorial. Symptoms of DIAM may have in part been exacerbated by progressive LC; however, prior to ITT, symptoms had shown slow but persistent progression rather than significant, acute changes in severity. Retrial of the offending agent was not attempted due to patient risk; thus, a cause-and-effect relationship cannot be established. This event is a “possible” drug-induced adverse event scoring 2 on the Naranjo algorithm. Conclusions: Use of ITT for LC has been frequently reported in recent literature with substantial efficacy and lack of adverse events. This is the first published report of any significant adverse event associated with ITT. Clinicians need to be aware of the possibility of DIAM with ITT and explore options to prevent or manage this severe complication.

All that glitters is not gold: differential diagnosis of clover-leaf lymphocytes

A 43-year-old, healthy, Iraqi male with no prior exposure to tuberculosis (TB) presented with a 4-month history of fever of unknown origin, described as episodic, occurring approximately two times per week with a maximum temperature of 38.5–39.5 C. This was associated with cyclic, intermittent arthralgias, crampy periumbilical pain, nonbloody, watery diarrhea, anorexia, malaise, and unintended weight loss of 16 kg over 4 months. Extensive workup during prior hospitalizations remained negative for an infectious or autoimmune etiology. Initial laboratory testing revealed a mild normocytic, normochromic anemia with no associated leucopenia, leukocytosis, or thrombocytopenia. CT imaging showed mild mediastinal lymphadenopathy with central necrosis and abdominal lymphadenopathy. PPD test was positive at 25 mm while the Quantiferon gold test was indicative of cellular immunity to TB. Acid-fast stain of the patient’s sputum was negative in three separate samples. Hematology was consulted to perform a bone marrow biopsy to rule out a neoplastic process. A peripheral blood smear showed around 10 % of lymphocytes with an atypical morphology with enlarged, clover-leaf shaped, lobated nuclei (flower cells) suggestive of T cell lymphoma, including Sézary syndrome (Fig. 1a–h). The patient underwent surgical excision of a clinically palpable supraclavicular lymph node, which demonstrated granulomatous inflammation with caseating necrosis (Fig. 2). Histochemical and immunostaining were negative for acid-fast and fungal organisms, as well as mycobacteria. There was no evidence of metastatic disease or immunophenotypic evidence of a mature B or T lymphoid neoplasm in excised lymph node or bone marrow biopsy. Serum hepatitis panel and viral studies for HIV, HLTV1, and HLTV2 were all negative. IgG for EBV, and CMV was positive. However, IgM was negative, suggesting chronic exposure. The decision was made to empirically treat for possible TB lymphadenitis based on risk factors. He was discharged home on a four-drug anti-TB regimen. 3 weeks later, PCR and cultures of the lymph node tissue detected Mycobacterium tuberculosis. In addition, his symptoms improved with the treatment, including complete remission of his episodic fevers. Repeated peripheral blood smear after 3 months did not detect any lymphocytes with atypical morphology; these had apparently disappeared during the anti-tuberculosis therapy.

Unrelated HLA mismatched microtransplantation in a patient with refractory secondary acute myeloid leukemia

Microtransplantation (MST), a type of HLA-mismatched allogeneic cellular therapy, is a promising, cellular therapy for acute myeloid leukemia (AML). MST transfuses granulocyte colony-stimulating factor (G-CSF)-mobilized, HLA-mismatched donor peripheral blood stem cells into patients undergoing conventional chemotherapy. MST, using haploidentical donors, has been shown to yield clinical benefit without any permanent marrow engraftment in AML. Consequently, graft-versus-host disease concerns are rendered irrelevant with no need for immunosuppression. We describe the first reported patient with refractory AML who underwent salvage MST from an unrelated, complete HLA-mismatched donor. The patient achieved remission without complication, warranting further study of unrelated HLA-mismatched donor MST in AML.

The role of FLT3 inhibitors as maintenance therapy following hematopoietic stem cell transplant

Activating mutations in FLT3 in acute myeloid leukemia (AML) portend a poor prognosis, and targeting FLT3 with a tyrosine kinase inhibitor has been an area of intense research recently. Most FLT3 mutated AML patients undergo hematopoietic stem cell transplantation (HSCT) as standard of care but a significant proportion of patients relapse. Although the use of FLT3 inhibitors in the pre-HSCT perspective is more clearly defined, its use in the post-HSCT scenario, when most relapses occur, remains unclear. In this review, we comprehensively present the data on the recent and ongoing studies evaluating the role of various FLT3 inhibitors in AML with a particular focus in the post-HSCT setting.