Setting Of Hematologic Malignancies Research Articles

Psychological burden and depressive symptoms in caregivers of hemato-oncological patients: the role of medical visits

AbstractInformal caregivers of patients with cancer are known to experience extensive burdens, whereas this issue remains unresolved in the setting of hematological malignancies. Yet, these diseases are characterized by a prolonged course, numerous relapses, and implementation of multiline therapy, administered in outpatient facilities. This study aimed to assess the factors contributing to burden and depressive symptoms in informal caregivers of patients with hematological malignancies, while concentrating on the role of medical visits. The study population comprised patients and their caregivers, recruited at the Rambam Hematology Ambulatory Unit. Participants completed validated questionnaires, including the Center for Epidemiologic Studies Depression Scale and the Zarit Caregiver Burden Interview. The cohort (n = 185) included 115 patients (average age, 62.8 ± 14.5 years; 54 males) and 70 caregivers. Among caregivers, 80% reported high psychological burden, and 50% reported significant depressive symptoms. The burden was higher if caregivers were females and if patients were less educated, less healthy, and more depressed. The caregiver burden and depressive symptoms were significantly linked, and the medical visit frequency predicted the level of both. The caregiver burden fully mediated the link between the independent variables of self-rated health and medical visits and the dependent variable of caregiver depressive symptoms. Informal caregivers of ambulatory patients with hemato-oncological malignancies experience high levels of psychological burden and depressive symptoms. This is partly attributed to the medical visit frequency. Hence, a decrease in the number and length of such visits via the implementation of advanced technology could essentially reduce burden and depressive symptoms of caregivers, without compromising patient outcomes.

Targeting TAG-72 in cutaneous T cell lymphoma

PurposeCurrent monoclonal antibody-based treatment approaches for cutaneous T cell lymphoma (CTCL) rely heavily on the ability to identify a tumor specific target that is essentially absent on normal cells. Herein, we propose tumor associated glycoprotein-72 (TAG-72) as one such target. TAG-72 is a mucin-associated, truncated O-glycan that has been identified as a chimeric antigen receptor (CAR)-T cell target in solid tumor indications. To date, TAG-72 targeting has not been considered in the setting of hematological malignancies. Experimental designCD3+ cells from patients with CTCL were analyzed for TAG-72 expression by flow cytometry. Immunohistochemistry was used to assess TAG-72 expression in CTCL patient skin lesions and a TAG-72 ELISA was employed to assess soluble TAG-72 (CA 72-4) in patient plasma. TAG-72 CAR transduction was performed on healthy donor (HD) and CTCL T cells and characterized by flow cytometry. In vitro CAR-T cell function was assessed by flow cytometry and xCELLigence® using patient peripheral blood mononuclear cells and proof-of-concept ovarian cancer cell lines. In vivo CAR-T cell function was assessed in a proof-of-concept, TAG-72+ ovarian cancer xenograft mouse model. ResultsTAG-72 expression was significantly higher on total CD3+ T cells and CD4+ subsets in CTCL donors across disease stages, compared to that of HDs. TAG-72 was also present in CTCL patient skin lesions, whereas CA 72-4 was detected at low levels in both CTCL patient and HD plasma with no differences between the two groups. In vitro cytotoxicity assays showed that anti-TAG-72 CAR-T cells significantly, and specifically reduced CD3+TAG-72+ expressing CTCL cells, compared to culture with unedited T cells (no CAR). CTCL CAR-T cells had comparable function to HD CAR-T cells in vitro and CAR-T cells derived from CTCL patients eradicated cancer cells in vivo. ConclusionThis study shows the first evidence of TAG-72 as a possible target for the treatment of CTCL.

Prevention of hepatitis B reactivation in patients with hematologic malignancies treated with novel systemic therapies: Who and Why?

The risk of reactivation in patients with chronic or past/resolved hepatitis B virus (HBV) infection receiving chemotherapy or immunosuppressive drugs is a well-known possibility. The indication of antiviral prophylaxis with nucleo(t)side analogue is given according to the risk of HBV reactivation of the prescribed therapy. Though the advent of new drugs is occurring in all the field of medicine, in the setting of hematologic malignancies the last few years have been characterized by several drug classes and innovative cellular treatment. As novel therapies, there are few data about the rate of HBV reactivation and the decision of starting or not an antiviral prophylaxis could be challenging. Moreover, patients are often treated with a combination of different drugs, so evaluating the actual role of these new therapies in increasing the risk of HBV reactivation is difficult. First results are now available, but further studies are still needed. Patients with chronic HBV infection [hepatitis B surface antigen (HBsAg) positive] are reasonably all treated. Past/resolved HBV patients (HBsAg negative) are the actual area of uncertainty where it could be difficult choosing between prophylaxis and pre-emptive strategy.

#5902 KIDNEY INVOLVEMENT IN HAEMATOLOGICAL MALIGNANCIES: THE IMPORTANCE OF EARLY NEPHROLOGICAL REFERRAL

Abstract Background and Aims Kidney is often injured in the setting of hematological malignancies. Although, kidney involvement negatively influences the prognosis of these patients, often the referral to clinical nephrology is late. The aims of this study were to investigate the long-term outcomes of haematological diseases with renal involvement demonstrated by kidney biopsy and the association between nephrological referral earliness and survival. Method Monocentric retrospective study evaluating overall survival (OS) (time to death) and renal free survival (RFS) (time to renal replacement therapy) in patients affected by hematologic malignancies with renal involvement demonstrated by kidney biopsy. Data have been collected by January 1st 2009 to December 30th 2021. Results reported as median (min-max) and percentage (%). Results 46 patients; M/F = 1.3; age: 70 years (39.5-91.2). Follow-up: 17,8 months (0.13-125.4). Data at kidney biopsy: creatinine was 3.13 mg/dL (0.6-14), eGFR was 20 ml/min/1.73 m2 (3-110), proteinuria was 5.1 g/24h (0.15-38.6), Bence-Jones proteinuria detected in 74% of patients. Clinical presentations: AKI (63.1%), Nephrotic syndrome (36.9%). Patient referral by Nephrologist (28.2%), Hematologist (26.1%), General Practitioner (21.7%); Emergency Department (17.4%), Others (6.6%). The most frequent histological diagnosis was amyloidosis (32.7%), followed by cast nephropathy (19.2%). Renal Replacement Therapy was required in 41.3% patients. Treatment: 38 patients underwent chemotherapy (56.4% complete/very good hematologic response; 12.8% partial and 30.6% without response). Overall Survival at 24 months was 63.8% and it was reduced in patients with AKI at presentation (Fig. 1) and in patients without treatment response (Fig. 2). RFS was shorter in patients who presented with AKI and affected by Myeloma Cast. Early Nephrological referral was associated with a better RFS (Fig. 3). Conclusion Haematological malignancies with renal involvement causing AKI have the worst prognosis. Kidney biopsy has a prognostic significance and early nephrological referral associated with haematological treatment response correlate with a better renal outcome. These data point to the central role of a multidisciplinary team aimed to the detection and treatment of renal damage due to hematologic malignancies.

Tumor lysis syndrome in hematological inpatients, experience from a university hospital in Brazil: A retrospective cohort study

The tumor lysis syndrome is a medical emergency. Its presentation can be spontaneous or secondary, as a consequence of the established treatment. The diagnosis and treatment of the tumor lysis syndrome (TLS) has become a crucial goal to the evolution and improvement of treatments and targeted therapies. Between January 2014 and December 2019, we retrospectively reviewed inpatients aged over 18 years with hematological neoplasms from a tertiary hospital in Brazil. We identified 112 episodes of TLS in 97 patients. The incidence was 10.5% and the median OS was 13.0 months (95%CI 6.2 - 19.7). The median age was 56 years (IQR 39.5 - 64). The most frequent diagnoses were multiple myeloma (18.6%), acute myeloid leukemia (17.5%) and diffuse large B-cell lymphoma (17.5%). All patients received intravenous (IV) hydration. The management also included the administration of allopurinol in 76% of the cases and rasburicase in eight patients. Renal replacement therapy was necessary in 37% of the cases. In the multivariate analysis, age, HIV status and ICU treatment were significantly associated with OS. The TLS is a serious complication in the setting of hematological malignancies. The use of scores for risk stratification, as well as the inclusion of prophylactic measures and prompt treatment with frequent laboratory monitoring, is essential to reduce morbidity and mortality in the comprehensive treatment of these patients.

Abstract 3858: Exploring Exportin-1 as a therapeutic vulnerability in squamous cell carcinoma

Abstract Introduction: Squamous cell carcinomas (LUSCs) account for 25-30% cases of non-small cell lung cancers, making them the second most common histology of lung cancer after adenocarcinomas. For the latter, molecular characterization has defined tumor subsets with discrete driver alterations sensitive to targeted inhibitors, leading to significant improvement in patient survival. However, for LUSCs, to date no specific drivers have been described that are amenable for pharmacological targeting and no targeted therapies are approved for use in this setting. Despite decades of research, LUSCs are still treated with cytotoxic chemotherapy, and now concomitant immunotherapy, which does not achieve durable responses in most patients. Thus, identification of targetable vulnerabilities in this setting remains a critical unmet clinical need. Preliminary data from our lab has identified the nuclear exporter exportin 1 as a therapeutic vulnerability in small cell lung carcinomas. Exportin 1 (XPO1) inhibition with Selinexor, a drug approved for clinical use in the setting of hematological malignancies, induces significant sensitivity in combination with cisplatin and irinotecan. Here, we explored the role of XPO1 as a therapeutic target in LUSC. Methods: We performed a comprehensive multi-omic molecular characterization of a library of LUSC patient-derived xenografts (PDXs) (N=28, with 17 clinical samples being matched pairs). IHC, RNA-seq and NGS via MSK-IMPACT were performed on 27 samples. To examine the potential of XPO1 inhibition as sensitizer to chemotherapy in LUSC, we performed genetic and pharmacological inhibition experiments in LUSC cell lines exhibiting high XPO1 expression. Results: Of the 28 models, 19 samples (68%) were from primary tumors and 9 samples (32%) from metastasis. The sample set were roughly split in half with regard to treatment status; 15 samples (54%) were treatment naïve and 13 sample were treated (46%).XPO1 is highly expressed in LUSCs clinical specimens compared to other tumor types, and its knockdown reduces tumorigenic features of LUSC cell lines with high XPO1 expression, including proliferation and anchorage-independent growth. Targeted XPO1 inhibition with selinexor induces chemotherapy sensitization to carboplatin and paclitaxel, drugs currently used in the treatment of LUSC, as depicted by high cytotoxic synergy scores of selinexor with either drug. Conclusion: Our data suggest that XPO1 expression may exert pro-oncogenic effects in LUSC, consistent with its upregulation in this tumor setting, and that its inhibition with selinexor may strongly sensitize to chemotherapy. Assessment of efficacy of combination therapies with selinexor in vivo will assess the potential of these combinations as a therapeutic approach for LUSC tumors. The clinical availability of selinexor would allow immediate clinical translation of the results generated in this project. Citation Format: Vidushi Durani, Rebecca Caeser, Charles M. Rudin, Alvaro Quintanal-Villalonga, Harsha Sridhar, Parvathy Manoj, Sam E. Tischfield, Marina Asher, Umeshkumar Bhanot, Jacklynn V. Egger, Nicholas D. Socci D. Socci, Nisargbhai S S. Shah, Elisa de Stanchina, Natasha Rekhtman. Exploring Exportin-1 as a therapeutic vulnerability in squamous cell carcinoma. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3858.

The Use of Virtual Care in Patients with Hematologic Malignancies: A Scoping Review.

There is increasing interest from cancer patients and their healthcare providers in the use of virtual care in routine clinical practice. In the setting of hematologic malignancy, where patients often undergo complex and immunodepleting treatments, understanding how to use virtual care safely and effectively is critically important. We aimed to describe the use of virtual care in patients with hematologic malignancies and to examine physician- and patient-reported outcomes in the form of a systematic scoping review. An electronic search of PubMed, Ovid MEDLINE, Elsevier Embase, Scopus, and EBSCO CINAHL was conducted from January 2000 to April 2021. A comprehensive search strategy was used to identify relevant articles, and data were extracted to assess the study design, population, setting, patient characteristics, virtual care platform, and study results. Studies were included if they described the use of virtual care for patients with hematologic malignancies; commentaries were excluded. Fifteen studies met the inclusion criteria after abstract and full-text review. Three studies found that app-based tools were effective in monitoring patient symptoms and triggering alerts for more urgent follow-up. Four studies described the use of phone-based interventions. Five studies found that videoconferencing, with both physicians and oncology nurses, was highly rated by patients. Emerging themes included high levels of patient satisfaction across all domains of virtual care. Provider satisfaction scores were rated lower than patient scores, with concerns about technical issues leading to challenges with virtual care. Four studies found that virtual care allowed providers to promptly respond to patient concerns, especially when patients were experiencing side-effects or had questions about their treatment. Overall, the use of virtual care in patients with hematologic malignancies appears feasible, and resulted in high patient satisfaction. Further research is needed in order to evaluate the optimal method of integrating virtual care into clinical practice.

A Multicenter Retrospective Experience of Hematologic Neoplasms in Pregnancy

INTRODUCTION: Cancer is diagnosed in 0.07% to 0.1% of pregnancies and represent the second cause of maternal death after vascular complications. Hematologic malignancies account for 25% of all malignancies in pregnancy. It is always a challenge to confront a case of a pregnant woman with any type of cancer, requires a great multidisciplinary team and so far there is no a world-wide expert group in the treatment of this type of patients. The world's experience on approach and treatment of women with cancer is limited to cases series and recommendations with low scientific evidence. Latin America and particularly Mexico has a different clinical behavior to that reported in the developed countries and does not have a consensus of treatment for these patients.OBJETIVES: To report our multicenter experience in the setting of hematologic malignancies during the pregnancy.MATERIALS AND METHODS: This is a retrospective multicenter study that collects the information available in the databases of 9 hospitals in Mexico from January 1993 to June 2017 with diagnosis of pregnancy and hematologic cancer. Epidemiological data in relation to type of cancer, treatment as well as features of pregnancy, childbirth and newborn were colected.RESULTS: A total of 101 patients from 9 Mexican medical institutions were diagnosed with the following hematologic malignancies: 88 cases of leukemia (16% acute myeloid leukemia (AML), 34% acute lymphoblastic leukemia (ALL), 2 cases of T ALL, 3% Mixed lymphocytic leukemia, 35% chronic myeloid leukemia (CML), 7 cases of Hodgkin's lymphoma, 5 cases of non-Hodgkin's lymphoma, 1 case of myelofibrosis. The mean age at diagnosis was 23 years old (14-41), 46% were diagnosed before week 20 of gestation, 49% during week 21 to 35 and 6% after week 36. 35 patients received no treatment (34.6%). Of the women who received treatment, the drugs used according to the type of neoplasia were imatinib (28.7%), interferon alpha (10.6%), hydroxyurea (7.5%), cytarabine + doxorubicin (18.1%), vincristine + doxorubicin + prednisone + L-asparaginase (24.2%), Hyper CVAD (4.5%), ABVD (4.5%), R-CHOP (1.98%). 51 cases (50.4%) were diagnosed with hematological malignancies and under treatment, prior to pregnancy. Within the Acute Leukemia group (51%) there were 20 deaths; In those diagnosed with lymphoma no deaths were recorded and there was 1 death due to blast crisis in CML. In the group that received chemotherapeutic treatment (65.3%) there were 12 fetal deaths, treatment-related structural alterations in only 3 newborns, 45% healthy and the rest had mild reversible complications.CONCLUSIONS: We report the largest series of cases in malignant hemopathies in pregnancy. The results show the need to organize multidisciplinary work teams to improve the care and treatment of this type of patients. DisclosuresNo relevant conflicts of interest to declare.

Abiotrophia and Granulicatella Infections in Cancer Patients: A Single-Center Chart Review Study

Objectives: Nutritionally Variant Streptococci (NVS) comprise two primary genera that have been identified from human specimens, particularly the Abiotrophia and Granulicatella species. These infections are often complicated to manage due to the difficulty identifying these organisms, indolent course of disease, and variable resistance to common antimicrobial agents. The wide breadth of disease presentations involving these organisms has not been fully elucidated, particularly in the immunosuppressed cancer patient population. Method: We performed a retrospective chart review on 28 patients from an academic cancer center with positive NVS cultures, from January 2012 to July 2018. We reviewed patient characteristics, culture data, immunodeficiency status, response to antibiotic therapy, and outcomes of infection. Results: Of twenty-eight patients, fifteen patients developed bacteremia from either Abiotrophia or Granulicatella species, while thirteen patients had positive wound or body fluid cultures. Most patients with bacteremia had underlying hematologic malignancies and neutropenia. Patients with positive wound or body fluid cultures had an invasive procedure at the related site. Intravenous (IV) vancomycin was the most common agent used, and all but two patients were treated with multiple antibiotic regimens. Conclusions: Infections with NVS have been reported with a variety of clinically infectious presentations and should be considered in cancer patients with neutropenia or in patients who have undergone invasive procedures. Bacteremia was the most common complication, especially in the setting of hematologic malignancy and neutropenia. Focal body site infection was also a common complication related to invasive procedures in immunocompetent patients. Overall mortality was low and related to complications of septic shock. J Microbiol Infect Dis 2020; 10(2):89-97.

Bullous Sweet’s syndrome in a patient with ulcerative colitis: a rare case report

Bullous Sweet's syndrome is an uncommon clinical presentation of classical Sweet's syndrome, often associated with various kinds of tumors, infections, and active inflammatory bowel diseases (IBDs), namely Crohn's disease and ulcerative colitis. Only a few cases of bullous Sweet's syndrome associated with ulcerative colitis are described in the literature. We report a case of a 62-year-old female patient with acute exacerbation of ulcerative colitis associated with infiltrating purple-erythematous skin plaques, which were partly vesicular, and oral ulcerative stomatitis. Biopsy was consistent with bullous Sweet's syndrome. Treatment with betamethasone sodium phosphate, starting at 5.5 mg, followed by gradual dose tapering for 12 weeks, resulted in improvement of the ulcerative colitis and disappearance of the cutaneous lesions. Bullous Sweet's syndrome most commonly occurs in the setting of hematologic malignancies, suggesting that physicians should perform long-term screening for early diagnosis of hematological and solid malignancies.

Modifiable Factors Associated with the Completion of Advance Treatment Directives in Hematologic Malignancy: A Patient-Caregiver Dyadic Analysis.

Objective: The completion rates of advance treatment preferences in patients with hematologic malignancies are low. To improve these rates, the modifiable factors associated with completion need to be determined. This study aimed to examine the associations of patient attitudes toward, and knowledge about, advance directives (ADs) with the patient-caregiver dyadic completion of advance treatment directive surveys. Methods: Using a nonexperimental correlational design, 44 patient-caregiver dyads completed the questionnaires, including a Korean-Advance Directive model. Cohen's kappa coefficient and multiple logistic regression analyses examined the extent of dyadic agreement and patient factors for the dyadic completion of the advance treatment directive survey, respectively. Results: A minor group of patients (4.5%-11.4%) and caregivers (11.4%-18.2%) preferred aggressive end-of-life treatments, whereas more patients (47.7%) and caregivers (68.2%) supported hospice care. The only significant patient-caregiver dyadic concordance on treatment directives was for chemotherapy with a moderately high agreement (kappa = 0.60: 95% CI: 2.51-3.73). One score increase in AD knowledge and having a history of hematopoietic stem cell transplant (HSCT) increased the likelihood of dyadic completion of the treatment directive survey by 43% (p = 0.039) and 917% (p = 0.047), respectively. Conclusions: The patient-caregiver dyads in the setting of hematologic malignancy had a moderately high concordance with chemotherapy but were not associated with other treatment options. A higher level of AD knowledge and HSCT were associated with dyadic completion of the AD survey. Educational support is important to increase knowledge regarding ADs through ongoing palliative discussions among hematologic patients and their caregivers.

VTE Rates and Safety Analysis of Newly Diagnosed Multiple Myeloma Patients Receiving Carfilzomib-Lenalidomide-Dexamethasone (KRD) with or without Rivaroxaban Prophylaxis

VTE Rates and Safety Analysis of Newly Diagnosed Multiple Myeloma Patients Receiving Carfilzomib-Lenalidomide-Dexamethasone (KRD) with or without Rivaroxaban Prophylaxis

A clinical approach to respiratory disease in patients with hematological malignancy, with a focus on respiratory infection.

Respiratory complications, in particular infections, are common in the setting of hematological malignancy and after hematopoetic stem cell transplant. The symptoms can be nonspecific; therefore, it can be difficult to identify and treat the cause. However, an understanding of the specific immune defect, clinical parameters such as speed of onset, and radiological findings, allows the logical diagnostic and treatment plan to be made. Radiological findings can include consolidation, nodules, and diffuse changes such as ground glass and tree-in-bud changes. Common infections that induce these symptoms include bacterial pneumonia, invasive fungal disease, Pneumocystis jirovecii and respiratory viruses. These infections must be differentiated from inflammatory complications that often require immune suppressive treatment. The diagnosis can be refined with the aid of investigations such as bronchoscopy, computed tomography (CT) guided lung biopsy, culture, and serological tests. This article gives a schema to approach patients with respiratory symptoms in this patient group; however, in the common scenario of a rapidly deteriorating patient, treatment often has to begin empirically, with the aim to de-escalate treatment subsequently after targeted investigations.

CART Immunotherapy: Development, Success, and Translation to Malignant Gliomas and Other Solid Tumors.

T cell chimeric antigen receptor (CAR) technology has allowed for the introduction of a high degree of tumor selectivity into adoptive cell transfer therapies. Evolution of this technology has produced a robust antitumor immunotherapeutic strategy that has resulted in dramatic outcomes in liquid cancers. CAR-expressing T-cells (CARTs) targeting CD19 and CD20 have been successfully used in the treatment of hematologic malignancies, producing sustained tumor regressions in a majority of treated patients. These encouraging results have led to a historic and unprecedented FDA approval of CTL019, Novartis' CAR T-cell therapy for the treatment of children and young adults with relapsed or refractory B-cell acute lymphoblastic leukemia (ALL). However, the translation of this technology to solid tumors, like malignant gliomas (MG), has thus far been unsuccessful. This review provides a timely analysis of the factors leading to the success of CART immunotherapy in the setting of hematologic malignancies, barriers limiting its success in the treatment of solid tumors, and approaches to overcome these challenges and allow the application of CART immunotherapy as a treatment modality for refractory tumors, like malignant gliomas, that are in desperate need of effective therapies.

Efficient identification of somatic mutations in acute myeloid leukaemia using whole exome sequencing of fingernail derived DNA as germline control

Recent advances in next-generation sequencing have made it possible to perform genome wide identification of somatic mutation in cancers. Most studies focus on identifying somatic mutations in the protein coding portion of the genome using whole exome sequencing (WES). Every human genome has around 4 million single nucleotide polymorphisms (SNPs). A sizeable fraction of these germline SNPs is very rare and will not be found in the databases. Thus, in order to unambiguously identify somatic mutation, it is absolutely necessary to know the germline SNPs of the patient. While a blood sample can serve as source of germline DNA from patients with solid tumours, obtaining germline DNA from patients with haematological malignancies is very difficult. Tumor cells often infiltrate the skin, and their DNA can be found in saliva and buccal swab samples. The DNA in the tips of nails stems from keratinocytes that have undergone keratinization several months ago. DNA was successfully extracted from nail clippings of 5 probands for WES. We were able to identify somatic mutations in one tumor exome by using the nail exome as germline reference. Our results demonstrate that nail DNA is a reliable source of germline DNA in the setting of hematological malignancies.

Abstract 970: Transforming NTRK2 and NTRK3 mutations as potential drivers of leukemia

Abstract The neurotrophic tyrosine receptor kinases (NTRKs) are a family of neuronal transmembrane receptors that signal through several pathways including JAK/STAT, PI3K/AKT, and MEK/ERK to promote proliferation, differentiation, and survival. Although much of the literature has focused on the importance of these receptors in neuronal development, over the past decade, gene fusions containing NTRK family members have been implicated in driving tumor growth in salivary gland, breast, lung, colon, and neuronal cancers. Moreover, expression of NTRK2 and NTRK3 has been reported in lymphoid and myeloid malignancies (Li, Z et al. Blood, 2009). Interestingly, NTRK3 expression has been associated with poorer prognosis. Despite these initial studies, the role of NTRK receptors largely remains under-investigated in the setting of hematologic malignancies. Herein, we describe somatic mutations in NTRK2 and NTRK3 that we identified using next-generation sequencing of primary leukemia patient samples. We evaluated changes in downstream signaling driven by these mutations in our previously validated Ba/F3 transformation model system. Lastly, we demonstrate that selective inhibition of NTRK2 and NTRK3 with entrectinib, a well-validated NTRK inhibitor currently in clinical trials for NTRK-fusion positive cancers, can inhibit proliferation and induce apoptosis of NTRK transformed cells. We found two point mutations in NTRK2 that were transforming — one in the extracellular domain (A203T) and one in the juxtamembrane domain (R458G). Similarly, we found two point mutations that were transforming in NTRK3. One was in the extracellular domain (E176D) and the other within the transmembrane domain (L449F). Immunoblot results suggest that expression of total and phosphorylated NTRK2 and NTRK3 is increased in mutant-transformed Ba/F3 cells relative to wild-type cells. Furthermore, NTRK2 and NTRK3 mutant-driven cells exhibited enhanced phosphorylation of AKT, SRC, and ERK compared to wild-type cells. While phosphorylation of STAT3 was significantly increased in Ba/F3 cells transfected with both NTRK3 mutants, it was increased only in one of the NTRK2 mutants (A203T). Upon treating NTRK mutant-transformed cells with entrectinib (0, 5, 25, and 100 nM), we observed a dose-dependent decrease in total and phosphorylated NTRK2 and NTRK3 in all mutants except for NTRK2 mutant R458G. With R458G, total and phosphorylated NTRK2 expression decreased up to 25 nM of entrectinib but that effect was diminished at 100 nM. Taken together, our data demonstrates that mutations in NTRK2 and NTRK3 have transformative potential to promote downstream survival signaling and leukemogenesis. More importantly, these activated pathways can be pharmacologically attenuated using entrectinib. Our findings contribute to ongoing efforts to understand molecular changes that drive hematological malignancies and could potentially alter current treatment modalities. Citation Format: Sunil K. Joshi, Kristin Qian, Jacob P. Wagner, Monika A. Davare, Cristina E. Tognon, Brian J. Druker. Transforming NTRK2 and NTRK3 mutations as potential drivers of leukemia [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 970.

OR34 Platelet refractoriness in a patient with 0% PRA due to a rare anti-CD36(NAKa) antibody

Platelet transfusion refractoriness in patients with hematological malignancies ranges from 7% to 34%. The etiology of platelet refractoriness in this patient population is typically attributable to due to formation of HLA antibodies (Abs) from pregnancy or previous transfusion. We report platelet refractoriness in the setting of induction chemotherapy for AML from allo-Abs to NAK a antigen/CD36/glycoprotein (GP) IV. A 66yo AAF presented with transfusion dependent AML with 70% circulating peripheral blasts and started on 7 + 3 regimen. She developed profound thrombocytopenia and her platelet count was 0 by day 13. As part of her evaluation for refractoriness, HLA antibody screening was done, but was negative. An Immucor ELISA assay was then performed and revealed positive Abs to GPIV (NAK a antigen/CD36). Abs against GPIIb/IIIa, GPIa/IIa, GPIb/IX, and HLA Class I were all negative. GPIV Abs were confirmed by Blood Center of Wisconsin using monoclonal Ab MBC 131.7 against CD36. Cross-matching was performed at our institution with multiple single donor apheresis platelets, all showing strong positive reactivity. Because CD36 in these units may be soluble, an incompatible leukoreduced, irradiated and washed single donor platelet unit was given which was tolerated well with a resultant increase to 14,000/ μ L. Despite strong reactivity of this unit in the crossmatch, the patient’s platelet count increased and 1 week later was 16,000/μL despite no transfusion support. Platelet refractoriness in the setting of hematological malignancy is well documented. Abs develop from prior pregnancy and transfusion in the setting of prolonged pancytopenia in hematological malignancies. Typically, allo-Abs develop against platelet membrane structures including human platelet antigens, HLA antigens, and rarely NAK a antigen on the CD36 glycoprotein molecule. CD36 is expressed in almost 100% of white Europeans and is not detectably expressed by 2% of sub-Saharan Africans and 10% of Asians. CD36 is a soluble antigen and is expressed on various cells such as erythroblasts and monocytes. We propose that washing platelets may be a useful strategy in treating platelet refractoriness in patients with abs to NAK a antigen as finding CD36 negative donors is extremely difficult and few blood banks in North America test donors for this antigen.

Molecular Pathways: Hypoxia-Activated Prodrugs in Cancer Therapy.

Hypoxia is a known feature of aggressive solid tumors as well as a critical hallmark of the niche in aggressive hematologic malignances. Hypoxia is associated with insufficient response to standard therapy, resulting in disease progression and curtailed patients' survival through maintenance of noncycling cancer stem-like cells. A better understanding of the mechanisms and signaling pathways induced by hypoxia is essential to overcoming these effects. Recent findings demonstrate that bone marrow in the setting of hematologic malignancies is highly hypoxic, and that progression of the disease is associated with expansion of hypoxic niches and stabilization of the oncogenic hypoxia-inducible factor-1alpha (HIF1α). Solid tumors have also been shown to harbor hypoxic areas, maintaining survival of cancer cells via the HIF1α pathway. Developing new strategies for targeting hypoxia has become a crucial approach in modern cancer therapy. The number of preclinical and clinical trials targeting low-oxygen tumor compartments or the hypoxic bone marrow niche via hypoxia-activated prodrugs is increasing. This review discusses the development of the hypoxia-activated prodrugs and their applicability in treating both hematologic malignancies and solid tumors. Clin Cancer Res; 23(10); 2382-90. ©2017 AACR.

Platelet Refractoriness Due to Anti-CD-36(NAKa) Ameliorated By Platelet Washing

▪Introduction:Platelet transfusion refractoriness in patients with hematological malignancies ranges from 7-34% (Blood 2015; 126:3484). The etiology of platelet refractoriness in this patient population is typically due to formation of HLA antibodies from pregnancy or previous transfusion. Although these patients receive leukoreduced products, alloimmunization is not completely prevented. We report platelet refractoriness in the setting of induction chemotherapy for acute myeloid leukemia (AML) from alloantibodies to NAKa antigen/CD-36/glycoprotein (GP) IV. We propose that washing platelets may be a potential strategy for treating platelet refractoriness in patients with NAKaantibodies as finding CD36 negative donors is extremely difficult and few blood banks in North America test donors for this antigen.Case:A 66 year old African American female presented with pancytopenia requiring transfusions. She was later diagnosed with AML with 70% circulating peripheral blasts and started on 7+3 regimen (Cytarabine for 7 days and Idarubicin for 3 days). She developed profound thrombocytopenia by day 7 and her platelet count was 0 by day 13. She was refractory to platelet transfusion from the outset. An Immucor ELISA assay was positive for anti-GPIV (NAKaantigen/CD-36). No antibody to GPIIb/IIIa, GPIa/IIa, GPIb/IX, and HLA Class I was present. Anti-GPIV was confirmed by Blood Center of Wisconsin utilizing monoclonal antibody MBC 131.7 (produced by Blood Center of Wisconsin) directed against CD36. Cross-matching was performed at our institution with multiple single donor apheresis platelets, all showing strong positive reactivity. Given the patient’s low platelet count and onset of urinary tract bleeding, an incompatible leukoreduced, irradiated, and washed single donor platelet unit was given. The patient tolerated the transfusion with no adverse events noted during or after transfusion. The patient’s platelet count rose from < 1 to 14,000/µL when measured 4 hours after the transfusion, and her count was sustained through the following day. Despite the strong, positive reactivity of this unit at crossmatch testing, this was the first successful response to multiple platelet transfusions. Unfortunately, her percentage of blasts in the peripheral blood increased and she maintained an absolute neutrophil count of 0. The patient and hematology team decided to switch to hospice as her AML was resistant to therapy and unfit for any other myelotoxic regimens. Her platelet count was checked the following week and it was 16,000/µL despite no transfusion support.Discussion:Platelet refractoriness in the setting of hematological malignancy has been well documented. Alloantibodies develop from prior pregnancy, prior transfusion or multiple transfusions in the setting of prolonged pancytopenia in hematological malignancies, especially AML. Typically, antibody develops against platelet membrane polymorphic structures including human platelet, ABO, HLA, and very rarely NAKa antigens on the CD36 glycoprotein molecule. CD36 is expressed in almost 100% of white Europeans and is not expressed by 2% of sub-Saharan Africans and 10% of Asians (Blood Transfus 2015: 13: 380). In screening of 871 US blood donors, Yamamoto et al. identified three platelet CD36 deficient individuals. Thus finding a CD36 negative platelet donor will most likely take an extended amount of time, which could be a challenge in these patients as bleeding risk is high during or after induction chemotherapy. CD36 is a soluble antigen and is expressed on various cells such as erythroblasts and monocytes. It has been proposed that when ABO mismatched platelets are transfused, circulating immune complexes may form between the soluble ABH antigens and the transfused antibody. Platelets may then be destroyed by binding of immune complexes to the Fc and C1q receptors. We speculate that a similar pathophysiology may occur in CD36 deficient patients as circulating anti-CD36 forms immune complexes with donor soluble CD36 antigen. Washing will remove most soluble CD36 and potentially mitigate the effect of immune complex formation. Based upon the limited experience with this patient, we suggest that washing in this setting may be beneficial and yield a sustained, incremental response in the platelet count in patients with platelet refractorinesssecondary to anti-NAKa. DisclosuresBlumberg:Biomet/Citra Labs: Consultancy, Honoraria.

Pharmacokinetics of Cefepime in Patients with Cancer and Febrile Neutropenia in the Setting of Hematologic Malignancies or Hematopoeitic Cell Transplantation.

To evaluate the steady-state pharmacokinetic parameters of standard cefepime dosing regimens in a hematologic malignancy and hematopoietic cell transplant patient population with febrile neutropenia. Open-label, single-center, prospective pharmacokinetic study. National Cancer Institute-designated cancer center. Nine adults with hematologic malignancies or hematopoietic cell transplants who had febrile neutropenia and were admitted to a hematology-oncology service between January and July 2014. Patients received empirical cefepime 2 g every 8 hours, administered as a 30-minute intravenous infusion, for febrile neutropenia. Steady-state cefepime serum concentrations were measured after at least 2 days of continuous therapy. Venous blood samples were intensively sampled between 0 and 8 hours after the start of the 30-minute infusion at steady state. Seven of the nine patients had a hematologic malignancy diagnosis of acute leukemia, lymphoma, or myeloma, and two patients had a germ cell tumor diagnosis. Noncompartmental analysis revealed mean ± SD parameters as follows at steady state: area under the plasma concentration-time curve from 0-8 hours 222.9 ± 72.9 mg hour/L, maximum concentration 120.9 ± 21.8 mg/L, clearance 9.7 ± 3.7 L/hour, apparent volume of distribution 19.2 ± 4.65 L, and elimination half-life 1.4 ± 0.3 hours. A one-compartment pharmacokinetic model identified a mean ± SD volume of distribution of 20.9 ± 1.3 L and an elimination rate constant of 0.39 ± 0.03 hour(-1) . The mean estimated percentage of time that drug concentration remains above the pathogen minimum inhibitory concentration (fT>MIC) in serum was 55%, 77%, and 99% at MICs of 16, 8, and 4 mg/L, respectively. Patients with hematologic malignancies or hematopoietic cell transplants who had febrile neutropenia demonstrated homogeneous calculated cefepime volumes and clearances. The population parameters presented in this study may aid in the calculation of patient-specific fT>MIC for similar patients.