Primary Hematologic Malignancies Research Articles

A case of Ph+ acute lymphoblastic leukemia and EGFR mutant lung adenocarcinoma synchronous overlap: may one TKI drug solve two diseases?

BackgroundPhiladelphia chromosome positive (Ph+) acute lymphoblastic leukemia (ALL) refers to ALL patients with t(9;22) cytogenetic abnormalities, accounting for about 25% of ALL. Lung adenocarcinoma (LUAD) is the most common pathological type of non-small-cell lung cancer, which has a frequency of approximately 45% cases with mutations in EGFR. Both Ph+ ALL and EGFR mutant LUAD are involved in the pathogenesis of the abnormal activation of the tyrosine kinase pathway. Although the second primary hematological malignancy after the treatment of solid tumors is common in clinics, the synchronous multiple primary malignant tumors of hematological malignancy overlap solid tumors are uncommon, even both tumors involved in the pathogenesis of the abnormal activation of the tyrosine kinase pathway are extremely rare.Case presentationAn 84-year-old man with fatigue and dizziness was diagnosed with Ph+ ALL. Meanwhile, a chest CT indicated a space-occupying lesions, characterized by the presence of void, in the right lower lope with the enlargement of mediastinal lymph node and right pleural effusion. After a few weeks, the patient was diagnosed with LUAD with EGFR exon 19 mutation. Both tyrosine kinase inhibitors (TKI) (Flumatinib) and EGFR-TKI (Oxertinib) was used for the patients, and finally have controlled both diseases.ConclusionAs far as we know, we for the first time reported a case of Ph+ ALL and EGFR mutant LUAD synchronous overlap, of which pathogenesis is related to abnormal tyrosine kinase activation. This patient was successfully treated with two different TKIs without serious adverse events.

CD73 Is an Immunometabolic Biomarker of Poor Prognosis in Patients With Primary Cutaneous Squamous Cell Carcinoma and Hematologic Malignancy.

Impaired immunity may drive the increased incidence and aggression of cutaneous squamous cell carcinoma (cSCC) in patients with hematologic malignancy; however, precise mechanisms and prognostic biomarkers remain undefined. CD73 maintains elevated immunosuppressive adenosine levels and is associated with poor prognosis in several tumor microenvironments. Identify poor outcome biomarkers in patients with cSCC and hematologic malignancy. Differentially expressed genes in tumors from patients with hematologic malignancy experiencing good (n = 8) versus poor (n = 7) outcomes were identified by NanoString analysis. Results were validated at the protein level using CD73 immunohistochemistry in cSCC patients with (n = 38) and without (n = 29) hematologic malignancy. Forty-eight genes were differentially expressed in tumors from patients with hematologic malignancy experiencing good versus poor outcomes. CD73 gene expression was >2-fold higher in patients with poor versus good outcomes or normal skin. Significantly increased CD73 protein levels were observed in cSCC tumors with poor versus good outcomes from patients with hematologic malignancies (p < .01), whereas no differences were noted in tumors with poor versus good outcomes from patients without hematologic malignancies (p = .49). CD73 is highly expressed in poor prognosis cSCC from patients with hematologic malignancy and may represent a useful biomarker and potential therapeutic target.

Subsequent malignant neoplasms after primary hematological malignancy in adult patients.

Patients with primary hematological malignancy (HM) are at an elevated risk of subsequent malignant neoplasms (SMNs), which is a common concern after treatment of primary cancer. We identified 45,533 patients aged ≥20 years and diagnosed with primary HM in Finland from 1992 to 2019 from the Finnish Cancer Registry and estimated standardized incidence ratios (SIR) and excess absolute risks per 1000 person-years (EAR) for SMNs. A total of 6076 SMNs were found (4604 solid and 1472 hematological SMNs). The SIRs were higher for hematological SMNs (SIR 4.9, 95% confidence interval [CI] 4.7-5.2) compared to solid SMNs (SIR 1.5, 95% CI 1.4-1.5). The SIRs for hematological SMNs were highest in the young HM patients aged 20-39 years (SIR 9.2, 95% CI 6.8-12.2 in males and SIR 10.5, 95% CI 7.2-14.7 in females) and decreased by age of first primary HM. However, EARs for hematological SMNs were highest in the older patients, aged 60-79 years at their first primary HM (EAR 5.7/1000 and 4.7/1000 in male and female patients, respectively). In conclusion, the incidence of both hematological and solid SMNs were increased in hematological cancer patients. The relative risk (SIR) was highest among younger HM patients with hematological SMNs. The absolute second cancer burden reflected by high EAR arises from solid malignancies in older patients. Our results accentuate the need for vigilance in the surveillance of HM patients.

Role of interim positron emission tomography/computed tomography in assessment of lymphoma treatment response

BackgroundLymphoma is the most common primary hematological malignancy. FDG PET/CT has recently become the standard imaging modality for clinical management owing to its ability to provide precise, non-invasive anatomical and functional data. The purpose of this study was to highlight the role of 18F FDG-PET/CT in the management of lymphoma by monitoring treatment response, providing a guide for response-adapted therapy, and predicting the final therapeutic outcome.MethodsThis was a prospective monocentric cohort observational study in which thirty-three patients with histopathologically proved lymphoma of different types performed FDG-PET/CT scanning several times throughout the 24-month duration of the study. Early-stage interim SUVmax of the most active lesion (both nodal and/or extra-nodal) was measured and statistically analyzed together with data of the international prognostic index parameters and score.ResultsAmong the included 33 patients of lymphoma, international prognostic index parameters and score together with the early-stage interim SUVmax of the predominant nodal and extra-nodal sites showed statistical significance in predicting the initial as well as the final treatment response after 24 months. Using ROC analysis, we could obtain cutoff values of SUVmax of the predominant nodal lesion of 2.75 (AUC 72%, 95% CI 0.42–1.0) and SUVmax of the predominant extra-nodal lesion of 3 (AUC 70.8% and 95% CI 0.23–1.0); therefore, SUVmax of higher than these values was related to stable or progressive disease, and lower levels than these values were related to complete or partial metabolic response based on Deauville 5-point scale and Lugano response criteria.ConclusionsEarly-stage interim PET-CT SUVmax of the predominant nodal and extra-nodal lesion could be a reliable parameter in predicting initial and final therapeutic outcome in lymphoma patients.

Abstract 2500: Technical feasibility of CRISPR-based functional profiling for solid tumor precision medicine

Abstract Introduction: Next generation sequencing (NGS) has revolutionized precision oncology by enabling identification of cancer patients harboring actionable mutations who may benefit from corresponding targeted therapies. However, sequencing-based biomarkers are not detected for most patients and imperfectly predict response to therapy even when present. To address this unmet need, we have developed a CRISPR-based diagnostics platform for ‘personalized functional genomics’, allowing identification of patient-specific therapeutic vulnerabilities irrespective of mutation status. We have previously applied this approach to primary hematologic malignancies, and here report application to solid tumor-derived samples. Methods: Patient-derived solid tumor samples from several tumor types including breast, ovarian, colon and lung were obtained from 3 sources: fresh tissue (obtained from patients via core biopsy, surgical resection, or malignant fluid sampling), primary Patient-Derived Cell Lines (PDCLs, generated from surgical material and adapted for ex vivo culture), and commercially obtained viably frozen dissociated tumor cells (DTCs). Samples were dissociated to single cell suspensions and transduced with a lentivirus encoding Cas9 and an sgRNA library covering a custom targeted oncology gene panel. The panel consists of genes encoding targets of FDA-approved oncology drugs, as well as reference genes. After a short culture period, transduced cells were harvested and relative sgRNA distribution was measured by amplicon NGS. Changes in sgRNA abundance were collapsed into gene-level log2-fold changes, and significantly depleted genes scored as functional dependencies. For select PDCLs, cells were treated with cognate small molecule inhibitors over the course of 4 days. Cell viability was read out using CTG assay and a calculated IC50 lower than 500nM inferred as inhibitor sensitive. Results: In a double-blind study using primary PDCLs, functional dependencies identified by CRISPR perfectly discriminated alpelisib sensitive (2/2) from resistant samples (6/6). Using fresh primary samples from varying cancer types and specimen sources, we achieve a technical success rate &amp;gt;70%. Among gene dependencies identified, targets of FDA-approved oncology drugs and those under late-stage clinical investigation were both observed including BRAF, CDK4/6, VEGFR1/2 and PARP1/2. Conclusion: We demonstrate technical proof of concept of the FX platform for CRISPR-based personalized functional genomics. This approach is feasible when applied to primary patient samples from a variety of tumor types and tissue sources, and results are validated by comparison with orthogonal methods. CRISPR-based functional profiling represents a powerful adjunct to traditional genomic profiling, for the first time allowing drug target dependency mapping in a patient-specific and mutation-agnostic manner. Citation Format: Karl Hodel, Andreas Varkaris, Nicholas Chevalier, Maci Meyers, Allison Kehlmann, Stephane Corbel, Anastasia Stavridi, Peter Kilfeather, Leonardo Hagmann, Kathleen Tran, Yali Li, Christian Schmedt, Ioannis Sanidas, Srinath Sampath, Srihari Sampath, Dejan Juric. Technical feasibility of CRISPR-based functional profiling for solid tumor precision medicine [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2500.

Emerging trends in the coexistence of primary lung Cancer and hematologic malignancy: a comprehensive analysis of clinicopathological features and genetic abnormalities

BackgroundThe incidence of multiple primary cancers (MPC), especially involving primary lung cancer (PLC) and primary hematologic malignancies (PHM), is rising. This study aims to analyze clinicopathological features, gene abnormalities, and prognostic outcomes in individuals diagnosed with PLC-PHM MPC.MethodsA retrospective analysis included 89 patients diagnosed with PLC-PHM MPC at the Respiratory or Hematology Departments of Ruijin Hospital from 2003 to 2022 (a total of 842,047 people). Next-generation sequencing (NGS) assessed lung cancer specimens, while Polymerase Chain Reaction (PCR) and NGS were used for hematologic malignancy specimens. Statistical analysis involved survival analysis and Cox regression.ResultsPLC-PHM MPC incidence surged from 1.67 per year (2011–2013) to 16.3 per year (2020–2022). The primary demographic for PLC-PHM MPC consists predominantly of elderly (average age 66 years) males (59.6%), with a high prevalence of metachronous MPC (89.9%). The prevailing histological types were lung adenocarcinoma (70.8%) in lung cancer (LC) and mature B-cell lymphomas (50.6%) in hematologic malignancies (HM). Notably, in a molecular testing cohort of 38 LC patients, 84.2% of lung cancer cases exhibited driver mutations, in which EGFR mutations frequence prevalent was 74.2%. In total group of 85 cases achieved a median overall survival (mOS) of 46.2 months, with a 5-year survival rate of 37.9% and advanced LC patients with LC gene mutations achieved a mOS was 52.6 months, with a 5-year OS rate of 30.6%. The median progression-free survival (PFS) following first-line treatment of 11 advanced patients with lung cancer-associated driver gene mutations is 26.6 months. Multivariate Cox regression revealed a favorable OS associated with surgery for LC, favorable PS score, adenocarcinoma pathology of LC, and the presence of genetic abnormalities associated with HM.ConclusionPLC-PHM MPC incidence is rising, characterized by a significant proportion of lung adenocarcinoma and a high prevalence of positive driver genes, especially in EGFR. Despite suffering from two primary tumors, the PLC-PHM MPC patients had superior data of both PFS and OS, suggesting an inherently intricate background of genetic abnormalities between the two kinds of tumors.

Total Marrow and Lymphoid Irradiation (TMLI) -Based Conditioning Regimen in Patients with Acute Leukemia Undergoing Allogeneic Hematopoietic Cell Transplant with Measurable Residual Disease

Relapse of primary hematologic malignancy remains the leading cause of treatment failure afterallogeneic Hematopoietic cell transplantation (allo-HCT). Multiple studies have shown that presence of measurable residual disease (MRD), at the time of HCT, irrespective of the detection method, is associated with lower overall survival (OS) and relapse-free survival (RFS). In a recent meta-analysis of 11,151 patients with AML, Short et al., reported 5-year disease-free survival (DFS) of 25% for patients who have detectable MRD pre -HCT, compared to 64% for those without MRD. The 5-year OS was 34% and 68% for patients with or without MRD at HCT (JAMA Oncology 2020). In AML patients with genomic evidence of MRD before allo-HCT, myeloablative conditioning (MAC) regimens result in improved survival when compared to reduced intensity conditioning (RIC); (Hourigan et al, JCO 2020). Our center has pioneered and developed Total marrow and lymphoid irradiation (TMLI) that allows for delivery of higher dose of radiation to the sites with high disease burden (bone marrow and lymphoid organs), while sparing healthy tissues. In an ongoing Phase 2 trial (NCT02094794), we delivered TMLI (20Gy) with high dose chemotherapy to patients with high-risk leukemias (ALL or AML) undergoing allo-HCT from an HLA matched or mismatched donor. Here, we report on the results of our prospective analysis on a subset of patients of NCT02094794 who underwent allo-HCT with morphologic remission but had detectable MRD status in their pre HCT bone marrow biopsy (n=30). Conditioning regimen comprised of TMLI on days -9 to -5 (total of 20Gy), etoposide (60 mg/kg) on day -4, and cyclophosphamide (100mg/kg) on day -2. Unmanipulated peripheral blood stem cells (PBSC) graft from 10/10 HLA matched related or unrelated donor was infused on day 0 and graft-versus-host disease (GVHD) prophylaxis was tacrolimus and sirolimus-based. TMLI was delivered by intensity modulated radiation therapy (IMRT). MRD assay was done by either University of Washington flow cytometry with 0.01% - 0.1 % sensitivity, FISH/conventional cytogenetics, or NGS-based assays. Patient and HCT characteristics are summarized in Table 1. Briefly, the median age at the time of HCT was 36 years (range: 16-59) with the majority of patients receiving PBSC grafts (87%). Donors were match related (67%) or match unrelated (33%). The underlying diagnosis was AML (n=22; 73%), ALL (n=7; 23%), or CML-BC (n=1; 3%). Karnofsky performance status was 80-100 in 90% of patients and HCT-CI ≥3 was seen in 35% of patients. Pre-HCT MRD + status was documented by Flow cytometry MRD assay in 17 patients [AML (n=14) and ALL (n=3)], with mean MRD positivity of 2.9 % (range: 0.02-5.6%) for AML and 0.4% (range: 0.003-1.7%) for ALL patients. Thirteen additional patients had MRD positive status confirmed by FISH/cytogenetics (n=6 patients) or NGS (n=7). With a median duration follow up of 22.3 months (range: 6.0-81.1), the 1 and 2-year OS were 68% (95% CI: 0.47-0.82) and 59% (95% CI: 0.38-0.75), respectively. The 1 and 2- year disease-free survival (DFS) were 55% (95% CI: 0.34-0.71) and 45% (95% CI: 0.26-0.63), while the cumulative incidence (CI) of relapse at 1 and 2 years were 28% (95% CI: 0.13-0.46) and 33% (95% CI: 0.16-0.51), respectively. At day 100 post-HCT, the CI of NRM was 7%, grade 2-4 acute GVHD was 40% and Grade 3-4 acute GVHD was 13%. The CI of NIH moderate- severe chronic GVHD at 1- year was 35% (95% CI: 0.17-0.52). No difference in outcomes were noted in patients who were MRD positive by UWFC vs FISH/NGS testing. In conclusion, TMLI based conditioning regimen in patients undergoing allo-HCT with MRD+ disease from matched donors is associated with improvement in 2-year RFS/OS and is associated with low NRM compared to historic controls. The current phase 2 study is enrolling patients at our center.

Abstract 5029: Determining the biological function of TNK1

Abstract Thirty-eight-negative kinase 1 (TNK1) is a poorly characterized member of the ACK family of non-receptor tyrosine kinases, which we recently identified as a driver of cell survival in a subset of primary hematological malignancies. However, the biological function of TNK1 is not well understood. We also found that TNK1 is unusual among kinases for the presence of a functional ubiquitin association (UBA) domain on its C-terminus. We discovered that the TNK1 UBA domain binds to poly-ubiquitin with high affinity and has no apparent preference for ubiquitin chain length or linkage type. Interestingly, the UBA domain is important for TNK1 function, given that deletion of the UBA domain (TNK1 ΔUBA) alters its localization and phospho-substrate network, while also weakening the oncogenic activity of TNK1 in cell transformation assays. Based on these data, we hypothesized that the UBA domain tethers TNK1 to its substrates. To test this hypothesis, we performed quantitative phospho-tyrosine proteomics using murine pro-B cells transformed with either TNK1 full length or TNK1 ΔUBA and identified TANK-binding kinase 1 (TBK1) as a putative UBA-dependent TNK1 substrate. TBK1 is a serine/threonine kinase involved in the regulation of inflammation, autophagy, and NF-ĸB signaling. During the selective autophagic degradation of misfolded proteins (aggrephagy), TBK1 phosphorylates p62 at S403 to increase its affinity to ubiquitin, and thereby increases p62-mediated recruitment of misfolded proteins into the condensate. Unchecked growth of ubiquitin condensates can overwhelm the size capacity of autophagosomes, potentially causing misfolded proteins to become proteotoxic aggregates. Our preliminary data suggest a model in which active TNK1 accumulates at ubiquitin condensates to phosphorylate and inhibit TBK1. Based on these data, we propose that TNK1 acts as a kinase sensor of poly-ubiquitin to control the TBK1-mediated growth of ubiquitin condensates. Citation Format: Emmalee Kohler, Tania Lopez-Palacios, Tsz-Yin Chan, Christina Egbert, Jacob Truman, Spencer Ashworth, Alec Vaughan, Joshua Andersen, D. Madhusanka. Determining the biological function of TNK1. [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 5029.

Etiological profile of febrile thrombocytopenia in children aged &lt;12 years in a tertiary care centre

Background: Febrile thrombocytopenia is platelet count &lt;1,50,000/mm3 associated with fever irrespective of age and gender. There is an increasing trend in the incidence of febrile thrombocytopenia with varied etiology. Though infections are the most common cause in tropical countries like India, sometimes non-infectious conditions like primary haematological disorders and malignancies can also present as febrile thrombocytopenia. Hence it is essential for the treating physicians to be fully aware of etiological factors for febrile thrombocytopenia and how to approach to the condition. Methods: A hospital based observational study done at Kamineni Institute of Medical Sciences during the study period October 2020 to December 2021 by collecting and analysing details of 100 patients between 1 month-12 years of age who presented with fever and thrombocytopenia at admission. Patients on drugs causing thrombocytopenia were excluded from the study. Results: Majority of the cases (51%) belonged to the age group of 1-6 years. Out of 100 subjects, 60% of them had dengue fever, 12% of cases had malaria and 10% of cases had enteric fever. Bleeding manifestations were seen in 12% of cases and blood product transfusion was done in 30% of the cases. 98% of cases had recovered and 2 deaths were reported. Conclusions: Febrile thrombocytopenia is a common clinical presentation in children. Majority of the dengue cases responded well to treatment given as per WHO guidelines. In most of the other infections, thrombocytopenia was transient and asymptomatic with lesser severity and resolved with the treatment of underlying condition.

DIC-like syndrome in a post-pre-eclampsia birth in a premature infant in a peri-COVID scenario

Abstract Objectives This article outlines an unusual presentation of a premature infant born from a pre-eclamptic mother born with a presentation resembling a disseminated intravascular coagulation syndrome. Case presentation Pregnancy-induced hypertension, also known as pre-eclampsia, and premature birth pose significant risks to neonates, making the fetus more susceptible to immunodeficiencies and coagulopathies. This article highlights a premature infant born to a pre-eclamptic mother with multiple complications. Our case involved jaundice, neonatal meningitis, thrombocytopenia, leukopenia, neutropenia, hemorrhage, apnea, gastrointestinal defects, and periventricular leukomalacia. Often these complications are seen immediately after birth; these symptoms may present after a certain amount of time lapses if the neonates if afflicted with malignancy or a viral, fungal, or bacterial infection. Here we describe the case of a premature neonate born to a preeclamptic mother that experienced these complications one day after her birth. Conclusions This is the first known case of an infant experiencing a “DIC-like” syndrome without any diagnosis of a primary hematological malignancy or infection after a certain amount of time had lapsed since her birth. As complications in premature infants as well as those from pre-eclamptic mothers are common, this case report highlights a successful model of care. We also explore the effect of a peri-COVID setting on the presentation of this patient, as similar cases have occurred post-COVID-19.

Survival analysis of breast cancer patients after diagnosis of second primary malignancies, focusing on the second primary hematologic malignancy.

Although the overall survival (OS) of breast cancer patients is increasing with improved detection and therapies, so is the risk of breast cancer patients developing subsequent malignancies. We investigated the OS of breast cancer survivors according to sites of second primary malignancies (SPM). The OS of the second primary hematologic malignancy (SPHM) was then compared with that of metastatic breast cancer (MBC). We retrospectively analyzed patients diagnosed with primary breast cancer between 1998 and 2019. Only those with SPM were eligible for analysis. First, the OS of patients with SPM diagnosed as the first event after the diagnosis of breast cancer was analyzed. Next, the OS of patients with SPHM, with or without breast cancer relapse, was compared with that of patients with MBC, matched using the propensity score. Patients diagnosed with SPM without breast cancer relapse as the first event had a significantly better OS than did patients with MBC, but the OS of those with SPHM as the first event did not differ significantly from that of patients with MBC (hazard ratio [HR], 1.558; 95% confidence interval [CI], 0.856-2.839; P = 0.147). The OS of patients with SPHM with or without breast cancer relapse was worse than that of the MBC group after propensity score matching (HR, 1.954; 95% CI, 1.045-3.654; P = 0.036). Prognosis of SPM diagnosed as the first event was statistically better than that of MBC, except in case of SPHM. Patients with SPHM, with or without MBC, showed poor OS before and after propensity score matching.

Controlled register-based study of road traffic accidents in 12,651 Finnish cancer patients during 2013-2019.

Little controlled evidence exists on road traffic accident (RTA) risk among patients diagnosed with cancer, while clinicians are often requested to comment their ability to drive. The aim of this study was to evaluate RTA risk in a population-based cohort of cancer patients living in Southwest Finland. All adult patients diagnosed with cancer in 2013-2019 were included. Acute appendectomy/cholecystectomy and actinic keratosis patients without cancer were selected from the same region as the control cohort. Participants were cross-referenced to a national driving licence database, yielding 12,651 cancer and 6334 control patients with a valid licence. Due to marked differences in their clinical presentation, the cancer cohort was divided into nine cancers of interest (breast, prostate, colorectal, lung, melanoma, head & neck, primary brain tumours, gynaecological and haematological malignancies). The nationwide law-regulated motor liability insurance registry was searched for all RTAs leading to injury with claims paid to not- or at-fault participants. At-fault drivers were verified based on sex and birth year. During a median follow-up of 34 months, 167 persons were at-fault drivers in RTAs leading to injury. Among the nine cancers of interest, RTA risk did not differ from the control cohort. Among cancer patients, multivariable regression suggested male sex and opioid use, but not advanced cancer stage or given systemic therapy, as the most influential risk factors for RTA. Cancer diagnosis itself was not associated with increased RTA risk, but other associated symptoms, medications, comorbidities or specific cancer subgroups may.

Novel Home-Based Transfusion Model of Palliative Care in Malignant Hematology

Background: Patients with hematologic malignancies often receive aggressive care at the end of life (EOL) and utilize hospice services less frequently than patients with solid tumors1. Hospice utilization rates are low, and patients enroll late in the disease, spending an average of 3 days on hospice2, thereby limiting the potential benefit of hospice care1,3. Access to transfusions has been identified as a major barrier to hospice enrollment in hematologic malignancies despite representing an important strategy that can help improve quality of life (QOL) and symptoms for these individuals4,5. Therefore, we hypothesized that the creation of a home-based transfusion system that allows patients to receive blood and platelet transfusions while enrolled in hospice would improve their QOL and symptom burden. Furthermore, we created a program with symptom-based triggers for transfusion, rather than the standard transfusion practices with complete blood count (CBC) triggers. In this interim analysis of our novel home-based transfusion pilot study, we sought to investigate feasibility, transfusion reaction incidence, QOL and symptom improvement, and hospice outcomes. Methods: Patients enrolled in hospice and participated in the home-based transfusion system from 8/17/2020 to 2/16/2022 (n=12 out of a planned 20). Eligibility criteria included: age ≥18 years, primary hematologic malignancy, transfusion dependence and an absence of previous blood transfusion reactions or difficulty with blood typing. Evaluable patients received one unit of packed red blood cells (RBCs) and/or platelet transfusions weekly based on trigger symptoms (Common Terminology Criteria for Adverse Events [CTCAE] defined grade 2+ symptoms secondary to anemia and/or thrombocytopenia) continued until unacceptable toxicities or death. Patients were assessed by study personnel via a phone call at the start of every week. All patients who received transfusions, received follow-up phone calls 48-72 hours after transfusion to assess for post-transfusion reactions, symptoms, and QOL via the EORTC QLQ C30 questionnaire. The primary end point was feasibility of home based transfusion system with secondary endpoints assessing QOL and symptoms, transfusion rate and reaction incidence, length of time on hospice, incidence of revocation of hospice, hospitalization while on hospice and site of death. Weekly CBC data was collected throughout the course of this study and CBC data was blinded to the study personnel until study completion. Results: 12 patients were enrolled. Median patient age was 66 (range 31-83) years. Patients’ diseases included Acute Myeloid Leukemia (9 [75%]), Non-Hodgkin Lymphoma (2 [16.7%]), and Myelodysplastic Syndrome (1 [8.3%]). The average number of transfusions per patient was 2.91 (n=11) with no reported transfusion reactions. The average number of reported grade 2+ symptoms decreased from 2.93 to 1.97, pre- and post-infusion respectively. Patients reported that pre-transfusion dyspnea and fatigue were the most common symptoms, both of which improved after transfusions by 55% (patients reported dyspnea 66.67% of the time pre-transfusion vs 30% post transfusion) and 22% (patients reported fatigue 90% of the time pre-transfusion and 70% post transfusion), respectively. Median time on hospice was 11.5 days. The mean number of transfusions per patient while on hospice was 2.67 (n=11) packed RBCs and 1.50 (n=10) platelets. The mean EORTC QOL score pre-transfusion was 50.49 and post transfusion 51.95 with a mean difference of 1.46. There was one hospitalization (for fever and severe thrombocytopenia), no ICU admissions and no hospice revocations. All 12 patients died at home. Conclusion: In this interim analysis, we described the potential feasibility of a novel home-based transfusion system, with high enrollment rates and no transfusion reactions. Notably, the number of transfusions required was quite small, and we found that patients’ most common symptoms improved following transfusion. In our small pilot study, the time on hospice increased from a standard 3 days to 11.5 days. No transfusion reactions were noted, and transfusions improved QOL. Future work is needed in a larger demonstration project to evaluate if home-based transfusion system could improve hospice utilization and quality of hospice care in patients with hematologic malignancies.

Subsequent Malignant Neoplasms after Primary Hematological Malignancy in Adult Patients (Aged ≥20 Years) - High Risk of Hodgkin Lymphoma in Patients with Chronic Lymphocytic Leukemia

Subsequent Malignant Neoplasms after Primary Hematological Malignancy in Adult Patients (Aged ≥20 Years) - High Risk of Hodgkin Lymphoma in Patients with Chronic Lymphocytic Leukemia

Acute Clinical Syndrome of HLH in Patients with Hematologic Malignancy and EBV Infection

Introduction: Hemophagocytic lymphohistiocytosis (HLH) is a syndrome characterized by dysregulation of the reticuloendothelial system, overactivation of macrophages and lymphocytes, hemophagocytosis, and cytokine storm collectively causing systemic inflammation and organ damage. Malignancy-associated HLH (M-HLH) is associated with poor prognosis and survival of 1-2 months (Daver N, et.al., Cancer. 2017). Viral infections such as Epstein-Barr Virus (EBV) can independently contribute to development of lymphoproliferative neoplasms and non-malignancy associated HLH. While both malignancy and EBV are recognized as independent risk factors for HLH, a syndrome of overlapping M-HLH and EBV-HLH remains underreported. The optimal long-term treatment strategy for M-HLH in EBV positive patients is unknown, with combinations of HLH and malignancy directed therapy reported in the literature without significant improvement in survival (Zhao A, et.al., Front Immunol. 2022). We report a case series of patients with EBV infection and newly diagnosed hematologic malignancies complicated by HLH demonstrating poor prognosis despite initial control of disease. Methods: Between July 2020 and July 2021, 8 patients >18 years of age hospitalized at Montefiore Medical Center were identified meeting diagnostic criteria of HLH with associated primary hematologic malignancy, and concomitant EBV infection. Data on demographics and clinical characteristics, laboratory studies, malignancy diagnosis, treatments received, and disease course were collected. HLH-04, H-Score were recorded for all patients. Data were analyzed using descriptive statistics. Results: The median age was 53.6 years old (range 29-75). Five out of 8 patients met systemic inflammatory response syndrome (SIRS) criteria on presentation. The median H-Score was 217.1 (range 183-247). All but one patient exceeded CD25 and ferritin parameters of optimized HLH inflammatory (OHI) index suggestive of high mortality risk. Classical Hodgkin Lymphoma (cHL) was seen in 4/8 patients; other diagnoses included large B cell lymphoma, angioimmunoblastic T cell lymphoma, intravascular large B cell lymphoma, and anaplastic large cell lymphoma. Dexamethasone was the backbone of treatment and the initial HLH directed therapy in all patients, starting on average 9 days after presentation (range 2-17) and preceding treatment with other HLH directed therapies by median of 7.2 days (range 0-33). Four out of 8 patients received dexamethasone, etoposide, and rituximab; 2 patients received dexamethasone with etoposide and 2 received dexamethasone alone. The administration schedule and cumulative doses of both rituximab and etoposide varied significantly between the patients. Initiation of malignancy directed chemotherapy lagged the initiation of dexamethasone by median of 16.5 days (range 0-53). Delays were due to patients' clinical condition, organ function, and pending diagnosis of malignancy. Median overall survival from the initial presentation was 102.5 days (range 33-219). Two out of 8 patients in our case series survived. One received dexamethasone and etoposide, followed by 6 cycles of malignancy-directed chemotherapy and autologous stem cell transplant. The second patient was treated with dexamethasone, rituximab, etoposide with addition of anakinra, followed by malignancy directed therapy without rituximab or etoposide. At the time of death, 4 out of 6 patients had active HLH and 3 out of 6 patients were treated for an overwhelming polymicrobial infection. Conclusion: HLH is the setting of EBV-positive malignancy results in a syndrome with an aggressive clinical course and high early mortality rate. Here we demonstrate that HLH-directed therapy prior to or incorporated into malignancy-directed therapy extended patients' survival to median 3 months, as compared to 1-2 months reported in the literature. Nevertheless, most patients suffered HLH relapse and succumbed to infectious complications of prolonged hospitalization and immunosuppression. Long term HLH therapy with immunomodulatory agents and EBV-directed therapies is needed to achieve sustained control of systemic inflammation. Patients who survive initial HLH episode need to be closely monitored for recurrence. Preemptive strategies such as autologous stem cell transplant should be considered in eligible patients to further reduce the risk of relapse. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Risk for Second Primary Hematologic Malignancies by Radiotherapy Technique in Prostate Cancer Survivors

<h3>Purpose/Objective(s)</h3> Among the most serious adverse effects after radiotherapy for prostate cancer is the development of second malignant neoplasms. Recent advances in radiotherapy techniques, such as the introduction of intensity-modulated radiation therapy (IMRT) and proton beam radiotherapy (PBRT), have aimed to reduce exposure to adjacent healthy tissues but may lead to greater bone marrow exposure. Risks for developing myelodysplastic syndrome/acute myeloid leukemia (MDS/AML) but not lymphoid malignancies after radiotherapy have been demonstrated. We quantified risks of hematologic malignancies following IMRT and PBRT compared to 3D conformal radiotherapy (CRT) in a large cohort of prostate cancer patients. <h3>Materials/Methods</h3> This retrospective cohort study used the linkage of Surveillance, Epidemiology, and End Results (SEER) cancer registry data with Medicare claims, including men who were diagnosed with first primary non-metastatic prostate cancer at ages 66-84 years from 2002-2014, received external beam radiotherapy (IMRT, PBRT, or CRT) but no chemotherapy in the first year after diagnosis, and survived ≥2 years after diagnosis without a second primary cancer. Using Cox regression, hazard ratios (HR) and corresponding 95% confidence intervals (CI) were computed to estimate risk of second primary hematologic malignancies, classified into subtypes according to the World Health Organization, after IMRT and PBRT vs CRT. Models were adjusted for age at prostate cancer diagnosis, tumor grade, race, Charlson comorbidity score, and receipt of initial prostate cancer therapy. <h3>Results</h3> The cohort (median follow-up=6.8 years) included 69,966 patients, of whom 23,806 received CRT alone, 43,901 received IMRT without PBRT, and 2,259 received PBRT. A total of 387 patients developed a myeloid malignancy, most commonly MDS/AML, N=291), and 739 developed a lymphoid malignancy, most commonly plasma cell neoplasms (N=178) and diffuse large B-cell lymphoma (N=159). Compared to patients who received CRT, neither IMRT nor PBRT was associated with risk of developing myeloid malignancies overall (IMRT: N=211, HR=0.89, 95%CI 0.70-1.13; PBRT: N=13, HR=0.97, 95%CI 0.55-1.74), with similar results for MDS/AML specifically. Similarly, neither IMRT nor PBRT was associated with risk of developing lymphoid malignancies overall (IMRT: N=390, HR=0.93, 95%CI 0.78-1.11; PBRT: N=24, HR=0.94, 95%CI 0.61-1.43) compared to CRT, with similar results for specific lymphoid malignancy subtypes. <h3>Conclusion</h3> This is among the first cohort studies analyzing risk of hematologic malignancies by subtype after prostate cancer radiotherapy. With longer follow-up and larger sample size compared to previous reports, the hypothesized change in risk for MDS/AML with IMRT/PBRT compared to CRT was not observed. As more data accumulates from patients receiving PBRT, we can gain greater insight into the technique's long-term effects.

Simultaneous occurrence of primary mediastinal germ cell tumor and myelodysplastic syndrome: A case study and a concise review

Primary mediastinal germ cell tumors are potentially aggressive neoplasms that are rarely associated with hematological malignancies in young men. The association between primary mediastinal germ cell tumors and hematological malignancies involves complex oncogenesis that has yet to be established, and these uncertainties are reflected in the unresponsiveness to the current therapeutic interventions, hence, leading to an unfavorable prognosis.

Clinical Manifestations of Pulmonary Mucormycosis in Recipients of Allogeneic Hematopoietic Stem Cell Transplantation: A 21-Case Series Report and Literature Review.

Introduction Mucormycosis is a rare, invasive disease caused by opportunistic pathogens related to the Mucorales order with high fatality rates in immunocompromised hosts, especially in recipients of allogeneic hematopoietic stem cell transplantation (allo-HSCT). Diagnosis and treatment of pulmonary mucormycosis in recipients of allo-HSCT remains challenging. Purpose The aim of this study is to summarize and analyze the clinical features of pulmonary mucormycosis in recipients of allo-HSCT to explore further clinical research directions for this rare fungal infection in the particular populations. Methods We retrospectively reviewed pulmonary mucormycosis in patients who received allo-HSCT in our hospital from January 2010 to December 2020. A total of 21 patients fulfilled the diagnostic criteria for pulmonary mucormycosis according to the European Organization for Research and Treatment of Cancer and Mycoses Study Group (EORTC/MSG) criteria. Demographic and clinical data, mycological and histopathological records, and treatment and prognosis data were collected. Clinical variables were compared between survivors and nonsurvivors. The survival days of patients with and without graft-versus-host disease (GVHD) and hemoptysis were compared separately. Results Most of the recipients of allo-HSCT were male patients with a mean age of 43 years. Acute myeloid leukemia (AML) was the most common primary hematologic malignancy. Extrapulmonary involvement accounted for 28.6%, of the cases, including central nervous system (n = 5) and skin and soft tissue (n = 1). The median time to infection was 96 days after allo-HSCT. Clinical presentations were nonspecific, including fever (76.2%) and cough (85.7%), as well as dyspnea (19.0%), chest pain (38.1%), and hemoptysis (61.9%). Ground-glass infiltrates (95.0%) and nodules/masses (80%) were the most common radiographic patterns on chest CT. The most common pathogen was Rhizopus (63.2%), and breakthrough infection accounted for 90.5%. Fifteen of the patients died within one year, and the median time from diagnosis to death was 47 days. Conclusion Mucormycosis is a fatal infection disease. Opportunistic infections in recipients of allo-HSCT are mainly breakthrough infections and may have a seasonal distribution (summer and autumn) and more cases of death in autumn. The marked reversed halo sign can be seen both in the initial stage of infection and after antifungal treatment. In our case series, patients with pulmonary mucormycosis with extrapulmonary involvement 100% died within one year. There are more patients with GVHD before infection and hemoptysis in nonsurvivors than survivors within 100 days. Patients with GVHD before infection and hemoptysis have a shorter survival time than those without.

Controversies about immunoglobulin replacement therapy in HSCT recipients with hypogammaglobulinemia.

The efficacy of immunoglobulin replacement therapy (IgRT) has been demonstrated for primary immune deficiency diseases and hematological malignancies such as chronic lymphocytic leukemia (CLL) or multiple myeloma with hypogammaglobulinemia. Clinical development of anti-B cell therapies including a monoclonal antibody, bispecific antibody, or chimeric antigen receptor T-cell therapy which could result in severe hypogammaglobulinemia accelerates the argument of prophylactic use of IgRT. Clinical guidelines for CLL describe immunoglobulin administration in patients with a low IgG who have experienced a severe/repeated bacterial infection. The utility in hematopoietic stem-cell transplantation (HSCT) remains unknown. Although an early randomized trial demonstrated that IgRT decreased infection risk and transplant-related mortality after HSCT, subsequent clinical trials could not validate the benefit. Consequently, a meta-analysis did not show the benefit of IgRT in HSCT. Most of the available data derives from matched-related HSCT using myeloablative regimen, and the impact in haploidentical and cord blood transplantation, or reduced-intensity HSCT remains unknown. One crucial issue is that no studies exist for patients with only hypogammaglobulinemia after HSCT. Other challenges are heterogeneous patient characteristics, or immunoglobulin formulation, dosage, schedule, route and duration of IgRT. Without evidence in HSCT, it would be reasonable to follow the guidelines for other diseases with hypogammaglobulinemia.

Primary Immunodeficiencies and Hematologic Malignancies: A Diagnostic Approach.

Primary Immunodeficiencies and Hematologic Malignancies: A Diagnostic Approach.