Tatiana Cruz

Bio: Tatiana Cruz is an academic researcher from Cornell University. The author has contributed to research in topics: CD8 & Survival rate. The author has an hindex of 2, co-authored 3 publications receiving 10 citations.

Interferon-alpha for treating polycythemia vera yields improved myelofibrosis-free and overall survival.

Abstract: Interferon-alpha (rIFNα) is the only disease-modifying treatment for polycythemia vera (PV), but whether or not it prolongs survival is unknown. This large single center retrospective study of 470 PV patients compares the myelofibrosis-free survival (MFS) and overall survival (OS) with rIFNα to two other primary treatments, hydroxyurea (HU) and phlebotomy-only (PHL-O). The median age at diagnosis was 54 years (range 20-94) and the median follow-up was 10 years (range 0-45). Two hundred and twenty-nine patients were women (49%) and 208 were high-risk (44%). The primary treatment was rIFNα in 93 (20%), HU in 189 (40%), PHL-O in 133 (28%) and other cytoreductive drugs in 55 (12%). The treatment groups differed by ELN risk score (p < 0.001). In low-risk patients, 20-year MFS for rIFNα, HU, and PHL-O was 84%, 65% and 55% respectively (p < 0.001) and 20-year OS was 100%, 85% and 80% respectively (p = 0.44). In high-risk patients, 20-year MFS for rIFNα, HU, and PHL-O was 89%, 41% and 36% respectively (p = 0.19) and 20-year OS was 66%, 40%, 14% respectively (p = 0.016). In multivariable analysis, longer time on rIFNα was associated with a lower risk of myelofibrosis (HR: 0.91, p < 0.001) and lower mortality (HR: 0.94, p = 0.012). In conclusion, this study supports treatment of PV with rIFNα to prevent myelofibrosis and potentially prolong survival.

Hematopoietic fitness of JAK2V617F Myeloproliferative Neoplasms is linked to clinical outcome

Abstract: Myeloproliferative Neoplasms (MPN) harbor highly recurrent driver mutations affecting targetable kinases yet treatment options for these phenotypically diverse diseases are limited, and patients experience significant morbidity and shortened survival. The most important disease-related complications—thrombosis, transformation and death—are not used as clinical trial endpoints due to the long follow-up required to assess such disease modifying activity. A reliable monitoring biomarker linking MPN biology with these important clinical outcomes is missing. MPN driver mutation allele frequency (MAF) from whole blood or marrow (WB) does not faithfully predict MPN phenotype, clinical progression or response. This is likely because WB MAF is a composite measure of alleles from a heterogenous and variable mixture of mature leukocytes and, as such, does not report any information about the critical MPN stem and progenitor cells (MPN-SPCs). Driver mutations allow MPN cells to outcompete their normal hematopoietic counterparts and this competitive advantage—increased “fitness”—underlies core biology of MPN pathogenesis. We developed an approach to directly measure MPN fitness from samples. We measured fitness in 115 samples from 84 patients with JAK2V617F MPNs by quantifying MAF of 11 well-defined and strictly validated hematopoietic stem, progenitor and mature cell populations purified from routinely collected blood and marrow specimens. Unsupervised, hierarchical clustering of MPN fitness revealed 4 major fitness levels: F1, F2, F3, and F4 with significantly different but overlapping clinical features and diagnoses. Notably, these four fitness levels were associated with significantly different event-free survival (EFS): 95% (F1), 81% (F2), 73% (F3), 50% (F4) at 24 months (log-rank p=0.017). In contrast, WB MAF quartile failed to predict EFS. Multivariable models showed that fitness was associated with event risk independent of age, sex, duration of disease, MPN diagnosis and WB MAF. Principal component analysis allowed convenient projection of the 11-component MAF fitness measures to reduce dimensionality and develop a model for relative risk (RR) of event that could be used to assess individual or serial samples. Serial samples with more than a year of follow-up was available for 13 patients. We found that a reduction of this RR score was associated with a therapeutic response (p=0.045). In contrast, increasing RR overtime portended a disease-related event (p=0.045). Changes in WB MAF did not correlate with RR (r2=0.022) possibly explaining why WB MAF failed to predict events. These data demonstrate that fitness dynamics from serial blood samples can be used as a monitoring biomarker to assess changes in RR over time. Thus, fitness risk is a promising endpoint alongside corresponding clinical parameters such as blood counts, spleen size and marrow fibrosis grade. Our study offers a feasible approach to monitor the MPN biology central to disease progression and can be used in clinical trials to efficiently identify disease-modifying, potentially life-prolonging treatments.

Abstract 3472: A tumor draining lymph node CD8 T cell memory response is pivotal for a decrease in recurrence after neoadjuvant anti PD-1 therapy for NSCLC

Abstract: Background: Non-small cell lung cancer (NSCLC) is the leading cause of cancer death worldwide. Even at early stages, death rates remain disproportionately high due to metastatic recurrence. Recently, blockade of the PD-1/PD-L1 axis has shown impressive increases in recurrence-free survival in a subset of patients. While efforts to decrease relapse have focused on decreasing residual micrometastatic disease at the time of definitive treatment, PD-1 directed therapy may allow for an adaptive immune response and the establishment of anti-tumor immunosurveillance. Building on results from a clinically relevant murine model of metastatic relapse after tumor resection and robust assays on systematically characterized tumor, lymph node and blood samples of early-stage lung cancer patients, we posit that immunologic CD8 T cell memory may be a primary mechanism of metastatic protection. Methods: We utilized a syngeneic murine model of metastatic lung adenocarcinoma (344SQ) after resection of tumor, tumor draining lymph node (tdLN) and non-draining lymph nodes (ndLN). Using bioluminescent imaging (BLI) and flow cytometric analysis we monitored T cell kinetics and anti-tumor activity after administration of anti-PD-1 antibody and/or KD033, a fusion antibody combining a high affinity anti-PD-L1 IgG1 antibody with an IL-15Rα sushi binding domain. Tumor/tdLN and ndLN T cells were characterized for PD-1/TCF-1/CD62L/CD44/CXCR5 memory phenotypes. In parallel, we analyzed resected tumor, tdLN and ndLN from early-stage NSCLC patients. Results: tdLN from murine models and early-stage patients maintain robust PD-1+ CXCR5+ CD8 T cell memory phenotypes not significantly found in the primary tumor, ndLN and peripheral blood. Neoadjuvant treatment with PD-1 blockade alone had a heterogenous response, with robust proliferation of T cell central and stem cell memory populations (CM & SCM) at the tdLN in responders compared to non-responders (p<0.05). Combination therapy with IL-15Rα agonist (KD033) potentiated diverse PD-1+ CXCR5+ CD8 stem cell like memory subsets in the tdLN and subsequent response at the primary tumor (100%) as well as displayed superior protection against metastatic recurrence up to 200 days compared to PD-1 inhibition or KD033 alone (median survival undetermined vs. 120d, 161d respectively p<0.05). Removal of tdLN or blockade of lymph node migration with FTY720 prior to therapy decreased a population of SCM and CM CD8 T cells found in the primary tumor, decreased primary tumor response and altered systemic memory subpopulations in the ndLN (p<0.05). Conclusions: Our data strongly points to a T cell memory response within the tumor draining lymph node as a possible driver of protection from systemic cancer recurrence, laying the groundwork for a new therapeutic strategy aimed at establishing CD8 immunosurveillance for protection from cancer recurrence. Citation Format: Tatiana Delgado Cruz, Geoffrey J. Markowitz, Mitchell Martin, Arshdeep Singh, Shelley Yang Bai, Nasser Altorki, Timothy McGraw, Vivek Mittal, Jonathan Villena-Vargas. A tumor draining lymph node CD8 T cell memory response is pivotal for a decrease in recurrence after neoadjuvant anti PD-1 therapy for NSCLC [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 3472.

Polycythemia vera: historical oversights, diagnostic details, and therapeutic views

Abstract: Polycythemia vera (PV) is a relatively indolent myeloid neoplasm with median survival that exceeds 35 years in young patients, but its natural history might be interrupted by thrombotic, fibrotic, or leukemic events, with respective 20-year rates of 26%, 16%, and 4%. Current treatment strategies in PV have not been shown to prolong survival or lessen the risk of leukemic or fibrotic progression and instead are directed at preventing thrombotic complications. In the latter regard, two risk categories are considered: high (age >60 years or thrombosis history) and low (absence of both risk factors). All patients require phlebotomy to keep hematocrit below 45% and once-daily low-dose aspirin, in the absence of contraindications. Cytoreductive therapy is recommended for high-risk or symptomatic low-risk disease; our first-line drug of choice in this regard is hydroxyurea but we consider pegylated interferon as an alternative in certain situations, including in young women of reproductive age, in patients manifesting intolerance or resistance to hydroxyurea therapy, and in situations where treatment is indicated for curbing phlebotomy requirement rather than preventing thrombosis. Additional treatment options include busulfan and ruxolitinib; the former is preferred in older patients and the latter in the presence of symptoms reminiscent of post-PV myelofibrosis or protracted pruritus. Our drug choices reflect our appreciation for long-term track record of safety, evidence for reduction of thrombosis risk, and broader suppression of myeloproliferation. Controlled studies are needed to clarify the added value of twice- vs once-daily aspirin dosing and direct oral anticoagulants. In this invited review, we discuss our current approach to diagnosis, prognostication, and treatment of PV in general, as well as during specific situations, including pregnancy and splanchnic vein thrombosis.

In utero origin of myelofibrosis presenting in adult monozygotic twins

Abstract: The latency between acquisition of an initiating somatic driver mutation by a single-cell and clinical presentation with cancer is largely unknown. We describe a remarkable case of monozygotic twins presenting with CALR mutation-positive myeloproliferative neoplasms (MPNs) (aged 37 and 38 years), with a clinical phenotype of primary myelofibrosis. The CALR mutation was absent in T cells and dermal fibroblasts, confirming somatic acquisition. Whole-genome sequencing lineage tracing revealed a common clonal origin of the CALR-mutant MPN clone, which occurred in utero followed by twin-to-twin transplacental transmission and subsequent similar disease latency. Index sorting and single-colony genotyping revealed phenotypic hematopoietic stem cells (HSCs) as the likely MPN-propagating cell. Furthermore, neonatal blood spot analysis confirmed in utero origin of the JAK2V617F mutation in a patient presenting with polycythemia vera (aged 34 years). These findings provide a unique window into the prolonged evolutionary dynamics of MPNs and fitness advantage exerted by MPN-associated driver mutations in HSCs.