The Grupo Argentino de Tratamiento de la Leucemia Aguda (GATLA) LH-05 trial evaluated positron emission tomography-computed tomography (PET-CT)-guided ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine) in patients with stage I-IV classic Hodgkin lymphoma (cHL). A total of 563 patients with cHL stages I-IV were included in the prospective, non-randomized GATLA LH-05 trial. Patients received three cycles of ABVD followed by PET-CT (PET3). Patients with PET3 Deauville score (DS) 1-2 discontinued treatment, DS 3-4 completed six ABVD with involved-field radiotherapy (IFRT) and DS 5 received salvage chemotherapy. Progression-free survival (PFS) and overall survival (OS) were estimated using the Kaplan-Meier method. Prognostic factors for PFS were assessed using Cox regression. After a median follow-up of 93.5 months Interquartile Range (IQR) 54-139, 5- and 10-year PFS for the whole cohort were 78.9% 95% Confidence Interval (CI) 75.5-82.6 and 76.2% (95% CI 72.4-80.2) respectively. Five- and 10-year OS were 95.2% (95% CI 93.3-97.0) and 93.7% (95% CI 91.5-96.0). All PET3-negative patients achieved 10-year PFS of 84.4%. PET3 was the strongest predictor of PFS, while disease stage had no independent prognostic significance. With extended follow-up, PET-CT-adapted therapy after three cycles of ABVD provides durable disease control while reducing exposure to chemotherapy and radiotherapy. These results support PET-CT-guided treatment discontinuation in PET3-negative patients across all stages of cHL.

Chronic myeloproliferative neoplasms are characterized by clonal myeloid expansion driven by activating mutations in the JAK2 pathway and chronic inflammation. The aim was to investigate the contribution of circulating inflammatory mediators to the abnormalities in the megakaryocytic lineage characteristic of MF and ET. Plasma samples from 30 MF and 28 ET patients were incubated with normal cord-blood CD34 + progenitors and megakaryo/thrombopoiesis was evaluated. MF plasma increased megakaryocyte output, which was attenuated in sequential samples from ruxolitinib-treated patients. JAK1/2, MAPK and NF-kB inhibitors reverted this effect, revealing the concomitant involvement of all three pathways. Elevated levels of circulating IL-1β and IL-6 correlated with megakaryocyte output, which was reverted by blocking antibodies, indicating this phenotype is partly driven by these inflammatory cytokines. Instead, ET plasma promoted enhanced proplatelet formation, which was coupled with increased NFE2 and Bcl-xL expression. Elevated levels of circulating RANTES correlated with ET plasma-induced proplatelet formation, which was partially reverted by RANTES receptor CCR5 antagonist Maraviroc, indicating RANTES is involved in this process. These findings indicate that, in addition to clonal mutations, extrinsic inflammatory mediators play a direct role in MF and ET megakaryocyte abnormalities. The distinct cytokine profile could potentially be useful for the development of targeted therapies.

Abstract Myelofibrosis (MF) is a rare myeloproliferative neoplasm associated with significant health burden, and limited access to newer therapies for MF in Latin America (LATAM) creates a significant barrier to optimal care. With this challenge in mind, an expert panel of 8 hematologists from the LATAM region developed evidence- and consensus-based clinical practice recommendations to standardize care and improve outcomes for patients with MF in the LATAM region. Using modified Delphi methodology, 5 key themes were addressed: (1) defining the thresholds for anemia and when to initiate or modify treatment; (2) defining when to initiate or modify treatment for thrombocytopenia; (3) Janus kinase inhibitor therapy: selection, initiation, and switching; (4) defining the most appropriate risk stratification model for MF in the LATAM region; and (5) defining allogeneic hematopoietic stem cell transplantation eligibility in the LATAM region. LATAM-specific and global systematic literature reviews were utilized alongside the clinical experience of the authors to draft recommendations. An extended faculty of 20 LATAM hematologists were invited to vote on the recommendations, which all achieved a high level of consensus. Although the presented recommendations aim to optimize MF care in the LATAM region, broader access to newer, more effective therapies for MF is essential to significantly improve patient outcomes in LATAM.

The introduction of tyrosine kinase inhibitors (TKIs) has improved the management of chronic myeloid leukemia (CML), making treatment-free remission (TFR) an attainable objective. Despite this, half of the patients lose their major molecular response (MMR) within the first six months after TKIs discontinuation. TFR continues to pose a significant challenge in low middle income countries. There is currently no biomarker that reliably predicts TFR in CML. The aim of our study is to identify plasma cytokines signature as predictive biomarkers that distinguish CML patients maintaining molecular remission following TKI discontinuation from those who relapse. This study is a subanalysis within the multicentric AST- Argentina Stop Trial which attempted TKI in CML patients meeting the main inclusion criteria of a sustained Deep Molecular Response (DMR) (BCR-ABL1IS ≤ 0.01%, or undetectable BCR-ABL1 i.e., MR4.0 or better) for a minimum of two years.A total of 81 CML patients from 15 centers in Argentina were included between February 2019 and April 2023. Peripheral blood samples were collected before stopping TKI treatment. Cytokines and chemokines in plasma were measured using multiplex bead assays on a Magpix® system. IL6, MCP-1, GCSF, IL-10, IL-12 (p70), MIP-1a, TNF-a, VEGFA were assessed. Patients were classified into two groups based on their response to TKI discontinuation the Relapsed (R) group, defined by the loss of MMR, and the Non-Relapsed (NR) group, comprising those who maintained molecular remission. Molecular relapse-free survival rates were estimated using Kaplan-Meier analysis, and group comparisons were performed with the log-rank test and Man whitney. A p-value of less than 0.05 was considered statistically significant.A classification tree algorithm was applied to the variables selected after preprocessing. All analyses were conducted using R statistical software (version 4.3.1). At the time of the analysis, the median molecular follow-up after TKI discontinuation was 60 months (range, 20 to 69 months). Thirty-two patients (39,5%) lost MMR, most frequently within the first 6 months, leading to a molecular relapse-free survival of 62% at 24 months and 60,5% for the entire follow-up period. Significant differences were found between NR and R patients in both the duration of DMR until discontinuation and the overall treatment duration (Mann–Whitney test; p =0.030 and p =0.013, respectively). stratification by a BCR-ABL/ABLIS(%) threshold of 0.0036%, close to the MR4.5 international standard (0.0032%), showed that patients below this threshold had significantly better molecular relapse-free survival time than those above it 61% vs 14% p=0.0010. The median duration of DMR was 90 m, (34-203) for NR patients and 74m ( 30-179) for R patients p=0.030. Regarding cytokine panel, significant differences between R and NR patients were observed; in particular, MCP-1 and IL-6 being significantly higher in the NR group with median concentrations of 289.1 vs 253.5 pg/mL (Mann-Whitney test; p = 0.012) and 3.9 vs 2.9 pg/mL (Mann-Whitney test; p = 0.007), respectively Decision tree analysis identified MCP-1 as the primary stratifying factor: patients with MCP-1 ≥ 264 pg/mL had a lower relapse risk (23%), while those with lower levels relapsed more frequently (58%). Among MCP-1^low patients, IL-6 further refined prognosis: relapse occurred in 72% of MCP-1^low/IL-6^low patients versus 12% in MCP-1^low/IL-6^high. This cytokine-based stratification significantly discriminated molecular relapse-free survival (log-rank p < 0.001). Predictive performance of the model was confirmed in a validation cohort, showing good sensitivity and no false positives A novel contribution of this work is the integration of cytokine profiles into the prediction of molecular relapse, extending beyond traditional clinical and functional molecular biomarkers. Our study suggests a potential role for IL-6 and MCP-1, in predicting molecular relapse following TKI discontinuation. The cytokine model achieved high specificity and a Positive Predictive Value of 100%, indicating that when predicts relapse, it is highly reliable.These findings support the notion that cytokine profiles may reflect aspects of the immune environment, suggesting an active role of these biomarkers in CML immunobiology, that help to early identify patients at higher risk of relapse toward a personalized TKI discontinuation approach.

Inflammation plays a pivotal role in the pathogenesis of primary and post-essential thrombocythemia or post-polycythemia vera myelofibrosis (MF) in close cooperation with the underlying molecular drivers. This inflammatory state is induced by a dynamic spectrum of inflammatory cytokines, although recent evidence points to the participation of additional soluble inflammatory mediators. Damage-associated molecular patterns (DAMPs) represent endogenous signals released upon cell death or damage which trigger a potent innate immune response. We assessed the contribution of two prototypical DAMPs, HMGB1 and S100A8/A9, to MF inflammation. Circulating HMGB1 and S100A8/A9 were elevated in MF patients in parallel to the degree of systemic inflammation and levels increased progressively during advanced disease stages. Patients with elevated DAMPs had higher frequency of adverse clinical features, such as anemia, and inferior survival, suggesting their contribution to disease progression. Monocytes, which are key players in MF inflammation, were identified as a source of S100A8/A9 but not HMGB1 release, while both DAMPs correlated with cell death parameters, such as serum LDH and cell-free DNA, indicating that passive release is an additional mechanism leading to increased DAMPs. HMGB1 and S100A8/A9 promote inflammation through binding to Toll-like receptor (TLR) 4, whereas the former also binds TLR2. Monocytes from MF patients were shown to be hyperactivated at baseline, as reflected by higher CD11b and tissue factor exposure and increased expression levels of proinflammatory cytokines IL-1β and IL-6. Patient monocytes showed preserved TLR4 and TLR2 expression and were able to mount normal or even exacerbated functional responses and cytokine upregulation following stimulation of TLR4 and TLR2. Elevated levels of endogenous TLR ligands HMGB1 and S100A8/A9 coupled to the finding of preserved or hyperreactive TLR-triggered responses indicate that DAMPs may promote monocyte activation and cytokine production in MF, fueling inflammation. Plasma IL-1β and IL-6 were elevated in MF and correlated with DAMPs levels, raising the possibility that DAMPs could contribute to cytokine generation in vivo. In conclusion, this study highlights that, in cooperation with classic proinflammatory cytokines, DAMPs represent additional inflammatory mediators that may participate in the generation of MF inflammatory state, potentially providing novel biomarkers of disease progression and new therapeutic targets.

Myelofibrosis (MF) is a clonal hematopoietic stem cell disorder classified among chronic myeloproliferative neoplasms, characterized by exacerbated myeloid and megakaryocytic proliferation and bone marrow fibrosis. It is induced by driver ( JAK2 / CALR / MPL ) and high molecular risk mutations coupled to a sustained inflammatory state that contributes to disease pathogenesis. Patient outcome is determined by stratification into risk groups and refinement of current prognostic systems may help individualize treatment decisions. Circulating cell-free (cf)DNA comprises short fragments of double-stranded DNA, which promotes inflammation by stimulating several pathways, including inflammasome activation, which is responsible for IL-1β and IL-18 maturation and release. In this work, we assessed the contribution of cfDNA as a marker of disease progression and mediator of inflammation in MF. cfDNA was increased in MF patients and higher levels were associated with adverse clinical outcome, a high-risk molecular profile, advanced disease stages and inferior overall survival, indicating its potential value as a prognostic marker. Cell-free DNA levels correlated with tumor burden parameters and markers of systemic inflammation. To mimic the effects of cfDNA, monocytes were stimulated with poly(dA:dT), a synthetic double-stranded DNA. Following stimulation, patient monocytes released higher amounts of inflammasome-processed cytokine, IL-18 to the culture supernatant, reflecting enhanced inflammasome function. Despite overexpression of cytosolic DNA inflammasome sensor AIM2, IL-18 release from MF monocytes was shown to rely mainly on the NLRP3 inflammasome, as it was prevented by NLRP3-specific inhibitor MCC950. Circulating IL-18 levels were increased in MF plasma, reflecting in vivo inflammasome activation, and highlighting the previously unrecognized involvement of this cytokine in MF cytokine network. Monocyte counts were higher in patients and showed a trend towards correlation with IL-18 levels, suggesting monocytes represent a source of circulating IL-18. The close correlation shown between IL-18 and cfDNA levels, together with the finding of enhanced DNA-triggered IL-18 release from monocytes, suggest that cfDNA promotes inflammation, at least in part, through inflammasome activation. This work highlights cfDNA, the inflammasome and IL-18 as additional players in the complex inflammatory circuit that fosters MF progression, potentially providing new therapeutic targets.

all pts. with positive PET ‐ CT + 3 (p < 0.0001). We perform a multi-variate analysis for EFS which included age, stage, IPS, bulky disease, extranodal areas and the result of the PET + 3. This last parameter together with age were the only ones with statistical significance (p = 0.001 and 0.046 respectively). Stage at diagnosis was not significant. With long term follow up the OS at 5 years is 97.3% and 87.3% for all PET + 3 negative vs PET + 3 positive pts. When comparing the results LH ‐ 05 with our previous clinical trial (LH ‐ 96) there is no difference in EFS and OS at 5 years but in LH ‐ 05 only 31% received more than 3 cycles of ABVD and IFRT compared to 61% and 100% in LH ‐ 96. This PET adapted approach reduces exposure to chemo and radiotherapy with no negative effect on long term outcome. Conclusion: This long term follow up data support the PET ‐ CT adapted approach for all stages of HL after a short course of ABVD. In the Cox regression model, PET ‐ CT at completion of treatment was the most significant factor associated to EFS. Treatment with 3 cycles of ABVD can be adequate for pts. with negative PET ‐ CT + 3 regardless their stage at diagnosis. Nevertheless, this long term follow up demonstrated that there is still room for improvement trying to identify PET ‐ CT + 3 negative patients that will relapse and escalating treatment in PET ‐ CT + 3 positive patients to improve outcome. GATLA is designing a trial with the aim to improve these two different risk groups.

Background: Treatment for classic Hodgkin lymphoma (cHL) in older age population continues to be a challenge. Comorbidity prevalence, increase toxicity to the standard treatments and the lack of inclusion in clinical trials all contribute to this phenomenon. The obtained results are inferior in comparison to young adults and there is shortage of evidence regarding effective therapeutic strategies. Recently, the GATLA LH-05 protocol has published the long-term follow-up of the results of the PET/CT adapted strategy after 3 cycles of ABVD, regardless of the presentation stage and no upper age limit. Aims: To assess the effectiveness and safety of the interim PET/CT adapted treatment in cHL patients older than 60 years old. Methods: A retrospective analysis of the LH-05 database was performed. Patients were included ≥ aged 60 with recent diagnosis of cHL stage I-IV and HIV negative. All patients received 3 cycles of ABVD and were evaluated with PET-TC (PET3). Those patients with negative PET (Deauville score 1 and 2) were considered to be in complete remission (CR) and they finalized the treatment. Patients with DS 3 and 4 completed 6 ABVD cycles and involved-field radiotherapy in hypermetabolic areas in interim PET3. Patients with DS 5 were considered to have progressive disease. Progression-free survival (PFS) and overall survival (OS) were evaluated. Kaplan-Meier method and Log-rank test were used for survival analysis. Results: Of a total of 490 patients included in the GATLA LH-05 protocol, 59 met the inclusion criteria. The mean age was of 66 years (range: 60-89), 90% presented a PS<2. The most frequent histological subtype was Nodular Sclerosis (54%) and 75% presented in localized stage (I-II). All patients received initial treatment with 3 cycles of ABVD and were evaluated by PET: 81% presented negative PET (DS 1-2) and 19% were positive. No GIII-IV toxicity or treatment-related deaths were recorded. With a median follow-up of 10 years, median PFS and OS were not reached. At 36 and 60 months, PFS was 86% and 78,9%, and OS was 90% and 85.5%, respectively. Negative PET3 patients had a PFS of 85.4%, while positive PET3 patients had a PFS of 43% (p=0,0001). In the multivariable analysis that included age (>60 vs. <60), stage (localized vs. advanced), IPS (<2 vs. >2), extranodal areas, bulky disease and PET3 result, only age and PET3 result had significant impact in PFS (p=0.046 and p=0,001 respectively). PFS of PET/TC- positive patients was significantly lower than in the cohort of patients younger than 60. OS at 36 and 60 months in PET negative patients was 97.5% and 94.5% respectively, versus 63.6% and 53% in PET/TC positive patients. Image:Summary/Conclusion: With the PET/TC adapted treatment after 3 cycles of ABVD in 59 patients > 60 years old, 81% of patients achieved negative PET and therefore received no further treatment. These patients had an excellent result with a PFS of 85.4% at 3 years, similar to the younger patient population. However, a significant reduction in PFS was observed in PET3 positive patients > 60 years old compared to younger ones. Implementation of this PET/TC guided strategy, regardless of stage at diagnosis, resulted in reduced exposure to chemotherapy and radiotherapy, contributing to the absence of severe treatment-related morbidity and mortality.

Background: ALL in adults is considered a heterogeneous disease with poor prognosis. However, adolescents and young adults (AYA) display intermediate characteristics as compared with children. Risk groups and response predictors are essential to guide the treatment.

Introduction: Up to 20% of patients (pts) with essential thrombocythemia (ET) and up to 10-15% of pts with polycythemia vera (PV) are diagnosed before the age of 40 years and the percentage is even lower in pts with primary myelofibrosis (PMF). Pregnancy (Pcy) in MPN is associated with an increased incidence of thrombotic and bleeding events and obstetric complications with live birth rates of 50% to 70%. There are no evidence-based guidelines for the management of these pts and most of the data come from case series of few pts. There are no validated variables that can predict outcomes in pregnant women with MPN. Objetives: Primary: To learn the incidence of thromboembolic, hemorrhagic and OC in pregnant women with MPN in Argentina. Secondary: To evaluate parameters such as mutational status, platelet count, history of complications in previous Pcy, use of aspirin (ASA), low molecular weight heparin (LMWH) or interferon (IFN) and their relationship with obstetric outcomes. Materials and methods: Retrospective evaluation of medical records of pts with diagnosis of MPN and Pcy. Quantitative variables were expressed as median and interquartile range (IQR) and qualitative variables as total number and percentage (%). Fisher's exact test was used to analyze variables and their association with events and Wilcoxon test for platelet counts. Results: A total of 30 Pcy in 23 women with a diagnosis of MPN were recorded, 20 Pcy in pts with ET, 4 Pcy in pts with PV and 6 MF pregnancies. Pcy was planned in 56.6% of cases. There were OC in 15/19 previous Pcy. The median age was 32.9 years (IC25-75% 30-36 years). Mutational status was assessed in 22 pts: 9/22 JAK2 +, 7/22 CALR +, 1/22 triple-negative, 1/22 JAK2-CALR- and MPL not performed, 6/22 JAK2- CALR and MPL without data. The overall number of live births and first trimester spontaneous abortions (SA) were 26(86%) and 4(13.3%) respectively, without cases of second (2T) and third trimester (3T) fetal loss or stillbirths. There was a case of neonatal death in a patient with MF. We detected 13 obstetric events (ET: 9/20, PV: 2/4, and MF 2/6): 4 SA, 5 cases of fetal growth retardation, 1 partial placental abruption and 3 placental hematomas. There was no significant association between JAK2 mutational state, history of complications in previous Pcy, platelet count, use of ASA, LMWH or IFN and obstetric outcomes. Two of the pts who had SA presented smoking as a cardiovascular risk factor. There was heterogeneity among hematologist regarding therapeutic management: ASA was indicated in 24 Pcy and LMWH in prophylactic doses during Pcy in 15. In 21/25 cases LMWH was indicated as postpartum prophylaxis, only in 3/21 it was extended for 6 weeks(wks). Before Pcy 17 cases received cytoreductive treatment: 2 with HU and 1 with anagrelide that were discontinued at the time Pcy was confirmed, 5 with peg IFN, and 9 conventional IFN. During Pcy 8 continued with cytoreductive treatment (6/9 conventional IFN, 2/9, pegIFN, including 1 patient previously receiving HU) and 5 initiated IFN (1/5 conventional, 4/5 pegIFN). Platelet counts in pts who did not require cytoreduction dropped from 600 x 109/L (290-1596 x 109/L) at the beginning of Pcy to 470 (240-1548) x 109/L, p=0.0068, and 423 (240-843) x 109/L, p=0.0005, in the 2T and 3T, respectively, with non-significant increase after delivery to 494 x 109/L (122-1600 x 109/L). No cases of maternal thrombosis and 2 episodes of major postpartum bleeding who required surgical intervention one of them with hysterectomy were found.The median time of delivery was at 38 wks of gestation (IC25-75% 36.5-38.5). Vaginal delivery was performed in 6 Pcy, caesarean section (CS) was required due to emergency in 2, because of lack of fetal progression in 2, and 16 were scheduled CS. The median birth weight was 2900g (IC25-75% 2500-3300g). No congenital malformations in live births were detected. Conclusions: Pcy is a rare but high-risk event in MPN pts with 11/30 OC in this cohort. The live birth rate was high compared to the literature. The risk of MC was low, without thrombotic complications and 2/30 episodes of major postpartum bleeding. There was no correlation between mutational status, platelet count or treatments received and obstetric outcomes. There was a significant reduction in the number of platelets in pts with thrombocytosis without requiring cytoreduction. The high percentage of pts who finished their pregnancy with scheduled CS is highlighted. Disclosures No relevant conflicts of interest to declare.

SummaryThe role of Ann Arbor staging in determining treatment intensity after achieving a negative positron emission tomography (PET) has not been established in classical Hodgkin lymphoma (cHL). Patients with stage I–IV cHL, received three cycles of ABVD (doxorubicin, bleomycin, vinblastine, dacarbazine) and an interim PET scan (PET3). PET3‐negative patients received no further therapy. PET3‐positive patients received three additional cycles of ABVD plus involved‐field radiation therapy or salvage chemotherapy, if refractory to ABVD, and were re‐evaluated by PET scan (PET6). Study endpoints were 3‐year progression‐free survival (PFS) and overall survival (OS) rates. Two hundred and thirty‐nine patients with early‐stage and 138 with advanced‐stage were evaluable. Overall, 260 patients (70%) were PET3‐negative and had higher 3‐year PFS (90% vs. 65%; P < 0·0001) and OS (98% vs. 92%; P = 0·007) rates than PET3‐positive patients. All PET3‐negative patients, regardless of disease stage at diagnosis, achieved similarly good PFS (90–91%; P = 0·76) and OS (97–99%). The only independent prognostic factor for PFS was PET3‐negativity (Hazard ratio 3·8; 95% confidence interval 2·4–6·3; P < 0·0001). This study suggests that cHL patients who achieve a negative PET3 following ABVD have an excellent outcome, regardless of stage at diagnosis. An appropriately powered, phase III trial will be necessary to confirm these findings.

Myelofibrosis is a myeloproliferative neoplasm associated with progressive cytopenias and high symptom burden. MF patients with thrombocytopenia have poor prognosis but the presence of thrombocytopenia frequently precludes the use of JAK2 inhibitors. In this study, we assessed quality of life and symptom burden in 418 MF patients with (n = 89) and without (n = 329) thrombocytopenia using prospective data from the MPN-QOL study group database, including the Myeloproliferative Neoplasm Symptom Assessment Form (MPN-SAF) and Total Symptom Score (MPN10). Thrombocytopenia, defined as platelet count <100 × 109/L (moderate 51–100 × 109/L; severe ≤50 × 109/L), was associated with anemia (76% vs. 45%, p < 0.001), leukopenia (29% vs. 11%, p < 0.001), and need for red blood cell transfusion (35% vs. 19%, p = 0.002). Thrombocytopenic patients had more fatigue, early satiety, inactivity, dizziness, sad mood, cough, night sweats, itching, fever, and weight loss; total symptom scores were also higher (33 vs. 24, p < 0.001). Patients with severe thrombocytopenia were more likely to have anemia (86% vs. 67%, p = 0.04), leukopenia (40% vs. 20%, p = 0.04), and transfusion requirements (51% vs. 20%, p = 0.002) but few differences in symptoms when compared to patients with moderate thrombocytopenia. These results suggest that MF patients with thrombocytopenia experience greater symptomatic burden than MF patients without thrombocytopenia and may benefit from additional therapies.

Introduction: Treatment of classical Hodgkin's lymphoma (cHL) in the elderly population remains a challenge. Prevalence of comorbidities, increased toxicity to standard treatments, and the lack of inclusion within clinical trials contribute to this phenomena. Results are often inferior compared to young adults, and there is a paucity of evidence regarding valid treatment approaches. Recently, the GATLA HL-05 protocol has reported the results of a PET/CT-adapted strategy after 3 cycles of ABVD, regardless of stage at presentation and without upper age limit for inclusion1. Methods: In order to evaluate the outcome of elderly patients included in this trial, a retrospective analysis was conducted on the HL-05 database. Patients (pts) equal or older than 60 years with a recent diagnosis of cHL and a negative HIV status were considered. Progression-free survival (PFS) was defined as time from treatment to relapse or death from any cause. Overall survival (OS) was defined as time from treatment to death from any cause. Duration of response (DOR) was defined as time from complete remission (CR) to relapse or death. The Kaplan-Meier and Log-rank test method were used for survival curves. The Pearson test was applied for comparison of variables within charts. An α level of 0.05 was regarded as significant. Results: Of a total 377 pts enrolled within HL-05, 43 met inclusion criteria. With a median age of 66 yeays (range, 60-89 y), 90% had a performance status of 1 to 2. Nodular sclerosis was the most frequent histological subtype (60% of pts), and 72% of pts were early stage (I-II non-bulky disease). These characteristics were similar to the younger cohort. All pts received initial therapy with 3 cycles of ABVD and underwent evaluation with a PET/CT scan: 81% achieved a negative scan (Deauville scores, 1-2). Of the remaining 19% positive scans, 12% were compatible with PR and 7% with PD. No grade III/IV toxicity events or treatment-related deaths were reported. Within a follow-up period of 68 months, median PFS and OS have not yet been reached, and PFS was 88% at 36 months. In comparison to the younger cohort, response rates after 3 and 6 cycles of treatment were statistically similar. Furthermore, there were no significant differences within PFS, OS, and DOR curves. In a multivariate analysis including age, stage, bulky disease, and negative PET/CT after 3 cycles, older age was not a predictive factor related to PFS. Conclusions: With a PET/CT-adapted therapy after 3 cycles of ABVD for 43 pts older than 60 years, 81% of pts reached a negative scan and thus received no further treatment. These pts had an excellent outcome with a PFS of 88% at 3 years, with no statistically significant differences compared to the younger cohort. The implementation of a PET/CT-guided strategy, regardless of stage at presentation, resulted in a reduced exposition to chemo and radiotherapy and may have contributed to the absence of severe morbidity or treatment-related deaths. Keywords: elderly; Hodgkin lymphoma (HL); positron emission tomography (PET)

Abstract BACKGROUND: The presence of constitutional symptoms has been associated with increased mortality risk in myelofibrosis (MF) (Blood 2010;115(9):1703-8). New therapies exist which alleviate the severe symptom burden profile observed in MF patients but are only approved for use in those with intermediate-2 or high risk disease (N Engl J Med 2012;366:787-798). However, it has been proposed that there are patients who may benefit from symptom based treatment regardless of prognostic score (Am Soc Hematol Educ Program 2014;2014:277-286). We have recently characterized symptom score cutoffs at which patients would statistically benefit from treatment based on symptom scores alone (Scherber et. al. EHA 2016: a2250). These treatment thresholds included aMyeloproliferative Neoplasm Symptom Assessment Form Total Symptom Score (MPN-SAF TSS or MPN-10) total score of greater than or equal to 20, a worst individual item score of greater than 5, or a combined criteria of those with both an MPN-10 total score of greater than or equal to 20 and a worst individual item score greater than 5. This abstract represents an additional analysis of our MF cohort to better characterize the profile of patients who meet criteria for symptom-based therapy. METHODS: Patient demographics, symptom burden via the MPN-10 score (JCO 2012;30(33)4098-103), and disease traits were collected from MF patients and their physicians at a single time point during therapy. Previously we identified MPN-10 cutoffs via AkaikeÕs Information Criterion (AIC) analysis (Ecology 2014;95: 631-6), which represented the optimal model among all models specified for the data at hand to determine which patients would most benefit from symptom-directed therapy. RESULTS: Demographics. 695 MF patients without previousruxolitinib therapy were included in this analysis. Overall, of 455 patients (65.4%) fit a cutoff of having a single worst symptom item of greater than 5/10. 401 patients (57.7%) had a MPN-10 score of equal to or greater than 20. A total of 381 (54.8%) patients fit both of these criteria. A distribution of worse MPN-10 individual scores is shown in Table 1. Mean TSS score was 26.4 (SD=17.7). Symptom Criteria Associations. Demographics and disease traits: Neither mean age or age greater than 60 was significantly associated with meeting any of the symptom score cutoff criteria. Females were significantly more likely to meet any of the symptom score cutoffs (for all criteria, p=0.0003 or less). Patients with splenomegaly, particularly spleen size of greater than 15cm below the LCM, were significantly more likely than those with a normal sized spleen to meet any of the three criteria (spleen enlargement of any size p=0.014 or less; spleen greater than 15cm p=0.0114 or less). Patients who met any of the three symptom criteria tended to have a longer MPN duration, although this trend did not meet significance. A prior history of thrombosis was not associated with achieving any cutoff criterions. Symptom burden: Individuals who met the any symptom criteria were significantly more likely to have higher DIPSS prognostic risk score (for all p=0.0002 or less). Laboratory values: For those meeting criteria for a worst symptom greater than 5, mean WBC was 11.7 vs 9.1 x 109/L (p=0.025) and platelet count was 238.7 versus 329.1 (p=0.023). For those meeting criteria for a TSS greater than or equal to 20, mean WBC was 11.8 vs 9.5 x 109/L (p=0.04). For individuals meeting both criteria, mean WBC was 11.9 vs 9.5 x 109/L (p=0.034). The presence of peripheral blasts were significantly more common in patients with an individual worst symptom score greater than 5 (p=0.0364). Hemoglobin level was not significantly associated with symptom criteria for any cutoffs. CONCLUSION: Our analysis indicates that patients who would be treated based on symptom criteria are similar to patients who would be treated based on high risk features such as high DIPSS prognostic score, concerning blood count abnormalities (i.e., leukocytosis, thrombocytopenia, presence of peripheral blasts), and splenomegaly (particularly massive splenomegaly). Thrombosis history and age were not associated with criterion cutoff assignment, and it is notable that elderly age nor history of thrombosis alone would likely alter treatment choice other than anticoagulation. This data supports that JAK2 inhibitor treatment be strongly considered in patients meeting symptom based criteria. Disclosures Dueck: Bayer: Honoraria. Kiladjian:Novartis: Honoraria, Research Funding; AOP Orphan: Membership on an entity's Board of Directors or advisory committees, Research Funding. Zweegman:Celgene: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Takeda: Honoraria, Research Funding. Schouten:Sanofi: Consultancy; Novartis: Consultancy. Etienne:ARIAD: Speakers Bureau; Pfizer: Speakers Bureau; novartis: Consultancy, Speakers Bureau; BMS: Speakers Bureau. Harrison:Shire: Honoraria, Speakers Bureau; Gilead: Honoraria, Speakers Bureau; Baxaltra: Consultancy, Honoraria, Speakers Bureau; Incyte Corporation: Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria, Other: travel, accommodations, expenses, Research Funding, Speakers Bureau. Radia:Novartis: Honoraria; Pfizer: Honoraria. Cervantes:Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Baxalta: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AOP Orphan: Membership on an entity's Board of Directors or advisory committees. Vannucchi:Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Mesa:Promedior: Research Funding; Celgene: Research Funding; CTI: Research Funding; Gilead: Research Funding; Incyte: Research Funding; Galena: Consultancy; Ariad: Consultancy; Novartis: Consultancy.

by Holly L. Geyer, Heidi Kosiorek, Amylou C. Dueck, Robyn Scherber, Stefanie Slot, Sonja Zweegman, Peter AW te Boekhorst, Zhenya Senyak, Harry C. Schouten, Federico Sackmann, Ana Kerguelen Fuentes, Dolores Hernández-Maraver, Heike L. Pahl, Martin Griesshammer, Frank Stegelmann, Konstanze Döhner, Thomas Lehmann, Karin Bonatz, Andreas Reiter, Francoise Boyer, Gabriel Etienne, Jean-Christophe Ianotto, Dana Ranta, Lydia Roy, Jean-Yves Cahn, Claire N. Harrison, Deepti Radia, Pablo Muxi, Norman Maldonado, Carlos Besses, Francisco Cervantes, Peter L. Johansson, Tiziano Barbui, Giovanni Barosi, Alessandro M. Vannucchi, Chiara Paoli, Francesco Passamonti, Bjorn Andreasson, Maria L. Ferrari, Alessandro Rambaldi, Jan Samuelsson, Keith Cannon, Gunnar Birgegard, Zhijian Xiao, Zefeng Xu, Yue Zhang, Xiujuan Sun, Junqing Xu, Jean-Jacques Kiladjian, Peihong Zhang, Robert Peter Gale, and Ruben A. Mesa

The myeloproliferative neoplasms, including polycythemia vera, essential thrombocythemia and myelofibrosis, are distinguished by their debilitating symptom profiles, life-threatening complications and profound impact on quality of life. The role gender plays in the symptomatology of myeloproliferative neoplasms remains under-investigated. In this study we evaluated how gender relates to patients' characteristics, disease complications and overall symptom expression. A total of 2,006 patients (polycythemia vera=711, essential thrombocythemia=830, myelofibrosis=460, unknown=5) were prospectively evaluated, with patients completing the Myeloproliferative Neoplasm-Symptom Assessment Form and Brief Fatigue Inventory Patient Reported Outcome tools. Information on the individual patients' characteristics, disease complications and laboratory data was collected. Consistent with known literature, most female patients were more likely to have essential thrombocythemia (48.6% versus 33.0%; P<0.001) and most male patients were more likely to have polycythemia vera (41.8% versus 30.3%; P<0.001). The rate of thrombocytopenia was higher among males than females (13.9% versus 8.2%; P<0.001) and males also had greater red-blood cell transfusion requirements (7.3% versus 4.9%; P=0.02) with shorter mean disease duration (6.4 versus 7.2 years, P=0.03). Despite there being no statistical differences in risk scores, receipt of most therapies or prior complications (hemorrhage, thrombosis), females had more severe and more frequent symptoms for most individual symptoms, along with overall total symptom score (22.8 versus 20.3; P<0.001). Females had particularly high scores for abdominal-related symptoms (abdominal pain/discomfort) and microvascular symptoms (headache, fatigue, insomnia, concentration difficulties, dizziness; all P<0.01). Despite complaining of more severe symptom burden, females had similar quality of life scores to those of males. The results of this study suggest that gender contributes to the heterogeneity of myeloproliferative neoplasms by influencing phenotypic profiles and symptom expression.