Clinical Features and Outcomes of Patients with Myelofibrosis and RAS Pathway Activating Mutations at the University of Michigan

Abstract Purpose: Myelofibrosis (MF) is a clonal stem-cell derived BCR-ABL negative myeloproliferative neoplasm characterized by atypical megakaryocytic proliferation leading to bone marrow reticulin and collagen fibrosis. About 90% of patients with MF harbor somatic driver mutations that constitutively activate the JAK-STAT pathway. There have been other high molecular risk genes identified (ASXL1, EZH2, IDH1, IDH2, SRSF2) that predict inferior survival and have been added to prognostic scoring systems (Cazzola et al, Blood 2014). RAS pathway activating mutations are common in myeloid malignancies. Mutations in NRAS or KRAS themselves have been reported in ~5% of MF cases, and are associated with more proliferative disease behavior, decreased overall survival, and decreased chances of response to JAK inhibitor therapy (Coltro et al, Blood Adv 2020; Santos et al, Leukemia 2020). Downstream mutations in other RAS pathway genes such as NF1, BRAF, CBL, or PTPN11 are relatively common in MF, although their impact on disease behavior or response to therapy is not yet well characterized. Here, we aim to characterize clinical features of RAS pathway activated MF, describe response to therapies including JAK inhibitors, and determine impact on patient outcomes. Methods: We retrospectively analyzed the medical records of 118 consecutive adult patients with myelofibrosis who were seen at our tertiary referral center between July 2011 and July 2021 and who had next generation sequencing (NGS) performed - either MiOncoseq (Roychowdhury et al, Sci Transl Med 2011) or Tempus myeloid NGS. We grouped patients by those with mutated NRAS and/or KRAS (n=27) and those without mutated NRAS or KRAS but with another RAS pathway activating mutation (CBL, NF1, BRAF, PTPN11; n=12). Results: Of our cohort with MF, 39 (33%) harbored a RAS pathway activating mutation: NRAS, n=17; KRAS, n=15; CBL, n=12; NF1, n=6; BRAF, n=2; PTPN11, n=4. Fifteen (38%) patients had at least 2 different RAS pathway mutations. All of these patients had a JAK2 (n=29), CALR (n=6) or MPL (n=5) mutation in addition to their RAS pathway mutation. Ruxolitinib was the most common first-line MF directed therapy in 27 patients (69%); other less common first-line treatments included clinical trials containing a JAK inhibitor (5), hydroxyurea (3), interferon alpha (2), or danazol (2). With first-line therapy, overall response rate by IWG-MRT criteria was 49% (n=19), 16 (41%) had stable disease, and 4 (10%) had resistant disease. There was no statistical difference in type of response to first-line ruxolitinib between the NRAS/KRAS mutated group and the other RAS pathway mutated group (p=0.8). Twenty-seven patients went on to receive second-line therapy - 14 patients on a clinical trial with a JAK inhibitor. Twelve patients (31%) received at least 3 unique lines of treatment. After median follow-up of 69 months, 13 (33%) were alive and 26 (67%) had died, with 22 of these deaths related to their myelofibrosis diagnosis. Median overall survival was 74.7 months, 65.3 months in the NRAS/KRAS mutated group, and 76.2 months in the other RAS pathway mutated group, with no difference in overall survival between the two groups (p=0.72). Twenty patients (74%) from the NRAS/KRAS mutated group had a cause of death related to MF compared to 6 patients (50%) in the other group. Overall, 12 patients (31%) had leukemic transformation, 9 (33%) in the NRAS/KRAS mutated group and 3 (25%) in the other RAS pathway mutated group (p=0.72). Conclusion: Most patients with RAS pathway mutations presented with intermediate risk clinical characteristics (based on the DIPSS risk status), splenomegaly, and constitutional symptoms. Among those treated first-line with JAK inhibitors, about 50% of patients responded to therapy, similar to prior studies looking at JAK inhibitors in MF, though duration of response was short in both of the RAS activated subgroups (24 months and 28 months). In comparing patients with direct NRAS/KRAS mutations to those with other RAS pathway mutations, there was no difference between risk status at diagnosis, treatment responses overall and to ruxolitinib specifically, or overall survival. While our sample size was limited, our data suggests that patients with direct NRAS/KRAS mutations had similar clinical features and outcomes compared to those with other RAS pathway mutations. Further studies with larger cohorts are warranted to help predict response to JAK inhibitors. Figure 1 Figure 1. Disclosures Talpaz: Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy; Imago: Consultancy; Constellation: Membership on an entity's Board of Directors or advisory committees; Takeda: Other: Grant/research support .

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Major Improvement of Invasive Aspergillosis Outcome Is Not Enough to Improve Overall Survival In Allogeneic Hematopoietic Stem Cell Transplant Recipients: Results From a Single-Center Retrospective Analysis

Blood ◽

10.1182/blood.v116.21.1244.1244 ◽

2010 ◽

Vol 116 (21) ◽

pp. 1244-1244

Author(s):

Géraldine Salmeron ◽

Raphaël Porcher ◽

Anne Bergeron ◽

Marie Robin ◽

Regis Peffault de Latour ◽

...

Keyword(s):

Overall Survival ◽

Board Of Directors ◽

Cumulative Incidence ◽

Research Funding ◽

Line Treatment ◽

First Line ◽

Advisory Committees ◽

Hematopoietic Stem ◽

Risk Of Death ◽

First Line Treatment

Abstract Abstract 1244 Background. Voriconazole (V) treatment has been shown to improve the 12 week (W) survival rate of hematological patients (pts) with invasive aspergillosis (IA), including recipients of allogeneic hematopoietic stem cell transplants (HSCT). We investigated whether this early survival advantage could translate into a significant increase in overall survival. Methods. We retrospectively reviewed all consecutive pts who received a transplant between Sept. 1997 and Dec. 2008 at Saint-Louis Hospital and were diagnosed as having IA. The temporal origin of the study was the date of IA diagnosis for each patient. Factors associated with survival were analyzed using Cox proportional hazard models. Separate models were estimated for survival up to 12 W and for survival between 12 W and 24 months (M) in pts surviving longer than 12 W. The deaths of pts with and without IA were analyzed with a competing risk framework. Cumulative incidence curves were compared using Gray's tests. Results. Our study examined 89 IA pts. The median follow-up was 70 M (range, 11–130 M). Two pts did not receive any antifungal treatment and were excluded from subsequent analyses. Of the 87 pts, 42 received first-line V and 45 primarily received a lipid formulation of amphotericin B (n=25), amphotericin B deoxycholate (n=10), caspofungin (n=8) or itraconazole (n=2). The primary characteristics of pts with IA and their causes of death, separated by V as first-line treatment, are shown in the table below. The median survival was 2.6 M, and the overall survival at 24 M was 19% (95% CI 12–30 M) (see figure). Overall, the survival rates of the two groups were significantly different (P= 0.010). However, the differences in survival were quite dramatic prior to 10 M, whereas both survival curves became very close after one year. At 18 M, the numbers of surviving pts were almost identical in the two groups [19% (95% CI: 11–34%) in pts who did not receive V as first-line treatment vs. 21% (95% CI 11–38%) in pts who did]. Pts who did not receive V as a first-line treatment displayed a higher probability of dying from IA than those who did (P=0.004), whereas opposite results were found for mortality in pts without IA (P=0.006). The 24-M cumulative incidence of death from IA was 47% (95% CI 31–61%) in the no V group and 19% (95% CI 9–33%) in the group treated with V. The 24-M cumulative incidence of death in pts without IA was 4% (95% CI 7–14%) in the no V group and 27% (95% CI 14–42%) in pts treated with V. The probability of death from another cause, with IA, was similar in both groups (29% vs. 36% at 24 M; P=0.46). After adjusting for donor type, conditioning regimen, progressive GVHD at diagnosis of IA and cumulated steroid dose (mg/kg) in the W preceding IA diagnosis, administration of V as first-line treatment was found to decrease the risk of death during the first 12 W by approximately 70% [HR=0.31 (95% CI 0.16–0.60); P=0.0005]. Conversely, analysis of mortality between 12 W and 24 M failed to identify any significant predictor of risk of death; however, only 24 pts died during this period. Conclusions. The finding that first-line treatment with V, which is associated with a tremendous improvement in IA outcome, does not translate into an increase in overall survival (even in the context of early diagnosis) is striking. Diagnosis of IA following HSCT, whatever the outcome, appears to be a strong marker for poor long-term prognosis. Disclosures: Bergeron: Pfizer: Speakers Bureau, none; Merck: Speakers Bureau, none; Schering: Speakers Bureau, none. Sulahian:Pfizer: Research Funding, non; Merck: Research Funding, none. Ribaud:Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau, none; Schering: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau, none; Gilead: Speakers Bureau, none.

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The Ki67/CD138 Ratio Independently Predicts Overall Survival in the Upfront Treatment of Newly Diagnosed Multiple Myeloma

Blood ◽

10.1182/blood.v124.21.2016.2016 ◽

2014 ◽

Vol 124 (21) ◽

pp. 2016-2016

Author(s):

Tomer M Mark ◽

Peter Forsberg ◽

Ihsane Ouansafi ◽

Adriana C Rossi ◽

Roger N Pearse ◽

...

Keyword(s):

Multiple Myeloma ◽

Bone Marrow ◽

Overall Survival ◽

Board Of Directors ◽

Research Funding ◽

Complete Response ◽

Newly Diagnosed ◽

First Line ◽

Advisory Committees ◽

Line Therapy

Abstract Background: Assessment of malignant plasma cell cycling via plasma cell labeling index (PCLI) has been a validated prognostic tool in multiple myeloma (MM) but the test requires specialized technical expertise and is not widely available. Ki67 is a well-known protein marker of cellular proliferation on immunohistochemical (IHC) staining with prognostic utility in other malignancies. In an effort to develop a simpler system to provide analogous information to PCLI, we used a novel IHC co-staining technique for CD138 and Ki67 to quantify plasma cells in active cycling. We then performed a retrospective analysis of the ratio of Ki67/CD138 (Ki67%) in newly diagnosed patients with multiple myeloma receiving 1st-line therapy to correlate with clinical outcomes. Methods: A retrospective cohort study of patients (pts) with treated symptomatic MM was performed by interrogation of the clinical database at the Weill Cornell Medical College / New York Presbyterian Hospital. For inclusion in the analysis, subjects must have started first-line treatment in the period of 2005-2010, and had available bone marrow biopsies. Double-staining with Ki67 and CD138 was performed by IHC. The Ki67% was calculated as the percent of plasma cells expressing CD138 that were also found to express Ki67. Treatment outcomes were stratified and compared based on %Ki67. Response was determined by monthly serum protein electrophoresis / immunofixation (IFX) with free light chain analysis according to International Multiple Myeloma Working Group (IMWG) guidelines. Pts who were IFX negative but had no subsequent bone marrow biopsy were classified as being in unconfirmed complete remission. Results: We identified 151 patients with newly diagnosed MM and available %Ki67 expression who received first-line therapy over the period of 2005-2010. Patient were subdivided into two groups based on %Ki67: Low: %ki67 <= 5%, n = 87; and High: %Ki67 >5, n=64, to allow for comparison of treatment response and survival analysis. Specific therapeutic agent exposure history did not differ significantly between patients. Both groups had similar depth of response rates (ORR) to front-line therapy, Table 1. Median progression-free survival for the high versus low %Ki67 groups approached statistical significance at 54 months (95% CI 30.8,67.4) versus 26.9 months (95% CI 21.6,40.2), respectively (P = 0.083). At data cut-off, there were 30 deaths in the low %Ki67 group (1-yr OS 93%, 5-yr OS 71%) and 36 deaths in the high %Ki67 group (1-yr OS 94%, 5-yr OS 62%). Median overall survival (OS) was not reached for Ki67% <= 5% (95% CI 97.3,NR) vs. 78.9 months (95% CI 55.9,93.1) for Ki67% > 5%, (P = 0.0434), Figure 1. Multivariate cox regression for factors with influence on OS showed that only high-risk cytogenetics (HR 2.05, 95% CI 1.17, 2.92, P = 0.027), ISS (HR 1.835, 95% CI 1.33, 3.60, P = 0.000), and %Ki67 group status had an independent effect on survival outcome. Low (<=5%) versus high (>5%) %Ki67 influenced overall survival with a hazard ratio of 1.76 (CI 1.07,2.92, P = 0.027). Survival after ASCT was significantly longer in the low %Ki67 group with median OS not reached (95%CI, 97.3, NR) versus 86.9 months (95% CI 43.9, NR) for high %Ki67 group (P = 0.04). Discussion: The ratio of IHC double positive Ki67 and CD138 of > 5% is an independent prognostic marker for overall survival in newly diagnosed MM undergoing 1st line therapy. The %Ki67 serves as a simpler and widely available analog to PCLI that can be presently performed in most hematopathology laboratories. Table 1: First Line Treatment and Best Response (modified IMWG Criteria) Ki67% <= 5(N = 87)n (%) Ki67% > 5(N = 64)n (%) P Treatment Exposure* Lenalidomide 59 (67.8) 48 (75) 0.34 Thalidomide 30 (34.5) 14 (21.9) 0.09 Bortezomib 25 (28.7) 14 (21.9) 0.34 Alkylating agent 11 (12.6) 4 (6.3) 0.19 ASCT 27 (31) 22 (34.4) 0.66 Best Response Overall Response (>= Partial response) 77 (88.4) 57 (89.1) 0.41 Complete response 15 (17.2) 22 (34.4) Unconfirmed complete response** 14 (16.1) 8 (12.5) Very good partial response 23 (26.4) 15 (23.4) Partial response 25 (28.7) 12 (18.8) Stable disease 9 (10.3) 5 (7.8) Progressive disease 1 (1.2) 2 (3.1) * Percentages do not add to 100% due to instances of concurrent therapy use ** Unconfirmed complete response: immunofixation negative, but no confirmatory bone marrow biopsy available Figure 1 Overall Survival by %Ki67 Figure 1. Overall Survival by %Ki67 Disclosures Mark: Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Millennium: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Onyx: Research Funding, Speakers Bureau. Rossi:Celgene: Speakers Bureau. Pekle:Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Millennium: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Perry:Celgene: Speakers Bureau. Coleman:Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Millennium: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Onyx: Honoraria. Niesvizky:Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Millennium: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Onyx: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau.

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Genotype-Resultant Morphology of Myelodysplastic Syndromes (MDS)

Blood ◽

10.1182/blood-2018-99-119345 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 1824-1824

Author(s):

Abhinav Goyal ◽

Inom Mirzaev ◽

Mohammad Fahad B. Asad ◽

Hassan Awada ◽

Cassandra M. Hirsch ◽

...

Keyword(s):

Board Of Directors ◽

Clinical Features ◽

Chromosomal Abnormalities ◽

Genetic Alterations ◽

Advisory Committees ◽

Ras Pathway ◽

Objective Standard ◽

Molecular Events ◽

Molecular Context ◽

Diagnosis And Classification

Abstract Morphology has dominated the diagnosis and classification of MDS for decades. With the advent of NGS, morphology is used as a gold standard to assess associations of specific disease sub-entities with individual mutations or their combinations. An example is the association between SF3B1 mutations and ringed sideroblasts, or with disease-defining lesions, such as t(8:21), 11q23 translocations, and EVI1 mutations. Beyond these discrete examples, assignments of diverse morphologic features to combinations of specific genotypes has been more challenging. To identify potentially novel paradigms of associations between molecular hits and morphologies we examined 835 patients with MDS. Common somatic mutations, chromosomal abnormalities and morphologic reviews were subjected to blinded, objective standard diagnostic criteria. Abnormalities included individual lineage dysplasia and cytopenias, monocytosis, fibrosis, and increased megakaryocytes, all classified using standard criteria. To correlate the presence of mutations to morphologic criteria, only mutations with a clonal burden >10% were used. In total, 794 out of 835 patients (95%) harbored at least one lineage dysplastic feature. Myeloid, erythroid and megakaryocytic dysplasia occurred in 56% (470/835), 71% (590/835) and, 70% (587/835) of patients, respectively. Bi- and tri-lineage dysplasia were also identified in 36% (297/835) and 33% (278/835). In 90% (753/835) of patients there was cytopenia: 48% (402/835) had neutropenia, 61% (510/835) anemia, and 61% (510/835) thrombocytopenia. More than 50% of patients had multiple-cytopenias; 23% (194/835) had pancytopenia. Monocytosis was present in 20% (168/835) of patients and 31% (256/835) had elevated numbers of megakaryocytes. For analysis all possible combinations (25 pairs in total) were queried and those present in >80 patients were evaluated. Based on NGS among 36 genes, TET2 (27%), SF3B1 (23%), ASXL1 (19%), del(5q) (16%), SRSF2 (14%), DNMT3A (11%) and del(7q) (10%),, were frequently mutated genes/CNAs, each present in >10% of patients. A number of relationships between phenotypic features and molecular context were uncovered. For example, patients with thrombocytopenia also commonly had tri-lineage dysplasia [38% (198/510) vs. 25%, (80/325), p<.001, q<.001] or more myeloid dysplasia [63% (321/510) vs. 46% (149/325), p<.0001, q<.0001] but no megakaryocyte dysplasia [72% (366/510) vs. 68% (221/325), p=.027]. Moreover lineage specific dysplasia was not associated with lineage specific cytopenias. In fact, myeloid or erythroid dysplasia had no significant association with neutropenia or anemia (p=.14 or p=.1, respectively). When we performed statistical analyses that sought correlations between clinical features and genetic alterations, 78 significant associations were identified. For instance, patients with erythroid dysplasia more frequently had SF3B1 mutations [in 15% of erythroid dysplasia patients, 90/590] than patients without it [6%, 15/245] (p=.0002, q=.001). In contrast, these patients were less likely to have EZH2 mutations [4.2% (25/590) vs. 11.4% (28/245), p<.001, q=.002]. Compared to patients with no myeloid dysplasia, patients with myeloid dysplasia were more likely to have TET2, STAG2, and SRSF2 mutations, and less likely to have SF3B1 mutations (p<.02). Compared to patients without megakaryocytic dysplasia, those with it more commonly had ASXL1, mutation, but less commonly SF3B1 and BCORL1 mutations. Patients with STAG2 mutations [8%, 66/835] were more likely to have neutropenia [62% (41/66) vs. 47% (361/769), p=.02, q=.08]. TP53 and ASXL1 mutations occurred frequently in patients with thrombocytopenia. Monocytosis co-existed more with 5 genetic mutations, including SRSF2 and RAS pathway genes. Using various conventional and more advanced strategies, we present the first comprehensive genotype-phenotype association study that linked somatic molecular events to morphologic and clinical features. We demonstrate that the complexities of how molecular context governs morphologic changes can be deciphered. Certain rigorously defined morphologic configurations show specific associations with individual mutations or their combinations. Disclosures Nazha: MEI: Consultancy. Sekeres:Opsona: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Opsona: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees. Maciejewski:Apellis Pharmaceuticals: Consultancy; Ra Pharmaceuticals, Inc: Consultancy; Apellis Pharmaceuticals: Consultancy; Alexion Pharmaceuticals, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Alexion Pharmaceuticals, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Ra Pharmaceuticals, Inc: Consultancy.

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Safety and Efficacy of JAK Inhibitor Therapy in BCR-ABL Negative MPN Patients with Underlying Portal Hypertension

Blood ◽

10.1182/blood-2021-149696 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 3652-3652

Author(s):

Marta Davidson ◽

Elliot Smith ◽

Dawn Maze ◽

Hassan Sibai ◽

Vikas Gupta ◽

...

Keyword(s):

Overall Survival ◽

Portal Hypertension ◽

Adverse Events ◽

Board Of Directors ◽

Research Funding ◽

Splanchnic Circulation ◽

Inhibitor Therapy ◽

Jak Inhibitor ◽

Advisory Committees ◽

Safety And Efficacy

Abstract Background The BCR-ABL-negative Myeloproliferative neoplasms (MPNs) are clonal stem cell disorders characterized by constitutive activation of the JAK-STAT pathway that include Polycythemia Vera, Essential Thrombocytosis, Primary (PMF) and Secondary Myelofibrosis (SMF). Splenomegaly is a characteristic feature of MPNs that can be ameliorated by JAK inhibitors (JAKi). Up-to one-third of MPN patients also experience portal hypertension (PH). Thrombosis of the splanchnic circulation is the most widely recognized etiology of PH in MPNs, however PH also occurs in the absence of intra-abdominal thrombosis. The influence of PH on outcomes of JAKi therapy in MPN patients has not been characterized. To this end, we aimed to determine the safety and efficacy of JAKi therapy in MPN patients complicated by PH with and without underlying splanchnic circulation thrombosis (ST). Methods All patients with MPNs assessed at Princess Margaret Hospital between 01/1998 and 01/2021 were identified from the MPN program's database. Patients who had undergone esophagogastroduodenoscopy (EGD) and had endoscopic evidence of PH, namely esophageal or gastric varices or portal hypertensive gastropathy were included. The study population was further limited to patients who started JAKi therapy following diagnosis of PH. Outcomes were compared between patients with and without underlying ST. The primary endpoint was palpable spleen reduction at 24 weeks. Secondary endpoints included best palpable spleen reduction within one year of starting JAKi, improvement in PH severity as determined by serial EGD assessments during JAKi therapy, overall survival, and ≥grade 3treatment emergent adverse events. Statistical differences in the frequencies of baseline characteristics were assessed using the Wilcoxon rank sum and Chi-Square tests. Overall-survival (OS) estimates were calculated by the Kaplan-Meier method using STATA/IC 16.1 software. Results All MPN patients with evidence of PH on endoscopy who started JAKi therapy after diagnosis of PH were included (n=33). Thirteen patients experienced ST prior to the start of JAKi. The proportion of younger patients and those with PH-related complications (i.e., variceal bleeding and/or ascites) was higher in patients with underlying ST (5/20 [25%] vs 9/13 [69%], p=0.01). The median palpable spleen change at approximately 24 weeks of therapy and the best palpable spleen reduction within the first year of therapy was -40.5% ([-100%[ -[+100%]) and -50% ([-100%]-0%) in the entire cohort, respectively. Better spleen responses with JAKi therapy were observed in PH patients without prior ST compared to those with underlying ST (median palpable spleen change at approximately 24 weeks was -58% (-24%-(-100%)] (n=13) vs -26.5% ([-100%]-[+100%]) (n=9), p=0.062; median best palpable spleen change at any time within 1 year of JAKi therapy start was -71% ([-14%]) -[-100%]) (n=17) vs -35% ([0%-[-100%]) (n=9), p=0.045). Of 21 patients with serial EGDs during JAKi treatment, improvement in PH severity as observed in 8 (38%). There were no differences in survival between patients with and without prior ST. Grade 3 treatment-emergent adverse events included anemia (5/33 [15%]), thrombocytopenia (5/33 [15%]), neutropenia (1/33 [3%]), and suspected Wernicke encephalopathy associated with Momelotinib (1/33 [3%]). Conclusion: In this observational study, JAK inhibitor therapy appears to be safe and effective in MPN patients complicated by PH, with a trend towards improved spleen responses among portal hypertensive patients without splanchnic circulation thrombosis. Disclosures Maze: Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene-BMS: Honoraria; Takeda: Research Funding; PharmaEssentia: Research Funding; Kronos Bio: Research Funding. Gupta: AbbVie: Consultancy, Honoraria; Incyte: Honoraria, Research Funding; Sierra Oncology: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Constellation Pharma: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Consultancy; Pfizer: Consultancy; BMS-Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees.

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Impact of Genomic Alterations on Outcomes in Myelofibrosis Patients Undergoing JAK1/2 Inhibitor Therapy

Blood ◽

10.1182/blood.v128.22.4263.4263 ◽

2016 ◽

Vol 128 (22) ◽

pp. 4263-4263

Author(s):

Jay Spiegel ◽

Caroline Jane McNamara ◽

Andrea Arruda ◽

Tony Panzarella ◽

James A. Kennedy ◽

...

Keyword(s):

Treatment Failure ◽

Board Of Directors ◽

Research Funding ◽

Univariate Analysis ◽

Inhibitor Therapy ◽

Jak Inhibitor ◽

Jak Inhibitors ◽

Advisory Committees ◽

Number Of Patients

Abstract Introduction: The advent of next generation sequencing (NGS) has brought intense interest to the complex genetic landscape of myeloproliferative neoplasms (MPN). However, data regarding clinical outcomes in the context of novel MPN therapies such as JAK inhibitors are scarce. Limited data indicate that high molecular risk signature (HMR, presence of at least one mutation in ASXL1, EZH2, IDH1/2, SRSF2) or multiple mutations may be associated with decreased spleen response and a shorter time to discontinuation of Ruxolitinib in myelofibrosis (Patel et al, Blood 2015). Methods: All myelofibrosis patients seen in the MPN program at Princess Margaret Hospital between November 2009 and May 2016 and treated with JAK1/2 inhibitor therapy were identified. NGS molecular profiling of 54 genes (39 hotspot region; 15 complete coding region coverage) was performed on peripheral blood or bone marrow samples using the TruSight Myeloid Sequencing Panel. Reporting was restricted to well-covered, exonic nonsynonymous, intronic splice site, and known pathogenic synonymous variants. Variants with global mean allele frequency >1% were identified using multiple population databases (1000 genomes, ESP, ExAC) and excluded. The primary endpoint was time from start of JAK1/2 inhibitor therapy to treatment failure (TTF) defined as treatment discontinuation, progression to accelerated phase or leukemic transformation, spleen progression or death. Secondary endpoints included best spleen, anemia and IWG response achieved by 48 weeks of treatment and overall survival. Response was assessed according to the 2013 revised IWG-MRT criteria. Transfusion dependency was assessed as any transfusion in 12 weeks prior to treatment or being identified as transfusion dependent in medical history. Results: Of 159 patients treated with JAK1/2 inhibitors at our institution, 102 met the inclusion criteria (see Table 1). Patients were excluded if; no sample was available for analysis (19), short use of JAK inhibitor prior to transplant (9), active clinical trial (5), in accelerated phase/acute leukemia (4) and others (20). First JAK inhibitor used was ruxolitinib in 77 patients and momelotinib in 25. At least one mutation was identified in every patient. Twenty (20%) patients had one mutation, 32 (31%) had 2 mutations and 50 (49%) patients had ≥ 3 mutations. Eighty (82%) patients had the JAK2V617F mutation, 15 (15%) had mutations in CALR, 4 (4%) had MPL mutations and one patient was triple negative. One patient had mutations in both CALR and JAK2 while another had mutations in MPL and CALR. Forty-eight (47%) patients had mutations consistent with HMR profile. Mutation profile is summarized in Table 2. With median follow-up of 2.5 years, 51 (50%) patients experienced treatment failure. On univariate analysis, TTF was associated with DIPSS, pre-treatment transfusion status and Hb <100 prior to initiating JAK inhibitor therapy. However, TTF was not associated with specific driver mutations, the number of mutations or HMR profile. Exploratory analysis of genes mutated in ≥5% of the population showed EZH2 (p=0.004) and CBL (p=0.005) mutated patients had shorter TTF. Multi-variable analysis employing anemia <100 and DIPSS with either of the number of mutations or HMR profile did not show any association with TTF. There was a trend towards TTF in patients with Hb<100 (HR 2.21, 95%CI: 0.99-4.95, p=0.05). Of 102 patients, 91 were evaluable for spleen response with 43 (47%) achieving a spleen response by 48 weeks of treatment. Twelve (23%) of the 53 patients evaluated met criteria for anemia response. Neither spleen nor anemia response was associated with the use of a particular JAK inhibitor. Of the 95 patients with at least 48-week follow-up, best response while on treatment was clinical improvement and spleen response in 29 (31%) and 19 (20%) patients respectively. Conclusions: In this study of myelofibrosis patients treated with JAK inhibitors, EZH2 and CBL mutated patients had shorter TTF. We did not find any association between TTF and number of mutations or other high risk mutations such as ASXL1/SRSF2. Anemia was the only significant independent predictor of shorter TTF. Our findings highlight the need for multicenter collaborative studies on a large number of patients and cautious use of mutation profiling results in routine clinical decision making with current treatment approaches. Spiegel and McNamara are co-primary authors. Disclosures Panzarella: Cellgene: Consultancy. Schimmer:Novartis: Honoraria. Schuh:Amgen: Membership on an entity's Board of Directors or advisory committees. Yee:Novartis Canada: Membership on an entity's Board of Directors or advisory committees, Research Funding. Kamel-Reid:BMS: Research Funding. Gupta:Novartis: Consultancy, Honoraria, Research Funding; Incyte Corporation: Consultancy, Research Funding.

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Prognostic Value of Circulating Bcl-2/Igh Levels before and after Treatment in 415 Patients with Advanced Follicular Lymphoma Receiving First-Line Immuno-Chemotherapy in 2 Prospective StiL Trials - the Effect of Rituximab Maintenance

Blood ◽

10.1182/blood-2018-99-118750 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 4149-4149

Author(s):

Guido Kobbe ◽

Sabrina Pechtel ◽

Fabian Zohren ◽

Jürgen Barth ◽

Alexander Christoph Burchardt ◽

...

Keyword(s):

Prognostic Factor ◽

Maintenance Therapy ◽

Follicular Lymphoma ◽

Board Of Directors ◽

Research Funding ◽

The Other ◽

First Line ◽

Advisory Committees ◽

Rituximab Maintenance

Abstract Introduction. The prognosis of patients with follicular lymphoma (FL) has improved during recent years following the introduction of immuno-chemotherapy and Rituximab maintenance. Nevertheless, some patients still relapse early and have a poor prognosis. Several prognostic scoring systems have been developed using clinical, laboratory as well as molecular data, while the early identification of high-risk patients remains a challenge. In this context, the relevance of circulating bcl2/IgH levels for patient stratification is not clear. We could show that high circulating bcl2/IgH levels in the peripheral blood (PB) before therapy were an independent adverse prognostic factor for progression free survival (PFS) in patients receiving R-CHOP or Bendamustine-Rituximab (B-R) in the NHL1 study of the German StiL group (Zohren et al, Blood 2015). Methods. Using a sensitive quantitative PCR method as previously described (Zohren et al, Blood 2015), a total of 2,491 circulating bcl-2/IgH level analyses were performed on PB samples before (n=415) and after (n=305) 6 cycles first-line immuno-chemotherapy and during follow-up (n=1,771). Results of these molecular studies were correlated with clinical outcome. We first present a 10-year update of the 107 bcl2/IgHpositive patients from the StiL-NHL1-trial. Secondly, we report the results from the StiL-NHL7-trial including bcl2/IgH analyses of 308 bcl2/IgHpositive patients who received B-R and Rituximab maintenance. Results. With a median follow-up of 10 years in the 107 bcl2/IgHpositive patients from the StiL-NHL1-trial, high PB bcl-2/IgH levels (bcl-2/IgH to reference gene (tPA) ratio >1) before treatment as compared to low (ratio <1) levels remained a major independent prognostic factor for PFS (median 22 vs 71 months, HR 2.27, 95% CI 1.37-3.75; p=0.001). We also confirm that patients who were still bcl-2/IgHpositive after six cycles of immuno-chemotherapy had significantly inferior PFS (13 vs 79 months, Hazard Ratio (HR) 2.97, 95% CI 1.53-5.78; p=0.001) and overall survival (OS, 128 months vs not reached , HR 3.90, 95% CI 1.39-11.00; p=0.010). In contrast, among the 308 bcl-2/IgHpositive patients of the StiL-NHL7-trial, who all received B-R and Rituximab maintenance, PB bcl-2/IgH levels (ratio >1 vs <1) before therapy were no longer prognostic for PFS (99 months vs not reached, HR 1.06, 95% CI 0.66 - 1.69; p=0.814) or OS. On the other hand, being bcl-2/IgHpositive after 6x B-R remained a poor prognostic factor for PFS (43 months vs not reached, HR 2.44, 95% CI 1.18-5.04; p=0.016 ) and OS (72 months vs not reached, HR 4.03, 95% CI 1.82-8.96; p=0.001) despite Rituximab maintenance. When comparing StiL-NHL1 and StiL-NHL7 patients with respect to bcl-2/IgH levels and the effect of Rituximab maintenance, we found that Rituximab maintenance led to a significantly better PFS. In patients with low (ratio <1) bcl-2/IgH levels before therapy the hazard ratio of 1.7 was modest (71 months vs not reached, HR 1.70, 95% CI 1.16-2.50; p=0.006) in comparison to 3.46 as observed in patients with high (ratio >1) bcl-2/IgH levels (22 vs 99 months, HR 3.46, 95% CI 1.93-6.20; p<0.000). These findings suggest that patients with high bcl-2/IgH levels before therapy have a greater benefit from Rituximab maintenance therapy. There was no difference with regard to OS between StiL-NHL1 and StiL-NHL7 patients who were still bcl-2/IgHpositive after 6 cycles of immuno-chemotherapy implying that these patients may not benefit from Rituximab maintenance. Conclusion. High circulating bcl-2/IgH levels in the PB before first line therapy identify a subgroup of patients with advanced FL who have significantly shorter PFS after standard immuno-chemotherapy. These patients greatly benefit from the addition of Rituximab maintenance, because pre-treatment bcl-2/IgH levels lose their predictive value with Rituximab maintenance therapy. On the other hand, patients who remain bcl-2/IgHpositive after standard immuno-chemotherapy have short PFS and OS despite treatment with Rituximab maintenance and therefore are candidates for experimental treatment approaches. Disclosures Kobbe: Amgen: Honoraria, Research Funding; Roche: Honoraria, Research Funding; Celgene: Honoraria, Other: Travel Support, Research Funding. Zohren:Pfizer Inc.: Employment. Buske:Roche: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Bayer: Research Funding. Germing:Celgene: Honoraria, Research Funding; Janssen: Honoraria; Novartis: Honoraria, Research Funding. Greil:Sandoz: Honoraria, Research Funding; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; MSD: Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Merck: Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astra Zeneca: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES, Research Funding; Janssen: Other: TRAVEL, ACCOMMODATIONS, EXPENSES. Schroeder:Celgene: Consultancy, Honoraria, Research Funding. Rummel:Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria; Astellas: Honoraria; Eisai: Honoraria; Mundipharma: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Symbio: Honoraria; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees.

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Chemotherapy Based Salvage Regimens Are Associated with Poor Outcomes in Refractory Classical Hodgkin Lymphoma

Blood ◽

10.1182/blood-2020-138815 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 21-21

Author(s):

Ashley Rose ◽

Dakota Jenneman ◽

Leidy Isenalumhe ◽

Julio C. Chavez ◽

Bijal Shah ◽

...

Keyword(s):

Overall Survival ◽

Board Of Directors ◽

Univariate Analysis ◽

Salvage Chemotherapy ◽

Late Relapse ◽

Classical Hodgkin Lymphoma ◽

First Line ◽

Advisory Committees ◽

Line Therapy ◽

The Difference

Introduction: The management of classical Hodgkin lymphoma (cHL) with first line therapy continues to evolve resulting in some of the best outcomes in oncology. Around 20-30% of patients with cHL relapse and have to undergo salvage chemotherapy followed by autologous hematopoietic cell transplant (Auto HCT). There are no randomized trials comparing the most common regimens used in second line to date. With the introduction of newer agents in the treatment of cHL, it is essential to identify patients that might benefit from a different approach in first salvage setting. The aim of this study is to assess patterns of relapse and differences in outcomes based on salvage regimens. Methods: We retrospectively identified 193 consecutive patients with cHL treated in our academic medical center. Adult patients treated with ABVD (Adriamycin, Bleomycin, Vinblastine, Decarbazine) for first line were included. The three most common salvage regimens used in our institution included ICE (Ifosfamide, Carboplatin, Etoposide), ESHAP (Etoposide, Steroids, Ara-C, Cisplatin), or IGEV (ifosfamide, Gemcitabine, Vinorelbine). Patients were divided into two groups: those progressing during ABVD or relapsing within 1 year are considered (refractory) versus all other as (late-relapse). Response to salvage therapy and performance of Auto HCT were compared using Chi-square test. Univariate comparison of OS was conducted using Log-rank test. Results: The majority of patients were refractory to front line therapy (69%). As expected, there was predominance of male gender (61%), with median age of 35 yrs (range 13-68 yrs). The distribution of baseline characteristics did not seem to be different between the two groups (Table 1). Refractory patients were more likely to have B symptoms and higher ESR on presentation (Table 1). Of the refractory patients, the majority had initial response to therapy then relapsed within 1 year (65%). On Univariate analysis, late-relapse patients had better overall survival compared to refractory disease (13.5 yrs vs 9 yrs respectively) (p<0.005) (Figure 1). The majority of the patients in both groups received ICE as the primary regimen, followed by ESHAP and IGEV (Table 1). The CR rate was not statistically different among the three salvage regimens (ICE, ESHAP, IGEV as 37%, 29%, 53% respectively) (P=0.248). Late-relapses were more likely to obtain a complete response (CR) to salvage therapy (48% vs 32% respectively) (P=0.025). However, when CR rate stratified by salvage regimen, only refractory patients treated with ICE demonstrated statistically significant worse CR rate compared to late-relapse treated with ICE (32% vs 48% respectively) (P=0.047). The difference was not statistically different for ESHAP and IGEV. While there was a difference in CR rate between relapsed and refractory patients, the difference was not observed in the rate of consolidative Auto HCT between the two groups. On univariate analysis, Auto HCT was associated with improved median overall survival compared to no Auto HCT (11.3 yrs vs 1.6 yrs, respectively) (P<0.001). Conclusions: To our knowledge, this is the largest retrospective comparison study on the outcome of the most common salvage chemotherapy regimens in cHL. Our study highlights the unmet need early introduction for novel non chemotherapy-based interventions in refractory patients. It also shows the consistent CR rate in real world experience in comparison with clinical trials and persistent need for Auto HCT in the salvage setting in the current chemotherapy era. Disclosures Chavez: BeiGene:Speakers Bureau;Bayer:Consultancy;Merck:Research Funding;Morphosys:Consultancy, Speakers Bureau;AstraZeneca:Speakers Bureau;Celgene:Consultancy;Novartis:Consultancy;AbbVie:Consultancy;Genentech:Speakers Bureau;Epizyme:Speakers Bureau;Gilead:Consultancy;Karyopharm:Consultancy;Kite, a Gilead Company:Consultancy, Speakers Bureau;Verastem:Consultancy;Pfizer:Consultancy.Shah:Kite/Gilead, Jazz, Incyte:Research Funding;Moffitt Cancer Center:Current Employment;NCCN: Vice-Chair, Acute Lymphoblastic Leukemia Working Group:Membership on an entity's Board of Directors or advisory committees;Kite/Gilead, Celgene/Juno/BMS, Novartis, Pfizer, Amgen, Spectrum/Acrotech, Precision Biosciences, Beigene, AstraZeneca, Pharmacyclics/Jansen, Adaptive:Honoraria;Kite/Gilead, Precision Biosciences, Novartis, AstraZeneca:Other: TRAVEL, ACCOMMODATIONS, EXPENSES.Sokol:EUSA Pharma:Consultancy, Honoraria, Speakers Bureau;Kyowa/Kirin Inc.:Membership on an entity's Board of Directors or advisory committees;Kymera Therapeutics:Membership on an entity's Board of Directors or advisory committees.Pinilla Ibarz:Takeda:Consultancy, Speakers Bureau;AstraZeneca:Consultancy, Speakers Bureau;Abbvie:Consultancy, Speakers Bureau;Novartis:Consultancy;Sunesis Pharmaceuticals:Consultancy;TG Therapeutics:Consultancy;Sanofi:Consultancy;Pharmacyclics:Consultancy, Speakers Bureau;Janssen:Consultancy, Speakers Bureau.Bello:Celgene:Consultancy, Honoraria, Speakers Bureau;Seattle Genetics:Consultancy, Honoraria, Speakers Bureau.

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Minimal Residual Disease Is a Predictor for Progression-Free and Overall Survival in Chronic Lymphocytic Leukemia (CLL) That Is Independent of the Type or Line of Therapy.

Blood ◽

10.1182/blood.v114.22.540.540 ◽

2009 ◽

Vol 114 (22) ◽

pp. 540-540 ◽

Cited By ~ 8

Author(s):

Marwan Kwok ◽

Andy C. Rawstron ◽

Abraham Varghese ◽

Peter Hillmen

Keyword(s):

Overall Survival ◽

Board Of Directors ◽

Minimal Residual Disease ◽

Residual Disease ◽

First Line ◽

Advisory Committees ◽

First Line Therapy ◽

Line Therapy ◽

Line Of Therapy ◽

Minimal Residual

Abstract Abstract 540 The depth of remission in CLL correlates with survival in a large number of trials regardless of the therapy used and the depletion of minimal residual disease (MRD), when reported, is usually associated with improved progression free and overall survival. However it is not clear whether this improved outcome is due to the attainment of MRD negativity or whether MRD eradication is a surrogate for other variables that predict for good response. In order to address the true impact of achieving MRD negativity we present data from 137 patients with CLL who were treated between 1996 and 2007, achieved a good clinical response and had bone marrow examined post-therapy to assess remission status including MRD. The MRD assessment was performed in a single laboratory (HMDS, Leeds, UK) using multicolor flow cytometry capable of detecting minimal residual disease (MRD) to a level of one CLL cell in 10000 leukocytes as recently recommended in the IWCLL Guidelines. Patients were followed for a median duration of 3.1 years (range 0.2 - 12.7) after treatment with chlorambucil (n=13), fludarabine (n=17), fludarabine and cyclophosphamide (n=58), fludarabine and cyclophosphamide with mitoxantrone and/or rituxumab (n=8), alemtuzumab (n=29), autologous stem cell transplantation (n=7) and various other treatments (n=5). Of these, 48 achieved a complete response (CR), 24 achieved a CR with incomplete marrow recovery (CRi), 27 achieved a nodular partial response (nPR) and 38 achieved a partial response (PR). Altogether 58 individuals (42.3%) were MRD negative at the end of treatment, including 28 CR, 20 CRi, 3 nPR and 7 PR patients. Results of the univariate and multivariate analyses are summarized below: Age, number of prior therapies and MRD negativity were independently correlated with overall survival. MRD negativity in the marrow at the end of therapy was independently significant in multi-variate analysis including when analysed against age, stage, prior therapy, IWCLL response assessment and cytopenia. One of the most striking findings was in patients having their first CLL treatment. Of the 58 patients in this series who had achieved a clinical response to first line therapy 24 patients (21 patients following FC, 1 FCR, 1 chlorambucil and 1 fludarabine à autologous SCT) achieved an MRD-negative remission and 34 were MRD-positive. With a median follow-up of 38 months (range 7-153) the 5 year PFS for MRD negative patients was 89% (95% CI 55-97%) compared to 0% for the MRD positive patient (95% CI <1%) and the 5 year OS was 95% (95% C.I. 61-99%) vs 53% (95% C.I. 15-74%) for MRD-negative vs. MRD-positive patients, respectively. Although achieving MRD-negativity with subsequent therapy is relatively beneficial, the greatest differences in outcome were seen in front-line treatment. This data suggests that achieving MRD-negativity after first-line therapy has a profound effect on overall survival. In conclusion, we demonstrate that achieving MRD negativity in CLL is an independent predictor of survival in multivariate even when a variety of different treatment approaches are considered and regardless of the line of therapy.. This is the strongest evidence yet that achieving MRD negativity is the most appropriate aim of therapy in CLL for patients who are fit enough for such an approach. Furthermore patients who achieve MRD negativity after their first therapy have a 5 year PFS of 89% and a 5 year overall survival of 95% suggesting that the optimal time to attempt to achieve MRD negativity is with first line therapy. Disclosures: Hillmen: Roche Pharmaceuticals: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; GlaxoSmithKline: Consultancy, Membership on an entity's Board of Directors or advisory committees.

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Clinical Significance of Emergent Leukocytosis in Patients with Myelofibrosis Receiving JAK Inhibitor Therapy

Blood ◽

10.1182/blood-2020-139936 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 22-22

Author(s):

Radovan Vasic ◽

Yuliang Shi ◽

Andrea Arruda ◽

Sarah Malik ◽

Jaime Claudio ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Median Overall Survival ◽

Female Gender ◽

Clinical Parameters ◽

Jak Inhibitor ◽

First Line ◽

Advisory Committees ◽

Paired Samples ◽

New Mutations

Ruxolitinib is the first available JAK inhibitor (JAKi) therapy for amelioration of constitutional symptoms or splenomegaly in myelofibrosis (MF). Duration of response varies, as patients discontinue ruxolitinib due to disease progression or drug toxicity. Ruxolitinib failure is a poorly defined clinical entity, but may include suboptimal or lost spleen response, worsening cytopenias, accelerated or blast phase (AP/BP) progression, or non-hematologic side effects. It is not clear what other clinical parameters should be considered indicative of JAKi failure. Leukocytosis is a known prognostic factor in MF and is included in various prognostic models. We have observed that some patients on stable doses of JAKi therapy develop progressive leukocytosis in the absence of other signs of MF progression. The significance of this event is not known, and it is not clear whether the onset of leukocytosis should prompt changes in clinical management. To assess the clinical significance of emergent leukocytosis, we evaluated leukocyte counts in our database of MF patients receiving Ruxolitnib or Momelotinib as first-line JAKi therapy. We defined emergent leukocytosis as any of:New onset of WBC ≥25 x 109/L in patients with WBC ≤12.5 x 109/L at JAKi start.Doubling of WBC from the nadir value in patients with WBC >12.5 x 109/L at JAKi start and nadir WBC >12.5 x 109/L.WBC ≥25 x 109/L in patients with WBC > 12.5 x 109/L at JAKi start after attaining a nadir WBC ≤12.5 x 109/L. Leukocytosis had to be sustained over consecutive blood counts at least one month apart and had to occur in the absence of infection, steroid therapy, AP/BP transformation, splenectomy or JAKi dose reduction. Exclusion criteria included concurrent hematologic diagnoses, and splenectomy or AP/BP MF preceding JAKi initiation. Of 290 patients with MF receiving JAKi therapy, 217 met study criteria. Of these 217 patients, 27 developed emergent leukocytosis while receiving JAKi. The cumulative incidence of leukocytosis was 4%, 10% and 15% at 1, 3, and 5 years from the start of JAKi therapy, respectively. Transformation to AP/BP, splenectomy, bone marrow transplant, or death from any cause were considered as competing risks in the calculation of cumulative incidence. In a multivariate analysis, clinical parameters associated with emergent leukocytosis included presence of baseline anemia (HR 4.94 [95% CI, 1.13-21.53]; p = 0.03) or leukocytosis (HR 5.01 [95% CI, 1.44-17.41]; p = 0.01) at JAKi start and female gender (HR 0.21 for male [0.08-0.06]; p=0.002). Baseline leukocytosis as WBC ≥25 x 109/L, and anemia was as a hemoglobin <100g/L. In patients with available targeted sequencing performed prior to JAKi therapy (n=141, 65%), TET2 mutations were associated with increased risk of leukocytosis (HR 5.48 [95% CI, 1.73-17.35]; p=0.004), but JAK2, CALR, MPL or ASXL1 mutations were not. Among 27 patients who experienced emergent leukocytosis, 21 were deceased while 6 are in ongoing follow-up. Median overall survival calculated from the date of leukocytosis was 14 months [95% CI, 8.6-27.9]. Overall, 7 patients transformed to AP/BP, 7 died from progressive MF, 4 underwent transplant, one underwent splenectomy, 6 died of miscellaneous causes and two remain on first-line JAKi without any complicating events. Among 27 patients experiencing leukocytosis, paired samples for molecular analysis at JAKi initiation and at the time of leucocytosis were available in 21 (78%). Results from targeted sequencing of a panel of 49 myeloid genes were available from 4 patients with paired samples (Table 1). New mutations at leukocytosis were seen in NRAS and CEBPA in the first patient, KRAS and SH2B3 in the second, and CBL in the third. The fourth patient acquired no new mutations but demonstrated marked expansion of a dominant clone. The remaining 17 paired samples have been submitted for sequencing with results pending. In summary, MF patients with baseline anemia, leukocytosis, or female gender are at higher risk for emergent leucocytosis while on JAKi therapy. The median overall survival of 14 months in patients who experience emergent leukocytosis is comparable to that observed in patients following ruxolitinib failure. Our data also suggest that onset of leukocytosis may be indicative of underlying clonal evolution, which will need to be confirmed in a larger number of patients. These findings suggest consideration of emergent leukocytosis as a criterion for JAKi failure in MF. Disclosures Maze: Novartis: Honoraria; Pfizer: Consultancy; Takeda: Research Funding. Gupta:Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Sierra Oncology: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bristol MyersSquibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy; Incyte: Honoraria, Research Funding.

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Epidemiology, Clinical Features, and Outcome of HTLV-1-Related Adult T-Cell Leukemia/Lymphoma in Latin America: A Study from the Latin American Group of Lymphoproliferative Disorders (GELL)

Blood ◽

10.1182/blood-2020-140630 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 18-21

Author(s):

Luis E Malpica Castillo ◽

Daniel J Enriquez ◽

Denisse A. Castro ◽

Camila Peña ◽

Henry Idrobo ◽

...

Keyword(s):

T Cell ◽

Board Of Directors ◽

Clinical Features ◽

Latin American ◽

Research Funding ◽

T Cell Leukemia ◽

Cell Leukemia ◽

First Line ◽

Advisory Committees ◽

Adult T Cell Leukemia

INTRODUCTION: Adult T-cell leukemia/lymphoma (ATLL) is a mature peripheral T-cell neoplasm caused by the Human T-cell Leukemia Virus Type 1 (HTLV-1). HTLV-1 infects up to 10 million people worldwide and is most endemic in Southwestern Japan, the Caribbean basin, South America, and Western Africa. In Latin America (LA), Peru and Brazil have the highest prevalence of HTLV-1-related diseases, however, data on ATLL in other LA countries is scarce. ATLL carries a dismal prognosis and is essentially incurable by conventional drugs. We describe the epidemiology, clinical features, treatment, and disease outcome of ATLL encountered in 11 countries in LA. METHODS: We retrospectively analyzed patients (pts) diagnosed with ATLL between January 1995 and December 2019. ATLL cases were classified according to the Shimoyama criteria into acute (A), lymphomatous (L), chronic (C) and smoldering (S). Treatment approaches used as first-line therapy were: 1) chemotherapy alone; 2) combined chemotherapy with zidovudine/interferon-alpha (AZT-IFN); and 3) AZT-IFN alone, as previously done with Miami cohort (Malpica and Ramos et al. Blood Advances 2018). Treatment response was assessed according to Tsukasaki et al. (JCO 2009) criteria. To be classified as complete response (CR), partial response and stable disease, these had to persist for a period of at least 4 weeks. Survival curves were estimated using the Kaplan-Meier method and Log rank test. RESULTS: A total of 253 pts with ATLL were identified. Two hundred twenty six pts (L=122, A=73, C=26, S=5) had sufficient data for analysis. Demographic and clinical features are shown in Figure 1 and Table 1. Median age at diagnosis was 57 years, with a female predominance in A (58%) and S (100%) types. Most ATLL pts were from Peru (n=159, 63%) followed by Chile (n=44, 17%), Argentina (n=20, 8%) and Colombia (n=17, 7%). B symptoms were high present in A, L and C types (73%, 72%, 58% vs. 8% S type, respectively, p=0.011). Hypercalcemia was highly associated with A type (57% vs. L 27%, p=0.014). The PIT score yielded to a more aggressive risk classification compared to the IPI score (high-risk: 55% vs. 29%, respectively, p<0.001). Strongyloidiasis (n=5) and pneumocystis jirovecii pneumonia (n=5) were the most commonly observed co-infections at diagnosis. Commonly affected extranodal sites other than bone marrow in all subtypes were skin 25% (n=63) and liver 9% (n=24). The therapy approach used during the first 2 therapy evaluations are summarized in Table 2. The median survival (MS) times were 4.3 months, 7.9 months, 21.1 months, and not reached for A, L, C and S form, with 4-year survival of 8%, 22%, 40% and 80%, respectively (Figure 2). First-line AZT-IFN resulted in overall response (OR) rate of 63% (CR 24%) for A (n=8) and 75% (CR 50%) for L (n=8), respectively (Table 3). The OR rates after first-line multi-agent chemotherapy alone for A vs. L were 21% (CR 8%) and 41% (CR 29%), respectively (Table 3). The most commonly used regimens were CHOP/CHOP-like (n=117, 59%) and CHOEP (n=40, 20%) regimens with OR rates of 29% (CR 12%) and 60% (CR 42%), respectively (Table 3). Progression-free survival (PFS) rates in pts with aggressive ATLL who achieved CR after chemotherapy vs. AZT-IFN (alone or in combination with chemotherapy) were 2.8 months vs. 30.4 months for A (n=8) type and 67.1 months vs. 17.7 months for L (n=30) type, respectively (Figure 3). Only 2 pts with L type underwent allogeneic hematopoietic stem cell transplant (allo-HSCT) with PFS of 12 and 17 months (Table 4). CONCLUSION: ATLL continues to carry a dismal outcome with conventional therapies thus urging the development of novel approaches. Our study found that Latin American ATLL variant presents at a younger age, has a female predominance, high incidence of L type, low incidence of indolent types and lower survival rates, suggesting that Latin American ATLL variant presents earlier and more aggressively than in Japanese pts. AZT-IFN produced durable responses in A type patients who achieved CR as compared to chemotherapy alone. Chemotherapy responses were more durable in L types who achieved CR as compared to A type. In conclusion, in the management of aggressive ATLL, chemotherapy remains the preferred choice for L type (with consideration of allo-HSCT upfront), while AZT-IFN is a good option to attempt for A type upfront. Figure Disclosures Peña: Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sandoz: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees; Amgen: Speakers Bureau; BindingSite: Research Funding. Idrobo:Amgen: Honoraria, Speakers Bureau; Janssen: Honoraria, Speakers Bureau; Tecnofarma: Honoraria, Speakers Bureau; Takeda: Honoraria, Speakers Bureau; Abbvie: Honoraria, Speakers Bureau. Altamirano:Hospital Nacional Guillermo Almenara Irigoyen: Other: Servicio de Hematologia. Perini:Abbvie: Speakers Bureau; Janssen: Honoraria, Speakers Bureau; Takeda: Honoraria. Castillo:Janssen: Consultancy, Research Funding; Abbvie: Research Funding; TG Therapeutics: Research Funding; Kymera: Consultancy; Pharmacyclics: Consultancy, Research Funding; Beigene: Consultancy, Research Funding. Ramos:NIH: Research Funding. Villela:Roche: Other: advisory board, Speakers Bureau; amgen: Speakers Bureau.

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