Baseline Splenomegaly Research Articles

A Phase 2 Study of Fedratinib in Patients with MDS/MPN and Chronic Neutrophilic Leukemia

Introduction MDS/MPNs are clinically and molecularly complex diseases that exhibit proliferative symptoms and aggressive clinical courses. Evaluation of mutational patterns and gene expression profiles suggest these diseases should be viewed as a spectrum rather than distinct disease entities. Treatment options are limited and poorly defined as patients (pts) are often excluded from clinical trials. The JAK1/JAK2 inhibitor, ruxolitinib, has shown clinical benefit in pts with MDS/MPN and pts harboring CSF3R mutations. The experience of JAK2 inhibitors in myelofibrosis (MF) has shown that non-JAK2 kinase targets of JAK inhibitors may result in unique profiles of clinical benefit. Fedratinib is a JAK2 inhibitor approved for higher-risk MF. Compared to ruxolitinib, it has a broader kinase inhibition profile which may convey enhanced efficacy in high-risk, molecularly complex disease. Fedratinib potently inhibits FLT3 and BRD4 and potently suppresses c-Myc expression which may have biologic relevance in MDS/MPN. Study Design This is a phase 2, multi-institutional, investigator-initiated clinical trial (NCT05177211) assessing the efficacy of fedratinib in pts with atypical chronic myeloid leukemia (aCML), chronic neutrophilic leukemia (CNL), MDS/MPN-unclassifiable (MDS/MPN-U), and MDS/MPN-ring sideroblasts and thrombocytosis (MDS/MPN-RS-T) per 2016 WHO classification. Inclusion criteria included splenomegaly (≥ 5 cm below left costal margin or ≥ 450 cc) and/or significant disease-related symptoms (MPN TSS ≥ 10). Pts with a platelet count < 35 x 10 9/L or peripheral/marrow blasts > 10% were excluded. There was no exclusion based on prior treatment. The primary endpoint of this ongoing study is overall response rate defined as complete or partial response or clinical benefit at 24 weeks per proposed MDS/MPN IWG response criteria. C-Myc (a potential biomarker for response) was stained in the bone marrow collected at baseline and week 24. C-Myc expression product was scored by multiplying % positive cells by intensity (0 = none, 1 = mild, 2 = moderate, 3 = marked). Fedratinib was given at a dose of 400 mg daily. Planned enrollment is 25 pts with an interim analysis completed after 9 pts are evaluable for efficacy. Results At time of data cut-off, 10 pts have been enrolled with a median follow-up of 5 months. Eight pts remain on treatment. Baseline demographics, genetic makeup, and treatment history are shown in table 1. Enrolled pts include 1 with aCML, 4 with CNL, 4 with MDS/MPN-RS-T, and 1 with MDS/MPN-U. Three or more mutations were present in 7 (70%) pts. Three of 5 (60%) evaluable pts responded at week 24. This included 3 (75%) symptom responses and 1 (20%) spleen response (1 pt with both). Six pts have completed 12 weeks of treatment with 1 spleen response and 2 symptoms responses (Figure 1). Among 6 pts with baseline splenomegaly who received 12 weeks of treatment, spleen volume decreased in 5 (83%) by an average of -23% (+5% to -71%). Among 5 pts with significant baseline symptom burden who received 12 weeks of treatment, 4 (80%) experienced an improvement in symptom burden by an average of -43% (range 0% to -76%). One pt who discontinued treatment prior to week 8 for reasons unrelated to disease or treatment was considered a spleen and symptom non-responder despite experiencing a 48% symptom improvement at week 4. At baseline, C-Myc expression was demonstrated by IHC staining in a median of 10% of cells (5-15%). Average baseline c-Myc expression product (% positive cells * staining intensity) was 26.5 (range 10-37.5). In pts with paired samples (n = 4), c-Myc expression product decreased in all cases by an average of 51% (25%-85%), p = 0.02. Ten pts were evaluable for safety. The most common AEs occurring in >2 pts were anemia, platelet count decrease, diarrhea, nausea, muscle cramp, and constipation. Grade ≥3 AEs were anemia (40%) and neutropenia (10%). There were no grade ≥ 3 non-hematologic AEs. Two pts discontinued study treatment: one due to disease progression after initial response and one due to pt decision unrelated to disease or treatment. Conclusion: Fedratinib demonstrates promising clinical efficacy in MDS/MPN and CNL pts with proliferative features. The safety profile is consistent with prior experience. Fedratinib's unique kinase inhibition profile may provide a mechanism for enhanced effectiveness in this pt population. Updated results will be presented at the meeting.

Long-term safety and clinical outcomes of olipudase alfa enzyme replacement therapy in pediatric patients with acid sphingomyelinase deficiency: two-year results

BackgroundOlipudase alfa is a recombinant human acid sphingomyelinase (ASM) enzyme replacement therapy (ERT) for non-central-nervous-system manifestations of acid sphingomyelinase deficiency (ASMD). We report 2-year cumulative safety and efficacy data after olipudase alfa treatment in 20 children (four adolescents [12–17 year], nine children [6–11 year], and seven infants/early child [1–5 year]) with baseline splenomegaly and growth deficits who completed the 1-year ASCEND-Peds clinical trial (NCT02292654) and who continue to receive olipudase alfa in a long-term study (NCT02004704). Efficacy endpoints include spleen and liver volumes, diffusing capacity of the lung for carbon monoxide (DLCO), high-resolution computed tomography (HRCT) lung imaging, lipid profiles, liver function tests, and height Z-scores.ResultsAll 20 former ASCEND-Peds patients completed at least 2 years of olipudase alfa treatment. No patient discontinued and no new safety issue arose during the second year of treatment; 99% of adverse events were mild or moderate. During year 2, one patient had two treatment-related serious events of hypersensitivity that resolved. Mean reductions from baseline in spleen and liver volumes were 61% and 49%, respectively (p < 0.0001) and mean percent-predicted-DLCO increased by 46.6% (p < 0.0001) in nine patients who performed the test at baseline. Lipid profiles and elevated liver transaminase levels that improved or normalized by 1 year remained stable. Mean height Z-scores improved in all age groups (mean change from baseline 1.17, P < 0.0001).ConclusionOlipudase alfa was generally well-tolerated during 2 years of treatment. Improvements in clinically relevant disease endpoints observed during the first year of treatment were maintained or augmented in the second year.Trial registration NCT02004704 registered 26 Nov 2013, https://clinicaltrials.gov/ct2/show/record/NCT02004704.

Safety and Efficacy of Splenic Irradiation for Non-Hodgkin Lymphoma

Background: Splenic infiltration and associated splenomegaly is a challenging complication of non-Hodgkin lymphoma (NHL). The choice between splenectomy and splenic radiation (RT) is controversial, with little data to provide guidance in NHL. We aim to assess the tolerability and efficacy of splenic RT in NHL. Methods: We reviewed NHL patients treated from 2002 to 2021 with RT to the spleen alone. Splenomegaly was defined as vertical length >13cm. Splenic volume was obtained by manual contouring in MIM PACS 6.9.7 on the baseline pre-RT CT scan and the CT scan at best splenic response post-RT. PET response was evaluated by Lugano criteria. Adverse events (AEs) were retrospectively graded by clinicians using CTCAE v5.0. Cell counts were collected at baseline pre-RT and through 90 days post-RT completion; cell counts were censored at initiation of cytotoxic chemo post-RT if received. Significance was assessed with the Kruskal Wallis test. Results: 21 patients (11 diffuse large B-cell lymphoma (DLBCL), 5 marginal zone lymphoma (MZL), 4 mantle cell lymphoma (MCL), 1 follicular lymphoma) were identified with 23 courses of splenic RT. Median age was 75 (42-94); median KPS was 80 (50-90). Most patients (57%) had splenic only disease. Median splenic height pre-RT was 13.6 cm (6.4-26.6); 13 patients (57%) had baseline splenomegaly. Median splenic volume was 682cc (104-3355). 11 patients (48%) were symptomatic pre-RT (most frequently with pain: n=7, dyspnea: n=4, or nausea: n=4). 91% had any cytopenia before RT with median baseline absolute neutrophil count (ANC) 2.3 (0.2-10.6), hemoglobin 9.8 (7.1-13.8), and platelets 93 (9-221). RT was performed with definitive (n=11) or palliative (n=9) intent, or as bridging to chimeric antigen receptor T cells (n=3). Median dose was 30Gy for DLBCL (10.8-45), and 4Gy for MCL/MZL/FL (0.6-20); 10 patients received ≥20Gy. RT was well tolerated with 43% of courses without AEs and 57% with G1-2 AEs. AEs with frequency >10% were G1 fatigue (n=6), G1 anorexia (n=5), G1 nausea (n=5), G1 diarrhea (n=4), and G2 fatigue (n=4). There were no G3-4 AEs. One patient died from respiratory failure secondary to fungal pneumonia which was not felt to be attributable to splenic RT. Median nadirs in the 19 patients with cell count data: ANC 1.6 (0.2-3.8), hemoglobin 10.1 (6-13.4), platelets 70 (6-182) with 8, 6, and 15 median days from RT start to nadir (Table 1). ANC and platelets were disproportionately affected (median reduction: 26% and 28% for ANC and platelets, respectively vs. 5% for hemoglobin; p=0.006). There were no significant differences in reductions in ANC, platelets, or hemoglobin by RT dose (≥20Gy vs. <20Gy; p>0.1). In 3 patients (14%) cytopenias completely normalized post-RT. In most patients, cell counts normalized to pre-RT baseline (see Table 1). 4/13 symptomatic patients (31%) experienced complete relief. Median reduction in splenic volume was 34% (0-90%) with no significant difference in cytoreduction between low and high dose RT groups (median 27% reduction in <20Gy and 46% in ≥20Gy; p=0.2), see Figure 1. Overall response rate (ORR) by PET was 85% (35% complete response, 50% partial response, 10% stable disease, 5% progressive disease). With a median follow up of 12mo, median duration of radiographic response was 8mo (0.5-103) with more durable response at ≥20Gy (median 35 vs. 4mo, p=0.01). Conclusion: Splenic RT was well tolerated and had a high ORR of 85%. Radiographic response was more durable at doses ≥20Gy. Larger sample sizes with homogenous histology are needed to further evaluate the impact of dose on cell counts, clinical toxicity, and symptomatic relief. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Efficacy and Safety of Ruxolitinib for Treatment of Symptomatic Chronic Myelomonocytic Leukemia (CMML): Results of a Multicenter Phase II Clinical Trial

Introduction CMML is a myelodysplastic/myeloproliferative neoplasm (MDS/MPN) with poor overall survival (OS). Like primary myelofibrosis, a large subset of CMML patients suffer from disease-related symptoms and splenomegaly that contribute to morbidity. We have demonstrated that CMML is molecularly characterized by hematopoietic stem and progenitor cell hypersensitivity to granulocyte-macrophage colony-stimulating factor (GM-CSF). As the sentinel kinase required for GM-CSF signaling, JAK2 represents a rational therapeutic target in CMML and pharmacologic inhibition has demonstrated activity in preclinical models and in a phase I/II clinical trial. The overall response rate in that trial was 38% by MDS/MPN IWG criteria and 43% of patients (pts) with baseline splenomegaly achieved a spleen response by palpation. However, that clinical trial did not systematically or objectively measure symptom burden or radiographic splenomegaly. Here, we report results of our second phase II clinical trial with ruxolitinib for treatment of CMML objectively measuring spleen responses and symptom improvement. Methods This was a phase II prospective multicenter study. Key eligibility criteria included confirmed diagnosis of CMML and having either symptomatic splenomegaly and/or a myeloproliferative neoplasms symptom assessment form (MPN-SAF) total score (TSS) >17, ANC ≥ 250/ul, and platelets ≥35,000 u/l. Ruxolitinib was administered at 20 mg po BID at the previously identified RP2D. Dose adjustments/holding occurred for both hematological and non-hematological parameters. The primary endpoint was clinical benefit or better response per International Working Group (IWG) criteria for MDS/MPNs and symptom improvement was assessed using the MPN-SAF TSS. Pts were treated at least for 16 weeks if no clear progression and those deriving a clinical benefit could continue on study. Serial blood counts, chemistry and bone marrow assessment were conducted to assure safety and assess efficacy. Spleen volume was measured by CT imaging and the percentage of spleen volume reduction (SVR) was captured. Daily measurements of the MPN-SAF were performed for up to 17 weeks while on study. Results A total of 29 pts were enrolled at 4 centers (Moffitt, John Hopkins, Cleveland Clinic and Dana Farber) between September 2019 and June 2022. The median age was 74 (63-87) years. The majority were white (93%) and male (62%) consistent with the known demographics of CMML. Most pts had CMML-0 (62%) and proliferative CMML (69%) by the French American British group criteria. Fifty nine percent were high risk by the Mayo Clinic CMML risk model. Two patients had prior hypomethylating agent treatment and two had prior hydroxyurea. The most common somatic mutations at baseline were TET2 (79%), SRSF2 (68%) and ASXL1(48%). NRAS (21%), CBL (37%), and JAK2 (21%) were seen at higher proportions than previously reported likely due to study inclusion criteria. The median duration of follow up was 16 months and at the data cut off 8 pts remains on treatment. The median duration on treatment was 4 mo (.5-23 mo). Treatment-related adverse events and reasons for discontinuation are similar to that reported in the initial phase 1/2 study. The overall response rate by MDS/MPN IWG criteria was 17%: 10% (3) partial response and 7% (2) marrow response; 69% (20) had stable disease and 14% (4) were not yet evaluable. In addition, a clinical benefit was achieved in 66% of pts (19/29). Among 20 pts evaluable for spleen response, 30% (6/20) achieved ≥ 35% SVR measured by CT scan and 10/20 (50%) had 10% or more SVR (Figure 1a). Fifty four percent of patients achieved MPN-SAF TSS >50% reduction at 60 days and all but four patients demonstrated an improvement in MPN-SAF TSS (Figure 1b). The estimated median overall survival was 24 months (95% CI 9-39). Conclusions Ruxoltinib demonstrated meaningful clinical activity in CMML patients with splenomegaly and/or high disease symptom burden. Two thirds of patients achieved clinical benefit, 33% had ≥ 35% SVR, and 54% had a reduction in TSS>50%. The overall survival compares favorably to historical data among higher risk CMML and the magnitude of symptomatic benefit is similar to that observed in primary myelofibrosis. Collectively, our data suggests that ruxolitinib is a viable therapeutic for patients with symptomatic CMML. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

The MDM2 antagonist idasanutlin in patients with polycythemia vera: results from a single-arm phase 2 study

Idasanutlin, an MDM2 antagonist, showed clinical activity and a rapid reduction in JAK2 V617F allele burden in patients with polycythemia vera (PV) in a phase 1 study. This open-label phase 2 study evaluated idasanutlin in patients with hydroxyurea (HU)-resistant/-intolerant PV, per the European LeukemiaNet criteria, and phlebotomy dependence; prior ruxolitinib exposure was permitted. Idasanutlin was administered once daily on days 1 through 5 of each 28-day cycle. The primary end point was composite response (hematocrit control and spleen volume reduction > 35%) in patients with splenomegaly and hematocrit control in patients without splenomegaly at week 32. Key secondary end points included safety, complete hematologic response (CHR), patient-reported outcomes, and molecular responses. All patients (n = 27) received idasanutlin; 16 had response assessment (week 32). Among responders with baseline splenomegaly (n = 13), 9 (69%) attained any spleen volume reduction, and 1 achieved composite response. Nine patients (56%) achieved hematocrit control, and 8 patients (50%) achieved CHR. Overall, 43% of evaluable patients (6/14) showed a ≥50% reduction in the Myeloproliferative Neoplasm Symptom Assessment Form Total Symptom Score (week 32). Nausea (93%), diarrhea (78%), and vomiting (41%) were the most common adverse events, with grade ≥ 3 nausea or vomiting experienced by 3 patients (11%) and 1 patient (4%), respectively. Reduced JAK2 V617F allele burden occurred early (after 3 cycles), with a median reduction of 76%, and was associated with achieving CHR and hematocrit control. Overall, the idasanutlin dosing regimen showed clinical activity and rapidly reduced JAK2 allele burden in patients with HU-resistant/- intolerant PV but was associated with low-grade gastrointestinal toxicity, leading to poor long-term tolerability. This trial was registered at www.clinincaltrials.gov as #NCT03287245.

Tagraxofusp (SL-401) in Patients with Chronic Myelomonocytic Leukemia (CMML): Updated Results of an Ongoing Phase 1/2 Trial

Tagraxofusp (SL-401) in Patients with Chronic Myelomonocytic Leukemia (CMML): Updated Results of an Ongoing Phase 1/2 Trial

First Line Chemo-Free Therapy with the BRAF Inhibitor Vemurafenib Combined with Obinutuzumab Is Effective in Patients with Hcl

First Line Chemo-Free Therapy with the BRAF Inhibitor Vemurafenib Combined with Obinutuzumab Is Effective in Patients with Hcl

A Phase 1/2 Study of Single Agent Tagraxofusp, a First-in-Class CD123-Targeted Therapy, in Patients with Myelofibrosis That Is Relapsed/Refractory Following JAK Inhibitor Therapy

A Phase 1/2 Study of Single Agent Tagraxofusp, a First-in-Class CD123-Targeted Therapy, in Patients with Myelofibrosis That Is Relapsed/Refractory Following JAK Inhibitor Therapy

Adding Hydroxyurea to Chronic Transfusion for Sickle Cell Anemia Reduces Transfusion Burden: Final Results of the HAT Prospective Trial

Background: Chronic red blood cell (RBC) transfusion is an established therapy to prevent stroke in patients with sickle cell anemia (SCA). Chronic transfusion, however, requires considerable blood resources and has risks so a strategy to decrease transfusion requirements is highly desirable especially given blood shortages. Chronic transfusion also can fail to prevent progressive cerebrovascular disease so further optimization of this therapy is needed. Hydroxyurea has been studied as an alternative to chronic transfusion, but alone it provides inadequate cerebrovascular protection for patients at highest risk for stroke. Combination therapy hydroxyurea and transfusion (HAT) may provide benefits over either therapy alone because each ameliorates the pathology of SCA via different mechanisms. To evaluate the feasibility and impact of HAT on transfusion requirements, we conducted a single-arm clinical trial (NCT03644953).Methods: Pediatric patients with SCA already receiving simple chronic transfusion for stroke prevention for at least one year were approached. Patients with poor adherence to chronic transfusion defined by having a hemoglobin (Hb) S >45% and a transfusion interval >5 weeks in the last year were excluded. Enrolled patients were started on hydroxyurea 20 mg/kg/day and continued on simple chronic transfusions with the same transfusion protocol. Transfusion volumes were based on the pre-transfusion Hb to achieve a target post-transfusion Hb of 11.5-12.0 g/dL. Hydroxyurea was dose escalated to achieve a HAT target dose (HAT-TD) defined by either an absolute neutrophil count <4000/µL, or a pre-transfusion Hb >10g/dL with HbS >30%. Transfusion volumes and pre-transfusion laboratory values were compared the year before HAT and the year after HAT-TD.Results: A total of 19 eligible patients were offered participation and 14 enrolled (74% recruitment ratio). The median age was 11.2 years (range 5.3-19.8). The primary indication for chronic transfusion was history of an abnormal transcranial Doppler ultrasound (n=7), overt stroke (n=6), and progression of cerebral vasculopathy (n=1). Five participants ended the study prematurely (care transferred to another hospital, nonadherence to transfusions, patient desire to not take medications, hair thinning, family concern after a hospitalization); none had a serious adverse event that was attributed to HAT. Among the 9 participants who completed the study, the median HAT-TD was 25 mg/kg/dose (range 20-30) and was achieved after a median of 18 weeks (range 0-26). The median hydroxyurea adherence ratio, measured by pill counts, was 91%. One patient with baseline splenomegaly developed splenic sequestration requiring hospitalization; there were no other serious adverse events attributed to HAT. One patient developed a pre-transfusion Hb >11 g/dL and HbS >45%. This patient had hydroxyurea held for 12 weeks and was changed to partial manual exchange transfusions. With HAT, patients had a significant increase in pre-transfusion total Hb, HbS, HbF, and MCV; and a significant decrease in ANC and LDH (Table). After HAT-TD, 8/9 participants received fewer RBCs with a significant median RBC volume reduction of 19.4 ml/kg/year (p=.02, Figure). The single patient who received more RBCs after HAT-TD had suspected nonadherence to hydroxyurea returning only 33% of dispensed hydroxyurea bottles. While receiving HAT 8/9 patients had brain magnetic resonance imaging for clinical monitoring after a median of 75 weeks (range 29-100), no patient had a new infarct or progressive vasculopathy.Conclusion: Hydroxyurea added to chronic transfusion therapy for patients with SCA is feasible. HAT effectively decreases transfusion volumes so can help conserve blood resources. While Hb S% increases with HAT, this increase is relatively small and markers of hemolysis improved. Most patients are able to safely continue simple transfusions when hydroxyurea is added, but a few may require exchange transfusions. The effect of HAT on cerebrovascular disease warrants further study. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Single-Arm Salvage Therapy with Pegylated Interferon Alfa-2a for Patients with High-Risk Polycythemia Vera or High-Risk Essential Thrombocythemia Who Are Either Hydroxyurea-Resistant or Intolerant: Final Results of the Myeloproliferative Disorders-Research Consortium (MPD-RC) Protocol 111 Global Phase II Trial

Abstract Background: Several phase 2 trials have independently reported high response rates with recombinant interferon treatment in patients with essential thrombocythemia (ET) and polycythemia vera (PV). To further clarify the role of interferon therapy, we carried out a large trial to investigate pegylated-rIFN-α2a (PEG) as therapy in ET/PV patients. Methods: MPD-RC 111 (NCT01259817) was an international, multicenter, phase 2 trial evaluating complete and partial response rates (ELN Criteria) toPEG in patients with high-risk ET/PV who were either refractory or intolerant to hydroxyurea (HU) (Modified ELN Criteria). The study was designed to accrue 74 patients with ET and 74 with PV, but it was closed after accrual of 115 patients for administrative reasons. The starting PEG dose was 45 mcg weekly and was titrated for response to a maximum of 180 mcg weekly. Results Patients : The study enrolled 65 patients with ET and 50 patients with PV from 02/2012 to 12/2015. The median age was 64.0 years (range 20-85) (Table 1). Median time from diagnosis was 37.3 months (0.4-290.9) for ET and 54.8 months (0.5-393.7) for PV, entire cohort 42.3 months (0.5-394). Prior thrombosis was present in 32.3% of ET and 22% of PV patients. Palpable splenomegaly was present in 18.5% of ET patients and 56% of PV patients. Response CR / PR (ORR=CR+PR) at 12 months were observed in 43.1% / 26.2% (69.2%) in ET, and 22% / 38% (60%) in PV. The intention-to-treat (ITT) best ORR was 70.8% for ET and 64% for PV. In 77 patients (42 ET and 35 PV) who completed 24 months on-study, the ITT ORR (CR) was 73.8% (47.6%) for ET and 74.3% (42.9%) for PV. Patients with disease duration 42.3 months with 57% ORR (p=0.115). Higher treatment doses of PEG were not associated with increase in response rate (mean 118.2 vs 106.2 mcg, p: 0.225). Age Mutational analysis at baseline was available for 107 patients. JAK2V617F, CALR and MPL mutations are listed in table 1. Additional mutations included ASXL1 in 10, and TP53 in 5 patients. CR rate was higher in CALR mutated patients (56.3% vs. 28.6%, p= 0.02). None of 5 patients with TP53 mutation, and only 3/10 of ASXL1 mutated patients achieved CR. Safety Seventy-two % of patients remained on therapy for over 12 months with a median (range) duration of 78.5 (1-245) weeks in ET and 82 (4-209) weeks in PV. The mean (SD) weekly dose of PEG was 102.7 (52.3) mcg for ET and 128.7 (46.4) for PV. The causes for discontinuation of therapy are listed in Table 2. Grade 3 AEs regardless of attribution occurred in 38% of patients. Five grade 4 AEs were reported (AML, depression, hyperuricemia, and 2 subjects with neutropenia). Four non-myeloid malignancies developed in study patients. There were 3 off-trial deaths to date: drug abuse, lung adenocarcinoma, and patient decision unknown. Conclusions PEG is an effective agent to treat patients with ET/PV, capable of achieving 12 month ORR in 69% and 60% of ET and PV patients, respectively. The presence of CALR at baseline was associated with superior CR rates in ET. Treatment was associated with significant numbers of AEs which can limit tolerability. Thrombotic events and evolution to MF or AML continued to occur during the treatment period. The effects of PEG on the mutational burdens will be available at the time of presentation. QOL data will be presented separately. Download : Download high-res image (294KB) Download : Download full-size image Disclosures Yacoub: Novartis: Speakers Bureau; Sandoz: Consultancy; CTI: Consultancy; Pfizer: Consultancy; Seattle Genetics: Consultancy, Speakers Bureau; Incyte: Consultancy, Speakers Bureau. Mascarenhas: Janssen: Research Funding; Merck: Research Funding; Novartis: Other: DSMB member , Research Funding; Incyte: Other: Clinical Trial Steering Committee , Research Funding; CTI Biopharma: Research Funding; Promedior: Research Funding. Berenzon: Incyte Corporation: Research Funding. Ritchie: Incyte: Consultancy, Speakers Bureau; Novartis: Consultancy, Other: Research funding to my institution, and travel, Speakers Bureau; Bristol-Myers Squibb: Other: Research funding to my institution; Celgene: Consultancy, Other: Travel, Speakers Bureau; Astellas Pharma: Other: Research funding to my institution; NS Pharma: Other: Research funding to my institution; Pfizer: Consultancy, Other: Research funding to my institution. Rambaldi: Novartis, Amgen, Celgene, Sanofi: Other: Travel, Accomodations, Expenses; Novartis, Roche/Genentech, Amgen, Italfarmaco: Consultancy. Vannucchi: Novartis: Honoraria, Speakers Bureau; Shire: Speakers Bureau. Hexner: Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding. Mesa: Promedico: Research Funding; Incyte Corporation: Research Funding; Novartis Pharmaceuticals Corporation: Consultancy; Celgene Corporation: Research Funding; Ariad: Consultancy; CTI BioPharma Corp.: Research Funding; Galena Biopharma, Inc.: Consultancy; Gilead Sciences, Inc.: Research Funding.

Primary Analysis of JUMP, a Phase 3b, Expanded-Access Study Evaluating the Safety and Efficacy of Ruxolitinib in Patients with Myelofibrosis (N = 2233)

BACKGROUND: Ruxolitinib is a potent JAK1/JAK2 inhibitor that proved superior to placebo and best available therapy in the phase 3 COMFORT studies in patients (pts) with intermediate (Int)-2- or high-risk myelofibrosis (MF). In these studies, ruxolitinib led to improvements in splenomegaly and MF-related symptoms as well as prolonged overall survival. JUMP is a large, phase 3b, expanded-access trial designed to assess the safety and efficacy of ruxolitinib in pts with MF who do not have access to ruxolitinib outside a clinical trial. Here, we report findings from the primary analysis of JUMP, which includes 2233 pts in 26 countries who received ruxolitinib treatment for ≥ 2 years. METHODS: Eligible pts had Int-2- or high-risk MF, with or without splenomegaly, or Int-1-risk MF with a palpable spleen (≥ 5 cm). The starting dose of ruxolitinib was based on platelet (PLT) counts at baseline (5 mg twice daily [bid; ≥ 50 to 200 × 109/L]) and could be titrated during treatment. The primary endpoint was assessment of safety and tolerability of ruxolitinib. Additional analyses included changes in palpable spleen length and symptom scores. Pts were treated for up to 24 months after the last patient9s first visit (23 December 2014), unless discontinuation criteria were met. RESULTS: This analysis includes 2233 pts (primary MF, 59.4% [n = 1326]). At baseline, median age was 67 y (range, 18-89 y), and 59.7% were aged ≥ 65 y; 54.5% were male; median palpable spleen length was 12 cm below the costal margin; median time since diagnosis was 25.8 months. Median hemoglobin (Hb) was 106 g/L (Hb Median exposure was 12.4 months; the mean average daily dose of ruxolitinib was 28.7 mg. 67.4% of pts had dose modifications, and 27.2% had a dose interruption. The most common grade (G) 3/4 hematologic AEs were anemia (34.8%), thrombocytopenia (16.5%), and neutropenia (4.6%), which led to discontinuation in 1.3%, 2.8%, and 0.1% of pts, respectively. Nonhematologic AEs were primarily G1/2, and the most common (≥ 10%) were pyrexia (16.0%; G3/4, 2.4%), asthenia (15.4%; G3/4, 2.2%), diarrhea (12.5%; G3/4, 1.1%), and fatigue (10.0%; G3/4, 1.0%). Rates of other G3/4 AEs were low (≤ 2%), except pneumonia (4.7%), which led to discontinuation in 10 pts (0.5%). Rates of infections were generally low; all-grade infections in ≥ 5% of pts included pneumonia (7.3%), urinary tract infection (5.9%), herpes zoster (5.2%), and nasopharyngitis (5.2%). Tuberculosis was reported in 5 pts (0.2%; G3/4, At wk 24 and 48, 56.5% (874/1546) and 61.4% (656/1068) of pts with baseline splenomegaly achieved a spleen response (ie, a ≥ 50% reduction from baseline in palpable spleen length); 23.3% (360/1546) and 18.9% (202/1068) had 25% to 50% reductions at wk 24 and 48. Most pts (70.7% [1470/2079]) experienced a ≥ 50% reduction at any time (Figure); the median time to response was 5.8 wk. Pts also experienced substantial improvements in symptoms. A large proportion of pts achieved a response (ie, a clinically significant improvement) on the FACT-Lym TS at wk 24 (53.7% [753/1403]) and wk 48 (53.7% [503/937]). Similar results were seen on the FACIT-Fatigue (wk 24, 49.1% [709/1443]; wk 48, 45.6% [434/952]). CONCLUSIONS: This was the primary analysis of JUMP, the largest study of pts with MF treated with ruxolitinib. Overall, ruxolitinib was effective in pts with MF, leading to reductions in splenomegaly and symptoms in most pts. Consistent with findings from previous studies, anemia and thrombocytopenia were the most common AEs but rarely led to discontinuation. Findings from this analysis, which included pts with Int-1-risk disease, those with low platelet counts (≥ 50 to Disclosures Al-Ali: Novartis: Consultancy, Honoraria, Research Funding; Alexion: Honoraria; Gilead: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding. Foltz: Pfizer: Consultancy; Incyte: Research Funding; Promedior: Research Funding; Gilead: Research Funding; Novartis: Consultancy, Honoraria, Research Funding. Palumbo: Novartis: Membership on an entity9s Board of Directors or advisory committees, Speakers Bureau; Celgene: Membership on an entity9s Board of Directors or advisory committees, Speakers Bureau; Amgen: Speakers Bureau; Jannsen: Membership on an entity9s Board of Directors or advisory committees; Teva: Speakers Bureau; Hospira: Membership on an entity9s Board of Directors or advisory committees. Le Coutre: Pfizer: Honoraria; Incyte: Honoraria; BMS: Honoraria; Novartis: Honoraria. Zaritskey: Janssen: Consultancy; Novartis: Consultancy, Speakers Bureau. Tavares: Novartis: Consultancy. Griesshammer: Gilead: Consultancy, Honoraria, Speakers Bureau; Sanofi: Honoraria, Speakers Bureau; Baxalta: Consultancy, Honoraria, Speakers Bureau; AOP Orphan: Consultancy, Honoraria, Speakers Bureau; Shire: Consultancy, Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria, Speakers Bureau. Gupta: Novartis: Consultancy, Honoraria, Research Funding; Incyte: Consultancy, Research Funding. Bouard: Novartis Pharma AG: Employment. Perez Ronco: Novartis Pharma AG: Employment. Tiwari: Novartis Healthcare Pvt Ltd: Employment. Vannucchi: Novartis: Honoraria, Speakers Bureau; Shire: Speakers Bureau.

Safety and Efficacy of Idasanutlin in Patients (pts) with Hydroxyurea (HU)-Resistant/Intolerant Polycythemia Vera (PV): Results of an International Phase II Study

Safety and Efficacy of Idasanutlin in Patients (pts) with Hydroxyurea (HU)-Resistant/Intolerant Polycythemia Vera (PV): Results of an International Phase II Study

MPN-379: Interim Results from an Ongoing Phase 1/2 Clinical Trial of Tagraxofusp, a CD123-Targeted Therapy, in Patients with Chronic Myelomonocytic Leukemia (CMML)

Background: Chronic myelomonocytic leukemia (CMML) is a clonal hematopoietic stem cell disorder with overlapping features of myelodysplastic syndromes and myeloproliferative neoplasms (MDS/MPN) with poor outcomes, particularly in the relapsed/ refractory (R/R) setting. Current FDA-approved therapies have limited clinical impact. Clinical outcomes appear particularly poor in patients with proliferative features (high WBC counts, splenomegaly, high symptom burden) and high-risk cytogenetic and/or genomic features. Tagraxofusp (TAG) targets CD123, a biomarker expressed on CMML blasts and clonal monocytes; additionally, there is evidence of microenvironmental clonal plasmacytoid dendritic cells. Collectively, these features provide a rationale to assess the role of TAG in CMML patients. Objectives: To assess safety and efficacy of TAG in patients with CMML refractory/resistant/intolerant to HMAs, hydroxyurea, or intensive chemotherapy. Methods: Multicenter Phase 1/2 trial with TAG being administered as a daily IV infusion at 7, 9, or 12 mcg/kg on days 1–3 every 21 days (cycle 1-4), 28 days (cycles 5-7), and 42 days (cycles 8+) in stage 1 and 12 mcg/kg in stage 2. Results: Twenty-nine patients, including CMML-1 [n=19] and CMML-2 [n=10]; the median age was 70 years (range 42–87). Thirteen patients (45%) had baseline splenomegaly (spleen palpable below the left costal margin [BCM]); nine of these patients had baseline splenomegaly ≥5 cm BCM. The most common treatment-related adverse events (TRAEs, incidence ≥25%) were hypoalbuminemia, thrombocytopenia, and anemia. The most common ≥ grade 3 TRAEs were thrombocytopenia (34%), anemia (17%), and nausea (3%). Capillary leak syndrome was reported in seven patients (4 with grade 1–2; 3 with grade 3). Three patients, all with splenomegaly at baseline, achieved complete bone marrow responses (BMCRs), including one patient who was allografted in CR. Of note, two of these three BMCRs had proliferative CMML with high-risk cytogenetic and genomic features. Analysis of clinical benefit demonstrated a clinical reduction in splenomegaly in all patients with baseline splenomegaly (14/14): 71% (10/14) had spleen size reduction of ≥50%, and 60% (6/10) with baseline spleen size ≥5 cm had spleen size reduction of ≥50%. Conclusions: The interim results represent the clinical efficacy and safety of TAG monotherapy in a cohort of CMML patients, including patients with splenomegaly, a recognized poor prognostic factor in CMML. ( NCT02268253 )

Baseline Splenic Volume as a Prognostic Biomarker of FOLFIRI Efficacy and a Surrogate Marker of MDSC Accumulation in Metastatic Colorectal Carcinoma.

Background: Predictive biomarkers of response to chemotherapy plus antiangiogenic for metastatic colorectal cancer (mCRC) are lacking. The objective of this study was to test the prognostic role of splenomegaly on baseline CT scan. Methods: This study is a sub-study of PRODIGE-9 study, which included 488 mCRC patients treated by 5-fluorouracil, leucovorin and irinotecan (FOLFIRI) and bevacizumab in first line. The association between splenic volume, and PFS and OS was evaluated by univariate and multivariable Cox analyses. The relation between circulating monocytic Myeloid derived suppressor cells (mMDSC) and splenomegaly was also determined. Results: Baseline splenic volume > 180 mL was associated with poor PFS (median PFS = 9.2 versus 11.1 months; log-rank p = 0.0125), but was not statistically associated with OS (median OS = 22.6 versus 28.5 months; log-rank p = 0.1643). The increase in splenic volume at 3 months had no impact on PFS (HR 0.928; log-rank p = 0.56) or on OS (HR 0.843; log-rank p = 0.21). Baseline splenic volume was positively correlated with the level of baseline circulating mMDSC (r = 0.48, p-value = 0.031). Conclusion: Baseline splenomegaly is a prognostic biomarker in patients with mCRC treated with FOLFIRI and bevacizumab, and a surrogate marker of MDSC accumulation.

Results from a Phase 1/2 Clinical Trial of Tagraxofusp (SL-401) in Patients with Intermediate, or High Risk, Relapsed/Refractory Myelofibrosis

Results from a Phase 1/2 Clinical Trial of Tagraxofusp (SL-401) in Patients with Intermediate, or High Risk, Relapsed/Refractory Myelofibrosis

CSF3R Mutations Are Exceedingly Rare Genetic Events Associated with Inferior Survival and Sensitivity to Ruxolitinib across Myeloid Malignancies

BACKGROUND: CSF3R mutations are rare genetic events that have been associated with clinical response to the kinase inhibitors ruxolitinib and dasatinib according to the location and type of mutation observed. Although it has been reported that CSF3R mutations are exclusively associated with chronic neutrophil leukemia (CNL), the clinical relevance and response to therapy across the breadth of myeloid neoplasms is largely unknown. To address this, we report the first case series of CSF3R mutations across a large cohort of myeloid neoplasms. METHODS: This study was approved by scientific and ethical review boards. Cases were profiled for all exons of CSF3R utilizing a CLIA-certified 54 gene myeloid Truseq panel or a commercial panel covering over 400 genes. All cases were sequenced on an Illumina instrument and had a target read depth of 200X and a variant allele frequency cut-off of 5%. Reads were aligned with Novoalign version 3.04.04 and variants called using Varscan version 2.3.6. Detected CSF3R variants were filtered through an analytic pipeline to include only those that have been previously reported as somatic and resulting in activated signaling. Clinical variables were abstracted from the medical record and analyzed using GraphPad Prism and SPSS. Kaplan-Meier curves were utilized to estimate overall survival. All cases were centrally reviewed by two expert hematopathologists. RESULTS: Between April of 2014 and January of 2019, a total of 6182 patients with myeloid neoplasms were subjected to next generation sequencing (NGS) testing and only 18 (0.29%) harbored somatic activating CSF3R mutations. The CSF3R variants observed included T618I in 12 cases, T640N in 2 cases, T615A in 1 case and truncating mutations in 3 cases. CSF3R mutations were seen at diagnosis in 89% (16) of cases. The median age of CSF3R mutated cases was 77 years old (range 32-87 years), and 72% were male. Most cases were pathologically consistent with CNL (44.4%, 8 cases) but two cases were pathologically consistent with chronic myelomonocytic leukemia, one with myelodysplastic syndrome (MDS), one with myeloproliferative neoplasm unclassifiable (MPN-U), and one with MDS/MPN-U. Five patients were diagnosed with acute myeloid leukemia. Most patients were thrombocytopenic with a median platelet count of 69 x103 cells/dL (range 19-428 x103 cells/dL) and anemic with a median Hgb of 9.5 g/dL (range 7.7-14.1). Splenomegaly was observed in four cases (23.5%) by physical exam. The vast majority had normal cytogenetics (94.1%, 16 cases), and the most commonly co-mutated genes were ASXL1 (11 cases), TET2 (11 cases) and SRSF2 (7 cases).The median overall survival of CSF3R mutated cases was 13.8 months. Seven cases were treated with ruxolitinib, 5 of which harbored T618I mutations. When considering bone marrow myeloblast reduction, improvement in transfusion requirements, cytoreduction, improvement in splenomegaly, or improvement in constitutional symptoms, 100% of cases derived clinical benefit from ruxolitinib. This included two patients with clinically meaningful hematologic improvements as well as improvement in splenomegaly in 2 out of 3 patients with baseline splenomegaly. Further, one patient with serial NGS demonstrated CSF3R mutation clearance after 5 months of ruxolitinib therapy. The median overall survival was improved in ruxolitinib treated cases but did not reach statistical significance (16.5 vs. 10.9 months, p=0.27). CONCLUSIONS: To our knowledge, this represents the largest collection of ruxolitinib treated CSF3R mutant myeloid neoplasms reported. Although enriched in CNL, CSF3R can occur in other myeloid neoplasms to include CMML and their overall prognosis is poor. Our data suggest that ruxolitinib should be considered in patients with membrane proximal CSF3R mutations. Disclosures List: Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding. Lancet:Agios Pharmaceuticals: Consultancy; Daiichi-Sankyo: Consultancy; Pfizer: Consultancy; Jazz Pharmaceuticals: Consultancy. Sallman:Celyad: Membership on an entity's Board of Directors or advisory committees. Komrokji:celgene: Consultancy; DSI: Consultancy; Agios: Consultancy; Novartis: Speakers Bureau; JAZZ: Speakers Bureau; Incyte: Consultancy; JAZZ: Consultancy; pfizer: Consultancy. Pinilla Ibarz:Sanofi: Speakers Bureau; Bayer: Speakers Bureau; TG Therapeutics: Consultancy; Teva: Consultancy; Janssen: Consultancy, Speakers Bureau; Abbvie: Consultancy, Speakers Bureau; Novartis: Consultancy; Bristol-Myers Squibb: Consultancy; Takeda: Consultancy, Speakers Bureau. Kuykendall:Abbvie: Honoraria; Janssen: Consultancy; Incyte: Honoraria, Speakers Bureau; Celgene: Honoraria. OffLabel Disclosure: Ruxolitinib for the treatment of CSF3R mutated myeloid malignancies.

First Line Chemo-Free Therapy with the BRAF Inhibitor Vemurafenib Combined with Obinutuzumab Is Effective in Patients with Hcl

First Line Chemo-Free Therapy with the BRAF Inhibitor Vemurafenib Combined with Obinutuzumab Is Effective in Patients with Hcl

Phase 2 Study of Ruxolitinib (RUX) in Combination with 5-Azacitidine (AZA) in Patients (pts) with Myelofibrosis

Phase 2 Study of Ruxolitinib (RUX) in Combination with 5-Azacitidine (AZA) in Patients (pts) with Myelofibrosis

PF672 RESULTS FROM ONGOING PHASE 1/2 CLINICAL TRIAL OF TAGRAXOFUSP (SL‐401) IN PATIENTS WITH RELAPSED/REFRACTORY CHRONIC MYELOMONOCYTIC LEUKEMIA (CMML)

Background:Patients with chronic myelomonocytic leukemia (CMML) have historically poor outcomes, with ∼6–7 month median overall survival (OS) in the relapsed/refractory (r/r) setting. Splenomegaly is a major cause of morbidity, is a poor prognostic factor and has emerged as a potential therapeutic target in CMML. Tagraxofusp (SL‐401) is a targeted therapy directed to CD123, a target expressed on CMML blasts, monocytes and neoplastic microenvironmental plasmacytoid dendritic cells (pDCs) that are part of the CMML malignant clone, as well as on a variety of additional malignancies. Tagraxofusp was approved by the US FDA for the treatment of blastic plasmacytoid dendritic cell neoplasm (BPDCN) and is being investigated in other CD123‐expressing malignancies.Aims:Primary objectives include assessment of safety, determining the recommended Phase 2 dose (RP2D) and schedule, and evaluating efficacy in patients with CMML.Methods:This multicenter, open‐label, Phase 1/2 clinical trial is enrolling patients with CMML. In Stage 1 (dose escalation), tagraxofusp was administered as a daily IV infusion at 7, 9, and 12 mcg/kg on days 1–3 every 21 days (cycle 1–4), every 28 days (cycles 5–7), and every 42 days (cycles 8 and beyond). In Stage 2 (expansion), patients receive the RP2D (12 mcg/kg).Results:20 patients with CMML (CMML‐1 [n = 12]; CMML‐2 [n = 8]) were treated with tagraxofusp, including 18 in the relapsed/refractory setting, with hypomethylating agents (HMAs) being the most commonly administered prior therapy. Median age was 69 years (range 43–80) and 80% were male. 10 patients (50%) had baseline splenomegaly (defined as spleen palpable below the left costal margin [BCM]), of which 6 had baseline splenomegaly ≥ 5 cm BCM. Most common treatment‐related adverse events (TRAEs, incidence ≥ 20%) were hypoalbuminaemia, thrombocytopenia, nausea, vomiting and fatigue. Most common ≥ grade 3 TRAEs were thrombocytopenia (35%) and nausea (5%). Capillary leak syndrome was reported in 3 patients (grade 1–2). 100% (10/10) of patients with baseline splenomegaly had a spleen response by physical exam: 80% (8/10) had spleen size reduction of ≥ 50% and 67% (4/6) with baseline spleen size ≥ 5 cm had spleen size reduction of ≥ 50%. Three patients treated with tagraxofusp achieved bone marrow complete responses (BMCRs), including 1 patient who was bridged to stem cell transplant in remission on tagraxofusp.Summary/Conclusion:Tagraxofusp demonstrated single agent activity in patients with CMML and splenomegaly, an area of potential unmet medical need. Given the expression of CD123 in CMML, tagraxofusp represents a rational therapeutic approach in this disease. Updated data will be presented, and a registrational trial is planned. Trial information: NCT02268253.

PF668 RESULTS FROM ONGOING PHASE 1/2 CLINICAL TRIAL OF TAGRAXOFUSP (SL‐401) IN PATIENTS WITH INTERMEDIATE, OR HIGH RISK, RELAPSED/REFRACTORY MYELOFIBROSIS

Background:Patients with myelofibrosis (MF) who fail or are intolerant to JAK inhibitors (JAKi) have limited treatment options. Tagraxofusp is a targeted therapy directed to CD123 that was approved by the US FDA for the treatment of patients with blastic plasmacytoid dendritic cell neoplasm (BPDCN). CD123 is expressed on a variety of malignancies including BPDCN, acute myeloid leukemia (AML), and certain myeloproliferative neoplasms (MPN), including MF. Moreover, CD123+ plasmacytoid dendritic cells (pDCs), the cell of origin of BPDCN, have been detected in the microenvironment of certain myeloid neoplasms, including MF, where they may play a tumor‐promoting role.1,2,3 Notably, pDCs share a common precursor cell with monocytes, and monocytosis has been reported as a poor prognostic factor, associated with rapid disease progression and shortened survival, suggesting an accelerated disease phase in MF.4 As such, tagraxofusp may offer a novel and rational therapeutic approach in patients with relapsed/refractory MF, including patients with monocytosis.Aims:Primary objectives include assessment of safety, determining the recommended Phase 2 dose (RP2D) and schedule, and evaluating efficacy in patients with MF who were relapsed, refractory, or unable to tolerate JAKi.Methods:This multicenter, open‐label Phase 1/2 trial is enrolling patients with MF. In the Stage 1 (dose escalation), tagraxofusp was administered as a daily IV infusion at 7, 9, and 12 mcg/kg on days 1–3 every 21 days (cycle 1–4), 28 days (cycles 5–7), and 42 days (cycles 8+). In Stage 2 (expansion), patients are receiving the RP2D (12 mcg/kg).Results:23 patients with MF received tagraxofusp, including 12 patients who received ≥ 3 prior lines of therapy. Median age 69 years (range 55–81), 61% were female, and 30% had baseline monocytosis (≥ 1x109/L). Baseline risk assessment based on the DIPSS Plus risk group assessment showed 1 patient (4%) with intermediate‐1, 12 patients (52%) with intermediate‐2, and 10 patients (44%) with high‐risk. At study entry, the median platelet count was 59 K/uL with 71% of patients had baseline platelets &lt;100 K/uL, of which 8 patients had platelets &lt;50 K/uL. 87% of patients had baseline splenomegaly (spleen palpable ≥ 5 cm below the left costal margin [LCM]). Most common treatment‐related adverse events (TRAEs, incidence ≥ 15%) include headache, hypoalbuminemia, alanine aminotransferase increased and thrombocytopenia. The most common ≥ grade 3 TRAE was thrombocytopenia (8%). Capillary leak syndrome was reported in 1 patient (grade 3). Among the 14 evaluable patients with baseline splenomegaly, 57% had spleen size reductions: 43% (6/14) had reductions of &gt; 25%, of which 3 patients had reductions of ≥ 45%. In 5 patients with baseline splenomegaly and monocytosis, 80% (4/5) had reductions of &gt; 25%, of which 2 had reductions of ≥ 45%. Six patients, including 3 patients with monocytosis and 5 patients with platelets &lt;100 K/uL, had treatment duration of 6 months or more.Summary/Conclusion:Tagraxofusp demonstrated single agent activity, with a predictable and manageable safety profile, in patients with relapsed/refractory MF, including in patients with monocytosis, a poor prognostic factor, both constituting potential areas of unmet medical need. Enrollment continues, and updated trial data will be presented. Registrational trial designs are being evaluated. Trial information: NCT02268253.