Ruxolitinib In Myelofibrosis Research Articles

Real-World Use of Ruxolitinib in Patients With Myelofibrosis and Anemia or Thrombocytopenia at Diagnosis.

Ruxolitinib is approved for treatment of myelofibrosis. We evaluated ruxolitinib in patients with anemia (hemoglobin <10 g/dL) or thrombocytopenia (platelet count ≤100×109/L) at diagnosis. This was a retrospective, secondary analysis of a Cardinal Health Oncology Provider Extended Network medical chart review of adults with myelofibrosis diagnosed between 2012-2016 who received first-line ruxolitinib. 176 patients received first-line ruxolitinib and were included in this analysis. At diagnosis, 120 patients had hemoglobin concentrations <10 g/dL and 59 had a platelet count ≤100×109/L. Most patients (95%) with thrombocytopenia also had anemia. Median time of observation after diagnosis was 21.4 months. Among patients with anemia or thrombocytopenia, ruxolitinib dose at end of study was ≥10 mg twice daily (bid) in 88.3% and 83.1%, respectively. Ruxolitinib treatment was ongoing in 76.1% of patients overall and was rarely discontinued for anemia or thrombocytopenia (n=2 total, 1.1%). Per the treating physician, 79.7% of patients had improved symptoms and 62.7% improved spleen size. Most patients with myelofibrosis and anemia or thrombocytopenia at diagnosis tolerated and maintained a ruxolitinib dose ≥10 mg bid for nearly 2 years, resulting in clinical benefit. This real-world evidence supports observations from prospective clinical trials of ruxolitinib in myelofibrosis.

Combinatorial BCL-2/ BCL2L1 Expression Predicts Clinical Response to Ruxolitinib in Myelofibrosis

Introduction: JAK inhibitors (JAKi) marked a revolutionary breakthrough in the treatment of patients (pts) with myelofibrosis (MF). The BCL-2 family of proteins have been implicated in both disease development and mechanisms of response/resistance to JAKi. This is further reinforced by preliminary evidence of therapeutic efficacy of combining JAK2 and BCL-xL inhibition. Aims&Methods: In the current study, we investigated the expression of three major BCL-2 family members in MF pts treated with ruxolitinib (RUX) at baseline and during treatment. Gene expression of BCL-2, BCL2L1 (encoding BCL-xL) and MCL-1 was analyzed by qPCR normalized to endogenous 18S gene using cDNA obtained from peripheral blood (PB) granulocytes; the relative gene expression (expressed as fold-change, FC) was calculated with reference to healthy controls using the Ct (2−ΔΔCt) method. Results: The study included 19 pts (10 males; median age 61 years) with MF (10 primary, 9 secondary) who received treatment with RUX. Sixteen pts were JAK2-mutated, 2 CALR-mutated, and 1 MPL-mutated. Treatment response was fully evaluable across the entire treatment period. After a median treatment time of 67 (range, 6-121) months, 7 (37%) pts achieved a spleen response (defined as a >50% reduction in palpable splenic length lasting >6 months) and were considered as responders, as compared to 12 (63%) non-responders. We did not find any significant correlation of baseline BCL-2/ BCL2L1/ MCL-1 expression with clinical and molecular characteristics, the only exception being the association between EZH2 mutation and higher BCL2L1 expression. First, we ascertained whether BCL2 family protein expression levels at baseline predicted response to RUX. We found that BCL2 and BCL2L1 were significantly more expressed in responders compared to non-responders, with median FC values of 0.14 vs 0.04 ( P=.0130) and 2.46 vs 0.51 ( P=.0096), respectively (Fig. 1A). A similar, not statistically significant, trend was observed for MCL-1 expression. Accordingly, in univariate regression logistic analysis, both BCL2 and BCL2L1 FCs correlated significantly with the probability of response to RUX. Then, we incorporated BCL-2 and BCL2L1 gene expression at baseline into a combinatorial score (CS) resulting from the product of the respective FCs (FC BCL-2 * FC BCL-xL). The CS outperformed the individual BCL2 family proteins expression in predicting RUX response, as confirmed in regression logistic analysis. ROC analysis identified 0.06 as the optimal cut-off value of the CS. In univariate analysis, pts with a baseline CS >0.06 had a significantly higher probability of responding to RUX (OR 27.5, 95% CI 2.1-236.7; P=.0037), with a superior cumulative incidence of RUX response at 24 weeks (50% vs 9%, respectively; P=.0045) (Fig. 1B). Finally, we prospectively assessed the changes in gene expression during treatment with RUX. Six out of seven responder pts had an available PB sample at the time of best response, while all non-responders were evaluated at some point during RUX therapy. Among responders, 5 lost response after a median time of 34 months, and 3/5 had an available sample for analyses at the time of response loss. Although we did not find any significant difference comparing gene expression at baseline and on treatment, we observed a trend for BCL-2 upregulation in responders at the time of best response. Furthermore, non-responders showed a down-regulation of MCL-1 expression during treatment ( P=.05). By comparing gene expression of responder pts at the time of best vs loss of response, we discovered a down-regulation for all the three genes, with a statistical significance that was reached only for BCL-2 ( P=.0471). Conclusion: Despite study limitations (mainly the small cohort), this preliminary data suggests that the expression levels of BCL2 family proteins may represent a predictor of response to RUX. Specifically, we developed a simple, combinatorial score includingbaseline BCL-2 and BCL2L1 expression that accurately discriminated pts who responded to RUX. Moreover, we showed that BCL2 family protein expression changes during RUX treatment, with potential correlations with both response achievement and loss. Further studies are needed in order to confirm and expand our data.

Real-world analysis of ruxolitinib in myelofibrosis: interim results focusing on patients who were naïve to JAK inhibitor therapy treated within the JAKoMo non-interventional, phase IV trial

Ruxolitinib (RUX) is a Janus kinase 1/2 inhibitor (JAKi) approved in the EU for treating disease‑related splenomegaly or symptoms in adults patients with myelofibrosis (MF). This is an interim analysis of JAKoMo, a prospective, non‑interventional, phase IV study in MF. Between 2012–2019 (cutoff March 2021), 928 patients (JAKi-naïve and -pretreated) enrolled from 122 German centers. This analysis focuses on JAKi-naïve patients. RUX was administered according to the Summary of Product Characteristics. Compared to the COMFORT-I, -II, and JUMP trials, patients in JAKoMo were older (median 73 years), had poorer Eastern Cooperative Oncology Group (ECOG) performance statuses (16.5% had ECOG ≥ 2), and were more transfusion dependent (48.5%). JAKoMo represents the more challenging patients with MF encountered outside of interventional studies. However, patients with low-risk International Prognostic Scoring System (IPSS) scores or without palpable splenomegaly were also included. Following RUX treatment, 82.5% of patients experienced rapid (≤ 1 month), significant decreases in palpable spleen size, which remained durable for 24 months (60% patients). Symptom assessment scores improved significantly in Month 1 (median –5.2) up to Month 12 (–6.2). Common adverse events (AEs) were anemia (31.2%) and thrombocytopenia (28.6%). At cutoff, 54.3% of patients had terminated the study due to, death, AEs, or deterioration of health. No new safety signals were observed. Interim analysis of the JAKoMo study confirms RUX safety and efficacy in a representative cohort of real-world, elderly, JAKi-naïve patients with MF. Risk scores were used in less than half of the patients to initiate RUX treatment.Trial registration: NCT05044026; September 14, 2021.

Ruxolitinib for myelofibrosis in elderly non-transplant patients: healthcare resource utilization and costs

AimThis study evaluated real-world healthcare resource utilization (HCRU), direct costs, and overall survival (OS) of patients who were Medicare beneficiaries and were newly diagnosed with myelofibrosis (MF) who filled ≥1 prescription of ruxolitinib versus those who did not.Patients and MethodsThis was a study of the US Medicare fee-for-service database. Beneficiaries were aged ≥65 years with an MF diagnosis (index) between January 1, 2012 − December 31, 2017. Data were summarized descriptively. OS was estimated using Kaplan-Meier analysis.ResultsPatients with ≥1 prescription fill of ruxolitinib (n = 2,787) had lower mean rates (per patient per month [PPPM]) versus patients who did not fill a prescription for ruxolitinib (n = 7,262) for hospitalizations (0.16 vs 0.32), length of inpatient stay (0.16 vs 2.44 days), emergency department visits (0.10 vs 0.14), physician office visits (4.68 vs 6.25), skilled nursing facility stays (0.02 vs 0.12), home health/durable medical equipment services (0.32 vs 0.47), and hospice visits (0.30 vs 1.70). Monthly medical costs were numerically lower in patients who had ≥1 fill of ruxolitinib versus those who did not fill a prescription for ruxolitinib ($6,553 vs $12,929), largely driven by inpatient costs ($3,428 vs $6,689). Pharmacy costs were $10,065 and $987 in patients who filled versus did not fill ≥1 prescription for ruxolitinib, respectively; total PPPM all-cause healthcare costs were $16,618 and $13,916, respectively. The median OS was 37.5 and 18.7 months for the cohorts of patients who filled versus did not fill ≥1 prescription for ruxolitinib, respectively (hazard ratio = 0.63, 95% CI = 0.59 − 0.67).ConclusionsRuxolitinib is associated with reduced HCRU and direct costs of medical care in addition to increased survival, suggesting it to be a cost-effective advance for patients with MF.

Pelabresib (CPI-0610): An Exciting Novel Drug for the Treatment of Myelofibrosis.

Myelofibrosis (MF) is a myeloproliferative neoplasm characterized by bone marrow fibrosis, megakaryocyte atypia, and inflammatory cytokine overproduction, resulting in progressive cytopenias, splenomegaly, and high symptom burden. Current backbone of care includes JAK inhibitor (JAKi) therapy, which offers limited benefits and significant discontinuation rates. Targeting the epigenetic modifiers bromodomain and extra-terminal domain (BET) proteins is a novel approach for harnessing the expression of genes involved in critical oncogenic signalling pathways implicated in MF and other malignancies. Here, we review preclinical and clinical data on Pelabresib (CPI-0610), an investigational oral small-molecule potent BET-inhibitor being explored in MF. BET inhibition has been shown to target multiple MF driver mechanisms in preclinical studies, with synergistic results using combination therapy with JAKi. Pelabresib is currently being evaluated in the phase II MANIFEST study as monotherapy and in combination with ruxolitinib for MF. Interim data showed favourable responses in symptoms and spleen volume after 24weeks of treatment, with correlated improvements in bone marrow fibrosis and mutant allele fraction reduction. Based on these encouraging results, the Phase III MANIFEST-2 study was initiated. Pelabresib offers a much-needed innovative treatment approach for patients with MF, either as monotherapy or in combination with the current standard of care.

Hypertrophic herpes simplex virus 2 infection resistant to acyclovir in an immunosuppressed patient.

KEY POINTS An 80-year-old man on ruxolitinib for myelofibrosis was referred to the infectious diseases clinic with a subacute, progressive mass over his left forehead. He also had type 2 diabetes mellitus and dyslipidemia, and was taking rabeprazole, simvastatin and metformin. Three years before

Pelabresib (CPI-0610) As Add-on to Ruxolitinib in Myelofibrosis: Durability of Response and Safety Beyond Week 24 in the Phase 2 MANIFEST Study

Background: Myelofibrosis (MF) is largely characterized by bone marrow (BM) fibrosis, splenomegaly and cytopenias. Progressive BM fibrosis results from aberrant megakaryopoiesis and proinflammatory cytokine expression, two processes that are tightly regulated by bromodomain and extraterminal domain (BET) protein-mediated expression of genes (eg NF-κB target genes, MYC and BCL-2) and often lead to myeloproliferation and cytopenias. Although the current standard of care for MF is treatment with the Janus kinase inhibitor (JAKi) ruxolitinib (RUX), many patients (pts) experience a suboptimal response to RUX monotherapy or must discontinue treatment due to cytopenias and therefore there is a significant unmet need for new therapies in this population. Pelabresib (CPI-0610; PELA) is an oral, small-molecule, investigational BET inhibitor that downregulates NF-κB signaling and other relevant genes involved in MF disease pathways (Mascarenhas J, et al. HemaSphere 2022;6:99-100). Aims: In the ongoing, open-label Phase 2 MANIFEST study (NCT02158858), PELA is under investigation as monotherapy and in combination with RUX in pts with MF. In Arm 2 of MANIFEST, pts with suboptimal/lost response to RUX are treated with PELA as 'add-on’ to RUX. In this abstract we will discuss results from the September 2021 data cut; updated data with longer follow-up on efficacy (≥35% reduction in spleen volume from baseline [BL; SVR35], ≥50% total symptom score reduction from BL [TSS50], duration of response and BM fibrosis improvement) and safety data from the planned July 2022 data cut will be presented. Methods: Pts in Arm 2 are stratified as transfusion dependent (TD; Arm 2A) and nontransfusion dependent (non-TD; Arm 2B). The primary endpoints are conversion from TD to transfusion independence (TI) in Arm 2A (TD cohort) and SVR35 at Week (Wk) 24 for Arm 2B (non-TD cohort). The secondary endpoints include TSS50 per MF Symptom Assessment Form v4.0 at Wk 24 and SVR35 at Wk 24 in Arm 2A (TD cohort). BM biopsies to assess BM fibrosis, durability of responses and safety data are evaluated. Data reported here are from the September 2021 data cut. Results: At Wk 24 in Arm 2 (N=86), 20% (16/81) of pts achieved SVR35 (Figures 1 and 2); 17% for Arm 2A (TD cohort) and 26% for Arm 2B (non-TD cohort). SVR35 at any time was achieved by 30% (24/81) of pts. At Wk 24, 27% (22/81) pts achieved ≥25% reduction in spleen volume from BL (SVR25); 26% (14/54) pts in Arm 2A (TD cohort) and 30% (8/27) pts in Arm 2B (non-TD cohort). Median spleen volume reduction for the full Arm 2 cohort was -18% at Wk 24. Durable (up to Wk 60) spleen volume reductions were observed as depicted in mean spleen volume change over time, and spleen volume reduction deepened over time (Figure 1). Twenty percent (16/80) pts had SVR35 response at Wk 48. In Arm 2A (TD cohort), the TD to TI rate was 16% (6/38). TSS50 at Wk 24 was 37% (30/81); 36% for Arm 2A (TD cohort) and 39% for Arm 2B (non-TD cohort). A total of 54% (46/86) of pts achieved TSS50 at any time. Median total symptom score reduction was -47% at Wk 24. As of data cut off, the median follow-up time was 24.4 (23.0-30.7) months and median treatment duration was 14.0 (8.4-20.6) months. After 24 wks of treatment, BM fibrosis improvement by ≥1 grade was achieved in 26% of evaluable pts by central pathology review; 50% of pts maintained the improvement at the next available assessment or longer. A total of 39% of pts achieved ≥1 grade improvement at any time (best response). The two most common hematologic treatment-emergent adverse events (TEAEs) of any grade were thrombocytopenia, reported in 52% (Grade ≥ 3: 33%) pts, and anemia, reported in 27% (Grade ≥ 3: 19%) pts. Low-grade gastrointestinal TEAEs and respiratory infections were observed but rarely a reason for treatment discontinuation. A total of 20 pts (23%) reported TEAEs that led to PELA discontinuation. Serious adverse events reported in ≥3 pts were anemia (6 pts), respiratory tract infections (4 pts) and urinary tract infections (3 pts). Conclusions: Based on these preliminary Phase 2 data, PELA as 'add-on’ to RUX in pts with a suboptimal/lost response to RUX monotherapy resulted in durable splenic and symptom responses, deepening of spleen responses over time, and was generally well tolerated. Additionally, improvement in BM fibrosis, as a marker of disease modification, was observed in 39% of treated pts. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

A Phase 1 Dose-Escalation Study of the Oral Epichaperome Inhibitor, Zelavespib (ZEL) in Combination with Ruxolitinib (RUX), in Patients with Relapsed Myelofibrosis: Results of the Dose Escalation Stage

Background: ZEL (PU-H71) is an oral synthetic purine-scaffold epichaperome inhibitor that selectively binds to epichaperome complexes found in cancer cells via the altered ATP binding site of disease-associated heat shock protein (HSP90). ZEL has shown efficacy in cell line and mouse models of myeloproliferative neoplasm (MPN) and specifically myelofibrosis (MF) by disrupting JAK2 protein stability, resulting in dose-dependent inhibition of cell growth and signaling. JAK2 inhibitors are the only currently approved class of therapies for intermediate/higher risk MF, but there is still an urgent unmet medical need for 2nd line and beyond therapies. An emerging approach is the add-on/add-back strategy, with the addition of the second/novel agent in the setting of suboptimal response to JAKi monotherapy. In a prior trial of ZEL as IV monotherapy in an advanced malignancy study (including both solid and hematologic malignancies), ZEL demonstrated clinical activity in patients with lymphoma and MF. Based on this efficacy signal, the tolerability profile of ZEL in hematological malignancies, and the potential for synergy between mechanisms of action, a study with ZEL in combination with RUX was initiated. The present phase 1 study is the first to establish the safety, MTD, and preliminary efficacy of oral ZEL when added to RUX in MF (NCT03935555). Methods: Patients with primary, post-polycythemia vera or post-essential thrombocythemia MF were eligible if age ≥18 years, ECOG performance status ≤2, treatment with RUX >3 months prior to start with persistent or worsening splenomegaly and disease-related symptoms (by MPN-SAF TSS), adequate cardiac, hepatic and renal function, platelets ≥ 25,000/uL, ANC ≥500/uL, and no active ocular pathology. Oral solution of ZEL was administered daily in continuous 21-day cycles in combination with each patient's stable baseline RUX dose. The initial dose of ZEL was 50 mg with each subsequent cohort dose-escalating by 50 mg QD increments. DLTs were assessed in Cycle 1 (21 days). Response was assessed by IWG-MRT and ELN criteria. Results: Eleven patients have been enrolled: 3 patients each in the 50 and 100 mg cohorts, and 5 in the 150 mg cohort following DLT-driven cohort expansion. Median age was 69 years (range 59-78). Baseline RUX dose ranged from 5-25 mg bid, with a median of 15 mg. Median number of ZEL cycles administered was 4 (range 1-25). Most AEs were Gr 1 and 2 and the most frequent were abdominal pain, diarrhea and fatigue. Gr 4 thrombocytopenia in 2 patients (150 mg) met DLT criteria with platelet nadirs of 7K and 22K during cycle 1. One patient (150 mg with symptomatic improvement) developed Grade 3 bone marrow hypoplasia after 22 cycles of treatment, an SAE judged by the Investigator to be related to treatment. To date, 2 patients (1 each at 100 and 150 mg) demonstrated symptom improvement without significant reduction in spleen size. One patient (50 mg) had stable disease maintained for 20 cycles and successfully bridged to allogeneic stem cell transplant. Allele burden, cytokine profiles, flow cytometry for biomarkers, and PK analyses are in progress and will be presented. Conclusions: The ZEL dose 100 mg QD was well tolerated and was selected as the RP2D in combination with RUX. Although ZEL has not been shown to cause myelosuppression as monotherapy, further evaluation is necessary to understand possible effects on bone marrow and megakaryocyte function when used in combination with RUX. Further exploration of the therapeutic potential of oral ZEL in the treatment of MF and other MPNs, as monotherapy and with RUX, is warranted.

Ruxolitinib for Myelofibrosis in Resource Limited Settings : A Slip between the Cup and the Lip

Background and Objective:Ruxolitnib, an orally bioavailable non-specific JAK inhibitor is a novel drug used for treating myelofibrosis by targeting the unique disease biology and has significantly reduced symptomatic burden in these patients. In resource limited countries, the data on post marketing experience with this relatively novel agent is limited. The major objectives of this study was to examine the challenges encountered with the use of Ruxolitinib in our resource limited setting. Methods:Patients with confirmed diagnosis of myelofibrosis and initiated on ruxolitinib therapy consecutively during the time period between December 2013 to March 2019 at our institute were included in the study. The data was collected from electronic medical records over a period of 12 months from March 2020 to March 2021. Results:This retrospective analysis included forty six patients and their baseline characteristics are summarized in Table 1. Twenty five (54.3%) patients received lower than the recommended dose for the corresponding platelet count. On response assessment, the mean MPN SAF ISS score showed reduction from 30 (6-64) to 15 (2-38).Among the 36 patients with splenomegaly documented in records, a spleen response below costal margin of <5cm was seen in 2 (5.5%), 5 - 10cm in 9 (25%) and >10cm in 22 (61.1%) patients. . The patients were followed up for a median of 29.5 months (0-76 months) after Ruxolitinib initiation.At the time of data locking, 12 (26%) patients were still on ruxolitinib, 13 (28.2%) patients were lost to follow up and 7 (15.2%) patients died. Rest of the fourteen (30.4%) patients discontinued ruxolitinib, the reasons being financial constraints in 7 (50%), disease progression in 3 (21.4%), haematological toxicity in 2 (14.2%) and intolerance due to non-haematological causes in 2 (14.2%). Haematological adverse events that necessitated dose reduction or cessation of drug were anemia and thrombocytopenia. The serious non-hematological adverse events were renal dysfunction, pancreatitis, COVID infection, DIC and pulmonary alveolar haemorrhage in one patient each and two cases of active tuberculosis. Seven (15.2%) patients died while on therapy or shortly after discontinuing ruxolitinib. The causes of death were pulmonary alveolar haemorrhage, disease progression, disseminated intravascular coagulation post cardiac valve surgery, pneumonia complicated by sepsis/ hemophagocytic lymphohistiocytosis (HLH) and COVID infection. Among these, 2 patients died within one month of stopping ruxolitinib. The possibility of ruxolitinib discontinuation syndrome (RDS) was considered retrospectively in these patients. The overall mean survival time was 145.4 ±16 months (95% CI: 114 - 176.8months). Discussion:At the time of last follow-up, more than half of the patients in our study group had either discontinued therapy or were lost to follow up. The most common reason for discontinuation was financial burden, the other reasons being disease progression and intolerance. In our setting, the patients entail an annual cost of approximately 2560 USD, 4530 USD and 4770 USD for 5mg BD, 15mg BD and 20mg BD respectively within patient assisted programs and much higher outside these programs. In a country like India with a nominal Gross Domestic Product (GDP) per capita of around 2191 USD, this not only reflects the high cost of the drug but also the discordant pricing of the different doses resulting in opting for lower doses. The financial burden of the drug is also reflected in the NICE Appraisal Committee recommendation that though ruxolitinib is clinically effective, it is not cost effective for symptomatic therapy CONCLUSION In spite of having a good symptom response, many of our patients discontinued the drug because of its "financial toxicity". In developing economies, better access to the drug and doing away with suboptimal doses need to be addressed so that the target population can reap its therapeutic effect in entirety. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

High Incidence of Herpes Zoster in Patients Using Ruxolitinib for Myeloproliferative Neoplasms: Need for Prophylaxis.

High Incidence of Herpes Zoster in Patients Using Ruxolitinib for Myeloproliferative Neoplasms: Need for Prophylaxis.

ALL-180 A Case of Refractory Philadelphia-Like Acute Lymphoblastic Leukemia Treated With Ruxolitinib/Blinatumomab and Ruxolitinib/Inotuzumab Ozogamicin Prior to Allogeneic Marrow Transplant

Philadelphia (Ph)-like acute lymphoblastic leukemia (ALL) is a high-risk subset associated with genomic alterations. These alterations can be grouped into major subclasses that either phenocopy BCR-ABL1 or activate JAK/STAT signaling. Ongoing trials suggest that patients harboring ABL-class fusions are candidates for ABL1 inhibitors, whereas alterations activating the JAK-STAT pathway may be amenable to treatment with JAK inhibitors. We hereby describe the first case of the use of ruxolitinib in combination with blinatumomab and inotuzumab in relapsed Ph-like ALL. Case report. Tertiary referral hospital. Ph-like ALL patient harboring a CRLF2 mutation. Our patient received three cycles of first-line Hyper-CVAD: 1A/1B and 2A. BMBx after the third cycle revealed persistent disease. He then received two cycles of second-line ruxolitinib/blinatumomab prior to disease progression. He was then treated with three cycles of third-line ruxolitinib/inotuzumab followed by allogeneic transplant. Reports encouraging the use of JAK inhibitors in CRLF2 Ph-like ALL exist for children, and trials are currently ongoing for adolescents and young adults [NCT03571321]. Ruxolitinib was used at a starting dose of 15 mg BID, as determined by initial dose escalation phase trials testing the safety of ruxolitinib in myelofibrosis. Dose titration (maximum 25 mg BID/100 mg QD) was implemented according to response and platelet and neutrophil counts. Complete response (CR) and measurable residual disease (MRD). After progressing on Hyper-CVAD, our patient switched to ruxolitinib/blinatumomab and achieved CR with negative MRD after only one cycle of treatment. He progressed on this regimen after cycle 2 and moved to third-line ruxolitinib/inotuzumab. After three cycles, he achieved CR and negative MRD and underwent allogeneic transplant from a matched unrelated donor. Today, our patient is 10 months post transplant and remains in clinical and molecular remission. The combination of ruxolitinib plus blinatumomab or inotuzumab is a promising chemotherapy-free salvage regimen given outpatient for relapsed Ph-like ALL. It achieved CR in our patient prior to allo SCT with a limited side effect profile. Further clinical trials adding ruxolitinib to front-line and next-line therapies are needed.

A Phase Ib Dose-finding Study of Panobinostat and Ruxolitinib in Myelofibrosis.

A Phase Ib Dose-finding Study of Panobinostat and Ruxolitinib in Myelofibrosis.

Multifocal Mycobacterium kansasii osteomyelitis in a patient on ruxolitinib

• The presence of non-caseating granulomas on biopsy does not preclude mycobacterial infection, and should trigger careful investigation. • JAK inhibitors such as ruxolitinib increase the risk of mycobacterial infections, making specific investigations critical to diagnostic certainty. • M. Kansasii infection in bones and joints is rare, and is mainly found in immunosuppressed patients. • Biopsy and culture including specifically for mycobacteria should be initiated if there is any clinical suspicion. Mycobacterium kansasii spinal infection is rare. This is the first reported case in a patient taking ruxolitinib. A 69-year-old woman attended the emergency department with severe debilitating lumbar back pain and right sided flank pain. She had experienced persistent right lower chest wall pain following 4 weeks of coryzal symptoms but denied fever or weight loss. She was being treated with ruxolitinib for myelofibrosis. C reactive protein was 9 mg/L. CT and MRI showed bilateral hilar and mediastinal lymphadenopathy, and lytic lesions in the T10 vertebral body and left iliac bone. Noncaseating granuloma were found on endobronchial ultrasound guided lymph node biopsy and on biopsy of the iliac crest, with sarcoid considered a possible diagnosis. On two occasions the patient had pain so severe that she required hospitalisation. Pulsed intravenous corticosteroids was given with symptomatic improvement. Iliac bone biopsy grew Mycobacterium Kansasii at 6-week culture. The patient completed 12 months of treatment (12 months rifampicin and isoniazid, 6 months ethambutol), with resulotion of pain. We present a challenging case of mycobacterial osteomyelitis where there was initial diagnostic uncertainty. Sarcoidosis can involve multiple bony lesions but would not typically cause a spondylodiscitis. A recent pharmacovigilance report highlights that JAK inhibitors such as ruxolitinib increase the risk of mycobacterial infections, making specific investigations critical to diagnostic certainty.

Real-world survival of US patients with intermediate- to high-risk myelofibrosis: impact of ruxolitinib approval

The Janus kinase inhibitor ruxolitinib is approved for the treatment of myelofibrosis (MF) and improved overall survival (OS) versus control therapy in the phase 3 COMFORT trials. The aim of this retrospective analysis was to examine the real-world impact of ruxolitinib on OS in patients with MF. The US Medicare Fee-for-Service claims database (parts A/B/D) was used to identify patients with ≥ 1 inpatient or ≥ 2 outpatient claims with an MF diagnosis (January 2010–December 2017). Eligible patients with MF were ≥ 65 years old (intermediate-1 or higher risk based on age). Patients were divided into 3 groups based on ruxolitinib approval status at diagnosis and ruxolitinib exposure: (1) preapproval, ruxolitinib-unexposed; (2) post-approval, ruxolitinib-unexposed; and (3) post-approval, ruxolitinib-exposed. In total, 1677 patients with MF were included (preapproval [all ruxolitinib-unexposed], n = 278; post-approval, n = 1399 [ruxolitinib-unexposed, n = 1127; ruxolitinib-exposed, n = 272]). Overall, median age was 78 years, and 39.8% were male. Among patients with valid death dates (preapproval, n = 119 [42.8%]; post-approval, ruxolitinib-unexposed, n = 382 [33.9%]; post-approval ruxolitinib-exposed, n = 54 [19.9%]), 1-year survival rates were 55.6%, 72.5%, and 82.3%, and median OS was 13.2 months, 44.4 months, and not reached, respectively. Risk of mortality was significantly lower post- versus preapproval regardless of exposure to ruxolitinib (ruxolitinib-unexposed: adjusted hazard ratio [HR], 0.67; ruxolitinib-exposed: adjusted HR, 0.36; P < 0.001 for both); post-approval, mortality risk was significantly lower in ruxolitinib-exposed versus ruxolitinib-unexposed patients (adjusted HR, 0.61; P = 0.002). Findings from this study complement clinical data of ruxolitinib in MF by demonstrating a survival benefit in a real-world setting.

Inflammatory Pathophysiology as a Contributor to Myeloproliferative Neoplasms.

Myeloid neoplasms, including acute myeloid leukemia (AML), myeloproliferative neoplasms (MPNs), and myelodysplastic syndromes (MDS), feature clonal dominance and remodeling of the bone marrow niche in a manner that promotes malignant over non-malignant hematopoiesis. This take-over of hematopoiesis by the malignant clone is hypothesized to include hyperactivation of inflammatory signaling and overproduction of inflammatory cytokines. In the Ph-negative MPNs, inflammatory cytokines are considered to be responsible for a highly deleterious pathophysiologic process: the phenotypic transformation of polycythemia vera (PV) or essential thrombocythemia (ET) to secondary myelofibrosis (MF), and the equivalent emergence of primary myelofibrosis (PMF). Bone marrow fibrosis itself is thought to be mediated heavily by the cytokine TGF-β, and possibly other cytokines produced as a result of hyperactivated JAK2 kinase in the malignant clone. MF also features extramedullary hematopoiesis and progression to bone marrow failure, both of which may be mediated in part by responses to cytokines. In MF, elevated levels of individual cytokines in plasma are adverse prognostic indicators: elevated IL-8/CXCL8, in particular, predicts risk of transformation of MF to secondary AML (sAML). Tumor necrosis factor (TNF, also known as TNFα), may underlie malignant clonal dominance, based on results from mouse models. Human PV and ET, as well as MF, harbor overproduction of multiple cytokines, above what is observed in normal aging, which can lead to cellular signaling abnormalities separate from those directly mediated by hyperactivated JAK2 or MPL kinases. Evidence that NFκB pathway signaling is frequently hyperactivated in a pan-hematopoietic pattern in MPNs, including in cells outside the malignant clone, emphasizes that MPNs are pan-hematopoietic diseases, which remodel the bone marrow milieu to favor persistence of the malignancy. Clinical evidence that JAK2 inhibition by ruxolitinib in MF neither reliably reduces malignant clonal burden nor eliminates cytokine elevations, suggests targeting cytokine mediated signaling as a therapeutic strategy, which is being pursued in new clinical trials. Greater knowledge of inflammatory pathophysiology in MPNs can therefore contribute to the development of more effective therapy.

Safety and efficacy of the combination of sonidegib and ruxolitinib in myelofibrosis: a phase 1b/2 dose-finding study

AbstractThe sonidegib and ruxolitinib combination was assessed in an open-label study in JAK inhibitor-naive patients with myelofibrosis (MF). The primary objective of phase 1b was to establish the maximum tolerated dose (MTD) and/or recommended phase 2 dose (RP2D) and phase 2 was to assess spleen volume reduction at weeks 24 and 48. Fifty patients were enrolled. In the dose-escalation phase (n = 23), doses for sonidegib once daily/ruxolitinib twice daily were 400/10 mg (level 1, n = 8), 400/15 mg (level 2, n = 10), and 400/20 mg (level 3, n = 5). Two patients had dose-limiting toxicity at level 2: increased blood creatine phosphokinase (grades 3 and 4, n = 1 each). MTD/RP2D was determined as sonidegib 400 mg daily + ruxolitinib 20 mg twice daily. In phase 1b expansion and phase 2 stage 1 (n = 27), by weeks 24 and 48, ≥35% reduction in spleen volume was observed in 44.4% and 29.6% patients, respectively. By weeks 24 and 48, 42.0% and 26.0% patients had ≥50% reduction in Myelofibrosis Symptom Assessment Form total symptom score, respectively. Most common treatment-related adverse events (grade 3/4) were increased blood creatine phosphokinase (18%), anemia (14%), and thrombocytopenia (12%). Four deaths were reported due to multiple organ dysfunction syndrome (on-treatment; no relationship with study treatment), acute myeloid leukemia, MF progression, and aspiration pneumonia. Although well tolerated, this combination will not be further developed in MF patients due to modest overall benefit compared with historical ruxolitinib monotherapy. This trial was registered at www.clinicaltrials.gov as #NCT01787552.

Tracing the decision-making process for myelofibrosis: diagnosis, stratification, and management of ruxolitinib therapy in real-word practice

The management of patients with myelofibrosis (MF) has dramatically changed since the introduction of ruxolitinib as a tailored treatment strategy. However, the perceptions about the use of this drug in clinical practice remain, at times, a matter of discussion. We conducted a survey about the diagnostic evaluation, prognostic assessment, and management of ruxolitinib in real-life clinical practice in 18 Italian hematology centers. At diagnosis, most hematologists do not use genetically or molecularly inspired score systems to assess prognosis, mainly due to scarce availability of next-generation sequencing (NGS) methodology, with NGS conversely reserved only for a subset of lower-risk MF patients with the aim of possibly improving the treatment strategy. Some common points in the management of ruxolitinib were 1) clinical triggers for ruxolitinib therapy, regardless of risk category; 2) evaluation of infectious risk before the starting of the drug; and 3) schedule of monitoring during the first 12 weeks with the need, in some instances, of supportive treatment. Further development of international recommendations and insights will allow the achievement of common criteria for the management of ruxolitinib in MF, before and after treatment, and for the definition of response and failure.

Analysis of Predictive Factors for Early Response to Ruxolitinib in 266 Patients with Myelofibrosis from the Polish Adult Leukemia Group (PALG) Registry

Background: Ruxolitinib (RUX), an inhibitor of JAK1/JAK2 kinases, is the only drug approved for the treatment of myelofibrosis (MF). The main clinical effects of RUX therapy include decrease of splenomegaly and reduction of burden of constitutional symptoms. Importantly, predictive factors influencing response and toxicity of RUX are largely unknown. Since 2017 therapy with RUX has been reimbursed in Poland for patients (pts) with MF, and large proportion of these pts has been followed for drug efficacy and tolerance within registry of the Polish Adult Leukemia Group (PALG). Objectives: The primary objective of the study was to identify baseline factors influencing probability of achievement of early response to RUX in MF. Patients and Methods: We retrospectively analyzed outcome of treatment with RUX after 6 months of therapy within the Polish Ministry of Health RUX reimbursement program in pts with primary MF (PMF) and MF secondary to polycythemia vera (post-PV MF) or essential thrombocythemia (post-ET MF). The inclusion criteria to the RUX reimbursement program were as follows: 1) diagnosis of MF confirmed by a recent bone marrow biopsy, 2) intermediate-2 or high risk IPSS, and 3) presence of splenomegaly and constitutional symptoms. Response to RUX was objectively categorized in regard to splenomegaly and MF symptoms. "Spleen Response" was defined as ≥ 50% reduction of the difference between baseline maximal length of spleen and upper limit of normal (120mm) measured by ultrasonography while "Symptoms Response" was defined as ≥50% reduction of the MF constitutional symptoms as assessed by MPN-SAF TSS score. Influence of potential prognostic factors (age, sex, time from MF diagnosis to RUX treatment, PMF vs post-ET MF and post-PV MF, leukocytosis, number of platelets, hemoglobin level, IPSS, DIPSS, grade of fibrosis in bone marrow, genetic status of MF) on probability of response was tested by univariate and multivariate logistic regression. Results: We enrolled 266 MF pts (56.8% PMF, 26.7% post-PV MF, 16.5% post-ET MF) undergoing treatment with RUX in 14 Polish hematology centers. Pts' median age was 67 years (range 21-86), while 59% of the group were females. Thirty-two% of pts were classified as high risk, 56% as intermediate-2 risk and 12% as intermediate-1 risk according to DIPSS score. JAK V617F mutation was found in 83%, CALR in 12%, MPL in 1.5%, and 3.5% of pts were triple negative. The median time from diagnosis of MF to start of RUX therapy was 30 months (range 0-321). At RUX therapy initiation median spleen length was 210 mm (range 100-300), and median symptoms score was 41 (range 4-93). During first six months the therapy has been continued in all but 26 (9.8%) pts in whom the treatment was withdrawn mainly because of lack of effectiveness. The most common hematologic adverse events included anemia (grade ≥3 in 27% of pts) and thrombocytopenia (grade ≥3 in 8% of pts). Major thrombotic events occurred in 3 pts. Among infectious complication 11 upper respiratory tract infections, 4 urinary tract infections, 3 herpes zoster infections, 3 pneumonias of unknown etiology and 1 case of tuberculosis were reported. Regarding the established categories of response to RUX, at 6th month of therapy "Spleen Response" was detected in 50% of patients. The only pre-treatment factor significantly associated with the probability of achievement of "Spleen Response" by multivariable analysis was leukocytosis ≥25 G/L (OR 3.57, 95%CI 1.40-9.06, p=.007). In contrast "Symptoms Response" after 6 months of RUX therapy was found in larger proportion of patients accounting for 77% of the studied population. Multivariable analysis revealed that time-interval between MF diagnosis and RUX start (p=.028) and platelets &gt;200 G/L (OR 2.09, 95%CI 1.16-3.77, p=.014) remained significant predictors of "Symptoms Response". Conclusions: In this study we found that in real life setting efficacy of RUX is more promising, especially in terms of symptoms reduction, and better tolerated, as compared to the results of randomized COMFORT studies. Furthermore, our analysis revealed that simple laboratory parameters such as leukocytosis and platelets number may constitute useful predictors of early response to RUX therapy. Finally, since shorter time interval between MF diagnosis and RUX therapy correlated with better "Symptoms Response", introducing RUX earlier during the course of the disease may be more beneficial for pts. Disclosures Gora Tybor: Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Golos:Novartis: Honoraria. Sacha:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Lewandowski:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Niesiobedzka-Krezel:Novartis: Honoraria. Bieniaszewska:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Grzybowska-Izydorczyk:Novartis: Honoraria. Seferynska:Novartis: Honoraria. Patkowska:Novartis: Honoraria. Świstek:Novartis: Honoraria. Jamroziak:Janssen: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding.

PP-24 - Combination therapy of pegylated interferon alpha 2a and ruxolitinib in myelofibrosis: a case report

PP-24 - Combination therapy of pegylated interferon alpha 2a and ruxolitinib in myelofibrosis: a case report

Ruxolitinib in myelofibrosis: solutions for side effects and treatment failure

Myelofibrosis(MF) is a type of myeloproliferative neoplasms which is difficult to be treated. With the discovery of V617F mutation in Janus kinase(JAK)2, JAK inhibitor provides a new treatment strategy for patients with myelofibrosis.Ruxolitinib is the first JAK1/2 inhibitor which approved by the Food and Drug Administration(FDA) for the treatment of patients with international prognostic scoring system(IPSS)intermediate-2 or high risk myelofibrosis. In clinical experiments, ruxolitinib demonstrates significant improvements in splenomegaly and disease-related constitutional symptoms, and prolongs patients′ overall survival. However, the side effects of the drug (hematocytopenia, infections and secondary neoplasms) and treatment failure of some patients has been observed in treatments. The adverse reaction and solutions of ruxlitinib; the definition, reason, high risk factors and prognosis of treatment failure; the salvage therapy after treatment failure will be discussed in this review. Key words: Primary myelofibrosis; Janus kinases; Treatment failure; Salvage therapy; Adverse reaction; Ruxolitinib