Background: Despite recent advances, follicular lymphoma (FL) remains incurable for most patients (pts). Relapsed/refractory (r/r) FL is associated with decremental treatment responses, accumulating toxicity, and poor survival among early failures of 1st line chemoimmunotherapy. Underscored by the recent approvals of idelalisib, copanlisib, and duvelisib, targeting B-cell receptor (BCR) signaling produces ORR of ~50% in r/r pts; however, new agents with a better therapeutic index over long-term administration are needed. SYK is a key regulator of BCR signaling (upstream of BTK and PI3K), and its inhibition results in clinical activity in FL. Compared with unaffected nodes, lymph nodes from FL pts have greater numbers of follicular helper T cells that express high levels of IL-4, which may support the tumor via the JAK1/3 pathway. Cerdulatinib, an oral, reversible inhibitor of SYK and JAK kinases (JAK1, JAK3, TYK2), previously reported a ~45% ORR in r/r FL as a single agent. Xenograft studies suggest cerdulatinib may combine with rituximab to enhance antitumor activity. We report updated results from a Ph2a study of single-agent cerdulatinib and initial results in combination with rituximab in r/r FL. Methods: This Ph2a study confirmed the safety and efficacy of cerdulatinib 30 mg BID in r/r B- and T-cell lymphoma pts. Dose reductions were permitted to 15 mg BID. Response was assessed by Lugano criteria. Results: As of Jan 2019, enrollment was 40 pts in the single-agent cohort and 11 in the rituximab combination cohort. Median (range) age was 64 (42-81) and median prior therapies was 3 (1-8). Fifty (98%) pts had prior anti-CD20 therapy, and 8 (16%) had prior PI3K or BTK inhibitors. The most common AEs of any grade were diarrhea (47%), nausea (37%), lipase increase (29%), and amylase increase (22%). Grade 3+ AEs in ≥5% pts were lipase increase (24%), diarrhea (12%), amylase increase (10%), nausea (8%), hypertension (8%), and neutropenia (6%). Grade 3+ infections occurred in 6 (12%) pts. One pt had grade 5 multi-organ failure potentially related to study drug. Amylase and lipase increases generally were not associated with abdominal pain or pancreatitis. The safety profile appeared similar in both cohorts. The ORR was 46% as a single agent (5 CRs, 13 PRs in 40 pts) and 67% in the combination cohort (4/6 PRs; 2 pts with SD had a >40% reduction in tumor volume at 1st re-scan). Responses typically occurred after 2 cycles and were durable in the single-agent cohort, with 10 pts on drug for >1 year. Enrollment in the combination cohort is ongoing. Updated safety and efficacy will be presented. Conclusion: The recommended cerdulatinib Ph2 dose of 30 mg BID was tolerable and efficacious in heavily pretreated r/r FL. The cerdulatinib + rituximab combination appears to be well tolerated, with tumor reductions in all evaluable pts. The safety profile and unique MOA of cerdulatinib support further combination studies in FL. Keywords: follicular lymphoma (FL); JAK/STAT; SYK. Disclosures: Smith, S: Consultant Advisory Role: Merck Sharp and Dohme Corp., AstraZeneca; Research Funding: Acerta Pharma BV, AstraZeneca, Ayala (spouse), Bristol-Myers Squibb (spouse), De Novo Biopharma, Genentech, Ignyta (spouse), Incyte Corporation, Merck Sharp and Dohme Corp., Pharmacyclics, Portola Pharmaceuticals, Seattle Genetics. Munoz, J: Consultant Advisory Role: Kite Pharma, Gilead, Pfizer, Pharmacyclics, Bayer, Bristol-Myers Squibb, Janssen, Seattle Genetics, Kyowa Hakko Kirin, Juno Therapeutics, Genentech, Celgene; Honoraria: Kite Pharma, Bayer, Pharmacyclics/Janssen, AstraZeneca, AbbVie/Genentech. Smith, S: Research Funding: Portola. Feldman, T: Consultant Advisory Role: Seattle Genetics/BMS; Honoraria: Takeda, Celgene, Seattle Genetics, AbbVie, Pharmacyclics, Janssen, KITE, BMS; Other Remuneration: Speakers Bureau: Takeda, Celgene, Seattle Genetics, AbbVie, Pharmacyclics, Janssen, KITE, BMS. Ye, J: Employment Leadership Position: Internal Medicine, University of Michigan, Rogel Cancer Center; Research Funding: Abbvie, Takeda, Celgene, Onyx, Sanofi, Karyopharm, Janssen, MingSight, Portola. de Vos, S: Consultant Advisory Role: Portola (participation in advisory board); Honoraria: Portola (participation in advisory board). Hess, B: Employment Leadership Position: MD, Assistant Professor at MUSC. Miller, C: Consultant Advisory Role: Consultant Verastem, Incyte; Honoraria: Verastem, Incyte, Takeda; Research Funding: Verastem, Incyte, Portola, Takeda. Khatcheressian, J: Employment Leadership Position: partners Virginia Cancer Institute. Birrell, M: Employment Leadership Position: Portola. Leeds, J: Employment Leadership Position: Portola; Stock Ownership: Portola. Coffey, G: Employment Leadership Position: Portola; Stock Ownership: Portola; Research Funding: Portola. Conley, P: Employment Leadership Position: Portola; Stock Ownership: Portola. Michelson, G: Employment Leadership Position: Portola; Stock Ownership: Portola. Curnutte, J: Employment Leadership Position: Executive Vice President, Research and Development, Portola Pharmaceuticals; Stock Ownership: Portola. Hamlin, P: Consultant Advisory Role: Sandoz, Karyopharm, Celgene, AstraZeneca, Juno; Research Funding: Portola, Molecular templates, Incyte, Seattle Genetics, Novartis, Janssen; Other Remuneration: Janssen DSMC.
Autologous bone marrow transplantation (BMT) has not been curative in chronic myeloid leukemia (CML), because of the inability to purge CML from the autograft and the absence of the allogeneic T cell-mediated antileukemic activity.However, recent advances demonstrate that normal progenitors can be selected from CML m a rrows by a variety of techniques, including isolation by their small size.Furt h e rm o re, we found that myeloid g rowth factors have a potent antileukemic effect against CML pro g e n i t o r s in vitro by inducing their terminal diff e rentiation.Based on these data, we initiated a trial of autologous BMT in patients with high-risk CML.Autografts w e re processed in an attempt to enrich for normal progenitors, first by isolating small cells by counterflow centrifugal elutriation and then incubating them in granulocyte-macrophage colony-stimulating factor (GM-CSF) for 72 hours.After a conditioning regimen of busulfan and cyclophosphamide, all patients received GM-CSF daily for 2 months.The median age of the 13 patients in the trial was 45 years (range 17-56 years).The median duration of disease before BMT was 24 months (range 13-72 months).Eight patients were in chronic phase (CP), and five were in accelerated phase (AP).All patients failed to achieve a cytogenetic response to interf e ro n -␣ and were 100% Philadelphia chromosome (Ph) ϩ b e f o re BMT.There were three transplant-related deaths, all AP patients.All of the remaining 10 patients engrafted with some degree of Ph -hematopoiesis; despite high-risk features, nine patients engrafted 100% Ph -.All patients relapsed cytogenetically at a median of 6 months (range 4-22 months).These results demonstrate that autologous BMT can consistently induce complete Ph -engraftment in CP patients.GM-CSF appears to produce a clinical antileukemic effect against CML after autologous BMT.
We hypothesized that chemoprophylaxis with the echinocandin micafungin would be an effective agent for antifungal prophylaxis during neutropenia in patients undergoing hematopoietic stem cell transplantation (HSCT). We therefore conducted a randomized, double-blind, multi-institutional, comparative phase III trial, involving 882 adult and pediatric patients, of 50 mg of micafungin (1 mg/kg for patients weighing <50 kg) and 400 mg of fluconazole (8 mg/kg for patients weighing <50 kg) administered once per day. Success was defined as the absence of suspected, proven, or probable invasive fungal infection (IFI) through the end of therapy and as the absence of proven or probable IFI through the end of the 4-week period after treatment. The overall efficacy of micafungin was superior to that of fluconazole as antifungal prophylaxis during the neutropenic phase after HSCT (80.0% in the micafungin arm vs. 73.5% in the fluconazole arm [difference, 6.5%]; 95% confidence interval, 0.9%-12%; P=.03). This randomized trial demonstrates the efficacy of an echinocandin for antifungal prophylaxis in neutropenic patients.
Many patients with chronic myeloid leukemia in chronic phase experience chronic treatment-related adverse events (AEs) during imatinib therapy. These AEs can impair quality of life and lead to reduced treatment adherence, which is associated with poor clinical outcomes.
Ruxolitinib has been the cornerstone of pharmacologic therapy for myelofibrosis for over a decade. However, the last several years have witnessed the regulatory approval of other Janus kinase (JAK) inhibitors for myelofibrosis, i.e. fedratinib, pacritinib, and US approval of momelotinib is widely anticipated in 2023.Due to the multifaceted clinical presentation of myelofibrosis, a watertight definition of ruxolitinib failure has remained elusive, as "progression" on ruxolitinib can take many forms and management is highly nuanced. Yet, the availability of other JAK inhibitors and potential future availability of non-JAK inhibitor agents for myelofibrosis make a consensus on management of ruxolitinib failure critically important. This consensus paper summarizes a discussion between multiple academic and community physician experts, a pharmacist and an advanced practice provider around the issues to be considered for the optimal care of patients with myelofibrosis whose disease is refractory to or does not respond adequately to ruxolitinib, or who exhibit intolerance to ruxolitinib.The panel identified several areas of consensus, as well as some areas where more data to inform evidence-based practice are needed. In some situations, maintaining ruxolitinib while adding another agent, e.g. to address anemia, is appropriate, whereas in others, switching to a different drug has merit.
The Philadelphia chromosome−negative myeloproliferative neoplasms (MPN) myelofibrosis (MF), polycythemia vera (PV), and essential thrombocythemia (ET) negatively affect patient quality of life (QoL) and are associated with increased risk of mortality. The MPN Landmark survey was conducted from May to July 2014 in patients with MF, PV, or ET under active management in the United States. The survey assessed respondent perceptions of disease burden and treatment management and included questions on overall disease burden, QoL, activities of daily living, and work productivity. Outcomes were further analyzed by calculated (ie, not respondent-reported) prognostic risk score and symptom severity quartile. The survey was completed by 813 respondents (MF, n = 207; PV, n = 380; ET, n = 226). The median respondent age in each of the 3 MPN subtypes ranged from 62 to 66 years; median disease duration was 4 to 7 years. Many respondents reported that they had experienced MPN-related symptoms ≥1 year before diagnosis (MF, 49 %; PV, 61 %; ET, 58 %). Respondents also reported that MPN-related symptoms reduced their QoL, including respondents with low prognostic risk scores (MF, 67 %; PV, 62 %; ET, 57 %) and low symptom severity (MF, 51 %; PV, 33 %; ET, 15 %). Many respondents, including those with a low prognostic risk score, reported that their MPN had caused them to cancel planned activities or call in sick to work at least once in the preceding 30 days (cancel planned activities: MF, 56 %; PV, 35 %; ET, 35 %; call in sick: MF, 40 %; PV, 21 %; ET, 23 %). These findings of the MPN Landmark survey support previous research about the symptom burden experienced by patients with MPNs and are the first to detail the challenges that patients with MPNs experience related to reductions in activities of daily living and work productivity.
7012 Background: The JAK1/JAK2 inhibitor RUX has demonstrated rapid and durable improvements in splenomegaly and symptoms and improved survival in the phase 3 COMFORT studies in pts with MF. Here we report final long-term safety and efficacy results after 5 years (y) of RUX treatment in COMFORT-I. Methods: In COMFORT-I, 309 pts were randomized (1:1) to RUX or placebo (PBO). RUX starting dose was based on baseline platelet count (100–200×109/L: 15 mg BID; > 200×109/L: 20 mg BID). Pts receiving PBO could crossover to RUX after the primary analysis (when all pts completed week [wk] 24 and half completed wk 36) or at any time if they had prespecified worsening of splenomegaly. The primary endpoint was the proportion of pts achieving ≥ 35% reduction in spleen volume (SV) at wk 24. Overall survival (OS) was estimated by Kaplan-Meier analysis according to randomized treatment. Results: Median follow-up was 268 wk at the time of this analysis. Of 154 pts randomized to PBO, 111 crossed over to RUX; median time to crossover was 41.1 wk. At wk 24, pts originally randomized to RUX had a mean SV reduction of 31.6%; this was durable for pts who continued on RUX (mean SV reduction at wk 264, 37.6%). Median duration of ≥ 35% SV reduction was 168.3 wk (range, 107.7–NE). OS favored RUX (HR 0.69; 95% CI: 0.50, 0.96; P= 0.025), with 69 and 82 deaths among pts originally randomized to RUX and PBO, respectively. Median OS has not been reached for RUX. Mean platelet count and Hgb initially decreased through 3 mo. Mean Hgb gradually increased toward baseline. After wk 24, mean Hgb and platelet count generally remain stable through 5 y. New onset grade 3 or 4 anemia was 25.2% for the RUX arm and 26.1% for PBO crossover; grade 3 or 4 thrombocytopenia occurred in 12.3% and 13.5% of pts, respectively. Notable AEs included herpes zoster (10.3% and 13.5% of RUX and PBO crossover pts, respectively); basal cell carcinoma (7.7% and 9.0%, respectively); acute myeloid leukemia (5 pts in each arm). Conclusions: After a median follow-up of 268 wk, the hazard ratio for OS favored pts randomized to RUX over those randomized to PBO, and SV reductions were sustained with long-term therapy. Collectively, these data support the durable efficacy and long-term safety of RUX in pts with MF. Clinical trial information: NCT00952289.
