Leukapheresis and Tisagenlecleucel Manufacturing Outcomes in Patients Age <3 Years with Relapsed/Refractory Acute Lymphoblastic Leukemia.

Tisagenlecleucel is approved for the treatment of relapsed/refractory (r/r) B cell acute lymphoblastic leukemia (B-ALL) in patients up to age 25 years based on the results of a pivotal trial (ELIANA) in pediatric and young adult patients. However, that trial did not include patients age <3 years because of the challenges posed by leukapheresis of very young and low-weight patients. Data on leukapheresis material and manufacturing outcomes among patients age <3 years have been collected since the time of global regulatory approval. Here we report leukapheresis characteristics and manufacturing outcomes for tisagenlecleucel produced for patients age <3 years in US and non-US commercial settings. Qualified patients with r/r B-ALL were age <3 years at the time of request for commercial tisagenlecleucel, with manufacturing data starting after August 30, 2017 (date of first US Food and Drug Administration approval). Leukapheresis and manufacturing outcomes data were stratified by age and weight. CD3+ cell count and CD3+/total nucleated cell (TNC) percentages were obtained from the leukapheresis material; leukocyte subpopulations were obtained via quality control vials. Of the 146 tisagenlecleucel quality control batches analyzed for CD3+ cell count and CD3+/TNC%, 86 batches (84 patients) were from US sites and 60 batches were from non-US sites. The median patient age and weight were 1.2 years and 10.4 kg at US sites and 1.5 years and 10.5 kg at non-US sites. Globally, 137 of 146 batches (94%) were manufactured within specifications across 16 countries. Among tisagenlecleucel batches manufactured in the United States between 2017 and 2021, there was a trend toward increasing CD3+ counts, CD3+/TNC%, and manufactured dose of chimeric antigen receptor (CAR) T cells; there was no difference in median days of collection by patient age or weight. Globally, a trend toward 1 or more potential additional collection days was observed for patients weighing ≤10 kg. Leukapheresis and tisagenlecleucel manufacturing in pediatric patients with r/r B-ALL age <3 years, including infants (<1 year), and low weight are feasible. As global experience with leukapheresis and patient identification for CAR-T cell therapy increased over time, a corresponding improvement in tisagenlecleucel manufacturing success has been observed. Clinical outcome data for these patients are currently being explored.

Three-Year Update of Tisagenlecleucel in Pediatric and Young Adult Patients With Relapsed/Refractory Acute Lymphoblastic Leukemia in the ELIANA Trial.

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported.In the primary analysis of the global phase II ELIANA trial (ClinicalTrials.gov identifier: NCT02435849), tisagenlecleucel provided an overall remission rate of 81% in pediatric and young adult patients with relapsed or refractory B-cell acute lymphoblastic leukemia (R/R B-ALL), with 59% of responders remaining relapse-free at 12 months. Here, we report an update on efficacy, safety, and patient-reported quality of life in 79 pediatric and young adult patients with R/R B-ALL following a median follow-up of 38.8 months. The overall remission rate was 82%. The median event-free survival was 24 months, and the median overall survival was not reached. Event-free survival was 44% (95% CI, 31 to 57) and overall survival was 63% (95% CI, 51 to 73) at 3 years overall (most events occur within the first 2 years). The estimated 3-year relapse-free survival with and without censoring for subsequent therapy was 52% (95% CI, 37 to 66) and 48% (95% CI, 34 to 60), respectively. No new or unexpected long-term adverse events were reported. Grade 3/4 adverse events were reported in 29% of patients > 1 year after infusion; grade 3/4 infection rate did not increase > 1 year after infusion. Patients reported improvements in quality of life up to 36 months after infusion. These findings demonstrate favorable long-term safety and suggest tisagenlecleucel as a curative treatment option for heavily pretreated pediatric and young adult patients with R/R B-ALL.

Assessment of Healthcare Resource Utilization and Hospitalization Costs in Patients With Relapsed or Refractory Follicular Lymphoma Undergoing CAR-T Cell Therapy With Tisagenlecleucel: Results From the ELARA Study.

Follicular lymphoma (FL) is generally considered an indolent disease, although patients with relapsing FL experience progressively shorter durations of response to second or later lines of therapy. The ongoing ELARA trial in adult patients with relapsed/refractory (r/r) FL treated with tisagenlecleucel demonstrated an overall response rate of 86.2% and a complete response rate of 69.1%, with no treatment-related deaths. Tisagenlecleucel was administered in the outpatient setting in 18% of patients in ELARA; however, there is limited knowledge concerning the impact of inpatient versus outpatient tisagenlecleucel administration on healthcare resource utilization (HCRU) among patients with r/r FL. Here, we present the first HCRU analysis among patients with r/r FL who received tisagenlecleucel in the Phase II, single-arm, multicenter ELARA trial. HCRU was characterized using hospitalization data from day 1 to month 2 after tisagenlecleucel infusion. Information on length of stay, facility use, and discharge was assessed in patients who received tisagenlecleucel in the outpatient or inpatient setting. All costs were inflated to 2020 US dollars. As of August 3, 2021 (20-month median follow-up), 17/97 (18%) r/r FL patients were infused in an outpatient setting. Patients infused in the outpatient setting generally had favorable Eastern Cooperative Oncology Group performance status and Follicular Lymphoma International Prognostic Index scores, and less bulky disease at baseline. However, the outpatients had higher proportions of patients with grade 3A FL, primary refractory disease, and >5 lines of prior therapy compared with inpatients. Forty-one percent of patients treated in the outpatient setting did not require hospitalization within 30 days after infusion, and outpatients who did require hospitalization had a shorter average length of stay compared with inpatients (5 versus 13 days). No outpatients required intensive care unit (ICU) admission, whereas 9% of inpatients were admitted to the ICU. The mean postinfusion hospitalization costs were $7477 and $40,054 in the outpatient and inpatient settings, respectively. Efficacy between both groups was similar. Tisagenlecleucel can be safely administered to some patients in the outpatient setting, which may reduce HCRU for patients with r/r FL.

Tisagenlecleucel in pediatric and young adult patients with Down syndrome-associated relapsed/refractory acute lymphoblastic leukemia.

Down syndrome-associated acute lymphoblastic leukemia (DS-ALL) patients suffer risk of chemotherapy-associated toxicities and poor outcomes. We evaluated tisagenlecleucel in 16 patients with DS-ALL in two phase 2 trials (ELIANA [NCT02435849], ENSIGN [NCT02228096]) and a phase 3b, managed access protocol (B2001X [NCT03123939]). Patients were 5-22 years old, had a median of two prior lines of therapy (range, 1-4), and four (25%) had prior stem cell transplants. Fourteen of 16 patients (88%) achieved complete remission (CR) or CR with incomplete blood count recovery (CRi); 12 of 14 (86%) with CR/CRi were minimal residual disease-negative. With a median follow-up of 13.2 months (range, 0.5-49.3 months), six patients (43%) relapsed after CR (three, CD19-negative; three, unknown) between 80-721 days post-infusion. Ongoing remissions in nine patients ranged from 6-48 months. Any-grade and grade 3/4 AEs occurred in 16 and 14 patients, respectively; 44% experienced grade 3/4 cytokine release syndrome and 13% experienced grade 3/4 neurological events. Grade 3/4 prolonged cytopenias occurred in 44% of patients. No grade 3/4 infections were observed. Tisagenlecleucel expansion and long-term persistence were consistent with previous reports. Comparable to ALL patients without DS, tisagenlecleucel produced high remission rates, manageable side-effects, and promising long-term outcomes in pediatric/young adult patients with DS-ALL.

Children with Down syndrome have a 20 times higher risk of developing a type of blood cancer called Down syndrome-associated acute lymphoblastic leukemia (ALL). Children who develop Down syndrome-associated ALL typically receive chemotherapy to treat their cancer; however, they can experience severe toxicity or other consequences from these therapies, especially stem cell transplant, and have a poor prognosis if their disease returns after treatment. These children need an effective but less toxic treatment option. Tisagenlecleucel is a chimeric antigen receptor-T cell therapy that specially modifies the patient's own T-cells to recognize and attack the cancer cells. Tisagenlecleucel is approved for use in children and young adults with ALL whose disease reappears after two or more treatments or whose disease doesn't respond to treatment. Here we present data from 16 patients across three clinical studies showing that tisagenlecleucel is well-tolerated and an effective treatment option for children and young adults with Down syndrome-associated ALL, and was similar to what is observed in patients without Down syndrome. Taken together, patients with Down syndrome-associated ALL have unique medical needs, and tisagenlecleucel may help them live longer, avoid stem cell transplantation, and the toxicity from chemotherapy.

Indirect comparison of tisagenlecleucel and blinatumomab in pediatric relapsed/refractory acute lymphoblastic leukemia.

In the absence of head-to-head trials, an indirect-treatment comparison can estimate the treatment effect of tisagenlecleucel in comparison with blinatumomab on rates of complete remission (CR) and overall survival (OS) in patients with relapsed or primary refractory (R/R) acute lymphoblastic leukemia (ALL). Patient-level data from two pivotal trials, ELIANA (tisagenlecleucel; n = 79) and MT103-205 (blinatumomab; n = 70), were used in comparisons of CR and OS, controlling for cross-trial difference in available patient characteristics. Five different adjustment approaches were implemented: stabilized inverse probability of treatment weight (sIPTW); trimmed sIPTW; stratification by propensity score quintiles; adjustment for prognostic factors; and adjustment for both prognostic factors and propensity score. Comparative analyses indicate that treatment with tisagenlecleucel was associated with a statistically significant higher likelihood of achieving CR and lower hazard of death than treatment with blinatumomab. The tisagenlecleucel group exhibited a higher likelihood of CR than the blinatumomab group in every analysis regardless of adjustment approach (odds ratios: 6.71-9.76). Tisagenlecleucel was also associated with a lower hazard of death than blinatumomab in every analysis, ranging from 68% to 74% lower hazard of death than with blinatumomab, determined using multiple adjustment approaches (hazard ratios: 0.26-0.32). These findings support the growing body of clinical trials and real-world evidence demonstrating that tisagenlecleucel is an important treatment option for children and young adults with R/R ALL.

Long-term clinical outcomes of tisagenlecleucel in patients with relapsed or refractory aggressive B-cell lymphomas (JULIET): a multicentre, open-label, single-arm, phase 2 study.

BACKGROUND: In the primary analysis of the pivotal JULIET trial of tisagenlecleucel, an autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy, the best overall response rate was 52% and the complete response rate was 40% in 93 evaluable adult patients with relapsed or refractory aggressive B-cell lymphomas. We aimed to do a long-term follow-up analysis of the clinical outcomes and correlative analyses of activity and safety in the full adult cohort. METHODS: In this multicentre, open-label, single-arm, phase 2 trial (JULIET) done at 27 treatment sites in ten countries (Australia, Austria, Canada, France, Germany, Italy, Japan, the Netherlands, Norway, and the USA), adult patients (≥18 years) with histologically confirmed relapsed or refractory large B-cell lymphomas who were ineligible for, did not consent to, or had disease progression after autologous haematopoietic stem-cell transplantation, with an Eastern Cooperative Oncology Group performance status of 0-1 at screening, were enrolled. Patients received a single intravenous infusion of tisagenlecleucel (target dose 5 × 108 viable transduced CAR T cells). The primary endpoint was overall response rate (ie, the proportion of patients with a best overall disease response of a complete response or partial response using the Lugano classification, as assessed by an independent review committee) at any time post-infusion and was analysed in all patients who received tisagenlecleucel (the full analysis set). Safety was analysed in all patients who received tisagenlecleucel. JULIET is registered with ClinialTrials.gov, NCT02445248, and is ongoing. FINDINGS: Between July 29, 2015, and Nov 2, 2017, 167 patients were enrolled. As of Feb 20, 2020, 115 patients had received tisagenlecleucel infusion and were included in the full analysis set. At a median follow-up of 40·3 months (IQR 37·8-43·8), the overall response rate was 53·0% (95% CI 43·5-62·4; 61 of 115 patients), with 45 (39%) patients having a complete response as their best overall response. The most common grade 3-4 adverse events were anaemia (45 [39%]), decreased neutrophil count (39 [34%]), decreased white blood cell count (37 [32%]), decreased platelet count (32 [28%]), cytokine release syndrome (26 [23%]), neutropenia (23 [20%]), febrile neutropenia (19 [17%]), hypophosphataemia (15 [13%]), and thrombocytopenia (14 [12%]). The most common treatment-related serious adverse events were cytokine release syndrome (31 [27%]), febrile neutropenia (seven [6%]), pyrexia (six [5%]), pancytopenia (three [3%]), and pneumonia (three [3%]). No treatment-related deaths were reported. INTERPRETATION: Tisagenlecleucel shows durable activity and manageable safety profiles in adult patients with relapsed or refractory aggressive B-cell lymphomas. For patients with large B-cell lymphomas that are refractory to chemoimmunotherapy or relapsing after second-line therapies, tisagenlecleucel compares favourably with respect to risk-benefit relative to conventional therapeutic approaches (eg, salvage chemotherapy). FUNDING: Novartis Pharmaceuticals.

Comparing the safety and efficacy of ruxolitinib in patients with Dynamic International Prognostic Scoring System low-, intermediate-1-, intermediate-2-, and high-risk myelofibrosis in JUMP, a Phase 3b, expanded-access study.

Ruxolitinib, a potent Janus kinase 1/2 inhibitor, has demonstrated durable improvements in patients with myelofibrosis. In this analysis of the Phase 3b JUMP study, which included patients aged ≥18 years with a diagnosis of primary or secondary myelofibrosis, we assessed the safety and efficacy of ruxolitinib in patients stratified by Dynamic International Prognostic Scoring System (DIPSS) risk categories. Baseline characteristic data were available to assess DIPSS status for 1844 of the 2233 enrolled patients; 60, 835, 755, and 194 in the low-, intermediate (Int)-1-, Int-2-, and high-risk groups, respectively. Ruxolitinib was generally well tolerated across all risk groups, with an adverse-event (AE) profile consistent with previous reports. The most common hematologic AEs were thrombocytopenia and anemia, with highest rates of Grade ≥3 events in high-risk patients. Approximately, 73% of patients experienced ≥50% reductions in palpable spleen length at any point in the ≤24-month treatment period, with highest rates in lower-risk categories (low, 82.1%; Int-1, 79.3%; Int-2, 67.1%; high risk, 61.6%). Median time to spleen length reduction was 5.1 weeks and was shortest in lower-risk patients. Across measures, 40%-57% of patients showed clinically meaningful symptom improvements, which were observed from 4 weeks after treatment initiation and maintained throughout the study. Overall survival (OS) was 92% at Week 72 and 75% at Week 240 (4.6 years). Median OS was longer for Int-2-risk than high-risk patients (253.6 vs. 147.3 weeks), but not evaluable in low-/Int-1-risk patients. By Week 240, progression-free survival (PFS) and leukemia-free survival (LFS) rates were higher in lower-risk patients (PFS: low, 90%; Int-1, 82%; Int-2, 46%; high risk, 15%; LFS: low, 92%; Int-1, 86%; Int-2, 58%; high risk, 19%). Clinical benefit was seen across risk groups, with more rapid improvements in lower risk patients. Overall, this analysis indicates that ruxolitinib benefits lower-risk DIPSS patients in addition to higher risk.

Efficacy and safety of a novel dosing strategy for ruxolitinib in the treatment of patients with myelofibrosis and anemia: the REALISE phase 2 study.

Anemia is a frequent manifestation of myelofibrosis (MF) and there is an unmet need for effective treatments in anemic MF patients. The REALISE phase 2 study (NCT02966353) evaluated the efficacy and safety of a novel ruxolitinib dosing strategy with a reduced starting dose with delayed up-titration in anemic MF patients. Fifty-one patients with primary MF (66.7%), post-essential thrombocythemia MF (21.6%), or post-polycythemia vera MF (11.8%) with palpable splenomegaly and hemoglobin <10 g/dl were included. Median age was 67 (45-88) years, 41.2% were female, and 18% were transfusion-dependent. Patients received 10 mg ruxolitinib b.i.d. for the first 12 weeks, then up-titrations of up to 25 mg b.i.d. were permitted, based on efficacy and platelet counts. Overall, 70% of patients achieved a ≥50% reduction in palpable spleen length at any time during the study. The most frequent adverse events leading to dose interruption/adjustment were thrombocytopenia (17.6%) and anemia (11.8%). Patients who had a dose increase had greater spleen size and higher white blood cell counts at baseline. Median hemoglobin levels remained stable and transfusion requirements did not increase compared with baseline. These results reinforce the notion that it is unnecessary to delay or withhold ruxolitinib because of co-existent or treatment-emergent anemia.

Long-term treatment-free remission in patients with chronic myeloid leukemia after second-line nilotinib: ENESTop 5-year update.

The ENESTop study evaluated treatment-free remission (TFR) in patients with chronic myeloid leukemia (CML) in chronic phase who had received ≥3 years of tyrosine kinase inhibitor therapy and achieved sustained deep molecular response only after switching from imatinib to nilotinib. After 1-year nilotinib consolidation, 126 patients attempted TFR. At 48 weeks (primary analysis), 57.9% (73/126) were in TFR. In the present analysis at 5 years, 42.9% (54/126) were in TFR. Since the 48-week analysis, among patients who left the TFR phase, 58% (11/19) did not have a loss of molecular response and discontinued for other reasons. Of the 59 patients who reinitiated nilotinib upon loss of major molecular response (MMR) or confirmed loss of MR4, 98.3% regained MMR, 94.9% regained MR4, and 93.2% regained MR4.5. Overall adverse event rates decreased over the 5 years of TFR. In patients reinitiating nilotinib, there was a cumulative increase in cardiovascular events with longer nilotinib exposure. No disease progression or CML-related deaths were reported. Overall, these results confirm the durability and safety of TFR for patients receiving second-line nilotinib. Cardiovascular risk should be carefully managed, particularly when reinitiating treatment after TFR.

Analysis of predictors of response to ruxolitinib in patients with myelofibrosis in the phase 3b expanded-access JUMP study.

Data from the large, prospective, multinational, phase 3b JUMP study were analyzed to identify factors predictive of spleen and symptom responses in myelofibrosis patients receiving ruxolitinib. Factors associated with higher spleen response rates included International Prognostic Scoring System (IPSS) low/intermediate-1 risk vs intermediate-2/high risk (43.1% vs 30.6%; adjusted OR [aOR] 0.65 [95% CI 0.44-0.95]), ruxolitinib as first- vs second- or later-line therapy (40.2% vs 31.5%; aOR 0.53 [95% CI 0.38-0.75]), and a ruxolitinib total daily dose at Week 12 of >20 mg/day vs ≤20 mg/day (41.3% vs 30.4%; aOR 0.47 [95% CI 0.33-0.68]). No association was seen between baseline characteristics or total daily dose at Week 12 and symptom response. Ruxolitinib led to higher spleen response rates in patients with lower IPSS risk, and when used earlier in treatment. Higher doses of ruxolitinib were associated with higher spleen response rates, but not with symptom improvement.Trial registrationINC424 for patients with primary myelofibrosis, post polycythemia myelofibrosis or post-essential thrombocythemia myelofibrosis (JUMP).2010-024473-39; NCT01493414Date of registration: 16 December 2011https://www.clinicaltrialsregister.eu/ctr-search/search?query=2010-024473-39https://clinicaltrials.gov/ct2/show/NCT01493414.

A subgroup analysis of JUMP, a phase IIIb, expanded-access study evaluating the safety and efficacy of ruxolitinib in patients with myelofibrosis in a Brazilian cohort

Abstract Introduction Ruxolitinib has been approved for the treatment of myelofibrosis (MF). In this study, we present safety and efficacy findings from an analysis of 104 patients with intermediate- and high-risk MF in a Brazilian cohort of the JUMP study who received treatment with ruxolitinib. Methods JUMP is a single-arm, open-label, phase IIIb, expanded-access study. The primary endpoint was to evaluate the safety and tolerability (frequency, duration, and severity of adverse events [AEs]) of ruxolitinib. Results All of the 104 patients received the treatment. Median duration of exposure was 35.8 months. The most common hematologic AEs were anemia (57.7), thrombocytopenia (38.5%), neutropenia (11.5%), and leukopenia (9.6%). Second malignancies (all grades) occurred in 19.2% of patients (n = 20). Serious AEs were reported in 62.5% of patients (n = 65). The proportions of patients with ≥50% reduction from baseline in palpable spleen length at weeks 24 and 48 were 62.7% and 69.2%, respectively. The mean change from the baseline in the Functional Assessment of Cancer Therapy (FACT)-Lymphoma total score was 10.8 [15.6%] at week 4, 12.6 [14.1%] at week 24, and 12.2 [14.3%] at week 48. The mean change from the baseline for the Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue scale was 3.9 [42.8%] at week 4, 4.9 [29.9%] at week 24, and 4.7 [28%] at week 48. At week 48, the estimated progression-free survival, leukemia-free survival, and overall survival probabilities were 91%, 91% and 93%, respectively Overall, 21 deaths were observed in the present study. Conclusion Findings from this study suggest that ruxolitinib could be evaluated as a standard-of-care treatment for the MF population in need of a viable treatment option. NCT01493414

Primary analysis of JUMP, a phase 3b, expanded-access study evaluating the safety and efficacy of ruxolitinib in patients with myelofibrosis, including those with low platelet counts.

Ruxolitinib is a potent Janus kinase (JAK) 1/JAK2 inhibitor approved for the treatment of myelofibrosis (MF). Ruxolitinib was assessed in JUMP, a large (N = 2233), phase 3b, expanded-access study in MF in countries without access to ruxolitinib outside a clinical trial, which included patients with low platelet counts (<100 × 109 /l) and patients without splenomegaly - populations that have not been extensively studied. The most common adverse events (AEs) were anaemia and thrombocytopenia, but they rarely led to discontinuation (overall, 5·4%; low-platelet cohort, 12·3%). As expected, rates of worsening thrombocytopenia were higher in the low-platelet cohort (all grades, 73·2% vs. 53·5% overall); rates of anaemia were similar (all grades, 52·9% vs. 59·5%). Non-haematologic AEs, including infections, were mainly grade 1/2. Overall, ruxolitinib led to meaningful reductions in spleen length and symptoms, including in patients with low platelet counts, and symptom improvements in patients without splenomegaly. In this trial, the largest study of ruxolitinib in patients with MF to date, the safety profile was consistent with previous reports, with no new safety concerns identified. This study confirms findings from the COMFORT studies and supports the use of ruxolitinib in patients with platelet counts of 50-100 × 109 /l. (ClinicalTrials.gov identifier NCT01493414).

Patient-reported long-term quality of life after tisagenlecleucel in relapsed/refractory diffuse large B-cell lymphoma.

The JULIET phase 2 trial evaluated a single infusion of tisagenlecleucel in adult patients with relapsed/refractory (r/r) diffuse large B-cell lymphoma (DLBCL). The objective of the current analysis was to evaluate patient-reported health-related quality of life (HRQoL) with a median follow-up of 19.3 months among patients infused with a single dose of tisagenlecleucel. Patients enrolled were ≥18 years of age with r/r DLBCL after ≥2 lines of therapy and had either undergone a failed autologous stem cell transplant or were ineligible for the procedure. Two validated HRQoL instruments, Functional Assessment of Cancer Therapy-Lymphoma (FACT-Lym) and Short Form-36 (SF-36) Health Survey, were used to measure HRQoL at baseline and months 3, 6, 12, and 18. At data cutoff (21 May 2018), 115 patients had received tisagenlecleucel infusion. Among the 99 patients evaluated, overall response rate was 54%, and 40% of patients achieved complete response (CR). Initially, 108 patients completed the HRQoL assessments at baseline, including 57 patients who eventually achieved CR or partial response (PR). Further, 30 and 21 patients in clinical response who completed assessments at baseline also completed assessments at months 12 and 18, respectively. Patients who achieved CR or PR sustained HRQoL improvement in all FACT scores at all time points. SF-36 instruments showed improvement above the minimal clinically important differences on 5 of 8 subscales. Long-term follow-up in the phase 2 JULIET study demonstrated that patients with r/r DLBCL who respond to tisagenlecleucel therapy had sustained, clinically meaningful improvements in HRQoL. This trial was registered at www.clinicaltrials.gov as #NCT02445248.

A subgroup analysis of JUMP, a phase IIIb, expanded-access study evaluating the safety and efficacy of ruxolitinib in patients with myelofibrosis in a Brazilian cohort.

INTRODUCTION: Ruxolitinib has been approved for the treatment of myelofibrosis (MF). In this study, we present safety and efficacy findings from an analysis of 104 patients with intermediate- and high-risk MF in a Brazilian cohort of the JUMP study who received treatment with ruxolitinib. METHODS: JUMP is a single-arm, open-label, phase IIIb, expanded-access study. The primary endpoint was to evaluate the safety and tolerability (frequency, duration, and severity of adverse events [AEs]) of ruxolitinib. RESULTS: All of the 104 patients received the treatment. Median duration of exposure was 35.8 months. The most common hematologic AEs were anemia (57.7), thrombocytopenia (38.5%), neutropenia (11.5%), and leukopenia (9.6%). Second malignancies (all grades) occurred in 19.2% of patients (n=20). Serious AEs were reported in 62.5% of patients (n=65). The proportions of patients with ≥50% reduction from baseline in palpable spleen length at weeks 24 and 48 were 62.7% and 69.2%, respectively. The mean change from the baseline in the Functional Assessment of Cancer Therapy (FACT)-Lymphoma total score was 10.8 [15.6%] at week 4, 12.6 [14.1%] at week 24, and 12.2 [14.3%] at week 48. The mean change from the baseline for the Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue scale was 3.9 [42.8%] at week 4, 4.9 [29.9%] at week 24, and 4.7 [28%] at week 48. At week 48, the estimated progression-free survival, leukemia-free survival, and overall survival probabilities were 91%, 91% and 93%, respectively Overall, 21 deaths were observed in the present study. CONCLUSION: Findings from this study suggest that ruxolitinib could be evaluated as a standard-of-care treatment for the MF population in need of a viable treatment option. NCT01493414.

Tisagenlecleucel in relapsed/refractory diffuse large B-cell lymphoma patients without measurable disease at infusion.

Tisagenlecleucel demonstrated high rates of durable responses in adult patients with relapsed or refractory diffuse large B-cell lymphoma (r/r DLBCL) in the JULIET trial. Most patients (92%) received bridging therapies to control disease after study entry and before tisagenlecleucel infusion. Here, we examine the efficacy and safety of tisagenlecleucel in the subset of 7 patients who achieved complete response (CR) after bridging therapy and before tisagenlecleucel infusion. Tisagenlecleucel rapidly expanded in all 7 patients, and the transgene levels were measurable for up to 2 years after infusion. After infusion, all 7 patients were still in CR at the month 3 evaluation, and 5 of 7 patients remained progression-free >12 months. Adverse events were similar to the overall JULIET population. Cytokine release syndrome (CRS) was reported in 4 of 7 patients (grade 2 = 2 and grade 3 = 2 using the Penn grading scale), and 1 patient experienced grade 1 neurotoxicity. No patient required tocilizumab or steroids for CRS management. These data provide preliminary evidence of tisagenlecleucel efficacy in patients with r/r DLBCL without detectable disease after bridging or salvage therapies and warrant further investigation of tisagenlecleucel as consolidative therapy in future trials. This trial was registered at www.clinicaltrials.gov as #NCT02445248.

Evaluation of Preoperative Serum Levels of CA 125 and Expression of p53 in Ovarian Neoplasms: A Prospective Clinicopathological Study in a Tertiary Care Hospital.

OBJECTIVES: To assess the preoperative serum levels of CA 125 with its diagnostic role and to evaluate the p53 expression in patients of primary ovarian neoplasms. We also wished to judge their relationship with other parameters like clinical staging and histopathologic tumor type. MATERIALS AND METHODS: The present study was conducted on 86 patients during the study period of 2.5 years. Preoperative CA 125 levels were evaluated by an automated immunoassay analyzer. p53 expression was judged immunohistochemically with pre-diluted monoclonal antibody. An objective scoring was done depending on distinct nuclear immunopositivity. RESULTS: Median value of preoperative CA 125 levels was 32 U/mL in benign surface epithelial-stromal tumors (BSEST), 53 U/mL in borderline surface epithelial-stromal tumors (BOT), 346 U/mL in malignant surface epithelial-stromal tumors (MSEST) and 560 U/mL in serous adenocarcinomas (SAC). Most of ovarian tumors were in the FIGO stage I (64 cases, 74.4%), but higher stages (II, III, IV) were observed mostly in MSESTs. SACs displayed the maximum p53 expression. Considering the cut-off value of more than 35 U/mL in CA 125 levels, the sensitivity to diagnose MSESTs was 94.7%. Preoperative CA 125 levels strongly and positively correlated with FIGO staging and p53 expression. Similarly p53 expression strongly and positively correlated with FIGO staging and histopathological categories. CONCLUSION: Higher values of preoperative CA 125 levels and higher expression p53 are associated with MSESTs and BOTs especially of serous type. They strongly correlate with each other and with tumor stage. But there is no serum CA 125 concentration that can clearly differentiate benign and malignant ovarian masses.