The Janus-kinase (JAK) pathway plays a critical role in normal hematopoiesis. In two phase 3 studies, the JAK1/JAK2 inhibitor ruxolitinib (RUX) demonstrated clinical benefit over placebo (COMFORT-I) ...or best available therapy (COMFORT-II) in patients with intermediate-2 or high-risk myelofibrosis (MF). Anemia and thrombocytopenia, the most common adverse events associated with RUX treatment, were dose-dependent and expected based on RUX's mechanism of action. These events were successfully managed and few RUX-treated patients discontinued for anemia or thrombocytopenia (<1% for each event). The ability to identify patients who would most likely benefit from a dose adjustment may contribute to improved patient management. Therefore, an analysis was conducted in patients who received RUX in COMFORT-I to identify patient characteristics that could help select patients who would potentially benefit from closer monitoring and dose titration in the early period after initiation of therapy.
In COMFORT-I, starting doses in the patients randomized to RUX were 15 mg twice daily (BID) for patients with baseline platelet counts of 100–200 ×109/L (n=55) and 20 mg BID for those with platelet counts >200 ×109/L (n=100). Dose reductions were required for protocol-defined decreases in platelet counts; there was no protocol-mandated dose change for anemia. The time course of dose adjustments and the most common titrated doses by starting dose were evaluated. Logistic regression analyses with baseline hemoglobin (Hgb) level, platelet count, IPSS risk category, sex, and MF type as model effects were conducted to determine predictors of: 1) titration to a RUX dose of ≤10 mg BID within 8 weeks of starting therapy (early dose titration event); or 2) development of grade ≥3 anemia or new need for RBC transfusions (≥2 units of packed RBCs) within 12 weeks of therapy initiation (anemia event). Only baseline platelet count and Hgb emerged as significant predictors (alpha=0.05). Receiver operating characteristics (ROC) analyses were also conducted for these two predictors to determine a clinically relevant cutoff of the underlying predictor variable with a positive predictive value (PPV), true positive rate (TPR), and false positive rate (FPR) obtained at all possible cutoffs and a general goal of obtaining a TPR ≥ 50%, an FPR ≤ 10%, and a high PPV.
Approximately 70% of patients had a dose adjustment within the first 12 weeks of initiating RUX treatment. At week 24, 77% of patients with baseline platelet counts of 100–200 ×109/L and 39% of those with baseline platelet counts >200 ×109/L had titrated to a reduced RUX dose relative to their starting dose. With longer-term follow-up (median 149 weeks), the mean dose over time in patients who continued on study was ∼10 mg BID for patients starting at 15 mg BID and ∼15 mg BID for those starting at 20 mg BID (Figure).
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ROC analyses identified that a baseline platelet count range of less than 150–175 x109/L may predict which patients would experience an early titration event, while a baseline Hgb level of less than 10 mg/dL may predict which patients would experience an anemia event (Table).
Table:Predictive Characteristics of Cut-points for Platelet Count and HgbPlatelet Count/ Early Dose Titration EventHgb/Anemia EventCut-point (x109/L)TPRFPRPPVCut-point (g/dL)TPRFPRPPV12518.5%3.3%80.0%8.513.6%0%100%15043.1%5.6%84.8%9.022.7%3.1%83.3%17552.3%7.8%82.9%9.531.8%4.6%82.4%20060.0%16.7%72.2%10.045.5%10.8%74.1%22569.2%21.1%70.3%10.561.4%18.5%69.2%
In COMFORT-I, most patients experienced a RUX dose adjustment in the first 12 weeks of treatment and stable doses were achieved with long-term therapy. Dose titration allowed most patients to maintain adequate platelet counts. After starting therapy at 15 or 20 mg BID, the majority of patients titrated to RUX doses of 10 mg BID or higher, which have been previously been shown to produce meaningful spleen volume reductions and symptom improvements (Mesa et al. 8th Annual Hematologic Malignancies Conference. Abstract 305; Verstovsek et al. ASH 2012. Abstract 800; Talpaz et al. ASH 2012. Abstract 176). A baseline platelet count of less than 150 ×109/L and baseline Hgb level of less than 10 g/dL may be clinically useful cutoffs for predicting which patients may benefit from closer monitoring shortly after treatment initiation of RUX and appropriate dose adjustments as needed.
Mesa:Lilly: Research Funding; Genentech: Research Funding; NS Pharma: Research Funding; Gilead: Research Funding; Incyte Corporation: Research Funding. Komrokji:Incyte Corporation: Membership on an entity's Board of Directors or advisory committees. Sun:Incyte Corporation: Equity Ownership; Incyte Corporation: Employment. Sandor:Incyte Corporation: Equity Ownership; Incyte Corporation: Employment. Verstovsek:Incyte Corporation: Research Funding.
Lamin A/C gene (
)-related dilated cardiomyopathy is a serious and life-threatening condition with a high unmet medical need. This phase 2 study assessed the effects of the oral selective p38 ...mitogen-activated protein kinase inhibitor ARRY-371797 on functional capacity and cardiac function in patients with
-related dilated cardiomyopathy.
Patients with
-related dilated cardiomyopathy in New York Heart Association class II-IIIA, on background heart failure treatment, received ARRY-371797 100 or 400 mg twice daily for 48 weeks. The primary end point was change from baseline in the 6-minute walk test distance at 12 weeks. Secondary end points included changes over time in 6-minute walk test distance, NT-proBNP (N-terminal pro-B-type natriuretic peptide) concentration, left ventricular ejection fraction, and quality-of-life scores on the Kansas City Cardiomyopathy Questionnaire. Data from the 2 dose groups were combined.
Twelve patients were enrolled; median (minimum, maximum) 6-minute walk test distance at baseline was 314 (246, 412) m. At week 12, the mean (80% CI) increase from baseline in 6-minute walk test distance was 69 (39, 100) m (median, 47 m). Median NT-proBNP concentration declined from 1409 pg/mL at baseline to 848 pg/mL at week 12. Mean left ventricular ejection fraction was stable at week 12. There was a trend toward improvement in Kansas City Cardiomyopathy Questionnaire Overall and Clinical Summary scores at week 12. No clinically significant drug-related safety concerns were identified.
ARRY-371797 was well tolerated and resulted in potential increases in functional capacity and lower concentrations of cardiac biomarker NT-proBNP in patients with
-related dilated cardiomyopathy.
URL: https://clinicaltrials.gov; Unique identifier: NCT02057341.
Prior to Janus kinase inhibitors, available therapies for myelofibrosis were generally supportive and did not improve survival. This analysis compares efficacy outcomes of patients with myelofibrosis ...in the control arms (placebo n=154 and best available therapy n=73) from the two phase 3 COntrolled MyeloFibrosis study with ORal JAK inhibitor Treatment (COMFORT) studies. Spleen volume was assessed by magnetic resonance imaging/computed tomography at baseline and every 12 weeks through week 72; spleen length was assessed by palpation at each study visit. Health-related quality of life and symptoms were assessed using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 Items at baseline and in weeks 4, 8, 12, 16 and 24 in COMFORT-I and in weeks 8, 16, 24 and 48 in COMFORT-II. The demographic and baseline characteristics were similar between the control arms of the two studies. One patient who received placebo and no patients who received best available therapy had a ≥35% reduction in spleen volume from baseline at week 24. At 24 weeks, neither placebo nor best available therapy had produced clinically meaningful changes in global quality of life or symptom scales. Non-hematologic adverse events were mostly grade 1/2; the most frequently reported adverse events in each group were abdominal pain, fatigue, peripheral edema and diarrhea. These data suggest that non-Janus kinase inhibitor therapies provide little improvement in splenomegaly, symptoms or quality of life as compared with placebo. Both COMFORT-I (NCT00952289) and COMFORT-II (NCT00934544) studies have been appropriately registered with clinicaltrials.gov.
Ruxolitinib is an oral Janus kinase (JAK) 1/JAK2 inhibitor approved in the US for the treatment of intermediate-or high-risk myelofibrosis (MF). Because thrombopoietin and erythropoietin signal ...through JAK2, dose-dependent cytopenias are expected with treatment. In the COMFORT-I (COntrolled Myelofibrosis study with ORal JAK inhibitor Treatment I) trial, these cytopenias were effectively managed with dose adjustments. These analyses were conducted to evaluate the relationship between ruxolitinib titrated doses and changes in platelet count and hemoglobin level as well as efficacy measures.
COMFORT-I was a randomized, placebo-controlled trial in 309 patients with intermediate-2 or high-risk MF and a platelet count ≥100 × 10(9)/L. Ruxolitinib starting doses were 15 and 20 mg twice daily (bis in die BID) for patients with baseline platelet counts of 100-200 × 10(9)/L and >200 × 10(9)/L, respectively. Percentage changes from baseline to week 24 in spleen volume and MF-related symptoms were assessed in subgroups defined by final titrated dose (average daily dose during weeks 21 to 24).
The median final titrated doses for patients starting at doses of 15 and 20 mg BID were 10 and 20 mg BID, respectively, at week 24. Most dose reductions occurred in the first 8-12 weeks of treatment and coincided with decreases in platelet count and hemoglobin level. Subsequently, platelet counts stabilized and hemoglobin levels gradually returned to near baseline levels (red blood cell transfusion rates followed a similar trend). Final titrated doses of ≥10 mg BID were associated with clinically meaningful improvements in MF-related symptoms that were comparable across doses, while marginally greater reductions in spleen volume were observed at higher doses.
This COMFORT-I analysis shows that dose-dependent cytopenias were effectively managed with ruxolitinib dose adjustments, and titrated doses of ≥10 mg BID were associated with clinically meaningful reductions in spleen volume and symptom improvement at week 24.
Abstract Patient-reported outcomes (PROs) and spleen size in patients not receiving therapy ( N = 154) in COMFORT-I, a randomized, double-blind study of the JAK1/JAK2 inhibitor ruxolitinib in ...patients with intermediate-2 or high-risk myelofibrosis were evaluated. Baseline PROs indicated considerable disease burden. European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 scores, modified Myelofibrosis Symptom Assessment Form v2.0 Total Symptom Score, and Patient Reported Outcome Measurement Information System Fatigue scores worsened from baseline through week 24. At weeks 4 and 24, 18.3 and 40.2% of patients evaluated their condition as having worsened from baseline on the Patient Global Impression of Change questionnaire. Spleen volume and palpable length increased in most patients. These results demonstrate the progressive and debilitating effects of myelofibrosis. The consequences of delayed intervention should be assessed in the management of patients with myelofibrosis and treatment should be considered as clinically indicated for symptomatic relief or splenomegaly control.
Abstract 1733
Patients with myelofibrosis (MF) suffer from cytopenias, debilitating symptoms, and splenomegaly, all of which may contribute to shortened life expectancy. Cachexia is a common ...manifestation of MF. Its causes are multifactorial and include elevated inflammatory cytokines and mechanical effects of splenomegaly. It is a predictor of poor survival in patients with MF. Cachexia manifests as weight loss with low body-mass index (BMI; <20–21 kg/m2) (Strasser F. Sixth Research Congress of the European Association of Palliative Care; Wagner PD. Eur Respir J. 2008;31:492–501) and with metabolic indicators of poor nutritional status including hypocholesterolemia (total cholesterol <150 mg/dL or <3.89 mmol/L), which has been linked to poor prognosis in MF (Mesa et al. Blood 2007;110:abstract 2548).
In the phase III, placebo-controlled, COMFORT-I study, ruxolitinib treatment significantly reduced spleen volume, improved MF-related symptoms, and exhibited a survival advantage compared with placebo in patients with MF. In this post hoc analysis, we investigated the effects of ruxolitinib treatment on weight and total cholesterol and the association of these changes with survival in COMFORT-I.
Eligible patients in COMFORT-I were randomized to receive placebo (n=154) or ruxolitinib (n=155) at starting doses of 15 and 20 mg PO BID depending on baseline platelet count. Body weight was measured at baseline, and weeks 4, 8, 12, 16, and 24 and then every 12 weeks thereafter. Total serum cholesterol was measured at baseline and weeks 4, 12, 24, and then every 24 weeks thereafter. All patients receiving PBO completed crossover or discontinued within 3 months of the primary data analysis (when all patients completed 24 weeks and when half the patients remaining on study completed 36 weeks of treatment); thus, data for these patients were available for up to week 36 for weight and week 24 for total cholesterol. Kaplan-Meier analyses of overall survival were conducted in patients randomized to ruxolitinib stratified into 2 groups based on the median values separately for maximum weight gain and for maximum increase in total cholesterol during randomized treatment.
At baseline, mean body weight was similar between the treatment groups (72 kg, both) and mean total cholesterol was low (<150 mg/dL) in both treatment groups (ruxolitinib: 118 mg/dL; placebo: 115 mg/dL). The proportion of patients with BMI <22 were similar between the treatment groups (ruxolitinib: 23%; placebo: 28%) as was the proportion with total cholesterol <150 mg/dL (82%, both). Patients randomized to ruxolitinib experienced a gradual increase in body weight that stabilized by week 36 of treatment whereas patients receiving placebo experienced decreases in body weight over time (Figure 1). Similarly, total cholesterol increased in patients randomized to ruxolitinib and decreased in patients receiving placebo (Figure 2). Although total cholesterol increased over time in ruxolitinib-treated patients, increases did not exceed the upper limit of normal (199 mg/dL or 5.15 mmol/L). Nearly all patients randomized to ruxolitinib experienced weight gain (96% of patients) or an increase in total cholesterol (97% of patients). In patients randomized to ruxolitinib, weight gain above the median was associated with prolonged survival relative to lesser degrees of weight gain (HR=0.40; 95% CI: 0.18, 0.90; P=0.022; Figure 3). Similarly, increase in total cholesterol above the median was also associated with prolonged survival relative to a lesser degree of total cholesterol increase (HR=0.46; 95% CI: 0.21, 1.01; P=0.048; Figure 4). Meaningful comparisons with the placebo group based on the same stratification criteria could not be conducted as the majority of such patients experienced weight loss and decreases in total cholesterol while on the study; however, overall survival favored both ruxolitinib groups relative to all patients randomized to placebo even for ruxolitinib-treated patients with lower than median levels of weight gain or increase in total cholesterol.
Ruxolitinib therapy promotes weight gain and improves total cholesterol in MF patients. These results suggest that the survival advantage exhibited by ruxolitinib over placebo in MF patients may be partly explained by reversal of the catabolic state and cachexia. Display omitted Display omitted Display omitted
Mesa:Incyte: Research Funding; Lilly: Research Funding; Sanofi: Research Funding; NS Pharma: Research Funding; YM Bioscience: Research Funding. Verstovsek:Incyte Corporation: Research Funding. Gupta:Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Research Funding; YM Biosciences: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi#x2610;#x0025; Aventis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Mascarenhas:Incyte Corporation: Consultancy; Novartis: Clinical Trial Support, Clinical Trial Support Other. Atallah:Incyte: Consultancy, Research Funding. Sun:Incyte Corporation: Employment, Equity Ownership. Sandor:Incyte Corporation: Employment, Equity Ownership. Gotlib:Incyte Corporation: Consultancy, Honoraria, Support for travel to meeting for the study or other purposes from Incyte Other.
Abstract 2847
Myelofibrosis (MF) is a progressive Philadelphia-negative myeloproliferative neoplasm characterized by debilitating symptoms, massive splenomegaly, and anemia, which severely impairs ...quality of life. When medical therapy is not effective or tolerated, splenectomy may be required to ease symptoms in patients with symptomatic portal hypertension, massive splenomegaly, and/or frequent red blood cell transfusions (Barbui et al. J Clin Oncol. 2011;29:761–770). In a recent study (Tefferi et al. Mayo Clin Proc. 2012;87:25–33) up to 27% of patients diagnosed with MF eventually underwent splenectomy. However, splenectomy is associated with limited duration of symptom response, high rates of perioperative morbidity and mortality, and acceleration of hepatomegaly.
Clinical studies in patients with MF have demonstrated that ruxolitinib, an oral JAK1/JAK2 inhibitor, provides significant and durable reductions in splenomegaly, the burden of MF-associated symptoms, and also improved quality of life. In this post hoc analysis of pooled data from these studies, we determined the incidence of splenectomy in patients treated with ruxolitinib and those who received placebo or best available therapy (BAT) to evaluate whether ruxolitinib therapy may affect the need for splenectomy.
This analysis included patients who participated in the ruxolitinib phase I/II trial (N=153; Verstovsek et al. N Engl J Med. 2010;363:1117–1127); COMFORT-I, a phase III, 24-month placebo-controlled trial of ruxolitinib (N=309; Verstovsek et al. N Engl J Med. 2012;366:799–807); and COMFORT-II, a phase III, 48-month randomized trial comparing the effects of ruxolitinib and BAT (N=219; Harrison et al. N Engl J Med. 2012;366:787–798). Incidence of splenectomy while on treatment or during the protocol-specified follow-up period, adjusted for differences in the duration of follow up, was calculated for patients on ruxolitinib, placebo, or BAT.
As a result of the crossover rules and a higher discontinuation rate on the comparator arms in the phase III studies, mean follow-up duration for placebo (0.67 years) or BAT (0.95 years) overall was substantially shorter than mean follow-up duration for ruxolitinib (1.78 years). Baseline characteristics of the 14 patients who underwent splenectomy were as follows: median age=63 years; median time since initial diagnosis=7.8 years; median spleen length (n=13): 17.0 cm (range: 0–28.0 cm); median spleen volume (in those with measurement, n=11)=2924 cm3 (range: 1203–6807 cm3); IPSS high risk=50%, intermediate-2 risk=43%, intermediate-1=7%. Among patients originally randomized and treated with ruxolitinib, the incidence of splenectomy was 1.1 events per 100 patient years (Table). For patients treated with placebo or BAT in the phase III studies, the incidence of splenectomy was approximately three times higher at 2.9 events per 100 patient years, despite the fact that patients on placebo or BAT were allowed to crossover to ruxolitinib if they had worsening symptomatic splenomegaly.
Although limited by small numbers, results of this analysis suggest that ruxolitinib reduces the need for splenectomy in patients with MF. Because of crossover to ruxolitinib and higher discontinuation rates in placebo and BAT, follow-up duration was shorter in these treatment arms compared with ruxolitinib. Further, ruxolitinib treatment in crossover patients may have prevented progression of symptomatic splenomegaly in some patients who may have otherwise become candidates for splenectomy. Our analysis may underestimate the true incidence of splenectomy among patients not receiving ruxolitinib therapy and therefore, the relative reduction in splenectomy rate in patients receiving this therapy. Longer-term follow up will better define the splenectomy rate in ruxolitinib-treated patients.Table:Incidence of Splenectomy During Clinical Studies of RuxolitinibPatient groupPatients, nPatient yearsSplenectomies, nSplenectomies (n) per 100 patient yearsEnrolled/randomized to ruxolitinib459818.091.10On BAT or placebo224170.752.93BAT, best available therapy.
Verstovsek:Incyte Corporation: Research Funding. Kiladjian:Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Shire: Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees; Celgene: Research Funding. Mesa:Incyte: Research Funding; Lilly: Research Funding; Sanofi: Research Funding; NS Pharma: Research Funding; YM Bioscience: Research Funding. Vannucchi:Novartis: Membership on an entity's Board of Directors or advisory committees. Gotlib:Incyte Corporation: Consultancy, Honoraria, Support for travel to meeting for the study or other purposes from Incyte Other. Kantarjian:Incyte: grant support Other. Sirulnik:Novartis: Employment, Equity Ownership. Peng:Incyte Corporation: Employment, Equity Ownership. Sandor:Incyte Corporation: An employee of Incyte and receiving stock options as part of his compensation Other, Employment. Harrison:Novartis: Honoraria, Research Funding, Speakers Bureau; YM Bioscience: Consultancy, Honoraria; Sanofi Aventis: Honoraria; Shire: Honoraria, Research Funding.
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Ruxolitinib is a potent JAK1/JAK2 inhibitor that has demonstrated improved survival, rapid and durable improvements in splenomegaly, disease-related symptoms, and quality of life measures in the 2 ...phase 3 COMFORT studies in patients with myelofibrosis (MF). Prolonged survival was observed in patients receiving ruxolitinib compared with both placebo (COMFORT-I) and best available therapy (BAT; COMFORT-II). Here, we conducted a pooled analysis of overall survival (OS) in the COMFORT studies.
The COMFORT studies are randomized, phase 3 studies comparing the safety and efficacy of ruxolitinib with placebo or BAT in patients with intermediate-2– or high-risk primary MF, post-polycythemia MF, or post-essential thrombocythemia MF. COMFORT-I is a double-blind study whereas COMFORT-II is open label. Patients initially received ruxolitinib 15 or 20 mg bid based on their platelet counts at baseline (100-200 and > 200 x 109/L, respectively) and were individually titrated to maximize safety and efficacy. The patient populations were generally similar and have been fully described. Patients were allowed to cross over from the control arms of each study upon protocol-defined progression events (primarily progressive splenomegaly, defined as a ≥ 25% increase in spleen volume from baseline or on-study nadir in COMFORT-I and –II, respectively). At the time of analysis, all ongoing control patients had crossed over to ruxolitinib. OS was a secondary endpoint in both studies. Here, OS was analyzed in an intent-to-treat analysis using a multivariate Cox proportional hazards model estimating effects of treatment, study, and IPSS risk (model 1). Effect of baseline spleen volume (per 5 dL) was evaluated using a Cox model adjusting for treatment, study, and IPSS risk (model 2). Two patients in COMFORT without defined IPSS risk status were excluded from model 1; 4 patients without baseline spleen volume measurements were excluded from model 2. For these exploratory analyses, all P values are provided for descriptive purposes only.
Overall, 301 patients were randomized to ruxolitinib (COMFORT-I, n = 155; COMFORT-II, n = 146), and 227 patients were randomized to placebo (n = 154) or BAT (n = 73). In the combined ruxolitinib group, 162 patients (54%) had high-risk MF, and 138 (46%) had intermediate-2 risk at baseline by IPSS criteria compared with 135 (59%) and 91 (40%) patients in the combined control group, respectively.
At this 3-year update, 71 patients (24%) died in the ruxolitinib group compared with 76 patients (33%) in the control group. Survival was consistent across both studies (HR = 1.1; 95% CI, 0.8-1.6; P = .54) and represented an OS benefit in favor of ruxolitinib (Figure A); the risk of death was reduced by 35% with ruxolitinib treatment compared with control (HR = 0.65; 95% CI, 0.46-0.90; P = .01). Patients with intermediate-2–MF had a reduced risk of death compared with high-risk patients (HR = 0.47; 95% CI, 0.33-0.67; P < .0001). Moreover, patients with high-risk MF who received ruxolitinib treatment had a Kaplan Meier–estimated survival similar to that of intermediate-2–risk patients in the control group (Figure B). Among all patients, larger spleen volume at baseline was prognostic for shortened survival; the risk of death increased by 9% for each additional 5 dL in spleen volume at baseline (HR = 1.09; 95% CI, 1.03-1.15; P = .003). Further analysis to evaluate the impact of potentially prognostic and predictive factors at baseline on survival as well as association of other relevant clinical endpoints, such as dynamics of spleen and symptom reduction, with survival will be presented.
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Patients who received ruxolitinib in the COMFORT studies had significantly prolonged survival compared with patients who received placebo or BAT. These benefits were seen for both intermediate-2– and high-risk patients, and high-risk patients in the ruxolitinib group appeared to have improved survival similar to that of intermediate-2–risk patients in the control group.
Vannucchi:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees. Hagop:BMS: Research Funding; Novartis: Research Funding; Ariad: Research Funding; Pfizer: Research Funding. Kiladjian:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Research Funding; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees; AOP Orphan: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Gotlib:Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Travel support Other. Cervantes:Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sanofi Aventis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Mesa:Incyte: Research Funding; Genentech: Research Funding; Lilly: Research Funding; Gilead: Research Funding. Sarlis:Incyte Corporation: Employment, Equity Ownership; Sanofi: Equity Ownership. Peng:Incyte Corporation: Employment. Sandor:Incyte Corporation: Employment, Equity Ownership. Sirulnik:Novartis: Employment. Hmissi:Novartis, A.G.: Employment. Stalbovskaya:Novartis Pharma AG: Employment. Gupta:Novartis: Grant support, Consulting fees and lecture fees Other; Incyte: Grant support, Consulting fees, Grant support, Consulting fees Other. Harrison:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; YM Bioscience: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria; Shire: Speakers Bureau; S Bio: Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees. Verstovsek:Incyte Corporation: Research Funding.
Primary CNS lymphoma (PCNSL) and primary intraocular lymphoma (IOL) are usually treated with radiation therapy alone or in combination with chemotherapy. The neurotoxicity of these treatments can be ...substantial. This study attempts to define the toxicity and efficacy of the treatment of this disease with chemotherapy alone.
Fourteen nonimmunocompromised patients were accrued to a chemotherapy regimen that incorporated a 24-hour infusion of high-dose methotrexate total dose of 8.4 g/m2 with leucovorin rescue; thiotepa 35 mg/m2; vincristine 1.4 mg/m2; dexamethasone; and intrathecal cytarabine (Ara-C) and methotrexate (MTV) administered in 21-day cycles. Seven patients were prospectively followed up with formal neuropsychologic assessments for evidence of CNS toxicity.
The response rate was 100% with 11 (79%) complete responses and three (21%) partial responses. Cumulative survival and progression-free survival rates at more than 4.5 years were 68.8% and 34.3%, respectively. Median survival has not been reached, and median progression-free survival was 16.5 months. Toxicity included severe leukoencephalopathy that was clearly attributable to chemotherapy (two patients), grade 3 or 4 neutropenia in 50% of the cycles administered, ileus (one patient), and seizures (two patients). Mucositis and renal and hepatic toxicity were mild and not therapy limiting.
The MTV regimen is generally well tolerated and produces a high complete response rate. Chemotherapy alone should be investigated further in this disease to assess the necessity of initial radiation therapy, either alone or in combined modality regimens, for the achievement of optimal response and survival.
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