Pentamidine: A Review

1991 ◽  
Vol 12 (6) ◽  
pp. 375-382 ◽  
Author(s):  
Michael W. Scheld ◽  
Brian Wispelwey ◽  
Richard D. Pearson
Keyword(s):  
High Risk ◽  
Clinical Results ◽  
Second Line ◽  
Second Line Therapy ◽  
Line Therapy ◽  
Aerosolized Pentamidine ◽  
Pentamidine Isethionate ◽  
Low Toxicity ◽  
Acquired Immunodeficiency ◽  
Immunodeficiency Syndrome

With the advent of the acquired immunodeficiency syndrome (AIDS), the therapeutic importance of pentamidine isethionate has increased greatly. This review summarizes the pharmacology, clinical experience in the treatment of Pneumocystis carinii pneumonia, and toxicity of pentamidine. Data are conflicting as to whether pentamidine is more or less effective than trimethoprim-sulfamethoxazole (TMP-SX) for the treatment of P carinii pneumonia in individuals with AIDS, but due to its toxicity and expense, it is considered as second-line therapy for P carinii pneumonia by many authorities. Hypoglycemia has been encountered in up to 27%, and nephrotoxicity in 25%, of treatment courses with pentamidine. In an attempt to circumvent the toxicities associated with parenteral administration, aerosolized delivery has been evaluated for both therapy and prevention of P carinii pneumonia. Aerosolized pentamidine, on the basis of early clinical results, convenience, and low toxicity, is being used extensively to prevent P carinii pneumonia in individuals at high risk. Relapses occur, however, and pneumothorax may be more common in those using this form of prophylaxis. Aerosolized pentamidine should not be used as sole therapy for acute P carinii pneumonia.

Treatment with Homoharringtonine and Cytarabine in Patients with High Risk Acute Myelogenous Leukemia (AML).

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 4555-4555
Author(s):  
Naibai Chang ◽  
Jianping Wei ◽  
Shengming Zhao ◽  
Hui Liu ◽  
Yun Fan ◽  
...  
Keyword(s):  
High Risk ◽  
Disease Free Survival ◽  
Leukemic Cell ◽  
Myelogenous Leukemia ◽  
Leukemic Cells ◽  
Second Line ◽  
Second Line Therapy ◽  
Conventional Dose ◽  
Line Therapy ◽  
Acute Myelogenous

Abstract Objective: To evaluate response of homoharringtonine in patients with high risk AML or as a second-line therapy in patients with AML refractory to anthracycline based chemotherapy. Patients and methods: From Jan 1998-Jan 2006, there were 66 patients enrolled in this regimen. Male:female=40:26. Median age was 47 (17–69). There were 48 newly diagnosed AML, 5 relapsed AML and 13 secondary AML (secondary to MDS) in this group. Among these patients, there were 40 patients untreated previously — 20 patients had unfavourable chromasomal abmormalities, 10 patients had pgp positive, 10 patients had normal chromasome but high CD34 expression on leukemic cells. The remaining 26 patients were previously treated with daunorubincin or mitoxantrane combined with cytarabine at least two cycles and failed to achieve response. Homoharringtonine was given at dose of 4mg/m2/d(2.5mg/m2/d for age≥60 years) intraveniously for 7 days. Cytarabine was given at dose of 100mg/m2/d at same time. The therapy was repeated every 21 days.Post remission therapy was divided into two cohot —same regimen maintainance in 20 cases and cytarabine 1g/m2/d q12h for 4 days at least 4 cycles in 20 cases. Results: 40/66 patients achieved complete remission. 3/66 achieved partial remission. In patients refactory to anthracycline based regimen, the CR rate was 57.7%(15/26). In previously untreated high risk AML patients,the CR rate was 62.5%(25/40). Median disease free survival were 4.25 months (2–30) in cohot 1 and 18 months (12–47) in cohot 2 (P<0.05). CD95(APO-1/Fas) was tested by flow cytometry during treatment. APO-1/Fas (CD95) increased from (9.56±5.58)% to (25.64±0.70)% after induction chemotherapy. Main toxicities were marrow suppression and infection. There were 7 early deaths, 5 patients died of cerebral hemorrage and 2 cardiovascular events. Conclusions: Homoharringtonine is effective in patients with high risk AML. It is also a choice of second line therapy in patients refractory to anthracycline based chemotherapy. Intensive post remission therapy is superior to conventional dose maintainance therapy in high risk AML. One of the ways for homoharringtonine to induce leukemic cell apoptosis is probably through Fas pathway.

Salvage Therapies in Patients with High-Risk Relapse After Fludarabine, Cyclophosphamide, Rituximab (FCR) for Chronic Lymphocytic Leukemia: The French CLL Intergroup Experience

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 1796-1796
Author(s):  
Luc-Matthieu Fornecker ◽  
Therese Aurran-Schleinitz ◽  
Anne-Sophie Michallet ◽  
Bruno Cazin ◽  
Jehan Dupuis ◽  
...  
Keyword(s):  
High Risk ◽  
Second Line ◽  
Complex Karyotype ◽  
First Line ◽  
Second Line Therapy ◽  
High Risk Patients ◽  
First Line Therapy ◽  
Line Therapy ◽  
Ultra High Risk ◽  
Risk Patients

Abstract Abstract 1796 Introduction: FCR chemoimmunotherapy is recommended as first line therapy for fit cll patients. Since the 2007 EBMT guidelines based on the previously published trials using FCR, the definition of high risk CLL has evolved, to include biologic parameters (TP53 disruption by deletion/mutation, high b2-microglobulin level, IgVH unmutated, complex karyotype), refractoriness (progression during fluda-based regimen or within 6mo of completion), and also remission duration (high risk if PFS after FCR <24mo, ultra-high risk if TTNT <24–36mo with TP53 del/mut). However, few data are available regarding the characteristiscs, response rate and outcome of CLL patients treated in second line after FCR first line. Patients and methods: In this multicentric retrospective study, we collected data from 117 patients who relapsed after FCR first line therapy and received second-line therapy (according to NCI2008 guidelines). Results: At the time of initial FCR therapy: patients characteristics were as follows: Binet B/C 87.2%, unmutated IgVH 52.2%, del11q 25.6% (n=30/81 with FISH available), del17p 6.8% (n=8/87 with FISH available), bulk>5cm 22%, complex karyotype 21% (n=12/57 with karyotype available). FCR yielded 93% ORR, with 66% clinical CR, 27% PR, and 7% failed to respond. Median PFS and TTNT were 27mo and 32.5mo, respectively. At the time of relapse: patients characteristics were as follows: del11q 16.4% (n=19/65 with FISH available), del17p 19% (n=22/77), bulk>5cm 26%, complex karyotype 44% (n=24/54 with karyotype available). According to FCR remission duration, 11.1% of patients were considered as truly FCR-refractory, 47% had PFS<24mo, 34.2% had TTNT<24mo. TTNT<24mo after FCR was correlated to age>65y, del17p (20% vs 0%) and complex karyotype (38% vs11%), but not with gender, IgVH status, del11q, or bulk>5cm. Based on FCR-refractoriness, or TTNT<24mo and/or del17p, 53 patients were considered as ultra-high risk (45.3%). Various regimen were used for second-line treatment after FCR: R-bendamustine (n=47, 40.2%), alemtuzumab-based therapy (single agent or with chemo/dexa, n=22, 18.8%), R-CHOP (n=15, 12.8%), FCR (n=14, 12%), and other miscellaneous regimens (as follows: R-alkylator (n=6, 5.1%), R-DHAP (n=4, 3.4%), R-methylprednisolone (n=3, 2.6%), or investigational drugs (n=6, 5.1%)). Thus, 74.3% of patients received a second course including rituximab-based chemotherapy. Overall response rate was 78.4%, with 13.8% clinical CR, 64.6% PR, and 21.6% failure/stable disease. 14 pts (12%) underwent stem cell transplantations, 8 had maintenance therapy ongoing (ofatumumab, alemtuzumab, or lenalidomide). With regards to factors defining high-risk relapse, distribution of salvage therapies was as follows: As expected, a second course of FCR was seldom used in high-risk patients. Among ultra-high risk patients, 30.3% received R-benda, 11.3% Alem-based Rx, 32% R-CHOP and 18% the miscellaneous regimens described above. After second-line therapy, median PFS was 12 months, median TTNT was 14mo, and median OS was 36mo (20 deaths). On univariate analysis, complex karyotype (p=0.04) but not del17p (p=0.1), PFS<24mo (p=0.028) and TTNT<24mo (p=0.04) correlated with OS. Regarding treatment, OS was significantly improved in R-bendamustine-treated patients, as compared to alem-based or CHOP regimen (p=0.01). Most importantly, patients who received an allogeneic transplant benefited from significantly prolonged OS (at 4y, 70% vs 40%, p=0.03). Of note, only one patient treated with R-benda received allotransplant. Conclusions: This study shows that there are no consensus for second line therapy after FCR. Second line trials after FCR therapy are warranted. Definition of high-risk subsets of patients at relapse after FCR is of upmost importance in the management of CLL, to compare second-line strategies. Our data suggest that R-bendamustine is an efficient regimen even in high-risk patients (complex karyotype, PFS<24mo, TTNT<24mo). These data are important since this immunochemotherapy is now used as the backbone for combination with new compounds (ibrutinib, GS1101, GDC-199). Disclosures: Aurran-Schleinitz: Roche: Honoraria. Leblond:Roche: Advisory Board Other, Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Mundipharma: Honoraria; Janssen-Cilag: Honoraria.

scholarly journals Characteristics of Patients (pts) Who Relapse and Die of Multiple Myeloma (MM) within One Year Post Frontline Autologous Stem Cell Transplant (ASCT) in the Novel Agent Era: An Ultra-High Risk Population

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 3440-3440 ◽  
Author(s):  
Hatem Alahwal ◽  
Heather J. Sutherland ◽  
Shruthi Ganeshappa Kodad ◽  
Stephen H. Nantel ◽  
Yasser Abou Mourad ◽  
...  
Keyword(s):  
High Risk ◽  
Control Group ◽  
Case Group ◽  
First Year ◽  
Advanced Stage ◽  
Second Line ◽  
Disease Relapse ◽  
Second Line Therapy ◽  
Line Therapy ◽  
One Year

Abstract Introduction: MM remains incurable but therapeutic advances has resulted in improved overall survival (OS) particularly for younger pts who are eligible for ASCT. Regardless OS improvements have been heterogeneous and it is well known that relapse within one year of ASCT is an independent negative prognostic factor. A particularly worse subgroup is pts who relapse and die of MM within a year of ASCT. There is limited data describing this subgroup of pts, the risk factors associated with their early relapse post ASCT and characteristics at relapse. Objective: Describe patient and disease related characteristics among MM pts who underwent ASCT and died of relapsed MM within the first year post ASCT in the era of novel agents. Methods: Pts were identified from the Leukemia/BMT Program of B.C. database, underwent ASCT between January 1st 2007 and July 31st 2016 and died of MM related causes within 365 days post ASCT. During this time period bortezomib (BORT) and lenalidomide (LEN) were available as second line therapy and BORT was available as induction pre-transplant for defined circumstances including high risk cytogenetics. Out of 752 ASCTs, 702 were performed as a part of initial therapy. The remaining ASCTs were performed as salvage or were the second of planned tandem ASCTs. Among the remaining 702 pts 37(5.3%) died within the first 365 days post ASCT. Of the 37 pts, 32 died from MM and related causes, 2 died of TRM from ASCT and 3 died from other causes not related to MM or ASCT. The 32 pts (4.6% of the total) who died of MM and related causes were matched with 64 controls (2:1 ratio) who were selected randomly from the remaining patient cohort and matched for age, gender, and year of transplantation. Results: There was no difference in Age at diagnosis (Median: case 61 VS control 60, P= .97) or gender (Male case 40.6% VS control 35.9%, P= .66). There was no significant difference in the prevalence of anemia, renal dysfunction, or hypercalcemia between both groups at diagnosis (table). Pts who died within the first year of ASCT had a more advanced stage at diagnosis compared to the control group (ISS Stage III: 53.1% vs 18.8%, P= .003). BORT based induction therapy was used in 84.4% of the cases compared to 53.1% in the control group, P= .001. The majority of pts in both groups had partial response or better to frontline therapy (Cases: 81.2% VS Controls 79.7%, P= .5). Only 9.4% of cases and 4.7% of controls had evidence of disease progression at the time of ASCT. High risk cytogenetics (t(4;14), t(14;16), or del 17p) were significantly more prevalent among pts who died within the first year post ASCT compared to the control (58.82% vs 31.67%, P= .009). There was no difference in the monoclonal protein subtype between the cases and controls, P= .55. The median time from ACST to disease relapse was 118 days (40-319) for the case group compared to 511 (107-1958) in the control group. Within the case group, 19 (59.3%) received LEN based therapy as second line therapy and 9 (28.1%) received BORT based therapy. Three patients (9.37%) were not candidates for any further therapy due to acute illness (2 sepsis, 1 subdural hemorrhage) related to fulminant MM relapse and one patient (3.1%) decided not to proceed with therapy due to functional decline. Overall, 17 pts (53.1%) received both BORT and LEN during the disease course, 12 (37.5%) received BORT only, 2 (6.25%) received LEN only and one received neither (3.1%). At the time of disease relapse, 9 (28.1%) had Hb level <85 g/l, 1 (3.1%) ANC<1000/mm3, 9 (28.1%) Plt <50/mm3, 9 (28.1%) GFR <20 ml/min, and 20 (62.5%) had at least one abnormal value (Hb, ANC, Plt, or Cr) and were not candidates for inclusion to clinical trials. Median OS (months) was Case 7.3 vs Control 63.8, P<.001. Conclusion: Approximately 5% of pts with MM who are ASCT eligible will die of MM within the first year post transplant. High risk cytogenetics (t(4;14), t(14;16), or del 17p) and advanced stage disease (ISS III) are risk factors for early mortality post ASCT for MM pts. These patient who relapse early typically have fulminant relapse with hematological and biochemical parameters outside of the range which would allow them to be enrolled on clinical trials and/or results in challenging standard of care management. Even in the era of novel agents, such pts do particularly poorly and represent a true unmet need in the treatment of MM. Further studies to understand the biology of their MM is required for identifying more potent therapeutic targets and protocols. Disclosures No relevant conflicts of interest to declare.

Life after Fludarabine, Cyclophosphamide, & Rituximab (FCR) - the Clinical Outcome of Patients with Chronic Lymphocytic Leukemia Who Receive Salvage Treatment after Frontline FCR.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 2090-2090 ◽  
Author(s):  
Constantine S. Tam ◽  
William G. Wierda ◽  
Susan O’Brien ◽  
Susan Lerner ◽  
Issa F Khouri ◽  
...  
Keyword(s):  
Stem Cell ◽  
High Risk ◽  
Stem Cell Transplantation ◽  
Allogeneic Stem Cell Transplantation ◽  
Salvage Treatment ◽  
Refractory Disease ◽  
Second Line ◽  
Second Line Therapy ◽  
Line Therapy

Abstract The FCR regimen is the most active treatment program in CLL, with 72% of frontline patients achieving a complete remission (CR) lasting a median of 7 years. However, most patients are not cured and will eventually relapse with CLL. In order to evaluate how these patients should be subsequently managed, we analyzed our institutional experience with 300 patients treated with frontline FCR (Blood 112:975). After a median follow-up of 6 years, 116 patients (39%) had failed FCR therapy with 13 primary refractory disease and 103 relapses from partial remission (PR), nodular PR (nPR) or CR. Compared with patients in ongoing remission, relapsed/refractory patients had more adverse baseline characteristics including a greater proportion with performance status ≥ 1 (71% vs 53% p=0.002), elevated β2m (54% vs 36% p=0.002), white cell count ≥ 150 x 10^9/L (25% vs 12% p=0.003), unmutated IgVH (81% vs 44% p&lt;0.001) and ZAP-70 positivity (78% vs 49% p&lt;0.001). The aim of the current analysis was to determine the duration of survival (OS) following second-line therapy in 97 patients who had completed salvage treatment. The median follow-up was 32 (range 3 – 69) months, and the median OS (mOS) was 32 months. Characteristics associated with favorable OS were: (1) previous best response to FCR of nPR/CR lasting ≥ 18 months (mOS 47 months, vs 13 months for primary refractory disease, PR or nPR/CR lasting &lt;18 months p=0.002); (2) β2m &lt; 3.0 mg/L (mOS not reached, vs 17 months p=0.0003) and (3) platelets ≥ 100x10^9/L (mOS 47 months, vs 15 months p=0.004). Poor risk cytogenetic abnormalities were common at FCR failure: among 38 assessable patients, 7 (18%) had 17p- and 18 (47%) had 11q- by conventional karyotyping and/or FISH. Although patients with 17p- or 11q- had an inferior survival, this survival disadvantage was confined entirely to those who also had an elevated β2m ≥ 3.0 mg/L. Surprisingly, patients relapsing after durable FCR remissions (≥ 5 years) and patients with slowly progressive relapse (time to salvage ≥ 12 months after FCR failure) had similar OS as their more adverse counterparts (p=0.76 and 0.86 respectively). A prognostic model comprising β2m and platelet count effectively divided patients into low, intermediate and high risk categories with mOS of &gt;45, 32 and 13 months respectively (p&lt;0.0001). Patients received treatment chosen at the discretion of individual treating physicians and the CR rate of second-line therapy were: FCR (n=30), 17%; rituximab (n=25), 4%; alemtuzumab ± rituximab (n=16), 31%; FCR & alemtuzumab (CFAR, n=9), 56%; lymphoma-type chemotherapy (n=5), 0%; other treatment (n=12), 0%. The CR rate for CFAR was significantly higher than that of FCR (p=0.03), although the median remission duration (30 vs 20 months) and OS (44 vs 32 months) were similar (p=0.87 and 0.51 respectively). None of the regimens showed a significant survival benefit. Allogeneic stem cell transplantation (SCT) was performed in 27 (28%) patients at a median of 15 months after first salvage. Patients receiving SCT had a significantly superior OS than those who did not undergo SCT (not reached vs 30 months, p=0.03). Of the 14 patients surviving for more than four years, 11 (79%) had undergone a SCT. Patients who fail FCR therapy had high risk disease features including elevated β2m, unmutated IgVH and ZAP-70 positivity, and most had adverse cytogenetic findings at relapse. Results of salvage therapy in this group were poor with a median survival of less than three years. The majority of long-term survivors had received allogeneic stem cell transplantation.

Aerosolized Pentamidine as Second Line Therapy in Patients with AIDS and Pneumocystis carinii Pneumonia

CHEST Journal ◽  
1989 ◽  
Vol 95 (4) ◽  
pp. 747-750 ◽  
Author(s):  
A. Bruce Montgomery ◽  
Robert J. Debs ◽  
John M. Luce ◽  
Kevin J. Corkery ◽  
Joan Turner ◽  
...  
Keyword(s):  
Pneumocystis Carinii Pneumonia ◽  
Pneumocystis Carinii ◽  
Second Line ◽  
Second Line Therapy ◽  
Line Therapy ◽  
Aerosolized Pentamidine

scholarly journals An Interim Analysis of the Turkish Myeloma Registry Among the Patients Who Have Received up to Two Lines of Therapy

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 4730-4730
Author(s):  
Omur Gokmen Sevindik ◽  
Zubeyde Nur Ozkurt ◽  
Can Boga ◽  
Sevgi Kalayoglu Besisik ◽  
Yildiz Ipek ◽  
...  
Keyword(s):  
High Risk ◽  
Conflicts Of Interest ◽  
High Dose ◽  
Main Concern ◽  
Second Line ◽  
Second Line Therapy ◽  
Line Therapy ◽  
High Risk Disease ◽  
Frontline Therapy

Abstract Introduction: To investigate the demographics and treatment details of the myeloma patients who were diagnosed and followed up in Turkey and received up to two lines of therapy. Methods: Patients who were recorded on the database of Turkish Myeloma Registry project were included in this study if they had only received one or two lines of therapy. Demographics, patient, and disease related parameters both at the time of diagnosis and at the follow up and treatment outcomes were presented. Results: A total of 532 patients were included in the study, and 44% of the patients were female. Median age at the time of diagnosis was 63 (30-106). 47.7% of the patients were diagnosed with IgG myeloma. According to the ISS risk stratification, 20.4% of patients had ISS 1, 34.7% of patients had ISS 2 and remaining 44.9% had ISS 3 disease. Defining high risk disease as harboring one or more of these following cytogenetic abnormalities; del 17p, t(4;14), t(14;16) or t(14;20); 7.1% of the patients were classified as having a high risk disease. Most commonly used frontline therapy approach was bortezomib cyclophosphamide dexamethasone combination (VCD) (76.5%) and followed by bortezomib dexamethasone (VD) (8.8%), and bortezomib lenalidomide and dexamethasone combination (VRd) (7.1%). Overall response rates (a better response than stable disease according to IMWG response assessment criteria) were 87.6% in VCD induced patients; 63.3% in VD induced patients and 92% in VRd induced patients. The PFS obtained by these frontline approaches was 17.8 months in patients who were able to proceed with high dose chemotherapy with ASCT support and 8.4 in patients who were not able to (p&lt;0.01), with an overall PFS of 15.3 months. With regard to the induction approach, PFS was 21.1 months for VRD, 15.3 months for VCD and 7.6 months for VD (p=0.08). Regarding maintenance, 23.6% of patients were maintained by lenalidomide alone, 62.7% of patients were maintained by a combination of lenalidomide and dexamethasone or bortezomib alone (2.7%). PFS after the first line of the treatment was 22.2 months in maintained patients and 12.2 in un-maintained patients (HR: 0.532, p=0.001, CI95% 0.359-0.790). Regarding the second line therapy Rd was the leading option (34.8%) and VRd (17.8%), Carfilzomib based (16.3%), VCD (8.1%) were the followings. Conclusion: As the main concern of this study was to document the demographic features and clinical parameters of a Turkish Myeloma population and to give an idea about the treatment patterns and outcomes in frontline setting and first relapse an overall survival was not calculated. Progression free survival obtained after frontline therapy was relatively shorter than the ones which were presented by other real- world registries. Outcomes of second line therapy will be presented as follow up after 2nd line therapy exceeds a certain threshold. We hope, the results obtained from this study can have a role in the approval and re-imbursement of the current standard of care options. Disclosures No relevant conflicts of interest to declare.

scholarly journals Surpass-ET Trial: A Phase 3, Open-Label, Multicenter, Randomized, Active-Controlled Study to Assess Pharmacokinetics and Compare the Efficacy, Safety, and Tolerability of P1101 Vs Anagrelide As Second Line Therapy for Essential Thrombocythemia

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 1491-1491
Author(s):  
Ruben A. Mesa ◽  
Norio Komatsu ◽  
Harinder Gill ◽  
Jie Jin ◽  
Sung-Eun Lee ◽  
...  
Keyword(s):  
High Risk ◽  
Sample Size ◽  
Essential Thrombocythemia ◽  
Research Funding ◽  
Controlled Study ◽  
Second Line ◽  
Open Label ◽  
Second Line Therapy ◽  
Phase 3 ◽  
Line Therapy

Abstract Background: Essential thrombocythemia (ET) is a subtype of chronic myeloproliferative neoplasms (MPN) characterized by thrombocytosis and disease-related symptoms, which may be difficult to manage. Patients with ET are also at higher risk of thrombosis and hemorrhage. Ideal therapeutic approaches should achieve adequate cytoreduction, reduce the risk of thrombo-hemorrhagic complications, and prevent progression to post-ET myelofibrosis (PET-MF) or secondary acute myeloid leukemia (AML). Low-dose aspirin with hydroxyurea (HU) is typically given as first-line therapy in high-risk patients. However, approximately 20-40% of ET patients become HU-intolerant or -resistant. In ET, resistance and/or intolerance portend an increased risk of thrombosis, hemorrhage, disease transformation and death. There is a paucity of prospective clinical trial data to guide management of ET patients who are HU resistant or intolerant. P1101 is a next generation monopegylated interferon (IFN) alfa-2b, developed specifically to treat MPNs, including ET. Study Design and Methods: The SURPASS-ET trial (NCT04285086) is a Phase 3, open-label, multicenter, randomized, active-controlled study to assess the efficacy, safety, tolerability, and pharmacokinetics (PK) of P1101 after 12 months of treatment compared with anagrelide as second line therapy for subjects with ET who have shown resistance or intolerance to HU. The primary endpoint is durable modified ELN composite response at 9 and 12 months from dosing. Cochran-Mantel-Haenszel test will be used for comparing the primary endpoint in the two treatment arms. The PK parameters of P1101, including (but not limited to) C min, T max, C max, and area-under-curve (AUC) will be derived using PPK analysis and the relationship between exposure and efficacy and safety endpoints will be examined using E-R analysis. Evaluation of efficacy will include clinical laboratory assessments, allelic burden measurements of CALR, JAK2, and MPL, spleen size measurements, bone marrow sampling (optional), EQ-5D-3L, and MPN Symptom Assessment Form Total Symptom Score (MPN-SAF TSS) assessments. A total of 130 randomized subjects is planned to detect a difference of 40% (P1101) versus 15% (anagrelide) in durable ELN response rate with 90% power at alpha level = 0.05 using the chi-square test. To account for possible non-evaluability (e.g., no follow-up data), approximately 160 subjects will be randomized in this study to get 130 completed patients. Because of uncertainty in the assumptions on which the calculation of the sample size is based, an interim analysis for sample size adjustment will be implemented. Major inclusion criteria include subjects diagnosed with high-risk ET (either older than 60 years and JAK2V617F-positive at screening or having disease-related thrombosis or hemorrhage in the past), diagnosed according to the World Health Organization (WHO) 2016 criteria, documented resistance/intolerance to HU and IFN naïve or anti-P1101 binding antibody negative. Key exclusion criteria include pregnant females, significant cardiovascular disease, documented autoimmune disease and a history or presence of clinically significant depression or neurological disease. The study involves approximately 65 sites across the US, Taiwan, Japan, China, Hong Kong, Singapore, S. Korea, Canada, and Europe. To-date 55 patients (54 Asians, 1 Caucasian) have been randomized. The mean and median age at recruitment was 58.9 years (SD: 14.34) and 63 years (range 21 to 80 years) respectively. Twenty-seven men (49.1%) and twenty-eight women (50.9%) were recruited. Forty-two subjects (76.4%) had a TSS &lt; 20. The study is being overseen by a Data Safety Monitoring Board (DSMB). Figure 1 Figure 1. Disclosures Mesa: Gilead: Research Funding; Promedior: Research Funding; AOP: Consultancy; Incyte Corporation: Consultancy, Research Funding; Abbvie: Research Funding; Genentech: Research Funding; La Jolla Pharma: Consultancy; Novartis: Consultancy; Sierra Oncology: Consultancy, Research Funding; Samus: Research Funding; Pharma: Consultancy; CTI: Research Funding; Celgene: Research Funding; Constellation Pharmaceuticals: Consultancy, Research Funding; CTI: Research Funding. Komatsu: Fujifilm Wako Pure Chemical Corporation: Research Funding; Fuso Pharmaceutical Industries, Ltd.: Research Funding; Japan Tobacco Inc.: Consultancy; Otsuka Pharmaceutical Co. Ltd: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis Pharma KK: Consultancy, Research Funding, Speakers Bureau; Shire Japan KK: Consultancy, Research Funding, Speakers Bureau; PharmaEssentia Japan KK: Consultancy, Current Employment, Research Funding; Chugai Pharmaceutical Co., Ltd.: Research Funding; Kyowa Hakko Kirin Co., Ltd.: Research Funding. Sato: PharmaEssentia Japan KK: Current Employment. Qin: PharmaEssentia Corp.: Current Employment. Urbanski: PharmaEssentia Corporation: Current Employment. Shih: PharmaEssentia Corporation: Consultancy. Zagrijtschuk: PharmaEssentia U.S.A. Corp.: Current Employment. Zimmerman: PharmaEssentia Corporation: Current Employment. Verstovsek: Gilead: Research Funding; Protagonist Therapeutics: Research Funding; NS Pharma: Research Funding; Incyte Corporation: Consultancy, Research Funding; PharmaEssentia: Research Funding; Ital Pharma: Research Funding; CTI BioPharma: Research Funding; Blueprint Medicines Corp: Research Funding; AstraZeneca: Research Funding; Promedior: Research Funding; Genentech: Research Funding; Celgene: Consultancy, Research Funding; Roche: Research Funding; Novartis: Consultancy, Research Funding; Sierra Oncology: Consultancy, Research Funding; Constellation: Consultancy; Pragmatist: Consultancy.

Gastrointestinal Acuity Score (GAS): A Comprehensive Risk Score Incorporating Histologic Grade and Clinical Factors to Predict Need for Second Line Therapy, Non-Relapse Mortality, and Overall Survival in Lower Gastrointestinal Graft Vs. Host Disease

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 3128-3128
Author(s):  
Jin S. Im ◽  
Rima M Saliba ◽  
Susan C Abraham ◽  
Asif Rashid ◽  
William Ross ◽  
...  
Keyword(s):  
Overall Survival ◽  
High Risk ◽  
Risk Group ◽  
Low Risk ◽  
Intermediate Risk ◽  
Second Line ◽  
Second Line Therapy ◽  
Cart Analysis ◽  
Line Therapy ◽  
Risk Patients

Abstract Lower Gastrointestinal Graft versus Host Disease (GI GVHD) is a major cause for GVHD related non-relapsed mortality (NRM). High dose corticosteroid is the initial therapy for suspected lower GI GVHD, and additional therapy is often required for steroid refractory cases. The identification of high-risk patients is critical as timely intensification of treatment through early institution of second line therapy improves outcomes. To develop a reliable lower GI GVHD risk scoring system, Gastrointestinal Acuity Score (GAS), we evaluated 210 consecutive patients who underwent endoscopic biopsy for suspected lower GI GVHD within 6 months from the transplant from 2009 to 2012 at M.D. Anderson Cancer Center. We first identified 5 significant prognostic factors that accounted for the increased NRM in lower GI GVHD using univariate analysis: histologic grade, clinical stage, age, multi-organ GVHD, and donor type (Table 1). Gender, donor cell type, conditioning regimen (myeloablative vs non-myeloablative), time of diagnosis, disease status did not significantly influence NRM. Next, we performed multivariate Classification and Regression Tree (CART) analysis that utilizes sequential binary decision nodes to categorize 197 patients into subgroups according to their risk profile and outcome (Figure 1). The decision tree identified 7 subgroups starting with the presence of multi-organ GVHD as the first major decision node. This was followed by clinical stage 3/4, Age > 40 years, histology grade 3/4, and histology grade 1. We then consolidated subgroups with comparable risk profiles into low, intermediate, and high NRM risk groups (Figure 1). The 3 NRM risk groups correlated with day 28 response, the need for second line therapy and overall survival (Figure 2). The complete response rates at day 28 from the initiation of steroid therapy were significantly lower in the high (15%, p<0.001) and intermediate (43%, p=0.003) risk group compared to the low-risk group (70%). Accordingly, the high-risk patients were 4.3 (p < 0.001) and 1.6 (p=0.02) folds more likely to need second line therapy compared to low and intermediate risk patients, respectively. The intermediate risk patients were 2.7 (p=0.02) folds more likely to need second line therapy compared to the low risk group. In addition, the high-risk group was associated with the highest NRM (HR 5.4, p<0.001), followed by the intermediate risk (HR 3.8, p<0.001) compared to the low risk group. This translated into worse overall survival at 1 year for the high-risk patients. Lastly, there was a trend towards a lower chronic GVHD rate in the low risk group (25%, HR=0.6, p 0.06) compared to the high and intermediate risk groups (37%). In conclusion, we developed a novel risk scoring system, Gastrointestinal Acuity Score (GAS), incorporating histologic grades and clinical factors through multivariate CART analysis, and demonstrated that GAS predicts both early outcomes (day 28 CR rate and need for second line therapy) and late outcomes (NRM and overall survival) in patients with lower GI GVHD. Once prospectively validated in a larger cohort of lower GI GVHD patients, it will be of great use for clinicians with limited access to GVHD biomarker analysis in making treatment decisions as our new risk scoring system utilizes readily available variables. Figure 1. Univariate Analysis of risk factors for NRM at 1 year in Lower GI GVHD Figure 1. Univariate Analysis of risk factors for NRM at 1 year in Lower GI GVHD Figure 2. CART Analysis: Decision Tree for Risk Assessment Figure 2. CART Analysis: Decision Tree for Risk Assessment Figure 3. Need for second line therapy, NRM and OS Figure 3. Need for second line therapy, NRM and OS Disclosures Alousi: Therakos, Inc: Research Funding.

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