Publications by authors named "Carole B Miller"

30 Publications

  • Page 1 of 1

Determining the recommended dose of pacritinib: results from the PAC203 dose-finding trial in advanced myelofibrosis.

Blood Adv 2020 11;4(22):5825-5835

Ichan School of Medicine at Mount Sinai, New York, NY.

PAC203 is a randomized dose-finding study of pacritinib, an oral JAK2/IRAK1 inhibitor, in patients with advanced myelofibrosis who are intolerant of or resistant to ruxolitinib. Patients were randomized 1:1:1 to pacritinib 100 mg once per day, 100 mg twice per day, or 200 mg twice per day. Enhanced eligibility criteria, monitoring, and dose modifications were implemented to mitigate risk of cardiac and hemorrhagic events. Efficacy was based on ≥35% spleen volume response (SVR) and ≥50% reduction in the 7-component total symptom score (TSS) through week 24. Of 161 patients, 73% were intolerant of and 76% had become resistant to ruxolitinib; 50% met criteria for both. Severe thrombocytopenia (platelet count <50 × 103/μL) was present in 44%. SVR rates were highest with 200 mg twice per day (100 mg once per day, 0%; 100 mg twice per day, 1.8%; 200 mg twice per day, 9.3%), particularly among patients with baseline platelet counts <50 × 103/μL (17%; 4 of 24). Although TSS response rate was similar across doses (100 mg once per day, 7.7%; 100 mg twice per day, 7.3%; 200 mg twice per day, 7.4%), median percent reduction in TSS suggested a dose-response relationship (-3%, -16%, and -27%, respectively). Pharmacokinetic and pharmacodynamic modeling based on all available data showed greatest SVR and TSS reduction at 200 mg twice per day compared with lower doses. Common adverse events were gastrointestinal events, thrombocytopenia, and anemia. There was no excess of grade ≥3 hemorrhagic or cardiac events at 200 mg twice per day. Pacritinib 200 mg twice per day demonstrated clinical activity and an acceptable safety profile and was selected as the recommended dose for a pivotal phase 3 study in patients with myelofibrosis and severe thrombocytopenia. This trial was registered at www.clinicaltrials.gov as #NCT03165734.
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http://dx.doi.org/10.1182/bloodadvances.2020003314DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7686901PMC
November 2020

ACVR1/JAK1/JAK2 inhibitor momelotinib reverses transfusion dependency and suppresses hepcidin in myelofibrosis phase 2 trial.

Blood Adv 2020 09;4(18):4282-4291

Gilead Sciences, Inc., Foster City, CA.

Momelotinib (MMB) is a JAK1/2 and ACVR1 inhibitor with demonstrated clinical activity in all 3 hallmarks of myelofibrosis (MF): anemia, constitutional symptoms, and splenomegaly. In this phase 2 open-label translational biology study (NCT02515630) of 41 transfusion-dependent patients with MF, we explored mechanisms underlying the favorable activity of MMB on MF-associated iron-restricted anemia, including its impact on serum hepcidin levels, and markers of iron storage and availability, erythropoiesis, and inflammation. A transfusion-independent response (TI-R), defined as red blood cell transfusion independence (TI) ≥12 weeks at any time on study, occurred in 17 patients (41%; 95% confidence interval [CI], 26%-58%), including 14 patients (34%; 95% CI, 20%-51%) who achieved TI-R by week 24. In addition, 78% of TI nonresponse (TI-NR) patients achieved a ≥50% decrease in transfusion requirement for ≥8 weeks. Adverse events (AEs) were consistent with previous studies of MMB in MF, with cough, diarrhea, and nausea as the most common. Twenty-one patients experienced grade ≥3 AEs, most commonly anemia and neutropenia. Consistent with preclinical data, daily MMB treatment led to an acute and persistent decrease in blood hepcidin associated with increased iron availability and markers of erythropoiesis. Baseline characteristics associated with TI-R were lower inflammation and hepcidin as well as increased markers of erythropoiesis and bone marrow function. Overall, the study demonstrates that MMB treatment decreases hepcidin in conjunction with improving iron metabolism and erythropoiesis, suggesting a mechanistic explanation for the reduced transfusion dependency observed in transfusion-dependent MF patients treated with MMB, thereby addressing the key unmet medical need in the MF population.
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http://dx.doi.org/10.1182/bloodadvances.2020002662DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7509854PMC
September 2020

Long-term efficacy and safety of ruxolitinib versus best available therapy in polycythaemia vera (RESPONSE): 5-year follow up of a phase 3 study.

Lancet Haematol 2020 Mar 23;7(3):e226-e237. Epub 2020 Jan 23.

The University of Texas MD Anderson Cancer Center, Houston, TX, USA.

Background: Polycythaemia vera is a myeloproliferative neoplasm characterised by excessive proliferation of erythroid, myeloid, and megakaryocytic components in the bone marrow due to mutations in the Janus kinase 2 (JAK2) gene. Ruxolitinib, a JAK 1 and JAK 2 inhibitor, showed superiority over best available therapy in a phase 2 study in patients with polycythaemia vera who were resistant to or intolerant of hydroxyurea. We aimed to compare the long-term safety and efficacy of ruxolitinib with best available therapy in patients with polycythaemia vera who were resistant to or intolerant of hydroxyurea.

Methods: We report the 5-year results for a randomised, open-label, phase 3 study (RESPONSE) that enrolled patients at 109 sites across North America, South America, Europe, and the Asia-Pacific region. Patients (18 years or older) with polycythaemia vera who were resistant to or intolerant of hydroxyurea were randomly assigned 1:1 to receive either ruxolitinib or best available therapy. Patients randomly assigned to the ruxolitinib group received the drug orally at a starting dose of 10 mg twice a day. Single-agent best available therapy comprised hydroxyurea, interferon or pegylated interferon, pipobroman, anagrelide, approved immunomodulators, or observation without pharmacological treatment. The primary endpoint, composite response (patients who achieved both haematocrit control without phlebotomy and 35% or more reduction from baseline in spleen volume) at 32 weeeks was previously reported. Patients receiving best available therapy could cross over to ruxolitinib after week 32. We assessed the durability of primary composite response, complete haematological remission, overall clinicohaematological response, overall survival, patient-reported outcomes, and safety after 5-years of follow-up. This study is registered with ClinicalTrials.gov, NCT01243944.

Findings: We enrolled patients between Oct 27, 2010, and Feb 13, 2013, and the study concluded on Feb 9, 2018. Of 342 individuals screened for eligibility, 222 patients were randomly assigned to receive ruxolitinib (n=110, 50%) or best available therapy (n=112, 50%). The median time since polycythaemia vera diagnosis was 8·2 years (IQR 3·9-12·3) in the ruxolitinib group and 9·3 years (4·9-13·8) in the best available therapy group. 98 (88%) of 112 patients initially randomly assigned to best available therapy crossed over to receive ruxolitinib and no patient remained on best available therapy after 80 weeks of study. Among 25 primary responders in the ruxolitinib group, six had progressed at the time of final analysis. At 5 years, the probability of maintaining primary composite response was 74% (95% CI 51-88). The probability of maintaining complete haematological remission was 55% (95% CI 32-73) and the probability of maintaining overall clinicohaematological responses was 67% (54-77). In the intention-to-treat analysis not accounting for crossover, the probability of survival at 5 years was 91·9% (84·4-95·9) with ruxolitinib therapy and 91·0% (82·8-95·4) with best available therapy. Anaemia was the most common adverse event in patients receiving ruxolitinib (rates per 100 patient-years of exposure were 8·9 for ruxolitinib and 8·8 for the crossover population), though most anaemia events were mild to moderate in severity (grade 1 or 2 anaemia rates per 100 patient-years of exposure were 8·0 for ruxolitinib and 8·2 for the crossover population). Non-haematological adverse events were generally lower with long-term ruxolitinib treatment than with best available therapy. Thromboembolic events were lower in the ruxolitinib group than the best available therapy group. There were two on-treatment deaths in the ruxolitinib group. One of these deaths was due to gastric adenocarcinoma, which was assessed by the investigator as related to ruxolitinib treatment.

Interpretation: We showed that ruxolitinib is a safe and effective long-term treatment option for patients with polycythaemia vera who are resistant to or intolerant of hydroxyurea. Taken together, ruxolitinib treatment offers the first widely approved therapeutic alternative for this post-hydroxyurea patient population.

Funding: Novartis Pharmaceuticals Corporation.
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http://dx.doi.org/10.1016/S2352-3026(19)30207-8DOI Listing
March 2020

DYNAMO: A Phase II Study of Duvelisib (IPI-145) in Patients With Refractory Indolent Non-Hodgkin Lymphoma.

J Clin Oncol 2019 04 11;37(11):912-922. Epub 2019 Feb 11.

19 University of Bologna, Bologna, Italy.

Purpose: Indolent non-Hodgkin lymphoma (iNHL) remains largely incurable and often requires multiple lines of treatment after becoming refractory to standard therapies. Duvelisib was approved by the Food and Drug Administration for relapsed or refractory (RR) chronic lymphocytic leukemia or small lymphocytic lymphoma (SLL) and RR follicular lymphoma (FL) after two or more prior systemic therapies. On the basis of the activity of duvelisib, a first-in-class oral dual inhibitor of phosphoinositide 3-kinase-δ,-γ, in RR iNHL in a phase I study, the safety and efficacy of duvelisib monotherapy was evaluated in iNHL refractory to rituximab and either chemotherapy or radioimmunotherapy.

Patients And Methods: Eligible patients had measurable iNHL (FL, SLL, or marginal zone B-cell lymphoma) double refractory to rituximab (monotherapy or in combination) and to either chemotherapy or radioimmunotherapy. All were treated with duvelisib 25 mg orally twice daily in 28-day cycles until progression, unacceptable toxicity, or death. The primary end point was overall response rate (ORR) using the revised International Working Group criteria for malignant lymphoma.

Results: This open-label, global phase II trial enrolled 129 patients (median age, 65 years; median of three prior lines of therapy) with an ORR of 47.3% (SLL, 67.9%; FL, 42.2%; MZL, 38.9%). The estimated median duration of response was 10 months, and the estimated median progression-free survival was 9.5 months. The most frequent any-grade treatment-emergent adverse events (TEAEs) were diarrhea (48.8%), nausea (29.5%), neutropenia (28.7%), fatigue (27.9%), and cough (27.1%). Among the 88.4% of patients with at least one grade 3 or greater TEAE, the most common TEAEs were neutropenia (24.8%), diarrhea (14.7%), anemia (14.7%), and thrombocytopenia (11.6%).

Conclusion: In the DYNAMO study, oral duvelisib monotherapy demonstrated clinically meaningful activity and a manageable safety profile in heavily pretreated, double-refractory iNHL, consistent with previous observations. Duvelisib may provide a new oral treatment option for this patient population of which many are elderly and in need of additional therapies.
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http://dx.doi.org/10.1200/JCO.18.00915DOI Listing
April 2019

Practical Measures of Clinical Benefit With Ruxolitinib Therapy: An Exploratory Analysis of COMFORT-I.

Clin Lymphoma Myeloma Leuk 2017 08 12;17(8):479-487. Epub 2017 May 12.

Division of Cancer Medicine, Department of Leukemia, The University of Texas M.D. Anderson Cancer Center, Houston, TX.

Background: The phase III COMFORT (Controlled Myelofibrosis Study With Oral JAK inhibitor Treatment)-I and COMFORT-II trials in patients with intermediate-2 or high-risk myelofibrosis (MF) showed that ruxolitinib was superior to placebo and best available therapy, respectively, for improvements in spleen volume, MF-related symptoms, and overall survival (OS). However, patients managed in community settings might not have access to the methods used in the COMFORT trials. In this exploratory analysis we summarize efficacy findings of COMFORT-I using practical, community-oriented measures of patient outcomes.

Patients And Methods: In this post hoc analysis of data from COMFORT-I we evaluated changes from baseline to week 12 in spleen size (palpable length and volume), patient-reported outcomes (Patient Global Impression of Change; Myelofibrosis Symptom Assessment Form; Patient-Reported Outcomes Measurement System Fatigue Scale), body weight, and serum albumin levels in 5 subgroups of ruxolitinib-treated patients on the basis of week 12 spleen length changes from baseline: (1-4) ≥ 50%, 25% to < 50%, 10% to < 25%, or < 10% reduction; and (5) worsening. OS was evaluated in ruxolitinib-treated patients with week 12 spleen length reductions from baseline ≥ 50%, 25% to < 50%, or < 25% (including worsening).

Results: In all spleen length subgroups, including patients with worsening spleen length at week 12, ruxolitinib (n = 150) was associated with improvements in spleen volume, patient-reported symptom burden, body weight, and serum albumin levels. Greater reductions in spleen length were associated with prolonged OS.

Conclusion: A variety of assessment methods beyond palpable spleen length that are easily accessible in the community setting might be useful in evaluating the clinical benefit of ruxolitinib over time in patients with MF.
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http://dx.doi.org/10.1016/j.clml.2017.05.015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8148882PMC
August 2017

Long-term treatment with ruxolitinib for patients with myelofibrosis: 5-year update from the randomized, double-blind, placebo-controlled, phase 3 COMFORT-I trial.

J Hematol Oncol 2017 02 22;10(1):55. Epub 2017 Feb 22.

Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Unit 418, Houston, TX, 77030, USA.

Background: The randomized, double-blind, placebo-controlled, phase 3 COMFORT-I trial evaluated the JAK1/JAK2 inhibitor ruxolitinib in patients with intermediate-2/high-risk myelofibrosis. The primary and planned 3-year analyses of COMFORT-I data demonstrated that ruxolitinib-the first myelofibrosis-approved therapy-reduced splenomegaly and prolonged overall survival versus placebo. Here, we present the final 5-year results.

Methods: Patients managed in Australia, Canada, and the USA were randomized centrally (interactive voice response system) 1:1 to oral ruxolitinib twice daily (15 or 20 mg per baseline platelet counts) or placebo. Investigators and patients were blinded to treatment. The secondary endpoints evaluated in this analysis were durability of a ≥35% reduction from baseline in spleen volume (spleen response) and overall survival, evaluated in the intent-to-treat population. Safety was evaluated in patients who received study treatment.

Results: Patients were randomized (September 2009-April 2010) to ruxolitinib (n = 155) or placebo (n = 154). At termination, 27.7% of ruxolitinib-randomized patients and 25.2% (28/111) who crossed over from placebo were on treatment; no patients remained on placebo. Patients randomized to ruxolitinib had a median spleen response duration of 168.3 weeks and prolonged median overall survival versus placebo (ruxolitinib group, not reached; placebo group, 200 weeks; HR, 0.69; 95% CI, 0.50-0.96; P = 0.025) despite the crossover to ruxolitinib. The ruxolitinib safety profile remained consistent with previous analyses. The most common new-onset all-grade nonhematologic adverse events starting <12 versus ≥48 months after ruxolitinib initiation were fatigue (29.0 vs 33.3%) and diarrhea (27.8 vs 14.6%). New-onset grade 3 or 4 anemia and thrombocytopenia both primarily occurred within the first 6 months, with no cases after 42 months. The most common treatment-emergent adverse event-related deaths in the ruxolitinib-randomized group were sepsis (2.6%), disease progression (1.9%), and pneumonia (1.9%).

Conclusion: The final COMFORT-I results continue to support ruxolitinib as an effective treatment for patients with intermediate-2/high-risk MF.

Trial Registration: ClinicalTrials.gov, NCT00952289.
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http://dx.doi.org/10.1186/s13045-017-0417-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5322633PMC
February 2017

Exploratory study on the impact of switching to nilotinib in 18 patients with chronic myeloid leukemia in chronic phase with suboptimal response to imatinib.

Ther Adv Hematol 2017 Jan 24;8(1):3-12. Epub 2016 Nov 24.

Clinical Cancer Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.

Background: The phase II, exploratory, open-label Exploring Nilotinib Effects (ENABL) study [ClinicalTrials.gov identifier: NCT00644878] assessed the impact of switching to nilotinib therapy in patients with chronic myeloid leukemia in chronic phase (CML-CP) who had a suboptimal molecular response with imatinib.

Methods: Patients with CML-CP who had previously achieved a complete cytogenetic response (CCyR), but had a suboptimal molecular response, with frontline imatinib therapy ( = 18) were assigned to receive nilotinib 300 mg twice daily. The primary endpoint was the change in transcript levels from baseline after 12 months; rates of major molecular response (MMR) and safety were also assessed.

Results: At 3 months after switching to nilotinib, 10 of 17 (59%) evaluable patients had achieved MMR. At 12 months, 9 of 12 (75%) evaluable patients had achieved MMR, and the median level among all patients remaining in the study was 0.020% on the International Scale (IS), equivalent to a 3.7-log reduction from the standardized IS baseline (primary endpoint). Adverse events (AEs) were typically grade 1/2 and manageable with dose interruptions. A total of three patients experienced serious study drug-related AEs, including pancreatitis, bradycardia, and vertigo. No deaths were reported.

Conclusions: Overall, results from this exploratory study suggest that switching to nilotinib due to suboptimal molecular response with imatinib can result in improved molecular response for patients with CML-CP.
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http://dx.doi.org/10.1177/2040620716678118DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5167080PMC
January 2017

Differences in treatment goals and perception of symptom burden between patients with myeloproliferative neoplasms (MPNs) and hematologists/oncologists in the United States: Findings from the MPN Landmark survey.

Cancer 2017 02 30;123(3):449-458. Epub 2016 Sep 30.

Division of Hematology and Medical Oncology, Icahn School of Medicine at Mount Sinai, New York, New York.

Background: This analysis of the myeloproliferative neoplasm (MPN) Landmark survey evaluated gaps between patient perceptions of their disease management and physician self-reported practices.

Methods: The survey included 813 patient respondents who had MPNs (myelofibrosis [MF], polycythemia vera [PV], or essential thrombocythemia [ET]) and 457 hematologist/oncologist respondents who treated patients with these conditions.

Results: Greater proportions of physician respondents reported using prognostic risk classifications (MF, 83%; PV, 59%; ET, 77%) compared with patient recollections (MF, 54%; PV, 17%; ET, 31%). Most physician respondents reported that their typical symptom assessments included asking patients about the most important symptoms or a full list of symptoms, whereas many patient respondents reported less specific assessments (eg, they were asked how they were feeling). Many patient respondents did not recognize common symptoms as MPN-related. For example, approximately one-half or more did not believe difficulty sleeping resulted from their MPN (MF, 49%; PV, 64%; ET, 76%). Physician respondents underestimated the proportion of patients who had symptomatic PV or ET at diagnosis compared with patient respondents. There was discordance regarding treatment goals: among patient respondents with MF or PV, "slow/delay progression of condition" was the most important treatment goal, whereas physician respondents reported "symptom improvement" and "prevention of vascular/thrombotic events," respectively. Finally, more than one-third of patient respondents were not "very satisfied" with their physician's overall management/communication.

Conclusions: The care and satisfaction of patients with MPN may be improved with increased patient education and improved patient-physician communication. Cancer 2017;123:449-458. © 2016 The Authors. Cancer published by Wiley Periodicals, Inc. on behalf of American Cancer Society.
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http://dx.doi.org/10.1002/cncr.30325DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5297986PMC
February 2017

Ruxolitinib versus best available therapy in patients with polycythemia vera: 80-week follow-up from the RESPONSE trial.

Haematologica 2016 07 21;101(7):821-9. Epub 2016 Apr 21.

Centre d'Investigations Cliniques (INSERM CIC 1427), Hôpital Saint-Louis and Université Paris Diderot, Paris, France.

RESPONSE is an open-label phase 3 study evaluating the Janus kinase 1/Janus kinase 2 inhibitor ruxolitinib versus best available therapy for efficacy/safety in hydroxyurea-resistant or intolerant patients with polycythemia vera. This preplanned analysis occurred when all patients completed the Week 80 visit or discontinued. Objectives included evaluating the durability of the primary response (Week 32 phlebotomy-independent hematocrit control plus ≥35% spleen volume reduction), its components, and that of complete hematologic remission; and long-term safety. Median exposure was 111 weeks; 91/110 (82.7%) patients randomized to ruxolitinib remained on treatment. No patients continued best available therapy (98/112 [87.5%] crossed over to ruxolitinib, most at/soon after Week 32). At Week 32, primary response was achieved by 22.7% vs. 0.9% of patients randomized to ruxolitinib and best available therapy, respectively (hematocrit control, 60.0% vs. 18.8%; spleen response, 40.0% vs. 0.9%). The probability of maintaining primary and hematocrit responses for ≥80 weeks was 92% and 89%, respectively; 43/44 spleen responses were maintained until Week 80. Complete hematologic remission at Week 32 was achieved in 23.6% of ruxolitinib-randomized patients; the probability of maintaining complete hematologic remission for ≥80 weeks was 69%. Among ruxolitinib crossover patients, 79.2% were not phlebotomized, and 18.8% achieved a ≥35% reduction from baseline in spleen volume after 32 weeks of treatment. New or worsening hematologic laboratory abnormalities in ruxolitinib-treated patients were primarily grade 1/2 decreases in hemoglobin, lymphocytes, and platelets. The thromboembolic event rate per 100 patient-years was 1.8 with randomized ruxolitinib treatment vs. 8.2 with best available therapy. These data support ruxolitinib as an effective long-term treatment option for hydroxyurea-resistant or intolerant patients with polycythemia vera. This trial was registered at clinicaltrials.gov identifier: 01243944.
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http://dx.doi.org/10.3324/haematol.2016.143644DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5004461PMC
July 2016

Evaluating the Impact of a Switch to Nilotinib on Imatinib-Related Chronic Low-Grade Adverse Events in Patients With CML-CP: The ENRICH Study.

Clin Lymphoma Myeloma Leuk 2016 05 16;16(5):286-96. Epub 2016 Feb 16.

Memorial Sloan Kettering Cancer Center, New York, NY.

Background: Many patients with chronic myeloid leukemia in chronic phase experience chronic treatment-related adverse events (AEs) during imatinib therapy. These AEs can impair quality of life and lead to reduced treatment adherence, which is associated with poor clinical outcomes.

Patients And Methods: In the phase II ENRICH (Exploring Nilotinib to Reduce Imatinib Related Chronic Adverse Events) study (N = 52), the effect of switching patients with imatinib-related chronic low-grade nonhematologic AEs from imatinib to nilotinib was evaluated.

Results: Three months after switching to nilotinib, 84.6% of the patients had overall improvement in imatinib-related AEs (primary endpoint). Of 210 imatinib-related AEs identified at baseline, 62.9% had resolved within 3 months of switching to nilotinib. Of evaluable patients, most had improvements in overall quality of life after switching to nilotinib. At screening, 65.4% of evaluable patients had a major molecular response (BCR-ABL1 ≤ 0.1% on the International Scale). After switching to nilotinib, the rate of the major molecular response was 76.1% at 3 months and 87.8% at 12 months. Treatment-emergent AEs reported with nilotinib were typically grade 1 or 2; however, some patients developed more serious AEs, and 8 patients discontinued nilotinib because of new or worsening AEs.

Conclusion: Overall, results from the ENRICH study demonstrated that switching to nilotinib can mitigate imatinib-related chronic low-grade nonhematologic AEs in patients with chronic myeloid leukemia in chronic phase, in conjunction with acceptable safety and achievement of molecular responses. This trial was registered at www.clinicaltrials.gov as NCT00980018.
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http://dx.doi.org/10.1016/j.clml.2016.02.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4965237PMC
May 2016

Myeloproliferative neoplasms (MPNs) have a significant impact on patients' overall health and productivity: the MPN Landmark survey.

BMC Cancer 2016 Feb 27;16:167. Epub 2016 Feb 27.

Icahn School of Medicine at Mount Sinai, Ruttenberg Treatment Center, 1470 Madison Avenue, 3rd Floor, New York, NY, 10029, USA.

Background: The Philadelphia chromosome-negative myeloproliferative neoplasms (MPN) myelofibrosis (MF), polycythemia vera (PV), and essential thrombocythemia (ET) negatively affect patient quality of life (QoL) and are associated with increased risk of mortality.

Methods: The MPN Landmark survey was conducted from May to July 2014 in patients with MF, PV, or ET under active management in the United States. The survey assessed respondent perceptions of disease burden and treatment management and included questions on overall disease burden, QoL, activities of daily living, and work productivity. Outcomes were further analyzed by calculated (ie, not respondent-reported) prognostic risk score and symptom severity quartile.

Results: The survey was completed by 813 respondents (MF, n = 207; PV, n = 380; ET, n = 226). The median respondent age in each of the 3 MPN subtypes ranged from 62 to 66 years; median disease duration was 4 to 7 years. Many respondents reported that they had experienced MPN-related symptoms ≥1 year before diagnosis (MF, 49 %; PV, 61 %; ET, 58 %). Respondents also reported that MPN-related symptoms reduced their QoL, including respondents with low prognostic risk scores (MF, 67 %; PV, 62 %; ET, 57 %) and low symptom severity (MF, 51 %; PV, 33 %; ET, 15 %). Many respondents, including those with a low prognostic risk score, reported that their MPN had caused them to cancel planned activities or call in sick to work at least once in the preceding 30 days (cancel planned activities: MF, 56 %; PV, 35 %; ET, 35 %; call in sick: MF, 40 %; PV, 21 %; ET, 23 %).

Conclusions: These findings of the MPN Landmark survey support previous research about the symptom burden experienced by patients with MPNs and are the first to detail the challenges that patients with MPNs experience related to reductions in activities of daily living and work productivity.
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http://dx.doi.org/10.1186/s12885-016-2208-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4769833PMC
February 2016

Efficacy, safety, and survival with ruxolitinib in patients with myelofibrosis: results of a median 3-year follow-up of COMFORT-I.

Haematologica 2015 Apr 23;100(4):479-88. Epub 2015 Jan 23.

The University of Texas MD Anderson Cancer Center, Houston, TX, USA.

In the phase III COMFORT-I study, the Janus kinase 1 (JAK1)/JAK2 inhibitor ruxolitinib provided significant improvements in splenomegaly, key symptoms, and quality-of-life measures and was associated with an overall survival benefit relative to placebo in patients with intermediate-2 or high-risk myelofibrosis. This planned analysis assessed the long-term efficacy and safety of ruxolitinib at a median follow-up of 149 weeks. At data cutoff, approximately 50% of patients originally randomized to ruxolitinib remained on treatment whereas all patients originally assigned to placebo had discontinued or crossed over to ruxolitinib. At week 144, mean spleen volume reduction was 34% with ruxolitinib. Previously observed improvements in quality-of-life measures were sustained with longer-term ruxolitinib therapy. Overall survival continued to favor ruxolitinib despite the majority of placebo patients crossing over to ruxolitinib [hazard ratio 0.69 (95% confidence interval: 0.46-1.03); P = 0.067]. Exploratory analyses suggest that crossover may have contributed to an underestimation of the true survival difference between the treatment groups. Ruxolitinib continued to be generally well tolerated; there was no pattern of worsening grade ≥ 3 anemia or thrombocytopenia with longer-term ruxolitinib exposure. These longer-term data continue to support the efficacy and safety of ruxolitinib in patients with myelofibrosis. The study is registered at clinicaltrials.gov: NCT00952289.
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http://dx.doi.org/10.3324/haematol.2014.115840DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4380721PMC
April 2015

Efficacy, safety and survival with ruxolitinib in patients with myelofibrosis: results of a median 2-year follow-up of COMFORT-I.

Haematologica 2013 Dec 13;98(12):1865-71. Epub 2013 Sep 13.

COMFORT-I is a randomized, double-blind, placebo-controlled trial of the Janus kinase 1/Janus kinase 2 inhibitor ruxolitinib in 309 patients with intermediate-2 or high-risk myelofibrosis. This analysis of COMFORT-I describes the long-term efficacy and safety of ruxolitinib (median follow-up, 2 years). Spleen volume was measured by magnetic resonance imaging, and quality of life was evaluated using the EORTC QLQ-C30. Overall survival was determined according to randomized treatment group. At the time of this analysis, 100 of 155 patients randomized to ruxolitinib were still receiving treatment. All patients randomized to placebo crossed over to ruxolitinib or discontinued within 3 months of the primary analysis (median time to crossover, 41 weeks). Mean spleen volume reductions in the ruxolitinib group were 31.6% at week 24 and 34.9% at week 96; improvements in quality of life measures were also maintained. Improved survival was observed for ruxolitinib (n=27 deaths) versus placebo (n=41 deaths) (hazard ratio=0.58; 95% confidence interval: 0.36, 0.95; P=0.03). The incidence of new-onset grade 3 or 4 anemia and thrombocytopenia decreased over time to levels observed in patients receiving placebo. These data indicate that ruxolitinib treatment provides durable reductions in spleen volume and improvements in quality of life and suggest a continued survival advantage for ruxolitinib over placebo.
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http://dx.doi.org/10.3324/haematol.2013.092155DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3856961PMC
December 2013

Effect of ruxolitinib therapy on myelofibrosis-related symptoms and other patient-reported outcomes in COMFORT-I: a randomized, double-blind, placebo-controlled trial.

J Clin Oncol 2013 Apr 19;31(10):1285-92. Epub 2013 Feb 19.

Division of Hematology-Oncology, Mayo Clinic Arizona, Scottsdale, AZ 85259, USA.

Purpose: To assess the effects of ruxolitinib on symptom burden and quality of life (QoL) and to evaluate the ability of the modified Myelofibrosis Symptom Assessment Form (MFSAF) v2.0 to measure meaningful changes in myelofibrosis-related symptoms in patients with myelofibrosis.

Patients And Methods: COMFORT-I (Controlled Myelofibrosis Study With Oral JAK Inhibitor Treatment-I) is a double-blind, placebo-controlled phase III study evaluating ruxolitinib in patients with intermediate-2 or high-risk myelofibrosis. Exploratory analyses were conducted on the following patient-reported outcomes (PROs) assessments: modified MFSAF v2.0 (individual symptoms and Total Symptom Score [TSS]), European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30), Patient Reported Outcomes Measurement Information System (PROMIS) Fatigue Scale, and Patient Global Impression of Change (PGIC).

Results: Patients receiving ruxolitinib experienced improvements in individual myelofibrosis-related symptoms, although patients receiving placebo experienced worsening (P < .001). The majority (91%) of ruxolitinib-treated patients designated as ≥ 50% TSS responders (≥ 50% TSS improvement) self-reported their condition as either "Much improved" or "Very much improved" on the PGIC. These patients achieved significant improvements in the EORTC QLQ-C30 functional domains and Global Health Status/QoL versus patients receiving placebo, who experienced worsening on these measures (P ≤ .0135). Ruxolitinib-treated patients with a lesser degree of symptom improvement (< 50% TSS responders) also achieved improvements over placebo on these measures. The degree of spleen volume reduction with ruxolitinib correlated with improvements in TSS, PGIC, PROMIS Fatigue Scale, and EORTC Global Health Status/QoL. Ruxolitinib-treated patients who achieved a ≥ 35% reduction in spleen volume experienced the greatest improvements in these PROs.

Conclusion: Ruxolitinib-treated patients achieved clinically meaningful improvements in myelofibrosis-related symptoms and QoL, but patients receiving placebo reported worsening of symptoms and other PROs.
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http://dx.doi.org/10.1200/JCO.2012.44.4489DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4979167PMC
April 2013

K562/GM-CSF immunotherapy reduces tumor burden in chronic myeloid leukemia patients with residual disease on imatinib mesylate.

Clin Cancer Res 2010 Jan;16(1):338-47

Johns Hopkins Medical Institute, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins and St Agnes Hospital, Baltimore, Maryland 21231, USA.

Purpose: Chronic myeloid leukemia (CML) can be responsive to T-cell-mediated immunity. K562/granulocyte macrophage-colony stimulating factor (GM-CSF) is a GM-CSF producing vaccine derived from a CML cell line that expresses several CML-associated antigens. A pilot study was developed to determine if K562/GM-CSF immunotherapy could improve clinical responses to imatinib mesylate (IM) in patients with chronic myeloid leukemia.

Experimental Design: Patients with chronic phase CML who achieved at least a major cytogeneic response but remained with persistent, measurable disease despite one or more years on imatinib mesylate were eligible. Each was given a series of four vaccines administered in three-week intervals, with or without topical imiquimod, while remaining on a stable dose of imatinib mesylate. CML disease burden was measured serially before and after vaccination.

Results: Nineteen patients were vaccinated, with a median duration of previous imatinib mesylate therapy of 37 (13-53) months. Mean PCR measurements of BCR-ABL for the group declined significantly following the vaccines (P = 0.03). Thirteen patients had a progressive decline in disease burden, 8 of whom had increasing disease burden before vaccination. Twelve patients achieved their lowest tumor burden measurements to date following vaccine, including seven subjects who became PCR-undetectable.

Conclusions: K562/GM-CSF vaccine appears to improve molecular responses in patients on imatinib mesylate, including achieving complete molecular remissions, despite long durations of previous imatinib mesylate therapy.
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http://dx.doi.org/10.1158/1078-0432.CCR-09-2046DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2804932PMC
January 2010

Circulating clonotypic B cells in classic Hodgkin lymphoma.

Blood 2009 Jun 2;113(23):5920-6. Epub 2009 Feb 2.

Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, The Johns Hopkins Medical Institutions, Baltimore, MD, USA.

Although Hodgkin and Reed-Sternberg (HRS) cells are B lymphoid cells, they are unlike any normal cells of that lineage. Moreover, the limited proliferative potential of HRS cells belies the clinical aggressiveness of Hodgkin lymphoma (HL). More than 20 years ago, the L428 HL cell line was reported to contain a small population of phenotypic B cells that appeared responsible for the continued generation of HRS cells. This observation, however, has never been corroborated, and such clonotypic B cells have never been documented in HL patients. We found that both the L428 and KM-H2 HL cell lines contained rare B-cell subpopulations responsible for the generation and maintenance of the predominant HRS cell population. The B cells within the HL cell lines expressed immunoglobulin light chain, the memory B-cell antigen CD27, and the stem cell marker aldehyde dehydrogenase (ALDH). Clonal CD27(+)ALDH(high) B cells, sharing immunoglobulin gene rearrangements with lymph node HRS cells, were also detected in the blood of most newly diagnosed HL patients regardless of stage. Although the clinical significance of circulating clonotypic B cells in HL remains unclear, these data suggest they may be the initiating cells for HL.
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http://dx.doi.org/10.1182/blood-2008-11-189688DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2700327PMC
June 2009

Combined DNA methyltransferase and histone deacetylase inhibition in the treatment of myeloid neoplasms.

Cancer Res 2006 Jun;66(12):6361-9

The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, Maryland 21287, USA.

Optimal reexpression of most genes silenced through promoter methylation requires the sequential application of DNA methyltransferase inhibitors followed by histone deacetylase inhibitors in tumor cell cultures. Patients with myelodysplastic syndrome or acute myeloid leukemia (AML) were treated with the methyltransferase inhibitor 5-azacitidine (aza-CR) followed by the histone deacetylase inhibitor sodium phenylbutyrate. Major responses associated with cytogenetic complete response developed in patients receiving prolonged dosing schedules of aza-CR. Bisulfite sequencing of the p15 promoter in marrow DNA during the first cycle of treatment showed heterogeneous allelic demethylation in three responding patients, suggesting ongoing demethylation within the tumor clone, but no demethylation in two nonresponders. Six of six responding patients with pretreatment methylation of p15 or CDH-1 promoters reversed methylation during the first cycle of therapy (methylation-specific PCR), whereas none of six nonresponders showed any demethylation. Gene demethylation correlated with the area under the aza-CR plasma concentration-time curve. Administration of both drugs was associated with induction of acetylation of histones H3 and H4. This study provides the first demonstration that molecular mechanisms responsible for responses to DNA methyltransferase/histone deacetylase inhibitor combinations may include reversal of aberrant epigenetic gene silencing. The promising percentage of major hematologic responses justifies the testing of such combinations in prospective randomized trials.
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http://dx.doi.org/10.1158/0008-5472.CAN-06-0080DOI Listing
June 2006

Autotransplantation versus HLA-matched unrelated donor transplantation for acute myeloid leukaemia: a retrospective analysis from the Center for International Blood and Marrow Transplant Research.

Br J Haematol 2006 Mar;132(6):755-69

University Hospitals of Cleveland, Ireland Cancer Center, Cleveland, OH, USA.

Most acute myeloid leukaemia (AML) patients lack human leucocyte antigen-identical sibling donors for transplantation. Autotransplants and unrelated donor (URD) transplants are therapeutic options. To compare autologous versus URD transplantation for AML in first (CR1) or second complete remission (CR2), we studied the outcomes of 668 autotransplants were compared with 476 URD transplants reported to the Center for International Blood and Marrow Transplant Research. Proportional hazards regression adjusted for differences in prognostic variables. In multivariate analyses transplant-related mortality (TRM) was significantly higher and relapse lower with URD transplantation. Adjusted 3-year survival probabilities were: in CR1 57 (53-61)% with autotransplants and 44 (37-51)% URD (P = 0.002), in CR2 46 (39-53)% and 33 (28-38)% respectively (P = 0.006). Adjusted 3-year leukaemia-free survival (LFS) probabilities were: CR1 53 (48-57)% with autotransplants and 43 (36-50)% with URD (P = 0.021), CR2 39 (32-46)% and 33 (27-38)% respectively (P = 0.169). Both autologous and URD transplantation produced prolonged LFS. High TRM offsets the superior antileukaemia effect of URD transplantation. This retrospective, observational database study showed that autotransplantation, in general, offered higher 3-year survival for AML patients in CR1 and CR2. Cytogenetics, however, were known in only two-thirds of patients and treatment bias cannot be eliminated.
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http://dx.doi.org/10.1111/j.1365-2141.2005.05947.xDOI Listing
March 2006

Durable molecular remissions with a single cycle of timed sequential consolidation chemotherapy in acute promyelocytic leukemia.

Am J Hematol 2005 Jun;79(2):119-27

The Sidney Kimmel Cancer Center at Johns Hopkins, Baltimore, Maryland 21231, USA.

In a pilot study to reduce the duration of treatment and potential long-term toxicities, 39 patients with acute promyelocytic leukemia in remission received a single cycle of intensive consolidation therapy, followed by intermittent ATRA maintenance. Consolidation therapy required prolonged hospitalization and was associated with a high incidence of mucositis (43% grade II or greater) and documented infection (45%). No deaths occurred during consolidation. Seven patients have relapsed; all other patients are in molecular remission (median follow-up, 2.75 years). Kaplan-Meier estimate of 3 year disease-free survival is 73% (95% confidence interval 55-91%). The relapse rate (0.06 relapses/patient-year of follow-up) is well within the range of larger published series that administer more prolonged consolidation. One patient has developed secondary myelodysplastic syndrome. These pilot data suggest that decreasing the total duration of consolidation chemotherapy did not compromise disease-free survival for APL patients induced with ATRA/anthracycline and given intermittent ATRA maintenance. However, the toxicity of the consolidation module and the development of secondary myelodysplasia despite decreased total therapy emphasize the need to further improve and refine curative therapy for APL.
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http://dx.doi.org/10.1002/ajh.20354DOI Listing
June 2005

Micafungin versus fluconazole for prophylaxis against invasive fungal infections during neutropenia in patients undergoing hematopoietic stem cell transplantation.

Clin Infect Dis 2004 Nov 27;39(10):1407-16. Epub 2004 Oct 27.

University of Minnesota, Minneapolis, MN, USA.

We hypothesized that chemoprophylaxis with the echinocandin micafungin would be an effective agent for antifungal prophylaxis during neutropenia in patients undergoing hematopoietic stem cell transplantation (HSCT). We therefore conducted a randomized, double-blind, multi-institutional, comparative phase III trial, involving 882 adult and pediatric patients, of 50 mg of micafungin (1 mg/kg for patients weighing <50 kg) and 400 mg of fluconazole (8 mg/kg for patients weighing <50 kg) administered once per day. Success was defined as the absence of suspected, proven, or probable invasive fungal infection (IFI) through the end of therapy and as the absence of proven or probable IFI through the end of the 4-week period after treatment. The overall efficacy of micafungin was superior to that of fluconazole as antifungal prophylaxis during the neutropenic phase after HSCT (80.0% in the micafungin arm vs. 73.5% in the fluconazole arm [difference, 6.5%]; 95% confidence interval, 0.9%-12%; P=.03). This randomized trial demonstrates the efficacy of an echinocandin for antifungal prophylaxis in neutropenic patients.
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http://dx.doi.org/10.1086/422312DOI Listing
November 2004

Oral valacyclovir as prophylaxis against herpes simplex virus reactivation during high dose chemotherapy for leukemia.

Leuk Lymphoma 2004 Nov;45(11):2215-9

The Sidney Kimmel Comprehensive Cancer Center, Divisions of Hematological Malignancies, Baltimore, Maryland 21287-8985, USA.

Reactivation of herpes simplex virus is a common event in patients undergoing dose-intensive remission induction or consolidation chemotherapy of acute leukemia, for which either intravenous or oral acyclovir provides effective prophylaxis. This drug's short serum half-life and low oral bioavailability make frequent dosing necessary, however, and we therefore sought to determine if the pro-drug valacyclovir, which has improved bioavailability, could be successfully substituted for this indication. Eighty-one patients with leukemia were randomized to receive either 500 mg or 1,000 mg of valacyclovir orally every 8 h and followed clinically, as well as with serial surveillance cultures. Over a total of 1,979 days on study between the groups, and 380 throat cultures, no documented episodes of herpes simplex reactivation were noted. Valacyclovir was tolerated well with no evident drug-related toxicities. We conclude that valacyclovir at either of the two doses studied can be safely substituted for oral or intravenous acyclovir, and that it provides effective prophylaxis against reactivation of herpes simplex virus in this patient population.
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http://dx.doi.org/10.1080/10428190410001733763DOI Listing
November 2004

A phase III, randomized, double-blind, placebo-controlled, multinational trial of iseganan for the prevention of oral mucositis in patients receiving stomatotoxic chemotherapy (PROMPT-CT trial).

Leuk Lymphoma 2003 Jul;44(7):1165-72

Department of Leukemia, The University of Texas, M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Unit 428, Houston, TX 77030, USA.

Microfloral invasion and colonization of oral cavity mucosal tissues contribute to the pathophysiology of ulcerative oral mucositis (UOM). Iseganan is an analog of Protegrin-1, a naturally occurring peptide with broad-spectrum microbicidal activity. A randomized, double-blind, placebo-controlled study was conducted to evaluate iseganan in preventing UOM after stomatotoxic therapy. Patients received an oral rinse of iseganan 9 mg or placebo, swished/swallowed 6 times daily, starting with stomatotoxic therapy and continuing for 21-28 days. One hundred sixty three and 160 patients, respectively, were randomized to receive iseganan or placebo. One hundred and two patients (32%) were affected by a drug dispensing error, caused by a flawed computerized allocation system. Among all 323 patients, analyzed according to randomization assignment, 43% and 33% of iseganan and placebo patients, respectively, did not develop UOM (P = 0.067). On an 11-point scale, iseganan patients experienced less mouth pain (3.0 and 3.8 (P = 0.041), throat pain (3.8 and 4.6 (P = 0.048)), and difficulty swallowing (3.9 and 4.7 (P = 0.074)), compared to placebo patients. On the 5-point NCI CTC scale, iseganan patients experienced lower stomatitis scores (1.6 and 2.0 (P = 0.0131). Iseganan was well tolerated; no systemic absorption was detected. Iseganan is safe and may be effective in reducing UOM and its clinical sequelae.
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http://dx.doi.org/10.1080/1042819031000079159DOI Listing
July 2003

Long-term follow-up of T cell-depleted allogeneic bone marrow transplantation in refractory multiple myeloma: importance of allogeneic T cells.

Biol Blood Marrow Transplant 2003 May;9(5):312-9

Johns Hopkins University, Sidney Kimmel Comprehensive Cancer Center, Department of Oncology, Baltimore, MD, USA.

Multiple myeloma may be cured by myeloablative conditioning and allogeneic blood or marrow transplantation (alloBMT), but this occurs at the expense of high transplant-related mortality. In an endeavor to reduce procedure-related toxicity, this study retrospectively evaluated the safety, tolerability, and efficacy of T cell depletion by counterflow centrifugal elutriation before alloBMT. Fifty-one patients with stage II (6) or III (45) multiple myeloma received alloBMTs using T cell depletion by elutriation. Fifty-three percent (27 of 51) of patients had primary refractory disease at the time of transplantation, 10% (5 of 51) had relapsed disease, and 4% (2 of 51) had refractory relapsed disease. The median age was 49 (range, 32 to 62) years, and the median time from diagnosis to transplantation was 9 (range, 4 to 58) months. Patients had received a median of 1 (range, 1 to 3) regimen and 4 (range, 2 to 16) cycles of chemotherapy. In this population, transplant-related mortality rate was 24% (12 of 51) with 2 patients dying of graft-versus-host disease (GVHD). Thirty-one of 39 evaluable patients have experienced relapse, and the probability of progression-free survival 5 years after alloBMT alone is 16%. Sixteen patients were given donor lymphocyte infusions (DLI) at the time of relapse (n = 11) or for persistent disease 1 year after transplantation (n = 5). Acute or chronic GVHD was seen in 63% (10 of 16) of patients given DLI. Responses were seen in 8 of 16 patients (6 complete response [CR], 2 partial response [PR]) with 6 of 8 responding patients having GVHD. Five recipients of DLI remain in a continuous CR, ranging from 3 to 64 months in duration. Thus, like chronic myelogenous leukemia, allogeneic T cells appear to have potent antimyeloma activity that is critical for achieving a cure. DLI-induced remissions of multiple myeloma can be durable, even in patients with refractory multiple myeloma. Unlike chronic myelogenous leukemia, the antimyeloma effect of allogeneic T cells rarely occurs in the absence of clinically significant GVHD.
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http://dx.doi.org/10.1016/s1083-8791(03)00075-2DOI Listing
May 2003

Comparison of outcome following allogeneic bone marrow transplantation with cyclophosphamide-total body irradiation versus busulphan-cyclophosphamide conditioning regimens for acute myelogenous leukaemia in first remission.

Br J Haematol 2002 Dec;119(4):1115-24

Mayo Clinic & Foundation, Rochester, MN, USA.

We evaluated transplant-related mortality (TRM), leukaemia relapse, leukaemia-free survival (LFS) and overall survival (OS) in patients receiving busulphan and cyclophosphamide (BuCy) or cyclophosphamide and total body irradiation (CyTBI) prior to allogeneic bone marrow transplantation (BMT) for acute myelogenous leukaemia (AML) in first remission. Outcomes of 381 human leucocyte antigen (HLA)-matched sibling transplants using BuCy were compared with 200 transplants using CyTBI performed between 1988 and 1996. The incidence of hepatic veno-occlusive disease was higher with BuCy (13%) than with CyTBI (6%) (P = 0.009). Risks of acute and chronic GVHD were similar. In multivariate analysis, relapse risk was higher in the BuCy group [relative risk (RR) = 1.72; 95% confidence interval (CI), 1.05-2.81; P = 0.031]. Eleven of 373 evaluable patients in the BuCy group had a central nervous system relapse in contrast to none of 194 evaluable patients in the CyTBI group (P = 0.016). There were no differences in TRM, LFS and OS. CyTBI conditioning may lower relapse risk but produces comparable TRM, LFS and OS to BuCy for HLA-matched sibling transplantation in first remission AML.
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http://dx.doi.org/10.1046/j.1365-2141.2002.03973.xDOI Listing
December 2002

Use of epoetin in patients with cancer: evidence-based clinical practice guidelines of the American Society of Clinical Oncology and the American Society of Hematology.

J Clin Oncol 2002 Oct;20(19):4083-107

Medical College of Wisconsin, Milwaukee, WI, USA.

Anemia resulting from cancer, or its treatment, is an important clinical problem increasingly treated with the recombinant hematopoietic growth factor erythropoietin. To address uncertainties regarding indications and efficacy, the American Society of Clinical Oncology and the American Society of Hematology developed an evidence-based clinical practice guideline for the use of epoetin in patients with cancer. The guideline panel found good evidence to recommend use of epoetin as a treatment option for patients with chemotherapy-associated anemia with a hemoglobin level less than 10 g/dL. Use of epoetin for patients with less severe anemia (hemoglobin < 12 g/dL but never below 10 g/dL) should be determined by clinical circumstances. Good evidence from clinical trials supports the use of subcutaneous epoetin thrice weekly (150 U/kg tiw) for a minimum of 4 weeks. Less strong evidence supports an alternative weekly (40,000 U/wk) dosing regimen, based on common clinical practice. With either administration schedule, dose escalation should be considered for those not responding to the initial dose. In the absence of response, continuing epoetin beyond 6 to 8 weeks does not appear to be beneficial. Epoetin should be titrated once the hemoglobin concentration reaches 12 g/dL. Evidence from one randomized controlled trial supports use of epoetin for patients with anemia associated with low-risk myelodysplasia not receiving chemotherapy; however, there are no published high-quality studies to support its use for anemia in other hematologic malignancies in the absence of chemotherapy. Therefore, for anemic patients with hematologic malignancies, it is recommended that physicians initiate conventional therapy and observe hematologic response before considering use of epoetin.
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http://dx.doi.org/10.1200/JCO.2002.07.177DOI Listing
October 2002

Use of epoetin in patients with cancer: evidence-based clinical practice guidelines of the American Society of Clinical Oncology and the American Society of Hematology.

Blood 2002 Oct;100(7):2303-20

Medical College of Wisconsin, Milwaukee, WI 53226, USA.

Anemia resulting from cancer or its treatment is an important clinical problem increasingly treated with the recombinant hematopoietic growth factor erythropoietin. To address uncertainties regarding indications and efficacy, the American Society of Clinical Oncology and the American Society of Hematology developed an evidence-based clinical practice guideline for the use of epoetin in patients with cancer. The guideline panel found good evidence to recommend use of epoetin as a treatment option for patients with chemotherapy-associated anemia with a hemoglobin (Hgb) concentration below 10 g/dL. Use of epoetin for patients with less severe anemia (Hgb level below 12 g/dL but never below 10 g/dL) should be determined by clinical circumstances. Good evidence from clinical trials supports the use of subcutaneous epoetin thrice weekly (150 U/kg) for a minimum of 4 weeks. Less strong evidence supports an alternative weekly (40 000 U/wk) dosing regimen, based on common clinical practice. With either administration schedule, dose escalation should be considered for those not responding to the initial dose. In the absence of response, continuing epoetin beyond 6-8 weeks does not appear to be beneficial. Epoetin should be titrated once the hemoglobin concentration reaches 12 g/dL. Evidence from one randomized controlled trial supports use of epoetin for patients with anemia associated with low-risk myelodysplasia not receiving chemotherapy; however, there are no published high-quality studies to support its use for anemia in other hematologic malignancies in the absence of chemotherapy. Therefore, for anemic patients with hematologic malignancies it is recommended that physicians initiate conventional therapy and observe hematologic response before considering use of epoetin.
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http://dx.doi.org/10.1182/blood-2002-06-1767DOI Listing
October 2002

Autologous bone marrow transplantation with 4-hydroperoxycyclophosphamide purging for acute myeloid leukaemia beyond first remission: a 10-year experience.

Br J Haematol 2002 Jun;117(4):907-13

Johns Hopkins Oncology Center, Bunting-Blaustein Cancer Research Building, Rm 246, 1650 Orleans Street, Baltimore, MD 21231, USA.

Between January 1987 and January 1997, 69 eligible patients with acute myeloid leukaemia (AML) in either second (CR2) or third (CR3) complete remission (CR2 = 60, CR3 = 9) underwent 4-hydroperoxycyclophosphamide-purged autologous bone marrow transplantation (BMT) at the Johns Hopkins Oncology Center. The patients' median age was 27 years (range 1-62) and all received busulphan and cyclophosphamide as their preparative regimen. The probability of event-free survival (EFS) at 5 years was 30% [95% Confidence Interval (CI): 19-42%] for CR2 patients and 22% (3-51%) for those in CR3, with a median follow up of 8 years in the surviving group. The median time to an absolute neutrophil count of 0.5 x 109/l was 45 d (range 20-185). Relapse was the major cause of failure with a relapse rate of 55% in CR2 and 44% in CR3, while the non-relapse, transplant-related mortality rate was 15% in CR2 and 33% in CR3. In univariate analysis, patient age, cytogenetics, white blood cell count at presentation, CR1 duration and the sensitivity of clonogeneic leukaemia (CFU-L) in the graft to 4HC were all prognostic for EFS. Using each of these significant variables in multivariate modelling, patient age and sensitivity of CFU-L to 4HC were determined to be predictors of EFS. 4HC-purged autologous BMT produced results similar to allogeneic BMT for AML patients beyond first remission.
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http://dx.doi.org/10.1046/j.1365-2141.2002.03530.xDOI Listing
June 2002

Imatinib induces hematologic and cytogenetic responses in patients with chronic myelogenous leukemia in myeloid blast crisis: results of a phase II study.

Blood 2002 May;99(10):3530-9

Department of Medicine and Molecular Biology Institute, University of California, Los Angeles, CA 90095, USA.

Blast crisis is the most advanced stage of chronic myelogenous leukemia (CML) and is highly refractory to therapy. CML is caused by expression of the chimeric BCR-ABL tyrosine kinase oncogene, the product of the t(9;22) Philadelphia translocation. Imatinib (Glivec, formerly STI571) is a rationally developed, orally administered inhibitor of the Bcr-Abl tyrosine kinase. A total of 260 patients with CML were enrolled in a phase II trial, of whom 229 had a confirmed diagnosis of CML in blast crisis. Patients were treated with imatinib in daily oral doses of 400 mg or 600 mg. Imatinib induced hematologic responses in 52% of patients and sustained hematologic responses lasting at least 4 weeks in 31% of patients, including complete hematologic responses in 8%. For patients with a sustained response, the estimated median response duration was 10 months. Imatinib induced major cytogenetic responses in 16% of patients, with 7% of the responses being complete. Median survival time was 6.9 months. Nonhematologic adverse reactions were frequent but generally mild or moderate. Episodes of severe cytopenia were also frequent and were attributable to the underlying condition and treatment with imatinib. Drug-related adverse events led to discontinuation of therapy in 5% of patients, most often because of cytopenia, skin disorders, or gastrointestinal reactions. These results demonstrate that imatinib has substantial activity and a favorable safety profile when used as a single agent in patients with CML in blast crisis. Additional clinical studies are warranted to explore the efficacy and feasibility of imatinib used in combination with other antileukemic drugs.
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http://dx.doi.org/10.1182/blood.v99.10.3530DOI Listing
May 2002

Impact of prolonged infusions of the putative differentiating agent sodium phenylbutyrate on myelodysplastic syndromes and acute myeloid leukemia.

Clin Cancer Res 2002 Apr;8(4):963-70

The Johns Hopkins Oncology Center, Department of Pediatrics, Johns Hopkins School of Medicine, Baltimore, Maryland 21231, USA.

The aromatic fatty acid sodium phenylbutyrate (PB) promotes cytostasis and differentiation in a wide variety of tumor types; among several molecular activities, inhibition of histone deacetylase (HDAC) may account for many of its pharmacodynamic effects. A Phase I study demonstrated promising preliminary evidence of clinical activity in acute myeloid leukemia and myelodysplastic syndrome; however, plasma concentrations achieved at the maximum tolerated dose were less than those targeted based on in vitro studies. Because prolonged exposure to suboptimal concentrations of PB in vitro led to pharmacodynamic changes similar to a more brief exposure to higher concentrations, a study of the feasibility of prolonged administration of sodium PB was performed. Selected patients with acute myeloid leukemia and myelodysplastic syndrome were treated with sodium PB as a continuous i.v. infusion via ambulatory infusion pump. Sequential cohorts were treated for 7 consecutive days out of 14 or with 21 consecutive days out of 28. Prolonged infusions were well tolerated; dose-limiting central nervous system toxicity developed in 1 of 23 patients treated. End-of-infusion plasma concentrations were maintained within a range sufficient to inhibit HDAC. Two patients on the 21/28 schedule developed hematological improvement. Prolonged infusions of PB are well tolerated making this an attractive platform for the clinical investigation of HDAC inhibition.
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April 2002
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