Phase II study of individualized adaptive stereotactic body radiotherapy (SBRT) for patients at high risk for liver damage.

424 Background: Patients (Pts) with pre-existing liver dysfunction are at high risk for further damage after SBRT. We completed a phase 2 study of individualized SBRT, utilizing pre- and during-treatment indocyanine green (ICG) clearance to adapt treatment and maximize both safety and efficacy. Methods: From 5/10-10/14, pts with hepatocellular carcinoma (HCC) or metastases (mets) were enrolled and underwent SBRT planning up to a target dose of 50-60 Gy or as limited by a 15% normal tissue complication probability for radiation-induced liver disease (RILD). ICG retention at 15 minutes (ICGR15) was measured prior to and 1 month after 3 of 5 planned treatments. Using a Bayesian adaptive model, RT dose was scaled down as necessary for the final 2 treatments to keep ICGR15 < 44% after the full treatment and thus minimize toxicity. Follow up was every 3 months for 2 years. Results: 90 pts received SBRT to 116 tumors and had at least 1 year of potential follow up. Median age was 62 years, range 34-85. 69 had HCC, 4 intrahepatic cholangiocarcinoma, and 17 mets. 62 had cirrhosis, most commonly HCV and alcoholic. Median Child-Pugh (CP) score was 6, range 5-9. 20 pts were CP B/C. Median pre-RT ICGR15 was 22, range 4-75, normal 4-10. Pts had a median of 1.5 (range 0-6) prior liver-directed therapies, most commonly transarterial chemoembolization (70), prior RT (36), and radiofrequency ablation (13). Median tumor size was 3 cm, and 12 had portal vein involvement. 63 received all 5 fractions (48 full dose, 15 with dose reduction due to elevated ICGR15); 27 received only 3 treatments. Median prescription dose was 47 Gy. Treatment was well tolerated with no classical RILD and a lower complication rate than expected without adaptation. 4 pts had grade 3 ascites. 2 pts had GI bleed after SBRT. 14% and 10% of pts experienced at least a 1 or 2 point increase in CP 6 months post SBRT. Local control (95%CI) at 1 and 2 yrs was 99 (96,100)% and 90 (81,100)%. 4 recurrent tumors were 3 HCC and 1 met, measuring 26, 12, 30, 38mm; treated to 30, 50, 33, 30 Gy. Conclusions: Individualized adaptive SBRT, based on ICG clearance is a promising method of allowing pts to receive the maximally aggressive dose based on each pt’s individual tolerance to RT. Funded by P01 CA59827

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Depth of response and minimal residual disease status in ultra high-risk multiple myeloma and plasma cell leukemia treated with daratumumab, bortezomib, lenalidomide, cyclophosphamide and dexamethasone (Dara-CVRd): Results of the UK optimum/MUKnine trial.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.8001 ◽

2021 ◽

Vol 39 (15_suppl) ◽

pp. 8001-8001

Author(s):

Martin F. Kaiser ◽

Andrew Hall ◽

Katrina Walker ◽

Ruth De Tute ◽

Sadie Roberts ◽

...

Keyword(s):

Multiple Myeloma ◽

High Risk ◽

Minimal Residual Disease ◽

Plasma Cell ◽

Residual Disease ◽

Cell Leukemia ◽

Ultra High Risk ◽

Grade 3 ◽

Minimal Residual

8001 Background: Patients with ultra high-risk (UHiR) newly diagnosed multiple myeloma (NDMM) and patients with plasma cell leukemia (PCL) continue to have dismal outcomes and are underrepresented in clinical trials. Recently, improved responses with anti-CD38 monoclonal antibody combination therapy have been reported for NDMM patients. We report here outcomes for NDMM UHiR and PCL patients treated in the OPTIMUM/MUKnine (NCT03188172) trial with daratumumab, cyclophosphamide, bortezomib, lenalidomide, dexamethasone (Dara-CVRd) induction, augmented high-dose melphalan (HDMEL) and ASCT. With final analysis follow-up surpassed in Feb 2021, we report here early protocol defined endpoints from induction to day 100 post ASCT. Methods: Between Sep 2017 and Jul 2019, 107 patients with UHiR NDMM by central trial genetic (≥2 high risk lesions: t(4;14), t(14;16), t(14;20), gain(1q), del(1p), del(17p)) or gene expression SKY92 (SkylineDx) profiling, or with PCL (circulating plasmablasts > 20%) were included in OPTIMUM across 39 UK hospitals. Patients received up to 6 cycles of Dara-CVRd induction, HDMEL and ASCT augmented with bortezomib, followed by Dara-VR(d) consolidation for 18 cycles and Dara-R maintenance. Primary trial endpoints are minimal residual disease (MRD) status post ASCT and progression-free survival. Secondary endpoints include response, safety and quality of life. Data is complete but subject to further data cleaning prior to conference. Results: Median follow-up for the 107 patients in the safety population was 22.2 months (95% CI: 20.6 – 23.9). Two patients died during induction due to infection. Bone marrow aspirates suitable for MRD assessment by flow cytometry (10-5 sensitivity) were available for 81% of patients at end of induction and 78% at D100 post ASCT. Responses in the intention to treat population at end of induction were 94% ORR with 22% CR, 58% VGPR, 15% PR, 1% PD, 5% timepoint not reached (TNR; withdrew, became ineligible or died) and at D100 post ASCT 83% ORR with 47% CR, 32% VGPR, 5% PR, 7% PD, 10% TNR. MRD status was 41% MRDneg, 40% MRDpos and 19% not evaluable post induction and 64% MRDneg, 14% MRDpos and 22% not evaluable at D100 post ASCT. Responses at D100 post ASCT were lower in PCL with 22% CR, 22% VGPR, 22% PR, 22% PD, 12% TNR. Most frequent grade 3/4 AEs during induction were neutropenia (21%), thrombocytopenia (12%) and infection (12%). Grade 3 neuropathy rate was 3.7%. Conclusions: This is to our knowledge the first report on a trial for UHiR NDMM and PCL investigating Dara-CVRd induction and augmented ASCT. Response rates were high in this difficult-to-treat patient population, with toxicity comparable to other induction regimens. However, some early progressions highlight the need for innovative approaches to UHiR NDMM. Clinical trial information: NCT03188172.

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Five-Year Outcomes of Stereotactic Body Radiation Therapy (SBRT) for Prostate Cancer-The Largest Experience in China

10.21203/rs.3.rs-190455/v1 ◽

2021 ◽

Author(s):

Xianzhi Zhao ◽

Yusheng Ye ◽

Haiyan Yu ◽

Lingong Jiang ◽

Chao Cheng ◽

...

Keyword(s):

Prostate Cancer ◽

High Risk ◽

Cox Regression ◽

Progression Free Survival ◽

Cox Regression Analysis ◽

Gu Toxicity ◽

Biochemical Progression ◽

Grade 3 ◽

Very High

Abstract Objective To evaluate the efficacy and toxicity of SBRT for localized prostate cancer (PCa). Moreover, it is the largest-to-date pilot study to report 5-year outcomes of SBRT for localized PCa from China. Methods In this retrospective study, 133 PCa patients in our center were treated by SBRT with CyberKnife (Accuray) from October 2012 to July 2019. Follow-up was performed every 3 months for evaluations of efficacy and toxicity. Biochemical progression-free survival (bPFS) and toxicities were assessed using the Phoenix definition and the Common Terminology Criteria for Adverse Events (CTCAE) v.5.0 respectively. Factors predictive of bPFS were identified with COX regression analysis. Results 133 patients (10 low-, 21 favorable intermediate-, 31 unfavorable intermediate-, 45 high-, and 26 very high risk cases on the basis of the NCCN risk classification) with a median age of 76 years (range: 54–87 years) received SBRT. The median dose was 36.25Gy (range: 34-37.5Gy) in 5 fractions. Median follow-up time was 57.7 months (3.5–97.2 months). The overall 5-year bPFS rate was 83.6% for all patients. The 5-year bPFS rate of patients with low-, favorable intermediate-, unfavorable intermediate-, high-, and very high risk PCa was 87.5%, 95.2%, 90.5%, 86.3%, and 61.6% respectively. Urinary symptoms were all alleviated after SBRT. All the patients tolerated SBRT with only 1 (0.8%) and 1 (0.8%) patient reporting grade-3 acute and late genitourinary (GU) toxicity, respectively. There were no grade 4 toxicities. Gleason score (P < 0.001, HR = 7.483, 95%CI: 2.686–20.846) was the independent predictor of bPFS rate after multivariate analysis Conclusion SBRT is an efficient and safe treatment modality for localized PCa with high 5-year bPFS rates and acceptable toxicities.

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Management of feline tibial diaphyseal fractures using orthogonal plates performed via minimally invasive plate osteosynthesis

Journal of Feline Medicine and Surgery ◽

10.1177/1098612x17692470 ◽

2017 ◽

Vol 20 (1) ◽

pp. 6-14 ◽

Cited By ~ 3

Author(s):

Andrew Craig ◽

Philip G Witte ◽

Tristram Moody ◽

Karen Harris ◽

Harry W Scott

Keyword(s):

Minimally Invasive ◽

Bone Healing ◽

Plate Osteosynthesis ◽

Plate Fixation ◽

Major Complication ◽

Minimally Invasive Plate Osteosynthesis ◽

Lower Complication ◽

Lower Complication Rate ◽

Diaphyseal Fractures

Objectives The objective was to assess the medium- and long-term outcomes (radiographic and owner questionnaire) of feline tibial diaphyseal fractures with orthogonal plate fixation via a minimally invasive plate osteosynthesis (MIPO) approach. Methods Medical records and radiographs of cats that had tibial diaphyseal fractures stabilised with orthogonal plates were obtained (2012–2016). Immediate postoperative radiographs were reviewed to assess the construct configuration and follow-up radiographs (where available) were used to assess bone healing and implant-related complications. An owner-completed questionnaire (feline musculoskeletal pain index [FMPI]) was used at a minimum of 6 months following surgery to assess the cats’ ability to perform normal activities. Results Eight feline tibial diaphyseal fractures met the inclusion criteria. One major complication was observed, most likely due to an operative technical error. There were no further complications following revision surgery. Six of the eight cases that had radiographic follow-up either had clinical bone union or showed evidence of bone healing. All cases were classified as successful according to FMPI. Conclusions and relevance Orthogonal plating of feline tibial diaphyseal fractures via an MIPO approach resulted in successful outcomes and a lower complication rate compared with previously reported techniques.

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R-FND Followed by Radioimmunotherapy for High-Risk Follicular Lymphoma

Blood ◽

10.1182/blood.v112.11.3056.3056 ◽

2008 ◽

Vol 112 (11) ◽

pp. 3056-3056 ◽

Cited By ~ 7

Author(s):

Peter McLaughlin ◽

Sattva Neelapu ◽

Michelle Fanale ◽

Maria Rodriguez ◽

Ana Ayala ◽

...

Keyword(s):

High Risk ◽

Follicular Lymphoma ◽

International Prognostic Index ◽

Prognostic Index ◽

Ibritumomab Tiuxetan ◽

Free Survival ◽

Grade 3 ◽

Anti Cd20 ◽

Better Than

Abstract Follicular lymphoma (FL) patients, (pts) with high-risk features using the FL International Prognostic Index (FLIPI) have an expected 5-year survival of only about 50% with conventional therapy. With the incorporation of anti-CD20 monoclonal antibody (mAb) therapy, results are improving (e.g., Buske, Blood2006; 108: 1504). Starting in 2003, we have treated high-risk (FLIPI ≥3) FL pts with R-FND (rituximab, fludarabine, mitoxantrone, dexamethasone) for 4 cycles, followed by radioimmunotherapy (RIT) with ibritumomab tiuxetan, and subsequent rituximab maintenance. Results for the first 35 pts are: complete (CR) and partial (PR) remission 83% and 14%; 3-year overall (OS) and failure-free survival (FFS) 89% and 74% (median follow-up 24 mo.). RIT converted 5 PR pts to CR. Toxicity was mainly hematologic. Five pts did not receive RIT, one because of neutropenia after R-FND. Following RIT, platelet and neutrophil nadirs were 28 and 0.3, occurring at 4–7 weeks. 16 pts required transfusions, and 27 received growth factors. 13 pts had infections, only 2 of which were grade 3. Recovery occurred by 3 weeks in most, with prolonged cytopenias in 6. There has been 1 case of myelodysplasia. In conclusion, the additional complexity of this RIT intensification strategy is warranted in this high-risk FL population, resulting in OS and FFS outcomes that are better than non-mAb therapies, and at least as good as published chemotherapy-rituximab combination therapy.

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Frontline Combined Chemoimmunotherapy with Fludarabine, Cyclophosphamide, Alemtuzumab and Rituximab (CFAR) in High-Risk Chronic Lymphocytic Leukemia.

Blood ◽

10.1182/blood.v114.22.208.208 ◽

2009 ◽

Vol 114 (22) ◽

pp. 208-208 ◽

Cited By ~ 2

Author(s):

Sameer A Parikh ◽

Michael Keating ◽

Susan O'Brien ◽

Alessandra Ferrajoli ◽

Stefan Faderl ◽

...

Keyword(s):

High Risk ◽

Chronic Lymphocytic Leukemia ◽

Single Agent ◽

Lymphocytic Leukemia ◽

Hematologic Toxicity ◽

Frontline Therapy ◽

Grade 3 ◽

Tract Infections ◽

Cmv Reactivation

Abstract Abstract 208 Background: Combined chemoimmunotherapy with fludarabine, cyclophosphamide and rituximab (FCR) has excellent clinical activity as frontline therapy for patients (pts) with chronic lymphocytic leukemia (CLL). In a subset of pts who exhibited high-risk features, such as serum beta-2 microglobulin (B2M) ≥4 mg/L; the complete remission (CR) was lower and time to progression (TTP) and overall survival (OS) were shorter; therefore characterizing these pts as high-risk. Alemtuzumab (A) has activity as a single-agent and in combination with F in pts with relapsed/refractory CLL. To improve the CR and OS for pts with high-risk CLL, we added A to the FCR regimen (CFAR) as frontline therapy in a Phase II clinical trial. Methods: All pts who met NCI-WG criteria to initiate therapy, were < 70 years and had a B2M ≥4 mg/L were eligible for the study. Frontline CFAR consisted of C-200 mg/m2 D3-5, F-20mg/m2 D3-5, A-30mg IV D1,3,5, and R-375–500 mg/m2 D2. Courses were repeated every 28 days for a total of 6 courses. All pts received pegylated filgrastim 6mg SC with each course of therapy. All pts received allopurinol for tumor lysis prophylaxis. Antibiotic prophylaxis with TMP/SMX DS and valacyclovir or valganciclovir was also given to all pts. CMV antigenemia was monitored before each course. Results: A total of 60 pts were enrolled from July 2005 through August 2008 (Table). One pt was lost to follow-up. The median age was 59 yrs (range 42–69) and 44 (75%) were male. Median B2M was 5.1 mg/L (4–11.6); HGB was 11.5gm/dL (5.5–15.1); PLT was 139 k/μL(41–446); WBC was 100k/μL (5–665); ALC was 92k/μL (4–619); and 30 pts (51%) were Rai stage III-IV. The median number of courses administered was 4 (2–6); reasons for not completing 6 courses included delayed recovery of counts (18), infection (8), AIHA (4), treatment failure (3) and pt. choice (2). CR was achieved in 70%, nPR in 3%, PR in 18%, and 7% pts did not respond, leading to an ORR of 92% (Table). There was no significant correlation between CR or OR with Rai Stage, IgVH mutation status, FISH status, ZAP70 and CD38 expression. After a median follow-up of 24 months (3–49), 19(32%) pts have progressive disease. Patients with 17p deletion and unmutated IgVH had significantly shorter TTP as shown in the >Table. Eleven (19%) pts have died: 4 with disease progression after achieving CR; 2 who did not respond; 2 with Richter's transformation; 1 transformed into AML; 1 due to metastatic lung cancer; and 1 due to severe pneumonia 8 months after achieving CR. Grade 3/4 neutropenia and thrombocytopenia occurred in 31% and 13% courses. Major infections, including pneumonia and sepsis, were reported for 10(17%) pts. Minor infectious such as bronchitis, urinary tract infections and herpes zoster were reported for 15(25%) pts. In a historic cohort of high-risk pts treated with FCR, grade 3/4 neutropenia and thrombocytopenia occurred in 31% and 10% courses; and major and minor infections were seen in 15% and 23% pts respectively, all comparable to that seen with frontline CFAR. A-associated infusion reactions occurred in 42 (71%) pts. CMV reactivation occurred in 7 (12%) pts, all of whom were on valacyclovir prophylaxis. There was 1 death due to CMV pneumonia; all other episodes of CMV reactivation were promptly treated with valaganciclovir leading to resolution of fever and/or antigenemia. The median OS for all pts has not been reached (49+mo) and the median TTP is 38 months. Conclusion: CFAR is an active frontline regimen in high-risk pts with CLL. Although CR rates in pts with other high-risk features such as 17p deletion and unmutated IgVH were >50%, TTP was significantly shorter for these pts than for pts without these features. With current follow-up, OS, TTP, infectious complications and grade 3/4 hematologic toxicity are comparable to historic high-risk pts treated with FCR. Disclosures: Keating: Genentech: Honoraria, Membership on an entity's Board of Directors or advisory committees. Wierda:Genentech: Consultancy, Honoraria; Genzyme: Research Funding.

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Efficacy and Toxicity of Rituximab and Brief Duration, High Intensity Chemotherapy with Filgrastim Support for Burkitt or Burkitt – Like Leukemia/Lymphoma: Cancer and Leukemia Group B (Calgb) Study 10002

Blood ◽

10.1182/blood.v116.21.858.858 ◽

2010 ◽

Vol 116 (21) ◽

pp. 858-858 ◽

Cited By ~ 10

Author(s):

David A. Rizzieri ◽

Jeffrey L Johnson ◽

John C. Byrd ◽

Gerard Lozanski ◽

Bayard L. Powell ◽

...

Keyword(s):

High Risk ◽

High Intensity ◽

International Prognostic Index ◽

Tumor Lysis Syndrome ◽

Prognostic Index ◽

Adult Patients ◽

Term Survival ◽

Risk Patients ◽

Grade 3

Abstract Abstract 858 Prior studies have shown that combination chemotherapy using high doses of antimetabolites and alkylating agents over a short duration is effective treatment for Burkitt leukemia and lymphoma. Adults able to tolerate this therapy have had > 50% long term survival, although those with higher risk by the International Prognostic Index (IPI) have had inferior outcomes. Between 5/2002 and 9/2009, we enrolled 105 adults (19-79 yrs old) with untreated Burkitt leukemia/lymphoma onto a phase II study of a high intensity chemo-immunotherapy regimen to assess the benefit of adding rituximab plus growth factor support to the intensive chemotherapy regimen developed in CALGB 9251 and evaluated patterns of relapse when prophylactic cranial irradiation was not given. All subjects were HIV negative and had serum creatinine and bilirubin ≤1.5 × upper limit. Complete data are available on 105 patients for toxicity and 103 patients for efficacy. Methods: Treatment began with cyclophosphamide (CY) 200 mg/m2 × 5 days and prednisone 60 mg/m2 × 7 days. Cycle 2 was started on Day 8 after entry. Cycles 2, 4, and 6 consisted of ifosfamide 800 mg/m2 on days 1–5, methotrexate (MTX) 1.5 g/m2 infused over day 1 with leucovorin rescue, vincristine (VCR) 2 mg day 1, Ara-C 1 gm/m2 days 4 and 5, VP-16 80 mg/m2 days 4 and 5, and dexamethasone 10 mg/m2 on days 1–5. Cycles 3, 5, and 7 included the same doses of MTX, VCR, and dexamethasone, with CY 200 mg/m2 IV on days 1–5 and doxorubicin 25 mg/m2 days 4 and 5. Cycles were delivered every 21 days if blood counts had recovered. Filgrastim was given at 5μg/kg/day SC beginning day 7 of each cycle and continuing until the absolute neutrophil count recovered to > 5000/μL. Rituximab was initiated during cycle 2 on day 8 at 50 mg/m2 and on days 10 and 12 at 375 mg/m2. During cycles 3 through 7, rituximab was infused only on day 8 of each course at 375 mg/m2. Central nervous system (CNS) prophylaxis consisted of triple intrathecal therapy on day 1 of cycles 2–7 (6 total doses). Results: 27% of patients were ≥60 years old; 70% were male; 46% had intermediate or high risk disease by the IPI (Table). Overall, 75 of 105 subjects completed all 7 planned courses of therapy. 82% attained a complete response (CR), and 87% of these remain in CR at last follow up. 7% had a partial response. With median follow up of survivors of 3.2 years, 2 year event free survival (EFS) and overall survival (OS) were 77% and 79%, respectively, with a trend favoring those <60 years old (87% and 87%, respectively). There were clear differences in outcome based on IPI score with 2 year EFS and OS for low risk patients of 90% and 92% versus 55% and 55% for high risk patients, respectively (Figure). This protocol did not use prophylactic CNS radiation, and 4 pts had documented CNS relapses; 2 had intermediate and 1 high IPI disease; the 4th was unknown. Relapse after 2 years was rare. 7 subjects (6.8%) died from treatment related causes (1 CNS bleed, 4 infections, 2 respiratory failure). Nearly all subjects experienced the anticipated severe hematologic toxicities. The most common grade 3 and 4 non-hematologic toxicities included stomatitis/upper GI toxicity (∼ 66%), nausea/vomiting (20%), fatigue (26%), rash or erythema multiforme (10%), diarrhea (10%), pulmonary or CNS bleeding (11%), clinically documented infections (72%), neurologic disturbances (8%), and dyspnea (10%). 8 pts (8%) had tumor lysis syndrome (all grade 3). Conclusion: This regimen provides a high rate of durable remissions in adult patients with a manageable side effect profile. Chemoimmunotherapy should be the standard for adult patients with Burkitt leukemia/lymphoma. Disclosures: Off Label Use: Rituximab for use in Burkitt's. Cheson:Genentech: Consultancy.

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Alemtuzumab Plus Oral Dexamethasone, Followed by Alemtuzumab Maintenance or Allogeneic Transplantation in Ultra High-Risk CLL: Interim Analysis of a Phase II Study of the GCLLSG and fcgcll/MW

Blood ◽

10.1182/blood.v118.21.2854.2854 ◽

2011 ◽

Vol 118 (21) ◽

pp. 2854-2854 ◽

Cited By ~ 2

Author(s):

Stephan Stilgenbauer ◽

Florence Cymbalista ◽

Véronique Leblond ◽

Alain Delmer ◽

Dirk Winkler ◽

...

Keyword(s):

High Risk ◽

Research Funding ◽

Response Rates ◽

Long Term Results ◽

High Dose ◽

Significant Difference ◽

Ultra High Risk ◽

Grade 3 ◽

The Impact

Abstract Abstract 2854 Alemtuzumab (A) proved to be efficacious in CLL patients (pts) with very poor prognosis, either due to fludarabine (F) refractoriness or due to unfavorable cytogenetics (17p-). However, rate and duration of remissions still remain unsatisfactory. Therefore, the French and German CLL study groups jointly embarked on this trial, trying to achieve higher overall response rates (ORR) by adding high-dose dexamethasone (D) to A and, simultaneously, investigating the consolidation effect of prolonged A maintenance or allogeneic stem-cell transplantation (allo-SCT), respectively. Induction treatment consisted of subcutaneous A 30 mg weekly × 3 for 28 days, combined with oral D 40 mg on days 1–4 and 15–18, and prophylactic pegfilgrastim 6 mg on days 1 and 15. Depending on the remission status, pts were treated for up to 12 weeks. If CR was documented at 4 or 8 weeks, or at least SD was achieved at 12 weeks, consolidation was scheduled with either allo-SCT or A maintenance with 30 mg every 14 days for up to 2 years (y), at the discretion of pt and physician. Between January 2008 and July 2011, 124 pts were recruited at 26 centers, 120 of whom were eligible. Pts were generally subdivided into three cohorts: 55 pts were refractory (i.e. no response or relapse within 6 months) to regimens containing F or a similar drug (i.e. pentostatin, cladribine, bendamustine). Non-refractory pts all exhibited 17p- and had either untreated (n=39) or relapsed CLL (n = 26) requiring therapy. The median age was high with 66/64/66 y in 17p- 1st line, 17p- relapse, and F-refractory pts, respectively. The three cohorts had 46/54/75% Binet C disease, 41/35/27% B symptoms, 38/42/53% reduced performance status (ECOG 1/2), median thymidine kinase levels of 35/49/24 U/L, median ß2MG levels of 3.8/5.5/4.6 mg/L, and IGHV was unmutated in 89/96/87%. In the F-refractory group, 53% exhibited 17p deletion and 22% had 11q deletion. Pretreated patients had received a median of 3 (F-refractory) or 2 prior lines (17p- relapse). 5 pts had previously undergone autologous and 1 pt allo-SCT. Treatment and efficacy data are currently available for 87 pts who completed induction therapy :17p- 1st-line (n=30), 17p- relapse (n=17), and F-refractory (n=40). Of these, 80/53/55% received the full induction of 12 weeks. ORR (best observed status) was generally high with 97/76/70%. CR was achieved in 20/0/5%. After a median follow-up of 11.8 months (mo), median progression-free survival (PFS) was 16.9/10.4/8.4 mo. Deaths are recorded in 13/27/36% of pts, with median overall survival (OS) not yet reached (>24 mo) in the 17p- 1st line group, and 15/12 mo in 17p- relapse/F-refractory pts. Consolidation treatment was performed as maintenance A (median duration 32 weeks, range 2 – 89) in 34%, and allo-SCT in 30%, with a median age of 66 and 61 y in these subgroups. The main reasons for going off-study without consolidation were death due to infection (14%, n=11, of these 6 without response, and 10 in the F-refractory cohort), CLL progression (12%), and other toxicity (5%). Among the 28 pts not receiving consolidation, there were 19 (68%) deaths, 15 of them in the F-refractory cohort. When comparing A maintenance and allo-SCT for consolidation, there were 9 (35%) and 7 (30%) PD events, respectively and there was so far no significant difference in PFS (median 17 mo in both groups) or OS. During induction, grade 3/4 hematotoxicity consisted of anemia in 28%, neutropenia in 47%, and thrombopenia in 44%. Grade 3/4 non-CMV infection occurred in 29% of 17p- 1st-line, 15% of 17p- relapsed, and 56% of F-refractory pts. CMV reactivation was observed in 54/25/40%, without severe sequelae recorded. During A maintenance, grade 3/4 toxicity consisted of neutropenia in 39% pts and thrombopenia in 4% pts with 6 SAEs (ITP, diarrhea, infection, erythema, tachycardia, and thrombosis). Conclusions: The combination of A and D shows high response rates in ultra high-risk CLL, with promising preliminary findings for PFS and OS, despite the high median age of the pts. The results compare favorably to ORR/CR of 68%/5%, and median PFS of 11.3 mo in the 17p- subgroup of the CLL8 study treated with FCR, consisting of younger pts (median 61 y). In F-refractory CLL however, when compared to the preceding CLL2H study with single agent A, the improved initial response by adding dexamethasone does not seem to translate into improved long-term results. More mature follow-up is needed, especially with respect to the impact of allo-SCT. Disclosures: Stilgenbauer: Amgen: Consultancy, Honoraria, Research Funding; Genzyme: Consultancy, Honoraria, Research Funding. Off Label Use: Alemtuzumab in 1st line CLL treatment. Cymbalista:Roche (d) Mundipharma (e) Genzyme (e): Honoraria, Research Funding. Hinke:WiSP (CRO): Employment.

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Ibrutinib In Combination With Rituximab (iR) Is Well Tolerated and Induces a High Rate Of Durable Remissions In Patients With High-Risk Chronic Lymphocytic Leukemia (CLL): New, Updated Results Of a Phase II Trial In 40 Patients

Blood ◽

10.1182/blood.v122.21.675.675 ◽

2013 ◽

Vol 122 (21) ◽

pp. 675-675 ◽

Cited By ~ 21

Author(s):

Jan A. Burger ◽

Michael J. Keating ◽

William G. Wierda ◽

Julia Hoellenriegel ◽

Ghayathri Jeyakumar ◽

...

Keyword(s):

High Risk ◽

Subdural Hematoma ◽

Research Funding ◽

Tp53 Mutation ◽

Single Agent ◽

Infectious Complications ◽

Lymphocytic Leukemia ◽

High Rate ◽

Grade 3

Abstract The Bruton tyrosine kinase (BTK) inhibitor ibrutinib is a promising new targeted therapy for patients with mature B cell malignancies, especially CLL and mantle cell lymphoma (MCL). Single agent ibrutinib induces an overall response rate (ORR) of 71% in relapsed CLL, based on the Phase 1/2 experience. To accelerate and improve responses to ibrutinib in high-risk CLL, ibrutinib was combined with rituximab; we update this Phase 2 single-center clinical trial with a median follow-up of 14 months. Methods Patients were treated with ibrutinib 420 mg PO daily continuously throughout the study Rituximab (375 mg/m2) was administered weekly for the first four weeks (cycle 1), then monthly until cycle 6.at which point patients continued on ibrutinib monotherapy. Study inclusion required high-risk disease (del17p or TP53 mutation [treated or untreated]), PFS < 36 months after frontline chemo-immunotherapy, or relapsed CLL with del11q. Results Characteristics of the 40 patients enrolled included median age of 65 (range 35–82) with a median of 2 prior therapies. There were14 female and 26 male patients. 20 patients had del17p or TP53 mutation (4 without prior therapy), and 13 patients had del11q. 32 patients had unmutated IGHV, only one patient mutated IGHV, the remaining patients had inconclusive IGHV results. The median β2 microglobulin was 4.2 mg/L (2.2 – 12.3), At a median follow up of 14 months, 32 of 40 patients continue on therapy (16 out of 20 with del17p or TP53 mutation) without disease progression. 39 patients were evaluable for response assessment per 2008 IWCLL guidelines; 34 (87%) achieved partial remission (PR), and three (8%) complete remission (CR), accounting for an ORR of 95%. One CR was negative for MRD by flow cytometry, The ORR in the 20 patients with del17p or TP53 mutation was 90% (16 PR, 2 CR). Among the 8 patients that came off study, 3 patient died from unrelated infectious complications (2 cases of sepsis, 1 case of pneumonia), and 1 died from unrelated respiratory and cardiovascular failure. Two patients came off study because of possibly ibrutinib-related toxicity (one subdural hematoma, one grade 3 mucositis), one patient had progressive disease, and one proceeded to stem cell transplantation. Treatment generally was well tolerated, with infectious complications (6 cases of pneumonia and 3 cases of upper respiratory infections) being the most common complication. There were two Grade 3, possibly related AEs: mucositis (n=1), and peripheral neuropathy (n=1). Milder toxicities included Grade 1-2 bruising (n=7), Grade 1 subdural hematoma (n=1), fatigue (n=2), bone pain, myalgias, and arthralgia (n=5), or diarrhea (n=1). Questionnaires revealed significantly improved overall health and quality of life (QOL) after 6 months, based on the EORTC-QOL-v.3 questionnaire, which coincided with a significant weight gain at 3 and 6 months. Conclusion Ibrutinib in combination with rituximab is a safe, well tolerated regimen for high-risk CLL patients, which induces high rates of durable responses. Responses were associated with significant improvements in QOL. Compared to ibrutinib monotherapy, the redistribution lymphocytosis resolves more rapidly and completely (see Figure), and consequently the ORR is higher. Whether the addition of rituximab to ibrutinib therapy translates into longer progression-free and overall survival will be addressed in an upcoming larger, randomized trial of ibrutinib versus iR in relapsed/refractory CLL. Disclosures: Burger: Pharmacyclics: Membership on an entity’s Board of Directors or advisory committees, Research Funding. Off Label Use: Ibrutinib (PCI-32765) for treatment of high-risk CLL patients. O'Brien:Pharmacyclics: Research Funding.

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A Prospective Study to Evaluate the Effect of Paclitaxel on Cardiac Ejection Fraction

Breast Care ◽

10.1159/000471759 ◽

2017 ◽

Vol 12 (4) ◽

pp. 255-259 ◽

Cited By ~ 3

Author(s):

Mohammed Osman ◽

Mohammad Elkady

Keyword(s):

High Risk ◽

Ejection Fraction ◽

Prospective Study ◽

Performance Status ◽

Primary Objective ◽

Cardiac Ejection Fraction ◽

Grade 3 ◽

A Prospective Study

Background: The primary objective of the study was to evaluate the long-term changes in ejection fraction (EF) associated with paclitaxel infusion. Methods: 50 patients were enrolled in this prospective study between 2011 and 2015. The study design included frequent follow-up visits to the clinic, EF evaluation at baseline, and regular EF assessment by echocardiography for 30 months after treatment. Results: The median baseline EF was 60% (95% confidence interval (CI) 50-80%). At 30 months, the median EF was 48% (95% CI 40-60%; p = 0.03). During the 30-month follow-up, 10 (20%) patients developed grade 1 and 2 cardiotoxicities; none developed grade 3 or 4 cardiotoxicities. Furthermore, paclitaxel cardiotoxicity increased among patients with high-risk features including associated diabetes mellitus, hypertension, prior radiotherapy to the chest wall, performance status of 2, and age > 60 years. Conclusion: Paclitaxel has cardiotoxic effects. Careful monitoring of cardiac function during and after paclitaxel infusion is required in patients with high-risk features.

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Burden of Disease and Clinical Responses in Low and Intermediate-1 Risk Myelofibrosis Patients Treated with Ruxolitinib

Blood ◽

10.1182/blood.v124.21.1834.1834 ◽

2014 ◽

Vol 124 (21) ◽

pp. 1834-1834

Author(s):

Ahmad Zarzour ◽

Ali Tabarroki ◽

Valeria Visconte ◽

Rokana Taftaf ◽

Heesun J. Rogers ◽

...

Keyword(s):

High Risk ◽

Adverse Events ◽

Burden Of Disease ◽

Costal Margin ◽

Severe Toxicity ◽

Spleen Size ◽

High Burden ◽

Clinical Responses ◽

Grade 3

Abstract Myelofibrosis (MF) is a hematologic neoplasm characterized by variable degrees of cytopenias/ myeloproliferation, extramedullary hematopoiesis, disease-related constitutional symptoms and an increased risk for acute myeloid leukemia (AML) transformation. Ruxolitinib, a JAK1/2 inhibitor is FDA approved for the management of intermediate to high-risk MF. However, intermediate-2 and high-risk MF patients accounted for 99% of patients (pts) in the 2 pivotal trials that led to the approval of ruxolitinib in North America, Australia and Europe (COMFORT 1 and COMFORT 2 studies). However, even low and intermediate-1 (int-1) risk MF pts could have a high burden of disease. Here we report our experience of using ruxolitinib in MF pts stratified as low and int-1 risk by the Dynamic International Prognostic Scoring System (DIPSS). A total of 25 pts with low and Int-1 risk disease were treated with ruxolitinib at the Cleveland Clinic and Northwestern University. The median age of the cohort was 61 yrs (range=33-87; males=9, females=16). The median total symptom score (TSS) by Myeloproliferative Neoplasm Symptom Assessment Form (MPN SAF) was 20. The median pre-treatment spleen size by palpation was 13 cm below the left costal margin. Baseline median bone marrow (BM) fibrosis grading was 2 (on a scale 0-3; grade 1 N=3, grade 2 N=11, and grade 3 N=11). The indications for starting ruxolitinib were constitutional symptoms (fatigue N=20, night sweats N=4, pruritus N=1) and splenomegaly (N=13). The median starting dose was 5 mg twice daily, 10mg twice daily at 3 months and 6 months, and 5mg twice daily at 12 months. The median dose at last follow up was 10 mg twice daily. The median duration of treatment was 12 months. There was a median 73% reduction in the MPN SAF TSS compared to baseline (P< 0.001). There was improvement in each of the parameters of the TSS. The percentage of reduction in spleen size by palpation at 3, 6, 12 months was 49, 57, and 64%, respectively. In 5 patients who had a repeat BM biopsy, there was an improvement in their BM fibrosis by at least 1 grade (N=3), stable fibrosis (N=1) or increased fibrosis (N=1). Hematologic adverse events were reported at 3, 6, 12 months of treatment. Using Common Terminology Criteria for Adverse Events (CTCAEv4.0), there were seven with grade 3/4 anemia and six with grade 3/4 thrombocytopenia. Non-hematologic adverse events reported at 3, 6, 12 months of treatment included dizziness (N=1), headaches (N=1) and infections (pneumonia N=2, cellulitis N=2, perineal abscess N=1, Herpes Zoster N=2, and gluteal abscess after BM biopsy N=1; only one required hospitalization). Ruxolitinib was discontinued in 5 patients due to lack of clinical response (N=3) and grade 3/4 anemia/thrombocytopenia (N=2). The remaining 20 patients are still on treatment. None of the pts progressed to AML or died. The median follow up of our cohort was 27 months. Further, using a multi-Analyte ELISArray Kit, plasma concentrations of interleukins (IL):IL1A, IL1B, IL2, IL4, IL6, IL8, IL10, IL12, IL17A, INFg, TNFa and GM-CSF were measured in low/int-1 risk pts (N=3) and intermediate-2/high risk patients (N=4) and no statistically significant difference was found between the two risk groups (P>0.05) further supporting the high burden of disease observed even in low and int-1 risk MF patients. In conclusion, pts with low/int-1 risk MF have a high burden of disease and can achieve meaningful clinical responses to ruxolitinib similar to int-2/ high risk MF pts without severe toxicity. Larger studies are needed to further evaluate the safety and efficacy of ruxoltinib in this patient population. Disclosures No relevant conflicts of interest to declare.

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