Final Report of the UKCLL02 Trial: A Phase II Study of Subcutaneous Alemtuzumab Plus Fludarabine in Patients with Fludarabine Refractory CLL (on Behalf of the NCRI CLL Trials Sub-Group).

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 34-34 ◽  
Author(s):  
Hazem A. Sayala ◽  
Paul Moreton ◽  
Richard A. Jones ◽  
Andy C. Rawstron ◽  
Sheila J. O’Connor ◽  
...  
Keyword(s):  
Median Survival ◽  
Germ Line ◽  
Combined Therapy ◽  
Final Report ◽  
Functional Assay ◽  
Skin Reactions ◽  
Poor Risk ◽  
Erythematous Skin ◽  
Grade 3 ◽  
Cmv Reactivation

Abstract Patients with fludarabine refractory CLL have a median survival of 10 months with conventional chemotherapy. Intravenous (IV) alemtuzumab results in 33 to 50% responses in refractory CLL. Combined alemtuzumab and fludarabine can induce responses in CLL refractory to both agents. Infusion reactions and 2-hour infusions 3× a week for 12 weeks are problems with IV alemtuzumab. Subcutaneous (SC) alemtuzumab is more convenient but pharmacokinetics reveal lower initial levels compared to IV. The UKCLL02 study assessed the safety and efficacy of SC alemtuzumab in fludarabine-refractory CLL. SC alemtuzumab was given at a dose of 30mg 3× a week (after dose escalation) for up to 24 weeks depending on 6-weekly marrow assessments. Patients failing to respond to alemtuzumab could receive oral fludarabine (40mg/m2/day for 3 days every 4 weeks) combined with SC alemtuzumab. Of 53 patients (median age 64, range 41 to 79) enrolled 2 patients died before receiving alemtuzumab and 1 withdrew consent. 50 patients have completed therapy and 49 are evaluable. Responses to alemtuzumab monotherapy (n=49) were 5 MRD negative CR, 2 MRD positive CR, 15 PR (including 1 MRD negative patient who remained cytopenic), 25 NR and 2 patients died on treatment. Alemtuzumab was given for a median of 18.8 weeks (range:1.6–24) with a median dose of 1370.5mg (range 106–2323mg). 17 patients (6 PRs and 11 NRs) received concurrent fludarabine and SC alemtuzumab (median 2 courses fludarabine [range 1–3]). 2 NR achieved a PR and 1 PR achieved a CR (MRD positive). Therefore the overall response rate for the whole cohort was 24/49(49%) including 6 MRD negative patients (5CRs and 1 PR). IgVH gene was unmutated (>98% germ line homology ) in 23/31 patients. FISH revealed poor risk deletions (11q and/or 17p) in 28/46 patients (17p- in 15, 11q- in 7, both in 6). 25/38 patients had dysfunction p53 in a functional assay. 22/38 patients (58%) with poor risk deletions (11q- and/or 17p-) and/or p53 dysfunction responded to treatment, including 5 patients who achieved MRD-negative CRs, 3 MRD-positive CR, and 14 PR. The initial alemtuzumab dose was associated with localised erythematous skin reactions in 26 patients (diameter 1 to 18cm), fever in 8 and rigors in 4. All reactions subsided in <48h. Serious infections during alemtuzumab monotherapy were: CMV reactivation (18); febrile neutropenia (10); invasive fungal infection (4); pneumonia (7) and septicaemia (2). On the combination, CMV reactivation (3 cases) and septicaemia in (1). All CMV reactivations resolved on antiviral therapy. Grade 3+ thrombocytopenia and neutropenia was seen in 26 and 41 patients on alemtuzumab monotherapy as well as in 1 and 5 patients on combined therapy, respectively. The median survival for responders was 25 months compared to 13 months for non-responders. In summary, we report that subcutaneous alemtuzumab is effective in poor-risk fludarabine-refractory CLL and is well tolerated compared to IV therapy. A longer duration of SC alemtuzumab therapy (up to 24 weeks) was given. The addition of oral fludarabine improves the response rates with acceptable toxicity.

Interim Report of the UKCLL02 Trial: A Phase II Study of Subcutaneous Alemtuzumab Plus Fludarabine in Patients with Fludarabine Refractory CLL (on Behalf of the NCRI CLL Trials Sub-Group).

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 2120-2120 ◽  
Author(s):  
Hazem Sayala ◽  
Paul Moreton ◽  
Jones A. Richard ◽  
Rawstron C. Andy ◽  
O’Connor Sheila ◽  
...  
Keyword(s):  
Overall Response Rate ◽  
Germ Line ◽  
Combined Therapy ◽  
Skin Reactions ◽  
Poor Risk ◽  
Serious Infections ◽  
Infusion Reactions ◽  
Erythematous Skin ◽  
Grade 3 ◽  
Cmv Reactivation

Abstract Patients with fludarabine refractory CLL have a median survival of 10 months with conventional chemotherapy. Intravenous (IV) alemtuzumab is approved in fludarabine refractory CLL resulting in 33 to 50% responses. Combined alemtuzumab and fludarabine can induce responses in CLL refractory to both agents. Infusion reactions and 2-hour infusions 3x a week for 12 weeks are problems with IV alemtuzumab. Subcutaneous (SC) alemtuzumab is more convenient but pharmacokinetics suggest the need for prolonged therapy with little efficacy data in fludarabine-refractory CLL. We report on the UKCLL02 study to assess the safety and effectiveness of SC alemtuzumab in fludarabine-refractory CLL. SC alemtuzumab was given at a dose of 30mg 3x a week (after dose escalation) for up to 24 weeks depending on 6-weekly marrow assessments. Patients failing to respond to alemtuzumab in the trial could receive oral fludarabine (40mg/m2/day for 3 days every 4 weeks) combined with SC alemtuzumab. In this planned interim analysis of the first 44 patients (median age 66, range 41 to 79) 2 patients died before receiving alemtuzumab, and 5 remain on therapy. Of the remaining 37 patients, one withdrew consent and 36 patients have completed therapy. Responses to alemtuzumab monotherapy (n=36) were 2 MRD negative CR, 1 MRD positive CR, 11 PR (including 1 MRD negative patient who remained cytopenic), 20 NR and 2 died. Alemtuzumab was given for a median 12 weeks (range: 2–24) with a median dose of 913mg (range 106 to 2173mg). 12 patients (8 NR and 4 PR) received concurrent fludarabine and SC alemtuzumab (median 2.5 courses fludarabine [range 1–3]). 2 non-responders achieved a PR and one of the partial reponders achieved a CR (MRD positive). Therefore the overall response rate for the whole cohort was 16/36 (44%) including 3 MRD negative patients (2 CRs and 1 PR). IgVH gene was unmutated (>98% homology to germ line DNA) in 11/14. FISH revealed poor risk deletions (11q and/or 17p) in 21/34 patients (17p- in 9; 11q- in 6 and both in 6). p53 functional analysis is available for 23. 20/23 had p53/ATM dysfunction or deletion. 10/21 evaluable cases with del (11q23)/del (17p) responded to therapy. The initial alemtuzumab dose was associated with localised erythematous skin reactions in 20 patients (diameter 1 to 18cm), fever in 7 and rigors in 3. All reactions subsided in <48h. Serious infections during alemtuzumab monotherapy were: CMV reactivation (10); febrile neutropenia (9); invasive fungal infection (3); pneumonia (2). On the combination, CMV reactivation in 2 cases but no other grade 3+ infections. All CMV reactivations resolved on antiviral therapy. Grade 3+ thrombocytopenia and neutropenia was seen in 16 and 25 patients on alemtuzumab monotherapy as well as in 1 and 2 patients on combined therapy, respectively. In summary, we report that subcutaneous alemtuzumab is effective in poor-risk fludarabine-refractory CLL and is well tolerated compared to IV therapy. A longer duration of SC alemtuzumab therapy (up to 24 weeks) is required. The addition of oral fludarabine improves the response rates with acceptable toxicity.

Combined chemotherapy and surgery for metastatic gallbladder cancer improve median survival

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 14136-14136
Author(s):  
J. O. Gallardo ◽  
B. Rubio ◽  
J. C. Díaz ◽  
F. Maluenda
Keyword(s):  
Overall Survival ◽  
Gallbladder Cancer ◽  
Median Survival ◽  
Combined Therapy ◽  
Mortality And Morbidity ◽  
R1 Resection ◽  
Post Surgery ◽  
Frequent Site ◽  
Grade 3 ◽  
Radio Chemotherapy

14136 Background: Metastatic gallbladder cancer (MGBC) is a rapidly progressive disease, orphan of treatment; its median survival is only 3 to 4 months. Since 1999 we had demonstrated that gemcitabine (Gem) and gemcitabine-cisplatin (Gem-plat) are active regimens against this disease, but median survival increases to only 8 months. We had seen some complete responses and cases with impressive partial responses, but all of them are transients, recurrence appears in all pts. The benefit of combining CHTx and surgery had not been tested in MGBC, but has demonstrated promising results in others GI cancers. Methods: A retrospective analysis was performed in data from 9 patients (pts) who had liver resection for MGBC. Gem o gem-plat was given to all patients. Between September 1999 and July 2005 we had included more than 70 pts in two trials and others 25 pts had been treated outside of clinical trials. Among then, 9 patients with metastases from MGBC who were treated with Gem ± plat, were sent for resection of residual tumors. All pts received radio-chemotherapy after resection The primary endpoint was overall survival. Safety was a secondary end point. Results: We report the results of the first 9 patients with at least 9 months follow-up post surgery. Median overall survival is 17 months (9+ - 24). Only one pt is free of recurrence, (at 9 months), all others died due to relapse. Liver was the most frequent site of recurrence (8/8), but also peritoneal cavity and duodenum. All pts presented recurrence distant to initial tumor site. Most possible explanation for recurrence in 3 cases was R1 resection. In the CHTx phase no one pts required a dose reduction. Grade ≥3 was rare, vomiting in 2.0%, febrile neutropenia in 1.3%. There was no toxic death. Surgical complications (within 30 days of surgery) were low, with no one requiring reoperation, and no deaths were observed. Conclusions: Chemotherapy with Gem ± cisplatin was safely administered. Surgical mortality and morbidity rates were low. Even though a high proportion of patients died due to relapse, and thus suggest that this approach in inconvenient, this combined therapy offer a double life expectancy compare to chemotherapy alone. No significant financial relationships to disclose.

scholarly journals Breast cancer in a patient with Birt-Hogg-Dubé syndrome (BHDS) with dramatic response to neoadjuvant chemotherapy

2020 ◽  
Vol 13 (2) ◽  
pp. e232226
Author(s):  
Vivek Yadala ◽  
Hassaan Jafri ◽  
Mary T Legenza ◽  
Maria Tirona
Keyword(s):  
Breast Cancer ◽  
Neoadjuvant Chemotherapy ◽  
Germ Line ◽  
Skin Lesions ◽  
Punch Biopsy ◽  
Bilateral Mastectomy ◽  
Invasive Mammary Carcinoma ◽  
Grade 3 ◽  
Brca1 Brca2 ◽  
Response To Neoadjuvant Chemotherapy

This is a case of 49-year-old white woman who presented with a rapidly growing right sided breast mass. A subsequent punch biopsy confirmed grade 3 invasive mammary carcinoma of no special type which was negative for oestrogen receptor, progesterone receptor and Her-2 neu overexpression. She was a carrier of folliculin gene mutation that is characteristic of Birt-Hogg-Dubé syndrome (BHDS), a condition known to cause skin lesions, renal cancers and pneumothoraces. Family history revealed patient’s mother, grandmother and maternal aunt developed renal cell carcinomas during their lifetime and were positive for the same germ line mutation. Tumour tissue was positive for TP53 mutation and negative for BRCA1, BRCA2 and other genes commonly associated with breast cancer. We report a patient with BHDS presenting with breast cancer that showed dramatic response to neoadjuvant chemotherapy prior to bilateral mastectomy, local chest wall radiation and 6 months of adjuvant capecitabine.

scholarly journals Radiotherapy using IMRT boosts after hyperbaric oxygen therapy with chemotherapy for glioblastoma

2016 ◽  
Vol 58 (3) ◽  
pp. 351-356 ◽  
Author(s):  
Katsuya Yahara ◽  
Takayuki Ohguri ◽  
Hiroki Udono ◽  
Junkoh Yamamoto ◽  
Kyosuke Tomura ◽  
...  
Keyword(s):  
Hyperbaric Oxygen ◽  
Tumor Volume ◽  
Combined Therapy ◽  
Survival Rates ◽  
Intensity Modulated Radiotherapy ◽  
Progression Free Survival ◽  
Hematological Toxicity ◽  
Free Survival ◽  
Promising Treatment ◽  
Grade 3

Abstract The purpose of this study was to evaluate the feasibility and efficacy of radiotherapy (RT) using intensity-modulated radiotherapy (IMRT) boosts after hyperbaric oxygen (HBO) therapy with chemotherapy in patients with glioblastoma. Twenty-four patients with glioblastoma were treated with the combined therapy, which was RT using IMRT boosts after HBO with chemotherapy, and were retrospectively analyzed. The RT protocol was as follows: first, 3D conformal RT [40 Gy/20 fractions (fr)] was delivered to the gross tumor volume (GTV) and the surrounding edema, including an additional 1.5–2.0 cm. The IMRT boost doses were then continuously delivered to the GTV plus 5 mm (28 Gy/8 fr) and the surrounding edema (16 Gy/8 fr). Each IMRT boost session was performed immediately after HBO to achieve radiosensitization. The planned RT dose was completed in all patients, while HBO therapy was terminated in one patient (4%) due to Grade 2 aural pain. The toxicities were mild, no non-hematological toxicity of Grade 3–5 was observed. The 2-year overall survival (OS) and progression-free survival rates in all patients were 46.5% and 35.4%, respectively. The median OS time was 22.1 months. In conclusion, the combined therapy of RT using IMRT boosts after HBO with chemotherapy was a feasible and promising treatment modality for patients with glioblastoma. The results justify further evaluation to clarify the benefits of this therapy.

Dose Adjusted EPOCH Chemotherapy Plus Rituximab Combination (DA-R-EPOCH), an Effective Upfront Therapy for Patients with Poor-Risk Aggressive B-Cell Lymphomas. Results of a Pilot Study in a Single Center.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 4716-4716
Author(s):  
Andrés López ◽  
Laura Gallur ◽  
Andrés Palacios ◽  
Mayda Navarrete ◽  
Carmen Ruiz-Marcellán ◽  
...  
Keyword(s):  
Pilot Study ◽  
B Cell ◽  
Bone Marrow Involvement ◽  
High Dose ◽  
B Cell Lymphomas ◽  
Poor Risk ◽  
Upfront Therapy ◽  
Grade 3 ◽  
Hodgkin's Lymphomas ◽  
Large B Cell

Abstract Poor risk aggressive non-Hodgkin’s lymphomas have a short EFS and OS when treated with conventional chemotherapy schedules. High dose therapy followed by stem cell rescue has been attempted with disparate results. Based on Wilson WH et al. schedule (Wilson WH, Grossbard ML, Pitaluga S et al. Blood2002; 99: 2685–93), a pilot study has been conducted in order to assess the efficacy and toxicity of DA-R-EPOCH in patients with Intermediate-High/High (IH/H) IPI score diffuse large B-cell (DLBCL) and follicular large (grade 3b) B-cell (G3bFL) lymphomas. No restrictions were done regarding the performance status. Methods. From August 2002 to May 2005, 28 untreated patients (pts) were enrolled in the study. Basically the regimen consisted on 6 cycles every 21 days of Rituximab (day 1) followed by a 96 hours infusion of etoposide, vincristine and doxorubicine and bolus cyclophosphamide on day 5 plus prednisone for 5 days. The doxorubicine, etoposide and cyclophosphamide doses were adjusted according to the hematological toxicity as reported by Wilson WH et al (Wilson WH, Gutierrez M, O’Connor P et al. 2002; 29 (Suppl. 2):41–7). Response rate and survivals were calculated in intention to treat. Pts not reaching a PR ≥ 70% after 3 cycles or a CR/CRu after completion of therapy were assigned as failure in the time to treatment failure (TTF) calculation. Results. Patients characteristics: median age 62,5 years (range:26–72); male/female: 11/17; DLBCL 21 (75%) and G3bFL 7 (25%); 19 (68%) had IV clinical stage; 13 (46%) B symptoms; PS (ECOG) > 2 in 12 pts (42%); 21 pts (75%) had extranodal and 10 (36%) bone marrow involvement; 32% had serum albumin < 3 g/dL; Hb < 100 g/L in 13 (46%); 46% had high b2microglobulin levels, and 100% elevated LDH. High age-adjusted IPI score in 15 pts (54%). Dose adjustment: Dose escalation could be done in most patients (18 out of 21 receiving all 6 cycles). There were an inverse correlation between the mean dose of doxurubicin given and age (r=−0.555; P2=0.009) and IPI (r=−0.507; P2=0.019). Response and survival: 17 out of 23 pts evaluated for response (74%) achieved a CR/CRu. There were 2 early deaths. At a median follow up of 14 months (range: 2–35) the estimated 2-year TTF and OS were 58% and 73% respectively. Toxicity: After 143 cycles administered grade 3–4 mucositis was observed in 9 courses (6%), grade 3–4 nueropathy in 1 (<1%) and neutropenic fever in 20 (14%). Conclusion. DA-R-EPOCH is a feasible approach and as effective as other more intensive chemotherapy schedules as upfront therapy in patients with intermediate-high or high risk IPI score aggressive large B-cell lymphomas (DLBCL and G3bFL) with acceptable toxicity. Updated data will be presented at the meeting.

Randomized Study of Decitabine Versus Observation or Continued Cytotoxic Chemotherapy in Patients with Intermediate and Poor Risk Acute Myeloid Leukemia in First or Subsequent Complete Remission.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 2859-2859 ◽  
Author(s):  
Farhad Ravandi ◽  
Jean-Pierre Issa ◽  
Stefan Faderl ◽  
Guillermo Garcia-Manero ◽  
Mary Hood ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Complete Remission ◽  
Clin Oncol ◽  
Myeloid Leukemia ◽  
Cytotoxic Chemotherapy ◽  
Cytotoxic Agents ◽  
High Dose ◽  
Poor Risk ◽  
Grade 3 ◽  
Acute Myeloid

Abstract The role of maintenance therapy in acute myeloid leukemia (AML) remains unclear. Continued therapy with cytotoxic agents similar to those used for induction and consolidation is associated with toxicity but can improve disease free survival (DFS). (Buchner T, J Clin Oncol. 2006;24:2480 and Lowenberg B, J Clin Oncol. 1998;16:872) Immune modulation in this setting may also be effective in prolonging DFS.(Brune M, Blood2006;108:88). Methylation status of tumor suppressor genes in clinical remission predicts the relapse risk in AML with earlier relapse in patients with increased DNA promotor methylation.(Agrawal S, Cancer Res. 2007;67:1370) Therefore, hypomethylating therapy may be effective in maintaining remission and prolonging survival in these patients. We are conducting a clinical trial comparing decitabine to cytotoxic chemotherapy or observation in patients with AML in their first or subsequent complete remission (CR). Patients with non-favorable risk AML (including intermediate and poor risk) receive induction therapy with idarubicin and high dose cytarabine followed by at least 2 cycles of cytarabine based consolidation. They are then stratified by age (≤ 60 vs. > 60) and cytogenetics (intermediate vs. poor risk) and randomized to receive decitabine 20 mg/m2 IV daily × 5 every 4 to 8 weeks for 12 cycles, or to continue chemotherapy/observation. Patients in > first CR are randomized after completion of salvage therapy. Serial samples for methylation studies and determination of minimal residual disease by flow cytometry are collected. To date, 19 (8 M, 11 F) patients with AML (including 14 in first CR and 5 in subsequent CR) have been enrolled onto the study. Median age of the patients is 56 years (range 31 – 74). Fourteen patients are ≤ 60 years. Cytogenetics at diagnosis was intermediate in 10 patients, poor-risk in 8 patients, and favorable [inv(16)] in one relapsed patient. Eight patients were randomized to decitabine and have received a median of 3 cycles (range 1 – 6). Eleven patients were randomized to observation/continued therapy and all, except 2 patients, have received further cytarabine based therapy after consolidation. With a median duration of follow up for the entire group of 5 months (range 1 – 9), 7/8 patients on the decitabine arm and 9/11 patients on the other arm have remained in remission. Toxicity in the decitabine treated patients was limited to 4 episodes of grade 3 neutropenia, 2 episode of grade 3 thrombocytopenia, and 1 episodes of grade 3 anemia. All of these cytopenias were short in duration and reversed without any associated adverse events. We conclude that administration of decitabine in CR at the above schedule/dose is safe and well tolerated.

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

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 208-208 ◽  
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.

Extracorporeal Photopheresis (ECP): Effective Therapy for Steroid Dependent and Refractory Acute Graft-Versus-Host Disease (GVHD)

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 1973-1973
Author(s):  
Ryan W Jacobs ◽  
Madan H. Jagasia ◽  
Bipin N. Savani ◽  
Anne T. Neff ◽  
Adetola A. Kassim ◽  
...  
Keyword(s):  
Median Survival ◽  
Salvage Therapy ◽  
Conflicts Of Interest ◽  
Chronic Gvhd ◽  
Randomized Study ◽  
Median Number ◽  
Systemic Steroids ◽  
Steroid Dependent ◽  
Grade 3 ◽  
Steroid Refractory

Abstract Abstract 1973 Introduction: Outcome of patients with steroid refractory acute GVHD (aGVHD) remains poor and the optimal therapy remains ill-defined. ECP has been successfully used for treating steroid-resistant chronic GVHD. We studied the efficacy and outcome of ECP used as salvage therapy in patients with steroid refractory/dependent aGVHD at 2 centers: Vanderbilt University, USA and Nottingham, UK. Methods: Transplant and aGVHD characteristics of patients treated with ECP from 1/2006 to 8/2010 were reviewed. Steroid doses at onset and completion of ECP were available. Steroid refractory aGVHD was defined as progression after 3 days or no response after 7 days of systemic steroids. Steroid dependent aGVHD was defined as recurrence of aGVHD during steroid taper. Responses to ECP were abstracted from medical records and were determined at completion of ECP. Patients were transplanted for hematological malignancies on standard of care or IRB approved protocols. Results: Fifty two patients (Vanderbilt-29; Nottingham-23) were treated with ECP for steroid dependent (15, 29%) or steroid refractory (32, 63%) aGVHD at a median of 59 days (range, 12–99) after transplant. Indication for ECP was missing for 5 patients. aGVHD was seen after first transplant (44, 85%), second transplant (1, 2%) or after donor lymphocyte infusion (7, 13%), respectively. Grade 3–4 aGVHD was present at onset in 29 (57%) patients. Stage 3–4 skin, GI, and liver involvement occurred in 28 (37%), 15 (29%) and 9 (18%) patients, with three organ involvement at onset in 9 (17%) patients. All patients received systemic steroids prior to ECP for a median of 18 days (range, 10–91). Initial therapy consisted of 1 mg/kg or 2 mg/kg prednisone equivalent in 24 (46%) and 26 (50%) patients, respectively. Forty-one patients (79%) had either no or partial response after 7 days of steroid. ECP was administered as 2 treatments per week on a weekly to bi-weekly frequency and then stopped or tapered depending on response. Steroids were tapered at the discretion of the treating physician. Median number of ECP treatments was 12 (range, 2–45) given over a median duration of 55 days. Thirty-two (63%) patients responded to ECP (CR-26, 50%; PR-6, 12%). At the end of ECP treatment, grade 3–4 aGVHD was present in 17 patients (33%) with stage 3–4 involvement in skin (4, 8%), GI (10, 20%) and liver (10, 20%), respectively. The median steroid dose at termination of ECP in ECP-responders and non-responders was 0.15 mg/kg (range, 0–0.75) and 2 mg/kg (range, 0.15–2.3), respectively (P<0.001). ECP response: Donor type, stem cell source, aGVHD grade at onset, and organ –specific stage did not impact response. ECP response was superior for aGVHD developing after ablative regimen compared with reduced intensity/non-ablative regimens (76% vs. 48%, P=0.05). Patients with response at day 7 after initial steroid and subsequent steroid dependent aGVHD had a better response with ECP (80% vs. 50%, P=0.042). In logistic regression analyses, adjusted for regimen intensity, response at day 7 of initial steroid showed a trend for predicting ECP response (OR=4.22, 95% CI 0.95–18.7, P=0.058). Survival: Of the 52 patients, 28 (54%) are deceased (GVHD-19, relapse/progression-5, infections-4). The median follow up of the cohort after onset of ECP is 309 days (range, 12–1657). Median and 2-yr overall survival (measured from onset of ECP) is 442 days (95% CI, 0–993) and 42%. In univariate analyses, median survival after ECP onset was superior for patients who had an ablative transplant (not reached vs. 44 days, P=0.05), and had grade 2 or less aGVHD at onset (not reached vs. 79 days, P=0.028) (Fig. 1A). Indication of ECP (steroid dependent or refractory) did not impact survival. Patients with ECP response had a superior survival (measured from end of ECP) compared to non-responders (median survival, not reached vs. 14 days, P<0.001) (Fig. 1B) with a 65% 2-yr survival in ECP responders. In Cox proportional analyses, response to ECP was an independent predictor of survival (HR 0.091, 95% CI 0.034–0.263, P<0.001), after adjusting for regimen intensity and grade of aGVHD at onset. Conclusion: ECP is an effective steroid-sparing salvage therapy for patients with steroid dependent or refractory aGVHD with a response rate of 63% and 2-yr survival of 65% in responders. Based on this data, it is reasonable to undertake a prospective randomized study of ECP versus other agents, in patients with steroid dependent or refractory aGVHD. Disclosures: No relevant conflicts of interest to declare.

Mutational Analysis of Therapy-Related MDS/AML

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 2802-2802
Author(s):  
Alan H. Shih ◽  
Stephen S. Chung ◽  
Emily K. Dolezal ◽  
Su-Jiang Zhang ◽  
Omar Abdel-Wahab ◽  
...  
Keyword(s):  
Clinical Outcomes ◽  
Median Survival ◽  
Somatic Mutations ◽  
Radioactive Iodine ◽  
De Novo ◽  
Point Mutations ◽  
Chromosome 17 ◽  
Chromosome 5 ◽  
Primary Malignancy ◽  
Poor Risk

Abstract Abstract 2802 Background: Therapy-related myelodysplastic syndromes and acute myelogenous leukemia (tMDS/AML) comprise a poor-risk subset of MDS/AML and are associated with a higher rate of cytogenetic abnormalities and complex karyotypes. Large scale mutation profiling efforts in de novo MDS have identified mutations that correlate with clinical features but such mutations have not been investigated in tMDS/AML. Methods: Cryopreserved (mononuclear cell fractions) bone marrow and peripheral blood samples from tMDS/AML patients were analyzed. Lymphocytes were depleted from these fractions by either fluorescence-activated cell sorting or affinity column selection. Genomic DNA was subjected to high throughput PCR and sequenced for TP53, TET2, DNMT3a, ASXL1, IDH1, IDH2, SF3B1, EZH2, EED, SUZ12, and RBBP4. Somatic mutations were validated by comparison to lymphocyte DNA controls. Patient selection was based on sample availability for tMDS/AML patients with untreated or active, previously treated disease. Results were correlated with clinical outcomes, cytogenetic profiles, and response to therapy. Results: Samples from 38 patients (20 males, 18 females) with tMDS/AML were analyzed. For their primary malignancy (≥ 2 malignancies, n=3; AML, n=1; breast, n=4; colorectal, n=3; Hodgkins or composite lymphoma, n=3; gastric, n=1; melanoma, n=2; NHL, n=12; ovarian, n=1; prostate, n=3; sarcoma, n=2; thyroid, n=3), patients received chemotherapy alone (n=17), radiation alone (n=4), radioactive iodine alone (n=1), chemotherapy plus radiotherapy (n=13), radiotherapy plus radioactive iodine (n=1), chemotherapy plus radiotherapy plus radioactive iodine (n=2). Median latency time between primary malignancy treatment and MDS diagnosis date was 5.68yrs (range, 0.71–30.88). Median age at MDS diagnosis was 65yrs (range, 34–83). Not surprising was the finding that of the 35 MDS patients with complete IPSS parameter data most were IPSS Int-2 (45%) or High Risk (13%) compared to Low (11%) or Int-1 Risk (24%) disease, and in contrast to expected proportions at diagnosis for de novo MDS. WHO Classifications were: RA, n=3; RCMD, n=11; RAEB-1, n=7; RAEB-2, n=7; AML, n=3; CMML-1, n=1; MDS-U, n=3; Unknown, n=3. The median survival was 16.8mo. Median time between MDS diagnosis and sample procurement was 3.0mo (range, 0–57.2) during which 2 patients progressed to AML, 11 received a DNA methyltransferase inhibitor (DNMTI), 1 induction chemotherapy, and 2 DNMTI plus induction. We identified somatic mutations in 15/38 (39.5%) patients. Including cytogenetic abnormalities, we identified somatic alterations in 34/38 (88%) of the patients in this cohort. TP53 mutations were most common, detected in 8/38 (21%) patients, followed by TET2 in 4/38 (10.5%), DNMT3a in 3/38 (7.9%), ASXL1 in 1/38 (2.6%), IDH1 in 1/38 (2.6%), and EZH2 in 1/38 (2.6%). No IDH2, SF3B1, EED, SUZ12, or RBBP4 mutations were detected. Only 2 patients had concurrent point mutations (one patient with TP53/TET2/DNMT3 mutations and one patient with TET2/EZH2 mutations). 7/38 (18.4%) patients had TP53 loss by FISH analysis or exhibited loss of chromosome 17/17p; 2 of these patients showed concurrent TP53 point mutations consistent with biallelic TP53 loss. 12/13 patients with TP53 abnormalities (point mutations, loss of TP53 by FISH, or loss of chromosome 17) had IPSS Poor Risk cytogenetics and 11/13 patients had abnormalities in chromosome 5 (del 5q or monosomy 5). In patients without TP53 abnormalities, 9/25 had Poor Risk cytogenetics and 5/25 had abnormalities in chromosome 5. The median survival for patients with TP53 abnormalities was 9.7mo compared to 64.4mo for patients with no TP53 abnormalities (p=0.0043). Of the 13 patients with TP53 abnormalities, 12 received treatment for tMDS/AML. 3/12 were refractory to the first line of therapy, and 7 were unable to receive an adequate course of therapy with hypomethylating agents due to toxicity or progressive disease. Conclusions: TP53 point mutations are more common in tMDS/AML than in de novo MDS (7.5%, Bejar et al) while incidence of TET2 and ASXL1 mutations were lower in tMDS/AML compared to de novo MDS (20.5% and 14.4%, respectively). TP53 and TET2 point mutations were more strongly associated with exposure to prior chemotherapy, but not with exposure to radiation therapy. Taken together, these data demonstrate that TP53 mutations are common in tMDS/AML and are correlated with adverse clinical outcomes. Disclosures: No relevant conflicts of interest to declare.

Final Report of a Phase I/II Study of Hyper-CVAD Plus RAD001 (Everolimus) in Patients with Relapsed/Refractory Acute Lymphoblastic Leukemia

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 3567-3567
Author(s):  
Yanis Boumber ◽  
Deborah A. Thomas ◽  
Farhad Ravandi ◽  
Michael E. Rytting ◽  
Marian R Love ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Phase I ◽  
Lymphoblastic Leukemia ◽  
Single Agent ◽  
Philadelphia Chromosome ◽  
Mtor Inhibitors ◽  
Median Number ◽  
Mtor Signaling ◽  
Final Report ◽  
Grade 3

Abstract Abstract 3567 Background: Acute lymphoblastic leukemia (ALL) is an aggressive lymphoproliferative disorder, responsive to frontline standard induction and consolidation chemotherapy. However, the prognosis of patients (pts) with relapsed/refractory ALL is extremely poor. Deregulation of the PI3K/Akt/mTOR signal transduction pathway is central to leukemic cell growth, proliferation and survival, and has been implicated in ALL pathogenesis. In a recent phase II study of pts with relapsed/refractory non-Hodgkin lymphoma, single agent mTOR inhibitor everolimus showed ORR 30% and acceptable toxicity in 77 heavily pretreated pts (Witzig TE et al, Leukemia 2011; 25,341–7). The purpose of this study was to establish the safety and efficacy of everolimus in combination with hyper-CVAD in pts with relapsed/refractory ALL, and to study effects of everolimus on AKT/mTOR signaling in ALL blasts. Methods: In this single center phase I/II study, pts aged 10 years or older with relapsed/refractory ALL or lymphoblastic lymphoma were treated with oral everolimus at a daily dose of 5 mg or 10 mg in combination with the standard hyper-CVAD regimen (Kantarjian HM et al, J Clin Oncol. 2000 Feb;18(3):547–61) until disease progression or unacceptable toxicity. Primary endpoints were to establish safety (after 2 cycles) and efficacy. Secondary endpoints included assessments of pharmacodynamics and pharmacokinetics. Results: Twelve pts have been enrolled and are evaluable for response. Median was age 24 years (range, 11–59). Five pts had T-ALL and 7 had Philadelphia chromosome negative precursor-B-ALL. Median number of prior treatments was 2 (range, 1–4); 5 pts were 1st salvage attempts. Three pts received everolimus 5 mg/day and 9 were treated with 10 mg/day continuously in combination with hyper-CVAD. Median number of cycles given was 2 (range, 1–4). Median follow-up was 12 months (range, 7–23). Three pts achieved CR (all were 1st salvage attempts) and 1 patient had CRi (second salvage); 2 pts achieved PR. No responses were seen beyond second salvage. Of the 9 pts completing 2 cycles, both EFS and OS were not reached for 3 pts in the 1st salvage, and were 8.5 weeks and 18.5 weeks respectively for pts in second salvage and beyond (P=.01 and P=0.04). Of the 12 pts (including 3 only treated with one cycle), both EFS and OS were not reached for 3 pts in the 1st salvage, and were 10 weeks and 18 weeks respectively for pts in second salvage and beyond (P=0.17 and P=0.05). Treatment-related toxicities in the 9 pts evaluable for MTD (completed 2 cycles) included 3 episodes of grade 3 mucositis, which was a dose-limiting toxicity, 3 episodes of grade 4 infections (sepsis) and 9 episodes of grade 3 infections (neutropenic fever, pneumonia, bacteremia). There was no deaths on-study. Inhibition of mTOR signaling (p-pS6K) was observed in 5 of 8 (62%) patient samples tested, at both the 5 and 10 mg dose levels, suggesting that 5 mg is sufficient to block the pathway. Lack of inhibition of p-pEBP1 and pAKT argues for potential benefit of second generation mTOR inhibitors or dual PI3K/mTOR inhibitors. Conclusions: We conclude that administration of hyper-CVAD plus everolimus is well-tolerated. The study warrants further investigation of next generation mTOR inhibitors in combination with hyper-CVAD for ALL in relapsed and frontline settings. Disclosures: Cortes: Novartis: Consultancy, Research Funding.

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