A Phase II Study of Decitabine In Advanced Chronic Myelomonocytic Leukemia (CMML)

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 1873-1873
Author(s):  
Thorsten Braun ◽  
Nathalie Droin ◽  
Benoit de Renzis ◽  
Francois Dreyfus ◽  
Kamel Laribi ◽  
...  
Keyword(s):  
Phase Ii ◽  
Conflicts Of Interest ◽  
Cytogenetic Response ◽  
Median Number ◽  
Costal Margin ◽  
Monocyte Count ◽  
Blood Monocytes ◽  
Grade 3 ◽  
Wbc Count

Abstract Abstract 1873 Background: CMML, now classified among MDS/MPN, is prognostically heterogeneous. We (JCO 1988 6:1417, Blood 1996 88:2480) and others found prognosis in CMML to depend on both “MDS factors” (% marrow blasts, cytopenias, karyotype) and “MPN” factors, ie splenomegaly (SMG), WBC count, extramedullary disease (EMD). Treatment of advanced CMML is difficult. The hypomethylating agents Azacitidine and Decitabine (DAC) have shown efficacy in CMML, but in prognostically heterogeneous cohorts. We conducted a phase II trial of DAC in a well defined cohort of advanced CMML. Methods: To be included, CMML (according to WHO) should have: if WBC<13G/l an IPSS≥1.5; if WBC≥13G/l, two of the following criteria: marrow blasts≥5%, Hb<10g/dl, plts<100G/l, abnormal cytogenetics, SMG >5cm below costal margin, (SMG>5cm), EMD, based on our previous prognostic factors. Pts received DAC 20mg/m2/d IV for 5 days every 28 days for at least 3 cycles. Response criteria were based on IWG 2006 for pts with WBC <13G/L and for pts with WBC > 13 G/L also included evolution of WBC, SMG and EMD (Blood 1996 88:2480). Results: Between Nov 2008 and June 2009, 41 pts were included in 16 centers, of whom 39 completed at least one cycle and were considered evaluable for response (the 2 other pts died from septic shock before and during the first cycle respectively). Median number of cycles was 9 (range 1–17). Median age was 71 years (range 54–88), M/F:30/9. Seventeen pts had CMML 1 and 22 had CMML 2 (including pts with up to 29% marrow blasts). Median WBC count was 29.5G/l (range 4.1–147.3), median blood monocytes 3G/l (range 1.05–95.7), and median BM blasts 10% (1-29). Nine pts had WBC<13G/l and 30 WBC≥13G/l. Abnormal karyotype was found in 18 (46.2%) pts, including +8 and -7 in 7 and 1 case, respectively. 15 pts (38.6%) had SMG>5cm and 8 (20.5%) EMD involving skin (n=5) and lymph nodes (n=3). Overall Response Rate (ORR,) was 38.6% with 4 (10.3%) CR, 8 (20.5%) marrow CR and 3 (7.7%) Stable Disease (SD) with HI. 1 CR pt received allo SCT. 18 (46%) pts had SD without HI and 6 (15.4%) pts progressed to AML. 8 (36.4%) of the 22 RBC transfused pts became RBC transfusion independent. 3/10 (30%) pts with plt<50G/l reached plt>100G/l. Four pts had cytogenetic response (3 CR and 1 PR) exclusively among pts with +8. Median peripheral monocyte count decreased from 4.8G/l to 0.3G/l after 3 cycles of DAC among responders. SMG disappeared in 6/15 (40%) pts and EMD in 6/8 (75%) pts. 16 pts were receiving Hydroxyurea (HY) at inclusion which could be stopped in 12 of them. With a median follow up of 10 months (1-18), 7 pts had died from progression (n=3), sepsis (n=3) and unrelated cause (n=1). Overall Survival (OS) estimate was 60% at 2 years (median not reached). By comparison, in our previous trial of HY in CMML where inclusion criteria were the same, 2 year survival was 43% (median OS 20 months; Blood 1996 88:2480), for a median follow up of 11 months (range1-43). The only factor associated with response to DAC was WHO subtype, CMML 2 pts showing significantly better ORR (30.8% vs 7.7% in CMML 1; p=0.041).There was no difference in survival between CMML 1 and 2 pts. Treatment with DAC was generally well tolerated with, except for usual grade 3/4 cytopenias, and grade 3 fatigue (n=1). Conclusion: DAC is active in advanced CMML and safe in these elderly pts. A possibly better survival than with HY will have to be confirmed in randomized trials. Correlative genetic studies identifying markers potentially predicting response and survival for DAC are currently underway in our lab. Disclosures: No relevant conflicts of interest to declare.

Erlotinib Is Not Effective In Patients (Pts) With JAK-2 V617F Positive Polycythemia Vera

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 1597-1597
Author(s):  
Mohamad Cherry ◽  
Mohamad Khawandanah ◽  
Zhizhuang Joe Zhao ◽  
Samer A Srour ◽  
Howard Ozer ◽  
...  
Keyword(s):  
Polycythemia Vera ◽  
Conflicts Of Interest ◽  
Growth Factor Receptor ◽  
Median Number ◽  
Preclinical Study ◽  
Spleen Size ◽  
University Of Oklahoma ◽  
Grade 3

Abstract Introduction Erlotinib is an epidermal growth factor receptor small-molecule inhibitor and is FDA approved for the treatment of lung and pancreatic cancers. In preclinical study, in vitro colony culture assays revealed that erlotinib at micro-molar concentrations effectively suppressed the growth and expansion of Polycythemia Vera (PV) hematopoietic progenitor cells while having little effect on normal cells. Several JAK inhibitors are being studied for the management of PV, one of which has been approved for the treatment of myelofibrosis (ruxolitinib). Aim To study the clinical effect of erlotinib in pts diagnosed with JAK2V617F + PV. Methods We conducted a single arm, prospective phase II study at the University of Oklahoma and the Oklahoma City VA hospitals in pts with WHO defined JAK-2 V617F positive PV from June 2010 to August 2012. Appropriate IRB approval was obtained in accordance with Hilsinki declaration. Pts had to be requiring phlebotomy. Toxicity was assessed by treating physicians using NCI version 4. Dose modification for erlotinib was done using label recommendations. Results Five Caucasian pts were enrolled (3 (60%) males, with median age at enrollment of 63 years, range 26-79). Pts had pretreatment median hemoglobin14.4 g/dL (10.4 -19.2 g/dL), median platelet count 511 x109 (424-681 x109), median white blood cell (WBC) 14.4 x109(7.8- 18.3 x109). Three pts had splenomegaly prior to treatment. Median number of prior pharmacologic treatments (hydroxyurea, anagralide or interferon) was 1, range 0-2. Pts were given erlotinib 150 mg orally daily for 16 weeks: responders (phlebotomy free or decrease in spleen size) were allowed to continue a total of 1 year of treatment, while non-responders were taken off the study. Three (60%) patients received therapy for 16 weeks and did not achieve hematological response or improvement in spleen size. Two (40%) pts were taken off the study after 2 doses secondary to severe toxicities (grade 3 colitis in 1 case, and grade 3 facial rash in 1case). No therapy continued beyond 16 weeks (due to toxicity or lack of response). All pts in the study developed rash (grade 1 – 3) and diarrhea (grade 1 – 2). Three pts developed mucositis (see Table 1). No death was observed during the study and follow up period (median follow up was 23 months, range 12-37 months). Study was closed due to lack of efficacy. Conclusions Despite in vitro efficacy of erlotinib as potent inhibitor of JAK-2 activity, erlotinib is not effective in pts with JAK-2 V617F positive PV with poor toxicity profile. Poor accrual was related to potential toxicity of erlotinib compared to alternative treatments in view of lack of clinical efficacy. Disclosures: No relevant conflicts of interest to declare.

Biweekly cetuximab and irinotecan as second-line therapy to patients with platinium-resistant gastroesophageal cancer

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. e15624-e15624 ◽  
Author(s):  
J. K. Bjerregaard ◽  
K. R. Schønnemann ◽  
H. A. Jensen ◽  
L. W. Vestermark ◽  
T. P. Hansen ◽  
...  
Keyword(s):  
Phase Ii ◽  
Performance Status ◽  
Haematological Toxicity ◽  
Median Number ◽  
National Board ◽  
Line Therapy ◽  
Grade 3 ◽  
Number Of Cycles ◽  
The Cost

e15624 Background: There is no established 2nd line therapy for patients (pts) with advanced gastroesophageal (GE) cancer. In 2004, the Danish government initiated a national health programme for pts with advanced cancer. Non- proven therapy may be offered after approval by an expert panel appointed by the National Board of Health that subsequently finances the cost of treatment. This programme has had a major impact on the management of cancer pts in Denmark and has accelerated the introduction and implementation of new therapies. Inspired by the excellent results in colorectal cancer a combination of cetuximab and irinotecan (CetIri) was chosen for platinum-resistant GE cancer. While awaiting approval of a phase II protocol CetIri was offered at a single institution. We report our preliminary experience with biweekly CetIri as 2nd line therapy in pts with GE cancer. Methods: All pts had histologically confirmed GE cancer (adeno- or squamous cell carcinoma) and all pts had previously received first line platinum based therapy. Pts received CetIri (cetuximab 500 mg/m2and irinotecan 180 mg/m2day 1) every 2nd week until progression or unacceptable toxicity. Response rate was evaluated by the investigator according to RECIST every 8th week. Toxicity was prospectively evaluated according to NCIC-CTC 3.0. Results: From December 2007 to August 2008, 31 consecutive pts was treated with CetIri. Median age was 62 years (33–76). Median performance status was 1 (0–2). Localisation of primary was: Esophagus 10%, GE junction 64%, gastric 26%. Twenty-seven pts (87%) had adenocarcimona. Median number of cycles were 6 (1–21). Most important grade 2–4 toxicities were non-haematological toxicity as diarrhea (25%), nausea (21%) and vomiting (11%). Three pts (11%) had grade 3 leukopenia, 1 had febrile neutropenia. Two pts had PR. Median PFS was 3.2 months. Fourteen pts (45%) received at least 6 courses (3 month of therapy). After a median follow-up of 6 month 5 pts continue CetIri without sign of PD. Conclusions: Biweekly CetIri is a convenient and well-tolerated 2nd line regimen in pts with GE cancer. Predictive factors are needed to select which pts will benefit from therapy. A confirmatory phase II study is ongoing. [Table: see text]

Phase II trial of sequential temozolomide (TMZ) and high-dose bolus (HDB) IL-2 in patients with metastatic melanoma

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 8037-8037
Author(s):  
S. S. Agarwala ◽  
A. A. Tarhini ◽  
J. M. Kirkwood ◽  
C. Cai ◽  
L. Stover ◽  
...  
Keyword(s):  
Metastatic Melanoma ◽  
Phase Ii ◽  
Single Agent ◽  
Stage Iv ◽  
Median Number ◽  
Chemotherapeutic Agents ◽  
High Dose ◽  
Female Age ◽  
Grade 3

8037 Background: Previous biochemotherapy (BCT) regimens for metastatic melanoma have utilized lower doses of IL-2 and multiple chemotherapeutic agents, adding to toxicity, but not to efficacy. Methods: We designed a 2-stage Simon phase II study testing a unique BCT approach of single agent chemotherapy with TMZ given in an extended schedule (75 mg/m² per day for 3 weeks PO) followed by HDB IL-2 (600,000 U/Kg/dose, maximum 14 doses administered over 5 days). Cycles were repeated every 28 days with a two-week interval between alternate cycles. The first stage accrued 20 patients with promising activity and safety permitting enrollment of additional patients. Results: Thirty-one patients (20 male, 11 female), age 27–74 (median 47) have been enrolled to date. All had AJCC stage IV melanoma (7 M1a, 5 M1b, 19 M1c) and had not previously received therapy for metastatic disease. Twelve had received prior adjuvant interferon. A total of 88 cycles of therapy have been administered (median of 2 cycles per patient; 5 patients continue on therapy). The median number of doses was 9 (range 7–12) during cycle 1, and 6 (range 4–11) during cycle 2. Three patients did not receive any IL-2 due to disease progression, and 6 patients received only one cycle of IL-2. Twenty two patients who received at least 2 cycles are evaluable for response. All 31 patients are evaluable for toxicity. Grade 3 toxicities included hepatic (8), hematologic (4 leukopenia, 2 thrombocytopenia), diarrhea (1). No grade 3–4 cardiovascular or renal toxicities were noted. Overall response rate is 22.7% (2 complete lasting 10.8 and 17+ months, 3 partial lasting 3.7 and 16+ months, 1+ month). Responses were seen in both M1a and M1c disease. Fourteen patients had stable disease after 2 cycles and 10 of these have progressed. As of 12/31/2005, the 4 month PFS rate is 74% [40%, 88%], median TTP is 24 weeks [11, 32] and median OS is 71 weeks (31.4, inf). Conclusions: HDB IL-2 can be safely administered in combination with single agent temozolomide in an extended schedule and appears to have promising efficacy and lower toxicity than previously used BCT regimens. Further follow-up will determine if durability of response exceeds that of single agent HDB IL-2. [Table: see text]

Results of a Phase II Trial of Dasatinib As Frontline Therapy for Chronic Myeloid Leukemia (CML) In Chronic Phase (CP)

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 1700-1700 ◽  
Author(s):  
Naveen Pemmaraju ◽  
Hagop M. Kantarjian ◽  
Rajyalakshmi Luthra ◽  
Susan O'Brien ◽  
Elias Jabbour ◽  
...  
Keyword(s):  
Pleural Effusion ◽  
Phase Ii ◽  
Research Funding ◽  
Phase Ii Trial ◽  
Cytogenetic Response ◽  
Hematologic Toxicity ◽  
Molecular Response ◽  
Significant Activity ◽  
Grade 3

Abstract Abstract 1700 Background: Dasatinib is approximately 300 times more potent than imatinib (IM) in vitro and has significant activity in patients (pts) with CML-CP resistant to or intolerant of IM. In 2005 we initiated a phase II trial to study the efficacy and safety of dasatinib in pts with previously untreated CML-CP. Objective: To determine the outcome of pts with CML-CP treated with front-line dasatinib. The primary endpoint was attainment of major molecular response (MMR) at 12 months (mos). Methods: Pts with previously untreated CML-CP within 6 mos from diagnosis were eligible and received dasatinib 100 mg/day, randomized to either 50 mg twice daily (BID) or 100 mg once daily (QD). After 66 pts were accrued, the BID arm was closed and all subsequent pts were treated with 100 mg QD. No prior therapy was allowed except for IM for no more than 1 month, or hydroxyurea. Results: From November 2005 to June 2011, 99 pts have been enrolled (66 on the QD schedule, 33 BID). For the purposes of this analysis, we considered all pts with clonal evolution at baseline (n=6) as accelerated phase and excluded them from the present analysis, therefore leaving 93 pts (62QD, 31 BID) for review. Median age was 48 years (yrs) (range 18–82); 56% were male. Median baseline counts: WBC 22.95 K/uL, PB blasts 0%, BM blasts 3%, BM basophils 2%, and platelets 315; 21 pts (23%) had brief prior exposure to IM. Sokal score by distribution: Low (81%), Intermediate (14%), High (5%). Median follow-up is 29 mos (3–67). Of the 80 evaluable pts who were not in CHR at the start of therapy, 79 (98%) achieved CHR. Of 87 evaluable pts (ie, followed for at least 3 mos), 83 (95%) achieved complete cytogenetic response (CCyR). MMR has been achieved in 75 pts (86%), including 54 pts (67%) with complete molecular response (CMR; ≤0.0032% IS). At 6 mos, 79 (94%) pts had achieved a CCyR and 56 (68%) an MMR; corresponding figures at 12 mos are 95% and 73%, respectively. Grade 3–4 non-hematologic toxicity included fatigue (9%), pain and dyspnea (6% each), memory impairment (5%), headache and sensory neuropathy (4% each), nausea, cardiac arrhythmia, and neurologic (3% each) and diarrhea, visual, and pleural effusion (2% each). Grade 3–4 hematologic toxicity (transient) included thrombocytopenia 13%, neutropenia 24%, and anemia 9%. Fifty-two (56%) of 93 pts required transient treatment interruptions and 36 (39%) have required dose reductions. The actual median daily dose for all pts was 100 mg (20–140). Thirteen pts lost CCyR: (including 3 because of non-compliance and 2 transient losses, regained spontaneously). The 24-mo probability of event-free survival (EFS) is 93%.There have been no transformations or deaths on study. Twelve (13%) pts have discontinued therapy: 3 pt's choice, 1 lost to follow up, 4 toxicity (2 pleural effusion, 1 congestive heart failure, 1 headaches), and 4 for loss of major cytogenetic response (MCyR). Three pts have had mutation assessment upon discontinuation and no mutations were identified. Conclusion: Rapid CCyR occurs in nearly all pts with previously untreated CML-CP treated with frontline dasatinib therapy with a favorable toxicity profile. None of the patients have transformed to AP/BP confirming the efficacy of dasatinib as initial therapy for CML-CP. Disclosures: Kantarjian: Novartis: Consultancy, Research Funding; BMS: Research Funding; Pfizer: Research Funding. Jabbour:Pfizer: Honoraria; BMS: Honoraria; Novartis: Honoraria. Ravandi:BMS: Honoraria, Research Funding. Cortes:Novartis: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding.

AR-67, a DNA Topo-Isomerase I Inhibitor, Demonstrates Acceptable Tolerability and Preliminary Activity in a Phase II Trial of Patients with Myelodysplastic Syndrome (MDS) and Chronic Myelomonocytic Leukemia (CMML),

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 3820-3820
Author(s):  
Naval Daver ◽  
Hagop M. Kantarjian ◽  
Guillermo Garcia-Manero ◽  
Gautam Borthakur ◽  
Farhad Ravandi ◽  
...  
Keyword(s):  
Phase Ii ◽  
Topoisomerase I ◽  
Conflicts Of Interest ◽  
Clinical Manifestations ◽  
Median Number ◽  
Dna Supercoiling ◽  
Clinical Activity ◽  
Hypomethylating Agent ◽  
Blast Count ◽  
Grade 3

Abstract Abstract 3820 Background: DNA topoisomerase I (TopoI) is an essential mammalian nuclear enzyme that relaxes DNA supercoiling generated by transcription, replication and chromatin remodeling. Topotecan and other Topo I inhibitors have shown clinical activity in MDS and CMML. AR-67 [(20S)-7-tert-butyldimethysilyl-10-hydroxycamptothecin] is a third generation camptothecin analog that effectively inhibits topoisomerase I enzyme. Aim: This phase II study was conducted to estimate the efficacy and toxicity of AR-67 in patients with MDS, CMML or MDS/MPD who have failed prior therapies. Method: Subjects with MDS (>5% blasts, or IPSS risk group intermediate-1, intermediate-2 or high risk), CMML or MDS/MPD who had failed or were unable to receive therapy with either a hypomethylating agent (alone or in combination) or patients with abnormalities in chromosome 5q who failed either a hypomethylating agent or lenalidomide were eligible. Patients with performance status 0–2 with adequate organ function and no active, uncontrolled intercurrent illness or infection, receive AR-67 IV at 7.5 mg/m2 for 5 consecutive days every 4 weeks. Results: 10 patients with MDS, CMML or MDS/ MPD were enrolled (6 MDS, 2 CMML and 2 MDS/MPD). The median age was 69 years (yrs) (range, 52–83 yrs). All patients had received prior therapy with hypomethylating agents. The most common prior therapies included: azacytidine (n=6), decitabine (n=5) and clofarabine (n=5); either alone or in combination. The median number of prior therapies was 2 (range 1 to 4). Of the 6 MDS patients; 4 were IPSS Int-2 and 2 were IPSS Int-1. Both CMML patients were CMML-2. Cytogenetics analysis showed diploid karyotype in 4, trisomy 21 in 2, chromosome 7 abnormalities in 1, and various other abnormalities in 3. Molecular analysis showed NRAS mutation in 3 and FLT-3 ITD mutation in 1 patient. No patients had mutations in c-Kit, JAK-2 or NPM1. 9 of 10 enrolled patients received at least 1 dose of the AR-67. One patient was enrolled but withdrew prior to initiation of therapy. Median number of cycles received was 2 (1–6). Of the 9 patients treated, 1 patient had hematological response per IWG criteria. The hemoglobin improved from 8.1 g/dl to 11.5 g/dl, platelet count improved from 47 K/μL to 81 K/μL, peripheral blast count decreased from 4% to 1% and bone marrow blast count decreased from 9% to 5%. The response lasted 170 days. This patient also had a significant improvement in clinical manifestations associated with CMML, including fatigue, and incapacitating arthralgias allowing him to return to work. Two other patients had stable disease over 3 months and 2 months; respectively. The most common drug related adverse events were thrombocytopenia (5 overall; 3 grade 1–2; 2 grade 3), neutropenia (5 all grade 1–2), and anemia (5 all grade 1–2). Other noted adverse effects were diarrhea (4 overall; 3 grade 1–2, 1 grade 4), nausea (2 overall; 1 grade 2, 1 grade 3), elevated uric acid (2 overall; 1 grade 2, 1 grade 3), possible typhlitis (1 grade 3), mucositis (1 grade 1) and fatigue (1 grade 3, 1 grade 1). Dose reduction from 7.5 mg/m2 to 6.3 mg/m2 was required in 2 patients due to grade 3 fatigue and grade 3 thrombocytopenia; respectively. Conclusion: AR-67 administered at 7.5 mg/m2 showed efficacy and was tolerable in subjects with previously treated MDS, CMML or MDS/MPD. Myelosuppression is the most common toxicity, but is usually manageable. Additional studies of AR-67 in these disease groups are warranted. Disclosures: No relevant conflicts of interest to declare.

A Phase II Study of Dasatinib in Patients with Chronic Myeloid Leukemia (CML) in Lymphoid Blast Crisis or Philadelphia-Chromosome Positive Acute Lymphoblastic Leukemia (Ph+ ALL) Who Are Resistant or Intolerant to Imatinib: The ‘START-L’ CA180015 Study.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 42-42 ◽  
Author(s):  
Oliver G. Ottmann ◽  
G. Martinelli ◽  
H. Dombret ◽  
H. Kantarjian ◽  
A. Hochhaus ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Dose Reduction ◽  
Phase Ii ◽  
Phase Ii Study ◽  
Blast Crisis ◽  
Cytogenetic Response ◽  
Molecular Response ◽  
Hematologic Response ◽  
Grade 3

Abstract Patients with CML in lymphoid blast crisis (LBC-CML) or advanced Ph+ ALL have an unsatisfactory and only brief response to imatinib mesylate (IM). Moreover, treatment options in pts who failed IM are extremely limited. Dasatinib (BMS-354825) is a novel, oral kinase inhibitor that targets BCR-ABL and SRC kinases, and has shown promising clinical activity in a Phase I dose escalating study in patients with BCR-ABL-positive leukemias. Between January 2005 and June 2005, 77 pts (42 CML-LBC and 35 Ph+ ALL) who had failed IM-based therapy were enrolled in this multinational Phase II study investigating the safety and efficacy of dasatinib. This preliminary analysis summarizes data on the first 28 pts accrued (13 CML-LBC and 15 Ph+ ALL) who were accrued prior to March 20, 2005. Dasatinib was administered orally at 70 mg twice daily (BID) on a continuous daily dosing schedule; dose escalation to 100 mg BID or dose reduction to 50 mg and 40 mg BID were allowed for poor initial response or persistent toxicity, respectively. Complete blood counts were performed weekly and bone marrow evaluation, including cytogenetic analysis, was scheduled every month. Mutation analyses were performed in all pts. 27 pts were IM resistant and 1 was IM intolerant; 17 (61%) pts had received prior IM doses &gt;600 mg/day, 13 (46%) pts received IM for &lt;1 year and 12 pts (43%) previously underwent stem cell transplantation. Response on prior IM regimen included complete hematologic response (CHR) in 19 (68%) pts and major cytogenetic response (MCyR) in 11 (39%) pts. Median time from leukemia diagnosis was 16.6 months (range 4.9–101.6). Median age was 44 years (range 20–84) and 61% of pts were male. At baseline, median platelet count was 37 x 103/mm3 (range 7–360) with median peripheral blood blasts of 35% (range 0–90) and median blasts in bone marrow of 81% (1–100). Dasatinib doses were escalated in 8 (29%) pts and 3 (11%) pts required dose reduction. 13 pts had a major hematologic response (7 CHR and 6 no evidence of leukemia, [CHR without complete recovery of PMN or platelets]) and 12 pts had a cytogenetic response within 1–3 months (11 complete and 1 minor). 9/13 pts (69% of responding pts) maintained their response after a median follow-up of 14+ weeks (range 10+ - 24+). Complete clearing of extramedullary sites was documented. Analysis of molecular response is ongoing. The majority of pts had grade 3 or 4 myelosuppression, which was pre-existing in most cases (63% with grade 3–4 neutropenia and 58% with grade 3–4 thrombocytopenia had the same grade at study entry); PMN &lt;500/mm3 in 64% of pts and platelets &lt;25 x 103/mm3 in 71% of pts. Non-hematologic toxicities included grade 1 and 2 peripheral edema (3 pts) and grade 1 facial edema (2 pts). GI intolerance was infrequent. In conclusion, dasatinib has significant and clinically meaningful efficacy in this heavily pretreated population of LBC-CML and Ph+ ALL pts with acquired resistance to imatinib. Updated data on all 77 patients with a minimum of 6 months’ follow-up will be presented.

A Phase II Trial of R-FM (Rituximab, Fludarabine and Mitoxantrone) Chemotherapy Followed by Yttrium 90 (90Y) Ibritumomab Tiuxetan (90Y-IT) for Untreated Follicular Lymphoma (FL) Patients.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 3743-3743 ◽  
Author(s):  
Pier Luigi Zinzani ◽  
Monica Tani ◽  
Alessandro Broccoli ◽  
Enrico Derenzini ◽  
Alessandro Pulsoni ◽  
...  
Keyword(s):  
Treatment Regimen ◽  
Phase Ii ◽  
Phase Ii Trial ◽  
Conflicts Of Interest ◽  
Stage Ii ◽  
Bulky Disease ◽  
Randomized Phase Ii ◽  
Grade 3 ◽  
Entire Treatment

Abstract Abstract 3743 Poster Board III-679 Introduction In 2008 we published a multicenter non-randomized phase II trial of fludarabine and mitoxantrone plus 90Y-IT in untreated patients with FL. By the end of the entire treatment regimen 95% of the patients achieved complete remission (CR). With a median follow-up of 30 months, 3-year PFS was estimated to be 76% and 3-year OS 100%. On the basis of these results we are currently conducting a prospective, multicenter, non-randomized, phase II study of R-FM followed by 90Y-IT in untreated patients with FL in which the number of fludarabine and mitoxantrone cycles has been decreased to four and in which rituximab is administered before each cycle. The rationale of the trial is to use different forms of treatment and to reduce the use of conventional chemotherapy and its related toxic effects. Patients and Methods Patients eligibility is represented by: age more than 18, stage II-IV, FL grade I-II, WHO performance status 0-2. Patients are treated with standard FM chemotherapy plus rituximab every 28 days for 4 cycles. Patients are restaged 4 to 8 weeks after completion of immunochemotherapy and those achieving at least a partial response are eligible for 90Y-IT. All patients receive a single dose of 90Y-IT 14,8 MBq/kg. At the time of the analysis we enrolled 55 patients. 25 patients were male and 30 female; the median age was 56 years (range 26-84); 12 patients were stage II, 13 stage III and 30 stage IV; 11 patients had a bulky disease. 52 patients completed the induction chemotherapy, all except 5 were eligible for the consolidation treatment with 90Y-IT and 44 patients were restaged after the entire treatment regimen. Results After the R-FM chemotherapy, the overall response rate was 92.3% (48/52) including 39 (75%) CR and 9 (17.3%) partial remissions (PR). Time to event analyses, including TTP and duration of response are pending further follow-up. Treatment was well tolerated grade 3-4 haematologic AEs (mostly neutropenia) were seen in 50% of the patients. Among the 44 patients (9 PR and 35 CR) subsequentially treated with 90Y-IT and reassessed for the response, 8/9 (88.9%) PR patients improved their remission status from PR to CR. 90Y-IT toxicity included mostly grade 3-4 neutropenia and thrombocytopenia and was comparable to the literature data. Conclusions These preliminary data indicate that radioimmunotherapy appears highly effective and feasible as “consolidation” after short (4 cycles) immunochemotherapy in FL patients, improving quality of response without any cumulative toxicity. Disclosures: No relevant conflicts of interest to declare.

The International Registry for Chronic Myeloid Leukemia (CML) in Children and Adolescents (I-CML-Ped-Study): Objectives and Preliminary Results

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 3741-3741 ◽  
Author(s):  
Frédéric Millot ◽  
Meinolf Suttorp ◽  
Joelle Guilhot ◽  
Pietr Sedlacek ◽  
Evelina S De Bont ◽  
...  
Keyword(s):  
Children And Adolescents ◽  
Conflicts Of Interest ◽  
Chronic Phase ◽  
Cytogenetic Response ◽  
Biological Data ◽  
Individual Treatment ◽  
Costal Margin ◽  
International Registry ◽  
Pediatric Study

Abstract Abstract 3741 Background: CML is a very rare disease in children and adolescents accounting for less than 5% of all CML cases. Only scant data is available regarding epidemiology, presenting features and outcome of CML in this age range. Aims: An international registry (I-CML-Ped Study) was established to assess epidemiology, management and outcome of CML in the pediatric population. The main objectives of the study are the following: i) to describe the clinical and biological characteristics of CML in a large cohort of patients less than 18 years of age, ii) to identify prognostic factors in this age-group in order to optimize individual treatment choices iii) to determine side effects and long term effects of treatments, mainly the tyrosine kinase inhibitor effect, on growth and development of a pediatric cohort. Methods: All national pediatric study groups were invited to participate. All newly diagnosed children and adolescents less than 18 years diagnosed later than January 2000 has to be notified and collection of the follow- up data is planned. The study is strictly observational and informed consent from the patient and/or the legal guardians is required for enrollment. The study was started in January 2011. Results: As of July 2012, 200 patients (pts) from 9 countries have been registered. There was a male preponderance (59%). The median age at diagnosis was 11.6 years (range, 8 months −18 years); 8% of the patients were younger than 4 years. Clinical and biological data at initial diagnosis so far is available in 150 pts. At time of diagnosis 92% were in chronic phase, 6% in accelerated phase and 2% in blastic phase according to the European Leukemia Net criteria. The Sokal risk group distribution was: 13% low, 33% intermediate and 55% high risk. The majority of the patients showed a Lansky score of 100 (67%) or 90 (16%). Splenomegaly was present in 76% of patients. The median of the spleen size below the costal margin was 8 cm (range: 0 to 25 cm). The median of the leukocyte count was 250×109/L (range: 5 to 1037). Additional chromosomal abnormalities in Ph-positive cells were observed in 2.3 % of the patients. The BCR-ABL transcript type was available in 100 patients: b3a2 51%, b2a2 40%, b3a2 plus b2a2 7% and b2a3 2%. The median follow-up time is 28 months (range, 2–138). Five deaths were recorded. The estimated overall survival rate at 42 months is 97% (CI 95%, 91–99). Forty seven (63%) of 75 assessable patients for cytogenetic response achieved complete cytogenetic response 12 months after the start of the treatment (imatinib: 43 pts, switch to dasatinib after imatinib failure: 3 pts, interferon + cytosine arabinoside: 1pt). Data collection regarding molecular assessment is ongoing and will be presented. Conclusion: This is the largest study reporting on children and adolescents with CML. The data indicates that children and adolescents with CML presented with clinical and biological differences compared to adult patients with CML. Whether these differences translate into a different outcome still remains to be determined. Acknowledgment: The I-CML Ped study is supported by an unrestricted grant from Novartis Pharmaceutical Company Disclosures: No relevant conflicts of interest to declare.

Phase II trial of combination of bortezomib and rituximab in relapsed and/or refractory Waldenstrom macroglobulinemia

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 8535-8535
Author(s):  
I. M. Ghobrial ◽  
J. Matous ◽  
S. Padmanabhan ◽  
A. Badros ◽  
S. Chuma ◽  
...  
Keyword(s):  
Peripheral Neuropathy ◽  
Complete Remission ◽  
Phase Ii ◽  
Median Number ◽  
Toxicity Assessment ◽  
Waldenström Macroglobulinemia ◽  
Waldenstrom Macroglobulinemia ◽  
Grade 3 ◽  
Relapsed Disease

8535 Background: This phase II study aimed to determine safety and activity of weekly bortezomib in combination with rituximab in patients with relapsed/refractory Waldenstrom macroglobulinemia (WM). Methods: Patients who had at least one previous therapy for WM and who had relapsed or refractory disease were eligible. NCI CTCAE v3.0 was used for toxicity assessment. All patients received bortezomib IV weekly at 1.6mg/m2 on days 1, 8, 15, q 28 days × 6 cycles, and rituximab 375 mg/m2 at days 1, 8, 15, 22, on cycles 1 and 4. Results: 37 pts (26 men and 11 women, median age 62 years, range 42 - 73) have been treated to date. The median number of lines of prior treatment was 3 (range 1 - 5). All patients had received prior rituximab and 5 pts received prior bortezomib. The median IgM at baseline was 3540 mg/dL (range 700-10,800). The median follow up is 12 months (range 5 - 26 months). Thirty-five pts are evaluable for response. Complete remission and near complete remission occurred in 2 (6%), partial remission in 17 (48%), and minimal response in 10 (29%). Progressive disease occurred in 1 (3%) and stable disease occurred in 5 (14%). Most patients achieved response rapidly within 3 months of therapy (2–7 months). Rituximab flare occurred only in 6 patients (20%). At 24 months of follow up, 8/35 pts have shown relapsed disease. The median time to progression and duration of response has not been reached. Patients tolerated therapy well without significant toxicities: grade 3 peripheral neuropathy occurred in only 2 pts. Grade 1 and 2 neuropathy occurred in 10 pts (26%). Other grade 3 and 4 toxicities included neutropenia in 5 patients, and anemia and thrombocytopenia in 4 patients. Grade 5 pneumonia and viral infection occurred in 1 patient who was within the first cycle of therapy and did not receive herpes zoster prophylaxis. Attributable toxicities otherwise proved manageable with appropriate supportive care and the combination was generally well tolerated. Conclusions: The combination of weekly bortezomib and rituximab has been well tolerated and demonstrates encouraging activity, with CR+ PR + MR in 83% of evaluable patients with relapsed WM. No significant peripheral neuropathy has been observed to date with this regimen. [Table: see text]

Phase II study of the IDH2-inhibitor enasidenib in patients with high-risk IDH2-mutated myelodysplastic syndromes (MDS).

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 7010-7010
Author(s):  
Sangeetha Venugopal ◽  
Courtney Denton Dinardo ◽  
Koichi Takahashi ◽  
Marina Konopleva ◽  
Sanam Loghavi ◽  
...  
Keyword(s):  
Phase Ii ◽  
Phase Ii Study ◽  
Single Agent ◽  
Median Number ◽  
International Prognostic Scoring System ◽  
Open Label ◽  
Isocitrate Dehydrogenase 2 ◽  
Treatment Naïve ◽  
Grade 3

7010 Background: Isocitrate dehydrogenase 2 ( IDH2) mutations occur in 5% of patients (pts) with MDS. Enasidenib (ENA) is a selective oral inhibitor of the mutant IDH2 enzyme with single-agent activity in relapsed/refractory acute myeloid leukemia (AML). We report the results of the open label phase II study designed to evaluate the efficacy and tolerability of ENA, as monotherapy or in combination with azacitidine (AZA) in pts with higher-risk IDH2-mutated MDS (NCT03383575). Methods: Pts with higher-risk [Revised International Prognostic Scoring System risk > 3 or high molecular risk (HMR)] MDS/CMML or LB AML naïve to hypomethylating agents (HMA) received ENA100 mg orally daily for 28 d of each 28-d cycle + AZA 75 mg/m2 IV or SC on d 1-7 of each cycle (ENA+AZA), and pts with refractory or progressive MDS to prior HMA therapy received ENA alone (ENA), in 28-d cycles until unacceptable toxicity, relapse, transformation to AML, or progression. The primary endpoint was overall response rate (ORR) [complete remission (CR), marrow CR (mCR), partial remission (PR) and hematologic improvement (HI)]. Other endpoints include safety, and survival outcomes. Results: 48 pts received ENA+AZA (n = 26) or ENA (n = 22). The median age was 73 yrs (range, 46-83). Most pts (72%) had HMR: ASXL1 (39%), and RUNX1 (17%). Median number Tx cycles was 4 (2–32) in the ENA+AZA, and 7 (1–23) in the ENA arm. Common Tx-related grade 3–4 AEs in the ENA+AZA arm were neutropenia (64%), thrombocytopenia (28%), and anemia (8%); these occurred in 10%, 0%, and 5%, in the ENA arm. Grade 3–4 infections occurred in 32% (ENA+AZA) and 14% (ENA). IDH differentiation syndrome occurred in 3 pts (12%) in the ENA+AZA and 5 pts (24%) in the ENA arm. Two deaths occurred during the initial 60 d, both unrelated to study and due to COVID. In response-evaluable pts (n=46), ORR was 84% (n = 21/25; 24% CR + 8% PR+44% mCR+ 8% HI] in the treatment naïve ENA+AZA and 43% (n = 9/21; 24% CR+5%PR+5% mCR+10% HI) in the HMA failure ENA arm (Table). Most common reason for Tx discontinuation was disease progression (ENA+AZA 20%, ENA 33%).5 pts (20%) received HCT in the ENA+AZA and 1 (5%) in the ENA arm. 7 pts in the ENA+AZA and 5 in the ENA arm were ongoing at data cutoff (Dec 31, 2020). After a median follow up of 12.6 mo, median OS was 32.2 mo in the ENA+AZA and 21.3 mo in the ENA arm. Conclusions: ENA is well tolerated and shows promising efficacy in IDH2-mutated higher risk MDS. Follow up and accrual is ongoing to better define duration and biomarkers of response. Clinical trial information: NCT03383575. [Table: see text]

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