Leukemia-Myelodysplastic Syndrome and Transplantation

Sesion 30 Octubre 2009

LEUKEMIA-MYELODYSPLASTIC SYNDROME AND TRANSPLANTATION

******7000. AML CALGB. NPM1 mut 54% de novo AML (cytogenetically normal; no t(8;21), inv 16, or t(16;16)) and only 15% in secondary AML. Better outcome in older patients.

*****7001. AML CALGB. Micro RNA 181ª in cytogwenetically normal de novo AML predicts better outcome in high risk group.

*********7002. AML CALGB. Younger <60 yo cytogenetically normal AML (low risk FLT3-ITD-, NPM1 mut, low ERG & high risk with CEBPA mut) and high risk (FLT3-ITD+, NPM1 wt, WT1 mut, and low risk with high ERG and high risk with CEBPA wt. This new classification provided CR 96% vs 79%; 5yDFS 69% vs 21%; & 5yOS 70% vs 31%.

********7003. AML ECOG. HD DOX induction 90 mg/m2 x 3 d vs 45 mg/m2 x 3 d + AraC 100 mg/m2/d x 7 . Then BMT Allo/Auto. MST 23.7 mo vs 15.1 mo. New standard in young patients.

*******7004. AML MDACC. Vorinostat 500 mg/m2 po tid x 3 ÆIDA 12 mg/m2/d x 3 + AraC 1.5 g/m2/d x 4 civi induction & then 5 consolidation cycles with Vorino similar + IDA 8 mg/m2/d x 2 + AraC 0.75 g/m2/d x 3 civi & finally 1 y maintenance vorinostat. N=22. CR 82%, only 2 relapses & PFS not reached (very high risk: WBC high, cytogenetic abnormal 71%, 8 secondary AML).

********7005. AML. Voreloxin (DNA intercalator/topo II inhibitor) + AraC in relapsed AML. N=52.. MTD 80 mg/M2 (AraC 400 mg/m2/d x 5 civi or bolus 1 g/m2/d x 5. Results: 9 CR seen in Phase Ib, on going. Good!!.

7006. CLL. GCS 100 (galactin-3 antagonist). N=24. 160 mg/m2 x 5d q 3 wk. 25% PR.

********7008. CML. Omacetaxine mepesuccinate 1.25 mg/m2 sc bid x 14 d q 4 wk in T315I mut. N=66. In CP N=25, CHR 80%, Cytogenetic OR 28%, 2yPFS 70%; In AP CHR 18%, PHR 18%; in BP PHR 13%. Good results in resistant CP.

7009. Romiplostim 750 ug sc q 2wk (peptide similar action to thrombopoietin) in MDS thrombocytopenic patients.

****7010. AML >60yo. Decitabine 20 mg/m2 iv x 10 d q 4 wk & repeat to induce or maintain (half dose 5 days). CR 42%.

****7011. MDS. Decitabine 3 d & 5 d. CR improved with high dose: 10-40%; PFS 7 to 9 mo also.

******7018. Sorafenib + IDA + HD AraC in <65 yo AML: CR 85%, specially in most patients with FLT3-ITD/TKD...

**7020. Clofarabine 40 mg/m2/d x 3 iv + CPA 200 mg/m2 iv q 12h x 3 d in adult ALL relapsed/refractory: OR 14%.

**7021. Sapacitabine 200 mg bid x 7 d q 3-4 wk in older AML/MDS. OR 31%

************7023. Acute steroid resistant GVHD: N=141, NIH data on AlloBMT). Daclizumab (antiIL2Ra) 1 mg/kg d 1, 4, 8, 15, & 22 + Infliximab (AntiTYNFa) 10 mg/kg d 1, 8, 15 & 22). N=23. 87% rersolved.

************7031. CLL-Richter syndrome (MDACC). LOHP 30 mg/m2 d 1-4 + Fludara 30 mg/m2 d 2- 4 + AraC 0.5 mg/m2 d 2-4 + Neulasta 6 ug d 6 (OFAR 2). N=55, del 17p 15; ZAP70+ 30. Results: CR 13% + PR 25%. 1yFFS 18%, 1 yOS 52% Richter sy and 6%+ 73% OR, 67% FFS, 75% OS in relapsed CLL.

1 ***********7043. CLL refractory Fludara & Alemtuzumab: Ofatumumab (Anti CD20 new MO Ab). 300 mg x 1--> 2 g wkly x 8 Æ monthly x 4. ORR 58%, MOS 13.7 mo. Very good!!.

**********7048. Voreloxin single agent AML >60yo. 72 mg/m2 q wk x 3. N=60. CR & CRp 38%. First month mortality 17%.

*************7061. All India Inastitute Med Sciences. A>SO-PCR monitoring CML mutation. Initial 100 CML treated with Imatinib 400 mg qd, M351T mut after 3 y therapy 40/100, when Imatinib was 800 mg qd 15/20 resolved and 5 developed T315I (fatal mut); F311C mut aft5er 3 y therapy 10/100 and 4 developed T351I fatal mut. Another 12 Imatinib resistant CML were treated wuith Dasatinib F317L mut present in 4/12 and died. Propose PCR method (allele specific oligionucleotide PCR monitoring, unexpensive and more sensitive than sequencing...

********7095. Plerixafor + GCSF in movilization failures. N=65. 81% obtained >2.10e6 CD34+/kg and had good recovery in poor risk patients.

*******7100. Plerixafior (AMD 3100) + GCSF in movilization failures. N=16. Fared well. Plerixafor is FDA approved.

LUNG CANCER- LOCAL & REGIONAL ADJUVANT THERAPY

7500. F Felip, Spain. Stage I-T3N1. Randomized Surgery vs TXL 200 + CBDCA AUC 6 q 3 wk x 3 NA (only 2% T3N1). 5yDFS 39% vs 40%.

*******7501. JBR10 adjuvant CDDP/NVB. N=482. 9 yF up analysis. Benefit N1 OS 6.8 vs 3.6; HR 0.68, N0 no benefit.

*******7502. MSH2 required for CDDP DNA repair. N=673 Æ38% MSH2+. When MSH2 was negative HR=0.76; MSH2-/ERCC1- had HR=0.65.

7503. TXL + CBDCA +/- Thalidomide. No differences. N=277 (ChX+RTx).

*7504. MitoC+NVB+CDDP = CPT+CBDCA 0 TXL+CBDCA together with RTx in stage III unresectable NSCLC. N=456.

7505. Locally advanced disease. Alimta + CBDCA +/- CETX/RT. OR 73%; 18 mo OS 57%. CETX do not add to the results .

************7508. TS levels in mesothelioma treated with Alimta. N=32. High TS TTP 8.7 vs 14.7 mo & MST 11.7 vs 24.7 mo.

*******7509. Van Scil. CHx + Surgery (pneumonectomy) + Postop RT in T3N1 mesothelioma. MPFS 13.3 mo. Success 42%. Considered not feasible...

*******7523. Adj Erlotinib/Gefitinib in EGFR+ reasected adenocarcinoma. MSKCC. N=150. DFS HR=0.38.

***********7526. Beta-tubulin IHC in evaluation in non CR NA chemotherapy of NSCLC after CDDP/GEM vs CBDCA/TXL. N=423. BTubIII positivity MPFS 230 vs 60 mo. Association with poor prognosis is very significant.

7578. Mesothelioma: BV+Alimta*CDDP = Alimta+CDDP. N=43. OR 41%, MST 11.5 mo.

***********7587. SLN in lung cancer (Cruces/Basurto). N=37. Accuracy 94.6%, sensitivity 86%, specificity 100%, positive predictive value 100%, negative predictive value 92%. Very interesting...

*******7589. Thymomas. Belinostat (HDACI) 1 mg d 1-5 iv q 3 wk. N=14: Thymoma 2 PR + 8 NC and Thymic carcinoma N=8, no responses.

************7590. Thymoma. GEM + XEL. N=12. OR: 2 CR + 8 PR + 2 NC. All patients were Pt refractory!!!

***********7591. Endobronchial obstruction due to lung cancer. CDDP intratumorally 1 mg/ml (max 2 ml) + Brachy endobronchial 500 cGy/sec x 4. Results: CR 14/16.

*************7597. Metanalysis of second line EGFR inhibition in lung cancer: 5 trials/4482 patients. OR=0.96 vs placebo, and OR=1 vs chemotherapy.

LUNG CANCER- METASTATIC

*************CRA8000. Maintenance PEMTX , 500 mg/m2 q 3 wk til PD vs placebo after Clinical Benefit chemotherapy of NSCLC. N663, randomized study. PEMTX better. MOS 13.4 vs 10.6 mo; MPFS 4.3 vs 2.6 mo; OR+ NC 51.7% vs 33.3%.

************8001. Maintenance Erlotinib 150 mg/d vs placebo (after non-PD Pt based chemotherapy. N=1949/ randomized tudy. PFS 0.71; OR 12% vs 5%.

***********LBA8002. Maintenance BV+Erlotinib vs BV (after Non-PD BV+CDDP). N=1160, randomized. MPFS HR=0.722 (4.8 mo vs 3.7 mo)...???

**********8003. Vandetanib (VEGFR, EGFR,RET)., po 100 mg/d +/- TXT in second line Rx. N=1391. Randomized blind study. MPFS HR=0.79, ORR 17% vs 10%, OS HR trend HR= 0.91. Active???.

************8004 First line Vorinostat (HDACI, 200 mg/m2/d) + TXL + CBDCA vs same ChX + Placebo. N=93. OR 34% vs 13.4%; MPFS 5.7 vs 4.1 mo....

8005. First line TXT + CBDCA +/- Celecoxib 400 mg bid. OR 33% vs 26%; MPFS 5.5; MOS 8.3 mo. NO differences.

8009. Vandetanib = Erlotinib in second line.

8010. Vandetanib + PMTX = PMTX

******8013. BIBW2992 (EGFR Her2 TKI) in second line EGFR mut (NSCLC Taiwan). N=289. OR 53% + NC 42%. Diarrhea and skin tioxcity.

8014. Cilengitide (Integrin inhibitor) < TXT

*****8015. TXL + CBDCA * CETX + BV. N=110. OR 54% + NC 23%; PFS 7 mo, OS 14 mo, 1yOS 57%.

*********8019. Recchia.- Italian group. CDDP + GEM + IL2 , 3 MU d 3-5, 9-11 & 15-17. N=241 randomized study. 1 yOS 45 vs 51%; MPFS 6.6 mo vs 6.9 mo. NO improvement.

8022. k-ras wt do niot predict CETX OR.

**********8023. Massuti/Rosell- Central Lab. Erlotinib in EGFR mut NSCLC. N=217 treated/358 mut/randomized study on a total of 2507 patients. CR 12.2%. (2yOS 94%; 3yOS 60%.7%), PR 60% (2yOS 55%, 3yOS 32%). Clearly outstanding selection...Randomized study comparing to conventional chemotherapy???.

***********8025. MSKCC rebiopsy: First EGFR mutation was: del 19: N=39, ex21L8582 and others N=35; second EGFR mutation T790: N=33, other N=2, none N=31, indeterminate N=10.

****8028. US study. Amrubicin > Topotecan Ext SCLC (aproved in Japan 40 mg/m2 d 1-3 q 3 wk).

**********8029. CPT = CBDCA + VP in Ext SCLC (German study). N=216. OR 62% vs 63%, MOS 10 mo both arms

8034. CDDP + TXL + GEM > CDDP + NVB

*********8053. Elderly monotherapy: Europe 48%, USA 39%, Japan 32%. Double therapy (+target) 72%, 47% & 81%; Young patients with triple therapy: Europe 14%, USA 36% & Japan 6.5%. Differences in first line therapy quite significant (evidence based???)

***8060. Everolimus 5 mg qd + TXT 60 mg/m2 q 3 wk. N=23. 1 PR + 10 NC. Continue Everolimus maintenance.

**********8064. Spain series EGFR mut. After PD to Erlotinib Æ Chemotherapy. OR 33%, MTTP 8 mo, MST 27 mo.

********8067. Erlotinib moniotherapy in non EGFR mut (Japan). N=30. OR 6% + NC 42%; MST 7 mo; MTTP 25 mo. Data similar to TXT.

*******8073. Retaspimycin (Hsp90 inhibitor) in refractory NSCLC, 400 mg/m2 biwk q 3 wk. EGFR wt 2PR + 7 NC/11 patients; EGFR mut 0 PR + 1 NC/8 patients. Interesting results in EGFRwt.

***********8105. Metanalysis CPT + P > EP in Western SCLC patients. 6 trials. N=1365. Japanese exclusive trial patients excluded.

PEDIATRIC CANCER

*************10009. NB. Fenretinide (4HPR) 1000-2200 mg/m2 qd po active doses. N=32. CR 4/15; MRD 1700 mg/m2/d x 7 d q 3 wks.

*******10011. NB. CPT + TMZ OR 16%.

10013. IMC-A12(antiIGF-1R MoAb) 9 mg/kg iv wkly MRD Phase II solid tumors to begin study.

*********10014. Vandetanib (inhibitor FGFR, RET & VGFR) in medullary ca MEN2B: 6/6 tumor decreased (all with M918T mut) and two patients exhibited a PR.

**********10018. MB. CPT 125 mg/m2x 5 + TMZ 100 mg/m2 d 1-5 & 8-12 iv or 125 mg/m2 d 1 & 8 q 3 wk. N=33. 6 PR + 3 NC + 7 PD. Active.

******10057. NB. Cisretinoic 130 mg/m2 po associated to Chemotherapy

SARCOMA

********10500 In vitro Sorafenib> Sunitinib>Imatinib in resistant GIST.

***********10501. Extra-abdominal fibromatosis. N=155. Exon 3 beta catenin mutation 84%: T41A 39%, S45P 9%, S45F 36.5% and del 2%. Mut 3Bcatenin fare worse than wt. 5yRFS 49% vs 93%.

4 *******10502. Microphtalmia trancription factor (MIT) associated tumors (Clear cell sa, alveolar soft part sa, clear cell renal carcinoma) ARQ197 (inhibitor c-MET) 120 mg po bid. N=28. Results: 1 PR + 15 NC + 4 PD. PR was observed in clear cell sarcoma. On going...

************10507. Masatinib (in Gleevec untreated GIST) 75 mg/kg/d. N=30. At 23.7 mo F up 6.7% CR + 43.3% PR + 46.7% NC + 3.3% PD. MTTR 5.3 mo, MPFS 27.2 mo; 2yPFS 60.2%. Better than Gleevec!!!

************10510. Denosumab (ant-RANKL) in Giant cell tumor of Bone N=35. OR 86%.

*****10509. Liposarcoma/leiomyosarcoma. Trabectedin 105 mg/m2 in 24 hr iv q 3 wk > Trabectedin 0.58 mg/m2 wkly x 3 q 4 wk. HR=0.8 death for 24 h civi. 1y OS 60% vs 50%.

**********10518. Aggressive fibromatosis-Desmoid tumor. Imatinib 400 mg/d (increasing to 800 mg/d in case of PD). N=40. At 3 mo 2% CR + 8% PR; at 1 y non-progression 66%. MTTP 9.5 mo; 2yPFS 55%; 2yOS 95%.

********10519. Aggressive fibromatosis-Desmoid tumor. Caelyx 40 mg/m2 N=10. All had prior systemic therapy. OR 4/10 + NC 5/10. All patients had clinical benefit MDR 4+ to 28+ mo. Very active!! (French group).

*******10520. Imatinib in Dermatofibrosarcoma protuberans t(17;22). Imatinib active 46% OR + 40% NC. MTTP 1.7 y. N=24 (EORTC & SWOG). Responses observed in DFSP and in Fobrosarcomatosis.

*********10522. BV in angiosarcoma. N=29. OR 12% + NC 62%.

********10523. Alveolar soft part sarcoma. Cediranib (VEGF inhibnitor). N=7. Results: 4 PR + 2 NC + 1 PD.

*************10525. Mixoid-roud cell mixosarcoma t(12q13;16p11) confirmed cases. Trabectedin bneadjuvant therapy. 1.5 mg/m2 24 hr civi q 3 wk. 20/25 evaluable. 3 CR + 6 PR + 7 NC. Very good!!!.

********* 10528. TXT + GEM uterine leiomyosarcoma OR 27% + NC 36%; MOS 578 d; MPFS 216 d; 6moPFS 57%.

********10529. DTIC + GEM > DTIC (Spanish Group) N=113; MPFS 4.2 mo vs 1.9 mo; MOS 17.1 mo vs 9.5 mo.

************10530. Trabectedin in uterine leiomyosarcoma. N=56. OR 21% + NC 29%; MPFS 3.6 mo; 6moPFS 41%.

************10564. Sorafenib after Imatinib/Sunitinib/Nilotinib resistant GIST. N=32. PR 19% + NC 41%; MPFS 20 wk; MOS 42 mo. Very active!!!!

*****10578. TXL175 mg/m2 q 3 wk in secondary angiosarcoma (lymphedema or RT induced). N=17. OR 8/14 + NC 1/8; MPFS 6 mo