Management of Relapsed APL

Transcription

1 THE INAUGURAL ASEAN FEDERATION OF HAEMATOLOGY SCIENTIFIC MEETING AND THE VIIITH MALAYSIAN NATIONAL HAEMATOLOGY SCIENTIFIC MEETING - SHANGRILA HOTEL KUALA LUMPUR, APRIL 2010 Management of Relapsed APL Dr Mammen Chandy Hematology Department Christian Medical College Vellore, India Tata Medical Center, Kolkata

2 APL - Diagnosis CD34=1.92% HLA-DR=1.13% CD13=70.9% CD33 =96.07%

3 Acute promyelocytic leukemia Stat 5b Blood 1999 Melnick et al.

4 Treatment of APL European APL 91 trial EFS at 2 years 84±4% Estimated 2 year survival 90% in those receiving maintenance therapy EFS Established role of administration of ATRA with chemotherapy in induction. Fenaux et al. Blood 1999

5 APL 2006 trial 250 patients 96% CR = 3 relapses J Clin Oncol. 2009;27(16):

6 Arsenic trioxide in APL Mechanism of action Induce apoptosis [ µM] downregulation of bcl2 increased expression of caspases activation of jun kinases reorganize POD disruption of cytoskeleton inhibition of NF B Induce differentiation [ <0.5µM] degradation of PML-RARα acetylation of histones 3, 4 As 2 O 3 Inhibits angiogenesis HUVEC apoptosis down regulates VEGF Altered cellular Redox status Reactive oxygen species (ROS) generation bind sulfhydryl rich proteins/enzymes such as glutathione - reduce level

7 Arsenic trioxide in newly diagnosed APML-CMCH Open trial initiated in Jan 1998 Inclusion criteria: All newly diagnosed cases of APML who in absence of this trial would have received palliative therapy [FAB criteria sufficient to start therapy, requires confirmation by karyotyping / FISH / RT-PCR to be included in analysis] Exclusion criteria: Pregnant women Patients clinical condition unsuitable for standard chemotherapy

8 Arsenic trioxide in APML As 2 O 3 was prepared in-house by the pharmacy Since 2001 INTAS Pharmaceuticals Administration : Adults 10 mg/day [1mg/ml vials] IV in 500ml Dextrose saline over 2 3 hours [ Adults <40 kg / Pediatric (<12 years) 0.15 mg/kg/day maximum of 10 mg ]

9 Cost : $10

10 APML As2O3 CMCH Vellore 72 patients 3 year Kaplan-Meier estimate of EFS, DFS and OS was 74.87±5.6%, 87.21±4.93% and 86.11±4.08% median follow up of 25 months (range: 8 92) 10 early deaths 7 IC bleed 2 sepsis 1 differentiation syndrome median hospital stay in induction was 22 days (range: 0 65). median time on antibiotics was 11.2 days (range: 0 56). Support red cell 2.5 units (range: 0 16 Platelet 15.5 units (range: 0 66) FFP 2 units (range: 0 16)

11 Figure 1. Regimen of single-agent arsenic trioxide Mathews, V. et al. Blood 2006;107: Copyright 2006 American Society of Hematology. Copyright restrictions may apply.

12 Figure 2. Kaplan-Meier product limit estimate of (A) overall survival (OS) and event-free survival (EFS) (n = 72) Mathews, V. et al. Blood 2006;107: Copyright 2006 American Society of Hematology. Copyright restrictions may apply.

13 Figure 3. Comparison of Kaplan-Meier product limit estimate of event-free survival (EFS) between the good-risk group (group A: WBC count, 20 x 109/L) and the rest (group B) Mathews, V. et al. Blood 2006;107: Copyright 2006 American Society of Hematology. Copyright restrictions may apply.

14 CMC APL future directions Risk Stratification: Platelet > 20 x 10 9 /L WBC < 5 x 10 9 /L Good Risk: High Risk: Platelet > 20 x 10e9/Lt WBC < 5 x 10e9/Lt Continue single agent As2O3 Use all available agents upfront

15 CMC APL future directions High Risk Induction Consolidation I Consolidation II DNR 60/m2 45/m2 ATRA 45mg/m2 (max 90 days) ATO 0.15mg/kg/day (max 10 mg) (Day 10) x 30 days x 28 days x 28 days maintenance x 2 years Cytosine 1gm/m2q12h Day1,3,5 Maintenance: RT PCR + allogeneic SCT Cap ATRA 45 mg/m2/day in two divided doses for 15 days every 3 months x 2 years. Inj ATO 10 mg/day (<45 kg 0.15 mg/kg) 10 days/month x 6 months (To be administered along with ATRA in Cycle 1, 3 and 6)

16 Can we reduce relapse rates in high risk patients by integrating the best agents that we have in a protocol Without increasing toxicity Or late complications of therapy

17 Why do some patients with APL relapse? If we understand this we can develop new targeted strategies and identify patients who need these

18 Prediction of Relapse Risk stratification Presence of MRD at the end of consolidation Additional CTG factors and molecular markers Pharmacokinetic and pharmacogenetic differences in the action of therapeutic agents.

19 Risk Stratification in APL WBC Platelet count > 10,000/mm3 < 40,000/mm3 High risk Intermediate risk Low risk Sanz et al. Blood 2000 Good Risk WBC <5 x 10 9 /Lt and Plat >20 x 10 9 /Lt High Risk WBC >5 x 10 9 /Lt and Plat <20 x 10 9 /Lt Mathews et al Blood 2006

20 BLOOD 2006 Risk Stratification Good Risk Group: 86% 75% WBC <5 x 10 9 /Lt and Plat >20 x 10 9 /Lt n=22 (30.5%) Rest High Risk n=50 (69.5%)

21 MRD monitoring by RQ-PCR The most powerful predictor of relapse-free survival (RFS) in multivariable analysis (hazard ratio, 17.87; 95% CI, 6.88 to 46.41; P <.0001) MRD monitoring far superior to presenting WBC (hazard ratio, 1.02; 95% CI, 1.00 to 1.03; P =.02) In MRD positive patients, early treatment with arsenic trioxide prevented progression to overt relapse in the majority RFS rate at 1 year from molecular relapse was 73%. By using this strategy, 3-year cumulative incidence of clinical relapse was only 5% in the Medical Research Council AML15 trial. Grimwade et al Journal of Clinical Oncology (2009) 27;22:

22 Risk Factors for Relapse Additional cytogenetic changes n = 69 Isolated t(15;17) 53 (76.8%) Additional CTG finding 16 (23.2%) Haematologica 2007

23 Risk Factors for Relapse FLT 3 mutations n = 94 FLT3-ITD 20 (21.3%) (increased WBC FLT3 D835V 11 (11.7%) (and increased bcr3) Haematologica 2007

24 Correlation of Clinical Outcome with Toxicity Profile n = 83 (7 early deaths none hepatotoxicity) Evaluated = 76 No toxicity 47 (61.8%) Grade 1 14 (18.4%) 2 7 (9.2%) 3 4 (5.3%) 4 4 (5.3%) Onset: Induction 19 (65.5%) Consolidation 3 (10.3%) Maintenance 6 (20.7% Follow up 1 (3.4%) Grade 3/4 8 All in induction 2 Hepatitis B ATO discontinued mean 22.6 days (range: 10 28) Re-challenged uneventfully 7 One recurrence on challenge changed protocol Leukemia 2007

25 RFS 1.0 Hepatotoxicity + : n = 29.8 Hepatotoxicity - : n = p= months Time (Months)

26 ng/10 7 cells Intracellular ATO concentration 60 P=0.5 n=39 n=9 P= Newly Diagnosed Relapsed Naive NB4 Resistant NB4 PBMNC

27 Micromolar 6 IC50 values P=0.34 n=33 n=12 P=< Newly Diagnosed Relapsed Naive NB4 R NB4

28 Gene expression profile of malignant promyelocytes in newly diagnosed, relapsed APL patients, naïve NB4 and resistant NB4 cell line. 44k human array Single color Agilent platform Data analysis using Gene Spring Software

29 Differentially Regulated Genes: Condition: Newly diagnosed vs. relapsed patients Fold difference: 2 fold and above Differentially expressed genes: 1744 There is apparent clustering of gene expression profile of relapsed vs. newly diagnosed cases. Relapsed Newly diagnosed

30 - 90 genes were commonly dysregulated in the same direction between relapsed patients and resistant NB4 cells ABCA1 BAX LEP XIST TUSC1 CAV1 TLR4 APOL6 S100A12 MDM2 COL5A1 COL2A1 CD34 TDT COLEC11 TRIM15 HSP90 BAG4 ADAMTS4 ALDH8A

31 Relapse in APL Clinical relapse Hematological Extra medullary: CNS ( %) Molecular relapse Defined by 2 successive PCR positive assays, with stable or rising PML-RAR transcript levels detected in independent samples analyzed in 2 laboratories? Justification for monitoring by RQ PCR every 3 months OS Molecular relapse: 92% 64%OS OS Hematological relapse(historical): 44% 24% Lo Coco Blood 1999, Esteve Leukemia 2007

32 European Leukemia Net Recommendations For patients with confirmed molecular relapse (defined as 2 successive PCRpositive assays, with stable or rising PML-RARA transcript levels detected in independent samples analyzed in 2 laboratories) preemptive therapy has to be started promptly to prevent frank relapse. IIa B

33 Treatment of Relapse Induction of second remission ATRA + Chemotherapy As2O3 Other agents Consolidation No further treatment Autologous Stem Cell transplant Allogeneic Stem Cell transplant

34 TREATMENT OF RELAPSING APL WITHOUT As2O3 564 patients <66 years in APL 91 and APL 93 trials :525 (93%) achieved CR. 122 /140 (87%) relapsing patients achieved CR2 ATRA:8 ATO:4 Chemotherapy(CT):24 ATRA+CT:98 47 pts received no auto or allograft: 3 year EFS of 36% APL and PETHEMA experience De Botton,JCO,2005

35 Arsenic trioxide in relapsing APL Ref Dose No CR Consolidatio n LFS Niu 0.15mg/kg 18 85% As2O3 only 12/18 relapse Shen 0.08mg/kg 20 80% variable yrs Kwong 10mg 8 100% Ida 7/8 Soignet 0.15mg/kg 52 87% SCT 40% Ohnishi 0.15mg/kg 14 78% As2O3 only Median 8m

36 Treatment of APL molecular relapse by Gemtuzumab ozogamycin(go) 16 pts with molecular relapse (8,5,2,1) GO 6mg/m2 x molecular CR achieved 7 pts still in CR (7+ to 31+ months),7 relapses after 3 to 15 months Lo Coco,Blood,2004

37 European Leukemia Net Recommendations Although ATRA in combination with chemotherapy can be used as salvage therapy, ATO-based regimens are presently regarded the first option for treatment of relapsed APL.-IV C

38 Bone Marrow Transplantation (2007) 39,

39 SCT for APL- EBMT 625 patients Allogeneic LFS at 5 years CR 1 (n144) - 68% CR 2 (n 137) 59% GVHD II IV - 35% chronic GVHD -39% Autologous LFS at 5 years CR1 (n149) 69% CR2 (n195) - 51% 15 patient s auto-grafted in CR 2: 7 PCR +: all relapsed (Meloni, Blood, 1997) Bone Marrow Transplantation (2007) 39,

40 Biol Blood Marrow Transplant 15: (2009)

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44 European Leukemia Net Recommendations Patients achieving second CR should receive intensification with SCT or chemotherapy, if possible. IV C Allogeneic HSCT is recommended for patients failing to achieve a second molecular remission. IV C Autologous HSCT is a valid option for patients without detectable MRD in the marrow and with an adequate PCR negative harvest. IIa B

45 European Leukemia Net Recommendations For patients with confirmed molecular relapse (defined as 2 successive PCR-positive assays, with stable or rising PML- RARA transcript levels detected in independent samples analyzed in 2 laboratories) preemptive therapy has to be started promptly to prevent frank relapse. - IIa B Although ATRA in combination with chemotherapy can be used as salvage therapy, ATO-based regimens are presently regarded the first option for treatment of relapsed APL.-IV C Patients achieving second CR should receive intensification with SCT or chemotherapy, if possible. IV C Allogeneic HSCT is recommended for patients failing to achieve a second molecular remission. IV C Autologous HSCT is a valid option for patients without detectable MRD in the marrow and with an adequate PCR negative harvest. IIa B Blood. 2009;113:

46 European Leukemia Net Recommendations 4.6. For patients in whom HSCT is not feasible, the available options include repeated cycles of ATO with or without ATRA with or without chemotherapy. IV C 4.7. For patients with CNS relapse, induction treatment consists of weekly triple intrathecal therapy (ITT) with methotrexate, hydrocortisone, and cytarabine until complete clearance of blasts in the cerebrospinal fluid, followed by 6 to 10 more spaced out ITT treatments as consolidation. Systemic treatment should also be given. IV C Blood. 2009;113:

47 tamibarotene Orally active, synthetic retinoid Specific retinoic acid receptor (RAR) alpha/beta agonist Ten times more potent than ATRA in inducing cell differentiation and apoptosis in HL-60 cell lines in vitro. Due to a lower affinity for cellular retinoic acid binding protein (CRABP), tamibarotene may show sustained plasma levels compared to ATRA. In addition, this agent may exhibit a lower toxicity profile than ATRA, in part, due to the lack of affinity for the RAR-gamma receptor, the major retinoic acid receptor in the dermal epithelium. Synonym: retinobenzoic acid Foreign brand names: Amnoid AMNOLAKE Code name: Am-80 Chemical structure name: 4 [(5,6,7,8- tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl) carbamoyl]benzoic acid

48 Active Clinical Trials with Tamibarotene Safety, Efficacy, & Pharmacokinetic Study of Tamibarotene to Treat Patients With Relapsed or Refractory APL Phase: Phase II Type: Treatment Status: Active Age: 18 and over Sponsor: Other Protocol IDs: INNO-507-P2, NCT Tamibarotene and Arsenic Trioxide for Relapsed Acute Promyelocytic Leukemia Phase: Phase I Type: Treatment Status: Active Age: 18 and over Sponsor: Other Protocol IDs: NU 08H9, NCT

49 Unlike other AML subtypes, 60-70% of patients with APL who relapse can be cured with reinduction and a stem cell transplant

50 Acknowledgments: Dr Vikram Mathews Dr Alok Srivastava Dr Biju George Dr Auro Viswabandya Dr Shaji Ramachandra, Dr Poonkuzhi B, Salamun Desire, Ezhilarasi Chendamarai, Maria Thomas Cytogenetics Unit Dr Vivi Srivastava Registrars over the years Nurses and paramedical staff