Chronic myelogenous leukemia

CML for residentClinical case 4
• 60 yr, male, U/D CAD, DLP • Present: persistent fatigue 2 mo, intermittent episode of palpitation, dizziness, weight loss, discomfort over LUQ • PE: palpable splenomegaly 11 cm • CBC: WBC 40,000, Hb 10.2, plt 335,000, increase eosinophils & basophils • BMBx; hypercellular, granulocytic proliferation • CS: t(9;22)(q34;q11) • FISH: BCR-ABL1 fusion gene
CML
• Abnormal pluripotent BM stem cells • BCR-ABL 1 fusion gene (philadelphia chromosome, t(9;22) )
Savage, D. G. et al. N Engl J Med 2002;346:683-693
Chromosome Rearrangement in Philadelphia Chromosome
BCR-ABL in CML and ALL
Frohling S and Dohner H. N Engl J Med 2008;359:722-734
Staging
• Chronic phase • Accelerated phase • Blastic phase
Clinical features • Fatigue • Weight loss • Night sweats • Anemia • Splenomegaly • Marked thrombocytosis • Sig. elevated WBC (as initial presentation in BP without previous of of CP)
Common presentation
Atypical presentation
Fatigue Neutrophilic leukocytosis with immaturity Weight loss Peripheral blast <10% Nocturnal sweats Thrombocytosis Left upper quadrant abdominal pain
Basophilia and/or eosinophilia
Low LAP score
BCR-ABL rearrangement(p210 BCR-ABL) Marrow: myeloid & megakaryocytic hyperplasia, mild/moderate fibrosis < 10%, < 10% blast, minimal dysplasia, t(9;22±other abnormalities)
BM finding: CP
• Cellularity: hypercellular • Myeloid: increase, left shift, blast<10% • Erythroid: vary in number, usually reduce in number and size • Megakaryocyte: smaller than normal (hypolobated nuclei; dwarf megakaryocytes) or normal, slightly decrease in number, 40-50% moderate to extensive megakaryocytes proliferation • Mild to moderate fibrosis
Clinical features of CML-AP Symptoms Lab WHO classification
Progressive splenomegaly & infarcts
Blood & BM blasts≥10%
Increasing marrow fibrosis
10-19% of WBC in PB and/or nucleated BM cells PB Basophils≥20% Persistent thrombocytopenia (plt<100,000) unrelated to tx., or thrombocytosis (>1,000,000) unresponsive to tx Increasing spleen size & WBC count unresponsive to tx.
Cytogenic evidence of cloncal evolution Megakaryocytic proliferation?
Definition of AP CML
Bleeding, bruising
Blood & BM blasts≥20%
Extramedullary blast proliferation
Treatment
• TKI: imatinib, nilotinib, dasatinib • Discontinuation of TKI • Stem cell transplantation • Therapy for advanced disease
Mechanism of Action of BCR-ABL and of Its Inhibition by Imatinib
Savage, D. G. et al. N Engl J Med 2002;346:683-693
BCR-ABL Tyrosine Kinase Inhibitors in CML
Imatinib: phase I in CP-CML
• Intolerant or resistant to IFN-α, doses >300 mg/d • CHR 98%, response occur by 4-6 wks • 31% MCyR, 13% CCyR at median time 5 months • 2 yr F/U, majority of pt maintain durable response on IM • US-FDA: initial dose for CP 400 mg/d
Imatinib VS IFN-α/AraC
Imatinib MCyR rate 69-78.9%
8-yr IRIS • 553 patients, MMR 86% • None of patients who achieved MMR at 12 months progressed to AP or BP CML • Estimated OS 85% & EFS 81% • Estimated freedom from progression to AP or BP CML 92% • Yearly rates of progression to AP/BP in years 4-8 after starting IM treatment (0.9%, 0.5%, 0%, 0%, 0.4%) • 3% of pt who CCyR progress to AP/BP
8-yr IRIS
• More patients (55%) remained on IM • Discontinue treatment • Insufficient therapeutic outcome (16%) • Side effects (6%) • Death (3%) • Other reasons (17%)
Phase II studies
• Higher dose IM yields higher rates of CCyR and MMRs at earlier time points for low or intermediate Sokal-risk CML • No significant difference in CCyR and MMR rates at 12 months between 400 mg/d VS 800 mg/d
Phase III: TOPS (Tyrosine kinase inhibitor optimization and selectivity prospective randamized trial)
• 800 mg/d IM VS 400 mg/d IM • Higher rate of CCyR and MMR at 6 months, but no diff at 12 months • 50% in high dose IM >>>reduction dose <600mg/d, higher rate of gr. 3,4 AE • No sig. diff in CCyR or MMR between two treatment based on Sokal risk scores
• ***high dose IM not recommend as initial treatment in newly diagnosed CP-CML
Proposed mechanisms of imatinib resistance, Hematology 2009
1. Denotes duplication or amplification Bcr-Abl sequence
2. Denotes mutations in Bcr-Abl sequence
3. Denotes imatinib export by the P- glycoprotein export protein
4. Denotes import of imatinib by hOCT1 protein
5. Denotes binding of imatinib in the plasma by α1-acid glycoprotein (AGP)
6. Denotes variability in plasma level of imatinib
7. Denotes activation of alternative signaling cascades leading to Bcr-Abl independent growth
8. Denotes alterations in the epigenetic regulation of the expression of the Bcr-Abl sequence.
Kinase domain mutation 50-90% Gene amplification of BCR-ABL <10%
IC50 values for bosutinib, imatinib, dasatinib, and nilotinib against 18 mutations of the Bcr-Abl sequence expressed in Ba/F3 transfected cells. IC50, relative concentration of the compound that inhibits 50% of the enzymes activity; WT, wild type; P loop, phosphatebinding loop; ATP, adenosine triphosphate; SH2, Src homology 2; A loop, activation loop.
JCO.2009;27:479-471
Imatinib
• Acquired resistance to IM in early & late CP 15% & 25% • Overall incidence of TKD mutation (256 pts): 26% in CP, 44% in AP, 73% in MBP,81% in LBP
Second-generation TKIs
Dasatinib (Sprycel)
• Mech: inh Src family kinase in addition to ABL kinases • Not rely on conformational change of ABL for binding, less susceptible to development of resistant TKD mutations • Approved for treatment • Newly diagnosed CP-CML • CP, AP, MBP, LBP with resistance or intolerance to prior therapy
START-C trial
• CP-CML with resistance or intolerance to IM • Switch to dasatinib 70 mg bid
• CHR 90% (median F/U 15 mos) • MCyR and CCyR 59% & 49% • No response in T315I • MMR rate at 12 months 25% • PFS at 15 months 90%, OS 96% • Average dose 100 mg/d
DASISION (Dasatinib versus Imatinib study in Treatment- Naïve CML- CP) • Phase 3 randomized open label trial • Dasatinib(100 mg/d) VS Imatinib (400 mg/d) • Dasatinib achieved higher CCyR (77% vs 66%) at 12 mos and MMR (46% vs 28%) • Rate of AP & BP progression less in dasatinib compare with imatinib (1.9% vs 3.5%) • Toxicities: myelosuppression, diarrhea, fatigue, pleural effusion (response rate & decrease toxicity in 100 mg dasatinib) • 2-yr F/U cumulative CCyR (86% vs 82%) • …Dasatinib superior to IM (MMR rate 64% vs 46%), deeper responses by 4.5 log reduction fo BCR-ABL (17% vs 8%), transformation to AP/BP (2.3% vs 5%)
Nilotinib (Tasigna)
• Structural derivative of IM • 30-fold more potent inhibitor of BCR-ABL activity • Approved for treatment • Newly diagnosed CP-CML • CP-CML, AP-CML in resistant or intolerant to prior therapy • Not in blast crisis CML
ENESTnd (Evaluating Nilotinib Efficacy and Safety in Clinical Trials- Newly Diagnosed Patients)
• 300mg bid/400mg bid Nilotinib vs 400mg/d Imatinib • CCyR in 12 months 89%/78% vs 65% • Decrease time to progression to AP/BP • 36 mos F/U MMR 73%/70% vs 53% • Deeper molecular response 4 log reduction 50%/44% vs 26% • Rate to AP/BP 2 pts (0.7%)/3 pts (1.1%) vs 12 pts (4.2%) • Estimated 3-yr OS not statistically sig. (95%/97% vs 94%)
Bosutinib • Dual Src/Abl kinase inhibitor • FDA approved for CP, AP, BP who resistant or intolerant to IM • Dose 500 mg/d • Study: 546 pts (73% IM resistant, 27% IM intolerant) • Endpoint: MCyR at week 24 for CP, confirm CHR % OHR by week 48 for AP/BP) • CP-CML, MCyR at wk 24: 33.8% (prior receive IM); 26.9% (prior receive IM followed by Nilo/Dasa) • AP/BP-CML, CHR at wk 48 (prior IM=30.4%), OHR 55.1% • BP-CML, 15% CHR, 28.3% OHR by wk 48
Bosutinib
• Most common nonhematologic A/E • N/V, diarrhea, abdominal pain, rash, fever, fatigue
• Approved for treatment • Not approve in frontline CP-CML (no diff in rate of CCyR at 12 mo; phase III BELA trial) • Bosutinib faster time to CCyR & MMR compare with IM • Fewer on treatment transformation to AP/BP • Associated with GI & liver-related S/E
T315I mutation • Investigational agents • Allogeneic SCT • IFN therapy • Ponatinib (third gen TKI) , oral pan-BCR-ABL inhibitor with potent activity against native enzyme and all tested resistant mutation – Phase 2 PACE trial, refractory CP/AP/BP or Ph+ ALL resistant or intolerant to dasatinib/nilotinib/T315I mutation – Ponatinib 45 mg oral OD, total of 88% of pt resistance to dasatinib/nilotinib – CP-CML 42% MCyR, CP & T315I mutation MCyR 57% – AP-CML, MCyR 74% – BP-CML or ALL MCyR 37%, T315I mutation 27% major HR
Most frequent AEs with TKIs and their management
Jabbour E, Deininger M, Hochhaus A. Management of adverse events associated with tyrosine kinase inhibitors in the treatment of chronic myeloid leukemia. Leukemia. 2011;25:201-210
Discontinuation of TKIs • Continuation VS discontinuation • Ross et al. (2008)
• 67% of CML pt (n=18) sustained CMR 12 mo after discontinuation, median F/U 7 mo
• STIM (prospective, multicenter nonrandomized study called Stop IM) • Stop in pt (previous treat with IM >2yr, ≥18yrs, and achieved CMR defined as > 5 log reduction in BCR-ABL and ABL level, undetectable transcripts by quantitative RT-PCR)
Discontinuation of TKIs
• Median F/U 17 mo, 69 pt had at least 12 mo F/U (median 24 mo), 39% CMR, 58% relapse within 6 mo after stop IM • All patient had molecular relapse, responded when retreat with IM • Prognostic factor predictive of maintenance of CMR after IM discontinuation include low Sokal risk, longer duration of IM therapy (≥50 mo) and male sex • Suggest: may be possible to stop IM but only in pt with sustained CMR at least 2 yr, high risk of relapse usually in first 6 mo after stop
Stem cell transplantation
• Allogeneic transplantation – Fail TKIs –Option first line in children and younger adults (early CP; MRD, 5 yr DFS 60- 85%, relapse 5-15%)
***curative in AP/BP, lower survival from high relapse rate & other complication related advance dz § Acute GVHD 8%-63%, conditioning regimen: Blu/Cy § Advanced stage CML: PB SCT show lower relapse rate & longer DFS compare with BM SCT
GVL effect and RIC
• CML: highly susceptible GVL • Lower relapse rate of leukemia in MUD compare with MRD (minor Ag disparity enhance GVL effect) • Higher relapse rate in T-cell-depleted stem cells compare with unmanipulated stem cells (donor graft immune function is important in clearing residual dz) • DLI for relapse dz after SCT induce remission 54-93% in early hematologic or cytogenetic relapse • Non MA>>>response, decrease TRM • IM after RIC: explore?? Cannot tolerate
MA because of age or comorbidity
Therapy for advanced disease
Imatinib in advanced disease
• Respond to aggressive induction-type CMT (25-30%) or IFNα (40% CHR rate) • Transient response >>>>rapid progression to blast crisis • IM superior to other treatment • Published phase II, OHRs 80% in AP (CHR, MCyR, CCyR: 53%, 24%, 17%) • OS & disease progression rate at 12 mo 78% & 44% (on IM 600 mg/d)
Imatinib in advanced disease
• Blast crisis: transiently control by IM • Both Lymphoid & myeloid phenotype respond with dose 600 mg/d for AP • OHRs in 50% of study subjects • 8-21% CHRs, 30% stable or sustained hematologic responses (lasting 4 wk) • MCyRs 16%, CCyRs 7% • Median OS for pt achieved sustained hematologic response 19 mo
Second-gen TKIs in advanced disease
• Dasatinib & nilotinib in AP or blast crisis CML resistant or intolerant to IM • Induce rapid & durable response • Dasatinib 70 mg bid (CHR 45%, MCyR 39%, CCyR 32%) in AP, 12 mo PFS & OS 66% & 82% • Nilotinib 400 mg bid, CHR 30%, MCyR 32%, CCyR 19%, 12 mo OS 82% • Dasatinib appear more activity in MBP/LBP than nilotinib • >>>>consider AlloSCT after HR from second TKI
Allogeneic transplantation • MA AlloSCT cure 40% in adult AP CML • Salvage rate of pt who receive transplantation in blast crisis is dismal
• If delay transplantation>>>induction tx or TKIs to second CP- CML (may improve success SCT, 20-40% long term DFS after transplantation)
• Induction CMT –MBP-CML: achieve second CP 20-30% – LBP-CML: achieve second CP 40-60% If no further therapy after second CP >>>>second blast crisis New study: induction CMT + TKI >>> increase response in Blast crisis (phase II & III not available)
Course and prognosis
Chronic phase
• After diagnosis>>>disease stable 3-5 yr before progress to AP/BP • Rate of transformation to BP 5-10% /yr during first 2 yr after diagnosis, increase to 25% per year thereafter • Before TKIs era with no SCT: survival 5-7 yr, 30% of pt survived beyond 10 yr • Sokal score/Hasford score: predict probability of achieving cytogenetic remission in pt on IM & second TKIs • CCyR rate 70-90%, 5-yr PFS 80%, OS 95%
Monitoring ELN 2009
CML CP treatment milestones: a comparison of the NCCN (2013) & ELN (2009) recommendations
ASH-hematology 2013
OS & PFS on first-line imatinib or dasatinib therapy
Updated outcomes of Southwest Oncology Group Study S0325 (NCT00070499): “Imatinib Mesylate or Dasatinib in Treating Patients with Chronic Phase Chronic Myelogenous Leukemia” (courtesy of SWOG Statistical Center). The 3-year OS is 97% and 97% for dasatinib and imatinib, respectively; 3-year PFS is 93% and 91% for dasatinib and imatinib, respectively. Hematology, 2013
Recommendations for monitoring individual ELN 2009
Monitoring ELN, NCCN
4.leukemia: an update of concepts and management recommendations of European LeukemiaNet. J Clin Oncol. 2009;27:6041-6051. 5. NCCN Clinical Practice Guidelines in Oncology. Chronic Myelogenous Leukemia. Version 2.2012. http://www.nccn.org/professionals/physician_gls/f_guidelines.asp#site. Accessed September 19, 2011.
Recommended testing for disease monitoring adapted from NCCN (2013) and ELN (2009 & 2013)
ASH-hematology 2013
Additional clonal cytogenetic aberrations (ACAs)
• Major-route ACAs: frequent abnormalities in Ph+ cells (trisomy 8, second Ph, isochrome 17q, or trisomy 19) associated with poorer PFS and OS compare without ACAs or minor ACAs1
• Variant translocations or deletion of derivative chromosome 9 (der 9q del) not affect cytogenetic or molecular response or outcome on IM or DAS or NIL2-4
1.Fabarius A, Leitner A, Hochhaus A, et al. Impact of additional cytogenetic aberrations at diagnosis on prognosis of CML: long-term observation of 1151 patients from the randomized CML Study IV. Blood. 2011;118(26):6760-6768 2.Fabarius A, Leitner A, Hochhaus A, et al. Impact of additional cytogenetic aberrations at diagnosis on prognosis of CML: long-term observation of 1151 patients from the randomized CML Study IV. Blood. 2011;118(26):6760-6768 3.Castagnetti F, Testoni N, Luatti S, et al. Deletions of the derivative chromosome 9 do not influence the response and the outcome of chronic myeloid leukemia in early chronic phase treated with imatinib mesylate: GIMEMA CML Working Party analysis. J Clin Oncol. 2010;28(16):2748-2754. 4. Castagnetti F, Testoni N, Luatti S, et al. Deletions of the derivative chromosome 9 do not influence the response and the outcome of chronic myeloid leukemia in early chronic phase treated with imatinib mesylate: GIMEMA CML Working Party analysis. J Clin Oncol. 2010;28(16):2748-2754.
Accelerated phase
• Median survival from onset of AP, without SCT or TKIs only 12-18 mo • Death cause: transformation to BP
Blast-phase CML (leukemic progression)
• May develop suddenly without intervening AP, in 1/4 of CP • Sudden transformation from CP
• On IFNα > 5% of pt • On IM annual rate 1-2%
• MBP >50%, LBP 1/3, undifferentiated acute leukemia (both lymphoid & myeloid) • p210BCR-ABL most case, p190BCR-ABL rare case • Cytogenetic additional to t(9;22) 65-80% • OS 3-6 mo for older pt, 8 mo for younger pt, LBP survive 4-5 mo longer than MBP • Death cause: metabolic derangement, infection, bleeding, end-organ extramedullary leukemic infiltration
Proposed treatment monitoring strategy
Figure modified with permission from Coveler and Oehler. Chronic myeloid leukemia. In: Estey E, Appelbaum F, eds. Leukemia and related disorders. New York, NY: Springer; 2012:97-147.
• *Failure and warning signs (or suboptimal response) are defined. • **Choice will be influenced by the type of warning sign. For example,
– No change may be appropriate for a patient with CCyR and declining BCR-ABL1 transcript level but no MMR at 18 months, whereas the absence of CCyR at 12 months may warrant consideration for switching to an alternative TKI (after assessing for ABL tyrosine kinase domain point mutations).
– The presence of a resistance-conferring mutation warrants a change in treatment strategy.
• †For CP patients who develop a T315I mutation on first-line therapy but who have no evidence of additional cytogenetic aberrations or other features of progression, I typically first switch to ponatinib and follow closely to determine the need to proceed to allogeneic transplantation.
• ‡Monitoring on second-line therapy (nilotinib, dasatinib, bosutinib, or ponatinib)is similar to monitoring on first-line therapy.