The speaker has no financial relationships with a commercial interest to disclose and no conflicts of interest to resolve.

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1 Hana Safah MD Professor of Medicine Tulane University School of Medicine Director of the SCT program, Tulane Medical Center The speaker has no financial relationships with a commercial interest to disclose and no conflicts of interest to resolve. 1

2 Overview of CML Epidemiology Diagnosis Treatment options Managing patients under therapy Epidemiology of CML 15% of adult leukemia About 5,920 new cases estimated in deaths in per 100,000 Median age is 67 years No clear genetic or environmental risk factors; there may be an increased risk with radiation exposure Fatal until 1980s 2

3 Clues to the diagnosis of CML Unexplained & persistent leukocytosis Unexplained thrombocytosis 30-50% Leukocyte alkaline phosphatase decreased Vitamin B12 increased Increased uric acid & LDH 3

4 Bone marrow biopsy Hyper cellular marrow, 75-90% Myeloid to erythroid ratio 10-30:1 WBC maturation stages present with myeloid predominance Megakaryocytes increased and may be dysplastic Fibrosis may be seen with disease progression The Philadelphia chromosome Chromosome translocation t(9;22)(q34;q11) BCR-ABL: fusion between BCR gene on chr 22 and ABL gene on chr 9 (p210 protein with deregulated tyrosine kinase activity in CML, p190 in ALL) 95% of CML patients have the Ph chromosome by Karyotype or FISH 30-40% of the 5% negative for Ph chr, are positive by PCR for BCR-ABL gene 4

5 Philadelphia chromosome BCR-ABL: 1. ABL protein becomes constitutively active as a protein tyrosine kinase enzyme 2. DNA protein binding activity of ABL is attenuated 3. The binding of ABL to the cytoskeletal actin microfilament is enhanced which increases proliferation, affects differentiation, and blocks apoptosis Hence the potential of tyrosine kinase inhibitor therapy 5

6 Phases of CML Chronic Phase 25-60% are asymptomatic Fatigue Left upper quadrant pain/mass Weight loss Splenomegaly in 30-70% Hyper viscosity: visual or mental status changes and priapism Median survival of untreated patients: years Accelerated phase 10-19% blasts, PB or BM Platelets <100 x10 9 /L (not related to therapy) 20% basophils in peripheral blood Clonal evolution Increasing in spleen size and increase in WBC count unresponsive to therapy 6

7 Blast phase 20% blasts in bone marrow, peripheral blood or both Extramedullary infiltrates with leukemic cells OS 3-6 months 70% have myeloid phenotype (25% have lymphoid phenotype and 5% are undifferentiated). Prognostic factors Age Spleen size WBC Platelet count Blast, eosinophil, basophil % in peripheral blood Deletion of chromosome 9, which is seen in 10-15%, is associated with a worse prognosis 7

8 Prognostic groups low, intermediate, high: Sokol score: age in years, spleen size, platelet count, blast cells. More commonly used especially in imatinib trials. Hasford score: age, spleen size, platelet count, blasts, basophils, eosinophil count Can calculate at Both predict the probability of response to tyrosine kinase inhibitors Trends in cancer treatment: 16 8

9 Historical Treatment Hydroxyurea : to control the WBC count. Interferon alpha: 70-80% may achieve a complete hematologic response % have cytogenetic response Interferon + Cytarabine: showed higher response than IFN alone Imatinib (Gleevec) Dasatinib (Sprycel) Nilotinib (Tasigna) Bosutinib (Bosulif) Ponatinib ( Iclusig) Other Omacetaxin ( Synribo) Allogeneic Stem Cell transplantation 9

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11 CML 11

12 Imatinib Selective inhibitor of BCR-ABL tyrosine kinase Also inhibits PDGF-R (platelet derived growth factor receptor) & ckit Effective in all phases of CML Oral therapy, 400 mg/day in chronic phase, 600 mg/day in blast crisis & accelerated phases Approved by FDA 12/2002 for 1 st line treatment of CML based on IRIS Imatinib IRIS trial NEJM 2003: Randomized imatinib vs. IFN + cytarabine in chronic CML Imatinib was associated with lower toxicity and better quality of life 19 month CCyR 73.8 vs. 8.5% favoring Imatinib Only 7% of patients progressed to accelerated or blast crisis Overall survival 89% at 60 months 12

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14 Imatinib toxicity Nausea Peripheral/ peri-orbital edema Diarrhea Rash Fatigue Muscle cramps Myelosuppresion: neutropenia in 45%, thrombocytopenia in 25%, anemia 10% CHF: 1.7% Imatinib failure Primary resistance, failure to achieve hematologic remission at 3 months 15-25% may have cytogenetic resistance (no cytogenetic response at 6 months, or major cytogenetic response at 12 months or complete cytogenetic response at 18 months) 40-60% is due to mutation of ABL T3151 is the most resistant mutation 14

15 Treatment of Imatinib failure Increase dose up to 800 mg QD More effective in those who had previously achieved cytogenetic response with prior standard dose Second generation TKI Dasatinib 2 nd generation BCR-ABL kinase inhibitor 325 x more potent than imatinib, dual inhibitor of ABL and SRC family of kinases, active against the active and inactive conformation of the ABL gene active against all mutations in vitro except the T315I FDA approved it in October 2010 as first line therapy, chronic phase CML Chronic phase: 100 mg daily. AP and BC: 140 mg daily 15

16 Dasatinib START C trial: Chronic phase, imatinib resistant or intolerant, at 24 month follow up: 91% CHR, 53% CCyR, 47% MMR. OS 94%, START- A trial: Accelerated phase, imatinib resistant or intolerant patients, 12 PFS 66%, OS 82% START B trial: CML in blast crisis. PFS 6.7 months, OS 11.8 months Naïve CML Patients: 519 patients randomized to dasatinib 100 mg vs. imatinib 400 mg PO daily, at 12 months, CCyR dasatinib 77% vs. Imatinib 66% (P=0.001) Adverse effects of dasatinib Reversible inhibition of platelet aggregation Pleural effusions (29% of chronic CML, 50% of accelerated CML, 33% with blast phase CML) Prior cardiac history or HTN are risk factors for pleural effusion, also 70 mg BID dosing Lymphocytosis with clonal expansion of NK/T cells 16

17 Nilotinib Selective inhibitor of BCR-ABL tyrosine kinase x more potent than imatinib resistant cell lines, 3-7 x more potent in sensitive lines FDA approved October 2007 (400 mg BID) for chronic & accelerated CML resistant or intolerant to imatinib FDA approved June 2010 (300 mg BID) for newly diagnosed chronic CML Nilotinib phase III multicenter study compared nilotinib 300 mg or 400 mg BID vs. imatinib 400 mg QD in newly diagnosed chronic CML MMR 43% at 300 mg vs. 43% at 400 mg for nilotinib vs. 22% for imatinib at 12 months CCyR 80% 300 mg vs. 78% 400 mg for Nilotinib vs. 65% for imatinib at 12 months Patients with high Sokal risk, the MMR rate at 3 years was 67% for nilotinib vs. 39% for imatinib with a lower progression rate 17

18 Nilotinib Phase II study in blast phase CML showed responses, but they were not durable If used in the 2 nd line setting, performance status & prior cytogenetic response to imatinib are associated with a better prognosis on 2 nd generations TKIs 18

19 Nilotinib toxicity QT prolongation & sudden cardiac death: a black box warning. Monitor EKG, avoid other drugs that prolong QT, replace electrolyte abnormalities prior to start Rare fluid retention, edema, muscle cramps Neutropenia, thrombocytopenia grade 3-4 in 29% Asymptomatic increase in lipase, bilirubin, glucose, hypophosphatemia Peripheral arterial occlusive disease (PAOD) Bosutinib Dual ABL/SRC Kinases Active against mutations that are resistant to imatinib, dasatinib, and nilotinib except for T315I and minimal inhibition of KIT and PDGFR Not recommended as first line therapy As second line of therapy in resistant/ intolerant CP-CML: CHR 86%, MCyR 53%, CCyR 41% at 24 months Effective in AP-CML and BP-CML Approved for all phases of CML, resistant or intolerant to prior TKI. QTc prolongation, diarrhea, otherwise well tolerated. 19

20 Ponatinib Multi-targeted Kinase inhibitor Active against many kinase domain mutations including T315I CCyR, in patient intolerant/ resistant in CP-CML were 46%, AP-CML 50% and 30% in BP-CML, response rate was higher in the T315I patients Approved for all phases of CML, resistant or intolerant to prior TKI. Arterial thrombosis, PE, MI, hepatotoxicity, pancreatitis Test Recommendation Bone marrow cytogenetics 2 At diagnosis to establish the disease phase. If collection of bone marrow is not feasible, FISH on peripheral blood specimen using dual probes for the BCR and ABL genes is an acceptable method of confirming the diagnosis of CML. At 3 months from initation of therapy, if QPCR using IS is not available At 12 months from initation of therapy, if there is no CCyR or MMR. At 18 months form initiation of therapy, if not in MMR and lack of CCyR at 12 months Rising levels of BCR-ABL transcript (1-log increase) without a MMR. Quantitative RT-PCR (QPCR) At diagnosis. Every 3 months when a patient is responding to treatment. After CCyR has been achieved, every 3 months for 3 years and every 3-6 months thereafter. If there is a rising level of BCR-ABL transcript (1-log increase) with a MMR, QPCR analysis should be repeated in 1-3 months. BCR-ABL kinase domain mutation analysis Chronic phase inadequate initial response (failure to achieve PCyR or BCR- ABL/ABL 10% (IS) at 3 months or CCyR at 12 and 18 months). Any sign of loss of response ( Hematologic or cytogenetic relapse) Disease progression to accelerated or blast phase. Version 1, 2014, 09/09/13 NCCN, Network, Inc. 20

21 Follow-up Response Treatment Recommendations FCR-ABL/ABL 10% (IS) or PCyR Continue the same dose of TKI 3 months BCR-ABL/ABL 10% (IS) or less than PCyR 1,2 Switch to alternate TKI 3 Evaluate for allogeneic HSCT depending on response to TKI therapy. CCyR Continue the same dose of TKI PCyR1 Switch to alternate TKI (preferred)3 Continue same dose of TKI Dose escalation of imatinib to maximum of 800 mg, as tolerated (if not a candidate for dasatinib, nilotinib, bosutinib, ponatinib or omacetaxine) 12 months Minor or no cytogenetic response 1-2 Switch to alternate TKI (preferred)3 Evaluate for allogeneic HSCT depending on response to TKI therapy Cytogenetic relapse 1-2 Switch to alternate TKI (preferred)3 Dose escalation of imatinib to a maximum of 800 mg, as tolerated (if not a candidate for dasatinib, nilotinib, bosutinib, ponatinib or omacetaxine) Evaluate for allogeneic HSCT depending on response to TKI therapy CCyR Continue the same dose of TKI 18 months PCyR or cytogenetic relapse 1-2 Switch to alternate TKI Evaluate for allogeneic HSCT depending on response to TKI therapy Version 1, 2014, 09/09/13 NCCN, Network, Inc Treatment Options Based on BCR-ABL Kinase Domain Mutation Status Mutation Treatment Options T3151 Ponatinib (preferred) or omacetaxine, HSCT or clinical trial V299L Consider ponatinib, nilotinib or omacetacine 4 T315A Consider ponatinib, nilotinib, imatinib 5, bosutinib, or omacetaxine 4 F317L/V/I/C Consider ponatinib, nilotinib, bosutinib or omacetaxine 4 Y253H, E255K/V, F359V/C/I Any other mutation Consider ponatinib, dasatinib, bosutinib or omacetaxine 4 Consider ponatinib, high-dose imatinib 6, dasatinib, nilotinib, bosutinib or omacetaxine 4 21

22 NCCN guidelines key points Imatinib, nilotinib, dasatinib are all category 1 recommendations for 1 st line treatment in chronic phase 2 nd generation TKIs may be better for intermediate or high risk patients If patient has failed 1 st line treatment with a 2 nd generation TKI, use the alternate 2 nd generation TKI as opposed to imatinib Patients with T3151 mutations should be considered for clinical trials or stem cell transplant 22

23 Allogeneic Stem Cell Transplantation Potentially curative More successful in first chronic phase as opposed to accelerated, blast phase ; 5-yr OS 75%,40%, 10% Faithfull monitoring of disease not to miss the chronic phase window. GVHD is the major morbidity 100 Probability of Survival after HLA-identical Sibling Donor Transplants for CML, By Disease Status and Transplant Year Probability of Survival, % AP, (N=333) AP, (N=300) CP, (N=2,524) CP, (N=2,291) P < Years 10 0 Slide 30 SUM-WW11_29.ppt 23

24 Indications for allogeneic SCT Not a 1 st line therapy of chronic CML due to excellent results with TKIs Appropriate for patient with T315I mutations and other BCR-ABL mutations that are resistant to all TKIs Disease progression to accelerated phase and blast phase, de novo or on TKI therapy ( use alternate TKI as a bridge to SCT) Intolerant to all TKIs 2-yr OS : 44% ( T315I) vs. 76% (TKI intolerance with out the mutation) 24

25 BCR-ABL positivity post transplant Timing of testing is important: if positive 6-12 months post transplant, there is a high rate of relapse (42% if positive vs. 3% PCR negative), 8% if positive > 36 months But late PCR + may have lower risk of relapse (14 %) Study of 379 patients with CML alive at >18 months post transplant showed 90 (24%) had at least 1 positive BCR- ABL (Radich et al) TKIs and allogeneic SCT Imatinib has shown a complete hematologic response in >70% with cytogenetic response in 58% after failure of BMT Imatinib probably not helpful if patients failed it prior to transplant 25

26 TKIs and allogeneic SCT Consider dasatinib or nilotinib if imatinib used prior to transplant TKIs may be used as maintenance for 1 yr post transplant for CML in Accelerated phase/blast phase to prevent relapse Donor lymphocyte infusion (DLI) Induces durable molecular remission More helpful in chronic phase vs. advanced phases Disease free survival appears higher with donor lymphocyte infusion vs. imatinib, but needs to be confirmed in randomized clinical trials Risk of graft vs. host disease and aplasia 26

27 Causes of Death after Transplants performed in HLA-identical Sibling Primary Disease (47%) New Malignancy (1%) GVHD (14%) Primary Disease (33%) Unrelated Donor New Malignancy (1%) GVHD (15%) Infection (12%) Organ Failure (4%) Other (21%) Primary Disease (73%) Autologous New Malignancy (1%) Other (29%) Organ Failure (6%) Infection (16%) Infection (8%) Organ Failure (2%) Other (16%) Slide 18 SUM-WW11_17.ppt Mortality, % day Mortality after Unrelated Donor Transplants, Early Disease Intermediate Disease Advanced Disease Chronic Phase Accelerated Phase Blast Phase Other 20 0 AML ALL CML MDS/MPS Aplastic Anemia Immune Deficiency Slide 17 SUM-WW11_16.ppt 27

28 Mortality, % day Mortality after HLA-identical Sibling Transplants, Early Disease Intermediate Disease Advanced Disease Chronic Phase Accelerated Phase Blast Phase Other 20 0 AML ALL CML MDS/MPS Aplastic Anemia Immune Deficiency Slide 16 SUM-WW11_15.ppt Infectious complication 28

29 Marrow and Blood Transplantation Complications: GVHD Acute GVHD become apparent in the first few weeks following transplantation -Affects 10% - 80% of allogeneic transplant recipients -Graded from I-IV according to number of organs involved Chronic GVHD become apparent at 100 to 400 days post transplant -Affect 30% - 50% of allogeneic transplant recipients -Classified as limited or extensive organ involvement Djubegovic B, et al.cancer Contol.2003 ASH Education Book, Jan 1,

30 Guidelines for screening for common cancers after SCT Site Breast Screening recommendations Mammogram annually starting at age 40 ; begin at age 25 or 8 years after radiation, which ever occurs later, in women who have received 20 Gy to the chest region Cervix PAP smear every year (for regular PAP test) or every 2 years (for liquid-based PAP test); after age 30, if patient has had 3 consecutive normal tests, may screen every 2-3 years Colorectal Beginning at age 50, fecal occult blood annually and/or flexible sigmoidoscopy every 5 years, or double contrast barium enema every 5 years, or colonoscopy every 10 years; certain high-risk groups (e.g., patients with inflammatory bowel disease) may need earlier initiation and more frequent screening Lung Oral Thyroid Skin Yearly pulmonary exam with imaging as appropriate Yearly oral cavity exam Yearly thyroid exam Skin exam as a part of periodic health exam *Adapted from Children s Oncology Group 25 and EBMT/CIBMTR/ASBMT Guidelines 42 Similar to American Cancer Society recommendations for general population cancer screening 30

31 Solid Cancers 3-5 years, increases with time Incidence at 5, 10, and 15yrs is 0.7%, 2.2%, and 6.7% compared to 0.3%, 0.6% and 0.8% in general population Risk Factor Young age, TBI, cgvhd (severity and >24 months use of immunosuppression) TBI solid cancers (Breast 17% in 25 yrs, thyroid, melanoma) cgvhd: cancer of the bucal mucosa, squamous cell cancer PTLD Incidence 1-2%, 80% within the 1 st year Arises in donor cells Early benign, polymorphic, monomorphic PTLD and Hodgkin s Lymphoma PTLD Risk Factors: EBV, T-Cell depletion, ATG, a GVHD, Graft from mismatched unrelated donor, cgvhd (>1yr) Follow copies of EBV, >1000 preemptive Rituximab 50-80% Response with Rituximab Multiple extra nodal disease and late onset, R-CHOP 31

32 MDS/AML 5-15% in Autologous SCT, 2-5 years (11q23, 5q and 7q) Risk factors, alkylating agents, TBI in conditioning regimen <1% post allo PBSCT Lingering Questions Are tyrosine kinase inhibitors better than allogeneic stem cell transplant in terms of survival? Will 2 nd generation TKIs have an improved survival benefit compared to imatinib? Cost of therapy vs. cancer survival? 32

33 Nowell & Hungerford (photo from Penn Medicine) 33