CASE PRESENTATION

• A 27 year old male with no significant past medical history presents to you with a 4 day history of sore throat, cough, rhinorrhea, greenish thick expectoration and subjective low grade fevers. He works in a health care industry. Recent travel history to North East USA. His symptoms started in the airport during return. After return he did two night shifts and due to worsening symptoms on 3rd day he has to exchange his admit shift and decided to come to you for antibiotics. He has diffuse body aches, malaise and frontal & temporal headaches. He used antihistamines and mucinex for two days with no relief.

TARGETED CANCER THERAPY THE ADVENT OF A NEW GENERATION OF CHEMOTHERAPY BEGINNING WITH IMATINIB

FOR CML.

-Rahul Ravilla

PGY3 Internal medicine

TARGETED THERAPY

• Targeted cancer therapies are drugs or other substances that block the growth and spread of cancer by interfering with specific molecules ("molecular targets") that are involved in the growth, progression, and spread of cancer.

HOW ARE THEY DIFFERENT FROM STANDARD CHEMOTHERAPY

• Targeted therapies act on specific molecular targets that are associated with cancer, whereas most standard chemotherapies act on all rapidly dividing normal and cancerous cells.

• Targeted therapies are deliberately chosen or designed to interact with their target, whereas many standard chemotherapies were identified because they kill cells.

• Targeted therapies are often cytostatic (that is, they block tumor cell proliferation), whereas standard chemotherapy agents are cytotoxic (that is, they kill tumor cells).

TYPES OF TARGETED THERAPY

• Hormone therapies eg. Flutamide, Bicalutamide, Tamoxifen, Exemastane

• Signal transduction inhibitors eg. Imatinib, Sunitinib, Transtuzumab.

• Gene expression modulators

• Apoptosis inducers eg. Bortezomib

• Angiogenesis inhibitors eg. Bevacizumab

• Immunotherapies eg. Ipilimumab

• Monoclonal antibodies that deliver toxic molecules eg. Transtuzumab emtansine, Brentuximab vedotin

COMMON NOMENCLATURE

• ib – Synthetic inhibitor- Imatinib, Crizotinib

• umab- Human monoclonal antibody- Ipilimumab, Adalimumab (Humira)

• zumab- Humanized- Bevacizumab, Transtuzumab

• ximab- Chimeric- Rituximab, Infliximab

• monab- Murine- Muromonab, Tositumomab

Mechanisms of Activation of Normal TKs.

Krause DS, Van Etten RA. N Engl J Med 2005;353:172-187.

Mechanisms of TK Dysregulation and Therapeutic Targeting in Cancer.

Krause DS, Van Etten RA. N Engl J Med 2005;353:172-187.

• Adenocarcinoma of the stomach or gastroesophageal junction: Trastuzumab (Herceptin®)

• Basal cell carcinoma: Vismodegib (Erivedge™)

• Brain cancer: Bevacizumab (Avastin®), Everolimus (Afinitor®)

• Breast cancer: Everolimus (Afinitor®), tamoxifen, toremifene (Fareston®), Trastuzumab (Herceptin®), fulvestrant (Faslodex®), anastrozole (Arimidex®), exemestane (Aromasin®), lapatinib (Tykerb®), letrozole (Femara®), pertuzumab (Perjeta™), ado-trastuzumab emtansine (Kadcyla™)

• Colorectal cancer: Cetuximab (Erbitux®), Panitumumab (Vectibix®), Bevacizumab (Avastin®), Ziv-aflibercept (Zaltrap®), Regorafenib (Stivarga®)

• Dermatofibrosarcoma protuberans: Imatinib mesylate (Gleevec®)

• Head and neck cancer: Cetuximab (Erbitux®)

• Gastrointestinal stromal tumor: Imatinib mesylate (Gleevec®), Sunitinib (Sutent®), Regorafenib (Stivarga®)

• Giant cell tumor of the bone: Denosumab (Xgeva®)

• Kaposi sarcoma: Alitretinoin (Panretin®)

• Kidney cancer: Bevacizumab (Avastin®), Sorafenib (Nexavar®), Sunitinib (Sutent®), Pazopanib (Votrient®), Temsirolimus (Torisel®), Everolimus (Afinitor®), Axitinib (Inlyta®)

• Leukemia: Tretinoin (Vesanoid®), Imatinib mesylate (Gleevec®), Dasatinib (Sprycel®), Nilotinib (Tasigna®), Bosutinib (Bosulif®), Rituximab (Rituxan®), Alemtuzumab (Campath®), Ofatumumab (Arzerra®), Obinutuzumab (Gazyva™), Ibrutinib (Imbruvica™), Idelalisib (Zydelig®)

• Liver cancer: Sorafenib (Nexavar®)

• Lung cancer: Bevacizumab (Avastin®), Crizotinib (Xalkori®), Erlotinib (Tarceva®), Gefitinib (Iressa®), Afatinib dimaleate (Gilotrif®), Ceritinib (LDK378/Zykadia)

• Lymphoma: Tositumomab and 131I-tositumomab (Bexxar®), Ibritumomab tiuxetan (Zevalin®), Denileukin diftitox (Ontak®), Brentuximab vedotin (Adcetris®), Rituximab (Rituxan®), Vorinostat (Zolinza®), Romidepsin (Istodax®), Bexarotene (Targretin®), Bortezomib (Velcade®), Pralatrexate (Folotyn®), Lenaliomide (Revlimid®), Ibrutinib (Imbruvica™), Siltuximab (Sylvant™), Idelalisib (Zydelig®), Belinostat (Beleodaq™)

• Melanoma: Ipilimumab (Yervoy®), Vemurafenib (Zelboraf®), Trametinib (Mekinist®), Dabrafenib (Tafinlar®)

• Multiple myeloma: Bortezomib (Velcade®), Carfilzomib (Kyprolis®), Lenaliomide (Revlimid®), Pomalidomide (Pomalyst®)

• Myelodysplastic/myeloproliferative disorders: Imatinib mesylate (Gleevec®)

• Pancreatic cancer: Erlotinib (Tarceva®), Everolimus (Afinitor®), Sunitinib (Sutent®)

• Prostate cancer: Cabazitaxel (Jevtana®), Enzalutamide (Xtandi®), Abiraterone acetate (Zytiga®), Radium 223 chloride (Xofigo®)

• Soft tissue sarcoma: Pazopanib (Votrient®)

• Stomach cancer: Ramucirumab (Cyramza™)

• Systemic mastocytosis: Imatinib mesylate (Gleevec®)

• Thyroid cancer: Cabozantinib (Cometriq™), Vandetanib (Caprelsa®), Sorafenib (Nexavar®)

CHRONIC MYELOID LEUKEMIA

• Chronic myeloid leukemia (also known as chronic myelocytic, chronic myelogenous, or chronic granulocytic leukemia) is a myeloproliferative neoplasm characterized by the dysregulated production and uncontrolled proliferation of mature and maturing granulocytes with fairly normal differentiation.

• Results from fusion of two genes: BCR (Break Point Cluster Region on chromosome 22) and ABL1 (Abelson murine leukemia viral oncogene homolog on chromosome 9) resulting in the BCR-ABL1 fusion gene.

• Reciprocal translocation between chromosomes 9 and 22, t(9;22)(q34;q11), that gives rise to an abnormal chromosome 22 called the Philadelphia (Ph) chromosome.

STATISTICS

• American Cancer Society's estimates for chronic myeloid leukemia (CML) in the United States for 2014 are:

• About 5,980 new cases will be diagnosed with CML (3,130 in men and 2,850 in women).

• About 810 people will die of CML (550 men and 260 women).

• Uptodate- Incidence of 1-2 cases per 100000.

• Median Age- 50 years in most clinical studies but in reality is thought to be 60-65 years.

• Male > Female- 1.3:1

• Caucasian > African American

PRESENTATION

• Asymptomatic in up to 50% of the cases- Incidental finding on routine blood tests.

• Fatigue, Malaise, weight loss, excessive sweating, Abdominal fullness, bleeding episode, abdominal pain and gouty arthritis.

• Clinical findings- Anemia, Leukocytosis, Thrombocytosis, splenomegaly.

PERIPHERAL SMEAR

• Leukocytosis (median 100000/µl)

• Blasts <2%

• Absolute basophilia

• Absolute eosinophilia

• Myelocytes > Metamyelocytes

• Thromobocytosis (>600k/µl)

• Normocytic Normochromic Anemia

BONE MARROW

• Granulocyte hyperplasia hyperplasia

• Dwarf Megakaryocytes

• Reduced erythroid islands

• Percentage of blasts vary with stage of the disease.

GENETICS

RT-PCR for BCR-ABL mRNAWestern Blotting for BCR-ABL fusion protein

STAGING OF DISEASE

Chronic phase

    None of the criteria for accelerated or blastic phase

Accelerated phase

    Blasts ≥ 15% in blood or BM

    Blasts plus progranulocytes ≥ 30% in blood or BM

    Basophilia ≥ 20% in blood or BM

    Platelets < 100 × 109/L unrelated to therapy

    Cytogenetic clonal evolution

Blast phase

    ≥ 30% blasts in blood or BM

    Extramedullary disease with localized immature blasts

Clinical Course: Phases of CML

Chronic phase

Median 5–6 years

stabilization

Accelerated phase

Median duration6–9 months

Blast crisis

Median survival3–6 months

Advanced phases

MANAGEMENT OF CHRONIC PHASE

• Pre Imatinib era—

Hydoxyurea & Busulfan- cytoreduction & palliative care

IFNα and IFNα with Ara C (Cytarabine)

Allogenic Hematopoietic Cell Transplant- Curative treatment

• Current Management

Hydroxyurea for cytoreduction until diagnosis is confirmed

Either 1st generation TKI (Imatinib) or 2nd Generation TKI (Nilotinib,Dasatinib,Bosutinib).

MONITORING • COMPLETE HEMATOLOGIC RESPONSE

PLATELET COUNT < 450 x 109/L

WBCC < 10 x 109/L

DIFFERENTIAL WITHOUT IMMATURE GRANULOCYTES (MC,PMC,MB) AND WITH LESS THAN 5% BASOPHILS

NON-PALPABLE SPLEEN

CHECK EVERY 2 WEEKS UNTIL ACHIEVED AND CONFIRMED, THEN EVERY 3 MONTHS UNLESS OTHERWISE REQUIRED

• CYTOGENETIC RESPONSE

COMPLETE Ph+ 0

PARTIAL Ph+ 1-35%

MINOR Ph+ 36-65%

MINIMAL Ph+ 66-95%

NONE Ph+ >95%

CHECK EVERY 6 MONTHS UNTIL A CCgR HAS BEEN ACHIEVED AND CONFIRMED, THEN EVERY 12 MONTHS

• MOLECULAR RESPONSE

COMPLETE = BCR-ABL TRANSCRIPTS NON QUANTIFIABLE AND NON DETECTABLE

MAJOR = BCR-ABLIS≤ 0.10* C

EVERY 3 MONTHS

Adverse events ManagementNonhematologic adverse events    Nausea and vomiting Take imatinib with food; antiemetics if necessary

    Diarrhea Loperamide or diphenoxylate atropine

    Fluid retention

        Peripheral edema Diuretics as needed (usually furosemide)

        Periorbital edema Steroid-containing cream

        Pleural effusionObservation if minimal; when intervention is required, stop TKI, use diuretics, corticosteroids may help in occasional patients; resume TKI with dose reduction when the effusion has significantly improved; thoracentesis if effusion not resolving or large and symptomatic

    Skin rash Symptomatic therapy (eg, antihistamines); topical steroids; occasionally systemic steroids; minimize sun exposure

    Muscle cramps Tonic water or quinine; calcium gluconate may sometimes help; electrolyte replacement if needed (eg, potassium)

    Arthralgia, bone pain NSAID (should be used with caution if platelet dysfunction is suspected, eg, with dasatinib)

    Elevated transaminasesMonitor if grade 1 or 2; interrupt therapy if grade 3; restart a lower dose when recovered to grade ≤ 1; corticosteroids may help some patients if recurrent

    Elevated bilirubinMonitor if grade 1 or 2; interrupt therapy if grade 3; restart a lower dose when recovered to grade ≤ 1; elevation of bilirubin common with nilotinib, particularly among patients with Gilbert syndrome; in those instances, may allow continuation of therapy in some instances with grade 3

    Elevated lipase, amylase (asymptomatic)

Monitor if grade 1 or 2; interrupt therapy if grade 3; restart at lower dose when recovered to grade ≤ 1

    HyperglycemiaMore common with nilotinib; stop therapy if grade ≥ 3; restart therapy when recovered to grade ≤ 1 with reduced dose; no contraindication to use nilotinib in patients with diabetes mellitus; close monitoring and adjustment of hypoglycemic agents as needed

Hematologic adverse events

    NeutropeniaHold therapy if grade ≥ 4 (ie, ANC < 0.5 × 109/L);†restart at the same dose if recovery to ANC ≥ 0.75 × 109/L within 2 wks; restart at lower dose if recovery after 2 wks; consider filgrastim if recurrent/persistent, or sepsis72*

    ThrombocytopeniaHold therapy if platelets < 40 × 109/L†; restart at the same dose if recovery within 2 wks to ≥ 75 × 109/L; restart at lower dose if recovery after 2 wks; consider IL-11 10 μg/kg 3-7 d/wk73*

    AnemiaTreatment interruption/dose reduction usually not indicated; consider erythropoietin or darbepoetin74*; transfusions rarely needed

CHOICE OF TKI• Dasatinib preferred in a patient with a history of pancreatitis, elevated

bilirubin, or hyperglycemia, while nilotinib might be chosen for a patient with a history of pleural or pericardial disease or effusions.

• Dasatinib crosses the blood-brain barrier and would therefore be preferred in patients with central nervous system involvement at relapse.

• Since both dasatinib and nilotinib can result in QT prolongation, they should be avoided in patients with baseline QT prolongation that cannot be normalized. Bosutinib is not known to prolong the QT interval.

• The T315I mutation has shown resistance to all currently available TKIs with the exception of ponatinib (which has limited availability). Omacetaxine has also demonstrated activity in some patients with the T315I mutation.

• The Y253H, E255K/V, and F359V/C/I mutations are resistant to imatinib and nilotinib but sensitive to dasatinib.

• The F317L/V/I/C, V299L, and T315A mutations are sensitive to nilotinib but shows intermediate sensitivity to imatinib and dasatinib.

Mechanisms of Resistance to TK-Inhibitor Therapy.

Krause DS, Van Etten RA. N Engl J Med 2005;353:172-187.

HOW TO MANAGE ACCELERATED PHASE

• Four-year disease-free survival (DFS) rates after allogenic HCT are 30 to 40 percent in patients with accelerated phase versus up to 80 percent in patients with chronic phase disease.

• Initiate TKI (preferably 2nd gen or high dose imatinib) and once best response is achieved do a allogenic HCT

HOW TO MANAGE BLAST CRISIS

• Lymphoid crisis (30% cases)- B-cell phenotype ALL. Usually managed with TKI + Hyper-CVAD (vincristine, cyclophosphamide, doxorubicin, dexamethasone)

• Myeloid crisis (70% cases)- Initial treatment with TKI and AML induction therapy if no response.

• Allogenic HCT

HOW ARE THEY DOING• IRIS Trial at 18 months

Complete hematologic response – 97 versus 69 percent

Major cytogenetic response – 87 versus 35 percent [19]

Complete cytogenetic response – 76 versus 14 percent

Major molecular response (absence of BCR-ABL using polymerase chain reaction [PCR]) – 39 versus 2 percent

Progression-free survival – 97 versus 92 percent

Drug intolerance – <1 versus 25 percent

Improved preservation of quality of life.

• At 60 months

Patients receiving imatinib as initial therapy for chronic phase CML had overall and event-free survivals of 89 and 83 percent, respectively.

The annual rate of progression to accelerated phase or blast crisis was 0.6 percent in the fifth year of therapy, which was lower than that seen during the first four years of treatment (1.5, 2.8, 1.6, and 0.9 percent, respectively).

Efficacy and Safety of a Specific Inhibitor of the BCR-ABL Tyrosine Kinase in Chronic Myeloid Leukemia

by Druker et al. NEJM May 2001

Study design

Phase 1 dose escalation trial.

Primary end point- Safety and tolerability of STI571

Secondary end point- Anti-leukemic activity

83 patients divided into 14 cohorts.

Dose escalation permitted in next cohort if none of the 3 patients or only 1 of the 6 patients develop grade 3 or grade 4 non hematologic adverse effect after 28 days of therapy.

Doses range from 25mg to 1000mg per day.

Inclusion criteria

Patients with CML in the chronic phase (less than 15 percent blasts or basophils in the peripheral blood or bone marrow).

18 years of age or older,

Positive for the Ph chromosome

Treatment with interferon alfa had failed.

Treatment failure defined as lack of a complete hematologic response despite three months of treatment with a regimen containing interferon alfa (hematologic resistance), the lack of a cytogenetic response despite one year of treatment with a regimen containing interferon alfa (cytogenetic resistance), or a hematologic or cytogenetic relapse.

Patients with severe intolerance to interferon alfa were included after safety data had been obtained for the first seven cohorts of patients treated with STI571.

Exclusion criteria

Platelet count <100000

Performance status

Adequate Renal, cardiac and hepatic function required (no definitions)

Characteristics of the 83 Patients.

Druker BJ et al. N Engl J Med 2001;344:1031-1037.

Monitoring

Complete blood counts obtained twice a week for the first four weeks, once a week for the next four weeks, and then once every two weeks.

Assessments of bone marrow, including cytogenetic analyses, were performed after 8 weeks of therapy and then once every 12 weeks.

Toxicity was graded in accordance with the Common Toxicity Criteria of the National Cancer Institute.

Pharmacokinetics on day 1 and day 28

BCR-ABL Tyrosine Kinase inhibition before 1st dose and 2 hours after 2nd dose.

Outcomes

Pharmacokinetics

400mg daily dose achieved peak concentration of 2.3µg/ml (4.6µM) and a trough of 0.72µg/ml (1.46µM).

In-vitro concentration required to inhibit 50% of BCR-ABL is 0.25µM.

Half life is 13-16 hours

Safety

Only 2 patients (among those receiving >300mg) discontinued therapy- one due to angina and one due to rash.

No deaths

Drug-Related Adverse Events According to the Daily Dose of STI571.

Druker BJ et al. N Engl J Med 2001;344:1031-1037.

Hematologic Responses.

Druker BJ et al. N Engl J Med 2001;344:1031-1037.

Hematologic Responses in Six Patients Receiving 500 mg of STI571 per day.

Druker BJ et al. N Engl J Med 2001;344:1031-1037.

Patients with a Major Cytogenetic Response.

Druker BJ et al. N Engl J Med 2001;344:1031-1037.

Immunoblot Assays Demonstrating the Degree of Phosphorylation of the BCR-ABL Substrate CRKL in Individual Patients in the Groups Receiving Daily Doses of 25,

85, 140, 250, and 750 mg of STI571.

Druker BJ et al. N Engl J Med 2001;344:1031-1037.

conclusion

Half the patients getting doses ≤ 85mg daily dose were removed due to increasing cell counts after 2 months

Of the patients treated with daily doses of 300 mg or more, 53 of 54 had complete hematologic responses

Complete hematologic response was evident within four weeks after the initiation of treatment.

Complete hematologic responses have been maintained in 51 of 53 patients with a median follow-up of 265 days.

29 of the 54 patients treated with doses of 300 mg or more per day (54 percent) had major or minor cytogenetic responses.

Levels of the drug that killed CML cells in vitro correlated well with clinical response and serum drug levels in the 400-mg group.

Imatinib Mesylate: Steady-State Pharmacokinetics

Rapidly and completely absorbed after oral

administration

Absolute bioavailability 98%

Terminal half-life (t1/2) 18–22 h; volume of

distribution

435 L; and clearance 14 L/h

Linear and dose-proportional increase in AUC

with doses 25 mg to 1000 mg

PHASE 2 TRIALSCML-CP, IFN failure (n = 532)

CML-AP (n = 235)

CML-BC (n = 260)

Hematologic response

88% 63% 26%

 CHR 88% 28% 4%

 NEL NAd 11% 3%

 RTC NA 24% 19%

MCyR 49% 21% 13.5%

Complete (confirmed)

30% (16%) 14% (4%) 5% (1%)

NEL- No Evidence of Leukemia, RTC- Return to Chronic Phase.FDA approved the drug in May 2001 after reviewing the results in 72 days (Fastest ever)

Rates of Best Observed Hematologic and Cytogenetic Responses in IRIS trail (Phase 3 study comparing Imatinib with Interferon and Low-Dose Cytarabine for Newly Diagnosed Chronic-

Phase Chronic Myeloid Leukemia with follow up period of 5.5 years)

O'Brien, S. et al. N Engl J Med 2003;348:994-1004

Enrollment, Outcomes, and Reasons for Crossover and Discontinuation in Five-Year Follow-up of Patients Receiving Imatinib for Chronic Myeloid Leukemia

Druker BJ et al. N Engl J Med 2006;355:2408-2417

Dr. Yellapragada Subbarow (Subbarao)(1895-1948).“Wizard of Wonder drugs”

Discovered the following while working at Lederle Labs, NY.

Folic acid ProductionCreatine phosphateVitamin B9MethotrexateHetrazanAureomycin