CML (February 2017): Molecular Oncology Tumor Boards

ASCO University
Feb 15, 2017 8:30 AM

User Instructions: Welcome to the Molecular Oncology Tumor Board Series! This educational initiative is a collaboration between the American Society of Clinical Oncology (ASCO), College of American Pathologists (CAP), and Association for Molecular Pathology (AMP).

A new case will be presented each month with discussions led by an expert  medical oncologist and pathologist. This month’s topic is led by Drs. Ellen K. Ritchie (medical oncologist) and Karen Mann (pathologist).

Participants are encouraged to leave comments and post questions about the case in order to generate a wide discussion among the cancer care community. You can also receive email notifications when new comments are posted by clicking the “Follow this Conversation” option located at the bottom of this page.

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Comments

14151

ASCO University
Re: CML (February 2017): Molecular Oncology Tumor Boards
Feb 15, 2017 8:40 AM

Patient Case Part 1
Age/Sex: 33 Male
Medical History: 33-year-old male with past medical history of possible infertility found to have elevated white cell count during screening for urologic procedure. He is otherwise asymptomatic. Physical examination is significant for spleen palpable 4 cm below costal margin.
Laboratory evaluation:
WBC 75,000, Hgb 9.4, PLTss 452
Peripheral smear: Leukoerythoblastic picture
Bone marrow aspiration and biopsy performed 100% cellular with blasts 2%
Karyotype 47,XY+8,t(9;22)(q34)
FISH positive for t(9;22) and trisomy 8 in 20% of cells
Type of Tumor: CML, chronic phase
Co-morbidities: infertility
Images/Scans/Pathology:
Images 1

Peripheral smear (A) demonstrates left-shifted leukocytosis with rare blast cells (thin arrow) and absolute basophilia (fat arrows)
Bone marrow aspirate smear (B) demonstrates markedly increased myeloid to erythroid ratio. Blast cells are not increased and micromegakaryocytes are present.
Core biopsy demonstrates hypercellular marrow with marked myeloid hyperplasia and micromegakaryocytes.

Attachment: 

http://connection.asco.org/sites/asco_connection/files/CML%20Image%201.jpg
Attachment:

14156

ASCO University
Re: CML (February 2017): Molecular Oncology Tumor Boards
Feb 15, 2017 8:41 AM

Discussion Questions
1.    How would you treat this patient?
2.    In addition to the BCR-ABL1 translocation, trisomy 8 was found on bone marrow biopsy; would this change your approach to this patient?
3.    Fertility is a primary concern.  Patient and his wife have been trying to have a baby for several years and are contemplating IVF. How would you counsel this patient?
4.    Upon further discussion with the patient, he reveals that he has a high stress job with international travel and he takes frequent TUMS and Prilosec prn.  How would this influence your therapy choice?
5.    Patient with father who had MI with sudden death at age 38.  How would this influence your choice of treatment and follow up of this patient?
6.    How will you monitor this patient’s response to therapy and what are your therapeutic goals?

14161

Anis Toumeh, MD
Re: CML (February 2017): Molecular Oncology Tumor Boards
Feb 15, 2017 1:45 PM

2- The presence of trisomy 8 is a risk factor for transition into an accelerated phase/blast crisis 

3- I would refer this patient to a fertility clinic for evaluation. If treatment is started then I would recommend avoiding sexual contact until he attains a complete molecular response for at least 2 years, at a time therapy discontinuation can be discussed with him. Having said that, and although his Sokal risk score is low, a second generation TKI might be a better choice for him since they have higher chance for acheiving earlier molecular response vs Imatinib 

5- I would do a baslines fasting glucose and lipids profile

Edward J. Brill, MD
Re: CML (February 2017): Molecular Oncology Tumor Boards
Feb 15, 2017 9:10 PM

trial of imatinib therapy

14176

Edward J. Brill, MD
Re: CML (February 2017): Molecular Oncology Tumor Boards
Feb 16, 2017 9:51 AM

I would try the imatinib therapy initally

14181

Ellen K. Ritchie, MD
Re: CML (February 2017): Molecular Oncology Tumor Boards
Feb 17, 2017 10:03 AM

Course Faculty Response

  • Tyrosine kinase inhibitors are the standard therapy for patients with CML.  Imatinib has been approved as front-line treatment since 2003 and is the only TKI that is available in a generic formulation.  Second-generation TKIs nilotinib, dasatinib, bosutinib have been developed with increased potency and different structures that allow them to be used to overcome most mutations causing resistance to TKIs.  Ponatinib was subsequently developed to overcome the T315I mutation.  In comparison to imatinib, the second-generation TKIs have been shown to have higher response rates and faster responses which have led to the approval of nilotinib and dasatinib for front line treatment.  The side effect profile and dosing schedules differ among TKIs and it is important to discuss these differences in the initial discussion with the patient.  Cost also may be an issue with some insurance plans that will not cover a second-generation TKI as initial therapy and require that treatment start with imatinib.
  • This patient presents with a second chromosomal abnormality with trisomy 8 found in 8 out of 20 metaphases and FISH positive for trisomy 8 in 45%.  In a paper from MD Anderson published in Leukemia 29 (2015) the treatment response and survival of patients with CML and trisomy 8 was evaluated.  In this study, 30% of patients had trisomy 8.  Those patients with trisomy 8 alone in addition to t(9;22) had a good response to TKI treatment and better survival than patients who presented with other chromosomal abnormalities in addition to t(9;22).  There is no evidence for the superior impact of one TKI therapy over another for patients with trisomy 8 in addition to t(9;22).  
  • This patient and his wife desperately want to have children in the near future. Plans were underway for the patient’s wife to have IVF therapy and for him to donate sperm.   There are some publications suggesting that TKI therapy may have a negative impact on spermatogenesis and the ability of sperm to fertilize an egg.  In discussion with the reproductive endocrinologist treating the couple, the patient should not be on TKI therapy when donating sperm for IVF.  The first IVF for this couple was scheduled in two months.  Patient will need to start therapy before donation.  Ideally, once the patient has obtained a response, drug can be stopped to allow him to donate sperm.  
  • Patient has a high stress job and travels frequently to other countries in different time zones.  Drug schedule is important to this patient.  A once daily agent is much easier for him to take.  His meal schedule also is erratic so if the drug needs to be taken on an empty stomach it may also be difficult for him to take.  Compliance is an issue with all CML patients. Given the lifestyle of this patient, an agent that can be taken once daily on full or empty stomach would be preferable.  Nilotinib would not be a preferable first-line agent for this patient because of its twice-daily dosing schedule and requirement that it be taken on an empty stomach.  Absorption of TKI drugs can be affected by antacids and PPI therapy.  This will need to be discussed with this patient.  Antacids are preferable to PPI therapy and should be taken several hours away from the dosing of the TKI.  If patient does not really need to take drugs that alter stomach Ph, it is preferable.
  • A meta-analysis of adult patients with chronic phase and accelerated phase CML treated with TKI therapy evaluated the risk of cardiovascular events in these patients.  Thirty-two studies were identified enrolling 16,218 patients.  Pooled incidence rates were compared among agents.  When compared with non-TKI treated patients, patients who receive imatinib and dasatinib had fewer cardiovascular events while the incidence was greater among patients receiving nilotinib, ponatinib and bosutinib.  In a patient who has a family history of MI at a young age with sudden death, control of cardiac risk factors should be a major focus while on therapy with a TKI for CML.  Involvement of the patient’s internist in controlling risks for vascular disease should be an important aspect of this patient’s care.  Initial treatment with a TKI less associated with cardiovascular disease would be preferable.  Treatment with imatinib or dasatinib would be a better choice for initial therapy.
  • In this case, imatinib was chosen as the best choice for initial therapy given once daily dosing and decreased risk as compared to the other TKIs for cardiovascular and pulmonary disease.  A second-generation TKI might be preferable with plan for sperm donation for IVF therapy because the response to the drug might be faster.  After discussion of risks and benefits with the patient, imatinib was started.
  • Patient was followed every three months after the initiation of therapy.  RT PCR using the international standard was sent from the peripheral blood at three month intervals.  During the first year, FISH for trisomy 8 was also sent at the same intervals.

14186

Karen Mann
Re: CML (February 2017): Molecular Oncology Tumor Boards
Feb 17, 2017 10:07 AM

Course Faculty Response

  • Approximately 10% of patients with chronic phase CML have additional chromosome abnormalities at diagnosis (http://atlasgeneticsoncology.org/Anomalies/CMLID1117.html) and additional patients will acquire abnormalities during chronic phase or upon progression to accelerated or blast phase. The most common single additional abnormalities include trisomy 8, -Y, an additional Philadelphia chromosome, i(17)(q10), -7/del7q, and 3q26.2 rearrangements. Of these, the presence of trisomy 8, -Y or an additional Philadelphia chromosome do not alter the survival of patients treated with TKI.    (Leukemia (2015) 29, 2263–2266; doi:10.1038/leu.2015.96; Blood. 2016;127(22):2742-2750). The remaining abnormalities [i(17)(q10), -7/del7q, and 3q26.2] are associated with a worse prognosis.
  • Monitoring of response to therapy is initially performed at 3 month intervals by quantitative RT-PCR (qPCR) on peripheral blood. If possible, this should be reported using the % International Standard (%IS) to allow interlaboratory comparison of results. Therapeutic goals have been defined and guidelines have been issued by a number of organizations including National Comprehensive Cancer Network (NCCN), European Leukemia Net and European Society for Medical Oncology (ESMO) (https://www.nccn.org/professionals/physician_gls/pdf/cml.pdf; Blood. 2013 Aug 8; 122(6): 872–884. Annals of Oncology 23 (Supplement 7): vii72–vii77, 2012). Important concepts include: Early molecular response (EMR) <10 %IS by 3-6 months; Major molecular response (MMR) <0.1% IS, MR3.0; and deep/complete molecular response (DMR, CMR), often defined as <0.0032 %IS, MR4.5. Of note accurate assessment of DMR or CMR requires assessment of the sensitivity of the assay on that specific analysis as judged by amplification of the control gene (Clin Cancer Res. 2014 Jan 15;20(2):310-22. doi: 10.1158/1078-0432.CCR-13-1988. Epub 2013 Oct 28. Hematology Am Soc Hematol Educ Program. 2016 Dec 2;2016(1):156-163.).  Clinical studies are underway that assess levels of DMR with the goal of being able to predict which patients can discontinue TKI therapy without relapse.

14191

ASCO University
Re: CML (February 2017): Molecular Oncology Tumor Boards
Feb 17, 2017 10:11 AM

Patient Case Part 2

  • After six months on imatinib therapy, the patient had not achieved a 1 log reduction (BCR-ABL1 level by Q-PCR >10% IS).  ABL1 mutation testing was done and no mutations were found.  The patient was placed on dasatinib.
  • Six months after starting dasatinib, the patient achieved a MMR.  Two months later, he developed shortness of breath and was found to have a pleural effusion.  Patient restarted dasatinib at 70mg daily and achieved a CMR six months later.  He remained in CMR for 3 years.  Trisomy 8 positive by FISH 10%.  

 

14196

ASCO University
Re: CML (February 2017): Molecular Oncology Tumor Boards
Feb 17, 2017 10:12 AM

Discussion Questions
1.    How would you have treated the patient at the time he developed the pleural effusion?
2.    What are the mechanisms of tyrosine kinase resistance?
3.    Would you consider a trial of treatment discontinuation?
4.    Did the patient ever go off drug to donate sperm for IVF therapy?
5.    How were cardiac risk factors managed given family history?

14216

Ellen K. Ritchie, MD
Re: CML (February 2017): Molecular Oncology Tumor Boards
Feb 22, 2017 8:51 AM

Course Faculty Response

  • The incidence of pleural effusion on dasatinib treatment is approximately 20%.  Pleural effusions associated with dasatinib are generally lymphocyte predominate exudates.  The mechanism may involve immune mediated pathways for off-target inhibition of the pDGFR receptor.  If an effusion occurs, dasatinib treatment should be interrupted.  If the effusion is large, it may require drainage.  If not, a short course of diuretics or corticosteroids can be initiated.  Drug can be restarted after improvement at a reduced dose.  
  • There are many mechanisms of drug resistance.  This patient presented with an additional chromosomal abnormality which may confer a baseline resistance to a particular TKI therapy.  There are many other mechanisms including mutations that occur on therapy to confer resistance.  The most common example is the emergence of T315I mutations on patients receiving first or second generation TKIs.  There can be modifications of cell signaling pathways and mechanisms of resistance related to drug influx and efflux that can occur in the absence of mutations found in the ABL1 kinase.  In patients who do not have optimal response to TKI therapy, it is important to test for ABL1 kinase mutations to determine if a new mutation has developed and to help direct treatment with a new TKI.
  • The NCCN has just released in 2016 guidelines for therapy discontinuation in CML patients.  Patients must be adults over age 18 with chronic phase CML on an approved TKI therapy. They must have prior evidence of quantifiable bcr-abl1 transcript.  The patient must have a stable molecular response of MR 4.5 for 2 or more years as documented on at least 4 tests at least 3 months apart.  They can have no history of resistance to any TKI therapy.  They must have access to reliable QPCR testing and able to comply with monthly monitoring in the first six months following TKI discontinuation, bi monthly from months 7-24 and quarterly monitoring thereafter for life.  Patients should have consultation with a CML specialty center to review the patient data and manage TKI withdrawl syndrome.  There needs to be prompt resumption of TKI therapy with loss of MMR with monthly monitoring for the first 6 months and every three months after if MMR is once again achieved.  This patient has an additional chromosomal abnormality which is not addressed by the NCCN guidelines.  He also was resistant to initial therapy with imatinib which makes him ineligible for TKI discontinuation by NCCN 2016 guidelines.
  • After initiation of dasatinib therapy, the patient achieved MMR at 6 months.  At this point, therapy was interrupted for a 2-week period of time for sperm donation.  Drug was then resumed.  Repeat RT PCR was done one month after resumption of therapy and he was still in MMR.  One year later, the patient and his wife wanted to have a second child and had IVF therapy a second time.  Patient had not yet achieved MR 4.5 but was still in MMR.  Again, he was taken off treatment for a two-week period of time to donate sperm.  He was restarted.  Repeat RT PCR one month after resumption of therapy and patient had stable response.
  • With initiation of TKI therapy, patient was sent to internist for evaluation of cardiac risk.  Patient found to have elevated cholesterol.  Initial management was with diet and exercise.  LDL continued to be significantly elevated and a statin was started.  Despite his busy schedule, the patient has chosen to lead a healthy lifestyle with adherence of low fat diet and regular aerobic exercise regimen.

14221

Karen Mann
Re: CML (February 2017): Molecular Oncology Tumor Boards
Feb 22, 2017 8:54 AM

Course Faculty Response

  • Resistance to TKI therapy can occur by a variety of mechanisms both BCR-ABL1 dependent and BCR-ABL1 independent (doi: 10.1182/asheducation-2009.1.461 ASH Education Book January 1, 2009 vol. 2009 no. 1 461-476; Cancer. 2011 May 1; 117(9): 1800–1811. Curr Cancer Drug Targets. 2016;16(4):323-45. Current Hematologic Malignancy Reports June 2015, Volume 10, Issue 2, pp 158–166). BCR-ABL1 dependent mechanisms of mutation include duplication/amplification of the BCR-ABL1 gene and point mutations in the kinase domain of ABL1. Mutations occur throughout the kinase domain and can be identified by sequencing of the ABL1 kinase domain.  This has most commonly been performed by Sanger sequencing, but more recently some laboratories have adopted next generation sequencing techniques. Identification of specific mutations can help guide changes in therapy. Specifically, some mutations will respond to dose-escalation and others to switch to second or third generation TKIs. The most clinically significant mutation is the T315I mutation as these patients will not respond to dose escalation or 2nd generation TKIs, but may respond to ponatinib.  (For a summary of common mutations and response to TKIS see https://www.mycancergenome.org/content/disease/chronic-myeloid-leukemia/...)
  • Following treatment, development of compound mutations can further complicate treatment choice. Non-BCR-ABL1 dependent resistance are believed to be secondary to changes in drug efflux or influx or in the development of alternate activation pathways.

14231

Ellen K. Ritchie, MD
Re: CML (February 2017): Molecular Oncology Tumor Boards
Mar 01, 2017 10:13 AM

Faculty Summary

  • Young patient with diagnosis of CML with additional chromosomal abnormality of trisomy 8. 
  • Numerous considerations given to initial TKI choice for treatment with need for easy dosing regimen, plan for family with assisted reproduction, and consideration of strong family history of cardiac disease and a father who died of MI at age 38.
  • Treatment with imatinib initiated but response by 6 months was suboptimal.  Switch was made to dasatinib treatment with achievement of MMR.
  • Cardiac risk factors aggressively managed during TKI treatment.
  • With development of MMR, treatment interruption was scheduled for donation of sperm for IVF therapy x 2.
  • Dasatinib treatment complicated by development of pleural effusion.  Effusion managed with interruption of therapy, diuresis and drug restarted at a lower dose. 
  • Patient achieved CMR/MR 4.5 on dasatinib and remained in CMR for 3 years.  He is not a candidate for discontinuation because of his trisomy 8 and his resistance to prior imatinib treatment.  Discontinuation was considered under guidelines established by the NCCN in 2016.

14236

Karen Mann
Re: CML (February 2017): Molecular Oncology Tumor Boards
Mar 01, 2017 10:15 AM

Faculty Summary

  • Young patient with CML, BCR-ABL1 positive presenting in chronic phase with classic blood and bone marrow findings.
  • Additional chromosomal abnormality, trisomy 8, present at diagnosis
  • Patient did not achieve EMR (>10 % IS at 6 months)
  • Patient achieved MMR following following switch to dasatinib
  • Patient achieved sustained CMR (3 years) as judged by qPCR
  • Patient had persistence of trisomy 8 by FISH

See Reference List Below

Attachment: 

http://connection.asco.org/sites/asco_connection/files/References_Feb2017MOTBCML.pdf

14241

ASCO University
Re: CML (February 2017): Molecular Oncology Tumor Boards
Mar 01, 2017 10:20 AM

Thank you to Drs. Ellen Ritchie and Karen Mann for leading the discussion of this case and also to all of those who contributed to the conversation! The forum is now closed to further comments but users have the opportunity to claim credit on ASCO University by clicking here.

Please check back in mid-March for a new case in this series.