ASHClinicalNews . org
ASHClinicalNews . org
Keith Stewart , MBChB , MBA , is the Carlson and Nelson Endowed Director of the Center for Individualized Medicine and the Vasek and Anna Maria Polak Professor of Cancer Research at Mayo Clinic in Scottsdale , Arizona .
Keith Stewart , MBChB , MBA
Richard T . Silver , MD , is professor of medicine , attending physician , and emeritus director of the Richard T . Silver , M . D . Myeloproliferative Neoplasms Center at Weill Cornell Medicine in New York .
ASH Clinical News
ASH Clinical News
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Letters to the Editor
Notes from the Field
Readers responded to two of our recent articles that offered a candid look into the daily lives of physician-researchers and advice for thriving as a hematologist .
Editor ’ s Corner
Have a comment about an article ? Let us know what you think ; we welcome your feedback . Email the editor at ACNeditor @ hematology . org .
M
The content of the Editor ’ s Corner is the opinion of the author and does not represent the official position of the American Society of Hematology unless so stated .
Have a comment about this editorial ? Let us know what you think ; we welcome your feedback . Email the editor at ACNEditor @ hematology . org .
Burnout ? What Burnout ?
UCH HAS BEEN WRITTEN in ASH Clinical News about the Orwellian nature of modern clinical trials , and for good reason : Almost all our readers have some experience with clinical research – it ’ s what we do . Consequently , I hope my story will resonate . To protect the innocent , the names and dates of the events herein have been changed and bear no resemblance to any real or living person , organization , time , or place ( sort of ). This is a reenactment of creeping awareness , acceptance , and ultimately … well for that , you have to read on .
I have , by now , participated in 53 clinical trials resulting in 89 publications over 24 years . And they used to be fun . Then one sunny Friday morning , a not-so-long time ago , they stopped being fun .
I arrived at my office to find an ominous-looking stack of EKGs , each stamped with an automated report of normality to which I dutifully signed NCS – not clinically significant , adding my initials and the date 23 times . Rather proud of myself for having expeditiously dealt with this “ nuisance ” before clinic started , I launched into the first emails of the day .
Two overnight messages requiring attention greeted me . The first reprimanded me for my overdue review of Investigator ’ s Brochure version 5.0 , to determine if , somewhere in its 129 pages , there were any new safety data that might require a revision to the trial ’ s informed-consent form . The email had , quite rightly , a vaguely threatening tone . I punted that delicious task for the weekend . The second request related to e-signing case-report forms in a system I didn ’ t recognize , never fully understood , and for which my password had long ago expired . I gave up and moved that one to Monday .
Then , by unfortunate coincidence , at a quarterly finance meeting with our research office later that day , I learned that one of my clinical trials was losing money , in quite large amounts . The loss was not because of bad budgeting , but because opening and activating the study took more effort and time than anyone reasonably expected . That was compounded by the realization that this early-stage trial had 11 active sites competing every six weeks for three slots and enough eligibility criteria to enter the Guinness Book of World Records for the most reasons patients are unqualified for a trial . In summary , accrual was low and slow , yet the paperwork was relentless and the expenses outpaced potential revenue . I left the meeting feeling discouraged .
Clinic ended a little early that day and , before quitting time , I replied “ yes to all ” with respect to my contributions to a trialabstract submission to a major medical conference . A quick read of said abstract awakened my dislike for using the words “ acceptable ” and “ manageable ” to describe an agent ’ s evident toxicities . So , in a Friday afternoon act of defiance , I sharpened my figurative pencil and composed an objection to both that wording and the claim that the agent would be a “ new standard of care ” for patients with an “ unmet need .” I am sure I upset the medical writer a little and the marketing team a lot , but I felt better – though I recognized that my solitary act of rebellion would change little .
Monday morning brought news that one of the trials in which I was engaged was being closed for “ business reasons .” No appeals would be allowed , but the medical team at the sponsoring company offered apologies . What would I tell my patient who had just enrolled in the study ? “ So sorry , but your contribution to the future of bloodcancer treatment was just cancelled without notice . Why don ’ t you keep volunteering to take the drug with unknown side effects or potential for benefit anyway ?”
I guess that was the last straw , the thousandth cut , the culmination , the end of the road .
July 2018 Editor ’ s Corner
Advice to the Graduating Hematologist
hen I was asked to collect some thoughts to share with hematology / oncology trainees upon completion of their fellowship , I thought back on my experiences and the attributes that are essential to a successful career in medicine .
Later , when you reflect on what I ’ ve said , I hope you don ’ t discard it as “ the same old stuff .” However , if you do hear familiar points , that is not an accident . There are generational truths that are true now and were true for our forebears , physicians or not . And , if you hear something new , it is because my professional and personal life is colored by my own unique features – as yours will be in the coming years .
Hopefully – and more likely – you ’ ll find that the advice I offer is a combination of both , because the more things change , the more they remain the same . But they do change . As physicians and human beings , we all share a common core of values that is modified by our own personal experiences and beliefs . And that is as it should be .
The Three A ’ s Through my years of observation , I developed a list of important attributes , what I call “ the three A ’ s ,” that I feel are necessary to lead a successful career and that I believe will sustain you as young physicians .
The first of “ the three A ’ s ” is availability . When a patient or colleague has a problem and asks “ Who should I call ?” the answer is to call the doctor who is always around and who is a nice person . No one ever recommends calling someone because he or she reads all the latest medical literature each month or graduated at the top of his or her medical class .
Recently , I tried to call one of our service ’ s busy gastroenterologists to discuss a patient she referred to me . I wanted her opinion about starting ruxolitinib in a patient who had myelofibrosis , splenomegaly , and ulcerative colitis . I am still waiting for the call back . I assure you that this is not a good way to maintain a consultation practice , let alone develop one .
The second attribute is affability . One of the most successful attending physicians I ever encountered as a young clinician was dapper , charming , and impeccably dressed . He had a huge practice ! He knew little about medicine , but he loved to practice it . He accompanied his patients to a consultation whenever possible .
Today , we would say he had a concierge practice : He was always available , and he was super-affable , but he really lacked the last “ A ”: ability . Of course , you all have ability – you wouldn ’ t be graduating if you didn ’ t .
Ability is related to “ smartness .” Never worry about whether people are smarter than you , or if you know enough . I guarantee you , there are many people smarter than you . You will likely never consider yourself smart enough to satisfy your own expectations . Indeed , in The New England Journal of Medicine , Suzanne Koven , MD , published a “ Letter to a Young Female Physician ” describing the problem as “ imposter syndrome .” This insecurity rears its head when young physicians are convinced that everyone else but them understands secondgeneration sequencing or the coagulation cascade . You may think you aren ’ t smart enough or you don ’ t know enough , so accept the fact that you will certainly never know everything .
Many years ago , I thought the guy who was constantly asking questions and admitting when he didn ’ t know something was the dumbest guy in my medical class . How surprised we were when he gave the AOA address as the top member of our class .
Just realize that you live in a world of ignorance , and don ’ t be frustrated by it . If someone makes a snide remark because you didn ’ t know something , don ’ t take it personally . No matter what your rank or position , never be afraid to say , “ I didn ’ t know that ,” or “ Thanks for telling me that .” I still do it all the time .
Never Stop Exploring Remember that , even after all your great training , you are just at the beginning of your careers . And , one of the remarkable things about a medical career is the number of opportunities available to you . So , keep exploring and trying new things .
The best opportunities happen by chance and often you don ’ t realize they are coming . On the other hand , if you push too hard for things to happen , most often they will not .
For instance , when I was a second-year resident , I was absolutely convinced that I would become a great cardiologist . Mandatory military obligation for all physicians during the Korean War , however , led me to the General Medicine Branch of the National Cancer Institute ( NCI ). Because I was not able to serve in the armed forces , the compromise was that I serve as an intern on the leukemia service – an unpleasant prospect for a second-year resident from a hot-shot , white-shoe hospital who wanted to be a cardiologist . At that time , the NCI ’ s clinical program of the NCI was considered the gulag of all the institutes , but it was a “ take-it-or-leave-it ” situation , so I took the opportunity and worked hard . My mentors were Emil J . Freireich , MD , Emil Frei III , MD , and James Holland , MD . It was the dawn of chemotherapy ,
10 ASH Clinical News
I had an epiphany of sorts that day : Everything I was experiencing – an increase in cynicism , apathy about the tasks at hand , irritability with people tasked with their required jobs , lack of satisfaction , and general disillusionment with the trial system – equated to what we now recognize as the dreaded “ burnout .”
I decided then and there to quit engaging in clinical trials . I had plenty of other more rewarding things to focus on , and , working with a motivated team , I was refreshed daily by a sense of community and visible progress towards a shared vision . In other words , the very opposite of the recent clinical trial experience .
I felt immediate and palpable relief . My colleagues were less than thrilled , but graciously agreed to take over the thankless , ceaseless , mundane clinical trial – related tasks . The conscientious clinical research staff reluctantly accepted my decision , though I suspect they also were secretly pleased that I would not be the one asking for eligibility review of three patients at once . The sponsoring companies were mute , but I can imagine they weren ’ t pleased either .
Meanwhile , I was jubilant . No more mandatory meetings with monitors lecturing on our failings as collators and custodians of the precious data ; no more investigator responsibility slideshows , mandatory Institutional Review Board videos , financial disclosures , case report form signoffs , investigator calls , slow-accrual guilt , toxicity attributions , tense discussions about pre-presentation press releases , or lawyerly monitoring of slides for compliance . No more lab signoffs , site initiation visits , site closing visits , budget reviews , market creep monitoring , or requests for conflict-of-interest disclosures .
Finally , released from the clinical trials club , I could be the one to ask the pointed questions at the end of a trial presentation . I could wax lyrical at journal club about poor design and biased reporting . An expanded universe of conflict-free consulting awaited me .
It took months , and repeated requests , to slowly reassign ownership or close each trial . ( For any readers considering the same path , be aware that like a romance documented on social media , a speeding ticket , or an inferior vena cava filter , participating in an industry-supported clinical trial is difficult to extricate yourself from .
Then , just as I cleared the last hurdle and was poised to skip merrily towards my new trial-free and resilient existence , the siren ’ s call arrived . The phone rang and a voice said , “ Dr . Stewart , would you like to participate in our CAR T-cell trial for myeloma ?” Five seconds passed before I answered : “ Yes .” Go ahead , judge me ! You may wonder why , with the goal line in sight , my resolve collapsed . I am still not entirely sure myself , but concluded that , at the end of the day , when there is still real unmet need , conducting trials of drugs with manageable toxicity and encouraging activity are what we do – burnout be damned .
To the editor : I found Dr . Stewart ’ s latest Editor ’ s Corner (“ Burnout ? What Burnout ?” July 2018 ) refreshing . Very seldom do you read of the daily life of a physician in such candid and honest terms . We need more of these articles because no physician ’ s job is really easy .
Guest Commentary
Richard T . Silver , MD , has been a hematologist and scientist for more than six decades , spending nearly his entire career at Weill Cornell Medicine in New York . Still practicing at age 89 , Dr . Silver was invited earlier this year to deliver remarks to the 2018 graduating class of hematology / oncology fellows at New York-Presbyterian Brooklyn Methodist Hospital . We excerpt his speech below , in which he offers advice to new graduates from a lifetime spent in hematology .
August 2018 Guest Commentary
Larry Parrott , MD Emeritus ASH member
Camden , SC and they were the fathers .
After I completed my training , I was asked to go to Salvador , Brazil , to help set up a residency program at the Federal University of Bahia . I had the opportunity to go to on an expedition to the Mato Grosso , the Upper Xingu region , where we discovered the third allele in the Kidd Blood Group system . Because of this , I was invited to join The Explorers Club , one of the most interesting clubs on earth . Here I ’ ve met Sir Edmund Hillary , all the astronauts , and the deep-sea divers who discovered the wreck of the Titanic . Through my adventures in medicine , a new unexpected dimension had been added to my life . So , remember that your lives are a series of experiences . Embrace and take advantage of new things as they occur , by chance or otherwise .
An Unavoidable Truth As Mark Twain said , “ The only place where success comes before work is in the dictionary .” Obviously , you have worked hard to get to this point ; that hard work doesn ’ t end with fellowship .
If you want to build your career , be prepared to go through dark and painful moments . Engage in the struggle . Nothing comes out of easy days . Be very conscious of how you spend your professional time and try not to waste this precious commodity . Make your work meaningful and do not fool around . If you do any research as clinicians , plan how you will be included as a co-author – not as a footnote – and how your effort related to the paper will be included before you get involved .
Remember : Success is not a race . You should always feel that you are continually growing . In fact , I have done some of my best research work after I turned 60 . But , when you try new things , and you have done your level best and it is still not working , learn when to let things go – especially before you turn 50 .
In closing , if you believe you have found a meaningful calling , and you commit to it because of your enthusiasm for your work , all good things are possible in medicine . Nothing is more meaningful , and if you can adjust to the external trivia of today ’ s climate and its limitations , you will have a satisfying professional life . Not many folks can say that . ●
UP FRONT
I agree with Dr . Silver ’ s advice about “ the three A ’ s ” ( availability , affability , and accessibility ) from “ Advice for the Graduating Hematologist ” in August 2018 . I suggest there is a fourth “ A ” that is becoming important to many of the payers : Affordability .
Joseph R . Holahan , MD South Texas Hematology and Oncology
San Antonio , TX
INDICATION AND IMPORTANT SAFETY INFORMATION FOR KYPROLIS
INDICATION
KYPROLIS ® ( carfi lzomib ) is indicated in combination with dexamethasone or with lenalidomide plus dexamethasone for the treatment of patients with relapsed or refractory multiple myeloma who have received one to three lines of therapy .
IMPORTANT SAFETY INFORMATION FOR KYPROLIS Cardiac Toxicities :
• New onset or worsening of pre-existing cardiac failure ( e . g ., congestive heart failure , pulmonary edema , decreased ejection fraction ), restrictive cardiomyopathy , myocardial ischemia , and myocardial infarction including fatalities have occurred following administration of KYPROLIS . Some events occurred in patients with normal baseline ventricular function . Death due to cardiac arrest has occurred within one day of administration .
• Monitor patients for signs or symptoms of cardiac failure or ischemia . Evaluate promptly if cardiac toxicity is suspected . Withhold KYPROLIS for Grade 3 or 4 cardiac adverse events until recovery , and consider whether to restart at 1 dose level reduction based on a benefi t / risk assessment .
• While adequate hydration is required prior to each dose in Cycle 1 , monitor all patients for evidence of volume overload , especially patients at risk for cardiac failure . Adjust total fl uid intake as clinically appropriate .
• For patients ≥ 75 years , the risk of cardiac failure is increased . Patients with New York Heart Association Class III and IV heart failure , recent myocardial infarction , conduction abnormalities , angina , or arrhythmias may be at greater risk for cardiac complications and should have a comprehensive medical assessment prior to starting treatment with KYPROLIS and remain under close follow-up with fl uid management .
Acute Renal Failure :
• Cases of acute renal failure , including some fatal renal failure events , and renal insuffi ciency adverse events ( including renal failure ) have occurred . Acute renal failure was reported more frequently in patients with advanced relapsed and refractory multiple myeloma who received KYPROLIS monotherapy . Monitor renal function with regular measurement of the serum creatinine and / or estimated creatinine clearance . Reduce or withhold dose as appropriate .
Tumor Lysis Syndrome :
• Cases of Tumor Lysis Syndrome ( TLS ), including fatal outcomes , have occurred . Patients with a high tumor burden should be considered at greater risk for TLS . Adequate hydration is required prior to each dose in Cycle 1 , and in subsequent cycles as needed . Consider uric acid lowering drugs in patients at risk for TLS . Monitor for evidence of TLS during treatment and manage promptly , and withhold until resolved .
Pulmonary Toxicity :
• Acute Respiratory Distress Syndrome ( ARDS ), acute respiratory failure , and acute diffuse infi ltrative pulmonary disease such as pneumonitis and interstitial lung disease have occurred . Some events have been fatal . In the event of drug-induced pulmonary toxicity , discontinue KYPROLIS .
Pulmonary Hypertension :
• Pulmonary arterial hypertension ( PAH ) was reported . Evaluate with cardiac imaging and / or other tests as indicated . Withhold KYPROLIS for PAH until resolved or returned to baseline and consider whether to restart based on a benefi t / risk assessment .
Dyspnea :
• Dyspnea was reported in patients treated with KYPROLIS . Evaluate dyspnea to exclude cardiopulmonary conditions including cardiac failure and pulmonary syndromes . Stop KYPROLIS for Grade 3 or 4 dyspnea until resolved or returned to baseline . Consider whether to restart based on a benefi t / risk assessment .
Hypertension :
• Hypertension , including hypertensive crisis and hypertensive emergency , has been observed , some fatal . Control hypertension prior to starting KYPROLIS . Monitor blood pressure regularly in all patients . If hypertension cannot be adequately controlled , withhold KYPROLIS and evaluate . Consider whether to restart based on a benefi t / risk assessment .
Learn more at KYPROLIS-HCP . com
Venous Thrombosis :
• Venous thromboembolic events ( including deep venous thrombosis and pulmonary embolism ) have been observed . Thromboprophylaxis is recommended for patients being treated with the combination of KYPROLIS with dexamethasone or with lenalidomide plus dexamethasone . The thromboprophylaxis regimen should be based on an assessment of the patient ’ s underlying risks .
• Patients using hormonal contraception associated with a risk of thrombosis should consider an alternative method of effective contraception during treatment .
Infusion Reactions :
• Infusion reactions , including life-threatening reactions , have occurred . Symptoms include fever , chills , arthralgia , myalgia , facial fl ushing , facial edema , vomiting , weakness , shortness of breath , hypotension , syncope , chest tightness , or angina . These reactions can occur immediately following or up to 24 hours after administration . Premedicate with dexamethasone to reduce the incidence and severity of infusion reactions . Inform patients of the risk and of symptoms and seek immediate medical attention if they occur .
Hemorrhage :
• Fatal or serious cases of hemorrhage have been reported . Hemorrhagic events have included gastrointestinal , pulmonary , and intracranial hemorrhage and epistaxis . Promptly evaluate signs and symptoms of blood loss . Reduce or withhold dose as appropriate .
Thrombocytopenia :
• KYPROLIS causes thrombocytopenia with recovery to baseline platelet count usually by the start of the next cycle . Monitor platelet counts frequently during treatment . Reduce or withhold dose as appropriate .
Hepatic Toxicity and Hepatic Failure :
• Cases of hepatic failure , including fatal cases , have occurred . KYPROLIS can cause increased serum transaminases . Monitor liver enzymes regularly regardless of baseline values . Reduce or withhold dose as appropriate .
Thrombotic Microangiopathy :
• Cases of thrombotic microangiopathy , including thrombotic thrombocytopenic purpura / hemolytic uremic syndrome ( TTP / HUS ), including fatal outcome , have occurred . Monitor for signs and symptoms of TTP / HUS . Discontinue if diagnosis is suspected . If the diagnosis of TTP / HUS is excluded , KYPROLIS may be restarted . The safety of reinitiating KYPROLIS is not known .
Posterior Reversible Encephalopathy Syndrome ( PRES ):
• Cases of PRES have occurred in patients receiving KYPROLIS . If PRES is suspected , discontinue and evaluate with appropriate imaging . The safety of reinitiating KYPROLIS is not known .
Increased Fatal and Serious Toxicities in Combination with Melphalan and Prednisone in Newly Diagnosed Transplant-ineligible Patients :
• In a clinical trial of transplant-ineligible patients with newly diagnosed multiple myeloma comparing KYPROLIS , melphalan , and prednisone ( KMP ) vs bortezomib , melphalan , and prednisone ( VMP ), a higher incidence of serious and fatal adverse events was observed in patients in the KMP arm . KMP is not indicated for transplant-ineligible patients with newly diagnosed multiple myeloma .
Embryo-fetal Toxicity :
• KYPROLIS can cause fetal harm when administered to a pregnant woman .
• Females of reproductive potential should be advised to avoid becoming pregnant while being treated with KYPROLIS . Males of reproductive potential should be advised to avoid fathering a child while being treated with KYPROLIS . If this drug is used during pregnancy , or if pregnancy occurs while taking this drug , the patient should be apprised of the potential hazard to the fetus .
ADVERSE REACTIONS
The most common adverse reactions in the combination therapy trials : anemia , neutropenia , diarrhea , dyspnea , fatigue , thrombocytopenia , pyrexia , insomnia , muscle spasm , cough , upper respiratory tract infection , hypokalemia .
Please see Brief Summary of full Prescribing Information on adjacent pages .