Cyrus M. Khan, MD, is an assistant professor of medicine at the Drexel University School of Medicine and assistant director of the Stem Cell Transplant Program at the Allegheny Health Network Cancer Institute in Pittsburgh, Pennsylvania. 

Dr Khan on the Evolution of BTK Inhibitors in CLL

"Compared with ibrutinib, the efficacy [of second-generation BTK inhibitors] is [slightly improved]; however, we go more by the safety profile [in clinical decision-making]. When we use second-generation BTK inhibitors, patients have fewer problems [and adverse effects]. "

Cyrus M. Khan, MD, an assistant professor of medicine at the Drexel University School of Medicine and assistant director of the Stem Cell Transplant Program at the Allegheny Health Network Cancer Institute, discussed the evolution of BTK inhibitors in chronic lymphocytic leukemia (CLL), comparing outcomes with first-generation ibrutinib (Imbruvica) with that of next-generation inhibitors.

Ibrutinib was the only first-generation BTK inhibitor FDA approved for patients with 

. However, as science progressed, more effective second-generation inhibitors were developed.

The primary motivation for developing newer agents stemmed from the safety profile associated with ibrutinib. Ibrutinib was known to cause significant adverse effects (AEs), including atrial fibrillation, atrial flutter, and dangerous ventricular arrhythmias. Other risks associated with the first-generation agent included a long-term hypertension risk and a general bleeding risk. Patients also commonly experienced nuisance AEs such as arthralgia and myalgia.

The goal of these second-generation BTK inhibitors was to inhibit the BTK site more tightly while having fewer off-target effects than ibrutinib. This preclinical hypothesis suggested fewer AEs, which has subsequently been proven clinically.

Although the efficacy of second-generation agents is only slightly improved, they have a better safety profile than ibrutinib, which is the key factor in clinical decision-making, Khan emphasized. When second-generation BTK inhibitors are used, patients experience fewer problems. With reduced risk of complications like atrial flutter, bleeding, arthralgias, and myalgias, patients are better able to continue treatment and maintain the benefit of BTK inhibition in CLL. Khan concluded that patients are likely to receive benefit from BTK inhibitors for a longer duration when second-generation drugs are utilized.

Videos

Cyrus M. Khan, MD, discusses how ibrutinib—a first-generation BTK inhibitor—compares with second-generation BTK inhibitors in CLL.

Cyrus M. Khan, MD, discusses the key BTK inhibitor updates for the treatment of patients with relapsed/refractory CLL from the 2025 ASCO Annual Meeting.

Dr Khan on Key BTK Inhibitor Updates in Relapsed/Refractory CLL

“There’s a lot of work being done to see how we can further improve upon what we currently have, and what we can do when the patients progress on the current crop of BTK inhibitors. There are also more real-world analyses coming out investigating BTK inhibition and what happens afterward.”

Cyrus M. Khan, MD, an assistant professor of medicine at the Drexel University School of Medicine and assistant director of the Stem Cell Transplant Program at the Allegheny Health Network Cancer Institute, discussed the key updates from the 

 in BTK inhibitors for the treatment of patients with relapsed/refractory chronic lymphocytic leukemia (CLL).

The main update presented at the 2025 ASCO Annual Meeting encompassed how to approach sequencing following the development of 

 mutations in CLL, Khan began. Available data with pirtobrutinib (Jaypirca), among other BTK inhibitors being developed, demonstrated that they could be effective in patients with 

 C481 and other mutations, he explained. Additionally, more research is currently underway to further identify sequencing strategies when patients experience disease progression on the currently available BTK inhibitors, he stated. Real-world analyses are also aiming to address gaps in investigating BTK inhibition and the approach following inhibition, he added. For example, determining how to use CAR T-cell therapy for the treatment of patients with CLL after disease progression on a BTK inhibitor and establishing whether BCL2 inhibitors work following progression on BTK inhibitors, he noted.

Furthermore, a notable abstract presented at the meeting 

 on using CAR T-cell therapy in patients with CLL and other patients with B-cell malignancies who had disease progression on the currently available novel agents, Khan continued. Of note, the real-world analysis included data from 5 trials: the phase 1 TRANSCEND NHL 001 trial (NCT02631044), the phase 1/2 TRANSCEND CLL 004 (NCT03331198), the phase 3 TRANSFORM (NCT03575351), the phase 2 TRANSCEND PILOT 017006 (NCT03483103), and the phase 2 TRANSCEND FL trials (NCT04245839), including data from the CIMBTR registry. B-cell malignancies included in the analysis consisted of relapsed/refractory diffuse large B-cell lymphoma, follicular lymphoma, CLL, small lymphocytic lymphoma, and mantle cell lymphoma.

Cyrus M. Khan, MD, detailed the development of second-generation BTK inhibitors and how they compare with first-generation BTK inhibitors in CLL.

Dr Khan on the Development of Second-Generation BTK Inhibitors in CLL

“The idea [behind] the development of the second-generation [BTK] drugs is that they are more tightly inhibiting the BTK site with [fewer] off-target effects, and that is why, preclinically, we thought that would lead to fewer [adverse] effects. Now we’ve proven that this is the case.”

Cyrus M. Khan, MD, an assistant professor of medicine at the Drexel University School of Medicine and the assistant director of the Stem Cell Transplant Program at the Allegheny Health Network Cancer Institute, detailed the development of BTK inhibitors from first generation to second generation in chronic lymphocytic leukemia (CLL).

The only first-generation BTK inhibitor was ibrutinib (Imbruvica), which was FDA approved in 2014 for the treatment of patients with relapsed/refractory CLL, Khan began. However, with evident advances in science and technology, he noted that newer second-generation BTK inhibitors, including acalabrutinib (Calquence), have demonstrated slightly improved efficacy. Although second-generation BTK inhibitors have demonstrated this improvement in efficacy, the safety profile remains a priority when selecting BTK inhibitors in clinical practice, he explained. For example, with ibrutinib, some patients experienced atrial fibrillation and atrial flutter, along with ventricular arrhythmias, and long-term hypertension, all of which should be carefully considered, he stated. Additionally, other types of adverse effects (AEs), such as myalgia and arthralgia, among others, were observed, he asserted.

When second-generation BTK inhibitors were developed, the aim was to have the drugs tightly inhibit the BTK site with fewer off-target effects compared with ibrutinib, Khan emphasized. He noted that in preclinical studies, investigators hypothesized that these second-generation BTKs would also lead to fewer AEs, which was determined to be true.

In clinical practice, when patients are treated with second-generation BTK inhibitors, they often experience fewer toxicities, according to Khan. Even when patients experience AEs, including atrial flutter, arthralgias, myalgias, and have a bleeding risk, they can continue receiving second-generation BTK inhibitors, and therefore continue receiving the benefit of BTK inhibition for CLL, he said.

Dr Khan on the Role of Acalabrutinib in the Current CLL Treatment Paradigm  

"We have data [with this agent] both in the frontline and relapsed/refractory setting, provided patients haven’t progressed on a BTK inhibitor in the frontline [setting]. [Therefore, in clinical practice,] there’s flexibility [to choose] whether [acalabrutinib is used as a] single agent or in addition to obinutuzumab. We have seen deeper responses [with the addition of obinutuzumab], and perhaps adding obinutuzumab can speed up remission."

Cyrus M. Khan, MD, an assistant professor of medicine at the Drexel University School of Medicine and the assistant director of the Stem Cell Transplant Program at the Allegheny Health Network Cancer Institute, discussed the evolving role of acalabrutinib (Calquence) in the management of chronic lymphocytic leukemia (CLL).

Acalabrutinib is a second-generation BTK inhibitor, Khan began. It received 

 for the treatment of both patients with treatment-naive and relapsed/refractory CLL and small lymphocytic lymphoma (SLL) in November 2019. This regulatory decision based on findings from the phase 3 ELEVATE-TN (NCT02475681) and ASCEND (NCT02970318) trials.

In the frontline setting, acalabrutinib demonstrated efficacy as monotherapy and in combination with the anti-CD20 antibody obinutuzumab (Gazyva), Khan detailed. The combination arm of ELEVATE-TN showed deeper responses compared with acalabrutinib alone, offering potential clinical benefit for patients presenting with autoimmune complications associated with CLL, Khan reported. This flexibility is one of the differentiating factors between acalabrutinib and other BTK inhibitors, and allows clinicians to tailor therapy based on disease characteristics and patient comorbidities, he explained.

In the relapsed/refractory setting, the ASCEND trial compared acalabrutinib with ibrutinib (Imbruvica), Khan continued. Although progression-free survival outcomes were comparable, acalabrutinib was associated with a lower incidence of adverse effects, particularly atrial fibrillation, atrial flutter, and bleeding, he noted. These safety data support the use of acalabrutinib in patients with cardiovascular risk factors or those who are intolerant to first-generation BTK inhibitors, Khan concluded.

Cyrus M. Khan, MD, discusses how acalabrutinib fits into the current treatment paradigm in chronic lymphocytic leukemia.


Dr Khan on the Role of Zanubrutinib in the Current CLL Treatment Paradigm

"[Zanubrutinib fits into the paradigm] in a multitude of ways. It can be used as a frontline treatment, but it can also be used as relapsed/refractory treatment, provided the patient has not already progressed on a BTK inhibitor [in the] frontline [setting].The other good aspect of zanubrutinib is that you can use it either once daily or twice a day. This allows for flexibility in dosing, which is its main benefit. "

Cyrus M. Khan, MD, an assistant professor of medicine at the Drexel University School of Medicine and the assistant director of the Stem Cell Transplant Program at the Allegheny Health Network Cancer Institute, discusses the role of zanubrutinib (Brukinsa) in the current chronic lymphocytic leukemia (CLL) treatment paradigm.

Khan began by noting that zanubrutinib can be integrated into both frontline and relapsed/refractory settings, provided patients have not previously progressed on a BTK inhibitor in the frontline. In the phase 3 ALPINE trial (NCT03734016), zanubrutinib was associated with improved progression-free survival and overall response rates compared with ibrutinib (Imbruvica) in patients with relapsed/refractory CLL. Moreover, zanubrutinib demonstrated a more favorable safety profile, including lower rates of atrial fibrillation, atrial flutter, and bleeding—adverse effects commonly associated with first-generation BTK inhibitors.

Zanubrutinib’s dosing flexibility offers another practical advantage, with the option for either once-daily or twice-daily administration, allowing clinicians to individualize therapy based on patient preference or tolerability, Khan continued. Beyond CLL, zanubrutinib has gained approval for several other B-cell malignancies, including Waldenström macroglobulinemia, marginal zone lymphoma, and follicular lymphoma in the relapsed/refractory setting, he noted. The agent’s broader utility in these indications has increased clinicians’ comfort and familiarity with its use.

Overall, zanubrutinib’s favorable efficacy, improved tolerability, and broader approval across B-cell malignancies support its role as a preferred BTK inhibitor for appropriate patient populations, Khan concluded. Given the reduced cardiotoxicity and manageable adverse effect profile compared with ibrutinib, zanubrutinib represents a meaningful option in both treatment-naive and relapsed/refractory patients with CLL.

Cyrus M. Khan, MD, discusses how zanubrutinib fits into the current treatment paradigm in chronic lymphocytic leukemia.


Dr Khan on the Role of Zanubrutinib in the Current CLL Treatment Paradigm  

A bone marrow aspirate and biopsy is the single most common procedure that hematologists and oncologists carry out day in and day out throughout their career. Therefore, it is also the most common procedure that fellows in hematology/oncology training programs have to learn and then perform during their training. It is very important for fellows to become proficient and confident in doing this procedure independently and safely. In order to achieve this level of competence, they must learn not only the necessary steps but also master the correct technique.

		Table. The evaluation criteria for observation of new fellows performing bone marrow biopsy procedures

					Understands what specimens are needed, ie, cytogenetics, flocytometry

					Explains the indication for the procedure

					Explains what the patient will experience

					Explains the potential risks; consent properly obtained

					Respects patient privacy and dignity

					Courteous to nursing and allied health staff

					Understands logistics of setting up a bone marrow biopsy

					Understands logistics of specimen handling, transportation to lab

Typically, in most training programs, new fellows learn how to do a bone marrow biopsy from either their senior fellows or attending physicians. They will usually observe a few procedures first and then learn to carry them out on patients under supervision. This training process is often unstructured, and there is no way to monitor the fellow’s progress or proficiency.

Moreover, different fellows and attending physicians have different procedural techniques and skills, as well as teaching ability. This combination leads to a haphazard method of learning for the new fellows in training.

At our institution, we recognized this deficiency and devised a plan to address it. We have recently developed a program for new fellows that allows them to learn the correct indications, contraindications, and technique for doing a bone marrow aspirate and biopsy. They can then demonstrate their learning by simulating it on a mannequin or patient actor. In order to help others who may want to set up a similar program, we will describe how we structured it.

The first step is to identify a space where the program will be run. At our institution, and at many academic centers, a simulation center is available. Such centers provide examination rooms, conference rooms, audiovisual equipment, medical instruments, monitors, and mannequins.

The next step is scheduling. It is important to arrange a suitable time when all of the new fellows will be free for 3 hours for the training program. Cross-coverage must be arranged if needed.

To run the program, you need to have the following equipment available: a bone marrow biopsy kit, an examination room, an anatomical model of the pelvis, and audiovisual equipment. We also employed the services of a patient actor for demonstration purposes.

Alternatively, if an anatomy lab is available, the procedure can be performed on a cadaver. Each fellow then demonstrated how he/she would carry out the procedure. Teaching faculty and senior fellows observed these demonstrations and provided critiques. They also demonstrated their ability in making slides, using fake blood. Specific attention was paid to the communication aspects of the demonstration, especially ensuring that correct consent was obtained, the indications and complications of the procedure were explained, and that adequate anesthetic and pain control was offered.

This simulation lesson must be followed up with reinforcement of the procedures taught in this program during livepatient encounters. We have developed an evaluation form that is used by an attending physician or a senior fellow to evaluate the junior fellows on their performance when they perform a bone marrow biopsy on their first 5 patients. This is an invaluable tool in helping to streamline the process of feedback and helps the fellows hone their skills further. The specific areas on which each fellow is graded are shown in the Table. In these areas, each fellow is graded on a 5-point scale from “superior performance,” “good,” “fair,” “sub-standard,” to “unable to grade because of lack of observation.”

Feedback from the participating fellows and attending physicians has been very encouraging. The fellows now have greater self-confidence when carrying out their first bone marrow biopsy and their learning curve is much steeper. We plan to offer this program to incoming fellows every year. We strongly believe that this program will streamline the process of fellows learning this essential procedure. The more detailed training offered in this program helps fellows become skilled at performing a bone marrow biopsy, and these abilities are practiced and reinforced further during their live-patient encounters.

		Malempati S, Joshi S, Lai S, et al. Videos in clinical medicine: bone marrow aspiration and biopsy. 

		Khan C, Moffa C. How to do the perfect bone marrow biopsy. 

When this article was written, Cyrus Khan, MD, was chief fellow in the hematology/oncology fellowship program at the West Penn Allegheny Health System in Pittsburgh, Pennsylvania. He is now a member of the faculty in the Division of Stem Cell Transplantation and Cellular Therapy at the same institution. Ghulam Rehman Mohyuddin is a final-year medical student at the Aga Khan University, Karachi, Pakistan, who has completed a clinical elective in hematology/oncology at the same institution.

Articles

A bone marrow aspirate and biopsy is the single most common procedure that hematologists and oncologists carry out day in and day out throughout their career.

Bone Marrow Biopsy Simulation Training for Fellows

	As hematology/oncology fellows, we work with colleagues from multiple specialties. However, the majority of our interactions are with the internal medicine service, so here we will help you to maximize the quality of your interactions with internal medicine residents. In the following paragraphs, you will find many ideas that if followed will not just help you to “do your time” during fellowship, but contribute to the internal medicine residency program. And who knows, you just might inspire a resident to pursue oncology as a career!

	Generally, fellows work with internal medicine residents on the consultation service and on the inpatient oncology service. Thus, I will focus on these settings. At the end, there are also some general considerations that can be applied throughout your fellowship.

	The consultation service is the bread and butter of the hematology/oncology fellowship. As a future consultant, you are expected to develop the skills necessary to become an effective and efficient team player. Remember, you have been consulted for clinical guidance in answering a question, no matter how simple it may seem to you. The following is a list of points to consider:

 Residents are not born hematologists/ oncologists—there is a reason why they are consulting you. Belittling a consult only creates tension between the consultant and primary team. Treat every consult as a learning and teaching opportunity.

 It is imperative to know what questions the consulting team are asking. This is best clarified by speaking to the primary team directly. Oncology patients frequently have multiple problems. You do not want to write a detailed note regarding management of lung cancer when help is requested to evaluate thrombocytopenia.

Once again, this is best established by speaking directly to the consulting team. As 7fellows, we receive many consults of varying urgencies. Triage is of utmost importance. A 5 pm consult for thrombotic thrombocytopenic purpura is very different from a 5 pm consult for a mild chronic anemia.

Gather all patient-related information yourself.

 For an effective consult, every piece of clinically relevant data must be known. If this requires calling different offices and physicians, it is far more efficient to do it yourself than to delegate it to the primary team. We are often searching for specific information from a hematology/ oncology perspective, which the primary resident may not yet be qualified to address. Not only is this a fellow’s responsibility, but it also expedites the consult, preventing the patient and primary team from waiting in limbo.

When you’re finished writing your note, it is best to call the resident on the consulting team and verbally communicate your recommendations. Most training programs require that consultants not place orders on patients and instead allow the primary team to write all orders. This prevents multiple orders on the same patient and also serves as an opportunity for resident teaching. Speaking with the residents also results in quicker implementation of your recommendations. If you are unsure about the specifics of a recommendation, check with your attending before writing them down.

 It is important to understand your role as a consulting fellow. It may seem natural to comment on issues like electrolyte disturbances, hypertension, and diabetes with recommendations on how to correct them. This is especially true for first-year fellows who are just coming out of residency and are used to managing every aspect of patient care. These comments are often not welcomed by the primary team or other consulting specialties. Thus, it is probably better to stick with making recommendations specific to your expertise, unless there is a glaring issue.

 Providing an article addressing the consulting topic improves patient care and resident education. Not only will this give credence to your recommendations, but it will serve as testament to your commitment to resident teaching. The extra effort to provide education today may even save you an extra consult on a busy day.

 Your role as a consultant does not end with the initial consult. It is your professional responsibility to provide appropriate follow-up until the primary team is satisfied that their question has been answered. Consultation can conclude when the primary team feels comfortable managing the issue for which you were consulted.

	Many programs have inpatient oncology, hematology, or bone marrow transplant services with resident and fellow coverage. The fellow serves as the junior attending and is encouraged to make decisions regarding patient care, as well as to take an active teaching role. It is important to make these services worthwhile for residents so that instead of considering the rotation a burden, they see it as an exceptional educational experience.

 Do not consider residents as simply “help.” They should be treated respectfully, and it is your responsibility to look after their well-being. The service runs far smoother if the residents feel they are part of the team and not just there to do grunt work.

Learn to run an efficient service from the get-go. As the liaison between the attending and the residents, you will be in the best position to coordinate a smooth service. This ensures that the resident’s time is not wasted waiting for rounds to finish, etc.

 Teach residents on a daily basis. Be it a 5-minute talk on common hematology/oncology topics or reviewing board questions, residents will appreciate your commitment to education. With education incorporated into resident interactions, the internal medicine program will see the value and continue to staff the inpatient oncology service with residents.

Try to help out the residents from time to time in areas where there is no educational value, such as appointment scheduling and gathering outside records. This goes a long way in establishing rapport with your residents.

	Outside of the 2 major settings described, there are many other opportunities to contribute to the internal medicine program.

Attend morning reports as a subject expert.

 Hematology/ oncology patients are invariably presented at morning report. Since it is hard to be well versed in our specialty at a resident’s level, it is of great benefit to the program to attend these sessions. This develops a healthy relationship between yourself and the program and establishes your commitment to resident education.

Another area where you can pitch in is at board review sessions. Many internal medicine programs will arrange these sessions for their third-year residents. You can provide guidance in how to approach hematology/ oncology questions and identify the key issues. This is an easy way to enhance the quality of the internal medicine program and cement resident-appropriate teaching points.

 In every program, there are residents aspiring to be fellows like yourself. They will invariably want to get involved in research projects. Attendings are often hard to get a hold of, so you can serve as a great resource. Include residents in your research or develop ideas with them that they can pursue on their own. This act of goodwill will help them advance their careers.

	Following the above advice will not only help you train as an effective teacher and team player, but will add immense value to the internal medicine residency program. As future hospitalists and internists, today’s residents will look to your teachings in their care of patients with hematological or oncological problems. In the end, remember this twist on the famous quote by John F. Kennedy: “Ask not what your residency program can do for you, ask what you can do for your residency program.”

There are many ideas that if followed will not just help you to "do your time" during fellowship, but contribute to the internal medicine residency program.

How Fellows Can Add Value to Their Internal Medicine Residency Program

“The bone marrow aspirate is dilute and cell morphology cannot be adequately determined. The biopsy specimen is inadequate to determine cellularity.” This is not the kind of result you’re looking forward to after putting your patient through an ordeal that’s best described by his comment: “Doc, this is the closest I’ll ever come to experiencing the pain of childbirth as a 45-year-old man.”

A successful bone marrow aspirate and biopsy require not only experience and good technique, but also patience and perseverance. The procedure can be challenging for you and the patient, but being cognizant of some important issues can lead to better-quality biopsies and make the experience more tolerable for the patient. The intent of this article is not to provide an expansive review of how to perform a bone marrow biopsy, as this can be found in many texts, but rather to emphasize some important tips in order to successfully perform the perfect bone marrow biopsy.

In Alan Lakein’s words, “Failing to plan is planning to fail.” As with any medical procedure, being well prepared cannot be overemphasized. Realizing that some important equipment is missing during the procedure or that the patient is not in the proper position can be very unsettling. It is also crucial that you determine in advance whether the biopsy will be taken from the more common and easily accessible posterior superior iliac spine, or from the sternum when there is difficulty in getting samples from the iliac spine (eg, such as in an obese patient or one with anatomical deformities).

It is important to be familiar with the patient’s history and understand why the biopsy is necessary. Just as important as the biopsy itself is ensuring that you order the correct studies on the specimen, which in turn depends on what diagnosis is being entertained. It is also equally imperative to know when not to do a biopsy. There are a few circumstances that are considered absolute contraindications, such as hemophilia, severe disseminated intravascular coagulation (DIC), and other bleeding disorders. Thrombocytopenia is usually not a contraindication. Also, remember that while a sternal aspirate is possible, a biopsy should never be attempted in this case due to the close proximity to vital structures of the thorax and the fact that only a thin bony plate is separating your needle from these structures.

It is generally understood that fellowship training is exceptionally busy and finding adequate time for the biopsy can be very challenging. It is important to choose a block of time in which you can carry out the procedure in an unrushed fashion. It is counterproductive to schedule a biopsy half an hour before an important conference or another important task; it is typically recommended to allocate at least 45 minutes for the procedure. The time it will take you to do a biopsy can be unpredictable. Some will be only 20 minutes while others may require an hour if complications arise. Make sure you give advance notice to the patient and their nurse and ensure that they are not scheduled for any other procedures during the dedicated time. Ideally, the biopsy should be done in a private patient room where there is more space and privacy; however, this may not always be possible in the hospital setting. Check that the patient’s bed is in working order and see that enough personnel are available to help in order to keep interruptions to a minimum.

Familiarize yourself with the specific biopsy kit that is used at your institution and gather any other necessary material that is not provided with the kit. Make a checklist. In general, the following equipment is needed: aspirate and biopsy needles, syringes with needles, sterile gloves, antiseptic swabs, gauze material, lidocaine, heparin, collection tubes and pathology specimen cups to send off the required samples (usually, these are aspirates for morphology, immunohistochemistry, flow cytometry, and cytogenetics, as well as a biopsy specimen for pathology), slides, and the necessary request forms. This list is a general guideline and should be modified to meet specific institutional needs.

Many patients cringe at the notion of having to go through a bone marrow biopsy, as they have inadvertently heard that it is a “horrible” procedure. It is important that you prepare the patient for the procedure to help ease his or her preconceived ideas. A conscious effort should be made to not trivialize the procedure, since it is probably the patient’s first experience.

Appropriately counsel the patient beforehand and go through each planned step in detail. Explain why the biopsy is necessary and what to expect during each step. Never say that the biopsy is painless, as this is typically not the case. Tactfully reiterate that you will do your best to minimize pain and discomfort and that the procedure is generally well tolerated with adequate use of local anesthesia. Obtain informed consent and be sure that you describe the possible complications, which are generally very rare.

 Prepare the patient for what to expect afterward, such as pain and discomfort in the area and how to care for the biopsy site. Tell the patient how long it usually takes for test results to become available at your institution. Ensure that the patient understands your instructions completely, will be able to cooperate during the procedure, and will answer any questions.

It is virtually impossible to completely eliminate pain from the biopsy procedure, but certain measures can help reduce the discomfort or at least the perception of pain. People have different pain thresholds, which is illustrated by the very different comments made by various patients postprocedure. One patient may feel very little pain (“I must be one of the lucky ones. I didn’t feel much pain (maybe a 4 or 5), mostly just a lot of pressure”), while another may have a completely different experience (“That was the most pain I have ever experienced in my life. When they broke through the bone into the marrow, a pain shot down my legs that caused me to break a sweat and curse like a drunken sailor”). In a study of 235 patients undergoing a bone marrow biopsy, 56% reported moderate pain while 32% reported severe pain.

 Another factor that may augment a patient’s perception of pain is the anxiety associated with the procedure. Up to 75% of patients in 1 study reported moderate to severe procedural anxiety.

 It is important that you are mindful of these facts and that you make an effort to individualize each patient’s pain and anxiety management. It cannot be overemphasized that the specimen obtained may be of much better quality if the patient is comfortable and cooperative.

Most patients do well with only local anesthesia but there may be some who need premedications, usually narcotic analgesia, anxiolytics, or even conscious sedation. If only local anesthesia is used, an adequate amount should be given. Anesthetize a wide area and don’t hesitate to use additional anesthetic if the adequacy of pain control is not optimal. Do not continue to poke and prod while trying to comfort the patient with words like “It’s going to be over soon” while the patient cries in pain. There is no reason why more local anesthetic cannot be given.

The choice and dose of the premedication may vary based on personal experience, but generally an IV or oral morphine derivative and lorazepam can be used to both provide some sedation and help with pain. If possible, the premedications should be given at least 30 minutes before the planned time of the procedure. A study of 138 patients undergoing a bone marrow biopsy reported that using 1 mg of lorazepam preprocedure did not reduce pain significantly but enhanced cooperation of the patient and his or her willingness to undergo another procedure.

 Another study evaluated 84 patients who had either 10 mg of oral oxycodone and 2 mg of lorazepam or placebo administered 30 minutes prior to the procedure. Compared with placebo, the combination regimen provided a 14% decrease in the perception of pain (P ≤.05).

There is no conclusive evidence that premedicating a patient necessarily reduces procedural pain, but it may be helpful under certain conditions and help get the actual procedure done more effectively and efficiently.

It is important that you learn correct biopsy technique early in your fellowship, because it is difficult to unlearn poor technique later on in your career. Before beginning to perform biopsies under supervision, observe attending physicians or other senior fellows who have developed a good technique. Once you have advanced to performing biopsies on your own, have them observe you until you have become proficient. There is a lot of variation among each procedure and while the first 10 biopsies may go smoothly, the 11th one may be challenging and require the help of a more experienced colleague. Another good way to learn is to watch a video (available to subscribers) at the 

Another testament to a good overall procedure is the quality of the sample provided. If you’re sending the aspirate specimen directly to the lab instead of preparing slides at the bedside, ensure that spicules are present. Getting a good-quality aspirate may not be possible under certain circumstances. When this situation is encountered a touch imprint can be provided to the pathologist to assist with the diagnosis. It is also critical to get a good-length biopsy specimen; it is generally accepted that a 2-cm specimen has greater diagnostic yield.

 Remember to collect adequate specimens for the various studies that will be ordered. In the situation where you cannot get good, adequate samples or find the correct location, try to switch sides, obtain a sternal aspirate, or even consult radiology to perform the procedure under radiological guidance. Toward the end, apply a pressure dressing and instruct the patient to lay supine for 20 to 30 minutes to allow for adequate hemostasis.

Take comfort in the fact that complications are quite rare. In a report published in 2003, there were only 26 adverse events out of a total of 55,000 procedures.

 In the event that a complication does occur, you will need to be prepared. Some common complications are bleeding from the biopsy site and local infections. Bleeding can generally be controlled with adequate and prolonged pressure to the site. Infections can be prevented by good antiseptic technique and are usually limited to the skin. Other complications are even rarer and can include needle breakage, transient neuropathy, or fracture due to underlying osteoporosis.

At the conclusion of the procedure, ensure that all sharps are discarded properly. Thank the patient and clean up behind yourself. You don’t want to be known as the notoriously sloppy fellow in nursing-gossip circles. Doublecheck that all samples are labeled correctly and sent to the correct departments. Hopefully, by following these general guidelines you will become more comfortable at performing bone marrow biopsies and every one of them will be perfect. 

1. Bain BJ. Bone marrow biopsy morbidity and mortality. 

2. Liden Y, Landgren O, Arner S, Sjolund KF, Johansson E. Procedurerelated pain among adult patients with hematologic malignancies. 

3. Brunetti GA, Tendas A, Meloni E, et al. Pain and anxiety associated with bone marrow aspiration and biopsy: a prospective study on 152 Italian patients with hematological malignancies [published online ahead of print February 2, 2011]. 

4. Park SH, Bang SM, Nam E, et al. A randomized double-blind placebocontrolled study of low-dose intravenous Lorazepam to reduce procedural pain during bone marrow aspiration and biopsy. 

5. Talamo G, Liao J, Bayerl MG, Claxton DF, Zangari M. Oral administration of analgesia and anxiolysis for pain associated with bone marrow biopsy. 

6. Malempati S, Joshi S, Lai S, Braner DA, Tegtmeyer K. Videos in clinical medicine: bone marrow aspiration and biopsy. 

7. Campbell JK, Matthews JP, Seymour JF, Wolf MM, Juneja SK. Optimum trephine length in the assessment of bone marrow involvement in patients with diffuse large cell lymphoma. 

Cyrus Khan, MD, is a third-year hematology/oncology fellow at the West Penn Allegheny Health System in Pittsburgh, Pennsylvania. He is planning a career in hematopoietic stem cell transplantation. Casey Moffa, DO, is a graduate of the Philadelphia College of Osteopathic Medicine and is currently a third-year hematology/oncology fellow for the West Penn Allegheny Health System in Pittsburgh, Pennsylvania. She is planning a career in community oncology.

Obtaining a high-quality bone marrow aspirate and biopsy is very important for the patientâ€”and for you. Following these general guidelines will help you do this successfully.

How to Perform the Perfect Bone Marrow Biopsy

	In this country, an estimated 46 million people—20.6% of all adults&mdash;smoke cigarettes. Cigarette smoking also happens to be the leading cause of preventable death in the United States, accounting for approximately 443,000 deaths, or 1 of every 5 deaths each year. Approximately 40% of these deaths are from cancer, of which lung cancer is the most prevalent.

	In addition to the disastrous impact that tobacco use has on our collective health as a nation, it wreaks havoc on our economy. Cigarette smoking is estimated to be responsible for $193 billion in annual health-related economic losses in the United States—that’s $96 billion in direct medical costs and approximately $97 billion in lost productivity. Cigarette smoking results in 5.1 million years of potential life lost in the United States annually.

	It is estimated that 70% of smokers want to quit completely and that 45% of smokers have tried to quit. Yet we realize from our interactions with patients that this is often a losing battle. Patients, even those with lung cancer, at some point in time will return to smoking. Compared with the billions of dollars that cigarette companies pour into marketing their products, the healthcare system is ill-equipped to respond. Smokers who want to quit often have limited resources available to them. As fellows and residents, we often know how important it is to counsel, yet have limited time with each patient to do so.

	There are many smoking cessation interventions available, group sessions being one of them. As effective as they are, they are often an option only for those who can pay for them. As fellows and residents, we not only have a responsibility to help fight this major public health hazard, but we are also in an excellent position to do so. Most training programs are affiliated with community health centers. Approximately 20 million Americans are served by such centers, with 40% of these affiliated with residency programs. The majority of patients that visit such centers are poor—the very people who smoke the most and who therefore need the most help. In the following sections, we provide an overview of how fellows/ residents can set up and successfully run a smoking cessation clinic.

	Planning is of paramount importance. You will need to speak with the health center director and ensure that resources are available to run such a clinic, which is held in a group meeting format in 2-hour-long sessions once a week for 4 weeks. The following are needed:

		A large conference room that can hold 10 to 15 people and that is available for a 2-hour slot on a specified day every week for 4 consecutive weeks

		A nurse and a medical assistant (MA) who are available each week for that 2-hour time period

		An attending physician who can be available for 30 minutes per session

		A whiteboard and pens and paper for the patients

	Once you have selected a day and a 2-hour time slot, begin by advertising the clinic. Print out flyers, hang them up in the clinic, and give them out to patients. Have a system in place where the MAs ask each patient coming through the clinic about his or her smoking status. If the patients smoke, at checkout have the staff off er to enroll them in your free smoking cessation clinic. Many will take you up on the off er. Once you have 10 to 15 patients enrolled, you are ready to start your very own smoking cessation clinic!

	Next, we will describe how you should conduct each of the 4 sessions. Note that the group sessions will last for approximately 1 hour, with the remaining 1 hour used for individual patient counseling in exam rooms. This counseling allows the clinic to bill for the sessions.

	Start off by congratulating the patients for joining. Introduce them to the notion of smoking cessation through behavior modification and group therapy along with pharmacotherapy, if necessary. Stress the importance of follow-up through subsequent sessions. Hand out printed smoking cessation material, if available.

	Next, talk about the harmful effects of smoking. Involve the group and ask them how much they know about the dangers associated with smoking. Discuss the heightened risk of cancer and chronic obstructive pulmonary disease (COPD). A useful exercise is to give out straws and ask the patients to pinch their noses and only breathe through the straws in their mouths; explain that if they do not stop smoking, this is how it will feel when they have emphysema.

	Discuss in detail the benefits of quitting smoking. Specifically mention the health benefits, such as having more energy and a reduced risk of cancer and heart and lung diseases. Emphasize the psychological benefits, such as increased self-esteem and self-respect and a sense of accomplishment in quitting. Next, talk about the financial benefits, such as reduced insurance premiums, decreased future healthcare costs, and an almost $2000 savings per year from not buying cigarettes.

	Wrap up by preparing patients for session 2. Prior to the next session, ask patients to think about what triggers their smoking. They should consider the reasons why they smoke as well as their desire to quit. Have them reflect on their past attempts to quit and why they failed and to start thinking about a quit date. Answer any questions that they may have. At the end of this and each subsequent session will be individualized patient sessions. (These are described at the end of the article.)

	This session will help patients understand the psychological aspects of smoking. It is designed to explore in detail the patients’ reasons for smoking and why they want to quit, and to reflect on past experiences with quit attempts.

	Start off by asking patients to discuss the reasons they smoke. Write them down on the whiteboard. Ask them if they think smoking is a psychological need or truly a physical addiction to nicotine. Ask them when they have their first cigarette in the morning. Then ask each patient why he or she likes or dislikes smoking. This exercise will start a discussion among the participants and help them realize the reasons they smoke so that they can plan to gradually eliminate those reasons.

	Discuss the circumstances in which they smoke each cigarette. Are they happy, sad, angry, frustrated, nervous, or something else? Make a list on the whiteboard of all the triggers for the different patients. They will soon realize that everyone has fairly similar triggers.

	Next, talk about the true desire of the patient to quit. Discuss why it is so important to do so. Make sure they understand that they may have to undergo many months—if not years&mdash;of self-reflection and attempts at quitting before finally being successful.

	Now, discuss in more detail the patients’ past quit attempts. Discuss the methods used. Ask them how long their quit periods lasted and whether the attempts were successful. Talk about the reasons why the patients feel that specific past interventions did not work.

	A useful exercise is to give out straws and ask the patients to pinch their noses and only breathe through the straws in their mouths; explain that if they do not stop smoking, this is how it will feel when they have emphysema. ”

	Toward the end of this session, you will discuss some strategies to cope with urges to smoke. Ask them to remember the “4 Ds” when they feel the need to smoke: delay, deep breath, drink water, and do something else. Ask each patient to come up with 3 situations that made him or her really want to smoke again. Write those on the whiteboard. Then ask them what they could do instead.

	Session 3: Arming Patients With the Tools to Quit

	Hopefully, by now the patients will have a clear idea of what makes them smoke and what strategies they can use to quit. This session is about dealing with recovery symptoms (ie, nicotine withdrawal) and the correct use and side effects of different smoking cessation products. At the end of this session the product of choice should be prescribed, if appropriate for the patient.

	It is important to teach patients how to deal with withdrawal. Explain that after quitting smoking, the body experiences both physical and psychological “recovery symptoms.” These symptoms decrease after the first few days and usually pass within 2 to 4 weeks. Specific interventions that can help are taking fluids for a dry mouth, sipping warm water for a cough, and having low-calorie snacks to combat hunger pangs. Other symptoms that are expected are insomnia, fatigue, headache, irritability, and constipation.

	Next, you will review products that can be used for smoking cessation. These include nicotine replacement (eg, patch, gum, lozenge, inhaler), bupropion, and varenicline (Chantix). Based on patient preference, any product or combination can be chosen. If nicotine replacement is chosen, it is best to prescribe the patch plus a short-acting nicotine product (eg, gum, lozenge) to deal with the cravings.

	You will need to describe in detail how to correctly use each product, their advantages and disadvantages, and their side effects. This sort of material is easily found on Web sites such as Uptodate.com.

	At this point, you hope that the patients have quit smoking and are perhaps also on a smoking cessation aid. This is the last session of the series and will mainly focus on relapse prevention and answering any questions that the patients might have about the program and the previous sessions.

	First off , discuss relapse-prevention techniques. Relapse prevention requires that patients develop a program that suits them and that they will follow if they begin to slip back to smoking. Talk about avoiding situations that serve as triggers to smoke. Exercising and taking up new hobbies often help. At the end, provide a short recap of all the sessions. If patients are using any of the smoking cessation aids, ensure that they are using them correctly. Answer any questions. Also be sure that you book follow-up visits with the patient’s primary care provider specifically for smoking cessation consultation.

	These sessions are required for billing purposes. The patients would already have had their vital signs taken by an MA when they registered for the course. The staff will bring them to the exam rooms and each meeting with the fellow or resident should not take more than 3 minutes. Briefly go over the specific reasons that the patient should quit. If the patient has a disease, such as coronary heart disease, the physician should tailor the smoking cessation plan accordingly. Briefly document your discussion and then precept with an attending physician. If needed, other patient complaints or concerns should be addressed on a separate visit. This meeting is only for smoking cessation.

	This program serves as a basic outline and can be tailored to your own specific needs and patient population. If you would like more details about running a smoking cessation clinic, please contact Dr Khan at 

Cyrus Khan, MD, is a second-year hematology/oncology fellow at the Western Pennsylvania and Allegheny General Hospital in Pittsburgh. Realizing that the lack of smoking cessation services was a major drawback to the efforts of patients who wanted to quit smoking, he helped start his community health center’s very first smoking cessation program.

	Alice Ulhoa-Cintra, MD, is a second-year hematology/oncology fellow at the Western Pennsylvania and Allegheny General Hospital in Pittsburgh. Her primary interests encompass all aspects of solid tumor oncology, including cancer-preventive strategies with the potential for a significant public health impact, such as smoking cessation initiatives.

Cigarette smoking is the leading cause of preventable death in the United States, accounting for approximately 443,000 deaths, or 1 of every 5 deaths each year.

Cyrus M. Khan, MD

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