Tania Jain, MBBS, director, Adult Chimeric Antigen Receptor T-cell Therapy Program for Hematological Malignancies, Sidney Kimmel Comprehensive Cancer Center, assistant professor of oncology, Johns Hopkins Medicine, discusses notable differences in baseline characteristics and donor sequencing, according to a retrospective study of patient outcomes following blood or marrow transplant in 4 common donor types of myelofibrosis.

This real-world retrospective study compared the outcomes of 4 common donor types in myelofibrosis. Data from 1057 adult patients who underwent a first allogenic stem cell transplant (allo-SCT) using a peripheral blood graft between 2013 and 2019 for chronic phase myelofibrosis were obtained from the CIBMTR and the CIBMTR is a working group of over 500 BMT centers. Patients had either a matched sibling donor (MSD), matched unrelated (MUD) donor, mismatched unrelated donor (MMUD), or a haploidentical donor (HD) with posttransplant cyclophosphamide.

Notable differences were observed at baseline in the study population, Jain begins. As expected, a majority of MSD, MUD and MMUD patients were White, she says. Specifically, about 40% of HD donors were of non-White ethnicities. This demographic breakdown is relevant to note, as recently published data have shown a difference in transplant outcomes in patients of non-White ethnicities, Jain explains. This discrepancy may not be solely attributable to socioeconomic factors, and could be influenced by biological factors, she says.

Furthermore, sequencing donor selection in clinic is different than that of clinical trials, Jain continues. Typically, MSDs are the preferred donor option for patients with myelofibrosis. If no MSDs can be identified, the search will expand to MUD, followed by the other 2 donor types. However, research has shown that it takes longer to identify a HD vs a MSD, Jain reports. This practical limitation often results in a longer delay in transplant for patients waiting for an MMUD or HD, she states.

Findings from the study showed that HD and posttransplant cyclophosphamide is a viable alternative to MUD for patients requiring allo-SCT who cannot find a MSD. These results indicate that this delay in transplant is not necessary for these patients, Jain says. Additionally, HDs are more readily available, and may be more affordable for some patients, she concludes.

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Tania Jain, MBBS, discusses notable differences in baseline characteristics and donor sequencing, according to a retrospective study of patient outcomes following blood or marrow transplant in 4 common donor types of myelofibrosis.

Dr Jain on Baseline Differences Across Different Donor Types in Myelofibrosis

Tania Jain, MBBS, director, Adult Chimeric Antigen Receptor T-cell Therapy Program for Hematological Malignancies, Sidney Kimmel Comprehensive Cancer Center, assistant professor of oncology, Johns Hopkins Medicine, discusses the use of haploidentical donors (HD) in myelofibrosis.

At the 2023 Transplantation and Cellular Therapy Meetings, investigators presented blood and marrow transplant outcomes with haploidentical and unrelated donor types in myelofibrosis. The aim of the study presented by Jain et al was to determine how haploidentical donors compare with other forms of donor selection for allogeneic transplant.

Results from a prior multicenter study demonstrated that the use of haploidentical donors was associated with an overall survival (OS) rate of 72% at 3 years, Jain explains, adding that this was a time when people were skeptical of haploidentical grafts and how it would fare against patient splenomegaly, Jain notes.

The present study used registry data from CIBMTR to provide a better comparison of donor types, Jain notes. Investigators compared all 4 donor types: matched sibling donor, matched unrelated donor, mismatched unrelated donor, and haploidentical donors with post-transplant cyclophosphamide and their outcomes in patients with myelofibrosis following transplant, Jain continues.

Investigators showed that matched sibling donors were associated with better OS compared with the other 3 donor options. However, within haploidentical donors, matched unrelated donors, and mismatched unrelated donors, there were no significant differences in OS, Jain expands. This is different compared with what the registry data showed over 10 years ago, Jain notes. This speaks to the progress that the transplant platforms, transplant treatments, and supportive management have done over the past decade, Jain concludes.

Tania Jain, MBBS, discusses the use of haploidentical donors in myelofibrosis.

Dr Jain on the Use of Haploidentical Donors in Myelofibrosis

Tania Jain, MBBS, director, Adult Chimeric Antigen Receptor T-cell Therapy Program for Hematological Malignancies, Sidney Kimmel Comprehensive Cancer Center, Assistant Professor of Oncology, Johns Hopkins Medicine, discusses the unmet needs for patients with myelofibrosis who receive an allogeneic stem cell transplant (allo-SCT).

At the 2023 Transplantation and Cellular Therapy Meetings, Jain presented data from a retrospective study evaluating outcomes for patients with myelofibrosis who had haploidentical donors (HD) and posttransplant cyclophosphamide vs other common donor types.

Findings from the study reflected that investigators still have considerable work to do in order to optimize allo-SCTs for patients with myelofibrosis, Jain begins. One area of need is relapse prevention, Jain says, adding that investigators are working to set up studies evaluating maintenance strategies post–allo-SCT to improve relapse rates.

Moreover, in the retrospective study, investigators showed that relapse rates were higher for patients with a larger spleen size going into transplant, Jain says. Novel agents currently under investigation in myelofibrosis could improve spleen response in patients, Jain continues. These could be beneficial for patients who will undergo allo-SCT, and it will be helpful to observe what a improved spleen responses with advanced therapies could mean for patients achieve in terms of transplant outcomes, Jain explains.

If patients with myelofibrosis are going to be referred for transplant, it should be done early before they have the chance to get worse or progress, Jain continues. The longer the patient is not referred, the quicker the window for transplant closes, and sicker patients do not do as well on clinical trials, Jain says. Moreover, it is important not to delay transplant looking for a perfectly matched donor when there are options with different donor types that can also help patients, which is important to consider, Jain concludes.

Tania Jain, MBBS, discusses the unmet needs for patients with myelofibrosis who receive an allogeneic stem cell transplant.

Dr. Jain on Unmet Needs in Patients with Myelofibrosis Undergoing Allo-SCT

Tania Jain, MBBS, director, Adult Chimeric Antigen Receptor T-cell Therapy Program for Hematological Malignancies, Sidney Kimmel Comprehensive Cancer Center, Assistant Professor of Oncology, Johns Hopkins Medicine, discusses post-transplant cyclophosphamide-based transplantation from haploidentical donors (HD) in myelofibrosis.

Data were presented at the 2023 Transplantation and Cellular Therapy Meetings from a retrospective study comparing the outcomes of 4 common donor types in myelofibrosis: matched sibling donor (MDS), matched unrelated (MUD) donor, mismatched unrelated donor (MMUD), and HD with post-transplant cyclophosphamide. Findings showed that overall survival (OS) favored patients with MSD; however, investigators aimed to better understand this difference, Jain says. In a multivariate analysis, investigators examined OS within the first 3 months post-transplant and the overall OS, Jain notes.

The significant difference in OS was found within the first 3 months, which investigators linked to higher instances of non-relapse mortality in patients in the MUD, MMUD, and HD arms, Jain explains. Beyond 3 months, there was no significant difference in OS, Jain adds. Moreover, there was no difference in relapse and notably, occurrence of graft-vs-host disease was better with patients who had an HD or MUD, Jain says.

A surprising result was high graft failure rate in patients with an HD, Jain continues, adding that investigators want to explore these findings deeper to better understand whether this is true a problem, or whether these data were a result of the growing pains following the introduction of HD to practice over the past decade, Jain notes.

HD came into practice around 2008, upon the publication of a Johns Hopkins research paper, and in 2013, the first haploidentical donors became evident in myelofibrosis, based on the registry data, Jain says. To better understand if rates of graft failure improved with increased experienced with HD, investigators are capturing a time-variable outcome in terms of graft failure, Jain concludes.

Tania Jain, MBBS, discusses post-transplant cyclophosphamide-based transplantation from haploidentical donors in myelofibrosis.

Dr. Jain on Transplantation from Haploidentical Donors in Myelofibrosis

Tania Jain, MBBS, assistant professor of oncology, Division of Hematological Malignancies and Stem Cell Transplantation, Johns Hopkins University, discusses the potential for graft-versus-host disease (GVHD) as a complication of allogeneic stem cell transplant (allo-SCT).

Acute GVHD may present as a skin rash, gastrointestinal (GI) symptoms, or liver disease, says Jain.

GVHD is thought to occur from inflammation caused by increased cytokine release resulting from tissue injury during conditioning, explains Jain.

The standard first-line treatment of GVHD is high-dose corticosteroids, says Jain. Though, ongoing research is investigating combination therapy with corticosteroids.

In May 2019, the FDA approved the JAK inhibitor ruxolitinib (Jakafi) for the treatment of patients with steroid-refractory acute GVHD. Another second-line option is extracorporeal photopheresis, says Jain.

Novel drugs currently in the pipeline include CD25-directed agents and abatacept (Orencia), concludes Jain.

Tania Jain, MBBS, discusses the potential for graft-versus-host disease as a complication of allogeneic stem cell transplant.



Dr. Jain on GVHD From Allogeneic Stem Cell Transplant

Tania Jain, MBBS, assistant professor of oncology, Division of Hematological Malignancies and Stem Cell Transplantation, Johns Hopkins University, sheds light on the mutations that confer worse prognosis in myelofibrosis.

 have high-risk myelofibrosis, says Jain. These patients typically have decreased leukemia-free survival and overall survival, explains Jain.

As a result, patients who harbor these mutations may be considered for allogeneic stem cell transplant sooner in their disease course compared with patients without these mutations, concludes Jain.

Tania Jain, MBBS, sheds light on the mutations that confer worse prognosis in myelofibrosis.

Dr. Jain on High-Risk Mutations in Myelofibrosis

Tania Jain, MBBS, assistant professor of oncology, Division of Hematological Malignancies and Stem Cell Transplantation, Johns Hopkins University, discusses treatment options for patients with myelofibrosis who progress following allogeneic stem cell transplant (allo-SCT).

Selecting a treatment for patients who progress following allo-SCT largely depends on what kind of relapse occurs, explains Jain.

For example, patients who have a molecular relapse in which a JAK mutation or other molecular driver is positive should be considered for a donor lymphocyte infusion (DLI). Though, DLI is associated with an increased risk of graft-versus-host disease, says Jain.

Additionally, all patients who relapse after allo-SCT can receive JAK inhibition to reduce symptoms or splenomegaly.

Patients whose myelofibrosis transforms to acute myeloid leukemia (AML) should receive therapies that are indicated for patients with AML, says Jain.

In rare circumstances, younger patients may be considered for a second allo-SCT, concludes Jain.

Tania Jain, MBBS, discusses treatment options for patients with myelofibrosis who progress following allogeneic stem cell transplant.

Dr. Jain on Treatment Options for Patients With Myelofibrosis Who Progress After Transplant

Tania Jain, MBBS, assistant professor of oncology, Division of Hematological Malignancies and Stem Cell Transplantation, Johns Hopkins University, discusses the role of allogeneic stem cell transplant (allo-SCT) in myelofibrosis.

Currently, allo-SCT is the only curative-intent treatment for patients with myelofibrosis, says Jain. Drugs like ruxolitinib (Jakafi) and fedratinib (Inrebic) may offer symptom management and reduction in spleen size. However, they do not alter the natural history of the disease. 

Patients with intermediate-2 and high-risk myelofibrosis according to the Dynamic International Prognostic Scoring System (DIPSS)-plus scoring system or those with transfusion-dependence complications should be considered for allo-SCT. Other factors that may influence transplant eligibility include age and organ function, says Jain.

Additionally, the Mutation-Enhanced International Prognostic Scoring System (MIPSS)70 and MIPSS70-plus version 2.0 scoring system may offer prognostic information that could shed additional light on transplant eligibility, concludes Jain.

Tania Jain, MBBS, discusses the role of allogeneic stem cell transplant in myelofibrosis.

Dr. Jain on the Role of Allogeneic Transplant in Myelofibrosis

Tania Jain, MBBS, assistant professor of oncology, Division of Hematological Malignancies and Stem Cell Transplantation, Johns Hopkins University, discusses the challenges faced with allogeneic transplant in patients with myelofibrosis.

Many patients with myelofibrosis are not considered for allogeneic transplant and therefore are not referred to tertiary centers for a transplant evaluation, says Jain. Although this approach has curative intent, the process is associated with morbidity and mortality.

In myelofibrosis, patients have a chronic malignancy they have been dealing with for years before they go on to receive transplant. During the time that they’re living with the disease, they tend to develop associated comorbidities, such as splenomegaly, decreased performance status, and pulmonary hypertension, among others. These comorbidities make patients less optimal candidates for transplant and thus these patients often experience inferior outcomes post-transplant compared with other malignancies, explains Jain.

A lot of work still needs be done in order to improve survival after allogeneic transplant in patients with myelofibrosis because this is the only curative option available, concludes Jain.

Tania Jain, MBBS, discusses the challenges with allogeneic transplant in patients with myelofibrosis.

Dr. Jain on Challenges With Allogeneic Transplant in Myelofibrosis

Tania Jain, MBBS, assistant professor at Johns Hopkins University, discusses hematopoietic recovering following treatment with a chimeric antigen receptor (CAR) T-cell therapy in patients with hematologic malignancies.

The most important thing to know, regarding this type of treatment, is that patients can remain cytopenic for a long time following CAR T-cell therapy. In some patients, they can remain cytopenic for months after receiving treatment, says Jain. The need for transfusions and risk for infections needs to be recognized.

Currently, there are no standard guidelines in terms of how long a patient should receive antimicrobial prophylaxis; this remains to be determined so it can prevent infections for a longer period of time in patients.

Tania Jain, MBBS, discusses hematopoietic recovering following treatment with a chimeric antigen receptor T-cell therapy in patients with hematologic malignancies.

Dr. Jain on Hematopoietic Recovery Following CAR T-Cell Therapy

During a typical afternoon, you have a cramped schedule with 8 to 9 patients to see during a 3-hour clinic. Your pager buzzes many times, in between these clinic encounters about another patient receiving chemotherapy under your care. The stage is set you to make a decision for your patient without thinking too much. Alternatively, you may rely too heavily on the information provided by another physician, which is (un)popularly known as “anchoring bias.”

An elderly woman was evaluated for new-onset strabismus. A magnetic resonance imaging (MRI) scan of her brain revealed a petrous-caval area lesion, which was reported to be a meningioma based on its radiographic appearance. She also reported worsening back pain. An MRI of her spine revealed a L4 lytic lesion. A biopsy of the vertebral lesion revealed findings of a plasmacytoma—an extramedullary version of monoclonal plasma cell neoplasm that is not related to meningioma in the oncology pedigree.

Initially, I was inclined to accept the radiological diagnosis as it was. After all, it was a busy day like any other and my decisions had to be made in the blink of the eye. However, I was unable to eliminate the ever-nagging question in my head: “What if...?”

After deliberating with the patient about the pros and cons, we decided to obtain a biopsy of the intracranial mass. Ironically, this biopsy revealed a plasmacytoma. This was important. It changed our management plan from focal radiation to the hip and spine for the solitary plasmacytoma to, instead, systemic therapy for multiple plasmacytomas and systemic disease. The long-term benefits have yet to be determined, but we hope and believe that our lastminute dramatic intervention allowed us to make the right decision for the patient.

At first, I didn’t think there was a reason to share this case. However, I was later inspired to share my story after attending a morbidity and mortality case conference during which the case mentioned below (case 2) was discussed.

A middle-aged man was evaluated for a metastatic melanoma located in the lung. The man’s brain scan revealed a lesion that was, incidentally, deemed to be a meningioma based on his radiology report. But was it? This time, a lack of time to consider the man’s options for diagnosis got the better of the clinician’s judgment.

The decision was made to start systemic therapy for melanoma while following the brain lesion, as would be done for a meningioma. As we know, intracranial metastasis from melanoma warrants radiation or surgical intervention. Nevertheless, treatment for melanoma was initiated with immunotherapy, a treatment consideration given former President Jimmy Carter’s case. As we have learned, the median time to treatment response is roughly 3 months with immunotherapy.

As oncologists, we don’t get many shots at being right. After a couple of weeks, the patient developed a change in mental status, which turned out to be secondary to increasing size of the brain lesion and worsening edema surrounding it. Upon surgical resection and microscopic evaluation at this time, the brain lesion was found to be metastatic melanoma, which was then managed with postoperative radiation in addition to systemic therapy.

After initially being signed out of the emergency department by his physician as having meningitis, as suggested by a high fever, tachycardia, headaches, and tremors, a patient was admitted to the medicine floor for further care. An additional elaborate patient history, obtained by a medical student on the hospital floor, revealed that the patient had a history of hyperthyroidism. The patient also mentioned that he had not taken his medication for the condition in a while. Fortunately, the medical student was neither shy nor slow to speak up. Based on the results of additional workup, a hyperthyroid crisis was diagnosed, which could have become potentially fatal if not recognized in time and managed appropriately.

Anchoring bias refers to a cognitive tendency to lock on to a clinical diagnosis too early, often by making decisions based on information provided by another physician. It’s the tendency to fit the symptom complex into the diagnosis box and anchor onto a diagnosis already provided to us.

Historically, anchoring bias was first conceptualized by professors Amos Tversky, PhD, and Daniel Kahneman, PhD. Anchoring bias is an issue not only recognized by physicians in healthcare, but also in other professions and even in our daily lives. Over the years, psychologists have tried to put together various theories describing the mechanism of this occurrence.2 Regardless of how it happens, it can potentially be catastrophic, although rarely so.

We all fall prey to it. After all, it’s convenient! Having said that, we can’t undermine the external factors that play a role in the execution of clinical errors (fatigue, stress, the distraction of a buzzing pager, supporting services such as laboratory data, system pressures to expedite discharges, etc). In a world where medicine is practiced in a more commercial manner, the ticking clock with every patient encounter only reinforces the possibility for errors in judgment.

It also is important to understand, as a trainee, that believing information already cooked and served to us can hamper critical thinking and kill the spirit of academic inquiry. It adversely affects what we try to seek, every moment of our professional lives—quality of patient care. It leads to clinical error, that “never-forgiven mistake” in medicine. Although anchoring bias may bring a transient sense of reward for being able to explain the story, it offers no long-term glory.

I have described several examples of how this fast and frugal approach could have dire and loathed consequences. It would be unjust and incomplete of me to end this article without sharing a few tips for addressing anchoring bias that I have learned through personal experience.

The first step to solving a problem is realizing that a problem does, in fact, exist. Although most physicians acknowledge that errors occur, they may not recall a diagnostic error of their own. Being cognizant of the fact that we are human and that pursuing a deeper understanding never hurts; it is a general tendency we are all expected to have been inculcated with. When juggling multiple medical complaints, which may or may not be relevant to a patient’s cancer or acute medical issue, it is imperative to separate out all relevant information.

When reviewing a case, I suggest taking some time to develop a mental list of things it “could be” and consider each possibility with an open mind. Following from the decree from French National Convention, which promoted “great responsibility follows inseparably from great power,” the importance of differential diagnosis can also be considered inseparable from the actual final diagnosis.

 I also suggest seeking insight from colleagues. Team members, whether junior or senior, can all play an integral role when making decisions about diagnosis and treatment. It’s not only helpful to us (as trainees), but encouraging as well, to keep an open mind when running through different variables. Nevertheless, there are, and will always be, unmodifiable factors that will influence our decisions. Therefore, we should accept them, identify them, and shout out to a colleague when appropriate.

Robert C, Ribas A, Wolchok JD, et al. Anti-programmeddeath-receptor-1 treatment with pembrolizumab in ipilimumabrefractory advanced melanoma: a randomised dose-comparison cohort of a phase 1 trial. 

 2014;384(9948):1109-1117. doi: 10.1016/S0140-6736(14)60958-2.

Furnham A, Boo HC. A literature review of anchoring bias. 

Articles

You may rely too heavily on the information provided by another physician, which is (un)popularly known as “anchoring bias.”

Tania Jain, MBBS