Jared Kaltwasser

Most of the time, evidence of a cancer therapy’s success in clinical trials is reassuring. This time, it was not.

Narjust Duma, MD, was treating a patient at the Mayo Clinic, in Rochester, Minnesota, where she was a hematology–medical oncology fellow. The patient asked the usual questions, and she responded with the usual answers: data describing the therapy’s overall odds of success and the odds of the cancer returning following therapy.

Unfazed, Duma explained that the data she was quoting were based on cancer stage and thus represented a reasonable expectation of a patient’s odds with that stage of cancer.

The patient, however, was not satisfied. He kept asking, over and over again, “What about me?”

“And when I finally stopped and I asked, ‘What do you mean?’” she said, “he [answered], “What about me? What about Black men like me?’

She did not know how to answer his question, Duma realized. “And I remember, my stomach was hollow for, like, 2 days,” she said.

The patient knew that as a Black man, his life expectancy was already shorter than that of his White peers. He wanted to know what the trial data showed about the success of the therapy in Black men, not just White men.

Duma tried to find out, but when she examined the study data, she found that of the thousands of patients recruited, just 5 were Black men—not nearlyenough to draw reasonable conclusions about the safety and efficacy of the therapy in Black men such as her patient.

. “I went back,” Duma said, “and I told my patient, ‘I don’t know.’ ”

Underrepresentation Is a Widespread, Long-Term Problem

The clinical trial process has birthed a revolution in cancer care, allowing a host of cutting-edge therapies to make it from the laboratory to the clinic. However, the success of the modern drug development pipeline obscures one important fact: The trials that are meant to prove the safety and efficacy of potential therapies consistently overrepresent White patients and often underrepresent racial and ethnic minorities, women, and individuals of lower socioeconomic status.

The problem connects to issues of health care access and equity, but it also underscores an uncomfortable truth: In many cases, the trial data available for minority populations are much less robust than the data available for members of majorities.

The problem is evident from the data. The FDA’s 2018 Drug Trials Snapshots, for instance, showed that of the more than 5000 patients that year who participated in oncology trials that led to approvals, just 4% were Black and 4% were Hispanic, despite the fact that 13.4% of the US population was Black and 18.1% was Hispanic.

 Women were also under-represented: They made up 38% of the trial population

 At the same time, Asian patients were overrepresented, making up 15% of the trial population but just 5.8% of the US population.

The problem is not new. In 1993, Congress passed the National Institutes of Health Revitalization Act, which directed the agency to develop guidelines to boost inclusion of women and minorities in clinical trials. Those guidelines were published the following year. However, in a landmark 2004 study, future US Surgeon General Vivek H. Murthy, MD, MBA, and colleagues reported that patients who were female, older, or Black or Hispanic were still considerably less likely than male, younger, and White patients to enroll in cooperative group cancer trials. They also found that Black participation in such trials had been decreasing, not increasing, in recent years.

The problem exists not just in a macro sense but also within specific cancer types. For instance, Black patients have 2 to 3 times the risk of being diagnosed with multiple myeloma (MM) compared with White patients, and Black patients also tend to be diagnosed with MM at a younger age than White patients. However, a survey of MM pivotal trials supporting FDA applications between 2003 and 2017 found that just 4.5% of patients in clinical trials were Black.

In a 2020 examination of racial disparities in MM risk and outcomes, corresponding author Timothy R. Rebbeck, PhD, of the Dana-Farber/Harvard Cancer Center in Boston, and colleagues said the lack of Black enrollment led to significant limitations in the conclusions that could be drawn from MM studies.

“The small numbers of Black [patients] enrolled in clinical trials not only limit the confidence in the reported results, but they raise questions as to whether the trends observed in the Black patients who did enroll are generalizable to broader patient populations,” Rebbeck and colleagues wrote.

or Duma, now an assistant professor at the University of Wisconsin School of Medicine and Public Health in Madison, the interaction with the patient was a call to action. She had seen the results of Murthy’s 2004 study, but she also knew that the study was based on National Cancer Institute (NCI)–funded trials, and since then, industry-funded trials had become more common.

“So I was wondering, are we doing better now that the whole drug development platform has changed?” she said.

Duma and colleagues decided to search the ClinicalTrials.gov database for US-based oncology clinical trials completed between 2003 and 2016. Of the 1012 trials involving the 7 most common cancers, 31% reported ethnicity, for a total of 55,689 patients. They found that Black and Hispanic patients were still significantly less likely than White patients to be enrolled in clinical trials.

When they compared their results with the historical data from 1996 to 2002 reported by Murthy,

 they found that enrollment had actually dropped for both Black (from 9.2% to 6.0%) and Hispanic patients (from 3.1% to 2.6%). Duma and colleagues also found that women were disproportionately under-enrolled in studies focusing on melanoma, lung cancer, and pancreatic cancer.

“Your race and your background will affect you if you are included in a trial and ultimately will affect the long-term outcome [of your disease],” Duma said.

That is one reason real-world evidence (RWE)—data collected outside of clinical trials—has grown in importance, according to a 2019 paper coauthored by Atul Batra, MBBS, MD, DM, and Winson Cheung, MD, MPH, both of the University of Calgary, in Alberta, Canada. Looking specifically at colorectal cancer, they wrote that RWE is an important complement to data from randomized controlled trials (RCTs) because it gives insights into the actual patient population, instead of just the potentially unrepresentative population included in the trials.

“Although RCTs remain the ‘gold standard’ for evaluating the efficacy of novel interventions in cancer, there is general acceptance that RCTs alone might not offer all the answers to relevant clinical or research questions,” Batra and Cheung wrote.

For community oncologists, the primary clinical questions revolve around safety, efficacy, and dosage. Duma said it is impossible to confidently answer such questions when treating patients whose demographic groups were not adequately represented in the associated trials.

“Safety is always the No. 1 rule in anything with medicine,” Duma said. “You need to be safe for your patients, but it’s unsafe to give a drug after it’s approved, but was [not tested] in the group [to which your patient belongs.]”

According to Batra and Cheung’s research, one issue that leads to disparities between trial populations and the general population is the use of stringent eligibility criteria in clinical trials. “Real-world” patients may have comorbidities and other traits that can lead to their exclusion from cancer trials that are designed for maximum clarity of data.

Lori J. Pierce, MD, professor and vice provost for Academic and Faculty Affairs at University Hospital, University of Michigan, Ann Arbor, and president of the American Society of Clinical Oncology (ASCO), has made increasing diversity in trials a focal point of her tenure at the organization. She and ASCO have worked with the NCI and FDA on efforts to expand trial eligibility criteria, hoping that broadening the potential pool of enrollees would help diversify trials without sacrificing the integrity of the results.

“They found out that by changing just 3 common eligibility criteria—renal function measures, the presence of brain metastases, and having a history of a prior cancer—the eligibility for clinical trials increased by almost 2-fold,” Pierce said during an interview with Targeted Therapies in Oncology.

Those results, noted Pierce, show that using more relaxed exclusion criteria can make a major difference in trial populations.

Another limiting factor that has seen progress is insurance coverage. Private insurers in the United States are required to cover costs associated with clinical trials, such as costs for blood tests and x-rays. However, the requirement does not extend to Medicaid. Although 15 states have long directed their state Medicaid programs to cover the costs, there was no federal coverage mandate.

That was a problem, Pierce noted, because underrepresented minorities tend to rely on Medicaid at disproportionately high rates.

ASCO has been pushing for Congress to extend the coverage mandate to Medicaid for a number of years. The effort finally paid off in December 2020, when Congress included the Clinical Treatment Act in its year-end coronavirus disease 2019 relief bill.

“We were popping the cork—I personally was popping the champagne cork—when this [legislation] was passed, because I really think that it will make a big difference,” Pierce said.

Duma agreed that the lack of Medicaid coverage has been a significant part of the problem, but she noted that individuals on the economic margins will still face significant cost burdens. For instance, an analysis conducted in 2019 found parking fees at NCI-designated cancer treatment centers can be very expensive. Such treatment centers tend to be located in the downtown areas of major cities, where parking can cost as much as $40 per day, although some cancer centers provide free parking.

 Duma said that trial sponsors should help cover parking and other transportation costs to make participation more feasible for all patients.

Although some hurdles can be overcome with straightforward policy adjustments, others require broader changes. One problem, Pierce noted, is that many clinicians do not have the time or the infrastructure in place to participate in trials, or to get their patients involved in trials. She suggested that better training of community oncologists to help them understand how to become involved in trials would help. So, too, would cultural awareness training and translation services to facilitate better communication with potential enrollees who do not speak English. However, she declared that success will require involvement by more than just physicians.

“Not everything needs to rest on the shoulders of the physician,” Pierce said. “It takes a village, right?”

In this case, the “village” means patient navigators, physician’s assistants, nurse practitioners, and others who can spend time getting to know patients, figuring out which patients would be a good fit for trials, and helping to walk those patients through fears and past barriers.

Building Trust in Marginalized Communities

At the same time, such interventions will work only if patients trust the health care system.

“Sometimes that lack of trust in the health care system is seen as though it doesn’t have a basis [in fact],” pointed out Duma. “It does have a basis.”

Duma noted, for instance, a 2020 whistleblower complaint in which a nurse working at an immigration detention center alleged that mostly Spanish-speaking women detained by US Immigration and Customs Enforcement were undergoing hysterectomies at alarming rates, raising questions about whether medical professionals there had consistently obtained informed consent.

One way to build up trust is by explaining and offering options to patients. This is good practice in general; it also helps those with distrust of the system to feel that they are in control of their own health care decisions.

Pierce said there is ample evidence that one way to boost diversity in clinical trials is simply to do a better job of informing patients about the option to participate. She pointed to a study by Joseph M. Unger, PhD, of the Fred Hutchinson Cancer Research Center in Seattle, and colleagues. They analyzed 35 cancer studies published between 2000 and 2020, comprising almost 10,000 patients.

They found that 55% of patients who were asked to participate in a trial agreed to do so, a figure that held firm for both treatment and cancer control trials. Notably, Black patients were just as likely as White patients (58% vs 55%) to say “yes” when asked (

Pierce said the Unger study should serve to contradict concerns that minority patients are reluctant to enroll in trials; the data show that they are not unwilling, when given ample opportunity and information. Although it is important to acknowledge the roots of mistrust, physicians can succeed in enrolling a diverse patient population if they take the time to explain studies and the safeguards.

“From a scientific point of view, to be able to prove the safety and prove the efficacy, and from a trust point of view...to be able to say, yes, members of various ethnic and racial groups were represented on this trial, I think are all very important,” Pierce said.

Last year, ASCO and the Association of Community Cancer Centers (ACCC) announced a partnership to develop solutions to the problem of underrepresentation of minorities in clinical trials.

 The partnership’s steering committee, which is cochaired by Pierce, is currently at work on a 3-pronged process to try to address the issue (

Their plan will join reports by the Enhancing Minority Participation in Clinical Trials (EMPaCT) consortium, which has published a number of papers and training tools for health care workers. Also finding success are other local efforts, such as a program by Andrea Silber, MD, to recruit more women in the New Haven, Connecticut, area into trials.

Pierce said the ASCO-ACCC initiative expects to unveil its plan, currently under development, in early 2022, adding that she hopes such efforts can make meaningful strides in addressing what has proven to be a durable problem. However, Pierce said that in the end, success may come not from overhauling systems, but from taking the current strategies that work and making them the norm.

“I [am not convinced] that we’ve got to come up with some brand-new idea that never has been thought of before,” she said. “Practical solutions that are consistently applied may be the solution here. So, I’m very optimistic.”



1. Nazha B, Mishra M, Pentz R, Owonikoko TK. Enrollment of racial minorities in clinical trials: old problem assumes new urgency in the age of immunotherapy. 

American Society of Clinical Oncology Educational Book

2. Kaiser Family Foundation. State health facts: population distribution by sex: timeframe 2018. Published October 23, 2020. Accessed February 6, 2021. 

3. Murthy VH, Krumholz HM, Gross CP. Participation in cancer clinical trials: race-, sex-, and age-based disparities. 

. 2004;291(22):2720–2726. doi:10.1001/jama.291.22.2720

4. Bhatnagar V, Gormley N, Kazandjian D, et al. FDA analysis of racial demographics in multiple myeloma trials. 

. 2017;130(Suppl 1):4352. doi:10.1182/BLOOD.V130.SUPPL_1.4352.4352

5. Marinac CR, Ghobrial IM, Birmann BM, Soiffer J, Rebbeck TR. Dissecting racial disparities in multiple myeloma. 

. 2020;10(2):19. doi:10.1038/s41408-020-0284-7

6. Duma N, Vera Aguilera J, Paludo J, et al. Representation of minorities and women in oncology clinical trials: review of the past 14 years. 

. 2018;14(1):e1-e10. doi:10.1200/JOP.2017.025288

7. Batra A, Cheung WY. Role of real-world evidence in informing cancer care: lessons from colorectal cancer. 

. 2019;26(Suppl 1):S53-S56. doi:10.3747/co.26.5625

8. Clinical trials coverage under Medicaid. Association for Clinical Oncology. December 15, 2020. Accessed February 9, 2021. 

9. ASCO in action: Congress passes sprawling year-end legislative package that impacts cancer research and delivery. American Society of Clinical Oncology. December 22, 2020. Accessed February 19, 2021. 

10. Lee A, Shah K, Chino F. Assessment of parking fees at National Cancer Institute-designated cancer treatment centers. 

. 2020;6(8):1295-1297. doi:10.1001/jamaoncol.2020.1475

11. ICE whistleblower: nurse alleges ‘hysterectomies on immigrant women in US.’ BBC News. September 15, 2020. Accessed February 6, 2021. 

12. Unger JM, Hershman DL, Till C, et al. “When offered to participate”: a systematic review and meta-analysis of patient agreement to participate in cancer clinical trials 

 Published online October 6, 2020. doi:10.1093/jnci/djaa155

13. ASCO in action: ASCO & ACCC join forces to increase participation of racial and ethnic minority populations in cancer treatment trials. American Society of Clinical Oncology. July 21, 2020. Accessed February 9, 2021. 

Articles

Oncology Leaders Take Action to Curb Lack of Diversity in Clinical Trials

A new multicenter study of patients with myeloproliferative neoplasms (MPNs) found that those with essential thrombocythemia (ET) have the greatest risk of venous thromboembolism (VTE) when infected with COVID-19.

The new data are notable in part because arterial thrombosis—rather than venous thrombosis—is widely considered the more common danger for patients with MPNs. The new study was published in the 

Although COVID-19 is primarily a respiratory ailment, corresponding author Tiziano Barbui, MD, of the Papa Giovanni XXIII Hospital, in Italy, and colleagues, noted in the published report that the disease can affect a number of organs, including the heart, kidney, and vascular system. These complications can include VTE and/or arterial thrombosis. It can be difficult to know the true rate of thromboembolic events in patients with COVID-19, they said, since not every patient is screened for them. However, existing evidence suggests thrombosis is a relatively common occurrence, particularly among patients transferred to intensive care units (ICUs), where the estimated prevalence was 22.7%.

Barbui and colleagues wrote that patients with certain pre-existing conditions might be at higher risk for VTE and arterial thrombosis, including patients with MPNs, which they said might be the most vulnerable of all patients. However, there was a lack of data to characterize the risk, in part because of the relatively low prevalence of MPNs and in part due to the novelty of the SARS-CoV-2 virus itself.

In hopes of evaluating the incidence of thrombosis and bleeding and identifying risk factors, Barbui and colleagues embarked on a major, multicenter, retrospective cohort study involving 38 European hematology centers. A total of 162 patients with MPNs and COVID-19 infection were identified and included in the study and followed for a median of 50.5 days (interquartile range [IQR], 16.0-69.0). Among those patients, 48 had ET, 42 had polycythemia vera, 56 had myelofibrosis, and the remaining 16 were categorized as prefibrotic myelofibrosis. Of those patients, 15 major thromboses were reported, spread across 14 patients. Of the 15 thromboses, just 3 were arterial and the remaining 12 were venous. All but 1 of those patients was receiving low molecular weight heparin (LMWH) as antithrombotic prophylaxis. After adjusting for competing risk of death, the investigators found that the incidence of arterial and venous thromboembolic events was 8.5% after 60 days of follow-up. In the study data, 8 of the 12 patients with VTE were in the ET group, suggesting those patients face the highest risk.

 that typically 60% to 70% of thromboembolic events in patients with MPNs are arterial, rather than venous.

“The opposite occurs in SARS-CoV-2 infection, where thromboses of the veins substantially prevail over those of the arteries,” he said. “This is due to several factors including bed rest, endothelial damage produced by the virus, activation of coagulation mediated by a series of factors, and the viral attack.”

Barbui said on the surface, the data suggest that patients with MPNs have the same risk of thrombosis as non-MPN patients, but he said such a comparison is not reliable, since these data are based on easier-to-diagnose manifest thromboses. He added that thrombosis of the lung is also a concern, though this is frequently diagnosed via autopsy.

The investigators noted that patients with MPNs had markedly lower platelet counts upon COVID-19 diagnosis compared to their most recent pre-COVID follow-up, particularly among patients with ET, where the decline was 23.3% (

 < .0001). The decline was associated with a higher mortality rate for pneumonia.

Risk factors for thrombosis were transfer to ICU (sub-distribution hazard ratio [SHR], 3.73; 95% CI, 1.14-12.23; 

 = .029), neutrophil/lymphocyte ratio (SHR, 1.16; 95% CI, 1.06-1.27; 

 = .001), and ET phenotype (SHR, 4.37; 95% CI, 1.51-12.64; 

= .006). They said the higher susceptibility to VTE and pneumonia among patients with ET may warrant new tailored antithrombotic regimens for those patients, including antiplatelet drugs.

Barbui and colleagues noted that most of the cases of thrombosis reported in the study took place in patients who were on LMWH prophylaxis. However, they said that antithrombotic prophylaxis was not treated as standard therapy for patients with COVID-19, and thus was only prescribed in 57% of MPN cases. Although LMWH was the chosen prophylactic in almost all cases, dosing varied significantly. The Scientific and Standardization Committee of the International Society of Thrombosis and Hemostasis has suggested universal thromboprophylaxis after assessment of bleeding risk, the authors wrote, but with the current dearth of evidence regarding dosing, most such decisions are made empirically.

“The problem of anti-thrombotic prophylaxis is still not well resolved,” Barbui said. “It must be done in patients hospitalized in intensive care units, but the doses are not yet codified by convincing studies. In particular, in patients with myeloproliferative diseases, attention should be paid to the onset of bleeding that occurred in our patients, mainly in myelofibrosis. Guidelines should therefore be followed, which are not evidence-based, but represent a consensus among experts.”

Barbui T, De Stefano V, Alvarez-Larran A, et al. Among classic myeloproliferative neoplasms, essential thrombocythemia is associated with the greatest risk of venous thromboembolism during COVID-19. 

. 2021;11(2):21. doi:10.1038/s41408-021-00417-3

Major thrombosis is a significant danger for patients with MPN who become infected with COVID-19, and antithrombotic prophylaxis does not appear to eliminate the risk.

Thrombosis Risk in Patients With MPNs and COVID-19 Highest for Patients With Essential Thrombocythemia

Expression or mutations in sterile alpha motif and histidine-aspartic domain-containing protein 1 (SAMHD1) does not appear to be linked with failure-free survival (FFS) or complete remission (CR) rates in patients with mantle cell lymphoma (MCL) who are treated with high-dose cytarabine-based chemotherapy, according to the results of a new study.

, also found that while high expression of the protein appears to mediate resistance to cytarabine in lab-based experiments, the problem only seems to apply to cytarabine monotherapy and not to combination therapy that includes cytarabine. The findings suggest oncologists treating patients with MCL do not need to limit the use of cytarabine in patients based on SAMHD1 anomalies.

A diagnosis of MCL comes with a difficult prognosis, but in recent years, 2 studies have been published that have made a considerable difference in the treatment choices made by oncologists and patients. The European Mantle Cell Lymphoma Network’s MCL Younger trial

 found that the addition of high-dose cytarabine to treatment regimens improves outcomes for patients with MCL who are ages 65 and younger. The network’s MCL Elderly trial,

 meanwhile, showed that rituximab (Rituxan) plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) led to more favorable outcomes in patients over the age of 65 who were unfit for high-dose therapy. That study also showed that rituximab maintenance therapy improved overall survival (OS).

SAMHD1 has been proposed as a possible biomarker for cytarabine response in patients with MCL. Corresponding author Sascha Dietrich, MD, of the University of Heidelberg, and colleagues, explained that high expression of SAMHD1 can theoretically counteract cytarabine by enhancing hydrolysis of the active metabolite in cytarabine. Similar drugs, such as fludarabine, may also have limited efficacy in hematologic malignancies of patients with high expression of SAMHD1, the authors said.

At the same time, SAMHD1 has also been found to be a tumor suppressor, and reduced suppression of SAMHD1 has been linked with Sézary syndrome and lung carcinoma, along with other adverse outcomes.

Dietrich and colleagues decided to try and better understand whether cytarabine- or fludarabine-based induction therapy led to negative outcomes in patients with MCL and SAMHD1 expression. They used data from 189 patients in the MCL Younger and Elderly trials to identify patients with 

 mutations and quantify expression levels of the protein. All of the patients had received polychemotherapy with cytarabine or fludarabine. The investigators also treated B-cell lymphoma cell lines with cytarabine, fludarabine, and other drug combinations to see whether and how varying levels of SAMHD1 expression affected responses to the drugs.

The results were similar and suggested SAMHD1 expression did not affect outcomes.

 mutations of 7.1% among 182 patients assessed. The presence of such mutations did not have a statistically significant effect on FFS (

 = .47). This was carried through even when adjusted for Mantle Cell Lymphoma International Prognostic Index (HR, 1.5; 

Similarly, the team found SAMHD1 expression levels did not have a significant impact. “We found that SAMHD1 expression was not associated with the CR rate or with FFS in patients treated with high-dose cytarabine- or fludarabine-containing regimes,” Dietrich and colleagues wrote.

The investigators noted that their findings differed from earlier studies, but in the previous research the patients received consolidation with single-agent high-dose cytarabine. They noted that when those authors investigated CR rates following acute myeloid lymphoma induction therapy with cytarabine and anthracycline, the correlation between SAMHD1 expression and CR was no longer statistically significant. In the current study, the subjects all received combination therapies.

That point was underscored by the other facet of the study. When Dietrich and colleagues looked at SAMHD1 expression in B-cell lymphoma cell lines, they found the response to cytarabine as a single agent was inversely related to SAMHD1 expression (

< .0001). When cytarabine was combined with other chemotherapeutics, the effect was reversed.

“We conclude that this might explain why we did not observe a significant association between SAMHD1 protein expression and the outcome of MCL patients upon cytarabine-based treatment,” the authors said.

Another potential factor is the use of myeloablative conditioning using the BEAM regimen (carmustine, etoposide, cytarabine, melphalan). Dietrich and colleagues said such therapy might have the effect of diluting and further overcoming cytarabine resistance; however, their study did not consider such conditioning in their assay. The investigators said their study was exploratory in nature, and thus they said they cannot rule out that some effect of SAMHD1 on outcomes in MCL might be possible.

1. Roider T, Wang X, Hüttl K, et al. The impact of SAMHD1 expression and mutation status in mantle cell lymphoma: An analysis of the MCL Younger and Elderly trial. 

. 2021;148(1):150-160. doi:10.1002/ijc.33202

2. Hermine O, Hoster E, Walewski J, et al. Addition of high-dose cytarabine to immunochemotherapy before autologous stem-cell transplantation in patients aged 65 years or younger with mantle cell lymphoma (MCL Younger): a randomised, open- label, phase 3 trial of the European Mantle Cell Lymphoma Network. 

 2016;388(10044):565-575. doi:10.1016/S0140-6736(16)00739-X

3. Kluin-Nelemans HC, Hoster E, Hermine O, et al. Treatment of older patients with mantle-cell lymphoma. 

 2012;367:520-531. doi:10.1056/NEJMoa1200920

Expression or mutations in SAMHD1 does not appear to be linked with failure-free survival or complete remission rates in patients with mantle cell lymphoma who are treated with high-dose cytarabine-based chemotherapy.

SAMHD1 Expression Not Associated With Outcome in Mantle Cell Lymphoma With Cytarabine Combo Treatment

Mutations of the additional sex combs like 1 (

) gene appear to have a significant adverse impact on the prognosis of patients with primary myelofibrosis (PMF), according to findings from a new meta-analysis that shows a higher probability of transformation to acute leukemia and shorter overall survival (OS) with alterations in 

The prognosis for patients with PMF is typically calculated using the International Prognostic Scoring System (IPSS) or the Dynamic International Prognostic Scoring System (DIPSS) and DIPSS-Plus system. The problem, according to corresponding author Xiaomei Hu, MD, of the China Academy of Chinese Medical Sciences, and colleagues, is that such systems typically focus on clinical characteristics and karyotypes of patients.

“In recent years, more and more studies have begun to pay attention to the role of gene mutations in the pathogenic mechanism of hematologic diseases, and its influence on the progression and survival of PMF has gradually emerged,” Hu and colleagues wrote.

Such advances have created an urgent need to update prognostic stratification methods, the investigators added.

“With the rapid development of sequencing technology, in addition to the driver genes, varieties of somatic gene mutations have been discovered in PMF patients, which may play a significant role in the pathogenesis and clinical prognosis of PMF patients,” they said.

 mutations are common in patients with PMF, with estimates suggesting mutations exist in between 13% and 38% of cases. Mutations can take the form of frameshift, nonsense, or missense mutations; frameshift mutations are the most common.

An increasing number of studies has suggested 

 mutations play a significant role in patient prognosis, but Hu and colleagues said that stance remains controversial because it is unclear what exact role the mutations play.

In order to get a better sense of whether 

 mutations are a meaningful prognostic indicator, the investigators conducted a meta-analysis of existing studies and trials that assessed the impact of 

 mutations in PMF and included data on OS and/or progression to acute leukemia. The search eventually yielded 14 studies, which together included 4501 patients, 30.95% of whom had 

All but one of the studies included OS data. Those studies involved 3527 patients. The meta-analysis showed that the overall hazard ratio (HR) for patients with the 

<.00001) compared to those with wild-type 

, suggesting patients with mutations have worse prognoses, Hu and colleagues said.

Three of the 14 studies included leukemia-free survival (LFS) as a metric; they showed an overall HR for LFS of 1.77 (95% CI, 1.30-2.42; 

= .0003) in the mutated group versus the non-mutated group.

Finally, 6 studies looked at transformation rates to acute leukemia. Hu and colleagues used data from those studies to calculate an odds ratio (OR) of 2.06 (95% CI, 1.50-2.83; 

<.00001) of transformation in patients with the mutation. The investigators said their data affirm earlier findings suggesting 

 mutations play a role in disease severity in PMF.

 are also prognostically detrimental in PMF, putting patients in a high molecular risk category, with shorter OS and a greater likelihood of progression.

However, the authors also noted that the poor prognosis linked with 

 could also have to do with the fact that the mutations are more common among patients older than 65 who are male and have a lower platelet count. They said insufficient data were available to conduct a full analysis of clinical features.

Hu and colleagues noted that the studies in their analysis were not uniform. They found significant heterogeneity in the results when it came to OS; however, when the team excluded 2 outlier studies from the data (due to the inclusion of more patients with overt PMF and lower risk DIPSS in these studies), they still found a significant correlation between 

 mutations and OS, suggesting that their conclusion is reliable.

The investigators said their findings are subject to limitations, such as the fact that all included studies were retrospective, observational studies, rather than prospective, randomized, controlled trials. They also noted that the studies had different confounding factors in their multivariate analyses, potentially increasing heterogeneity into the results.

Hu and colleagues said there is significant evidence that 

 should become an important molecular marker for risk stratification in PMF, though they said a large prospective cohort study is warranted to help solidify their findings.

“We believe that with the in-depth study of genetic variation and the development of next-generation sequencing technology, our understanding of the pathogenesis and risk factors for hematologic malignancies will be more profound,” they concluded.

Wang Z, Liu W, Wang M, et al. Prognostic value of ASXL1 mutations in patients with primary myelofibrosis and its relationship with clinical features: a meta-analysis. 

. 2021;100(2):465-479. doi:10.1007/s00277-020-04387-7

A new meta-analysis confirms that ASXL1 mutations could be an important prognostic indicator in patients with myeloproliferative neoplasms.

Jared Kaltwasser | Authors

Articles

Oncology Leaders Take Action to Curb Lack of Diversity in Clinical Trials

Thrombosis Risk in Patients With MPNs and COVID-19 Highest for Patients With Essential Thrombocythemia

SAMHD1 Expression Not Associated With Outcome in Mantle Cell Lymphoma With Cytarabine Combo Treatment

ASXL1 Mutations Linked with Survival, Progression in Primary Myelofibrosis