Jared Kaltwasser

A new study showed that patients with nonsevere hemophilia A (NSHA) develop inhibitors much sooner than previously thought, though the study found inhibitors did not increase the risk of mortality.

Hemophilia A is linked with altered x chromosomes, and is more common in males, who only have a single x chromosome. An estimated 23.2 out of 100,000 males are born with the condition.

 corresponding author Ming Lim, MBBCh, MSCr, of the University of Utah, and colleagues, noted that the most significant complication faced by patients with hemophilia A is the development of neutralizing antibodies to factor VIII (FVIII). These antibodies, called inhibitors, increase a patient’s risk of mortality. One study found patients with a current inhibitor were 70% more likely to die than patients without inhibitors.

However, Lim and her coauthors wrote that most of the existing research on hemophilia A relates to patients with severe hemophilia A. Much less has been reported about patients with the nonsevere form of the disease, a cohort that makes up about one-half of all patients with hemophilia.

The investigators sought to remedy the situation by analyzing the clinical characteristics and mortality rates of people with NSHA. The utilized the American Thrombosis and Hemostasis Network dataset, identifying 6624 patients with NSHA, 86% of whom were men. The data covered the period of 2010 to 2018 and patients were followed for an average of 8.5 years.

Their findings showed patients with NHSA develop inhibitors much earlier than previously thought. While a previous study of patients with NSHA found that the median age at which patients develop inhibitors was 38,

 Lim and colleagues found patients in their data set actually developed inhibitors at a median age of 13.

“The reason for this discrepancy is unclear,” Lim said. “We speculate that this may be due to the observed time period, as the availability of FVIII concentrates have evolved over the years, and may have been used more often from 2010 to 2018, which then increases the risk of inhibitor development.”

The previous study, dubbed INSIGHT, covered a time period from 1980 to 2011.

The new study also has a lower rate of inhibitor development, 2.6% versus 4.0% in the previous study. Lim said a future longitudinal study would be needed to better explain the discrepancies.

When it came to mortality, Lim and colleagues found that the development of inhibitors was not associated with an increased risk of death, even when age-adjusted. This contradicts earlier research, and Lim said it may be due in part by the older age at which patients in earlier studies developed inhibitors.

“Older people are more susceptible to age-related comorbidities and bleeding complications,” they wrote, “thus contributing to the increased mortality in the INSIGHT study.”

Overall, Lim and colleagues reported 136 deaths among their cohort, at a median age of 63. That resulted in an age-adjusted mortality rate of 3.3 deaths per 1000 person-years. Just 3 of those deaths in the study occurred in participants with inhibitors. Instead, age, male gender, hepatitis C, and HIV, were identified as risk factors for death. The most common cause of death among the cohort was malignancy (27 patients; 20%).

Lim and colleagues concluded that their study underscores the importance of regular monitoring of people with NSHA at hemophilia treatment centers. They said such monitoring is important regardless of age, since their data indicate inhibitors can become a problem much sooner than previously thought.

1. Lim MY, Cheng D, Recht M, Kempton CL, Key NS. Inhibitors and mortality in persons with nonsevere hemophilia A in the United States. 

. 2020;4(19):4739-4747. doi:10.1182/bloodadvances.2020002626

2. Walsh CE, Soucie JM, Miller CH; United States Hemophilia Treatment Center Network. Impact of inhibitors on hemophilia A mortality in the United States. 

. 2015;90(5):400-405. doi:10.1002/ajh.23957

3. Walsh CE, Soucie JM, Miller CH; United States Hemophilia Treatment Center Network. Impact of inhibitors on hemophilia A mortality in the United States. 

Articles

Up until now, it was thought most patients with hemophilia A developed inhibitors in middle-age. A new study suggests it usually happens in the early teens.

Study Finds Inhibitors Develop in Nonsevere Hemophilia A Earlier Than Previously Reported

More and more patients with relapsed or refractory multiple myeloma (R/R MM) are being treated with triplet therapies, and that change has resulted in an increase in survival and decrease in hospitalizations, according to a new study of a German data set.

, help to underscore the impact of new therapies on the treatment of MM worldwide.

Investigators from 2 German universities and Takeda Pharmaceutical Co. noted that drugs like lenalidomide (Revlimid) and bortezomib (Velcade) have typically been given as part of doublet therapy over the past 15 years. However, a spate of newer therapies, including the proteasome inhibitor (PI) carfilzomib (Kyprolis) and the monoclonal antibody (mAb) daratumumab (Darzalex) have typically been given in triplet combinations.

Existing data suggests uptake of these newer drugs is on the rise, but corresponding author Christof Scheid, MD, of the University Hospital of Cologne, and colleagues noted that, “it remains to be determined whether the increased use of triplet-based  therapy regimens including these new agents has resulted in improved clinical outcomes.”

To answer the question, the authors consulted a database from the Institute for Applied Health Research, which contains deidentified health data from 7 million Germans. The authors searched for patients with R/R MM who had at least one new prescription or therapeutic regimen during the years 2014 through 2017. Patients with a newly initiated therapy within 12 months of the start date of the study period were excluded.

The data yielded 1255 patients with R/R MM. They were divided into 6 therapy-based categories: immunomodulatory drug (IMiD)–based doublets, PI-based doublets, daratumumab monotherapy, PI-IMiD–based triplets, mAb-based triplets, and other treatments.

The authors sought to quantify use of the varying therapies, track changes over time, and see what impact, if any, those changes had on patient outcomes.

The data showed a dramatic shift. Triplet-based regimens were used in just 5.9% of cases in 2014, but by 2017 that number had jumped to 31.4%. Meanwhile, IMiD-based doublets were used in 74.3% of cases in 2014, but use of that regimen fell to 37.6% by 2017.

Over that same period of time, risk of death dropped by 32%, the authors said, and risk of hospitalization fell by 30%.

Though the proportions changed significantly, when taken as an overall patient population, the data showed that 70% of patients received doublet-based therapy, while just 18.6% received triplet-based therapy.

Scheid and colleagues wrote that it is not possible to say for sure that the new therapies and the use of triplet regimens are the cause, or the only cause, of the improved outcomes. For instance, changes to treatment guidelines or improvements in supportive care may also have played a role, they wrote.

“Furthermore, the availability of new agents and thus, much broader treatment repertoire and strategies allows timely and more efficacious interventions at each relapse phase,” they wrote.

The investigators also noted that there are a number of ways in which their studies are different from the phase 3 trials of the respective therapies, thus a direct comparison with data from those phase 3 trials is not possible.

Still, the authors said the data shows a clear trend toward triplet use, which appears to be benefiting patients. The investigators said the risks of adverse events did not change as the treatment regimens did.

Scheid C, Blau IW, Sellner L, Ratsch BA, Basic E. Changes in treatment landscape of relapsed or refractory multiple myeloma and their association with mortality: Insights from German claims database. 

Newer therapies have led to a boost in the number of patients with relapsed or refractory multiple myeloma (R/R MM) who are prescribed triplet regimens. As that shift has occurred, death rates appear to have dropped.

Use of Triplet Therapy Rose in R/R MM as Deaths Declined, Study Finds

Patients with follicular lymphoma (FL) who have a prior malignancy diagnosis (PMD) face a greater risk of secondary primary malignancy (SPM) and death, new data suggest, although the increased risk may be linked with the therapy chosen for the initial malignancy.

A team of Dutch researchers came to that conclusion following an analysis of a national database of more than 8000 patients who were diagnosed with FL over a nearly 2-decade period. Their findings were 

The treatment landscape, and thus prognosis, for patients with FL has significantly improved since the introduction of rituximab (Rituxan) and other therapies. As a result, patients with FL are living longer, though some evidence has suggested that these patients might face a higher risk of SPM, including hematological malignancies such as Hodgkin lymphoma and acute myeloid lymphoma, and solid tumors including stomach, lung, and kidney/pelvis cancer.

 of patients with multiple myeloma found an association between PMD and SPM and mortality. Those findings suggested that genetic susceptibility might be a factor for such patients. However, the evidence of a PMD’s impact on patients with FL has thus far been limited.

Hoping to change that, corresponding author Avinash G. Dinmohamed, MSc, PhD, of the Netherlands Comprehensive Cancer Organization, and colleagues, analyzed the Netherlands Cancer Registry to locate 8028 adult patients who were diagnosed with grades 1-3B FL from 1994 through 2012. The study included a follow-up period through 2017.

Of the 8028 patients, 6% (483 patients) had a prior malignancy. Of those, 17.2% (83 patients) developed an SPM. That compared with an SPM rate of 13.6% among the 1,023 patients who did not have a PMD. The median time between the PMD and the FL diagnosis was 5.3 years for patients who had an SPM and 5.4 years for patients without an SPM.

Patients with a PMD had an SPM subdistribution hazard ratio (SHR) of 1.30 (95% CI). The risk was especially high for carcinomas of the respiratory tract (SHR, 1.83) and cutaneous squamous cell carcinomas (SHR, 1.58). They also faced a higher risk of death (HR, 1.43; 95% CI).

However, the investigators also noticed a link between prior treatment and risk of SPM. They noted that patients with a PMD could experience prolonged immune dysfunction as a result of their prior treatment, and systemic therapy and/or radiotherapy could have a carcinogenic effect based on the dose. That effect could be compounded with treatment for FL.

“Thus, whenever a PMD was treated with systemic therapy and/or radiotherapy, the cumulative dose of potential carcinogens was likely higher for patients with a PMD, as compared to those without a PMD, due to prior cancer therapy,” they wrote.

Looking at mortality specifically, the authors found a heightened risk only among patients with a PMD who were treated with systemic therapy and/or radiotherapy.

“This finding might be explained by the (late) effects from the prior systemic therapy and/or radiotherapy, potentially leading to organ dysfunction, cardiovascular disease, and death,” they wrote.

Taken together, the authors said their findings need to be aware of the risk of SPMs in patients with FL, especially if the patient has a PMD and was treated with systemic therapy and/or radiotherapy.

Dinnessen, MA,Visser, O,Tonino, SH, et al.The impact of prior malignancies on the development of second malignancies and survival in follicular lymphoma: a population‐based study. 

. Published online October 8, 2020. doi: 

Jonsdottir G, Lund SH, Bjorkholm M, Turesson I, Hultcrantz M, Porwit A, et al. The impact of prior malignancies on second malignancies and survival in MM patients: a population‐based study. 

Previous research has found a link between a prior malignancy and secondary primary malignancy risk in patients with multiple myeloma. A new study suggests a similar association in follicular lymphoma.


Prior Malignancy Linked to Risk of Secondary Malignancy in Follicular Lymphoma

A new case report is raising the possibility that nivolumab (Opdivo) may be able to successfully treat an aggressive form of non-Hodgkin 

Burkitt lymphoma affects about 1200 people each year in the United States. While high-dose chemotherapy improves outcomes, corresponding author B. Scott Colton, MD, and colleagues at the University of California, Los Angeles, wrote that successfully treating patients with refractory disease is “formidable clinical challenge,” particularly when the disease is rapidly progressing.

Such was the case for a 72-year-old man who appeared at the hospital with abdominal comfort, was sent home after lab tests showed nothing notable, and then returned 4 days later, at which point he was diagnosed with Burkitt lymphoma.

The patient’s tumor cells were negative for Epstein-Barr virus and programmed cell death ligand 1 (PD-L1), though the investigators noted a very small number of macrophages and lymphocytes within the tumor were positive for PD-L1. Physicians diagnosed tumor lysis syndrome and began hemodialysis. The patient was given a dose of corticosteroid.

A lumbar puncture was negative for cancer cells, and the patient was given intrathecal methotrexate.

Next, physicians began administering the Magrath chemotherapy regimen, which calls for rituximab, cyclophosphamide, doxorubicin, vincristine, and methotrexate on cycles 1 and 3, and rituximab, ifosfamide, etoposide, and high-dose cytarabine on cycles 2 and 4.

After the first cycle, the patient had a marked reduction in tumor burden and reductions in lactate dehydrogenase (LDH) levels, a peripheral marker of cancer. However, LDH levels reversed course a few days before his second cycle of chemotherapy. That cycle caused his LDH levels to return to normal levels, but then they began to increase again, a sign that the disease was rapidly progressing.

At that point, the patient’s options were becoming very limited. The clinicians discussed the possibility of hospice care, but they also proposed another solution: nivolumab. The PD-L1 inhibitor has been used to treat other types of lymphoma, and Colton said there were promising reasons to suggest it might work here.

Colton noted that since the development of therapies like nivolumab, the drugs have shown promise in a number of different types of malignancies.

“One pattern that arose was that tumors that had increased antigen production and those associated with concurrent viral infections may have better responses to immunotherapy options,” he said. As a result, drugs like nivolumab began to be used successfully for types of lymphoma, though he said the reasons for the drug’s success in these cases is not yet fully understood.

“Given these patterns, our current knowledge of Burkitt’s lymphoma, and known examples where single agent nivolumab had shown to be effective in other types of lymphoma, we felt it was a viable option to attempt in this patient who had recently proven to have disease refractory to the standard-of-care chemotherapy treatment,” Colton told 

The American Journal of Managed Care® (AJMC®).

Colton said the patient was made aware of the possible side effects and the fact that it was not a proven treatment, but the patient liked the fact that checkpoint inhibitors are usually well-tolerated and was pleased that it would not require additional chemotherapy. The patient was put on a dose of 480 mg of nivolumab every 4 weeks. Doctors later added rituximab and lenalidomide to enhance disease control, but discontinued the latter after it resulted in severe fatigue.

Nivolumab decreased the patient’s LDH levels to normal range, and at the time of the case report’s writing, the patient’s levels remained in normal range for 5 months.

The patient had no symptoms and scans showed no evidence of disease 4 months after nivolumab treatment.

that it has now been 8 months without evidence of disease, so he and colleagues are cautiously optimistic about the patient’s prognosis. However, he added that the patient would face a very poor prognosis if he were to have a recurrence.

Still, he said the “exciting tail on the Kaplan Meier curves” that initially caused him and colleagues to propose nivolumab suggests the possibility of a sustained response or even cure.

“The longer out the patient gets from initiation of therapy, the better the chances his disease will not come back,” he said.

A 72-year-old patient with Burkitt lymphoma was successfully treated with nivolumab after standard-of-care chemotherapy failed.

Author | Jared Kaltwasser

Articles

Study Finds Inhibitors Develop in Nonsevere Hemophilia A Earlier Than Previously Reported

Use of Triplet Therapy Rose in R/R MM as Deaths Declined, Study Finds

Prior Malignancy Linked to Risk of Secondary Malignancy in Follicular Lymphoma

Case Report Suggests Nivolumab Is Effective in Burkitt Lymphoma