David Bai, PharmD

Five-year results from the extended randomized MGTX trial demonstrated that the addition of thymectomy to prednisone leads to long-lasting lower quantitative myasthenia gravis (QMG) scores and prednisone dosing.

Performing thymectomy in patients with nonthymomatous myasthenia gravis has remained controversial since the practice guideline in 2000 could not conclusively determine a benefit from the procedure. Since then, many of the authors of the practice guideline have been calling for a randomized controlled trial to adequately address this issue.

In 2006, investigators in the MGTX trial began to enroll patients with nonthymomatous myasthenia gravis and randomized them to receive either prednisone with thymectomy or prednisone alone. At the 3-year timepoint, patients who underwent thymectomy had superior improvements in myasthenic weakness and required lower corticosteroid requirements than patients only on prednisone. In a recent study, investigators report the results of the extension study for the MGTX trial to determine if the benefits continued past 3 years.

Patients were enrolled in the extension study if they completed the initial 36 months of MGTX. A total of 33 patients in the prednisone alone group and 35 patients in the thymectomy plus placebo group chose to participate. Among them, 26 patients in the thymectomy plus prednisone group and 24 patients in the prednisone alone group completed the 60-month visit.

At 60 months, patients in the thymectomy and prednisone group had significantly improved time-weighted mean QMG scores from month 0 to 60 compared with patients who only received prednisone (5.47 vs 0.34; 

 = .0007). Mean alternate-day prednisone doses were also significantly lower in the thymectomy group than the prednisone alone group (24 mg vs 48 mg; 

 = .0002). Benefits were seen across all subgroups, except for the analysis in men only, which did not show a significant difference in prednisone doses. Patients who were prednisone-naïve also did not have significantly different time-weighted mean QMG scores between the two groups.

Cumulative days spent in the hospital for myasthenia gravis exacerbations were similar between the 2 groups. However, the number of hospitalizations from nervous system disorders was much higher in the prednisone alone group compared with the thymectomy with prednisone group. Patients requiring azathioprine or intravenous immunoglobulin was also significantly lower in the thymectomy group versus the prednisone alone group. For the 2 additional years of observation, only 2 patients from each group had an increase of 2 points in QMG score. No deaths occurred during this extension period.

Based on the persisting thymectomy benefits over 5 years, investigators concluded that thymectomy should be favored in patients with nonthymomatous myasthenia gravis.

Wolfe GI, Kaminski HJ, Aban IB, et al. Long-term effect of thymectomy plus prednisone versus prednisone alone in patients with non-thymomatous myasthenia gravis: 2 -year extension of the MGTX randomized trial [published online January 25, 2019]. 

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Thymectomy Plus Prednisone Shows Benefit in Patients With Nonthymomatous Myasthenia Gravis

Molecular minimal residual disease (MRD) testing during the first 4 days of induction therapy does not differentiate responders and nonresponders and should not be used in predicting clinical response for patients with 

(AML), according to the results from a recent study.

Over recent years, MRD has become an essential prognostic tool for AML, with highly predictive capabilities. Patients with detectable MRD are usually nonresponders with poorer progression free and overall survival while patients with undetectable MRD generally have clinical response and much longer survival rates. The prognostic value of MRD has been seen at key treatment timepoints such as after 1 to 2 cycles of induction therapy; however, its use has not yet been seen during initial induction therapy. In a recent study, investigators determined whether MRD quantification can predict clinical response during the first 4 days of intensive cytotoxic therapy.

Blood was collected daily from days 1 through 5 from 45 adult patients with AML, 10 of whom had relapsed or refractory disease. Two different molecular techniques were used for AML MRD quantification: 

 expression by quantitative polymerase chain reaction (qPCR) and targeted DNA sequencing for common myelodysplastic syndrome/AML variants. Of the 45 patients, 19 of them achieved a complete remission (CR) after cytotoxic treatment (42%).

Of the 45 patients in this study, 34 of them had enough RNA for a qPCR analysis. On day 1, 91% of the patients had overexpressed 

. By day 4, the percentage dropped to 68%. Of the 13 patients who achieved a CR, 7 of the patients had a 4-fold reduction in 

 expression. Of the 21 patients who were nonresponders, 7 of them also had at least a 4-fold reduction in 

 expression. Based on the scattered results, investigators concluded that 

 expression between day 1 and 4 appeared to be uninformative of clinical response.

All 45 patients had enough DNA for sequencing and a total of 163 variants were found in 43 patients (2 patients had no variants for disease tracking). The most frequent mutations were seen at 

. No differences in the number of coding variants at baseline in CR versus nonresponders were observed. The only 2 mutations that had predictive significance were 

, both already used with the current prognostic risk classification.

 mutations did not achieve remission and all 5 patients with 

Early DNA sequencing also produced varied results in predicting post-remission relapse. In 1 patient, there were no changes in wild type to mutated sequence ratios during the first 4 days of therapy and mutation levels remained negligible. For the other patient, 

 decreased during the first 4 days of therapy and 

 remained stable. Once the patient was in remission, both mutations became undetectable and reappeared after relapse, with the addition of a second 

Aside from the clinical utility of monitoring 

 variants, investigators concluded that molecular testing during the first few days of induction therapy does not appear to be predictive of response in patients with AML. MRD should instead be used during follow-up evaluations rather than early AML treatment.

Wong HY, Sung AD, Lindblad KE, et al. Molecular measurable residual disease testing of blood during AML cytotoxic therapy for early prediction of clinical response. 

. 2019;8:669. doi: 10.3389/fonc.2018.00669.

Molecular minimal residual disease (MRD) testing during the first 4 days of induction therapy does not differentiate responders and nonresponders and should not be used in predicting clinical response for patients with acute myeloid leukemia (AML), according to the results from a recent study.

MRD Can't Predict Response in Early Days of Intensive AML Therapy, Study Says

Results from a recent study showed that white matter lesions and clinical migraine characteristics have no effect on cortical thickness and volume of bilateral lobes. Instead, only age affects cortical thickness or volume and only intracranial volume affects cortical volume.

Migraine is a neurological disorder that affects the structure and functional aspects of the cerebral cortex. Some patients with migraine have intracerebral white matter lesions (WMLs) caused from cortical changes because of the migraine attacks. Although WMLs are likely to be microvascular, the effects that they exert on cortical thickness and volume is relatively unknown. In a recent study, investigators assessed patients with migraines with or without WMLs to compare potential cortical thickness and volume differences between them.

During a recruitment period of 7 years, investigators enrolled 161 female patients. Gender similarity was used to exclude any gender-related differences, such as longer headache duration and higher intensity of attacks. Forty healthy patients were also included as a control group. Patients with WMLs were significantly older than patients without WMLs (

 = .0003) and patients who were healthy (

 = .018). Total number of migraine attacks, disease duration, and rate of aura were also significantly higher in the WMLs group compared with the group without the lesions.

Among the groups, left and right sided lobular and insular volumes and thickness were not significantly different. Cortical thickness and volume for the frontal, parietal, temporal, occipital, and insular were all not statistically different among the 3 groups.

Although the presence of lesions did not significantly affect cortical thickness and volume, patient age did. Age had a significant negative association with both thickness and volume for each of the 5 regions (

 < .001). In contrast, intracranial volume had a positive association with cortical volume. Intracranial volume only affected cortical volume, and not thickness (

 < .001). There were no significant interactions between group with age, group with intracranial volume, or age with intracranial volume. 

From this female migraine group, investigators found that neither lesions nor any other clinical characteristics affected cortical thickness or volume. For each region, cortical thickness and volume were practically equivalent and within the predefined relevant limit of ±0.1mm. Only age was shown to be a significant predictor of cortical thickness and volume, and intracranial volume for cortical volume.

Komáromy H, He M, Perlaki G. Influence of hemispheric white matter lesions and migraine characteristics on cortical thickness and volume. 

. 2019;20(1):4. doi: 10.1186/s10194-019-0959-2.

Results from a recent study showed that only age affects cortical thickness or volume, and intracranial volume affects cortical volume in migraine.
 

White Matter Lesions Does Not Affect Cortical Thickness or Volume

According to the results of a recent study, patients with acute myeloid leukemia (AML) who are ineligible for intensive chemotherapy tend to have poor health-related quality of life (HRQoL) scores that are independent predictors of poor survival.

AML is an aggressive disease with a poor prognosis and a 5-year survival of 26%. Treatments for AML are typically divided between intensive chemotherapy and nonintensive chemotherapy. For patients who are younger than 60, treatments are generally intensive and consist of the “7+3” regimen, 7 days of treatment with cytarabine and 3 days of treatment with an anthracycline. For patients who are older than 70, treatments are nonintensive and include hypomethylating agents and best supportive care.

The median age for AML is 68, indicating that many of these patients will be ineligible to receive intensive chemotherapy. However, the HRQoL of the patients has not been evaluated for this patient population. In this study, investigators reported on the HRQoL among patients with AML not eligible for intensive chemotherapy.

Investigators extracted data from 12 original studies. Most of the studies utilized the EORTC QLQ-C30 and 5 studies reported EQ-5D values. Other scales used included FACT, Hospital Anxiety and Depression Scale, and global fatigue scale. Data from the 4 original randomized controlled trials indicated that nonintensive chemotherapy achieved meaningful improvements in the fatigue and global health status of EORTC QLQ-C30. In 1 prospective study, patients treated with azacitidine who responded had significantly superior EQ-5D scores as well as lower FACIT-fatigue scores compared with patients who did not respond to therapy. In another prospective study, patients treated with nonintensive chemotherapy had significantly improved physical function and fatigue scores in the EROTC QLQ-C30.

HRQoL also correlates with overall survival (OS). Patients with low initial scores at diagnosis had much shorter survival compared with patients with higher scores. Fatigue and distress were the symptoms most reported. Some of the scores that were found to be lower were physical functioning, role function, and fatigue scores. Scores were especially better for patients with first-line disease than patients who with refractory or relapsed disease.

Compared with the general population, patients with AML had more fatigue, pain, dyspnea, and appetite loss. Based on a 0-100 scale, with lower scores indicating poorer health, patients with AML on nonintensive chemotherapy had low baseline HRQoL scores, particularly in fatigue (33) and global health status (50). In the 1 cost-effective analysis that was included in this report, investigators found patients receiving a hypomethylating agent had better quality of life than patients receiving best supportive care. Transfusion dependency was also a factor related to HRQoL assessments.

Patient reported outcomes such as HRQoL has become an important assessment tool in accounting for treatment objectives to that the patient finds important. Because many of these quality of life measures are independent prognostic factors for OS, trials should account for these measures to evaluate treatment impacts in a patient’s life.

Forsythe A, Kwon CS, Bell T, Smith TA, Arondekar B. Health-related quality of life in acute myeloid leukemia patients not eligible for intensive chemotherapy: results of a systematic literature review. 

. 2019;11:87-98. doi://10.2147/CEOR.S187409.

Patients with acute myeloid leukemia (AML) who are ineligible for intensive chemotherapy tend to have poor health-related quality of life (HRQoL) scores that are independent predictors of poor survival, a recent study reported.

Author | David Bai, PharmD

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