Karen O. Klein, MD

: Hello. My name’s Dr Karen Klein from the University of California San Diego in San Diego, California. And I will be discussing a 

article today. The title is “Importance of individualizing treatment decisions in girls with central precocious puberty when initiating treatment after age 7 years or continuing beyond a chronological age of 10 years or a bone age of 12 years.” The first author is Dr Marcela Vargas Trujillo, one of my colleagues at the University of California San Diego. This program is sponsored by AbbVie. I need to disclose that the contents are consistent with all applicable FDA guidelines. I’ve been selected by AbbVie, and I’m presenting on their behalf.

In the discussion of the paper, we talk about the rate of bone maturation slowing throughout treatment, which is known from other studies; the increase in predicted adult height continuing with longer duration. And then the key new findings are the predicted adult height increase in 91% of those who started treatment after a chronological age of 7 years. The girls who initiated treatment who were greater than 7 years of age had comparable predicted adult height increases, as well, and almost 85% of the girls who continued treatment after a bone age of 12 continued to have further increases in predicted adult height. Girls in this study reached a final height similar to the predicted adult height achieved during treatment. And all of this led to our conclusion that treatment decisions should be individualized. Initiation and cessation of treatment should not be based solely on bone age or chronological age alone. In our discussion, we included a few factors that influence that decision, if it’s an individualized decision. What are we thinking about when we’re deciding whether to start treatment? Well, girls with rapid progression of puberty have lower height outcomes than those with slow progression. Those with slow progression may not need treatment. Again, individualized. Further decrease in predicted adult height is due to the rapid bone maturation. If the bones are advanced, they’re going to continue to advance. The predicted adult height at the start of treatment, or when you’re considering treatment, is going to decrease from there, again, if they’re rapidly advancing.

Don’t base your decision on that one predicted adult height alone. And then predicted adult height compared to midparental height, of course, is important because genetics also plays a role in the growth potential of our children. The impending onset of menarche, of course, is a separate discussion not related to growth. But it’s a very important reason to start treatment in girls who might have their menarche at very young ages.

What about the other end of the spectrum, the factors influencing the decision to stop treatment? We want pubertal progression concurrent with peers once we’ve started treatment. We want to remember that bone maturation is going to accelerate post-treatment. If there was rapid acceleration of bones prior to treatment, whatever is causing that is going to resume once we stop treatment. Treatment pauses it, and then bone age accelerates again. And calculating predicted adult height has to consider that. We’ve already talked about, of course, that it matters how tall your family is. We’ve already talked about losing predicted adult height based on these factors. In general, it’s reasonable to continue treatment until predicted adult height is close to midparental height and growth is still reasonable. If growth velocity continues to slow down and chronological age is nearing bone age, and predicted adult height is not improving any further, then discontinuation of treatment is reasonable. If bone age indicates growth potential and predicted adult height is still improving, then even growth velocity alone might not dictate the cessation of treatment. Again, it’s important to individualize the decision with all these factors. A major part of the discussion in this publication is regarding the discussion of the Kaplowitz paper from 2018, which raised the issue of, in general, discontinuing treatment no later than a chronological age of 10 years. And many people have started to use that as sort of a guideline. They do talk in that paper about the rare cases of severe psychosocial stress, and very low predicted adult height. In the present study, the mean chronological age at the end of treatment was 11 and a half years of age, and predicted adult height had continued to improve a year prior to that. Stressing that there are some examples of when just basing discontinuation of treatment on chronological age alone maybe is not a good idea, once they’ve already had many years of treatment. For example, a girl with a chronological age of 10 years and a bone age of 10 has more growth potential than a girl with a chronological age of 10 years and a bone age of 12. This latter child might need to remain on treatment longer to continue to slow the rate of bone maturation and make up for the loss in predicted adult height—again, based partly on how tall they are and where we’re expecting them to be compared with their family. Two children, each age 10 but with different heights, might have different treatment plans, or different bone ages might have different treatment plans. Menses onset is also very important. 

The Kaplowitz paper suggests that since menses occurs an average of 18 months after cessation of treatment, the girl who stops treatment at 10 years of age would have menses at an average of 11 and a half years, consistent with the general population. However, we raised the caution that this reasoning is based on the average of when menses occur, but we know that the range is from 3 months to 3 years. If someone is 10 years of age and had more rapid progression or later onset of treatment and is more likely to start menses sooner—maybe within 3 months—consider in the decision-making…whether that’s reasonable. Based on how she’s doing psychosocially, where she is with her peers, our goals that we want to reach, and her height. The Kaplowitz paper also discussed cost-effectiveness. Again, that needs to be individualized based on all these other factors, and this is not a major topic of the current paper. There’s the presentation of the 

 discussion, we always like to review the strengths and limitations—even if I wasn’t one of the authors. The strengths are that it’s actually a relatively large study for central precocious puberty. It’s not easy to do these studies, and it’s a very long-term follow-up in which we had lots of data and final height in many girls. The diversity of age at initiation of treatment helps us try to address some of these issues. And the rigorous criteria to define central precocious puberty meant that we had rapidly-progressing girls. When we look at some of the other studies in the literature, there’s a wide range of how many girls with slowly-progressing puberty, but their bone age wasn’t that advanced. They weren’t accelerating that rapidly. That affects how much benefit treatment has. And some studies are difficult to interpret, based on the diversity of patients. Limitations: There weren’t enough subjects for a prediction model of who benefits from continued treatment and who doesn’t. We still must put all those factors together. But it gives data to consider all those factors. And then the subgroup analyses that we did were too small for statistical testing. Again, they are just descriptive and are not definitive. And then we didn’t have parental heights in all the patients. Of course, that’s a limitation.

In conclusion, the variability in change of predicted adult height emphasizes the multifactorial influences on height and the importance of individualizing treatment decisions. The girls who initiated treatment after a chronological age of 7 years had improvements in predicted adult height similar to the younger girls. The continuation of treatment after a chronological age of 10 years or a bone age of 12 led to continued increase in predicted adult height in almost all girls. The initiation of treatment despite the chronological age greater than 7 years, and continuation of treatment after a bone age of 12 should be considered in some girls, with the aim of attaining optimal growth. Treatment decisions should be individualized, and initiation or cessation of treatment should not be based on bone age or chronological age alone. Thank you very much for your attention to the discussion of this publication.

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Karen O. Klein, MD, leads a discussion of the Trujillo et al study on the importance of individualizing treatment decisions in girls with CPP, including factors that influence the decision to begin and cease treatment.

Trujillo CPP Study Review: Conclusion

The first figure in the paper looks at the change in bone age to chronological age ratio over time. As I mentioned, at baseline, it’s about 1.5—very advanced bone age ratio. And then it steadily decreases throughout treatment to about 1.2, and 1.1 by the end of treatment. Also importantly, 31% of the girls reached a point with a bone age less than a year beyond their chronological age. Growth velocity declined. I’m not showing that data. But it also declined appropriately from pubertal rates prior to treatment to prepubertal rates during treatment. Figure 2A is the change in predicted adult height during treatment, which continued to increase with longer duration of treatment. That’s also been previously shown. And then Figure 2B shows this unique distribution. But the change of predicted adult height during treatment was not based on the age that they started treatment. Now, we didn’t have as many that were younger, and you can see the younger girls had a great improvement in predicted adult height over baseline. But when we look at the girls who started at 7 and 8 years old, they also had many girls—and we’ll go through those details—who had significant changes in predicted adult height. Forty-five of the 48 girls has some increase. The line is drawn at 0. There’s a couple that didn’t increase in their predicted adult height during treatment. Figure 2C again shows us that change in predicted adult height, but with the solid dots representing the girls who were less than 7 years of age doing very well. And more than half of the girls who were greater than 7 years of age doing just as well with continued predicted adult height, irrespective of their chronological age at the start of treatment. Another way to summarize it is that predicted adult height increased in 91% of the girls who started treatment at a chronological age greater than or equal to 7 years of age. Forty-six percent of those who initiated greater than or equal to 7 years had at least a 5-centimeter cm increase in predicted adult height. And 16%, 6 of 37 girls, had greater than 10 cm increase in predicted adult height. The sample size was too small to reach statistical significance but makes the point that many girls continue to benefit. And not just 2- to 4-cm benefit, but greater than 5 or even 10 cm in some of the girls. Figure 2D again shows the change in predicted adult height, but by bone age. And you can see, even beyond a bone age of 12, there continues to be increases in predicted adult height. This table separates the girls who were less than 7 years of age at the start of treatment with those who were greater than or equal to 7 years of age at the start of treatment. The numbers are too small to reach statistical significance. But you can see similar numbers, proportionately, of those who achieved at least 5 cm of improvement or greater than 10 cm of improvement. Girls who initiated treatment at a chronological age less than 7 years and girls who initiated treatment at a chronological age greater than or equal to 7 years had comparable increases in predicted adult height during treatment and comparable final height. Table 3 compares those with a bone age less than 12 years to those with a bone age greater than or equal to 12. Eighty-four percent of our population in this study who continued treatment beyond a bone age of 12 continued to increase their predicted adult height. Not all, but most. The 3 girls who did not show improvement were either already at or near their midparental height, shown on the right side, and continued improvement of predicted adult height 1 year prior to near the end of treatment, at and then final height. Interestingly, in this study with girls who were treated longer, final height was close to that last assessment of predicted adult height. There are other studies published that show the risk of final height decreasing after the end of treatment, and our data suggests that might be based on stopping treatment too soon. Although we can’t directly conclude that from this study, I want you to notice that, in this study, where children were treated longer, they did reach those heights, on average. Thirty girls were followed to final height. I’ve already mentioned the key points of this figure. Sixteen girls had a decrease from their greatest predicted adult height. There is some loss of predicted adult height, but 58% reached or surpassed their midparental height.

Karen O. Klein, MD, reviews data and study results from the Trujillo et al study on the importance of individualizing treatment decisions in girls with CPP.

Trujillo CPP Study Review: Study Results

We will do a quick overview of central precocious puberty, [CPP] as background to the 

discussion. Central precocious puberty occurs when the hypothalamic-pituitary-gonadal axis is activated prematurely, which leads to increased gonadal steroid hormone secretion, which leads to the physical and hormonal changes seen in children with precocious puberty. We’re going to use the classic definition of onset of puberty as less than 8 years of age in girls, and less than 9 years of age in boys. The signs, as I’ve mentioned, include the physical secondary characteristics, and accelerated bone maturation and growth. We usually define this as at least progression of 1 pubertal stage or Tanner stage per year and a bone age that’s at least 2 standard deviations beyond the chronological age—it’s out of the normal range—and a growth rate consistent with the stage of puberty. The consequences, if left untreated, of central precocious puberty can lead to the changes of physical development that aren’t consistent with peers, and the problems that come with that; the risk of premature menarche, and then the long-term consequences: premature fusion of the growth plates and reduction of adult short stature. Early diagnosis and prompt referral help ensure the best possible treatment outcomes.

Gonadotropin releasing hormone agonists are the standard of care for treating central precocious puberty. With that background, looking at the paper, which is a new retrospective analysis of leuprolide depot data…we can look at these 2 main points. We don’t have a lot of published data. Looking at when treatment is started—before a chronological age of 7, or continued past a chronological age of 10, or a bone age of 12—we wanted to examine the height outcomes in girls with central precocious puberty, when treatment is initiated at a chronological age greater than 7, as well as continued past a bone age of 12.There are 2 knowledge gaps on the spectrum of treating children with central precocious puberty. The study design was based on a large study with 1 monthly injection of depot leuprolide. We have 48 treatment-naïve girls from that study. We only included girls, so that the numbers could have statistical power, since not as many boys were in the study. We took the 48 girls. They had to have breast onset before 8 years of age, a peak stimulated LH [luteinizing hormone] to define central puberty greater than 10 years of age. It was a very robust definition to make sure these were true rapidly-progressing girls with central puberty. All the girls had a chronological age of less than 9 years of age at the beginning of the study, and a bone age of at least 1 year advanced. They were screened and then started on treatment, where they received monthly doses based on their weight at that time, and had monthly examinations, a physical exam and laboratory testing, bone age measurement, and safety measures were applied. And then after the end of treatment, they had a long follow-up period, where they had a visit every 6 months until they reached pubertal levels and then annual visits or questionnaires until the age of 21. We also have long-term outcome published data from this population. But for the purposes of this paper, we wanted to look back at this robust data source and look at the changes in predicted adult height and growth rate between the girls who started treatment at less than age 7 and greater than 7 years of age, and between the girls with bone ages greater than 12 or less than 12. The statistical analyses were straightforward, with correlations between the variables assessed by linear regression, and then changes over time, from baseline, using paired t-tests. All the values are presented as mean plus standard deviations unless otherwise noted. And the software was SAS [statistical analysis system] version 9.4. Table 1 shows the baseline characteristics of race, ethnicity, mean chronological age, which—you can see the mean age was 6.8, but the range was from a girl that was 1 year old to a girl who was 9 years old, the upper limit of our inclusion criteria. The breast stages are shown here, so that you can see most of them. Fifty percent were stage 3—in the middle of puberty. And then the other important thing on this table is how advanced the bone age actually was. There are a couple of ways to look at it. The bone age to chronological age ratio, average 1.5. The difference in bone age and chronological age averaged 3 years. Significantly advanced bone age predicted adult height and midparental height are shown here—obviously with great discrepancy.

Karen O. Klein, MD, provides an overview of CPP (central precocious puberty) as well as a review of the study design and baseline characteristics from the Trujillo et al study on the importance of individualizing treatment decisions in girls with CPP.

Karen O. Klein, MD

Articles

Trujillo CPP Study Review: Conclusion

Trujillo CPP Study Review: Study Results

Trujillo CPP Study Review: Overview and Baseline Characteristics