Bi-Specific Antibodies for Refractory Lymphoma

Just a short post today. I've been very busy for the last few weeks, and that will keep up for a few more days, but I wanted to post something, so here it is: an interview with Dr. Elizabeth Budde about bi-specific antibodies, published by MedPage Today.

As you might remember, Bispecifics are similar to monoclonal antibodies like Rituxan and Obinutuzumab, in that they can find and attach themselves to proteins on the surface of B cells that become cancerous in diseases like Follicular Lymphoma. But they are different in that they also attach to other cells at the same time -- usually T cells, another important immune cell (they're the T in "CAR-T"). So they work by bringing a cancer cell into close contact with an immune cell that might eliminate it. 

Bi-specifics are one of those newer treatments that get oncologists very excited. (I often ask my oncologist what gets him excited in the world of Lymphoma, and bi-specifics were one of the first things he told me about, just before they started to get talked about widely.)

In this interview, Dr. Budde talks specifically about the results of a phase 2 trial for Mosunetuzumab, one of several Bi-specifics being tested now for FL. This bi-specific caused a lot of excitement at the ASH conference in December, and you can see form the interview that Dr. Budde is excited about it as well. 

She compares the treatment to CAR-T, pointing out that CAR-T needs to be given in a very particular setting, but a bi-specific like Mosunetuzumab can be given in a regular treatment room, like Rituxan or chemotherapy. She also compares it to PI3K Inhibitors, and shows how much more durable (long-lasting) Mosunetuzumab compared to inhibitors. 

It's a short interview, but an interesting one, and confirms how likely it is that bi-specifics will be a part of our treatment options soon, and for a long time. 

More later, after things slow down for me.

Stay well.

 

Good News (for the EU) and Bad News (for PI3K Inhibitors)

I know I (sort of) promised to stop giving bad news about PI3K Inhibitors, but I can't help it if they keep giving me things to talk about. I'll try to balance it with some good news this time, though.

You really haven't needed to have been reading this blog for long to know that PI3K Inhibitors for Follicular Lymphoma have really been having troubles over the last few months. In December, Duvelisib was taken off the market (for FL) by the manufacturer for "business reasons." It was given accelerated approval by the FDA based on a phase 2 clinical trial, but a larger, longer phase 3 trial was basically seen as not worth it. Pretty much the same thing happened in January with Idelalisib. It was trying to conduct a phase 3 trial after getting accelerated approval, but was having trouble getting patients enrolled, which they blamed on Covid (though, given the troubles that other PI3K inhibitors are having, I think it was probably more than that).

Then later in January, the manufacturers of Parsaclisib withdrew from the FDA approval process. This one had not been given FDA approval (unlike the other two), but was in the process of getting accelaterated approval from the FDA when they also made a "business decision" to not go any further in the process.

Then in February, the FDA stopped all clinical trials involving Umbralisib because of a possible increased chance of death. Umbralisib had already been approved, and it looks like this was done out of an abundance of caution, but it just added more bad news to the treatment class.

And just to make sure we didn't break the streak of monthly bad news, this week FDA "discouraged" the maker of the PI3K inhibitor called Zandelisib from seeking accelerated approval. They had conducted what seemed like a successful phase 2 clinical trial (in face, I wrote about it a few weeks ago in an attempt to be positive about PI3K inhibitors). But the FDA told them that the limited data from that small study wouldn't be enough for approval, and suggested that a larger phase 3 trial would be necessary (something they had already begun doing). The FDA also suggested they look more into dosing (how much each patient is given during treatment). The company suggested that the size of the phase 2 trials isn't necessarily the problem. Instead, they are looking for randomized trials, rather than single arm trials. In other words, instead of giving the treatment to 50 patients and then comparing it to a study that was conducted a few years ago, the FDA wants a study with a direct comparison (100 patients in the study, with 50 getting Zandelisib and 50 getting some other treatment). Randomized trials are much more reliable than single-arm studies, since the researchers can control who is in the trial and make sure every patient is as alike as possible. But it takes more time and money to conduct that kind of trial.

For now, the plan is to go forward with the phase 3 trial. Zandelisib might very well end up being approved in the future. The phase 2 trail looks very promising. But they might also decide to stop, for "business reasons." 

When I wrote about Parsaclisib, I mentioned the problems with accelerated approvals by the FDA, and how that seemed to be a common issue with PI3K inhibitors. The comments from the maker of Zandelisib say that the FDA's thinking has "evolved" when it comes to accelerated approval for PI3K inhibitors. In other words, we're probably not going to see any more accelerated approvals. That's too bad, in some ways, since it meant getting access to new treatments much sooner. But good, too, in a way, if it means safety will be less of an issue.

I'll keep you updated on any other bad news that comes this way. 

(I'm still confused that there is so little discussion of this in the lymphoma research community. I'm waiting for the "What's the Future of PI3K Inhibitors for FL?" article in one of the medical journals. Nothing I've seen so far.)

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I promised good news, too, and this is what I had planned to write about all along:

The Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) has suggested that the the European Union approve the use of the CAR-T treatment Kymriah (also known as Tisagenlecleucel), for patients with Relapsed or Refractory (R/R) Follicular Lymphoma who have already received two lines of systemic therapy.

The approval is based on the results of the phase 2 ELARA trial, which involved 94 patients. In the trial, 86% of patients had a response, including 69% who had a Complete Response. The response was durable -- 87% of patients who experienced a CR still had a response after nine months.

The Safety profile was also very positive. While 49% of patients experienced cytokine release syndrome (CRS), none were very serious (grade 3 or higher), and only 3% of patients had grade 3 or 4 neurological side effect.

Results from this trail were reported at last year's ASCO conference, and caused a lot of excitement.  

It would be pretty wonderful if our friends in the EU had CAR-T as a treatment option. The European Commission plans to review the CHMP recommendation and make a final decision in about two months. Of they approve, CAR-T will be available to R/R FL patients in all 27 EU countries, plus Iceland, Norway and Liechtenstein.

I'll keep an eye out for news about this, too. I look forward to sharing some happy news when I can.

 

POD24 in Follicular Lymphoma

Important research from the journal Blood. 

In the article called "Validation of POD24 as a Robust Early Clinical End Point of Poor Survival in FL from 5225 Patients on 13 Clinical Trials,"the authors confirm that POD24 is an important concept in Follicular Lymphoma.

POD24 stands for "Progression of Disease before 24 months." (It is sometimes called EFS24 -- Event-Free Survival before 24 months.) The idea is simple, but unfortunate -- for FL patients who have had immunochemotherapy (like Bendamustine + Rituxan, or R-CHOP), if the treatment is successful, but the disease returns within 24 months, their Overall Survival is much worse than for most FL patients. Specifically, the 5 year survival is about 50%, while the 5 year survival for other FL patients is about 90%. 

The concept of POD24 has been around for a few years. It first came out in the GALLIUM study (see the link for more). It's important to understand what POD24 means. There isn't necessarily something magical about 24 months. It's that, statistically, there seems to be a greater chance of lower survival at about that point. Like all statistics, the 24 month cut off is not a guarantee of anything. Patients who progress before that point might be just fine. (Remember the numbers are about medians -- half will do better and half will do worse.)

Also, the treatment -- immunochemotherapy -- doesn't necessarily affect whether or not a patient does well or poorly. Statistically, patients who have only Rituxan (like me) don't have POD24 problems the way immunochemo patients do. But this doesn't mean Rituxan is more effective than chemo. It means people who are given Rituxan are more likely to have a less aggressive disease than a patient whose doctor recommends chemo. 

My point is, this study confirms that POD24 is a real thing, and it looked at 5225 patients in 13 different clinical trials (not just the 1200 patients in the GALLIUM trial) to make sure. But my other point is this -- remember that statistics tell a story about a particular group of people at a particular point in the past. Everyone's situation is different.

The research didn't just confirm that POD24 is legitimate. It also tried to understand why it exists. The problem right now with POD24 is that, while it affects about 20% of FL patients, no one knows whether or not a patient will be POD24 until their disease progresses. What we need is something to tell us, as soon as diagnosis if possible, whether a patient is likely to progress before 24 months after immunochemotherapy.

And the researchers did find some possible clues. 

And remember -- think of these as trends, not guarantees. 

Patients who did not progress at 24 months were more likely to have "Patients without progression at 24 months at baseline had favorable performance status (PS), limited-stage (I/II) disease, low-risk FL International Prognostic Index (FLIPI) score, normal baseline hemoglobin, and normal baseline β₂ microglobulin (B2M) level."

Patients who did progress were more likely to be male, have a Performance status greater than or equal to 2, and have a high-risk FLIPI score (3-5).

Some of those things don't need an explanation like being male. But others probably do. I've written a lot about FLIPI before; you can read more about it here.  It's basically a measure of some particular traits in FL patients (like age and how many places in your body the lymphoma has shown up). A patient is given a score based on how many of the traits she possesses. A high score means higher risk. Performance Status is similar, in that it looks at certain traits in a cancer patient (not just an FL patient, but all cancer patients), and assigns a score. But PS looks at how well the patient can perform some every day activities. A PS of 0 (the best) means fully active with no restrictions, while a PS of 2 (the cut off for this study) means the patient is able to walk but usually not able to work. A 3 means confined to bed more than half of the time. (Read more about PS here.)

So, essentially, patients are more likely to do well after treatment when they are healthy, and less likely when they have health issues or have more advanced disease. That's an over-simplifiction (a big one), but it makes sense. 

And that's helpful, but it's not enough. The article I have been discussing was accompanied by another article, commenting on it. This one is called "POD24 in Follicular Lymphoma: Time to be 'Wise'," written by Dr. John Leonard. He makes a point that lots of expert commentators make -- we need to do a better job of predicting, right from diagnosis, which patients will likely be POD24, and take care of them right from the start. He talks briefly about a study being done that looks at some biomarkers that might help identify patients who are POD24. In other words, researchers are trying to specific features of the cancer cells, not just general traits about the patient, that could help show which patients are likely to progress before 24 months. That's what we need.

This is an important study, if only because it gets people talking about how important POD24 is for 20% of FL patients. I wish those researchers luck in finding some answers. There's a real lack of answers for most of us with FL. 

 

 

 

Biosimilars for Follicular Lymphoma

The journal JAMA Oncology recently published a review of 31 biosimilars for different cancers, including Follicular Lymphoma. The results were very positive. It has some good implications for FL patients.

Some background first.

When a cancer treatment is developed, it usually takes years before it is available to all patients who could benefit from it. It goes from the laboratory, to being tested on cancer cells in test tubes, to being tried out on animal models (like mice), to then being tried on humans in a stage 1 clinical trial, and then if that goes well, in stage 2 and 3 trials. The maker of the treatment spends a lot of time and money developing and testing the treatment -- millions of dollars. When the treatment is finally available (and less than 10% of treatments will make it through a phase 3 trial), the maker is given a patent, where no one else is allowed to profit from that treatment. In the U.S. and Europe, the patent lasts 20 years. The idea is that the maker of the treatment is allowed all of that time to make back the money that they spend on developing the treatment.

After 20 years, the patent expires, and other companies are allowed to make their own versions of the treatment. If the treatment is made up of chemicals (something like a traditional chemotherapy), the new version is called a "generic." They are relatively easy to make -- it's a matter of figuring out the chemical formula and putting the right chemicals together. It's like following a recipe.

But if the treatment being copied was developed from something that was alive --something like Rituxan, that is developed from mouse cells -- it's a little more complicated. Living things tend to want to be different from other living things. It's why kids aren't exactly like their parents (which is probably good a lot of times, and not so good other times). I like to think of it this way. Creating a generic, where you're copying a chemical formula, is like following a recipe to bake a cake. But creating a biosimilar is like baking a cake, but first you have to grow the wheat and get chickens to lay the eggs, and hope that growing conditions on the farm are all OK and there isn't too much rain to affect the wheat and the chickens don't eat something weird that affects the taste of the eggs. And if everything works out, you can harvest the wheat and eggs and then make your cake. It's just more complicated -- there are more factors that have to be dealt with when the treatment is a biosimilar because it involves living things.

Because it's more difficult to develop a biosimilar -- to copy something that was alive once -- it's a big deal when one is developed and then tested and shown to be as effective and as safe as the original. 

The JAMA Oncology article, called "Characteristics of Clinical Trials Evaluating Biosimilars in the Treatment of Cancer: A Systematic Review and Meta-analysis," looks at 31 different clinical trials, involving 12,310 patients, that tested biosimilars for 3 different cancer treatments. One of them was Rituxan, and the trials tested biosimilars for patients with FL and other blood cancers. 

(Just to be clear -- this study didn't test biosimilars; it looked at studies that were already conducted.)

In reviewing all of these trials, the researchers found that the biosimilars were as effective and as safe as the treatments that they were copied from. That's not a surprise -- they wouldn't have been approved if they weren't. But what the study found was even more impressive. Basically, the clinical trials for the biosimilars were even better than the trials for the originals. They involved more patients, and the designed was better (more of them involved direct comparisons between Rituxan and the biosimilars). So basically, the developers of the biosimilars made sure that the trials were as rigorous as possible, so there were no questions about whether or not the treatments were really safe and effective.

So why does al of this matter? What's so great about biosimilars?

The big reason for using a biosimilar is that it is less expensive than the original. The original treatment was developed over years, and cost millions of dollars. The biosimilar's makers didn't need to spend all of that money. They can afford to sell it for less money.

And that's good for individual patients who have to pay for treatments on their own, as is the case for some patients in the U.S. But it's good for people in other countries as well. Lower medical costs are good for everyone.

In the U.S., the question is, will doctors prescribe biosimilars instead of the original? Will insurance companies insist on the biosimilars? 

Whatever the case, it's likely that more of us will see Rituxan biosimilars in the future. 

 

 

Reconsidering PFS (Progression Free Survival)

This month, the medical journal called The Lancet (a very influential journal) published an article called "Progression-Free Survival: It Is Time for a New Name." The authors of the article think we need to reconsider what we use Progression-Free Survival for, and even what we call it.

In some ways, the article is about something that really should only matter to oncologists, but I would argue that there is little about cancer and cancer research that doesn't matter to us as patients. Read on and I'll tell you why.

I write about Progression-Free Survival (or PFS) a lot. It comes up pretty much every time I describe a clinical trial, because it's one of the main "end-points" of most trials -- the ways they measure if a trial is successful. 

PFS is, simply, a measure of how long a patient has gone between starting treatment (or starting a trial) and having their disease progress (get worse), or die (of any cause). By using PFS as an end-point for a trial, researchers can compare different treatments to see which is most effective. Suppose a current treatment for patients had a median PFS of 36 months in a clinical trial (that is, if half of the patients had disease that came back before 36 months, and half had it come back later than 36 months, or not at all). A new treatment has a clinical trial where the PFS is 39 months. We can say that the new treatment is more effective than the old one, and make an argument that it should be approved for use.

The authors of the article make an interesting case as to why we shouldn't rely on PFS so much, and why we should change the name. The big reason behind their suggestion is that PFS doesn't really help patients as much as it seems to. 

According to the authors, "Disease progression is defined by the Response Evaluation Criteria in Solid Tumors as an increase in the sum of maximum tumor diameters of at least 20%, the development of any new lesions, or an unequivocal increase in non-measurable malignant disease." So in order to say that a patient's cancer has progressed after treatment, there has to be some way of measuring whether or not the cancer is worse than before the treatment. One way, for example, is to say that a solid tumor (that is, a non-blood cancer) has gotten 20% bigger. A 3 cm tumor is now 3.6 cm. 

But as they point out, in terms of the actual impact on a patient's life, a tumor that has grown from 3 cm to 3.5 cm is not considered to have "progressed" -- it has grown just under 20%. The patient is still considered "progression-free," and the treatment is considered successful. But is that really a "success" for the patient, who now knows that their tumor has gotten bigger, and not smaller?

To be clear -- that example is for a solid tumor, like for breast cancer or colon cancer, rather than a "liquid tumor" like lymphoma. The same 20% growth would hold for lymph nodes. But the other measures in that definition above still matter for blood cancers -- "new lesions" (the cancer showing up in a different place on a scan) or "unequivocal increase in non-measurable malignant disease" (the cancer is clearly gotten worse, and there's not argument about it).

There are other issues with PFS as well, including how the progression is measured, and who is measuring it. (A researcher who really wants the new treatment to work might measure a tumor as being a little bit smaller than it really is, even if they aren't aware that they are doing it. Here's an interesting look at the different ways that PFS measurement can be biased, if you're interested.)

The last issue with PFS has to do with the name itself. Calling it a measure of "survival" might be confusing to some people (it was for me, to be honest, when I first started reading about trials). "Survival" isn't really the thing being measured by PFS (though it does include death as counting against the PFS measurement). The authors suggest changing the name to "Progression-Free Interval," which puts the emphasis on progression, rather than survival.

I can see both sides of that, looking at it as a patient. I like the idea of "survival" as being part of the name -- it's a reminder that I'm still alive, even if the treatment has stopped working.

On the other hand, "survival" also makes the measurement seem more positive than it really is. I'm still alive, but that's not really the point. My disease is getting worse, and it might not be worse enough to even be "officially" worse if it's under 20%. Focusing on "survival" seems like it's avoiding the bad news. That doesn't do anything for my mental health.

In the end, I'd probably rather have it be called "Interval." It just seems more accurate. I have "Overall Survival" as a common statistic if I need a reminder that I' still alive. "Interval" reminds me that this is just one segment of my life as a cancer patient, and if the disease is progressing, it's time to move on to the next segment. That seems especially important to me as a Follicular Lymphoma patient. I might have a bunch of those intervals over 20 or 30 years.

The reason I find the article so fascinating is that it reminds me of how important language is for us as cancer patients. The words we use matter. Some people really like to think of themselves as cancer "warriors," who are "battling" the disease. Others hate the idea that this is a "fight" that they have to "win." Those words can help or hurt. We all use words differently.

I'm working on a project now that looks at the language we use to talk about cancer. I'm excited about it, and I hope I'll be able to tell you more about it soon. In my non-cancer life, thinking about how we use language is a big part of what I do. It's kind of fun to be able to combine those lives -- the cancer patient one and the non-cancer patient one. More on that soon.

In the meantime, I'm going to keep an eye out for reactions from the cancer community to this proposal to rethink how we use PFS and what we call it. And I'll pay more attention to how I describe PFS when I share information about trials.

Living Each Day

I don't usually go back and re-post things I have written in the past, but I've been thinking a lot about a famous cancer-related event lately. 

The event was a speech by a basketball coach named Jim Valvano, known as Jimmy V, who was especially famous for leading his college team to a national championship when no one expected them to be as good as they were. A few years later, he was diagnosed with cancer, started the V Foundation to fund cancer research (they give a lot of money for blood cancer research), and received an award for his courage.

When he received the award, he gave a truly inspiring speech about how to live a full life, whether you have cancer or not. I think about the speech a lot. The advice is pretty basic, I think.

Today (March 4, 2022) is the 29th anniversary of that speech. Four years ago, when the 25th anniversary came up, I wrote about it in a piece for The Mighty. Below, I'm posting the video of his speech, and copying my article from The Mighty.

Seems like a good time to reflect on how we live our lives each day.

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What It Meant to Hear Jimmy V's ESPY Speech Again as a Cancer Patient

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March 4 is the 25th anniversary of one of the most famous cancer speeches in history.

Jim Valvano, perhaps better known as Jimmy V, received the first Arthur Ashe Courage and Humanitarian Award at the first ESPY awards ceremony on March 4, 1993. Jimmy V was most famous at that time for being the coach of the North Carolina State University men’s basketball team, underdogs who won the national championship in 1983.

When Jimmy V won the Arthur Ashe award and gave his speech, he was just a couple of months away from the end of his life. He had metastasized adenocarcinoma, a glandular cancer.

In his speech at the ESPYs, he offered some advice:

To me, there are three things we all should do every day. We should do this every day of our lives. Number one is laugh. You should laugh every day. Number two is think. You should spend some time in thought. Number three is you should have your emotions moved to tears, could be happiness or joy. But think about it. If you laugh, you think and you cry, that’s a full day. That’s a heck of a day. You do that seven days a week, you’re going to have something special.

I saw Jimmy V make that speech 25 years ago on TV. At the time, I thought it was inspiring, but as a young healthy man, it didn’t mean much to me.

Five years ago, on its 20th anniversary, I heard it again, on the radio as I was driving.

That time, it meant something.

Like Jimmy V, I was a cancer patient. I still am – in January, I celebrated 10 years with follicular lymphoma, an incurable blood cancer.

On that day five years ago, Jimmy V’s words hit me hard. And it made me think a lot about what my days were like and whether I was living the kind of “full days” he was urging me to live.

Laugh, think, cry: it’s as good a guide for living as I have ever seen. Doing it really will lead to a heck of a life, as he says.

But I’m not saying it’s easy.

Even if we don’t take his advice literally, his point is worth taking to heart. We should live life deliberately.

Here’s what I mean.

Laughing every day is actually pretty easy for me. My parents loved to laugh, and they passed that on to me. Even when I was first diagnosed with cancer, I couldn’t help but laugh. It was absurd – a healthy 40-year-old man with cancer? It was (and still is) ridiculous to me, and I refuse to let cancer take away my joy.

But to laugh, you have to be in the mood. If you’ve ever watched a funny movie with someone who isn’t in the mood to laugh, you know what I mean. Laughing isn’t easy for lots of people with cancer or other illnesses. It takes effort.

For me, crying was the harder thing to do. I’m a man, and a husband and father, and I’ve been conditioned to think I am supposed to be the rock for my family. That’s not the case so much for me anymore. I give myself permission to cry now. Hearing a sad song will do it most days. So will videos of soldiers surprising their families when they return home.

And thinking? Of course we all think. But sometimes it’s easier to just not think about certain things, especially about our disease. It can be overwhelming. But not thinking sometimes means letting others make choices for us about all aspects of our lives. Thinking guarantees we at least let our voices be heard.

Laughing, thinking, crying – sometimes they come easy. But not always, and not for everyone.

To live the kind of life that Jimmy V says we should live, you have to make the choice to open yourself up. To laughter. To tears. To thought.

You have to live deliberately. That’s how you end up with “something special.”

You might do one or two of those things every day – laughing, thinking, crying– without choosing deliberately.

It takes work to choose to do all three in a day.

But what a great choice…

 

Opportunities to Hear from Lymphoma Experts

Many thanks to Shelly, a long-time reader, who has let me know about two opportunities to hear from Lymphoma experts.

The first has actually already passed, but it's really valuable. It's a video from the Leukemia and Lymphoma Society's "Ask an Expert" series, where patients can ask a lymphoma specialist any questions about their disease. As I said, this one already happened -- it was posted on February 25. The session features Dr. Erel Joffe from the Memorial Sloan Kettering Cancer Center in New York. 

Dr. Joffe spends some time comparing a few different first line treatments for Follicular Lymphoma -- Rituxan + chemotherapy, Rituxan + Lenalidomide (R-Squared), and a clinical trial of Rituxan + Lenalidomide + Venetoclax + Ibrutinib. 

One of the main points that Dr. Joffe makes in the video is the importance of clinical trials. Many people think of them as experimental, and in some ways they are. But they are also rigorous -- a treatment won't make it to a trial if there hasn't already been evidence that it will wok and it will be safe, especially for phase 2 and phase 3 trials. There are no guarantees, of course, that a clinical trial will be successful for any individual patient. But there's no guarantee that an approved treatment will be successful either. I like the way Dr. Joffe describes being in a trial -- you're getting the treatment of the future, today."

Dr. Joffe goes through the results of a few trials and gives some advice on what to look for when you're trying to decide whether or not to participate in a trial. It's extremely valuable advice. (He also gets into the whole issue of being "cured," and whether that matters, at about 14 minutes int the video. Sounds familiar.) If you've ever considered a trial, or you're not sure about them, I highly recommend the video. (Be warned, though -- the sound is not very good. Shelly recommended I watch with the captions on, and I think that's a good suggestion.)

The second opportunity hasn't happened yet, which is good news. This one is sponsored by the Lymphoma Research Foundation, and it's part of their "Ask a Doctor About Lymphoma" series. There are actually three of them coming up in the series, all of them being conducted online (they often do these in person). But Shelly specifically pointed out that the session on March 9 is being led by Dr. Bruce Cheson, who I am fond of, as Shelly knows. (I didn't think it was so obvious that I am kind of what my kids call a "Super Fan" of Dr. Cheson. But then I searched for him on this blog to see if I could link to him, and I'm a little embarrassed by how often I talk about how much I like him, so I'm not going to link to him. You can search his name on your own if you want to read more.)

All three of the Ask the Doctor sessions should be great. Pick one that works for your schedule and sign up, and ask a question if you have one. It's a nice opportunity to get some answers.

And if you've never explored the sites for LLS and LRF, this is a good time to do so. They both have lots of great information for Lymphoma patients, and resources (like their "ask" series) that provide direct assistance in many different ways.