FLT3 Inhibitors for AML Update

Introduction

Mutations in the FLT3 (fms-like tyrosine kinase 3) gene are the most common mutations seen in Acute Myeloid Leukemia (AML) patients. FLT3 mutations are seen in about 30% of AML patients. There are 2 different FLT3 mutations, FLT3-ITD (internal tandem duplication) mutation and tyrosine kinase domain mutations (TKD) mutation. Here I report some newer results of treatments with FLT3 inhibitors, that I have come across in the last several months.

There are quite a few drugs that target the FLT3 gene, including:

First generation drugs:

  • Sorafenib (Nexavar)
  • Midostaurin (Rydapt)
  • Lestaurtinib clinical development of lestaurtinib has been discontinued as it did not provide significant clinical benefit.

Second generation drugs, which tend to have fewer and less severe side effects and are more effective include:

  • Gilteritinib (Xospata)
  • Quizartinib (Vanflyta) – Only for ITD mutations.
  • Crenolanib – Not FDA approved.

FLT3 inhibitors are effective treatments for AML with a FLT3 mutation. However, there are still a number of open questions. How should FLT3 inhibitors be used, with induction chemo, with consolidation chemo and/or for maintenance after a stem cell transplant (SCT) or chemo? Can they be used as a single agent for treating patients who are not good candidates for chemotherapy? Do they work well with newer treatments, specifically with azacitidine and ventoclax regimens? There have not been a lot of comparison between the different drugs. Finally, there is the question of why all these drugs have names that are barely pronounceable!

Gilterinib

There is a new study looking at the use of gilterinib as maintenance after SCT. This was a multi-national randomized study, comparing maintenance with gIlterinib against placebo. The result was overall the patients who received gilterinib had better relapse-free survival (RFS) compared to patients who received placebo. However, this difference was not considered statically significant.  However, the trial had a pre-specified secondary objective to look at the subgroup of patients who had measurable residual disease (MRD), that is they were MRD+.

About half of the patients were MRD+ either before SCT or after (or both). In this group, the RFS survival in the patients receiving gilterinib was significantly greater than the placebo group. Unfortunately, there were more side effects in the gilterinib group. It is likely that, because of this study, patients who are FLT3+ and undergoing a transplant will get gilterinib as maintenance if they are MRD+ and not if they are MRD-. The use of gilterinib or other FLT3 inhibitors as maintenance therapy will continue to be a subject of active research.

Quizartinib

I wrote a post on quizartiinb: Quizartinib in FLT3-ITD-Positive AML that was an overview of a trial of this drug along with induction and consolidation chemo and as maintenance after chemotherapy. In July, 2023, Quizartinib was approved for treatment of FLT3-ITD AML in the United States by the FDA.

Crenolanib

Crenolanib is a second-generation FLT3 agent that works for both FLT3-ITD and FLT3-TKD mutations. In Crenolanib and Intensive Chemotherapy for Adults With Newly Diagnosed FLT3-Mutated AML, crenolanib was given with “7+3:” induction and then with consolidation chemotherapy and as maintenance therapy after consolidation chemo and after a SCT. About 2/3 of patients were younger than 60, but patients as old as 75 were included. Although this was not a randomized trial and was fairly small (44 patients), it seemed that Crenolanib added to chemotherapy and as maintenance improved survival compared to midostaurin (the first drug approved for FLT3 AML) and quizartiinb (described above).

Sorafenib

While sorafenib is an FLT3 inhibitor, this first study is on its use in AML patients even if they did have a FLT3 mutation. Previous studies had shown sorafenib improved survival when given with standard “7+3” induction for AML. This study (Sorafenib Plus Cladribine, High-Dose Cytarabine, G-CSF, and Mitoxantrone for Untreated AML) looked at sorafenib with cladribine, high-dose cytarabine, granulocyte colony–stimulating factor, and mitoxantrone (CLAG-M). The first part of the study (Phase I) tried increasing doses of sorafenib and mitoxantrone. The Phase II part of the study used the recommended phase 2 dose (RP2D) to treat more patients. When compared with historical controls who received CLAG-M without sorafenib, the patients who received the RP2D had improved survival.

Finally, there is a report on the long term follow-up of a trial looking at using sorafenib as maintenance therapy after a transplant (Sorafenib Maintenance After Allogeneic HSCT in Patients With AML With FLT3 Internal Tandem Duplications). The use of sorafenib as maintenance reduced relapse which improved survival in patients with FLT3-ITD AML. The non-relapse mortality and the incidence of chronic Graft-Versus-Host Disease (GVHD) in those who had a transplant was similar in patients who received sorafenib and those who did not. This result was sustained long-term (with a median follow-up of about 5 years).

Conclusion

The best way to use FLT3 inhibitors in patients with FLT3 mutation is still an area of active research. Newer agents promise better results – fewer side effects and better survival.

Further Reading

FLT3 Tyrosine Kinase Inhibitors for the Treatment of Fit and Unfit Patients with FLT3-Mutated AML: A Systematic Review, Int J Mol Sci. 2021 Jun; 22(11): 5873.

Molecular Mechanisms of Resistance to FLT3 Inhibitors in Acute Myeloid Leukemia: Ongoing Challenges and Future Treatments, Cells 2020, 9(11), 2493.

Gilteritinib as Posttransplant Maintenance for AML With Internal Tandem Duplication Mutation of FLT3, Practice Update (registration required, free), March 26, 2024.

Gilteritinib as Post-Transplant Maintenance for Acute Myeloid Leukemia With Internal Tandem Duplication Mutation of FLT3, Medscape, June 21, 2023.

Gilteritinib as Post-Transplant Maintenance for Acute Myeloid Leukemia With Internal Tandem Duplication Mutation of FLT3, Journal of Cinical Oncology. March 12, 2024..

Quizartinib Approval Adds New Treatment Option for AML, Including in Older Patients , National Cancer Institute, Cancer Currents Blog , August 15, 2023.

Crenolanib and Intensive Chemotherapy for Adults With Newly Diagnosed FLT3-Mutated AML, Practice Update (registration required, free), March 4, 2024.

Crenolanib and Intensive Chemotherapy in Adults With Newly Diagnosed FLT3-Mutated AML (JCO article) Journal of Clinical Oncology February 07, 2024.

Sorafenib Plus Cladribine, High-Dose Cytarabine, G-CSF, and Mitoxantrone for Untreated AML Practice Update (registration required, free), July 25, 2023.

Phase 1/2 study of sorafenib added to cladribine, high-dose cytarabine, G-CSF, and mitoxantrone in untreated AML, Blood Adv (2023) 7 (17): 4950–4961.

Sorafenib Maintenance After Allogeneic HSCT in Patients With AML With FLT3 Internal Tandem Duplications, Practice Update (registration required, free), July 25, 2023.

Sorafenib maintenance after allogeneic haemopoietic stem-cell transplantation in patients with FLT3-ITD acute myeloid leukaemia: long-term follow-up of an open-label, multicentre, randomised, phase 3 trial, The Lancet, Volume 10, ISSUE 8, e600-e611, August 2023

Olutasidenib for Relapsed or Refractory Acute Myeloid Leukemia with IDH1 Mutation

Introduction 

Once again a new drug that was recently FDA approved for some Acute Myeloid Leukemia (AML) patients. Olutasidenib (brand name: Rezlidhia) was approved in December 2022 for AML patients who have relapsed or are refractory to treatment (R/R) with a mutation in the Isocitrate Dehydrogenase 1 (IDH1) gene. There is a different gene called IDH2, which can also be mutated in patients with AML, but different medications are used for IDH2 mutations. 

An existing drug, called ivosidenib (brand name: Tibsovo) was already approved for patients with AML and a mutation in IDH1. It was initially approved in July 2018 as a single agent for patients with R? AML with a IDH1 mutation. Later it was approved for use in combination with azacytidine for newly diagnosed AML patients with an IDH1 mutation. There was also a specific test (the Abbott RealTime IDH1 Assay) approved along with the initial approval of ivosidenib. This test was also approved to select patients to be treated with olutasicdenib.

Results of the Current Study 

The study used to support the approval was a non-randomized trial (all patients received olutasidenib). The study included patients with AML and ones with Myelodysplastic Syndrome (MDS) who had a mutation in the IDH1 gene. Patients were treated with olutasidenib as a single agent (monotherapy) as well as combined with azacytidine. The approval was based on the results of the 147 patients who received olutasidenib monotherapy (the results are described in detail here). 

In the study, about 35% of patients achieved a complete remission (CR) or complete remission with partial hematologic recovery (CRh) – the latter means that they appear to be in remission, but their blood counts are not normal. In addition, about one third of patients who were platelet and/or red blood transfusion dependent at the start of the trial eventually did not require transfusions for 8 or more consecutive weeks (transfusion independent). All patients experienced 1 or more adverse events (AEs) and almost all experience a serious (Grade III or IV) AE. These AEs are expected in patients with AML, particularly older patients, as most of the patients were. 

Comparison with Ivosidenib 

Now that there are 2 drugs approved for AML patients with an IDH1 mutation, the question becomes which drug should be used and in which circumstances. There have been no studies (at least ones that are published) that directly compare the drugs. According to the paper from Bload Advances on the responses to olutasidenib and ivosidenib as single agents was about the same, however the length of remission in the patients receiving olutasidenib (a median of 25.9 months) compared to ivosidenib (8.2 months0. The big caveat is that, since the comparison was not randomized, it is difficult to determine if there were differences in risks in each group. My guess is that there will not be a randomized comparison of these two groups.

It will be more interesting to look at these drugs in combination with azacytadine and also as a 3 drug combination of azacytidine and venetoclax. In addition, these drugs could be combined with existing intensive chemotherapy regimens (for instance, so-called 7+3 induction with cytarabine and daunorubicin). Likely the combinations would produce more remissions but might have significantly more side effects. 

In summary, the good news is that there is another drug that can help some patients with AML, the bad news is that the determination of the best therapy is yet more complicated. 

Further reading 

Olutasidenib: 

Ivosidenib: 

AML Patient Profile: Jordan Supino

As Jordan Supino shares his acute myeloid leukemia (AML) patient story, it’s quite striking to hear his love of life and passion for helping others. Calling himself “The Cancer Killer,” Jordan has an inspiring dedication to fitness, faith, family, finance, and fun, for overall health and wellness. He shares the perspective he’s gained, “People need to understand that there’s a purpose for everything. We go through situations, and you have to see it for what it is. What’s the message? You may be listening to the doctor, but you need to hear what it’s preparing you for. I believe that everything that we go through in life is truly preparing us to grow later in life. If you learn to start cooperating instead of chasing, those tests will become your testimony for the world. There’s a greater good in learning to help others.”

As for Jordan’s cancer journey, it began with being hit with hot and cold sweats along with major leg cramps that he’d never experienced before. He dismissed the symptoms and returned for a gym workout a few days later when his body started trembling, which brought on a partial collapse and his legs becoming locked up in extreme pain. Jordan was diagnosed with AML in July 2011, which led to him being hospitalized for about two months while he received high-dose chemotherapy.

After completing that round of chemotherapy, Jordan’s doctors informed him that he’d need to return for his next round of chemo in 4-1/2 weeks and to prepare for a bone marrow transplant. Much to his doctors’ surprise, he vowed to them that God would be granting him a miracle and that the power of his mindset would eliminate the cancer and any thought of a bone marrow transplant. Jordan further promised that he’d bench press 500 pounds before his next round of chemo to demonstrate the power that can come from the combined power of one’s faith and mindset and the cancer would disappear.

When Jordan was in the hospital, he had hundreds of people go to visit him. He recalls about the visits, “I was just blown away by all these people. And a lot of them I didn’t know or couldn’t remember. They were sharing stories with me about how they’d crossed paths with me sometime in my life. Whether it was some words of wisdom that I gave them or helped them pay a bill or took them to dinner or something, they felt indebted to come pay it back to me. And I felt like if God decides to take me now, I’m okay with that, but I’m not ready just yet.” He knew he’d done a lot of good in the world helping people but felt that his work wasn’t finished yet. 

Jordan continued with his chemotherapy treatment for 4 months. But he decided that he wanted to do some shopping for gifts before Christmas. Jordan wore a mask and bundled up for his shopping outing, but another test hit Jordan on December 27 when he woke up with a 107-degree temperature and was partially blind. He collapsed at the hospital and went through enduring pneumonia, heart failure, kidney failure, liver failure, blood clots, fluid-filled and blood-filled lungs, bloodline infections, full septic shock, and a 24-day induced coma. Jordan’s body and spirit weren’t ready to surrender, however. He woke up, and his doctors told him it could take up to a month to start walking again. Jordan blew away that estimate and was walking in two days. His doctors also told him it could take up to a year for his full recovery, but he gained 50 pounds in six weeks and was unrecognizable to hospital ICU staff due to his drastic health change.

While in the hospital, Jordan made it part of his routine to help others. He recalls of his hospital stays,
“I made it a point to not just survive adversity, because I’m someone who thrives against adversity. People tell me I’m a cancer survivor, but I say that I’m a cancer killer and that I rise above it. You can’t control what happens to you in life, but you can control how you react. It sounds cliche, but how many people actually hear it? How many people actually adopt it? How many people actually apply it and see the results of it? I’m a walking testament to that.” Jordan decided to help other people in the hospital who didn’t have visitors to see them. Hospital staff called him affectionately “Dr. Real Deal or No Deal.” The doctors would call him when people were having a hard time or felt like giving up. He’d visit several people each day and sit with them. And Jordan would learn about them or tell them stories from his life. “Whether I was preaching to them, laughing, doing some cardio down the hallways, or just getting them moving and grooving and feeling good about themselves; it was so magical to see all these people just start living. They stopped saying, ‘Why me’ and started adopting the ‘Why not me?’” Hospital staff brought in creative items where the staff and patients created inspirational artwork with motivational sayings that made an immediate impact and has continued to do so over the years. The huge pieces of artwork were transferred to the new oncology unit in a new building and are still making an impact on patients and their families today. 

As for advice for other cancer patients, Jordan shares, “I don’t allow myself to stress. I don’t allow myself to create anxiety. And I don’t allow myself to get depressed. If I feel anything trying to creep up on me, I find these different things to do to get myself through and grow. Whether it’s going out and getting some sun or going out and feeding the ducks and meditating by a pond or going for a walk knowing that when the body moves the brain grooves or putting on some music or lifting some weights at the gym, knowing how to control your mindset is key. You have to know that you’re in control, and you have to act like the change you want has already happened. When you’re feeling bad, just punch it in the mouth to get better. How much have you ever pushed yourself to the limit? You become a little bit stronger and a little bit wiser from pushing yourself. Life is all about perspective in any situation we go through.”

Jordan has come to many realizations over the span of his life and time with cancer. He believes in changing your environment to what you need. “When you’re struck with adversity and things like cancer, it’s okay to rest, but there’s still more work to be done. This is your story and the card that you’ve been dealt to serve a bigger purpose. If the hospital food isn’t cutting it, find a friend who can cook. If you’ve got a negative person around you, find someone who’s joyful. If that person who’s hugging you isn’t a good hugger, get a good hugger. If you don’t like that background music, change the music. This is your world, and you become what you surround yourself with. You need to just focus on being the best version of you. If you stop chasing and start seeing cancer as the gift that it may possibly be, then you’ll learn how to cooperate and to ultimately become just an amazing masterpiece and things for others to witness.”

Through his work, Jordan coaches people one on one – emotionally, mentally, physically, spiritually, financially – whatever the case may be. And for those facing a cancer diagnosis, he poses this question, “Do you want to live, or do you want to die? I want to live. You die only once. You live every day. I’m going to live and enjoy blessings, prosperity, and goodness in helping others.”

Becoming an Empowered and [ACT]IVATED AML Patient

Patient Empowerment Network (PEN) is committed to helping educate and empower patients and care partners in the acute myeloid leukemia (AML) community. AML is shown to impact younger patients compared to other types of blood cancer. In addition, there are some marginalized communities of Black and Latinx AML patients that experience disparities in health outcomes. Recent studies in AML have shown higher mortality rates and higher rates of AML recurrence in Black and Latinx patient groups. PEN aims to help empower patients in their care. With this goal in mind, we kicked off the [ACT]IVATED AML program, which aims to inform, empower, and engage patients to stay abreast of the latest in AML care.

Disparities in AML Treatment and Health Outcomes

AML research studies show that Black and Latinx patients experience disparities in AML treatment and health outcomes. Some of the study findings include:

A recent study in Blood Advances showed that Black adolescent and young adult (AYA) patients with AML have higher mortality rates and higher rates of AML recurrence in comparison to white patients. The study compared clinical outcomes between 1983 and 2016 for AYA patients between the ages of 18 and 29. The early mortality rate of Black AYA patients was 16 percent compared to 3 percent for white AYA patients. When examining complete AML remission rates, 66 percent of Black AYA patients experienced complete remission compared to 83 percent of white AYA patients. The authors of the study looked at the research data and determined that delayed diagnosis and treatment in the Black AYA patients as well as genetic differences of AML likely led to the higher mortality rate for this group. In comparison, Black and white patients between the ages of 30 and 39 showed no significant differences in their survival rates.

Lead study author Dr. Karilyn Larkin, a hematologist at the OSUCCC – James, shared, “To our knowledge, this is the first study to examine how molecular genetic alterations contribute to outcomes in young Black people with AML compared with their white counterparts.” Study of genetics is extremely vital in developing new and refined AML treatments, and this is why it’s more important than ever for more Black AYA patients to join clinical trials to create a larger pool of participants to learn from.

Another recent study in Blood showed that Hispanic/Latinx and Black AML patients have higher mortality rates in comparison to white AML patients. The study analyzed several factors in the disparities including health care access, tumor biology, treatment patterns, ICU admission during induction chemotherapy, comorbidities, and structural racism. Neighborhood measures of structural racism were found to be a major predictor of AML mortality rates. The neighborhood measures that were tracked in the study included census tract disadvantage, segregation, and affluence. The study authors concluded that more research must be done to learn the ways that structural racism relates with different AML treatment and predictive factors to impact health outcomes. Then more actions can be taken to help decrease the health disparities for these patient groups.

[ACT]IVATED AML Patient and Expert Tips

Black and Latinx patients who more frequently experience AML disparities are key groups for patient advocacy and empowerment. AML specialists, patients, and patient advocates have pooled some valuable advice through their experiences in treating and living with AML with the goal of improving care for all AML patients. PEN has been fortunate to receive some tips from patient and AML Empowerment Lead Sasha Tanori and AML specialists Dr. Catherine Lai and Dr. Naval Daver toward patient activation and empowerment.

Sasha talked about her AML experience as a Mexican American and the delay in her diagnosis. “You didn’t go out and seek care if you are hurt, you just sucked it up, you went to work, you went to school, you did your job, you took care of your family, and that was it. If you had any type of ailments or illness, you would just rub some Vaseline and do the sana sana and just move on about your day.”

Sasha’s care in a rural healthcare setting also contributed to the delay in her diagnosis. “In my local town they had no clue what was wrong, they didn’t know it was cancer, they didn’t know what was going on. They just kept doing tests after tests after tests, and they’re on blood work, and finally, they were just like, ‘We have no clue, we’ve got to send you somewhere else. You’ve got to get in an ambulance and leave.’”

Dr. Lai and Dr. Daver Tips

Dr. Lai advises patients to take proactive actions in their care. “Ask your physician and your oncologist when you’re talking with them about what all the newest therapies are and what would be specifically the best treatment for their specific leukemia with respect to the different mutations.

Testing has become a key factor in optimizing treatment for each patient’s specific AML. Dr. Daver also stresses the importance of testing. “Patients, when they transformed what we call secondary AML or MDS, seemed to have a higher predilection for certain high-risk communications such as TP53, and these are best treated with ongoing frontline clinical trials at large academic centers.”

Dr. Daver also explained the importance of genetic mutations currently under study in combination clinical trials. “Patients should be checked for arrangements like MLL rearrangement NPM1 mutation, new fusions as these may be amenable to therapy with the menin inhibitors, there are multiple trials with five different menin inhibitors, single agent trials and also combination trials now ongoing across multiple centers both in the U.S. and ex-U.S.”

The future of AML care is full of hope, and Dr. Lai shared her perspective. “There are a lot of new, exciting therapies that are coming out, and that it’s really novel sequencing strategies and combinations that I think will be the future of AML.”

Clinical trial participation continues its vital role in improving AML care, and Dr. Daver took the opportunity to stress the importance of trials. “Clinical trials are critical, both for the patients themselves to get access to what we call tomorrow’s medicine today as well as potentially to help move the entire field forward.”

[ACT]IVATED AML Program Resources

The [ACT]IVATED AML program series takes a three-part approach to inform, empower, and engage both the overall AML community and AML patient groups who experience health disparities. The series includes the following resources:

  • [ACT]IVATED Expert Interviews with experts Dr. Catherine Lai and Dr. Naval Daver moderated by an AML patient
  • [ACT]IVATED Resource Guide  (en Espanol here)  a downloadable, printable support resource packed with a newly diagnosed patient checklist, expert tips, AML facts, AML mutations, cytogenetic abnormalities, and support resources
  • [ACT]IVATED Patient Vignettes to learn valuable experiences and lessons learned from other AML patients
  • [ACT]IVATED Activity Guide – a downloadable, printable support resource packed with information and activities to educate, empower, and support AML patients and care partners in their journeys through care

Though the underrepresented AML groups of Black and Latinx patients have experienced health and care disparities, experts and patient advocates are taking action to improve care for all. By shining the light on gaps in care, PEN aims to aid in reducing these gaps along with continued research advances and clinical trial participation. AML patients can educate and empower themselves to become more confident and active partners in their care. By doing so, they can make more informed decisions for improved health outcomes. We hope you can continue to use the [ACT]IVATED AML program resources to advance your path to becoming an informed, empowered, and engaged patient. 

Share Your Feedback About [ACT]IVATED AML

Three Phases of AML Therapy

What are the three phases of acute myeloid leukemia (AML) therapy for patients? In the “What Are the Phases of AML Therapy?” program, expert Dr. Eytan Stein from Memorial Sloan Kettering Cancer Center shares insight about the three phases of induction therapy, consolidation therapy, and maintenance therapy. 

1. Induction Therapy

The AML therapy phase of induction therapy is also referred to as induction chemotherapy. In this phase of therapy, AML patients can expect to receive an extremely intensive chemotherapy that they’ll need a hospital stay to receive. Even though the typical hospital stay is approximately three to four weeks, the portion of time that patients will receive the chemotherapy itself is about one week. Patients can expect to spend about another two to three weeks in the hospital as recovery from the effects of receiving the intensive chemotherapy to become well enough to return to life at home.

2. Consolidation Therapy

After the phase of induction therapy, a phase called consolidation therapy will follow for AML patients. Complete remission, or absence of disease, doesn’t always happen for all patients. So the proactive phase of induction therapy is carried out in case AML was still in a patient’s body where it couldn’t be located in bone marrow biopsies. Consolidation chemotherapy will kill any leukemia cells that remain in the body and will create a deeper remission for AML patients.

 3. Maintenance Therapy

After AML patients have received induction therapy followed by consolidation therapy, another therapy called maintenance therapy will be used to further protect them against relapse. Maintenance therapy has been used in both multiple myeloma and acute lymphoblastic leukemia (ALL) patients for a substantial period of time. The use of maintenance therapy for AML patients started within the last one or two years, and the approach of maintenance therapy is to use a reasonably non-toxic therapy that can be taken by patients over a sustained period of time to safeguard their health. 

Treatment for AML follows an established order of phases of induction therapy, consolidation therapy, and maintenance therapy for optimal patient health over the long term. If you want to learn more about AML care and treatments, check out our AML information.

Quizartinib in FLT3-ITD-Positive AML

Introduction 

I generally think of treatments for AML as old, meaning they were around when I was diagnosed in 1992, or new ones that were developed after that. In the first 25 or so years since I was diagnosed, there were very few new treatments. In the last 5-7 years, however, there have been several new treatments. There are targeted treatments like, Ivosidenib (which I wrote about in November: Ivosidenib and Azacitidine for IDH1-Mutated AML) as well as Ventoclax which is used with a number of different drugs (Azacitidine, Decitibine and low dose Ara C). This post is about a new (to the U.S. anyway) drug, Quizartinib, which is used in AML patients who have a specific mutation FLT3 (fms-like tyrosine kinase 3), specifically a FLT3-ITD (internal tandem duplication) mutation. 

Overview of FLT-3 

There are two different mutations in the FLT3 gene, ITD and tyrosine kinase domain mutations (TKD). The most common mutation in AML is in the FLT3 gene. About 30% of AML patients have an FlT3 mutation, with FLT3-ITD mutations more common than FLT3-TKD ones. Some of the existing drugs for FLT3 mutations treat both. Midostaurin (Rydapt) and Gilteritinib (Xospata) are used in patients with either FLT3 mutation. Quizartinib is only used to treat patients with a FLT3-ITD mutation. 

Current Study of Quizartinib 

The current study, the results of which were presented at the 2022 European Hematology Association (EHA) Annual Meeting in Vienna, tested standard chemotherapy with Quizartinib or with a placebo, followed by maintenance with Quizartinib or placebo for 3 years. More than 500 patients with a FLT3-ITD mutation were treated in the trial. Quizartinib or a placebo were added to the “7+3” standard induction therapy, which consists of 7 days of cytarabine (Ara-C) plus 3 days of daunorubicin or idarubicin. Patients who were in remission after induction either went on to up to 4 rounds of high dose cytarabine consolidation with Quizartinib or placebo and/or an allogeneic (donor) stem cell transplant, followed by up to 3 years of maintenance therapy with Quizartinib or placebo. 

The patients who received Quizartinib had a median overall survival of more than double the patients who received the placebo. Almost all patients in both arms experienced side effects of the treatment (emergent adverse events or AEs). This is not a surprise, most patients treated for AML have significant side effects. Patients who received Quizartinib had more side effects, in particular there was a higher incidence of significant neutropenia (low white counts) and more patients who received Quizartinib discontinued treatment because of adverse events. There were 56 treatment related deaths in the trial, somewhat more in those who received Quizartinib. 

Quizartinib looks like a promising treatment for FLT3-ITD AML patients. I believe that this is the only randomized (Phase III) trial that has been completed of a drug that treats mutations in the FLT-3 gene along with standard chemotherapy. It will be interesting to see how it compares to other drugs for patients with FLT-3 mutations. On the downside, it is only used for FLT3-ITD mutations, unlike Midostaurin and Gilteritinib. 

Further Reading 

Quizartinib Doubles Overall Survival in FLT3-ITD-Positive AML, article from Medscape on the trial of Quizartinib and Chemotherapy, June 13, 2022. 

Quizartinib Prolonged Survival VS Placebo Plus Intensive Induction and Consolidation Therapy Followed by Single-Agent Continuation in Patients Aged 18-75 Years With Newly Diagnosed FLT3-ITD+ AML, from 2022 European Hematology Association (EHA) Annual Meeting in Vienna. 

Daiichi Sankyo’s survival data mean it may finally be ready to compete with Novartis’, Astellas’ marketed AML meds, an article from Fierce Biotech, which covers the biotechnology industry. 

Xospata FDA Approval History, from Drugs.com, gives a history of the FDA approval of Xospata (gilteritinib). 

Overcoming Resistance: FLT3 Inhibitors Past, Present, Future and the Challenge of Cure, Capelli, D.; Menotti, D.; Fiorentini, A.; Saraceni, F.; Olivieri, A. Cancers 2022, 14, 4315. A long journal article on treating FLT-3 AML (I have not read all of it). 

FLT3 Inhibitor Quizartinib Improves Survival in AML reports on an older study showing patients with relapsed/refractory FLT3-ITD-positive AML have improved survival with Quizartinib, given as a single agent compared with standard-of-care chemotherapy. Medscape, July 02, 2018. 

On Recovering After a Stem Cell Transplant

As a transplant survivor and peer volunteer, I have met with over 150 transplant patients. The most common question I hear concerns what recovery looks like. People want to know about timelines, precautions, complications, medications, benchmarks, and much more.

I can only answer these questions from my experience, and no two outcomes are the same. But I’ve read and heard enough other stories to know where mine is typical or exceptional, so I can also place my story in a broader context.

In June of 2016, I was diagnosed with acute myeloid leukemia. I underwent induction chemotherapy and achieved a temporary remission. In October of 2016, I received a double cord blood stem cell transplant. I fully recovered and have returned to all my prior activities, so mine is a very positive story. Along the way, however, there were several memorable challenges.

Prelude to a transplant

My initial treatment required a five-and-a-half-week hospital stay. It was one week for the traditional “7+3” chemotherapy regimen, and another four and a half weeks to monitor and treat the inevitable infections that followed in the wake of chemotherapy-induced immunosuppression.

My diagnosis was routine for my providers but shocking for me. I was asymptomatic and feeling perfectly healthy at my annual physical. But low white blood cell counts triggered a bone marrow biopsy that established my diagnosis. I was hospitalized the next day and started chemotherapy the day after that. My treatment was underway before I even understood my disease and its bleak prognosis.

When they told me to expect a 5-6-week hospital stay, I was dumbfounded. I quickly realized that I needed ways to cope with how my world had suddenly become very small and quite precarious. Over the ensuing weeks, I developed and honed several crucial strategies.

First, I relied upon mindfulness, meditation, and yoga. It helped me banish thoughts about the past and anxieties about the future, and to non-judgmentally accept and live in each moment as it unfolded.

Second, I did as much physical exercise as my circumstances would allow. My routines included stretching, isometric exercises, extensive hall walking, squats, lunges and pushups. I did it mindfully, and these routines structured my days, increased my energy, and lifted my spirits.

Third, I was a pro-active patient. I cultivated good communication with my doctors and nurses. I asked lots of questions about my treatment and became a collaborator in decisions about medications, dosing, and deciphering and treating the many infections and side effects that came my way.

Fourth, I maintained my robust sense of humor. Sharing jokes and witty banter with my medical providers broke the ice, resolved the tension, and humanized our consults. It also gave friends and family a way to relate to me as the person I’d always been rather than the patient I’d recently become.

Fifth, I relied on a supportive belief system. For some, that’s religion. For me, it was a secular worldview based on my social science background. It encouraged me to learn about my condition and fostered a practical, problem-solving orientation to all the challenges it posed.

Finally, I wrote my story from the very first week. I sent detailed reports about my status and reflections as a cancer patient to a large group of email correspondents. Writing for others forced me to understand my journey so I could articulate it for them. This writing became a psychic survival mechanism (and a subsequent memoir).

When the time for transplant arrived, I packed a bag, grabbed my laptop, and took these coping strategies with me. As doctors cured my body, these strategies sustained me throughout everything that was to come.

The Transplant and Hospitalization

Like many patients, I was admitted to my transplant hospital one week before the actual procedure (day -7). I underwent conditioning chemotherapy and full body radiation. Upon my transplant (day 0), I was told to expect another three to five weeks in the hospital before I could be safely discharged.

Days 1-7 were uneventful except for some moderate nausea due my prior chemotherapy and radiation. I got some relief from a drug called marinol that allowed me to eat regular meals during this time. As my counts hit bottom, I was closely monitored for fevers and infections. Even so, I felt good enough to do daily exercise, walk on a treadmill, do yoga, and be as active as possible while confined to my room.

On day 8, my doctors said I was doing so well they were thinking of discharging me in a couple more days – much earlier than expected. But then I developed an infection and a recurring fever that spiked every twelve hours for several days and delayed my discharge.

By day 19, my infection and fevers had resolved, and I went home under the watchful eye of my caregivers. I thus left the hospital in just under three weeks since transplant – much quicker than the 3-5-week hospitalization I had been told to expect.

A Memorable Month at Home

From day 20 to 50, the plan was for daily clinic visits to monitor counts, treat symptoms, and assess progress. On day 21, a bone marrow biopsy revealed that one of my donors was 99% engrafted, which was an unusually early and complete success for a cord blood transplant. With engraftment underway, we then watched for signs of graft-vs.-host disease.

During this month (day 20-50), my caregivers were essential. They drove me to daily clinic visits for blood draws, provider consultations and needed treatments. From day 20-26, I received daily transfusions of platelets and several transfusions of red blood cells. Several more transfusions as well as injections of growth factor medications to spur new white blood cells followed throughout this month. After the second week, however, they reduced my clinic visits to fewer and fewer days each succeeding week.

That first month at home (day 20-50) was also when I felt the side-effects from my treatment most keenly. The lingering impacts of chemotherapy and radiation, the engraftment process, and multiple medications produced several memorable symptoms. There were aches and pains from the engraftment itself that I treated with ibuprofen, and ongoing bouts of nausea that I managed with marinol. I was also taking about 20 scheduled pills a day, including prophylactic antibiotics, anti-viral and anti-fungal medications, anti-rejection medications, and several pills to manage side effects of these medications.

My most memorable symptom during this period was a staggering level of fatigue as my body underwent this transformation. I was sleeping eight to nine hours a night but still required lengthy naps in the late morning and late afternoon. I couldn’t stay awake for more than four hours at a time and was totally exhausted by nightfall.

On day 39, routine blood work detected a cytomegalovirus infection. It’s one of many critters that can reside in our gut our whole lives unbeknownst to us. But with immunosuppression, the virus can become active and pose serious danger. It is usually well controlled if detected early and treated quickly, so I was immediately put on a more powerful antiviral drug to address the infection.

The virus drastically reduced my white blood cell count while the antiviral medication added further immunosuppressive effects. For a few days, I had additional fatigue, aches, chills, and nausea. When the virus and anti-viral forces fought to a standstill, they contemplated admitting me back into the hospital for several days of IV, antiviral treatments. Instead of re-hospitalization, however, the compromise treatment was an outpatient infusion of IV immunoglobulin to boost my white blood cell count while the antiviral medication gradually tamed the virus. With that, I continued my recovery at home.

Through the First 100 Days

From day 50 to day 100, I experienced gradual if uneven improvement. Clinic visits tapered to once a week or less. Bone aches ceased and nausea all but disappeared. Fatigue also decreased, and when I did feel tired, I could usually trace it to increased activity levels compared to my first 30 days at home. As I was able to reduce doses or eliminate some medications, my mind cleared and my energy increased. While I experienced minor rashes, dry eyes, and sinus headaches, there was nothing that required major medical treatment or raised suspicions of graft-vs.-host disease.

By day 58, I began experiencing neuropathy in my feet. This is a common side-effect of chemotherapy, but in my case, it has been blessedly mild. It mainly presents as numbness and tingling under the balls of both feet. I was told it might resolve within a year, but it remains the only side effect that has persisted and which I now regard as permanent. It has not responded to acupuncture or cortisone injections. My best adaptation has been specially designed shoes and custom insoles that take pressure off the sensitive areas and make the condition quite tolerable.

By day 60, I was having trouble lining up caregivers but still needed to get to weekly clinic visits. I had been prohibited from driving or being without a caregiver for the first 100 days, but that was no longer practical. I carefully began driving myself to clinic visits. By then, I knew how my medications affected me and so I delayed my antifungal medication and the blurry vision it caused until I safely returned from my outings.

On day 78, my oncologist recommended removing the “Power Hickman” central line that had served me well for almost seven months. It had been with me since the beginning of my treatment and had facilitated painless blood draws and countless infusions of blood, platelets, IV medications, and chemotherapy. But with the reduction in all these procedures, the risk of an infected line was becoming greater than the benefits of keeping it in place. An added benefit was being able to take a shower without wrapping my entire upper torso in Saran Wrap to protect the gizmo.

Day 100 was a significant benchmark for several reasons. I had another bone marrow biopsy that confirmed full engraftment and no residual leukemia. Reviewing my biopsy results, blood tests, and overall progress, my oncologist said my recovery to date was “as good as it gets.”

At this time, I was able to eliminate or reduce many of my medications. More importantly, I began to gradually taper my anti-rejection medication (cyclosporine) over the next three-month period. The gradual pace of this taper was meant to allow my old body and my new immune system to learn to get along with each other, restore full immunity, and avoid GVHD

By this time, I was feeling much better and was eager to return to my regular activities. Since my blood counts were all good, I asked my oncologist her advice. She provided a rather technical explanation of why I was still at considerable risk and needed to avoid crowds, continue wearing my mask in public, and follow other precautions.

My layman’s interpretation of her explanation was that even though I had sufficient white blood cells and neutrophils, my anti-rejection medication would still prevent them from fully activating in case of infection. So despite feeling better and having good counts, I needed to maintain precautions until my anti-rejection medication had run its course and my immune system was more functional and able to protect me in a germ-filled world.

Completing the Marathon

From day 100 to day 180, I continued gradual improvement and weathered some minor bumps in the road. My clinic visits were now spaced out every couple weeks, and I began to see other practitioners to assess some peripheral issues arising from my diagnosis and treatment.

Since my leukemia put me at risk for skin cancer, I saw a dermatologist who detected a small, basal cell carcinoma that was easily excised. I continue to see her every six months for full body skin checks with no further issues. My leukemia had also caused some retinal hemorrhaging that was diagnosed before transplant. A follow up visit during this period showed that all retinal issues had completely resolved with the eradication of my leukemia.

Even though I was now tapering my anti-rejection medication, its cumulative impact produced numerous unpleasant side effects. While I avoided the most serious ones, I nonetheless experienced flushing, hypertension, nausea, altered kidney function, neuropathy, weight loss, leg cramps, sinus irritation, abdominal swelling, and night sweats. I began a temporary regimen of blood pressure medication and rode out the other issues. To top it off, I also had a flare up of the cytomegalovirus, which once again was quickly detected and effectively treated with specialized antiviral medication.

On day 180, I had my 6-month biopsy which reconfirmed full engraftment and no residual leukemia. At this time, I stopped my anti-rejection medication and its unwanted side effects began to dissipate. I was also able to stop virtually all of my remaining pills with the exception of an antiviral medication which continued until day 365. With adequate immunity restored, I was cleared to do any activity I wanted with one exception: I had to avoid fungal sources of infection (yard work, turning over soil, fresh mushrooms, etc.) for the next six months because such infections are easy to contract and difficult to eradicate.

For me, this was a major psychological turning point. I accepted that I was actually better, resumed my “normal” life, and let go of lingering anxieties about my status. When my transplant oncologist said she didn’t need to see me for another six months, it was initially unnerving after such intensive monitoring. At the same time, it reinforced my sense that I had reached a major milestone in my recovery.

“As Good As It Gets” (and Some Cheap Advice)

After day 180, my care shifted back to my initial oncologist at my induction hospital. Monthly blood draws and bimonthly consultations gradually became less frequent. Four years out from my initial diagnosis, I now have blood draws four times a year and see this oncologist twice a year.

At year one and two (days 365 and 730), I returned to my transplant oncologist for my final two biopsies which found no residual disease.  At year one, they re-did my childhood vaccinations from dead viral sources; at year two, I received my remaining vaccinations from live viral sources.

There’s good reason to say my story is “as good as it gets.” First, I got into remission on the first round of induction chemotherapy. This does not happen for a significant minority of AML patients who require multiple rounds of chemotherapy or other treatments to attain remission.

Second, I had full donor engraftment in three weeks. Most patients achieve engraftment, but it typically takes longer or doesn’t happen as completely as it did in my case. In the worst-case scenario, a small percentage of patients never experience engraftment and face a very poor prognosis.

Third, I have had no graft-vs.-host disease. I had been told there was a 60-70% chance of acute (within the first 100 days) GVHD in cases like mine, but I had no symptoms that could be attributed to this cause. That reduced my chances of chronic (after the first 100 days) GVHD to 20%. Although it can appear years after transplant, I’ve had no symptoms as of this writing.

What is typical about my story are the various infections, unpleasant side-effects, and minor complications documented here. They are simply part and parcel of the disease, treatment, and transplant; few if any patients escape them altogether. But in my case, they were quite manageable with the excellent support I received from my medical practitioners and caregiver team. Thanks to them, I left my transplant hospital on day 19 and never returned.

Advice is cheap, so here’s my two cent’s worth. Even in the best-case scenario, recovery is so gradual that it’s hard to realize when you are actually making progress (especially when there are periodic setbacks). I learned to pay attention to even small steps of improvement and took heart when they occurred.

Here’s one example. Around day 40, I ran up a flight of stairs at home and became short of breath. I initially found this discouraging, but then I realized I hadn’t even run up a flight of stairs since my diagnosis, and that this was progress not regress. Recovery happens through small, incremental changes that eventually culminate in qualitative improvement. It helps to be aware of these small steps as they occur; you may even want to record them in a weekly journal to fully appreciate them.

Finally, some clichés bear repeating. Recovery is a marathon, not a sprint. Moreover, it’s a marathon on an obstacle course of potential complications. Don’t hesitate to ask for help from your doctors or accept assistance from your caregivers. It’s not a burden; it actually makes them feel better when they can help you out. Finally, cultivate patience, resilience, and fortitude as you go the distance. It will serve you well.

Confused About Immunotherapy and Its Side Effects? You Aren’t Alone

“You don’t look like you have cancer.”

More than one patient undergoing immunotherapy to treat cancer has reported hearing statements like that. Immunotherapy is one of the recent advances in cancer treatment that belie the stereotypes about the effects of cancer treatment. 

The side effects of immunotherapy are different from those associated with chemotherapy and radiation. However, that does not mean immunotherapy does not have side effects. Patients and care partners need to be aware of these potential side effects and to be vigilant in addressing them with their oncologists because they can signal more serious complications if left untreated.

What is Immunotherapy?

Despite the increase of immunotherapy treatment options in recent years and considerable media attention paid to advancements in this field, there remains confusion about immunotherapy and its side effects. Many cancer patients are unaware of whether immunotherapy treatments are available for their specific diagnosis. Others don’t know that genetic profiling of their tumors is usually required to determine if immunotherapy is an option and not all treatment centers routinely conduct genetic profiles of tumors. A  survey by The Cancer Support Community found that the majority of patients who received immunotherapy knew little to nothing about it prior to treatment and were unfamiliar with what to expect.

Immunotherapy works by manipulating the patient’s immune system to attack cancer cells. It is perceived as gentler and more natural than chemotherapy and radiation, without the same destructive effect on the body’s healthy tissues.  This, combined with a lack of prior understanding of immunotherapy, can lead patients and care partners ill-prepared for possible side effects.

Furthermore, immunotherapy is a category of therapies, not a single type of treatment. There are a variety of immunotherapy drugs, most of which are administered via infusion.  Side effects will vary by drug, the cancer and its location, treatment dose, and the patient’s overall health.

The following are the most common types of immunotherapy.

  • Checkpoint inhibitors use drugs to block proteins in the patient’s immune system that would otherwise restrain the immune system, often referred to as taking the “brakes” off the immune system.
  • CAR-T therapy modifies the patient’s T-cells in a lab to enhance their ability to bind to cancer cells and attack and kill them.
  • Oncolytic virus therapy uses genetically modified viruses to kill cancer cells.
  • Another therapy uses cytokines (small proteins that carry messages between cells) to stimulate the immune cells to attack cancer.

Immunotherapy can be part of combination therapy. It might be combined with chemotherapy. It might be used to shrink a tumor that is then surgically removed.  Or multiple immunotherapy drugs might be used simultaneously.

What Are The Side Effects?

With immunotherapies, side effects typically occur when the immune system gets too revved up from the treatment. The most common side effects for immunotherapy treatments are fatigue, headache, and fever with flu-like symptoms. Some people also experience general inflammation often in the form of a rash. Many melanoma patients report blotchy skin discoloration, called vitiligo, during treatment. These milder side effects can usually be managed with over-the-counter remedies and adjustments to daily activities.

For checkpoint inhibitors, the fastest growing segment of immunotherapy treatments, mild side effects occur in 30% – 50% of patients. Serious side effects typically occur in less than 5% of patients. (See “Understanding Immunotherapy Side Effects” from the National Comprehensive Cancer Network and the American Society of Clinical Oncology.)

Less common side effects are blisters, joint pain, thyroid inflammation, and colitis (inflamed colon resulting in diarrhea with cramping). Some patients who receive CAR T-cell therapy develop a condition known as cytokine release syndrome, which causes fever, elevated heart rate, low blood pressure, and rash. 

In rare cases, immunotherapy has resulted in lung inflammation, hepatitis, inflammation of the pituitary, and detrimental effects on the nervous and endocrine systems. In most cases, the conditions clear up when treatment ends.  However, there have been outcomes in which immunotherapy caused diabetes or tuberculosis.

“Overall there are fewer side effects [with immunotherapy],” explained Dr. Justin Gainor, a lung and esophageal cancer specialist at Mass General during an Immunotherapy Patient Summit hosted by the Cancer Research Institute. “But the immune system can affect anything from the top of the head down to the toes. Any organ has the potential to be affected.”

As the application of immunotherapy has expanded, so has our understanding of the potential side effects. Like most medical treatments, how one person responds to immunotherapy can be different from another even when the cancer diagnosis and drug therapy are the same.

The essential thing patients and care partners need to know about side effects is they should always be reported to their oncologist or nurse oncologist.

Why Patients Should Talk to Their Provider About Immunotherapy Side Effects

Because immunotherapy has created newer therapy options, there isn’t the volume of experiences as with older treatments. The infinite number of variables that patients provide once a treatment moves beyond clinical trials and into the general patient population generate more diverse outcomes.  And, as most therapies are less than 10 years old, there hasn’t been an opportunity to study the long-term effect of these therapies. This is why oncologists advise patients and their caregivers to be extra vigilant in noting any changes experienced during and after treatment.

Many side effects are easy to treat but medical providers want patients to be forthcoming in discussing any and all side effects. This is in part to improve understanding of side effects, but also because a mild cough or a case of diarrhea might be harbingers of a more systemic issue that will grow worse if left untreated.

Patients should not be hesitant to discuss side effects because they fear they will be taken off immunotherapy.  Sometimes a pause in treatment might be necessary, but the earlier the oncologist is made aware of a side effect, the less likely that will be necessary.

In addition, patients undergoing immunotherapy should always take the name(s) of their immunotherapy drugs and the name of their oncologist when seeing medical professionals outside of their cancer treatment team. This is especially important when visiting the ER.  Because immunotherapy drugs are newer and highly targeted to certain cancers, many medical professionals remain unfamiliar with drug interactions and treating related side effects.

Immunotherapy On The Rise

Immunotherapy treatments have resulted in reports of remission in cases that would’ve been deemed hopeless just five or 10 years ago.  The Federal Drug Administration (FDA) has approved various immunotherapy treatments for melanoma, lung cancer, head and neck cancer, bladder cancer, cervical cancer, liver cancer, stomach cancer, lymphoma, breast cancer, and most recently bladder cancer.  (Here is a list of  immunotherapies by cancer type from the Cancer Research Institute.)

“It’s revolutionized how we treat our patients,” says Dr. Gainor of Mass General about immunotherapy’s impact on lung and esophageal cancer.

Advances in immunotherapy research and trials continue to generate optimism and excitement. A clinical study in Houston is looking at using immunotherapy to prevent a recurrence. Researchers in Britain recently announced a discovery that might lead to advances in immunotherapy treatments to a much broader array of cancers.

While there is excitement around the field of immunotherapy and it has resulted in unprecedented success in treating some previously hard-to-treat cancers, it remains an option for a minority of cancer diagnoses.  It works best on solid tumors with more mutations, often referred to as having a high-mutational load or microsatellite instability (MSI) high. And it is not universally successful for every patient.

With hundreds of clinical trials involving immunotherapy alone or in combination with other therapies, it is certain more treatment options are on the horizon. As more therapies are developed and more patients with a greater variety of conditions undergo immunotherapy, we will also increase our understanding of potential side effects.

Side effects should not dissuade patients and care partners from considering immunotherapy if it is available or from advocating for genetic tests to deteimine if it is an option. Many patients undergoing immunotherapy have previously undergone chemotherapy and report that the side effects are fewer and milder by comparison.  The important thing is that patients and their partners know what to expect and communicate with their treatment team.

If the next 10 years in immunotherapy research and development are anything link eth elast 10, we can expect more exciting advancements in the battle against cancer. For more perspective on what’s ahead for immunotherapy see the Cancer Research Institute’s article: Cancer Immunotherapy in 2020 and Beyond.

Understanding Clinical Trials: A Jargon Buster Guide

When it comes to cancer treatment you or a loved one may be considering participating in a clinical trial as a treatment option.  Clinical trials are designed to evaluate the safety and effectiveness of a treatment. They may involve researchers administering drugs, taking blood or tissue samples, or checking the progress of patients as they take a treatment according to a study’s protocol.

Learning about clinical trials can be a steep learning curve – not least because the process comes with a lot of new terms, acronyms and jargon.  To help you, I’ve put together this list of the most common terms you will find when you are researching clinical trial information. This is not an exhaustive list but it is a helpful starting point. At the end of this article you will see links to find more information.

Adverse Effects (AE)

Also called Adverse Events, or Adverse Drug Reaction, AEs are any harmful event experienced by a person while they are having a drug or any other treatment or intervention. In clinical trials, researchers must always report adverse events, regardless of whether or not the event is suspected to be related to or caused by the drug, treatment or intervention.

Arm

Subsection of people within a study who have a particular intervention.

Bias

Bias is an error that distorts the objectivity of a study. It can arise if a researcher doesn’t adhere to rigorous standards in designing the study, selecting the subjects, administering the treatments, analysing the data, or reporting and interpreting the study results. It can also result from circumstances beyond a researcher’s control, as when there is an uneven distribution of some characteristic between groups as a result of randomization.

Blinding

Blinding is a method of controlling for bias in a study by ensuring that those involved are unable to tell if they are in an intervention or control group so they cannot influence the results. In a single-blind study, patients do not know whether they are receiving the active drug or a placebo. In a double-blind study, neither the patients nor the persons administering the treatments know which patients are receiving the active drug. In a triple-blind study, the patients, clinicians/researchers and the persons evaluating the results do not know which treatment patients had. Whenever blinding is used, there will always be a method in which the treatment can be unblinded in the event that information is required for safety.

Comparator

When a treatment for a specific medical condition already exists, it would be unethical to do a randomized controlled trial that would require some participants to be given an ineffective substitute. In this case, new treatments are tested against the best existing treatment, (i.e. a comparator). The comparator can also be no intervention (for example, best supportive care).

Completed

A trial is considered completed when trial participants are no longer being examined or treated (i.e. no longer in follow-up); the database has been ‘locked’ and records have been archived.

Control

A group of people in a study who do not have the intervention or test being studied. Instead, they may have the standard intervention (sometimes called ‘usual care’) or a dummy intervention (placebo). The results for the control group are compared with those for a group having the intervention being tested. The aim is to check for any differences. The people in the control group should be as similar as possible to those in the intervention group, to make it as easy as possible to detect any effects due to the intervention.

Efficacy

How beneficial a treatment is under ideal conditions (for example, in a laboratory), compared with doing nothing or opting for another type of care. A drug passes efficacy trials if it is effective at the dose tested and against the illness for which it is prescribed.

Eligibility Criteria/ Inclusion and Exclusion Criteria

Eligibility criteria ensures patients enrolling in a clinical trial share similar characteristics (e.g. gender, age, medications, disease type and status) so that the results of the study are more likely due to the treatment received rather than other factors.

Follow-up

Observation over a period of time of participants enrolled in a trial to observe changes in health status.

Informed Consent

A process (by means of a written informed consent form) by which a participant voluntarily agrees to take part in a trial, having been informed of the possible benefits, risks and side effects associated with participating in the study.

Intervention

The treatment (e.g., a drug, surgical procedure, or diagnostic test) being researched. The intervention group consists of the study participants that have been randomly assigned to receive the treatment.

Investigator

A person responsible for the conduct of the clinical trial at a trial site. If a trial is conducted by a team of individuals at a trial site, the investigator is the responsible leader of the team and may be called the principal investigator (PI).

Multicentre Trial

A clinical trial conducted according to a single protocol but at more than one site, and therefore, carried out by more than one investigator.

Number needed to treat (NNT)

The average number of patients who need to receive the treatment or other intervention for one of them to get the positive outcome in the time specified.

Outcome Measures

The impact that a test, treatment, or other intervention has on a person, group or population.

Phase I, II, III and IV Studies

Once the safety of a new drug has been demonstrated in tests on animals, it goes through a multi-phase testing process to determine its safety and efficacy in treating human patients. If a drug shows success in one phase, the evaluation moves to the next phase

  • Phase 1 tests a drug on a very small number of healthy volunteers to establish overall safety, identify side effects, and determine the dose levels that are safe and tolerable for humans.
  • Phase II trials test a drug on a small number of people who have the condition the drug is designed to treat. These trials are done to establish what dose range is most effective, and to observe any safety concerns that might arise.
  • Phase III trials test a drug on a large number of people who have the condition the drug is designed to treat. Successful completion of Phase III is the point where the drug is considered ready to be marketed.
  • Phase IV trials can investigate uses of the drug for other conditions, on a broader patient base or for longer term use.

Placebo

A fake (or dummy) treatment given to patients in the control group of a clinical trial.  Placebos are indistinguishable from the actual treatment and used so that the subjects in the control group are unable to tell who is receiving the active drug or treatment. Using placebos prevents bias in judging the effects of the medical intervention being tested.

Population

A group of people with a common link, such as the same medical condition or living in the same area or sharing the same characteristics. The population for a clinical trial is all the people the test or treatment is designed to help.

Protocol

A plan or set of steps that defines how something will be done. Before carrying out a research study, for example, the research protocol sets out what question is to be answered and how information will be collected and analysed.

Randomized Controlled Trial (RCT)

A study in which a number of similar people are randomly assigned to 2 (or more) groups to test a specific drug, treatment or other intervention. One group has the intervention being tested; the other (the comparison or control group) has an alternative intervention, a placebo, or no intervention at all. Participants are assigned to different groups without taking any similarities or differences between them into account. For example, it could involve using a computer-generated random sequence. RCTs are considered the most unbiased way of assessing the outcome of an intervention because each individual has the same chance of having the intervention.

Reliability

The ability to get the same or similar result each time a study is repeated with a different population or group.

Sample

People in a study recruited from part of the study’s target population. If they are recruited in an unbiased way, the results from the sample can be generalised to the target population as a whole.

Subjects

In clinical trials, the people selected to take part are called subjects. The term applies to both those participants receiving the treatment being investigated and to those receiving a placebo or alternate treatment.

Trial Site

The location where trial-related activities are conducted.


References

The Canadian Institutes of Health Research (CIHR)

TROG Cancer Research

ICH.org

NICE

Further Resources

American Society of Clinical Oncology’s Cancer.Net trials site

National Cancer Institute (NCI) Clinical Trials lists open and closed cancer clinical trials sponsored or supported by NCI. 

ClinicalTrials.gov database of privately and publicly funded clinical studies

CenterWatch Clinical Trials Listing

How to Read and Understand a Scientific Paper

In a previous article, How to Read Beyond the Headline: 9 Essential Questions to Evaluate Medical News, I recommended you should always try to read an original study (if cited) to evaluate the information presented. In this follow-on article, you will learn how to read a scientific research paper so that you can come to an informed opinion on the latest research in your field of interest.  Understanding research literature is an important skill for patient advocates, and as with any skill, it can be learned with practice and time.

Let’s start by looking at what exactly we mean by the term “scientific paper”. Scientific papers are written reports describing original research findings. They are published in peer reviewed journals, which means they have been refereed by at least two other experts (unpaid and anonymized) in the field of study in order to determine the article’s scientific validity.

You may also come across the following types of scientific papers in the course of your research.

•       Scientific review papers are also published in peer reviewed journals, but seek to synthesize and summarize the work of a particular sub-field, rather than report on new results.

•       Conference proceedings, which may be published in a journal, are referred to as the “Proceedings of Conference X”. They will sometimes go through peer review, but not always.

•       Editorials, commentaries and letters to the editor offer a review or critique of original articles. They are not peer-reviewed.

Most scientific journals follow the IMRD format, meaning its publications will usually consist of an Abstract followed by:

•       Introduction

•       Methods

•       Results

•       Discussion

 

Let’s look at each of these sections in turn.

(a) Introduction  

The Introduction should provide you with enough information to understand the article. It should establish the scientific significance of the study and demonstrate a relevant context for the current study.  The scope and objectives of the study should be clearly stated.

When reading the Introduction, ask yourself the following questions:

·       What specific problem does this research address?

·       Why is this study important?

(b) Methods

The Methods section outlines how the work was done to answer the study’s hypothesis. It should explain new methodology in detail and types of data recorded.

As you read this section, look for answers to the following questions:

  • What procedures were followed?
  • Are the treatments clearly described?
  • How many people did the research study include? In general, the larger a study the more you can trust its results. Small studies may miss important differences because they lack statistical power. Case studies (i.e. those based on single patients or single observations) are no longer regarded as scientific rigorous.
  • Did the study include a control group? A control group allows researchers to compare outcomes in those who receive a treatment with those who don’t.

 (c) Results

The Results section presents the study’s findings.  It should follow a logical sequence to answer the study hypothesis.  Pay careful attention to any data sets shown in graphs, tables, and diagrams. Try to interpret the data first before reading the captions and details.  If you are unfamiliar with statistics, you will find a helpful glossary of terms here.  Click here for an online guide to help you understand key concepts of statistics and how these concepts relate to the scientific method and research.

Consider the following questions:

  • Are the findings supported by persuasive evidence?
  • Is there an alternative way to interpret these findings?

(d) Discussion 

The Discussion places the study in the context of the broader field of research. It should explain how the research has moved the body of scientific knowledge forward and outline the next steps for further study.

Questions to ask:

•       Does the study have any limitations? Limitations are the conditions or influences that cannot be controlled by the researcher.  Any limitations that might influence the results should be mentioned in the study’s findings.

  • How are the findings new or supportive of other work in the field?
  • What are some of the specific applications of the study’s findings?

The IMRD format provides you with a useful framework to read a scientific paper. You will need to read a paper several times to understand its findings. Consider your first reading of the study as a “big picture” reading.  Scan the Abstract for a summary of the study’s principal objectives, the methods it used and the principal conclusions. A well-written abstract should allow you to identify the basic content of an article to determine its relevance to you.  In describing how she determines the relevance of a study, research RN, Katy Hanlon, focuses on “key words and phrases first. Those that relate to the author/s base proposal as well as my own interests”.  Medical writer, Nora Cutcliffe, also scans upfront “to gauge power and relevance of clinical trial data”. She looks for “study enrollment (n), country and year”. It’s important to note the publication date to determine if this article contains the latest findings or if there is more up-to-date research available. Cutcliffe also advises you should “note author affiliations and study sponsors”.  Here you are looking out for any potential bias or vested interest in a particular outcome.  Check the Acknowledgments section to see if the author(s) declare any financial interests in the research which might bias their findings. Finally, check if the article is published in a credible journal.  You will find reputable biomedical journals indexed by Pubmed and Web of Science.

Next, circle or take note of any scientific terms or keywords you don’t understand and look up their meaning before your second reading. Scan the References section – you may even want to read an article listed here first to help you better understand the current study.

With the second reading you are going to deepen your comprehension of the study. You’ll want to highlight key points, consult the references, and take notes as you read.  According to the scientific publisher, Elsevier, “reading a scientific paper should not be done in a linear way (from beginning to end); instead, it should be done strategically and with a critical mindset, questioning your understanding and the findings.”  Scientist, Dr Jennifer Raff, agrees. “When I’m choosing papers to read, I decide what’s relevant to my interests based on a combination of the title and abstract”, she writes in How to read and understand a scientific paper: a guide for non-scientists. “But when I’ve got a collection of papers assembled for deep reading, I always read the abstract last”. Raff explains she does this “because abstracts contain a succinct summary of the entire paper, and I’m concerned about inadvertently becoming biased by the authors’ interpretation of the results”.

When you have read the article through several times, try to distill it down to its scientific essence, using your own words. Write down the key points you have gleaned from your reading such as the purpose of the study, main findings and conclusions. You might find it helpful to develop a template for recording notes, or adapt the template below for use. You will then have a useful resource to find the correct reference and to cross reference when you want to consult an article in the future.

In the example below I have taken an article published in 2015, as an example. You can read the paper Twitter Social Media is an Effective Tool for Breast Cancer Patient Education and Support: Patient-Reported Outcomes by Survey on PubMed.

Template for Taking Notes on Research Articles

 

 

Further reading

How to Read Beyond the Headline: 9 Essential Questions to Evaluate Medical News

Ben Goldacre writing in Bad Science classified science reporting as falling into three categories – wacky stories, scare stories and breakthrough stories; the last of which he views as ”a more subtly destructive category of science story”. Whether you get your news through digital or traditional means, you can’t fail to notice the regularity with which journalists report on the latest medical breakthroughs. Some of these reports are sensationalist (“coffee causes cancer”) and fairly easy to dismiss; but do you know how to separate fact from fiction when it comes to less sensationalist headlines?

The foundation of empowered patient-hood is built on reliable health information. This means not only knowing where to find medical information, but being able to evaluate it and knowing how it can be applied to your own, or your loved-ones’ particular circumstances. Headlines often mislead people into thinking a certain substance or activity will prevent or cure chronic disease. As patient advocates we must learn to read beyond the headlines to filter out the good, the bad, and the questionable. The following questions are designed to help sort the signal from the noise next time you read the latest news story heralding a medical breakthrough.

1. Does the article support its claims with scientific research?

Your first concern should be the research behind the news article. If an article contains no link to scientific research to support its claims, then be very wary about treating those claims as scientifically credible.

2. What is the original source of the article?

If the article cites scientific research you should still treat the findings with caution. Always consider the source. Find out where the study was done. Who paid for and conducted the study? Is there a potential conflict of interest?

3. Does the article contain expert commentary to back up claims?

Look for expert independent commentary from doctors or other healthcare providers to explain the findings (there should be an independent expert source quoted – someone not directly connected with the research).

4. Is this a conference presentation?

Journalists frequently report on research presented at large scientific meetings. It’s important to realize that this research may only be at a preliminary stage and may not fulfill its early promise.

5. What kind of clinical trial is being reported on?

If the news relates to results from a clinical trial, it’s important you understand how, or even if, the results apply to you. Quite often, news publications report on trials which have not yet been conducted on humans. Many drugs that show promising results in animals don’t work in humans. Cancer.Net and American Cancer Society have useful guides to understanding the format of cancer research studies.

6. What stage is the trial at?

Research studies must go through several phases before a treatment can be considered safe and effective; but many times journalists report on early phase trials as if these hold all the answers. The testing process in humans is divided into several phases:

  •  Phase I trials: Researchers test a new drug or treatment in a small group of people for the first time to evaluate its safety, determine a safe dosage range, and identify side effects.
  • Phase II trials: The drug or treatment is given to a larger group of people to see if it is effective and to further evaluate its safety.
  • Phase III trials: The drug or treatment is given to large groups of people to confirm its effectiveness, monitor side effects, compare it to commonly used treatments, and collect information that will allow the drug or treatment to be used safely.

Source: ClinicalTrials.gov

7. How many people did the research study include?

In general, the larger a study the more you can trust its results. Small studies may miss important differences because they lack statistical power.

8. Did the study include a control group?

A control group allows researchers to compare outcomes in those who receive a treatment with those who don’t. The gold standard is a “randomised controlled trial”, a study in which participants are randomly allocated to receive (or not receive) a particular intervention (e.g. a treatment or a placebo).

9. What are the study’s limitations?

Many news stories fail to point out the limitations of the evidence. The limitations of a study are the shortcomings, conditions or influences that cannot be controlled by the researcher. Any limitations that might influence the results should be mentioned in the study’s findings, so always read the original study where possible.

Useful Resources

  • Sense about Science works with scientists and members of the public to equip people to make sense of science and evidence. It responds to hundreds of requests for independent advice and questions on scientific evidence each year.
  • Trust It or Trash is a tool to help you think critically about the quality of health information (including websites, handouts, booklets, etc.).
  • Understanding Health Research (UHR) is a free service created with the intention of helping people better understand health research in context. It gives clear and understandable explanations of important considerations like sampling, bias, uncertainty and replicability.