ASH 2020: The Next Wave

CRISPR-Driven Treatment Proves “Transformative” for Patients With Sickle Cell Disease, Beta Thalassemia

For the patients with beta thalassemia, the blood transfusions have stopped. For those with sickle cell disease (SCD), the painful episodes that landed them in the hospital over and over again have ceased, a change that treating physicians call “transformative.”

Reports of 10 patients treated with therapy using CRISPR gene editing—the same technology that won the 2020 Nobel Prize in chemistry¹—headlined the plenary session on December 6, 2020, at the 62nd meeting of the American Society of Hematology (ASH).² Results also appeared in the New England Journal of Medicine (NEJM).³

The technique calls for targeting BCL11A, which interferes with the production of fetal hemoglobin: If BCL11A could be silenced by an infusion of modified CD34+ homeopathic stem and progenitor cells, the patient could produce fetal hemoglobin, and the debilitating conditions of both blood disorders would be held in check.

And so far, as presented by Haydar Frangoul, MD, a pediatric hematologist and medical oncologist with Tristar Medical Group in Nashville, Tennessee, the approach looks like a home run. While the number of patients is still small and the follow-up is comparatively short—the longest duration Frangoul reported is 21.5 months—all signs point to that elusive word: cure.

“For patients with beta thalassemia, they have been transfusion independent, and for patients with sickle cell disease, they have been vaso-occlusive crisis–free,” Frangoul said. Both fetal hemoglobin and total hemoglobin levels rose early after treatment and have been maintained, and the safety profile matches that of patients who have received autologous bone marrow transplants.

The news has been anticipated for a year, since the first glimmers of the treatment were reported at ASH 2019.⁴ One of Frangoul’s patients was profiled on National Public Radio.⁵ The FDA approved new disease-modifying therapies for sickle cell disease in 2019,^6-7 and transplants are increasingly common. But graft-vs-host disease remains a major challenge, and for some patients, a sibling donor may not be available.

“Allogeneic bone marrow transplantation can cure both [transfusion-dependent beta-thalassemia] and SCD, but [fewer] than 20% of eligible patients have a related human leukocyte antigen–matched donor,” the authors wrote in NEJM.³

The CDC estimates that SCD affects 1 of every 100,000 Americans overall, but it occurs in about 1 of every 365 births among Black Americans and 1 of every 16,300 births among Hispanic Americans.⁸ The life-changing nature of what Frangoul called a “functional cure” for SCD and beta thalassemia, a related condition, cannot be overstated. A 2019 paper in Hematology found that 64% of adults and 43% of children with SCD had been admitted to the hospital within the past year, with uncontrolled pain being the most common reason.⁹ The coronavirus disease 2019 (COVID-19) pandemic has hit patients with SCD hard, with a separate paper at ASH 2020 reporting that even higher percentages of patients with SCD and COVID-19 were hospitalized.¹⁰

A New Approach

The treatment presented during ASH, which is currently named CTX001, is being developed by Vertex Pharmaceuticals and CRISPR Therapeutics. The trials, called CLIMB-THAL-11111 and CLIMB-SCD-121,12 are phase 1/2, single-arm, open-label studies that will enroll 45 patients each, aged 12 to 35 years.

CLIMB-THAL-111 is measuring how many patients will be able to achieve a sustained reduction of infusions of at least 50% for at least 6 months, starting 3 months after infusion. CLIMB-SCD-121 is measuring how many patients with 20% fetal hemoglobin or more can sustain that level for at least 3 months, starting 6 months after infusion.

For those with SCD, targeting BCL11A appears “particularly advantageous,” according to a separate group of authors from Dana-Farber/Boston Children’s Cancer and Blood Disorders Center, who also published results in NEJM.13 According to those authors, when BCL11A is suppressed, the rise in fetal hemoglobin is accompanied by a drop in sickle hemoglobin. Even small changes in these levels have major effects on the process that alters red blood cells, which creates the misshapen “sickle” effect that causes these cells to clog blood vessels and restrict oxygen flow.

CLIMB-THAL-111

Frangoul reported on the 7 patients in the beta thalassemia trial. In CLIMB-THAL-111, fetal hemoglobin accounted for about half of total hemoglobin on average by the 2-month mark (5.1 of 10.5 Hb g/dL) and by the 12-month mark, Of 12.4 Hb g/dL total hemoglobin, almost all—12.1 Hb g/dL— was fetal hemoglobin.¹¹

No patient needed a transfusion after the 2-month mark, and the first enrolled patient in the study has not had a transfusion in 22 months, after previously receiving 34 units of red blood cells a year.

CLIMB-SCD-121

Frangoul reported the data on the 3 patients individually; each has seen gradual improvement in fetal hemoglobin levels. The patient who has been infused the longest has gone from 9% fetal hemoglobin prior to infusion to 43% at 15 months post infusion.¹²

In both CLIMB-SCD-121 and CLIMB-THAL-111, measures of the BCL11A gene editing in patients bone marrow are holding at the 6-month mark, and at the 12-month mark for those who have reached it.

Adverse Events (AEs)

In all 7 patients in the CLIMB-THAL-111 trial, the safety profile was consistent with patients taking busulfan myeloablation, given to patients preparing for stem cell transplant. Four serious AEs were reported in 1 patient with headache, hemophagocytic lymphohistiocytosis (HLH), acute respiratory distress syndrome, and idiopathic pneumonia syndrome; all were in the context of HLH and had resolved by the time of the analysis. One long-term consequence is not known: whether women who receive this treatment will be able to become pregnant, given the production of fetal hemoglobin. No other SAEs were reported for the TDT patients or for any SCD patients.

When Frangoul was asked if the CRISPR technology resulted in off-target edits, he replied that this was examined in the NEJM paper and none were found. “We are tracking patients with sequential marrows to evaluate for any long-term genetic abnormalities,” he said. “We have not seen any yet.”

Perhaps the most important outcome was not precisely measured: One questioner asked what it’s been like for patients when a life with chronic illness has changed for the better.

Frangoul brightened with the perspective of a physician who has treated many sickle cell patients. “This has been transformative to their lives. It really changed them for the better,” he said. “I cannot tell you how grateful patients are and how well they feel.”

References

1. The Nobel Prize in Chemistry 2020. News release. The Royal Swedish Academy of Sciences; October 7, 2020. Accessed December 12, 2020. https://www.nobelprize.org/prizes/chemistry/2020/press-release/

2. Frangoul H, Bobruff Y, Domenica Cappellini M, et al. Safety and efficacy of CTX001 in patients with transfusion-dependent β-thalassemia and sickle cell disease: early results from the CLIMB THAL-111 and CLIMB SCD-121 studies of autologous CRISPR-CAS9–modified CD34+ hematopoietic stem and progenitor cells. Presented at: 62nd American Society of Hematology Annual Meeting and Exposition; December 5-8, 2020; virtual. Abstract 4. https://ash.confex.com/ash/2020/webprogram/Paper139575.html

3. Frangoul H, Altshuler D, Domenica Cappellini M, et al. CRISPR-Cas9 gene editing for sickle cell disease and β-thalassemia. N Engl J Med. Published online December 5, 2020. doi:10.1056/NEJMoa2031054

4. Williams DA. BCL11A as therapeutic target in SCD: gene therapy trial. Presented at: 61st American Society of Hematology Annual Meeting and Exposition; December 7-10, 2019; Orlando, FL. Accessed January 14, 2020. https://www.youtube.com/watch?v=oqbmuPxDeEs

5. Stein R. CRISPR for sickle cell disease shows promise in early test. National Public Radio. Published November 19, 2019. Accessed December 6, 2020. https://www.publicradioeast.org/post/crispr-sicklecell-disease-shows-promise-early-test

6. FDA approves crizanlizumab-tmca for sickle cell disease. FDA. November 15, 2019. Accessed December 13, 2020. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-crizanlizumab-tmca-sickle-cell-disease

7. FDA approves voxelotor for sickle cell disease. FDA. November 25, 2019. Accessed December 13, 2020. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-voxelotor-sickle-cell-disease

8. Data and statistics on sickle cell disease. CDC. Updated December 16, 2020. Accessed December 16, 2020. https://www.cdc.gov/ncbddd/sicklecell/data.html

9. Cronin RM, Hankins JS, Byrd J, et al. Risk factors for hospitalizations and readmissions among individuals with sickle cell disease: results of a U.S. survey study. Hematology. 2019;24(1):189-198. doi:10.1080/16078454.2018.1549801

10. Cohen AJ. Impact of the COVID19 pandemic on admissions and emergency department visits of adults with sickle cell disease. Presented at: 62nd American Society of Hematology Annual Meeting and Exposition; December 5-8, 2020; virtual. Abstract 2492. https://ash.confex.com/ash/2020/webprogram/Paper142803.html

11. A safety and efficacy study evaluating CTX001 in subjects with transfusion-dependent ž-thalassemia. ClinicalTrials.gov. Updated December 14, 2020. Accessed December 16, 2020. https://clinicaltrials.gov/ct2/show/NCT03655678

12. A safety and efficacy study evaluating CTX001 in subjects with severe sickle cell disease. ClinicalTrials.gov. Updated August 6, 2020. Accessed December 6, 2020. https://clinicaltrials.gov/ct2/show/NCT03745287

13. Esrick EB, Lehmann LE, Biffi A. Post-transcriptional genetic silencing of BCL11A to treat sickle cell disease. N Engl J Med. Published online December 5, 2020. doi:10.1056/NEJMoa2029392

Genetic Tracing Discovery: Mutations for Blood Cancer Appear Decades Before Diagnosis

If you had a crystal ball and knew you would develop a blood cancer in the future, would you do something to stop it? That’s the question sparked by research presented on the final day of the 62nd annual meeting of the American Society of Hematology.

The findings, highlighted at a session featuring late-breaking studies, showed how scientists at the Wellcome Sanger Institute and the University of Cambridge, in the United Kingdom, used bone marrow and blood samples to trace the genetic beginnings of a blood cancer in 10 people. To their surprise, the researchers found that cancer driver mutations appeared in childhood, decades before a diagnosis—and some mutations were present before patients were born.

The study’s senior author said during a press briefing that the opportunity exists to repeat this research strategy in patients with other blood cancers, to see if the driver mutations show up just as early. And the question of whether next-generation sequencing (NGS) could be used to sniff out potential cancers in healthy people years ahead of time is not theoretical.

When does cancer start?

Senior study author Jyoti Nangalia, MD, who presented the findings, said the results answer a common question among patients: When did my cancer start growing? In some cases, she said, “We were able to study how these particular cancers developed over the entire lifetime of individual patients.”

The Wellcome Sanger study involved Philadelphia-negative myeloproliferative neoplasms (MPNs), which are driven by JAK2 V617F mutations in most patients. For the 10 patients with MPNs, whose ages ranged from 20 to 76 years, the researchers first performed whole-genome sequencing on single-cell–derived hematopoietic colonies of the blood cancer from each patient to isolate the driver mutation. Then they resequenced older blood samples available for each patient, tracing the timing of the cancer-causing mutation alongside hundreds of thousands of other somatic mutations that occurred along the way.

“We identified 448,553 somatic mutations, which were used to reconstruct phylogenetic trees of hematopoiesis, tracing blood cell lineages back to embryogenesis,” the authors wrote. “We timed driver mutation acquisition, characterized the dynamics of tumor evolution, and measured clonal expansion rates over the lifetime of patients.”

When the JAK2 mutation that was the focus of the study acted alone to drive a patient’s cancer, the researchers found it was acquired early, often at the dawn of life. For this group, they estimate the mutation appeared a few weeks after conception, with upper range estimates between 4.1 months and 11.4 years. For these patients, the mean length of time between acquiring a mutation and cancer appearing was 34 years.

Even when the JAK2 mutation was a second driver, acting with another mutation, there was still a latency period of 12 to 27 years before cancer appeared.

What about other cancers?

In response to a question, Nangalia said the research methods used in the study are generally applicable for other cancers, including solid tumors.

“We already know in myeloma that some of the chromosomal aberrations occur early compared with others,” she said. “In myeloma, we know the relative timing of one coming before the other or after, but what we don’t know is the absolute timing in terms of whether these mutations or chromosomal aberrations occurred in childhood, in utero, or indeed, much later in life, closer to when the patient presented.”

Based on the surprise of the MPN study, she wouldn’t make any guesses about multiple myeloma or any other disease. For 1 patient in the MPN study, the JAK2 mutation appeared more than 50 years before cancer was diagnosed. Given these results, Nangalia said, “I really don’t know what to predict about other cancers.”

When asked if the findings have implications for broader use of NGS, Nangalia said they clearly do. NGS, she said, is being used more often in both cancer diagnostics and prognostics, and to find therapeutic targets. “However, I think our study opens a whole new application for next-generation sequencing in terms of potentially identifying...individuals who do not yet have a diagnosis, to see which…are at risk of a future blood cancer.

“That will require further work to get there and validate this approach,” she said. But, given that patients in the study with MPNs had mutations for 10 to 40 years before blood cancer appeared, “We would have been able to detect these mutations with next-generation sequencing decades before their diagnosis. And we think we would have also been able to understand and predict which patients were on a path to future disease by estimating their rate of growth,” noted Nangalia.

The opportunity exists, she said, for researchers to use NGS to study healthy individuals to understand which patients are at risk of cancer.

Reference

Williams N, Lee J, Moore L, et al. Driver mutation acquisitions in utero and childhood followed by lifelong clonal evolution underlie myeloproliferative neoplasms. Presented at: 62nd American Society of Hematology Annual Meeting and Exposition; December 5-8, 2020; virtual. Abstract LBA-1. https://ash.confex.com/ash/2020/webprogram/Paper143813.html