Results from clinical trials being presented during the 62nd American Society of Hematology (ASH) Annual Meeting, and Exposition held virtually from December 5 – 8, 2020, provide support for new clinical approaches, including alternate treatment delivery methods, updated uses for existing therapies, and earlier referrals to specialty care. These opportunities may help improve care for patients with a variety of blood disorders.

“These are very practical trials with real-world implications,” said Lisa Hicks, MD, of St. Michael’s Hospital and the University of Toronto, Ontario, Canada.

“They address important questions relevant to everyday practice in the clinic,” Hicks added.

One study supports administering the monoclonal antibody daratumumab (Darzalex®; Janssen Biotech) for multiple myeloma, which persists or recurs after first-line treatments, via a quick subcutaneous injection instead of an intravenous infusion. This approach could save significant time for patients and clinics.

Patients given subcutaneous daratumumab along with the immunomodulator pomalidomide and the anti-inflammatory steroid dexamethasone were 37% less likely to die or have their disease worsen compared to patients who received pomalidomide and dexamethasone alone in the phase III trial.

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“This is an effective combination with a predictable safety profile that allows for the use of subcutaneous daratumumab along with oral pomalidomide and dexamethasone for patients who have received at least one prior line of therapy that included lenalidomide and a proteasome inhibitor,” said senior study author Meletios A. Dimopoulos, M.D., of National and Kapodistrian University of Athens in Athens, Greece, who presents the study results in an oral presentation on Sunday, December 6, at 12:00/noon Pacific time.

“Subcutaneous daratumumab is much easier for the patient and reduces the time they need to spend at the outpatient chemotherapy unit,” Dimopoulos added.

The combination of intravenous daratumumab and pomalidomide with dexamethasone has been widely adopted in the U.S. as second-line therapy for patients whose multiple myeloma does not respond durably to lenalidomide and proteasome inhibitors.

“But delivering daratumumab intravenously typically requires patients to spend a full day at the clinic for each infusion. Administering the therapy via a five-minute subcutaneous injection can substantially reduce the burden for patients and clinics,” Dimopoulos noted.

The researchers enrolled 304 patients in 12 European countries. Half were randomly assigned to receive daratumumab plus pomalidomide with dexamethasone and half only received pomalidomide with dexamethasone. Patients underwent 28-day treatment cycles until their disease worsened or they experienced unacceptable side effects.

About one-third of patients died during the trial’s median follow-up period of about 17 months. The study met its primary endpoint, showing a significantly higher rate of progression-free survival at 12 months among patients receiving the combination therapy. Participants receiving the daratumumab-pomalidomide combination were treated for a median of nearly 12 months, substantially longer than the median treatment duration of fewer than seven months among those receiving pomalidomide alone.

Patients receiving daratumumab experienced adverse events at a rate consistent with previous studies, raising no new safety concerns.

Dimopoulos noted that the findings suggest the combination therapy can be a good option for patients who have not experienced lasting benefits from lenalidomide and proteasome inhibitors, particularly those whose cancer is resistant to lenalidomide. He noted that the study suggested a slight trend toward increased survival in the daratumumab arm, but additional follow-up is necessary to assess any survival benefit.

No prevention of Bleeding
The second study found that, despite being routinely used in clinical practice, the clot stabilizer tranexamic acid (Cyklokapron®; Pfizer/Pharmacia and Upjohn) does not prevent bleeding when used for patients undergoing treatment for blood cancers with prophylactic platelet transfusions.

Researchers left open the possibility that tranexamic acid may be an effective treatment option, such as its use in treating bleeding related to childbirth, surgery, or inherited blood disorders.

A different kind of bleeding
“Clearly patients with low platelet counts and blood cancers have a different kind of bleeding than the bleeding experienced by patients who have suffered some kind of trauma or surgery,” said senior study author Terry B. Gernsheimer, MD, of the University of Washington School of Medicine, who will present the study results in a plenary presentation on Sunday, December 6, 2020, at 7:00 a.m.

“Their bleeding likely is due to endothelial damage, [that is] damage to the lining of blood vessels, that tranexamic acid would not treat. To prevent bleeding in these patients, we may need to look at ways to speed the healing of the endothelium that occurs with chemotherapy, radiation, and graft-versus-host disease in patients receiving a transplant,” Gernsheimer added.

Between 48% and 70% of patients undergoing treatment for blood cancers experience bleeding complications of World Health Organization (WHO) grade 2 or higher. Though not life-threatening, grade 2 bleeding, which may, for example, be a nosebleed lasting longer than 30 minutes,  can be concerning. Bleeding of grade 3 or 4 can be life-threatening and warrant blood transfusions. Most patients undergoing treatment for blood cancers are routinely given platelet transfusions to prevent bleeding, but, nonetheless, many continue to experience bleeding episodes.

Mechanism of action
Tranexamic acid works by slowing the process by which blood clots naturally break down. To determine whether tranexamic acid could help to further reduce bleeding in these patients, the researchers enrolled 327 patients undergoing treatment for blood cancers at three U.S. medical centers. Half were randomly assigned to receive tranexamic acid and half received a placebo, administered either orally or intravenously three times a day until they recovered their platelet count, or for up to 30 days. Researchers regularly followed up with participants to assess bleeding events both in and outside of the hospital.

The results revealed no significant differences among the study groups in terms of the number of bleeding events, the number of red blood cell transfusions, or the number of platelet transfusions patients required during the treatment period and for up to 14 days afterward. Patients receiving tranexamic acid had a significantly higher rate of occlusions in their central venous line (a catheter placed in a large vein commonly used for delivering cancer drugs) which required clearing with a clot-dissolving drug, but there was no difference in the occurrence of clots in patients’ veins or arteries.

“Other studies could help elucidate whether the drug may be helpful for specific subgroups of patients with blood cancers or as a treatment for bleeding, rather than as a preventive measure in these patients. It may also be useful to prevent or treat bleeding in patients with other causes of low platelet counts,” Gernsheimer concluded.

Chronic Graft-versus-host Disease
The third study reports that ruxolitinib (Jakafi®; Incite/Jakavi®; Novartis), a selective Janus kinase (JAK1 and JAK2) inhibitor, can offer relief for patients with chronic graft-versus-host disease (GVHD) after a stem cell transplant.

The results from the phase III REACH3 trial (NCT03112603) show that ruxolitinib brought relief from the debilitating effects of chronic graft-versus-host disease at twice the rate of the best available therapy.

The researchers noted that these findings represent a major step forward for patients with chronic GVHD that is not resolved by taking corticosteroids. There is currently no approved second-line therapy for chronic forms of the disease.

“This is the first multicenter randomized controlled trial for chronic, steroid-refractory or steroid-dependent GVHD that is positive,” explained the senior study author Robert Zeiser, Ph.D., of University Medical Center, Freiburg Im Breisgau, Germany, who presented the study results in an oral presentation on Saturday, December 5, at 8:00 a.m. Pacific time.

“It shows a significant advantage for ruxolitinib. It is likely that this trial will lead to approval for this indication and change the guidelines for the treatment of this disease,” Zeiser added.

Graft-versus-host disease remains a major limiting complication of allogeneic hematopoietic (stem) cell transplantation, a therapy used to treat blood cancers. It occurs when T-cells (the graft) received from a donor through the transplant see the patient’s healthy cells and tissue (the host) as foreign and start to attack them. On average, half of all patients undergoing a stem cell transplant develop GVHD. Half of these patients are able to resolve their symptoms with a temporary course of corticosteroids, a class of drugs that lower inflammation in the body. The remaining patients either do not respond to steroids, cannot take them, or must take them continuously to stave off symptoms.

Ruxolitinib is designed to block a molecular signal involved in triggering inflammation. A previous trial (REACH2; NCT02913261), found that ruxolitinib offered benefits for patients with acute GVHD, a severe form of GVHD with a mortality rate of 80%.[5]

In the REACH3 trial researchers aimed to determine whether the drug could bring similar benefits for the much larger number of patients affected by chronic GVHD. While chronic GVHD is not nearly as deadly as acute GVHD, the symptoms, which include weight loss, skin stiffness, and multiple disabilities, can severely and permanently affect patients’ health-related quality of life (hrQoL).

In the trial, researchers enrolled 329 patients with moderate-to-severe chronic GVHD. Half were randomly assigned to receive ruxolitinib (n = 165) for six 28-day cycles. The other half received one of nine alternative treatments, representing the best available therapy (n = 164), at the discretion of their physician. At the end of the six treatment cycles, researchers assessed the symptoms of 125 patients who had completed the full course of treatment to which they were assigned.

Crossover from best available therapy to ruxolitinib was allowed on or after cycle 7 day 1 (C7D1) in patients who did not achieve or maintain complete or partial response (CR/PR, developed toxicity to best available therapy or had a Chronic GVHD flare.

Baseline characteristics were balanced in the 2 arms; 61% were male, and the median age was 49 years (range, 12-76 years). Twelve patients were < 18 years old. Overall, 48% and 52% of patients had moderate and severe cGVHD, respectively.

The trial met its primary endpoint, with the efficacy boundary crossed at interim analysis (ORR, P = 0.0003), showing a clear and substantial improvement in the overall response to treatment among patients taking ruxolitinib.

Of the 125 patients assessed, 50% of those receiving ruxolitinib had at least some reduction in symptoms, compared to only 25% among those receiving the best available therapy.

At cycle 7 day 1 (C7D1), the overall response rate was significantly higher in the ruxolitinib arm versus vest available therapy (50% vs. 26%; odds ratio, 2.99; P < 0.0001). Seven percent of those taking ruxolitinib saw their symptoms resolve completely, compared to only 3% among those receiving the best available therapy.

Participants in both arms of the study experienced similar rates of adverse events, which aligned with the health challenges commonly faced by patients with chronic GVHD, suggesting ruxolitinib has an acceptable safety profile in these patients, Zeiser explained in his presentation.

The study results indicated, however, that ruxolitinib demonstrated superior efficacy compared to the best available therapy, measured by a higher overall response rate, longer failure-free survival, and greater symptom improvement. Ruxolitinib was effective for moderate or severe steroid-refractory or dependent (SR/D) chronic GVHD and its safety profile is consistent with that expected for this drug and this population.

Curative Transplant Improves Survival
Data presented during the 62nd American Society of Hematology (ASH) Annual Meeting supports referring older patients with myelodysplastic syndromes to transplant centers for allogeneic hematopoietic cell transplantation.

The Blood and Marrow Transplant Clinical Trials Network’s Study 1102 (NCT02016781), co-funded by the National, Heart, Lung and Blood Institute (NHLBI) and the National Cancer Institute (NCI), both part of the National Institutes of Health, demonstrated that this approach is an important shift from current practice that could offer many more patients the potential for a cure.

In a trial, allogeneic hematopoietic cell transplantation nearly doubled the rate of survival among patients 50 to 75 years old with myelodysplastic syndrome. But despite being the only known cure for myelodysplastic syndrome, this therapy is typically only offered to younger patients.

One of the reasons why this treatment is generally given to younger patients is that the benefits for older adults have not previously been proven. Researchers say the study offers the most definitive evidence to date that this type of stem cell transplantation significantly improves the outlook for older adults who would otherwise face a high likelihood of dying.

“Transplantation has been underutilized, historically, in this patient group,” said senior study author Corey Cutler, M.D., MPH, of Dana-Farber Cancer Institute, who presented the study results in an oral presentation on Saturday, December 5, at 7:30 a.m. Pacific time

“Based on our findings, all patients should at least be referred to a transplant center so that those who are eligible and who have a suitable donor can undergo a transplant and have better survival. It is important to refer these patients early so that the transplant center can work on finding an optimal donor right from the get-go,” Cutler explained.

Allogeneic hematopoietic cell transplantation
Allogeneic hematopoietic (stem) cell transplantation is a process designed to replace a recipient’s stem cells and the immune system with cells from a healthy donor. It is the only known method to cure patients with myelodysplastic syndrome. The Centers for Medicare and Medicaid Services (CMS) covers transplantation for myelodysplastic syndrome as part of a Coverage with Evidence Development program. CMS approved the design of the trial and is expected to consider the findings when determining future payment policies.

Researchers from the Blood and Marrow Transplant Clinical Trials Network enrolled 384 patients treated for myelodysplastic syndrome at 34 U.S. medical centers.

Participants in the multicenter study included patients with a higher risk of de novo myelodysplastic syndrome (IPSS Intermediate-2 (Int-2) or High) who were candidates for reduced-intensity conditioning (RIC) allogeneic hematopoietic (stem) cell transplantation.

Eligible patients were referred to transplant centers, which searched for suitable stem cell donors, and enrolled prior to a formal donor search, before or after myelodysplastic syndrome treatment was initiated.

The 260 patients who were matched with a donor within 90 days were assigned to receive a stem cell transplant; the other 124 patients with no suitable donor received standard supportive care. Participants were followed for roughly three years from their date of enrollment.

In an intent-to-treat analysis, adjusted overall survival at 3 years from study enrollment was much higher in patients assigned to receive a stem cell transplant – 47.9% (95% CI: 41.3%-54.1%) compared with 26.6% (95% CI: 18.4%-35.6%) in those who were not  (p=0.0001, absolute difference 21.3%, 95% CI: 10.2%-31.8%).

Leukemia-free survival at 3 years was also higher in those assigned to receive a transplant (35.8%, 95% CI: 29.8%-41.8%) compared in those who were not (20.6%, 95% CI: 13.3%-29.1%, p=0.003)(35.8%). The researchers observed no significant differences among subgroups and no differences in health-related quality of life between the two study arms.

The study authors observed a significant overall survival advantage in older patients with a higher risk of de novo myelodysplastic syndrome (IPSS Intermediate-2 (Int-2) or High) who were candidates for reduced-intensity conditioning and have an HLA-matched donor, when compared with those without a donor.

They also noted that the benefit of having a matched donor was seen across subgroups, including those who were of Medicare age (>65) and below. They concluded that hematopoietic (stem) cell transplantation should be offered to all individuals between the ages of 50-75 with a higher risk of de novo myelodysplastic syndrome (IPSS Intermediate-2 (Int-2) or High) in whom a suitable donor can be identified.

Cutler said that starting the transplantation process as early as possible can increase a patient’s chance of finding a suitable donor and successfully proceed with a transplant.

Clinical trials
Safety and Efficacy of Ruxolitinib Versus Best Available Therapy in Patients With Corticosteroid-refractory Acute Graft vs. Host Disease After Allogeneic Stem Cell Transplantation (REACH2) – NCT02913261
A Study of Ruxolitinib vs Best Available Therapy (BAT) in Patients With Steroid-refractory Chronic Graft vs. Host Disease (GvHD) After Bone Marrow Transplantation (REACH3) – NCT03112603
Allo vs Hypomethylating/Best Supportive Care in MDS (BMT CTN 1102)NCT02016781

Highlights of Prescribing Information
Daratumumab (Darzalex®; Janssen Biotech) [Prescribing Information]
Lenalidomide (Revlimid®; Celgene/Bristol Myers Squibb)[Prescribing Information]
Tranexamic acid (Cyklokapron®; Pfizer/Pharmacia and Upjohn)[Prescribing Information]
Ruxolitinib (Jakafi®; Incyte)[Prescribing Information]

Summary of Product Characteristics (Europe)
Ruxolitinib (Jakavi®; Novartis)[SPC/EPAR]

[1] Dimopoulos MA, Terpos E, Boccadoro M, Delimpasi S, Beksac M, Katodritou E, Moreau P, Baldini L, et al. Apollo: Phase 3 Randomized Study of Subcutaneous Daratumumab Plus Pomalidomide and Dexamethasone (D-Pd) Versus Pomalidomide and Dexamethasone (Pd) Alone in Patients (Pts) with Relapsed/Refractory Multiple Myeloma (RRMM) (Abstract #412)
[2] Gernsheimer TB, Brown SP, Triulzi DJ, Key NS, El Kassar N, Herren H, and Susanne May S. Effects of Tranexamic Acid Prophylaxis on Bleeding Outcomes in Hematologic Malignancy: The A-TREAT Trial (Abstract #2)
[3] Ruxolitinib (RUX) Vs Best Available Therapy (BAT) in Patients with Steroid- Refractory/Steroid-Dependent Chronic Graft-Vs-Host Disease (cGVHD): Primary Findings from the Phase 3, Randomized REACH3 Study (Abstract 77)
[4] Nakamura R, Saber W, Martens MJ, Ramirez A, Scott BL, Oran B, Leifer E, Tamari R, Mishra A, et al. A Multi-Center Biologic Assignment Trial Comparing Reduced Intensity Allogeneic Hematopoietic Cell Transplantation to Hypomethylating Therapy or Best Supportive Care in Patients Aged 50-75 with Advanced Myelodysplastic Syndrome: Blood and Marrow Transplant Clinical Trials Network Study 1102 (Abstract 75)

[5] Zeiser R, von Bubnoff N, Butler J, Mohty M, Niederwieser D, Or R, Szer J, Wagner EM, Zuckerman T, Mahuzier B, Xu J, Wilke C, Gandhi KK, Socié G; REACH2 Trial Group. Ruxolitinib for Glucocorticoid-Refractory Acute Graft-versus-Host Disease. N Engl J Med. 2020 May 7;382(19):1800-1810. doi: 10.1056/NEJMoa1917635. Epub 2020 Apr 22. PMID: 32320566.

Featured image: Impressions from ASH 2017. Photo Courtesy: © 2017 – 2020 American Society of Hematology. Used with permission.

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