63rd ASH Annual Meeting and Exposition
December 11-14, 2021

Late-Breaking Abstracts Session


Hervé Tilly, Franck Morschhauser, Laurie H. Sehn, et al.

Compared to R-CHOP, the Pola-R-CHP combination reduced the relative risk of disease progression, relapse, or death in patients with DLBCL by 27 percent. The safety profile was similar to that for first-line treatment.


Polatuzumab Vedotin in Previously Untreated Diffuse Large B-Cell Lymphoma

H. Tilly and Others

Read also the ASH PRESS RELEASE:
Study in ASH Late-Breaking Abstracts session represents the first significant improvement over standard of care for newly diagnosed DLBCL

(WASHINGTON, Dec. 14, 2021) – A new trial found patients with diffuse large B-cell lymphoma (DLBCL) had a significantly higher likelihood of survival without disease progression two years after receiving a new drug combination known as pola-R-CHP compared with those who received the standard of care, a combination known as R-CHOP. The findings, presented at the 63rd American Society of Hematology (ASH) Annual Meeting and Exposition, represent the first significant improvement over standard of care for newly diagnosed DLBCL reported in more than two decades, according to the authors. Although the trial found no significant difference in complete response rates or overall survival at two years, those who received the new drug combination were less likely to need additional treatment compared with those receiving R-CHOP.

“I think this could be a practice-changing result,” said Gilles Salles, MD, PhD, Chief of the Lymphoma Service at Memorial Sloan Kettering Cancer Center (MSK). “This is the first randomized phase III study that has shown a benefit in patients with first-line DLBCL. It shows that it is possible to significantly reduce disease progression, including in patients with difficult-to-treat subtypes.”

R-CHOP, the current standard of care which consists of a combination of rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone, is curative in only about 60-70% of patients with newly diagnosed DLBCL. The new study compared R-CHOP to a modified drug combination that omits vincristine and includes polatuzumab vedotin along with rituximab, cyclophosphamide, doxorubicin, and prednisone (pola-R-CHP). Polatuzumab vedotin was previously approved for treating patients with relapsed DLBCL.

“With this disease, it can be difficult to achieve a cure in some patients with more extensive disease or older age,” said Dr. Salles, pointing to a need for therapies that work better for higher-risk patients. “Despite the fact that a high percentage respond initially to R-CHOP, many ultimately relapse after therapy is completed.”

The trial enrolled 879 patients with previously untreated DLBCL in 23 countries. Half of the participants were randomly assigned to receive pola-R-CHP and half to receive R-CHOP. At two years, 76.7% of those receiving pola-R-CHP and 70.2% of those receiving R-CHOP survived without disease progression or relapse. The trial met its primary endpoint with a 27% reduction in the relative risk of disease progression, relapse, or death associated with pola-R-CHP.

The results also showed a significant improvement with pola-R-CHP in terms of secondary endpoints, event-free survival, and disease-free survival. However, there was no significant difference in the rate of complete response to treatment, which was seen in 78% of those receiving pola-R-CHP and 74% of those receiving R-CHOP, or overall survival at two years (88.7% and 88.6% for pola-R-CHP and R-CHOP, respectively). Researchers noted that further follow-up could help elucidate whether pola-R-CHP brings a survival benefit in the longer term. In either case, Dr. Salles said the new regimen should reduce the risk of relapse and help patients avoid intensive treatments such as stem cell transplantation and chimeric antigen receptor (CAR) T-cell therapy.

Study participants on both treatments experienced a similar rate of adverse events, which included low blood cell counts and peripheral neuropathy, a condition causing weakness, numbness, or pain in the hands and feet. The rate of drug dose reduction or drug discontinuation was similar in both groups. “It is quite satisfying that we were able to improve outcomes without significantly impairing patients’ quality of life,” said Dr. Salles.

The trial will continue to follow participants for insights into longer-term outcomes. In addition, researchers are analyzing patient subgroups to determine whether tumor biology or other factors may influence which patients are likely to benefit most from the new drug combination.

This international study was sponsored by Genentech, Inc. and F. Hoffmann-La Roche Ltd, and designed by the sponsor in collaboration with the cooperative group LYSA (the Lymphoma Study Association).

Dr. Salles has provided consulting and advisory services to Roche and Genentech.


Alok Srivastava, Savita Rangarajan, Kaan Kavakli, et al.

Fitusiran 80 mg once monthly prophylaxis subcutaneously reduced ABR, AsBR, and AJBR (all ~ 90%) in patients with severe hemophilia A or B without inhibitors significantly compared to OD treatment. This also significantly improved the HRQoL.

Read also the ASH PRESS RELEASE:
Study in ASH Late-Breaking Abstracts session may offer patients with severe hemophilia an improved quality of life

(WASHINGTON, Dec. 14, 2021) – Fitusiran, an experimental hemophilia therapy administered through a monthly subcutaneous injection, met its primary endpoint in a phase III trial being presented at the 63rd American Society of Hematology (ASH) Annual Meeting and Exposition. The drug dramatically reduced bleeding events, with half of those receiving it experiencing no bleeds and 85% experiencing an annualized bleed rate of three or fewer bleeds over the study period of about eight months.

Fitusiran is designed to maintain a steady level of the drug starting about four weeks after initiation, thus helping patients form clots (maintain hemostasis) to prevent spontaneous bleeding or stop bleeding after a minor injury.

“This is a new class of drugs that brings a high level of hemostasis, well beyond what we would have imagined,” said Alok Srivastava, MD, of Christian Medical College in Vellore, India. “The convenience of this drug, and the high proportion of people who have zero or only a few bleeds, suggests we can really make a difference in the quality of life for people with severe hemophilia.”

Hemophilia is a rare blood disorder that reduces a person’s ability to clot blood due to a deficiency of FVIII or FIX clotting factors. It can cause serious and debilitating symptoms such as severe pain and uncontrolled bleeding (mostly in joints), and lead to early degeneration of the joints. Standard treatment consists of frequent intravenous infusions of blood clotting factors to prevent bleeds. While this treatment has greatly improved the outlook for people with hemophilia, patients must still be cautious to avoid contact sports that could cause bleeding when their factor levels are low. Nearly a quarter of patients develop inhibitors that counteract the infused clotting factors, a serious complication.

Small interfering RNA (siRNA) therapies are a new class of drugs designed to interfere with the production of specific proteins. Fitusiran, the first siRNA developed for hemophilia, targets antithrombin, a protein that reduces blood clotting, in order to increase clotting ability. Given this mechanism, fitusiran is the first drug for hemophilia which is effective in both FVIII and FIX deficiency even with inhibitors.

For the phase III trial, researchers across 19 countries enrolled 120 males aged 12 or older with severe hemophilia A or B. None of the patients had clotting factor inhibitors and all experienced frequent bleeding on the episodic or on-demand treatment regimen for bleeds that they were following before the study. Two-thirds of participants were randomly assigned to receive fitusiran injections once a month along with factor infusions when needed. The remaining patients continued to receive factor infusions when needed. After the study period ended, these patients could cross over to receive fitusiran.

During the study period, those receiving fitusiran experienced a median of zero bleeds while those in the control group experienced a median of 21.8 bleeds. This translates to a 90% reduction in the annualized bleeding rate with fitusiran, meeting the trial’s primary endpoint.

Participants taking fitusiran also reported a significant improvement in quality of life, which researchers attributed to the reduced frequency of bleeding events and reduced need for disruptive and time-consuming factor infusions and hospital visits.

“With a monthly medication, hemophilia becomes easier to treat,” said Dr. Srivastava. “You can reduce the number of times you have to receive intravenous injections, and the steady blood level of the drug means you can feel safer being more active and perhaps a little less fearful of bleeding in your daily activities.”

Among participants receiving fitusiran, 78.5% experienced adverse events compared with 45% of those in the control group. Fitusiran was associated with an increased rate of elevated liver enzymes, gallbladder inflammation and gallstones, and upper respiratory symptoms, most of which were mild and reversible.

Additional studies are underway to help determine the optimal dosing and frequency for the drug. Dr. Srivastava suggested future studies would also be aimed at guiding the management of special situations such as surgery or trauma in patients taking fitusiran.

The trial was funded by Sanofi, developer of fitusiran.


Margarete A Fabre, Jose Guillherme de Almeida, Edoardo Fiorillo, et al.

The findings provide information about the lifelong natural history of CH as well as fundamental insights into the interactions between somatic mutation, aging, and clonal selection.


Michael R. Bishop, Michael Dickinson, Duncan Purtill, et al.

Please consult the abstract.


Second-Line Tisagenlecleucel or Standard Care in Aggressive B-Cell Lymphoma

M.R. Bishop and Others

Read also the ASH PRESS RELEASE:
Study in ASH Late-Breaking Abstracts session gives new insights into the administration of CAR T-cell therapy

(WASHINGTON, Dec. 14, 2021) – In a phase III trial presented during the 63rd American Society of Hematology (ASH) Annual Meeting and Exposition, the chimeric antigen receptor (CAR) T-cell therapy tisagenlecleucel (tisa-cel) was not found to improve event-free survival over what was seen with standard of care as a second-line treatment for patients with aggressive non-Hodgkin lymphoma. The results, which come as a surprise after previous CAR-T trials have shown improved clinical outcomes, may reflect variability in the patient population, timing and administration of tisa-cel and stem cell transplants, and use of chemotherapy in real-world settings, according to researchers.

In CAR T-cell therapies, a patient’s T cells are removed and a gene for a receptor that binds a specific protein on cancer cells is added to help them find and destroy cancer cells. Then, the modified cells are infused back into the patient. Tisa-cel has previously been found beneficial as a third-line treatment for patients with aggressive non-Hodgkin lymphoma who typically have an extremely poor prognosis. The new study sought to determine whether tisa-cel could offer benefits earlier in the course of treatment as a second-line therapy before attempting a stem cell transplant.

“We were surprised that event-free survival was identical in both study arms,” said Michael R. Bishop, MD, of The David and Etta Jonas Center for Cellular Therapy, University of Chicago. “This suggests there is still a lot to be learned about the proper administration of CAR-T therapies. As this field progresses, we’re learning that there may be more variables to consider as we seek to optimize CAR-T therapies.”

The trial enrolled 322 patients with aggressive B-cell non-Hodgkin lymphoma who did not respond to initial chemotherapy or relapsed within 12 months. Patients were randomly assigned to receive tisa-cel or standard of care, which consisted of chemotherapy followed by an autologous stem cell transplant for patients responding to chemotherapy. The majority of patients randomized to receive tisa-cel also received chemotherapy before their CAR T-cell therapy, a treatment strategy known as “bridging,” at their physician’s discretion. At the time of reporting, researchers had tracked patient outcomes for a median of 10 months.

The results showed no significant difference between study arms for the primary endpoint of event-free survival, defined as death at any time or progressive or stable disease at or after 12 weeks. Twenty-eight percent of patients in both study arms showed a complete response to treatment, and the overall response rate was also similar (46% in those receiving tisa-cel versus 43% in those receiving standard of care).

Researchers identified several factors that may have potentially contributed to the current results. As an international trial conducted in 18 countries, researchers observed some real-world variability in the treatment strategies used in different regions and countries. Use of bridging therapy was not uniform, and this led to more patients with progressive disease at infusion, which was associated with a worse outcome. In particular, patients treated in non-U.S. centers tended to receive more cycles of bridging chemotherapy. Time to infusion was also quite variable; overall, patients waited a median of 52 days for their CAR-T infusion after leukapheresis (the first step in CAR T-cell therapy), which is relatively long given the aggressive nature of the disease. Time to infusion was shorter in the U.S. compared with non-U.S. countries. In addition, patients in the standard of care arm were allowed to receive up to two different regimens before the strategy was considered a failure. Researchers also noted some potentially meaningful differences between the treatment arms in specific patient groups in terms of disease biology and prognostic factors, and they plan to further analyze the data to understand how these factors may have played a role in the results.

“These findings show the importance of doing randomized trials and comparing their results to help improve outcomes for patients,” said Dr. Bishop. “It gives us tremendous insights into the biology of these very aggressive diseases and points to an opportunity to more closely examine many factors, in particular the role and timing of bridging therapy.”

About half of patients randomized to receive standard of care crossed over to receive tisa-cel, with outcomes similar to those found in previous trials of tisa-cel as a third-line therapy in the same patient population. Both patient groups experienced a relatively high rate of adverse events, but the overall safety profile was consistent with previous studies in this patient population. Fatal adverse events occurred in 10 patients who received tisa-cel and 13 who received standard of care.

The investigators are now performing additional analyses to determine factors that may have affected outcomes in both treatment arms.

The study was funded by Novartis Pharmaceuticals Corporation.


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