Despite the fact that a majority of diffuse large B-cell lymphoma (DLBCL) patients respond well to initial chemoimmunotherapy (e.g., combinations containing the CD20-targeting monoclonal antibody rituximab), 10-15 percent will develop primary refractory disease within 3 months after beginning treatment. Additionally, another 20-35 percent of these patients will have a relapse.
Roughly 40-60 percent relapsed or refractory DLBCL patients will respond to second-line chemotherapy; of these, 50 percent will subsequently undergo autologous hematopoietic stem cell transplantation (HSCT), with approximately 30-40 percent remaining progression-free 3 years post-transplantation. Those patients unable to receive high-dose chemotherapy and HSCT as second-line therapy have poor prognoses, with a median overall survival of approximately 4 months.
Good levels of efficacy have been noted for the anti-CD19 CAR T-cell therapy tisagenlecleucel (formerly CTL019) in a phase I/IIa study (NCT01626495) of children and young adults with relapsed or refractory acute lymphoblastic leukemia (ALL). Consequently, in August 2017, the FDA approved tisagenlecleucel for the treatment of ALL patients up to the age of 25 years with disease that is refractory or in second or later relapse. In that same announcement, the FDA also approved for use in patients 2 years of age or older tocilizumab for the treatment of cytokine release syndrome (CRS).
High response rates have also been observed using tisagenlecleucel in adult patients with relapsed or refractory DLBCL in a phase IIa, single-center study (NCT02030834). At 3 months, the response rate was 50 percent, while at 6 months, 43 percent of the patients showed a complete response (CR). For those patients showing a CR at 6 months, none had a relapse at follow-up (a median of 28.6 months) (N Engl J Med 2017;377:2545-2554).
On the basis of this and other studies, the phase II JULIET study (NCT02445248) was initiated to evaluate the safety and efficacy of tisagenlecleucel in adults with relapsed or refractory DLBCL. JULIET is an international study conducted at 27 sites in 10 countries in Asia, Australia, Europe, and North America. Results from this study were published recently (N Engl J Med 2019;380:45-56). One of the participating clinicians in this study is Constantine Tam, MD, Director of Hematology and the Lead for Chronic Lymphocytic Leukemia and Low-Grade Lymphoma Program at Peter MacCallum Cancer Centre and the Victorian Comprehensive Cancer Centre of St. Vincent's Hospital, and Associate Professor at the University of Melbourne.
“This study—along with those of other CD19 CAR-T—indicate that CAR-T is the standard of care for patients unsuitable for autologous transplantation, or those who failed autologous transplantation,” Tam stated. “It represents the only realistic chance of cure and long-term survival for such patients.”
As a result of the findings obtained in this study, in May 2018, the FDA granted approval to tisagenlecleucel for the treatment of adults having relapsed or refractory large B-cell lymphoma after two or more lines of systemic therapy, including DLBCL not otherwise specified, high-grade B-cell lymphoma, and DLBCL arising from follicular lymphoma.
DLBCL Study Background
“Patients with relapsed or refractory DLBCL, particularly those who are not fit enough to undergo autologous stem cell transplantation and those who relapsed after transplantation, have poor survival and no prospect of cure with currently available therapy,” Tam explained. “The main challenge is the refractoriness of the disease—salvage chemotherapy and various investigational agents are only able to temporarily control the disease (if at all) before the lymphoma ultimately progresses aggressively and kills the patient.
“Autologous transplantation provides a cure in approximately 30-40 percent of patients, but patients with short previous remissions (i.e., less than 12 months), those who can't get into complete remission before transplant, and those with adverse biology (e.g., double hit status) have low cure rates of 15 percent or less,” he noted. “Additionally, many patients cannot tolerate autologous transplantation due to age and accompanying comorbidities.”
When asked if there were characteristics associated with DLBCL that made it a good candidate for CAR-T therapy, Tam stated, “Yes—malignant cells overexpress CD19, which is the target of currently available CAR-T therapies. Although there was some initial doubt that an immune-based therapy can treat fast-growing blood cancers, the story in ALL gave us confidence that CAR-T should be effective in DLBCL.”
Methods in JULIET Study
The JULIET study is an international, single-group, open-label, phase II study evaluating the CD19-targeting tisagenlecleucel CAR-T therapy in adults with relapsed or refractory DLBCL. Among the inclusion criteria were the following:
- age of 18 years or older;
- received at least two prior lines of therapy (including rituximab and anthracycline chemotherapy);
- ineligible for or had relapse after autologous transplantation;
- DLBCL or DLBCL having transformed from follicular lymphoma; and
- high-grade B-cell lymphoma patients having rearrangements of MYC plus BCL2, BCL6, or both genes (termed double-hit or triple-hit).
Exclusion criteria included diagnosis of primary mediastinal DLBCL, DLBCL with active central nervous system involvement, prior CD19-targeted therapy, and prior allogenic transplant.
Once eligible patients provided informed written consent, their T cells were isolated via leukapheresis. Their enrollment was considered complete when the isolates were cryopreserved and sent to the appropriate manufacturer for ex vivo modification. If necessary, bridging therapy was permitted for participants. Patients having white cell counts greater than 1,000 cells/mm3 within 1 week prior to tisagenlecleucel infusion received lymphodepletion consisting of either 90 mg/m2 bendamustine daily for 2 days or 25 mg/m2 fludarabine plus 250 mg/m2 cyclophosphamide daily for 3 days. Patients having white cell counts of 1,000 cells/mm3 or less within the same time frame did not require lymphodepleting therapy.
This study's primary endpoint was independent committee-assessed best overall response rate (ORR), which was defined as the percentage of patients displaying a complete or partial response (CR or PR). Secondary endpoints included the following: overall survival (OS), duration of response (DOR), safety measured by adverse events (AEs), and cellular kinetics data (for all patients receiving an infusion). Grading of the potentially serious CRS was done using the University of Pennsylvania scale.
A total of 238 patients were screened and 165 were enrolled in this study between July 2015 and the data cutoff date (Dec. 8, 2017). Of the 165 enrolled patients, 111 (67%) received a tisagenlecleucel infusion; at the time of analysis, four patients (2%) were awaiting infusion.
Infusions were delivered in either an inpatient or an outpatient setting, with the median time between enrollment and infusion being 54 days. A total of 90 percent of participants received an infusion between days 30 and 92 post-enrollment, while the median time between infusion and data cutoff was 14 months (range: 0.1-26 months). For the enrolled patients, the baseline characteristics were similar to those patients who had received an infusion.
“However, the patients who did not receive an infusion tended to have a lower performance status score than those receiving an infusion,” Tam noted. “A greater proportion of the patients who did not receive an infusion had disease that was refractory to the last therapy they received prior to enrollment.”
Prior to infusion, the majority of patients (92%) received bridging therapy, which included combinations of rituximab (54%), gemcitabine (40%), etoposide (26%), dexamethasone (25%), cisplatin (19%), cytarabine (19%), and newer agents such as the Bruton's tyrosine kinase inhibitor ibrutinib (9%) and the immunomodulator lenalidomide (7%). Of the 111 patients who received tisagenlecleucel infusion, 93 percent required lymphodepleting chemotherapy: fludarabine-cyclophosphamide combination (73%) and bendamustine (20%). For the 111 patients receiving a single infusion of tisagenlecleucel, the median dose was 3.0×108 CAR-positive viable T cells (range: 0.1×108-6.0×108).
In the efficacy analysis set, the best ORR was 52 percent (95% CI: 41-62%) for the 93 patients who had 3 months or more of follow-up or had discontinued participation in the study before 3 months. For these responders, 40 percent displayed a CR, while 12 percent showed a PR. The ORR at 3 months and 6 months was 38 percent and 33 percent, respectively, while the rates of CR were 32 percent (3 months) and 29 percent (6 months). Interestingly, the response rates were not appreciably different according to the type of lymphodepleting therapy received.
“Univariate analyses showed a fairly uniform and consistent treatment effect across the major demographic and prognostic subgroups, including the subgroup based on disease response to prior therapy,” Tam added.
As of the data cut-off, the median DOR had not been reached (95% CI: 10 months-not reached), although, 79 percent (95% CI: 60-89%) of those having a CR and 65 percent (95% CI: 49-78%) of all responding patients are projected to be relapse-free at 12 months post-response.
For those patients showing a CR, the median PFS had not been reached as of the data cut-off. Among patients displaying a CR or PR at 3 months, the 12-month estimated rate of PFS was 83 percent. For those patients receiving an infusion of modified T cells, the median OS was 12 months (95% CI: 7 months-not reached). Among patients having a CR, the estimated probability of survival at 12 months was 90 percent (95% CI: 74-96%), while that value was 49 percent (95% CI: 39-59%) for all patients.
In patients displaying a durable response, persistent CAR transgene levels were observed for up to 2 years post-infusion. There was no apparent relationship between dose and maximal in vivo expansion, with clinical responses being obtained over a wide range of doses.
The most commonly observed AEs of any grade included the following: CRS—58 percent; anemia—48 percent; pyrexia—35 percent; lowered neutrophil count—34 percent; lowered platelet count—33 percent; lowered white cell count—33 percent; amd diarrhea—32 percent. Grade 3 or 4 AEs of special interest, observed within the first 8 weeks post-infusion, included: CRS—22 percent; cytopenias (not resolved by day 28)—32 percent; infections—20 percent; neurologic events—12 percent; and febrile neutropenia—15 percent.
“The fact that 54 percent of patients responded (and of these, 40% were CR), and with an updated median follow-up of 19.3 months, 60 percent of patients have maintained their responses with no relapses beyond 12 months,” Tam explained. “This is considered to be indicative of a cure in those patients who responded and do not relapse in the first 12 months.
“With respect to survival—non-responders die very quickly, while responders tend to do rather well. With respect to things that predict response—the exciting thing is that there were none,” Tam observed. “Those with the highest tumor burden (i.e., greater than 100 mL) had only slightly lower response rates, but this was not statistically significant. Otherwise, age, International Prognostic Index, activated B-cell versus germinal center B-cell, double-hit versus not—they responded; furthermore, the oldest patient on study was 76 years old.
“Although CRS occurred in 58 percent of patients,” Tam noted, “grade 3 or 4 CRS occurred in only 22 percent of the patients, and most cases responded to tocilizumab. By monitoring the patients for fever, which is the first symptom of CRS, and ensuring that the syndrome was managed by appropriately trained site personnel using a protocol-specified algorithm, this potentially serious toxicity was controlled without fatal events. No deaths in this study were attributed to tisagenlecleucel, CRS, or cerebral edema.”
Regarding the future directions for evaluating tisagenlecleucel, Tam stated, “One logical avenue is to evaluate this therapy is in earlier lines of treatment—for example, in trials comparing it against autologous transplantation.”
Richard Simoneaux is a contributing writer.
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