Leukemia
is a type of blood cancer of the bone marrow and blood-forming cells. The
result is the production of abnormal blood cells, mostly the white blood cells.
Leukemia is divided into several types based on the speed of growth and the
types of cells the cancer starts in (myeloid cells vs lymphoid cells).
Fast-growing leukemias are considered to be acute. Slower growing leukemias are
considered to be chronic. The classifications of leukemias include acute
lymphocytic leukemia (ALL), acute myelogenous leukemia (AML), chronic
lymphocytic leukemia (CLL), and chronic myelogenous leukemia (CML). ALL and AML are the two most common types of
leukemia found in children. AML and CLL are the two most common types of leukemia
found in adults. Treatment includes a combination of chemotherapy, biologicals,
radiation therapy, and hematopoietic stem cell transplantation (HSCT).
Lymphoma
is also a blood cancer, but is a cancer of the lymphatic system. Lymphomas
account for approximately half of all blood cancers that occur yearly.
Lymphomas are divided into two categories: Hodgkin lymphomas (HLs) and
non-Hodgkin lymphomas (NHLs). NHLs are differentiated as being T-cell lymphomas
or B-cell lymphomas (BCLs). The majority of NHLs are BCLs and can be
categorized as either high-grade cancers that grow quickly or low-grade cancers
that grow slowly. The list of BCLs is numerous and includes diffuse large
B-cell lymphoma (DLBCL), primary mediastinal BCL, follicular lymphoma (FL),
small lymphocytic lymphoma (SLL; this type of cancer is so closely related to
CLL that they are treated the same), mantle cell lymphoma (MCL), and marginal
zone lymphoma (MZL; these include extranodal marginal zone BCL [also known as
mucosa-associated lymphoid tissue lymphoma {MALT; can either be gastric or
non-gastric}], nodal marginal zone BCL, or splenic marginal zone BCL). Like
leukemias, treatment includes a combination of chemotherapy, biologicals,
radiation therapy, and hematopoietic stem cell transplantation (HSCT).
Multiple myeloma (MM) is also a type of blood cancer,
particularly of the plasma cells within the bone marrow. Like leukemia and
lymphoma, the cancer affects the immune system of the individual with the
malignancy. Like leukemia and lymphoma, treatment includes a combination of
chemotherapy, biologicals, radiation therapy, and hematopoietic stem cell
transplantation (HSCT).
Chimeric antibody receptor (CAR) T-cell therapy is a method whereby the T cells (a type of white blood cell) are
altered in a laboratory in order to have them find and destroy cancer cells or other
disease-producing cells. Each dose of CAR T is customized to the individual and
their cancer or disease. The individual's T cells are collected during a
process called leukapheresis and sent to a manufacturing center where they are
genetically modified to include a new CAR-gene. The modified T cells target and bind to the specific protein on the
surface of the antigen causing the cancer or disease and trigger the individual’s
own immune system to help destroy the target. Prior to initiating the CAR T
infusion, individuals undergo lymphodepleting chemotherapy to reduce the
level of white blood cells and help the body accept the reprogrammed CAR T
cells.
AXICABTAGENE CILOLEUCEL (YESCARTA)
On October 18, 2017, the US Food and
Drug Administration (FDA) approved axicabtagene ciloleucel (Yescarta) for the treatment of
adult individuals with relapsed or refractory (R/R) large
B-cell lymphoma after two or more lines of therapy. Axicabtagene ciloleucel
(Yescarta) is the second cluster of differentiation (CD)19-directed genetically modified autologous T-cell
immunotherapy available in the United States. Like tisagenlecleucel (Kymriah),
axicabtagene ciloleucel (Yescarta) is customized to the individual after the T
cells are harvested. The T cells are genetically modified to express a chimeric
antigen receptor that targets CD19-expressing cells.
The
safety and efficacy of axicabtagene ciloleucel (Yescarta) for the
treatment of adult individuals with R/R B-cell NHL were evaluated in a
single arm, open-label, multicenter trial, phase 1/2 trial (ZUMA-1; NCT02348216).
Individuals eligible for the trial had refractory disease to the most recent
therapy or relapse within 1 year of autologous HSCT. The primary endpoint was objective response rate (ORR). Key secondary endpoints included duration of response (DOR) and safety data. Of the
101 individuals who received the axicabtagene ciloleucel (Yescarta) infusion, the ORR was
82 percent (95 percent confidence interval [CI], 73 to 89) with 54 percent
achieving a complete remission (CR) and 28 percent achieving a partial
remission (PR). At the median follow-up of 7.9 months, individuals in CR had not reached the estimated DOR. Grade 3 or
higher adverse events occurred in 95 percent of the individuals. Grade 3 or
higher cytokine-release syndrome (CRS) occurred in 17 percent of individuals and
grade 3 or higher neurologic events occurred in 28 percent of individuals. There
were four deaths, two of which were believed to be related to the infusion. A
long-term follow-up for a median of 27.1 months (range, 25.7 to 28.8) was also
published. The ORR was now 83 percent with a CR of 58 percent and PR of 25
percent. The median DOR was 11.1 months (95 percent CI, 4 to not estimable).
The median PFS was 5.9 months (95 percent CI, 3.3 to 15.0). The median overall
survival (OS) was not reached (95 percent CI, 12.8 to not estimable). No
participants were lost to follow-up.
The safety and efficacy of
axicabtagene ciloleucel (Yescarta) for the treatment of adult individuals with
R/R indolent NHL, including FL and MZL, were evaluated in a single-arm,
open-label, multicenter, phase 2 trial (ZUMA-5; NCT03105336). Individuals
eligible for the trial had indolent NHL, including FL and nodal or extranodal
MZL, that was R/R after two or more previous lines of therapy. Exclusion
criteria included autologous HSCT within the previous 6 months, previous allogeneic
HSCT, previous CD19-targeted therapy, or previous CAR T-cell therapy. Disease
assessments via positron emission tomography-computed tomography (PET-CT) or CT were performed by the investigators and an
independent review committee. The primary endpoint of the trial was ORR. Key secondary endpoints included DOR, PFS, OS, and safety. A total of 153
individuals underwent leukapheresis and 148 were transfused with axicabtagene
ciloleucel (Yescarta). The median follow-up was 17.5 months (range, 14.1 to 22.6). Of 109 individuals who were able to be assessed in the updated analysis,
the ORR was 92 percent [95 percent CI, 85 to 97]) with 83 individuals (76
percent) having a CR. At a cutoff of 18 months, the estimated PFS rate was 64.8
percent (95 percent CI, 54.2 to 73.5). DOR was not reached. At the 18-month
cutoff, the OS rate was 87.4 percent (95 percent CI, 79.2 to 92.5). Among all
individuals who were transfused with axicabtagene ciloleucel (Yescarta), 147
(99 percent) experienced treatment-emergent adverse events with 128 (86
percent) experiencing grade 3 or higher events. CRS occurred in 121 individuals
(82 percent) with grade 3 or higher occurring in 10 individuals (7 percent). Neurological
events occurred in 87 individuals (59 percent) with grade 3 or higher occurring
in 28 individuals (19 percent). A total of 19 individuals died after
transfusion with axicabtagene ciloleucel (Yescarta) but only one death was felt
to be due to the infusion.
The safety and efficacy of axicabtagene ciloleucel (Yescarta) for the treatment of adult individuals with R/R large
B-cell lymphoma versus standard of care (SOC) were evaluated in a randomized,
open-label, multicenter, phase 3 trial (ZUMA-7; NCT03391466). Individuals with
large B-cell lymphoma that had become R/R after no more than 12 months after
receiving first-line chemoimmunotherapy were randomly assigned in a 1:1 ratio to
receive either axicabtagene ciloleucel (Yescarta) or SOC therapy (two or three
cycles of investigator-selected, protocol-defined chemoimmunotherapy; if the
individual responded to the chemoimmunotherapy, they received high-dose
chemotherapy and autologous HSCT). The primary end point of the trial was
event-free survival (EFS) based on assessment by a blinded central reviewer. Key secondary endpoints included OS and response to the treatment. In the trial,
180 individuals were randomly assigned into the axicabtagene ciloleucel
(Yescarta) cohort and 179 individuals into the SOC cohort. At a median follow-up of 24.9 months, the median EFS in the axicabtagene ciloleucel (Yescarta)
cohort was 8.3 months versus 2.0 months in the SOC cohort. The 24-month EFS was
41 percent in the axicabtagene ciloleucel (Yescarta) cohort versus 16 percent
in the SOC cohort (hazard ratio [HR] for event/death, 0.40; 95 percent CI, 0.31 to 0.51; P<0.001). The OS rate at 24 months was 61 percent in the
axicabtagene ciloleucel (Yescarta) cohort and 52 percent in the SOC cohort. A
response occurred in 83 percent of individuals in the axicabtagene ciloleucel
(Yescarta) cohort and 50 percent of individuals in the SOC cohort, with a complete
response occurring in 65 percent of individuals in the axicabtagene ciloleucel
(Yescarta) cohort versus 32 percent in the SOC cohort. Grade 3 or higher
adverse events occurred in 91 percent of individuals in the axicabtagene
ciloleucel (Yescarta) cohort and 83 percent of the SOC cohort. Grade 3 or
higher CRS occurred in six percent and grade 3 or higher neurological events
occurred in 21 percent of individuals receiving axicabtagene ciloleucel
(Yescarta), but no deaths related to either CRS or neurologic events were
reported.
BREXUCABTAGENE AUTOLEUCEL
(TECARTUS)
On July 24, 2020, the FDA approved brexucabtagene autoleucel (Tecartus) for
the treatment of adult individuals with R/R MCL. Brexucabtagene autoleucel (Tecartus) is a CD19-directed
genetically modified autologous T-cell immunotherapy and is customized to
the individual after the T cells are harvested. The T cells are genetically
modified to express a chimeric antigen receptor that targets CD19-expressing
cells.
Safety and efficacy of
brexucabtagene autoleucel (Tecartus) for the treatment of adult
individuals with R/R MCL, who had previously received anthracycline- or
bendamustine-containing chemotherapy, an anti-CD20 antibody, and a Bruton
tyrosine kinase (BTK) inhibitor (ibrutinib or acalabrutinib), were evaluated in a single arm, open-label, multicenter phase 2 trial
(ZUMA-2; NCT02601313). Eligible individuals had disease progression after
their last regimen or refractory disease to their most recent therapy. A
total of 74 individuals were enrolled. Brexucabtagene autoleucel (KTE-X19) was manufactured for 71 individuals and administered
to 68. The primary efficacy analysis showed that 93 percent (95 percent
CI, 84 to 98) had an objective response as assessed by an
independent radiologic review committee with 67 percent (95 percent CI,
53 to 78) having a CR. At a median follow-up of
12.3 months (range, 7.0 to 32.3), 57 percent of the 60 individuals in the
primary efficacy analysis were in remission. At 12 months, the estimated PFS and OS were
61 percent and 83 percent, respectively. Common adverse events
of grade 3 or higher were cytopenias (in 94 percent of the
individuals) and infections (in 32 percent). Grade 3 or higher CRS and neurologic events occurred in
15 percent and 31 percent of individuals, respectively; none
were fatal.
The safety and efficacy of brexucabtagene autoleucel (Tecartus) for the treatment
of adult individuals with ALL were evaluated in
a single-arm, open-label, multicenter, phase 1/2 trial (ZUMA-3; NCT02614066).
Individuals were eligible for treatment if they had primary refractory ALL, had a first relapse after a remission that lasted 1 year or less, had R/R ALL
after second- or higher-line of therapy, or R/R ALL 100 days or more after
allogeneic HSCT. A total of 71
individuals were enrolled. Brexucabtagene autoleucel (KTE-X19) was manufactured
for 65 individuals and administered to 55. The primary endpoint was the rate of
overall CR or CR with incomplete hematological recovery by central assessment.
Fifty-six percent of the individuals achieved a CR (95 percent CI, 37.8 to 65.7) and 15 percent of the individuals achieved a CR with incomplete
hematological recovery. Median OS was 18.2 months in the treated individuals
and was not reached in individuals who responded to the treatment. All the
treated individuals experienced at least one adverse event. Grade 3 or higher
cytopenia occurred in 76 percent of individuals, CRS occurred in 89 percent of
individuals, and neurological events occurred in 60 percent of individuals. Six
of the treated individuals (11 percent) died secondary to grade 5 adverse
events, with two of these believed to be treatment related.
CILTACABTAGENE
AUTOLEUCEL (CARVYKTI)
On February
28, 2022, the FDA approved ciltacabtagene autoleucel (Carvykti) for the treatment of adult individuals with R/R
MM after four or more prior lines of therapy, including a
proteasome inhibitor, an immunomodulatory agent, and an anti-CD38 monoclonal
antibody. Ciltacabtagene autoleucel (Carvykti) is a B-cell maturation antigen (BCMA)-directed
genetically modified autologous T-cell immunotherapy.
The safety
and efficacy of ciltacabtagene autoleucel (Carvykti) for the treatment of adult
individuals with MM were evaluated in a single-arm, open-label, multicenter,
phase 1b/2 trial (CARTITUDE-1; NCT03548207). Individuals were eligible for
treatment if they had a diagnosis of R/R MM and had received three or more
previous lines of therapy or were double-refractory to a proteasome inhibitor and
an immunomodulatory drug, and had received a proteasome inhibitor, an immunomodulatory
drug, and an anti-CD38 antibody. One of the primary endpoints was overall
response rates along with safety data. Key secondary endpoints included DOR and PFS. A total of 113 individuals were enrolled in
the study and 97 individuals received the ciltacabtagene autoleucel (Carvykti)
infusion. The overall response rate was 97 percent (95 percent CI, 91.2 to 99.4
in 94 of 97 individuals). A stringent complete response was achieved by 65
individuals (67 percent). Neither median DOR (95 percent CI, 15.9 to not
estimable) nor median PFS (95 percent CI, 16.8 to not estimable) was reached as
of the data cut-off (median follow-up, 12.4 months). At 1 year, the PFS
was 77 percent (95 percent CI, 66.0 to 84.3) and overall survival rate was 89
percent (95 percent CI, 80.2 to 93.5). All of the transfused individuals
experienced an adverse event, with hematological adverse events being the most
common. CRS occurred in 95 percent (92 of 97) of individuals, but only four
percent were grade 3 or 4. Fourteen individuals died during the study, with six
of these believed to be treatment related.
The safety and efficacy of ciltacabtagene autoleucel (Carvykti) for the treatment of adult individuals with MM who were refractory to lenalidomide were evaluated in a phase 3, randomized, open-label study (CARTITUDE-4; NCT04181827) versus the provider’s choice of effective standard therapy (pomalidomide, bortezomib, dexamethasone [PVd] or daratumumab, pomalidomide, dexamethasone [DPd]) in individuals who had received one to three lines of prior therapy that included a proteasome inhibitor and an immunomodulatory drug. The primary endpoint was PFS up to 6 years or death due to any cause, whichever occurred first. Key secondary endpoints included ORR and percentage of individuals with CR or better (stringent CR). A total of 419 individuals were randomly assigned in a 1:1 ratio to treatment with ciltacabtagene autoleucel (Carvykti) or standard therapy. At a median follow-up of 15.9 months, the medium PFS was not reached for the ciltacabtagene autoleucel (Carvykti) cohort versus 11.8 months for the standard therapy cohort (P<0.0001). The ORR was 84.6 percent for the ciltacabtagene autoleucel (Carvykti) cohort versus 67.8 percent for the standard therapy cohort (P<0.0001). The percentage of individuals that experienced a complete response or better in the ciltacabtagene autoleucel (Carvykti) cohort was 74.1 percent versus 22.3 percent for the standard therapy cohort (P<0.0001). Of the individuals in the ciltacabtagene autoleucel (Carvykti) cohort, 76.1 percent experienced CRS; 1.1 percent grade 3 or 4, none grade 5. The percentage of adverse events were similar between the two cohorts.
IDECABTAGENE
VICLEUCEL (ABECMA)On February
28, 2022, the FDA approved idecabtagene vicleucel (Abecma) for the treatment of adult individuals with R/R MM after four or more prior lines of therapy, including a proteasome
inhibitor, an immunomodulatory agent, and an anti-CD38 monoclonal antibody. Idecabtagene
vicleucel (Abecma) is a BCMA-directed genetically
modified autologous T-cell immunotherapy.The safety
and efficacy of idecabtagene vicleucel (Abecma) for the treatment of adult
individuals with MM were evaluated in a single-arm, open-label, multicenter,
phase 2 trial (KarMMa; NCT03361748). Individuals were eligible for treatment if
they had a diagnosis of R/R MM and had received three or more previous lines of
therapy including an immunomodulatory agent, a proteasome inhibitor, and an
anti-CD38 monoclonal antibody. The primary endpoint was an overall response of
partial response or better. A key secondary end point was the rate of complete
response or better. A total of 140 individuals were enrolled with 128
individuals being transfused with target doses of 150 × 106 CAR T
cells, 300 × 106 CAR T cells, or 450 × 106 CAR T cells.
Ninety-two percent of the individuals had received a prior autologous HSCT. At
a median follow-up of 13.3 months (range, 0.2 to 21.2), 94 individuals (73
percent; 95 percent CI, 66 to 81) had a response to the infusion (P<0.001),
and 42 individuals (33 percent) had a complete or stringent complete response.
The median DOR for any dose was 10.7 months (95 percent CI, 9.0 to 11.3) with a
median DOR of 11.3 months (95 percent CI, 10.3 to 11.4) for the 450 × 106 cohort. The median PFS
for any dose was 8.8 months (95 percent CI, 5.6 to 11.6), with a PFS of 12.1
months (95 percent CI, 8.8 to 12.3) for the 450 × 106 cohort. All of
the individuals who were transfused reported adverse events, with 99 percent (127
of 128) experiencing grade 3 or 4 events that were mostly hematological. Infections
occurred in 88 individuals (69 percent). CRS occurred in 107 individuals (84
percent) with most being grade 1 or 2. A total of 44 individuals (34
percent) died during the study period, with four of these believed to be treatment
related.
The safety and efficacy of idecabtagene
vicleucel (Abecma) for the treatment of adult individuals with R/R MM who had
received two to four prior lines of therapy, including an immunomodulatory agent, a
proteasome inhibitor, and daratumumab, and were refractory to the most recent
regimen were evaluated in a phase 3, randomized, open-label study (KarMMa-3; NCT03651128) versus
the provider’s choice of effective standard therapy (daratumumab, pomalidomide,
dexamethasone [DPd], daratumumab, bortezomib, dexamethasone [DVd], ixazomib,
lenalidomide, dexamethasone [Ird], carfilzomib, dexamethasone [Kd], elotuzumab,
pomalidomide, dexamethasone [EPd] depending on what treatment the individual
had previously received. The primary endpoint was PFS. Key secondary endpoints
included ORR and the percentage of individuals who achieved a CR or better
(stringent CR). A total of 386 individuals were randomly assigned in a 2:1 ratio to
treatment with idecabtagene vicleucel (Abecma) or standard therapy. At a median
follow-up of 18.6 months, the median PFS was 13.3 months in the idecabtagene
vicleucel (Abecma) cohort versus 4.4 months in the standard treatment cohort
(P<0.0001). The ORR was 71 percent for the idecabtagene vicleucel (Abecma)
cohort versus 42 percent for the standard therapy cohort (P<0.0001). The
percentage of individuals in the idecabtagene vicleucel (Abecma) cohort who
achieved CR or better was 98 percent versus 7 percent in the standard therapy
cohort. In the idecabtagene vicleucel (Abecma) cohort, 88 percent experienced
CRS, with five percent being grade 3 or higher. The percentage of adverse events
were higher in the idecabtagene vicleucel (Abecma) cohort than in the standard
therapy cohort, but were consistent with previous studies. No new safety
signals were identified.
LISOCABTAGENE
MARALEUCEL (BREYANZI)
On February
5, 2021, the FDA approved lisocabtagene maraleucel (Breyanzi) for the treatment of adult
individuals with R/R large B-cell lymphoma after two or more lines of systemic
therapy, including DLBCL not otherwise specified
(including DLBCL arising from indolent lymphoma), high-grade B-cell lymphoma,
primary mediastinal large B-cell lymphoma, and FL grade 3B.
Lisocabtagene maraleucel (Breyanzi) is a CD19-directed genetically modified
autologous T-cell immunotherapy. During the lisocabtagene maraleucel (Breyanzi)
manufacturing process, CD8+ and CD4+ T cells are selected from leukapheresis
material and then independently activated, transduced, and expanded. Both of
these are then infused into the individual.
The safety
and efficacy of lisocabtagene maraleucel (Breyanzi) for the treatment of adult
individuals with R/R large B-cell lymphoma after two or more lines of systemic therapy were evaluated in a single-arm,
open-label, multicenter phase 1 trial (TRANSCEND-NHL-001; NCT02631044). Primary
endpoints were ORR assessed by an independent review
committee, adverse events, and dose-limiting toxicities. A total of 344
individuals underwent leukapheresis, with 269 individuals being transfused with
target doses of 50 × 106 CAR T cells (one or two doses), 100 × 106
CAR T cells, or 150 × 106 CAR T cells, and 25 individuals
received an infusion of a nonconforming CAR T-cell product (i.e., one
component did not meet criteria). At a median follow-up of 18.8 months (95
percent CI, 15.0 to 19.3), an ORR was achieved by 186 individuals (73 percent;
95 percent CI, 66.8 to 78.0; P<0.0001) in the efficacy-evaluable set (256
individuals who had received the infusion and had PET-positive disease) with a
CR being achieved in 136 individuals (53 percent; 95 percent CI, 46.8 to 59.4;
P<0.0001). The median DOR was not reached at a median follow-up of 12 months
(95 percent CI, 11.2 to 16.7). The median PFS was 6.8 months (95 percent CI,
3.3 to 14.1) after a median follow-up of 12.3 months. Median OS was 21.1 months
(95 percent CI, 13.3 to not estimable) after a median follow-up of 17.5 months
(95 percent CI, 12.9 to 17.8). CRS occurred in 113 individuals (42 percent)
with grade 3 or higher occurring in six individuals (two percent). Nine
individuals (six percent) experienced a dose-limiting toxicity including one
individual who died from diffuse alveolar damage after receiving a dose of 50 × 106 CAR T cells. A total of seven individuals (three percent) of the
total individuals who were infused died from treatment-emergent event.
On June 24, 2022, the FDA approved lisocabtagene maraleucel (Breyanzi) for the treatment of adult individuals with refractory large B-cell lymphoma to first-line chemoimmunotherapy or relapse within 12 months of first-line chemoimmunotherapy who were eligible for autologous HSCT. This was based on a randomized, parallel-group, open-label, multicenter phase 3 trial (TRANSFORM; NCT03575351). A total of 184 individuals were divided 1:1 into two cohorts. One cohort received a standard of care (SOC) regimen, and the other cohort received lisocabtagene maraleucel (Breyanzi). The primary endpoint was EFS. Secondary endpoints were CRR, PFS, OS, ORR, DOR, and adverse events. At the interim data analysis, the median EFS for the lisocabtagene maraleucel (Breyanzi) cohort was 10.1 months (95 percent CI, 6.1 to not reached) compared to 2.3 months (95 percent CI, 2.2 to 4.3) for the SOC cohort; P<0.0001. The CRR for the lisocabtagene maraleucel (Breyanzi) cohort was 66 percent (95 percent CI, 56 to 76) versus 39% (95 percent CI, 29 to 50) for the SOC cohort. The ORR in the lisocabtagene maraleucel (Breyanzi) cohort was 85 percent (95 percent CI, 77 to 92) versus 48 percent (95 percent CI, 37 to 59) in the SOC cohort. The most common grade 3 or worse adverse event was neutropenia in 80 percent of the lisocabtagene maraleucel (Breyanzi) cohort and 51 percent of the SOC cohort. Grade 3 CRS occurred in one percent, and neurological events occurred in four percent of individuals treated with lisocabtagene maraleucel (Breyanzi). There were no treatment-related deaths in the lisocabtagene maraleucel (Breyanzi) cohort and one treatment-related death in the SOC cohort.
The safety and efficacy of lisocabtagene maraleucel (Breyanzi) in adult individuals with R/R large B-cell lymphoma after first-line treatment and who were ineligible for HSCT (based on age, performance status, and/or comorbidities) were studied in TRANSCEND-PILOT (NCT03483103). This was a single-arm, open-label, multicenter phase 2 study that enrolled 61 participants. The primary endpoint was ORR; the secondary endpoints were CRR, DOR, PFS, EFS, OS, and adverse events. The ORR was 80 percent (95 percent CI, 68 to 89): P<0.0001. At a median follow-up of 13.0 months, the median PFS was 9.03 months (95 percent CI, 4.17 to not reached). At a median follow up of 15.5 months, the median DOR was 12.09 months (95 percent CI, 6.24 to not reached). In the intention-to-treat population, the CRR was 46 percent (95 percent CI, 34 to 58). In this same group, the median EFS was 8.15 months (95 percent CI, 4.37 to 13.34). Median OS was not reached. CRS occurred in 38 percent (one grade 3) of participants and neurological events occurred in 31 percent (three grade 3) of individuals. There were no grade 4 events and no deaths.
The safety and efficacy of lisocabtagene maraleucel (Breyanzi) in adult individuals with R/R CLL or SLL after two or more lines of therapy for individuals with high-risk features, or after three or more lines of therapy for individuals with standard-risk features was studied in a phase 1/2 open-label study (TRANSCEND CLL 004; NCT03331198). The individuals were required to have received a Bruton tyrosine kinase (BTK) inhibitor and a BCL2 inhibitor as part of their prior therapy. The phase 1 portion of the study was the dose-finding portion of the study that determined the dose of lisocabtagene maraleucel (Breyanzi) that would be used in the phase 2 portion of the study. The primary endpoint of the phase 2 portion of the study was the ORR or remission at 24 months. Key secondary endpoints were DOR, PFS, and OS. Of the 113 individuals who underwent leukapheresis, 94 received lisocabtagene maraleucel (Breyanzi). The ORR was 45 percent. The median DOR was 35.3 months. The median PFS was 11.9 months. The median OS was 30.3 months. In individuals who received lisocabtagene maraleucel (Breyanzi), nine percent experienced grade 3 CRS; none experienced grade 4 or 5. One death from macrophage activation syndrome-hemophagocytic lymphohistiocytosis (MAS/HLH) was believed to be related to treatment. There was a higher incidence of CRS and neurological events in treated individuals, which is consistent with other studies in individuals with CLL.
The safety and efficacy of lisocabtagene maraleucel (Breyanzi) in adult individuals with R/R FL after two or more lines of therapy were studied in a phase 2 open label study (TRANSCEND FL; NCT04245839). The individuals were required to have received an anti-CD20 and alkylating agent as part of their prior therapy. The primary endpoint was ORR. Key secondary endpoints included the percentage of CRs and DOR. Of the 114 individuals who underwent leukapheresis, 107 received lisocabtagene maraleucel (Breyanzi). The ORR was 95.7 percent. The CR rate was 73.4 percent. At a median of 18 months, the DOR has not been reached. CRS occurred in 58 percent of treated individuals, but only 1 percent was grade 3 with none being grade 4 or 5. Two deaths were felt to be treatment related. One was from MAS/HLH, and the other was due to progressive multifocal leukoencephalopathy after the 90-day treatment-emergent period.
The safety and efficacy of lisocabtagene maraleucel (Breyanzi) in adult individuals with R/R MCL after two or more lines of therapy was studied in a phase 1 open label study (TRANSCEND-NHL 001, MCL cohort; NCT NCT02631044). The individuals were required to have received an alkylating agent, a BTK inhibitor, and either rituximab or other CD20-targeted agent as part of their prior therapy. A key primary endpoint included ORR at 24 months. Key secondary endpoints included percentage of CRs and DOR. Of the 89 individuals who underwent leukapheresis, 71 received lisocabtagene maraleucel (Breyanzi). The ORR was 85.3 percent. The CR rate was 67.6 percent. The median DOR was 13.3 months. CRS was reported in 61 percent of treated individuals with one percent being grade 4, and none being grade 3 or 5. Only one death was considered to be related to treatment.
TISAGENLECLEUCEL (KYMRIAH)
On August 30, 2017, the FDA approved tisagenlecleucel (Kymriah)
for the treatment of
individuals up to 25 years old with B-cell precursor ALL that is refractory or in second or later stage relapse. Tisagenlecleucel
(Kymriah) is a CD19-directed genetically modified autologous T-cell
immunotherapy.The efficacy and safety of
tisagenlecleucel (Kymriah) in pediatric and young adult individuals
with R/R B-cell ALL were evaluated
in
a single-arm, open-label, multicenter, phase 2 study (ELIANA; NCT02435849). Enrolled individuals had to
have received at least one prior line of therapy. The
primary outcome of this trial is the ORR within 3
months of infusion of tisagenlecleucel (Kymriah). Secondary outcomes included DOR, EFS, OS, and safety. Of 92
individuals who were enrolled, 75 received an infusion. Of the 75
individuals
infused with tisagenlecleucel (Kymriah) and who had at least 3 months of
follow-up, the ORR was 81 percent (95 percent CI, 71 to 89) with 45 individuals (60 percent) achieving CR and 16 individuals (21 percent) having CR with incomplete
hematologic recovery and all of them were minimal residual disease (MRD) negative. DOR was defined as the time since onset of CR to
relapse or death due to underlying cancer, whichever is earlier. A median
duration of remission DOR was not reached by any of the 61 individuals
who
achieved a CR or CR with incomplete hematologic recovery. The rate of
relapse-free survival was 80 percent (95 percent CI, 65 to 89) at 6 months
and 59 percent (95 percent CI, 41 to 73) at 12 months. The rate of EFS at 6 months was 73 percent (95 percent CI, 60 to 82) and at 12 months was 50 percent
(95 percent CI, 35 to 64) with median EFS not being achieved. The rate of OS
for all 75 individuals who received an infusion was 90 percent (95 percent CI,
81 to 95) at 6 months and 76 percent (95 percent CI, 63 to 86) at 12 months.
Of the 75 individuals who received an infusion, 71 (95 percent) experienced an
adverse event that was believed to be related to the infusion. CRS occurred in 77
percent of the individuals who received an infusion, and neurologic events
occurred in 40 percent. Nineteen individuals died after receiving an
infusion, but only three were believed to be due to the infusion.
On May 1, 2018, the FDA approved tisagenlecleucel (Kymriah) for the treatment of adults with R/R DLBCL after at least two prior lines of therapy. The efficacy
and safety of tisagenlecleucel (Kymriah) were evaluated in an open-label, single-arm multicenter,
phase 2 trial (JULIET; NCT02445248). The
study included adults with R/R DLBCL who had received two or
more lines of chemotherapy, including rituximab and anthracycline, or were ineligible
for autologous HSCT or had relapsed following autologous HSCT. The primary endpoint was ORR. Key secondary endpoints included DOR, OS, and safety data. A total of 165
individuals were enrolled and 111 received an infusion. Of the 93 individuals
in the efficacy analysis set (individuals who had received an infusion and who
were able to be followed up for at least 4 months after), the ORR was 52
percent (95 percent CI, 41 to 62) with 40 percent obtaining a CR and 12 percent
a PR. The median DOR was not reached (95 percent CI, 10 months to not
estimable). The estimated rate of PFS at 12 months was 83 percent. The median
OS among individuals who had received an infusion was 12 months (95 percent CI,
7 months to not reached). The percentage of individuals who received an
infusion who experienced grade 3 or higher CRS was 22 percent. The percentage
of these individuals who experienced a neurologic event of grade 3 or higher
was 12 percent. Although three individuals died after receiving an infusion, none
of these were due to the infusion but were from disease progression. On May 27, 2022, the FDA approved tisagenlecleucel (Kymriah) for the treatment of adults with R/R FL after two or more lines of systemic therapy. This indication was approved under accelerated approval and continued approval may be contingent upon verification and description of clinical benefit in confirmatory trials. The efficacy and safety of tisagenlecleucel (Kymriah) were evaluated in an open-label, single-arm multicenter, phase 2 trial (ELARA; NCT03568461). The study included 98 adults with R/R FL grades 1 to 2 who had previously received two or more lines of treatment or had relapsed after autologous HSCT. Individuals were not eligible for the study if they had previously undergone allogeneic HSCT or had active CNS malignancy. The primary endpoint was CRR. Key secondary endpoints included ORR, DOR, PFS, OS, and safety. Based on interim data, the CRR was 69.1 percent (95 percent CI, 58.8 to 78.3). The ORR was 86.2 percent (95 percent CI, 77.5 to 92.4). The data for the other secondary endpoints have not matured yet. At the time of the publication of the data, the rate of CRS was 48.5 percent (with none grade 3 or higher) and the rate of neurological events was 37.1 percent (3 percent were grade 3 or higher). There have not been any treatment-related deaths. OFF-LABEL INDICATIONS
There may be additional indications contained in the Policy section of this document due to evaluation of criteria highlighted in the Company’s off-label policy, and/or review of clinical guidelines issued by leading professional organizations and government entities.