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Annual inventory of new drugs and new protocols approved by the FDA for hematologic malignancies in 2022

 Last Update: 2023-02-03
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February 28, 012022

The FDA approved ciltacabtagene autoleucel for the treatment of adult patients
with relapsed or refractory multiple myeloma who have received ≥ 4 lines of therapy, including proteasome inhibitors [PIs], immunomodulators [IMiD], and anti-CD38 monoclonal antibodies.

THE APPROVAL IS BASED ON THE CARTITUDE-1 STUDY, DETAILS OF WHICH CAN BE STAMPED: FDA UPDATE | Approved ciltacabtagene autoleucel for patients with relapsed or refractory multiple myeloma

The recommended dose range for Ciltacabtagene autoleuce is 0.
5-1.
0×10⁶ CAR-T cells/kg, with a maximum dose of 1×10⁸ CAR-T cells
per infusion.

April 1, 022022

FDA approved axicabtagene ciloleucel for use in adult patients with large B-cell lymphoma (LBCL) refractory to first-line chemoimmunotherapy or relapsed within 12 months of first-line chemoimmunotherapy, and is not intended for the treatment of patients
with primary central nervous system lymphoma.

The approval is based on the ZUMA-7 study, a randomized, open-label, multicenter trial
of adult patients with primary refractory LBCL or relapse within 12 months of completion of first-line therapy.
Patients are not being treated for relapsed or refractory lymphoma and are candidates for autologous hematopoietic stem cell transplantation (ASCT).

A total of 359 patients were randomized 1:1 to receive fludarabine and cyclophosphamide lymphocyte debulking chemotherapy followed by a single infusion of axicabtagene ciloleucel or to receive second-line standard therapy, including 2 or 3 cycles of chemoimmunotherapy, followed by high-dose chemotherapy and ASCT
in patients who achieved complete or partial response.

The primary efficacy measure was event-free survival (EFS)
as determined by an Independent Review Committee (IRC).
EFS was significantly longer in the axicabtagene ciloleucel group, with a hazard ratio (HR) of 0.
40 (95% CI: 0.
31, 0.
51; stratified p-< 0.
0001).

。 The estimated 18-month EFS rates were 41.
5% (95% CI: 34.
2, 48.
6) and 17.
0% (95% CI: 11.
8, 23.
0) in the axicabtagene ciloleucel group and standard care groups, respectively, and the estimated median EFS was 8.
3 months (95% CI: 4.
5, 15.
8) and 2.
0 months (95% CI: 1.
6, 2.
8),
respectively 。 Of those randomized to standard care, 35% received ASCT; Lack of response to chemotherapy is the most common reason
for not receiving HSCT.
The best objective response rate assessed by IRC in the axicabtagene ciloleucel group was significantly higher than in the standard care group, at 83% (95% CI: 77, 88) and 50% (95% CI: 43, 58),
respectively.

The prescribing information for axicabtagene ciloleucel has a boxed warning
about cytokine release syndrome (CRS) and neurotoxicity.
In studies of patients with non-Hodgkin lymphoma treated with axicabtagene ciloleucel, the incidence of CRS was 90% (grade ≥3, 9%) and the incidence of neurotoxicity was 78% (grade ≥3, 25%)
.
The most common non-laboratory adverse reactions (incidence ≥30%) were CRS, fever, hypotension, encephalopathy, fatigue, tachycardia, headache, nausea, febrile neutropenia, diarrhea, musculoskeletal pain, infection of unknown pathogen, chills, and decreased
appetite.

The recommended dose of axicabtagene ciloleucel is 2x10 per kilogram of^body weight for 6 chimeric antigen receptor (CAR)-positive live T cells and up to 2x10^{for 8} CAR-positive live T cells
.

May 20, 032022

FDA approved azacitidine for the treatment of pediatric patients
with newly diagnosed juvenile myelomonocytic leukemia (JMML).

The approval is based on the AZA-JMML-001 study, as detailed in the FDA Update | Azacitidine is approved for the treatment of patients with juvenile myelomonocytic leukemia (JMML).

The recommended dose is 2.
5 mg/kg for patients from 1 month to under 1 year of age or < 10 kg in body weight, and 75 mg^{/m for} patients ≥ 1 year of age and weighing ≥ 10
kg2.

February 042022, 5

The FDA approved ivosidenib in combination with azacitidine for use in newly diagnosed patients
with acute myeloid leukemia (AML) with susceptible IDH1 mutations.

The approval is based on the AG120-C-009 study, details of which can be stamped: FDA Update | Approval of ivosnib in combination with azacitidine for the treatment of newly diagnosed patients with acute myeloid leukemia

The recommended dose of ivoranib is 500 mg orally once daily, with or without food, until disease progression or intolerable toxicity
.
Evoridib is started on day 1 of cycle 1, combined with azacitidine 75 mg/^m2 subcutaneously or intravenously (28 days as a cycle)
on days 1-7 (or days 1-5 and 8-9) of each cycle.
For patients who have no disease progression or do not develop intolerable toxicity, treatment is recommended for at least 6 months to allow for a clinical response
.

February 052022, 5

FDA accelerated approval of tisagenlecleucel for the treatment of adult patients
with relapsed or refractory follicular lymphoma (FL) following ≥ 2-line systemic therapy.

The approval is based on the ELARA study, details of which can be stamped: FDA Update | Tisagenlecleucel is approved for use in patients with relapsed or refractory follicular lymphoma

The recommended dose of tisagenlecleucel is 0.
6-6.
0x10⁸CAR-positive live T cells
.

February 062022, 6

FDA approved Lisocabtagene maraleucel for refractory first-line chemoimmunotherapy or relapse within 12 months of first-line chemoimmunotherapy; or adult patients with large B-cell lymphoma (LBCL) refractory to first-line chemoimmunotherapy or relapsed after first-line chemoimmunotherapy and who are not suitable for HSCT due to comorbidities or age
, are not suitable for the treatment of patients with primary central nervous system lymphoma.

The TRANSFORM study was a randomized, open-label, multicenter trial evaluating the efficacy of adult patients with primary refractory LBCL or relapse within 12 months of achieving complete remission (CR) with first-line therapy
.
Patients are not being treated for relapsed or refractory lymphoma and are candidates for ASCT.

A total of 184 patients were randomized in a 1:1 ratio to receive fludarabine and cyclophosphamide lymphocyte debulking chemotherapy followed by a single infusion of Lisocabtagene maraleucel or receive second-line standard therapy, including three cycles of chemoimmunotherapy, followed by high-dose chemotherapy and ASCT
in patients who achieved complete and partial response.
The primary efficacy measure was event-free survival (EFS)
as determined by an Independent Review Committee (IRC).

EFS was significantly longer in the Lisocabtagene maraleucel group, with a hazard ratio (HR) of 0.
34 (95% CI: 0.
22, 0.
52; p-value <0.
0001).

。 The estimated 1-year EFS rates were 45% (95% CI: 29, 59) and 24% (95% CI: 14, 35) in the Lisocabtagene maraleucel and standard care groups, respectively, and the estimated median EFS was 10.
1 months (95% CI: 6.
1, not assessable) and 2.
3 months (95% CI: 2.
2, 4.
3),
respectively.
Of the patients randomized to standard care, 47% received ASCT as planned, and lack of response to chemotherapy was the most common reason
for not receiving HSCT.
Progression-free survival as assessed by IRC in the Lisocabtagene maraleucel group was also significantly longer, with an HR of 0.
41 (95% CI: 0.
25, 0.
66; p-value 0.
0001).

Efficacy was also evaluated in the PILOT study, a single-arm, open-label, multicenter trial
conducted in patients with LBCL who relapsed or were refractory to transplantation after first-line chemoimmunotherapy.
The study enrolled patients
who were not suitable for high-dose chemotherapy and HSCT due to organ function or age, but had sufficient organ function for CAR-T cell therapy.
Efficacy is based on CR rates and duration of response (DOR)
as determined by IRC.
Of the 74 patients (median age 73 years) who underwent leukoapheresis, 61 (82%) received lisocabtagene maraleucel, of which 54% (95% CI: 41, 67) achieved CR.

The median DOR (95% CI: 11.
2 months, not achieved) was not achieved in patients who achieved CR and 2.
1 months (95% CI: 1.
4, 2.
3)
in patients with PR.

Due to the risk of fatal cytokine release syndrome (CRS) and neurotoxicity, the FDA approved Lisocabtagene maraleucel with risk assessment and mitigation strategies
.
In the study of Lisocabtagene maraleucel as a second-line treatment for LBCL, 45% of patients developed CRS (≥3, 1.
3%) and 27% (grade 3, 7%) developed neurotoxicity
.
Serious adverse reactions
occurred in 33% to 38% of patients.

The recommended dose for second-line therapy with Lisocabtagene maraleucel is 90-110×10 6 CAR-positive T cells with a ratio of CD4 and CD8 components of 1:1
.

February 072022, 8

The FDA approved ibrutinib for children with chronic graft-versus-host disease (cGVHD) who ≥ 1 year of age who have failed prior ≥-line systemic therapy, including capsules, tablets, and oral suspensions
.

The approval is based on the iMAGINE study, please stamp for details: FDA UpdateApproval of ibrutinib in children with chronic graft-versus-host disease

The recommended dose of ibrutinib is 420 mg orally once daily for cGVHD patients aged ≥ 12 years and 240 mg/m2 orally once daily (maximum 420 mg) for cGVHD patients aged 1 to¹² years until cGVHD progresses, underlying malignancy recurs, or intolerable toxicity
.

February 082022, 8

FDA approved pemigatinib for use in adult patients
with relapsed or refractory myeloid/gonorrhea tumors (MLN) with fibroblast growth factor receptor 1 (FGFR1) rearrangement.

The approval is based on the FIGHT-203 study, please stamp for details: FDA UpdateApproval of pemigatinib for the treatment of relapsed or refractory myeloid/gonorrhea tumors with FGFR1 rearrangement

The recommended dose of pemitinib is 13.
5 mg orally once daily until disease progression or intolerable toxicity
.

February 092022, 10

FDA accelerated approval of the B-cell maturation antigen (BCMA)/CD3 bispecific T cell adaptor teclistamab-cqyv for adults with relapsed or refractory multiple myeloma (prior to at least four-line therapy, including proteasome inhibitors, immunomodulators, and anti-CD38 monoclonal antibodies).

The approval is based on the MajesTEC-1 study, please stamp the FDA Update | Approval of TeclistAMAB-CQYV for the treatment of relapsed or refractory multiple myeloma

The recommended dose for TECshamb-CQYV is 0.
06 mg/kg subcutaneously on day 1, 0.
3 mg/kg on day 4, 1.
5 mg/kg subcutaneously on day 7, and then 1.
5 mg/kg weekly until disease progression or intolerable toxicity
.

February 102022, 11

The FDA approved bbutuximab in combination with doxorubicin, vincristine, etoposide, prednisone, and cyclophosphamide for the treatment of untreated, high-risk classic Hodgkin lymphoma (cHL) children
≥ 2 years of age.

For details, please stamp: FDA UpdateApproval of vebutuximab in combination with chemotherapy for the treatment of children with classic Hodgkin lymphoma

For children 2 years of age and older, the recommended dose of vebutuximab is 1.
8 mg/kg, up to 180 mg, in combination with AVEPC once every 3 weeks, up to 5 doses
.

February 112022, 11

The FDA approves a new dosing regimen
for asparaginase erwinia chrysanthemi (recombinant) [Asparaginase (recombinant) asparaginase]-rywn.
In the new protocol, patients are injected intramuscularly with A.
chrysanthemum (recombinant) asparaginase 25 mg/m2 on Monday and Wednesday morning, and 50 mg/^m2
intramuscularly on Friday afternoon.
It is also approved to be administered every 48 hours at a dose of 25 mg/^m2
.

In June 2021, the FDA approved Chrysanthemum ensemble (recombinant) asparaginase-rywn as an integral part of a multi-agent chemotherapy regimen in children and adults with acute lymphoblastic leukemia (ALL) and lymphoblastic lymphoma (LBL) allergic to E.
coli-derived
asparaginase (≥ 1 month).

JZP458-201 (NCT04145531) is an open-label, multicenter study that evaluated the pharmacokinetics of Asparaginase-rywn in 225 patients with Recombinant Juwn administered by A.
chrysanthemum (recombinant) Asparaginase-rywn at different doses and routes to predict serum asparaginase activity
at different time points.

The primary efficacy endpoint was to achieve and maintain serum asparaginase activity nadir (NSAA) ≥0.
1 units/mL
.
The study data showed that the proportion of patients who maintained NSAA ≥ 0.
1 U/mL after intramuscular injection of 25 mg/m2 on Wednesday morning was 91.
6% (95% CI: 90.
4%, 92.
8%), and the proportion after 50 mg/m2 intramuscular injection on Friday afternoon was 91.
4% (95% CI: 90.
1%,^{92.
6}%)
.

In terms of safety, all patients treated with the recommended dose as a component of multi-agent chemotherapy developed neutropenia, anemia, or thrombocytopenia
.
The most common non-hematologic adverse reactions (incidence >20%) in patients were abnormal liver function tests, nausea, musculoskeletal pain, infection, fatigue, headache, febrile neutropenia, fever, bleeding, stomatitis, abdominal pain, decreased appetite, drug hypersensitivity, hyperglycemia, diarrhea, pancreatitis, and hypokalemia
.

February 122022, 12

FDA approved olutasidenib for adult patients
with relapsed/refractory (R/R) acute myeloid leukemia (AML) susceptible to isocitrate dehydrogenase-1 (IDH1) mutations.

Study 2102-HEM-101 (NCT02719574) is an open-label, single-arm, multicenter clinical study that included 147 adults with
R/R AML with IDH1 mutations.
Olutasidenib is administered orally 150 mg twice daily until disease progression, intolerable toxicity, or hematopoietic stem cell transplantation
.
The median duration of treatment was 4.
7 months (range: 0.
1 to 26 months).

Sixteen (11%) patients received hematopoietic stem cell transplantation
after olutasidenib treatment.

The primary endpoints were complete response (CR) rate + CR with partial haematological recovery (CRh), duration of CR + CRh, and conversion from transfusion-dependent to non-dependent
.
The study data showed that the CR+CRh rate was 35% (95% confidence interval [CI]: 27%, 43%), including 32% CR and 2.
7% CRh
.
The median time to CR+CRh was 1.
9 months (range: 0.
9 to 5.
6 months) and the median duration of CR+CRh was 25.
9 months (95% CI: 13.
5 months, not reached).

Of the 86 patients who relied on red blood cell (RBC) and/or platelet transfusion at baseline, 29 (34%) became RBC and platelet transfusion-free
within 56 days of baseline.
Of the 61 patients who did not rely on RBC and platelet transfusions at baseline, 39 (64%) remained transfusion-free for 56 days after baseline
.

In terms of safety, the most common adverse reactions (≥20%) were nausea, fatigue/malaise, arthralgia, constipation, leukocytosis, dyspnea, fever, rash, mucositis, diarrhea, and elevated
aminotransferases.
Prescribing information has a boxed warning
alerting healthcare professionals and patients to a possible risk of fatal differentiation syndrome.

The recommended dose of olutasidenib is 150 mg orally twice daily on an empty stomach (at least 1 hour before or 2 hours after meals) until disease progression or the appearance of intolerable toxicity
.
For patients without disease progression or intolerable toxicity, treatment is recommended for at least 6 months to achieve clinical remission
.

On December 22, 132022, the FDA accelerated approval of mosunetuzumab-axgb, a CD20×CD3 bispecific antibody, for adults with relapsed/refractory (R/R) follicular lymphoma (FL) after ≥ 2 lines of systemic therapy
.

GO29781 (NCT02500407) is an open-label, multicenter, multicohort study to evaluate the efficacy
of mosunetuzumab-axgb in patients with R/R FL who have previously received ≥ 2 lines of systemic therapy, including anti-CD20 monoclonal antibodies and alkylating agents.

The primary efficacy endpoint was objective response rate (ORR).

The data showed that the ORR of 90 patients with evaluable efficacy was 80% (95% CI: 70, 88) and 60% achieved complete remission
.
The median follow-up for responders was 14.
9 months, the estimated median duration of response (DOR) was 22.
8 months (95% CI: 10, not reached), and the estimated DOR rates at 12 and 18 months were 62% and 57%,
respectively.

Prescribing information has a boxed warning
about cytokine release syndrome (CRS) that is severe or life-threatening.
Of the 218 patients treated with the recommended dose of mosunetuzumab-axgb, 39% developed CRS, 39% developed neurotoxic adverse reactions (including 1% of immune effector cell-associated neurotoxic syndromes [ICANS]), 17% developed serious infections, and 4% developed tumor-burning reactions
.
Grade 2, 3, and 4 CRS occurred in 15%, 2%, and 0.
5%,
respectively.

The most common adverse reactions (≥20%) in 218 patients were CRS, fatigue, rash, fever, and headache
.
The most common grade 3 to 4 laboratory abnormalities (≥10%) are low lymphocyte count, low phosphate, elevated glucose, low neutrophil count, elevated uric acid, low white blood cell count, low haemoglobin, and low
platelets.

The recommended dose of mosunetuzumab-AXGB is 1 mg on day 1 of cycle 1, 2 mg on day 8 of cycle 1, 60 mg on day 15 of cycle 1, 60 mg on day 1 of cycle 2, and 30 mg
on day 1 of subsequent cycles.
One treatment cycle is 21 days with 8 cycles of continuous dosing until intolerable toxicity or disease progression
.
After 8 cycles, patients with complete remission should discontinue treatment
.
Patients with partial remission or stable disease receive up to 17 cycles of treatment until disease progression or intolerable toxicity
.
Reference source: Finishing: Quinta Typesetting: Quinta Execution: Cherry

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