In the 54th American Society of Hematology (ASH) annual meeting,
from more than 30 countries, more than 17,000 experts and scholars in
the field of hematology and exchanges around the world to listen to from
basic research to clinical treatment experience and progress. For
lymphoma, the current ASH meeting described as having a "revolutionary"
or "epoch-making" significance - for the first time explicitly put
forward the traditional sense of the treatment of lymphoma chemotherapy may reduce, and even the "away from the chemotherapy" possible.
"Lymphoma traditional chemotherapy may reduce" the ideas put forward is based on the tumor cell surface antigens against lymphoid, intracellular signaling pathways and cellular microenvironment targeting drug research has made significant progress, especially against B-cell receptor (BCR) signaling pathway BTK kinase inhibitor ibrutinib clinical studies, the drug in indolent and aggressive B-cell lymphoma have received satisfactory results, and its efficiency and low toxicity characteristics may even change our understanding Ⅰ the traditional understanding of the clinical study, namely "maximum tolerated dose" may no longer be targeted drug era Ⅰ clinical research objectives.
For the same pathway downstream target of PI3K kinase inhibitor, idelalisib (CAL-101, GS-1101) is particularly prominent in this meeting, a new targeted drugs. Indolent B-cell lymphoma drug in Phase Ⅰ clinical study showed a better efficacy and safety, but also large-scale clinical studies are in discussion.
By the new or old bare antibodies derived from several types of competing antibody coupled to emerge, especially for anti-B-cell lymphoma CD79B and anti-CD22 antibody coupled, both combined with anti-tubulin drugs MMAE, coupled with anti-CD30 antibody SGN35 exactly the same, and their effects are worthy rival. Other drugs such as histone deacetylase inhibitors (HDACi) combined with chemotherapy, or in combination with other targeted agents in mantle cell lymphoma (MCL) and follicular lymphoma (FL) application also shows good prospects. Here's the new drug in three aspects of clinical applications briefly.
Indolent B-cell lymphoma
BTK inhibitor ibrutinib
BTK tyrosine kinase inhibitor ibrutinib
(PCI-32765) in indolent B-cell lymphoma in the excellent efficacy and good safety is not news. The annual report of the drug treatment of relapsed or refractory chronic lymphocytic leukemia (CLL) of Ⅰ b / Ⅱ clinical study results: either 420 mg or 840 mg group group, the effective rate reached 70%. The drug even in 17p-, large lumps, nucleoside chemotherapy drug resistance in patients also received the same treatment. Although the follow-up time is not long enough, but the patient remission time can be as long as several years. The drug in previously untreated CLL / small lymphocytic lymphoma (SLL) in patients with Ⅰ b / Ⅱ clinical study also received a 74% total efficiency (ORR).
Ibrutinib treatment of recurrent FL Ⅰ clinical studies have also shown good efficacy, 16 patients were treated with rituximab and a variety of chemotherapy regimens, including even autologous stem cell transplantation. Doses ≥ 2.5 mg / kg, ORR reached 54.5%, the effective duration of 12.3 months, median progression-free survival (PFS) of 13.4 months, the side effects can be tolerated.
PI3-kinase δ inhibitor
PI3-kinase δ inhibitor (GS-1101, CAL-101) alone or in combination with rituximab ± bendamustine treatment of relapsed or refractory indolent B-cell lymphoma have achieved good initial results, the report 76 patients in the three groups were efficiency of 77%, 85% and 77%, 1-year PFS rate of over 75%, well tolerated.
R2 program
The conference announced the "Rituximab + Lenalidomide" (ie R2 program also known as R-squared, or R-squared solution) treatment of indolent B-cell lymphoma of the latest research results become the hottest topic world. The study enrolled a total of all types of untreated advanced indolent lymphoma 110 patients, lenalidomide dose of 20 mg daily orally for 21 days, rituximab 375 mg/m2, every 28 days repeated dose , a total of six cycles, effective in patients up to 12 cycles. In 103 cases evaluable patients, ORR reached 90%, FL patients is as high as 98%, complete remission (CR) rate of 87%, adverse reactions was well tolerated.
This is the first proof of lymphoma, a simple combination of targeted drugs targeted drugs can surpass previous chemotherapy regimens. Currently compare R2 and rituximab Union
Combined chemotherapy for indolent B-cell lymphoma of randomized controlled clinical study has commenced, China will also join this clinical study. To R2-based, targeted, or in combination with other chemotherapeutic agents in the treatment of various combinations of indolent B-cell lymphoma related research are being or will be, or even been extended to a variety of aggressive B-cell lymphoma, the results seen.
A new generation of anti-CD20 mAb
GA101 and ofatumumab, a new generation anti-CD20 monoclonal antibody used to treat patients with newly diagnosed and relapsed FL. Germany GAUDI Ⅰ clinical studies have shown, GA101 and cyclophosphamide, doxorubicin, vincristine, prednisone (CHOP) programs or bendamustine combination with first-line treatment for patients with FL satisfactory outcome, ORR were 95% and 92.7%. The other one is prompted Ⅱ clinical study, ofatumumab and CHOP regimen combined with treatment-naïve patients with FL, in the median follow-up 33.8 months, even the follicular lymphoma international prognostic index (FLIPI) 3 ~ 5 minutes patients whose PFS period is also up to 27.6 months.
Other
U.S. one Ⅱ clinical study found that the humanized anti-PD-1 monoclonal antibody with rituximab combined with relapsed patients with FL, ORR was 60%, CR rate of 52%, and well tolerated by patients . Another clinical study was conducted in patients with relapsed FL and MCL application deacetylase inhibitor PCI-24781, ORR was 40%, and even if the drug is also effective in patients with relapsed multiple times, 3 to 4 degrees of cytopenia The incidence of <20%.
Targeted drugs, especially targeted small molecule drugs on the efficacy of aggressive B-cell lymphoma is still significant thin, targeted drug combinations of two or more programs to become aggressive B-cell lymphoma clinical research programs of the mainstream.
"Lymphoma traditional chemotherapy may reduce" the ideas put forward is based on the tumor cell surface antigens against lymphoid, intracellular signaling pathways and cellular microenvironment targeting drug research has made significant progress, especially against B-cell receptor (BCR) signaling pathway BTK kinase inhibitor ibrutinib clinical studies, the drug in indolent and aggressive B-cell lymphoma have received satisfactory results, and its efficiency and low toxicity characteristics may even change our understanding Ⅰ the traditional understanding of the clinical study, namely "maximum tolerated dose" may no longer be targeted drug era Ⅰ clinical research objectives.
For the same pathway downstream target of PI3K kinase inhibitor, idelalisib (CAL-101, GS-1101) is particularly prominent in this meeting, a new targeted drugs. Indolent B-cell lymphoma drug in Phase Ⅰ clinical study showed a better efficacy and safety, but also large-scale clinical studies are in discussion.
By the new or old bare antibodies derived from several types of competing antibody coupled to emerge, especially for anti-B-cell lymphoma CD79B and anti-CD22 antibody coupled, both combined with anti-tubulin drugs MMAE, coupled with anti-CD30 antibody SGN35 exactly the same, and their effects are worthy rival. Other drugs such as histone deacetylase inhibitors (HDACi) combined with chemotherapy, or in combination with other targeted agents in mantle cell lymphoma (MCL) and follicular lymphoma (FL) application also shows good prospects. Here's the new drug in three aspects of clinical applications briefly.
Indolent B-cell lymphoma
BTK inhibitor ibrutinib
BTK tyrosine kinase inhibitor ibrutinib
(PCI-32765) in indolent B-cell lymphoma in the excellent efficacy and good safety is not news. The annual report of the drug treatment of relapsed or refractory chronic lymphocytic leukemia (CLL) of Ⅰ b / Ⅱ clinical study results: either 420 mg or 840 mg group group, the effective rate reached 70%. The drug even in 17p-, large lumps, nucleoside chemotherapy drug resistance in patients also received the same treatment. Although the follow-up time is not long enough, but the patient remission time can be as long as several years. The drug in previously untreated CLL / small lymphocytic lymphoma (SLL) in patients with Ⅰ b / Ⅱ clinical study also received a 74% total efficiency (ORR).
Ibrutinib treatment of recurrent FL Ⅰ clinical studies have also shown good efficacy, 16 patients were treated with rituximab and a variety of chemotherapy regimens, including even autologous stem cell transplantation. Doses ≥ 2.5 mg / kg, ORR reached 54.5%, the effective duration of 12.3 months, median progression-free survival (PFS) of 13.4 months, the side effects can be tolerated.
PI3-kinase δ inhibitor
PI3-kinase δ inhibitor (GS-1101, CAL-101) alone or in combination with rituximab ± bendamustine treatment of relapsed or refractory indolent B-cell lymphoma have achieved good initial results, the report 76 patients in the three groups were efficiency of 77%, 85% and 77%, 1-year PFS rate of over 75%, well tolerated.
R2 program
The conference announced the "Rituximab + Lenalidomide" (ie R2 program also known as R-squared, or R-squared solution) treatment of indolent B-cell lymphoma of the latest research results become the hottest topic world. The study enrolled a total of all types of untreated advanced indolent lymphoma 110 patients, lenalidomide dose of 20 mg daily orally for 21 days, rituximab 375 mg/m2, every 28 days repeated dose , a total of six cycles, effective in patients up to 12 cycles. In 103 cases evaluable patients, ORR reached 90%, FL patients is as high as 98%, complete remission (CR) rate of 87%, adverse reactions was well tolerated.
This is the first proof of lymphoma, a simple combination of targeted drugs targeted drugs can surpass previous chemotherapy regimens. Currently compare R2 and rituximab Union
Combined chemotherapy for indolent B-cell lymphoma of randomized controlled clinical study has commenced, China will also join this clinical study. To R2-based, targeted, or in combination with other chemotherapeutic agents in the treatment of various combinations of indolent B-cell lymphoma related research are being or will be, or even been extended to a variety of aggressive B-cell lymphoma, the results seen.
A new generation of anti-CD20 mAb
GA101 and ofatumumab, a new generation anti-CD20 monoclonal antibody used to treat patients with newly diagnosed and relapsed FL. Germany GAUDI Ⅰ clinical studies have shown, GA101 and cyclophosphamide, doxorubicin, vincristine, prednisone (CHOP) programs or bendamustine combination with first-line treatment for patients with FL satisfactory outcome, ORR were 95% and 92.7%. The other one is prompted Ⅱ clinical study, ofatumumab and CHOP regimen combined with treatment-naïve patients with FL, in the median follow-up 33.8 months, even the follicular lymphoma international prognostic index (FLIPI) 3 ~ 5 minutes patients whose PFS period is also up to 27.6 months.
Other
U.S. one Ⅱ clinical study found that the humanized anti-PD-1 monoclonal antibody with rituximab combined with relapsed patients with FL, ORR was 60%, CR rate of 52%, and well tolerated by patients . Another clinical study was conducted in patients with relapsed FL and MCL application deacetylase inhibitor PCI-24781, ORR was 40%, and even if the drug is also effective in patients with relapsed multiple times, 3 to 4 degrees of cytopenia The incidence of <20%.
Targeted drugs, especially targeted small molecule drugs on the efficacy of aggressive B-cell lymphoma is still significant thin, targeted drug combinations of two or more programs to become aggressive B-cell lymphoma clinical research programs of the mainstream.
Aggressive B-cell lymphoma
Diffuse large B-cell lymphoma (DLBCL) treatment could surpass R-CHOP program? With DLBCL basic research, as well as for the "two-hit" and "three strike" DLBCL cognitive improvement, to further improve the living conditions of patients with DLBCL and efficacy has become possible. The efficacy of several new drugs have been created, such as BTK inhibitors has shown a good trend in relapsed or refractory non-germinal center type DLBCL has gained 40% of the single-agent efficiency. Anti-CD22 antibody and anti-CD79B antibody coupled, Bcl-2 inhibitor ABT-199, and R2-CHOP have also achieved good effect, and accordingly has launched a much larger and more diverse clinical study.
Although the efficacy and prognosis of patients with MCL is still not optimistic, enhance chemotherapy and even stem cell transplantation is still dominant, but in the bendamustine combined with rituximab (BR) program, based on further joint bortezomib meters or BTK inhibitor, Bcl-2 inhibitors, may have been a viable option. BTK inhibitor ibrutinib in relapsed or refractory MCL in monotherapy efficiency even up to 60%, which goes beyond any previous treatment regimens and efficacy of drugs.
However, compared with indolent B-cell lymphoma, targeted drugs, especially small molecular targeted drugs in aggressive B-cell lymphoma efficacy is still noticeable thin, targeted drug combinations of two or more programs to become aggressive B-cell lymphoma research program of the mainstream, but even so, over a longer period of time is still dominated chemotherapy is an indisputable fact.
T / NK cell lymphoma
SGN35
SGN35 is an antibody - Drug coupling agent, has now expanded to anaplastic large cell lymphoma in first-line treatment, and extended to other CD30 + T-cell lymphoma treatment. Some scholars have reported SGN35 monotherapy in relapsed or refractory anaplastic large cell lymphoma (ALCL) phase Ⅱ study the latest follow-up results. 58 patients, the median age was 52 years (14 to 76 years), 72% of ALK-, 62% of primary drug resistance cases, 26% of autologous hematopoietic stem cell transplantation losers. ORR was 86%, CR rate of 59%, with a median follow-up time was 22.8 months, the median duration of treatment was 13.2 months. Median PFS was 14.6 months, and median overall survival (OS) of not reached. ALK status has nothing to do with the PFS.
Fanale and other reports SGN35 combined initial treatment with CHOP-risk ALCL (including ALCL and ALK-of IPI ≥ 2, ALK + of ALCL) and other CD30 + peripheral T-cell lymphoma (PTCL), multi-center Phase Ⅰ findings. 26 cases of patients enrolled, the median age was 55.5 years (21 to 82 years), 19 cases of ALCL, 7 cases of other CD30 + of PTCL. ORR was 100%, CR rate was 88%, well tolerated by patients. The researchers are planning to conduct Ⅲ randomized controlled study comparing SGN35 combination with CHOP and CHOP PTCL initial treatment efficacy.
Mogamulizumab
Mogamulizumab (KW-0761) is a humanized anti-CCR4 monoclonal antibody by going to play fucosylated of antibody-dependent cell-mediated cytotoxicity (ADCC) function. Previous studies showed that the treatment of relapsed or refractory adult T-cell lymphoma / leukemia (ATLL) an ORR of 50%. The drug in 2012 was approved for marketing in Japan for the treatment of relapsed or refractory ATLL.
Perhaps in the near future, only the rational combination of several types of targeted drugs can cure some patients with lymphoma, or aggressive lymphoma into chronic disease patients without chemotherapy can make high-quality long-term survival.
At this meeting, the Japanese study group reported a mogamulizumab monotherapy CCR4 + relapsed or refractory PTCL and cutaneous T-cell lymphoma (CTCL), multi-center phase Ⅱ study. 37 cases of patients enrolled, the median age was 64 years (33 to 80 years), PTCL29 cases, CTCL 8 例, ORR was 35%, CR rate of 14%. Researchers believe mogamulizumab acceptable monotherapy efficacy, toxicity can be tolerated, further clinical studies should be carried out.
Romidepsin
Romidepsin is a HDACi, has been the U.S. Food and Drug Administration (FDA) approved for the treatment of relapsed or refractory PTCL and CTCL. Coiffier reported a phase Ⅱ study (GPI-06-0002) of the latest follow-up results. 130 cases of relapsed or refractory PTCL patients received romidepsin monotherapy (14 mg/m2, d1, 8,15, q28d) treatment of 6 cycles, ORR was 25%, CR rate was 15%, with a median treatment duration of 28 months. 19 cases were CR or CR in patients with uncertain 25.8 months median follow-up after
13 cases (68%) remained in remission.
French Dupuis reported romidepsin in combination with CHOP initial treatment of PTCL Ⅰ b clinical study (Ro-CHOP) results. CHOP with standard doses, romidepsin 10 mg/m2, d1, 8, 18 patients were enrolled previously untreated patients with PTCL, which Buffett shaped peripheral T-cell lymphoma (PTCL-NOS) 10 cases of angioimmunoblastic T-cell lymphoma ( AITL) 4 cases, other PTCL 4 cases, 17 cases of advanced stage. ORR was 78%, partial response (PR) rate was 21.4%, CR rate was 57.1%, toxicity can be tolerated. In this result, the dose adjustment phase Ⅱ study (romidepsin 12 mg/m2, d1, 8) in progress.
Bortezomib panbinostat
Preclinical studies have shown that proteasome inhibitors and synergy between HDACi. Tan (Tan) and other reports bortezomib panbinostat (another HDACi) treatment of relapsed or refractory PTCL is a multi-center phase Ⅱ study interim results. 11 patients with a median age of 52 years (35 to 72 years), before receiving different types of chemotherapy, the median value of 2 (1 to 3), 27% of patients received prior autologous hematopoietic stem cell transplantation. ORR was 54.5%, CR rate was 18%, PR 36%, median PFS of 6 months after stopping the median time to tumor progression was 2.5 months, toxicity can be tolerated. Based on these results, this research continues into the group, taking into account the effects after discontinuation of short duration, follow-up studies should be considered when selecting maintenance therapy to prolong patient benefit.
Cancer treatment philosophy is changing, increasingly strong voice targeted therapy, perhaps in the near future, merely rational combination of several targeted drugs can cure some patients with lymphoma, or transformed into chronic aggressive lymphoma diseases, thus obviating the need chemotherapy can allow patients access to quality long-term survival. We believe this will make ASH annual day in the near future!
Diffuse large B-cell lymphoma (DLBCL) treatment could surpass R-CHOP program? With DLBCL basic research, as well as for the "two-hit" and "three strike" DLBCL cognitive improvement, to further improve the living conditions of patients with DLBCL and efficacy has become possible. The efficacy of several new drugs have been created, such as BTK inhibitors has shown a good trend in relapsed or refractory non-germinal center type DLBCL has gained 40% of the single-agent efficiency. Anti-CD22 antibody and anti-CD79B antibody coupled, Bcl-2 inhibitor ABT-199, and R2-CHOP have also achieved good effect, and accordingly has launched a much larger and more diverse clinical study.
Although the efficacy and prognosis of patients with MCL is still not optimistic, enhance chemotherapy and even stem cell transplantation is still dominant, but in the bendamustine combined with rituximab (BR) program, based on further joint bortezomib meters or BTK inhibitor, Bcl-2 inhibitors, may have been a viable option. BTK inhibitor ibrutinib in relapsed or refractory MCL in monotherapy efficiency even up to 60%, which goes beyond any previous treatment regimens and efficacy of drugs.
However, compared with indolent B-cell lymphoma, targeted drugs, especially small molecular targeted drugs in aggressive B-cell lymphoma efficacy is still noticeable thin, targeted drug combinations of two or more programs to become aggressive B-cell lymphoma research program of the mainstream, but even so, over a longer period of time is still dominated chemotherapy is an indisputable fact.
T / NK cell lymphoma
SGN35
SGN35 is an antibody - Drug coupling agent, has now expanded to anaplastic large cell lymphoma in first-line treatment, and extended to other CD30 + T-cell lymphoma treatment. Some scholars have reported SGN35 monotherapy in relapsed or refractory anaplastic large cell lymphoma (ALCL) phase Ⅱ study the latest follow-up results. 58 patients, the median age was 52 years (14 to 76 years), 72% of ALK-, 62% of primary drug resistance cases, 26% of autologous hematopoietic stem cell transplantation losers. ORR was 86%, CR rate of 59%, with a median follow-up time was 22.8 months, the median duration of treatment was 13.2 months. Median PFS was 14.6 months, and median overall survival (OS) of not reached. ALK status has nothing to do with the PFS.
Fanale and other reports SGN35 combined initial treatment with CHOP-risk ALCL (including ALCL and ALK-of IPI ≥ 2, ALK + of ALCL) and other CD30 + peripheral T-cell lymphoma (PTCL), multi-center Phase Ⅰ findings. 26 cases of patients enrolled, the median age was 55.5 years (21 to 82 years), 19 cases of ALCL, 7 cases of other CD30 + of PTCL. ORR was 100%, CR rate was 88%, well tolerated by patients. The researchers are planning to conduct Ⅲ randomized controlled study comparing SGN35 combination with CHOP and CHOP PTCL initial treatment efficacy.
Mogamulizumab
Mogamulizumab (KW-0761) is a humanized anti-CCR4 monoclonal antibody by going to play fucosylated of antibody-dependent cell-mediated cytotoxicity (ADCC) function. Previous studies showed that the treatment of relapsed or refractory adult T-cell lymphoma / leukemia (ATLL) an ORR of 50%. The drug in 2012 was approved for marketing in Japan for the treatment of relapsed or refractory ATLL.
Perhaps in the near future, only the rational combination of several types of targeted drugs can cure some patients with lymphoma, or aggressive lymphoma into chronic disease patients without chemotherapy can make high-quality long-term survival.
At this meeting, the Japanese study group reported a mogamulizumab monotherapy CCR4 + relapsed or refractory PTCL and cutaneous T-cell lymphoma (CTCL), multi-center phase Ⅱ study. 37 cases of patients enrolled, the median age was 64 years (33 to 80 years), PTCL29 cases, CTCL 8 例, ORR was 35%, CR rate of 14%. Researchers believe mogamulizumab acceptable monotherapy efficacy, toxicity can be tolerated, further clinical studies should be carried out.
Romidepsin
Romidepsin is a HDACi, has been the U.S. Food and Drug Administration (FDA) approved for the treatment of relapsed or refractory PTCL and CTCL. Coiffier reported a phase Ⅱ study (GPI-06-0002) of the latest follow-up results. 130 cases of relapsed or refractory PTCL patients received romidepsin monotherapy (14 mg/m2, d1, 8,15, q28d) treatment of 6 cycles, ORR was 25%, CR rate was 15%, with a median treatment duration of 28 months. 19 cases were CR or CR in patients with uncertain 25.8 months median follow-up after
13 cases (68%) remained in remission.
French Dupuis reported romidepsin in combination with CHOP initial treatment of PTCL Ⅰ b clinical study (Ro-CHOP) results. CHOP with standard doses, romidepsin 10 mg/m2, d1, 8, 18 patients were enrolled previously untreated patients with PTCL, which Buffett shaped peripheral T-cell lymphoma (PTCL-NOS) 10 cases of angioimmunoblastic T-cell lymphoma ( AITL) 4 cases, other PTCL 4 cases, 17 cases of advanced stage. ORR was 78%, partial response (PR) rate was 21.4%, CR rate was 57.1%, toxicity can be tolerated. In this result, the dose adjustment phase Ⅱ study (romidepsin 12 mg/m2, d1, 8) in progress.
Bortezomib panbinostat
Preclinical studies have shown that proteasome inhibitors and synergy between HDACi. Tan (Tan) and other reports bortezomib panbinostat (another HDACi) treatment of relapsed or refractory PTCL is a multi-center phase Ⅱ study interim results. 11 patients with a median age of 52 years (35 to 72 years), before receiving different types of chemotherapy, the median value of 2 (1 to 3), 27% of patients received prior autologous hematopoietic stem cell transplantation. ORR was 54.5%, CR rate was 18%, PR 36%, median PFS of 6 months after stopping the median time to tumor progression was 2.5 months, toxicity can be tolerated. Based on these results, this research continues into the group, taking into account the effects after discontinuation of short duration, follow-up studies should be considered when selecting maintenance therapy to prolong patient benefit.
Cancer treatment philosophy is changing, increasingly strong voice targeted therapy, perhaps in the near future, merely rational combination of several targeted drugs can cure some patients with lymphoma, or transformed into chronic aggressive lymphoma diseases, thus obviating the need chemotherapy can allow patients access to quality long-term survival. We believe this will make ASH annual day in the near future!
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