Abstract
Romidepsin (histone deacetylase inhibitor), lenalidomide (immunomodulatory agent), and carfilzomib (proteasome inhibitor), have efficacy and lack cumulative toxicity in relapsed/refractory lymphoma.
We performed two investigator initiated sequential phase I studies to evaluate the maximum tolerated dose (MTD) of romidepsin and lenalidomide (regimen A) and romidepsin, lenalidomide, and carfilzomib (regimen B) in relapsed/refractory lymphoma. Cohorts in T-cell lymphoma (TCL), B-cell lymphoma (BCL) were enrolled at the MTD.
49 patients were treated in study A (27 TCL, 17 BCL, 5 HL) and 27 (16 TCL, 11 BCL) in study B. The MTD of regimen A was romidepsin 14 mg/m2 IV on days 1, 8, and 15 and lenalidomide 25 mg oral on days 1-21 of a 28-day cycle. The MTD of regimen B was romidepsin 8mg/m2 on days 1 and 8, lenalidomide 10mg oral on days 1-14 and carfilzomib 36mg/m2 IV on days 1 and 8 of a 21-day cycle. In study A, 94% had AEs ≥Grade 3, most commonly neutropenia (49%), thrombocytopenia (53%), and electrolyte abnormalities (49%). In study B 59% had AEs ≥Grade 3, including thrombocytopenia (30%) and neutropenia (26%).
In study A the ORR was 49% (50% TCL, 47% BCL, 50% HL). In study B the ORR was 48% (50% TCL, 50% BCL). For study A and B the median progression free survival (PFS) was 5.7 months and 3.4 months respectively with 11 patients proceeding to allogeneic transplant.
The combinations of romidepsin and lenalidomide and of romidepsin, lenalidomide and carfilzomib showed activity in relapsed/refractory lymphoma with an acceptable safety profile.
Keywords: T-cell lymphoma, romidepsin, lenalidomide, B-cell lymphoma, histone deacetylase inhibitors, carfilzomib
Introduction
Relapsed and refractory B- and T-cell lymphomas remain an ongoing challenge with repeated courses of cytotoxic chemotherapy often yielding diminishing returns. Therefore, novel non-chemotherapeutic approaches for non-Hodgkin lymphoma are of significant clinical interest.
Romidepsin, lenalidomide and carfilzomib have independently shown clinical activity in lymphomas and have demonstrated synergy in preclinical studies. In an effort to develop more effective therapeutic platforms and combination regimens, we investigated the safety and preliminary activity of combinations of romidepsin with lenalidomide and subsequently romidepsin, lenalidomide and carfilzomib in sequential studies.
Romidepsin is a potent histone deacetylase (HDAC) inhibitor which is FDA approved for the treatment of relapsed/refractory peripheral T-cell lymphoma (PTCL) and cutaneous T-cell lymphomas (CTCL) with single agent response rates of 25% and 34% in the pivotal trials respectively.1,2 While romidepsin has not been studied as a single agent in B-cell lymphomas, other HDAC inhibitors have shown modest clinical activity in early phase studies of B-cell lymphomas.3–6 7,8
Lenalidomide is an immunomodulatory drug (IMiD) that is FDA approved for multiple hematologic malignancies and has demonstrated activity across several lymphoma histologies.9–13 Studies of lenalidomide alone in Hodgkin lymphoma and aggressive and indolent B-cell lymphoma showed an overall response rate of 50%, 33% and 23% respectively but with complete response rates less than 15%.10,11,14,15 Studies of single agent lenalidomide in relapsed PTCL and CTCL showed an overall response rate of 22-42%.16–21 Carfilzomib is a second generation, irreversible proteasome inhibitor approved for treatment of multiple myeloma with weekly dosing.22
Preclinical studies have suggested that these three classes of agents may be synergistic. In Burkitt lymphoma, preclinical studies of lenalidomide combined with valproic acid, a histone deacetylase inhibitor, showed synergistic apoptosis.23 In T-cell lymphoma cell lines lenalidomide and romidepsin may be synergistic with regards to induction of apoptosis through generation of reactive oxygen species, caspase activation, and downregulation of PI3K/AKT and MAPK/ERK pathways.24,25 Furthermore, in multiple myeloma cells, a combination of lenalidomide with panobinostat, another HDAC inhibitor, has shown additive activity in both in vitro and in vivo models.26,27 In patients with relapsed/refractory multiple myeloma, the combination of a histone deacetylase inhibitor, vorinostat, in combination with lenalidomide has shown an acceptable safety profile with an overall response rate of 47%. 28
In xenograft models of diffuse large B-cell lymphoma and multiple myeloma, synergy was seen with the addition of a novel HDACi with bortezomib.29,30 Other groups have shown that in multiple myeloma models, the combination of lenalidomide with proteasome inhibitors demonstrate significant synergy.31,32
This provided the rationale for exploring this platform in two sequential multi-institutional phase Ib/IIa studies. We first tested a doublet and then a triplet regimen to evaluate the safety, toxicity and efficacy of the combinations of lenalidomide and romidepsin (regimen A) in relapsed/refractory lymphoma and myeloma and then the combination of lenalidomide, romidepsin and carfilzomib (regimen B) in relapsed/refractory lymphomas. We describe our results of the lymphoma cohorts.
Methods
Patient Selection
The studies were performed sequentially. Study A enrolled patients from 12/2012-11/2014 and included an expansion in ATLL that continued through 12/2016. Study B enrolled from 1/2015-12/2017. In both studies, patients were required to have histologically confirmed relapsed/refractory non-Hodgkin’s lymphoma or Hodgkin lymphoma after at least one prior systemic therapy. For both studies, patients were required to be at least 18 years old; have ECOG performance status ≤2 and those in the expansion cohort had measurable disease. Prior romidepsin, lenalidomide, or carfilzomib exposure was not exclusionary unless patients discontinued these agents due to toxicity. All patients were registered on the mandatory Revlimid REMS program.
At screening and at the start of a cycle for both studies, patients were required to meet the following laboratory criteria: absolute neutrophil count of greater than 1000/μL, total bilirubin ≤ 1.5 times upper institutional limit of normal (ULN), AST/ALT ≤ 3 times ULN (or 5 times ULN if liver involvement) and creatinine clearance of ≥ 50 mL/min in the phase I portion. Entry criteria that differed between studies included: creatinine clearance in the cohort expansion portion ( ≥ 30 mL/min for regimen A, ≥ 40 mL/min for regimen B); platelet count (≥70,000/μL for regimen A, ≥80,000/uL for regimen B). In both studies, patients with platelet counts >50,000/μL were permitted if thrombocytopenia was due to bone marrow involvement by lymphoma.
Patients were permitted to start a new cycle if they met the aforementioned laboratory criteria or if they had platelet counts within 10K of baseline and creatinine <2.0 x the upper limit of normal.
Patients who had a history of central nervous system involvement or active cardiac disease were excluded.
The study protocols were approved by the institutional review boards at all participating institutions, and all subjects gave written informed consent. The studies were conducted according to good clinical practice and the Declaration of Helsinki and is registered at ClincialTrials.gov (NCT01755975 and NCT02341014).
Study Design
Both studies were phase Ib/IIa studies to evaluate the safety and tolerability of the combination of romidepsin and lenalidomide (regimen A doublet) or romidepsin with lenalidomide and carfilzomib (regimen B triplet) in patients with relapsed or refractory NHL or HL. The primary objectives of both studies were to define the maximum tolerated dose (MTD) and characterize the safety and toxicity of the novel combination. The secondary objectives were to assess the overall response rate (ORR), time to response (TTR), duration of response (DOR), and event free survival (EFS) to these therapies in lymphoma as well as by lineage specific subgroups (B-cell lymphoma, T-cell lymphoma).
A standard 3+3 dose escalation was performed to determine the MTD of each regimen (Supplemental Table 1). Dose limiting toxicities (DLT) were defined in cycle 1 as ≥grade 3 non-hematologic toxicities, grade 4 hematologic toxicities, grade 3 thrombocytopenia or neutropenia that resulted in a >3 day delay in romidepsin dosing, or greater than 1 week delay in initiating cycle 2 day 1 due to continued drug related toxicity.
Both studies included expansion cohorts at the optimal dose or MTD in patients with B-cell lymphoma and T-cell lymphoma. The T-cell and B-cell expansion cohorts consisted of 15 patients each in the study of regimen A and 10 patients each in the study of regimen B. In the study of romidepsin and lenalidomide, 6 additional patients ATLL were enrolled in a disease specific cohort. The study of romidepsin and lenalidomide included a cohort of patients with multiple myeloma that is not reported here. The assessment of toxicity and efficacy was performed within the entire cohort evaluable at MTD. Patients were treated with the combination until disease progression, toxicity or removal from the study.
Adverse events were assessed at baseline, throughout the treatment, and during the 28-day period after treatment discontinuation and were graded by the National Cancer Institute Common Terminology Criteria for Adverse Events Version 4.0. Patients underwent QTc monitoring following antiemetics but before romidepsin infusion in cycle 1, and in subsequent cycles if prolonged QTc was persistently noted.
Beyond cycle 1, romidepsin and lenalidomide were held for grade 3 or higher neutropenia or thrombocytopenia, and for grade 3 or 4 non-hematologic toxicity. Treatment resumption was allowed on recovery to ≤ grade 2 (hematologic toxicities) or ≤grade 1 (non-hematologic toxicities) with mandated dose adjustments. If treatment was delayed for ≥28 days, patients were removed from protocol. After the DLT period, granulocyte-colony-stimulating factor was permitted at the discretion of the treating physician for grade ≥3 neutropenia. Prophylactic antiplatelet agents or anticoagulation were recommended.
Response Evaluations
Response assessments were performed at baseline and the end of cycle 2. In the romidepsin and lenalidomide doublet study, response assessments occurred every 2 cycles through cycle 6 and were every third cycle thereafter. In the romidepsin, lenalidomide, carfilzomib triplet study, they occurred every 3 cycles after cycle 2. . Response and progression of disease were evaluated using a modification of the international criteria proposed by the modified Cheson criteria with incorporation of PET/CT.33 For patients with cutaneous T-cell lymphoma, patients were assessed using the CTCL Global Response Criteria.34
Statistics
The primary objectives of these studies were to define the MTD and characterize the safety and toxicity of each of the novel combinations. The secondary objectives were to evaluate the overall response rate, complete response rate, partial response rate, time to response, duration of response and event free survival. Patients who pursued allogeneic transplant following treatment were censored at their date of transplantation. Median and event-free survival and overall survival were estimated using the Kaplan-Meier method.
Data Sharing Statement
For original data, please contact horwitzs@mskcc.org. Deidentified participant data can be shared. The study protocols are included as a data supplement available with the online version of this article.
Results
Patient Characteristics of Romidepsin and Lenalidomide (Regimen A, doublet)
A total of 49 patients with relapsed/refractory lymphoma were treated in this study and an additional eight patients did not receive therapy due to blood counts inadequate to meet treatment parameters, as defined above, prior to cycle 1 day 1. The median age was 61 years (range: 25-84 years), 53% of the patients were men. Patients with a spectrum of lymphoma histologies were treated including 5 patients with Hodgkin lymphoma, 17 patients with B-cell lymphoma, and 27 patients with T-cell lymphoma. (Table 1) Patients had a median of 3 prior systemic therapies (range: 1-12) with 13 patients with prior autologous transplant and 2 patients with prior allogeneic transplant. All patients who received at least one dose of romidepsin and lenalidomide were evaluable for safety (n=49). Four patients were not evaluable for response to therapy. Three of the four patients discontinued therapy due to toxicity but without progression during cycle 1. Additionally, one patient received steroids for immune thrombocytopenic purpura with subsequent PET normalization prior to dose 1 and was not evaluable for efficacy as a result.
Table 1:
Patient demographics for regimen A and regimen B.
| Characteristics | Regimen A Romidepsin + Lenalidomide n=49 |
Regimen B Romidepsin + Lenalidomide + Carfilzomib n=27 |
|---|---|---|
| Age | ||
|
| ||
| Median (range) | 61 (25-84) | 57 (36-83) |
|
| ||
| Gender | ||
|
| ||
| Male, n (%) | 26 (53%) | 21 (78%) |
| Female, n (%) | 23 (47%) | 6 (22%) |
|
| ||
| Race, n (%) | ||
|
| ||
| White | 32 (65%) | 24 (89%) |
| African-American or Black | 10 (20%) | 1 (4%) |
| Asian | 6 (12%) | 1 (4%) |
| Unknown | 1 (2%) | 1 (4%) |
|
| ||
| Treatment History | ||
|
| ||
| Prior # therapies, median (range)* | 3 (1-12) | 3 (1-11) |
| Prior Transplants, n (%) | ||
| Auto | 13 (27%) | 6 (22%) |
| Allo | 2 (4%) | 1 (4%) |
| Prior Romidepsin | 4 (8%) | 4 (15%) |
|
| ||
| Disease Subtype, n (%) | ||
|
| ||
| Hodgkin Lymphoma | 5 (10%) | - |
|
| ||
| B-cell non-Hodgkin Lymphoma | 17 (35%) | 11 (41%) |
|
| ||
| DLBCL | 11 (23%) | 5 (19%) |
| - GCB | 6 (12%) | 2 (7%) |
| FL | 5 (10%) | 2 (7%) |
| MZL | 1 (2%) | - |
| MCL | - | 2 (7%) |
| Other | - | 2 (7%) |
|
| ||
| T-cell non-Hodgkin Lymphoma | 27 (55%) | 16 (59%) |
|
| ||
| Peripheral T-cell Lymphoma | 17 (35%) | 13 (48%) |
| PTCL-NOS | 5 (10%) | 7 (26%) |
| ATLL | 7 (14%) | - |
| AITL | 3 (6%) | 5 (19%)** |
| NK/TCL | 1 (2%) | 1 (4%) |
| T-PLL | 1 (2%) | - |
| Cutaneous T-cell Lymphoma | 10 (20%) | 3 (11%) |
| MF | 7 (14%) | 1 (4%) |
| - Transformed | 3 (6%) | - |
| SS | 3 (6%) | 2 (7%) |
| - Transformed | - | 2 (7%) |
therapies include ASCT
One AITL patient has concurrent DLBCL
Patient Characteristics of Romidepsin, Lenalidomide and Carfilzomib (Regimen B, triplet)
A total of 27 patients with relapsed/refractory lymphoma were treated and an additional eight patients did not initiate therapy due to blood counts inadequate to meet treatment parameters, as defined above, prior to cycle 1 day 1. The median age was 57 years (range: 36-83 years), 78% of the patients were men. Patients with a spectrum of lymphoma histologies were treated including 11 patients with B-cell lymphoma and 16 patients with T-cell lymphoma. (Table 1) Patients had a median of 3 prior systemic therapies (range: 1-11) with 6 patients with prior autologous transplant and 1 patient with prior allogeneic transplant. All patients who received at least one dose of romidepsin and lenalidomide were evaluable for safety (n=27). Two patients in the expansion cohort were not evaluable for response to therapy and discontinued therapy due to toxicity (thrombocytopenia) but without progression during cycle 1.
Safety and Tolerability of Romidepsin and Lenalidomide (Regimen A, doublet)
All patients experienced at least one adverse event in both studies. In the romidepsin lenalidomide study, the most frequent events treatment emergent events of all grades are summarized in Table 2.
Table 2:
Toxicities occurring in ≥10% of participants and all grade 3 and 4 toxicities for regimen A (romidepsin and lenalidomide) and regimen B (romidepsin, lenalidomide and carfilzomib).
| Regimen A | Regimen B | |||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Any Grade Occuring in ≥10% | Grade 3 | Grade 4 | Any Grade Occuring in ≥10% | Grade 3 | Grade 4 | |||||||
| Hematological Toxicities | 43 | 88% | 24 | 49% | 18 | 37% | 16 | 59% | 6 | 22% | 5 | 19% |
| Anemia | 16 | 33% | 13 | 27% | -- | -- | 9 | 33% | 2 | 4% | -- | -- |
| Febrile Neutropenia | -- | -- | 3 | 6% | -- | -- | -- | -- | 1 | 2% | -- | -- |
| Neutropenia | 28 | 57% | 15 | 31% | 9 | 18% | 7 | 26% | 3 | 6% | 4 | 8% |
| Thrombocytopenia | 30 | 61% | 18 | 37% | 8 | 16% | 14 | 52% | 6 | 12% | 2 | 4% |
| Lymphocyte count decreased | 28 | 57% | 16 | 33% | 9 | 18% | -- | -- | -- | -- | -- | -- |
| White blood cell decreased | 22 | 45% | 18 | 37% | 4 | 8% | 10 | 37% | 2 | 4% | 1 | 2% |
| Liver Function Toxicities | 9 | 18% | 2 | 4% | -- | -- | 4 | 15% | -- | -- | -- | -- |
| Alanine aminotransferase increased | -- | -- | -- | -- | -- | -- | -- | -- | -- | -- | -- | -- |
| Aspartate aminotransferase increased | -- | -- | -- | -- | -- | -- | -- | -- | -- | -- | -- | -- |
| Alkaline Phosphatase increased | -- | -- | 1 | 2% | -- | -- | -- | -- | -- | -- | -- | -- |
| Blood Billirubin Increased | 5 | 10% | 1 | 2% | -- | -- | -- | -- | -- | -- | -- | -- |
| Hypoalbuminemia | -- | -- | -- | -- | -- | -- | 4 | 15% | ||||
| Electrolyte Toxicities | 27 | 55% | 24 | 49% | -- | -- | 9 | 33% | 2 | 4% | -- | -- |
| Hyperglycemia | 8 | 16% | 7 | 14% | -- | -- | -- | -- | -- | -- | -- | -- |
| Hypermagnesemia | 10 | 20% | 10 | 20% | -- | -- | -- | -- | -- | -- | -- | -- |
| Hypocalcemia | 5 | 10% | 5 | 10% | -- | -- | -- | -- | 1 | 2% | -- | -- |
| Hypoglycemia | -- | -- | -- | -- | -- | -- | -- | -- | -- | -- | -- | -- |
| Hypokalemia | 6 | 12% | 6 | 12% | -- | -- | 2 | 4% | -- | -- | ||
| Hypomagnesmia | -- | -- | -- | -- | -- | -- | 4 | 15% | -- | -- | -- | -- |
| Hyponatremia | -- | -- | 1 | 2% | -- | -- | -- | -- | -- | -- | -- | -- |
| Hypophosphatemia | 8 | 16% | 8 | 16% | -- | -- | -- | -- | -- | -- | -- | -- |
| Creatinine increased | -- | -- | -- | -- | -- | -- | -- | -- | -- | -- | -- | -- |
| Other Toxicities | 48 | 98% | 20 | 41% | -- | -- | 26 | 96% | 6 | 22% | -- | -- |
| Abdominal Pain | 6 | 12% | -- | -- | -- | -- | -- | -- | -- | -- | -- | -- |
| Anorexia | 18 | 35% | 1 | 2% | -- | -- | 12 | 44% | -- | -- | -- | -- |
| Arthralgia | -- | -- | 1 | 2% | -- | -- | -- | -- | -- | -- | -- | -- |
| Chills | -- | -- | -- | -- | -- | -- | 3 | 11% | -- | -- | -- | -- |
| Constipation | 19 | 39% | -- | -- | -- | -- | 7 | 26% | -- | -- | -- | -- |
| Dehydration | 3 | 6% | -- | -- | -- | -- | -- | -- | ||||
| Diarrhea | 19 | 39% | -- | -- | -- | -- | 11 | 41% | 1 | 2% | -- | -- |
| Dysgeusia | 30 | 61% | -- | -- | -- | -- | 17 | 63% | -- | -- | -- | -- |
| Dyspnea | 5 | 10% | 1 | 2% | -- | -- | 1 | 2% | ||||
| Electrocardiogram QT corrected interval prolonged | -- | -- | 1 | 2% | -- | -- | -- | -- | -- | -- | ||
| Fatigue | 31 | 63% | 11 | 22% | -- | -- | 22 | 81% | -- | -- | -- | -- |
| Fever | 5 | 10% | -- | -- | -- | -- | 7 | 26% | 1 | 2% | -- | -- |
| Generalized muscle weakness | -- | -- | 1 | 2% | 3 | 11% | 1 | 2% | -- | -- | ||
| Headache | -- | -- | -- | -- | -- | -- | 3 | 11% | -- | -- | -- | -- |
| Hypotension | -- | -- | -- | -- | -- | -- | -- | -- | 1 | 2% | -- | -- |
| Lung Infection | 3 | 6% | -- | -- | 1 | 2% | -- | -- | ||||
| Malaise | -- | -- | -- | -- | -- | -- | 5 | 19% | -- | -- | -- | -- |
| Myalgias | 7 | 14% | -- | -- | -- | -- | 3 | 11% | -- | -- | -- | -- |
| Nausea | 30 | 63% | -- | -- | -- | -- | 16 | 59% | -- | -- | -- | -- |
| Phlebitis | -- | -- | -- | -- | -- | -- | 4 | 15% | -- | -- | -- | -- |
| Rash Maculo-Papular | -- | -- | 1 | 2% | -- | -- | 1 | 2% | ||||
| Syncope | -- | -- | 1 | 2% | -- | -- | -- | -- | -- | -- | -- | -- |
| Tumor lysis syndrome | -- | -- | 1 | 2% | -- | -- | -- | -- | -- | -- | -- | -- |
| Upper Respiratory Infection | -- | -- | 1 | 2% | -- | -- | -- | -- | -- | -- | -- | -- |
| Vomiting | 15 | 27% | -- | -- | -- | -- | 12 | 44% | 1 | 2% | -- | -- |
| Weight Loss | 12 | 22% | -- | -- | -- | -- | 4 | 15% | 1 | 2% | -- | -- |
Serious adverse events occurred in 53% of patients who received treatment on the romidepsin and lenalidomide study (26 patients). Of these, 11 patients had 12 SAEs that were at least possibly related to study treatment and included febrile neutropenia in 4 (2 URI, 1 pneumonia, 1 without source), and hospitalizations for: symptomatic anemia (N=1), deep vein thrombosis and pulmonary embolism (N=1), diarrhea and neutropenia (N=1), infection without neutropenia (pneumonia, N=2), dyspnea (N=1), fever without neutropenia and unclear source (N=1), and thrombocytopenia (N=1). Serious adverse events unrelated to the study treatment included hospitalizations for progression of disease, syncope (in a patient with a history of recurrent syncope prior to therapy), appendicitis, a skin infection, dehydration and fracture.
In the study of regimen A, one patient each experienced a dose-limiting toxicity at a dose of romidepsin 8mg/m2 and lenalidomide 25mg (pneumonia), and at romidepsin 14mg/m2 and lenalidomide 25mg (grade 3 thrombocytopenia). The dose limited toxicity threshold was not exceeded at romidepsin 14mg/m2 and lenalidomide 25mg. Therefore, the recommended dose for the expansion cohorts was romidepsin 14mg/m2 and lenalidomide 25mg. Patients who received multiple cycles of regimen A often required dose reduction due to the later development of toxicities. Of the patients evaluable for toxicity, 31/49 (63%) required dose reductions of romidepsin and lenalidomide. The reasons for dose reductions were fatigue (n=12), thrombocytopenia (n=14), neutropenia (n=14), rash (n=3), diarrhea (n=2), arthralgia (n=1), anorexia (n=1). The median doses of romidepsin and lenalidomide for patients who received ≥4 cycles of therapy were romidepsin 8mg/m2 and lenalidomide 10mg. Sixteen patients discontinued therapy due to toxicity with a median duration of treatment of 4.2 months (range: 0.3 months-68.4 mo). Given the cumulative toxicity with this regimen, when designing regimen B, we chose romidepsin 8mg/m2, lenalidomide 15mg and carfilzomib 36mg/m2 as dose level 1.
Safety and Tolerability of Romidepsin, Lenalidomide and Carfilzomib (Regimen B)
In the romidepsin, lenalidomide, carfilzomib study, treatment emergent events of all grades that occurred in >10% patients are summarized in Table 2.
Serious adverse events related to therapy occurred in 6 patients on the romidepsin, lenalidomide, carfilzomib study including one patient with each of the following: grade 3 heart failure, pneumonia in cycle 1 and febrile neutropenia; grade 3 fever with hypotension without identified source of infection; grade 3 generalized weakness; grade 3 thrombocytopenia; grade 4 thrombocytopenia; and grade 3 vomiting.
In the study of regimen B, two patients experienced a dose limiting toxicity at dose level 2 (romidepsin 8mg/m2, lenalidomide 15mg, carfilzomib 45mg/m2). One had grade 3 thrombocytopenia resulting in a treatment delay and one had grade 4 thrombocytopenia. Therefore, the maximum tolerated dose was named as dose level 1: romidepsin 8mg/m2, lenalidomide 10mg, carfilzomib 36mg/m2. Of the 11 patients who were on therapy for more than 4 cycles, 6 required dose reductions due to thrombocytopenia (n=2), neutropenia (n=1), neutropenia and thrombocytopenia (n=1), rash (n=1), and weakness (n=1). Three patients discontinued therapy due to toxicity at a median of 2.0 months (range: 0.5 months-32.6 months)
Efficacy (Regimen A)
In the study of the romidepsin and lenalidomide doublet, 49 patients were treated and 45 patients were evaluable for efficacy. The overall response rate among the evaluable patients was 49% (n=22) with a complete response rate of 18% (n=8) and partial response rate of 31% (n=14). (Table 3; Figure 1) Among the 34 evaluable patients treated at the recommended dose for the expansion cohort (romidepsin 14mg/m2, lenalidomide 25mg), 6 (18%) demonstrated CR, 11 (32%) with PR. Two additional patients treated at this dose were not evaluable for response due to discontinuation of therapy within cycle 1. The median progression free survival was 5.7 months. The median overall survival was 24.0 months. (Supplemental Figure 1) The median duration of response was 15.7 months (range 0.5-69.9 months). The median time to best response was 3.7 months. At the time of data locking, all patients are off therapy.
Table 3:
Efficacy of regimen A and regimen B.
| Regimen A | Regimen B | |||||||||
|---|---|---|---|---|---|---|---|---|---|---|
| Romidepsin + Lenalidomide | Romidepsin + Lenalidomide + Carfilzomib | |||||||||
| Histology | Treated | Evaluable | ORR | CR | PR | Treated | Evaluable | ORR | CR | PR |
| n | n | n(%) | n(%) | n(%) | n | n | n(%) | n(%) | n(%) | |
| Hodgkin Lymphoma | 5 | 4 | 2 (50%) | 1 (25%) | 1 (25%) | - | - | - | - | - |
| B-cell non-Hodgkin Lymphoma | 17 | 17 | 8 (47%) | 4 (24%) | 4 (24%) | 12 * | 10 * | 5 (50%) * | 1 (10%) * | 4 (44%) |
|
| ||||||||||
| DLBCL | 11 | 11 | 4 (36%) | 3 (27%) | 1 (9%) | 6* | 5* | 4 (80%)* | 1 (20%)* | 3 (75%) |
| - GCB | 6 | 6 | 4 (67%) | 3 (50%) | 1 (17%) | 2 | 2 | 2 (100%) | 0 | 2 (100%) |
| FL | 5 | 5 | 4 (80%) | 1 (20%) | 3 (60%) | 2 | 2 | 0 | 0 | 0 |
| MZL | 1 | 1 | 0 | 0 | 0 | - | - | - | - | - |
| MCL | - | - | - | - | - | 2 | 2 | 1 (50%) | 0 | 1 (50%) |
| Other | - | - | - | - | - | 2 | 1 | 0 | 0 | 0 |
|
| ||||||||||
| T-cell non-Hodgkin Lymphoma | 27 | 24 | 12 (50%) | 3 (13%) | 9 (38%) | 16 | 16 | 8 (50%) | 5 (31%) | 3 (19%) |
|
| ||||||||||
| Peripheral T-cell Lymphoma | 17 | 15 | 8 (53%) | 2 (13%) | 6 (40%) | 13 | 13 | 7 (54%) | 5 (39%) | 2 (15%) |
| PTCL-NOS | 5 | 5 | 2 (40%) | 0 | 2 (40%) | 7 | 7 | 2 (29%) | 1 | 1 |
| ATLL | 7 | 6 | 3 (50%) | 1 (17%) | 2 (33%) | - | - | - | - | - |
| AITL | 3 | 2 | 2 (100%) | 1 (50%) | 1 (50%) | 5* | 5* | 5 (100%)* | 4 (80%)* | 1 (20%) |
| NK/TCL | 1 | 1 | 0 | 0 | 0 | 1 | 1 | 0 | 0 | 0 |
| T-PLL | 1 | 1 | 1 (100%) | 0 | 1 (100%) | - | - | - | - | - |
| Cutaneous T-cell Lymphoma | 10 | 9 | 4 (44%) | 1 (11%) | 3 (33%) | 3 | 3 | 1 (33%) | 0 | 1 (33%) |
| MF | 7 | 6 | 3 (50%) | 1 (17%) | 2 (33%) | 1 | 1 | 0 | 0 | 0 |
| - Transformed | 3 | 2 | 1 (50%) | 0 | 1 (50%) | - | - | - | - | - |
| SS | 3 | 3 | 1 (33%) | 0 | 1 (33%) | 2 | 2 | 1 (50%) | 0 | 1 (50%) |
| - Transformed | - | - | - | - | - | 2 | 2 | 1 (50%) | 0 | 1 (50%) |
|
| ||||||||||
| TOTAL | 49 | 45 | 22 (49%) | 8 (18%) | 14 (31%) | 27 | 25 | 12 (48%) | 5 (20%) | 7 (28%) |
One AITL patient has concurrent DLBCL and is counted towards both cohorts. However, this patient is not counted two times in Total Overall Cohort
Figure 1:
Swimmer Plots for Regimens A and B by histology. (A) Swimmer plots of regimen A for patients with B-cell lymphoma and Hodgkin Lymphoma. (B) Swimmer plots of regimen A for patients with T-cell lymphoma. (C) Swimmer plots of regimen B for patients with B-cell lymphoma. (D) Swimmer plots of regimen B for patients with T-cell lymphoma.
Among the 24 patients with T-cell lymphoma, the overall response rate was 50% (n=12) with a complete response rate of 13% (n=3) and a partial response rate of 38% (n=9). Complete responses were seen in patients with mycosis fungoides (n=1), adult T-cell leukemia/lymphoma (ATLL) (n=1) and AITL (n=1). Partial responses were seen in patients with AITL (1/2), T-cell prolymphocytic leukemia (T-PLL) (1/1), ATLL (2/6), PTCL-NOS (2/5), mycosis fungoides (2/6) and Sezary Syndrome (1/3). The median progression free survival for patients with T-cell lymphoma was 4.8 months and the median overall survival was 18.3 months. One patient with AITL and two with ATLL proceeded to allogenic transplant after treatment with romidepsin and lenalidomide. One patient with PTCL-NOS, who achieved a partial response and then progressed ultimately proceeded to an allogeneic transplant and was censored at the time of transplant.
Among the 17 patients with B-cell lymphoma, the overall response rate was 47% (n=8) with a complete response rate of 24% (n=4) and a partial response rate of 24% (n=4). Complete responses were seen in patients with germinal center phenotype DLBCL (n=3) and follicular lymphoma (n=1). Partial responses were seen in patients with germinal center phenotype DLBCL (n=1) and follicular lymphoma (n=3). The median event free survival for patients with B-cell lymphomas was 7.2 months. The median overall survival for patients with B-cell lymphomas was not reached. One patient with DLBCL with a complete response and one patient with follicular lymphoma with a partial response proceeded to allogeneic transplant after treatment with romidepsin and lenalidomide. There were no responses seen in the 5 patients with non-germinal center phenotype DLBCL.
Of the two evaluable patients with Hodgkin lymphoma, one complete response and one partial response was seen.
Efficacy (Regimen B)
In the study of romidepsin, lenalidomide and carfilzomib triplet, 27 patients were treated and 25 patients were evaluable for efficacy. The overall response rate among the evaluable patients was 48% (n=12) with a complete response rate of 20% (n=5) and partial response rate of 28% (n=7). (Table 3; Figure 1) Among the 20 patients treated at the recommended dose for the expansion cohorts, 4 (22%) demonstrated CR, 4 (22%) with PR. Two patients amongst these 20 were not evaluable for response due to discontinuation of therapy without progression in cycle 1. The median progression free survival was 3.4 months. The median overall survival was 26.5 months (Supplemental Figure 1). The median duration of response was 10.6 months (range: 0.9-34.5 months) and all patients have discontinued therapy. 6 patients achieved a sufficient response to proceed to an allogeneic transplant including 2 with PTCL-NOS, 2 with germinal center DLBCL, 1 with mantle cell lymphoma and 1 with concurrent AITL and DLBCL.
Among the 16 patients with T-cell lymphoma, the overall response rate was 50% (n=8) with a complete response rate of 31% (n=5) and partial response rate of 19% (n=3). Complete responses were seen in patients AITL (n=4) and PTCL-NOS (n=1). Partial responses were seen in patients with AITL (1/5), PTCL-NOS (1/7) and Sezary Syndrome (1/2). The median event free survival for patients with T-cell lymphoma was 3.0 months and the median overall survival was 21.9 months.
Among the 10 patients with B-cell lymphoma, the overall response rate was 50% (n=5). Of these, 1 patient with concurrent AITL and DLBCL had a complete response. Partial responses were seen in patients with DLBCL (3/5) and mantle cell lymphoma (1/2). The median event free and overall survival for patients with B-cell lymphomas was 3.8 months and not reached, respectively. Two patients with DLBCL and one with mantle cell lymphoma proceeded to an allogeneic transplant following treatment on this study. Patients with both germinal center phenotype (n=2) and non-germinal center phenotype DLBCL (n=2) achieved a response to the combination.
Discussion
Relapsed and refractory lymphomas, and particularly T-cell lymphomas, remain a challenging group of disorders to treat. The 5-year overall survival (OS) in transplant ineligible patients with B- and T-cell lymphomas was 32% and 20%, respectively.35,36 Patients who are able to undergo an allogeneic transplant can have a 2 year OS of up to 60%, as seen in T-cell lymphomas.37 Therefore, a significant need remains for more therapies that can bridge to curative treatments as well as long-term or maintenance treatments employing drugs without cumulative toxicity for those who are not candidates for allogeneic transplants due to age, donor status, or comorbidities. Ultimately, active regimens studied in the relapsed setting, with high rates of CR and PFS could be candidates for future trials as initial therapy. Therefore, in two sequential studies we evaluated the combination of romidepsin and lenalidomide and then romidepsin, lenalidomide, carfilzomib in relapsed/refractory lymphomas. These studies represent the first to demonstrate safety and tolerability of the combination of histone deacetylase inhibition and lenalidomide based therapy in the treatment of relapsed and refractory lymphomas. In T-cell lymphomas, where the activity of these combinations is notable, romidepsin and lenalidomide are available treatment options as single agents as they are FDA approved or NCCN compendium listed.
With the exception of brentuximab vedotin for patients with anaplastic large cell lymphoma, the single agent therapies approved for patients with PTCL carry overall response rates between 25-30% and median duration of response of approximately 4 months.38–41 In both of these regimens, the overall response rate in T-cell lymphomas in 40 patients was 50%. Our findings compare favorably to the single agent response rates of romidepsin and lenalidomide which are 25% and 30% respectively.17,42 In cutaneous T-cell lymphomas, the single agent response rate of romidepsin and lenalidomide are 34% and 28% respectively.43,44 In comparison, in this study, romidepsin and lenalidomide based combinations led to an overall response rate of 42% and 50% in peripheral T-cell lymphomas and cutaneous T-cell lymphomas respectively in a heavily pretreated population. Of note, two patients with mycosis fungoides who had partial responses lasting more than two years had previously been treated with romidepsin. Furthermore, collectively 6 patients (2 ATLL, 2 PTCL-NOS, 2 AITL) achieved remission sufficient to bridge directly to allogeneic stem cell transplant. Responses were seen across a number of histologies including complete responses in mycosis fungoides and transformed mycosis fungoides. Interestingly, all 7 patients with AITL on these studies responded (CR-5, PR-2) and an additional patient with AITL did not have evaluable disease but achieved a complete remission and was consolidated with an allogenic transplant and remains in remission now over 7 years later. One patient with T-PLL demonstrated a partial response and was removed from therapy due to refractory thrombocytopenia and anemia. This represents the first report of efficacy of lenalidomide based therapy in T-PLL. In ATLL, the overall response rate to romidepsin and lenalidomide was 50%. In addition to the aforementioned patients who were able to pursue a curative transplant, another patient with ATLL achieved a partial response and remained on therapy for 25 weeks. This is notable in diseases that have traditionally been very challenging to treat and confirms the activity of lenalidomide based therapy in ATLL.20 While the median progression free survival in T-cell lymphomas was 3.0-4.8 months, 11 of the best responding patients were censored at the time of transplant.
Previous studies in B-cell lymphomas have shown some modest activity of HDAC inhibitors. For example, vorinostat, an HDAC class I and II inhibitor, has shown an overall response rate of 29% in follicular and marginal zone lymphoma and 5% in diffuse large B-cell lymphoma. 7,45 Lenalidomide has carried ORR between 19-28% as a single agent in DLBCL.10,11 In comparison, with these romidepsin and lenalidomide based combinations, the overall response rate in B-cell lymphomas was 48%. In the 5 patients with follicular lymphoma, the ORR for romidepsin and lenalidomide was 80% which is higher than is seen with lenalidomide alone.46,47 Amongst the 16 patients with diffuse large B-cell lymphoma, the overall response rate to these regimens was 50% with 4 patients who proceeded to an allogeneic transplant (3 CR and 1 PR). Interestingly, all 4 responses to regimen A were seen in patients with germinal center subtype of diffuse large B-cell lymphoma. In contrast, no responses were seen in the 4 patients with non-germinal center subtype diffuse large B-cell lymphoma. Both patients with germinal center DLBCL on regimen B responded to therapy, but responses were also seen in 2 patients with non-germinal center DLBCL. In previous studies, lenalidomide has been associated with higher activity in non-germinal center diffuse large B-cell lymphoma.48,49 While the sample sizes are small, the responses in germinal center DLBCL are an interesting observation and warrants further investigation. It is possible that this population of germinal center DLBCL and FL is enriched in mutations that could confer sensitivity to histone deacetylase inhibitor based therapy such as those involving EZH2, EP300 and CREBBP and histone acetyltransferases.50–52
In the study A, the maximum tolerated dose within cycle 1 was not exceeded at the standard single agent doses for lenalidomide and romidepsin. However, the majority of patients who remained on therapy for multiple cycles required dose reduction due to later or cumulative toxicity. For the 27 patients who remained on therapy for ≥4 cycles, median doses of romidepsin and lenalidomide were romidepsin 8mg/m2 and lenalidomide 10mg. The most frequent reasons for dose modifications were fatigue, thrombocytopenia and anemia. Generally, when the lymphoma was controlled, anemia and thrombocytopenia were manageable with transfusion support and were reversible after holding romidepsin and lenalidomide. Electrolyte abnormalities were common with these agents and patients were given magnesium and potassium supplementation to achieve a normal range while on therapy. In study B, 6/11 patients who were on for more than 4 cycles similarly required dose reduction. Therefore, while this regimen could be safely given for repeated cycles, dose reduction were required to mitigate against toxicity and disease control was nonetheless maintained. Furthermore, most of the toxicities were reversible hematologic toxicities and electrolyte abnormalities. Therefore, for patients being treated for palliative purposes, starting at lower doses (e.g. romidepsin 10mg/m2 and lenalidomide 20mg) seems optimal.
Although these studies were performed sequentially and not designed for formal comparison, they were performed in similar patient populations and both showed considerable activity in relasped T-cell lymphomas where there remains a significant unmet need. The overall response rates of the regimens were similar. Regimen A appeared to be more tolerable for longer term or maintenance therapy with 9 patients continuing for more than 12 months. On the other hand, regimen B was associated with a higher rate of complete remission in T-cell lymphomas (including 4/5 CR in those with AITL) and with a higher proportion of patients proceeding to an allogeneic transplant. Patients who proceeded to allogeneic transplant were censored at the time of transplant and therefore, not reflected in the PFS and OS assessments. Based on the safety and efficacy described above, these regimens could be applied on an individualized basis, particularly in AITL and other T-cell lymphomas, depending on the goals of therapy. We are continuing to explore other combination therapies in the relapsed setting including these and other agents with activity in T-cell lymphoma. Other investigators are currently studying the doublet of romidepsin and lenalidomide in the frontline setting. (NCT02232516)
In summary, romidepsin and lenalidomide based combinations were relatively well tolerated with a signal of efficacy across a variety of lymphoma subtypes including T-cell lymphomas. Further disease and subtype specific studies would be needed to more precisely define the efficacy of these regimens. While the maximum tolerated dose was not exceeded at romidepsin 14mg/m2 and lenalidomide 25mg, most patients who were on for multiple cycles required dose reductions due to fatigue, anemia, and thrombocytopenia. Lower doses were required due to hematologic toxicity when combining romidepsin, lenalidomide and carfilzomib. Additionally, studies to identify predictors of response and resistance would be particularly informative in understanding how best to apply these combinations and in which patients they could be moved forward.
Supplementary Material
Funding:
This study was approved and funded by the National Comprehensive Cancer Network (NCCN) Oncology Research Program from general research support provided by Amgen. This study was also supported by Celgene and NIH/NCI Cancer Center Support Grant P30 CA008748. NMS was supported by an American Society of Hematology Research Training Award for Fellows. NMS is also supported by the Lymphoma Research Foundation (CDA number 610181).
Conflict of Interest Disclosures:
NMS has institutional research funding from Celgene/Bristol-Myers Squibb, Genentech/Roche, Verastem Pharmaceuticals, Innate Pharmaceuticals, Corvus Pharmaceuticals. NMS has served a consultant for Kyowa Hakka Kirin, C4 Therapeutics, and Karyopharm. AK has research funding from Adaptive Biotechnologies, Abbvie Pharmaceuticals, Celgene, Pharmacyclics, Seattle Genetics, and Astra Zeneca. AK has also served as a consultant for Celgene, KiTE Pharmaceuticals, and has served on an advisory board for Astra Zeneca. AN has research funding from Pharmacyclics Rafael Pharma. AN has served on an advisory board for Jansen, Morphosys and has served as a consultant for Pharmacyclics. AM has received research support from ADC Therapeutics, Miragen, Seattle Genetics, Merck, Bristol-Myers Squibb, and Incyte; and honoraria from Imbrium Therapeutics L.P., Janpix Ltd., Merck, Purdue Pharma L.C., and Seattle Genetics. JPL has served as a consultant for Sutro, Miltenyi, AstraZeneca, Epizyme, BMS/Celgene, Regeneron, Bayer, Gilead/Kite, Karyopharm, GenMab, Genentech/Roche, Abbvie, and Incyte. JR has received research support and has served as a consultant with Celgene/BMS. MLP has received personal or consulting fees from Novartis, Merck, Pharmacyclics and KiTE Pharmaceuticals. SH has consulted, received honorarium from, or participated in advisory boards for; ADC Therapeutics, C4 Therapeutics, Celgene, Janssen, Kura Oncology, Kyowa Hakko Kirin, Myeloid Therapeutics, Seattle Genetics, Takeda,Trillium Therapeutics, Verastem, and Vividion Therapeutics. SH has also received research support for clinical trials from ADC Therapeutics, Affimed, Aileron, Celgene, Daiichi Sankyo, Forty Seven, Inc., Kyowa Hakko Kirin, Millennium/Takeda, Portola Pharmaceuticals, Seattle Genetics, Trillium Therapeutics, and Verastem. PL, PM, EM, SN, TS, VM, DJS, HS, JR, WS, NG and NG have no relevant conflicts of interest to disclose.
Footnotes
These studies were presented at the International Conference on Malignant Lymphoma 2015 and the ASH Annual Meeting 2017.
References:
- 1.Coiffier B, Pro B, Prince HM, et al. Results From a Pivotal, Open-Label, Phase II Study of Romidepsin in Relapsed or Refractory Peripheral T-Cell Lymphoma After Prior Systemic Therapy. Journal of Clinical Oncology. 2012;30(6):631–636. [DOI] [PubMed] [Google Scholar]
- 2.Whittaker SJ, Demierre MF, Kim EJ, et al. Final results from a multicenter, international, pivotal study of romidepsin in refractory cutaneous T-cell lymphoma. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2010;28(29):4485–4491. [DOI] [PubMed] [Google Scholar]
- 3.Younes A, Sureda A, Ben-Yehuda D, et al. Panobinostat in patients with relapsed/refractory Hodgkin’s lymphoma after autologous stem-cell transplantation: results of a phase II study. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2012;30(18):2197–2203. [DOI] [PubMed] [Google Scholar]
- 4.Younes A, Ong TC, Ribrag V, et al. Efficacy of Panobinostat in Phase II Study in Patients with Relapsed/Refractory Hodgkin Lymphoma (HL) After High-Dose Chemotherapy with Autologous Stem Cell Transplant. Blood. 2009;114(22):380–381.19383971 [Google Scholar]
- 5.O’Connor OA, Heaney ML, Schwartz L, et al. Clinical experience with intravenous and oral formulations of the novel histone deacetylase inhibitor suberoylanilide hydroxamic acid in patients with advanced hematologic malignancies. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2006;24(1):166–173. [DOI] [PubMed] [Google Scholar]
- 6.Oki Y, Buglio D, Fanale M, et al. Phase I study of panobinostat plus everolimus in patients with relapsed or refractory lymphoma. Clin Cancer Res. 2013;19(24):6882–6890. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 7.Crump M, Coiffier B, Jacobsen ED, et al. Phase II trial of oral vorinostat (suberoylanilide hydroxamic acid) in relapsed diffuse large-B-cell lymphoma. Annals of oncology : official journal of the European Society for Medical Oncology/ESMO. 2008;19(5):964–969. [DOI] [PubMed] [Google Scholar]
- 8.Batlevi CL, Crump M, Andreadis C, et al. A phase 2 study of mocetinostat, a histone deacetylase inhibitor, in relapsed or refractory lymphoma. Br J Haematol. 2017;178(3):434–441. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 9.List A, Dewald G, Bennett J, et al. Lenalidomide in the myelodysplastic syndrome with chromosome 5q deletion. The New England journal of medicine. 2006;355(14):1456–1465. [DOI] [PubMed] [Google Scholar]
- 10.Wiernik PH, Lossos IS, Tuscano JM, et al. Lenalidomide Monotherapy in Relapsed or Refractory Aggressive Non-Hodgkin’s Lymphoma. Journal of Clinical Oncology. 2008;26(30):4952–4957. [DOI] [PubMed] [Google Scholar]
- 11.Witzig TE, Wiernik PH, Moore T, et al. Lenalidomide Oral Monotherapy Produces Durable Responses in Relapsed or Refractory Indolent Non-Hodgkin’s Lymphoma. Journal of Clinical Oncology. 2009;27(32):5404–5409. [DOI] [PubMed] [Google Scholar]
- 12.Andorsky DJ, Coleman M, Yacoub A, et al. MAGNIFY: Phase IIIb interim analysis of induction R-2 followed by maintenance in relapsed/refractory indolent non-Hodgkin lymphoma. Journal of Clinical Oncology. 2019;37(15). [Google Scholar]
- 13.Leonard JP, Trneny M, Izutsu K, et al. AUGMENT: A Phase III Study of Lenalidomide Plus Rituximab Versus Placebo Plus Rituximab in Relapsed or Refractory Indolent Lymphoma. J Clin Oncol. 2019;37(14):1188–1199. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 14.Boll B, Borchmann P, Topp MS, et al. Lenalidomide in patients with refractory or multiple relapsed Hodgkin lymphoma. Br J Haematol. 2010;148(3):480–482. [DOI] [PubMed] [Google Scholar]
- 15.Fehniger TA, Larson S, Trinkaus K, et al. A phase 2 multicenter study of lenalidomide in relapsed or refractory classical Hodgkin lymphoma. Blood. 2011;118(19):5119–5125. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 16.Zinzani PL, Pellegrini C, Broccoli A, et al. Lenalidomide monotherapy for relapsed/refractory peripheral T-cell lymphoma not otherwise specified. Leuk Lymphoma. 2011;52(8):1585–1588. [DOI] [PubMed] [Google Scholar]
- 17.Dueck G, Chua N, Prasad A, et al. Interim report of a phase 2 clinical trial of lenalidomide for T-cell non-Hodgkin lymphoma. Cancer. 2010;116(19):4541–4548. [DOI] [PubMed] [Google Scholar]
- 18.Morschhauser F, Fitoussi O, Haioun C, et al. A phase 2, multicentre, single-arm, open-label study to evaluate the safety and efficacy of single-agent lenalidomide (Revlimid) in subjects with relapsed or refractory peripheral T-cell non-Hodgkin lymphoma: the EXPECT trial. European journal of cancer. 2013;49(13):2869–2876. [DOI] [PubMed] [Google Scholar]
- 19.Toumishey E, Prasad A, Dueck G, et al. Final report of a phase 2 clinical trial of lenalidomide monotherapy for patients with T-cell lymphoma. Cancer. 2015;121(5):716–723. [DOI] [PubMed] [Google Scholar]
- 20.Ishida T, Fujiwara H, Nosaka K, et al. Multicenter Phase II Study of Lenalidomide in Relapsed or Recurrent Adult T-Cell Leukemia/Lymphoma: ATLL-002. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2016;34(34):4086–4093. [DOI] [PubMed] [Google Scholar]
- 21.Querfeld C, Rosen ST, Guitart J, et al. Phase II Multicenter Trial of Lenalidomide: Clinical and Immunomodulatory Effects in Patients with CTCL. Blood. 2011;118(21):712–712.21555741 [Google Scholar]
- 22.Lendvai N, Hilden P, Devlin S, et al. A phase 2 single-center study of carfilzomib 56 mg/m2 with or without low-dose dexamethasone in relapsed multiple myeloma. Blood. 2014;124(6):899–906. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 23.Verhelle D, Corral LG, Wong K, et al. Lenalidomide and CC-4047 inhibit the proliferation of malignant B cells while expanding normal CD34+ progenitor cells. Cancer research. 2007;67(2):746–755. [DOI] [PubMed] [Google Scholar]
- 24.Cosenza M CM, Fiorcari S, Pozzi S,Marcheselli L, Valentina Liardo E, Bari A, and Sacchi S. Romidepsin and Lenalidomide Show a Synergistic Effect In T–Cell Lymphoma Cell Lines Blood 2013;122:5148. [Google Scholar]
- 25.Cosenza M, Civallero M, Fiorcari S, Pozzi S, Marcheselli L, Sacchi S. Romidepsin Synergizes with Lenalidomide in T Cell Lymphoma Cell Lines By Increasing Reactive Oxygen Species and Modulating PI3K/AKT and MAPK/ERK Signaling Pathways. Blood. 2014;124(21). [Google Scholar]
- 26.Ocio EM, Vilanova D, Atadja P, et al. In vitro and in vivo rationale for the triple combination of panobinostat (LBH589) and dexamethasone with either bortezomib or lenalidomide in multiple myeloma. Haematologica. 2010;95(5):794–803. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 27.Ocio EM, Vilanova D, San-Segundo L, et al. Triple combinations of the HDAC inhibitor panobinostat (LBH589) plus dexamethasone with either lenalidomide or bortezomib are highly effective in a multiple myeloma mouse model. Blood. 2007;110(11):453a–453a. [Google Scholar]
- 28.Siegel DS, Richardson P, Dimopoulos M, et al. Vorinostat in combination with lenalidomide and dexamethasone in patients with relapsed or refractory multiple myeloma. Blood cancer journal. 2014;4:e182. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 29.Amengual JE, Johannet P, Lombardo M, et al. Dual Targeting of Protein Degradation Pathways with the Selective HDAC6 Inhibitor ACY-1215 and Bortezomib Is Synergistic in Lymphoma. Clin Cancer Res. 2015;21(20):4663–4675. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 30.Santo L, Hideshima T, Kung AL, et al. Preclinical activity, pharmacodynamic, and pharmacokinetic properties of a selective HDAC6 inhibitor, ACY-1215, in combination with bortezomib in multiple myeloma. Blood. 2012;119(11):2579–2589. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 31.Siegel DS, Dimopoulos MA, Ludwig H, et al. Improvement in Overall Survival With Carfilzomib, Lenalidomide, and Dexamethasone in Patients With Relapsed or Refractory Multiple Myeloma. J Clin Oncol. 2018;36(8):728–734. [DOI] [PubMed] [Google Scholar]
- 32.Stewart AK, Rajkumar SV, Dimopoulos MA, et al. Carfilzomib, lenalidomide, and dexamethasone for relapsed multiple myeloma. N Engl J Med. 2015;372(2):142–152. [DOI] [PubMed] [Google Scholar]
- 33.Cheson BD. The International Harmonization Project for response criteria in lymphoma clinical trials. Hematology/oncology clinics of North America. 2007;21(5):841–854. [DOI] [PubMed] [Google Scholar]
- 34.Olsen EA, Whittaker S, Kim YH, et al. Clinical end points and response criteria in mycosis fungoides and Sezary syndrome: a consensus statement of the International Society for Cutaneous Lymphomas, the United States Cutaneous Lymphoma Consortium, and the Cutaneous Lymphoma Task Force of the European Organisation for Research and Treatment of Cancer. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2011;29(18):2598–2607. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 35.Vose J, Armitage J, Weisenburger D, International TCLP. International peripheral T-cell and natural killer/T-cell lymphoma study: pathology findings and clinical outcomes. J Clin Oncol. 2008;26(25):4124–4130. [DOI] [PubMed] [Google Scholar]
- 36.Philip T, Guglielmi C, Hagenbeek A, et al. Autologous bone marrow transplantation as compared with salvage chemotherapy in relapses of chemotherapy-sensitive non-Hodgkin’s lymphoma. The New England journal of medicine. 1995;333(23):1540–1545. [DOI] [PubMed] [Google Scholar]
- 37.Mehta-Shah N, Teja S, Tao Y, et al. Successful Treatment of Mature T-Cell Lymphoma with Allogeneic Stem Cell Transplantation: The Largest Multicenter Retrospective Analysis. Blood. 2017;130. [Google Scholar]
- 38.O’Connor OA, Horwitz S, Masszi T, et al. Belinostat in Patients With Relapsed or Refractory Peripheral T-Cell Lymphoma: Results of the Pivotal Phase II BELIEF (CLN-19) Study. J Clin Oncol. 2015;33(23):2492–2499. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 39.O’Connor OA, Pro B, Pinter-Brown L, et al. Pralatrexate in patients with relapsed or refractory peripheral T-cell lymphoma: results from the pivotal PROPEL study. J Clin Oncol. 2011;29(9):1182–1189. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 40.Piekarz RL, Frye R, Prince HM, et al. Phase 2 trial of romidepsin in patients with peripheral T-cell lymphoma. Blood. 2011;117(22):5827–5834. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 41.Pro B, Advani R, Brice P, et al. Brentuximab vedotin (SGN-35) in patients with relapsed or refractory systemic anaplastic large-cell lymphoma: results of a phase II study. J Clin Oncol. 2012;30(18):2190–2196. [DOI] [PubMed] [Google Scholar]
- 42.Coiffier B, Pro B, Prince HM, et al. Results from a pivotal, open-label, phase II study of romidepsin in relapsed or refractory peripheral T-cell lymphoma after prior systemic therapy. J Clin Oncol. 2012;30(6):631–636. [DOI] [PubMed] [Google Scholar]
- 43.Piekarz RL, Frye R, Turner M, et al. Phase II multi-institutional trial of the histone deacetylase inhibitor romidepsin as monotherapy for patients with cutaneous T-cell lymphoma. J Clin Oncol. 2009;27(32):5410–5417. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 44.Querfeld C, Rosen ST, Guitart J, et al. Results of an open-label multicenter phase 2 trial of lenalidomide monotherapy in refractory mycosis fungoides and Sezary syndrome. Blood. 2014;123(8):1159–1166. [DOI] [PubMed] [Google Scholar]
- 45.Kirschbaum M, Frankel P, Popplewell L, et al. Phase II study of vorinostat for treatment of relapsed or refractory indolent non-Hodgkin’s lymphoma and mantle cell lymphoma. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2011;29(9):1198–1203. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 46.Leonard JP, Jung SH, Johnson J, et al. Randomized Trial of Lenalidomide Alone Versus Lenalidomide Plus Rituximab in Patients With Recurrent Follicular Lymphoma: CALGB 50401 (Alliance). J Clin Oncol. 2015;33(31):3635–3640. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 47.Witzig TE, Wiernik PH, Moore T, et al. Lenalidomide oral monotherapy produces durable responses in relapsed or refractory indolent non-Hodgkin’s Lymphoma. J Clin Oncol. 2009;27(32):5404–5409. [DOI] [PubMed] [Google Scholar]
- 48.Hernandez-Ilizaliturri FJ, Deeb G, Zinzani PL, et al. Higher response to lenalidomide in relapsed/refractory diffuse large B-cell lymphoma in nongerminal center B-cell-like than in germinal center B-cell-like phenotype. Cancer. 2011;117(22):5058–5066. [DOI] [PubMed] [Google Scholar]
- 49.Nowakowski GS, LaPlant B, Macon WR, et al. Lenalidomide combined with R-CHOP overcomes negative prognostic impact of non-germinal center B-cell phenotype in newly diagnosed diffuse large B-Cell lymphoma: a phase II study. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2015;33(3):251–257. [DOI] [PubMed] [Google Scholar]
- 50.Lue JK, Prabhu SA, Liu Y, et al. Precision Targeting with EZH2 and HDAC Inhibitors in Epigenetically Dysregulated Lymphomas. Clin Cancer Res. 2019;25(17):5271–5283. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 51.Chapuy B, Stewart C, Dunford AJ, et al. Molecular subtypes of diffuse large B cell lymphoma are associated with distinct pathogenic mechanisms and outcomes. Nat Med. 2018;24(5):679–690. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 52.Krysiak K, Gomez F, White BS, et al. Recurrent somatic mutations affecting B-cell receptor signaling pathway genes in follicular lymphoma. Blood. 2017;129(4):473–483. [DOI] [PMC free article] [PubMed] [Google Scholar]
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