Patient characteristics
MCL patients from March 1, 2009, to April 12, 2016 who were treated with lenalidomide following ibrutinib therapy were enrolled. The data cutoff for all patients was November 1, 2016. The study enrolled 58 patients at a total of 11 study sites, including 10 sites in the USA and one site in England (Additional file
1: Table S1). Seven patients signed informed consent forms (one patient signed consent prior to initiating lenalidomide treatment), and 51 patients had IRB/EC waivers. Thirteen patients were treated with lenalidomide monotherapy, 11 with lenalidomide plus rituximab, and 34 with other lenalidomide combinations (Additional file
1: Table S2). Two patients initially identified for analysis were excluded from this observational cohort because they did not meet all eligibility criteria (one patient treated with lenalidomide plus rituximab had not relapsed while on ibrutinib and one patient was not treated with lenalidomide); these two patients are not included in the overall enrolled set of 58 patients.
Patients had a median age of 71 years (range, 50–89), and 71% were aged ≥ 65 years (Table
1). Forty-eight percent of patients had an Eastern Cooperative Oncology Group performance status of 0–1, 29% had high tumor burden, and 14% had bulky disease (≥ 7 cm). The Mantle Cell International Prognostic Index (MIPI) score could not be derived for most patients due to a lack of the required data to complete appropriate calculations for 30 patients (i.e., 52% missing data for MIPI; Ki-67 data were not collected).
Table 1
Patient characteristics at study entry
Median age, years (range) | 67 (54–83) | 70 (58–84) | 71 (50–89) | 71 (50–89) |
≥ 65 | 6 | 46 | 9 | 82 | 26 | 76 | 41 | 71 |
Sex |
Male | 11 | 85 | 8 | 73 | 25 | 74 | 44 | 76 |
Female | 2 | 15 | 3 | 27 | 9 | 26 | 14 | 24 |
ECOG PS |
0–1 | 7 | 54 | 5 | 45 | 16 | 47 | 28 | 48 |
2–4 | 3 | 23 | 1 | 9 | 4 | 12 | 8 | 14 |
Missing | 3 | 23 | 5 | 45 | 14 | 41 | 22 | 38 |
Tumor burdena
|
High | 4 | 31 | 1 | 9 | 12 | 35 | 17 | 29 |
Low | 1 | 8 | 5 | 45 | 13 | 38 | 19 | 33 |
Missing | 8 | 62 | 5 | 45 | 9 | 26 | 22 | 38 |
Bulky diseaseb
|
Yes | 2 | 15 | 0 | 0 | 6 | 18 | 8 | 14 |
No | 2 | 15 | 6 | 55 | 17 | 50 | 25 | 43 |
Missing | 9 | 69 | 5 | 45 | 11 | 32 | 25 | 43 |
Time from diagnosis to first lenalidomide dose, months |
Median | 58 | 47 | 46 | 49 |
Range | 15–144 | 6–105 | 4–214 | 4–214 |
Time from end of last prior antilymphoma therapy to first dose of lenalidomide, weeks |
Median | 0.7 | 0.3 | 0.7 | 0.7 |
Range | 0.1–3.5 | 0.1–21.7 | 0.1–12.6 | 0.1–21.7 |
Patients had received a median of four prior lines of systemic anti-lymphoma therapy (range, 1–13), 88% had three or more prior therapies, and 79% had received ibrutinib as monotherapy (Table
2). Most patients (60%) had lenalidomide-containing therapy as their next line of therapy, and 40% patients had ≥ 1 line(s) of other therapy preceding the lenalidomide regimen. Median duration of ibrutinib treatment was 4.3 months (range, 0.5–47.6). Eighty-eight percent of patients discontinued ibrutinib treatment for one or more reason, due to relapse/PD (
n = 27) and/or refractoriness (
n = 25), six patients discontinued due to toxicity, and one patient completed ibrutinib as planned but had relapsed/PD at the end of ibrutinib treatment. Besides ibrutinib, the most common previous systemic therapies were rituximab (97%), cyclophosphamide (84%), glucocorticoids (78%), vincristine (78%), doxorubicin (72%), bendamustine (57%), and cytarabine (52%) (Additional file
1: Table S3; note that multiple treatment names could be used to collect this information). The median time from last dose of ibrutinib to first dose of lenalidomide was 1.3 weeks (range, 0.1–21.7) (Table
3).
Table 2
Treatment history of enrolled patients
No. of prior antilymphoma treatment regimens |
Median | 4 | 3 | 4 | 4 |
Range | 3–7 | 2–8 | 1–13 | 1–13 |
No. of prior antilymphoma therapies |
1 | 0 | 0 | 0 | 0 | 1 | 3 | 1 | 2 |
2 | 0 | 0 | 4 | 36 | 2 | 6 | 6 | 10 |
3 | 5 | 38 | 3 | 27 | 10 | 29 | 18 | 31 |
≥ 4 | 8 | 62 | 4 | 36 | 21 | 62 | 33 | 57 |
Missing | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
Type of ibrutinib treatment |
Combination regimen | 1 | 8 | 1 | 9 | 10 | 29 | 12 | 21 |
Monotherapy | 12 | 92 | 10 | 91 | 24 | 71 | 46 | 79 |
Ibrutinib status at study inclusion |
Relapse/PD | 6 | 46 | 2 | 18 | 15 | 44 | 23 | 40 |
Refractory | 2 | 15 | 8 | 73 | 15 | 44 | 25 | 43 |
Intolerant | 3 | 23 | 0 | 0 | 3 | 9 | 6 | 10 |
Missing | 2 | 15 | 1 | 9 | 1 | 3 | 4 | 7 |
Duration of ibrutinib treatment, months |
Median | 4.8 | 3.9 | 4.3 | 4.3 |
Range | 1.2–13.9 | 2.0–16.6 | 0.5–47.6 | 0.5–47.6 |
Best response on ibrutinib |
CR | 2 | 15 | 0 | 0 | 6 | 18 | 8 | 14 |
PR | 5 | 38 | 2 | 18 | 11 | 32 | 18 | 31 |
SD | 0 | 0 | 1 | 9 | 0 | 0 | 1 | 2 |
Relapse/PD | 5 | 38 | 8 | 73 | 15 | 44 | 28 | 48 |
Unknown | 1 | 8 | 0 | 0 | 2 | 6 | 3 | 5 |
Primary reason for ibrutinib discontinuation |
Lack of efficacy | 9 | 69 | 11 | 100 | 31 | 91 | 51 | 88 |
Toxicity to ibrutinib | 3 | 23 | 0 | 0 | 2 | 6 | 5 | 9 |
Toxicity attribution unknown | 0 | 0 | 0 | 0 | 1 | 3 | 1 | 2 |
Completed ibrutinib treatment | 1 | 8 | 0 | 0 | 0 | 0 | 1 | 2 |
Time from end of last dose of ibrutinib to first dose of lenalidomide, weeksa
|
Median | 1.4 | 0.4 | 1.3 | 1.3 |
Range | 0.1–7.4 | 0.1–21.7 | 0.1–16.8 | 0.1–21.7 |
Table 3
Efficacy outcomes with lenalidomide in patients with MCL after ibrutinib failure or intolerance
Best response by investigator’s assessment |
ORR | 2 | 15 | 3 | 27 | 12 | 35 | 17 | 29 |
95% CI | 2–45% | 6–61% | 20–54% | 18–43% |
CR | 0 | 0 | 1 | 9 | 7 | 21 | 8 | 14 |
PR | 2 | 15 | 2 | 18 | 5 | 15 | 9 | 15 |
SD | 0 | 0 | 1 | 9 | 3 | 9 | 4 | 7 |
Relapse/PD | 8 | 62 | 3 | 27 | 16 | 47 | 27 | 47 |
Unknown | 3 | 23 | 2 | 18 | 3 | 9 | 8 | 14 |
Missing | 0 | 0 | 2 | 18 | 0 | 0 | 2 | 3 |
Duration of response, weeks |
KM median | 3 | 20 | NA | 20 |
95% CI | NA to NA | NA to NA | 16.4 to NA | 2.9 to NA |
Efficacy
Among the 58 patients, the median duration of treatment was 8.4 weeks for single-agent lenalidomide and 7.4 weeks for lenalidomide-containing combination therapy (Table
4). Eight patients achieved a CR and nine achieved a PR with lenalidomide-based therapy, for an ORR of 29% (95% CI, 18–43%; Table
3), which exceeded the predefined lower boundary of the 95% confidence threshold of 10% ORR. Seven of the eight patients with CR had CT ± PET/CT assessments. Two of the 13 patients (15%) who had single-agent lenalidomide (fourth line of therapy for both) reported a best response of relapse/PD to ibrutinib; 3/13 (23%) patients on single-agent lenalidomide had unknown response status with 8/13 (62%) reporting relapse/PD.
Table 4
Lenalidomide treatment exposure (safety population)
Lenalidomide treatment duration, weeks |
Median | 8.4 | 14.0 | 7.0 | 8.4 |
Range | 0.4 to 30.0 | 0.9 to 37.9 | 1.1 to 77.9 | 0.4 to 77.9 |
Number of lenalidomide cycles |
Median | 2.0 | 2.0 | 1.0 | 2.0 |
Range | 1.0 to 7.0 | 1.0 to 9.0 | 0.0 to 11.0 | 0.0 to 11.0 |
Duration of other therapy combined with lenalidomide, weeks |
Median | NA | 8.3 | 7.2 | 7.4 |
Range | NA | 0.1 to 35.9 | 0.7 to 77.7 | 0.1 to 77.7 |
The median DOR for responders was 20 weeks (95% CI, 2.9 to not reached); of the 17 responders, 14 (82%; 7 CR and 7 PR) were censored from the DOR analysis due to lack of follow-up data on PD or death. At the last available assessment of the 14 censored patients, three were ongoing, three had completed lenalidomide treatment as planned, and eight patients discontinued lenalidomide treatment early (withdrew consent [n = 1], patient decision [n = 1], enrolled in a clinical trial for oral treatment [n = 1], started other lines of treatment [n = 3; because of lung cancer, physician’s decision, or bone marrow transplant], and toxicity [n = 2]). One of the censored patients who had a first response of PR and best response of CR had the last censored DOR at 25 weeks before stopping therapy. For the three uncensored patients, two had a best response of PR and one had CR, with an estimated DOR of 2.9, 19.7, and 16.4 weeks, respectively. Univariate analysis showed a median DOR of 16 weeks (95% CI, 2.9–19.7) in the three uncensored patients (14 patient responders were censored; total of 17 responders).
Safety
Overall, patients received a median of two cycles (range, 0–11) of lenalidomide-based treatment. Most patients received lenalidomide 10–25 mg/day on days 1–21 of each 28-day cycle. As of the cutoff date of November 1, 2016, 54 patients had discontinued lenalidomide-based therapy and four patients continue to receive lenalidomide (three censored for efficacy analyses), one in combination with weekly bortezomib/dexamethasone/rituximab, two in combination with weekly rituximab, and one in combination with weekly obinutuzumab. The primary reasons for lenalidomide treatment discontinuation were lack of efficacy (n = 27); toxicity (n = 10); other reasons (n = 9), such as initiation of another therapy (e.g., based on physician or patient choice) or trial (also an oral therapy), undergoing stem cell transplantation, or primary clinician/patient decision to stop therapy; completion of lenalidomide treatment (n = 5); and missing data (n = 3).
Of the 58 patients analyzed for safety, 48 (83%) had one or more TEAE during lenalidomide treatment. Twenty (34%) patients had at least one serious TEAE (lenalidomide alone 23%; lenalidomide + rituximab 36%; lenalidomide + others 38%). The most frequently reported serious TEAEs of any grade were febrile neutropenia (
n = 4; 7%), hypotension (7%), deep vein thrombosis (DVT) (
n = 3; 5%), pneumonia (5%), pancytopenia (5%), fall (5%), acute kidney injury (5%), dyspnea (
n = 2; 3%), sepsis (3%), and respiratory failure (3%). Overall, nine (16%) patients had at least one TEAE leading to dose discontinuation (lenalidomide alone 8%; lenalidomide + rituximab 18%; lenalidomide + others 18%). These TEAEs included pancytopenia, thrombocytopenia, and rash, each experienced by two patients (3%), and anemia, febrile neutropenia, neutropenia, sepsis, fall, squamous cell lung carcinoma, dyspnea, pleural effusion, and orthostatic hypotension, each experienced by one patient (2%). The most common all-grade TEAEs were fatigue, cough, dizziness, dyspnea, nausea, peripheral edema, anemia, rash, thrombocytopenia, and neutropenia (Table
5).
Table 5
Documented treatment-emergent all-grade adverse events in ≥ 10% of patients (safety population)
Hematologic |
Anemia | 2 | 15 | 3 | 27 | 5 | 15 | 10 | 17 |
Thrombocytopenia | 1 | 8 | 1 | 9 | 7 | 21 | 9 | 16 |
Neutropenia | 1 | 8 | 1 | 9 | 6 | 18 | 8 | 14 |
Pancytopenia | 1 | 8 | 3 | 27 | 3 | 9 | 7 | 12 |
Febrile neutropenia | 0 | 0 | 0 | 0 | 6 | 18 | 6 | 10 |
Nonhematologic |
Fatigue | 4 | 31 | 4 | 36 | 14 | 41 | 22 | 38 |
Nausea | 2 | 15 | 2 | 18 | 7 | 21 | 11 | 19 |
Dizziness | 2 | 15 | 2 | 18 | 7 | 21 | 11 | 19 |
Dyspnea | 2 | 15 | 3 | 27 | 6 | 18 | 11 | 19 |
Peripheral edema | 0 | 0 | 2 | 18 | 9 | 26 | 11 | 19 |
Rash | 2 | 15 | 1 | 9 | 7 | 21 | 10 | 17 |
Cough | 1 | 8 | 3 | 27 | 7 | 21 | 11 | 19 |
Decreased appetite | 2 | 15 | 0 | 0 | 5 | 15 | 7 | 12 |
Diarrhea | 0 | 0 | 1 | 9 | 7 | 21 | 8 | 14 |
Headache | 3 | 23 | 1 | 9 | 2 | 6 | 6 | 10 |
Pyrexia | 1 | 8 | 0 | 0 | 5 | 15 | 6 | 10 |
Vomiting | 0 | 0 | 2 | 18 | 4 | 12 | 6 | 10 |
Constipation | 0 | 0 | 0 | 0 | 6 | 18 | 6 | 10 |
Laboratory investigations |
Platelet count decreased | 2 | 15 | 1 | 9 | 3 | 9 | 6 | 10 |
White blood cell count decreased | 1 | 8 | 1 | 9 | 4 | 12 | 6 | 10 |
As of the cutoff date, 28 (48%) patients had died, 12 (21%) during treatment with lenalidomide, and 15 (26%) during follow-up (one unknown). Overall, 20 (34%) patients died from malignant disease (i.e., MCL) or its complications, five from unknown causes (not assessable or insufficient data), one reported another cause of end-stage renal disease, and two due to AEs. Of the two patients who died due to AEs, the first patient included a 68-year-old man in the lenalidomide-alone group who died during treatment (83 days after the first lenalidomide dose). This patient had a PR 2 months after lenalidomide initiation but died due to a pulmonary embolism, suspected to be related to lenalidomide therapy, as well as had incidences of other grade 5 AEs (DVT and cardiac arrest). Although this patient was receiving aspirin, therapy was stopped during study admission. For most patients, it is not known if the patients received antithrombotic treatment, since concomitant treatments were not part of the collected data. The second patient who died due to an AE was a 71-year-old man who received one treatment cycle of lenalidomide in combination with ibrutinib, rituximab, bortezomib, and dexamethasone. This second patient died while on study treatment (25 days after the first dose of lenalidomide) because of progression of MCL (which included acute kidney injury, lactic acidosis, respiratory failure, and hypotension).