Clinical endpoint definitions†
| Clinical endpoint . | Patients . | Definition . | Comments . |
|---|---|---|---|
| Objective response rate (ORR*) | CR and PR only unless maintenance trial | Proportion of patients with CR and PR | All changes in tumor measurements should be confirmed by repeat assessment no less than 4 wk after criteria for OR is first met. The skin or global ORR has value for documenting the potential efficacy of a given treatment but is less beneficial if duration is limited. The duration of response is from time of onset of at least a PR* until no longer meets the definition of PR. |
| Objective response rate 4 mo (ORR4) | CR and PR only | Proportion of patients with CR or PR in whom a confirmed OR lasts at least 4 mo. | This is a new clinical endpoint, used in a clinical trial of MF/SS. The duration of response is from time of onset of at least a PR until no longer meets the definition of PR. Useful endpoint in aggressive disease but 4 mo duration of OR may not be significant in all patients with PCL |
| Duration stable disease | All patients | Date of initiation of treatment to first date meets criteria for PD* | May be useful endpoint in early stage disease |
| Time to next treatment (TTNT) | All patients | Time from initiation of treatment in a clinical trial to date of initiation of next lymphoma therapy | This is a useful endpoint to help to determine the utility of those treatments that produce either less than an OR or less than the desired response but that have achieved a clinically meaningful response and have proven tolerable over time. What constitutes the next lymphoma therapy/therapies and what skin-directed treatments might be excluded should be clearly defined in the study design prior to trial initiation.53,54 |
| Time to response (TTR) | CR and PR only | Date of initiation of treatment to date when criteria for response (PR or CR) first met* | Provides expectations for speed of response |
| Response duration | CR and PR only | Date when criteria for response (CR or PR) first met until date response first lost; date of loss of response = date when first meets criteria for PD* | Responders should have assessments at regular intervals (generally monthly) to avoid undocumented and potentially incorrect recording of persistence of response |
| Freedom from relapse (FFR) or relapse-free survival (RFS) | CR only | Date when criteria for CR first met* until time of loss of CR* (relapse/recurrence): if global CR, recurrence of disease in any one category or death from any cause | Although a patient with a CR who no longer maintains complete clearing would no longer be disease free, he/she would remain a responder until date PR criteria is first lost |
| Disease-free survival (DFS) | CR only | Date when criteria for CR first met* until time of relapse/recurrence (if global CR, recurrence of disease in any one category) or death (as a result of lymphoma or acute toxicity of treatment) | DFS is useful in the setting of adjuvant therapy used after a definitive treatment leading to CR where survival is predicted to be prolonged; 3- and 5-y DFS are of particular relevance |
| Time to progression (TTP) | All patients | Date of initiation of treatment to first date meets criteria for PD* or death as a result of lymphoma | In TTP, death from causes other than lymphoma is censored either at the time of death or at an earlier assessment and represent a random pattern of loss from the study |
| Progression-free survival (PFS) | All patients | Date of initiation of treatment to first date meets criteria for PD or death as a result of any cause | PFS is particularly useful as a primary endpoint in early MF or indolent PCLs. For some patients who may not meet the criteria for PR, disease stabilization and extended PFS may be meaningful patient-related outcomes, especially if supported by QoL or other validated patient outcome measures. |
| Time to treatment failure (TTF) and freedom from treatment failure (FFTF) | All patients | Date of initiation of treatment until abandonment of therapy | Abandonment of therapy in TTF/FFTF does not apply to the conclusion of a standard regimen of a given therapy or discontinuation of therapy in cases of CR; causes of abandonment of therapy may include inadequate response to therapy, intolerable side effects or toxicity, disease progression, and patient withdrawal for whatever reason. |
| Overall survival | All patients | Date of initiation of therapy to date of death | Evaluation of survival is not optimal in clinical trials of the indolent PCLs or in MF with early disease but may be useful in those with late stage disease who have failed standard therapies, have a low performance score and in whom the duration of the planned trial is long enough to assess the predicted survival. |
| Clinical endpoint . | Patients . | Definition . | Comments . |
|---|---|---|---|
| Objective response rate (ORR*) | CR and PR only unless maintenance trial | Proportion of patients with CR and PR | All changes in tumor measurements should be confirmed by repeat assessment no less than 4 wk after criteria for OR is first met. The skin or global ORR has value for documenting the potential efficacy of a given treatment but is less beneficial if duration is limited. The duration of response is from time of onset of at least a PR* until no longer meets the definition of PR. |
| Objective response rate 4 mo (ORR4) | CR and PR only | Proportion of patients with CR or PR in whom a confirmed OR lasts at least 4 mo. | This is a new clinical endpoint, used in a clinical trial of MF/SS. The duration of response is from time of onset of at least a PR until no longer meets the definition of PR. Useful endpoint in aggressive disease but 4 mo duration of OR may not be significant in all patients with PCL |
| Duration stable disease | All patients | Date of initiation of treatment to first date meets criteria for PD* | May be useful endpoint in early stage disease |
| Time to next treatment (TTNT) | All patients | Time from initiation of treatment in a clinical trial to date of initiation of next lymphoma therapy | This is a useful endpoint to help to determine the utility of those treatments that produce either less than an OR or less than the desired response but that have achieved a clinically meaningful response and have proven tolerable over time. What constitutes the next lymphoma therapy/therapies and what skin-directed treatments might be excluded should be clearly defined in the study design prior to trial initiation.53,54 |
| Time to response (TTR) | CR and PR only | Date of initiation of treatment to date when criteria for response (PR or CR) first met* | Provides expectations for speed of response |
| Response duration | CR and PR only | Date when criteria for response (CR or PR) first met until date response first lost; date of loss of response = date when first meets criteria for PD* | Responders should have assessments at regular intervals (generally monthly) to avoid undocumented and potentially incorrect recording of persistence of response |
| Freedom from relapse (FFR) or relapse-free survival (RFS) | CR only | Date when criteria for CR first met* until time of loss of CR* (relapse/recurrence): if global CR, recurrence of disease in any one category or death from any cause | Although a patient with a CR who no longer maintains complete clearing would no longer be disease free, he/she would remain a responder until date PR criteria is first lost |
| Disease-free survival (DFS) | CR only | Date when criteria for CR first met* until time of relapse/recurrence (if global CR, recurrence of disease in any one category) or death (as a result of lymphoma or acute toxicity of treatment) | DFS is useful in the setting of adjuvant therapy used after a definitive treatment leading to CR where survival is predicted to be prolonged; 3- and 5-y DFS are of particular relevance |
| Time to progression (TTP) | All patients | Date of initiation of treatment to first date meets criteria for PD* or death as a result of lymphoma | In TTP, death from causes other than lymphoma is censored either at the time of death or at an earlier assessment and represent a random pattern of loss from the study |
| Progression-free survival (PFS) | All patients | Date of initiation of treatment to first date meets criteria for PD or death as a result of any cause | PFS is particularly useful as a primary endpoint in early MF or indolent PCLs. For some patients who may not meet the criteria for PR, disease stabilization and extended PFS may be meaningful patient-related outcomes, especially if supported by QoL or other validated patient outcome measures. |
| Time to treatment failure (TTF) and freedom from treatment failure (FFTF) | All patients | Date of initiation of treatment until abandonment of therapy | Abandonment of therapy in TTF/FFTF does not apply to the conclusion of a standard regimen of a given therapy or discontinuation of therapy in cases of CR; causes of abandonment of therapy may include inadequate response to therapy, intolerable side effects or toxicity, disease progression, and patient withdrawal for whatever reason. |
| Overall survival | All patients | Date of initiation of therapy to date of death | Evaluation of survival is not optimal in clinical trials of the indolent PCLs or in MF with early disease but may be useful in those with late stage disease who have failed standard therapies, have a low performance score and in whom the duration of the planned trial is long enough to assess the predicted survival. |
Based on Olsen et al8 and Cheson et al.55
This assumes that the response has been maintained for at least 4 weeks.
Definition of any endpoints utilized in a clinical trial, including whether deaths from second malignancies are censored in relevant ones, should be clearly outlined at protocol design and in study reports.