Consensus recommendations for eligibility criteria in first-line DLBCL RCTs based on a Delphi-method survey of lymphoma clinical trials experts
| Criterion . | Recommendation . |
|---|---|
| Essential criteria | |
| Pregnancy status | Pregnant women should be excluded from enrollment. |
| Breastfeeding status | Breastfeeding should be prohibited during trial participation. |
| Female: contraception or abstinence | Effective contraception or abstinence from heterosexual intercourse is required for enrollment if of childbearing potential. |
| Male: contraception or abstinence | Effective contraception or abstinence from heterosexual intercourse is required for enrollment. |
| Participation in other study or treatment with other investigational drug | Study participants should receive no concurrent treatment with any other investigational therapy. Study participants should have received no treatment within the last 30 d with any other investigational therapy. Participation in nontherapeutic studies (eg, subject registries) is permitted. |
| IPI score | We recommend inclusion of IPI score as an eligibility criterion. No single IPI score range is recommended. IPI score range should be determined based on the target population for a given study. Alternately, consider using discrete elements of IPI as eligibility criteria rather than total IPI value. |
| Ann Arbor stage | Patients with Ann Arbor stages II-IV should be eligible for enrollment. Inclusion of patients with stage-I disease should depend on the study hypothesis and should be determined on a trial-by-trial basis. |
| Age at diagnosis | At baseline, patients aged ≥ 18 y should be eligible for trial participation. Determine final age range based on study intervention and target population, though most first-line RCTs do not require additional age cutoffs beyond age ≥ 18 y. |
| Performance status | We recommend including patients with PS of ECOG 0-2 and ECOG 3 if poor PS is due to lymphoma. |
| Renal function | Exclude patients based on a selected threshold value for renal function unless renal dysfunction is attributable to lymphoma. Selection of threshold value should take into account specific therapies in trial. Allow for use of both a Cr threshold and a CrCl threshold from the following ranges:
|
| Hepatic function | Exclude patients based on selected threshold values for hepatic function unless hepatic dysfunction is attributable to lymphoma or Gilbert’s syndrome. Selection of threshold values should take into account specific therapies in trial. Select baseline eligibility thresholds from the following ranges:
|
| CNS involvement | No known CNS involvement by lymphoma should be permitted in frontline trials evaluating strategies to improve standard of care therapy. Testing for CNS lymphoma is not required for enrollment and should be performed only when based on clinical suspicion. |
| Presence of other significant, uncontrolled, concomitant disease at investigator’s discretion | No other significant, uncontrolled, concomitant disease should be permitted at investigator’s discretion. |
| Unnecessary criteria | |
| CD20 positivity | Assessment of CD20 positivity is standard for diagnosis but should not be included as an eligibility criterion for enrollment in first-line clinical trials unless the investigational drug requires CD20 positivity to be efficacious. |
| Central pathology review prior to enrollment | Do not include central pathology review prior to enrollment as an eligibility criterion. |
| History of other malignancies | Do not enroll patients with another currently active malignancy at investigator's discretion, other malignancy requiring treatment that would preclude administration of study drugs, or other malignancy likely to be fatal during the trial evaluation window. Otherwise, do not include history of other malignancies as an eligibility criterion. |
| History of stroke or intracranial hemorrhage | If the experimental drug is known to increase risk for future CVA, do not include patients with a history of stroke or intracranial hemorrhage in the past 6 mo. |
| Psychiatric illness | Do not include psychiatric illness as an eligibility criterion. Inability to comply with study protocols, demonstrate decision-making capacity, or participate in informed consent (unless a legally authorized representative provides consent on the patient's behalf) should preclude study enrollment, regardless of the underlying reason. |
| HIV status | Although HIV testing should be performed as part of standard clinical practice, HIV infection should not preclude trial enrollment. Patients with HIV who have adequate viral suppression and disease control should be evaluated and monitored for potential drug-drug interactions with experimental therapies but otherwise should be considered eligible for trial participation. |
| HBV status | Although HBV testing should be performed as part of standard clinical practice, HBV infection should not preclude trial enrollment. Patients with HBV who have adequate viral suppression and disease control should be evaluated and monitored for potential drug-drug interactions with experimental therapies but otherwise should be considered eligible for trial participation. |
| HCV status | Although HCV testing should be performed as part of standard clinical practice, HCV infection should not preclude trial enrollment. Patients with HCV who have adequate viral suppression and disease control should be evaluated and monitored for potential drug-drug interactions with experimental therapies but otherwise should be considered eligible for trial participation. |
| Minimum life expectancy | Do not include minimum life expectancy as an eligibility criterion. |
| Unresolved criteria | |
| Prior DLBCL treatment | Generally speaking, no prior DLBCL treatment should be permitted for enrollment except treatment with corticosteroids or 1 cycle of chemotherapy at investigator’s discretion. This criterion should be tailored to the hypothesis and target population in a given study. |
| Cardiac function | Determine whether to include assessment of cardiac function as an eligibility criterion based on the toxicity profile of study drugs. If the study includes an anthracycline, include assessment of cardiac function as an eligibility criterion using the following criteria:
|
| Platelet count | Patients with platelet count ≥75 000 platelets/µL are eligible for enrollment unless levels are attributable to bone marrow infiltration or spleen involvement by DLBCL. If the study drug is known to cause thrombocytopenia, consider a higher threshold value. If low platelets are due to lymphoma, patients with platelet count ≥50 000 platelets/µL are eligible for enrollment. If the study drug is known to cause thrombocytopenia, consider a higher threshold value. Alternately, if low platelets are due to lymphoma, it may be reasonable to consider no threshold value for enrollment. |
| Active infection requiring systemic therapy | Patients with a serious, active infection at investigator's discretion should not be permitted to enroll. If a patient with an active infection is enrolled, resolution of infection at investigator’s discretion is required prior to initiation of study therapy. |
| History of transformed lymphoma | Patients with a history of treated, indolent lymphoma should not be eligible for enrollment. Patients with untreated, indolent lymphoma under observation should be eligible for enrollment. Composite lymphoma does not preclude enrollment. |
| Cell-of-origin subtype | Include COO subtype as an eligibility criterion only if the study is designed to target a COO subtype using the investigational drug in question. Otherwise, do not include COO subtype as an eligibility criterion. |
| Peripheral neuropathy | If the experimental drug is known to cause peripheral neuropathy, then exclude patients with neuropathy using a severity threshold based on the experimental drug’s known toxicity profile. Otherwise, exclude only patients with severe neuropathy, and include instructions for vincristine dose adjustment for patients with mild and moderate underlying peripheral neuropathy. |
| Criteria showing disagreement | |
| Measurable disease on imaging | If the primary endpoint in the trial is treatment response, then patients with measurable disease on imaging ≥1.5 cm in ≥1 diameter should be eligible for enrollment. Otherwise, do not include measurable disease on imaging as an eligibility criterion. Any evidence of disease is sufficient for enrollment. |
| White blood cell count | Patients with ANC ≥1000 cells/µL should be eligible for enrollment. Exclude patients with ANC <1000 cells/µL unless low levels are attributable to bone marrow infiltration or spleen involvement by DLBCL. If low ANC is due to lymphoma, do not use a threshold value for enrollment. |
| Criterion . | Recommendation . |
|---|---|
| Essential criteria | |
| Pregnancy status | Pregnant women should be excluded from enrollment. |
| Breastfeeding status | Breastfeeding should be prohibited during trial participation. |
| Female: contraception or abstinence | Effective contraception or abstinence from heterosexual intercourse is required for enrollment if of childbearing potential. |
| Male: contraception or abstinence | Effective contraception or abstinence from heterosexual intercourse is required for enrollment. |
| Participation in other study or treatment with other investigational drug | Study participants should receive no concurrent treatment with any other investigational therapy. Study participants should have received no treatment within the last 30 d with any other investigational therapy. Participation in nontherapeutic studies (eg, subject registries) is permitted. |
| IPI score | We recommend inclusion of IPI score as an eligibility criterion. No single IPI score range is recommended. IPI score range should be determined based on the target population for a given study. Alternately, consider using discrete elements of IPI as eligibility criteria rather than total IPI value. |
| Ann Arbor stage | Patients with Ann Arbor stages II-IV should be eligible for enrollment. Inclusion of patients with stage-I disease should depend on the study hypothesis and should be determined on a trial-by-trial basis. |
| Age at diagnosis | At baseline, patients aged ≥ 18 y should be eligible for trial participation. Determine final age range based on study intervention and target population, though most first-line RCTs do not require additional age cutoffs beyond age ≥ 18 y. |
| Performance status | We recommend including patients with PS of ECOG 0-2 and ECOG 3 if poor PS is due to lymphoma. |
| Renal function | Exclude patients based on a selected threshold value for renal function unless renal dysfunction is attributable to lymphoma. Selection of threshold value should take into account specific therapies in trial. Allow for use of both a Cr threshold and a CrCl threshold from the following ranges:
|
| Hepatic function | Exclude patients based on selected threshold values for hepatic function unless hepatic dysfunction is attributable to lymphoma or Gilbert’s syndrome. Selection of threshold values should take into account specific therapies in trial. Select baseline eligibility thresholds from the following ranges:
|
| CNS involvement | No known CNS involvement by lymphoma should be permitted in frontline trials evaluating strategies to improve standard of care therapy. Testing for CNS lymphoma is not required for enrollment and should be performed only when based on clinical suspicion. |
| Presence of other significant, uncontrolled, concomitant disease at investigator’s discretion | No other significant, uncontrolled, concomitant disease should be permitted at investigator’s discretion. |
| Unnecessary criteria | |
| CD20 positivity | Assessment of CD20 positivity is standard for diagnosis but should not be included as an eligibility criterion for enrollment in first-line clinical trials unless the investigational drug requires CD20 positivity to be efficacious. |
| Central pathology review prior to enrollment | Do not include central pathology review prior to enrollment as an eligibility criterion. |
| History of other malignancies | Do not enroll patients with another currently active malignancy at investigator's discretion, other malignancy requiring treatment that would preclude administration of study drugs, or other malignancy likely to be fatal during the trial evaluation window. Otherwise, do not include history of other malignancies as an eligibility criterion. |
| History of stroke or intracranial hemorrhage | If the experimental drug is known to increase risk for future CVA, do not include patients with a history of stroke or intracranial hemorrhage in the past 6 mo. |
| Psychiatric illness | Do not include psychiatric illness as an eligibility criterion. Inability to comply with study protocols, demonstrate decision-making capacity, or participate in informed consent (unless a legally authorized representative provides consent on the patient's behalf) should preclude study enrollment, regardless of the underlying reason. |
| HIV status | Although HIV testing should be performed as part of standard clinical practice, HIV infection should not preclude trial enrollment. Patients with HIV who have adequate viral suppression and disease control should be evaluated and monitored for potential drug-drug interactions with experimental therapies but otherwise should be considered eligible for trial participation. |
| HBV status | Although HBV testing should be performed as part of standard clinical practice, HBV infection should not preclude trial enrollment. Patients with HBV who have adequate viral suppression and disease control should be evaluated and monitored for potential drug-drug interactions with experimental therapies but otherwise should be considered eligible for trial participation. |
| HCV status | Although HCV testing should be performed as part of standard clinical practice, HCV infection should not preclude trial enrollment. Patients with HCV who have adequate viral suppression and disease control should be evaluated and monitored for potential drug-drug interactions with experimental therapies but otherwise should be considered eligible for trial participation. |
| Minimum life expectancy | Do not include minimum life expectancy as an eligibility criterion. |
| Unresolved criteria | |
| Prior DLBCL treatment | Generally speaking, no prior DLBCL treatment should be permitted for enrollment except treatment with corticosteroids or 1 cycle of chemotherapy at investigator’s discretion. This criterion should be tailored to the hypothesis and target population in a given study. |
| Cardiac function | Determine whether to include assessment of cardiac function as an eligibility criterion based on the toxicity profile of study drugs. If the study includes an anthracycline, include assessment of cardiac function as an eligibility criterion using the following criteria:
|
| Platelet count | Patients with platelet count ≥75 000 platelets/µL are eligible for enrollment unless levels are attributable to bone marrow infiltration or spleen involvement by DLBCL. If the study drug is known to cause thrombocytopenia, consider a higher threshold value. If low platelets are due to lymphoma, patients with platelet count ≥50 000 platelets/µL are eligible for enrollment. If the study drug is known to cause thrombocytopenia, consider a higher threshold value. Alternately, if low platelets are due to lymphoma, it may be reasonable to consider no threshold value for enrollment. |
| Active infection requiring systemic therapy | Patients with a serious, active infection at investigator's discretion should not be permitted to enroll. If a patient with an active infection is enrolled, resolution of infection at investigator’s discretion is required prior to initiation of study therapy. |
| History of transformed lymphoma | Patients with a history of treated, indolent lymphoma should not be eligible for enrollment. Patients with untreated, indolent lymphoma under observation should be eligible for enrollment. Composite lymphoma does not preclude enrollment. |
| Cell-of-origin subtype | Include COO subtype as an eligibility criterion only if the study is designed to target a COO subtype using the investigational drug in question. Otherwise, do not include COO subtype as an eligibility criterion. |
| Peripheral neuropathy | If the experimental drug is known to cause peripheral neuropathy, then exclude patients with neuropathy using a severity threshold based on the experimental drug’s known toxicity profile. Otherwise, exclude only patients with severe neuropathy, and include instructions for vincristine dose adjustment for patients with mild and moderate underlying peripheral neuropathy. |
| Criteria showing disagreement | |
| Measurable disease on imaging | If the primary endpoint in the trial is treatment response, then patients with measurable disease on imaging ≥1.5 cm in ≥1 diameter should be eligible for enrollment. Otherwise, do not include measurable disease on imaging as an eligibility criterion. Any evidence of disease is sufficient for enrollment. |
| White blood cell count | Patients with ANC ≥1000 cells/µL should be eligible for enrollment. Exclude patients with ANC <1000 cells/µL unless low levels are attributable to bone marrow infiltration or spleen involvement by DLBCL. If low ANC is due to lymphoma, do not use a threshold value for enrollment. |
ANC, absolute neutrophil count; CD20, cluster of differentiation 20; CNS, central nervous system; Cr, creatinine; CrCl, creatinine clearance; CVA, cerebrovascular accident; EF, ejection fraction; PS, performance status; R-CHOP + X, R-CHOP plus targeted therapy; ULN, upper limit of normal.