Statements pertinent to clinical trials for RT
| Statement number . | Grade . | Eligibility criteria for clinical trials . |
|---|---|---|
| 3.1.1 | R | If at all possible, patients with RT should be treated on clinical trials. |
| rk | We recognize that enrollment to clinical trials can be difficult given rapid disease progression, concurrent CLL, and comorbidities of patient population. | |
| 3.1.2 | R | Because of rapid disease progression attributed to RT, disease stabilization with 1 cycle of protocol-specific debulking treatment should not be considered an absolute exclusion criterion from clinical trials evaluating treatment-naïve regimens. |
| rk | Clinical trials should be designed to facilitate rapid initiation of therapy. However, it is common for patients with RT to present with reduced performance status or organ dysfunction due to the disease and may require therapy for stabilization. Therefore, we believe that therapy meant to stabilize the disease should be allowable before clinical trial enrollment for treatment-naïve disease. “One cycle of debulking treatment” could include a course of steroids but not immune or chemotherapy to minimize the risk of a biased efficacy or toxicity assessment of experimental treatments. | |
| 3.1.3 | R | Allow for the minimal or no washout period possible when considering prior therapy. |
| 3.1.4 | R | New RT-directed clinical trials should ensure liberal inclusion and exclusion criteria. |
| rk | Given the need for novel therapies for patients with RT we believe all patients should be treated on trial. Therefore, patients with comorbid conditions that could tolerate the treatment entailed in the trial, should be allowed on trial. Specifically, we should not be excluding patients from trial if patients have cytopenia due to the underlying CLL or RT, or if the disease is responsible for poor performance status. | |
| 3.1.5 | R | Active or symptomatic CLL should not be an exclusion to enroll on RT clinical trials. |
| Statement number | Grade | End points of clinical trials |
| 3.2.1 | R | Given the short survival of patients with RT, we consider a survival end point (ie, PFS, and OS) to be the primary end point of choice for RT phase 3 or randomized phase 2 clinical trials. |
| 3.2.2 | R | RT clinical trials should assess depth of response and correlate it with survival outcomes. |
| 3.2.3 | R | Samples should be collected prospectively on trials for exploratory analysis. |
| rk | Plasma is typically a biological sample feasible for prospective collection; however, nodal tissue can be stocked during and after treatment. Sample collection is particularly worthwhile at time of progression. | |
| Statement number | Grade | Response assessments |
| 3.3.1 | R | Given that RT is associated with short survival, we recommend designing clinical trials that include an early response assessment, typically within 1-3 cycles of treatment. |
| 3.3.2 | R | We strongly recommend using the PET-CT–based response per the Lugano criteria to assess response of patient with RT treated on clinical trials. |
| 3.3.3 | R | In clinical trials, we recommend PET-CT monitoring at regular intervals (eg, 3-6 months), and a PET-CT scan if there is suspicion for progression. |
| 3.3.4 | R | A biopsy to distinguish residual CLL from refractory RT is recommended when the end-of-treatment PET-CT scan demonstrates persistent Deauville 4 or 5 lesions. |
| rk | The biopsy should be of the highest SUV avid lesion, that is, most amenable to biopsy. If at all possible, the biopsy should be an excisional biopsy. This biopsy can also be used to distinguish whether these lesions represent nonmalignant changes vs residual/refractory disease. | |
| 3.3.5 | R | As recommended for standard of care, in clinical trials, we recommend a pretreatment bone marrow biopsy to determine the extent of CLL and RT in the bone marrow. |
| 3.3.6 | R | For patients with pretreatment marrow disease, we recommend a bone marrow biopsy at restaging to determine the extent of CLL and RT disease status to confirm CR. |
| rk | Patients with detectable CLL by peripheral blood flow cytometry at restaging do not need an additional bone marrow biopsy to assess CLL disease response. | |
| 3.3.7 | R | Response of RT and CLL should be objectively assessed and reported based on both Lugano criteria as well as iwCLL guidelines. |
| Statement number | Grade | Toxicity assessment |
| 3.4.1 | R | We recommend using CTCAE criteria to assess nonhematologic toxicity grade. |
| 3.4.2 | R | We recommend using iwCLL criteria for assessing hematologic toxicity grade. |
| Statement number | Grade | Other |
| 3.5.1 | R | In clinical trials, we recommend determining clonality. |
| rk | RT trials should not be limited to clonally related disease. We recommend preplanned subgroup analysis of patients with clonally related vs unrelated disease. All efforts should be made to determine clonality in a timely fashion with the possibility in the future to stratify patients at enrollment based on the clonal relatedness. Central determination of clonal relationship should be considered; additionally, results of clonal relationship are not needed to begin therapy on clinical trials. | |
| 3.5.2 | R | If possible, on-clinical-trial central review of pathology by an expert hematopathologist should occur.∗ |
| Statement number . | Grade . | Eligibility criteria for clinical trials . |
|---|---|---|
| 3.1.1 | R | If at all possible, patients with RT should be treated on clinical trials. |
| rk | We recognize that enrollment to clinical trials can be difficult given rapid disease progression, concurrent CLL, and comorbidities of patient population. | |
| 3.1.2 | R | Because of rapid disease progression attributed to RT, disease stabilization with 1 cycle of protocol-specific debulking treatment should not be considered an absolute exclusion criterion from clinical trials evaluating treatment-naïve regimens. |
| rk | Clinical trials should be designed to facilitate rapid initiation of therapy. However, it is common for patients with RT to present with reduced performance status or organ dysfunction due to the disease and may require therapy for stabilization. Therefore, we believe that therapy meant to stabilize the disease should be allowable before clinical trial enrollment for treatment-naïve disease. “One cycle of debulking treatment” could include a course of steroids but not immune or chemotherapy to minimize the risk of a biased efficacy or toxicity assessment of experimental treatments. | |
| 3.1.3 | R | Allow for the minimal or no washout period possible when considering prior therapy. |
| 3.1.4 | R | New RT-directed clinical trials should ensure liberal inclusion and exclusion criteria. |
| rk | Given the need for novel therapies for patients with RT we believe all patients should be treated on trial. Therefore, patients with comorbid conditions that could tolerate the treatment entailed in the trial, should be allowed on trial. Specifically, we should not be excluding patients from trial if patients have cytopenia due to the underlying CLL or RT, or if the disease is responsible for poor performance status. | |
| 3.1.5 | R | Active or symptomatic CLL should not be an exclusion to enroll on RT clinical trials. |
| Statement number | Grade | End points of clinical trials |
| 3.2.1 | R | Given the short survival of patients with RT, we consider a survival end point (ie, PFS, and OS) to be the primary end point of choice for RT phase 3 or randomized phase 2 clinical trials. |
| 3.2.2 | R | RT clinical trials should assess depth of response and correlate it with survival outcomes. |
| 3.2.3 | R | Samples should be collected prospectively on trials for exploratory analysis. |
| rk | Plasma is typically a biological sample feasible for prospective collection; however, nodal tissue can be stocked during and after treatment. Sample collection is particularly worthwhile at time of progression. | |
| Statement number | Grade | Response assessments |
| 3.3.1 | R | Given that RT is associated with short survival, we recommend designing clinical trials that include an early response assessment, typically within 1-3 cycles of treatment. |
| 3.3.2 | R | We strongly recommend using the PET-CT–based response per the Lugano criteria to assess response of patient with RT treated on clinical trials. |
| 3.3.3 | R | In clinical trials, we recommend PET-CT monitoring at regular intervals (eg, 3-6 months), and a PET-CT scan if there is suspicion for progression. |
| 3.3.4 | R | A biopsy to distinguish residual CLL from refractory RT is recommended when the end-of-treatment PET-CT scan demonstrates persistent Deauville 4 or 5 lesions. |
| rk | The biopsy should be of the highest SUV avid lesion, that is, most amenable to biopsy. If at all possible, the biopsy should be an excisional biopsy. This biopsy can also be used to distinguish whether these lesions represent nonmalignant changes vs residual/refractory disease. | |
| 3.3.5 | R | As recommended for standard of care, in clinical trials, we recommend a pretreatment bone marrow biopsy to determine the extent of CLL and RT in the bone marrow. |
| 3.3.6 | R | For patients with pretreatment marrow disease, we recommend a bone marrow biopsy at restaging to determine the extent of CLL and RT disease status to confirm CR. |
| rk | Patients with detectable CLL by peripheral blood flow cytometry at restaging do not need an additional bone marrow biopsy to assess CLL disease response. | |
| 3.3.7 | R | Response of RT and CLL should be objectively assessed and reported based on both Lugano criteria as well as iwCLL guidelines. |
| Statement number | Grade | Toxicity assessment |
| 3.4.1 | R | We recommend using CTCAE criteria to assess nonhematologic toxicity grade. |
| 3.4.2 | R | We recommend using iwCLL criteria for assessing hematologic toxicity grade. |
| Statement number | Grade | Other |
| 3.5.1 | R | In clinical trials, we recommend determining clonality. |
| rk | RT trials should not be limited to clonally related disease. We recommend preplanned subgroup analysis of patients with clonally related vs unrelated disease. All efforts should be made to determine clonality in a timely fashion with the possibility in the future to stratify patients at enrollment based on the clonal relatedness. Central determination of clonal relationship should be considered; additionally, results of clonal relationship are not needed to begin therapy on clinical trials. | |
| 3.5.2 | R | If possible, on-clinical-trial central review of pathology by an expert hematopathologist should occur.∗ |
B, background statement; CTCAE, common terminology criteria for adverse events; G, good practice statement; PFS, progression-free survival; R, research statement; rk, remark to earlier statement.
It is recommended to implement a central pathological review of diagnostic samples by expert hematopathologists to ensure the correct diagnostic assessment. We envision a future when central review will assess eligibility of enrollment, thanks to the sharing of the actual specimens or diagnostic slides, the latter potentially in a digital fashion.