Pretreatment patient and disease assessments in CLL or SLL
| Assessment . | Description and role in prognosis and treatment selection . |
|---|---|
| Patient preference | |
| Shared decision-making discussion | As there are frequently multiple reasonable treatment options for patients with CLL/SLL, patients should be engaged in treatment discussions at all lines of therapy. This is especially crucial in the frontline setting, when deciding between a cBTKi and Ven-O (Section 4.2; Figure 1A) and in the third-line setting for patients with prior Ven and a cBTKi, when deciding between pirtobrutinib and liso-cel (Section 6.1). |
| Performance status and physical examination | |
| ECOG performance status | We assess performance status before each line of therapy (supplemental Table 12). |
| Physical examination | We evaluate for distribution and size of lymphadenopathy, splenomegaly, in addition to a complete physical examination (eg, skin, head/neck, heart, lungs, and abdomen). |
| Feasibility | |
| Transportation to medical center | Ven w/wo anti-CD20 mAb: frequent visits are required during the ramp-up. |
| Resources at treating facility | Ven w/wo anti-CD20 mAb: facility must have ability to perform STAT laboratory testing and interventions if needed based on results during the ramp-up. Liso-cel: facility must be accredited for CAR T-cell therapy administration. |
| Financial implications | High copayments for oral therapies: high copayments can be prohibitive for some patients, although copayment assistance programs are available through foundations and free drug programs are available through pharmaceutical companies to address this. Refer to LRF patient assistance. Liso-cel: patient must have companion and remain within 2 h of the facility for 1 mo from cell infusion, which may require temporary leave from work for patient and companion. |
| Comorbidities | |
| AF | We evaluate for past medical history, active comorbidities, and concomitant medications that can influence treatment selection between a second-generation cBTKi vs Ven-O for previously untreated patients with CLL/SLL (Table 3; Figure 1). Additional workup w/wo referral to relevant consultants, for example, cardio-oncology, may be helpful based on initial evaluation. |
| Heart failure | |
| Hypertension | |
| Major bleeding | |
| Ventricular arrhythmia | |
| Concomitant medications | |
| Anticoagulation | Careful review of medications is necessary before each therapy, as concomitant administration of warfarin, a nonwarfarin anticoagulant, single or dual antiplatelet therapy, may influence treatment selection or require modification (Section 4.3; Figure 1). Additionally, we recommend screening patient medications for potential interactions with the therapies under consideration. When interactions exist, we work with prescribing providers to determine whether there are acceptable alternatives, and with oncology pharmacy colleagues to determine impact on dosing. |
| Warfarin | |
| LMWH, DOACs | |
| Antiplatelet therapy | |
| Dual antiplatelet therapy | |
| Single antiplatelet therapy | |
| Drug interactions | |
| Organ function | |
| Kidney and liver function | We obtain a comprehensive metabolic panel to assess for kidney and liver dysfunction and follow the treatment package inserts for dosing.9-12 Kidney dysfunction can also increase TLS risk. |
| Disease burden | |
| Hematologic function | In patients with significant neutropenia, anemia, or thrombocytopenia, a bone marrow biopsy with aspirate is useful to determine the direct cause, such as CLL/SLL-related causes (eg, marrow infiltration, splenic sequestration, autoimmune hemolytic anemia, or immune thrombocytopenia) vs other causes (eg, myelosuppression or myelodysplasia from prior treatment, or alternative causes). |
| CT imaging | Baseline CT scan may be useful at diagnosis for patients with palpable lymphadenopathy or splenomegaly, or if warranted clinically based on symptoms. Pretreatment CT imaging should be obtained in patients considering treatment with Ven w/wo an anti-CD20 mAb to assess TLS risk. CT imaging is usually not required for diagnosis, serial monitoring, surveillance, routine monitoring of treatment response, or progression. |
| TLS risk | Greater disease burden measured by CT imaging (eg, LN ≥ 10 cm or LN ≥ 5 cm with ALC ≥ 25 000/μL as defined in the Ven package insert), and presence of significant kidney dysfunction, may increase TLS risk. We follow treatment package inserts for TLS monitoring and preventive measures. |
| Related conditions | |
| Autoimmune complications | Presence of clinically significant autoimmune complications can influence treatment selection toward a therapy that includes an anti-CD20 mAb (Section 3). |
| Molecular testing | |
| IGHV mutation status | Diagnosis: we assess IGHV mutation status at diagnosis given association with time to initial therapy. Because IGHV mutation status is a fixed risk factor, this is assessed once, and not repeated with subsequent therapies. |
| Testing for mutations in TP53 | Diagnosis: although we often perform TP53 mutation testing at diagnosis, we acknowledge a TP53 mutation would not affect management for a patient who does not meet iwCLL 2018 criteria to initiate therapy. Prior to each line of therapy: we perform TP53 mutation testing before each line of therapy, as presence of a TP53 mutation can influence treatment selection (Section 4.4; Figure 1C). Some panels include additional genes ATM, NOTCH1, SF3B1, and RAS/RAF mutations, which provide additional biological information about a patient’s disease, but these do not affect patient management. Previously treated with a BTKi: for patients who were previously treated with a BTKi, detecting mutations in BTK and/or PLCG2 associated with resistance to BTKis may provide biological information about a patient’s disease and potential emerging resistance, but patients may continue to respond to BTKis despite the detection of these mutations (Section 11). |
| FISH for 17p del, 11q del, +12, and 13q del, and for t(11;14), if applicable | Diagnosis: although we often obtain FISH to assess for 17p deletion, 11q deletion, 13q deletion, and trisomy 12, before each line of therapy, we acknowledge a 17p deletion would not affect management for a patient who does not meet iwCLL 2018 criteria to initiate therapy. Before each line of therapy: we obtain FISH to assess for 17p deletion, 11q deletion, 13q deletion, and trisomy 12, before each line of therapy, as presence of 17p deletion can influence treatment selection (Section 4.4; Figure 1C). Although an 11q deletion carried a negative prognosis with traditional chemoimmunotherapy, this does not appear so with modern therapies.13 Note regarding t(11;14): FISH for t(11;14) may be necessary to evaluate for mantle cell lymphoma, if CLL is otherwise diagnosed in peripheral blood only. FISH for t(11;14) is typically sufficient to rule out mantle cell lymphoma, although in some cases (eg, when circulating disease immunophenotype is otherwise typical of mantle cell lymphoma [eg, CD200− and CD23−] histologic confirmation may be necessary). |
| CpG-stimulated karyotype | Diagnosis: we obtain CpG-stimulated metaphase karyotype or SNP array to assess for karyotypic complexity at diagnosis. However, these results would not affect management for a patient who does not meet iwCLL 2018 criteria to initiate therapy. Before each line of therapy: we obtain CpG-stimulated metaphase karyotype or SNP array to assess for karyotypic complexity, as this is relevant to understanding prognosis. However, this does not currently affect treatment selection (Section 4.4). |
| Prognostic systems | |
| CLL-IPI score | The CLL-IPI is a validated prognostic model for patients with CLL/SLL receiving frontline therapy, for whom it predicts PFS (targeted therapies or traditional chemotherapy) w/wo OS (traditional chemotherapy), as well as for treatment-naïve patients on active surveillance, for whom it predicts time to initial therapy.14-16 The risk score is available on Calculate by QxMD. |
| BALL risk score | The BALL score was derived in patients with R/R CLL/SLL receiving cBTKis, and has been validated for patients with R/R CLL/SLL on a cBTKi, PI3Kδ, or Ven-based therapy, for whom it is prognostic for OS.17,18 Additionally, a low-risk BALL score (0-1) is associated with a higher likelihood of achieving response to liso-cel.19 The risk score is available on Calculate by QxMD. |
| 4-Factor model | The 4-factor model was derived and validated in patients with CLL/SLL receiving ibrutinib, for whom it is prognostic for PFS, OS, and cumulative incidence of BTK and PLCG2 mutations.20 |
| Suspicion for Richter transformation | |
| Assess for clinical suspicion of Richter transformation to DLBCL or HL. | Richter transformation should be considered in patients with B-symptoms, rapid progression, asymmetric progression, or significantly elevated lactate dehydrogenase without an alternative cause (eg, presence of hemolysis). |
| FDG-PET/CT imaging to direct biopsy | FDG-PET imaging should be obtained if Richter transformation is suspected. Because CLL/SLL is typically not hypermetabolic on FDG-PET imaging, we use FDG-PET/CT imaging to identify more FDG-avid sites of disease for biopsy to exclude Richter transformation (excisional biopsy preferred when feasible). |
| Assessment . | Description and role in prognosis and treatment selection . |
|---|---|
| Patient preference | |
| Shared decision-making discussion | As there are frequently multiple reasonable treatment options for patients with CLL/SLL, patients should be engaged in treatment discussions at all lines of therapy. This is especially crucial in the frontline setting, when deciding between a cBTKi and Ven-O (Section 4.2; Figure 1A) and in the third-line setting for patients with prior Ven and a cBTKi, when deciding between pirtobrutinib and liso-cel (Section 6.1). |
| Performance status and physical examination | |
| ECOG performance status | We assess performance status before each line of therapy (supplemental Table 12). |
| Physical examination | We evaluate for distribution and size of lymphadenopathy, splenomegaly, in addition to a complete physical examination (eg, skin, head/neck, heart, lungs, and abdomen). |
| Feasibility | |
| Transportation to medical center | Ven w/wo anti-CD20 mAb: frequent visits are required during the ramp-up. |
| Resources at treating facility | Ven w/wo anti-CD20 mAb: facility must have ability to perform STAT laboratory testing and interventions if needed based on results during the ramp-up. Liso-cel: facility must be accredited for CAR T-cell therapy administration. |
| Financial implications | High copayments for oral therapies: high copayments can be prohibitive for some patients, although copayment assistance programs are available through foundations and free drug programs are available through pharmaceutical companies to address this. Refer to LRF patient assistance. Liso-cel: patient must have companion and remain within 2 h of the facility for 1 mo from cell infusion, which may require temporary leave from work for patient and companion. |
| Comorbidities | |
| AF | We evaluate for past medical history, active comorbidities, and concomitant medications that can influence treatment selection between a second-generation cBTKi vs Ven-O for previously untreated patients with CLL/SLL (Table 3; Figure 1). Additional workup w/wo referral to relevant consultants, for example, cardio-oncology, may be helpful based on initial evaluation. |
| Heart failure | |
| Hypertension | |
| Major bleeding | |
| Ventricular arrhythmia | |
| Concomitant medications | |
| Anticoagulation | Careful review of medications is necessary before each therapy, as concomitant administration of warfarin, a nonwarfarin anticoagulant, single or dual antiplatelet therapy, may influence treatment selection or require modification (Section 4.3; Figure 1). Additionally, we recommend screening patient medications for potential interactions with the therapies under consideration. When interactions exist, we work with prescribing providers to determine whether there are acceptable alternatives, and with oncology pharmacy colleagues to determine impact on dosing. |
| Warfarin | |
| LMWH, DOACs | |
| Antiplatelet therapy | |
| Dual antiplatelet therapy | |
| Single antiplatelet therapy | |
| Drug interactions | |
| Organ function | |
| Kidney and liver function | We obtain a comprehensive metabolic panel to assess for kidney and liver dysfunction and follow the treatment package inserts for dosing.9-12 Kidney dysfunction can also increase TLS risk. |
| Disease burden | |
| Hematologic function | In patients with significant neutropenia, anemia, or thrombocytopenia, a bone marrow biopsy with aspirate is useful to determine the direct cause, such as CLL/SLL-related causes (eg, marrow infiltration, splenic sequestration, autoimmune hemolytic anemia, or immune thrombocytopenia) vs other causes (eg, myelosuppression or myelodysplasia from prior treatment, or alternative causes). |
| CT imaging | Baseline CT scan may be useful at diagnosis for patients with palpable lymphadenopathy or splenomegaly, or if warranted clinically based on symptoms. Pretreatment CT imaging should be obtained in patients considering treatment with Ven w/wo an anti-CD20 mAb to assess TLS risk. CT imaging is usually not required for diagnosis, serial monitoring, surveillance, routine monitoring of treatment response, or progression. |
| TLS risk | Greater disease burden measured by CT imaging (eg, LN ≥ 10 cm or LN ≥ 5 cm with ALC ≥ 25 000/μL as defined in the Ven package insert), and presence of significant kidney dysfunction, may increase TLS risk. We follow treatment package inserts for TLS monitoring and preventive measures. |
| Related conditions | |
| Autoimmune complications | Presence of clinically significant autoimmune complications can influence treatment selection toward a therapy that includes an anti-CD20 mAb (Section 3). |
| Molecular testing | |
| IGHV mutation status | Diagnosis: we assess IGHV mutation status at diagnosis given association with time to initial therapy. Because IGHV mutation status is a fixed risk factor, this is assessed once, and not repeated with subsequent therapies. |
| Testing for mutations in TP53 | Diagnosis: although we often perform TP53 mutation testing at diagnosis, we acknowledge a TP53 mutation would not affect management for a patient who does not meet iwCLL 2018 criteria to initiate therapy. Prior to each line of therapy: we perform TP53 mutation testing before each line of therapy, as presence of a TP53 mutation can influence treatment selection (Section 4.4; Figure 1C). Some panels include additional genes ATM, NOTCH1, SF3B1, and RAS/RAF mutations, which provide additional biological information about a patient’s disease, but these do not affect patient management. Previously treated with a BTKi: for patients who were previously treated with a BTKi, detecting mutations in BTK and/or PLCG2 associated with resistance to BTKis may provide biological information about a patient’s disease and potential emerging resistance, but patients may continue to respond to BTKis despite the detection of these mutations (Section 11). |
| FISH for 17p del, 11q del, +12, and 13q del, and for t(11;14), if applicable | Diagnosis: although we often obtain FISH to assess for 17p deletion, 11q deletion, 13q deletion, and trisomy 12, before each line of therapy, we acknowledge a 17p deletion would not affect management for a patient who does not meet iwCLL 2018 criteria to initiate therapy. Before each line of therapy: we obtain FISH to assess for 17p deletion, 11q deletion, 13q deletion, and trisomy 12, before each line of therapy, as presence of 17p deletion can influence treatment selection (Section 4.4; Figure 1C). Although an 11q deletion carried a negative prognosis with traditional chemoimmunotherapy, this does not appear so with modern therapies.13 Note regarding t(11;14): FISH for t(11;14) may be necessary to evaluate for mantle cell lymphoma, if CLL is otherwise diagnosed in peripheral blood only. FISH for t(11;14) is typically sufficient to rule out mantle cell lymphoma, although in some cases (eg, when circulating disease immunophenotype is otherwise typical of mantle cell lymphoma [eg, CD200− and CD23−] histologic confirmation may be necessary). |
| CpG-stimulated karyotype | Diagnosis: we obtain CpG-stimulated metaphase karyotype or SNP array to assess for karyotypic complexity at diagnosis. However, these results would not affect management for a patient who does not meet iwCLL 2018 criteria to initiate therapy. Before each line of therapy: we obtain CpG-stimulated metaphase karyotype or SNP array to assess for karyotypic complexity, as this is relevant to understanding prognosis. However, this does not currently affect treatment selection (Section 4.4). |
| Prognostic systems | |
| CLL-IPI score | The CLL-IPI is a validated prognostic model for patients with CLL/SLL receiving frontline therapy, for whom it predicts PFS (targeted therapies or traditional chemotherapy) w/wo OS (traditional chemotherapy), as well as for treatment-naïve patients on active surveillance, for whom it predicts time to initial therapy.14-16 The risk score is available on Calculate by QxMD. |
| BALL risk score | The BALL score was derived in patients with R/R CLL/SLL receiving cBTKis, and has been validated for patients with R/R CLL/SLL on a cBTKi, PI3Kδ, or Ven-based therapy, for whom it is prognostic for OS.17,18 Additionally, a low-risk BALL score (0-1) is associated with a higher likelihood of achieving response to liso-cel.19 The risk score is available on Calculate by QxMD. |
| 4-Factor model | The 4-factor model was derived and validated in patients with CLL/SLL receiving ibrutinib, for whom it is prognostic for PFS, OS, and cumulative incidence of BTK and PLCG2 mutations.20 |
| Suspicion for Richter transformation | |
| Assess for clinical suspicion of Richter transformation to DLBCL or HL. | Richter transformation should be considered in patients with B-symptoms, rapid progression, asymmetric progression, or significantly elevated lactate dehydrogenase without an alternative cause (eg, presence of hemolysis). |
| FDG-PET/CT imaging to direct biopsy | FDG-PET imaging should be obtained if Richter transformation is suspected. Because CLL/SLL is typically not hypermetabolic on FDG-PET imaging, we use FDG-PET/CT imaging to identify more FDG-avid sites of disease for biopsy to exclude Richter transformation (excisional biopsy preferred when feasible). |
ALC, absolute lymphocyte count; BALL, β2-microglobulin (≥5mg/dL), Anemia (HGB <12 g/dL for men or <11 g/dL for women), LDH (above upper limit of normal), and Last therapy (time from initiation of last therapy ≥24 months); CAR, chimeric antigen receptor; CLL-IPI; CLL-International Prognostic Index; CpG, cytidine monophosphate guanosine oligodeoxynucleotide; CT, computed tomography; DLBCL, diffuse large B-cell lymphoma; DOAC, direct oral anticoagulant; ECOG, Eastern Cooperative Oncology Group; FDG-PET, fludeoxyglucose positron emission tomography; FISH, fluorescence in situ hybridization; HL, Hodgkin lymphoma; LMHW, low molecular weight heparin; LN, lymph node; SNP, single-nucleotide polymorphism; STAT, statim (Latin for “immediate”); TLS, tumor lysis syndrome.