Chronic lymphocytic leukemia (CLL) is characterized by the progressive accumulation of functionally incompetent monoclonal lymphocytes. CLL is the most common adult leukemia in the Western world, accounting for approximately seven percent of non-Hodgkin lymphomas 1. In Canada, the median age at diagnosis is approximately 72 years, with ten percent of cases diagnosed in patients younger than 50 years of age. Age-adjusted incidence rates are 7.5 per 100,000 person-years, with males representing approximately 56 percent of the cases. The five-year survival is approximately 80 percent in men and 85 percent in women 2. In determining the optimal treatment for CLL, individual patient characteristics including performance status and disease characteristics must be considered.
Guideline Questions 1. What are the recommended diagnostic and staging criteria for adult patients in Alberta with CLL? 2. What are the recommended treatment strategies for adult patients in Alberta with newly diagnosed, relapsed, or refractory CLL? 3. What are the recommended follow-up and supportive care practices for adult patients in Alberta with CLL?

# Search Strategy
No formal literature search was conducted for the 2023 update, the update was based on a consensus meeting held in 2023. An updated review of the literature was conducted by searching journal articles using the Medline (1950 to May, Week 1, 2015), EMBASE (1980 to May, Week 1, 2015), Cochrane Database of Systematic Reviews, and PubMed electronic databases. The MeSH heading "Leukemia, Lymphocytic, Chronic, B-Cell" was combined with the search terms "drug therapy" and "therapy". The results were limited to adults, practice guidelines, systematic reviews, meta-analyses, multicentre studies, randomized controlled trials, and clinical trials. Articles were excluded from the final review if they: had a non-English abstract, were not available through the library system, or were published before the year 2000. The references and bibliographies of articles identified through these searches were scanned for additional sources. A search for practice guidelines published since January 2000 was conducted by accessing the websites of the following organizations: Cancer Care Ontario, British Columbia Cancer Agency, the National Comprehensive Cancer Network, the European Society for Medical Oncology, and the Italian Society of Hematology/Italian Group for Bone Marrow Transplantation.

# Target Population
The following guidelines apply to adults over 18 years of age. Different principles apply to pediatric patients.
Diagnosis and Prognosis 1. The initial diagnosis of CLL relies on the detection of a circulating B-lymphocyte count greater than or equal to 5 x 10 9 /L in the peripheral blood, for the duration of at least 3 months associated with a characteristic flow cytometry immunophenotype profile. Small lymphocytic lymphoma (SLL) is diagnosed when a lymph node or other tissue biopsy demonstrates a malignant lymphocytic infiltration with cells showing the same immunophenotype as CLL, but associated with a circulating B-lymphocyte count that does not exceed 5 x 10 9 /L. CLL and SLL are considered to be biologically the same disease and the management of SLL should follow CLL treatment guidelines (not guidelines for other indolent non-Hodgkin lymphoma subytpes) 3. 2. FISH cytogenetic analysis for del(17p) and TP53 mutation analysis should be performed at the time when patients require treatment. FISH analysis is not recommended at diagnosis in patients who do not require therapy, outside of clinical trials. 3. IgVH mutation testing should be performed at the time when patients require. This test should not be repeated at later time points (the results will not change over time). 4. Hepatitis B Surface Antigen (HBsAg), Hepatitis B Surface Antibody (anti-HBs), and Hepatitis B Core Antibody (total anti-HBc) must be done prior to initiating therapy. Patients who are HBsAg positive are either acutely or chronically infected and require consultation with Hepatology.
Patients who are HBsAg negative/anti-HBc positive (regardless of anti-HBs titre levels) and are going to be treated with B-cell depleting therapy should receive prophylactic therapy with entecavir or tenofovir. see Figure 1 for summary of HBV prophylaxis

# I. Diagnosis
CLL is described by the World Health Organization (WHO) as a neoplasm composed of monomorphic small, round-to-slightly irregular B-lymphocytes in the peripheral blood, bone marrow, spleen, and lymph nodes, admixed with prolymphocytes and paraimmunoblasts forming proliferation centres in tissue infiltrates 1. According to the 2008 International Workshop on CLL (IWCLL) guidelines, the diagnosis of CLL requires a circulating B-lymphocyte count greater than or equal to 5 x 10 9 /L in the peripheral blood, for the duration of at least 3 months 9. Although CLL and small lymphocytic lymphoma (SLL) are categorized by the WHO as similar entities, the term SLL is used to indicate neoplastic tissue infiltration in lymph nodes, spleen, or other organs associated with a circulating B-lymphocyte count that does not exceed 5 x 10 9 /L. 1 Monoclonal B-cell lymphocytosis (MBL) is a condition that resembles CLL,but does not require treatment. As many as 12 percent of healthy individuals over the age of 40 may have low levels (less than 5 x 10 9 /L) of circulating monoclonal B-cells that are phenotypically identical to CLL cells, but with no evidence of tissue infiltration 4. High count MBL progresses to CLL at a rate of one to two percent of patients per year 10,11.
Clinical features of CLL vary in their presentation, course, and outcome. Patients are often asymptomatic at diagnosis, but fatigue, autoimmune hemolytic anemia, infections, splenomegaly, hepatomegaly, lymphadenopathy, or extra-nodal infiltrates may be present. Some patients may also exhibit a small serum monoclonal protein, an M-component. Although in rare cases patients may not have lymphocytosis at diagnosis, peripheral blood and bone marrow are usually involved as the disease progresses. Lymph nodes, liver, and spleen are commonly infiltrated, with other extra-nodal sites becoming involved in some patients. 1 Although some CLL cases may have an atypical immunophenotype, the characteristic profile includes CD19/CD5/CD23/CD43/CD200 positivity with weak CD20 and CD11c positivity and dim surface immunoglobulin expression with restricted light chain expression 1.

# II. Staging
Two widely accepted staging methods, the modified Rai and the Binet systems, are used in both patient care and for clinical trials; the modified Rai system is the most commonly used in Canada. These staging systems are relatively simple, relying solely on physical examination and standard laboratory tests .

# Stage Description Median Survival (years)
A Hemoglobin 100 g/L and platelets 100 x 10 9 /L and  10 B Hemoglobin 100 g/L and platelets 100 x 10 9 /L and 3 involved nodal areas 5 C Hemoglobin <100 g/L and or platelets <100 x 10 9 /L and any number of involved nodal areas 2.0-4.0

# III. Prognostic and Predictive Biomarkers
A number of predictive and prognostic markers have been identified that may predict for responsiveness to chemotherapy and survival.

# Cytogenetic testing:
Interphase fluorescence in situ hybridization (FISH) can be used to identify cytogenetic abnormalities in more than 80 percent of patients. In general, patients with a normal karyotype or isolated del(13q) can be categorized as low risk with prolonged time to disease progression and better chances of long-term survival, whereas patients with del(17p), and del(11q) are more likely to have a poor prognosis. 15 Del(17p) leads to loss of the TP53 tumour suppressor gene, which mediates cell death induced by alkylating agents and purine analogues. Mutations in TP53 confer the same inferior prognosis as del(17p). Testing for TP53 mutations is thus recommended in patients who are not already known to harbor del(17p). 16 (However, such testing is not yet routinely available in Canada). Patients with del(17p) and/or TP53 mutation are typically less responsive to chemo-immunotherapy, but respond well to the novel agents including BCR inhibitors (BTKi and idelalisib + rituximab) 17 or BCL-2 inhibitors 10,18. FISH studies for del(17p) and TP53 mutation analysis should thus be performed when therapy is required. Other cytogenetic abnormalities do not impact treatment decision-making and are not routinely required outside of clinical trials.

# IgHV mutational status and VH3.21 gene usage:
Approximately half of all CLL patients have leukemic cells with somatic hyper-mutations in the immunoglobulin heavy chain variable region (IgHV) genes. Patients with mutated CLL have improved survival as compared to those with unmutated CLL 10,15. Patients with unmutated CLL exhibit faster disease progression, atypical peripheral blood cell morphology, adverse cytogenetic features, and clonal evolution. 15 The VH3.21 ("subset 2") gene is also an unfavourable prognostic marker, regardless of IgHV mutational status. 10 IgHV mutation status should influence treatment decision. Patients with mutated IgHV have excellent outcomes with fixed duration therapy (FCR or VO). BTK inhibitors appear to be equally efficacious in patients with mutated and unmutated IgHV and thus have most relative benefit in the unmutated IgHV subgoup. Initiating treatment: The IWCLL guidelines describe the initiation of treatment based on a combination of clinical staging, the presence of symptoms, and disease activity 5. These criteria include:
- Evidence of progressive marrow failure as manifested by the development or worsening of anemia and/or thrombocytopenia
- Massive (at least 6 cm below the left costal margin), progressive, or symptomatic splenomegaly - Massive nodes (at least 10 cm in the longest diameter), or progressive or symptomatic lymphadenopathy - Progressive lymphocytosis, with an increase of more than 50 percent over two months, or lymphocyte doubling time of less than six months (factors contributing to lymphocytosis or lymphadenopathy other than CLL such as infections should be excluded) - Autoimmune anemia and/or thrombocytopenia poorly responsive to corticosteroids/standard therapy
In addition, any one of the following symptoms may also be present:
- Unintentional weight loss of ten percent or more within the previous six months - Significant fatigue - Inability to work or perform usual activities - Fever higher than 38.0C for two weeks or more without other evidence of infection - Night sweats for more than one month without evidence of infection Assessing response to treatment: In assessing the response to treatment, a thorough physical examination and blood analysis should be performed. Although useful in clinical trials, imaging studies, including CT scans, are not recommended in general practice for routine screening/staging. 10,19 Patients in remission should be re-evaluated every three to six months to monitor disease status. 20,21 Given data suggesting possibly indefinite responses following FCR and remission of many years following VO, less frequent follow-up and care transitioned back to primary care are appropriate following fixed duration therapy in good risk patients. Additionally, early-stage patients who show limited progression of disease should have their active surveillance transitioned back to their primary care provider.

# V. Treatment First Line Treatment Options for CLL:
The ultimate treatment goal in CLL is to achieve a long overall survival, while minimizing toxicities and improving quality of life. In the absence of a survival benefit, achieving a long PFS is a reasonable goal of therapy. Consideration of the patient's preference is always important in the determination of any treatment decision.

# Fludarabine-cyclophosphamide-rituximab (FCR)
The phase III GCLLSG CLL8 trial compared the primary endpoint of PFS after treatment with FCR or FC in younger fit CLL patients. 22 22 Based on the results from the CLL-8 trial, FCR became the standard of care chemo-immunotherapy for firstline treatment of young, fit CLL patients. Long term follow-up studies of FCR suggest that the good risk subgroup of patients with mutated IgHV and no TP53 aberrations may potentially be cured with this approach or at least experience very prolonged PFS. 23

# Venetoclax + Obinutuzumab
Venetoclax-obinutuzumab was compared to chlorambucil-obinutuzumab in a randomized, phase 3, open-label trial of previously untreated CLL patients with coexisting conditions. 24 In total, N=432 patients were randomized (1:1). Median age was 72 years, cumulative Illness Rating Scale score was median 8, and median creatinine clearance was 66.4 mL/min. Follow-up data after a median 39.6 months 25 reported significantly longer PFS in the venetoclax-obinutuzumab arm (not reached) versus the chlorambucil-obinutuzumab arm (35.6 months) (HR: 0.31; 95%CI: 0.22-0.44, p<0.001). Serious adverse events occurred in 53% and 48% respectively. Treatment-related death occurred in n=1 (sepsis) patient in the venetoclax-obinutuzumab arm, and n=2 (n=1 septic shock, n=1 metastatic skin squamous carcinoma) patients in the chlorambucil-obinutuzumab arm.

# BTK inhibitors Ibrutinib
The open-label, phase III RESONATE-2 trial 26 randomized (1:1) 269 patients who were at least 65 years of age (range: 85-89; median 73 years) with a diagnosis of CLL/SLL to ibrutinib (420mg once daily) or up to 12 cycles of chlorambucil monotherapy. 26 The 24-month OS was also significantly improved with ibrutinib (98%) vs. chlorambucil (85%), despite a cross-over design of the study.
Adverse events (any grade) occurred in at least 20% of ibrutinib patients, including diarrhea, fatigue, cough, and nausea. The OS advantage demonstrated by ibrutinib in the firstline treatment of CLL at a short median follow-up is important; however, the comparator arm (chlorambucil monotherapy) was not a standard of care treatment option, which limited the value of this study's results.
Several subsequent Phase 3 studies have compared BTK inhibition with chemo-immunotherapy.
The Alliance A041202 study compared ibrutinib with or without rituximab against bendamustine and rituximab (BR) in previously-untreated, older ( 65 years) patients with CLL. 27 PFS was significantly improved with the use of ibrutinib (87%) compared to BR (74%, HR, 0.39; 95% CI, 0.26 to 0.58; p<0.001) while the addition of rituximab (88%) did not improve outcomes over ibrutinib monotherapy (HR, 1.00; 95% CI, 0.62 to 1.62; P = 0.49). Ibrutinib was not without toxicity and non-hematological toxicities were higher than in the BR arm (grade 3-5 non-hematological toxicities 74% for ibrutinibcontaining regimens compared to 63% for BR) while hematological toxicities were higher with BR (grade 3-5 hematological adverse events 61% with BR compared to 41% with ibrutinib). Adverse events of interest with ibrutinib including atrial fibrillation and hypertension were common with atrial fibrillation occurring in 17% of patients in the ibrutinib group and 14% in the ibrutinib + rituximab group, compared to 3% with BR. Grade 3 or higher hypertension occurred in approximately 30% of ibrutinib-treated patients. Importantly, several treatment-related deaths occurred with ibrutinib including sudden cardiac deaths and 1 major bleeding event. No overall survival (OS) difference has yet been reported in this study.
The ECOG 1912 study compared ibrutinib + rituximab to chemoimmunotherapy with fludarabine, cyclophosphamide and rituximab (FCR) in a young and fit CLL population. 28 The  29 Given data suggesting the possibility of very lengthy remissions and even potential cure with FCR in patients with mutated IGHV, we would continue to favour FCR in these patients 44. Ibrutinib toxicities were much less marked in these younger patients with only 1% of patients dying from an unexplained event (likely sudden cardiac death).
The GCLLSG CLL11 defined chlorambucil + Obinutuzumab (CLB-O) as the previous preferred CIT for older and unfit patients. 32 CLB-O conferred an overall survival benefit over CLB monotherapy (HR 0.41, p=0.002) and CLB-rituximab. CLB-O remains an effective therapy for elderly and/or very unfit patients who refuse VO but otherwise, has limited use in Alberta today.
The phase III GCLLSG CLL10 trial compared BR to FCR in young, fit CLL patients. While BR was more tolerable, particularly in older patients, the non-inferiority hypothesis was not rejected such that FCR is the preferred regimen for a young, fit patient who is considered for CIT. All patients who are not appropriate for FCR would be recommended to receive VO with limited use for BR predicted in Alberta today.

# Special Consideration
While it is acknowledged that there are no prospective trials for stopping continuous BTKi therapy for those who have achieved a durable remission, consideration could be given to stopping treatment for patients who have a reduced life expectancy due to co-morbidity. Patients who stopped BTKi therapy due to intolerance in a frontline treatment study, were shown to have a lengthy time to recurrence of disease (median 25 months) with an unknown time to next treatment. 33

# Summary of frontline treatment approach in CLL:
Given the improved PFS of targeted therapies over CIT in CLL, the only subgroup of patients who are recommended to consider CIT are the young, favourable risk group who may experience cure or very prolonged remission with FCR. VO is favoured over CIT in all other patients with favourable risk CLL. Indefinite BTKi therapy has not been compared against finite duration VO; however, patients with high risk disease (del(17p) and TP53 mutation and/or unmutated IgHV) obtain relatively greater benefit from BTKi over CIT and VO. Because of the predicted exponential increase in cost of indefinite BTKi therapy, we favour VO in all CLL patients without TP53 aberrations who are not appropriate for FCR.

# BTKi for Patients with del(17p) and/or TP53 mutation
Patients with TP53 aberrations were included in several of the novel therapy vs CIT studies (Alliance, iLLUMINATE, ELEVATE-TN and CLL14). Outcomes in patients with TP53 aberrations were inferior to those with intact TP53 in the CLL14 study patients who received VO while outcomes are not notably different in TP53 aberrant vs intact for the BTKi studies, making indefinite BTKi the preferred treatment for patients with del(17p) and/or TP53 mutation. 34

# Second and Subsequent Line Treatment Options for Relapsed and Refractory Patients with CLL:
Recommendations for second-line treatment of CLL should consider individual factors such as comorbidities and choice of prior therapy and its outcome.

# BCL2 inhibitor (Venetoclax)
The open-label phase 3 MURANO trial randomized (N=389) relapsed or refractory CLL patients who had received one to three previous treatments (including at least one chemotherapy-containing regimen) to venetoclax-rituximab (VenR) or bendamustine plus rituximab (BR)..

# BTK inhibitors:
The multicenter, open-label, phase 3 RESONATE trial randomized 391 patients with relapsed or refractory CLL or small lymphocytic lymphoma to receive daily ibrutinib or ofatumumab. Ibrutinib significantly improved progression free survival and overall survival compared to ofatumumab. 37
The phase III ASCEND trial 38 randomized (N=398) relapsed/refractory CLL patients to receive acalabrutinib monotherapy, or investigator's choice (idelalisib plus rituximab (IR) (n=119) or bendamustine plus rituximab (BR)(n=36)). After a median follow-up of 16.1 months, median progression-free survival was superior in the acalabrutinib arm (not reached vs. 16.5 months; HR: 0.31; 95%CI: 0.20-0.49; p<0.001; estimated 12-month PFS was 88% vs 68%). Serious adverse events occurred in 29% of patients treated with acalabrutinib, 56% of patients treated with IR, and 26% of patients treated with BR. Deaths occurred in 10%, 11%, and 14%, respectively.
The ELEVATE-R/R was the first Phase 3 study to provide a head-to-head comparison between 2 BTKis (ibrutinib and acalabrutinib in an unblinded comparison). 39 Patients (N=533) with relapsed/refractory CLL with del(17p) and/or del(11q) were randomised 1:1 to ibrutinib or acalabrutinib. The included patients had a median age of 66 years and a median of 2 prior lines of therapy. After a median of 41 months of follow-up, the hazard ratio for PFS was 1.0, (95% CI 0.79-1.27), meeting the primary endpoint of non-inferiority of PFS. The incidence of adverse events atrial fibrillation, hypertension and all grade bleeding were statistically significantly lower in the acalabrutinib treated patients compared to the ibrutinib-treated patients.
The multicenter, randomized phase 3 ALPINE study 40 randomized (1:1) N=652 relapse/refractory CLL patients who had received at least one previous therapy to either zanubrutinib or ibrutinib until disease progression or unacceptable toxicity. After a median follow-up of 29.6 months, zanubrutinib had superior PFS (HR:0.65; 95%CI: 0.49-0.86; p=0.002). Longer PFS was observed in patients with 17p deletion, TP53 mutation or both. The safety profile of zanubrutinib was better than that of ibrutinib, with fewer adverse events leading to treatment discontinuation and fewer cardiac events, including fewer cardiac events leading to treatment discontinuation or death. 41 The ELEVATE-RR and ALPINE studies confirm that second generation BTKi are better tolerated that ibrutinib. The reduced cardiac toxicities are particularly important given that rare cardiac deaths are observed with ibrutinib. These studies were performed in relapsed/refractory patients who were younger than average suggesting that this improved safety effect could be even more notable in the general population of CLL patients who are expected to be older and with more comorbidities than clinical trial selected patients. For this reason, second generation BTKi are favoured for all new BTKi starts (including firstline therapy). There is no comparative data between acalabrutinib and zanubrutinib with no evidence-based reason to favour one second-generation BTKi over the other.

# Idelalisib + rituximab
The randomized, multicenter, double-blind, placebo-controlled, phase 3 trial NCT01539512 compared Idelalisib (150 mg twice daily) plus rituximab to placebo plus rituximab in relapsed CLL patients. Patients in the idelalisib + R had improved overall survival at 12-months (92% vs 80%; p=0.02) compared to the placebo arm. Serious, adverse events were reported in 40% of patients in the idelalisib arm, compared to 35% in the placebo arm 42 with the most common serious adverse events being pneumonia (6%), pyrexia (6%), and febrile neutropenia (5%) (rates were similar in the placebo arm). Grade 3-4 diarrhea on idelalisib has been reported from 16-42%. 37,43,44 This therapy is rarely used in Canada due to high rates of toxicity and treatment discontinuations. It would currently only be recommended as a bridge to allogeneic transplant or clinical trial in motivated patients.

# Choosing between novel agents ibrutinib, acalabrutinib, venetoclax + rituximab or idelalisib +/-rituximab:
All of the novel agents have demonstrated impressive efficacy in patients with relapsed/refractory CLL. Most of these studies include patients previously treated with CIT so the move to novel therapies frontline should be considered when treating future patients. Several factors can be considered when selecting between agents including expected toxicities and desire for time-limited therapy. No head-to-head studies have compared BTKi to VenR; however, time-limited therapy provides an expected cost savings, which favour VenR over BTKi when possible. Patients with del(17p) or TP53 mutation have better disease control with indefinite BTKi such that BTKi is preferred in those patients. Idelalisib + rituximab has limited role given a lack of efficacy in patients who have failed BTKi, the high rate of toxicities and the availability of multiple BTKi options now.

# Venetoclax monotherapy:
A multicenter, open-labelled, non-randomized, phase 2 trial of adult patients with relapsed or refractory CLL, previously treated with ibrutinib, negative for Richter's transformation, has reported interim outcomes from 91 patients after treatment with venetoclax. 45 After a median follow-up of 12 months, 59 of 91 (65%, 95% CI 53-74) patients had an overall response. Disease progression was responsible for 7 of 17 deaths in the cohort, none of which were treatment-related deaths. A smaller phase 2 study of 36 patients with refractory/relapsed CLL after ibrutinib or idelalisib were treated with venetoclax (20mg daily, followed by ramp-up to 400mg daily). 45 Estimated 12-month progression free survival was 79%, with 2 patients achieving complete remission. Based on these data, indefinite venetoclax monotherapy was recommended for patients who fail BCRi.

# Allogeneic stem cell transplantation:
Allogeneic stem cell transplantation may be considered for fit patients younger than 70 years who:
- Have refractory CLL - Have CLL with del(17p) abnormalities (patient should be assessed for HSCT when starting a second novel therapy) - Have progressed on a targeted therapy (BCR inhibitor, venetoclax, etc) - Have Richter's transformation after achievement of remission of the aggressive lymphoma As the novel therapies (BTKi, venetoclax + rituximab and idelalisib + rituximab) have excellent reported response rates in high risk patients, allogeneic HSCT should be individualized in patients receiving novel agents (considering transplant-related factors of donor availability and patient preference). High risk disease features that should prompt earlier consideration of HSCT include 1) poor response or loss of response to novel agent, 2) high risk cytogenetic features including del(17p), TP53 mutation, del(11q), complex karyotype by conventional cytogenetics 3)  3 prior lines of therapy.

# VI. Managing Complications and Supportive Care in CLL Prevention and management of infections:
Patients with CLL often have compromised immune systems due to the disease itself and/or its associated treatments. Infections are therefore common, and prophylaxis is appropriate, depending on the type of treatment given. The use of live vaccines in patients with CLL is not recommended. However, the use of inactivated vaccines such as annual influenza and COVID-19 and pneumococcal vaccination (Canadian guidelines recommend that high risk patients (which includes patients with malignant hematological disorders) receive a Pneumo-C vaccine, followed by a Pneumo-P 8 weeks later. If a patient has received Pneumo-P, they should wait 1 year before receiving Pneumo-C. Pneumo-C ( 13) is covered by public health for CLL patients in Alberta. for patients not yet treated or in remission for more than three months is recommended. 46,47 Screening for tuberculosis should be considered in patients from endemic areas. Screening for Hepatitis B is recommended before anti-CD20 monoclonal Ab or BTKi therapy so should be performed in all patients. The new inactivated Varicella Zoster vaccine has not been tested in patients with CLL but should be considered. Vaccinations are not recommended until 6-9 months post-anti-CD20 therapy. Table 6 summarizes antibiotic prophylaxis and recommended vaccinations for patients with CLL. Where patients experience recurrent infections that require intravenous antibiotics or hospitalization, antimicrobials should be given as needed. In patients with recurrent bacterial infections and where serum IgG is less than 5 g/L, monthly intravenous or subcutaneous immunoglobulins can be given at 0.3-0.5 g/kg; dose and interval should be adjusted to maintain a nadir level of more than 5 to 7 g/L. 48

# Autoimmune cytopenias:
Patients with CLL are at increased risk of developing autoimmune cytopenias, such as autoimmune hemolytic anemia (AIHA), idiopathic thrombocytopenia purpura (ITP), and pure red cell aplasia (PRCA). AIHA will develop in approximately 11 percent of advanced-stage CLL patients. 49 AIHA is diagnosed by the presence of at least one marker of hemolysis (increased indirect bilirubin not due to liver disease, increased lactate dehydrogenase without alternative etiology, increased absolute reticulocyte count, increased bone marrow erythropoiesis in the absence of bleeding, or decreased haptoglobin) with direct or indirect evidence of an autoimmune mechanism (positive direct antiglobulin test (DAT) for either IgG or C3d, cold agglutinins, or at least two markers of hemolysis in the absence of evidence of bleeding or hypersplenism). 50 ITP is less common, occurring in two to three percent of CLL patients at diagnosis or during early stage disease. 49 ITP can be identified where platelet counts are less than or equal to 100  10 9 /L with no evidence of hypersplenism, no evidence of increased platelet consumption due to other causes, and normal or increased megakaryocytes on bone marrow examination. 51 PRCA is present in six percent of CLL patients that are tested. 49 PRCA can be diagnosed when hemoglobin concentration is less than or equal to 120 g/L, with reticulocytopenia and isolated absence of erythrocyte precursors in the bone marrow. Parvovirus infection must be ruled out, which can be done by using a blood polymerase chain reaction (PCR) assay. 52 ITP and AIHA, as a single abnormality caused by CLL, should be treated initially using glucocorticoids. Alternatively, RCD (rituximab, cyclophosphamide and decadron) appears to have good response rates for control of refractory AIHA and as a CLL-therapy. 53,54 Second-line options for AIHA can include splenectomy and intravenous immunoglobulins though these are typically not used currently where effective therapy for CLL is preferred. Good responses have been obtained using rituximab and BTKi 5. Refractory cases could be considered for immune suppressive therapy with cyclosporine A, azathioprine, or low-dose cyclophosphamide, although these agents are associated with high rates of infection and other complications. Most patients with PRCA will respond to therapy with cyclosporine A or corticosteroids, but prolonged high doses are usually needed; steroid-sparing agents such as cyclophosphamide may therefore be required. 50,51 Rituximab may be an additional option for the treatment of PRCA, but success rates are lower than those seen for AIHA or ITP. 50

# Richter syndrome:
Richter transformation (RT) of CLL into an aggressive DLBCL occurs in 1-5% of patients with CLL.
RT is associated with a dismal prognosis with PFS <25% with CHOP-based chemoimmunotherapy and median survival 6-12 months.  Given these poor outcomes, consolidation with allogeneic HCT should be considered for eligible patients with responding disease who have relapsed RT or other high-risk features, such as previous therapy for CLL, failure to achieve a complete response to R-CHOP, TP53 aberrations, or clonally related RT.  Although <10% of all patients with RT will ever undergo allogeneic HCT, this may represent a curative therapy for selected cases with 3-year PFS 43%, OS 52%, relapse incidence 30%, and NRM 27% in a CIBMTR study of 118 allogeneic HCT recipients. 62 Outcomes were best for patients in complete response (3-year PFS 66%) or partial response (3-year PFS 43%) at the time of HCT compared to those with resistant disease (3-year PFS 5%). The majority of patients with RT receive reduced intensity conditioning, which has been associated with similar to improved outcomes in this setting compared to myeloablative conditioning. 62,63 Importantly, patients with RT arising from treatment naive CLL appear to have comparatively better outcomes with R-CHOP and may not require allogeneic HCT. 57,58 In an Alberta study of 99 patients with RT, those with treatment naive CLL had higher response rates to first line chemoimmunotherapy (71% versus 40%) and superior 2-year OS (51% versus 28%) compared to those with previously treated CLL. Nevertheless, 2-year OS remained suboptimal at 53% for the 13 patients 70 years old with RT and treatment naive CLL, which suggests there may be a role to consider consolidation with autologous HCT for these patients, similarly as other high risk aggressive lymphomas. Although data is lacking on the outcomes of autologous HCT as part of first-line therapy for RT, a CIBMTR study of 53 patients undergoing autologous HCT for predominantly relapsed RT reported 3-year PFS 48%, OS 52%, and relapse incidence 37%. 62 In an EBMT study of 34 patients who underwent autologous HCT, only 11 of 17 relapses were related to RT (the remainder were due to CLL), suggesting autologous HCT may eradicate the RT component in many patients even though the underlying CLL may persist. 63 It should be noted that even if allogeneic HCT may not be required as a part of primary therapy for patients with lower-risk RT, a referral for transplant consultation and HLA typing is suggested at diagnosis in all patients who are potentially eligible for allogenic HCT by age and/or comorbidities, given the significant risk of relapse/refractory disease with RT.
Less commonly, patients with CLL may develop a Hodgkin lymphoma variant of RT which is often clonally unrelated to the CLL. Available evidence suggests that Hodgkin-variant RT has similar outcomes with standard chemotherapy as de novo Hodgkin lymphoma in this age group. 64,65 As such, there is not an established role for consolidation with HCT in these cases. 61

# Tumour lysis syndrome:
Tumour lysis syndrome occurs when the release of large amounts of intracellular components of lysed malignant cells leads to a number of metabolic imbalances. Resulting hyperuricemia, hyperkalemia, and hyperphosphatemia may then lead to renal failure and cardiac arrhythmias. Tumour lysis syndrome usually occurs within two or three days after the initiation of therapy, with rare cases occurring after second-line treatment. Major risk factors include high tumour burden, high rate of proliferation, and disease that is highly responsive to therapy. 66 Before the initiation of treatment with anti-CD20 mAb, patients with a white blood cell (WBC) count higher than 50,000/mm 3 should be adequately hydrated and monitored frequently. In outpatients, frequent monitoring of serum electrolytes and uric acid is recommended as a preventative measure. 66 Prophylactic allopurinol (300 mg/day orally) is necessary when a rapid lysis of large numbers of lymphocytes is anticipated (initial WBC count >200 x 10 9 /L). Allopurinol can also be considered for patients with significant renal dysfunction or chronic hyperuricemia. In the advent of TLS, it may be necessary to interrupt treatment until symptoms are resolved. Rasburicase may also be considered for the treatment of TLS. Consideration may be given to dividing the dose of intravenous rituximab over two days for the first infusion. Specific TLS prophylaxis recommendations exist for venetoclax as the agent has been associated with fatal TLS cases in early phase studies. A slow dose-escalation over 5 weeks is also required for all patients initiating venetoclax therapy to prevent TLS events. 67,68 Blood product support:
Transfusion-related graft-versus-host disease has been described in patients actively receiving fludarabine, bendamustine or alemtuzumab. Thus, patients treated with fludarabine, bendamustine or alemtuzumab should receive irradiated blood products.

# Development and Revision History
This guideline was developed by a multidisciplinary working group comprised of members from the Alberta Provincial Hematology Tumour Team, external participants identified by the Working Group Lead, and a methodologist from the Guideline Resource Unit. The draft guideline was externally reviewed and endorsed by members of the Alberta Provincial Hematology Tumour Team who were not involved in the guideline's development, including surgical oncologists, radiation oncologists, medical oncologists, hematologists, nurses, pathologists, and pharmacists. A detailed description of the methodology followed during the guideline development process can be found in the Guideline Resource Unit Handbook.
This guideline was originally developed in 2010.
A formal review of the guideline will be conducted in 2023. If critical new evidence is brought forward before that time, however, the guideline working group members will revise and update the document accordingly.