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 38.0°C for two weeks or more without other evidence of infection
• Night sweats for more than one month without evidence of infection

• The majority of patients with early-stage CLL are managed initially with watchful waiting. The
  decision to initiate treatment should be based upon symptoms, advanced disease (bulky or
  symptomatic adenopathy/ splenomegaly or cytopenias), or evidence for rapid disease progression
  (e.g. lymphocyte count doubling within 6 months).
• Patients whose CLL possesses del(17p) and/or TP53 mutation have poor responses to standard
  chemotherapy and as such, targeted therapy with a preference for indefinite Bruton’s tyrosine
  kinase (BTK) inhibitors are the preferred treatment choice for these patients.
• Patients with unmutated IgHV have inferior outcomes compared to patients with mutated IgHV
  when treated with chemo-immunotherapy (CIT), making targeted therapy the preferred firstline
  treatment for these patients. Shorter remissions are still noted for unmutated IGHV patients with
  time-limited targeted therapy; however, given the lack of head-to-head comparison of indefinite
  BTKi over venetoclax-obinutuzumab (VO) in this population, we favour finite therapy with VO for
  reasons of cost. Patients in whom VO therapy cannot be safely administered (ex. those who
  reside a long distance from a regional or tertiary cancer centre where TLS monitoring can be
  performed) could consider BTKi inhibitor therapy.
• Patients with mutated IgHV can experience lengthy remissions with many different therapies. In fit
  (ie. Cumulative Illness Rating Scale (CIRS) <=6) patients with mutated IgHV who are able to
  tolerate aggressive treatment, the combination of fludarabine + cyclophosphamide + rituximab
  (FCR) may lead to very durable (possibly indefinite) remissions and is, thus, recommended. VO is
  the preferred regimen for patients who are not appropriate or refuse FCR. Other chemo-
  immunotherapy regimens have demonstrated efficacy in older or less fit patients including
  bendamustine + rituximab (BR), fludarabine + rituximab (FR) or chlorambucil + obinutuzumab
  (CLB-Ob) and remain as options for patients with good risk CLL who are not appropriate for VO

1. Venetoclax in combination with rituximab with a fixed 2-year duration of therapy is a highly
   effective option for relapse/refractory CLL (after prior CIT) and is the preferred second line therapy
   for most patients due to its fixed duration of therapy.
2. BTKi monotherapy leads to lengthy remissions in patients with relapsed/refractory CLL and is
   another high effective option for secondline therapy and preferred for patients with TP53
   abnormalities.
3. Second generation BTK inhibitors (acalabrutinib, zanubrutinib) have improved tolerability and
   lower risk of cardiac and bleeding toxicities compared to 1st generation (ibrutinib) and are thus the
   preferred choice of BTKi. There is no data currently to support switching patients from ibrutinib to
   second generation BTKi in patients with good disease control and acceptable tolerability.
4. Venetoclax, a BCL2-inhibitor, as indefinite monotherapy, has demonstrated efficacy in patients
   who fail or are intolerant to BCR-inhibitors (ibrutinib or idelalisib + rituximab). Patients who
   progress on BTKi have a poor prognosis and should receive indefinite venetoclax therapy and/or
   contemplation of clinical trials and/or allogeneic ASCT if appropriate. Patients who discontinue
   BTKi for reasons of intolerance after good disease control should wait to be re-treated at the time
   of achieving iwCLL treatment criteria and can consider VR or an alternate BTKi.
5. Idelalisib in combination with rituximab can lead to durable responses but has high rates of
   infectious toxicity and is rarely used in Alberta.
6. Chemoimmunotherapy (ex bendamustine and rituximab) may be considered in patients who have
   failed all other therapeutic options, particularly in those attempting to progress to curative ASCT
   but it is no longer standard of care for relapsed/refractory CLL.
7. Allogeneic stem cell transplantation (ASCT) should be considered for fit patients who are younger
   than 70 years of age, require treatment and, have progressed on a targeted therapy or who have
   Richter’s transformation with remission to the aggressive lymphoma. Allogeneic stem cell
   transplantation may be delayed in patients achieving responses to novel agents; however HLA
   typing should be performed to identify a possible transplant donor. High risk features that should
   prompt earlier consideration of HSCT include patients who have had ≥ 3 prior lines of therapy,
   those who have confirmed progression on BTKi and those with complex karyotypes by
   conventional cytogenetics.