Chronic Lymphocytic Leukemia (CLL)
Treatment Options & Assessment of Response

Updated: February 2011 

Indications for Therapy

See Publications for IWCLL reference

Multiple well conducted multicentre studies have demonstrated no advantage to therapy for CLL for early stage asymptomatic patients.

Therapy is therefore recommended for:

    1. Symptomatic early stage patients

    2. Advanced stage patients

    3. In the setting of active/symptomatic disease including:

• Evidence of progressive marrow failure as manifested by the development of, or worsening of, anemia and/or thrombocytopenia
• Massive (≥ 6cm below costal margin) or progressive or symptomatic splenomegaly
• Massive (≥ 10cm) or progressive or symptomatic lymphadenopathy
• Progressive lymphocytosis with an increase of more than 50% over a 2-month period or lymphocyte doubling time (LDT) of less than 6 months
• Autoimmune anemia and/or thrombocytopenia poorly responsive to corticosteroids

• Constitutional symptoms including:

  • Unintentional weight loss of 10% or more within the prior 6 months
  • Significant fatigue (ECOG ≥ 2) - including inability to work or perform usual activities
  • Fevers higher than 38°C for 2 or more weeks without evidence of infection
  • Night sweats for more than 1 month without evidence of infection

 

Therapy for Advanced Stage & Symptomatic CLL

Initial Therapy

• See BCCA website in addition to the information provided below
• FR
• With presence of 17p deletion, refer to L/BMT Program for allo SCT to be performed as consolidation of response to primary therapy or most recent therapy

Therapy at Progression

Therapy is dependent upon response depth and duration to last therapy. If good response and long lasting, > 3 years, consider re-use of first therapy. See BCCA website in addition to the information provided below.

Useful therapies may include:

    1. FR or FCR

    2. C(V may be given or omitted)PR or CHOP R

    3. GDP R - may be useful if bulky disease

    4. Alemtuzumab

• May be useful in cases without bulky disease
• Special handling/monitoring of infection including prophylaxis of viral infection and monitoring for CMV reactivation

NOTE:

• If 17p deletion, refer to L/BMT Program for allo SCT as consolidation of therapy
• If transformation, refer to L/BMT Program for allo SCT as consolidation of therapy

Referral to the L/BMT Program

Patients should be considered for referral to the L/BMT Program for evaluation of suitability for SCT in the setting of poor risk CLL. This may include:

1. Presence of 17p deletion requiring therapy

• This is an indication for consolidation of best therapy with allografting either as initial therapy when required or when 17p deletion is detected at any time with CLL

2. Non-response (< PR) or early progression after purine analog containing therapy (< 1 to 2 years)

3. Progression within approximately 2 years after purine analog containing combination therapy or therapy of similar efficacy

 

Stem Cell Transplant

Pre-SCT Work-Up

1. History

2. Physical

3. Blood work:

• As per Diagnosis but include B2 microglobulin, DAT, FISH, viral serologies including Hepatitis, SPEP and quant Igs
• Chimerism testing to be sent on patient and donor if reduced intensity/NMA SCT considered

4. Marrow to include % lymphs and imaging as appropriate to include CT scan to be done from neck to groin within approximately 1 month prior to SCT

 

To Document Pre-SCT

1. Max Rai stage reached pre-SCT and date

2. Presence of B symptoms ever pre-SCT and date

3. Response/disease status pre-SCT - i.e., CR, PR, etc. (IWCLL criteria)

4. Response to:

• Last therapy pre-SCT:
  ? > PR = sensitive to last treatment
  vs.. < PR = refractory to last treatment
• Fludarabine therapy administered:
  if PR or >, code as fludarabine sensitive
  if < PR, code as fludarabine resistant

5. Code number of prior therapies

6. Document presence or absence of transformation to a higher grade, i.e., Richter's transformation, PLL, or other and date

7. Presence of current or prior autoimmune cytopenias related to the CLL such as anemia (autoimmune hemolytic anemia), thrombocytopenia (ITP), neutropenia, pure red cell aplasia (PRCA) and date

8. If alemtuzumab (campath) has been used as part of therapy, note date of start and finish of campath and ideally delay SCT until at least 30 days and ideally 100 days have elapsed following completion of campath

 

Conditioning Regimens

1. Non-myeloablative: fludarabine/cyclophosphamide

    a. This is suitable primarily for CLL patients who have the following:

• Matched sibling donor
• Responsive disease - PR or > to last therapy
• Lack of deletion 17p in FISH

2. Reduced-intensity: busulfan/fludarabine

    a. This is suitable for CLL patients with the following:

• Either sibling donor or unrelated donor
• Responsive or resistant disease (< PR to last therapy)
• 17p deletion in FISH

    b. If donor is unrelated add antibody - thymoglobulin

3. Reduced-intensity: treosulfan/fludarabine/thymoglobulin

    a. Only in case of second or > SCT such as:

• Allo post auto SCT
• Second allo SCT for graft failure if inter-transplant duration is less than 1 year

    b. Discussion with L/BMT group and pharmacy etc. as the following is required:

• Health Canada approval
• CAP approval

4. Although there is some evidence for a dose-response in CLL, most available evidence supports advancement of conditioning in cases where the CLL is not sensitive as outlined above, but there is no strong evidence to support the use of myeloablative SCT in CLL

 

Donors

See Outcomes for Pre-SCT Factors

There is no detectable difference in OS for CLL with use of fully matched related vs. unrelated donors.  Our results and those in the literature support somewhat suboptimal outcomes with use of mismatched as opposed to fully matched unrelated donors, so that this type of SCT should only be considered in selected high risk situations where no other reasonable options are present.

 

Comorbidity Index

See Outcomes for  Pre-SCT Factors

Our results and those of others indicate less optimal survivals for patients with CLL proceeding to allo-SCT with higher comorbidity indices. Results are best for patients with comorbidity scores of 0-2. Only in selected circumstances after discussion with the L/BMT group should allo-SCT be considered for CLL with CoI of 3. Allo-SCT for CLL should in general not be performed for patients with CoI of over 3.

 

Assessment of Response Post SCT

Post SCT Work-Up

As clinically indicated but to include:

1. Day +75: peripheral blood chimerism lymphoid, myeloid

Notes on Chimerism:
Chimerism testing should be done to determine at least once that full donor chimerism has been reached – as defined by > 90% donor cells lymphoid and myeloid in peripheral blood

• If gender mismatch donor, do FISH X:Y

• If not fully chimeric at day +75, should be rechecked until document full donor chimerism at:

  • after d/c immunosuppression cyclosporine or FK506 (~ 1-3 months after stopped)
  • after onset of immunosuppression - GVHD
  • 1 year post SCT
• If fully chimeric, and no evidence of active CLL/progression/graft failure, no need to recheck unless substantial disease progression or evidence of graft failure occurs
• Document date full donor chimerism achieved (>90% donor in all fractions tested, or by FISH X/Y if gender mismatch donor)

2. Day +100

• Blood work including CBCD platelets, lytes, BUN, CR
• LFTs including LDH, SPEP and quant Igs
• FISH peripheral blood if not normal pre-SCT or if change in disease status (i.e., if CLL progression and FISH previously normal)
• FISH X:Y if gender mismatch donor
• Marrow for % lymphs/assessment of remission status
• Imaging of previously involved areas for lymph size/remission status

3. 1 year: same as Day +100. Aim for CR at 1 year.

4. Thereafter as appropriate to document CR as defined by IWCLL criteria. All of the following must be met as assessed at least 2 months after completion of therapy:

• peripheral blood lymphocyte count < 4 x 10⁹/L

• absence of significant lymphadenopathy

  • nodes < 1.5 cm by physical exam
  • post SCT CT scan neck/chest, abdomen/pelvis desirable if previously abnormal or if symptoms abnormal on exam
• no hepatomegaly or splenomegaly on exam
• post SCT CT abdomen should be performed if previously abnormal
• absence of constitutional symptoms

• blood counts otherwise in the normal range:

  • ANC > 1.5 x 10⁹/L
  • platelets > 100 x 10⁹/L
  • hemoglobin > 110 x 10⁹/L

 

Other Recommendations

• Date of CR post SCT should be documented
• Date of clearance of FISH abnormalities post SCT should be documented
•  Achievement of CR and resolution of FISH abnormalities is strongly associated with GVHD
• Ideally CR would be achieved by 1 year
• Escape from GvL can occur – watch parameters including blood counts, physical exam, % lymphs in marrow, FISH testing, size of nodes on imaging – want to see all improving and heading towards CR – if not, i.e., if increase in % lymphs, % FISH abnormalities, nodal size or similar then manipulate situation if possible with decrease in immunosuppression, treatment of CLL with agents to include antibody (rituxan) or DLI as appropriate

 

Progressive Disease (IWCLL criteria)

• This is defined as appearance of any new lesion such as enlarged nodes, splenomegaly, hepatomegaly or other organ infiltrates or an increase in 50% or more of greatest diameter of any previous site.

• Document date of occurrence if occurring post SCT.

1. Lymphadenopathy – appearance of new nodes or increase in size by 50% or > in greatest determined diameter of any previous site

2.  De Novo hepato or splenomegaly or increase in enlargement by 50% or more

3.  Increase in number of blood lymphocytes by 50% or more with at least 5 x 10⁹/L lymphs

4. Transformation to a more aggressive histology – ideally confirm by biopsy

5. Occurrence of a cytopenia attributable to CLL

 

 

 

The information contained in these guidelines is a statement of consensus of Leukemia/BMT Program of BC professionals regarding their views of currently accepted approaches to treatment. Any clinician seeking to apply or consult these documents is expected to use independent medical judgment in the context of individual clinical circumstances to determine any patient’s care or treatment. Use of these guidelines and documents is at your own risk and is subject to the Leukemia/BMT Program of BC’s terms of use available at Terms of Use.