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The Leukemia/Bone Marrow Transplant Program of BC

Healthcare Professionals
Cancer Management Guidelines

Chronic Lymphocytic Leukemia (CLL)

Updated: February 2011 - currently under review

Diagnosis

CLL (Chronic Lymphocytic Leukemia)

  • Least 5 x109/ B lymphocytes/L in peripheral blood
  • Clonality confirmed by flow cytometry

SLL (Small Lymphocytic Leukemia)

  • Lymphocytes in peripheral blood not greater than 5 x 109/L
  • Lymphadenopathy and / or splenomegaly
  • Confirmation of dx by marrow and / or histopathologic exam of node biopsy

MBL (Monoclonal B-cell Lymphocytosis)

  • Absolute B-cell lymphocytye count < 5 x 109/L
  • Absence of lymphadenopaty, organomegaly, cytopenias, or disease related symptoms
  • All lymph nodes < 1.5 cm
  • No cytopenias
  • No symptoms
  • Progression to CLL at a rate of 1 to 2% per year

Diagnosis and Testing

1. Immunophenotyping (can be done at VGH, BCCA or SPH):

  • typical is co-expression of CD5+ and B-cell antigens CD19+, CD20 dim, CD23+, sIg dim+, and cyclin D1-, with kappa or lambda light chain restriction
  • FISH for t(11:14) should be done in all cases with atypical immunophenotype – i.e., CD23 dim or negative, CD20 bright, sIg bright

2. History with attention to:

  • B symptoms
  • Performance status
  • Infections
  • Bleeding
  • Auto-immune disorders
  • Skin and other cancers
  • FHx of CLL and lymphoid malignancy (See also Lymphoid Cancer Families Study)

3. Physical with attention to:

  • Lymph node size and location of enlargement
  • Spleen and liver size
  • Signs of infection

4. Blood work:

  • CBC Diff plats retic count and peripheral blood smear
  • Lytes, BUN, CR, LFTs including LDH, uric acid, calcium
  • Direct antiglobulin test
  • ;B2 microglobulin
  • SPEP and quantitative Igs
  • Hepatitis serologies to include HIV, HCV, HBsAg, Anti-HBc, Anti-HBs

Staging

Document clinical stage at diagnosis and at progression. In BC, the Rai stage is most commonly used:

 Modified Rai Stage

Classical Rai Stage

Findings

 Low risk

 0

Lymphocyte count > 5.0 x 109/L. Bone marrow contains > 40% lymphocytes 

 Intermediate risk

 1

Stage 0 + lymphadenopathy

 2

Stage 0 + hepatomegaly and splenomegaly

 High risk

 3

Stage 0 + anemia (Hgb < 110 g/L)

 4

Stage 0 + thrombocytopenia (Platelets < 100 x 109/L)

Recommended Prior to Treatment

  1. As per diagnosis but also:
    • Hepatitis panel including Hep B/C, HIV, MCV, HSV, VZV
    • FISH for: Del 17p, Dep 11q, Del 13q, +12
    • At VGH or RCH, FISH testing is also done to look for IgH abnormalities
  2. FISH should be repeated prior to each major change in treatment and for change in disease behaviour, i.e., for more aggressive disease behaviour
  3. Chest x-ray
  4. Prior to treatment it may be helpful depending upon clinical circumstances to consider imaging (CT scans) and marrow aspirate and biopsy if appropriate
  5. Marrow aspirate and biopsy should always be done in the situation of unexplained cytopenias, evaluation of possible transformation, and prior to SCT

Prognosis & Risk Stratification

Prognostic factors in CLL include:

  1. Stage - advanced 3 or 4 shorter overall survival
  2. Bulky disease
  3. B-symptoms
  4. Transformation of CLL
  5. B2 microglobulin
  6. FISH:
  7.  Unfavourable

    17p del

    Short time to progression / time to therapy and overall survival
    Refer for consideration of allo SCT once 17p- is found and therapy is required 

     

     11q del

    Suboptimal TTP, TTT, OS
    Early consideration for allo SCT - likely around first progression

     Neutral

    normal 

     

     

    +12

     

    Favourable

    13q del as sole abnormality

  8. IgVH mutation status: Mutated IgVH has better prognosis, however it is not clear how this may impact on therapeutic decisions, and not widely available, not currently available in BC
  9. Flow cytometry: CD 38+ less favourable than CD 38-

Treatment

Indications for Therapy

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. Physicial
  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. 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. 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
    • If donor is unrelated add antibody - thymoglobulin
  3. Reduced-intensity: treosulfan/fludarabine/thymoglobulin
    • 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
    • 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

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

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
  2. 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)
  3. 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
  4. 1 year: same as Day +100. Aim for CR at 1 year.
  5. 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

Algorithms

Click images to enlarge.

CLL Treatment Algorithm

Protocols

BCCA Chemotherapy Protocols and PPOs

Outcomes

Coming soon.

Publications

  1. Dreger P, Döhner H, Ritgen M, Böttcher, Busch R, Dietrich S, Bunjes D, Cohen S, Schubert J, Hegenbart U, Beelen D, Zeis M, Stadler M, Hasenkamp J, Uharek L, Scheid C, Humpe A, Zenz T, Winkler D, Hallek M, Kneba M, Schmitz N, Stilgenbauer S. Allogeneic stem cell transplantation provides durable disease control in poorrisk chronic lymphocytic leukemia: long-term clinical and MRD results of the GCLLSG CLL3X trial. Blood 116(14):2438-2447, 2010.
  2. Gerrie AS, Gillan TL, Bruyere H, Chan MJ, Dalal C, Toze CL. Impact of Immunoglobulin Heavy Chain (IGH) Translocations in Chronic Lymphocytic Leukemia (CLL): Negative Effect on Patients with Isolated Deletion 13q Abnormality. Blood (ASH Annual Meeting Abstracts), November 2010; 116:2434.
  3. Toze C, Dalal CB, Gillan TL, Nevill TJ, Barnett MJ, Nantel SH, Hogge DE, Forrest DL, Sutherland H, Song K, Broady R, Power M, Narayanan S, Smith CA, Shepherd J. Allogeneic Hematopoietic Stem Cell Transplantation for CLL: Eradication of Specific FISH Abnormalities with Relation to Gvhd and Transplant Outcomes. Blood (ASH Annual Meeting Abstracts), November 2010; 116:3465.
  4. Dreger P. Allotransplantation for chronic lymphocytic leukemia. American Society of Hematology 2009, 602-609.
  5. Hallek M, Cheson BD, Catovsky D, Caligaris-Cappio F, Dighiero G, Döhner H, Hillmen P, Keating MJ, Montserrat E, Rai KR, Kipps TJ. Guidelines for the diagnosis and treatment of chronic lymphocytic leukemia: a report from the InternationalWorkshop on Chronic Lymphocytic Leukemia updating the National Cancer Institute–Working Group 1996 guidelines. Blood 111:5446-5456, 2008.
  6. Schetelig J, van Biezen A, Brand R, Caballero D, Martino R, Itala M, Garcia-Marco JA, Volin L, Schmitz N, Schwerdtfeger R, Ganser A, Onida F, Mohr B, Stilgenbauer S, Bornhäuser M, de Witte T, Dreger P. Allogeneic Hematopoietic Stem-Cell Transplantation for Chronic Lymphocytic Leukemia With 17p Deletion: A Retrospective European Group for Blood and Marrow Transplantation Analysis. J Clin Oncol 26:5094-5100, 2008.

 

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 patientís care or treatment. Use of these guidelines and documents is at your own risk and is subject to the Leukemia/BMT Program of BCís terms of use available at Terms of Use.

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