CLL Summary

Epidemiology:

• CLL is the most prevalent adult leukemia in the western countries.
• It is more common in men than in women (ratio 1.7 to 1).
• There is no known risk factors for CLL.
• Median age at diagnosis between 67 and 72 years.

Diagnosis:

• Sustained increase in mature appearing lymphocytes in the peripheral blood to more than 5,000/mm3.
• The majority of cases are B-CLL.
• IHC stains: CD5, low density expression of surface Ig, CD20 & CD22 unlike mantle cell lymphomas which has higher expression of CD20 and surface Ig.
• The bone marrow usually is infiltrated by at least 30% lymphocytes.
• Although a bone marrow biopsy is not needed to make the diagnosis, they are strongly recommended if cytopenias in other cell lines are present before starting therapy.

Cytogenetic and molecular abnormalities

• Conventional techniques identify cytogenetic abnormalities in 50% of cases.
• FISH allows for identification of cytogenetic abnormalities in > 80% of cases.
• The most common abnormality is deletion of long arm of chromosome 13 (13q), which is present in 55% of cases. The disease course is benign and patient have a normal life span.
• The 2nd common abnormality is deletion of long arm of chromosome 11(11q), which is present in 15%-20% of cases. The disease is associated with massive lymphadenopathy, out of proportion to the increase in the peripheral blood lymphocyte count.
• Trisomy 12 can be found in 15%-20% of cases.
• Abnormalities in the short arm of chromosome 17 (17p) leads to disruption of the TP53 gene. It is found in about 15% of cases. Associated with higher likelihood of Richter transformation, advanced stage, more prolymphocytes, resistance to chemotherapy and  poor prognosis.
• More than ⅓ of patients have complex abnormalities.
• Translocations associated with BCL-2 (t[14;18]) and BCL-3 (t[14;19]) are detected in 5% to 10% of cases. However, overexpression of the BCL-2 gene is present in > 70% of cases.
• The ratio of the antiapoptotic gene BCL-2 expression to the proapoptotic gene BAX is increased in CLL cells, which favor cell survival. These findings support the concept that CLL is more a disorder of prolonged cell survival than a hyperproliferative disease, although both factors probably contribute.
• ⅕ of patients have unmutated VH genes. The survival significantly shorter for the group with unmutated VH genes. ZAP-70 expression distinguish the unmutated from the mutated population
• Increased ZAP-70 expression is associated with enhanced signal transduction through the BCR complex, which may contribute to an aggressive course.
• Unfavorable cytogenetic abnormalities (17p, 11q) occur in the unmutated group, whereas the more favorable mutations (13q) occur in the mutated group. Trisomy 12 tend to have unmutated VH genes.
• Cytogenetics and molecular markers in CLL may change over time, requiring their reassessment if the tempo of disease seems to be changing.

Staging and prognosis:

• The 5 stage Rai classification is most commonly used in the United States.

Stage	Clinical features	Median Survival
0	lymphocytosis only	>12.5 yrs
I	Lymphadenopathy	8.5 yrs
II	Splenomegaly with or w/o hepatomegaly	6 yrs
III	Anemia	1.5 yrs
IV	Thrombocytopenia	1.5 yrs

• The 3 stage Binet system is most often applied in Europe.

Stage	Symptoms	Median Survival
A	< 3 node bearing areas	> 10 yrs
B	> 3 node bearing areas	5 yrs
C	Anemia and/or thrombocytopenia	2 yrs

Clinical features:

• Most patients are generally asymptomatic at the time of presentation.
• the diagnosis is often made incidentally when lymphocytosis is noted during routine CBC.
• Lymphadenopathy and/or hepatosplenomegaly observed in about 40%-50% of patients.
• Involvement of other organs is unusual and suggest the possibility of transformation to Richter syndrome.
• There is increased susceptibility to infections which reflects the hypogammaglobulinemia that worsens with disease progression.
• The use of IVIG or antimicrobial agents should be reserved for select patients with documented, repeated bacterial infections
• Richter Transformation:
• For 3% to 15% of the patients the disease will evolve into a more aggressive lymphoid malignant process, most  often Richter syndrome,
• Presents with increasing lymphadenopathy, hepatosplenomegaly, fever, abdominal pain, weight loss, progressive anemia, and thrombocytopenia with a rapid rise in the peripheral blood lymphocyte count and increased serum LDH level.
• Evaluation of lymph node biopsy may indicate a large cell lymphoma.
• Response to systemic therapy is poor, with median survival of 4 to 5 months when treatment involves alkylating agents; survival may be longer after the use of nucleoside analog based regimens.
• CLL may evolve into prolymphocytic leukemia which is associated with progressive anemia, thrombocytopenia with at least 55% of prolymphocytes in the peripheral blood.
• Transformation to ALL, plasma cell leukemia, multiple myeloma, or Hodgkin’s lymphoma has been noted in anecdotal reports.
• Autoimmunity:
• Positive Coombs antiglobulin test is present in 20% to 30% of CLL cases, with clinical hemolysis in 10% to 25% of patients.
• The frequency of immune thrombocytopenia seems to be approximately 2%.
• AIHA or IT generally respond to corticosteroids such as prednisone at a dose of 60 mg/day to 100 mg/day, which may be tapered after 1 to 2 weeks after evidence of response.
• Patients who do not respond to corticosteroids may experience a response to high dose IVIG.
• Rituxan and alternative immunosuppressants such as cyclosporine or azathioprine may also sometimes be useful.
• Splenectomy may be considered when systemic approaches fail.
• Radiation therapy to the spleen induces only transient responses.
• Pure red cell aplasia:
• Manifest as severe anemia without a reticulocyte response or bone marrow normoblasts and without neutropenia or thrombocytopenia.
• Corticosteroids as well as cyclosporine and rituxan may be effective.
• Secondary malignant diseases:
• The most frequent tumors are skin cancer (including melanomas), colon cancer, lung cancers, and myeloid leukemias.

Starting Therapy:

• CLL is not curable with currently available therapies, with the exception of allogenic HCT.
• There is no evidence that treating patients with early stage disease (Rai 0 to 2 or Binet A) extends life expectancy.Therefore asymptomatic patients with early stage should be monitored rather than treated.
• If early stage patients developed disease related symptoms like ‘B’ symptoms, hepatomegaly, splenomegaly, lymphadenopathy, AIHA, IT or recurrent infections, they may be considered for therapy
• A rapid lymphocyte doubling time (less than 6 months) also may support the decision to treat.

Initial Therapy:

• Purine analogs:
• Fludarabine is the most active agent in CLL treatment.
• As initial therapy it garners a response rate of approximately 70%, including a 5% to 30% rate of CR.
• The major toxicities associated with Fludarabine are moderate myelosuppression and severe immunosuppression, with occasional neurotoxicities.
• The number of lymphocyte cells, notably CD4, decreases within weeks, and the count doesn’t return to normal for 1 year or more after therapy has been discontinued.
• It has been associated with opportunistic infections.
• Tumor lysis syndrome occurs in less than 0.4% of patients.
• Fludarabine can induced autoimmune hemolytic anemia and thrombocytopenia. Whether patients with these conditions can continue to receive the drug remains controversial.
• The risk of 2ry malignancy doesn’t seem to be increased with the use of fludarabine alone.
• There is increased risk of myelodysplasia when Fludarabine is combined with alkylating agent.
• Cladribine and pentostatin are active in CLL, although to a lesser extend than fludarabine.
• There is a limited activity but considerable toxicity from these agents when used to treat disease in patients for whom fludarabine has failed.

• Alkylating agents:
• Oral chlorambucil achieves disease response in approximately 20%-70% of previously untreated patients, although few of these responses are complete.
• In a large prospective trial, chlorambucil was found to be inferior to fludarabine in terms of response rates and time to disease progression. when adding fludarabine to chlorambucil there was increased toxicity and response rates that was not better than fludarabine alone (NEJM 2000;343;1750)
• Fludarabine/Alkylating agent combinations:
• The most thoroughly studied combination is fludarabine plus cyclophosphamide, which in 2 prospective randomized trials was found to result in higher complete response rates (23% vs 4% in one study and 24% vs 7% in the other) and overall response rates (74% vs 60% in one study and 94% vs 83% in the other) , as well as longer response durations (31 vs 19 months in one study and 48 vs 20 months in the other) than fludarabine alone. To date there is no difference in overall survival. (JCO;2007;25;793), (blood;2006;107;885).
• Rituximab containing combinations:
• Rituximab has only modest single agent activity in CLL.
• Rituximab with fludarabine seems very active:
• A retrospective comparison of 104 patients on 2 phase II trials (CALGB 9712 & 9011) of fludarabine plus rituximab with 178 patients receiving fludarabine alone on a previous trial using exactly the same study criteria showed improved 2 yr PFS and OS with the combination. (Blood; 2005; 105;49)
• Rituxan added to fludarabine and cyclophosphamide (FCR):
• A randomized phase III trial in 408 treatment-naive, physically fit patients (aged 30–81 yrs) has shown improved PFS (65% vs 45% at 3 yrs) and OS (87% vs 82% at 3 yrs) with FCR compared to FC. There were more grade 3 & 4 neutropenia and leukopenia but other side effects including severe infections were not increased. (Lancet;2010; 376;1164).
• Rituxan with Bendamustine combination (BR):
• Bendamustine is a bifunctional agent with one moiety that serves as an alkylating agent and a 2nd that is a nucleoside analog.
• BR regimen was tested in phase II trial of 81 patients with relapsed CLL. ORR was 59% with CR in 9%, PR in 47%. ORR was 45% in fludarabine refractory patients and 60% in fludarabine sensitive patients.
• BR regimen was tested as frontline therapy in multicenter phase II trial of the German CLL study group in 117 patients (age 34-78 yrs). ORR was 88% with CR of 23% and PR of 65%. Median event free survival was 33.9 months. Grade 3 or 4 severe infections occurred in 7.7% of patients. Grade 3 or 4 adverse events for neutropenia, thrombocytopenia and anemia were documented in 19.7%, 22.2%, & 19.7%. (JCO;2012;30(26);3209)
• FCR vs BR:
• Results Of a Planned Interim Analysis Of The CLL10 Trial, An International, Randomized phase III Study Of The German CLL Study Group. (Blood 2013; 122:526 (ASH meeting 2013 abstract))
• Comparing FCR vs BR in  In 688 previously untreated and physically fit patients.
• There were significantly more pts with unmutated IGVH in the BR arm (68%) in comparison to the FCR arm (55%).
• The ORR was identical in both arms with 97.8%.  CR with FCR was 47.4% vs  38.1% with BR.  
• PFS was 85.0% at 2 yrs in the FCR arm vs 78.2% in the BR arm
• There was no difference in OS rate for the FCR vs BR arm (94.2% vs 95.8% at 2 years p=0.593)
• there was a significant difference in pts < 65 yrs between both treatment arm (median PFS for BR 36.5 mo vs not reached for FCR; p=0.016), the difference disappeared in elderly pts (not reached vs. 45.6 mo; p=0.757).
• There were higher rate of grade 3-4 adverse events including severe neutropenia and severe infections especially in elderly pts in the FCR arm compared to the BR arm.
• FCR seems more efficient than BR in the first-line treatment of fit CLL pts with regard to higher CRR, as well as longer PFS and EFS. These advantages might be balanced by a higher rate of severe adverse events, in particular neutropenia and infections,
• Others Combinations:
• Ofatumumab plus Chlorambucil: (Blood 2013;122:528 (ASH meeting 2013 abstract))
• A randomized multicenter phase III trial (OMB110911) of 447 patients considered inappropriate for fludarabine-based therapy due to advanced age and/or co-morbidities were randomized (1:1) to receive either O+CHL or CHL.
• Median age was 69 years with 82% ≥65 years and/or having ≥2 comorbidities.
• ORR was higher for O+CHL vs CHL (82% vs 69%), with a superior CR (12% vs 1%).
• PFS was significantly prolonged in the O+CHL arm (22.4 months) compared to CHL alone (13.1 months).
• Grade ≥3 infusion-related AEs were reported in 10% of patients. No fatal infusion reactions were reported. Grade ≥3 infections were reported in 15% (O+CHL) and 14% (CHL) of patients, with the most common infection being pneumonia
• (O+CHL) demonstrated clinically important improvements with a manageable side effect profile in patients with CLL who have not received prior therapy and who are considered inappropriate for fludarabine based therapy.
• Obinutuzumab plus Chlorambucil vs Rituximab plus Chlorambucil (GCIb vs RCIb): (blood:2013;122;216, (ASH meeting 2013 abstract))
• CLL11 trial is a large randomized phase 3 trial investigating first-line chemoimmunotherapy in CLL patients with comorbidities.
• Final results of the stage 2 analysis: Median observation time was 19 months.
• Median age was 73 yrs and CrCl was 63 mL/min.
• ORR was 78% vs 65% with CR of 21% vs 7% respectively.
• Median PFS was 26.7 vs 15.2 months respectively.
• Median OS not reached in both arms.
• Grade 3-5 adverse events happened in 66% vs 47% respectively.
• Infusion related reaction happened in 20% vs 4%.
• GCIb is superior to RCIb in previously untreated CLL patients with comorbidities.

Treatment for relapsed or refractory disease:

• Treatment is not necessarily needed for relapsed or refractory disease after initial therapy; treatment in this setting is based on the same indications as for initial therapy.
• Patients who experience relapse within 6 months of previous therapy should be switched to an alternative regimen.
• Disease refractory to therapy with fludarabine sometimes responds to the FCR or BR combination.
• Alemtuzumab:
• It is a humanized anti-CD52 monoclonal antibody.
• It is expressed on all  lymphocytes at various stages of differentiation, as well as monocytes, macrophages, and eosinophils, but no hematopoietic stem cells, erythrocytes, or platelets.
• FDA approved for treatment in fludarabine refractory CLL based on results of large international study. (blood;2002;99;2554)
• In the pivotal trial, 93 pts from 21 center worldwide with treatment failure to fludarabine and alkylating agents, received the drug.
• ORR of 33% with 2% CR. the median duration of response was 9 months.
• The most frequent adverse events include rigors (90% of pts), fever (85%), nausea (53%), vomiting (38%) and rash (33%). These events decrease over the duration of treatment.
• Reactivation of CMV may occur in as many as 25% of patients. Thus routine monitoring for CMV should be performed weekly by PCR as well as intervention with Ganciclovir.
• Antimicrobial prophylaxis should also include Bactrim and acyclovir.
• CMV monitoring should be continued for up to a year after treatment.
• Alemtuzumab seems to be as active when administered SubQ as when administered IV but with fewer infusional complications.
• Effective in patients with high risk genetic markers such as deletions of chromosome  11 or 17 and TP53 mutations.
• Unfortunately, it is no longer licensed, but remains available in some countries ona compassionate use basis.
• Ofatumumab:
• It is an IgG1 humanized anti-CD20 monoclonal antibody reactive with an epitope distinct from that seen in Rituximab, resulting in increased binding affinity to CD20, prolonged dissociation rate, and increased cell kill.
• The pivotal trial leading to its FDA approval involved 138 patients who were fludarabine and alemtuzumab-refractory or with fludarabine-refractory with bulky ( >5 cm) lymphadenopathy. The ORR was approximately 50% with median duration of response of approximately 6 months. (JCO; 2010; 28;10;1749)
• Ibrutinib:
• Potent and irreversible Bruton’s tyrosine Kinase (BTK) inhibitor. The BTK is an integral component of the B-cell receptor (BCR). BTK inhibition results in decreased malignant B-cell proliferation and survival.
• It is FDA approved in 02/2014 for treatment of CLL patients who have received at least 1 prior therapy.
• the approval was based on the results of a multicenter, single arm trial of 48 patients with previously treated CLL.
• The median age was 67 yrs (37-82) with baseline ECOG performance of 0-1.
• The median number of prior treatments was 4.
• Administered orally at 420 mg once daily until POD or unacceptable toxicity.
• ORR was 58%. No CR observed.
• The response duration ranged from 5.6 to 24.2 months, the median was not reached.
• The most common adverse reactions occurring in at least 20% of the patients was thrombocytopenia, diarrhea, bruising, neutropenia, anemia and URI.
• In 01/2014 the RESONATE trial was stopped early based on favorable results of a planned interim analysis. This is a phase III trial randomized patients to either ibrutinib or ofatumumab. Patients entered this trial had previously treated CLL or SLL and were not considered candidate for treatment with purine analogue based treatment. The trial was reported to demonstrate an improvement in PFS  and OS.

Hematopoietic cell transplantation:

• A study from Seattle, demonstrated 32% 5 yr disease free survival for patients with refractory CLL.
• Studies from MD Anderson cancer center, Dana-Farber cancer institute and the CIBMTR provide further evidence that prolonged disease free survival can be achieved in CLL with allogeneic transplantation.
• In a study from Seattle, 64 patients with advanced CLL received a reduced intensity regimen, with a 52% disease free survival rate at 2 years post-transplant. (JCO; 2005;23;3819)
• Reduced intensity allogeneic transplantation seems to be a reasonable option for patients with fludarabine refractory disease who are otherwise in reasonably good health.
• Patients with del (17p) have such a poor prognosis with conventional therapy that they can reasonably be considered for allogeneic transplantation even in first remission.

Supportive Measures:

• Splenectomy:
• May provide palliation for pts whom systemic therapy failed and have persistent splenomegaly or cytopenia that precludes chemotherapy.
• It should also be considered in pts with AIHA or autoimmune thrombocytopenia who do not experience a response to more conservative measures, such as steroids, IVIG or rituximab.
• Leukopheresis:
• Transient reduction in circulating lymphocytes and is not recommended for general practice as pts with CLL rarely experience tumor cell aggregates, regardless of the number of circulating cells.
• Systemic therapy is usually adequate to reduce the number of circulating lymphocytes, when indicated.
• Erythropoietin:
• Epoetin may reduce transfusion requirements for approximately two-thirds of patients with CLL.
• Responses are rarely seen in patients with high endogenous erythropoietin levels (> 500 U/L).