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Chronic lymphocytic leukemia (CLL)

1982

The most common adult leukemia, representing 83% of leukemias.

The most common adult leukemia in the Western world.

Represents 25% of all leukemias.

Represents 11% of all hematologic neoplasms.

About 1.3% of all cancers.

In 2019, an estimated 20,720 people were diagnosed with CLL in the USA, and estimated 3930 people will have died.

Represents about 75 of non-Hodgkin’s lmphomas.

One of the most common malignant lymphoid diseases.

CLL cells proliferate in secondary lymphoid organs-lymph nodes and spleen.
B-Cell receptor signaling promotes the expansion of the monoclonal B lymphocytes.

Not considered curable outside of allogeneic stem cell transplantation.

Approximately 18,960 new cases of CLL are diagnosed in the United States each year.

Estimated 20,000 new cases reported in 2017.

Annual age-adjusted incidence 4.2 per hundred thousand individuals, and age-adjusted death rate 1.5 per hundred thousand individuals (SEER).

Accounts for more than 4500 deaths per year in the US, accounting for about 29% of CLL deaths.

Median age at diagnosis between 67-72 years, and risk increases with age.

More males affected than females.

A lifetime risk of one in 210 in the US.

Incidence lower among Asian individuals. Incidence higher among Ashkenazi Jews.

B cell malignant disorder.

B-cell receptor signaling is a central driver of disease.

B cell lymphocytosis of greater than 5×10 to the ninth/L in the peripheral blood for at least six months is diagnostic.

Characterized by accumulation of phenotypically mature malignant B lymphocytes primarily in the peripheral blood, bone marrow, and lymph nodes.

Results from a neoplastic transformation B cell lymphocyte population expressing CD5.

Characterized by accumulation of CD5 positive monoclonal B cells in peripheral blood, bone marrow, primary and secondary lymphoid tissues.

Characterized by CD5 and CD10 surface expression.

CLL cells co-express B-cell surface antigens CD19 and CD20 together with CD5, CD 23, CD43 and CD 200.
The levels of surface CD20, surface immunoglobulin and CD79b are characteristically low compared with those found a normal B cells.
Ammonia cell surface markers detected by flow cytometry, immunohistochemistry, or methylation CD 38, CD49d, and ZAP-70, CD 49d, CD49 is the strongest predictor of overall survival and treatment free survival.
ZAP positivity may be a strong indicator of clinical outcomes than IGHV Mutation status or CD 38.ZAP

Diagnosis requires an absolute clonal lymphocyte count to 5000 cells per millimeter cubed or more in a characteristic phenotype combining the presence of CD19, the T cell antigen CD5, and CD23.

Typical lymphocytes have a narrow border of cytoplasm, a dense nucleus without nucleoli, and aggregated chromatin.

Distinguishable from small lymphocytic lymphoma by its leukemia appearance.

Diagnosis requires the presence of more than or equal to 5 x 10 to the 9th/L B lymphocytes in the peripheral blood for a duration of at least 3 months.

The presence of monoclonal B lymphocytes in the peripheral blood is confirmed by demonstrating light chain restriction using flow cytometry.
Leukemia cells in the blood smear characterized as being small, mature appearing lymphocytes with a narrow border of cytoplasm and a dense nucleus lacking discernible nucleoli and having partially aggregated chromatin.
Larger come atypical lymphocytes or prolymphocytes may be seen but not exceed 55%.

5% of patients present with clinical features of small lymphocytic lymphoma without the leukemic component.

Small lymphocytic lymphoma (SLL) refers to non-leukemic cases with tissue morphology and immunophenotyping of CLL with lymphadenopathy, with no cytopenis due to bone marrow infiltration and fewer than 5×10 to the ninth/L of clonal lymphocytes in the peripheral blood.

CLL is 10-20 times is common in western countries than in Asia suggesting genetic factors, environmental factors, or both influence susceptibility to the disease.

The presence of immunophenotypic cells typical of CLL cells but with fewer than 5000 B cells per microliter, and the absence of lymphadenopathy is defined presently as monoclonal B lymphocytosis (Rawstron AC et al).

Characteristic phenotype combines the presence of CD19, the T-cell antigen CD5, and CD23.

Expression of CD 20 is generally weak.

Malignant cells at either Kappa or lambda light chain restricted.

It is unknown what percent of patients with monoclonal B lymphocytosis that will progress to CLL

Clonality of the circulating B lymphocytes need to be confirmed by flow

Typical cells may be admixed with atypical or larger cells, cleaved cells, prolymphocytes, which comprise as many as 55% of lymphocytes.

Smudge cells, Gumprecht nuclear shadows, are cell debris are characteristic findings on the peripheral blood smears.

Smudge cells result from lymphocyte debris at the periphery of a blood smear is a pathognomonic feature of CLL.

Most common form reflects a clonal proliferation of mature B cell markers and low levels of surface immunoglobulin M.

B cells express CD5 molecule which is a marker of a minor subset of normal B cells and CD23.

Risk of disease progression includes elevated serum levels of bets2-microglobulin, soluble CD23 levels, diffuse bone marroe infiltration, and short lymphocytic doubling time (Shanafelt TD).

An elevated beta-two microglobulin that is a strong independent prognostic indicator for treatment free interval, response to treatment, and overall survival impatience treated with first line chemo immunotherapy regimens.

Highest incidence of familial leukemia and believed to be polygenetic.

Thought to arise from CD5+ B cell splenic marginal zone subpopulation.

Immunophenotyping co-expresses CD5 and CD19 as well as CD20, CD21, CD23, and CD24.

Has expression of CD20, and CD79b, and IgGk or Lamba light chain restriction

Up to 80% patients have cytogenetic abnormalities, most frequently involving chromosomes 12, 13 or 14; Del 13q, 55%, del11q, 18%, trisomy 12, 16%. del17p, 7% and del6q 7%, what are the most common abnormalities at the time of diagnosis.

Del13q is associated with a favorable prognosis and the longest median survival approximately 133 months.
DEL11q is often associated with extensive lymphadenopathy, disease progression and a shorter median survival is 79 months.

 

Utilizing FISH one or more chromosome abnormalities can be found in more than 80% of patients, including del11q, trisomy 12, del17p, del6q.

Del(17p), del(11q), and TP53 mutations are associated with a poor prognosis.

TP 53 aberrancy means either del(17p) or TP53 mutation determined by next generation sequencing.

Del13q.14 occurs in more than 50% of patients and is associated with a good prognosis.

Median survival 5-7 years although a substantial number of patients live more than 10 years.

Many patients present with at least one coexisting medical conditions, requiring consideration of treatment.

There is sufficient evidence of an association between herbicides and chronic lymphoid leukemias, including HCL to consider these diseases linked to exposure.

Treatment is based on the patient’s fitness, age and disease risk.

Patients fitness requires evaluation organ function and comorbidities, and assessment including bone marrow, functional status, and performance status.

Approximately 1/3 of patients have an indolent form of the disease that does not require treatment and it does not modified survival, while another third of patients will require treatment and their life will be effective both in quality and length of survival.

Patients with early-stage (low- risk) CLL (lymphocytosis alone; Rai stage 0, Binet stage A) have an estimated median life expectancy of approximately 13 years and normally are not treated.

 

Patients with intermediate-stage CLL (lymphocytosis with lymphadenopathy, hepatosplenomegaly, or both; Rai stage I or II, Binet stage B) have an estimated median life expectancy of 8 years and can be treated if they have signs of disease activity. 

The median time to initial therapy is seven years for patients with low or intermediate risk disease and accounts were approximately 75% of patients with CLL, as compared with two years for patients with high or very high risk CLL, approximately 25% of patients.

Indications to start treatment include: B symptoms, of fever, night sweats, and weight loss, marrow failure, anemia, thrombocytopenia, progressive or symptomatic node/liver/spleen growth, autoimmune complications, autoimmune hemolytic anemia, and immune thrombocytopenia.

Many patients present without symptoms and CLL is an incidental finding.

Active disease manifests with progressive lymphocytosis, cytopenias, lymphadenopathy, and hepatosplenomegaly, B Symptoms, fatigue, recurrent infections, or autoimmune complications.
Auto immune complications, most commonly autiimmune thrombocytopenia or hemolytic anemia can occur without other signs of CLL progression and without reflecting in alteration the natural history of disease for the prognosis and should be treated primarily with glucocorticoids.

Approximately 2-8% of CLL patients develop the Richter’s syndrome, represented in most cases as a diffuse large cell B-cell lymphoma.

The presence of cytogenetic changes are associated with a poorer prognosis.

With advancing disease and with successive cycles of remission and relapse cytogenetic changes in del(17p13) results in loss of p53.

With advancing disease and with successive cycles of remission and relapse cytogenetic changes in del(11q22) results in loss of ataxia telangiectasia mutated tumor suppressor genes.

Approximately 5% of patients with untreated disease have del(17p3) cytogenetic change, while nearly 50% of patients with multiply relapsed or refractory disease have loss of 17p13.

The deletion of 17p(del17p) contains the TP53 gene, and it’s presence is a clinical indication for treatment as this is a high risk group with a short survival.

Del(17p) reflects the loss of the TP 53 gene and is associated with short treatment free interval, short median survival of 32 months, and poor response to chemotherapy.

Del(17p) is more frequently observed in patients previously treated for CLL, suggesting acquisition and/or expansion of CLL clones with del (17p) may occur during the course of treatment.

Loss of tp53 is a marker for resistance to chemotherapy and is associated with poorer survival.

TP 53 abnormalities can occur in the absence of del(17P) and are identified as predictors of resistance to fludarabine based or bendamustine based regimens and poor survival, independent of 17 Pchromosomes status.

17p deletion has the worse prognosis of the major cytogenetic abnormalities and therapy is much less effective in this group of cytogenetic abnormalities.

A majority of patients with del(17p) also harborTP53 mutations, suggesting that both alleles are affected.

Hazard ratio for overall survival for deletion 17p is about 6.

In a study of patients with 17p deletion at diagnosis, 53% required therapy over the next 3 years, most within 18 months (Tam CS et al), but some are indolent.

Maintenance therapy with rituximab for two years improves progression free survival and overall survival only in patients with CLL carrying chromosome deletion 11q or deletion 17P who are at high risk of disease progression.

TP53 mutations are not present in 20-30% of patients with del(17p) and, conversely such mutations are detected in approximate 3-5% of untreated patients with CLL who do not have del (17p).

TP53 mutations is an important predictive and prognostic marker and should be considered before initiation of treatment for CLL as it identifies a subset of patients with lack of response to treatment and poor overall outcome, and its predicate identifies an extra 3-5% of patients with poor outcome.

Micro RNA-155 is a biomarker for CLL and it’s increased expression is correlated with poor survival and therapeutic response.

SF3B1 mutations associated with more aggressive disease and shorter survival and can be used as a prognostic marker.

SF3B1 is a critical component of the splicing machinery catalyzing the removal of introns from precursor mRNA.

Majority of patients are asymptomatic at the time of presentation.

Diagnosis is often made when there is coincidental finding of leucocytosis send lymphocytosis on routine laboratory examination.

Lymph node biopsy confirmation is not routinely required for the diagnosis as using flow cytometry of the peripheral blood is usually definitive.

Lymph nodes biopsy is reserved for cases in which different or transformed lymphoid malignancies are thought to to coexist with the CLL.

A combination of alemtuzumab and methylprednisolone appears to be the most effective induction regimen for patients with TP53 chronic lymphocytic leukemia with an objective response of 82%, median progression free survival 11.8 months.

Highest incidence of familial leukemia and believed to be polygenetic.

About 3.5% of persons older than 40 years of age with sensitive techniques have a monoclonal population of B lymphocytes indistinguishable from CLL, but most do not go onto frank CLL.

Disease increases with age and more than 90% of patients older than 50 years.

20-30% are age 60 years or younger, and 5-10% are age 50 or younger.

Affects males two times more often than females.

Equal incidence among blacks and whites and is uncommon in people of Asian descent.

Low risk group comprises two-thirds of patients with median age of 64 years and a median survival of greater than 10 years.

Low risk patients are those with early stage disease, a more nodular pattern of bone marrow infiltration, longer lymphocyte count double time of greater than 12 months, low CD38 and ZAP-70 expression, and more favorable chromosome alterations.

 
Patient with early stage CLL, Rai stage zero, Binet stage A  have an estimated median life expectancy of approximately 13 years they normally are not treated.
 
Patients with intermediate stage CLL, lymphocytosis with lymphadenopathy, hepatosplenomegaly or both; Rai stage I II, Binet stage B have an estimated median life expectancy of eight years and can be treated if they have signs of disease activity.
Patients with advanced stage CLL-lymphocytosis with lymphadenopathy, hepatosplenomegaly, or both, as well as marrow infiltration related anemia, thrombocytopenia or both; Rai stage III or IV, Binet stage C should always be treated: as these patients formerly had  an estimated median life expectancy of only two years.

Higher-risk patients have unfavorable chromosome abnormalities, rapidly progressive white blood cell count or doubling times.

Median age at diagnosis is 72 years.

About 10% of patients are younger than 55 years.
There is inherited genetic susceptibility with a 6-9 fold increase risk for family members of patients with CLL.

Prevalence higher in Caucasians, and males.

Prevalence up, but not incidence.

Over half of the patients are diagnosed with early-stage disease, Rai Stage 0.

Most patients, including 50% of patients with early stage disease, will die from progression of disease or disease related complications.

15-30% of early stage disease have an aggressive course with a high risk of early clinical progression.

Deferring patient in low risk disease does not compromise survival.

The disease does not require treatment until symptoms develop or the disease progresses and there is severe cytopenia.

Acute respiratory infections is a common complication with untreated disease, with an average of one day in every 11, during a respiratory virus season (High KP et al).

Most common presenting symptoms are lymph node swelling with fewer presenting with fever, weight loss or night sweats.

25% of patients are asymptomatic.

Most common physical findings are lymphadenopathy (87%), splenomegaly (57%), and hepatomegaly (14%).

About 10% present with Coombs positive autoimmune hemolytic anemia.

Autoimmune hemolytic anemia observed in 4-25% of CLL patients.

ITP occurs in about 5% of cases.

Unmutated IGHV is associated with a sure progression free and overall survival.
Un mutated IGHV, TP 53 mutation, and DEL (17p)  are the strongest predictors of shorter progression free survival, and overall survival in CLL.

Patients had a greater than eightfold higher incidence of malignant neoplasms than the general population.

Patients have greater than a twofold risk of developing a second cancer, including melanoma, soft tissue sarcomas, breast cancer, lung cancer, prostate cancer, G.I. malignancies and skin cancers.

The most common secondary cancer is skin cancer.

Second tumors tend to occur at sites similar to those observed in renal transplant patients, suggesting a possible link with this entity and immunologic defects.

Vitamin D deficiency associated with a shorter time to treatment and overall survival (Shanafelt et al).

After 2 years the incidence of second cancers in patients with 17p deletion and/or 6q deletion who developed other cancers is 8%, while incidence with 11q deletion and/or trisomy 12 is 3%, and at 4 years the incidences are 12 and 14%, respectively.

The incidence of second cancers in patients with other cytogenetic abnormaltities is 5% at 2 years and 10% at 4 years.

Factors associated with increased risk for secondary cancers include age grade 60 years, beta two microglobulin, of greater than 3 mg per liter, creatinine of 1.6 mg a deciliter or greater, LD H. above normal, hemoglobin less than 11 g , and the presence of splenomegaly.

Heterogeneous course includes some patients with rapidly progressing disease, with death within two years, while others live 20 years without symptoms or need for therapy.

About 10% of patients have hypogammaglobulinemia and 15% have hypergammaglobulinemia or even a monoclonal gammopathy.

In patients with CLL there is a significant increased risk of squamous cell carcinoma of the skin and basal cell carcinoma.

Bone marrow examination reveals normal to high cellularity with a B cell lymphocytic population that is monoclonal for kappa or lambda light chain expression.

Usually treatment is started when disease related symptoms appear or there is progression to a more advanced stage.

No indication that therpy will alter the rate of complicatins, such as autoimmune cytopenias, Richter’s trnformation, hypogammaglobulinemia, and secondary malignancy.

Any rapidly enlarging lymph node should be excised for analysis to exclude the presence of Richter’s transformation.

Alkylating agent based treatment has not demonstrated survival advantage.

Original therapy was the use of alkylating agents such as chlorambucil or cyclophosphamide as single agents, in combination with steroids.

Chlorambucil initial overall response rate of 60-90%, with a complete response rate of up to 20%.

Alkylating agents provide approximately 70% response rates with complete response rates of 5-10%.

Greater than 25% of low risk patients die of causes related to CLL, 40% progress to advance disease and 50% ultimately require treatment.

Approximately 70% of patients will require chemotherapy because of progressive symptoms.

Deferring patient in low risk disease does not compromise survival.

Chemoimmunotherapy was the standard therapy, until recently.

Chemoimmunotherapy is not considered curative therapy.

Chemoimmunotherapy is limited in its efficacy in patients with high risk cytogenetic features such as del(17p).

Median survival for treated groups with fludarabine, chlorambucil, chlorambucil and fludarabine are 66, 56 and 55 months respectively.

Rituximab at 375 mg/m squared weekly times 4 doses associated with a response rate of 40-50% and a median time to progression of 6-13 months.

Fludarabine and rituximab given concurrently has a response rate of 90% with a complete response rate of 47% compared to a response rate of 77% for the same drugs given sequentially.

Complete response rate for fludarabine alone is 20%.

Overall response rate of 50-60% with fludarabine.

In any randomized phase 3 trial of fludarabine versus observation in patients with high risk CLL, the drug was associated with a significantly longer progression free survival in 188 evaluable patients of 24.2 versus 15.9 months, with no difference in overall survival (Bergmann MA).

Median time to progression and overall survival for fludarabine alone is 12-13 months and 20-25 months, respectively.

In patients that fail purine analog treatment there is a median survival of 10 months and a 5-year survival of less than 10%.

German CLL study group phase 3 trial indicated that the addition of rituximab to standard fludarabine and cyclophosphamide nearly doubled the complete remission rate and length in progression free survival by 10 months: 817 untreated patients randomized to 6 courses of FC or FCR-complete remission 44.5% for FCR vs. 22.9% FC group.

FCR a combination of fludarabine, cyclophosphamide and rituximab for bendamustine plus rituximab are appropriate choices for patients who have no comorbidities and a normal life expectancy.

FCR is the standard first-line therapy for untreated CLL in fit patients and particularly those with unmutated IGVH, and bendamustine/riruximab is an alternative for ellderly patients or those with previous infections.

FCR therapy substantially benefits patients with I GHV unmutated CLL.

FCR has the best complete response and progression free survival with one third of patients still in remission at 10 years.

Rituximab and bendamustine has a shorter progression free survival than FCR.

Bendamustine plusr Rituximab results in an overall response rate of 88% and at a median of 27 months PFS was 34 months and OS 90.5%.

The combination of ventoclax (Venclexta) and rituximab significantly improved progression free survival compared with rituximab and bendamustine in patients with relapsed or refractory CLL (MURANO study).

Rituximab plus pentostatin associated with a response rate of 44% and the same drugs plus cyclophosphamide results in a high overall response rate.

FCR-In a study of 300 patients with previously untreated CLL, and a median follow-up of 12.8 years, the overall response rate was 95%, with 72% achieving complete response, median progression free survival was 6.4 years, and overall 12.8 year progression free survival rate was 30.9% and 53.9% for those with mutated IGHV and 8.74 for unmutated IGHV.

Majority of patients respond to chemotherapy or immunotherapy treatments but relapse occurs, almost universally, within 1-2 years.

95% of cases exhibit a B cell phenotype and 5% exhibit a T phenotype.

Rai stage 0-median survival 150 months.

Rai-stage I-median survival 101 months.

Rai stage II-median survival 71 months.

Rai stage III-median survival 19 months.

Rai stage IV-median survival 19 months.

Binet stage A median survival comparable to age-matched controls.

Binet stage B-median survival 84 months.

Binet stage C-median survival 24 months.

Neither the Rai or Binet staging system are effective for predicting early disease progression.

Routine imaging is not recommended for staging of CLL.

Visceral disease may occur early in the disease and may predict early progression.

Overall response rate of 63% with a 20% complete response rate to fludarabine.

2CdA (cladribine) has similar response rates to fludarabine.

Alemtuzumab response rate in heavily pretreated patients 33-42%.

Alemtuzumab response rate in first-line therapy 87% with 19% complete remission rate.

With alemtuzumab response rate higher with little or no lymphadenopathy and poor when lymph nodes are greater than 5 cm.

Allogeneic stem cell transplant offers the only curative treatment.

Plasma soluble CD52 level correlates with all important prognostic markers in CLL.

Patients with mutated immunoglobulin variable region (IgVh) genes usually have a benign process with a median survival of 25 years.

CLL associated with mutated heavy chain variable originates from a mature cell and is thus associated with a more favorable outcome than unmutated IGHV CLL.

Unmutated IGHV is associated with poor prognosis and significantly decreased survival compared with muted IGHV, irrespective of the stage and ofthe disease.

Patients with unmutated IgVh genes usually have an aggressive type of disease with a median survival of 8 years.

VH3-21 gene is associated with poor outcomes, shorter treatment free intervals and survival outcomes.

CD38+ antigen correlates with IgVH gene mutation status with 92% accuracy.

Elevated expression levels of CD38 and ZAP-70 are both associated with shorter survival.

Cells are resistant to apoptosis through members of the Bcl-2 ant apoptotic protein family.

Overexpression of BCL-2 is near universal.

A deletion on chromosome 13q is common in CLL and it removes a regulatory element, a micro RNA, that normally functions to suppress the expression of BCL-2.

Patients with ≥30% CD38+ leukemia have a poor prognosis with a median survival of 10 years.

Patients with ≤30% CD38+ leukemia have a median survival of greater than 19 years.

ZAP-70 (Zeta-associated protein of 70-kD) is preferentially expressed in CLL B cells whose immunoglobulin have not undergone mutation while mutated immunoglobulin CLL B cells most often lack such expression.

Patients with deletion of 11q or the 17p locus tend to do poorly with fludarabine plus cyclophosphamide or fludarabine plus rituximab.

Fludara plus cyclophosphamide (FC) vs. fludara plus cyclophosphamide plus rituximab (FCR) in untreated patients: FCR associated with higher response rates (95% vs 88.4%), longer median progression free survival (51.8 months vs 32.8 months, and improved overall survival (at 3 years 87.2% vs 82.5%)(Hallek M).

FCR in the above study particularly effective in subgroups -del(11q), del(13q) and trisomy 12, but not effective in preventing relapse and death in patients with del(17p).

FCR is first line treatment for younger CLL patients, because EO’s high complete remission rates, more negativity for minimal residual disease , and longer progression free survival and other regimens.

Chemotherapy for patients with mutated immunoglobulin heavy chain variable gene disease is very successful with two thirds of patients treated with FCR will have PFS beyond 10 years.

The REACH (Rituximab in the Study of Relapsed Chronic Leukemia) study showed that fludarabine, cyclophosphamide and rituximab (FCR)significantly improved overall response rates, including complete response rates and progression free survival relative to chemotherapy alone with fludarabine and cyclophosphamide (FC0 in 522 relaxed patients (Robak T et al).

Maintenance therapy after chemotherapy with fludarabine, Cytoxan, mitixanthone-rituximab with rituximab improved the quality of the response and prolonged progression free survival (Abrisqueta P et al).

Progression free survival 15.2 months with combination chlorambucil and rituximab versus 26.7 months with combination chlorambucil and obinutuzumab in CLL.

In a randomized study of previously untreated CLL patients randomized to chlorambucil, chlorambucil plus obinutuzumab, or rituximab plus chlorambucil: combining an anti-CD20 antobodies with chemotherapy improved outcomes in patients with a CLL and coexisting conditions-Obinutuzumab was superior torituximab when each was combined with chlorambucil (German CLL study group).

In the above studies the median progression free survival was 26.7 months with Obinutuzumab plus chlorambucil versus 11.1 months with chlorambucil alone, versus 16.3 months with rituximab plus chlorambucil.

In the above studies treatment with Obinutuzumab plus chlorambucil compared to rituximab plus chloambucil resulted in prolongation of progression free survival and higher rates of complete response 20.7% versus 7%, respectively.

In the above study del(17p) and elevated beta-2 microglobulin levels were strongest predictors of treatment failure (Hallek M).

Phase III trial of 305 patients with untreated CLL treated with bendamustine 100 mg/m2 IV on days 1 and 2 vs. chlorambucil 0.8 mg/kg orally days 1 and 15, every 28 days for up to 6 cycles: overall response rate 68% in bendamustine group vs 39% in chlorambucil group, with a complete remission rate of 39% vs 2%, respectively (Knauf).

Knauf study progression free survival of bendamustine 21.7 months compared to 9.3 months for chlorambucil, with median duration of remission of 18.9 months vs 6.1 months, respectively.

German CLL study group treatment of pretreated patients noted responses 9 of 16 patients treated with bendamustine (Treanda)-recommended doses 70 mg/m2 days 1 and 2 every 4 weeks-median duration of response was 42.7 months, with a median survival for all patients was 45.6 months.

Bendamustine in combination with rituximab in 117 patients with untreated CLL, overall response rate 90.9% with 32.7% CR, and 90% with 11q deletion, 89.5% with chromosome 12 trisomy and 88.9% in patients with unmutated IgVh

CLL B cell expression of ZAP-70 (Zeta-associated protein of 70-kD) level associated with a more aggressive course.

Genomic aberrations are associated with shorter survival: Shorter survival noted with 17p, 6q deletions, age at 60 years, beta-2 microglobulin at least 2 mg/L, albumin of less than 3.5 g/dL, creatinine of at least 1.6 mg/dL and in the presence of ZAP70 positive disease treatment is started earlier than with patients without that risk factors (Dohner H).

In general asymptomatic relapse can be followed expectantly, and reinitiation of treatment follows the same guidelines as for untreated patients.

The standard treatment for Binet  stage A CLL is watch and wait, and in a comparison of patients who receive chemo immunotherapy the five-year survival is not different.

Treatment for relapsed disease depends on the patient’s age, performance status, extent of previous treatment, clinical manifestations of disease, and genetic abnormalities within the CLL cells.

For relapsed disease first-line therapy can be repeated if the duration of response has lasted more than one year.

Treatment for patients with refractory disease or with 17p deletion andTP53 mutation is difficult.

Lenalidomide overall response rates in relapsed or refractory disease 32-47%.

Phase II studies suggest significant activity in untreated CLL patients with lenalidomide, with dramatic reductions in lymphocytes with 70% partial response rates by the end of cycle 2, utilizing 5mg/day or less dosage.

Bone marrow they put her on the hypocalcemia overall response rate in treatment naive and relapsed /refractory patients nearly 70% with a median follow-up of 20.3 months, and a 71% response in high-risk relapse/refractory patients at a median follow-up of 15.7 months: 26 months estimated overall survival 96% and 83%, respectively (Byrd JR et al).

Ibrutinib (Imbruvica) was the first BTK inhibitor approved by the FDA for CLL or SLL, followed by the approval of the second-generation BTK inhibitor, acalabrutinib (Calquence). 

Ibrutinib is an irreversible BTK inhibitor that abrocates CLL related cell signaling, adhesion, proliferation, and homing in vitro and in vivo.

Ibrutinib + Rituximab in high risk patients with CLL overall response rate of 83% (Burger J et al).

Ibrutinib-Rituximab is superior to treatment with standard chemoimmunotherapy resulting in a longer progression free survival and overall survival among patients 70 years or younger with previously untreated CLL (ShanafeltTD).

Ibrutinib efficacious for del(17p) IGHV and del(11q) status.

In a multicenter phase 3 study of 391 randomly assigned 391 patients with relapsed or refractory CLL or SLL to receive daily ibrutinib or the anti–CD20 antibody : Ibrutinib, as compared with ofatumumab, significantly improved progression–free survival, overall survival, and response rate among patients with previously treated CLL (RESONATE).

((Zanubrutinib)) highly effective for CLL.

In the above study Ibrutinib also significantly improved overall survival with a hazard ratio for death, 0.43,

In the above study at 12 months, the overall survival rate was 90% in the ibrutinib group and 81% in the ofatumumab group.

In the above study the overall response rate was significantly higher in the ibrutinib group than in the ofatumumab group, 42.6% vs. 4.1%.

Ibrutinib treatment among patients as a single agent in CLL for relapsed or refractory disease lead to a medium progression free survival of 52 months.

83% of patients with CLL remain alive five years after starting frontline ibrutunib  and 55% of patients with relapsed to refractory CLL remain alive seven years if the starting ibrutunib nerve salvage therapy.

The most frequent nonhematologic adverse events were diarrhea, fatigue, pyrexia, and nausea in the above study.

In patients with relapsed disease targeted therapy outperforms chemoimmunotherapy and should be front line.

Ibrutinib has been improved in the front-line setting and is especially useful high risk patients providing alternative to monoclonal antibodies administered alone or with chlorambucil.

Among older patients with untreated CLL treatment with Ibrutinib was superior to the treatment with bendamustine plus rituximab with regard to progression free survival, and no significant difference between Ibrutinib and Ibrutinib Plus ritiximab with regard to progression free survival.

CAR-T cell therapy has a greater than 70% response rate in refractory CLL.

In patients with relapsed, refractory disease with a 17p deletion median progression free survival duration with Ibritinib it is about two years.

11q deletion chromosome abnormality associated with an unfavorable prognosis, extensive lymph node involvement, disease progression and shortened survival, with most patients experiencing progressive disease within two years.

With 11q deletion treatment with FCR (fludarabine, cyclophosphamide, rituximab) is the preferred regimen, and the only regimen to show improved overall survival.

11q deletion associated with extensive lympadenopathy and shorter survival, 79 months (Dohner H).

17p deletion associated with loss of P53 gene.

11q deletion associated with loss of ATM gene.

Patients with 17p deletions have a lower response rate, shorter remission duration, and shorter overall survival with fludarabine based chemotherapy.

Patients with 17p13 deletions have an average survival of 3 years.

17p13 deletion associated with shorter treatment free intervals, shorter survival and resistance to therapy (Dohner H).

Patients with 17p deletion do not respond to alkylating agents, purine analogs, but do respond to monoclonal antibodies, such as alemtuzumab, and to intensive treatment with fludarabine, cyclophosphamide and rituximab, albeit with lowered complete response rate than in patients with other chromosome abnormalities.

With 17p deletion regimens with alemtuzumab should be considered.

With 11q deletion fludarabine plus cyclophosphamide regimen are preferred.

The presence of 13q deletion as the sole abnormality associated with a better prognosis.

Zap-70 and IGVH mutation analysis not presently useful for directing drug therapy.

Most frequent deletion of genomic DNA occurs in chromosome 13q13.4 and occurs in about 50% of cases.

13q13.4 deletion associated with a long interval between diagnosis and need for therapy in CLL.

13q cytogenetic abnormality associated with the longest survival of 133 months (Dohner H).

Noncoding RNA’s miR-15alpha, and miR-16-1 located in the smallest region of the deletion at 13q13.4 are frequently deleted or down regulated in CLL cells.

As CLL is an indolent disease, endpoints such as PFS have been accepted as measures of clinical efficacy

It is known from trial data that achieving a complete response (CR) in CLL is clinically meaningful.

In CLL, minimal residual disease (MRD) is assessed in samples from the peripheral blood and/or bone marrow.

Minimal residual disease has prognostic and predictive significance and both flow cytometry and polymerase Chain Reaction methods, take advantage of the disease immunophenotype or rearranged immunoglobulin heavy chains respectively, have the ability to detect residual

cells at a level of 1 CLL cell per thousand leukocytes.

MRD is detected by polymerase chain reaction (PCR) or flow cytometry, which are highly sensitive laboratory testing techniques that can detect 1 leukemic cell in as many as 10,000 leukocytes.

MRD negativity is achieved when no CLL cells are detected using these methods.

MRD is a surrogate endpoint for progressive free survival, and  is a measure of depth of response to guide clinical decision making

With chimeric antigen receptor therapy(CAR-T cell) in patients with relasped/refractory disease a 50-70% response rate has been recorded with 25-35% of patients achieving a complete remission.

The combination of ibrutinib plus venetoclax yielded a high rate of undetectable minimal residual disease (MRD) when used as first-line treatment for chronic lymphocytic leukemia (CLL), according to the CAPTIVATE trial.

Venetoclax as a BCL2 inhibitor approved as a monotherapy or in combination with rituximab or obinutuzumab for CLL—has previously demonstrated complete response rates of up to 50% in patients with this disease.

77% of patients in the CAPTIVATE trial had undetectable blood MRD after just six cycles of combined treatment.

In the above study 14 patients completing 12 cycles of the combination, 86% had undetectable bone marrow MRD, including all complete responders and most of the partial responders.

MRD negativity in CLL is an independent predictor of survival, regardless of treatment.

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