Oncology

Chronic lymphocytic leukemia/B-cell prolymphocytic leukemia

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Chronic lymphocytic leukemia/B-cell prolymphocytic leukemia

What every physician needs to know:

Chronic lymphocytic leukemia (CLL) is the most common leukemia in the Western world, and is generally a disease of older adults, with a median age at diagnosis of around 70. Given the heterogeneity in behavior of the disease, a number of prognostic factors have been developed to help risk-stratify patients. Rai stage, cytogenetics, mutation status of the immunoglobulin heavy chain variable region (IgVH), and a variety of other novel markers can help predict patient survival.

In general, CLL patients can be divided into three prognostic groups:

  • Those with favorable cytogenetics and mutated IgVH have the best prognosis

  • Those with favorable cytogenetics and unmutated IgVH have an intermediate prognosis

  • Those with unfavorable cytogenetics have a poor prognosis, likely regardless of IgVH status

Favorable risk patients can often be observed without the need for treatment for years, and many in this group may never require treatment at all. Intermediate and poor risk patients usually require treatment sooner. Indications for treatment include systemic symptoms, progressive cytopenias, rapidly enlarging lymph nodes, spleen, or liver, or a refractory autoimmune process.

Standard front-line treatment for fit patients is the chemoimmunotherapy regimen FCR (fludarabine, cyclophosphamide, rituximab). For patients with poorer performance status or comorbidities, a dose-reduced fludarabine containing regimen, other purine analog containing regimen, bendamustine, or chlorambucil can be offered. Patients with the high risk del(17p) marker now also have the recently FDA-approved oral agent ibrutinib available as a front-line option.

Second-line treatment options are extensive, and include a variety of different approved and investigational agents. No conventional therapy is currently curative for CLL, and although allogeneic stem cell transplantation does provide a potentially curative modality, the morbidity and mortality of this procedure remain relatively high. Therefore, whenever possible, CLL patients in all phases of the course of their disease should be encouraged to enroll in clinical trials.

B-cell prolymphocytic leukemia (B-PLL) is a rare disease that may evolve from CLL or present as de novo disease. B-PLL typically presents similarly to CLL, but the circulating cells are greater than 55% prolymphocytes. Given the rarity of B-PLL, the optimal treatment regimens are not well-defined, and the disease carries a poorer prognosis overall than CLL.

Are you sure your patient has chronic lymphocytic leukemia/B-cell prolymphocytic leukemia? What should you expect to find?

To establish the diagnosis of CLL, the following two criteria must be met:

  • Absolute B-lymphocyte count greater than or equal to 5,000 per uL, with mainly mature-appearing lymphocytes

  • Demonstration of clonality and appropriate immunophenotype of these cells by peripheral blood flow cytometry

The malignant cells will typically express B cell-associated antigens (CD19, CD23, and dim CD20), low-level surface immunoglobulin (Ig) (K or L), and the T cell-associated antigen, CD5.

B-PLL can present similarly to CLL, but has greater than 55% prolymphocytes (typically greater than 90%) that are often CD5-negative and may have brighter expression of CD20 and surface immunoglobulin.

Beware of other conditions that can mimic chronic lymphocytic leukemia/B-cell prolymphocytic leukemia:

Lymphocytic lymphoma

Patients with small lymphocytic lymphoma (SLL) have lymph node-only involvement by malignant CLL cells, with fewer than 5,000 circulating clonal B cells. The two entities can be thought of as one disease, since many, but not all patients with SLL will subsequently develop circulating disease consistent with CLL.

Mantle cell lymphoma

Mantle cell lymphoma (MCL), particularly a more indolent variant of MCL with circulating disease, is another CD5-positive B-cell malignancy that can be mistaken for CLL. Cyclin D1 expression and FISH (fluorescence in situ hybridization) for the t(11;14) (IgH/CCND1) are both positive in MCL and negative in CLL.

Follicular lymphoma

Follicular lymphoma with circulating disease can also mimic CLL, but can be distinguished by the cleaved nuclei with irregular contours characteristic of centrocytes in follicular lymphoma and by immunophenotype.

T-cell prolymphocytic leukemia

T-cell prolymphocytic leukemia (T-PLL) has a similar presentation and cellular morphology as B-PLL, but a different immunophenotype, which is typically positive for T-cell antigens CD2, CD3, CD7, and/or CD53.

Hairy cell leukemia

Hairy cell leukemia can also have circulating disease, but again with a different phenotype with CD11c, CD103, and CD25 expression.

Lymphoplasmacytic lymphoma

Lymphoplasmacytic lymphoma typically has CD5-negative plasmacytoid-appearing cells and is associated with significant paraproteinemia.

Splenic marginal zone lymphoma

Splenic marginal zone lymphoma can have a similar presentation and immunophenotype as CLL (that is, may be CD5-positive, even though more commonly CD5-negative), but typically has a bright surface immunoglobulin and CD20, and bone marrow examination often reveals lymphocytes with notched nuclei.

Which individuals are most at risk for developing chronic lymphocytic leukemia/B-cell prolymphocytic leukemia:

Most cases of CLL/B-PLL are spontaneous and do not have clearly identifiable risk factors.

Monoclonal B-cell lymphocytosis (MBL) is thought to be a precursor to most cases of CLL, and individuals with MBL are known to be at increased risk of developing CLL requiring treatment, at about 1% per year.

Caucasians are at higher risk for CLL, with Asians at the lowest risk, for unknown reasons.

There is also a male predominance in CLL of about 1.7 to 1.

The risk of developing CLL increases with age.

There are no definitive studies to suggest that environmental factors cause CLL, despite scattered case reports of excess risk in farmers and those with long-term exposure to heavy solvents or benzene.

Family history represents the most significant risk for developing CLL. Certain genetic polymorphisms may predispose patients to hereditary CLL, and this is currently an area of active investigation.

What laboratory studies should you order to help make the diagnosis and how should you interpret the results?

Peripheral blood flow cytometry is the most sensitive and specific test to establish the diagnosis of CLL/B-PLL. The following two criteria must be met:

  • Absolute B lymphocyte count greater than or equal to 5000 per uL, with mainly mature-appearing lymphocytes

  • Demonstration of clonality

With a typical pattern of expression of B cell associated antigens (CD19, CD23, and dim CD20), low-level surface Ig (K or L), and the T cell associated antigen CD5.

B-PLL can present similarly to CLL, but has greater than 55% prolymphocytes (typically greater than 90%) that are often CD5 negative. With advanced or progressive CLL, or CLL with high-risk del 17p, evolution toward PLL is often observed.

Peripheral blood should also be sent for interphase FISH cytogenetics to evaluate for common cytogenetic abnormalities such as del 13q14, trisomy 12, del 11q, and del 17p, which can affect both prognosis and selection of treatment. Sending peripheral blood for an analysis of the mutation status of the immunoglobulin heavy-chain variable region (IgVH) can help predict the pace of the disease, time to first treatment, and overall survival (OS). Due to the complexity of the assay for IgVH mutation status, it is recommended that samples only be sent to a lab with significant experience performing this test.

Zap-70status has been shown to have prognostic value in clinical studies, but the variability in the methodologies and discordant results of this test in the real-world setting, have precluded its routine clinical use to this point. CD38 status may also be associated with prognosis, but has no incremental prognostic value for predicting time to treatment, independent of Zap-70 and IgVH analysis, and the test results can vary from day to day, or based on the source tissue.

What imaging studies (if any) will be helpful in making or excluding the diagnosis of chronic lymphocytic leukemia/B-cell prolymphocytic leukemia?

In general, routine imaging studies are not necessary to establish the diagnosis of CLL/B-PLL. While imaging may help better define the precise extent of the disease, this information does not generally alter management.

In select situations, imaging may be useful. For example, patients with del11q abnormality may harbor occult bulky internal lymphadenopathy that should be monitored closely, so that treatment can be initiated when indicated. Also, it is generally useful to obtain baseline imaging prior to initiating therapy for CLL. CT (computed tomography) of the neck, chest, abdomen, and pelvis is the preferred test, and there are no robust data to support the routine use of PET (positron emission tomography) and CLL is generally not significantly FDG (fluorodeoxyglucose) avid.

In patients for whom there is a suspicion clinically of transformed disease (for example, Richter's transformation), a PET/CT scan may be useful to help identify an area suspicious for transformation, so that a biopsy could be directed toward that site.

If you decide the patient has chronic lymphocytic leukemia/B-cell prolymphocytic leukemia, what therapies should you initiate immediately?

It is not typically necessary to initiate emergent therapy for CLL/B-PLL. Even in cases with extreme lymphocytosis, it is generally preferable to establish a definitive diagnosis prior to starting treatment. Cases where there is an acute onset of anemia or thrombocytopenia may be suspicious for an autoimmune hemolysis or thrombocytopenia which may be driven by the CLL, but are not indications for treatment of the CLL itself. In these cases, the prompt institution of steroids (typically prednisone at 1mg/kg daily) will usually lead to prompt resolution of the anemia or thrombocytopenia.

Tumor lysis syndrome may be seen in patients following initial treatment or with transformed disease, and should be treated with intravenous hydration, allopurinol and/or rasburicase, and intensive electrolyte management.

What are the indications for therapy in CLL/B-PLL?

Indications for treatment include systemic symptoms (fever, night sweats, weight loss, fatigue, painful lymphadenopathy), progressive anemia or thrombocytopenia, rapidly enlarging lymph nodes, spleen, or liver, or refractory autoimmune processes. Lymphocyte doubling time of less than 6 months is a relative indication for treatment, though the magnitude of the change and the specific clinical scenario must be taken into account.

More definitive therapies?

The choice of definitive therapy for patients with CLL depends on their physical condition, prognostic risk factors, and stage. Early stage patients (Rai stages 0-II) without symptoms can generally be followed with close observation. Initially, complete blood counts should be checked at least every 3 months, and in patients who prove stable over time, this can be spaced out to every 6 months. Those with more advanced disease (stage III/IV) or symptoms should undergo treatment.

In general, although long-term remissions can be achieved, conventional treatment for CLL is not currently curative. Reduced-intensity allogeneic stem cell transplantation is a potentially curative approach, but carries with it significant procedure-related morbidity and mortality and is generally reserved for younger patients, those with poor prognostic factors, or those with multiply relapsed or refractory disease.

For fit patients who require therapy, the standard first-line approach is to use combination chemoimmunotherapy with FCR (fludarabine 25mg/m 2 on days 1, 2, and 3, cyclophosphamide 250mg/m 2 on days 1, 2, and 3, and rituximab 375mg/m 2[first cycle only] or 500mg/m 2 [cycle 2 and subsequent cycles] on day 1) for 6 monthly cycles.

This regimen has been shown in a large phase III trial to have an overall response rate (ORR) of 90%, with a complete response rate (CRR) of 45%. The median progression free survival (PFS) was 51.8 months, and the addition of rituximab to chemotherapy led to an absolute improvement in OS of 4% at 3 year follow-up, which was statistically significant. For patients with low risk disease or poorer performance status or serious co-morbidities, first-line treatment options include BR (bendamustine 90 mg/m 2 on days 1 and 2 and rituximab 375mg/m 2 on day 1 of cycle 1 and 500 mg/m 2 of cycle 2 and subsequent cycles), FR (fludarabine 25mg/m 2 on days 1 to 5 and rituximab 375mg/m 2 on day 1) for 6 monthly cycles, dose-reduced fludarabine as monotherapy or with cyclophosphamide, or the oral alkylating agent chlorambucil, which can be given on a variety of different doses and schedules, with a common one being 0.4 to 0.8mg/kg orally, every 2 weeks. Two new options for older patients with co-morbidities are the recently approved regimens combining chlorambucil and an anti-CD20 monoclonal antibody. One option uses chlorambucil at 0.5 mg/kg days 1 and 15 with obinutuzumab (100 mg day 1, 900 mg day 2, 1000 mg days 8 and 15 of cycle 1, and day 1 of cycles 2 through 6). The other option uses chlorambucil at 10 mg/m 2 days 1-7 plus ofatumumab (300 mg day 1, 1000 mg day 8 in cycle 1, and 1,000 mg weekly for a total of 8 weeks, followed by 1,000 mg monthly for 4 additional months to complete a 6 month course. Another option for frontline treatment is ibrutinib, a B cell receptor (BCR) pathway inhibitor that targets Bruton’s tyrosine kinase (BTK). In a randomized phase III trial RESONATE-2, ibrutinib was found to have superior PFS and OS compared to chlorambucil (median PFS not reached vs. 18.9 months and 24 month OS 98% vs. 85%). The FDA label for ibrutinib was recently expanded to include CLL patients regardless of line of therapy; however, the RESONATE-2 study was restricted to patients aged 65 or older and the comparator arm was the older, less effective drug chlorambucil. The efficacy and safety of ibrutinib relative to chemoimmunotherapy with FCR or BR, the current frontline standards of care, remain under investigation.

Patients with 17p deletion, the worst prognostic factor, are particularly challenging to treat. In general, the goal has been to achieve a deep remission (preferably a complete remission) and take these patients for a reduced-intensity allogeneic stem cell transplantation in first remission. Patients with 17p deletion treated frontline with the FCR combination have significantly inferior responses compared to patients without 17p deletion (17p ORR (68%) and CRR (5%), median PFS (11.3 months)).l. Ibrutinib has shown good efficacy in a limited number of del17p patients in the front line setting, with a 97% ORR including 55% PR and 42% PR with lymphocytosis. PR with lymphocytosis occurs when patients are radiographically in PR but have a persistent lymphocytosis, which is a class effect of BCR inhibitors. This effect is typically asymptomatic and self-limited, but can take several months to resolve. The follow-up on this study remains short, but for del(17p) CLL patients treated with ibrutinib in the relapsed refractory setting the estimated median PFS for patients with 17p deletion is 28 months. Based on these data, ibrutinib has become a new standard of care option for frontline treatment of del(17p) CLL, since its efficacy even in relapse exceeds prior therapies available for del(17p).

Alternative front-line options for patients with deletion 17p include the anti-CD52 monoclonal antibody alemtuzumab (30mg subQ [subcutaneous injection] three times a week, for 16 to 18 weeks), which in del 17p patients has an ORR of 64% with a PFS of 10.7 months, or high-dose methylprednisolone (1g/m 2 days 1 to 5 and weekly rituximab (375mg/m 2) given in monthly cycles, which in a smaller study without del 17p patients showed a 96% ORR, 32% CRR, and a median PFS of 30.3 months. A study of 39 patients combined alemtuzumab with high-dose methylprednisolone and found an 88% ORR, 65% CRR, and a median PFS of 38.9 months in the 17 untreated patients; the substantial hematologic and infectious toxicities that occur with this regimen in the relapsed setting were not as severe in the untreated setting, but care is certainly warranted.

Another subpopulation worthy of discussion is del(11q) patients, who were previously considered to carry a poor prognosis. There are now data to suggest that alkylating agents with purine analogues in this group may be able to overcome the previous poor prognosis, so the FCR regimen should be considered the standard regimen used as initial therapy in the fit population receiving chemoimmunotherapy. Consideration can also be given to using ibrutinib as frontline therapy in del(11q) patients and those with other higher risk markers such as unmutated IGHV, recognizing that complete remissions are rare and patients must remain on continuous ibrutinib. It remains unknown how difficult it will be to rescue these patients when they progress on ibrutinib. The early data in relapsed patients suggest that outcomes are poor.

When patients relapse, a key factor in choosing a regimen for second-line treatment has historically been the duration of first remission. Patients with a remission of at least 3 years on a modern chemoimmunotherapy regimen such as FCR can be considered for repeating the same therapy as used first-line, provided that they have mutated IGHV and haven't acquired deletion of 17p or 11q. These patients may also be considered for maintenance therapy with ofatumumab, which recently gained FDA-approval for patients with at least a partial response after at least 2 lines of therapy based on an improvement in median PFS from 15.2 mo. with observation to 29.4 mo. with 2 years of ofatumumab in the recently reported phase III PROLONG trial. The time to next treatment was only improved by 6 months, however, and at the cost of increased neutropenia and infections.

Patients with a shorter remission, treatment-refractory disease (defined as relapse within 24 months of first-line therapy) or an acquired poor risk cytogenetic abnormality should be considered for kinase inhibitors. These patients should receive a different therapy from the original regimen they received, and they should also be considered for enrollment in a clinical trial, where available. Treatment options in the relapsed setting include all of the options described above in the first-line setting, as well as the oral delta-isoform specific PI3K inhibitor idelalisib plus rituximab, ofatumumab, a bendamustine-based regimen, and subsequently allogeneic stem cell transplantation with curative intent, in fit patients with poor prognostic markers in whom a reasonable remission is achieved.

Ibrutinib and idelalisib plus rituximab are both regimens that are FDA-approved for relapsed/refractory CLL. In randomized phase III data in heavily pretreated relapsed refractory patients, ibrutinib was found to have a 43% IW-CLL ORR, with an additional 20% of patients achieving a PR with lymphocytosis. The median PFS was not reached at a median follow-up of 9.4 months, and there was an overall survival advantage for ibrutinib versus the comparator ofatumumab (OS at 12 months - 90% in the ibrutinib group vs. 81% in the ofatumumab group).

In a heavily pretreated relapsed/refractory CLL population, idelalisib monotherapy was found to have a 39% IW-CLL ORR with an additional 33% meeting PR with lymphocytosis criteria. The median PFS for all patients was about 16 months. In a phase III study, idelalisib given in combination with rituximab was shown to extend overall survival compared to rituximab alone (OS at 12 months - 92% in the idelalisib + rituximab group vs. 80% in the rituximab alone group).

Another exciting new therapeutic modality being evaluated in CLL is an autologous cellular immunologic therapy known as chimeric antigen receptor (CAR) T-cells. Clinical data on CAR T-cells in CLL are relatively limited, but promising. For example, in a report of 30 patients treated with CTL019 therapy, the overall response rate was 35%, and genetically modified T cells with ongoing functional activity lasting beyond 3 years have been documented. Several groups are now developing CAR T-cells in collaboration with industry partners, and CLL patients refractory to multiple therapies including kinase inhibitors can be considered as candidates for these clinical trials.

What other therapies are helpful for reducing complications?

Given the intensity of treatment in CLL, supportive medications are critical to safely getting patients through therapy. In patients on chemoimmunotherapy or alemtuzumab, myelosuppression is common, and transfusion support is often required. Growth factor support with pegfilgrastim should be provided when the absolute neutrophil count is less than 1,000.

The risk of opportunistic infections with these regimens is also high, and prophylactic antibiotics are required. Patients should be started on trimethoprim/sulfamethoxazole for Pneumocystis pnueminia (PCP) prophylaxis (atovaquone in patients with thrombocytopenia) and acyclovir or valacyclovir for herpes simplex virus/varicella-zoster virus (HSV/VZV) prophylaxis. These prophylactic medications should be continued for at least 6 months after completing therapy in the first-line setting, and indefinitely in the relapsed setting, potentially guided by CD4-count recovery.

Patients receiving alemtuzumab should have baseline and then weekly viral PCR (polymerase chain reaction) testing of the peripheral blood for Cytomegalovirus (CMV) viral load. If CMV is detected in the blood, immediate therapy with valganciclovir should be instituted, and the CMV viral load monitored to ensure it becomes undetectable. Valgancyclovir should be continued for the duration of alemtuzumab therapy and for at least several months afterwards.

Other supportive measures include pre-medication for the antibody-containing regimens with diphenhydramine, acetaminophen, and hydrocortisone to minimize the risk of infusion reactions, and for the chemotherapy-based regimens using prophylactic antiemetics such as ondansetron. Patients with a high burden of disease (for example, high WBC [white blood cell] count, bulky lymph nodes) should also be started on allopurinol prior to starting treatment, although the risk of tumor lysis syndrome is relatively low.

What should you tell the patient and the family about prognosis?

CLL is typically an indolent lymphoproliferative disorder, with a long natural history. Many effective therapies are available that can induce long term remission for years at a time; however, currently none of these conventional therapies are curative, and the goal of therapy should be to prevent complications from the CLL while optimizing quality of life. Rai stage can be used to estimate OS with stage 0 patients (lymphocytosis), stage I patients (palpable lymphadenopathy), stage II patients (palpable hepatosplenomegaly), and stage III/IV patients (anemia/thrombocytopenia), having median survivals of 150, 101, 71, and 19 months in the original report. Given advancements in treatment, median survival has improved significantly at all stages of disease, particularly in those with advanced (stage III/IV) disease.

Prognosis can be refined further by grouping CLL patients into three main categories. The patients with the poorest prognosis have unfavorable cytogenetic abnormalities such as del 17p or complex cytogenetics. The remaining patients without high-risk cytogenetics can be divided into two groups, one group with mutated IgVH, and one with unmutated IgVH. These mutated IgVH patients have an excellent prognosis, and many will never require treatment of their CLL. The unmutated IgVHpatients have an intermediate prognosis, and are likely to require treatment sooner than their mutated IgVH counterparts.

"What if" scenarios.

Misdiagnosis

An elderly patient presents with several months of lymphocytosis, the immunophenotype is CD5-positive CD23-negative B cells, and they are diagnosed with CLL.

It is critical in patients such as this that FISH be sent to rule out the t(11;14) IgH-CCND1 translocation or immunostaining be done for cyclin D1 to rule out mantle cell lymphoma (MCL). There is an indolent form of MCL that can mimic CLL in the early stages, but has a different natural history, and once treatment is indicated, requires different chemotherapeutic regimens.

Conflicting prognostic markers

A newly-diagnosed patient is found to have del 13q14, but the IgVH status comes back as unmutated. How should this patient be counseled about their risk?

Patients without high-risk cytogenetics can be divided into two groups--those with mutated and those with unmutated IgVH. Those in the latter group tend to have a steadily rising WBC count and have an inferior OS, compared to the former group, but better OS than those with poor risk cytogenetics. Patients with unmutated IgVH CLL should be counseled that they are likely to require treatment sooner than patients with mutated IgVH, that their duration of remission may be shorter, and that their overall prognosis is also poorer.

Over treatment

A patient with a long-standing history of indolent CLL suddenly develops severe anemia or thrombocytopenia. Do they require immediate CLL directed therapy?

A common pitfall in this situation would be to initiate chemotherapy for progressive CLL, but one must first rule out a new autoimmune hemolytic anemia (AIHA) or immune thrombocytopenic purpura (ITP). Patients should have common hemolysis laboratory tests checked (bilirubin, LDH [lactate dehydrogenase], haptoglobin, reticulocyte count, as well as a direct Coombs' test). If these tests come back positive, a trial of immunosuppressive therapy (for example, prednisone 1mg/kg/day) should be initiated, and patients who respond well, often do not require CLL specific therapy at that time. Those who have progression of their CLL concomitant with their autoimmune process should also be treated for their CLL, and the autoimmune phenomenon will frequently resolve.

Changing or initiating therapy too quickly

A patient starts on FCR and is responding well, but during cycle two contracts a viral upper respiratory infection and during the illness the white blood cell count trends up and lymph nodes increase in size. Should therapy be changed?

It is quite common for CLL to flare in the setting of acute infection, both in patients on treatment and in untreated patients. Large elevations of the WBC count and marked increase in the size of lymph nodes can be seen in this setting, likely as an exaggerated response to the infection. Treatment of the underlying infection often results in improvement in the lymphadenopathy and WBC count and allows for continuation of the current CLL-directed therapy or observation.

Pushing treatment too aggressively

A patient is started on FCR, and after two cycles, the platelet count trends down from a baseline of 100 to 75. Should treatment be continued?

FCR can be a highly myelosuppressive regimen, particularly in older persons, even if they are otherwise fit. The platelet count should be allowed to recover to at least 90% of the baseline value prior to resuming the next cycle of therapy. Sometimes this can lead to weeks, even months of treatment delay. However, pushing through and treating with additional cycles despite worsening thrombocytopenia can have profound long-term effects and cause severe cytopenias that lead to future complications and limit additional treatment options.

Pathophysiology

CLL is a lymphoproliferative disorder that arises from mature B cells and leads to the development of functionally incompetent, clonal malignant cells. In some patients, this process will be so indolent that although the lymphocytes can be shown to possess a CLL phenotype, their absolute number remains low, a condition known as monoclonal B cell lymphocytosis (MBL). A similar pathophysiology is believed to underly B-PLL, with the exception being, that the malignant cells are less mature prolymphocytes that may proliferate more rapidly and exhibit aggressive behavior. Accumulation of large numbers of CLL cells leads to the characteristic clinical findings of the disease, which include lymphocytosis, lymphadenopathy, and hepatosplenomegaly in early stage disease, and cytopenias due to crowding out the bone marrow in advanced disease.

Cytogenetic abnormalities associated with CLL are well described, and in some cases may be related to the pathogenesis of the disease. The molecular genetic events affected by these cytogenetic abnormalities are now being elucidated. For example, deletion 17p results in decreased or absent TP53 activity, which may lead to a poor response to chemotherapy and poor outcome. Deletion 11q may lead to deletion of the ataxia telangiectasia-mutated (ATM) gene, a key component of the DNA damage response.

Deletion of 13q14 may result in loss of two critical microRNA genes, mir-15a and mir-16-1, which can no longer perform their usual function of inhibiting the anti-apoptotic protein Bcl-2, and thereby lead to the overexpression of Bcl-2 characteristic of CLL. It has also recently been recognized that TCL-1 may be an oncogene important in aggressive forms of CLL. While most of these abnormalities are likely somatic, genetic susceptibility to CLL has also been demonstrated, with about 10% of patients with CLL reporting a family history of leukemia or lymphoma. Additional areas of investigation in CLL currently include the role of epigenetic alterations and the microenvironment.

What other clinical manifestations may help me to diagnose chronic lymphocytic leukemia/B-cell prolymphocytic leukemia?

Twenty-five percent or more of CLL patients are asymptomatic at diagnosis, but those who are not, exhibit a wide range of presentations. New lymphadenopathy is frequently the first presenting symptom, and many patients will describe a long history of waxing and waning lymph nodes. Rarely, patients will present with "B symptoms" (fever, drenching night sweats, weight loss). In patients who present with more advanced disease, there may be evidence of cytopenias such as fatigue due to anemia or easy bleeding/bruising due to thrombocytopenia. Autoimmune phenomena may also lead to anemia due to an autoimmune hemolytic anemia and thrombocytopenia due to ITP.

As CLL can impair the normal immune system, frequent infections are also a common manifestation of the disease. CLL patients are also at increased risk for second malignancies, and the CLL diagnosis may also sometimes be made in the context of the diagnosis of a different cancer.B-PLL is typically more aggressive than CLL, and presents with a rapidly rising WBC count (often greater than 100,000 per uL), anemia and thrombocytopenia, splenomegaly, and "B symptoms". Lymphadenopathy is not typically as prominent as in CLL.

What other additional laboratory studies may be ordered?

Beta-2 microglobulin and LDH

Beta-2 microglobulin and LDH should be ordered as general markers of disease burden. Serum protein electropheresis should be evaluated to rule out monoclonal gammopathy, which is often associated with CLL. There is emerging evidence that serum free light chains may also have prognostic value in CLL.

HIV and hepatitis B and C

Patients starting on treatment should be tested for HIV and hepatitis B and C, as it may be important to initiate treatment for these other disorders prior to starting CLL therapy, and the risk of hepatitis B reactivation on rituximab therapy is significant.

FISH cytogenetics

FISH cytogenetics should be performed, both at diagnosis and at time of relapse, as there is frequently clonal evolution that would potentially alter further management.

Bone marrow biopsy

Bone marrow biopsy is not required at the time of initial presentation, as the diagnosis can be made from peripheral blood flow cytometry, and the degree of bone marrow involvement at diagnosis has not been shown to confer additional prognostic value, independent of other factors. Bone marrow biopsy should be performed prior to starting treatment to establish a baseline, after completing treatment to assess response, and at time of relapse to obtain a new baseline.

Other times to consider bone marrow biopsy are in cases where despite a thorough work-up, the issue of autoimmune cytopenias versus progressive disease cannot be resolved, or mid-treatment when it is not clear whether a patient with prolonged cytopenias still has significant disease in the marrow versus myelosuppression due to treatment, or in the case where transformed disease is suspected.

What’s the evidence?

Badoux, XC, Keating, MJ, Wang, X. "Fludarabine, cyclophosphamide, and rituximab chemoimmunotherapy is highly effective treatment for relapsed patients with CLL". Blood. vol. 11. 2011. pp. 3016-24.

(Report of a large experience of using FCR in the relapsed setting.)

Brown, JR, Byrd, JC, Coutre, SE. "Idelalisib, an inhibitor of phosphatidylinositol 3-kinase p110-delta, for relapsed/refractory chronic lymphocytic leukemia". Blood. vol. 123. 2014 May 29. pp. 3390-7.

(Report on the original phase I trial of idelalisib (GS-1101, CAL-101) in CLL.)

Burger, JA, Tedeschi, A, Barr, PM. "Ibrutinib as Initial Therapy for Patients with Chronic Lymphocytic Leukemia". N Engl J Med. vol. 373. 2015 Dec 17. pp. 2425-37.

(Randomized phase III study that led to the FDA broadening the label of ibrutinib to include frontline use)

Byrd, JC, Brown, JR, O'Brien, S. "Ibrutinib versus ofatumumab in previously treated chronic lymphoid leukemia". N Engl J Med. vol. 371. 2014, Jul 17. pp. 213-23.

(Randomized phase III study that led to the full FDA-approval of ibrutinib for relapsed/refractory CLL.)

Castro, JE, Sandoval-Sus, JD, Bole, J. "Rituximab in combination with high-dose methylprednisolone for the treatment of fludarabine refractory high-risk chronic lymphocytic leukemia". Leukemia. vol. 11. 2008. pp. 2048-53.

(Important treatment option, particularly for refractory patients with poor risk cytogenetics and bulky lymphadenopathy.)

Dreger, P, Corradini, P, Kimby, E. "Indications for allogeneic stem cell transplantation in chronic lymphocytic leukemia: the EBMT transplant consensus". Leukemia. vol. 21. 2007. pp. 12-17.

(Helpful guide for patient selection for stem cell transplantation.)

Farooqui, MZ, Valdez, J, Martyr, S. "Ibrutinib for previously untreated and relapsed or refractory chronic lymphocytic leukaemia with TP53 aberrations: a phase 2, single-arm trial". Lancet Oncol.. vol. 16. 2015 Feb. pp. 169-76.

(Single-arm phase II study providing data on the outcomes of both frontline and relapsed/refractory patients with TP53/17p aberrations treated with ibrutinib.)

Furman, RR, Sharman, JP, Coutre, SE. "Idelalisib and rituximab in relapsed chronic lymphocytic leukemia". N Engl J Med. vol. 370. Mar 13. pp. 997-1007.

(Randomized phase III study that led to the FDA-approval of idelalisib.)

Goede, V, Fischer, K, Busch, R. "Obinutuzumab plus chlorambucil in patients with CLL and coexisting conditions". N Engl J Med. vol. 370. 2014; Mar 20. pp. 1101-10.

(Randomized phase III study that led to the FDA-approval of obinutuzumab.)

Hallek, M, Cheson, BD, Catovsky, D. "Guidelines for the diagnosis and treatment of chronic lymphocytic leukemia: a report from the International Workshop on Chronic Lymphocytic Leukemia updating the National Cancer Institute-Working Group 1996 guidelines". Blood. vol. 111. 2008. pp. 5446-56.

(Definitive synopsis of current consensus recommendations for diagnosis, treatment, and response assessment in CLL.

Hallek, M, Fischer, K, Fingerle-Rowson, G. "Addition of rituximab to fludarabine and cyclophosphamide in patients with chronic lymphocytic leukemia: a randomised, open-label, phase 3 trial". Lancet. vol. 376. 2010. pp. 1164-74.

(Landmark trial that provides data on a large experience with FCR.)

Hillmen, P, Robak, T, Janssens, A. "Ofatumumab + Chlorambucil Versus Chlorambucil Alone In Patients With Untreated Chronic Lymphocytic Leukemia (CLL): Results Of The Phase III Study Complement 1 (OMB110911)".

(Randomized phase III study that led to the FDA-approval of ofatumumab in the front-line setting.)

Keating, MJ, Flinn, I, Jain, V. "Therapeutic role of alemtuzumab (Campath-1H) in patients who have failed fludarabine: results of a large international study". Blood. vol. 99. 2002. pp. 3554-3561.

(Report on the registration trial of alemtuzumab in relapsed CLL.)

Melo, JV, Catovsky, D, Galton, DA. "The relationship between chronic lymphocytic leukaemia and prolymphocytic leukaemia. I. Clinical and laboratory features of 300 patients and characterization of an intermediate group". Br J Haematol. vol. 63. 1986. pp. 377-87.

(Helpful description of the differences between patients with B-PLL and CLL.)

O'Brien, S, Furman, RR, Coutre, SE. "Ibrutinib as initial therapy for elderly patients with chronic lymphocytic leukaemia or small lymphocytic lymphoma: an open-label, multicentre, phase 1b/2 trial". Lancet Oncol. vol. 15. 2014 Jan. pp. 48-58.

(Report on the initial cohort of patients treated with ibrutinib as initial therapy.)

Pettitt, AR, Jackson, R, Carruthers, S. "Alemtuzumab in combination with methylprednisolone is a highly effective induction regimen for patients with chronic lymphocytic leukemia and deletion of TP53: final results of the national cancer research institute CLL206 trial". J Clin Oncol. vol. 30. 2012 May 10. pp. 1647-55.

(Report on the combination of alemtuzumab with methylprednisolone in high risk patients.)

Porter, DL, Frey, NV, Melenhorst, JJ. "Randomized, Phase II Dose Optimization Study of Chimeric Antigen Receptor Modified T Cells Directed Against CD19 (CTL019) in Patients with Relapsed, Refractory CLL". Blood. vol. 124. 2014.

(Preliminary report on efficacy of CTL019 CAR T-Cells at the 2014 ASH Annual Meeting.)

Rai, KR, Peterson, BL, Appelbaum, FR. "Fludarabine compared with chlorambucil as primary therapy for chronic lymphocytic leukemia". N Engl J Med. vol. 343. 2000. pp. 1750-7.

(Report on the superiority of purine analog-based therapy in CLL.)

Rai, KR, Sawitsky, A, Cronkite, EP. "Clinical staging of chronic lymphocytic leukemia". Blood. vol. 46. 1975. pp. 219-34.

(Seminal paper laying out the Rai staging system for CLL.)

Tam, CS, O'Brien, S, Wierda, W. "Long-term results of the fludarabine, cyclophosphamide, and rituximab regimen as initial therapy of chronic lymphocytic leukemia". Blood. 112. pp. 975-980.

(Provides long-term data on the results with the FCR regimen.)

van Oers, MHJ, Kuliczkowski, K, Smolej, L. "Ofatumumab maintenance versus observation in relapsed chronic lymphocytic leukaemia (PROLONG): an open-label, multicentre, randomised phase 3 study [published online ahead of print September 13, 2015]". Lancet Oncol.

(Randomized, phase III data showing a PFS benefit to maintenance ofatumumab in relapsed/refractory CLL after chemoimmunotherapy.)
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