CHRONIC LEUKEMIAS

CHRONIC LEUKEMIAS

Current Diagnosis

Chronic Myelogenous Leukemia

•   Clinical symptoms

   •   Constitutional symptoms

   •   Splenomegaly (abdominal discomfort, early satiety)

•   Laboratory parameters

   •   Increased white blood cell count, commonly >100,000/µL, with differential counts showing granulocytes in all stages of differentiation, and two peaks involving neutrophils and myelocytes

   •   Absolute basophilia

•   Genetic parameters

   •   Demonstration of bcr-abl by standard cytogenetic analysis, fluorescent in situ hybridization, or polymerase chain reaction

Chronic Lymphocytic Leukemia

•   Clinical symptoms

   •   B symptoms (fever, night sweats, and weight loss)

   •   Lymphadenopathy and organomegaly

   •   Recurrent infections

•   Laboratory parameters

   •   Increased white blood cell count with absolute lymphocytosis

   •   Anemia, thrombocytopenia

•   Immunophenotypic analysis (flow cytometry)

   •   Demonstration of monoclonal population of light chain–restricted mature B lymphocytes expressing CD19, CD20 (dim), and CD23 and coexpressing pan-T cell antigen CD5

Current Ther

Chronic Myelogenous Leukemia: Chronic Phase

•   Initial therapy

   •   Imatinib mesylate (Gleevec) 400–600 mg daily

   •   Dasatinib (Sprycel)

   •   Nilotinib (Tasigna)

•   Second-line therapy:

   •   Imatinib mesylate 800 mg daily

   •   Dasatinib (Sprycel)

   •   Nilotinib (Tasigna)

   •   Bosutinib (Bosulif)

   •   Ponatinib (Iclusig)

   •   Omacetaxine (Synribo)

•   High risk for failure:

   •   Allogeneic stem cell transplantation

Chronic Lymphocytic Leukemia

•   Chemotherapy drugs

   •   Fludarabine (Fludara)

   •   Deoxycoformycin (Pentostatin [Nipent])

   •   Cyclophosphamide (Cytoxan)

   •   Chlorambucil (Leukeran)

   •   Bendamustine (Treanda)

•   Targeted therapy drugs

   •   Idelalisib (Zydelig)

   •   Ibrutinib (Imbruvica)

•   Immunotherapy (monoclonal antibodies):

   •   Rituximab (Rituxan)

   •   Alemtuzumab (Campath)

   •   Ofatumumab (Arzerra)

   •   Obinutuzumab (Gazyva)

Chronic Myelogenous Leukemia

Chronic myelogenous leukemia (CML) is a chronic myeloproliferative disorder defined by the presence of a chimeric gene, bcr-abl, encoded by translocation between chromosomes 9 and 22, the Philadelphia chromosome. Discovered in 1960, the Philadelphia chromosome was the first chromosomal abnormality implicated in carcinogenesis. This was followed by decades of unraveling of leukemogenic process, which culminated in a development of the bcr-abl inhibitor imatinib mesylate (Gleevec). As a result, in 2001 CML became the first human neoplasm in which the rationally designed therapeutic agent to target a carcinogenic pathway demonstrated great clinical efficacy.

Epidemiology and Risk Factors

CML accounts for 7% to 15% of all cases of leukemia in adults. The median age at diagnosis is 45 to 55 years. The disease is extremely rare in children and the overall incidence increases with age. There is slight male predominance, with a male-to-female ratio of 1.4 to 1.0. There is no association with geographic distribution or race. The etiology of CML is unknown. High-dose radiation exposure is the only well-established environmental risk factor. No genetic predisposition is thought to play any role in pathogenesis of CML.

Pathogenesis

bcr-abl is created by a reciprocal translocation of genetic material between the long arm of chromosome 9 (containing the protooncogene c-abl) and the long arm of chromosome 22 (containing the bcr gene). This is the Philadelphia chromosome, and it is correctly annotated t(9;22)(q34.1;q11.21). The translocation results in constitutive upregulation of tyrosine kinase activity of abl, which triggers downstream transduction pathways of a signaling cascade of oncogenic events.

The natural course of CML is one of inevitable progression from an initial chronic phase to a more-aggressive accelerated phase and eventually to a rapidly fatal myeloid or lymphoid blast phase. It is thought that the transformation proceeds as a consequence of the accumulation of additional molecular changes in genetically unstable bcr-abl–containing cells. Supportive of this hypothesis, up to 80% of patients with advanced CML have secondary cytogenetic abnormalities.

Clinical and Laboratory Characteristics

CML is a clonal myeloproliferative disorder that develops through accumulation of maturing cells of myeloid, erythroid, and megakaryocytic origin. CML has a biphasic or triphasic clinical course. Patients usually present in the initial chronic phase, exhibiting a cluster of specific clinical and laboratory features (listed in the Current Diagnosis box). More than half of patients with CML diagnosed in the chronic phase are asymptomatic, and the diagnosis is established following the incidental discovery of elevated white blood cell (WBC) count on a routine screening test.

The median time to the development of terminal blast phase is 3 to 6 years. The disease typically progresses through slow evolution into an accelerated phase and then blast phase, but it can transform rapidly directly into the blast phase. The detection of a change in the pace of the disease may be difficult and therefore definitions of accelerated phase vary and are imprecise. The blast phase is defined by the presence of extramedullary disease or at least 30% blasts or blasts and promyelocytes in the bone marrow or peripheral blood. Leukemic cells in blast phase are characterized by arrested maturation, and they proliferate rapidly, similar to acute leukemia cells. The symptoms of blast phase are also those typically seen in acute leukemia.

Diagnosis

The diagnosis of CML can be usually made with reasonable certainty based on the results of peripheral blood cell counts and examination of the peripheral blood smear (see the Current Diagnosis box). The detection of the Philadelphia chromosome or bcr-abl by cytogenetic analysis, fluorescent in situ hybridization (FISH), or polymerase chain reaction (PCR) confirms the diagnosis: all patients positive for the Philadelphia chromosome by standard cytogenetic analysis will have a bcr-abl fusion gene detectable by FISH or PCR; however, in approximately 5% of patients with bcr-abl detectable by FISH or PCR, the Philadelphia chromosome could not be appreciated by standard cytogenetics. The bone marrow biopsy is usually not necessary for diagnosis but should be performed for staging purposes in all patients with newly diagnosed CML.

Differential Diagnosis

At presentation, the differential diagnosis of CML usually involves distinction from leukemoid reaction. Among hematologic malignancies, CML may be difficult to differentiate from other myeloproliferative disorders (essential thrombocytosis, polycythemia vera, and mutagenic myeloid metaplasia), chronic neutrophilic leukemia, chronic myelomonocytic leukemia, juvenile chronic myeloid leukemia, and eosinophilic leukemia. In most cases, the detection of bcr-abl is sufficient to make the distinction. However, the differentiation between CML presenting in lymphoid-blast phase and Philadelphia chromosome–positive acute lymphoblastic leukemia might not be possible.

Prognosis

Before the effective therapies became available, the expected median survival of patients with CML was 39 to 47 months, with less than 20% surviving longer than 8 years. Allogeneic stem cell transplantation (SCT) and interferon (IFN) alfa-2b (Intron-A)1 or INF alfa 2a (Roferon-A) in the 1990s improved median survival to 60 to 65 months. However, the availability of tyrosine kinase inhibitors (TKIs) in 2000s transformed CML into a chronic disease associated with near- normal life expectancy: The 8-year update of the IRIS trial (International Randomized Study of Interferon and STI- 571) reported 85% overall survival and 93% survival in patients with only CML- related deaths. At this time, it is still unclear if TKIs are capable of curing CML; and continuation of therapy to maintain the remission is generally considered the standard of care. However, the increasing body of evidence suggests that as many as 30% of imatinib-treated patients who stopped the treatment after ≥2 years of undetectable minimal residual disease by conventional PCR may be able to sustain their remission off treatment. Patients who are suboptimal responders, who are poor responders, or whose disease is refractory to imatinib have poorer prognosis than patients who met expected response criteria (Table 1). The Sokal prognostic score, originally derived from 800 patients treated in the early 1960s and 1970s, still helps to identify patients who are at high risk for failure in era of TKI.

Table 1

European LeukemiaNet Response Definitions for any TKI first line, and second line in case of intolerance, all patients (CP, AP, BP)

Time after Diagnosis Failure                                     Warning/Suboptimal
Baseline High risk

Major route CCA/Ph+

3 mo No CHR Ph+ >95% BCR-ABL*>10% Ph+ 36–95%
6 mo BCR-ABL >10%

Ph+ >35%

BCR-ABL* 1–10%

Ph+ 1–35%

12 mo BCR-ABL*>1% Ph+ >0% BCR-ABL* 0.1–1%
Then and at any time Loss of CHR, CCyR or MMR Mutations**

CCA/Ph+

CCA/Ph– (–7, or 7q–)

Reprinted with permission from Baccarani M, Deininger MW, Rosti G, et al: European LeukemiaNet recommendations for the management of chronic myeloid leukemia. Blood 2013;122(6):872–884. http://www.leukemia- net.org/content/leukemias/cml/recommendations/e8078/infoboxContent10260/PocketCard_UP (accessed 20.8.2014).

Abbreviations: CCgR = complete cytogenetic response; MMR = major molecular response; PCgR = partial cytogenetic response; Ph = Philadelphia chromosome. Major route CCA/Ph+ are clonal cytogenetic abnormalities in Ph+ cells: +8, 2nd Ph+ CCA/Ph+ are trisomy 8, [+der(22)t(9;22)(q34;q11)], isochromosome 17\[i(17)(q10)], trisomy 19, and ider(22) (q10)t(9;22)(q34;q11)

*  IS International Scale

**  Confirmed by two consecutive tests, of which one is  ≥1%

Definitions of Response and Monitoring of Therapeutic Efficacy

The goal of CML therapy is the maximum possible reduction of leukemia burden. The status of the response is routinely evaluated by peripheral blood counts, cytogenetic analysis and FISH, and real-time quantitative PCR (RQ-PCR). The uniform criteria for hematologic, cytogenetic, and molecular responses have been developed to guide therapy and facilitate meaningful analysis of efficacy data across clinical trials (Tables 1 and 2). Close follow-up of response is critically important to predict when other therapies, such as alternative TKIs or transplantation, should be considered. Selective testing for bcr-abl kinase domain mutations is recommended for all patients who fail to respond to the first-line agent.

Table 2

European LeukemiaNet Definitions and Monitoring Recommendations

 

Reprinted with permission from Baccarani M, Saglio G, Goldman J, et al: Evolving concepts in the management of chronic myeloid leukemia: Recommendations from an expert panel on behalf of the European LeukemiaNet. Blood 2006;108:1809–20; Baccarani M, Cortes J, Pane F, et al: Chronic myeloid leukemia: an update of concepts and  management recommendations of European LeukemiaNet. J Clin Oncol 2009;  27:6041–51.

Abbreviations: Ph = Philadelphia chromosome; WBC = white blood  cell.

Treatment

Chronic Phase

Throughout most of the 20th century CML was considered incurable. The principal options for treating CML included busulfan (Myleran, Busulfex) or hydroxyurea (Hydrea). Such therapy, although successful in alleviating symptoms, did not alter the natural course of the disease. Introduction of allogeneic SCT in 1980s for the first time offered CML patients a prospect of cure. However, the high treatment-related morbidity and mortality associated with this procedure greatly limited its use to patients who were young and fit and for whom an HLA-identical donor could be identified. The alternative was treatment with IFN alfa 2b (Intron-A)1 or IFN alfa 2a (Roferon-A), which offered prolongation of survival but generally only to a minority of patients who could tolerate it.

First-Line Therapy

In 2001, imatinib mesylate (Gleevec), the first selective bcr-abl tyrosine kinase inhibitor, was introduced into clinical practice. The trial that established imatinib as the treatment of choice for newly diagnosed CML in the chronic phase was the International Randomized Study of Interferon Alpha Versus STI571 (IRIS). Between June 2000 and January 2001 IRIS accrued and randomized 1106 patients to imatinib 400 mg daily versus what was then the standard of care, interferon alfa plus subcutaneous cytarabine (Cytosar). After a median of 5 years, 382 of the 553 patients (69%) randomized to imatinib were still receiving it.

The estimated progression-free survival was 83% and overall survival was 89%. The responding patients whose disease did not progress in any way in their first 3 years were unlikely to relapse and unlikely to suffer from late-onset side effects.

The recommended dose of imatinib for patients with CML in the chronic phase is 400 mg orally once daily. The drug is well tolerated by the majority of patients; the most common side effects are nausea, vomiting, edema (fluid retention), muscle cramps, skin rash, diarrhea, heartburn, and headache. Hematologic toxicity is quite common, particularly in patients with advanced CML, and the package insert contains exact guidelines for its management. Occasional severe hepatotoxicity has been reported.

Most patients with CML in the chronic phase today achieve and maintain excellent disease control with imatinib and seem to enjoy near-normal survival and quality of life. Given that continuation of TKI in a majority of patients seems necessary to maintain the remission, adherence to therapy is crucial and has recently become an avid focus of clinical investigations.

Since introduction of imatinib, three more second-generation TKIs have been developed and approved for treatment of CML: dasatinib (Sprycel), nilotinib (Tasigna) and bosutinib (Bosulif). All three have been studied extensively and demonstrated efficacy in the setting of imatinib failure. Dasatinib and nilotinib have subsequently been studied and received FDA approval for use as first-line agents. Phase III studies comparing dasatinib (DASISION) or nilotinib (ENESTnd) to imatinib as initial therapy for CML in the chronic phase demonstrated faster and deeper responses; however, a longer follow-up will be required to determine if this is going to translate into clinically significant long-term benefits such as improved survival. At this time the choice of a front line TKI is often determined by the patient’s tolerance of the drug, as each of the TKIs has some unique and non- overlapping toxicities. Bosutinib has not yet been approved in the first-line setting. A randomized study comparing bosutinib to imatinib (BELA) in newly diagnosed patients indicated comparable response rates but higher rate of GI toxicity associated with bosutinib. Neutropenia, musculoskeletal events, and edema were less frequent.

A fourth generation TKI, ponatinib (Iclusig), is the newest agent of this class granted accelerated FDA approval after demonstrating high levels of response rates on PACE trial in heavily pretreated patients, including those carrying the T315I mutation. Soon after it’s approval ponatinib received a black box warning in highlighting the increased risk of serious vascular events and hepatic toxicity. More recently an increased risk of serious complications associated with the long term use of the other second generation TKI have also been reported, emphasizing the relative safety of the first drug in this class, namely imatinib.

The long-term follow up of patients in the IRIS trial indicates that despite the favorable toxicity profile and efficacy, as many as 30% of patients will eventually fail imatinib therapy. Patients who are intolerant to first-line TKIs should be offered, and may be able to tolerate and respond to, other TKIs. Consensus recommends that patients who fail imatinib by progression or relapse should be screened for other medications that could affect metabolism and thus compromise the clinical efficacy of TKIs, for compliance and for abl mutations. More than 50 mutations in bcr-abl have been described, detection of which may help guide selection of second-line TKI therapy. Younger and otherwise fit patients should be evaluated for an allogeneic SCT.

Other Therapeutic Options

Patients who fail imatinib and/or second-generation TKI have particularly poor prognoses. Those who are not transplant candidates may be treated with omacetaxine (Synribo), which has recently been approved for patients resistant and/or intolerant to two or more tyrosine kinase inhibitors.

Advanced Phase

Imatinib mesylate is indicated for advanced CML in accelerated phase and blast phase. The recommended dosages are higher: 600 mg daily for CML accelerated phase and 800 mg daily for CML in the blast phase. Patients who satisfy criteria for acceleration are a heterogeneous group, because the disease biologically varies from slightly more advanced than late chronic phase to verging on blast phase. Up to 80% of patients achieve a hematologic remission, and approximately 40% achieve a complete cytogenetic response, which is considered a prerequisite to long-term survival. All second and third generation TKIs are approved for treatment of advanced CML: dasatinib at 140 mg once daily (or 70 mg twice daily), nilotinib at 400 mg twice daily, bosutinib 500 to 600 mg once daily, and ponatinib 45 mg once daily. Patients who progress to accelerated phase on the first-line TKI should be screened for bcr-abl mutations. In general the likelihood of response to a second-line TKI is 30 to 40 percent, and the identification of a mutation and selection of the second-line agent accordingly may improve those odds. Ponatinib is the only TKI with significant activity in CML associated with T315I mutation. Once the maximum response has been realized, patients who are suitable transplant candidates are offered an allogeneic stem cell transplantation.

Patients presenting in blast phase require a more-aggressive approach and are generally treated with a combination of TKI and chemotherapy or with a second-generation tyrosine kinase inhibitor with or without chemotherapy. Patients who achieve responses are immediately evaluated for an allogeneic SCT. The outcome of allogeneic SCT in advanced CML is much worse than in chronic phase, but a minority of patients can definitely be cured.

Allogeneic Stem Cell Transplantation

The curative potential of allogeneic SCT is well established, and transplantation remains the widely accepted regimen for patients who failed imatinib. Historically, in the pre-imatinib era the allogeneic SCT has been reported to produce long-term survival between 50% and 60%—and even as high as 80% for larger, more experienced centers— in patients who underwent transplantation in the chronic phase.

Chronic Lymphocytic Leukemia

CLL has historically been considered an indolent disease of older patients. The general approach to treatment was conservative and the few therapies available were only marginally effective; since the 1990s, new treatments namely purine analongs and monoclonal antibodies started to change the face of this disease. Intensive research over the past several years provided a greatly improved insight into the pathogenesis of CLL and lead to development of several targeted treatment approaches that will likely dramatically change the way we treat CLL. The availability of novel agents that are less toxic and more effective has rekindled hope that treatments with higher curative potential can be developed.

Epidemiology and Risk Factors:

The median age at diagnosis is 70 years. The incidence is higher in men, and the male-to-female ratio is 1.7:1. It is the most common leukemia in the Western world; it is rare is Asian people and remains rare in people of Japanese origin who live in Hawaii, suggesting a genetic rather than environmental predisposition. An increased risk of developing the disease has been described in first-degree relatives of patients with CLL.

Pathogenesis

CLL develops by progressive accumulation of genetically altered mature lymphocytes in the blood, bone marrow, and lymphoid tissue. The CLL cell of origin is a B cell arrested in its pathway of differentiation, intermediate between a pre-B cell and mature B cell.

One of the most important genetic parameters defining clinical behavior and prognosis is the mutation status of the variable segments of immunoglobulin heavy chain VH gene: CLL with unmutated VH shows an unfavorable course with rapid progression, whereas CLL with mutated VH typically shows slow progression and long survival.

FISH detects genetic aberrations in more than 80% of patients with CLL. The FISH CLL panel typically includes probes for 13q, 11q, 17p, and 6q deletions and for 12q duplication. The most common abnormality is deletion of 13q, which occurs in more than 50% of patients. Persons showing 13q14 abnormalities have a relatively benign disease that usually manifests as stable or slowly progressive isolated lymphocytosis. Trisomy 12 is associated with atypical morphology and progressive disease. Deletions of bands 11q22-q23 are associated with extensive lymph node involvement, aggressive disease, and shorter survival. Deletion of 17p results in loss of function of p53 and is associated with a particularly poor prognosis.

Clinical Manifestations

The clinical features of CLL are variable and depend on the stage of the disease. Up to 30% of patients with CLL are asymptomatic, and the diagnosis is established following the incidental discovery of leukocytosis and/or absolute lymphocytosis on routine screening tests. The remaining patients present with lymphadenopathy, splenomegaly, or B symptoms (fever, night sweats, and weight loss), alone or in combination. Anemia and thrombocytopenia are considered late signs of the disease but can be present at the time of diagnosis. Due to their immunocompromised state, patients can present with recurrent or persistent infections.

Diagnosis

The diagnosis of CLL requires demonstration of absolute lymphocytosis of greater than 5000/mL and an immunophenotypic evidence of monoclonal population of mature B cells expressing CD19, CD20 (dim), and CD23 and coexpressing pan–T-cell antigen CD5. The malignant cells express low density of monoclonal surface immunoglobulin (IgM or IgD) with either κ or λ light chain. Patients are evaluated and grouped prognostically based on physical examination and complete blood count. The bone marrow biopsy and CT scans are not required for diagnosis but may be indicated based on symptoms.

Differential Diagnosis

The immunophenotypic profile of CLL is quite characteristic, but at times it has to be differentiated from other low-grade lymphoproliferative disorders: hairy cell leukemia, prolymphocytic leukemia, (splenic) marginal zone lymphoma, and lymphoplasmacytic lymphoma. Most importantly, CLL needs to be differentiated from mantle cell lymphoma, which also coexpresses CD5 but is characteristically CD23 negative and cycline D1 positive by immunohistochemical staining.

Prognosis

The natural history of CLL is extremely variable, with survival times ranging from 2 to 20 (or more) years. Clinical staging using the Rai or Binet system provides a good estimate of prognosis but is not very reliable in an individual patient; for example, among patients presenting with early clinical stage disease, up to 30% never progress and eventually die of causes unrelated to CLL, and another 30% progress much more rapidly than expected. A number of additional prognostic factors are considered in estimating prognosis in an individual case: clinical characteristics such as age, sex, and performance status; laboratory parameters reflecting the tumor burden or disease activity such as lymphocyte count, lactate dehydrogenase (LDH), bone marrow infiltration pattern, or lymphocyte doubling time; serum markers such as soluble CD23 and β2-microglobulin; and genetic markers such as genetic aberrations (see earlier), the VH mutation status, or its surrogate markers (CD38, ZAP- 70).

Treatment

Early alkylating drug based treatment strategies in CLL offered control of symptoms but little impact on the natural course of the disease. The introduction of purine analogs in the 1980s represented a definite progress but it was not until they were combined with monoclonal antibodies that deeper and more meaningful remissions were experienced, The analyses of historical series suggests that immunotherapeutic regimens offer a modest prolongation of survival.

The BCR pathway kinase inhibitors approved in the past few years are certainly very promising in this regard. However at present, short of allogeneic stem cell transplant, CLL is still considered incurable.

Asymptomatic patients with CLL are followed expectantly. The treatment is initiated upon progression of the disease or appearance of symptoms such as rapid lymphocyte doubling time, bulky lymphadenopathy or organomegaly, disease-related B symptoms, and autoimmune or nonautoimmune cytopenias. CLL is quite sensitive to many chemo- and immunotherapeutic agents. However, remissions are rarely durable. The disease follows a remitting and relapsing pattern, and most patients receive at least a few different regimens throughout the course of their disease.

First-Line Therapy

The first-line treatment usually consists of purine analogue fludarabine (Fludara)-based chemotherapy in combination with the anti-CD20 monoclonal antibody rituximab (Rituxan). FR (fludarabine and rituximab) and FCR (fludarabine, cyclophosphamide [Cytoxan], and rituximab) are the chemoimmunotherapy combinations used most commonly. The overall response rates for these regimens are respectively 90% and 95%. FCR offers a higher complete remission rate of 70% vs 47% for FR; however, FR offers a more acceptable toxicity profile. Median overall survival with each of these regimens seems comparable: approximately 5 years. FCR may be particularly effective in CLL associated with del(11q). However, in general choice between the regimens is made based upon the patient’s characteristics and the goals of therapy. The treatment cycles are administered every 28 days for up to 6 cycles.

Other treatment options used in the newly diagnosed progressive disease setting include PCR (deoxycoformycin (Pentostatin [Nipent]),1 cyclophosphamide, and rituximab); bendamustine (Treanda); the anti- CD25 antibody alemtuzumab (Campath); or chlorambucil (Leukeran). Deoxycoformycin is another purine analogue, and the PCR regimen offers an alternative to FCR. The fludarabine-based regimens are only marginally effective in high-risk disease defined by the presence of del(17p). Patients with del(17p) either do not respond to initial treatment or relapse soon after achieving remission. Therefore, other therapies, including investigational therapies, are often offered in this setting. Alemtuzumab is the only FDA-approved agent that has demonstrated activity in cells lacking p53 function, as seen in patients with deletion of chromosome 17p.

Bendamustine (Treanda) is a new alkylating agent approved for treatment of CLL in March 2008. Based on the results of a randomized trial, like fludarabine, it offers a higher response rate and progression- free survival in comparison to single agent chlorambucil. The toxicity of bendamustine seems intermediate between that of fludarabine and chlorambucil. In the past few years the combination of bendamustine and rituximab (BR) has become an acceptable alternative for patients who are unable to tolerate fludarabine due to co-morbid conditions or due to age. Many older patients too frail to tolerate either fludarabine or bendamustine could still be treated with chlorambucil combined with a novel anti-CD20 antibody either obinutuzumab (Gazyva) or ofatumumab (Arzerra). Both antibodies have been approved for this indication based on greater improvement in response rates and progression-free survival demonstrated in randomized trials. The initial results of those trials also suggest a benefit in overall survival.

Other Therapeutic Options

Relapsed disease occurs in a patient who achieved at least a partial remission that lasted more than 6 months after completion of treatment. Many of those patients can be re-treated successfully with the same medications or can be switched to an alternative strategy.

Specifically, it has been demonstrated that patients initially treated with fludarabine often achieve another durable response upon re- treatment. Whether patients treated with fludarabine-containing combination regimens or other newer therapies such as alemtuzumab or bendamustine will respond to re-treatment equally well is not yet known.

Patients who fail to achieve at least a partial remission or whose disease progresses within 6 months from completion of treatment have refractory disease, which is associated with a poor prognosis. Patients refractory to fludarabine historically had expected median survival of 48 weeks and only an 11% likelihood of responding to other therapies, which included alkylating drugs, other purine analogs, high dose steroids, monoclonal antibodies (rituximab, alemtuzumab, ofatumumab). The year 2014 was remarkable for FDA approval of two novel agents for treatment of relapsed/refractory CLL. Ibrutinib (Imbruvica) is an oral BTK inhibitor. A randomized trial in relapsed/refractory CLL confirmed a superior response rate and survival when compared with ofatumumab. The drug produces rapid and sustained decrease in lymphadenopathy coupled by lymphocytosis. Idelalisib (Zydelig) is an oral inhibitor of PI3K kinase, which in combination with rituximab was shown to have a superior therapeutic activity over rituximab. A Phase III randomized trial was stopped prematurely after it demonstrated improved response rate and improved survival over rituximab alone.

Both drugs can be taken by mouth and are well tolerated.

Interestingly both drugs generally induce only partial remission, yet, they translate to prolongation of survival. Furthermore it appears that continuation of the drugs is necessary to maintain remissions.

At this time it is still unclear what role these new drugs will play in treatment of CLL.

Patients are encouraged to participate in clinical trials. Those who are potential transplant candidates are considered for an allogeneic stem cell transplant.

Allogeneic stem cell transplantation remains the only potentially curative treatment modality. Unfortunately, data on the use of allogeneic stem cell transplantation is limited to small case series.

Allogeneic stem cell transplantation is associated with considerable treatment-related morbidity and mortality and is usually not considered until definitive evidence of poor prognosis.

Complications

Major complications of CLL include cytopenias and immune dysfunction. Anemia and thrombocytopenia can result from direct infiltration of the bone marrow and hypersplenism, in which case response to treatment usually results in improvement. Splenectomy obtained either surgically or via splenic irradiation is clinically useful in patients with splenomegaly and profound cytopenias unresponsive to chemotherapy. Autoimmune hemolytic anemia and thrombocytopenia seen in a significant percentage of patients often respond to steroids. Danazol,1 high-dose intravenous immunoglobulin (IVIg) (Gammagard),1 cyclosporine (Neoral),1 and rituximab1 have all also been used in this setting.

Infections are the major cause of mortality in CLL. They result from hypogammaglobulinemia, impaired T-cell function, and neutropenia. Patients with repeat major bacterial infections are candidates for treatment with high-dose IVIg.1 Patients treated with purine analogues and alemtuzumab are at high risk for opportunistic infections by herpes simplex virus and herpes zoster virus, Listeria monocytogenes, Pneumocystis jirovecii, and cytomegalovirus and should be offered prophylaxis with acyclovir (Zovirax),1 trimethoprim- sulfamethoxazole (Bactrim), or aerosolized pentamidine (NebuPent) and antifungal agents. Patients receiving alemtuzumab should be monitored for cytomegalovirus reactivation or disease.

Patients with CLL have been reported to have a higher risk of developing other hematologic and solid malignancies. It is unknown how much of this increased risk is due to the underlying disease and accompanying chronic immunosuppression and how much is due to the treatments given. In 5% to 10% of patients with CLL, the disease transforms into an aggressive large-cell lymphoma (Richter’s transformation) or prolymphocytic leukemia.

References

1.     Baccarani M., Deininger M.W., Rosti G., et al. European LeukemiaNet recommendations for the management of chronic myeloid leukemia: 2013. Blood. 2013;122(6):872–884.

2.    Byrd J.C., Rai K., Peterson B.L., et al. Addition of rituximab to fludarabine may prolong progression-free survival and overall survival in patients with previously untreated chronic lymphocytic leukemia: an updated retrospective comparative analysis of CALGB 9712 and CALGB 9011. Blood. 2005;105:49–53.

3.     Deininger M.W., O’Brien S.G., Ford J.M., Druker B.J. Practical management of patients with chronic myeloid leukemia receiving imatinib. J Clin Oncol. 2003;21:1637–1647.

4.    Druker B.J., Guilhot F., O’Brien S.G., et al. Five-year follow-up of patients receiving imatinib for chronic myeloid leukemia. N Engl J Med. 2006;355:2408–2417.

5.     Goldman J.M. Initial treatment for patients with CML. Am Soc Hematol Educ Program. 2009;453–460.

6.      Hallek M. Chronic lymphocytic leukemia: 2013 update on diagnosis, risk stratification and treatment. Am J Hematol. 2013;88(9):803–816.

7.    Hallek M. Signaling the end of chronic lymphocytic leukemia: new frontline treatment strategies. Blood. 2013;122(23):3723–3734.

8.    Kantarjian H. Shah NP, Hochhaus A, et al. Dasatinib versus imatinib in newly diagnosed chronic-phase chronic myeloid leukemia. N Engl J Med. 2010;363:2260–2270.

9.       Keating M.J., Chiorazzi N., Messmer B., et al. Biology and treatment of chronic lymphocytic leukemia. Hematology Am Soc Hematol Educ Program. 2003;153–175.

10.     Lee S.J. Chronic myelogenous leukaemia. Br J Haematol. 2000;111:993–1009.

11.    Lozanski G., Heerema N.A., Flinn I.W., et al. Alemtuzumab is an effective therapy for chronic lymphocytic leukemia with p53 mutations and deletions. Blood. 2004;103:3278–3281.

12.       Saglio G., Kim D.W., Issaragrisil S., et al. Nilotinib versus imatinib for newly diagnosed chronic myeloid leukemia. N Engl J Med. 2010;362:2251–2259.

13.    Sokal risk score calculator. Available at: http://www.mdcalc.com/sokal-index-for-cml (accessed July 19, 2016).

14.    Tam C.S., O’Brien S., Wierda W., et al. Long-term results of the fludarabine, cyclophosphamide, and rituximab regimen as initial therapy of chronic lymphocytic leukemia. Blood. 2008;112:975–980.

1 Not FDA approved for this indication

1 Not FDA approved for this indication

1 Not FDA approved for this indication

1  Not FDA approved for this  indication

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