AUTHOR AND EDITOR INFORMATION

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INTRODUCTION

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Background

Acute lymphoblastic leukemia (ALL) is a malignant (clonal) disease of the bone marrow in which early lymphoid precursors proliferate and replace the normal hematopoietic cells of the marrow. ALL may be distinguished from other malignant lymphoid disorders by the immunophenotype of the cells, which is similar to B- or T-precursor cells. Immunochemistry, cytochemistry, and cytogenetic markers also may aid in categorizing the malignant lymphoid clone.

Pathophysiology

The malignant cells of ALL are lymphoid precursor cells (ie, lymphoblasts) that are arrested in an early stage of development. This arrest is caused by an abnormal expression of genes, often as a result of chromosomal translocations. The lymphoblasts replace the normal marrow elements, resulting in a marked decrease in the production of normal blood cells. Consequently, anemia, thrombocytopenia, and neutropenia occur to varying degrees. The lymphoblasts also proliferate in organs other than the marrow, particularly the liver, spleen, and lymph nodes.

Frequency

United States

ALL is the most common type of leukemia in children. In adults, it is less common than acute myelogenous leukemia (AML). In the United States, approximately 1000 new cases of ALL occur in adults each year.

International

The highest incidence of ALL occurs in Italy, the United States, Switzerland, and Costa Rica.

Mortality/Morbidity

Only 20-40% of adults with ALL are cured with current regimens.

Sex

ALL is slightly more common in men than in women.

Age

ALL is more common in children than in adults.

CLINICAL

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History

• Patients with ALL present with either (1) symptoms relating to direct infiltration of the marrow or other organs by leukemic cells or (2) symptoms relating to the decreased production of normal marrow elements.
• • Infiltration of the marrow by massive numbers of leukemic cells frequently manifests as bone pain.
  • This pain can be severe and is often atypical in distribution.

• Uncommonly (10-20%), patients may present with left upper quadrant fullness and early satiety due to splenomegaly.
• Other patients, particularly those with T-cell ALL, present with symptoms related to a large mediastinal mass, such as shortness of breath.
• Although patients may present with symptoms of leukostasis (eg, respiratory distress, altered mental status) because of the presence of large numbers of lymphoblasts in the peripheral circulation, leukostasis is much less common in persons with ALL than in persons with AML and occurs only in patients with the highest WBC counts, ie, several hundred thousand per microliter.
• Patients with ALL also present with symptoms related to a depletion of normal marrow elements. Symptoms of anemia are common and include fatigue, dizziness, palpitations, and dyspnea upon even mild exertion.
• Patients with ALL often have decreased neutrophil counts, despite an increased total WBC count. As a result, they are at increased risk of infection. The prevalence and severity of infections are inversely correlated with the absolute neutrophil count, which is defined as the number of mature neutrophils plus bands per unit of volume. Infections are common when the absolute neutrophil count is less than 500/µL and are especially severe when it is less than 100/µL.
• Patients with ALL often have fever without any other evidence of infection. However, in these patients, one must assume that all fevers are from infections until proven otherwise because a failure to treat infections promptly and aggressively can be fatal. Infections are still the most common cause of death in patients undergoing treatment for ALL.
• Approximately 10% of patients with ALL have disseminated intravascular coagulation (DIC) at the time of diagnosis, usually as a result of sepsis. Consequently, some patients may present with hemorrhagic or thrombotic complications. Bleeding symptoms are usually more often the result of a coexisting thrombocytopenia caused by marrow replacement. The thrombocytopenia, however, tends to be less severe than that observed in patients with AML.

Physical

• Patients commonly have physical signs of anemia, including pallor and a cardiac flow murmur.
• Fever and other signs of infection, including lung findings of pneumonia, can occur. Fever should be interpreted as evidence of infection, even in the absence of other signs.
• Patients with thrombocytopenia usually demonstrate petechiae, particularly on the lower extremities. A large number of ecchymoses is usually an indicator of a coexistent coagulation disorder such as DIC.
• Signs relating to organ infiltration with leukemic cells include hepatosplenomegaly and, to a lesser degree, lymphadenopathy.
• Occasionally, patients have rashes resulting from infiltration of the skin with leukemic cells.

Causes

• Less is known about the etiology of ALL in adults compared with AML. Most adults with ALL have no identifiable risk factors.
• An increased prevalence of ALL was noted in survivors of the Hiroshima atomic bomb but not in those who survived the Nagasaki atomic bomb. Most leukemias occurring after exposure to radiation are AML rather than ALL.
• Rare patients have an antecedent hematologic disorder (AHD) such as myelodysplastic syndrome (MDS) that evolves to ALL. However, most patients with MDS that evolves to acute leukemia develop AML rather than ALL.
• Increasingly, cases of ALL with abnormalities of chromosome band 11q23 following treatment with topoisomerase II inhibitors for another malignancy have been described. However, most patients who develop secondary acute leukemia after chemotherapy for another cancer develop AML rather than ALL.

DIFFERENTIALS

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Other Problems to be Considered

Acute biphenotypic leukemia
NK-cell leukemia

WORKUP

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Lab Studies

• A CBC count with differential demonstrates anemia and thrombocytopenia to varying degrees. Patients with ALL can have a high, normal, or low WBC count, but usually exhibit neutropenia.
• Abnormalities in the prothrombin time/activated partial thromboplastin time/fibrinogen/fibrin degradation products may suggest concomitant DIC, which results in an elevated prothrombin time, decreased fibrinogen levels, and the presence of fibrin split products.
• A review of the peripheral blood smear confirms the findings of the CBC count.
• • Circulating blasts are usually seen.
  • Schistocytes are sometimes seen if DIC is present.

• A chemistry profile is recommended.
• • Most patients with ALL have an elevated lactic dehydrogenase level and frequently have an elevated uric acid level.
  • Liver function tests and BUN/creatinine determinations are necessary prior to the initiation of therapy.

• Appropriate cultures, in particular blood cultures, should be obtained in patients with fever or with other signs of infection without fever.

Imaging Studies

• Chest x-ray films may reveal signs of pneumonia and/or a prominent mediastinal mass in some cases of T-cell ALL.
• Multiple gated acquisition scan or ECG is needed when the diagnosis is confirmed because many chemotherapeutic agents used in the treatment of acute leukemia are cardiotoxic.

Other Tests

• ECG is recommended prior to treatment.

Procedures

• Bone marrow aspiration and biopsy are the definitive diagnostic tests to confirm the diagnosis of leukemia. Immunophenotyping helps elucidate the subtype.
• • Aspiration slides should be stained for morphology with either Wright or Giemsa stain. The diagnosis of ALL is made when at least 30% lymphoblasts (FAB classification) or 20% lymphoblasts (WHO classification) are present in the bone marrow and/or peripheral blood.
  • In addition, slides should be stained with myeloperoxidase (or Sudan black) and terminal deoxynucleotidyl transferase (TdT), unless another method is used, such as flow cytometry.
  • Bone marrow samples should also be sent for cytogenetics and flow cytometry. Approximately 15% of patients with ALL have a t(9;22) translocation (ie, Philadelphia chromosome), but other chromosomal abnormalities also may occur, such as t(4;11), t(2;8), and t(8;14).


• A negative myeloperoxidase stain and a positive TdT is the hallmark of the diagnosis of most cases of ALL. However, positive confirmation of lymphoid (and not myeloid) lineage should be sought by flow cytometric demonstration of lymphoid antigens, such as CD3 (T-lineage ALL) or CD19 (B-lineage ALL), in order to avoid confusion with some types of myeloid leukemia (eg, M0, acute monocytic leukemia), which also stain negative with myeloperoxidase. Although more than 95% of cases of the L1 or L2 subtype of ALL are positive for TdT, TdT is not specific for ALL. TdT is present in some subtypes of AML such as M0. Additionally, TDT is absent in cases of L3 type ALL. However, TdT helps distinguish ALL from malignancies of more mature lymphocytes (ie, NHL).
• In cases of acute leukemia that are MPO negative, TdT positive, the distinction between AML and ALL is made based on the analysis of flow cytometry results. Patients with AML demonstrate myeloid markers such as CD33, whereas patients with ALL demonstrate lymphoid markers. Further confusion arises because some patients with ALL have aberrant expression of myeloid markers, such as CD13. However, if the cells are TdT-positive, myeloperoxidase-negative, and CD33-negative and demonstrate lymphoid markers, the leukemia is considered ALL.
• Studies for bcr-abl analysis by polymerase chain reaction or cytogenetics may help distinguish patients with Philadelphia chromosome positive ALL from those with the lymphoid blastic phase of chronic myelogenous leukemia. Most patients with Ph+ ALL have the p190 type of bcr-abl, whereas patients with lymphoid blastic CML have the p210 type of bcr-abl.
• Newer studies are analyzing ALL subtypes by gene expression profiling. In children with ALL, Bogni et al distinguished 3 groups of patients. Interestingly, one of these groups had a significantly increased risk of developing treatment-related AML following chemotherapy for their ALL.

Histologic Findings

French-American-British Classification

• L1 - Small cells with homogeneous chromatin, regular nuclear shape, small or absent nucleolus, and scanty cytoplasm; subtype represents 25-30% of adult cases
• L2 - Large and heterogeneous cells, heterogeneous chromatin, irregular nuclear shape, and nucleolus often large; subtype represents 70% of cases (most common)
• L3 - Large and homogeneous cells with multiple nucleoli, moderate deep blue cytoplasm, and cytoplasmic vacuolization that often overlies the nucleus (most prominent feature); subtype represents 1-2% of adult cases

The WHO classifies the L1 and L2 subtypes of ALL as either precursor B lymphoblastic leukemia/lymphoblastic lymphoma or precursor T lymphoblastic leukemia/lymphoblastic lymphoma depending on the cell of origin. The L3 subtype of ALL is included in the group of mature B-cell neoplasms, as the subtype Burkitt lymphoma/leukemia.

Cytogenetic abnormalities occur in approximately 70% of cases of ALL in adults. These abnormalities included balanced translocations as occur in cases of AML. However, abnormalities of chromosome number (hypodiploidy, hyperdiploidy) are much more common in ALL than in AML.

Table 1. Common Cytogenetic Abnormalities in ALL

Table 2. Effect of Chromosome Number on Prognosis

Eighty-five percent of cases of ALL are derived from B cells. The primary distinction is between (1) early (pro-B) ALL, which is TDT positive, CD10 (CALLA) negative, surface Ig negative; (2) precursor B ALL, which is TDT positive, CD10 (CALLA) positive, surface Ig negative; and (3) mature B cell (Burkitt) ALL, which is TdT negative, surface Ig positive. Fifteen percent of cases are derived from T cells. These cases are subclassified into different stages corresponding to the phases of normal thymocyte development. The early subtype is surface CD3 negative, cytoplasmic CD3 positive, and either double negative (CD4^-, CD8^-) or double positive (CD4⁺, CD8⁺). The latter subtype is surface CD3 positive, CD1a negative, and positive for either CD4 or CD8, but not both.

Table 3. Immunophenotyping of ALL Cells - ALL of B-Cell Lineage (85% of cases of adult ALL)

*Cytoplasmic immunoglobulin

†Surface immunoglobulin

‡See Image 1.

Table 4. Immunophenotyping of ALL Cells - ALL of T-Cell Lineage (15% of cases of adult ALL)

TREATMENT

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Medical Care

Currently, only 20-30% of adults with ALL are cured with standard chemotherapy regimens. Consequently, all patients must be evaluated for entry into well-designed clinical trials. If a clinical trial is not available, the patient can be treated with standard therapy. Traditionally, the 4 components of ALL treatment are induction, consolidation, maintenance, and CNS prophylaxis. Other aspects of treatment are also discussed.

• Induction therapy
  • Standard induction therapy typically involves either a 4-drug regimen of vincristine, prednisone, anthracycline, and cyclophosphamide or L-asparaginase or a 5-drug regimen of vincristine, prednisone, anthracycline, cyclophosphamide, and L-asparaginase given over the course of 4-6 weeks.

  • Using this approach, complete remissions are obtained in 65-85% of patients. The rapidity with which a patient's disease enters complete remission is correlated with treatment outcome.

  • In a large French study (French Group on Therapy for Adult Acute Lymphoblastic Leukemia 1987), patients with greater than 5% blasts in their bone marrow on day 15 had a lower response rate (34% vs 91%), worse disease-free survival, and worse overall survival than patients with low blast counts on day 15.

  • Several other studies have shown that patients whose disease is in complete remission within 4 weeks of therapy have longer disease-free survival and overall survival than those whose disease enters remission after 4 weeks of treatment.

• Consolidation therapy
  • The use of consolidation chemotherapy is supported by several studies. In 1987, Fiere et al compared consolidation therapy with daunorubicin and cytosine arabinoside (Ara-C) versus no consolidation therapy in adults with ALL. The 3-year, leukemia-free survival rate was 38% for subjects receiving consolidation and maintenance therapy compared with 0% for those receiving maintenance therapy without consolidation (P <.05).

  • In a 1984 study reported by Hoelzer et al, subjects whose disease was in remission after induction received consolidation therapy consisting of dexamethasone, vincristine, and doxorubicin (Adriamycin), followed by cyclophosphamide, Ara-C, and 6-thioguanine beginning at week 20. Subjects also received maintenance therapy with 6-mercaptopurine and methotrexate during weeks 10-20 and 28-130. The median remission of 20 months was among the longest reported at the time.

  • In the United Kingdom Acute Lymphoblastic Leukemia XA study, subjects were randomized to receive early intensification with Ara-C, etoposide, thioguanine, daunorubicin, vincristine, and prednisone at 5 weeks; late intensification with the same regimen at 20 weeks; both; or neither. The disease-free survival rates at 5 years were 34%, 25%, 37%, and 28%, respectively. These data suggest a benefit to early, rather than late, intensification.

  • One study by the Cancer and Leukemia Group B (CALGB) did not show a benefit to consolidation therapy. Subjects whose disease was in complete remission were randomized to receive maintenance therapy or intensification with 2 courses of Ara-C and daunorubicin followed by maintenance. Remission duration and overall survival were not affected by the randomization.

  • Because most studies showed a benefit to consolidation therapy, regimens using a standard 4- to 5-drug induction usually include consolidation therapy with Ara-C in combination with an anthracycline or epipodophyllotoxin.
• Maintenance therapy
  • The effectiveness of maintenance chemotherapy in adults with ALL has not been studied in a controlled clinical trial. However, several phase 2 studies without maintenance therapy have shown inferior results compared with historical controls.

  • A CALGB study of daunorubicin or mitoxantrone, vincristine, prednisone, and methotrexate induction followed by 4 intensifications and no maintenance was closed early because the median remission duration was shorter than in previous studies. A Dutch study using intensive postremission chemotherapy, 3 courses of high-dose Ara-C in combination with amsacrine (course 1), mitoxantrone (course 2), and etoposide (course 3), without maintenance, also yielded inferior results.

  • Although maintenance appears necessary, using a more intensive versus less intensive regimen does not appear to be beneficial. Intensification of maintenance therapy from a 12-month course of a 4-drug regimen compared with a 14-month course of a 7-drug regimen (Gruppo Italiano Malattie Ematologiche Maligne dell'Adulto 0183) did not show a difference in disease-free survival between the 2 groups.
• CNS prophylaxis
  • In contrast to patients with AML, patients with ALL frequently have meningeal leukemia at the time of relapse. A minority of patients have meningeal disease at the time of initial diagnosis. As a result, CNS prophylaxis with intrathecal chemotherapy is essential.

  • Cortes analyzed the prevalence of CNS leukemia in 4 consecutive clinical trials at the M.D. Anderson Cancer Center.
    • In the first group, subjects received standard systemic chemotherapy without CNS prophylaxis. In the second, subjects received high-dose systemic chemotherapy and no CNS prophylaxis. The third group received high-dose systemic chemotherapy and intrathecal chemotherapy for high-risk subjects after achieving remission. The fourth group received hyperfractionated cyclophosphamide, vincristine, doxorubicin (Adriamycin), and dexamethasone (ie, hyper-CVAD protocol).

    • All subjects received intrathecal chemotherapy starting in induction. High-risk subjects received 16 intrathecal treatments, and low-risk subjects received 4 intrathecal treatments.

    • Overall, CNS relapse rates were 31%, 18%, 17%, and 3%, respectively.

  • This study demonstrated that high-dose systemic chemotherapy reduces CNS relapse; however, early intrathecal chemotherapy is necessary to achieve the lowest risk of CNS relapse.
• Newer approaches
  • Standard induction regimens are modeled after pediatric programs and were originally developed when supportive care was significantly inferior to what is available today. Few antibiotics were available, and transfusion capabilities were minimal. Consequently, milder regimens were designed in an attempt to minimize early deaths during induction.

  • With the addition of third-generation cephalosporins and sophisticated blood-banking techniques, the ability to support patients through a pancytopenic phase has increased dramatically. As a result, the use of more intensive induction approaches is being studied. Two notable examples are the Memorial ALL-2 protocol and the hyper-CVAD protocol.

  • The ALL-2 protocol uses an intensive, high-dose, mitoxantrone-based, AML-style induction regimen. In a phase 1 study of high-dose mitoxantrone combined with high-dose Ara-C, Arlin et al reported that 8 of 8 patients newly diagnosed with ALL and 8 of 10 patients with ALL who relapsed achieved complete remission.

  • In 1996, Weiss et al reported treatment of 37 subjects with newly diagnosed ALL with this induction regimen followed by a first consolidation with vincristine, prednisone, L-asparaginase, and methotrexate; a second consolidation with Ara-C and etoposide; and then 2 years of maintenance therapy. Of these subjects, 84% achieved complete remission. The median remission duration was 17 months, and median survival was 20 months.

  • In a randomized phase III trial comparing the ALL-2 regimen with the L-20 regimen, the complete remission (CR) rate was 83% for patients receiving ALL-2 compared to 70% for patients receiving L-20 (p=0.05). Overall survival at 4 years was superior for patients receiving ALL-2 (40%) versus those receiving L-20 (22%).

  • The hyper-CVAD regimen is based on the success achieved with short-term, dose-intensive chemotherapy regimens in children. It incorporates hyperfractionated cyclophosphamide and intensive doses of Ara-C and methotrexate in combination with dexamethasone and vincristine. Maintenance therapy with prednisone, vincristine (Oncovin), methotrexate, and mercaptopurine (Purinethol) (ie, POMP protocol) is given to patients with nonmature B-cell ALL.

  • From 1992-2000, 288 patients received hyper-CVAD at MDACC. The Philadelphia chromosome was present in 17% of patients, and 13% had T-cell ALL. Overall, 92% of patients obtained a CR. The 5-year survival and percentage of patients in CR at 5 years were both 38%. Patients with Ph+ ALL had a 92% CR rate, but only a 12% 5- year survival. Patients with T-cell ALL had a 75% CR rate and a 48% 5-year survival. Patients with Burkitt ALL had a 93% CR rate and a 67% 5-year survival.
• Treatment of mature B-cell ALL
  • Mature B-cell ALL is a special type, representing only 5% of adult patients with ALL. The hallmark of mature B-cell ALL is the presence of surface immunoglobulin on the lymphoblasts. Using conventional regimens, only 30-40% of patients enter complete remission and few patients survive long-term.

  • Newer short-term intensive therapies are showing improved results. A report of the hyper-CVAD regimen showed that disease in 93% of subjects entered complete remission, median survival was 16 months, and disease in 67% of subjects alive at 5 years.

  • In a 1996 report by Hoelzer et al, using regimens containing intensive cyclophosphamide and intermediate methotrexate or ifosfamide and high-dose methotrexate, complete remission rates were 63% and 74%, respectively. Disease-free survival rates increased to 50% and 71%, respectively, and overall survival increased to 50% compared with 0% for historical controls. Although previously these patients were referred for transplantation in first remission, many physicians now defer transplantation for the time of relapse because of these improved results.

• Burkitt ALL cell are CD20 positive. This allows for the addition of targeted therapy with rituximab. Many studies are have demonstrated improved efficacy, including prolonged survival, when rituximab is added to chemotherapy in these patients.

• Treatment of Philadelphia chromosome positive ALL
  • In the past, Ph+ ALL was treated with the same regimens as other types of ALL, with poor results. However, imatinib inhibits the bcr-abl fusion protein of Ph+ ALL and thus allows targeted therapy of this disease. As a single agent, imatinib has limited activity.

  • In an early study of patients with Ph+ ALL or CML in lymphoid blast crisis, only 4 of 20 patients had a complete response, and all patients progressed in less than 6 months. Several newer studies are demonstrating improved outcomes when imatinib is added to chemotherapy.

• Treatment of the younger adult
  • Older children and younger adults can be referred to either adult or pediatric hematologists. Usually, the patient will receive either an adult or pediatric regimen based on this referral pattern. However, several recent studies suggest that younger patients are best treated on pediatric protocols. For example, in a retrospective analysis of patients aged 15-20 years treated on either the FRALLE 93 or LALA 94 trials, the CR rate was 94% for patients receiving the pediatric regimen compared with 83% for those receiving the adult regimen (p=0.04). The 5-year survival was 67% and 41%, respectively (p <0.0001). Patients treated on the pediatric regimen were younger than those treated on the adult regimen (15.9 vs 17.9 years, respectively); however, prognostic factors were otherwise matched.

  • Similarly, the CCG and CALGB performed an analysis on patients aged 16-21 years treated on their studies. Again, event free and overall survival were improved for patients treated on the CCG protocols.

• Transplantation
  • Relatively few studies have compared transplantation with chemotherapy in adults with ALL. In a study by the Groupe Ouest Est d'etude des Leucenies et Autres Maladies du Sang, subjects younger than 45 years who had a sibling donor and whose disease was in remission were assigned to allogeneic transplantation. The remaining subjects received methylprednisolone, Ara-C, mitoxantrone, and etoposide chemotherapy followed by autologous bone marrow transplantation (BMT). For subjects undergoing allogeneic BMT, the rate of freedom from relapse was 70% at 4 years. However, because of transplant-related complications, the event-free survival rate was only 33%. No toxic deaths occurred in the subjects who underwent autologous BMT. However, the event-free survival rate was only 17% at 4 years because of a high rate of relapse.

  • The Bordeaux, Grenoble, Marseille, Toulouse group conducted a prospective nonrandomized trial comparing allogeneic with autologous BMT and also tested the impact of recombinant interleukin 2 after autologous BMT. The treatment arm was selected based on the availability of an HLA-matched sibling donor. The 3-year probability of disease-free survival was significantly higher in the group assigned to allogeneic BMT compared with subjects assigned to autologous BMT (68% vs 26%, respectively, P <.001). No benefit was observed with the addition of interleukin 2 after autologous BMT.

  • In the French Group on Therapy for Adult Acute Lymphoblastic Leukemia 1987 study, subjects aged 15-40 years whose disease was in complete remission and who had an HLA-compatible sibling donor underwent allogeneic BMT. The other subjects were randomized to receive autologous BMT or chemotherapy. Overall, no difference in was observed in 5-year survival between the groups.

  • When only high-risk patients were considered (ie, Ph+, null ALL, >35 y, WBC count >30,000/µL, or time to complete remission > 4 wk), overall survival rates (44% vs 20%) and disease-free survival rates (39% vs 14%) were superior for those undergoing allogeneic BMT versus those undergoing either autologous BMT or chemotherapy. Other phase 2 studies have confirmed a benefit for high-risk patients who undergo allogeneic BMT, with as many as 50% achieving long-term remissions.

  • In the GOELAL02 study, patients with any high-risk feature (age >35 y, non–T-ALL, WBC >30,000, adverse cytogenetics: t[9;22], t[4;11], or t[1;19], or no CR after induction) received either allogeneic or autologous stem cell transplantation. For patients younger than 50 years, the 6-year overall survival rate was improved for patients receiving allogeneic transplantation, 75% versus 40%, respectively (p=0.0027).

  • The MRC UKALL XII/ECOG E2993 is a very large randomized study that will evaluate the role of transplant in ALL. To date, early results are reported in 1521 patients. The CR rate for induction therapy is 93% for patients with Ph- ALL and 83% for patients with Ph+ ALL. All patients younger than 50 years with a matched sibling donor are assigned to allogeneic transplantation. The remaining patients are randomized to either autologous stem cell transplantation or consolidation and maintenance therapy for 2.5 years. The long-term results of this study are awaited.

  • Because of the toxicity of ablative allogeneic transplantation, many centers are evaluating the efficacy of nonmyeloablative transplants in these patients. These studies are ongoing.

  • Allogeneic transplantation is also effective therapy for patients who have experienced relapse after chemotherapy. Martino et al treated 37 consecutive patients with primary refractory or relapsed ALL with intensive salvage chemotherapy.
    • Of the 29 patients whose disease went into complete remission, 10 were assigned to allogeneic BMT based on the availability of a sibling donor. The remaining 19 patients were assigned to autologous BMT.

    • Of the latter 19 patients, 10 did not reach transplantation, mostly because of early relapse; 9 received transplants. Of these, 1 died early and 8 experienced relapse 2-30 months after transplantation.

    • Of the 10 patients who received allogeneic BMT, 4 died early and 6 were alive and free from disease 9.7-92.6 months after the transplantation.

  • These results are similar to those in patients in earlier stages, indicating that transplant-related complications are increased in the allogeneic setting. However, a significant number of patients can be cured. On the other hand, although autologous transplantation is relatively safe, it is associated with a high relapse rate, making this modality of little use in patients with ALL.

  • For patients without a sibling donor, an alternative is an unrelated donor (URD) transplant. Weisdorf et al compared the results of 6 years of consecutive autologous transplantations (n = 214) with URD transplantations from the National Marrow Donor Program (n = 337). Autologous BMT was associated with a lower transplant-related mortality rate. However, URD transplantations had a lower risk of relapse. In patients whose disease was in second complete remission, URD transplantations resulted in a superior rate of disease-free survival.

  • In summary, most authorities agree that allogeneic transplantation should be offered to young patients with high-risk features whose disease is in first remission. Young patients without adverse features should receive induction, consolidation, and maintenance therapy. In these patients, transplantation is reserved for relapse. Older patients whose disease is in complete remission may be considered for such investigational approaches as allogeneic transplantation with nonmyeloablative chemotherapy (ie, minitransplants). Although previously patients with mature B-cell ALL would have been referred for transplantation when their disease was in first complete remission, with improving results from more intensive chemotherapy regimens, many are reserving transplantation for patients who have experienced relapse.
• Treatment of relapsed ALL
  • Patients with relapsed ALL have an extremely poor prognosis. Most patients are referred for investigational therapies. Young patients who have not previously undergone transplantation are referred for such therapy. Reinduction regimens include the hyper-CVAD protocol and high-dose Ara-C–based regimens.

  • As noted above, the hyper-CVAD regimen is based on hyperfractionated cyclophosphamide and intermediate doses of Ara-C and methotrexate. In a study at the M.D. Anderson Cancer Center of 66 patients with relapsed ALL, the complete remission rate was 44% and median survival was 42 weeks.

  • Arlin et al reported that 8 of 10 patients with relapsed ALL achieved complete remission with high-dose Ara-C and high-dose mitoxantrone. A similar regimen using a single high dose of idarubicin in combination with Ara-C (the Memorial ALL-3 protocol) resulted in complete remission rates of 58-78% in patients who experienced relapse.

  • In the Italian ALL R-87 study, 61 subjects with ALL in first relapse received induction chemotherapy with intermediate-dose Ara-C, idarubicin, and prednisone.
    • Subjects whose disease was in remission were to receive consolidation chemotherapy and then BMT. Of these subjects, 56% achieved complete remission; however, only 9 of the responders underwent BMT.

    • The remaining subjects did not undergo transplantations because of either early relapse or excessive toxicity.

    • Of the 4 subjects who underwent allogeneic BMT, 3 were alive and achieved remission at 22, 43, and 63 months, whereas only 1 of the 5 subjects who underwent autologous BMT was alive.

    • This study suggests that a small number of patients who experience relapse will survive long-term after allogeneic BMT. However, autologous BMT is less useful because it is associated with a high rate of relapse.

• Newer drugs
  • A number of new drugs are currently in development for the treatment of ALL. A few examples are as follows.

  • Clofarabine is a novel nucleoside analogue that was recently approved for the treatment of pediatric patients with refractory or relapsed ALL. Clofarabine inhibits DNA synthesis at both DNA polymerase I and at RNA reductase. Overall response rates average 25%.

  • 506U78 (nelarabine [Arranon]) is a novel purine nucleoside that is a prodrug of ara-G. It was approved as an orphan drug by the FDA in October, 2005. Complete responses are reported in 31% of patients and in 54% of patients with T-cell ALL. The dose-limiting toxicity of this drug is neurotoxicity.

  • Dasatinib is a dual ABL-SARC inhibitor that differs from imatinib in that it binds to both the active and inactive form of the ABL kinase. Dasatinib is active against most bcr-abl mutations (except T315I) that render the kinase resistant to imatinib. In a preliminary study, 8 of 10 patients with Ph+ ALL had a major hematologic response and major cytogenetic response to dasatinib. However response durations were brief.

  • Supportive care with replacement of blood products
    • Patients have a deficiency in the ability to produce normal blood cells, and they need replacement therapy. This deficiency is temporarily worsened by the addition of chemotherapy. All blood products must be irradiated to prevent transfusion-related graft versus host disease, which is almost invariably fatal.

    • Packed red blood cells are given to patients with a hemoglobin level of less than 7-8 g/dL or at a higher level if the patient has significant cardiovascular or respiratory compromise.

    • Platelets are transfused if the count is less than 10,000-20,000/µL. Patients with pulmonary or gastrointestinal hemorrhage receive platelet transfusions to maintain a value greater than 50,000/µL. Patients with CNS hemorrhage are transfused to achieve a platelet count of 100,000/µL.

    • Fresh frozen plasma is given to patients with a significantly prolonged prothrombin time, and cryoprecipitate is given if the fibrinogen level is less than 100 g/dL.

  • Supportive care with antibiotics
    • These are given to all febrile patients. At a minimum, include a third-generation cephalosporin (or equivalent), usually with an aminoglycoside. In addition to this minimum, other antibiotics are added to treat specific documented or possible infections.

    • Patients with persistent fever after 3-5 days of antibacterial antibiotics should have an antifungal antibiotic (liposomal or lipid complex amphotericin, new generation azole or echinocandin) added to their regimen. Patients with sinopulmonary complaints would receive anti-Aspergillus treatment. Particular care is warranted for patients receiving steroids as part of their treatment because the signs and symptoms of infection may be subtle or even absent.

    • The use of prophylactic antibiotics in neutropenic patients who are not febrile is controversial. However, most clinicians prescribe them for patients undergoing induction therapy. A commonly used regimen includes the following:
      • Ciprofloxacin (500 mg PO bid)

      • Fluconazole (200 mg PO daily) or itraconazole (200 mg PO bid)

      • Acyclovir (200 mg PO 5 times/d) or Valtrex (500 mg PO daily)

    • Once patients taking these antibiotics become febrile, they are switched to intravenous antibiotics per above.

  • Supportive care with growth factors
    • The use of granulocyte colony-stimulating factor (G-CSF) during induction chemotherapy is supported by several studies. In a randomized phase 3 trial conducted by Ottoman, 76 subjects received either G-CSF or no growth factor with the induction chemotherapy (ie, cyclophosphamide, Ara-C, 6-mercaptopurine, intrathecal methotrexate, and cranial irradiation). The median duration of neutropenia was 8 days in subjects receiving G-CSF versus 12 days in subjects receiving no growth factor (P <.002), and the prevalence of nonviral infections was decreased by 50% in subjects receiving G-CSF. No difference in disease-free survival was observed between the 2 groups.

    • In a randomized phase 3 study reported by Geissler et al, 53 subjects received either G-CSF beginning on day 2 of induction chemotherapy (ie, with daunorubicin, vincristine, L-asparaginase, and prednisone) or chemotherapy without G-CSF. G-CSF markedly decreased the proportion of days with neutropenia of less than 1000/µL (29% for G-CSF vs 84% for controls, P <.00005), reduced the prevalence of febrile neutropenia (12% vs 42% in controls, P <.05), and decreased the prevalence of documented infections (40% vs 77%, P <.05). No difference was observed in response, remission duration, or survival between the 2 groups.

    • In the CALGB 9111 study, 198 subjects were randomized to receive either placebo or G-CSF beginning on day 4 of induction chemotherapy. Again, subjects in the G-CSF group had significantly shorter durations of neutropenia and significantly fewer days of hospitalization. In this study, subjects receiving G-CSF also had higher complete remission rates because fewer deaths occurred during remission induction. Again, no significant effect on disease-free survival or overall survival was observed.

    • The importance of the early use of G-CSF is demonstrated by the study of Bassan et al, in which subjects received induction chemotherapy with idarubicin, vincristine, L-asparaginase, and prednisone. Twenty-eight subjects received G-CSF beginning on day 15, and 37 subjects received G-CSF beginning on day 4. Subjects receiving G-CSF on day 4 recovered significantly faster from neutropenia, had fewer infectious complications, and required less antibiotic than subjects beginning G-CSF on day 15.

    • Currently, little data support the use of granulocyte-macrophage colony-stimulating factor (GM-CSF) in patients with ALL, outside of the setting of a clinical trial. The Groupe Ouest Est d'etude des Leucenies et Autres Maladies du Sang randomly assigned 67 subjects to receive GM-CSF or placebo during induction chemotherapy with idarubicin, methylprednisolone, and high-dose Ara-C. No difference was observed in the complete remission rate, the duration of neutropenia, or days with fever for the 2 groups. Mucositis of higher than grade 3 was reduced in subjects receiving GM-CSF (2 of 35 patients vs 6 of 29 patients, respectively, P = .03). In a GET-LALA study, patients received G-CSF, GM-CSF, or no growth factor during induction therapy. The median time for neutrophil recovery was 17 days for G-CSF, 18 days for GM-CSF, and 21 days for no growth factors.

    • Allopurinol at 300 mg 1-3 times/d is recommended during induction therapy until blasts are cleared and hyperuricemia resolves. High-risk patients (those with very high LDH or leukemic infiltration of the kidneys) can benefit from rasburicase.

Surgical Care

Placement of a central venous catheter, such as a triple lumen, Broviac, or Hickman catheter, may be necessary.

Diet

A neutropenic diet is recommended.

• No fresh fruits or vegetables may be eaten.
• All foods must be cooked.
• Meats are to be cooked until well done.

Activity

Activity may occur as tolerated by the patient, but the patient may not participate in strenuous activities such as lifting or exercise.

MEDICATION

Section 7 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

The medications used to treat acute leukemia cause severe bone marrow depression. Only physicians specifically trained in their use should administer these medications. In addition, access to appropriate supportive care is required.

Drug Category: Corticosteroids

May be used during induction, consolidation, and/or maintenance therapy.

Drug Category: Antineoplastics

Used for induction, consolidation, maintenance, and CNS prophylaxis.

Drug Name	Asparaginase (Elspar)
Description	Breaks down extracellular asparagine into aspartic acid and ammonia. Normal cells are capable of synthesizing their own asparagine but many malignant cells are not.
Adult Dose	6,000-12,000 U/m2 IM
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity; history of pancreatitis
Interactions	May inhibit effect of methotrexate on neoplastic cells; toxicity may increase with vincristine or prednisone
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Monitor patients for potential toxic effects, including allergic reactions, pancreatitis, thrombotic or bleeding episodes (due to effects on clotting factors), and hyperglycemia

Drug Name	Methotrexate (Folex, Rheumatrex)
Description	Antimetabolite of folic acid analog type. Inhibits dihydrofolate reductase, resulting in inhibition of DNA synthesis, repair, and cellular replication.
Adult Dose	15 mg/m2 PO qwk during maintenance therapy
Pediatric Dose	Not established
Contraindications	Do not use high dose in patients with a CrCl <60 mL/min; increased toxicity can occur in patients with ascites or pleural effusions
Interactions	PO aminoglycosides may decrease absorption and blood levels of concurrent PO MTX; charcoal lowers levels; coadministration with etretinate may increase hepatotoxicity; folic acid or its derivatives contained in some vitamins may decrease response Coadministration with NSAIDs may be fatal; indomethacin and phenylbutazone can increase plasma levels; may decrease phenytoin serum levels; probenecid, salicylates, procarbazine, and sulfonamides (including TMP-SMZ) may increase effects and toxicity; may increase plasma levels of thiopurines
Pregnancy	X - Contraindicated in pregnancy
Precautions	Monitor CBC counts monthly and liver and renal function q1-3mo during therapy (monitor more frequently, ie, daily, during initial dosing, dose adjustments, or when risk of elevated levels, eg, dehydration); has toxic effects on hematologic, renal, GI, pulmonary, and neurologic systems Discontinue if significant drop in blood counts; aspirin, NSAIDs, or low-dose steroids may be administered concomitantly (possibility of increased toxicity with NSAIDs, including salicylates, has not been tested)

Drug Name	Mercaptopurine (Purinethol)
Description	Antimetabolite of purine analog type. Primary effect is inhibition of DNA synthesis.
Adult Dose	100 mg/m2 PO qd during maintenance
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity
Interactions	Concurrent use with allopurinol may result in greatly increased activity and toxicity; toxicity increases when administered with allopurinol; hepatic toxicity increases when used in combination with doxorubicin
Pregnancy	D - Unsafe in pregnancy
Precautions	Exercise caution in patients with renal or hepatic impairment; use associated with high risk of pancreatitis, monitor for myelosuppression

Drug Name	Cyclophosphamide (Cytoxan)
Description	Alkylating agent of nitrogen mustard type. Inhibits cell growth and proliferation.
Adult Dose	1 g/m2 IV during induction
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity; severely depressed bone marrow function
Interactions	Allopurinol may increase risk of bleeding or infection and enhance myelosuppressive effects; may potentiate doxorubicin-induced cardiotoxicity; may reduce digoxin serum levels and antimicrobial effects of quinolones Chloramphenicol may increase half-life while decreasing metabolite concentrations; may increase effect of anticoagulants; coadministration with high doses of phenobarbital may increase rate of metabolism and leukopenic activity; thiazide diuretics may prolong cyclophosphamide-induced leukopenia and neuromuscular blockade by inhibiting cholinesterase activity
Pregnancy	D - Unsafe in pregnancy
Precautions	Regularly examine hematologic profile (particularly neutrophils and platelets) to monitor for hematopoietic suppression; regularly examine urine for RBCs, which may precede hemorrhagic cystitis

Drug Name	Cytosine arabinoside (Cytosar-U)
Description	Antimetabolite that induces activity as a result of activation to cytarabine triphosphate and includes inhibition of DNA polymerase and incorporation into DNA and RNA.
Adult Dose	100 mg/m2 IV as 24-h infusion qd for 7 d 3 g/m2 IV as 3-h infusion qd for 5 d
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity
Interactions	Decreases effects of gentamicin and flucytosine; other alkylating agents and radiation increase toxicity
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	If significant increase in bone marrow suppression, reduce number of treatment days; patients with hepatic or renal insufficiencies are at higher risk for CNS toxicity after a high dose (reduce dose)

Drug Name	Daunorubicin (Cerubidine)
Description	Anthracycline that inhibits topoisomerase II. Also inhibits DNA and RNA synthesis by intercalating between DNA base pairs.
Adult Dose	45-60 mg/m2 IV as a 30-min infusion qd for 3 d
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity; congestive heart failure
Interactions	None reported
Pregnancy	D - Unsafe in pregnancy
Precautions	Monitor patients for myelosuppression; check cardiac ejection fraction frequently in patients receiving high cumulative doses; significant dose reduction is required in patients with hepatic or renal insufficiency

Drug Name	Idarubicin (Idamycin)
Description	Topoisomerase II inhibitor. Inhibits cell proliferation by inhibiting DNA and RNA polymerase.
Adult Dose	12 mg/m2 IV as 30-min infusion qd for 3 d
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity; congestive heart failure
Interactions	None reported
Pregnancy	D - Unsafe in pregnancy
Precautions	Monitor patients for myelosuppression; check cardiac ejection fraction frequently in patients receiving high cumulative doses; significant dose reduction required in hepatic or renal insufficiency

Drug Name	Mitoxantrone (Novantrone)
Description	Topoisomerase II inhibitor. Inhibits cell proliferation by intercalating DNA and inhibiting topoisomerase II.
Adult Dose	12 mg/m2 IV as 30-min infusion qd for 3 d
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity; congestive heart failure; hepatic and/or renal insufficiency require significant dose reduction
Interactions	None reported
Pregnancy	D - Unsafe in pregnancy
Precautions	Caution in impaired hepatic function and preexisting cardiac disease (cardiotoxicity commonly observed after cumulative dose of 120-160 mg/m2); perform baseline and follow-up cardiac function tests (2-dimensional echo and ejection fraction measurements); monitor patients for myelosuppression

Drug Name	Dasatinib (Sprycel)
Description	Multiple tyrosine kinase inhibitor. Inhibits growth of cell lines overexpressing BCR-ABL. Orphan drug indicated for Philadelphia chromosome–positive acute lymphoblastic leukemia (Ph+ ALL) in individuals resistant to or intolerant of prior therapy.
Adult Dose	70 mg PO bid; continue until disease progression or no longer tolerated Advanced-phase Ph+ ALL: May increase to 100 mg PO bid Coadministration with CYP3A4 inhibitors: 20-40 mg PO qd Coadministration with CYP3A4 inducers: May need to increase dose If clinically viable, an alternate medication with no or minimal enzyme inhibition or induction is recommended
Pediatric Dose	Not established
Contraindications	None known
Interactions	CYP450 3A4 substrate and inhibitor; CYP3A4 inhibitors (eg, ketoconazole, itraconazole, erythromycin, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin) may increase serum concentrations; CYP3A4 inducers (eg, dexamethasone, phenytoin, rifampin, phenobarbital, carbamazepine, St John's wort) may decrease serum concentrations coadministration with antacids or other drugs that decrease gastric pH (eg, H2 blockers [famotidine], proton pump inhibitors [omeprazole]) may decrease AUC and Cmax; may increase plasma levels of CYP3A4 substrates (eg, alfentanil, cyclosporine, fentanyl, pimozide, quinidine, sirolimus, tacrolimus, ergot alkaloids, simvastatin)
Pregnancy	D - Unsafe in pregnancy
Precautions	Adverse effects include fluid retention (including pleural effusion), bleeding, diarrhea, rash, pyrexia, infections, headache, fatigue, and nausea; frequently causes anemia, neutropenia, or thrombocytopenia; because of extensive liver metabolism, caution in patients with hepatic impairment (may need to decrease dose); swallow tab whole, do not crush or cut

Drug Name	Nelarabine (Arranon)
Description	Prodrug of the deoxyguanosine analogue 9-beta-D-arabinofuranosylguanine (ara-G). Converted to the active 5'-triphosphate, ara-GTP, a T-cell–selective nucleoside analog. Leukemic blast cells accumulate ara-GTP. This allows for incorporation into DNA, leading to inhibition of DNA synthesis and cell death. Approved by FDA as orphan drug to treat persons with T-cell acute lymphoblastic leukemia whose disease has not responded to or has relapsed with at least 2 chemotherapy regimens.
Adult Dose	1500 mg/m2 IV (infuse over 2 h) on days 1, 3, and 5; repeat q21d
Pediatric Dose	650 mg/m2 IV (infuse over 1 h) qd for 5 consecutive days; repeat q21d
Contraindications	Documented hypersensitivity
Interactions	None reported
Pregnancy	D - Unsafe in pregnancy
Precautions	Common adverse effects include hematologic toxicity (eg, leukopenia, thrombocytopenia, anemia, neutropenia), hypokalemia, hypoalbuminemia, hyperbilirubinemia, fatigue, nausea, vomiting, and diarrhea; severe neurologic events reported and include extreme somnolence, convulsions, demyelination, ascending peripheral neuropathies similar to Guillain-Barré syndrome, and peripheral neuropathy ranging from numbness and paresthesia to motor weakness and paralysis; do not dilute prior to administration; preventive measures for hyperuricemia of tumor lysis syndrome (eg, hydration, urine alkalinization, allopurinol prophylaxis) must be taken

Drug Category: Colony-stimulating factors

Act as hematopoietic growth factors that stimulate development of granulocytes. Used to treat or prevent neutropenia when receiving myelosuppressive cancer chemotherapy and to reduce period of neutropenia associated with BMT. Also used to mobilize autologous peripheral blood progenitor cells for BMT and in management of chronic neutropenia.

Drug Name	Pegfilgrastim (Neulasta)
Description	Long-acting filgrastim created by covalent conjugate of recombinant G-CSF (ie, filgrastim) and monomethoxypolyethylene glycol. As with filgrastim, acts on hematopoietic cells by binding to specific cell surface receptors, thereby activating and stimulating production, maturation, migration, and cytotoxicity of neutrophils.
Adult Dose	6 mg SC once per chemotherapy cycle
Pediatric Dose	<45 kg: Not established >45 kg: Administer as in adults
Contraindications	Documented hypersensitivity to Escherichia coli–derived proteins‚ PEG, or filgrastim
Interactions	Do not administer for 14 d before and 24 h after administration of cytotoxic chemotherapy or radiation because increases sensitivity of rapidly dividing myeloid cells to cytotoxic chemotherapy; lithium may potentiate release of neutrophils
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Splenic rupture has been reported rarely; ARDS may occur secondary to influx of neutrophils to sites of inflammation in lungs; may precipitate sickle cell crisis; may cause bone pain; risk of developing myelodysplastic syndrome or acute myeloid leukemia in certain patients; leukocytosis; possible tumor growth

FOLLOW-UP

Section 8 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Further Inpatient Care

• Patients require admission for induction chemotherapy and require readmission for consolidation chemotherapy or for the treatment of toxic effects of chemotherapy.

Further Outpatient Care

• Maintenance therapy is administered in an outpatient setting.
• Patients come to the office to be monitored for disease status and the effects of chemotherapy.

Transfer

• Patients are best treated at a center with personnel who have significant experience in the treatment of leukemia.
• Patients admitted to hospitals that lack appropriate blood product support facilities, leukapheresis capabilities, or physicians and nurses familiar with the treatment of patients with leukemia should be transferred to an appropriate (generally tertiary care) hospital.

Deterrence/Prevention

• While talking chemotherapy, patients with leukemia should avoid exposure to crowds and people with contagious illnesses, especially children with viral infections.

Complications

• Death may occur as a result of uncontrolled infection or hemorrhage. This may occur even after the use of appropriate blood product and antibiotic support.
• The most common complication is failure of the leukemia to respond to chemotherapy. These patients do poorly because they usually do not respond to other chemotherapy regimens.

Prognosis

• Patients with ALL are divided into 3 prognostic groups.
• • Good risk includes (1) no adverse cytogenetics, (2) age younger than 30 years, (3) WBC count of less than 30,000/µL, and (4) complete remission within 4 weeks.
  • Intermediate risk does not meet the criteria for either good risk or poor risk.
  • Poor risk includes (1) adverse cytogenetics [(t9;22), (4;11)], (2) age older than 60 years, (3) precursor B-cell WBCs with WBC count greater than 100,000/µL, or (4) failure to achieve complete remission within 4 weeks.

• The effect of immunophenotype on prognosis are as follows:
• • Czuczman et al studied 259 patients treated with several CALGB protocols for newly diagnosed ALL. B-lineage phenotype was expressed in 79% of patients; one third of these coexpressed myeloid antigens. Seventeen percent of patients demonstrated T-lineage ALL; one quarter of these coexpressed myeloid antigens. No significant difference in response rates, remission duration, or survival was observed for patients expressing versus not expressing myeloid antigens. T-lineage ALL was associated with younger age, male sex, presence of a mediastinal mass, higher WBC count and hemoglobin level, longer survival, and longer disease-free survival. The number of T markers expressed also had prognostic significance. Patients expressing 6 or more markers had longer disease-free and overall survival compared with patients expressing 3 or fewer markers.
  • In a report by Preti et al, 64 of 162 patients with newly diagnosed ALL coexpressed myeloid markers. Patients coexpressing myeloid markers were significantly older, had a higher prevalence of CD34 expression, and had a lower prevalence of common ALL antigen expression than patients without myeloid expression. A trend toward a decreased remission rate was observed for patients coexpressing myeloid markers (64% vs 78%, respectively, P = .06). However, no significant effect on remission duration or overall survival was observed.

• The effect of chromosome number on prognosis is displayed in Table 2.

Patient Education

• Patients should be instructed to immediately seek medical attention if they are febrile or have signs of bleeding.
• For excellent patient education resources, visit eMedicine's Blood and Lymphatic System Center and Cancer and Tumors Center. Also, see eMedicine's patient education article Leukemia.

MISCELLANEOUS

Section 9 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Medical/Legal Pitfalls

• Patients with ALL are best treated by physicians who have significant experience in the treatment of patients with acute leukemia. In addition, these patients should be treated in a setting where appropriate supportive care measures (high-level blood banking and leukapheresis) are available.

MULTIMEDIA

Section 10 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Media file 1:  Diagnostic workup of a patient with pre–B-cell acute lymphoblastic leukemia. Bone marrow aspiration revealed French-American-British L2 morphology.
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Media type:  Image

Media file 2:  Diagnostic workup of a patient with pre–B-cell acute lymphoblastic leukemia. Flow cytometry shows that the cells were positive for CD10, CD19, CD22, CD34, and terminal deoxynucleotidyl transferase.
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