Acute Lymphoblastic Leukemia Treatment & Management
- Author: Karen Seiter, MD; Chief Editor: Emmanuel C Besa, MD more...
Acute lymphoblastic leukemia (ALL) is best treated by physicians who have significant experience in the treatment of patients with acute leukemia. In addition, these patients should receive treatment in a setting where appropriate supportive care measures (high-level blood banking and leukapheresis) are available. 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.
Traditionally, the four components of ALL treatment are induction, consolidation, maintenance, and central nervous system (CNS) prophylaxis; these are briefly reviewed in the following sections. Other aspects of treatment are also discussed. See also Acute Lymphoblastic Leukemia Treatment Protocols.
Patients with ALL require hospital admission for induction chemotherapy, and they require readmission for consolidation chemotherapy or for the treatment of toxic effects of chemotherapy. Surgical intervention may be required for the placement of a central venous catheter, such as a triple lumen, Broviac, or Hickman catheter.
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.
Standard induction therapy typically involves either a four-drug regimen of vincristine, prednisone, anthracycline, and cyclophosphamide or L -asparaginase or a five-drug regimen of vincristine, prednisone, anthracycline, cyclophosphamide, and L -asparaginase given over the course of 4-6 weeks. Using this approach, complete remissions (CRs) are obtained in 65-85% of patients.
The rapidity with which a patient's disease enters CR correlates with treatment outcome. Several studies have shown that patients whose disease is in CR within 4 weeks of therapy have longer disease-free survival and overall survival than those whose disease enters remission after 4 weeks of treatment.
In a large French study, 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.
The use of consolidation chemotherapy in acute lymphoblastic leukemia (ALL) is supported by several studies. Fiere et al compared consolidation therapy with daunorubicin and cytosine arabinoside (Ara-C) versus no consolidation therapy in adults with ALL, demonstrating a 38% 3-year, leukemia-free survival rate for subjects receiving consolidation and maintenance therapy compared with 0% for those receiving maintenance therapy without consolidation.
In a study reported by Hoelzer et al, subjects whose disease was in remission after induction received consolidation therapy consisting of dexamethasone, vincristine, and doxorubicin, 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.
A 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 have 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.
The effectiveness of maintenance chemotherapy in adults with acute lymphoblastic leukemia (ALL) has not been studied in a controlled clinical trial. However, several phase II studies without maintenance therapy have shown inferior results compared with historical controls.
A Cancer and Leukemia Group B (CALGB) study of daunorubicin or mitoxantrone, vincristine, prednisone, and methotrexate induction followed by four 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, three 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 four-drug regimen compared with a 14-month course of a seven-drug regimen did not show a difference in disease-free survival between the two groups.
In contrast to patients with acute myelogenous leukemia (AML), patients with acute lymphoblastic leukemia (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, central nervous system (CNS) prophylaxis with intrathecal chemotherapy is essential.
Cortes et al analyzed the prevalence of CNS leukemia in four consecutive clinical trials at the MD Anderson Cancer Center and found that that high-dose systemic chemotherapy reduces CNS relapse. However, early intrathecal chemotherapy is necessary to achieve the lowest risk of CNS relapse.
CNS relapse rates were 31% for group 1 (standard chemotherapy, no CNS prophylaxis), 18% for group 2 (high-dose systemic chemotherapy, no CNS prophylaxis), 17% for group 3 (high-dose systemic chemotherapy, intrathecal chemotherapy for high-risk subjects after achieving remission), and 3% for group 4 hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone (hyper-CVAD). All subjects received intrathecal chemotherapy starting in induction. High-risk subjects received 16 intrathecal treatments, and low-risk subjects received four intrathecal treatments.
Newer Induction 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, more intensive induction approaches are used by many physicians. Two notable examples are the Memorial Acute Lymphoblastic Leukemia–2 (ALL-2) protocol and the hyper-CVAD (cyclophosphamide, vincristine, doxorubicin, and dexamethasone) protocol.
The ALL-2 protocol uses an intensive, high-dose, mitoxantrone-based, acute myelogenous leukemia (AML)-style induction regimen. In a phase I study of high-dose mitoxantrone combined with high-dose cytosine arabinoside (Ara-C), Arlin et al reported that all eight patients newly diagnosed with ALL and eight of 10 patients with ALL who relapsed achieved complete remission (CR).
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 CR. 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 (vincristine, prednisone, cyclophosphamide and doxorubicin), the CR rate was 83% for patients receiving ALL-2 compared with 70% for patients receiving L-20. 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 MD Anderson Cancer Center, which 17% of patients had the Philadelphia (Ph) chromosome, 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.
Newer modifications of the hyper-CVAD regimen include the addition of imatinib to patients whose leukemia is Philadelphia chromosome positive, and rituxan to patients whose leukemia is CD20 positive. Both of these approaches have resulted in improvements in disease-free survival (see below).
Treatment of Mature B-Cell ALL
Mature B-cell acute lymphoblastic leukemia (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 (CR) and few patients survive long term.
Newer short-term intensive therapies show improved results. A report of the hyper-CVAD regimen showed that disease in 93% of subjects entered CR, median survival was 16 months, and disease in 67% of subjects alive at 5 years.
In a report by Hoelzer et al, with the use of regimens containing intensive cyclophosphamide and intermediate methotrexate or ifosfamide and high-dose methotrexate, CR rates were 63% (cyclophosphamide + intermediate methotrexate) and 74% (ifosfamide + high-dose methotrexate).
Disease-free survival rates increased to 50% in the first group and 71% in the second group, 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 cells 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. The combination of hyper-CVAD (hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone) plus rituxan resulted in an overall 3-year survival of 80% compared with 50% for historical controls treated without rituxan.
Treatment of Ph Chromosome–Positive ALL
In the past, Philadelphia chromosome–positive (Ph+) acute lymphoblastic leukemia (ALL) was treated with the same regimens as other types of ALL, with poor results. However, the tyrosine kinase inhibitor 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 chronic myelogenous leukemia (CML) in lymphoid blast crisis, only 4 of 20 patients had a complete response, and all patients progressed in less than 6 months.
The German Multicenter ALL (GMALL) trial conducted a randomized study of imatinib versus standard induction therapy for patients with Ph-positive ALL older than 55 years and reported the overall complete remission (CR) rate was 96.3% in patients randomly assigned to imatinib and 50% in patients allocated to standard chemotherapy. Severe adverse events were significantly more frequent during standard induction chemotherapy (90% vs 39%). The estimated overall survival of all patients was 42% at 24 months, with no significant difference between the 2 cohorts.
The addition of imatinib to chemotherapy has resulted in significantly improved outcomes. The addition of imatinib to hyper-CVAD (hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone) resulted in a 3-year disease-free survival rate of 66% and overall survival of 55% compared with a 14% 3-year disease-free survival rate and 15% overall survival for patients treated with hyper-CVAD without imatinib. Similar results have been reported when imatinib is added to other chemotherapy regimens.
Newer tyrosine kinase inhibitors have been developed for patients with chronic myelogenous leukemia (CML) that has become resistant to imatinib. These agents are also being studied in Ph-positive ALL.
Nilotinib and dasatinib
Nilotinib is a tyrosine kinase inhibitor that has a higher binding affinity and selectivity for the ABL kinase than imatinib. Nilotinib has 20 to 50 times the inhibitory activity against imatinib-sensitive CML cell lines relative to imatinib. In a phase II study in patients with relapsed/refractory Ph-positive ALL, complete responses were reported in 10 (24%) patients treated with nilotinib.
Dasatinib is a potent, orally active inhibitor of the BCR-ABL, c-KIT and the SRC family of kinases. Dasatinib is a more potent inhibitor of BCR-ABL and c-KIT than imatinib mesylate, and it is effective in patients with CML that is resistant to or intolerant of imatinib.
The Gruppo Italiano Malattie Ematologiche dell'Adulto (GIMEMA) presented the interim results of a prospective study of dasatinib in patients with newly diagnosed Ph-positive ALL. Prednisone was started 7 days before the first dasatinib administration and continued until day 31. Dasatinib was administered for a total of 84 days. At the time of the report, all 23 patients treated showed a complete hematologic response by day 22.
Although nilotinib and dasatinib are clearly active in Ph-positive ALL, it is likely that, similar to the results seen with imatinib, these responses will likely not be durable. Therefore each of these agents is currently being studied in combination with standard chemotherapy regimens.
That said, these new tyrosine kinase inhibitors are not without their drawbacks and adverse events. Dasatinib has been associated with pleural effusions and pulmonary arterial hypertension, while nilotinib has been linked to biochemical changes in liver function and QT-interval prolongation. Development of resistance may also occur with these agents.
In the GIMEMA LAL1205 protocol, patients who had newly diagnosed Ph+ ALL received only dasatinib (for 84 d), steroids (for the first 32 d), and intrathecal chemotherapy as induction therapy. Fifty-three patients were able to be evaluated (median age, 53.6 y). All patients achieved a complete hematologic remission; 49 patients (92.5%) achieved this at day 22. Postinduction management was decided by the investigator and included no further treatment (2 patients), tyrosine kinase inhibitor alone (19 patients), tyrosine kinase inhibitor plus chemotherapy and/or autografting (14 patients), and allografting (18 patients). At 20 months, the overall survival was 69.2% and disease-free survival was 51.1%. Twenty-three patients relapsed after completing induction.
Ponatinib (Iclusig), a kinase inhibitor, was approved by the US Food and Drug Administration (FDA) in December 2012 for patients with Ph+ ALL that is resistant or intolerant to prior tyrosine kinase inhibitor therapy, including those with the T315I mutation. Because ponatinib has a high risk for thromboembolic events, its use is restricted to patients for whom no other tyrosine kinase inhibitor therapy is indicated.
In the phase II PACE trial, 54% of chronic-phase chronic myeloid leukemia (CML) patients, including 70% of patients with the T315I mutation, achieved a major cytogenetic response. In patients with advanced disease, 52% of those with accelerated-phase CML, 31% of those with blast-phase CML, and 41% of those with Ph+ ALL achieved a major hematologic response to ponatinib. These results confirm the phase I cinical trial results.
In October 2013, at the FDA’s request, ponatinib was temporarily removed from the market because of safety concerns. The FDA cited an increased risk for life-threatening blood clots and severe narrowing of blood vessels. Ponatinib was returned to the US market within 2 months, but with new safety measures to address the risk for serious cardiovascular and thrombotic events.
The revised indications for patients with ALL are now limited to two groups: adults with T315I-positive Ph+ ALL; and adults with Ph+ ALL for whom no other tyrosine kinase inhibitor therapy is indicated.
The revised labeling also states that the optimal dose of ponatinib has not been determined. The recommended starting dose remains at 45 mg PO once daily with or without food, but additional information has been included regarding dose decreases and discontinuations. The boxed warning has been revised to include the risk for heart failure, including fatalities, and the incidence of vascular occlusion (at least 27%).
Treatment of the Younger Adult
Older children and younger adults with acute lymphoblastic leukemia (ALL) 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 studies have suggested 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 complete remission (CR) rate was 94% for patients receiving the pediatric regimen compared with 83% for those receiving the adult. The 5-year survival was 67% in the pediatric-regimen group and 41% in the adult-regimen group. Patients treated on the pediatric regimen were younger (15.9 y) than those treated on the adult regimen (17.9 y); however, prognostic factors were otherwise matched.
Similarly, the Children’s Cancer Group (CCG) and CALGB performed an analysis on patients aged 16-21 years treated on their studies and, again, event-free and overall survival were improved for patients treated on the CCG protocols.
In a study by the Programme for the Study of Therapeutics for Haematological Malignancies (PETHEMA), adolescents and young adults were treated with a pediatric regimen (ALL-96), demonstrating a response to therapy that was similar to previously reported, although a slight increase in hematologic toxicity was observed in the adult patients.
The majority of children with ALL are cured with frontline chemotherapy regimens. Many investigators are trying to translate these results into the adult population. Areas being studied include increased intensity of standard agents including asparaginase, risk-adapted chemotherapy, and evaluation of minimal disease.
Most authorities agree that allogeneic transplantation should be offered to young patients with high-risk features whose acute lymphoblastic leukemia (ALL) 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 (CR) may be considered for such investigational approaches as allogeneic transplantation with nonmyeloablative chemotherapy (ie, mini-transplants). Previously, patients with mature B-cell ALL would have been referred for transplantation when their disease was in first CR; however, with improving results from more intensive chemotherapy regimens, many clinicians are reserving transplantation for patients who have experienced relapse.
Hematopoietic stem cell transplantation (HSCT) seems to be a valuable option for a subgroup of infants with mixed-lineage ALL carrying poor prognostic factors that include age younger than 6 months and either poor response to steroids at day 8 or leukocyte levels of 300 g/L or higher.
Relatively few studies have compared transplantation with chemotherapy in adults with ALL. In a study by the Groupe Ouest-Est des Leucemies Airgues et Maladies du Sang (GOELAMS), 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 bone marrow transplantation (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.
In a prospective, nonrandomized trial, the Bordeaux, Grenoble, Marseille, Toulouse group found that the 3-year probability of disease-free survival was significantly higher with allogeneic BMT (68%) than with autologous BMT (26%). No benefit was observed with the addition of recombinant interleukin 2 (IL-2) after autologous BMT.
In the French Group on Therapy for Adult Acute Lymphoblastic Leukemia study, subjects aged 15-40 years whose disease was in CR and who had a human leukocyte antigen (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.
However, when only high-risk patients were considered (ie, Philadelphia chromosome–positive (Ph+), null ALL; >35 y; white blood cell [WBC] count >30,000/µL; or time to CR > wk), allogeneic BMT proved superior to autologous BMT or chemotherapy with respect to overall survival rates (44% vs 20%) and disease-free survival rates (39% vs 14%). 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.
Stem cell transplantation
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%) compared with those receiving autologous transplantation (40%).
The United Kingdom Medical Research Council Acute Lymphoblastic Leukemia joint trial with the Eastern Cooperative Oncology Group (MRC UKALL XII/ECOG E2993) demonstrated that matched related allogeneic transplantations for ALL in first complete CR provide the most potent antileukemic therapy and considerable survival benefit for standard-risk patients. A donor versus no-donor analysis showed that Ph-negative patients with a donor had a 5-year improved overall survival, 53% versus 45% (P = 0.01), and that the relapse rate was significantly lower.
The survival difference was significant in standard-risk patients but not in high-risk patients with a high nonrelapse mortality rate in the high-risk donor group. Patients randomized to chemotherapy had a higher 5-year overall survival (46%) than those randomized to autologous transplantation (37%). However, the transplantation-related mortality for high-risk older patients was unacceptably high and abrogated the reduction in relapse risk.
Allogeneic transplantation can also be 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 19 patients assigned to autologous BMT, 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. Yet, although autologous transplantation is relatively safe, it is associated with a high relapse rate, making this modality of little use in patients with ALL.
Unrelated donor transplantation
For patients without a sibling donor, an alternative is an unrelated donor (URD) transplant. Weisdorf et al found that autologous BMT was associated with a lower transplant-related mortality rate, but URD transplantations had a lower risk of relapse. In patients whose disease was in second CR, URD transplantations resulted in a superior rate of disease-free survival.
Although peripheral blood has come to be preferred to bone marrow as the source for stem cells from unrelated donors (about 75% of transplants), a randomized phase III trial found that peripheral-blood stem cells did not yield improved survival as compared with bone-marrow cells and were significantly associated with chronic graft-vs-host disease (GVHD)[39, 40] ; the authors suggested that peripheral-blood stem cells might be appropriate for patients at higher risk for graft failure and bone-marrow cells for all others.
Treatment of Relapsed ALL
Patients with relapsed acute lymphoblastic leukemia (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 (cyclophosphamide, vincristine, doxorubicin, dexamethasone) protocol and high-dose cytosine arabinoside (Ara-C)–based regimens.
As noted earlier, the hyper-CVAD regimen is based on hyperfractionated cyclophosphamide and intermediate doses of Ara-C and methotrexate. In a study at the MD Anderson Cancer Center of 66 patients with relapsed ALL, the complete remission (CR) rate was 44% and median survival was 42 weeks.
Arlin et al reported that 8 of 10 patients with relapsed ALL achieved CR 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 CR rates of 58-78% in patients who experienced relapse.
The Italian ALL R-87 study suggested that a small number of patients who experience relapse will survive long-term after allogeneic bone marrow transplantation (BMT) ; however, autologous BMT is less useful because it is associated with a high rate of relapse. Sixty-one 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 CR; however, only nine of the responders underwent BMT.
The remaining subjects did not undergo transplantations because of either early relapse or excessive toxicity. Of the four subjects who underwent allogeneic BMT, three were alive and achieved remission at 22, 43, and 63 months, whereas only one of the five subjects who underwent autologous BMT was alive.
In August 2012, the US Food and Drug Administration (FDA) approved vincristine liposomal (Marqibo) for the treatment of Philadelphia chromosome negative (Ph-) ALL in adults. It is indicated for patients in second or greater relapse or whose disease has progressed following two or more anti-leukemia therapies. This product is a sphingomyelin/cholesterol liposome-encapsulated formulation of vincristine. In a trial of 65 patients that received at least one dose of vincristine liposomal, 15.4% of the patients had CR lasting a median of 28 days.
In December 2012, the FDA approved the kinase inhibitor ponatinib for Ph+ ALL that is resistant or intolerant to prior tyrosine kinase inhibitor therapy. For more information, see Treatment of Ph Chromosome–Positive ALL.
Blinatumomab (Blincyto), a bispecific T-cell engager (BiTE) antibody, was approved by the FDA in December 2014 for Ph- relapsed or refractory B-cell precursor ALL. Its approval was based on results of a Phase 2, multicenter, single-arm open-label study. Eligible patients were >18 years of age with Ph- relapsed or refractory B-cell precursor ALL. Of the 185 patients evaluated in the trial, 41.6% (77/185; 95% CI: 34.4-49.1) achieved complete remission or complete remission with partial hematologic recovery (Cr/CRh) within 2 cycles of treatment with blinatumomab, which was the primary endpoint of the study. The majority of responses (81% [62/77]) occurred within the first cycle of treatment. Among patients who achieved CR/CRh, 39% (30/77) went on to HSCT, and 75.3% (58/77 95% CI: 64.2-84.4) achieved minimal residual disease (MRD) response, a measure of eradication of residual disease at the molecular level.[43, 44]
Clofarabine is a novel nucleoside analogue that is approved for the treatment of pediatric patients with refractory or relapsed ALL. This agent 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 guanine arabinoside (ara-G). This agent was approved as an orphan drug by the US Federal Drug Administration (FDA) in October 2005. Complete responses have been reported in 31% of patients and in 54% of patients with T-cell ALL. The dose-limiting toxicity of this drug is neurotoxicity.
Novel and Experimental Drug Therapies
CAR T-cells are genetically engineered T-cells that are designed to target a specific molecule on cancer cells. For patients with ALL, CAR T-cells targeting CD19 have yielded high response rates in patients with refractory disease. Toxicities include cytokine release syndrome and seizures. This therapy is currently investigational.
Supportive Care - Blood Products
Patients with acute lymphoblastic leukemia (ALL) 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-relatedgraft 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 central nervous system 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 (PT). Cryoprecipitate is given if the fibrinogen level is less than 100 g/dL.
Supportive Care - Therapy and Prophylaxis for Infection
Antibiotics 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 antibiotic agents 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 (oral [PO] 500 mg twice daily [bid])
Fluconazole (200 mg PO daily), itraconazole (200 mg PO bid), or posaconazole (200 mg PO three times daily [tid])
Acyclovir (200 mg PO 5 times/d) or valacyclovir (500 mg PO daily)
Once patients taking these antibiotics become febrile, they are switched to intravenous antibiotics.
Supportive Care - Growth Factors
The use of granulocyte colony-stimulating factor (G-CSF) during induction chemotherapy for acute lymphoblastic leukemia (ALL) 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, cytosine arabinoside (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, 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 III study reported by Geissler et al, subjects who received G-CSF beginning on day 2 of induction chemotherapy (ie, with daunorubicin, vincristine, L -asparaginase, and prednisone) had a marked decrease in the proportion of days with neutropenia of less than 1000/µL (29% for G-CSF vs 84% for controls), a reduction in the prevalence of febrile neutropenia (12% vs 42% in controls), and a decrease in the prevalence of documented infections (40% vs 77%) relative to those who received chemotherapy without G-CSF. No difference was observed in response, remission duration, or survival between the 2 groups.
In the Cancer and Leukemia Group B (CALGB) 9111 study, subjects who received G-CSF beginning on day 4 of induction chemotherapy had significantly shorter durations of neutropenia and significantly fewer days of hospitalization compared with those in the group that received placebo. In this study, subjects receiving G-CSF also had higher complete remission (CR) 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 FOR ALL was demonstrated by the study of Bassan et al, in which subjects who received induction chemotherapy with idarubicin, vincristine, L -asparaginase, and prednisone and 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.
Outside of the setting of a clinical trial, few data support the use of granulocyte-macrophage colony-stimulating factor (GM-CSF) in patients with ALL. The GOELAMS investigators randomly assigned 67 subjects to receive GM-CSF or placebo during induction chemotherapy with idarubicin, methylprednisolone, and high-dose Ara-C and observed no difference in the CR rate, the duration of neutropenia, or days with fever for the two groups. In addition, mucositis of higher than grade 3 was reduced in subjects receiving GM-CSF (two of 35 patients vs six of 29 patients, respectively.
In a Groupe d'Etude et de Traitement de la Leucemie Aigue Lymphoblastique de l'Adulte (GET-LALA) study, in patients who 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.
Hyperuricemia and Tumor Lysis Syndrome
Tumor lysis syndrome is a potentially life-threatening complication that may be seen in patients receiving chemotherapy for acute leukemias and high-grade non-Hodgkin lymphomas. This syndrome is characterized by elevated blood levels of uric acid, phosphate, and potassium; decreased levels of calcium; and acute renal failure.
As mentioned earlier, patients with a high tumor burden, particularly those with severe hyperuricemia, can present in renal failure. Allopurinol at 300 mg 1-3 times per day is recommended during induction therapy until blasts are cleared and hyperuricemia resolves. High-risk patients (those with very high lactate dehydrogenase [LDH] or leukemic infiltration of the kidneys) can benefit from rasburicase.
In a study by Cortes et al, adults with hyperuricemia or those at high risk for tumor lysis syndrome not only had an improved plasma uric acid response rate with rasburicase alone (0.20 mg/kg/d intravenously [IV], days 1-5) (87%) or in combination with allopurinol (IV rasburicase 0.20 mg/kg/d, days 1-3, followed by oral [PO] allopurinol 300 mg/d, days 3-5) (78%) than with allopurinol alone (300 mg/d PO, days 1-5) (66%), but they also had more rapid control of their plasma uric acid with rasburicase alone (4 h) or with allopurinol (4 h) than with allopurinol alone (27 h).
Patients with acute lymphoblastic leukemia (ALL) are monitored on an outpatient basis for disease status and the effects of chemotherapy. Maintenance therapy for these patients is also administered in an outpatient setting.
In addition, all patients should be on trimethoprim-sulfamethoxazole (TMP-SMZ) to prevent Pneumocystis jiroveci pneumonia, and patients may benefit from receiving oral nystatin or clotrimazole troches to reduce the risk of candidiasis. Patients with a high risk of relapse may also need additional antifungal therapy, such as itraconazole.
Cancer Facts & Figures 2016. American Cancer Society. Available at http://www.cancer.org/acs/groups/content/@research/documents/document/acspc-047079.pdf. Accessed: April 22, 2016.
Czuczman MS, Dodge RK, Stewart CC, Frankel SR, Davey FR, Powell BL, et al. Value of immunophenotype in intensively treated adult acute lymphoblastic leukemia: cancer and leukemia Group B study 8364. Blood. 1999 Jun 1. 93(11):3931-9. [Medline].
Preti HA, Huh YO, O'Brien SM, Andreeff M, Pierce ST, Keating M, et al. Myeloid markers in adult acute lymphocytic leukemia. Correlations with patient and disease characteristics and with prognosis. Cancer. 1995 Nov 1. 76(9):1564-70. [Medline].
Ness KK, Hudson MM, Pui CH, et al. Neuromuscular impairments in adult survivors of childhood acute lymphoblastic leukemia: associations with physical performance and chemotherapy doses. Cancer. 2012 Feb 1. 118(3):828-38. [Medline]. [Full Text].
[Guideline] NCCN Clinical Practice Guidelines in Oncology: Acute Lymphoblastic Leukemia, Version 2:2015. National Comprehensive Cancer Network. Available at http://www.nccn.org/professionals/physician_gls/pdf/all.pdf. Accessed: October 14, 2015.
Fiere D, Archimbaud E, Extra JM, Marty M, David B, Witz F, et al. Treatment of adult acute lymphoblastic leukemia. Preliminary results of a trial from the French Group. Haematol Blood Transfus. 1987. 30:125-9. [Medline].
Fiere D, Extra JM, David B, Witz F, Vernand JP, Gastaut JA, et al. Treatment of 218 adult acute lymphoblastic leukemias. Semin Oncol. 1987 Jun. 14(2 Suppl 1):64-6. [Medline].
Hoelzer D, Thiel E, Löffler H, Bodenstein H, Plaumann L, Büchner T, et al. Intensified therapy in acute lymphoblastic and acute undifferentiated leukemia in adults. Blood. 1984 Jul. 64(1):38-47. [Medline].
Durrant IJ, Prentice HG, Richards SM. Intensification of treatment for adults with acute lymphoblastic leukaemia: results of U.K. Medical Research Council randomized trial UKALL XA. Medical Research Council Working Party on Leukaemia in Adults. Br J Haematol. 1997 Oct. 99(1):84-92. [Medline].
Cuttner J, Mick R, Budman DR, Mayer RJ, Lee EJ, Henderson ES, et al. Phase III trial of brief intensive treatment of adult acute lymphocytic leukemia comparing daunorubicin and mitoxantrone: a CALGB Study. Leukemia. 1991 May. 5(5):425-31. [Medline].
Dekker AW, van't Veer MB, Sizoo W, Haak HL, van der Lelie J, Ossenkoppele G, et al. Intensive postremission chemotherapy without maintenance therapy in adults with acute lymphoblastic leukemia. Dutch Hemato-Oncology Research Group. J Clin Oncol. 1997 Feb. 15(2):476-82. [Medline].
Mandelli F, Annino L, Rotoli B. The GIMEMA ALL 0183 trial: analysis of 10-year follow-up. GIMEMA Cooperative Group, Italy. Br J Haematol. 1996 Mar. 92(3):665-72. [Medline].
Cortes J, O'Brien SM, Pierce S, Keating MJ, Freireich EJ, Kantarjian HM. The value of high-dose systemic chemotherapy and intrathecal therapy for central nervous system prophylaxis in different risk groups of adult acute lymphoblastic leukemia. Blood. 1995 Sep 15. 86(6):2091-7. [Medline].
Arlin ZA, Feldman EJ, Finger LR, Ahmed T, Mittelman A, Cook P, et al. Short course high dose mitoxantrone with high dose cytarabine is effective therapy for adult lymphoblastic leukemia. Leukemia. 1991 Aug. 5(8):712-4. [Medline].
Weiss M, Maslak P, Feldman E, Berman E, Bertino J, Gee T, et al. Cytarabine with high-dose mitoxantrone induces rapid complete remissions in adult acute lymphoblastic leukemia without the use of vincristine or prednisone. J Clin Oncol. 1996 Sep. 14(9):2480-5. [Medline].
Weiss MA, Heffner L, Lamanna N, et al. A randomized trial demonstrating the superiority of cytarabine with high-dose mitoxantrone compared to a standard vincristine/prednisone-based regimen as induction therapy for adult patients with ALL abstract. Presented at: Annual Meeting of the American Society of Clinical Oncology; May 13-15, 2005; Orlando, Fla. J Clin Oncol. 2005. 25:6516a.
Kantarjian H, Thomas D, O'Brien S, Cortes J, Giles F, Jeha S, et al. Long-term follow-up results of hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone (Hyper-CVAD), a dose-intensive regimen, in adult acute lymphocytic leukemia. Cancer. 2004 Dec 15. 101(12):2788-801. [Medline].
Hoelzer D, Ludwig WD, Thiel E, Gassmann W, Löffler H, Fonatsch C, et al. Improved outcome in adult B-cell acute lymphoblastic leukemia. Blood. 1996 Jan 15. 87(2):495-508. [Medline].
Thomas TA, Kantarjian H, Faderl S, et al. Update of the modified hyper-CVAD regimen with or without rituximab as frontline therapy of adults with acute lymphocytic leukemia (ALL) or lymphoblastic lymphoma (LL) [abstract]. Blood. 2007. 110:2824a. [Full Text].
Druker BJ, Sawyers CL, Kantarjian H, Resta DJ, Reese SF, Ford JM, et al. Activity of a specific inhibitor of the BCR-ABL tyrosine kinase in the blast crisis of chronic myeloid leukemia and acute lymphoblastic leukemia with the Philadelphia chromosome. N Engl J Med. 2001 Apr 5. 344(14):1038-42. [Medline].
Ludwig WD, Rieder H, Bartram CR, Heinze B, Schwartz S, Gassmann W, et al. Immunophenotypic and genotypic features, clinical characteristics, and treatment outcome of adult pro-B acute lymphoblastic leukemia: results of the German multicenter trials GMALL 03/87 and 04/89. Blood. 1998 Sep 15. 92(6):1898-909. [Medline].
Thomas DA, Faderl S, Cortes J, O'Brien S, Giles FJ, Kornblau SM, et al. Treatment of Philadelphia chromosome-positive acute lymphocytic leukemia with hyper-CVAD and imatinib mesylate. Blood. 2004 Jun 15. 103(12):4396-407. [Medline].
Kantarjian H, Giles F, Wunderle L, Bhalla K, O'Brien S, Wassmann B, et al. Nilotinib in imatinib-resistant CML and Philadelphia chromosome-positive ALL. N Engl J Med. 2006 Jun 15. 354(24):2542-51. [Medline].
Talpaz M, Shah NP, Kantarjian H, Donato N, Nicoll J, Paquette R, et al. Dasatinib in imatinib-resistant Philadelphia chromosome-positive leukemias. N Engl J Med. 2006 Jun 15. 354(24):2531-41. [Medline].
FDA. Sprycel (dasatinib): Drug Safety Communication – Risk of Pulmonary Arterial Hypertension. US Food and Drug Administration. Available at http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm275176.htm. Accessed: October 11, 2011.
Foa R, Vitale A, Vignetti M, et al. Dasatinib as first-line treatment for adult patients with Philadelphia chromosome-positive acute lymphoblastic leukemia. Blood. 2011 Dec 15. 118(25):6521-8. [Medline].
Cortes JE, Dong-Wook K, Pinilla-Ibarz J, le Coutre P, Paquette R, Chuah C, et al. A pivotal phase 2 trial of ponatinib with chronic myeloid leukemia (CML) and Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) resistant or intolerant to dasatinib or nilotinib, or with the T315I BCR-ABL mutation: 12-month follow-up of the PACE trial. Presented at the 54th American Society of Hematology Annual Meeting. December 8-11, 2012. Atlanta, GA. [Full Text].
Cortes JE, Kantarjian H, Shah NP, Bixby D, Mauro MJ, Flinn I, et al. Ponatinib in refractory Philadelphia chromosome-positive leukemias. N Engl J Med. 2012 Nov 29. 367(22):2075-88. [Medline].
Iclusig (ponatinib) [package insert]. Cambridge, MA.: Ariad Pharmaceuticals, Inc. December 2013. Available at [Full Text].
Boissel N, Auclerc MF, Lhéritier V, Perel Y, Thomas X, Leblanc T, et al. Should adolescents with acute lymphoblastic leukemia be treated as old children or young adults? Comparison of the French FRALLE-93 and LALA-94 trials. J Clin Oncol. 2003 Mar 1. 21(5):774-80. [Medline].
Stock W, Sather H, Dodge RK, et al. Outcome of adolescents and young adults with ALL: a comparison of Children’s Cancer Group (CCG) and Cancer and Leukemia Group B (CALGB) regimens [abstract]. Blood. 2000. 96 (suppl):476a.
Ribera JM, Ortega JJ, Oriol A, Fontanillas M, Hernández-Rivas JM, Brunet S, et al. Late intensification chemotherapy has not improved the results of intensive chemotherapy in adult acute lymphoblastic leukemia. Results of a prospective multicenter randomized trial (PETHEMA ALL-89). Spanish Society of Hematology. Haematologica. 1998 Mar. 83(3):222-30. [Medline].
Mann G, Attarbaschi A, Schrappe M, De Lorenzo P, Peters C, Hann I, et al. Improved outcome with hematopoietic stem cell transplantation in a poor prognostic subgroup of infants with mixed-lineage-leukemia (MLL)-rearranged acute lymphoblastic leukemia: results from the Interfant-99 Study. Blood. 2010 Oct 14. 116(15):2644-50. [Medline].
Hunault M, Harousseau JL, Delain M, Truchan-Graczyk M, Cahn JY, Witz F, et al. Better outcome of adult acute lymphoblastic leukemia after early genoidentical allogeneic bone marrow transplantation (BMT) than after late high-dose therapy and autologous BMT: a GOELAMS trial. Blood. 2004 Nov 15. 104(10):3028-37. [Medline].
Attal M, Blaise D, Marit G, Payen C, Michallet M, Vernant JP, et al. Consolidation treatment of adult acute lymphoblastic leukemia: a prospective, randomized trial comparing allogeneic versus autologous bone marrow transplantation and testing the impact of recombinant interleukin-2 after autologous bone marrow transplantation. BGMT Group. Blood. 1995 Aug 15. 86(4):1619-28. [Medline].
Rowe JM, Buck G, Burnett AK, Chopra R, Wiernik PH, Richards SM, et al. Induction therapy for adults with acute lymphoblastic leukemia: results of more than 1500 patients from the international ALL trial: MRC UKALL XII/ECOG E2993. Blood. 2005 Dec 1. 106(12):3760-7. [Medline].
Martino R, Bellido M, Brunet S, Sureda A, Peyret M, Guárdia R, et al. Allogeneic or autologous stem cell transplantation following salvage chemotherapy for adults with refractory or relapsed acute lymphoblastic leukemia. Bone Marrow Transplant. 1998 May. 21(10):1023-7. [Medline].
Weisdorf DJ, Billett AL, Hannan P, Ritz J, Sallan SE, Steinbuch M, et al. Autologous versus unrelated donor allogeneic marrow transplantation for acute lymphoblastic leukemia. Blood. 1997 Oct 15. 90(8):2962-8. [Medline].
Mulcahy N. Practice-changing transplant study in blood cancers. Medscape Medical News. October 17, 2012. [Full Text].
Anasetti C, Logan BR, Lee SJ, Waller EK, Weisdorf DJ, Wingard JR, et al. Peripheral-blood stem cells versus bone marrow from unrelated donors. N Engl J Med. 2012 Oct 18. 367(16):1487-96. [Medline]. [Full Text].
Giona F, Annino L, Rondelli R, Arcese W, Meloni G, Testi AM, et al. Treatment of adults with acute lymphoblastic leukaemia in first bone marrow relapse: results of the ALL R-87 protocol. Br J Haematol. 1997 Jun. 97(4):896-903. [Medline].
Marqibo (vincristine liposomal) [package insert]. South San Francisco, CA: Talon Therapeutics, Inc. August 2012. Available at [Full Text].
Topp MS, Gokbuget N, Zugmaier G, Klappers P, Stelljes M, Neumann S, et al. Phase II Trial of the Anti-CD19 Bispecific T Cell-Engager Blinatumomab Shows Hematologic and Molecular Remissions in Patients With Relapsed or Refractory B-Precursor Acute Lymphoblastic Leukemia. J Clin Oncol. 2014 Nov 10. [Medline].
Topp MS. Confirmatory open-label, single-arm, multicenter phase 2 study of the BiTE antibody blinatumomab in patients (pts) with relapsed/refractory B-precursor acute lymphoblastic leukemia (r/r ALL). Presented at the 2014 ASCO Annual Meeting, May 30 – June 3, 2014; Chicago, IL. J Clin Oncol 32:5s, 2014 (suppl; abstr 7005). [Full Text].
Kantarjian H, Gandhi V, Cortes J, Verstovsek S, Du M, Garcia-Manero G, et al. Phase 2 clinical and pharmacologic study of clofarabine in patients with refractory or relapsed acute leukemia. Blood. 2003 Oct 1. 102(7):2379-86. [Medline].
Kurtzberg J, Ernst TJ, Keating MJ, Gandhi V, Hodge JP, Kisor DF, et al. Phase I study of 506U78 administered on a consecutive 5-day schedule in children and adults with refractory hematologic malignancies. J Clin Oncol. 2005 May 20. 23(15):3396-403. [Medline].
Geissler K, Koller E, Hubmann E, Niederwieser D, Hinterberger W, Geissler D, et al. Granulocyte colony-stimulating factor as an adjunct to induction chemotherapy for adult acute lymphoblastic leukemia--a randomized phase-III study. Blood. 1997 Jul 15. 90(2):590-6. [Medline].
Larson RA, Dodge RK, Linker CA, Stone RM, Powell BL, Lee EJ, et al. A randomized controlled trial of filgrastim during remission induction and consolidation chemotherapy for adults with acute lymphoblastic leukemia: CALGB study 9111. Blood. 1998 Sep 1. 92(5):1556-64. [Medline].
Bassan R, Lerede T, Di Bona E, Rossi G, Pogliani E, Rambaldi A, et al. Granulocyte colony-stimulating factor (G-CSF, filgrastim) after or during an intensive remission induction therapy for adult acute lymphoblastic leukaemia: effects, role of patient pretreatment characteristics, and costs. Leuk Lymphoma. 1997 Jun. 26(1-2):153-61. [Medline].
Ifrah N, Witz F, Jouet JP, François S, Lamy T, Linassier C, et al. Intensive short term therapy with granulocyte-macrophage-colony stimulating factor support, similar to therapy for acute myeloblastic leukemia, does not improve overall results for adults with acute lymphoblastic leukemia. GOELAMS Group. Cancer. 1999 Oct 15. 86(8):1496-505. [Medline].
Thomas X, Boiron JM, Huguet F, Reman O, Sutton L, Turlure P, et al. Efficacy of granulocyte and granulocyte-macrophage colony-stimulating factors in the induction treatment of adult acute lymphoblastic leukemia: a multicenter randomized study. Hematol J. 2004. 5(5):384-94. [Medline].
Cortes J, Moore JO, Maziarz RT, Wetzler M, Craig M, Matous J, et al. Control of plasma uric acid in adults at risk for tumor Lysis syndrome: efficacy and safety of rasburicase alone and rasburicase followed by allopurinol compared with allopurinol alone--results of a multicenter phase III study. J Clin Oncol. 2010 Sep 20. 28(27):4207-13. [Medline].
Bogni A, Cheng C, Liu W, Yang W, Pfeffer J, Mukatira S, et al. Genome-wide approach to identify risk factors for therapy-related myeloid leukemia. Leukemia. 2006 Feb. 20(2):239-46. [Medline].
Chustecka Z. FDA Approves Ponatinib for Rare Leukemias. Available at http://www.medscape.com/viewarticle/776195. Accessed: January 16, 2013.
Matutes E, Pickl WF, Van't Veer M, Morilla R, Swansbury J, Strobl H, et al. Mixed-phenotype acute leukemia: clinical and laboratory features and outcome in 100 patients defined according to the WHO 2008 classification. Blood. 2011 Mar 17. 117(11):3163-71. [Medline].
Ribera JM, Oriol A, Sanz MA, Tormo M, Fernández-Abellán P, del Potro E, et al. Comparison of the results of the treatment of adolescents and young adults with standard-risk acute lymphoblastic leukemia with the Programa Español de Tratamiento en Hematología pediatric-based protocol ALL-96. J Clin Oncol. 2008 Apr 10. 26(11):1843-9. [Medline].
Thomas DA, Kantarjian HM, Ravandi F, et al. Long-term follow-up after frontline therapy with the hyper-CVAD and imatinib mesylate regimen in adults with Philadelphia (Ph) positive acute lymphocytic leukemia (ALL) abstract. Blood. November 2007. 110:9a.
Yanada M, Takeuchi J, Sugiura I, Akiyama H, Usui N, Yagasaki F, et al. High complete remission rate and promising outcome by combination of imatinib and chemotherapy for newly diagnosed BCR-ABL-positive acute lymphoblastic leukemia: a phase II study by the Japan Adult Leukemia Study Group. J Clin Oncol. 2006 Jan 20. 24(3):460-6. [Medline].
|Chromosome Number||3-Year Event-Free Survival|
|Abnormality||Genes Involved||3-Year Event-Free Survival|
|* Traditional regimens.
† Hyper-CVAD (cyclophosphamide, vincristine, doxorubicin [Adriamycin], dexamethasone) with rituxan.
‡ Hyper-CVAD with imatinib.
|Early B-precursor ALL||+||+||-||-||-|
|ALL = acute lymphoblastic leukemia; Cylg = Cytoplasmic immunoglobulin; SIg =Surface immunoglobulin; TdT = terminal deoxynucleotidyl transferase.|
|ALL Cells||TdT||Surface CD3||CD4/CD8|
|Early T-precursor ALL||+||-||+/+ or -/-|
|T-cell ALL||+||+||+/- or -/+|