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Induction therapy for Philadelphia chromosome negative acute lymphoblastic leukemia in adults

Induction therapy for Philadelphia chromosome negative acute lymphoblastic leukemia in adults
Literature review current through: May 2024.
This topic last updated: Aug 23, 2022.

INTRODUCTION — Once the diagnosis of acute lymphoblastic leukemia (ALL) is established, induction chemotherapy is given with the following primary goals:

Rapid restoration of bone marrow function, using multiple chemotherapy drugs at acceptable toxicities, in order to prevent the emergence of resistant subclones.

Use of adequate initial and prophylactic treatment of sanctuary sites, such as the central nervous system (CNS), since CNS relapse is associated with a poor prognosis.

Induction therapy aims to reduce the total body leukemia cell population from approximately 1012 to below the cytologically detectable level of 5 percent blasts, which corresponds with a total load of about 109 cells. The remaining burden of leukemia cells (ie, measurable residual disease, MRD; also referred to as minimal residual disease) will lead to relapse if no further therapy is administered. Reducing the level of residual ALL in the bone marrow at the end of induction to <0.01 percent as measured by flow cytometry, has been shown to predict for better long-term outcomes.

The induction chemotherapy for adults with newly diagnosed ALL is reviewed here. The following related subjects are discussed separately:

The clinical and pathologic features, and diagnosis of ALL in adults (see "Clinical manifestations, pathologic features, and diagnosis of B cell acute lymphoblastic leukemia/lymphoma" and "Clinical manifestations, pathologic features, and diagnosis of precursor T cell acute lymphoblastic leukemia/lymphoma")

Post-remission therapy for ALL (see "Post-remission therapy for Philadelphia chromosome-negative acute lymphoblastic leukemia in adults")

Treatment of relapsed or refractory ALL (see "Treatment of relapsed or refractory acute lymphoblastic leukemia in adults")

Treatment of ALL in children (see "Treatment of acute lymphoblastic leukemia/lymphoma in children and adolescents")

Detection of MRD following treatment of ALL (see "Detection of measurable residual disease in acute lymphoblastic leukemia/lymphoblastic lymphoma" and "Clinical use of measurable residual disease detection in acute lymphoblastic leukemia")

Familial acute leukemia and myelodysplastic syndromes (see "Familial disorders of acute leukemia and myelodysplastic syndromes")

PRETREATMENT EVALUATION — In addition to a history and physical examination, it is our practice to perform the following pretreatment studies in patients with ALL:

Laboratory studies include a complete blood count with differential, chemistries with liver and renal function and electrolytes, glucose, lactate dehydrogenase (LDH), calcium, phosphorus, uric acid, albumin and total protein, and serology for hepatitis B, herpes simplex virus (HSV) and cytomegalovirus (CMV) infection. Human leukocyte antigen (HLA) typing should be performed for patients who are candidates for future hematopoietic cell transplantation (HCT). Females of child-bearing age should undergo a pregnancy test.

We routinely test thiopurine methyltransferase (TPMT) enzyme activity (phenotype) before starting 6-mercaptopurine (6-MP), and we use reduced doses for patients with low or absent activity. An acceptable alternative is to reserve testing for patients with unexpectedly severe or prolonged myelosuppression following 6-MP. TPMT genotype testing is not specifically recommended by the US Food and Drug Administration prior to treatment with 6-MP, and patients with normal TPMT status can still exhibit bone marrow and/or liver toxicity in a dose-related fashion. Some of this toxicity, especially in Eastern Asian and Hispanic patients, may be due to a variant in the NUDT15 gene [1]. (See "Overview of pharmacogenomics", section on 'Thiopurines and polymorphisms in TPMT and NUDT15'.)

Unilateral bone marrow aspiration and biopsy is recommended for all patients. This sample should be sent for pathologic review, immunophenotyping, cytochemistry, cytogenetics, and genetic profiling. Marrow aspirate or peripheral blood blasts should be sent for reverse transcriptase polymerase chain reaction (RT-PCR) analysis for BCR-ABL1 in order to rapidly identify Philadelphia chromosome positive ALL. If the bone marrow is not aspirable, RT-PCR can be performed on peripheral blood blast cells. In some centers, a fluorescence in situ hybridization (FISH) analysis aimed at excluding BCR-ABL1 can be performed rapidly. If a satisfactory aspirate for cytogenetics is not obtained, peripheral blood analysis for 11q23 abnormalities at least should be done using FISH analysis. While FISH studies for MLL rearrangements, ETV5/RUNX1, and trisomies 4, 10, and 17 are routinely performed in children, given their infrequent occurrence in older patients, these studies may not be necessary in adults with a good sample for metaphase cytogenetic analysis.

A chest radiograph, an electrocardiogram (EKG), and a study of cardiac function (eg, ejection fraction measured by echocardiogram or radionuclide ventriculography) should be performed at baseline, especially for patients with a cardiac history, prior anthracycline exposure, or cardiovascular symptoms.

Dental evaluation for possible infection foci is warranted [2].

Patients with neurologic signs or symptoms should undergo imaging studies to evaluate for meningeal disease, or central nervous system bleeding. Lumbar puncture is indicated in all patients to examine the cerebrospinal fluid (CSF) for leukemic involvement. Care must be taken to avoid contaminating the CSF specimen with peripheral blood if blasts are present. CSF should be sent for both cytology (examination of stained cytospin slides) and flow cytometry.

Central venous access must be placed. Two or three independent ports aid medical management of transfusions, chemotherapy, antibiotics, and other intravenous support. (See "Central venous access in adults: General principles".)

Individuals with child-bearing potential should receive counseling about the potential effect of treatment on their fertility and options for fertility-preserving measures. Given the urgent need for treatment, options for females are limited, but males can often participate in sperm banking. Typically, the drugs used to induce remission in ALL may not cause sterility in younger patients. (See "Fertility and reproductive hormone preservation: Overview of care prior to gonadotoxic therapy or surgery".)

The speed with which intensive remission induction chemotherapy should begin varies with the individual patient's condition and treatment options. In general, it is far more important to stabilize a patient's condition and correct or control comorbidities, such as infection, bleeding, hyperuricemia, dehydration, renal dysfunction, anemia, and thrombocytopenia, than it is to immediately start chemotherapy. Oral hydroxyurea or glucocorticoids can be used for cytoreduction of an elevated peripheral blast cell count while these problems are addressed. This interval of several days also allows for complete genetic screening where the results will have an impact on the choice of treatment.

CHEMOTHERAPY — Combination chemotherapy is the primary treatment modality for patients with ALL. Multiple induction regimens have been developed, most often based on pediatric regimens, but they have not been directly compared in a prospective randomized trial. As such, there is no single best regimen for induction therapy in ALL and patients should be encouraged to participate in clinical trials whenever possible.

These chemotherapy regimens have evolved empirically into complex schemes that use numerous agents in various doses, combinations, and schedules. Few of the individual components have been tested rigorously in randomized trials. Thus, it is difficult to critically analyze the absolute contribution of each drug or dose schedule to the ultimate outcome. Numerous non-randomized trials have attempted to answer these questions, but multiple alterations in study design between sequential trials have made it difficult to assess the exact merit of each modification.

Most chemotherapy regimens for ALL contain vincristine, a glucocorticoid (ie, prednisone or dexamethasone), and an anthracycline (table 1) [3-9]. In addition, some form of central nervous system (CNS) prophylaxis is incorporated. With these regimens, more than 80 percent of newly diagnosed adults with ALL enter complete remission (CR). Protocols that have added other agents (eg, cyclophosphamide, cytarabine, methotrexate, 6-mercaptopurine, etoposide and teniposide, or asparaginase) have not improved the CR rate; however, some have demonstrated a faster time to achievement of CR, which may be associated with prolonged remissions [10-12].

The following are examples of the most commonly used regimens:

Cancer and Leukemia Group B (CALGB) study 8811 or 9111 ALL regimen [13,14]

CALGB study 10403 ALL regimen for adolescents and young adults (AYA) [15]

Dana Farber Cancer Institute (DFCI) ALL Consortium study for patients 18 to 50 years old [16]

Standard or augmented Berlin-Frankfurt-Munster (BFM), which has been used by the Children's Cancer Group for children and adolescents [17]

Hyperfractionated cyclophosphamide, vincristine, doxorubicin and dexamethasone (hyper-CVAD) alternating with high-dose methotrexate and cytarabine [18]

French GRAALL 2003 regimen for younger adults [19]

French GRAALL 2005 regimen for adults up to 55 years old [20]

Details on these specific regimens are provided in the sections that follow. All patients with newly diagnosed ALL require induction chemotherapy with the goal of achieving a CR. Patients should be encouraged to participate in clinical trials whenever possible. If a clinical trial is not available or if the patient chooses not to participate in a clinical trial, any of the regimens above would be reasonable and a choice should be made based on the physician's comfort with administration. We typically use CALGB ALL clinical trial regimens at our institution.

There is interest in incorporating immunotherapy into frontline therapy, particularly for older patients who might not tolerate chemotherapy or for patients with measurable residual disease after induction despite a morphological CR. As an example, preliminary data using blinatumomab as a sole induction agent for patients older than 60 years have been reported in abstract form [21].

General considerations

Anthracyclines — Inclusion of an anthracycline in induction therapy achieves superior outcomes compared to the same regimen without an anthracycline. In CALGB 7612, addition of daunorubicin to a regimen that included vincristine, prednisone, and L-asparaginase for adults with ALL achieved superior rates of CR (83 versus 47 percent) and median remission duration (18 versus 5 months), when compared with those who did not receive daunorubicin [22]. Attempts have been made to escalate the dose of daunorubicin but any benefit has been balanced by greater toxicity [12]. Doxorubicin, daunorubicin, rubidazone, and mitoxantrone appear to produce comparable results [4,11,13,22-29].

Cyclophosphamide — A prospective trial that randomly assigned treatment of 778 adults with newly diagnosed ALL to receive induction therapy (vincristine, prednisone, daunorubicin, asparaginase) with or without a single dose of cyclophosphamide reported similar rates of CR (81 and 83 percent) and eight-year disease-free survival (DFS; 34 and 31 percent) [26]. Other trials that have investigated the addition of cyclophosphamide into the treatment regimen of ALL have suggested that cyclophosphamide may increase the rapidity with which CR is achieved and may increase remission duration. Two sequential cooperative group trials involving 379 adults reported a similar CR rate (85 percent) and a median remission duration of 28 months [30]. However, the median remission duration varied according to the rapidity of CR attainment, being 34 months for the 237 patients who achieved CR within 30 days, compared with 20 months for the 88 patients who required more than 30 days to enter into remission.

Asparaginase — For adults, asparaginase is a component of CALGB, DFCI, BFM, GRAALL 2003 and 2005, and modified hyper-CVAD regimens; it is not included in the standard hyper-CVAD regimen.

Asparaginase is a key component of the ALL regimens for children leading to superior CR and DFS rates [23,31]. The importance of asparagine depletion in adults was illustrated in a prospective study of pegylated asparaginase that demonstrated a significant improvement in median overall survival (OS; 31 versus 13 months) in those patients who achieved plasma asparagine depletion [32]. Further support comes from pediatric trials that suggest that clinical outcomes improve as the period of complete asparagine depletion in the plasma increases. Protocols for adults must balance the desire to achieve maximum asparagine depletion with the understanding that prolonged depletion is difficult for most adults to tolerate. Asparaginase can be associated with allergic reactions, coagulopathies, acute pancreatitis, and increased liver transaminases [33]. Asparaginase induces a hypercoagulable state that can result in catastrophic thrombosis of the inferior vena cava or the superior sagittal sinus in addition to deep vein thromboses of the legs or arms. In addition, adults receiving asparaginase commonly develop fatigue, anorexia, confusion, and listlessness. Infusion reactions to and thrombosis with asparaginase are discussed separately. (See "Infusion reactions to systemic chemotherapy", section on 'Asparaginase' and "Antithrombin deficiency", section on 'Patients receiving asparaginase'.)

Pegylated asparaginase has become the preferred preparation for most circumstances because it appears to be less immunogenic while providing equal or greater efficacy compared with the other formulations [32,34-37]. Patients who receive pegylated asparaginase appear to be less likely to develop antibodies that increase clearance of asparaginase from the circulation and may reduce efficacy [38-45].

Our suggestions for treatment with asparaginase follow:

Pegylated asparaginase – Reasonable schedules for pegaspargase (pegylated Escherichia coli asparaginase) are:

2000 units/m2 every two weeks

1000 units/m2 weekly

The half-life of pegaspargase is approximately six days. These doses should result in asparagine depletion in most adults for a two-week period. Generally, this is intercalated between courses of more cytotoxic therapy or the combination of vincristine plus glucocorticoids. The dose is often capped in larger adults at 3750 units total (one vial). Older patients have had fewer adverse events when lower doses were used.

Another pegylated asparaginase formulation, calaspargase pegol, enables a longer interval between doses compared to pegaspargase. Calaspargase pegol is approved by the US Food and Drug Administration (FDA) for treatment of ALL in patients 1 month to 21 years. Approval was based on maintenance of nadir serum asparaginase activity >0.1 units/mL using calaspargase pegol 2500 units/m2 intravenously every three weeks [46].

Non-pegylated preparations – Non-pegylated asparaginase preparations are more immunogenic and require more frequent administration.

Non-pegylated products include:

Native E. coli asparaginase - Not available in the United States; half-life is approximately one day. The dose of L-asparaginase ranges from 6000 units/m2 (in the CALGB regimen) to a fixed dose of 20,000 units (in the modified hyper-CVAD regimen) [15,47]. Frequency of administration depends on the regimen and ranges from daily to every three to four days, while it is given weekly in the modified hyper-CVAD regimen.

Erwinia asparaginase – Not available in the United States. Half-life is approximately 8 hours when given intravenously and 16 hours when given intramuscularly. A typical regimen is 25,000 units/m2 administered three times weekly.

Recombinant Erwinia asparaginase – Approved by the US FDA for patients with hypersensitivity to E. coli asparaginase. It is also useful for patients with allergic reactions to PEG. Half-life is approximately 14 hours. Dosing regimens include 25 mg/m2 administered every 48 hours or 25 mg/m2 on Monday and Wednesday and 50 mg/m2 on Friday.

In many patients who develop antibodies to asparaginase, serum drug levels are non-detectable or minimal, which suggests that there is no active drug available. If asparaginase levels are non-detectable with one preparation, an alternative preparation may be more effective. The best time to measure asparaginase activity depends on the formulation, dosing, and schedule of asparaginase used. As an example, when using pegylated asparaginase, asparaginase activity is measured 7 and 14 days after the first dose during induction and seven days following every reintroduction after a break in asparaginase treatment [48]. A level below 0.1 international units (IU)/mL on day 7 and/or undetectable levels on day 14 are consistent with silent inactivation. We incorporate routine antibody monitoring in our practice, but this practice is not widespread.

Because of the relatively high incidence of infusion reactions, asparaginase should only be administered in a setting where anaphylaxis can be appropriately managed. Subcutaneous or intramuscular administration appears less likely to cause anaphylactic reactions than intravenous dosing. Premedication with glucocorticoids is helpful. Patients who develop an anaphylactic reaction to one preparation may be considered for treatment with another preparation. This is discussed in more detail separately. (See "Infusion reactions to systemic chemotherapy", section on 'Asparaginase'.)

Choice of glucocorticoid — Dexamethasone is the glucocorticoid that is most often used, but the optimal glucocorticoid, dose, and schedule for adults is not well defined. Historically, prednisone was incorporated most ALL induction regimens, but dexamethasone penetrates the blood-brain barrier more effectively. In children, patients treated with dexamethasone have lower rates of relapse and fewer thrombotic complications than those treated with prednisone [49-54]. On the other hand, dexamethasone has not demonstrated a survival benefit and is associated with a higher rate of avascular necrosis of hips and shoulders, which is seen commonly in adolescents and young adults than in younger children.

Addition of rituximab for CD20+ ALL — For younger adults (<60 years of age) with CD20-positive ALL, we suggest the addition of rituximab to standard induction regimens. Rituximab appears to improve outcomes for younger adults with CD20-positive ALL, based on non-randomized and randomized studies in which rituximab was added to hyper-CVAD, BFM, and GRAALL regimens. The benefit of rituximab in older patients with ALL is not proven.

A single center study reported superior survival rates for adults <60 years with de novo Philadelphia chromosome negative precursor B cell ALL treated with a modified hyper-CVAD regimen plus rituximab when compared with historical controls treated with standard hyper-CVAD without rituximab [47]. In contrast, older adults (≥60 years) did not appear to benefit from the addition of rituximab. The GMALL study group subsequently evaluated 196 standard-risk patients and 67 high-risk patients and reported that those cohorts that had received rituximab with chemotherapy had significantly higher molecular remission rates and longer OS [55,56].

In a multicenter randomized trial, 209 adults with previously untreated CD20-positive, Philadelphia chromosome negative, precursor B cell ALL were randomly assigned to the pediatric inspired GRAALL regimen with or without the addition of 16 to 18 infusions of rituximab spanning induction through maintenance [57]. Although the arms were well balanced for known risk factors, a higher percentage of patients treated with rituximab received an allogeneic hematopoietic cell transplantation (HCT) in first CR (34 versus 20 percent). At a median follow-up of 30 months, the addition of rituximab resulted in:

Similar complete response rates (92 versus 90 percent).

No difference in non-relapse mortality at two years (12 versus 12 percent).

Lower cumulative incidence of relapse at four years (25 versus 41 percent).

Longer event-free survival (EFS; 55 versus 43 percent at four years; HR 0.52; 95% CI 0.31-0.89).

No statistically significant difference in OS (61 versus 50 percent at four years; HR 0.70; 95% CI 0.46-1.07) among the group overall. When patients who received allogeneic transplant in first CR were censored at the time of transplant, OS was improved in the rituximab arm (HR 0.55; 95% CI 0.34-0.91).

Ofatumumab is another anti-CD20 monoclonal antibody that has been safely administered with chemotherapy for Philadelphia chromosome negative ALL [58].

CNS prophylaxis — The exact risk of CNS involvement for ALL is difficult to ascertain, because all current treatment regimens include CNS prophylaxis. ALL has a high risk of CNS involvement with some studies reporting rates as high as 78 percent at some point in the disease course in patients not given CNS prophylaxis [59-61]. This rate appears to decrease to less than 20 percent when CNS prophylaxis is routinely administered. Less than 10 percent of patients will have CNS involvement at the time of diagnosis.

The method of CNS prophylaxis used should be consistent with that included in the prospective studies investigating the particular treatment regimen chosen (eg, intrathecal methotrexate plus cranial irradiation or intrathecal therapy plus high-dose methotrexate) [62]. The treatment of central nervous system involvement at diagnosis is discussed below. (See 'Central nervous system involvement' below.)

CALGB 8811/9111 ALL regimen — The Cancer and Leukemia Group B (CALGB) 8811/9111 ALL regimen uses a five-drug combination modified from regimens used for high-risk pediatric ALL [13,14]. Treatment is given in five courses that span 24 months.

A phase II multicenter prospective clinical trial was performed in 197 patients with newly diagnosed ALL (age 16 to 80; median age 32) [13]. CR was obtained in 85 percent; 7 percent were refractory and 9 percent died during induction. After a median follow-up of 43 months, the median survival was 36 months and the median remission duration was 29 months. Severe (grade 3/4) toxicities included leukopenia (98 percent), thrombocytopenia (94 percent), anemia (65 percent), infection (54 percent), and increased transaminases (25 percent). There were eight episodes of clinically significant pancreatitis. Most deaths were related to gram-negative bacteremia or fungemia in older patients.

In CALGB 9111, 198 adults with untreated ALL (median age, 35 years; range, 16 to 83) were randomly assigned to receive either placebo or G-CSF (5 mg/kg/d) subcutaneously, beginning four days after starting intensive remission induction chemotherapy and continuing until the neutrophil count was >1000/microL for two days [14]. Patients initially assigned to G-CSF then continued to receive G-CSF through two monthly courses of consolidation therapy. Compared to the patients assigned to placebo, patients who received G-CSF had a higher rate of CR and fewer deaths during remission induction, shorter median time to recover neutrophils >1,000/microL (16 versus 22 days), shorter durations of neutropenia and thrombocytopenia, and fewer days in the hospital (median, 22 versus 28 days). However, after a median follow-up of 4.7 years, there were no significant differences in either the DFS or OS.

CALGB 10403 regimen — To address the feasibility and efficacy of using a pediatric treatment regimen for AYA patients with newly diagnosed B cell and T cell ALL administered by adult treatment teams, a prospective study, CALGB 10403, used the identical doses and schedule in the Children's Oncology Group study AALL0232 [15]. Among the 295 eligible and evaluable patients, the median age was 24 years (range, 17 to 39). Use of the pediatric regimen was safe; overall treatment-related mortality was 3 percent and there were only two post-remission deaths. The median EFS is 78.1 months (95% CI 41.8-not reached), which was more than double the historical control of 30 months (95% CI 22-38 months). Rates of estimated three-year OS were 73 percent (95% CI 68-78 percent) and EFS 59 percent (95% CI 54-65 percent); median OS was not reached after follow-up of 64 months. Pretreatment risk factors associated with worse treatment outcomes included obesity and the presence of the Philadelphia-like gene expression signature.

BFM regimen — The Berlin-Frankfurt-Munster (BFM) regimen is frequently used for the treatment of pediatric ALL and can be considered for young adults with a good performance status. There are two basic versions: the standard BFM regimen and a more intensive "augmented BFM" regimen. Both versions include the same induction therapy that consists of vincristine, daunorubicin, prednisone, asparaginase, intrathecal cytarabine, and intrathecal methotrexate.

A retrospective comparison of 321 adolescents (age 16 to 20 years) with newly diagnosed ALL reported that patients treated by the Children's Cancer Group (CCG) using BFM had superior rates of seven-year EFS (63 versus 34 percent) and OS (67 versus 46 percent) when compared with those treated by the CALGB using the CALGB ALL regimen [17]. Patients receiving BFM received more intensive central nervous system prophylaxis and higher doses of non-myelosuppressive agents. (See 'Young adults/adolescents' below.)

A retrospective single institution study of standard or augmented BFM in 29 adults (age 19 to 70) with newly diagnosed ALL reported a CR rate of 93 percent [63]. At a median follow-up of 6.7 years, rates of five-year EFS were 39 and 50 percent for patients who received standard and augmented BFM, respectively. There were two toxic deaths. The most common non-hematologic toxicities were infections (89 percent severe) and sensory neuropathy (mostly mild).

Hyper-CVAD — The combination of hyperfractionated cyclophosphamide, vincristine, doxorubicin and dexamethasone (hyper-CVAD) alternating with high-dose methotrexate and high-dose cytarabine has also been used in adults with ALL [18,64-67]. This regimen includes a risk-stratified schedule of central nervous system prophylaxis with intrathecal methotrexate and intrathecal cytarabine. The dose-intensive phase spans six to seven months and is followed by 24 to 30 months of maintenance therapy.

A prospective trial of a hyper-CVAD-based regimen in 204 patients with newly diagnosed ALL (median age 39) reported a 91 percent CR rate and 6 percent mortality rate during induction [18]. Five-year OS was 39 percent. Severe, prolonged myelosuppression was universal. Median times to granulocyte and platelet recovery were 18 and 21 days, respectively. Common toxicities included infection (55 percent), fever of unknown origin (45 percent), neurotoxicity (6 percent), moderate to severe mucositis (6 percent), moderate to severe diarrhea (3 percent), ileus (2 percent), and disseminated intravascular coagulation (2 percent).

Further follow-up (median of 63 months) of 288 patients with newly diagnosed ALL treated with this hyper-CVAD-based regimen reported a CR rate of 92 percent and five-year OS rates of 38 percent [66]. Induction mortality varied with patient age being 2 and 15 percent for patients <60 or ≥60 years of age, respectively.

Additional studies have continued to modify the hyper-CVAD regimen further for certain patient populations. As an example, one study using historical controls reported that the addition of rituximab to the hyper-CVAD regimen resulted in superior survival rates in younger patients with ALL that expressed CD20 [47]. There was no benefit for older patients. (See 'Addition of rituximab for CD20+ ALL' above.)

For older adults, the doses of the chemotherapy drugs have been reduced in the mini-hyperCVD regimen, and the doxorubicin has been eliminated [68].

GRAALL 2003 regimen — The GRAALL-2003 regimen is another pediatric-inspired therapy that includes remission induction with high doses of prednisone, vincristine, and asparaginase in combination with daunorubicin, cyclophosphamide, and intrathecal methotrexate [19].

A phase II trial of GRAALL 2003 in 225 adults patients (median age 31 years) with Philadelphia chromosome negative ALL reported a CR rate of 94 percent [19]. Severe (grade 3/4) non-hematologic toxicities during induction included liver toxicity (20 percent), thromboembolism (4 percent), intolerance to asparaginase (2 percent), and peripheral neuropathy (1 percent). There were 14 deaths during induction due to sepsis (nine patients), stroke (four patients), and liver failure (one patient). Estimated EFS and OS rates at 42 months were 55 and 60 percent, respectively. In an exploratory subgroup analysis, patients over the age of 45 years had a similar incidence of relapse (30 versus 32 percent), but significantly higher rates of chemotherapy-related deaths (23 versus 5 percent) and deaths during first CR (22 versus 5 percent) when compared with patients 45 years or younger.

A separate phase II trial evaluated a modified GRAALL 2003 in 148 adults with lymphoblastic lymphoma (LL) [69]. Induction mortality was 3 percent. Among the 131 patients with T-lineage LL, 91 percent achieved a CR and the estimated EFS and OS rates at three years were 63 and 69 percent, respectively. Among the 17 patients with B-lineage LL, 76 percent achieved a CR. Survival rates could not be estimated due to the small numbers of B-lineage LL.

Based on these phase II trials, the GRAALL 2003 regimen appears to be an acceptable treatment option for young adults with newly diagnosed ALL or LL. However, treatment-related toxicities limit its use in patients over the age of 45 years.

GRAALL 2005 regimen — In this large prospective trial, 787 evaluable patients (525 B cell and 262 T cell) with a median age of 36.1 years (range, 18 to 59 years) were randomly assigned to receive a standard dose of cyclophosphamide or hyperfractionated cyclophosphamide during first induction and late intensification, in addition to the previous GRAALL 2003 chemotherapy backbone. Overall CR rate was 92 percent. With a median follow-up of 5.2 years, the five-year rate of EFS and OS rates were 52 percent (95% CI 48.5-55.7 percent) and 59 percent (95% CI 55-62 percent), respectively. Randomization to the hyperfractionated cyclophosphamide arm did not increase the CR rate or prolong EFS or OS. Overall, tolerability of this intensive pediatric-derived treatment was poor in patients >55 years of age [20].

MONITORING DURING TREATMENT — Chemotherapy for ALL is highly toxic, primarily to the hematopoietic system. Most patients will require hospitalization with blood product support, but selected patients may be treated as outpatients. Daily laboratory testing should be performed and generally includes a complete blood count and chemistries with renal function, glucose, and electrolytes. Calcium, phosphorus, and uric acid levels should be monitored until normal. Liver function tests should be assessed at least weekly.

Asparaginase activity levels are used to monitor for silent inactivation in patients receiving regimens that contain asparaginase. (See 'Asparaginase' above.)

If there is unexpectedly severe or prolonged myelosuppression in patients taking 6-mercaptopurine or 6-thioguanine, the medication should be stopped and a genetic analysis obtained for determining thiopurine methyltransferase activity. (See "Overview of pharmacogenomics", section on 'Thiopurines and polymorphisms in TPMT and NUDT15'.)

SUPPORTIVE CARE — Supportive care is a critical component to the treatment of patients with acute leukemia. Toxicity can result from the chemotherapy or from the rapid elimination of a large tumor burden (ie, tumor lysis syndrome). Life-threatening adverse effects of induction therapy include tumor lysis syndrome, thrombosis, bleeding, infection, renal failure, and anaphylaxis. Other acute side effects include mucositis, pancreatitis, acute liver failure, hypertriglyceridemia, and hyperglycemia.

Tumor lysis syndrome – Tumor lysis syndrome is an oncologic emergency caused by massive tumor cell lysis and the release of large amounts of potassium, phosphate, and uric acid into the systemic circulation. Deposition of uric acid and/or calcium phosphate crystals in the renal tubules can result in acute kidney injury. There is significant risk of tumor lysis syndrome in patients treated for ALL. Preventative measures incorporate aggressive intravenous hydration, allopurinol or rasburicase, and correction of any prior electrolyte disturbances and elements of reversible renal failure. For patients presenting with very high white blood cell counts, a three- to seven-day "prophase" with glucocorticoids and cyclophosphamide can often debulk the tumor and reduce the likelihood that tumor lysis syndrome will occur when the intensive multiagent induction therapy begins. (See "Tumor lysis syndrome: Prevention and treatment".)

Thrombosis – The use of thrombosis prophylaxis is controversial, although venous thrombosis is a recognized complication of asparaginase therapy due to its effect on reducing anticoagulants such as antithrombin III, protein C, and protein S. We aim to keep the fibrinogen level >100 mg/dL using infusions of cryoprecipitate. Antithrombin infusions have also been used in an attempt to reduce deep venous thrombosis (DVT) [70]. DVT of the legs or inferior vena cava and pulmonary embolism can occur. Intracranial thrombosis (eg, dural sinus thrombosis) is uncommon but most serious and may also be complicated by hemorrhage. Presenting findings of dural sinus thrombosis may include headache, focal neurologic findings, or encephalopathy. Appropriate laboratory testing and neuroimaging are presented separately. (See "Antithrombin deficiency", section on 'Patients receiving asparaginase' and "Cerebral venous thrombosis: Etiology, clinical features, and diagnosis", section on 'Diagnosis'.)

Anemia and thrombocytopenia – All patients will develop anemia and thrombocytopenia requiring transfusion support.

In general, we transfuse packed red blood cells to all symptomatic patients with anemia or any asymptomatic patient with a hemoglobin ≤7 to 8 g/dL. We aim to maintain the hemoglobin between 8 and 9 g/dL, depending on the patient's age, symptoms, and comorbid conditions. (See "Indications and hemoglobin thresholds for RBC transfusion in adults".)

We transfuse platelets prophylactically for patients with platelet counts <10,000/microL or to any patient with signs of overt bleeding, such as oral purpura. For non-bleeding patients with platelet counts <10,000/microL, prophylactic transfusion of multiple platelet units beyond a single plateletpheresis unit is not beneficial [71]. (See "Platelet transfusion: Indications, ordering, and associated risks", section on 'Leukemia, chemotherapy, and HSCT'.)

Blood products should be leukoreduced to reduce the risk of febrile non-hemolytic transfusion reactions (FNHTR). Irradiation is essential for hematopoietic cell transplant (HCT) candidates to prevent transfusion-associated graft-versus-host disease (ta-GVHD). Cytomegalovirus (CMV)-negative patients who are HCT candidates should receive CMV-negative blood products. (See "Practical aspects of red blood cell transfusion in adults: Storage, processing, modifications, and infusion", section on 'Pre-storage leukoreduction' and "Transfusion-associated graft-versus-host disease".)

Infections – The prolonged period of neutropenia associated with chemotherapy in patients with ALL is frequently associated with neutropenic fevers and a high risk of infection with bacteria or fungi and viral reactivation. In order to minimize the risk of infection, patients are typically placed on "neutropenic precautions" with or without the addition of prophylactic antibiotics, antifungals, and/or antivirals. Patients who develop neutropenic fever require prompt evaluation and immediate administration of parenteral antibiotics tailored to the predominant organisms and resistance patterns of the institution. (See "Treatment of neutropenic fever syndromes in adults with hematologic malignancies and hematopoietic cell transplant recipients (high-risk patients)" and "Prophylaxis of infection during chemotherapy-induced neutropenia in high-risk adults" and "Hepatitis B virus reactivation associated with immunosuppressive therapy".)

Anaphylaxis – Some chemotherapy and supportive medications, such as asparaginase, the epipodophyllotoxins (etoposide and etopophosphamide), rituximab, and rasburicase, can cause significant allergic reactions, including anaphylaxis. Medications used to treat anaphylaxis should be readily available when these drugs are administered. Anaphylactic reactions to PEG-asparaginase can be delayed by several hours. Because of this delay, a period of observation following administration of PEG-asparaginase has become common practice at many institutions. (See "Infusion reactions to systemic chemotherapy", section on 'Asparaginase'.)

Hepatotoxicity – Abnormal liver function tests in patients with ALL can be a result of leukemic infiltration, medications (eg, asparaginase, antifungals), infections (eg, hepatitis reactivation), and comorbidities. Asparaginase can be associated with increases in serum transaminases, alkaline phosphatase, bilirubin, and triglycerides. Patients with hepatosteatosis (eg, from diabetes) may be at increased risk for hepatotoxicity from asparaginase.

Hyperglycemia and acute pancreatitis – Acute pancreatitis is seen in 5 percent of adults receiving asparaginase, while hyperglycemia related to the use of asparaginase and glucocorticoids is seen in approximately 25 percent [72,73]. In most cases of hyperglycemia, blood glucose can be regulated with insulin and asparaginase continued. Asparaginase is usually continued in the setting of asymptomatic pancreatitis identified only by laboratory or radiologic findings. In contrast, asparaginase is discontinued in the setting of clinical pancreatitis (eg, vomiting, severe abdominal pain, and elevated amylase or lipase).

EVALUATION OF RESPONSE — The initial response to treatment is typically evaluated with a unilateral bone marrow aspirate and biopsy once adequate values for absolute neutrophil count (>1000/microL) and platelet count (>100,000/microL) are obtained. A core biopsy is required to assess marrow cellularity.

The primary goal of ALL therapy is achievement of an initial complete remission (CR), defined as the eradication of all detectable leukemia cells (less than 5 percent blasts) from the bone marrow and blood and the restoration of normal hematopoiesis (>25 percent cellularity and normal peripheral blood counts). The importance of achieving a CR was shown in the International ALL trial; patients achieving or not achieving CR had overall survival rates of 45 versus 5 percent, respectively [10]. However, once a CR is achieved, therapy must continue for an extended period of time to eliminate subclinical disease (measurable residual disease, MRD; also referred to as minimal residual disease) known to contribute to relapse. (See "Post-remission therapy for Philadelphia chromosome-negative acute lymphoblastic leukemia in adults".)

While CR has historically been defined based upon morphologic criteria, an assessment of MRD using immunological or molecular techniques can better define prognosis [74]. Patients who become MRD negative have had better outcomes than those who remain MRD positive [75]. As yet, prospective studies have not demonstrated that altering therapy based on evidence of MRD leads to a better outcome, but decisions regarding allogeneic transplantation in first remission are now largely based on MRD status [76]. (See "Detection of measurable residual disease in acute lymphoblastic leukemia/lymphoblastic lymphoma" and "Clinical use of measurable residual disease detection in acute lymphoblastic leukemia".)

Patients who do not achieve a CR with initial induction therapy are considered to have resistant disease. Early allogeneic transplantation can rescue some of these patients. (See "Treatment of relapsed or refractory acute lymphoblastic leukemia in adults".)

POST-REMISSION TREATMENT — Attainment of a CR is the first step in the treatment of ALL. However, relapse can be expected in the following weeks to months if no further therapy is given. Post-induction therapy is an essential component of the treatment of ALL. This is presented separately. (See "Post-remission therapy for Philadelphia chromosome-negative acute lymphoblastic leukemia in adults".)

SPECIAL SCENARIOS — There are a number of high-risk ALL variants that may require special treatment programs. Some of these are listed below.

Philadelphia chromosome positive ALL — Patients with ALL who demonstrate the Philadelphia chromosome (Ph+) or its gene fusion product (BCR-ABL1) should be treated with a regimen that incorporates a tyrosine kinase inhibitor, as discussed separately. (See "Induction therapy for Philadelphia chromosome positive acute lymphoblastic leukemia in adults" and "Philadelphia chromosome-positive acute lymphoblastic leukemia in adults: Post-remission management".)

Ph-like ALL — Philadelphia chromosome (Ph)-like ALL is a high-risk subtype with a gene-expression profile similar to that of BCR-ABL1-positive ALL but lack the BCR-ABL1 fusion gene [77-79]. Genetic alterations targeting B-lymphoid transcription factors, including IKZF1 (Ikaros) are common. The prevalence of Ph-like ALL rises from 10 percent in standard-risk childhood ALL to more than 25 percent in adolescents and young adults (AYA) (21 to 39 years) and adults (>40 years). Among 148 patients with newly diagnosed B cell ALL who received frontline chemotherapy at MD Anderson Cancer Center and underwent gene expression profiling of leukemic cells, 33 percent had Ph-like, 31 percent had Ph+, and 36 percent had other B-ALL subtypes. Within the Ph-like ALL cohort, 61 percent had cytokine receptor-like factor 2 (CRLF2) overexpression. Patients with Ph-like ALL had significantly worse overall survival (OS) and event-free survival (EFS) compared with other non-Ph+ ALL with a five-year survival of 23 versus 59 percent. Sixty-eight percent of patients with Ph-like ALL were of Hispanic ethnicity. Next-generation sequencing of the CRLF2+ group identified mutations in the JAK-STAT and RAS pathways in 85 percent of patients, and 20 percent had a CRLF2 mutation. Within the CRLF2+ group, JAK2 mutation was associated with inferior outcomes. The majority of kinase alterations in Ph-like ALL can be targeted with either ABL or JAK inhibition, and these trials are underway [80].

Central nervous system involvement — The exact risk of central nervous system (CNS) involvement for ALL is difficult to ascertain, because all current treatment regimens include CNS prophylaxis. ALL has a high risk of CNS involvement with some studies reporting rates as high as 78 percent at some point in the disease course in patients not given CNS prophylaxis [59-61]. This rate appears to decrease to less than 20 percent when CNS prophylaxis is routinely administered. Less than 10 percent of patients will have CNS involvement at the time of diagnosis.

CNS leukemia is defined by the presence of leukemic blasts in a centrifuged preparation of cerebrospinal fluid (CSF) that does not have evidence of blood contamination [62]. While the ideal treatment of patients with CNS involvement at the time of diagnosis is unknown, these patients are felt to be at higher risk for relapse. Cranial irradiation plus intrathecal chemotherapy has been the mainstay of treatment of overt CNS involvement [81]. Typically, 2400 cGy of radiation is given to the entire cranium over 12 doses. In addition, at least six doses of intrathecal methotrexate should be administered. (See "Treatment of leptomeningeal disease from solid tumors".)

It is not clear if patients who present with CNS involvement require more intensive therapy, such as allogeneic hematopoietic cell transplantation, after clearing of their CNS disease.

An exploratory subgroup analysis of 48 patients with CNS disease at presentation cleared with CNS-directed therapy reported outcomes similar to those for the over 700 patients without CNS disease at presentation [82].

A prospective, international trial designed to evaluate the role of HCT in newly diagnosed adult ALL performed an exploratory subset analysis on the 77 of 1508 total patients (5 percent) that had CNS involvement at diagnosis [83]. Sixty-nine of the 77 patients (90 percent) attained a complete response (CR). Post-remission therapy included allogeneic hematopoietic cell transplantation (HCT; 30 patients), autologous HCT (six patients), and chemotherapy (27 patients). Thirteen of 30 patients (43 percent) that went on to allogeneic HCT and 7 of the 27 patients (26 percent) treated with chemotherapy alone were alive after follow-up that ranged from 21 to 137 months.

T cell lymphoblastic lymphoma/T cell ALL/LBL — Biologically, T cell lymphoblastic lymphoma (LBL) and T cell ALL appear to be a single disease; by convention, T cell ALL has greater than 25 percent blasts in the marrow or blasts in the blood. Patients with T cell lineage ALL/LBL are generally treated with the same regimens as those used for B cell lineage ALL/LBL. Often, these are young males with mediastinal lymphadenopathy. The initial white blood cell count may be markedly elevated, but this does not have the same poor prognostic importance in T cell ALL/LBL as does hyperleukocytosis in precursor B cell ALL/LBL. There is a high incidence of CNS involvement so prophylaxis is routine even for limited stage T-lymphoblastic lymphoma cases with no visible involvement of the blood or marrow. (See "Clinical manifestations, pathologic features, and diagnosis of precursor T cell acute lymphoblastic leukemia/lymphoma".)

In a study from the German Multicenter Group for Adult ALL/LBL, 45 patients with T cell lymphoblastic lymphoma/T cell ALL/LBL were treated with a regimen designed for adult ALL/LBL, which included an eight-drug standard induction regimen, prophylactic cranial and mediastinal irradiation, followed by consolidation and reinduction therapy [84]. Total treatment time was 6 to 12 months, with a CR rate of 93 percent; estimated disease-free survival (DFS) at seven years was 62 percent. The majority of relapses occurred in the mediastinum (47 percent) despite 24 Gy of irradiation in six of seven patients. Neither stage, nor age, nor lactate dehydrogenase (LDH) had an influence on outcome.

In the Italian GIMEMA 0288 trial, one of the largest adult ALL/LBL trials to date, 778 patients were randomly assigned to receive induction therapy (vincristine, prednisone, daunorubicin, asparaginase) with or without a single dose of cyclophosphamide [26]. The rates of initial CR and continuous CR at eight years were similar in the two arms, being 81 versus 83 percent and 34 versus 31 percent for the five-drug versus the four-drug combination, respectively [26].

Complete remission rates for B-lineage ALL/LBL (precursor B ALL/LBL), T-lineage ALL/LBL (precursor T ALL/LBL), and ALL/LBL with co-expression of myeloid markers were 83, 85, and 71 percent, respectively, while OS rates at eight years were similar at 30, 27, and 26 percent, respectively. A discussion of the differences among these disease variants can be found elsewhere. (See "Clinical manifestations, pathologic features, and diagnosis of B cell acute lymphoblastic leukemia/lymphoma" and "Clinical manifestations, pathologic features, and diagnosis of precursor T cell acute lymphoblastic leukemia/lymphoma".)

Burkitt-type ALL-L3 — The recommended treatment for Burkitt-type ALL, a highly aggressive non-Hodgkin lymphoma variant, is discussed in detail separately. (See "Treatment of Burkitt leukemia/lymphoma in adults".)

Young adults/adolescents — Patients diagnosed with ALL between the ages of 16 and 21 are a special group in that they may be treated by either adult or pediatric hematologists [85]. The NIH has expanded the age range for AYA patients from 16 to 39 years old. Some but not all retrospective comparative analyses have reported that young adults/adolescents with ALL treated on pediatric protocols demonstrate superior EFS and OS rates when compared with similar patients enrolled on adult ALL protocols [17,86-92]. Accordingly, a number of prospective trials are evaluating the outcomes of young adults when treated by adult hematologists using pediatric regimens [93-95]. Preliminary data suggest that pediatric regimens can be used without excess toxicity in younger adults up to 50 years old [19,69,96]. (See 'CALGB 10403 regimen' above.)

Older or medically unfit adults — Older adults (ie, older than 55 or 65 years) or less medically-fit patients (eg, multiple comorbid conditions) may be unable to tolerate the intensive, multiagent chemotherapy regimens described above [97]. A comprehensive geriatric assessment can be useful in assessing comorbidity and functional status, thereby aiding in the formulation of an appropriate, individualized treatment plan. Special considerations for the use of chemotherapy in the older adult population are discussed separately. (See "Comprehensive geriatric assessment for patients with cancer" and "Systemic chemotherapy for cancer in older adults".)

Treatment with lower-intensity regimens may be tolerated in older or less-fit patients with Philadelphia chromosome negative ALL. Examples of regimens include asparaginase, vincristine, and an anthracycline at reduced doses [98] and treatment with blinatumomab induction therapy followed by POMP (prednisone, vincristine, methotrexate, mercaptopurine) [21].

Outcomes are worse for older or less fit adults than for younger adults. As an example, a post hoc analysis compared the outcomes of 100 older adults (age 55 to 65 years) to those of 1814 younger patients (age 14 to 54 years) treated on a prospective trial of intensive chemotherapy in patients with newly diagnosed ALL [99]. At five years, compared with the younger cohort, older adults had lower rates of CR (73 versus 93 percent), OS (21 versus 41 percent), and EFS (19 versus 37 percent).

Patients with Down syndrome — Patients with Down syndrome who develop ALL have more treatment-related complications, including an increased frequency and severity of infections and mucositis [100]. Although this increased sensitivity relates to numerous chemotherapy agents, such patients have a particular sensitivity to methotrexate [101,102]. As an example, a retrospective analysis of 131 children with ALL (44 of whom also had Down syndrome) receiving methotrexate demonstrated that children with Down syndrome had significantly higher rates of severe (grade 3/4) mucositis (26 versus 4 percent) [103]. There was also a trend toward an increased rate of leukopenia (23 versus 10 percent of courses). There did not appear to be a difference in pharmacokinetics between the two populations in this study. However, other studies have suggested that an increased rate of methotrexate toxicity in this population may be due to increased activity of the reduced folate carrier gene on chromosome 21, which enhances the intracellular transport of methotrexate [104]. In addition, the increased rate of infections may be due to a higher incidence of hyperglycemia among patients with Down syndrome treated with glucocorticoids [105,106]. They also have an increased risk of developing cardiotoxicity after treatment with anthracyclines [107,108]. (See "Acute lymphoblastic leukemia/lymphoblastic lymphoma: Outcomes and late effects of treatment in children and adolescents".)

Mixed-phenotype acute leukemia — Mixed-phenotype acute leukemia (MPAL) is a rare entity accounting for less than 5 percent of acute leukemias [109]. Diagnosis and management of MPAL is discussed separately. (See "Mixed phenotype acute leukemia".)

CLINICAL TRIALS — Often there is no better therapy to offer a patient than enrollment onto a well-designed, scientifically valid, peer-reviewed clinical trial. Additional information and instructions for referring a patient to an appropriate research center can be obtained from the United States National Institutes of Health (www.clinicaltrials.gov).

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Acute lymphoblastic leukemia".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient education" and the keyword(s) of interest.)

Basics topics (see "Patient education: Acute lymphoblastic leukemia (ALL) (The Basics)" and "Patient education: Leukemia in adults (The Basics)")

Beyond the Basics topics (see "Patient education: Acute lymphoblastic leukemia (ALL) treatment in adults (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS

Once the diagnosis of acute lymphoblastic leukemia/lymphoma (ALL) is established, induction chemotherapy is given with the goal of rapidly restoring bone marrow function and attaining a complete remission (CR). Combination chemotherapy is the primary treatment modality for patients with ALL. There is no role for surgery or total body radiation therapy in the induction phase. (See 'Chemotherapy' above.)

Multiple induction regimens have been developed, most often based on pediatric regimens. None have been directly compared in a prospective randomized trial. As such, there is no single best regimen for induction therapy in ALL, and patients should be encouraged to participate in clinical trials whenever possible.

If a clinical trial is not available or if the patient chooses not to participate in a clinical trial, any of the following regimens would be reasonable and a choice should be made based upon the patient's age and performance status and the physician's comfort with administration:

Cancer and Leukemia Group B (CALGB) ALL regimen

CALGB 10403 regimen for adolescent and young adult patients with ALL

Dana Farber Cancer Institute ALL Consortium regimen

Standard or augmented Berlin-Frankfurt-Munster (BFM) for adolescents

Hyperfractionated cyclophosphamide, vincristine, doxorubicin and dexamethasone alternating with high-dose methotrexate and cytarabine (hyper-CVAD)

French GRAALL 2003 or GRAALL 2005 regimens for younger adults up to age 50 years

These chemotherapy regimens contain vincristine, a glucocorticoid (ie, prednisone or dexamethasone), and an anthracycline in addition to other agents. Some form of central nervous system (CNS) prophylaxis is also incorporated. With these regimens, more than 80 percent of newly diagnosed adults with ALL enter CR. (See 'Chemotherapy' above.)

For younger adults (<60 years) with CD20-positive ALL, we suggest the addition of rituximab therapy to the induction regimen (Grade 2B). (See 'Addition of rituximab for CD20+ ALL' above.)

Approximately 25 percent of adults have "Ph-like" ALL characterized by fusion genes and activated kinases but lacking BCR/ABL1. This subset has an unfavorable prognosis, and consideration should be given to an early allogeneic transplant.

Chemotherapy for ALL is highly toxic, primarily to the hematopoietic system. Most patients will require hospitalization with daily laboratory monitoring and supportive care with blood products and antibiotics. (See 'Monitoring during treatment' above and 'Supportive care' above.)

Attainment of a CR is the first step in the treatment of ALL. However, relapse can be expected in the following weeks to months if no further therapy is given. Post-induction therapy is an essential component of the treatment of ALL. This is presented separately. (See "Post-remission therapy for Philadelphia chromosome-negative acute lymphoblastic leukemia in adults".)

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Topic 4524 Version 57.0

References

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