Pediatric Acute Lymphoblastic Leukemia Treatment & Management

Updated: Jul 22, 2022
  • Author: Vikramjit S Kanwar, MBBS, MBA, MRCP(UK); Chief Editor: Jennifer Reikes Willert, MD  more...
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Approach Considerations

Acute lymphoblastic leukemia (ALL) is a systemic disease, and treatment is primarily based on chemotherapy. Thus, surgical care is generally not required in the treatment of ALL, except for the placement of a central venous catheter for administering chemotherapy, blood products, and antibiotics, and for obtaining blood samples.

Different forms of ALL require different approaches for optimal results, nevertheless ALL treatment typically consists of a remission-induction phase, intensification (consolidation) phase, and continuation therapy targeted at eliminating residual disease. Central nervous system (CNS) directed therapy is critical for improved survival rates. The addition of cyclophosphamide and asparaginase is also beneficial in the treatment of T-cell ALL. Mature B-cell ALL needs to be treated like disseminated Burkitt lymphoma, with short-term intensive chemotherapy, including high-dose methotrexate (MTX), cytarabine, and cyclophosphamide over a 6-month period. Because of the use of MTX, avoid folate supplementation.

Initially transfer children to a facility in which they can be in the care of a pediatric oncologist, preferably a center that participates in multi-institutional clinical trials. Immediately admit any patient who is neutropenic and who develops chills or fever to administer intravenous (IV) broad-spectrum antibiotics. Frequent hospitalizations may be required to deal with complications of ALL therapy, including the need for blood transfusions or antibiotics.


Tumor Lysis Syndrome

Before and during the initial induction phase of chemotherapy, patients may develop tumor lysis syndrome, which refers to the metabolic derangements caused by the systemic and rapid release of intracellular contents as chemotherapy destroys leukemic blasts. Because some cells can die before therapy, such metabolic changes can occur even before therapy begins.

Primary features of tumor lysis syndrome include hyperuricemia (due to metabolism of purines), hyperphosphatemia, hypocalcemia, and hyperkalemia. Hyperuricemia can lead to crystal formation with tubular obstruction and acute renal failure requiring dialysis. Therefore, electrolyte and uric acid levels should be closely monitored throughout initial therapy.

To prevent complications of tumor lysis syndrome, patients should initially receive intravenous (IV) fluids at approximately twice the maintenance rates without potassium; this rate may vary depending on the condition of the patient.

Sodium bicarbonate may be added to the IV fluid to achieve moderate alkalinization of the urine (pH level, 7.5-8) to enhance the excretion of uric acid. A urine pH level higher than this should be avoided to prevent crystallization of hypoxanthine or calcium phosphate.

The standard prophylactic treatment for malignancy-associated hyperuricemia includes allopurinol. By blocking the enzyme xanthine oxidase, allopurinol blocks uric acid formation. Patients at high risk for tumor lysis still need to excrete preexisting uric acid, which is unaffected by the use of allopurinol. Rasburicase, a recombinant urate oxidase, has the ability to catalyze the enzymatic oxidation of uric acid to a much more urine soluble product, allantoin, and is invaluable is situations with high uric acid build up (eg, ALL with hyperleukocytosis). Owing to its expense, rasburicase is not routinely recommended for every ALL patient.

By definition, hyperleukocytosis refers to WBC counts in excess of 100,000/mcL (100 x 109/L), but patients with ALL (unlike patients with AML) have blasts that are less adherent to blood vessel walls, and are unlikely to suffer complications until WBC counts exceed 300,000/mcL (300 x 109/L). St Jude Children’s Research Hospital was unable to demonstrate a clear benefit from leukophoresis for newly diagnosed patients with ALL with WBC counts exceeding 200,000/mcL (200 x 109/L), and it is therefore no longer routinely recommended.


The phases and duration of chemotherapy for acute lymphoblastic leukemia (ALL) are briefly discussed in this section.

Phases of therapy

The treatment of childhood ALL, with the exception of mature B-cell ALL, commonly has several components: induction, consolidation, interim maintenance, delayed intensification, and maintenance.

The goal of induction is to achieve remission, previously defined as less than 5% blasts in the bone marrow, recovery of blood counts and no evidence of leukemia at other sites. Induction therapy generally consists of 3 or 4 drugs, which includes a glucocorticoid, vincristine, asparaginase, and possibly an anthracycline. This type of therapy induces complete remission based on morphology in more than 98% of patients. However, the measurement of minimal residual disease (MRD) by flow cytometry or polymerase chain reaction (PCR) has been shown to be much more specific and sensitive than the morphologic examination of blast cells, and the goal is to have less than 0.01% blasts in bone marrow at the end of induction.

Current childhood ALL clinical trials incorporate MRD as a criterion for determining rapid early responder versus slow early responder status during induction chemotherapy. Based on MRD measurements, treatment may be intensified in patients with high amounts of residual blasts at the end of induction therapy.

Consolidation therapy is given soon after remission is achieved to further reduce the leukemic cell burden before the emergence of drug resistance and relapse in sanctuary sites (ie, testes, central nervous system [CNS]). In this phase of therapy, the patient is given different drugs (eg, cyclophosphamide, cytarabine, and/or 6-mercaptopurine [6-MP]). Consolidation therapy improves the long-term survival of patients with standard-risk disease.

Interim  maintenance involves non-myelosuppressive chemotherapy (eg, vincristine and intravenous MTX) that are administered to maintain remission and allow the bone marrow to recover. This occurs for 4-8 weeks.

Delayed intensification is a repeat of the first 2 months of induction and consolidation in high-risk and very-high-risk ALL protocols that includes some new agents (substituting dexamethasone for prednisone, doxorubicin for daunorubicin, and 6-thioguanine for 6-MP and repeating others). The goal is to eliminate residual drug-resistant cells. Pioneered by Dr Riehm and the BFM group, this phase was found to be beneficial for patients in all risk groups, including standard-risk and low-risk ALL.

Maintenance (or continuation therapy) is the last and longest phase of treatment. This consists of intrathecal MTX at least every 3 months, vincristine and steroid pulses every 1-3 months, daily 6-MP, and weekly MTX. The doses of last 2 agents are adjusted based on peripheral neutrophil counts, in order to optimize therapy. Although vincristine and steroid pulses may improve outcomes, they can be associated with avascular necrosis of the bone and vincristine neuropathy, and there continues to be debate about their benefit or how frequently they should be administered, which ongoing trials may help resolve.

Duration of therapy

Whereas mature B-cell acute lymphoblastic leukemia (ALL) is treated with a 6-month to 8-month course of intensive therapy, achieving acceptable cure rates for patients with B-lineage and T-lineage ALL requires approximately 2-2.5 years of continuation therapy. Attempts to reduce this duration resulted in high relapse rates after therapy was stopped. In the United States, in current B-lineage ALL clinical trials, the total duration of continuation therapy for girls is 2 years from the start of interim maintenance; for boys, it is 3 years from the start of interim maintenance.

The use of continuous dexamethasone in adolescents has been associated with an unacceptably high rate of osteonecrosis of the hips of around 40%, [16] and this medication is therefore omitted from induction and continuation therapy in older children. No data support the hypothesis that a second block of delayed intensification confers any extra benefit.


Management of CNS Disease

Central nervous system (CNS) disease is divided into the following:

  • CNS 1 - Absence of blasts on cytospin preparation of cerebrospinal fluid (CSF), regardless of the number of white blood cells (WBCs)

  • CNS 2 - WBC count of less than 5/mL and blasts on cytospin findings, or WBC count of more than 5/mL but negative by Steinherz-Bleyer algorithm findings* (if traumatic tap)

  • CNS 3 - WBC count of 5/mL or more and blasts on cytospin findings and/or clinical signs of CNS leukemia, such as facial nerve palsy, brain/eye involvement, and hypothalamic syndrome. (Additional intrathecal therapy is only given for CNS 3 disease.)

*If the patient has blasts in the peripheral blood and the lumbar puncture is traumatic (containing ≥5/mL WBCs and blasts), treat as CNS 3 if the CSF WBC count divided by the CSF red blood cell (RBC) count is greater than 2 times the blood WBC count divided by the blood RBC count.

CNS-2 patients are probably at increased risk for relapse. Although the Dutch Cancer and Leukemia Study group (DCLSG) demonstrated that for 526 patients on protocols ALL-7 and ALL-8, CNS-2 accounted for approximately 20% of patients and was not associated with inferior outcome. [17] More recent data from the COG Standard Risk ALL protocol suggest patients with CNS-2 had inferior outcome. Traumatic lumbar puncture at diagnosis with blasts present is also associated with poor outcome, and this has been confirmed by several study groups. For patients with ALL, the initial diagnostic lumbar puncture should be done with an adequate platelet count by an experienced pediatric oncologist.

Treatment of subclinical CNS leukemia is an essential component of acute lymphoblastic leukemia therapy. The mainstay of prophylactic treatment is intrathecal methotrexate administered at routine intervals; the COG AALL1131 trial showed no benefit to adding cytarabine and hydrocortisone ("triple intrathecal chemotherapy") in high risk B-ALL patients. [3] Risk factors for CNS relapse included genetic abnormality, CNS involvement at diagnosis, and T-cell immunophenotype.

Cranial irradiation

Although cranial irradiation (CXRT) effectively prevents overt CNS relapse, concern about subsequent neurotoxicity and brain tumors led to a desire to replace this modality with intensive intrathecal and systemic chemotherapy.

The UKALL XI trial (1990-97) administered high-dose intravenous methotrexate (HDMTX) (6–8 g/m2) with intrathecal methotrexate (ITMTX) compared with ITMTX alone, and demonstrated decreased isolated and combined CNS relapse for patients with standard risk ALL with the former. For patients with high-risk ALL, HDMTX with ITMTX were compared with CXRT and ITMTX, and although CNS relapses were significantly fewer with the latter, 10-year EFS was not significantly different (55·2% vs 52·1%). [18]

The DLCSG ALL-7 and ALL-8 trials (1988-1997) omitted CXRT except for 2% of patients who had overt CNS-3 disease and were still able to demonstrate an overall CNS relapse rate of only 5.5%. [19]

Pui et al confirmed these findings in the study Total XV (2000-2007); prophylactic CXRT was omitted from treatment for all groups of patients, including CNS-3, with an overall CNS relapse rate of 3.9%. [20]

Currently, whether prophylactic CXRT is necessary for patients with very-high-risk ALL is unclear. The current COG VHR ALL and Ph+ ALL trials do not routinely administer prophylactic CXRT, although patients with CNS-3 continue to receive CXRT.


Management of High-Risk Disease

The optimal treatment for patients with very high-risk (VHR) acute lymphoblastic leukemia (ALL) has not been determined [21] ; however, some centers recommend allogeneic hematopoietic stem cell transplantation (HSCT) soon after first remission (CR1) is achieved. For the subset of patients with BCR-ABL gene rearrangement, the addition of imatinib to intensified chemotherapy produced survival results equivalent to allogeneic HSCT. [22, 12]  HSCT also does not appear to improve outcome for ALL patients with hypodiploidy. [23]  Although novel agents are urgently needed, the COG randomized trial AALL1131 looked at the use of the experimental agent clofarabine in conjunction with intensified chemotherapy for VHR ALL, but was forced to abandon that agent owing to unexpected toxicity.

A review of 1041 patients with ALL and induction failure showed this population to be highly heterogeneous in their clinical features. Patients with T-cell ALL appeared to have a better outcome with allogeneic HSCT, whereas for patients with B-cell ALL and either age younger than 6 years or high hyperdiploidy, the value of HSCT was less certain. [24] For patients without a matched family donor, HSCT from an unrelated donor would therefore no longer be a reasonable treatment option for that subset, although it may be for other patients with VHR ALL. Large, multi-institutional, controlled trials are needed to confirm this recommendation.

Management of Down syndrome with ALL

Patients with Down syndrome and ALL (DS-ALL) constitute only 2-3% of all patients diagnosed with ALL, but are highly vulnerable to toxicity from the chemotherapy agents used as well as infection. [25]

Methotrexate is linked to systemic toxicity and neurotoxicity. Patients are usually treated on a modified ALL protocol with omission of high-dose methotrexate, leucovorin rescue after intrathecal methotrexate, and decreased exposure to dexamethasone and vincristine.

Death from infection is a significant risk. Patients with DS-ALL are kept inpatient during the induction phase, febrile patients receive early antibiotics (or antifungals as needed), and serum IgG levels are carefully monitored throughout the course of treatment, with IVIG infused as needed.

Management of relapse

Relapse occurs in 20% of children with ALL, when blasts reappear after complete remission (CR) is achieved. The site of relapse in the vast majority of cases involves the bone marrow, but other sites include the CNS or testes. Isolated CNS relapse (< 5% of total relapse) or isolated testicular relapse (1-2% of total relapse) is rare with current ALL therapy, but if it occurs more than 18 months from diagnosis, it has good outcome with local and aggressive systemic chemotherapy. Patients at high risk for further relapse and poor survival are those with B-lineage ALL with early relapse in bone marrow (which may be combined with other sites, such as CNS) and all T-lineage ALL. [26]

Early relapse is defined as bone marrow relapse that occurs within 36 months of initial diagnosis or within 6 months of completion of primary therapy; outcomes are poor, with only 35-40% of these patients achieving long-term remission. Late relapse occurs outside this time frame, and outcomes are better than for early relapse, with over half of these patients achieving long-term remission. Unfortunately, the vast majority of patients with T-lineage ALL suffer early relapse.

In patients with relapsed ALL, a multidrug-resistant clone has been selected so that leukemia cells are more resistant to chemotherapy. [27] Nevertheless, patients often respond to the same agents initially used for induction; the problem is in keeping them in remission. Standard treatment phases for ALL with first relapse is reinduction chemotherapy to get patients back into remission (CR2), followed by postreinduction consolidation therapy for patients who achieve CR2, discussed below.


Blinatumomab (Blincyto) was approved for adults and children with Ph- relapsed or refractory B-precursor ALL.

Approval was based on an open-label, phase I/II, single-arm study that included 93 pediatric patients with relapsed or refractory B-cell precursor ALL after receiving at least 2 prior therapies or in relapse after receiving prior allogeneic hematopoietic stem cell transplantation. Median age of patients was 8 years, ranging from 7 months to 17 years. Patients received blinatumomab as a continuous infusion for 4 weeks, followed by 2 weeks off. Overall, the mean number of treatment cycles was 1.5. 

Overall, 23 (32.9%) patients had a CR or CR with partial hematologic recovery within 2 treatment cycles. Seventy-three percent (n=17) of the responses occurred within the first cycle. [28]

Blinatumomab was also granted accelerated approval for the treatment of CD19-positive B-cell precursor ALL in first or second complete remission with minimal residual disease (MRD) of  ≥0.1% in adults and children. 

Efficacy was evaluated in an open-label, multicenter, single-arm study, the BLAST study, that included patients (n=86) who were ≥18 years of age and had received at least 3 chemotherapy blocks of ALL therapy. Overall, undetectable MRD was achieved by 80 patients (52 patients in first complete remission [CR1] and 18 patients in second complete remission [CR2]). The median estimated hematologic relapse-free survival with the majority of patients transplanted was 35.2 (range: 0.4, 53.5) months for patients in CR1 and 12.3 (range: 0.7, 42.3) months for patients in CR2. [29]


In July 2022, clofarabine (Clolar) was approved by the US Food and Drug Administration (FDA) for the treatment of relapsed or refractory ALL in pediatric patients aged 1 to 21 years who have failed at least two prior regimens.

Approval was based on the single-arm, open-label study, which enrolled 61 pediatric patients with relapsed/refractory ALL. Clofarabine induced a response rate of 30%, consisting of seven complete remissions (CR), five CRs without platelet recovery (CRp), and six partial remissions. [30]

In a second phase II study in 42 patients (median age, 13 years; range, 2-22 years), the response rate was 26% and included one CR without platelet recovery and 10 partial responses. The median duration of response was 20 weeks. [31]


Most standard regimens use a four-drug induction backbone, with glucocorticoid, vincristine, an anthracycline (such as daunorubicin or doxorubicin), and asparaginase; this was shown as early as the 1980s to achieve second remission in more than 90% of relapsed ALL patients in a Pediatric Oncology Group Study (POG 8303). COG AALL01P2 used this 4-drug treatment regimen, and gave additional blocks of intensive chemotherapy with cyclophosphamide/etoposide and/or high dose cytarabine. Using this regimen, of the 63 patients in early relapse, 68% achieved CR2, and of 54 patients in late relapse, 96% achieved CR2.

The UK ALL R3 regimen studied 212 patients with relapsed ALL and compared the anthracycline drug mitoxantrone to idarubicin in a four-drug induction regimen, and obtained a long-term progression-free survival rate of 64% at 3 years in 103 patients with relapsed ALL on the mitoxantrone arm. [32]


After reinduction, consolidation treatment is intended to prevent further relapse and achieve long-term cure. For patients with an early relapse, HSCT is desirable. Patients with elevated MRD prior to HSCT are more likely to suffer relapse; however, whether multiple cycles of intensive chemotherapy with or without newer agents (such as bortezomib or clofarabine) can ameliorate this risk factor is unclear. [33]

For patients with late relapse, the risks of HSCT often outweigh potential benefit, and intensified chemotherapy alone is recommended to achieve long-term remission (>50% of patients). Standard drugs are used in higher doses, along with additional agents, such as etoposide.

Second relapse or refractory disease

Despite successful reinduction and consolidation, many patients with ALL eventually relapse a second time. With regard to second and subsequent relapse, no standard treatment regimen has been established; oncologists must choose among various combinations of drugs. Long-term survival for all patients with ALL after a second relapse remains poor, in the range of 10-20%, and some families may opt for palliative care.

The FDA approved the first CAR T-cell therapy in August 2017. Tisagenlecleucel is a CD19-directed genetically modified autologous T-cell immunotherapy indicated for patients aged 25 years or younger with B-cell precursor ALL that is refractory or in second or later relapse. [34]

Hematopoietic stem cell transplantation (HSCT)

HSCT has been used in very high risk patients in first remission (CR1) as well as in patients with ALL relapse at high risk for further relapse (eg, early BM relapse). Although most patients with relapse achieve second remission (CR2), because two thirds of patients with early relapse eventually have a second relapse, this makes HSCT a recommended option for this group of patients. The improved outcomes of VHR ALL for some categories of patients, such as Ph+ ALL receiving chemotherapy incorporating imatinib, means the role of HSCT in patients with VHR ALL is still debated. [21]

In a collaborative study between the COG and the Center for International Blood and Marrow Transplant Research (CIBMTR), Eapen et al studied 374 children with ALL in CR2 after a marrow relapse who received either a matched sibling donor hematopoietic stem cell transplant (MSD HSCT) (n=186) or ongoing chemotherapy (n=188). [35] The study confirmed better leukemia-free survival in patients with early relapse who received total body irradiation (TBI) based conditioning regimens. The presence of MRD before HSCT is a negative predictor of outcome after HSCT; however, whether aggressive attempts to reduce MRD before HSCT translate into improved long-term survival remains unclear.

Similarly, in the ALL-REZ BFM 90 trial, MSD HSCT benefited patients with higher risk relapse (10-year EFS 40% vs 20% for chemotherapy alone) but did not improve 10-year EFS for lower-risk patients (10-year EFS 52% vs 49% for chemotherapy alone).

With advances in HSCT technique and supportive care, alternative donors (eg, matched unrelated donors) can also be used with equivalent survival outcomes if a MSD is not available.

Molecular-targeted therapy

A drug targeted at the underlying molecular defect that is unique to certain leukemias can have potent and specific antileukemic activity while producing minimal toxicity to normal cells. [36] The best example of molecular targeted therapy is imatinib mesylate, a selective BCR-ABL tyrosine kinase inhibitor, that is standard front-line treatment for Ph-positive chronic myeloid leukemia (CML). Combination regimens with imatinib and conventional chemotherapy have shown efficacy in Ph-positive acute lymphoblastic leukemia. [37, 22]

Imatinib is approved for children newly diagnosed with Ph+ ALL. Its approval was based on a trial involving 92 patients in which children (1 year or older) and young adults were divided into 5 groups to receive different durations of imatinib therapy along with conventional chemotherapy. Among the 50 children receiving the longest duration of imatinib, the 4-year progression-free survival rate was 70%. Increasing duration of imatinib therapy was associated with lower overall mortality. [22]

The use of tyrosine kinase inhibitor or JAK2 inhibitor therapy for Ph-like ALL is being evaluated in ongoing clinical trials.

The addition of nelarabine improved 4-year disease-free survival for patients with T-cell ALL (88.9% vs 83.3%) in the clinical trial COG AALL0434, but did not benefit patients with high-risk T-cell lymphoma. [38]

Cellular therapy

Although HSCT with its graft versus leukemia (GVL) effect is the most commonly used cellular therapy, several other interventions are possible, as follows: [39]

  • Donor leukocyte infusion (DLI): T-cell DLI in a postallogeneic HSCT setting, provide GVL benefit for relapsed chronic myeloid leukemia and EBV-induced lymphoproliferative disease and, rarely, for induced durable remissions in relapsed ALL.

  • Natural killer (NK) cell infusion: NK cell infusions in the setting of haploidentical transplantations and killer cell Ig–like receptor (KIR) ligand mismatches has shown benefit in a minority of AML patients, but the value in ALL is uncertain.

  • In chimeric antigen receptor (CAR) T-cell therapy, the patient's own T-cells are collected from peripheral blood and genetically engineered to express a CAR that targets a specific molecule on cancer cells. The modified T-cells are then expanded and reinfused into the patient, after lymphodepletion with conditioning chemotherapy. [40] Studies of treatment with CAR T-cells targeting CD19 have reported high rates of complete and long-lasting remissions in patients with refractory acute lymphoblastic leukemia (ALL). Toxicities, which can be fatal, include cytokine release syndrome (CRS), B-cell aplasia, and cerebral edema. [40]  

    In August 2017, the FDA approved the anti-CD19 CAR T-cell therapy agent tisagenlecleucel (Kymriah) for the treatment of patients up to 25 years of age with B-cell precursor ALL that is refractory or in second or later relapse. Because of the risk of adverse effects, the FDA approval includes a risk evaluation and mitigation strategy, which requires special certification for hospitals and clinics that administer the treatment and additional training for their physicians and other staff. [41, 34]

    Approval of tisagenlecleucel was based on results of an open-label, multicenter single-arm trial (Study B2202). Eighty-eight children and young adults were enrolled, 68 were treated, and 63 were evaluable for efficacy. Among the 63 treated patients, 52 responded. Of these 52 responders, 40 patients (63%) had a complete response within the first 3 months after infusion, and 12 (19%) had a complete remission with incomplete blood count recovery. All of these were associated with minimum residual disease–negative status in the bone marrow. [42]

    In conjunction with the approval of tisagenlecleucel, the FDA also expanded the approval of tocilizumab to include the treatment of severe or life-threatening CRS resulting from CAR T-cell therapy in patients 2 years of age or older. In clinical trials, 69% of patients with CRS related to CAR T-cell therapy had complete resolution of CRS within 2 weeks after receiving one or two doses of tocilizumab. [34]

Genetic studies and future challenges

More than 80% of children with ALL now can be cured. [1] However, the cause of treatment failure in the remaining 20% of patients is largely unknown, although several clues have emerged from GWAS. Poor outcome has been correlated with alteration of IKZF1, which encodes the lymphoid transcription factor IKAROS, [43] and Janus kinase mutations have been associated with a high risk of treatment failure. [44]

Because of the diverse nature of the disease, use of risk-directed therapy for all patients on the basis of molecular and pharmacogenetic characterization of the leukemic cells at the time of diagnosis is favored, and the COG has an ongoing clinical trial to evaluate the use of tyrosine kinase inhibitors for Ph-like ALL.


Numerous consultations may be obtained, depending on the clinical circumstances of patients with newly diagnosed ALL, including the following:

  • Pediatric surgeon: Patients require placement of a central venous catheter.

  • Psychosocial team: Involve psychologists and social workers in the care of patients with acute lymphoblastic leukemia to aid them and their families in navigating all of the difficult issues surrounding their care.

  • Radiation oncologist: Consultation may be appropriate if there is extramedullary disease not responding to induction therapy (eg, testicular involvement) or that associated with high-risk disease (eg, CNS-3 in patients with T-lineage ALL).

  • Other subspecialists: Consultations with other specialists (ie, infectious disease specialist, nephrologist) may be appropriate, depending on the clinical circumstances.


Long-Term Monitoring

Frequent clinic visits are required to administer outpatient chemotherapy, to monitor blood counts, and to evaluate new symptoms. In addition, all patients should be on trimethoprim- sulfamethoxazole (TMP-SMZ) or a similar agent, such as monthly IV pentamidine, to prevent Pneumocystis carinii pneumonia (PCP). Patients with infant leukemia may benefit from oral fluconazole prophylaxis to reduce the risk of candidiasis.