Central nervous system leukemia in childhood and adolescent acute lymphoblastic leukemia: How to prevent? How to treat?

Full text

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A. Baruchel

Pediatric Hematology Department, Hôpital Robert Debré and University Paris-Diderot, Paris, France

Hematology Education:

the education program for the annual congress of the European Hematology Association 2011;5:302-310

Central nervous system leukemia in childhood and adolescent acute lymphoblastic leukemia:

How to prevent? How to treat?

Introduction

Acute lymphoblastic leukemia (ALL) is the most common cancer in children. The prog- nosis of children with ALL has progressively but dramatically improved over the last forty years. A 5-year event-free survival (EFS) of 80-85% is currently observed in the devel- oped countries. The major contributors to this result are the risk-adapted therapies, the central nervous system (CNS)-directed ther- apy and the improvement of supportive care, administered by dedicated teams using clinical research-grade protocols. This review will focus on the problem of CNS in child- hood ALL.

Why a focus on CNS and acute lymphoblastic leukemia?

It is known from older studies that in the absence of any prevention, a 50% incidence of CNS relapse is observed1. Currently this rate has been reduced to less than 5%

through the introduction of cranial irradia- tion, intrathecal chemotherapy with metho - trexate alone or in combination with other drugs (cytarabine and steroids), and systemic administration of chemotherapies which penetrate the CNS (high-dose methotrexate, dexamethasone, and high-dose cytarabine) or deprive the blood and secondarily the CSF of an essential amino-acid (L-asparaginase).

Nevertheless, strategies to prevent CNS relapse must first avoid over-treatment (resulting in potential sequaelae) or under- treatment (resulting in CNS and/or marrow relapse). Second, CNS relapses may now represent as high as 30 to 40% of first relaps- es, particularly in the low and intermediate- risk ALLs.2-4

What are we talking about when saying “CNS”?

In fact ALL cells can invade meninges and, more rarely, the nerve roots or the brain itself. Their migration to these compart- ments is not fully understood. The leukemic cells can migrate from the skull marrow into the subarachnoid space via the bridging veins and enter the cerebrospinal fluid (CSF) via the choroid plexus. They can directly

infiltrate the leptomeninges via osseous lesions of the skull. They can invade cerebral parenchyma via brain capillaries. Leukemic cells can also grow along nerve roots and invade the subarachnoid space. Very rarely in ALL, multiple solid central nervous sys- tem tumors composed of leukemic cells are found. Leukemic cells can also enter the CNS via a local CNS hemorrhage when the circu- lating blood contains blasts, particularly in situations where leucostasis is described (mainly cases of ALL with a very high leuco- cyte count). Finally, leukemic cells can be introduced at the time of the first lumbar puncture, especially when traumatic.

How to diagnose initial CNS leukemia?

Clinical signs (see Table 1)

Only cerebral palsies are taken as possible direct diagnostic signs of CNS involvement (CNS3 status, cf. section 4). Some coopera- tive groups consider cranial-nerve palsy by itself a criterion of CNS3 (e.g., Children’s Oncology Group, St-Jude, EORTC, FRALLE).

Others accept these palsies (or a cerebral mass) only if they are associated with the presence of blasts after cytocentrifugation (BFM group).5 More recently, palsies or the presence of a cerebral mass were also accept- ed by this group as sole evidence of CNS involvement (trial AIEOP-BFM ALL 2000, personal communication).

Radiological signs of CNS involvement in ALL MRI is known to be far more sensitive in the detection of leptomeningeal tumor spread than CT. Findings may include an abnormal MR appearance of the subarach- noid space on pre-contrast imaging. If the subarachnoid space is not of appropriate sig- nal intensity on T1, T2-weighted and, above all, FLAIR images, the possibility of leukemic meningitis should be raised. Abnormal meningeal enhancement, in the cisterns or along the pial surface of the brain or spinal cord, is a good sign of leukemic meningitis.

This type of enhancement is, however, non- specific. Non-malignant meningeal enhance- ment may be observed following diagnostic or therapeutic lumbar puncture. Dural spread of leukemia is best detected radiolog- ically as abnormally thickened and brightly

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enhanced dura on post-contrast images.

In rare cases of ALL, images compatible with unique or multiple solid central nervous system tumors, in fact consisting of leukemic cell aggregates, are found.

Examination of the CSF after lumbar puncture

Lumbar puncture (LP): considering the negative impact of a traumatic LP (cf. section 6), adequate conditions should be met when performing the first lumbar punc- ture: experienced doctor, deep sedation, platelet count above 50.000/mm3(> 100.000/mm3for some authors), immediate first age-adjusted intrathecal injection of chemotherapy. Moreover, the use of the smallest nee- dle possible is recommended to decrease the leak of CSF and prevent post-puncture headache. Finally, prone position for at least 30 minutes would be a way to increase the intra-ventricular concentration of chemotherapy.6

CSF cyto-morphology: despite being viewed as the gold standard, there are issues related to CSF cytology:

– Linked to the technique: amount of available CSF, simple or double cytocentrifugation, use of medium or fetal calf serum or bovine serum albumin, speed and length of centrifugation, type of staining, number of cells on the slides7,8

– Linked to the cytopathologist: experience and skill are obviously needed.

Additional techniques: they may help to distinguish normal lymphocytes from leukemic cells in cases with difficult morphology. The three main techniques are terminal deoxynucleotidyl transferase staining, flow cytometry (FC) and PCR-based techniques. A recent study has compared the performance of FC and cyto- morphology in patients with CNS hematological malig- nancies: leukemic cells were found in the CSF at diag- nosis by FC in 44 patients (73%) versus 19 (32%) by cytomorphology.9 Questionably, four samples were positive by cytomorphology while negative by FC.9 The development of PCR as a diagnostic technique based on the detection of clonal rearrangements of the immunoglobulin/T-cell receptor genes has been pro- posed as a sensitive way to detect CSF involvement.

Few studies have yet explored this aspect in ALL.1-13 Pine et al. have used a sensitive RQ-PCR and have found PCR positive samples in three out of 23 CNS1 pts.1Scrideli et al. reported on 37 pts without traumatic LP.1With an unknown sensitivity, 17 PCR positive sam- ples were identified vs. only two by morphology.

Interestingly, the patients with positive PCR samples had a worse outcome than the patients without CNS PCR positivity.12 These preliminary results need to be confirmed in large prospective studies.

How to classify CNS disease?

Patients who have a non-traumatic diagnostic lumbar puncture may be placed into one of three categories according to the number of white blood cells/µL and the presence/absence of blasts on cytospin, as follows:

– CNS1: Cerebrospinal fluid (CSF) that is negative for blasts after cytospin, regardless of WBC count.

– CNS2: CSF with fewer than five WBC/µL and cytospin positive for blasts.

– CNS3: CSF with five or more WBC/µL and cytospin positive for blasts.

Patients with an initial traumatic LP (≥10 erythro- cytes/µL) should be classified in two further categories:

– Traumatic LP with blasts (TLP+): ≥10 erythrocytes/µL plus blast after cytospin.

– Traumatic LP without blasts (TLP-): ≥10 erythro- cytes/µL with no blast after cytospin.

To determine whether a patient with a traumatic lum- bar puncture (with blasts) should be considered as CNS3, the Children’s Oncology Group (COG) uses an algorithm relating the white blood cell and red blood cell counts in the spinal fluid and the peripheral blood:

If CSF WBC/RBC is two times greater or more than the blood WBC/RBC ratio, the patient is considered to have CNS disease at diagnosis.

Who are the children and adolescents at risk of initial CNS involvement?

All cooperative groups report a 2 to 3% similar inci- dence of CNS3 pts (see Pui and Howard14for review).

This mean number, nevertheless, does not reflect the heterogeneity of the disease, children with standard risk B-lineage ALL having the lowest incidence (~1-2%), or infants and patients with T-ALL having the highest (~10%). It should be noted that some B-lineage ALL with poor-risk cytogenetics are also associated to a higher incidence of CNS3 status (~5%) (Table 2).15-17

Who are the children at risk of CNS relapse?

There is an obvious overlap between risk factors of initial CNS involvement and risk factors for CNS relapse (see “table 2” and “table 3”).

– Compared with patients classified as CNS1 or CNS2, children with ALL who present with CNS disease at diagnosis (i.e., classified as CNS3 patients) are at a higher risk of treatment failure (both within the CNS and systemically).14 The adverse prognostic signifi- cance associated with CNS2 status, initially reported by the St-Jude group,18has been questioned5,19and may Table 1. Clinical signs of possible CNS involvement.

Increased intra-cranial pressure Visual disturbances CNS palsies Other

Headaches, vomiting, papilledema, lethargy, Diplopia, blurred vision, blindness, photobia VII, VI Myelopathy, auditory abnormalities, vertigo, ataxia,

seizures, coma hallucinations, nystagmus, bulimia

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be overcome by the application of more intensive intrathecal therapy, especially during the induction phase and/or systemic treatment with CNS penetra- tion, i.e., dexamethasone, high-dose methotrexate.5,20,21 A traumatic lumbar puncture (≥10 erythrocytes/µL) (TLP) that includes blasts at diagnosis appears to be associated with increased risk of CNS and systemic relapse and indicates an overall poorer outcome.5,22,23It should be avoided as much as possible (Section 3). A Japanese group has proposed delaying the first lumbar puncture at D8 of steroid prophase.24A standard 2.9%

incidence of CNS3 was found, but a very low 0.8% of TLP was shown.24After an initial TLP, many protocols recommend at least reinforced intrathecal treatment during induction.

It must be emphasized that if all groups report an overall similar 2 to 3% incidence of CNS3 pts, the incidence of CNS2 pts (2.5-21%) and the incidence of traumatic lumbar puncture (2.5-12%) are highly vari- able between groups, likely reflecting the existence of many conflicting factors and the heterogeneity of clin- ical and biological practice (Table 4).5,20-23

– T-cell ALL, especially if a high leucocyte count (>100.000/mm3) is encountered, is associated with a high risk of CNS and systemic relapse in children and adolescents, explaining why many groups still recom- mend irradiation of this subgroup.14,25

– Children with pre-B-ALL and the t(1;19) translocation have also a higher risk of CNS relapse.26

– High-risk cytogenetic features such as MLL rearrange- ment in infants, hypodiploidy and t(9;22) are associat- ed with a higher incidence of CNS relapse in the 5 to 10% range (Table 3).15-17

– Other biologic features have recently emerged as risk factors for CNS relapse:

• A higher expression of interleukin-15 was found in children with ALL and initial CNS involvement compared to children without. A high expression was also predictive of CNS relapse in children with- out initial CNS involvement.27

• Certain host gene polymorphisms have been pro- posed as potential factors to describe the hetero- geneity in the risk of CNS relapse, particularly through their role in drug disposition or transport (e.g., methotrexate): They include the thymidilate synthase 3/3 genotype for low risk-ALL and the vitamin D receptor start site and intron 8 genotypes for high-risk ALL.28 They also include polymor- phisms of the genes coding for the Glutathione S- Transferase P1 and P-glycoprotein. These proteins are implicated in resistance to a variety of chemotherapeutic agents and are involved in the blood-brain barrier. Some of these polymorphisms were associated with a reduction of the CNS relapse risk in intermediate or high-risk ALL in a recent German study.29 All these data nevertheless must be confirmed in large prospective studies before a possible clinical use.

• It is to be anticipated that homing and adhesion molecules will be important players in the predic- tion of CNS involvement or relapse risk.

Interestingly, in a mouse model, the chemokine receptor CCR7 seems to be an essential adhesion signal required for the targeting of leukemic T-cells into the CNS. Indeed, silencing of either CCR7 or its chemokine ligand CCL19 specifically inhibits Table 2. Initial CNS involvement and CNS relapse in patients with ALL and poor-risk cytogenetics.

Number of pts (%) with CNS involvement at diagnosis Number of pts (%) with isolated CNS relapse after CR

Infants* 44/405 (10.8%) 23/445 (5.2%)

Philadelphia Chromosome 11/275 (4%) 16/267 (6%)

Hypodiploidy < 45 chromosomes 8/130 (6.1%) 10/130 (7.7%)

*80% of infants have an MLL gene rearrangement induced by a translocation involving 11q23.

From Pieters R et al.,15Arico M et al.,16Nachman J et al.17

Table 3. Risk factors associated with CNS relapse in children and adolescents with ALL.

• Blast in the CNS

– CNS3 (CSF with 5 or more WBC/µL and cytospin positive for blasts and/or clinical/radiological signs) – Traumatic lumbar puncture with blasts after cytospin

– CNS2 +/-

• Hyperleucocytosis

• T-Cell ++ if WBC>100.000/mm3

• t(1;19)/ E2A-PBX1

• Infants -t(4;11)/MLL-AF4

• t(9;22)/BCR-ABL

• hypodiploidy < 45 chromosomes

• Gene polymorphisms (Vitamin D receptor start site, Thymidylate synthase)

• High IL-15 expression

• CCR7 expression (T-ALL model in mice)

• Suboptimal asparagine depletion

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CNS infiltration. Furthermore, murine CNS-target- ing by human T-ALL cells depends on their ability to express CCR7.30

– Factors related to sub-optimal treatment (e.g., subop- timal exposure to asparaginase) will be considered in the next paragraph.

How to prevent CNS relapse?

– Cranial irradiation historically has been the first method of prevention since the 1960s. Nevertheless, its use must be carefully weighed due to the numer- ous and severe complications associated with it:

increased risk of secondary tumors (meningiomas, malignant CNS tumors, thyroid cancers and other car- cinomas), neuro-cognitive defects, growth hormone deficiency and other endocrinopathies. Currently most protocols restrict the use of CNS irradiation to the 2 to 20% of the patients envisaged to be at higher risk of CNS relapse, at a dose ranging from 12 to 18 gy.14Unfortunately, there may be no safe dose: a 12 gy irradiation has resulted in a projected cumulative inci- dence of second neoplasms of 1.7% at 15 years in a population of 1,779 children treated in the BFM stud- ies (11 observed tumors).31Even the low doses (1-2 gy) used in the 1950s for tinea capitis have increased the incidence of brain tumors, thyroid cancers and oth- ers.32 Three cooperative groups have reported very interesting results while completely omitting CNS prophylactic or curative irradiation (Table 5).20,21,33 Moreover, a BFM-based study in Israel suggests that extended intrathecal therapy may allow the replace- ment of radiotherapy without apparent damage in the population of patients with T-cell ALL and good early response to prednisone, whatever the white blood

cell count.34 Thus omission of prophylactic cranial therapy in childhood and adolescent ALL is a feasible goal to achieve, even if fully exhaustive mid-term and long-term studies focusing on the impact of replace- ment therapies (systemic treatment intensity, pro- longed intrathecal therapy, high-dose dexametha- sone, high-dose methotexate) are still lacking.

– Intrathecal therapy: despite the estimate that only 10% of the dose injected after lumbar puncture reach- es the lateral ventricles, a successful CNS prophylaxis is achieved in the vast majority of the patients.14The three major drugs which are used intrathecally in var- ious combinations are methotrexate, cytarabine and hydrocortisone. Variations between protocols include the nature of the first IT (mainly cytarabine in the US, versus methotrexate in Europe), simple (methotrex- ate) versus triple IT for continuation of the therapy directed at the CNS, total number of ITs (ranging from 12 to 25 ITs), and administration or not of ITs during maintenance treatment. These variations are partly linked to the three other main orientations of the CNS treatment: no high-dose methotrexate and no irradia- tion, high-dose methotrexate and no-irradiation, high-dose methotrexate and CNS irradiation. A recent randomized study (CCG-1952) has compared simple (methotrexate alone) versus triple IT in children with standard-risk ALL.35It was found, paradoxically, that if a reduction of CNS relapse was shown, an increase of bone marrow and testis relapses was document- ed.35Indeed the 6-year cumulative incidence estimates of isolated CNS relapse were 3.4% +/- 1.0% for triple ITs and 5.9% (SE: 1.2%) for simple IT (p = .004).

Because the salvage rate after bone marrow relapse is inferior to that after CNS relapse, logically the 6-year overall survival rate for children assigned to receive triple ITs was 90.3% (SE: 1.5%) versus 94.4% (SE:1.1%) Table 4. Distribution of CSF involvement and traumatic LP at diagnosis in selected studies.

CNS1 and non TLPan(%) TLP-n (%) “CNS1” TLP-bincluded n(%) CNS2 n(%) CNS3 n(%) TLP+cn(%) Total TLP n(%) St-Jude

Total therapy 336 54 390 80 16 60 114

XI/XII22 (61.5) (9.9) (71.4) (14.6) (2.9) (11) (20.8)

(546 pts) St-Jude

Total therapy 359 102 9 28 ?

XV*20 ? ? (72) (20.5) (1.8) (5.6) ?

(498 pts)

BFM 95*5 1605 111 1716 103 58 135 246

(2012 pts) (79.77) (5.51) (85.28) (5.12) (2.88) (6.7) (12.2)

DCOG*23

304 39 343 111 10 62 101

ALL-7/ALL-8

(58) (7) (65) (21) (1.9) (12) (19)

(526 pts)

EORTC 58881**21 ? ? 1866 50 49 60 ?

(2025 pts) (92) (2.46) (2.4) (2.9) ?

aTLP: traumatic lumbar puncture.

bTLP-: traumatic lumbar puncture without blast after cytospin.

cTLP+: traumatic lumbar puncture with blasts after cytospin.

*Definition of TLP: ≥ 10 erythrocytes / µl in the CSF.

**Definition of TLP: ≥ 100 erythrocytes / µl in the CSF.

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for IT methotrexate (p=0.01). It thus appears that triple IT therapy improves pre-symptomatic CNS treatment but does not improve overall outcome in standard-risk ALL.

A liposomal sustained release formulation of cytara- bine has been recently proposed.36-42The cytarabine in this formulation has a prolonged half-life (100-263 h) versus 3-4 hours for the free drug.36It seems effective but toxicity can be associated with its use, including arachnoiditis and central CNS neurotoxicity, particu- larly if high-dose cytarabine or high-dose methotrex- ate are used concomitantly.42 Trials are ongoing in adult and pediatric protocols to define its real efficacy and safety profile.

– Systemic chemotherapy is of paramount importance to prevent CNS relapse.

• Intensity of the treatment: CCG-105 was the first randomized study to document the importance of systemic treatment in the prevention of CNS relapse.43Indeed, for intermediate-risk patients less than 10 years of age, IT methotrexate with an inten- sified systemic regimen provided a CNS prophylax- is comparable to that provided by cranial radiother- apy, whereas older patients had fewer systemic relapses if they received CNS irradiation.43

• High-dose methotrexate (HD-MTX): despite its extensive use, the benefits of HD-MTX seem more pronounced on the prevention of hematological relapse than on CNS relapse in a meta-analysis.44 One French randomized study suggested an advan- tage of HD-MTX (4 cycles of 8 g/m2) in intermedi- ate-risk B lineage ALL, the benefit being seen in good early responders to chemotherapy in terms of reduction of bone marrow and extra-medullary relapse.45 The current 5 g/m2 dose used in many groups is suggested to result in consistently cyto- toxic concentrations in the CSF(> 1 micromolar). An adequate exposure to methotrexate (≥ 36h) before beginning the rescue by folinic acid is mandatory, as well as keeping this rescue to the minimum.

• High-dose cytarabine: less-used in ALL than in AML or Burkitt’s lymphoma, no definite proof of its use- fulness exists. No benefit of intermediate or moder- ate high-dose has been shown in medium-risk ALL in the BFM-95, nor in EORTC 58881 studies.46,47

• Dexamethasone versus prednisone: the possible superiority of dexamethasone is still controversial.

Some trials have documented this superiority, par- ticularly in terms of CNS relapse, comparing 6

mg/m2/d of dexamethasone to 40 mg/m2/d of pred- nisone or 10 mg/m2/d to 60 mg/m2/day during induction therapy.48-50Others comparing 8 mg/m2/day of dexamethasone to 60 mg/m2/day of prednisone did not find a difference.51

• Thiopurines: Three randomized trials have com- pared 6-Thioguanine (40 mg/m2/day) and 6- Mercaptopurine (60 mg/m2/day).52-54 Despite an advantage in terms of CNS relapse reduction, an unacceptable increase of veno-occlusive disease was documented.53,54

• Optimal administration of L-Asparaginase: two tri- als have demonstrated the role of L-Asparaginase in CNS relapse prevention. Indeed the EORTC group and the DFCI group have randomized the adminis- tration of Erwinia asparaginase versus native E.Coli asparaginase at the same dose and at the same rhythm.55,56 In both trials an excess of CNS relapses was documented in the Erwinia asparaginase arm.

This excess was documented only in the non-irradi- ated patients in the DFCI protocol (no irradiation in the EORTC protocol).55,56Despite the lack of formal proof, this was most probably due to the shorter half-life of Erwinia, resulting in a lesser asparagine depletion both in plasma and CNS.

• Dasatinib for ALL with Philadelphia chromosome:

it has been recently documented that 11 clinically evaluable patients with CNS disease responded to dasatinib, a more potent tyrosine kinase inhibitor than imatinib.57 Complete responses, defined as either disappearance of leukemic blasts from CSF or radiologic findings in magnetic resonance imaging, were observed in 7 patients. Four of these were achieved with dasatinib monotherapy. The CNS penetration of dasatinib, a more potent tyrosine kinase inhibitor, seems considerably higher than that achieved by imatinib.57

• Thiotepa: A US trial has studied the possible role of thiotepa for CNS relapse management, using an upfront therapeutic window.58 At the 65 mg/m2 dose (one IV infusion), a complete clearance of blasts at D8 was seen in 4 out of 9 patients with B- precursor ALL.58

Finally, all these items point to the importance of sys- temic treatment in the prevention of CNS relapse in ALL.

An analysis of ten trials performed in the 1990s, involving 15,222 patients, was recently conducted by Pui and Howard.14It showed that the variable associa- tion of all these methods of CNS relapse prevention cur- Table 5. Results of published protocols omitting CNS irradiation.

n number of CNS3 pts (%) EFS of all cohort EFS of CNS3 pts CIaof isolated CNS relapse CI of any CNS relapse EORTC 5888121 2025 49 (2.4) 69.6 % (SE:1%) 68.3 % (SE:6.2%) 3.57% (SE:0.42%) 7.6% (SE:0.6%)

(1989-1996) at 8 years at 8 years at 8 years at 8 years

COG ALL-933 859 21 (2.4) 81% (SE:1%) 67% (SE:10%) ? ?

(1997-2004) at 5 years at 5 years

St-Jude Total Therapy XV20 498 9 (1.8) 85.6% (SE:5.7%) 43.2% (SE:23%) 2.7% (SE:0.8%) 3.9% (SE:1%)

(2000-2007) at 5 years at 5 year at 5 years at 5 years

aCI : Cumulative incidence.

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rently results in a less than 5% cumulative incidence of CNS relapse at 5 years (from 0.8% to 5%).14

How to treat initial CNS involvement or CNS relapse?

1. CNS3 pts

This problem has been evoked in the previous section (see also “Table 5”). The importance of the systemic treatment for these patients must be emphasized again, particularly in protocols trying to omit irradiation. As an example, the CNS 3 pts, treated without CNS irradia- tion in the EORTC 58881, received either 9 or 10 cours- es of HD MTX (5 g/m2), depending on their other risk- criteria.21Their prognosis in that trial conducted in the beginning of the 1990s did not differ from the one of the CNS1 pts (8 year EFS 68.3 % versus 69.7%).21Also, in the DCOG ALL-9 study, considering CNS3 as a high- risk criterion per se, a 5-year EFS of 67% was observed, with an overall survival of 80%.33These results compare favorably to those of the BFM-95 (5-year EFS: 50%), obtained with the use of a 18gy cranial irradiation after 4 courses of HD-MTX (5 g/m2).5

2. CNS relapse

As CNS relapses are rare and first line treatments are evolving, no gold standard exists. A recent study from the UKALL MRC group, reviewing the outcome of 5,564 children with ALL, treated from 1985 to 2001, has shown a marked trend towards a decrease in com- bined relapses, with a progressive shift towards later relapses (≥ 30 months).59 Although isolated relapses declined, the proportional incidence and timing of relapses remained unchanged. CNS relapses in the UK MRC studies thus represent 18% of all relapses and are very early relapses (i.e. CR1 < 18 months) in roughly 37% of the cases.59

The main points to be considered when tailoring the treatment of a child with CNS relapseare the length of first remission (less than 18 months or not), the immunophenotype (T-cell ALL versus BCP-ALL), the characteristics of the CNS relapse (isolated or combined), the presence of minimal disease in the marrow, and a his- tory of previous CNS irradiation. An additional prognos- tic factor found in B-lineage ALL is the NCI classification, with standard-risk NCI patients having the best progno- sis after an isolated CNS relapse (even if there is some correlation between length of CR1 and NCI risk).58,59

Due to this heterogeneity, to small numbers and sometimes to a long recruitment period, it is not sur- prising to find variable outcomes across the studies (Table 6).58-63

Some common principles can nevertheless be accepted:

– To delay cranial or cranio-spinal irradiation for 6 to 12 months allows initial intensification of systemic chemotherapy. This has led to second EFS rates of 70% to 80% in children with isolated CNS relapse.58,61,62

– To reduce as much as possible the dose of irradiation, investigators of the Children’s Oncology Group have proposed that patients with an initial remission dura- tion of <18 months receive 24gy cranial and 15gy spinal irradiation (4-year EFS: 52%), while those with a longer initial remission receive only 18gy cranial irradiation at 12 months of treatment while not com- promising the 4-year EFS of 77.7%.58 These good results are observed in children with B-lineage ALL who did not receive cranial irradiation during initial treatment. As in first line, some groups are trying to eliminate CNS irradiation, at least in late isolated CNS relapses (Beshuizen A, Erasmus, Rotterdam, as cited by Pui and Howard14).

To intensively treat children with very early CNS relapse (first remission <18 months) and/or those with T-cell ALL. Interesting results have been reported with hematopoietic stem cell transplantation.64,65,66

– Albeit logical, the predictive value of submicroscopic marrow disease evaluation at the time of CNS relapse and its potentially decisional role is yet to be demon- strated in prospective studies.67

– To envisage differently the treatment of children with prior cranial irradiation. This includes in particular the use of intra-ventricular chemotherapy through a reser- voir and possibly innovative drugs like liposomal cytarabine (cf. section 7).

Conclusions

Despite steady progress, the problem of CNS in ALL is still a matter of research in terms of understanding, precise diagnosis, prophylaxis and treatment of relapse.

CNS irradiation is to be given up in the vast majority of the children, if not all. This is likely to be a major step forward in decreasing the therapy burden of children with ALL.

Table 6. Results of selected studies for isolated CNS relapse of childhood ALL.

n Era OS of all cohort EFS of all cohort EFS if CR1 <18 months EFS 18<CR1< 30-36 EFS CR1 >30-36

%(SE) %(SE) %(SE) %(SE) %(SE)

Winnick et al.60 120 1983-1990 NA 46(7) NA NA NA

Ribeiro et al.61 20 1983-1989 NA 71 (11) NA NA NA

Ritchey et al.62 83 1990-1993 NA 71.1(5.3) 46.2(3) 83.3(5.3)

Barredo et al.58 76 1996-2000 NA 77.2(5.3) 49.4 (11.1) 77.7 (6.4)

Tallen et al.63 35 1990-1995 NA NA 33 (14) 47(12) 50(25)

Krishnan S et al.59 307 1985-2001 46·3(5.7) NA NA NA NA

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