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Keywords:

  • acute lymphoblastic leukaemia;
  • chemotherapy;
  • allogeneic stem cell transplantation;
  • leukaemia

Summary

  1. Top of page
  2. Summary
  3. Methods
  4. Results
  5. Discussion
  6. Acknowledgements
  7. References

Between 2000 and 2006, 85 adult BCR-ABL negative acute lymphoblastic leukaemia (ALL) patients between 18 and 60 years of age were treated using a modified paediatric regimen, which included high doses of asparaginase delivered weekly for 30 weeks during intensification. The complete response rate with induction therapy was 89%, and decreased with increasing age, mainly due to higher induction mortality. All post-induction treatments were delivered on an outpatient basis. The most common complications during intensification were infections (47%), osteonecrosis (32%), venous thromboembolism (23%) and neuropathy (22%). At a median follow-up of 4 years, the 5-year overall survival (OS) and relapse-free survival (RFS) were 63% and 71%, respectively. Significant adverse predictors for OS were age >35 years, high white blood cell count, MLL rearrangement, allogeneic stem cell transplantation in first complete remission and <80% of the planned asparaginase dose delivered during intensification. Patients aged ≤35 years had a 3 year OS of 83%, as compared to 52% for patients aged >35 years. We conclude that the administration of this paediatric regimen is feasible and has considerable activity in adult ALL, particularly in younger patients. Effective delivery of asparaginase dosing appears to be important in achieving an optimal antileukaemic effect.

Acute lymphoblastic leukaemia (ALL) accounts for approximately 20% of adult and nearly 80% of childhood acute leukaemias. There has been considerable improvement in results with childhood ALL in recent years, with CR rates of 95% and 5-year disease-free survivals of 80% with modern protocols (Schrappe et al, 2000; Silverman et al, 2001; Pui & Evans, 2006). However, results in adults with ALL are far inferior, with survival rates of 35–45% in patients aged 18–60 years (Annino et al, 2002; Thomas et al, 2004; Goldstone et al, 2008). This is partly related to a higher incidence of BCR-ABL (Philadelphia chromosome) positive disease in adults. However, even in BCR-ABL negative patients, results are inferior. Adult ALL is also characterized by a higher frequency of other poor risk features, such as high white blood cell count (WBC) presentation, other karyotypic abnormalities and a lower frequency of favourable risk features, such as hyperdiploidy and the ETV6-RUNX1 (TEL-AML1) fusion gene (Mancini et al, 2005; Rowe et al, 2005; Moorman et al, 2007).

Treatment regimens used by paediatric and adult oncologists also vary considerably. Paediatric regimens use more intensive doses of certain drugs, such as asparaginase, as compared to adult regimens. Recently, retrospective data have been published demonstrating that those adolescents and young adults with ALL who have been treated with a paediatric ALL regimen have superior event-free and overall survival as compared to adult-based therapy (Barry et al, 2007; Ribera et al, 2008). In light of encouraging results reported regarding the Dana Farber Cancer Institute paediatric protocol DFCI 91-01 in adolescent ALL (Silverman et al, 2001; Barry et al, 2007), we have been treating all newly diagnosed ALL patients aged 18–60 years with a modified version of this protocol, and now report our results.

Methods

  1. Top of page
  2. Summary
  3. Methods
  4. Results
  5. Discussion
  6. Acknowledgements
  7. References

Patients

From June 2000 until September 2006, 85 consecutive newly diagnosed BCR-ABL negative ALL patients aged 18–60 years were initiated on a modified DFCI 91-01 protocol. This regimen was used as the standard frontline ALL regimen at Princess Margaret Hospital during this time period. Patients were identified from the leukaemia database; data were collected from the leukaemia database and by chart review. All data were updated as of December 2008. Institutional Review Board approval was obtained prior to initiation of retrospective chart review.

Treatment

Treatment details are outlined in Table I. Induction therapy was administered on the inpatient leukaemia unit, while all post-remission therapy was administered on an outpatient basis. Patients with a positive initial cerebrospinal fluid (CSF) received twice weekly intrathecal (IT) chemotherapy until the CSF cleared. Patients with progressive peripheral neuropathy during intensification or maintenance were switched from vincristine to vinblastine. Escherichia coli-derived asparaginase was used for all patients. Dose modifications during post-remission therapy were as follows: for Day 1 of each cycle, if the absolute neutrophil count (ANC) was <0·5 × 109/l or platelet count <50 × 109/l, the cycle was delayed for 1 week and the 6-mercaptopurine (6-MP) and methotrexate (Mtx) doses were subsequently reduced by 20%. If ANC and platelet counts were normal at Day 1 of each cycle, the 6-MP and Mtx doses were increased by 20% (up to a maximum of 150% for 6-MP and 133% for Mtx). If the serum aspartate transaminase (AST) or alanine transaminase (ALT) was >8×, or serum bilirubin > 1·8×, the upper limit of normal (ULN), the asparaginase dose was held for that week, and the 6-MP and Mtx doses were reduced by 20%.

Table I.   Treatment protocol.
  1. *Cytarabine/methotrexate/hydrocortisone triple intrathecal therapy.

  2. †Substitute vinblastine 10 mg IV for ileus or neuropathy.

  3. ‡Substitute amsacrine 85 mg/m2 if cardiac ejection fraction <50%.

Induction (4 weeks)
 Prednisone10 mg PO QID Days 0–28
 Doxorubicin30 mg/m2 IVDays 0 and 1
 Vincristine2 mg IVDays 0, 7, 14, 21
 Methotrexate4 g/m2 IV over 1 hDay 2 (with leucovorin rescue)
 Asparaginase25 000 IU/m2 IMDay 4
 Cyt/Mtx/HC*40/12/15 mg ITDays 0, 14
CNS therapy (3 weeks)
 Doxorubicin30 mg/m2 IVDay 1
 Vincristine†2 mg IVDay 1
 6-Mercaptopurine50 mg/m2 PO QHSDays 1–14
 Cranial radiation1200 cGyOver 8 d
 Cyt/Mtx/HC*40/12/15 mg ITDays 1, 4, 8, 11
Intensification therapy: 30 weeks (10 cycles–21 d/cycle)
 Doxorubicin‡30 mg/m2 IVDay 1 (cycles 1–7 only)
 Vincristine†2 mg IVDay 1
 6-Mercaptopurine50 mg/m2 PO QHSDays 1–14
 Dexamethasone9 mg/m2 PO BIDDays 1–5
 Asparaginase12 500 IU/m2 IMDays 1, 8, 15
 Methotrexate30 mg/m2 IVDays 2, 9, 16 (cycles 8–10 only)
 Cyt/Mtx/HC*40/12/15 mg ITEvery 18 weeks
Maintenance therapy: 72 weeks (24 cycles–21 d/cycle)
 Vincristine†2 mg IVDay 1
 6-Mercaptopurine50 mg/m2 PO QHSDays 1–14
 Dexamethasone6 mg/m2 PO BIDDays 1–5
 Methotrexate30 mg/m2 IV/IMDays 1, 8, 15
 Cyt/Mtx/HC*40/12/15 mg ITEvery 18 weeks

All patients received trimethoprim–sulfamethoxazole 800/160 mg three times weekly as prophylaxis against Pneumocystis carinii from induction until the completion of maintenance therapy. After March 2002, antifungal prophylaxis was also used during induction (either low-dose amphotericin 0·3 mg/kg/d IV or fluconazole 400 mg daily). Febrile neutropenia was treated with IV broad-spectrum antibiotics. Patients also received bisphosphonate therapy plus calcium and vitamin D from the start of intensification to prevent corticosteroid-inducted osteopenia.

Prior to December 2002 all patients in first complete remission (CR1) were offered myeloablative allogeneic stem cell transplant (alloBMT) if a suitable matched sibling donor was available, using cyclophosphamide and total body irradiation (TBI) as previously reported (Gupta et al, 2004). After this date only high-risk patients were offered alloBMT; high-risk features were defined as WBC >30 × 109/l (pre-B phenotype) or >100 × 109/l (T phenotype), or the presence of the MLL gene rearrangement.

Laboratory tests

The diagnosis of ALL was established by standard morphological and immunophenotypic analysis, using a panel of lymphoid and myeloid markers, by flow cytometry. All specimens were confirmed to be negative for the BCR-ABL1 gene rearrangement by reverse transcription polymerase chain reaction (RT-PCR). Cytogenetics was determined by standard karyotyping. For patients with cytogenetic abnormalities involving chromosome 11, fluorescence-in situ hybridization or PCR for 11q23 (MLL rearrangement) was also performed.

Statistical analysis

Complete remission (CR) was defined as <5% blasts in a normocellular marrow, with ANC > 1·0 × 109/l and platelets > 100 × 109/l. Overall survival (OS) was defined as the time from diagnosis to death from any cause. Relapse-free survival (RFS) was defined as the time from CR1 after induction until either disease relapse or death from any cause; only patients achieving CR with DFCI induction were analysed for RFS. Analysis of predictors for CR was made using logistic regression model, while comparisons of RFS and OS were made using the Kaplan–Meier method and log-rank test. Results were considered significant if the P-value was <0·05. All analyses were performed using sas 9.1 (SAS Institute, Cary, NC, USA).

Results

  1. Top of page
  2. Summary
  3. Methods
  4. Results
  5. Discussion
  6. Acknowledgements
  7. References

Patient characteristics

The characteristics of the 85 patients are outlined in Table II. Sixteen patients were identified as high-risk (six with high WBC at presentation, three with MLL and seven with both of these features). Of the 13 high WBC presentations, 11 were pre-B. Of the 23 patients with T-ALL, 20 were male and 14 presented with large mediastinal masses. Of the five patients with prior chemotherapy or radiotherapy for malignancies, three had breast cancer treated with CEF (cyclophosphamide, epirubicin, fluorouracil) chemotherapy, one had Hodgkin lymphoma treated with ABVD (doxorubicin, bleomycin, vinblastine, dacarbazine) and one had a thymoma treated with etoposide/cisplatin. Of these, two had MLL rearrangements (one t(4;11) and one t(1;11)), one had complex cytogenetic abnormalities, one had normal karyotype and one was not evaluable.

Table II.   Baseline patient characteristics (n = 85).
  1. *Expression of at least one myeloid marker.

  2. †High WBC = >30 × 109/l (Pre-B), >100 × 109/l (T).

  3. ‡Lactate dehydrogenase, normal up to 243 U/l.

  4. §Nine had t(4;11), one had t(1;11).

  5. ECOG, Eastern Cooperative Oncology Group; CNS, central nervous system.

Age (years), median (range)37 (18–60)
Male : female58:27
Prior therapy for malignancy5 (6%)
Performance status (ECOG)
 0–164
 217
 34
Phenotype(%)
 Pre-B61 (72)
 T24 (28)
Aberrant myeloid phenotype*41 (48)
WBC at presentation (×109/l)
 Median (range)10·5 (0·9–280)
 Low72 (85%)
 High†13 (15%)
LDH u/l‡, Median (range)509 (73–9910)
CNS disease at presentation14 (16%)
Cytogenetics (%)
 Normal24 (28)
 MLL rearrangement§10 (12)
 Hyperdiploid3 (4)
 t(1;19)3 (4)
 Other simple17 (20)
 Complex (≥3 abnormal)11 (13)
 Not evaluable17 (20)

Response to induction

The outcome of the patients is summarized in Fig 1. Seventy-six patients (89%) achieved bone marrow confirmed CR. There were four primary non-responders (two T cell and two Pre-B); only one had high-risk features (high WBC). The remaining five patients died from infectious causes during induction, four with suspected or proven Candida sepsis (three of these prior to the institution of antifungal prophylaxis) and one with brain abscesses of unknown aetiology.

image

Figure 1.  Summary of patient outcomes (NR, non-responder; CR, complete remission; BMT, bone marrow transplantation; CCR, continuous complete remission; CR2, 2nd complete remission).

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The following predictors were analysed for attainment of CR: age, presenting WBC, immunophentype and MLL rearrangement. Of these, only age predicted for achievement of CR. For patients aged ≤35 years, the complete response rate was 98% (41/42), vs. 81% (35/43) for patients aged >35 years (P = 0·03). Within the older age group, the complete response rate decreased with increasing age – from 86% for patients aged 36–49 years, to 73% for patients aged ≥50 years. There was a trend for an increase in induction mortality by age: 0% for age ≤35 years, 8% for age 36–49 years, and 20% for age ≥50 years.

Post-remission therapy

Of the 76 CR patients who were eligible for central nervous system (CNS) directed prophylaxis, one proceeded to early BMT with TBI and did not receive cranial radiotherapy (RT). The remaining 75 completed cranial RT and IT chemotherapy as per Table I.

At least one cycle of intensification was administered to 74 patients; two patients proceeded directly to alloBMT without intensification. Fifty-seven patients (77%) completed all 10 intensification cycles. One patient stopped after cycle 2 due to poor compliance and one after cycle 3 due to severe intolerance. There were two deaths during intensification, one due to sepsis after cycle 3 and one with multiple intracranial masses of unknown aetiology. Three patients relapsed during intensification, after cycles 3, 4 and 7, respectively. The remaining 10 patients proceeded to alloBMT at varying points during cycles 1–7 of intensification.

Survival

The median follow-up of the surviving patients was 48 months (range 30–89 months) from the start of therapy. Overall, 13 patients relapsed (three in the CNS and 10 in the bone marrow), and 29 patients died. Causes of death included induction-related complications (five patients), intensification-related complications (two), transplant-related complications (five), primary refractory leukaemia (four), recurrent metastatic breast cancer (one) and relapse (12). One relapsed patient achieved a CR2 with hyperCVAD (fractionated cyclophosphamide, vincristine, doxorubicin, dexamethasone) as salvage therapy, and was 2 months post-unrelated BMT at the time of writing. The 3-year OS for the entire group was 67% [95% confidence interval (CI) 57–78%], while the 3-year RFS for all the CR patients was 71% (95% CI 61–82%). The respective 5-year OS was 63% (95% CI 51–73%) and the 5-year RFS was 71% (95% CI 59–80%).

Of the five patients who had received prior chemoradiotherapy for malignancy, three have relapsed, including the t(4;11), complex karyotype and inevaluable cytogenetics. When these were excluded, the 3-year OS of the remaining 80 patients was 71% (95% CI 59–79%) and the 3-year RFS was 75% (95% CI 63–84%).

The analysis of prognostic factors for RFS and OS is summarized in Table III. As shown in Fig 2, age >35 years was significantly associated with inferior OS, and showed a trend toward inferior RFS. High WBC (>30 × 109/l for Pre-B ALL or >100 × 109/l for T-ALL) and the presence of MLL gene rearrangement were each associated with inferior RFS and OS (Table III and Fig 3). Other cytogenetic features (normal, single or complex abnormalities) did not significantly influence RFS or OS (data not shown), nor did immunophenotype or the presence of CNS leukaemia.

Table III.   Analysis of prognostic factors.
 3-year RFS % (95% CI)P3-year OS % (95% CI)P
  1. RFS, relapse-free survival; OS, overall survival; WBC, white blood cell count; CNS, central nervous sytem; LDH, lactate dehydrogenase.

Age (years)
 ≤3577 (59–88)0·1183 (72–95)0·003
 >3560 (41–74)52 (37–67)
Immunophenotype
 Pre-B66 (53–79)0·1764 (51–76)0·34
 T85 (69–99)79 (63–95)
Aberrant myeloid phenotype
 No74 (56–86)0·5367 (49–79)0·69
 Yes63 (44–77)63 (46–76)
WBC
 Low risk76 (65–90)0·0173 (62–83)0·007
 High risk45 (16–75)38 (12–64)
CNS disease
 Yes80 (55–99)0·5864 (39–89)0·80
 No70 (58–81)68 (57–79)
LDH (u/l)
 <100076 (65–88)0·1971 (59–83)0·36
 ≥100062 (41–83)61 (40–81)
MLL rearrangement
 Present44 (12–77)0·0140 (10–70)0·01
 Absent75 (64–86)71 (61–82)
% Asparaginase delivered
 <80%55 (25–84)0·00267 (40–93)0·003
 ≥80%88 (77–98)91 (82–99)
% Vinca given as vinblastine
 <50%67 (53–81)0·2770 (56–84)0·18
 ≥50%77 (63–91)86 (73–99)
AlloBMT in CR1
 Yes42 (14–70)0·00750 (22–78)0·005
 No77 (66–88)81 (71–91)
image

Figure 2.  Survival by age. (A) Relapse-free survival of patients achieving complete remission, and (B) overall survival of all patients, according to age ≤ or >35 years.

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image

Figure 3.  Survival by WBC or MLL. Overall survival of all patients according to (A) presenting WBC (high defined as >30 × 109/l for Pre-B and >100 × 109/l for T), and (B) presence of MLL gene rearrangement.

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Twelve patients received <80% (median 31%, range 6–73%), of the total planned asparaginase dose during intensification due to intolerance (excluding patients who received alloBMT or whose treatment was stopped due to relapse or death during intensification); six of these were aged >35 years. The reasons for reduced asparaginase dosing were hypersensitivity reactions (four patients), pancreatitis (four) and deterioration in overall performance status (four). Patients who received at least 80% of the planned asparaginase dosing had a significantly higher 3-year OS (P = 0·003) and RFS (P = 0·002), and a lower cumulative risk of relapse (P = 0·01), compared to those who received <80% of the planned dosing due to intolerance (Fig 4).

image

Figure 4.  Outcome by asparaginase dosing. (A) Relapse-free survival and (B) cumulative incidence of relapse, according to the cumulative % of targeted asparaginase dose delivered during intensification (dashed line > 80%, solid line ≤ 80%).

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A total of 28 patients received >50% of their planned vinca alkaloid dosing as vinblastine during intensification; almost all of these patients were continued on vinblastine through maintenance therapy. There was no significant difference in RFS and OS between this group and the group that received >50% of the planned dose as vincristine (Table III).

A total of 12 patients underwent related alloBMT in CR1; three were transplanted due to high-risk disease (MLL+ and/or high presenting WBC), while the remaining nine were standard risk patients. The frequency of high-risk patients in the transplanted group (25%) was not significantly different compared to the patients who were not transplanted in CR1 (18%). The median age of the transplanted patients was 41 (range 25–58) years. Seven transplanted patients have died, five due to transplant-related complications and two due to relapse. As shown in Table III, patients who underwent alloBMT in CR1 had an inferior RFS and OS compared to the 64 patients who were not transplanted in CR1.

Toxicities

The most common toxicity during the induction phase was infection; this included culture negative febrile neutropenia (13 patients), bacteraemia (13), invasive fungal infections (nine), suspected herpes simplex meningitis (two) and dental abscess (one). Noninfectious toxicities included steroid-inducted hyperglycaemia (10 patients), grade III mucositis (five), neuropathy/ileus (four), seizures, acute renal failure (two patients each), myopathy, gastro-intestinal haemorrhage, neutropenic enterocolitis and myocardial infarction (one patient each). The CNS prophylaxis phase was well tolerated, with the major toxicities being Grade I–II headache and nausea.

The major toxicities during intensification included infections, primarily bacterial (47%), osteonecrosis (32%), venous thromboembolism (VTE) (23%), neuropathy (22%), serum AST/ALT > 5× ULN (13%), pancreatitis (7%), hyperglycemia requiring insulin (6%), hypersensitivity reaction to asparaginase (5%) and steroid myopathy (4%). VTE included deep vein thrombosis (nine patients), pulmonary embolism (three), central venous catheter-associated thrombosis (three) and retinal vein thrombosis (one). In most cases of VTE, the asparaginase was interrupted for 2–3 weeks and then restarted with continued anticoagulation, without recurrence.

Osteonecrosis (ON) was, in many cases, diagnosed later during maintenance therapy. However, most patients with this complication were symptomatic by the end of intensification. Sites of ON included hips (17 cases, 14 bilateral), knees and/or femoral shaft (nine) and shoulder (one); several had more than one site. The median age of the patient diagnosed with ON was 33 (range 18–57) years. Three patients to date have proceeded to successful total hip replacement surgery. Maintenance therapy was well tolerated with few complications.

Discussion

  1. Top of page
  2. Summary
  3. Methods
  4. Results
  5. Discussion
  6. Acknowledgements
  7. References

We have demonstrated that treatment with this modified paediatric regimen is feasible in ALL patients between the ages of 18 and 60, with acceptable overall toxicity. As this was an unselected series of consecutive patients treated at a single institution, which is the regional centre for the treatment of acute leukaemia, selection bias would not be a factor. Our patient population is typical when compared to adult patients studied using other regimens; therefore, differences in outcome can be inferred to arise from our treatment strategy and not from differences in tumour biology. The OS and RFS obtained in this series are superior to results reported in Philadelphia chromosome negative patients using adult ALL regimens, including Leucémies Aiguës Lymphoblastiques de l’Adulte (LALA)-94 (41% 3-year DFS) (Thomas et al, 2004), Hyper-CVAD (45% 5-year OS) (Kantarjian et al, 2000) and Medical Research Council (MRC) UKALL XII/Eastern Cooperative Oncology Group (ECOG) E2993 (43% 5-year OS) (Goldstone et al, 2008). The results also compare favourably with other recent reports using paediatric regimens in young adults (Ribera et al, 2008; Huguet et al, 2009), and further support the concept that such paediatric regimens have superior activity as compared to adult protocols.

The most impressive results were seen in the young adult population up to 35 years of age; the 83% 3-year OS is comparable to results reported in the adolescent population using this regimen (Silverman et al, 2001; Barry et al, 2007). As determined in other reports for adult ALL, older patients had a significantly inferior survival. This was partly related to a higher induction mortality. The Group for Research on Adult Acute Lymphoblastic Leukaemia (GRAALL)-2003 study (Huguet et al, 2009), using another paediatric regimen, also reported a higher induction death rate in older patients (13% for patients aged 46–60 years). The 20% induction mortality in patients aged ≥50 years in our study can potentially be addressed by improved infection prophylaxis and surveillance, or by modifying the induction itself – one possibility would be to move the high-dose methotrexate to the post-remission phase in older patients, in order to reduce mucosal toxicity during induction.

Patients aged >35 years achieving CR also trended toward a lower RFS. This might be partly related to differences in disease biology in older ALL patients. However, older patients were also less likely to achieve 80% of the targeted asparaginase dosing during intensification, suggesting that an inability to deliver adequate dose intensity in older patients, due to decreased tolerance, may be an important factor in their inferior outcome. Nevertheless, the results in the over-35 age group also compare favourably with previously reported series (Annino et al, 2002; Thomas et al, 2004; Goldstone et al, 2008).

Certain other high-risk groups still appear to have inferior outcomes with this protocol, including patients presenting with high WBC and those with MLL rearrangements, particularly the t(4;11) karyotype. The latter was strongly associated with high presenting WBC. These high-risk patients may benefit from alloBMT in CR1 (Annino et al, 2002; Vey et al, 2006), or from modifications to the post-remission regimen, such as the incorporation of high-dose cytarabine or cyclophosphamide. However, this needs to be further addressed in prospective studies.

Acute lymphoblastic leukaemia occurring in patients treated for a prior malignancy, although previously reported (Pagano et al, 2000), is rare and has not been a well-recognized entity. Our analysis suggests that this does occur and may represent a poor prognosis subgroup (3/5 relapses). However, this needs to be fully addressed with a larger series, as our numbers are small and it is unclear whether this is a reflection of poor risk karyotype or an independent prognostic feature.

Among the distinguishing features of this protocol is the heavy reliance on high doses of asparaginase during the intensification phase of treatment. This agent forms the backbone of the intensification phase; in total, the protocol delivers at least four times more asparaginase than most adult protocols. Our results suggest that, as reported in the paediatric population (Silverman et al, 2001), treatment with at least 80% of the targeted dose for asparaginase remains critical for optimal outcomes. The 3-year RFS of 88% in patients receiving this target dosing is comparable to outcomes in the adolescent population. Our experience is that this target can be achieved in approximately 80% of patients up to 60 years of age. It is not possible to ascertain definitively whether the inferior outcomes with reduced asparaginase dosing were specifically related to this drug, or were a reflection of overall reduced dosing intensity, because asparaginase intolerant patients tended to receive less of other drugs as well. Furthermore, as only 12 patients did not receive 80% of the targeted dose, confirming the importance of asparaginase dosing as an independent prognostic factor would require a larger series of patients.

The presence of CNS leukaemia did not predict for an adverse outcome. Most patients experienced a rapid clearance of CSF blasts with intrathecal chemotherapy plus high-dose intravenous methotrexate during induction, and CNS recurrence was infrequent. These findings are in keeping with those reported in the LALA-94 trial (Thomas et al, 2004). In contrast, Lazarus et al (2006) reported that patients with CNS leukaemia had a somewhat inferior OS (29% vs. 38% for those without CNS disease). However, even in the latter study, CNS involvement was far less predictive of survival than other factors, such as age and WBC, by multivariate analysis.

Vincristine-induced neuropathy is a common and sometimes debilitating occurrence in these patients. There have been concerns that substituting vinblastine for vincristine could potentially adversely impact outcomes, possibly by increased myelosuppression necessitating reductions in doses of other agents, such as 6-MP. Our results demonstrated that the substitution of vinblastine does not adversely impact survival; there was actually a trend toward a superior RFS and OS in the vinblastine-treated group.

Osteonecrosis (ON) was diagnosed in nearly one-third of patients who received intensification. This rate is higher than reported in retrospective paediatric ALL series (Vaidya et al, 1998; Patel et al, 2008), and is probably related to the high doses of corticosteroids used in this protocol, possibly exacerbated by the high doses of asparaginase. However, the cumulative incidence may actually be higher, as magnetic resonance imaging scans were mainly performed in symptomatic patients and not routinely; ON is frequently asymptomatic in the early stages (Ojala et al, 1997). ON can progress to joint destruction, eventually requiring hip replacement surgery. Postulated mechanisms of ON include increased intra-osseous pressure causing vascular occlusion, impaired fibrinolysis (French et al, 2008) and cytokine effects (Assouline-Dayan et al, 2002). Future strategies need to focus on elucidating the pathogenesis of this complication; this may lead to useful pharmacological preventative strategies. Reducing corticosteroid doses, or using a different ‘paediatric’ regimen that contains lower doses, may decrease the frequency of ON and may therefore be more suitable to the adult population. However, it is unclear what impact such modifications would have on relapse rates. ON can have a substantial impact on patients’ quality of life following the completion of therapy. We have not evaluated quality of life issues in our patients, but such an evaluation is currently being planned.

Venous thromboembolism events were also common, primarily during intensification. This is probably related to the high doses of asparaginase, which is associated with an increased risk of VTE secondary to decreased levels of antithrombin III and other anticoagulants (Beinart & Damon, 2004). Although none of these events were fatal, they were potentially life threatening and a cause of significant morbidity. Prophylactic low-dose anticoagulation with low-molecular weight heparin may potentially reduce the incidence, but has not been studied prospectively in this setting. As the asparaginase could be successfully restarted in most cases with continued anticoagulation, VTE did not have a major adverse impact on the ability to administer optimal asparaginase dosing.

A recent MRC/ECOG study found that standard risk ALL patients had an overall survival benefit of approximately 10% with alloBMT in CR1 as compared to a no donor group (Goldstone et al, 2008). However, there was no benefit seen in high-risk patients. Standard risk patients included those under age 35 years; the OS in the non-transplanted group of younger standard risk patients in that report (52% 5-year OS) was lower than that obtained in our series (83% 3-year OS which was maintained at 5 years, as shown in Fig 1). This suggests that the net benefit of alloBMT versus chemotherapy may be critically dependent on the chemotherapy regimen used. Our data do not definitely address this question, as the number of transplanted patients in this series was small and the group was selected. However, it would be difficult to improve on our survival results in patients aged <35 years with alloBMT, given the inherent treatment-related risks associated with the latter. Therefore, we do not favour transplanting standard risk young patients in CR1 treated with this protocol. However, this question would need to be evaluated in a proper comparative trial. It is possible that other approaches to evaluate patients at higher risk of relapse, such as minimal residual disease (MRD) evaluation (Bassan et al, 2009), could identify a subpopulation of patients that may benefit from BMT, but this requires further evaluation. MRD monitoring was not performed in our patients.

In summary, our results demonstrate the feasibility of using this modified paediatric regimen to treat adults with ALL up to the age of 60 years. Patients up to the age of 35 years appear to have particularly favourable results; outcomes are superior to previously reported series in adult ALL. Future strategies should focus on reducing some of the complications associated with the intensification portion of the regimen, particularly infections and osteonecrosis, as well as improving results in high-risk patients. Nevertheless, the overall results indicate that this is a highly effective antileukaemic regimen for adult ALL.

Acknowledgements

  1. Top of page
  2. Summary
  3. Methods
  4. Results
  5. Discussion
  6. Acknowledgements
  7. References

We would like to thank all the inpatient and outpatient leukaemia nurses, as well as the inpatient clinical associate physicians, for the outstanding care they have provided to our patients. We would also like to thank Dr Steven Sallan who was constantly open to discussion and consultation as the Dana Farber Cancer Institute protocol was adapted to the adult population.

References

  1. Top of page
  2. Summary
  3. Methods
  4. Results
  5. Discussion
  6. Acknowledgements
  7. References
  • Annino, L., Vegna, M.L., Camera, A., Specchia, G., Visani, G., Fioritoni, G., Ferrara, F., Peta, A., Ciolli, S., Deplano, W., Fabbiano, F., Sica, S., Di Raimondo, F., Cascavilla, N., Tabilio, A., Leoni, P., Invernizzi, R., Baccarani, M., Rotoli, B., Amadori, S. & Mandelli, F. (2002) Treatment of adult acute lymphoblastic leukemia (ALL): long-term follow-up of the GIMEMA ALL 0288 randomized study. Blood, 99, 863871.
  • Assouline-Dayan, Y., Chang, C., Greenspan, A., Shoenfeld, Y. & Gershwin, M.E. (2002) Pathogenesis and natural history of osteonecrosis. Seminars in Arthritis and Rheumatism, 32, 94124.
  • Barry, E., DeAngelo, D.J., Neuberg, D., Stevenson, K., Loh, M.L., Asselin, B.L., Barr, R.D., Clavell, L.A., Hurwitz, C.A., Moghrabi, A., Samson, Y., Schorin, M., Cohen, H.J., Sallan, S.E. & Silverman, L.B. (2007) Favorable outcome for adolescents with acute lymphoblastic leukemia treated on Dana-Farber Cancer Institute Acute Lymphoblastic Leukemia Consortium protocols. Journal of Clinical Oncology, 25, 813819.
  • Bassan, R., Spinelli, O., Oldani, E., Intermesoli, T., Tosi, M., Peruta, B., Rossi, G., Borlenghi, E., Pogliani, E.M., Terruzzi, E., Fabris, P., Cassibba, V., Lambertenghi-Deliliers, G., Cortelezzi, A., Bosi, A., Gianfaldoni, G., Ciceri, F., Bernardi, M., Gallamini, A., Mattei, D., Di Bona, E., Romani, C., Scattolin, A.M., Barbui, T. & Rambaldi, A. (2009) Improved risk classification for risk-specific therapy based on the molecular study of MRD in adult ALL. Blood, doi: DOI: 10.1182/blood-2008-11-185132
  • Beinart, G. & Damon, L. (2004) Thrombosis associated with l-asparaginase therapy and low fibrinogen levels in adult acute lymphoblastic leukemia. American Journal of Hematology, 77, 331335.
  • French, D., Hamilton, L.H., Mattano, L.A., Sather, H.N., Devidas, M., Nachman, J.B. & Relling, M.V. (2008) A PAI-1 (SERPINEI) polymorphism predicts osteonecrosis in children with acute lymphoblastic leukemia: a report from the Children’s Oncology Group. Blood, 111, 44964499.
  • Goldstone, A.H., Richards, S.M., Lazarus, H.M., Tallman, M.S., Buck, G., Fielding, A.K., Burnett, A.K., Chopra, R., Wiernik, P.H., Foroni, L., Paietta, E., Litzow, M.R., Marks, D.I., Durrant, J., McMillan, A., Franklin, I.M., Luger, S., Ciobanu, N. & Rowe, J.M. (2008) In adults with standard-risk acute lymphoblastic leukemia, the greatest benefit is achieved form a matched allogeneic transplantation in first complete remission, and an autologous transplantation is less effective than conventional consolidation/maintenance chemotherapy in all patients: final results of the International ALL Trial (MRC UKALL XII/ECOG E2993). Blood, 111, 18271833.
  • Gupta, V., Yi, Q.-L., Brandwein, J., Minden, M.D., Schuh, A.C., Wells, R.A., Tsang, R., Daly, A., Lipton, J.H. & Messner, H.A. (2004) The role of allogeneic bone marrow transplantation in adult patients below the age of 55 years with acute lymphoblastic leukemia in first complete remission: a donor vs no donor comparison. Bone Marrow Transplantation, 33, 397404.
  • Huguet, F., Leguay, T., Raffoux, E., Thomas, X., Beldjord, K., Delabesse, E., Chevallier, P., Buzyn, A., Delannoy, A., Chalandon, Y., Vernant, J.P., Lafage-Pochitaloff, M., Chassevent, A., Lhéritier, V., Macintyre, E., Béné, M.C., Ifrah, N. & Dombret, H. (2009) Pediatric-inspired therapy in adults with Philadelphia chromosome-negative acute lymphoblastic leukemia: the GRAALL-2003 study. Journal of Clinical Oncology, 27, 911918.
  • Kantarjian, H.M., O’Brien, S., Smith, T.L., Cortes, J., Giles, F.J., Beran, M., Pierce, S., Huh, Y., Andreeff, M., Koller, C., Ha, C.S., Keating, M.J., Murphy, S. & Freireich, E.J. (2000) Results of treatment with hyper-CVAD, a dose-intensive regimen, in adult acute lymphocytic leukemia. Journal of Clinical Oncology, 18, 547561.
  • Lazarus, H.M., Richards, S.M., Chopra, R., Litzow, M.R., Burnett, A.K., Wiernik, P.H., Franklin, I.M., Tallman, M.S., Cook, L., Buck, G., Durrant, I.J., Rowe, J.M. & Goldstone, A.H. (2006) Central nervous system involvement in adult acute lymphoblastic leukemia at diagnosis: results from the international ALL trial MRC UKALL XII/ECOG E2993. Blood, 108, 465472.
  • Mancini, M., Scappaticci, D., Cimino, G., Nanni, M., Derme, V., Elia, L., Tafuri, A., Vignetti, M., Vitale, A., Cuneo, A., Castoldi, G., Saglio, G., Pane, F., Mecucci, C., Camera, A., Specchia, G., Tedeschi, A., Di Raimondo, F., Fioritoni, G., Fabbiano, F., Marmont, F., Ferrara, F., Cascavill, N., Todeschini, G., Nobile, F., Grazia Kropp, M., Leoni, P., Tabilio, A., Luppi, M., Annino, L., Mandelli, F. & Foà, R. (2005) A comprehensive genetic classification of adult acute lymphoblastic leukemia: analysis of the GIMEMA 0496 protocol. Blood, 105, 34343441.
  • Moorman, A.V., Harrison, C.J., Buck, G.A.N., Richards, S.M., Secker-Walker, L.M., Martineau, M., Vance, G.H., Cherry, A.M., Higgins, R.R., Fielding, A.K., Foroni, L., Paietta, E., Tallman, M.S., Litzow, M.R., Wiernik, P.H., Rowe, J.M., Goldstone, A.H. & Dewald, G.W. (2007) Karyotype is an independent prognostic factor in adult acute lymphoblastic leukemia (ALL): analysis of cytogenetic data from patients treated on the Medical Research Council (MRC) UKALLXII/Eastern Cooperative Oncology Group (ECOG) 2993 trial. Blood, 109, 31893197.
  • Ojala, A.E., Lanning, F.P., Paakko, E. & Lanning, B.M. (1997) Osteonecrosis in children treated for acute lymphoblastic leukemia: a magnetic resonance imaging study after treatment. Medical Pediatric Oncology, 29, 260265.
  • Pagano, L., Pulsoni, A., Mele, L. & Leone, G. (2000) Clinical and epidemiologic features of acute lymphoblastic leukemia following a previous malignancy. Leukemia and Lymphoma, 39, 465475.
  • Patel, B., Richards, S.M., Rowe, J., Goldstone, A.H. & Fielding, A.K. (2008) High incidence of avascular necrosis in adolescents with acute lymphoblastic leukemia: a UKALL XII analysis. Leukemia, 22, 308312.
  • Pui, C.-H. & Evans, W.E. (2006) Treatment of acute lymphoblastic leukemia. New England Journal of Medicine, 354, 166178.
  • Ribera, J.-M., Oriol, A., Sanz, M.-A., Tormo, M., Fernandez-Abellan, P., Del Potro, E., Abella, E., Bueno, J., Parody, R., Bastida, P., Grande, C., Heras, I., Bethencourt, C., Feliu, E. & Ortega, J.-J. (2008) Comparison of the results of the treatment of adolescents and young adults with standard-risk acute lymphoblastic leukemia with the Programa Espanol de Tratamiento en Hemtologica pediatric-base Protocol ALL-096. Journal of Clinical Oncology, 26, 18431849.
  • Rowe, J.M., Buck, G., Burnett, A.K., Chopra, R., Wiernik, P.H., Richards, S.M., Lazarus, H.M., Franklin, I.M., Litzow, M.R., Ciobanu, N., Prentice, H.G., Durrant, J., Tallman, M.S. & Goldstone, A.H. (2005) Induction chemotherapy for adults with acute lymphoblastic leukemia: results of more than 1500 patients from the international ALL trial: MRC UKALL XII/ECOG E2993. Blood, 106, 37603767.
  • Schrappe, M., Reiter, A., Ludwig, W.D., Harbott, J., Zimmermann, M., Hiddemann, W., Niemeyer, C., Henze, G., Feldges, A., Zintl, F., Kornhuber, B., Ritter, J., Welte, K., Gadner, H. & Riehm, H. (2000) Improved outcome in childhood acute lymphoblastic leukemia despite reduced use of anthracyclines and cranial radiotherapy: results of trial ALL BFM90. Blood, 95, 33103322.
  • Silverman, L.B., Gelber, R.D., Dalton, V.K., Asselin, B.L., Barr, R.D., Clavell, L.A., Hurwitz, C.A., Moghrabi, A., Samson, Y., Schorin, M.A., Arkin, S., Declerck, L., Cohen, H.J. & Sallan, S.E. (2001) Improved outcome for children with acute lymphoblastic leukemia: results of Dana Farber Consortium Protocol 91-01. Blood, 97, 12111218.
  • Thomas, X., Boiron, J.-M., Huguet, F., Dombret, H., Bradstock, K., Vey, N., Kovacsovics, T., Delannoy, A., Fegueux, N., Fenaux, P., Stamatoullas, A., Vernant, J.-P., Tournilhac, O., Buzyn, A., Reman, O., Charrin, C., Boucheix, C., Gabert, J., Lhéritier, V. & Fiere, D. (2004) Outcome of treatment in adults with acute lymphoblastic leukemia: Analysis of the LALA-94 trial. Journal of Clinical Oncology, 22, 40754086.
  • Vaidya, S., Saika, S., Sirohi, B., Pai, S. & Advani, S. (1998) Avascular necrosis of bone – a complication of aggressive therapy for acute lymphoblastic leukemia. Acta Oncology, 37, 175177.
  • Vey, N., Thomas, X., Picard, C., Kovascovicz, T., Charin, C., Cayuela, J.M., Dombret, H., Dastugue, N., Huguet, F., Bastard, C., Stamatoulas, A., Giollant, M., Tournilhac, O., Macintyre, E., Buzyn, A., Bories, D., Kuentz, M., Dreyfus, F., Delannoy, A., Raynaud, S., Gratecos, N., Bordessoule, D., De.Botton, S., Preudhomme, C., Reman, O., Troussard, X., Pigneux, A., Bilhou, C., Vernant, J.P., Boucheix, C. & Gabert, J. (2006) Allogeneic stem cell transplantation improves the outcome of adults with t(1;19)/E2A-PBX1 and t(4;11)/MLL-AF4 positive B-cell acute lymphoblastic leukemia: results of the prospective multicenter LALA-94 study. Leukemia, 20, 21552161.