The use of pediatrics-inspired protocols in adolescent and young adult (AYA) acute lymphoblastic leukemia (ALL) results in superior survival compared with the adult protocols. Pediatrics-inspired protocols carry an increased risk of toxicity and treatment-related mortality in low resource settings, which can offset the potential benefits. We studied the outcomes and prognostic factors in the treatment of AYA ALL with a pediatrics-inspired regimen. We retrieved data regarding demographics, investigations, treatment details, and toxicities from the electronic medical records of patients diagnosed with ALL in the 15- to 25-year-old age group who were initiated on a modified Berlin-Frankfurt-Münster 90 (BFM-90) protocol between January 2013 and December 2016 at the Tata Memorial Centre. A total of 349 patients in the 15- to 25-year-old age group were treated with a modified BFM-90 protocol. The use of this pediatrics-inspired protocol resulted in a 3-year event-free survival (EFS) and overall survival (OS) of 59.4% and 61.8%, respectively. Only 15 patients underwent an allogeneic stem cell transplant. Minimal residual disease (MRD) persistence postinduction emerged as the only factor predictive of poor outcomes. A modified BFM-90 protocol is an effective and safe regimen for AYA ALL with an OS and EFS comparable to the published literature.

Acute lymphoblastic leukemia (ALL) in adolescents and young adults (AYAs) accounts for less than one-fourth of the total ALL cases but leads to 80% of ALL-related deaths.1  The AYA cohort has inferior outcomes compared with the younger children, who achieve cure rates of >90%.2-6  They fall at the transition between pediatric and adult populations because a uniform treatment strategy has never been followed and they are underrepresented in clinical trials.7  An increase in the incidence of high-risk subtypes, such as early thymic precursor (ETP) ALL, Philadelphia-positive (Ph+), and Ph-like ALL, also accounts for the inferior outcomes.8,9  Pediatric protocols deliver higher cumulative doses of nonmyelosuppressive drugs like asparaginase, vincristine, and steroids, whereas the adult protocol uses a higher dose of cytarabine and hematopoietic stem cell transplantation (HSCT). Treatment in this age group with pediatric protocols resulted in superior outcomes compared with adult protocols.7,10-14  In addition to the inferior outcomes with the adult protocols in the resource-poor setting,15-19  a major hindrance is its reliance on HSCT as a modality of dose intensification. HSCT frequencies are much lower in the developing world in comparison with the developed world.20,21  On the other hand, the use of pediatric dose-intensification strategies in adults is often compounded by increased risk for infections and other complications such as avascular necrosis, hepatitis, and pancreatitis.22-26 

Herein, we report the single-center experience with a modified BFM-90 protocol, a pediatrics-inspired regimen, in AYA ALL patients aged 15 to 25 years. We aimed to evaluate the efficacy and safety and identify the impact of prognostic factors (minimal residual disease [MRD], baseline white blood cell [WBC] count, cytogenetics, cerebrospinal fluid [CSF] status, toxicities, and infections) on survival outcomes.

Patients

We included treatment-naive patients (between 15 and 25 years of age) with ALL (B-cell [B-ALL] and T-cell [T-ALL]) who were treated at the Tata Memorial Centre, a tertiary cancer care center in India, between January 2013 and December 2016. The study was approved by the Institutional Ethics Committee (IEC/0319/3209/001). Patients who had received up to a week of steroids or 1 dose of vincristine were also included in the study. Data were retrieved from the electronic medical records.

Diagnosis

The diagnosis of ALL was established by peripheral blood and /or bone marrow morphologic assessment and flow cytometry (FCM). Cytogenetics by fluorescent in situ hybridization (FISH) and ploidy analysis was performed for risk stratification. For ploidy analysis, Giemsa-stained metaphases were captured using the Applied Spectral Imaging (Netser Sereni, Israel) GenASIs platform; modal chromosome counting was done on 20 to 30 metaphases and reported according to the International System for Human Cytogenetic Nomenclature (ISCN). Central nervous system (CNS) involvement was ascertained by CSF examination with both cytomorphology and FCM; the CNS status was defined as per the standard criteria.27  A mediastinal mass or lymphadenopathy with <25% lymphoblasts in the bone marrow was defined as T-lymphoblastic lymphoma (T-LBL).28 

Risk stratification

Patients were risk-stratified based on the baseline WBC count (>30 × 109/L for B-ALL and >100 × 109/L for T-ALL), cytogenetics [high-risk cytogenetics included t(9;22), t(4;11), t(1;19)], and ploidy (hypodiploidy).29,30  Patients with any of these factors were risk-stratified as high risk and others as standard risk.

Chemotherapy

Patients were administered a modified Berlin-Frankfurt-Münster 90 (BFM-90) protocol.31  The following modifications were made: native Escherichia colil-asparaginase was administered at a dose of 10 000 U/m2 either as a deep intramuscular (IM) injection or as an IV infusion. During the protocol M phase, high-dose methotrexate (HDMTx) was administered at a dose of 3 g/m2 along with leucovorin rescue. During phase 2 reinduction, all patients received cranial radiation therapy (RT) at a dose of 18 Gy per 10 fractions for CSF+ cases or 12.6 Gy per 7 fractions for CSF cases. Patients with the diagnosis of T-LBL did not receive cranial or mediastinal irradiation. Intrathecal methotrexate (12 mg) was administered during phase 1a, 1b, protocol M, and reinduction phase 2. In comparison with the original BFM protocol in the ALL-BFM-90 trial, we used reduced doses of 6-mercaptopurine (6MP) during phase 1b and maintenance because of the poor tolerance with the use of standard doses (60 mg/m2) of 6MP in our patients. The starting dose of 6MP was determined by the body surface area (BSA) of the patient (Table 1) and the doses were subsequently titrated based on tolerance. Similarly, with the concerns of increased toxicity with 5 g/m2 HDMTx, 3 g/m2 was used for our patients. Standard dosing for HDMTx ranges from 2 to 5 g/m232-34  During reinduction phase 2, in comparison with the original protocol, either 6 thioguanine (6TG) or 6MP were used. Change to 6MP was due to the nonavailability of the 6TG in India from 2017 onward.

Table 1.

Protocol: modified BFM-90 protocol for patients with AYA ALL

AgentsDose and timing
Induction phase 1a, days 1-35  
 Prednisolone 60 mg/m2 days 1-28 
 Vincristine 1.5 mg/m2 IV push (maximum dose 2 mg) on days 8, 15, 22, 29 
 Daunorubicin 30 mg/m2 IV push on days 8, 15, 22, 29 
 l-asparaginase 10000 U/m2 deep IM or IV over 30 min on days 12, 15, 18, 21, 24, 27, 30, 33 (8 doses) l-asparaginase stopped if the patient initiated on TKIs in Ph+ ALL* 
 IT methotrexate CNS disease: methotrexate 12 mg IT days 1, 15, 29
CNS+ disease: methotrexate 12 mg IT days 1, 8, 15, 22, 29 
 TKIs Imatinib 600 mg once daily or dasatinib 100 mg once daily
Started as soon as the cytogenetics (FISH) report was available 
Induction phase 1b, days 36-64  
 Cyclophosphamide 1000 mg/m2 IV infusion over 1 h with mesna 500 mg/m2 at 0 and 3 h on days 36 and 64 
 Cytosine arabinoside 75 mg/m2 on days 38-41, 45-48, 52-55, 59-62 
 6-MP, days 36-63 6MP dosing according to the BSA
BSA <1.3-50 mg 5 d/wk
BSA 1.3-1.6-50 mg/d every day
BSA >1.6-50 mg for 5 d and 100 mg for 2 d 
 IT methotrexate Methotrexate 12 mg intrathecally days 45, 59 
 TKIs Imatinib 600 mg once daily or dasatinib 100 mg once daily 
Protocol M, days 1-56  
 Methotrexate 3 g/m2 IV over 24 h on days 8, 22, 36, 50 
 Leucovorin rescue Starting dose at 42 h: 30 mg/m2
Further dosing based on the methotrexate levels at 42 h:
>1-2 μmol/L: leucovorin 30 mg/m2
>2-3 μmol/L: leucovorin 45 mg/m2
>3-4 μmol/L: leucovorin 60 mg/m2
>4-5 μmol/L: leucovorin 75 mg/m2
>5 μmol/L: MTX S.Conc. μmol/L × body weight (kg)
Leucovorin rescue continued until the methotrexate levels are <0.25 μmol/L 
 6-MP 25 mg/m2 from day 1 onward 
 IT methotrexate 12 mg IT on day 1 of methotrexate infusion 
 TKIs Imatinib 600 mg once daily or dasatinib 100 mg once daily
TKI stopped during methotrexate infusion* 
Reinduction phase 1, days 1-29  
 Dexamethasone 8 mg/m2 orally from days 1-21, taper from day 22 and stop by day 29 
 Vincristine 1.5 mg/m2 IV push (maximum dose 2 mg) on days 8, 15, 22, 29 
 Doxorubicin 30 mg/m2 IV push on days 8, 15, 22, 29 
 l-asparaginase 10 000 U/m2 deep IM or IV over 30 min on days 8, 11, 15, 18 (4 doses) l-asparaginase stopped if the patient initiated on TKIs in Ph+ ALL* 
 TKIs Imatinib 600 mg once daily or dasatinib 100 mg once daily 
Reinduction phase 2, days 30-50  
 Cyclophosphamide 1000 mg/m2 IV infusion over 1 h with mesna 500 mg/m2 at 0 and 3 h on day 36 
 Cytosine arabinoside 75 mg/m2 on days 38-41, 45-48 
 6-MP/6-TG, days 30-50 6TG: 60 mg/m2
6MP dosing according to the BSA
BSA < 1.3-50 mg 5 d/wk
BSA 1.3-1.6-50 mg/d every day
BSA > 1.6-50 mg for 5 d and 100 mg for 2 d 
 TKIs Imatinib 600 mg once daily or dasatinib 100 mg once daily 
 IT methotrexate Methotrexate 12 mg IT on days 38 and 45 
 Cranial RT 18 Gy/10 fractions for CSF+ cases
12.6 Gy/7 fractions for CSF cases 
Maintenance phase, days 1-730  
 6-MP* 6MP dosing according to the BSA
BSA < 1.3-50 mg 5 d/wk
BSA 1.3-1.6-50 mg/d every day
BSA > 1.6-50 mg for 5 d and 100 mg for 2 d 
 Methotrexate* 20 mg/m2 
 TKIs Imatinib 600 mg once daily or dasatinib 100 mg once daily 
AgentsDose and timing
Induction phase 1a, days 1-35  
 Prednisolone 60 mg/m2 days 1-28 
 Vincristine 1.5 mg/m2 IV push (maximum dose 2 mg) on days 8, 15, 22, 29 
 Daunorubicin 30 mg/m2 IV push on days 8, 15, 22, 29 
 l-asparaginase 10000 U/m2 deep IM or IV over 30 min on days 12, 15, 18, 21, 24, 27, 30, 33 (8 doses) l-asparaginase stopped if the patient initiated on TKIs in Ph+ ALL* 
 IT methotrexate CNS disease: methotrexate 12 mg IT days 1, 15, 29
CNS+ disease: methotrexate 12 mg IT days 1, 8, 15, 22, 29 
 TKIs Imatinib 600 mg once daily or dasatinib 100 mg once daily
Started as soon as the cytogenetics (FISH) report was available 
Induction phase 1b, days 36-64  
 Cyclophosphamide 1000 mg/m2 IV infusion over 1 h with mesna 500 mg/m2 at 0 and 3 h on days 36 and 64 
 Cytosine arabinoside 75 mg/m2 on days 38-41, 45-48, 52-55, 59-62 
 6-MP, days 36-63 6MP dosing according to the BSA
BSA <1.3-50 mg 5 d/wk
BSA 1.3-1.6-50 mg/d every day
BSA >1.6-50 mg for 5 d and 100 mg for 2 d 
 IT methotrexate Methotrexate 12 mg intrathecally days 45, 59 
 TKIs Imatinib 600 mg once daily or dasatinib 100 mg once daily 
Protocol M, days 1-56  
 Methotrexate 3 g/m2 IV over 24 h on days 8, 22, 36, 50 
 Leucovorin rescue Starting dose at 42 h: 30 mg/m2
Further dosing based on the methotrexate levels at 42 h:
>1-2 μmol/L: leucovorin 30 mg/m2
>2-3 μmol/L: leucovorin 45 mg/m2
>3-4 μmol/L: leucovorin 60 mg/m2
>4-5 μmol/L: leucovorin 75 mg/m2
>5 μmol/L: MTX S.Conc. μmol/L × body weight (kg)
Leucovorin rescue continued until the methotrexate levels are <0.25 μmol/L 
 6-MP 25 mg/m2 from day 1 onward 
 IT methotrexate 12 mg IT on day 1 of methotrexate infusion 
 TKIs Imatinib 600 mg once daily or dasatinib 100 mg once daily
TKI stopped during methotrexate infusion* 
Reinduction phase 1, days 1-29  
 Dexamethasone 8 mg/m2 orally from days 1-21, taper from day 22 and stop by day 29 
 Vincristine 1.5 mg/m2 IV push (maximum dose 2 mg) on days 8, 15, 22, 29 
 Doxorubicin 30 mg/m2 IV push on days 8, 15, 22, 29 
 l-asparaginase 10 000 U/m2 deep IM or IV over 30 min on days 8, 11, 15, 18 (4 doses) l-asparaginase stopped if the patient initiated on TKIs in Ph+ ALL* 
 TKIs Imatinib 600 mg once daily or dasatinib 100 mg once daily 
Reinduction phase 2, days 30-50  
 Cyclophosphamide 1000 mg/m2 IV infusion over 1 h with mesna 500 mg/m2 at 0 and 3 h on day 36 
 Cytosine arabinoside 75 mg/m2 on days 38-41, 45-48 
 6-MP/6-TG, days 30-50 6TG: 60 mg/m2
6MP dosing according to the BSA
BSA < 1.3-50 mg 5 d/wk
BSA 1.3-1.6-50 mg/d every day
BSA > 1.6-50 mg for 5 d and 100 mg for 2 d 
 TKIs Imatinib 600 mg once daily or dasatinib 100 mg once daily 
 IT methotrexate Methotrexate 12 mg IT on days 38 and 45 
 Cranial RT 18 Gy/10 fractions for CSF+ cases
12.6 Gy/7 fractions for CSF cases 
Maintenance phase, days 1-730  
 6-MP* 6MP dosing according to the BSA
BSA < 1.3-50 mg 5 d/wk
BSA 1.3-1.6-50 mg/d every day
BSA > 1.6-50 mg for 5 d and 100 mg for 2 d 
 Methotrexate* 20 mg/m2 
 TKIs Imatinib 600 mg once daily or dasatinib 100 mg once daily 

IT, intrathecal; mesna, 2-mercaptoethane sulfonate sodium; S.Conc, serum concentration.

*

Doses of 6MP and methotrexate titrated every 2 to 3 months to maintain target absolute neutrophil count(ANC) 0.75 × 109/L, and target total leukocyte count (TLC) 2 × 109/L; doses of the drugs were escalated or deescalated 1 drug at a time by 25% to reach the target counts.

6TG was used as per the ALL-BFM-90 protocol. However, from 2017 onwards, 6TG was not available in India. 6TG was replaced with 6MP.

Treatment protocol for patients with Ph+ ALL included tyrosine kinase inhibitor (TKI), either imatinib at a dose of 600 mg once daily or dasatinib at a dose of 100 mg once daily after the cytogenetic confirmation. Given the documented evidence of increased toxicity associated with l-asparaginase and TKI combination, l-asparaginase was omitted from all phases in patients with Ph+ ALL.35,36  Further details of the protocol can be found in Table 1.

Prophylaxis

As part of the protocol, cotrimoxazole prophylaxis was initiated from the third week of phase 1a induction. Given the interactions between azoles and vinca alkaloids, fungal prophylaxis with azole was not administered. Antibacterial prophylaxis with quinolones was not used as a standard practice because of the high incidence of quinolone resistance in our population.37 

Response assessment

Response assessment was performed at the end of phase 1a induction with bone marrow morphology and MRD assessment by FCM and cytogenetics studies (those with baseline abnormalities). Bone marrow response was assessed using the M bone marrow criteria for ALL; if M0 to M1 status (blast cells <5%) was achieved, the patient was considered to be a responder (in clinical remission) as reported by Stock et al.38  MRD assessment was performed at the end of phase 1a induction on the first-pull bone marrow aspirate sample using 8- to 10-color FCM assays.39-41  Further details of the MRD assessment are provided in supplemental Appendix 1. An MRD level of <0.01% was considered as negative and ≥0.01% was considered as positive.42  In case MRD was positive at the end of phase 1a induction, repeat MRD assessment was performed at subsequent time points (either phase 1b, M phase, or reinduction). In patients with Ph+ ALL, in addition to FCM-based MRD, MRD assessment was also performed using real-time quantitative polymerase chain reaction (qPCR) testing for BCR-ABL transcripts. High-risk patients with Ph+ ALL, MLL translocation, or postinduction MRD+ status were counseled for allogeneic HSCT. The treatment was not modified in poor prednisolone responders or patients with positive MRD postinduction. The treatment was delivered as an outpatient except for HDMTx. Patients were also admitted for the management of grade 3/4 toxicities that warranted hospitalization.

Toxicities

Toxicities that were captured include infections (bacterial or fungal or viral), pancreatitis, hyperglycemia, avascular necrosis, posterior reversible encephalopathy syndrome (PRES), and seizures. Infections leading to discontinuation of therapy, change of protocol, or death of the patient were recorded. In patients suspected of having pneumonia (fungal or bacterial), noncontrast computed tomography (NCCT) imaging of the thorax was performed along with serum galactomannan. Antifungals were initiated in those with radiologic suspicion or positive galactomannan. Whenever feasible, bronchoalveolar lavage fluid analysis was performed to confirm the etiology of the infection. Fungal infections were defined as possible, probable, and proven fungal infection as per the revised European Organisation for Research and Treatment of Cancer (EORTC) and Mycoses Study Group Education and Research Consortium (MSGERC) definitions.43 

Relapse

Relapse was diagnosed in patients who had achieved complete remission (CR) and subsequently developed a recurrence of the disease. Relapses were classified as medullary, extramedullary (CNS, testicular, or other sites), or combined. Time to relapse was calculated from the date of CR. Relapse was classified as very early relapse, early relapse, and late relapse according to the BFM classification of relapsed ALL.44 

Statistical analysis

The primary end points of the study were event-free survival (EFS) and overall survival (OS) for the overall population and separately within B-ALL and T-ALL subsets. Secondary end points were Complete response (CR) rate, MRD-positive rate, the impact of MRD on EFS and OS, the impact of known poor-risk features (like elevated WBC count, high-risk cytogenetics, and hypodiploidy) on EFS and OS, and the impact of toxicities on EFS and OS.

EFS was defined as the time from registration to any event defined as induction failure, relapse, or death. OS was defined as the time from registration to death resulting from any cause. Patients who were deemed palliative after relapse and subsequently lost to follow-up were counted as an event for OS analysis. Patients lost to follow-up but in remission were censored on the date of last follow-up. EFS and OS were analyzed using the Kaplan-Meier method. Univariate analyses by log-rank tests and multivariate analyses by the Cox proportional hazards model was used to assess the impact of known prognostic variables on EFS and OS.

Baseline parameters

We registered 463 patients with ALL during the study period, of whom 349 (273 male [78.2%], 76 female [21.7%]) received the modified BFM-90 protocol. The remaining 114 patients could not be included as they opted to take treatment elsewhere or were lost to follow-up before treatment initiation. The baseline parameters between these 2 groups of patients are similar and are presented in Table 2.

Table 2.

Baseline characteristics

Characteristics Included in the analysis, n (%) No treatment, n (%)
Total no. of patients 349 114 
Median age (range), y 18 (15-25) 19.9 (15-25) 
Sex   
 Male 273 (78.2) 92 (80.7) 
 Female 76 (21.7) 22 (19.3) 
Diagnosis     
 T-ALL (includes T-LBL) 133 (38.1) T-LBL: 13
ETP/Near ETP: 33
Others: 87 
39 (34) T-LBL: 3
ETP/Near ETP: 11
Others: 25 
 B-ALL 216 (61.8) 73 (64) 
 Not characterized 0 (0) 2 (1.7) 
Hyperleukocytosis at presentation (total WBC count >100 × 109/L) 36 (10.6) 19 (16.6) 
CSF FCM + morphology   
 FCM+ + morphology+ 4 (1.1) 5 (4.3) 
 FCM alone positive 7 (2) 0 (0) 
 Morphology alone positive 9 (2.5) 4 (3.5) 
 Total patients with CNS involvement 20 (5.7) 9 (7.8) 
 CSF not done 7 (2) 63 (55) 
CNS stage   
 CNS 1 323 (92) 39 (34.2) 
 CNS 2 9 (2.5) 3 (2.6) 
 CNS 3 11 (3.1) 6 (5.2) 
Ploidy analysis   
 Diploidy 50 (14.3) 15 (13.1) 
 Hypodiploidy 36 (10.3) 11 (9.6) 
 Hyperdiploidy 35 (10) 12 (10.5) 
 Pseudodiploidy 9 (2.6) 5 (4.3) 
 Endoreduplication 6 (1.7) 0 (0) 
 Not feasible 180 (51.7) 0 (0) 
 Not available 33 (9.4) 71 (62) 
Cytogenetics   
B-ALL 216 73 
  BCr/ ABL + t(9;22) 37 (17.12) 11 (15) 
  MLL translocation 2 (0.9) 2 (2.7) 
  TCF3/PBX1 t(1;19) 16 (7.4) 4 (5.4) 
  t(12:21) ETV6:RUNX1 1 (0.4) 1 (1.3) 
  9p21 deletion 3 (1.3) 0 (0) 
  Others 57 (26.3) 19 (26) 
  Negative 87 (40.2) 30 (41) 
  Not done 8 (3.7) 6 (8.2) 
  Not characterized 5 (2.3) 0 (0) 
T-ALL 133 39 
  9p21 deletion 39 (29.3) 12 (30.7) 
  TCR rearrangement 12 (9.0) 1 (2.5) 
  Others 10 (7.5) 2 (5.1) 
  Negative 46 (34.6) 12 (30.7) 
  Not done 25 (18.7) 12 (30.7) 
  Not characterized 1 (0.7) 0 (0) 
High risk and standard risk*   
 High risk 119 (34) 39 (34.2) 
 Standard risk 230 (65.9) 75 (65.7) 
Risk stratification according to baseline WBC count   
 High-risk T-ALL (>100 × 109/L) 18 (13.5) 9 (23) 
 Low-risk T-ALL (<100 × 109/L) 115 (86.5) 30 (76) 
 High-risk B-ALL (>30 × 109/L) 69 (31.9) 20 (27.3) 
 Low-risk B-ALL (>30 × 109/L) 147 (68.1) 53 (72.6) 
Characteristics Included in the analysis, n (%) No treatment, n (%)
Total no. of patients 349 114 
Median age (range), y 18 (15-25) 19.9 (15-25) 
Sex   
 Male 273 (78.2) 92 (80.7) 
 Female 76 (21.7) 22 (19.3) 
Diagnosis     
 T-ALL (includes T-LBL) 133 (38.1) T-LBL: 13
ETP/Near ETP: 33
Others: 87 
39 (34) T-LBL: 3
ETP/Near ETP: 11
Others: 25 
 B-ALL 216 (61.8) 73 (64) 
 Not characterized 0 (0) 2 (1.7) 
Hyperleukocytosis at presentation (total WBC count >100 × 109/L) 36 (10.6) 19 (16.6) 
CSF FCM + morphology   
 FCM+ + morphology+ 4 (1.1) 5 (4.3) 
 FCM alone positive 7 (2) 0 (0) 
 Morphology alone positive 9 (2.5) 4 (3.5) 
 Total patients with CNS involvement 20 (5.7) 9 (7.8) 
 CSF not done 7 (2) 63 (55) 
CNS stage   
 CNS 1 323 (92) 39 (34.2) 
 CNS 2 9 (2.5) 3 (2.6) 
 CNS 3 11 (3.1) 6 (5.2) 
Ploidy analysis   
 Diploidy 50 (14.3) 15 (13.1) 
 Hypodiploidy 36 (10.3) 11 (9.6) 
 Hyperdiploidy 35 (10) 12 (10.5) 
 Pseudodiploidy 9 (2.6) 5 (4.3) 
 Endoreduplication 6 (1.7) 0 (0) 
 Not feasible 180 (51.7) 0 (0) 
 Not available 33 (9.4) 71 (62) 
Cytogenetics   
B-ALL 216 73 
  BCr/ ABL + t(9;22) 37 (17.12) 11 (15) 
  MLL translocation 2 (0.9) 2 (2.7) 
  TCF3/PBX1 t(1;19) 16 (7.4) 4 (5.4) 
  t(12:21) ETV6:RUNX1 1 (0.4) 1 (1.3) 
  9p21 deletion 3 (1.3) 0 (0) 
  Others 57 (26.3) 19 (26) 
  Negative 87 (40.2) 30 (41) 
  Not done 8 (3.7) 6 (8.2) 
  Not characterized 5 (2.3) 0 (0) 
T-ALL 133 39 
  9p21 deletion 39 (29.3) 12 (30.7) 
  TCR rearrangement 12 (9.0) 1 (2.5) 
  Others 10 (7.5) 2 (5.1) 
  Negative 46 (34.6) 12 (30.7) 
  Not done 25 (18.7) 12 (30.7) 
  Not characterized 1 (0.7) 0 (0) 
High risk and standard risk*   
 High risk 119 (34) 39 (34.2) 
 Standard risk 230 (65.9) 75 (65.7) 
Risk stratification according to baseline WBC count   
 High-risk T-ALL (>100 × 109/L) 18 (13.5) 9 (23) 
 Low-risk T-ALL (<100 × 109/L) 115 (86.5) 30 (76) 
 High-risk B-ALL (>30 × 109/L) 69 (31.9) 20 (27.3) 
 Low-risk B-ALL (>30 × 109/L) 147 (68.1) 53 (72.6) 

ETP, early T-cell precursor ALL; near ETP, near early T-cell precursor ALL.

*

Risk stratification: high risk includes: patients with elevated baseline WBC count (>30 × 109/L for B-ALL, >100 × 109/L for T-ALL) or with high-risk cytogenetics [t(9;22), t(4;11), t(1;19)] or with hypodiploidy on ploidy analysis.

Ploidy analysis was not available for this set of patients, risk stratification based on baseline WBC count, and cytogenetics.

Treatment details

All the 349 patients were treated with the modified BFM-90 protocol (Table 1). The course of treatment is summarized in Figure 1. Of the 37 patients diagnosed with Ph+ ALL, imatinib was used in 28 patients and dasatinib in 9 patients.

Figure 1.

Graphical representation of the treatment and follow-up of the 349 patients. *High dose AraC (Leg2 I2A of MCP841 protocol)  started in view of ongoing infection (empyema). Allo HSCT, allogeneic HSCT; Ara C, cytarabine; BMT, bone marrow transplantation; CML, chronic myeloid leukemia; CVT, cerebral venous thrombosis; HDAraC, high-dose cytarabine; LFU, lost to follow-up.

Figure 1.

Graphical representation of the treatment and follow-up of the 349 patients. *High dose AraC (Leg2 I2A of MCP841 protocol)  started in view of ongoing infection (empyema). Allo HSCT, allogeneic HSCT; Ara C, cytarabine; BMT, bone marrow transplantation; CML, chronic myeloid leukemia; CVT, cerebral venous thrombosis; HDAraC, high-dose cytarabine; LFU, lost to follow-up.

Efficacy

Remission assessment.

Among the 349 patients, 285 patients (81.6%) achieved CR at the end of induction. There were 21 deaths (6%) and 43 discontinued treatment before phase 1b (12%). Almost half of the induction deaths and discontinuation could be attributed to life-threatening infections (30 [47%]). Other reasons included patients not in remission (22 [34%]), CNS bleed (1 [1.5%]), and lost to follow-up (9 [(14%]). Twenty-five patients did not achieve CR even after completion of phase 1b. Of the 25 patients, 12 were T-ALL and 13 were B-ALL. Of these 12 patients with T-ALL, 8 were ETP/near ETP-ALL.

MRD assessment.

Among the 349 patients, MRD assessment was available for 272 patients. MRD was negative in 167 patients (61.39%) at the end of phase 1 induction. An additional 61 patients achieved MRD status subsequently (phase 1b, 34; postprotocol M, 21; postreinduction, 6). Details of the time points of the repeat MRD assessment are summarized in Table 3. There was no difference in the postinduction MRD+ rates between B-ALL (30.2%) and T-ALL (30.4%). Molecular response in patients with Ph+ ALL is summarized in Table 4.

Table 3.

Time points of repeat MRD assessment

Repeat MRD assessment in patients who were MRD positive after phase 1 inductionFrequency
Post-phase 1b 45 
Post-M phase 15 
Postreinduction 
Post-phase 1b MRD+ and underwent MRD assessment after M phase 14 
Post-phase 1b MRD+, post-M phase MRD+ and underwent MRD assessment after reinduction 
Others 
Not done further MRD 21 
Total patients with positive MRD after phase 1 105 
Repeat MRD assessment in patients who were MRD positive after phase 1 inductionFrequency
Post-phase 1b 45 
Post-M phase 15 
Postreinduction 
Post-phase 1b MRD+ and underwent MRD assessment after M phase 14 
Post-phase 1b MRD+, post-M phase MRD+ and underwent MRD assessment after reinduction 
Others 
Not done further MRD 21 
Total patients with positive MRD after phase 1 105 
Table 4.

Molecular response in patients with Ph+ ALL

Molecular response category*No. of patients (%)
Total no. of patients 37 
MMR 6 (16.2) 
CMR 25 (67.5) 
CMR at 3 mo 
CMR at 3-6 mo 
CMR at >6 mo 12 
Molecular response category*No. of patients (%)
Total no. of patients 37 
MMR 6 (16.2) 
CMR 25 (67.5) 
CMR at 3 mo 
CMR at 3-6 mo 
CMR at >6 mo 12 
*

MMR: ≤0.1% BCR-ABL according to the international scale as measured by real-time qPCR; CMR or MR4.0: detectable disease ≤0.01% BCR-ABL (IS) or undetectable disease in cDNA with ≥10 000 ABL transcripts.

Time of achievement of MMR: 4 patients achieve within 6 mo, other 2 achieve after 6 mo.

Relapse and death

After a median follow-up of 41 months, 79 patients relapsed (22.6%) and 82 patients died (23.5%). Among the 79 patients who relapsed, 54 had a medullary relapse (68%), 18 had CNS relapse (23%), 5 had both medullary and CNS relapse (6.3%), 1 had both medullary and testicular relapse (1.2%), and 1 had other site of relapse. The median time to relapse was 14months (interquartile range [IQR], 8-23 months). Very early relapse (<18 months from diagnosis) occurred in 48 patients (61%), early relapse (>18 months from diagnosis but <6 months from completion of therapy) occurred in 27 patients (34%), and late relapse (>6 months after completion of therapy) occurred in 4 patients (5%). Among the 82 patients who died, 60 patients were not in CR (73%) and 22 patients were in CR (26.8%).

EFS and OS

The survival outcomes are summarized in Table 5. Median OS and EFS were not reached. After a median follow-up of 41 months, the 3-year EFS and OS of the cohort were 59.4% and 61.8%, respectively. ETP-ALL and near ETP-ALL had inferior EFS and OS in comparison with the non-ETP T-ALL. Survival curves are represented in Figures 2 and 3.

Table 5.

EFS and OS of the overall population and subgroups

Disease typen3-y EFS3-y OS
%95% CI%95% CI
Overall 349 59.4 54.4-64.9 61.8 57-67 
B-ALL (including Ph+ ALL) 216 58.1 51.9-65.2 61.1 54.9-68.1 
B-ALL (excluding Ph+ ALL) 179 59.8  53-67.5 62.3 55-70 
Ph+ALL 37 51.4 37.5-70.3 61.9 48.1-79.8 
T-ALL (excluding TLBL) 120 59.3 50.9-69 60.9 52.6-70.6 
T-ALL (including TLBL) 133 60.7 52-69 62.6 54-71 
ETP 33 30.4 17.6-52.3 32.5 19.5-54 
Non-ETP 87 69.4 60.3-80 71.3 62.3-81.7 
T-LBL 13 83.9 65.7-100 83.9 65.7-100 
Postinduction MRD 167 77.4 71.2-84.1 79.2 73.2-85.7 
Postinduction MRD+ 105 41 32.4-52 44.8 35.9-56 
MRD negativity during or beyond consolidation 61 54.1 42.6-68.6 57.2 45.7-71.6 
Persistent MRD+ 38 17.1 7.8-37.3 22.1 11.2-43.5 
Standard risk* 230 60.5 54.4-67.3 61.2 55.1-68 
High risk* 119 57.3 49-67.1 63.1 54.9-72.5 
Disease typen3-y EFS3-y OS
%95% CI%95% CI
Overall 349 59.4 54.4-64.9 61.8 57-67 
B-ALL (including Ph+ ALL) 216 58.1 51.9-65.2 61.1 54.9-68.1 
B-ALL (excluding Ph+ ALL) 179 59.8  53-67.5 62.3 55-70 
Ph+ALL 37 51.4 37.5-70.3 61.9 48.1-79.8 
T-ALL (excluding TLBL) 120 59.3 50.9-69 60.9 52.6-70.6 
T-ALL (including TLBL) 133 60.7 52-69 62.6 54-71 
ETP 33 30.4 17.6-52.3 32.5 19.5-54 
Non-ETP 87 69.4 60.3-80 71.3 62.3-81.7 
T-LBL 13 83.9 65.7-100 83.9 65.7-100 
Postinduction MRD 167 77.4 71.2-84.1 79.2 73.2-85.7 
Postinduction MRD+ 105 41 32.4-52 44.8 35.9-56 
MRD negativity during or beyond consolidation 61 54.1 42.6-68.6 57.2 45.7-71.6 
Persistent MRD+ 38 17.1 7.8-37.3 22.1 11.2-43.5 
Standard risk* 230 60.5 54.4-67.3 61.2 55.1-68 
High risk* 119 57.3 49-67.1 63.1 54.9-72.5 
*

Risk stratification: high risk: B-ALL baseline total WBC >30 × 109/L, T-ALL baseline total WBC, >100 × 109/L; cytogenetics abnormality: t(9;22), MLL translocation, t(1;19); ploidy analysis: hypodiploidy.

Figure 2.

EFS and OS survival curves for the overall population and subgroups. (A) Overall population. (B) B-ALL subgroup (including BCR-ABL positive). (C) BCR-ABL positive subgroup. (D) T-ALL subgroup. (E) T-LBL subgroup. (F-G): OS and EFS for ETP/near ETP vs non-ETP ALL.

Figure 2.

EFS and OS survival curves for the overall population and subgroups. (A) Overall population. (B) B-ALL subgroup (including BCR-ABL positive). (C) BCR-ABL positive subgroup. (D) T-ALL subgroup. (E) T-LBL subgroup. (F-G): OS and EFS for ETP/near ETP vs non-ETP ALL.

Figure 3.

EFS and OS according to the postinduction MRD and risk stratification. OS (A) and EFS (B), postinduction MRD negative vs positive. OS (C) and EFS (D), MRD negative postinduction vs MRD negative during or after consolidation. OS (E) and EFS (F) for high-risk vs low-risk patients.

Figure 3.

EFS and OS according to the postinduction MRD and risk stratification. OS (A) and EFS (B), postinduction MRD negative vs positive. OS (C) and EFS (D), MRD negative postinduction vs MRD negative during or after consolidation. OS (E) and EFS (F) for high-risk vs low-risk patients.

Allogeneic HSCT

Among these 349 patients, only 15 underwent HSCT. Details of these patients are described in Table 6.

Table 6.

Patients who underwent HSCT from our cohort

Characteristics n (total N = 15)
Diagnosis  
 Ph+ ALL 
 B-ALL (Ph
 T-ALL 
Risk stratification  
 High risk 10 
 Standard risk 
Indication for transplant  
 Relapse 
 Postinduction MRD+ 
 Ph+ ALL 
 Standard risk 
Conditioning regimen used  
 Flu-TBI 
 Flu-Treo-TBI 
 Cy-TBI 
 Flu-Mel 
 Bu-Cy 
Type of donor  
 MSD 11 
 Haploidentical 
Current status  
 Alive 12 
 Death 
Characteristics n (total N = 15)
Diagnosis  
 Ph+ ALL 
 B-ALL (Ph
 T-ALL 
Risk stratification  
 High risk 10 
 Standard risk 
Indication for transplant  
 Relapse 
 Postinduction MRD+ 
 Ph+ ALL 
 Standard risk 
Conditioning regimen used  
 Flu-TBI 
 Flu-Treo-TBI 
 Cy-TBI 
 Flu-Mel 
 Bu-Cy 
Type of donor  
 MSD 11 
 Haploidentical 
Current status  
 Alive 12 
 Death 

Bu, busulfan; Cy, cyclophosphamide; Flu, fludarabine; Mel, melphalan; MSD, matched sibling donor; TBI, total body irradiation; Treo, treosulfan.

Univariate and multivariate analysis

A univariate Cox regression analysis identified that baseline CNS involvement (CNS 2 or 3), positive postinduction MRD, positive MRD beyond induction, and development of infections were associated with poorer outcomes (EFS and OS). On multivariate analyses, positive postinduction MRD and positive MRD beyond induction were associated with poorer survival. Univariate and multivariate analyses are summarized in Tables 7 and 8.

Table 7.

Univariate analysis for EFS and OS

Variable (reference)Comparator parameterOR for EFS95% CI (P)OR for OS95% CI (P)
Sex (male) Female sex 1.164 0.78-1.71 (.44) 1.218 0.82-1.79 (.322) 
T-ALL (TLC <100 × 109/L) TLC >100 × 109/L 0.789 0.337-1.846 (.585) 0.799 0.342-1.87 (.606) 
B-ALL (TLC <30 × 109/L) TLC >30 × 109/L 1.58 1.041-2.406 (.032) 1.485 0.96-2.29 (.074) 
CSF disease status (CSF involved) CSF uninvolved 0.548 0.303-0.99 (.046) 0.532 0.29-0.96 (.037) 
CNS stage (CNS stage 1) CNS stage 3 2.9 1.42-5.94 (.004) 2.814 1.37-5.75 (.005) 
CSF FCM (CSF FCM+CSF FCM 0.51 0.24-1.09 (.084) 0.515 0.24-1.1 (.08) 
Postinduction MRD (negative status) Positive status 3.34 2.3-4.9 (<.001) 3.413 2.28-5.09 (<.001) 
MRD status beyond induction (negative status) Positive status 5.351 3.464-8.26 (<.001) 4.88 3.12-7.65 (<.001) 
WBC-based risk stratification* (B-ALL <30 × 109/L; T ALL <100 × 109/L) Elevated WBC 1.336 0.93-1.91 (.114) 1.265 0.87-1.83 (.212) 
Cytogenetic risk stratification (standard risk) High risk 1.032 0.662-1.608 (.891) 0.967 0.61-1.53 (.888) 
Ploidy status (others apart from hypodiploidy) Hypodiploid status 0.757 0.39-1.44 (.40) 0.73 0.37-1.42 (.356) 
Risk groups (standard risk) High risk 1.09 0.779-1.531 (.610) 1.020 0.72-1.44 (.91) 
Infections (development of infection) Nondevelopment of infections 0.68 0.49-0.943 (.02) 0.65 0.46-0.91 (.011) 
Variable (reference)Comparator parameterOR for EFS95% CI (P)OR for OS95% CI (P)
Sex (male) Female sex 1.164 0.78-1.71 (.44) 1.218 0.82-1.79 (.322) 
T-ALL (TLC <100 × 109/L) TLC >100 × 109/L 0.789 0.337-1.846 (.585) 0.799 0.342-1.87 (.606) 
B-ALL (TLC <30 × 109/L) TLC >30 × 109/L 1.58 1.041-2.406 (.032) 1.485 0.96-2.29 (.074) 
CSF disease status (CSF involved) CSF uninvolved 0.548 0.303-0.99 (.046) 0.532 0.29-0.96 (.037) 
CNS stage (CNS stage 1) CNS stage 3 2.9 1.42-5.94 (.004) 2.814 1.37-5.75 (.005) 
CSF FCM (CSF FCM+CSF FCM 0.51 0.24-1.09 (.084) 0.515 0.24-1.1 (.08) 
Postinduction MRD (negative status) Positive status 3.34 2.3-4.9 (<.001) 3.413 2.28-5.09 (<.001) 
MRD status beyond induction (negative status) Positive status 5.351 3.464-8.26 (<.001) 4.88 3.12-7.65 (<.001) 
WBC-based risk stratification* (B-ALL <30 × 109/L; T ALL <100 × 109/L) Elevated WBC 1.336 0.93-1.91 (.114) 1.265 0.87-1.83 (.212) 
Cytogenetic risk stratification (standard risk) High risk 1.032 0.662-1.608 (.891) 0.967 0.61-1.53 (.888) 
Ploidy status (others apart from hypodiploidy) Hypodiploid status 0.757 0.39-1.44 (.40) 0.73 0.37-1.42 (.356) 
Risk groups (standard risk) High risk 1.09 0.779-1.531 (.610) 1.020 0.72-1.44 (.91) 
Infections (development of infection) Nondevelopment of infections 0.68 0.49-0.943 (.02) 0.65 0.46-0.91 (.011) 
*

Elevated WBC count: for B-ALL, >30 × 109/L; for T-ALL, >100 × 109/L.

High-risk cytogenetics: t(9;22), t(1;19), MLL translocation.

High-risk subgroup: Patients with either elevated WBC count as per above (*) or high-risk cytogenetics or hypodiploidy.

Table 8.

Multivariate analysis for EFS and OS

Variable (reference)Comparator parameterOR for EFS95% CI (P)OR for OS95% CI (P)
CSF disease status (CSF involved) Uninvolved 1.655 0.56-4.86 (.360) 1.426 0.603-3.371 (.419) 
Postinduction MRD (negative status) Positive status 2.400 1.324-4.352 (.004) 2.583 1.592-4.193 (<.001) 
MRD Status beyond induction (negative status) Positive status 2.371 1.218-4.615 (.011) 1.732 0.999-3.003 (.05) 
B-ALL (TLC <30 × 109/L) TLC >30 × 109/L 1.659 0.98-2.808 (.059) NA NA 
Infections (development of infection) Nondevelopment infections 0.881 0.522-1.487 (.634) 0.701 0.463-1.061 (.093) 
Variable (reference)Comparator parameterOR for EFS95% CI (P)OR for OS95% CI (P)
CSF disease status (CSF involved) Uninvolved 1.655 0.56-4.86 (.360) 1.426 0.603-3.371 (.419) 
Postinduction MRD (negative status) Positive status 2.400 1.324-4.352 (.004) 2.583 1.592-4.193 (<.001) 
MRD Status beyond induction (negative status) Positive status 2.371 1.218-4.615 (.011) 1.732 0.999-3.003 (.05) 
B-ALL (TLC <30 × 109/L) TLC >30 × 109/L 1.659 0.98-2.808 (.059) NA NA 
Infections (development of infection) Nondevelopment infections 0.881 0.522-1.487 (.634) 0.701 0.463-1.061 (.093) 

NA, not available.

Toxicity

In total, 164 patients had developed infections (all grades) and 104 developed fungal nodules. There were a total of 21 induction deaths, which were predominantly attributable to infection (19 [82.6%]). The occurrence of infections declined as we proceeded from phase 1a induction to protocol M. During the reinduction phase, there were a total of 6 episodes of life-threatening infections, 5 of which were fatal. The number and severity of the infections during the various phases are summarized in Table 9 and 10.43  During the treatment, commonly encountered treatment-related toxicity included cortical venous thrombosis (6.3%), pancreatitis (4.8%), avascular necrosis (1.1%), hyperglycemia (2.5%), PRES (1.4%), and seizures (12.8%) (Table 11).

Table 9.

Infections during the treatment

Total infectionsN = 164 (all grades)
Radiographic evidence of infections: 104 Possible fungal pneumonia: 85
Probable fungal pneumonia: 11
Proven fungal pneumonia: 2
Other proven infection: 6 
Total infectionsN = 164 (all grades)
Radiographic evidence of infections: 104 Possible fungal pneumonia: 85
Probable fungal pneumonia: 11
Proven fungal pneumonia: 2
Other proven infection: 6 

Possible and probable fungal pneumonia was defined as per revised EORTC and MSGERC definitions.38 

Table 10.

Infections during the treatment leading to discontinuation or death

Phase of treatment, nTreatment discontinuationDeathInfection type (organism, type, resistance, no.)
Phase 1a    
 31 12 19 Salmonella bacteremia: 1
Group A β hemolytic streptococci: 1
E coli (CRO): 5
Klebsiella pneumoniae (CRO): 7
K pneumoniae (ESBL): 1
Acinetobacter baumannii (ESBL): 2
K pneumoniae (Pansensitive): 2
Pseudomonas aeruginosa (Pansensitive): 2
Enterococcus (ampicillin resistant): 1
Probable fungal pneumonia: 5*
Possible fungal pneumonia: 8*
Pneumonia (culture negative): 4
Hepatosplenic candidiasis: 2
Candidemia (Candida tropicalis): 3
CMV viremia: 1
Osteomyelitis: 1 
Phase 1b    
 0 
Protocol M    
 3 Probable fungal pneumonia: 1
Cellulitis: 1
Empyema: 1 
Reinduction phase    
 6 Nosocomial pneumonia: 1
K pneumoniae (ESBL): 1
E coli (Pansensitive): 2
K pneumoniae (Pansensitive): 1
Shewanella putrefaciens: 1
Probable fungal pneumonia: 1*
Candidemia: 1
CMV viremia: 1 
Maintenance phase    
 0 
Phase of treatment, nTreatment discontinuationDeathInfection type (organism, type, resistance, no.)
Phase 1a    
 31 12 19 Salmonella bacteremia: 1
Group A β hemolytic streptococci: 1
E coli (CRO): 5
Klebsiella pneumoniae (CRO): 7
K pneumoniae (ESBL): 1
Acinetobacter baumannii (ESBL): 2
K pneumoniae (Pansensitive): 2
Pseudomonas aeruginosa (Pansensitive): 2
Enterococcus (ampicillin resistant): 1
Probable fungal pneumonia: 5*
Possible fungal pneumonia: 8*
Pneumonia (culture negative): 4
Hepatosplenic candidiasis: 2
Candidemia (Candida tropicalis): 3
CMV viremia: 1
Osteomyelitis: 1 
Phase 1b    
 0 
Protocol M    
 3 Probable fungal pneumonia: 1
Cellulitis: 1
Empyema: 1 
Reinduction phase    
 6 Nosocomial pneumonia: 1
K pneumoniae (ESBL): 1
E coli (Pansensitive): 2
K pneumoniae (Pansensitive): 1
Shewanella putrefaciens: 1
Probable fungal pneumonia: 1*
Candidemia: 1
CMV viremia: 1 
Maintenance phase    
 0 

CRO, carbapenem-resistant organism; ESBL, extended spectrum β-lactamase–producing organism.

*

Possible and probable fungal pneumonia was defined as per revised EORTC and MSGRC definitions.38 

Table 11.

Noninfectious toxicities during treatment

Toxicity (CTCAE grading v4.03)n (%)
Cortical venous thrombosis (grade 4) 22 (6.3) 
Bacterial infections (episodes) (grade 2-5) 91 
Fungal infections (episodes) (grade 2-5) 104 (29.7) 
Pancreatitis (grade 3-5) 17 (4.8) 
Hyperglycemia (grade 3-5) 9 (2.5) 
Avascular necrosis (grade 2-5) 4 (1.1) 
PRES (grade 4) 5 (1.4) 
Seizures (grade 2-5) 45 (12.8)* 
Toxicity (CTCAE grading v4.03)n (%)
Cortical venous thrombosis (grade 4) 22 (6.3) 
Bacterial infections (episodes) (grade 2-5) 91 
Fungal infections (episodes) (grade 2-5) 104 (29.7) 
Pancreatitis (grade 3-5) 17 (4.8) 
Hyperglycemia (grade 3-5) 9 (2.5) 
Avascular necrosis (grade 2-5) 4 (1.1) 
PRES (grade 4) 5 (1.4) 
Seizures (grade 2-5) 45 (12.8)* 

Possible and probable fungal pneumonia was defined as per revised EORTC and MSGERC definitions.38 

CTCAE, Common Terminology Criteria for Adverse Events.

*

Thirteen patients had CVT.

This study shows that AYAs with ALL treated with a pediatrics-inspired protocol achieved 3-year EFS and OS of 59.4% and 61.8%, respectively. Our study cohort belongs to the 15- to 25-year-old age group, which is underrepresented in literature. In previous trials utilizing pediatric protocols, the upper age limit varied from 18 years to 39 years, underlining the ambiguity in the definition of this age group in literature45-47  (Table 12). Other studies performed in the 15- to 30-year-old age group showed EFS and OS ranging from 61% to 86% and 66% to 88%, respectively.14,48-53 

Table 12.

Previous AYA ALL trials: age group 15 to 30 y

Age group, yNo.T-ALL/B-ALL, n (%)Baseline TLC, ×109/L (%)Cytogenetics (%)CNS disease (%)HSCT rate, %Cranial RTEFS, %; OS, %Poor prognostic factors
CCG 196148  16-21 262 47 (17)/174 (66)* <50: 193 (73.6)
≥50: 69 (26.3) 
t(9;22): 10 (6.9)
t(4;11): 2 (1.3)
t(1;19): 9 (6.2)
Hypodiploid: 1 (0.6)
Hyperdiploidy: 10 (6.9) 
CNS 1: 229 (87)
CNS 2: 21 (8)
CNS 3: 12 (4.5) 
18 Gy cranial radiation 5 y:
72;
78 
Baseline WBC count:
> 50 × 109/L
t(9;22)
t(4;11) 
DFCI 9101/950149  15-18 51 15 (9)/6 (70) Median 6.5 (1.3-563)
 
TEL-AML1 (PCR):
13 (25) 
CNS 2 or 3: 4(8) Not recorded Cranial irradiation was administered only to patients with high presenting WBC count, or CNS 3 disease or T-cell phenotype 5 y:
78;
81 
NR 
Total therapy XV50  15-18 89 28 (31)/61 (69) <10: 46 (51.6);
10-100: 29 (32.5);
>100: 14 (15.7) 
t(9;22): 3 (3.3)
t(4;11): 3 (3.3)
t(1;19): 3 (3.3)
t(12;21): 3 (3.3) 
CNS 1: 60 (67)
CNS 2: 20 (22)
CNS 3: 3 (3.3)
Traumatic with blasts: 6 (6.7) 
11 No cranial irradiation 5 y:
86;
88 
NR 
FRALLE 200014  15-19 77 23 (29)/54 (70) Median: 17.9 (1-458) t(9;22): 1 (1.2)
t(4;11): 2 (2.5)
t(1;19): 5 (6.5)
t(12;21): 3 (3.9)
Normal: 24 (31)
Hyperploid: 6 (7.7)
Hypodiploidy: 2 (2.5) 
Not available 12 Cranial irradiation given 5 y:
74;
80 
NR 
Modified DFCI 91-0169  18-60 85 24 (28)/61 (72) Median: 10.5
High WBC count, >30 for pre-B and >100 for T ALL,
13 (15) 
Normal: 24 (28)
MLL: 10 (12)
t(1;19): 3 (4)
Hyperdiploidy: 3 (4)
Ph patients only* 
CNS disease:
14 (16) 
NR Cranial RT administered 1200 cGy/8 d 3 y:
77;
83 
Age >35 y
Increased
WBC count >30 × 109/L in B-ALL and >100 × 109/L in T-ALL
MLL gene re-arrangement 
PETHEMA ALL 9651  15-30 81 17 (20)/64 (79) Mean WBC,
7.8 
*t(9;22), t(4;11),
t(1;19) were excluded 
NR Not received cranial RT 6 y:
61;
69 
Slow response to induction therapy 
FRALLE 2000BT52  15-29 89 NR NR Ph patients only* CNS disease:
5 (5.6) 
28 NR 5 y:
61;
66 
Age time to first delayed intensification 
JALSG ALL 202 U53  16-24 139 31 (22)/107 (77) Median: 10.5;
<50-104 (75);
≥50-35 (25) 
Standard risk: 2 (1)
Intermediate risk: 110 (79)
High risk: 11(8)
Very high risk:15 (11)
Unknown: 1 (1)
Ph patients only* 
CNS+ disease:
7 (5) 
15 No cranial RT administered 5 y:
67;
73 
No significant prognostic factor identified 
CCG 1882, 19017  16-20 197 16/65 Median: 12.2 t(9;22): 2 (3)
t(4;11): 2 (3) 
NR 3 (1.5) CNS patients: 1800 cGy/10 fractions
CNS+ disease = 2400 cGy/12 fractions and 600 cGy/3 fractions 
7 y:
63;
67 
Baseline WBC count,
>50 × 109/L 
DCOG ALL 6-910  15-18 47 26/72 Median: 7.5 t(9;22): 1 (2)
t(1;19): 3 (7) 
3 (6) NR 5 y:
69;
79 
NR 
Age group, yNo.T-ALL/B-ALL, n (%)Baseline TLC, ×109/L (%)Cytogenetics (%)CNS disease (%)HSCT rate, %Cranial RTEFS, %; OS, %Poor prognostic factors
CCG 196148  16-21 262 47 (17)/174 (66)* <50: 193 (73.6)
≥50: 69 (26.3) 
t(9;22): 10 (6.9)
t(4;11): 2 (1.3)
t(1;19): 9 (6.2)
Hypodiploid: 1 (0.6)
Hyperdiploidy: 10 (6.9) 
CNS 1: 229 (87)
CNS 2: 21 (8)
CNS 3: 12 (4.5) 
18 Gy cranial radiation 5 y:
72;
78 
Baseline WBC count:
> 50 × 109/L
t(9;22)
t(4;11) 
DFCI 9101/950149  15-18 51 15 (9)/6 (70) Median 6.5 (1.3-563)
 
TEL-AML1 (PCR):
13 (25) 
CNS 2 or 3: 4(8) Not recorded Cranial irradiation was administered only to patients with high presenting WBC count, or CNS 3 disease or T-cell phenotype 5 y:
78;
81 
NR 
Total therapy XV50  15-18 89 28 (31)/61 (69) <10: 46 (51.6);
10-100: 29 (32.5);
>100: 14 (15.7) 
t(9;22): 3 (3.3)
t(4;11): 3 (3.3)
t(1;19): 3 (3.3)
t(12;21): 3 (3.3) 
CNS 1: 60 (67)
CNS 2: 20 (22)
CNS 3: 3 (3.3)
Traumatic with blasts: 6 (6.7) 
11 No cranial irradiation 5 y:
86;
88 
NR 
FRALLE 200014  15-19 77 23 (29)/54 (70) Median: 17.9 (1-458) t(9;22): 1 (1.2)
t(4;11): 2 (2.5)
t(1;19): 5 (6.5)
t(12;21): 3 (3.9)
Normal: 24 (31)
Hyperploid: 6 (7.7)
Hypodiploidy: 2 (2.5) 
Not available 12 Cranial irradiation given 5 y:
74;
80 
NR 
Modified DFCI 91-0169  18-60 85 24 (28)/61 (72) Median: 10.5
High WBC count, >30 for pre-B and >100 for T ALL,
13 (15) 
Normal: 24 (28)
MLL: 10 (12)
t(1;19): 3 (4)
Hyperdiploidy: 3 (4)
Ph patients only* 
CNS disease:
14 (16) 
NR Cranial RT administered 1200 cGy/8 d 3 y:
77;
83 
Age >35 y
Increased
WBC count >30 × 109/L in B-ALL and >100 × 109/L in T-ALL
MLL gene re-arrangement 
PETHEMA ALL 9651  15-30 81 17 (20)/64 (79) Mean WBC,
7.8 
*t(9;22), t(4;11),
t(1;19) were excluded 
NR Not received cranial RT 6 y:
61;
69 
Slow response to induction therapy 
FRALLE 2000BT52  15-29 89 NR NR Ph patients only* CNS disease:
5 (5.6) 
28 NR 5 y:
61;
66 
Age time to first delayed intensification 
JALSG ALL 202 U53  16-24 139 31 (22)/107 (77) Median: 10.5;
<50-104 (75);
≥50-35 (25) 
Standard risk: 2 (1)
Intermediate risk: 110 (79)
High risk: 11(8)
Very high risk:15 (11)
Unknown: 1 (1)
Ph patients only* 
CNS+ disease:
7 (5) 
15 No cranial RT administered 5 y:
67;
73 
No significant prognostic factor identified 
CCG 1882, 19017  16-20 197 16/65 Median: 12.2 t(9;22): 2 (3)
t(4;11): 2 (3) 
NR 3 (1.5) CNS patients: 1800 cGy/10 fractions
CNS+ disease = 2400 cGy/12 fractions and 600 cGy/3 fractions 
7 y:
63;
67 
Baseline WBC count,
>50 × 109/L 
DCOG ALL 6-910  15-18 47 26/72 Median: 7.5 t(9;22): 1 (2)
t(1;19): 3 (7) 
3 (6) NR 5 y:
69;
79 
NR 

NR, not recorded.

*

Forty-one not determined.

Karyotyping was done in only 144 patients.

Cytogenetic subgroups: Very high-risk group: t(4;11), complex karyotype, low hypodiploidy/near triploidy; high-risk group: MLL translocations, monosomy 7 with <5 abnormalities, t(1;19); intermediate-risk group: normal karyotype, or other miscellaneous abnormal karyotypes; standard risk: high hyperdiploidy.

Improvement in survival across the various age groups has been attributed to intensification of therapy after remission induction, and various approaches have been used over the last 50 years.54,55  Various retrospective analyses and trials performed in the 15- to 30-year-old age group have used pediatric protocols with intensive postremission treatment consisting of vincristine, l-asparaginase, cytarabine, cyclophosphamide, and etoposide resulting in varied EFS and OS rates of 61% to 86% and 66% to 88%, respectively.14,48-56  Strategies used to dose intensify in these studies are summarized in supplemental Table 1. Even though these trials have proven the benefit of dose intensification, the representation of the AYA population was minimal with many of the trials excluding or having underrepresentation of patients with high-risk features (baseline WBC count and cytogenetics).14,48-53,55  So a clear strategy for dose intensification is not available from literature in the AYA population. In our patients, postinduction therapy consisted of phase 1b (4 blocks of cytarabine, 2 doses of cyclophosphamide, and intrathecal methotrexate) followed by protocol M (HDMTx with leucovorin rescue) followed by delayed intensification (vincristine, dexamethasone, adriamycin, and l-asparaginase). Dose intensification was kept uniform for standard risk as well as for high risk irrespective of the postinduction MRD status. We planned for all patients to receive prophylactic cranial RT except the patients with a diagnosis of T-LBL. Vincristine or prednisolone pulses were not used during the maintenance. With the use of intensive pediatric and pediatrics-inspired regimens, the need for HSCT has declined in the AYA population. In our cohort, only 15 patients (4.3%) underwent HSCT, whereas the other trials utilizing pediatric-inspired protocols had HSCT rates ranging from 3% to 30%. Children’s Cancer Group (CCG; 1882-1901) and Dutch Childhood Oncology Group (DCOG; 6-9) retrospective analyses were the 2 studies that had transplant rates less than our cohort. Utilizing a risk-adapted approach, the 7-year EFS and OS rates in the CCG 1882-1901 were 63% and 67%, respectively.7,48,55  Using a dose-intensified approach, 5-year EFS and OS rates in the DCOG 6-9 were 69% and 79%, respectively.10 

Our cohort comprised 39% T-ALL and 61% B-ALL subtype, substantiating the fact that with increasing age the incidence of T-ALL increases.14,38,48-50,57  Hyperleukocytosis was found in 10% of our patients. With increasing age, good-risk cytogenetics like t(12;21) decreases and the poor-risk cytogenetics like t(9;22) and t(1;19) increases, which is evident from our cohort with the incidences being 0.6%, 11%, and 4.6%, respectively.14,48,50  CNS involvement in our cohort is 5.5%, which is similar to the other studies with a reported incidence of 5% to 25%. The use of a pediatric protocol has uniformly resulted in CR rates >90% in the previous trials.58  In our population, the CR rate was 81.6%. The low CR rate is due to the infections that led to induction deaths (6%) and treatment discontinuation (3.4%).

Our analyses prove that postinduction MRD trumps all other baseline disease-related characteristics in determining the overall outcome of the patients. Among the 272 patients who achieved CR at the end of phase 1 induction, 167 (61.4%) were MRD and 105 (38.6%) were MRD+, which is similar to what is described in literature.59,60  The EFS and OS of the MRD (compared with MRD+) patients in our cohort were 77.4% (vs 41%) and 79.2% (vs 44.8%), respectively (Table 5). The odds ratios for occurrence of relapse or death in a patient with a positive postinduction MRD was 2.4 and2.583, respectively (Table 8). Similar findings were reported from the US intergroup trial, the MD Anderson Cancer Center (MDACC) trial, and the German Multicenter ALL Study Group (GMALL) July 2003 trial.61-63 In the GMALL June 1999 study, which included only standard-risk adult (15-64 years) patients (MLL, Ph+, WBC count >30 × 109/L were excluded), patients with MRD+ status(>0.01%) had a 2.4-fold higher risk of relapse in comparison with the patients with MRD <0.01%.42  MRD assessment performed in 256 pediatric T-ALL patients treated with the MCP841 protocol in our institute also showed that MRD+ status had a hazard ratio (HR) of 2.01 and 1.64 for 3-year EFS and OS.64  MRD assessment in 167 patients (1-41 years of age) treated with the MCP-841 protocol from the Regional Cancer Centre in western India also showed that MRD negativity was associated with longer survival (29 months) in comparison with MRD+ patients (22 months).65  As per the literature, MRD negativity rates increased as the intensive therapy continues from 6% on day 11 to 36% on day 26 to 70% on day 71.66,67  Even in our cohort additional patients achieved MRD negativity by the end of phase 1b induction or consolidation (Table 3). In the end, only 38 patients (10.8%) remained MRD+. Achievement of MRD negativity during and after consolidation does confer a survival advantage in comparison with those who remain MRD+, however, they fare worse than those who became MRD postinduction (Table 5). Similar to the pediatric population, postinduction MRD can be used as a tool to further intensify the subsequent treatment in patients with positive MRD. Also, as the achievement of negative MRD results in better outcomes, we must develop strategies to improve MRD clearance.

Risk stratification based on the WBC count, baseline cytogenetics, and baseline ploidy analysis did not impact the outcome in our cohort. Previous studies have identified each of these factors to be detrimental in the outcome of the patients.38,48,62,68-70  This could be explained by the increased representation of the high-risk cytogenetics with Ph+ ALL and lesser representation with MLL and t(1;19). Outcomes of Ph+ ALL have improved after the utilization of TKIs along with multiagent chemotherapy.71  The EFS and OS of the Ph+ subgroup were considerably lesser (51.4% and 61.9%) in comparison with the rest of the B-ALL subgroup. Previous studies have shown that intensive chemotherapy along with TKI results in 5 year OS ranging from 40% to 50%.35,72-75  Among the 37 patients with Ph+ ALL, 7 patients underwent HSCT. Despite such low HSCT rates, the EFS and OS at 3 years were comparable to cohorts with much greater HSCT rates. So, the practice must be to achieve remission using chemotherapy with TKI backbone. HSCT must be considered only when a fully matched donor is available. Furthermore, the patients also must be risk-stratified based on MRD clearance using real-time PCR for BCR-ABL1 transcripts and the presence of IKZF1 at diagnosis.76  Achievement of complete molecular response (CMR) at 3 months has already been proven to be a significant factor in the overall outcome of these patients.77  In our cohort, 8 patients achieved CMR at 3 months.

Cranial irradiation was planned to be administered to all the patients as part of the protocol except in T-LBL patients. Our patients received intrathecal chemotherapy (methotrexate 12 mg), HDMTx (3 g/m2), and cranial irradiation as CNS-directed therapy. In pediatric ALL, the use of cranial radiotherapy has reduced especially because intrathecal and systemic chemotherapy provide similar results and due to the risk of neurocognitive impairment with cranial irradiation.78  However, there is no consensus regarding the utilization of cranial irradiation in the AYA population. No uniform pattern is seen in previous studies, some of them using the cranial irradiation for patients with T-ALL and CNS+ leukemia and others using for the whole cohort.38,61,68,69  In the Total Therapy Study performed at the St. Jude Children Research Hospital, cranial irradiation was omitted for all its patients. The incidence of CNS relapse was 4%.50  In our cohort, CNS relapse occurred in 23 patients (6.5%). On analyzing the baseline CNS status of these patients, 3 patients had CNS 2 or 3 disease and 20 had CNS 1 disease. Thus, future studies must aim to objectively define the place of cranial irradiation in the treatment protocol for patients with AYA ALL.

In terms of the complications, unlike the western studies that predominantly documented complications related to steroids and l-asparaginase, our analyses revealed an increased incidence of infections both bacterial as well as fungal. Our induction mortality was 6.5% similar to other studies from India.19,20,79,80  Of the 21 induction deaths, 19 (82%) were due to infections. The high induction death rate is a major concern and future efforts must be made to prevent infection-related induction deaths with the use of prophylactic antifungals during induction, rigorous implementation of preventive measures, and early deintensification of therapy in those patients who are likely to improve. Despite the outpatient-based treatment and increased number of induction deaths in our cohort, 178 patients (51%) have either completed maintenance (177 patients) or continuing maintenance (1 patient) at the time of data analysis.

One of the major strengths of this study was the use of a single regimen uniformly in all of the patients. Another strength of this study is also its major flaw, we did not use a risk-stratified or response-adapted strategy. HSCT was the only intensification used but limited to a few patients. Although this is not considered an optimal strategy in the present age, it provides an opportunity to understand the prognostic factors and also question the place of HSCT in this setting. The major limitation of this study is that it is a single-center experience. There have been recent efforts in conducting multicenter analyses in India, like the Hematology Cancer Consortium of India, which presented the retrospective analyses of 1454 patients in the AYA age group (15-29 years) from 9 centers across India over 6 years using both pediatrics-inspired and adult protocols. This analysis showed that Ph+ status (HR, 1.56; P = .044) and use of adult protocol (HR, 1.6; P < .001) were the only factors associated with inferior outcome. We await complete analyses of these data.81  Another limitation would be that newer molecular higher-risk features like Ph-like features and IKZF1 deletions for B-ALL, NOTCH1/FWBX7 mutation, and RAS/PTEN expression were not assessed in our patients to help in further risk stratification. This is especially important as these baseline factors seemed to influence the outcome significantly in recent studies.38,45  Finally, due to the retrospective nature of the data collection, the OS data are not accurate because of the losses to follow-up of patients who have relapsed or have not responded. Future research must be focused on better risk stratification, the use of targeted therapies, and response adaptation.

Conclusion

This study illustrates that it is possible to treat patients in the 15- to 25-year-old age group with a pediatrics-inspired modified BFM-90 protocol, with low treatment-related mortality and comparable outcomes as that of the published literature.

Requests for data may be e-mailed to the corresponding author, Manju Sengar, at manju.sengar@gmail.com.

The authors acknowledge the help of Neha Sharma, Monisha Pillai, Seena Porathur, Gauri Patil, and Himanshi Gupta in data capturing.

Contribution: A.R., Hasmukh Jain, V.N.A.B., L.N., J.T., and M.S. designed and implemented the study; A.R., Hasmukh Jain, V.N.A.B., L.N., D.S., J.T., Hemani Jain, N.K., A.G., S.P., B.B., and M.S. contributed to the acquisition of the data and the documentation process; A.R., Hasmukh Jain, V.N.A.B., L.N., P.T., D.S., J.T., Hemani Jain, P.G.S., N.P., G.C., S.M., and M.S. planned and conducted data analysis; A.R., Hasmukh Jain, V.N.A.B., L.N., P.T., D.S., J.T., and M.S. drafted the manuscript; A.R., Hasmukh Jain, V.N.A.B., L.N., P.T., D.S., J.T., Hemani Jain, P.G.S., N.P., G.C., and M.S. contributed to the critical revision of the manuscript; and all authors reviewed the manuscript and approved the final version for publication.

Conflict-of-interest disclosure: The authors declare no competing financial interests.

Correspondence: Manju Sengar, Adult Hematolymphoid Unit, Tata Memorial Centre, affiliated with Homi Bhabha National University, E Borges Rd, Mumbai, 400 012, Maharashtra, India; e-mail: manju.sengar@gmail.com.

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