Very high-risk ALL

Infants younger than 1 year, especially if there is a KMT2A gene rearrangement present. For more information about infants with ALL, see the Infants With ALL section.

Patients with adverse cytogenetic abnormalities, including BCR::ABL1, TCF3::HLF, KMT2A gene rearrangements, and low hypodiploidy (<44 chromosomes).

Patients who achieve CR but have a slow early response to initial therapy, including those with a high absolute blast count after a 7-day steroid prophase, and patients with high MRD levels at the end of induction (week 4) or later time points (e.g., week 12).

Patients who have morphologically persistent disease after the first 4 weeks of therapy (induction failure), even if they later achieve CR.

In a European cooperative group study conducted between 1995 and 2000, very high-risk patients were defined as one of the following: morphologically persistent disease after a four-drug induction, BCR::ABL1 or KMT2A::AFF1 fusions, or poor response to prednisone prophase in patients with either T-cell phenotype or presenting white blood cells (WBC) >100,000/μL. These patients were assigned to receive either an allogeneic HSCT in first CR (based on the availability of a human lymphocyte antigen–matched related donor) or intensive chemotherapy.[39]

In a European cooperative group study conducted between 1995 and 2000, very high-risk patients were defined as one of the following: morphologically persistent disease after a four-drug induction, BCR::ABL1 or KMT2A::AFF1 fusions, or poor response to prednisone prophase in patients with either T-cell phenotype or presenting white blood cells (WBC) >100,000/μL. These patients were assigned to receive either an allogeneic HSCT in first CR (based on the availability of a human lymphocyte antigen–matched related donor) or intensive chemotherapy.[39]

Using an intent-to-treat analysis, patients assigned to allogeneic HSCT (on the basis of donor availability) had a superior 5-year DFS rate compared with patients assigned to intensive chemotherapy (57% ± 7% for transplant vs. 41% ± 3% for chemotherapy, P = .02).

In a European cooperative group study conducted between 1995 and 2000, very high-risk patients were defined as one of the following: morphologically persistent disease after a four-drug induction, BCR::ABL1 or KMT2A::AFF1 fusions, or poor response to prednisone prophase in patients with either T-cell phenotype or presenting white blood cells (WBC) >100,000/μL. These patients were assigned to receive either an allogeneic HSCT in first CR (based on the availability of a human lymphocyte antigen–matched related donor) or intensive chemotherapy.[39]

There was no significant difference in OS rates (56% ± 6% for transplant vs. 50% ± 3% for chemotherapy; P = .12).

In a European cooperative group study conducted between 1995 and 2000, very high-risk patients were defined as one of the following: morphologically persistent disease after a four-drug induction, BCR::ABL1 or KMT2A::AFF1 fusions, or poor response to prednisone prophase in patients with either T-cell phenotype or presenting white blood cells (WBC) >100,000/μL. These patients were assigned to receive either an allogeneic HSCT in first CR (based on the availability of a human lymphocyte antigen–matched related donor) or intensive chemotherapy.[39]

For patients with T-ALL and a poor response to prednisone prophase, both DFS and OS rates were significantly better with allogeneic HSCT.[92]

In a large retrospective series of patients with initial induction failure, the 10-year OS rate for patients with persistent leukemia was 32%.[41]

In a large retrospective series of patients with initial induction failure, the 10-year OS rate for patients with persistent leukemia was 32%.[41]

A trend for superior outcome with allogeneic HSCT, compared with chemotherapy alone, was observed in patients with T-cell phenotype (any age) and with B-ALL who were older than 6 years.

In a large retrospective series of patients with initial induction failure, the 10-year OS rate for patients with persistent leukemia was 32%.[41]

Patients with B-ALL who were aged 1 to 5 years at diagnosis and did not have any adverse cytogenetic abnormalities (KMT2A rearrangement, BCR::ABL1) had a relatively favorable prognosis, without any advantage in outcome with the utilization of HSCT compared with chemotherapy alone.

The AIEOP ALL-BFM-2000 (NCT00430118) study (2000–2006) classified patients as high risk if they met any of the following criteria: poor response to prednisone prophase, failure to achieve CR at the end of the first month of treatment, high MRD levels after induction IB (day 78 of therapy), and KMT2A::AFF1 fusion. These patients were allocated to allogeneic HSCT in first CR per protocol on the basis of donor availability and investigator preference.[95][Level of evidence B4]

The AIEOP ALL-BFM-2000 (NCT00430118) study (2000–2006) classified patients as high risk if they met any of the following criteria: poor response to prednisone prophase, failure to achieve CR at the end of the first month of treatment, high MRD levels after induction IB (day 78 of therapy), and KMT2A::AFF1 fusion. These patients were allocated to allogeneic HSCT in first CR per protocol on the basis of donor availability and investigator preference.[95][Level of evidence B4]

The overall 5-year EFS rate of patients meeting high-risk criteria was 58.9%.

The AIEOP ALL-BFM-2000 (NCT00430118) study (2000–2006) classified patients as high risk if they met any of the following criteria: poor response to prednisone prophase, failure to achieve CR at the end of the first month of treatment, high MRD levels after induction IB (day 78 of therapy), and KMT2A::AFF1 fusion. These patients were allocated to allogeneic HSCT in first CR per protocol on the basis of donor availability and investigator preference.[95][Level of evidence B4]

The 5-year EFS rate was 74% for patients whose only high-risk feature was prednisone-poor response. There was no significant difference in DFS (P = .31) or OS (P = .91) when comparing HSCT and chemotherapy for patients with poor prednisone response in whom HSCT was allowed per protocol (those with T-ALL and/or WBC ≥100,000/mm3).

The AIEOP ALL-BFM-2000 (NCT00430118) study (2000–2006) classified patients as high risk if they met any of the following criteria: poor response to prednisone prophase, failure to achieve CR at the end of the first month of treatment, high MRD levels after induction IB (day 78 of therapy), and KMT2A::AFF1 fusion. These patients were allocated to allogeneic HSCT in first CR per protocol on the basis of donor availability and investigator preference.[95][Level of evidence B4]

All other high-risk patients (i.e., those with initial induction failure, high day 78 MRD and/or KMT2A::AFF1 fusion) had EFS rates less than 50%. For these patients, there was no statistically significant difference in DFS between those who received HSCT (n = 66) and those who received chemotherapy only (n = 88), after adjusting for waiting time to HSCT (5.7 months).

On the NOPHO ALL2008 (NCT00819351) protocol, patients were allocated to HSCT in first CR if they had MRD levels of 5% or greater at the end of induction or MRD levels of 0.1% or greater at end of consolidation. All patients allocated to HSCT received at least three blocks of intensive chemotherapy before HSCT to reduce levels of MRD.[96]

On the NOPHO ALL2008 (NCT00819351) protocol, patients were allocated to HSCT in first CR if they had MRD levels of 5% or greater at the end of induction or MRD levels of 0.1% or greater at end of consolidation. All patients allocated to HSCT received at least three blocks of intensive chemotherapy before HSCT to reduce levels of MRD.[96]

In the intent-to-treat analysis of 69 patients who met HSCT criteria (10 of whom did not undergo HSCT), the 5-year DFS rate was 78%.

On the NOPHO ALL2008 (NCT00819351) protocol, patients were allocated to HSCT in first CR if they had MRD levels of 5% or greater at the end of induction or MRD levels of 0.1% or greater at end of consolidation. All patients allocated to HSCT received at least three blocks of intensive chemotherapy before HSCT to reduce levels of MRD.[96]

Comparing the patients in this cohort who did and did not receive HSCT, receipt of HSCT was not significantly associated with survival (HR, 1.4; P = .69).

On the NOPHO ALL2008 (NCT00819351) protocol, patients were allocated to HSCT in first CR if they had MRD levels of 5% or greater at the end of induction or MRD levels of 0.1% or greater at end of consolidation. All patients allocated to HSCT received at least three blocks of intensive chemotherapy before HSCT to reduce levels of MRD.[96]

For patients who underwent HSCT, superior outcomes (better DFS and lower cumulative incidence of relapse) were observed in patients who had nondetectable MRD before HSCT.

In the DCOG ALL-10 and ALL-11 trials, patients with very high-risk features received an intensified treatment regimen that included three high-dose chemotherapy blocks after consolidation. After the three blocks, 60 patients received an allogeneic HSCT, and 22 patients continued with a chemotherapy-only approach, which included three additional high-dose blocks. In these trials, very high-risk disease was defined by any of the following features: morphologically detectable disease at end of induction, high end-consolidation MRD (time point 2), t(4;11), or poor response to a prednisone prophase.[91]

In the DCOG ALL-10 and ALL-11 trials, patients with very high-risk features received an intensified treatment regimen that included three high-dose chemotherapy blocks after consolidation. After the three blocks, 60 patients received an allogeneic HSCT, and 22 patients continued with a chemotherapy-only approach, which included three additional high-dose blocks. In these trials, very high-risk disease was defined by any of the following features: morphologically detectable disease at end of induction, high end-consolidation MRD (time point 2), t(4;11), or poor response to a prednisone prophase.[91]

The 5-year EFS rate was 72.8% for all patients.

In the DCOG ALL-10 and ALL-11 trials, patients with very high-risk features received an intensified treatment regimen that included three high-dose chemotherapy blocks after consolidation. After the three blocks, 60 patients received an allogeneic HSCT, and 22 patients continued with a chemotherapy-only approach, which included three additional high-dose blocks. In these trials, very high-risk disease was defined by any of the following features: morphologically detectable disease at end of induction, high end-consolidation MRD (time point 2), t(4;11), or poor response to a prednisone prophase.[91]

In a landmark analysis of EFS from the end of the third high-dose chemotherapy block, no difference was observed in the outcomes of patients who received HSCT versus those who received chemotherapy only.

Two retrospective analyses investigated the role of HSCT in first CR for patients with hypodiploid ALL. The studies showed no clear evidence that HSCT improved outcomes when 1) transplanting all patients with hypodiploid ALL, or 2) transplanting hypodiploid patients deemed at high risk on the basis of high MRD after induction. The studies did not examine the strategy of HSCT for persistent MRD after consolidation, nor did they analyze the status of MRD at the time of HSCT.

Two retrospective analyses investigated the role of HSCT in first CR for patients with hypodiploid ALL. The studies showed no clear evidence that HSCT improved outcomes when 1) transplanting all patients with hypodiploid ALL, or 2) transplanting hypodiploid patients deemed at high risk on the basis of high MRD after induction. The studies did not examine the strategy of HSCT for persistent MRD after consolidation, nor did they analyze the status of MRD at the time of HSCT.

In a study of 306 hypodiploid patients from 16 ALL cooperative groups treated between 1997 and 2013, a subgroup of 228 patients (42 who underwent HSCT) with 44 or fewer chromosomes who achieved remission were analyzed.[97][Level of evidence C2]

Two retrospective analyses investigated the role of HSCT in first CR for patients with hypodiploid ALL. The studies showed no clear evidence that HSCT improved outcomes when 1) transplanting all patients with hypodiploid ALL, or 2) transplanting hypodiploid patients deemed at high risk on the basis of high MRD after induction. The studies did not examine the strategy of HSCT for persistent MRD after consolidation, nor did they analyze the status of MRD at the time of HSCT. › In a study of 306 hypodiploid patients from 16 ALL cooperative groups treated between 1997 and 2013, a subgroup of 228 patients (42 who underwent HSCT) with 44 or fewer chromosomes who achieved remission were analyzed.[97][Level of evidence C2]

Favorable prognostic factors included a chromosome number of 44 (compared with 43 or fewer), MRD less than 0.01% after induction, and treatment on an MRD-stratified protocol that intensified therapy for patients with higher MRD after induction.

Two retrospective analyses investigated the role of HSCT in first CR for patients with hypodiploid ALL. The studies showed no clear evidence that HSCT improved outcomes when 1) transplanting all patients with hypodiploid ALL, or 2) transplanting hypodiploid patients deemed at high risk on the basis of high MRD after induction. The studies did not examine the strategy of HSCT for persistent MRD after consolidation, nor did they analyze the status of MRD at the time of HSCT. › In a study of 306 hypodiploid patients from 16 ALL cooperative groups treated between 1997 and 2013, a subgroup of 228 patients (42 who underwent HSCT) with 44 or fewer chromosomes who achieved remission were analyzed.[97][Level of evidence C2]

After correction for median time to transplant, patients with low MRD who underwent HSCT had a DFS rate of 73.6%, compared with a DFS rate of 70% for those treated with chemotherapy alone (P = .81). Patients with higher MRD after induction who underwent HSCT had a DFS rate of 55.9%, compared with a DFS rate of 40.3% for those treated with chemotherapy (P = .29).

Two retrospective analyses investigated the role of HSCT in first CR for patients with hypodiploid ALL. The studies showed no clear evidence that HSCT improved outcomes when 1) transplanting all patients with hypodiploid ALL, or 2) transplanting hypodiploid patients deemed at high risk on the basis of high MRD after induction. The studies did not examine the strategy of HSCT for persistent MRD after consolidation, nor did they analyze the status of MRD at the time of HSCT.

The COG published an analysis of 113 evaluable patients with hypodiploid ALL who were treated between 2003 and 2011; 61 of those patients underwent HSCT in first CR.[98][Level of evidence C1]

Two retrospective analyses investigated the role of HSCT in first CR for patients with hypodiploid ALL. The studies showed no clear evidence that HSCT improved outcomes when 1) transplanting all patients with hypodiploid ALL, or 2) transplanting hypodiploid patients deemed at high risk on the basis of high MRD after induction. The studies did not examine the strategy of HSCT for persistent MRD after consolidation, nor did they analyze the status of MRD at the time of HSCT. › The COG published an analysis of 113 evaluable patients with hypodiploid ALL who were treated between 2003 and 2011; 61 of those patients underwent HSCT in first CR.[98][Level of evidence C1]

The 5-year EFS rate was 57.4% for patients who underwent HSCT and 47.8% for patients in the chemotherapy cohorts (P = .49). The OS rate was 66.2% for patients who underwent HSCT and 53.8% for patients in the chemotherapy cohorts (P = .34).

Two retrospective analyses investigated the role of HSCT in first CR for patients with hypodiploid ALL. The studies showed no clear evidence that HSCT improved outcomes when 1) transplanting all patients with hypodiploid ALL, or 2) transplanting hypodiploid patients deemed at high risk on the basis of high MRD after induction. The studies did not examine the strategy of HSCT for persistent MRD after consolidation, nor did they analyze the status of MRD at the time of HSCT. › The COG published an analysis of 113 evaluable patients with hypodiploid ALL who were treated between 2003 and 2011; 61 of those patients underwent HSCT in first CR.[98][Level of evidence C1]

Patients with high MRD after induction (≥0.01%) had a very poor EFS rate of 26.7% at 5 years, with no difference between the patients who received HSCT and the patients who received chemotherapy.