Treatment options for infants with KMT2A rearrangements

The international Interfant-99 trial used a cytarabine-intensive chemotherapy regimen, with increased exposure to both low- and high-dose cytarabine during the first few months of therapy.[23]

The international Interfant-99 trial used a cytarabine-intensive chemotherapy regimen, with increased exposure to both low- and high-dose cytarabine during the first few months of therapy.[23]

The 5-year EFS rate was 37% for infants with KMT2A rearrangements.

The COG tested intensification of therapy with a regimen that included multiple doses of high-dose methotrexate, cyclophosphamide, and etoposide.[22]

The COG tested intensification of therapy with a regimen that included multiple doses of high-dose methotrexate, cyclophosphamide, and etoposide.[22]

The 5-year EFS rate was 34% for infants with KMT2A rearrangements.

On the COG P9407 (NCT00002756) trial, infants were treated with a shortened (46-week) intensive chemotherapy regimen.[24][Level of evidence B4]

On the COG P9407 (NCT00002756) trial, infants were treated with a shortened (46-week) intensive chemotherapy regimen.[24][Level of evidence B4]

The 5-year EFS rate was 36% for infants with KMT2A rearrangements.

The international Interfant-06 study tested whether acute myeloid leukemia (AML)-style consolidation chemotherapy was superior to ALL-style chemotherapy.[30][Level of evidence B4]

The international Interfant-06 study tested whether acute myeloid leukemia (AML)-style consolidation chemotherapy was superior to ALL-style chemotherapy.[30][Level of evidence B4]

The 6-year EFS rate was 46.1%, and the OS rate was 58.2%. These rates were not statistically different from the rates observed in the predecessor Interfant-99 protocol.

The international Interfant-06 study tested whether acute myeloid leukemia (AML)-style consolidation chemotherapy was superior to ALL-style chemotherapy.[30][Level of evidence B4]

For infants with KMT2A rearrangements, the 6-year EFS rate was 36.4%, with no significant difference between the AML and ALL approach.

The international Interfant-06 study tested whether acute myeloid leukemia (AML)-style consolidation chemotherapy was superior to ALL-style chemotherapy.[30][Level of evidence B4]

In a subsequent analysis of the subset of KMT2A-rearranged patients in whom MRD was evaluated, both end-of-induction (EOI) and end-of-consolidation (EOC) MRD were strongly predictive of outcome. Patients who were EOI MRD positive, but became EOC MRD negative, had similar outcomes to those who were EOI MRD negative (6-year DFS rates, 65.7% and 72.0%, respectively). Patients with high EOC MRD had dismal outcomes (6-year DFS rate, 13.1%). Patients with negative EOI MRD had a higher 6-year DFS rate when treated with the ALL approach (78.2%) than did patients who were treated with the AML approach (45%). However, patients with high EOI MRD (≥5 × 10-4) who were treated with an AML approach had a superior 6-year DFS rate (45.9%) when compared with patients who were treated with the ALL approach (23.2%).[34][Level of evidence B1]

In a follow-up pilot trial conducted by the Interfant study group, 30 infants with KMT2A-rearranged ALL were treated using the Interfant-06 chemotherapy backbone, with the addition of one 28-day course of blinatumomab after the induction phase.[35]

In a follow-up pilot trial conducted by the Interfant study group, 30 infants with KMT2A-rearranged ALL were treated using the Interfant-06 chemotherapy backbone, with the addition of one 28-day course of blinatumomab after the induction phase.[35]

Blinatumomab was well tolerated, without any excessive or unexpected toxicity in these infant patients.

In a follow-up pilot trial conducted by the Interfant study group, 30 infants with KMT2A-rearranged ALL were treated using the Interfant-06 chemotherapy backbone, with the addition of one 28-day course of blinatumomab after the induction phase.[35]

With short median follow-up (26.3 months), the 2-year DFS rate was 81.6% (95% CI, 60.8%–92.0%), and the 2-year OS rate was 93.3% (95% CI, 75.9%–98.3%).

In a follow-up pilot trial conducted by the Interfant study group, 30 infants with KMT2A-rearranged ALL were treated using the Interfant-06 chemotherapy backbone, with the addition of one 28-day course of blinatumomab after the induction phase.[35]

These outcomes were superior to the 2-year DFS and OS rates of historical controls who were treated in the Interfant-06 protocol (DFS and OS rates, 49.4% and 65.8%, respectively).

On the MLL-10 trial conducted by the Japanese Pediatric Leukemia/Lymphoma Study Group (JPLSG), infants with KMT2A rearrangements were treated with an intensified chemotherapy backbone that included multiple phases using high-dose methotrexate, cyclophosphamide, etoposide, and high-dose cytarabine. Patients classified as high-risk on the basis of age and CNS status (75% of KMT2A-rearranged patients) were allocated to HSCT in first CR.[25]

On the MLL-10 trial conducted by the Japanese Pediatric Leukemia/Lymphoma Study Group (JPLSG), infants with KMT2A rearrangements were treated with an intensified chemotherapy backbone that included multiple phases using high-dose methotrexate, cyclophosphamide, etoposide, and high-dose cytarabine. Patients classified as high-risk on the basis of age and CNS status (75% of KMT2A-rearranged patients) were allocated to HSCT in first CR.[25]

The 5-year EFS rate was 66%, and the 5-year OS rate was 82%.

In the COG AALL0631 (NCT00557193) trial, infants with KMT2A-rearranged ALL were assigned to receive an intensive chemotherapy regimen with or without lestaurtinib, an FLT3 inhibitor (administered during postinduction treatment phases).[28]Exploratory studies were conducted to evaluate the impact of sufficient lestaurtinib blood levels to achieve FLT3 inhibition and to evaluate the impact of ex vivo sensitivity of leukemia cells to lestaurtinib.

In the COG AALL0631 (NCT00557193) trial, infants with KMT2A-rearranged ALL were assigned to receive an intensive chemotherapy regimen with or without lestaurtinib, an FLT3 inhibitor (administered during postinduction treatment phases).[28]Exploratory studies were conducted to evaluate the impact of sufficient lestaurtinib blood levels to achieve FLT3 inhibition and to evaluate the impact of ex vivo sensitivity of leukemia cells to lestaurtinib.

The overall 5-year EFS rate for all participants was 34%, and the 5-year OS rate was 41%.

In the COG AALL0631 (NCT00557193) trial, infants with KMT2A-rearranged ALL were assigned to receive an intensive chemotherapy regimen with or without lestaurtinib, an FLT3 inhibitor (administered during postinduction treatment phases).[28]Exploratory studies were conducted to evaluate the impact of sufficient lestaurtinib blood levels to achieve FLT3 inhibition and to evaluate the impact of ex vivo sensitivity of leukemia cells to lestaurtinib.

There was no difference in outcome between patients on the lestaurtinib arm versus those who received chemotherapy only.

In the COG AALL0631 (NCT00557193) trial, infants with KMT2A-rearranged ALL were assigned to receive an intensive chemotherapy regimen with or without lestaurtinib, an FLT3 inhibitor (administered during postinduction treatment phases).[28]Exploratory studies were conducted to evaluate the impact of sufficient lestaurtinib blood levels to achieve FLT3 inhibition and to evaluate the impact of ex vivo sensitivity of leukemia cells to lestaurtinib.

Only 38% of lestaurtinib-treated patients demonstrated in vivo FLT3 inhibition. This subset of patients appeared to have a better outcome than other patients on the lestaurtinib arm, as did those whose blasts demonstrated ex vivo sensitivity to FLT3 inhibition.

On a trial conducted by the JPLSG between 1998 and 2002, all infants with KMT2A rearrangements were intended to proceed to allogeneic HSCT from the best available donor (related, unrelated, or umbilical cord) 3 to 5 months after diagnosis.[36]

On a trial conducted by the JPLSG between 1998 and 2002, all infants with KMT2A rearrangements were intended to proceed to allogeneic HSCT from the best available donor (related, unrelated, or umbilical cord) 3 to 5 months after diagnosis.[36]

The 3-year EFS rate for all enrolled infants was 44%. This outcome resulted, in part, from the high frequency of early relapses, even with intensive chemotherapy. Of the 41 infants with KMT2A rearrangements on that study who achieved CR, 11 infants (27%) relapsed before proceeding to transplant.

In a follow-up trial conducted by the JPLSG between 2011 and 2015, allocation to HSCT in first CR was restricted to the patients with KMT2A rearrangements and classified as high risk (age <6 months and/or CNS3 status at diagnosis).[25]

In a follow-up trial conducted by the JPLSG between 2011 and 2015, allocation to HSCT in first CR was restricted to the patients with KMT2A rearrangements and classified as high risk (age <6 months and/or CNS3 status at diagnosis).[25]

Of the 56 patients that were classified as high risk (75% of all KMT2A-rearranged patients enrolled on the trial), 49 achieved CR, and 38 underwent HSCT.

In a follow-up trial conducted by the JPLSG between 2011 and 2015, allocation to HSCT in first CR was restricted to the patients with KMT2A rearrangements and classified as high risk (age <6 months and/or CNS3 status at diagnosis).[25]

In an intent-to-treat analysis of all high-risk patients enrolled on the trial, the 5-year EFS rate was 56.6%.

In a follow-up trial conducted by the JPLSG between 2011 and 2015, allocation to HSCT in first CR was restricted to the patients with KMT2A rearrangements and classified as high risk (age <6 months and/or CNS3 status at diagnosis).[25]

For the subset of patients who also met Interfant-06 criteria for high risk (age <6 months and WBC >300,000/µL or a prednisolone poor responder), the 5-year EFS rate was 45.2%.

In a COG report that included 189 infants treated on CCG or POG infant ALL protocols between 1996 and 2000, there was no difference in EFS between patients who underwent HSCT in first CR and those who received chemotherapy alone.[37]

The Interfant clinical trials group, after adjusting for waiting time to transplant, also did not observe any difference in DFS in high-risk infants (defined by prednisone response) with KMT2A rearrangements treated on the Interfant-99 trial with either allogeneic HSCT in first CR or chemotherapy alone.[23]

The Interfant clinical trials group, after adjusting for waiting time to transplant, also did not observe any difference in DFS in high-risk infants (defined by prednisone response) with KMT2A rearrangements treated on the Interfant-99 trial with either allogeneic HSCT in first CR or chemotherapy alone.[23]

In a subset analysis from the same trial, allogeneic HSCT in first remission was associated with a significantly better DFS for infants with KMT2A rearrangements who were younger than 6 months at diagnosis and had either a poor prednisone response at day 8 or leukocyte counts of at least 300,000/µL.[38] In this subset, HSCT in first remission was associated with a 64% reduction in the risk of failure resulting from relapse or death compared with chemotherapy alone.

On the Interfant-06 study, infants considered to be high risk (all of the following: KMT2A rearrangements, age <6 months, and WBC ≥300,000/μL) were considered eligible for allogeneic HSCT in first CR.[30][Level of evidence B4]

On the Interfant-06 study, infants considered to be high risk (all of the following: KMT2A rearrangements, age <6 months, and WBC ≥300,000/μL) were considered eligible for allogeneic HSCT in first CR.[30][Level of evidence B4]

About one-half of the high-risk patients did not proceed to transplant in the first CR primarily because of early relapse.

On the Interfant-06 study, infants considered to be high risk (all of the following: KMT2A rearrangements, age <6 months, and WBC ≥300,000/μL) were considered eligible for allogeneic HSCT in first CR.[30][Level of evidence B4]

The 6-year EFS rate of the entire high-risk group was 21%.

On the Interfant-06 study, infants considered to be high risk (all of the following: KMT2A rearrangements, age <6 months, and WBC ≥300,000/μL) were considered eligible for allogeneic HSCT in first CR.[30][Level of evidence B4]

For the highly-selected population who underwent HSCT, the 4-year DFS rate was 44%.