Do high-risk PH-ALL patients with negative MRD still need to undergo transplantation?

For high-risk (HR) Philadelphia chromosome-negative (PH-) acute lymphoblastic leukemia (ALL) patients with minimal residual disease (MRD) status, the necessity of allogeneic hematopoietic stem cell transplantation (allo-HSCT) is still unclear.

A prospective study evaluated the effect of allo-HSCT on the treatment outcome of PH-ALL patients based on the MRD levels of PH-ALL patients after induction therapy and consolidation therapy.

The main results of the study are summarized as follows for the reference of readers.

Key points: HR PH-ALL patients with better MRD status after induction therapy and early consolidation therapy still have a better prognosis without receiving allo-HSCT.

For patients with poor efficacy after induction therapy, early allocation of allo-HSCT can improve the long-term survival of these patients.

Research methods The study included patients with HR PH-ALL aged 15-60 years and ECOG scores of 0-2.

The patient first received 4 weeks of induction therapy with vincristine, prednisone, daunorubicin, and asparaginase.

CR patients who have not achieved complete remission (CR) after induction therapy or with an MRD level ≥0.
1% after induction therapy will receive fludarabine, cytarabine, granulocyte colony stimulating factor (G-CSF), and idarubicin Strengthen the induction treatment program.

Patients who fail to achieve CR after two induction treatments will be excluded from the study of follow-up treatment.

Patients who reach CR after induction therapy and have an MRD level of <0.
1% will receive 3 cycles of high-dose methotrexate, cytarabine, and asparaginase consolidation therapy until the patient achieves a 2-year CR status.

 For patients who reach CR after induction therapy but MRD level ≥0.
1% or MRD level ≥0.
01% after early consolidation treatment, they will receive allo-HSCT if they have a suitable donor.

Research Results The study included 348 patients with HR PH-ALL from 51 centers in Spain from August 2011 to October 2019.

Among them, 212 (61%) patients were male, the median age at start of treatment was 40 years (range: 15-60 years), and 262 (75%) patients were 30-60 years old.

241 patients (69%) had B-cell ALL, of which 184 patients had B-cell precursor ALL, and 70 patients (38%) had positive CD20 expression.

Extramedullary diseases were observed in 90 patients, and the most common sites were the central nervous system (n=38) and the mediastinum (n=51).

Cytogenetic abnormalities were observed in 24 patients (7%).

 289 patients (83%) achieved CR after the first induction therapy, of which 220 patients had MRD levels less than 0.
1%, 66 patients had MRD levels greater than or equal to 0.
1%, and 3 patients had undetectable MRD levels.

179 patients obtained a deeper level of MRD negative (MRD level ≤0.
01%).

Among 24 patients with t(v;11q23) rearrangement, 18 patients reached CR after the first induction therapy, and 7 patients (39%) had MRD levels ≤0.
01%.

Among 23 patients with acute early T-cell lymphocytic leukemia (ETP-ALL), 11 patients achieved CR after the first induction therapy, and 4 patients (36%) had MRD levels ≤0.
01%.

 99 patients received the second induction therapy (41 patients failed the first induction therapy; 58 patients reached CR after the first induction therapy, but the MRD level was ≥0.
1%).

Among 58 patients with CR after the first induction therapy but with an MRD level ≥0.
1%, 3 patients did not complete the second induction therapy, 7 patients died during the treatment, and 2 patients had disease refractory (losing previous CR) Status), 2 patients relapsed before consolidation treatment, 44 patients maintained CR (MRD level of 42 patients can be assessed, and MRD level of 29 patients is less than 0.
01%).

Among the 41 patients who failed the first induction therapy, 1 patient was still receiving the second induction therapy, 5 patients died during the treatment, 7 patients were refractory to treatment, and 28 patients reached CR.

Two patients subsequently left the study due to other medications (belituzumab).

After two induction treatments, 315 (91%) of the 348 patients included in the study achieved CR.

 Among 109 patients who did not reach CR or MRD level ≥0.
1% after the first induction therapy, 106 patients received allo-HSCT, and 3 patients were lost to follow-up.

Among 99 patients who received the second induction therapy, 70 patients received follow-up consolidation therapy, of which 57 patients received allo-HSCT.

 Of the 315 patients who received CR, 89 patients relapsed, of which 63 patients relapsed during treatment, and 26 patients relapsed after treatment.

The 5-year cumulative recurrence rate (CIR) of the patients in the study was 43% (95% CI: 36%-50%).

Compared with other patients, the CIR of ETP ALL patients was higher (64% vs 39%) (but not statistically significant).

 At a median follow-up of 2.
4 years (range: 0.
2-7.
7 years), 132 patients died and 216 patients survived.
The median overall survival (OS) was 4.
2 years.
The expected 5-year OS rate was 49% (95%CI: 42%-56%).

The cause of death of the patient was disease recurrence (n=78), side effects of treatment (n=48), and second tumor (n=6).

Compared with other patients, patients with ETP ALL had worse OS (31% vs 66%; P=0.
06).

 The 5-year OS rate of 48 patients with MRD level <0.
01% after induction therapy was 82% (95%CI: 69%-95%), which was significantly higher than that of patients with MRD level ≥0.
01%.

In 18 of the 48 patients, the MRD level was still less than 0.
01% after the completion of the consolidation treatment, and the 5-year OS rate of this part of the patients was 91% (95%CI: 51%-99%).

Research conclusions The research results show that for HR PH-ALL patients with better MRD levels after induction therapy and consolidation therapy, not receiving allo-HSCT will not affect the better prognosis of these patients.

For patients who achieve remission after treatment but have poor MRD levels, it is necessary to find better alternative therapies.

References: Josep-Maria Ribera, Mireia Morgades, Juana Ciudad, Pau Montesinos, et al.
Chemotherapy or allogeneic transplantation in high-risk Philadelphia chromosome–negative adult lymphoblastic leukemia.
Blood (2021) 137 (14): 1879–1894.
; https://doi.
org/10.
1182/blood.
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