Prognostic impact of Philadelphia chromosome in mixed phenotype acute leukemia (MPAL): A cancer registry analysis on real‐world outcome

Abstract

Mixed phenotype acute leukemia (MPAL) is thought to have poor outcome, and presence of the Philadelphia chromosome (Ph+) has been considered to be an adverse prognostic marker. However, most of these reports were in the pre‐tyrosine kinase inhibitors (TKIs) era. Recent limited reports indicate improved outcomes for MPAL with the addition of TKIs. We examined the outcomes of 241 cases of MPAL according to the 2008 WHO classification from the Surveillance, Epidemiology, and End Results registry. The MLL+ patients had a median age of 6 years while other subtypes occurred mostly in adults and had comparable age. On multivariate analyses and after adjustment for age, year of diagnosis and chemotherapy status, Ph+ MPAL patients had reduced risk of death in comparison to Ph(–) MPAL patients (hazard ratio [HR] = 0.28, P = .002). So, MLL+ MPAL had the worst outcome with a 10‐fold increased risk of death in comparison to Ph+ MPAL patients (HR = 10.2, P < .001). Importantly, the outcome of Ph+ MPAL was comparable to Ph+ acute lymphoblastic leukemia in a 1:1 matched case‐control analysis. In conclusion, this is the largest registry study which examines the outcomes of MPAL subtypes. We confirm that MPAL is a heterogenous disease. Note, Ph+ MPAL nowadays has a better OS in comparison to other subtypes and is comparable to Ph+ ALL patients. This is most likely secondary to changes in practice and more utilization of TKIs. On the other hand, MLL rearrangement is associated with infantile MPAL and has a dismal prognosis.

Mixed-Phenotype Acute Leukemia: Clinical Diagnosis and Therapeutic Strategies

“…In patients with BCR-ABL fusion positive MPAL, the addition of a tyrosine kinase inhibitor (TKI) to the chemotherapy backbone is highly recommended. Patients with Philadelphia positive (Ph+) MPAL who received TKIs had a significant reduction in the risk of death in comparison to Ph (-) MPAL patients (hazard ratio [HR] = 0.28, p = 0.002) [ 50 , 51 ]. However, the KMT2Ar subset of patients showed conflicting results: some reports show no difference in survival [ 38 , 52 ], whereas recent data show poorer survival with a tenfold increase in death compared Ph+ MPAL (HR = 10.2, p < 0.001) [ 35 , 51 ].…”

Megakaryocytic emperipolesis in a therapy‐related acute‐mixed phenotypic leukemia

“…MPAL with t(9;22) may have better survival than other subtypes of MPAL, but therapy‐related MPAL with t(9;22) is extremely rare and may confer a poor prognosis 1 2 …”

Pediatric Mixed-Phenotype Acute Leukemia: What’s New?

“…For example, MLL-AF4 is predominantly associated with a lymphoid phenotype and MLL-AF9 with a myeloid phenotype [ 47 ]; however, the role of fusion partners in determining MPAL phenotype or lineage switch remains unclear [ 48 ]. Compared with Ph + MPAL, the MLL + MPAL patients have significantly inferior survival odds (HR = 10.2, p < 0.001) [ 49 ], and are transplanted, upfront, if induction failure occurs, or at relapse [ 11 , 50 , 51 ]. New emerging targets blocking the MLL fusion complex are under evaluation, include menin [ 52 ], disruptor of telomeric silencing 1-like ( DOTL1 ) inhibitors [ 53 ], and spleen tyrosine kinase ( SYK ) inhibitors [ 54 ].…”

“…Ph + acute ALL, with t(9;22)(q34:q11.2), constitute 25% of MPAL, and are more common in adults than children, and often present with a B/myeloid phenotype and a p190 BCR-ABL transcript and have a high incidence of CNS involvement [ 3 , 8 , 11 ]. With the advent of successful TKI therapy directed against BCR-ABL , the treatment paradigm has shifted, and outcomes have improved significantly [ 49 ]. An ALL-chemotherapy backbone combined with a TKI is increasingly utilized, with comparable outcomes to Ph+ non-MPAL ALL [ 49 ].…”

“…With the advent of successful TKI therapy directed against BCR-ABL , the treatment paradigm has shifted, and outcomes have improved significantly [ 49 ]. An ALL-chemotherapy backbone combined with a TKI is increasingly utilized, with comparable outcomes to Ph+ non-MPAL ALL [ 49 ]. However, Ph + MPAL must be distinguished from CML with mixed blast crisis, as the latter is treated with AML-like therapy followed by allogeneic transplant.…”