Complete Molecular Response at Three Months: An Independent Predictor of Survival in Ph+ Acute Lymphocytic Leukemia

While monitoring minimal residual disease (MRD) is a valuable prognostic tool in certain hematologic malignancies, the prognostic significance of MRD and molecular response in patients with Philadelphia chromosome-positive (Ph+) acute lymphocytic leukemia (ALL) has not been established. In a study published in Blood, Nicholas J. Short, MD, of the Division of Cancer Medicine at The University Texas MD Anderson Cancer Center in Houston, Texas, and authors found that adult patients with Ph+ ALL who achieved a complete molecular response (CMR) at three months after treatment with first-line chemotherapy plus a tyrosine kinase inhibitor (TKI) have higher rates of survival, compared with patients who achieve lesser molecular responses.

“Those who are in complete molecular remission at three months are at significantly reduced risk of relapse and have a good chance of long-term success without a stem cell transplant,” the study’s corresponding author, Farhad Ravandi, MD, from the Department of Leukemia at the University of Texas MD Anderson Cancer Center, told ASH Clinical News. “Potential complications of transplant can be averted without reducing the likelihood of long-term, disease-free remission.”

The study included 202 adult patients with previously untreated Ph+ ALL who were enrolled at The University of Texas MD Anderson Cancer Center between April 2001 and December 2015. Patients received induction and post-remission therapy chemotherapy (hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone alternating with methotrexate and high-dose cytarabine) plus a TKI that was continued indefinitely as maintenance therapy.

A total of 196 patients (97%) achieved complete remission (CR); 122 of these patients had MRD assessment for BCR-ABL1 by quantitative polymerase chain reaction at both CR and at three months. Patients who underwent hematopoietic cell transplantation (HCT) during first CR (n=37) were excluded, leaving 85 patients available for analysis. Dasatinib was the most commonly used TKI (n=39; 46%), followed by imatinib (n=23; 27%) and ponatinib (n=23; 27%).

Almost all patients (98%) achieved CR after one treatment cycle, with the remaining two patients requiring two treatment cycles. The median follow-up was 44 months (range = 5-171 months).

At the time of CR:

  • 29 patients (34%) reached a CMR (defined as the absence of a detectable BCR-ABL1 transcript with a sensitivity of 0.01%)
  • 10 patients (12%) reached a major molecular response (MMR; defined as a BCR-ABL1:ABL1 ratio ≤0.1% on the International Scale for p210 BCR-ABL1 or a 3-log reduction in transcripts for p190 BCR-ABL1 but not meeting criteria for CMR)
  • 46 patients (54%) achieved a response less than MMR

At three months:

  • 51 patients (60%) reached CMR
  • 16 patients (19%) reached MMR
  • 18 patients (21%) achieved a response less than MMR

CMR rates at both CR and at three months varied based on the TKI used, but were highest with ponatinib. CMR at CR was 22 percent for those receiving imatinib, 31 percent for dasatinib, and 52 percent for ponatinib (p=0.25); CMR at three months was 39 percent for imatinib, 54 percent for dasatinib, and 87 percent for ponatinib (p=0.001). “In our cohort, the CMR rate at three months in patients who received ponatinib was more than two-fold that of patients who received imatinib,” the authors wrote.

However, among patients who achieved CMR at three months, the specific TKI used did not significantly affect overall survival (OS) or relapse-free survival (RFS; p=0.22 and p=0.40, respectively). Molecular response at CR also did not affect OS or RFS in this group of patients (p=0.76 and p=0.85, respectively).

Notably, Dr. Short and colleagues reported that MRD status at three months was a better predictor of OS (p=0.001) and RFS (p=0.002) than MRD status at CR (p=0.11 and p=0.04, respectively).

At CR, rates of OS and RFS did not differ between those who achieved CMR (p=0.26) and those with a lesser molecular response (p=0.15). At three months, though, patients who achieved CMR had a significantly longer median OS (127 vs. 38 months; hazard ratio [HR] = 0.42; 95% CI 0.21-0.82; p=0.01) and RFS (126 vs. 18 months; HR=0.43; 95% CI 0.21-0.78; p=0.01) than those with a lesser molecular response.

Rates of four-year OS and RFS for patients with CMR at three months were 66 percent and 63 percent, respectively. “The survival rates achieved seemed to be better with each successive generation of TKI,” the authors wrote.

After a median time to relapse of 16 months (range = 10-59 months), 12 of the 51 patients who achieved CMR at three months (24%) relapsed. However, 10 of these patients achieved remission after salvage therapy, and five underwent HCT during the second CR. Two patients died after four years, both of whom had achieved CMR. One death was related to post-HCT infectious complications and another resulted from an infection while in CR.

Of the seven patients who did not achieve CMR at three months who were alive without relapse at four years, all eventually achieved CMR, after a median of 14 months (range = 8-87 months).

“These findings suggest that patients with Ph+ ALL treated with first-line chemotherapy plus a TKI who achieve CMR by three months have excellent long-term survival, which is independent of any baseline factors or the TKI received,” the authors concluded. “Among this cohort of patients who did not receive HCT in first CR, the four-year OS rate for patients achieving CMR by three months was 66 percent and median OS was more than 10 years.”

The study is limited by its small patient population and retrospective design, variations in treatment approaches, as well as its use of three different TKIs, which led to variable results.


Reference

Short NJ, Jabbour E, Saski K, et al. Impact of complete molecular response on survival in patients with Philadelphia chromosome-positive acute lymphoblastic leukemia. Blood. 2016;128:504-7.

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