More Intrathecal Chemotherapy Significantly Reduces CNS Relapse Risk in Ph+ ALL

Intrathecal chemotherapy is “essential” to prevent central nervous system (CNS) relapse in patients with Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL), but the effectiveness of the prophylaxis depends upon how many times it is administered, according to recent research.

Shilpa Paul, PharmD, BCOP, of the MD Anderson Cancer Center, and colleagues published their findings in correspondence to the American Journal of Hematology.

They conducted the research because treatment protocols with hyper-fractionated cyclophosphamide, dexamethasone, vincristine, and doxorubicin alternating with high-dose methotrexate and cytarabine (hyper-CVAD) plus a BCR-ABL1 tyrosine kinase inhibitor for adults with Ph+ ALL were amended in 2012 to increase the number of prophylactic intrathecal chemotherapy doses from eight to 12.

Dr. Paul and colleagues compared the rate of CNS relapse in 150 consecutive adult patients with Ph+ ALL who received intrathecal chemotherapy eight or 12 times with hyper-CVAD plus or minus rituximab with imatinib, dasatinib, or ponatinib between July 2001 and January 2019.

They excluded patients who had CNS disease at diagnosis. Intrathecal chemotherapy “consisted mainly” of methotrexate 12 mg alternating with cytarabine 100 mg given via lumbar puncture during each cycle for up to six cycles, according to Dr. Paul and colleagues.

Most patients (71%) received eight or fewer doses of intrathecal chemotherapy, while 29% received more than eight doses. Significantly higher proportions of patients who received more than eight doses underwent therapy with rituximab or ponatinib than patients who received eight or fewer doses. Other than those differences, patient characteristics were “similar between groups,” according to Dr. Paul and colleagues.

Both groups had a 100% complete remission rate in response to frontline therapy, but patients who received more than eight doses of intrathecal chemotherapy had a higher three-month complete molecular remission rate (70%) than patients who received eight or fewer doses (53%; P=0.08).

Intrathecal Chemotherapy Improves CNS Remission in Ph+ ALL

The median follow-up time was 125.8 months for patients who received more than eight doses of intrathecal chemotherapy and was 76.9 months for patients who received eight or fewer doses.

CNS relapse occurred in 11 patients, all of whom received eight or fewer doses, with a CNS relapse incidence of 10% in the group who received eight or fewer doses and 0% in patients who received more than eight doses (P=.023).

The three-year CNS relapse-free survival rate was 92% in the group receiving eight or fewer doses and was 100% in the group receiving more than eight doses (P=.06). The six-year relapse-free survival rate was 91% in the group receiving eight or fewer doses, while it was 100% in those receiving more than eight doses (P=.04).

CNS relapses occurred after a median of 17 months. The researchers detected BCR-ABL1 transcript in the peripheral blood or bone marrow of all patients who experienced a CNS relapse. In four of the 11 (36%) patients, CNS relapse co-occurred with systemic relapse, with one patient experiencing systemic relapse after an isolated CNS relapse. Of the 11 patients who relapsed, 45% underwent allogeneic hematopoietic stem cell transplantation (HSCT) during their treatment course, with allogeneic HSCT preceding CNS relapse in one case.

“Treatment of CNS relapse varied from systemic chemotherapy to craniospinal irradiation, but all continued [tyrosine kinase inhibitors] with [intrathecal chemotherapy], consisting of cytarabine, alternating with methotrexate, with hydrocortisone, or combination given twice weekly until CNS clearance,” Dr. Paul and colleagues.

All patients achieved CNS clearance, with 36% experiencing subsequent CNS relapses. The median survival from time of first CNS relapse was 14.7 months (95% CI, 8.6-20.8). At the time of data cutoff, only one patient remained alive after CNS relapse, the researchers reported.

Of the 10 patients who died after CNS relapse, five died due to infectious complications, one died from intracranial hemorrhage, two died from cardiac arrest, and two died from progressive leukemia.

“In conclusion, [intrathecal chemotherapy] is essential in preventing CNS disease in Ph+ ALL, and effectiveness depends on the total number of [times that intrathecal chemotherapy is] administered,” Dr. Paul and colleagues wrote. “Our study shows that 12 [intrathecal chemotherapy doses] should be administered with [hyper]-CVAD plus a BCR-ABL1 [tyrosine kinase inhibitor] to reduce the risk of CNS relapse.”

Reference

Paul S, Kantarjian H, Sasaki K, et al. Intrathecal prophylaxis with 12 versus 8 administrations reduces the incidence of central nervous system relapse in patients with newly diagnosed Philadelphia chromosome positive acute lymphoblastic leukemia. Am J Hematol. 2023;98(1):E11-E14. doi:10.1002/ajh.26622