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A 36-year-old man presents to the emergency department complaining of severe low back pain. He reports a six-week history of progressive fatigue and worsening night sweats, and he notes gingival bleeding when he brushes his teeth. Physical examination is notable for borderline tachycardia and scattered ecchymoses on the extremities. His laboratory results reveal the following:

White blood cell differential is notable for 82 percent blasts. Bone marrow aspiration and biopsy is performed, revealing a hypercellular marrow involved with B cell precursor (BCP) acute lymphocytic leukemia (ALL), with malignant lymphocytes comprising 65 percent of total cellularity. Cytogenetics reveal a single abnormality — the t(11;19)(q23;p13.3)/MLL-ENL fusion — associated with a poorer prognosis in BCP-ALL. The patient has no other significant medical history and is in excellent physical health. Prior to his presentation, he was very active, engaging in high-intensity exercise four times weekly. He is admitted to the hospital to initiate induction chemotherapy for ALL.

Based on new and emerging studies, which of the following approaches to ALL therapy is most likely to result in the highest likelihood of long-term cure in this patient?

1. A regimen incorporating intensive use of myelosuppressive agents including daunorubicin, cytarabine, and cyclophosphamide, with allogeneic stem cell transplantation in first remission.
2. A regimen incorporating intensive use of myelosuppressive agents including daunorubicin, cytarabine, and cyclophosphamide, with addition of the tyrosine kinase inhibitor imatinib.
3. A regimen incorporating a backbone of glucocorticoids, vincristine, asparaginase, early and frequent CNS prophylaxis, and prolonged maintenance therapy.
4. A regimen utilizing glucocorticoids and the tyrosine kinase inhibitor dasatinib as the primary anti-leukemic agents.

Answer

3. A regimen incorporating a backbone of glucocorticoids, vincristine, asparaginase, early and frequent CNS prophylaxis, and prolonged maintenance therapy.

This approach to ALL therapy describes the so-called Berlin-Frankfurt-Munster (BFM) backbone of pediatric ALL therapy. In the modern era, long-term survival for children with ALL now exceeds 80 percent. Unfortunately, adults, including older adolescents and young adults (AYAs), have historically had inferior outcomes, with long-term survival in the 30 to 40 percent range. The National Cancer Institute has defined the AYA population as those patients with cancer between age 15 and 39 years. Most AYAs had previously been treated similarly to other adults with ALL, receiving regimens incorporating intensive use of myelosuppressive agents including daunorubicin, cytarabine, and cyclophosphamide, with allogeneic stem cell transplantation in first remission (answer choice A); use of these approaches has yielded the historic survival numbers in the sub-50 percent range. Recognition of this has led to a number of trials in the past decade examining the use of “pediatric-inspired” regimens in the treatment of AYA patients with ALL, given the dramatic differences in long-term outcome between children and adults with ALL. A central hypothesis in these trials was the concept that the difference in outcome between adults and children with ALL may not be fully explained by biological differences in the disease between the two groups, and rather may be significantly impacted by the differences in therapy. Pediatric regimens are more intensive and therefore associated with higher levels of toxicity and reduced tolerability. Despite this, multiple prospective, randomized studies have now shown that pediatric-inspired regimens utilized in AYA patients have resulted in event-free survival rates approaching 70 percent.

Answer choices B and D describe ALL treatment protocols for patients with Philadelphia chromosome positive (Ph+) ALL. The patient described in the vignette has Philadelphia chromosome negative (Ph–) ALL, as shown by the cytogenetics performed on the bone marrow sample. While there are cytogenetic abnormalities other than the BCR-ABL1 fusion in which ABL kinase inhibitors are used in treatment of ALL, such as the NUP214-ABL1 fusion, ABL kinase inhibitors would not be expected to have activity in treating BCP-ALL with an MLL rearrangement, as in the case given in the vignette.

Case study submitted by Hanny Al-Samkari, MD, of Massachusetts General Hospital, Dana-Farber Cancer Institute, Harvard University, Boston, MA.

References 

1. Curran E, Stock W. . Blood. 2015; 125:3702-3710
2. DeAngelo DJ, Stevenson KE, Dahlberg SE, et al. . Leukemia. 2015; 29:526-534.
3. Duployez N, Grzych G, Ducourneau B, et al. . Haematologica. 2016; 101:e133-e134.