Genomics finds potential treatment targets in new subtype of acute lymphocytic leukemia (ALL)

According to Kathryn Roberts, PhD, of St. Jude Children's Research Center in Memphis, patients with the new ALL subtype do not have the Philadelphia (PH) chromosome, but share some disease characteristics with patients who do. For that reason, the researchers have dubbed the new subtype PH-like ALL, Roberts told reporters at the annual meeting of the American Society of Hematology.

Importantly, some patients with PH-like ALL may be able to be treated with the same drugs aimed at the Philadelphia chromosome, the tyrosine kinase inhibitors imatinib (Gleevec) and dasatinib (Sprycel). Still others may benefit from treatment with inhibitors of the janus tyrosine 2 (or JAK2), which is involved in cytokine signaling, Roberts said.

Before the current study, Roberts said, the genetic underpinning of PH-like ALL was unknown. To fill the gap, she and colleagues turned to new techniques to look at the so-called transcriptome or the RNA of 12 patients with PH-like ALL.

"Strikingly, we identified novel alterations activating tyrosine or cytokine signaling in 11 of the 12 patients we studied," Roberts said, including rearrangements, structural changes, and sequence mutations. Some of them involved genes known to be involved in other leukemias, including ABL1, platelet derived growth factor receptor beta (PDGFRB), and JAK2.

In lab studies, cells containing changes in ABL1 and PDGFRB were shown to be susceptible to imatinib and dasatinib, while those with JAK2 rearrangements were susceptible to ruxolitinib (Jakafi), she said.

Having found the variations, Roberts said, the researchers looked at a cohort of 40 other patients with PH-like ALL and found similar changes, "suggesting that these lesions are a hallmark of PH-like ALL."

The findings suggest that treatment with the drugs, in addition to standard chemotherapy, may improve outcomes for at least some of the patients with the PH-like disease.

Source: Roberts KG, et al "Novel chromosomal rearrangements and sequence mutations in high-risk PH-like acute lymphoblastic leukemia" ASH 2011; Abstract 67.

Bone Marrow Best for Unrelated Donor SCT

According to Moffitt Center researchers, relapse rates and survival after stem cell transplants from unrelated donors in patients with a variety of leukemias and lymphomas were no better with cells sourced from peripheral blood rather than bone marrow, a researcher said here. Moreover, the burden of graft-versus-host disease (GVHD) was greater with the peripheral blood stem cell transplants in the three-year, randomized, 551-patient study.

Claudio Anasetti, MD, of Moffitt Cancer Center in Tampa, FL, said the study results would warrant a change in practice for at least some patients with hematologic malignancies. However, he emphasized that the trial protocol involved complete myeloablative conditioning prior to transplant and results would not necessarily apply to stem cell transplants involving less intensive conditioning.

Recently, peripheral blood has gained favor in the wake of studies indicating that relapse rates and survival have been somewhat better than with bone marrow transplants. Some 75% of unrelated-donor stem cell transplants are now performed with peripheral blood, Anasetti said. But many centers have reported higher rates of acute and chronic GVHD with peripheral blood stem cell transplants, he said, suggesting that a prospective, randomized trial was needed.

The peripheral blood stem cells did perform better than bone marrow in one respect: Engraftment was significantly faster by five to seven days and graft failures were significantly less common in patients receiving the peripheral blood cells (2.7% versus 9.1%). And early in the follow-up period, survival appeared slightly better in these patients than in those receiving the marrow transplants.

But at two years, the 51% overall survival rate with peripheral blood transplant was not significantly better than the 46% rate seen in the bone marrow transplant group (P=0.214). And at three years, the rates were nearly identical at about 43%.

Relapse rates also did not differ significantly after the one-year mark, with about 27% of patients relapsing by the end of year three regardless of the form of transplant.

Extensive chronic GVHD, meanwhile, was significantly more common in the peripheral blood stem cell transplant group, affecting 48% of recipients. In comparison, 32% of the bone marrow transplant group developed extensive chronic GVHD (P<0.001).

Source: Anasetti C, et al "Increased incidence of chronic graft-versus-host disease (GVHD) and no survival advantage with filgrastim-mobilized peripheral blood stem cells (PBSC) compared to bone marrow (bm) transplants from unrelated donors: results of Blood and Marrow Transplant Clinical Trials Network (BMT CTN) Protocol 0201, a phase III, prospective, randomized trial" ASH 2011; Abstract 1.