Genetic abnormalities in ALK-negative ALCLs may guide therapy

Anaplastic large cell lymphomas (ALCLs) are rare, CD30-positive T-cell lymphomas. Approximately half of them exhibit a chromosomal translocation of the anaplastic lymphoma kinase (ALK) gene, an important prognostic marker and target for therapy. Although clinically aggressive, ALK-positive tumors respond well to standard interventions, with five-year overall survival rates of about 90 percent.

ALK-positive tumors have been extensively studied, but far less is known about ALCLs lacking ALK rearrangements (ALK-negative ALCLs), in part because no genetic biomarkers exist to distinguish them from other CD30-positive peripheral T-cell lymphomas.

To better understand ALK-negative ALCLs, Andrew L. Feldman, M.D., and colleagues at Mayo Clinic's campus in Minnesota began studying the genetics of the disease. "Very little is known about the genetics of T-cell lymphomas," Dr. Feldman notes. "These are rare and extremely heterogeneous cancers. The World Health Organization lymphoma classification system contains 15 subtypes of T-cell lymphoma, all of which are different clinically, biologically and pathologically. It's very difficult for any one center to accumulate enough cases to study recurrent genetic abnormalities."

Nevertheless, using a Mayo cohort of samples, next-generation DNA sequencing and a unique bioinformatic algorithm, Dr. Feldman's group identified two novel recurrent chromosomal rearrangements seen almost exclusively in ALK-negative ALCL. One involved dual-specificity phosphatase 22 (DUSP22) on 6p25.3 and the other tumor protein p63 TP63 on 3q28. The findings appeared in the January 2011 and September 2012 issues of Blood.

The goal then became to determine whether this genetic information could be used to develop a test that would predict clinical outcomes. "We already know that patients with ALK-negative lymphomas have a poorer prognosis than those with ALK-positive cancers. Furthermore, treatment of ALK-negative ALCL is controversial," Dr. Feldman says.

The controversy turns in part on the role of autologous stem cell transplantation, an aggressive therapy for ALK-negative patients that may or may not benefit them and whose use varies among institutions. "At Mayo, the approach is to transplant early, but other institutions feel it's better to wait until a patient relapses or the disease progresses," Dr. Feldman explains. "The problem is potential morbidity because of the high doses of chemotherapy. If we had a prognostic indicator, we could reserve transplantation for patients likely to do poorly with standard chemotherapy alone."

Based on their earlier findings, Mayo investigators undertook a multi-institutional study of associations among pathology, genetics and clinical outcomes in 105 ALCL cases — 73 ALK-negative ALCLs and 32 ALK-positive ALCLs. For inclusion in the study, cases required a consensus diagnosis of ALCL by at least two of three outside experts blinded to the genetic data in a two-tier pathology review.

Genetics and outcomes of ALK-negative ALCLs

Of the 73 ALK-negative ALCLs, 22 (30 percent) had DUSP22 rearrangements and 6 (8 percent) had TP63 rearrangements. Not only were the two rearrangements mutually exclusive, they were also not observed in any ALK-positive ALCL. Forty-five cases that lacked both rearrangements as well as ALK expression were referred to as triple-negative ALCLs.

Not surprisingly, the degree of consensus among the expert panel varied by genetic subtype. All ALK-positive ALCLs were diagnosed unanimously. Consensus was unanimous in 96 percent of DUSP22-rearranged cases, 83 percent of TP63-rearranged cases and 78 percent of triple-negative cases.

Far more striking was that patients with DUSP22-rearranged ALCLs had significantly better outcomes; their five-year overall survival rates were 90 percent — nearly identical to patients with ALK-positive ALCLs.

Conversely, patients with TP63-rearranged ALCLs had dismal outcomes, with five-year overall survival rates of just 17 percent. Those with triple-negative ALCLs fell in the middle, with overall survival rates of 42 percent, similar to those reported for ALK-negative ALCLs as a whole.

The findings, which were pre-published online in Blood First Edition, are significant because patients with ALK-positive tumors respond well to standard chemotherapy (typically cyclophosphamide, doxorubicin, vincristine and prednisone) and generally do not undergo stem cell transplantation.

"Now we've identified another group — patients with DUSP22-rearranged ALCLs — who might do just as well with standard chemotherapy only," Dr. Feldman says. "On the other hand, most patients with TP63-rearranged ALCLs did not live long enough to undergo transplantation. Of course, there were only six patients to draw conclusions from — but from a prognostic standpoint, they did very badly."

That leaves the group in the middle, the triple-negative ALCL patients, as the group who might be most likely to benefit from early stem cell transplant. It is not yet known, however, whether triple-negative ALCL is a homogenous or heterogeneous group.

Dr. Feldman notes: "I hesitate to say that ALK-negative patients should be treated differently, because treating clinicians would want further clinical data. And that is where future work needs to be done. But the data are very strong and suggestive, so at this point, we would recommend that all ALK-negative ALCLs undergo testing for rearrangements involving DUSP22 or TP63. That is important prognostic information to provide to patients and clinicians, especially when there is institutional controversy over treatment. In our own practice at Mayo, that will be a routine part of the classification algorithm."

In addition to prognostic and diagnostic uses, these genetic abnormalities could be potential targets for drug therapy. "When recurrent chromosomal abnormalities are seen in multiple patients, there is the suggestion that this is not random, that the abnormalities may have some role in tumor formation. Identification of the BCR-ABL fusion in CML patients, which led to the development of imatinib, is a notable example. Ultimately, individualized medicine tells us that at the end of the day every patient is different, and a more in-depth understanding of the genetic makeup of tumors will help us identify new therapies," Dr. Feldman says.

For more information

Feldman AL, et al. Discovery of recurrent t(6;7) (p25.3;q32.3) translocations in ALK-negative anaplastic large cell lymphomas by massively parallel genomic sequencing. Blood. 2011;117:915.

Vasmatzis G, et al. Genome-wide analysis reveals recurrent structural abnormalities of TP63 and other p53-related genes in peripheral T-cell lymphomas. Blood. 2012;120:2280.

Castellar ERP, et al. ALK-negative anaplastic large cell lymphoma is a genetically heterogeneous disease with widely disparate clinical outcomes. Blood First Edition. In press.