Evaluating Risk of Developing Second Cancers in Patients With Ph-Negative Myeloproliferative Neoplasms

According to results from a nested case-control study, patients with Philadelphia chromosome (Ph)–negative myeloproliferative neoplasms (MPNs) are at an increased risk of developing secondary malignancies – owing in part to the diseases’ intrinsic properties and to certain MPN-directed treatments. The study was published in Leukemia by Tiziano Barbui, MD, from the Research Foundation at Ospedali Riuniti di Bergamo in Italy, and colleagues.

Dr. Barbui and researchers designed the study to describe the types and frequency of secondary cancers (including hematologic and solid tumor malignancies) and to determine whether treatment with cytoreductive agents was a risk factor for developing secondary cancers.

A total of 1,881 patients with Ph-negative MPNs (polycythemia vera [PV], essential thrombocythemia [ET], or primary and secondary myelofibrosis [MF]) were identified from the European Leukemia Net database. Patients were matched for sex, age at MPN diagnosis, date of MPN diagnosis, and MPN disease duration, then categorized as either “cases” (development of a secondary cancer) or “controls” (no secondary cancer).

The authors identified 1,234 controls and 647 cases. Characteristics were similar between cases and controls, the authors noted, with comparable demographics and types of MPNs. However, the proportion of patients who developed major arterial thrombosis and monoclonal gammopathy of undetermined significance was higher in the case group (TABLE).

Secondary cancer diagnoses included:

  • carcinoma: 426 (65.8%)
  • nonmelanoma skin cancer: 127 (19.6%)
  • hematologic cancer: 62 (9.6%)
  • melanoma: 32 (4.9%)

Of patients who developed carcinoma, the most common types were prostate, breast, colorectal, and lung cancers. There was a trend for a higher frequency of carcinoma in patients with ET and PV than MF, but it did not reach statistical significance (p=0.079).

“In a quarter of cases, diagnosis of MPN was synchronous with hematological cancer, revealing an intrinsic predisposition even in untreated MPN patients,” the authors added. “Therefore, although the association of MPN and secondary cancers in the same patient is a relatively uncommon event, a careful surveillance of possible co-existence of hematological malignancy in MF from the beginning of diagnosis may be indicated.”

Looking at treatment of MPNs, the researchers found that hydroxyurea was the most frequently prescribed agent, with a similar proportion of case and control patients exposed to the drug (70.5% and 69.7%; p=0.793).

Patients who eventually developed a secondary cancer had higher rates of exposure to ruxolitinib as a single agent during any line of therapy (4.2% vs. 2.5%; p=0.048). Cases also more frequently were treated with multiple cytoreductive drugs in combination or sequentially (19.6% vs. 19.1%; p=0.038), although this finding was not confirmed in multivariable analysis.

Single-agent hydroxyurea treatment did not appear to increase the risk of any secondary cancer, compared with patients who did not receive hydroxyurea (odds ratio [ORs] = 1.06; 95% CI 0.82-1.38; p value not reported). In cancer-specific analysis, though, hydroxyurea exposure was associated with a twofold higher risk of nonmelanoma skin cancer (OR=2.28, 95% CI 1.15-4.51).

In a sensitivity analysis to confirm the interactions between treatments and secondary cancer risks, the investigators found that the following drugs increased risk:

  • pipobroman (OR=2.10; 95% CI 1.09-4.06), regardless of line of treatment
  • ruxolitinib (OR=5.24; 95% CI 1.47-18.71) as firstline monotherapy
  • exposure to multiple cytoreductive agents in different lines of treatment (OR=1.46; 95% CI 1.02-2.09)

“As hydroxyurea continues to have a prominent role in the treatment of PV, ET, and MF, clinicians must be aware that the exposure to this drug in our study was limited to a median period of three years (range = 1.2-6.1) and, with this exposure duration, hydroxyurea did not increase the risk of melanoma, carcinoma, and hematologic second cancer,” the authors noted.

In addition, they stressed that “the hypothesis that ruxolitinib exposure may be associated with increased risk of developing cancer must be taken with great caution given the limited number of patients, but it represents a signal to suggest appropriate strict pharmacovigilance programs.”

The implications of this study are limited by its retrospective design and the possibility of residual confounders, which might have influenced the occurrence of outcomes. “Moreover, a bias related to the limited follow-up and, consequently, to the limited exposure time to drugs, as well as a selection bias of cases and controls cannot be excluded,” the authors wrote.

The authors report relationships with Novartis.

Reference

Barbui T, Ghirardi A, Masciulli A, et al. Second cancer in Philadelphia negative myeloproliferative neoplasms (MPN-K). A nested case-control study. Leukemia. 2019 May 29. [Epub ahead of print]

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