Promising treatments for blood cancers

Research highlights from the John Theurer Cancer Center included a global clinical trial of a new type of medication (HDAC inhibitor) against relapsed multiple myeloma led at the John Theurer Cancer Center; an examination of treatment outcomes for more than 900 lymphoma patients who received stem cell transplants at the John Theurer Cancer Center; an analysis of Phase III data for a new cancer drug as it applies to older chronic myeloid leukemia patients; results from a Phase III, 50-center study of stem cell versus bone marrow transplantation for high-risk leukemia patients; a laboratory analysis of a gene-encoded protein that may have a protective role in difficult-to-treat mantle cell lymphoma; and a comparison study of the best transplant options for myeloma patients who relapse after autologous stem cell transplantation.

Highlights of the John Theurer Cancer Center presentations include:

Results of a Phase III Prospective, Randomized Trial of Filgrastim-Mobilized Peripheral Blood Stem Cells Compared to Bone Marrow Transplants from Unrelated Donors

As part of a 50-center study by the Blood and Marrow Transplant Clinical Trials Network, Scott D. Rowley, M.D., Chief, Blood and Marrow Stem Cell Transplantation, led the John Theurer Cancer Center arm of a Phase III randomized, multi-center trial of unrelated donor peripheral blood stem cell vs. bone marrow transplantation for patients with high-risk leukemia.

The purpose of the NIH-funded study was to examine both two-year survival and the incidence of graft-versus-host disease (GVHD). GVHD is a condition in which the transplanted cells attack the patient's body after a transplant.

Previous randomized trials showed that high-risk leukemia patients receiving peripheral stem cell transplants activated by filgrastim, an infection-fighting drug that helps in gathering stem cells, had better engraftment (acceptance of the cells by their body's bone marrow) than patients who received bone marrow transplants from siblings with identical human leukocyte antigens (HLA, a type of blood protein). The stem cell patients had increased risks of acute and chronic GVHD, but decreased incidence of relapse as well as improved survival. Retrospective studies, however, did not show the same protective effect from stem cells.

In the current study, 551 patients were randomized to receive either an unrelated donor peripheral blood stem cell transplant or bone marrow transplant. At two years post-treatment, there were no significant differences in patient survival between the study arms. Patients who received stem cells, however, had a higher incidence of chronic GVHD.

Final Result of a Global Phase IIB Trial of Vorinostat with Bortezomib in Patients with Relapsed Multiple Myeloma

David S. Siegel, M.D., Ph.D., Chief of Multiple Myeloma at the John Theurer Cancer Center, led a global Phase IIB clinical trial of vorinostat (Zolinza), a medication that is already approved to treat cutaneous T-cell lymphoma, against multiple myeloma. Dr. Siegel previously led other studies of vorinostat, which is a histone deacetylase (HDAC) inhibitor, the first in a class of drugs that regulate enzymes involved in cell signaling.

In the current study, Dr. Siegel and colleagues conducted an open label, single-arm (all patients received the same study medications) Phase IIB trial of vorinostat plus bortezomib for multiple myeloma patients unresponsive to bortezomib or unresponsive, intolerant, or ineligible for immunomodulatory therapies. All study participants had received two or more prior anti-myeloma treatments, and relapsed or progressed following earlier systemic therapy. One hundred forty-three patients, who had myeloma for a median of 4.6 years, were enrolled from 41 centers in 12 countries.

All patients in the study received 21-day cycles of bortezomib administered intravenously on days 1,4,8 and 11 plus oral vorinostat (400 mg) on days one to 14. If a patient had no change after four treatment cycles, or progressive disease after two cycles, oral dexamethasone (20 mg) was added for subsequent cycles.

The researchers concluded that the combination of vorinostat and bortezomib is active in patients whose disease is considered refractory to prior bortezomib and immunomodulatory drugs and may offer a new treatment option for heavily pretreated, double-refractory myeloma patients.

Two Decades of Stem Cell Transplantation in Lymphoma: Outcomes of 938 Transplants Performed at John Theurer Cancer Center. (Abstract number 3086; poster session, December 11, 6:00 -- 8:00 p.m.) Anthony R. Mato, M.D., Hematologist/Oncologist, Lymphoma and a team of 12 fellow researchers from the John Theurer Cancer Center conducted a retrospective cohort analysis of the survival of 938 lymphoma patients who underwent either autologous (with one's own cells) or allogeneic (with another's cells) stem cell transplants at the Theurer Center between 1990 and 2011.

While John Theurer Cancer Center physicians have used both types of transplants combined with chemotherapy for relapsed lymphoma patients, there remains little long-term follow up data for either treatment to guide clinical decision-making.

The researchers' statistical analysis revealed that patients treated with autologous stem cell transplantation had a median overall survival of 149 months, while those treated with allogeneic transplants had a median overall survival of 39 months. The donor source of stem cells (matched sibling vs. matched unrelated donor) in allogeneic transplants did not seem to affect overall survival, nor did whether the cells were from peripheral blood or bone marrow. The researchers will continue to conduct ongoing studies of whether immune-based therapies after transplantation of autologous cells improve survival.

Safety and Efficacy of Nilotinib in Older Chronic Myeloid Leukemia (CML) Patients in the Chronic Phase Compared with Younger Chronic-Phase CML Patients

The multi-center, international Phase III study ("ENESTnd"study) comparing nilotinib (Tasigna®) with imatinib (Gleevec®) found that newly diagnosed CML patients receiving nilotinib had significantly higher levels of disease response and lower levels of disease progression. A team at the John Theurer Cancer Center, led by Stuart L. Goldberg, M.D., Chief, Leukemia, took part in the initial ENESTnd study as well as the current study.

In the new study, Dr. Goldberg and colleagues analyzed the ENESTnd data to evaluate the efficacy and safety of nilotinib (both 300 and 400 mg) for newly diagnosed CML patients, age 65+, who were in the chronic phase. Their response to treatment was compared with that of younger patients, and the drug's safety was also evaluated. The analysis covered 64 older patients who were followed a minimum of 24 months, in comparison to a much larger group of younger patients.

The study used a number of measures. One was major molecular response (MMR), which is based on a blood or bone marrow test that measures certain leukemia-related proteins, indicating a major treatment response. Complete cytogenic response (CCyR) was another measure used. The CCyR test measures levels of the Philadelphia chromosome, the abnormality that causes CML. Drug safety was also evaluated, as was progression to the "blast" phase of CML. CML has two phases: "chronic," in which it is relatively dormant, and "accelerated" or "blast," in which It is active.

Older patients' response to the medication was promising, and comparable to that of younger patients. CCyR rates at 24 months for the older patients were 83% and 68%, respectively, for those treated with 300 mg and 400 mg doses, and 87% for the younger patients at both dose levels. By 24 months, MMR was achieved for 72% (300 mg) and 61% (400 mg) of older patients; for younger patients, the respective rates were 71% and 67%. Five patients progressed to the blast phase, all of them under age 65. Despite increased risks and the presence of other health conditions in the older patients, adverse events were low.

The authors state that these data support the use of 300 mg nilotinib for newly diagnosed older patients with CML in the chronic phase.

Novel Binding Targets and Prognostic Role for SOX11 in Mantle Cell Lymphoma

This research involves a collaborative effort between Dr. Samir Parehk, M.D., associate professor from Montefiore Cancer Center of Albert Einstein Medical School, and K. Stephen Suh, Ph.D., Director of Genomics and Biomarkers Program and Dr. Andre Goy, Chief of Lymphoma and Medical Director of Tissue Bank of the John Theurer Cancer Center. The collaboration led to a better understanding of genetic factors related to treatment success for mantle cell lymphoma (MCL), a difficult-to-treat blood cancer.

SOX11 is a gene-encoded transcription factor (molecule involved in regulating gene expression, the synthesis of a functional gene product such as a protein), which binds to DNA and causes changes that facilitate the binding of other transcription factors, in turn enhancing the expression of target genes. Previous reports suggested that SOX11 activity was specific to MCL and significantly contributes to disease progression, but its function and direct binding targets are largely unknown. Recent data supports a relationship between SOX11 expression status and poor MCL survival.

As part of a multi-center research team, Drs. Suh and Goy helped to conduct molecular analyses at Dr. Samir Parehk's lab to identify the target genes that directly bind to SOX11. By using a high-resolution whole genome sequencing method known as "ChIP-Seq" (chromatin immunoprecipitation sequencing), the team performed a multi-level analysis and showed that human genome has more than 800 novel direct binding targets for SOX11. This large number of binding sites strongly indicates that SOX11 activity can significantly influence the aggressiveness of the disease and patient's clinical outcome.

When SOX11 protein expression was histologically analyzed by MCL tissue microarray and scored by pathologists, the overexpression of SOX11 proteins was directly correlated with a better survival rate (41 months for high SOX11 expression vs. 11 months for low SOX11 expression). However, this result was not repeated with a second set of tissue microarray with different set of MCL samples and the data showed no significant difference in survival. The authors conclude that a longer survival may be associated with high SOX11 expression in a subset of MCL patients.

Second Transplants in Relapsed Multiple Myeloma: Autologous Vs. Allogeneic Transplantation

While there is not a standard therapy for multiple myeloma, which has recurred after autologous hematopoetic stem cell transplantation (AHCT), a second AHCT has been shown to result in additional progression-free survival. Another type of stem cell transplant, the nonmyeloablative/reduced intensity conditioning (NST/RIC) allogeneic transplantation (alloHCT), which uses donated stem cells and does not involve the intensive radiation or chemotherapy preparation that is typically done before an allogeneic transplant, is becoming more commonly used after an initial AHCT. This type of second transplant has been shown to have the potential to lead to remission, however, few studies have compared second AHCT with NST/RSC alloHCT.

David H. Vesole, M.D., Ph.D., F.A.C.P., Co-Chief and Director of Research, Multiple Myeloma Division, John Theurer Cancer Center and colleagues from other cancer centers analyzed data from the Center for International Blood and Marrow Transplant Research in order to compare outcomes for the two procedures for patients with multiple myeloma who relapsed after an initial AHCT. Data from 137 autologous transplant and 152 allogeneic transplant patients was examined.

The researchers' statistical analysis revealed a higher risk of death and lower survival rates for alloHCT patients. These patients were also at a higher risk for treatment-related mortality. The authors conclude the data demonstrates that the value of alloHCT for multiple myeloma patients after prior relapse from AHCT is limited.