ASH Highlights Included New Data in Myeloma, Lymphoma, and Leukemia, plus Studies of Mucositis and Graft-vs-Host Disease


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The 54th Annual Meeting of the American Society of Hematology (ASH) featured about 5,000 abstracts, including oral sessions and posters, as well as named lectures and symposia. In addition to our regular news coverage from the meeting, below are capsule summaries of a few news highlights that we hope you will find of interest.

Pomalidomide/Carfilzomib Promising in Relapsed/Refractory Myeloma

In a phase I/II trial in heavily pretreated multiple myeloma patients, the combination of pomalidomide, carfilzomib (Kyprolis), and dexamethasone led to high response rates and delays in progression. All 32 patients had a median of six prior lines of therapy (range, 1–15) and were relapsed/refractory to lenalidomide (Revlimid); 30 of 32 were also bortezomib (Velcade)-refractory.1 Of 30 evaluable patients, 15 (50%) responded, with 37% achieving a partial response, 13% achieving at least a very good partial response, and 67% attaining clinical benefit (minor response or better), reported Jatin Shah, MD, of The University of Texas MD Anderson Cancer Center, Houston.

Median progression-free survival was 7.4 months, and overall survival at 1 year was 90%. “The combination has encouraging preserved response rates and survival independent of FISH/cytogenetic risk status,” he commented.

The most common toxicities were neutropenia (84%), anemia (63%), and thrombocytopenia (57%). Febrile neutropenia occurred in 6%. The hematologic toxicities were “all reversible and manageable,” Dr. Shah said.

The maximum tolerated doses in the regimen were determined to be carfilzomib at 20/27 mg/m2 (initiated at 20 mg/m2 and escalated to 27 mg/m2), pomalidomide at 4 mg, and dexamethasone at 40 mg in relapsed/refractory myeloma. Enrollment is ongoing in a phase II study of 82 patients.

A second retrospective study evaluated the impact on overall survival of the two drugs as separate treatments in 65 dual-refractory patients, showing approximately a 50% reduction in mortality risk, vs nonreceipt of these novel agents (P = .047).2 Other predictors of poor survival, present prior to receipt of the new drugs, were low hemoglobin, prior treatment with bortezomib/lenalidomide/dexamethasone, and advanced lytic lesions, investigators from Washington University in St. Louis reported.

Daratumumab Moving Forward in Myeloma

Data continue to accumulate for the monoclonal antibody daratumumab in multiple myeloma. In a phase I/II study in 32 patients, clinical benefit was achieved in almost half the heavily pretreated relapsed/refractory population.Torben Plesner, MD, of Vejle Hospital in Vejle, Denmark, reported that 47% of patients demonstrated a reduction in the amount of monoclonal (M) protein in the blood or urine, which corresponded to a 13% partial response rate, 19% minor response rate, and 16% stable disease rate. A reduction in plasma cell infiltration of the bone marrow was also observed. The maximum tolerated dose of the drug has not been established.

“The infusion was surprisingly well tolerated,” Dr. Plesner noted. The investigators found a dose-dependent reduction in natural killer cells that was reversible after treatment discontinuation.

Brentuximab Vedotin Prolongs Survival in Hodgkin Lymphoma

Several studies at the ASH meeting validated the use of brentuximab vedotin (Adcetris) in Hodgkin lymphoma and suggested that indications for the drug may be expanded. Treatment with brentuximab after autologous stem cell transplant prolonged overall survival compared to standard therapy, in relapsed/refractory Hodgkin lymphoma patients in a study from The University of Texas MD Anderson Cancer Center. The investigators took a retrospective look at 102 patients who received brentuximab and compared them to 756 treated with standard therapy (matched by age). They also performed a multivariate analysis on a smaller cohort of patients with known disease characteristics and treatment history.4

They found a highly significant overall survival benefit in patients receiving brentuximab (median, 91 months) over standard therapy (median, 28 months; P < .0001). Neither age nor sex impacted overall survival, reported Meghan S. Karuturi, MD.

“There was an improvement in overall survival irrespective of the time to relapse from transplant,” she said.

Among complete responders to brentuximab, negativity by positron-emission tomography (PET) after seven cycles was correlated with longer progression-free survival (P < .013). PET status (negative vs positive) after both four and seven cycles among all patients who received brentuximab in the phase II clinical trial was significantly associated with improved progression-free and overall survival, she reported.

Several phase I studies also found encouraging activity for first-line brentuximab. In a study from The University of Texas MD Anderson Cancer Center, brentuximab combined with CHP (cyclophosphamide, doxorubicin, and prednisone) produced complete remissions in 23 of 26 patients with systemic anaplastic large-cell lymphoma (19 patients) or a CD30-positive mature T-cell or natural killer cell lymphoma (7 patients). The other three patients achieved partial remissions.5 All 7 of the mature T-cell or natural killer cell lymphoma patients had a complete remission, reported Michelle A. Fanale, MD. A phase III trial is planned for next year.

Predicting Risk for Oral Mucositis

Bayesian networks based on single-nucleotide polymorphisms (SNPs), developed from saliva-sourced DNA, predicted the occurrence of oral mucositis with 81% accuracy in a study presented by Stephen Sonis, DMSc, of Harvard School of Dental Medicine, Boston.6 The assay is being developed by Inform Genomics, Inc, in Boston.

Dr. Sonis and fellow investigators noted single-nucleotide polymorphism–based Bayesian networks for risk assessment offer significant advantages over classic candidate gene and genome-wide association studies. They are also finding single-nucleotide polymorphism networks associated with other treatment-related toxicities. Advances in bioinformatics and computational power have enabled the development of learned networks using a Bayesian methodology, which is a means of estimating probabilities.

The oral mucositis study presented at the ASH meeting included 153 patients in the discovery set (82 myeloma patients and 71 with Hodgkin disease or non-Hodgkin lymphoma) undergoing stomatotoxic conditioning regimens prior to autologous hematopoietic stem cell transplantation. The genetic analysis revealed 82 single-nucleotide polymorphisms within the network, and these identified patients who developed mucositis with an accuracy of 99.3%, Dr. Sonis reported.

To assist in sample size calculations for future studies, the predictive validity of the single-nucleotide polymorphism network was tested in an exploratory set of 16 demographically similar patients. The network predicted mucositis in the cohort with an accuracy of 81%. Of 8 patients without mucositis, all were accurately identified and there were no false-positives. Of 8 patients who did not develop mucositis, 5 were accurately identified and there were 3 false-negatives.

Dr. Sonis suggested that future stratification by conditioning regimen is likely to further improve the predictive accuracy of the analytical method. The clinical application of such a network could identify patients who would benefit from prophylaxis with agents such as palifermin (Kepivance), he said.

This approach to personalized medicine could become available for routine patient care if results from these studies can be validated in a multicenter study.

Blinatumomab in Relapsed/Refractory ALL

A phase II single-arm study showed that the anti-CD19 bispecific T-cell engager (BiTE) antibody blinotumomab induced high complete remission rate and prolonged overall survival in adults with relapsed/refractory B-cell acute lymphoblastic leukemia (ALL). 7

Blinatumomab is an orphan drug that engages T cells and tumor cells, placing the T cells within reach to inject toxins into the tumor cell, triggering apoptosis. Blinatumomab directs the T cells to target cells that express CD19, a protein on the surface of most B-cell derived leukemias and lymphomas.

The study established a dose regimen of 5 μg/m2/d for week 1, followed by 15 μg/m2/d in weeks 2, 3, and 4, and subsequent cycles. The most common adverse events were pyrexia, fatigue, headache, tremor, and leukopenia. Medically important but fully reversible adverse events included cytokine release syndrome and central nervous system events.

At the ASH meeting, Max S. Topp, MD, Wuerzburg University Medical Center, in Wuerzburg, Germany, reported “unprecedented” single-agent activity of blinatumomab with among 36 patients enrolled in the phase II trial. The complete remission rate was 69%. Molecular remission was achieved in 88% of hematologic responders. Median overall survival was 9.8 months, and median relapse-free survival was 7.6 months.

A global phase II trial has been launched in adults with relapsed/refractory B-cell ALL.

Vorinostat plus Standard Therapy Reduces Graft-vs-Host Disease

Targeting histone deacetylases with the oral anticancer drug vorinostat (Zolinza) appears to prevent graft-vs-host disease in patients undergoing hematopoietic stem cell transplantation, according to results of a first-in-human phase I/II trial presented by Sung W. Choi, MD, University of Michigan Bone Marrow Transplant and Hematologic Malignancies Program, Ann Arbor.8

The single-arm study enrolled 47 adult patients slated for matched related donor-reduced intensity conditioning hematopoietic stem cell transplantation from the University of Michigan and Washington University in St. Louis. Patients were treated with oral vorinostat from day 10 through day 100 on top of a standard regimen after stem cell transplantation and were compared with 25 historical controls for the cumulative incidence of graft-vs-host disease.

Graft-vs-host disease occurred in 21% of patients in the experimental arm vs 48% of historical controls. Compared with control data, the experimental arm had a lower rate of grade 3/4 graft-vs-host disease (4% vs 20%) and a lower incidence of transplant-related mortality at 1 year (13% vs 19%). No differences between groups were reported in infectious complications or risk of relapse, suggesting that vorinostat helped reduce the incidence of graft-vs-host disease without further compromising patients’ immune systems, Dr. Choi said.

The next step is to determine whether vorinostat improves outcomes in patients undergoing unrelated donor myeloablative hematopoietic stem cell transplant and to assess its effect in patients at high risk for grade 2-4 acute graft-vs-host disease. A phase III clinical trial would be needed for confirmatory evidence.

Lenalidomide in Relapsed/Refractory Mantle Cell Lymphoma

A large phase II trial called MCL-001 EMERGE found that single-agent lenalidomide achieved rapid and durable efficacy in patients with mantle cell lymphoma (MCL) who either relapsed or were refractory to bortezomib.9

Lenalidomide shows durable efficacy in very heavily pretreated MCL patients regardless of number of prior therapies, including bortezomib, said lead author Andre Goy, MD, the John Theurer Cancer Center, Hackensack, New Jersey.

Mantle cell lymphoma comprises about 6% of all non-Hodgkin lymphomas and has only one FDA-approved treatment—bortezomib. The phase II trial included 134 MCL patients who had relapsed or experienced disease progression after bortezomib therapy, or were refractory to bortezomib; patients had a median of four previous therapies (range, 2–10).

Lenalidomide was given at 25 mg/d (21/28-day cycles), overall response rate was 28%, complete response rate 8%, and median duration was 16.6 months according to independent central review. According to investigator assessment, the overall response rate was 32%, complete response rate was 16%, and median duration of response was 18.5 months. As determined by central review, median progression-free survival was 4 months and median overall survival was 19 months. Response rates were consistent across subgroups, regardless of bulky disease or number of prior therapies.

Dose reduction was required in 38%, and 19% discontinued treatment, mainly due to myelosuppression, as seen in myeloma. The most common grade 3/4 adverse events were neutropenia (43%), thrombocytopenia (28%), anemia (11%), pneumonia (8%), and fatigue (7%). ■

Disclosure: Drs. Shah, Karuturi, Fanale, Sonis, Topp, Choi, and Goy reported no potential conflicts of interest. Dr. Plesner is a consultant for Genmab, on advisory boards for Janssen and Celgene, an investigator for Genmab, Janssen, Celgene, Bristol-Myers Squibb, Novartis, Roche, Nordic Myeloma Study Group, HOVON, German CLL Study Group, a teacher for Janssen, Celgene, Novartis, and Nonpharma/Mundipharma, and has received research grants from Janssen, Celgene, Roche, and Novartis.

References

1. Shah J, Orlowski R, Thomas S, et al: 2012 ASH Annual Meeting. Abstract 75. Presented December 9, 2012.

2. Wang T-F, Fiala M, Ahluwalia R, et al: 2012 ASH Annual Meeting. Abstract 4050. Presented December 10, 2012.

3. Plesner T, Lokhorst H, Gimsing P, et al: 2012 ASH Annual Meeting. Abstract 73. Presented December 9, 2012.

4. Karuturi M, Arai S, Chen R, et al: 2012 ASH Annual Meeting. Abstract 3701. Presented December 1, 2012.

5. Fanale M, Shustov A, Forero-Torres A, et al: 2012 ASH Annual Meeting. Abstract 60. Presented December 9, 2012.

6. Sonis S, Antin J, Alterovitz G, et al: 2012 ASH Annual Meeting. Abstract 735. Presented December 10, 2012.

7. Topp M, Goekbuget N, Zugmaier G, et al: 2012 ASH Annual Meeting. Abstract 670. Presented December 10, 2012.

8. Choi S, DiPersio J, Braun T, et al: 2012 ASH Annual Meeting. Abstract 740. Presented December 10, 2012.

9. Goy A, Sinha R, Williams MJ, et al: 2012 ASH Annual Meeting. Abstract 905. Presented December 11, 2012.



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