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Concise Reviews of Studies Relevant to Hematology Oncology Pharmacy

JHOP - February 2021 Vol 11, No 1 - From the Literature
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With commentaries by Robert J. Ignoffo, PharmD, FASHP, FCSHP, FHOPA
Clinical Professor Emeritus, University of California, San Francisco;
Professor Emeritus, Touro University–California, Mare Island, Vallejo, CA
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In This Article


Sitagliptin, a DPP-4 Inhibitor, Reduces the Incidence of Acute GVHD After Stem-Cell Transplant

BACKGROUND: Acute graft-versus-host disease (GVHD) is a major complication after allogeneic hematopoietic stem-cell transplant (HSCT). The rate of GVHD is between 34% to 51% within 100 days of undergoing transplant. Dipeptidyl peptidase (DPP)-4 acts as a co-stimulatory factor for T-cell activation. In a preclinical model, down-regulation of DDP-4 expression prevented the incidence of acute GVHD and preserved graft-versus-tumor effects. In addition, a previous study of sitagliptin, a selective DPP-4 inhibitor, in core-blood transplants in adults with hematologic malignancies had an acceptable side-effect profile and decreased incidence of acute GVHD.

METHODS: This single-group, open-label, phase 2 clinical trial included 36 patients who underwent HSCT for 1 of several hematologic malignancies. In all, 13 patients had matched related donors, and the remaining 23 had unmatched related donors. All patients received sitagliptin 600 mg every 12 hours beginning the day before the transplant and continuing until day 14 after transplant, along with a standard immunosuppressive regimen of tacrolimus and sirolimus. The primary end point was grade II to IV acute GVHD by day 100. Secondary end points included mortality not related to disease relapse, disease relapse, and the incidence of chronic GVHD.

RESULTS: Of the 36 patients enrolled in the study, 2 patients had acute GVHD by day 100; 1 patient had grade II acute GVHD involving the gut (stage 1), liver (stage 1), and skin (stage 3) on day 81. Yet another patient had grade IV acute GVHD involving the skin (stage 3), gut (stage 4), and liver (stage 4) on day 29. Overall, the incidence of grade II to IV GVHD was 5%, and the incidence of grade III to IV acute GVHD was 3%. A total of 28 patients received 80% or more of the planned 32 doses of sitagliptin. The rate of disease relapse was 0% at 1 year, confirming the safety and tolerability of the drug. After 1 year, the incidence of disease relapse was 26% (95% confidence interval [CI], 13-41), and the incidence of chronic GVHD was 37% (95% CI, 22-53). A total of 46% (95% CI, 29-62) of the patients had GVHD-free, relapse-free survival. No additional side effects were reported beyond those observed in patients undergoing allogeneic HSCT; in particular, no episodes of hyperglycemia were noted. “The incidence of acute GVHD in our trial appears to be lower than in other trials testing other agents,” the researchers observed.

Source: Farag SS, Zaid MA, Schwartz JE, et al. Dipeptidyl peptidase 4 inhibition for prophylaxis of acute graft-versus-host disease. N Engl J Med. 2021;384:11-19.

Commentary by Robert J. Ignoffo

Sitagliptin is approved for the treatment of type 2 diabetes. With its ability to inhibit DPP-4 activity, sitagliptin is effective in preventing acute GVHD, but the effective dose is 1200 mg daily versus the 100 mg daily used for the treatment of diabetes. Despite this high dose, sitagliptin did not have more adverse events than the sirolimus-tacrolimus immunomodulatory regimen. Adding sitagliptin produced a substantially lower incidence (5%) of grade II to IV acute GVHD versus 26% to 47% with tacrolimus-sirolimus, and 3% for grade III to IV versus 7% to 19% with tacrolimus-sirolimus. Treatment with sitagliptin also lowered the incidence of chronic GVHD to 37% versus 59% with tacrolimus-sirolimus.

The question arises whether we should wait for a randomized clinical trial before sitagliptin is approved for the prevention of GVHD. Further studies are needed to compare it with other standard prophylactic regimens. Farag and colleagues spent 2.5 years to obtain and publish their results; it may take twice as long to obtain enough patients to conduct a randomized study.

Another issue is that sitagliptin’s dosing was studied at 600 mg twice daily. Sitagliptin is sold as 100-mg oral tablets and costs approximately $500. Without a larger study, the manufacturer may not produce a dosage as high as 600 mg that could easily be administered. It is also questionable whether insurance companies would pay for sitagliptin without FDA approval. It remains to be seen if this very promising study will result in the off-label use of sitagliptin for the prevention of acute GVHD.

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Pembrolizumab Shows Long-Term Benefits in Patients with Metastatic Colorectal Cancer and MSI-H or dMMR

BACKGROUND: Chemotherapy is currently the standard of care for patients with microsatellite instability-high (MSI-H) or mismatch repair-deficient (dMMR) colorectal cancer (CRC); however, some patients have disease that is refractory to chemotherapy. Programmed-cell death (PD)-1 inhibitors have emerged as a highly effective therapy in this setting.

METHODS: KEYNOTE-177 was a multicenter, international, open-label, phase 3 study that enrolled 307 treatment-naïve patients with metastatic MSI-H or dMMR CRC. Patients were randomized in a 1:1 ratio to pembrolizumab 200 mg every 3 weeks or to chemotherapy with 5-fluorouracil–based therapy (with or without bevacizumab or cetuximab) every 2 weeks. Crossover from chemotherapy to pembrolizumab was allowed after disease progression. The median duration of patients’ exposure to treatment was 11.1 months in the pembrolizumab group and 5.7 months in the chemotherapy group. Pembrolizumab therapy was continued for a maximum of 35 treatments or until disease progression, unacceptable side effects, illness, or withdrawal. The primary end points were progression-free survival (PFS) and overall survival.

RESULTS: After a median follow-up of 32.4 months, PFS was doubled in the pembrolizumab group compared with the chemotherapy group, for a median of 16.5 months versus 8.2 months, respectively (hazard ratio, 0.60; P = .0002). More patients were alive and progression-free at 12 months and at 24 months in the pembrolizumab group (55.3% and 48.3%, respectively) compared with the chemotherapy group (37.3% and 18.6%, respectively). “After an initial crossing of the progression-free survival Kaplan–Meier curves, a pronounced separation of the curves for pembrolizumab and chemotherapy was observed, which indicated a meaningful long-term benefit with pembrolizumab,” the researchers noted. As of the data cutoff date, 56 patients in the pembrolizumab group and 69 patients in the chemotherapy group had died. Data on overall survival were still evolving and remain blinded until the final analysis. The overall (partial or complete) response was 43.8% in the pembrolizumab group versus 33.1% in the chemotherapy group. The overall ongoing response rate at 24 months was also greater in the pembrolizumab group (83%) compared with the chemotherapy group (35%). The incidence of grade 3 or 4 adverse events was lower with pembrolizumab (56%) versus chemotherapy (78%). In addition, patients in the PD-1 inhibitor group had fewer treatment-related adverse events (22%) than in the chemotherapy group (66%), and 1 death was reported in the chemotherapy group. “These data represent another step forward for biomarker-driven studies targeting MSI-H–dMMR colorectal cancers….Pembrolizumab should be considered an option for initial therapy for patients with MSI-H–dMMR metastatic colorectal cancer,” the authors noted.

Source: André T, Shiu KK, Kim TW, et al; for the KEYNOTE-177 investigators. Pembrolizumab in microsatellite-instability–high advanced colorectal cancer. N Engl J Med. 2020;383:2207-2218.

Commentary by Robert J. Ignoffo

This study is likely to change practice. The PD-1 inhibitor pembrolizumab is significantly more effective than chemotherapy for the treatment of patients with MSI-H or dMMR metastatic CRC. In addition, fewer grade ≥3 toxicities occurred with pembrolizumab (22%) than with chemotherapy (66%). No neutropenia was reported in the pembrolizumab arm versus 15% in the chemotherapy arm. Furthermore, 59% of patients who received chemotherapy crossed over to the immunotherapy cohort.

In his accompanying editorial, Axel Grothey, MD, stated that for CRC with MSI-H or dMMR, “the durability of response, better safety profile, and improved quality of life associated with immunotherapy as compared with chemotherapy make pembrolizumab the preferred choice.” This is a major advance in immunotherapy for this type of CRC. Another PD-1 inhibitor, nivolumab, has also had good responses in phase 2 studies of patients with MSI-H or dMMR CRC.1

What impact will this new treatment standard have in the United States? The prevalence of CRC with MSI-H or dMMR is 4% to 5%.1 Several researchers have indicated that the MSI-H phenotype has a poor prognosis in metastatic CRC.1 There are almost 148,000 new cases of CRC diagnosed annually in the United States, with approximately 22% diagnosed in patients with metastatic disease2; thus, approximately 3000 patients annually will be eligible for treatmzent with a PD-1 inhibitor. A better understanding of MSI-H status and other actionable targets is reshaping the therapeutic approach for metastatic CRC.

  1. Overman MJ, McDermott R, Leach JL, et al. Nivolumab in patients with metastatic DNA mismatch repair-deficient or microsatellite instability-high colorectal cancer (CheckMate 142). Lancet Oncol. 2017;18:1182-1191.
  2. National Cancer Institute SEER Program. Cancer stat facts: colorectal cancer. https://seer.cancer.gov/statfacts/html/colorect.html. Accessed February 9, 2021.

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Last modified: February 24, 2021