A few days back I ran a post about how improvements in the way allogeneic transplants are administered may help reduce the number and severity of side-effects:
In my post, I refer to some experimentation that lead Moffitt Cancer Center BMT doc, Mellissa Alsina, has been doing with the high dose chemotherapy mix.
Although I didn’t mention it by name, Dr. Alsina has been using Velcade–along with reducing the melphalan dose just a bit during the high dose chemotherapy phase–to achieve her excellent results reducing graft/host disease substantially.
Here is an article about a Stage I study–soon to be Stage II–using which also uses Velcade in a slightly different way, following a transplant during the recovery process. Either way seems to produce positive results:
Bortezomib shows promise in reducing graft-versus-host disease and reconstituting immune system in some stem cell transplant patients
December 6, 2011
A drug that has become a mainstay of multiple myeloma treatment may outperform alternative therapies in re-establishing the immune system of patients who have received stem cell transplants from unrelated, partially matched donors, according to early clinical trial results from Dana-Farber Cancer Institute investigators.
The trial was designed to determine whether the drug bortezomib (trade name Velcade®), when added to routine agents (tacrolimus, methotrexate), can improve control of graft-versus-host disease (GVHD) and improve immune system recovery following a transplant from a mismatched-unrelated donor.
GVHD is a common and potentially severe side effect of blood-forming stem cell transplants, in which donor immune cells attack normal patient cells and tissues. GVHD is more frequent in patients receiving transplants from mismatched-unrelated donors (in comparison with matched-related donors).
Based on bortezomib’s effect in preclinical models, and in multiple myeloma patients who have received donor stem cell transplants, Dana-Farber’s John Koreth, MBBS, DPhil, and colleagues theorized that it could help control the overactivity of immune cells responsible for GVHD in stem cell transplant patients.
Bortezomib inhibits the activity of antigen-presenting cells, which help initiate the immune attack in GVHD, and reduces activity of an important protein called nuclear factor-kB in T cells, which undertake the immune attack.
In preclinical studies, bortezomib has been shown to selectively deplete T cells that can target patients’ normal cells. Mouse transplant studies have shown that early administration of bortezomib protects against GVHD without reducing the transplanted stem cells’ ability to settle in the bone marrow.
The new Phase I clinical trial involved 23 patients who received bortezomib-based therapy (bortezomib, tacrolimus, and methotrexate) after reduced-intensity stem cell transplants from mismatched-unrelated donors.
Three dosage levels of bortezomib were tested. In updated results on 35 bortezomib-based, mismatched-unrelated patients, GVHD rates and extent of immune system reconstitution were compared with patients who had received sirolimus-based therapy (sirolimus, tacrolimus, and methotrexate) after transplants from matched-related donors, matched-unrelated donors, and mismatched-unrelated donors.
The results show that the bortezomib-based therapy was safe and had little toxicity. Transplanted stem cells took root or “engrafted” reliably, and the rate of GVHD in the bortezomib-based mismatched-unrelated transplants was comparable to that in sirolimus-based matched-related transplants.
Interestingly, immune cell reconstitution was significantly improved in the bortezomib-based patients in the early post-transplant period (3-6 months), compared with the sirolimus-based patients.
“Our results suggest that borezomib is a promising novel immunomodulatory agent in donor stem-cell transplantation,” Koreth says. “A Phase II trial is now accruing patients to help determine its ultimate effectiveness.”
The study’s senior author is Dana-Farber’s Edwin Alyea, MD. Co-authors are Kristen Stevenson, Haesook Kim, PhD, Michael Garcia, Vincent Ho, MD, Philippe Armand, MD, Corey Cutler, MD, Jerome Ritz, MD, Joseph Antin, MD, and Robert Soiffer, MD, all of Dana-Farber.
The study was supported by Millennium Pharmaceuticals Inc. and the National Institutes of Health.
Another example of how using existing drugs–sometimes for what seems to be completely unrelated purposes–can help patients.
Special thanks to regular reader and allo transplant survivor, Mark, for forwarding me info about that study after reading about Dr. Alsina’s “off label” experimentation with Velcade and donor transplants last week.
Mark also forwarded me this piece of great news, directly from the National Center for Biotechnology, which gives specific details about the study’s results. Here is that abstract:
Graft-versus-host disease (GVHD) is a significant complication of allogeneic stem cell transplantation (alloSCT). The proteasome inhibitor bortezomib has immunomodulatory properties of potential benefit for GVHD control. We undertook a phase 1 trial of bortezomib, tacrolimus, and methotrexate for GVHD prophylaxis after reduced-intensity conditioning alloSCT using human leukocyte antigen-mismatched unrelated donors. Twenty-three patients were enrolled. Bortezomib dose levels of 1, 1.3, and 1.5 mg/m2 were evaluated with 5, 3, and 5 patients, respectively. Ten additional patients were accrued at the 1.3 mg/m2 bortezomib dose level. Bortezomib-related toxicity was minimal. With a 12-month median follow-up, grade II-IV acute GVHD occurred in 3 patients, a 180-day cumulative incidence of 13%. Chronic GVHD occurred in 9 patients, a 1-year cumulative incidence of 41%. At 1-year, the nonrelapse mortality was zero, cumulative incidence of relapse/progression was 29%, and overall, progression-free, and event-free survival were 75%, 64%, and 59%, respectively. Bortezomib is a promising novel immunomodulatory agent in allogeneic transplantation
I have placed two very important outcomes in bold. Note that all of the patients who participated in the study are alive after one year. Outstanding!
Also please note the encouraging progression-free and event-free survival stats.
Here is a LINK to the National Center for Biotechnology’s site if you would like to check-out some helpful graphs and read the entire study.
This is exciting–even inspirational news! By reducing the dose of chemotherapy at the front end of these transplants–and hopefully adding a wider variety of chemo drugs, along with with Velcade during and after the process–real progress if being made on all donor transplant fronts.
Keep it up, guys and gals! This may just be an option for me in a few years when my myeloma rears it’s ugly head once again.
Feel good and keep smiling! Pat