'Unprecedented Crisis': Dacarbazine Shortage Prompts Search for Substitute Hodgkin Therapy

M. Alexander Otto, PA, MSS

May 04, 2022

The persistent shortage of dacarbazine has led to an "acute and unprecedented crisis" in the treatment of patients with advanced classical Hodgkin lymphoma, experts say.

Dacarbazine, an essential part of the four-drug standard of care for managing Hodgkin lymphoma, has been in short supply since last summer, prompting experts to search for a viable substitute.

In a recent review, oncologists scoured decades of data to find the best alternatives for a range of scenarios. For fit adults younger than 60, the group recommends the seven-drug regimen BEACOPP — bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone.

"Among all available regimens," BEACOPP has "the most robust evidence" as a substitute for the four-drug standard ABVD, which includes doxorubicin, bleomycin, vinblastine, and dacarbazine, Pallawi Torka, MD, a hematologic oncologist at Roswell Park Comprehensive Cancer Center, Buffalo, New York, and two colleagues write in JCO Oncology Practice.

Last October, the US Food and Drug Administration (FDA) posted a notice about the dacarbazine shortage. According to the notice, the shortage occurred because of "manufacturing delays" and a "demand increase" affecting three companies supplying the US market — Fresenius Kabi USA, Hikma Pharmaceuticals, and Teva. In an update issued today, the FDA says that 100-mg and 200-mg vials of the drug are now available from Fresenius. An update from April 8 says that 200-mg vials are now available from Hikma.

Dacarbazine is hardly the only oncology drug to fall into short supply. Recent data show that shortages of oncology drugs have become more common in the US in recent years, particularly generic drugs and those targeting hematologic malignancies.

In a recent national survey of oncology pharmacists, researchers found that almost two thirds of institutions reported at least one drug shortage in the past month, representing a 34% increase between 2018 and 2019.

"This shortage of [dacarbazine] is not the first shortage of oncolytic drugs, and it certainly will not be the last," Nicole Soriano, PharmD, hematology/oncology clinical pharmacist at Northwestern Memorial Hospital, Chicago, and two colleagues write in a commentary accompanying the review.

According to Soriano and co-authors, "some studies have found that shortages are significant across many oncology disciplines and may lead to delays, changes in therapy, interference with clinical research, increased risk of medication errors, adverse outcomes, and increased costs."

Finding a Substitute

In the current analysis, Torka and her team conducted an exhaustive literature review in which they examined studies going back decades.

The authors highlight more than 10 alternative regimens for treating advanced classical Hodgkin lymphoma. They also provide a detailed treatment algorithm to help oncologists choose the best option for their individual patients as well as strategies for reintegrating ABVD into patient care should the supply of dacarbazine return to normal.

The first considerations: Can patients tolerate intensive chemotherapy, and are patients younger than 60?

For fit adults younger than 60, Torka and colleagues conclude that the BEACOPP regimen is the "preferred" option. In trials comparing ABVD to BEACOPP, both regimens demonstrated similar overall survival. And while BEACOPP may provide slightly "better disease control," this approach may also come with greater toxicities in the short and long term compared with ABVD, depending on the dosing strategy.

The authors also propose an alternative treatment strategy in case the supply of dacarbazine returns to normal mid-treatment. In this scenario, patients could receive an escalated BEACOPP regimen for two cycles and then undergo an interim positron-emission tomography scan. If the scan is negative and dacarbazine is available, the patient's regimen could be de-escalated to ABVD for four cycles without affecting disease control.

For patients younger than 22 years, the authors recommend the ABVE-PC regimen, which includes six drugs — doxorubicin, bleomycin, vincristine, etoposide, prednisone, and cyclophosphamide. Data show that the 5-year overall survival among pediatric patients receiving ABVE-PC is 95%.

Stanford V-C — cyclophosphamide, doxorubicin hydrochloride, vinblastine, vincristine, bleomycin, etoposide, and prednisone — is another "acceptable approach" for patients during the current shortage, the authors note.

For older patients with advanced disease or those unfit for intensive chemotherapy, the authors suggest evaluating them for fitness for anthracyclines to determine whether doxorubicin, in particular, is an option.

If doxorubicin-eligible, the researchers suggest one of the following three strategies: PVAG (prednisone, vinblastine, doxorubicin, and gemcitabine), CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone), or EVA (etoposide, vinblastine, and doxorubicin).

For those unfit for anthracyclines, the options include COPP (cyclophosphamide, vincristine, procarbazine, and prednisone) or ChlVPP (chlorambucil, vinblastine, procarbazine, and prednisone).

For frail patients who are ineligible for chemotherapy, the team recommends brentuximab alone or in combination with nivolumab.

Given the limited availability of dacarbazine, the authors say that the "current supply should be triaged to prioritize patients whose therapy cannot be changed and those without alternative acceptable options."

To stretch available dacarbazine supplies as much as possible, the researchers and editorialists advocate for rounding doses within 5% to 10% of the prescribed dose.

For example, Torka and colleagues explain, rounding a dose from 750 mg down to 700 mg would save one vial of dacarbazine.

Vial sharing and using drugs beyond their use dates by compounding with closed-system transfer devices are other strategies to preserve the existing supply of dacarbazine.

The goal of this review "is to give as many patients as possible the most optimal and efficacious therapy even with the strain on supply," the editorialists write.

No funding for the study was reported. Torka is an advisor for Genentech, ADC Therapeutics, and TG Therapeutics. Soriano has disclosed no relevant financial relationships.

JCO Oncol Pract. Published online March 7, 2022. Full text, Commentary

M. Alexander Otto is a physician assistant with a master's degree in medical science. He is an award-winning medical journalist who worked for several major news outlets before joining Medscape and is an MIT Knight Science Journalism fellow. Email: aotto@mdedge.com.

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