Clinical review of substitutions or alternatives for critical chemotherapy drug shortages in hematologic malignancies

Abstract

Purpose

Over the past decade, drug shortages have become increasingly more problematic for clinicians, with over 300 drug shortages reported in the first quarter of 2023. Shortages of chemotherapy drugs can have a negative impact on patient care, as omission or delay of treatment can lead to worse outcomes. Although many articles have been published on this topic, currently no review articles discuss strategies for using alternative regimens or substitutions in the event of severe chemotherapy drug shortages.

Summary

In this article, we review the literature on antineoplastic agents used to treat hematologic malignancies that experienced a drug shortage from 2010 through 2023, providing recommendations for substitutions and alternative regimens in the event of a critical shortage. In particular, we discuss how shortages of fludarabine, cytarabine, daunorubicin, methotrexate, and platinum agents may be addressed, including supporting clinical evidence.

Conclusion

Further publications assessing possible alternatives and substitutions for chemotherapy agents and examining the efficacy of previous strategies are needed to mitigate potentially devastating interruptions to care for patients with cancer during severe drug shortages.

Severe drug shortages over the past decade have had a negative impact on patient care by potentially delaying or preventing optimal care. A multitude of factors arising in the past 3 years have also added stress to the healthcare system in the US and the rest of the world, with the most prominent of these being the economic impact from the coronavirus disease 2019 (COVID-19) pandemic, during which strict quarantine measures created significant supply chain issues.^1-4 On the basis of recent data, the University of Utah Drug Information Services and American Society of Health-System Pharmacists (ASHP) reported that the number of active drug shortages has been slowly trending up since 2018 and reached a 5-year high in 2023, with over 300 drug shortages in the first quarter of 2023, including for 14 oncology drugs.⁵ Reasons for drug shortages include issues with the supply chain and manufacturing, supply/demand mismatches, regulatory challenges, and business decisions.^5,6 From a clinical perspective, a drug shortage resulting in the omission of a chemotherapy agent or a delay in its administration can significantly impact disease progression and mortality outcomes associated with the regimen. In severe drug shortages, healthcare institutions and providers have been compelled to consider utilizing alternative agents that have fewer studies to support their use, potentially compromising efficacy and safety along with incurring higher medication costs. In addition, chemotherapy shortages can disrupt operational workflows and result in significant financial costs for healthcare institutions because additional resources are expended to procure the limited drug supply.⁷ Ethical considerations about how to allocate a limited supply of life-saving medications to patients with cancer warrant coordination among different healthcare providers alongside compliance officers and/or bioethics committees, costing personnel time and resources.⁸ Given the complexity of the management of patients with cancer in oncologic drug shortages, this review aims to compile all the data detailing substitution options and alternative treatment regimens to address antineoplastic drug shortages that have occurred over the past decade in patients with hematologic malignancies.

Methods

We identified potential drug shortages from January 1, 2010, to May 31, 2023, using the ASHP database and filtered search results to medications classified as an antineoplastic agent and indicated for use in hematologic malignances.⁵ We then searched the PubMed database for primary literature in adult patients for analysis in this review. This review will mainly focus on the antineoplastic agents that experienced a critical shortage in the US that led to widespread mainstream media attention. This review will exclude agents that are predominantly utilized in the hematopoietic transplantation setting as part of conditioning.

Cytarabine in acute leukemias and lymphomas

During the early 2010s, cytarabine (Ara-C) experienced a critical drug shortage that affected many patients with acute leukemias with no available alternatives at the time. Leaders in the field spoke out to raise awareness of the negative impact shortages were having on their patients.⁹ Ara-C is considered one of the core drugs for the treatment of acute myeloid leukemia (AML), is part of postinduction therapy in acute lymphoblastic leukemia (ALL), and is used in various settings in lymphomas and as central nervous system (CNS) prophylaxis via intrathecal therapy. Unfortunately, there are no direct substitutions for Ara-C in acute leukemias, as other pyrimidine analogs (eg, gemcitabine) have not demonstrated enough potency in vitro in leukemia, and the optimal strategy would be focused on utilizing alternative regimens to conserve inventory until more supply becomes available.^10,11 For lymphomas, gemcitabine has been shown to be effective in the salvage setting and to be noninferior to Ara-C as part of R-DHAP (rituximab, dexamethasone, cytarabine, and cisplatin).^12,13 In the NCIC-CTG LY.12 trial, gemcitabine 1,000 mg/m² given on days 1 and 8 was compared to Ara-C 2 g/m² given every 12 hours for 2 days and could be considered a potential substitute for DHAP with or without rituximab in lymphoma when an alternative regimen cannot be utilized and Ara-C is unavailable.

For more than 2 decades, patients with newly diagnosed AML (ND-AML) who are medically fit have traditionally received induction chemotherapy according to the 7 + 3 regimen, which combines an anthracycline for 3 days with continuous infusion of Ara-C 100 to 200 mg/m² over 7 days.¹⁴ Initially, providers should consider treating patients with Ara-C at 100 mg/m² instead of 200 mg/m² as a CALGB study by Dillman et al¹⁵ found no difference in remission rates for the 2 doses. When faced with a critical shortage, many would have to resort to induction that does not include conventional Ara-C, such as liposomal daunorubicin and Ara-C (CPX-351) or a lower-intensity treatment regimen combining hypomethylating agents with venetoclax (HMA-VEN) if no targetable mutations are present. Results for HMA-VEN have been promising in the upfront setting, with a composite remission rate of 66.7% and median overall survival (OS) of 14.7 months in previously untreated patients who were medically unfit.¹⁶ When HMA-VEN (using decitabine for 10 days) was compared to intensive chemotherapy regimens containing Ara-C at a dose of 1 g/m² or higher in patients who were at low risk for treatment-related mortality and eligible for intensive chemotherapy, patients receiving HMA-VEN had higher remission rates (70% vs 43%, P < 0.01) and longer median OS (15.2 vs 6.8 months, P = 0.02) than patients who received intensive chemotherapy.¹⁷ An ongoing trial comparing azacitidine with venetoclax to the 7 + 3 regimen (CPX-351 in the case of secondary AML) in medically fit patients with ND-AML should elucidate the potential of HMA-VEN as an alternative to intensive chemotherapy.¹⁸ CPX-351 has been directly compared to the 7 + 3 regimen but only in older patients with newly diagnosed secondary AML. Despite the narrow study population, CPX-351 resulted in higher remission rates and a longer median OS compared to the 7 + 3 regimen.¹⁹ On the basis of the promising results for these 2 regimens in ND-AML, it is reasonable to consider utilizing these agents for patients who are medically fit during a critical drug shortage. During a critical shortage of Ara-C, it would be fruitful to consider refraining from using intermediate-dose (IDAC) and high-dose (HiDAC) Ara-C induction regimens in the newly diagnosed setting as these regimens have not been demonstrated to be superior to 7 + 3. Conversely, in AML consolidation with HiDAC after achieving remission with 7 + 3 is considered the standard of care in patients who are medically fit.²⁰ Therefore, discussion is warranted on which patients would benefit the most from HiDAC, the number of Ara-C consolidation cycles to give, and which patients could be treated with IDAC, as some studies have reported similar outcomes with IDAC.^21,22 Another option would be a combination approach for consolidation with the goal of utilizing less Ara-C, such as 5 + 2 or FLAG-IDA (fludarabine, cytarabine, and idarubicin with or without filgrastim) alone or with venetoclax (FLAG-IDA-VEN). Purine analog–based regimens have been shown to be quite effective in ND-AML, with response rates ranging from 80% to 90% together with promising survival outcomes, while using significantly less Ara-C for consolidation.^23-25

In ALL, Ara-C is mainly used for consolidation, with doses varying depending on the regimen used to treat these patients. To preserve inventory, avoiding regimens that utilize high doses of Ara-C such as HyperCVAD should be considered. No studies have definitively shown one ALL induction strategy to be superior to the others, as many regimens contain the same core drugs of anthracycline, steroids, and vincristine with or without cyclophosphamide and pegylated asparaginase.²⁶ The situation is similar in patients with lymphoma, as Ara-C is mainly used as part of salvage therapy or upfront in certain aggressive lymphomas such as mantle cell and Burkitt’s lymphomas. In both scenarios, suitable alternative regimens are available during a critical shortage, with the only exception being first-line treatment for aggressive mantle cell lymphoma.^27-30 Therefore, our recommendation is that Ara-C be allocated for patients with aggressive lymphomas that have the potential for cure.

Daunorubicin in acute leukemias

Following the Ara-C shortage, a significant shortage of daunorubicin occurred a year later, which affected the treatment of AML and ALL. This resulted in senators proposing legislation requiring drug companies to notify the Food and Drug Administration about pending drug shortages.³¹ In AML, daunorubicin is only utilized in the 7 + 3 regimen. Therefore, if another shortage should occur, substitution would be rather straightforward and idarubicin would become the preferred anthracycline in this regimen. Idarubicin is synthetically derived from daunorubicin, and the only structural difference between them is the presence of a 4-methoxyl group in daunorubicin.^32,33 Some earlier studies suggested that idarubicin might be more effective in achieving remission, based on its higher lipophilicity allowing it to achieve higher intracellular concentrations and the higher potency of its metabolite, idarubicinol, which results in higher killing in AML.^34-39 However, many of these studies did not show a significant impact on OS. Lee et al⁴⁰ theorized that the better remission rates seen with idarubicin in these earlier AML studies could be explained by the daunorubicin doses not being equivalent. Lee et al⁴⁰ did not find significant differences in remission rates, relapse, survival, or safety between the 2 anthracyclines, aside from daunorubicin yielding better results within the FLT3-ITD subgroup.

The critical shortage of daunorubicin in 2011 was more difficult to address in ALL because no direct substitutions were available at this time. During the shortage, many institutions substituted daunorubicin with doxorubicin because doxorubicin has been used in HyperCVAD and as part of consolidation in various ALL regimens.^41-43 Doxorubicin differs from daunorubicin structurally by only a single hydroxyl group, and the most recent in vitro studies have not shown significant differences in activity between these agents.^44,45 CoALL 07-03 compared daunorubicin 30 or 40 mg/m² to doxorubicin 30 mg/m² in pediatric patients with ND-ALL, demonstrating similar responses in vivo for the anthracyclines with no statistically significant difference in the incidence of infectious complications (although the incidence of these was higher for doxorubicin at 19.1% compared to a rate of 9.9% to 15.5% for daunorubicin, P = 0.11).⁴⁶ Subsequently, CoALL 08-09 used the 2 anthracyclines for delayed intensification, finding that daunorubicin had lower rates of myelosuppression, shorter duration of neutropenia, and less mucositis, resulting in significantly lower incidence of infection (59% vs 27%, P < 0.0001) without sacrificing efficacy.⁴⁷ Patel et al⁴⁸ reported similar results in a retrospective study that used doxorubicin at a 1:1 conversion ratio for 10 patients receiving either CALGB 9511 or 10403, finding equivalent efficacy but longer recovery times and higher rates of mucositis and sepsis. Similarly, a retrospective study in 9 pediatric patients with high-risk ALL conducted by Gardner et al⁴⁹ demonstrated higher incidence of toxicity from mucositis and fungal infections with doxorubicin although similar efficacy results were achieved. On the basis of these studies, doxorubicin could be suggested as a suitable replacement in terms of efficacy, but close monitoring may be necessary with higher toxicity.

Mitoxantrone is an anthracenedione that is commonly mentioned among the anthracyclines and has been shown to have activity in both AML and ALL. In AML, mitoxantrone can be utilized during induction or as salvage treatment in the relapsed or refractory setting. As part of induction, mitoxantrone can be used as a direct substitution for the anthracycline in the 7 + 3 regimen with no difference in outcomes. However, the ECOG study focused only on older adults and compared mitoxantrone 12 mg/m² to daunorubicin 45 mg/m² instead of the dose of 60 to 90 mg/m² currently considered to be the standard.⁵⁰ In addition, alternative AML regimens that contain mitoxantrone can be considered, such as CLAG-M (cladribine, cytarabine, mitoxantrone, and filgrastim) and MEC (mitoxantrone, etoposide, and cytarabine), as both have been studied in the newly diagnosed and relapsed or refractory settings.^51-54 Use of mitoxantrone in ALL has traditionally been limited to patients with relapsed or refractory disease, although these regimens are not commonly utilized due to their modest efficacy and the introduction of immunotherapy such as blinatumomab and chimeric antigen receptor T (CAR-T) cell therapy.^55-57 A small study of 11 pediatric patients with ALL who received mitoxantrone 6.25 mg/m² as a substitution for daunorubicin 25 mg/m² (1:4 ratio) showed similar responses and toxicity.⁵⁸ This 1:4 ratio was also used in the aforementioned ECOG study, and therefore this conversion ratio could be considered in the event daunorubicin becomes unavailable.

Fludarabine in acute leukemias, CAR-T lymphodepletion, and HSCT conditioning

Fludarabine is a purine analog frequently used in AML, conditioning for allogeneic hematopoietic stem cell transplantation (HSCT), and lymphodepletion therapy before CAR-T cell immunotherapy in chronic lymphocytic leukemia and other lymphoid malignancies. A critical shortage of fludarabine occurred in 2022, resulting in a Senate committee hearing in December 2023 to discuss ways to combat drug shortages leading to suboptimal care for many patients who require treatment.⁵⁹ Although other purine analogs exist (cladribine, clofarabine, and pentostatin), they are not easily interchangeable and each presents its own unique and select toxicities. Fludarabine is commonly used in AML regimens in combination with other agents in both the newly diagnosed and relapsed or refractory settings. It is frequently used in combination with Ara-C, given the potentiation effects fludarabine has on Ara-C when these are given sequentially.⁶⁰ The potentiation effects on Ara-C have also been described for other purine analogs used in AML, including for cladribine and clofarabine. Despite the similarity of these agents in belonging to the same class of purine analogs and potentiation of Ara-C, the literature has shown that the different purine drug combinations have different activity and toxicity. For purine analog–based regimens in the newly diagnosed setting, the National Comprehensive Cancer Network (NCCN) guidelines for AML provide recommendations for a FLAG-GO (fludarabine, cytarabine, G-CSF [granulocyte colony-stimulating factor], and gemtuzumab ozogamicin) regimen for ND-AML with favorable-risk genetics or FLAG-IDA for ND-AML classified as intermediate- or poor-risk disease.⁶¹ In relapsed or refractory AML, the NCCN guidelines include several purine analog–based therapies, including fludarabine, cladribine (CLAG with or without mitoxantrone or idarubicin), and clofarabine (clofarabine with or without cytarabine with or without idarubicin).

Cladribine-based regimens in the newly diagnosed setting are currently not recommended by NCCN. Some published studies have assessed intensive induction regimens that are similar to FLAG-based regimens, such as CLAG-M and cladribine in combination with venetoclax, which have yielded promising results when given upfront in AML.^52,62 Currently, studies comparing fludarabine and cladribine are limited in AML. A phase 3 study by Holowiecki et al⁶³ compared the addition of either fludarabine (DAF) or cladribine (DAC) to 7 + 3 in ND-AML. Improved complete response (CR) rates and OS were found with addition of cladribine but not fludarabine. Neither neutrophil nor platelet recovery was different when comparing DAC and DAF, and the incidence of grade 3 or 4 nonhematologic adverse events was also similar. Cladribine-based regimens can be considered in the relapsed or refractory setting as recommended by NCCN, with a retrospective study by Park et al⁶⁴ demonstrating similar CR rates when compared to fludarabine.

Clofarabine is a second-generation purine analog developed to minimize neurotoxicity and overcome resistance pathways associated with previous purine analogs.⁶⁵ Early clinical results were promising, with CR rates ranging from 30% to 40%, and the most frequently reported adverse effects were transaminitis, mucositis, and myelosuppression, which were minimized through dose reduction.^65-68 As with cladribine, regimens including clofarabine used synergistically with intermediate doses of Ara-C (GCLAC) are recommended only in the relapsed or refractory setting by NCCN. In the newly diagnosed and relapsed or refractory settings, CR/CRi (incomplete platelet recovery only) rates ranging from 60% to 80% have been published, and the most commonly reported nonhematologic grade 3 adverse events have been infection and pulmonary and hepatic toxicity.^68-70 Subsequently, a phase 2 study by Jabbour et al⁷¹ evaluated idarubicin and Ara-C with clofarabine (CIA) or fludarabine (FIA) in patients with ND-AML, finding that the 2 groups had similar CR/CRi rates of approximately 80% with no difference in event-free survival or OS. However, treatment with CIA was associated with more adverse events compared to FIA, including higher rates of transaminitis, hyperbilirubinemia, and rash, although there was no difference in mortality within the first 30 days of treatment. Another retrospective study by Becker et al⁷² found that GCLAC had better CR rates (46% vs 20%) and median OS (8.8 vs 3.8 months, P = 0.09) than FLAG. Comparisons of clofarabine and cladribine have been limited, and only a retrospective study by Muluneh et al⁷³ found GCLAC and CLAG to be similar in relapsed or refractory AML in terms of efficacy and safety outcomes. Recently, we published our experience utilizing cladribine instead of fludarabine in combination with idarubicin and venetoclax in response to the recent shortage, finding similar response rates but higher rates of nonhematologic grade 3 or 4 adverse effects with cladribine.⁷⁴

Fludarabine is frequently used as a conditioning agent before HSCT, with most regimens containing dual alkylators used less frequently given the significant toxicities and veno-occlusive disease/sinusoidal obstructive syndrome associated with these regimens. Many conditioning regimens have been published, and a consideration during a critical shortage of fludarabine would be to select a different conditioning regimen that does not include this drug. Some studies have compared another purine analog to fludarabine or omitted fludarabine due to theoretical improved efficacy and safety. The 2 purine analogs most often used for conditioning, other than fludarabine, are clofarabine and pentostatin. Clofarabine has been utilized as a direct replacement for fludarabine in regimens that contain busulfan for myeloablative conditioning or those containing melphalan for reduced-intensity conditioning and has been demonstrated to be effective and well tolerated.^75-77 Cladribine has also been studied, but the 2 trials assessing its use were closed early due to excessive nonrelapse mortality and inferiority compared to the fludarabine arm.^78,79 Pentostatin is a purine analog that causes irreversible inhibition of the adenosine deaminase (ADA) enzyme, which has been found at high concentrations in lymphoid cells, explaining the specificity of pentostatin for lymphocytes. Early murine studies concluded that pentostatin had similar lymphodepletion and immunosuppression effects on T cells as fludarabine, and a few studies assessing pentostatin as a conditioning agent had encouraging results.^80-83 However, no studies directly comparing pentostatin to fludarabine have been performed. Both clofarabine and pentostatin are reasonable substitution choices, but we believe that clofarabine might be the better choice based on its safety profile and the available studies assessing it as a direct replacement for fludarabine in conditioning.

Lastly, fludarabine is essential for lymphodepletion in combination with cyclophosphamide, and early studies using it demonstrated improved expansion and persistence of CAR-T cells, which directly corresponds to overall response rate (ORR).⁸⁴ Additional data have suggested that suboptimal fludarabine exposure is associated with higher risk of relapse.⁸⁵ All commercially available CAR-T products recommend fludarabine plus cyclophosphamide (Flu/Cy) for lymphodepletion; however, the package insert for tisagenlecleucel lists an alternative option of bendamustine for patients with previously documented cyclophosphamide resistance or a history of hemorrhagic cystitis.⁸⁶ Other approaches that have previously been reported in this context include total body irradiation, etoposide, carboplatin/gemcitabine, and pentostatin; however, the data are limited.⁸⁷ A post hoc analysis from the JULIET study compared Flu/Cy vs bendamustine and reported that 24-month progression-free survival (PFS) was shorter in patients who received lymphodepletion with bendamustine compared to those who received Flu/Cy (14.1 vs 38.2 months).⁸⁸ Although this finding should be carefully extrapolated given that the analysis was post hoc and the comparison was not evaluated statistically, 2 retrospective studies have compared bendamustine to Flu/Cy for lymphodepletion in patients with lymphoma (one with tisagenlecleucel and one with axicabtagene ciloleucel) during the shortage, finding similar median PFS with reduced CAR-T cell–related toxicity.^89,90 In addition, bendamustine was determined to be comparable to Flu/Cy in a study of 56 patients with multiple myeloma who received either idecabtagene vicleucel or ciltacabtagene autoleucel.⁹¹ However, a couple of studies published recently have raised concerns about bendamustine potentially having inferior ORR and median PFS, warranting future studies of its potential use as a replacement.^92,93 Other purine analogs have not been well studied as potential lymphodepletion agents in CAR-T cell therapy and therefore are not recommended in this setting.

Methotrexate in acute leukemias and lymphomas

Methotrexate, an antifolate agent, entered a critical shortage in 2023 and, because of its use in a multitude of oncologic (eg, ALL, lymphomas, and osteosarcomas) and nononcologic (eg, rheumatoid arthritis) conditions, this shortage threatened to have an overarching impact on patient care. Because of the importance of methotrexate in a variety of cancers, the first step in a critical shortage would be to have comprehensive discussions to determine how to prioritize supply to maximize benefit. In ALL and lymphoma, where there is no sufficient substitute for methotrexate, many centers have focused on prioritizing supply or selecting regimens with lower methotrexate doses as a conservation measure. Pralatrexate and pemetrexed are newer antifolates, but their use in leukemias and lymphomas has been limited. Preclinical data showed potential superiority of pralatrexate to methotrexate; however, a phase 1/2 study in refractory non-Hodgkin’s lymphomas showed limited overall response in B cell lymphomas compared to T cell lymphomas, suggesting lineage-specific activity at the studied doses.^94-96 Therefore, pralatrexate is used exclusively in T cell lymphomas. Pemetrexed was studied in a phase 1 trial as monotherapy in highly refractory AML and ALL and was found to have limited antileukemic activity.⁹⁷

The methotrexate shortage proved to be particularly challenging to navigate for treatments that utilize high-dose methotrexate (HD-MTX) (≥500 mg/m²), especially in primary CNS lymphoma (PCNSL), where the standard methotrexate dose is 8 g/m².^98-103 Some studies have utilized methotrexate 3.5 g/m² because it is widely accepted that methotrexate doses of at least 3 to 3.5 g/m² are necessary to penetrate the blood-brain barrier and achieve therapeutic levels in cerebrospinal fluid.^104-109 Multiple retrospective studies have been performed to determine the optimal dosing strategy for HD-MTX in PCNSL. Wang et al¹¹⁰ demonstrated that HD-MTX doses between 3 and 5 g/m², when given in combination with rituximab, had an ORR of 81.8% and CR of 50%, which is similar to findings with higher doses of methotrexate in patients with PCNSL. In addition, Dalia et al¹¹¹ reported no significant difference in PFS or OS in patients who received 8 g/m² vs 3.5 g/m². However, one single-center study with 73 patients with ND-PCNSL receiving methotrexate 8 g/m² vs methotrexate 3.5 g/m² found improved CR (68.29% vs 43.75%, P = 0.03) and median time to progression (17.7 vs 9.05 months, P = 0.016) but no difference in OS in patients receiving the higher dose of 8 g/m².¹¹² Prospective randomized clinical trials are still needed to confirm the optimal dosage of HD-MTX for PCNSL. However, utilizing lower methotrexate doses of at least 3.5 g/m² for PCNSL induction remains a feasible option, especially in patients who may have impaired tolerance to higher doses, to help conserve methotrexate supply while still maintaining efficacy.

Platinum agents and other antineoplastic agents experiencing significant shortages

Carboplatin and cisplatin were 2 platinum agents that experienced critical shortages nationwide in 2023.⁵ Both agents are predominantly utilized in solid cancers, although they may be considered in the salvage setting for relapsed or refractory lymphoma. During a critical shortage, it would be prudent to utilize alternative salvage regimens for ICE (ifosfamide, carboplatin, and etoposide) with or without rituximab and DHAP (dexamethasone, high-dose cytarabine, and cisplatin) with or without rituximab, even though both have been shown to be very effective in this setting. Cisplatin was the initial platinum agent used in ICE and could be used for substitution if available during a carboplatin shortage.^113,114 In the event cisplatin is unavailable, oxaliplatin and carboplatin have been studied as direct replacements for cisplatin to minimize nephrotoxicity and ototoxicity, and neither showed a difference in efficacy outcomes. In fact, Tessoulin and colleagues^115-118 have compared oxaliplatin as part of R-DHAOx (rituximab, dexamethasone, high-dose cytarabine, and oxaliplatin) to R-DHAP with either cisplatin or carboplatin and showed improved 4-year PFS for R-DHAOx compared to R-DHAP (92% vs 75.9%; hazard ratio [HR], 0.37; P = 0.03) and OS (HR, 0.36; P = 0.045).

Other platinum-sparing approaches may be considered such as MINE (mesna, ifosfamide, mitoxantrone, and etoposide) with or without rituximab or use of antibody-drug conjugates such as polatuzumab in combination with bendamustine and rituximab (Pola-BR) or tafasitamab-cxixl with lenalidomide. Other emerging therapies in this space are bispecific antibody therapies, such as epcoritamab-bysp and glofitamab for patients receiving third-line and subsequent therapy.

Patients with Hodgkin’s lymphoma have been hit particularly hard by the ongoing shortage crisis over the past decades, when essential agents such as dacarbazine (DTIC), vinblastine, and bleomycin have experienced shortages. In the context of such shortages, the recommendation would be to consider alternative regimens that do not include the affected agents, such as utilizing A+AVD (brentuximab + doxorubicin, vinblastine, and DTIC) instead of ABVD (doxorubicin, bleomycin, vinblastine, and DTIC). If there is an absolute need for a substitution, oral procarbazine could be considered instead of DTIC while vinorelbine/vincristine could take the place of vinblastine (and vice versa).^119-122 These alternative regimens^123-142 are summarized in Table 1 with more detailed information on impact on response and safety.

Discussion

Critical drug shortages over the past few decades have compounded the difficulty of treating patients with hematologic malignancies, which has been further exacerbated by the shortage of medications that are used for supportive care in patients with hematologic malignancies (eg, sodium bicarbonate and leucovorin). Over the years, many papers have discussed how to increase transparency to better predict shortages and provide incentives for manufacturers to produce these agents.¹⁴⁵ NCCN has released a statement on how to mitigate the impact of chemotherapy drug shortages and called for the federal government, pharmaceutical industry, providers, and payors to be proactive in navigating these critical shortages.¹⁴⁶ There have been calls for increased oversight and regulation from the federal government to motivate pharmaceutical companies to produce necessary medications for patients with cancer that do not provide significant profit. In addition, payors should be more flexible during times of shortages to ensure alternative regimens are approved in a timely manner.¹⁴⁶ Unfortunately, this problem does not seem like it will have an answer anytime soon, and policies and procedures should be established at every major cancer institution to adjust for these drug shortages.

From the perspective of providers and institutions, there have been many suggestions on how to ethically allocate supply for patients as we navigate these critical shortages. The American Society of Clinical Oncology (ASCO) has published ethical principles and allocation strategies for institutions to consider during a shortage.¹⁴⁷ ASCO provides considerations for developing a multidisciplinary approach for inventory allocation, which includes taking into account the lives/years saved, prioritizing those with inferior alternatives, treating the youngest patients first, using a lottery, taking a first-come/first-served approach, considering instrumental value, and enacting reciprocity. However, there is an unmet need for publications addressing whether the alternatives we have used in the past were actually successful. Many smaller cancer centers would benefit from this information, as they may lack the resources and experience to make these difficult clinical decisions. ASCO has also recently published guidelines on how to navigate a drug shortage with ethical implementation strategies to preserve inventory to maximize use for patients and has recently formed an advisory committee to provide clinical guidance for clinicians seeking alternative treatments for patients with solid cancers in the event of a drug shortage.¹⁴⁸ We hope our review will provide a similar resource for clinicians searching for guidance in treatment of their patients with hematologic malignancies during a critical drug shortage.

Data availability

No new data were generated or analyzed in support of this article.

Disclosures

The authors have declared no potential conflicts of interest.

Additional information

Dr. Agrawal and Dr. Ngo contributed equally as senior authors. Dr. Tinajero and Dr. Markary contributed equally as first authors.

References