Table 1. Open in new tab Summary of...

Table 1.

Summary of Antineoplastic Agents Utilized for Hematologic Malignancies on Shortage From 2010 to 2023 With Clinical Data Behind Potential Substitution and Alternative Regimens

Drug on shortage	Hematologic malignancy affected	Year(s) on shortage	Potential substitution	Clinical data/commentary
Azacitdine (AZA)	AML, MDS	2020	DEC IV (AML/MDS) and oral (MDS) AZA oral (AML)	Both AZA and DEC recommended for AML/MDS by NCCN. DEC 20 mg/m² for 5 days (for MDS) and 5-10 days (for ND or R/R AML).⁶¹ Dosing for AZA IV and oral not considered interchangeable
Bendamustine	NHL, CLL, HL, MM	2018	NA	Bendamustine + rituximab in NHL:^127,128 BRIGHT 2014¹⁴³ (N = 447): BR vs R-CHOP or R-CVP for ND indolent NHL or MCL demonstrated noninferiority¹⁴⁴ R-CHOP considered to have more toxicity than BR
Bleomycin	HL	2017, 2023	NA	Brentuximab has been studied as a replacement for bleomycin in ND HL to minimize pulmonary toxicity.^123,124 ECHELON-1 2018 (N = 664): A+AVD had superior efficacy to ABVD in stage III or IV HL with less pulmonary toxicity but greater peripheral neuropathy and neutropenia.¹²⁹ Damaschin et al¹²⁴ BrECADD (N = 52): demonstrated 3-year PFS of 89.7% in ND HL for ages 18-60 years
Carboplatin	NHL, HL	2015, 2023	Cisplatin	ICE ± R in lymphomas as salvage therapy:^113,114 Can consider alternative salvage regimens containing platinum agent (eg, DHAP, ESHAP, GDP, etc). Historically, carboplatin replaced cisplatin in combination with ifosfamide and etoposide to minimize nephrotoxicity with similar ORR and CR rates.
Cisplatin	NHL, HL, MM	2023	NHL/HL: carboplatin, oxaliplatin	DHAP ± R in lymphomas as salvage therapy:^115-118 Can consider alternative salvage regimens containing platinum agent (eg, ICE, GemOx, etc) Tessoulin et al¹¹⁵ (N = 199): retrospective study in NHL/HL of utilizing carboplatin AUC 5 yielded similar ORR and similar ASCT rates to cisplatin. Tixier et al¹¹⁶ (N = 276): retrospective study in NHL/HL comparing safety of oxaliplatin 130 mg/m² in R-DHAOx vs RDHAP with cisplatin/carboplatin showed higher rate of G1/2 neurotoxicity (77.6%) but less nephrotoxicity/ototoxicity and BMS. Tessoulin et al¹¹⁷ (N = 298): oxaliplatin 130 mg/m² in R-DHAOx in MCL demonstrated better 4-year PFS and OS than R-DHAP with cisplatin/carboplatin with similar G3/4 toxicities.
Cytarabine (Ara-C)	AML, ALL, NHL, HL	2010, 2015, 2021	NHL/HL: gemcitabine	Ara-C in AML induction/consolidation: Consider not utilizing regimens with intermediate or high doses of Ara-C (eg, FLAG-IDA) for induction and regimens with intermediate doses of Ara-C for consolidation Liposomal daunorubicin:cytarabine can be considered for ND AML as a substitution for 7 + 3 in patients with ND AML based on results in older patients with secondary AML, although no comparison studies have been done in de novo AML. HMA + venetoclax can be considered in ND AML or R/R AML if Ara-C supply is critically low in patients with high PS.
				Ara-C in ALL and lymphomas: Consider alternative regimens that do not utilize high doses of Ara-C (eg, HyperCVAD) Preserve supply for patients undergoing ASCT with BEAM conditioning and first-line treatment for aggressive lymphomas with potential of cure
				Gemcitabine as a substitution in lymphomas:¹³ NCIC-CTG LY.12 2014 (N = 619): gemcitabine 1,000 mg/m² on days 1 and 8 was compared to Ara-C 2 g/m² every 12 hours for 2 days in R-DHAP and demonstrated noninferiority with similar remission rates and rate of HSCT.
Dacarbazine (DTIC)	HL	2021	Procarbazine	DTIC in ND HL:^119,125 Consider alternative regimens that do not include DTIC.¹²⁵ ◦ BEACOPP or Stanford V can be considered in patients aged 18-60 years. ◦ CHOP, COPP, or brentuximab ± nivolumab can be considered in patients aged >60 years or patients with significant comorbidities. Ferme et al¹¹⁹ (N = 533): procarbazine 100 mg/m² for 14 days in ABVPP for 6-8 cycles ± RT (n = 267) resulted in 10-year OS of 77% to 90% compared to MOPP/ABV for 6-8 cycles ± RT (78% to 82%).
Daunorubicin (DNR)	ALL, AML	2015	ALL: DOX (1:1) AML: IDA, MXN (1:4)	DOX/DNR in ALL:^46-49 CoALL 07-03 (N = 743): In pediatric ND ALL, responses were similar with no increased infection (19.1% vs 9.9%-15.5%, P = 0.11). CoALL 08-09 (N = 307): In pediatric DI, DOX had similar responses with higher BMS, longer neutropenia (G2: 34.9% vs 17.1%, P = 0.0005), and higher rates of mucositis (G2+: 23% vs 11%, P = 0.0003), leading to higher rates of infection (59% vs 27%, P < 0.0001). Patel et al⁴⁸ (N = 93): In adult ND ALL, DOX on CALGB 9511/10403 (n = 10) resulted in similar responses with greater incidence of mucositis and sepsis and longer recovery. Gardener et al⁴⁹ (N = 46): In pediatric ND ALL, DOX (n = 9) had higher rates of mucositis and typhlitis, leading to more missed chemotherapy (44.4% vs 10.8%, P = 0.036).
				IDA/DNR in ND AML:⁶¹ Both are category 1 recommendations for 7 + 3 in ND AML (IDA, 12 mg/m²; DNR, 60-90 mg/m²) per NCCN.
				MXN/DNR in ND AML:^51-54 Rowe et al⁵⁰ (N = 362): In adult (55+) ND AML, MXN 12 mg/m² compared to IDA 12 mg/m² or DNR 45 mg/m² resulted in no difference in efficacy or safety.
				CLAG-M and MEC have been studied in ND AML but are not recommended by NCCN.
Decitabine	AML, MDS	2023	AZA IV (AML/MDS) and oral (MDS) DEC oral (MDS)	Both AZA and DEC are recommended for AML/MDS by NCCN. AZA 75 mg/m² for 7 days for both MDS and ND AML. Dosing for DEC IV and oral not considered interchangeable⁶¹
Doxorubicin (DOXO)	ALL, NHL, HL, MM	2015	NHL: etoposide (VP-16) 50-100 mg/m² IV for 3 days for DOXO 50 mg/m² NHL/HL/MM: L-DOXO 30-40 mg/m² for DOXO 50 mg/m²	Results for R-CEOP vs R-CHOP in NHL have been mixed.^126,127 Moccia et al¹²⁶ (N = 210): R-CEOP in anthracycline-ineligible patients compared to R-CHOP in cases matched 2:1 demonstrated similar 10-year TTP and DFS (53% vs 62%, P = 0.089 and 58% vs 67%, P = 0.251), but OS was inferior with R-CEOP (30% vs 49%, P = 0.02), attributed to the frailty of the population (median age was 73 years). Puckrin et al¹²⁷ (N = 552): This retrospective study matching 1:3 for age and IPI showed that R-CEOP was inferior in terms of 4-year PFS (32% vs 52%, P < 0.0001) and disease-specific survival (48% vs 69%, P < 0.0001) to R-CHOP.
				L-DOXO in lymphomas:^128-132 R-CDOP in ND DLBCL: ◦ 33 older patients received pegylated L-DOXO 30 mg/m² with CVP with ORR of 64% and 1-year OS of 55%. G3-4 neutropenia in 64% of patients ◦ Arcari et al¹²⁹ (N = 1,163): Nonpegylated L-DOXO 50 mg/m² was similar to DOXO in older patients, with similar 3-year PFS and OS (P = 0.059) and no difference in dose interruptions (P = 0.079) even though the L-DOXO arm was older and more unfit. ◦ Fridrik et al¹³⁰ (N = 76): Nonpegylated L-DOXO showed no difference in cardiotoxicity compared to DOXO with R-CVP, although DOXO had more serious adverse events due to infection. CDOP in ND AIDS-related lymphoma: 24 patients received nonpegylated L-DOXO 40-80 mg/m² with CVP with an ORR of 88%, CR of 75%, and 1-year OS of 58%. G3/4 neutropenia in 87% of patients, with febrile neutropenia in 13% of patients. CODOX-M/IVAC in Burkitt’s lymphoma: 25 patients receiving pegylated L-DOXO 40 mg/m² instead of DOXO 50 mg/m² experienced a CR of 92% with 2-year PFS of 80% and 2-year OS of 84%. ABVD with HL: 94 older (median age, 75 years) patients or patients with concurrent cardiac disease received nonpegylated L-DOXO 25 mg/m² had CR rates in stages I-II of 100% and stages III-IV of 68% and 3-year OS in stages I-II of 70% and stages III-IV of 43%.
				L-DOXO in myeloma:¹³³ DT-PACE ± bortezomib: Pegylated L-DOXO 40 mg/m² demonstrated ORR of 75% in 12 patients with a median PFS of 18 months (range, 2-23 months) and one death due to infection (pneumonia, sepsis). The study utilized lenalidomide instead of thalidomide.
				Consider BFM-based induction regimens instead of HyperCVAD in ALL.
Liposomal doxorubicin (Doxil)	MM, cTCL	2015	NA	Consider alternative R/R regimens utilized in MM and cTCL
Etoposide (VP-16)	T-ALL, AML, B/T cell lymphomas	2017	NA	No alternative for VP-16; could consider oral substitution (1:2 IV:oral) although limited studies exist utilizing oral VP-16 in lymphomas and leukemia^134,135 Consider alternative conditioning regimens for FTBI/VP-16
Fludarabine (FLU)	AML, ALL, CLL, HSCT, CAR-T	2017, 2019	AML: CLAD, CLO HSCT conditioning: CLO CAR-T lymphodepletion: bendamustine 90 mg/m² for 2 days	CLAD/CLO as substitution for FLU in AML:^61,69-74 CLAG ± MXN or IDA and G-CLAC ± IDA are recommended by NCCN for R/R AML. ◦ Becker et al^69,70 utilized CLO in 50 patients with ND AML (aged 18-64 years) with a CR of 76% and the most common G3 toxicities were infection and pulmonary and hepatic toxicity. In a retrospective analysis in 2013 in R/R disease, CLO showed similar responses to FLU. ◦ Jabbour et al⁷¹ conducted a phase 2 trial comparing FLU to CLO in combination with IDA and Ara-C in 182 patients with ND AML, demonstrating similar responses with higher rates of transaminitis, hyperbilirubinemia, and rash. ◦ Muluneh et al⁷³ compared CLO- and CLAD-based regimens and showed similar responses and safety. ◦ CLAD has also demonstrated activity with venetoclax-based intensive regimens (eg, FLAG-IDA-VEN) in ND AML; however, doses of Ara-C utilized were lower. Retrospective comparison of CLIA-VEN and FLAG-IDA-VEN as result of shortage in R/R AML showed higher toxicity with CLAD but similar responses.
				CLO/CLAD as substitution for FLU/melphalan conditioning in HSCT:^76-79 A phase 1 study demonstrated activity of CLO instead of FLU with melphalan in high-risk leukemia/MDS. Trials comparing CLAD with FLU as part of conditioning were closed due to excessive NRM and inferiority with CLAD.
				FLU/Cy lymphodepletion for CAR-T therapy:^89-91 Bendamustine has been shown to be an effective replacement for Flu/Cy for lymphodepletion in lymphoma and myeloma. ◦ Ghilardi et al⁸⁹ (N = 132): 90 patients received bendamustine and 42 received Flu/Cy before tisagenlecleucel. Lymphocyte count was higher before CAR-T therapy, but similar response rates (50% vs 42.9%, P = 0.444) were seen with potentially lower CRS (40% vs 66.7%, P = 0.04) and ICANS (7.8% vs 21.4%, P = 0.018), fewer infections, and better recovery. ◦ Ong et al⁹⁰ (N = 69): 27 patients received bendamustine before axicabtagene ciloleucel with no difference in 6-month OS and PFS. Lower rates of ICANS of any grade with bendamustine ◦ Sidana et al⁹¹ (N = 56): 12 patients receiving bendamustine before BCMA CAR-T therapy had similar ORR and safety.
Methotrexate (MTX)	ALL, NHL	2015, 2016, 2023	NA	Consider alternative regimens that do not require high doses of MTX. Consider capping high-dose MTX doses at 3.5 g/m² because response rates have been shown to be similar to those with 8 g/m² in PCNSL^104-110
Nelarabine	T-ALL	2018	NA	Consider alternative regimens utilized in T-ALL.
Vinblastine	HL	2016, 2020, 2021, 2023	HL: vinblastine, vinorelbine	Vinblastine in HL:^120-122,125 Consider alternative regimens that do not include vinblastine¹²⁵ ◦ BEACOPP or Stanford V can be considered in patients aged 18-60 years. ◦ CHOP, COPP, or brentuximab ± nivolumab can be considered in patients aged >60 years or patients with significant comorbidities. Vincristine and vinorelbine both have been studied in HL, but no studies have utilized either as a substitution for vinblastine. Can consider vincristine 1.4 mg/m² (max 2 mg) or vinorelbine 20 mg/m² as a potential substitution if vinblastine is not available
Vincristine	ALL, NHL, HL	2018, 2019	HL: vinblastine, vinorelbine	Vincristine in ALL: Consider alternative induction regimens with less vincristine (eg, HyperCVAD)
Vincristine	ALL, NHL, HL	2018, 2019	HL: vinblastine, vinorelbine	Vincristine in lymphomas:^136-141 Consider alternatives in newly diagnosed setting: ◦ Pola-R-CHP in DLBCL: similar 2-year OS and safety profile to R-CHOP ◦ VR-CAP in NHL: similar efficacy and safety to R-CHOP in 164 patients with non-GCB DLBCL. No difference in efficacy in 487 patients with MCL, but higher rate of G3+ hematological toxicities. Demonstrated activity in 51 patients with FL ◦ R-CEPP in NHL: CEPP was published in 1990 in both ND and R/R settings before introduction of rituximab with a CR of 64% in poor-risk ND setting. ◦ Vinorelbine in DBLCL (N = 987): 199 patients received vinorelbine 30 mg as a substitution after neuropathy with vincristine. Responses were similar to those for 406 patients receiving vincristine. Consider using vinblastine-based (eg, ABVD) or brentuximab-based (eg, A+AVD) regimens for ND HL that utilize vincristine (eg, BEACOPP)¹⁴²

Drug on shortage	Hematologic malignancy affected	Year(s) on shortage	Potential substitution	Clinical data/commentary
Azacitdine (AZA)	AML, MDS	2020	DEC IV (AML/MDS) and oral (MDS) AZA oral (AML)	Both AZA and DEC recommended for AML/MDS by NCCN. DEC 20 mg/m² for 5 days (for MDS) and 5-10 days (for ND or R/R AML).⁶¹ Dosing for AZA IV and oral not considered interchangeable
Bendamustine	NHL, CLL, HL, MM	2018	NA	Bendamustine + rituximab in NHL:^127,128 BRIGHT 2014¹⁴³ (N = 447): BR vs R-CHOP or R-CVP for ND indolent NHL or MCL demonstrated noninferiority¹⁴⁴ R-CHOP considered to have more toxicity than BR
Bleomycin	HL	2017, 2023	NA	Brentuximab has been studied as a replacement for bleomycin in ND HL to minimize pulmonary toxicity.^123,124 ECHELON-1 2018 (N = 664): A+AVD had superior efficacy to ABVD in stage III or IV HL with less pulmonary toxicity but greater peripheral neuropathy and neutropenia.¹²⁹ Damaschin et al¹²⁴ BrECADD (N = 52): demonstrated 3-year PFS of 89.7% in ND HL for ages 18-60 years
Carboplatin	NHL, HL	2015, 2023	Cisplatin	ICE ± R in lymphomas as salvage therapy:^113,114 Can consider alternative salvage regimens containing platinum agent (eg, DHAP, ESHAP, GDP, etc). Historically, carboplatin replaced cisplatin in combination with ifosfamide and etoposide to minimize nephrotoxicity with similar ORR and CR rates.
Cisplatin	NHL, HL, MM	2023	NHL/HL: carboplatin, oxaliplatin	DHAP ± R in lymphomas as salvage therapy:^115-118 Can consider alternative salvage regimens containing platinum agent (eg, ICE, GemOx, etc) Tessoulin et al¹¹⁵ (N = 199): retrospective study in NHL/HL of utilizing carboplatin AUC 5 yielded similar ORR and similar ASCT rates to cisplatin. Tixier et al¹¹⁶ (N = 276): retrospective study in NHL/HL comparing safety of oxaliplatin 130 mg/m² in R-DHAOx vs RDHAP with cisplatin/carboplatin showed higher rate of G1/2 neurotoxicity (77.6%) but less nephrotoxicity/ototoxicity and BMS. Tessoulin et al¹¹⁷ (N = 298): oxaliplatin 130 mg/m² in R-DHAOx in MCL demonstrated better 4-year PFS and OS than R-DHAP with cisplatin/carboplatin with similar G3/4 toxicities.
Cytarabine (Ara-C)	AML, ALL, NHL, HL	2010, 2015, 2021	NHL/HL: gemcitabine	Ara-C in AML induction/consolidation: Consider not utilizing regimens with intermediate or high doses of Ara-C (eg, FLAG-IDA) for induction and regimens with intermediate doses of Ara-C for consolidation Liposomal daunorubicin:cytarabine can be considered for ND AML as a substitution for 7 + 3 in patients with ND AML based on results in older patients with secondary AML, although no comparison studies have been done in de novo AML. HMA + venetoclax can be considered in ND AML or R/R AML if Ara-C supply is critically low in patients with high PS.
				Ara-C in ALL and lymphomas: Consider alternative regimens that do not utilize high doses of Ara-C (eg, HyperCVAD) Preserve supply for patients undergoing ASCT with BEAM conditioning and first-line treatment for aggressive lymphomas with potential of cure
				Gemcitabine as a substitution in lymphomas:¹³ NCIC-CTG LY.12 2014 (N = 619): gemcitabine 1,000 mg/m² on days 1 and 8 was compared to Ara-C 2 g/m² every 12 hours for 2 days in R-DHAP and demonstrated noninferiority with similar remission rates and rate of HSCT.
Dacarbazine (DTIC)	HL	2021	Procarbazine	DTIC in ND HL:^119,125 Consider alternative regimens that do not include DTIC.¹²⁵ ◦ BEACOPP or Stanford V can be considered in patients aged 18-60 years. ◦ CHOP, COPP, or brentuximab ± nivolumab can be considered in patients aged >60 years or patients with significant comorbidities. Ferme et al¹¹⁹ (N = 533): procarbazine 100 mg/m² for 14 days in ABVPP for 6-8 cycles ± RT (n = 267) resulted in 10-year OS of 77% to 90% compared to MOPP/ABV for 6-8 cycles ± RT (78% to 82%).
Daunorubicin (DNR)	ALL, AML	2015	ALL: DOX (1:1) AML: IDA, MXN (1:4)	DOX/DNR in ALL:^46-49 CoALL 07-03 (N = 743): In pediatric ND ALL, responses were similar with no increased infection (19.1% vs 9.9%-15.5%, P = 0.11). CoALL 08-09 (N = 307): In pediatric DI, DOX had similar responses with higher BMS, longer neutropenia (G2: 34.9% vs 17.1%, P = 0.0005), and higher rates of mucositis (G2+: 23% vs 11%, P = 0.0003), leading to higher rates of infection (59% vs 27%, P < 0.0001). Patel et al⁴⁸ (N = 93): In adult ND ALL, DOX on CALGB 9511/10403 (n = 10) resulted in similar responses with greater incidence of mucositis and sepsis and longer recovery. Gardener et al⁴⁹ (N = 46): In pediatric ND ALL, DOX (n = 9) had higher rates of mucositis and typhlitis, leading to more missed chemotherapy (44.4% vs 10.8%, P = 0.036).
				IDA/DNR in ND AML:⁶¹ Both are category 1 recommendations for 7 + 3 in ND AML (IDA, 12 mg/m²; DNR, 60-90 mg/m²) per NCCN.
				MXN/DNR in ND AML:^51-54 Rowe et al⁵⁰ (N = 362): In adult (55+) ND AML, MXN 12 mg/m² compared to IDA 12 mg/m² or DNR 45 mg/m² resulted in no difference in efficacy or safety.
				CLAG-M and MEC have been studied in ND AML but are not recommended by NCCN.
Decitabine	AML, MDS	2023	AZA IV (AML/MDS) and oral (MDS) DEC oral (MDS)	Both AZA and DEC are recommended for AML/MDS by NCCN. AZA 75 mg/m² for 7 days for both MDS and ND AML. Dosing for DEC IV and oral not considered interchangeable⁶¹
Doxorubicin (DOXO)	ALL, NHL, HL, MM	2015	NHL: etoposide (VP-16) 50-100 mg/m² IV for 3 days for DOXO 50 mg/m² NHL/HL/MM: L-DOXO 30-40 mg/m² for DOXO 50 mg/m²	Results for R-CEOP vs R-CHOP in NHL have been mixed.^126,127 Moccia et al¹²⁶ (N = 210): R-CEOP in anthracycline-ineligible patients compared to R-CHOP in cases matched 2:1 demonstrated similar 10-year TTP and DFS (53% vs 62%, P = 0.089 and 58% vs 67%, P = 0.251), but OS was inferior with R-CEOP (30% vs 49%, P = 0.02), attributed to the frailty of the population (median age was 73 years). Puckrin et al¹²⁷ (N = 552): This retrospective study matching 1:3 for age and IPI showed that R-CEOP was inferior in terms of 4-year PFS (32% vs 52%, P < 0.0001) and disease-specific survival (48% vs 69%, P < 0.0001) to R-CHOP.
				L-DOXO in lymphomas:^128-132 R-CDOP in ND DLBCL: ◦ 33 older patients received pegylated L-DOXO 30 mg/m² with CVP with ORR of 64% and 1-year OS of 55%. G3-4 neutropenia in 64% of patients ◦ Arcari et al¹²⁹ (N = 1,163): Nonpegylated L-DOXO 50 mg/m² was similar to DOXO in older patients, with similar 3-year PFS and OS (P = 0.059) and no difference in dose interruptions (P = 0.079) even though the L-DOXO arm was older and more unfit. ◦ Fridrik et al¹³⁰ (N = 76): Nonpegylated L-DOXO showed no difference in cardiotoxicity compared to DOXO with R-CVP, although DOXO had more serious adverse events due to infection. CDOP in ND AIDS-related lymphoma: 24 patients received nonpegylated L-DOXO 40-80 mg/m² with CVP with an ORR of 88%, CR of 75%, and 1-year OS of 58%. G3/4 neutropenia in 87% of patients, with febrile neutropenia in 13% of patients. CODOX-M/IVAC in Burkitt’s lymphoma: 25 patients receiving pegylated L-DOXO 40 mg/m² instead of DOXO 50 mg/m² experienced a CR of 92% with 2-year PFS of 80% and 2-year OS of 84%. ABVD with HL: 94 older (median age, 75 years) patients or patients with concurrent cardiac disease received nonpegylated L-DOXO 25 mg/m² had CR rates in stages I-II of 100% and stages III-IV of 68% and 3-year OS in stages I-II of 70% and stages III-IV of 43%.
				L-DOXO in myeloma:¹³³ DT-PACE ± bortezomib: Pegylated L-DOXO 40 mg/m² demonstrated ORR of 75% in 12 patients with a median PFS of 18 months (range, 2-23 months) and one death due to infection (pneumonia, sepsis). The study utilized lenalidomide instead of thalidomide.
				Consider BFM-based induction regimens instead of HyperCVAD in ALL.
Liposomal doxorubicin (Doxil)	MM, cTCL	2015	NA	Consider alternative R/R regimens utilized in MM and cTCL
Etoposide (VP-16)	T-ALL, AML, B/T cell lymphomas	2017	NA	No alternative for VP-16; could consider oral substitution (1:2 IV:oral) although limited studies exist utilizing oral VP-16 in lymphomas and leukemia^134,135 Consider alternative conditioning regimens for FTBI/VP-16
Fludarabine (FLU)	AML, ALL, CLL, HSCT, CAR-T	2017, 2019	AML: CLAD, CLO HSCT conditioning: CLO CAR-T lymphodepletion: bendamustine 90 mg/m² for 2 days	CLAD/CLO as substitution for FLU in AML:^61,69-74 CLAG ± MXN or IDA and G-CLAC ± IDA are recommended by NCCN for R/R AML. ◦ Becker et al^69,70 utilized CLO in 50 patients with ND AML (aged 18-64 years) with a CR of 76% and the most common G3 toxicities were infection and pulmonary and hepatic toxicity. In a retrospective analysis in 2013 in R/R disease, CLO showed similar responses to FLU. ◦ Jabbour et al⁷¹ conducted a phase 2 trial comparing FLU to CLO in combination with IDA and Ara-C in 182 patients with ND AML, demonstrating similar responses with higher rates of transaminitis, hyperbilirubinemia, and rash. ◦ Muluneh et al⁷³ compared CLO- and CLAD-based regimens and showed similar responses and safety. ◦ CLAD has also demonstrated activity with venetoclax-based intensive regimens (eg, FLAG-IDA-VEN) in ND AML; however, doses of Ara-C utilized were lower. Retrospective comparison of CLIA-VEN and FLAG-IDA-VEN as result of shortage in R/R AML showed higher toxicity with CLAD but similar responses.
				CLO/CLAD as substitution for FLU/melphalan conditioning in HSCT:^76-79 A phase 1 study demonstrated activity of CLO instead of FLU with melphalan in high-risk leukemia/MDS. Trials comparing CLAD with FLU as part of conditioning were closed due to excessive NRM and inferiority with CLAD.
				FLU/Cy lymphodepletion for CAR-T therapy:^89-91 Bendamustine has been shown to be an effective replacement for Flu/Cy for lymphodepletion in lymphoma and myeloma. ◦ Ghilardi et al⁸⁹ (N = 132): 90 patients received bendamustine and 42 received Flu/Cy before tisagenlecleucel. Lymphocyte count was higher before CAR-T therapy, but similar response rates (50% vs 42.9%, P = 0.444) were seen with potentially lower CRS (40% vs 66.7%, P = 0.04) and ICANS (7.8% vs 21.4%, P = 0.018), fewer infections, and better recovery. ◦ Ong et al⁹⁰ (N = 69): 27 patients received bendamustine before axicabtagene ciloleucel with no difference in 6-month OS and PFS. Lower rates of ICANS of any grade with bendamustine ◦ Sidana et al⁹¹ (N = 56): 12 patients receiving bendamustine before BCMA CAR-T therapy had similar ORR and safety.
Methotrexate (MTX)	ALL, NHL	2015, 2016, 2023	NA	Consider alternative regimens that do not require high doses of MTX. Consider capping high-dose MTX doses at 3.5 g/m² because response rates have been shown to be similar to those with 8 g/m² in PCNSL^104-110
Nelarabine	T-ALL	2018	NA	Consider alternative regimens utilized in T-ALL.
Vinblastine	HL	2016, 2020, 2021, 2023	HL: vinblastine, vinorelbine	Vinblastine in HL:^120-122,125 Consider alternative regimens that do not include vinblastine¹²⁵ ◦ BEACOPP or Stanford V can be considered in patients aged 18-60 years. ◦ CHOP, COPP, or brentuximab ± nivolumab can be considered in patients aged >60 years or patients with significant comorbidities. Vincristine and vinorelbine both have been studied in HL, but no studies have utilized either as a substitution for vinblastine. Can consider vincristine 1.4 mg/m² (max 2 mg) or vinorelbine 20 mg/m² as a potential substitution if vinblastine is not available
Vincristine	ALL, NHL, HL	2018, 2019	HL: vinblastine, vinorelbine	Vincristine in ALL: Consider alternative induction regimens with less vincristine (eg, HyperCVAD)
Vincristine	ALL, NHL, HL	2018, 2019	HL: vinblastine, vinorelbine	Vincristine in lymphomas:^136-141 Consider alternatives in newly diagnosed setting: ◦ Pola-R-CHP in DLBCL: similar 2-year OS and safety profile to R-CHOP ◦ VR-CAP in NHL: similar efficacy and safety to R-CHOP in 164 patients with non-GCB DLBCL. No difference in efficacy in 487 patients with MCL, but higher rate of G3+ hematological toxicities. Demonstrated activity in 51 patients with FL ◦ R-CEPP in NHL: CEPP was published in 1990 in both ND and R/R settings before introduction of rituximab with a CR of 64% in poor-risk ND setting. ◦ Vinorelbine in DBLCL (N = 987): 199 patients received vinorelbine 30 mg as a substitution after neuropathy with vincristine. Responses were similar to those for 406 patients receiving vincristine. Consider using vinblastine-based (eg, ABVD) or brentuximab-based (eg, A+AVD) regimens for ND HL that utilize vincristine (eg, BEACOPP)¹⁴²

Abbreviations: A+AVD, brentuximab vedotin + doxorubicin, vinblastine, and dacarbazine; ABV, doxorubicin, bleomycin, and vincristine; ABVD, doxorubicin, bleomycin, vinblastine, and dacarbazine; ABVPP, doxorubicin, bleomycin, vinblastine, procarbazine, and prednisone; AIDS, acquired immunodeficiency syndrome; ALL, acute lymphoblastic leukemia; AML, acute myeloid leukemia; ASCT, autologous stem cell transplantation; BEACOPP, bleomycin, etoposide, doxorubicin, cyclophosphamide, procarbazine, and prednisone; BFM, Berlin-Frankfurt-Munich; BMS, bone marrow suppression; BR, bendamustine and rituximab; BrECADD, brentuximab vedotin, etoposide, cyclophosphamide, doxorubicin, dacarbazine, and dexamethasone; CAR-T, chimeric antigen receptor T; CLAD, cladribine; CLAG, cladribine, cytarabine, and granulocyte colony-stimulating factor; CLIA-VEN, cladribine, idarubicin, cytarabine, and venetoclax; CLL, chronic lymphocytic leukemia; CLO, clofarabine; CODOX-M/IVAC, cyclophosphamide, vincristine, doxorubicin, high-dose methotrexate/ifosfamide, etoposide, and high-dose cytarabine; COPP, cyclophosphamide, procarbazine, and prednisone; CRS, cytokine release syndrome; cTCL, cutaneous T cell lymphoma; DEC, decitabine; DHAP ± R, dexamethasone, high-dose cytarabine, and cisplatin ± rituximab; DOX, doxorubicin; DT-PACE, dexamethasone, thalidomide, cisplatin, doxorubicin, cyclophosphamide, and etoposide; ESHAP, etoposide, methylprednisolone, high-dose cytarabine, and cisplatin; FLAG-IDA-VEN, fludarabine, cytarabine, granulocyte colony-stimulating factor, idarubicin, and venetoclax; Flu/Cy, fludarabine/cyclophosphamide; FTBI/VP-16, total body irradiation/etoposide; G, grade; GCB DLBCL, germinal center B cell diffuse large B cell lymphoma; GDP, gemcitabine, dexamethasone, and cisplatin; GemOx, gemcitabine and oxaliplatin; G-CLAC, granulocyte colony-stimulating factor, clofarabine, and cytarabine; HSCT, hematopoietic stem cell transplantation; HL, Hodgkin’s lymphoma; ICANS, immune effector cell–associated neurotoxicity syndrome; ICE ± R, ifosfamide, carboplatin, and etoposide ± rituximab; IDA, idarubicin; IPI, International Prognostic Index; IV, intravenous; L-DOXO, liposomal doxorubicin; MDS, myelodysplastic syndrome; MM, multiple myeloma; MOPP, mechlorethamine, vincristine, procarbazine, and prednisone; MXN, mitoxantrone; NA, not applicable; ND, newly diagnosed; NHL, non-Hodgkin’s lymphoma; PCNSL, primary central nervous system lymphoma; Pola-R-CHP, polatuzumab, rituximab, cyclophosphamide, doxorubicin, and prednisone; R-CDOP, rituximab, cyclophosphamide, liposomal doxorubicin, and prednisone; R-CEOP, rituximab, cyclophosphamide, etoposide, and prednisone; R-CEPP, cyclophosphamide, etoposide, procarbazine, and prednisone; R-CHOP, rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone; R-CVP, rituximab, cyclophosphamide, vincristine, and prednisone; R-DHAOx, rituximab-dexamethasone, high-dose cytarabine, and oxaliplatin; R/R, relapsed or refractory; RT, radiation therapy; VR-CAP, bortezomib, cyclophosphamide, doxorubicin, and prednisone.

Table 1.

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Summary of Antineoplastic Agents Utilized for Hematologic Malignancies on Shortage From 2010 to 2023 With Clinical Data Behind Potential Substitution and Alternative Regimens

Drug on shortage	Hematologic malignancy affected	Year(s) on shortage	Potential substitution	Clinical data/commentary
Azacitdine (AZA)	AML, MDS	2020	DEC IV (AML/MDS) and oral (MDS) AZA oral (AML)	Both AZA and DEC recommended for AML/MDS by NCCN. DEC 20 mg/m² for 5 days (for MDS) and 5-10 days (for ND or R/R AML).⁶¹ Dosing for AZA IV and oral not considered interchangeable
Bendamustine	NHL, CLL, HL, MM	2018	NA	Bendamustine + rituximab in NHL:^127,128 BRIGHT 2014¹⁴³ (N = 447): BR vs R-CHOP or R-CVP for ND indolent NHL or MCL demonstrated noninferiority¹⁴⁴ R-CHOP considered to have more toxicity than BR
Bleomycin	HL	2017, 2023	NA	Brentuximab has been studied as a replacement for bleomycin in ND HL to minimize pulmonary toxicity.^123,124 ECHELON-1 2018 (N = 664): A+AVD had superior efficacy to ABVD in stage III or IV HL with less pulmonary toxicity but greater peripheral neuropathy and neutropenia.¹²⁹ Damaschin et al¹²⁴ BrECADD (N = 52): demonstrated 3-year PFS of 89.7% in ND HL for ages 18-60 years
Carboplatin	NHL, HL	2015, 2023	Cisplatin	ICE ± R in lymphomas as salvage therapy:^113,114 Can consider alternative salvage regimens containing platinum agent (eg, DHAP, ESHAP, GDP, etc). Historically, carboplatin replaced cisplatin in combination with ifosfamide and etoposide to minimize nephrotoxicity with similar ORR and CR rates.
Cisplatin	NHL, HL, MM	2023	NHL/HL: carboplatin, oxaliplatin	DHAP ± R in lymphomas as salvage therapy:^115-118 Can consider alternative salvage regimens containing platinum agent (eg, ICE, GemOx, etc) Tessoulin et al¹¹⁵ (N = 199): retrospective study in NHL/HL of utilizing carboplatin AUC 5 yielded similar ORR and similar ASCT rates to cisplatin. Tixier et al¹¹⁶ (N = 276): retrospective study in NHL/HL comparing safety of oxaliplatin 130 mg/m² in R-DHAOx vs RDHAP with cisplatin/carboplatin showed higher rate of G1/2 neurotoxicity (77.6%) but less nephrotoxicity/ototoxicity and BMS. Tessoulin et al¹¹⁷ (N = 298): oxaliplatin 130 mg/m² in R-DHAOx in MCL demonstrated better 4-year PFS and OS than R-DHAP with cisplatin/carboplatin with similar G3/4 toxicities.
Cytarabine (Ara-C)	AML, ALL, NHL, HL	2010, 2015, 2021	NHL/HL: gemcitabine	Ara-C in AML induction/consolidation: Consider not utilizing regimens with intermediate or high doses of Ara-C (eg, FLAG-IDA) for induction and regimens with intermediate doses of Ara-C for consolidation Liposomal daunorubicin:cytarabine can be considered for ND AML as a substitution for 7 + 3 in patients with ND AML based on results in older patients with secondary AML, although no comparison studies have been done in de novo AML. HMA + venetoclax can be considered in ND AML or R/R AML if Ara-C supply is critically low in patients with high PS.
				Ara-C in ALL and lymphomas: Consider alternative regimens that do not utilize high doses of Ara-C (eg, HyperCVAD) Preserve supply for patients undergoing ASCT with BEAM conditioning and first-line treatment for aggressive lymphomas with potential of cure
				Gemcitabine as a substitution in lymphomas:¹³ NCIC-CTG LY.12 2014 (N = 619): gemcitabine 1,000 mg/m² on days 1 and 8 was compared to Ara-C 2 g/m² every 12 hours for 2 days in R-DHAP and demonstrated noninferiority with similar remission rates and rate of HSCT.
Dacarbazine (DTIC)	HL	2021	Procarbazine	DTIC in ND HL:^119,125 Consider alternative regimens that do not include DTIC.¹²⁵ ◦ BEACOPP or Stanford V can be considered in patients aged 18-60 years. ◦ CHOP, COPP, or brentuximab ± nivolumab can be considered in patients aged >60 years or patients with significant comorbidities. Ferme et al¹¹⁹ (N = 533): procarbazine 100 mg/m² for 14 days in ABVPP for 6-8 cycles ± RT (n = 267) resulted in 10-year OS of 77% to 90% compared to MOPP/ABV for 6-8 cycles ± RT (78% to 82%).
Daunorubicin (DNR)	ALL, AML	2015	ALL: DOX (1:1) AML: IDA, MXN (1:4)	DOX/DNR in ALL:^46-49 CoALL 07-03 (N = 743): In pediatric ND ALL, responses were similar with no increased infection (19.1% vs 9.9%-15.5%, P = 0.11). CoALL 08-09 (N = 307): In pediatric DI, DOX had similar responses with higher BMS, longer neutropenia (G2: 34.9% vs 17.1%, P = 0.0005), and higher rates of mucositis (G2+: 23% vs 11%, P = 0.0003), leading to higher rates of infection (59% vs 27%, P < 0.0001). Patel et al⁴⁸ (N = 93): In adult ND ALL, DOX on CALGB 9511/10403 (n = 10) resulted in similar responses with greater incidence of mucositis and sepsis and longer recovery. Gardener et al⁴⁹ (N = 46): In pediatric ND ALL, DOX (n = 9) had higher rates of mucositis and typhlitis, leading to more missed chemotherapy (44.4% vs 10.8%, P = 0.036).
				IDA/DNR in ND AML:⁶¹ Both are category 1 recommendations for 7 + 3 in ND AML (IDA, 12 mg/m²; DNR, 60-90 mg/m²) per NCCN.
				MXN/DNR in ND AML:^51-54 Rowe et al⁵⁰ (N = 362): In adult (55+) ND AML, MXN 12 mg/m² compared to IDA 12 mg/m² or DNR 45 mg/m² resulted in no difference in efficacy or safety.
				CLAG-M and MEC have been studied in ND AML but are not recommended by NCCN.
Decitabine	AML, MDS	2023	AZA IV (AML/MDS) and oral (MDS) DEC oral (MDS)	Both AZA and DEC are recommended for AML/MDS by NCCN. AZA 75 mg/m² for 7 days for both MDS and ND AML. Dosing for DEC IV and oral not considered interchangeable⁶¹
Doxorubicin (DOXO)	ALL, NHL, HL, MM	2015	NHL: etoposide (VP-16) 50-100 mg/m² IV for 3 days for DOXO 50 mg/m² NHL/HL/MM: L-DOXO 30-40 mg/m² for DOXO 50 mg/m²	Results for R-CEOP vs R-CHOP in NHL have been mixed.^126,127 Moccia et al¹²⁶ (N = 210): R-CEOP in anthracycline-ineligible patients compared to R-CHOP in cases matched 2:1 demonstrated similar 10-year TTP and DFS (53% vs 62%, P = 0.089 and 58% vs 67%, P = 0.251), but OS was inferior with R-CEOP (30% vs 49%, P = 0.02), attributed to the frailty of the population (median age was 73 years). Puckrin et al¹²⁷ (N = 552): This retrospective study matching 1:3 for age and IPI showed that R-CEOP was inferior in terms of 4-year PFS (32% vs 52%, P < 0.0001) and disease-specific survival (48% vs 69%, P < 0.0001) to R-CHOP.
				L-DOXO in lymphomas:^128-132 R-CDOP in ND DLBCL: ◦ 33 older patients received pegylated L-DOXO 30 mg/m² with CVP with ORR of 64% and 1-year OS of 55%. G3-4 neutropenia in 64% of patients ◦ Arcari et al¹²⁹ (N = 1,163): Nonpegylated L-DOXO 50 mg/m² was similar to DOXO in older patients, with similar 3-year PFS and OS (P = 0.059) and no difference in dose interruptions (P = 0.079) even though the L-DOXO arm was older and more unfit. ◦ Fridrik et al¹³⁰ (N = 76): Nonpegylated L-DOXO showed no difference in cardiotoxicity compared to DOXO with R-CVP, although DOXO had more serious adverse events due to infection. CDOP in ND AIDS-related lymphoma: 24 patients received nonpegylated L-DOXO 40-80 mg/m² with CVP with an ORR of 88%, CR of 75%, and 1-year OS of 58%. G3/4 neutropenia in 87% of patients, with febrile neutropenia in 13% of patients. CODOX-M/IVAC in Burkitt’s lymphoma: 25 patients receiving pegylated L-DOXO 40 mg/m² instead of DOXO 50 mg/m² experienced a CR of 92% with 2-year PFS of 80% and 2-year OS of 84%. ABVD with HL: 94 older (median age, 75 years) patients or patients with concurrent cardiac disease received nonpegylated L-DOXO 25 mg/m² had CR rates in stages I-II of 100% and stages III-IV of 68% and 3-year OS in stages I-II of 70% and stages III-IV of 43%.
				L-DOXO in myeloma:¹³³ DT-PACE ± bortezomib: Pegylated L-DOXO 40 mg/m² demonstrated ORR of 75% in 12 patients with a median PFS of 18 months (range, 2-23 months) and one death due to infection (pneumonia, sepsis). The study utilized lenalidomide instead of thalidomide.
				Consider BFM-based induction regimens instead of HyperCVAD in ALL.
Liposomal doxorubicin (Doxil)	MM, cTCL	2015	NA	Consider alternative R/R regimens utilized in MM and cTCL
Etoposide (VP-16)	T-ALL, AML, B/T cell lymphomas	2017	NA	No alternative for VP-16; could consider oral substitution (1:2 IV:oral) although limited studies exist utilizing oral VP-16 in lymphomas and leukemia^134,135 Consider alternative conditioning regimens for FTBI/VP-16
Fludarabine (FLU)	AML, ALL, CLL, HSCT, CAR-T	2017, 2019	AML: CLAD, CLO HSCT conditioning: CLO CAR-T lymphodepletion: bendamustine 90 mg/m² for 2 days	CLAD/CLO as substitution for FLU in AML:^61,69-74 CLAG ± MXN or IDA and G-CLAC ± IDA are recommended by NCCN for R/R AML. ◦ Becker et al^69,70 utilized CLO in 50 patients with ND AML (aged 18-64 years) with a CR of 76% and the most common G3 toxicities were infection and pulmonary and hepatic toxicity. In a retrospective analysis in 2013 in R/R disease, CLO showed similar responses to FLU. ◦ Jabbour et al⁷¹ conducted a phase 2 trial comparing FLU to CLO in combination with IDA and Ara-C in 182 patients with ND AML, demonstrating similar responses with higher rates of transaminitis, hyperbilirubinemia, and rash. ◦ Muluneh et al⁷³ compared CLO- and CLAD-based regimens and showed similar responses and safety. ◦ CLAD has also demonstrated activity with venetoclax-based intensive regimens (eg, FLAG-IDA-VEN) in ND AML; however, doses of Ara-C utilized were lower. Retrospective comparison of CLIA-VEN and FLAG-IDA-VEN as result of shortage in R/R AML showed higher toxicity with CLAD but similar responses.
				CLO/CLAD as substitution for FLU/melphalan conditioning in HSCT:^76-79 A phase 1 study demonstrated activity of CLO instead of FLU with melphalan in high-risk leukemia/MDS. Trials comparing CLAD with FLU as part of conditioning were closed due to excessive NRM and inferiority with CLAD.
				FLU/Cy lymphodepletion for CAR-T therapy:^89-91 Bendamustine has been shown to be an effective replacement for Flu/Cy for lymphodepletion in lymphoma and myeloma. ◦ Ghilardi et al⁸⁹ (N = 132): 90 patients received bendamustine and 42 received Flu/Cy before tisagenlecleucel. Lymphocyte count was higher before CAR-T therapy, but similar response rates (50% vs 42.9%, P = 0.444) were seen with potentially lower CRS (40% vs 66.7%, P = 0.04) and ICANS (7.8% vs 21.4%, P = 0.018), fewer infections, and better recovery. ◦ Ong et al⁹⁰ (N = 69): 27 patients received bendamustine before axicabtagene ciloleucel with no difference in 6-month OS and PFS. Lower rates of ICANS of any grade with bendamustine ◦ Sidana et al⁹¹ (N = 56): 12 patients receiving bendamustine before BCMA CAR-T therapy had similar ORR and safety.
Methotrexate (MTX)	ALL, NHL	2015, 2016, 2023	NA	Consider alternative regimens that do not require high doses of MTX. Consider capping high-dose MTX doses at 3.5 g/m² because response rates have been shown to be similar to those with 8 g/m² in PCNSL^104-110
Nelarabine	T-ALL	2018	NA	Consider alternative regimens utilized in T-ALL.
Vinblastine	HL	2016, 2020, 2021, 2023	HL: vinblastine, vinorelbine	Vinblastine in HL:^120-122,125 Consider alternative regimens that do not include vinblastine¹²⁵ ◦ BEACOPP or Stanford V can be considered in patients aged 18-60 years. ◦ CHOP, COPP, or brentuximab ± nivolumab can be considered in patients aged >60 years or patients with significant comorbidities. Vincristine and vinorelbine both have been studied in HL, but no studies have utilized either as a substitution for vinblastine. Can consider vincristine 1.4 mg/m² (max 2 mg) or vinorelbine 20 mg/m² as a potential substitution if vinblastine is not available
Vincristine	ALL, NHL, HL	2018, 2019	HL: vinblastine, vinorelbine	Vincristine in ALL: Consider alternative induction regimens with less vincristine (eg, HyperCVAD)
Vincristine	ALL, NHL, HL	2018, 2019	HL: vinblastine, vinorelbine	Vincristine in lymphomas:^136-141 Consider alternatives in newly diagnosed setting: ◦ Pola-R-CHP in DLBCL: similar 2-year OS and safety profile to R-CHOP ◦ VR-CAP in NHL: similar efficacy and safety to R-CHOP in 164 patients with non-GCB DLBCL. No difference in efficacy in 487 patients with MCL, but higher rate of G3+ hematological toxicities. Demonstrated activity in 51 patients with FL ◦ R-CEPP in NHL: CEPP was published in 1990 in both ND and R/R settings before introduction of rituximab with a CR of 64% in poor-risk ND setting. ◦ Vinorelbine in DBLCL (N = 987): 199 patients received vinorelbine 30 mg as a substitution after neuropathy with vincristine. Responses were similar to those for 406 patients receiving vincristine. Consider using vinblastine-based (eg, ABVD) or brentuximab-based (eg, A+AVD) regimens for ND HL that utilize vincristine (eg, BEACOPP)¹⁴²

Drug on shortage	Hematologic malignancy affected	Year(s) on shortage	Potential substitution	Clinical data/commentary
Azacitdine (AZA)	AML, MDS	2020	DEC IV (AML/MDS) and oral (MDS) AZA oral (AML)	Both AZA and DEC recommended for AML/MDS by NCCN. DEC 20 mg/m² for 5 days (for MDS) and 5-10 days (for ND or R/R AML).⁶¹ Dosing for AZA IV and oral not considered interchangeable
Bendamustine	NHL, CLL, HL, MM	2018	NA	Bendamustine + rituximab in NHL:^127,128 BRIGHT 2014¹⁴³ (N = 447): BR vs R-CHOP or R-CVP for ND indolent NHL or MCL demonstrated noninferiority¹⁴⁴ R-CHOP considered to have more toxicity than BR
Bleomycin	HL	2017, 2023	NA	Brentuximab has been studied as a replacement for bleomycin in ND HL to minimize pulmonary toxicity.^123,124 ECHELON-1 2018 (N = 664): A+AVD had superior efficacy to ABVD in stage III or IV HL with less pulmonary toxicity but greater peripheral neuropathy and neutropenia.¹²⁹ Damaschin et al¹²⁴ BrECADD (N = 52): demonstrated 3-year PFS of 89.7% in ND HL for ages 18-60 years
Carboplatin	NHL, HL	2015, 2023	Cisplatin	ICE ± R in lymphomas as salvage therapy:^113,114 Can consider alternative salvage regimens containing platinum agent (eg, DHAP, ESHAP, GDP, etc). Historically, carboplatin replaced cisplatin in combination with ifosfamide and etoposide to minimize nephrotoxicity with similar ORR and CR rates.
Cisplatin	NHL, HL, MM	2023	NHL/HL: carboplatin, oxaliplatin	DHAP ± R in lymphomas as salvage therapy:^115-118 Can consider alternative salvage regimens containing platinum agent (eg, ICE, GemOx, etc) Tessoulin et al¹¹⁵ (N = 199): retrospective study in NHL/HL of utilizing carboplatin AUC 5 yielded similar ORR and similar ASCT rates to cisplatin. Tixier et al¹¹⁶ (N = 276): retrospective study in NHL/HL comparing safety of oxaliplatin 130 mg/m² in R-DHAOx vs RDHAP with cisplatin/carboplatin showed higher rate of G1/2 neurotoxicity (77.6%) but less nephrotoxicity/ototoxicity and BMS. Tessoulin et al¹¹⁷ (N = 298): oxaliplatin 130 mg/m² in R-DHAOx in MCL demonstrated better 4-year PFS and OS than R-DHAP with cisplatin/carboplatin with similar G3/4 toxicities.
Cytarabine (Ara-C)	AML, ALL, NHL, HL	2010, 2015, 2021	NHL/HL: gemcitabine	Ara-C in AML induction/consolidation: Consider not utilizing regimens with intermediate or high doses of Ara-C (eg, FLAG-IDA) for induction and regimens with intermediate doses of Ara-C for consolidation Liposomal daunorubicin:cytarabine can be considered for ND AML as a substitution for 7 + 3 in patients with ND AML based on results in older patients with secondary AML, although no comparison studies have been done in de novo AML. HMA + venetoclax can be considered in ND AML or R/R AML if Ara-C supply is critically low in patients with high PS.
				Ara-C in ALL and lymphomas: Consider alternative regimens that do not utilize high doses of Ara-C (eg, HyperCVAD) Preserve supply for patients undergoing ASCT with BEAM conditioning and first-line treatment for aggressive lymphomas with potential of cure
				Gemcitabine as a substitution in lymphomas:¹³ NCIC-CTG LY.12 2014 (N = 619): gemcitabine 1,000 mg/m² on days 1 and 8 was compared to Ara-C 2 g/m² every 12 hours for 2 days in R-DHAP and demonstrated noninferiority with similar remission rates and rate of HSCT.
Dacarbazine (DTIC)	HL	2021	Procarbazine	DTIC in ND HL:^119,125 Consider alternative regimens that do not include DTIC.¹²⁵ ◦ BEACOPP or Stanford V can be considered in patients aged 18-60 years. ◦ CHOP, COPP, or brentuximab ± nivolumab can be considered in patients aged >60 years or patients with significant comorbidities. Ferme et al¹¹⁹ (N = 533): procarbazine 100 mg/m² for 14 days in ABVPP for 6-8 cycles ± RT (n = 267) resulted in 10-year OS of 77% to 90% compared to MOPP/ABV for 6-8 cycles ± RT (78% to 82%).
Daunorubicin (DNR)	ALL, AML	2015	ALL: DOX (1:1) AML: IDA, MXN (1:4)	DOX/DNR in ALL:^46-49 CoALL 07-03 (N = 743): In pediatric ND ALL, responses were similar with no increased infection (19.1% vs 9.9%-15.5%, P = 0.11). CoALL 08-09 (N = 307): In pediatric DI, DOX had similar responses with higher BMS, longer neutropenia (G2: 34.9% vs 17.1%, P = 0.0005), and higher rates of mucositis (G2+: 23% vs 11%, P = 0.0003), leading to higher rates of infection (59% vs 27%, P < 0.0001). Patel et al⁴⁸ (N = 93): In adult ND ALL, DOX on CALGB 9511/10403 (n = 10) resulted in similar responses with greater incidence of mucositis and sepsis and longer recovery. Gardener et al⁴⁹ (N = 46): In pediatric ND ALL, DOX (n = 9) had higher rates of mucositis and typhlitis, leading to more missed chemotherapy (44.4% vs 10.8%, P = 0.036).
				IDA/DNR in ND AML:⁶¹ Both are category 1 recommendations for 7 + 3 in ND AML (IDA, 12 mg/m²; DNR, 60-90 mg/m²) per NCCN.
				MXN/DNR in ND AML:^51-54 Rowe et al⁵⁰ (N = 362): In adult (55+) ND AML, MXN 12 mg/m² compared to IDA 12 mg/m² or DNR 45 mg/m² resulted in no difference in efficacy or safety.
				CLAG-M and MEC have been studied in ND AML but are not recommended by NCCN.
Decitabine	AML, MDS	2023	AZA IV (AML/MDS) and oral (MDS) DEC oral (MDS)	Both AZA and DEC are recommended for AML/MDS by NCCN. AZA 75 mg/m² for 7 days for both MDS and ND AML. Dosing for DEC IV and oral not considered interchangeable⁶¹
Doxorubicin (DOXO)	ALL, NHL, HL, MM	2015	NHL: etoposide (VP-16) 50-100 mg/m² IV for 3 days for DOXO 50 mg/m² NHL/HL/MM: L-DOXO 30-40 mg/m² for DOXO 50 mg/m²	Results for R-CEOP vs R-CHOP in NHL have been mixed.^126,127 Moccia et al¹²⁶ (N = 210): R-CEOP in anthracycline-ineligible patients compared to R-CHOP in cases matched 2:1 demonstrated similar 10-year TTP and DFS (53% vs 62%, P = 0.089 and 58% vs 67%, P = 0.251), but OS was inferior with R-CEOP (30% vs 49%, P = 0.02), attributed to the frailty of the population (median age was 73 years). Puckrin et al¹²⁷ (N = 552): This retrospective study matching 1:3 for age and IPI showed that R-CEOP was inferior in terms of 4-year PFS (32% vs 52%, P < 0.0001) and disease-specific survival (48% vs 69%, P < 0.0001) to R-CHOP.
				L-DOXO in lymphomas:^128-132 R-CDOP in ND DLBCL: ◦ 33 older patients received pegylated L-DOXO 30 mg/m² with CVP with ORR of 64% and 1-year OS of 55%. G3-4 neutropenia in 64% of patients ◦ Arcari et al¹²⁹ (N = 1,163): Nonpegylated L-DOXO 50 mg/m² was similar to DOXO in older patients, with similar 3-year PFS and OS (P = 0.059) and no difference in dose interruptions (P = 0.079) even though the L-DOXO arm was older and more unfit. ◦ Fridrik et al¹³⁰ (N = 76): Nonpegylated L-DOXO showed no difference in cardiotoxicity compared to DOXO with R-CVP, although DOXO had more serious adverse events due to infection. CDOP in ND AIDS-related lymphoma: 24 patients received nonpegylated L-DOXO 40-80 mg/m² with CVP with an ORR of 88%, CR of 75%, and 1-year OS of 58%. G3/4 neutropenia in 87% of patients, with febrile neutropenia in 13% of patients. CODOX-M/IVAC in Burkitt’s lymphoma: 25 patients receiving pegylated L-DOXO 40 mg/m² instead of DOXO 50 mg/m² experienced a CR of 92% with 2-year PFS of 80% and 2-year OS of 84%. ABVD with HL: 94 older (median age, 75 years) patients or patients with concurrent cardiac disease received nonpegylated L-DOXO 25 mg/m² had CR rates in stages I-II of 100% and stages III-IV of 68% and 3-year OS in stages I-II of 70% and stages III-IV of 43%.
				L-DOXO in myeloma:¹³³ DT-PACE ± bortezomib: Pegylated L-DOXO 40 mg/m² demonstrated ORR of 75% in 12 patients with a median PFS of 18 months (range, 2-23 months) and one death due to infection (pneumonia, sepsis). The study utilized lenalidomide instead of thalidomide.
				Consider BFM-based induction regimens instead of HyperCVAD in ALL.
Liposomal doxorubicin (Doxil)	MM, cTCL	2015	NA	Consider alternative R/R regimens utilized in MM and cTCL
Etoposide (VP-16)	T-ALL, AML, B/T cell lymphomas	2017	NA	No alternative for VP-16; could consider oral substitution (1:2 IV:oral) although limited studies exist utilizing oral VP-16 in lymphomas and leukemia^134,135 Consider alternative conditioning regimens for FTBI/VP-16
Fludarabine (FLU)	AML, ALL, CLL, HSCT, CAR-T	2017, 2019	AML: CLAD, CLO HSCT conditioning: CLO CAR-T lymphodepletion: bendamustine 90 mg/m² for 2 days	CLAD/CLO as substitution for FLU in AML:^61,69-74 CLAG ± MXN or IDA and G-CLAC ± IDA are recommended by NCCN for R/R AML. ◦ Becker et al^69,70 utilized CLO in 50 patients with ND AML (aged 18-64 years) with a CR of 76% and the most common G3 toxicities were infection and pulmonary and hepatic toxicity. In a retrospective analysis in 2013 in R/R disease, CLO showed similar responses to FLU. ◦ Jabbour et al⁷¹ conducted a phase 2 trial comparing FLU to CLO in combination with IDA and Ara-C in 182 patients with ND AML, demonstrating similar responses with higher rates of transaminitis, hyperbilirubinemia, and rash. ◦ Muluneh et al⁷³ compared CLO- and CLAD-based regimens and showed similar responses and safety. ◦ CLAD has also demonstrated activity with venetoclax-based intensive regimens (eg, FLAG-IDA-VEN) in ND AML; however, doses of Ara-C utilized were lower. Retrospective comparison of CLIA-VEN and FLAG-IDA-VEN as result of shortage in R/R AML showed higher toxicity with CLAD but similar responses.
				CLO/CLAD as substitution for FLU/melphalan conditioning in HSCT:^76-79 A phase 1 study demonstrated activity of CLO instead of FLU with melphalan in high-risk leukemia/MDS. Trials comparing CLAD with FLU as part of conditioning were closed due to excessive NRM and inferiority with CLAD.
				FLU/Cy lymphodepletion for CAR-T therapy:^89-91 Bendamustine has been shown to be an effective replacement for Flu/Cy for lymphodepletion in lymphoma and myeloma. ◦ Ghilardi et al⁸⁹ (N = 132): 90 patients received bendamustine and 42 received Flu/Cy before tisagenlecleucel. Lymphocyte count was higher before CAR-T therapy, but similar response rates (50% vs 42.9%, P = 0.444) were seen with potentially lower CRS (40% vs 66.7%, P = 0.04) and ICANS (7.8% vs 21.4%, P = 0.018), fewer infections, and better recovery. ◦ Ong et al⁹⁰ (N = 69): 27 patients received bendamustine before axicabtagene ciloleucel with no difference in 6-month OS and PFS. Lower rates of ICANS of any grade with bendamustine ◦ Sidana et al⁹¹ (N = 56): 12 patients receiving bendamustine before BCMA CAR-T therapy had similar ORR and safety.
Methotrexate (MTX)	ALL, NHL	2015, 2016, 2023	NA	Consider alternative regimens that do not require high doses of MTX. Consider capping high-dose MTX doses at 3.5 g/m² because response rates have been shown to be similar to those with 8 g/m² in PCNSL^104-110
Nelarabine	T-ALL	2018	NA	Consider alternative regimens utilized in T-ALL.
Vinblastine	HL	2016, 2020, 2021, 2023	HL: vinblastine, vinorelbine	Vinblastine in HL:^120-122,125 Consider alternative regimens that do not include vinblastine¹²⁵ ◦ BEACOPP or Stanford V can be considered in patients aged 18-60 years. ◦ CHOP, COPP, or brentuximab ± nivolumab can be considered in patients aged >60 years or patients with significant comorbidities. Vincristine and vinorelbine both have been studied in HL, but no studies have utilized either as a substitution for vinblastine. Can consider vincristine 1.4 mg/m² (max 2 mg) or vinorelbine 20 mg/m² as a potential substitution if vinblastine is not available
Vincristine	ALL, NHL, HL	2018, 2019	HL: vinblastine, vinorelbine	Vincristine in ALL: Consider alternative induction regimens with less vincristine (eg, HyperCVAD)
Vincristine	ALL, NHL, HL	2018, 2019	HL: vinblastine, vinorelbine	Vincristine in lymphomas:^136-141 Consider alternatives in newly diagnosed setting: ◦ Pola-R-CHP in DLBCL: similar 2-year OS and safety profile to R-CHOP ◦ VR-CAP in NHL: similar efficacy and safety to R-CHOP in 164 patients with non-GCB DLBCL. No difference in efficacy in 487 patients with MCL, but higher rate of G3+ hematological toxicities. Demonstrated activity in 51 patients with FL ◦ R-CEPP in NHL: CEPP was published in 1990 in both ND and R/R settings before introduction of rituximab with a CR of 64% in poor-risk ND setting. ◦ Vinorelbine in DBLCL (N = 987): 199 patients received vinorelbine 30 mg as a substitution after neuropathy with vincristine. Responses were similar to those for 406 patients receiving vincristine. Consider using vinblastine-based (eg, ABVD) or brentuximab-based (eg, A+AVD) regimens for ND HL that utilize vincristine (eg, BEACOPP)¹⁴²

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