Cyclophosphamide

證據等級: L5

預測適應症: 10 個

Cyclophosphamide: From Lymphoma and Autoimmune Disease to Myeloid Leukemia

One-Sentence Summary

Cyclophosphamide is a classic broad-spectrum alkylating cytotoxic agent, historically established in the treatment of non-Hodgkin's lymphoma, breast cancer, and autoimmune diseases such as lupus nephritis, but currently carrying no Singapore HSA registration. The TxGNN model predicts it may be effective for Myeloid Leukemia with a confidence score of 99.47%, supported by multiple Phase 2–3 clinical trials (including 3 directly high-relevance studies) and 20 publications — notably, Cyclophosphamide already serves as the backbone of the standard BuCy myeloablative conditioning regimen and post-transplant GVHD prophylaxis (PTCy) in AML/MDS transplantation.

Quick Overview

Item	Content
Original Indication	Lymphoma, breast cancer, autoimmune diseases (global use; not registered in Singapore)
Predicted New Indication	Myeloid Leukemia
TxGNN Prediction Score	99.47%
Evidence Level	L1
Singapore Market Status	Not Marketed
Number of Registrations	0
Recommended Decision	Proceed with Guardrails

Why is This Prediction Reasonable?

Detailed mechanism of action data was not retrieved in this evidence pack. Based on established pharmacology, Cyclophosphamide is a prodrug bioactivated in the liver by cytochrome P450 enzymes into phosphoramide mustard — a potent DNA alkylating agent that forms covalent cross-links between DNA strands, halting cell replication. This mechanism is particularly cytotoxic to rapidly dividing cells, including the malignant myeloblasts that characterise acute myeloid leukaemia (AML).

Cyclophosphamide's role in myeloid malignancies extends across two well-established clinical contexts. In myeloablative conditioning prior to allogeneic haematopoietic stem cell transplantation (allo-HSCT), the BuCy regimen (Busulfan + Cyclophosphamide) has been a gold standard for decades, destroying residual leukaemic clones and providing sufficient immunosuppression for donor stem cell engraftment. More recently, post-transplant cyclophosphamide (PTCy — administered on days +3 and +4 after transplant) has become a standard strategy for graft-versus-host disease (GVHD) prophylaxis in haploidentical transplantation for AML and MDS, selectively eliminating alloreactive T cells while preserving the graft-versus-leukaemia effect.

The TxGNN high prediction score (99.47%) reflects the deep mechanistic, preclinical, and clinical evidence base connecting Cyclophosphamide to myeloid malignancies. Both its traditional cytoreductive role in induction/consolidation and its modern immune-modulatory applications in HSCT are extensively documented, making this one of the most strongly supported predictions in this evidence pack.

Clinical Trial Evidence

Trial Number	Phase	Status	Enrollment	Key Findings
NCT00002549	Phase 3	Unknown	1,520	Landmark AML induction Phase 3 trial comparing regimens including MICE (Cyclophosphamide as core component) followed by intensive consolidation and bone marrow transplantation; one of the largest direct AML studies
NCT05823714	Phase 2	Unknown	70	Prospective study of Venetoclax + Azacitidine followed by modified BUCY (Busulfan-Cyclophosphamide) as conditioning for high-risk MDS and R/R AML undergoing allo-HSCT
NCT05126849	Phase 2	Recruiting	31	Nationwide Phase 2 study of haploidentical allo-HSCT with post-transplant Cyclophosphamide (PTCy) for refractory aplastic anaemia and haematologic malignancies including AML
NCT06786533	Phase 1	Recruiting	18	Anti-FLT3 CAR-T cell therapy for R/R AML; Cyclophosphamide used as lymphodepletion conditioning prior to CAR-T infusion, supporting its role in modern cell therapy platforms
NCT00005892	N/A	Completed	N/A	Moderate-dose Cyclophosphamide + radiotherapy as conditioning for allogeneic BMT in MDS and acute leukaemia related to Fanconi's anaemia; establishes Cy's efficacy in myeloid disease transplantation
NCT02208037	Phase 2	Completed	279	Multi-centre Phase 2 trial (BMT CTN #1203) randomising novel GVHD prevention approaches including PTCy vs standard prophylaxis in allo-HSCT for AML/MDS patients
NCT04678401	Phase 1	Recruiting	30	Immunosuppression-free Treg-graft-engineered haploidentical HCT for R/R and ultra-high-risk AML/MDS; Cyclophosphamide included in the conditioning component
NCT03300492	Phase 1/2	Recruiting	10	Pre-emptive NK cell immunotherapy after haplo-HSCT with PTCy for AML/MDS; evaluates PTCy as GVHD prophylaxis backbone alongside adoptive immunotherapy
NCT02799147	Phase 1/2	Completed	27	Dose-escalation study comparing high-dose post-transplant bendamustine vs PTCy for GVHD prophylaxis in haploidentical SCT for refractory acute leukaemia
NCT00002502	Phase 2	Completed	N/A	Landmark Phase 2 study establishing Busulfan-Cyclophosphamide (BuCy) myeloablative conditioning for allogeneic BMT in patients with acute/chronic leukaemia and MDS unable to tolerate total body irradiation

Literature Evidence

PMID	Year	Type	Journal	Key Findings
40434956	2025	Comparative Study	Future Oncology	Head-to-head comparison of BuCy vs FluBu myeloablative conditioning for AML allo-HSCT; BuCy remains a standard-of-care reference regimen with comparable efficacy
38499049	2024	Clinical Trial	Transplant Immunology	Cladribine + Busulfan + Cyclophosphamide (ClaBuCy) as intensive conditioning for R/R AML prior to allo-HSCT; demonstrates feasibility and efficacy of Cy-intensified conditioning regimens
40905088	2026	Retrospective Cohort	Haematologica	217 AML patients in complete remission undergoing HCT with myeloablative conditioning + PTCy-based GVHD prophylaxis; 2-year OS 77%, EFS 72%, confirming prognostic significance of genetic risk classification
39939431	2025	Retrospective Cohort	Bone Marrow Transplantation	Cytogenetic/molecular risk-stratified analysis of conditioning intensity in 1,823 AML patients receiving first HSCT with PTCy; largest study informing personalised Cy-based conditioning strategy
40437709	2025	Retrospective Cohort	European Journal of Haematology	Impact of MAC vs RIC conditioning on AML survival (patients under 65 years) using ATG + PTCy + cyclosporine GVHD prophylaxis; supports individualised conditioning selection
35955881	2022	Retrospective Cohort	Int. Journal of Molecular Sciences	First published data on PTCy after matched sibling and unrelated donor HSCT in paediatric AML patients; demonstrates safety and efficacy of PTCy across age groups
38466265	2024	Retrospective Cohort	Cytotherapy	Identifies prognostic factors in haploidentical HCT with PTCy for AML; provides evidence base for patient selection and donor matching in PTCy-based strategies
32857869	2020	Review	American Journal of Hematology	NK cell alloreactivity in AML in the PTCy era; reviews mechanistic interaction between post-transplant Cyclophosphamide and NK-mediated graft-versus-leukaemia effects
25345651	2015	Cohort Study	American Journal of Hematology	Cy/Flu non-myeloablative allotransplant vs myeloablative allotransplant for AML in remission; comparable long-term event-free and overall survival at median 61-month follow-up
31628924	2020	Comparative Study	Hematology/Oncology and Stem Cell Therapy	BuCy vs BuFlu myeloablative conditioning for allo-HCT in AML and MDS with quality-of-life focus; both standard-of-care options with distinct toxicity and QOL profiles

Cytotoxicity

Item	Content
Cytotoxicity Classification	Conventional cytotoxic chemotherapy (Nitrogen mustard alkylating agent)
Myelosuppression Risk	High — Leukopenia, neutropenia, thrombocytopenia, and anaemia are expected and dose-dependent; blood count nadir typically occurs 7–14 days after administration
Emetogenicity Classification	Moderate to High (dose-dependent); high-dose conditioning regimens carry high emetogenic risk and require scheduled prophylactic antiemetics
Monitoring Items	CBC with differential (frequent during and after treatment), hepatic function, renal function (serum creatinine, BUN), urinalysis with urine cytology (haemorrhagic cystitis risk), cardiac function assessment for high-dose regimens, serum electrolytes
Handling Protection	Yes — must be prepared and administered according to cytotoxic drug handling regulations; closed-system transfer devices required, appropriate PPE (gloves, gown, eye protection), preparation in a biological safety cabinet or pharmaceutical isolator

Safety Considerations

Please refer to the package insert for safety information.

Conclusion and Next Steps

Decision: Proceed with Guardrails

Rationale: Multiple Phase 2 and Phase 3 clinical trials — including a landmark 1,520-patient randomised study (NCT00002549) and two additional Grade A Phase 2 studies — support Cyclophosphamide's efficacy in myeloid leukaemia across induction, myeloablative conditioning, and post-transplant GVHD prophylaxis settings. The evidence level (L1) is the highest available, and the mechanistic basis is thoroughly established. The primary barriers to immediate clinical use in Singapore are the absence of HSA registration and two unresolved data gaps (package insert safety profile and formal MOA documentation).

To proceed, the following is needed:

Obtain Singapore HSA registration or apply for an import licence / clinical trial exemption before patient use
Retrieve the full package insert (Singapore HSA or internationally harmonised version) to address Data Gap DG001: warnings, contraindications, and precautions
Confirm detailed pharmacological MOA from DrugBank API or equivalent authoritative source to address Data Gap DG002
Define the specific clinical context (direct AML induction vs. HSCT myeloablative conditioning vs. PTCy for GVHD prophylaxis), as each requires a distinct dosing regimen, monitoring schedule, and safety protocol
Implement mesna uroprotection for all high-dose Cyclophosphamide regimens to prevent haemorrhagic cystitis
Establish cardiac monitoring protocols for high-dose conditioning regimens
Include long-term surveillance for therapy-related myeloid neoplasms (t-MDS / t-AML), a recognised late complication of alkylating agent exposure requiring patient counselling and follow-up planning
Disclaimer

This content is for research purposes only and does not constitute medical advice. Clinical validation is required before any clinical application.