Cyclophosphamide
| Evidence Level: L2 | Predicted Indications: 5 |
Table of Contents
Cyclophosphamide: From Its Existing Indications to Myeloid Leukemia
One-Sentence Summary
Cyclophosphamide is a marketed alkylating chemotherapy agent in the US, with 20 license records on file. The TxGNN model predicts it may be useful for myeloid leukemia, and the pack lists 50 clinical trials and 20 publications on this direction. Most of this evidence describes cyclophosphamide as one component of stem cell transplant regimens, not as a stand-alone leukemia treatment.
Quick Overview
| Item | Content |
|---|---|
| Original Indication | Not listed in the available license records |
| Predicted New Indication | Myeloid leukemia |
| TxGNN Prediction Score | 99.47% |
| Evidence Level | L2 |
| US Market Status | ✓ Marketed |
| Number of NDAs | 20 license records (ANDA numbers) |
| Recommended Decision | Proceed with Guardrails |
Why is This Prediction Reasonable?
Cyclophosphamide is a prodrug. The liver enzyme CYP2B6 converts it to phosphoramide mustard, which cross-links DNA and gives the drug both cytotoxic and lymphodepleting effects. The structured mechanism-of-action field is empty in this record, so this description comes from the candidate’s mechanistic analysis.
In myeloid leukemia, cyclophosphamide is used mainly in two transplant roles:
- Conditioning: it is part of myeloablative regimens such as busulfan-cyclophosphamide (BuCy).
- Post-transplant cyclophosphamide (PTCy): it is given after transplant to prevent graft-versus-host disease (GVHD).
The prediction is therefore reasonable, but the drug acts as a backbone agent in transplantation, not as a stand-alone antileukemic. The original indication is also missing from the data, so the “repurposing” framing should be checked against the current US label before it is used.
Clinical Trial Evidence
| Trial Number | Phase | Status | Enrollment | Key Findings |
|---|---|---|---|---|
| NCT02065154 | Phase 2 | Completed | 39 | PTCy for acute GVHD prevention after matched or mismatched unrelated donor transplant |
| NCT03128359 | Phase 2 | Completed | 38 | High-dose PTCy with tacrolimus and mycophenolate in mismatched unrelated donor transplant for hematologic malignancies |
| NCT01010217 | Phase 2 | Completed | 176 | Three-arm transplant study (haploidentical, mismatched, matched unrelated donors) using high-dose PTCy |
| NCT02120157 | Phase 2 | Completed | 35 | Pediatric haploidentical bone marrow transplant with PTCy in high-risk leukemia |
| NCT00003340 | Phase 2 | Completed | Not reported | Cyclophosphamide followed by topotecan in refractory or relapsed acute myelogenous leukemia; the most direct antileukemic use of cyclophosphamide in this list |
| NCT02744742 | Phase 2/3 | Completed | 202 | Randomized comparison of G-CSF + decitabine + BuCy versus BuCy conditioning in MDS-related AML |
| NCT03256071 | Phase 2/3 | Unknown | 90 | Randomized comparison of low-dose decitabine + modified BuCy versus modified BuCy in high-risk AML |
| NCT00723099 | Phase 2 | Completed | 73 | Reduced-intensity cord blood transplant in hematologic malignancies; conditioning commonly includes cyclophosphamide |
| NCT00125606 | Phase 3 | Terminated | 30 | Randomized comparison of TBI 8 Gy/fludarabine versus TBI 12 Gy/cyclophosphamide conditioning in AML in second remission; terminated early |
| NCT06802315 | Phase 2 | Recruiting | 38 | Total marrow irradiation added to fludarabine/busulfan conditioning, with PTCy for GVHD prophylaxis, in high-risk AML, CML and MDS |
Points to keep in mind:
- The cyclophosphamide-specific trials are single-arm Phase 2 studies of PTCy; none isolates cyclophosphamide’s own contribution.
- The only Phase 3 trial listed here (NCT00125606) was terminated with 30 patients.
- Several other trials in the pack were withdrawn or terminated with very few patients (for example NCT03602898, withdrawn with 0 enrolled).
Literature Evidence
No randomized controlled trials were retrieved. The list below is led by the systematic review, then the most relevant cohort studies.
| PMID | Year | Type | Journal | Key Findings |
|---|---|---|---|---|
| 36357773 | 2023 | Systematic review / network meta-analysis | Bone Marrow Transplant | Compares myeloablative conditioning regimens, including Bu/Cy, in adult AML in first remission |
| 39939431 | 2025 | Cohort | Bone Marrow Transplant | 1,823 AML patients transplanted with PTCy; conditioning intensity analyzed by cytogenetic and molecular risk (EBMT) |
| 40434956 | 2025 | Cohort | Future Oncol | Compares BuCy, the standard myeloablative regimen, with fludarabine-busulfan in AML allogeneic transplant |
| 40437709 | 2025 | Cohort | Eur J Haematol | Reduced-intensity versus myeloablative conditioning in AML patients under 65 given ATG and PTCy |
| 38466265 | 2024 | Cohort | Cytotherapy | Prognostic factors in haploidentical transplant with PTCy for AML |
| 35955881 | 2022 | Cohort | Int J Mol Sci | PTCy after matched sibling and unrelated donor transplant in pediatric AML |
| 40905088 | 2026 | Cohort | Haematologica | 217 AML patients in remission given myeloablative conditioning and PTCy; 2-year overall survival 77% and event-free survival 72% |
| 38499049 | 2024 | Cohort | Transpl Immunol | Cladribine + busulfan + cyclophosphamide conditioning in relapsed or refractory AML |
| 33325761 | 2021 | Case series | Leuk Lymphoma | High-dose cyclophosphamide (60 mg/kg) for cytoreduction in 27 patients with AML or blast-phase CML with hyperleukocytosis or leukostasis |
| 29039989 | 2017 | Case series | Pediatr Hematol Oncol | Clofarabine + cyclophosphamide + etoposide in 17 children with relapsed or refractory AML; 7 (41%) responded |
US Market Information
The 5 records provided contain only 3 unique authorizations. The approved indication text is empty for all of them, so that column is omitted.
| Authorization Number | Product Name | Dosage Form | Manufacturer |
|---|---|---|---|
| ANDA215892 | Cyclophosphamide | Capsule | Alembic Pharmaceuticals Inc. |
| ANDA218644 | Cyclophosphamide | Injection, powder, for solution | Epic Pharma, LLC |
| ANDA211757 | Cyclophosphamide | Injection, powder, lyophilized, for solution | XGen Pharmaceuticals DJB, Inc. |
Other dosage forms on record include tablets, injection solution and injection. Both oral and injectable routes are therefore available.
Cytotoxicity
| Item | Content |
|---|---|
| Cytotoxicity Classification | Conventional cytotoxic (alkylating agent, nitrogen mustard prodrug) |
| Myelosuppression Risk | Moderate to high, dose-dependent; higher at conditioning doses |
| Emetogenicity Classification | Moderate to high for high-dose IV use; lower with oral low-dose use |
| Monitoring Items | CBC with differential, liver and renal function, electrolytes, urinalysis for hemorrhagic cystitis; cardiac monitoring at high doses |
| Handling Protection | Must follow cytotoxic drug handling regulations |
These entries reflect general knowledge of the drug class, not DrugBank toxicity data. Please refer to the package insert warnings and precautions.
Safety Considerations
Please refer to the package insert for safety information.
Conclusion and Next Steps
Decision: Proceed with Guardrails
Rationale: Cyclophosphamide is an established backbone agent in AML transplant regimens (BuCy conditioning and PTCy), and the model score is very high. The evidence, however, is mostly single-arm Phase 2 or observational, and it does not isolate cyclophosphamide’s effect from the rest of the regimen, so it should not be treated as a stand-alone antileukemic.
To proceed, the following is needed:
- The current US label indication text, to confirm whether myeloid leukemia is already covered (the original indication is missing from the pack)
- Package insert warnings and contraindications, which are still missing and block safety screening
- Structured mechanism-of-action data from DrugBank
- Arm-level review of the trials to confirm the cyclophosphamide-containing arms and to separate conditioning use from PTCy use
- A safety monitoring plan for high-dose use (myelosuppression, hemorrhagic cystitis, cardiotoxicity)
Disclaimer
This content is for research purposes only and does not constitute medical advice. Clinical validation is required before any clinical application.