Learning objectives and key messages
- Learning objectives: after this lesson you should be able to (1) classify the indications for autologous and allogeneic transplant by disease and disease status; (2) estimate the risks of non-relapse mortality and relapse with HCT-CI and DRI; (3) apply an algorithm for choosing the donor and cell source; and (4) know conditioning intensity and the common regimens with exact doses.
- The 2025 European Society for Blood and Marrow Transplantation (EBMT) classification places each indication in one of four categories: "standard" (S), "clinical option" (CO), "developmental" (D) and "generally not recommended" (GNR); the ASTCT guideline has a similar classification [1, 2].
- In AML, allogeneic transplant in first complete remission (CR1) is recommended for adverse risk and most intermediate-risk patients; in favourable risk only if measurable residual disease (MRD) does not clear [1].
- HCT-CI predicts non-relapse mortality and DRI predicts relapse and overall survival; they complement each other and should be assessed together [3, 4].
- A matched sibling or a fully matched unrelated donor is preferred; with post-transplant cyclophosphamide (PTCy), haploidentical and mismatched unrelated donors are also valid options. In a large study, the only non-HLA donor characteristic associated with survival was donor age (younger donors were better) [1, 5].
- In the BMT CTN 0901 trial, reduced-intensity conditioning (RIC) lowered treatment-related mortality but increased relapse so much that long-term overall survival was better with myeloablative conditioning (MAC); the benefit of MAC was seen especially in patients with genomic MRD [6, 7].
Principles and types of haematopoietic stem cell transplantation
Haematopoietic cell transplantation (HCT) means any procedure in which haematopoietic stem cells from any type of donor and source are infused into a recipient with the aim of replacing the haematopoietic system completely or partly; the cell source can be bone marrow, peripheral blood or cord blood [1].
- Autologous transplant: the patient's own cells are collected before high-dose chemotherapy and returned afterwards, allowing more intensive treatment. A classic example is the randomised PARMA trial in chemosensitive relapsed non-Hodgkin lymphoma, in which high-dose chemotherapy and autologous transplant gave 5-year event-free survival of 46% vs 12% and overall survival of 53% vs 32% [8].
- Allogeneic transplant: donor T cells recognise recipient antigens as foreign; this same response produces both the graft-versus-leukaemia (GVL) effect and graft-versus-host disease (GVHD). 30 to 50% of allogeneic recipients develop acute GVHD and about 14% the severe form (grade III to IV) [9].
Allogeneic donors fall into three groups: matched sibling donors (MSD); fully matched unrelated donors (MUD; 10/10 at HLA-A, -B, -C, -DRB1 and -DQB1 by high-resolution typing); and mismatched alternative donors (MMAD), including cord blood, haploidentical family donors and mismatched unrelated donors [1].
| Disease and status | Allogeneic (MSD / MUD / MMAD) | Autologous | CAR-T |
|---|---|---|---|
| AML in CR1, favourable risk and MRD-negative | GNR / GNR / GNR | CO | — |
| AML in CR1, favourable risk and MRD-positive | S / CO / CO | GNR | — |
| AML in CR1, intermediate risk | S / CO / CO | CO | — |
| AML in CR1, adverse risk | S / S / S | GNR | — |
| Philadelphia-negative ALL in CR1, high risk | S / S / CO | GNR | — |
| Philadelphia-positive ALL in CR1, MRD-positive | S / S / S | GNR | — |
| High or very high risk MDS (IPSS-R) or moderate-high to very high risk (IPSS-M) | S / S / S | — | — |
| Large B-cell lymphoma, primary refractory or early relapse with refractory or unassessed disease | GNR / GNR / GNR | GNR | S |
| Large B-cell lymphoma, late chemosensitive relapse (CR2 or later) | GNR / GNR / GNR | S | CO |
| Hodgkin lymphoma, chemosensitive relapse without a previous autologous transplant | D / D / GNR | S | GNR |
| Multiple myeloma, first line with standard risk | CO / CO / GNR | S | — |
| Mantle cell lymphoma in CR1 | GNR / GNR / GNR | S | D |
S: standard of care; CO: clinical option after careful weighing of benefit and harm; D: developmental (needs trials); GNR: generally not recommended. MSD: matched sibling donor; MUD: matched unrelated donor (8/8, 10/10 or 9/10 with a mismatch only at DQB1); MMAD: mismatched alternative donor (cord blood, haploidentical, mismatched unrelated). Dash: not listed in the reference table. In MCL, trials that added ibrutinib to first-line treatment have questioned the benefit of autologous transplant in CR1 [1, 10].
Patient assessment: comorbidity (HCT-CI) and disease risk (DRI)
The decision to perform an allogeneic transplant rests on the balance between "the risk of relapse without transplant" and "non-relapse mortality (NRM) from the transplant". NRM risk is usually estimated with the HCT-specific comorbidity index (HCT-CI) and relapse risk, independent of comorbidity, with the disease risk index (DRI); donor and graft characteristics should also be considered [1].
HCT-CI consists of 17 weighted comorbidities; liver and kidney are defined by laboratory data and lung and heart by functional tests, and it also includes obesity, peri-transplant infection and psychiatric disturbance [3]. This index identified 62% of patients with a score above zero (vs 12% with the Charlson index) and predicted survival better [11]. DRI places patients, regardless of age, conditioning intensity, cell source or donor type, into four groups with 2-year overall survival from 64% to 24% [4].
Pre-transplant assessment
- Organ function: lung function tests, cardiac assessment, creatinine and liver tests (components of HCT-CI) [3].
- Infection screening: serology for CMV, HSV, VZV, EBV and toxoplasma, and HBV and HCV screening before transplant [12]; in a person with past HBV (HBsAg-negative and anti-HBc-positive), stem cell transplant is among the high-risk treatments for reactivation and antiviral prophylaxis is needed [13].
- In any mismatched transplant, especially in women with previous pregnancies: testing for donor-specific anti-HLA antibodies (DSA) [5].
| Tool | What it measures | Groups and outcome |
|---|---|---|
| HCT-CI | 17 weighted comorbidities with laboratory and functional definitions; predicts non-relapse mortality and survival [3, 11] | Scores of 0, 1 to 2 and 3 or more in the validation group: non-relapse mortality 14%, 21% and 41%, and survival 71%, 60% and 34% [3] |
| DRI | Disease type and status at transplant; predicts overall survival [4] | Four groups (low, intermediate, high and very high) with 2-year overall survival from 64% to 24% in 13,131 patients in the CIBMTR registry [4] |
| Combining HCT-CI and disease risk (AML and MDS) | Comorbidity together with disease risk | After MAC: HCT-CI 0 to 2 with low-risk disease, 2-year non-relapse mortality 11% and survival 78%; HCT-CI 3 or more with intermediate- or high-risk disease, non-relapse mortality 46% and survival 24% [3] |
HCT-CI predicts non-relapse mortality and DRI predicts relapse independently of comorbidity; alongside these, EBMT also considers donor and graft characteristics in decision-making [1].
Choosing the donor and cell source
A practical algorithm for choosing a donor
- 1
Early typing
Disease stage is one of the main determinants of transplant outcome, and in high-risk disease a rapid transplant gives the best results; so the likelihood of a successful unrelated donor search should be estimated early to avoid delay from a fruitless search [5].
- 2
Matched sibling or 8/8 unrelated donor
Without an MSD, an unrelated donor matched 8/8 at HLA-A, -B, -C and -DRB1 by high-resolution typing is chosen. Among several equivalent donors, a younger donor, a permissive mismatch or a match at DPB1, and the fewest mismatches at DRB3/4/5 and DQB1 are preferred [5]. In a large study, the only non-HLA characteristic associated with survival was donor age [5].
- 3
Alternative donor
If a matched donor is not available in time, a haploidentical donor, a mismatched unrelated donor or cord blood are valid options; without definitive comparative data, the NMDP/CIBMTR guideline does not consider any of them superior [5]. The use of PTCy in haploidentical and mismatched unrelated transplant has widened the donor pool [1]. In the BMT CTN 1101 trial (reduced-intensity transplant), 2-year progression-free survival did not differ significantly between haploidentical bone marrow and double cord blood (41% vs 35%), but non-relapse mortality was lower (11% vs 18%) and overall survival higher (57% vs 46%) with haploidentical transplant [14].
- 4
Testing for anti-HLA antibodies (DSA)
About a third of adults with haematological malignancies have anti-HLA antibodies, and sensitisation is 2 to 3 times more common in women and increases with the number of pregnancies; DSA is strongly associated with primary graft failure [5]. In the EBMT consensus, an MFI above 1000 is considered positive and an MFI above 5000 carries a much higher risk and also requires a C1q test; the priority is choosing a donor who lacks the antigen targeted by the DSA, and otherwise desensitisation (plasmapheresis, rituximab, IVIG, infusion of donor buffy coat or platelets) is performed [15].
- 5
Choosing the cell source
In the BMT CTN 0201 trial (unrelated donors), 2-year survival did not differ significantly between peripheral blood and bone marrow (51% vs 46%); graft failure was lower with peripheral blood (3% vs 9%) and chronic GVHD higher (53% vs 41%) [16].
| Donor or source | Key points | Evidence |
|---|---|---|
| Matched sibling (MSD) | The preferred option in most indications | In AML, MSD or MUD are the preferred options [1] |
| Matched unrelated (MUD) | High-resolution matching; younger donor; permissive DPB1; avoid antigens targeted by DSA | NMDP/CIBMTR guideline [5] |
| Haploidentical family donor | Rapid availability; needs PTCy; DSA testing essential | Graft failure 13% in the first PTCy study with non-myeloablative conditioning [17]; better overall survival than double cord blood in BMT CTN 1101 [14] |
| Cord blood | Less stringent matching: at least 4/6 (antigen-level HLA-A and -B and high-resolution DRB1) and 4/8 at high resolution; single unit: TNC at least 2.5 × 10⁷ and CD34-positive cells at least 1.5 × 10⁵ per kg | NMDP/CIBMTR guideline [5] |
| Peripheral blood vs bone marrow | Peripheral blood: less graft failure; bone marrow: less chronic GVHD | BMT CTN 0201 [16] |
MMAD is a single category in the EBMT indications table, but the relative value of each approach is discussed separately in each disease section [1].
Conditioning intensity: MAC, RIC and NMA
Treatment regimens and doses: index9 regimens
Regimen intensity is defined by the duration of cytopenia and the need for stem cell support: myeloablative (MAC) regimens cause profound, usually irreversible pancytopenia within 1 to 3 weeks that is fatal without stem cell infusion (for example TBI of at least 5 Gy single dose or 8 Gy fractionated, or busulfan above 8 mg/kg orally or the IV equivalent); non-myeloablative (NMA) regimens cause minimal cytopenia and are tolerable without stem cell support (such as TBI of at most 2 Gy with or without a purine analogue, or fludarabine + cyclophosphamide); and any regimen that fits neither group is reduced intensity (RIC), usually reducing the alkylator or TBI dose by at least 30% [18].
In the phase 3 BMT CTN 0901 trial (272 patients aged 18 to 65 with AML or MDS, HCT-CI at most 4 and bone marrow blasts below 5%), accrual was stopped early because of much higher relapse in the RIC arm: relapse 48.3% vs 13.5%, treatment-related mortality 4.4% vs 15.8% and 18-month survival 67.7% vs 77.5% (P=0.07); the authors considered MAC the standard for fit patients [19]. At a median follow-up of 51 months, overall survival was significantly better with MAC (4-year survival 62.0% vs 49.0%; hazard ratio for death with RIC 1.54) [6]. A genomic analysis of the same trial showed that in patients with a detectable mutation before transplant, 3-year relapse was 19% with MAC and 67% with RIC, but in patients without a detectable mutation survival was similar [7]. EBMT also concludes that RIC reduces non-relapse mortality and MAC reduces relapse, and that MAC benefits MRD-positive patients most [1].
- Busulfan: seizure prophylaxis (a benzodiazepine, phenytoin, valproate or levetiracetam) from 12 hours before the first dose to 24 hours after the last dose; an AUC above 1500 µmol·min is associated with a higher risk of hepatic sinusoidal obstruction syndrome; daily liver tests until 28 days after transplant [20].
- Busulfan interactions: metronidazole, itraconazole, deferasirox and paracetamol (within 72 hours before or at the same time) reduce its clearance; phenytoin increases clearance [20].
- High-dose melphalan: prophylactic antiemetics are needed; in patients weighing more than 130% of ideal body weight, calculate body surface area from adjusted ideal body weight [21].
- Carmustine: pulmonary toxicity is well recognised, especially at doses above 600 mg/m² or with cyclophosphamide [22].
Conditioning regimens for allogeneic transplant in AML and MDS
Busulfan + cyclophosphamide (BuCy; myeloablative)
Allogeneic transplant in a patient fit for myeloablative conditioning; the regimen in the FDA label for IV busulfan (CML) and one of the MAC regimens allowed in BMT CTN 0901 for AML and MDS
Allogeneic transplant in a patient fit for myeloablative conditioning; the regimen in the FDA label for IV busulfan (CML) and one of the MAC regimens allowed in BMT CTN 0901 for AML and MDS
| Drug | Dose | Route | Schedule |
|---|---|---|---|
| Conditioning | |||
| IV busulfan | 0.8 mg/kg every 6 hours (ideal or actual weight, whichever is lower); equivalent to 3.2 mg/kg a day | IV, 2-hour infusion through a central catheter | Days −7 to −4 (16 doses) |
| Cyclophosphamide | 60 mg/kg a day | IV, 1-hour infusion | Days −3 and −2 (at least 6 hours after the 16th busulfan dose) |
The dose and schedule follow the FDA label for IV busulfan (Busulfex); in obese patients, calculate the dose from adjusted ideal body weight (AIBW = IBW + 0.25 × (actual weight − IBW)). Give antiemetics before the first dose and on a fixed schedule [20]. In BMT CTN 0901 the same regimen was used with total busulfan 12.8 mg/kg IV (or 16 mg/kg orally) and total cyclophosphamide 120 mg/kg [6, 23].
Fludarabine + four-day busulfan (FluBu4; myeloablative)
AML or MDS in a patient fit for MAC; one of the MAC regimens allowed in BMT CTN 0901
AML or MDS in a patient fit for MAC; one of the MAC regimens allowed in BMT CTN 0901
| Drug | Dose | Route | Schedule |
|---|---|---|---|
| Conditioning | |||
| IV busulfan | 3.2 mg/kg a day (12.8 mg/kg in total) | IV | Days −5 to −2 |
| Fludarabine | 30 mg/m² a day (120 mg/m² in total) | IV | Days −5 to −2 |
Doses as in the BMT CTN 0901 protocol registered on ClinicalTrials.gov; that protocol also allowed pharmacokinetically guided busulfan dosing with a target Css of 900 ± 100 ng/mL [23]. In the final paper, the total fludarabine dose in fludarabine-containing regimens was reported as 120 to 180 mg/m² [6]. Seizure prophylaxis and busulfan interaction considerations are as for the previous regimen [20].
Cyclophosphamide + total body irradiation (CyTBI; myeloablative)
A radiation-based MAC regimen; one of the regimens allowed in BMT CTN 0901
A radiation-based MAC regimen; one of the regimens allowed in BMT CTN 0901
| Drug | Dose | Route | Schedule |
|---|---|---|---|
| Conditioning | |||
| Total body irradiation (TBI) | 1200 to 1420 cGy (total) | Radiotherapy | Days −7 to −4 |
| Cyclophosphamide | 60 mg/kg a day (120 mg/kg in total) | IV | Days −3 and −2 |
Doses as in the BMT CTN 0901 protocol registration [23]; in this trial, high-dose TBI was an uncommon choice in AML (8 patients) [6]. In childhood ALL, TBI 12 Gy has been superior to chemotherapy-based regimens in reducing relapse; EBMT considers thiotepa- and busulfan-based regimens an alternative in ALL when myeloablative TBI is unavailable or not tolerated, and does not recommend TBI in myeloma transplant because of more toxicity without benefit [1].
Fludarabine + melphalan (FluMel; reduced intensity)
AML or MDS in an older patient or with comorbidities (high HCT-CI) who is not a candidate for MAC
AML or MDS in an older patient or with comorbidities (high HCT-CI) who is not a candidate for MAC
| Drug | Dose | Route | Schedule |
|---|---|---|---|
| Conditioning | |||
| Fludarabine | 30 mg/m² a day (120 mg/m² in total) | IV | Days −5 to −2 |
| Melphalan | 140 mg/m² | IV | Day −2 |
Fludarabine + two-day busulfan (FluBu2; reduced intensity)
AML or MDS in a patient unfit for MAC
AML or MDS in a patient unfit for MAC
| Drug | Dose | Route | Schedule |
|---|---|---|---|
| Conditioning | |||
| Fludarabine | 30 mg/m² a day (150 mg/m² in total) | IV | Days −6 to −2 |
| Busulfan | 3.2 mg/kg a day IV or 4 mg/kg a day orally (6.4 or 8 mg/kg in total) | IV or oral | Days −5 and −4 |
Treosulfan + fludarabine
AML or MDS in adults and children aged one year and over (FDA label); in the trial, patients aged 50 or over or with HCT-CI above 2
AML or MDS in adults and children aged one year and over (FDA label); in the trial, patients aged 50 or over or with HCT-CI above 2
| Drug | Dose | Route | Schedule |
|---|---|---|---|
| Conditioning | |||
| Treosulfan | 10 g/m² a day | IV, 2-hour infusion | Days −4, −3 and −2 |
| Fludarabine | 30 mg/m² a day | IV | Days −6 to −2 |
Dose as in the FDA label (Grafapex). In the randomised phase 3 MC-FludT.14/L trial (570 patients), compared with busulfan (0.8 mg/kg every 6 hours on days −4 and −3) + fludarabine, the hazard ratio for death was 0.67 (0.51 to 0.90); with unrelated donors almost all patients received ATG, and all received ciclosporin + methotrexate [24, 25].
Doses follow the trial protocol, guideline or official drug label (source given in the notes of each regimen). Before prescribing, check blood counts, renal and hepatic function, drug interactions and the patient’s condition, and adjust the dose according to the drug label.
Conditioning regimens for autologous transplant
High-dose melphalan (Mel200)
Multiple myeloma; first-line autologous transplant in a fit patient
Multiple myeloma; first-line autologous transplant in a fit patient
| Drug | Dose | Route | Schedule |
|---|---|---|---|
| Conditioning | |||
| IV melphalan | 100 mg/m² a day (200 mg/m² in total) | IV, 30-minute infusion | Days −3 and −2 |
Dose as in the FDA label for IV melphalan (Evomela) for conditioning before transplant in myeloma; prophylactic antiemetics are needed, and with weight above 130% of ideal body weight, calculate body surface area from adjusted ideal body weight. Engraftment syndrome was more common in patients aged 65 and over (28% vs 7%) [21]. EBMT does not consider adding TBI, bortezomib or lenalidomide to the conditioning regimen beneficial [1].
BeEAM (bendamustine, etoposide, cytarabine, melphalan)
Chemosensitive relapsed lymphoma (large B-cell, mantle cell, follicular); an alternative to BEAM
Chemosensitive relapsed lymphoma (large B-cell, mantle cell, follicular); an alternative to BEAM
| Drug | Dose | Route | Schedule |
|---|---|---|---|
| Conditioning | |||
| Bendamustine | 200 mg/m² a day | IV | Days −7 and −6 |
| Etoposide | 200 mg/m² a day | IV | Days −5 to −2 |
| Cytarabine | 400 mg/m² a day | IV | Days −5 to −2 |
| Melphalan | 140 mg/m² | IV | Day −1 |
Doses as in the randomised phase 2 BEB trial (108 patients aged 18 to 75). The primary outcome, a fall of at least 20% in DLCO at month 3, did not differ (19.5% vs 25.6%); 1-year survival (92.5% vs 89.1%) and complete response (76.7% vs 74.3%) were similar to BEAM. The authors considered a phase 3 trial necessary to prove non-inferiority, and late toxicities seemed more common with BeEAM [22].
BEAM (carmustine, etoposide, cytarabine, melphalan)
The most common conditioning regimen for autologous transplant in lymphoma
The most common conditioning regimen for autologous transplant in lymphoma
| Drug | Dose | Route | Schedule |
|---|---|---|---|
| Conditioning | |||
| Carmustine (BCNU) | 300 mg/m² | IV | Day −6 |
| Etoposide | 200 mg/m² a day | IV | Days −5 to −2 |
| Cytarabine | 400 mg/m² a day | IV | Days −5 to −2 |
| Melphalan | 140 mg/m² | IV | Day −1 |
Doses follow the trial protocol, guideline or official drug label (source given in the notes of each regimen). Before prescribing, check blood counts, renal and hepatic function, drug interactions and the patient’s condition, and adjust the dose according to the drug label.
Timing of transplant in common diseases
Acute myeloid leukaemia (AML)
Allogeneic transplant in CR1 is recommended for adverse risk and most intermediate-risk patients by ELN, and is not recommended in favourable risk (CBF with t(8;21) or inv(16), NPM1 mutation without FLT3-ITD, CEBPA mutation with a normal karyotype) unless MRD fails to clear; for example a reduction of less than 3 logs in CBF transcripts after two cycles, or positive NPM1 MRD after two cycles in younger adults [1, 26]. In patients over 60, transplant is recommended for adverse and intermediate risk in those fit for intensive chemotherapy, and primary refractory AML is a candidate for transplant if a donor is found quickly and non-relapse mortality is acceptable [1]. In FLT3-ITD AML, sorafenib maintenance after transplant gave 5-year survival of 72.0% vs 55.9% (hazard ratio 0.55) [27].
Acute lymphoblastic leukaemia (ALL)
In Philadelphia-negative ALL, MRD is the most important prognostic factor: MRD above 0.01% after three blocks of standard treatment is an indication for allogeneic transplant, and high-risk cytogenetics (low hypodiploidy, KMT2A translocations, t(8;14) and complex karyotype) raise the question of transplant even with negative MRD. In Philadelphia-positive ALL treated with imatinib and chemotherapy, transplant in CR1 improves survival, but with third-generation TKIs plus new antibodies and deep MRD responses, the indication may become narrower. With persistent or recurrent MRD, a change of treatment before transplant is recommended, and blinatumomab is the only drug that has shown MRD clearance (78%) and a survival benefit in this setting [1].
Myelodysplastic syndrome (MDS)
Allogeneic transplant is the only potentially curative treatment for high-risk MDS. In the biological assignment trial BMT CTN 1102 (384 patients aged 50 to 75 with intermediate-2 or high-risk MDS), 3-year survival was 47.9% in the group with a donor and 26.6% in the group without [28]. An IPSS-M-based decision model in 7118 patients showed that low and moderate-low risk groups benefit from delayed transplant, and moderate-high, high and very high risk groups from immediate transplant [29]. The need for blast-reducing treatment before transplant has not been proven in a prospective trial, and stable marrow blasts are not a contraindication to transplant [1].
Multiple myeloma
First-line autologous transplant with high-dose melphalan remains standard for younger, fit patients [1]. In IFM 2009, adding transplant to RVD increased median progression-free survival from 36 to 50 months, without a difference in 4-year overall survival (81% vs 82%) [30]; in DETERMINATION with lenalidomide maintenance until progression, median progression-free survival was 67.5 vs 46.2 months and 5-year survival did not differ (80.7% vs 79.2%) [31]. In a meta-analysis of three trials, lenalidomide maintenance after transplant increased overall survival (hazard ratio 0.75) [32]. Allogeneic transplant is considered only for selected high-risk patients in experienced centres [1].
Lymphomas
In primary refractory large B-cell lymphoma or relapse within the first 12 months, CAR-T (axicabtagene ciloleucel or lisocabtagene maraleucel) gave better event-free survival than salvage chemotherapy and autologous transplant and is now the standard; late relapse remains an indication for autologous transplant [1, 33, 34]. In Hodgkin lymphoma, autologous transplant is standard for chemosensitive relapse, and in patients with risk factors, consolidation with 16 cycles of brentuximab vedotin 1.8 mg/kg every 3 weeks (starting 30 to 45 days after transplant) improved progression-free survival (hazard ratio 0.57; median 42.9 vs 24.1 months) [1, 35].
Key trials and guidelines
Scientific evidence for this lesson
8 itemsDiagnosis and management of AML in adults: 2022 recommendations from an international expert panel on behalf of the ELN
Sorafenib maintenance after allogeneic haemopoietic stem-cell transplantation in patients with FLT3-ITD acute myeloid leukaemia: long-term follow-up of an open-label, multicentre, randomised, phase 3 trial
Diagnosis, prognostic factors, and assessment of ALL in adults: 2024 ELN recommendations from a European expert panel
Lenalidomide, Bortezomib, and Dexamethasone with Transplantation for Myeloma
Lenalidomide Maintenance After Autologous Stem-Cell Transplantation in Newly Diagnosed Multiple Myeloma: A Meta-Analysis
Ibrutinib combined with immunochemotherapy with or without autologous stem-cell transplantation versus immunochemotherapy and autologous stem-cell transplantation in previously untreated patients with mantle cell lymphoma (TRIANGLE): a three-arm, randomised, open-label, phase 3 superiority trial of the European Mantle Cell Lymphoma Network
Axicabtagene Ciloleucel as Second-Line Therapy for Large B-Cell Lymphoma
Lisocabtagene maraleucel versus standard of care with salvage chemotherapy followed by autologous stem cell transplantation as second-line treatment in patients with relapsed or refractory large B-cell lymphoma (TRANSFORM): results from an interim analysis of an open-label, randomised, phase 3 trial
Practical and exam points
- MAC vs RIC (BMT CTN 0901): 4-year relapse 19.8% vs 60.7%, transplant-related mortality 25.1% vs 9.9% and 4-year survival 62.0% vs 49.0% [6].
- MRD before transplant: in patients with a mutation detectable by NGS, 3-year relapse was 19% with MAC and 67% with RIC [7].
- Peripheral blood or bone marrow: peripheral blood gives less graft failure (3% vs 9%) but more chronic GVHD (53% vs 41%); survival did not differ [16].
- High-risk MDS at age 50 to 75: having a donor gave 3-year survival of 47.9% vs 26.6% [28].
- Donor: the only non-HLA characteristic associated with survival is donor age; prefer a younger donor [5].
- DSA: MFI above 1000 is positive and above 5000 high risk; in that case a C1q test and desensitisation or a change of donor [15].
- Single cord blood unit: TNC at least 2.5 × 10⁷ and CD34-positive cells at least 1.5 × 10⁵ per kg [5].
- Definition of MAC: TBI at least 5 Gy single dose or 8 Gy fractionated, or busulfan above 8 mg/kg orally [18].
Self-assessment: questions and answers
A 45-year-old man with NPM1-mutated AML without FLT3-ITD is still MRD-positive after two cycles of chemotherapy. What is the place of allogeneic transplant?
Favourable-risk AML with positive MRD in CR1 is "standard" for transplant from a matched sibling and a "clinical option" for unrelated or alternative donors in the EBMT 2025 classification; younger adults with NPM1 who remain MRD-positive after two cycles relapse more often and appear to benefit from transplant [1].
A 58-year-old patient with adverse-risk AML, HCT-CI of 2 and positive NGS MRD before transplant. Which conditioning intensity do you choose?
Myeloablative conditioning. In BMT CTN 0901, long-term overall survival was better with MAC, and in the subgroup with a detectable mutation before transplant, RIC was associated with more relapse (hazard ratio 6.38) and death (hazard ratio 1.97) [6, 7]. RIC is reserved for older patients or those with high comorbidity who cannot tolerate MAC [1].
A 52-year-old woman with three previous deliveries is a candidate for haploidentical transplant from her son. Which test is essential before transplant, and what do you do if it is positive?
Testing for donor-specific anti-HLA antibodies (DSA); sensitisation is 2 to 3 times more common in women and increases with the number of pregnancies, and DSA is strongly associated with primary graft failure [5]. If the MFI is high (especially above 5000), a C1q test is done and another donor without the target antigen is preferably chosen; otherwise desensitisation (plasmapheresis, rituximab, IVIG, donor buffy coat) is performed before transplant [15].
Is first-line autologous transplant still standard in a 58-year-old with newly diagnosed myeloma?
Yes; EBMT 2025 considers it the standard of care [1]. In IFM 2009 and DETERMINATION, transplant lengthened progression-free survival (50 vs 36 months; 67.5 vs 46.2 months) but did not change overall survival [30, 31]; lenalidomide maintenance after transplant increased overall survival in a meta-analysis [32].
A 68-year-old patient with MDS and moderate-low IPSS-M, without blasts above 5%, an adverse karyotype, profound cytopenia or severe fibrosis. Immediate or delayed transplant?
Delayed transplant. EBMT 2025 places this group without additional factors in the "developmental" category and with additional factors (blasts above 5%, adverse karyotype, profound cytopenia or severe fibrosis) in the "standard" category [1], and in the IPSS-M-based model, the low and moderate-low groups benefited from a delayed strategy [29].
A patient with large B-cell lymphoma relapsed 8 months after R-CHOP. Autologous transplant or CAR-T?
Relapse within the first 12 months (early relapse) is an indication for CAR-T; in the ZUMA-7 and TRANSFORM trials, CAR-T gave better event-free survival than salvage chemotherapy and autologous transplant [33, 34]. Autologous transplant is a "clinical option" in chemosensitive early relapse and "standard" in late relapse [1].
Related cancer types
Treatment regimens (physicians)
Physician tools and lessons
References
35 referencesShow all references, 7 with a study cardClose the reference list
Numbers in the text, such as [1], refer to these sources. Sources with a “Study card” button are summarised in the site’s evidence library.
- 1
- 2Indications for Hematopoietic Cell Transplantation and Immune Effector Cell Therapy: Guidelines from the American Society for Transplantation and Cellular Therapy
- 3
- 4
- 5
- 6
- 7
- 8Autologous Bone Marrow Transplantation as Compared with Salvage Chemotherapy in Relapses of Chemotherapy-Sensitive Non-Hodgkin's Lymphoma
- 9Acute Graft-versus-Host Disease — Biologic Process, Prevention, and Therapy
- 10Ibrutinib combined with immunochemotherapy with or without autologous stem-cell transplantation versus immunochemotherapy and autologous stem-cell transplantation in previously untreated patients with mantle cell lymphoma (TRIANGLE): a three-arm, randomised, open-label, phase 3 superiority trial of the European Mantle Cell Lymphoma Network
- 11
- 12Guidelines for Preventing Infectious Complications among Hematopoietic Cell Transplantation Recipients: A Global Perspective
- 13Hepatitis B Virus Screening and Management for Patients With Cancer Prior to Therapy: ASCO Provisional Clinical Opinion Update
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- 17HLA-Haploidentical Bone Marrow Transplantation for Hematologic Malignancies Using Nonmyeloablative Conditioning and High-Dose, Posttransplantation Cyclophosphamide
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- 19Myeloablative Versus Reduced-Intensity Hematopoietic Cell Transplantation for Acute Myeloid Leukemia and Myelodysplastic Syndromes
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- 24GRAFAPEX (treosulfan) for injection — prescribing information
- 25Treosulfan or busulfan plus fludarabine as conditioning treatment before allogeneic haemopoietic stem cell transplantation for older patients with acute myeloid leukaemia or myelodysplastic syndrome (MC-FludT.14/L): a randomised, non-inferiority, phase 3 trial
- 26Diagnosis and management of AML in adults: 2022 recommendations from an international expert panel on behalf of the ELN
- 27Sorafenib maintenance after allogeneic haemopoietic stem-cell transplantation in patients with FLT3-ITD acute myeloid leukaemia: long-term follow-up of an open-label, multicentre, randomised, phase 3 trial
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- 30Lenalidomide, Bortezomib, and Dexamethasone with Transplantation for Myeloma
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- 32Lenalidomide Maintenance After Autologous Stem-Cell Transplantation in Newly Diagnosed Multiple Myeloma: A Meta-Analysis
- 33Axicabtagene Ciloleucel as Second-Line Therapy for Large B-Cell Lymphoma
- 34Lisocabtagene maraleucel versus standard of care with salvage chemotherapy followed by autologous stem cell transplantation as second-line treatment in patients with relapsed or refractory large B-cell lymphoma (TRANSFORM): results from an interim analysis of an open-label, randomised, phase 3 trial
- 35Brentuximab vedotin as consolidation therapy after autologous stem-cell transplantation in patients with Hodgkin's lymphoma at risk of relapse or progression (AETHERA): a randomised, double-blind, placebo-controlled, phase 3 trial
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