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The impact of targeted treatment and immunotherapies on the role of hematopoietic stem cell transplantation in the treatment of blood cancers

Apr 9, 2020

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Hematopoietic stem cell transplantation (HSCT) has been used for the treatment of different types of blood cancers for many decades. Autologous (auto)-HSCT became a standard of care for patients with multiple myeloma (MM) and aggressive lymphomas. While allogeneic (allo)-HSCT is considered to be currently the only available cure for patients with high-risk acute leukemias, including acute myeloid leukemia (AML).

However, not all patients are suitable for HSCT, and even in suitable patients it is associated with serious side effects, such as graft-versus-host disease (GvHD), which is the leading cause for non-relapse related morbidity and mortality. Moreover, the duration of response varies, and many patients face the risk of relapse. Therefore, novel safe and therapeutic agents with an anti-tumor activity that could replace or be used in combination with HSCT are needed.

Steven M. Bair and colleagues recently published a review in Cancer on the current role of HSCT in the treatment of patients with hematological cancers and how those novel therapies have changed the role of HCT in managing patients with hematological malignancies.1 Here we present a summary of this article.

Novel approaches

Different novel therapeutic approaches have been developed over the last 20 years. Those approaches include harnessing the immune system to fight malignant cells using cellular therapies, monoclonal antibodies, antibody-drug conjugates, and immunomodulatory drugs, but also targeting specific signaling pathways essential for cancer growth and survival with small molecule inhibitors. Table 1 presents novel targeted therapies and immunotherapies that have been approved for the treatment of hematologic malignancies.

Table 1. Approved novel targeted therapies and immunotherapies for selected blood cancers

ABL, Abelson murine lymphosarcoma kinase; AML, acute myeloid leukemia; ALL, acute lymphocytic leukemia; Bcl-2, B-cell lymphoma 2; BiTE, bispecific T-cell engager, BTK, Bruton tyrosine kinase; CLL, chronic lymphocytic leukemia; CML, chronic myeloid leukemia; DLBCL, diffuse large B-cell lymphoma; FLT3, Fms-like tyrosine kinase 3; GvHD, graft-versus-host disease; HDAC, histone deacetylase; IDH, isocitrate dehydrogenase; MCL; mantle cell lymphoma; MDS, myelodysplastic syndrome; MM, multiple myeloma; MZL, Marginal zone lymphoma, Ph, Philadelphia chromosome; R/R, recurrent/refractory; SLL, small lymphocytic lymphoma; XPO1, exportin 1

Therapeutic agent

Selected indication

Mechanism of action

Tyrosine kinase inhibitors

















Waldenström’s macroglobulinemia

Chronic GvHD


AML (FLT3 mutated)

R/R AML (FLT3 mutated)






BTK inhibitor





BTK inhibitor

FLT inhibitor

FLT inhibitor

ABL kinase inhibitor


ABL kinase inhibitor

IDH inhibitors




R/R AML (IDH2 mutated)

R/R AML (IDH1 mutated)


IDH2 inhibitor

IDH1 inhibitor

Immunomodulatory drugs











Immunomodulation via interaction with ubiquitin E3 ligase cereblon

Immunomodulation via interaction with ubiquitin E3 ligase cereblon

Proteasome inhibitors











Inhibitor of 20S component of proteasome

Inhibitor of 20S component of proteasome

Inhibitor of 20S component of proteasome





R/R AML (patients aged ≥ 75 years unsuitable for intensive induction)



Bcl-2 inhibitor

Nuclear export inhibitor





XPO1 inhibitor

HDAC inhibitors





HDAC inhibitor

Monoclonal antibodies







CD38-directed antibody

SLAMF7-directed antibody

Antibody-drug conjugates

Inotuzumab ozogamicin

Gemtuzumab ozogamicin


R/R B-cell ALL (adult)

 AML (CD33+)


CD22-directed antibody-drug conjugate

CD33-directed antibody-drug conjugate




B-cell ALL (adult and pediatric)


CD19-directed CD3 T-cell engager

Cellular therapy

Axicabtagene ciloleucel






Pediatric ALL


CD19-directed cell-mediated killing

CD19-directed cell-mediated killing

However, more work is needed to assess where those novel agents should be placed in the treatment schedule. Should they be given in combination with HSCT, would patients benefit from them as further/earlier lines of therapies, or maybe they can replace the transplants altogether.  Several clinical trials trying to address those questions are ongoing. Table 2 presents selected ongoing trials in acute leukemias, aggressive B-cell lymphomas, and MM.

Table 2. Selected ongoing trials involving novel therapies in combination with or comparing with HSCT

Allo-HSCT, allogeneic hematopoietic stem cell transplantation; AML, acute myeloid leukemia; auto-HSCT, autologous hematopoietic stem cell transplantation; BCMA, B-cell maturation antigen; CAR T, chimeric antigen receptor T cell; DLBCL, diffuse large B-cell lymphoma; D-VRd, daratumumab, bortezomib, lenalidomide, and dexamethasone; FLT3, Fms-like tyrosine kinase 3; HCT, hematopoietic stem cell transplantation; HDT, high-dose chemotherapy; huCART19, humanized CD-directed CAR T cell; IDH, isocitrate dehydrogenase; KCd, carfilzomib, cyclophosphamide, and dexamethasone; KRd, carfilzomib, lenalidomide, and dexamethasone; MCL, mantle cell lymphoma; MDS, myelodysplastic syndrome; MM, multiple myeloma; MPN, myeloproliferative neoplasm; PFS, progression-free survival; R-CHOP, rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone; R-DHAP, rituximab, dexamethasone, high-dose cytarabine, and cisplatin; R/R, recurrent/refractory; VRd, bortezomib, lenalidomide, and dexamethasone.

Trial registration number (name)

Disease type



Acute leukemias
























AML (IDH2-mutated)








AML (IDH2-mutated)



AML (IDH1-mutated



AML (FLT3-mutated)



AML (FLT3-mutated)



AML (FLT3-mutated

























To evaluate the safety and efficacy of enasidenib as maintenance therapy after allo-HSCT

To evaluate the efficacy of standard-of-care allo-HSCT followed by gemtuzumab ozogamicin in patients with average risk

To examine the efficacy of venetoclax in combination with a standard allo-HSCT conditioning regimen prior to allo-HSCT

To evaluate the efficacy of CD123 CAR T cells


To evaluate the efficacy and safety of ivosidenib compared with conventional regimens in older patients


To compare the efficacy of ivosidenib and placebo in combination with azacitidine in previously untreated patients


To evaluate the efficacy of gilteritinib administered as maintenance therapy after allo-HSCT


To evaluate the efficacy of crenolanib administered as maintenance therapy after allo-HSCT


To compare the efficacy of crenolanib with that of midostaurin when administered after induction chemotherapy, consolidation chemotherapy, and bone marrow transplantation in newly diagnosed patients

Aggressive B-cell lymphomas



NCT03570892 (BELINDA)




























To compare the safety and efficacy of the standard-of-care strategy (HDT–auto-HSCT) vs JCAR017

To compare the efficacy, safety, and tolerability of tisagenlecleucel vs standard of care (HDT–auto-HSCT) after failure of rituximab and anthracycline-containing frontline chemoimmunotherapy

To evaluate the clinical efficacy of axicabtagene ciloleucel vs standard-of-care second-line therapy (auto-HSCT)

To establish one of three study arms as standard of care: R-CHOP/R-DHAP plus auto-HSCT vs R-CHOP/R-DHAP plus ibrutinib vs R-CHOP/R-DHAP plus ibrutinib plus auto-HSCT in previously untreated patients
















(BMT CTN 1901)





High-risk MM









High-risk MM



High-risk MM
























To test anti-BCMA CAR T cells in combination with huCART19 as consolidation of early therapy

To evaluate the efficacy and safety of induction with KRd or KCd followed by auto-HSCT and KRd/KCd consolidation vs KRd without transplantation, each followed by maintenance

To evaluate the efficacy of induction therapy with KRd with or without auto-HSCT

To evaluate the activity of D-VRd vs VRd in transplant-eligible patients

To evaluate the efficacy and safety of bb2121 in patients with early recurrence after one line of therapy (both including and excluding auto-HSCT as well as those with an inadequate response to initial therapy

To determine PFS in patients with poor-risk myeloma undergoing BCMA CAR T-cell therapy after auto-HSCT

To compare outcomes in patients with VRd induction followed by auto-HSCT and lenalidomide maintenance vs no transplantation and lenalidomide maintenance


According to current clinical guidelines from the European LeukemiaNet and the National Comprehensive Cancer Network allo-HCT should be considered for

  • fit patients with AML in first remission with intermediate-risk or adverse-risk cytogenetics, 
  • or refractory/recurrent (R/R) AML

Find out more here.

However, before allo-HSCT, patients need to undergo induction therapy, which in the past involved multi-agent chemotherapy, and required the patient to be in remission. After successful induction patients may be considered for allo-HSCT or receive consolidation chemotherapy. More information on the comparison of those two approaches in patients with AML can be found here. Recently, minimal residual disease (MRD) negativity has been identified as a marker for optimal outcome after allo-HSCT (you can find out more about the use of MRD in allo-HSCT here).

Impact of novel treatments

The introduction of novel agents (Table 1) gave more options for induction and consolidation therapies. CPX-351, a new liposomal formulation of the traditional cytarabine and daunorubicin, which more specifically targets leukemia cells, can now be used to induce remission in patients with high-risk AML and has been shown to induce better survival after transplantation. (Read more about it here).

Another, approved induction treatment is gemtuzumab ozogamicin (GO), an antibody-drug conjugate targeting CD33. Fractionated doses of GO added to standard chemotherapy showed significantly prolonged event-free survival in patients with previously untreated de novo AML and benefited patients with a favorable and intermediate-risk karyotype (Read more about GO efficacy here.) A recent study revealed that the benefit of GO  in patients with AML depends on mutational status and level of CD33 expression. However, due to the increased risk of veno-occlusive disease  with GO treatment, allo-HSCT is restricted within 90 days of receiving the drug. It should be kept in mind that GO is most commonly used in patients with core-binding factor AML, in whom transplantation is typically not considered in the early stages of the disease.

Venetoclax, a selective BH3 mimetic that inhibits Bcl-2, had a big impact on the therapeutic field of AML. It allows for more selective targeting of malignant cells and was shown to improve the efficacy of hypomethylating agents or low-dose cytarabine in patients ineligible for intensive therapy. As a result of more patients being in remission, venetoclax containing regimens allow more patients to proceed to allo-HSCT and achieve long-term remissions (read more here). 

In recent years a more targeted approach became available for patients with internal tandem duplications (ITDs) and mutations in Fms-like tyrosine kinase 3 (FLT3), associated with a worse prognosis in patients with AML, which can now be targeted during induction with a FLT3 inhibitor, midostaurin. (Watch Jorge Sierra giving an overview of midostaurin) The drug was shown to improve overall survival (OS) when added to standard induction and consolidation chemotherapy for patients with FLT3 ITD and tyrosine kinase domain–mutant AML. Patients receiving midostaurin had also improved transplant outcomes.

Patients with R/R AML carrying isocitrate dehydrogenase (IDH) mutations can now be treated with IDH inhibitors enasidenib and ivosidenib. Both drugs are also being investigated as post-transplant maintenance therapy (Table 2) and in combination with hypomethylating agents as frontline therapy. 


Targeted therapies have improved rates of remission and have shown to improve transplant outcomes. Immunotherapies, including bispecific T-cell engagers (BiTEs) and CAR T-cell therapies show promise and may potentially in the future replace the need for the transplant. However, that will depend on the results of the long-term follow-ups and overcoming technical challenges. Until then, allo-HSCT will still play an important role in the treatment of patients with AML.

Watch a debate on whether advances in diagnostics and new therapies reduce the need for allogeneic transplant in AML.

Aggressive lymphomas

High-dose chemotherapy followed by auto-HSCT is a second-line standard of care for patients with recurrent diffuse large B-cell lymphoma (DLBCL), and a frontline treatment in mantle cell lymphoma (MCL). However, with recent improvements in the efficacy of frontline therapy for MCL, some patients defer transplantation decision to second or subsequent remission.

The use of allo-HSCT after disease recurrence after auto-HSCT in aggressive B-cell lymphomas is limited to clinical trials but remains a potentially curative option.

Impact of novel agents

Although novel agents in the frontline treatment of patients with aggressive B-cell lymphomas did not  improve outcomes, a few of the novel agents have been recently approved in the R/R settings (Table 1), and others are being investigated (Table 2).  

Lenalidomide, an immunomodulatory drug, has demonstrated efficacy in patients with R/R DLBCL and R/R MCL, as well as in the frontline settings. The drug was shown to be suitable as a maintenance therapy in patients with relapsed DLBCL who are transplant ineligible or experienced a post-transplant relapse.2 Another promising agent is ibrutinib, a BTK inhibitor, that demonstrated robust and durable responses in patients with R/R MCL, and in combination with rituximab and lenalidomide induced high response rates in patients with DLBCL of the non-germinal center  molecular subtype.

Bortezomib added to R-CHOP has failed to improve progression-free survival (PFS) in patients with DLBCL but showed more promise in patients with R/R MCL. Results of one of the studies, showed PFS benefit from the addition of bortezomib consolidation and maintenance post‐transplant and R-CHOP, but the toxicity was increased.3

Amongst novel therapies CAR T-cell products revealed the biggest potential, with tisagenlecleucel and axicabtagene ciloleucel already approved for the treatment of R/R DLBCL, and JCAR017 (lisocabtagene maraleucel) also demonstrating high levels of efficacy with manageable toxicity profile. We have previously explored the topic of CAR T-cells in DLBCL and an overview is available here. CAR-T cell therapy is currently under investigation for replacing auto-HSCT in patients with R/R DLBCL (watch interviews with Marie-Jose Kersten and Gilles Salles).

Further evidence puts into question a routine use of transplantation in patients with aggressive B-cell lymphomas. In patients with DLBCL, who relapse within 12 months of first-line therapy, fail intensive frontline treatment, or those with positive positron emission tomography/computed tomography scans prior to transplantation do not benefit from auto-HSCT.

However, current efforts to identify optimal settings for novel agents in combination with existing standard-of-care regimens in both the frontline and R/R settings did not provide enough evidence of superior efficacy over auto-HSCT in DLBCL. Trials in patients with MCL investigating kinase inhibitors as adjuvant therapies or as a replacement for auto-HSCT in first-line settings are ongoing (Table 2). The impact of CAR T-cell therapies is also being evaluated.


For the time being, the role of auto-HCST in the management of patients with R/R DLBCL and MCL remains unchanged. However, in the future, cellular and targeted therapies may play a more important role in the treatment of patients with R/R DLBCL who do not benefit from standard salvage immunochemotherapy followed transplantation. Similarly, patients with MCL who achieve durable remission with novel agents added to first-line combination chemotherapy could potentially have transplantation deferred or even avoided.

Results of ongoing trials comparing outcomes in patients receiving CAR T-cell therapies vs transplantation will reveal if cellular therapies could change the current standard of care.

Multiple myeloma

Transplantation has long been part of the treatment pathway for patients with MM, with auto-HSCT more commonly used than allo-HSCT. We have previously explored the topic and an overview and can be found here

Allo-HSCT with reduced-intensity conditioning regimens can offer potentially curative graft-versus-myeloma effect while reducing treatment-related mortality seen with the use of myeloablative conditioning. An overview of the allo-HCST in MM is available here.

Patients have been shown to benefit more from transplants than standard chemotherapy. The introduction of induction regimens based on highly active novel drugs like bortezomib and lenalidomide did not change the value of transplantation (Table 1). However, it raised questions about the optimal timing of transplant (Read more about it here). In eligible patients, auto-HSCT is usually considered directly after induction therapy, however, some patients may prefer to delay it until the second remission. The therapy is not routinely offered to older patients, but, efficacy in patients aged ≥ 70 years has been recently demonstrated. 

Impact of novel therapies

Several novel agents have been recently approved for MM in R/R settings (Table 1).

The combination of daratumumab with lenalidomide and dexamethasone has been approved as front-line treatment in patients who are ineligible for transplant and based on the reports from clinical trials may be also approved as induction therapy in transplant-eligible patients improving outcomes in these patients. Information on other anti-CD38-based antibodies, such as daratumumab and isatuximab, can be found here

Early reports from a study comparing the efficacy of carfilzomib, lenalidomide, and dexamethasone alone or followed by auto-HSCT (Table 2) suggest high efficacy of this induction combination with transplantation. An updated efficacy analysis by risk status is available here.

Several immunotherapies, including BiTE antibodiesCAR T-cell therapies, and antibody-drug conjugates, are being investigated. Some researchers believe that in the future they may replace transplantation. You can find a more detailed overview of novel immunotherapies in myeloma treatment here. So far, the most widely studied target in MM has been B-cell maturation antigen (BCMA), with different trials ongoing (Table 2) using CAR T-cell products and antibody-drug conjugates. Other immunotherapies are using CD38, CD138, CD19, kappa light chain, NY-ESO-1, and SLAMF7 as targets. However, at this stage, it is difficult to predict if immunotherapies will be as successful for patients with MM as they have been for other hematologic cancers.


Auto-HSCT as consolidation therapy remains the standard of care for eligible patients. Ongoing studies will provide evidence on whether combining auto-HSCT with novel agents will improve patient outcomes. The impact of CAR T-cell products and immunotherapies in high-risk groups is showing encouraging results, however, it will not be known until the final results of the ongoing trials are reported. 

Allo-HSCT remains a valid treatment option for patients with high-risk MM who are young and fit.

Read about the impact of donor type on outcomes of allo-HSCT.

  1. Bair SM, Brandstadter JD, Ayers EC, Stadtmauer EA. Hematopoietic stem cell transplantation for blood cancers in the era of precision medicine and immunotherapy. Cancer. 2020. DOI: 10.1002/cncr.32659

  2. Ferreri AJ, Sassone M, Zaja F, et al. Lenalidomide maintenance in patients with relapsed diffuse large B-cell lymphoma who are not eligible for autologous stem cell transplantation: an open label, single-arm, multicentre phase 2 trial. Lancet Haematol. 2017;4(3):e137-e146. DOI: 10.1016/S2352-3026(17)30016-9
  3. Kaplan LD, Maurer MJ, Stock W, et al. Bortezomib Consolidation or Maintenance Following Immunochemotherapy and Autologous Stem Cell Transplantation for Mantle Cell Lymphoma: CALGB/Alliance 50403. Am J Hematol. 2020. DOI: 10.1002/ajh.25783


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