Clinical practice guidelines for transplant and cellular therapies in mantle cell lymphoma: recommendations from ASTCT, CIBMTR, and EBMT

Mantle cell lymphoma (MCL) is a B-cell lymphoma with marked heterogeneity in clinical presentation, molecular profile, and management—in both the frontline and relapsed/refractory (R/R) settings. Treatment options for frontline therapy include induction followed by high dose therapy and autologous (auto-) hematopoietic cell transplantation (HCT) consolidation, or combination chemoimmunotherapy regimens alone without subsequent high dose therapy consolidation. In high-risk R/R MCL, selection of treatment modality is even more complicated due to newer therapies such as Bruton’s tyrosine kinase (BTK) inhibitors, lenalidomide, and chimeric antigen receptor (CAR) T-cell therapy.

Due to the complexities associated with the treatment of MCL, it is important to have guidance on the contemporary role, optimal timing, and sequencing of cellular therapies in MCL to help experts in making better treatment related decisions.

Recently, Munshi, et al.¹ published recommendations developed by joint effort of the American Society of Transplantation and Cellular Therapy (ASTCT), the Center of International Blood and Marrow Transplant Research (CIBMTR), and the European Society for Blood and Marrow Transplantation (EBMT) regarding the role, timing, and sequencing of auto-HCT, allogeneic (allo-) HCT and CAR T-cell therapy for patients with newly diagnosed and R/R MCL.

Methods

Panel composition

A steering committee comprised of six members—one representative each from ASTCT, EBMT and CIBMTR, two project coordinators, and an independent methodologist—drafted the protocol and initial consensus statements and practice considerations and set up a panel of experts. The panel consisted of 33 physicians and investigators with diverse geographical representation and expertise in the field of MCL, cellular therapy, and transplant.

Consensus methodology

The RAND-modified Delphi method was used to generate consensus statements addressing the role, timing, and sequencing of HCT and CAR T-cell therapies in patients with newly diagnosed and R/R MCL. The following steps were involved in the development of consensus statements (Figure 1 provides an outline for the process):

• concept development and approval by CIBMTR, EBMT, ASTCT
• protocol development according to the modified Delphi method
• identification of participant baseline demographics
• determination of project scope
• review of results of baseline demographics and project scope
• generation of questions related to sequence of cellular therapy and practice scenario for first voting survey (issued to panel)
• revision and modification of recommendations not reaching consensus threshold
• development of second voting survey including revised clinical practice recommendation statements
• drafting of manuscript if consensus has been reached based on pre-defined threshold

Mantle cell lymphoma (MCL) is a B-cell lymphoma with marked heterogeneity in clinical presentation, molecular profile, and management—in both the frontline and relapsed/refractory (R/R) settings. Treatment options for frontline therapy include induction followed by high dose therapy and autologous (auto-) hematopoietic cell transplantation (HCT) consolidation, or combination chemoimmunotherapy regimens alone without subsequent high dose therapy consolidation. In high-risk R/R MCL, selection of treatment modality is even more complicated due to newer therapies such as Bruton’s tyrosine kinase (BTK) inhibitors, lenalidomide, and chimeric antigen receptor (CAR) T-cell therapy.

Due to the complexities associated with the treatment of MCL, it is important to have guidance on the contemporary role, optimal timing, and sequencing of cellular therapies in MCL to help experts in making better treatment related decisions.

Recently, Munshi, et al.¹ published recommendations developed by joint effort of the American Society of Transplantation and Cellular Therapy (ASTCT), the Center of International Blood and Marrow Transplant Research (CIBMTR), and the European Society for Blood and Marrow Transplantation (EBMT) regarding the role, timing, and sequencing of auto-HCT, allogeneic (allo-) HCT and CAR T-cell therapy for patients with newly diagnosed and R/R MCL.

Methods

Panel composition

A steering committee comprised of six members—one representative each from ASTCT, EBMT and CIBMTR, two project coordinators, and an independent methodologist—drafted the protocol and initial consensus statements and practice considerations and set up a panel of experts. The panel consisted of 33 physicians and investigators with diverse geographical representation and expertise in the field of MCL, cellular therapy, and transplant.

Consensus methodology

The RAND-modified Delphi method was used to generate consensus statements addressing the role, timing, and sequencing of HCT and CAR T-cell therapies in patients with newly diagnosed and R/R MCL. The following steps were involved in the development of consensus statements (Figure 1 provides an outline for the process):

• concept development and approval by CIBMTR, EBMT, ASTCT
• protocol development according to the modified Delphi method
• identification of participant baseline demographics
• determination of project scope
• review of results of baseline demographics and project scope
• generation of questions related to sequence of cellular therapy and practice scenario for first voting survey (issued to panel)
• revision and modification of recommendations not reaching consensus threshold
• development of second voting survey including revised clinical practice recommendation statements
• drafting of manuscript if consensus has been reached based on pre-defined threshold

Figure 1. Outline of the steps for manuscript development  

BD & S, baseline demographics and scope; SC, steering committee.
*Adapted from Munshi, et al.¹

Results

The steering committee methodologist analyzed and summarized the results.

Demographic information about the members of consensus panel is included in Table 1.

Table 1. Demographic information of consensus panel members*

First voting survey

The first voting survey consisted of 19 statements which were:

• specific to the role of auto-HCT in eligible patients with newly diagnosed MCL (6 statements)
• for patients with R/R MCL (2 statements)
• about allo-HCT for newly diagnosed patients with MCL (3 statements)
• about allo-HCT and/or CAR T-cell therapy for R/R MCL (8 statements)

All but five statements achieved consensus by predefined criteria (<75% agreement); four were revised and one was abandoned. Of the five statements that did not achieve consensus, three were proposed for the second voting survey after discussion via virtual video conference.

Second voting survey

The three statements included in the second voting survey (two reformulated statements and one merged statement) met the predefined criteria for consensus.

Consensus statements in the front-line setting for MCL

Final clinical practice guideline consensus statements for transplantation and CAR T-cell treatments in the frontline setting for MCL are stated in Table 2.

Table 2. Clinical practice recommendations for HCT in the frontline setting for MCL

Consensus statements for R/R-MCL

Final clinical practice guidelines consensus statements for transplantation and CAR T-cell treatments for relapsed and/or refractory MCL are stated in Table 3.

Table 3. Final clinical practice guidelines statements for HCT for R/R-MCL

Conclusion

The guidelines and recommendations reported in this article, for the use of HCT in the treatment of newly diagnosed and R/R MCL, would be useful to address the gaps in knowledge regarding optimal timing and sequencing of these therapies in patients with MCL.

These guidelines recommend auto-HCT consolidation in the first-line setting as standard-of-care in eligible patients, though the panel acknowledged that, due to a lack of evidence for a survival benefit with upfront auto-HCT consolidation, some centers do not routinely recommend auto-HCT after frontline intensive induction regimens.

In the R/R setting, the preferential option is CAR T-cell therapy, especially in patients with MCL not responding/ intolerant to at least one BTK inhibitor, due to increased toxicities and life-threatening complications of allo-HCT. Allo-HCT is recommended if CAR T-cell therapy fails, if the patient achieves complete or partial remission, or if the patient has stable disease with subsequent anti-lymphoma treatment.

The authors concluded that RAND-modified Delphi methodology is effective in providing a formal framework for the development of consensus recommendations for the timing and sequence of cellular therapies for MCL. Lack of evidence for certain modalities, such as allo-HCT and CAR T-cell therapy, has limited their use in clinical practice; however, the treatment algorithm will eventually evolve with progress in the area of CAR T-cell therapy and BTK inhibitors.