Alberta Bone Marrow and Blood Cell Transplant Program ...

1 Alberta Bone Marrow and Blood Cell Transplant Program : Standard Practice Manual BMT Standard Practice Manual Guideline Resource Unit Cancer Care Alberta BMT Standard Practice Manual Table of Contents Indications & Conditioning AML ALL MDS CML MPN (Ph neg) CLL Lymphoma Symptomatic Myeloma and AL Amyloidosis Aplastic Anemia Hemoglobinopathies Multiple Sclerosis Scleroderma Germ Cell Tumours Conditioning Complications GVHD CMV,VZV, HSV, HHV6 EBV/PTLD Bacterial/Pneumocytis Prophylaxis Fungal Prophylaxis Graft Failure and Poor Graft Function DLI/2nd HCT for Relapse Fever CVAD complications Hepatic Complications and Viral Hepatitis Cytokine Release Syndrome and Neurotoxicity Transfusions and Management of Cytopenias Early Post-HSCT Other Topics Patient Eligibility Donor Selection stem Cell Mobilization Chimerism Vaccination UCBT ABO Incompatibility Long Term Follow Up Microbially Contaminated & Non-Conforming Cellular Products Nutritional Support BMT Standard Practice Manual Additional Information Copyright Conflict of Interest Glossary of Abbreviations Revision History BMT Standard Practice Manual Indications and Conditioning 1 BMT Standard Practice Manual Last Reviewed.

2 June 15, 2021 Effective Date: June 15, 2021 Acute Myeloid Leukemia (AML) Presented by: Lynn Savoie Summary Disease risk stratification will be based on the cytogenetic and molecular features of the tumor cells , response to first induction, presence of secondary or therapy related disease, white Blood cell (WBC) at diagnosis and measurable residual disease. Patients with favorable cytogenetics and no unfavorable molecular changes show good response to chemo-immunotherapy and in the majority of cases will enter a second remission if relapse occurs. Patients with t(8;21) or inv(16) / t(16;16) without evidence of a KIT mutation should undergo allogeneic stem cell Transplant in CR2. Patients with a normal karyotype who are FLT3 ITD negative and either NPM1 mutation positive or CEBP biallelic mutation positive are expected to have a favorable outcome to chemo-immunotherapy and should be offered an allogeneic stem cell Transplant in CR2.

3 Patients in the intermediate cytogenetic risk group may be offered a Transplant from a matched sibling or a matched unrelated donor in CR1. This includes patients with a normal karyotype as well as non-informative cytogenetic changes. Patients with t(8;21) or inv(16) / t(16;16) and a KIT mutation appear to fall into this risk group. Patients with FLT3 ITD at low allelic ratio and with FLT3 TKD mutation also appear to fall into this risk group. Patients with high-risk features will likely not be salvageable at relapse and should be offered Transplant in first complete remission. This includes high-risk cytogenetics, those with a normal karyotype who are FLT3 ITD positive, various molecular findings on NGS, those requiring more than one chemotherapy cycle to achieve a complete remission, as well as those with secondary or therapy related disease or measurable residual disease after two cycles of chemotherapy.

4 Patients who relapse after conventional chemotherapy should undergo stem cell transplantation in CR2. It is preferable for patients to be in complete remission (defined as fewer than 5% blasts and no active extra-medullary disease) at the time of transplantation. Patients with untreated or refractory CNS disease or with circulating blasts are not eligible for transplantation. Patients should receive at least one cycle of post-remission therapy prior to transplantation if transplantation cannot occur within 4 weeks of the complete remission being achieved. Background Risk stratification in AML has traditionally relied on patient and disease characteristics at diagnosis (chiefly: age, cytogenetics, white Blood cell count at diagnosis and the presence of an antecedent hematological disorder or therapy related disease) and on the response to induction chemotherapy.

5 While patients in favorable risk categories may enjoy long-term disease free survival, AML may be virtually incurable with conventional treatment in patients with high-risk features and those with poor response to chemotherapy. Recently, the interaction of molecular abnormalities with cytogenetic risk groups has been defined. Risk-adapted therapy attempts to avoid exposing favorable-risk patients to 2 BMT Standard Practice Manual Last Reviewed: June 15, 2021 Effective Date: June 15, 2021 the morbidity and mortality risks of stem cell Transplant while directing high-risk patients to up-front Transplant in order to minimize relapse risk early in the course of therapy. Measurable residual disease (MRD) after induction and/or consolidation chemotherapy is also becoming more reliably prognostic.

6 Prognosis Cytogenetic Risk Groups Table 1. Southwest Oncology Group (SWOG) and Medical Research Council (MRC) criteria for favorable, intermediate, unfavorable and unknown cytogenetic risk groups. Classification SWOG Criteria MRC Criteria (as for SWOG, except): Favorable t(15; 17) with any other abnormality inv(16)/t(16; 16)/del(16q) with any other abnormality t(8; 21) without del(9q) or complex karyotype t(8; 21) with any other abnormality Intermediate +8, -Y, +6, del(12p) normal karyotype abnormal 11q23 del(9q),del(7q) without other abnormalities Complex karyotypes (> 3 abnormalities, but <5) All abnormalities of unknown prognostic significance Unfavorable -5/del(5q), -7/del(7q), t(8; 21) with del(9q) or complex karyotype inv(3q), abn11q23, 20q, 21q,del9q, t(6; 9) t(9.)

7 22), abn17p, Complex karyotypes (>3 abnormalities) Complex karyotypes (>5 abnormalities) Unknown All other clonal chromosomal aberrations with fewer than 3 abnormalities Table 2. Results with conventional chemotherapy. Results with Conventional Chemotherapy Favorable Cytogenetics Intermediate Cytogenetics Unfavorable Cytogenetics CR 80-90% ~70% 30-50% DFS 70-85% 40-55% 10-20% Abbreviations: CR = complete remission; DFS = disease-free survival. 3 BMT Standard Practice Manual Last Reviewed: June 15, 2021 Effective Date: June 15, 2021 Table 3. Relapse rates associated with post-remission therapies. Relapse Rates with post-remission therapies Study Allogeneic Transplant Autologous Transplant Chemotherapy GIMEMA 1995 24% 40% 57% GOELAM 1997 28% 45% 55% MRC 1998 19% 35% 53% ECOG/SWOG 1998 29% 48% 61% Data for children excluded.

8 In the MRC study, BMT was compared with an observation arm after 4 cycles of chemotherapy, rather than a direct comparison with high dose chemotherapy as in the other studies. Molecular Risk Groups Patients with normal cytogenetics make up the largest group of patients with AML, yet they show significant variability in outcomes with standard treatment. The likely explanation for this finding is the influence of molecular abnormalities that go undetected by standard cytogenetics. Among these abnormalities, mutations of NPM-1 and CEBPA are associated with significantly better overall survival (OS) compared to patients with the wild-type loci. Mutations to FLT-3 confer inferior OS on patients who harbor these mutations. Similarly, while cytogenetic abnormalities that disrupt Core Binding Factor (t (8;21) and inv(16)) are typically associated with favorable outcomes with conventional therapies, the presence of mutations of c-Kit in these disorders confers a significantly shorter OS and a marked increase in the cumulative incidence of relapse.

9 Patients with these abnormalities should be considered for early allogeneic stem cell Transplant . Next-generation sequencing is now done routinely in Transplant eligible patients and allows for the detection of many other known mutations of potential clinical significance. RUNX1 and AXSL1 mutations, each occurring in 10-15% of AML patients, have each been associated with adverse prognosis, particularly when occurring in intermediate risk disease, and these patients appear to benefit from Transplant in CR1. Similarly, TP53 and splicing factor mutations ( SRSF2) have also been associated with independently adverse prognosis. RUNX1, ASXL1 and TP53 mutated disease have been assigned to the adverse risk group in the 2017 ELN classification, except when they occur in otherwise ELN favorable risk disease.

10 Therefore, this mutational information can be helpful in risk stratification. With respect to other mutations ( DNMT3A, IDH, TET2) the data regarding prognosis are less clear. Combined Cytogenetic and Molecular Risk Groups Table 4 outlines the risk groups according to the European LeukemiaNet (ELN) classification. 4 BMT Standard Practice Manual Last Reviewed: June 15, 2021 Effective Date: June 15, 2021 Table 4. Risk groups according to the ELN classification. Risk category Genetic Abnormality Favorable t(8;21) (q22; ); RUNX1-RUNX1T1 ivn(16)( ) or t(16;16)( ;q22); CBFB-MYH11 Mutated NPM1 without FLT3-ITD or with FLT3-ITDlow Biallelic mutated CEBPA Intermediate Mutated NPM1 and FLT3-ITDhigh Wild-type NPM1 without FLT3-ITD or with FLT3-ITDlow (without adverse-risk genetic lesions) t(9;11)( ; ); MLLT3-KMT2A Cytogenetic abnormalities not classified as favourable or adverse Adverse t(6;9)(p23; ); DEK-NUP214 t(v; ); KMT2A rearranged t(9;22)( ; ); BCR-ABL1 inv(3)( ) or t(3;3)( ; ); GATA2,MECOM(EVI1) -5 or del(5q); -7.