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 chemoimmunotherapy and should be offered an allogeneic stem cell transplant in CR2.#
- 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.
- 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.
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. 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 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.
Cytogenetic Risk Groups Abbreviations: CR = complete remission; DFS = disease-free survival.

# 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. 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 (e.g. 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. Therefore, this mutational information can be helpful in risk stratification. With respect to other mutations (e.g. DNMT3A, IDH, TET2) the data regarding prognosis are less clear.   5 adds measurable residual disease after 2 cycles of chemotherapy (e.g., 1 induction and 1 consolidation) and other prognostic factors to the cytogenetic and molecular risk stratification to further help with decision on allogeneic stem cell transplantation in first complete remission. Abbreviations: CA = cytogenetic abnormalities; CBF = core binding factor; CN = cytogenetically normal; CRe = early complete remission; EBMT = European Group for Blood and Marrow Transplantation; HCT-CI= hematopoietic cell transplantation comorbidity index; ITD = internal tandem duplication; MK = monosomal karyotype; NA = not applicable; NRM = non-relapse mortality; -X -Y = deleted X or Y chromosome.

# Combined Cytogenetic and Molecular Risk Groups
If CR has been achieved further therapy is necessary for potential cure. The nature of consolidation therapy must be individualized for each patient based on a risk analysis of the risk of relapse of the AML versus the risk of the proposed consolidation therapy. This will depend on prognostic features of the leukemia, response to therapy, performance status and type of hematopoietic stem cell donor available. High dose Ara-c (HiDAC) is the mainstay of consolidation chemotherapy as there has been shown to be a dose intensity effect to cytarabine suggesting that HiDAC is necessary in induction or consolidation. Additional agents such as FLT3 inhibitors or gemtuzumab ozogamicin are added as indicated and CPX-351 can replace HiDAC in the appropriate patients. Generally at least one cycle is administered in all patients if only to allow for planning of an allogeneic stem cell transplant although the absolute need for this is controversial. Autologous stem cell transplantation shows some superiority in event-free survival over chemotherapy alone for consolidation, however is not routinely recommended unless a donor is not available.
- Favorable risk patients: In patients with AML with t(8;21), inv 16 or isolated NPM1 mutation data suggests that provided there are no additional risk factors multiple cycles of HiDAC provide higher overall survival than lower doses of cytarabine or stem cell transplant. Our recommendation is 2-4 cycles of HiDAC post induction chemotherapy accompanied by gemtuzumab ozogamicin for the first two cycles.
- Intermediate risk patients: HiDAC has been shown to be preferable to lower dose cytarabine in this cytogenetic group as well but its superiority over stem cell transplantation has not been established. It is generally recognized that an allogeneic stem cell transplant provides a decreased relapse rate at a cost of increased treatment related mortality when compared to consolidation chemotherapy or autologous transplantation. The transplant related mortality gap between match related and unrelated donors has been shown to be significantly reduced in recent years. A suitable hematopoietic stem cell donor should be sought and myeloablative stem cell transplantation should proceed as soon as possible, ideally after one cycle of HiDAC based on a risk/benefit analysis.
- High risk patients: All efforts should be undertaken to find a suitable donor for eligible high-risk patients. During that time the patient should receive ongoing cycles of HiDAC chemotherapy up to a total of 4 cycles or CPX-351 up to 2 cycles. The patient should proceed to allogeneic stem cell transplantation as soon as a donor is identified.
- The search for a donor should be undertaken for all patients, including those with standard risk disease until it has been proven that they can tolerate the intensification portion of the chemotherapy protocol. - Transplantation in first complete remission will be offered to patients who meet other eligibility criteria and who have any one of the following: o A high white blood cell count at diagnosis (pre-B cell phenotype > 30, pre-T cell phenotype > 100). o Failure to enter complete measurable residual disease negative remission within 28 days of starting induction chemotherapy. o Complex (>5 abnormalities), low hypodiploid (30-39 chromosomes) or near triploid (66-79 chromosomes) karyotypes. o t(8;14), KMT2A gene rearrangements or IKZF1 mutations. o Philadelphia-like disease. o Intolerance of post-induction chemotherapy such that less than 80% of scheduled chemotherapy is likely to be delivered. - Transplantation in first complete remission should be considered in patients with Philadelphia chromosome positivity who do not achieve early MRD clearance or who are unable to tolerate planned chemotherapy - Patients without documented CNS disease should receive at least four doses of intrathecal chemotherapy for CNS prophylaxis prior to transplant. - Patients should be in remission (defined as fewer than 5% blasts in a normocellular bone marrow and no active extramedullary disease or circulating blasts) at the time of transplantation. - BCR-ABL will be monitored post-transplant and TKI therapy re-instituted upon any evidence of molecular positivity. TKI prophylaxis should be considered for those with high-risk disease at the time of transplant (see below for details). - Stem cell transplantation should be offered to all transplant-eligible patients with recurrent ALL, a suitable donor and meeting general eligibility criteria (including remission status) for transplantation. - CAR-T therapy with Tisagenlecleucel may be offered in the setting of relapsed or refractory disease.
The age-adjusted incidence rate of ALL in the US is 1.6 per 100,000 individuals per year, with approximately 6070 new cases and 1430 deaths estimated in 2013 1,2. The median age at diagnosis is 2 www.ahs.ca/guru BMT Standard Practice Manual Last Reviewed: October 11, 2022 Effective: October 11, 2022 14 years; 60% of patients are diagnosed at younger than 20 years, whereas 24% are diagnosed at 45 years or older 2. The potential years of life lost due to leukemia in Canada has been reported to be 37,000 3. The large number of years lost for a relatively uncommon diagnosis reflects the occurrence of leukemia among very young individuals and the high mortality these patients experience.
With current treatment regimens, the cure rate among children with ALL is approximately 80-90% 4. The long-term prognosis for adults with ALL treated with conventional chemotherapy regimens, however, remain poor, with cure rates of only 30 to 40% . This reflects the greater tendency for older individuals to have adverse chromosomal markers (notably t (9; 22)) and other unfavorable prognostic indicators (high white blood cell (WBC) count, longer time to complete response). Multidrug chemotherapy regimens have been the standard approach to treatment of adults with ALL. Such regimens generally consist of 4-or 5-drug induction protocols followed by intensive re-induction, consolidation or intensification to address residual disease. These regimens also feature CNS prophylaxis in the form of whole brain radiotherapy or intrathecal chemotherapy and prolonged antimetabolite-based maintenance, as has been used successfully in management of pediatric cases.
In recent years, a growing body of data has shown that, at least for late adolescents and young adults (defined variably up to 40 years of age), treatment with pediatric-based protocols produces superior outcomes to the regimens standardly used in adults . Canadian data has shown that a pediatric approach can safely be extended to adults up to the age of 60 with only minor modifications 18. This protocol is heavily dependent on L-Asparaginase in intensification and has been shown to have the best outcomes if 80% of L-Asparaginase doses can be delivered; this has been shown to be possible in 80% of patients. Meaningful comparisons of this strategy with early transplantation have yet to be published.
Many novel therapies are being studied in the management of ALL and may affect the need for or the outcome of stem cell transplantation in the future. These include Blinatumomab 19 Inotuzumab 20 the addition of Rituximab to chemotherapy 21 and CAR-T cell therapy 22.
CNS prophylaxis in the form of, intrathecal chemotherapy and/or high dose systemic chemotherapy has been shown to be necessary throughout chemotherapy and prior to stem cell transplantation.

# Risk Stratification in ALL
Risk stratification in adult ALL has been based on disease (molecular findings, cytogenetics, WBC at diagnosis, response to treatment) and patient (chiefly age) factors. Leukemic blasts with T-cell or mature B-cell immunophenotype or the presence of a mediastinal mass are associated with overall improved survival. Blasts bearing the Philadelphia chromosome or t(4; 11), older patient age, high WBC or poor response to chemotherapy (> 4 weeks to complete response) portend a poor outcome The use of minimal residual disease (MRD) has been well-established in children with ALL. Studies in adults have also shown the strong correlation between MRD and risks for relapse, and the prognostic significance of MRD measurements during and after initial induction therapy. How to ultimately use MRD in deciding on the need for hematopoietic stem cell transplantation has not yet been fully established but is likely to play a role, particularly when tested after induction .

# Hematopoietic Stem Cell Transplant (HSCT)

# Transplantation in First Complete Remission
At any stage of disease, allogeneic bone marrow transplantation (BMT) results in lower relapse risk than standard chemotherapy. Many investigators have been unable to demonstrate an improvement in overall survival using this strategy as a result of high treatment-related mortality in this modality. Investigators at Princess Margaret Hospital reported their experience with a policy of allogeneic HSCT for all patients with ALL younger than 55 who had a related donor. Patients with Philadelphiachromosome positive ALL were offered transplantation from a matched, unrelated donor if one was available. This strategy resulted in 3-year EFS of 40% for patients with donors and 39% for patients without. This strategy of universal allogeneic stem cell transplantation in ALL failed to improve outcome of patients with Philadelphia-negative ALL, while outcome was equivalent among patients with Philadelphia-positive disease.
In other cases the difference between allogeneic blood cell transplantation (BCT) and conventional chemotherapy has been more pronounced. The French LALA '87 trial demonstrated improved overall survival among high-risk patients undergoing alloHSCT in CR1 (10-year OS 44%), compared with those who received chemotherapy or autologous BCT (10-year OS 11%). A similar impact on survival Transplantation in first complete remission will be offered to patients who meet other eligibility criteria and who have any one of the following: o A high white blood cell count at diagnosis (pre-B cell phenotype > 30, pre-T cell phenotype > 100). o Failure to enter complete measurable residual disease negative remission within 28 days of starting induction chemotherapy. o Complex (>5 abnormalities), low hypodiploid (30-39 chromosomes) or near triploid (66-79 chromosomes) karyotypes. o Philadelphia chromosome (or BCR-Abl), t(8;14), KMT2A gene rearrangements or IKZF1 mutations. o Philadelphia-like disease. o Intolerance of post-induction chemotherapy such that less than 80% of scheduled chemotherapy is likely to be delivered.

# Philadelphia-positive Acute Lymphoblastic Leukemia
Twenty to forty percent of transplant-eligible adults with ALL will be found to have the Philadelphia chromosome as a sole or contributing cytogenetic abnormality. Patients with this abnormality tend to have other adverse prognostic features and have the lowest CR rate (< 65%) and shortest remission durations (median remission duration ~ 9 months) with conventional therapy. Overall survival is between 0 -16%. In single-institution, non-randomized studies, leukemia-free survival after allogeneic BCT for Philadelphia-positive ALL is 30-40%.

# CAR-T Therapy
Tisagenlecleucel is indicated in Canada for the treatment of relapsed or refractory acute lymphoblastic leukemia in patients under the age of 26. This indication is based partly on the results of a single-cohort, multi-center phase II trial (ELIANA) conducted by Maude et al 54. In this study, children and young adults with relapsed or refractory CD19+ B-cell ALL received a single infusion of tisagenlecleucel after lymphodepleting chemotherapy. The primary end point, the overall remission rate at 3 months, was 82%, with all responding patients negative for MRD by flow cytometry. Eventfree and overall survival were 50% and 76% at one year. Cytokine release syndrome occurred in 77% of patients, with tocilizumab required in 48%. Neurological events occurred in 40%. There were significant improvements in patient-reported outcomes (PedsQL and EQ-5D) three months after treatment 55. Real world evidence in 255 patients with relapsed or refractory ALL further supports the use of tisagenlecleucel in this context. In this report twelve-month EFS and OS were 52.4% and 77.2% 56.
Brexucabtagene autoleucel has been approved by the FDA for use in adults with relapsed or refractory ALL based on the ZUMA-3 phase II study. This showed that in patients aged 28-52 with a median followup of 16.4 months, 39 patients had complete remission or complete remission with incomplete haematological recovery, with 31 (56%) patients reaching complete remission. Median duration of remission was 128 months, median relapse-free survival was 116 months and median overall survival was 182 months. Among responders, the median overall survival was not reached, and 38 (97%) patients had MRD negativity 57.
As yet there is no data to guide the sequencing of CAR-T cell therapy and transplantation in this setting.
- All patients should have risk stratification including calculation of the Revised International Prognostic Scoring System (R-IPSS) at diagnosis.
- Patients with high (>4.5 to 6 points) or very high (>6 points) R-IPSS should be offered HCT if they are transplant-eligible.
- Patients with intermediate (>3 to 4.5 points) R-IPSS with symptomatic cytopenias or evidence of disease progression, who are transplant-eligible, can be considered for allogeneic HCT; with consideration of patient values and discussion around risks of transplant compared to the underlying disease.
- Sibling typing should be initiated at the earliest opportunity for all transplant-eligible patients.
- Disease control as a bridge to transplant with induction chemotherapy (consider if blasts >10% and no TP53 mutation and/or adverse cytogenetic profile) or hypomethylating agents such as azacitidine should be considered for patients with higher risk disease or elevated blast counts at presentation. The optimal therapy in this setting is not clear.
- Consider minimizing iron overload pretransplant to minimize the adverse effects of iron overload on treatment-related mortality.
- Myeloablative conditioning is preferred over non-myeloblative conditioning in patients who are fit to improve patient outcomes. Our standard conditioning is myeloablative busulfan + fludarabine + 4Gy TBI (see Conditioning chapter).
- Patients under the age of 40 or with an appropriate family history should be screened for congenital causes of MDS (i.e. Fanconi, dyskeratosis congenita). Appropriate consideration of hereditary syndromes should be made during donor search and planning of conditioning.
- In very high-risk patients, i.e., complex karyotype and p53 mutation, alternatives to transplant should be considered.
Myelodysplastic syndromes are a heterogeneous group of related clonal stem cell disorders featuring dysplastic changes in one or more bone marrow cell lines, ineffective hematopoiesis, bone marrow failure, and often clonal evolution and/or transformation to acute leukemia. It is a disorder of the elderly, with a median age of 65-70 years at diagnosis. Allogeneic stem cell transplantation remains the only curative option; however the majority of patients are not eligible for transplantation due to age and/or comorbidity. For those who are eligible, the variable natural history of the disease and relative toxicity of transplant are important factors in the decision between supportive care, hypomethylating agents, lenalidomide, medical therapy including growth factors and allogeneic transplantation, and clinical trials.
A history and physical exam should investigate for potential etiology of MDS:
- Ionizing radiation - Cytotoxic agents (i.e., alkylating agents, topoisomerase inhibitors)
- Occupational or environmental carcinogens (i.e., viruses, benzenes, heavy metals)
- Inherited disorders (i.e., Fanconi anemia) especially in consideration of related donors - Antecedent hematologic disorders (i.e. paroxysmal nocturnal hemoglobinuria, aplastic anemia).
Cytogenetic abnormalities are found in 40-70% of de novo MDS, and 95% of therapy-related MDS.    Incorporation of molecular data into the Revised IPSS score has been found to improve prognostication in MDS. Independent significant prognostic factors for survival include age, R-IPSS, EZH2, SF3B1 and TP53 3. A linear predictive model was built which resulted in four prognostic groups (low, intermediate-1, intermediate-2 and high) with a median overall survival of 37.4, 23.2, 19.9 and 12.2 months, respectively, (P<0.001).

# Intensity of Treatment in Allogeneic Stem Cell Transplantation for MDS
Reduced intensity conditioning therapy is known to have a higher relapse rate in MDS but lower treatment-related mortality. In a retrospective study of 836 patients with MDS transplanted with an HLA matched sibling, the 3-year relapse rate was higher in patients given reduced intensity conditioning (HR 1.6, p=0.001) but a corresponding decrease in 3-year non-relapse mortality (NRM) resulted in similar progression-free survival (PFS, 33% vs. 39%) and overall survival (OS) rates (41% vs. 45%). 4 The role of treatment intensity was evaluated in a randomized multicenter phase III clinical trial comparing reduced intensity conditioning (RIC) including FluBu2 (2 days busulfan) to myeloablative conditioning regimens including our current conditioning fludarabine and busulfan without TBI. 5 The study was stopped early due to increased relapse rates with RIC 48% vs 13.5%) with a nonsignificant reduction in OS at 18 months (68% vs 78% for RIC and MAC, respectively) and a lower relapse-free survival with RIC (47% vs 68%). Notably, TRM was lower at 4.4% with RIC vs 15.8% with MAC. Outcomes with FLUBUP/TBI remain to be determined but compare favorably with these series. Local outcomes comparing the use of TBI in patients with MDS from 1999-2010 suggest improved 2-year DFS in patients given FLUBUP/TBI compared to FLUBUP alone (2-year DFS 67% vs. 41%) although with small numbers the difference is not statistically significant. The decision has been made to incorporate TBI in the transplant regimen of patients with MDS.

# Outcomes with Allogeneic Transplantation
An EBMT review of 1333 patients age >50 with high risk MDS or secondary AML who received allogeneic sibling (61%) or unrelated donor (39%) hematopoietic stem cell transplant with a myeloablative (38%) or reduced intensity conditioning (62%) regimen. 6 Of the 1333 patients, 449 (34%) were >60y of age. Four-year OS was 31%. Factors associated with higher risk of relapse include use of RIC (HR 1.44, P<0.01) and advanced disease stage at transplantation (HR, 1.51; P<0.01). Factors associated with increased non-relapse mortality include advanced disease stage at transplantation (HR, 1.43; 95% CI, 1.13 to 1.79; P = 0.01), use of an unrelated donor (P = 0.03), and RIC (HR, 0.79; 95% CI, 0.65 to 0.97; P =0.03). The major factor associated with 4-year OS was disease stage at transplantation (HR, 1.55; P<0.01) and challenges remain in with both higher relapse rates posttransplant and higher treatment-related mortality with MDS compared to de novo AML.
A single-centre study at the University of Wisconsin describes the importance of pre-transplant disease burden (as reflected by the proportion of bone marrow blasts at transplant). Patients entering transplant with 5% blasts): relapse rates were similar for patients with >5% blasts, regardless of whether myeloablative or non-myeloablative conditioning was used (28% (CI 8-48%) vs. 50% (CI 18-82%), p=0.33).
As NGS studies become available and more information is available about disease prognostication with transplant. A Japanese study of 797 patients with MDS showed that in patients with cytogenetics and NGS testing, cox regression analysis showed approximately 70% of the hazard ratio of transplant was related to clinical factors ie performance status, comorbidities, transfusion history and 30% contributed by adverse genetic risk. 8 An especially high risk category of patients with both mutation TP53 and complex karyotype did very poorly with transplant with a median survival of 4.8 months; 38% died before day 100 and >80% within 2 years of transplant, largely due to early relapse in 60% of patients. A retrospective review of 1514 patients with MDS undergoing stem cell Bridge to HCT. The use of azacitidine provides further options for care and potentially for bridge to transplantation and cytoreduction. Several case series using azacitidine as bridge to transplantation shows this treatment is feasible; effect on transplant outcomes is being determined.  An EBMT retrospective review of 209 patients with higher risk MDS showed that outcomes at 3 years were not significantly different between patients treated with hypomethylating agents or chemotherapy prior to HCT with respect to OS (42% versus 35%), RFS (29% versus 31%), cumulative incidence of relapse (45% versus 40%), and NRM (26% versus 28%), despite younger age and a higher proportion of patients with primary refractory disease in the hypomethylating group arm. 15 In patients with very high blast counts >10% and a planned rapid progression to transplant, chemotherapy can provide a faster response and is more likely to result in a CR to help bridge to transplant, but has more toxicities. For patients with monosomy 7, del 7q, 3 chromosomal abnormalities, or mutation of TP53, hypomethylating agents are recommended over intensive chemotherapy or supportive care due to poor response rates to intensive chemotherapy in MDS patients with these features. For patients with high-risk disease, treatment is recommended as a bridge to curative therapy during transplant workup. First Line Therapy:
- First line therapy is with a tyrosine kinase inhibitor (TKI) (imatinib, dasatinib or nilotinib)
- Molecular monitoring with quantitative PCR (polymerase chain reaction) every 3 months o Cytogenetics and mutation analysis as per the chronic myeloid leukemia (CML) treatment guidelines o Assess milestones as per provincial CML treatment guidelines Subsequent Therapy:
- Adjust TKI therapy as per CML treatment guidelines for patients showing resistance or intolerance to first-line therapy, options include imatinib, dasatinib, nilotinib, bosutinib, ponatinib or asciminib - In patients on a second generation TKI showing warning signs, who experience a suboptimal response or failure and are otherwise transplant eligible, perform human leukocyte antigen (HLA) typing of patient and siblings followed by a search for a volunteer unrelated donor (VUD) if no suitable family member is identified - Transplantation should be undertaken for eligible patients who fail to meet the provincial treatment guideline milestones for response to two second generation TKIs and/or asciminib - Transplantation should be undertaken in eligible patients who are unable to tolerate tyrosine kinase inhibitors such that compliance becomes an issue - Patients found to carry the T315I mutation should receive ponatinib or asciminib during the donor search and workup periods

# Accelerated Phase
- HLA type patients and siblings and proceed with VUD search if no family match identified - Use tyrosine kinase inhibitors as a bridge to transplantation in eligible patients (may be sufficient in good prognosis groups such as clonal progression only) - Allogeneic stem cell transplantation preferred in eligible patients

# Blast Phase
- HLA type patients and siblings and proceed with VUD or alternate donor search if no family match identified - Attempt to induce CP2 prior to allogeneic stem cell transplantation with chemotherapy and TKIs - Transplantation is contraindicated in blast phase

# Monitoring for Relapsed/Refractory CML Post Transplantation
- Quantitative peripheral blood PCR for brc/abl transcript every 3 months for 2 years then every 6 months to 5 years and then yearly to coincide with scheduled follow up appointments

# Treatment of Relapsed Disease Posttransplant
Molecular relapse or relapse in chronic phase:
- Minimize immunosuppression - Initiate therapy with a second generation TKI, preferably one not used pre-transplant if a positive PCR is detected at 6 months post-transplant or if the BCR/ABL ratio is rising prior to that - If no response toTKI a mutation analysis should be sent prior to proceeding to escalating doses of TKI Accelerated phase relapse:
- Minimize immunosuppression - Perform mutation analysis - Initiation of TKI therapy with a second generation TKI preferably one not used pre-transplant - If no response to TKI proceed to escalating doses of TKI - Consider TKI in conjunction with DLI - Consider a second transplant based on GVHD status, age, comorbidities and time from first transplant

# Blast phase relapse:
- Minimize immunosuppression - Perform mutation analysis - Re-induce chronic phase prior to a second transplant in eligible patient-overall prognosis poor; palliation is a reasonable choice Background Chronic myelogenous leukemia makes up 14% of new leukemias, with a median age of 67 years. It is associated with the Philadelphia chromosome t(9;22) and p190, p210 or p230 bcr/abl fusion proteins. The Philadelphia chromosome is found in multiple cell lineages including granulocyte, erythroid, megakaryocyte, and B lymphocyte lineages. Progression of disease is often associated with cytogenetic evolution with common additional abnormalities including +Ph, +8, i(17q) and +19. of 76% with the BuCy (busulfan + cyclophosphamide) protocol (p-value not significant). Transplantrelated mortality at 3 years was 0% compared to 24% with BuCy (p=0.03). Further data is being accrued.

# Allotransplants in the Post TKI Era
There is no evidence that transplant outcomes are worse in patients who have received prior tyrosine kinase inhibitors. A recent IBMTR analysis of 409 patients transplanted with prior imatinib exposure (9% imatinib intolerance, 37% imatinib failures, remainder planned transplants up front) and 900 patients without imatinib exposure revealed than in patients transplanted in first chronic phase, prior imatinib was associated with better overall survival, and no difference in transplant-related mortality, relapse, or leukemia-free survival. 9 This was confirmed in a matched pairs analysis. In patients with advanced CML, there was no difference between groups in transplant-related mortality, relapse, leukemia-free survival, and overall survival. No difference was seen in rates of acute GVHD. A single institution study of 12 patients receiving a second generation TKI after imatinib failure showed no negative impact on transplant engraftment, relapse rate of transplant-related toxicity when compared to historical controls. 10 A report by the Swedish CML registry 11 reviewed 118 patients transplanted between 2002 and 2017. 47.4% received an allo-HSCT in first CP. TKI resistance was the most common transplant indication (62.5%). For patients diagnosed with CML in CP at <65 years of age, the cumulative probability of undergoing allo-HSCT within 5 years was 9.7%. Overall 5-year survival was 96.2%, 70.1% and 36.9% when transplanted in first CP, second or later CP, and in accelerated phase or blast crisis, respectively. Non-relapse mortality for patients transplanted in CP was 11.6%.

# Timing of Transplantation
Multiple studies showed better outcomes in the pre-imatinib era if patients are transplanted in the first year after diagnosis. For example, in one study, patients transplanted within one year of diagnosis in chronic phase had a survival of 70% compared with 40% when transplanted beyond one year. 12 In the TKI era, early transplantation is no longer undertaken in patients meeting their milestones.

# Blood versus Marrow Stem Cell Source
Less relapse is seen in patients treated with peripheral blood stem cells (PCR positivity 44% with bone marrow versus 7% with peripheral blood at 4 years, p<0.009) but more chronic GVHD with peripheral blood. 12 Overall survival has been higher in peripheral blood transplants than bone marrow stem cell sources. In vivo T cell depletion with ATG decreases GVHD. The impact that ATG makes on altering relapse and GVHD outcomes between peripheral blood and bone marrow with the FLUBUP protocol is not fully understood.

# Molecular Monitoring Post HCT for CML
A retrospective review of 346 patients followed with PCR every 3 months post-transplant found that while in the first 3 months post-transplant, PCR positivity did not correlate with worse outcome. At 6 months or later, it was highly correlated with relapse (42% PCR+ relapse versus 3% PCR-, p<0.0001; 4-year OS 74% versus 93%, p=0.002). 14 Between 6 and 12 months, the PCR+ patients had a relative risk of relapse of 26.0. However, at greater than 36 months, the short-term risk of relapse was much less; 15/59 were qualitative PCR+ but only 1 patient relapsed.
Quantitative PCR can be helpful in predicting relapse risk; at 3 to 5 months post-transplant, increasing PCR positivity is associated with increased risk of relapse. Relapse risk is 17% if PCR-, 43% if low level PCR+ (0.02%). 15 In a study of 379 patients alive at 18 months, 90 had at least 1 positive test at 18 months, but only 14% relapsed (median 40,000 copies/ug) compared to 1% of PCR-patients relapsing (69 had only 1 test positive with mean 24 copies/ug). 18 In a study of 98 patients, 69 had undetectable, decreasing, or low 50 copies/ug) titers (p<0.00001). 16 The correlation between blood and marrow PCR positivity is approximately 90%.
Based on this quantitative peripheral blood PCR for brc/abl transcript should be done every 3 months for 2 years then every 6 months to 5 years and then yearly to coincide with scheduled follow up appointments.

# Treatment of Relapsed Disease

# Treatment of Relapsed Disease Post-AlloHCT:
Imatinib is one therapy with moderate effectiveness in advanced relapsed disease post allogeneic HCT; in a review of 28 (5 chronic phase, 15 accelerated phase, 8 blast phase, 13  imatinib-naive patients who relapsed post-allotransplant, overall response to imatinib was 22/28, CCR 9/28 (35%), complete molecular response (CMR) 4/28. 17 All chronic phase patients attained CHR compared to 83% of the accelerated phase patients and 43% of the blast phase patients; one year overall survival was 74%. Five patients reactivated GVHD; three had grade III disease.
The second and third generation TKI's have not been systemically studied post transplantation but are presumed to be equally if not more efficacious than imatinib. One study published in abstract form only supports this. 19 DLI is also effective and can induce a complete molecular response in about 70% of patients. These can be durable, with a probability of 80-90% DFS at three years and improvement of OS from 53% without DLI to 95% with DLI at three years (p=0.0001). 7,15 There is an approximately 40% chance of GVHD greater than or equal to grade 2 and 30% chance of myelosuppression post-DLI. Responses are not generally durable in second chronic phase disease. The role of imatinib plus DLI is being investigated and a small number of patients have been reported with encouraging results. 20 A recent CIBMTR study retrospectively reviewed the outcomes of TKI vs. DLI vs. DLI + TKI in the setting of post-transplant relapse in the TKI era 21. They found that patients who received a DLI alone had inferior survival compared with those who received a TKI with a DLI. Those who received a TKI alone had similar survival compared with those who received a TKI with a DLI supporting the use of a TKI alone following relapse. Therefore, initiation of TKI therapy with a second generation TKI, preferably one not used pre-transplant should be initiated if a positive PCR is detected 6 months posttransplant or if the BCR/ABL ratio is rising prior to that. If there is no response to TKI alone a mutation analysis should be sent. If there is no mutation proceed to escalating doses of TKI as per the relapse guideline section.
There is very little current data for more advanced phase relapses post-transplant. A mutation analysis should be sent. The next step is the minimization of immunosuppression as well as TKI therapy with-or without DLI should be considered in the accelerated phase potentially as a bridge to second transplant if the patient remains eligible. In the blast phase induction type chemotherapy in conjunction with TKI therapy should be undertaken prior to a second transplant if eligible. In this situation, the overall prognosis is poor and palliation is a reasonable choice. with refractory, transfusion-dependent anemia, peripheral blood blasts >2%, or adverse cytogenetics, and should have a donor search performed. 1 - All patients being considered for allotransplant should have mutation analysis by NGS and cytogenetics performed, if possible, to inform decision-making. - Patients in blast phase (>20% bone marrow blasts) should be given induction chemotherapy prior to proceeding with stem cell transplantation. - There is no convincing data to support the requirement for splenectomy or splenic radiation before transplantation. We do not recommend routine splenectomy or splenic irradiation pre-transplant. - Our standard conditioning is myeloablative busulfan + fludarabine + 4Gy TBI (see Conditioning chapter). - The use of JAK inhibitors pre-transplant is associated with improvement in constitutional symptoms and performance status, and decrease in spleen size, and can help improve clinical status prior to transplant. JAK inhibitors should be discontinued at the start of the conditioning for HSCT.
Myeloproliferative neoplasms (MPNs) originate from acquired mutations that target the hematopoietic stem cell and induce dysregulation of kinase signaling, clonal myeloproliferation, and abnormal cytokine expression. The JAK2 V617F mutation is most frequent. Other mutations include CALR, MPL, and other mutations including some with adverse prognostic implications such as ASXL1 (38%), EZH2 (7%), IDH1/2 (45), SFSF2 (14%) and U2AF1Q157 (8%) mutations 2,3,4. Patients with triple negative disease status for JAK2, CALR and MPL are recognized to have adverse prognosis.
The 2016 WHO MPN classification is used to diagnose MPNs into categories including polycythemia vera (PV), essential thrombocythemia (ET), primary myelofibrosis (PMF), chronic neutrophilic leukemia, atypical CML, myeloid/lymphoid neoplasms associated with eosinophilia and rearrangements of PDGFRA, PDGFRB, or FGFR1 or with PCM1-JAK2, and overlap syndromes including chronic myelomonocytic leukemia and myelodysplastic/myeloproliferative neoplasm with ring sideroblasts and thrombocytosis. 5 abnormalities, autosomal trisomies (except +9), monosomal and complex non-monosomal karyotypes. High risk GPSS was also associated with higher blast transformation rate (HR 7.4, 95% CI 2. 1-26.3). In patients who had ambiguous prognosis based on differing scores by GPSS and by DIPSS-plus, those found to be higher risk on the GPSS were associated with poorer survival outcomes. 12 Secondary Myelofibrosis: None of the above prognostic tools were developed in patients who have secondary myelofibrosis after progression from polycythemia vera or essential thrombocytosis. In practice, the tools above are used but in a non-validated setting. There has been a model for prognosis developed in patients post-PV and post-ET: Myelofibrosis Secondary to PV and ET-Prognostic Model (MYSEC-PM), based on multivariate analysis of 685 patients with a median survival of 9.3 years. Secondary MF patients were divided into four risk categories based on: hemoglobin, circulating blasts, CALR status, platelet count and constitutional symptoms. Median survival according to risk group was: low (survival not reached), intermediate-1 (9.3 years), intermediate-2 (4.4 years), and high risk (2 years). 13 A calculator is available for the MYSEC-PM: /

# Transplantation outcomes in myelofibrosis:
Allogeneic HCT is currently the only treatment option in myelofibrosis that is capable of inducing complete hematologic, cytogenetic, and molecular remissions. However, there are associated risks of treatment-related mortality, graft failure, and disease relapse.
A multicentre analysis of 100 consecutive transplants for myelofibrosis in patients treated with JAK inhibitors found that 2-year overall survival (OS) was 61%, but 91% for those who experienced clinical improvement pretransplant on JAK inhibitors, and 32% for those with leukemic transformation on JAK inhibitor therapy. 14 Age of the patients was 32-72 years (median 59). Response to JAK transformation increases with disease duration, affecting 3-10% in the first decade after diagnosis and 6-20% in the second decade. Progression to acute leukemia occurs in a small minority of patients, with incidences of 1-2.5% in the first decade after diagnosis, and 5-8% in the second decade, and continuing to increase thereafter. Similar patterns are seen with PV, with leukemic transformation reported as high as 20%. The use of cytoreductive therapy, including alkylating agents, is known to increase the rate of leukemic transformation, and thus the true rate of transformation is unknown. Very little literature exists of transplantation for these diseases, usually in the form of case reports. Prognosis with DIPSS-plus score is not validated in this population although it is commonly used. The problems and complications associated with myelofibrotic transformation of either ET or PV are similar to de novo PMF, thus therapy of post-ET MF or post-PV MF should be approached in the same manner.

# Use of JAK2 Inhibitors Prior to HSCT for Myelofibrosis
The JAK2V617F activating kinase mutation is seen in the many patients with BCR-ABL1 negative myeloproliferative patients, and Ruxolitinib, an oral JAK1/JAK2 inhibitor, is approved for the treatment of patients with symptomatic myelofibrosis, based on the data from two randomized phase 3 studies. Treatment is effective in patients without this specific mutation as other mutations in this pathway also cause symptoms. COMFORT-I and COMFORT-II compared ruxolitinib with placebo and bestavailable therapy (BAT), respectively, and found significant reductions in splenomegaly and improvement in constitutional symptoms. 20,21 Increased caloric intake and enhanced performance status as a result of improved constitutional symptoms and reduced splenomegaly could contribute to improved survival estimates for patients treated with ruxolitinib (71% vs. 54%, HR 0.48). 22,23 Longer follow-up will be needed.
It has been postulated that the anti-JAK2 mediated reduction in both cytokines and splenomegaly, as well as improvement in performance status, might improve outcome after allogeneic HSCT in patients with myelofibrosis. Some patients improve performance status and become transplant eligible. The down-regulation of inflammatory cytokines might have a beneficial impact on graft failure and has been seen to provide benefit in acute GVHD. The largest retrospective study examining transplant outcomes post ruxolitinib is outlined above and shows that pretransplant ruxolitinib therapy is feasible and patients responding to ruxolitinib have overall better transplant outcomes. 14 There were concerns that abrupt discontinuation of ruxolitinib in advance of transplant may result in cytokine storm reaction and severe inflammatory response. Preliminary reports from the JAK ALLO trial 24 of ruxolitinib prior to HSCT included ten patients who discontinued ruxolitinib, 7 of whom developed life-threatening events (including cardiogenic shock, tumor lysis syndrome, severe GVHD), with two deaths within 3 weeks of drug withdrawal. This pattern has not been seen in subsequent studies; the retrospective series of 100 patients above showed two with significant adverse events after they stopped drug more than 6 days pretransplant. 14 For this reason it is recommended to continue JAK1/2 inhibitors until the day before conditioning. 18 The average time to treatment failure with JAK 1/2 inhibitors in myelofibrosis is between two and three years. Ideally, patients should be referred for consideration of HSCT before they lose their response to these agents in order for them to undergo transplantation during a time of relatively good health. Several factors have been associated with a short (less than one year) time to treatment failure. These factors include "triple negative" myelofibrosis (negative for JAK2, MPL and CALR mutations) and ASXL-1 and EZH2 mutations, a high DIPSS-Plus score and those requiring transfusions at the time JAK 1/2 inhibitors are started. Patients with any of these risk factors should be referred at the time JAK1/2 inhibitors are started so that they can proceed to HSCT within one year or sooner. Patients with mutated CALR, 0-2 subclonal mutations without ASXL-1 or EZH2 mutations and those with mismatched donors should be followed closely and transplanted at the first sign of progression. 25 Fedratinib, another JAK2 inhibitor selective for JAK2 relative to other kinases has now been approved by Health Canada and funding recommendations made by CADTH for treatment of splenomegaly and/or disease-related symptoms in adult patients with intermediate-2 or high-risk primary myelofibrosis, post-polycythemia vera myelofibrosis, or post-essential thrombocythemia myelofibrosis, including patients who have been previously exposed to ruxolitinib. It is recommended for patients who are intolerant of ruxolitinib and not for patients with progressive symptoms after ruxolitinib therapy. Approval was made on the basis of the JAKARTA phase 3 randomized MF study for intermediate 2 and high risk disease with placebo and JAKARTA-2 in patients previously treated with ruxolitinib and who were refractory or intolerant. Reduction in spleen volume by 35% was seen in 30-40% of patients and there was improvement in Total Symptoms Score by 50% in one third of patients. Thiamine levels are required and supplementation is necessary, and monitoring for symptoms of encephalopathy is required. Other side effects include cytopenias and GI intolerance that should be proactively managed. Current data supports fedratinib's use post ruxolitinib failure if funding is available. For patients planned for allogeneic stem cell transplant, transplant should occur earlier in the course of disease prior to multidrug resistance and before second line therapy is required for refractory disease. If fedratinib is used frontline prior to stem cell transplant, there is no evidence around management of medication prior to BMT and we would discontinue medication as per ruxolitinib protocol.
www.ahs.ca/guru BMT Standard Practice Manual
- Factors favoring allogeneic stem transplantation over conventional therapy include higher disease risk (high risk cytogenetics, MRD positive, short duration of response, Richter transformation) and low transplant risk (younger age, lack of co-morbidities, well-matched donor) - Allogeneic stem cell transplantation may be offered to CLL patients with:
- Relapse after at least 1 prior novel agent (BTKi and/or BCL2 inhibitor), preferably responding to a second agent as salvage treatment o Richter transformation responding to treatment, particularly if high-risk features such as previously treated CLL, TP53 mutated or clonally related Richter transformation, relapsed disease, or failure to achieve complete response to R-CHOP - Autologous stem cell transplantation is not indicated to treat CLL but may be considered in selected patients with chemosensitive Richter transformation Background Chronic lymphocytic leukemia (CLL) represents one of the most common lymphoid malignancies of adults. With a median age at diagnosis of 70 years, many patients with this disease will die of other causes. For young patients however, this diagnosis represents a serious threat to life and aggressive management with high-dose therapy and blood stem cell transplantation (SCT) is a reasonable treatment option. This is particularly the case for patients whose CLL is associated with deletion chromosome 17p13.1 which is observed in 5% of untreated CLL cases but in up to 30% of relapsed and refractory cases. CLL with del(17p) usually require therapy within 1 year of diagnosis and is now being treated with frontline BTK inhibitors such as ibrutinib. Even novel agents such as ibrutinib do not control del(17p)-associated CLL for long durations of time. A recent study by O'Brien and colleagues involving 144 patients with relapsed del(17p) CLL reported 2-year progression-free survival (PFS) rates of approximately 60% (mPFS of 30mo) and 24-month OS of 75% 1.
For a review of the diagnosis, staging, prognosis, assessments of patient fitness and response, and current treatment recommendations of the Alberta Provincial Hematology Tumour Team, please refer to the CLL Clinical Practice Guideline (LYHE-007).

# Stem Cell Transplantation in CLL
Data from the Center for International Blood and Marrow Transplant Research (CIBMTR) suggests that CLL is an infrequent indication for transplant. The majority of transplants reported were allogeneic, many of which were carried out after reduced intensity or non-myeloablative conditioning.

# Allogeneic Stem Cell Transplantation in CLL
Long-term survival after allogeneic SCT for CLL of the largest series of patients (n=2589), who underwent transplant between 2000 and 2010, has been reported from the European Group for Blood and Marrow Transplantation (EBMT) 2. In this series, long-term disease control was established for patients, but with longer follow-up both event-free and overall survival decreased over time (62% at 2 years vs. 35% at 10 years for OS; 49% at 2 years vs. 28% at 10 years for EFS). The incidence of relapse was 21% at 2 years vs. 32% at 10 years, and non-relapse mortality 30% at 2 years vs. 40% at 10 years. The presence or absence of del(17p)/TP53 mutation has not been shown to impact outcome of alloSCT 3,4. Risk factors for relapse included active disease at time of transplant, T-cell depletion with alemtuzumab, prior autologous SCT, and use of mismatched donor, while absence of MRD at 12 months was highly prognostic for reduced relapse risk 2,3,4.
In regards to donor selection, the EBMT analyzed 368 chronic lymphocytic leukemia patients who underwent allogeneic hematopoietic stem cell transplantation between 1995 and 2007 5. There were 198 HLA-identical siblings; among unrelated transplants, 31 were well matched in high resolution ('well matched' unrelated donor, WMUD), and 139 were mismatched (MM), including 30 matched in low resolution; 266 patients (72%) received reduced-intensity conditioning and 102 (28%) received standard. There was no difference in OS at 5 years between HLA-identical siblings (55% (48)(49)(50)(51)(52)(53)(54)(55)(56)(57)(58)(59)(60)(61)(62)(63)(64)) and WMUD (59% (41-84)), p=0.82. In contrast, OS was significantly worse for MM (37% (29-48) p=0.005) due to a significant excess of transplant-related mortality. HLA matching had no significant impact on relapse (siblings: 24% (21-27); WMUD: 35% (26-44), p=0.11 and MM: 21% (18-24), p=0.81); alemtuzumab T-cell depletion and stem cell source (peripheral blood) were associated with an increased risk. As the toxicity of haploidentical transplants have been greatly decreased with the use of post-transplant cyclophosphamide, donor availability for transplantation has increased. The EBMT has reported the outcome of 117 CLL patients who had received an allogeneic SCT with a haploidentical donor, with results appearing almost identical to those with HLA-matched donors; 5-yr OS 38%, PFS 31%, CI of relapse 26%, and NRM 44% 6.
Myeloablative conditioning (MAC) is associated with improved overall survival in acute myeloid leukemia (AML), where the increased risks of NRM and acute and chronic GVHD associated with MAC were offset by the significant reduction in relapse 7. It is unclear if these results can be extrapolated to patients with CLL, given that CLL is an indolent disease with high susceptibility to GVL which may not necessarily require intensive chemotherapy; patients with CLL may be at higher risk of NRM due to older age and underlying immune dysregulation; allotransplant recipients with CLL are heavily pre-treated which may confer greater resistance to MAC; and there may be more options to treat relapse after allotransplant in CLL, such as donor lymphocyte infusion and emerging therapies (e.g. non-covalent BTK inhibitors, CAR-T cells). Retrospective and transplant registry studies conclude that reduced intensity conditioning (RIC) is associated with lower risks of NRM, less acute and chronic GVHD, and similar or improved OS compared to MAC in CLL 8,9,10,11,12,13. Indeed, intensive conditioning is not necessarily indicated since CLL has among the lowest relapse risk after non-myeloablative (NMA) conditioning of any hematologic malignancy 14. An EBMT registry study also concluded that selected patients receiving NMA conditioning have similar relapse incidence, relapsefree survival (RFS), and overall survival as recipients of RIC in CLL 15. As a result, the majority of allotransplants (75-80%) performed for CLL in North America and Europe employ RIC or NMA conditioning, and ASTCT guidelines recommend RIC or NMA conditioning for all patients undergoing allotransplant for CLL 2,16,17. MAC with FluBu4 was utilized for most allotransplant recipients with CLL in Alberta until 2022, at which time a review of local outcomes revealed high rates of acute and chronic GVHD and low mod/severe chronic GVHD and RFS (cGRFS) despite the use of ATG (Table 3). As a result, in February 2023 RIC was adopted as the preferring conditioning regimen for patients with CLL to reduce their risks of acute and chronic GVHD as well as other acute toxicities and NRM.  The EBMT studied 44 patients with 17p-CLL who received allogeneic hematopoietic SCT between March 1995 and July 2006 from a matched sibling (n = 24) or an alternative donor (n = 20) 20. Patients had received a median of 3 lines of chemotherapy before SCT, and at the time of transplantation, 53% of patients were in remission. RIC was applied in 89% of patients. Acute or extensive GVHD occurred in 43% and 53% of patients, respectively. Nineteen patients were alive at the last follow-up (median observation time 39 months), and no late relapse occurred in 9 patients with a follow-up longer than 4 years. The 3-year OS and PFS rates were 44% and 37%, respectively.
It is clear that with the approval of novel agents including BTK inhibitors (e.g. ibrutinib, acalabrutinib), PI3 kinase inhibitors (e.g. idelalisib), and the BCL2 inhibitor venetoclax, the number of transplants being performed for CLL continues to decline, particularly for those patients without high risk cytogenetics. In a study of 65 patients with prior novel agent exposure who underwent alloSCT, the 24 month PFS, OS, NRM, and relapse incidence was 63%, 81%, 13%, and 27%, respectively 12. Poor-risk disease characteristics, prior NA exposure, complete vs. partial remission status, and transplant characteristics were not independently associated with PFS; 1 vs.  novel agents, or ibrutinib vs. venetoclax as the line of therapy immediately pre-alloHSCT had no impact on PFS or OS; only HCT-CI independently predicted for PFS. It remains to be seen whether combinations of these agents will alter the natural history of the disease, or whether they are just delaying the use of allogeneic SCT until later in the disease course. Allogeneic SCT will continue to have a role for patients who fail or are intolerant to these therapies.
Overall, allogeneic stem cell transplantation (HSCT) should be considered for fit patients who are younger than 65 years of age and have CLL that did not respond or have progressed after treatment with at least one novel agent (either BTKi and/or venetoclax). This is especially important in patients with higher disease risk, including complex karyotype, high risk cytogenetics (del17p/TP53), short duration of response, and MRD positive (on venetoclax).

# Richter Transformation:
Richter transformation (RT) of CLL into an aggressive DLBCL occurs in 1-5% of patients with CLL. RT is associated with a dismal prognosis with PFS <25% with CHOP-based chemoimmunotherapy and median survival 6-12 months 21,22,23,24. Given these poor outcomes, consolidation with allogeneic HCT should be considered for eligible patients with responding disease who have relapsed RT or other high-risk features, such as previous therapy for CLL, failure to achieve a complete response to R-CHOP, TP53 aberrations, or clonally related RT 24,25,26,27. Although <10% of all patients with RT will ever undergo allogeneic HCT, this may represent a curative therapy for selected cases with 3year PFS 43%, OS 52%, relapse incidence 30%, and NRM 27% in a CIBMTR study of 118 allogeneic HCT recipients 28. Outcomes were best for patients in complete response (3-year PFS 66%) or partial response (3-year PFS 43%) at the time of HCT compared to those with resistant disease (3-year PFS 5%). The majority of patients with RT receive reduced intensity conditioning, which has been www.ahs.ca/guru BMT Standard Practice Manual Last Reviewed: February 1, 2023 Effective: February 3, 2023 associated with similar to improved outcomes in this setting compared to myeloablative conditioning 28,29,30,31.
Importantly, patients with RT arising from treatment naive CLL appear to have comparatively better outcomes with R-CHOP and may not necessarily require allogeneic HCT 23,24. In an Alberta study of 99 patients with RT, those with treatment naive CLL had higher response rates to first line chemoimmunotherapy (71% versus 40%) and superior 2-year OS (51% versus 28%) compared to those with previously treated CLL. Nevertheless, 2-year OS remained suboptimal at 53% for the 13 patients 70 years old with RT and treatment naive CLL, which suggests there may be a role to consider consolidation with autologous HCT for these patients, similarly as other high risk aggressive lymphomas. Although data is lacking on the outcomes of autologous HCT as part of first-line therapy for RT, a CIBMTR study of 53 patients undergoing autologous HCT for predominantly relapsed RT reported 3-year PFS 48%, OS 52%, and relapse incidence 37% 28. In an EBMT study of 34 patients who underwent autologous HCT, only 11 of 17 relapses were related to RT (the remainder were due to CLL), suggesting autologous HCT may eradicate the RT component in many patients even though the underlying CLL may persist 29. It should be noted that even if allogeneic HCT may not be required as a part of primary therapy for patients with lower-risk RT, a referral for transplant consultation and HLA typing is suggested at diagnosis in all patients who are eligible for allogenic HCT by age and/or comorbidities, given the significant risk of relapse/refractory disease with RT.
Less commonly, patients with CLL may develop a Hodgkin lymphoma variant of RT which is often clonally unrelated to the CLL. Available evidence suggests that Hodgkin-variant RT has similar outcomes with standard chemotherapy as de novo Hodgkin lymphoma in this age group 32,33. As such, there is not an established role for consolidation with HCT in these cases 27.

# Autologous Stem Cell Transplantation in CLL
Case series from a number of institutions report high overall survival (4-year OS 65-94%) with low TRM (4-10%) of autologous stem cell transplantation (ASCT) for CLL; however, to date, no randomized study has demonstrated an OS advantage for the use of ASCT in CLL. Despite a strong PFS advantage in the published studies of ASCT, ASCT is now rarely used for CLL . This is because FCR (fludarabine, cyclophosphamide, and rituximab) is now used as front-line therapy for most young CLL patients, as it has been shown in a randomized, controlled trial, to provide an OS advantage. Published studies of ASCT in CLL predate the introduction of FCR chemotherapy so the role that ASCT could play in the era of FCR is unclear. Additionally, the use of 6 cycles of a fludarabine-containing regimen significantly impairs the subsequent ability to mobilize and collect autologous blood stem cells. With the emergence of novel agents for relapsed CLL, the role of ASCT is even more unclear. At present, there are no definite indications for ASCT for CLL.   An excisional lymph node biopsy of the largest regionally involved lymph node is the optimal specimen for initial diagnostic assessment. Similarly, a sizable biopsy from the organ of origin in extranodal lymphomas is also suitable. Occasionally, needle core biopsies may be adequate but this needs to be assessed on a case-by-case basis. Whenever possible, a reference lymphoma pathologist should confirm the diagnosis. The following histological sub classification of the malignant lymphomas is an adaptation of the World Health Organization (WHO) classification and is based on the light microscopic interpretation complemented by special stains, immunophenotyping, cytogenetics and other information as available. The specific lymphomas are divided into three major groups for treatment planning. All B-Cell lymphomas should be immunophenotyped to determine if they are positive for CD20. Abbreviations: aaIPI = age-adjusted international prognostic index; Alk P = alkaline phosphatase; ALT = alanine aminotransferase; ASCT = autologous stem cell transplant; BL = Burkitt lymphoma; CBC = complete blood count; CSF = cerebrospinal fluid; CT = computerized tomography; DLBCL = diffuse large B cell lymphoma; ECOG = Eastern Cooperative Oncology Group; HDCT = high-dose chemotherapy; LBL = lymphoblastic lymphoma; LDH = lactate dehydrogenase; LP = lumbar puncture; PA = posterior-anterior; PET = positron-emission tomography. Absence of any one of these factors does not constitute an absolute contraindication to HDCT/ASCT, and successful outcomes have been reported in a variety of poor prognosis settings, even HIV infection. 2,3 It is widely accepted, however, as the number of unmet eligibility criteria increases, the likelihood of a poor outcome from SCT also increases. feasible, but most disease-related outcomes are statistically inferior to younger patients. 4,5 For example, in multivariate analysis, while adjusting for patient-, disease-, and treatment-related variables, older patients with aggressive histologies were 1.86 times (95% CI 1.43-2.43, P <.001) more likely than younger patients to experience treatment-related mortality (TRM). 5

# Staging System

# Autologous Stem Cell Transplantation Eligibility Criteria
A. Diffuse Large B-cell Lymphoma (DLBCL)

# Indications and Outcomes:
Diffuse Large B-cell Lymphoma (DLBCL) accounts for approximately 1/3 of all lymphomas, and represents the majority of patients treated in SCT studies for aggressive lymphoma. 6 HDCT/ASCT has been standard therapy for chemosensitve relapsed/refractory DLBCL ever since the results of the PARMA study were published more than a decade ago. 7 The PARMA study is the only randomized controlled trial (RCT) of high dose versus conventional dose salvage chemotherapy for relapsed, chemosensitive NHL, and demonstrated a significant failure-free (51% vs. 12%) and overall survival (OS) (53% vs. 32%) advantage for high dose BEAC (BCNU, etoposide, Ara-C, cyclophosphamide) and ASCT over standard-dose DHAP (dexamethasone, Ara-C, cisplatin). This was found despite the fact that not all patients allocated to the HDCT arm of the trial actually received HDCT, and many patients in the control arm eventually underwent HDCT/ASCT at the time of second disease progression.
The major prognostic factors for outcome of relapsed DLBCL include the time to relapse, IPI (international prognostic index) risk factors, and chemosensitivity. In the PARMA study, time to relapse <1 year was associated with a 40% response to DHAP, and only 13% 8 year OS. 8 Costa and colleagues reported mean OS of only 5 months for patients with both a time to relapse <18 months as well as IPI=3-5, suggesting that these poor prognosis patients should not be subjected to ASCT. 9 Hamlin and colleagues reported that the salvage aaIPI predicts outcome of relapsed DLBCL with PFS rates of approximately 69%, 46%, 25% for chemosensitive relapsed DLBCL patients with aaIPI scores of 0, 1, and 2-3, respectively. 10 More recently, in the first interim analysis of 200 patients treated in the CORAL study (R-ICE Versus R-DHAP in relapsed DLBCL patients, followed by ASCT +/-maintenance rituximab) reported by Gisselbrecht and colleagues, factors associated with response to salvage therapy were refractory or relapse <12 months (52% vs. 88%), sIPI (second-line International Prognostic Index) 2-3 (54% vs. 77%), and relapse after prior rituximab (54% vs. 82%). 11 (  13 For NHL, the 2-year FFS was 67%, 56%, 26%, and 12% for aaIPI 0, 1, 2, 3, respectively. The 2-year failure-free survival (FFS) by PET response to salvage DHAP-VIM was 72% for complete response (CR), 38% for partial response (PR) and 10% for no response (NR). The two factors were combined by assigning 0 points for CR, 1 point for PR, and 2 points for NR on PET imaging. The 2year FFS rates were 82%, 58%, 24% and 5% for patients with a combined risk score of 0-1, 2, 3, and 4-5 points, respectively. 13 Using evidence from the above studies, it is therefore probable that relapsed DLBCL patients can be appropriately excluded from ASCT if they have three, and possibly even two of the following adverse prognostic factors:
- time to relapse of <12months
- relapse aaIPI scores of 2-3
- chemoresistance as defined as lack of at least a PR to salvage chemotherapy
No RCT has been conducted to evaluate potential benefit of HDCT/ASCT for patients with chemoresistant relapsed/refractory large cell lymphoma (i.e. patients who do not respond to secondline chemotherapy) or for patients who have experienced failure of more than one prior chemotherapy regimen. Retrospective reports, however, suggest only low rates of long-term progression-free survival (PFS) following HDCT for these poor prognosis patients. As such, in many transplant centres, ASCT is not offered in these settings.
Conflicting results have been reported from RCTs evaluating first remission-consolidation with HDCT/ASCT for aggressive NHL. 14 Many studies were negative, while a few have shown significant PFS benefits from HDCT. Criticisms of these studies, however, are numerous. Many studies had inadequate statistical power, most did not use the aaIPI as an eligibility or stratification criterion, and overall they were extremely heterogeneous with respect to histological subtypes, choice of standard and HDCT regimens, and timing of HDCT relative to number of induction chemotherapy cycles. Some studies used a non-conventional, intensive chemotherapy "control arm". These studies reported that up to 40% of patients in the HDCT arm never received the assigned HDCT, often due to an inadequate response to abbreviated induction chemotherapy prior to planned HDCT/ASCT. The use of abbreviated induction therapy followed by a single HDCT/ASCT is not considered a viable strategy for future trials. Greb and colleagues performed a systematic meta-analysis searching the Cochrane Library, MEDLINE and other databases (1990 to 2005) for studies that evaluated the efficacy of frontline HDCT relative to conventional chemotherapy in aggressive NHL. 15 32). There was, however, improved OS in the subgroup of aaIPI=3 patients (82% vs. 64%). 17 Other approaches still worthy of study involve multiple cycles of high dose sequential induction chemotherapy as pioneered by groups in Italy, 18 or early identification of patients who are unlikely to be cured by standard induction therapy through the use of interim response PET/CT imaging after 2-4 cycles of chemotherapy, and then treating unfavorable responders with immediate salvage HDCT/ASCT. 19 HDCT/ASCT as Part of Initial Therapy for DLBCL: Secondary CNS Lymphoma:  Selected patients with CNS relapse/progression may be candidates for aggressive therapy. One of 3 induction regimens is recommended for transplant-eligible patients and one of two options for transplant in-eligible patients, based on presentation:
1) Isolated CNS lymphoma: HDMTX-based induction then RDHAP for stem cell mobilization and collection, then R-TBuM/ASCT for transplant eligible or HDMTX/AraC then ifosfamide for transplant ineligible.
2) Early Systemic and CNS lymphoma (prior to completing RCHOP x6): RCHOP and HDMTX x4 cycles then RDHAP for stem cell mobilization and collection, then R-TBuM/ASCT for transplant eligible or RCHOP/MTX followed by AraC then ifosfamide in transplant ineligible.
3) Late relapse (prior RCHOP x6) with systemic and CNS lymphoma: HDMTX-ifosfamideetoposide x2 then RDHAP for stem cell mobilization and collection, then R-TBuM/ASCT for transplant eligible or palliation for transplant ineligible.
Unfortunately, most patients with secondary CNS lymphoma experience poor response to salvage therapy, including high dose methotrexate/cytarabine-based regimens. These patients who are unfit to receive or do not respond to high dose methotrexate/cytarabine-based therapy are best managed with palliative intent, including possible use of intrathecal chemotherapy or palliative cranial radiotherapy.
BMT Standard Practice Manual

# Double hit lymphoma with MYC and BCL2 mutations/rearrangements by FISH.
The largest multicentre retrospective analysis of 311 double hit lymphoma patients reported an OS rate of 80% if IPI=0. 27 In addition, the OS rate was approximately 90% for 39 patients who achieve CR following induction chemotherapy and then underwent SCT compared to 60% for 112 patients who achieved CR but did not receive SCT. Although this numerical difference was not statistically significant (p=0.1), it was very clinically significant, indicating that the study was underpowered to draw any meaningful conclusions regarding the role of ASCT consolidation.
More recently, reported outcomes of 159 patients with double-hit lymphoma who achieve CR following induction therapy. 28 This study demonstrated that PFS and OS were superior with an intensive regimen relative to RCHOP, and that ASCT only improve outcomes for patients who initially received RCHOP, but not an intensive regimen. These studies suggest that DHL patients treated with RCHOP should be considered for ASCT consolidation, especially those with IPI=2-5 at diagnosis, however other patients who achieve CR after an intensive induction regimen (such as DA-EPOCH-R or R-CODOXM/IVAC) probably should not receive ASCT consolidation. Due to the lack of prospective randomized controlled studies, however, it is impossible to determine if the optimal approach involves RCHOP induction followed by ASCT or an intensive induction chemotherapy regimen.
Alberta recommendations for special DLBCL entities.

# B. Primary CNS Lymphoma
Conventional therapy for primary central nervous system lymphoma (PCNSL) involves high dose methotrexate-based induction, potentially followed by cranial radiation, although long term outcomes are poor, especially for patients over age 50 years or with poor performance status at diagnosis. 29,30 In addition, high dose methotrexate followed by cranial radiation is associated with a high risk of dementia and neurotoxic death in patients over age 50-60 years. 31 If patients refuse radiotherapy because of the concern regarding radiation-induced dementia, and fulfill standard eligibility for ASCT, they should be considered for high dose thiotepa, busulfan-based chemotherapy and autologous stem cell transplantation as part of their initial treatment, or at the time of first relapse following initial therapy since reports suggest long term progression free survival rates of 40-50% with this approach. 32,33 Choice of Re-induction Therapy Prior to HDCT/SCT: Several salvage chemotherapy regimens exist for relapsed DLBCL, but RCTs have not been performed to determine whether one regimen is superior to another. 34 Most regimens involve prolonged intravenous administration and therefore, require hospitalization. The GDP regimen (gemcitabine 1g/m 2 IV days 1 and 8, dexamethasone 40mg p.o. days 1-4, cisplatin 75mg/m 2 IV day 1) can easily be administered on an outpatient basis, and has been reported by the NCIC CTG to give 49% response rate in 51 patients with the relapsed/refractory NHL. 35 This is similar to other salvage chemotherapy options such as ICE or DHAP. The NCIC CTG LY12 trial is currently evaluating RDHAP versus RGDP for relapsed/refractory aggressive NHL, with responding patients proceeding to HDCT/ASCT and then to a second randomization between observation and rituximab consolidation therapy every 2 months for one year. The other RCT examining salvage regimens for relapsed DLBCL, the CORAL study, thus far shows similar response rates and PFS rates for the RICE and RDHAP treatment arms. 11 There is some suggestion from phase II studies that intensive salvage therapy prior to HDCT/ASCT may improve OS rates, but this needs to be proven in well conducted RCT before wide adoption. 36,37 Finally, rituximab combined with salvage chemotherapy has been shown in a RCT and several historically controlled studies to improve post-ASCT outcomes relative to salvage chemotherapy alone.  The majority of this data involves patients who did not receive rituximab with their primary CHOP-like initial induction therapy prior to relapse. Nevertheless, rituximab is now commonly added to salvage therapy regimens, at least for patients who relapsed more than 6-12 months after completing initial RCHOP, or who never received rituximab with primary chemotherapy.

# High Dose Therapy Regimen:
The most common HDCT regimens used for lymphoma include: cyclophosphamide, etoposide, carmustine (CEB or CBV), carmustine, etoposide, cytarabine, melphalan (BEAM), fractionated totalbody irradiation (fTBI) with cyclophosphamide (Cy) and possibly etoposide (VP-16) (CyTBI or VPCyTBI) and, melphalan, etoposide with or without TBI (MeVPTBI). RCTs comparing these regimens for lymphoma have not been conducted. Non-randomized retrospective studies suggest somewhat better efficacy and tolerability for BEAM over CBV or the TBI-containing regimens in the setting of aggressive lymphoma.  For example, Salar and colleagues investigated the impact of the preparative regimens on the outcome of 395 patients with diffuse large cell lymphoma, consecutively reported to the registry of the Spanish GEL/TAMO. 45 Conditioning consisted of chemotherapy-only in 348 patients (BEAM, n=164; BEAC, n=145; and CBV, n=39) and CyTBI in 47 patients. Median times to engraftment and discharge were significantly shorter in the chemotherapyonly group, and early TRM was significantly higher with CyTBI. Survival rates of patients conditioned with BEAM or BEAC (58%, 95% CI 50-66) was more favourable than with CBV (40%, 95% CI 24-56), and significantly better than with CY-TBI (31%, 95% CI 18-44), a finding that persisted in multivariate analysis. Other studies suggest that high TBI doses (>12Gy) or combinations of TBI and etoposide may increase the risk of secondary myelodysplasia/AML, and are to be discouraged. 46,47 Perhaps the use of targeted TBI though radioimmunoconjugates will improve the efficacy while reducing toxicity of TBI, however, this has yet to be proven in randomized studies. 48 Primary CNS Lymphoma requires chemotherapy agents that cross well through the blood brain barrier such as busulfan and thiotepa (eg. thiotepa 600mg/m 2 busulfan 9.6 mg/kg) rather than agents that penetrate poorly such as melphalan and etoposide. 32 Post-ASCT Therapy: G-CSF 5g/kg/day is generally given to all ASCT patients starting day +7 post-SCT until ANC >1. hospital stay compared to no G-CSF, as well as trials showing no significant benefit of using higher doses of G-CSF or starting G-CSF earlier post-SCT.

# C. Mantle Cell Lymphoma
Mantle-cell lymphoma (MCL) is characterized by poor prognosis with a median survival of only 3 to 5 years following conventional therapy, and little improvement in outcome when rituximab is added to conventional CHOP. 53,54 In 1996, the European MCL Network initiated a randomized trial comparing consolidation with CyTBI/ASCT (TBI 12 Gy, cyclophosphamide 120 mg/kg) to a conventional interferon maintenance (6x10 6 IE IFN- 3x weekly) for patients under 65 years of age who were in first remission after a CHOP-like induction regimen. 55 A total of 232 previously untreated patients with advanced stage MCL were randomized upfront. Only 173 (76%) of 228 evaluable patients responded to initial induction chemotherapy, and 151 of these (87%) proceeded to the assigned consolidation therapy. Baseline characteristics were comparable in the per-protocol and intent-to-treat cohorts. By intent-to-treat, and after a median follow-up of 6.1 years, patients in the ASCT study arm experienced a significantly longer median time to treatment failure of 2.6 versus 1.4 years (p=0.0001) as well as longer median OS of 7.5 versus 5.3 years (p = 0.031). 55 Accordingly, first-remission HDCT/ASCT represents the current therapeutic standard in younger MCL patients. The second Nordic MCL phase II trial in 160 patients suggests that HDCT/ASCT outcomes can possibly be improved upon by the addition of high dose Ara-C and rituximab, with projected 6-year overall, event-free, and progressionfree survival rates of 70, 56 and 66%, respectively, with no relapses occurring after 5 years. 56 Other single centre reports suggest R-HyperCVAD induction followed by HDCT/ASCT may also a reasonable strategy, but confirmatory RCTs are lacking. 57 Because virtually all MCL patients eventually relapse following autologous SCT, and relapse rates are known to be lower following allogeneic SCT, allogeneic SCT may be the preferred strategy for eligible patients in poor prognosis situations including first partial remission with several IPI risk factors or peripheral blood involvement at diagnosis, or patients in first relapse.  Robinson and colleagues recently reported a large retrospective EBMT study of reduced intensity SCT (RIST) in MCL. 61 Between 1998 and 2006 279 patients with MCL received RIST with 210 procedures performed after the year 2001. Patients had received a median of 3 lines (range 1-9) of prior therapy and 119 (43%) had undergone a previous autologous SCT. The median time from diagnosis to transplant was 30 months (range 3-161). Conditioning for RIST was achieved with fludarabine plus an alkylating agent in 66%, fludarabine plus TBI in 13%, and a variety of other reduced intensity regimens in 20%. The 100 day, 1 year and 3 year non-relapse mortality rates were 13, 32 and 41% respectively. The Kaplan-Meier estimate of the PFS at 1 and 3 years was 49% and 29% respectively. PFS was significantly worse for patients with refractory disease (response rate (RR)=2.2, p<0.001), poor PS (RR=2.6, p=0.005) or those transplanted prior to 2002 (RR=1.5, p=0.03).

# D. Peripheral T-Cell Lymphoma
In North America, peripheral T-cell lymphomas (PTCL) represent 5-10% of all lymphomas. 62  www.ahs.ca/guru 16 lymphoma (AITL) (16%). With the exception of CD30+ anaplastic large cell lymphoma (ALCL), PTCLs are associated with only 10-20% chance of long-term progression-free survival following conventional chemotherapy. Some small single-centre reports of HDCT/ASCT for relapsed/refractory PTCL suggest poor PFS rates of only 10-20%, 63,64 while other reports, including larger transplant registry series, suggest outcomes similar to those for relapsed DLBCL,  with uniformly superior outcomes for ALCLs compared to other PTCLs.
Nickelsen and colleagues reported a retrospective analysis on 424 patients with mature T-cell lymphoma who received HDCT/ASCT in EBMT centres between 2000 and 2005. 68 Histological subtypes were ALCL=98, PTCLu=176, AITL=120, unknown=30. Median time from diagnosis to ASCT was 9 months (range=4-99), and median follow up for surviving patients was 36 months (range=0. 17 patients who received their transplants in CR were 70% and 56%, compared to 42% and 30% for patients with chemotherapy-sensitive relapsed disease, and 23% at both time points for patients with chemotherapy-refractory disease. Available retrospective and phase II evidence, therefore, suggests that PTCL patients can benefit from HDCT/ASCT when used in the settings of chemosensitive relapse, or first remission consolidation. 74 RCTs evaluating treatments for these uncommon lymphomas are lacking, however.

# E. Lymphoblastic Lymphoma
Lymphoblastic lymphoma (LBL) is a rare, clinically aggressive neoplasm of the young that frequently involves the bone marrow and/or central nervous system. 75 These patients require aggressive combination chemotherapy (similar to acute lymphoblastic leukemia therapy) with induction, consolidation, prophylactic intrathecal chemotherapy and either maintenance therapy or first remission autologous stem cell transplantation. Sweetenham and colleagues reported a prospective RCT comparing a first remission HDCT/ASCT to conventional-dose consolidation and postremission maintenance chemotherapy in adults with lymphoblastic lymphoma. 76 77 Randomization was stratified based upon duration of remission, remission status, and prior cranial irradiation. A total of only 43 patients were enrolled. At a median follow-up of 43 months, event-free survival was 29% in the busulfan arm and 58% in the TBI arm (p=0.03). 77 Because LBL is similar to ALL, some centers prefer allogeneic hematopoietic SCT to autologous SCT. The IBMTR and ABMTR databases were retrospectively analyzed for outcomes of LBL patients who underwent autologous (auto, n=128) or HLA-identical sibling (allo, n=76) SCTs from 1989 to 1998. 78 Allogeneic SCT (alloSCT) recipients had higher TRM at 6 months (18% versus 3%, p=0.002), and this disadvantage persisted at 1 and 5 years. Significantly lower relapse rates were observed in alloSCT recipients at 1 and 5 years (32% versus 46%, p=0.05; and 34% versus 56%, p=0.004, respectively), but no differences were noted in 5 year lymphoma-free survival rates (36% versus 39%, p=0.82) or 5 year OS (44% versus 39%, p=0.47) between alloSCT and autoSCT. Multivariate analyses to account for confounding factors confirmed these results. In summary, alloSCT for LBL is associated with fewer relapses compared to autoSCT, but higher TRM offsets any potential survival benefit. Independent of SCT type, bone marrow involvement at the time of transplantation and disease status more advanced than first complete remission were associated with inferior outcomes.

# F. Burkitt Lymphoma
True Burkitt lymphoma is rare, representing <1% of all lymphomas. 80 As such, treatments for this entity have not been evaluated in RCTs. Conventional primary induction therapy consists of intensive chemotherapy with CNS prophylaxis using regimens such as CODOX-M/IVAC. 81 SCT is generally reserved for recurrent disease or chemo-sensitive primary induction failures. There is very little data on SCT for Burkitt lymphoma, and no evidence that allogeneic SCT is superior to autologous SCT for this disease. Therefore, patients with relapsed/refractory Burkitt lymphoma who fulfill standard eligibility criteria for autologous SCT indicated above, are usually treated with this approach. The largest series of Burkitt lymphoma patients undergoing SCT was reported by the EBMT in 1996 by Sweetenham and colleagues. 82 This study of 117 patients included Burkitt and Burkitt-like lymphomas in first remission (n=70) or relapse/refractory states (n=47). The 3 year OS rate following SCT was 72% for patients in first remission, 37% in chemo-sensitive relapse, and 7% for chemo-resistant patients.