Author: Auro Viswabandya, MD, DM
Dr. Auro Viswabandya has completed his specialty training in India and then did a 3 year fellowship in "Malignant Hematology and Stem Cell Transplantation" in Princess Margaret Cancer Center. He was a staff in the largest Hematology center in India for 10 years before moving to Princess Margaret Cancer Center as an active staff in Allogeneic Stem Cell Transplant Division. Dr. Auro Viswabandya is appointed as an Assistant Professor in the Division of Medical Oncology, Department of Medicine, University of Toronto. He is currently the Associate Director and Fellowship Supervisor in the Allogeneic Stem Cell Transplant Program at PMH.
He has published more than 100 peer reviewed journal articles and 5 book chapters to his credit. His areas of interest are GVHD prophylaxis in allogeneic stem cell transplant and Haploidentical stem cell transplantation. He specifically looks at the combination of Anti-Thymocyte Globuline (ATG) and post-transplant Post Transplant Cyclophosphamide (PTCy) in patients undergoing allogeneic stem cell transplantation. Currently, Dr. Viswabandya is the fellowship and residents (PGY5) supervisor of allotransplant at Princess Margaret Cancer Centre, and Treasurer of the CBMTG. Education is his passion and he is currently the member of Education Committee of CBMTG and ASBMT. He is a member of Stem Cell Transplantation Advisory Committee of Cancer Care Ontario.
Reviewed by: Sita Bhella, MD
Who needs transplant?
Although treatment with JAK1/2 inhibitors (JAKi) has revolutionized management algorithms in patients with MF, JAKi are not curative and do not decrease the risk of leukemic transformation. Cure of MF is currently possible only with allogeneic SCT (SCT). However, SCT is associated with significant morbidity and mortality and traditionally it is offered to patients who are destined to have poor survival based on prognostic risk scores (DIPSS and DIPSS-plus). Median survival of patients with intermediate -2 /high risk groups is usually less than 5 years. So, transplant related morbidity and mortality can be justified for these patient groups as there is an overall survival benefit with transplant.
However, as our understanding of pathogenesis becoming clearer, the dogma of restricting SCT to only Intermediate-2 / high risk groups is also changing. SCT also can be justified for patients who have transfusion dependent anemia, persistent and progressive thrombocytopenia or abnormal cytogenetics as these group of patients do not do well as shown by DIPSS –plus scoring prognostication. Leukemia transformation (LT) remains as an important parameter in treatment decision. In DIPSS-plus cohort, patients with thrombocytopenia (platelets less than 100 x 10^9/l), persistent peripheral blasts of more than 2% and high risk cytogenetics were independently associated with higher progression to leukemia.
With our newer understanding regarding the prognosis and underlying genetic factors, mutational status in patients with MF can affect the decision making. Patients with MF who have ‘high molecular risk’ group (positive for either AXSL1, SRSF2, EZH2, IDH 1 and IDH 2, TET-2 and TP53 gene) do poorly and tend to have inferior survival. Patients with CALR- /ASXL1+ tend to have worse survival too. So, it will be logical to consider patients with intermediate-1 risk category who have transfusion dependent anemia (failing to conventional therapy), thrombocytopenia, high peripheral blast count or adverse cytogenetics for SCT particularly if they are young, have a low HCT-CI score and a suitable matched donor. Newer prognostic scoring systems like MIPSS 70 and MIPSS 70 plus incorporate these criteria and patients are recommended transplant if they are either MIPSS 70 high risk or MIPSS 70 plus high or very high-risk category.
Patient factors (age, co-morbidities, performance status), disease factors (associated portal hypertension, pulmonary hypertension, high risk of leukemia transformation) and transplant factors (well matched donor) need to be considered while offering transplant to patients with MF.
Ideally decision of transplant should be individualized for each patient with a detailed discussion regarding the pros and cons of transplant vs. non-transplant strategies. Other parameters like age, availability of a suitable matched donor, HCT-CI should be kept in mind while making this decision. Even if patients who are responding to JAK inhibitors, it is appropriate to look at these parameters to decide whether a transplant option can be offered to them.
The EBMT / ELN International Working Group specific recommendation for patients with MF who are being planned for transplant are below.
1. All patients with intermediate-2 or high-risk disease according to IPSS, DIPSS or DIPSS-plus and age less than 70 years should be considered potential candidates for Allo-SCT.
2. Patients with intermediate 1 risk disease and less than 65 years should be considered candidates for Allo SCT if they present with either refractory transfusion dependent anemia or peripheral blood blasts> 2% or adverse cytogenetics.
3. Patients with low risk disease should not undergo all SCT. They should be monitored and evaluated for transplant when disease progression occurs.
4. Patients with blast transformation (PB or BM blasts >/= 20%) are not good candidates for Allo SCT. They should receive debulking therapy and be reconsidered for transplant after achieving a partial or complete remission of leukemia.
5. Although the use of molecular risk classification for the identification of candidates for Allo SCT among intermediate-1 risk patients deserves further clinical validation, patients in this risk category who are triple negative (JAK V617F, CALR and MPL negative) or ASXL1 positive or both should be considered for Allo SCT.
6. Individual transplant-specific prognostic factors should be considered in every patient for Allo-SCT to arrive at an individual decision. Transplant specific high-risk factors include: spleen > 22 cm, > 20 units of blood transfusions, HLA non-identical donor, ECOG > 2, HCT-CI> 3 and portal hypertension.
JAK inhibitors and Transplant – Challenging decision:
Advances in supportive care, newer conditioning regimens, GVHD prophylaxis, high resolution HLA typing has significantly improved the outcome of SCT in MF patients. JAKi improve splenomegaly and constitutional symptoms and as a result more number of patients may be eligible to proceed with Allo SCT. Unfortunately, at present, there is no comparative data on the outcome of SCT vs. JAK inhibitors vs. other available treatment options making the decision of appropriate therapeutic management difficult particularly for those high-risk patients who are showing a clinical response to JAKi. Though early SCT can be associated with significant TRM and loss of quality of life in a few, delaying SCT can be associated with risk of LT and worse outcome. About 50% patients discontinue JAKi at 3 years.
A recent study, though with limited number of patients in Germany has shown that the outcomes of transplantation were better for those who were responding to JAK inhibitors rather than those who have failed or lost response. A retrospective multicenter trial confirmed this observation too in limited number of patients. However, preliminary results from a prospective multicenter study in France have demonstrated serious adverse events like cardiogenic shock and tumor lysis syndrome. Prospective trials are underway to evaluate role of JAKi pre transplant. Pre transplant use of JAKi does not seem to affect both neutrophil and platelet engraftment. Data from small retrospective studies show that if used pre-transplant, it is important to taper JAKi over a period of 5-7 days before starting conditioning regimen and last dose to be given within 24 hours of starting conditioning regimen to prevent withdrawal effect and cytokine storm.
Overall survival for MF patients undergoing SCT is approximately 60% at 5 years from an HLA matched sibling donor. Outcomes for matched unrelated donor is 50-55% and significantly lower for mismatched donor transplantation which is approximately 30-35% at 5 years. EBMT study has shown that cumulative incidence of NRM is less in completely matched donor vs. mismatched donors (12% vs 38%). And, the cumulative incidence of NRM does not differ between HLA identical siblings vs 10/10 matched unrelated group (10% vs 13%). UCB transplant is associated with high risk of graft failure. A recent Eurocord analysis showed 2 year OS and EFS of 44% and 30% respectively. Data on role of haploidentical transplant in MF is emerging with promising outcome from some single center publication.
Preferably, in patients who are responding to JAK-1/2 inhibitor therapy and without very
high-risk features of LT, HCT need to be considered only if a suitable MSD or well-matched URD is available. Conversely, HCT with alternate donors can be considered for those who are at a very high risk of leukemic transformation, or those who lose response to, or become intolerant to JAK inhibitor therapy.
Graft source, Conditioning Regimen, splenectomy and graft failure:
Recent transplants are mainly done using PBSC rather than BM as the stem cell source. No comparison between BM or PBSC has been published in primary myelofibrosis. A phase III randomized trial in unrelated transplant using myeloablative regimen found no difference in OS between sources of stem cells though chronic GVHD was more with PBSC. As the incidence of graft failure is higher in MF, and PBSC is associated with less graft failure, most transplant physicians prefer to use PBSC as source of stem cell in patients with MF for theoretical advantages.
The optimal intensity of conditioning regimen still needs to be defined in MF. Though there are no prospective comparison between myeloablative and reduced intensity conditioning regimens in MF, the overall survival does not differ between these regimens in retrospective analysis. In a recently published report of RIC transplant in MF, 72% of patients were of less than 60 years, and the median age was 55 years (range: 19-79). In this group the probability of OS at 5 years was 47%. These data suggest that RIC is a potentially curable option even in younger patients but doesn't not answer whether it is superior or not in this age group. Among the reduced intensity regimens, Flu-Mel and Flu-Bu are most commonly used regimens and there are no significant differences in outcome between these two commonly used RIC regimens.
Splenomegaly is associated with delayed hematopoietic recovery and splenectomy is associated with faster engraftment. However, the evidence supporting improvement of transplant outcome with splenectomy is not sufficient enough to recommend splenectomy as a standard pre transplant procedure. Pre transplant splenectomy in refractory splenomegaly and cytopenia settings should be considered on a case by case basis. Spleen irradiation is not recommended. Whether reduction of splenomegaly with JAK inhibitors will result in better hematopoietic recovery, is still an open question.
The incidence of graft failure post-transplant is higher than other diseases and it is in the range of 5-25% most likely due to the bone marrow fibrosis. The incidence is higher in unrelated or mis-matched donor than HLA matched sibling donor. Splenectomy has not been shown to reduce incidence of graft failure.
Post -transplant Follow Up:
In MF, resolution of bone marrow fibrosis may take up to 12 months after HCT. Resolution of fibrosis is an inadequate tool for early detection of relapse. Persistence of splenomegaly up to 1-year post transplant should be considered the normal process of disease clearance and does not need specific management unless there is severe pancytopenia and transfusion dependency. New or worsening splenomegaly after allo-SCT should raise the suspicion of relapse of PMF.
In patients with evidence of minimal residual disease or with decreasing donor chimerism post-transplant, discontinuation of immune-suppressive drugs, donor lymphocyte infusion (DLI) or both are strategies to avoid clinical relapse. Currently there is no evidence to suggest that JAK inhibitors can modulate donor cell chimerism or will be helpful in clearance of minimal residual disease and should not be used as standard therapeutic intervention. Potential negative role of JAK inhibitions on hematopoiesis should be taken into consideration. It may be used for those with persistent splenomegaly or constitutional symptoms, but only as part of a well-designed clinical trial.
HSCT remains a highly relevant option in the era of JAK inhibitors. However, choosing the right candidate in the era of advanced risk stratification with available newer genomic data remains a challenge. A prospective well controlled trial is necessary to compare outcome between allogeneic stem cell transplant and modern best available non-transplant therapies in high risk patients.
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