Ask the Expert

Transplantation In Myelofibrosis 101: An Update

Thu, 28 Feb 2019 22:26:59 GMT

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.

Donor status:

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.

Unanswered Questions:

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.

References:

1. Kröger N, Holler E, Kobbe G, et al: Allogeneic stem cell transplantation after reduced-intensity conditioning in patients with myelofibrosis: a prospective, multicenter study of the Chronic Leukemia Working Party of the European Group for Blood and Marrow Transplantation. Blood 2009; 114:5264-5270.

2. Gupta V, Malone AK, Hari PN, et al: Reduced-intensity hematopoietic cell transplantation for patients with primary myelofibrosis: a cohort analysis from the center for international blood and marrow transplant research. Biol Blood Marrow Transplant 2014; 20:89-97.

3. Devlin R, Gupta V. Myelofibrosis: to transplant or not to transplant? Hematology American Society of Hematology Education Program 2016;2016(1):543-51.

4. Shanavas M, Popat U, Michaelis LC, et al. Outcomes of Allogeneic Hematopoietic Cell Transplantation in Patients with Myelofibrosis with Prior Exposure to Janus Kinase 1/2 Inhibitors. Biology of blood and marrow transplantation: journal of the American Society for Blood and Marrow Transplantation 2016;22(3):432-40.

5. Scott BL, Gooley TA, Sorror ML, et al. The Dynamic International Prognostic Scoring System for myelofibrosis predicts outcomes after hematopoietic cell transplantation. Blood 2012;119(11):2657-64.

6. Kroger N, Giorgino T, Scott BL, et al. Impact of allogeneic stem cell transplantation on survival of patients less than 65 years of age with primary myelofibrosis. Blood 2015;125(21):3347-50.

7. Kroger N, Deeg JH, Olavarria E, et al. Indication and management of allogeneic stem cell transplantation in primary myelofibrosis: a consensus process by an EBMT/ELN international working group. Leukemia. 2015;29(11):2126-2133.

8. Tamari R, Rapaport F, Zhang N, McNamara C, Kuykendall A, Sallman DA, Komrokji R, Arruda A, Najfeld V, Sandy L, Medina J, Litvin R, Famulare CA, Patel MA, Malloy M, Castro-Malaspina H, Giralt S, Weinberg RS, Mascarenhas JO, Mesa R, Rondelli D, Dueck AC, Levine RL, Gupta V, Hoffman R, Rampal RK. Impact of high molecular risk mutations on transplant outcomes in patients with myelofibrosis.
Biol Blood Marrow Transplant. 2019 Jan 6. pii: S1083-8791(19)30005-9. doi: 10.1016/j.bbmt.2019.01.002. [Epub ahead of print]

9. Lavi N, Rowe JM, Zuckerman T. Allogeneic stem-cell transplantation for myelofibrosis. Curr Opin Hematol. 2017 Nov;24(6):475-480.

10. Jain T , Mesa RA, Palmer JM. Allogeneic Stem Cell Transplantation in Myelofibrosis. Biol Blood Marrow Transplant. 2017 Sep;23(9):1429-1436

11. Viswabandya A, Devlin R, Gupta V. Myelofibrosis-When Do We Select Transplantation or Non-transplantation Therapeutic Options? Curr Hematol Malig Rep. 2016 Feb;11(1):6-11.

Role of Hematopoietic Stem Cell Transplantation for Hemoglobinopathies

Tue, 28 Aug 2018 19:08:46 GMT

Author: Gregory Guilcher, MD, FRCPC, FAAP

Dr. Guilcher is an associate professor of oncology and paediatrics at the University of Calgary. His clinical and research focus is hematopoietic cell transplantation (HCT) for non-malignant diseases. He also studies acute and late effects of oncologic and BMT therapies. He serves as the Vice Chair of the Board of Directors and Clinical Operations for the Sickle Transplant Alliance for Research and is the Chair Mentee of the HCT Late Effects Taskforce for the Children's Oncology Group.

He is Program Director for Pediatric Hematology/Oncology at the University of Calgary, volunteers in several roles with the Royal College of Physicians and Surgeons of Canada and teaches regularly in Mbarara, Uganda.

Reviewed by: Kylie Lepic, MD, FRCPC

Hemoglobinopathies comprise the most common monogenetic disorders worldwide. With newborn screening programs and immigration from endemic regions, Canadian hematology clinics across the country are providing comprehensive care to more children, adolescents and adults with transfusion dependent thalassemias (TDT) and sickle cell disease (SCD) than ever before. While supportive care is improving and novel therapies are emerging, long-term complications of iron burden or sickling crises prompt patients, families and care providers to explore potential curative options. Hopefully gene therapy will become an accessible reality in the coming years. At present, allogeneic hematopoietic cell transplantation (HCT) is the only established cure for TDT and SCD.

HCT has been applied to children with TDT and SCD for over 30 years. Historically HCT was offered more routinely to children with TDT, since patients with these genotypes have, by definition, a clear phenotype with more clearly defined risks of chronic transfusion and iron burden and impact on quality of life. However, with newer chelation agents and generally good self-reported quality of life, those with TDT can maintain good health in higher resource settings for decades. Despite better supportive care, many patients and families want to explore HCT as a curative option.

HCT for Transfusion Dependent Thalassemias

The likelihood of a full sibling being an unaffected HLA-matched donor is 15-20%, with trait donors acceptable. This leaves the majority of patients with TDT without a familial match, and unrelated donor HCT carries lower rates of thalassemia-free survival (TFS) due to risks of graft rejection, graft-versus-host disease (GVHD) and transplant-related mortality (TRM). Infertility risk with myeloablation is an important consideration. We also know that children under 7 years of age have fewer transplant-related complications, with adults typically faring more poorly. Pesaro classification of iron burden is also an important prognostic factor to consider. However, with newer reduced toxicity approaches using either reduced-intensity conditioning (RIC) or less toxic myeloablative agents such as treosulfan, rates of TFS exceed 80% for both matched-sibling and matched-unrelated donors with lower iron burden. Treosulfan-based regimens and the addition of alkylating agents such as thiotepa have- in some series- negated the prognostic value of matched related vs unrelated donors, as well as Pesaro status. Our centre has adopted an Italian protocol consisting of treosulfan (14 g/m2/day x 3), fludarabine (40 mg/m2/day x 4), and thiotepa (8 mg/kg/day x 1), with ATG added for matched unrelated donor transplants. Marrow allografts are typically preferred by most centres. While haploidentical-HCT offers the hope of cure to all patients, the data is still in its infancy but is evolving quickly.

For patients with TDT I would recommend:

a) All children and adolescents with TDT be offered HLA typing of full siblings and parents (particularly if there is a history of consanguinity)
b) HLA-matched sibling donor reduced toxicity HCT be offered routinely to children and adolescents after appropriate counselling, including a discussion of best supportive care and late effects such as infertility
c) HLA-matched unrelated living donor HCT can be considered by centres with expertise, with consideration of a reduced-toxicity conditioning approach
d) Unrelated umbilical cord blood, mismatched unrelated and haploidentical HCT remain experimental and should only be performed in the context of a well designed clinical trial
e) HCT for adults with TDT should be undertaken with caution at centres with expertise, with consideration of a reduced-toxicity conditioning approach
f) Fertility counselling and preservation options should be offered

HCT for Sickle Cell Disease

Who and when to offer HCT for SCD has been the topic of great debate since the first successful HCT was described in 1984. Phenotypes can vary, with sometimes unpredictable and devastating complications such as stroke. Better supportive care options such as penicillin prophylaxis, vaccination, transcranial Doppler screening, hydroxyurea and chronic transfusions for select patients have allowed over 95% of children to reach late adolescence and young adulthood in high income countries. Newer targeted agents hold promise to further improve quality of life by reducing crises and time in hospital. However, even with optimal supportive care in 2018, many patients still have strokes and other significant morbidities which impact quality and quantity of life into adulthood. Restrictive pulmonary disease and right-sided heart failure, while rare in childhood, are ominous predictors of mortality in adulthood.
Further complicating the debate are clearly superior outcomes when HCT is performed at a younger age, perhaps when a patient’s phenotype may not be severe. The risk of GVHD increases with age, as does potential alloimmunization with associated risk of graft rejection. With the high risk of infertility with traditional myeloablative approaches, the decision to refer a child for consideration of HCT has been difficult for hematologists and families, and HCT physicians have had appropriate reservations about offering transplantation.

At present, children with a matched sibling donor can expect ~95% chance of cure with HCT. Rates of GVHD have been in the range of ~20% for aGVHD and ~5-15% for cGVHD; children over 14 years of age are at higher risk of this undesired complication, which is the main cause of TRM in HCT for SCD. While such high rates of cure are promising and position well against lifetime risks of SCD, these rates of GVHD are not insignificant. Again, only 15-20% of full siblings will be unaffected HLA-matches (HbAA or HbAS acceptable), limiting access to HCT.
Fortunately, newer RIC and nonmyeloablative offer the possibility of cure with fewer acute and late adverse effects. Fertility preservation is possible, the importance of which should not be underestimated. Experience with very low intensity regimens such as one developed at the National Institutes of Health (USA) has been administered in over 60 children and adults (many of these adults having significant co-morbidities) with very high rates of success (87-100% event-free survival) and no cases of acute or chronic GVHD. This regimen includes alemtuzumab/300 cGy total body irradiation with sirolimus for GVHD prophylaxis. The NIH regimen employs unmanipulated peripheral blood stem cells with no maximum cell dose, in contrast to most published sibling donor HCT regimens for SCD which stipulate bone marrow allografts. As regimens become safer and novel targeted supportive care agents are developed, the position of HCT against best supportive care is in constant evolution.

HCT for SCD should be undertaken with unique supportive care precautions. HbS levels should be less than 30-40% prior to HCT to avoid crisis during HCT. These HbS levels can be achieved with either simple or exchange transfusions. Platelets should be maintained greater than 50 x 109/L to avoid intracranial hemorrhage, particularly in those with neurovascular disease. Due to high rates of posterior reversible encephalopathy syndrome- as high as 20-40% when cyclosporine is used for GVHD prevention- it is advised to avoid hypertension and keep magnesium levels normal. Hb levels should be maintained between 90-110 g/L to avoid both hypoxia and hyperviscosity. G-CSF is avoided pre-engraftment due to the risk of splenic sequestration in patients with SCD.

If engraftment is successful, it is hoped that no new sickling injury will occur, while existing organ dysfunction is unlikely to improve. Even 20-25% donor myeloid chimerism can be curative, and HbS levels of the recipient should reflect those of the donor. Sickling crises are not expected if the HbS level is less than 50%. Studies of long-term outcomes including neurocognitive measures, self-reported pain metrics and more detailed descriptions of end organ function into adulthood should be the focus of future research efforts.

All trials of alternative donor HCT have had either unacceptably high rates of GVHD or graft failure. Promising areas of research include novel GVHD prevention strategies with agents such as abatacept and haploidentical HCT with either post-HCT cyclophosphamide or ex-vivo graft manipulation. Given that many patients with SCD do not have fully matched related or unrelated donors, strategies which allow for safe HCT with mismatched unrelated or haploidentical donors are critical to expand access to cure. International consortia such as the CBMTG, Sickle Transplant Alliance for Research (STAR) and Monacord are dedicated to advancing safe curative therapies for SCD using HCT.

For patients with SCD I would recommend:

a) All patients with SCD be offered HLA typing of full siblings and parents (particularly if there is a history of consanguinity)
b) HLA-matched sibling donor HCT be offered routinely to children and adolescents after appropriate counselling, including a discussion of best supportive care and late effects such as infertility
c) HCT for adults with an HLA-matched sibling donor should be undertaken with caution at centres with expertise, with consideration of a reduced-toxicity approach
d) Alternative donor HCT should only be performed in the context of a well designed clinical trial
e) Fertility counselling and preservation options should be offered

References:

1. Angelucci E. Hematology Am Soc Hematol Educ Program. 2010;2010:456-62.
2. Chaudhury S, Ayas M, Rosen C, Ma M, Viqaruddin M, Parikh S, et al. A multicenter Retrospective analysis stressing the importance of long-term follow-up after hematopoietic cell transplantation for β-thalassemia. Biol Blood Marrow Transplant. 2017 Oct;23(10):1695-1700.
3. King AA, Kamani N, Bunin N, Sahdev I, Brochstein J, Hayashi RJ, et al. Successful matched sibling donor marrow transplantation following reduced intensity conditioning in children with hemoglobinopathies. Am J Hematol. 2015 Dec;90(12):1093-8.
4. Bernardo ME, Piras E, Vacca A, Giorgiani G, Zecca M, Bertaina A, et al. Allogeneic hematopoietic stem cell transplantation in thalassemia major: results of a reduced-toxicity conditioning regimen based on the use of treosulfan. Blood. 2012 Jul 12;120(2):473-6.
5. DeBaun MR, Clayton EW. Primum non nocere: the case against transplant for children with sickle cell anemia without progressive end-organ disease. Blood Adv. 2017 Dec 8;1(26):2568-2571.
6. Fitzhugh CD, Walters MC. Fitzhugh CD, Walters MC. The case for HLA-identical sibling hematopoietic stem cell transplantation in children with symptomatic sickle cell anemia. Blood Adv. 2017 Dec 8;1(26):2563-2567
7. Vichinsky E. Chronic organ failure in adult sickle cell disease. Am Soc Hematol Educ Program. 2017 Dec 8;2017(1):435-439.
8. Hsieh MM, Fitzhugh CD, Tisdale JF. Allogeneic hematopoietic stem cell transplantation for sickle cell disease: the time is now. Blood. 2011 Aug 4;118(5):1197-207.
9. Cappelli B, Tozatto-Maio K, Volt F, Paviglianiti A, Ferster A, Dupont S, et al. Risk factors and outcomes according to age at transplant with an HLA Identical sibling for sickle cell disease. Blood 2017 130:3317
10. Bernaudin F, Socie G, Kuentz M, Chevret S, Duval M, Bertrand Y, et al. Long-term results of related myeloablative stem-cell transplantation to cure sickle cell disease. Blood. 2007 Oct 1;110(7):2749-56.
11. Guilcher GMT, Truong TH, Saraf SL, Joseph JJ, Rondelli D, Hsieh MM. Curative therapies: Allogeneic hematopoietic cell transplantation from matched related donors using myeloablative, reduced intensity, and nonmyeloablative conditioning in sickle cell disease. Semin Hematol. 2018 Apr;55(2):87-93
12. Chaudhury S, Laskowski J, Rangarajan H, Abraham A, Haight A, Guilcher G, et al. Abatacept for GVHD prophylaxis after hematopoietic stem cell transplantation (HCT) for pediatric sickle cell disease (SCD): A Sickle Transplant Alliance for Research (STAR) Trial. Biology of Blood and Marrow Transplantation, Vol. 24(3), S91

When should patients with chronic lymphocytic leukemia (CLL) be transplanted in the era of new agents?

Thu, 26 Oct 2017 21:30:22 GMT

Author: Mona Shafey, MD, FRCPC

Dr. Mona Shafey is a Clinical Assistant Professor in the Division of Hematology and Hematological Malignancies at the University of Calgary. Her clinical and research interests focus on malignant hematology, with a focus in lymphoma and CLL, and the use of stem cell transplantation for those diseases.

Reviewed by: Auro Viswabandya, MD, DM

When one thinks of a young, fit, transplant-eligible patient with CLL, the standard “go-go” approach prevails, the aim of which is the deepest remission/highest efficacy, usually at the expense of increased toxicity of the treatment. Allogeneic stem cell transplantation is at the extreme end of the therapy spectrum for CLL, and is currently the only potential curative option, accompanied by a significant risk of morbidity from chronic GVHD, and treatment-related mortality. For most patients with this “disease of the elderly”, this approach is not possible, and as a result new, efficacious and well-tolerated therapies have developed over the last decade that have completely changed the way this disease is being treated, including the role of allogeneic stem cell transplant.

Allogeneic HSCT is recommended for patients with high risk CLL, and traditionally this included patients with disease associated with deletion 17p/TP53 mutations, and/or disease refractory to purine analogues (i.e. disease relapse within 2 years after purine analogue combination therapy). The basis of HSCT in CLL is a strong graft-versus-leukemia effect, supported by lower relapse risk after chronic GVHD1, higher relapse risk associated with T-cell depletion2, and MRD clearance in the context of chronic GVHD or immune interventions such as tapering of immunosuppression or donor lymphocyte infusion3,4. The 5-year progression-free survival is 30-35%, with 5-year overall survival 50-60%, with better outcomes in those who are chemosensitive, with non-bulky disease at time of HSCT5,6. Reduced-intensity conditioning has improved early mortality of HSCT, increasing tolerability, and allowing older patients with co-morbidities (i.e. the typical CLL patient) to proceed with HSCT. However, non-relapse mortality is still high in this patient population, approximately 20-30%, with GVHD and its associated complications the main cause of death. Moreover, in those who survive HSCT, chronic GVHD, which is frequently extensive, significantly impairs the quality of life long-term in about 25% of patients.

Greater understanding of the pathobiology behind CLL has led to the development of more targeted therapies, such as ibrutinib and idelalisib, which target the Bruton tyrosine kinase and phosphatidylinositol 3-kinase, respectively, in the B-cell receptor signaling pathway. Long-term results with ibrutinib in the relapsed setting are now available, and with a median of 4 prior lines of therapy, the use of ibrutinib resulted in a median PFS of 52 months, and overall survival was not reached7. In patients without del17p or del 11q, the 5-year PFS was 66-91%, and OS was 80-91%. Patients with del17p had median PFS of 26 months, and this was 55 months for del11q, both of which were significantly higher than expected outcomes with FCR in the front line setting. This has led to the use of ibrutinib as first line therapy for del17p associated CLL. This drug is generally well tolerated, with fatigue, arthralgias, rash, and infections being common but mild side effects, and hypertension and atrial fibrillation (in up to 10% of patients) and increased risk of bleeding being long-term effects of the drug. Idelalisib has also shown efficacy in patients with relapsed disease in patients without del17p, and is another suitable option for these patients, at the expense of high rates of opportunistic infections (CMV, PJP pneumonia), and inflammatory conditions (e.g. colitis, pneumonitis)8. Based on the available data, all patients who have relapsed after FCR, regardless of duration of initial response, should be treated with one of these novel agents prior to consideration for allogeneic stem cell transplantation.

BCL2 has also become a key target, as it is an important antiapoptotic protein. Venetoclax is an oral active potent small molecule BCL2 protein inhibitor, displacing sequestered antiapoptotic proteins, and has been shown to have durable responses in CLL after failure of ibrutinib and/or idelalisib. In a study of 64 patients with relapsed/refractory disease (43 prior ibrutinib of which 39 were resistant; 21 prior idelalisib), the 12 month PFS was 80% and OS was 90%.9 The drug is very well tolerated, and the major side effects noted included tumor lysis, which is now well managed with risk stratification, and neutropenia. These data suggest that Venetoclax is a reasonable salvage therapy in patients who have failed another novel agent.

Richter’s transformation, defined as a transformation from CLL into an aggressive lymphoma (most commonly DLBCL, rarely Hodgkin lymphoma), occurs in up to 10% of CLL patients, with median time to occurrence 1.8-5 years from diagnosis. Risk factors for this unfortunate complication includes advanced stage and bulky disease (>3 cm LN) at time of diagnosis, IGHV unmutated status, and del17p. Median survival after transformation is 8-14 months due to poor response rates to chemotherapy. Allogeneic HSCT in this setting as a post remission therapy is important, with 3 year survival probability of 75% for those transplanted in CR or PR, compared to 21% for patients who undergo HSCT after relapsed/refractory disease, or 27% who responded to chemotherapy but do not undergo HSCT10. Data for the use of the novel agents in Richter’s transformation is lacking at this time.

Similar to what was seen when TKIs were introduced for CML, the availability of targeted therapies for CLL has clearly changed our definition of “high-risk CLL”, and this will lead to less stem cell transplants for this disease, with better outcomes and quality of life for the majority of patients with CLL. It is important, however, that HSCT not be considered a last resort treatment, offered to patients only after all other options have been exhausted. Based on the current available data, in fit patients with a suitable donor, I would recommend allogeneic HSCT in the following cases:

(a) Del17p-associated CLL

(b) Relapse after ibrutinib or idelalisib

For these patients, I generally proceed with HSCT once maximal response to therapy has been achieved.

CLL treatment will continue to advance and evolve quite rapidly, thus it is necessary to continually factor in new evidence that will lead to adjustment of these recommendations.

(a) Del17p-associated CLL

(b) Relapse after ibrutinib or idelalisib

For these patients, I generally proceed with HSCT once maximal response to therapy has been achieved.

CLL treatment will continue to advance and evolve quite rapidly, thus it is necessary to continually factor in new evidence that will lead to adjustment of these recommendations.

(a) Del17p-associated CLL

(b) Relapse after ibrutinib or idelalisib

For these patients, I generally proceed with HSCT once maximal response to therapy has been achieved.

CLL treatment will continue to advance and evolve quite rapidly, thus it is necessary to continually factor in new evidence that will lead to adjustment of these recommendations.

References:

1. Farina et al. Qualitative and quantitative polymerase chain reaction monitoring of minimal residual disease in relapsed chronic lymphocytic leukemia: early assessment can predict long-term outcome after reduced intensity allogeneic transplantation. Haematologica. 2009. 94(5)654-662

2. Gribben et al. Autologous and allogeneic stem cell transplantation for poor risk chronic lymphocytic leukemia. Blood 2005. 106 (13):4389-4396

3. Hahn et al. Timing of immunosuppression tapering, chronic GVHD, and minimal residual disease (MRD) eradication in patients allografted for poor-risk chronic lymphocytic leukemia (CLL). EBMT consensus criteria: a single center experience [abstract]. Bone Marrow Transplant 2013. 48(S2): S72

4. Moreno et al. Clinical significance of minimal residual disease, as assessed by different techniques, after stem cell transplantation for chronic lymphocytic leukemia. Blood 2006. 107(11): 4563-4569

5. Sorror et al. Five-year follow-up of patients with advanced chronic lymphocytic leukemia treated with allogeneic hematopoietic cell transplantation after nonmyeloblative conditioning. J Clin Oncol2008. 26(30): 4912-4920.

6. Brown et al. Long-term follow-up of reduced-intensity allogeneic stem cell transplantation for chronic lymphocytic leukemia: prognostic model to predict outcome. Leukemia 2013 27(2): 362-369

7. O’Brien et al. 5-year experience with single-agent ibrutinib in patients with previously untreated and relapsed/refractory chronic lymphocytic leukemia/small lymphocytic leukemia [abstract]: ASH Meeting 2016 Abstract 233

8. Furman et al. Idelalisib and rituximab in relapsed chronic lymphocytic leukemia. N Eng J med2014. 370: 997-1007

9. Jones et al. Venetoclax (VN) monotherapy for patients with chronic lymphocytic leukemia (CLL who relapsed after or were refractory to ibrutinib or idelalisib [abstract]. ASH Meeting 2016 Abstract 637

10. Tsimberidou et al. Clinical outcomes and prognostic factors in patients with Richter’s syndrome treated with chemotherapy or chemoimmunotherapy with or without stem cell transplantation. J Clin Oncol 2006 24(15): 2343-2351