Page 1085 - Hematology_ Basic Principles and Practice ( PDFDrive )

968 Part VII Hematologic Malignancies

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to prevent the emergence of graft-versus-host disease. A full discus- (PIM kinase inhibitors, B-catenin degraders ), and radioisotope-
sion of posttransplant considerations is outside the scope of this conjugated monoclonal antibodies. As mentioned earlier, whether
chapter, but most aspects of this area are less specific to MDS than any of these drugs will significantly change the landscape of MDS
those discussed previously. therapy is unclear.
As mentioned, despite being potentially curative therapy, trans-
plant in MDS is associated with significant morbidity and mortality.
One study has suggested that 50% to 60% of lower-risk patients and FUTURE DIRECTIONS
20% to 40% with higher-risk disease can expect long-term disease-
523
free survival following transplant, but the alternative view of these While the last ten years have witnessed substantial improvements in
data is that a substantial proportion of patients (40%–50% of low our understanding of the molecular pathophysiology underlying
risk and 60%–80% of high risk) either relapse or die of nonrelapse MDS, similar strides have not been made in its treatment: at the time
complications of transplant. of this writing, it has been almost 10 years since the FDA last
Numerous studies have attempted to dissect patient and disease approved a new drug for treatment of MDS (decitabine in 2006).
attributes that may predict outcomes following transplant. Poor-risk There are few therapies in clinical trials that offer hope of broad or
524
cytogenetics, including monosomy 7 and complex karyotypes, deep efficacy, and much of the ongoing clinical effort is directed at
have been shown to predict a high rate of relapse, and recent data incremental changes to current practice, such as adjusting dosing
suggest that pathogenic TP53, DNMT3A, and TET2 mutations are schedules of currently approved therapies or using modestly effective
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predictors of poor outcomes following transplantation as well. So drugs in combination. The lack of progress is to a great extent caused
far, no cytogenetic or genetic profiles have been clearly associated with by unfortunate facts of MDS biology, including its origin in quiescent
a favorable response to transplant. Preexisting neutropenia has been stem cells, a paucity of targetable activating mutations, and enrich-
shown to predict an increased risk of serious infections in the post- ment for poorly targetable mutations with much more subtle effects
525
transplant setting. On the other hand, a low blast count (fewer on growth and differentiation. Efforts are further complicated by the
than 5%) is associated with better outcomes, and other data show heterogeneity of biology both between and within individual patients,
that patients who achieved a remission or significant response to as well as the advanced age and poor overall health of many patients
pretransplant chemotherapy have better outcomes as well. 526 with MDS.
Despite these significant challenges, there is nevertheless great
Other Therapies for Higher-Risk Disease opportunity for improvements in care. Advances in stem cell trans-
plant techniques, including the availability of alternative donor
sources, refinements of posttransplant immunosuppression, and
Autologous Stem Cell Infusion augmentation of the graft-versus-tumor effect, should continue to
improve the outcomes for MDS patients able to undergo transplant.
Though rarely used in current practice, infusion of autologous stem An equally difficult challenge lies in treatment of those patients ineli-
cells has been attempted in the past, primarily for patients with oli- gible for transplant, and it is in these patients that effective unification
goblastic disease. 527,528 There are a number of reasons why this of our improving biologic understanding of MDS with clinical care
approach is suboptimal for MDS patients. The most obvious draw- is most essential.
back is that MDS is by definition a disorder of stem cells, such that
any autologous infusion will ultimately lead to repopulation of the
marrow with the original malignant clone, but without the graft-
versus-leukemia effect imparted by an allogeneic transplant. Moreover, SUGGESTED READINGS
autologous stem cell infusion is really meant to serve as a rescue after
high-dose chemotherapy, and is thus most successful when given for Abel GA, Klaassen R, Lee SJ, et al: Patient-reported outcomes for the
a chemotherapy-sensitive disease, which MDS is not. Finally, given myelodysplastic syndromes: a new MDS-specific measure of quality of
the ineffective hematopoiesis many patients experience before treat- life. Blood 123(3):451–452, 2014.
ment, hematopoietic recovery following high-dose chemotherapy is Bejar R, Stevenson K, Abdel-Wahab O, et al: Clinical effect of point muta-
often poor. Since most patients who would be candidates for autolo- tions in myelodysplastic syndromes. N Engl J Med 364(26):2496–2506,
gous stem cell rescue would also be eligible for other, more effective 2011.
modalities of therapy, there are usually few reasons to pursue this Bejar R, Stevenson KE, Caughey B, et al: Somatic mutations predict poor
avenue. outcome in patients with myelodysplastic syndrome after hematopoietic
stem-cell transplantation. J Clin Oncol 32(25):2691–2698, 2014.
Bejar R, Stevenson KE, Caughey BA, et al: Validation of a prognostic model
Other Drugs and the impact of mutations in patients with lower-risk myelodysplastic
syndromes. J Clin Oncol 30(27):3376–3382, 2012.
Most drugs known to have activity in AML have been tried for MDS Cogle CR, Iannacone MR, Yu D, et al: High rate of uncaptured myelodys-
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as well, usually with suboptimal results. These include etoposide, plastic syndrome cases and an improved method of case ascertainment.
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irinotecan, gemcitabine, low-dose melphalan, idarubicin, and Leuk Res 38(1):71–75, 2014.
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clofarabine. Both hydroxyurea and low-dose oral etoposide can be Damm F, Fontenay M, Bernard OA: Point mutations in myelodysplastic
used to control proliferation in patients with excess blasts, but they syndromes. N Engl J Med 365(12):1154–1155, author reply 155,
do not target the underlying disease. Clofarabine is sometimes effec- 2011.
tive as a bridge to transplant therapy in patients with excess blasts Della Porta MG, Tuechler H, Malcovati L, et al: Validation of WHO
despite hypomethylating agent therapy, but renal and hepatic toxicity classification-based Prognostic Scoring System (WPSS) for myelodysplas-
and severe skin rash are limiting. 533 tic syndromes and comparison with the revised International Prognostic
As with lower-risk disease, there are a number of ongoing trials Scoring System (IPSS-R). A study of the International Working Group
for patients with high-risk MDS as of this writing. Reflective of the for Prognosis in Myelodysplasia (IWG-PM). Leukemia 2015.
poorer prognosis of these patients compared to those with lower-risk Genovese G, Kähler AK, Handsaker RE, et al: Clonal hematopoiesis and
disease, many of these trials either examine different combinations blood-cancer risk inferred from blood DNA sequence. N Engl J Med
of high-dose chemotherapy or modification of protocols for alloge- 371(26):2477–2487, 2014.
neic stem cell transplant, and are often open to both MDS and Gerds AT, Gooley TA, Estey EH, et al: Pretransplantation therapy with
AML patients. However, there are a number of novel or repurposed azacitidine vs induction chemotherapy and posttransplantation outcome
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agents in trials as well, including immunotherapies (ipilimumab, in patients with MDS. Biol Blood Marrow Transplant 18(8):1211–1218,
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adoptive T-cell transfer, and NK cell therapy ), small molecules 2012.