Autologous Hematopoietic Stem Cell Transplantation for Non-Hodgkin Lymphoma

CHAPTER 14

Autologous Hematopoietic Stem Cell Transplantation for Non-Hodgkin Lymphoma MUHAMMAD AYAZ MIR, MBBS, FACP  •  QAISER BASHIR, MD

INTRODUCTION Non-Hodgkin Lymphomas (NHLs) include a very diverse group of nearly 70 subentities in updated World Health Organization (WHO) Classification of Lymphoid Tumors (Fig. 14.1). Spectrum includes low-grade small lymphocytic lymphoma (SLL) and follicular lymphoma (FL) which are indolent and may be observed for years without therapy to Burkitt’s lymphoma, which may require therapy on the day of presentation. Therapeutic approach to these tumors is not thus uniform. Some are transplanted in the first complete remission (CR1), others in CR2 or beyond, and some may merit consideration of another chemo or immunotherapy instead of transplant even at relapse. NHL represents the second most common indication for autologous hematopoietic stem cell transplantation (auto-HSCT) after myeloma in the USA [∼4100 performed in 2016: Center for Blood and Marrow Transplantation (CIBMTR) data, summary slide]. With a low treatment-related mortality (TRM) and ability to induce long-term durable remissions in a significant number of patients, auto-HSCT remains an attractive treatment option for NHL. Following is a summary of clinical approach and evidence regarding auto-HSCT in major NHL subtypes. 

DIFFUSE LARGE B CELL LYMPHOMA (DLBCL) For the commonest NHL, R–CHOP (rituximab, cyclophosphamide, hydroxydaunorubicin, vincristine, prednisone) remains a standard of care for initial disease. However, a third of patients will have refractory/stable disease, early relapse (<1  year), or delayed relapse, despite 6–8 cycles of standard R–CHOP chemotherapy.1 Parma Study laid the foundation of auto-HSCT in relapsed NHL, showing 5-year event-free survival ([EFS] 46 versus 12%, P = .001) and overall survival ([OS] 53

versus 32%, P = .038) benefit, although numbers randomized to transplant versus conventional salvage were small (∼50 patients each) and chemo-resistant patients were excluded.2 Moreover, in Parma, rituximab was not a part of treatment arms, which is universally the case today. Perfect salvage regimen before auto-HSCT is not well defined. R-ICE (rituximab, ifosfamide, carboplatin, and etoposide), which can be given as a fractionated outpatient regimen,3 is at least as effective as R-DHAP (rituximab, dexamethasone, ara-C, and cisplatin) with overall response rate of >80% with both regimens (CORAL Study4). Platinum-based regimens such as R-gemcitabine-oxaliplatin appear to have a survival benefit based on retrospective data.1 With any regimen, half of the patients will have adequate salvage, making them eligible for auto-HSCT, and of these, approximately half will relapse despite transplantation.5 Positron Emission Tomography (PET) scans before and after auto-HSCT if both negative (-pre/-post) ensure best prognosis as compared to + pre/- post or -pre/+ post groups.6 Double-hit lymphomas (DHLs) represent ∼ 5% of DLBCL and have translocations of MYC gene with either Bcl-2 and/or Bcl-6 resulting in dismal prognosis. When present as proteins expressed on immunohistochemistry, the term double expresser lymphoma (DEL) is used, which still has a worse prognosis than non-DEL DLBCL. In a Southwestern Oncology Group study of CHOP +/− rituximab with or without auto-HSCT, transplant appeared to salvage some DEL but none of DHL patients. Best therapy for this subset thus remains controversial.7,8 Transplantation in CR1 as consolidation for those with high International Prognostic Index scores has been explored showing improvement (randomized after 5 R–CHOP to either 3 more R–CHOP or 1 additional R–CHOP and Auto HSCT) in progression-free

Hematopoietic Cell Transplantation for Malignant Conditions. https://doi.org/10.1016/B978-0-323-56802-9.00014-6 Copyright © 2019 Elsevier Inc. All rights reserved.

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FIG. 14.1  Epidemiology of non-Hodgkin lymphoma Mucosa Associated Lymphoid Tissue (MALT). (WHO

Classification 2008.)

survival [(PFS) 69% versus 55% at 2 years, P = .005] but not in OS in the auto-HSCT group.9 Mobilization can be performed using granulocyte colony-stimulating factor, chemotherapy such as cyclophosphamide, and adding plerixafor for heavily pretreated patients.10 Most well-studied conditioning regimen for autoHSCT is BEAM with slight variations (Fig. 14.2: BCNUCarmustine, Etoposide, Ara-C, and Melphalan). In general, TRM with this regimen is <5%, and auto-HSCT can be performed safely as an outpatient therapy, which may also be associated with some cost reduction as well ($17,000 saved per patient).11 Shortages of carmustine have led to search for alternatives including BeEAM 12(bendamustine replacing carmustine) and FEAM (fortemustine replacing carmustine).13 Rituximab purging of graft and maintenance therapy after auto-HSCT have been studied in small series with encouraging results but is not the standard of care at this time.14 Transformed lymphoma (Richter’s transformation) signifies evolution of an indolent lymphoma into an aggressive variant of DLBCL. Although some authorities advocate allogeneic rather than auto-HSCT in CR1, data on both sides are limited and retrospective.15 Secondary CNS involvement at onset or in relapsed DLBCL is ominous. Auto-HSCT with busulfan and thiotepa may offer survival benefit to a subset.16

Primary CNS lymphoma is histologically DLBCL in most cases (95%) and represents distinct challenges. Auto-HSCT with conditioning using CNS-penetrating drugs such as thiotepa and BCNU has resulted in 3-year OS >75%, which is remarkable for this aggressive disease, although all available prospective data to date are phase II only, due to rarity of the disease.17 Primary mediastinal lymphoma is a special subset of DLBCL confined to mediastinum with additional therapy (usually additional etoposide or radiation therapy) incorporated in the initial treatment. While chimeric antigen receptor T-cells therapy is FDA approved for relapsed refractory primary mediastinal lymphoma, conventional auto-HSCT has shown excellent results (85%–100% 3-year OS in CR1 and CR>1 and >40% in chemorefractory disease) and is commonly used for this entity.18 

FOLLICULAR LYMPHOMA Follicular lymphoma (FL) is the second most common NHL and represents the prototype of indolent lymphoma with a span of years without any chemoimmunotherapy in many cases. Despite mostly indolent course, about 2% of patients per year will transform to a more aggressive histology with poor prognosis. This means a substantial subset for a disease which may last 2 decades. FL International Prognostic Index

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FIG. 14.2  BEAM conditioning regimen. Conditioning is usually done starting from day −6 to −1 in the

manner shown (Ara C = Cytarbine, BCNU = Carmustine).

score and histologic tumor grade are prognostic but do not always guide initiation of therapy or proceeding to transplantation. Even when symptoms develop, options include radiotherapy or chemoimmunotherapy (such as rituximab-bendamustine, obinutuzumab, R–CVP (rituximab, cyclophosphamide, vincristine, and prednisone), and R–CHOP). Relapsed disease merits consideration of a second period of observation of asymptomatic, smallmolecular inhibitors including idelalisib, copanlisib (Phosphoinositide 3 Kinase (PIK)-αδ inhibitors), and ibritumomab (Yttrium-90 labeled, CD20 based radioimmunotherapy). Availability of these myriad options have pushed auto-HSCT further down in the algorithm for FL treatment, which never was an enthusiastic indication for transplant, invoking controversy for decades. Keeping this in mind, of ∼10,000 cases of FL diagnosed per year in the USA, only 240 were reported by CIBMTR as having undergone auto-HSCT in a 10-year period, and referral for transplantation remained very low at < 3%.19 Auto-HSCT has been attempted at first and subsequent relapses, and unlike DLBCL, for which autoHSCT is the standard of care in relapsed disease, for FL, appropriate timing is not well defined. Two relatively

less-contested indications for auto-HSCT in FL include early relapse (<12 months) 20 after initial therapy and transformed disease.21 With blinding transplant versus no transplant being impossible, the only randomized open label trial (CUP study 1993-97 randomizing merely 89 patients across Europe to Chemo, Unpurged and Purged arms) to show PFS (26% vs. 58%–55% at 2 years) and OS (46% vs. 71%–77% at 4 years) benefit of auto-HSCT in relapsed FL was performed before rituximab was approved, making it of questionable relevance today.22 Retrospective data attempting to show benefit of auto-HSCT have time and again demonstrated that exposure to rituximab and not transplant made the difference in outcomes.23 Similar to aggressive lymphomas, auto-HSCT in CR1 (as initial consolidation in untreated disease almost certain to relapse) has been studied demonstrating PFS but no OS benefit in a summarized Cochrane Review of all five published trials meeting inclusion criteria.24 Conventional conditioning regimens included total-body irradiation in the past, but increased risk of secondary myelodysplastic syndrome/acute myeloid leukemia has steered most centers to BEAM-like regimens as in other forms of NHL.25 Rituximab purging of graft has not shown to be

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beneficial, but maintenance rituximab after auto-HSCT (3 monthly for 2 years) may prolong PFS without much impact on OS.26 Relapsed patients after auto-HSCT should preferably be enrolled in clinical trials and may be considered for allogeneic HSCT when no other salvage options are available. 

largely obsolete. One caveat, as mentioned previously, is Richter’s transformation, for which both auto- and allogeneic-HSCT have been studied. With auto-HSCT, 3-year OS of ∼60% and PFS of 45% may be expected.15 

MANTLE CELL LYMPHOMA

Posttransplant lymphoproliferative disorder usually occurs in a triad of transplant, immunosuppression, and Epstein–Barr Virus activation. Depending on the degree of histologic transformation (early lesion, monomorphic, or polymorphic), therapy may range from decreasing immunosuppression, single-agent rituximab, or R–CHOP–like chemotherapy. Postchemotherapy cytopenias may be challenging in this immunosuppressed population at high risk of transplanted organ dysfunction. Data regarding auto-transplant at relapsed disease are limited to case reports.32 

Mantle cell lymphoma (MCL), arising from the mantle zone outside the follicles, is characterized by t11; 14 (Cyclin D1) and frequently involves gut, spleen, blood, and marrow. It presents a diverse clinical spectrum with a subset of patients on observation without therapy for years and other falling through multiple lines of chemotherapy within a few months. Presence of SOX-11 mutation, high MIPI score, and Ki-67 pronounces aggressive disease. Owing to rarity of the disease, clinical trial enrollment is encouraged in both initial and relapsed MCL. Initial treatment may range from low-intensity regimens such as R-bendamustine to intermediate R–CHOP and high-intensity R-hyper CVAD/Nordic/ Maxi-CHOP–like regimens although later approach has fallen out of favor in recent years (87% grade IV hematologic toxicity).27 Ultimately it is not the initial regimen used but ability to achieve CR that impacts outcomes in MCL. R–CHOP as sole therapy is deemed inadequate and should be followed by auto-HSCT and/ or rituximab maintenance.28 Most centers recommend, in absence of a randomized trial, auto-HSCT in CR1 particularly if less-intense induction therapy such R–CHOP is used (favored by retrospective data),29 followed by rituximab maintenance for 2–4 years.30 In elderly and frail individuals, a low/intermediate intensity regimen may be considered followed by rituximab maintenance only, without putting the patient through auto-HSCT.27 

MARGINAL ZONE LYMPHOMA Marginal zone lymphoma is mostly indolent. Data for auto-HSCT are scarce, and most recommendations are extrapolated from FL, considering auto-HSCT in CR2 and beyond.31 

SMALL LYMPHOCYTIC LYMPHOMA/ CHRONIC LYMPHOCYTIC LEUKEMIA With the advent of multiple novel agents (ibrutinib, idelalisib, obinutuzumab, and venetoclax), transplant for small lymphocytic lymphoma/chronic lymphocytic leukemia (SLL/CLL), even with p53 mutation, is becoming

POSTTRANSPLANT LYMPHOPROLIFERATIVE DISORDER

PLASMABLASTIC LYMPHOMA Plasmablastic lymphoma is an aggressive CD20-negative variant of DLBCL, sometimes associated with HIV and other immunocompromised states. It is characterized by early relapse despite aggressive treatments such as doseadjusted Rituximab, Etoposide, Oncovin, Cyclophos, Hydroxydaunorubicin (R-EPOCH) with or without bortezomib with a median survival of 3–4 months. Expert consensus recommends auto-HSCT in CR1 along with institution of antiretroviral therapy when applicable.33 

CONCLUSION Auto-HSCT remains the standard of care in certain subtypes of NHL (relapsed DLBCL), is being displaced in others by novel targeted agents “ibs and mabs”(SLL), and remains controversial in some (FL). Maintenance therapy is emerging in several subtypes, e.g., MCL, and may eventually translate into OS benefit in addition to PFS benefit. Challenges such as DHLs and refractory/ transformed disease await smarter answers.

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FURTHER READING 1. Hamadani M. Autologous hematopoietic stem cell transplantation: an update for clinicians by. Ann Med. 2014;46:619–632. 2. Lahoud OB, Sauter CS, Hamlin PA, et al. High-dose chemotherapy and autologous stem cell transplant in older ­patients with lymphoma. Curr Oncol Rep. 2015;17(9):42. 3. Krischbaum M, Frankel P, Popplewell L, et al. Phase II Study of Vorinostat for the treatment of relapsed or refractory indolent non-Hodgkin lymphoma and Mantle cell lymphoma. J Clin Oncol. 2011;29(9):1198–1203. 4. Alvarnas JC, Le Rademacher J, Wang Y, et al. Autologous hematopoietic stem cell transplantation for HIV-related lymphoma: results of the BMT-CTN 0803/AMC071 trial. Blood. 2016;128(8):1050–1058.