Allogeneic Hematopoietic Cell Transplantation for Acute Lymphoblastic Leukemia (ALL) in Adults

Abstract

Purpose of review

Acute lymphoblastic leukemia (ALL) is a heterogeneous disease, for which treatment guidelines are still evolving. Allogeneic hematopoietic cell transplantation is a potentially curative therapeutic modality for ALL and this review describes recent studies and current practice patterns concerning the who, when, and how of alloHCT in the management of ALL.

Recent findings

Allogeneic stem cell transplantation is the treatment of choice for patients with ALL after first relapse, and is also recommended for high-risk patients in first complete remission (CR1). Minimal residual disease evaluation and monitoring is developing as an important prognostic factor and could guide physicians in determining which patients, especially those with standard risk, might require transplant. Tyrosine kinase inhibitor (TKI) therapy allows a much higher proportion of Philadelphia-chromosome-positive ALL patients to attain remission and proceed to transplant with improved results; post-transplant TKI maintainance therapy may also provide survival benefit. Reduced-intensity conditioning regimens are a reasonable alternative for patients who would otherwise be ineligible for transplant due to age or co-morbidity.

Summary

For patients with high-risk features, there is general agreement that allogeneic hematopoietic cell transplantation in CR1 is a potentially curative option; however, there is no consensus on early transplant for standard risk patients.

INTRODUCTION

Approximately 5,000 patients annually are diagnosed with acute lymphoblastic leukemia (ALL), of which about 1,400 will die (1). Despite high induction remission rates for ALL (80–90%), the overall survival rate is low in the adult population (30–40%) (2). Over the last few years a variety of factors have contributed to prolongation of survival in adult ALL: improved outcomes with allogeneic hematopoietic cell transplantation, addition of tyrosine kinase inhibitors for Philadelphia chromosome positive ALL, and increased use of intensified pediatric-like chemotherapy protocols for adolescent and young adult populations. This article will focus on the role of allogeneic hematopoietic cell transplantation (alloHCT) in treatment of adult ALL.

WHICH PATIENTS SHOULD BE TRANSPLANTED?

The high relapse rate of ALL has increasingly led us to consider alloHCT as a post-induction consolidation modality, especially in the high-risk ALL population.

Prognostic factors in ALL

Prognostic factors in ALL determine not only the likelihood of long-term survival, but the need for intensive post-induction therapy, particularly alloHCT. Known adverse prognostic factors at diagnosis include age, high white blood cell count, cytogenetic status [t(9;22), t(4;11), −7, +8](3, 4)] and CD20 positivity (5, 6). Post-induction prognostic factors include prolonged time to reach complete remission, the need for more than one induction cycle to achieve remission, induction failure and frank relapse. Other factors that have recently acquired significance are persistence of minimal residual disease post-induction, molecular and genetic markers such as BCR-ABL, IKAROS and BAALC; and pharmacogenetics (7–9*). Table 1 shows prognostic markers that typically confer eligibility for alloHCT at first possible remission (10).

Table 1.

High-risk prognostic features for adult ALL

	B-ALL	T-ALL
At Diagnosis
Age	>35
WBC	>30 × 109	>100 × 109
Cytogenetics	t(9;22), t(4;11), −7, +8, t(8;14) Hypodiploidy	t(1;19)*
	Complex cytogenetics
Molecular genetics	BCR-ABL IKAROS BAALC+	BAALC+ HOX11L2 ERG+
Immunophenotype	Pro B CD10-neg pre-B CD20	Early T Mature T
After Induction
Time to CR1	> 4 weeks
MRD	> 10−4
Clinical Relapse	> CR1

^*Recent report by Burmeister et. al [10]. shows no adverse prognosis with t(1;19)

WBC = white blood cell count, MRD = minimal residual disease, CR1= First complete remission

Philadelphia Chromosome positive BCR-ABL ALL

The incidence of Philadelphia chromosome positivity (Ph⁺) in ALL is 15–30% with some evidence that incidence increases with age, reaching up to 50% in elderly patients (11–14). The prognosis of Ph⁺ ALL is poor, especially in older populations, and alloHCT remains the only potential curative option (15). In the French LALA94 trial the estimated 3-year overall survival (OS) for patients who had donors and achieved CR1 was 37% versus 12% for other patients (P = 0.02) (16). The benefit of alloHCT has also been observed in long-term followup of patients receiving alloHCT in CR1 at City of Hope (COH) and Stanford University, with a 10-year OS of 54% (17). Since introduction of imatinib, a tyrosine kinase inhibitor (TKI), for treatment of BCR-ABL malignancies, there has been interest in combining TKIs with induction chemotherapy and/or HCT in patients with Ph⁺ ALL. Imatinib has been studied both as a single agent and incorporated within induction chemotherapy regimens for newly diagnosed Ph⁺ ALL, demonstrating high response rates, improved survival in combination settings, and feasibility and tolerability in older populations (18–22*). TKIs such as imatinib, dasatinib and nilotinib are now standard therapy for Ph⁺ patients and the resultant increase in initial remission rates has allowed greater eligibility for alloHCT. A recent study by Mizuta et al. compared 51 patients who received imatinib in combination with chemotherapy followed by alloHCT in CR1, with 122 patients who received alloHCT in CR1 during the pre-imatinib era. The 3-year OS of the imatinib group was 65% compared to 44% for the pre-imatinib group (23). Patients with BCR-ABL transcript positivity after alloHCT seem to experience higher relapse rates compared to BCR-ABL-negative patients (45% vs. 23%, P = 0.0013) (24). This phenomenon led to early initiation of post-transplant TKI therapy, when leukemic cell burden is minimal; some suggest beginning at 90 days post transplant (25, 26). The optimal duration of TKI therapy post-alloHCT has not yet been determined, but some physicians continue using TKI as long as patients tolerate it. In a recent study the median duration of imatinib therapy after alloHCT was ~1 year (range, 3–50 months) (27).

Relapsed and Refractory Patients

Patients with ALL refractory to primary chemotherapy or who relapse have extremely poor prognoses; alloHCT is the only curative option if they can achieve remission pre-transplantation. According to the LALA94 study, OS at 5 years is only 9% for relapsed patients after alloHCT; however, for the patients who had available donors and were able to achieve a second CR and survive until alloHCT (61/421), 5-year OS was 33% (28). Likewise, outcomes from 609 patients on the MRC/ECOG 2993 study showed a 23% 5-year OS for patients receiving a sibling alloHCT (n=42), while patients receiving matched unrelated donor alloHCT (n=65) had a 5-year OS of 16%, compared to 15% for autologous hematopoietic cell transplantation (autoHCT) and 4% for chemotherapy (29). Marks et al. recently demonstrated that the relative risk of relapse is significantly higher for patients with Ph⁺ ALL in CR2 compared to CR1, particularly for those patients whose duration of CR1 was less than 1 year (30). Outcomes for patients with active disease are dismal and this contributes to the argument that perhaps all patients should be transplanted in CR1, since CR2 is frequently not achieveable.

Patients with minimal residual disease (MRD)

In addition to age and cytogenetics at diagnosis, the most important prognostic factor, and a direct reflection of sensitivity to chemotherapy, is the achievement of complete remission. Assessing disease status post-induction by morphological examination of the bone marrow is limited due to the similarity between malignant lymphoblasts and B-lymphocyte progenitors. More accurate and sensitive quantification of malignant cell persistence post-induction can prevent undertreatment of patients with residual disease, and overtreatment of disease-free patients (31*). Studies in pediatric ALL populations demonstrate an association between adverse outcomes and persistence of MRD (32–37). The role of MRD quantitation to evaluate treatment response and predict relapse is evolving in adult populations, with exploration of flow cytometry and real-time quantitative polymerase-chain-reaction techniques. Presence of MRD is associated with adverse outcomes even in patients otherwise considered at standard risk and these patients may benefit from early alloHCT in CR1 (31, 35, 38–41). The question is: at what MRD level do we consider the patient at risk of disease relapse? Stow et al. find that pediatric patients with MRD of ≥0.001% (one malignant cell per 100,000 cells) have a significantly higher 5-year cumulative risk of relapse (12.7% ± 5.1%), compared to patients with <0.001% (5.0% ± 1.5%), with P < .047 (42). The authors point out that even 0.001% represents an estimated total leukemic burden of 10⁷ to 10⁸ malignant cells. Until further investigation, an MRD level of 10⁻⁴ (0.01%) or greater is the current determinant of high risk for disease relapse (43–45)*

WHEN SHOULD TRANSPLANT BE PERFORMED?

Should a patient receive a high-risk classification, there is generalized agreement to proceed to allogeneic hematopoietic cell transplant. There is a dilemma when a patient has standard risk for relapse; should we transplant in CR1 or wait until they have relapsed? In the future, MRD will play a greater role in this decision, but most previous studies on this issue do not take MRD into account.

Transplant in CR1 for high-risk patients

Early randomized trials that compared alloHCT to chemotherapy or autoHCT have relied on a genetic randomization based on the availability of an HLA-matched sibling. The French multi-center randomized trial, LALA-87, found that only patients with high-risk features (Ph⁺ ALL, WBC>30 ×10⁹, undifferentiated ALL, age > 35 years, or time to CR1 > 4 weeks) have better OS (P=0.03) and disease-free survival (DFS) (P =0.01) with alloHCT, while patients with standard risk showed no significant advantage of alloHCT over chemotherapy or autoHCT (46). This was confirmed in a larger study from the same group, LALA-94, which additionally concluded that there is no significant difference in DFS between autoHCT and chemotherapy for high-risk patients (47) as detailed in Table 2.

Table 2.

LALA-94 Comparison of treatments based on risk

Subgroup	Age (median)	Number of Pts	OS 10-yr	P-value
Allo-BMT		116	46%	0.04
-High-Risk	<40 (26)	41	44%	0.009*
-Standard-Risk		75	49%	NS
Auto-BMT		95	34%	NS
-High-Risk	<50 (25)	32	10%	NS
-Standard-Risk		63	49%	NS
Chemotherapy		141	31%	NS
-High-Risk	<50 (28)	55	11%	NS
-Standard-Risk		86	40%	NS

Several other reports indicate that alloHCT offers some groups of high-risk patients in CR1, long-term survival rates of between 40% and 60% (48–51). COH and Stanford University updated two series of patients with high-risk features who underwent allogeneic HCT in CR1 with a median follow-up of greater than 5 years. Selection criteria included white blood cell count (WBC) >25,000/ml, chromosomal translocations t(9;22), t(4;11), t(8;14); age older than 30 years; extramedullary disease at the time of diagnosis; and/or requiring >4 weeks to achieve CR1. AlloHCT during CR1 in this patient population, who would otherwise have been expected to fare poorly, led to an event-free survival (EFS) of 64% with a relapse rate of 15% (52).

Transplant in CR1 for standard-risk patients?

The recently reported MRC/EGOG trial compared alloHCT, auto HCT and chemotherapy alone, in ALL patients in CR1. ALL Ph⁺ patients with either a related or unrelated donor proceeded to alloHCT, but standard and high-risk patients underwent a sibling donor versus no-sibling donor biological allocation to alloHCT. Patients without donors were then randomized to autoHCT or chemotherapy. AlloHCT resulted in improved disease control in all adult patients with ALL, but with long-term benefit seen most significantly in younger patients with lower-risk disease (Table 3) (53, 54). Considering the previously reported data indicating benefit from transplant in high-risk patients in CR1, and the high treatment-related mortality from alloHCT, this trial has led to considerable debate about the implications for patients with ALL; some experts advocate early transplant for nearly all patients, whereas others caution for continued individual assessment.

Table 3.

MRC-ECOG UKALLXII/EC2993: outcomes by risk classification

Patient Group	# of Patients	5-Yr Overall Survival (%)	5-Yr Relapse Rate (%)	5-Yr Non-relapse Mortality (%)
Standard Risk	512
Sibling Donor	218	62	24	20
No Donor	294	52	49	7
High Risk	401
Sibling Donor	171	41	37	36
No Donor	230	35	63	14
Ph+ Very High Risk	267
Sibling Allo HCT	45	44	43	27
MUD Allo HCT	31	36	34	47
Chemotherapy	82	19	90	17

^*High-risk is defined as age ≥35 years, WBC > 30,000/μL for patients with B-cell disease or WBC > 100,000/μL for patients with T-cell disease, or time to attain CR > 4 weeks.

WHICH TRANSPLANT REGIMEN?

Traditionally, high intensity preparative regimens are used for ALL, but more recently, there have been multiple observations pointing to a graft-versus-leukemia effect that have led to the introduction of less toxic regimens, making transplant more feasible for patients who otherwise would not be candidates.

Myeloablative regimens

The ideal preparative regimen for alloHCT in ALL should maximize anti-leukemic effects while maintaining efficient engraftment and tolerable toxicity. Total body irradiation (TBI)-based regimens have been the mainstay of ALL preparative regimens due to their ability to eradicate leukemic cells within the central nervous system and testicles, providing prolonged EFS and lower relapse rates (55–57). TBI in combination with cyclophosphamide (TBI/Cy) is the most common ALL transplant preparative regimen. Due to radiation toxicities including secondary malignancies, cataracts and interstitial pneumonitis, other preparative regimens have been explored.

Busulfan/cyclophosphamide (Bu/Cy) conditioning shows comparable OS, relapse rate, and DFS to the TBI/Cy regimen; however, it is also associated with serious side effects, including hepatic sinusoidal obstruction syndrome (SOS) – previously veno-occlusive disease, VOD – and hemorrhagic cystitis (58–60). Conversion from oral to IV busulfan in the Bu/Cy regimen, has decreased incidence of SOS and improved 100-day survival (61). More recently IV Bu/Cy in CR1 patients produces 30-month OS and relapse rates of 65.7% and 40% with decreased transplant-related mortality (TRM) and SOS (62).

City of Hope substituted etoposide (VP16) for cyclophosphamide in combination with fractionated TBI (13.2 Gy) followed by alloHCT for ALL (63). DFS was 57% with a 32% relapse rate, suggesting the regimen has significant activity in patients with advanced ALL. This result was confirmed in a subsequent trial by the Southwest Oncology Group comparing TBI/VP16 with Bu/Cy (64). A comparative analysis of TBI combined with either cyclophosphamide or etoposide chemotherapy (65) concluded there is an advantage in substituting etoposide for CY or, when CY is used, in increasing the TBI dose to >13 Gy.

The role of the graft versus leukemia effect and reduced intensity conditioning

Although the primary therapeutic effect of alloHCT in ALL is believed to result from eradication of the leukemic cells using high-dose therapy, there is also evidence of a graft-versus-leukemia (GVL) effect. Observations of higher relapse rates after autologous or syngeneic HCT compared with alloHCT, lower incidence of relapse in patients with GVHD, and increased relapse rates in recipients of T-cell-depleted marrow grafts, all point to GVL (66). A recent report from Fred Hutchinson Cancer Research Center indicates that early withdrawl of immunosuppressive therapy in patients who do not develop GVHD decreases the risk of disease relapse in the first 18 months after transplant (67).

The general consensus that the intensity of myeloablative conditioning is important for disease control after alloHCT has limited its availability to patients with advanced age or comorbidities. Results of the MRC/EGOG study revealed significant TRM for ALL alloHCT patients over age 35 compared to consolidation chemotherapy, resulting in no improvement in DFS despite better disease control. This and similar data stimulated investigations of reduced intensity conditioning (RIC) therapy (68, 69). A retrospective analysis of high-risk ALL patients receiving alloHCT demonstrates a promising 2-year OS/DFS of 61%, relapse rate of 21%, and non-relapse mortality (NRM) of 21.5% (70). An EBMT retrospective study compares RIC with conventional myeloablative conditioning, finding a higher relapse rate with RIC (P = 0.03, HR = 0.59), but a correspondingly decreased NRM (P = 0.0001, HR = 1.98) (71*). More recently, a prospective study of 51 patients with high-risk ALL, reveals a 3-year relapse rate of 40% with 28% NRM. The 3-year OS for patients in CR1 are: 52% for CR1, 62% for CR1 Ph⁺ (received imatinb post-engraftment), and 73% for patients with no evidence of MRD (27). These studies contradict the dogma that RIC is inadequate to affect cure in ALL, and indicate it is a reasonable choice for patients with advanced age or co-morbidities.

WHICH DONOR CELL SOURCE?

Matched related donors have been the ideal choice for ALL transplant, due to lower incidence and severity of GVHD. Advances in HLA typing-technology, alternative donor sources, and GVHD prophylaxis have opened up new stem cell sources for patients without available matched related donors.

Unrelated donors versus related donors

Outcomes after transplantation from unrelated donors were previously inferior to those observed after matched-sibling transplantation due to increased rates of graft rejection and GVHD. Improvements in donor/recipient allele-level molecular matching in class I and II histocompatibility genes, GVHD prophylaxis, and supportive care (72) have made donor allografts safer. Recently a retrospective analysis in 221 patients reported 5-year DFS after alloHCT in CR1 from matched unrelated donors of 45%, compared to 42% in patients with matched related donors (73). More recently a study of 1139 patients, revealed the 4-year OS for alloHCTin CR1 was not different between related versus unrelated donors at 65% vs 62%, respectively (P = 0.19) (74). These data suggest that unrelated donors are a reasonable option for patients with ALL who do not have an available related donor.

Haploidentical donors/umbilical cord donors

One major obstacle to initiation of transplant is the timely availability of a donor. Recent reports in pediatric populations indicate that alloHCT from haploidentical donors (75) or from cord blood (76) is feasible and can provide promising alternatives for patients who lack HLA-matched donors. In the adult population, the data is still evolving, but early reports suggest the feasibility of such approaches (77, 78). Further development of alternative cell sources needs to be carefully evaluated in a prospective fashion.

TREATMENT STRATEGY FOR ALL

ALL is a hetrogenous disease and management should be tailored for each patient. The National Comprehensive Cancer Network is in the process of developing a general practice guidline for ALL; until then, our suggested treatment strategy is outlined in Figure 1.

Figure 1.

Treatment algorithm for adult patients with ALL

CONCLUSIONS

There are multiple ALL trials in process to test immunotherapeutic modalities such as incorporation of targeted CD52 or CD22 monoclonal antibodies with chemotherapy, or bi-specific T-cell engagers (BiTEs). Very recently, reports by Brentjens, Porter and colleagues revealed the feasibility and safety of adoptive redirected CD-19 T-cell therapy in B-Cell malignancies with very promising early results in CLL (79, 80). Currently an IND and clinical protocol are under development at City of Hope to explore adoptive T-cell therapy using a similar CD-19 adoptive T-cell therapy for B-Cell ALL. In addition to development of novel therapeutic agents, a crucial area of research will be refinement of MRD monitoring to improve patient selection and timing for alloHCT. Future prospects for adults with ALL are hopeful, as we expand our understanding of the disease and incorporporate multiple treament modalities, including alloHCT.

KEY POINTS.

• Allogeniec hematopoietic cell transplantation remains a potential curative therapy for patients with high risk features and patients with relapsed disease.

• Based on MRC/ECOG data, it is worth considering allogeneic transplant for standard-risk patients, as the relapse rate is high and the prospects of achieving CR2 are uncertain.

• The importance of minimal residual disease (MRD) monitoring is evolving as a prognostic factor and an indication for allogeneic transplant.

• Peri-transplant use of tyrosine kinase inhibitors might improve the outcome in adult patients with Ph⁺ ALL.

• Recent advances in transplant, including feasibility of reduced-intensity conditioning for ALL, and alternative stem cell sources have improved outcomes and made transplant accessible to a wider range of patients.