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Allogeneic Hematopoietic Cell Transplantation for Patients With Acute Lymphoblastic Leukemia
Introduction
Acute lymphoblastic leukemia (ALL) is a heterogeneous group of hematologic malignancies with an annual age-adjusted incidence rate of 1.73 per 100,000 people in the United States and with a median age of 14 years. It is estimated that 5690 new cases of ALL in adults and children will be diagnosed in the United States in 2021. With the use of modern risk-adapted chemotherapy over the past several decades, the 5-year survival rate in children with ALL has significantly improved (88.6%) compared with older (age ≥ 60 years) adults, which has remained dismal (~20%). However, in infants it remains low (54.7%). Younger adults (age 18–35 years) treated with pediatric-inspired regimens also have improved overall survival (OS) (4-year OS, 67%). The poor survival outcomes in adults with ALL stem from their higher risk of relapse and despite risk-adapted therapy, adults with relapsed ALL have a poor prognosis with poor long-term outcomes.
The indications for remission consolidation with allogeneic hematopoietic cell transplantation (HCT) in both adult and pediatric patients in first complete remission (CR1) and in a subset of pediatric patients in second complete remission (late marrow or late isolated central nervous system [CNS] relapse) remain controversial. HCT is potentially curative for some subsets of patients in CR1 who have high-risk cytogenetic and molecular features, such as B-cell ALL (B ALL) with KMT2A gene rearrangement (most common in infants with ALL [70%–80%]; e.g., t[4;11]), complex karyotype (i.e., ≥ 5 aberrations), low hypodiploidy or near haploidy (often associated with TP53 mutations), Philadelphia chromosome positive (Ph+) B ALL without molecular CR (BCR-ABL polymerase chain reaction [PCR] > 0.1% 2–3 months in CR), and persistent measurable residual disease (MRD) after induction therapy ( Table 15.1 ). It should be noted that the outcomes of allogeneic HCT for patients with Ph–like B ALL in CR1 are not well studied and both children and adults with this subtype have a poor prognosis. Mutations of cyclin-dependent kinase inhibitors tumor suppressor genes A and B have been reported in both pediatric and adult ALL (T lineage > B lineage) and are associated with inferior outcomes. Intrachromosomal amplification of chromosome 21 (iAMP21) is associated with a higher risk of relapse and worse outcomes in pediatric B ALL, especially when treated as a standard risk B ALL. Treatment of iAMP21 patients as high risk and with more intensive chemotherapy (without HCT) provides a significant improvement in outcome. Patients with Down syndrome (DS) (both children and adults) have a 10% to 30% increased risk of developing acute leukemia, most commonly ALL. Children with DS-ALL have lower rates of favorable cytogenetics and OS is inferior compared to children without DS. They also have increased treatment-related toxicities and require special consideration because of associated comorbidities. The available literature supports the use of myeloablative HCT in high-risk DS-ALL patients in CR1, with persistent MRD and high-risk cytogenetic and molecular features. Disease relapse is the major cause of death, rather than treatment or transplant-related mortality, in patients with DS-ALL in CR2 and beyond. Early T cell precursor (ETP) ALL (immunophenotype CD3+, CD1a−, CD4−, CD5 dim, CD8−, CD34+, CD117+, CD19−, MPO-) is a high-risk subgroup of T ALL and is associated with a higher risk of disease relapse and inferior survival in adults. ETP ALL in pediatric patients, while associated with higher MRD after induction, has similar reported survival to non-ETP ALL. The prognosis for patients with relapsed ALL is poor, and HCT is recommended in patients, regardless of age, if second remission is achieved. except in pediatric Ph-negative B ALL patients with late marrow or late isolated CNS relapse who achieve MRD negative CR2 and have no high-risk cytogenetic and/or molecular features (e.g., t[1;19], hypodiploidy of KMT2A gene rearrangement) and may have comparable outcomes with or without HCT. The outcome of allogeneic HCT in pediatric and adult patients with ALL has significantly improved over the last decade ( Figs. 15.1 and 15.2 ). Key studies that will be discussed in this review are summarized in Table 15.2 .
Table 15.1
Commonly Accepted High-Risk Factors in Adult and Pediatric Acute Lymphoblastic Leukemia
| Patient Characteristic | High-Risk Factors | |
|---|---|---|
| Adult | Pediatric | |
| Clinical factors | ||
| Age | >35 years | ≤1 or ≥10 years |
| Leukocytosis | >30 × 10 9 /L (B-lineage); > 100 × 10 9 /L (T-lineage) | >50 × 10 9 /L (B-lineage) |
| Immunophenotype | Early T-cell precursor | T immunophenotype |
| Extramedullary disease involvement | N/A | CNS-3 status; overt testicular leukemia |
| Karyotype | t(9;22)(q34;q11.2) or BCR-ABL1 in pre-TKI era; complex karyotype (≥ 5 chromosomal abnormalities); hypodiploidy (< 44 chromosomes); KMT2A rearranged (t[44;11] or others); iAMP21 | t(9;22)(q34;11.2) or BCR-ABL1; hypodiploidy (< 44 chromosomes); KMT2A rearranged (t[4;11] or others); iAMP21 |
| Molecular profile | IKZFI; CRLF2 (Ph-like); TP53 | Alterations of IKZE1; TCF-HLF (t(17;19)); BCR-ABLI-like (Ph-like) ALL (JAK-STAT (CRLF2r, EPORr, JAK1/2/3r, TYK2r, mutations of SH2B3, 1L7R, JAK 1/2/3, ABL class, TCF3-PBX1 fusion/t(1; 19) |
| Treatment related factors | ||
| Time to morphologic CR > 4 weeks | Steroid pretreatment | |
| Persistent MRD up to 10–12 weeks postinduction | End of induction MRD > 0.01% | |
ALL , Acute lymphoblastic leukemia; CNS , central nervous system; CR , complete remission; iAMP , intrachromosomal amplification; L , liter; MRD , minimal residual disease; N/A, not applicable; TKI , tyrosine kinase inhibitors.
Table 15.2
Key Studies Utilizing Hematopoietic Cell Transplant in the Management of Pediatric and Adult Acute Lymphoblastic Leukemia
| Reference | HCT Patient Population (Age, Diagnosis, and Number | Donor Source | Conditioning Regimen | GVHD Incidence | EFS/RFS/Relapse Rate | DFS/OS | Comments |
|---|---|---|---|---|---|---|---|
| Ribera et al. | Age range 15–60 years Ph negative ALL +HR features (n = 106) | MSD, MUD, UCB, haploidentical | TBI based MAC < 55 years and good clinical status RIC with fludarabine/melphalan for > 55 years or poor clinical condition | NR | Intention-to-treat analysis: 5-year CIR HCT: 40% Chemotherapy: 45% | Intention-to-treat analysis: 5-year OS probabilities: HCT: 38% Chemotherapy: 59% (po.001) | Patients with persistent MRD postinduction, or required 2 cycles of induction to achieve CR were allocated to the HCT group; consequently, more patients with high-risk cytogenetics or molecular phenotype (11q23 and ETP) were in the HCT group |
| Eapen et al. | Children younger than 18 years Isolated BM or combined relapse n = 186 | All received MSD | TBI+Cy (64%), TBI+ _ other (18%), Busulfan +Cy (18%) | 1% of HCT related deaths were caused by GVHD |
|
8-year probability of OS HCT with TB!: 44% Fla with non-TBI: 18% Chemotherapy: 32% | HCT did not improve outcome for later BM or combined relapse compared to intensive chemotherapy |
| Eapen et al. | Children younger than 18 years Isolated CNS relapse n = 60 | All received MSD | 33% MAC TBI based | 4 MCI deaths were related to GVHD | 2-, 5-, and 8-year probability of second relapse (early CNS relapse group) KT: 47%, 50%, 50% Chemotherapy: 31%, 40%, 40% |
|
7 of the 10 recipients of non-TBI conditioning regimens relapsed compared to 10 of 50 recipients of TBI- based regimens |
| Pui et al. | Age range 0–21 years Hypodiploid ALL (n = 42) | MSD (n = 11), MUD rest of patients has incomplete HCT information | Protocol based | NR |
|
|
HCT did not improve outcome regardless of the hypodiploidy subgroup (low hypodiploidy or near haploidy) or EOI MRD status |
| Fielding et al. | Age range 15–60 years Ph+ve ALL (n = 83) | MSD (n = 45), MUD (n = 31), autologous (n = 7) | TBI 1320 cGy — etoposide | Any aGVFID MSD: 64% (13% grade 3–4) MUD: 48% (6% grade 3–4) |
|
5-year OS HCT: MSD 44%, MUD 36%, autologous 29% Chemotherapy: 19% | This study was conducted in the pre-TKI era |
| Jabbour et al. | Adults (39–61 years) Ph-ye ALL (74%090, 25% p210) (n = 15) | MSD (n = 8), MUD (n = 5), haploid entical (n = 2) | NR | NR | 11 of the 15 HCT patients were alive at the time of manuscript publications One patient died of disease relapse and 3 died because of SCT related complications |
|
HCT may be omitted in adults with Ph+ve ALL who achieves CMR by 3 months with new generation TKIs in combination chemotherapy |
| Schultz et al. | Age range 1–21 years Ph+ve ALL (n = 34) | MSD (n = 21), MUD (n = 13) | TBI (1200 cGy), etoposide, cyclophosphamide | NR | 5-year EFS 71% for intensive chemotherapy 5-year EFS MSD 64%, MUD 63% ( P = .77 |
|
Intensive chemotherapy in combination with prolonged TKIs improved survival of children with Ph+ve ALL without the need of allogeneic HCT |
| Slayton et al. |
|
MSD (n = 11), MUD (n = 8) | TBI 1200 eGy/thiotepa (10 mg/kg/Cy (120 mg/kg) | NR | 5-year EFS 60% chemo, 61% HCT (63% in HR group and 76% in SR group) | 5-year OS 88% chemo, 83% HCT | Half of the patients who underwent HCT were HR based on MRD |
| Tanguy Schmidt et al. | Age range 16–59 Ph+ve ALL (n = 45) | MSD (n = 15)> MUD (n = 9), autologous (n = 10) | TBI 1200 cGy +Cy (120 mg/kg) | NR | 4-year incidence of relapse HCT group MSD: 27%, MUD: 11%, autologous: 50% No HCT group: 39% |
|
Autologous transplant is generally not recommended in Ph+ve ALL |
| Koller et al. | Age range 17–60 CRLF2 overexpressed Ph-like ALL (n = 20) | MRD 14%, MUD 50%, KMUD 5%, haploidentical 36% |
|
Grade 2–4 aGVHD 25%cGVHD 23% | 2-year PFS 45% | 2-year OS 56%, GRFS 33%, NRM 21% | 2-year PFS is 67% in patients with MRD-negative disease at the time of Ha and 0% in patients with MRD-positive disease at time of HCT |
| Roberts et al. | Children (1–18 years) Ph-like ALL high risk (EDI MRD? 1%) (n = 6) (Total Therapy XV study) | MSD, MUD, MMRD | Most patients received TBI based MAC | Cumulative incidence 5.5% for all cohort (n = 37) | 5-year CUR for Total Therapy XV study (all patients n = 37) 17.5% | 5 patients were alive and in CR at the time of manuscript publication (follow-up 5+ years) One patient dies of respiratory failure after HCT at 0.7 years | Pediatric patients with Ph-like ALL and high (? 1%) E01 MRD by flow cytometry may benefit from allogeneic Ha |
| Bond et al. | Adults with T ALL. Non-ETP T ALL (47), EIP T ALL (n = 23) | Non-ETP: MSD 40.4%, MUD 40.4%, MMUD 12.8%, UCB 6.4% ZIP: MSD 56.5%, MUD 21.7%, MMUD 17.4%, UCB 4.3% |
|
|
|
|
|
| Schrappe et al. | Children 1–18 years T ALL MRD-HR group and HCT (n = 55) Non MRD-HR group and HCT (n = 31) | MSD, MUD, MMUD |
|
|
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|
|
aGVHD , Acute GVHD; ALL , acute lymphoblastic leukemia; BM , bone marrow; cGVHD , chronic GVHD; cGy , centiGrey; CIR , cumulative incidence of relapse; CMR , complete molecular response; CNS , central nervous system; CR , complete remission; Cy , cyclophosphamide; DFS , disease-free survival; EFS , event-free survival; EOI , end of induction; ETP , early T cell precursor; GRFS , GVHD relapse-free survival; GVHD , graft-versus-host disease; HCT , hematopoietic cell transplantation; HR , high risk; kg , kilograms; MAC , myeloablative conditioning; mg , milligram; MMRD , mismatched related donor; MRD , minimal residual disease; MSD , matched sibling donor; MUD , matched unrelated donor; NR , not reported; NRM , nonrelapse mortality; OS , overall survival; PFS , progression-free survival; Ph , Philadelphia chromosome ; RFS , relapse-free survival; RIC , reduced intensity conditioning; SR , standard risk; TBI , total body irradiation; TKI , tyrosine kinase inhibitors; UCB , umbilical cord blood.
Hematopoietic Cell Transplantation in Acute Lymphoblastic Leukemia Poststandard Chemotherapy
Ph–Negative B Acute Lymphoblastic Leukemia
The American Society for Transplantation and Cellular Therapy (ASTCT) and European Society for Blood and Marrow Transplantation (EBMT) have recently published guidelines and position statements for indications of HCT in pediatric and adult patients with ALL. These guidelines, which are based on published data from multiple prospective and retrospective studies, state that myeloablative (preferably total body irradiation [TBI]-based) allogeneic (not autologous; preferably human leukocyte antigen [HLA]-matched sibling donor [MSD] or HLA-matched unrelated donor [MUD]) HCT is an appropriate intensive therapy in young adults (<35 years) with ALL in CR1 for all disease risk groups and is indicated in adults with ALL and high-relapse-risk features (see Table 15.1 and Table 15.3 ). However, not all studies support these broad guidelines. For instance, the bulk of more recent reports now suggests that HCT may be avoided in adults who are treated with intensified pediatric-inspired chemotherapy regimens and are in MRD-negative CR1, regardless of the presence of other high-risk features. The results of a recent study by the PETHEMA group showed that avoiding allogeneic HCT does not impact the outcome of high-risk Ph-negative ALL patients up to 60 years of age who achieved adequate MRD response by 8-color flow cytometry after induction (< 0.1%) and consolidation (<0.01%). In pediatric Ph–negative ALL, allogeneic HCT is indicated in patients with primary induction failure who subsequently achieve CR1, patients in CR2 after an early marrow relapse (<36 months from diagnosis) or early isolated CNS relapse (<18 months from diagnosis), and patients in CR3 and after (see Table 15.3 ). A large retrospective multinational study collected data on 306 children with hypodiploid ALL who were treated between 1997 and 2013; the 4-year disease-free survival (DFS) and OS in the HCT group were 59.8% and 68.9 % versus 53% and 57.7% in the intensive chemotherapy group ( P = .47 and .21, respectively). Another retrospective study that reviewed the outcomes of children and young adults with hypodiploid B ALL who were enrolled in different Children’s Oncology Group (COG) trials found that outcomes for patients undergoing HCT in CR1 were not significantly improved. The 5-year event-free survival (EFS) and OS for the HCT group were 57.4% and 66.2%, compared with 47.8% and 53.8%, respectively ( P = .49 and .34, respectively) for those who did not undergo transplantation. Patients with MRD of 0.01% or greater at the end of induction had 5-year EFS and OS of 26.7% and 29.3%, respectively, and HCT had no significant impact on outcomes. HCT had no significant benefit on outcome regardless of the end of induction MRD status or National Cancer Institute risk stratification in pediatric patients with hypodiploid ALL. The role of HCT in infants with ALL is not well defined. The COG tested the hypothesis that HCT would improve the outcome of this very high-risk group ( KMT2A rearranged infantile ALL) and data analysis showed that the 5-year EFS rate was 48.8% in the HCT group compared to 48.7% for the intensive chemotherapy group ( P = .60). They concluded that the routine use of HCT in infants with ALL is not indicated. One caveat is that in this study, the HCT group included both intermediate ( KMT2A rearranged, age > 3 months, white blood cells [WBC] < 300,000 cells/µL, and MRD negative after consolidation) and high-risk infants ( KMT2A rearranged and age < 3 months with any WBC or age < 6 months with WBC ≥ 300,000 cells/µL; or MRD positive postconsolidation [any age or WBC]). This could dilute the impact of HCT in the high-risk subgroup. Results of the Interfant-99 Study reported improved outcomes in infants with KMT2A rearranged ALL and high-risk features (age < 6 months and either poor response to steroids at day 8 of induction or with WBC ≥ 300,000 cells/µL). HCT was associated with a significantly superior 4-year DFS and OS, compared to the chemotherapy only group (59% vs. 22.2%, P = .01 and 66% vs. 19.3%, P = .001 respectively). The current National Comprehensive Cancer Network guidelines recommend considering HCT in infants in CR1 with high-risk features, as defined earlier.
Allogeneic HCT Indications in Children and Adults With Ph-Negative B ALL
-
Allogeneic HCT is considered in patients with persistent MRD postinduction therapy.
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Allogeneic HCT may be omitted in young adults (< 35 years) with ALL who achieve MRD negative CR1, without high-risk features, and treated with pediatric inspired regimens.
-
Most children with ALL in CR1 can be cured without allogeneic HCT
-
Allogeneic HCT is indicated in adults with ALL in CR2 and beyond. However, children with ALL in CR2, with no high-risk cytogenetic or molecular features and either early isolated marrow or CNS relapse, can be treated without HCT.
-
In infants with ALL and high-risk features ( KMT2A rearrangement, age < 3 months, WBC > 300,000 cells/µL or persistent MRD postconsolidation), HCT should be considered. B ALL , B cell acute lymphoblastic leukemia; CNS , central nervous system; CR , complete remission; HCT , hematopoietic cell transplant; MRD , minimal residual disease; WBC , white blood cell.
Table 15.3
Indications of Allogeneic Hematopoietic Cell Transplant in Adults Versus Pediatric Acute Lymphoblastic Leukemia
| ALL Subtype | Adults | Pediatrics | |
|---|---|---|---|
| Philadelphia chromosome negative B ALL | CR1 |
|
|
| CR2 |
|
|
|
| CR3 | All | All | |
| Philadelphia chromosome like B ALL | CR1 |
|
|
| CR2 | All | All | |
| CR3 | All | All | |
| Philadelphia chromosome positive B ALL | CR1 |
|
|
| CR2 | All | All | |
| CR3 | All | All | |
| All B ALL subtypes | CR Post-CAR |
|
|
| T ALL | CR1 |
|
|
| CR2 | All | All | |
| CR3 | All | All | |
ALL , Acute lymphoblastic leukemia; CAR , chimeric antigen receptor; CMR , complete molecular remission; CR , complete remission; EM , extra medullar; EOI , end of induction; HCT , hematopoietic cell transplantation; MRD , minimal residual disease; MSD , matched sibling donor; MUD , matched unrelated donor; Ph , Philadelphia; TKI , tyrosine kinase inhibitor; WBC , white blood cells count.
Ph+ B Acute Lymphoblastic Leukemia
In the era before tyrosine kinase inhibitors (TKIs), the international ALL trial MRC UKALLXII/ECOG2993 showed that allogeneic HCT was superior to chemotherapy in 267 adults with Ph+ ALL (5-year OS was 44% after matched sibling allogeneic HCT, 36% after MUD HCT, and 19% after chemotherapy only). The introduction of BCR-ABL1 targeted therapy with highly potent TKIs significantly improved the outcomes of both adult and pediatric patients with Ph+ ALL. These treatments enabled many patients to achieve CR and undergo remission consolidation with high-dose chemoradiotherapy and HCT, which was considered the standard of care. However, the combination of chemotherapy and TKIs, especially newer generation TKIs, may result in durable relapse-free survival even without HCT, especially in older patients. This brings into question the broad recommendation for HCT in all patients with Ph+ ALL. Jabbour et al. reported the outcomes of combination chemotherapy with the new generation TKI ponatinib in adult patients (≥ 18 years old) with Ph+ ALL (83% were previously untreated and 17% were previously treated with one or two cycles of chemotherapy). All patients with active disease at the time of study enrollment achieved CR and 99% were MRD negative by multiparameter flow cytometry. The complete molecular response (CMR) at 3 months, which is defined as an absence of quantifiable BCR-ABL1 transcripts by reverse transcriptase-quantitative PCR with a sensitivity of 0.01% and has a significant impact on long-term outcomes, was 73%. Twenty percent underwent HCT while in CR1. The 3-year OS was 70% for patients who underwent HCT compared to 87% for patients who did not ( P = .32). Based on the data reported from this study, patients who receive chemotherapy in combination with a newer generation TKI and achieve CMR at 3 months might not need HCT. Larger multicenter clinical trials are needed to validate the results of this single center’s results.
The COG reported the long-term outcomes of children and adolescents with Ph+ ALL and concluded that there was no advantage for allogeneic HCT over intensive chemotherapy in combination with TKIs. The 5-year DFS rate was 70% ± 12% for patients treated with chemotherapy plus imatinib (n = 28), 65% ± 11% for patients who underwent MSD HCT (n = 21), and 59% ± 15%, for patients who underwent MUD HCT (n = 13; P = .60). Another trial reported by the COG confirmed that HCT is not necessary in most children with Ph+ ALL in CR1 and limited the HCT indications in slow responders (MRD positive after 11 weeks of chemotherapy). This study also suggested a potential role for HCT in rapid responders who have IKZF1 deletions. However, there is no consensus on the indications for HCT in pediatric Ph+ ALL. It is generally reserved for patients with slow responses to chemotherapy in combination with TKIs or in patients beyond CR1. The ongoing COG phase 3 international clinical trial AALL 1631 (NCT03007147) is evaluating HCT in pediatric patients with high-risk Ph+ ALL, which is defined as MRD ≥ 0.05% at the end of two cycles of induction chemotherapy. The role of autologous transplant in Ph+ ALL continues to be investigational, with the ability of achieving durable deep remissions with newer generation TKIs. The GRAAPH-2003 study reported long-term follow-up of 45 adolescent and adult patients with de novo Ph+ ALL. Four-year OS was 50% after allogeneic HCT (n = 24), 33% in patients without an HCT (n = 9), and 80% after autologous HCT (n = 10, patients without allogeneic donor or older than 55 years, including seven in CMR). Results from the CALGB Study 10001 (Alliance) reported similar OS (median 6.0 years vs. not reached) and DFS (median 3.5 vs. 4.1 years) between adults with Ph+ ALL who underwent autologous HCT (n = 19) and those who underwent allogeneic HCT (n = 15). Ten patients relapsed (eight from the autologous HCT group and two from the allogeneic HCT group). There was no statistical difference in relapse rates between the two HCT modalities ( P = .1285). Based on the most recent guidelines from the ASTCT, autologous HCT is generally not recommended in Ph+ ALL in adult and pediatric patients. Taken together and based on current reports, allogeneic HCT is recommended in adult patients in CR1 treated with older generation TKIs and may be omitted in patients treated with third generation TKIs who achieve CMR by 3 months. HCT is also recommended in slow responding pediatric patients with Ph+ ALL (positive MRD after 11 weeks of therapy with any generation TKIs) (see Table 15.3 ).
Allogeneic HCT Indications in Children and Adults With Ph-Positive B ALL
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Allogeneic HCT may be omitted in adults with Ph+ ALL who achieve complete molecular remission CR1 by 3 months and are treated with newer generation tyrosine kinase inhibitors.
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An ongoing Children’s Oncology Group clinical trial is evaluating the role of allogeneic HCT in pediatric patients with Ph+ ALL who have persistent MRD (> 0.05% by flow cytometry) after two cycles of induction chemotherapy. B ALL , B cell acute lymphoblastic leukemia; CR , complete remission; HCT , hematopoietic cell transplant; MRD , minimal residual disease.
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