ELIAS JABBOUR, MD (left) is Associate Professor in the Leukemia Department of the University of Texas MD Anderson Cancer Center. HAGOP M. KANTARJIAN, MD, is Professor and Chairman of the Department of Leukemia and the Samsung Distinguished University Chair in Cancer Medicine at the University of Texas MD Anderson Cancer Center.
Acute lymphoblastic leukemia (ALL) is characterized by clonal proliferation of lymphoid progenitors. Significant advances have been made in the last decade toward understanding the disease pathogenesis, refinement of prognostic groups and development of novel therapies that target specific subsets of ALL. These risk-adapted therapies are transforming the treatment strategies for adults with ALL and are beginning to result in significant improvements in survival. With the current treatment regimens, long-term survival is achieved in approximately 50 percent of patients with B-cell ALL, 50 to 60 percent of those with Philadelphia-chromosome-positive ALL, 80 percent of those with Burkitt’s leukemia, and 60 percent of those with T-ALL.
Adolescent and Young Adult (AYA) ALL
The outcomes of AYAs with ALL treated on pediatric protocols were reported to be superior to those of similar patients treated with adult protocols in historical retrospective comparisons, with one exception (HCVAD regimen). Most of the adult ALL regimens in the analysis had abandoned many of the basic therapeutic principles used in pediatric ALL, opting for shorter maintenance durations, lower dose-schedules of the non-myelosuppressive ALL drugs, and favoring AML-like strategies including autologous and allogeneic stem cell transplantation (ASCT) early in complete remission (CR).
Recently, a United States intergroup study treated 318 AYAs with a pediatric-inspired regimen (COG regimen), reporting two-year event-free and overall survival rates of 66 percent and 78 percent, respectively. A recent comparison of a pediatric Augmented Berlin-Frankfurt-Münster (ABFM) regimen (n=107) with the Hyper-CVAD -/+ rituximab (n=102) in AYA patients established similar efficacy: the rates of CR, five-year CR duration, and five-year overall survival were 93 and 98 percent, 53 and 55 percent, and 60 and 60 percent, respectively.
These were associated with different toxicity profiles--mostly asparaginase-related with ABFM and myelosuppression-related with Hyper-CVAD. Thus, for AYA patients with ALL, both approaches are equivalent.
Mature B-cell ALL
The outcome for mature B-cell ALL has improved substantially with use of short-term dose-intensive treatment programs. The addition of rituximab to chemotherapy has improved the cure rates in mature B-cell ALL. Three different studies have reported a significant improvement in the survival rates from 51 percent to 78 percent after the addition of rituximab.
Furthermore, the results of the LMBA02 randomized study confirmed the initial findings: the addition of rituximab to chemotherapy improved event-free (80% vs. 60%; p=0.046) and overall survival (84% vs. 68%; p=0.024).
To further reduce early morbidity and mortality, a pilot study investigated dose-adjusted EPOCH in combination with rituximab in 30 patients (median age of 33 years; age >40 years, 40%) diagnosed with Burkitt disease. The progression-free and overall survival rates were 95 to 100 percent and 90 to 100 percent, respectively. Of note, the majority of patients (90%) were of low- and intermediate-risk disease. Ongoing trials are assessing this regimen in mature B-cell ALL.
Precursor B-cell ALL
The addition of rituximab to the Hyper-CVAD regimen in newly diagnosed patients with Philadelphia-negative, CD20-positive ALL was evaluated, adding two doses of rituximab with each of the first four cycles of intensive chemotherapy (total of eight doses of rituximab). Rituximab was also incorporated into early and late intensification cycles (months 6 and 18 of maintenance therapy).
Among patients younger than 60 years old, the addition of rituximab improved CR duration (70% vs. 38%; P < .001%) and three-year survival rates (75% vs. 47%; P = 0.003). The German Multicenter Study Group for ALL (GMALL) also reported an improvement in the minimal residual disease (MRD) negativity, the five-year remission duration, and survival rates with the addition of rituximab to standard induction and consolidation chemotherapy in patients younger than age 55.
The addition of rituximab to chemotherapy was assessed in the GRAAL-R 2005 randomized study: the addition of rituximab improved the two-year event-free survival (EFS) rates (primary endpoint) from 52 percent to 65 percent (p=0.038) and the overall survival rates from 63 percent to 74 percent (p=0.18) after censoring for allo-SCT.
Ofatumumab, a more potent second-generation anti-CD20 monoclonal antibody is being tested in combination with Hyper-CVAD. Early results are promising, with two-year progression-free and overall survival rates of 68 percent and 87 percent, respectively.
Therapy of patients with T-cell ALL is similar to those with B-cell ALL. Nelarabine is a deoxyguanosine analog that selectively accumulates in T-cells, thus making it an intriguing compound for the management of T-ALL. The drug is currently approved as a third-line option in pediatric and adult patients with relapsed ALL, and may be of optimal use in the frontline setting.
We have developed a Hyper-CVAD/nelarabine regimen in which two cycles of nelarabine are given during consolidation and two cycles are given during maintenance. Forty-eight patients were treated so far, with a CR rate of 93 percent. With a median follow-up of 41 months, the five-year survival rate is 66 percent (for AYA < 40 years, it is 70%). These rates were 38 percent and 70 percent for patients with early T-cell precursor (ETP) and mature T-ALL, respectively.
ETP-ALL is a distinct pathobiological entity that confers a poor prognosis with use of standard intensive chemotherapy. ETP-ALL is characterized by distinct cell-surface features that readily enable diagnosis: absence of CD1a, surface CD3, and CD8 expression, weak CD5 expression, and expression of one or more myeloid-associated or stem-cell associated markers. Anti-ALL therapy followed by allogeneic stem cell transplantation should be considered in first remission in patients with ETP-ALL.
Philadelphia Chromosome (Ph)-positive ALL
The combination of cytotoxic chemotherapy with a TKI has become the standard of care in patients with Ph-positive ALL. Ponatinib is a more potent BCR-ABL1 inhibitor. It also suppresses the T315I clones, a common cause of relapse in patients with Ph-positive ALL. The combination of ponatinib with Hyper-CVAD induced CR, complete cytogenetic response, major molecular response (MMR), and complete molecular response rates of 100, 100, 95, and 70 percent, respectively. The two-year survival rate is 80 percent.
To avoid vascular toxicities, the dose of ponatinib was reduced from 45 mg to 30 mg after the first course and further reduced to 15 mg if a complete molecular response was achieved.
While allogeneic stem cell transplantation (allo-SCT) has improved the outcome of patients with Ph-positive ALL, there is now some debate as to who should be referred for allo-SCT in first CR. We evaluated the predictive value of MRD assessment in patients with Ph-positive ALL treated with combination chemotherapy and TKIs, but without an allo-SCT. Patients achieving MMR at three, six, nine, and 12 months had a better survival rate: the three-year survival rates were 67 and 47 percent (p=0.02), 67 and 50 percent (p=0.04), 67 and 49 percent (p=0.05), and 80 and 48 percent (p=0.01), in patients with and without MMR, respectively.
Therefore, MRD monitoring by PCR may identify patients in first CR in whom further consolidation with allo-SCT may not be needed.
Minimal Residual Disease (MRD)
Persistence or reappearance of MRD after induction chemotherapy is the most important adverse prognostic factor in patients with ALL and identifies chemo-refractory disease. More than 90 percent of patients who have persistent MRD after chemotherapy experience a clinical relapse, despite continued chemotherapy with a median time to relapse of four to five months.
Blinatumomab, a bispecific T-cell engaging (BiTE) antibody represents the first agent in a class that redirects host T-cells to cell surface antigen-expressing cancer cells. Blinatumomab contains the variable domains of a CD19 antibody and a CD3 antibody which are joined by a non-immunogenic linker.
In the first study, 21 patients in hematologic and morphologic CR with persistent or reappearing MRD during consolidation chemotherapy were treated with blinatumomab at 15 mcg/m2/day as a continuous infusion for 28 days every six weeks, for up to four total cycles or proceed to allogeneic stem cell transplantation if a donor was available.
MRD conversion after one cycle was noted in 16 of 20 evaluable patients (80%). In a long-term follow-up update (median observation time 33 months), 12 of the 20 patients remained in CR. The estimated three-year relapse-free survival was 60 percent. Nine patients underwent allogeneic stem cell transplantation, but interestingly, non-transplanted patients had similar favorable outcome compared with the transplant group.
In a confirmatory open-label multicenter Phase II trial in 116 patients in morphologic CR with positive MRD positive, the overall rate of conversion to the MRD negativity was 80 percent (78% occurring after one cycle of treatment). The median relapse-free and overall survival was 35 and seven months, and 40 and 12 months, for patients with negative and positive MRD after one cycle of blinatumomab. Of note, allo-SCT did not confer a survival or a relapse-free survival advantage.
In elderly patients with ALL, intensive chemotherapy results in a CR rate of 80 percent with a high rate of toxicities. One-third of patients achieving CR may die of myelosuppression-associated complications, and many relapse. The long-term cure rate among such patients is only 15 to 20 percent. The goal with our regimens is to maintain efficacy but reduce toxicity.
The early results of low-intensity Hyper-CVAD (cyclophosphamide and dexamethasone at 50% dose reduction, no anthracycline, methotrexate at 75% dose reduction, ara-C at 0.5 g/m2 x 4 doses) with inotuzumab ozogamycin given on Day 3 of each of the first four courses, are very promising. The overall response rate was 97 percent (CR 80%). All patients achieving a response also had a negative MRD status, 75 percent of them after one cycle. The two-year overall survival rate is 64 percent (versus 38 percent for historical data).
Molecular studies uncover gene mutations that may result in aberrant pathway activation and cell survival. ALL genomes have a lower burden of genetic alterations than many solid tumors, with focal deletions being the hallmark of lymphoid leukemia.
Using genome-wide gene-expression arrays, investigators identified patients without BCR-ABL1 fusion protein expressed from the t(9;22)(q34;q11.2) having a gene expression profile similar to BCR-ABL1 ALL. This new identity was defined as Ph-like ALL. This so-called BCR-ABL1-like disease had a poor prognosis, similar to the historical poor prognosis of Ph-positive ALL prior to the addition of BCR-ABL1 TKIs to chemotherapy for this ALL subset.
The frequency of Ph-like ALL is 10 percent among children with standard-risk ALL and as high as 25 to 30 percent among young adults with ALL. This subgroup of BCR-ABL1-like ALL is characterized by the high recurrence of a diverse repertoire of novel fusions and mutations which frequently result in enhanced tyrosine kinase and cytokine receptor signaling. This subgroup could be targeted with appropriate tyrosine kinase inhibitors.
A Phase II study assessing the combination of ruxolitinib or dasatinib with chemotherapy in patients with R/R Ph-Like ALL is ongoing. Patients who have CRLF2 overexpression by flow are eligible for the ruxolitinib arm (irrespective of the JAK2 mutation status). Patients without CRLF2 overexpression are assessed for the fusion assay. Depending on the fusion results, the patient may be eligible for the ruxolitinib (JAK2 fusions), or dasatinib (ABL2, ABL1 fusions).
Despite an exceptionally high rate of initial CR, many adults with ALL will relapse. Cytotoxic chemotherapy results in modest CR rates of 30 to 40 percent in first salvage and 10 to 20 percent in later salvages.
Few patients can be bridged to allo-SCT--five to 10 percent in some studies but as high as 30 to 40 percent in the German trials. This bridging to allo-SCT offers a chance of long-term remissions and cures (<20-30%).
Blinatumomab was first assessed in patients with positive MRD and subsequently studied in patients with relapsed/refractory (R/R) ALL. In the pivotal trial, the overall response rate (ORR; CR or CR with incomplete count recovery) within two cycles of therapy was 69 percent. The estimated median survival was 9.8 months.
In a confirmatory open-label, single-arm, multicenter Phase II study in 189 patients with relapsed/refractory disease, the ORR was 43 percent, with 80 percent of the responses occurring within the first cycle. The median response duration and overall survival were nine and six months, respectively.
Blinatumomab is currently being assessed in a Phase III trial in patients with ALL in first or second relapse randomized to either blinatumomab or an investigator’s choice chemotherapy regimen.
Inotuzumab ozogamicin is an anti-CD22 monoclonal antibody conjugated to calecheamicin, which is a natural product of micromonospora echinospora and is significantly more toxic than chemotherapy. It binds to the minor DNA groove and causes double-strand DNA breaks resulting in cell apoptosis. Inotuzumab binds to CD22 with subnanomolar affinity, is rapidly internalized, and delivers the conjugated calecheamicin intracellularly.
We conducted two studies of inotuzumab in refractory/relapsed ALL--one with 1.3-1.8 mg/m2 single dose every 3-4 weeks (n=49), and a second with a weekly dose (0.8 mg/m2 on day 1, 0.5 mg/m2 on day 9 and day 15; every three weeks) (n=41).
In the 90 patients treated, the marrow CR rate was 55 percent. The median survival was 6.3 months. These encouraging results led to an international study comparing weekly inotuzumab with standard ALL chemotherapy in ALL Salvage 1-2. The objective response rates were 81 and 33 percent, respectively.
Among responders, the MRD-negativity rates were 78 and 28 percent, respectively. The median response duration was 4.6 versus 3.1 months (p=0.017), respectively. Inotuzumab in combination with lower-intensity Hyper-CVD chemotherapy was tested in 52 patients with R/R ALL.
The objective response rate was 77 percent; the two-year PFS and OS rates were 60 percent and 32 percent, respectively. Furthermore, the two-year survival rate was 50 percent in patients treated in Salvage 1. When compared with single-agent inotuzumab, the combination improved the two-year and median survival from 17 percent to 32 percent, and six to 11 months (p=0.03), respectively.
Due to the occurrence of veno-occlusive disease in patients treated with inotuzumab, a lower-dose schedule (50% dose reduction, 0.6 mg/m2 on Day 1 and 0.3 mg/m2 on Day 8) of single-agent inotuzumab is being explored.
Chimeric Antigen Receptor T-cells (CAR T-cells) Therapies
Harnessing the patient’s immune system to eliminate malignant cells has been an area of oncologic research for decades. Chimeric antigen receptor-modified T-cells have emerged as an effective approach for patients with lymphoid malignancies. Autologous T-cells are engineered to express a receptor directed at CD19 which mediates cytotoxicity. These cells have been noted to expand and persist in vivo: this mechanism may confer response durability.
Several pilot trials in children and adult patients with ALL reported high CR rates (70% to 90%) with an estimated 12-month survival rate of 50 to 70 percent. Severe cytokine release syndromes were reported in 30 to 40 percent of patients. Multiple Phase trials in patients with relapsed/refractory ALL are currently ongoing.
Improvements in the therapy of adult ALL are highly encouraging. Targeted therapies have been shown to improve survival when combined with conventional chemotherapy. Blinatumomab and inotuzumab have demonstrated marked activity even in multiply-refractory patients.
The role of monoclonal antibodies, the chimeric CAR-T cell therapies, and other novel targeted approaches in adult ALL continue to be defined. The majority of these agents are currently being evaluated in the salvage setting, although the most active agents will likely need to be incorporated into the frontline treatment plan to optimize efficacy and decrease toxicities.
Strategies such as these will continue to be developed and refined with the goal of further improving the cure rates in adults ALL.