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The outcome of adult acute lymphoblastic leukemia (ALL) has improved substantially in the last decade; by intensification and optimization of chemotherapy, risk-adapted use of stem cell transplantation (SCT) has improved supportive care and individualized treatment strategies based on prognostic factors, including the evaluation and monitoring of minimal residual disease (MRD). However, results in adult patients still are considerably inferior to those in pediatric ALL, and treatment-related toxicity is a barrier to further intensification of standard chemotherapy, particularly in older patients. A major breakthrough in the treatment of acute lymphoblastic leukemia was the availability of targeted therapies—either targeting specific transcripts like bcr-abl fusion protein by tyrosine kinase inhibitors (TKIs) or by targeting specific antigens using monoclonal antibodies (MoAbs). Therapy with MoAbs is not only targeted but is also subtype-specific and, compared with chemotherapy, has different mechanisms of action and side effects, as recently reviewed.[1, 2]

Antigens for Monoclonal Antibody Therapies

ALL blast cells express a variety of specific antigens, eg, CD19, CD20, CD22, CD33, and CD52, which serve as targets for MoAbs. The most experience is available for anti-CD20 (rituximab), which has been combined with chemotherapy for the treatment of mature B-ALL/Burkitt lymphoma or B-precursor (pre-B) ALL. Another antigen, CD19, is of great interest because of its very high rate of expression in ALL. For example, it can be targeted by a bispecific MoAb, blinatumomab, directed against CD19 and CD3. Smaller studies or case reports also are available for the anti-CD52 antibody (alemtuzumab), or anti-CD33 (gemtuzumab).

In this issue of Cancer, Kantarjian and coworkers report promising results with a MoAb directed against CD22, a highly expressed antigen in ALL.[3] In this review, I focus on clinical studies with the CD22 antibodies epratuzumab and inotuzumab ozogamicin.

CD22 Expression

CD22 is a 135-kDa, B-cell–specific adhesion molecule that is expressed on the cells of 60% to 90% of B-cell malignancies. It is not expressed on hematopoietic stem cells or on any other nonlymphoid hematopoietic or nonhematopoietic cells.

The expression of CD22 on ALL cells is high. Two large studies have evaluated CD22 expression in more detail. In the first, 584 adult ALL patients (ages 15-65 years) had CD22 expression in 60% to 85% of cells with a cutoff of >20% of cells.[1] Within the B-lineage subtypes, there were differences in CD22 expression (E. Thiel, S. Schwartz, personal communication) (CD22 expression: early pre-B [pro-B] ALL, 60% of cells; common ALL, 85% of cells; pre-B ALL, 75% of cells; mature B-ALL, 69% of cells). In another large series, CD22 expression was analyzed in 427 patients with B-lineage ALL. In that series, 93% of patients were positive for CD22 expression, with either total antigen expression (defined as antigen expression on the entire leukemic population) in 79.9% or as partial antigen expression only on a percentage of leukemic cells in 13.1%, and 7% of patients were CD22 negative. In that cohort, 30% of patients were children or adolescents in the groups ages 2 to 14 years or 15 to 21 years. Also in that series, there was an increase in the percentage of CD22-positive cases identified from pro-B cells to mature B-ALL cells.[4]

The differences in CD22 expression evident in those studies may be because of different cutoffs, defined as >20% of cells in a study by Thiel et al (personal communication), and the distinction between total and partial antigen expression, as reported by Raponi et al.[4] Whether CD22 expression is age-related remains an open question but may well be in accordance with the higher CD22 expression rates reported in the few pediatric series.

Also, the degree of antigen expression measured by mean fluorescence intensity and antibody binding capacity has been evaluated.[4] An increased CD22 expression level was documented from pro-B to B-mature ALL. Again, it remains open whether this difference in expression level may have a clinical impact. A large, ongoing, prospective trial with the CD22 antibody in the relapsed/refractory ALL setting may reveal differences in outcomes for age cohorts, B-lineage subtypes, and CD22 expression levels.

Clinical Studies With Anti-CD22 Antibodies

Epratuzumab

Epratuzumab, a fully humanized MoAb directed against CD22, is rapidly internalized after binding and appears to modulate B-cell activation and signaling.[5] It was first studied in children with bone marrow relapse of pre-B ALL. Patients received epratuzumab as a single agent at a dose of 360 mg/m2 intravenously twice weekly for 4 doses followed by weekly doses for 4 weeks in combination with standard 4-drug reinduction therapy. In combination with chemotherapy, 9 patients achieved complete remission (CR), and 7 achieved negative MRD status. Dose-limiting toxicity included 1 grade 4 seizure and 1 asymptomatic increase in liver enzymes.[6] That study was later amended to give epratuzumab twice weekly for 8 doses in combination with chemotherapy. There was no change in the CR rate of 65% to 66% versus 67% in a historic control group. However, the rate of molecular response increased from 25% to 42%.

The Southwest Oncology Group combined epratuzumab with clofarabine and cytarabine in a phase 2 trial for adults with refractory/relapsed ALL.[7] In 32 of 35 patients who were evaluable, the CR/incomplete CR rate was 50% compared with a CR/incomplete CR rate of 17% when patients received clofarabine and cytarabine without epratuzumab.

Inotuzumab ozogamicin

The antibody-antigen complex is rapidly internalized upon binding to CD22. Calicheamicin is released inside the tumor cell, whereby calicheamicin is more potent than other cytotoxic chemotherapeutic agents. Calicheamicin binds to DNA, inducing double-stranded DNA breaks and leading to apoptosis.

Inotuzumab demonstrated encouraging results in non-Hodgkin lymphomas in phase 1/2 studies.[8] Response rates ranged from 60% to 80% and were durable. The phase 2 proposed dose schedule was 1.8 mg/m2 intravenously once every 3 to 4 weeks. Dose-limiting toxicities were myelosuppression and reversible liver function abnormalities.

These encouraging results led to a phase 2 study in relapsed and refractory B-lineage ALL, in which 49 patients received inotuzumab 1.3 to 1.8 mg/m2 intravenously once every 3 to 4 weeks; of those patients, 30% had Philadelphia chromosome-positive ALL or translocation t(4;11). Overall, 9 patients (18%) achieved a CR, 14 (29%) had a bone marrow CR without recovery of platelets, and 5 patients (10%) had a bone marrow CR without recovery of neutrophil or platelet counts. The overall response rate was 57%.[9] Of 27 patients who were investigated by multiparameter flow cytometry, negative MRD status was achieved in 63%. The median survival of all patients was 4.5 months. Among the 9 patients who achieved a CR, the estimated 9-month survival rate was 78%. Twenty-two of the 49 patients were able to proceed to subsequent allogeneic SCT. Adverse effects included liver function abnormalities, which were severe in 31% but were reversible. Five patients who underwent allogeneic SCT developed veno-occlusive disease; the investigators believe this may be related to the preparative regimens, which included ThioTEPA (N,N′N′-triethylenethiophosphoramide) and clofarabine.

In the study reported by Kantarjian et al in this issue, the schedule was modified in 41 patients to weekly inotuzumab 0.8 mg/m2 on day 1 and 0.5 mg/m2 on days 8 and 15 every 3 to 4 weeks, based on greater in vitro efficacy with more frequent exposure. The overall response rates were similar for single-dose and weekly dose inotuzumab (57% vs 59%, respectively), but the toxicities—particularly reversible bilirubin elevation, fever, and hypotension—were observed less frequently on the weekly dose. Allogeneic SCT in 40% of the 90 patients resulted in a lower rate of veno-occlusive disease with less alkylators in the preparative regimen. The high response rate and the median survival of 6.2 months (5.0 months with single-dose inotuzumab and 7.3 months with weekly inotuzumab) demonstrated high single-agent activity of inotuzumab in relapsed/refractory ALL.[4]

Stem Cell Transplantation After Therapy With Monoclonal Antibodies

Allogeneic SCT provides the best chance of a cure in adult patients with relapsed-refractory ALL. When a second remission can be obtained, the survival rate is approximately 30% compared with <10% with chemotherapy alone.[10, 11] Consequently, when MoAbs are applied in refractory adult ALL, after the achievement of a CR, SCT is recommended in most trials. However, in the current study by Kantarjian et al, the survival was censored for allogeneic SCT, because there was no advantage of SCT (see Fig. 1 in Kantarjian et al). However, in a current study with the bispecific antibody blinatumomab directed against CD3/CD19 applied in adult patients with relapsed/refractory B-lineage ALL, which also has a high response rate and a molecular CR rate of 66%, it remains to be determined whether SCT will be advantageous for patients.[12]

Blinatumomab also was received by adult patients with ALL who had MRD failure after induction or molecular relapse, indicating a lower tumor burden (and probably fewer assistance mechanisms). In that study, 80% of patients achieved negative MRD status, and those patients were candidates for SCT. Somewhat unexpectedly, their survival after SCT was not superior to that in a small cohort of patients who were supposed to undergo SCT but did not for a variety of reasons. Their survival was encouraging without any further therapy.[13]

It is too early to draw any conclusion from this limited experience with MoAb therapy followed by SCT, but it should draw our attention. The question may arise whether SCT in patients with relapsed/refractory or MRD-positive B-lineage ALL, after responding to MoAb therapy, is the best option.

Minimal Residual Disease Evaluation as an Endpoint for Monoclonal Antibody Therapy

There is increasing evidence that the evaluation of MRD, defined as <10−4 blast cells in the bone marrow, is a much better prognostic marker for further outcome compared with a hematologic CR.[14] In the MoAb studies described above, the rates of negative MRD status obtained were remarkably high and certainly were superior to those achieved with multiagent chemotherapy. In the epratuzumab study of relapsed/refractory childhood ALL,[6] the authors did not report whether patients who achieved a molecular remission had a longer response compared with those who had a hematologic CR only. In the current study by Kantarjian and colleagues, the attainment of negative MRD status seems to have had only marginal benefit, if any (see Fig. 2 in Kantarjian et al), although the small patient cohorts have to be considered. In contrast, molecular remission obtained after induction/consolidation in first-line therapy in both pediatric and adult ALL has high prognostic relevance. Thus, in the relapsed/refractory setting, the impact of MRD seems to be different. This may indicate that negative MRD status has a distinct impact in the de novo and relapsed/refractory situation, an observation that most likely is not restricted to MoAb treatment. Possible explanations may include, eg, that MRD-negative status in the first-line setting is “deeper,” not ascertainable to date (but probably will be in the future using next-generation sequencing), or (more likely) that resistance mechanisms unrevealed by MRD are responsible.

Conclusions and Future Direction

Treatment with MoAbs directed against surface antigens is highly effective in relapsed/refractory ALL, as also convincingly demonstrated in the report by Kantarjian et al, resulting in high rates of CR and molecular remission.[3] Better scheduling will reduce the toxicities, which, to date, are not negligible. Large, prospective, international trials, which are ongoing for inotuzumab as well as for blinatumomab, will establish the basis of these targeted therapies and also of future combinations with chemotherapy or other targeted therapies, eg, TKIs. Also of great interest is whether all age groups will profit from antibody therapy, particularly elderly patients who are not suitable candidates for intensive chemotherapy because of toxicity. The value of MRD as a surrogate marker in these studies has to be exploited along with the setting of MoAb therapy in the context of SCT.

FUNDING SUPPORT

  1. Top of page
  2. FUNDING SUPPORT
  3. CONFLICT OF INTEREST DISCLOSURES
  4. REFERENCES

No specific funding was disclosed.

CONFLICT OF INTEREST DISCLOSURES

  1. Top of page
  2. FUNDING SUPPORT
  3. CONFLICT OF INTEREST DISCLOSURES
  4. REFERENCES

Dr. Hoelzer is a member of the boards of Amgen, BMS, and Medac and has acted as a consultant for BMS and Medac.

REFERENCES

  1. Top of page
  2. FUNDING SUPPORT
  3. CONFLICT OF INTEREST DISCLOSURES
  4. REFERENCES
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