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Keywords:

  • inotuzumab;
  • acute lymphocytic leukemia;
  • refractory;
  • relapsed;
  • monoclonal antibody

Abstract

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. FUNDING SUPPORT
  8. CONFLICT OF INTEREST DISCLOSURES
  9. REFERENCES

BACKGROUND

CD22 expression occurs in >90% of patients with acute lymphocytic leukemia (ALL). Inotuzumab ozogamicin, a CD22 monoclonal antibody bound to calicheamicin, is active in ALL.

METHODS

Patients with refractory-relapsed ALL received treatment with inotuzumab. The first 49 patients received single-dose, intravenous inotuzumab at doses of 1.3 to 1.8 mg/m2 every 3 to 4 weeks. In the next 41 patients, the schedule was modified to inotuzumab weekly at a dose of 0.8 mg/m2 on day 1 and at a dose of 0.5 mg/m2 on days 8 and 15, every 3 to 4 weeks, based on higher in vitro efficacy with more frequent exposure.

RESULTS

Ninety patients were treated; 68% were in salvage 2 or beyond. Overall, 17 patients (19%) achieved a complete response (CR), 27 (30%) had a CR with no platelet recovery (CRp), and 8 (9%) had a bone marrow CR (no recovery of counts), for an overall response rate of 58%. Response rates were similar for single-dose and weekly dose inotuzumab (57% vs 59%, respectively). The median survival was 6.2 months overall, 5.0 months with the single-dose schedule, and 7.3 months with the weekly dose schedule. The median survival was 9.2 months for patients in salvage 1 (37% at 1 year), 4.3 months for patients in salvage 2, and 6.6 months for patients in salvage 3 or later. The median remission duration was 7 months. Reversible bilirubin elevation, fever, and hypotension were observed less frequently on the weekly dose. In total, 36 of 90 patients (40%) underwent allogeneic stem cell transplantation. Veno-occlusive disease was noted in 6 of 36 patients after stem cell transplantation (17%), was less frequent after the weekly schedule (7%), and with less alkylators in the preparative regimen.

CONCLUSIONS

Inotuzumab single-agent therapy was highly active, safe, and convenient in patients with refractory-relapsed ALL. A weekly dose schedule appeared to be equally effective and less toxic than a single-dose schedule. Cancer 2013;119:2728–2736. © 2013 American Cancer Society.


INTRODUCTION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. FUNDING SUPPORT
  8. CONFLICT OF INTEREST DISCLOSURES
  9. REFERENCES

Modern multiagent combination chemotherapy regimens in adults with acute lymphocytic leukemia (ALL) result in complete response (CR) rates of 80% to 90% and long-term survival rates of 35% to 50%.[1-3] Improvement of adult ALL therapy is unlikely to result from further intensification therapy, because the current regimens are already associated with significant toxicities.

Leukemic ALL cells express cluster of differentiation 20 (CD20) (a B-lymphocyte antigen) in approximately 50% of patients, and CD22 (an inhibitory receptor for B-cell receptor signaling) and CD19 (a B-lymphocyte antigen) in 90% of patients. This provides opportunities to use new monoclonal antibodies in ALL, alone or in combinations with chemotherapy or with other monoclonal antibodies. Rituximab as a single agent had minimal activity in ALL but improved survival when combined with chemotherapy in CD20-positive ALL.[4-8] This encouraged investigational therapies with other monoclonal antibodies directed against ALL surface markers.[9, 10]

Inotuzumab ozogamicin is a CD22 monoclonal antibody bound to calicheamicin, a natural product of Micromonospora echinospora, which is significantly more toxic than cytotoxic chemotherapy.[11] Inotuzumab binds CD22 with subnanomolar affinity and is rapidly internalized, delivering the conjugated calicheamicin intracellularly. Calicheamicin binds to the minor DNA groove, causing double-strand DNA breaks, resulting in cell apoptosis. A phase 2 study of single-dose inotuzumab 1.3 to 1.8 mg/m2 every 3 to 4 weeks in patients with refractory and relapsed ALL resulted in a bone marrow CR rate of 57%. Adverse events included fever, brief episodes of hypotension, and liver function abnormalities.[12] Preclinical studies suggested that lower dose, more frequent schedules of inotuzumab may improve anti-ALL efficacy and reduce toxicities. This resulted in amending the study to change the inotuzumab dose schedule to weekly 0.8 mg/m2 on day 1 and 0.5 mg/m2 on days 8 and 15 every 3 to 4 weeks for the same total dose of inotuzumab 1.8 mg/m2 per course. In this report, we update our experience in 90 patients with refractory and relapsed ALL who received weekly inotuzumab (n = 41) and the previously reported (and now updated) single-dose inotuzumab (n = 49).

MATERIALS AND METHODS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. FUNDING SUPPORT
  8. CONFLICT OF INTEREST DISCLOSURES
  9. REFERENCES

Study Group

Patients with a confirmed diagnosis of refractory or relapsed pre-B ALL were eligible. Eligibility criteria were identical for the single-dose and weekly inotuzumab schedules.[12] Inclusion criteria were an Eastern Cooperative Oncology Group performance status from 0 to 3; adequate liver function (bilirubin ≤1.5 mg/dL and liver enzymes ≤3 times the upper limit of normal, unless considered because of leukemia) and renal function (creatinine ≤2.0 mg/dL); adequate cardiac function (those with New York Heart Association class ≥3 or an ejection fraction <45% were excluded). Exclusion criteria included allogeneic stem cell transplantation (SCT) in the previous 4 months, pregnant or breast-feeding women, and patients with known hepatitis B disease.

This was a single-institution study conducted at The University of Texas MD Anderson Cancer Center. The study protocol was approved by the Institutional Review Board, in compliance with institutional guidelines. Patients signed informed consent in compliance with the Declaration of Helsinki.

Therapy

Patients received single-dose inotuzumab from 1.3 to 1.8 mg/m2 as a short, intravenous infusion once every 3 to 4 weeks. Weekly inotuzumab was given at a dose of 0.8 mg/m2 on day 1 and 0.5 mg/m2 on days 8 and 15, for a total dose of 1.8 mg/m2 per course. Courses were repeated every 3 to 4 weeks. Patients received the recommended premedication with oral acetaminophen 650 mg, intravenous diphenhydramine 10 to 25 mg, and intravenous hydrocortisone 25 mg.

Inotuzumab was given as a short infusion over 1 hour. Courses were given every 3-4 weeks, depending on the recovery of the counts and of the bone marrow status on days 21 and 28. Briefly, if the bone marrow studies revealed persistent or increasing leukemia on days 21 and 28, then patients received a subsequent course of inotuzumab regardless of peripheral counts. If the blasts were reduced or were <5% by days 21 through 28, patients received a subsequent course only after recovery of the counts to at least pretreatment levels. Persistent thrombocytopenia was not a condition to delay therapy. In contrast to the previous study with single-dose inotuzumab,[12] the weekly dose schedule study did not include the addition of rituximab for patients who had stable disease or who had no improvement or progression after 2 courses of inotuzumab. Patients who achieved a CR or a bone marrow CR after 1 or 2 courses of therapy were allowed to receive 2 additional courses of therapy, for a maximum of 4 cycles. Additional treatments were based on response and liver toxicities in the previous 4 cycles. Patients who achieved any response also could continue on treatment for up to 8 cycles. Subsequent cycles of inotuzumab were given at the same dose. Patients with grade 3 or worse toxicity and a favorable response to therapy could receive inotuzumab in subsequent cycles at a 25% dose reduction. Patients who developed central nervous system (CNS) leukemia on inotuzumab and who had a positive response were allowed to continue on therapy and receive CNS-directed intrathecal chemotherapy after an assessment of the patient's benefit:risk ratio.

Patients received antibiotics, antifungals, and antiviral agents according to institutional guidelines. Antifungal azoles prophylaxis was delayed for at least 24 hours after the completion of inotuzumab. Patients with rapid increases in white blood cell counts could receive hydroxyurea or a short course of steroids at the beginning of the first cycle.

Suitability for allogeneic SCT was assessed in all patients. Whenever possible, eligible patients were considered for allogeneic SCT after achieving at least a bone marrow CR. Minimal residual disease (MRD) status was assessed by 6-color multiparameter flow cytometry of abnormal ALL surface antigen expression levels, according to standard protocols. The panel included 15 antigens: CD10, CD13, CD15, CD19, CD20, CD22, CD25, CD33, CD34, CD38, CD45, CD52, CD58, CD66c, and CD81. One million cells were stained with a stain-lyse-wash technique, and 200,000 cells were analyzed per sample on FacsCanto II instruments (BD Biosciences, San Diego, Calif). Data were analyzed with FCS Express 3 software (De Novo Software, Los Angeles, Calif). Negative status was defined as the presence of <10−4 lymphocytic cells.

Statistical Considerations

Response criteria were standard. A CR was defined as the disappearance of all disease with bone marrow blasts ≤5%, neutrophils ≥1.0 × 109/L, and a platelet count >100 × 109/L. A bone marrow CR with incomplete recovery of platelets (CRp) was defined as a CR but without platelet recovery to ≥100 × 109/L. A bone marrow CR with incomplete recovery (CRi) was defined as CR but without recovery of platelets to ≥100 × 109/L or recovery of neutrophil counts to ≥109/L. Survival and response duration were calculated using the Kaplan-Meier method.

Early stopping rules for both single-dose and weekly inotuzumab were planned for futility if the CR + CRi + CRp + partial response of total treated was ≤0 of 10 patients, 1 of 17 patients, 2 of 24 patients, 3 of 31 patients, and 4 of 37 patients. Overall, 40 patients were planned to receive single-dose inotuzumab. This was expanded to 60 patients because of high efficacy. However, the schedule was modified to a weekly schedule, which was approved by the institutional review board and modified after 49 patients had received single-dose inotuzumab. In total, 90 patients, including 41 patients on weekly inotuzumab, were planned to receive treatment.

When analyzing the weekly and single-dose inotuzumab study groups, the chi-square method was used to compare parameters. Univariate analyses were conducted using standard methods.

RESULTS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. FUNDING SUPPORT
  8. CONFLICT OF INTEREST DISCLOSURES
  9. REFERENCES

Study Group

The 49 patients who received single-dose inotuzumab were accrued between June 2010 and March 2011, and the 41 patients who received weekly inotuzumab were accrued between March 2011 and September 2012. The median patient age in the entire study group was 39.5 years (range, 4-84 years); 25 patients (28%) were aged ≥60 years, and 6 patients (7%) were aged ≤18 years. Nine patients (10%) had a performance status of 2 or 3. Twenty-nine patients (32%) received inotuzumab as first salvage treatment (Salvage 1), 34 patients (38%) received it as Salvage 2, and 27 patients (30%) received it as Salvage ≥3. Ten patients (11%) had undergone prior allogeneic SCT. The study group characteristics indicate the heavily treated nature of this refractory-relapsed ALL study group (Table 1). All patients expressed high levels of CD22 positivity in ≥50% leukemic cells.

Table 1. Characteristics of the Study Group, n = 90
 No. of Patients Receiving Inotuzumab Therapy (%)
CharacteristicSingle-Dose, n = 49Weekly, n = 41Overall, n = 90
  1. Abbreviations: Allo-SCT, allogenic stem cell transplantation; CD22, cluster of differentiation 22 (B-cell receptor); CRD1, duration of first remission; ECOG PS, Eastern Cooperative Oncology Group performance status; HCVAD, hyperfractionated cyclophosphamide, vincristine, and doxorubicin; Ph, Philadelphia chromosome.

  2. a

    Patients receiving weekly inotuzumab were more frequently in salvage 1 with CRD1 <12 months (P = .003), whereas patients receiving single-dose inotuzumab were more frequently in salvage 2 (P = .016). No other significant differences were evident in the 2 study group characteristics.

Age, y   
≤183 (6)3 (7)6 (7)
≥6012 (24)13 (32)25 (28)
ECOG PS   
0-144 (90)37 (90)81 (90)
≥25 (10)4 (10)9 (10)
Salvage statusa   
S113 (27)16 (39)29 (32)
S1, CRD1 <12 mo3 (6)12 (29)15 (17)
S1, CRD1 ≥12 mo7 (14)2 (5)9 (10)
S224 (49)10 (24)34 (38)
≥S312 (24)15 (37)27 (30)
Prior HCVAD regimen28 (57)29 (71)57 (63)
Karyotype   
Diploid12 (24)9 (22)21 (23)
Ph-positive7 (14)8 (20)15 (17)
Translocation (4;11)5 (10)3 (7)8 (9)
Other25 (51)21 (51)46 (51)
Prior Allo-SCT7 (14)3 (7)10 (11)
CD22-positive, %   
>9028 (57)31 (76)59 (66)
70-8914 (29)8 (20)22 (24)
50-697 (14)2 (5)9 (10)

Response

Overall, 17 patients (19%) achieved a CR, 27 patients (30%) had a CRp, and 8 patients (9%) had a CRi. Thirty-four patients (38%) had resistant disease, and 4 patients (4%) died within 4 weeks of starting therapy. Thus, responses were observed in 52 of the 90 patients who received treatment, for an overall response rate of 58%. Response rates with weekly and single-dose inotuzumab were similar (Table 2). The median number of cycles was 2 (range, 1-6 cycles) with weekly and 2 (range, 1-5 cycles) with single-dose inotuzumab.

Table 2. Responses
 No. of Patients Receiving Inotuzumab Therapy (%)
ResponseSingle-Dose, n = 49Weekly, n = 41Overall, n = 90
  1. Abbreviations: CR, complete response; CRi, bone marrow complete response with incomplete recovery; CRp, bone marrow complete response with incomplete recovery of platelets; PR, partial response.

CR9 (18)8 (20)17 (19)
CRp14 (29)13 (32)27 (30)
CRi, bone marrow CR5 (10)3 (7)8 (9)
PR000
Resistant19 (39)15 (37)34 (38)
Death <4 wk2 (4)2 (5)4 (4)

Among the 52 patients who achieved a response to inotuzumab, 29 patients had chromosomal abnormalities at the start of therapy and had sufficient metaphases for analysis at morphologic CR. Among these, a cytogenetic CR was observed in 26 patients (90%). The rate of cytogenetic CR by morphologic responses was as follows: 8 cytogenetic CR/9 morphologic CR (89%); 11 cytogenetic CR/13 morphologic CRp (85%); and 7 cytogenetic CR/7 a morphologic CRi (100%). Multiparameter flow cytometric studies for MRD were performed in 50 patients who achieved a morphologic bone marrow CR. Negative MRD status was observed in 36 of 50 responding patients (72%). Considering the total study group, negative MRD status was achieved in 17 of 41 patients who received weekly inotuzumab (41%) and in 19 of 49 patients (39%) who received single-dose inotuzumab (P value not significant). The rate of MRD-negative status according to morphologic response was as follows: 14 MRD-negative/17 CR (82%); 19 MRD-negative/25 CRp (76%); and 3 MRD-negative/8 CRi (38%).

Most patients who achieved a CR obtained it early (there were 14 CRs after 1 course and 3 CRs after 2 or more courses). Among the patients who achieved a CRp, 16 achieved it after 1 course, and 11 achieved it after 2 or more courses. Among the patients who achieved a CRi, 1 achieved it after 1 course, and 7 achieved it after 2 or more courses.

In the total study group, lower response rates were observed among patients who had Philadelphia chromosome-positive ALL and those who had translocation t(4,11) (38%-40% vs 57%-81% for others; P = .047). The response rate was also lower in patients who were treated in Salvage 2 or later (48%-50% vs 76% in Salvage 1; P = .056) (Table 3). Considering the small numbers, the trends of associations were similar with the weekly and single-dose inotuzumab schedules.

Table 3. Association of Characteristics With Response, n = 90
CharacteristicNo. of PatientsNo. of Responders (%)P
  1. Abbreviations: Allo-SCT, allogenic stem cell transplantation; CD22, cluster of differentiation 22 (B-cell receptor); CRD1, duration of first remission; ECOG PS, Eastern Cooperative Oncology Group performance status; Ph, Philadelphia chromosome.

Age, y   
<606537 (57).79
≥602515 (60) 
ECOG PS   
0-18148 (59).39
≥294 (44) 
Salvage status   
S12922 (76).056
S1, CRD1 <12 mo1511 (73) 
S1, CRD1 ≥12 mo97 (78) 
S23417 (50) 
≥S32713 (48) 
Karyotype   
Diploid2117 (81).047
Ph-positive156 (40) 
Translocation (4;11)83 (38) 
Other4626 (57) 
CD22-positive, %   
>905933 (56).823
70-892213 (59) 
50-6996 (67) 
Prior Allo-SCT105 (50) 

Outcome

The median overall survival of patients who received inotuzumab was 6.2 months (Fig. 1). Censoring for the time of allogeneic SCT revealed similar survival, suggesting a lack of benefit from allogeneic SCT. The median survival was 5.0 months with the single-dose schedule and 7.3 months with the weekly schedule. The median remission duration was 7 months (1-year rate, 42%). Survival by salvage number, response to treatment, and MRD status among responders is illustrated in Figure 2A-C for the entire study group of 90 patients. Patients who received treatment in Salvage 1 had a median survival of 9.2 months and an estimated 1-year survival rate of 37%. The median survival was 13.1 months for patients who achieved a CR, 7.4 months for those who achieved a CRp + CRi, and 3.1 months for those who had resistant disease. Although survival did not differ between MRD-positive patients (n = 14) and MRD-negative patients (n = 36; median survival, 7.8 months vs 7.9 months, respectively; 1-year survival rate, 9% vs 32%, respectively; P = .48), remission duration tended to favor MRD-negative patients (median remission duration, 5.1 months vs 11.5 months, respectively; P = .25). There were no differences in these 3 parameters according to whether patients received weekly or single-dose inotuzumab.

image

Figure 1. Survival of the study group is illustrated with and without censoring for allogeneic stem cell transplantation.

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image

Figure 2. Survival is illustrated by (A) salvage status, response to therapy (B), and (C) achievement of minimal residual (MRD) status. CRp indicates complete response without platelet recovery; CRi, complete response with incomplete platelet or neutrophil recovery.

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Pharmacokinetic Studies

Measurements of inotuzumab levels were conducted at the end of infusion, 3 hours after the end of infusion, and on days 7 and 8. Patients who achieved a bone marrow CR had lower clearance rates and higher area under the curve (AUC) levels compared with patients who failed to achieve a response (Fig. 3A and B). Higher inotuzumab peak levels were observed with single-dose inotuzumab (data not shown), but inotuzumab peak levels did not correlate with response rates. (Fig. 3C).

image

Figure 3. (A,B) Slower clearance and higher areas under the curve (AUCs) were observed in patients who achieved a bone marrow complete response (CR) versus others. (C) Maximum inotuzumab plasma concentrations (Cmax) did not correlate with response.

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Treatment Side Effects

With weekly inotuzumab, previously observed, prominent side effects associated with single-dose inotuzumab were less frequent, in particular, fever and hypotension within 48 hours of drug administration and liver function abnormalities. With weekly inotuzumab, 2 patients experienced grade 1 or 2 bilirubin elevations, and no patients had grade 3 bilirubin elevations. Grade 1 or 2 elevations of liver enzymes were observed in 9 patients, and grade 3 elevations were observed in 2 patients. All were reversible within 1 or 2 weeks. Single-dose inotuzumab was associated with persistent liver function abnormalities in 2 of 49 patients, but no such occurrences were noted with weekly inotuzumab. (Table 4)

Table 4. Nonmyelosuppressive Adverse Events During the First Cycle of Therapya
 No. of Patients
 Weekly InotuzumabSingle-Dose Inotuzumab
Adverse EventGrade 1-2, n = 41Grade 3-4, n = 41Grade 1-2, n = 49Grade 3-4, n = 49
  1. a

    Grade 1 and 2 side effects were significantly lower with weekly inotuzumab in relation to drug-related fever (P < .0001), increased bilirubin (P = .01), and increased liver enzymes (P = 0.001). No significant differences were observed in grade 3 and 4 side effects with weekly versus single-dose inotuzumab schedules.

Drug-related fever, d 1-236209
Drug-related hypotension, d 1-260121
Raised bilirubin concentration20122
Raised aminotransferase concentration92271
Raised lipase or amylase concentration1001
Nausea5060
Vomiting0030
Diarrhea1030
Mucositis0001
Anorexia0010
Headache1010
Constipation0010
Hypokalemia0101
Hypoalbuminemia0010

Feasibility of Subsequent Allogeneic Stem Cell Transplantation

The median follow-up was 4 months (range, 1-19 months) on weekly inotuzumab and 21 months (range, 5.4-28 months) on single-dose inotuzumab. Among the 41 patients who received weekly inotuzumab, 14 patients (34%) were able to proceed to allogeneic SCT (6 related donors, 5 match unrelated donors, 2 haploidentical related donors, and 1 cord donor). Among the 49 patients who received single-dose inotuzumab, 22 patients (45%) were able to proceed to allogeneic SCT (7 related donors, 14 unrelated donors, and 1 mismatched cord donor). Currently, 9 of 14 patients on weekly inotuzumab and 4 of 22 patients on single-dose inotuzumab remain in remission and alive after undergoing allogeneic SCT. The median time from the start of inotuzumab therapy to allogeneic SCT was 11 weeks (range, 5-25 weeks), and the median time from the end of inotuzumab therapy to allogeneic SCT was 5 weeks (range, 2-14 weeks). With the current follow-up, 13 patients remain alive without evidence of disease. Veno-occlusive disease (VOD) was observed in 1 of 14 patients who underwent allogeneic SCT after weekly inotuzumab and in 5 of 22 patients who underwent allogeneic SCT after single-dose inotuzumab. This also may be related to the preparative regimen: VOD was observed in 5 of 13 patients who received a preparative regimen that included 2 alkylating agents but in only 1 of 21 patients who received a regimen that included 1 alkylating agent (P = .02).

DISCUSSION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. FUNDING SUPPORT
  8. CONFLICT OF INTEREST DISCLOSURES
  9. REFERENCES

In this study of 90 patients with refractory-relapsed ALL who received treatment with inotuzumab on 2 different schedules, weekly (n = 41) and single-dose (n = 49), we identified inotuzumab as 1 of the most potent anti-ALL agents. Overall, 58% of patients achieved a bone marrow CR. There was no difference in the response rate according to whether patients received weekly or single-dose inotuzumab. Despite the achievement of deep levels of remission, as determined by cytogenetic CRs and negative MRD status, response durations were brief, and the median overall survival was 6.2 months (1-year survival rate, 20%). Thus monoclonal antibody therapy with inotuzumab, and with monoclonal antibodies (blinatumomab) that target other ALL surface markers (CD19), have demonstrated very promising anti-ALL activity with bone marrow CR rates from 50% to 75%, depending on the patient and the leukemia characteristics. These monoclonal antibodies potentially offer the first highly active modalities that produce bone marrow CR rates equivalent or superior to those observed with intensive chemotherapy but without the notorious toxicities of the latter. Compared with our historic experience using intensive chemotherapy in 292 patients with refractory-relapsed ALL, the CR+CRi rate with inotuzumab in this study was 47% versus 29% overall. In Salvage 1, the CR+CRi rate was 61% versus 40%; in Salvage 2, the CR+CRi rate was 44% versus 16%; and in Salvage 3 or later, the CR+CRi rate was 37% versus 16%.[13, 14] In the future, combining different monoclonal antibodies or using combinations of chemotherapy with monoclonal antibodies may prolong survival in ALL salvage and improve the cure rate in patients with newly diagnosed ALL.

Lower response rates were observed among patients known historically to have more refractory disease, including patients with Philadelphia chromosome-positive ALL and those with ALL and t(4,11), as expected. Similarly, response rates were lower in patients who received inotuzumab in Salvage 2 or later compared with Salvage 1. However, even among the worst patient categories, inotuzumab was able to produce a bone marrow CR rate substantially higher than what is expected with intensive chemotherapy, although these responses have been transient.

Single-dose inotuzumab therapy has been associated with liver function abnormalities, occasional VOD after allogeneic SCT, and transient febrile and hypotensive episodes. These were less frequent with the weekly schedule of inotuzumab and were probably related to the peak levels of inotuzumab. Peak inotuzumab levels were not associated with differences in the response rate, whereas inotuzumab cumulative AUC levels, which were equivalent with weekly and single-dose inotuzumab, were associated with significant differences in the bone marrow response rate. Thus, the weekly versus single-dose clinical experience, supported by pharmacokinetic studies, indicates that weekly inotuzumab is as effective and is less toxic than single-dose inotuzumab. On the basis of these experiences, a pivotal trial of weekly inotuzumab versus intensive chemotherapy in patients with refractory and relapsed ALL in first or second salvage is ongoing.

Despite the high response rates observed, responses were not durable, and median survival was modest. However, the responses obtained with inotuzumab allowed >40% of patients to proceed to allogeneic SCT, compared with only 17% of patients who achieved a CR with intensive chemotherapy in our historic experience (5% of the total salvage population).[14] This suggests that, with proper modifications of the preparative regimens and perhaps with combinations of inotuzumab and chemotherapy before SCT, in the future, we may achieve long-term disease-free survival in a substantial proportion of patients using sequential combined modality strategies and allogeneic SCT. Future studies will also evaluate inotuzumab in combination with chemotherapy to improve the cure rates in newly diagnosed patients with adult ALL.

FUNDING SUPPORT

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. FUNDING SUPPORT
  8. CONFLICT OF INTEREST DISCLOSURES
  9. REFERENCES

This research is supported in part by the National Institutes of Health through MD Anderson's Cancer Center Support Grant CA016672 and is funded by a research grant from Pfizer Oncology.

CONFLICT OF INTEREST DISCLOSURES

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. FUNDING SUPPORT
  8. CONFLICT OF INTEREST DISCLOSURES
  9. REFERENCES

Dr. Kantarjian has received research grants from BMS, Novartis, ARIAD, and Pfizer and has acted as a nonpaid consultant to Novartis.

REFERENCES

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. FUNDING SUPPORT
  8. CONFLICT OF INTEREST DISCLOSURES
  9. REFERENCES
  • 1
    Gokbuget N, Hoelzer D, Arnold R, et al. Treatment of adult ALL according to protocols of the German Multicenter Study Group for Adult ALL (GMALL). Hematol Oncol Clin North Am. 2000;14:1307-1325.
  • 2
    Bassan R, Hoelzer D. Modern therapy of acute lymphoblastic leukemia. J Clin Oncol. 2011;29:532-543.
  • 3
    Faderl S, O'Brien S, Pui CH, et al. Adult acute lymphoblastic leukemia. Cancer. 2010;116:1165-1176.
  • 4
    Thomas DA, Faderl S, O'Brien S, et al. Chemoimmunotherapy with hyper-CVAD plus rituximab for the treatment of adult Burkitt and Burkitt-type lymphoma or acute lymphoblastic leukemia. Cancer. 2006;106:1569-1580.
  • 5
    Gokbuget N, Hoelzer D. Rituximab in the treatment of adult ALL. Ann Hematol. 2006;85:117-119.
  • 6
    Rizzieri D, Johnson J, Byrd J, et al. Efficacy and toxicity of rituximab and brief duration, high intensity chemotherapy with filgrastim support for Burkitt or Burkitt-like leukemia/lymphoma: Cancer and Leukemia Group B (CALGB) study 10002 [abstract]. Blood (ASH Annual Meeting Abstracts). 2010;116. Abstract 858.
  • 7
    Thomas D, O'Brien S, Faderl S, et al. Chemoimmunotherapy with a modified hyper-CVAD and rituximab regimen improves outcome in de-novo Philadelphia chromosome-negative precursor B-lineage acute lymphoblastic leukemia. J Clin Oncol. 2010;28:3880-3889.
  • 8
    Hoelzer D, Huettmann A, Kaul F, et al. Immunochemotherapy with rituximab improves molecular CR rate and outcome in CD20+ B-lineage standard and high risk patients; results of 263 CD20+ patients studied prospectively in GMALL study 07/2003 [abstract]. Blood (ASH Annual Meeting Abstracts). 2020;116. Abstract 170.
  • 9
    Raetz E, Cairo M, Borowitz M, Blaney S, et al. Chemoimmunotherapy reinduction with epratuzumab in children with acute lymphoblastic leukemia in marrow relapse: a Children's Oncology Group pilot study. J Clin Oncol. 2008;26:3756-3762.
  • 10
    Topp M, Kufer P, Gokbuget N, et al. Targeted therapy with the T-cell-engaging antibody blinatumomab of chemotherapy-refractory minimal residual disease in B-lineage acute lymphoblastic leukemia patients results in high response rate and prolonged leukemia-free survival. J Clin Oncol. 2011;29:2493-2498.
  • 11
    Thorson J, Sievers E, Ahlert J, et al. Understanding and exploiting nature's chemical arsenal: the past, present and future of calicheamicin research. Curr Pharm Des. 2000;6:1841-1879.
  • 12
    Kantarjian H, Thomas D, Jorgensen J, et al. Inotuzumab ozogamicin, an anti-CD22-calicheamicin conjugate, for refractory and relapsed acute lymphocytic leukaemia: a phase 2 study. Lancet Oncol. 2012;13:403-411.
  • 13
    O'Brien S, Thomas D, Ravandi F, et al. Outcome of adults with acute lymphocytic leukemia after second salvage therapy. Cancer. 2008;113:3186-3191.
  • 14
    Thomas D, Kantarjian H, Smith T, et al. Primary refractory and relapsed adult acute lymphoblastic leukemia. Cancer. 1999;86:1216-1230.