Phase II Trial of Inotuzumab Ozogamicin in Children and Adolescents With Relapsed or Refractory B-Cell Acute Lymphoblastic Leukemia: Children's Oncology Group Protocol AALL1621

PURPOSE Children's Oncology Group trial AALL1621 was conducted to prospectively determine the safety and efficacy of inotuzumab ozogamicin (InO) in pediatric and adolescent patients with relapsed or refractory (R/R) B-cell acute lymphoblastic leukemia (B-ALL). PATIENTS AND METHODS This single-arm phase II trial enrolled patients age 1-21 years with R/R CD22-positive B-ALL. In cycle 1, InO dosing was 0.8 mg/m2 intravenously on day 1 and 0.5 mg/m2 on days 8 and 15 of a 28-day cycle with response evaluation at day 28. Using a two-stage design, the trial was continuously monitored for dose-limiting toxicities and sinusoidal obstruction syndrome (SOS). CD22 expression was retrospectively evaluated by central flow cytometry. RESULTS Forty-eight patients were evaluable for response and toxicity; 19 had complete response (CR) and nine CR with incomplete count recovery (CRi) after cycle 1 (CR/CRi rate: 58.3%; two-sided 90% CI, 46.5 to 69.3). Twenty-seven of 28 patients with CR or CRi had minimal residual disease measured by flow cytometry; 18 (66.7%) had minimal residual disease < 0.01%. Seven of 28 patients (25%) with CR or CRi had delayed count recovery past day 42 in cycle 1. Three (6.3%) patients had grade 3 ALT elevation and one patient had grade 3 hyperbilirubinemia in cycle 1. Of 21 patients undergoing hematopoietic stem-cell transplantation after InO, 6 (28.6%) developed grade 3 SOS. Partial CD22 expression and lower CD22 site density were associated with lower likelihood of response to InO. CONCLUSION InO is effective and well tolerated in heavily pretreated children and adolescents with R/R CD22-positive B-ALL. SOS after hematopoietic stem-cell transplantation and prolonged cytopenias were notable. CD22 modulation was identified as a mechanism of resistance. Expanded study of InO combined with chemotherapy is underway.

Synchronous B-Cell Acute Lymphoblastic Leukemia and Serous Ovarian Carcinoma: A Case Report

Adult patients with B-cell acute lymphoblastic leukemia (ALL) have higher rates of antecedent and subsequent malignancies. However, synchronous identification of ALL and ovarian cancer is exceedingly rare. We report the unique case of a 65-year-old woman with synchronous B-cell ALL and low-grade serous ovarian carcinoma diagnosed after surgical intervention for a small bowel obstruction. Treatment with inotuzumab ozogamicin followed by adnexal mass resection and postoperative letrozole was successful in achieving complete remission for both her leukemia and ovarian cancer.

Final Induction Therapy Results of an Open Label Phase II Study Using Inotuzumab Ozogamicin for Induction Therapy, Followed By a Conventional Chemotherapy Based Consolidation and Maintenance Therapy in Patients Aged 56 Years and Older with Acute B-Lymphoblastic Leukemia (INITIAL-1 trial)

Introduction: Acute lymphoblastic leukemia (ALL) represents approx. 5% of all newly diagnosed leukemias in patients between 55 and 70 years of age. Despite recent advances especially in younger patients, the prognosis of elderly patients with ALL remains dismal, even after moderately intensive chemotherapy. Incorporation of antibody-based therapies in the first line induction therapy bears the potential of a significant increased response rate and survival with the reduction of treatment toxicity. Methods: This open label phase II study of the German Multicenter Study Group on Adult Acute Lymphoblastic Leukemia was conducted at 13 centers. Patients aged &gt;55 years with newly diagnosed Ph/BCR-ABL negative acute B-precursor ALL were eligible. Leukemic blasts had CD22 surface expression of at least 20%. The 1st induction cycle consisted of InO 0.8mg/m2 on day1 and 0.5mg/m2 on d8 and d15 together with dexamethasone 10 mg/m2 (day7-8, day14-17) and one intrathecal injection (i.th.) of methotrexate (MTX), cytarabine (AraC) and dexamethasone (Dex). The 2nd and 3rd induction cycle consisted of InO 0.5mg/m2 on day 1, 8 and 15 plus i.th. MTX/AraC/Dex. Patients achieving a complete remission (CR) were offered to receive 5 conventional consolidation therapies (3 x ID-MTX/asparaginase; 2 x ID-AraC) and one reinduction therapy (idarubicine/ AraC/ cyclophosphamide / Dex.) in combination with rituximab (for CD20+ ALL), followed by a maintenance therapy with 6-MP/MTX. The primary endpoint was event free survival (EFS) at 12-months follow-up. An event was defined as any of the following: persisting bone marrow blasts after 2 cycles of InO, relapse or death. An event rate of ≤40% at 12 months follow-up was considered to qualify the experimental treatment as very promising for additional testing. Under the assumption of one-sided type I error of 5% and 80% power, 42 evaluable patients were needed for primary endpoint analysis (registered with ClinicalTrials.gov, identifier: NCT03460522). Results: As of July 2021, 45 patients were included, with induction results available for 43 patients. Two patients were excluded per protocol from further analysis, as they received only one induction: 1 prolonged toxicity (CR after induction), 1 withdrawn consent. Median age at initial diagnosis was 64 years (range 56-80 years). 38 patients were diagnosed with a common- and 5 with a pro-B ALL. Median CD22 expression on leukemic blasts was 69% (range 21-99%). Due to suspected therapy related liver toxicities, a single patient received only 2 induction cycles (complete remission after 1st induction). All other patients completed 3 cycles of induction therapy and achieved complete remission (CR/CRi), mainly after the 1st induction. Results of minimal residual disease (MRD), measured by real-time quantitative PCR, are available for all 43 patients, with 23/43 (53%) and 31/42 (74%) patients being MRD negative after 2nd and 3rd induction therapy, respectively. Four patients with MRD failure (≥10 -4) after the 3rd induction therapy are still in CR (2 were treated with conventional chemotherapy per this protocol, one proceeded to allogeneic stem cell transplantation (aSCT), one received blinatumomab). MRD below the threshold of 10 -4 was detected in 15 patients after the 2nd induction (no relapse occurred so far). 8 of these 15 patients were MRD negative after the 3rd induction. So far, 7 events have been reported (during year 1: 3 deaths in CR and 1 relapsed ALL; during year 2: 1 death in CR and 2 patients with relapse). With a median follow-up of 422 days, the probability of OS at 1 and 2 years is 91% (95% C.I. 80-100%) and 77% (95% C.I. 57-96%), respectively. 4 patients received an aSCT in 1st CR, 1 patient in 2nd CR. Regarding adverse events (AEs) during induction cycles 1, 2 and 3, most common AEs ≥CTC grade 3 reported were leukocytopenia (in 60%, 12% and 3% of all cases, respectively), anemia (28%, 2%, 0%), thrombocytopenia (35%, 7%, 3%) and elevation of liver enzymes (14%, 5%, 0%). So far, one patient has been reported with suspected veno occlusive disease (after 2nd induction therapy). Conclusion: Three cycles of InO as induction therapy for the treatment of elderly patients with acute B-cell ALL results in very high remission rates with MRD-response in up to 90% (MRD negativity or MRD-levels &lt;10 -4). The promising EFS and survival rates of these patients warrant further investigation of this novel induction therapy in a prospective randomized trial. Figure 1 Figure 1. Disclosures Stelljes: Pfizer: Consultancy, Research Funding, Speakers Bureau; Amgen: Consultancy, Speakers Bureau; Medac: Speakers Bureau; MSD: Consultancy, Speakers Bureau; Novartis: Consultancy, Speakers Bureau; Celgene/BMS: Consultancy, Speakers Bureau; Kite/Gilead: Consultancy, Speakers Bureau. Wäsch: Sanofi: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Pfizer: Consultancy; Takeda: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Novartis: Consultancy; BMS/Celgene: Consultancy; Gilead: Consultancy. Nachtkamp: Jazz: Honoraria; Bsh medical: Honoraria; Celgene: Other: Travel Support. Haenel: Jazz: Consultancy, Honoraria; GSK: Consultancy; Bayer Vital: Honoraria; Takeda: Consultancy, Honoraria; Roche: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Amgen: Consultancy; Celgene: Consultancy, Honoraria. Berdel: Philogen S.p.A.: Consultancy, Current equity holder in publicly-traded company, Honoraria, Membership on an entity's Board of Directors or advisory committees. Goekbuget: Amgen: Consultancy, Other: Invited talks for company sponsored symposia (with honoraria); Research funding for institution; Astra Zeneca: Other: Invited talk for company sponsored symposia (with honor); Erytech: Consultancy; Cellestia: Consultancy; Incyte: Other: Research funding for Institution; Jazz Pharmaceuticals: Other: Research funding for institution; Novartis: Consultancy, Other: Research funding for Institution; Gilead/Kite: Consultancy; Morphosys: Consultancy; Pfizer: Consultancy, Other: Research funding for institution; Servier: Consultancy, Other; Abbvie: Other. OffLabel Disclosure: Inotuzumab Ozogamicin

Fractionated Inotuzumab Ozogamicin Combined with Low-Intensity Chemotherapy Provides Very Good Outcome in Older Patients with Newly Diagnosed CD22+ Philadelphia Chromosome-Negative B-Cell Precursor Acute Lymphoblastic Leukemia: First Results from the EWALL-INO Study

On behalf of the GRAALL group, the Czech Republic ALL group, the Finland ALL group and the EWALL group. Introduction. Treatment of older patients (pts) with B-cell precursor acute lymphoblastic leukemia (BCP-ALL) remains an unmet medical need. Inotuzumab ozogamicin (INO), an anti-CD22 antibody conjugated to calicheamicin, is approved for the treatment of relapsed/refractory BCP-ALL in adults, sinusoidal obstruction syndrome (SOS) being the major adverse event associated with INO. A previous first line study conducted by the MDACC in pts 60 years or older successfully used INO in combination with a lower intensity version of the hyper-CVAD (mini-hyper-CVD). Due to the occurrence of SOS, the total doses were fixed at 1.3 mg/m² for cycle 1 followed by 3 cycles at 1 mg/m² (Kantarjian H et al. Lancet Oncol, 2018). Here, we aimed to assess the activity and safety of fractionated INO at a reduced dosage in combination with low-intensity chemotherapy as frontline therapy for older pts with CD22+ Philadelphia chromosome-negative (Ph-neg) BCP-ALL. Methods. EWALL-INO is a single arm prospective phase 2 multicentric study conducted in European centers belonging to the EWALL group. Eligibility criteria were pts aged 55y or older, performance status ≤2, and newly diagnosed CD22+ (20% or more of positive blast cells) Ph-neg BCP-ALL without central nervous system involvement. After a prephase including 5 days (D) of dexamethasone (DEX) 10mg per D and a single intrathecal injection (IT), the induction regimen was begun and split in 2 parts. Induction part I (Induc1) consisted of one triple IT, vincristine (VCR) 2 mg (1 mg over 70y) D1 D8 D15 D22 and DEX 20 mg D1D2 D8D9 D15D16 D22D23 combined with 3 injections of INO (0.8 mg/m² D1, 0.5 mg/m² D8 and D15). Induction part II (Induc2) was offered to pts in CR or CRp (CR with platelets &lt; 100 G/l) after Induc1 or as salvage therapy. Induc2 consisted of DEX 20mg D1D8, cyclophosphamide (CY) 300 mg/m² D1 to D3, one triple IT D2 and 2 injections of INO (0.5 mg/m² D1 and D8). Pts in CR/CRp were programmed to receive 6 blocks of consolidation (Ara-C 1.5g/m²/12h adapted to renal clearance D1D2 and DEX 10mg/12h D1D2, cycles 1 and 4; Methotrexate (MTX) 1.5 g/m² over 24h D1, VCR 1 or 2 mg D1, one triple IT D2 and 6-mercaptopurin (6-MP) D1 to D7, cycles 2 and 5; CY 500 mg/m² D1D2, VP16 75 mg/m² D1D2, one triple IT D2 and MTX 25 mg/m² D1, cycles 3 and 6) followed by a POMP maintenance (VCR, 6-MP, MTX, DEX) during 18 months. Allograft was allowed after at least 3 blocks of consolidation at the discretion of the investigators. The evaluable population was pts who received at least 1 dose of INO. Analyses were by modified intention to treat and performed JUN 28, 2021. All pts gave informed consent. The study is registered at ClinicalTrials.gov under the NCT number: NCT03249870. Results. Between DEC 29, 2017 and JUN 22, 2021, 115 pts (out of 130 planned pts) were enrolled including 6 pts with screen failure. The first 90 eligible pts (up to MAR 1, 2021) were considered for this analysis to obtain a minimum of 4 months follow-up. Median age was 69y (range 55-84) and median follow-up for alive pts was 1.18 years (range 0.3-3.5). At time of analysis, 90 and 88 pts had started induc1 and induc2, respectively. Treatment related mortality was 2.2% (2/90) and CR/CRp rate was 85.5% (77/90, 6 CRp) after induc1. Three cases relapsed between induc1 and induc2 and 5 pts were salvaged by induc2 allowing to a CR/CRp rate of 87.7% (79/90, 8 CRp) after induc2. One pts died from refractory disease during induc2. One, 2, 3 4 and 5 injections of INO were administered to 2 (2.2%), 2(2.2%), 11 (12.2%), 2 (2.2%) and 73 pts (81.1%) respectively. Only 6 pts were allografted. One-year OS was estimated to be 78.5% (95%CI 68-85.9) and median OS was not reached. One-year relapse free survival was 74.5% (95CI 63.5-82.6) (Figure 1). Grade 3-4 liver toxicity was observed in 8 pts (8.8%) during the study including 3 pts (3.3%) developing SOS, 2 related to INO during induc1 and one occurred after transplant. Twenty-nine pts died during the follow-up, 16 from relapses (overall incidence 18%) and 13 from adverse events (overall incidence 14.4%), including one COVID19 fatal infection during consolidation. Conclusion. Fractionated inotuzumab ozogamicin at reduced doses (0.8/0.5/0.5/0.5 mg/m²) combined with low-intensity chemotherapy is a very active and well tolerated frontline therapy for older patients with CD22+ Ph-neg BCP-ALL. Figure 1 Figure 1. Disclosures Doubek: Janssen-Cilag, AbbVie, AstraZeneca, Amgen, Gilead, Novartis: Honoraria, Research Funding. Huguet: Novartis: Other: Advisor; Jazz Pharmaceuticals: Other: Advisor; Celgene: Other: Advisor; BMS: Other: Advisor; Amgen: Other: Advisor; Pfizer: Other: Advisor. Raffoux: ABBVIE: Consultancy; PFIZER: Consultancy; CELGENE/BMS: Consultancy; ASTELLAS: Consultancy. Boissel: CELGENE: Honoraria; Servier: Consultancy, Honoraria; Incyte: Honoraria; Amgen: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding; PFIZER: Consultancy, Honoraria; JAZZ Pharma: Honoraria, Research Funding; SANOFI: Honoraria. Dombret: Amgen: Honoraria, Research Funding; Incyte: Honoraria, Research Funding; Jazz Pharmaceuticals: Honoraria, Research Funding; Novartis: Research Funding; Pfizer: Honoraria, Research Funding; Servier: Research Funding; Abbvie: Honoraria; BMS-Celgene: Honoraria; Daiichi Sankyo: Honoraria. Rousselot: Incyte, Pfizer: Consultancy, Research Funding. OffLabel Disclosure: Inotuzumab ozogamicin as first line therapy in newly diagnosed CD22+ Philadelphia chromosome-negative B-cell precursor acute lymphoblastic leukemia

Results of the Compassionate Program of Inotuzumab Ozogamicin for Adult Patients with Relapsed or Refractory Acute Lymphoblastic Leukemia in Spain

Background and objective. Inotuzumab ozogamicin (InO) was approved for patients (pts) with relapsed/refractory (R/R) CD22-positive acute lymphoblastic leukemia (ALL) based on the results of INO-VATE trial (Kantarjian et al, 2016). There are scarce studies evaluating the results of InO therapy in real life in similar pts as those from the INO-VATE trial. Our objective was to analyze the outcomes of pts included in the compassionate program of InO in Spain (June 2013-April 2018) before definitive approval. Patients and Methods. Inclusion criteria were age &gt;18 yrs., CD22+ ALL, R/R resistant to ≥2 previous lines, Ph+ ALL resistant/intolerant to TKI, ECOG ≤2 or &gt;2 if due to ALL, Bilirubin &lt;1.5 ULN, AST & ALT &lt;2.5 ULN, Creatinine ≤ 1.5 ULN. Exclusion criteria included mature B ALL, active CNS leukemia, chemotherapy in the two previous weeks, HSCT in the previous 6 months, grade ≥2 aGVHD or cGVHD, acute or chronic hepatitis B or C, HIV infection, VOD/SOS and antecedent chronic liver disease. Cycles of InO (0.8 mg/m 2 IV d1, and 0.5mg/m 2 IV on d8 and d15) were given every 21 days. Main outcomes: early death, CR/CRi, CR duration, PFS, OS and HSCT realization after InO. Results. 34 pts were included in the trial, 21 males, median age 43 yrs (range 19-73), ECOG &lt;2 22/26, WBC count 7.8 x10 9/L (0.3-388), pro B ALL 4/33, common 26/33, pre-B 3/33, Ph+ ALL 5/34 (15%), BM blast cells &gt;50% 15/33 (45%). 25/34 (73%) of pts received &gt;2 previous lines of therapy and 20 (59%) were previously transplanted. The duration of first CR remission before InO was &lt;12 months in 16/33 pts (49%) and 16/34 pts were refractory to the last treatment before InO. The median number of InO cycles was 2 (1-6). One pt withdrew the study before evaluation, 5 (15%) dead during therapy and 21 (64%) achieved CR/CRi. Ten pts (29%) were transplanted. With a median follow-up for alive patients after InO start of 26 months, the medians (95%CI) of DR, PFS and OS were 4.7 months (2.4-7.0), 3.5 (2.0-5.0) and 4.0 months (1.9-6.1), respectively. CR duration, PFS and OS were significantly shorter in refractory ALL (Figure 1A), pts with first CR (CR1) duration &lt;12 months (Figure 1B) and in those without previous HSCT. The number of previous lines of therapy did not show impact on outcome. The most frequent adverse events were hepatic (24%), infectious (18%), hematologic (15%) and gastrointestinal (9%). 3/10 transplanted patients showed grade 3-4 VOD/SOS. Grade 5 toxic events were hepatic (n=2), infection (n=2) and hemorrhage (n=1). Conclusion. The results in this series of compassionate use of InO for R/R ALL before approval for clinical use were slightly inferior to that of the INO-VATE trial. However, patients form this series had poorer risk factors than those included in that trial. The frequency and type of AE were similar to that of observed in the INO-VATE trial. Supported in part by grant 2017 SGR288 (GRC) Generalitat de Catalunya and "La Caixa" Foundation. Figure 1. Overall survival according to ALL status at inotuzumab start (A) and to duration of first complete remission (B) Figure 1 Figure 1. Disclosures Ribera: AMGEN: Consultancy, Research Funding, Speakers Bureau; SHIRE: Consultancy, Speakers Bureau; ARIAD: Consultancy, Research Funding, Speakers Bureau; TAKEDA: Consultancy, Research Funding, Speakers Bureau; NOVARTIS: Consultancy, Speakers Bureau; Pfizer: Consultancy, Research Funding, Speakers Bureau. Hernández-Rivas: Celgene/BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees.