Haploidentical vs. sibling, unrelated, or cord blood hematopoietic cell transplantation for acute lymphoblastic leukemia

The role of haploidentical hematopoietic cell transplantation (HCT) using posttransplant cyclophosphamide (PTCy) for acute lymphoblastic leukemia (ALL) is being defined. We performed a retrospective, multivariable analysis comparing outcomes of HCT approaches by donor for adults with ALL in remission. The primary objective was to compare overall survival (OS) among haploidentical HCTs using PTCy and HLA-matched sibling donor (MSD), 8/8 HLAmatched unrelated donor (MUD), 7 /8 HLA-MUD, or umbilical cord blood (UCB) HCT. Comparing haploidentical HCT to MSD HCT, we found that OS, leukemia-free survival (LFS), nonrelapse mortality (NRM), relapse, and acute graft-versus-host disease (aGVHD) were not different but chronic GVHD (cGVHD) was higher in MSD HCT. Compared with MUD HCT, OS, LFS, and relapse were not different, but MUD HCT had increased NRM (hazard ratio [HR], 1.42; P = .02), grade 3 to 4 aGVHD (HR, 1.59; P = .005), and cGVHD. Compared with 7/8 UD HCT, LFS and relapse were not different, but 7/8 UD HCT had worse OS (HR, 1.38; P = .01) and increased NRM (HR, 2.13; P <_ .001), grade 3 to 4 aGVHD (HR, 1.86; P = .003), and cGVHD (HR, 1.72; P <_ .001). Compared with UCB HCT, late OS, late LFS, relapse, and cGVHD were not different but UCB HCT had worse early OS (<_18 months; HR, 1.93; P < .001), worse early LFS (HR, 1.40; P = .007) and increased incidences of NRM (HR, 2.08; P < .001) and grade 3 to 4 aGVHD (HR, 1.97; P < .001). Haploidentical HCT using PTCy showed no difference in survival but less GVHD compared with traditional MSD and MUD HCT and is the preferred alternative donor HCT option for adults with ALL in complete remission

Spontaneous Remission of an Untreated, MYC and BCL2 Coexpressing, High-Grade B-Cell Lymphoma: A Case Report and Literature Review

Non-Hodgkin lymphomas (NHL) are a heterogeneous group of hematologic malignancies typically treated with multiagent chemotherapy. Rarely, spontaneous remissions can be observed, particularly in more indolent subtypes. The prognosis of aggressive NHL can be predicted using clinical and histopathologic factors. In aggressive B-cell NHL, the importance of MYC and BCL2 proto-oncogene coexpression (as assessed by immunohistochemistry) and high-grade histologic features are particularly noteworthy. We report a unique case of spontaneous remission in a patient with an aggressive B-cell NHL which harbored high-risk histopathologic features, including MYC protein expression at 70–80%, BCL2 protein expression, and morphologic features suggestive of high-grade B-cell lymphoma, NOS (formerly B-cell lymphoma unclassifiable with features intermediate between diffuse large B-cell lymphoma and Burkitt lymphoma [BCLU]). After undergoing a biopsy to confirm this diagnosis, he opted to forego curative-intent chemotherapy. The single, yet relatively large area of involvement noted on 18F-fluorodeoxyglucose positron emission tomography-computed tomography steadily resolved on subsequent follow-up studies. He remained without evidence of recurrence one year later, having never received treatment. This case emphasizes the potential for spontaneous remission in NHL and demonstrates that this phenomenon can be observed despite contemporary high-risk histopathologic features

Reevaluating Patient Eligibility for Inotuzumab Ozogamicin Based on CD22 Expression: Is Dim Expression Sufficient?

Salvage options for patients with relapsed B-cell acute lymphoblastic leukemia (B-ALL) include inotuzumab ozogamicin (InO), a recombinant, humanized anti-CD22 monoclonal antibody conjugated to the cytotoxic antibiotic calicheamicin. However, the benefit of InO in patients with dim CD22 expression remains unclear. We present a case of a patient with B-ALL who responded to InO despite only dim surface expression of CD22 by flow cytometry, achieving a survival benefit concordant with that reported in the literature and maintaining a good quality of life as a transfusion-independent outpatient. Our observation has broad relevance to clinicians who manage patients with B-ALL who are candidates for InO.Medicine, Faculty ofAlumniNon UBCReviewedFacult

A Window Study of Ixazomib in Untreated B-NHL

Background: Window of opportunity studies are rarely conducted in lymphoma, but permit evaluation of novel therapies before resistance mechanisms emerge. Identification of a minimum acceptable response rate in the first-line setting may expedite drug development and is most attractive for testing relatively nontoxic, oral targeted agents that may offer substantial logistical and clinical benefits (1). Ixazomib, an orally bioavailable proteasome inhibitor, showed promising activity in a single small study that included relapsed/refractory indolent B-cell NHL (i-NHL) (2). We designed a frontline "window" study to assess the activity of ixazomib monotherapy in patients with i-NHL. Methods: This single-arm, open-label investigator-initiated phase II trial (NCT 02339922) is being conducted at the University of Washington / Fred Hutch Cancer Research Center. Patients must have a diagnosis of i-NHL and a clinical indication for treatment per NCCN guidelines. Other criteria are ECOG ≤ 2, and no prior systemic anti-neoplastic treatment except in cases of mucosa-associated marginal zone lymphoma relapsed after or refractory to antibiotics. Ixazomib is administered at 4 mg orally once a week on consecutive 28-day cycles until disease progression or unacceptable toxicity. The window period closes after 6 cycles, with four doses of weekly rituximab added during the 7th cycle to test the safety and efficacy of this combination. The primary endpoint is investigator-assessed response rate performed every 2 cycles. An overall response rate of ≥ 19 of 36 is required to conclude promising efficacy. Secondary endpoints include duration of response, progression free survival, time to next treatment, and safety / tolerability. Correlative studies are being performed on tumor tissue samples collected pre-treatment and paired with biopsies obtained, as able, within 2 months after initiation of ixazomib and with clinically suspected disease progression to gain insight into potential molecular predictors of response. Correlates under investigation include gene expression profiling using the Nanostring platform and immunohistochemical evaluation of pathways associated with lymphoma proliferation and proteasome inhibition. The study opened in May 2016 and as of June 2019, 32 patients were screened. Of 23 patients treated the median age is 64 (range 41 to 85) and 15 (65%) are male. Fifteen (65%) patients had follicular lymphoma, 4 (17%) mantle cell lymphoma, 3 (13%) marginal zone lymphoma, and 1 (4%) chronic lymphocytic leukemia. No unexpected toxicities have emerged to date. The study is supported by Takeda Oncology. Glimelius B, Lahn M. Window-of-opportunity trials to evaluate clinical activity of new molecular entities in oncology. Ann Oncol. 2011;22(8):1717-25.Assouline SE, Chang J, Cheson BD, Rifkin R, Hamburg S, Reyes R, et al. Phase 1 dose-escalation study of IV ixazomib, an investigational proteasome inhibitor, in patients with relapsed/refractory lymphoma. Blood Cancer J. 2014;4:e251. Disclosures Graf: BeiGene: Research Funding; AstraZeneca: Research Funding; TG Therapeutics: Research Funding. Lynch:Johnson Graffe Keay Moniz & Wick LLP: Consultancy; Incyte Corporation: Research Funding; Juno Therapeutics: Research Funding; T.G. Therapeutics: Research Funding; Rhizen Pharmaceuticals S.A: Research Funding; Takeda Pharmaceuticals: Research Funding. Ujjani:Gilead: Consultancy; Astrazeneca: Consultancy; Atara: Consultancy; Genentech: Honoraria; AbbVie: Honoraria, Research Funding; Pharmacyclics: Honoraria; PCYC: Research Funding. Cowan:Abbvie: Research Funding; Celgene: Consultancy, Research Funding; Sanofi: Consultancy; Cellectar: Consultancy; Juno: Research Funding; Janssen: Consultancy, Research Funding. Smith:Pharmacyclics: Research Funding; Seattle Genetics: Research Funding; Portola Pharmaceuticals: Research Funding; Genentech: Research Funding; Ayala (spouse): Research Funding; AstraZeneca: Membership on an entity's Board of Directors or advisory committees, Research Funding; Denovo Biopharma: Research Funding; Ignyta (spouse): Research Funding; Merck Sharp & Dohme Corp: Consultancy, Research Funding; Incyte Corporation: Research Funding; Acerta Pharma BV: Research Funding; Bristol-Myers Squibb (spouse): Research Funding. Shadman:BeiGene: Research Funding; Sound Biologics: Consultancy; Celgene: Research Funding; Gilead: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding; TG Therapeutic: Research Funding; Sunesis: Research Funding; Astra Zeneca: Consultancy; Atara Biotherapeutics: Consultancy; Mustang Bio: Research Funding; ADC Therapeutics: Consultancy; Verastem: Consultancy; AbbVie: Consultancy, Research Funding; Acerta Pharma: Research Funding. Libby:Alnylam: Consultancy; Abbvie: Consultancy; Pharmacyclics and Janssen: Consultancy; Akcea: Consultancy. Cassaday:Amgen: Consultancy, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; Incyte: Research Funding; Kite/Gilead: Research Funding; Merck: Research Funding; Seattle Genetics: Research Funding; Seattle Genetics: Other: Spouse's disclosure: employment, stock and other ownership interests. Fromm:Merck, Inc.: Research Funding. Gopal:Teva, Bristol-Myers Squibb, Merck, Takeda, Seattle Genetics, Pfizer, Janssen, Takeda, and Effector: Research Funding; Seattle Genetics, Pfizer, Janssen, Gilead, Sanofi, Spectrum, Amgen, Aptevo, BRIM bio, Acerta, I-Mab-pharma, Takeda, Compliment, Asana Bio, and Incyte: Honoraria; Seattle Genetics, Pfizer, Janssen, Gilead, Sanofi, Spectrum, Amgen, Aptevo, BRIM bio, Acerta, I-Mab-pharma, Takeda, Compliment, Asana Bio, and Incyte.: Consultancy. OffLabel Disclosure: Ixazomib is not approved for use in indolent B-NHL

Myeloablative I-131-Tositumomab with Escalating Doses of Fludarabine and Autologous Hematopoietic Transplantation for Adults Age ≥ 60 Years with B Cell Lymphoma

AbstractMyeloablative therapy and autologous stem cell transplantation (ASCT) are underutilized in older patients with B cell non-Hodgkin (B-NHL) lymphoma. We hypothesized that myeloablative doses of 131I-tositumomab could be augmented by concurrent fludarabine, based on preclinical data indicating synergy. Patients were ≥ 60 years of age and had high-risk, relapsed, or refractory B-NHL. Therapeutic infusions of 131I-tositumomab were derived from individualized organ-specific absorbed dose estimates delivering ≤ 27 Gy to critical organs. Fludarabine was initiated 72 hours later followed by ASCT to define the maximally tolerated dose. Thirty-six patients with a median age of 65 years (range, 60 to 76), 2 (range, 1 to 9) prior regimens, and 33% with chemoresistant disease were treated on this trial. Dose-limiting organs included lung (30), kidney (4), and liver (2) with a median administered 131I activity of 471 mCi (range, 260 to 1620). Fludarabine was safely escalated to 30 mg/m2 × 7 days. Engraftment was prompt, there were no early treatment-related deaths, and 2 patients had ≥ grade 4 nonhematologic toxicities. The estimated 3-year overall survival, progression-free survival, and nonrelapse mortality were 54%, 53%, and 7%, respectively (median follow up of 3.9 years). Fludarabine up to 210 mg/m2 can be safely delivered with myeloablative 131I-tositumomab and ASCT in older adults with B-NHL

Ixazomib-Rituximab in Untreated Indolent B-NHL: An Effective, Very Low Toxicity Regimen

Background: Most individuals diagnosed with indolent B-cell non-Hodgkin lymphoma (iB-NHL) should be expected to have a normal or near normal life span (Maurer et al., 2016). Thus, a major goal is identifying treatments that maintain efficacy while reducing toxicity and improve ease of administration. Window-of-opportunity studies are well-suited to evaluate the likely ceiling of activity of single agent therapies - assuming highest efficacy may be observed prior to emergence of resistance mechanisms or cumulative host toxicities. We hypothesized that oral ixazomib (Ix) would be safe and effective in untreated iB-NHL based on safety data in myeloma and efficacy data with the intravenous formulation (Assouline et al., 2014), and sought to evaluate it in the frontline setting both as a single agent (with a lead-in period) and together with rituximab (R). Methods: This single-arm, open-label phase II investigator-initiated trial (NCT 02339922) was conducted at the University of Washington / Fred Hutch Cancer Research Center / Seattle Cancer Care Alliance. Eligibility included an indication for treatment of iB-NHL per National Comprehensive Cancer Network guidelines, ECOG ≤ 2, and radiographically measurable disease. Prior standard systemic treatment of iB-NHL was permitted only for cases of mucosa-associated marginal zone lymphoma (MZL) relapsed after or refractory to antibiotics. Ix was administered at 4 mg orally once a week on consecutive 28-day cycles. A single course of 4 weekly doses of R at 375 mg/m2 was added during the 7th cycle, closing the window period; Ix alone was continued until disease progression or unacceptable toxicity. The primary endpoint was investigator-assessed overall response rate (ORR) after independent radiology review. Response assessment occurred at every 2 cycles using standard (Lugano) criteria. Results: Between February 2017 and January 2020 a total of 33 patients began treatment. The median age was 62 years (range 38 to 85) and 67% were men. Histologic subtypes included follicular lymphoma (FL, n = 20), MZL (n = 7), mantle cell lymphoma (MCL, n = 4), and small lymphocytic lymphoma (SLL, n = 2). The most common indications for therapy were bulky disease (42%) and symptoms due to lymphoma (27%). In cases of FL, 35% had > 6 cm tumor bulk and 20% had Follicular Lymphoma International Prognostic Index score ≥ 3. Median follow-up was 16.8 months (range 1.2 - 39.8). In the 6-month Ix-only window, the ORR was 24% for the entire cohort and 35% for FL [complete response (CR) rate 3% and 5%, respectively] (Figure 1). Reduction of disease was seen in 23 (70%), including 15 (75%) of FL, 4 (57%) of MZL, and 3 (75%) of MCL. Overall, the ORR was 45% and 60% for FL (CR rate 27% and 35%, respectively) as of June 1, 2020 (at which point 3 patients had yet to undergo evaluation post R). Progression free survival (PFS) at 2 years for all subjects was 62% and for those with FL was 69%; median PFS was not reached (Figure 2). For the 15 patients with objective response, the median time to response was 5.5 months (range 1.8 - 11.0) and the median duration of response was not reached (87% in remission at 2 yrs). Adverse events (AEs) > grade 3 deemed related to treatment were not observed and such grade 3 events occurred in 5 unique patients (15%). Serious AEs were recorded in 2 patients (6%). Most AEs were grade 1-2 and included nausea (58%, typically only for few a few hours after the weekly dose), diarrhea (39%), headache (30%), and vomiting (30%). Peripheral neuropathy (PN) was reported by 12% (motor PN in 9% and sensory PN in 3%); all cases were grade 1 except one case (3%) of grade 2 motor PN. Toxicity from Ix resulted in dose-holds in 21%, dose-reduction to 3 mg weekly in 9%, and discontinuation in 6% (one case of grade 3 hyponatremia and one case of grade 2 confusion). Conclusion: Once weekly oral Ix has a favorable safety profile and shows considerable activity in frontline treatment of iB-NHL, with the best results in FL. Combined with a single 4-week course of R, Ix can achieve durable disease control with very low toxicity in a majority of patients with FL, representing a convenient regimen amenable to remote management if indicated. This approach has the potential to support the overall strategy of lowering the burden of treatment while maintaining expected excellent outcomes in most patients with FL. Disclosures Graf: TG Therapeutics: Research Funding; BeiGene: Research Funding; MorphoSys: Consultancy; Acerta Pharma: Research Funding. Lynch:TG Therapeutics: Research Funding; Genentech: Research Funding; Juno Therpeutics: Research Funding; Incyte: Research Funding; Bayer: Research Funding; MorphoSys: Consultancy; Cyteir: Research Funding; Rhizen Pharmaceuticals: Research Funding; Takeda: Research Funding. Ujjani:MorphoSys: Consultancy; Genentech: Consultancy, Honoraria; Atara: Consultancy, Honoraria; Gilead/Kite: Consultancy, Research Funding; Verastem Oncology: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria, Research Funding; AstraZeneca: Consultancy, Honoraria, Research Funding. Cowan:Bristol Myers Squibb: Research Funding; Sanofi: Consultancy; Cellectar: Consultancy; Abbvie: Research Funding; Janssen: Consultancy, Research Funding. Smith:Bristol Meyers Squibb: Research Funding; Incyte: Research Funding; Ayala: Research Funding; Bayer: Research Funding; AstraZeneca: Research Funding; Acerta Pharma BV: Research Funding; Merck: Research Funding; Pharmacyclics: Research Funding; Portola: Research Funding; Seattle Genetics: Research Funding; AstraZeneca: Consultancy; Millenium/Takeda: Consultancy; Beigene: Consultancy; Karyopharm: Consultancy; De Novo Biopharma: Research Funding; Genentech: Research Funding; Ignyta: Research Funding. Shadman:Abbvie, Genentech, Astra Zeneca, Sound Biologics , Pharmacyclics, Verastem, ADC therapeutics, Beigene, Cellectar, BMS, Morphosys and Atara Biotherapeutics: Consultancy; Mustang Bio, Celgene, Pharmacyclics, Gilead, Genentech, Abbvie, TG therapeutics, Beigene, Astra Zeneca, Sunesis, Beigene: Research Funding. Godwin:Pfizer Inc.: Research Funding; Immunogen Inc.: Research Funding. Cassaday:Amgen: Consultancy, Research Funding; Kite/Gilead: Consultancy, Research Funding; Merck: Research Funding; Pfizer: Honoraria, Research Funding; Seattle Genetics: Current Employment, Current equity holder in publicly-traded company; Vanda Pharmaceuticals: Research Funding. Fromm:Merck: Research Funding. Gopal:Seattle Genetics; Janssen; IMab Bio; TG Therapeutics; Astra Zeneca; Merck; Gilead; ADC Therapeutics; Nurix; TG therapeutics, Cellectar; Actinium: Consultancy; Seattle Genetics; Janssen; Takeda; IgM Bio; IMab Bio; BMS; Astra Zeneca; Merck; Gilead: Research Funding; imab bio, takeda,astrazeneca,gilead: Research Funding; IgM bio, BMS, merck: Research Funding. OffLabel Disclosure: Ixazomib has not been approved for use in treating indolent B-NHL