Phase 1 trial of rituximab, lenalidomide, and ibrutinib in previously untreated follicular lymphoma: Alliance A051103

Chemoimmunotherapy in follicular lymphoma is associated with significant toxicity. Targeted therapies are being investigated as potentially more efficacious and tolerable alternatives for this multiply-relapsing disease. Based on promising activity with rituximab and lenalidomide in previously untreated follicular lymphoma (overall response rate [ORR] 90%-96%) and ibrutinib in relapsed disease (ORR 30%-55%), the Alliance for Clinical Trials in Oncology conducted a phase 1 trial of rituximab, lenalidomide, and ibrutinib. Previously untreated patients with follicular lymphoma received rituximab 375 mg/m 2 on days 1, 8, 15, and 22 of cycle 1 and day 1 of cycles 4, 6, 8, and 10; lenalidomide as per cohort dose on days 1 to 21 of 28 for 18 cycles; and ibrutinib as per cohort dose daily until progression. Dose escalation used a 3+3 design from a starting dose level (DL) of lenalidomide 15 mg and ibrutinib 420 mg (DL0) to DL2 (lenalidomide 20 mg, ibrutinib 560 mg). Twenty-two patients were enrolled; DL2 was determined to be the recommended phase II dose. Although no protocol-defined dose-limiting toxicities were reported, a high incidence of rash was observed (all grades 82%, grade 3 36%). Eleven patients (50%) required dose reduction, 7 because of rash. The ORR for the entire cohort was 95%, and the 12-month progression-free survival was 80% (95% confidence interval, 57%-92%). Five patients developed new malignancies; 3 had known risk factors before enrollment. Given the increased toxicity and required dose modifications, as well as the apparent lack of additional clinical benefit to the rituximab-lenalidomide doublet, further investigation of the regimen in this setting seems unwarranted. The study was registered with www.ClinicalTrials.gov as #NCT01829568

Concurrent Diagnosis of Chronic Myeloid Leukemia and Follicular Lymphoma: An Unreported Presentation

Lymphadenopathy in chronic myeloid leukemia (CML) is usually due to extramedullary involvement with accelerated or blast phases of the disease. The occurrence of non-Hodgkin lymphoma (NHL) as a synchronous malignancy with CML is rare. We report a case of a 73-year-old male who presented with dyspnea and right-sided lower extremity edema in the setting of leukocytosis. Bone marrow evaluation indicated a chronic phase chronic myeloid leukemia (CML), confirmed by molecular testing. Imaging of the chest for persistent dyspnea revealed supraclavicular and mediastinal lymphadenopathy. Biopsy of the cervical node showed expanded lymphoid follicles with atypical germinal centers that were positive for CD10, BCL-2, and BCL-6, consistent with follicular lymphoma (FL). Nodal PCR demonstrated clonal IGH and IGK gene rearrangements, and FISH analysis was positive for IGH-BCL-2 fusion. Together, these tests supported the diagnosis of FL. Additionally, the lymph node showed paracortical expansion by maturing pan-hematopoietic elements, no blastic groups, and positive RT-PCR analysis for BCR-ABL1, indicating concomitant involvement by chronic phase-CML. To our knowledge, this is the first reported case of a patient with a concurrent diagnosis of CML and FL

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

Oral Ixazomib in Untreated Follicular Lymphoma Permits COVID-19 Vaccine Response and Its Efficacy Is Associated with Clinical Factors and Gene Expression Signatures

Abstract Background: Standard chemoimmunotherapy for first-line treatment of follicular lymphoma (FL) achieves high rates of disease control but is not curative and carries significant toxicities including prolonged immunosuppression that may attenuate response to vaccinations (Marcus et al., NEJM 2017). While proteasome inhibitors have shown modest activity in R/R FL (Goy et al., JCO 2005), limited data address their use frontline. The comparatively favorable toxicity profile and convenient oral dosing of ixazomib support its investigation in this space. Methods: We evaluated ixazomib and its combination with short-course rituximab (R) for FL as part of an open-label, phase II investigator-initiated trial at the University of Washington / Fred Hutch Cancer Research Center / Seattle Cancer Care Alliance (NCT 02339922). Eligibility included an indication for treatment per NCCN guidelines and no prior standard systemic FL therapy. Ixazomib was administered at 4 mg orally once a week until disease progression or unmanageable toxicity. One course of R at 4 weekly doses of 375 mg/m 2 was added during the 7 th 28-day cycle, after an initial 6-cycle "window" on ixazomib alone. Available pretreatment formalin-fixed, paraffin-embedded tissue biopsies were subjected to RNA extraction by standard methods and gene expression profiling (GEP) using the NanoString™ PanCancer IO 360 panel to query pathways in proteasomal degradation and lymphomagenesis. Standard GEP quality control and data processing were performed with the ROSALIND® platform. Patients vaccinated per standard of care for COVID-19 while actively receiving ixazomib and ≥ 6 mo after completing R were evaluated for serologic response ≥ 2 weeks after the final dose of vaccine using the Roche Elecsys® Anti-SARS-CoV-2 S assay against the spike protein receptor binding domain. Results: Twenty pts began therapy between Feb 2017 and January 2020. All had grade I/II FL and FLIPI score was 2 in 20% and ≥ 3 in 20%; FLIPI score in all other patients was 0 or 1. Eleven (55%) pts met GELF criteria for high tumor burden disease including 6 (30%) pts with a tumor mass ≥ 7 cm. Median follow-up was 32.1 months (range 5.7 - 51.6). The ORR by Lugano criteria was 35% (CR 5%) during the ixazomib window and 65% (CR 45%) overall. At data cut (June 15, 2021) all patients were alive and 8 (40%) remained progression-free on treatment (Figure 1). By KM estimate, median PFS was 25.8 mo and median DOR was not reached at a median follow-up of 29.6 mo. As expected, high-grade treatment-related AEs were infrequent for ixazomib and R, including grade ≥ 3 events in 3 unique pts (15%; diarrhea, transaminitis, and cytopenias). No grade ≥ 4 or serious AEs were observed. Toxicities led to study-directed drug interruptions in 4 (20%) pts and dose reduction to ixazomib 3 mg weekly in 2 pts (10%). Higher ORR to ixazomib monotherapy was associated with FLIPI > 1 (p = 0.04) and, by exploratory GEP, downregulation of components of proteasomal degradation and upregulation of NF-KB and chemokine signaling (Figure 2). High tumor burden by GELF (p = 0.89) and tumor mass ≥ 7 cm (p = 0.26) were not associated with ORR to ixazomib. All 6 of 6 patients evaluated to date for response to COVID-19 vaccination, administered at a median of 32.5 mo (range 7.0 - 41.0) after last dose of R, achieved positive anti-spike protein antibodies (median anti-S 163.8 AU/mL, range 13.3 - 1139); none was diagnosed with COVID-19. Conclusions: The simple outpatient regimen of weekly oral ixazomib and the addition of 4 doses of R shows significant long-term activity with low toxicity in untreated FL. Extended DOR is achievable especially in patients who respond to ixazomib monotherapy. Ixazomib efficacy was associated with higher FLIPI scores and gene expression signatures implicated in proteasomal degradation and B-cell signaling pathways. Ixazomib deserves further investigation as a biomarker-driven therapeutic in untreated FL, particularly as an option that prioritizes outpatient management and serologic responsiveness to immunization. Figure 1 Figure 1. Disclosures Graf: MorphoSys: Consultancy, Research Funding; TG Therapeutics: Research Funding; AstraZeneca: Research Funding; BeiGene: Research Funding; GSK: Research Funding. Lynch: Incyte: Research Funding; SeaGen: Research Funding; TG Therapeutics: Research Funding; Cyteir: Research Funding; Genentech: Research Funding; Morphosys: Consultancy; Bayer: Research Funding; Juno Therapetics: Research Funding. Ujjani: Gilead: Honoraria; ACDT: Honoraria; Kite, a Gilead Company: Honoraria; Adaptive Biotechnologies: Research Funding; Janssen: Consultancy; TG Therapeutics: Honoraria; Loxo: Research Funding; Atara Bio: Consultancy; Epizyme: Consultancy, Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding; AstraZeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Cowan: Bristol Myers Squibb: Research Funding; Secura Bio: Consultancy; Sanofi Aventis: Consultancy, Research Funding; Harpoon: Research Funding; Abbvie: Consultancy, Research Funding; Nektar: Research Funding; GSK: Consultancy; Cellectar: Consultancy; Janssen: Consultancy, Research Funding. Smith: Millenium/Takeda: Consultancy; ADC Therapeutics: Consultancy; KITE pharm: Consultancy; Incyte Corporation: Research Funding; Beigene: Consultancy, Research Funding; Merck Sharp & Dohme Corp: Research Funding; Portola Pharmaceuticals: Research Funding; Ignyta (spouse): Research Funding; Genentech: Research Funding; AstraZeneca: Consultancy, Research Funding; Karyopharm: Consultancy; De Novo Biopharma: Research Funding; Bristol Myers Squibb (spouse): Research Funding; Incyte: Consultancy; Acerta Pharma BV: Research Funding; Bayer: Research Funding; Ayala (spouse): Research Funding. Shadman: Mustang Bio, Celgene, Bristol Myers Squibb, Pharmacyclics, Gilead, Genentech, Abbvie, TG Therapeutics, Beigene, AstraZeneca, Sunesis, Atara Biotherapeutics, GenMab: Research Funding; Abbvie, Genentech, AstraZeneca, Sound Biologics, Pharmacyclics, Beigene, Bristol Myers Squibb, Morphosys, TG Therapeutics, Innate Pharma, Kite Pharma, Adaptive Biotechnologies, Epizyme, Eli Lilly, Adaptimmune , Mustang Bio and Atara Biotherapeutics: Consultancy. Libby: Janssen: Consultancy, Research Funding; BMS: Research Funding; Genentech: Research Funding; GSK: Research Funding. Godwin: Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company; Pfizer: Research Funding. Gopal: Genetech: Consultancy, Honoraria, Research Funding; Karyopharm: Consultancy, Honoraria; Incyte: Honoraria; Acrotech: Consultancy, Honoraria; ADC Therapeutics: Consultancy, Honoraria; Kite: Consultancy, Honoraria; MorphoSys: Honoraria; Epizyme: Consultancy, Honoraria; Gilead: Consultancy, Honoraria, Research Funding; Teva: Research Funding; IGM Biosciences: Research Funding; Bristol Meyers Squibb: Research Funding; Astra-Zeneca: Research Funding; Cellectar: Consultancy, Honoraria; Agios: Research Funding; Takeda: Research Funding; Merck: Consultancy, Honoraria, Research Funding; Servier: Consultancy, Honoraria; I-Mab bio: Consultancy, Honoraria, Research Funding; Nurix Inc: Consultancy, Honoraria; Beigene: Consultancy, Honoraria; SeaGen: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding. OffLabel Disclosure: Ixazomib is not approved for use in follicular lymphoma

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

Considerations for Managing Patients With Hematologic Malignancy During the COVID-19 Pandemic: The Seattle Strategy.

In January 2020, the first documented patient in the United States infected with severe acute respiratory syndrome coronavirus 2 was diagnosed in Washington State. Since that time, community spread of coronavirus disease 2019 (COVID-19) in the state has changed the practice of oncologic care at our comprehensive cancer center in Seattle. At the Seattle Cancer Care Alliance, the primary oncology clinic for the University of Washington/Fred Hutchinson Cancer Consortium, our specialists who manage adult patients with hematologic malignancies have rapidly adjusted clinical practices to mitigate the potential risks of COVID-19 to our patients. We suggest that our general management decisions and modifications in Seattle are broadly applicable to patients with hematologic malignancies. Despite a rapidly changing environment that necessitates opinion-based care, we provide recommendations that are based on best available data from clinical trials and collective knowledge of disease states