Over the past three decades, the treatment of lymphoproliferative disorders has undergone profound changes, notably due to the increasing availability of innovative therapies with the potential to redefine clinical management paradigms. A major impact is related to the development of monoclonal antibodies, checkpoint inhibitors, bispecific antibodies, and chimeric antigen receptor T (CAR-T) cell therapies. This review discusses the current landscape of clinical trials targeting various hematological malignancies, highlighting promising early-phase results and strategies to overcome resistance. Lymphoproliferative disorders encompass a range of conditions: while in Hodgkin lymphoma (HL) the goal is to reduce chemotherapy-related toxicity by integrating immunotherapy into the frontline setting, peripheral T cell lymphoma (PTCL) lacks effective targeted therapies. The review emphasizes a shifting therapeutic landscape towards precision medicine and treatment modalities that are less toxic yet more effective.

Beyond Chemotherapy: Present and Future Perspectives in the Treatment of Lymphoproliferative Disorders


 Background: HZ-H08905 is a first-class and potent CK1ε/PI3Kδ dual inhibitor, which was previously reported (Abstract 5502, ASH 2022). Phase I study is ongoing in China, and here we present preliminary results of HZ-H08905 monotherapy in hematologic malignancies.
 Methods: HZ-H08905-101 is an ongoing Phase 1, first-in-human, open-label, multicenter, multiple-dose escalation and expansion study in China (CTR20213233). Primary objectives: safety/tolerability, maximum tolerated dose (MTD), and recommended phase 2 dose (RP2D) of HZ-H08905 monotherapy; secondary objectives: pharmacokinetic properties and preliminary anti-tumor activity of HZ-H08905 in patients with relapsed/refractory (R/R) non-Hodgkin lymphoma (NHL), including B-cell lymphoma (BCM) and T-cell lymphoma (TCL). HZ-H08905 was administered orally once daily in 28-day cycles until disease progression or unacceptable toxicity. The dose escalation part was initiated with a dose titration in the initial cohort (50mg once daily), followed by a 3 + 3 design (100mg, 300 or 450 mg once daily). Dose-limiting toxicity (DLT) for each cohort was evaluated in the first 28-day cycle. Dose expansion was conducted in selected doses and cohorts. Safety was assessed per CTCAE 5.0 and efficacy was measured according to IWWM-7 for WM, or IWCLL 2018 for CLL/SLL, or Lugano 2014 criteria for other NHL.
 Results: At the data cutoff date of 25 May 2023, 38 pts were analyzed, including 26 R/R TCL [12 AITL, 10 PTCL-NOS, 2 ALK negative ALCL, 1 NKTCL 1 EATCL] and 12 R/R BCM [5 DLBCL, 3 FL, 2 WM, 1 CLL, 1 MCL]. 1 pt received 50mg/d, 9 pts received 100mg/d, 14 pts received 200mg/d, 13 pts received 300mg/d and 1pts received 450mg/d. No DLT occurred and MTD was not reached. Pts were with a median age of 61 years (range: 38-78), median ECOG 1 (range: 0-2) and a median of 2 prior systemic therapies (range: 1-5). 35 of 38 pts (92%) experienced a treatment related adverse event (TRAE). TRAEs of ≥Grade 3 (≥5%) were neutropenia (26.3%), pneumonia (7.9%), leukopenia (5.3%), elevated aspartate aminotransferase (5.3%), elevated alanine aminotransferase (5.3%) and herpes zoster (5.3%). 10 pts (26.3%) had dose interruption, 3pts (7.9%) had dose reduction, and 1 pt (2.6%) discontinued from the study due to TRAEs. Of 35 pts available for tumor assessment (26 TCL; 12 BCM), the overall response rate (ORR) was 60% (95%CI: 42.11, 76.13), including 17% (6 pts) complete response (CR), 40% (14 pts) partial response (PR), 3% (1 pt) minor response (MR) and 20% (7 pts) stable disease (SD), contributing to an 80% (95%CI: 63.06, 91.56) disease control rate (DCR). The median time to response (mTTR) was 1.9 months (95%CI: 1.87, 2.10). The median duration of response (mDOR) and median progression free survival (mPFS) had not been reached, with 21 pts (55%) are still on HZ-H08905 treatment. HZ-H08905 exhibited excellent antitumor efficacy in several NHL subtypes, including CLL, DLBCL, FL, MCL, PTCL and WM, with ORR ranged from 50%~100% and DCR ranged from 76%~100%.
 Conclusions: These results demonstrated that HZ-H08905 monotherapy was well tolerated and showed promising efficacy in patients with R/R NHL. A Phase 2 R/R PTCL registration study in China is currently planned.

A Phase I Study Evaluating the Safety, Tolerability, Pharmacokinetics, and Preliminary Antitumor Activity of Dual CK1ε/PI3Kδ Inhibitor HZ-H08905 in Adult Patients with Relapsed and/or Refractory Hematologic Malignancies

Dual CK1ε/PI3Kδ Inhibitor HZ-H08905, Exhibits As a Potential Therapeutic Strategy for Hematologic Malignancies

HZ-a-018 Is a Highly Selective and Potent BTK Inhibitor with CNS-Penetrating Profile for Central Nervous System Lymphoma


 Background: HZ-A-018 is a highly selective and potent covalent BTK inhibitor with CNS-penetrating profile, which was previously reported (Abstract 5501, ASH 2022). Phase I/II study is ongoing in China, and here we present preliminary results of HZ-A-018 monotherapy of the phase I part in central nervous system lymphoma.
 Methods: HZ-A-018-102 is an ongoing phase I/II study (CTR20210181) to evaluate the safety, tolerability, pharmacokinetics, and antitumor activity of HZ-A-018 in central nervous system lymphoma. The primary objective for phase I monotherapy was to determine the safety and tolerability and the recommended phase 2 dose (RP2D), and secondary objectives included preliminary antitumor activity and pharmacokinetics in patients with relapsed/refractory primary/secondary CNS lymphoma (R/R PCNSL/SCNSL) and primary vitreoretinal lymphoma (PVRL) who had received ≥1 prior therapy. HZ-A-018 was administered orally once daily in 28-day cycles until disease progression or unacceptable toxicity.
 Results: At the data cutoff date of 30 May 2023, 21 pts from the phase I monotherapy were analyzed, including 18 R/R PCNSL and 3 R/R SCNSL. 3 pts received 300mg/d, 12 pts received 450mg/d and 6 pts received 600mg/d. 600mg was the highest dose pre-defined in the study and MTD was not reached. Pts were with a median age of 62 years (range: 36-80), median KPS 80 (range: 60-90) and a median of 2 prior systemic therapies (range: 1-5). 20 pts (95.2%) presented with brain parenchyma, and 1 pt (4.8%) presented with intraocular (IO) involvement. All patients had received HD-MTX based chemotherapy, 19 pts (90.5%) had received rituximab and 1 pt had received whole brain radiation therapy (WBRT). 16 of 21 pts (76.2%) experienced a treatment related adverse event (TRAE). The most common TRAEs (≥10%) were thrombocytopenia (42.9%), neutropenia (23.8%), leukopenia (23.8%), and hypokalemia (14.3%), majority of which were grade 1 to 2. DLTs occurred in 1 pt at 450 mg/d and 1 pt at 600 mg/d. 4 pts (19.0%) had dose interruption, no pts had dose reductions, and no pts discontinued from the study due to TRAEs. The plasma and cerebrospinal fluid (CSF) pharmacokinetics showed HZ-A-018 was rapidly absorbed and could cross the blood-brain barrier with CSF HZ-A-018 concentration ranged from 5.94 to 17.5 ng/mL two hours post-dose. Of 19 pts available for tumor assessment (16 PCNSL with brain parenchyma, 1 PCNSL with IO and 2 SCNSL with brain parenchyma) and 2 pts not evaluable (1 PCNSL with brain parenchyma, and 1 SCNSL with brain parenchyma), the overall response rate (ORR) was 52.4% (95%CI: 29.8, 74.3), including 23.8% (5 pts) complete response(CR)/unconfirmed complete response(CRu), 28.6% (6 pts) partial response (PR), and 19.0% (4 pts) stable disease (SD), contributing to an 71.4% (95%CI: 47.8, 88.7) disease control rate (DCR). At 600mg/d, all 6 pts had achieved high and deep responses, contributing to 100% ORR and 50% CRR, with the 3-month duration of response (DOR) rate not reached. Dose expansion was ongoing at 600mg QD.
 Conclusions: These results demonstrated that HZ-A-018 was efficacious and well-tolerated in CNS lymphoma patients with high CNS penetrating profile. The monotherapy RP2D for R/R PCNSL was determined as 600 mg QD and a phase 2 R/R PCNSL registration study in China is currently planned.

A Phase I/II Study Evaluating the Safety, Tolerability, Pharmacokinetics, and Preliminary Antitumor Activity of BTK Inhibitor HZ-a-018 in Adult Patients with Relapsed and/or Refractory Central Nervous System Lymphoma

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A Phase I Study Evaluating the Safety, Tolerability, Pharmacokinetics, and Preliminary Antitumor Activity of Dual CK1ε/PI3Kδ Inhibitor HZ-H08905 in Adult Patients with Relapsed and/or Refractory Hematologic Malignancies

Dual CK1ε/PI3Kδ Inhibitor HZ-H08905, Exhibits As a Potential Therapeutic Strategy for Hematologic Malignancies

HZ-a-018 Is a Highly Selective and Potent BTK Inhibitor with CNS-Penetrating Profile for Central Nervous System Lymphoma

A Phase I/II Study Evaluating the Safety, Tolerability, Pharmacokinetics, and Preliminary Antitumor Activity of BTK Inhibitor HZ-a-018 in Adult Patients with Relapsed and/or Refractory Central Nervous System Lymphoma